Kedong
Yuan
and
Henri
Doucet
*
Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes 1, Organométalliques: Matériaux et Catalyse, Campus de Beaulieu, 35042 Rennes, France. E-mail: henri.doucet@univ-rennes1.fr; Fax: +33 0223236939
First published on 3rd October 2013
The palladium-catalysed coupling of benzenesulfonyl chlorides with thiophene derivatives allows regioselective access to β-arylated thiophenes. The reaction proceeds with easily accessible catalyst, base and substrates, without oxidant or ligand and tolerates a variety of substituents on both the benzene and thiophene moieties.
A few examples of such β-arylations3 have been reported using new catalysts, reactants and/or reaction conditions.4–9 Some of them employ a directing group on the thiophene derivative such as a 2-pyridyl or a carboxanilide function to control the regioselectivity of the arylation.4,5 In 2009, Itami and co-workers established a catalytic system that promotes the β-selective arylation of thiophene derivatives with aryl iodides without a directing group on the thiophenes. This β-functionalisation was obtained using PdCl2 associated with a phosphite ligand using Ag2CO3 as the base (Scheme 1, top).6 Glorius and co-workers have very recently reported an heterogeneously catalyzed C–H arylation of benzo[b]thiophenes.7 They demonstrated that, using Pd/C catalyst without additional ligands or directing groups on benzothiophene, but in the presence of 10 mol% CuCl, the less reactive β-position of benzothiophenes was arylated with excellent selectivity. Studer and Itami have also developed a method for the β-arylation of thiophenes with arylboronic acids under Pd/TEMPO catalysis (Scheme 1, middle).8 The same year, Bach et al. reported that thiophenes substituted at C3 by CH2COOEt or CH2PO(OEt)2 undergo a regioselective oxidative coupling reaction at C4 with various arylboronic acids in the presence of silver oxide, cesium trifluoroacetate [Cs(tfa)], benzoquinone (BQ), and Pd(tfa)2 catalyst in trifluoroacetic acid.9 In 2012, Oi et al. described the direct arylation of (benzo)thiophenes with aryltrimethylsilanes. The use of PdCl2(MeCN)2 catalyst in the presence of CuCl2 as oxidant also gives β-arylated thiophenes (Scheme 1, middle).10
Scheme 1 Procedures for Pd-catalysed β-arylations of thiophene derivatives without directing groups. |
In 2009, Dong and co-workers reported the Pd-catalysed coupling of 2-phenylpyridine with benzenesulfonyl chlorides to prepare sulfones.11 However, in the course of this study they also observed, in one case, a desulfitative12 direct arylation of a quinoline derivative when using elevated temperature in the presence of Ag2CO3 and CuBr. The use of benzenesulfonyl chlorides13–15 as the coupling partners for the palladium-catalysed desulfitative direct arylation of benzoxazoles derivatives has been recently described by Cheng et al.16 Using 10 mol% Pd(OAc)2 catalyst, K2CO3 as base and 1 equiv. of CuI as additive, the 2-arylbenzoxazoles were obtained in high yields. On the other hand, to the best of our knowledge, the desulfitative direct arylation of thiophenes with benzenesulfonyl chlorides has not been reported.
We first examined the influence of several reaction conditions on the product formation (Table 1). The reaction of 4-methylbenzenesulfonyl chloride with 2-methylthiophene using Pd(OAc)2 catalyst and K2CO3 as the base only gave decomposed benzenesulfonyl chloride (Table 1, entry 1). The use of PdCl(C3H5)(dppb) or PdCl2 catalysts led to the desired product 1b in trace quantities (Table 1, entries 2 and 3). On the other hand, Pd(PhCN)2Cl2 catalyst in the presence of a mixture of K2CO3/LiCl gave product 1b in 30% yield (Table 1, entry 4). The addition of 1 equiv. of CuI to the reaction mixture or the use of DMSO or toluene as the solvents resulted in very low yields of 1b. The reaction temperature was found to be a crucial factor for such couplings, as the use of 140 °C instead of 120 °C allowed to increase the yield of 1b to 75% (Table 1, entry 8). Moreover, an excellent regioselectivity was observed, as 1b was produced to a level of 99%. The desired product 1b was obtained in 43% yield using Li2CO3 without additive in the presence of Pd(PhCN)2Cl2 catalyst; whereas similar conditions using Pd(MeCN)2Cl2 catalyst gave 1b in 80% yield (Table 1, entries 9 and 10). Then, we examined the influence of several bases at 140 °C using Pd(MeCN)2Cl2 catalyst. Lower yields of 1b were obtained using three equiv. of K3PO4, KOAc, Na2CO3 or K2CO3 (Table 1, entries 11–14). A complete decomposition of 4-methylbenzenesulfonyl chloride, without formation of 1b, was observed in the presence of Cs2CO3 (Table 1, entry 15). This difference between carbonated bases might be due to the higher solubility of Cs2CO3 compared with Li2CO3, Na2CO3 or K2CO3 in dioxane. A longer reaction time allowed to increase the yield of 1b to 84% with complete conversion of 4-methylbenzenesulfonyl chloride (Table 1, entry 17). Finally, the influence of a few other solvents was examined. NMP, DMF and DMSO gave only decomposed benzenesulfonyl chloride (Table 1, entries 18–20); whereas ethylbenzene and xylene gave 1b in very low yields (Table 1, entries 21 and 22).
Entry | Catalyst | Base (equiv.) | Additive (equiv.) | Solvent | Temp. (°C) | Yield in 1b (%) |
---|---|---|---|---|---|---|
a Conditions: [Pd] 5 mol%, 4-methylbenzenesulfonyl chloride (1 equiv.), 2-methylthiophene (1.5 equiv.), yield determined by GC and crude 1H NMR, 20 h, yields in parenthesis are isolated 1b. b 40 h. | ||||||
1 | Pd(OAc)2 | K2CO3 (2) | — | Dioxane | 120 | 0 |
2 | PdCl(C3H5)(dppb) | K2CO3 (2) | — | Dioxane | 120 | <5 |
3 | PdCl2 | K2CO3 (2) | LiCl (4) | Dioxane | 120 | <5 |
4 | Pd(PhCN)2Cl2 | K2CO3 (2) | LiCl (4) | Dioxane | 120 | 30 (25) |
5 | Pd(MeCN)2Cl2 | K2CO3 (2) | LiCl (1)/CuI (1) | Dioxane | 120 | <5 |
6 | Pd(PhCN)2Cl2 | K2CO3 (2) | LiCl (1) | DMSO | 120 | 0 |
7 | Pd(PhCN)2Cl2 | K2CO3 (2) | LiCl (1) | Toluene | 120 | <5 |
8 | Pd(PhCN)2Cl2 | K2CO3 (3) | LiCl (2) | Dioxane | 140 | 75 (71) |
9 | Pd(PhCN)2Cl2 | Li2CO3 (2) | — | Dioxane | 140 | 43 (40) |
10 | Pd(MeCN)2Cl2 | Li2CO3 (3) | — | Dioxane | 140 | 80 (62) |
11 | Pd(MeCN)2Cl2 | K3PO4 (3) | — | Dioxane | 140 | 48 |
12 | Pd(MeCN)2Cl2 | KOAc (3) | — | Dioxane | 140 | 56 |
13 | Pd(MeCN)2Cl2 | Na2CO3 (3) | — | Dioxane | 140 | 41 |
14 | Pd(MeCN)2Cl2 | K2CO3 (3) | — | Dioxane | 140 | 31 |
15 | Pd(MeCN)2Cl2 | Cs2CO3 (3) | — | Dioxane | 140 | 0 |
16 | Pd(MeCN)2Cl2 | Li2CO3 (6) | — | Dioxane | 140 | 62 (60)b |
17 | Pd(MeCN)2Cl2 | Li2CO3 (3) | — | Dioxane | 140 | 84 (75)b |
18 | Pd(MeCN)2Cl2 | Li2CO3 (3) | NMP | 140 | 0 | |
19 | Pd(MeCN)2Cl2 | Li2CO3 (3) | DMF | 140 | 0 | |
20 | Pd(MeCN)2Cl2 | Li2CO3 (3) | DMSO | 140 | 0 | |
21 | Pd(MeCN)2Cl2 | Li2CO3 (3) | Ethylbenzene | 140 | <5% | |
22 | Pd(MeCN)2Cl2 | Li2CO3 (3) | — | p-Xylene | 140 | <5% |
Then, the scope of the substituents on the benzenesulfonyl chloride moiety for reaction with 2-methylthiophene was examined using 5 mol% Pd(MeCN)2Cl2 catalyst in the presence of Li2CO3 (Scheme 2). We initially employed electron-deficient benzenesulfonyl chlorides. Nitro- and cyano-substituents at C4 of benzenesulfonyl chlorides gave regioselectively (>98%) the 4-arylated 2-methylthiophenes 2 and 3 in 78% and 71% yields, respectively. It should be noted that from 4-trifluoromethylbenzenesulfonyl chloride the β-arylation product 3 was only obtained with 92% regioselectivity.
Good yields and high regioselectivities (98%) were also obtained for the coupling of 4-chloro and 4-bromo-benzenesulfonyl chlorides with 2-methylthiophene, as the desired products 5 and 6 were isolated in 67% and 81% yields, respectively. It should be noted that for these two reactions, no cleavage of the C–Cl and C–Br bonds was observed allowing further transformations. A good yield of 88% of 7 was also obtained from the slightly electron-deficient 4-fluorobenzenesulfonyl chloride. On the other hand, poor yields of 9 and 10 were produced from the congested naphthalene-1-sulfonyl chloride and from the electron-rich 4-methoxybenzenesulfonyl chloride.
The influence of the substituents at C2 on the thiophene moiety was also evaluated (Scheme 3). Three benzenesulfonyl chlorides were coupled with 2-n-butylthiophene. Again, satisfactory yields of 11 and 12 were obtained in the presence of 4-chloro or 4-methyl substituents on the benzene ring, whereas a 4-methoxy substituent led to a poor yield of 13. The arylation of unsubstituted thiophene was also found to proceed at the β-position. However, moderate yields of 14 and 15 were obtained due to some formation of 3,4-diarylated thiophenes. Both chloro- and bromo-substituents at C2 of thiophene were also tolerated, and the 4-arylated 2-halothiophenes 16–22 were obtained in moderate to high yields. Even the use of protected 2-acetylthiophene led to the desired products 23 and 24 with high regioselectivity and moderate to good yields. The reaction of 4-trifluoromethyl- or 4-bromo-benzenesulfonyl chlorides with [2,2′]bithiophenyl also afforded the desired β-arylated compounds 25 and 26 in 78% and 60% yields, respectively.
The 4-arylation of 3-substituted thiophenes was also found to proceed under these reaction conditions (Scheme 4). We first examined the reactivity of 3-methylthiophene in the presence of two benzenesulfonyl chlorides. A high yield of 86% of 27 was obtained using benzenesulfonyl chloride; whereas from 4-methylbenzenesulfonyl chloride, 28 was isolated in only 55% yield. The coupling of benzenesulfonyl chlorides with 3-chlorothiophene also produced the desired 4-arylated 3-chlorothiophenes 29–31. It should be noted that no cleavage of the C–Cl thiophene bond was observed.
Finally, we examined the regioselectivity of the arylation of benzothiophene (Scheme 5). Glorius et al. have recently reported that benzothiophenes can be arylated at the β-position with aryl chlorides using an heterogeneous palladium catalyst associated to copper.7
Using our reaction conditions, in all cases the β-aryl-benzothiophenes were regioselectively produced. Again the best yields were obtained in the presence of electron-deficient benzenesulfonyl chlorides. For example, the use of 4-chloro- or 4-trifluoromethyl-benzenesulfonyl chlorides led to 35 and 37 in 88% yields, respectively. Again, from 4-trifluoromethylbenzenesulfonyl chloride the α-arylation product was also detected with 8% selectivity by GC/MS analysis. Benzenesulfonyl chloride also reacts nicely with benzothiophene to give 32 in 83% yield. It is worth noting that 4-bromobenzenesulfonyl chloride allows the formation of 36 in 83% yield. A reaction of benzothiophene with methyl 3-chlorosulfonylthiophene-2-carboxylate gave 39 in 51% yield, due to an α:β arylation ratio of 11:89; but without formation of bithiophene from self-coupling. This lower regioselectivity might arise from the steric hindrance of this chlorosulfonyl derivative.
Although the mechanism cannot yet be elucidated, a catalytic cycle shown in Scheme 6 can be proposed. The first step of the catalytic cycle is probably the oxidative addition of the benzenesulfonyl chloride to Pd(II) to afford the Pd(IV) intermediate A, as in the reactions reported by Dong.11 Such oxidative additions to Pd(II) have been found to proceed even at room temperature.11b Then, after elimination of SO2, the coordination of thiophene gives B. The migration of the aryl group to the β-carbon atom of thiophene gives C. Finally, base-assisted proton abstraction gives the β-arylated thiophene and regenerates the Pd(II) species.
Footnote |
† Electronic supplementary information (ESI) available: Procedures and 1H and 13C NMR spectra. See DOI: 10.1039/c3sc52420e |
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