Ammonium iodide-induced sulfonylation of alkenes with DMSO and water toward the synthesis of vinyl methyl sulfones

Abstract

A novel ammonium iodide-induced sulfonylation of alkenes with DMSO and water toward the synthesis of vinyl methyl sulfones is described. The process proceeded smoothly under metal-free conditions with high stereoselectivity and good functional group tolerance. The reaction mechanism was revealed to proceed through a domino reaction of oxidation and elimination after the radical addition to alkenes.

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Vinyl sulfones are important compounds in organic and medicinal chemistry due to their versatile reactivities and potential biological activities.¹ In the last few decades, the synthesis of vinyl sulfones has attracted more and more attention from chemists.^2–6 Traditional pathways for the preparation of vinyl sulfones typically include the direct oxidation of vinyl sulfides and Heck reaction of aryl halides with vinyl sulfones.^2,3 However, these methods suffer from poor selectivity or expensive starting materials. In recent years, some efficient metal-catalyzed approaches have been investigated such as cross-coupling reactions of olefins and their derivatives (vinyl halides, stannanes, and arylboronic acids) with sulfone reagents including sulfinate salts, sulfonyl chlorides, or sulfonyl hydrazides (Scheme 1a).⁴ Recently, some researchers have achieved this transformation in the absence of transition-metal catalysts.⁵ Despite remarkable improvement and efficiency of such reactions, the discovery of sulfone sources from inexpensive and readily available reagents is highly desired. Very recently, Loh and co-workers published an alternative Cu-catalyzed methyl sulfonylation of alkynes using DMSO and O₂ as a methyl sulfone source (–SO₂Me) (Scheme 1b).⁶ Herein, we disclose a novel and efficient ammonium iodide-induced sulfonylation of alkenes in which DMSO and H₂O are used as the starting materials to provide the source of –SO₂Me (Scheme 1c). To the best of our knowledge, such a route for the synthesis of vinyl methyl sulfones has not been reported under metal free conditions.

Scheme 1 Different routes for the synthesis of vinyl methyl sulfones.

Using styrene (1a) and DMSO as the substrates, optimal conditions were first examined for the sulfonylation. After screening a variety of reaction parameters, the sulfonylation of 1a gave 2a in an excellent yield with sole stereoselectivity under the standard conditions (Table 1, entry 1: 4.0 equiv. NH₄I, 0.5 mL H₂O, 1.0 mL DMSO, at 130 °C for 24 h; optimization details, see ESI†). The effects of the other factors on the reaction are shown in entries 2–13. Neither the organic tetrabutylammonium iodide (n-Bu₄NI) nor the inorganic KI did afford the desired product (entries 2 and 3), suggesting that the iodide anion is not the real form for NH₄I participated in this conversion. No desired transformation was observed employing a similar ammonium salt NH₄Br (entry 4), ruling out the function of NH₄⁺ in this reaction. When using 2.0 equiv. of I₂ instead of 4.0 equiv. of NH₄I, 2a was not obtained with only benzoic acid as the product, whereas 15% yield of 2a was determined with 0.5 equiv. of I₂ (entries 5 and 6). In addition, when the reaction was performed with aqueous ammonia, the yield of the product was not improved (entry 7). However, in the presence of catalytic amounts of I₂, no desired product was obtained only recovering the unreacted styrene (entry 8). These results clearly indicated that I₂ was indeed the actual form to promote this conversion and its concentration had a great impact on the selectivity of reaction. It was also observed that both the amount of NH₄I added and reaction temperature were important parameters for a high yield (entries 10–12). In the absence of water, the yield of the target product dramatically decreased (entry 13).

Table 1 Effect of various factors on the reaction

Entry	Variation from the standard conditions	Yield^a/%
a Determined by ^1H NMR (internal standard: 1,3,5-trimethyl benzene). b Run for 32 h. c 1.0 equiv. of radical trapper was used.
1	None	98
2	Bu4NI instead of NH4I	0
3	KI instead of NH4I	0
4	NH4Br instead of NH4I	0
5	2.0 equiv. of I2 instead of NH4I	0
6	0.5 equiv. of I2 instead of NH4I	15
7	0.5 equiv. of I2 + 0.5 mL NH3·H2O instead of NH4I	17
8	10 mol% I2 instead of NH4I	0
9	HI instead of NH4I	8
10	1.0 equiv. of NH4I	0
11	100 °C instead of 130 °C	0
12	120 °C instead of 130 °C	39
13	Without adding H2O	12
14^b	Under N2 atmosphere	91
15^c	Adding TEMPO	0
16^c	Adding BHT	0

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With the optimal conditions in hand, we next evaluated the substrates scope and limitations of our protocol (Tables 2 and 3). In general, the reactions of alkenes bearing electron-withdrawing groups gave slightly higher yields of product than those containing electron-donating moieties, as well as much faster reaction rates (2a–2n). All of the reactions proceeded with excellent regioselectivity, and various functional groups such as methyl, methoxyl, fluoro, chloro, bromo, ester, cyanide, nitro, and trifluoromethyl groups at the meta or para positions of the aromatic ring were reasonably well tolerated under the standard conditions. The reaction of disubstituted alkenes was also efficient (2o, 2q). Polyaryl substrates such as 2-naphthalene and 9-phenanthrene retarded the reaction even after an extended reaction time, albeit in moderate yields (2s–2t), possibly due to the steric interference. In addition, heteroaromatic olefins proceeded smoothly to afford the target products in good yields (2r, 2u). Gratifyingly, interminal alkenes were also productive, exclusively forming (E)-sulfonyl product (2v) either from the cis- or trans-β-methylstyrene. However, allylbenzene failed to give the corresponding product (2w), and a similar result was also observed with alkyl alkenes as substrates. In contrast conjugated diene afforded the target product in a moderate yield (2x), indicating that conjugative effect played an important role in stabilizing the intermediate.⁷

Table 2 Scope of alkene substrates^a

a Reaction conditions: alkene (1 mmol), NH₄I (4.0 equiv.), H₂O (0.5 mL), DMSO (1.0 mL) and 130 °C. Isolated yield. b cis-β-Methylstyrene. c trans-β-Methylstyrene.

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Table 3 Scope of 1,1-disubstituted alkene substrates^a

a Reaction conditions: as shown in Table 2. Isolated yield.

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Interestingly, when α-methylstyrene (1y) was applied as the substrate, an isomerization product (2y) was obtained instead of the desired vinyl sulfone (Table 3). Other similar olefins were tested under the standard conditions, producing the isomerized products in good yields (2z–2ab) as well. These results suggested that a different elimination protocol existed for 1,1-disubstituted olefins. This isomerization result is consistent with the previous studies by Jiang^4b and Li.^5c

Moreover, the reaction is scalable and practical as an excellent yield (95%) of 2a was obtained when the reaction was performed on a 10.0 mmol scale (eqn (1)).⁸

In order to investigate the reaction mechanism, a series of control experiments were carried out. Under the protection of N₂, the target product 2a could be obtained in an excellent yield (Table 1, entry 14), indicating that the oxygen atom of the sulfone group in 2a does not come from O₂. The isotopic labeling experiment with H₂¹⁸O was conducted (eqn (2)).⁸ These experimental results make sure that one oxygen atom of the sulfone group of 2a is from H₂O and the other results from DMSO. The deuterium labeling experiment with DMSO-d₆ (eqn (3)) confirms that methylthiyl (MeS) originates from DMSO. Furthermore, a reaction profile was obtained in the sulfonylation of styrene (1a) under the standard conditions (Fig. 1). Within a reaction time of 4 h, 2-(methylthio)-1-phenylethanol (3a) was firstly detected in 20% yield, and then 2-(methylsulfonyl)-1-phenylethanol (4a) and (E)-(2-(methylsulfonyl)vinyl)benzene (2a) were produced. During the reaction process, 3a and 4a remained in a low concentration in the reaction mixture and disappeared at the end of the reaction. Simultaneously, the concentration of 2a increased with the reaction time, thus implying that 3a and 4a were the intermediates in this conversion. Indeed, discrete 3a and 4a both could be completely converted to 2a under the otherwise identical conditions.⁸ In addition, when the reaction was performed in the presence of a stoichiometric amount of TEMPO or BHT under the standard conditions, 2a was not obtained (Table 1, entries 15 and 16). These results suggested that the present reaction presumably proceeded through a radical pathway.

Fig. 1 Reaction profile in the NH₄I-induced sulfonylation of 1a.

Based on the above results, a plausible reaction mechanism is proposed in Scheme 2. First, the radical initiator I₂ and precursor MeSH are generated through a series of reactions, as shown in eqn (4)–(6).^9–11 Then, I₂ is decomposed to form an iodine radical (eqn (7)),¹² which attacks on MeSH to give a methylthiyl radical MeS˙ (eqn (8)).¹³ Subsequently, the radical MeS˙ is added to the alkene to generate a radical intermediate I.¹⁴ At the same time, the MeS˙ abstracts hydrogen from water to afford a hydroxyl radical (OH˙). The rapid coupling reaction between the radical intermediate I and OH˙ produces intermediate 3a, which is further oxidized by DMSO¹⁵ and H₂O₂ resulting from self-coupling of the radical OH˙,¹⁶ to form intermediate 4a. Finally, with the assistance of the newly formed sulfone group, 2a is generated via acid-catalysed dehydration of 4a.

Scheme 2 Proposed reaction mechanism.

In conclusion, we have developed a novel and efficient protocol of ammonium iodide-induced sulfonylation of olefins with DMSO and water, achieving excellent stereoselectivity and high functional group tolerance. In addition, this procedure provides a new valuable method of generating a methylthiyl radical (MeS˙) from DMSO. Further studies on the details of the reaction mechanism and applications in organic synthesis are currently underway in our laboratory.

We thank the National Natural Science Foundation of China (21172079, 21322606, and 21436005), and Guangdong Natural Science Foundation (10351064101000000) for financial support.

Notes and references

1. For reviews, see: (a) B. A. Frankel, M. Bentley, R. G. Kruger and D. McCafferty, J. Am. Chem. Soc., 2004, 126, 3404; (b) M. V. Reddy, N. M. Iqbal, K. A. Robell, A. D. Kang and E. P. Reddy, J. Med. Chem., 2008, 51, 86; (c) J.-N. Desrosiers and A. B. Charette, Angew. Chem., Int. Ed., 2007, 46, 5955.
2. (a) M. Tiecco, L. Testaferri, M. Tingoli, D. Chianelli and M. Montanucci, J. Org. Chem., 1983, 48, 4795; (b) P. Caramella, E. Albini, T. Bandiera, A. C. Coda, P. Grünanger and F. M. Albini, Tetrahedron, 1983, 39, 689.
3. A. Battace, T. Zair, H. Doucet and M. Santelli, Synthesis, 2006, 3495.
4. (a) N. Taniguchi, Synlett, 2011, 1308; (b) X. Li, Y. Xu, W. Wu, C. Jiang, C. Qi and H. Jiang, Chem. – Eur. J., 2014, 20, 1; (c) M. Bian, F. Xu and C. Ma, Synthesis, 2007, 2951; (d) S. S. Labadie, J. Org. Chem., 1989, 54, 2496; (e) F. Huang and R. A. Batey, Tetrahedron, 2007, 63, 7667; (f) A. Kar, I. A. Sayyed, W. F. Lo, H. M. Kaiser, M. Beller and M. K. Tse, Org. Lett., 2007, 9, 3405.
5. (a) S. Tang, Y. Wu, W. Liao, R. Bai, C. Liu and A. Lei, Chem. Commun., 2014, 50, 4496; (b) Y. Xu, X. Tang, W. Hu, W. Wu and H. Jiang, Green Chem., 2014, 16, 3720; (c) X. Li, X. Xu and C. Zhou, Chem. Commun., 2012, 48, 12240; (d) S. Liang, R. Zhang, G. Wang, S. Chen and X. Yu, Eur. J. Org. Chem., 2013, 7050; (e) P. Katrun, S. Chiampanichayakul, K. Korworapan, M. Pohmakotr, V. Reutrakul, T. Jaipetch and C. Kuhakarn, Eur. J. Org. Chem., 2010, 5633.
6. Y. Jiang and T.-P. Loh, Chem. Sci., 2014, 5, 4939.
7. B. Giese, Angew. Chem., Int. Ed., 1983, 22, 753.
8. See the ESI† for details.
9. A. Smith and R. P. Calvert, J. Am. Chem. Soc., 1914, 36, 1363.
10. H. Gilman and J. Eisch, J. Am. Chem. Soc., 1955, 77, 3862.
11. V. J. Traynelis and W. L. Hergenrother, J. Org. Chem., 1964, 29, 221.
12. J. Gromada and K. Matyjaszewski, Macromolecules, 2001, 34, 7664.
13. A. Fava, G. Reichenbach and U. Peron, J. Am. Chem. Soc., 1967, 89, 6696.
14. (a) C. Walling and W. Helmreich, J. Am. Chem. Soc., 1959, 81, 1144; (b) L. Lunazzi, G. Placucci and L. Grossi, J. Chem. Soc., Perkin Trans. 2, 1981, 703.
15. S. Searles Jr and H. R. Hays, J. Org. Chem., 1958, 23, 2028.
16. (a) E. Brillas and I. Sirés, Chem. Rev., 2009, 109, 6570; (b) J. Kiwi, K. Kalyanasundaram and M. Graetzel, Struct. Bonding, 1982, 49, 39.

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Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures, characterization of products, and NMR spectral charts. See DOI: 10.1039/c4cc07606k

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