Question

Problem 3 In an early benzodiazepine synthesis, the following reaction was carried out, with the aim of making the first product. Was it reasonable to expect the displacement of chloride when the starting material was treated with methylamine? Show a mechanism to explain what actually happens, and give a rationale for why the ring expansion occurs instead of the first reaction. N CH,CI NCH NHCH CH3NH2 ENO not produced Ph Ph NHCH3 N LNCHCI CH3NH2 actual product Y NO

Answer 1

The actual product is forming due to the rearrangement reaction. In the mechanism of second step, firstly methyl amine gives nucleophilic addition at the antibonding of the C=N bond and forms a quaternary carbon center. In the first step, the electrophilicity of the chlorocarbon is much less for the attack of the nucleophile, while in C=N bond, the electrophilicity of carbon increase after nucleophilic addition which generates negatively charged nitrogen atom stabilized by conjugation with the benzene ring.

NH₂ CH₂ N CH₂-4. Yoo in NHCH3 Fooo Ph Actual product