Mild Synthesis of N-Alkyl- and N-Alkyl-b-carboline Anhydoro-bases Using Trifluoromethanesulfonates

Abstract

indoles (1 -3) were quaternized in good yield using various alkyl trifluoromethanesulfonates generated in sit" from the corresponding alcohol and trifluoromethanesulfonic anhydride in the presence of diisopropylethylamine in CH2ClZ.The resulting salts ( 4 -13) were allowed to react with Cs2C03 in refluxing DME to give the corresponding P -~~~b ~l i n e anhydro-bases (14 -23).While attempts to N-acylate compounds (I -1) intermolecularly with different acylating agents failed, intramolecular acylation of the carbonylic acid derivative 24 using trifluoromethanesulfDnic anhydride and diisopropylethyl-mine at -78'C succeeded, to give the l,4-benzodiazepine 28.The intermediacy of the mixed sulfonic-carboxylic anhydride in this z.~~lation reaction was strongly supported by the novel, direct acylation of benzene with benzoic acid under the same conditions.Relevant spectroscopic data of these new compounds are discussed.3-Substituted pyrido13,4-b]indoles (or P-carbolines, e.g. 2 and 3) are known to interact with 1 the benzodiazepine receptor of the m m a l i a n central nervous system.various ~tudies of the structure-activity relationships in this series have shorn the influence of substitutions on all but the 2-position (pyridinyl nitrogen) of a-carbolines ?and 3 on their binding affinities.We report herein the results of our attempts to alkylate and acylate 3-substituted B-carbolines in the 2-position.We first tried to quaternize compound 2 by use of an excess of methyl iodide in dichloromethane at room temperature.However, after 144 hours of reaction, only traces of salt could be detected.This can be easily understood in terms of steric hindrance and electron withdrawing effects of the C-3 substituent.Similar problems have been reported in the quaternization of ortho-substituted pyridine~~'~.To overcome these difficulties, we decided to use the highly reactive trifluoromethanesulfonate (triflate) group, rather than iodide, as the leaving group.The triflates of various alcohols (R20H, Table I) were @nerated ~ & ( e x c e p t for comer-Procedure A ( R = CH, )' CF,SO, Prncedurc B' H H 6 Hq ppm nD 4 5 6 7 8 9 10 11 12 13 m p (~olv.)~ "C VC=N+ cm-I aScc enpetimcntal section.b~ecrystallisation solvcnl :