Highly Diastereoselective Friedel–Crafts Alkylation Reactions via Chiral α‐Functionalized Benzylic Carbocations

Abstract

A series of chiral 1-aryl-1-alkanols, which carry different functional groups (FGs) at the 2-position, were subjected to an acid (HBF4)-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. > or = 90:10, whereas cyano-, trimethylsilylalkynyl-, or chloro-substituted substrates delivered only with certain arenes products with high selectivity (d.r. > or = 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 Theta between -78 and -40 degrees C. There was no correlation between the selectivity and theta. A model is suggested to explain the facial diastereoselectivity based on a preferred conformation of the putative intermediate carbocation.

A review of new developments in the Friedel–Crafts alkylation – From green chemistry to asymmetric catalysis

“…In general, the diastereoselectivity can be explained by comparing the A-values (an estimation of the steric demand) of the α-functional groups. If the A-value of the functional group is higher than the A-value of the methyl group, Re -attack is favoured giving the corresponding anti products and vice versa [119]. …”

HBF4‐Catalysed Nucleophilic Substitutions of Propargylic Alcohols

“…In particular, the Friedel–Crafts alkylation of benzylic alcohols in the presence of an excess of HBF 4 · OEt 2 solution at –78 °C has been reported 14. Even though high diastereoselectivities could be achieved with this methodology, the excess of acid and low reaction temperatures represent important drawbacks.…”

Enantioselective synthesis of tatanans A–C and reinvestigation of their glucokinase-activating properties

“…1b 21,22 . The C4″ triisopropylsilyl ether 15 was prepared via straightforward modification of reactions used in the total synthesis of tatanan A (Fig.…”