Palladium-Catalyzed Enantioselective Three-Component Synthesis of α-Substituted Amines

Abstract

The first general palladium-catalyzed, enantioselective three-component synthesis of α-arylamines starting from sulfonamides, aldehydes, and arylboronic acids has been developed. These reactions generate a wide array of α-arylamines with high yields and enantioselectivities. Notably, this process is tolerant to air and moisture, providing an operationally simple approach for the synthesis of chiral α-arylamines.

Pd(OAc)2-catalyzed asymmetric hydrogenation of sterically hindered N-tosylimines

“…Previous methods of choice for the preparation of these chiral bulky amines (only one or two examples) have relied on chiral substrates, auxiliaries, or resolving agents, and suffered from low enantioselectivities and/or yields 30 – 38 . For example, in 2007, the catalytic enantioselective addition of HN 3 to ketenes was disclosed by Fu and co-workers to give chiral methyl(2,2-dimethyl-1-phenylpropyl)carbamate with 76% ee 33 .…”

Recent Developments in Enantioselective Metal‐Catalyzed Domino Reactions

“…Arylboronic acids 49 have also been reacted by Manolikakes and Beisel with sulfonamides 348 and aldehydes 171 to develop the first general enantioselective palladium‐catalyzed three‐component synthesis of α‐arylamines 349 (Scheme ) 152. A wide variety of commercially available substrates were tolerated, delivering a range of chiral α‐arylamines 349 with uniformly good yields of up to 99% and enantioselectivities of up to 98% ee when the reactions were promoted by a catalyst in situ generated from Pd(TFA) 2 and chiral bisoxazoline 350 in nitromethane at 40 °C.…”

Rhodium‐Catalyzed Enantioselective Arylation of Aliphatic Imines

“…For example, in 2011, Lin and co‐workers reported a rhodium/diene‐catalyzed enantioselective arylation of N ‐tosyl or ‐nosyl aliphatic aldimines . Recently, Beisel and Manolikakes reported a convenient enantioselective arylation of aromatic and aliphatic imines that were synthesized in situ from aldehydes and sulfonamides …”

“…The reaction of the simplest substrate 1 g showed a high enantioselectivity to give 3 ga in 58 % yield with 96 % ee , a high enantioselectivity that has never been achieved by catalytic arylation (Table , entry 3). Although some catalytic systems are known to promote asymmetric arylation of alkyl aldimines, there is only one report for the arylation of 1 g with insufficient results, despite their structural potential including the NPS R‐568 and Cinacalcet . When the R group was changed from methyl to other primary alkyl groups, the reactions also proceeded smoothly to afford the corresponding chiral products in good yields and with high enantioselectivities (entries 4 and 5).…”