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. 1045-10751054 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