Synthesis of Indolizine Derivatives by Electrocyclization

Abstract

Significance: A rapid and efficient synthesis of indolizine derivatives is presented. The silylated enyne pyridine and quinoline precursors, obtained by a Wittig-Sonogashira sequence, undergo an unexpected electrocyclic ring closure, which is triggered by a fluoride-mediated desilylation reaction under mild conditions. A plausible mechanism is proposed on the basis of analysis of deuterium labelling experiments.Comment: The indolizine ring constitutes the core of a class of natural products (e.g.). The present synthesis appears to be a general and efficient method for the construction of fused indolizines from readily accessed starting materials. Furthermore, the use of other O, N, and S nucleophiles for the preparation of functionalized systems may be anticipated. N O 1) t-BuOK, N 2) TMS-CCH, Et 3 N PdCl 2 (Ph 3 P) 2 , CuI TMS CsF ROH N RO up to quant. yield N N RO electrocyclic ROH R = Alk, All, Bn R-O N OMe D D 87%, MeOD was used (Ph 3 P + CH 2 Br)Br -SYNFACTS Contributors: Victor Snieckus, Oleg M. Demchuk Synfacts 2006, 1, 0025-0025 P u b l i s h e d o n l i n e : 0 5 . 0 1 .

Direct Synthesis of Monofunctionalized Indolizine Derivatives Bearing Alkoxymethyl Substituents at C-3 and Their Benzofused Analogues

“…In this paper, we wish to report an unprecedented cyclization reaction of the silicon-capped ( Z )-2-pyridine vinylacetylene with various basic alcohol solutions to give 3-alkoxymethyl-substituted indolizines. Likewise, 1-alkoxymethylpyrrolo[1,2- a ]quinolines (benz[ e ]indolizine) derivatives were successfully obtained from the cyclization of ( Z )-2-quinoline vinylacetylene 11a…”

“…Our laboratory recently described the preparation of silylated vinylacetylene derivatives 7 and 8 from commercially available 2-pyridine and 2-quinoline carboxaldehydes by means of modified Wittig bromoolefination/Sonogashira coupling procedures 11b. The treatment of silylated conjugated acetylenic derivatives with basic alcoholic solutions or fluoride ions has been known to afford the corresponding terminal acetylenes .…”

“…In some cases (Table , entries 1−5, and Table , entries 1−6), the desired products were simply extracted from the reaction mixture with excellent purity, thereby eliminating the need for further chromatographic purification. It is of interest to note that, when the desilylation reactions were performed at 0 °C (basic methanolic solution or TBAF), the desilylated vinylacetylenes were obtained 11b. However, when the reactions were allowed to warm to room temperature, the indolizine products eventually prevailed.…”