Synthesis of 2-fluoro-2-pyrrolines via tandem reaction of α-trifluoromethyl-α,β-unsaturated carbonyl compounds with N-tosylated 2-aminomalonates

Abstract

A simple base-mediated tandem SN2'/SNV reaction of the readily available α-trifluoromethyl-α,β-unsaturated carbonyl compounds with N-tosylated 2-aminomalonates was developed, which provide an efficient access to functionalized tetrasubstituted 2-fluoro-2-pyrrolines in good to excellent yields. In contrast, simple 1,2-nucleophilic adducts were produced when α-trifluoromethyl styrenes were used.

Synthesis of Fluorinated Benzo[a]quinolizidines via Visible Light‐induced Tandem Substitution of Two Fluorine Atoms in a CF3 Group

“…This strategy was first demonstrated by Ichikawa in a formal [3+2] cyclization between α‐trifluoromethyl alkenes and hydrazines for 3‐fluoropyrazole synthesis . Following this report, Zhang and co‐worked reported one‐pot approaches to 2‐fluoro‐4H‐pyrans and 2‐fluoro‐2‐pyrrolines via base‐mediated reactions of α‐trifluoromethyl alkenes with 1,3‐dicarbonyl compounds and N ‐tosylated 2‐aminomalonates respectively. Very recent, Ichikawa also developed the construction of fluorinated seven‐membered carbocycles from α‐CF 3 alkenes and 2,2′‐diceriobiaryls .…”

“…Moreover, the S N 2′ reaction of nucleophiles with α‐trifluoromethyl alkenes leads to 1,1‐difluoro‐1‐alkenes, which are susceptible to further nucleophilic substitution in a S N V manner to give monofluoroalkenes . Consequently, the combination of binucleophiles with α‐trifluoromethyl alkenes would allow straightforward ring construction via two consecutive C−F substitutions by the sequential S N 2′‐type/S N V process (Scheme , eq 1) . This strategy was first demonstrated by Ichikawa in a formal [3+2] cyclization between α‐trifluoromethyl alkenes and hydrazines for 3‐fluoropyrazole synthesis .…”

“…[14] Consequently, the combination of binucleophiles with a- Figure 1. [15] Following this report, Zhang and co-worked reported one-pot approaches to 2-fluoro-4H-pyrans [16] and 2-fluoro-2-pyrrolines [17] via base-mediated reactions of a-trifluoromethyl alkenes with 1,3-dicarbonyl compounds and N-tosylated 2aminomalonates respectively. [15][16][17][18] This strategy was first demonstrated by Ichikawa in a formal [3 + 2] cyclization between a-trifluoromethyl alkenes and hydrazines for 3-fluoropyrazole synthesis.…”

“…[13] Moreover, the S N 2' reaction of nucleophiles with a-trifluoromethyl alkenes leads to 1,1-difluoro-1-alkenes, which are susceptible to further nucleophilic substitution in a S N V manner to give monofluoroalkenes. [15][16][17][18] This strategy was first demonstrated by Ichikawa in a formal [3 + 2] cyclization between a-trifluoromethyl alkenes and hydrazines for 3-fluoropyrazole synthesis. Examples of bioactive compounds with specific benzo[a]quinolizidine skeletons trifluoromethyl alkenes would allow straightforward ring construction via two consecutive CÀF substitutions by the sequential S N 2'-type/S N V process (Scheme 1, eq 1).…”

Synthesis of Monofluoroalkenes: A Leap Forward

“…241 In 2016, a similar approach was used in which α-(trifluoromethyl)-α,β-unsaturated carbonyl compounds were reacted with 2-(tosylamino)malonates to give 2-fluoro-4,5-dihydropyrroles generally in good to excellent yields (Scheme 271). 242…”