Intramolecular alkene Friedel–Crafts cyclization of 1-allyl-1-N- (ortho-alkylphenylamino)cyclohexanes. A useful route to alkyl substituted dihydrospiro[(1H)quinoline-2,1 0 -cyclohexanes]. Unprecedented ipso-substitution of alkyl groups q Vladimir V. Kouznetsov, a, * Fedor I. Zubkov, b, * Eugenia V. Nikitina b and Luz Dary Avellaneda Duarte a a Laboratory of Fine Organic Synthesis, Research Center for Biomolecules, School of Chemistry, Industrial University of Santander, A.A. 678, Bucaramanga, Colombia b Organic Chemistry Department of the Russian Peoples Friendship University, 6, Miklukho-Maklayia St, Moscow 117198, Russian Federation Received 11 November 2003; revised 8 December 2003; accepted 18 December 2003 Abstract—An unprecedented intramolecular Friedel–Crafts ipso-alkylation at the ortho-alkyl group of the N-arylamino moiety of 1-allyl-1-N-arylaminocycloalkanes to give alkyl substituted dihydrospiro[(1H) quinoline-2,1 0 -cycloalkanes] is reported. Unexpected results were explained in the context of intramolecular ipso-substitution of alkyl groups and their 1,2-rearrangement. A plausible mechanism for this type of Friedel–Crafts alkylation by an alkene moiety promoted by a Br€ onsted acid (H 2 SO 4 ) is proposed. Ó 2004 Elsevier Ltd. All rights reserved. Many biologically and pharmacologically active alka- loids bear quinoline or tetrahydroquinoline fragments. The most general method to obtain tetrahydroquino- lines involves intramolecular cyclizations starting from substituted aniline derivatives. Among these, intramo- lecular Friedel–Crafts reactions 1 promoted by Br€ onsted and Lewis acids are considered to be a powerful method for the effective construction of these heterocyclic com- pounds 2 or carbocyclic compounds. 3 Moreover, many new methods for the synthesis of tetrahydroquinoline derivatives have been developed. 4;5 However, there are very few examples that describe the construction of the di- or tetrahydroquinoline ring spiro annulated at position C-2 with cycloalkanes or heterocycles. Thus, the chemistry and biological activity of this type of spiroheterocompounds remain largely unexplored. As part of our research program aimed at the preparation of bioactive nitrogen-containing heterocycles from imi- nes, we developed a practical synthesis of the dihydro- spiro[(1H)quinoline-2,1 0 -cycloalkanes], which is based on the reactivity of accessible ketimines 6 (Scheme 1). HN CH 3 R 2 R 1 HN R 2 R 1 N R 2 R 1 NH 2 R 2 R 1 O ( )n n = 1 - 4 ( )n ( )n ( )n MgBr Scheme 1. Keywords: Spiroquinolines; ipso-Intramolecular electrophilic alkyl- ation; Intramolecular Friedel–Crafts reaction. q Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2003.12.148 * Corresponding authors. Fax: +57-76-349069; e-mail addresses: kouznet@uis.edu.co; fzubkov@sci.pfu.edu.co 0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2003.12.148 Tetrahedron Letters 45 (2004) 1981–1984 Tetrahedron Letters