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Regioselective Lithiation and Electrophilic Quenching of N ‐Boc‐3‐phenyltetrahydroisoquinoline
Author(s) -
Talk Ruaa A.,
ElTunsi Ashraf,
Robertson Craig C.,
Coldham Iain
Publication year - 2019
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.201900238
Subject(s) - chemistry , electrophile , regioselectivity , medicinal chemistry , substrate (aquarium) , tetrahydroisoquinoline , nitrogen atom , amine gas treating , electrophilic substitution , stereochemistry , isoquinoline , organic chemistry , group (periodic table) , catalysis , oceanography , geology
Tetrahydroisoquinolines are found in many natural products and drug compounds and a convenient method to access 1‐substituted derivatives is to carry out the lithiation at C‐1 followed by trapping with an electrophile. Here we explore the feasibility of lithiation at C‐3 by using a substrate with a benzylic proton on both sides of the nitrogen atom such that lithiation with n BuLi could occur at either C‐1 or C‐3 of the tetrahydroisoquinoline. The regioselectivity in the lithiation was determined using the substrate N ‐ tert ‐butoxycarbonyl (Boc)‐3‐phenyltetrahydroisoquinoline. The lithiation could be followed by in situ ReactIR spectroscopy and the rate of rotation of the carbamate group was determined (barrier to rotation was approximately ΔG ‡ 58 kJ/mol at –50 °C). Subsequent trapping of the organolithium species with an electrophile gave a mixture of two regioisomeric products with a preference for reaction at C‐1. This led to the isolation of 1,3‐disubstituted tetrahydroisoquinolines with trans relative stereochemistry. Removal of the Boc group from the nitrogen atom gave secondary and tertiary amine products.