FAM‐Ag‐catalyzed asymmetric synthesis of heteroaryl‐substituted pyrrolidines

Abstract

New derivatives of FAM (ferrocenyl aziridinyl methanol) ligands NFAM1-4 (naphthyl ferrocenyl aziridinyl methanol) and CFAM1-4 (cyclohexyl ferrocenyl aziridinyl methanol) were synthesized to form a small ligand library and used as chiral catalysts with AgOAc for the asymmetric synthesis of heteroaryl-substituted pyrrolidines by the 1,3-dipolar cycloaddition (1,3-DC) reaction of azomethine ylides. 2-Thienyl, 2-furyl, 2-, 3-, and 4-pyridyl aldimines were prepared and used with N-methylmaleimide, dimethyl maleate, tert-butyl acrylate, methyl acrylate, and acrylonitrile to form the corresponding heteroaryl-substituted pyrrolidines. 1,3-DC reactions yielded the expected cycloadducts in up to 89% yield and up to 76% ee that could be increased up to 95% ee upon crystallization. New chiral ligands NFAM1-4 and CFAM1-4 were fully characterized, and their absolute stereochemistry was determined by single-crystal X-ray analysis.

Asymmetric synthesis of aryl‐substituted pyrrolidines by using CFAM ligand–AgOAc chiral system via 1,3‐dipolar cycloaddition reaction

“…Chiral ligands PFAM1–4 , CFAM1–4 , and NFAM1–4 shown in Figure 1 were prepared by using the literature procedure reported by our group 21 …”

“…Our group is also interested in developing new chiral ligand–transition metal catalyst systems for the synthesis of enantiomerically enriched aryl‐substituted pyrrolidines 18–21 . Recently, we have reported the synthesis of naphthyl ferrocenyl aziridinyl methanol ( NFAM ) and cyclohexyl ferrocenyl aziridinyl methanol ( CFAM ) chiral ligands and their use with AgOAc for the synthesis of 2‐thienyl, 2‐furyl, 2‐pyridyl‐substituted pyrrolidines via 1,3‐DC reaction of heteroaryl‐aldimines with different dipolarophiles.…”

“…[12][13][14][15][16][17] Our group is also interested in developing new chiral ligand-transition metal catalyst systems for the synthesis of enantiomerically enriched aryl-substituted pyrrolidines. [18][19][20][21] Recently, we have reported the synthesis of naphthyl ferrocenyl aziridinyl methanol (NFAM) and cyclohexyl ferrocenyl aziridinyl methanol (CFAM) chiral ligands and their use with AgOAc for the synthesis of 2-thienyl, 2-furyl, 2-pyridyl-substituted pyrrolidines via 1,3-DC reaction of heteroaryl-aldimines with different dipolarophiles. The current work describes our efforts to obtain aryl-substituted pyrrolidines using phenyl ferrocenyl aziridinyl methanol PFAM 1-4, NFAM1-4, and CFAM1-4 ligands with AgOAc employing N-methyl, N-phenyl, and N-benzylmaleimide dipolarophiles.…”

Catalytic Enantioselective [3+2] Cycloaddition of N‐Metalated Azomethine Ylides

“…The Dogan group described the synthesis of novel ferrocenyl aziridinyl methanol (FAM) ligands and their use in the Ag-catalyzed asymmetric [3 + 2] cycloaddition of imino esters derived from heterocyclic aldehydes 1 with various dipolarophiles 55, including N-methylmaleimide, dimethyl maleate, tert-butyl acrylate, methyl acrylate, vinyl sulfone, chalcone and acrylonitrile. [40] Ligand L13 with AgOAc was shown to be optimal for this process. In general, 2-thienylsubstituted imino esters performed well to give products in 68-75 % yield with 9-76 % ee, whereas 2-furyl -imino ester gave products in 22-87 % yield with 4-63 % ee (Scheme 31).…”

“…The Dogan group described the synthesis of novel ferrocenyl aziridinyl methanol (FAM) ligands and their use in the Ag‐catalyzed asymmetric [3+2] cycloaddition of imino esters derived from heterocyclic aldehydes 1 with various dipolarophiles 55 , including N ‐methylmaleimide, dimethyl maleate, tert ‐butyl acrylate, methyl acrylate, vinyl sulfone, chalcone and acrylonitrile [40] . Ligand L13 with AgOAc was shown to be optimal for this process.…”