Preparation and Selective Reactions of Mixed Bimetallic Aromatic and Heteroaromatic Boron–Magnesium Reagents

Abstract

Dedicated to Professor Peter Stanetty on the occasion of his 60th birthdayThe selective functionalization of aryl and heteroaryl compounds is an important synthetic task. The resulting polyfunctional (hetero)aryl derivatives are often essential building blocks in the synthesis of pharmaceuticals, agrochemicals, and new organic materials.[1] We envisaged that bimetallic [2] aromatic derivatives of type 1, which bear two metal-centered substituents of distinctly different reactivity, would be useful reagents. Their stepwise reaction with two electrophiles E 1 and E 2 would provide products of type 2 and 3 (Scheme 1).Unfortunately, the reaction of para-iodoboronic ester 4 a [3] with iPrMgCl afforded only the corresponding isopropylboronate, which results from the attack of the Grignard reagent at the boronic ester functionality. However, the reaction with the new reagent iPrMgCl·LiCl [4] (À78 8C, 2 h) furnished the desired magnesiated boronic ester 5 a, which reacted with a variety of electrophiles to provide boronic esters of type 6 in good yields (Scheme 2, Table 1). Thus, the reaction of 5 a with allylic bromides in the presence of a catalytic amount of CuCN·2 LiCl [5] furnished the expected allylated boronic esters 6 a and 6 b in 77 and 67 % yield, respectively (Table 1, entries 1 and 2). Acylation reactions proceeded best when the Grignard reagents 5 a and 5 b were transmetalated stoichiometrically with CuCN·2 LiCl. Both aliphatic and aromatic acid chlorides reacted smoothly to give the keto-substituted boronic esters 6 c, 6 d, and 6 i in 72, 73, and 71 % yield, respectively (Table 1, entries 3, 4, and 9). The magnesiated boronic esters 5 a-b also added directly to benzaldehyde to provide the hydroxy-substituted boronic esters 6 e and 6 h in 83 and 71 % yield, respectively (Table 1, entries 5 and 8). The boronic ester cuprates underwent a smooth addition-elimination reaction with 3-iodocyclohexenones to furnish the expected b-substituted unsaturated ketones 6 f (78 %), 6 g (79 %), and 6 j (76 %; Table 1, entries 6, 7, and 10). Preliminary experiments showed that the ortho-magnesiated phenylboronic ester 5 c displayed a lower reactivity towards electrophiles. However, its allylation gave the boronic ester 6 k in 71 % yield (Table 1, entry 11).By using the readily available heterocyclic diiodides 7, [6] 8, [7] and 9, [8] it was possible to prepare the iodoheteroaryl boronic esters 11 (76 %), 12 (76 %), and 13 (81 %) by an I/Mg exchange followed by treatment with the dioxaborolane 10 (Scheme 3). These boronic esters were readily converted by treatment with iPrMgCl·LiCl at À78 8C into the related magnesiated species 14-16, which reacted with various electrophiles as found for the magnesiated carbocyclic boronic esters. Thus, the copper(i)-catalyzed allylation of 14 and 16 provided the allylated heterocyclic boronic esters 17 a and 17 c in 83 and 91 % yield, respectively (Table 2, entries 1 and 3). Transmetalation of the magnesiated 2-indolyl boronic ester 15 with CuCN·2 LiCl, followed by treatment with Scheme 1....

Review. Regioselective Functionalization of Pyridines using a Directed Metalation or a Halogen/Metal Exchange

“…Thus, after copper-catalyzed allylation, the allylated boronic ester 77 is obtained in 83 % yield (Scheme 20) [63]. iPrMgCl·LiCl can also be applied to perform Br/Mg-exchange under mild conditions.…”

Recent progress in the synthesis of pyridinylboronic acids and esters

“…8 Stable cyclic pyridinylboronic esters (1B) can also be obtained from intermediate 5 by a "one-pot" procedure with the addition of an alkanediol (such as pinacol), or an alkanediol derivatives (path B via 4a-d, R = R 1 ); 8 When a cyclic borate (4e-g) is used, the cyclic pyridinylboronic ester (1C) is obtained as described by path C after quenching the reaction mixture with aqueous acid or base. 14 There are two general protocols employed that use the metal-halogen exchange, both of which typically use either an organolithium (RLi) or an organomagnesium halide (RMgX). The usual procedure often refers to the procedure where the addition of the organometal to the halopyridine occurs first and is followed by the addition of the trialkyl borate.…”

“…14 The selectivity depends upon the halogens and their positions in the pyridine ring. Systematic studies by Rault et al 5,[23][24][25][26][27][28] and Bryce et al [29][30][31][32] resulted in the preparation of shelf-stable halopyridinylboronic acids and esters.…”

Preparation and Reactions of Heteroaryl Organomagnesium Compounds

“…25 It is also possible to prepare heteroaryl Grignard reagents of the corresponding boronic esters by an I/Mg-exchange (Scheme 11). 26 Thus, heterocyclic magnesiated indole and quinoline boronic esters such as 71 and 74 obtained from the respective iodo derivatives 70 and 73 furnish the keto substituted indole boronic ester 72 and the quinolyl alcohol 75 in excellent yields on reaction with propionyl chloride and benzaldehyde respectively (Scheme 11). 26 These polyfunctionalized boronic esters like 72 and 75 can be further elaborated to more complex heterocycles via the Suzuki cross-coupling reaction 26 to give potential building blocks for the synthesis of pharmaceuticals, agrochemicals and new materials.…”