《杂环合成》（英文版）Recent developments in indole ring synthesis—methodology and applications

Recent developments in indole ring synthesis--methodology and applications Gordon w. gribble Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA Received (in Cambridge, Uk)14th December 1999 Covering: 1994-1999. Previous review: Contemp. Org. Synth, 1994, 1, 145 1 Introduction 8.1 Palladium 2 Sigmatropic rearrangements 8.1.1 Hegedus-Mori-Heck indole synthesis 2.1 Fischer indole synthesis 8.1.2 Yamanaka-Sakamoto indole synthesis 2.1.1 Methodology 8.1.3 Larock indole synthesis 2.1.2 Applications 8.1.4 Buchwald indoline synthesis 2.1.3 Mechanism 8. 1.5 Miscellaneous 2.2 Gassman indole synthesis 8.2 Rhodium and ruthenium 2.3 Bartoli indole synthesis 8.3 Titanium 8.3.1 Furstner indole synthesis 2.5 Julia indole synthesis 8.3.2 Miscellaneous Miscellaneous sigmatropic rearrangements 8.4 Zirconium Nucleophilic cyclization 3.1 Madelung indole 8.5.1 Castro indole synthesis 3.2 Schmid indole synthesis 8.5.2 Miscellaneous 3.3 Wender indole synthesis 8. 6 Chromium 3.4 Couture indole synthe 8.7 Molybdenum 3.5 Smith indole synthesis 9 Cycloaddition and electrocyclization 3.6 Kihara indole synthesis 9.1 Diels-Alder cycloaddition 3.7 Nenitzescu indole synthesis 9.2 Photocyclization 3.8 Engler indole synthesis 9.2.1 Chapman photocyclization e s 9.2.2 Miscellaneous photochemical re 3.10 Wright indoline synthesis 9.3 Dipolar cycloaddition 3.11 Saegusa indole synthesis 9. 4 Miscellaneous 3.12 Miscellaneous nucleophilic cyclizations 10 Indoles from pyrroles 4 Electrophilic cyclization 10.1 Electrophilic cyclization 4.1 Bischler indole synthesis 10.1.1 Natsume indole synthesis 4.2 Nordlander indole synthesis 10.1.2 Miscellaneous 4.3 Nitrene cyclization 10.2 Palladium-catalyzed cyclization 4.3.1 Cadogan-Sundberg indole synthesis 10.3 Cycloaddition routes 4.3.2 Sundberg indole synthesis 10.3.1 From vinylpyrroles 4.3.3 Hemetsberger indole synthes 10.3.2 From pyrrole-2, 3-quinodimethanes 4.4 Queguiner azacarbazole synthesis 10.3.3 Miscellaneous 4.5 Iwao indole synthesis 10.4 Radical cyclization 4.6 Magnus indole synthesis 11 Aryne intermediates 11.1 Aryne Diels-Alder cycloaddition 4.8 Miscellaneous electrophilic cyclization 11.2 Nucleophilic cyclization of arynes 5 Reductive cyclization 12 Miscellaneous indole syntheses 5.1 0 B-Dinitrostyrene reductive cyclization 12.1 Oxidation of indolines 5.2 Reissert indole synthesis 12.2 From oxindoles, isatins and indoxyl 5.3 Leimgruber-Batcho indole synthesis 12.3 Miscellaneous 5.4 Makosza indole synthes 6 Oxidative cyclization Refe 6.1 Watanabe indole synthesis 6.2 Knolker indole-carbazole synthesis 7 Radical cyclization 7.1 Tin-mediated cyclizatic Indole and its myriad derivatives continue to capture th 7.2 Samarium-mediated cyclization attention of synthetic organic chemists, and a large number of 7.3 Murphy indole- indoline synthesis original indole ring syntheses and applications of known 7. 4 Miscellaneous radical cyclizations methods to new problems in indole chemistry have been 8 Metal-catalyzed indole syntheses reported since the last review by this author in 1994. 2 DOI:10.1039/a909834h J. Chem. Soc. Perkin Trans. 2000. 1045-1075 1045 This journal is o The Royal Society of Chemistry 2000

1 PERKIN REVIEW DOI: 10.1039/a909834h J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075 1045 This journal is © The Royal Society of Chemistry 2000 Recent developments in indole ring synthesis—methodology and applications Gordon W. Gribble Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA Received (in Cambridge, UK) 14th December 1999 Covering: 1994–1999. Previous review: Contemp. Org. Synth., 1994, 1, 145. 1 Introduction 2 Sigmatropic rearrangements 2.1 Fischer indole synthesis 2.1.1 Methodology 2.1.2 Applications 2.1.3 Mechanism 2.2 Gassman indole synthesis 2.3 Bartoli indole synthesis 2.4 Thyagarajan indole synthesis 2.5 Julia indole synthesis 2.6 Miscellaneous sigmatropic rearrangements 3 Nucleophilic cyclization 3.1 Madelung indole synthesis 3.2 Schmid indole synthesis 3.3 Wender indole synthesis 3.4 Couture indole synthesis 3.5 Smith indole synthesis 3.6 Kihara indole synthesis 3.7 Nenitzescu indole synthesis 3.8 Engler indole synthesis 3.9 Bailey–Liebeskind indole synthesis 3.10 Wright indoline synthesis 3.11 Saegusa indole synthesis 3.12 Miscellaneous nucleophilic cyclizations 4 Electrophilic cyclization 4.1 Bischler indole synthesis 4.2 Nordlander indole synthesis 4.3 Nitrene cyclization 4.3.1 Cadogan–Sundberg indole synthesis 4.3.2 Sundberg indole synthesis 4.3.3 Hemetsberger indole synthesis 4.4 Quéguiner azacarbazole synthesis 4.5 Iwao indole synthesis 4.6 Magnus indole synthesis 4.7 Feldman indole synthesis 4.8 Miscellaneous electrophilic cyclizations 5 Reductive cyclization 5.1 o,
-Dinitrostyrene reductive cyclization 5.2 Reissert indole synthesis 5.3 Leimgruber–Batcho indole synthesis 5.4 Makosza indole synthesis 6 Oxidative cyclization 6.1 Watanabe indole synthesis 6.2 Knölker indole-carbazole synthesis 7 Radical cyclization 7.1 Tin-mediated cyclization 7.2 Samarium-mediated cyclization 7.3 Murphy indole-indoline synthesis 7.4 Miscellaneous radical cyclizations 8 Metal-catalyzed indole syntheses 8.1 Palladium 8.1.1 Hegedus–Mori–Heck indole synthesis 8.1.2 Yamanaka–Sakamoto indole synthesis 8.1.3 Larock indole synthesis 8.1.4 Buchwald indoline synthesis 8.1.5 Miscellaneous 8.2 Rhodium and ruthenium 8.3 Titanium 8.3.1 Fürstner indole synthesis 8.3.2 Miscellaneous 8.4 Zirconium 8.5 Copper 8.5.1 Castro indole synthesis 8.5.2 Miscellaneous 8.6 Chromium 8.7 Molybdenum 9 Cycloaddition and electrocyclization 9.1 Diels–Alder cycloaddition 9.2 Photocyclization 9.2.1 Chapman photocyclization 9.2.2 Miscellaneous photochemical reactions 9.3 Dipolar cycloaddition 9.4 Miscellaneous 10 Indoles from pyrroles 10.1 Electrophilic cyclization 10.1.1 Natsume indole synthesis 10.1.2 Miscellaneous 10.2 Palladium-catalyzed cyclization 10.3 Cycloaddition routes 10.3.1 From vinylpyrroles 10.3.2 From pyrrole-2,3-quinodimethanes 10.3.3 Miscellaneous 10.4 Radical cyclization 11 Aryne intermediates 11.1 Aryne Diels–Alder cycloaddition 11.2 Nucleophilic cyclization of arynes 12 Miscellaneous indole syntheses 12.1 Oxidation of indolines 12.2 From oxindoles, isatins and indoxyls 12.3 Miscellaneous 13 Acknowledgements 14 References 1 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

Although most of the examples herein involve the indole ring system, a few novel syntheses of indolines, oxindoles, t isatins, t 65°C indoxyl, t carbazoles, and related ring systems are included in this review. The organization follows that adopted earlier, 3 albeit with the inclusion of several additional classifications. 79% Unfortunately, space limitations preclude detailed discussions of these reactions. 2 Sigmatropic rearrangements 2.1 Fischer indole synthesis The venerable Fischer indole synthesis has maintained prominent role as a route to indoles, both new and old, and to the large-scale production of indole pharmaceutical intermedi 138°C ates. Furthermore, new methodologies have been developed and new mechanistic insights have been gleaned for the Fischer ~100% indole reaction since the last review 2.1.1 Methodology Scheme 2 A one-pot synthesis of indoles from pheny hydrazine hydro- chloride and ketones in acetic acid with microwave irradiation 3-one gives 3-sec-butyl-2-ethyl-I-methylindole as the only shows improvement in many cases(higher yields and reaction isolable product, and the Z-isomer yields 1, 3-dimethyl-2-(2 times of less than a minute)over the conventional thermal ethylbutyl)indole with high regioselectivity. The results are reaction conditions. .6 Microwave irradiation in a pressurized ascribed to regioselective enehydrazine formation by preferen reactor with water as solvent(220C, 30 min)gives 2, 3-dimethyl- tial proton abstraction by the hindered base DATMP. indole in 67% yield from phenylhydrazine and butan-2-one. Buchwald and co-workers have utilized the palladium- The use of montmorillonite clay and ZnCl, under microwave catalyzed coupling of hydrazones with aryl bromides as an conditions affords 2-(2-pyridyl)indoles at much lower temper- entry to N-arylhydrazones for use in the Fischer idolization. atures and with solvent-free acid (Scheme 1). The use of Subsequent hydrolysis and trapping with a ketone under acidic natural clays(bentonite)and infrared irradiation also furnishes conditions leads to indoles(Scheme 3) indoles in high yield from phenylhydrazine and ketones. For example, acetone affords 2-methylindole in 85% yield NH? ZnCl/K mIcrowave Scheme 1 Zeolites in the Fischer indole synthesis are highly shape- selective catalysts and can reverse the normal regiochemistry Scheme 3 seen with unsymmetrical ketones. 0, For example, 1-phenyl butan-2-one furnishes 2-benzyl-3-methylindole as the major 2.1.2 Applications somer(83: 17)in the presence of zeolite beta, whereas with The Fischer indole synthesis was used extensively during the no zeolite present this is the minor isomer and the major isomer is 2-ethyl-3-phenylindole(24: 76). The solid phase Examples include 5-methoxy-2-phenylindole used in arylhydrazines and polymer-bound piperidine-4-carbaldehyde photolysis study, 8 2-ethoxycarbonyl-5-chloro-3-methylindot 9 has been reported. This research group has described the 2-ethoxycarbonyl-6-chloro-5-methoxy-3-methylindole, and 2- preparation of 2-arylindoles on a solid support 3and th thoxycarbonyl-6-methoxy-3-methy indole for use in indole nd 2-ethoxycarbonyl-7-methoxy synthesis of an indole combinatorial library using dendrimer 4-nitroindole21 2-ethoxycarbonyl-7-methoxy.5-nitroindole, 2-ethoxycarbonyl-4-methoxy-7-nitroindole, 21 and 2-ethoxy- The thermal cyclization of N-trifluoroacetyl enehydrazines carbonyl-S-methoxy-7-nitroindole 2 for use in the synthesis ads to indoles(or indolines)under relatively mild conditions of coenzyme pQQ (pyrroloquinoline quinone) analogs. (Scheme 2), apparently due to a lowering of the LUMO energy The last studies 9-22 utilize the Japp-Klingemann reaction of level of the trifluoroacetyl-substituted olefin that facilitates an aryl diazonium salt with a-substituted ethyl acetoacetate to new catalyst, diethylaluminum 2.2 6, 6-tetramethylpiperidinide reaction was also used with malonates to prepare 2-alkoxy (DATMP), provides excellent regioselectivity in the Fischer carbonyl-5-methoxyindoles on an industrial scale in high yields indole synthesis of 2, 3-dialkylindoles from unsymmetrical ketones via the isomeric (Z)-and (E)-hydrazones. 6 For and with little waste.23 The reaction of 1, 5-di(p-tolyD)pentane- 1, 3, 5-trione with 2 equivalents of phenylhydrazine gives rise example,(E)-N-methyl-N-phenylhydrazone of 5-methylheptan- to 3-[1-phenyl-5-(p-tolyl)pyrazol-3-yl1-2-(p-tolyl)indole, and bis-Fischer idolization of the bisphenylhydrazone of 2, 5 The IUPAC name for oxindole is indolin-2-one, for indoxyl is indol-3. dimethylcyclohexane-1, 4-dione affords 5, 11-dimethyl-6, 12- ol and for isatin dihydroindolo[3, 2-b]carbazole in 80% yield 2 1046 J. Chem. Soc.. Perkin Trans. 1. 2000. 1045-1075

1046 J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075 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 Sigmatropic rearrangements 2.1 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 intermedi￾ates. 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 A one-pot synthesis of indoles from phenylhydrazine hydro￾chloride 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-dimethyl￾indole 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 temper￾atures 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. Zeolites in the Fischer indole synthesis are highly shape￾selective catalysts and can reverse the normal regiochemistry seen with unsymmetrical ketones.10,11 For example, 1-phenyl￾butan-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￾Scheme 1 † The IUPAC name for oxindole is indolin-2-one, for indoxyl is indol-3- ol and for isatin is indoline-2,3-dione. 3-one gives 3-sec-butyl-2-ethyl-1-methylindole as the only isolable product, and the Z-isomer yields 1,3-dimethyl-2-(2- methylbutyl)indole with high regioselectivity. The results are ascribed to regioselective enehydrazine formation by preferen￾tial proton abstraction by the hindered base DATMP. Buchwald and co-workers have utilized the palladium￾catalyzed 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). 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 2- ethoxycarbonyl-6-methoxy-3-methylindole 20 for use in indole alkaloid synthesis,19,20 and 2-ethoxycarbonyl-7-methoxy- 4-nitroindole,21 2-ethoxycarbonyl-7-methoxy-5-nitroindole,21 2-ethoxycarbonyl-4-methoxy-7-nitroindole,21 and 2-ethoxy￾carbonyl-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-alkoxy￾carbonyl-5-methoxyindoles on an industrial scale in high yields and with little waste.23 The reaction of 1,5-di(p-tolyl)pentane- 1,3,5-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 2,5- dimethylcyclohexane-1,4-dione affords 5,11-dimethyl-6,12- dihydroindolo[3,2-b]carbazole in 80% yield.25 Scheme 2 Scheme 3

The synthesis of the marine alkaloid eudistomidin-A R NH2 featured a Fischer idolization( Scheme 4); this paper describes the preparation of other 7-oxygenated indoles under conditions that preclude formation of the"abnormal" indole product Along these lines, Szczepankiewicz and Heathcock employe an oxygen bridge in a hydrazone to prevent the abnormal cyclization. Subsequent elimination and hydrolysis to remove R=H MeF Cl Br. OMe Pr the oxyethylene bridge furnishes the desired 7-hydroxy-4- nitrotryptophanol derivative (Scheme 5). The loss of an R=H, OMe(R=H) ortho-oxygen substituent was encountered by White et al. in a synthesis of 6. 7-dimethoxytryptophanol, to afford the NMe2 PPA COE R2=H, Me, CI 5 R4 R-H. Me, CLF R4=H Me. CL F. Br. OMe Et Ph (2and E (TsOH/PhH; 55%) Scheme 4 OBn 5-sulfosalicylic acid R2=H. BI R=H OMe, Br 6 82% and phenylhydrazones of bulky ketones can lead to rearranged Several indole alkaloid studies feature a Fischer indole syn- thesis as a key step, including studies on uleine, aspidosperma- 1. NaOEt DMSO ine, and ibophyllidine alkaloids The core of the leptosin 2 HCI EtOH alkaloid family was nicely crafted by Crich et al. in this fashion (Scheme 7). Scheme 5 1. PhNHNH2 HCI pyr The indole diol 1 was easily crafted from a 2, 3-dideoxy pentose as shown in Scheme 6. The initial Fischer indole NN202ZnC2170°C product was a mixture of two isomeric hydroxybenzoates PhO?s CO Me resulting from benzoyl migration 71% 1. PhNHNH2-HC 2. aq. H SOa heat R2 D2s CO?Me R=BZ R2=H Scheme 7 H H rt The Fischer indole synthesis has been used to construct numerous carbazoles including simple carbazole alkaloids, rutaecarpine analogs. 0 biscarbazole alkaloids, benzo indoloquinolines, thiazolocarbazoles, thienocarbazoles, 4 Scheme 6 C-14 labelled benzocarbazole 55 and other fused-indoles such as indolo[3, 2-djbenzoazepinones 6 Novel 14-alkoxyindolo- Numerous tryptamine derivatives have been synthesized via morphinans (eg, 8), 4-hydroxy- 3-methoxyindolomorph- the Fischer indole synthesis and some of these are listed below inans, and indolinosteroids(e.g, 9)9 are readily synthesized (2,334). Other tryptamines have been prepared via Fischer via Fischer idolization, as are pyridoindolobenzodiazepines lization and studied as novel antagonists for the vascular (eg, 10), decal-l-one-derived indoles, radiolabelled naltrin- HTIB- like receptors, 33,34 5-HTID receptor agonists, doles, and 3-indolylcoumarins. melatonin analogs. Several novel tetrazolylindoles 5 have also a series of novel fused indoles has been synthesized using a been prepared in this fashion, and improvements in the Fischer indole strategy and one example is shown in Scheme Fischer indole step in the synthesis of the migraine treatment 8.Ketoindoles and ketobenzothiophenes were also employed drug sumatriptan and analogs"have been described. Both in this reaction. 2-and 3-indolylquinazolinones(e.g, 6) are readily prepared. Spiroindolines and spiroindolenines are readily synthesized and the thiocarbamates 7 are available in good yields by a using the Fischer idolization and examples include a Fischer indolization. An unexpected result in the Fischer crown-linked spiroindolenine used to make new signa dole protocol gives rise to 3-aminoindole-2-carboxylates, transducers, novel antipsychotics, and MK-677, a growth J. Chem. Soc. Perkin Trans. 2000. 1045-1075 1047

J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075 1047 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-4- nitrotryptophanol 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 The indole diol 1 was easily crafted from a 2,3-dideoxy￾pentose as shown in Scheme 6.29 The initial Fischer indole product was a mixture of two isomeric hydroxybenzoates resulting from benzoyl migration. 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 sumatriptan38 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 Scheme 4 Scheme 5 Scheme 6 and phenylhydrazones of bulky ketones can lead to rearranged products.43 Several indole alkaloid studies feature a Fischer indole syn￾thesis as a key step, including studies on uleine,44 aspidosperm￾idine,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 The Fischer indole synthesis has been used to construct numerous carbazoles including simple carbazole alkaloids,48 rutaecarpine analogs,49,50 biscarbazole alkaloids,51 benzo￾indoloquinolines,52 thiazolocarbazoles,53 thienocarbazoles,54 C-14 labelled benzocarbazole,55 and other fused-indoles such as indolo[3,2-d]benzoazepinones.56 Novel 14-alkoxyindolo￾morphinans (e.g., 8),57 4-hydroxy-3-methoxyindolomorph￾inans,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 naltrin￾doles,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 Scheme 7

deprotonation to form the enehydrazine, whereas under weakl NINH acidic conditions tautomerization is sufficiently rapid that the [3, 3]-sigmatropic rearrangement is rate determining. MNDO AMI calculations have been performed on the conformation CF3CO2H HOAC heat and sigmatropic rearrangement ethyl pyruvate and acetaldehyde 5.76 Murakami and co-workers continue their investigations of the effects of ortho-substituents on the regiochemistry and rate of Fischer indole cyclizations, -and, as shown in Scheme 10, hydrazone 13 undergoes cyclization to the more electron-rich Zncl2 HOAc F3C R= CH2C3Hs. CH2 CH=CH2 Scheme 10 R=H Me A novel abnormal rearrangement has been uncovered in the ischer idolization of the naltrexone N-methyl-N-(5, 6, 7, 8 tetrahydro-l-naphthyl)hydrazone. 0 Huisgen and co-workers have found that under fischer indole reaction conditions ene- hydrazine 14 stops at the 2-aminoindoline stage 15, since indole formation is precluded by ring strain in the product (Scher l1).81.2 hormone secretagogue. The Fischer indole sequence has been used on an industrial scale in the manufacture of a pharm aceutical intermediate, to prepare pyrrolo[2, 3-d]pyrimidines synthesize 7-bromo-2, 3-bis( methoxycarbonyl)indole as a useful COoMe ubstrate for Pd-catalyzed cross coupling reactions leading to 7-substituted indoles. COM er,on rare occasions the Fischer indole synthesis proceeds poorly or even fails altogether. For example, hydra zone 11 afforded only 15% of the indole product, the major Scheme 11 product (41%)being an indazole, and hydrazone 12 failed to cyclize to an indole under all conditions tried(Scheme 9), 2.2 Gassman indole synthesis presumably because of the deactivating effect of the (proton- ated) pyridine ring. The beautiful Gassman indole-oxindole synthesis, -b6 which features a [2, 31-sigmatropic rearrangement, has been used to prepare efficiently 6.7-dihydroxyoxindole, a subunit of the alkaloids paraherquamide a and marcfortine A. Wright et al ylene 135C ave developed a modification of the Gassman synthesis that affords improved yields in many cases. The key feature of the OMs Wright modification is the facile formation of the chlorosulf- onium salt 16, which avoids elemental chlorine(Scheme 12) OMs COC CCH2CO2Et CH2 C2 /+CH,CO,Et Scheme 9 CO,Et SMe 2.1.3 Mechanism 1以N.人 M An exhaustive study of the effects of acidity on the mechanism 2. 2M HCl of the Fischer indole synthesis reveals that four different mech- anistic variations can occur over the acidity range of Ho=+2 to-8. Thus, in strong acid the rate-determining step is Scheme 12 1048. Chem. Soc.. Perkin Trans. 1.2000. 1045-1075

1048 J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075 hormone secretagogue.67 The Fischer indole sequence has been used on an industrial scale in the manufacture of a pharm￾aceutical intermediate,68 to prepare pyrrolo[2,3-d]pyrimidines as potential new thymidylate synthase inhibitors,69,70 and to synthesize 7-bromo-2,3-bis(methoxycarbonyl)indole as a useful substrate for Pd-catalyzed cross coupling reactions leading to 7-substituted indoles.71 However, on rare occasions the Fischer indole synthesis proceeds poorly or even fails altogether. For example, hydra￾zone 11 afforded only 15% of the indole product, the major product (41%) being an indazole,72 and hydrazone 12 failed to cyclize to an indole under all conditions tried73 (Scheme 9), presumably because of the deactivating effect of the (proton￾ated) pyridine ring. 2.1.3 Mechanism An exhaustive study of the effects of acidity on the mechanism of the Fischer indole synthesis reveals that four different mech￾anistic variations can occur over the acidity range of H0 = 2 to 8.74 Thus, in strong acid the rate-determining step is Scheme 8 Scheme 9 deprotonation to form the enehydrazine, whereas under weakly acidic conditions tautomerization is sufficiently rapid that the [3,3]-sigmatropic rearrangement is rate determining. MNDO AM1 calculations have been performed on the conformations and sigmatropic rearrangement of the phenylhydrazones of ethyl pyruvate and acetaldehyde.75,76 Murakami and co-workers continue their investigations of the effects of ortho-substituents on the regiochemistry and rate of Fischer indole cyclizations,77–79 and, as shown in Scheme 10, hydrazone 13 undergoes cyclization to the more electron-rich benzene ring.77 A novel abnormal rearrangement has been uncovered in the Fischer indolization of the naltrexone N-methyl-N-(5,6,7,8- tetrahydro-1-naphthyl)hydrazone.80 Huisgen and co-workers have found that under Fischer indole reaction conditions ene￾hydrazine 14 stops at the 2-aminoindoline stage 15, since indole formation is precluded by ring strain in the product (Scheme 11).81,82 2.2 Gassman indole synthesis The beautiful Gassman indole-oxindole synthesis,83–86 which features a [2,3]-sigmatropic rearrangement, has been used to prepare efficiently 6,7-dihydroxyoxindole, a subunit of the alkaloids paraherquamide A and marcfortine A.87 Wright et al. have developed a modification of the Gassman synthesis that affords improved yields in many cases.88 The key feature of the Wright modification is the facile formation of the chlorosulf￾onium salt 16, which avoids elemental chlorine (Scheme 12). Scheme 10 Scheme 11 Scheme 12

2.3 Bartoli indole synthesis The fascinating Bartoli protocol, 0 which features a [3, 31- R2 sigmatropic rearrangement analogous to the Fischer ation step, has been used to prepare 7-bromo-4-ethylind synthesis of (+)-cis-trikentrin A, and 7-bromoindole 3)in a synthesis of hippadine 92 R=Me, Et, BI R=H CI THF-70°C Scheme 16 CI Scheme 13 Thyagarajan indole 2.H2O Thyagarajan and co-workers discovered a novel indole ring forming reaction that involves sequential [2, 3]- and [3, 31- propynylamine 17(Scheme 14)3-5 the N-oxide of the ary 110° ( many examples) MCPBA 一 2.6 Miscellaneous sigmatropic rearrangement A tandem Wittig-Cope reaction sequence converts a 2- B1% allylindoxyl to the corresponding indole in excellent yield (Scheme 18) R Pha P=CHCO2Me °C In continuation of the original work, Majumdar et al. have xtended this reaction to the preparation of cyclic bisethers con- Scheme 18 taining two indole units(Scheme 15), 6, 9and to the synthesis of dihydro-lH-pyrano[3, 2-eindol-7-ones. The mechanism is 3 Nucleophilic cyclization proposed to involve dimerization of 3-methyleneindoline 18. 3.1 Madelung indole synthesis Ithough the classical Madelung synthesis is rarely employed owadays, the excellent Houlihan modification, 'which ut MCPBA izes buli or lda as bases under milder conditions than the CHCl05°C original Madelung harsh conditions, has been extended 56% several ways. For example, benzylphosphonium salts such as 20 undergo facile cyclization to indoles under thermal condition Scheme 19). 4, 10s The phosphonium salt can be generated benzyl methyl ether 21. The tion a synthesis of 2-perfluoroalkyl indoles, although the yields are quite variable. The base OH catalyzed version of this reaction has been adapted to solid 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). This reaction, which was first reported by Clark et aL, os has been A related tandem [2, 3]-and [3, 3]-sigmatropic rearrangement utilized in a synthesis of novel pyrano[2, 3-e]indoles as potential quence is suggested to explain the formation of N-alkyl ew dopaminergic agents. An aza-Wittig reaction of iminophosphorane 23 with acyl 2-vinylindoles from N-alkyl-N-allenylmethylanilines upon cyanides leads to a novel indole synthesis(Scheme 21). i0 (Scheme 16), MMPP (magnesium monoperoxyphthalate) Moreover, quenching 23 with phenyl isocyanate yields carbo- diimides which cyclize to 2-anilinoindoles with base. These 2.5 Julia indole synthesis methods are excellent for the preparation of 2-aryl-3-(aryl- sulfonyl)indoles and 2-anilino-3-(arylsulfonyl)indoles. Julia and co-workers have uncovered a novel indole ring syn- Cyclization of phenylacetate imides such as 24 occurs readily thesis involving the [3, 3]-sigmatropic rearrangement of the under the influence of base(Scheme 22). 1 readily available sulfinamides 19(Scheme 17). 0 More recently An interesting attempt to cyclize the imines derived from these workers have published a full account of their work trifluoromethylaryl ketones and o-toluidines with lithium including many examples of this clever reaction. o amides to indoles was not successful, yielding only amidines. J. Chem. Soc. Perkin Trans. 2000. 1045-1075 1049

J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075 1049 2.3 Bartoli indole synthesis The fascinating Bartoli protocol,89,90 which features a [3,3]- sigmatropic rearrangement analogous to the Fischer indoliz￾ation step, has been used to prepare 7-bromo-4-ethylindole in a synthesis of (±)-cis-trikentrin A,91 and 7-bromoindole (Scheme 13) in a synthesis of hippadine.92 2.4 Thyagarajan indole synthesis Thyagarajan and co-workers discovered a novel indole ring￾forming reaction that involves sequential [2,3]- and [3,3]- sigmatropic rearrangements from the N-oxide of the aryl propynylamine 17 (Scheme 14).93–95 In continuation of the original work, Majumdar et al. have extended this reaction to the preparation of cyclic bisethers con￾taining two indole units (Scheme 15),96,97 and to the synthesis of dihydro-1H-pyrano[3,2-e]indol-7-ones.98 The mechanism is proposed to involve dimerization of 3-methyleneindoline 18. A related tandem [2,3]- and [3,3]-sigmatropic rearrangement sequence is suggested to explain the formation of N-alkyl- 2-vinylindoles from N-alkyl-N-allenylmethylanilines upon exposure to MMPP (magnesium monoperoxyphthalate) (Scheme 16).99 2.5 Julia indole synthesis Julia and co-workers have uncovered a novel indole ring syn￾thesis involving the [3,3]-sigmatropic rearrangement of the readily available sulfinamides 19 (Scheme 17).100 More recently, these workers have published a full account of their work including many examples of this clever reaction.101 Scheme 13 Scheme 14 Scheme 15 2.6 Miscellaneous sigmatropic rearrangements A tandem Wittig–Cope reaction sequence converts a 2- allylindoxyl to the corresponding indole in excellent yield (Scheme 18).102 3 Nucleophilic cyclization 3.1 Madelung indole synthesis Although the classical Madelung synthesis is rarely employed nowadays, the excellent Houlihan modification,103 which util￾izes BuLi or LDA as bases under milder conditions than the original Madelung harsh conditions, has been extended in several ways. For example, benzylphosphonium salts such as 20 undergo facile cyclization to indoles under thermal conditions (Scheme 19).104,105 The phosphonium salt can be generated in situ from the corresponding benzyl methyl ether 21. The reac￾tion is especially valuable for the synthesis of 2-perfluoroalkyl￾indoles, although the yields are quite variable. The base￾catalyzed version of this reaction has been adapted to solid phase synthesis.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).107 This reaction, which was first reported by Clark et al., 108 has been utilized in a synthesis of novel pyrano[2,3-e]indoles as potential new dopaminergic agents.109 An aza-Wittig reaction of iminophosphoranes 23 with acyl cyanides leads to a novel indole synthesis (Scheme 21).110 Moreover, quenching 23 with phenyl isocyanate yields carbo￾diimides which cyclize to 2-anilinoindoles with base.110 These methods are excellent for the preparation of 2-aryl-3-(aryl￾sulfonyl)indoles and 2-anilino-3-(arylsulfonyl)indoles. Cyclization of phenylacetate imides such as 24 occurs readily under the influence of base (Scheme 22).111 An interesting attempt to cyclize the imines derived from trifluoromethylaryl ketones and o-toluidines with lithium amides to indoles was not successful, yielding only amidines.112 Scheme 16 Scheme 17 Scheme 18

人 1. BuLi THF 0C CF?CF3 92% Neu2.(CO2Et2-78℃0 59-87% 2M HCI DME 79-89% R=H. 4-OMe, 4,5-diOMe, 7-F, 5-CF3, 6-CF3 34-82% R=HB Scheme 23 =H OMe intermediate is an acyllithium species which cyclizes onto the urea carbonyl group. This lithiation-carbonylation strategy was Scheme 19 adapted to the synthesis of 3-hydroxyoxindoles by the lithiatic of N-pivaloylanilines. Smith and co-workers have alse 1 BuLi THF employed the original Wender indole synthesis to the synthesis of N-dimethylurea-protected indoles involving the dilithiation HBoc 2. R'CONMeR of N-phenyl-N, N-dimethylurea. 7 6384% R=H Me 3. 4 Couture indole svnthesis R"=Me, OMe No new examples were reported since the last review Scheme 20 3.5 Smith indole synthesis The Smith indole synthesis, which involves dilithiation of N-trimethylsilyl-o-toluidine and subsequent reaction with a N二PPh non-enolizable ester to afford the 2-substituted indole has been 48-74% used to synthesize 2-trifluoromethylindole in 47% yield by quenching the above mentioned dianion with ethyl trifluor acetate SOR R=Ph, p-Tol 3.6 Kihara indole svnthesis 80-90°C R= Ph, p-Tol Kihara et al. have described an indole ring formation that involves an intramolecular Barbier reaction of phenyl and alkyl N-(2-lodophenyl)-N-methylaminomethyl ketones as summarized in Scheme 24. 2 The hydroxyindoline by-product if obtained, can be converted to the indole with aqueous CO, Me HCI R= Me, Cg H11, Ph (+17-29% of the 3.7 Nenitzescu indole synthesis The past five years have seen a resurrection of the Nenitzescu 3.2 Schmid indole svnthesis indole synthesis and this classic sequence was used to construct No new examples were uncovered since the last review. methyl 5-hydroxy-2-methoxymethylindole-3-carboxylate, the ey intermediate in a synthesis of the antitumor indolequinor 3.3 Wender indole svnthesis Eo 9. 2 This reaction has also been used to prepare a series of -aryl-5-hydroxyindoles, 2 and it was utilized in the synthesis The Wender indole synthesis, which involves the ortho- of a key indole(Scheme 25)used to prepare potent and selectiv lithiation of N-phenylamides followed by reaction of the s-PLA2 inhibitors 23 resulting dianion with a-haloketones and subsequent ring closure and dehydration, has been extended to a convenient COMe Thesis of isatins by quenching with diethyl pyruvate Scheme 23). 14 MeNO 2 A related isatin synthesis has been described by Smith and co-workers> that involves the carbonylation of the dianion derived from N'-(2-bromoaryl)-N, N-dimethylureas. The key 1050 J. Chem. Soc.. Perkin Trans. 1. 2000. 1045-1075

1050 J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075 3.2 Schmid indole synthesis No new examples were uncovered since the last review. 3.3 Wender indole synthesis The Wender indole synthesis,113 which involves the ortho￾lithiation of N-phenylamides followed by reaction of the resulting dianion with α-haloketones and subsequent ring closure and dehydration, has been extended to a convenient synthesis of isatins by quenching with diethyl pyruvate (Scheme 23).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,N-dimethylureas. The key Scheme 19 Scheme 20 Scheme 21 Scheme 22 intermediate is an acyllithium species which cyclizes onto the urea carbonyl group. This lithiation–carbonylation strategy was adapted to the synthesis of 3-hydroxyoxindoles by the lithiation of N-pivaloylanilines.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.117 3.4 Couture indole synthesis No new examples were reported since the last review. 3.5 Smith indole synthesis The Smith indole synthesis,118 which involves dilithiation of N-trimethylsilyl-o-toluidine and subsequent reaction with a non-enolizable ester to afford the 2-substituted indole, has been used to synthesize 2-trifluoromethylindole in 47% yield by quenching the above mentioned dianion with ethyl trifluoro￾acetate.119 3.6 Kihara indole synthesis Kihara et al. 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 24.120 The hydroxyindoline by-product, if obtained, can be converted to the indole with aqueous HCl. 3.7 Nenitzescu indole synthesis 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, the key intermediate in a synthesis of the antitumor indolequinone EO 9.121 This reaction has also been used to prepare a series of N-aryl-5-hydroxyindoles,122 and it was utilized in the synthesis of a key indole (Scheme 25) used to prepare potent and selective s-PLA2 inhibitors.123 Scheme 23 Scheme 24 Scheme 25

3. 8 Engler indole synthesis In a series of papers rich in detail, Engler and co-workers have BrCH(CO2Et)2 described a new indole synthesis based on the Lewi COCF KOBU' THF N CO2Et romoted reactions of enol ethers and styrenes with quinone imines. 124-127 An example is shown in Scheme 26 and 60-76% COCF the reaction has obvious similarities to the Nenitzescu indole R=H M ring synthesis. Engler can manipulate the reaction to afford benzofurans instead of indoles by simply changing the Lewis Scheme 28 nitrogen can be readily deprotected (Mg-MeOH) and functionalized as desired (acylation, alkylation). Pre- TiCle/Ti(OPr)4 these indolines can be converted to indole-2-carboxyl cHC-78℃c ates by decarboxylation and oxidation sOpH OMe 3.11 Saegusa indole synthes The cyclization of ortho-lithiated o-tolylisocyanides 1. Mel K2 COs acetone ul indole synthesis discovered by Saegusa and co 1977(Scheme 29). .56, 137 The reaction is very ger 2 DD Phh reflux OMe (VNS)reaction as developed by MakOSA EEBAR. been exploited by Makosza and co-workers in a synthesis of 5-allyloxy-3-(4-tolylsulfonyl)-lH-indole for use in 1, 3, 4,5-tetra hydrobenzocdindole studies. 38 The requisite isocyanide pre- sor was synthesized by Scheme 26 Kita and colleagues have reported a closely related to the Engler synthesis. 2 involves the reaction of a-methylstyrene Scheme 29 ulfide with p-methoxy-N-tosylaniline under the influence of phenyliodonium bistrifluoroacetate, conditions that generate The elegant free-radical cyclization version of the Saegusa benzoquinone intermediates similar to the Engler inter- indole synthesis as developed by Fukuyama is presented in mediates Section 7.1 3.9 Bailey-Liebeskind indole synthesis 3.12 Miscellaneous nue Bailey and Liebeskind independently discovered the novel The known indoxyl dianion 26, which is used to synthesize indole ring-forming reaction shown in Scheme 27 and involving indigo, has now been successfully intercepted with carbon anionic cyclization onto an N-allyl unit 30,1 The resulting disulfide to furnish indoxyl and indoles(Scheme 30). The indoline anion can be further treated with an electrophile and trapped indoxyl ketene dithioacetals 27 and 28 can be used in hen oxidized with chloranil t to the indole. The N-allylindole cycloaromatization reactions to make carbazoles, e. g, 29 can be deprotected with Pd. This new synthesis has been used to prepare a novel benzol indole amino acid as a fluorescent CO,H probe, 'and Bailey ha as extende ed the reaction to include the termediacy of aryne intermediates in the sequence, the result ing that the alkyllithium used to generate the aryne ACO2H260℃C corporated into the cyclized indoline at the C-4 position. 1. C5. 1.CS2,0°C 2o pentane -78C SMe TMEDA CH.CN SMe E=H, D, TMS, CHO, Br, BusSn, CH2OH, CO2Et 67% 2. H3POA NaH, DME 27 Wright and co-workers have developed an efficient synthesis COMe of indoline-2, 2-dicarboxylates by the tandem bis-alkylation of SMe o-bromomethyltrifluoroacetanilides 25 (Scheme 28).The t Chloranil is 2, 3, 5, 6-tetrachloro-p-benzoquinone J Che. Soc., Perkin Trans. 1, 2000, 1045-1075 1051

J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075 1051 3.8 Engler indole synthesis In a series of papers rich in detail, Engler and co-workers have described a new indole synthesis based on the Lewis acid￾promoted reactions of enol ethers and styrenes with benzo￾quinone imines.124–127 An example is shown in Scheme 26 and the reaction has obvious similarities to the Nenitzescu indole ring synthesis. Engler can manipulate the reaction to afford benzofurans instead of indoles by simply changing the Lewis acid. Kita and colleagues have reported a synthesis of indoles closely related to the Engler synthesis.128,129 Kita’s variation involves the reaction of α-methylstyrene and phenyl vinyl sulfide with p-methoxy-N-tosylaniline under the influence of phenyliodonium bistrifluoroacetate, conditions that generate benzoquinone intermediates similar to the Engler inter￾mediates. 3.9 Bailey–Liebeskind indole synthesis Bailey and Liebeskind independently discovered the novel indole ring-forming reaction shown in Scheme 27 and involving anionic cyclization onto an N-allyl unit.130,131 The resulting indoline anion can be further treated with an electrophile and then oxidized with chloranil ‡ to the indole. The N-allylindole can be deprotected with Pd.132 This new synthesis has been used to prepare a novel benzo[ f ]indole amino acid as a fluorescent probe,133 and Bailey has extended the reaction to include the intermediacy of aryne intermediates in the sequence, the result being that the alkyllithium used to generate the aryne is incorporated into the cyclized indoline at the C-4 position.134 3.10 Wright indoline synthesis Wright and co-workers have developed an efficient synthesis of indoline-2,2-dicarboxylates by the tandem bis-alkylation of o-bromomethyltrifluoroacetanilides 25 (Scheme 28).135 The Scheme 26 Scheme 27 ‡ Chloranil is 2,3,5,6-tetrachloro-p-benzoquinone. indole nitrogen can be readily deprotected (Mg–MeOH) and further functionalized as desired (acylation, alkylation). Pre￾sumably, these indolines can be converted to indole-2-carboxyl￾ates by decarboxylation and oxidation. 3.11 Saegusa indole synthesis The cyclization of ortho-lithiated o-tolylisocyanides is a power￾ful indole synthesis discovered by Saegusa and co-workers in 1977 (Scheme 29).136,137 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 1,3,4,5-tetra￾hydrobenzo[cd]indole studies.138 The requisite isocyanide pre￾cursor was synthesized by a vicarious nucleophilic substitution (VNS) reaction as developed by Makosza.139,140 The elegant free-radical cyclization version of the Saegusa indole synthesis as developed by Fukuyama is presented in Section 7.1. 3.12 Miscellaneous nucleophilic cyclizations The known indoxyl dianion 26, which is used to synthesize indigo, has now been successfully intercepted with carbon disulfide to furnish indoxyls and indoles (Scheme 30).141 The trapped indoxyl ketene dithioacetals 27 and 28 can be used in cycloaromatization reactions to make carbazoles, e.g., 29. Scheme 28 Scheme 29 Scheme 30

Filler et al. have improved the synthesis of 4,5,6,7-tetra- fuoroindole by the two-step reaction sequence of KF-induced cyclization of 2, 3, 4, 5, 6-pentafiuorophenethylamine and DDQ oxidation of the resulting 4, 5,6, 7-tetrafluoroindoline.Heat- (R=Bn) ng B, B-difluorostyrenes bearing o-tosylamido groups with NaH leads to the corresponding 2-fluoroindoles by a presumed disfavored 5-endo-trig cyclization( Scheme 31). 43 =H8% Scheme 34 Cm· Me>NNH cat CH3 CH2CO2H q THF B1-84% EtoAc-40° 61 %(2 steps) 1. MSCI ELN THF Sutherland has uncovered a novel indole ring for 2. ALO3 CH2Cl2 involving DBU nucleophilic addition to an electron-deficient benzene ring and elimination of a nitro group from an inter 3. NIS CCL reflux o Ts mediate Meisenheimer complex 30(Scheme 32). In the case of methyl 3, 5-dinitrobenzoate, an isoc depending on the initial site of attack by DBU Scheme 35 A new indoline ring-forming reaction leads to the formation of N-(cyanoformylindoline (Scheme 36), and the reaction between bislithiated substituted methylnitriles and methy sulfones with oxalimidoyl chlorides provides 3-iminoindoles in CHCI one step(Scheme 3 R= CO, Me, NO, NO CH2Cl2 r.t. me 36 2.2 eq. BuLI A novel use of sulfonium ylides has led to 2-substit es(Scheme 33). 45 In the case of the non-stabilized (R=H), only N-tosylindoline was isolated (76%) >955.Ez e3 RCHSN 4 Electrophilic cyclization 16-82% OPh. COEt CN Several of the numerous electrophilic cyclization routes to Scheme 33 indoles have been available to synthetic organic chemists for 100 Arcadi and Rossi have published a very simple years or more. Nevertheless, new examples and applications esis of of this indole ring-forming strategy continue to appear in the benzylamine or ammonia to pent-4-ynones(scheme 34). 46 This iterature. addition-elimination-cycloamination sequence was used to prepare a pyrrolosteroid from 178-hydroxyandrost-4-en-3-one 4.1 Bischler indole svnthesis As will be seen in Section 10, these tetrahydroindoles can Moody and Swann have described a modification of the ually be readily converted into indoles. Kim and Fuchs have reported the reaction of cyclic epoxy ketones are prepared by a rh-catalyzed insertion reaction. ketones with N, N-dimethylhydrazine to afford bicyclic per- Acid-catalyzed cyclization completes the synthesis( Scheme 38) hydroindoles. Subsequent manipulation gives tetrahydroindoles Further examples of rhodium-catalyzed indole ring forming such as 31 (Scheme 3 reactions are in Section 8.2 1052. Chem. Soc.. Perkin Trans. 1.2000. 1045-1075

1052 J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075 Filler et al. have improved the synthesis of 4,5,6,7-tetra- fluoroindole by the two-step reaction sequence of KF-induced cyclization of 2,3,4,5,6-pentafluorophenethylamine and DDQ oxidation of the resulting 4,5,6,7-tetrafluoroindoline.142 Heat￾ing β,β-difluorostyrenes bearing o-tosylamido groups with NaH leads to the corresponding 2-fluoroindoles by a presumed disfavored 5-endo-trig cyclization (Scheme 31).143 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 inter￾mediate Meisenheimer complex 30 (Scheme 32).144 In the case of methyl 3,5-dinitrobenzoate, an isoquinolone also forms depending on the initial site of attack by DBU. A novel use of sulfonium ylides has led to 2-substituted indoles (Scheme 33).145 In the case of the non-stabilized ylide (R = H), only N-tosylindoline was isolated (76%). Arcadi and Rossi have published a very simple synthesis of 4,5,6,7-tetrahydroindoles by the nucleophilic addition of benzylamine or ammonia to pent-4-ynones (Scheme 34).146 This addition–elimination–cycloamination sequence was used to prepare a pyrrolosteroid from 17β-hydroxyandrost-4-en-3-one. As will be seen in Section 10, these tetrahydroindoles can usually be readily converted into indoles. Kim and Fuchs have reported the reaction of cyclic epoxy ketones with N,N-dimethylhydrazine to afford bicyclic per￾hydroindoles. Subsequent manipulation gives tetrahydroindoles such as 31 (Scheme 35).147 Scheme 31 Scheme 32 Scheme 33 A new indoline ring-forming reaction leads to the formation of N-(cyanoformyl)indoline (Scheme 36),148 and the reaction between bislithiated substituted methylnitriles and methyl￾sulfones with oxalimidoyl chlorides provides 3-iminoindoles in one step (Scheme 37).149 4 Electrophilic cyclization Several of the numerous electrophilic cyclization routes to indoles have been available to synthetic organic chemists for 100 years or more. Nevertheless, new examples and applications of this indole ring-forming strategy continue to appear in the literature. 4.1 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.150 Acid-catalyzed cyclization completes the synthesis (Scheme 38). Further examples of rhodium-catalyzed indole ring forming reactions are in Section 8.2. Scheme 34 Scheme 35 Scheme 36 Scheme 37

This research group has also used this methodology to synthesize the indole alkaloids cryptosanguinolentine (33) and cryptotackieine(34)from the common starting azide alkaloids 33 and 34 was reported earlier by Timar et ol lse 32 (Scheme 41). to cat Rh2(oAc)4 or CHCh reflux 60-89% R= Me Et Ph 31-87% tol reflux R2- Me, Et R=H.7-Br7-OMe, 5-C1.5-NO 5-OMe, 5. 7-diOMe n人 N CO2R 40% microwav Ithough no new examples of this modification of the bischler indole synthesis were found per se, Zard and co-workers have effected the Lewis acid induced cyclization of 2, 2-dimethoxy arylacetanilides to 3-aryloxindoles 4.3 Nitrene cyclization Scheme 41 4.3.1 Cadogan-Sundberg indole synthesis Depending on the solvent, the photolysis of 2-a This powerful indole ring formation method involves the azidobiphenyl yields small amounts of 4-aminocarbazole and ngst two non-indolic ethyl phosphite and cyclization of the resulting nitrene products. Thermolysis of l-benzylpyrazole affords a-carbol- form an indole. Holzapfel and Dwyer have used this method ine as the major product. The reaction is proposed to involve to synthesize several carbazoles and norharman from the a pyridylnitrene. We have used the Sundberg indole synthesis appropriate 2-nitrobiphenyls, and also several 2-methoxy- to synthesize the previously unknown 2-nitroindole from carbonylindoles from methyl o-nitrocinnamates 152 Another 2-(2-azidophenylI)nitroethylene in 54% yield group has synthesized several 2, 2-biindolyls by the deoxyee153 4.3.3 Hemetsberger indole synthesis The presumed novel generation of nitrenes from o-nitro- The Hemetsberger indole synthesis is related to the Sundberg ation of carbonyl selenide(COSe)which is thepose the form. indole synthesis except that the azido group is on the side stilbenes using CO and Se leads to an efficient synthesis of 2-arylindoles(Scheme 39). The author chain (ie, a-azidocinnamate)rather than on the benzene ring. agent. Both 2-and 3-methylindole can be synthesized in goo This indole synthesis has been used to prepare 2-methoxy yields(70%, 69%)from the corresponding o-nitrostyrenes, and carbonyl-6-cyanoindolel6z and 2-ethoxycarbonyl-3-methyl- he precursor a-azidocinnamates by azide ring opening of epoxides. The Hemetsberger protocol has been used to syn- thesize the abC rings of nodulisporic acid, 6 the thiene [3, 2-g]indole and thieno[3, 2-e indole ring systems, 3 and CO 5 atm recursor(35) to CC-1065 and related antitumor alkaloids ( Scheme42).1° DMF Et3N Boc I R=Me, OMe CF3 COmE Scheme 39 reflux COm 4.3.2 Sundberg indole synthesis Molina et al. have employed the indole synthesis Scheme 42 which involves the thermolysis of renes and cyclic- ation of the resulting nitrene to doles, to prepare Molina et al. have described a variation of the Hemetsberger 2-(Q2-azidoethyl)indole(Scheme 40). The lack of reactivity synthesis involving the thermolysis of 2-alkyl- and 2-aryl of the aliphatic azido group is noteworthy mino-3-(2-azidoethyl)quinolines to give the corresponding pyrrolo[2, 3-b]quinolines in 39-70% yield 160°C DI No 44 Queguiner azacarbazole synthesis tol sealed tube 61% Queguiner and co-workers have extended their short and efficient synthesis of azacarbazoles to the construction of a-substituted 8-carbolines(Scheme 43) J. Chem. Soc. Perkin Trans. 2000. 1045-1075 1053

J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075 1053 4.2 Nordlander indole synthesis Although no new examples of this modification of the Bischler indole synthesis were found per se, Zard and co-workers have effected the Lewis acid induced cyclization of 2,2-dimethoxy￾arylacetanilides to 3-aryloxindoles.151 4.3 Nitrene cyclization 4.3.1 Cadogan–Sundberg indole synthesis This powerful indole ring formation method involves the deoxygenation of o-nitrostyrenes or o-nitrostilbenes with tri￾ethyl phosphite and cyclization of the resulting nitrene to form an indole. Holzapfel and Dwyer have used this method to synthesize several carbazoles and norharman from the appropriate 2-nitrobiphenyls, and also several 2-methoxy￾carbonylindoles from methyl o-nitrocinnamates.152 Another group has synthesized several 2,2-biindolyls by the deoxygen￾ation–cyclization of the appropriate 2-(o-nitrostyryl)indoles.153 The presumed novel generation of nitrenes from o-nitro￾stilbenes using CO and Se leads to an efficient synthesis of 2-arylindoles (Scheme 39).154 The authors propose the form￾ation of carbonyl selenide (COSe) which is the deoxygenation agent. Both 2- and 3-methylindole can be synthesized in good yields (70%, 69%) from the corresponding o-nitrostyrenes, and indole is obtained in 55% yield. 4.3.2 Sundberg indole synthesis Molina et al. have employed the Sundberg indole synthesis, which involves the thermolysis of o-azidostyrenes and cycliz￾ation of the resulting nitrene to form indoles, to prepare 2-(2-azidoethyl)indole (Scheme 40).155,156 The lack of reactivity of the aliphatic azido group is noteworthy. Scheme 38 Scheme 39 Scheme 40 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).157 A very similar strategy to synthesize the alkaloids 33 and 34 was reported earlier by Timári et al. 158 Depending on the solvent, the photolysis of 2-amino-2- azidobiphenyl yields small amounts of 4-aminocarbazole and 4,10-dihydroazepino[2,3-b]indole, amongst two non-indolic products.159 Thermolysis of 1-benzylpyrazole affords α-carbol￾ine as the major product.160 The reaction is proposed to involve a pyridylnitrene. We have used the Sundberg indole synthesis to synthesize the previously unknown 2-nitroindole from 2-(2-azidophenyl)nitroethylene in 54% yield.161 4.3.3 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.e., α-azidocinnamate) rather than on the benzene ring. This indole synthesis has been used to prepare 2-methoxy￾carbonyl-6-cyanoindole 162 and 2-ethoxycarbonyl-3-methyl￾indole.163 The latter study includes a new preparation of the precursor α-azidocinnamates by azide ring opening of epoxides. The Hemetsberger protocol has been used to syn￾thesize the ABC rings of nodulisporic acid,164 the thieno- [3,2-g]indole and thieno[3,2-e]indole ring systems,165 and a precursor (35) to CC-1065 and related antitumor alkaloids (Scheme 42).166 Molina et al. have described a variation of the Hemetsberger synthesis involving the thermolysis of 2-alkyl- and 2-aryl￾amino-3-(2-azidoethyl)quinolines to give the corresponding pyrrolo[2,3-b]quinolines in 39–70% yield.167 4.4 Quéguiner azacarbazole synthesis Quéguiner and co-workers have extended their short and efficient synthesis of azacarbazoles to the construction of α-substituted δ-carbolines (Scheme 43).168 Scheme 41 Scheme 42

4.8 Miscellaneous electrophilic cyclizations R 1. pyr- HCl heat Several new routes to o-aminophenylacetaldehyde derivatives have provided new indole ring syntheses Oxidative cleavage of 2. NH4OH the allyl side chain in aniline 36 affords indole 37, used in a synthesis of (+)-desmethoxymitomycin A(Scheme 47), 4and 72-98% a similar osmium tetroxide oxidative cyclization yields 1-acetyl- R=H, Et, Ph, heteroaryl 5-methoxycarbonyl-7-chloro-4-methoxyindole(77%)from the Scheme 43 corresponding o-allylacetanilide. The use of 2-(2-amino- phenyl)acetaldehyde dimethyl acetal to synthesize a series 4.5 Iwao indole svnthesis of N-acylindoles by acid-catalyzed cyclization has been described. The N-acylindoles can be converted into esters, Iwao has published a new indole synthesis in which the ring- amides, and aldehydes, but not ketones, by treatment with forming step is a thermal sila-Pummerer rearrangement suitable nucleophiles. (Scheme 44). 6%Oxidation of the 2-thioindolines with MCPBA furnishes the corresponding indoles(R=R=H, 100%).A related Pummerer rearrangement leading to an indole inter- Me0 OBn 1. NalA Oso mediate was used by Fukuyama and Chen in an elegant cotone r.t. Meo synthesis of (-)-hapalindole G. 70 NHAc2.HOAc80° 1. BuLi THF R OMe 3. K2CO3 MeOH OMe 91% from the corresponding NHBOC R2 R2 me 47 A synthesis of psilocin revealed the interesting indole syn- thesis shown in Scheme 48 wherein 2, 3-dihydro-2, 5-dimethoxy furan 38, prepared by Pd-catalyzed cross-coupling, is cyclized o indole 39. An unexpected rearrangement of 4-amino- NHBoC SPh 2-methylbenzofurans to 4-hydroxy-2-methy under strongly acidic conditions was recently reported. The authors propose the generation of a vinyl carbocation by opening of the 27-54% overall furan ring and then cyclization to the more stable indole ring R=H Me, OMe CL F CF. system OMe 4.6 Magnus indole synthesis MeO 入。 OMe Magnus and Mitchell have discovered that terminal tri- isopropylsilylprop-2-ynylanilines afford 3-methylindoles upon NHBoc Pd(oAc)2 NHBoC treatment with methanesulfonic acid (Scheme 45). 7 nETo|80° e TFA CH2CL rt 32% overall Meo CH2Cl r t Meo 69% (+7% of the C-4 methoxyindole Scheme 48 Scheme 4 Ishikawa and co-workers have uncovered a remarkable tw step rearrangement while studying the Bischler-Napieralski 4.7 Feldman indole svnthesis reaction of 40. a double transformation that leads to 41 Feldman and co-workers have nat phenyl(propynyl).(Scheme 49), and a"cume question par excellence iodonium triflate reacts with N-phenyl-p-toluene The mechanism of the previously known aromatization of to afford indole operation(Scheme cyclic p-quinomethanes to indoles has been investigated and he is believed to involve a vinyl carbene extended to the synthesis of benzo[e]indoles. 8,1,Thus, the which undergoes electrophilic cyclization to form an indole 1. BuLi THF gives 5-mesyl-3-benzylbenzolelindole in 58% yield. The cyclization of diazoanilides to oxindoles, which is normally performed with rhodium(cf Section 8.2), can also be accom Me plished with Nafion-H. i8s The authors propose an electrophilic -I-Ph mechanism by protonation of the diazo group and loss of N2 Tfo presumably to a carbene intermediate. An example is shown in Scheme 50. Noteworthy is that the methoxycarbonyl group is invariably lost under these conditions, and the azetidin-2-ones 1054 J. Chem. Soc.. Perkin Trans. 1. 2000. 1045-1075

1054 J. Chem. Soc., Perkin Trans. 1, 2000, 1045–1075 4.5 Iwao indole synthesis Iwao has published a new indole synthesis in which the ring￾forming step is a thermal sila-Pummerer rearrangement (Scheme 44).169 Oxidation of the 2-thioindolines with MCPBA furnishes the corresponding indoles (R1 = R2 = H, 100%). A related Pummerer rearrangement leading to an indole inter￾mediate was used by Fukuyama and Chen in an elegant synthesis of ()-hapalindole G.170 4.6 Magnus indole synthesis Magnus and Mitchell have discovered that terminal tri￾isopropylsilylprop-2-ynylanilines afford 3-methylindoles upon treatment with methanesulfonic acid (Scheme 45).171 4.7 Feldman indole synthesis Feldman and co-workers have found that phenyl(propynyl)- iodonium triflate reacts with lithiated N-phenyl-p-toluene￾sulfonamide to afford indoles in one operation (Scheme 46).172,173 The reaction is believed to involve a vinyl carbene which undergoes electrophilic cyclization to form an indole. Scheme 43 Scheme 44 Scheme 45 Scheme 46 4.8 Miscellaneous electrophilic cyclizations Several new routes to o-aminophenylacetaldehyde derivatives have provided new indole ring syntheses. Oxidative cleavage of the allyl side chain in aniline 36 affords indole 37, used in a synthesis of ()-desmethoxymitomycin A (Scheme 47),174 and a similar osmium tetroxide oxidative cyclization yields 1-acetyl- 5-methoxycarbonyl-7-chloro-4-methoxyindole (77%) from the corresponding o-allylacetanilide.175 The use of 2-(2-amino￾phenyl)acetaldehyde dimethyl acetal to synthesize a series of N-acylindoles by acid-catalyzed cyclization has been described.176 The N-acylindoles can be converted into esters, amides, and aldehydes, but not ketones, by treatment with suitable nucleophiles. A synthesis of psilocin revealed the interesting indole syn￾thesis shown in Scheme 48 wherein 2,3-dihydro-2,5-dimethoxy￾furan 38, prepared by Pd-catalyzed cross-coupling, is cyclized to indole 39. 177 An unexpected rearrangement of 4-amino- 2-methylbenzofurans to 4-hydroxy-2-methylindoles under strongly acidic conditions was recently reported.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. Ishikawa and co-workers have uncovered a remarkable two￾step rearrangement while studying the Bischler–Napieralski reaction of 40, a double transformation that leads to 41 (Scheme 49),179,180 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.181,182 Thus, the reaction of vinylmagnesium bromide with 2-benzylamino￾naphtho-1,4-quinone followed by treatment with MsCl–Et3N gives 5-mesyl-3-benzylbenzo[e]indole in 58% yield. The cyclization of diazoanilides to oxindoles, which is normally performed with rhodium (cf. Section 8.2), can also be accom￾plished with Nafion-H.183 The authors propose an electrophilic mechanism by protonation of the diazo group and loss of N2, presumably to a carbene intermediate. An example is shown in Scheme 50. Noteworthy is that the methoxycarbonyl group is invariably lost under these conditions, and the azetidin-2-ones Scheme 47 Scheme 48