Magnetically separable nano-copper catalyzed unprecedented stereoselective synthesis of E-vinyl sulfones from tosylmethyl isocyanide and alkynes: TosMIC as a source of the sulfonyl group

Abstract

We have developed an unprecedented efficient and mild catalytic route for stereoselective synthesis of E-vinyl sulfones from terminal alkynes and tosylmethyl isocyanide (TosMIC) in the presence of magnetically separable nano-copper (0) stabilized on Fe₃O₄. A variety of vinyl sulfones were obtained in moderate to good yields. In this newly developed protocol TosMIC acts as a sulfonyl source. The catalyst was magnetically removed and recycled easily five times without any appreciable loss in activity.

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Vinyl sulfones are important key structural units present in a plethora of fine chemicals and pharmaceuticals.¹ In addition they are widely used as building blocks for the construction of complex molecular architectures.² Vinyl sulfones are well recognised as Michael acceptors and utilized in various reactions such as nucleophilic conjugate additions and cycloadditions,³ cyclopropanations,⁴ epoxidations⁵ and aza Michael addition.⁶ Furthermore, they are known to possess various biological inhibitory activities such as cysteine proteases,⁷ inducible VCAM-1 expression,⁸ dipeptidyl peptidase I (DPPI),⁹ transpeptidase¹⁰ and neuroprotective agents toward Parkinson's disease therapy.¹¹

Owing to their importance and utilities, substantial attention has been paid to develop mild and efficient methods for vinyl sulfones.¹² Amongst them, a few important methodologies that were recently developed are illustrated in Fig. 1. Shi and co-workers reported the iodine mediated decarboxylative coupling reaction of cinnamic acid and sodium sulfinate in the presence of TBHP as an oxidant (Fig. 1, eqn (1)).¹³ Furthermore, the Yuan group pursued a green and efficient method by carrying out a similar reaction in aqueous medium (Fig. 1, eqn –(2)).¹⁴ In another report, N. Taniguchi developed a copper-catalyzed oxidative hydrosulfonylation of alkynes with sodium sulfinates (Fig. 1, eqn (3)).¹⁵ Very recently, Zhang's group described Cu/Fe catalyzed sulfonylation of propiolic acid/phenylacetylene with sulfonyl hydrazides in the presence of di-tert-butyl peroxide (DTBP) (Fig. 1, eqn (4)).¹⁶ While all these methods provide access to vinyl sulfones, there are certain limitations associated with them such as the use of external oxidants, expensive ligands, harsh reaction conditions, prolonged reaction time, tedious workup procedures, selectivity and recovery of catalysts. Therefore, the development of a mild and efficient approach to E-vinyl sulfones is still highly desired.

Fig. 1 Previous approaches for the synthesis of useful vinyl sulfones along with the current work.

Tosylmethyl isocyanide (TosMIC) has long been renowned for its reactivity in numerous synthetic transformations^17,18 including [3 + 2] cycloaddition reaction with substrates containing C=O, C=N, C=C, and C≡C groups, offering access to a large number of chemicals such as oxazoles, pyrroles and imidazoles. As a part of our continuing interest towards developing various biologically important heterocyclic frameworks,^19,20 herein we report a novel and efficient stereoselective synthesis of E-vinyl sulfones using TosMIC, alkynes and magnetically recoverable and reusable Cu⁰/Fe₃O₄. Notably in this newly developed protocol, TosMIC acts as a source of the sulfonyl group instead of acting as a typical 1,3 dipole. Furthermore, the magnetic separation of catalysts from reaction medium makes this strategy more convenient and practical to access vinyl sulfones.

Results and discussion

Recently, we reported the nano-copper catalyzed regio selective synthesis of 2,4 disubstituted pyrroles from terminal alkynes and isocyanides.^20a When we tried to expand the substrate scope by reacting phenyl acetylene (1a) and tosylmethyl isocyanide (2) under previously optimised conditions, we unexpectedly obtained E-vinyl solfone as the sole product albeit in low yield (20%). Worth mentioning here is that the expected 2,4-disubstituted pyrrole (2a′) was never detected with TosMIC (Scheme 1). At this stage the structure of E-vinyl sulfone (3a) was well characterized using all spectroscopy techniques and a single X-ray diffraction analysis was carried out for one compound (3e, vide infra). Since this reaction represents a new route to access E-vinyl sulfones, we carried out an extensive optimization of the reaction conditions (Table 1).

Scheme 1 Unexpected formation of E-vinyl sulfone (3a).

Table 1 Optimization of reaction conditions^a

Entry	Catalyst	Base	Solvent	Temp. [°C]	Yield^d [%]
Reaction conditions:a Phenyl acetylene 1a (1.0 mmol), TosMIC 2, (1.0 mmol), K2CO3 (1.0 mmol) and Cu^0/Al2O3 (40 mg) at 85 °C for 2 h, under a N2 atmosphere.b Under an air atmosphere.c Under an O2 atmosphere.d Isolated yield; n.o. = not observed.
1	Cu^0/Al2O3	K2CO3	DMSO	85	20^a
2	Cu^0/Al2O3	K2CO3	DMSO	85	45^b
3	Cu^0/Al2O3	K2CO3	DMSO	85	71^c
4	Cu ^0 /Fe 3 O 4	K 2 CO 3	DMSO	85	84
5	Cu^0/Fe2O3	K2CO3	DMSO	85	67^c
6	Cu^0/rGO	K2CO3	DMSO	85	55^c
7	CuOTf2	K2CO3	DMSO	85	n.o.^c
8	CuI	K2CO3	DMSO	85	n.o.^c
9	Cu^0/Fe3O4	Na2CO3	DMSO	85	79^c
11	Cu^0/Fe3O4	Cs2CO3	DMSO	85	78^c
12	Cu^0/Fe3O4	DBU	DMSO	85	56^c
13	Cu^0/Fe3O4	Et3N	DMSO	85	42^c
14	Cu^0/Fe3O4	t-BuOK	DMSO	85	82^c
15	Cu^0/Fe3O4	K2CO3	DMF	85	55^c
16	Cu^0/Fe3O4	K2CO3	DME	85	61^c
17	Cu^0/Fe3O4	K2CO3	CH3CN	85	41^c
18	Cu^0/Fe3O4	K2CO3	Toluene	85	15^c
19	Cu^0/Fe3O4	K2CO3	EtOH	85	55^c
20	Cu^0/Fe3O4	K2CO3	CHCl3	85	n.o.^c
21	Cu^0/Fe3O4	K2CO3	DMSO	100	75^c
22	Cu^0/Fe3O4	K2CO3	DMSO	60	53^c

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At this stage we presumed that under these conditions the active methylene group of TosMIC was oxidised to generate a tosyl radical which eventually attacked the terminal carbon acetylene to give an unexpected E-vinyl sulfone (for more details see Scheme 4). The reaction performed in an open air atmosphere gave a better yield (45%) of the desired sulfone 3a (Table 1, entry 2). A further increase in the yield (71%) of 3a was observed by performing the reaction under an oxygen atmosphere (Table 1, entry 3). It is important to note that, under these catalytic conditions Z-vinyl sulfone was never detected. To our delight, a further increase in the yield (84%) of desired 3a was observed when magnetite Cu⁰/Fe₃O₄ was employed as a catalyst (Table 1, entry 4) under an oxygen atmosphere. Various other supported nano-catalysts such as commercially available Cu⁰/Fe₂O₃ and Cu⁰/rGO were found to be less efficient, and furnished 3a in 67% and 55% yield respectively (Table 1, entries 5 and 6). During our investigations, several copper salts such as CuOTf₂ and CuI were also tested but no product formation was observed (Table 1, entries 7 and 8). Next, several bases such as Na₂CO₃, Cs₂CO₃, DBU, Et₃N and t-BuOK were screened for the reaction but they all furnished lower yields of the vinyl sulfone 3a (Table 1, entries 9–14). Replacing DMSO with various other solvents such as DMF, DME, CH₃CN, toluene and EtOH, produced inferior yield of 3a (Table 1, entries 15–20). We found that the reaction temperature noticeably influenced the yield of the desired product 3a. At an elevated temperature (100 °C), 75% yield of the desired product was achieved (Table 1, entry 21) whereas 53% yield of 3a was observed at a lower temperature (60 °C) (Table 1, entry 22).

With the optimal conditions in hand (Table 1, entry 4), the substrate scope of the present study with respect to various aryl alkynes (1a–1o) was evaluated and the results are summarised in Table 2. Both electron donating (EDGs) and electron withdrawing groups (EWGs) (1b–1n) on phenyl rings were well tolerated and the corresponding desired E-vinyl sulfones (3b–3n) were obtained in moderate yields. A wide range of aryl acetylenes having tert-butyl (1d) alkoxy (1e–1h), fluoro (1i), bromo (1j), trifluoromethyl (1k), nitro (1l) and cyano (1m) groups afforded corresponding E-vinyl sulfones (3d–3m) in moderate to high yields. Moreover, bicyclic and tetracyclic aryl alkynes such as 6-methoxy-2-ethynylnaphthalene (1h) and pyrenes (1o) gave products in 69% and 75% yields respectively. Furthermore, heteroaryl alkyne²¹1n effectively reacted under the optimised reaction conditions and furnished the corresponding vinyl sulfone 3n in 65% yield. Unambiguous proof for the stereochemical assignment of the vinyl sulfones was obtained by single crystal X-ray crystallography of 3e (Fig. 2).

Fig. 2 ORTEP diagram of 3e with the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level. CCDC No. 1053806.

Table 2 Substrate scope^a

Reaction conditions:a Acetylenes 1a–1o (1.0 mmol), TosMIC (1.0 mmol), K₂CO₃ (1.0 mmol) and Cu⁰/Fe₃O₄ (40 mg) at 85 °C, under an oxygen atmosphere, 2 h.

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In order to expand the synthetic competence of our strategy, a gram-scale synthesis of 3a was performed under the standard conditions. Pleasingly, E-vinyl sulfone 3a was obtained in a satisfactory yield (75%) when the reaction was conducted on a 10 mmol scale (Scheme 2). It indicates that there is a potential for industrial application too.

Scheme 2 Synthesis of 3a on a larger scale.

This initial success propelled us to investigate the application of the present method in one pot synthesis of cyclopropane. Thus, a mixture of phenyl acetylene (1.0 mmol), TosMIC (1.0 mmol) and t-BuOK was heated in DMSO (4.0 mL) at 85 °C. After 3 h of heating trimethyl sulfoxonium iodide (1.0 mmol) was slowly added to the above mixture and the reaction was stirred at the same temperature for another 10 h. Surprisingly, the expected cyclopropane 4 was not formed and the reaction gave an allylic sulfone 5 (60%). The spectral data of 5 were found in good agreement with the reported value (Scheme 3).²²

Scheme 3 One pot synthesis of allylic sulfones.

Next we have demonstrated the recovery and reusability of the catalyst. After completion of the reaction, the catalyst was separated magnetically and washed thoroughly with diethyl ether, dried at 100 °C overnight and used directly for the next round of reaction. The catalyst was reused five times without any significant loss of activity (Fig. 3).

Fig. 3 Recycle potential diagram of Cu(0)/Fe₃O₄ for the preparation of E-vinyl sulfones. Reaction conditions: 1a (1.0 mmol), 2 (1.0 mmol), cat. (Cu 8 wt%, 40 mg) and K₂CO₃ (1.0 mmol) at 85 °C for 2 h.

The mechanism of nano-copper catalyzed synthesis of E-vinyl sulfone from alkynes and TosMIC can be rationalized as depicted in Scheme 4. The active methylene of ToSMIC gets oxidised to give intermediate 7. The intermediate 7 in the presence of copper gives a tosyl radical 8, which reacts with copper acetylide to form 9 which eventually takes a proton from the solvent to furnish the desired E-vinyl sulfone.

Scheme 4 Plausible mechanism.

Conclusions

In summary, we have achieved a catalytic, mild and efficient method for the synthesis of E-vinyl sulfones from readily available starting materials in very good yields. Furthermore, the nano-copper catalyst was magnetically separated and reused five times without any significant loss of activity. In this newly developed protocol TosMIC acts as a source of the sulfonyl group. The ready availability of starting materials, broad substrate scope, and operational simplicity make the present method an attractive option for the synthesis of vinyl sulfones. Further study on the wider applications of the current methodology is under progress in our laboratory.

Acknowledgements

The authors thank the Department of Science and Technology (DST) New Delhi, India, for financial support in the form of the INSPIRE Faculty and startup research grant for young researchers (GAP 0414 and 0512 respectively). MP thanks UGC, New Delhi for a research fellowship. The authors are grateful to the Director, CSIR-IICT for providing the necessary infrastructure.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1053806. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00063k

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