Synthesis and asymmetric resolution of a dopaminergic compound: 2-amino-5-methoxyindane

Abstract The racemic synthesis and subsequent resolution of 2-amino-5-methoxyindane enantiomers were achieved starting from 5-bromoindan-2-ol in six steps with 38% total yield. The first step involved the substitution of the Br atom by using NaOMe in the presence of CuI to afford 5-methoxyindan-2-ol. The OH group of 5-methoxyindan-2-ol was converted into its mesylate ester, which was converted into the corresponding azide by reaction with sodium azide. The Pd–C-catalyzed hydrogenation of the azide functional group in the presence of CHCl 3 , followed by neutralization of the amine hydrochloride salt with NaOH, furnished the rac -2-amino-5-methoxyindane. Next, rac -2-amino-5-methoxyindane was converted into its diastereomeric amide derivatives by reaction with ( R )-mandeloyl chloride. The diastereomeric amide mixture was separated by recrystallization to give the ( R , S )- and ( R , R )-diastereomers. The absolute configuration of the ( R , S )-isomer was determined by X-ray crystallography. The hydrolysis of these diastereomers gave ( R )- and ( S )-2-amino-5-methoxyindane with high enantiopurity.