TiCl₄-n-Bu₃N-mediated cascade annulation of ketones with α-ketoesters: a facile synthesis of highly substituted fused γ-alkylidene-butenolides

Abstract

A facile protocol for the synthesis of highly substituted fused γ-alkylidene butenolides using direct annulation of ketones with α-ketoesters, via TiCl4-n-Bu3N mediated aldol addition followed by an intramolecular enol-lactonization/cyclization cascade, is reported.

TiCl4‐Et3N‐mediated one‐step synthesis of γ‐alkylidenebutenolides from ketones: Application to natural product synthesis

“…Overall, based on our results and literature reports, [13,14] a modified Palange's reaction pathway is proposed (Scheme 4). [14] The TiCl 4 -Et 3 N combination directs the cross-aldol addition through the transition state A and gives…”

“…Particularly, with the use of methyl pyruvate ( 2a ), the yield of 3a dramatically improved when Et 3 N was used in the reaction (Table , entry 6), relative to n Bu 3 N (Table , entry 7). Whereas the ethyl pyruvate combined with n Bu 3 N reported by Palange and co‐workers is optimal combination, which also confirmed by us (Table , entry 7). This dramatic difference in the reactivity may be attributed to the difference in the electron‐withdrawing ability between –OMe and –OEt.…”

“…[5a, 6b, 12] Interestingly, Kontham's group and us were inspired to work on the synthesis of γ-alkylidenebutenolides at the same time by Tanabe's protocol for the synthesis of trialkylsubstituted 2-(5H)-furanones (butenolides) using ketones and α,α-dimethoxy ketones (Scheme 1, a) and the combination of TiCl 4 -n-Bu 3 N. [13] Recently, Kontham et al reported a method for the construction of γ-alkylidenebutenolides through direct TiCl 4 -n Bu 3 N mediated cascade annulation of ketones with α-ketoesters (Scheme 1, b). [14] Our work involves the development of a similar methodology that differs in the use of a different ketoester and the base (Scheme 1, c). While our reaction is similar to Kontham's report, we discovered some interesting aspects of this reaction in our study, and importantly, the study reveals the precise mechanism of the reaction.…”

Efficient and Scalable Synthesis of Ketoprofen: A Pyrolytic Aromatization Approach

“…Tanabe’s group exploited a one-pot annulation of ketones with α,α-dimethoxyketones to afford trialkylsubstituted furanones, which proceeded through TiCl 4 -Bu 3 N-mediated aldol addition, followed by an intramolecular enol-lactonization/cyclization cascade . Subsequently, Kontham and co-workers utilized a similar protocol to accomplish the synthesis of highly substituted fused γ-alkylidene butenolides using ketones and α-ketoesters . These elegant works encouraged us to envision that the TiCl 4 -Bu 3 N system could be effective in our aldol-triggered cyclization.…”

“…19 Subsequently, Kontham and co-workers utilized a similar protocol to accomplish the synthesis of highly substituted fused γ-alkylidene butenolides using ketones and α-ketoesters. 20 These elegant works encouraged us to envision that the TiCl 4 -Bu 3 N system could be effective in our aldol-triggered cyclization. With this working hypothesis in mind, we initiated our studies by performing the reaction with ketone 12 (1.0 mmol scale) and ethyl pyruvate 11 (1.5 equiv,) employing TiCl 4 (1.5 equiv) in the presence of tributylamine (Bu 3 N, 2.0 equiv) in DCM; however, the low conversion rate (66%) was measured by GC−MS after the reaction proceeded for 12 h from −78 °C to rt (Table 1, entry 1).…”