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 1051J. 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