Extending the utility of [Pd(NHC)(cinnamyl)Cl] precatalysts: Direct arylation of heterocycles

Extending the utility of [Pd(NHC)(cinnamyl)Cl] precatalysts: Direct arylation of heterocycles Anthony R. Martin, Anthony Chartoire, Alexandra M. Z. Slawin and Steven P. Nolan* Full Research Paper Address: EaStCHEM School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK Open Access Beilstein J. Org. Chem. 2012, 8, 1637–1643. doi:10.3762/bjoc.8.187 Email: Steven P. Nolan* - Received: 22 June 2012 Accepted: 24 August 2012 Published: 27 September 2012 * Corresponding author This article is part of the Thematic Series "C–H Functionalization". Keywords: C–H functionalization; direct arylation; heterocycles; N-heterocyclic carbenes; palladium Guest Editor: H. M. L. Davies © 2012 Martin et al; licensee Beilstein-Institut. License and terms: see end of document. Abstract The use of [Pd(NHC)(cinnamyl)Cl] precatalysts in the direct arylation of heterocycles has been investigated. Among four different precatalysts, [Pd(SIPr)(cinnamyl)Cl] proved to be the most efficient promoter of the reaction. The C–H functionalization of sulfuror nitrogen-containing heterocycles has been achieved at low catalyst loadings. These catalyst charges range from 0.1 to 0.01 mol % palladium. Introduction As a powerful addition to the classic palladium cross-coupling reactions, C–H bond functionalization has become a growing field of research over the last few years. The ubiquity of C–H bonds makes them a convenient and cost-effective anchoring position within viable substrates, as no derivatisation to form an organometallic reagent is required. Moreover, among the plethora of C–H bonds present on a molecule, it is often possible to target one C–H linkage specifically, taking advantage of directing groups or particular catalyst selectivity [1-5]. Thus, heteroaromatic scaffolds, which are a common feature in biologically relevant compounds and in materials science [6,7] can be selectively arylated as the heteroatom can act as an intrinsic orientating group [8]. Despite the efficiency of well-defined palladium catalysts bearing NHC (N-heterocyclic carbene) ancillary ligands in classical cross-coupling reactions, they have rarely been applied to direct arylation procedures [9-16]. Among the family of [Pd(NHC)] complexes, the [Pd(NHC)(cin)Cl] (cin = cinnamyl) species are known for their ease of activation through the reduction of the metal centre from Pd(II) to Pd(0) [17]. Therefore, we have investigated the use of such precatalysts in the direct arylation of heteroaromatic compounds in order to compare them to ligand-free or phosphine-bearing catalytic systems, and in the end to see whether the reactivity and application scope of these commercially available complexes could be broadened to include C–H bond functionalization transformations. 1637 Beilstein J. Org. Chem. 2012, 8, 1637–1643. We now report the activity of the [Pd(NHC)(cin)Cl] complexes 1–4 in the direct arylation of heterocycles with NHC ligands being SIPr (1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene), IPr (1,3-bis(2,6-diisopropylphenyl)imidazol2-ylidene), IPr* (1,3-bis(2,6-bis(diphenylmethyl)-4methylphenyl)imidazol-2-ylidene) and IPr* Tol (1,3-bis(2,6bis(di-p-tolylmethyl)-4-methylphenyl)imidazol-2-ylidene) (Figure 1). Complexes 1 and 2 are commercially available and have proven to be highly efficient in Suzuki–Miyaura coupling and Buchwald–Hartwig amination reactions [17-20]. We have also evaluated the recently reported [Pd(IPr*)(cin)Cl] (3), which has shown potency in Suzuki–Miyaura couplings [21] and Buchwald–Hartwig N-arylations [22] even with challenging substrates. To complete this study and to examine the effect of bulky ligands about the metal centre, we have synthesised a new complex [Pd(IPr*Tol)(cin)Cl] (4), which is a IPr* congener. tion File 1). Subsequently, 5 was treated with KOt-Bu in dry THF to generate the corresponding free carbene in situ. The expected [Pd(IPr*Tol)(cin)Cl] was then obtained in an excellent yield (97%) by a simple fragmentation of the palladium dimer [{Pd(cin)(µ-Cl)}2] using the free carbene solution (Scheme 1). Results and Discussion The newly synthesized complex 4 was unequivocally characterised by X-ray diffraction [24] (Figure 2, Supporting Information File 2 and Supporting Information File 3) after suitable crystals were grown from slow diffusion of hexane in dichloromethane. Based on this crystal structure, the percentage buried volume (%V Bur ) of the IPr* Tol ancillary ligand was determined by using the “SambVca” web application [25] and compared to complexes 1–3 (Table 1) [21]. IPr*Tol featured a %VBur in the same range as IPr* (+0.4% difference). SIPr and IPr have been reported as less hindered ligands with %VBur of 37.0 and 36.7, respectively. The length of the Pd–C1 bond in 4 was also examined and is close to the one observed in 3. The study begins with the preparation of the palladium complex 4. Following the strategy recently reported by Markó [23], we were successful in the synthesis of the IPr*Tol·HCl imidazolium salt 5 in a 53% overall yield (see Supporting Informa- With complexes 1–4 in hand, their catalytic activity towards the direct arylation of heteroaromatic compounds was evaluated. For this purpose, the arylation of benzothiophene (6) with Figure 1: [Pd(NHC)(cin)Cl] catalysts examined in direct arylation. Scheme 1: Synthesis of [Pd(IPr*Tol)(cin)Cl] (4). 1638 Beilstein J. Org. Chem. 2012, 8, 1637–1643. Table 2: Catalyst screening for the direct arylation of benzothiophene (6). Catalyst Conversion (%)a [Pd(SIPr)(cin)Cl] (1) [Pd(IPr)(cin)Cl] (2) [Pd(IPr*)(cin)Cl] (3) [Pd(IPr*Tol)(cin)Cl] (4) 76 50 8 49 aConversion of the starting material into C–H arylated product determined by GC, [6] = 0.3 M. Figure 2: Molecular structure of 4. H atoms were omitted for clarity. Selected bond lengths (Å) and angles (°): Pd1–C1 2.034(0), Pd1–Cl1 2.352(5), Pd1–C85 2.132(8), Pd1–C86 2.119(7), Pd1–C87 2.226(6); C1–Pd1-C85 102.9(5), C85–Pd1–C87 71.2(6), C87–Pd1–Cl1 93.3(8), Cl1–Pd1–C1 91.8(6). Table 1: Comparison of the %VBur and d(Pd–C1) in the [Pd(NHC)(cin)Cl] family. NHC %VBura Pd–C1 (Å) SIPr IPr IPr* IPr*Tol 37.0 36.7 44.6 45.0 2.025(7) 2.041(9) 2.038(6) 2.034(0) a%V Bur Figure 3: Previously reported catalytic systems in the direct arylation of benzothiophene (6). to efficiently activate the [Pd(NHC)(cin)Cl] precatalysts [17]. DMA was selected as the solvent and the reaction was conducted at 140 °C. calculated for a 2.00 Å Pd–C1 length. 4-bromotoluene (7) was selected as a benchmark reaction (Table 2). This C–H functionalization, initially described by Ohta [26], was then reported by Bhanage and Mori using 2–10 mol % of well-defined palladium catalysts [27,28] (Figure 3). Alternatively, Fagnou and Kappe proposed a Pd/phosphine system involving 1–2 mol % of palladium and 2–4 mol % of phosphine [29,30], but no example of this reaction involving a well-defined [Pd(NHC)] complex has been described. However, it is note (...truncated)