The synthesis of 1-haloalkyl-1,3,4,5-tetrahydro-2-benzoxepins

Short, efficient routes to several 7,8-dimethoxy-1-haloalkyl-1,3,4,5-tetrahydro-2-benzoxepins were developed. These benzoxepins were prepared by the Lewis acid catalyzed condensation of the acetals of chloropropionaldehyde or bromoacetaldehyde with 3-(3,4-dimethoxyphenyl)-1-propanol. This condensation was facilitated by methyl substitution on the propanol. In an alternate route, ethyl 3-(3,4-dimethoxyphenyl)propanoate was acylated with 3-chloropropionyl chloride. The adduct was reduced with lithium aluminum hydride. The resultant 3-2-(3-chloro-1-hydroxypropyl)-4,5-dimethoxyphenyl]propanol was dehydrated to the corresponding tetrahydrobenzoxepin. By these two general routes, 7,8-dimethoxy-1,3,4,5-tetrahydro-2-benzoxepins were produced which were substituted by hydrogen or methyl at benzoxepin C-4 and chloroethyl or bromomethyl at benzoxepin C-1.