Benzenesulfonyl chlorides: new reagents for access to alternative regioisomers in palladium-catalysed direct arylations of thiophenes

Abstract

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.

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Introduction

In recent years, metal-catalysed functionalization of C–H bonds has emerged as a powerful method for simpler access to molecules useful for materials or biological applications. If specific C–H bonds of (hetero)arenes can be easily coupled with arenes, it becomes one of the simplest methods to access bi(hetero)arenes.¹ From thiophene derivatives and aryl halides as the coupling partners, the α-arylated products were easily obtained using palladium catalysts under various conditions (Fig. 1, left).^1g,2 On the other hand, until recently, relatively little effort has been expended towards developing such metal-catalysed direct arylation reactions for the synthesis of β-arylated thiophenes (Fig. 1, right).³

Fig. 1 Regioselectivity for the arylation of thiophene.

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 chlorides^13–15 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.

Results and discussion

Herein, we describe a novel route to β-arylated thiophene derivatives using desulfitative palladium-catalysed C–H functionalisation, from thiophenes and benzenesulfonyl chlorides as the coupling partners (Scheme 1, bottom). The influence of both the benzenesulfonyl chloride and thiophene substituents is 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).

Table 1 Influence of the reaction conditions for the palladium-catalysed desulfitative coupling of 4-methylbenzenesulfonyl chloride with 2-methylthiophene^a

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%

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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.

Scheme 2 Structural variation of the benzenesulfonyl chloride partner.

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.

Scheme 3 Variation of C2-substituents on the thiophene partner.

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.

Scheme 4 Variation of C3-substituents on the thiophene partner.

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

Scheme 5 β-Arylations of benzo[b]thiophene.

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.

Scheme 6 Proposed catalytic cycle.

Experimental

General procedure for synthesis of arylated (benzo)thiophenes

To a 25 mL oven dried Schlenk tube, arylsulfonyl chloride (1 mmol), thiophene derivative (1.5 mmol), Li₂CO₃ (6 mmol, 0.444 g), 1,4-dioxane (2 mL) and bis(acetonitrile)dichloropalladium(II) (0.05 mmol, 12.9 mg) were successively added. The reaction mixture was evacuated by vacuum–argon cycles (5 times) and stirred at 140 °C (oil bath temperature) for 40 hours. After cooling the reaction to room temperature and concentration, the crude mixture was purified by silica column chromatography (Et₂O/PE) to afford the C3 or C4 arylated products.

Conclusions

In summary, we report here the first palladium-catalysed desulfitative arylation of thiophene derivatives. The reaction was found to provide, in most cases, very regioselectively (≥98%) the β-arylated thiophenes. The reaction proceeds with easily accessible ligand-free Pd(MeCN)₂Cl₂ catalyst and Li₂CO₃ as base and tolerates a wide variety of substituents both on the benzenesulfonyl chloride and thiophene moieties. Due to the wide availability of diversely functionalised benzenesulfonyl chlorides, such simple reaction conditions (no expensive base and ligand) should be very attractive to synthetic or materials chemists for access to β-arylthiophenes.

Acknowledgements

We thank the Ministère de la Recherche for a fellowship to K. Y. and the Centre National de la Recherche Scientifique and “Rennes Metropole” for providing financial support.

Notes and references

1. (a) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174–238; (b) T. Satoh and M. Miura, Chem. Lett., 2007, 36, 200–205; (c) L.-C. Campeau, D. R. Stuart and K. Fagnou, Aldrichimica Acta, 2007, 40, 35–41; (d) I. V. Seregin and V. Gevorgyan, Chem. Soc. Rev., 2007, 36, 1173–1193; (e) B.-J. Li, S.-D. Yang and Z.-J. Shi, Synlett, 2008, 949–957; (f) C. Lewis, R. G. Bergman and J. A. Ellman, Acc. Chem. Res., 2008, 41, 1013–1025; (g) F. Bellina and R. Rossi, Tetrahedron, 2009, 65, 10269–10310; (h) L. Ackermann, R. Vicente and A. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792–9826; (i) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094–5115; (j) O. Daugulis, H.-Q. Do and D. Skabashov, Acc. Chem. Res., 2009, 42, 1074–1086; (k) L. Joucla and L. Djakovitch, Adv. Synth. Catal., 2009, 351, 673–714; (l) C.-L. Sun, B.-J. Li and Z.-J. Shi, Chem. Commun., 2010, 46, 677–685; (m) C. Fischmeister and H. Doucet, Green Chem., 2011, 13, 741–753; (n) L. Ackermann, Chem. Rev., 2011, 111, 1315–1345; (o) L. McMurray, F. O'Hara and M. J. Gaunt, Chem. Soc. Rev., 2011, 40, 1885–1898; (p) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord and F. Glorius, Angew. Chem., Int. Ed., 2012, 51, 10236–10254; (q) J. Yamaguchi, A. D. Yamaguchi and K. Itami, Angew. Chem., Int. Ed., 2012, 51, 8960–9009; (r) S. R. Neufeldt and M. S. Sanford, Acc. Chem. Res., 2012, 45, 936–946; (s) J. Wencel-Delord and F. Glorius, Nat. Chem., 2013, 5, 369–375.
2. For Pd-catalysed arylation at C5 of thiophenes with aryl halides: (a) A. Ohta, Y. Akita, T. Ohkuwa, M. Chiba, R. Fukunaga, A. Miyafuji, T. Nakata, N. Tani and Y. Aoyagi, Heterocycles, 1990, 31, 1951–1958; (b) B. Liégault, I. Petrov, S. I. Gorelsky and K. Fagnou, J. Org. Chem., 2010, 75, 1047–1060.
3. J. Roger, A. L. Gottumukkala and H. Doucet, ChemCatChem, 2010, 2, 20–40.
4. (a) T. Okazawa, T. Satoh, M. Miura and M. Nomura, J. Am. Chem. Soc., 2002, 124, 5286–5287; (b) K. Si Larbi, H. Y. Fu, N. Laidaoui, K. Beydoun, M. Miloudi, D. El Abed, S. Djebbar and H. Doucet, ChemCatChem, 2012, 4, 815–823.
5. (a) S. Kirchberg, T. Vogler and A. Studer, Synlett, 2008, 2841–2845 ; For similar reaction with Rh catalyst; (b) T. Vogler and A. Studer, Org. Lett., 2008, 10, 129–131 ; For similar reaction with PhMgBr and an Fe catalyst; (c) N. Yoshikai, S. Asako, T. Yamakawa, L. Ilies and E. Nakamura, Chem.–Asian J., 2011, 6, 3059–3065 ; For similar reaction with Ru catalyst; (d) R. K. Chinnagolla and M. Jeganmohan, Org. Lett., 2012, 14, 5246–5249.
6. (a) S. Yanagisawa, K. Ueda, H. Sekizawa and K. Itami, J. Am. Chem. Soc., 2009, 131, 14622–14623; (b) K. Ueda, S. Yanagisawa, J. Yamaguchi and K. Itami, Angew. Chem., Int. Ed., 2010, 49, 8946–8949.
7. D.-T. D. Tang, K. D. Collins and F. Glorius, J. Am. Chem. Soc., 2013, 135, 7450–7453.
8. (a) S. Kirchberg, S. Tani, K. Ueda, J. Yamaguchi, A. Studer and K. Itami, Angew. Chem., Int. Ed., 2011, 50, 2387–2391; (b) K. Yamaguchi, J. Yamaguchi, A. Studer and K. Itami, Chem. Sci., 2012, 3, 2165–2169; (c) K. Yamaguchi, H. Kondo, J. Yamaguchi and K. Itami, Chem. Sci., 2013, 4, 3753–3757.
9. (a) I. Schnapperelle, S. Breitenlechner and T. Bach, Org. Lett., 2011, 13, 3640–3643; (b) I. Schnapperelle and T. Bach, ChemCatChem, 2013, 5, 3232–3236.
10. K. Funaki, T. Sato and S. Oi, Org. Lett., 2012, 14, 6186–6189.
11. (a) X. Zhao, E. Dimitrijevic and V. M. Dong, J. Am. Chem. Soc., 2009, 131, 3466–3467; (b) X. Zhao and V. M. Dong, Angew. Chem., Int. Ed., 2011, 50, 932–934; (c) For sulfonylations of quinolines using CuI as catalyst: Z. Wu, H. Song, X. Cui, C. Pi, W. Du and Y. Wu, Org. Lett., 2013, 15, 1270–1273 ; For reviews on Pd(II)/Pd(IV) catalysis; (d) K. Muniz, Angew. Chem., Int. Ed., 2009, 48, 9412–9423; (e) A. J. Canty, Dalton Trans., 2009, 10409–10417; (f) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147–1169.
12. For desulfitative couplings using Ru catalysts: (a) N. Kamigata, M. Yoshikawa and T. Shimizu, J. Fluorine Chem., 1998, 87, 91–95; (b) D. A. Nagib and D. W. C. MacMillan, Nature, 2011, 480, 224–228.
13. For a review on transition-metal mediated C–S bond activation: L. Wang, W. He and Z. Yu, Chem. Soc. Rev., 2013, 42, 599–621.
14. For Heck type reaction with benzenesulfonyl chlorides: (a) M. Miura, H. Hashimoto, K. Itoh and M. Nomura, Tetrahedron Lett., 1989, 30, 975–976; (b) M. Miura, H. Hashimoto, K. Itoh and M. Nomura, J. Chem. Soc., Perkin Trans. 1, 1990, 2207.
15. For Stille, Negishi or Suzuki couplings with benzenesulfonyl chlorides: (a) S. R. Dubbaka and P. Vogel, J. Am. Chem. Soc., 2003, 125, 15292–15293; (b) S. R. Dubbaka and P. Vogel, Org. Lett., 2004, 9, 95–98; (c) S. R. Dubbaka and P. Vogel, Angew. Chem., Int. Ed., 2005, 44, 7674–7684.
16. (a) M. Zhang, S. Zhang, M. Lui and J. Cheng, Chem. Commun., 2011, 47, 11522–11524 ; For reactions with sodium sulfinates; (b) B. Liu, Q. Guo, Y. Cheng, J. Lan and J. You, Chem.–Eur. J., 2011, 17, 13415–13419; (c) R. Chen, S. Liu, X. Liu, L. Yang and G.-J. Deng, Org. Biomol. Chem., 2011, 9, 7675–7679.

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Footnote

† Electronic supplementary information (ESI) available: Procedures and ¹H and ¹³C NMR spectra. See DOI: 10.1039/c3sc52420e

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