Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. 2018, 20, 6687−6690
Synthesis of (E)‑β-Selenovinyl Sulfones through a Multicomponent Regio- and Stereospecific Selenosulfonation of Alkynes with Insertion of Sulfur Dioxide Kai Sun,*,† Zuodong Shi,† Zhenhua Liu,‡ Baixue Luan,† Jiali Zhu,† and Yanru Xue† †
College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang 455000, P. R. China College of Chemistry, Shandong Normal University, Jinan 250014, P. R. China
‡
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S Supporting Information *
ABSTRACT: A novel and practical method for the selenosulfonation of alkynes with the insertion of sulfur dioxide has been developed. A series of β-(seleno)vinyl sulfones with high levels of regio- and stereoselectivity have been prepared. The key features of this reaction include a broad substrate scope, excellent functional-group tolerance, and amenability to scale-up synthesis. A plausible radical mechanism is proposed to illustrate this reaction.
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Scheme 1. Methods for the Selenosulfonylation of Alkynes
ith the importance of sulfonyl-containing compounds in organic synthesis and medicinal chemistry, methods used to introduce sulfonyl units into organic molecules have attracted much attention.1 Vinyl sulfones are unique motifs in biological molecules and are useful synthetic intermediates in organic synthesis.2 As a result, considerable efforts have been made by chemists to construct such structures.3 Among these, sulfonative functionalization of alkynes may be an ideal strategy to prepare vinyl sulfones.4 Sulfur dioxide (SO2), being inexpensive and readily available, might be the obvious reagent for the introduction of SO2 functionality. However, safety concerns and the necessity for specialized equipment to handle this toxic gas have hampered the use of sulfur dioxide in organic synthesis. Therefore, the use of a bench-stable sulfur dioxide surrogate that is easy to handle may be preferable as an alternative experimental technique for SO2 insertion reactions. Pioneered by Willis,5 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) is a solid SO2 surrogate that has resulted in significant developments for the assembly of sulfonyl derivatives. Recently, the potential of sulfur dioxide as a building block in radical transformations has been well evaluated.6 Vinyl selenides are useful synthetic skeletons and therapeutic entities that display a wide range of biological activities, thus rendering these motifs highly important synthetic targets.7 In 1983, Back et al. reported the azodiisobutyronitrile (AIBN)induced radical selenosulfonation of alkynes with preprepared PhSeSO2Ph reagent (Scheme 1a).8 As part of our interest in the synthesis of organic selenium,9 we recently described a cationic-species-induced selenosulfonation process for the generation of β-sulfonyl vinyl selenides.9a Meanwhile, Zhang et al. have achieved copper-catalyzed highly regio- and stereospecific radical selenosulfonation of alkynes (Scheme 1b).10 This approach resulted in the generation of the sulfonyl radical in the presence of copper salt and K2S2O8 via a single electron transfer and deprotonation process. In view of the © 2018 American Chemical Society
potential of sulfur dioxide as a building block in radical transformations and inspired by the previous reports,11 we envisaged that a tandem radical addition of an aryl radical (generated in situ from aryldiazonium salt) to sulfur dioxide and an alkyne would provide a β-sulfonyl vinyl radical, which could be subsequently trapped by a phenyl selenol group to produce β-sulfonyl vinyl selenides (Scheme 1c). To the best of our knowledge, this procedure for the synthesis of β-sulfonyl vinyl selenides utilizing a direct incorporation of sulfur dioxide has never been reported. We expect that this approach will allow evaluation of the practical applications of sulfur dioxide and provide an alternative pathway to β-sulfonyl vinyl selenides. Received: August 26, 2018 Published: October 22, 2018 6687
DOI: 10.1021/acs.orglett.8b02733 Org. Lett. 2018, 20, 6687−6690
Letter
Organic Letters Scheme 2. Scope of Alkynesa,b
We thus started to explore the practicability of the proposed route as shown in Scheme 1c. Initially, phenylacetylene 1a, 4methylphenyldiazonium tetrafluoroborate 2a, DABSO, and diphenyl diselenide 3a were chosen as model substrates to optimize the reaction conditions. To our delight, the selenosulfonation occurred in dichloroethane (DCE) at 60 °C under Ar protection, and the desired (E)-β-selenovinyl sulfone 4a was obtained in 18% yield (Table 1, entry 1). Upon Table 1. Screening of Reaction Conditionsa
entry
oxidant
solvent
temp
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14
none TBHP DTBP (NH4)2S2O8 K2S2O8 K2S2O8 K2S2O8 K2S2O8 K2S2O8 K2S2O8 K2S2O8 K2S2O8 K2S2O8 K2S2O8
DCE DCE DCE DCE DCE MeCN EtOAc THF DMSO THF THF THF THF THF
60 60 60 60 60 60 60 60 60 40 80 100 80 80
18 31 34 37 55 45 0 69 0 42 77 76 84c 43d
a
Reaction conditions: 1 (0.3 mmol), 4-methylphenyldiazonium tetrafluoroborate 2a (0.6 mmol), DABSO (0.6 mmol), and diphenyl diselenide 3a (0.3 mmol) in THF (3.0 mL) at 80 °C, under Ar protection. bYields of isolated products.
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), DABSO (0.3 mmol), 3a (0.3 mmol), and oxidants (0.6 mmol) mixed in 3 mL of solvent for 6 h, under Ar protection. bYield of isolated product. c2.0 equiv amount of DABSO was employed. dOpen to air.
product (E)-4c was determined by X-ray crystallography analysis. The sterically encumbered internal alkynes 1k−1m were also examined, and the desired products 4k−4m were obtained in high yields, as expected. The structure of compound (E)-4m was confirmed by X-ray crystallography analysis. Moderate yields with aliphatic alkynes 1n and 1o were obtained; this may be due to the lower stability of the alkylsubstituted alkenyl radical intermediates than the corresponding aryl-substituted alkenyl radicals. It is noteworthy that, in all reactions, consistently high levels of regio- and stereoselectivity (anti-Markovnikov selectivity) were observed for unsymmetrical terminal alkynes and internal alkynes. Inspired by the above results, we further evaluated the fourcomponent selenosulfonation of alkynes (Scheme 3). Various aryldiazonium tetrafluoroborates with different functional groups, including electron-donating (OMe), electron-neutral (H), and electron-withdrawing (F and Cl) groups, were active substrates in the reactions, delivering the corresponding products 4p−4s in high yields. In addition, diphenyl diselenides were also scanned. 2-Bromo- and 4-chlorosubstituted diphenyl diselenides underwent the selenosulfonation to give the desired products 4t and 4u in high yields. To demonstrate the synthetic utility of this strategy, we also conducted a 5 mmol scale selenosulfonylation reaction with 1,2-bis(4-methoxyphenyl)diselane, which provided 4v in 70% yield. Furthermore, 1,2-di(thiophen-2-yl)diselane was also a good partner in this reaction and gave the corresponding 4w in moderate yield. Unfortunately, 1,2-dimethyldiselane was incompatible in this reaction and did not generate the desired product. Finally, 1,2-diphenylditellane was tested in this
addition of tert-butyl hydroperoxide (TBHP, 70% in water, 2 equiv) as an oxidant, the yield of 4a was raised to 31% (Table 1, entry 2). Further screening of oxidants, including di-tertbutyl peroxide (DTBP), (NH4)2S2O8, and K2S2O8, showed that K2S2O8 gave the best result, increasing the yield of 4a to 55% (Table 1, entries 3−5). Among CH3CN, ethyl acetate (EtOAc), tetrahydrofuran (THF), and dimethyl sulfoxide (DMSO), THF was the best solvent and increased the yield of 4a to 69% (Table 1, entries 6−9). In addition, the reaction yield was sensitive to temperature with the yield of 4a decreasing at lower temperature (Table 1, entry 10) and increasing to 77% at 80 °C (Table 1, entry 11). A similar result was obtained when the reaction was performed at 100 °C (Table 1, entry 12). Furthermore, improved efficiency was observed and a higher yield of 4a was obtained when 2.0 equiv of DABSO were employed (Table 1, entry 13). When the reaction was performed open to the air, the yield of 4a fell to 43% (Table 1, entry 14). With the optimized reaction conditions (Table 1, entry 13), we next explored the scope of the selenosulfonation process with respect to terminal alkynes and internal alkynes 1. As shown in Scheme 2, aromatic terminal alkynes bearing electron-withdrawing groups (F, Cl, Br, NO2, and CF3) or electron-donating groups (Me, and OMe) on the benzene ring were compatible with this reaction, regardless of their different electronic properties and sites to afford the desired (E)-βselenovinyl sulfones 4b−4j in 73%−89% yields. The synthetically attractive halogens, which can readily undergo further transformation, were suitable for the reaction. The structure of 6688
DOI: 10.1021/acs.orglett.8b02733 Org. Lett. 2018, 20, 6687−6690
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Organic Letters
detected, and in the absence of alkynes, we isolated 6 in 13% yield (Scheme 4c). Therefore, the reaction of 1a (0.3 mmol) with preprepared adduct PhSeSO2Ph 6 (0.3 mmol) was then performed (Scheme 4d). Under optimized conditions, no reaction occurred, and the PhSeSO2Ph 6 was recovered completely. This result showed that the selenosulfonate intermediate 6 was formed in situ but was not involved in the selenosulfonation process. On the basis of the experimental results and previously reported studies,10,11 a radical mechanism for this multicomponent reaction is proposed in Scheme 5. We reasoned
Scheme 3. Scope of Aryldiazonium Tetrafluoroborates and Diphenyl Diselenidesa,b
Scheme 5. Plausible Catalytic Cycle
a
Reaction conditions: 1 (0.3 mmol), phenyldiazonium tetrafluoroborate 2 (0.6 mmol), DABSO (0.6 mmol), and diselenides 3 (0.3 mmol) in THF (3.0 mL) at 80 °C, under Ar protection. bYields of isolated products.
that the combination of a aryldiazonium cation with DABSO generates the complex A, which is prone to collapse and provides sulfur dioxide, nitrogen, an aryl radical, and tertiary amine radical cation B. Then, the addition of the aryl radical to sulfur dioxide produces arylsulfonyl radical C, which subsequently, regiospecifically adds to alkynes 1 to form a relatively stable β-sulfonyl vinyl radical D. Finally, with the help of K2S2O8, a phenyl selenol radical is generated and couples with C to afford the thermodynamically stable (E)-βselenovinyl sulfone 4. In conclusion, a novel and practical regio- and stereospecific selenosulfonation of alkynes has been successfully developed. A series of structurally diverse vicinal β-sulfonyl vinyl selenides were effectively obtained via SO2 insertion. This multicomponent cascade reaction is the first example of the use of DABSO as a SO2 surrogate to synthesize β-sulfonyl vinyl selenides. This methodology features inexpensive and readily available reagents, good regio- and stereoselectivity, excellent functional-group compatibility, and amenability to scale-up synthesis. Preliminary studies on the reaction mechanism showed that this reaction proceeds via a radical pathway. Further work toward expanding this protocol and further applications are anticipated.
reaction. Pleasingly, the corresponding 4x was obtained in a satisfactory yield. To investigate the reaction mechanism, some control experiments were conducted (Scheme 4). When 2.0 equiv of Scheme 4. Mechanism Study
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02733. Experimental procedures and details of the characterization of all of the new compounds (PDF)
(2,2,6,6-tetramethyl-1-piperidinyl)oxyl (TEMPO) were added to the reaction of 1a (0.3 mmol) under standard conditions, the yield of 4a decreased to 27%. Upon addition of 2.0 equiv of 2,6-di-tert-butyl-4-methylphenol (BHT) or 1,1-diphenylethylene, the selenosulfonylation was suppressed and only a trace amount of 4a was detected (Scheme 4a). In the absence of 1a, we mixed 2a, 3a (0.3 mmol), DABSO, and 1,1-diphenylethylene under standard conditions, and the coupling product 5 was isolated in a high yield of 79% (Scheme 4b). These results suggested that the selenosulfonation might proceed via a radical pathway. It is noteworthy that, during the selenosulfonylation reaction, the adduct PhSeSO2Ph 6 was
Accession Codes
CCDC 1863966−1863968 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. 6689
DOI: 10.1021/acs.orglett.8b02733 Org. Lett. 2018, 20, 6687−6690
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Organic Letters
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Ed. 2016, 55, 11925−11929. (c) Xiang, Y.-C.; Kuang, Y.-Y.; Wu, J. Chem. - Eur. J. 2017, 23, 6996−6999. (d) Wang, Y.; Deng, L.-L.; Deng, Y.; Han, J.-L. J. Org. Chem. 2018, 83, 4674−4680.
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Kai Sun: 0000-0002-0041-6044 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (U1504210), Program for Innovative Research Team of Science and Technology in the University of Henan Province (18IRTSTHN004), Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis (130028833), and aynu201708 for the financial support of this research.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b02733 Org. Lett. 2018, 20, 6687−6690
