Nucleophilic 5-endo-trig cyclization of 2-(trifluoromethyl)allylic metal enolates and enamides: Synthesis of tetrahydrofurans and pyrrolidines bearing exo-difluoromethylene units

Abstract

Ketones and imines bearing a 2-(trifluoromethyl)allylic moiety successfully underwent nucleophilic 5-endo-trig cyclization via their metal enolates and enamides. O-or N-Cyclization proceeded exclusively in each case to afford the corresponding five-membered heterocycles with both exo-difluoromethylene and exo-alkylidene units. On treatment with potassium hexamethyldisilazide (KHMDS) or lithium diisopropylamide (LDA), 2-(trifluoromethyl)allylic ketones or imines provided the corresponding tetrahydrofurans or pyrrolidines bearing a Zalkylidene group with perfect or substantial stereoselectivity, respectively.

Facile Synthesis of 2‐Fluorobenzofurans: 5‐endo‐trig Cyclization of β,β‐Difluoro‐o‐hydroxystyrenes

“…Previously, we have developed an alternative approach to obtain ring‐fluorinated heterocycles through the intramolecular cyclization of fluoroalkenes, which simultaneously induced the construction of heterocycle skeletons and regioselective installation of the fluorine substituents [1,15–24] . We achieved 5‐ endo ‐ trig cyclization of the β,β‐difluorostyrene bearing a hydroxy group at the ortho ‐position, which leads to the synthesis of 3‐alkylated 2‐fluorobenzofuran ( Scheme 1 ,a ) [20,21] .…”

“…Previously, we have developed an alternative approach to obtain ring-fluorinated heterocycles through the intramolecular cyclization of fluoroalkenes, which simultaneously induced the construction of heterocycle skeletons and regioselective installation of the fluorine substituents. [1,[15][16][17][18][19][20][21][22][23][24] We achieved 5endo-trig cyclization of the β,β-difluorostyrene bearing a hydroxy group at the ortho-position, which leads to the synthesis of 3-alkylated 2-fluorobenzofuran (Scheme 1,a) [20,21] . Although 5-endo-trig cyclization is considered to be difficult according to Baldwin's rules [25 -35] , this type of cyclization is enabled by the abnormally polarized double bonds in difluoroalkenes.…”