Chem. Rev.2009, 109, 2551–2651 2551 Mitsunobu and Related Reactions: Advances and Applications K. C. Kumara Swamy,* N. N. Bhuvan Kumar, E. Balaraman, and K. V. P. Pavan Kumar School of Chemistry, University of Hyderabad, Hyderabad - 500046, A. P., India Received July 30, 2008 Contents 1. General Introduction 2. Mechanism 3. Carboxylic Acids/Phosphorus-Based Acids as Nucleophiles: Esterification Including Macrolactonization 3.1. Esterification with Inversion 3.2. Esterification with Retention (in the Intermolecular Mitsunobu Reaction) 3.3. Competitive Esterification 3.4. Lactonization/Macrolactonization 3.5. Other Esterification Reactions Including Those of Phosphates/Phosphonates 4. Phenols and Alcohols as Nucleophiles: Ether Formation 4.1. Etherification without Cyclization 4.2. Etherification with Cyclization 4.3. O-Alkylation (Ether Formation) via an NHC(O) to NdC(OH) Proton Shift 5. Amines, Amides (Including Nucleobases), or Azides as Nucleophiles 5.1. N-Alkylation Using Phthalimide and Related Imides 5.2. N-Alkylation with Sulfonamides and Related Nucleophiles 5.3. N-Alkylation of Heterocyclic Compounds (Excluding Nucleobases) 5.4. N-Alkylation of Nucleobases Including 6-Chloropurine 5.5. Mitsunobu Reaction with Azides 6. Sulfur Nucleophiles: C-S Bond Forming Reactions 7. Carbon Nucleophiles: C-C Bond Forming Reactions 8. Miscellaneous Reactions 8.1. Halogenation 8.2. Reaction in the Presence of CO2 8.3. Use of Oximes as Nucleophiles 8.4. Reaction in the Absence of a Nucleophile 8.5. Formation of Tetrazoles via Thioamides and Azide 8.6. Reactivity toward Carbonyl Compounds 8.7. Synthesis of Fluorophosphoranes 8.8. Alcohol Dehydration 8.9. Some Unusual Reactions 8.10. Additional Literature 9. Modification of Mitsunobu Protocol 2551 2555 2556 2556 2560 2561 2562 2567 2568 2569 2574 2578 2581 2581 2584 2593 2595 2598 2601 2604 2605 2605 2605 2607 2607 2608 2608 2609 2609 2609 2610 2611 9.1. Polymer Supports in the Mitsunobu Reaction 9.2. Other Modified Reagent Systems (Including Fluorous Reagents) 10. Patented Literature 10.1. Esterification 10.2. Ether Formation 10.2.1. Etherification without Cyclization 10.2.2. Etherification with Cyclization 10.3. N-Alkylation 10.4. Other Reactions 11. Summary and Outlook 12. Note Added in Proof 13. Abbreviations Used in This Review 14. Acknowledgments 15. Supporting Information Available 16. References 2611 2613 2616 2616 2619 2619 2624 2625 2627 2628 2628 2629 2629 2630 2630 1. General Introduction The substitution of primary or secondary alcohols with nucleophiles mediated by a redox combination of a trialkylor triarylphosphine and a dialkyl azodicarboxylate is popularly known as the Mitsunobu reaction. Since its discovery in 1967 by Professor Oyo Mitsunobu (1934-2003),1,2 this reaction has enjoyed a privileged role in organic synthesis and medicinal chemistry because of its scope, stereospecificity, and mild reaction conditions. Several important variations were discovered by Mitsunobu and his co-workers in the early stages of its development as a synthetic tool.3-14 This reaction is often used as a key step in natural product syntheses. Its importance and utility can be gauged from the fact that in SciFinder, for explicit use of the phrase “Mitsunobu reaction”, there were 1615 citations from 1996 to 2008 including 186 patents. This topic has been reviewed in several places earlier, and during the last several years, the focus has been to cover specific areas.15-39 In this review, we have made an attempt to give an overall picture, taking examples mostly from the literature during the last ten years. Apart from esters, a wide range of compounds that include amines, azides, ethers, cyanides, thiocyanides, thioesters, and thioethers can be synthesized using a Mitsunobu protocol (cf. Scheme 1). The azido or phthalimido derivatives so obtained can be readily transformed into amines while thioesters can be converted to thiols in a single step, allowing facile conversion of an alcoholic -OH group to a -NH2 or -SH group. It is also possible to readily convert primary amines to isocyanates using CO2 as an additional component. Thus, this reaction permits C-O, C-S, C-N, or C-C bond formation by the condensation of an acidic component with a primary or a secondary alcohol in the presence of triphenylphosphine (or another suitable phosphine) and * To whom correspondence should be addressed. E-mail: kckssc@ uohyd.ernet.in or
[email protected]. 10.1021/cr800278z CCC: $71.50 2009 American Chemical Society Published on Web 04/21/2009 2552 Chemical Reviews, 2009, Vol. 109, No. 6 Swamy et al. K. C. Kumara Swamy is currently a Professor in the School of Chemistry, University of Hyderabad. He received his Ph.D. from Indian Institute of Science under the guidance of Prof. S. S. Krishnamurthy and Prof. A. R. Vasudeva Murthy. He was a postdoctoral fellow with Prof. Robert R. Holmes (University of Massachusetts, Amherst; 1986-89) and an Alexander-von-Humboldt fellow with Prof. Dr. Michael Veith (Universitat ¨ des Saarlandes, Germany; 1991, 1994, and 2000). His research interests include Organophosphorus Chemistry and Main Group Chemistry. He has over 115 publications so far and is a fellow of the Indian Academy of Sciences, Bangalore. E. Balaraman was born in Kancheepuram, Chennai, India, in 1980. He received his M.Sc. in Chemistry from Vivekananda College [Madras University (2002)] and his Ph.D. degree in the areas of organophosphonates and modified BINOLs under the guidance of Prof. K. C. Kumara Swamy. Presently he is a postdoctoral fellow with Professors David Milstein and Ronny Neumann at the Weizmann Institute of Science, Israel. N. N. Bhuvan Kumar was born in Cherukupalli, Guntur, India. After completing his B.Sc. from Nagarjuna University, he joined the School of Chemistry, University of Hyderabad, as a postgraduate student in the year 2000 and obtained his Master’s degree in Chemistry. Currently, he is pursuing a Ph.D. on Organophosphonates under the supervision of Prof. K. C. Kumara Swamy. K. V. P. Pavan Kumar was born in Hyderabad (Andhra Pradesh), India, in 1979. He obtained his B.Sc. (Chemistry Honors) and M.Sc. (Chemistry) degrees from Sri Sathya Sai Institute of Higher Learning, Puttaparthi, A.P., India. He obtained his Ph.D. degree under the guidance of Prof. K. C. Kumara Swamy in October 2006. Presently he is working as a postdoctoral fellow in the area of hydroamination reactions using new titanium catalysts with Prof. Pierre Le Gendre at the Universite de Bourgogne, France. ´ diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD). Given below are some of the salient features of this reaction: (i) The substrates are primary or secondary alcohols. Chiral secondary alcohols undergo a complete inVersion of configuration unless sterically very congested.40-42 This aspect has been positively exploited in numerous reactions. In general, tertiary alcohols are less reactive, but there is at least one report of the synthesis of alkyl-aryl ethers (with complete inversion of configuration) starting from tertiary alcohols.43 (ii) The nucleophile (or pronucleophile) is normally a relatively acidic compound containing an O-H, S-H, or an N-H group with pKa e 15, preferably below 11. Some common nucleophiles are carboxylic acids, phenols, imides, purine/pyrimidine bases, and related heterocycles, hydrazoic acid (HN3), thiocarboxylic acids, thiols, fluorinated alcohols, and hydroxamates. Phosphoric/phosphonic acids can also be used. In place of HN3, it is possible to employ diphenylphosphoryl azide (DPPA), trimethylsilyl azide, or zinc azide, which is far easier to handle. With suitable modification of the phosphine, if necessary, one can use even C-H-based nucleophiles such as malonate esters, β-diketones, β-keto esters, and triethylmethane tricarboxylate [HC(CO2Et)3, TEMT]. (iii) As can be expected, an intramolecular Mitsunobu reaction leading to lactones, lactams, cyclic ethers, and amines is possible. A large excess of Ph3Pazodicarboxylate is utilized quite often in macrolactonization to obtain the products in decent yields. In many cases, addition of a base such as triethylamine could help in increasing the yield of the product. (iv) In the presence of additional components such as acyl/alkyl halides or lithium/zinc halides, alcohols are converted to halides, with inversion of configuration. Use of additional CO2 leads to carbamates Mitsunobu and Related Reactions Scheme 1 Chemical Reviews, 2009, Vol. 109, No. 6 2553 (v) (vi) while a combination of a primary amine along with CO2 gives isocyanates. Common solvents for the reaction are tetrahydrofuran (THF), toluene, benzene (Caution: Benzene is a carcinogen and may be replaced by toluene whereVer possible.), dimethyl formamide (DMF), diethyl ether, acetonitrile, dichloromethane, and 1,4dioxane. The first two solvents normally give better results. The reaction is generally conducted between 0 °C and 25 °C. The preferred PIII component is triphenylphosphine (Ph3P) or tributylphosphine (n-Bu3P), both of which are quite cheap and commercially available. The triphenylphosphine oxide byproduct as well as unreacted Ph3P are water-insoluble, and very often chromatography is required for the separation of the products. This is one of the major limitations in Mitsunobu chemistry. The phosphine Me3P is volatile but a safety hazard. Although n-Bu3P works well in many cases,44 this phosphine is still not as popular as triphenylphosphine. An alternative is to use either diphenyl(2-pyridyl)phosphine (1) or (4-dimethylaminophenyl)diphenylphosphine (2) or tris-(4-dimethylaminophenyl)phosphine (3).45-47 In such a case, the corresponding phosphine oxide can be removed by washing the reaction mixture with dilute hydrochloric acid. If the required product is fairly soluble in the chosen organic solvent, such as toluene or THF, a diphosphine such as 1,2-diphenylphosphinoethane (DPPE, 4) may be a better choice, since the byproduct phosphine oxide is insoluble and hence can be removed by filtration.48 The use of polymer supports, other phosphines, and fluorous reagents to alleviate some of the problems has been reviewed recently.32,33,35 A brief survey of these aspects is also given in later sections. Scheme 2 Scheme 3 Another alternative to Ph3P is the ferrocenylappended phosphine 5.49 Use of this compound, together with di-tert-butyl azodicarboxylate (DTBAD), could alleviate the problem of column chromatography. The ferrocenyl-appended phos- phine oxide byproduct 6 can be oxidized at the iron center to the cation 7 (anion: chloride). The resulting species is rather insoluble in less polar media and, hence, can be separated from the required product. Di-tert-butyl azodicarboxylate (DTBAD) and the corresponding hydrazine byproduct are decomposed by treatment with aqueous hydrochloric acid. The cationic species 7 can be reverted back to 5 by reduction of the iron center (via Na2S2O3), followed by treatment with HSiCl3 (Scheme 2). By employing a phosphine or/and an azocarboxylate tagged with a phosphonium (salt) side chain, the reagents as well as the resulting byproducts can be made insoluble in a less polar solvent such as diethyl ether. A simple filtration will then remove the byproducts, alleviating the problem of tedious column chromatography. Thus, in the esterification reactions of 2-octanol and menthol using the redox system 8a-9a (cf. Scheme 3) in ether medium, the phosphine oxide and the hydrazine byproducts are conveniently removed by filtration.50-52 The phos- upon treatment with aqueous HCl. smaller scale operations are recommended.61 Barring the cost.50 (vii) Both diisopropyl azodicarboxylate (DIAD) and diethyl azodicarboxylate (DEAD) can be used interchangeably in most cases [Note: Azodicarboxylate esters are susceptible to explosion upon strong heating or impact.7-hexahydro-1.2554 Chemical Reviews.47 The tagged reagents Ph2P(CH2CH2CO2-t-Bu) and t-BuO2CCH2NHC(O)NdNC(O)NHCH2CO2-t-Bu are other alternatives. (viii) Very often DEAD or DIAD is added (∼5 min for the 1 mmol scale) to a solution of Ph3P.as in 8a. while the hydrazine 9b is oxidized to azocarboxylate 9a by iodobenzene diacetate.56 Generally. 2009. while the use of Ph3P-DEAD gave a negligible yield of C-alkylated product. 11) has been conveniently prepared via hydrazine 10 starting with p-chlorobenzyl alcohol as shown in Scheme 4.N′-tetramethyl azodicarboxamide [Me2NC(O)-NdNC(O)NMe2. more active coupling reagents such as 1.1′-(azodicarbonyl)dipiperidine [(cycl-C 5 H 10 N)C(O)-NdNC(O)(cycl-NC 5 H 10 ). Another interesting approach by Curran and co-workers is noteworthy. or DHTD afforded a much better yield (56%.N. They are commercially available. TMAD] in combination with tributylphosphine (nBu3P. the combination of diphenyl(2-pyridyl)phosphine (1) and the acid labile DTBAD is very convenient because.]. 13 and the corresponding hydrazine products have longer retention times in cyclodextrin-bonded silica gel compared to normal Mitsunobu hydrazine byproducts that facilitate ready separation/purification of the expected Mitsunobu products. TMAD. the Ph3P-DEAD/DIAD system is useful for acidic nucleophiles with pKa < 11. Vol. 66%. the former (or its oxide) is removed while the latter is converted to gaseous byproducts.4-position of the aromatic ring instead of 1. and N. WhereVer possible. or 75%.26. DHTD}. it is preferred that they are handled in solution. 4-Cl-C6H4C(H)dC(H)-C6H4-4-Cl. Most of the byproduct hydrazine 10 formed in the Mitsunobu reaction can be precipitated from dichloromethane. 6 Swamy et al.8-dione {[MeNCH2CH2NMe][C(O)NdNC(O)]. 109. TBP) or trimethylphosphine (Me3P) have been developed. respectively). DMEAD].67 The azo compounds 12.7-tetrazocin-3. They can also be prepared by starting with hydrazine hydrate. Thus di-4-chlorobenzyl azodicarboxylate (DCAD.60.N′. 4.65 Modification of the organic group on the azodicarboxylate reagent for convenient handling is of some value. DIAD is less effective.53-55 Only in a very few cases.68 They point out that the highly polar and water soluble nature of 14 is an advantage and also that the preparation of 14 is easier than that of DEAD or DIAD.61 In the reaction of dimethyl malonate with benzyl alcohol. while the azocarboxylate-phosphonium salt 9a is prepared by starting with 4-chlorophenylstilbene. but the former is cheaper. No. Hence.57-64 The reagent DHTD can be prepared by starting with diphenyl azodicarboxylate and N.7-dimethyl-3. The polarity of 10 is quite different from those arising from DIAD/ DEAD which facilitates separation of the products more readily during chromatography.66 This stable orange crystalline compound can be stored at room temperature and is nearly as efficient as DEAD or DIAD in the reactions studied. Sugimura and Hagiya have introduced the new azocarboxylate 14 [di-2-methoxyethyl azodicarboxylate.3. followed . the acid tag can be unmasked in subsequent steps. Scheme 4 phine-phosphonium salt 8a is prepared by starting with diphenyl(3-bromophenyl)phosphine.5.N′-dimethylethylene diamine. ADDP]. The phosphine oxide 8b is reduced back to phosphine 8a by trichlorosilane.4.34. What is important to note is that if the two phosphorus atoms are in the 1. For those having a pKa > 11. reactions do not proceed that well. a combination of n-Bu3P with ADDP.2. acetic acid is a byproduct. this methodology could work out to be a very useful one. The first step is the irreversible formation of the Morrison-BrunnHuisgen (MBH) betaine 15. It may be noted that. in the oxidation with PhI(OAc)2. In specific cases such as N-alkylation of N-hydroxyphthalimide with prenyl alcohol. which upon reacting with the alcohol forms the key alkoxyphosphonium salt 18 and the hydrazine RO2CNH-NHCO2R. this procedure was quite useful and provided the product in nearly 96% yield. which is in equilibrium with 18 and the phosphorane 21. the hydrazide from the DIAD did not get oxidized back to the precursor (i. this phosphorane may also lead to the alkoxyphosphonium salt 18 upon reacting with the acid (step 3a). is formed in step 4. this betaine 15 deprotonates the carboxylic acid to form the ionic species 16.Mitsunobu and Related Reactions Scheme 5 Chemical Reviews. followed by addition of aqueous sodium thiosulfite (to remove peroxide).87 In step 2. a more useful protocol can be developed.e. radical cations of type (Ph3P+)-N(CO2R)-N•-(CO2R)89 or (Ph3P+)-O-C(OR)dN-N•(CO2R). DIAD) to any significant extent (1H NMR). that converted the hydrazine back to the DEAD (Scheme 5).9 (R ) Et). This is essentially what Toy and co-workers have achieved recently by introducing an additional component. we can devise methodologies to remove the byproducts. whose identity has been established by multinuclear NMR [31P NMR: δ 44.1 mol equiv with respect to the alcohol) was used in these reactions. 44. degradation of 16 may take place to lead to 19 as well as the phosphine oxide Ph3P(O). 25) formed by the [4+1] cycloaddition (with the nitrogen and a carbonyl oxygen of DIAD/DEAD attached to phosphorus) when the PIII precursor contains at least two oxygen atoms connected .41-43.69 It was found that. The inversion product 20. 42. betaine 15 can react first with the alcohol (depending on the order of addition) to lead to the pentacoordinate phosphorane 17.2 (R ) i-Pr). or accompanied by. as shown in step 2a. In cases where retention product 23 is observed. in the normal Mitsunobu reaction. are still a subject of debate and intensive studies. It may be noted that. this “organocatalytic” idea is quite novel and needs further exploration in view of the fact that it avoids wastage of the expensive DEAD/ DIAD. By washing the reaction mixture with a solution of 15 wt % hydrogen peroxide.103 It is important to note that. if it can be reverted back to azodicarboxylate. particularly if very large amounts of the reagents are used. Therefore. the intermediacy of the acylphosphonium salt 22. Formation of the anhydride 24 via 22 is a complicating factor in some cases. 109.g. the hydrazine byproduct is a waste. all Ph3P will be converted to the highly polar Ph3P(O) oxide. At this stage. This observation suggests that the nature of the intermediate in the Mitsunobu reaction could vary depending upon the PIII precursor. intermediates other than 15 have been obtained in the first step of the reaction with DIAD/DEAD.71-103 A possible pathway in the esterification process is shown in Scheme 6.70 Only a catalytic amount of DEAD (0. Postulated Mechanism for the Mitsunobu Esterification (ix) (x) by an alcohol and an acidic component (the orangered color of DEAD/DIAD disappears immediately). during this brief exposure to hydrogen peroxide. when a secondary alcohol is used. No. 2009. by altering the electronic environment at the PIII precursor. Vol. However. The reverse addition of Ph3P to the solution of the other three components as well as the use of a premixed solution of Ph3P + DEAD/DIAD is also possible. In lieu of using new types of reagents. EPR spectroscopy shows that the betaine 15 may be formed via. Mechanism Despite the fact that the Mitsunobu reaction is widely used in synthetic organic chemistry. Alternatively. the use of Ph3P or n-Bu3P using a Mitsunobu protocol afforded different isomers of 2-oxazolidones from CO2 and ethanolamines (section 8). As long as it does not interfere in the expected reaction.6 (R ) tert-Bu)]76 and ESI-MS. 2. the mechanistic details. These include the following: (a) pentacoordinate phosphoranes (e. 6 2555 Scheme 6. is invoked.94 The intensity of the EPR signal varies as n-Bu3P < Ph3P< (Me2N)3P in reactions with DIAD. Indeed. the authors have suggested precautions that will be handy. Although the yields were slightly lower than the uncatalyzed reactions and secondary alcohols afforded poor results under these conditions. PhI(OAc)2. particularly at the intermediate stages. which can be filtered off through silica gel. intermediacy of the acyloxy phosphonium salt 22 is invoked.g.g.78.81.101.102 Partial degradation of 16 to 19 may also occur when a very weak acid (pKa > 15) is used. Fitzjarrald and Pongdee have proposed the involvement of an acyloxy phosphonium intermediate (cf.g. and many compounds of this type can be readily synthesized (e. 6 Scheme 7 Swamy et al. even for the simplest possible system (PH3.111 Formation of a racemic phosphine oxide.76.92 In a recent study on the coupling 3.93 It may be noted that while in etherification reactions phenol is used as the nucleophile (see section 4). The order of addition of acid and alcohol to betaine 15 in the Mitsunobu esterification has a profound effect on the reaction pathway.95 The species {RO2CN-(P+Ph3)-NH-CO2R}(R′′CO2-) (16) is formed from the reaction between the acid R′′COOH and 15. 30). The reaction is inherently sensitive to the steric environment of the alcohol. Primary alcohols. react in preference to more sterically encumbered secondary alcohols.41) or chloroacetic acid (pKa 2. Esterification with Inversion Alcohols react with carboxylic acids smoothly at room temperature (or lower) to afford the esters in good yields. hence.112-114 This aspect was studied in detail for the esterification of (-)-menthol (32.95 Reaction of 16 with R′OH or 17 with R′′CO2H leads to the phosphonium-carboxylate salt [Ph3P+(OR′)](R′′CO2-) (18). No.g.97 In most esterifications. 31). In case a crystalline product with inversion is . the inversion process is shown in Scheme 7. and (c) phosphinimines with a P(dN-tertBu)[N(CO2R)-NH(CO2R)] moiety (e. to phosphorus.110. For the more general case wherein the nucleophile is Nu-H and alcohol is chiral (RaRbCHOH). MeO2CNdNCO2Me.40.g.) is preferred. indicates the involvement of analogous pentacoordinate dialkoxyphosphorane. It is likely that the acids of lower pKa prefer the oxyphosphonium intermediate structure 18 over a phosphorane of type 17. CH3CO2H).79.80.90 The stability of this species may be enhanced by hydrogen bonding. For a few examples in which retention of configuration (species 23) is observed or when the acid anhydride (24) is the major product. preferably <11.40.85 Thus.81 Crystallographic evidence for a protonated compound of type 16 has been recently provided.104-107 The products 27-28 are the tautomeric forms of the expected betaine and. 2009.106 Some of the derivatives as obtained in parts (a)-(c) can take part in the Mitsunobu esterification.101. 26). 4-nitrobenzoic acid (pKa 3. Oxyphosphorane intermediates Ph3P(OR′)2 (17) are formed by the reaction of 15 with alcohols.77.84. but not such a strong nucleophile that it reacts with the cation in 16 (cf. 109.79.101.101. here it has taken the role of the alcohol (substrate). attack of the carboxylate anion R′′CO2.97 Calculations also reveal that it is possible to divert the Mitsunobu procedure to a retention channel with judicious selection of experimental conditions. generally in high enantiomeric purity. to effect the inversion of configuration of chiral secondary alcohols. Carboxylic Acids/Phosphorus-Based Acids as Nucleophiles: Esterification Including Macrolactonization 3. Hydrolysis of the product subsequent to esterification affords the inverted alcohol.108. 29).84.102.83.83. in general.100. This is one of the “trump cards” of the Mitsunobu esterification route over many other methods. For successful esterification. configurational inversion of alcohol occurs under mild and essentially neutral conditions. Vol.1. Scheme 6) faster than the alcohol.at the alkoxy carbon in 18 is assumed for the formation of the configurationally inverted ester 20. Many such compounds are now well-characterized.86) in a solvent such as THF or benzene (Cautionary note: It is adVisable to use toluene in place of benzene in View of the carcinogenic nature of the latter. when a chiral phosphine [e. The pKa of the usable acid must be below 13. of substituted benzoic acids with various phenols that afforded aryl benzoates (e. a delicate balance is required such that the carboxylate anion is a strong enough base to initiate alcohol activation.89.90. MeOH. When a chiral secondary alcohol is used.109 leaving room to explore the viability of other PIII compounds for specific transformations. Scheme 8).90. (b) dipolar cycloaddition when a functional group such as -NCO is present on the phosphorus precursor (e. give credence to the proposed first step in Scheme 6.85. (cyc-C6H11)(1-naphthyl)(Me)P in place of Ph3P] and excess alcohol are used.2556 Chemical Reviews.41. 27-28) if phosphorus initially had a -NH-tert-Bu group. Recent theoretical calculations by Anders and co-workers show that the hypersurface of the Mitsunobu reaction is far more complex than is generally assumed. implying potential duality of the mechanism. especially with regard to substituents at phosphorus. 120 4-Nitrobenzoic acid was used as the preferred nucleophile to prepare the stereodefined precursor 37 in the synthesis of octalactins A and B (Scheme 10a). wherein the configuration at the secondary alcohol 38 was inverted to lead to the formation of 39 (Scheme 10b). although the yields in the Mitsunobu Scheme 10 esterification were only moderate in the cases studied.118 The utility of an inversion process is nicely illustrated in the total synthesis of (()-ginkgolide B. The product 42. 109.121 The Mitsunobu reaction was one of the useful steps in the total synthesis of the marine alkaloid (()-fasicularin (40). picolinic acid is another option that can be considered. are useful in ring closure metathesis leading to salicylihalamide. Compounds such as 42.116 Use of 4-benzyloxybutyryl esters for which deprotection may be effected by Pd-C/H2 may be yet another choice. an -OH group was converted to the required inverted thiocyanate compound 40 using the combination Ph3P-DEAD/HSCN.5:2.119 In the esterification of sterically hindered 17-hydroxy steroids. A toluene solution of acid and DIAD was added to the solution of phosphine and alcohol using the stoichiometry 1:5:2. 6 2557 Scheme 9 required. but with a bulkier protecting group [such as (i-Pr)3Si in place of Me3Si]. 3. it was found that a more acidic nucleophile provided a better yield of the inverted product. compound 42 could be readily synthesized (Scheme 11a). the cleavage of this group later would require catalytic Yb(OTf)3.122 In the final step.123 Using the acetylenic alcohol 41 and a normal Mitsunobu protocol.5 [alcohol/acid/phosphine/DIAD].115 The (prenyloxymethyl)benzoic acid gives good yields of the inverted esters with secondary alcohols.117 There is an example in which Zn(O-p-Ts)2 is used instead of the pure acid for Mitsunobu inversion. Vol.5-dinitrobenzoic acid could be a good choice as the acidic partner. The advantage of using this acid is that the resulting esters can be cleaved under essentially neutral conditions using Cu (OAc)2/methanol. In place of substituted nitrobenzoic acids. after con- Scheme 11 .Mitsunobu and Related Reactions Scheme 8 Chemical Reviews. where the undesired anti acetylenic alcohol 34 was efficiently converted to syn35 by the Mitsunobu protocol (Scheme 9). No. 2009. 124 The Mitsunobu protocol has been successfully employed for esterification with inversion of methyl β-D-glucopyranoside 47. A novel domino Mitsunobu-intramolecular nitrone cycloaddition process has been reported by Goti et al. 2009. The example given in Scheme 11b leading to the purine derivative 46 illustrates the manipulation of the configuration at the alcohol center by judicious choice of the nucleophile in different steps. (Scheme 13).2558 Chemical Reviews. led to 43. which contained the required basic rings present in salicylihalamide. No. with that of compound 48 being ∼50% (Scheme 12). which contains three secondary alcohol residues. 109. Scheme 13 verting the -SiMe3 group to -Si(i-Pr)3.125 A 4. the reaction of maleic acid monoester with the Chart 1. The results are significant in the sense that they give a better understanding of the reactivity of different -OH groups toward esterification in a polyol system.8-molar excess of Ph3P-DEAD-benzoic acid was used to furnish four differently benzoylated methyl β-D-allopyranosides in a very good overall yield. Vol.126 Here. (Location of the Inversion Process Is Marked by an Arrow in Each Case) . followed by ring closure via Grubbs’ catalyst. 6 Scheme 12 Swamy et al. a Mitsunobu protocol can be effectively utilized for stereochemical inversion. In the synthesis of carbocyclic nucleoside analogues. 9. with the arrows indicating the position of inversion.216 (lxiii) taxol precursors (a .179 (xxvi) deoxynucleic guanidine (DNG) oligonucleotide.206 (liii) phospholipid diastereomers.150 diospongin A (69). 1-(1-naphthyl)ethanol]. 61 from ref 142).50).679).192 (xxxix) 3-methylcyclopentadecanol. 4-dimethylaminophenyldiphenylphosphine (2) instead of Ph3P worked better].N-ligands with a cyclohexane backbone. 53 (from ref 130)].170 (xviii) mycalamide A (natural product).145 phomactin B2 (64).158 (vii) reduced products of cis.212 (lix) azidosphingosine.197 (xliv) 4-hydroxytetrahydropyranone.132 fluoroproline (e.136 khafrefungin 59.202 (xlix) 1-β-O-glucoronide esters.3.11.13.g.152 The structures of 50-70. 1-tetralol.182 (xxix) (4R.196 (xliii) cyclopenta[d]pyridazinediol.g.g.166 (xiv) 6-epiaucubin. In addition to the above.157 (vi) Scheme 15 macroviracins. 109.207 (liv) enantiomerically enriched aryl-alkyl carbinols [e.155 (iv) tubronic acid. These pertain to the synthesis of (i) pregnanone derivatives.180 (xxvii) D-hica.167 (xv) hydroxyethylene dipeptide isosteres (e.194 (xli) chiral P.15-octols (16 diastereomers). 2009.177 (xxiv) protected aminooxyprolines. this exhibited antitumor activity against lung cancer similar to cisplatin).208 (lv) the chlorohydrin precursor for NPS-2143 (calcilytic agent).135 dihydroaquilegiolide (e.153 (ii) glucosphingolipids.156 (v) enantiopure butanoates.3S. 62).113. No.199 (xlvi) tetracyclic lactones as structural analogues of kaurane diterpenoids.209 (lvi) (S)-4-benzyloxy-5.g. The product 49 was later utilized for the synthesis of (-)-rosmarinecine.4R)-1.g.2.g.137 benzo-fused macrolactones (precursor to 60).g. Mitsunobu inversion/epimerization is utilized in numerous diverse syntheses that include bicycliclactams(e.172 (xx) leucascandrolide A (natural product with a sterically congested carbon).5R)-muricatacins. in place of the more common nucleophile 4-nitrobenzoic acid.154 (iii) pyrrolidine-amide oligonucleotide mimics.3-isopropylidenedioxy-4-phenylbutanoate.151 and 7-ethyl-8indolizidinol (70).131 (S)-epimeric carbaspironucleosides (e.200 (xlvii) pyrrolidine-trans-lactones. 54).3. a component of kulokekahilide2.184 (xxxi) functionalized β-C-glycosyl aldehydes (a part of ambruticin).183 (xxx) trioxilins.135 Due to the large number of other applications involving similar inversion/epimerization.and (4S.Mitsunobu and Related Reactions Scheme 14 Chemical Reviews.1-difluoro-4-hydoxy-3-(palmitoylamino)-4-phenylbutylphosphonic acid (sphingomyelinase inhibitor).β-unsaturated lactones). the necine base portion of many pyrrolizidine alkaloids.133 (R)-cytoxazone (e. Et3N/THF was used for hydrolysis during the workup.164 (xii) the acetate of the triol derived from jasminine.185 (xxxii) pyrrolidinols.7.193 (xl) optically active β-methylγ-alkyl-γ-butyrolactone.148 magellanine 67.129 intermediates for dihydroxyvitamin D3 [e.186 (xxxiii) carbocyclic nucleosides.162 (x) (2S.147 azafulvenium precursor (pyrroloindolizine) 66.203 (l) trans-dihydrodiols.195 (xlii) optically active aminobenzindanol.4R)-4-(tert-butyldimethylsilyloxy)-2.213 (lx) a pseudoenantiomeric bisoxane fragment of phorboxazole A.178 (xxv) carbahexopyranose stereoisomers.191 (xxxviii) sesquiterpene lactones. It may be noted that.5S).211 (lviii) a tetracyclic diol precursor in the synthesis of cylindrospermopsin.204 (li) aigialomycin D.174 (xxi) L-lyxose esters.189 (xxxvi) (+)-cardiobutanolide.169 (xvii) long chain pentadeca-1.168 (xvi) orobanchol (a germination stimulant). 6 2559 hydroxy-substituted nitrone afforded an interesting cycloadduct 49 that must have come from the initially formed ester with inversion at the chiral center.163 (xi) dihydroxycholesterol.159 (viii) stereoinversion of myoinositol into scyllo-inositol.128 D-fructose-Lsorbose interconversion (e.175 (xxii) cryptophycin (5-hydroxy acid subunit). picolinic acid or formic acid was employed for the synthesis of 53 and 55. L-682.205 (lii) butenolides (R.138 salicylihalamide (e.134.g.190 (xxxvii) 3-amino-2. 58).144 (-)-clavosolide B intermediate 63. 56 and 57).139-143 azidomethyl-substituted pyrrolidine esters (e.176 (xxiii) polycyclic carbohydrates.146 6-benzyl-2-methoxy-8-(4-methoxybenzyl)-6.5-dimethoxypentanoic acid.215 (lxii) C(1)-C(9) and C(12)-C(26) subunits of macrolide rhizoxin. Vol.149 cycloheptenol 68.and transhexahydronaphthalenones.214 (lxi) 1-aminoalkyl-γ-lactones. we only list them here.6trideoxysugars.130. 1-indanol.g.181 (xxviii) methylsulfonate esters. 52).130.g.160 (ix) orthogonally-protected and unprotected depsipeptides such as L-Lys-D-Ala-D-Lac161 and Boc-(S)-HOMeVal-(R)-Hmb. 55). the structural drawings pertaining to these references are given in the Supporting Information (Table S1). are shown in Chart 1.201 (xlviii) sporiolide B. respectively.210 (lvii) (3S.165 (xiii) stereochemically inverted products of xylofuranosyl derivatives.173.2]nonane (65.g.171 (xix) murisolin (natural product).127 dictyoprolene(51).198 (xlv) alkynic esters as precursors to chiral substituted phthalides.187 (xxxiv) ∆2-OPC-8:0 (a substituted cyclopentanone derivative).5. 1-phenylethanol.133 For the conversion of 4-nitrobenzoate ester precursor to 57.188 (xxxv) fluorescence-labeled probes based on phyllanthurinolactone [in these cases.8-diazabicyclo[3. 3dihydroxy-1.2-diol.227 (lxxiii) N-Cbz-protected 6-aminotalose and 6-aminogulose. It may be noted that this reaction took place via a pentacoordinate phosphorus intermediate rather than a betaine analogous to 15.4-epoxybutane-1. phthalimide.5. Scheme 16 bicyclo[9.221 (lxviii) segment C of tautomycin. on microwaveassisted synthesis) is available.3.236 (lxxxii) configuration confirmation (not total synthesis) of 6-epikericembrenolide A (1S. retention of configuration leading to product 74 was encountered in an intermediate step (Scheme 15). a fairly high percentage .2.2diols.2S.279 (cxxii) trans-4-N3-benzoylthymin-1-yl-2-(Boc)aminomethyl pyrrolidine.232 (lxxviii) tropane alkaloids. Esterification with Retention (in the Intermolecular Mitsunobu Reaction) In intermolecular Mitsunobu esterification.234 (lxxx) the hydroxyl.5-dideoxy5-C-branched-chain hexulopyranose derivatives.1′-bi-2-naphthoxy-based PIII compound (+)-(1.273 (cxvi) 17R-estradiol derivatives.257 (ci) optically active 1.254 (xcviii) trilobacin. an antiherpetic drug approved by the FDA for topical applications. incomplete consumption of the starting material 73 was noticed even after prolonged stirring at room temperature.268 (cxi) (S)-timolol.6tetrasubstituted tetrahydropyrans.264 (cvii) (+)-asperlin.261 (cv) 7-deoxyxestobergsterol A (a pentacyclic steroid). DEAD.237 (lxxxiii) modified 1β-methyl carbapenem antibiotic S-4661.280 (cxxiii) (R)-3-iodocyclohexenyl acetate.241 (lxxxv) 8-(phenylsulfonyl)de-A. only an unexpected dehydration side product with an internal double bond was obtained almost exclusively. 109.108 However.and aldehydesubstituted cyclohexene part of the guanacastepene skeleton.275 (cxviii) 3.230 (lxxvi) enantiomers of 1-phenylethan-1. The reaction would then proceed with the acyloxyphosphonium intermediate.250 (xciv) 17Rdihydroequilenin (a steroid).3-propanediol.278 (cxxi) (+)-broussonetine C.217 (lxiv) 2.249 (xciii) amphidinolide A (presumed structure).225 (lxxi) bengamide B.260 (civ) 3. No.251 (xcv) cis-methyl-3-hydroxy2-pyrrolidone-5-carboxylates. Use of the phthalimide route [Ph3P-DEAD. if the alcohol is sterically hindered.235 (lxxxi) 4-deacetoxyagosterol A.3.248 (xcii) C10 esters of dihydroartemisinin.285 It is of some interest to see whether kinetic resolution of secondary alcohols can be effected or not by a Mitsunobu protocol.1′-C20H12O2)P(NMe2) (71) with DIAD to effect kinetic resolution as shown by Kellogg and co-workers (Scheme 14). This was not favored in view of the regioselectivity observed in the reaction.288 3. the unreacted alcohol could be obtained in yields of 44% with an ee of ∼90%.274 (cxvii) (+)-muscarine iodide.266 (cix) 8-O-4′-neolignans.2560 Chemical Reviews.1]pentadecatriene derivative).271 (cxiv) a precursor to amphidinolide H1.255 (xcix) trans-(2R. In reactions using allyl alcohols also.3-cyclopentanetriols.3S)-2-hydroxymethyl-3-hydroxypyrrolidine.222 (lxix) the C(3)-C(13) segment of the macrolide rhizoxin. It is important to note that the investigators had to saturate the reaction medium with a large excess of the carboxylic acid as well as the reagents to effect the reaction.6R).283 (cxxvi) (-)-3-hydroxybaikiain. 6 Swamy et al.259 (ciii) an intermediate for the β-adrenergic receptor antagonist MY336 (results obtained in the esterification were utilized).263.2-dio1.267 (cx) (-)-andrachcinidine. it has now been established that the controlled microwave heating minimized the time required.258 (cii) protected 3-hydroxy-4-cyclohexenylcarbinol. essentially complete esterification of (S)-sulcatol to the (R)-acetate using ∼2 equiv of the reagents could be accomplished within 5 min at 180 °C under sealed-vessel microwave conditions.281 (cxxiv) the acetate of chiral dihydropyranol. When they tried to perform the reaction at 40-50 °C.282 (cxxv) cyclic ADPcarbocyclic xylose.218 (lxv) N-Boc-β-methylphenylalanines. Vol.2-dihydrobenzenes. When they used the normal procedure of premixing acid and alcohol followed by addition of Ph3P-DEAD.284 and (cxxvii) an epimer of 5R-cholestan-3R-ol.276 (cxix) the L-enantiomer of trifluridine.246 (xc) trans-2.265 (cviii) an enantiomer of lubeluzole.240.B-cholestane precursors to hydroxyvitamin D3.224. In the total synthesis of (+)-zampanolide reported by Smith and co-workers.277 (cxx) unsaturated aminopyranosides.252 (xcvi) tetrahydrolipostatin.231 (lxxvii) 3-O-dimethoxytrityl-2(S)-(N-thymin-1-ylacetyl)-amino-1(R)-phenyl-1.219 (lxvi) cis-2-amino-1-indanol.5 mol equiv each of Ph3P. and racemic alcohol] also gave moderate ee of the resolved alcohols.262 (cvi) (-)-hastanecine.272 (cxv) panclicins A-E (pancreatic lipase inhibitors).233 (lxxix) macrosphelides C and F. It has been noted that while the conventional protocol at room temperature was sluggish. and (1S)-(+)-ketopinic acid with 1 mol of racemic (()-PhMeCHOH.247 (xci) 7-hydroxy-5dodecanolides.287 An excellent review on this as well as N-alkylation (in general.238 (lxxxiv) vitamin D3 A ring precursor diols239 and chiral cyclohexenols (analogues of dihydroxyvitamin-D3 A ring synthons). In the reaction using 0. First was the failure of the Morrisson-Brunn-Huisgen intermediate to activate the alcohol because of steric congestion. 2009.243 (lxxxvii) 2′-deoxy-4′-thio-1′purine nucleosides.245 (lxxxix) D-isomannide.226 (lxxii) chiral substituted cyclopentenols. retention of configuration may be favored.220 (lxvii) 4-amino-1.223 (lxx) macrosphelide A/B. the enantiomeric excess (ee) was only moderate (up to 39%) and the yields were not very high.228 (lxxiv) (-)-lasubine II.244 (lxxxviii) the aplasmomycin tetrahydrofuran ring.289 Two possible reasons were considered.242 (lxxxvi) bullatacin.270 (cxiii) the C4 epimer of 7-oxa-phomopsolide E.229 (lxxv) L-lyxose dibenzyl dithioacetal from D-ribose dibenzyl dithioacetal.109 Although the Mitsunobu reaction is conducted typically at low temperatures.2.286 It was also possible to use the pentacoordinate derivative 72 obtained by reacting 1.253 (xcvii) cyclohexylnorstatine.256 (c) syn-R-hydroxy-β-amino acids. The second possibility was the formation of an oxonium intermediate followed by ring opening by the carboxylate.269 (cxii) the cytotoxic agent (-)-macrolactin A. g. Discrimination between alcoholic and phenolic hydroxyls has also been recently utilized in the total synthesis of (-)-oleocanthal (77).306 After forming the oxyphosphonium salt (88).305-307 The yields of the γ adducts can be maximized by using non-cross-linked polystyrene-based triphenylphosphine 87. Jeong et al. this need not be the case with 1.301 In an intermediate step in the total synthesis of R-(-)-argentilactone.290 several earlier reports also have revealed such a feature.297 In the synthesis of vanillin nonanoate 76 (Scheme 16b). Baylis-Hillman adducts (allylic alcohols)304 behave differently. 75) of biomedical and nutritional relevance (Scheme 16a).291-293 The observation of retention is attributed to deviations from the normal mechanistic pathways involving SN2′ or SN1 processes or to the participation of neighboring groups.298 In cases where two secondary alcoholic groups are available.2-ethanediol) underwent a highly chemoselective monobenzoylation with Ph3P-DEAD/benzoic acid. it can be expected that the sterically less hindered site is the one that will preferentially take part in esterification with inversion. or Yb(OTf)3 (cat. Vol. 109. observed minor retention products in esterification (as well as azidation) and ascribed it to the participation of sulfur of the nucleoside skeleton.g. In contrast to the normal alcohols. the carboxylate anion attacks the olefinic γ-carbon rather than the normally expected R-carbon leading to the E-isomer of . Similar selectivity has also been observed by Voelter and co-workers.83.303 This reaction illustrates that the ozonide functionality does not interfere with triphenylphosphine. Such a distinction has been utilized in the synthesis of the shark repellent pavoninin-4 recently (Scheme 17a).299 However. other routes [X ) Cl using pyridine and X ) OH using DCC/DMAP (cat. with the latter predominating (Scheme 19a). similarly phenyl ethers also are synthesized. The ozonide-acid 85 reacts with 1-(2-hydroxyethyl)imidazole to form the ozonide imidazole ester 86 (Scheme 18) in decent yield. it provides a broadly applicable entry into various phenolics and polyphenolics (e.).302 In this case.294.). the authors found it more convenient to prepare the di-4-nitrobenzoate ester and then hydrolyze it to get the inverted diol (R)-PhCH2CH(OH)CH2OH in high yield and excellent ee (98%). 2009. leading to secondary benzoate 81 as the major product.2-butanediol (S)-PhCH2CH(OH)CH2OH.2-λ5-dioxaphospholane species 80 was the key intermediate. This result is important to be noted whenever one is using a 1. affording both kinetically and thermodynamically least stable secondary benzoate (Scheme 17b).2-diol in the Mitsunobu reaction. Unsymmetrical 1. 1. No. While preparing isodideoxythionucleosides.3.300 The 1. they obtained 80% of the secondary monobenzoate 83 with <5% of the dibenzoate 84 when 1 mol equiv of Ph3P-DEAD was used (Scheme 17c).2-diols.2-diols (e.295 Retention of configuration was also reported recently by Qing and co-workers in the synthesis of fluorinated nucleosides. anti-inflammatory and antioxidant agent (Scheme 16c). in its conversion to the oxyphosphonium salt.2-propanediol and 1-phenyl1. 6 2561 of retention product is usually obtained. THF] gave poor yields or a mixture of products.296 Scheme 18 3. the proton transfer from the acid occurred predominantly at the least hindered site. One more example of this type has been reported recently by Wang and Yue in connection with the synthesis of (R)-(-)-dihydrokavain by starting with (S)-4phenyl-1. Competitive Esterification Since the Mitsunobu reaction effectively differentiates between alcoholic and phenolic hydroxyls in esterification reactions. Both the R and γ adducts are formed.Mitsunobu and Related Reactions Scheme 17 Chemical Reviews. DEPC/ TEA.3. a naturally occurring nonsteroidal. 6 Scheme 19 Swamy et al.41. earlier. and the Mitsunobu protocol has long been known to be one of the viable methods to effect this. the data are shown in Table 1. when the hydroxy acid 101a was treated with Ph3P-DEAD in THF.321 These results reported by DeShong and co-workers are of paramount importance in assigning the stereochemistry during macrolactonization involving natural product syntheses.4.and R.S.312 A possible pathway involving one of the nitrogen lone pairs of electrons [N4 in the scheme] was put forth by the authors to rationalize this result.308. Thus. Vol.12. 2009. 89. For the preparation of S. Lactonization/Macrolactonization An intramolecular esterification will lead to lactonization. the authors could obtain a 4:1 ratio of the products 94a/94b. This problem was overcome by using diphenyl(2-pyridyl)phosphine (1). Product Distribution in the Mitsunobu Esterification of 93 (cf.4R. a likely pathway for the formation of 91 has also been suggested by the authors.4.311 . although esterification did occur (Scheme 21). as reported by Persky and Albeck. found ring contraction to 1. Stereoselective transformations (along with esterification) of polyhydroxyazepanes to piperidine or pyrrolidine derivatives were also reported by Lohray et al. in the case of 101b. However.5.322 Involvement of a carbocation intermediate was invoked to explain this observation. Possible mechanistic pathways are also discussed in the paper.6R)-3.7-tetrabenzyloxy-6-hydroxy-1-heptene (93) yielded an unexpected major rearranged product (Scheme 20).4-piperazine-2-one (96). The Mitsunobu reaction on the glucose derivative (3S.2562 Chemical Reviews.5R. 109.309 The reaction proceeded predominantly with both inversion and allylic rearrangement.314-320 Although inversion of configuration takes place during normal Mitsunobu esterification most often. Fleming and Ghosh had also observed retention of configuration during lactonization leading to a five-membered ring.323 The isolated compounds were the products of Mitsunobu cyclization with retention of configuration. a Data taken from ref 310. very likely through the intermediacy of an acyloxyphosphonium salt followed by acyl transfer to the alcohol. Scheme 20 Scheme 21 Table 1. which could be removed in the workup by an aqueous acid wash (cf. A stereo.313 3. Scheme 23a). Knapp et al. retention is observed during lactonization of the hindered alcohol 99 (Scheme 22).310 The product distribution varied with the stoichiometry of the reagents as well as the solvent used. it was difficult to purify the products due to persistence of Ph3PO and the hydrazine. No. b The authors observed minor cyclization product 94c also.5-diones 102a. Scheme 20)a product ratio mole ratio Ph3P 4 2 2 2 2 acid 4 2 10 2 10 DEAD 4 2 2 2 2 Et3N 5 25 5 25 solvent THF THF THF toluene toluene 94a 1 2 1 4 1 94b 5b 1 2 1 1 In an attempted epimerization of 6-hydroxy-1. Similar epimerization in other reactions leading to selectively labeled D-fructose and D-fructose phosphate analogues is also reported by the same authors. Because these results are instructive for any future work.R-configured morpholine2. by suitably modifying the ratios of the reactants and solvents.4-diazepan2-one (95) by a normal Mitsunobu protocol.and regioselective rearrangement was also observed by Chung and co-workers while attempting to esterify a conduritol (an allylic alcohol) derivative (Scheme 19b). Slow addition (1-2 h) of the hydroxy acid to the premixed solution of Ph3P + DEAD resulted in 102b. These were then coupled with amino acids followed by oxetane ring opening by appropriate thiols in the presence of Cs2CO3 to lead to peptidomimics. deprotection of the amine by CF3COOH in the presence of p-toluenesulfonic acid afforded the p-toluenesulfonate salts of optically active 3-amino-3alkyl-2-oxetanes. The authors have pointed out that this was the first example of Mitsunobu cyclization with a different stereochemical outcome depending on the rate of addition.324 Cyclization of N-Boc-R-alkylserines leading to 2-oxetanones 108 was efficiently carried out by cyclization of N-Boc-R-alkylserines 107 using a Mitsunobu protocol (Scheme 25a). In the synthesis of spiroketals 104-106 from 103. This paper also summarizes some of the earlier results with regard to retention/inversion in the lactonization process.56 Here. These studies were done in connection with the total synthesis of bassiatin and its stereoisomers. while fast addition (10 min) afforded 102b′ (Scheme 23b). 6 2563 Scheme 23 Scheme 24 Scheme 25 the configuration of the product was dependent on the addition time. have found that a less polar solvent mixture can avoid the interference due to retention as well as other byproducts by using benzene-hexane (2:1) medium in place of THF (Scheme 24).325 Another useful alternative is to open the four-membered lactone ring (obtained via the Mitsunobu protocol) with an amine to give various modified amino acids . 2009. Vol. An analogous lactonization has been used in the synthesis of enantioenterobactin.Mitsunobu and Related Reactions Scheme 22 Chemical Reviews. 109. No. Lopez et al. 356 (xii) lasiodiplodin. A similar macrocycle was also prepared by Krauss et al. a five-membered lactone was involved in an intermediate step. in this case.336. Macrolactonization involving primary alcohols does not have this problem of stereochemistry.337 (iv) suspensolide. the latter is shown in Scheme 28a. The other two unprotected hydroxyl groups do not seem to have interfered in this lactonization. an interesting observation was made. the enantiomer of the naturally occurring (+)-peloruside.366 Considering the fact that an 18-membered macrocycle 116 is formed. one involving etherification and the other incorporating a macrolactonization. 2009. have used Mitsunobu lactonization to generate a spirobicyclic β-lactone-γ-lactam that is present in oxazolomycin.333-335 (iii) (+)-milbemycin β3.363 A solid as well as solution phase synthesis (based on Wang resin) of two 19-membered ring containing macrolactones via the hydroxy acids has been reported by Gragnon et al. since use of Ph3P itself posed separation problems.360 In the synthesis of zearalenone dimethyl diether.331 Macrolactonization Creation of large lactone rings (macrolactonization) is a synthetic challenge. as shown by Moura and Pinto (Scheme 25b).350-353 (x) erythromycin derivatives.349 (ix) cyclodepsipeptides.358. This yield was higher than that obtained by other routes such as the Keck-Boden protocol or Yamaguchi esterification. No.330 Polymer-supported triphenyl phosphine along with DIAD was utilized recently in a lactonization step by Burke and co-workers in the synthesis of thrombaxane B2. (() Zearalanone. Perhaps because of the mild reaction conditions.355 (xi) cyclothialinide.364 Mitsunobu lactonization was utilized by De Brabander and co-workers in the synthesis of (-)-114.348 (viii) 19epi-avermectin B1. They rationalized this result on the basis of geometrical/ conformational constraints that could have precluded the formation of C15 epimeric lactones and enforced the cyclization of substrate 110a via an acyloxyphosphonium intermediate (retention) and 110b via the alkoxyphosphonium intermediate (inversion). In the synthesis of several other macrocycles that include (-)-dactylolide368 and (-)-spongidepsin.326 Mohapatra et al. an inversion of configuration at the secondary alcohol site is observed. a decent yield of ∼66% (including a preceding deprotection of allyl ester) in the Mitsunobu cyclization is noteworthy. thus providing a nice illustration of a configuration dependent mechanistic switch. a marine metabolite (Scheme 26). Li and O’Doherty utilized the Mitsunobu reaction in two important steps. In recent work on the synthesis of one of these members (118). Several members of the family of structurally complex milbemycins have shown significant activity against agricultural pests as well as parasites.332 (ii) the griseoviridin core (9membered macrocycle).339 (v) latrunculins A and B. A recent example of this type is involved in the synthesis of (+)-tedanolide (Scheme 27).361 Bracher and Krauss have reported a simple Mitsunobu route to the saturated analogue.345-347 (vii) (+)-brefeldin C.354. By starting with either 110a or the isomeric 110b.367 The NaSEt used in the last step was to remove the methyl protecting group.359 and (xiv) (()-patulolide C. polymer-supported alkyl diazocarboxylate afforded a better yield (42%) compared to the classical route (8%). Both Mitsunobu and Mukaiyama procedures worked well in this case. It may be noted that.327 A γ-lactone intermediate with a five-membered ring required in the total synthesis of pyranicin. was prepared in excellent yield via Mitsunobu lactonization by Takahashi et al. with low toxicity to plants. the authors ended up with the same macrocyclic compound 111.340-344 (vi) (+)-gloeosporone. a cytotoxic acetogenin. while preparing its protected C13 epimer 111. which contains two intact phenolic -OH groups.357 (xiii) antifungal dilactones UK-2A and UK-3A.365 More importantly.369 inversion . The yield in the Mitsunobu step was 79%. the Mitsunobu protocol is quite popular in this area and is utilized very frequently in natural product syntheses.329 A bicyclic tetronate that is a part of the core structure in the antibiotic abyssomicin-C was prepared by Maier and co-workers via Mitsunobu transannular lactonization.338.2564 Chemical Reviews. 6 Scheme 26 Swamy et al. 109. Earlier reports on the macrolactonization route relate to (i) verrucarin A.328 In the preparation of 1-deoxy-D-galactohomonojirimycin reported by Achmatowicz and Hegedus also. by macrolactonization. Vol.362 The yield in the cyclization step was 42%. Mitsunobu and Related Reactions Scheme 27 Chemical Reviews, 2009, Vol. 109, No. 6 2565 Scheme 28 of configuration at the secondary alcohol site was effected by Mitsunobu esterification. In the preparation of (+)amphidinolide 120, the antipode of the natural antitumor macrolide, the macrolactonization took place by inversion of configuration at the secondary alcoholic carbon site (Scheme 28b).370 The structure of compound 120 has been established by single crystal X-ray diffraction studies. Lactonization with inversion of configuration at the chiral center has also been observed in the synthesis of (i) the naturally occurring macrocycle (S)-citreofuran 121 [using Ph3P-DEAD/toluene] reported by Bracher and Schulte,371 (ii) the potent antitumor macrolide lobatamide C (122) [Ph3P (10 equiv)/DIAD (10 equiv)/THF] reported by Porco et al.,372-374(iii) the cell growth inhibitor (-)-laulimalide 123 reported by Paterson et al.375,376 as well as Crimmins et al.,377 and (iv) the marine metabolite xestodecalactone A reported by Danishefsky and co-workers.378 In the lactonization leading to the DNA gyrase inhibitor (cyclothialidine analogue) 124379 again, inversion was the pathway; approximately 1:1.3 mol equiv of the substrate to reagents in toluene was used to obtain reasonable yields (53%) of the cyclized product. Analogous core structures with different ring sizes have been prepared by Hebeisen and co-workers.380 Inversion at the chiral alcohol center was utilized in the construction of the 9-membered thiolactone core (e.g. 125a) of griseoviridin under dilute conditions (0.014 M) in toluene-THF medium.381 In the synthesis of the same core with different substituents (125b; yield 68%) reported by Marcantoni et al., use of (2-pyridyl)PPh2 and DTBAD alleviated the problem of tedious chromatography.382 The authors have pointed out the crucial importance of adding the precursor hydroxyl acid very slowly, which might have avoided high stationary concentrations of the substrate. The corresponding methyl ester had been prepared earlier by Meyers and Amos by a traditional Mitsunobu reaction using Ph3P-DEAD.333 In a later paper, Meyers and co-workers have prepared the lactone with the same skeleton but as an allyl (in place of methyl or ethyl) ester that was obtained in 50-70% yields;383 this was an intermediate in their synthesis of (-)-griseoviridin. The 14-membered ring containing macrolides required for the synthesis of hypothemycin 126 were prepared more efficiently via a Mitsunobu macrolactonization (64-70%, inversion at the secondary alcohol chiral center) than via an intramolecular Suzuki coupling, by maintaining a concentration of 0.007-0.01 M of the precursor in toluene.384 For the macrolactonization in the synthesis of leucascandrolide A (127), Wipf and Reeves added the required hydroxyl acid via syringe to a premixed Ph3P (25 equiv)-DIAD (20 equiv) solution in THF at 0 °C to obtain a yield of 58% of the protected intermediate lactone. Only the inversion pathway was observed here.385 Paterson and Tudge also used an excess of Ph3P-DEAD (∼6 equiv to 1 equiv of the hydroxyl acid) to obtain a decent yield of ∼50% at the lactonization step while preparing this compound.386 In another paper, for the macrolactonization step in the synthesis of (+)-leucascandrolide A, the same authors could get a 65% yield. In the 2566 Chemical Reviews, 2009, Vol. 109, No. 6 Swamy et al. Scheme 29 penultimate step, a Mitsunobu inversion (81% yield) was effected on a chiral secondary alcohol center.387 Scheme 30 A convergent stereoselective synthesis of the macrolactone ring of the bacterial DNA primase inhibitor Sch 642305 (128) was established using the Mitsunobu cyclization with inversion of configuration; 1:5 mol equiv of the substrate to the reagents was utilized.388 Mitsunobu cyclization was also employed for (i) the synthesis of polyhydroxylated oxamacrolide 129 (97% yield) wherein only a primary alcoholic group was involved in the cyclization step,389 (ii) the construction of a 14-membered ring (73% yield) of the spiromacrolide retipolide (present in North American mushrooms),390 and (iii) an intermediate stage while preparing the benzolactone 130 (78% yield), a model for the naturally occurring queenslandon.391 In the synthesis of one of the enantiomers of zearalane [(R)-131], Mitsunobu lactonization with inversion was a key step. About 8 mol equiv of the reagents per substrate was utilized to obtain a 50% yield during cyclization.392 Scheme 31 High dilution conditions, in general, should favor formation of cyclic products. In this context, polymer-supported phosphines/azocarboxylates which give rather low concentrations of the reactants, in addition to the fact that the products can be removed by filtration, may offer advantages over the traditional Ph3P-DEAD system. Resin-bound triphenylphosphine in conjunction with DEAD was found to be more effective (yield 43%) compared to resin-bound DEAD along with free Ph3P in the ring closure leading to lactone 132 (Scheme 29), an intermediate in the synthesis of salicylihalamides A and B.393 Actually, there was no reaction in the latter case. Use of DIAD in place of DEAD reduced the yields to ca. 25%. The resulting compound is a 12-membered macrocycle. In a later work, the same group has reported the total synthesis of salicylihalamides A and B that involved (i) Suzuki cross-coupling and intramolecular Mitsunobu cyclization as well as (ii) Mitsunobu esterification and ring- closing metathesis.143 Two other syntheses involving macrolactonization are those of (a) combretastatin D-4, which inhibits cell proliferation of colon carcinoma cells reported by Nishiyama and co-workers,394 and (b) macrocyclic glycopeptides reported by Wong and his co-workers.395 Although we have discussed success stories of Mitsunobu macrolactonization above, there are cases wherein difficulties have surfaced. For example, in the total synthesis of the antibiotic lonomycin A that was reported by Evans and coworkers (Scheme 30), use of DEAD/THF/25 °C resulted only in the DEAD substrate acylation (85%) but not the required macrocyclic intermediate 133.396 Changing the solvent to benzene afforded 133 in a yield of only 47%. The problem was solved by the use of hindered DIAD in conjunction with a less polar solvent such as toluene, which gave the best yields (95%); a 1:4 mole ratio of the substrate to reagents was utilized. In another study on the synthesis of the natural product (-)-spinosyn A, Frank and Roush observed that although macrolactonization from 134 to 135 in THF solvent occurred, the hydrazide N-alkylated product 136 was also obtained in significant amounts (Scheme 31). Use of DIAD (48% yield of 135) in place of DEAD also did not help much in this case.397 Nicolaou and co-workers have recently explored different approaches for the construction of the macrocycle present in palmerolide isomers. Despite the fact that the Mitsunobu route afforded the expected macrolactone, side products that contained the diethyl azodicarboxylate residue also had formed.398 It was mentioned above (cf. Scheme 19) that the Baylis-Hillman alcohols, which are allylic in nature, lead to both R and γ esters and thus behave differently from normal alcohols. Even in the synthesis of macrolactonization, use of allyl alcohols is not straightforward, as pointed out by Campagne and co-workers.37 Rychnovsky and Hwang Mitsunobu and Related Reactions Scheme 32 Scheme 34 Chemical Reviews, 2009, Vol. 109, No. 6 2567 Scheme 33 used both allylic 137 and its corresponding saturated substrate (138) and found that only the saturated substrate underwent smooth macrolactonization to lead to 140 (Scheme 32). They rationalized the results owing to a competing SN1 side reaction because of conjugation to an electron-rich aromatic ring in the case of an allylic substrate, and they have used this methodology in the synthesis of the natural product combretastatin D1.399 Couladouros et al. obtained an excellent yield (91%) in the macrolactonization step by slow addition of the saturated seco-hydroxy acid (7 h) and maintaining a concentration of <2 mM.400-402 Simon and co-workers noted that addition of p-toluenesulfonic acid and an excess (>20 fold) of the reagents prevented the side reactions of the allylic alcohol substrate in the synthesis of cyclodepsipeptides.353 A similar approach was adapted by Chen et al. for the synthesis of 141, a precursor for the natural product depsipeptide FR-901375 (142) (Scheme 33).403 3.5. Other Esterification Reactions Including Those of Phosphates/Phosphonates Use of a primary or a saturated achiral alcoholic substrate generally does not pose a problem in the Mitsunobu process, and hence, only a list of compounds wherein it is used is provided here. These include (i) photoresponsive esters with an azobenzene group, using the reaction of the mesogenic alcohols with fumaric acid or maleic acid,404 (ii) cyclohexyl nitronic ester by starting with cyclohexanol,405 (iii) polar functional PPV derivatives with ester groups for sensor applications,406 (iv) capsular polysaccharides,407 (v) acetylenic esters of 2,3-dibromomaleic acid408 and isophthalate esters409 as precursors for dendrimers, (vi) enfumafungin,410 (vii) buprestin A and B,411 (viii) cinnamyl monoglyceride,412 (ix) β-acyl glucuronides,413-415 (x) 17O-enriched esters of carbohydrates with PhC(O)17OH,416 (xi) bromoacetylation of Wang resin,417 (xii) (()-6-myoporol,418 (xiii) multiple porphyrin arrays through ester linkages,419 (xiv) 3,5-hexadienyl acrylates,420 (xv) mono- and di-esters of sucrose with long chain carboxylic acids,421 (xvi) (S)-(-)-camphanic acid esters of (hydroxymethyl)pyrroles,422 (xvii) syn, syn-bicyclo[3.3.0]octyl2-benzoate,423 (xviii) an esterification step in the synthesis of syn-enol ethers,424 (xix) glass forming liquid crystals,425 (xx) conjugated reactive mesogen 2-methyl-1,4-bis[2-(4acryloylpropyloxyphenyl)ethenyl]benzene,426 (xxi) 6,6′-diO-p-nitrobenzoyl-2,3,4,3′,4′-penta-O-benzyl-1′-methoxymethylsucrose,427 (xxii) poly(triacetylene) oligomers with ester linkages,428 (xxiii)β-anomersofbileacid24-acylglucuronides,429,430 (xxiv) geodiamolide A (an 18-membered cytotoxic depsipeptide from marine sponges),431 (xxv) 5′-O-acyl derivatives of nucleosides,432,433 (xxvi) the acetate of (R)-1-indanol,434 (xxvii) side chain copolymers containing liquid crystalline and photoactive chromophores,435 (xxviii) dimethyl-3-((1Z)propenyl)cyclopropanecarboxylic acid methyl ester,436 (xxix) oligothiophene containing photorefractive material with NLO chromophore,437 and (xxx) 4-flurobenzyl 4-(4-nitrophenyl)butyrate.438 The structural drawings pertaining to these references are given in the Supporting Information (Table S2). Generally, the phenolic -OH group participates as an acidic component in the Mitsunobu reaction. Apart from the report of Fitzjarrald and Pongdee cited above,93 esterification of phenols was employed by Attias and co-workers in the synthesis of polyester-based low molecular weight copolymer 143 [Mn ) 5.3 × 103, Mw ) 6.3 × 103, Tg ) 75 °C], incorporating the fluorescent center for application in PLEDs (Scheme 34).439 The resulting polymer had properties similar to those obtained by using the normal acid chloride route. Organophosphates/phosphonates and sulfates can also undergo Mitsunobu esterification.15,440-451 Nonhydrolyzable methylene bridged polyphosphate analogues are useful as probes for and inhibitors of enzymes and other proteins that bind or hydrolyze polyphosphates. Mitsunobu coupling of the phosphonic acid with the nucleosides can be a convenient route to such compounds. Recently, Taylor and co-workers have utilized this method to obtain bismethylene triphosphate analogues.452,453 While the synthesis of 144 from the precursor acid smoothly proceeded to afford 79% yield, the authors had to use the triethylammonium salt to get a good yield in the case of 145 (Scheme 35a).452 This result is consistent with earlier observations on the beneficial effects of the addition of Et3N/pyridine in such reactions. Previously, Salaski and Maag as well as Imamura and Hashimoto had If the substrate is a diol.456. An example of this is shown in Scheme 37. the compound (MeO)2P(OPh) [slow reaction] can also be obtained by this route. 6 Scheme 35 Swamy et al. but when its ester is prepared.462 The reaction probably occurs Via (MeO)2P[N(CO2-i-Pr)NH(CO2-i-Pr)]. These reactions will lead to cyclic or acyclic . apart from the 14-membered phosphacycle 150.454. Another interesting application of the Mitsunobu reaction involves Ph3P · HBF4 as the nucleophilic source in reactions with alcohols to obtain the phosphonium salts [Ph3PR]+[BF4]-. Phenols and Alcohols as Nucleophiles: Ether Formation Phenols. intramolecular dehydration can also occur even though both -OH groups are alcoholic.458 Pyridine was used in this reaction to preserve the full integrity of the acid sensitive moieties.457 Phosphonate esters of type 146 have been prepared before by a similar route (Scheme 35b). and alcohols with strongly electron withdrawing groups attached to the carbon. this is the oxygen to which the alcoholic residue gets connected. Scheme 36 Scheme 37 also used alkylammonium salts for the phosphonate esterification in the synthesis of nucleoside-appended phosphonates.2568 Chemical Reviews. they have also used the corresponding triethylamine salt during the esterification with the 6-OH moiety of a mannosaminyl residue.455 Lay and co-workers have made extensive use of the Mitsunobu protocol in their synthesis of phosphonoesters.460 Macrocycles can also be generated by using phosphonates. Interestingly. the salt 147 reacted with 3′-O-acetylthymidine under Mitsunobu conditions to give the dinucleotide 148 (Scheme 36).459 In this reaction. A thiophosphate salt is expected to have the PdO unit intact.464. Vol. 109. In place of the phosphonic acid. phenol takes the role of the nucleophile. it has been claimed that the phosphorus configuration is controlled. we may note that.465 4.glycinates. When a free thiophosphate is used. 2009. S-alkylation could also occur.and N-(acyl)dimethoxyphosphoryl. in several other reactions such as etherification. a 28-membered diphospha-heterocycle 151 is also isolated in small quantities starting with the acid 149. wherein. can act as nucleophiles in the Mitsunobu coupling.461 It is possible to prepare phosphite esters (MeO)2P(OR) from the phosphites such as (MeO)2P(O)H and Ph3P-DIAD in toluene.463 This system has been utilized for the synthesis of N-(acyl)-triphenylphosphonio. Thus. No. Etherification without Cyclization Aryl R-sialosides (e. 109. Vol. depending on whether the reaction is intra.469 The resulting compounds are useful in the synthesis of biologically active chromans.or intermolecular. has been employed by Luscombe et al. fluorous solid-organic liquid filtration.g. Later on. protected 3. For example. 159) rate is achieved (Scheme 41). 6 2569 Scheme 39 Scheme 40 ethers. Chiral secondary alcohols undergo Mitsunobu etherification with inversion in their reaction with substituted 3-pyridinols by using the n-Bu3P-TMAD combination.471 Compound 157 upon reduction followed by etherification with the phenol 155 led to more branched species.1. carried out at high concentrations combined with sonication.473 An analogous iterative two-step protocol involving Mitsunobu coupling and carbonyl reduction has been utilized for the synthesis of a library of 84 ether oligomers. In the reaction of phenols with alcohols. Hexafluoroacetone hemihydrate reacts with the fluoroalcohols . if sufficiently electronegative groups are provided at the R-carbon of an alcohol so that the pKa becomes low. 152) that are often used as chromogenic substrates for detecting and quantifying sialidase activity are readily synthesized along with their β diastereomers Via Mitsunobu etherification by the reaction of carbohydrate substrates with the weakly acidic phenols.475 The Mitsunobu reaction is extensively used for the preparation of alkyl-aryl ethers under mild conditions. followed by the ones that give cyclic products. with 155 as the phenolic precursor.477 Similar ethers have been prepared by using perfluoro-tert-butanol by the same research group. a vast increase in product formation (e. Species 157 and its subsequent dendritic products have potential in molecularly imprinted dendrimers (MIDs).476 As mentioned above. However. A similar strategy. where either or both are sterically hindered.466 We shall first discuss those in which acyclic ethers are formed. we shall also briefly allude to special cases wherein NHC(O) to NdC(OH) tautomerization precedes ether formation. 4. (F3C)3COH [nucleophile] can be coupled with CnF2n+1CH2CH2CH2OH.474 In reactions of guanidinium mimetics and N-substituted 5-hydroxyindoles to prepare compounds that antagonize integrin-ligand interactions. Inversion of configuration in general may be expected if the substrate is a chiral secondary alcohol. It is then possible to couple it with other alcohols. The best stereoselectivity is observed with 2-naphthol (R/β 74:26) (Scheme 38). leading to the formation of fluorophilic ether (F3C)3COCH2CH2CH2CnF2n+1 (160). a Mitsunobu etherification protocol is employed.468.472 For the synthesis of dendrons.43 Sequential allylation of a dihydric phenol using a Mitsunobu protocol can lead to dendrimeric structures.478 The products were isolated using fluorous extraction. No. such an alcohol can behave as a nucleophile in the Mitsunobu reaction. In such later steps. although there are a few cases in which retention is observed. the reaction becomes slow in the case of sterically hindered substrates. recently in the high yield synthesis of perfluorinated dendrons with thiol residues that may find application in generating selfassembled monolayers (SAMs) for attachment to a gold surface via the thiol. or steam-distillation.470 A rare example in which a tertiary alcohol takes part in the etherification is that of the reaction of chiral (S)-153 with a phenol (Scheme 39) at eleVated temperatures to afford the desired ether 154 in moderate yields with inversion of configuration.Mitsunobu and Related Reactions Scheme 38 Chemical Reviews. the Mitsunobu protocol was found to be superior to Williamson’s etherification route.g. 2009.467 Configurational inversion of (R)-3-chloro-1-phenyl-1-propanol (a secondary alcohol) in etherification with 2-bromophenol takes place readily.5-bis(methoxycarbonyl)phenols.5-bis(hydroxymethyl)phenols can also be coupled with 3. A nice example of such a situation is the allyl ether system 155 f 156 f 157 ff shown in Scheme 40. Details on further steps are not clear.1. 7.2570 Chemical Reviews.g. Vol. Scheme 42 CnF2n+1(CH2)3OH [n ) 4. similar reactions utilizing many other substituents in place of the Ph(CH2)3. Thus. Other similar applications include the synthesis of (a) oligonucleotides containing a hexafluoroacetone ketal internucleotide linkage.moiety on the lactam ring were not successful. after protection of the other two hydroxyls. a geiparvarin analogue with a fluorinated segment has been synthesized by Amato and Calas. and tertiary fluoroalkyl alcohols (pKa 9-12) and pentafluorophenol (cf. . Both the silyl and N-2.3hexafluoropropanols with 3-perfluorooctylpropanol using the Ph3P-DEAD/PhCF3 system.487 The best result (yield 80%) was obtained using Ph3P-DEAD and 8 equiv of 4-methylumbelliferone at the reflux temperature of toluene.3.484 (c) fluoroalkyl ethers of dihydroartemisinin. 8. 10] using Ph3P-DEAD in ether solution to lead to the ketals [(CF3)2C(O(CH2)3CnF2n+1)2]. However. 6 Scheme 41 Swamy et al.3.494 This modification perhaps needs more studies for general applicability. Scheme 42). however. m ) 3.2. 109. n ) 1.490 Alkylation of L-ascorbic acid (165) with primary alcohols preferentially takes place on the 3-OH group to lead to ethers 166. the combination n-Bu3P/ADDP was utilized to effect the reaction (cf. isopropyl alcohol) in the presence of high-intensity ultrasound reduced the time required from 5 h (conventional method) to 1 h and gave better yields.1.486 The steric factor imposed by the di-tert-butylsilylene protection can alter the stereochemical outcome in the etherification reactions.482 The reaction proceeds under comparatively mild conditions. 164.485 and (d) perfluoro-tert-butyl ethers. 161) from primary. n ) 8) were obtained in high yields.493 Etherification of 4-hydroxycoumarin with alcohols (e. secondary. by etherification using umbelliferone.2-trichloroethoxycarbonyl (Troc)-protection Scheme 43 influenced the observed retention of stereochemistry at the alcohol site. most often in isolated yields of above 70%. Ando and co-workers reacted the silyl protected hemiacetal 162 with 4-methylumbelliferone using various combinations of phosphines and azodicarboxylates (Scheme 43a). reaction of codeine and 2-bromophenol led cleanly to the etherification with inversion and without any interference from the allylic double bond of codeine. and 31P NMR). The resulting compound was useful for the final synthesis of 4-methylumbelliferyl (4-MU) T-antigen. A similar alkylation at the 3-hydroxy position of L-ascorbic acid is also reported by Deleris and co-workers. 13C. In analogous chemistry. compound 167′ could be isolated (assignment of the structure is based on 1H.481 similar ethers derived from normal alcohols have also been reported before.483 (b) perfluorinated ethers as oils/amphiles. In another study.491 An intermediate of type 167 is invoked for the observed reaction (Scheme 44). by reacting 2-aryl-1.g. 6. No.492 This route avoided ´´ the unwanted alkoxide alkylation (Williamson’s procedure).488 The Mitsunobu glycosylation using lactam-substituted phenols and protected sugars led to the glucuronides in good yield after subsequent deprotection.479 Fluorophilic ethers with the formula ArC(CF3)2O(CH2)m(CF2)nF (m ) 1.480 Mitsunobu etherification offers the best possible synthetic route to fluoroalkyl and fluoroaryl glycosides (e.489 Here. Scheme 43b). 2009. Interestingly. and poses problems in purification. it appears that.Mitsunobu and Related Reactions Scheme 44 Chemical Reviews. An interesting microwaveassisted combined Mitsunobu etherification-Claisen rearrangement of allylic alcohols is reported by Jacob and Moody. in their studies on epi-gallocatechin gallate (EGCG) analogues as proteasome inhibitors.7-dihydroxyquinazoline (e.499 An example (172) from their studies is given in Scheme 46a. which could later be hydrolyzed to the acid 174 by TFA/CH2Cl2 (Scheme 46b). The authors noted that even though Mitsunobu chemistry is environmentally unfriendly. No. leading to an SN1′-reaction product (89% yield). In the scale-up operations to produce multi-kilogram quantities of 171. 2009. A report by Wang and Gutsche on calixarenes is also interesting. 6 2571 difficult to remove completely by column chromatography. Thus. the mono. they have also prepared syn-O.495 For the alcohol R1R2CHOH. 109. Wallace et al. by using proximal bistriflate substitution. Here. Hattori and co-workers could achieve an antiselective dialkylation of thiacalixarenes. is atom uneconomical. NMR analysis using NOE experiments suggested the formation of only one isomeric ether in which the aryl and the ether groups were on the same side. for the less reactive alcohol.498 Although the phosphine oxide was Scheme 45 The somewhat unusual behavior of Baylis-Hillman (allyl) alcohols was discussed above. the authors observed both O-alkylation and C-alkylation on the calixarene (Scheme 45). the likelihood of C-alkylation is greater. Vol. it worked better. with the reactivity being determined by both steric and electronic factors. essentially C-alkylated product 170 was isolated.496 In addition.and bis-O-alkylated products 168-169 were obtained when R1 ) Ph and R2 ) H. In another study. a subsequent work-up procedure that included a saponification step gave the desired compound 171 in 99% purity and 66% yield over two steps without recourse to chromatography.g.503 Use of polymer-supported substrates/reagents in the synthesis of small molecules constitutes an important modification in the Mitsunobu etherification process (see section 9 also). 175) via polystyrene-supported phosphine [PS-PPh3] and DTBAD has . These results were later utilized for the synthesis of primin natural products and unusual nitrogen containing 3-alkyl-1. Selective alkylation of pharmaceutically important ethers derived from 6.502 Similar but polymer bound species 173 underwent reaction with phenol.4-benzoquinones. A plausible rationalization for the unusual C-alkylation is also suggested in the same paper. for R1 ) 4-O2NsC6H4 and R2 ) CHdCH2.501 A similar rearrangement in the etherification using allylic alcohols was reported by Wan et al. found that the Mitsunobu protocol was a better approach than Williamson’s etherification. buchapine was thus obtained from 4-hydroxyquinolone and dimethylallyl alcohol.500 Such rearrangements have also been reported in the reaction of 4-hydroxycoumarin with prenyl alcohol.O′′-bis(2-aminoethyl)-p-tertbutylthiacalix[4]arenes by starting with thiacalixarene and N-(2-hydroxyethyl)phthalimide. While R1 ) 4-O2N-C6H4 and R2 ) H led only to mono-O-alkylated product.497 The benzazepin 171 (SB-273005) is a known vitronectin receptor antagonist. 4:3. been reported by Harris and co-workers. have developed an automated Mitsunobu protocol using PS-PPh3 along with DTBAD that is useful for etherification.504 There was no interference from competitive N-alkylation. also have earlier shown the utility of PS-PPh3 in ether (e.g.532 (xx) 5-substituted oxazoles via (5-hydroxymethyl)oxazoles. others are given as Supporting Information (Table S3). and the alcohol were employed in DMF solvent medium.6-trisubstituted pyrimidines (e.527 (xv) 4-alkoxyacetophenones. 2009.2572 Chemical Reviews.514 (ii) tyrosine containing cyclic peptides using fmoc protected resin (181).5 significantly improved the yield.530 (xviii) tentagel-supported peptide containing disperse red residue. while in the case of secondary alcohols double addition of DTBAD with the overall stoichiometry of phenol/PS-PPh3/DTBAD/alcohol maintained at 1:4.517 (v) polymer-supported chiral amines (e.521 (ix) germanium-based linker (aryl-alkyl ether) for solid phase synthesis of pyrazoles. 182) with ether linkages. imidazolyl. benzyl.524 (xii) 2/4-hydroxyl acetophenone linked Wang resin useful for the synthesis of 2.2:2.536 and (xxiv) aryl-allyl (e.523 (xi) ethers derived from OHterminal Wang resin and hydroxybenzenesulfonate esters.531 (xix) aryloxypropanolamines (e.522 (x) polymer-bound alkyl-bromophenyl ethers for nickel-catalyzed couplings. propargylic. Gentles et al. 176) formation. and allylic ethers.550-588 (ii) substituted benzofurans589 and benzopyrans590 with ether linkages. 109.542-549 Compounds 179-190 are shown in Chart 2. Mitsunobu etherification can be performed on polymers with appropriate functional groups to lead to new polymers for further applications or small target molecules after delinking the polymer backbone. 5 equiv each of Ph3P.533 (xxi) luminescent polymers of distyrylbenzenes with oligo(ethylene glycol) spacers.g. Three other examples of the use of PS-PPh3 include diverse aryl alkyl ethers.507 palmarumycin analogues (e.509 In the second example. resin bound phenols were used as the acidic substrates.513 Other related applications include synthesis of (i) 2-substituted 4-aminopyrido[2.505 Primary alcohols reacted with not much difficulty.g.528 (xvi) Shikimic acid-based arylallyl ethers (185).519 (vii) resin-bound aryl-cyclohexyl ethers (e. a 4500 member library of tyrphostin ethers was obtained by Player and co-workers.506 only the sterically unhindered phenolic -OH reacted in this case. (iii) indolyl.4. and the yields were very good with no contamination from the homodialkylated product.537-540 There are also applications related to the synthesis of NLO active polymers (e. Vol. cinnamyl.510 Dendritic resins with an efficiency comparable to that of tentagel (polystyrene-PEG) resin have been used in the synthesis of aryl-alkyl ethers. In view of the multitude of other reports on normal Mitsunobu etherification.525 (xiii) polymer-bound seleno-alkyl-aryl ethers.g.g. indazole-pyridyl [protein kinase-B .515 (iii) functionalized phenolic amino acids. For the Mitsunobu step in the preparation of 188.g.g. 183). Using an fmoc-protected PL-Rink resin as the solid support for phenols. These include the synthesis of (i) aryl-alkyl.518 (vi) non-PEG derived polyether resins. 189) and aryl-alkyl ethers.516 (iv) tellurium bound polymer with an ether linkage.520 (viii) amphiphilic poly(para-phenylene)s.529 (xvii) 6-arylpyridazin-3(2H)-one precursors.g. 184). No.526 (xiv) oxindole-quinazolines with a side-chain ether linkage. 186).508 and ethers derived from N-protected amino alcohols (e.O(THP)-protected cis-hydroxyproline derivatives and 2-(3. 177). 178). 190) containing disperse red 1 (DR1)541 or other suitable chromophores. DIAD. in the last one. Tunoori et al.535 (xxiii) dendritic macromolecules. the presence of an added base such as triethylamine in the reaction medium was beneficial.g.3d]pyrimidines (179) using etherified Wang resin (180).511 Here. use of PS-PPh3 greatly facilitated purification while. Azobenzene-modified cellulose polymers have been successfully synthesized through linking of 4-cyanophenylazophenol to natural cellulose of ultrahigh molecular weight by Mitsunobu coupling (Ph3P-DEAD in DMF).5-dimethoxy-4-formylphenoxy) ethoxymethyl polystyrene (FDMP).534 (xxii) precursors to biphenyl tetrazoles (187. 188). only a consolidated list is provided here. 6 Scheme 46 Swamy et al.512 The same group has also developed a procedure for solid-phase synthesis of ethers starting from N(fmoc). 613 (xxiii) the neolignans rhaphidecursinol A and virolongin B. No.617 (xxvii) prodrugs derived from the reaction of hydroxymethylimides (saccharin.631 (xli) ethers from methyl vanillate-aliphatic diols (yield was better than that of Williamson’s synthesis).626 (xxxvi) phosphinated dendrimers.616 (xxvi) hydroxysubstituted rosiglitazone derivatives.591-594 (iv) tropolonyl ethers of saccharides (192). and other N-heterocyclic-alkyl/aryl and aryl/sec-alkyl ethers.596 (vi) lupiwighteone.Mitsunobu and Related Reactions Chart 2 Chemical Reviews.597 (vii) dianhydrohexitole-based benzamidines.600 (x) constrained arylpiperidines.599 (ix) the carbamate protected Cdc42 inhibitor secramine A. 2009.598 (viii) (4S)-phenoxy-(S)-proline.611 (xxi) the codeine precursor allyl ether 194.620 (xxx) ferrocenyl units linked to perfluoroethers.595 (v) side chain modified riboside phosphoramidites. 109.608 (xviii) 3′-O-(carboxyalkyl)fluorescein labels.606 (xvi) 2′O-benzyladenosine.601 (xi) repinotan [a 2-(aminomethyl)chroman derivative.610 (xx) chiral ferroelectric thiobenzoates.632 (xlii) fluorenylaminoserine-acridine conjugates (sonication was used).) with substituted phenols.5-dihydro-1H-pyrrol-2-ylmethoxy)pyridines (analogues of epibatidine and tebanicline).637 (xlvii) histamine H3-receptor antagonists possessing a 4-(3-(phenoxy)propyl)-1H-imidazole .630 (xl) dibromotyrosine alkaloids. benzotriazole.627 (xxxvii) 3-{4-(2-aminoethoxy)phenyl}propanoic acid derivatives.3.622 (xxxii) 3-aryloxymethylindolequinones. an antiplasmodial agent].605 (xv) ferrocenemodified artificial ditopic nucleobase receptors.618 (xxviii) (-)episilvestrol and (-)-silvestrol (195).633 (xliii) 5′-ethers derived from 2′-deoxyuridine.624 (xxxiv) precursor 197 for the alkaloid (-)-galanthamine (a drug to treat Alzheimer’s disease).625 (xxxv) epicalyxin F.634 (xliv) dendrimers with tridentate pyridylthioether coordination sites.8-bicyclic γ-alkylidenebutenolides.614 (xxiv) virologins.602 (xii) BILN 2061 (a protease inhibitor). 6 2573 (Akt) inhibitors (191)].612 (xxii) amino-/ guanidino-G-clamp PNA monomers.607 (xvii) CMI-977 [a 5-lipoxygenase (5LO) inhibitor].5-trisubstituted benzene moiety. etc.635 (xlv) (+)-(S)-dapoxetine (198).615 (xxv) 5.628 (xxxviii) 3-(2.636 (xlvi) highly functionalized cis-decalins via ethers derived from protected hydroquinones and dienols.619 (xxix) optically pure cyclopenta[b]benzofurans. Vol.609 (xix) cored dendrimers with a 1.621 (xxxi) a functionally rigid rotaxane precursor (196). a potent 5-hydroxytryptamine antagonist].629 (xxxix) nonbasic quinolone GnRH antagonists via 4-hydroxyquinolone.623 (xxxiii) xanthohumol and isoxanthohumol.603 (xiii) ziziphine N [193.604 (xiv) O6-alkyl derivatives of triacyl-2′-deoxyguanosines. 641 (li) optically pure (R.645 (lv) azobenzene-modified cellulose (azocellulose).652 (lix) calixarene-sugars. 4.657 (lxiv) photo-cross-linkable polyimide-based polymers with a decyl alcohol residue.and 6-alkoxy-l.4-thiadiazoles.6-disubstituted cyclohex-2-enones/azafluorenones/thiadiazoles.676 (lxxxi) liquid crystals based on 4-arylbutyric acid [aryl ) 2′.667 (lxxiv) ether derived from poly(4-vinyl phenol) (P4VP). although many possibilities exist. the rest are given in the Supporting Information (Table S4). 2009.646-648 (lvi) mono-O-alkylated BINOL derivatives.3.642 (lii) photoaffinity-labeled 3-(4alkoxyphenyl)-3-trifluoromethyldiazirine derivatives.662 (lxix) C5-substituted imidazolines. Etherification with Cyclization Mitsunobu cyclodehydration of 1. leading to the formation of the three-membered ring. In the reaction shown in Scheme 48a.658 (lxv) bicyclic peptidomimetic inhibitors.677 (lxxxii) aryloxy-alkylpyridines.1′:5′. Thus. 109. 6 Chart 3 Swamy et al.6-diarylalkyloxybenzaldehydes.656 (lxiii) chiral perfluoroalkyl-substituted hexahydrofuro[2.681 A combination of tricyclohexylphosphine and DIAD in THF gave the best results. 201) in substrates lacking electron donating substituents (Scheme 47).2′′-tetraol.661 (lxviii) isoflavanones.g.2′-biphenol.653 (lx) (R)-(+)-O-coumarinyllactic acid.679 Chart 3 shows the structures of 191-199.669 (lxxvi) chiral liquid crystalline 3.639 (xlix) succinate-derived hydroxamic acids incorporating a macrocyclic ring as inhibitors of matrix metalloproteinases.ω-bis(4-cyanobiphenyl-4′-yloxy)alkanes.R)-1. No.g.678 and (lxxxiii) chiral liquid crystalline materials.665 (lxxii) benzoxazole containing thiazolidinediones.674 (lxxix) 2-alkoxyethoxy-substituted nematic Scheme 47 crystals.668 (lxxv) erythro 8-O4′-neolignans.6′benzo-6-methoxy-2.649.3.650 (lvii) (R)-5′.680-682 Although the nucleophilic site is most often not acidic. optically active phenethane-1.4-tetrahydroisoquinolines.2-diol (e. Remarkably. only the epoxide 202 is formed preferen- . the cyclization takes place readily.659 (lxvi) naphthyl O-glycoside.670-672 (lxxvii) R.2574 Chemical Reviews.3′-difluoro-4′-(2-(E-4-pentylcyclohexyl)ethyl)-biphenyl-1-yl]. Vol.654 (lxi) C2 symmetric 2.1′′-ternaphthalene-2.2.3-b]pyran derivatives.2-diols readily leads to the epoxides.644 (liv) neoisopinocampheyl-aryl ethers.640 (l) mono(6-chloropyridin-2-yloxy)cholane (199).666 (lxxiii) chiral ferrocene-labeled tyrosine PNA monomer.673 (lxxviii) ferroelectric liquid crystals bearing a chiral pyrrolidinetype ring. use of Ph3P produced more inVersion whereas tricyclohexylphosphine resulted in retention.638 (xlviii) oligophenylenevinylene derivatives with long alkyl chains and a carboxylic acid that show liquid crystalline phases.675 (lxxx) chiral liquid crystals based on 2-amino1.6′. and poly(ethylene glycol)methyl ether (MPEG) for lithium battery electrolyte applications. 200) led to the stereoselective formation (up to 99%) of styrene oxide (e.655 (lxii) N-alkylated 5.663 (lxx) duloxetine. structure.643 (liii) (-)-gallocatechin.2.651 (lviii) (R)-l-(4-trifluoromethylphenoxy)-1-phenyl-3-butene.2′.664 (lxxi) 4-substituted R-tolylgalactosides.660 (lxvii) 2′-benzyl-substituted 6-chloropurine 3′-O-benzoylriboside. 686 and substituted porphyrins. A Mitsunobu-type procedure using zinc N. Guianvarch et al.689 The thymine nucleophile did not react.692 The epoxide was formed under carefully controlled conditions (Scheme 50).g. albeit as minor products.684 Other examples wherein epoxide formation via a Mitsunobu protocol is effected include several anhydro-carbohydrate derivatives685. it can be isolated as the major product (e.690.N-dimethyldithiacarbamate [(Me2NCS2)2Zn.g.697 Cirelli et al.1disubstituted 1. decomposed in dichloromethane solution at room temperature to give 204a with 79% ee. The authors were also able to isolate the pentacoordinate intermediate 205. 212) are formed by dehydration (Scheme 51c). which. an intramolecular etherification of sterically cumbersome substrate leading to a furan skeleton was accessed using the Mitsunobu reaction (Scheme 53a). In reaction b. the two enantiomers of the final epoxides (204a and b) are formed in high enantiomeric excess (Scheme 49). Kurihara and coworkers have studied the Mitsunobu cyclization of 221.687 In the esterification of sucrose also.706 Other examples of intramolecular . is proposed. dehydration led to the ketones sesquiterpene 214 and isocaryolan-9-one 215.700.694 Even in the case of 213. The work by Barrero also gives more insight into the different possibilities that exist in reactions using 1.g. A 31P NMR investigation suggested the intermediacy of the phosphorane 219. In each case. Similar ring closure is feasible in xylofuranoside chemistry also.683 The epoxide. involvement of an intermediate of type 208 was proposed for formation of the aziridine ring.691 A full account of the aforementioned work is now published. have reported a stereoselelctive synthesis ´ of heterocyclic (indole. 109. imidazole.2diols.2-diols such as 211.703-705 These investigations were directed toward the synthesis of new histamine derivatives. and prepared a 1:1 mixture of (trans+cis)-cyclization product 222 in 97% yield (Scheme 53b). Synthesis of compound 210 has also been reported previously in an earlier work. 217) is the intramolecular dehydration of 1.702 In selected instances. 210. involving pentacoordinate species of type 205 that converted into different intermediate alkoxyphosphonium salts prior to epoxide formation. which was obtained by starting with L-glutamic acid.699 Such a ring closure by dehydration leading to a furan system should be quite general and is used in the synthesis of several C-nucleosides. and 6iodobenzimidazole) C-nucleosides.693 Similarly. However.Mitsunobu and Related Reactions Scheme 48 Chemical Reviews. only 203 with the formation of a furan ring. one of the anomers was obtained exclusively or as a predominant product. Here. shown in Scheme 48. based on their more recent studies on the reaction of hexa-N-Boc neomycin B 206 with 4-nitrobenzoic acid. suggested that epoxide (207) formation is much more likely than aziridine or azetidine formation.6-dideoxy-4-O-methyl-R/ β-D-altropyranose. Verdaguer and co-workers have recently shown that Mitsunobu cyclodehydration is very effective in transforming triaryl-1. Jenkins.272 In an elegant study. Molinier et al.3-diol-2-bromo-2. it was reported that a product with doubleintramolecular ring closure leading to an aziridine ring and a four-membered N-heterocyclic ring were formed in 78% yield. Houston. have provided unequivocal evidence for the formation of anhydro-derivatives.2-diols yield ketones. Thus. Interestingly. a mechanistic pathway.2-diols. benzimidazole.2-trisubstituted 1.3-diols of type 216. Similar furan ring construction (using n-Bu3P-TMAD) in the synthesis of C-aryl nucleotides has been reported by Wengel and co-workers. 1. is formed. depending on the phosphine used. they have used n-Bu3P-TMAD/benzene in place of Ph3P-DEAD/THF for better results.688 More importantly. could be minimized by using toluene as the reaction medium in the presence of 2 mol equiv of Ziram@. substituted tetrahydrofuran 218. Vol. while the use of Ph3P led to retention.2-ethanediols stereospecifically into their corresponding chiral nonracemic epoxides. and not an aziridine.1. This result may be contrasted with that shown in Scheme 47. use of an electron-rich phosphine such as n-Bu3P provided the corresponding epoxide with inversion of configuration. were also successful in generating the oxetane ring present in thromboxane A2 from the precursor 1. carbonyl compounds (e. The configuration of the products was also dependent on the aryl groups of the 1. over a period of a month. and their co-workers. No. 6 2575 Scheme 49 tially.4-dianhydro-d-talitol is also readily obtained from its mannitol precursor. Ziram@] as an additive worked very well for their stereoselective synthesis (Scheme 52).6-di-O-benzoyl-2. On the basis of this.698 In the synthesis of excitatory amino acid analogue 220. When a multifunctional substrate such as N-Boc neomycin B was utilized in the Mitsunobu reaction with N3-benzoyl thymine. 1. These results are quite useful when one intends to use a multifunctional substrate in Mitsunobu coupling. if the intermediate pentacoordinate phosphorane is sufficiently stabilized. but subsequently under more forcing conditions. Although epoxides (e.701 Imanishi and coworkers have also utilized a similar strategy to obtain C-nucleosides. If one were to use 1. which has literature precedence.695 A common method for the synthesis of oxetanes (e. This aziridine formation could be blocked by protecting the primary alcoholic group of the ribosyl ring (as a 4-nitrobenzoate ester) in the precursor.5:3. Scheme 51b). aziridine ring formation also took place. 209) are formed in many cases (Scheme 51a). 2009.g.696 The amount of the byproduct. 723 The structural drawings corresponding to these references are given in the Supporting Information (Table S5).711 (vi) indole/thiazole-appended C-nucleosides.725 Jew et al.720 (xv) 4(5)-(β-D-ribofuranosyl)imidazole.717 (xii) 2-amino-5-(2-deoxy-β-D-ribofuranosyl)pyridine.g.714 (ix) cycloalkenobenzofurans. 109. 223-224) is achieved by diol cyclization as shown in Scheme 54 (a and b).7-diol.l]octane-6.721 (xvi) 8-oxa-3-azabicyclo[3.2. A ready access to chiral substituted morpholines and dioxanes (e.3-dihydrobenzofurans.712 (vii) isonucleosides. to alleviate the problem arising from oligomerization.722 and (xvii) 3′-β-C-branched anhydrohexitol nucleosides.726 It may be .1 M) conditions.710 (v) (R-D-xylofuranosyl)imidazoles. a member of the category of 3-flavanols.719 (xiv)pharmaceutically interesting chiral tetrahydrofurans.707 (ii) epoxy- phenylmorphans. No. 2009.4-dicarboxylic acid.715 (x) 3-aryl-2.708 (iii) flavone C-glycosides.2576 Chemical Reviews. employed Mitsunobu cyclization for preparing (2R.3R)3-aminotetrahydrofuran-2-yl]imidazole. Scheme 51 Scheme 53 Scheme 52 etherification leading to a five-membered ring involve (i) 3′β-C-branched anhydromannitol nucleosides. the authors used dilute (0.718 (xiii)β-ribofuranosides.709 (iv) [(2R. Vol. Enantiomerically pure arylmorpholin-2-ylethanols have also been prepared earlier by a similar route.713 (viii) furan-3.724 In the synthesis of 224. 6 Scheme 50 Swamy et al.3S)-(+)-catechin 225 (Scheme 54c).716 (xi) fluorescent 3-aminobiphenyl-Cnucleosides. This type of chroman ring is fairly easily synthesized if suitable OH groups are available at the 1. Another example that led to the fused ring system 227. as shown by Dondoni et al.6dimethylchroman-4-one730 and other 2-substituted chroman4-ones. No.731 The author has pointed out that the specific rotation of the synthetic (S)-2.741 Intramolecular etherification leading to the formation of dihydrobenzo[f][1.752 Naturally occurring S-amino acids have been employed as chiral synthons for enantiomerically pure benzannulated .3-dimethylchromanones required for (+)-calanolide A.738 This reaction showed that intramolecular ether formation could be readily achieved in an inactivated system also. is also reported (Scheme 55c). the reaction took place preferentially with phenolic -OH. an anti-HIV agent.750 Novel prolinebased 16. have synthesized 4-hydroxyproline derived macrocycles that showed HCV NS3 serine protease inhibitory activity.13dioxabenzo[3.Mitsunobu and Related Reactions Scheme 54 Scheme 55 Chemical Reviews. The δ-altro-2. and the yield for the cyclization step was quite good (66%).743 Oxepane/oxepin derivatives. the macrocyclization was accomplished by a Mitsunobu protocol using Ph3P-ADDP. 6 2577 noted that a five-membered ring also might have formed in this reaction. The same saturated six-membered ring in flavanone (both enantiomers).742 The amide functionality did not appear to adversely affect the reaction. utilizing TMAD that enhanced the reactivity of these nucleophiles.736 and (iii) the structural elucidation of capituloside reported by Zhou and coworkers. via intramolecular etherification using the combination Ph3P-ADDP. were prepared by a Mitsunobu intramolecular cyclization. despite the presence of two additional phenolic -OH groups in the precursor.746 Dehydration leading to the construction of the seven-membered oxygen heterocycle in dihydro-6.739 Reduced phenoxazines that contain a sixmembered ring have also been prepared by Mitsunobu etherification.732-734 Other applications leading to six-membered heterocycles involve (i) heliquinomycinone reported by Danishefsky and co-workers.737 The electron-poor benzopyran 226 could be obtained via intramolecular cyclization using a Mitsunobu protocol (Scheme 55a).4]diazepinones. 109.735 (ii) functionalized steroid-like molecules reported by Yus and co-workers. The intermediates 2-methyl. ring enlargement to piperidines also took place.749.and 17-membered macrocycles have been prepared by Chen et al.4]cycloheptanaphthalene was also accomplished readily via etherification.747 In the synthesis of hepatitis C virus (HCV) protease inhibitors 229-230 that are potent therapeutic agents. 2009. including (-)-pinostrobin.6-dihydroxy-hexonolactones underwent efficient Mitsunobu dehydration by ring closure of the C2-OH onto C6 to lead to tetrahydropyrans (bicyclic lactones).729 Hodgetts has also utilized the Mitsunobu protocol for the cyclization step leading to the saturated ring in the asymmetric synthesis of (S)-2.740 In the etherification of protected polyhydroxy pyrrolidines bearing a CH2OH connected to the carbon adjacent to the nitrogen of the ring.727 and 3-hydroxyflavanones728 was also constructed using the Mitsunobu etherification protocol. Arasappan et al.and 2. which contains a seven-membered ring.751 The authors stated that bubbling the reaction solution with argon gas helped in obtaining a better yield. An analogous route is adapted by the same research group to prepare many other tetrahydrobenzo[1. Vol.5-positions.6dimethylchroman-4-one was higher than that for the natural product. 2-methylchromanone.744-746 including the naturally occurring radulanin E. in addition to the expected ethers. were synthesized similarly. and the best results were achieved by using DEAD in the presence of triethylamine (∼65% yield). Such a macrocyclization leading to a 17membered macrocycle has been used later by the same research group for the synthesis of potent inhibitors of the hepatitis C virus.748 Although an NHC(O) group was present in the precursor.62 This paper also dealt with a variety of other heterocycles generated via Mitsunobu cyclization. is shown in Scheme 55b.4]oxazepin-5-one (228). 754 Cyclization was effected by intermolecular dehydration. Reynolds and co-workers have reported compounds of type 236 as well as those derived from 1. for applications to sensory electroactive polymers) have been synthesized by a similar route.753 Both inter.3. in the Mitsunobu coupling of 2. and N atoms in the chain763 and (ii) macrocyclic ethers containing two calixarene units. diazepine. the reaction was completed in a few hours at room temperature. Scheme 56).766 4. were observed depending upon the type of glycol used (Scheme 58). and 1:2 couplings.and diethers with residual -Cl or -Br functionalities were needed for the generation of macrocycles. 109. S. except in the case of 1.1′-bi-2-napthoxy derivatives could be accomplished. Thus. they obtained the corresponding poly(ethylenedioxythiophene). 2009. Use of a chiral glycol led to an inverted product. It was also shown that the sterically less hindered 1. and diazocine compounds (e. oxazepine. after the removal of the carboxylate group.and eight-membered ring systems.764 Chiral macrocycles capped by carboxamide bridges were also synthesized by chemoselective intramolecular ring closure on the phenolic OH groups of p-tert-butylthiacalix[4]arene-1.3-diethers were readily formed by using simple alcohols.and intramolecular Mitsunobu reactions have been used to construct these heterocycles.2578 Chemical Reviews. Both achiral (236) and chiral (237) monomers were readily synthesized by using a Mitsunobu protocol (Scheme 57).765 Bartsch and co-workers have also reported calixarene-crown ethers that were prepared using a Mitsunobu route and used later for competitive metal ion extraction.g. The thiacalixarene 241 underwent an unusual reaction with 1. ether formation instead of N-alkylation was the preferred pathway. In all cases.5′tri-O-acetyl-6-N-trityl-8-oxoadenosine with 2.6-tetra-Obenzylmannopyranose.3-diols (that lead to seven membered rings) in place of 1. leading to 242-246.761 The resulting mono.2cyclohexane diol.760 This observation was later used to obtain ethers with long chain chloro and bromo alcohols. a widely used antistatic coating in photographic films and an electrode material for solid electrolyte capacitors. is substituted 3. and the structure 247 was assigned to the product. the yields were moderate to good.757.756 Analogous pyrrole derivatives and crown ethers based on such thiophene/pyrrole skeletons (e. effectively via the NdC(OH) tautomeric form. synthesis of macro- cycles containing 1. In the glycosylation of the 8-oxo-purine nucleoside 2′. Sugimura and co-workers have obtained the O-alkylated product in excellent yield. thiazepine. Mitsunobu coupling using such a compound as a nucleophile often leads to O-alkylation. Vol. Either N-alkylation or ether formation was used in the cyclization process with the normal reagent system of Ph3P-DEAD in THF (0 °C to room temperature) to obtain yields of >63%.6di(pyridin-2-yl)pyridin-4(1H)-one (248). 6 Scheme 56 Scheme 57 Swamy et al. No. The yields were in the range 60-95%.3-bis(N-hydroxyalkylamides) under Mitsunobu conditions recently.769 O-Alkylation via a NHsC(O) to NdC(OH) tautomeric shift was used by Maruyama and . The authors have stated that this was the first example where the Mitsunobu approach was utilized for the construction of S-amino acidbased seven. oxazocine.4-ethylenedioxythiophene (EDOT). The monomer for poly(3. Following the same approach. O-Alkylation (Ether Formation) via an NHC(O) to NdC(OH) Proton Shift When there is an NHsC(O) group in the molecule.759 The 1:1.2-diols in the presence of Ph3P-DEAD.758 Selective ring closures of p-tert-butylcalix[4]arene (240) and p-tert-butylthiacalix[4]arene (241) with diols have been effected using a Mitsunobu protocol in very short reaction times. 2:2.768 In the Mitsunobu reaction of N-(2-hydroxyethyl)ureas PhNHC(O)NRC(R′R′′)CH2OH using Ph3P-DEAD.767 This method has been utilized to obtain 249 with a terminal alkyne unit.3.3-phenolic positions were more prone to alkylation and the corresponding 1. 238-239.3′. a mixture of Oand N-alkylation products or a single isomer was obtained.4.g. 231-235.762 The same principles were extended to the preparation of (i) oligoethylene glycol analogues composed of O.2-diols.4-ethylenedioxythiophene) (PEDOT). depending on the substrates. as shown by Hovinen (Scheme 59).755 Qing and co-workers have also prepared compounds of the type 236 with R ) H and R′ ) -CH2-n-C6F13. L-pyranoses were obtained .781 Upon Mitsunobu etherification conditions. an exocyclic NHC(O)CH3 group connected to guanosine underwent only N-alkylation leading to N2-alkylguanosine.779 An unwanted oxazoline formation was noted by Jackson and Zhang in the course of their studies on the carbacephem antibiotic loracarbef.777 Oxazoline formation by this route appears to be facile.770 However.783 The O-alkylation product was obtained in 94% yield with none of the N-alkylation product detected in the cyclization process.773 Here also. Pfleiderer and co-workers utilized an O-alkylation in an intermediate step for protection of an amide functionality. 109. Another interesting case entails a highly effective route for the synthesis of polymer-bound 2-(3-aryl-1H-pyrazol-4-yl)-1.780 In the reactions of saccharins. Scheme 60d) have been synthesized. in which a key step was the cyclization of γ-hydroxyalkoxamate 254 (Scheme 61).5-lactones. the n-Bu3P-DEAD reagent system was employed. Woodward and co-workers observed Oalkylation with alcohols using a Mitsunobu protocol.774 Here. an NH to OH tautomerization is required prior to cyclization and crude dihydroxyaryl diimides could be used directly.771 In the synthesis of pteridine-N8-nucleosides. while that using alkyl halide and a base afforded N-alkylated derivatives.775 A similar intramolecular etherification afforded interesting carbocyclic nucleosides such as 252 (Scheme 60c). and many useful ligands for transition metals and an intermediate for norpseudoephedrine (253.782 D-Mannono-1. An earlier report by Wang and Haske also involved an analogous solid phase synthesis. No. 6 2579 Scheme 59 co-workers to obtain a uric acid derivative. A possible mechanism involving the phenolate salt of [(EtO2C)HN-N(CO2Et)PPh3]+ was also proposed by the authors. while β-hydroxy thioamides gave either thiazines (S-alkylation) or pyrrolidines (N-alkylation) depending on the substituents present in the precursors. Vol.4-lactone was efficiently converted into L-ribose 256. 2009.776 the derivative with a PMB group in place of triphenylmethyl (Trt) is also known. Using D-glycono-1.772 An interesting case of O(S)-alkylation with cyclization involved bisbenzoxazoles and bisbenzothiazoles of type 250 (Scheme 60a). The reaction did not go to completion when Ph3P was used instead of n-Bu3P.778.Mitsunobu and Related Reactions Scheme 58 Chemical Reviews. β-hydroxy amides gave oxazines (O-alkylation).3-benzoxazole 251 but by using a stepwise solid phase path with Mitsunobu cyclization as the key step (Scheme 60b). 9.786 For O6-protection in the synthesis of N2benzyl[2-15N]guanosine787 and 2.g. The yields were quite good in both the cases. Sulfahydantoins reacted with hydroxyl acids (e.and O-alkylation occurred.783.and trans-isomers of substituted pyrrolidines 258-259 (Scheme 63). in which cyclization led to a fused spirocyclic five-membered ring system.788 a similar etherification with 2-(4-nitrophenyl)ethanol has been utilized. ethyl (S)lactate) to lead to O-substituted compounds rather than the expected N-alkylated ones.793 In the synthesis of many isoquinoline/isoquinolinone-based prodrugs. Balagopala and co-workers have described a high yield route to this compound using a Mitsunobu protocol (Scheme 62). Threadgill and co-workers used both O-alkylation and ring N-alkylation. It is interesting to note that the configuration at the secondary alcohol site was retained after azidation. N-alkylation was observed in a few cases with O-alkylated product still predominating.789 In the first step. where the coupling probably occurred via a NHC(O) to NdC(OH) tautomerization.797 In an earlier study by Overman and Zipp.. have synthesized oligonucleotides containing an alkyl interstrand cross-link between the two O6 atoms of deoxyguanosine by using a Mitsunobu protocol. 2009. Scheme 63 Scheme 61 similarly. for the synthesis of many AZT analogues. Christopher Wilds et al. the trans-derivative gave a different product 261. Vol. Here also NHsC(O) to NdC(OH) tautomerization might have occurred prior to O-alkylation. Banfi et al. the authors noted that alkylation was selective for the allylic when compared to alkyl sites of the alcohol substrates. In the reaction of 3-methyl-4H-[1.792 While the cis-isomer gave the O-cyclized eight-membered ring containing product 260.g. Mitsunobu dehydration converted thymidine into 2.4]oxadiazol-5-one.798 N3-Benzoyl thymine gave more of the O-alkylated product while the primary base thymine itself underwent predominantly N-alkylation with 2-(tetrahydropyran-2′-yloxymethyl)hexahydropyrrolo[1. which upon heating with NaN3 gave AZT in an overall yield of 62%.2]isoxazol-4ol in the Ph3P-DEAD/dioxane system.N2-diacetylguanine reacted with 2-(p-nitrophenyl)-ethanol to give the O-alkylated compound N2-acetyl-O6-(2-(p-nitrophenyl)ethyl)guanine.785 Similarly. it was noted that [PhC(O)]2NH underwent Mitsunobu O-alkylation with allylic alcohols [e.799 O-Alkylation after tautomerization was also employed in the preparation of isoxanthopterin N8-(2′-deoxy-β-D-ribonucleosides by Lehbauer and Pfleiderer.784 O-Alkylation on purine bases was also employed in the synthesis of protected O6-deoxyguanosine derivatives via NHC(O) to NdC(OH) tautomerization. A similar chemistry has been utilized by Marquez et al. Here. Azidothymidine (AZT)/Zidovudine (ZDV)/Retrovir/Retrovis (257) is a drug approved for treatment of HIV.791 In the synthesis of 1-sulfonyl-1. encountered an interesting difference in reactivity between the cis. No.4-diazepan-5-ones. 6 Scheme 60 Scheme 62 Swamy et al. depending on the stereochemistry of the substituents. PhCHdCHsC(Me)(OH)] to afford allylic N-(benzoyl)benzimidates. in which the nucleosides are anchored onto the resin . although both N.2580 Chemical Reviews. The two types of proton shifts [NHsC(O) to NdCs(OH) and CHsC(O) to CdC(OH)] coupled with different orientations of the reactive functional groups might have contributed to this difference.794 Isoquinolin-1-ones795 and 3-methyl1-phenyl-2-pyrazolin-5-ones796 underwent predominantly Oalkylation with benzyl alcohol under Mitsunobu conditions.8-disubstituted guanosine derivatives also.2.790 In another study. 109.800 Synthesis of nucleoside-based solid supports.3′-anhydrothymidine. These results also show that different amidic groups can interfere with the expected course of the Mitsunobu reaction. 807 Yuan. A mixture of three bis-isomers of 265 (A. or Azides as Nucleophiles The utility of the Mitsunobu reaction in the conversion of alcohols to amines using acidic imide derivatives as nucleophiles is well-known.3:1. a potent in Vitro inhibitor of ras prenyl transferase and synthetic precursor to several squalene synthase inhibitors (Scheme 64a). high yields.803 The yields were pretty good. Linares et al. 6 2581 through the base.Mitsunobu and Related Reactions Scheme 64 Chemical Reviews. and high isomeric purity. diphenylphosphoryl azide (DPPA). These aspects are discussed below.801 The authors were able to obtain high yields of the products using the normal reagents Ph3P-DEAD in THF-CH2Cl2 medium. 4. and R-cyclodextrin with DMF as a solvent at room temperature. Amides (Including Nucleobases).805 Deguin and co-workers were able to introduce more than one NH2 group using a phthalimide protocol in the conversion of aucubin into aminoside antibiotic analogues. 5. has been reported by Di Fabio and coworkers.g. Since the resulting phthalimides or azide functionalities can be conveniently transformed into amines or heterocycles. 109. N-Alkylation Using Phthalimide and Related Imides Allylic amines can be prepared by the reaction of corresponding allylic alcohols with phthalimide under Mitsunobu conditions followed by treatment with methylamine. such as trimethylsilyl azide.808 The monosubstituted derivative 264 was obtained in 41% yield using a 3.802 Buser and Vasella have utilized phthalimide for the synthesis of 7-oxanorbornanyl amino alcohols (e. This procedure was used for the preparation of farnesyl amine 262. Vol. one can use nucleobases. the Mitsunobu protocol is useful in various organic syntheses. For the removal of the phthalimide residue later. a similar reaction was not possible on neomycin B. Deprotection using methylamine rather than hydrazine hydrate would alleviate the problem of allylic rearrangement and destruction of sensitive functionalities. Fujita. No. 2009. they used hydrazine (Scheme 64b). and co-workers have been successful in the conversion of two adjacent primary face -OH groups of R-cyclodextrin (R-CD) to phthalimide derivatives.1. 263). 5. o-nitrobenzenesulfonyl) can readily take part in Nalkylation. reported that although the phthalimido group could be readily introduced at the 5′′-position of ribostamycin.8:2. Amines. do take part in this reaction. Suitably protected amino acid moieties also contain activated NH moieties that readily undergo Mitsunobu alkylation.806 They had earlier prepared polyfunctionalized tetrahydro-1H-cyclopenta[c]furan glucosides also by starting with aucubin. C) and the mono compound (yields of 22%. besides providing very mild reaction conditions. DEAD. Gotor and co-workers obtained orthogonally protected cis.3-diamines in high yields using the phthalimide route. Ph3P.g. In place of phthalimide.6%. HN3 or any of its alternative sources.804 The inversion process (>99% ee) in this reaction was corroborated by a combination of NMR spectroscopy and molecular modeling.5%. and zinc(II) azide.15 Phthalimides and related compounds in which an NH is connected to an electronegative group (e.and trans-indane-1. B. and 13%. thus expanding the scope of this reaction enormously. wherein a competitive bicyclization process involving other functional groups occurred. 9. diamino-dideoxyaucubin and triamino-trideoxyaucubin. respectively) were obtained . Finally.4:1 molar ratio of phthalimide. and 1. involved phthalimide mediated conversion of -OH to NH2 (and then to hydrochloride) at the lower rim of tolylpyridine-bridged cavitands for use as watersoluble molecular receptors.827 (x) ditopic ligands containing both tetrazole and 1. except in carbohydrates where the success rate was low.817 (ii) the amine-functionalized crown chalcogenide 6-amino[14]aneS4.832. Scheme 66 using a 7:4.811 N-Alkylation of nitrophthalimide using DEAD incorporated nanoporous magnesium aluminometasilicate tablets has been reported recently.856 Many other applications on func- . 2009. In a competition experiment between phthalimide and the tetrachloro counterpart.25-dihydroxyvitamin D3 analogues.847 (xxix) the pineal hormone melatonin.816 Other examples wherein a similar phthalimide route was put to use include the synthesis of (i) the antitumour agent batracylin.825 (viii) diaminocyclopentathiaphenes.826 (ix) optically and diastereomerically pure N-protected (2S.5]undecane.833 (xv) chiral macrocyclic bisamides derived from D-mannitol and L-threitol.. 270. The χ(2)33 value of 272 with a quartz crystal as the reference was found to be 82 pmV-1 (the SHG signal was stable up to 150 °C).848 (xxx) 10-unedecene1-amine.830 (xiii) azaanalogues of batracylins.844 (xxvi) a bisubstrate inhibitor bound to the enzyme catechol-O-methyltransferase.837 (xix) R-aminophosphonates [(Boc)NHP(O)(OEt)2. All the monomeric imide was consumed during the reaction.824 (vii) 4-aminoN-methylproline derivatives (CLX peptide).809 In a reaction reported by Morita and Krause. Vol.810.4-triazole moieties.834 (xvi) chiral trans-2.836 (xviii) amino di(ethylene glycol)terminated alkylthiol (AEG2) designed to form self-assembled monolayers (SAMs) on gold.854 Secondary alcohols also reacted readily. however.853. 109.822 (v) amino-substituted triazoles.823 (vi) gem-difluoroallenylamines. Krchnak reported that adding DIAD to a solution of Ph3P ˇ´ and phthalimide in anhydrous DMF and then adding the solution to the resin avoided the formation of side products significantly. N-Alkylation has been applied for synthesizing a variety of donor tethered phthalimides and naphthalimides (e.6-dimethoxyphenyl)ethyl]acetamide. The utility of this precursor for the macrocyclization process was also demonstrated by the authors in the same paper.829 (xii) (R)-3-aminooctanoic acid (D-BAOA) from (S)-1-octyn-3-ol.835 (xvii) N-[1-(2-allyl-3-benzyloxy-4.2582 Chemical Reviews.815 In the preparation of phthalimide derivatives of resin-linked benzyl alcohol.850 and (xxxii) 2′-O-aminoethyl adenosine.845 (xxvii) fused carbolines.841 (xxiii) polyhydroxypiperidines.and (+)-(S)mexiletine.813 An elegant use of Mitsunobu N-alkylation for the synthesis of chiral synthons has been developed by Grycko et al.812 A phthalimide analogue supported on aminomethyl polystyrene resin has been prepared and used for the solid phase synthesis of 5′-amino-5′-deoxy-N6benzyladenosine by Aronov and Gelb. Another important reaction is reported by Yan and Rajan Babu in which the more reactive benzylic alcohol reacted with phthalimide to afford 269 (Scheme 66b).852 The more acidic tetrachlorophthalimide has been shown to be an excellent agent for displacement of primary OH groups in a wide variety of substrates.3R)-2-amino-3-fluoroundecanoic and (3R)-3-amino-2.6:4:1 stoichiometry of the same reagents.839 (xxi) 4-(aminoalkyl)estradiols. were prepared by Lee and co-workers. the allenyl alcohol 266 was converted to the R-aminoallene 267 in good yield with complete inversion as depicted in Scheme 65.840 (xxii) tert-butyl methyl-N-tributylstannyliminodicarbonates. also for NLO usage. HN3 route was also used]. No. the phosphine reagent has not been specified.2-difluoroundecanoic acids. no trace of a product from the former could be found.g.838 (xx) nor-seco-taxoids.842 (xxiv) 2-azaspiro[5.828 (xi) N-methylphthalimide.849 (xxxi) chiral N-substituted phthalimides for liquid crystalline applications. the chiral diamine 268 was obtained by starting with L-tartaric acid. 6 Scheme 65 Scheme 67 Swamy et al. Analogous polymers using a similar alcohol but with an azo functionality. The reaction using phthalimide can be extended to those containing two phthalimide units that lead to polymeric materials with useful properties. as shown in Scheme 66a. by Pirondini et al. Another recent report.818 (iii) gem-diamine 1-N-iminosugars [R-L-fucosidase/glycosidase inhibitors]. Yoon and Shim have reported the synthesis of several NLO-functionalized polyimides by N-alkylation (Scheme 68).819-821 (iv) R.851 The structural drawings pertaining to these references are given in the Supporting Information (Table S6).831 (xiv) 1R-amino.855 These polymers showed high nonlinearity and good temporal stability.846 (xxviii) 5′-ethylenic modified L-nucleosides.814 For example. Thus.3-diaminosubstituted 1R.843 (xxv) (-)-(R).3-bis(aminomethyl)norbornane. Scheme 67) that underwent interesting photochemical reactions such as the one leading to 271.2. In this process.R-difluoro-β-amino acids. All these intermediates could be successfully converted to the amino compounds by hydrazinolysis. when the amino alcohol 281 was used.883 A moderate excess of the reagents (1.886 some of these were employed later for the preparation of uridine hybrids. Donor-acceptor macrocycles incorporating tetrathiafulvalene and pyromellitic diimide were also synthesized using a similar strategy. 286) in very good overall yields.864.Mitsunobu and Related Reactions Scheme 68 Scheme 70 Chemical Reviews. N-Alkylation of triazolopyridazines possessing a -C(O)-NH-C(O). N-Alkylation of phthalimide as well as a large number of analogous cyclic imides has been employed for the preparation of a variety of P2X7 receptor antagonists.g. Compound 282 was the sole product in the absence of maleimide and neopentyl alcohol. maleimide moieties of poly(R-methylstyrene-co-maleimide) were connected to disperse red 1 (DR1) chromophore via the Mitsunobu reaction. No. Removal of one of the protecting groups led to R-hydrazino esters (e.877 In another report.857-863.g. Cl.880 The degree of substitution of the chromophore was dependent on the solvent as well as steric factors.884 The resulting product 285 was then converted in later steps to muscarinic M3 receptor antagonists. Vol. the diaryl imidazolidin-2-ones.881 The yield was excellent in the case of phthalimide but moderate in the case of other cyclic imides (e. Using 2-methylfuran-protected maleimide and an appropriate alcohol.879 the same research group has also reported many other similar nonlinear optical polyimides using etherification. Tweig and co-workers have synthesized a sizable number of dicyanodihydrofuran (DCDHF) fluorophores (e. These derivatives might be useful in single molecule fluorescence imaging.700-703 Use of a diimide in place of a monoimide can lead to macrocycles. 278). the N-alkylated compound 280 was obtained (Scheme 71a). Substituted hydantoins 284 have a (O)C-NH-C(O) skeleton similar to phthalimide. 275) utilizing Mitsunobu alkylation of diimides (Scheme 69).g. and this has been made use of in Mitsunobu N-alkylation (Scheme 71b).876 However.875.866 A rapid and efficient two-step synthesis of monoalkylated tert-butylcarbazates via a Mitsunobu protocol using N-tertbutoxycarbonylaminophthalimide and other acylphthalimides as acid partners was developed by Jamart-Gregoire and co´ workers (Scheme 70). thiazolidine-2.5 mol equiv) afforded good yield of the product.875-878 Thus.874 In place of phthalimide.865 The same route led to the novel catenane 276 [275 + naphthyl crown ether] by the Mitsunobu N-alkylation of 273 with 274 in the presence of a naphthyl crown ether. The same research group has also shown that aminophthalimide derivatives are better acidic partners than the aminoimidodicarbonate (NBoc2) analogues and have reduced steric hindrance. 6 2583 Scheme 69 tionalized second-order NLO active polyimides have been reported.4-dione).skeleton was similarly effected to obtain the corresponding Nalkylated derivatives. maleimide has also been utilized as the nucleophilic component.882 There is also a report on the use of cantharidinimide and 4-RC6H4CH2OH (R ) Me. 109. An elegant display of such a result has been reported by Sanders and co-workers in the synthesis of a series of macrocycles (e. by starting with 279.887 Polyimides that can be coated on .g. Even glutaramide was used in the synthesis of (()-lasubine I and (()-lasubine II. 2009. leading to the cyclic compounds 282 and 283 (Scheme 71a).873 Solid phase synthesis of orthogonally protected R-hydrazine acid derivatives using activated phthalylhydrazines has been reported by Brosse and co-workers.867-872 Synthesis of compounds such as 277 could be extended to obtain optically pure R-hydrazino esters. NO2) in the Mitsunobu N-alkylation.885 Solid supports linking nucleoside scaffolds have been obtained by alkylating hydroxyalkyl TentaGel-resin with an imino function of suitably modified nucleosides. unusual reactions took place. 897 Using this methodology.893-895 The viability of this protocol has been improved upon by Guisado et al. is available.899. 2009. films and show optical anisotropy have been synthesized at room temperature by the reaction of diols with diimides using the Mitsunobu protocol.900 In this case. Fukuyama and co-workers have utilized their protocol in the total synthesis of lipogrammistin-A and (-)-ephedradine A. Vol.or 4-substituted) or 2. N-Alkylation with Sulfonamides and Related Nucleophiles In Fukuyama’s modification (Fukuyama-Mitsunobu reaction. either nitrobenzenesulfonamide (2.g. Liskamp and co-workers have used N-(o-Ns) activation for .g. the sulfonamide portion can be readily removed by treatment with thiols. N-alkylation of secondary sulfonamides under Mitsunobu conditions).898 Here. 109. the normal reagent system Ph3P-DEAD did not work. 288.888 This procedure was deemed useful for temperature sensitive applications. 287) are the final products. No. through the use of the diphenylpyridinylphosphine and DTBAD. they were successful in obtaining several somatostatin receptor analogues.4-dinitrobenzenesulfonamide is employed as a pronucleophile (Scheme 72a).2584 Chemical Reviews.892 After the N-alkylation. (Boc)NH(oNs) (o-Ns ) o-nitrobenzenesulfonyl).2. Secondary amines (e. Scheme 72b) for peptidomimetic drug design were conveniently obtained by Zapf and co-workers by an intramolecular Fukuyama-Mitsunobu reaction.889-891 A useful procedure for the preparation of one of the pronucleophiles. 6 Scheme 71 Swamy et al. Chiral and achiral peptide nucleic acid (PNA) monomers have been prepared via N-(o-Ns) protected amino acid esters. Scheme 72 5. Pyrazine heterocycles (e. In the synthesis of tripeptides that are useful as potential peptide turn mimetics. deprotection of the o-Ns group in a later step was accomplished by PhSH-K2CO3 in acetonitrile.896 Using this technique. Viirre and Hudson used the Fukuyama-Mitsunobu reaction on a resin bound amino acid to obtain similar PNA monomers. they have prepared a complex lipopeptide (lung-targeted gene delivery agent). the combination n-Bu3P-TMAD in the presence of an excess of base had to be used. 109. The synthesis of the racemic form was reported before.906 This Fukuyama modification has also been utilized recently for the solid-phase synthesis of mono-N-protected diamino acids 291 and 292 (Scheme 73a). the Me3P-ADDP combination worked satisfactorily for 1. Vol. by Hone and Payne. Franzyk. Scheme 73b).903 Olsen. 294.3).916 A primary amino group can be made more nucleophilic by converting it to a pernosylated [o-Ns] derivative.908 Other interesting applications of solid-phase methodology include the synthesis of (i) agel 416. Functionalized piperazin-2ones were also readily synthesized by intramolecular cyclization of precursor amino alcohols possessing an NH(oNs) group via the Mitsunobu protocol. No. and co-workers have checked various reagent combinations and found that the normal Ph3P-DEAD or DIAD combination is sufficient to effect N-monoalkylation of peptides and sulfonamides. the Et3P-DEAD combination gave reasonable yields. including a previous step) via Mitsunobu N-alkylation. as shown by Fukuyama and co-workers in the enantioselective total synthesis of antitumor antibiotic FR900482 (297) (Scheme 74a).4-diazepanecarboxylic acid 292 but not for the piperazinecarboxylic acid 291.912 Generation of an eight-membered ring is also not too difficult.913 The intermediate 296 was obtained in good yield (71%. as can be seen by the examples cited above. The resin part was cleaved subsequent to the Fukuyama-Mitsunobu reaction using trifluoroacetic acid to obtain the desired products. Nuss and co-workers synthesized N-substituted R-amino acids and trisubstituted diketopiperazines (DKPs) in the solid phase and obtained excellent yields of the products with high purity. The precursors 289-290 in these reactions were obtained by the aminolysis of p-nitrobenzenesulfonyl (p-Ns) activated aziridines.901. 2009. This feature has been utilized in the synthesis of azamacrocycles of type 299 (Scheme 75a).910 (iii) tetrahydropyrazine-2-ones by Kung and Swayze.911 and (iv) hydroxyindoline-derived tricyclic derivatives by Arya and coworkers.Mitsunobu and Related Reactions Scheme 73 Chemical Reviews.914 They have also shown that this route is more general and can be adapted for the preparation of cyclic amines with eight to ten membered rings by starting with (o-Ns)NH(Boc). and this was identified as a limitation of the Fukuyama-Mitsunobu reaction in the solid phase synthesis of polyamines by starting with secondary alcohols.917 It should be noted that preparation of these . an acylpolyamine found in spiders.907 Here.905.904 In successive alkylation steps the yields dropped.902 5 mol equiv of the reagents per mole of the nucleophile were utilized.3. 6 2585 Scheme 74 N-alkylation.g. Their group as well as Bycroft and co-workers have earlier used the same reaction for the solid-phase synthesis of polyamine toxins (e.g.915 The key macrocyclization step in the synthesis of the natural product vinblastine 298 was also accomplished via the Mitsunobu protocol by Fukuyama’s group recently (Scheme 74b). PhTX4.909 (ii) amine-bridged cyclic enkephalin analogues by Rew and Goodman. For the latter. This protocol was applied for the preparation of enantiopure piperazine carboxylic acid derivatives (e. Using a similar activation at the nitrogen center. No. 2009. Scheme 76 Scheme 78 1. As discussed above (Scheme 74). Many other amine nucleophiles and deprotection methods have been investigated for use.2. In a few cases. Further reaction with Me3P-ADDP gave the bis-alkylated product readily in 66% yield. however. The same research group also used tosyl-substituted nucleophiles to prepare structural analogues of tirofiban. Chiral cyanohydrins and an N-protected sulfonamide as substrates in N-alkylation afforded new amino acids (e.5. Scheme 78a).8-pentamethylchroman-6-sulfonyl) has been utilized. Pmc ) 2. intramolecular cyclization using amine and alcohol functionalities on the same molecule is also feasible.918 The tosyl group was subsequently cleaved using Mg/MeOH to obtain the free amine for further reactions.4.932 Alternatively. furnished the free thioester 307. upon treatment with trifluoroacetic acid. 305. Vol.924 This situation is different from that seen for esterification of 1.930 Some of these amino acids have been obtained in high enantiomeric purity.923 When (R. 109.7. RNdCH(CN).83. reaction of tertbutoxycarbonyl-protected amino alcohols with Pmc-protected amino esters (pKa ∼ 12.927 A similar reaction leading to o-Ns protected pseudopeptides was also reported by Boyarskaya et al. A highly efficient synthesis of such molecules was achieved by using the Mitsunobu reaction in a multistep synthesis (Scheme 77). monoalkylation (63% yield) occurred predominantly at the primary alcohol site to lead to 302 (Scheme 76a). Subsequent base-catalyzed elimination of trifluoromethanesulfinate yielded synthetically valuable iminoacetonitriles. Dominguez and co-workers . The same route was utilized to construct four-membered rings919 as well as macrocycles.300 Only 4% of the dialkylation product was isolated.920 N-Alkylation of o-Ns-substituted amines was one of the important steps in solid phase combinatorial synthesis of macroheterocycles921 developed by Ramaseshan et al. N-Alkylation of peptides (e. adenine base protection was not required.931 The product 306.922 Protected (R)R-phenylproline derivatives were prepared by a similar methodology by Betsbrugge et al.g. 6 Scheme 75 Scheme 77 Swamy et al. Falkiewicz has reported the synthesis of a PNA type monomer backbone with a reduced peptide bond using Boc-aminoet- hanol (derived from an amino acid) and resin-bound onitrobenzenesulfonylglycine.7-triazacyclodecanes was not possible by starting with the corresponding tosylate in DMF in the presence of Cs2CO3. there was no significant ee. This was readily alkylated using Ph3P-DEAD (81-94% yield) and an appropriate alcohol.2diols discussed above. which spontaneously rearranged to the thioester with a protected peptide. this.925 For the synthesis of many pseudo-peptides. 306) containing a sulfonamide linker with a protected 2-mercaptoethanol has been conducted in solid phase (Scheme 78b) (fmoc ) 9-fluorenylmethoxycarbonyl).929 Here.928 5′-Aziridinoadenylates of the type 304 and related nitrogen mustard variants allow conversion of biological methyltransferases into nucleoside transferases.3-butanediol was subjected to alkylation with 2-nitro-N(2-phenylethyl)benzenesulfonamide [PhCH2CH2NH(o-Ns)] using the n-Bu3P-TMAD reagent pair. Scheme 76b). Thus.S)-1. thus providing powerful tools for investigating S-adenosyl-L-menthionine (SAM)dependent methylation. One such precursor is HN(SO2CF3)(CH2CN). particularly in cases where sensitive functionalities are involved.g. upon thiol deprotection (TBAF/ AcOH) led to the corresponding thiol. the amino alcohol 300 readily gave pyrrolidine 301 upon treatment with Ph3P-DIAD (Scheme 75b). 303.g.926 The best conversion was obtained with the n-Bu3P-TMAD reagent system. Kirillova and coworkers have shown that Mitsunobu condensation is a universal preparative method which allows the formation of different reduced peptides (e.2586 Chemical Reviews. Mitsunobu and Related Reactions Scheme 79 Scheme 80 Chemical Reviews. An interesting application of N-isopropylidene-N′2-nitrobenzenesulfonyl hydrazine (IPNBSH.g. Boc-hydrazones required electron-withdrawing substituents for the reaction to take place. Mitsunobu N-alkylation of a toluene sulfonamide [e. Vol. Earlier. after the extrusion of nitrogen and arylsufinic acid. 312. o-nitrobenzenesulfonylhydrazine proved to be the best.g. (Boc)NH(SO2N(Me)Ph)] with alcohols using microwave heating (1-4 min). the reaction of NBSH with RCH2OH yielded the alkane via the sequence RCH2N(NH2)SO2(2O2NC6H4) f [RCH2NdNH] f RCH3.934 Here.g. products were isolated by fluorous extraction and fluorous solid-organic liquid filtration. In another work. Wanner and co-workers utilized 1-phenyl-3-(2. 2009. C8F17SO2NH(Et). and it afforded a yield of 80% with only very minor amounts of side products (Scheme 79).942-945 Among several such nucleophiles. (cyanomethylene)tributylphosphorane (CMBP).937 and (iii) CF3SO2NH(Et).and Boc-hydrazones are effective nucleophiles in the Mitsunobu reaction.3-dioxan2-yl)ethylsulfonyl (Dios) amides (e. 6. the Boc-group was removed later using silica-bonded toluenesulfonic acid. The protective group can be readily removed later by fluoride ion.939 While tosyl hydrazones reacted cleanly with primary and secondary alcohols (ROH) when coadministered to a cooled Ph3P-DTBAD or Ph3P-DEAD complex to afford products of type 311.950 The final sulfamides were released by treating the polymer sulfonate salt with NH3/MeOH. substituted trifluoromethanesulfonamides CF3SO2N[(CH2)3R]2 (R ) CnF2n+1.g. 317) for activating the amino group in reactions using their alternative Mitsunobu reagent. The silyloxy-substituted 1.938 It is known that tosyl.392).5 equiv) in THF at -15 °C and then adding the propargylic alcohol (1 equiv) and finally the substituted hydrazine (1 equiv) afforded the allenes in 72-77% yield in a single operation. Scheme 81 Synthesis of a diverse class of substituted allenes (e. since a large number of optically active propargylic alcohols are available.936 (ii) perfluoroalkanesulfonamide.946-948 Bis(β-trimethylsilylethanesulfonyl)imide (Me3SiCH2CH2SO2)2NH is another synthetically valuable precursor developed by Weinreb and co-workers. 109.g.941 There. (Ts)NH(2-vinyl-C6H4)] was employed as one of the key steps by Theeraladanon et al. 315) was achieved by Myers and Zheng in a single step starting from propargylic alcohols (e. Premixing Ph3P (1. 6 2587 utilized N-trifluoromethanesulfonamide as a pronucleophile to convert -OH to an -NHR group in the synthesis of clavizepine analogue 310.951 Tsunoda and co-workers have recently developed 2-(1.5 equiv) and DEAD (1. Scheme 80) in the reduction of alcohols has been reported by Movassaghi and Ahmad recently. L-786. It is also reported in the same paper that preformation of Ph3P-DEAD complex prior to the addition of alcohol and hydrazones gave superior results. This transformation proceeded with complete stereospecificity. This compound is stable under basic as well as reductive conditions and can be removed by heating in a hot aqueous .8-naphthosultams 316 have been utilized to prepare many pharmacologically active anti-MRS carbapenem derivatives (e. No. It provides access to a wide range of optically active allenes. 8.g. 10) were obtained in high yields using CF3SO2NH2 and perfluoroalkanols in the presence of Ph3P-DEAD/diethyl ether. This procedure has been adapted to obtain the triene 313 from farnesol.2-trifluoroacetyl)urea [PhNHC(O)NHC(O)CF3] in N-alkylation reactions to prepare many glycine equivalents.935 Three other useful perfluoroalkyl group containing nucleophiles that have been shown to undergo facile N-alkylation are (i) substituted trifluoroacetamide. n ) 4. 314) using an activated hydrazine nucleophile (Scheme 81). a similar reaction using o-nitrobenzenesulfonylhydrazine (NBSH) was published by Meyers et al.933 This substrate was regarded as more efficient than N-tosyl derivatives (discussed below).2.940 The Mitsunobu derivative after removal of the sulfonate group underwent loss of nitrogen from monoalkyl diazene intermediate to afford the final product. in the synthesis of (+)-(S)-angustureine. a novel quinoline alkaloid. The trifluoromethanesulfonamide group was replaced later by hydrogen via Red-Al. cf.949 Many protected amine derivatives have been prepared by starting with this nucleophile. Unsymmetrical sulfamides were prepared by Ghassemi and Fuchs by alkylation of Bocsulfamides [e. 968 (xii) cyclic oxazo derivatives via HN(p-Ns)(CH(Bn)CHdCH2).999 and (xlii) N-sulfamoyloxazolidinone and chiral substituted 1.983 (xxvii) 4-methoxybenzenesulfonyl-N-benzylleucinamide (solid phase).982 (xxvi) substituted oxopiperazines via sulfonamide activated amines. an N-alkylation of the allyl compound HN(CO2-allyl)2. was utilized (Scheme 83). 2009. in which the proton connected to nitrogen is sufficiently acidic. Many of them were readily prepared by a Schotten-Bauman route in which an ice-cold aqueous THF solution of HONH2 · HCl containing sodium carbonate was reacted with 2 equiv of the respective chloroformate. which were required later for the synthesis of heterocyclic oximes. 109.1-dioxides.963 (vii) azabicyclic enones [and the alkaloid (-)-brunsvigine] using (Ts)NH(CH2)nCON(OMe)Me.g.987 (xxxi) azasugars.994 (xxxvii) benzhydryl N-methyl-N-tosyl-Saminosulfeniminocephalosporinate. No. This reaction shows that a phosphoryl group together with another activating group can make nitrogen sufficiently nucleophilic to undergo N-alkylation even with the traditional Ph3P-DIAD system.1006 A variety of protecting groups (Alloc.4.4-dimethoxybenzyl arylhydrazine (DMBAH) linker (solid phase).979 (xxiii) N-linked carbohydrate derivatives via glucose-6-sulfonamides. the presence of two electronwithdrawing groups on nitrogen should lower the pKa of the N-H bond.1001 The structural drawings pertaining to these references are given in the Supporting Information (Table S7).974 (xviii) tosyl-substituted iodoanilines 322.973 (xvii) queuine from ribose and (oNs)NH[CH2CH2CH2OTBDMS].6-pyridine-dimethanol. and antifungal agent phoslactomycin B (325) via 324.955 The compound Ts-NH-Boc as the nucleophile led to either N-tosylated or N-Boc-protected amines (e.959 (iii) cyclic sulfamides via acyclic sulfonamides of the type RN(H)SO2NH(Boc).991 (xxxv) N-tosylated allylamines. . solution of trifluoroacetic acid.998 (xli) reversed chain modified oligopeptides.1003 The deallylation at the nitrogen end to the amine was accomplished by Pd(PPh3)2Cl2/Bu3SnH in a later step to afford the required compound 325.992. Sun and Pelletier have recently reported that the reaction of alcohols with PS-PPh3-DTBAD/(Boc)2NH followed by addition of trifluoroacetic acid in a single vessel is a convenient procedure to convert alcohols to primary amines.5-trihydroxy-2-piperidin-2-ones (solid phase) via (o-Ns)NH[CH(CO2Me)CH2CHMe2].997 (xl) cyclic sulfamoyl carbamates/ ureas.957 Other applications of sulfonamide activation include the synthesis of (i) highly functionalized isoxazoles via HN(Boc)(SO2Ph). bis-protected hydroxylamines are good Mitsunobu nucleophiles. and hence.4-dinitroN-phenylbenzenesulfonamides.1004 The phosphoramidate 326 underwent ready alkylation with n-butanol under Mitsunobu conditions (Scheme 84).986 (xxx) N-alkylamino acids.976 (xx) fosmidomycin (antimalarial drug) analogues via (o-Ns)NHOBn.954 Synthetic procedures for N-activated precursors [o-NsNHBoc.964 (viii) an N-connected NAD analogue via [PhCH2NHSO2]2CH2.977 (xxi) (-)metazocine via MeC(O)CH(CH2Ar)NH(o-Ns).988 (xxxii) aminodeoxyconduritols. 6 Swamy et al.1005 As was mentioned earlier.978 (xxii) orthogonally-protected R.] that are useful in peptide chemistry.2.993 (xxxvi) N-acyl-N-arylalanine ethyl esters.N-bis[[6-(hydroxymethyl)pyridin-2-yl]methyl]-2-nitrobenzenesulfonamide using (oNs)NH2 and 2.985 (xxix) N-alkylsulfonamides (solid phase).β-diaminopropionic acids via (Ts)NH(Boc). 318-319) via Mitsunobu N-alkylation followed by appropriate choice of the next deprotection step (Scheme 82).981 (xxv) ketopiperazines using a sulfonamide connected to a 2.989 (xxxiii) amino acid-carbohyhydrate hybrids.971 (xv) aspidospermidine via 2-IC6H4NHMs.970 (xiv) multisubstituted urea derivatives of hydrazines via tosylated hydrazine precursors.984 (xxviii) 2-chloroethylnitrososulfamides. Ts-NH-Boc.1002 For the synthesis of the antitumor.965 (ix) compound 320 via (Ts)HNCH2CtC(TMS).972 (xvi) pitiamide A via (o-Ns)NH[C(O)CH2CH2CHd CHCH2CH2CH3].975 (xix) fluoride containing RCM precursors via (Ts)NHCH2C(dCH2)F. use of HN(CO2-allyl)2 offers another alternative for the conversion of a primary alcohol to the corresponding primary amine.967 (xi) substituted N-hydroxysulfamides via (Boc)HNSO2N(Me)(OTMBMS). revealed that the selectivity was dependent on both steric factors and the pKa values of the substrates.961 (v) (solid phase) polyamines via nosyl terminal secondary amines.990 (xxxiv) Boc-protected blastidic acid.5thiadiazolidine 1.980 (xxiv) functionalized cyclopentenyl amines via BocNH(o-Ns). Thus.1000.969 Scheme 82 (xiii) chiral 3.966 (x) species 321 via 2.962 (vi) fmoc-protected amides via (fmoc)(Ts)NH. antibacterial.2588 Chemical Reviews.956 The same precursor was also employed by Taguchi and co-workers to prepare several tosylated tertiary amines. This nucleophile has also been utilized for the synthesis of tricyclic carbapenems (trinems) before. Vol. as well as several N-alkylations using these.N5-substituted five-membered cyclic sulfamides.960 (iv) N.952 They have also reported that even p-toluenesulfonamide could be readily alkylated by CMBP.953 An interesting study on competitive O(phenolic) vs N-(sulfonated/acylated) alkylation of tyrosine derivatives by Attolini et al.995 (xxxviii) diprotected alkylhydrazines.996 (xxxix) N2. have been reported by Kołodziejczyk and co-workers. etc.958 (ii) marine product R-kainic acid via (substituted allyl)HN-(tosyl). THF) Troc. the cyclized product 334 was obtained in a significant amount (33%) and became predominant when the solvent system was DMF/THF (1:10).1011 The yield of the products was critically dependent on the reaction conditions. but recently procured samples usually restored good yields. Yields of N-Alkyl Hydroxylamines Using a Mitusnobu Protocol (Ph3P + DIAD.1007 The nitrogen nucleophile was prepared via hydroxylamine hydrochloride and phenylchloroformate. Boc) for the N.O-protection of hydroxylamine 327 could be utilized for the synthesis of N-alkylhydroxylamines via a Mitsunobu protocol. 6 2589 Scheme 84 Scheme 85 Chart 4. Similar cyclized derivatives were the only products obtained when the base residue was guanine.type activation. A similar Mitsunobu protocol has also been utilized in the synthesis of an oxepane derivative. It was noted that older samples of the azodicarboxylate often deliVered inferior yields.1008 In the cyclization of TBDMS-protected δ-hydroxybenzyloxamate 329 that also has a -O-NHC(O). 109. DMSO. Thus.Mitsunobu and Related Reactions Scheme 83 Chemical Reviews. in the reaction using uracil compound 332 (B ) uracil residue). Vol.O-bis(phenoxycarbonyl)hydroxylamine HN[C(O)(OPh)][OC(O)(OPh)] followed by aminolysis afforded 5-lipoxygenase inhibitor CMI-977 (328.1009 Similar N-cyclization has been reported by the same research group in the synthesis of 1-deoxy-azasugars. and EtCN (Scheme 85b). MeCN. a higher ratio of O-cyclization (330) was observed in C6F6 and toluene while N-cyclization (331) preferentially occurred in CH2Cl2. No. Reaction of the homopropargyl alcohol with N. 2009. see Scheme 85a).1010 Li and Miller utilized N-(tert-butoxycarbonyl)-O-(benzyloxycarbonyl)hydroxylamine (BocNHOCbz) to prepare a variety of 5′-deoxy-5′-N-hydroxylaminonucleosides (Scheme 86). Use of (Boc)HN[OCH2CtCH] has been made in the synthesis of cyclic peroxides by Tae and co-workers after N-alkylating . as shown in Chart 4. the nitrogen center is sufficiently reactive because of the attachment of two electronegative groups. 343) were also synthesized by starting with chiral 1.1022 It is even possible to use a substrate such as HN(CO2Me)(Boc)..and transisomers of the aziridine 342 were synthesized in high yields from the diastereomeric alcohols 341 using a Mitsunobu protocol (Scheme 90a). A unique additive dependent regiochemical switching of cyclization mode of vicinal diamines with pendant hydroxyl group leading to 345 or 346 has been recently reported by Anderson and Chapman (Scheme 90d).or -6-bromo-9H-purines were also readily alkylated. Obviously. Vol. 2009.1014-1016 An elegant approach to these involving the extrusion of pyrazole is depicted in Scheme 87. Chiral aziridines (e. Scheme 88) in good yields after suitable deprotection. The cis.1025 The trityl group also activates nitrogen in aziridine formation from 1-amino-2-alcohols. For the preparation of guanidyl-substituted (at the side chain) prolines.1028 2-Acetamido-6-chloro. The Mitsunobu route involving the reaction of primary and secondary amines with activated benzyl alcohols of type 338 afforded the substituted benzylamines 339 (Scheme 89). but still the reaction took place readily. Mitsunobu cyclodehydrative N-alkylation allows access to a good number of nitrogen heterocycles. This method was shown to be more useful compared to the sulfate ester route to aziridines for small scale synthesis.4-Amino alcohols that contain a double bond between C(2) and C(3) also underwent Mitsunobu aziridination readily to lead to vinylaziridines 344 (Scheme 90c). Only amines with pKa < 9 or sterically hindered ones gave low yields. Here.2-amino alcohols without any activation at the nitrogen center (Scheme 90b). was proposed for the observed reactivity. species 336 is the proposed intermediate prior to the formation of the product 335.1034 The straightforward route to NH-vinylaziridines by ring-closure of vicinal amino alcohols possessing vinyl substituents via a Mitsunobu protocol gave good yields of the products.1029 the reaction worked better with the bromopurine using (iPrO)3P-DIAD.1026.1032 It is important to note that here the amine nucleophile was not activated. these have been used in the synthesis of R-helix mimetics by Oguri et al. 337. has been reported by Patek et al. 109. Involvement of an azaquinomethane intermediate of type 340. (Boc)NHC(NH2)dNBoc.1013 In general. as reported by Somfai and co-workers.g.g.1026 1. good yields were obtained.1031 Benzylamines are versatile intermediates for the synthesis of a variety of pharmaceutically active nitrogen heterocycles.1030 Resin-bound carbamates underwent Nalkylation to afford secondary aryl or heteroaryl amines.2590 Chemical Reviews. also involving pyrazole displacement and Mitsunobu Nalkylation.1019 Other viable precursors in this connection are (Cbz)NHC(NH2)dNCbz. HN(Cbz)2.. or ethyl oxamate [EtO2CC(O)NHBoc] to prepare N-Boc amines (e.1017 To effect ´ optimal conversion. No. 6 Scheme 86 Scheme 89 Swamy et al. they used a 25-fold excess of the alcohol and the reagents.1020 mimics of cyclic CXCR4 pentapeptide antagonists by Cluzeau et al. N-alkylation utilizing tri-Boc guanidine has been successful.1012 Govuverneur and Lalloz used PhOC(O)NHO(Boc) and R-hydroxy phosphonates to obtain N-hydroxy-R-aminophosphonate derivatives.1021 and guanidine containing ketopiperazines by Chen et al. no side products were detected and the products were obtained in good yields.1023-1025 The latter nucleophile EtO2CC(O)NHBoc has been obtained by starting with ethyl oxamate.1035 In general. reorganization of the substituents must have taken place at an intermediate stage in order to form the three-membered ring in this reaction.1014 Solid-phase synthesis of an 880-member library of trisubstituted arylguanidines.1018 Sim and co-workers utilized N. only a limited number of routes exist. It was crucial to have the ortho-functionality (OH or NH2) for this reaction to be effective. Other examples involving aziridine formation pertain .1036 The authors have offered a possible rationalization based on the involvement of Et3N · HCl for these interesting results. formed after the elimination of Ph3PO and the hydrazine.N′-BocNHC(SMe)dNBoc as the masked guanidine nucleophile in the synthesis of guanidinoglycosides.1027 Kim and Kahn have performed the Mitsunobu N-alkylation of Boc-protected amino-oxazoles and -thiazoles with lysinol and argininol to obtain reduced peptidyl azoles.1033 This procedure gave higher yields than the one using DAST. For the synthesis of disubstituted guanidines. and [(Boc)HN]2CdNH. Scheme 87 Scheme 88 this compound with allylic alcohols. 780 This result clearly shows that.c. Scheme 92) have been synthesized. 353. Synthesis of five-membered ring heterocycles.3-amino(amido) alcohols is fairly straightforward.g. The β-lactam ring that contains a four-membered ring is the key component of commonly used antibiotics such as penicillin. The synthesis of azafenestrane with a strained four-membered ring could also be efficiently accomplished by means of Mitsunobu cyclization.c-[4.1038 (iii) pyrrolyl aziridines via the corresponding inactivated 1. was accomplished by Ma and Zhang using a similar protocol.1050 3-(hydroxymethyl)carbacephalosporin.1039 (iv) aziridine sulfides based on reduced (R)-cysteine. Here the nucleophilic NH center was activated by the presence of an adjacent carbonyl group and an aromatic residue. etc.1048 N-Tosyl-2-C-carbamoyl glycosides possessing the R-L-arabino. Thus.1051 azapeptidomimetics. had to be used. Vol. thienamycin.1045 Prior conversion of β-lactones to the corresponding N-benzyloxyhydroxamic acid derivatives was achieved under neat conditions. isotussilagine and tussilagine. 2009. 352. Using an acyl hydroxylamine functionality and an internal alcoholic OH group. however.1049 There was no interference from either epoxide or γ-lactam formation in this case.g. section 2).g.1043 Direct formation of a lactam ring from 1.4. Interestingly. The mechanistic pathway also could be different (cf. Formation of four membered azetidinone lactams was also utilized in the synthesis of lankacidins.2-diazetidines1056 were also easily generated via N-tosylated 1. bicyclic β-lactamase inhibitors (e. 6 2591 to the synthesis of (i) 2-(2-hydroxy-substituted) piperidine alkaloids. in the enantioselective synthesis of the carbacephem antibiotic loracarbef.1040 (v) nosyl-substituted aziridines derived from L-serine.2-dicarboxylate. The support was delinked later using SmI2. (EtO)3P-DIAD in toluene at elevated temperature (90 °C) was found to be the best for the β-lactam formation. Confirmation of the structure (X-ray crystallography) was done by means of the analogous BF3 adduct 349.1054 Highly functionalized azetidines1055 and 1.5.1042 and (vii) tosyl aziridine-2-carboxylates.c. 347) via hydroxyhydroxamic acid derivatives and involving an intramolecular Mitsunobu reaction has been reported by Yang and Romo (Scheme 91a).1058 N-unprotected azacyclopentylidene complexes of chromium and tungsten that contain a five-membered nitrogen heterocycle have been .1046 The corresponding borane adduct c.and β-D-xylo-configurations led to a β-lactam ring that was fused to the pyranoid ring. carbapenem.1053 and an intermediate for thienamycin.2aminoalcohols. Scheme 91d) have been obtained by an intramolecular Mitsunobu cyclization.5]1-azafenestrane · BH3 (348) was readily separated from the byproducts in 87% overall yield (Scheme 91b).3-amino alcohols and 1-(1-hydroxypropan-2-yl)hydrazine-1.5. Mitsunobu N-alkylation with cyclization can lead to pyrrolidinones with heterocyclic functionality that is not compatible with other known methodologies.1037 (ii) peptidomimetics via a N-2.1041 (vi) exocyclic γ-aminoolefins. at least in some cases. the traditional phosphine [Ph3P] can be replaced by a more readily hydrolytically degradable phosphite. respectively.1047 Five mole equivalents of DEAD and 10 mol equiv of Ph3P per mole of the substrate 350. mild conversion of β-lactones to β-lactams (e. The lactams 351 with such a fourmembered ring were conveniently synthesized by using solid support and freshly distilled DEAD in THF medium (Scheme 91c).1052. No. and several examples of this type are known.Mitsunobu and Related Reactions Scheme 90 Scheme 91 Chemical Reviews.6-trimethylphenylsulfonyl (Mts)-protected amino alcohol.1057 A variety of substituents on the amide nitrogen were tolerated. many optically active 3-aminopyrrolidinones with a β-lactam skeleton (e.1044 An elegant single-pot. 109. In their studies on the synthesis of batzelladine D.1062 An elegant use of N-alkylation with cyclization has been reported recently by Azzouz et al. the main products were those with N-cyclization. Synthesis of (+)-batzelladine A has also been reported by the same research group.1064 Bicyclic γ-lactams 356. the reagent combination n-Bu3P-ADDP provided a good yield of the product.2592 Chemical Reviews. Achmatowicz and Hegedus generated a six-membered nitrogen heterocycle via N-alkylation (Scheme 96b).1059-1061 Poullennec and ¨ Romo utilized a system with a (Cbz)NH(O2CR) group in an N-alkylation with cyclization for the enantioselective total synthesis of (+)-dibromophakellstatin. For the preparation of 1-deoxy-D-galactohomonojirimycin 362. This route was used in the total synthesis of 1-epi-lentiginosine alkaloid 354 (Scheme 93). Vol. Nagasawa and co-workers have reported an interesting cyclization reaction involving Nalkylation on an imine nitrogen leading to 363.1071 Here.1073 A similar cyclization leading to a six-membered ring was employed in the . There is also another report of N-alkylation with cyclization leading to a fused five-membered Nheterocycle. 109. enantiomerically pure dihydroimidazole-4-carboxylic acid derivatives (e.1067 Although S-cyclization was also possible. and a solid phase synthesis of imidazolones 357 has been reported recently (Scheme 94b). Batzelladines are polycyclic guanidine alkaloids isolated from Bahamian and Jamaican sponges. a pyridinium salt played the role of the nucleophile and a fivemembered ring was formed preferentially. Scheme 93 Scheme 94 Scheme 96 prepared by Dotz and co-workers. but the reaction was performed with a neutral precursor using pyridine as the solvent. Substituted.1066 Such annulations leading to fivemembered rings are generally straightforward. as shown in Scheme 95a. Highly substituted γ-lactams with five-membered rings that are analogues of a thiazolidine follicle stimulating hormone receptor have been synthesized by Pelletier et al.1072 Batzelladine D was obtained in a later step by treating 363 with TFA/CH2Cl2.1069 In a recent paper by Roberge.1070 Here. 358) were prepared by N-alkylation at an imine center.1063 In this case. and co-workers. N-Alkylation of p-toluenesulfonamide has been used to synthesize the intermediate 361 in the preparation of deoxynupharidine (Scheme 96a). two protons need to be shifted for the cyclization process to occur. competitive inhibitors of β-lactamases. were efficiently synthesized using intramolecular coupling reactions of amide functionalities 355 with alcohols in the solid phase (Scheme 94a).1068 The reaction occurred stereoselectively. a unique Mitsunobu dehydration assisted by Me3SiN3 leading to triazolo pyridines (359) and pyrimidines (360) has been reported (Scheme 95b and c). Ewinge. No. they have also described a lactonization with retention of configuration at the chiral alcohol center. 2009.g. 6 Scheme 92 Scheme 95 Swamy et al.1065 An earlier study by Page and co-workers involved a similar lactam formation in solution phase.329 in the same paper. CF3C(O)-. both the regioisomers of the trisubstituted derivatives were formed (Scheme 101).1096 However. 6 2593 polyaminocarboxylic acids (e.5-trihydroxypiperidine.1090 This route was more efficient than the one using DMF/rt/12 h without the MW conditions.3.1089 Taddei and co-workers adapted high-temperature MW conditions for the preparation of conformationally constrained peptidomimetics (e.g.1093 The choice of such a solvent (which reduced the O-alkylated products) was based upon a previous paper by Chu and coworkers.1075 (iii) thyrotropinreleasing hormone (thyroliberin.1084 and (x) piperazic acid derivatives.4-dihydropyrimidin2(1H)-ones 368 to lead to 369 was accomplished using the highly reactive coupling reagent combination n-Bu3PTMAD and primary alcohols (Scheme 99a). With the n-Bu3P-TMAD combination (2 mol equiv) in dry dioxane. or tert-BuOC(O)-(Boc). a library of products could thus be obtained. 366) based on the 1. the yields of the products 372 could be substantially improved. 4-O2NC6H4C(O)-.4-triazoles 373-374 were readily synthesized by N-alkylation of disubstituted triazoles with amino alcohols.3-triazines. A brief discussion of this aspect is presented in this section.group (Scheme 97b). with the N2 isomer as the major product.4)-diazepin-2-ones in which a seven-membered ring was newly generated.1097 Trisubstituted 1.1088 The Mitsunobu protocol was used by Goldstein and Wipf in the synthesis of the tricyclic hydroindole core system of a Stemona alkaloid that involved the formation of a seven-membered Nheterocycle.1085 Lazaro and co-workers utilized both tosyl and trimethylsilylethylsulfonyl (SES) groups for N-activation in the synthesis of perhydro-(1.Mitsunobu and Related Reactions Scheme 97 Chemical Reviews.1091 5. Steglich and co-workers could effect ring N-alkylation by using the normal Ph3P-DEAD system.1082 (ix) N-arylpiperazinones. only one product prevailed over a period of time.5disubstituted piperidin-2-ones (e. when the corresponding nitrogen was fairly activated by means of groups such as 4-Me-C6H4-SO2. complete conversion was achieved in about 1 h.(Ts). 4 mol equiv of the reagents had to be used.1080 (vii) piperaz-2-ones (δ-lactams).1083. For the preparation of chiral N-alkyl-substituted imidazoles and the corresponding ionic liquids. and this is what Ko and co-workers have reported recently (Scheme 100).1076 (iv) N-alkoxy analogues of 3. 109.1081 (viii) 6-substituted analogues of 1-deoxymannojirimycin that contain a piperidine ring. the Mitsunobu reaction offers a convenient route.5) and hence is less reactive as a nucleophile. which was useful when the polarities of the products and Ph3P(O) were similar in terms of isolation.1099 Guo et al. Although imidazole has rather a high pKa (14.1086.2.1074 (ii) cis-4. 364) using a reactive HN(OBn)C(O). Use of the tosyl group gave the best yields (Scheme 98a).1100 The best compound (375) from the initial SAR study had a Ki value of 37 nM. No. i. substitution at either N1 or at N2 occurred.4. N-Alkylation of Heterocyclic Compounds (Excluding Nucleobases) The NH group of several unsaturated heterocycles readily undergoes Mitsunobu N-alkylation.1092 Although the n-Bu3P-ADDP combination also worked well.2. In the alkylation of naphtha-1.6-dimethyl piperazines. in the synthesis of pyrrole alkaloid polycitone A.1087 Functionalized benzazepine derivatives 365 could be obtained by intramolecular Mitsunobu reaction.1095 Although alkylation occurred at both the ring nitrogen atoms. A comparative study of N-alkylation of 1H-indole and 9Hcarbazole derivatives with alcohols leading to 376-377 was performed using classical Mitsunobu reaction conditions. A regioselective N1-alkylation of 3.1079 (vi) 2.1094 N-Alkylation of cinnolines was conveniently performed in the solid phase by Sereni et al.g. Brandi and co-workers have demonstrated the synthesis of pyrolidine derivatives.1078.5-dione skeleton (Scheme 98b).1077 (v) pipecolinic acid derivatives. The authors also utilized solid-supported triphenylphosphine to synthesize these compounds.g. affording exclusively N1alkylated derivatives using unprotected pyrimidine bases 370 (Scheme 99b) by judicious choice of the solvent. reported the synthesis of several GnRH antagonists wherein Mitsunobu N-alkylation was utilized in the penultimate step (Scheme 102). Vol. 367) have also been prepared using a similar methodology. 2009. Scheme 98 synthesis of (i) the cytotoxin lepadiformine.e. which posed problems during purification. under slightly forcing conditions using an excess of the reagents n-Bu3P-TMAD. Thiol-appended pyridine-based . TRH) analogues.1098 Interestingly.4-diazepan-2. 1109 (iv) precursors for poly(Nsubstituted pyrrole)s.1117 (xii) a library of N9-alkylated monoand trisubstituted purines.4-oxadiazol-5-one1108 (iii) N-substituted 1. which depicts the formation of the seven-membered heterocycle 381.1138 The structural drawings pertaining to these references are given in the Supporting Information (Table S8). However.1125 (xix) N-methylated diketopiperazines. application of this method to larger quantities was beset with difficulties in separation.1136 (xxix) (+)-(S)-3-(4-nitropyrazol-1-yl)-propane-1.1101 The authors concluded that CMMP was the reagent of choice for the N-alkylation of 1H-indole and 9H-carbazole derivatives with alcohol derivatives.4-triazolones.2.1124 (xviii) N-alkylated isatoic anhydride (pKa 8. Interesting cyclization reactions leading to different types of 6-membered rings occurred when the heterocycle 378 was subjected to Mitsunobu N-alkylation (Scheme 104a).2-diol.5triazine-2.1113 (viii) 3-aryl-2-pyridones. or using phosphorane derivatives such as Me3PdCH(CN) [CMMP.25).1130 (xxiv) reversed azole nucleosides.1126 (xx) N3-alkylated flavins. 109.1115 (x) alkylated mellitic triamide (residue obtained by decomposition of ammonium mellate).1121 (xv) N1-substituted indazoles. The NH of a pyrrole is also sufficiently active to take part in the Mitsunobu reaction as shown in Scheme 104b. .1111 (vi) bicyclic pyridones.1120 (xiv) tussilagine and isotussilagine (pyrrolidine alkaloids).1107 (ii) polymer-bound 1.1103 Zembower and co-workers noted that Ph3P-DIAD was effective in the N-glycosylation of indoles also.1110 (v) N3-alkylation products of 1.1118.1105 Formation of 380 probably involved a proton shift prior to cyclization.1112 (vii) pseudonucleosides containing oxazolidin-2-ones.1132 (xxvi) 1-alkyl-4-aminopyrazoles. 2009.1128 (xxii) 1-alkyl-4chloropyrazolo[3. Vol.2.2594 Chemical Reviews.1119 (xiii) (solid phase) D.9disubstituted1135 or 2.and L-cycloserine derivatives.4-d]pyrimidines. Scheme 103].1102 2-Chlorobenzimidazole also did not need any activation and readily reacted with alcohols such as 2-(2hydroxyethyl)pyridine under normal Mitsunobu conditions at 0 °C to afford the N-alkylated products.3. cf. Two equivalents of the reagents were needed to get good yields. 6 Scheme 99 Swamy et al. The reaction was conducted using the reagent combination Ph3P-DEAD. This Scheme 102 approach has been utilized by Sahagun and co-workers in ´ the synthesis of unsymmetrical indolopyrrolocarbazoles.1122 (xvi) 1-(primary alkyl)benzotriazoles.1104 This protocol was a key step in the total synthesis of indolocarbazole topoisomerase I poisons reported by these researchers.1129 (xxiii) 2-substituted tetrazoles.3. No.1127 (xxi) Nalkylated indoles via 2-cyanoindole.1114 (ix) the N1-functionalized xanthine scaffold for phosphodiesterase 5 PDE5 inhibitors.1131 (xxv) N-substituted phthalazinones (along with ring rearranged products). Scheme 100 Scheme 101 Ph3P-DEAD or n-Bu3P-TMAD.6. the acidity of the NH can be increased by introducing 2-chloro-substitution (carbon next to nitrogen) to make the N-alkylation proceed smoothly.1137 and (xxx) N3-alkyl-5-fluorouracils.4oxadiazol-2(3H)-ones.1116 (xi) N3-alkylated 1. In indolyl compounds.1134 (xxviii) 2.1106 Other useful applications of N-alkylation on nitrogen heterocycles include synthesis of the following: (i) bridged aza-rebeccamycin analogues with a 7-azaindole moiety.4-diones.1123 (xvii) camptothecin analogue GI147211C1.1133 (xxvii) dissymmetric indolocarbazole glycosides.9-trisubstituted purines. are discussed below. as investigated by several researchers in this area. The second problem is the selectivity. amination of the C-Cl bond was required.4. adenine is a poor nucleophile with low solubility in the most common solvent. 2009. However. coupling of nucleobases with suitable alcohols including carbohydrates.1140 In a competitive reaction of the -OH groups with 6-chlo- . N7 products were also obtained. which may sometimes be enhanced by suitable protection. in principle. 385) of antiviral potential (Scheme 105a). should lead to a large number of medicinally useful derivatives. 6 2595 Scheme 104 Scheme 105 5. but in general. as shown by Schneller and co-workers recently. one of the major problems in using direct Mitsunobu coupling is the solubility of the nucleobases/carbohydrates. since this chlorine can later be readily substituted by other groups. To convert the product into an adenine derivative. No.Mitsunobu and Related Reactions Scheme 103 Chemical Reviews. Thus. straightforward use of adenine may be thought of. Abacavir (383) as its sulfate (Ziagen) is a carbocyclic nucleoside and is effective for the treatment of HIV-1. Scheme 106 The coupling of 6-chloropurine with several cyclopentylbased secondary alcohols provided an efficient entry into N9- substituted 3-deazapurine carbocyclic nucleosides (e. 109. In lieu of this. Vol. For example. entecavir (382. These aspects.1139 In some cases.g. Carbovir (384) is another compound with analogous activity. Baraclude) is an oral antiviral drug used in the treatment of hepatitis B infection approved by the FDA. There is enough scope for improving the efficacy of these compounds by changing the substituents. THF. N-Alkylation of Nucleobases Including 6-Chloropurine There are a large number of pharmaceutically important molecules that contain a nucleobase residue. The NH end of these bases is sufficiently nucleophilic under Mitsunobu conditions. This problem was circumvented by replacing the NH2 with a N(Boc)2 group in adenine that increased both solubility and reactivity. Reactions using 6-chloropurine are also included here. the overall yield (388 + 389) was good.1143 Although the N-alkylation took place at two sites of the 6-chloropurine to lead to a mixture of products. No. A related reaction involving a thiophenyl group was also reported by the same group.1146-1149 . 386) as compared to the homoallylic position. There are also several other cases in which 6-chloropurine or 2. it was found beneficial to use a sterically bulky tert-butyldimethylsilyl rather than benzoyl protecting group to avoid the formation of elimination product in Mitsunobu Nalkylation with 6-chloropurine (Scheme 107). the trans-product 391a that arose from the cis-390 could not be obtained. as expected.1145 When the benzoyl protecting group was used. 2009.6-dichloropurine has been utilized to introduce nucleoside bases indirectly.1144 In the synthesis of cyclohexyl nucleosides 391a–b. have reported an interesting 1. substitution of the primary hydroxyl group occurred preferentially at the allylic (e.2596 Chemical Reviews. 109. the success was rather limited when an attempt was made to optimize N9/N7 regioselectivity using N-protected adenine derivatives.g. 6 Scheme 107 Scheme 109 Swamy et al. most likely due to enhanced acidity and/or the assistance of the neighboring π-system (Scheme 105b). The cis-product 391b was obtained in fair yields when either of the protecting groups was employed. Hence.1141 However.1142 In the glycosylation of 6-chloropurine with the selenocarbohydrate 387. Only the elimination product 391c was isolated. this method may be applicable for the synthesis of many other nucleosides. In another study. Poopeiko et al. Vol. Chart 5 Scheme 110 Scheme 108 Scheme 111 ropurine Via a Mitsunobu procedure. alkylation of a chiral secondary alcohol with 6-chloropurine led to inversion.2-selenophenyl migration as shown in Scheme 106. 1166 Normally the benzyl protecting group does not reorganize in the Mitsunobu reaction.1151 An overall yield of 59% was obtained by starting with D-ribose.1154-1156 Synthesis of cyclohexene analogues of 394 (in place of a cyclopentene ring).1158 It is possible that extension of this work will lead to many pharmaceutically interesting phosphonates. 6-chloro2-iodopurine or 6-chloro-2-methylthiopurine.1220. More importantly.6-diaminopurine. coupling of protected cytosine and alcohol gave an O-alkylated product. in the alkylation of the alcohol 403 with N3-benzoyl thymine. but the yield was relatively low.1180. The protected bases (392a-e) used in this study are shown in Chart 5. observed such a feature and obtained 404 and 405 in the ratio 3:1 (Scheme 113). were synthesized through a key Mitsunobu step (Scheme 111).1164 The yield of the product 401 is quite good (80%). thymine.1160 A similar method was employed to prepare the analogous cytosine and adenine derivatives. and (Boc)2adenine [Note: Removal of Boc can be effected with 50% HCO2H]. anisoyl cytosine/adenine. and uracil derivatives could be used without protection in this reaction. 3′-O-protection of the nucleoside was not required and the Mitsunobu products were obtained in high yields (Scheme 110).1219. O-alkylation could also occur. In the reaction of 2′-deoxy-5′-O-(4. a seven-membered ring is generated via N-alkylation. A series of purine and pyrimidine cis-substituted cyclohexenyl and cyclohexanyl nucleosides (e. Somewhat analogous cyclization has also been reported recently by Chun et al.1176. Mathe ´ and co-workers reported that coupling of the precursor alcohol with 6-chloropurine (instead of adenine itself) gave low isolated yields of the intermediate alkylated product required for the synthesis of (-)-neplanocin F.1217. N3-benzoyl uracil.1161 Another interesting recent paper by Ganesh and co-workers relates to ferrocene linked thymine-uracil conjugates (e. 2009. 4-tert-butylbenzoyl cytosine.1249 . has been reported recently by Herdewijn and coworkers. N2-acetyl-6-O-diphenylcarbamoylguanine.144. thymine.155.1245. 2. This residual -OH group underwent facile Mitsunobu coupling with adenine to give the N-alkylated product 397 (Scheme 109). adenine. O-protected-2-N-isobutyrylguanine.1165 Another cyclization reaction leading to the fused heterocycle 402 was reported by Pappo and Kashman. the product 396 with an intact -OH group was obtained.713. 6 2597 Scheme 112 In an important study that should be useful while using Mitsunobu N-alkylation in nucleoside chemistry. 6-azauracil. There are numerous other reports on the normal ring N-alkylation of nucleobases. 109. additional data is provided in the Supporting Information (Table S9). is a potent antiviral and antitumor agent (but is cytotoxic).1167 When adenine or thiophenol was used as a nucleophile.1150 However. Michel and Strazewski have successfully synthesized 393 in an enantiopure form in the highest published overall yield using N6bis-Boc-protected adenine (Scheme 108). However. only the normal products were observed. Marsac et al.187.1170-1172. by simple N-methylethanolamine addition to the allenes.1304 The resulting products are generally carbocyclic nucleosides.1157 In another study.1152 Synthesis of (-)-neplanocin A and many analogues was reported earlier by Chu and co-workers. some of which showed moderate antiviral activity against HSV1 and coxsackie viruses. N3-benzoyl-5-chlorouracil.4′-dimethoxytrityl)uridine with alcohols to lead to N3-substituted derivatives 398. isolated from the soil fungus Ampulliariella regularis.1178.1218. (-)-Neplanocin C (394) and (-)-neplanocin F (395) have also been isolated from the same fungus. Vol.1168-1303 In some cases.1257 For N3-benzoyl uracil and N3-benzoylthymine. 2-amino-6-chloropurine.1162 Bucci et al. 2-amino-6-benzoyloxy purine.g. (-)-Neplanocin A (393).g. the authors noted that the guanine. N4-benzoylcytosine. using suitably protected/masked purine/pyrimidine bases. guanine.1153 Several other publications on the synthesis of neplanocin A and C analogues wherein a Mitsunobu protocol is used are also available. 399). isobutyryl/diphenyl-carbamoyl guanine. adenine. and uracil derivatives were prepared directly by coupling the protected base with 1. using unprotected adenine as the nucleophile.1201. 400).Mitsunobu and Related Reactions Chemical Reviews. The structures of some of these (406-419) are given in Chart 6. adenine.1221. thus offering adenyl functionality at the ω-position of the phosphonate. have also reported a ferrocenemethylthymidine nucleoside by the Mitsunobu route. N6-phenoxyacetyladenine. a carbocyclic nucleoside. In these studies. dioxane or dioxane-DMF mixtures could be a convenientreactionmedium.1159 It is noteworthy that the functionalities on the alcohol also did not adversely affect the reaction.1240.1163 Scheme 113 Cyclonucleosides have also been prepared by intramolecular Mitsunobu N-alkylation.1236. thymine. N3benzoyl thymine. 5-chlorouracil. No. In the reactions shown in Scheme 112. Adenine itself could be used for the N-alkylation. the nucleobase used is one or more of 6-chloropurine.6-heptadien4-ol. If one needs to use unprotected adenine.707. 1 equiv each time.1214 (3) Use of adenine as nucleophile sometimes led to both N9 and N3 coupled products. the results obtained vindicated an SN2 process in the Mitsunobu N-alkylation.1194 (5) For guanine-based nonsugar nucleosides.5. as can be realized from the following discussion. while 1-pentanol or benzyl alcohol provided the N-alkylation exclusively. to achieve maximum N1alkylated product.799 2-Amino-6-chloropurine may give problems because of insolubility. N3-BOM protection was the best for Nalkylation. (6) Di Fabio and co-workers reported that a 2-(phenylthio)ethyl residue could be easily and regiospecifically inserted at the N3-position of the pyrimidine by 2-(phenylthio)ethanol to selectively achieve O-alkylation of ribose moieties connected to the nucleobase at a later stage. Inversion is the expected outcome where a chiral center is involved. Cytosine derivatives could be prepared via uracil to cytosine base conversion.6-dimethyl-benzoyl group led exclusively to O2-alkylation.1198 In general. No. In addition. THF works well in many cases but N3-benzoylthymine does lead to O-alkylation also. sodium azide.2-trichloroethanol gave a 3:2 mixture of N1:O2 alkylated products. 2. the benzyloxymethyl group (BOM) on N3 of pyrimidines led to an improved product N1/O2 ratio compared to the standard benzoyl protected derivative using MeCN as the solvent. or nicotinoyl azide do take part in Mitsunobu coupling with alcohols. respectively.1252 although success has been achieved in some cases. diphenyl phosphoryl azide [(PhO)2P(O)N3.1247 For these reactions dioxane is a better solvent.1306 .and 6-O-glycosylinosine and N3-glycosyluridine derivatives.1206 This result has been utilized to obtain 6-chloropurine derivatives in good yields.2. 2009.1197 With N3-benzoylthymine. Since the resulting azides can be readily transformed to other functional groups. Catalytic quantities of phenol may activate an alcohol toward azidation by HN3. DPPA].1304 Some more useful points are listed below.1239 Thymine-O2 alkylated derivatives were also obtained as minor products. this protocol has been widely utilized in various syntheses.1305 The protective group could be removed by oxidation followed by a β-elimination process. provided the best yields. 6 Chart 6 Swamy et al. in the synthesis of pyrimidine nucleosides.1191 and the reaction may not work well. They reported that. while the use of the 2.1199 (2) Mitsunobu ribosylation/glucosylation of inosine and uridine using n-Bu3P-ADDP afforded the N1.1219 (4) N4-Benzoyl cytosine has a poor solubility in THF/ dioxane. Mitsunobu Reaction with Azides Hydrazoic acid or a suitable azide source such as trimethylsilyl azide (Me3SiN3). 109. use of Ocarbamate-N-acetate protected guanine as the nucleophile in THF at 70 °C with Ph3P-DIAD added twice. Vol. zinc azide. They used cyclopentanol as the reference alcohol for these studies. 5. in the coupling of thymine with cyclopentanol. MeCN or DMF was a better choice as solvent.2598 Chemical Reviews. (1) Ludek and Meier noted that. 4-epoxycyclohexene. leading to 426 (Scheme 117).1329 The configurational inversion accompanying the Mitsunobu protocol offers a means for syn/anti diastereochemical diversity. 109.1325 Many enantiopure β-aminophosphonates could thus be synthesized.1331.1310-1320 The bridge-head nitrogen in (+)-epibatidine 421 is introduced in this way (Scheme 114b). and two recent examples include (i) the synthesis of (3-aminocyclopentene)>alkylphosphinate 420 by Hanrahan and co-workers (Scheme 114a)1307 and (ii) a similar azidation on cyclopentenyl alcohol synthesis of the transferRNA nucleoside queuosine by Carell and co-workers. Skmewski and Gupta as well as Sasaki et al. Me3SiN3.4-diol. 6 2599 Scheme 117 Scheme 115 Scheme 118 A noteworthy point is that if the phosphine is used in a larger stoichiometry (than the azodicarboxylate). and tosylation of syn-2.1326. In their work using R. 2009. Vol. and Zn(N3)2(pyr)2 did not. In earlier studies. In the azidation of fmoc-protected amino alcohols [e. obtained diazides from diols. The NdPPh3 group can be transformed to an -NH2 group rather readily.1327 A recent review by Gajda and Gajda highlights the work on azidophosphonates that includes Mitsunobu azidation. 424) could later be converted to the corresponding R-aminophosphonates that show a wide range of biological activity.1309 Amination of an alcohol can be conducted by means of an azide functionality introduced via the Mitsunobu protocol through either hydrazoic acid or a metal azide as the nucleophile. 3. benzoylation. cis-cyclohept-2-ene-1. fmocGly-ol] also.group.1330 These azide groups were later converted to other functionalities.1323 The R-hydroxyphosphonates 423 underwent ready azidation Via Mitsunobu reaction using HN3 (Scheme 116). Thus.4-epoxycycloheptene. Between the two general Mitsunobu protocols to convert -OH to -NH2. the azide product may react with the phosphine to lead to products with a R3PdN. epoxides 427 react with HN3 under Mitsunobu conditions to yield 1.1332 Interestingly. one using the phthalimide/hydrazine and the other using HN3/ Staudinger/hydrolysis.4-diol.1308 In the latter case.g. and trans-2-azidocyclohept-3-en-1ol gave a mixture of cis-3. Similarly.1328 Azidation. Both diols and epoxides can undergo double azidation.1333 Likewise. Mitsunobu azidation of R-hydroxyphosphonates via HN3 with inversion has been found to be quite effective.1324 These azides (e. the authors also reported that rearrangement of the allylic azide could be suppressed by performing the reaction at 0 °C. also utilized HN3 as the nucleophile for the azidation of the precursor alcohol.Mitsunobu and Related Reactions Scheme 114 Scheme 116 Chemical Reviews. β-hydroxyphosphonates have been converted to β-azidophosphonates and then to β-aminophosphonates. 3. or trans-2-azidocyclohex-3-en-1-ol gave a mixture of cis-3.g.1310 Inversion of stereochemistry at two different secondary alcohol sites sequentially by azide substitution (cf. Carter et al.4-diazidocyclohexene (429b) (Scheme 118b). No.3-dihydroxy esters 425 under Mitsunobu conditions exhibit complete regioselection for the β-hydroxyl group.1322 They noted that Zn(N3)2 or DPPA failed in their system. 422) followed by deprotection of the second site and esterification as utilized by Cohen and Overman (Scheme 115) illustrates the value of the Mitsunobu protocol nicely. Such a procedure is quite common. In the synthesis of sialyltransferase transition-state analogue inhibitors also. thus enhancing selectivity.β-diaminobutyramide derivatives. the latter was found to be simpler and time-saving. HN3 worked while DPPA.2-diazides 428 stereospecifically (Scheme 118a).1321 This sequence has been useful in ascertaining the correct structure of batzelladine F later. the double Mitsunobu azidation of cis-cyclohex-2-ene-1.7-diazidocycloheptene and cis- .6-diazidocyclohexene (429a) and cis-3. 1373(xxvi) 2-acetamido-4-amino2.3′-dideoxy-β-L-adenosines.6-trideoxy-L-hexoses.and regiochemistry. Bringmann et al.1364 (xvii) chiral azido pyrrolidines.1352 (v) the insecticide (-)-spinosyn A. Scheme 120c).1356 (ix) C2-symmetric chiral 1.1354 (vii) 3-azido/4-azido-substituted L-proline.1365 (xviii) l-azido-2-(R)-hydroxy-3-phenylbutane.1341 It was shown that the regio.1348 Although the latter was not the intended reaction. The ee of 1.4-diamines. toluene gave the best regioselectivity for 1.2600 Chemical Reviews.1381 Such a route was utilized in the synthesis of a larger fragment of pamamycin-607 (439).1372 (xxv) γ-amino-βhydroxy acid of hapalosin. Application of the same reaction conditions to a 1.1378 and (xxxi) polyprotected 2-deoxystreptamine (2-DOS) derivatives. Vol.13-desoxyepothilone B.1357 (x) 3-azido-2.Ndimethyldithiacarbamate) led only to cyclic 3.3-diamino carboxylic acids.1349 (ii) desferrisalmycin B. 433.and stereospecific azidation reactions of 1. Spino and coworkers reported that the allylic alcohols 430 undergo Mitsunobu azidation to give the rearranged allylic azides 431a exclusively (Scheme 118c) with no detectable amount of the SN2 product 431b.3-diols (e.1358 (xi) malamycin A analogues. Thus.1339 and (vi) enantiomerically pure amines from (2S.5-anhydro product (440) without azidation although use of HN3 did ..1369 (xxii) 1-r-(C-4-ethylcyclohexa-2. cyclization involving the pyridine nitrogen of the 2-aminopyridine group took place.4-diol led to the exclusive formation of the cyclic ether rather than the azido product.3-diamino esters.1370 (xxiii) 1.4-di-O-benzyl-5-deoxy-1.3-diols was essentially unaltered during the course of the reaction. enantioselective synthesis of (R. dichloromethane.1334 Azidation via HN3 is also utilized to prepare (i) 5-azido-3.2-O-isopropylidene-R-D-xylofuranose via Ph3P-DIAD/Zn(N3)2 (or zinc thiocyanate or zinc N.1366 (xix) (+)-1-deoxylycorine.1371 (xxiv) amiclenomycin.1338 (v) kabiramide C analogues.1336 (iii) antibacterial 3-fluoroD-alanine.1344 This is perhaps a safer approach than directly using the hydrazoic acid.1343 was proposed for the observed stereo. 2009. 1376 (xxix) the hexahydroazepine moiety of (-)-balanol. No. Scheme 119). and toluene]. 432) with azidotrimethylsilane (Me3SiN3) Via a Mitsunobu protocol predominantly led to substitution of the secondary rather than the primary hydroxyl group (e. In a more recent application of this reagent in Mitsunobu azidation.1361 (xiv) vancomycin skeleton.1360 (xiii) azido-2′.3.1382 In another paper by Moravcova et al. it is reported that the reaction of 1.1351 (iv) the side chain of the aminoglycoside amikacin.1355 (viii) dolastatin 10.1350 (iii) apratoxin A.1377 (xxx) methyl 3b-azido-5b-cholan-24-oate. The commercially available diphenylphosphoryl azide (DPPA) has been utilized earlier for amination via azide formation.1345 In the synthesis of the alkaloid ent-WIN 64821.2and 1.2-diols. 438.3] sigmatropic rearrangement. when the 2-amino group was sufficiently blocked by two Boc groups or a (Boc+benzyl) group.1368 and (xxi) (-)slaframine alkaloid. The stereoselectivity was also very good.1380 It has been shown earlier that zinc azide along with Ph3P-DIAD in toluene is effective in the azidation of secondary alcohols.1353 (vi) unnatural β-Lenantiomers of 2-chloroadenine pentofuranonucleoside derivatives.RS)-1-(p-tolysulfinyl)-2-butanol.1342 Among the solvents used [THF.1362 (xv) methoxy-substituted 1-aminotetrahydronaphthalene.1347 Thus.1367 (xx) 5-amino-2-fluorocyclohex-3-enecarboxylic acid (GABA aminotransferase inactivator).1337 (iv) protected 2.g. The results were rationalized by invoking a [3. stereospecific incorporation of two C-N bonds for converting two secondary alcohol functionalities to the corresponding azides with inversion of configuration has been accomplished (Scheme 120b). This reaction is similar to the one reported earlier by Yasuda et al. In a protected 2-aminopyridine system.1335 (ii) epothilone analogues 15(R). A phosphorane (434) mediated pathway.2.R)-solenopsin B was accomplished.1346 The “inverted” diazide 437 thus obtained from 436 was converted to the desired ent-WIN 64821 in several other steps. have prepared the optically pure azido diether 435 (Scheme 120a) in 86% yield.5dienyl)amine hydrochloride.g.6-trideoxy-D-galactopyranose.1375 (xxviii) the dimethyl ester of 1-deoxyL-idonojirimycin-1-methylenphosphonate. originally suggested by Mathieu-Pelta and Evans. use of the HN3 route gave better yields (Scheme 121a).4. however.4-diazidocycloheptene.or 15(S)aza-12. it added to the variety of reactions which the Mitsunobu reagent combination Ph3P-DEAD could do. This reagent combination along with DPPA has been utilized in the synthesis of (i) HIV-1 protease inhibitors based on acyclic carbohydrates. 3.1363 (xvi) azido-substituted POEPOP1500 resin. Silverman and co-workers were able to do the required azidation by remote group protection. When the NH(Boc) was present instead of N(Boc)2. 6 Scheme 119 Scheme 120 Swamy et al.1340 and (vii) 3 β-aminosteroids.2-O-isopropylidene-R-Lsorbopyranose.1359 (xii) (R)-(-)-rolipram (antidepressant). 109.and 1.1379 Nicotinoyl azide has also been used instead of DPPA for the conversion of alcohols to azides.1374 (xxvii) 3-aminocholan24-oic acid esters. they were able to obtain the normal Mitsunobu reaction of the alcoholic group with inversion (cf. in which they had prepared the thioacetate of methyl R-Dglucopyranoside. however. a solid-phase reaction was employed (Scheme 123a). The authors noted that this reaction was accelerated if (4-Cl-C6H4)3P in conjunction with an additional base such as i-Pr2NEt was used in place of the traditional Ph3P. probably because of the oxidation of the sulfur nucleophile by the azodicarboxylate. afforded the C5-substituted products in decent yields (60-65%). 2009. was used. 109.1392 A similar methodology was employed earlier for the preparation of oxytocin antagonists. unprotected D-glucitol led to 5-O-acetyl-1. this method was applied to introduce the sulfur functionality leading to 444 (Scheme 122a).1388 Here a thioacid.g.Mitsunobu and Related Reactions Scheme 121 Chemical Reviews. but the acetyl group was cleaved by using NaOH. cortisol. Vol. only moderate yields were obtained here. and D-xylofuranosides could be converted into their corresponding S-acetyl5-thio derivatives. Sulfur Nucleophiles: C-S Bond Forming Reactions It has long been known that appropriately activated sulfur nucleophiles will participate in the Mitsunobu reaction with alcohols to lead to thioesters or thioethers with inversion of configuration.1396 Such thiobenzoate esters of steroids (e.1386 6.1387 In the preparation of terphenylalkanethiols with different chain lengths. The yields varied depending on the reaction time and the molar ratio of reagents. The cleavage of the acetyl group was accomplished by KOH/MeOH to obtain the thiols.g. Unprotected L-arabinofuranosides.2-O-isopropylidene-R-D-ribofuranose as a substrate. to suppress disulfide formation) was employed.1390 This study was in continuation of the previous work by the same research group. Removal of the PhC(O). which were subsequently transformed to 445 (Scheme 122b). to obtain aminoalkylazetidines (after subsequent treatment of the azide with NaBH4 in the presence of NiCl2 · 6H2O)1384 and by Wulff and co-workers for the synthesis of allocolchicine.group can be done by treatment with NaOMe/ MeOH. For conversion of ester to thiol. Thiobenzoic acid can also be used as the acidic component in these reactions. a solid support based on Rapp TentaGel S-NH2 resin with a mild acid-cleavable HMPB linker was used. prednisolone) have been synthesized as precursors for potential glucocorticoid receptor imaging agents by Wuest et al. D-ribofuranosides. Zn(N3)2(pyr)2 has been effectively used by Wu et al.1393 Polchow-Stein and Voss have similarly prepared methyl-1-S-acetyl-1-thioL-sorbofuranosides with mesylate leaving groups.4-anhydro-6-thio-D-glucitol in one step by this thio-Mitsunobu reaction. an excellent yield of 92% with inversion at the chiral alcohol center was achieved. Use of NaN3 for azidation in the synthesis of 2′-modified nucleosides is also reported. ammonium hydroxide in the presence of dithiothreitol (DTT. which is a better nucleophile than a thiol.1397 Two equivalents of Ph3P-DIAD and .1394 In the synthesis of thioester and thiol inhibitors (e.1385 In the latter case. 446) of IMP-1 metallo-β-lactamase.1391 Mitsunobu thioesterification using thioacetic acid has been utilized for the synthesis of amide alkaloids.1383 Use of 1.1389 However.1395 Here. 6 2601 Scheme 122 Scheme 123 yield a mixture of azido products 441-442 along with a small quantity of dehydration product 443 (Scheme 121b). No. recently. 2009.1435 Ethane-1. Vol.1414 (xvi) allenic monocarboxylates. which was converted to the thiol by treatment with LiAlH4 (cf. 449. Use of Ziram in the preparation of mercaptides has also been reported by Jacobi and co-workers and earlier by Rollin.1. In this work.1405 (vii) mercaptopyrrolidines.1416 (xviii) azole nucleoside 5′monophosphate mimics (PIMs).1433 Thiophenols also reacted with primary alcohols in the presence of n-Bu3P-ADDP.1426 and thiol-modified nucleoside phosphoramidites.1417 and (xix) anhydrothiohexofuranosides. the primary alcohol 450 was treated with 1-phenyl-1H-tetrazolo-5-thiol (PTS-H) and Ph3P-DEAD in THF at 0 °C to obtain the tetrazolo sulfide 451 (Scheme 126a). the stereochemistry of the products was dependent upon the substituents on the nitrogen.1428 As one of the key steps for the synthesis of the macrolide (+)-zampanolide. 109.2602 Chemical Reviews.289.1411 (xiii) S-adenosyl-L-homocysteine analogues.2.1401 (iii) anhydro-thiohexofuranosides. glycosyl amino acid ester 457 (Scheme 128b).1. Thus.1-tris(mercaptomethyl)undecane (447a) and 1.2-dithiol gave a polymeric material whereas propane-1.1440 THF as a solvent promoted good solvation of the polymer backbone.1404 (vi) thio-disaccharides. the authors used tritylmercaptan as the sulfur nucleophile. this reaction was used to synthesize chiral sulfoximines.g.2.1434 In the absence of any alcohol.1410 (xii) R-acetylsulfanylphosphonates. in the synthesis . Three recent examples of this type of reaction pertain to the synthesis of (i) cyclindramide subunit 452 by Laschat and co-workers (Scheme 126b).1431 and (iii) a library of murisolin stereoisomers (as many as 28 isomers) with fluorous phase separation technology (Scheme 126c) by Curran and co-workers.g. Similarly.5-anhydro-2-azido-3-thio-D-lyxofuranosides.1399 These compounds are potential substrates for the monolayer protection of 2D surfaces and nanoparticles. ω-dithiols reacted with Ph3P-DIAD and were converted into monomeric and polymeric disulfides.1423 2-(4-bromocholest-4-en-3R-ylthio)benzothiazole. Such a study has been extended for the one-pot preparation of S-glycosyl amino-acid building blocks suitable for automated combinatorial syntheses of highly glycosylated β-peptides that can serve as potential mimics for complex oligosaccharides (e. No.1403 (v) (2S. Thioglycosides have been synthesized from 1-thiosugars and a series of alcohols using a Me3P-ADDP combination (cf. but the azodicarboxylate used is not clear. the resulting compound 453 was an intermediate in the synthesis of murisolin isomers. With suitable intramolecular -OH and -SH groups at the 1.1437 The final product. Mitsunobu esterification also was utilized extensively for inversion of configuration at a secondary alcohol.1406 (viii) 2-oxa-7thiabicyclo[4.1412 (xiv) 3-mercaptoproline derivatives. was removed by aqueous workup.1402 (iv) dihydrothiophene derivatives.4. this route offers a way to distinguish between a primary and a secondary alcohol in the transformation of -OH to -SH functionality.1427 In the last example.1438 Ichikawa and co-workers have used the combination n-Bu3P-ADDP in the synthesis of a β-N-acetylglucosaminyl1-thio-N-fmoc-serine derivative that was obtained in 53% yield.1439 In an analogous thioetherification.5-anhydro-3-azido-2-thio-D-lyxofuranosides and 3.1400 (ii) highly oxygenated triterpene quassinoids.1424 benzothiazolyl sulfides. 458) or for studying carbohydrate-protein interactions.1-tris(mercaptomethyl)dec-9-ene (447b) were synthesized by starting with the corresponding tris(hydroxymethyl) compounds (Scheme 123b).1409 (xi) diastereoisomeric 3-methoxy-2-oxa6-thiabicyclo[3. Scheme 128a).1422 Thiols as nucleophiles have been exploited for the synthesis of neuroprotective A1 agonists (e. Unsymmetrical alkyl thioethers 454 were. Scheme 124). 6 Scheme 124 Scheme 125 Swamy et al.5-positions.1415 (xvii) C5 thioalkynyl nucleosides.0]octane derivatives with the D-galacto and D-gulo configurations.1436 The conditions were compatible with a large number of functionalities and protecting groups. 448. as shown by Hashimoto et al. In the thioesterification [with MeC(O)SH or PhC(O)SH] of 2-amino-l.2-dithiolan. suitably protected L-aspartic acid pentafluorophenyl ester 456 underwent smooth thioetherification with 5-aminopentanol in the presence of Me3P-ADDP.1398 The tristhiols 1. 455.3E)5-(isopropylsulfanyl)-3-pentenes. thiacyclization leading to a six-membered ring takes place. There is also a report on the synthesis of S-ribosyl-L-homocysteine.1432 In the last case.1421. could be separated easily because one of the byproducts.1407 (ix) functionalized long-chain etherlinked thiols for use in developing monolayers of gold. Related chemistry using thioacids has been made use of in the synthesis of (i) 2. prepared from aliphatic thiols and unhindered alcohols under modified conditions with Me3P-ADDP in the presence of 2 equiv of imidazole (Scheme 127).4-trifuoro-2-mercaptobutyric acid starting from (S)-malic acid. however. thiobenzoic acid were used to obtain decent yields (75-82%) of the thioesters. aliphatic thiols generally lack sufficient acidity to participate in Mitsunobu condensation efficiently.1418 Another route to thiol from a primary alcohol involved the use of zinc dimethyldithiacarbamate (Ziram) in the Mitsunobu protocol.1419.3-propanediols.1425 saccharidic benzothiazol-2-yl sulfones. resin bound thiosugars were employed by Malkinson and Falconer to prepare C-terminal thio-linked glycopeptides. Me3P(O). As mentioned above.1429 This reaction nicely illustrates the use of aryl/ heteroaryl thiols as nucleophiles.3-dithiol afforded 1.1430 (ii) (+)-brefeldin A by Trost and Crawley.1420 A primary -OH group selectively formed the dithiacarbamate. Scheme 125).0]heptan-4-ols.1413 (xv) L-methionine/L-homocysteine from the protected homoserine.1408 (x) (R)-4. xanthates (O. it is worth noting that only N-cyclization of N-(2-hydroxyethyl)thioureas took place in the solid-phase synthesis of 2-imidazolidinethiones. It was proposed that the initially formed dithiacarbamic acid reacted with MBH betaine followed by reaction with the alcohol to generate the alkoxyphosphonium-dithiacarbamate salt in the intermediate steps.1455 (ii) thioalkylated pyrimidine nucleosides. and substituted ureas.Mitsunobu and Related Reactions Scheme 126 Chemical Reviews.1452. No. and carbon disulfide (Scheme 129).and S-cyclized products.1443 DMSO was the solvent of choice. By contrast.1441 Protected lanthionines have been prepared by Tabor and co-workers via a Mitsunobu thioetherification of N-trityl(R)-serine allyl ester with fmoc-Cys-O-tert-Bu using Me3PADDP in the presence of zinc tartrate as an additional component. 6 2603 Scheme 127 Scheme 129 Scheme 128 of both R and β forms of 5-thio-D-glucopyranosides. trithiocarbonates.1459 Firouzabadi and co-workers have reported a selective method using Ph3P-DEAD and NH4SCN for conversion of .1444-1449 Analogous to the occurrence of O-alkylation when a nucleophile with a NHsC(dO) group is available. Vol. 2009.1453 A similar S-alkylation has been utilized by Wrona and Zakrzewski for the synthesis of ferocenyl conjugates of cholesterol and stigmasterol.2′-S-cyclopurinenucleoside. This was demonstrated by Dallemagne and co-workers in the synthesis of 1. 109. Chaturvedi and Ray have reported an efficient one-pot Mitsunobu protocol for the high-yield synthesis of a large number of dithiacarbamates RC-S-C(S)NHR′ (459) starting with alcohols.1450 The authors stated that the main problem was the difficulty in separation.1442 A single isomer of the required product was obtained. Salkylation is possible if NHsC(dS) is present.1454 Other applications involving thioether formation involve the synthesis of (i) phosphonylated thiazolines.3-thiazine derivatives 460 by starting with thioamides (Scheme 130a).3-d]pyrimidine 462 have also been reported (Scheme 130b and c).1457 (iv) curacin A.1458 and (v) 8.Sdialkyl dithiacarbamates). A similar approach has been adapted by the same group for the preparation of carbamates. amines.1451 Selective sulfur alkylations leading to cyclic thioethers 461 and tricyclic pyrrolo[2.867 Reaction of N-(2-hydroxyethyl)-N′-phenylthioureas under Mitsunobu conditions gave both N.1456 (iii) methyl 5′-thio-R-isomaltoside. 15 Macor and co-workers found that (o-nitroaryl)acetonitriles were also good nucleophiles in the Mitsunobu reaction. 7. Scheme 133 Scheme 131 alcohols/tetrahydropyranyl ethers. Use of Ph3P-DEAD/NH4SCN has also been made in the synthesis of the marine alkaloid (-)fasicularin (compound 464.1472 Morphine (469) is an efficient analgesic and has been in use for the treatment of pain associated with cancer. Carbon Nucleophiles: C-C Bond Forming Reactions In early work. silyl ethers. 467. thiols. (-)-pyrrolam A. R-D-mannose) has been done using bis(2.2. the best results were obtained with the sterically less crowded phosphine Me3P (2 equiv). . and silyl carboxylates to thiocyanates.1461 In this route. R-D-glucose. Fukuyama and co-workers have made use of the Mitsunobu reaction in two important steps.88 For carbon nucleophiles such as triethyl methanetricarboxylate (TEMT.2. Scheme 133a). it is possible to convert -OH to -CN using lithium cyanide or acetone cyanohydrin by a Mitsunobu protocol in the case of primary and unhindered secondary alcohols. Vol.g.2604 Chemical Reviews. One of these is the inversion of configuration at the secondary alcohol 470 (Scheme 134). Use of acetone cyanohydrin has also been reported in the synthesis of (+)-jasplakinolide.1470 Use of 1. In many cases.1473 More interesting is the reaction using acetone cyanohydrin Me2C(OH)CN and a primary alcohol.1475 Use of ADDP instead of DEAD.1467-1469 Either n-Bu3P-TMAD or (cyanomethylene)trimethylphosphorane (CMMP) mediated transformation of primary and secondary alcohols into the corresponding nitriles in the presence of acetone cyanohydrin (source of hydrogen cyanide) has been accomplished (e.33 M) rather than in THF. and allylic alcohols to obtain reasonable yields of the products. and a fairly concentrated solution in toluene (0. had earlier utilized TEMT for alkylating primary.1466 Similar to the conversion of -OH to -N3 using metal azides. giving 85% of the product 465 in a THF-toluene mixture (1:1) at low temperature (Scheme 132a). in which the net result is the conversion of an -OH group in 471 to a -CN group in 472. a 19-membered cyclic depsipeptide. carboxylic acids. though the product was isolated in low yield with poor enantiomeric purity. Neutral and electron-poor substrates underwent mostly inversion while electron-rich and biaryl systems led to significant racemization.2trifluoroethyl)malonate as nucleophile to give 473 (Scheme 135).1465 The same carbon nucleophile was employed by Palmisano and co-workers in the synthesis of the pyrrolizidine alkaloid. In a recent report on the synthesis of its racemic form.1460.1464 They reported that the use of bis(2. as shown by the synthesis of R-nitrocyclopropanes 468 (Scheme 133b).1471 The methylene group in the -CH2NO2 moiety is also sufficiently activated to undergo an internal Mitsunobu cyclization. Scheme 131). 2009. Mitsunobu and co-workers showed that the -OH group in (R)-2-octanol could be displaced with ethyl cyanoacetate using Ph3P-DEAD. No. with the product 466 (Scheme 132b) being obtained in high yield and high enantiomeric excess.5-3 equiv of reagents gave better yields.1470. the CMMP reagent worked better. NH4SCN can be construed as a masked source of the nucleophile HSCN. In a later paper on the synthesis of cycloalkyl[b]indoles also.2-trichloroethyl) azodicarboxylate in place of DEAD provided higher enantiomeric purity. made a similar observation that the sterically less hindered Me3P worked better. 6 Scheme 130 Scheme 132 Swamy et al. commercially available) with a reasonably low pKa value of 7. Hillier et al. 109. benzylic. such as conversion of 3β-cholestanol to 3R-cyanocholestane or for the synthesis of carbasugar derivatives.1474 Chain elongation of the primary alcohol end of saccharides is of chemical as well as biological interest.1462 An interesting rearrangement has taken place while forming 464 from 463.5. Toluene as the reaction medium helped in some cases to preserve optical purity. Such an elongation of the primary alcohol of saccharides (R-D-ribose.1463 No reaction was observed when the sterically crowded phosphine (cyclohexyl)3P was used in place of Me3P. Cravotto et al. Halogenation Halogenation of alcohols can be effected if a metal salt (e. 109. The latter reaction took place via the tautomeric form (F3CCH2CO2)CHdC(OH)(OCH2CF3)2. Considering the yield and the enantiomeric purity. Salaun and co-workers ¨ have reported the intramolecular reaction of the allylic alcohol (6S)-478 in the presence of 2 equiv of Me3P-DEAD in THF at room temperature.2-trifluoroethyl)malonate CH2(CO2CH2CF3)2 also took part in C-alkylation when it reacted with the hydroxyl at the C6 position. For example. leading to a cyclopropane ring via the formation of a new C-C bond. 6 2605 Scheme 135 gave better yields.1484 It may be noted that the saturated six-membered ring in 476 is replaced by fiveand three-membered rings in 477.1490 Inversion at the chiral center is an important outcome. Scheme 137a).1488 Although there are several methods for halogenation of alcoholic -OH groups. The product 484 was an important precursor for the synthesis of the antibacterial agent levofloxacin. 2009.and (Z)-479 (77% yield.2. Vol. lithium halide) is used in addition to Ph3P-DEAD (Scheme 139a.2. along with 480 (15%) (Scheme 137b). has been utilized in the synthesis of antitumor antibiotic natural product (+)-duocarmycin A (477. Another interesting reaction. toluene was a good solvent (Scheme 136b). 8.5trimethylphenol reacted with (R)-1-phenylbutan-1-ol under Mitsunobu conditions to afford the ortho-alkylated compound 475 in high enantiomeric purity in yields of 7-40% depending on the solvent. they gave other products such as carbamoyl hydrazine 487 or/and triazolinone 488 in addition to the isocyanate 486. prepared 6β-bromo-codeine and morphine derivatives using the precursor codeine and morphine hydrochloride salts as the source for halogen.1476 Alkylation of polymer-supported alcohol (polymer)4-HN(O)C-C6H4-CH2OH with active methylene compounds (EtO2C)CRR′H [R ) H. the Mitsunobu approach may be useful when other sensitive functionalities are present in the substrate. de 82%). from ref 1489).1483 This iodination route was used earlier by Dormoy. the reaction led only to the former in this case.1486 The yield and diastereoselectivity were lower when n-Bu3P was used in place of Me3P.1477 Even compounds of type RCH(CN)SO2Ph and Meldrum’s acid were utilized in similar Calkylation reactions. Me.3. leading to the spiro-cyclopropyl derivative 481 (Scheme 138).1480 Here the normal reagent combination of Ph3P-DEAD worked well and pharmaceutically interesting compounds such as monofluoromethylated Vitamin D3 (474.1482 Transannular spirocyclization under Mitsunobu conditions using n-Bu3P-ADDP.1492 Reaction in the absence of ZnCl2 gave very poor (or none) yield of the cyclization product. 2. depending upon the amine. Thus. Reaction in the Presence of CO2 Primary alkylamines gave high yields of isocyanates 485 when treated with carbon dioxide and Morrison-BrunnHuisgen intermediate 15 in dichloromethane (Scheme 140). the combination Ph3P-DEAD/CBr4 has also been used. Similar mono. C(O)Me. which was facilitated by the additional component ZnCl2. For bromination of the primary alcohol groups.1496 With aromatic amines.1483.g. which led to a 73:7 mixture of (E).1491 It is likely that the cyclization shown in Scheme 139c.1467.1494 8. Miscellaneous Reactions 8. R′ ) CO2Et. from ref 1467).1481 The Mitsunobu reaction of ortho-substituted phenol derivatives with an optically active benzyl alcohol also leads to C-C bond formation. has been reported by Coppola.] in the presence of n-Bu3P-TMAD afforded the desired monoalkylated products (polymer)-4-HN(O)C-C6H4CH2C(CO2Et)RR′. but it underwent O-alkylation when the reaction occurred at the C1 position of protected mannose. It is also possible to use methyl iodide in conjunction with Ph3P-DEAD for iodination in some cases (Scheme 139b.1493 Simon et al.1495.1487 This result was rationalized by tautomerization of the precursor to its 4-keto form. etc. which has a highly acidic proton at the C3 carbon.1485. although the cyclopropane ring is more strained compared to five-membered furan rings. also occurred via a chlorinated intermediate as shown.1489. Scheme 136a) could be synthesized.Mitsunobu and Related Reactions Scheme 134 Scheme 136 Chemical Reviews. No.and dialkylations using the same nucleophile have been reported earlier by Takacs et al. The bis(2. cyclopropanation (instead of cyclic ether formation). The traditional phosphine Ph3P was ineffective.1478.1479 A unique stereoselective monofluoromethylation of primary and secondary alcohols using a sulfonated fluorocarbon nucleophile in Mitsunobu Calkylation has recently been reported by Surya Prakash et al. .1. 1.1498 The best . Dinsmore and Mercer have recently shown that the stereochemical course is dependent on whether the carbamic acid intermediate is N-substituted with hydrogen (retention) or carbon (inversion). 109. 2009. 6 Scheme 137 Swamy et al. use of n-Bu3P improved the yield of the isocyanates dramatically. Vol. Since there was a significant change in the product ratios depending upon the phosphine used. it was assumed that there was a change in the mechanistic pathway at the intermediate stages. No.2606 Chemical Reviews. Scheme 138 Scheme 140 Scheme 139 Scheme 141 In such cases. Aniline.103 Such a reaction can be considered for the fixation of CO2.1497 An intermediate of type 490 was proposed for the reaction. however.2-Aminoalcohols reacted with CO2/Et3N under Mitsunobu conditions to lead to 2-oxazolidones 491a–b (Scheme 141b). A novel one-step process for the synthesis of N-alkyl carbamate esters 489 by mild carboxylation of alkylamines with CO2 followed by O-alkylation with an alcohol has been developed using a Mitsunobu protocol (Scheme 141a). gave mainly carbamoyl hydrazine with either Ph3P or n-Bu3P The pathway for the formation of isocyanates is also shown in Scheme 140. tripeptides and sulfonamido hydroxamic acids that could be useful as inhibitors of metalloproteinases were synthesized.Mitsunobu and Related Reactions Scheme 142 Scheme 143 Chemical Reviews.1509 (ix) allyl hydroxylamine derivatives.1508 (viii) methylene(methylimino) (MMI) linked oligodeoxyribonucleotide dimers.2benzoxazoles have also been prepared similarly. 8. The best result was obtained when a spacer was provided between the polymer backbone and the phthalimide residue as in 498.1512 In place of N-hydroxyphthalimide.1511 A review on dehydrative glycosylation with 1-hydroxy donors including N-hydroxyphthalimide is also available. 1-Hydroxyimidazole was also easily loaded onto -CH2OH terminal Wang resin using a n-Bu3P-ADDP reagent system.1505 (v) 2′-O-[2-[(1.1510 and (x) R-aminoxy amino acids.3-dioxo2H-isoindol-2-yl)oxy]ethyl] nucleosides.1507 (vii) chiral β3-aminoxy acids or amides. containing a saturated six-membered ring.1502 (ii) N-ethoxy-morpholino-oxime ethers with antifungal properties.3. the protecting group was also removed. As an alternative to the above. Use of Oximes as Nucleophiles Oximes contain the dNsOH group that can act as the nucleophile in the Mitsunobu reaction.1517 By using this route.1 equiv each). Thus.1506 (vi) N-/Oglycosylated R-aminooxy acids. 499) with yields in the range 51-94%.1501 The hydroxyphthalimide route has been employed to prepare (i) chiral diamides that are useful in conformational studies related to N-O turns in peptides. it was possible to use compound 496.4.1520 A new protocol using the Mitsunobu reaction was used for the synthesis of furazan 502 Via vicinal dioximes that have pKa values in the range 8-11 (Scheme 144b). these dioximes behave in a manner similar to diols.1503 (iii) pyrazolyl propynyl-hydroxylamines that can serve as precursors for isoxazoles. The other substrate in these cases was a protected hydroxy acid. 109. No. Floyd et al. D-PhthN-O-Lys(Boc)-OH (495).1500 This reagent was quite useful in the synthesis of many aminooxy acids.1499 It was surmised that the Z-isomer was the one that reacted. Reaction in the Absence of a Nucleophile In case a nucleophile is not available. 6 2607 Scheme 144 conditions for the formation of carbamate with normal amino alcohols were found to be (i) to pretreat the amino alcohol with DBU (0.1 equiv)-CO2 for 45 min and (ii) to use n-Bu3P and DTBAD (2.1513 The hydroxylamine Bz[H2CdCHsC(O)]NOH1514 and N-hydroxy-4-methylthiazole-2(3H)-thione1515 are also nucleophiles that undergo similar O-alkylation. Vol. The latter product was a precursor for trichostatin D (Scheme 142c). a lysine analogue. to obtain 497.1516 This study also highlighted the importance of the linker and a specific base effect for the Mitsunobu reaction. 8. In an earlier study. the alcohol itself can react with the azocarboxylate intermediates to lead to .1518 Salicylhydroxamic acids 500 underwent cyclization to form 1. The Mitsunobu reaction was carried out at room temperature during 24 h in CH2Cl2 using 5 equiv of Ph3P-DIAD/ imidazole to obtain various O-alkyl hydroxylamines (after subsequent methylaminolysis. modified Wang resin using N-hydroxyphthalimide to prepare polymer bound O-hydroxylamine-hydroxamic acids. Thus. 2009. the N-hydroxyphthalimide moiety was anchored to a polymer solid support and then the normal reaction was performed (Scheme 143).1521 During the course of the reaction.1504 (iv) protected spermidine and spermine oxa-analogues.g. Thus. an intramolecular Mitsunobu procedure was utilized for the synthesis of herbicidal benzoxazines 493 from 2(hydroxyiminomethyl)benzyl alcohols 492 (Scheme 142a).1519 Substituted 1. was prepared from commercially available L-NH(Boc)-Lys(Cbz)-OH (494) (Scheme 142b).3-dihydro-1.2-benzisoxazolin-3-ones 501 rather readily under Mitsunobu conditions (Scheme 144a). One can use the more readily available N-hydroxylphthalimide as a nucleophile to couple intermolecularly with different alcohols. e. Scheme 148 Scheme 146 Scheme 149 protected hydrazines of type 503 (Scheme 145a).5.g.1524 The reaction shown in Scheme 146 leading to pyrazole 506 is an important one because if one uses substrates containing activated alkynes in the Mitsunobu reaction.1523 New triazoles (e. derivatives such as hydrazones 511 are formed as major products rather than the expected alkyl aryl ethers (Scheme 149a). the reaction was sluggish and only thioamides gave better results.1531 It was proposed that this reaction took place via the MBH betaine 15 and the pentacoordinate intermediate 513. Scheme 148 above). 109.1526 A similar methodology was utilized for the preparation of many other polyamines bearing 1H-tetrazol-5-yl units.6. Reactivity toward Carbonyl Compounds The Morrison-Brunn-Huisgen intermediate 15 showed excellent reactivity toward carbonyl compounds to generate a variety of products (e. ketones.2-diones with Ph3P-DEAD afforded N. if the betaine is not able to abstract the proton of the nucleophilic precursor (pKa >13). Products analogous to 509 were observed previously by Liu et al. This reaction may be contrasted with that of Otte et al.1530 The reaction of diaryl1.N′-ditritylated ω-amino thioamides and trimethylsilyl azide (Scheme 147). it is possible that products (such as pyrazoles) other than the expected ones may form by just utilizing the acetylenic functionality.N-dicarboethoxymonohydrazones 512 by a novel nitrogen to nitrogen migration of a carboethoxy group (Scheme 149b). wherein other types of products were obtained with aldehydes.g.1528 Although this is not a Mitsunobu reaction. 504.2608 Chemical Reviews.1529 In the reactions of 2-hydroxybenzaldehydes with the Ph3P-DTBAD combination. Although the corresponding amides reacted. and Liu et al.1528.1527 present in the substrate. it is possible that the hydrazine portion of the reagent may itself react with the alcohol (cf.1529 8.1522 Also. Vol. when ketones were treated with tributylphosphine and dimethyl azodicarboxylate in dichloromethane at room temperature. one needs to be aware of this possibility when such functional groups are . or keto-esters (cf. 505) may be formed if isocyanates are present (Scheme 145c). the phosphine can pick up the oxygen from the azodicarboxylate (instead of an alcohol) to form the phosphine oxide. 6 Scheme 145 Scheme 147 Swamy et al. 2009.1525 As can be seen from the reaction. 8. Scheme 145b). 508-510) depending on the substituents present on the carbonyl carbon (Scheme 148). Formation of Tetrazoles via Thioamides and Azide Bis-tetrazole derivatives 507 have been conveniently prepared from N. No. 109.1534 Such dehydration (followed by ring closure) has been elegantly utilized by Greshock and Williams in the total synthesis of complex alkaloids such as stephacidin A. and subsequent conjugate addition of nitromethane was presented by Meunier et al. 6 2609 Scheme 151 from what was there in the precursor. compound 519) while synthesizing serine derivatives (e. Synthesis of Fluorophosphoranes In the presence of pyridine · HF.1548. These compounds are quite stable and can be isolated in good yields by using sonication (Scheme 150).137 8.1545 The same product was obtained via oxidation of the precursor with lead tetraacetate. Scheme 154b) of the proteasome inhibitor TMC-95A. Alcohol Dehydration In the synthesis of butenolactone 516. This method. a 0.1532 8. The bonds that were cleaved/formed are shown by an arrow in the drawing. In another reaction involving the synthesis of a part of the skeleton (526.8. 2009. Vol. Evans and co-workers have reported an unusual skeletal rearrangement (Wagner-Meerwein) of the bicyclo[3. a decarboxylative 1.1544 The reaction shown in Scheme 153 is a bit peculiar in the sense that a dehydrogenation rather than a dehydration has occurred to lead to the product 524 (25% yield).0058 M concentration of the substrate.3-elimination step utilizing Mitsunobu conditions was involved and lactonization did not take place. Scheme 154a) were readily synthesized via the reaction of an R-cyanoketone with ethyl glyoxylate followed by treatment of the vinyl ether so obtained with NaH. is limited to the synthesis of 5-alkyl-. 5-aryl-. No. (Scheme 151c).1533 The driving force here was perhaps the extended conjugation in the product. protective groups have a role to suppress the side reactions (like elimination.1539 N-Protected serine methyl esters underwent ready β-elimination rather than azidation with HN3 under Mitsunobu conditions. 521). Me2N. a tautomeric -CH2sCdO to -CHdC(OH) shift of the proton may be envisaged prior to the product formation. The formation of 524 is almost certainly a result of MBH betaine-catalyzed cyclization followed by aerial oxidation during workup. and 2. An analogous water elimination reaction leading to butenolides has also been reported by O’Doherty and co-workers.N′-tetramethylazodicarboxamide) was used in place of DIAD.N′. A dehydrative decarboxylation route was used in the preparation of isomers of the anti-androgen cyoctol 518 by Mulzer et al. Some Unusual Reactions N3-Benzyluracil when treated with N-hydroxymethylphthalimide in the presence of the Mitsunobu reagent gave an unusual product 522. the difluorophosphoranes.1543 particularly when TMAD (N.7. cf.1538 A large scale synthesis of optically pure trans-(+)-sobrerol by dehydration was reported by Wang et al.1541 As shown in Scheme 151d. Compound 517 was characterized by X-ray crystallography. but the fivemembered ring present in the final compound was different . bearing a hydrazylmethyl group and or the condensate 523 (Scheme 152).2 equiv of DEAD.1546 3-Aminofuran-2-carboxylate esters (e.1540 Nitro derivatives of nitrilotriacetic acid and ethylenediaminetetraacetic acid were prepared by dehydration of serine derivatives. The best result (yield 58%) was obtained with 2. however.1536 It may be noted that dehydration occurred in one of the six-membered rings.1549 This reaction is similar to that shown in Scheme 151c for the formation of 518. R3PF2 (514) [R ) Ph.4 equiv of 4-nitrobenzoic acid as a proton source under reflux for 1 h.9. MeO] have been isolated. and 4.1. 525. Schmidt-Leithoff and Bruckner used the Mitsunobu dehydration of alcohol ¨ 515 (Scheme 151a).l]heptanol skeleton under standard Mitsunobu conditions 8.Mitsunobu and Related Reactions Scheme 150 Chemical Reviews.N.1542 Kobayashi and co-workers have utilized alcohol dehydration as well as Mitsunobu inversion in the total synthesis of khafrefungin. the DEAD may get attached to the acid RC(O)OH to lead to a derivative of the type RC(O)-O-N(CO2Et)-NH(CO2Et). n-Bu.1537 Ollp and Bruckner have ¨ utilized antiselective dehydration of γ-(R-hydroxyalkyl)butenolides under Mitsunobu conditions to obtain γ-alkylidenebutenolides.1547 In the first step.1535 An unusual dehydration/ rearrangement is observed in the Mitsunobu reaction involving kaurene derivatives which was reported by Takeya and co-workers (Scheme 151b). If the expected Mitsunobu reaction is not feasible due to steric or other reasons.g. wherein a simple dehydrogenation had taken place.g. Another interesting reaction is the in situ quantitative formation of triphenylphosphinimines from polymer bound 2-aminobenzimidazoles and Ph3PDEAD reported by Houghten and co-workers.5-fused bicyclic furans. 1558 (iv) benzothiadiazine dioxide.1577 (xxii) 20-hydroxyhepoxilins (inversion/rearrange- (Scheme 155a).1568 (xiii) the monomethyl ether of 1.1572 (xvii) aminopropyl phosphonate nucleosides with purine and pyrimidine bases. Vol.1553 There is also a report on the N-alkylation of sulfamides with alkyl bromides using MBH betaine 15 as a mild base.g.1567 (xii) pseudo-aminosugars.1]ketone. 6 Scheme 152 Swamy et al. (+)-valienamine and (+)-validamine. a search through SciFinder revealed a few more cases wherein the Mitsunobu reaction has been applied.1565 (x) prenylflavanones. These include the preparation of (i) 2-substituted 2.1557 (iii) cyclic peptolides.2.1552 A very unusual reaction reported by Hanessian and coworkers involved fragmentation of the sugar-like ring in bafilomycin A 1 and isobafilomycin A 1.1555 .1574 (xix) liquid crystalline aromatic azo compounds (esterification).1554 Seth and co-workers have developed a solid-phase synthesis of N-aryl-N′-carboalkoxy guanidines based on Mitsunobu alkylation of resin-bound Fmocguanidines with a variety of alcohols.1559 (v) thymine containing pseudopeptides via Nalkylation by o-Ns activation. leading to an olefinic ester.1563 (ix) C(1)-C(7) and C(17)-C(28) subunits of didemnaketal A and B.1′-binaphthol as a precursor for poly(meth)acrylates with a pendant 1.1566 (xi) boonein from bisbenzyloxymethyl-substituted bicyclo[2. 529. No.1′binaphthyl group. Scheme 153 Scheme 155 Scheme 154 8.L-alcohol with the selone (e.10.g.1550 A possible pathway for the formation of the product 527 has been proposed by the authors. 109.1576 (xxi) chiral liquid crystalline polyacrylates based on L-isoleucine (esterification). 2009.1571 (xvi) pregnane ketols.1564. Reaction of D.1569 (xiv) esters of syn-diisopropyl-1-bromo2-hydroxy-2-(p-methoxyphenyl)ethylphosphonate. respectively.1573 (xviii) high glass transition polyimides via etherification for NLO applications. Additional Literature In addition to what has been discussed in the above sections.1570 (xv) racemic cyclopent-3-en-1-yl nucleoside analogues.1556 (ii) entecavir.1575 (xx) peptide nucleic acid monomers based on N-[2-(tert-butoxycarbonylaminomethyl)-trans-4-hydroxy]tetrahydropyrrole acetic acid Me ester.1562 (viii) furan containing macrolactones.3-dihydro4-quinolones by sulfonamide activated N-alkylation.2-λ5-azaphosphetidine 530 with pentacoordinate phosphorus (Scheme 155c) reported by Kawashima et al.1551 Another novel reaction involved intramolecular N-P and O-P bond formation to give the N-apical 1.1561 (vii) 5-{4-[2-(methyl-p-substituted phenylamino)ethoxy]benzyl}thiazolidine-2.1560(vi) anhydro-nucleosides from cyclization of 6-amino-7H-purine-8(9H)-thione.4-diones by O-alkylation (ether formation). Scheme 155b) in yields ranging from 82 to 92%. 528) chiral derivatizing agent (CDA) via the Mitsunobu reaction has given rise to Se-alkylated adducts (e.2610 Chemical Reviews. and (S)-(+)-ibuprofen. Scheme 158) that are suitable for robotic synthesizers. the conversion of alcohol to benzylbenzoate ester proceeded better. Sardari. phosphine or azodicarboxylate. The byproducts are also insoluble in ethyl acetate.1592-1594 Two excellent reviews. phenyl alanine. and polymerassisted phase-switching or solid phase immobilization.1598 In general. a nonpolar microenvironment could be used to enhance the reactivity of the intermediates and the rate of product formation. was polymerbound. With an increase in the number of unsubstituted phenyl groups and decreasing the number of ligand sites. only one of the reagents.1595.1589 N-(β-phenethyl)-N-triflylvaline (N-alkylation). several reports are already covered under different sections above.1. which may anchor either the reagents or the substrates.4-epimino derivatives of 1.1602 Here. No. This method has been utilized for the preparation of substituted amino acids wherein the -COOH end of the amino acid is first protected by Mitsunobu esterification using a polymer-supported alcohol (Scheme 156a). is polymer bound in most of the applications because of solubility problems. proline) esterified with Wang resin (1% cross-linked polystyrene with Wang linker) reacted with aliphatic alcohols in the presence of n-Bu3P-ADDP/i-Pr2NEt (or Et3N) to yield O-alkyl carbamates (cf. Reduction of the oxide back to reusable resin can be effected by treating it with trichlorosilane.1587 protected (3-N-hydroxyamino-1-alkenyl)phosphonates via BocNHOBoc.3-dideoxy-2.g.Mitsunobu and Related Reactions Chemical Reviews.1586 (xxxi) reversed imidazole nucleosides.1599 Two mole equivalents of each of these reagents were used during the esterification reactions.1578 (xxiii) R-mercaptomethyl amino acids from R-hydroxymethyl amino acids. have appeared fairly recently.1591 9. postreaction sequestration (solution or solid-phase reaction). in such a system. Mitsunobu esterification was also readily conducted (with no interference by other groups present) on a secondary alcohol present in ortho-disubstituted polyfunctionalized arene chromium dicarbonyl species immobilized onto a solid support.1b]quinazolin-11-ones. The use of polystyryldiphenylphosphine resin (used in excess) can circumvent the problem of removal of Ph3PO because the resulting oxide is also anchored to the polymer and thus can be readily filtered off.β-caroten-3-ol.6-anhydro-β-D-hexopyranoses. They also noted that primary alcohols gave good results.506.33.32.1585 (xxx) tetrahydropyrido[2. Many efforts have been directed toward modifying triphenylphosphine or azodicarboxylate reagents to facilitate isolation and purification of the products.1581 (xxvi) deuterium.1584 (xxix) azaoxamacrobicyclic ligands. The authors proposed that the reaction proceeded via O-alkylation of an intermediate carbamate anion 536.4-dideoxy-3.1601 A second system wherein both the phosphine and azodicarboxylate are soluble (THF) involves the reagents 534-535 (Scheme 157). A chromatography-free protocol in which both the polymeric reagents and byproducts were removed by precipitation cum Scheme 157 filtration to afford high purity esterified products is reported.1582 (xxvii) acyl glucuronides of R-(-). but yields using secondary alcohols were not satisfactory.1588 (xxxii) poly(etherimide)s with attached NLO moieties.1605 Here the substrate.1604 Zaragoza and Stephensen have reported that fmocprotected amino acids (e. but not the reagents.32 This section primarily deals with polymer-supported reagents/ reactions. as demonstrated by Rigby and Kondratenko.1580 (xxv) (3R)-2′3′-dihydroβ.1579 (xxiv) β-lactamase hydrolysis resistant penicillin analogues. 6 2611 Scheme 156 ment).1597. one by Dembinski and the other by Dandapani and Curran.1583 (xxviii) 2.1596 Esterification may be conveniently performed on the Wang resin-based solid phase. Modification of Mitsunobu Protocol 9.1590 and (xxxiv) (-)-cladospolide B. The authors also reported that their polymer-based phosphine 532 worked better than JandaJel-PPh3 and solid-supported PPh3 reagents.1603 They proposed that.3-epimino and 3. and Parang gives an overall picture of solid-supported reagents. three types of separation approaches are established with their own limitations: acidic or basic aqueous workup. making the separation process much easier (Scheme 156 (b and c)).1592 Polymer-supported triphenylphosphine prepared from brompolystyrene (bead size up to 600 nm) has also been utilized for esterification reactions.1600.and tritium-labeled multidrug resistance modulator LY 335979 (etherifcation). Vol. Polymer Supports in the Mitsunobu Reaction The generation of phosphine oxide and hydrazinecarboxylate as byproducts in the Mitsunobu reaction often haunts the synthetic chemist in the isolation of the desired product. In this context. 2009.35 Another review by Nam. Alexandratos and Miller used benzyldiphenylphosphines derived from copolymers of vinylbenzylchloride and styrene. the supporting dendritic polymer was prepared by anionic polymerization of glycidol. The polymersupported reagents 532-533 are soluble in THF but insoluble in ethyl acetate. Tertiary . In another earlier study. 109. were more efficiently performed using n-Bu3P-ADDP in CH2Cl2.1613 The yields were nearly the same as those using the PS-PPh3 system in most cases. esters. With an excess of hydroxypyridazine. as well as ethers has been reported by Lan et al. 6 Scheme 158 Swamy et al.1615 The authors pointed out that the azodicarboxylate and its corresponding hydrazine product could be readily separated from the desired products by simple filtration.1610 Use of an additional base (i-Pr2NEt) perhaps had helped in enhancing the yield in this case.1608 One more report by the same group also relates to polymer-bound ethers. and methanol and shaking this mixture for 3 days at room temperature. Nicolaou and co-workers have also utilized a polymeric backbone for the synthesis of a dodecasaccharide (cf. a polymerbound azodicarboxylate and anthracene tagged phosphine for the Mitsunobu reaction leading to phthalimides. acted as a new ammonia equivalent for solid-phase synthesis of primary amines 547 (Scheme 164a). In a different report. Scheme 159 Scheme 160 benzylamines could be synthesized readily by first converting the amines to the corresponding ammonium iodides. Vol. Scheme 160b) using the Mit- sunobu protocol as a primary step.1593 The purity of the product 545 so obtained was ∼90%.1611 The first Mitsunobu reaction was efficiently carried out with Ph3P-DIAD in THF.g. The coupling of N-Boc-L-tyrosine methyl ester with hydroxymethyl polystyrene resin proceeded in practically quantitative yield in the presence of a tertiary amine under Mitsunobu conditions. water. Humphries et al. 544) were caught by adding the ionic resin Bondesil SCX. allowing the introduction of an aliphatic spacer linked to a second phenolic moiety and leading to 541. (Scheme 161). were attached to a polymeric solid support.1594 Recently.1607 Here.1617 Oxime resin supports have been useful in the synthesis of sulfahydantoins. Subsequent washing with MeOH-toluene and MeOH-water followed by treatment with NH3-MeOH afforded the products in 79-84% yield.1612 They have also demonstrated its use in the synthesis of alkylaryl ethers.1606 Peroxisome proliferator-activated receptors (PPARs) have great potential as pharmaceutical targets for many applications. In a preliminary communication. ethers. formic acid.1609 the “one bead-one compound mix and split strategy” was adapted to combine 20 natural amino acids. No.1618 . Although 3-hydroxypyridazine exists predominantly in the oxo form.530 Both the O-alkylated (542) and the N-alkylated (543) products [ratio 2:3] were obtained. it does undergo Mitsunobu coupling with polymer bound benzyl alcohols as shown by Salives et al. prepared by the reaction of Wang resin with N-(chlorocarbonyl)isocyanate and tert-butyl alcohol. by Pelletier and Kincaid. unwanted substituted hydrazine products were also obtained. use of DEAD in place of DIAD reduced the time required to 2 h.2612 Chemical Reviews. (Scheme 162). Ac-Tyr-OH and N-(4-hydroxybenzoyl)glycine. Aromatic hydroxy acids. when DEAD was used in place of ADDP. an interesting concept based on ionic resin-based purification combined with simultaneous cleavage of the protecting group was recently implemented by Meier and Muller. 10 aromatic hydroxy acids. A high-loading soluble star-polymer based on a cyclophosphazene skeleton has been prepared by Reed and Janda. and esters was readily obtained using a PS-PPh3-DTBAD reagent system and without using chromatography.g. 109. have disclosed a method for the synthesis of PPAR agonists (e. 540. 2009.1616 The polymer bound iminodicarbonate (546).1614 After ¨ the normal Mitsunobu etherification reaction. The precursors 548 for these sulfahydantoins were prepared by using Mitsunobu N-alkylation (Scheme 164b). complete alkylation of the resin-bound alcohol was achieved in 5 h. It may be noted that the N-alkylation occurred only at one of the available nitrogen sites. Synthesis of a soluble poly(ethylene glycol)supported triphenylphosphine conjugate and its utility in the production of alkyl-aryl ethers were also reported earlier by the same group. 538) using the PS-PPh3-ADDP reagent system (Scheme 159). A library of substituted amines. achieved a chromatography-free Mitsunobu reaction of an alcohol with a carboxylic acid or phthalimide using PS-PPh3 and bis(5-norbornenyl-2-methyl) azodicarboxylate (DNAD) (Scheme 163). Barrett et al. the products (e. and 21 alcohols in the library of 4200 products. A solid phase synthesis of a number of monoamino and diamino derivatives as potential dual binding site AChE inhibitors was developed by Leonetti et al. whereas the two subsequent reactions. and the phenolic hydroxy groups reacted with a variety of primary and secondary alcohols under Mitsunobu conditions (Ph3P-DEAD) in THF to give the ethers 539 (Scheme 160a). Yoakim et al. In a different study.1623 The type of polymer system used in this work has been discussed above (cf. that involved similar N-alkylation. 109. Scheme 156b and c). which in step (b) underwent further alkylation with 4-O2N-C6H4CH2OH followed by cleavage of the N-S bond to lead to the product 550.1621.1625 The purification was effected by post-reaction sequestration onto an ammonium functionalized ArgoPore resin. instead of removing the Boc group.1599 Recently. in Scheme 165. Jackson and Routledge tagged crown ethers to phosphines and used the resulting compounds (e.1619 A large number of amines were prepared by using this linker. A subsequent aqueous base wash greatly facilitated the purification of the product. No. 551) for Mitsunobu etherification.1624 ´ 9.1627 The ester linkage on the phosphine reagent was cleaved by tetrabutylammonium fluoride or with trifluoroacetic acid/CH2Cl2. and their co-workers have developed a capture-ring-opening metathesis polymerization-release (capture-ROMP-release) method for obtaining pure amines and alkylhydrazines and for ring-closing metathesis. Alternatively.Mitsunobu and Related Reactions Scheme 161 Chemical Reviews. a thiophenol-DBU combination was utilized. Vol. the sulfonamide group could also be cleaved. In another study. removal of both the Boc and sulfonamide groups after the first N-alkylation led to primary amines.2. Flynn. The authors also reported the 31P NMR spectrum The polymer bound versatile amine releasing N-Boc-onitrobenzenesulfonamide (Boc-ONBS) 549 has been employed in the synthesis of primary and secondary amines by sequential substitution of the sulfonamide moiety using the Mitsunobu reaction. In step (a). 2009.1626.1622 the same methodology was applied to the synthesis of Oalkylhydroxylamines using a chromatography-free protocol. Falkiewicz has shown the utility of Merrifield resin-bound o-nitrobenzenesulfonylglycine in the synthesis of peptide nucleic acids (PNAs) containing a reduced peptide bond. solid phase synthesis of optically pure N-aminodipeptide derivatives using a solid-supported R-hydroxy acid and a free phthaloylated R-Z-N-aminohydrazide has been reported by Jamart-Gregoire and co-workers. 552.g. step (a) led to (poly)-ArSO2N(CH2CH2-2-Np)Boc and then to (poly)ArSO2NH(CH2CH2-2-Np). δ(P) -7.1] greatly facilitated isolation of the desired etherification products.1620 For subsequent cleavage of the N-S bond. Other Modified Reagent Systems (Including Fluorous Reagents) In one study. 6 2613 Scheme 162 Scheme 163 the reaction further. The yield in the reaction of 7-hydroxycoumarin with benzyl alcohol to lead to 7-benzyloxycoumarin was comparable to that using Ph3P. which expanded the scope of . Thus. Hanson. reported that the use of 4-(diphenylphosphinyl)benzoic acid 2-(trimethylsilyl)ethyl ester [DPPBE. the Ph3P-benzoyl peroxide combination also works well.4 in DMSO. This reagent and geranyl phenyl sulfone were also utilized for the preparation of norfaranal.8]. 6 Scheme 164 Swamy et al. compound 556). Most of the side products in the esterification. It has been used in the alkylation of primary and secondary alcohols with prenyl and geranyl phenyl sulfone (Scheme 166c.1630 Another alternative to using Ph3P-DEAD is dimethylmalonyltributylphosphorane (DMTP. 2009. but the reaction still worked well (Scheme 166a.300 While this reaction conducted in DMF using L-menthol as the substrate led to retention.98 This compound can be readily prepared by the reaction of n-Bu3P with dimethyl-2-chloromalonate. 557) [δ(P) 27.b).2 M Na2CO3). in the esterification of L-menthol. The corresponding methyl analogue cyanomethylenetrimethylphosphorane (Me3PdCHCN. an analogue of the pheromone produced by Pharaoh’s ant. which can be considered to be an equivalent of n-Bu3P-DEAD.57-64.1470. and it may actually be advantageous. CMMP) is another valuable reagent.62 It is possible to utilize this reagent in coupling reactions involving unprotected p-toluenesulfonamide also. which simplifies the purification.61.2614 Chemical Reviews. stereochemistry with retention/inversion varied depending on the .1629 Excellent yields of the products were obtained. CMMP Scheme 168 mediated one pot cyanation of alcohols and efficient alkylation of primary and secondary alcohols with arylmethyl phenyl sulfones were reported by the same group. This reagent has been utilized for C-C bond formation even with nucleophiles with pKa > 20 to give compounds of type 555. cf.99. the presence of an additional bulky amine such as tert-butylamine favored the inverted product.1628 It is prepared by starting with chloroacetonitrile and tributylphosphine.99 Another useful system is the cyanomethylene-tri-n-butylphosphorane 553 (CMBP). for benzoylation. It is stable at room temperature under an argon atmosphere. The substrate 554 has a pKa ) 23. No. care has to be exercised in handling. 109. Scheme 167 In contrast to other esterifications.63 The only handicap is that this reagent is sensitive to air and moisture. developed by Tsunoda and co-workers. since the hydrazine byproduct is avoided. Vol. and hence. Earlier. More importantly.1] that was formed after the addition of DIAD to the phosphine.34.58. can be removed by aqueous base partitioning (0. Scheme 165 Scheme 166 of the corresponding MBH betaine [δ(P) -41. tributylphosphine oxide and dimethylmalonate. 4benzoquinone or 2. 2.1632 The normal Mitsunobu reaction afforded only a hydrazine-substituted product of tetronic acid. 569). in the Mitsunobu reaction. 571) for use in the Mitsunobu reaction.6-trimethylbenzoic acid gave a 0. Thus. with propylene spacers that help in alleviating the separation problems have been introduced. For the microwave (MW) assisted esterification of pharmacologically important dihydropyrimidine C5 acids. The tedious step of column chromatography was also avoided because the phosphine oxide was bound to the polymer backbone and easily filtered off.1638-1641 The reaction worked with tertiary alcohols also.35.1644. this material could be readily recovered and reused several times without loss of efficiency because the product phosphine oxide. and alkoxydiphenylphosphine. Kappe and co-workers employed the fluorous phosphine F-TPP (571) and the fluorous azodicarboxylate 569. and F-DEAD-3 (569).1650 Separation of the fluorous byproducts was easily achieved by fluorous liquid extraction.5-cyclohexadienone//Zn(N3)2(pyr)2 in azidation reactions has also been reported. esterification of secondary alcohols took place with retention of configuration as a result of the formation of the triflate salt of acylated DMAP. Scheme 6) is involved in most of the reactions. peptide. reverted back to 565. upon treatment with triflic anhydride. Hendrickson’s reagent [Ph3POPPh3]2+[CF3SO3-]2 (560) is a compound of that type.Mitsunobu and Related Reactions Chemical Reviews.1649 Dobbs and McGregor-Johnson also have independently developed the fluorous reagent 570 and effectively utilized it in the O-alkylation of N-hydroxyphthalimide. 1. In the presence of 4-dimethylaminopyridine (DMAP). use of Ph3P/2.829. and it gave high yields.4.6-tetrabromo-2. an intermediate alkoxyphosphonium salt (cf. Dahan and Portnoy have employed compound 566 to obtain poly(aryl benzyl ether) dendrimers on core Wang resin support.8 equiv each of the alcohol. also introduced fluorous phosphine like C8F17(CH2)2C6H4PPh2 (F-TPP. They have The betaine 566 is another equivalent of the MorrisonBrunn-Huisgen intermediate and can effect Mitsunobu type reactions. Thus.5: 99.1646 A simple chromatography-free fluorous Mitsunobu protocol using a highly fluorinated substituted benzoic acid has also been developed by Dembinski and co-workers.1643-1647 Two new fluorous reagents. However. No.1648. while 4-nitrobenzoic acid gave a 95:5 ratio in favor of retention. 109.1636 The products thus obtained could later be converted to amine derivatives. respectively. C8F17(CH2)3O2CNdNCO2-tert-Bu (F-DEAD-2. Likewise. 2009. Use of the same fluorous phosphine was also reported by Zhang and Lu in the same year for automatic (96 parallel reactions) fluorous solid phase extraction in Mitsunobu esterification/etherification/ N-alkylation. Scheme 167). Dialkyl ethers could be obtained in good to high yields Via fluoranil. F-TPP (571).6-dimethyl-1. The results were rationalized by invoking an alkoxyphosphonium species for inversion and an acyloxyphosphonium intermediate for retention similar to that proposed in normal Mitsunobu esterification. Vol. species 18.1645 Other useful phosphines introduced by the same research group are [RfCH2CH2-C6H4]2PPh [Rf ) C6F13 and C8F17].1651 The best conditions were THF as solvent. 6 2615 Scheme 169 acid. The byproducts could be separated either by fluorous flash chromatography or fluorous solid-phase separation. it was found that the classical reagent system Ph3P-DIAD was better than the fluorous one in these cases.1652. this reagent offers a lot of scope for further work.5 ratio in favor of the inverted product (559.4-benzoquinone to obtain an oxophosphonium zwitterion of type Ph2P+(OR)(OAr-O-) which then reacted with carboxylic acids or phenols to give esters or ethers. Thus. More importantly. 570) for use with sterically hindered alcohols.1634 Species 565 was especially useful in ester. anhydride. It can be noted that. ether.4. amide.1653 In the alkylation of various 2-nitrobenzenesulfonyl-substituted sulfonamides (using PS-PPh3-DTBAD).1644 These were found to be better than (C6F13(CH2)2O2CNdNCO2(CH2)2C6F13 (F-DEAD1. Synthetic routes to the reagents 568-5691644 and 5701650 have also been described in detail.1631 O-Alkylation of tetronic acids 561 leading to 562-563 was done very efficiently using this reagent (Scheme 168).4. alcohols.1635 An example of its use in the synthesis of trisubstituted amine 567 is shown in Scheme 169. this procedure offered an easy method for the purification of the hydrazine byproduct from the Mitsunobu reaction. Thus. and nitrile formation reactions.1633.1637 Mukaiyama and co-workers used a reaction of the in situ generated Ph2P(OR) with 1. Jenkins and co-workers have developed analogous polymersupported coupling/dehydrating agents 564-565. and microwave irradiation at 110 °C for 10 min for a conversion of ∼80% (HPLC). one can think of using phosphonium ions [R3POPR3]+ in Mitsunobu type reactions. use of a fluorous scavenger . using a perfluoro solvent. 568) and C6F13(CH2)3O2CNdNCO2(CH2)3C6F13 (F-DEAD-3.1642 Curran and co-workers have been developing new approaches to circumvent the problem of separation in the Mitsunobu reaction. 1644 In a competitive reaction.1656-1658 Thus.249 While former compound 573 is claimed to be particularly effective for the treatment of malaria and neosporosis.6-dicyanobenzoquinone (DDQ). A large number of applications involve ether formation or N-alkylation reactions.1654 A nice review by Zhang and Curran on fluorous solid-phase separation has alsoappearedrecently.829 Firouzabadi and co-workers have been looking at alternative systems with phosphine as one of the components.2616 Chemical Reviews. C8F17CH2CH2CH2I has been reported by Basle et al. Esterification A normal Mitsunobu protocol has been utilized in the synthesis of the artemisinin derivative 573 and the tryptophan amide 574. Mitsunobu esterification with inversion of configuration at the secondary alcoholic carbon Scheme 172 has been employed in the synthesis of losartan (antihypertensive).174. where multistep syntheses are involved.1658 In a different type of reaction.3-dichloro-5. it was also possible to convert R-hydroxyphosphonates to R-thiocyanatophosphonates. 2009. esterification of the phosphonates .1. Although essentially no new insight into the mechanistic aspects is offered in a majority of cases. the latter compound 574 is useful as a tachnykinin (NK2) antagonist.173.385-387 In the preparation of oligosaccharides conjugated with proteins. 6 Scheme 170 Scheme 171 Swamy et al. the connectivity resulting from the Mitsunobu reaction is shown by an arrow for the reader’s convenience. Patented Literature A sizable number of patents (>150) subsequent to the year 1996 make use of the Mitsunobu reaction explicitly.g. Chart 7 10. and analogues of leucascandrolide A (antitumor active) derivatives.t-C4F9O(CH2)3OC(O)-NdN-C(O)O-(CH2)3O-t-C4F9.1661 A publication related to dihydroartemisinin has also appeared. used n-Bu3P-ArSeCN to convert an alcoholic -OH to -SeAr (Ar ) o-nitrophenyl) group in their synthesis of absinthin. when used in place of DEAD for the conversion of an alcohol or a thiol to a cyano compound (e. No.1659 10. was quite effective (Scheme 170). Vol. to ´ facilitate the isolation of amine products. Zhang et al. primary alcohols reacted much faster than secondary alcohols.1655 Thenewgreenerreagent. they found that 2. 109. has also been reported recently by Curran’s group.1657 Facile conversion of alcohol ethers to bromides could also be effected by the same combination along with a bromide source. Using a Ph3P-DDQ combination.1662-1664 Pertinent publications on leucascandrolide A have been discussed above.1660. 572). In the presentation below. the efforts are directed toward the pharmaceutical industry or materials and hence this literature is of practical significance. calanolide (antiviral). Vol. 109. No. 2009. 6 2617 .Mitsunobu and Related Reactions Scheme 173 Chemical Reviews. Vol. 109. 2009. 6 Scheme 173. (Continued) Swamy et al. .2618 Chemical Reviews. No. 1728 In the synthetic route given for 638. an intermediate in the synthesis of duloxetine hydrochloride 591 (cymbalta. the pharmacological activity of the compound is indicated.1683 and (xi) trans-(+)-sobrerol. atherosclerosis.4-dichlorphenolic residue has been prepared as a therapeutic agent for treating hypertensive conditions. In the synthesis of 628. that are active as PPARγ agonists/antagonists. No.1667 (iii) intermediates for the preparation of halichondrin B. that are useful in the treatment of Alzheimer’s disease. were claimed to be useful as Meningitidis A vaccines. was prepared by starting with the appropriate chiral secondary alcohol and 1-naphthol (Scheme 173b).1684 The structures of compounds 578-583 are shown in Chart 7. have been prepared by Mitsunobu etherification followed by saponification (Scheme 173d). it appears that molecular modeling could be of some help to have a more active compound for PPAR activity. used for major depressive disorder).1666 (ii) (S)-R.1679 (viii) chiral propargylic alcohol and ester intermediates of himbacine analogues. ursodeoxychloic acid. The ether linkage here was provided by a simple Mitsunobu protocol (Scheme 173l).1697 Here. the key connectivity with 5-methyl1H-pyrazol-3-ol was made via Mitsunobu etherification (Scheme 173j).1680 (ix) paclitaxel.1675 (iv) (R)-propargylic alcohol 581. respectively. are claimed for this compound.1676 (v) isoursodeoxychloic acid 582 (a bile acid). the reaction mixture was treated with MgCl2 and Celite twice and then distilled with isopropanol to remove toluene.1693 Compound 596 bound to ERR and ERβ human recombinant estrogen receptors in vitro with IC50 values of 107 nM and 1. It is interesting to note that isoursodeoxychloic acid 582 is almost completely converted back to its epimer.1669.1699 The trifluoromethyl-substituted phenolic ether 607.4-dioxyphenyl ether 603. respectively. Vol. (Continued) Chemical Reviews. it is claimed that the use of tris(4-chlorophenyl)phosphine and a large excess of triethylamine in place of just triphenylphosphine increased the yield to nearly two-fold.131. Normal esterification was also employed in the synthesis of (i) ethyl 4-cyano-3-hydroxybutyric acid.1677 (vi) orlistat 583 (a drug designed to treat obesity). and taxol (partial synthesis). Starting with a pyridinol and protected phenylalaninol. was prepared in two steps by etherification of the appropriate protected phenol with the required alcohol followed by deprotection (Scheme 173m). which was prepared by reacting the allyl alcohol 601 with the phenol 602 (Scheme 173i). 2009. and inflammation.1701-1746 The bond at which ether formation is effected is shown by an arrow mark in each case.1665 In these cases. have been obtained via pyridinols as shown in Scheme 173c.1674 (iii) epicoleonol 580. a large number of applications. cardiovascular diseases including atherosclerosis. memory loss.1689 The benzooxazinones 593. However. and hypercholesterolemia.4-dimethyl-2-(4-trifluoromethylphenyl)-5-thiazolemethanol. in rat livers.1694 It showed inhibition against EGFR and erbB2 tyrosine kinases with IC50 values of 3 nM and 59 nM. docetaxel. even with the stronger reagent system n-Bu3P-ADPP.1. The pyridyl ethers 592. diphenyl(2-pyridyl)phosphine (1) was used in place of Ph3P.8 nM. no chromatography was used.1700 In addition to the above.2. With a halide (X) present as C*(OH)-CH2X.1668 (iv) hexahydrofurofuranols. Compound 604 is claimed to be useful in the treatment of cardiovascular diseases. Etherification without Cyclization Numerous reports on etherification on pharmaceutically important compounds exist in the patented literature. Multisubstituted cyclopentane derivative 606 with an ether linkage to a 2.1685 Some details on the esterification of thiophosphate salts which were patented earlier are now published and have been discussed already.459. The PPARR and PPARγ activities are also exhibited by the 1. 109.1678 (vii) dehydroepiandrosterone derivatives for use in cosmetics. The indole carboxylic acid derivatives 588 that are active against hepatitis C virus have been prepared in decent yields (Scheme 173a) with the use of DTBAD in place of the usual DEAD or DIAD. The tyrosine kinase inhibitor piperidyl-quinazoline derivative 598 was prepared using Mitsunobu etherification as a primary step (Scheme 173g). the yield was only moderate.1692 In the synthesis of estrogen receptor modulator 596. a convenient route to optically pure epoxides 586 has been developed as shown in Scheme 172. or dementia and analgesia.1682 (x) hydroxyvitamin D. For the synthesis of the diether 594 (Scheme 173e).Mitsunobu and Related Reactions Scheme 173.1688 This method had the advantage that no racemic product was formed.1690.2. . there are several other pharmaceutically important derivatives wherein Mitsunobu etherification-connectivity played a key role.1696 Looking at the structures of 600 and 603.407. Mitsunobu etherification was one of the key steps (Scheme 173f). 6 2619 was required (Scheme 171). that included treatment of type I and II diabetes. compound 593 was reported to give a 64.1681.1670 (v) 12-aryl prostaglandin analogues as antiglaucoma agents.1671 and (vi) fluorinated polymers and membranes containing a 4-phenolsulfonic acid residue. Derivatives of the product 577.9-fold increase over control.1686 10. For 633. after deprotection.1672 Inversion of configuration at the secondary alcoholic carbon site has been reported in the synthesis of (i) cyclopentenone derivatives 578 (intermediates for prostaglandins).1691 In an agonist intrinsic activity assay for induction of aP2 mRNA production. Orlistat 583 is claimed to be useful against type II diabetes.1687 The thienyl derivative 590. Ether Formation 10.1698 it is claimed to be useful for treating cancer and arthritis. claimed to be useful for treatment of diseases modulated by LXRR and LXRβ agonists. Compound 6001695 showed PPARδ whereas derivative 593 showed PPARγ activity.1723 The product was claimed to have no detectable Ph3P(O). compound 605 has been prepared in several steps (Scheme 173k).1673 (ii) hydroxydibenzazepinecarboxamides 579. Wherever possible. Chart 8 shows some of these. Vol. 2009. . 109.2620 Chemical Reviews. No. 6 Chart 8 Swamy et al. 109. 6 2621 . (Continued) Chemical Reviews. 2009. No.Mitsunobu and Related Reactions Chart 8. Vol. No. 2009. (Continued) Swamy et al.2622 Chemical Reviews. 6 Chart 8. 109. Vol. . 4′-diamine (R ) Cl.1764 (xix) phenalkyloxy phenyl derivatives for use in conditions associated with insulin resistance.1763 (xviii) oxazolylethyltyrosine and oxazolylethoxyarylserine derivatives as hypoglycemic and hypolipidemic agents.1753 (viii) acyclic hydrazides for use as cannabinoid receptor modulators. CN. etc.1768 (xxiii) phenylalkanoic acid derivatives as preventive or remedial agents for digestive tract diseases.1774.1736 Details on patented compounds of type 648 (compound 236 above.1773 (xxviii) prolines/proline analogues for preventing neuropathic pain and as acromelic acid analogues/allodynia inducers.1775 (xxix) triazolyl thiophenecarboxamides as inhibitors of pololike kinases. unprotected D-glucose was used with methyl cyanide as the solvent. with chromophores attached via ether linkages by the Mitsunobu reaction.757 Other patents that make use of the simple Mitsunobu etherification pertain to (i) polyimides from 3.1748 (iii) 2.1761 (xvi) heterocyclic ethers as neuronal nicotinic receptor ligands. No.) for liquid crystal applications.1765 (xx) aminoindazole derivatives active as kinase inhibitors.1770 (xxv) substituted 3-phenylpropionic acid derivatives with PPARR and PPARδ modulatory activities.1747 (ii) 3.1755 (x) indanyloxy-substituted pyridine derivatives and analogues.1771 (xxvi) 4-substituted pyrrolidine-2-carboxylic acid derivatives.1760 (xv) bridged biaromatic and triaromatic ring compounds. 2009. useful as phosphodiesterase inhibitors.1756 (xi) benzoxazinone and benzopyrimidinone piperidinyl tocolytic oxytocin receptor antagonists. 651-652. and intermediates for their production.1759 (xiv) tricyclic spiro Scheme 174 compounds (5-HT1D receptor antagonists). 109.1778 and (xxxii) duloxetine (using HF elimination from 1-fluoronaphthalene).755. 6 2623 the phosphine appears to be missing in the reaction sequence.1749 (iv) antimitotic agents.1769 (xxiv) aza-ring derivatives and their use as monoamine neurotransmitter re-uptake inhibitors.1772 (xxvii) 3-aryl3-heteroaryloxy-1-propanamine derivatives useful as serotonin and norepinephrine re-uptake inhibitors.1779 An interesting class of polyimide derivatives.Mitsunobu and Related Reactions Chemical Reviews.3′-anhydro-5′-O-tert-pentanol deoxythymidine. useful in nematic liquid crystal devices.6-dialkyloxypyromellitic dianhydrides.1752 (vii) fluoxetine.1754 (ix) 1H-quinolin-2-one derivatives as antagonists of gonadotropin releasing hormone (GnRH).3′-bis((4-R-4-stilbenyl)oxyalkyloxy)biphenyl-4.1733 In the case of 641. has also been patented.1766 (xxi) 11a-aza-11a-homoerythromycin compounds as antibacterial agents. Vol.5-dione derivatives.1762 (xvii) 5-[(4-piperidinyl)methoxy]-2-indolecarbonyl-2(S)-phenylsulfonylamino-β-alanine as a fibrinogen receptor antagonist.1751 (vi) solid support based on selenium useful in solid phase reactions.1780 Synthesis of a nonlinear optical (NLO) polymer using a similar reaction is also claimed.1767 (xxii) substituted 3-phenyl-2-alkoxypropanoic acids and analogues as modulators of peroxisome proliferator activated receptors.1776 (xxx) retinoid-based polyunsaturated compounds.1781 .1757 (xii) dihalopropene compounds as insecticides/acaricides.1758 (xiii) cyclic guanidine derivatives for treatment of thromboembolic disorders.1750 (v) 3-indolyl-4phenyl-1H-pyrrole-2.1777 (xxxi) oxazoles and thiazoles as PPAR modulators. R ) R′ ) H) have been published as full papers. 732-734 The macrocyclization in the case of 659 was also accomplished by a Mitsunobu etherification as shown in Scheme 175b. seborrhea. This compound and its analogues have been claimed to be useful in treating tuberculosis.1791 Asymmetric dihydrobenzofuran derivative 661 has been obtained through internal cyclization in good yields (76%) as shown in Scheme 175d. a seven-membered ring containing both nitrogen and oxygen have been generated via Mitsunobu etherification. 2009. was utilized for this purpose.1785 Compound 656 is an inhibitor of steroid sulfatase and is claimed to be useful against acne. Vol.1786-1789 related work has been published earlier. etc. was prepared by a novel cyclization reaction as shown in Scheme 174a.1794 The cyclization shown in Scheme 176a for the synthesis of NK-1 receptor antagonist 662 is slightly different from previous ones in the sense that no phenolic -OH is involved. 6 Scheme 175 Swamy et al. psychotic disorder. species 251) have already been mentioned above.2.2. their single biaryl atropisomers were readily prepared in high yields with high stereoselectivity via a Scheme 176 Mitsunobu procedure (Scheme 175c). 109. an antiallergy agent.g.1784 As mentioned above. 655) have been claimed to be good protein kinase inhibitors. etc.774 This type of cyclization is quite common. inflammatory or autoimmune diseases.1790 Some of these cyclized peptide derivatives are inhibitors of matrix metalloproteinases and tumor necrosis factor R secretion.709 A more active reagent system.1792 Derivatives of this compound are claimed to be useful for treating schizophrenia. Species of type 660 are glucocorticoid receptor agents. Mitsunobu ether formation cum cyclization prior to reduction of a keto group was one of the key steps in the synthetic strategy.1782 a related publication has also appeared. (+)-calanolide A (658) is a potent HIV reverse transcriptase inhibitor.1796 Citalopram and escitalopram (663. 10. n-Bu3P-TMAD. and two more examples. Several indole-based multiring compounds as inhibitors of HCV replication have been prepared recently through a multistep procedure. These compounds (e. 656-657. androgen-dependent cancer. No. In some of these.1783 intermediates of type 654 (cf. are depicted in Scheme 174c. as shown in Scheme 175a. In the cyclization shown in Scheme 174b.2624 Chemical Reviews. Scheme 176b) are known active ingredients commonly used for .1793.1795. Etherification with Cyclization The flavone C-glycoside.1784. tautomerization of NHC(O) to NdC(OH) could precede oxazolyl ring formation. The preferred molar ratio of the phosphine. Other patents wherein cyclization is involved are (i) NK-1 receptor antagonists for treating sexual dysfunction1798 and (ii) isoflavan/isoflavene derivatives. 664) that are useful as CB1 receptor antagonists. Compound 670 was a precursor to other trans-cyclohexane derivatives that were intermediates for VLA-inhibitors. etc.Mitsunobu and Related Reactions Scheme 177 Chemical Reviews. N-Alkylation In the synthesis of aminomethylpyridine derivatives (e.1807 As discussed in the earlier sections. it has been claimed that this process is particularly advantageous for escitalopram. Introduction of nitrogen by means of phthalimide was again a key step in the synthesis of the imidazo-pyrazine 665. a tyrosine kinase inhibitor (Scheme 177b). and the substrate was 3:5.1799 Chart 9 10.1806 This method of converting -OH to an -NH2 group was found to be quite convenient and hence was adapted for synthesizing oligoamines that were useful as antineoplastic and anticancer agents. No. Both of these have been prepared via Mitsunobu cyclization. since it permits cyclization of the diol with high stereoselectivity.g. psychotic disorders.1797 In particular.3:1 in the presence of the strong base sodium tert-butylate with THF as the reaction medium (60% yield).1808 A synthetic route to ultrabroad- spectrum injectable antibiotic doripenem 671 involved this inexpensive phthalimide protocol with no necessity for column chromatography purification. wherein N-alkylation has been . Compound 664 was shown to have very good in vitro affinity for the cannabinoid CB1 receptor.1801 Compounds 666-670 have also been synthesized via phthalimide. Chart 10 shows compounds 673-678. no phenolic -OH was involved in the cyclization process. Thus. 109. the amino nitrogen can be activated by having a sulfonyl group attached to it.1802-1806 but in the case of 6711807 the species of interest was the N-substituted phthalimide itself (Chart 9).1800 The phthalimide residue was subsequently removed by hydrazine hydrate in most cases. Vol. optically pure 672 (Scheme 178) has been obtained. gastrointestinal diseases. with IC50 e 5 × 10-7 M.1809 Interestingly. inflammatory phenomena. 6 2625 the treatment of depression. Nalkylation via phthalimide and a benzylic alcohol was utilized (Scheme 177a). Here also. immune system disorders. many such sulfonamides themselves are of significant pharmaceutical interest. and claimed uses include treatment or prevention of appetite disorders. DEAD. 2009. metabolic disorders.3. Other examples of N-alkylation involve the synthesis of (i) taxane intermediates.1827-1831 In the example leading to 690. 109. though.1832 This type of reaction has been described in section 8 above.1817 In one case. bis(tert-butoxycarbonyl) imide (Boc)2NH was used as the nitrogen source to build an oligomeric peptide nucleic acid (PNA) combinatorial library.1818. pyrimidines.1837 (iv) N3-aminoalkyl derivatives of (Z)5-arylidenehydantoin. which is claimed to be useful as a psychotherapeutic agent (Scheme 179b).1841 Intramolecular N-alkylation has led to the formation of many important cyclic amines such as 692-695 (Scheme 181).1842-1844 Rings of several sizes could be generated employing this approach.1811 substituted azetidines. Finally. etc. Chemistry analo- . a new benzodiazepine ring was generated via the hydrazino residue. Chart 10 performed.1833 (ii) substituted purine heterocyclics. one patent dealing with the synthesis of carbamate esters using the Mitsunobu protocol has been recently awarded.4-diamino precursor itself was sufficiently reactive. Vol. is amenable to Mitsunobu Nalkylation. Five reactions of this type leading to compounds 682-686 are shown in Scheme 180. as exemplified by the synthesis of the indole derivative 680.1812 and phenylsulfonamides (the OSiR3 group was later replaced by a OC(O)NR2 group). anti-inflammatory agent).1815 A solid-supported synthesis of sulfonated 2-oxopiperazines 679.1816 Trifluoroacetamide NH appears to be more reactive than sulfonamide. pyrimidones. Mitsunobu N-alkylation was a key step.1839 (vi) N-(3-amino-2-hydroxypropyl)benzenesulfonamide derivatives as GlyT1 transporter inhibitors. 6 Scheme 178 Scheme 179 Swamy et al. These were intermediates for doripenem (doribax).1821 The ring NH moiety in purines.1813 respectively.1842-1847 In compound 692 (claimed to be anticonvulsant).1810 dorzolamide.1820. involved an initial Mitsunobu alkylation.1840 and (vii) polymer conjugates of therapeutic agents and food additives.2626 Chemical Reviews. In the synthesis of the target sulfanilide 677. imidazoles.1834-1836 (iii) 5′-nor-1-homo-N-carbonucleosides as antiviral and antitumor agents.1838 (v) tetrahydrocarbazole and cyclopentanoindole derivatives as antagonists of the prostaglandin D2 receptor. Compound 675 was obtained in a decent yield (45%) without performing chromatography. No. 2009.1822-1826 Chart 11 presents a few more compounds (687-691) where this type of N-alkylation has been utilized.1819 In another.1814 A large number of (poly)azanaphthalenyl carboxamides of type 676 as HIV integrase inhibitors have been prepared by starting with MeN-[(4-methylphenyl)sulfonyl]glycinate and related compounds. shown in Scheme 179a. PhOCONHOCO2Ph was utilized for the synthesis of a hydroxamic acid derivative of cyclohexygenase-2 and 5-lipoxygenase inhibitors (681. the cyclic 1. C-C bond formation by the Mitsunobu protocol is difficult. the nucleophilic partner in the Mitsunobu reaction can be HN3 (via Me3SiN3). Other Reactions As discussed in section 8.3-dipolar cycloaddition of Me3SiN3 to an intermediate nitrilium ion. wherein a formation of tetrazole is shown. a solid-supported reagent of the type RNHCOC6H4(CH2OH)-4 (R ) resin) was condensed with diethyl malonate (in solution) in the presence of Ph3P/ Me2NCONdNCONMe2. is an ECE inhibitor. This S-alkylation reaction may be contrasted with that for the thiophosphate salt shown in Scheme 36 (compound 147 above) where O-alkylation . the LTA4 hydrolase-inhibiting compound 698 (Ki ) 62 nM) was synthesized by esterifying the precursor alcohol 697 with thioacetic acid followed by hydrolysis (Scheme 183a).1852 a similar thioacylation was utilized. Vol. 6 2627 gous to that for the synthesis of 693 has been published. osteoarthritis. Azidation using this nucleophile and subsequent reactions can be done on a NHC(O) group that can tautomerize to NdC(OH). The final target molecule. 109.1083. C-N. No. Relatively speaking. This is shown in Scheme 182. In one such rare example.1849 Subsequent cleavage of the resin led to 4-(H2NCO)C6H4CH2CH(CO2Et)2. 2009. compared to C-O. phosphonate 696.1850 In the synthesis of mercaptobenzene sulfonamide 699 (Scheme 183b. the Mitsunobu protocol offers a simple route to thiols from alcohols.1526 These reactions probably involve 1. or C-S bonds. Thus.4. claimed uses: rheumatoid arthritis. tumor metastasis)1851 and N-(mercaptoethyl) amino acid derivative 700 (active against neutral endopeptidase).Mitsunobu and Related Reactions Scheme 180 Chemical Reviews. 10.1084 As mentioned earlier.1848 a similar cyclization with the NHC(S) group is discussed above. was reported. has been versatile and applicable for a variety of organic transformations. Also.1626. No.50-52 Tavonekham and co-workers (compound 536 above). despite our (unbiased) attemt to be as comprehensive as possible in this review utilizing SciFinder search. 2009. It is expected that this aspect is going to be much sought after. This could also be a fruitful area for a physical organic chemist to probe in detail.1853. Synthetic chemists tend to rely on its various facets. stereochemistry at the chiral secondary alcohol can be reversed is a valuable asset. Finally. and hence. have been published1643-1647 and hence are not discussed further. particularly in the area of nucleobase alkylation. an efficient and inexpensive way to recycle the reagents or to make the reaction fully catalytic is desirable. the unprotected amino functionalities did not interfere in the process. the Mitsunobu reaction. also need to be considered in the future. reflects its popularity. mainly as a result of the mild conditions employed during the reaction. by Charette and co-workers. to simplify the purification process. Another aspect worth looking into would be to synthesize a water soluble but degradable phosphine/phosphite of low toxicity. along with its modifications.1855 Parts of the patents on three of the phosphine modifications. and hence make the system more atom economical and greener. 12. 109.2628 Chemical Reviews. these are not added. be it natural product synthesis or nucleobase alkylation or etherifcation. we might have missed some articles. inclusion of these would require another review process. Summary and Outlook As mentioned in the Introduction. the complexity of the initial steps when different PIII precursors are used is intriguing. 6 Chart 11 Swamy et al. As far as the future of this reaction is concerned. The large number of publications. In the preparation of thioethers 701 and 702. Recoverable polymer bound phosphonium salts of type 565 that avoid the wastage of phosphine as well as azodicarboxylate.1854 Mercaptans such as 703 that are intermediates for antibacterial agents have also been synthesized using similar procedures. 11. Note Added in Proof Since the number of articles htat appeared after the first submission of this review is large (>100).1627 and Curran’s group. particularly by the pharmaceutical industry. although a major part of the mechanistic pathways is fairly well understood. The aforesaid points become important if we desire to employ the Mitsunobu route for large scale synthesis. Vol. The ease with which Scheme 181 . .B. No. 6 2629 tert-butoxycarbonyl benzoyl benzyloxycarbonyl (cyanomethylene)tributylphosphorane (cyanomethylene)trimethylphosphorane m-chloroperbenzoic acid diethylaminosulfur trifluoride 1.N.B. V. Due acknowledgment is made to Drs. 2009. V. Baskar. Rama Suresh. Venu Srinivas. Nagarajan as well as our laboratory colleagues.2.1′-(azodicarbonyl)dipiperidine benzyl . Acknowledgments We thank the Department of Science and Technology (DST. Anjaneyulu.V. and K. E. A. Sahoo. for 13. We are also grateful to the Council of Scientific and Industrial Research (New Delhi) for fellowships to N. Ramesh.N′-tetramethyl azodicarboxamide trimethyl(2.N-dimethyldithiacarbamate [(Me2NCS2)2Zn] Scheme 183 14.4.6-dibromo-4-(N-maleimido)phenoxy)silane trimethylsilyl N-2.N.5. Sajna. and R. and M.2.N′-dicyclohexylcarbodiimide 5.8-dione diisopropyl azodicarboxylate dimethylaminopyridine dimethoxybenzyl di-2-methoxyethyl azodicarboxylate dimethyl sulfoxide dimethylmalonyltributylphosphorane dimethoxytrityl bis(5-norbornenyl-2-methyl) azodicarboxylate diphenylphosphoryl azide 1.8-pentamethylchroman-6-sulfonyl trimethylsilylethylsulfonyl tetrabutylammonium fluoride tert-butyldimethylsiloxy (see also TBS) tert-butyldipheylsilyl tri-n-butylphosphine tert-butyldimethylsilyl triethylamine triethylmethanetricarboxylate triethylsilyl trifluoroacetic acid tetrahydropyranyl thyminyl residue triisopropylsilyl N.2-diphenylphosphinoethane di-tert-butyl azodicarboxylate dithiothreitol N-(3-dimethylaminopropyl)-N-ethylcarbodiimide 9-fluorenylmethoxycarbonyl 4-hydroxymethyl-3-methoxyphenoxybutyric acid methoxymethyl methanesulfonamide o-nitrobenzenesulfonylhydrazine N-methylpyrrolidinone o-nitrobenzenesulfonyl p-nitrobenzenesulfonyl phenylfluorenyl p-methoxybenzyl 2.K. Abbreviations Used in This Review ADDP Bn 1. K.N′.. K. O. New Delhi) for financial support.K.2-trichloroethoxycarbonyl p-toluenesulfonyl N. 109. Phani Pavan. Nagarjuna Reddy.0]undec-7-ene di-p-chlorobenzyl azodicarboxylate N.4.P.7.7-hexahydro-1.6-dicyanobenzoquinone diethyl azodicarboxylate diethyl pyrocarbonate 4. M. Vol.7-tetrazocin3.7-dimethyl-3.5.Mitsunobu and Related Reactions Scheme 182 Boc Bz Cbz CMBP CMMP m-CPBA DAST DBU DCAD DCC DDQ DEAD DEPC DHTD DIAD DMAP DMB DMEAD DMSO DMTP DMTr DNAD DPPA DPPE DTBAD DTT EDCI fmoc HMPB MOM Ms NBSH NMP o-Ns p-Ns PhF PMB Pmc SES TBAF TBDMS TBDPS TBP TBS TEA TEMT TES TFA THP Thy TIPS TMAD TMBMS TMS Troc Ts Ziram@ Chemical Reviews.2.8-diazabicyclo[5.P. 121. J. Paquette. 1997. Chem. Chem. 35. C. Tetrahedron Lett. Y. Nakajima. 28. I. In Electronic Encyclopedia of Reagents for Organic Synthesis. J. J. (20) Hughes. 10. (Yuki Gosei Kagaku ˆ Kyokaishi) 1994. O. J. Bull. (75) Grochowski. A. Wiley: New York.. Soc. M. (61) Tsunoda. Organic Synthesis. 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