Atsushi Tarui

Mechanistic Studies on α-Trifluoromethylation of Ketones via Silyl Enol Ethers and Its Application to Other Carbonyl Compounds

Synthesis of alpha-CF(3) carbonyl compounds has been recognized to be difficult up to now because the polarization of CF(3)(delta-)-I(delta+) is opposite to that of CH(3)(delta+)-I(delta-), and this makes it difficult to introduce CF(3)(+) unit to enolates. We recently reported an effective alpha-trifluoromethylation of ketones by using Et(2)Zn with Rh catalyst, but the mechanism has not fully been cleared. Now, we carried out the detailed mechanistic studies and found the involvement of a highly reactive alkylrhodium complex which derived from Et(2)Zn and RhCl(PPh(3))(3) in this alpha-trifluoromethylation. Furthermore, this alpha-trifluoromethylation was applied to other types of carbonyl compounds in good yields.

Direct Synthesis of 1,3-Diketones by Rh-Catalyzed Reductive α-Acylation of Enones

1,3-Diketones were synthesized from alpha,beta-unsaturated ketones by treatment with acid chlorides and Et(2)Zn in the presence of RhCl(PPh(3))3. This is a very simple and extremely chemoselective reaction to give the adduct at the alpha-position of alpha,beta-unsaturated ketones.

Simple synthesis of β-trifluoromethylstyrenes using (E)-trimethyl-(3,3,3-trifluoroprop-1-enyl)silane.

(E)-trimethyl-(3,3,3-trifluoroprop-1-enyl)silane (1) was synthesized as a reagent for use in Hiyama cross-coupling reactions for the production of β-trifluoromethylstyrene derivatives. Cross-coupling of 1 with electronically diverse aryl iodides was achieved by treatment with CsF in the presence of catalytic amounts of palladium to afford the desired products in moderate to good yields.

The diastereoselective synthesis of difluoro-β-lactam using Reformatsky-Honda reaction

The high diastereoselective synthesis of chiral difluoro-β-lactams (3) was attained by treatment of ethyl bromodifluoroacetate (1), 2-hydroxy-l-phenylethyl group substituted imines (2) and diethylzinc in the presence of rhodium-catalyst. The absolute configuration of 3 was determined by X-ray analysis of 3,5-dinitrobenzoate (6) derived from 3.

Nickel-Catalyzed Negishi Cross-Coupling of Bromodifluoroacetamides

A nickel-catalyzed Negishi coupling of bromodifluoroacetamides with arylzinc reagents has been developed. This reaction allows access to difluoromethylated aromatic compounds containing a variety of aryl groups and amide moieties. Furthermore, highly effective transformation of the functionalized difluoromethyl group (-CF2CONR(1)R(2)) was realized via microwave-assisted reduction under mild conditions. The notable features of this strategy are its generality and its use of a low-cost nickel catalyst and ligand; thus, this reaction provides a facile method for applications in drug discovery and development.

Csp3–Csp3 Homocoupling Reaction of Benzyl Halides Catalyzed by Rhodium

A highly reactive alkylrhodium complex was formed from Me(2)Zn and RhCl(PPh(3))(3) and effectively catalyzed a Csp(3)-Csp(3) homocoupling reaction of benzyl halides. A Csp(3)-Csp(3) coupling reaction using Rh catalyst has not been reported up to now. The reaction proceeded under very mild conditions and gave the corresponding homocoupling products even if they had reactive substituents such as an uncovered formyl or hydroxymethyl group.

Diastereoselective synthesis of 2-fluoroaziridine-2-carboxylates by Reformatsky-type aza-Darzens reaction

Abstract The reaction of ethyl dibromofluoroacetate with imines using zinc metal gave 2-fluoroaziridine-2-carboxylates via aza-Darzens reaction of the primary product of the Reformatsky reaction with high diastereoselectivity in excellent yields (quantitative yield and Dr=85:15). This chemoselective formation of 2-fluoroaziridines was achieved by using CH3CN as a solvent. Interestingly, the reaction proceeded without activation of zinc metal, which was necessary for the Reformatsky reaction of bromodifluoroacetate. None of α-bromo-α-fluoro-β-lactams, four-membered cyclization products, and noncyclized 3-amino-2-bromo-2-fluorocarboxylic esters, usual Reformatsky adducts, were formed.

Ligand-Promoted Asymmetric Imino-Reformatsky Reaction of Ethyl Dibromofluoroacetate

An enantioselective Reformatsky reaction has been developed for the reaction of ethyl dibromofluoroacetate (1) with an imine. This method represents the first ligand-promoted imino-Reformatsky approach to use a halofluoroacetate. The use of an amino alcohol ligand allowed for the preparation of enantioenriched α-bromo-α-fluoro-β-lactams in good yields with enantioselectivities up to 96% ee. This process also provided access to β-lactam rings bearing two stereogenic centers.

Diastereoselective Synthesis of syn-β-Lactams Using Rh-Catalyzed Reductive Mannich-Type Reaction of α,β-Unsaturated Esters.

The combination of Et2Zn and RhCl(PPh3)3 led to the facile generation of a rhodium-hydride complex (Rh-H) that catalyzed the 1,4-reduction of α,β-unsaturated esters. The resulting rhodium enolate performed as a Reformatsky-type reagent and reacted with various imines to give syn-β-lactams in good to excellent yields with high diastereoselectivity.

Direct and diastereoselective alkylation and aldol reactions of α-bromo-α-fluoro-β-lactams.

Herein, we describe the development of a method for the direct alkylation and aldol reaction of α-bromo-α-fluoro-β-lactams. This method provides facile access to a wide range of 3-alkyl- and 3-hydroxyalkyl-fluoro-β-lactams in good yields under mild conditions. The products were obtained with complete diastereoselectivity with regard to the relative configuration of the β-lactam ring at C3 and C4 positions. The reaction conditions were tolerant of a broad range of electrophiles, which highlights the overall scope and utility of this procedure.