A copper(II)-catalyzed three-component reaction of aryldiazonium tetrafluoroborates, sulfur dioxide, with alkenes

Abstract

A three-component reaction of aryldiazonium tetrafluoroborates, sulfur dioxide, with alkenes catalyzed by copper(II) bromide is developed, which provides an efficient route to (E)-alkenyl sulfones or allylic sulfones via the insertion of sulfur dioxide. A radical process is believed to be involved in the reaction.

---

In the past few years, progress in the synthesis of sulfonyl compounds via insertion of sulfur dioxide has been achieved rapidly.^1–3 Usually, the easily handled DABCO-(SO₂)₂ and inorganic sulfites were used as the source of sulfur dioxide in organic transformations, instead of toxic gaseous sulfur dioxide. It is well known that sulfonyl compounds are largely present in pharmaceutical and agrochemical molecules.^4,5 Consistent with our continuing interest in the development of methods and construction of libraries of natural product-like compounds,⁶ we are also interested in the generation of bioactive compounds with the sulfonyl unit. Recently, we reported several routes for the preparation of sulfonyl compounds via the insertion of sulfur dioxide through a radical process.³ For instance, aryl N-aminosulfonamides could be efficiently synthesized via a coupling of aryldiazonium tetrafluoroborates, DABCO·(SO₂)₂ and hydrazines under metal-free conditions.^3a This reaction was demonstrated to proceed through a radical process. Further exploration of this work revealed that the aminosulfonylation through insertion of sulfur dioxide could be extended to aryl/alkyl halides enabled by photoenergy.^3b Due to the importance of vinyl sulfones in natural products and biologically active molecules,⁷ as well as in organic synthesis,⁸ we envisioned that the radical process of fixation of sulfur dioxide might be applied to the synthesis of vinyl sulfones.

So far, many approaches have been reported for the preparation of vinyl sulfones.^9,10 For example, Tiwari and co-workers reported the stereoselective synthesis of E-vinyl sulfones catalyzed by Cu⁰/Fe₃O₄ from tosylmethyl isocyanide and alkynes.^10h Among the methods developed, using sulfur dioxide as the source of sulfonyl groups would be an ideal route. In 2015, Feng and co-workers reported the synthesis of vinyl sulfones via iodide-catalyzed radical alkenylation of aryl diazonium salts, terminal alkenes and DABCO·(SO₂)₂ in the presence of an oxidant (TBHP).^2q However, we found that some results could not be reproducible. For instance, to our surprise, only a trace amount of the product of (E)-(2-(phenylsulfonyl)vinyl)benzene was detected for the reaction of phenyldiazonium tetrafluoroborate, sulfur dioxide, with styrene under the reported conditions. Additionally, ethyldiazonium tetrafluoroborate which is extremely unstable and cannot be accessible, was applied successfully in the reaction, as described by Feng.^2q Prompted by the importance of vinyl sulfones and encouraged by our previous work for the insertion of sulfur dioxide with aryldiazonium tetrafluoroborates, we wished to explore the reaction of aryldiazonium tetrafluoroborates, sulfur dioxide, with alkenes. Herein, we report our recent efforts for the generation of vinyl sulfones through a copper(II)-catalyzed reaction of aryldiazonium tetrafluoroborates, sulfur dioxide, and alkenes. In some cases, allylic sulfones were obtained under the conditions.

Initially, a three-component reaction of phenyldiazonium tetrafluoroborate 1a, sulfur dioxide, with styrene 2a was selected as the model for reaction development. Since the presence of a copper catalyst would enable aryldiazonium tetrafluoroborate to produce the aryl radical, at the outset, the reaction was performed in the presence of copper(I) bromide (10 mol%) in MeCN at 80 °C (Table 1, entry 1). To our delight, the desired (E)-alkenyl sulfone 3a was isolated in 38% yield. A slightly lower yield (33%) was observed when the solvent was changed to DMF (Table 1, entry 2). No better results were obtained when the reaction was performed in DMSO, toluene, 1,4-dioxane, or DCE (Table 1, entries 3–6). A similar yield was generated when the reaction took place at 100 °C (Table 1, entry 7). However, an inferior yield was isolated when the reaction temperature was changed to 60 °C (Table 1, entry 8). Interestingly, the yield was increased to 46% when the amount of copper(I) bromide was changed to 20 mol% (Table 1, entry 9). Other copper catalysts were examined subsequently (Table 1, entries 10–16). Since Cu(II) could be converted to Cu(I) in the presence of sulfur dioxide,¹¹ several copper(II) salts were evaluated as well. It was found that the reaction proceeded efficiently when copper(II) bromide was employed, giving rise to the corresponding product 3a in 50% yield (Table 1, entry 14). An improved yield was observed when 2.5 equivalents of DABCO·(SO₂)₂ were used in the reaction (Table 1, entry 17). We conceived that the presence of an acid would promote the release of sulfur dioxide from the complex of DABCO·(SO₂)₂. Therefore, further screening of acids as additives was performed, which revealed that the yield could be dramatically improved (Table 1, entries 18–20). Gratifyingly, the reaction proceeded smoothly in the presence of acetic acid, leading to the expected product 3a in 90% yield (Table 1, entry 18). The yield was lower when the amount of acetic acid was reduced to 0.5 equivalents (Table 1, entry 21).

Table 1 Initial studies for the three-component reaction of phenyldiazonium tetrafluoroborate 1a, sulfur dioxide, with styrene 2a ^a

Entry	[Cu]	Additive	Solvent	T (°C)	Yield^b (%)
a Reaction conditions: phenyldiazonium tetrafluoroborate 1a (0.2 mmol), DABCO·(SO2)2 (0.25 mmol), styrene 2a (0.4 mmol), copper catalyst (10 mol%), additive (1.0 equiv.), solvent (1.0 mL), under N2. b Isolated yield based on phenyldiazonium tetrafluoroborate 1a. c In the presence of 20 mol% copper catalyst. d In the presence of 2.5 equivalents of DABCO·(SO2)2. e In the presence of 0.5 equivalents of HOAc.
1	CuBr		MeCN	80	38
2	CuBr		DMF	80	33
3	CuBr		DMSO	80	25
4	CuBr		Toluene	80	Trace
5	CuBr		Dioxane	80	Trace
6	CuBr		DCE	80	<10
7	CuBr		MeCN	100	37
8	CuBr		MeCN	60	29
9^c	CuBr		MeCN	80	46
10^c	CuCl		MeCN	80	10
11^c	CuI		MeCN	80	21
12^c	CuOAc		MeCN	80	<10
13^c	Cu2O		MeCN	80	<10
14^c	CuBr2		MeCN	80	50
15^c	CuCl2		MeCN	80	19
16^c	Cu(OAc)2		MeCN	80	<10
17^c^,^d	CuBr2		MeCN	80	63
18^c^,^d	CuBr2	HOAc	MeCN	80	90
19^c^,^d	CuBr2	PhCO2H	MeCN	80	82
20^c^,^d	CuBr2	TFA	MeCN	80	63
21^c^,^d^,^e	CuBr2	HOAc	MeCN	80	72

---

Since the optimized conditions shown in Table 1 were effective for the generation of (E)-alkenyl sulfones 3, we thus started to explore the scope of the three-component reaction of aryldiazonium tetrafluoroborates 1, sulfur dioxide, with alkenes 2 catalyzed by copper(II) bromide. The result is shown in Table 2. It was found that various aryldiazonium tetrafluoroborates 1 coupled well in the reactions of sulfur dioxide and styrene 2a, providing the corresponding (E)-alkenyl sulfones 3 in good to excellent yields. A wide range of functional groups was found to be compatible under the standard reaction conditions, including methoxy, chloride, bromide, and ester groups. For instance, ester-substituted sulfone 3e was obtained in 80% yield. It is noteworthy that the reactions of (hetero)aryldiazonium tetrafluoroborates 1 with sulfur dioxide and styrene 2a proceeded efficiently as well, leading to the desired products (compounds 3j and 3k). Different alkenes were examined subsequently in the reaction of phenyldiazonium tetrafluoroborate 1a and sulfur dioxide. Electron-withdrawing and electron-donating groups attached on the aromatic ring of styrenes were all tolerated under the conditions. 2-Vinylthiophene was a good coupling partner as well in the reaction, which afforded the corresponding product 3t in 86% yield. Reactions of 1,2-disubstituted olefins were explored in the meantime. As expected, the desired products were generated in moderate yields (compounds 3u and 3v). Ethene-1,1-diyldibenzene reacted with phenyldiazonium tetrafluoroborate 1a and sulfur dioxide, providing the expected product 3w in 88% yield. However, no reaction occurred when 1-hexene was employed as a replacement.

Table 2 Scope exploration of the three-component reaction of aryldiazonium tetrafluoroborates 1, sulfur dioxide, with alkenes 2 ^a

a Isolated yield based on aryldiazonium tetrafluoroborate 1.

---

Interestingly, different outcomes were obtained when prop-1-en-2-ylbenzene was used as a substrate in the reaction of phenyldiazonium tetrafluoroborate 1a with sulfur dioxide. Allylic sulfones were formed instead of (E)-alkenyl sulfones. The result is summarized in Table 3. Optimization of preliminary conditions revealed that the reaction proceeded efficiently at 60 °C, leading to the corresponding allylic sulfone 4a in 80% yield. Again, the substitutions attached onto the aromatic ring of aryldiazonium tetrafluoroborate 1 were well tolerated under the conditions. For example, the ester group remained intact during the reaction process, which provided the corresponding product 4e in 51% yield. Reactions of other alkenes with phenyldiazonium tetrafluoroborate 1a and sulfur dioxide were investigated subsequently. As shown in Table 3, all reactions proceeded smoothly to afford the corresponding products in good yields.

Table 3 Scope exploration of the three-component reaction of aryldiazonium tetrafluoroborates 1, sulfur dioxide, with 2-substituted 2-propenes^a

a Isolated yield based on aryldiazonium tetrafluoroborate 1.

---

Based on our previous reports,^3a we postulated that this reaction might proceed through a radical process. Thus, the following experiments were designed and performed (Scheme 1). For the three-component reaction of compound 5, sulfur dioxide and styrene, we observed the formation of the desired product 6 (Scheme 1, eqn (a)). The result indicated that a radical tandem process might be involved. Addition of TEMPO into the reaction of phenyldiazonium tetrafluoroborate 1a, sulfur dioxide and styrene 2a afforded compound 7 (Scheme 1, eqn (b)), which confirmed our hypothesis. The further deuterium experiment revealed that the formation of a double bond was not the rate-determining step (Scheme 1, eqn (c)).

Scheme 1 Several experiments for the mechanistic studies.

A plausible mechanism for the copper(II)-catalyzed three-component reaction of aryldiazonium tetrafluoroborates, sulfur dioxide, with alkenes was then proposed (Scheme 2). We reasoned that Cu(II) would be converted to Cu(I) in the presence of sulfur dioxide,¹¹ which would promote the formation of aryl radical A. The subsequent insertion of sulfur dioxide would occur to produce radical B, which would then undergo addition to the double bond of alkene 2 to afford radical C. Followed by electron transfer would lead to cation D, which would go through deprotonation to furnish the corresponding product 3.

Scheme 2 A plausible mechanism for the copper(II)-catalyzed three-component reaction of aryldiazonium tetrafluoroborates, sulfur dioxide, with alkenes.

In conclusion, we have reported a three-component reaction of aryldiazonium tetrafluoroborates, sulfur dioxide, with alkenes catalyzed by copper(II) bromide. This transformation provides an efficient route to (E)-alkenyl sulfones or allylic sulfones via the insertion of sulfur dioxide. A radical process is believed to be involved in the reaction. This approach is attractive, and the corresponding (E)-alkenyl sulfones or allylic sulfones can be obtained in moderate to good yields.

Acknowledgements

Financial support from the National Natural Science Foundation of China (no. 21372046, 21532001) and the Opening Project of Gannan Medical University Collaborative Innovation Center for Gannan Oil-tea Camellia Industrial Development is gratefully acknowledged.

Notes and references

1. For reviews: (a) G. Liu, C. Fan and J. Wu, Org. Biomol. Chem., 2015, 13, 1592; (b) P. Bisseret and N. Blanchard, Org. Biomol. Chem., 2013, 11, 5393; (c) A. S. Deeming, E. J. Emmett, C. S. Richards-Taylor and M. C. Willis, Synthesis, 2014, 2701. For examples, see: (d) D. Zheng, R. Mao, Z. Li and J. Wu, Org. Chem. Front., 2016, 3, 359; (e) S. Ye and J. Wu, Chem. Commun., 2012, 48, 7753; (f) S. Ye and J. Wu, Chem. Commun., 2012, 48, 10037; (g) S. Ye, H. Wang, Q. Xiao, Q. Ding and J. Wu, Adv. Synth. Catal., 2014, 356, 3225; (h) Y. Luo, X. Pan, C. Chen, L. Yao and J. Wu, Chem. Commun., 2015, 51, 180; (i) A. S. Tsai, J. M. Curto, B. N. Rocke, A. R. Dechert-Schmitt, G. K. Ingle and V. Mascitti, Org. Lett., 2016, 18, 508; (j) R. Mao, D. Zheng, H. Xia and J. Wu, Org. Chem. Front., 2016, 3, 693; (k) D. Zheng, M. Chen, L. Yao and J. Wu, Org. Chem. Front., 2016, 3, 985; (l) D. Zheng, Y. Kuang and J. Wu, Org. Biomol. Chem., 2015, 13, 10370; (m) W. Zhang and M. Luo, Chem. Commun., 2016, 52, 2980.
2. (a) B. Nguyen, E. J. Emmet and M. C. Willis, J. Am. Chem. Soc., 2010, 132, 16372; (b) E. J. Emmet, C. S. Garcia-Rubia, B. Nguyen, A. B. Garcia-Rubia, R. Hayter and M. C. Willis, Org. Biomol. Chem., 2012, 10, 4007; (c) L. Martial, Synlett, 2013, 1595; (d) W. Li, H. Li, P. Langer, M. Beller and X.-F. Wu, Eur. J. Org. Chem., 2014, 3101; (e) W. Li, M. Beller and X.-F. Wu, Chem. Commun., 2014, 50, 9513; (f) X. Wang, L. Xue and Z. Wang, Org. Lett., 2014, 16, 4056; (g) A. S. Deeming, C. J. Russell and M. C. Willis, Angew. Chem., Int. Ed., 2015, 54, 1168; (h) C. C. Chen and J. Waser, Org. Lett., 2015, 17, 736; (i) A. S. Deeming, C. J. Rusell, A. J. Hennessy and M. C. Willis, Org. Lett., 2014, 16, 150; (j) B. N. Rocke, K. B. Bahnck, M. Herr, S. Lavergne, V. Mascitti, C. Perreault, J. Polivkova and A. Shavnya, Org. Lett., 2014, 16, 154; (k) E. J. Emmett, B. R. Hayter and M. C. Willis, Angew. Chem., Int. Ed., 2013, 52, 12679; (l) E. J. Emmett, B. R. Hayter and M. C. Willis, Angew. Chem., Int. Ed., 2014, 53, 10204; (m) A. Shavnya, S. B. Coffey, A. C. Smith and V. Mascitti, Org. Lett., 2013, 15, 6226; (n) M. W. Johnson, S. W. Bagley, N. P. Mankad, R. G. Bergman, V. Mascitti and F. D. Toste, Angew. Chem., Int. Ed., 2014, 53, 4404; (o) A. Shavnya, K. D. Hesp, V. Mascitti and A. C. Smith, Angew. Chem., Int. Ed., 2015, 54, 13571; (p) A. S. Deeming, C. J. Russell and M. C. Willis, Angew. Chem., Int. Ed., 2016, 55, 747; (q) W. Fan, J. Su, D. Shi and B. Feng, Tetrahedron, 2015, 71, 6740.
3. (a) D. Zheng, Y. An, Z. Li and J. Wu, Angew. Chem., Int. Ed., 2014, 53, 2451; (b) Y. Li, D. Zheng, Z. Li and J. Wu, Org. Chem. Front., 2016, 3, 574; (c) Y. An, D. Zheng and J. Wu, Chem. Commun., 2014, 50, 11746; (d) D. Zheng, Y. Li, Y. An and J. Wu, Chem. Commun., 2014, 50, 8886; (e) K. Zhou, H. Xia and J. Wu, Org. Chem. Front., 2016, 3, 865; (f) D. Zheng, J. Yu and J. Wu, Angew. Chem., Int. Ed., 2016, 55 DOI:10.1002/anie.201607292.
4. (a) M. Bartholow, Top 200 Drugs of 2011. Pharmacy Times. http://www.pharmacytimes.com/publications/issue/2012/July2012/Top-200-Drugs-of-2011, accessed on Jan 9, 2013; (b) For a list of topdrugs by year, see: http://cbc.arizona.edu/njardarson/group/top-pharmaceuticals-poster, accessed on Jan 9, 2013; (c) J. Drews, Science, 2000, 287, 1960.
5. (a) P. J. Crowley, J. Fawcett, B. M. Kariuki, A. C. Moralee, J. M. Percy and V. Salafia, Org. Lett., 2002, 4, 4125; (b) N. S. Simpkins, Sulfones in Organic Synthesis, Pergamon Press, Oxford, 1993.
6. For selected reviews and accounts, see: (a) G. Qiu and J. Wu, Chem. Rec., 2016, 16, 19; (b) Y. Luo, X. Pan, X. Yu and J. Wu, Chem. Soc. Rev., 2014, 43, 834; (c) G. Qiu, Q. Ding and J. Wu, Chem. Soc. Rev., 2013, 42, 5257; (d) G. Qiu, Y. Kuang and J. Wu, Adv. Synth. Catal., 2014, 356, 3483; (e) H. Wang, Y. Kuang and J. Wu, Asian J. Org. Chem., 2012, 1, 302; (f) L. He, H. Nie, G. Qiu, Y. Gao and J. Wu, Org. Biomol. Chem., 2014, 12, 9045; (g) G. Qiu and J. Wu, Synlett, 2014, 2703.
7. For selected examples, see: (a) U. Mahesh, K. Liu, R. C. Panicker and S. Q. Yao, Chem. Commun., 2007, 1518; (b) G. Wang, U. Mahesh, G. Y. J. Chen and S. Yao, Org. Lett., 2003, 5, 737; (c) I. Forristal, J. Sulfur Chem., 2005, 26, 163; (d) F. Hof, A. Schutz, C. Fah, S. Meyer, D. Bur, J. Liu, D. E. Goldberg and E. Diederich, Angew. Chem., Int. Ed., 2006, 45, 2138; (e) L. Ni, X. Zheng, P. K. Somers, L. K. Hoong, R. R. Hill, E. M. Marino, K. L. Suen, U. Saxena and C. Meng, Bioorg. Med. Chem. Lett., 2003, 13, 745; (f) J. T. Palmer, D. Rasnick, J. L. Klaus and D. Brcmme, J. Med. Chem., 1995, 38, 3193; (g) M. M. M. Santos and R. Moreira, Mini-Rev. Med. Chem., 2007, 7, 1040; (h) R. Ettari, E. Nizi, M. E. D. Francesco, M. A. Dude, G. Pradel, R. Vicik, T. Schirmeister, N. Micale, S. Grasso and M. Zappala, J. Med. Chem., 2008, 51, 988.
8. For selected examples, see: (a) M. N. Noshi, A. El-Awa, E. Torres and P. L. Fuchs, J. Am. Chem. Soc., 2007, 129, 11242; (b) J. N. Desrosiers and A. B. Charette, Angew. Chem., Int. Ed., 2007, 46, 5955; (c) G. Pandey, K. N. Tiwari and V. G. Puranik, Org. Lett., 2008, 10, 3611; (d) K. Oh, Org. Lett., 2007, 9, 2973.
9. For selected examples, see: (a) S. Choi, J. Yang, M. Ji, H. Choi, M. Kee, K. Ahn, S. Byeon, W. Baik and S. Koo, J. Org. Chem., 2001, 66, 8192; (b) A. A. Linden, L. Kruger and J. Backvall, J. Org. Chem., 2003, 68, 5890; (c) E. Baciocchi, M. F. Gerini and A. Lapi, J. Org. Chem., 2004, 69, 3586; (d) F. G. Gelalcha and B. Schulze, J. Org. Chem., 2002, 67, 8400; (e) M. Matteucci, G. Bhalay and M. Bradley, Org. Lett., 2003, 5, 235; (f) S. Chodroff and W. F. Whitmore, J. Am. Chem. Soc., 1950, 72, 1073; (g) P. B. Hopkins and P. L. Fuchs, J. Org. Chem., 1978, 43, 1208; (h) R. A. Gancarz and J. L. Kice, Tetrahedron Lett., 1980, 21, 4155; (i) J. M. Baskin and Z. Wang, Org. Lett., 2002, 4, 4423; (j) W. Zhu and D. Ma, J. Org. Chem., 2005, 70, 2696; (k) M. Bian, F. Xu and C. Ma, Synthesis, 2007, 2951; (l) D. C. Reeves, S. Rodriguez, H. Lee, N. Hahhad, D. Krishnamurthy and C. H. Senanayake, Tetrahedron Lett., 2009, 50, 2870; (m) S. Cacchi, G. Fabrizi, A. Goggiamani, L. M. Parisi and R. Bernini, J. Org. Chem., 2004, 69, 5608; (n) J. Sinnreich and M. Asscher, J. Chem. Soc., Perkin Trans. 1, 1972, 1543; (o) W. E. Truce and C. T. Goralski, J. Org. Chem., 1971, 36, 2536; (p) N. Taniguchi, Synlett, 2011, 1308.
10. For selected examples, see: (a) F. Huang and R. A. Batey, Tetrahedron, 2007, 63, 7667; (b) V. Nair, A. Augustine, T. G. George and L. G. Nair, Tetrahedron Lett., 2001, 42, 6763; (c) J. Chen, J. Mao, Y. Zheng, D. Liu, G. Rong, H. Yan, C. Zhang and D. Shi, Tetrahedron, 2015, 71, 5059; (d) Y. Xu, J. Zhao, X. Tang, W. Wu and H. Jiang, Adv. Synth. Catal., 2014, 356, 2029; (e) S. Tang, Y. Wu, W. Liao, R. Bai, C. Liu and A. Lei, Chem. Commun., 2014, 50, 4496; (f) P. Katrun, S. Chiampanichayakul, K. Korworapan, M. Pohmakotr, V. Reutrakul, T. Jaipetch and C. Kuhakarn, Eur. J. Org. Chem., 2010, 5633; (g) R. Song, Y. Liu, Y. Liu and J. Li, J. Org. Chem., 2011, 76, 1001; (h) M. Phanindrudu, D. K. Tiwari, B. Sridhar, P. R. Likhar and D. K. Tiwari, Org. Chem. Front., 2016, 3, 795.
11. H. Meerwein, G. Dittmar, R. Gollner, K. Hafner, F. Mensch and O. Steinfort, Chem. Ber., 1957, 90, 841.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00350h

---