Preparation of substituted tetrahydro-1-benzazepines by lithiation-trapping

The tetrahydro‐1‐benzazepine or benzo[b]azepine ring system is found in a number of drug molecules although methods to access 2,2‐disubstituted derivatives are rare. Here we report the preparation of N‐tert‐butoxycarbonyl‐2‐phenyltetrahydro‐1‐benzazepine followed by lithiation and trapping with electrophiles. The metallation reaction was optimized by using React‐IR spectroscopy, and VT‐NMR spectroscopy allowed the determination of the rate of rotation of the Boc group (approximate ΔG‡ 63 kJ/mol at –50 °C). The resulting organolithium was quenched to give either 2,2‐disubstituted products or, with certain electrophiles, the ortho‐substituted products, presumably through an η3‐coordinated benzyllithium intermediate. The chemistry was shown to be amenable to extension to the 7‐methoxy analog. Removal of the Boc group from the nitrogen atom led to amine products.