Efficient Synthesis of Substituted Styrenes and Biaryls (or Heteroaryls) with Regioselective Reactions of ortho-, meta-, and para-Bromobenzyl Bromide

Abstract

Regio-and stereoselective reactions of ortho-, meta-, and para-bromobenzyl bromide under Stille and (or) Suzuki crosscoupling reactions are described that provided substituted styrene monomers and biaryls in two steps. By controlling the experimental conditions, the first coupling provided access to allylarene or diarylmethane intermediates, and the second reaction led to the desired styrenes and biaryls, substituted by a spacer arm in the ortho, meta or para position depending on the starting material.Styrenes and biaryls are useful building blocks for fine chemical synthesis. 1,2 Biaryl moieties with important physical or biological properties are widely represented in organic molecules. 3 As pharmacophores, they are found in many medicinally important compounds such as antibiotic, anti-inflammatory, antihypertensive, and anticancer drugs, among others. Di-or triaromatic rings are the backbone of some of the most efficient and selective ligands for asymmetric catalysis, especially when atropoisomerism is possible. 4Styrenes are of particular interest as monomers in the polymer industry, 5 conferring different properties on the polymers depending on the nature of the substituents present on the derivatives. The development of efficient, selective, and high-yielding methods for the preparation of these molecules will, therefore, continue well into the future. In continuation of our previous studies on the different reactions of the two bromine atoms of bromobenzyl bromide 6 by cross-coupling reactions and recognizing that a chemoselective reaction could be valuable, we have developed an efficient and versatile method to synthesize a wide range of styrenes and biaryls very easily and selectively. We have investigated the selective substitution reaction under two successive Stille 7 and Suzuki 7g,8 crosscoupling reactions with o-, m-, and p-bromobenzyl bromides (Scheme 1). Scheme 1 Preparation of styrene and biaryl compoundsThe first coupling permitted regioselective access to allylarene or diarylmethane intermediates I and II, and the second reaction allowed the synthesis of styrenes and biaryls. Synthesis of Intermediates I and IIUsing 0.95 to 1 equivalents of an organometallic reagent and starting from o-, m-or p-bromobenzyl bromides, we were able to substitute benzylic bromide, rather than arylic bromide, regioselectively by Stille or Suzuki cross-coupling reactions in the presence of a palladium salt. The regioselective reaction of these two types of bromide has already been demonstrated by other reactions (e.g., nucleophilic or metallic substitution), however few reports have investigated this regioselectivity by cross-coupling catalysis. 6,9 We accessed bromo-substituted allylarenes 1a-j (intermediates I) or brominated diarylmethanes 1k-r (intermediates II) depending on the type of palladium catalysis and the organometallic reagent used. The reaction conditions were classical (Table 1), but the temperature of the reaction should not exceed 80 °C, otherwise partial isomerization of the double bond of the ally...