Metal-free, high yielding synthesis of unsymmetrical biaryl, bi(heteroaryl), aryl vinyl, aryl alkyl sulfones via coupling of aryne with sulfinic acid salts

Abstract

Here, we report a metal-free, high yielding method for the synthesis of unsymmetrical biaryl sulfones via coupling of aryne with sulfinic acid salts. The optimized condition also works efficiently for bi(heteroaryl), aryl vinyl and aryl alkyl sulfones. The present method took comparatively shorter reaction times and has good functional group compatibility.

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Organosulfones represent an important class of compounds because of their presence in many bio-active molecules¹ as well as their chemical properties.² Organosulfones are known for their; (i) medicinal properties viz., dapsone (A, as anti-bacterial),^1d casodex (B, anti-androgen),^1e eletriptan (C, anti-migraine),^1f mesotrione (D, herbicide);^1g (ii) antagonist properties (E and F, serotonin 5-HT6 receptor antagonist)^1h,1i and (iii) enzyme inhibitory properties (G, HIV-1 non-nucleoside reverse transcriptase inhibitor).^1j Very recently, aryl vinyl sulfones H were reported as potent neuroprotective agents for the treatment of Parkinson's disease.^1k In addition to this, aryl alkyl and heteroaryl alkyl sulfones are also used as synthons³ in organic transformations such as Julia-olefination⁴ and the Ramberg–Backlund rearrangement.⁵ (Fig. 1)

Fig. 1 Examples of important sulfones.

Traditionally organosulfones were prepared either by oxidation of sulphides^6a or by sulfonation of arene in the presence of strong acid.^6b,6c Keeping in view the importance of organosulfones, several metal-catalysed methods have been developed.⁷ However, emergence of metal-free synthesis is the choice of interest these days and therefore attempts have also been made to develop metal-free synthesis of organosulfones as shown in Fig. 2.⁸ These methods are specific to some particular class among the diverse range of organosulfones. Moreover, benzyne mediated organic synthesis has attracted the attention and have been extensively explored in last decade for the diverse range of organic synthesis.⁹ In this present study, we have explored first time the use of reactive benzyne intermediates for the synthesis of unsymmetrical biaryl, bi(heteroaryl), aryl vinyl, aryl alkyl sulfones.

Fig. 2 Previous and present approaches for the synthesis of sulfones.

Initially, we have chosen 2-(trimethylsilyl)phenyl trifluoromethanesulfonate 1a, the benzyne precursor and benzene -sulfinic acid sodium salt 2a as standard substrates to optimize suitable conditions for this reaction (Table 1). The reaction of 1a with 2a in the presence of CsF in CH₃CN solvent at room temperature for 12 h under nitrogen atmosphere provided biaryl sulfone 3a in 75% yield (Table 1, entry 1). The best yield (85%) was obtained upon increasing the temperature from rt to 80 °C in CsF (Table 1, entry 2), this effect may be due to the rate of reaction was enhanced by increasing the temperature. A similar result was achieved when the reaction was performed under oxygen atmosphere (Table 1, entry 3) ruled out the possibilities of involvement of radical intermediacy. Upon switching the fluoride source to KF/18-crown-6 and TBAF, comparatively slightly lesser yield of coupled product 3a was obtained (Table 1, entry 4 and 5). Keeping the fluoride sources KF/18-crown-6 and TBAF constant and by changing the solvent CH₃CN to THF, also didn't give any improvement (Table 1, entry 6 and 7).

Table 1 Optimization studies^a

Entry	F^− source	Solvent	Temp (°C), Time (h)	Yield^b (%)
a Reaction conditions (unless otherwise stated): 1a (0.25 mmol, 1.0 equiv.), 2a (0.5 mmol, 2.0 equiv.), F^− source (1.0 mmol, 4.0 equiv.), solvent 4 ml, under N2.b Isolated yield.c Reaction was done in presence of oxygen.
1	CsF	CH3CN	rt, 12	75
2	CsF	CH3CN	80, 2	85
3^c	CsF	CH3CN	80, 3	82
4	KF/18-crow-6	CH3CN	80, 5	62
5	TBAF	CH3CN	80, 5	83
6	KF/18-crow-6	THF	70, 5	65
7	TBAF	THF	70, 5	80

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With the optimized reaction conditions established, we next explored the scope of the various sulfinic acid sodium salts and all the results are summarized in Table 2. Firstly, benzene sulfinic acid sodium salt when treated with benzyne precursor (1a) afforded the desired product in 85% yield (3a). Moreover, aryl sulfinates bearing electron-donating groups due to their high nucleophilic nature furnished good to excellent yields of corresponding products (examples 3b–3g, except 3c). p-Methyl substituted sulfinate proceeded smoothly and gave the corresponding diarylsulfone 3b with 88% yield. Mesitylene sulfinate gave the corresponding coupled product 3c with 55% yield, the comparatively lower yield might be due to steric hindrance. To our delight, methoxy substituted benzene sulfinates gave the corresponding products in an excellent yields of coupled products (3d–3f). Additionally, sodium 2,3-dihydrobenzo[b][1,4]dioxine-6-sulfinate also provided the corresponding product 3g in 80% yield. On the other hand, electron-withdrawing groups containing aryl sulfinates gave corresponding coupled products with moderate to good yields. When 2,4-dichloro benzene sulfinic acid sodium salt was subjected to the reaction, 55% yield of the corresponding biaryl sulfone 3h obtained. 4-F and 4-CF₃ benzene sulfinates were also proceeded well and afforded the desired products 3i and 3j with 82%, 80% yield respectively. To verify the vast substrate scope of this method we have chosen different (naphthyl, acetamido, trifluoromethyl) sulfinates, which also gave respective coupled products 3k–3m with good yields. Nevertheless, when di-nitro substituted sulfinate 3n was used no reaction took place. The presence of two nitro groups makes respective sulfinate 3n weak nucleophile and responsible for non-reactivity. Encouraged by the results obtained, we turned our interest to heterocyclics; sodium benzo[d]thiazole-2-sulfinate was also efficiently transformed to sulfone 3o with a 66% yield. Additionally, it was found that substituted styrene sulfinate also worked well and afforded the desired vinyl sulfone 3p in 80% yield.

Table 2 Coupling of different sulfinic acid salts with benzyne^a

a Reaction conditions: Aryne precursor 1a (0.25 mmol, 1.0 equiv.), arene sulfinic acid sodium salt 2 (0.5 mmol, 2.0 equiv.), CsF (1.0 mmol, 4.0 equiv), solvent 4 ml, 80 °C, under N₂.

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The versatility of the present reaction was also explored with substituted arynes (Table 3). Methyl (at 6^th position) substituted benzyne precursor 1b underwent coupling with benzene sulfinic acid sodium salt 2a and gave an unseparable mixture of coupled products 4a/a′ with 55% yield in the ratio of 37 : 63 (ratio was determined by GC-MS). Methoxy (at 5^th position) substituted benzyne precursor 1c when tried, also underwent coupling and gave 62% of coupled products 4b and 4b′ in the ratio of 45 and 55 (determined by GC-MS) which were easily separated by column chromatography. On the other hand, methyl (at 4^th position) benzyne precursor 1d also gave an inseparable mixture of coupled products 4c/c′ with 58% yield. Further, naphthalene containing benzyne precursor 1e also underwent coupling smoothly and gave a 2-napthyl phenyl sulfone 4d with 50% yield. Effect of temperature on regio-selectivity was also studied by performing all the reactions at room temperature but no improvement in the regio-selectivity was observed, however the reactions gave comparatively lower yields (Table 3).

Table 3 Coupling of benzenesulfinic acid salt with substituted benzynes^a

Entry	Aryne precursor	Products	Yield^b (%)
a Reaction conditions: Aryne precursor 1b–e (0.25 mmol, 1.0 equiv.), 2a benzene sulfinic acid sodium salt (0.5 mmol, 2.0 equiv.), CsF (1.0 mmol, 4.0 equiv.), solvent 4 ml, 80 °C, under N2.b Ratio was determined by GC-MS analysis.c Reactions were performed at rt for 18 h.d Unseparable mixtures.
1			55/35^c (37 : 63)^d
2			62/43^c (45 : 55)
3			58/55^c (53 : 47)^d
4			50

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To gain further insight into the reaction mechanism, the coupling reaction was performed in the presence of D₂O (Scheme 1), wherein the corresponding coupled product 3a was formed with 20% deuterium incorporation which was confirmed by LC-MS (details given in ESI†). Based on our finding (reactions in presence of O₂ and D₂O) and literature precedent,^8b,9 a plausible mechanism can be described by the nucleophilic attack of aryl sulfinate^8b on the aryne⁹ derived from 2a followed by proton capture resulting in the formation of the corresponding sulfones.

Scheme 1 Coupling in the presence of D₂O.

In conclusion, we have developed an efficient and general method for the synthesis of unsymmetrical sulfones under metal-free condition. The optimized method works well for the synthesis of diverse range of sulfones such as unsymmetrical biaryl, bi(heteroaryl), aryl vinyl, aryl alkyl sulfones. The present method gave good to excellent yields and also have a good functional group compatibility. Further, the efforts towards the bi-functionalization as well as sulfonation with other benzyne precursor to expand the generality are presently underway and will be published in due course.

Acknowledgements

Authors acknowledge the financial support of CSIR with research grant # HCP 0001 and BSC 0108. SKA, KR and GM thanks UGC and CSIR for their Fellowship. IIIM communication number: IIIM/1697/2014.

Notes and references

1. For some selected references, see: (a) R. A. Hartz, A. G. Arvanitis, C. Arnold, J. P. Rescinito, K. L. Hung, G. Zhang, H. Wong, D. R. Langley, P. J. Gilligan and G. L. Trainor, Bioorg. Med. Chem. Lett., 2006, 16, 934; (b) T. Otzen, E. G. Wempe, B. Kunz, R. Bartels, G. Lehwark-Yvetot, W. Hansel, K. J. Schaper and J. K. Seydel, J. Med. Chem., 2004, 47, 240; (c) M. Pal, V. R. Veeramaneni, M. Nagabelli, S. R. Kalleda, P. Misra, S. R. Casturib and K. R. Yeleswarapua, Bioorg. Med. Chem. Lett., 2003, 13, 1639; (d) R. L. Lopez de Compadre, R. A. Pearlstein, A. J. Hopfinger and J. K. Seyde, J. Med. Chem., 1987, 30, 900; (e) L. Kirkovsky, A. Mukherjee, D. Yin, J. T. Dalton and D. D. Miller, J. Med. Chem., 2000, 43, 581; (f) N. A. McGrath, M. Brichacek and J. T. Njardarson, J. Chem. Educ., 2010, 87, 1348; (g) R. Beaudegnies, A. J. F. Edmunds, T. E. M. Fraser, R. G. Hall, T. R. Hawkes, G. Mitchell, J. Schaetzer, S. Wendeborn and J. Wibley, Bioorg. Med. Chem., 2009, 17, 4134; (h) K. G. Liu, A. J. Robichaud, R. C. Bernotas, Y. Yan, J. R. Lo, M.-Y. Zhang, Z. A. Hughes, C. Huselton, G. M. Zhang, J. Y. Zhang, D. M. Kowal, D. L. Smith, L. E. Schechter and T. A. Comery, J. Med. Chem., 2010, 53, 7639; (i) A. V. Ivachtchenko, E. S. Golovina, M. G. Kadieva, V. M. Kysil, O. D. Mitkin, S. E. Tkachenko and I. M. Okun, J. Med. Chem., 2011, 54, 8161; (j) G. La Regina, A. Coluccia, A. Brancale, F. Piscitelli, V. Gatti, G. Maga, A. Samuele, C. Pannecouque, D. Schols, J. Balzarini, E. Novellino and R. Silvestri, J. Med. Chem., 2011, 54, 1587; (k) S. Y. Woo, J. H. Kim, M. K. Moon, S.-H. Han, S. K. Yeon, J. W. Choi, B. K. Jang, H. J. Song, Y. G. Kang, J. W. Kim, J. Lee, D. J. Kim, O. Hwang and K. D. Park, J. Med. Chem., 2014, 57, 1473.
2. (a) The Chemistry of Sulfones and Sulfoxides, ed. S.Patai, Z.Rappoport and C. J. M.Stirling, Wiley, New York, 1988; (b) N. S. Simpkins, Sulfones in Organic Synthesis, Pergamon Press, Oxford, 1993.
3. (a) P. J. Crowley, J. Fawcett, B. M. Kariuki, A. C. Moralee, J. M. Percy and V. Salafia, Org. Lett., 2002, 4, 4125.
4. (a) M. Julia and J. M. Paris, Tetrahedron Lett., 1973, 14, 4833; (b) P. R. Blakemore, J. Chem. Soc., Perkin Trans. 1, 2002, 23, 2563; (c) N. S. Simpkins, Sulfones in Organic Synthesis, ed. J. E.Baldwin, Pergamon Press, Oxford, 1993.
5. (a) L. Ramberg and B. Bäcklund, Ark. Kemi, Mineral. Geol., 1940, 13A, 1–50 (Chem. Abstr., 1940, 34, 4725); (b) S. C. Söderman and A. L. Schwan, J. Org. Chem., 2012, 77, 10978.
6. (a) W. G. Trankle and M. E. Kopach, Org. Process Res. Dev., 2007, 11, 913; (b) B. M. Graybill, J. Org. Chem., 1967, 32, 2931; (c) M. Ueda, K. Uchiyama and T. Kano, Synthesis, 1984, 323.
7. (a) A. Kar, I. A. Sayyed, W. F. Lo, H. M. Kaiser, M. Beller and M. K. Tse, Org. Lett., 2007, 9, 3405; (b) F. Huang and R. A. Batey, Tetrahedron, 2007, 63, 7667; (c) J. M. Baskin and Z. Wang, Org. Lett., 2002, 4, 4423; (d) H. Suzuki and H. Abe, Tetrahedron Lett., 1995, 36, 6239; (e) W. Zhu and D. Ma, J. Org. Chem., 2005, 70, 2696; (f) M. Bian, F. Xu and C. Ma, Synthesis, 2007, 2951; (g) D. C. Reeves, S. Rodriguez, L. Heewon, N. Haddad, D. Krishnamurthy and C. H. Senayake, Tetrahedron Lett., 2009, 50, 2870; (h) S. Cacchi, G. Fabrizi, A. Goggoamani, L. M. Parisi and R. Bernini, J. Org. Chem., 2004, 69, 5608; (i) S. Cacchi, G. Fabrizi, A. Goggiamani and L. M. Parisi, Org. Lett., 2002, 4, 4719.
8. (a) K. M. Maloney, J. T. Kuethe and K. Linn, Org. Lett., 2011, 13, 102; (b) N. Umierski and G. Manolikakes, Org. Lett., 2013, 15, 188; (c) R. Chawl, R. Kapoor, A. K. Singh and L. D. S. Yadav, Green Chem., 2012, 14, 1308; (d) S. Liang, R.-Y. Zhang, L.-Y. Xi, S.-Y. Chen and X.-Q. Yu, J. Org. Chem., 2013, 78, 11874; (e) F. Xiao, H. Chen, H. Xie, S. Chen, L. Yang and G.-J. Deng, Org. Lett., 2014, 16, 50.
9. B. Anup, R. Y. Santhivardhana and A. T. Biju, Chem. Soc. Rev., 2012, 41, 3140.

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Footnote

† Electronic supplementary information (ESI) available: Synthesis and characterization data. See DOI: 10.1039/c4ra07370c

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