Palladium(0)-Catalysed Arylations using Pyrrole and Indole 2-Boronic Acids

Abstract

A versatile synthesis of 2-arylpyrroles and 2-arylindoles is described based on the use of either N-(Boc) pyrrole-2-boronic acid or N-(Boc) indole-2-boronic acid as components for Suzuki coupling.We have described the design of a series of 2,5-disubstituted pyrroles 1 as selective dopamine D 3 receptor antagonists, the synthesis of which required 2-arylpyrroles 2 as key intermediates. 1 Initial approaches to 2 involved reaction of the appropriate benzoyl chloride 3 with Grignard reagent 4 and subsequent treatment with ammonium acetate in a modification of a known procedure. 2 This method is, however, incompatible with the presence of acidic protons or basic nitrogens in 2, and each desired substitution pattern requires repetition of a lengthy reaction sequence. An alternative strategy based on palladium-catalysed aryl cross-coupling methodology offered promise as a shorter, direct and more flexible route and here we describe the successful implementation of this approach.The few literature examples of palladium-catalysed cross coupling involving metallated pyrroles have mainly described the use of magnesium, zinc and tin species. 3,4,5 The use of N-(triisopropylsilyl)pyrrole-3-boronic acid as a Suzuki coupling substrate has been reported, 5 and more recently, the coupling of N-(Boc) pyrrole-2-boronic acid 6 5 to a pyrrole-2-triflate has been described. 7 The use of N-(phenylsulfonyl) pyrrole-2-boronic acid in Suzuki couplings has also been reported. However, the synthesis of this boronic acid starting material proceeds in only 7.5% yield. 8The wide availability of aryl halides, together with the reported stability of 5 suggested a general methodology for the synthesis of 2-arylpyrroles. The N-Boc pyrrole 5 can be readily prepared on a 20 g scale according to the procedure of Martina et al. 6 and the cross coupling reactions of 5 with a range of aryl halides were carried out using the Gronowitz conditions. 9 A mixture of the appropriate aryl iodide or bromide (ArX), tetrakis-(triphenylphosphine)palladium(0) (5 mol%) and 5 (1.4 equivalents) in 1,2-dimethoxyethane, with an excess of aqueous sodium carbonate as base, was heated at reflux for 0.5-18 h to give the corresponding N-Boc aryl pyrroles 6 10 (Scheme 1). The results of the study are summarised in Table 1. For the simple monosubstituted and unsubstituted aryl halides (entries 1-7), a trend was observed towards greater reactivity with increased electron deficiency of the Ar group. In the case of Ar = Ph, iodobenzene (entry 1) gave a cleaner reaction than bromobenzene (entry 2).In all instances the major competing side reactions were deboronation of 5 to give N-(Boc) pyrrole and production of the homodimer 7. 11 The 2-methoxy substituted halides (entries 8-11) gave particularly high yields, possibly due to participation by the 2-methoxy group in the coordination of the intermediate arylpalladium species, and this methodology proved to be compatible with the presence of acidic NH residues (entries 9 and 10) and with the presence of a basic nitrogen centre (entry ...

Highly Efficient Suzuki–Miyaura Coupling of Heterocyclic Substrates through Rational Reaction Design

“…In a comprehensive study of the reactivity of haloindoles and indoleboronic acids in Suzuki cross-couplings, Giralt et al [30] noted that unprotected indoleboronic acid is not well suited for Suzuki reactions. It is thus not surprising that most of the known cross-coupling protocols either utilize N-protected indoleboronic acids, [80] accepting the need for a protection/deprotection sequence, or otherwise are restricted to the use of the more active aryl bromides as coupling partners. [29,34,41,81,82] Recently, the use of improved catalysts and modified reaction protocols has allowed the coupling of aryl chlorides with unprotected indoleboronic acids-unfortunately, though, this requires catalyst loadings of 2-5 mol %.…”

Recent applications of the Suzuki–Miyaura cross-coupling reaction in organic synthesis

“…In this connection, the Johnson and the Lee groups have reported the synthesis of the 2-and 3-substituted pyrroles 62 and 63 via a Pd(PPh 3 ) 4 -catalysed SM cross-coupling reaction. 128,129 Compound 62 can be further used for synthesising 2,5-disubstituted pyrroles. The Pd(PPh 3 ) 4 -catalysed cascade cyclisationcoupling reaction furnished the 3-arylmethylpyrrolidines 64 via a b-hydride elimination process.…”

Solvent‐Assisted Organized Structures Based on Amphiphilic Anion‐Responsive π‐Conjugated Systems

“…As the precursors of amphiphilic anion receptors of type A, diketones 2 a'-c', with two, four, and six triethyleneglycol (TEG) chains, respectively, and 2 d', with six hexaethyleneglycol (HEG) substituents, at the 3,4,5-positions of their aryl rings were obtained in 26,61,56, and 24 % yields, respectively, from the corresponding arylpyrroles (which were in turn synthesized through Suzuki cross-coupling reactions [14] ) and malonyl chloride in CH 2 Cl 2 . [7][8][9]15] Subsequent treatment with BF 3 ·OEt 2 led to the formation of the highly fluorescent BF 2 complexes 2 a-d (Scheme 1 c) in moderate yields.…”

“…[30] The mixture was heated at reflux for 6 h, allowed to cool, and then partitioned between water and CH 2 Cl 2 . The combined extracts were dried over anhydrous MgSO 4 and concentrated to give an oil.…”