Chem. Pharm. Bull. 54(12) 1715—1719 (2006)

ologically important products proceeds efficiently through the action of enzymes without requiring protection of reactive functional groups. However, only a few studies of synthetic reactions using unprotected (free) amino acids have been reported. Most of the synthetic transformations to natural products, pharmaceuticals, and chiral auxiliaries have been performed with protected amino acids to increase solubility in organic solvents and avoid side reactions. We have reported a three-step synthesis of optically active clavicipitic acids (6), ergot alkaloids, from 4-bromoindole (1) and dl-serine (2) that involved a reaction of unprotected amino acids in aqueous media as a key step (Chart 1). Thus, Pd-catalyzed reaction of 4-bromotryptophan [S-(3)] with 1,1dimethylallylalcohol (4) under strong basic conditions selectively yielded the Heck product (5), which spontaneously cyclized to give clavicipitic acids (6) in one pot. This route indicated that the reaction of unprotected amino acids in aqueous media showed promise for developing unique synthetic reactions. Here, we present another reaction of free amino acids in aqueous media, e.g., the direct bromination of unprotected aromatic amino acids (7) under strong acidic conditions (Chart 2, Route A). Results and Discussion Bromination of Phenylalanine An aromatic bromide is an important synthetic intermediate for the introduction of carbon side chain by palladium catalyzed cross-coupling reaction. Generally, bromination of aromatic amino acid (7) is carried out after protection of the amino group, because amino acids are decomposed by the attack of bromonium cations to a carboxyl or amino group (10a or 10b in Route B of Chart 2). Direct bromination of unprotected aromatic amino acids, however, should be possible under strongly acidic conditions because the amino groups are protected by complete protonation to form 8. The choice of the brominating reagent is very important, because the reagent should be stable under strong acidic conditions in aqueous media. Bromoisocyanuric acid monosodium salt (BICA-Na, 11) was selected because it is used as a strong brominating reagent for electron deficient aromatic compounds in concentrated sulfuric acid. Initially, bromination of phenylalanine (15) was conducted in the presence of 1.1 eq of BICA-Na (11). The reaction proceeded smoothly in 60% H2SO4 under mild conditions (0 °C, 2 h). The ortho(16) and para-bromophenylalanine (17) were obtained in 36% and 58% yield, respectively (Table 1, run 2). The total yield of mono-brominated products was very high (94%), and separation of each products (16, 17) was easy by using the reverse phase (ODS) column chromatography. Furthermore, these products were not racemized despite the strong acidic conditions. We previously reDecember 2006 1715 Chem. Pharm. Bull. 54(12) 1715—1719 (2006)