Sonogashira reaction of heteroaryl halides with alkynes catalysed by a palladium-tetraphosphine complex

Abstract

cis,cis,cis-1,2,3,4-Tetrakis(diphenylphosphinomethyl)cyclopentane/(1/2)[PdCl(C₃H₅)]₂ system catalyses the Sonogashira reaction of heteroaryl halides with a range of alkynes with moderate to high substrate/catalyst ratios in good yields. A variety of heteroaryl halides such as pyridines, quinolines, a pyrimidine, an indole, thiophenes, or a thiazole have been used successfully. The reaction also tolerates several alkynes such as phenylacetylene and alk-1-ynols. The nature of the heteroaromatics and the substituent of the alkynes have both an important effect on the reaction rates. High reaction rates were generally observed with phenylacetylene. With this alkyne substrate/catalyst ratios up to 10,000 have been used successfully. An effect of the position of the alcohol function on the reaction rates was observed with alk-1-ynols. Higher substrate/catalyst ratios could be used with but-3-yn-1-ol, pent-4-yn-1-ol or hex-5-yn-1-ol than with propargyl alcohol. The nature and the position of the halide on the heteroaromatics have also an important effect on the reaction rates. As expected, higher reaction rates were obtained with heteroaryl iodides than with heteroaryl bromides or chlorides.

Introduction

The so-called Sonogashira cross-coupling palladium-catalysed reaction between aryl halides and alkynes is among the most widely used methodology in organic synthesis [1], [2], [3], [4]. In recent years, the efficiency of several palladium catalysts for this reaction has been described [5], [6], [7], [8], [9], [10], [11], [12]. The reaction of heteroaryl halides has attracted less attention than the coupling with aryl halides, and suffers generally from high catalysts loadings. A few ligands have been successfully employed for the reaction with these substrates [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]. The first one was triphenylphosphine, however, the catalyst formed by association of this ligand with palladium complexes is not very efficient in terms of substrate/catalyst ratio and 3–10% catalyst had to be used [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25]. Recently, new palladium catalysts have been successfully employed for the alkynylation reactions with heteroaryl halides [26], [27], [28], [29], [30], [31], [32]. In the monophosphine ligand series, interesting results have been reported [26], [27], [28]. Soheili et al. described that P(t-Bu)₃ associated to [(allyl)PdCl]₂ is a good ligand for the reaction of 3-bromopyridine or 3-bromothiophene with phenylacetylene, without CuI, at room temperature [26]. Buchwald et al. obtained high yields of alkynylation adducts using 1% of a catalyst derived from PdCl₂(CH₃CN)₂ and a bulky electron-rich ortho-biphenylphosphane ligand [27]. 3-Bromopyridine reacts with phenylacetylene employing 2.5% Pd(OAc)₂ and an aminophosphine ligand [28]. With an imidazolium carbene ligand good results were obtained for the coupling of 2-iodothiophene using 3% of palladium catalyst [29], [30]. One of the most efficient catalyst reported for this reaction is a palladium(II) complex containing a ferrocene-based phosphinimine-phosphine ligand which gave good yields of adducts using 2-iodo- or 2-bromothiophene as reactants [31]. A palladium-phosphinous acid catalysed Sonogashira cross-coupling reaction that proceeds in water under air atmosphere in the absence of organic co-solvents has been recently developed by Wolf et al. [32]. With this system the coupling of 3-bromo- or 3-chloropyridine with phenylacetylene gave the expected adduct employing 10 mol.% catalyst. Finally, the reaction of 3-iodopyridine with alkynes proceeds in absence of ligand and CuI using 1% PdCl₂ as catalyst [33]. Despite these recent advances, there still remains a need for a general protocol employing low catalyst loadings for the coupling of heteroaryl halides with terminal alkynes.

In order to find a stable and efficient palladium catalyst, we have prepared the tetrapodal phosphine ligand, cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl) cyclopentane or Tedicyp (Fig. 1) [34] in which the four diphenylphosphinoalkyl groups are stereospecifically bound to the same face of the cyclopentane ring. We have already reported the results obtained in allylic substitution [34], in Heck reaction [35], in Suzuki cross-coupling [36] and in Sonogashira reaction [37] using Tedicyp as ligand. For example, we obtained a turnover number (TON) of 2,800,000 for the coupling of 3,5-bis(trifluoromethyl)bromobenzene with phenylacetylene [37a]. We have also recently reported the coupling of alkynes with sterically congested aryl bromides [37b], with a range of aryl chlorides [37c], with alkynols [37d] or propargyl amines [37e]. We have also reported preliminary results using heteroaryl bromides and alkynes [38]. Here, we wish to describe our results involving heteroaryl bromides such as halopyridines, haloquinolines, a bromopyrimidine, a bromothiazole, a bromoindole and halothiophenes with terminal alkynes such as phenylacetylene or alk-1-ynols.