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Highly Diastereoselective Friedel–Crafts Alkylation Reactions via Chiral α‐Functionalized Benzylic Carbocations
Author(s) -
Stadler Daniel,
Bach Thorsten
Publication year - 2008
Publication title -
chemistry – an asian journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.18
H-Index - 106
eISSN - 1861-471X
pISSN - 1861-4728
DOI - 10.1002/asia.200700241
Subject(s) - chemistry , carbocation , racemization , diastereomer , friedel–crafts reaction , steric effects , selectivity , nitro , aryl , medicinal chemistry , substitution reaction , stereochemistry , alkylation , organic chemistry , catalysis , alkyl
A series of chiral 1‐aryl‐1‐alkanols, which carry different functional groups (FGs) at the 2‐position, were subjected to an acid (HBF 4 )‐catalyzed reaction with various arenes. An S N 1 substitution reaction was observed, in the course of which 1,1‐diarylalkanes were formed. In most cases (40 out of 51 reactions), yields were very good to excellent (75–99 %). The diastereoselectivity of the reaction was heavily dependent on the FG at the 2‐position. If the FG was methoxycarbonyl, nitro, hydroxy, cyano, trimethylsilylethynyl, or chloro, the corresponding anti products were favored and with a decreasing preference in this order. The methoxycarbonyl‐substituted substrates gave the anti products with diastereomer ratios (d.r.) that exceeded 92:8 (16 examples). Nitro‐ and hydroxy‐substituted products were obtained in most instances with d.r.≥90:10, whereas cyano‐, trimethylsilylalkynyl‐, or chloro‐substituted substrates delivered only with certain arenes products with high selectivity (d.r.≥90:10). The sterically more demanding FGs ethylsulfonyl, ethoxysulfonyl, and diethoxyphosphonyl induced diastereofacial selectivity in favor of the corresponding syn products, with diethoxyphosphonyl being the most effective. The substrate with FG=PO(OEt) 2 delivered, with eight different arenes, the corresponding syn substitution products (d.r.=80:20 – >95:5). The relative configuration of the products was elucidated by spectroscopic and synthetic methods. On selected examples, the reactions were shown to proceed stereoconvergently, under kinetic control, and without racemization. Depending on the functional group, the onset of the reactions between 2‐methylthiophene and some representative alcohols was found to occur at a temperature Θ between −78 and −40 °C. There was no correlation between the selectivity and Θ . A model is suggested to explain the facial diastereoselectivity based on a preferred conformation of the putative intermediate carbocation.