Synthesis of functionalized α-trifluoroethyl amine scaffolds via Grignard addition to N-aryl hemiaminal ethers

Abstract

The synthesis of a variety of a-branched trifluoroethyl amines was achieved by reaction of N-aryl hemiaminal ethers with organomagnesium reagents.

Directed Metalation–Suzuki–Miyaura Cross-Coupling Strategies: Regioselective Synthesis of Hydroxylated 1-Methyl-phenanthrenes

“…While i -PrMgCl produced mixtures of the desired decarbamoylated 7a , together with the normal ( 7i ) and isomeric ( 7j ) Kumada–Corriu cross-coupled products in varying amounts (entries 2 and 3), rapid injection of i -PrMgCl·LiCl afforded high ratios of 7a to the two coupled products (entries 4 and 5). The i -PrMgCl·LiCl complex is considered to be more nucleophilic compared to i -PrMgCl, and its use in a Grignard reaction has shown increased amounts of reduction products, but, to our knowledge, this result constitutes the first intentional use of the turbo-Gringard reagent as a hydride source. For small-scale experiments, the higher 10 mol % catalyst loading is recommended to achieve fast completion of the reaction, although, as gleaned from the experiments, large-scale reactions should be feasible with low catalyst loading and thereby avoidance of environmental problems with excessive Ni residues.…”

Discovery of a novel allosteric inhibitor scaffold for polyadenosine-diphosphate-ribose polymerase 14 (PARP14) macrodomain 2

“…Aminophenyl intermediate 48 was further converted into the urea analogue 49 by treatment with tert -butyl isocyanate ( Scheme 6 ). Since α-trifluoroethylamines are known as bioisosteres of amide groups from peptide chemistry, 25 we also prepared compound 51 for SAR studies. Intermediate 48 was thus converted into 1,1,1-trifluoropropan-2-imine 50 by Pd-catalysed cross-coupling with 2-bromo-3,3,3-trifluoro-1-propene; 26 subsequent reduction with sodium borohydride gave the racemic target compound 51 .…”

One-Pot Synthesis of Functionalized β-Fluoroalkylated Mannich-Type Products from N-Aryl N,O-Acetals

“…In contrast to the corresponding aldimines, trifluoromethylated N,O-acetals derived from 1-ethoxy-2,2,2-trifluoroethanol are readily available and shelf-stable compounds. 17,18 Upon base treatment a transient aldimine intermediate is formed, which subsequently can be attacked by C-nucleophiles to furnish the desired β-amino-β-trifluoromethyl carbonyl compounds. In our studies, we focused on ketones, but also other C-H acidic compounds (esters, nitriles) can be employed as nucleophiles.…”