Palladium(II)-Catalyzed Enantioselective Synthesis of α-(Trifluoromethyl)arylmethylamines

Abstract

We describe a method for the synthesis of α-(trifluoromethyl)arylmethylamines that consists of the palladium(II)-catalyzed addition of arylboroxines to imines derived from trifluoroacetaldehyde. Palladium acetate is used as a catalyst with electron-neutral or electron-rich arylboroxines, and it was found that addition of an ammonium or silver salt was crucial to promote the reaction of electron-poor boroxines. With (S)-t-Bu-PyOX as the chiral ligand, this method delivers a variety of α-trifluoromethylated amines in 57-91% yield and with greater than 92% ee in most cases.

Strategies for the Catalytic Enantioselective Synthesis of α-Trifluoromethyl Amines

“…Lautens and co-workers later reported a modified catalytic system to address some of the synthetic challenges they had encountered (Scheme 6, bottom). 36 Switching to Cl 2 Pd-(PyOX) complex 8 with a silver additive that renders the Pd(II) species cationic facilitates transmetalation of the arylboroxine. Similar cationic Pd(II) catalysts have been utilized by the Stoltz group 37 for conjugate addition with arylboron nucleophiles and by Hayashi and co-workers 38 for addition to cyclic sulfonyl imines.…”

“…Lautens and co-workers later reported a modified catalytic system to address some of the synthetic challenges they had encountered (Scheme , bottom) . Switching to Cl 2 Pd­(PyOX) complex 8 with a silver additive that renders the Pd­(II) species cationic facilitates transmetalation of the arylboroxine.…”

Direct Asymmetric Addition of Heteroatom Nucleophiles to Imines

“…[49] As direct precursors of imines and iminium ions, N,O-aminals were converted through asymmetric organocatalysis or metal catalysis to diverse enantiomerically enriched compounds including Nheterocycles. [50] For example, it has been observed that N,O-aminals have been involved in asymmetric Mannich reactions, [51][52][53][54][55] asymmetric nucleophilic alkylations, [56][57][58] asymmetric aza-Petasis-Ferrier rearrangement, [59] asymmetric Suzuki-Miyaura crosscoupling reactions, [60,61] asymmetric aza-Friedel-Crafts reactions, [62][63][64] asymmetric aza-Morita-Baylis-Hillman reactions [65,66] etc.…”

MCM‐41‐Supported Linear Alkylamine‐Catalyzed In Situ Generation of Unstable Trifluoroacetaldehyde and Successive syn‐Selective Direct Aldol Reaction with Cyclic Ketones

“…On the other hand, the aldol reaction using trifluoroacetaldehyde (CF 3 CHO) have been widely developed for the synthesis of various secondary α‐trifluoromethylated alcohols and amines as precursors for antidepressants inhibitors of β‐Amyloid self assembly, calcimimetic drug, and liquid crystals . However, since CF 3 CHO is gaseous and unstable aldehydes, it can not be stored and normally exists as a hydrate or hemiacetal form due to the strong electron‐withdrawing property of the trifluoromethyl group.…”