Phenol → Naphthalene

Participants

Reaction Steps

Preparation of the starting material in case of naphthalenes at ring A is described in Scheme 4. One isomer of naphthalene may be prepared by adopting the procedure shown in the literature [Ashworth, I. W. et al. Org. Process Res. Dev. 2003, 7, 74-81; Huan, Y. et al. J. Med. Chem. 2001, 44, 1815-1826]. Thus, 4-bromo-2-naphthoate 16 is obtained by the Diels-Alder addition of 3-bromocoumalate 15 to in situ-generated benzyne in 87% yield and 4-bromo-1-methoxy-2-naphthoate 19 is obtained by the bromination at the 4-position of 1-hydroxy-2-naphthoic acid 17 using bromine in glacial acetic acid and then methylation of both phenol and carboxylic acid with dimethyl sulfate under basic conditions in 72% yield for the two steps. The other isomer of naphthalene is prepared by adopting AstraZeneca's procedure [Moseley, J. D. et al, Org. Process Res. Dev. 2003, 7, 58-66]. Thus, 1,8-naphthalic anhydride 20 is brominated at the 3-position with bromine in concentrated nitric acid in low yield, and mercury(II) acetate-mediated decarboxylation proceeds by digestion. Acidic hydrolysis of a mixture of organo-Hg intermediates, and subsequent selective crystallization from acetic acid give 3-bromo-1-naphthoic acid 22 in 58% yield for the three steps.

Provenance & Evidence