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Preparation of Substituted Tetrahydro‐1‐benzazepines by Lithiation‐Trapping
Author(s) -
Aeyad Tahani,
Jones Callum G.,
Coldham Iain
Publication year - 2018
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201800868
Subject(s) - chemistry , benzazepines , azepine , electrophile , nitrogen atom , benzazepine , ring (chemistry) , amine gas treating , medicinal chemistry , nuclear magnetic resonance spectroscopy , spectroscopy , adduct , amidine , stereochemistry , combinatorial chemistry , organic chemistry , catalysis , physics , quantum mechanics
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 η 3 ‐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.