A new synthesis of 2-cyano-6-hydroxybenzothiazole, the key intermediate of D-luciferin, starting from 1,4-benzoquinone

2-cyano-6-hydroxybenzothiazole is the key intermediate for the synthesis of D-luciferin, the natural substrate of firefly luciferases. A new synthesis of 2-cyano-6-hydroxybenzothiazole has been realized starting from the reaction of 1,4-benzoquinone with L-cysteine ethyl ester, followed by an oxidation-cyclization of the intermediate ethyl (R)-2-amino-3-(2,5-dihydroxyphenylsulfanyl)propanoate hydrochloride to 2-carbethoxy-6-hydroxybenzothiazole. A suitable protection of this intermediate and a conversion to the corresponding nitrile gave, after deprotection, 2-cyano-6-hydroxybenzothiazole (32% yield from 1,4-benzoquinone). This nitrile reacts with D-cysteine to afford D-luciferin at room temperature in a nearly quantitative yield (90-95%).