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.