A Versatile Synthesis of 3-Substituted Indolines and Indoles Dawei Zhang and Lanny S. Liebeskind* Sanford S. Atwood Chemistry Center, Emory University, 1515 Pierce Drive, Atlanta, Georgia 30322 Received February 14, 1996 Indolines and their oxidized counterparts, indoles, are very important pharmacophores that appear in numerous biologically active compounds, most notably those affect- ing the central nervous system. 1,2 In addition to classical methods for the construction of the heteroatom ring of these molecules, 3-5 newer procedures mediated by transi- tion metal species have been documented. 6-18 Herein is reported a new method for the synthesis of 3-substituted indolines and indoles whose operational simplicity and generality should find favor in many applications. During an attempt to lithiate 2-bromo-4-methoxy-N,N- diallylaniline with t-BuLi for use in another project, a surprisingly facile cyclolithiation to N-allyl-3-(lithiometh- yl)-5-methoxyindoline occurred, as judged by isolation of N-allyl-3-(deuteriomethyl)-5-methoxyindoline in 86% yield after quenching of the reaction with D 2 O (eq 1). Recog- nizing the potential of this transformation as a versatile construction of 3-substituted indolines and indoles, and noting the inherent advantages that accrued from the use of a symmetrically substituted N,N-diallylaniline group in the chemistry (ease of synthesis, conformational symmetry about the Csp 2 -N bond, ease of deprotection of the resulting N-allylindoline), we undertook a brief study of this cyclolithiation process. Bailey and others have described a variety of related intramolecular car- bolithiations of alkenes and alkynes. 19-26 Results of the study are depicted in Table 1 and demonstrate that N-allylindolines and N-allylindoles possessing a variety of substitution patterns can be rapidly constructed. Readily available o-bromo-N,N- diallylanilines 1a, 17 1b, 17 1c, 17 and 1d (see the supporting information) were treated with 2 equiv of t-BuLi in tert- butyl methyl ether (TBME) at -78 °C, and then the lithiation reaction mixtures were allowed to warm to room temperature. Protonation of the intermediate 3-(lithiomethyl)indolines thus formed provided a variety of 3-methylindolines in good to high yields (2a - 2d, 61%-95%). The indolines 2a - 2c were carried forward to their respective 3-methylindoles 6a - 6c by treatment with 1 equiv of o-chloranil in TBME at room temperature. By quenching the intermediate 3-(lithiomethyl)indolines formed on cyclolithiation of 1a and 1c with prochiral carbonyl compounds (3-methoxy-4-(benzyloxy)benzalde- hyde 27 and 3,4-diisopropylsquarate 28 ), the 3-substituted indolines 3a, 3c, 4a, and 4c were produced as mixtures of the diastereomers (3a, 2:1; 3c, 1:1; 4a, 1:1; 4c, 1:1) in yields between 55% and 78%. Each of the diastereomeric mixtures converged to a single 3-substituted indole (7a, 7c, 8a, 8c, respectively) on oxidation with o-chloranil in TBME at room temperature. 3-Substituted indoles bearing a basic alkylamino side chain were easily constructed using this cyclolithiation protocol. The indolines 5a and 5b were obtained in 57% and 62% yields, respectively, upon reaction of N-meth- ylenepiperidinium chloride 29 with the 3-(lithiomethyl)- indolines formed by cyclolithiation of o-bromoanilines 1a and 1b. Oxidation to the corresponding indoles 9a and 9b proceeded uneventfully with 1 equiv of o-chloranil in TBME at room temperature (64% and 53%, respectively). On the basis of analysis of the ratios of indoline to uncyclized products, the cyclolithiation process began slowly at 0 °C and was complete after 2 h at room temperature in tert-butyl methyl ether. Both n-BuLi and t-BuLi were used to effect the cyclolithiation in either diethyl ether or tert-butyl methyl ether, the latter orga- nolithium reagent and solvent pair proving the superior combination. An inherent benefit of the intramolecular carbolithia- tion of o-lithio-N,N-diallylanilines is the production of N-allyl-protected indolines, which should be susceptible to deprotection by a variety of known N-deallylation protocols. 17,30,31 To assess the feasibility of N-allylindoline deprotection, N-allylindolines 2a and 2b were treated * To whom correspondence should be addressed: Tel: (404) 727- 6604. Fax: (404) 727-0845. 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