3070705-indole-synth-review-199499

Recent developments in indole ring synthesis—methodology and applicationsGordon W. Gribble Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA Received (in Cambridge, UK) 14th December 1999 1 PERKIN REVIEW Covering: 1994–1999. Previous review: Contemp. Org. Synth., 1994, 1, 145. 1 2 2.1 2.1.1 2.1.2 2.1.3 2.2 2.3 2.4 2.5 2.6 3 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 3.10 3.11 3.12 4 4.1 4.2 4.3 4.3.1 4.3.2 4.3.3 4.4 4.5 4.6 4.7 4.8 5 5.1 5.2 5.3 5.4 6 6.1 6.2 7 7.1 7.2 7.3 7.4 8 Introduction Sigmatropic rearrangements Fischer indole synthesis Methodology Applications Mechanism Gassman indole synthesis Bartoli indole synthesis Thyagarajan indole synthesis Julia indole synthesis Miscellaneous sigmatropic rearrangements Nucleophilic cyclization Madelung indole synthesis Schmid indole synthesis Wender indole synthesis Couture indole synthesis Smith indole synthesis Kihara indole synthesis Nenitzescu indole synthesis Engler indole synthesis Bailey–Liebeskind indole synthesis Wright indoline synthesis Saegusa indole synthesis Miscellaneous nucleophilic cyclizations Electrophilic cyclization Bischler indole synthesis Nordlander indole synthesis Nitrene cyclization Cadogan–Sundberg indole synthesis Sundberg indole synthesis Hemetsberger indole synthesis Quéguiner azacarbazole synthesis Iwao indole synthesis Magnus indole synthesis Feldman indole synthesis Miscellaneous electrophilic cyclizations Reductive cyclization o, -Dinitrostyrene reductive cyclization Reissert indole synthesis Leimgruber–Batcho indole synthesis Makosza indole synthesis Oxidative cyclization Watanabe indole synthesis Knölker indole-carbazole synthesis Radical cyclization Tin-mediated cyclization Samarium-mediated cyclization Murphy indole-indoline synthesis Miscellaneous radical cyclizations Metal-catalyzed indole syntheses 8.1 8.1.1 8.1.2 8.1.3 8.1.4 8.1.5 8.2 8.3 8.3.1 8.3.2 8.4 8.5 8.5.1 8.5.2 8.6 8.7 9 9.1 9.2 9.2.1 9.2.2 9.3 9.4 10 10.1 10.1.1 10.1.2 10.2 10.3 10.3.1 10.3.2 10.3.3 10.4 11 11.1 11.2 12 12.1 12.2 12.3 13 14 1 Palladium Hegedus–Mori–Heck indole synthesis Yamanaka–Sakamoto indole synthesis Larock indole synthesis Buchwald indoline synthesis Miscellaneous Rhodium and ruthenium Titanium Fürstner indole synthesis Miscellaneous Zirconium Copper Castro indole synthesis Miscellaneous Chromium Molybdenum Cycloaddition and electrocyclization Diels–Alder cycloaddition Photocyclization Chapman photocyclization Miscellaneous photochemical reactions Dipolar cycloaddition Miscellaneous Indoles from pyrroles Electrophilic cyclization Natsume indole synthesis Miscellaneous Palladium-catalyzed cyclization Cycloaddition routes From vinylpyrroles From pyrrole-2,3-quinodimethanes Miscellaneous Radical cyclization Aryne intermediates Aryne Diels–Alder cycloaddition Nucleophilic cyclization of arynes Miscellaneous indole syntheses Oxidation of indolines From oxindoles, isatins and indoxyls Miscellaneous Acknowledgements References Introduction Indole and its myriad derivatives continue to capture the attention of synthetic organic chemists, and a large number of original indole ring syntheses and applications of known methods to new problems in indole chemistry have been reported since the last review by this author in 1994.1,2 J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075 1045 DOI: 10.1039/a909834h This journal is © The Royal Society of Chemistry 2000 Although most of the examples herein involve the indole ring system, a few novel syntheses of indolines, oxindoles,† isatins,† indoxyls,† carbazoles, and related ring systems are included in this review. The organization follows that adopted earlier,1 albeit with the inclusion of several additional classifications. Unfortunately, space limitations preclude detailed discussions of these reactions. 2 2.1 Sigmatropic rearrangements Fischer indole synthesis The venerable Fischer indole synthesis 3,4 has maintained its prominent role as a route to indoles, both new and old, and to the large-scale production of indole pharmaceutical intermediates. Furthermore, new methodologies have been developed and new mechanistic insights have been gleaned for the Fischer indole reaction since the last review. 2.1.1 Methodology Scheme 2 A one-pot synthesis of indoles from phenylhydrazine hydrochloride and ketones in acetic acid with microwave irradiation shows improvement in many cases (higher yields and reaction times of less than a minute) over the conventional thermal reaction conditions.5,6 Microwave irradiation in a pressurized reactor with water as solvent (220 C, 30 min) gives 2,3-dimethylindole in 67% yield from phenylhydrazine and butan-2-one.7 The use of montmorillonite clay and ZnCl2 under microwave conditions affords 2-(2-pyridyl)indoles at much lower temperatures and with solvent-free acid (Scheme 1).8 The use of natural clays (bentonite) and infrared irradiation also furnishes indoles in high yield from phenylhydrazine and ketones.9 For example, acetone affords 2-methylindole in 85% yield. 3-one gives 3-sec-butyl-2-ethyl-1-methylindole as the only isolable product, and the Z-isomer yields 1,3-dimethyl-2-(2methylbutyl)indole with high regioselectivity. The results are ascribed to regioselective enehydrazine formation by preferential proton abstraction by the hindered base DATMP. Buchwald and co-workers have utilized the palladiumcatalyzed coupling of hydrazones with aryl bromides as an entry to N-arylhydrazones for use in the Fischer indolization.17 Subsequent hydrolysis and trapping with a ketone under acidic conditions leads to indoles (Scheme 3). Scheme 1 Zeolites in the Fischer indole synthesis are highly shapeselective catalysts and can reverse the normal regiochemistry seen with unsymmetrical ketones.10,11 For example, 1-phenylbutan-2-one furnishes 2-benzyl-3-methylindole as the major isomer (83 : 17) in the presence of zeolite beta, whereas with no zeolite present this is the minor isomer and the major isomer is 2-ethyl-3-phenylindole (24 : 76).10 The solid phase Fischer indole synthesis of spiroindolines using substituted arylhydrazines and polymer-bound piperidine-4-carbaldehyde has been reported.12 This research group has described the preparation of 2-arylindoles on a solid support 13 and the synthesis of an indole combinatorial library using dendrimer supports.14 The thermal cyclization of N-trifluoroacetyl enehydrazines leads to indoles (or indolines) under relatively mild conditions (Scheme 2), apparently due to a lowering of the LUMO energy level of the trifluoroacetyl-substituted olefin that facilitates the [3,3]-sigmatropic rearrangement of the enehydrazine.15 A new catalyst, diethylaluminium 2,2,6,6-tetramethylpiperidinide (DATMP), provides excellent regioselectivity in the Fischer indole synthesis of 2,3-dialkylindoles from unsymmetrical ketones via the isomeric (Z)- and (E)-hydrazones.16 For example, (E)-N-methyl-N-phenylhydrazone of 5-methylheptan† The IUPAC name for oxindole is indolin-2-one, for indoxyl is indol-3ol and for isatin is indoline-2,3-dione. Scheme 3 2.1.2 Applications The Fischer indole synthesis was used extensively during the past five years to access a wide range of indoles and derivatives. Examples include 5-methoxy-2-phenylindole used in a photolysis study,18 2-ethoxycarbonyl-5-chloro-3-methylindole,19 2-ethoxycarbonyl-6-chloro-5-methoxy-3-methylindole,19 and 2ethoxycarbonyl-6-methoxy-3-methylindole 20 for use in indole alkaloid synthesis,19,20 and 2-ethoxycarbonyl-7-methoxy4-nitroindole,21 2-ethoxycarbonyl-7-methoxy-5-nitroindole,21 2-ethoxycarbonyl-4-methoxy-7-nitroindole,21 and 2-ethoxycarbonyl-5-methoxy-7-nitroindole 22 for use in the synthesis of coenzyme PQQ (pyrroloquinoline quinone) analogs.21,22 The last studies 19–22 utilize the Japp–Klingemann reaction of an aryl diazonium salt with α-substituted ethyl acetoacetate to obtain the requisite arylhydrazone. The Japp–Klingemann reaction was also used with malonates to prepare 2-alkoxycarbonyl-5-methoxyindoles on an industrial scale in high yields and with little waste.23 The reaction of 1,5-di(p-tolyl)pentane1,3,5-trione with 2 equivalents of phenylhydrazine gives rise to 3-[1-phenyl-5-(p-tolyl)pyrazol-3-yl]-2-(p-tolyl)indole,24 and a bis-Fischer indolization of the bisphenylhydrazone of 2,5dimethylcyclohexane-1,4-dione affords 5,11-dimethyl-6,12dihydroindolo[3,2-b]carbazole in 80% yield.25 1046 J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075 The synthesis of the marine alkaloid eudistomidin-A featured a Fischer indolization (Scheme 4); this paper describes the preparation of other 7-oxygenated indoles under conditions that preclude formation of the “abnormal” indole product.26 Along these lines, Szczepankiewicz and Heathcock employed an oxygen bridge in a hydrazone to prevent the abnormal cyclization.27 Subsequent elimination and hydrolysis to remove the oxyethylene bridge furnishes the desired 7-hydroxy-4nitrotryptophanol derivative (Scheme 5). The loss of an ortho-oxygen substituent was encountered by White et al. in a synthesis of 6,7-dimethoxytryptophanol, to afford the abnormal product 4-methoxytryptophanol.28 Scheme 4 and phenylhydrazones of bulky ketones can lead to rearranged products.43 Several indole alkaloid studies feature a Fischer indole synthesis as a key step, including studies on uleine,44 aspidospermidine,45 and ibophyllidine alkaloids.46 The core of the leptosin alkaloid family was nicely crafted by Crich et al. in this fashion (Scheme 7).47 Scheme 5 The indole diol 1 was easily crafted from a 2,3-dideoxypentose as shown in Scheme 6.29 The initial Fischer indole product was a mixture of two isomeric hydroxybenzoates resulting from benzoyl migration. Scheme 7 Scheme 6 Numerous tryptamine derivatives have been synthesized via the Fischer indole synthesis and some of these are listed below (2,30 3,31 4 32). Other tryptamines have been prepared via Fischer indolization and studied as novel antagonists for the vascular 5-HT1B-like receptors,33,34 5-HT1D receptor agonists,35 and melatonin analogs.36 Several novel tetrazolylindoles 5 have also been prepared in this fashion,37 and improvements in the Fischer indole step in the synthesis of the migraine treatment drug sumatriptan 38 and analogs 39 have been described. Both 2- and 3-indolylquinazolinones (e.g., 6) are readily prepared,40 and the thiocarbamates 7 are available in good yields by a Fischer indolization.41 An unexpected result in the Fischer indole protocol gives rise to 3-aminoindole-2-carboxylates,42 The Fischer indole synthesis has been used to construct numerous carbazoles including simple carbazole alkaloids,48 rutaecarpine analogs,49,50 biscarbazole alkaloids,51 benzoindoloquinolines,52 thiazolocarbazoles,53 thienocarbazoles,54 C-14 labelled benzocarbazole,55 and other fused-indoles such as indolo[3,2-d]benzoazepinones.56 Novel 14-alkoxyindolomorphinans (e.g., 8),57 4-hydroxy-3-methoxyindolomorphinans,58 and indolinosteroids (e.g., 9) 59 are readily synthesized via Fischer indolization, as are pyridoindolobenzodiazepines (e.g., 10),60 decal-1-one-derived indoles,61 radiolabelled naltrindoles,62 and 3-indolylcoumarins.63 A series of novel fused indoles has been synthesized using a Fischer indole strategy and one example is shown in Scheme 8.64 Ketoindoles and ketobenzothiophenes were also employed in this reaction. Spiroindolines and spiroindolenines are readily synthesized using the Fischer indolization and some examples include a crown-linked spiroindolenine used to make new signal transducers,65 novel antipsychotics,66 and MK-677, a growth J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075 1047 74 Thus.81. has been used to prepare efficiently 6. hydrazone 13 undergoes cyclization to the more electron-rich benzene ring. 2000.7. whereas under weakly acidic conditions tautomerization is sufficiently rapid that the [3. MNDO AM1 calculations have been performed on the conformations and sigmatropic rearrangement of the phenylhydrazones of ethyl pyruvate and acetaldehyde.83–86 which features a [2. 1. 1045–1075 Scheme 12 .3-bis(methoxycarbonyl)indole as a useful substrate for Pd-catalyzed cross coupling reactions leading to 7-substituted indoles.71 However.2 Gassman indole synthesis The beautiful Gassman indole-oxindole synthesis. have developed a modification of the Gassman synthesis that affords improved yields in many cases. on rare occasions the Fischer indole synthesis proceeds poorly or even fails altogether.82 hormone secretagogue.76 Murakami and co-workers continue their investigations of the effects of ortho-substituents on the regiochemistry and rate of Fischer indole cyclizations.67 The Fischer indole sequence has been used on an industrial scale in the manufacture of a pharmaceutical intermediate.7-dihydroxyoxindole. in strong acid the rate-determining step is 1048 J.3 Mechanism An exhaustive study of the effects of acidity on the mechanism of the Fischer indole synthesis reveals that four different mechanistic variations can occur over the acidity range of H0 = 2 to 8.3-d]pyrimidines as potential new thymidylate synthase inhibitors. the major product (41%) being an indazole.80 Huisgen and co-workers have found that under Fischer indole reaction conditions enehydrazine 14 stops at the 2-aminoindoline stage 15.87 Wright et al..75. Scheme 9 2.88 The key feature of the Wright modification is the facile formation of the chlorosulfonium salt 16. a subunit of the alkaloids paraherquamide A and marcfortine A. Chem. Scheme 11 2.68 to prepare pyrrolo[2.6. which avoids elemental chlorine (Scheme 12).1. since indole formation is precluded by ring strain in the product (Scheme 11). as shown in Scheme 10.3]-sigmatropic rearrangement. hydrazone 11 afforded only 15% of the indole product.77 Scheme 8 Scheme 10 A novel abnormal rearrangement has been uncovered in the Fischer indolization of the naltrexone N-methyl-N-(5.70 and to synthesize 7-bromo-2. Soc. For example.72 and hydrazone 12 failed to cyclize to an indole under all conditions tried 73 (Scheme 9).3]-sigmatropic rearrangement is rate determining.69. Perkin Trans. presumably because of the deactivating effect of the (protonated) pyridine ring.deprotonation to form the enehydrazine.8tetrahydro-1-naphthyl)hydrazone.77–79 and. 1045–1075 1049 .3].104.105 The phosphonium salt can be generated in situ from the corresponding benzyl methyl ether 21.97 and to the synthesis of dihydro-1H-pyrano[3.98 The mechanism is proposed to involve dimerization of 3-methyleneindoline 18.102 Scheme 14 In continuation of the original work.2. Majumdar et al. The reaction is especially valuable for the synthesis of 2-perfluoroalkylindoles. these workers have published a full account of their work including many examples of this clever reaction.4 Thyagarajan indole synthesis Thyagarajan and co-workers discovered a novel indole ringforming reaction that involves sequential [2.3 Bartoli indole synthesis The fascinating Bartoli protocol. For example.3]sigmatropic rearrangement analogous to the Fischer indolization step. the excellent Houlihan modification.110 Moreover.3].and [3.112 J.90 which features a [3. Cyclization of phenylacetate imides such as 24 occurs readily under the influence of base (Scheme 22). Soc.111 An interesting attempt to cyclize the imines derived from trifluoromethylaryl ketones and o-toluidines with lithium amides to indoles was not successful.2-e]indol-7-ones.100 More recently.96.3-e]indoles as potential new dopaminergic agents. which was first reported by Clark et al.106 A Madelung–Houlihan variation in which an intermediate dianion derived from pyridine 22 is quenched with amides to yield azaindoles has been described (Scheme 20). Chem.5 Julia indole synthesis Julia and co-workers have uncovered a novel indole ring synthesis involving the [3.and [3.6 Miscellaneous sigmatropic rearrangements A tandem Wittig–Cope reaction sequence converts a 2allylindoxyl to the corresponding indole in excellent yield (Scheme 18).92 Scheme 16 Scheme 13 2. Perkin Trans.3]sigmatropic rearrangements from the N-oxide of the aryl propynylamine 17 (Scheme 14).3]-sigmatropic rearrangement sequence is suggested to explain the formation of N-alkyl2-vinylindoles from N-alkyl-N-allenylmethylanilines upon exposure to MMPP (magnesium monoperoxyphthalate) (Scheme 16).1 Nucleophilic cyclization Madelung indole synthesis Scheme 15 A related tandem [2.. 1. yielding only amidines. have extended this reaction to the preparation of cyclic bisethers containing two indole units (Scheme 15).110 These methods are excellent for the preparation of 2-aryl-3-(arylsulfonyl)indoles and 2-anilino-3-(arylsulfonyl)indoles..103 which utilizes BuLi or LDA as bases under milder conditions than the original Madelung harsh conditions.108 has been utilized in a synthesis of novel pyrano[2.89.3]-sigmatropic rearrangement of the readily available sulfinamides 19 (Scheme 17).101 Although the classical Madelung synthesis is rarely employed nowadays. has been used to prepare 7-bromo-4-ethylindole in a synthesis of (±)-cis-trikentrin A. Scheme 18 3 3.107 This reaction.91 and 7-bromoindole (Scheme 13) in a synthesis of hippadine. although the yields are quite variable. quenching 23 with phenyl isocyanate yields carbodiimides which cyclize to 2-anilinoindoles with base. 2000. has been extended in several ways.93–95 Scheme 17 2.99 2.109 An aza-Wittig reaction of iminophosphoranes 23 with acyl cyanides leads to a novel indole synthesis (Scheme 21). The basecatalyzed version of this reaction has been adapted to solid phase synthesis. benzylphosphonium salts such as 20 undergo facile cyclization to indoles under thermal conditions (Scheme 19). The key 1050 J. This lithiation–carbonylation strategy was adapted to the synthesis of 3-hydroxyoxindoles by the lithiation of N-pivaloylanilines.114 A related isatin synthesis has been described by Smith and co-workers 115 that involves the carbonylation of the dianion derived from N -(2-bromoaryl)-N. the key intermediate in a synthesis of the antitumor indolequinone EO 9.5 Smith indole synthesis The Smith indole synthesis.4 Couture indole synthesis No new examples were reported since the last review.116 Smith and co-workers have also employed the original Wender indole synthesis to the synthesis of N-dimethylurea-protected indoles involving the dilithiation of N -phenyl-N.N-dimethylurea. 2000.117 3.. 1045–1075 The past five years have seen a resurrection of the Nenitzescu indole synthesis and this classic sequence was used to construct methyl 5-hydroxy-2-methoxymethylindole-3-carboxylate.120 The hydroxyindoline by-product. Scheme 24 Scheme 22 3. Chem. Perkin Trans.3 Wender indole synthesis The Wender indole synthesis.N-dimethylureas.119 3. have described an indole ring formation that involves an intramolecular Barbier reaction of phenyl and alkyl N-(2-iodophenyl)-N-methylaminomethyl ketones as summarized in Scheme 24.6 Kihara indole synthesis Scheme 21 Kihara et al. has been used to synthesize 2-trifluoromethylindole in 47% yield by quenching the above mentioned dianion with ethyl trifluoroacetate. has been extended to a convenient synthesis of isatins by quenching with diethyl pyruvate (Scheme 23). can be converted to the indole with aqueous HCl.121 This reaction has also been used to prepare a series of N-aryl-5-hydroxyindoles. 1.118 which involves dilithiation of N-trimethylsilyl-o-toluidine and subsequent reaction with a non-enolizable ester to afford the 2-substituted indole.7 Nenitzescu indole synthesis 3.123 Scheme 25 .Scheme 23 Scheme 19 intermediate is an acyllithium species which cyclizes onto the urea carbonyl group. Soc. Scheme 20 3. 3. if obtained.2 Schmid indole synthesis No new examples were uncovered since the last review.113 which involves the ortholithiation of N-phenylamides followed by reaction of the resulting dianion with α-haloketones and subsequent ring closure and dehydration.122 and it was utilized in the synthesis of a key indole (Scheme 25) used to prepare potent and selective s-PLA2 inhibitors. 139. The N-allylindole can be deprotected with Pd.130. these indolines can be converted to indole-2-carboxylates by decarboxylation and oxidation.3.128.135 The ‡ Chloranil is 2. 29.133 and Bailey has extended the reaction to include the intermediacy of aryne intermediates in the sequence. Soc. alkylation).124–127 An example is shown in Scheme 26 and the reaction has obvious similarities to the Nenitzescu indole ring synthesis.12 Miscellaneous nucleophilic cyclizations Bailey and Liebeskind independently discovered the novel indole ring-forming reaction shown in Scheme 27 and involving anionic cyclization onto an N-allyl unit. Engler can manipulate the reaction to afford benzofurans instead of indoles by simply changing the Lewis acid.11 Saegusa indole synthesis The cyclization of ortho-lithiated o-tolylisocyanides is a powerful indole synthesis discovered by Saegusa and co-workers in 1977 (Scheme 29). 3.1. 1045–1075 1051 .3. 3. Scheme 27 3. Chem.10 Wright indoline synthesis Wright and co-workers have developed an efficient synthesis of indoline-2.132 This new synthesis has been used to prepare a novel benzo[ f ]indole amino acid as a fluorescent probe.140 Scheme 26 Kita and colleagues have reported a synthesis of indoles closely related to the Engler synthesis. has now been successfully intercepted with carbon disulfide to furnish indoxyls and indoles (Scheme 30). Presumably. e. Scheme 28 indole nitrogen can be readily deprotected (Mg–MeOH) and further functionalized as desired (acylation.8 Engler indole synthesis In a series of papers rich in detail.138 The requisite isocyanide precursor was synthesized by a vicarious nucleophilic substitution (VNS) reaction as developed by Makosza.129 Kita’s variation involves the reaction of α-methylstyrene and phenyl vinyl sulfide with p-methoxy-N-tosylaniline under the influence of phenyliodonium bistrifluoroacetate.134 The known indoxyl dianion 26.137 The reaction is very general and has been exploited by Makosza and co-workers in a synthesis of 5-allyloxy-3-(4-tolylsulfonyl)-1H-indole for use in 1. 1.5. the result being that the alkyllithium used to generate the aryne is incorporated into the cyclized indoline at the C-4 position.g.3.136. 2000.141 The trapped indoxyl ketene dithioacetals 27 and 28 can be used in cycloaromatization reactions to make carbazoles.9 Bailey–Liebeskind indole synthesis Scheme 29 The elegant free-radical cyclization version of the Saegusa indole synthesis as developed by Fukuyama is presented in Section 7.6-tetrachloro-p-benzoquinone.131 The resulting indoline anion can be further treated with an electrophile and then oxidized with chloranil ‡ to the indole. Perkin Trans.2-dicarboxylates by the tandem bis-alkylation of o-bromomethyltrifluoroacetanilides 25 (Scheme 28). conditions that generate benzoquinone intermediates similar to the Engler intermediates.5-tetrahydrobenzo[cd]indole studies..4. 3. which is used to synthesize indigo. Engler and co-workers have described a new indole synthesis based on the Lewis acidpromoted reactions of enol ethers and styrenes with benzoquinone imines. Scheme 30 J.. Subsequent manipulation gives tetrahydroindoles such as 31 (Scheme 35). have improved the synthesis of 4.6-pentafluorophenethylamine and DDQ oxidation of the resulting 4.143 Scheme 34 Scheme 31 Sutherland has uncovered a novel indole ring formation involving DBU nucleophilic addition to an electron-deficient benzene ring and elimination of a nitro group from an intermediate Meisenheimer complex 30 (Scheme 32).142 Heating β.Filler et al.5.6. Scheme 37 4 Scheme 33 Electrophilic cyclization Arcadi and Rossi have published a very simple synthesis of 4. 1.148 and the reaction between bislithiated substituted methylnitriles and methylsulfones with oxalimidoyl chlorides provides 3-iminoindoles in one step (Scheme 37).146 This addition–elimination–cycloamination sequence was used to prepare a pyrrolosteroid from 17β-hydroxyandrost-4-en-3-one.5-dinitrobenzoate.3.147 1052 J.N-dimethylhydrazine to afford bicyclic perhydroindoles. an isoquinolone also forms depending on the initial site of attack by DBU.7-tetrafluoroindoline. Soc.6. 4. only N-tosylindoline was isolated (76%). new examples and applications of this indole ring-forming strategy continue to appear in the literature.144 In the case of methyl 3.7-tetrafluoroindole by the two-step reaction sequence of KF-induced cyclization of 2.5. Nevertheless.5.149 Scheme 36 Scheme 32 A novel use of sulfonium ylides has led to 2-substituted indoles (Scheme 33). As will be seen in Section 10. .2.. Chem. Scheme 35 A new indoline ring-forming reaction leads to the formation of N-(cyanoformyl)indoline (Scheme 36). Further examples of rhodium-catalyzed indole ring forming reactions are in Section 8. 1045–1075 Several of the numerous electrophilic cyclization routes to indoles have been available to synthetic organic chemists for 100 years or more. these tetrahydroindoles can usually be readily converted into indoles.4.5.6.150 Acid-catalyzed cyclization completes the synthesis (Scheme 38).β-difluorostyrenes bearing o-tosylamido groups with NaH leads to the corresponding 2-fluoroindoles by a presumed disfavored 5-endo-trig cyclization (Scheme 31). Perkin Trans.7-tetrahydroindoles by the nucleophilic addition of benzylamine or ammonia to pent-4-ynones (Scheme 34).145 In the case of the non-stabilized ylide (R = H). Kim and Fuchs have reported the reaction of cyclic epoxy ketones with N. 2000.1 Bischler indole synthesis Moody and Swann have described a modification of the Bischler synthesis wherein the intermediate α-(N-arylamino)ketones are prepared by a Rh-catalyzed insertion reaction. Both 2. to prepare 2-(2-azidoethyl)indole (Scheme 40).158 Scheme 38 4.3. Zard and co-workers have effected the Lewis acid induced cyclization of 2.3-b]quinolines in 39–70% yield.. Depending on the solvent.2 Nordlander indole synthesis Although no new examples of this modification of the Bischler indole synthesis were found per se. and indole is obtained in 55% yield.151 4.167 4. have employed the Sundberg indole synthesis. Molina et al.152 Another group has synthesized several 2.168 J.and 3-methylindole can be synthesized in good yields (70%.159 Thermolysis of 1-benzylpyrazole affords α-carboline as the major product.153 The presumed novel generation of nitrenes from o-nitrostilbenes using CO and Se leads to an efficient synthesis of 2-arylindoles (Scheme 39). the photolysis of 2-amino-2 azidobiphenyl yields small amounts of 4-aminocarbazole and 4.3 Hemetsberger indole synthesis The Hemetsberger indole synthesis is related to the Sundberg indole synthesis except that the azido group is on the side chain (i.161 4. Chem.163 The latter study includes a new preparation of the precursor α-azidocinnamates by azide ring opening of epoxides.e. Soc.4 Quéguiner azacarbazole synthesis Scheme 40 Quéguiner and co-workers have extended their short and efficient synthesis of azacarbazoles to the construction of α-substituted δ-carbolines (Scheme 43). 69%) from the corresponding o-nitrostyrenes.3 4.157 A very similar strategy to synthesize the alkaloids 33 and 34 was reported earlier by Timári et al.2-dimethoxyarylacetanilides to 3-aryloxindoles. 1045–1075 1053 .This research group has also used this methodology to synthesize the indole alkaloids cryptosanguinolentine (33) and cryptotackieine (34) from the common starting azide 32 (Scheme 41).3. We have used the Sundberg indole synthesis to synthesize the previously unknown 2-nitroindole from 2-(2-azidophenyl)nitroethylene in 54% yield.and 2-arylamino-3-(2-azidoethyl)quinolines to give the corresponding pyrrolo[2. α-azidocinnamate) rather than on the benzene ring. The Hemetsberger protocol has been used to synthesize the ABC rings of nodulisporic acid.. which involves the thermolysis of o-azidostyrenes and cyclization of the resulting nitrene to form indoles. 2000.10-dihydroazepino[2.166 Scheme 39 4.2-e]indole ring systems.154 The authors propose the formation of carbonyl selenide (COSe) which is the deoxygenation agent. amongst two non-indolic products.160 The reaction is proposed to involve a pyridylnitrene. Holzapfel and Dwyer have used this method to synthesize several carbazoles and norharman from the appropriate 2-nitrobiphenyls. 1. and also several 2-methoxycarbonylindoles from methyl o-nitrocinnamates.3.164 the thieno[3.3-b]indole.2-g]indole and thieno[3.2 Sundberg indole synthesis Scheme 42 Molina et al.2 -biindolyls by the deoxygenation–cyclization of the appropriate 2-(o-nitrostyryl)indoles.1 Nitrene cyclization Cadogan–Sundberg indole synthesis Scheme 41 This powerful indole ring formation method involves the deoxygenation of o-nitrostyrenes or o-nitrostilbenes with triethyl phosphite and cyclization of the resulting nitrene to form an indole.156 The lack of reactivity of the aliphatic azido group is noteworthy.165 and a precursor (35) to CC-1065 and related antitumor alkaloids (Scheme 42). have described a variation of the Hemetsberger synthesis involving the thermolysis of 2-alkyl. This indole synthesis has been used to prepare 2-methoxycarbonyl-6-cyanoindole 162 and 2-ethoxycarbonyl-3-methylindole. Perkin Trans.155. 182 Thus.170 Several new routes to o-aminophenylacetaldehyde derivatives have provided new indole ring syntheses. Noteworthy is that the methoxycarbonyl group is invariably lost under these conditions. 1. 2000.. Chem. A related Pummerer rearrangement leading to an indole intermediate was used by Fukuyama and Chen in an elegant synthesis of ( )-hapalindole G. which is normally performed with rhodium (cf. is cyclized to indole 39. Oxidative cleavage of the allyl side chain in aniline 36 affords indole 37. Section 8. Scheme 44 4.180 and a “cume” question par excellence! The mechanism of the previously known aromatization of cyclic p-quinomethanes to indoles has been investigated and extended to the synthesis of benzo[e]indoles.183 The authors propose an electrophilic mechanism by protonation of the diazo group and loss of N2. and the azetidin-2-ones 1054 J. by treatment with suitable nucleophiles.178 The authors propose the generation of a vinyl carbocation by opening of the furan ring and then cyclization to the more stable indole ring system.176 The N-acylindoles can be converted into esters.4-quinone followed by treatment with MsCl–Et3N gives 5-mesyl-3-benzylbenzo[e]indole in 58% yield.169 Oxidation of the 2-thioindolines with MCPBA furnishes the corresponding indoles (R1 = R2 = H. Scheme 47 A synthesis of psilocin revealed the interesting indole synthesis shown in Scheme 48 wherein 2. and aldehydes. a double transformation that leads to 41 (Scheme 49).5-dimethoxyfuran 38. 1045–1075 . the reaction of vinylmagnesium bromide with 2-benzylaminonaphtho-1.3-dihydro-2. An example is shown in Scheme 50. amides. Perkin Trans.181. The cyclization of diazoanilides to oxindoles. can also be accomplished with Nafion-H.2). prepared by Pd-catalyzed cross-coupling. used in a synthesis of ( )-desmethoxymitomycin A (Scheme 47).8 Miscellaneous electrophilic cyclizations Scheme 43 4.177 An unexpected rearrangement of 4-amino2-methylbenzofurans to 4-hydroxy-2-methylindoles under strongly acidic conditions was recently reported. Soc. presumably to a carbene intermediate. 100%).5 Iwao indole synthesis Iwao has published a new indole synthesis in which the ringforming step is a thermal sila-Pummerer rearrangement (Scheme 44).179.175 The use of 2-(2-aminophenyl)acetaldehyde dimethyl acetal to synthesize a series of N-acylindoles by acid-catalyzed cyclization has been described.172.6 Magnus indole synthesis Magnus and Mitchell have discovered that terminal triisopropylsilylprop-2-ynylanilines afford 3-methylindoles upon treatment with methanesulfonic acid (Scheme 45).173 The reaction is believed to involve a vinyl carbene which undergoes electrophilic cyclization to form an indole.4. but not ketones. Scheme 46 Ishikawa and co-workers have uncovered a remarkable twostep rearrangement while studying the Bischler–Napieralski reaction of 40.174 and a similar osmium tetroxide oxidative cyclization yields 1-acetyl5-methoxycarbonyl-7-chloro-4-methoxyindole (77%) from the corresponding o-allylacetanilide.7 Feldman indole synthesis Feldman and co-workers have found that phenyl(propynyl)iodonium triflate reacts with lithiated N-phenyl-p-toluenesulfonamide to afford indoles in one operation (Scheme 46).171 Scheme 48 Scheme 45 4. 1 o.197 The modified Reissert reaction. Chem.184 The ancient Sandmeyer isatin synthesis.6-methylenedioxyindole by the catalytic reduction of the corresponding o.185 A new entry to 1.204.198 Kraus and Selvakumar have employed the reductive cyclization of a nitro aldehyde to synthesize a tricyclic indole related to the pyrroloiminoquinone marine natural products. This modification was employed in the preparation of 7-acetoxy-6-methoxyindole and 4-acetoxy5-methoxyindole.6dihydroxyindole can be synthesized using the Zn-controlled conditions shown in Scheme 52.205 Scheme 53 Scheme 51 5 Reductive cyclization The reductive cyclization of o-nitrophenylacetic acids or esters leading to oxindoles has been employed by Williams and co-workers to prepare 6-hydroxy-7-methoxyoxindole in a synthesis of ( )-paraherquamide B. involving the reductive cyclization of o-nitrophenylpyruvic acid to indole-2-carboxylic acid.3 Leimgruber–Batcho indole synthesis Like the Fischer indole synthesis.170 The synthesis of 5.β-dinitrostyrene proceeds in 94% yield. and several new developments have been described in recent years. and the numerous variations of electrophilic cyclization to indoles. followed by reductive cyclization to an indole. and the Madelung cyclization and its modifications. Ochi and co-workers have used this protocol to prepare 6-bromo-5-methoxyindole for use in the synthesis of J. -Dinitrostyrene reductive cyclization Corey and co-workers 191 have used the Borchardt modification (Fe–HOAc–silica gel–tol–reflux) 192 of the reductive cyclization of o. which were used in syntheses of gastropod indolequinones.207 5. has been employed in a synthesis of the marine natural product convolutamydine A via 4.196 and by Sato en route to a series of tricyclic indole derivatives.6-tetrahydro-2H-indol-2-ones involves 5-endo-trig cyclization of a sulfoxide amide 42 in a Pummerer rearrangement (Scheme 51).193 Fukuyama and Chen have used this reductive cyclization to prepare a potential indole precursor to a synthesis of hapalindole G.203 Rawal and Kozmin have utilized a Reissert reaction in a synthesis of tabersonine that features an elegant construction of the requisite nitro ketone 44 using the new reagent o-nitrophenylphenyliodonium fluoride (NPIF) to join the o-nitrophenyl unit to silyl enol ether 43 (Scheme 54). Scheme 52 Scheme 49 5.199 Related synthetic targets have been attacked by Joule and co-workers and a reductive cyclization step (Scheme 53) was used in a synthesis of several of these alkaloids. Smith et al.5.. which involves the electrophilic cyclization of an α-isonitrosoacetanilide. 2000.6-dibromoisatin.5.7-dimethoxyindole in a total synthesis of aspidophytine.186 Padwa et al. has been adapted to solid-phase synthesis.206 and a similar reduction sequence yielded several chlorinated oxindoles and isatins. have developed elegant “domino Pummerer” cycloaddition 187 or cyclization 188 protocols to construct complex oxindoles.194 The very labile 5. involving the reductive cyclization of an o-nitrophenylacetaldehyde or o-nitrophenyl methyl ketone. 1045–1075 1055 .189. was used by Shin and co-workers to prepare a series of 2-ethoxycarbonyl-4-alkoxymethylindoles in a synthesis of fragment E of nosiheptide. have studied this cyclization to oxindoles as influenced by zeolite catalysts and they speculate that different carbenes are involved in the formation of oxindoles and azetidin-2-ones.195 All other conditions tried were unsatisfactory. Perkin Trans. The Leimgruber–Batcho indole synthesis involves the conversion of an o-nitrotoluene to a β-dialkylamino-o-nitrostyrene with dimethylformamide acetal. reductive cyclization of nitro aromatics is a powerful means of forming indoles.200–202 Zard and co-workers have used formamidinesulfinic acid as a reducing agent in the reductive cyclization of nitroketones to pyrroles and a tetrahydroindole. Soc.190 The classic Reissert indole synthesis. 1.2 Reissert indole synthesis Scheme 50 are minor products.β-dinitrostyrenes to prepare 6.4. 223.219 Remarkably. Shim.218 The selectivity observed in the nitro group reduction is noteworthy. 2000. indicating that the less hindered nitro group is reduced first.215 Scheme 57 5. Makosza has used this method to 1056 J.220.213 Prashad and co-workers have also used this tactic to construct 3-methoxycarbonylindoles by exposing the Leimgruber– Batcho enamine to phosgene and then methanol.140 of hydrogen to install the requisite side chain (usually acetonitrile) for reductive cyclization onto a nitro group. Chem.208 and Showalter et al. A related electrolytic cyclization of o-nitrophenethylamines gives N-aminoalkylindoles.and 6-nitroindoles.211 It has been used in a large-scale synthesis of 6bromoindole. and the related intramolecular cyclization of o-aminophenethyl alcohols to indoles.2-de]quinolines for use in the synthesis of the marine pyrroloiminoquinone alkaloids (Scheme 56). 6 6. Scheme 54 marine bromoindoles.221 This oxidative cyclization has also been used to prepare a wide range of substituted indoles from ringsubstituted (methyl. rather. Soc.1 Oxidative cyclization Watanabe indole synthesis The Watanabe indole synthesis is the metal-catalyzed indole synthesis from anilines and glycols. and co-workers have now extended this reaction to the synthesis of N-alkylindoles in yields up to 78% (N-methylindole) from the reaction of N-alkylanilines with triethanolamine and the catalyst RuCl2(PPh3)3. isopropyl. The similarity of this oxidative substitution of hydrogen to the VNS reaction is clear.210 and in a synthesis of arcyriacyanin A.217.7-tetrahydroindoles and pyrroles. 1045–1075 . which was reductively N-alkylated. Clark and co-workers have acylated this intermediate enamine to yield 45 which was converted to indole 46 after reductive cyclization (Scheme 55).222 Other catalysts have been studied in this reaction and CdBr2 3KBr is particularly effective. Subsequent amine carbonyl condensation yields the indole. prior to reductive cyclization.2 Knölker indole-carbazole synthesis Over the past several years Knölker and co-workers have parlayed the oxidative cyclization of tricarbonyliron–cyclohexadiene complexes into a remarkably versatile synthesis of The essence of the Makosza indole synthesis is the vicarious nucleophilic substitution (VNS) 139. imines are not involved in this reaction. oxidative nucleophilic substitution of hydrogen by the ketone enolate occurs. but. chloro. synthesized 6-amino-5-ethoxycarbonylindole and 6-amino-7-ethoxycarbonylindole from the appropriate o-nitrotoluenes. Thus. Watanabe.4 Makosza indole synthesis 6.. Perkin Trans.216 and to prepare several pyrrolo[4. dimethyl.3.224 The intramolecular version of this reaction occurs with an aluminium orthophosphate–Pd system 225 and also with tetrakis(triphenylphosphine)palladium (Scheme 57).5.214 An enamine dimer was also identified in this study. shorter reduction periods lead to the cyanoquinolone.209 The Leimgruber–Batcho method has been used to make C-4 substituted indoles for elaboration to conformationally-restricted analogs of indolmycin. dimethoxy) anilines. Scheme 56 Makosza has also described the condensation of m-nitroaniline with ketones under strongly basic conditions to form 4.227 Scheme 55 Coe and co-workers have interrupted the Leimgruber– Batcho sequence by converting the intermediate enamine to an o-nitrophenylacetaldehyde acetal. 1.synthesize a series of N-hydroxyindoles and indoles.6. and then cyclized with acid to give a series of 1-alkyl-6-methoxycarbonylindoles. or ethanolamines. methoxy.226 This method also furnishes 4.212 An important extension of this indole ring synthesis is the functionalization of the intermediate βdialkylamino-o-styrene. Scheme 60 Scheme 61 Scheme 58 This oxidative cyclization sequence has been applied to the synthesis of the 2.252 Curran and co-workers who also were pioneers in the development of tin-mediated 5-exo-trig cyclization to indolines.3..245 onto a linked dihydropyrrole ring leads also to a spirooxindole and a pyrrolidinoquinolone in a 7 : 3 ratio. Scheme 59 Patel and co-workers have improved upon this method by effecting a similar 5-exo-trig cyclization onto a tethered vinyl chloride (Scheme 60).235 hyellazole. 1045–1075 1057 .254.230 G and H.248 Jones and co-workers have reported a similar tin-mediated cyclization of o-bromoacryloylanilides leading to oxindoles. 2000.265 Others have used the Fukuyama synthesis to prepare 6hydroxyindole-3-acetic acid 266 and 3-(trimethylsilyl)methylindoles. Chem. has been used in concert with the Hemetsberger indole synthesis to prepare a duocarmycin model.7a-tetrahydroindole nucleus by two groups.260 Parsons and co-workers have presented a full account of his elegant tandem radical cyclization leading to lysergic acid derivatives 261 and to a pseudocopsinine model.237 4a.233 neocarazostatin B.259 The Boger cyclization.3-disubstituted indoles in good to excellent yields (Scheme 63). 1. especially.239 and furostifolin.249 This group has also described the radical cyclization onto a pyrrole ring leading either to spirooxindoles or to the martinelline core (pyrrolo[3.253 have described the fluorous and the microwavepromoted fluorous versions of this reaction. Recent synthetic successes in this arena include carazostatin.1 Tin-mediated cyclization Boger has been one of the pioneers in the development of tinmediated radical cyclization.231 A and B. and several new such methodologies have been invented in recent years for the construction of indoles.234 lavanduquinocin.264 and has been featured in syntheses of indolocarbazoles.228 carquinostatin A.250. a method which employs in situ N-silylation to bias the requisite conformation for cyclization.251 The tin-mediated cyclization Scheme 62 Fukuyama and co-workers have extended their indole radical cyclization chemistry to the use of o-alkenylthioanilides.9a-dihydro-9H-carbazoles.240 The key oxidation cyclization step can usually also be accomplished with active manganese dioxide or ferricenium hexafluorophosphate– sodium carbonate.263.indoles and.242 7 Radical cyclization As was true in the earlier review.255 Other 5-exotrig variations include the cyclization of 2-allyl thiocarbazones to hexahydroindoles.269 J.258 and cyclization of the o-bromo benzimidate of phenethylamine to N-benzoylindoline.166 Murphy and coworkers have reported the tin-induced cyclization of an orthoiodo tethered vinyl bromide leading. carbazoles. Soc.264 and total syntheses of (±)-vincadifformine and ( )-tabersonine.256 the cyclization of o-bromo α-cyanoanilines to spiroindoxyls.243–247 An example is depicted in Scheme 59.236.267 The latter paper describes both the tin-mediated and a thiol-mediated cyclization of an o-isocyanophenyl trimethylsilyl alkyne to indoles. Perkin Trans.3-dihydroindoles. 7. but in the case shown in Scheme 58 these reagents led to decomposition.238 indolo[2.229 carbazomycins C and D.263–265 This powerful methodology leads to 2-substituted indoles by a Stille palladium-cross coupling reaction of the intermediate 2-stannylindole.1 radical cyclization routes to indoles and indolines are very popular amongst synthetic chemists. notably in the area of CC-1065 and duocarmycin synthetic studies. to a tetrahydrocarbazole.3-b]carbazole (Scheme 58). apparently independently. after loss of HBr.257 cyclization of o-haloaryl allenylmethyl amines to afford 3-ethenyl-2.241.264 biindolyls. These substrates furnish 2.2-c]quinolone) (Scheme 61).232 carbazoquinocin C.3a.262 An exciting development in the area of radical cyclization is Fukuyama’s tin-mediated indole synthesis featuring the cyclization of o-isocyanostyrenes via an α-stannoimidoyl radical (Scheme 62). which uses a TEMPO radical trap.268 Fukuyama has also developed a phosphorus-initiated radical cyclization of thioanilides in the context of a synthesis of (±)-catharanthine. featuring a new source of nitrogen centered radicals. 1.N-diprenyl-2-iodoaniline (Scheme 66).260 but the method is particularly useful for the construction of the tetracyclic-indoline core of Aspidosperma alkaloids. for example.288–293 Mori 294.271 Scheme 67 Scheme 64 7.297–300 Two of the original examples are shown in Scheme 69 288. 2000..Scheme 63 Scheme 66 7. proper credit (I hope!) has been given to the several discoverers of this chemistry.1 Hegedus–Mori–Heck indole synthesis Scheme 65 7.280 the cyclization of α-xanthylanilides to oxindoles (Scheme 67). Soc.4 Miscellaneous radical cyclizations The application of the intramolecular Heck reaction to the synthesis of indoles. depending on the cyclization substrate.273.289 and Scheme 70.α.277 the electrochemical-induced cyclization of N-allyl-2-chloroacetanilides. These workers found that Pd effects the cyclization of either o-allylanilines or N-allyl-o-haloanilines to indoles under standard Heck conditions.301 such that.α-trichloroanilides to oxindoles.287 to indoles. 1045–1075 Larock and Babu have greatly improved upon the original Hegedus conditions for the cyclization of N-allyl-o-haloanilines and N-acryloyl-o-haloanilides.279 the thermal radical cyclization of α.3 Murphy indole-indoline synthesis Scheme 68 Murphy and co-workers have engineered an elegant new radical cyclization methodology involving “radical-polar crossover chemistry”.275 This methodology has been extended to the use of polymersupported TTF reagents. These include Mn() cyclization of α-thioamides.295 and Heck.259 the tris(trimethylsilyl)silane-induced cyclization onto an alkene and the radical so-formed onto an azide. was apparently discovered independently by Hegedus.290 Several newer means to effect a radical cyclization leading to indoles or indolines have recently appeared in the literature. the . Perkin Trans.260.291 Hegedus was also the first to report the CO insertion version of this Pd-catalyzed cyclization reaction leading to indoline-2-acetic acid derivatives.1.281 the tris(trimethylsilyl)silane-induced cyclization onto the nitrogen of an imidate ester.1 Metal-catalyzed indole synthesis Palladium Scheme 69 Scheme 70 The use of palladium in indole and indoline ring synthesis has 1058 J.284 and the thiol-triggered cyclization of o-alkynylanilines 285 and o-alkynylphenyl azides 286.2 Samarium-mediated cyclization Samarium iodide has been used with o-iodoaniline derivatives to synthesize spirooxindoles. with a TEMPO trap. 8.1 More importantly.282 the NBS-triggered cyclization of lactam m-cyclophanes to yield tricyclic indoles (Scheme 68). Chem. indolines (Scheme 64).296 although Hegedus was the first in print. oxindoles and indolines. which uses tetrathiafulvalene (TTF) or sodium iodide to mediate the 5-exo-trig cyclization to indolines or indoles.283 the Mn()-induced coupling of ethyl α-nitroacetate with 2-aminonaphthoquinones to furnish benzoindoloquinones.272–275 A simple indole example is shown in Scheme 65.276 received such extraordinary attention that this section has been further subdivided from those divisions in the earlier review.278 the Grignard-induced cyclization of N. 8 8.270 and. These novel reactions would seem to offer enormous promise for future development and applications in synthesis. 320 and. including applications to the synthesis of CC-1065 precursors.331 and to 2-benzyloxycarbonyl-4-hydroxymethyl-3-methylindoles from a 2-(o-iodoanilino) unsaturated ester. Scheme 74 Scheme 71 Numerous examples of the Hegedus–Mori–Heck indole synthesis have been described.317 and oxindoles 318 has been adapted to the solid phase. 2000.332 A nice variation on this theme utilizes the in situ preparation of o-iodoanilino enamines (Scheme 77). it has long been known that 2-(o-bromoanilino) enones undergo the intramolecular Heck reaction to form 3-acylindoles.315 Grigg and co-workers have described a series of Pd-catalyzed cyclizations leading to indoles.329 This cyclization has been applied to the synthesis of 3-ethoxycarbonyl-2-trifluoromethylindoles from the appropriate o-haloanilino vinylogous carbamates 330..322 cyclization protocols to yield 3-spiroindolines. 1045–1075 1059 . via a spectacular bis-Pd-catalyzed cyclization (Scheme 74). and oxindoles. Larock and co-workers have extended this Pd-mediated cyclization in other ways.333 Scheme 76 Scheme 73 The Pd-catalyzed synthesis of indoles 316. Perkin Trans.1. with shorter reaction time and less catalyst to give 3-methylindole in 97% yield.reaction shown in Scheme 70 can be performed at lower temperature.324 and cyclization–anion capture sequences to construct various indoles (Scheme 75).and 7-methylindole featuring a new ortho-vinylation of anilines with SnCl4– Bu3N.313 7-bromoindoles related to sumatriptan (Scheme 73).327 Likewise.3. 1.311 3-siloxyindoles.323. and new fluorinated phosphine palladium complexes in supercritical carbon dioxide have been invented for these reactions. and they have used this to synthesize 4. including the reaction of o-haloanilines with vinyl halides or triflates and CO to produce 3-spiro-2-oxindoles. for total syntheses of chimonanthine and calycanthine.328 A recent example of this version of the Hegedus–Mori–Heck indole synthesis is shown in Scheme 76.319 Overman and co-workers have utilized the oxindole version of this reaction in the course of total syntheses of the Calabar bean alkaloids physostigmine and physovenine.310 indole-3-pyruvic acid oxime ethers. Chem.309 indole-3-acetic acids.314 and a total synthesis of the alkaloid gelsemine.and 6-hydroxyindoles.325.312 δ-carbolines from the cyclization onto a cyano group (Scheme 72).321 Scheme 77 J. indolines. Soc.302–305 notably involving the cross-coupling of o-allylic and o-vinylic anilides with vinyl halides and triflates to produce 2-vinylindolines 303–305 (Scheme 71).305 The related “Larock indole synthesis” is presented in Section 8.326 Scheme 75 Scheme 72 Rawal and co-workers have reported that the Pd-catalyzed cyclization of N-(2-bromoallyl)anilines affords indoles.306–308 5-methyl. The prototypical reaction is shown in Scheme 79.345 oxygenated indoles. Chem.335 This cyclization has been used in the synthesis of biscarbazoles. This reaction is also related to the copper-promoted Castro indole synthesis (Section 8.1).349 A carbonylation variation provides 3-acylindoles. Two examples of this cascade process are shown in Schemes 83 360 and 84. For example. 1.350 and 3-aryl2-unsubstituted indoles 351 and 3-allylindoles 352 are readily crafted using Pd-catalyzed coupling. Perkin Trans. contributions in this general area of indole ring construction.2 Yamanaka–Sakamoto indole synthesis The Yamanaka–Sakamoto indole synthesis has been used in a synthesis of carazostatin. 1045–1075 .1.356 2-dienylindoles.342 The cyclization is either spontaneous or involves Pd mediation. these workers reported that copper is beneficial to the overall reaction (Scheme 80).339 (±)-carquinostatin A.337 carbazomycins G and H. Although the Yamanaka–Sakamoto indole synthesis does not necessarily involve Pd in the indole ring-forming step.344 and this combination of catalysts has been used to effect a synthesis of 7-substituted indoles.334 Recently.347 and 3-alkenylindoles by an in situ Heck reaction..51 kinamycin analogs.348 The power of this indole ring synthesis has not gone unnoticed.353 the solid-phase syntheses of 2.3-disubstituted indole6-carboxylic acids. The Yamanaka–Sakamoto indole synthesis 298 features a Pdcatalyzed coupling of a terminal alkyne with an o-haloaniline to afford an o-alkynylaniline derivative which then readily cyclizes with base to yield an indole. This cyclization can also be effected with fluoride. 2000.338 carbazoquinocin C.354 and 3-substituted indoles 355 and 2. followed by cyclization.340 and 8.357 and biindolyls 358.343 Scheme 82 Grigg and co-workers have extended this methodology to cyclization reactions of o-iodo-N-alkynylanilines leading to polycyclic indoles.346 3-methoxycarbonylindoles by CO carbonylation.361 Scheme 79 In subsequent papers.10dimethoxyellipticine.359 (Scheme 82). vinyl triflates react with o-aminophenylacetylene to afford 2-substituted indoles in excellent yield (Scheme 81). Soc.341 The final cyclization involves a diaryl amine precursor. this research group has extended this reaction to additional examples (Scheme 78). and Cacchi and co-workers have made outstanding Scheme 83 Scheme 80 Scheme 84 1060 J.More than 20 years ago Åkermark and co-workers first reported that 2-anilino-p-benzoquinones are cyclized to carbazolequinones with Pd(OAc)2.359 the latter of which utilizes the Cacchi variation.5. it is included in this section in view of its close similarity to both the Hegedus–Mori–Heck and the Larock indole syntheses.336. Scheme 81 Scheme 78 8. 386 Indole 48.366 pyrrolo[3.382 and 1-sulfonyl-1. was readily synthesized using a Pd-mediated cyclization of 47 (Scheme 90).2.391. Perkin Trans. Examples of allenes and alkenes functioning in this manner are also cited in this section.363 Scheme 89 7-azaindolinones following ozonolysis of the initially formed exo-methyleneindoline.376 and some alkenes.377–379 For example. including asymmetric synthesis (Scheme 89).375.4 Scheme 85 Buchwald indoline synthesis The Larock indole synthesis with internal alkynes has been used to synthesize 5-azaindoles. 6-.368a isoindolo[2.387 Scheme 86 The Larock method has been applied to solid-phase synthesis.384 8. 1045–1075 1061 .1.380.372–374 terminal alkynes.369 tetrahydroindoles.394 A related cyclization of o-aminophenethyl alcohol was cited earlier. Chem. 2000.378 Scheme 90 This intramolecular Pd-catalyzed amination is applicable to the synthesis of N-substituted optically active indolines.376 including chiral examples (Scheme 87).363 refers to the intermolecular Pd-catalyzed reaction of o-haloanilines and alkynes (usually internal) to give indoles in one operation.393.2-c]quinolines.394 both for simple indoles (Scheme 92) 393 and fused indoles (Scheme 93). An example is shown in Scheme 85.365 7-azaindoles (Scheme 86).364 5-.8. which has been used in the total syntheses of the marine alkaloids makaluvamine C and damirones A and B.388 and o-bromobenzylic bromides can be employed in this indole ring synthesis (Scheme 91).226 J. Soc.3-dienes in the Larock methodology lead to 2-vinylindolines.389 Recently.5 Miscellaneous Scheme 88 Larock has also utilized allenes to craft 3-methyleneindolines. The indole ring can be easily fashioned by the Pd-catalyzed cyclization of o-nitrostyrenes.368b 5(triazolylmethyl)tryptamine analogs..367 pyrrolo[3. this last combination was used to synthesize indole-3-acetic acid (Scheme 88).392 Söderberg and co-workers have developed this “reductive N-heteroannulation” reaction into a very attractive and general indole ring synthesis. Yang and Buchwald have described improvements in this methodology.390 Scheme 87 Scheme 91 8. and 7-azaindoles.1.383 1-Oxygenated dienes also work well.371 Buchwald has parlayed a powerful aryl amination technology 385 into a simple and versatile indoline synthesis.370 and N-(2-pyridyl)indoles.1-ij ]quinolines.1-a]indoles. 1.3 Larock indole synthesis The Larock indole synthesis 362.381 Allenes in this Pd-catalyzed indole synthesis variation lead to Several examples of Pd-mediated cyclization leading to indoles or indolines do not fit into the previous categories and are presented here.1. 2-disubstituted mitosene 49 (Scheme 95).3.3diphenylindole in 90% yield. 1.395 8.400 and Rh() also catalyzes the carbenoid insertion into a C–H bond of a pyrrolidine leading to 1.413 flavopereirine and other indolo[2. 1045–1075 An improvement over the original procedure is the so-called “instant” method utilizing TiCl3–Zn. Witulski has reported a very general Rh-catalyzed aromatic ring-forming reaction with alkynes leading to indolines (Scheme 97).396–399 Notably.413. and co-workers have made several important contributions in this area. and these newer conditions have been employed to synthesize a variety of bi-. Chem.412 camalexin.1 Titanium Fürstner indole synthesis Scheme 94 The use of chiral α-diazocarbonyl compounds in this process preserves the optical activity in furnishing N-substituted oxindoles. ter-.414 and secofascaplysin.3-a]quinolizine alkaloids. Soc. Perkin Trans.411 Fürstner et al.410 8.2 Rhodium and ruthenium azobenzene reacts with diphenylacetylene to give N-anilino-2.406. the use of a perfluorinated carboxamide ligand on the rhodium catalyst decidedly promotes attack on the aromatic ring rather than leading to a β-lactam or other products.7tetrasubstituted indolines in good to excellent yields.3 8.416 Scheme 98 Scheme 95 The Rh-catalyzed hydroformylation of functionalized anilines leads to tryptophanols and tryptamines (Scheme 96). 2000.415 including highly strained examples (2.408 This [2 2 2] cycloaddition provides 4.404 The Rh-catalyzed carbonylation of o-alkynylanilines yields oxindoles.409 and a 3-enylalkynylindole to a carbazole in low yield.Scheme 92 Scheme 96 Scheme 93 Yang has reported the Pd-induced cyclization of an arylbromide to a pendant cyano group leading to γ-carbolines and related compounds.2 Miscellaneous Mori and co-workers have continued their use of Ti–nitrogen . The rhodium()-catalyzed decomposition of α-diazocarbonyl compounds to yield oxindoles is an important synthetic operation. indoles 50 and 51 can be easily assembled using this Ti-induced “zipper reaction”. Padwa..417 For example.5. under these conditions 1062 J. and Moody.398 Scheme 97 A ruthenium catalyst converts o-alkylbenzonitriles to indoles. This reaction is a key step (Scheme 94) in a synthesis of the marine alkaloid convolutamydine C by Moody and co-workers. It is also particularly useful for the preparation of 2-arylindoles.414 The reaction is general for simple indoles (Scheme 98).401–403 This cyclization is also effected by chiral bis(oxazoline)copper() catalysts to give some enantioselectivity. has been discovered that converts azobenzenes into N-anilinoindoles.3-di-tert-butyl-1-methylindole 412). have revealed the enormous power and versatility of this coupling reaction.407 For example. using Wilkinson’s catalyst. 8. and quaterindoles (Scheme 99). The Fürstner indole synthesis is the Ti-induced reductive cyclization of oxo amides leading to an indole ring. illustrated by total syntheses of the indole alkaloids ( )-aristoteline.6.405 and a Rh-catalyzed process.3. 387 Scheme 103 8.433 In some cases the Castro cyclization of o-alkynylanilines succeeds where the Larock method of Pd-catalyzed coupling of o-iodoaniline with an alkyne fails. other indole ring-forming reactions prompted this separate section.428b The reaction of o-ethynyltrifluoroacetanilide with Cu(OAc)2 yields both indole and 2-alkynylindoles resulting from alkyne coupling and mono-cyclization. this method has been used to make carbazoles (Scheme 104) 45 and carbazole quinone alkaloids. involving intramolecular alkene insertion into a zirconium-stabilized aryne complex and subsequent oxidation.418.421 8.6-g]indole. 1.420 and Cha and co-workers have utilized an intramolecular Ti-coupling procedure to construct mitomycin indole analogs from o-imidostyrenes. both of which are illustrated in Scheme 102.424–427 Their early contributions to this field are often overlooked.437 Copper() has been used in a modified intramolecular Goldberg amide arylation to forge several β-carbolines.306.436 More recently. were the first to discover the metal-catalyzed cyclization of o-alkynylanilines to indoles using copper. Chem.423 and dehydrobufotenine.1 Scheme 99 Castro indole synthesis Castro et al. Soc.422 tryptophans and serotonin analogs (Scheme 101).5.7-difluoro.307 8.6.435.5 Copper Although copper has played a role in earlier indole ring synthesis (vide supra). has been used by Buchwald and co-workers to prepare 3.429 a series of 5. Perkin Trans.4-disubstituted indoles. 8.2 Miscellaneous Scheme 101 Early uses of copper() in combination with NaH to effect the cyclization of o-halogenated β-cyano.5.2dialkyl-5-nitroindoles.430 5.7-disubstituted indoles and pyrroloindoles.359 The Buchwald indole-indoline ring synthesis. 1045–1075 1063 .7-trifluoroindole.428 an indolo[7. but Castro’s discoveries include the copper acetylide coupling with o-iodoanilines and the CuI-induced cyclization of o-alkynylanilines to yield indoles.419 Scheme 102 Scheme 100 The low-valent titanium reductive cyclization of aryl isothiocyanates to afford indole-2-carbothioamides has been described.4 Zirconium The Castro indole synthesis has been used to prepare 5azaindoles.and β-oxoenamines to indoles were discovered by Kametani 434 and Suzuki. complexes (nitrogen fixation) in pyrrole ring formation leading to tetrahydroindoles (Scheme 100).and 5.364 a 2-(benzotriazolylmethyl)indole.438 and we have already cited the use of CuOTf to promote the decomposition of α-diazo carbonyl compounds and C–H bond J..Tietze and Grote have employed this intramolecular insertion reaction of zirconocene-stabilized aryne complexes to synthesize the indoline portion of the CC-1065 pharmacophore. 2000.432 and α-C-mannosylindole 52 (Scheme 103).431 1. Scheme 107 Scheme 104 insertion leading ultimately to tricyclic indoles. Soc.453 Photocyclization routes to indoline spirolactones.6 Chromium 9.and β-carbolinones.456 and spirolactams 456 have also been developed.190. have found that substituted indoles are formed from anilino-substituted Fischer chromium carbenes having o-alkenyl substituents on the benzene ring (Scheme 107).448 Scheme 105 Barluenga et al.341 fluorocarbazoles.440 Scheme 110 Scheme 106 Intramolecular Diels–Alder reactions of pyrazin-2(1H)ones.442 Rahm and Wulff have described the Cr-induced cyclization of amine-tethered bisalkyne carbene complexes leading to 5-hydroxyindolines (Scheme 108).439 Scheme 108 Scheme 109 9 9..and intramolecular Diels–Alder reactions of 2-substituted aminofurans to effect the syntheses of indolines and indoles. Chem.441 The related cyclization of o-alkynylanilino chromium carbene complexes leads to indol-3-ylketene complexes by a tandem alkyne insertion–carbonylation sequence.454 spiroimides.455.7 Molybdenum The well-established Chapman photocyclization of N-arylenamines to indolines 451 has been used in the synthesis of 8.3-disubstituted indoles (Scheme 106).456 McDonald and Chatterjee have discovered the molybdenumpromoted cyclization of 2-ethynylanilines to indoles (Scheme 109).443 8.329 and hexahydrocarbazolones. 1045–1075 .444 1064 J.452 azatetrahydrocarbazolones.2.442 Benzocarbazoles and other fused indoles were prepared using this methodology. indoline 53 was crafted in this fashion and then used to synthesize the alkaloid oxoassoanine (Scheme 110). with an o-alkynylanilino side chain.1 Cycloaddition and electrocyclization Diels–Alder cycloaddition Padwa and co-workers have used inter. 2000. Perkin Trans. Söderberg et al.450 9.445–449 For example.401–403 A nice variation of this latter reaction leads to the indole ring directly from acylenamines and methyl diazoacetate (Scheme 105). have been employed to access α. have reported a novel copper-promoted carbometalation of o-bromo-N-(2-bromoallyl)anilines leading to 2-substituted or 2.10-dimethoxyellipticine.2 Photocyclization Chapman photocyclization 8. An example of the latter transformation is 54 to 55.1 Chromium is a new entrée to the indole ring synthesis arena. Chromium removal and hydrolysis furnishes indole-3-acetic acids. 1. 1 Scheme 113 Ishar and Kumar have described 1.1 Indoles from pyrroles Electrophilic cyclization Natsume indole synthesis 10.458. 2000.473 as well as to the syntheses of several of these marine alkaloids.3dipolar cycloaddition of an N-methyloxazolium species to an alkyne giving rise to indoloquinones.457 and the photolysis of the benzotriazolyladamantane 56 leads to oxindole 57 after hydrolysis (Scheme 111).. has been used to construct the indole J.465 A münchnone generation and intramolecular cycloaddition protocol by Martinelli and co-workers leads to 4-oxo-4.462.461 Scheme 114 9. Above this temperature tetrameric indole 60 forms in high yield (Scheme 112). 1.459 This reaction. the result of a novel sequence of molecular reorganizations (Scheme 114).7-tetrahydroindoles (Scheme 113).2 Miscellaneous photochemical reactions The photolysis of o-alkynyltelluroimidates yields 3-acylindoles. This synthetic strategy. Chem. Soc.3-b]quinolines. Scheme 115 Cava and co-workers discovered the surprising cyclization shown in Scheme 116 en route to the preparation of a wakayin model system.3 Dipolar cycloaddition Vedejs and Monahan have reported the intramolecular 1.1. Scheme 112 Giese has observed that o-acylaniline derivatives undergo photocyclization to 3-hydroxyindolines.9.472 The N-methyl group was necessary for a successful reaction.5.4 Scheme 111 Miscellaneous Photolysis of α-diazo ketone 58 affords indolylketene 59 which is only stable below 58 K.2.6. 1045–1075 1065 . which was first discovered by Wender and Cooper.3-dipolar cycloadditions between allenic esters and nitrones to yield benzo[b]indolizines.468 Natsume and co-workers have adapted their indole synthesis to the preparation of herbindole and trikentrin model compounds.460 has been employed in a total synthesis of gelsemine.469–471 including fused indoles such as benzocarbazoles (Scheme 115) 470 and indolo[2.467 Scheme 116 10 10. as the NH compound failed to undergo formation of the pyrrole ring.471 These reactions appear to involve a stepwise biradical alternative mechanism to the concerted Myers–Saito cycloaromatization pathway. Perkin Trans.464 9.474 This latter study established the absolute configuration of these indole alkaloids.463 The biradical cyclization of enyne-ketenimines and enynecarbodiimides is a powerful route to nitrogen heterocycles.466. which involves electrophilic cyclization to C-2 or C-3 of a suitably tethered pyrrole substrate. and several new examples of this .495 and 7-azaindoles are fashioned in one-pot by the annulation of 2-aminopyrroles with the enolates of 3. 1.477 and Katritzky et al.5. have developed an alternative route to the Natsume cyclization substrates using the lithiation of 2-benzotriazolylmethylpyrroles followed by reaction with α.2 Scheme 118 Palladium-catalyzed cyclization Palladium has been employed in a synthesis of duocarmycin SA as illustrated in Scheme 122.7-tetrahydroindole which was employed in Pd-catalyzed cross-coupling reactions.6. initiated by the reaction of ethyl pyrrole-2-carboxylate and succinic anhydride (Scheme 118).492 and 1-benzyl-3-phenylindole and related indoles. Perkin Trans. and DDQ oxidation (Scheme 120).476 Scheme 119 Scheme 117 2-alkoxycarbonyl-3-hydroxyindoles that involves a Diels–Alder cycloaddition.485.6. 2000.491 4. the reaction of γ-valerolactone and N-methylpyrrole with AlCl3 affords 1.494 The Natsume protocol has been used to synthesize (S)-( )pindolol and chuangxinmycin. pyrrole ring formation from the tricarbonyl cycloadduct 61..7-tetrahydroindole in 65% yield.5.497.481 10.5.6.3 10. including the synthesis of 6-aminomethyl derivatives 487 and the enol triflate of N-tosyl-4-oxo4.4dimethyl-7-oxo-4.2 Miscellaneous Murakami and co-workers have described an electrophilic cyclization route to 7-oxo-4.482 Another route to oxotetrahydroindoles involves the Friedel–Crafts acylation of N-methylpyrrole with lactones.1.493 Wasserman and Blum have reported a general synthesis of 1066 J.6.1 Cycloaddition routes From vinylpyrroles The Diels–Alder cycloaddition of 2. Other routes to 4-oxo-4.496 Scheme 121 10.483 For example.7-tetrahydroindoles have been described. Chem. Natsume and co-workers have synthesized ( )-duocarmycin SA using his indole ring synthesis. Soc.7-tetrahydroindole. 1045–1075 Scheme 122 10.3dimethoxy-2-formylpropanenitrile and ethyl 3.486 which were used to prepare indolequinones.498 4-Oxotetrahydroindoles are important indole precursors and Edstrom and Yu have employed these intermediates in concise syntheses of 5-azaindole analogs 484 and 3-substituted 4-hydroxyindoles.483 Scheme 120 The interesting rearrangement of nicotine pyrrole 62 to 1-methylindole-7-carbaldehyde has been uncovered (Scheme 121).3-diethoxy-2formylpropanoate.5.ring in hapalindole O 475 and in mitosene analogs related to FR 900482 and FR 66979.490 7-chloroindoles.5.3.489 novel fused indoles as potential dopamine receptor agonists.6.488 Other electrophilic cyclization methodologies for converting pyrroles to indoles have been reported for the synthesis of 6-azaindoles.and 3-vinylpyrroles is an attractive route to indoles.7-tetrasubstituted and related indoles (Scheme 119).476 The method is particularly effective for the preparation of 4-hydroxyindoles (Scheme 117).478–480 Recently.β-unsaturated aldehydes and ketones. respectively.509 The thermolysis of N-alkyl-N-vinylprop-2-ynylamines provides 7-oxo-4. reported in the last review. this group has extended this methodology to an efficient synthesis of 2-substituted indoles by the arynic cyclization of halogenated aryl imines (Scheme 129). have discovered a novel “domino hydroamination aryne cyclization reaction” to give N-aryl indolines from o-chlorostyrenes in good yields (Scheme 130).3-quinodimethanes.6.7-tetrahydroindoles involving the radical cyclization of an iodoalkyl-tethered pyrrole (Scheme 127) 511 and a 2-alkenyl-tethered 3-iodopyrrole have been elaborated.3.4 Radical cyclization An approach to the alkaloid martinelline utilizes an indiumcatalyzed Diels–Alder reaction between aryl imines and N-acyl2. which may involve a pyrrole intermediate.513 Scheme 128 Scheme 124 11.3.3-quinodimethanes New routes to 4.1 Aryne intermediates Aryne Diels–Alder cycloaddition The ergot model 63 was obtained in essentially quantitative yield via the intramolecular aryne cycloaddition reaction shown in Scheme 128.506 10. has been extended to a general synthesis of these compounds (Scheme 124).515 Beller et al.5.and 3-vinyl-1-(phenylsulfonyl)pyrroles and examined their Diels–Alder chemistry. Soc.512 The synthesis of 3-nitroindoles via the electrocyclization of nitropyrrole-2. Chem.505 and photolysis of thiobenzamide and 3-furylpropenal.strategy have been reported in recent years.501 studies that suggest the existence of two competitive mechanisms depending on the solvent: an asynchronous concerted mechanism and a stepwise mechanism (Michael addition reaction). have presented theoretical studies of the reactions of 1-methyl2-vinylpyrroles with dimethyl acetylenedicarboxylate. Perkin Trans.6. a similar cycloaddition reaction with N-methylpyrrole gives 5.504 Photolysis of 2-styrylpyrroles affords indoles. 1045–1075 1067 .500.514 More recently. J.3-dihydropyrroles.2 From pyrrole-2. 1.5-dicyanopyridazine with indole or N-methylindole affords the corresponding 2.508 However. 2000.4-diene reacts with anilines in the presence of fluoride to yield pyrroloquinoline derivatives (Scheme 125).6-dicyano-1-methylindole in only 15–17% yield. Perfluoro3.499 Domingo et al.7-tetrahydroindoles in good yield (Scheme 126). affords benzo[g]indoles.502.503 Scheme 125 Scheme 126 Scheme 123 10.3-dicyanocarbazoles in 59% and 53% yields.507 Scheme 127 11 11.. Ketcha and Xiao have synthesized 2.3 Miscellaneous The sealed-tube reaction of 4.510 Nucleophilic cyclization of arynes Caubère and co-workers have described in full their synthesis of tetrahydrocarbazoles and other indoles using the complex base NaNH2–t-BuONa to generate the requisite arynes for cyclization.2 10.516 This method is superior to previous cyclizations of 2-(2-chlorophenyl)ethylamines.5.4-dimethylhexa-2. Harman and co-workers have developed an indole synthesis from Diels–Alder reactions of pentaammineosmiumpyrrole complexes (Scheme 123). and bromine affords. 1045–1075 Scheme 134 Ciufolini et al.517 12 12. Perkin Trans. the corresponding isatin (Scheme 132).2-dicarboximides leads to 2-acyl.525 and isatins are converted into oxindoles with hydrazine. N-alkylformanilides and POCl3 yield the indolo[3. exposure of formanilides sequentially to oxalyl chloride. Barluenga and co-workers have found that the treatment of N-(2-bromoallyl)-N-methyl-2-fluoroaniline with tert-butyllithium gives 1. which was used to prepare the RNA-binding fluorochrome Fluoro Nissl Green.529 and flash vacuum pyrolysis of 1-phenyl-4-methoxycarbonyl-1.2 -biindolyls. Sakamoto and co-workers have used a tandem Wittig–Cope reaction sequence on 2-allylindoxyls to prepare 3-substituted indoles (Scheme 18).532–534 Under slightly different conditions. Williams and co-workers have employed the combination of NaBH4 and BF3 OEt2 to reduce an oxindole to an indole in their synthesis of ( )-paraherquamide B. general method for this oxidation reaction.518 The generality of this conversion remains to be seen. have used the cyclization of 2-amino-2.519 and Giethlen and Schaus have investigated the mechanism of the oxidation of indolines with potassium nitrosodisulfonate (Frémy’s salt) to furnish either indoles or 5-hydroxyindoles.523 The chloroalkylidene oxindoles can also be easily transformed into 3-alkynylindoles. Quenching this intermediate with suitable electrophiles affords the 4-functionalized indoles. there has never been an efficient.522 and Beccalli and Marchesini have synthesized 3-acyl-2-vinylindoles from chloroalkylidene oxindoles 1068 J. after hydrolysis.2-dihydrocinnoline-1.3dihydrobenzoquinone monoketals to obtain fused indolines after appropriate manipulation.2.and 3-ethoxycarbonyl-1. Carter and Van Vranken have observed the photooxidation of 2-indol2-ylindolines to 2.3-dihydroindoles) are an obvious vehicle for the synthesis of indoles.539 Studies by Paz and Hopkins .524 The reduction of N-acylisatins to N-alkylindoles proceeds excellently with diborane. Black and Rezaie have coupled oxindoles with benzofurans using triflic anhydride to give 2indolylbenzofurans.534 Scheme 132 Scheme 133 An unusual cyanide-induced skeletal rearrangement of 3acyl.2-b]quinolines (Scheme 133). 2000. Ketcha et al. Soc.532–534 Thus.9).1 Miscellaneous indole syntheses Oxidation of indolines Although indolines (2.520 It was determined by isolation that an intermediate iminoquinone forms in this reaction.536–538 Scheme 131 12. a few new methods to address this problem have been described in recent years. 1.Scheme 129 using a Stille reaction on the corresponding indolyl-2triflates.535 a reaction based on similar rearrangements discovered earlier.526 Merlic and co-workers have effected a Friedlander quinoline synthesis on an N-acylindoxyl to afford a quindoline. Hünig’s base.3-dimethyl-4-lithioindole by intramolecular aryne cyclization. However. isatins..6). isatins and indoxyls Since we have included in this review the synthesis of oxindoles. Chem. have utilized Mn() in the oxidation of 2-methyl1-(phenylsulfonyl)indolines to the corresponding 2-acetoxymethylindoles (Scheme 131).102 Earlier work showed that Wittig reactions of indoxyls that cannot undergo a Cope reaction afford 3substituted indoles.3 Miscellaneous Scheme 130 In chemistry similar to the Bailey–Liebeskind indole synthesis (Section 3.530 Treatment of N-(methyl)anthranilic acids with the Vilsmeier reagent (POCl3–DMF) leads to 3-chloroindole-2-carbaldehydes. The use of catalytic tetra-n-propylammonium perruthenate in the presence of N-methylmorpholine N-oxide is reported by Goti and Romani to oxidize indoline to indole in 73% yield. and indoxyls.527 As mentioned earlier (Section 2.206 Other reduction methods were unsuccessful.521 The thermolysis (900 C) of N-(2-acetoxyethyl)acetanilide yields many products including some indole.531 Meth-Cohn has uncovered interesting chemistry when Vilsmeier reagents are generated under basic conditions.and 2-ethoxycarbonyl-3-cyanoindoles (Scheme 134).528 12.3triazole affords a small amount of 3-methoxycarbonylindole via an imino carbene intermediate. it seems appropriate to cite newer methods and applications for the conversion of these compounds to indoles.2 From oxindoles. 551 Scheme 137 13 Acknowledgements The author wishes to thank Professor Phil Crews and his colleagues and students at the University of California. W. Griffin. R.. 6621. D. H. 1998. 29. M. Davey. A. Kim. 12577. Naito. 8853. J. R. 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