Masaaki Omote

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.

Synthesis of fluorinated analogs of natural porphyrins potentially useful for the diagnosis and therapy of cancer

Abstract We have synthesized a number of fluorinated analogs of naturally important porphyrin derivatives, such as protoporphyrin and hematoporphyrin, which would be useful for the diagnosis and therapy of cancer, starting from deuteroporphyrin or using ring-closure methodology. Fluorovinyl derivatives of protoporphyrin were synthesized using the Wittig reaction or by employing organozinc reagents. The introduction of trifluorohydroxyethyl groups into deuteroporphyrin gave fluorinated analogs of hematoporphyrin, some of which were resolved to chiral isomers. Ring-closure of pyrrole derivatives carrying trifluorohydroxyethyl groups gave much better yields of chiral fluorinated analogs of hematoporphyrin than the resolution method. This review presents our syntheses of these fluorinated analogs and provides information on localizations of these porphyrins in some tumor cells and tissues.

A novel axially dissymmetric ligand with chiral 2,2,2-trifluoro-1-hydroxyethyl groups

Novel axially dissymmetric ligands (1) with two more chiral carbons were synthesized through homo-coupling of o-bromo-(R or S)-(2,2,2-trifluoro-1-acetoxyethyl)benzene. A high asymmetric induction was accomplished using 5 mol% of the Ti complex of this ligand for the reaction of benzaldehyde with Et2Zn giving 85% ee of 1-phenylpropanol in 97% isolation yield.

Synthesis of organofluorine compounds using ene type reaction of N-(p-toluenesulfonyl)trifluoroacetaldehyde imine

Abstract N -Tosyltrifluoroacetaldehyde imine ( 4 ) reacted as an enophile, but it is very sensitive to moisture and the yields of ene products were low. N -(2,2,2-Trifluoro-1-ethoxyethyl)tosylamide ( 11 ), obtained by the reaction of trifluoroacetaldehyde ethyl hemiacetal ( 1 ) with tosylamide ( 3 ) in the presence of TiCl 4 followed by addition of ethanol, was found to react as a good substitute for 4 to give the same products from the ene reaction of 4 in much better 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.

Synthesis of new fluorovinylzinc reagents and their application for synthesis of fluorine analogs of protoporphyrin

Abstract Treatment of chlorotrifluoroethene (4) or 2-chloro-1,1-difluoroethene (5) with sec-butyllithium in the presence of zinc chloride gave new fluorovinyl zinc reagents (12 or 13). These were distinguished by 19F NMR from trifluorovinylzinc chloride (7) or 1-chloro-2,2-difluorovinylzinc chloride (8) obtained by Normant’s group, via preliminary formation of fluorinated vinyllithium reagents by treatment of 4 or 5 with sec-butyllithium followed by addition of zinc chloride. Reaction of 12 or 13 with 3,8-diiododeuteroporphyrin dimethyl ester (9) in the presence of a palladium catalyst produced 3,8-bis(trifluorovinyl) or 3,8-bis(1-chloro-2,2-difluorovinyl)deuteroporphyrin dimethyl ester (10 or 11) quantitatively, while the same reaction of metal complex of 9 with the reagents (7 or 8) formed by Normant’s method gave 10 or 11 in the yields of 23 or 56%, respectively.

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.