Toshimasa Katagiri

α-Trifluoromethylated Carbanion Synthons

Trifluomethylated organic compounds often have properties that make them suitable for diverse applications, including materials science, agrochemistry, and pharmaceutical industry. But of all the therapeutic drugs currently available, about 10% of them have a partially fluorinated moiety. Thus, a great deal of attention is being paid to the development of reliable methodologies for trifluoromethylation. Introduction of a trifluoromethyl group into the target molecules mostly relies on either trifluoromethylating reagents or trifluoromethylated synthetic blocks. The chemistry of trifluoromethyl carbanions, nucleophilic trifluoromethylating agents such as the Ruppert-Prakash reagent, and organometallic species has been intensively developed for their important synthetic applications. But the chemistry of beta,beta,beta-trifluoroethyl carbanions (alpha-trifluoromethyl carbanions) and organometallic species has remained undeveloped despite their potential usefulness in organic synthesis. The issue needs to be addressed. This Account outlines successful alkylations and useful synthetic applications of alpha-trifluoromethyl carbanions, such as alpha-substituted beta,beta,beta-trifluoroethyl, alpha-trifluoromethylethenyl, trifluoroacetimidoyl, alpha-trifluoromethyloxiranyl, and related alpha-trifluoromethylated carbanions. The strong electron-withdrawing effect of the alpha-trifluoromethyl group may stabilize the carbanion species electronically. But alpha-trifluoromethyl carbanions and their corresponding organometallic species mostly release fluoride spontaneously to produce difluoroalkenes. This notorious decomposition of alpha-trifluoromethylated carbanions and anionoids has hindered the development of these species for organic synthesis. A well-designed device for the generation, stabilization, and acceleration for alkylation of the alpha-trifluoromethylated carbanions is needed for their synthetic application, as well as stabilization by the electron-withdrawing alpha-substituent. The reported alpha-substituted alpha-trifluoromethyl carbanions can be roughly categorized into three classes based on their structures. The first category, A, is pi-conjugation-stabilized carbanions, which are stabilized by ester, nitro, sulfone, carbonyl, or phenyl groups. alpha-Substituents of these carbanions can delocalize the negative charges on their pi-system with large sigma R electron-withdrawing effects; this prevents accumulation of negative charge on the fluorine atoms. The second category, B, consists of carbanions with sp(3) orbitals either of highly halogenated carbanionsexamples include pentafluoroethyl(trimethyl)fluorosilicate, pentafluoroethyllithium, and alpha,alpha-dichloro-beta,beta,beta-trifluoroethylzinc speciesor of cyclic structures such as oxiranyl- and aziridinyllithiums. Both of these carbanions are also stabilized since they reduce molecular orbital (MO) overlapping of the carbanion orbital to C-F bond orbitals. The third category, C, has carbanions with their anion center at the sp(2) orbital, such as alpha-trifluoromethylated alkenyl carbanions and imidoyl carbanions. These sp(2) orbitals of the carbanion center usually have a small overlap with the C-F bonds of trifluoromethyl groups. The small overlap is able to suppress the E2-type eliminations. alpha-Trifluoromethylated carbanions are, in general, unstable. Their stability is largely affected by factors like hybridization of the orbital that accommodates lone pair electrons, the electronic nature of the alpha-substituents, the degree of covalency in a bond between the carbon and metal, the class of countercation, stabilization by chelation of a metal cation, and so on. The stability, therefore, can be sometimes controlled by tuning these factors adequately so that they can be used for organic synthesis. The chemistry of alpha-trifluoromethylated carbanions for organic synthesis has been progressing steadily. However, the simplest trifluoroethyl and trifluoroacetyl carbanions have never been successfully produced and employed for organic synthesis. Elegant generation and synthetic application of these metal species are one of the most attractive and challenging subjects for active investigation in the future.

Optical Purifications via Self-Disproportionation of Enantiomers by Achiral Chromatography: Case Study of a Series of α-CF3-containing Secondary Alcohols

This work demonstrates that self-disproportionation of enantiomers via achiral chromatography can be recommended as inexpensive and general method for optical purification of enantiomerically enriched compounds. In particular, the advantage of this approach over conventional recrystallization is that it can be used for both crystalline as well as liquid compounds.

Trifluoromethylated amino alcohols as chiral ligands for highly enantioselective Reformatsky reaction

The enantioselective Reformatsky reaction of PhCHO was achieved by the use of trifluoromethylated amino alcohols as chiral ligands to afford the corresponding optically active β-hydroxy ester with up to 90% ee.

Generation and reactions of α-trifluoromethyl stabilized aziridinyl anion, a general synthetic precursor for stereospecific construction of α-amino-α-trifluoromethylated quaternary carbon

Optically pure α-trifluoromethylated aziridinyl anions react with various electrophiles to give the corresponding optically pure 2-trifluoromethyl-2-substituted aziridines, which are general synthetic precursors for optically pure α-amino-α-trifluoromethylated compounds, such as trifluoromethylated α/β-amino acids, in good yields.

PREPARATION OF 2,2-DIFLUOROENOL SILYL ETHERS BY ELECTROREDUCTIVE DEFLUORINATION OF TRIFLUOROMETHYL KETONES

Abstract 2,2-Difluoroenol silyl ethers ( 5 ) were prepared by electroreductive defluorimation of trifluoromethyl ketones ( 4 ) in the presence of chlorotrialkylsilanes (TMSCl, TESCl, TBDMSCl).

Tandem alkylation-defluorination reaction: Synthesis of 2-(N-alkyl-N-aryl)amino-3,3-difluoropropenoates from 2-(N-aryl)imino-3,3,3-trifluoropropanoates

A novel synthesis of fluoroolefins from trifluoromethylated compounds with organometallic reagents was developed. The reaction seems to proceed via 1,4-alkylation on imino nitrogen followed by defluorination of the trifluoromethyl group. Diethylzinc was found to be an efficient reagent for the preparation of 2-(N-aryl-N-ethyl)amino-3,3-difluoropropenoates in excellent yield. A similar synthesis of monofluoroolefin with Grignard reagent was also developed.

Palladium-catalyzed chloroimination of imidoyl chlorides to a triple bond: an intramolecular reaction leading to 4-chloroquinolines.

In this paper, a new type of effective chloroimination was reported. This reaction afforded 4-chloro-2-perfluoroalkyl quinolines from fluorinated imidoyl chlorides in high yields. This is the first achievement of oxidative addition-reductive elimination type C-Cl bond activation by chloropalladation.

Intramolecular SN2 reaction at α-carbon of trifluoromethyl group: preparation of optically active 2-trifluoromethylaziridine

Abstract We have succeeded in intramolecular nucleophilic substitution of the hydroxyl group in (S)-1-(alkylamino)-3,3,3-trifluoro-2-propanol. The reaction provides an optically pure (R)-1-benzyl-2-trifluoromethylaziridine in good yield from optically pure (S)-3-(benzylamino)-1,1,1-trifluoro-2-propanol, which was prepared from (S)-3,3,3-trifluoropropene oxide (75% ee).

Isomorphic supramolecular structures via one-dimensional hydrogen bonding motifs in crystals of chiral difluorolactates, trichlorolactates and trifluorolactates

Optically pure difluorolactates and trichlorolactates were prepared and their crystal structures were determined and compared with those of trifluorolactates. One-dimensional hydrogen bonding networks of these compounds involve infinite OH⋯OH, OH⋯OC, and C–H⋯OC hydrogen bonds. The crystal structure of a single-headed difluorolactate showed a weak intermolecular C–H⋯F hydrogen bond between difluoromethyl (CF2H) groups, leading to a one-dimensional C–H⋯F chain as a hydrogen bonding motif of the CF2H group. In the case of trichlorolactates, the steric effect of the trichloromethyl group on the hydrogen bonding system was revealed. Two-dimensional hydrogen bonding networks by double-headed trifluorolactates, difluorolactate and trichlorolactate provided isomorphic layered crystal structures.

Preparation of optically pure α-trifluoromethyl-α-amino acids from N-tosyl-2-trifluoromethyl-2-alkyloxycarbonyl aziridine.

The preparation of optically pure α-trifluoromethyl-α-amino acids from N-tosyl-2-trifluoromethyl-2-alkyloxycarbonylaziridine is described. Optically pure aziridine was prepared with a 60% yield via three steps from optically pure 2,3-epoxy-1,1,1-trifluoropropane (TFPO). Ring-opening reactions of the aziridine with a variety of nucleophiles and subsequent deprotection of the N-tosyl moieties gave the optically pure β-substituted-α-trifluoromethyl-α-amino acids in moderate to good yields (up to 85%) without racemization at the quaternary stereogenic center of the amino acid.