Stereoselective Nucleophilic Trifluoromethylation of N-(tert-Butylsulfinyl)imines by Using Trimethyl(trifluoromethyl)silane

Trifluoromethylated amines are important building blocks for pharmaceutical research.[1] The CF3 group, because of its strongly electron withdrawing nature, lowers the basicity of the amide bond towards nonspecific proteolysis[2] when these amines are incorporated into peptides, as well as modify the solubility and desolvation properties.[3] In spite of its prime importance in the drugs industry, direct asymmetric synthesis of trifluoromethylated amines is a challenge. Pirkle et al.[4] and Mosher and Wang[5] prepared 2,2,2-trifluoro-1-phenylethylamine, and Soloshonok and Ono[6] recently reported an elegant method for the preparation of perfluorinated amines by a novel [1,3]-proton shift reaction. However, all of these methods require fluorinated ketones. Nucleophilic transfer of aCF3o to nitrones and imines for direct preparation of trifluoromethylated amines was recently achieved by Nelson et al.[7] and Blazejewski et al.,[8] respectively. These methods suffer from low yield and lack generality. We now report the first stereoselective synthesis of trifluoromethylated amines by using TMSCF3 2 (TMSˆ SiMe3). Our systematic investigation began as an extension of our earlier work,[9] based on the fact that imines are less electrophilic than carbonyl compounds, and that OÿSi bonds are stronger than NÿSi bonds. We predicted that strongly electrophilic imines might be a solution to this problem under noncatalytic conditions. When N-sulfonylaldimines[10] were used as imine sources the reaction indeed proceeded smoothly in the presence of CsF and gave only the trifluoromethylated adducts in 45 ± 95 % yield. Next we turned our attention to sulfinylimines 1 to make this reaction stereoselective. When chiral sulfinylimines[11] were subjected to similar reaction conditions little or no products were obtained. Sulfinylimines were recovered intact, but TMSCF3 decomposed. We surmised that sulfinylimines are not reactive enough to add TMSCF3. Use of different aprotic solvents and excess of reagents was not helpful. When an excess of TMSCF3 was used, a number of unidentified fluorinated products with little or none of the expected adduct were obtained. TMSImidazole,[8] was recently reported to facilitate addition of TMSCF3 to imines. In our case, however, it was ineffective. In all experiments the starting material was recovered. The above results indicate that TMSCF3 decomposes prior to reacting with the starting material. Hence, we thought that increasing the substrate concentration might be a solution to this problem. Indeed, when neat TMSCF3 was added to a concentrated solution of the imines, the desired adduct was obtained. The mass balance corresponds to recovered starting material. Attempts to complete the reaction by using excess of reagent in different solvents was, however, unsuccessful. Imines were treated with TMSCF3 in the presence of a stoichiometric amount of CsF to give the corresponding trifluoromethylated sulfinamides in 50 ± 65 % yields of isolated products (Table 1, entries 1 ± 7, values in parentheses). Imines with acidic a-hydrogen atoms gave lower yields because of competitive deprotonation. The diastereoselectivity was not very high. During these investigations we thus encountered two problems: a) Conversion of imines was incomplete even in the presence of excess TMSCF3 and CsF; b) imines with an ahydrogen atom failed to react with TMSCF3 because of the basic nature of CsF. However, we overcame these problems by employing a nonmetallic fluoride source. DeShong et al. reported that tetrabutylammonium difluorotriphenylsilicate (TBAT),[12] a soluble fluoride source, is very effective for nucleophilic displacement reactions. We found that TBAT is also effective in our system. Reaction of N-sulfonylaldimines In a typical catalytic dihydroxylation, the 3 b material (100 mg) was added to a mixture of the olefin (1.6 mmol), NMO (1.6 mmol), and water (200 mL) in tBuOH:CH2Cl2 (3 mL; 2:1) solvent. The mixture was stirred at room temperature and regularly analyzed by GC.