Tetrahedron Letters xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Tetrahedron Letters

journal homepage: www.elsevier .com/ locate/ tet le t

Direct difunctionalization of alkenes with sulfinic acids and NBSleading to b-bromo sulfones

http://dx.doi.org/10.1016/j.tetlet.2015.02.0430040-4039/� 2015 Published by Elsevier Ltd.

⇑ Corresponding author. Tel./fax: +86 537 4458317.E-mail address: huawang_qfnu@126.com (H. Wang).

R1 + R2SO2XX = NHNH2, H, Na

R1

OSOO

R2

R1 + R2 R1

OHSOO

R2SO

OH

Previous work:

Ar1 + Ar2 Ar1

BrSOO

ASO

OH

This work:

NBS

+ O2

+ O2

+THF

+ R3SO2XX = NHNH2, H

Oxysulfonylation of alkenes

Arylsulfonylation of activated alkenes

Pyridine

Catalyst

Catalyst

Catalyst-freeAdditive-free

Bromosulfonylation of alkenes

NR4

O

R2

R1N

O

R2 SO

O

RR1

Scheme 1. Difunctionalization of alkenes to access sulfone-containing com

Please cite this article in press as: Wei, W.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.02.043

Wei Wei, Xiaoxia Liu, Daoshan Yang, Ruimei Dong, Ying Cui, Fei Yuan, Hua Wang ⇑The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, School of Chemistry and ChemicalEngineering, Qufu Normal University, Qufu 273165, Shandong, China

a r t i c l e i n f o a b s t r a c t

Article history:Received 5 January 2015Revised 12 February 2015Accepted 15 February 2015Available online xxxx

Keywords:b-Bromo sulfonesAlkenesSulfinic acidsNBSDifunctionalization

A new and metal-free method has been developed for the synthesis of b-bromo sulfones through thedirect difunctionalization of alkenes with sulfinic acids and NBS. This protocol provides a simple,convenient, and efficient approach to various b-bromo sulfones in moderate to good yields with excellentselectivity, and especially does not require any catalyst or additive.

� 2015 Published by Elsevier Ltd.

r2

3

(A)

(B)

(C)

pounds.

Sulfone groups are a very important class of functionalities,which extensively exist in various bioactive compounds, naturalproducts, and organic functionalized materials.1 Thus, the intro-duction of sulfone functionality into organic molecules to constructvarious organic sulfone compounds has drawn great interests ofchemists.2 On the other hand, the difunctionalization of alkenes,involving the formation of two new chemical bonds, has recentlybecome a powerful and fascinating tool for the construction of var-ious complex and highly valuable compounds in organic synthesisand medicinal chemistry.3 Over the past several years, someimportant difunctionalization reactions such as diamination,4

dioxygenation,5 aminooxygenation,6 and oxyphosphorylation7 ofalkenes have been effectively developed. Despite the significanceof these reactions, difunctionalization of alkenes to simultaneouslyincorporate the sulfone group and other different functional groupremains a challenging but attractive target to pursue. In 2013, Lei’sgroup8 reported a novel oxysulfonylation of alkenes with dioxygenand sulfinic acids to access b-hydroxysulfones (Scheme 1, A). Veryrecently, metal-catalyzed procedures for the construction ofb-ketosulfones via oxysulfonylation of alkenes have been described(Scheme 1, A).9 Li,10a Jiao10b and our group10c also reportedindependently the arylsulfonylation of activated alkenes leadingto sulfonated oxindoles (Scheme 1, B).

Herein, we wish to present a new and efficient synthesismethod for the direct bromosulfonylation of alkenes with sulfinicacids and NBS to access b-bromo sulfones (Scheme 1, C).

Table 1Screening of the reaction conditionsa

SOH

2a

O

+ NBS

1a

+SolventT(oC)

3aa

SBr O

O

Entry Solvent T (�C) Yieldb (%)

1 DCE 80 792 DME 80 383 1,4-Dioxane 80 604 THF 80 835 EtOAc 80 706 CH3CN 80 Trace7 Toluene 80 Trace8 EtOH 80 Trace9 DMF 80 nr10 DMSO 80 nr11 H2O 80 nr12 THF 25 1813 THF 60 3314 THF 80 75c

15 THF 80 71d

16 THF 80 67e

a Reaction conditions: styrene 1a (0.6 mmol), benzenesulfinic acid 2a (0.5 mmol),NBS (0.5 mmol), solvent (2 mL), 25–80 �C, 10 h (sealed tube).

b Isolated yields based on 2a.c 1a (0.5 mmol), 2a (0.5 mmol), NBS (0.5 mmol).d 1a (0.5 mmol), 2a (0.6 mmol), NBS (0.5 mmol).e 1a (0.5 mmol), 2a (0.5 mmol), NBS (0.6 mmol).

Table 2Results for the reactions of alkenes with sulfinic acids and NBSa

Entry 1 Time (h)

1 1a 8

2 1b 8

3 1c 10

4 1d 8

5 F 1e 10

6 Cl 1f 8

7

Cl

1g 10

8 Br 1h 10

2 W. Wei et al. / Tetrahedron Letters xxx (2015) xxx–xxx

Please cite this article in press as: Wei, W.; et al. Tetrahedron Lett. (201

Traditionally, b-bromo sulfones were synthesized by the bromi-nation of bis(2-phenethyl)sulfone with N-bromosuccinimide in thepresence of benzoyl peroxide,11 the bromination of b-hydroxysul-fones with phosphorus tribromide,12 and the bromosulfonylationof alkenes with bromine and sulfinates or sulfonyl bromide.13

Nevertheless, most of these methods might suffer from somelimitations such as the use of stoichiometric amounts of potentiallydangerous oxidants, unreadily-available starting materials,relatively harsh reaction conditions, and poor selectivity or lowyields. Alternatively, the present methodology provides a simpleand convenient approach to various b-bromo sulfones in moderateto good yields with excellent stereo- and regioselectivities underthe toxic metal catalyst-free and additive-free conditions.

In an initial experiment, styrene 1a and benzenesulfinic acid 2a,were chosen as the model substrates to optimize the reaction con-ditions in the presence of NBS. Among the solvents examined, THFwas found to be the most efficient reaction medium for this reac-tion (Table 1, entry 4). In contrast, only a trace amount of product3aa was detected when reaction was performed in CH3CN, toluene,or EtOH (Table 1, entries 6–8). None of product was obtained inDMF, DMSO, or H2O (Table 1, entries 9–11). Further optimizationof reaction temperature revealed that the best yield of 3aa wasobtained when reaction was conducted at 80 �C and a lower reac-tion temperature led to a significantly lower yield of product(Table 1, entries 4 and 12–13). The appropriate proportion of thestyrene 1a, benzenesulfinic acid 2a, and NBS was 1.2:1:1(Table 1, entries 14–16).

Product Yieldb (%)

SO2PhBr

3aa83

SO2PhBr

3ba80

SO2PhBr

3ca79

SO2PhBr

3da73

SO2PhBr

F 3ea

70

SO2PhBr

Cl 3fa

73

SO2PhBr

Cl

3ga67

SO2PhBr

Br 3ha

66

5), http://dx.doi.org/10.1016/j.tetlet.2015.02.043

Table 2 (continued)

Entry 1 Time (h) Product Yieldb (%)

9 NC 10

NC

BrSO2Ph

3ia

Trace

10 1a 10SO

O

Br

3ab81

11 Cl 1f 10SO

O

Br

Cl 3fb

75

12 1a 10SO

O

Br

Cl3ac

67

13 1a 10SO

O

Br

Br 3ad

74

14 1a 12SO

O

Br CF3

3ae

50

a Reaction conditions: alkenes 1 (0.6 mmol), sulfinic acids 2 (0.5 mmol), NBS (0.5 mmol), THF (2 mL), 80 �C, 8–12 h (sealed tube).b Isolated yields based on 2.

+SOH

ONBS S

O

O

R1i R =H

1j R= F

1k R= Cl

2a

THF,80oC

4ia R =H, 60%

4ja R= F, 61%

4ka R= Cl, 58%

R

Scheme 2. Method for the synthesis of allylic sulfones.

SOH

O

+ NBS

6a (76%)

SO O

BrTHF80oC

PhS

O O

Ph

Br

PhSOH

2a

O+ NBS

1a

+

3aa

TEMPO(2 equiv)

THF, 80oC(1)

(2)

SO O

Br

1a (0.3 mmol)

+THF80oC Ph

SO

Ph

Br

3aa (54%)6a (0.25 mmol)

(3)

1a (0.5 mmol)

O

(0.5 mmol)

Scheme 3. Investigation into the reaction mechanism.

Ar2 SO

O

1NBS

6Ar1 S

OO

Ar2

Br

3

Ar1

Ar2SO

OH2

Ar2SOO

Br[O]

5

Scheme 4. Postulated reaction pathway.

W. Wei et al. / Tetrahedron Letters xxx (2015) xxx–xxx 3

With the optimized reaction conditions in hand, we started toexplore the scope and limitations of the reaction of alkenes withsulfinic acids and NBS. As demonstrated in Table 2, in general,

Please cite this article in press as: Wei, W.; et al. Tetrahedron Lett. (201

aromatic alkenes bearing an electron-donating group or anelectron-withdrawing group could react smoothly to give the cor-responding products in good to excellent yields (3aa–3ha).

Substrates bearing a methyl group in the para-, meta-, orortho-position of the phenyl were subjected to the optimizedreaction conditions (1b–d). The results showed that the reactionefficiency was not obviously affected by the steric hindrance.Moreover, halogen groups including F, Cl, and Br were compatiblewith this reaction leading to the products 3ea–3ha, which could beemployed for further transformations. Only a trace amount ofdesired product 3ia was obtained when 4-vinylbenzonitrile wasemployed as substrate. Nevertheless, when an aliphatic alkenesuch as 1-octene was used as the substrate, none of the desiredproduct was obtained. In addition to benzenesulfinic acid, substi-tuted benzenesulfinic acids containing either electron-rich orelectron-deficient groups were all suitable for this reaction to gen-erate the corresponding products in good yields (3ab–3ad). Thesterically-hindered substituted arylsulfinic acids such as 2-(trifluoro-methyl)benzenesulfinic acid could also be smoothly transformed tothe desired b-bromo sulfone (3ae).

Interestingly, when a-methyl styrenes such as prop-1-en-2-yl-benzene 1i, 1-fluoro-4-(prop-1-en-2-yl)benzene 1j, and 1-chloro-4-(prop-1-en-2-yl)benzene 1k were used as the substrates, thecorresponding allylic sulfones 4ia–4ka were obtained in goodyields (Scheme 2). Therefore, this reaction system offers a usefuland attractive strategy for the construction of allylic sulfone

5), http://dx.doi.org/10.1016/j.tetlet.2015.02.043

4 W. Wei et al. / Tetrahedron Letters xxx (2015) xxx–xxx

structural motifs, which are exceptionally valuable and versatilebuilding blocks in synthetic and pharmaceutical chemistry.14

Considering that sulfonyl radicals were easily formed from sul-finic acids under air,8,9d,10b,c,15 we supposed a radical pathwaymight be involved in this reaction system. As shown in Scheme 3(Eq. 1), the model reaction was completely inhibited when 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO, a well-known radicalscavenger) was added into the reaction system, suggesting that aradical pathway could be involved in the present transformation.Moreover, when the reaction of benzenesulfinic acid 2a with NBSwas conducted in the absence of styrene, benzenesulfonyl bromide6a was obtained in 76% yield (Scheme 3, Eq. 2). Furthermore, treat-ment of benzenesulfonyl bromide 6a with styrene 1a under thestandard procedure led to the formation of desired product 3aa(Scheme 3, Eq. 3). The above results indicated that sulfonylbromide might be the critical intermediate in the present reactionsystem.

Although the detailed reaction mechanism is still unclear at thepresent stage, based on the above experiments and previousstudies,8–10,13,15 a possible reaction pathway is proposed asdescribed in Scheme 4. Firstly, the sulfonyl radical 5 was generatedfrom sulfinic acids 2 under air. Subsequently, sulfonyl radical 5interacted with NBS to give sulfonyl bromide 6. Finally, theaddition of sulfonyl bromide 6 to alkene 1 would lead to theformation of the desired b-bromo sulfone 3.

In conclusion, a novel and efficient method has been devel-oped for the construction of b-bromo sulfones through the directdifunctionalization of alkenes with sulfinic acids and NBS. Thisprotocol, which utilizes simple and readily available startingmaterials and catalyst-free conditions, provides a convenientand highly attractive route to various b-bromo sulfones.Further studies on the scope and application of this reactionare underway.

Acknowledgements

This work was supported by the National Natural ScienceFoundation of China (Nos. 21302109, 21302110, and 21375075),the Taishan Scholar Foundation of Shandong Province, theExcellent Middle-Aged and Young Scientist Award Foundation ofShandong Province (BS2013YY019), National Training Programsof Innovation and Entrepreneurship for Undergraduates(201410446018), and the Scientific Research Foundation of QufuNormal University (BSQD 2012020).

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.tetlet.2015.02.043.

Please cite this article in press as: Wei, W.; et al. Tetrahedron Lett. (201

References and notes

1. For selected examples, see: (a) Simpkins, N. S. Sulfones in Organic Synthesis;Pergamon Press: Oxford, 1993; (b) Wolf, W. M. J. Mol. Struct. 1999, 474, 113; (c)Petrov, K. G.; Zhang, Y.; Carter, M.; Cockerill, G. S.; Dickerson, S.; Gauthier, C. A.;Guo, Y.; Mook, R. A.; Rusnak, D. W.; Walker, A. L.; Wood, E. R.; Lackey, K. E.Bioorg. Med. Chem. Lett. 2006, 16, 4686; (d) Noshi, M. N.; El-Awa, A.; Torres, E.;Fuchs, P. L. J. Am. Chem. Soc. 2007, 129, 11242; (e) Desrosiers, J. N.; Charette, A.B. Angew. Chem., Int. Ed. 2007, 46, 5955; (f) Ettari, R.; Nizi, E.; Di Francesco, M.E.; Dude, M.-A.; Pradel, G.; Vicik, R.; Schirmeister, T.; Micale, N.; Grasso, S.;Zappala, M. J. Med. Chem. 2008, 51, 988; (g) Kotha, S.; Chavan, A. S. J. Org. Chem.2010, 75, 4319.

2. For selected examples, see: (a) Hof, F.; Schutz, A.; Fah, C.; Meyer, S.; Bur, D.; Liu,J.; Goldberg, D. E.; Diederich, E. Angew. Chem., Int. Ed. 2006, 45, 2138; (b)Cassani, C.; Bernardi, L.; Fini, F.; Ricci, A. Angew. Chem., Int. Ed. 2009, 48, 5694;(c) Sikervar, V.; Fleet, J. C.; Fuchs, P. L. Chem. Commun. 2012, 9077; (d) Sikervar,V.; Fleet, J. C.; Fuchs, P. L. J. Org. Chem. 2012, 77, 5132; (e) Rodkey, E. A.; McLeod,D. C.; Bethel, C. R.; Smith, K. M.; Xu, Y.; Chai, W.; Che, T.; Carey, P. R.; Bonomo,R. A.; Akker, F.; Buynak, J. D. J. Am. Chem. Soc. 2013, 135, 18358; (f) Emmett, E. J.;Hayter, B. R.; Willis, M. C. Angew. Chem., Int. Ed. 2013, 52, 12679.

3. For recent reviews: (a) Sibbald, P. A. Palladium-Catalyzed OxidativeDifunctionalization of Alkenes: New Reactivity and New Mechanisms; ProQuest,UMI Dissertation Publishing, 2011; (b) Jacques, B.; Muiñz, K. In CatalyzedCarbon–Heteroatom Bond Formation; Yudin, A. K., Ed.; Wiley-VCH: Weinheim,2011; pp 119–135; (c) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S.Chem. Rev. 2007, 107, 5318; (d) Li, G.; Kotti, S. R. S. S.; Timmons, C. Eur. J. Org.Chem. 2007, 2745; (e) Muñiz, K. Angew. Chem., Int. Ed. 2009, 48, 9412; (f)Chemler, S. R. Org. Biomol. Chem. 2009, 7, 3009; (g) Jensen, K. H.; Sigman, M. S.Org. Biomol. Chem. 2008, 6, 4083; (h) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev.2011, 111, 2981; (i) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464.

4. Selective examples: (a) Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J.Am. Chem. Soc. 2005, 127, 7308; (b) Streuff, J.; Hçvelmann, C. H.; Nieger, M.;MuÇiz, K. J. Am. Chem. Soc. 2005, 127, 14586; (c) Du, H.; Zhao, B.; Shi, Y. J. Am.Chem. Soc. 2008, 130, 8590.

5. Selective examples: (a) Zhang, Y.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129,3076; (b) Li, Y.; Song, D.; Dong, V. M. J. Am. Chem. Soc. 2008, 130, 2962; (c)Wang, A.; Jiang, H.-F.; Chen, H.-J. J. Am. Chem. Soc. 2009, 131, 3846; (d) Su, Y.;Sun, X.; Wu, G.; Jiao, N. Angew. Chem., Int. Ed. 2013, 52, 9808.

6. Selective examples: (a) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc.2005, 127, 7690; (b) Michaelis, D. J.; Shaffer, C. J.; Yoon, T. P. J. Am. Chem. Soc.2007, 129, 1866; (c) Fuller, P. H.; Kim, J.-W.; Chemler, S. R. J. Am. Chem. Soc.2008, 130, 17638.

7. Wei, W.; Ji, J.-X. Angew. Chem., Int. Ed. 2011, 50, 9097.8. Lu, Q.; Zhang, J.; Wei, F.; Qi, Y.; Wang, H.; Liu, Z.; Lei, A. W. Angew. Chem., Int. Ed.

2013, 52, 7156.9. (a) Wei, W.; Liu, C.; Yang, D.; Wen, J.; You, J.; Suo, Y.; Wang, H. Chem. Commun.

2013, 10239; (b) Singh, A. K.; Chawla, R.; Yadav, L. D. S. Tetrahedron Lett. 2014,55, 4742; (c) Shi, X.; Ren, X.; Ren, Z.; Li, J.; Wang, Y.; Yang, S.; Gu, J.; Gao, Q.;Huang, G. Eur. J. Org. Chem. 2014, 5083; (d) Wei, W.; Wen, J.; Yang, D.; Wu, M.;You, J.; Wang, H. Org. Biomol. Chem. 2014, 12, 7678.

10. (a) Li, X.; Xu, X.; Hu, P.; Xiao, X.; Zhou, C. J. Org. Chem. 2013, 78, 7343; (b) Shen,T.; Yuan, Y.; Song, S.; Jiao, N. Chem. Commun. 2014, 4115; (c) Wei, W.; Wen, J.;Yang, D.; Du, J.; You, J.; Wang, H. Green Chem. 2014, 16, 2988.

11. (a) Lotspeich J. Org. Chem. 1965, 30, 2068; (b) Iriuchisima, S.; Tsuchihashi, G.Synthesis 1970, 588.

12. Marshall, D. R. et al J. Chem. Soc., Perkin Trans. 1977, 1914.13. (a) Zakharkin, L. I.; Zhigareva, G. G. J. Org. Chem. USSR 1973, 9, 918; (b)

Harwood, L. M.; Julia, M.; Thuillier, G. L. Tetrahedron 1980, 36, 2483.14. Selective examples: (a) Jiang, L.; Lei, Q.; Huang, X.; Cui, H.-L.; Zhou, X.; Chen,

Y.-C. Chem.-Eur. J. 2011, 17, 9489; (b) Gembus, V.; Postikova, S.; Levacher, V.;Briere, J.-F. J. Org. Chem. 2011, 76, 4194; (c) Diez, D.; Garcia, P.; Marcos, I. S.;Garrido, N. M.; Basabe, P.; Broughton, H. B.; Urones, J. G. Org. Lett. 2003, 5,3687; (d) Li, X.; Xu, X.; Zhou, C. Chem. Commun. 2012, 12240.

15. (a) Lu, Q.; Zhang, J.; Zhao, G.; Qi, Y.; Wang, H.; Lei, A. W. J. Am. Chem. Soc. 2013,135, 11481; (b) Wei, W.; Wen, J.; Yang, D.; Jing, H.; You, J.; Wang, H. RSC Adv.2015, 5, 4416.

5), http://dx.doi.org/10.1016/j.tetlet.2015.02.043