Synlett 2022; 33(15): 1539-1545
DOI: 10.1055/s-0040-1719934
letter

Nitric Acid Promoted Metal-Free Bromothiolation of Internal Alkynes with Hydrobromic Acid and Disulfides

Han Sun
,
,
Zhi-Xiang Yao
,
Hui Su
This project was financially supported by the National Natural Science Foundation of China (No. 21602036).
 


Abstract

A novel, metal-free bromo-thiolation of internal alkynes with hydrobromic acid and disulfides has been developed. The reaction is promoted by commercial-grade nitric acid and is used to construct a series of unexplored β-bromoalkenyl sulfides in moderate to good yield. Most products were obtained with high stereoselectivity as syn-configured tetrasubstituted alkenes. Both sulfide groups of the disulfide reagent were used in this method.


#

Alkenyl sulfides are widely utilized as versatile building blocks[1] and key components in the synthesis of many natural products and biologically active molecules.[2] Consequently, new effective synthetic methods for these convenient intermediates has attracted much attention,[3] especially for β-haloalkenyl sulfides, which are easily converted into various alkenes and alkynyl sulfides as coupling partners in nucleophilic substitutions and transition-metal-catalyzed cross-coupling reactions.[4] Since the original work reported by Modena’s group,[5] numerous methods have been developed to prepare a variety of β-haloalkenyl sulfides, including chloro,[6] bromo,[7] and iodo[8] groups. However, approaches that can be used to access β-bromoalkenyl sulfides have been less extensively investigated.[9]

Typically, β-bromoalkenyl sulfides are synthesized by bromo-thiolation of alkynes using different sulfenylating agents (Scheme [1a–d]). Montevecchi and co-workers realized the addition of sulfenyl bromine to alkynes in 1993.[7a] Belova’s group developed the reactions of alkynes and sulfonamides activated by phosphorus oxohalides (POCl3, POBr3).[7b] Subsequently, Taniguchi reported copper-catalyzed addition of halides and sulfide groups to alkynes utilizing disulfides and thiols.[7c] [d] Recently, Zeng and Xu’s group developed a regio- and stereoselective halothiolation of alkynes using lithium halides (Br, Cl, I) and N-thiosuccinimides as starting materials.[7f] Nevertheless, the products of these strategies were anti-configured, while the other syn-additive isomers come out as byproducts. Moreover, terminal and dialkyl alkynes are more tolerant to these preparations, and diarly acetylenes are not so compatible. Furthermore, some of them suffer from the disadvantages of requiring metal catalysts and unstable sulfenylating agents, which are hard to transfer to an industrial scale. Therefore, the development of metal-free catalyzed, easy-to-handle, stereo- and regioselective synthetic methods for syn-configured bromoalkenyl sulfides remains a significant and challenging task.

Zoom Image
Scheme 1Bromothiolation of alkynes

Herein, we present a method for direct bromo-thiolation of internal alkynes using hydrobromic acid (40% aqueous solution) and disulfides, only promoted by commercial-grade nitric acid (65% aqueous solution) (Scheme [1e]). The reported reaction can selectively afford the corresponding syn-configured tetrasubstituted alkenes containing two good leaving groups, a thiolate and a bromide, and uses both sulfide groups of the disulfide reagent. Notably, the method can be scaled up to gram-scale with no loss in yield.

Zoom Image
Figure 1 ORTEP drawing of compound 3awith thermal ellipsoids set at 50% probability

Table 1 Optimization of reaction conditionsa

Entry

[Br] (equiv)

Additive (equiv)

Solvent

Yield (%)b

Z/E c

 1

HBr (10.0)

DCE

 0

 2

HBr (10.0)

HNO3 (0.5)

DCE

50

40:60

 3

HBr (10.0)

HNO3 (0.5)

CH2Cl2

91

99:1

 4

HBr (10.0)

HNO3 (0.5)

CHCl3

28

50:50

 5

HBr (10.0)

HNO3 (0.5)

THF

 0

 6

HBr (10.0)

HNO3 (0.5)

DMSO

 0

 7

NaBr (10.0)

HNO3 (0.5)

CH2Cl2

26

99:1

 8

NH4Br (10.0)

HNO3 (0.5)

CH2Cl2

22

99:1

 9

TBAB (10.0)

HNO3 (0.5)

CH2Cl2

 0

10

HBr (10.0)

H2SO4 (0.5)

CH2Cl2

trace

11

HBr (10.0)

HClO4 (0.5)

CH2Cl2

trace

12d

HBr (10.0)

HNO3 (0.5)

CH2Cl2

50

38:62

13e

HBr (10.0)

HNO3 (0.5)

CH2Cl2

trace

14

HBr (10.0)

HNO3 (0.25)

CH2Cl2

80

86:14

15

HBr (5.0)

HNO3 (0.5)

CH2Cl2

67

72:28

16f

HBr (10.0)

HNO3 (0.5)

CH2Cl2

88

91:9

a Reaction conditions: 1a (0.40 mmol), 2a (0.22 mmol), mixture of HBr and HNO3, solvent (4 mL), under air, 40 °C, 8 h.

b Isolated yield.

c Z/Eratio determined by 1H NMR analysis.

d At 20 °C.

e At 60 °C for 1 h.

f 1a (4.0 mmol), 2a (2.2 mmol), solvent (30 mL), 6 h.

Initially, we chose the reaction of diphenylacetylene (1a) and p-toyl disulfide (2a) as the model, given that the Z/E ratio of the corresponding product can be determined by 1H NMR analysis more clearly (Table [1]). It should be noted that the reaction did not occur in the absence of HNO3, which suggested that HNO3 played an important role in this transformation (entry 1). Screening of solvents showed that the solvent was crucial to the transformation (entries 2–6). CH2Cl2 proved to be the best option and improved both the yield and Z/E selectivity significantly (entry 3), whereas the use of either THF or DMSO did not produce 3a at all (entries 5 and 6). NaBr and NH4Br could also be used as bromine sources with excellent selectivity, while TBAB did not work (entries 7–9). When HNO3 was replaced with H2SO4 and HClO4, only a trace amount of product could be detected by GC-MS (entries 10 and 11). Lower and higher temperature resulted in poor yield of the product (entries 12 and 13). In addition, when the amounts of HNO3 and HBr were decreased to 0.25 equiv and 5.0 equiv, respectively, the product yield and selectivity decreased to 80% (Z/E: 86/14, entry 14) and 67% (Z/E: 72/28, entry 15). To our delight, the reaction could be scaled up to 4.0 mmol, and 1.3 g 3a (88%) was isolated with only slightly loss in selectivity (Z/E, 91:9, entry 16 and the Supporting Information).

To confirm the configuration of (Z)-3a unambiguously, the product was purified by using column chromatography and analyzed by single-crystal X-ray crystallography (Figure [1]).

With the optimized conditions in hand, various disulfides were applied in the reaction to establish the scope of this protocol (Table [2]). The results disclosed that numerous combinations of diaryl or dialkyl disulfides and diphenylacetylene (1a) could produce the corresponding β-bromoalkenyl sulfides in moderate to excellent yields. In general, diaryl disulfides afforded a higher yield and had good syn-selectivity (entries 1–8); however, a strong electron-donating group (OMe) adversely affected the regioselectivity (entry 2). Lower yields were observed when ortho-substituted substrates were used as coupling partner, because of increased steric hindrance. For example, 2e, 2g, and 2i, bearing an o-fluoro, o-bromo, and o-methy group, respectively, reacted with 1a to give desired products in 78, 67, and 53% yield (entries 4, 6, and 8). Regrettably, dialkyl disulfides showed lower reactivity and selectivity. When dibenzyl and dicyclohexyl disulfides participated in the reaction, yields and Z/E ratio decreased to 77% (50:50) and 60% (33:67), while a substrate with a n-dibutyl substituent gave the product in 43% yield (entries 9–11).[10]

Table 2 Scope of Disulfides for the Synthesis of β-Bromoalkenyl Sulfidesa

Entry

Disulfide 2

Product 3

Yield (%)b (Z/E)c

1

2b

3b

90 (99:1)

2

2c

3c

88 (83:17)

3

2d

3d

82 (99:1)

4

2e

3e

78 (99:1)

5

2f

3f

84 (99:1)

6

2g

3g

67 (99:1)

 7

2h

3h

71 (99:1)

 8

2i

3i

53 (99:1)

 9

2j

3j

77 (50:50)

10

2k

3k

60 (33:67)

11

2l

3l

43 (61:39)

a Reaction conditions: 1a (0.40 mmol), 2 (0.22 mmol), mixture of HBr (4.0 mmol) and HNO3 (0.2 mmol), in CH2Cl2 (4 mL), under air, 40 °C, 8 h.

b Isolated yield.

c Z/Eratio determined by 1H NMR analysis.

Subsequently, a series of alkynes were further examined for the bromothiolation of 2a. As showed in Table [3], symmetrical arylacetylenes, substituted at the para-position including chloro and bromo groups, reacted smoothly, while fluoro and methyl substituents gave a mixture of the Z/E isomers (entries 1–4). To our delight, unsymmetrical alkynes 1f and 1g could be used to selectively produce the β-bromoalkenyl sulfides in 54 and 41% yields, respectively, although the configurations were not confirmed (entries 5 and 6). When dialkylacetylene 1h was examined, the anti-configured product (E)-3t [7c] [d] was afforded in 49% yield. Unfortunately, terminal alkynes, phenylacetylene and 1-heptyne, were not suitable for the reaction (entries 8 and 9).

Zoom Image
Scheme 2 Control experiments

To identify the possible reaction mechanism, control experiments were conducted (Scheme [2]). Firstly, we introduced unsymmetrical disulfide[11] 2m into the reaction with diphenylacetylene (1a). Both sulfide groups were added to alkyne, and afforded the corresponding products 3a in 20% yield and 3l in 40% yield (based on 0.4 mmol of 1a; Eq. 1). Then, the radical scavenger 2,2,6,6-tetramethylpiperidinooxy (TEMPO) was added to the model reaction. The reaction was not inhibited in the presence of TMEPO (3 equiv), giving 3a in 33% yield.[10] Moreover, no adduct of radical quencher was detected, which indicated a radical pathway was unlikely (Eq. 2).[12]

Based on the above results, a proposed mechanism for bromothiolation of diphenylacetylene (1a) with diary disulfide 2a is illustrated (Scheme [3]). Initially, nitric acid mixes with excess hydrobromic acid to generate nitrosyl bromide,[13] which can react with 1a to form p-toluensulfenyl bromide A.[14] Then, the addition of A to alkyne 2a gives a thiirenium intermediate, which is represented as a covalent species B or a tight ion pair C.[5] Finally, the intermediate complex collapses to afford the product 3a, yielding the syn-configured adduct. The high Z-selectivity of reaction can be rationalized by the tight ion pair C, which may dissociate into free thiirenium ion without the influence of good solvent for Br and the stabilizing effect of aryl groups.

Table 3 Scope of Diarylacetylenes for the Synthesis of β-Bromoalkenyl Sulfidesa

Entry

Diarylacetylene 1a

Product 3

Yield (%)b (Z/E)c

1

1b

3m

72 (99:1)

2

1c

3n

77 (95:5)

3

1d

3o

66 (61:39)

4

1e

3p

52 (68:32)

5

1f

3q

54 (99:1)

6

1g

3r

41 (89:11)

7

1h

3s

49 (1:99)

8

1i

3t

trace

9

1j

3u

trace

a Reaction conditions: 1a (0.40 mmol), 2 (0.22 mmol), mixture of HBr (4.0 mmol) and HNO3 (0.2 mmol), in CH2Cl2 (4 mL), under air, 40 °C, 8 h.

b Isolated yield.

c Z/Eratio determined by 1H NMR analysis.

Zoom Image
Scheme 3 Proposed reaction mechanism

In summary, we have developed a metal-free bromothiolation of internal alkynes with disulfides under simple and mild conditions. This unprecedented protocol offers β-bromoalkenyl sulfides with good functional tolerance and high syn-stereoselectivity, and showed great promise for the synthesis of bioactive complex alkenyl sulfides. In addition, a scale-up experiment revealed the potential application value of this protocol.


#

Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

  • References and Notes

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    • 1b Kuniyasu H, Kambe N. Chem. Lett. 2006; 35: 1320
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    • 1d Li Q, Dong T, Liu X, Lei X. J. Am. Chem. Soc. 2013; 135: 4996
    • 1e Itami K, Higashi S, Mineno M, Yoshida J.-I. Org. Lett. 2005; 7: 1219
    • 2a Nieves I, Garrido M, Abad JL, Delgado A. Synlett 2010; 2950
    • 2b Allan RD, Duke RK, Hambley TW, Johnston GA. R, Mewett KN, Quickert N, Tran HW. Aust. J. Chem. 1996; 49: 785
    • 3a Yu G, Ou Y, Chen D, Huang Y, Yan Y, Chen Q. Synlett 2020; 31: 83
    • 3b Mulina OM, Doronin MM, Kostyagina VA, Timofeev GP. Russ. J. Org. Chem. 2021; 57: 1302
    • 3c Lu F, Xu J, Li H, Wang K, Ouyang D, Sun L, Huang M, Jiang J, Hu J, Alhumade H, Lu L, Lei A. Green Chem. 2021; 23: 7982
    • 3d Li X, Zhang B, Yu Z, Zhang D, Shi H, Xu L, Du Y. Synthesis 2022; 54: 1375
    • 3e Zhang D, Zhang J, Li X, Yu Z, Li Y, Sun F, Du Y. Synthesis 2022; 54: 411
    • 4a Miyaura N, Suzuki A. Chem. Rev. 1995; 95: 2457
    • 4b Negishi E.-I, Anastasia L. Chem. Rev. 2003; 103: 1979
    • 4c Nicolaou KC, Bulger PG, Sarlah D. Angew. Chem. Int. Ed. 2005; 44: 4442
    • 4d Johansson Seechurn CC. C, Kitching MO, Colacot TJ, Snieckus V. Angew. Chem. Int. Ed. 2012; 51: 5062
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    • 6b Capozzi G, Caristi C, Lucchini V, Modena G. J. Chem. Soc., Perkin Trans. 1 1982; 2197
    • 6c Capozzi G, Romeo G, Lucchini V, Modena G. J. Chem. Soc., Perkin Trans. 1 1983; 831
    • 6d Iwasaki M, Fujii T, Nakajima K, Nishihara Y. Angew. Chem. Int. Ed. 2014; 53: 13880
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      For alkynes thiolation see:
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    • 9h Minozzi M, Monesi A, Nanni D, Spagnolo P, Marchetti N, Massi A. J. Org. Chem. 2011; 76: 450
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  • 10 Synthesis of 3; General procedure: Alkyne 1 (0.40 mmol) and disulfide 2 (0.22 mmol) were added into a 25 mL oven-dried flask and dissolved in dichloromethane (4 mL), then hydrobromic acid (40% aqueous, 10 equiv) mixed with nitric acid (65% aqueous, 0.5 equiv) was added dropwise. The solution was then stirred for 8 h at 40 °C. After the reaction was finished, the reaction mixture was cooled to room temperature, diluted in diethyl ether (15 mL), and washed with brine (2 × 15 mL). The aqueous phase was re-extracted with diethyl ether (15 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuum and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford product 3. Spectroscopic data of (Z)-(2-bromo-1,2-diphenylvinyl)(p-tolyl)-sulfane (3a): Yield: 136.7 mg (91%); white solid; mp 105.0–106.1 °C. 1H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 8.0 Hz, 2 H), 7.34–7.43 (m, 5 H), 7.17–7.27 (m, 3 H), 7.00 (d, J = 8.0 Hz, 2 H), 6.88 (d, J = 8.0 Hz, 2 H), 2.19 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 140.7, 139.7, 137.2, 136.4, 131.9, 130.1, 129.7, 129.3, 129.2, 128.6, 128.2, 127.8, 127.7, 121.5, 21.0. HRMS (ESI): m/z [M + H]+ calcd for C21H18 78.9183BrS: 381.0307; found: 381.0298. HRMS (ESI): m/z [M + H]+ calcd for C21H18 80.9163BrS: 383.0287; found: 383.0273. See the Supporting Information for 3as.
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Corresponding Author

Xiao-Cheng Huang
Guangxi Key Laboratory of Green Processing of Sugar Resources, College of Biological and Chemistry Engineering, Guangxi University of Science and Technology
P. R. of Liuzhou, 545006
China   

Publication History

Received: 06 March 2022

Accepted after revision: 01 June 2022

Article published online:
20 July 2022

© 2022. Thieme. All rights reserved

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  • References and Notes

    • 1a Kondo T, Mitsudo T.-A. Chem. Rev. 2000; 100: 3205
    • 1b Kuniyasu H, Kambe N. Chem. Lett. 2006; 35: 1320
    • 1c Marcantoni E, Massaccesi M, Petrini M, Bartoli G, Bellucci MC, Bosco M, Sambri L. J. Org. Chem. 2000; 65: 4553
    • 1d Li Q, Dong T, Liu X, Lei X. J. Am. Chem. Soc. 2013; 135: 4996
    • 1e Itami K, Higashi S, Mineno M, Yoshida J.-I. Org. Lett. 2005; 7: 1219
    • 2a Nieves I, Garrido M, Abad JL, Delgado A. Synlett 2010; 2950
    • 2b Allan RD, Duke RK, Hambley TW, Johnston GA. R, Mewett KN, Quickert N, Tran HW. Aust. J. Chem. 1996; 49: 785
    • 3a Yu G, Ou Y, Chen D, Huang Y, Yan Y, Chen Q. Synlett 2020; 31: 83
    • 3b Mulina OM, Doronin MM, Kostyagina VA, Timofeev GP. Russ. J. Org. Chem. 2021; 57: 1302
    • 3c Lu F, Xu J, Li H, Wang K, Ouyang D, Sun L, Huang M, Jiang J, Hu J, Alhumade H, Lu L, Lei A. Green Chem. 2021; 23: 7982
    • 3d Li X, Zhang B, Yu Z, Zhang D, Shi H, Xu L, Du Y. Synthesis 2022; 54: 1375
    • 3e Zhang D, Zhang J, Li X, Yu Z, Li Y, Sun F, Du Y. Synthesis 2022; 54: 411
    • 4a Miyaura N, Suzuki A. Chem. Rev. 1995; 95: 2457
    • 4b Negishi E.-I, Anastasia L. Chem. Rev. 2003; 103: 1979
    • 4c Nicolaou KC, Bulger PG, Sarlah D. Angew. Chem. Int. Ed. 2005; 44: 4442
    • 4d Johansson Seechurn CC. C, Kitching MO, Colacot TJ, Snieckus V. Angew. Chem. Int. Ed. 2012; 51: 5062
    • 4e Wu W, Jiang H. Acc. Chem. Res. 2014; 47: 2483
  • 5 Calo V, Scorrano G, Modena G. J. Org. Chem. 1969; 34: 2020
    • 6a Lucchini V, Modena G, Valle G, Capozzi G. J. Org. Chem. 1981; 46: 4720
    • 6b Capozzi G, Caristi C, Lucchini V, Modena G. J. Chem. Soc., Perkin Trans. 1 1982; 2197
    • 6c Capozzi G, Romeo G, Lucchini V, Modena G. J. Chem. Soc., Perkin Trans. 1 1983; 831
    • 6d Iwasaki M, Fujii T, Nakajima K, Nishihara Y. Angew. Chem. Int. Ed. 2014; 53: 13880
    • 6e Iwasaki M, Fujii T, Yamamoto A, Nakajima K, Nishihara Y. Chem. Asian J. 2014; 9: 58
    • 6f Surineni N, Buragohain P, Saikia B, Barua NC, Baruah RK. Tetrahedron Lett. 2015; 56: 6965
    • 6g Liang S, Jiang L, Yi W.-B, Wei J. Org. Lett. 2018; 20: 7024
    • 7a Benati L, Montevecchi PC, Spagnolo P. Tetrahedron 1993; 49: 5365
    • 7b Zyk NV, Beloglazkina EK, Belova MA, Zefirov NS. Russ. Chem. Bull. 2000; 49: 1846
    • 7c Taniguchi N. Synlett 2008; 849
    • 7d Taniguchi N. Tetrahedron 2009; 65: 2782
    • 7e Bao Y, Zhong L, Hou Q, Zhou Q, Yang F. Chin. J. Chem. 2018; 36: 1063
    • 7f Liu S, Zheng X, Xu B. Org. Chem. Front. 2020; 7: 1690
    • 8a Lin Y.-M, Lu G.-P, Cai C, Yi W.-B. Org. Lett. 2015; 17: 3310
    • 8b Bao Y, Yang X, Zhou Q, Yang F. Org. Lett. 2018; 20: 1966

      For alkynes thiolation see:
    • 9a Truce WE, Tichenor GJ. W. J. Org. Chem. 1972; 37: 2391
    • 9b Ogawa A, Ikeda T, Kimura K, Hirao T. J. Am. Chem. Soc. 1999; 121: 5108
    • 9c Taniguchi T, Fujii T, Idota A, Ishibashi H. Org. Lett. 2009; 11: 3298
    • 9d Shiu H.-Y, Chan T.-C, Ho C.-M, Liu Y, Wong M.-K, Che C.-M. Chem. Eur. J. 2009; 15: 3839
    • 9e Jim CK. W, Qin A, Lam JW. Y, Mahtab F, Yu Y, Tang BZ. Adv. Funct. Mater. 2010; 20: 1319
    • 9f Banerjee B, Litvinov DN, Kang J, Bettale JD, Castle SL. Org. Lett. 2010; 12: 2650
    • 9g Jin Z, Xu B, Hammond GB. Eur. J. Org. Chem. 2010; 168
    • 9h Minozzi M, Monesi A, Nanni D, Spagnolo P, Marchetti N, Massi A. J. Org. Chem. 2011; 76: 450
    • 9i Nurhanna Riduan S, Ying JY, Zhang Y. Org. Lett. 2012; 14: 1780
    • 9j Singh R, Raghuvanshi DS, Singh KN. Org. Lett. 2013; 15: 4202
    • 9k Truong VX, Dove AP. Angew. Chem. Int. Ed. 2013; 52: 4132
    • 9l Chen J, Chen S, Xu X, Tang Z, Au C.-T, Qiu R. J. Org. Chem. 2016; 81: 3246
    • 9m Ye Y, Huang C, Zhao C, Ren B, Xiao H, Li X. Synth. Commun. 2016; 46: 1634
    • 9n Pramanik M, Choudhuri K, Chakraborty S, Ghosh A, Mal P. Chem. Commun. 2020; 56: 2991
  • 10 Synthesis of 3; General procedure: Alkyne 1 (0.40 mmol) and disulfide 2 (0.22 mmol) were added into a 25 mL oven-dried flask and dissolved in dichloromethane (4 mL), then hydrobromic acid (40% aqueous, 10 equiv) mixed with nitric acid (65% aqueous, 0.5 equiv) was added dropwise. The solution was then stirred for 8 h at 40 °C. After the reaction was finished, the reaction mixture was cooled to room temperature, diluted in diethyl ether (15 mL), and washed with brine (2 × 15 mL). The aqueous phase was re-extracted with diethyl ether (15 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuum and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford product 3. Spectroscopic data of (Z)-(2-bromo-1,2-diphenylvinyl)(p-tolyl)-sulfane (3a): Yield: 136.7 mg (91%); white solid; mp 105.0–106.1 °C. 1H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 8.0 Hz, 2 H), 7.34–7.43 (m, 5 H), 7.17–7.27 (m, 3 H), 7.00 (d, J = 8.0 Hz, 2 H), 6.88 (d, J = 8.0 Hz, 2 H), 2.19 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 140.7, 139.7, 137.2, 136.4, 131.9, 130.1, 129.7, 129.3, 129.2, 128.6, 128.2, 127.8, 127.7, 121.5, 21.0. HRMS (ESI): m/z [M + H]+ calcd for C21H18 78.9183BrS: 381.0307; found: 381.0298. HRMS (ESI): m/z [M + H]+ calcd for C21H18 80.9163BrS: 383.0287; found: 383.0273. See the Supporting Information for 3as.
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Scheme 1Bromothiolation of alkynes
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Figure 1 ORTEP drawing of compound 3awith thermal ellipsoids set at 50% probability
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Scheme 2 Control experiments
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Scheme 3 Proposed reaction mechanism