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 ortholithiation 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 trifluoroacetate.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 acidpromoted reactions of enol ethers and styrenes with benzoquinone 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 intermediates. 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). Presumably, these indolines can be converted to indole-2-carboxylates by decarboxylation and oxidation. 3.11 Saegusa indole synthesis The cyclization of ortho-lithiated o-tolylisocyanides is a powerful indole synthesis discovered by Saegusa and co-workers in 1977 (Scheme 29).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-tetrahydrobenzo[cd]indole studies.138 The requisite isocyanide precursor 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 Heating 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 intermediate 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 perhydroindoles. 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 methylsulfones 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-dimethoxyarylacetanilides 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 triethyl 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-methoxycarbonylindoles from methyl o-nitrocinnamates.152 Another group has synthesized several 2,2-biindolyls by the deoxygenation–cyclization of the appropriate 2-(o-nitrostyryl)indoles.153 The presumed novel generation of nitrenes from o-nitrostilbenes using CO and Se leads to an efficient synthesis of 2-arylindoles (Scheme 39).154 The authors propose the formation 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 cyclization 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-carboline 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-methoxycarbonyl-6-cyanoindole 162 and 2-ethoxycarbonyl-3-methylindole.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 synthesize 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-arylamino-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 ringforming 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 intermediate 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 triisopropylsilylprop-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-toluenesulfonamide 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-aminophenyl)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 synthesis shown in Scheme 48 wherein 2,3-dihydro-2,5-dimethoxyfuran 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 twostep 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-benzylaminonaphtho-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 accomplished 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