《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