[3 + 2]-Annulation of gem-Difluoroalkenes and Pyridinium Ylides: Access to Functionalized 2-Fluoroindolizines

Abstract

A [3 + 2]-annulation of gem-difluoroalkenes and pyridinium ylides was developed employing ambient air as the sole oxidant in an open-vessel manner, affording a series of multifunctionalized 2-fluoroindolizines in moderate to good yields. In this reaction, gem-difluoroalkene acts as a C2 synthon and entirely avoids the competitive addition–elimination process, which provides facile access to 2-fluoroindolizines.

Recent Advances in Alkenyl sp2 C–H and C–F Bond Functionalizations: Scope, Mechanism, and Applications

“…By taking advantage of 2,2-difluorovinyl tosylate as the fluorinated synthon, the group of Wu and Wang in 2004 elaborated the direct synthesis of 2-fluoroindolizines from in situ generated N -ylides of pyridiniums (Scheme a) . Inspired by this precedential work, Ren’s group recently illustrated a base-promoted oxidative annulation reaction of gem -difluoroalkenes and pyridinium ylides with ambient air as the sole oxidant under benign conditions (Scheme b) . The protocol underwent a formal [3 + 2] annulation process of the generated pyridinium ylide with gem -difluoroalkenes followed by facile β-F elimination to afford a series of multisubstituted 2-fluoroindolizines in good yields.…”

Oxidative [3+2] Annulation of Pyridinium Salts with gem‐Difluoroalkenes: Synthesis of 2‐Fluoroindolizines

“…Herein, we report an oxidative [3+2] annulation of gem ‐difluoroalkenes with pyridinium salts for the synthesis of multi‐substituted 2‐fluoroindolizines. (Scheme 1d) [9] …”

“…(Scheme 1d). [9] Initially, 1-(2-oxo-2-phenylethyl)pyridin-1-ium bromide 1 a and 2-(2,2-difluorovinyl)naphthalene 2 a were selected as model substrates to evaluate the feasibility of this reaction. To our delight, when a solution of pyridinium salt 1 a and gemdifluoroalkene 2 a in toluene was stirred at 110 °C in the presence of Cs 2 CO 3 under air condition for 5 h, the desired 2fluoroindolizine product 3 aa was successfully obtained in 14% yield (Table 1, entry 1).…”

Rapid and Simple Access to α-(Hetero)arylacetonitriles from Gem-Difluoroalkenes

“…31,32 Recently, gem-difluoroalkenes have emerged as versatile C2 synthons, which have been successfully applied to various organic synthetic methodologies. 33−40 Inspired by our previous research, 41 we speculated that gem-difluoroalkenes might react with aqueous ammonia which would undergo a sequential nucleophilic addition and double hydrogen fluoride elimination processes, affording the desired α-aryl nitriles (Scheme 1).…”

“…Although many elegant strategies with existing “CN” or “CN-free” units have been well established for the synthesis of nitriles, there are still drawbacks in terms of toxicity of reagents, harsh reaction conditions, or substrate scope. Therefore, the development of new and facile procedures by using readily available and inexpensive reagents such as aqueous ammonia as the “N” sources is still highly desirable. , Recently, gem -difluoroalkenes have emerged as versatile C2 synthons, which have been successfully applied to various organic synthetic methodologies. − Inspired by our previous research, we speculated that gem -difluoroalkenes might react with aqueous ammonia which would undergo a sequential nucleophilic addition and double hydrogen fluoride elimination processes, affording the desired α-aryl nitriles (Scheme ).…”