New Silane Reduction of Aromatic Ketones Mediated by Titanium Tetrachloride: A Synthesis of g- and d-Aryl Substituted Amino Acids

Abstract

Several N-protected 4-ql-2-aminobutanoic acids ( y -q l substituted amino acids ; 7a-f) and N-protected 5-ql-2-aminopentanoic acids ( & q l substituted amino acids ; 8 a , b and d) were prepared in good yields by reduction of the corresponding aromatic or heteroaromatic ketones (3 and 4) with triethylsilane (Et,SiH) or dimethylphenylsilane (PhMe2SiH) in the presence of titanium tetrachloride (TiCI,), respectively.The reduction proceeded without racemization and was successfully applied to the synthesis of optically active y- and 6-aryl substituted amino acids (14a and 15a).HETEROCYCLES, Vot.49,1998 Nordlander and his co-workers reported the reduction of aromatic ketones bearing amino acid moiety with E t $ H in the presence of CF3C0,H or BF3.0Et, for preparation of 4-phenyl-2-aminobutanoic acid derivatives."Theirmethod gave satisfactory results only in the case of the substrates which cany methoxy groups on their aromatic ring.These results were thought to be due to the stabilization of an intermediate benzylic cation by electron-donating groups, e.g.methoxy groups.Indeed, in the case of the substrates without electron-donating groups on the aromatic ring, reductions resulted in the formation of 4-arylhutyrolactones or in the poor yields of the desired products.We recently reported a convenient method for preparation of several y-aryl substituted amino acids (7a-f) by reduction of 3 and their t~imethylsilyl esters using Et,SiH and TiCl4.'.'Yn this paper, we wish to describe full details of our results and also describe that this reduction method can be applied to the synthesis of 6-aryl substituted amino acids (8a,b and d) successfully. HETEROCYCLES. VOI. 49,1998isolated yield of product (7a) was, however, 67% (entry 5).Hydrogen chloride, generated in sim by the formation of titanium saltS from 3a and TiCl,, is likely to lower the yield of 7 a (Scheme 1). Scheme 1In order to prevent the generation of hydrogen chloride, we converted the free acid (3a) into its methyl (5a) and trimethylsilyl ester (6a).The reduction of methyl ester (5a) gave the desired product (9a) in only 25% yield, which was accompanied with chlorinated product (10) in 38% yield (entry 6).On the other hand, the reduction of trimethylsilyl ester (6a), converted in siru from 3a, gave the desired N-protected 4ql-2-aminobutanoic acid (7a) in an excellent yield (88%, entry 7).Chloroform or 1,2-dichloroethane as solvent also gave good results as similar as dichloromethane.When the reduction was carried out using K l , , reduction also proceeded smoothly, however, the isolated products were a mixture of 7 a and olefinic product (12a) (entry 8).No reaction occurred when the reduction was carried out using SnCI, as aLewis acid (entry 9).Several examples of the synthesis of y -q l substituted amino acids by the Et,SiH-TiCl4 reduction are demonstrated in Table 3.Besides phenyl and 4-methoxyphenyl ketone (3b and 3c), halogen substituted aromatic and heteroaromatic ketones (3a, 3d, 3e and 3f) were readily reduced, v i a trimethylsilyl ester, into the corresponding 2-(methoxycarbonylamino)hutanoic acids (7a-f) without removal of halogen suhstituent in high yields (83-95%).6carhamate.See experimental section.