Efficient hydroarylation and hydroalkenylation of vinylarenes by Brønsted acid catalysis

Abstract

Brønsted acid Tf₂NH alone catalyzed Friedel–Crafts-type hydroarylation and head-to-tail hydroalkenylation of vinylarenes under mild reaction conditions have been realized, providing a readily scalable, metal-free, and practical access to the 1,1-diarylalkane scaffolds and trans-1,3-diaryl-1-butenes in high yields and excellent regioselectivities.

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The direct catalytic hydroarylation and hydroalkenylation of vinylarenes are highly atom-economical and fundamental methods for the synthesis of 1,1-diarylalkane (branched) scaffolds, which are core fragments existing in a number of complex natural and synthetic molecules. These compounds always display some biological activities and are potential therapeutic agents against cancer, smallpox, and insomnia, as well as other diseases (Fig. 1).¹ Hence, much attention has been paid to achieve such transformations and numerous elegant developments have been reported (Scheme 1). According to the mechanism, the catalytic reactions can be classified into two major types: (1) hydroarylation through C–H activation by transition metal catalysts,^2,3 and (2) Friedel–Crafts-type alkylation in the presence of Lewis or Brønsted acid.⁴ The former method usually requires a directing group on the arene and preferentially affords the linear adduct, with a few exceptions.⁵ In contrast, 1,1-diarylethanes are generally obtained from Friedel–Crafts-type hydroarylation due to the stability of positive charge on the α-position of styrene that develops upon Lewis acid coordination^4a–g or Brønsted acid protonation^4h–k (Scheme 1, A and B). Recently, Pospech group reported a hydroarylation of styrene derivatives catalyzed by phosphate with indoles as reactive partner. However, the presence of hydroxyl group was necessary for forming more reactive quinonemethide-like intermediate to accomplish the whole reaction (Scheme 1, C).⁶ With the advent of modern ‘super acids’, especially triflimide (Tf₂NH, pK_a = 0.67 in HOAc⁷), we recognized that hydroarylation of simple vinyl arenes might be catalyzed by the strong Brønsted acid via the generation of the intermediate B (Scheme 1, i).

Fig. 1 Representative bioactive 1,1-diarylethanes.

Scheme 1 Hydroarylation and hydroalkenylation of vinylarenes.

Additionally, hydroalkenylation of olefins is one of the current interesting and useful protocols to synthesize essential intermediates for fine and industrial chemicals.⁸ Generally, such reactions could be carried out following three ways to date: head-to-head (h–h),⁹ head-to-tail (h–t)¹⁰ and tail-to-tail (t–t).¹¹ Since a new allylic carbon stereogenic center is formed, the h–t dimerization is considered more attractive. Although a range of metal catalytic systems have been developed for this transformation: Dawans^10a and Yi¹⁰ⁱ disclosed that nickel-based catalyst could catalyze dimerization of styrenes. Shirakawa^10e and Cheng^10f reported that the catalyst containing metal center of palladium and cobalt also showed highly catalytic activity to the reaction. Other development was linked to the discovery that the cooperation of iron and silver salts^10k to facilitate the formation of trans-1,3-diaryl-1-butenes. Although these methods are efficient, the need of expensive phosphorus ligands and additives, as well as generation of oligomers or polymers was a huge drawback. Therefore, in view of the demand for most simple and less expensive processes, the dimerization of styrenes catalyzed by organic catalyst, especially easily accessible Brønsted acids, is a very promising alternative to above-mentioned methodologies. And we suppose that the benzyl cation generated under the catalysis of Tf₂NH could be captured by vinylarenes themselves through nucleophilic addition, followed by deprotonation to form the dimerized product (Scheme 1, ii). In this paper, we describe the successful results obtained in both intramolecular Friedel–Crafts hydroarylation and hydroalkenylation of vinylarenes catalyzed by Tf₂NH alone under mild reaction conditions.¹²

The initial investigation was carried out using a model reaction between styrene 1a and anisole 2a (Table 1). We found that the Friedel–Crafts hydroarylation could take place with Tf₂NH as a catalyst. The screening of solvents showed that dioxane was superior to other solvent and the product was obtained in 71% yield at 80 °C with 4 mol% of Tf₂NH (entries 1–5). Lowering the temperature to 60 °C resulted in 38% yield (entry 6). Because of the challenge to separate two isomers 3a′ of 2- and 4-regioselectivities with anisole 2a, and more importantly, for the development of a practical access to analogues of potential therapeutic agents I–III (Fig. 1),¹ we finally selected 1,2,3-trimethoxybenzene 2b as the reactant to continue our study (entries 7–9), and the further improved reaction condition was obtained in a 5 : 1 molar ratio of arene 2b to 1a at 90 °C with a 4 mol% catalyst loading that led to 75% yield of product 3a exclusively (entry 9). No reaction occurred in the absence of acid catalyst (entry 10).

Table 1 Optimization of reaction conditions for the hydroarylation^a

Entry	Substrate 2	Tf2NH (%)	Solvent	t (°C)	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol) and 2 (0.4 mmol) in 1.0 mL of solvent for 12 h in a sealed tube.b Isolated yield.c The reaction was conducted in a 5 : 1 molar ratio of arene 2b (0.5 mmol) to styrene 1a (0.1 mmol).d In the absence of acid, no reaction determined by GC.
1	2a	2	Et2O	rt	Trace
2	2a	2	THF	80	66
3	2a	2	Cyclohexane	80	62
4	2a	2	Dioxane	80	68
5	2a	4	Dioxane	80	71
6	2a	4	Dioxane	60	38
7	2b	4	Dioxane	80	68
8^c	2b	4	Dioxane	80	73
9^c	2b	4	Dioxane	90	75
10^d	2b	—	Dioxane	90	n.r.

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With the optimized reaction conditions established, we then examined the substrate scope of the hydroarylation between various vinylarenes 1 and 2b (Table 2). Significantly, besides 1a, the transformations took place smoothly to assemble (1-(3,4,5-trimethoxyphenyl)ethyl)-arenes exclusively with other substituted vinylarenes and self-dimerization of 1 was tremendously suppressed. Basically, the relatively electron-rich styrenes were more reactive than electron-deficient ones. For instance, styrenes 1b and 1c with ortho-/para-methyl substituent converted into the corresponding adducts 3b and 3c in 86% and 82% yields, respectively (entries 2 and 3). Compound 3d was readily obtained in 88% yield employing 4-tert-butyl styrene 1d as the substrate (entry 4). The best result was obtained by introducing two methyl groups on 2,5-position of the benzene ring to furnish 3e in 92% yield (entry 5). When electron-withdrawing halogen atom was attached to the aromatic ring in styrenes, the good outcomes was gained. 4-Halogen-containing (F, Cl, and Br) styrenes 1f–h were all compatible with this transformation and cleanly led to 3f–h in 75–50% yields (entries 6–8).

Table 2 Scope of vinylarenes for the hydroarylation^a

Entry	R	3	Yield^b (%)
a Reaction conditions: 1 (0.10 mmol), 2b (0.50 mmol), Tf2NH (4 mol%), dioxane (1 mL), 90 °C, 12 h.b Isolated yield.
1	H	3a	75
2	2-Me	3b	86
3	4-Me	3c	82
4	4-tert-Butyl	3d	88
5	2,5-Dimethyl	3e	92
6	4-F	3f	75
7	4-Cl	3g	62
8	4-Br	3h	50

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To highlight the potential application of the highly atom-economic hydroarylation process, we conducted the reactions of 2-vinylnaphthalene 1i with 2b (Scheme 2, eqn (1)), and 1f with benzofuran 2c and benzo[b]thiophene 2d to gram-scale (eqn (2)). Accordingly, treating 1i (3.0 mmol, 0.462 g) with 2b (15.0 mmol, 5 equiv.), and 1f (6.0 mmol, 0.73 g) with 2c (5.0 mmol, 0.59 g) and 2d (5.0 mmol, 0.67 g) to the standard reaction conditions, readily provided the potent of tubulin polymerization 3i,^1d 3j, and 3k in 80–84% yields. Notably, 3k is a very useful material for the synthesis of anti-insomnia agent benzothiophene IV.^1d

Scheme 2 Gram-scale hydroarylations.

During the period of our studies on above hydroarylation between vinylarenes and anisole, it was found that a small quantity of homodimerized products generated. We reasoned that such dimerization of styrene derivatives might be also catalyzed by Brønsted acids (Table 3). Examination of usual Brønsted acids in THF at 80 °C revealed that Tf₂NH is optimal which promoted the homodimerization successfully to provide the desired product 4a in 70% (entries 1–4). Changing the solvent THF to a mixed solvent of THF and cyclohexane in a 3 : 1 volume ratio increased the yield up to 82% (entry 5). Enlarging the Tf₂NH-loading to 6 mol% didn't improve the reaction (entry 6). A sharp decrease of yield was observed from 80 °C to 60 °C, while raising the temperature to 90 °C didn't afford improvement in the yield (entries 7 and 8).

Table 3 Optimization of reaction conditions for the hydroalkenylation^a

Entry	Acid (mol%)	Solvent	t (°C)	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), acid (4–6 mol%), solvent (1 mL), 60–90 °C, 12 h.b Isolated yield.c Detected by GC analysis.
1	p-TSA (4)	THF	80	—
2	TFA (4)	THF	80	—
3	CF3SO3H (4)	THF	80	60
4	Tf2NH (4)	THF	80	70
5	Tf2NH (4)	THF : cyclohexane (3 : 1)	80	82
6	Tf2NH (6)	THF : cyclohexane (3 : 1)	80	81
7	Tf2NH (4)	THF : cyclohexane (3 : 1)	60	<10^c
8	Tf2NH (4)	THF : cyclohexane (3 : 1)	90	80

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Next, the scope and generality of this homodimerization were explored using various commercially available vinylarenes (Table 4). Besides styrene, both alkyl-substituted and halogenated vinylarenes were all able to participate in the dimerization to provide smoothly the corresponding products. Methyl group in ortho- and para-position had no apparent effect on the yields of products (entries 1–2). Notably, tert-butyl substituent could also tolerate the reaction conditions and provided 4d in 82% yield (entry 3). Gratifyingly, the fluorinated substrates underwent well the process, and gave the trans-1,3-diaryl-1-butenes 4f, and 4j–k in good yields regard less of the substituted position (entries 4–6). Yields of more than 60% were obtained when Cl and Br substituted vinylarenes were used as reaction substrates (entries 7 and 8). With 1-vinylnaphthalene 1l as substrate, the satisfied yield was achieved (entry 9). Prop-1-en-2-ylbenzene 1m and the bicyclic compounds 1n and 1H-indene 1o are also compatible with this transformation, providing 4m–o in acceptable yields (entries 10–12). It is noteworthy that the current homo-hydroalkenylation of 1o is easily scaled up to 10 mmol scale, producing 0.88 g of 4o in 76% yield (entry 12).

Table 4 Homo-hydroalkenylation of diverse vinylarenes^a

Entry	Substrate	Product	Yield^b (%)
a Reaction conditions: 1 (0.2 mmol), Tf2NH (4 mol%), 1.0 mL mixed solvent of THF and cyclohexane with a 3 : 1 volume ratio, 80 °C, 12 h.b Isolated yield.c 10 mmol of 1o run the reaction to give 0.88 g of 4o.
1	2-Me, 1b	4b	82
2	4-Me, 1c	4c	91
3	4-tert-Butyl, 1d	4d	82
4	2-F, 1j	4j	78
5	3-F, 1k	4k	70
6	4-F, 1f	4f	90
7	4-Cl, 1g	4g	60
8	4-Br, 1h	4h	85
9	2-Vinylnaphthalene, 1l	4l	80
10	Prop-1-en-2-ylbenzene, 1m	4m	84
11	1,2-Dihydronaphthalene, 1n	4n	75
12^c	1H-indene, 1o	4o	76

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Remarkably, the cross-hydroalkenylation process occurred efficiently (Table 5). Treatment of 1f (5.0 equiv.) with another vinylarenes, including 1b, 1d, 1p, and 1g, to the standard reaction conditions afforded the desired products 5b–e in 55–89% yields.

Table 5 Cross-hydroalkenylation of vinylarenes^a

Entry	1	5	Yield^b (%)
a Reaction conditions: 1f (1.0 mmol), 1 (0.2 mmol), acid (4 mol%), mixed solvent of THF/cyclohexane (3 : 1, 1 mL), 80 °C, 12 h.b Isolated yield.
1	4-Me, 1b	5b	86
2	4-tert-Butyl, 1d	5c	78
3	2,5-Dimethyl, 1p	5d	89
4	4-Cl, 1g	5e	55

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In conclusion, we described a readily scalable, mild, and efficient method for hydroarylation and head-to-tail hydroalkenylation of vinylarenes with Brønsted acid Tf₂HN as the same only catalyst, which provides an easy access to bioactive 1,1-diarylalkane scaffold and trans-1,3-diaryl-1-butenes. This is the first example of highly regioselective hydroarylation and hydroalkenylation with only one organic catalyst.

Acknowledgements

Financial support from Hundred Talent Program of Chinese Academy of Sciences (CAS) is gratefully acknowledged.

Notes and references

1. (a) G. Beaton, W. J. Moree, F. Jovic, T. Coon and J. Yu, US Pat., 2006/0014797 A1, 2006; (b) M. Alami, S. Messaoudi, A. Hamze, O. Provot, J. D. Brion, J.-M. Liu, J. Bignon and J. Bakala, Patent WO 2009/147217 A1, 2009; (c) A. V. Cheltsov, M. Aoyagi, A. Aleshin, E. C.-W. Yu, T. Gilliland, D. Zhai, A. A. Bobkov, J. C. Reed, R. C. Liddington and R. Abagyan, J. Med. Chem., 2010, 53, 3899; (d) B. L. H. Taylor, E. C. Swift, J. D. Waetzig and E. R. Jarvo, J. Am. Chem. Soc., 2011, 133, 389.
2. For reviews, see: (a) F. Kakiuchi and N. Chatani, Adv. Synth. Catal., 2003, 345, 1077; (b) F. Kakiuchi and T. Kochi, Synthesis, 2008, 3013; (c) D. A. Colby, R. G. Bergman and J. A. Ellman, Chem. Rev., 2010, 110, 624.
3. For selected examples, see: (a) S. Murai, F. Kakiuchi, S. Sekine, Y. Tanaka, A. Kamatani, M. Sonoda and N. Chatani, Nature, 1993, 36, 529; (b) F. Kakiuchi, S. Sekine, Y. Tanaka, A. Kamatani, M. Sonoda, N. Chatani and S. Murai, Bull. Chem. Soc. Jpn., 1995, 68, 62; (c) T. Matsumoto, R. A. Periana, D. J. Taube and H. Yoshida, J. Mol. Catal. A: Chem., 2002, 180, 1; (d) C.-H. Jun, C. W. Moon, J.-B. Hong, S.-G. Lim, K.-Y. Chung and Y.-H. Kim, Chem.–Eur. J., 2002, 8, 485; (e) K. L. Tan, R. G. Bergman and J. A. Ellman, J. Am. Chem. Soc., 2002, 124, 13964; (f) R. Martinez, R. Chevalier, S. Darses and J. P. Genet, Angew. Chem., Int. Ed., 2006, 45, 8232; (g) R. Martinez, J. P. Genet and S. Darses, Chem. Commun., 2008, 3855; (h) K. Jaesung, O. Youhwa, J. Yousung and C. Sukbok, J. Am. Chem. Soc., 2012, 134, 17778; (i) G. E. M. Crisenza, N. G. McCreanor and J. F. Bower, J. Am. Chem. Soc., 2014, 136, 10258; (j) G. E. M. Crisenza, O. O. Sokolova and J. F. Bower, Angew. Chem., Int. Ed., 2015, 54, 14866.
4. For selected examples with Lewis acid catalysis, see: (a) J. Kischel, I. Jovel, K. Mertins, A. Zapf and M. Beller, Org. Lett., 2006, 8, 19; (b) H.-B. Sun, B. Li, R. Hua and Y. Yin, Eur. J. Org. Chem., 2006, 4231; (c) M. Rueping, B. J. Nachtsheim and T. Scheidt, Org. Lett., 2006, 8, 3717; (d) Z. Zhang, X. Wang and R. A. Widenhoefer, Chem. Commun., 2006, 3717; (e) S. Hajra, B. Maji and S. Bar, Org. Lett., 2007, 9, 2783; (f) Y. Yamamoto and K. Itonaga, Chem.–Eur. J., 2008, 14, 10705; (g) K. M. Reddy, N. S. Babu, P. S. S. Prasad and N. Lingaiah, Catal. Commun., 2008, 9, 2525. With Brønsted acid catalysis, see: (h) A. E. Cherian, G. J. Domski, J. M. Rose, E. B. Lobkovsky and G. W. Coates, Org. Lett., 2005, 7, 5135; (i) X. Zhao, Z. Yu, T. Xu, P. Wu and H. Yu, Org. Lett., 2007, 9, 5263; (j) B. Das, M. Krishnaiah, K. Laxminarayana, K. Damodar and D. N. Kumar, Chem. Lett., 2009, 38, 42; (k) T. P. Pathak, J. G. Osiak, R. M. Vaden, B. E. Welm and M. S. Sigman, Tetrahedron, 2012, 68, 5203. With other organic catalysts, see: (l) C.-M. Chu, W.-J. Huang, J.-T. Liu and C.-F. Yao, Tetrahedron Lett., 2007, 48, 6881; (m) R. D. Patil, G. Joshi and S. Adimurthy, Monatsh. Chem., 2010, 141, 1093.
5. (a) Y. Uchimaru, Chem. Commun., 1999, 1133; (b) Y. Nakao, N. Kashihara, K. S. Kanyiva and T. Hiyama, J. Am. Chem. Soc., 2008, 130, 16170; (c) T. Mukai, K. Hirano, T. Satoh and M. Miura, J. Org. Chem., 2009, 74, 6410; (d) Y. Nakao, N. Kashihara, K. S. Kanyiva and T. Hiyama, Angew. Chem., Int. Ed., 2010, 49, 4451; (e) S. Pan, N. Ryu and T. Shibata, J. Am. Chem. Soc., 2012, 134, 17474; (f) L.-P. Sheng and N. Yoshikai, Angew. Chem., Int. Ed., 2013, 52, 1240; (g) Z. Yang, H. Yu and Y. Fu, Chem.–Eur. J., 2013, 19, 12093; (h) J. Dong, P.-S. Lee and N. Yoshikai, Chem. Lett., 2013, 42, 1140; (i) G. E. M. Crisenza, N. G. McCreanor and J. F. Bower, J. Am. Chem. Soc., 2014, 136, 10258; (j) P.-S. Lee and N. Yoshikai, Org. Lett., 2015, 17, 22; (k) M. Y. Wong, T. Yamakawa and N. Yoshikai, Org. Lett., 2015, 17, 442.
6. I. Fleischer and J. Pospech, RSC. Adv., 2015, 5, 493.
7. (a) The pK_a Values in glacial acetic acid were measured by ¹H NMR spectroscopy, see: B. M. Rode, A. Engelbrecht and J. Schantl, Z. Phys. Chem., 1973, 253, 17; (b) The pK_a Values of Tf₂NH and HOTf in glacial acetic acetic acid are 7.8 and 4.2, respectively, see: J. Foropoulos and D. D. DesMarteau, Inorg. Chem., 1984, 23, 3720.
8. (a) Y. Chauvin and H. Olivier, in Applied Homogeneous Catalysis with Organometallic Compounds, ed. B. Cornils and W. Herrmann, VCH, New York, 1996, vol. 1, p. 258; (b) J. Skupinska, Chem. Rev., 1991, 91, 613; (c) T. Alderson, E. Jenner and R. V. Lindsey, J. Am. Chem. Soc., 1965, 87, 5638; (d) M. Brookhart, P. S. White and G. M. Direnzo, J. Am. Chem. Soc., 1996, 118, 6225; (e) B. L. Small and A. J. Marcucci, Organometallics, 2001, 20, 5738; (f) B. L. Small, Organometallics, 2003, 22, 3178; (g) T. Mitsudo, T. Suzuki, S.-W. Zhang, D. Imai, K. Fujita, T. Manabe, M. Shiotsuki, Y. Watanabe, K. Wada and T. Kondo, J. Am. Chem. Soc., 1999, 121, 1839.
9. T. Kondo, D. Takagi, H. Tsujita, Y. Ura, K. Wada and T. Mitsudo, Angew. Chem., Int. Ed., 2007, 46, 5958.
10. (a) F. Dawans, Tetrahedron Lett., 1971, 12, 1943; (b) A. Sen, T.-W. Lai and R. R. Thomas, J. Organomet. Chem., 1988, 358, 567; (c) Z. Jiang and A. Sen, Organometallics, 1993, 12, 1406; (d) T. Tsuchimoto, S. Kamiyama, R. Negoro, E. Shirakawa and Y. Kawakami, Chem. Commun., 2003, 852; (e) T. Tsuchimoto, S. Kamiyama, R. Negoro, E. Shirakawa and Y. Kawakami, Chem. Commun., 2003, 852; (f) C.-C. Wang, P.-S. Lin and C.-H. Cheng, Tetrahedron Lett., 2004, 45, 6203; (g) C.-C. Wang, P.-S. Lin and C.-H. Cheng, Tetrahedron Lett., 2004, 45, 6203; (h) G. W. Kabalka, G. Dong and B. Venkataiah, Tetrahedron Lett., 2004, 45, 2775; (i) C. Yi, R. Hua and H.-X. Zeng, Catal. Commun., 2008, 9, 85; (j) J. R. Cabrero-Antonino, A. Leyva-Prez and A. Corma, Adv. Synth. Catal., 2010, 352, 1571; (k) H. Ma, Q. Sun, W. Li, J. Wang, Z. Zhang, Y. Yang and Z. Lei, Tetrahedron Lett., 2011, 52, 1569.
11. (a) G. Wu, A. L. Rheingold and R. F. Heck, Organometallics, 1987, 6, 2386; (b) G. Wu, S. J. Geib, A. L. Rheingold and R. F. Heck, J. Org. Chem., 1988, 53, 3238; (c) R. N. Das, K. Sarma, M. G. Pathak and A. Goswami, Synlett, 2010, 2908; (d) C.-Y. Ho and L. He, Angew. Chem., Int. Ed., 2010, 49, 9182.
12. A recent review on strong Brønsted acids as catalysts, see: T. Akiyama and K. Mori, Chem. Rev., 2015, 115, 9277.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and characterization data for new compounds. See DOI: 10.1039/c6ra16627j

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