Formation of Benzyl Oxazole, A Competitive Path with the Classical Bishler-Napieralski Reaction

1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids (TIC) are of considerable interest due to their biological activity and as an important structural element in several important alkaloids and other medically useful products1. Moreover, TIC is a phenylalanine analogue in which the dihedral angle is limited to a very small range because of its bicyclic nature2. In connection with the design of topographically constrained peptides, TIC has been utilized in several instance as a replacement o…

Formation of Benzyl Oxazole, A Competitive Path with the Classical Bishler-Napieralski Reaction

Several aromatic ring-substituted N-acetyl-phenylalanine methyl esters were treated with POCl3 in refluxing benzene, which is the typical condition of B-N reaction. It was found that the normal B-N product 3, 4-dihydroisoquinoline-3-carboxylic acid methyl ester and/or 5-benzyl-2-methyl-4-methoxy oxazole could be obtained. The result depended mainly upon the electron-donating property of the substitutes on the benzene ring. Strong electron-donating groups located at para- or ortho- to the cyclization site will facilitate the formation of the normal B-N product 2. On the other hand, the absence or weak electron-donating groups tended to yield the oxazole product 3. It was established that the formation of benzyl oxazole is the competitive path with the B-N reaction. In this article, an explanation was given based on the mechanism of Bishler-Napieralski reaction.