Copper-catalyzed trifluoromethylthiolation of aryl and vinyl boronic acids with a shelf-stable electrophilic trifluoromethylthiolating reagent

Abstract

A new high yielding method for the preparation of a shelf-stable electrophilic trifluoromethylthiolating reagent, N-(trifluoromethylthio)phthalimide, is described. Reaction of this reagent with a variety of aryl and vinyl boronic acids in the presence of a copper catalyst generated the trifluoromethylthiolated arenes and alkenes in good to excellent yields.

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Aryl trifluoromethylsulfide (ArSCF₃) is a key structure motif in many biologically active compounds, drugs and agrochemicals.¹ It is well-known that the introduction of trifluoromethylthio group into arenes generally enhances their chemical and metabolic stability because of the electron-withdrawing nature of the trifluoromethylthio group. In addition, incorporation of the trifluoromethylthio group generally improves the compound's lipophilicity since the CF₃S group is known to have one of the highest Hansch lipophilicity parameters (π = 1.44). As a consequence, the development of new methodologies for the construction of an aryl trifluoromethylsulfide moiety has become the subject of intensive research.²

Traditional methods for arene trifluoromethylthiolation formation include halo-fluorine exchange or radical trifluoromethylation of sulphur-containing compounds.² These methods usually require harsh reaction conditions that limit functional group tolerance. More recently, efficient direct trifluoromethylthiolation methods utilizing group 10 transition metal catalysts have been developed. For example, Buchwald and coworkers reported a palladium-catalyzed trifluoromethylthiolation of aryl bromides with AgSCF₃ under mild conditions.^3a Likewise, Vicic and Zhang reported a Ni-catalyzed trifluoromethylthiolation of aryl bromides or iodides by using [NMe₄][SCF₃] as the nucleophilic CF₃S source.^3b

In addition to group 10 transition metals, catalysts based on copper provide an alternative approach for trifluoromethylthiolation since copper is much cheaper and readily available. Qing^4a,b and Vicic^4c have independently reported a Cu-mediated oxidative trifluoromethylthiolation of aryl boronic acids with in situ formed nucleophilic CF₃S reagent or [NMe₄][SCF₃]. Li and Duan have reported an oxidative trifluoromethylthiolation using CF₃CO₂Na as the trifluoromethyl source, albeit in moderate yields.^4f Weng has reported the isolation of a stable trifluoromethylthiolated copper complex that enables the direct trifluoromethylthiolation of aryl iodides in excellent yields.^4d Furthermore, a copper-catalyzed C–H activation/trifluoromethylthiolation of directed arenes was reported by Daugulis and co-workers,^4l thus providing a powerful and straightforward method for the formation of aryl trifluoromethyl thioethers.

Another strategy for arene trifluoromethylthiolation involves the electrophilic trifluoromethylthiolating reagents (Fig. 1).^5–9 In this respect, several electrophilic trifluoromethylthiolating reagents such as reagents 3 ⁶, 4 ⁷ and 5 ^8b have been developed that were allowed to react with aryl Grignard reagent, aryl lithium or aryl boronic acids to give the trifluoromethylthiolated compounds in excellent yields.

Fig. 1 Electrophilic trifluoromethylthiolating reagents.

A NBS-like electrophilic trifluoromethylthiolating reagent, N-(trifluoromethylthio)phthalimide 1,⁹ has been previously prepared by Munavalli and co-workers by nucleophilic substitution of potassium phthalimide with trifluoromethylsulfenyl chloride (CF₃SCl) at 0 °C. Owing to its highly toxic and corrosive nature, the use of CF₃Cl is limited to those with special equipment and the necessary expertise. This shortcoming limited the use of N-(trifluoromethylthio)phthalimide 1 as a general trifluoromethylthiolating reagent. Herein, we report that N-(trifluoromethylthio)phthalimide 1 and its analog 2 can be prepared by an extremely simple and efficient method. In addition, we demonstrate that N-(trifluoromethylthio)phthalimide 1 was capable of coupling with a variety of aryl or vinyl boronic acids in the presence of a copper catalyst. The reactions proceeded under mild conditions and were compatible with a variety of functional groups.

N-(Trifluoromethylthio)phthalimide 1 and its analog 2 were prepared by treatment of N-bromophthalimide or NBS with AgSCF₃ in anhydrous CH₃CN at room temperature for 3 h. Reagents 1 and 2 were isolated in 93% and 95% yields, respectively. The reactions can be scaled up to 5.3 g with the same yields. Both reagents are crystalline, air- and moisture-stable compounds that remained unchanged even after one month on shelf as determined by ¹⁹F and ¹H NMR spectroscopy.

With these reagents in hand, we then explored the reactivity of reagents 1 and 2 with aryl boronic acids.^10,11 The trifluoromethylthiolation of 4-biphenyl boronic acid with reagent 1 was chosen at the start of our investigation as a model reaction. Reaction in the presence of 10 mol% of CuI and 10 mol% of bipyridine (bpy) in THF or diglyme occurred smoothly at 60 °C for 12 h to give the desired product in 79% and 82% yields, respectively (Table 1, entries 1 and 2). Reactions in other solvents such as dioxane, CH₂Cl₂ or CH₃CN were much less effective (Table 1, entries 3–5). Reaction in a polar solvent such as DMF was much slower to give the coupled product in less than 10% yield (Table 1, entry 6). Other copper salts were also evaluated and it was found that using other Cu(I) salts such as CuCl, CuBr or CuSCN resulted in lower yields (Table 1, entries 7–9). When CuCl₂·H₂O was used, the yield was comparable with those obtained using CuI as the catalyst (Table 1, entry 10). We then further investigated whether the yield could be further improved by adding other chelating ligands. Interestingly, the choice of ligand did not affect the yield of the reaction dramatically. Reactions using L1–L5 resulted in 71–83% yields, while a reaction using ^tBu-bpy (L3) gave the highest yield (Table 1, entry 13). The reaction was sensitive to the base. Using bases such as NaHCO₃, KF, K₂CO₃, K₃PO₄, or LiOH·H₂O provided the products in 5–75% yields (Table 1, entries 16–20). Lowering the amount of the catalyst to 5 mol% generated the product in 81% yield when the reaction was conducted for 15 h (Table 1, entry 21). Finally, reagent 2 was much less effective than reagent 1 under otherwise identical conditions (Table 1, entry 22).

Table 1 Optimization of the reaction conditions for the copper-catalyzed trifluoromethylthiolation of 4-biphenyl boronic acid with reagent 1 or 2^a

Entry	CuX	Ligand	Base	Solvent	Yield^b (%)
a Reaction conditions: 4-biphenyl boronic acid (0.05 mmol), reagent 1 (0.075 mmol), copper salt (10 mol%), ligand (10 mol%) and base (0.1 mmol) in diglyme (1.0 mL) at 60 °C for 12 h. b Yields were determined by ^19F NMR analysis of the crude reaction mixture with trifluoromethylbenzene as an internal standard. c The reaction was conducted in the presence of 5 mol% of the catalyst using 0.5 equiv. of Na2CO3 for 15 h. d Reagent 2 was used.
1	CuI	bpy	Na2CO3	THF	79
2	CuI	bpy	Na2CO3	Diglyme	82
3	CuI	bpy	Na2CO3	Dioxane	68
4	CuI	bpy	Na2CO3	CH2Cl2	65
5	CuI	bpy	Na2CO3	CH3CN	65
6	CuI	bpy	Na2CO3	DMF	9
7	CuCl	bpy	Na2CO3	Diglyme	73
8	CuBr	bpy	Na2CO3	Diglyme	72
9	CuSCN	bpy	Na2CO3	Diglyme	47
10	CuCl2·2H2O	bpy	Na2CO3	Diglyme	81
11	CuI	L1	Na2CO3	Diglyme	79
12	CuI	L2	Na2CO3	Diglyme	78
13	CuI	L3	Na2CO3	Diglyme	83
14	CuI	L4	Na2CO3	Diglyme	71
15	CuI	L5	Na2CO3	Diglyme	80
16	CuI	L3	Na2CO3	Diglyme	77
17	CuI	L3	KF	Diglyme	5
18	CuI	L3	K2CO3	Diglyme	26
19	CuI	L3	K3PO4	Diglyme	57
20	CuI	L3	LiOH·H2O	Diglyme	75
21	CuI	L3	Na2CO3	Diglyme	81^c
22	CuI	L3	Na2CO3	Diglyme	70^d

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On the basis of the results summarized in Table 1, the reaction conditions of entry 21 in Table 1 were chosen to study the scope of CuI/L3 catalyzed trifluoromethylthiolation of aryl and alkenyl boronic acids, and the results are summarized in Table 2. Reactions of simple aryl boronic acids gave the corresponding trifluoromethylthio-substituted arenes in good to excellent yields (Table 2, entries 1–7). Challenging functionalized aryl boronic acids were compatible with the reaction conditions. Reactions of aryl boronic acids with functional groups such as iodine, bromide, enolizable ketone, ester, amide cyano and alkene resulted in good yields (Table 2, entries 8–13). Pharmaceutically interesting trifluoromethylthio-substituted heteroarenes such as thiophene or pyridine derivatives were synthesized in good yields (Table 2, entries 15 and 16). It is interesting to note that alkenyl boronic acid also converted effectively into trifluoromethylthio substituted olefin in 50% yields (Table 2, entry 17). No isomerization was observed for the vinyl trifluoromethylthioether.

Table 2 The scope of copper-catalyzed trifluoromethylthiolation of aryl boronic acid with reagent 1^a

Entry	Product	Yield^b (%)	Entry	Product	Yield^b (%)
a Reaction conditions: aryl boronic acid (0.5 mmol), reagent 1 (0.75 mmol), CuI (5 mol%), L3 (5 mol%) and Na2CO3 (0.25 mmol) in diglyme (4.0 mL) at 60 °C for 15 h. b Isolated yields. c Yields were determined by ^19F NMR analysis of the crude reaction mixture with trifluoromethylbenzene as an internal standard. d The reactions were conducted at 80 °C for 20 h.
1		80	10		92
2		85	11		87
3		77	12		79
4		82	13		56 (81^c)
5		90	14		84
6		80	15		74^c
7		90	16		62
8		93	17		50 (74^c^,^d)
9		89

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The reaction can be conducted under air, albeit in much lower yield. For example, a reaction of 4-biphenyl boronic acid with reagent 1 in the presence of 10 mol% of CuI and 10 mol% of L3 using Na₂CO₃ as the base at 60 °C under air afforded after 15 h the desired product in 62% yield.

Conclusions

We have developed an efficient method for the preparation of a NBS-like electrophilic trifluoromethylthiolating reagent, N-(trifluoromethylthio)phthalimide 1.¹² Reactions of reagent 1 with a variety of aryl and vinyl boronic acids including heteroaryl boronic acids and substrates with a variety of different functional groups generated the trifluoromethylthiolated arenes and alkenes in excellent yields under mild reaction conditions. Mechanistic studies and synthetic applications of these transformations are ongoing in our laboratory.

Acknowledgements

The authors gratefully acknowledge financial support from the National Basic Research Program of China (2012CB821600), the Key Program of the Natural Science Foundation of China (21032006), the National Natural Science Foundation of China (21172245/21172244/21372247) and SIOC for financial support.

Notes and references

1. (a) A. Leo, C. Hansch and D. Elkins, Chem. Rev., 1971, 71, 525; (b) C. Hansch, A. Leo and R. W. Taft, Chem. Rev., 1991, 91, 165; (c) R. Filler, Biomedical Aspects of Fluorine Chemistry, Kodansha, Tokyo, 1982; (d) L. M. Yagupolskii, A. Y. Ilchenko and N. V. Kondratenko, Russ. Chem. Rev., 1974, 43, 32; (e) A. Becker, Inventory of Industrial Fluoro-Biochemicals, Eyrolles, Paris, 1996.
2. (a) V. N. Boiko, Beilstein J. Org. Chem., 2010, 6, 880; (b) A. Tlili and T. Billard, Angew. Chem., Int. Ed., 2013, 52, 6818; (c) T. Liang, C. N. Neumann and T. Ritter, Angew. Chem., Int. Ed., 2013, 52, 8214; (d) F. Toulgoat, S. Alazet and T. Billard, Eur. J. Org. Chem., 2014 DOI:10.1002/ejoc.201301857.
3. (a) G. Teverovskiy, D. S. Surry and S. L. Buchwald, Angew. Chem., Int. Ed., 2011, 50, 7312; (b) C.-P. Zhang and D. A. Vicic, J. Am. Chem. Soc., 2012, 134, 183.
4. (a) C. Chen, L.-L. Chu and F.-L. Qing, J. Am. Chem. Soc., 2012, 134, 12454; (b) C. Chen, Y. Xie, L.-L. Chu, R.-W. Wang, X.-G. Zhang and F.-L. Qing, Angew. Chem., Int. Ed., 2012, 51, 2492; (c) C.-P. Zhang and D. A. Vicic, Chem.–Asian J., 2012, 7, 1756; (d) Z. Weng, W. He, C. Chen, R. Lee, D. Dan, Z. Lai, D. Kong, Y. Yuan and K.-W. Huang, Angew. Chem., Int. Ed., 2013, 52, 1548; (e) K.-P. Wang, S. Y. Yun, P. Mamidipalli and D. Lee, Chem. Sci., 2013, 4, 3205; (f) L. Zhai, Y. Li, J. Yin, K. Jin, R. Zhang, X. Fu and C. Duan, Tetrahedron, 2013, 69, 10262; (g) M. Rueping, N. Tolstoluzhsky and P. Nikolaienko, Chem.–Eur. J., 2013, 19, 14043; (h) Q.-Y. Chen and J.-X. Duan, J. Chem. Soc., Chem. Commun., 1993, 918; (i) D. J. Adams and J. H. Clark, J. Org. Chem., 2000, 65, 1456; (j) D. J. Adams, A. Goddard, J. H. Clark and D. J. Macquarrie, Chem. Commun., 2000, 987; (k) W. Tyrra, D. Naumann, B. Hoge and Y. L. Yagupolskii, J. Fluorine Chem., 2003, 119, 101; (l) L. D. Tran, I. Popov and O. Daugulis, J. Am. Chem. Soc., 2012, 134, 18237.
5. Selected examples for electrophilic trifluoromethylthiolation using CF₃SCl: (a) L. M. Yagupolskii, N. V. Kondratenko and G. N. Timofeeva, J. Org. Chem. USSR, 1984, 20, 103; (b) T. Umemoto and S. Ishihara, Tetrahedron Lett., 1990, 31, 3579; (c) M. R. c. Gerstenberger, A. Hass and F. Liebig, J. Fluorine Chem., 1982, 19, 461; (d) W. Mendelson, J.-H. Liu, L. B. Killmer and S. H. Levinson, J. Org. Chem., 1983, 48, 298; (e) A. Hass and G. Moller, Chem. Ber., 1996, 129, 1383; (f) S. Munawalli, D. K. Rohrbaugh, F. R. Longo and H. D. Durst, Phosphorus, Sulphur Silicon Relat. Elem., 2002, 177, 1073; (g) S. Munawalli, D. K. Rohrbaugh, D. I. Rossman, W. G. Wagner and H. D. Durst, Phosphorus, Sulphur Silicon Relat. Elem., 2002, 177, 1021.
6. (a) A. l. Ferry, T. Billard, B. R. Langlois and E. Bacque, J. Org. Chem., 2008, 73, 9362; (b) A. Ferry, T. Billard, B. R. Langlois and E. Bacque, Angew. Chem., Int. Ed., 2009, 48, 8551; (c) A. Ferry, T. Billard, E. Bacque and B. R. Langlois, J. Fluorine Chem., 2012, 134, 160; (d) Y. Yang, X.-L. Jang and F.-L. Qing, J. Org. Chem., 2012, 77, 7538; (e) J. Liu, L. L. Chu and F.-L. Qing, Org. Lett., 2013, 15, 894; (f) F. Baert, J. Colomb and T. Billard, Angew. Chem., Int. Ed., 2012, 51, 10382; (g) S. Alzzet, L. Zimmer and T. Billard, Angew. Chem., Int. Ed., 2013, 52, 10814; (h) Q. Xiao, J. Sheng, Z. Chen and J. Wu, Chem. Commun., 2013, 49, 8647; (i) J. Sheng, S. Li and J. Wu, Chem. Commun., 2014, 50, 578.
7. (a) X.-X. Shao, X.-Q. Wang, T. Yang, L. Lu and Q. Shen, Angew. Chem., Int. Ed., 2013, 52, 3457; (b) E. V. Vinogradova, P. Müller and S. L. Buchwald, Angew. Chem., Int. Ed., 2014 DOI:10.1002/anie.201310897.
8. (a) T. Umemoto and S. Ishihara, J. Am. Chem. Soc., 1993, 115, 2156; (b) Y.-D. Yang, A. Azuma, E. Tokunaga, M. Yamasaki, M. Shiro and N. Shitaba, J. Am. Chem. Soc., 2013, 135, 8782.
9. (a) S. Munavalli, D. K. Rohrbaugh, D. I. Rossman, F. J. Berg, G. W. Wagner and H. D. Durst, Synth. Commun., 2000, 30, 2847–2854; (b) T. Bootwicha, X. Liu, R. Pluta, I. Atodiresei and M. Rueping, Angew. Chem., Int. Ed., 2013, 52, 12856.
10. For copper-catalyzed coupling of aryl boronic acids with N-thioarylimides: see: C. Savarin, J. Srogl and L. S. Liebeskind, Org. Lett., 2002, 4, 4309.
11. For transition metal-catalyzed thiolation of aryl halides: (a) T. Kondo and T. Mitsudo, Chem. Rev., 2000, 100, 3205; (b) J. X. Qiao and P. Y. S. Lam, Synthesis, 2011, 829; (c) H.-L. Kao, C.-K. Chen, Y.-J. Wang and C.-F. Lee, Eur. J. Org. Chem., 2011, 1776; (d) Y.-Y. Lin, Y.-J. Wang, C.-H. Lin, J.-H. Cheng and C.-F. Lee, J. Org. Chem., 2012, 77, 6100; (e) J.-H. Cheng, C.-L. Yi, T.-J. Liu and C.-F. Lee, Chem. Commun., 2012, 48, 8440.
12. During the review of this manuscript, Rueping and co-workers reported the preparation of reagent 1 from N-chlorophthalimide with CuSCF₃ in acetonitrile and its subsequent copper-catalyzed coupling reactions with aryl/alkenyl boronic acids and alkynes. R. Pluta, P. Nikolaienko and M. Rueping, Angew. Chem., Int. Ed., 2014, 53, 1650.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3qo00068k

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