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Regioselective Synthesis of Sulfonyl-Containing Benzyl Dithiocarbamates through Copper-Catalyzed Thiosulfonylation of Styrenes Miao Lai, Zhiyong Wu, Shi-Jun Li, Donghui Wei, and Mingqin Zhao J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01829 • Publication Date (Web): 15 Aug 2019 Downloaded from pubs.acs.org on August 15, 2019

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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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The Journal of Organic Chemistry

Regioselective

Synthesis

of

Sulfonyl-Containing

Benzyl

Dithiocarbamates through Copper-Catalyzed Thiosulfonylation of Styrenes Miao Lai,a Zhiyong Wu,*a Shi-Jun Li,b Donghui Wei,b and Mingqin Zhao*a a

Flavors and Fragrance Engineering & Technology Research Center of Henan Province, College

of Tobacco Science, Henan Agricultural University, Zhengzhou 450002, P. R. China b

College of Chemistry and Molecular Engineering, Center of Computational Chemistry,

Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, P. R. China *E-mail: [email protected]; [email protected]

TOC Graphic:

R N

S R1

+ R2SO2Cl +

R3

N R3

R3 R3 N

3

S

S

R3

S

Cu(OAc)2

S

O O S R2

S

1,4-dioxane, 100 oC,12 h, air R1

An

efficient

approach

for

no ligands or additives

high regioselectivity

simple reaction conditions

broad substrate scope

the

preparation

of

49 examples up to 88% yields

sulfonyl-containing

benzyl

dithiocarbamates has been developed using tetraalkylthiuram disulfides as the thiolating agents and sulfonyl chlorides as the sulfonyl sources in the presence of copper catalyst. The dithiocarbamate group together with sulfonyl group were simultaneously introduced into styrene in chemo- and regioselective manners. This protocol provides a convenient procedure, with good yields and functional group tolerance to various important sulfonyl-containing benzyl dithiocarbamates.

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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INTRODUCTION The organo sulfur compounds have proven to be useful building blocks in organic synthesis, medicinal chemistry, chiral ligands and functional materials.1 Among the privileged scaffolds, benzyl dithiocarbamates have been the object of in-depth investigation both in the development of synthetic methodologies and further applications in pharmaceuticals and materials, in part probably because of their promising bio-activities (Figure 1).2 Meanwhile, the aryl alkyl sulfones have also been extensively investigated for their outstanding biological activities.3 Due to the significance of these substructures in various fields, considerable efforts have been devoted to the synthesis of them. Figure 1. Applications of representative benzyl dithiocarbamates S S

N

NH2

S S

S

HN

N

N N HN N b

a Herbicidal activity, ref. 2h

S N

O c

Medicinal molecules, ref. 2a

Synthetic intermediates, ref. 2i

The conventional methods for the preparation of benzyl dithiocarbamates typically involved the following approaches: (1) the reactions of amines, carbon disulfide with benzyl

halides,4

methylarenes5

or

benzaldehyde;6

(2)

the

reactions

of

N,N-dimethylthiocarbamoyl chloride with the corresponding thiolates;7 (3) the interactions

of

mercaptans,

amines,

with

bis(benzotriazolyl)methanethione.8

Moreover, Knochel et al. described a reaction of benzylzinc bromide with tetramethylthiuram

disulfide

affording

the

corresponding

benzyl

N,N-dimethyldithiocarbamate in excellent yield (Scheme 1a).9 However, these methods are inevitably accompanied with problems such as the need of extra preparation steps for the unstable and moisture sensitive precursors, the unpleasant smell of substrates, which limit their application in pharmaceutical synthesis. In addition, the reactions between tetraalkylthiuram disulfides and benzyl halides have been developed by Dong10a and our groups10b (Scheme 1b). These methodologies are efficient approachs for the synthesis of benzyl dithiocarbamates but incapable of


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preparing α-poision functionalized motifs. Therefore, the development of an alternative approach for the facile and efficient synthesis of functionalized benzyl dithiocarbamates should be of great significance. Scheme 1. Strategies towards the synthesis of benzyl dithiocarbamates Previous work: N S

ZnBr +

N

S

R1

R2 N

S +

R2

N R2

S

S

H

S

(a)

r.t., 2h

S

Cl

S

THF-CH2Cl2

N

S

R2 R2 N Conditions

R2

S

(b)

H

S

S R1

Conditions a: K2CO3, H2O, 100 oC, 0.5-3 h; Dong's work, ref. 10a Conditions b: Cs2CO3, DMSO, r.t., 24 h; Our work, ref. 10b R3 R3 N

This work R3 N

S + R SO2Cl + 2

R1

R3

N R3

S

S S

3

R

Cu(OAc)2 (20 mol%)

S S

1,4-dioxane, 100 oC

SO2R2 (c)

R1

In recent years, transition-metal-catalyzed difunctionalization of alkenes has emerged as a powerful method in organic synthesis, as it could introduce two functional groups into an alkene in one-step through the addition of a C−C double bond, and provide access to rapid construction of complex molecules with high regioselectivity and stereoselectivity.11 Consequently, significant progress has been achieved on this topic not only by transition-metal (Copper,11k-m,12 Palladium,11a-d,13 Nickel,14 Gold,15 Rhodium,16 Iron,17 Silver,18 Cobalt,19 Manganese,20 and other metals21) catalyzed difunctionalization of alkenes but also under transition-metal-free22 conditions. Based on our ongoing interest in the development of new methods for the formation of C–S bond,10b,23 we envisioned whether both sulfonyl and dithiocarbamate groups could be introduced simultaneously into the styrenes to form the sulfonyl-containing benzyl dithiocarbamates by a single operation. Herein, we report our latest work on the copper-catalyzed thiosulfonylation of styrenes under simple conditions (Scheme 1c).



The sulfonyl-containing benzyl dithiocarbamates can be obtained with this new strategy in chemo- and regioselective manners, which make it a useful tool towards the synthesis of various bio-active compounds.

RESULTS AND DISCUSSION For our initial study, we chose styrene 1a, benzenesulfonyl chloride 2a and tetramethylthiuram disulfide 3a as model substrates. Pleasingly, this reaction proceeded as anticipated in the presence of 20 mol% of CuI together with 2 equivalent of t-BuOK in 1,4-dioxane at 100 °C, affording the desired product 4a in 21% yield (Table 1, entry 1). No product of 4a was detected in the absence of copper catalyst (Table 1, entry 2), which indicated that the copper catalysts played a crucial role in this transformation. Further screening of other copper catalysts indicated that Cu(OAc)2 was obviously superior to the others, providing the desired product in 46% isolated yield (Table 1, entry 8 vs. entries 3-7). CuCl2 was also found to promote the reaction, although the yield was inferior to that of Cu(OAc)2 (Table 1, entry 6 vs. entry 8). Subsequently, we evaluated the effect of other bases to further improve the yields of this transformation (Table 1, entries 9-13). However, all of the bases screened here failed to improve the yields of the reaction. Interestingly, an improved yield (69%) was obtained when the reaction was conducted in the absence of inorganic base (Table 1, entry 16). Inspired by the reported results,12a the evaluation of ligands was conducted and the results indicated that none of the screened ligands benefited the outcome (49-58%, Table 1, entries 14-15 vs. 16). Further examination of solvents indicated that the new screened solvents such as toluene, DCE, MeCN and THF were found ineffective to proceed the reaction (Table 1, entries 17-18, 22-23), while DMSO, DMF and NMP were thoroughly invalid (Table 1, entries 19-21). Gratifyingly, when the mole ratio of 1a, 2a and 3a was modified from 1:2:1 to 1:2:2, the reaction provided the best yield (85%) of 4a (Table 1, entry 24 vs. entry 16). The reaction time was also examined (Table 1, entries 25-26), and 12 hours was found to be the best choice. The effect of reaction temperature and catalyst loading were also


Page 4 of 47

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studied, however, no better resulsts were obtained in these tests (Table 1, entries 27-29). The nitrogen protected reaction was also carried out, and a similar result was obtained in this reaction compared with the reaction in air (Table 1, entry 30 vs. entry 24, 86% vs. 85%). Finally, the optimal reaction conditions were identified as follows: 20 mol% of Cu(OAc)2 as the catalyst in 1,4-dioxane at 100 °C under air atmosphere for 12 h. Table 1. Optimization of the reaction conditionsa N S

S + PhSO2Cl +

N

S

N

S

conditions

O O S

S

S 1a

2a

3a

4a

Entry

Catalyst

Additive

Solvent

Yield (%) b

1

CuI

t-BuOK

1,4-dioxane

21

2

-

t-BuOK

1,4-dioxane

N.R.

3

CuCl

t-BuOK

1,4-dioxane

29

4

CuO2

t-BuOK

1,4-dioxane

28

5

CuBr2

t-BuOK

1,4-dioxane

25

6

CuCl2

t-BuOK

1,4-dioxane

41

7

Cu(OTf)2

t-BuOK

1,4-dioxane

23

8

Cu(OAc)2

t-BuOK

1,4-dioxane

46

9

Cu(OAc)2

t-BuOLi

1,4-dioxane

10

10

Cu(OAc)2

t-BuONa

1,4-dioxane

40

11

Cu(OAc)2

K2CO3

1,4-dioxane

19

12

Cu(OAc)2

KF

1,4-dioxane

37

13

Cu(OAc)2

NaOAc

1,4-dioxane

22

14

Cu(OAc)2

PPh3

1,4-dioxane

49

15

Cu(OAc)2

Xantphos

1,4-dioxane

58



aReaction

Page 6 of 47

16

Cu(OAc)2

none

1,4-dioxane

69

17

Cu(OAc)2

none

Toluene

65

18

Cu(OAc)2

none

DCE

60

19

Cu(OAc)2

none

DMSO

N.R.

20

Cu(OAc)2

none

DMF

N.R.

21

Cu(OAc)2

none

NMP

N.R.

22

Cu(OAc)2

none

MeCN

60

23

Cu(OAc)2

none

THF

59

24c

Cu(OAc)2

none

1,4-dioxane

85

25c,d

Cu(OAc)2

none

1,4-dioxane

50

26c,e

Cu(OAc)2

none

1,4-dioxane

76

27c,f

Cu(OAc)2

none

1,4-dioxane

64

28c,g

Cu(OAc)2

none

1,4-dioxane

78

29c,h

Cu(OAc)2

none

1,4-dioxane

38

30c,i

Cu(OAc)2

none

1,4-dioxane

86

conditions: 1a (0.1 mmol), 2a (0.2 mmol), 3a (0.1 mmol), catalyst (20 mol%), additive (2.0 equiv.)

solvent (0.5 mL), 100 °C, 12 h, under air. b Isolated yields. cMole ratio: 1a (0.1 mmol), 2a (0.2 mmol), 3a (0.2 mmol). dRun for 6 h. eRun for 24 h. f10 mol% of Cu(OAc)2 was added. gRun at 120 °C. hRun at 80 °C. iRun under N2.

With the optimized reaction conditions in hand, the scope of this thiosulfonylation chemistry was then investigated, and the results were summarized in Table 2. Firstly, various substituents at different position of benzenesulfonyl chloride were well tolerated and moderate to good isolated yields of products were achieved (46-88%, 4a-4n). A series of functional groups, including electron-donating (-CH3, -OCH3, and -t-butyl) and -withdrawing groups (-F, -Cl, -Br, and -CF3) were all compatible with this reaction. In particular, 2-fluorobenzenesulfonyl chloride 2m showed excellent activity in this reaction giving the corresponding product 4m in 88% yield. However, only 46-48% yields of the desired products (4k and 4n) were detected when 2-methylbenzenesulfonyl chloride 2k and 2,4,6-trimethylbenzylsunfonyl chloride 2n


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were used as the substrates, perhaps due to the steric hindrance and electronic effects of methyl on the benzene ring. Electron-withdrawing groups seemed to be more beneficial

to

the

reaction

than

electron-donating

groups.

For

example,

4-bromobenzenesulfonyl chloride 2e and 4-(trifluoromethyl)benzenesulfonyl chloride 2h gave 77-86% yields of the desired products, while the methyl and methoxyl counterpart resulted in only 53-72% yields (4e and 4h vs. 4b and 4d). Similar results were

observed

when

making

a

comparison

of

the

substrates

between

2-methylbenzenesulfonyl chloride 2k and 2-fluorobenzenesulfonyl chloride 2m (4m vs. 4k, 88% vs. 48%). Ortho, meta and para chloro or bromo- substituted benzenesulfonyl chlorides worked well and gave the desired products in moderate to good yields (4e-f, 4i-j and 4l, 65-86%), which make this reaction particularly attractive for further transformation by transition-metal-catalyzed coupling reactions. 1-Naphthalenesulfonyl

chloride

2o,

2-chloropyridine-5-sulfonyl

chloride

2p,

ethanesulfonyl chloride 2q and cyclopropanesulfonyl chloride 2r also reacted well to give the desired products 4o, 4p, 4q and 4r with good yields of 56%, 84%, 69% and 68%, respectively. These results greatly expanded the substrate scope of this reaction. Table 2. Substrate scope of sulfonyl chlorides for the thiosulfonylation reactionsa,b



Page 8 of 47

O O S R2

N S + R2SO2Cl +

N

S

N S

2

O O S

N

3a

S

S

S

1,4-dioxane, 100 oC, 12 h, air

S 1a

Cu(OAc)2 (20 mol%)

N

S

S

4

N

O O S

Me

S

S

4b 72% N

O O S

S

OMe

S

4c 66%

O O S

S

N Br

S

S

F

4g 68% Cl

O O S

S

CF3

O O S

S

4f 75% Br

S

Cl S

4e 86%

N

O O S

N

O O S

S S

4d 53%

N

tBu

S

4a 85% N

O O S

N S

S

N

O O S

S

S

O O S

S Me

4i 65%

4h 77%

N S

O O S

N S

S

O O S

S

N Cl N

4p 84%

S

O O S

S

4k 48%

N Me

S

O O S

S Me

4m 88%

O O S

S

aReaction

S F

4l 76%

S

Me O O S

N

S Cl

N

4j 73%

4n 46% N S

4o 56%

O O S

S

4q 69%

4r 68%

conditions: 1 (0.1 mmol), 2 (0.2 mmol), 3 (0.2 mmol), Cu(OAc)2 (20 mol%), 1,4-dioxane (0.5 mL), 100

°C, 12 h, under air. bIsolated yields.

Next, the scope of the thiosulfonylation reaction was evaluated on various styrenes, and the results were summarized in Table 3. Styrenes with different substituents on the aromatic ring, including electron-donating and -withdrawing groups can be transformed into the corresponding products in moderate to good yields. When benzenesulfonyl chloride and tetramethylthiuram disulfide were used as the organosulfur sources, the methyl, bromo, chloro and fluoro-substituted styrenes could be converted into the corresponding products in moderate to good yields (5a-e,


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66-74%). Tosyl chloride was also used as the sulfonyl source. Ortho, meta and para-substituted styrenes gave similar yields of the desired products, which indicated that the position of substituents on the benzene ring of styrene had a slight effect on the reaction. When 2-chlorostyrene 1h, 3-chlorostyrene 1g and 4-chlorostyrene 1l were subjected to the reaction, the corresponding products were obtained in similar yields (57%, 53% and 58%, respectively). In addition, the electron-donating groups (methyl and t-butyl) and electron-withdrawing groups (bromo, chloro and fluoro) seemed to have the similar electronic effect to the reaction (5i-j vs. 5k-m, 52-53% vs. 50-77%). Moreover, we found that 2-chloropyridine-5-sulfonyl chloride was also a suitable sulfonyl source to check the reactivity of styrene derivatives. All the functional groups substituted styrenes reacted efficiently under the reaction conditions and gave the desired products 5n-5t in moderate to good yields (62-77%). Table 3. Substrate scope of styrenes for the thiosulfonylation reactionsa,b



Page 10 of 47

N S + ArSO2Cl +

R1

S

Cu(OAc)2 (20 mol%)

N

S

N S

2 O O S

R1

N

O O S

S

S

N S

O O S

N

Me

S

F

5c 68%

N

O O S

S

S

S

Cl

5b 74%

O O S

S

S

Br

5

N

O O S

S

S

5a 66%

S

3a N

N

O O S

S

5d 70%

O O S

S

Me

Cl Br

5e 68%

S

O O S

N Me

S

Me

O O S

S

Me

O O S N

S

5q 62%

S

5r 69%

Br

Br

5s 72%

O O S

S

Cl N

S

5p 72%

N

O O S

S

Cl N

S

5o 66%

N

O O S

S

Cl N

tBu

N

Me

5l 58%

N

O O S

S

Cl

O O S

S

Cl

5k 77%

S

Cl

O O S

S

F

N Me S

N

O O S

5n 77%

N Cl

5h 57%

O O S

S

Br

N

Me

5m 50%

S

aReaction

S S

N

Cl

N

O O S

5j 52%

N Me

5g 53%

S

tBu

5i 53%

S

F

S

Cl

5f 59%

S

N

Me

S

S

Cl

N

O O S Ar

1,4-dioxane, 100 oC,12 h, air

S 1

Me

N

S

Cl N

S

Cl

5t 76%



Finally, we also briefly tested the scope of tetraalkylthiuram disulfides (Table 4). As expected, these reactions proceeded smoothly when N,N,N′,N′-tetraethylthiuram disulfide (TETD) and N,N,N′,N′-tetrabutyl thiuram disulfide (TBTD) served as the substrates, affording the corresponding products 6a-6k in moderate to good yields


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(49-77%). It was worth mentioning that the yields were modulated by the presence of different alkyl substituents on the tetraalkylthiuram disulfides. Slightly lower yields were obtained when longer chain substituted tetraalkylthiuram disulfides were used in these reactions (6b vs. 6i). Table 4. Substrate scope of tetraalkylthiuram disulfides for the thiosulfonylation reactionsa,b

R3 N

S R + ArSO2Cl + 3 N R3

R1 1

S

S

R3 R3 N R3

S

2

Cu(OAc)2 (20 mol%)

R1

Et S

S

1,4-dioxane, 100 oC,12 h, air

3

Et Et N

O O S

S

S

6

Et

Et

Et N

O O S Ar

S

Et N Me S

O O S

S

Et N

O O S

S

S

F

O O S

S Cl

6a 66%

6b 74%

Et

Et

Et N S

O O S

Cl

nBu

S

Et N

O O S

Cl N

S

tBu

6e 56%

S

nBu N Me

S

S

Me

O O S

S

Br

Br 6g 77%

6h 62%

nBu O O S

S

6i 56%

S

Cl N

S

nBu O O S

nBu N

O O S

S

6f 69%

nBu nBu N

6d 74%

Et

Et N N

S

aReaction

6c 71%

nBu N Me

S

O O S

Me

S

6j 49%

Br

6k 59%



In order to demonstrate the synthetic utility of this reaction, we further expanded the reaction scale to 1 mmol and 5 mmol. In these cases, product 4p was obtained in 75% and 63% yields, respectively, indicating good scalability of the reaction (Scheme 2). Scheme 2. Gram-scale reaction of 1a, 2p and 3a



+

O S O Cl

Cl N

1a 1.0 mmol, 104 mg 5.0 mmol, 521 mg

N

S +

Page 12 of 47

N

S

standard conditions

N

S

S

O O S

Cl N

S

S 4p 75% yield, 0.75 mmol, 298 mg 63% yield, 3.15 mmol, 1260 mg

3a 2.0 mmol, 480 mg 10.0 mmol, 2400 mg

2p 2.0 mmol, 430 mg 10.0 mmol, 2150 mg

In consideration of the versatile nature of the copper-catalyzed difunctionalization processes, we became interested in elucidating its mode of reaction. Initially, the reactions were performed in the presence of different radical inhibitors (2.0 equiv of TEMPO, BHT or galvinoxyl free radical), which gave the desired product 4a in 60%, 66% and 60% yields, respectively. The results were exhibited in Scheme 3 (eq. 1), suggesting that the reaction is more likely to be an ionic type pathway. The zinc dust was also added into the reaction system under the optimized conditions. However, no desired product was observed in this reaction which indicated a zinc reduced step to generate the Cu(I) from Cu(II)24 could be excluded in this transformation. Scheme 3. Mechanistic experiments N

S + PhSO2Cl +

N

S

N

S

2a

3a

TEMPO BHT galvinoxyl free radical

N

S

N

S S

1a

2a

S

(1)

4a

60% yield 66% yield 60% yield N

S + PhSO2Cl +

O O S Ph

radical scavenger (2 equiv.)

S 1a

standard conditions

S

standard conditions

S

O O S Ph

S

(2)

Zn dust (2 equiv.)

3a

4a, 0% yield

In order to explore the detailed mechanism of the copper(I)-catalyzed reaction among the three reactants, we have theoretically studied the proposed pathway by performing DFT calculations, which has been widely used in the mechanistic studies of organic and organometallic reactions.25 As shown in Scheme 4, the complexion of Cu(I)OAc and R1 would be the first step in the whole reaction, and the Gibbs free energy would


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decrease for 32.4 kcal/mol, showing that the process is spontaneous. In the following, the exchange of ligands for the copper(I) would conduct by the two stepwise processes, i.e. oxidative addition of R1 and reductive elimination of S-O. The corresponding Gibbs free energy barriers are 18.2 and 26.7 kcal/mol, respectively. Subsequently, the addition of R2 has to overcome a Gibbs free energy barrier of 23.5 kcal/mol and the Gibbs free energy would increase for 23.1 kcal/mol. Owing to the unstable PhSO2Cl, the addition of R3 would be barrierless and the M4 would decrease the Gibbs free energy for 25.0 kcal/mol. At last, the reductive elimination of S-C leads to the formation of P with the Gibbs free energy of 8.3 kcal/mol, and the exchange of R1 and P would be make the whole reaction cycle execute. Scheme 4. Computational reaction mechanism Cu(I)OAc (A) G=-32.4

Cl

N

S

N

S

N

(B)

S AcO Cu

P' G=6.5

Cl Cu

S

G=-3.8 G‡=18.2

S

S Com1

(H)

N

S

AcO Cu

P''

N

N

N S

S

S R1

S

S

S

S

N

Ph

S P

R1

Cu

N

M2 (D) G=23.1 G‡=23.5

Ph PhO2S Cl Cu S M5

S N

N

(C) G=4.7 G‡=26.7

(G) G=-1.6 S

O S

M1

N

M6 PhO2S

S

S

S

S

(F)

S Ph

G=-25.0 (E)

S Cl PhO2S

Cu

S M4

N

PhSO2Cl

R3


Cu

S M3

S N S

Ph R2

Ph

G=8.3 G‡=-28.0

O S P'

N


Page 14 of 47

Considering the experimental evidence as well the previous reports,11k,26 a plausible reaction mechanism was tentatively proposed and described in Scheme 5. The suggested initial step is the formation of the Cu(I)OAc intermediate,27 then, the complexion of Cu(I)OAc and 3 can produce the thiocopper species A (step ii). In step iii, the exchange of ligands for the copper(I) would provide the thiocopper species B along with the release of compound P'. The addition of the thiocopper species B to styrenes 1 affords the β-thioalkylcopper intermediate C.26c The following oxidative addition of sulfonyl chlorides 2 to the intermediate C affords the Cu(III) intermediate D.23a,28 Subsequently, the second formation of carbon-sulfur bond through reductive elimination affords the thiosulfonylation products of styrenes, simultaneously, the Cl-Cu-S intermediate E is formed by the interaction of CuCl with compound 3. Finally, intermediate E undergoes an anion exchange process and regenerates the thiocopper species A to finish the catalytic cycle. Scheme 5. Plausible reaction mechanism

R1 N R1

O S O S P'

S

Cu(OAc)2 R1 N

S i

R1

N R1

Cu(I)OAc

S 3

S

R1 N

S

S

R1

ii

N R1 AcO

S

S

Cu(I)

S

1

iv R1

R1

N

R1

S

S

Ar1

C

Cu(I)

S A

i: disproportionation reaction Cl S

Ar1

B

iii R1

R1 N R1

S Cu(I)

R1 N R1

v P' vii

P''

R1 N

S R1

N R1

O O S Cl

R2

S

S

Cu(I) Cl E

R1 R1

S

3 vi

N

S

R1 O O S R2 Cu (III)

S

Ar1

Cl D

R1

N

S

R1 S

Ar1

CONCLUSION


O O S R2

2

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In conclusion, we have developed a highly regioselective thiosulfonylation reactions of styrenes with tetraalkylthiuram disulfides and sulfonyl chlorides through copper catalysis to simultaneously construct two new C-S bonds. This novel method proceeds without addition of any ligands or bases and exhibits broad substrate scope and excellent functional group compatibility, which make this transformation sustainable and environmentally friendly. Owing to the ready availability of starting material, mild reaction conditions, the significance of resulting functionalities and high flexibility, the application of the novel strategy established here in synthetic and medicinal chemistry is positively expected. Further investigations of the mechanistic details and applications of the reaction are currently underway in our laboratory.

Experimental Section General information. All reactions were carried out under air atmosphere in a dried tube. All the reagents were obtained commercially and used without further purification. Silica gel was purchased from Qing Dao Hai Yang Chemical Industry Co. Analytical thin layer chromatography (TLC) was performed on precoated silica gel F254 plates. Compounds were visualized by irradiation with UV light (254 nm). 1H

NMR and 13C NMR spectra data were recorded by a BRUKER AVANCE III 400

MHz spectrometer (1H 400 MHz,

13C

100 MHz), using CDCl3 as the solvent with

tetramethylsilane (TMS) as the internal standard at room temperature. 1H NMR spectral data are given as chemical shifts in ppm followed by multiplicity (s- singlet; d- doublet; t- triplet; q- quartet; m- multiplet), number of protons and coupling constants.

13C

NMR chemical shifts are expressed in ppm. Infrared spectra were

recorded with a Thermo Scientific Nicolet 6700 FT-IR Spectrometer. HRMS data were obtained using AB SCIEX Triple TOF 5600+ high resolution mass spectrometer (USA). The products listed below were determined by 1H and

13C

NMR spectra.

Single crystal was detected on single crystal diffractometer of Agilent Gemini E with double light source X-ray. Melting points were measured on a microscopic apparatus and were uncorrected.



General procedure for the preparation of products. Under air atmosphere, styrene 1a (10.5 mg, 0.1 mmol), benzenesulfonyl chloride 2a (35.4 mg, 0.2 mmol), tetramethylthiuram disulfide 3a (48.0 mg, 0.2 mmol) and Cu(OAc)2 (3.6 mg, 20 mol%) were charged into a 10 mL sealable tube equipped with a magnetic stirring bar. After the addition of 1,4-dioxane (0.5 mL), the resulting mixture was stirred at 100 °C for 12 h in oil bath. After cooling down, the reaction mixture was diluted with 10 mL dichloromethane and washed with 10 mL H2O. The aqueous layer was extracted twice with dichloromethane. The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: petroleum ether/EtOAc 3/1) to give the pure products 4a in 85% (30.9mg) yield. The products 4b-4r, 5, and 6 were all prepared according to this procedure. 1-Phenyl-2-(phenylsulfonyl)ethyl dimethylcarbamodithioate (4a). Purification by column chromatography on silica gel (Rf = 0.29, petroleum ether/ethyl acetate = 3:1) yielded 4a (31.0 mg, 85%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.76-7.74 (m, 2H), 7.60-7.56 (m, 1H), 7.47-7.43 (m, 2H), 7.29-7.26 (m, 5H), 5.24 (dd, J = 11.2, 3.7 Hz, 1H), 4.29 (dd, J = 14.2, 3.7 Hz, 1H), 3.85 (dd, J = 14.2, 11.2 Hz, 1H), 3.46 (s, 3H), 3.22 (s, 3H);

13C

{1H} NMR (100 MHz, CDCl3): δ 193.8, 139.3,

135.8, 133.5, 129.0, 128.8, 128.6, 128.5, 128.4, 60.0, 50.9, 45.1, 41.3; IR(KBr): 3361, 3061, 2921, 2850, 1732, 1637, 1498, 1449, 1379, 1318, 1252, 1151, 1084, 980, 907, 779, 746, 694, 553 cm-1; HRMS (ESI) calcd. for C17H20NO2S3: [M+H]+: 366.0656, found: 366.0655. 1-Phenyl-2-tosylethyl dimethylcarbamodithioate (4b). Purification by column chromatography on silica gel (Rf = 0.29, petroleum ether/ethyl acetate = 2:1) yielded 4b (27.3 mg, 72%) as a white solid; m. p. 169-170 oC; 1H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.2 Hz, 2H), 7.30-7.28 (m, 5H), 7.28-7.26 (m, 2H), 5.25 (dd, J = 11.1, 3.6 Hz, 1H), 4.28 (dd, J = 14.2, 3.7 Hz, 1H), 3.85 (dd, J = 14.1, 3.6 Hz, 1H), 3.49 (s,


Page 16 of 47

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3H), 3.25 (s, 3H), 2.44 (s, 3H);

13C

{1H} NMR (100 MHz, CDCl3): δ 193.9, 144.5,

136.4, 135.9, 129.6, 128.8, 128.6, 128.5, 128.4, 60.1, 50.9, 45.0, 41.3, 21.6; IR(KBr): 3059, 3031, 2924, 2854, 1597, 1497, 1378, 1319, 1252, 1151, 1086, 981, 908, 815, 769, 752, 697, 552 cm-1; HRMS (ESI) calcd. for C18H22NO2S3: [M+H]+: 380.0813, found: 380.0812. 2-((4-(tert-Butyl)phenyl)sulfonyl)-1-phenylethyl dimethylcarbamodithioate (4c). Purification by column chromatography on silica gel (Rf = 0.35, petroleum ether/ethyl acetate = 3:1) yielded 4c (27.8 mg, 66%) as a white solid; m. p. 129-130 oC; 1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.29-7.26 (m, 5H), 5.34 (dd, J = 11.2, 3.7 Hz, 1H), 4.28 (dd, J = 14.2, 3.8 Hz, 1H), 3.85 (dd, J = 14.1, 11.2 Hz, 1H), 3.49 (s, 3H), 3.25 (s, 3H), 1.35 (s, 9H);

13C

{1H} NMR (100

MHz, CDCl3): δ 193.8, 157.3, 136.4, 135.9, 128.7, 128.6, 128.4, 128.2, 125.9, 60.1, 50.9, 45.1, 41.3, 35.2, 31.1; IR(KBr): 3361, 2961, 2921, 2852, 1594, 1495, 1455, 1377, 1317, 1258, 1152, 1107, 1084, 981, 805, 776, 698 cm-1; HRMS (ESI) calcd. for C21H28NO2S3: [M+H]+: 422.1282, found: 422.1283. 2-((4-Methoxyphenyl)sulfonyl)-1-phenylethyl dimethylcarbamodithioate (4d). Purification by column chromatography on silica gel (Rf = 0.28, petroleum ether/ethyl acetate = 3:1) yielded 4d (21 mg, 53%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.68-7.65 (m, 2H), 7.30-7.28 (m, 5H), 6.92-6.89 (m, 2H), 5.23 (dd, J = 11.1, 3.8 Hz, 1H), 4.25 (dd, J = 14.2, 3.8 Hz, 1H), 3.86 (s, 3H), 3.82 (dd, J = 14.4, 11.2 Hz, 1H), 3.47 (s, 3H), 3.23 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.9, 163.7, 136.0, 130.9, 130.6, 128.8, 128.6, 128.4, 114.1, 60.2, 55.6, 51.0, 45.0, 41.3; IR(KBr): 3356, 2959, 2920, 2850, 1732, 1595, 1496, 1377, 1320, 1259, 1137, 1088, 1023, 981, 805, 754, 697 cm-1; HRMS (ESI) calcd. for C18H22NO3S3: [M+H]+: 396.0762, found: 396.0761. 2-((4-Bromophenyl)sulfonyl)-1-phenylethyl

dimethylcarbamodithioate

(4e).

Purification by column chromatography on silica gel (Rf = 0.29, petroleum ether/ethyl acetate = 3:1) yielded 4e (38 mg, 86%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.59-7.54 (m, 4H), 7.29-7.25 (m, 5H), 5.23 (dd, J = 11.2, 3.7 Hz, 1H), 4.30



Page 18 of 47

(dd, J = 14.3, 3.7 Hz, 1H), 3.84 (dd, J = 14.3, 11.2 Hz, 1H), 3.47 (s, 3H), 3.23 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.7, 138.3, 135.5, 132.2, 129.9, 128.9, 128.8, 128.6, 60.1, 50.8, 45.1, 41.3; IR(KBr): 3359, 3002, 2923, 2850, 1734, 1657, 1573, 1496, 1469, 1378, 1320, 1252, 1151, 1083, 1010, 980, 907, 822, 773, 698, 575 cm-1; HRMS (ESI) calcd. for C17H19BrNO2S3: [M+H]+: 443.9761, found: 443.9762. 2-((4-Chlorophenyl)sulfonyl)-1-phenylethyl


(4f).

Purification by column chromatography on silica gel (Rf = 0.31, petroleum ether/ethyl acetate = 3:1) yielded 4f (29.9 mg, 75%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.66-7.64 (m, 2H), 7.41-7.39 (m, 2H), 7.30-7.25 (m, 5H), 5.22 (dd, J = 11.2, 3.7 Hz, 1H), 4.31 (dd, J = 14.3, 3.7 Hz, 1H), 3.84 (dd, J = 14.2, 11.2 Hz, 1H), 3.47 (s, 3H), 3.23 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.7, 140.3, 137.8, 135.5, 129.9, 129.2, 128.9, 128.6, 128.5, 60.1, 50.8, 45.1, 41.3; IR(KBr): 3361, 3060, 2963, 2920, 2850, 1497, 1449, 1378, 1318, 1251, 1136, 1084, 980, 778, 746, 693 cm-1; HRMS (ESI) calcd. for C17H19ClNO2S3: [M+H]+: 400.0266, found: 400.0265. 2-((4-Fluorophenyl)sulfonyl)-1-phenylethyl


(4g).

Purification by column chromatography on silica gel (Rf = 0.26, petroleum ether/ethyl acetate = 3:1) yielded 4g (26 mg, 68%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.76-7.72 (m, 2H), 7.28-7.26 (m, 5H), 7.11 (t, J = 8.5 Hz, 2H), 5.22 (dd, J = 11.2, 3.5 Hz, 1H), 4.30 (dd, J = 14.3, 3.6 Hz, 1H), 3.85 (dd, J = 14.2, 11.3 Hz, 1H), 3.47 (s, 3H), 3.23 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.7, 165.7 (d, J = 254.3 Hz), 135.5, 135.3 (d, J = 3.0 Hz), 131.3 (d, J = 9.6 Hz), 128.9, 128.6, 128.5, 116.2 (d, J = 22.5 Hz), 60.1, 50.9, 45.1, 41.3; IR(KBr): 3358, 2961, 2921, 2851, 1733, 1657, 1590, 1493, 1378, 1322, 1291, 1238, 1149, 1085, 980, 908, 838, 756, 698 cm-1; HRMS (ESI) calcd. for C17H19FNO2S3: [M+H]+: 384.0562, found: 384.0563. 1-Phenyl-2-((4-(trifluoromethyl)phenyl)sulfonyl)ethyl dimethylcarbamodithioate (4h). Purification by column chromatography on silica gel (Rf = 0.33, petroleum ether/ethyl acetate = 3:1) yielded 4h (33.3 mg, 77%) as a white solid; m. p. 170-172 oC; 1H

NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H),

7.25-7.22 (m, 5H), 5.27 (dd, J = 11.2, 3.6 Hz, 1H), 4.36 (dd, J = 14.4, 3.7 Hz, 1H),


Page 19 of 47 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


3.87 (dd, J = 14.4, 11.3 Hz, 1H), 3.47 (s, 3H), 3.23 (s, 3H);

13C

{1H} NMR (100

MHz, CDCl3): δ 193.6, 142.9, 135.3, 135.0 (q, J = 32.9 Hz), 128.9 128.8, 128.7, 128.6, 125.9 (q, J = 3.6 Hz), 123.2 (q, J = 271.6 Hz), 60.1, 50.7, 45.1, 41.3; IR(KBr): 3358, 3194, 2957, 2920, 2851, 1658, 1632, 1503, 1454, 1381, 1323, 1305, 1254, 1139, 1088, 976, 838, 805, 699 cm-1; HRMS (ESI) calcd. for C18H19F3NO2S3: [M+H]+: 434.0530, found: 434.0531. 2-((3-Bromophenyl)sulfonyl)-1-phenylethyl


(4i).

Purification by column chromatography on silica gel (Rf = 0.31, petroleum ether/ethyl acetate = 3:1) yielded 4i (30.2 mg, 65%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.78-7.77 (m, 1H), 7.68-7.66 (m, 2H), 7.33-7.31 (m, 1H), 7.29-7.26 (m, 5H), 5.24 (dd, J = 11.2, 3.7 Hz, 1H), 4.32 (dd, J = 14.3, 3.7 Hz, 1H), 3.86 (dd, J = 14.3, 11.3 Hz, 1H), 3.48 (s, 3H), 3.23 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.6, 141.2, 136.5, 135.3, 131.4, 130.4, 128.9, 128.8, 128.6, 126.8, 122.9, 60.1, 50.8, 45.1, 41.3; IR(KBr): 3359, 2958, 2921, 2851, 1733, 1658, 1496, 1455, 1377, 1321, 1252, 1139, 1096, 980, 908, 781, 734, 697, 676, 580, 526 cm-1; HRMS (ESI) calcd. for C17H18BrNNaO2S3: [M+Na]+: 465.9581, found: 465.9582. 2-((3-Chlorophenyl)sulfonyl)-1-phenylethyl


(4j).

Purification by column chromatography on silica gel (Rf = 0.26, petroleum ether/ethyl acetate = 3:1) yielded 4j (29.1 mg, 73%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.64-7.62 (m, 2H), 7.53-7.50 (m, 1H), 7.40-7.36 (m, 1H), 7.28-7.24 (m, 5H), 5.25 (dd, J = 11.3, 3.7 Hz, 1H), 4.32 (dd, J = 14.3, 3.7 Hz, 1H), 3.86 (dd, J = 14.3, 11.3 Hz, 1H), 3.48 (s, 3H), 3.23 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.6, 141.1, 135.4, 135.1, 133.6, 130.2, 128.8, 128.7, 128.6, 128.5, 126.4, 60.2, 50.8, 45.1, 41.3; IR(KBr): 3361, 2959, 2920, 2851, 1498, 1455, 1379, 1322, 1297, 1251, 1149, 1115, 1076, 979, 790, 698 cm-1; HRMS (ESI) calcd. for C17H19ClNO2S3: [M+H]+: 400.0266, found: 400.0267. 1-Phenyl-2-(o-tolylsulfonyl)ethyl dimethylcarbamodithioate (4k). Purification by column chromatography on silica gel (Rf = 0.29, petroleum ether/ethyl acetate = 3:1) yielded 4k (18.2 mg, 48%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.71



Page 20 of 47

(d, J = 7.9 Hz, 1H), 7.44 (td, J = 7.6, 1.0 Hz, 1H), 7.29-7.26 (m, 5H), 7.24-7.19 (m, 2H), 5.25 (dd, J = 11.2, 3.8 Hz, 1H), 4.30 (dd, J = 14.1, 3.8 Hz, 1H), 3.85 (dd, J = 14.1, 11.2 Hz, 1H), 3.49 (s, 3H), 3.23 (s, 3H), 2.72 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.8, 138.4, 137.4, 136.0, 133.5, 132.5, 130.6, 128.7, 128.5, 128.4, 126.3, 59.2, 50.9, 45.0, 41.3, 20.7; IR(KBr): 3362, 2959, 2923, 2852, 1733, 1657, 1496, 1453, 1378, 1314, 1253, 1152, 1126, 1059, 980, 906, 807, 749, 698, 556 cm-1; HRMS (ESI) calcd. for C18H22NO2S3: [M+H]+: 380.0813, found: 380.0814. 2-((2-Chlorophenyl)sulfonyl)-1-phenylethyl


(4l).

Purification by column chromatography on silica gel (Rf = 0.29, petroleum ether/ethyl acetate = 3:1) yielded 4l (30.3 mg, 76%) as a white solid; m. p. 161-162 oC; 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 7.8 Hz, 1H), 7.40-7.36 (m, 2H), 7.24-7.21 (m, 2H), 7.20-7.16 (m, 1H), 7.14-7.09 (m, 3H), 5.41 (dd, J = 11.0, 3.0 Hz, 1H), 4.47 (dd, J = 14.6, 4.0 Hz, 1H), 4.27 (dd, J = 14.6, 11.0 Hz, 1H), 3.48 (s, 3H), 3.24 (s, 3H);

13C

{1H} NMR (100 MHz, CDCl3): δ 193.5, 137.2, 135.8, 134.3, 132.6, 131.8, 131.4, 128.6, 128.4, 127.1, 58.2, 51.0, 45.1, 41.3; IR(KBr): 3063, 3004, 2922, 2851, 1733, 1576, 1496, 1453, 1378, 1322, 1253, 1152, 1040, 981, 907, 760, 698, 574, 533 cm-1; HRMS (ESI) calcd. for C17H19ClNO2S3: [M+H]+: 400.0266, found: 400.0267. 2-((2-Fluorophenyl)sulfonyl)-1-phenylethyl


(4m).

Purification by column chromatography on silica gel (Rf = 0.29, petroleum ether/ethyl acetate = 3:1) yielded 4m (33.7 mg, 88%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.61-7.57 (m, 1H), 7.55-7.49 (m, 1H), 7.28-7.25 (m, 2H), 7.20-7.16 (m, 3H), 7.15-7.09 (m, 2H), 5.38 (dd, J = 11.2, 3.7 Hz, 1H), 4.44 (dd, J = 14.5, 3.8 Hz, 1H), 4.08 (dd, J = 14.5, 11.2 Hz, 1H), 3.50 (s, 3H), 3.27 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.5, 159.5 (d, J = 253.8 Hz), 135.9, 135.7 (d, J = 7.4 Hz), 130.7, 128.7, 128.5, 127.4, 127.4, 124.4 (d, J = 3.7 Hz), 116.8 (d, J = 21.1 Hz), 59.6, 50.8, 45.1, 41.3; IR(KBr): 3361, 3006, 2922, 2852, 1733, 1599, 1497, 1475, 1452, 1377, 1324, 1251, 1151, 1071, 980, 908, 826, 767, 700, 558 cm-1; HRMS (ESI) calcd. for C17H19FNO2S3: [M+H]+: 384.0562, found: 384.0563.


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2-(Mesitylsulfonyl)-1-phenylethyl dimethylcarbamodithioate (4n). Purification by column chromatography on silica gel (Rf = 0.39, petroleum ether/ethyl acetate = 3:1) yielded 4n (18.7 mg, 46%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.34-7.30 (m, 2H), 7.29-7.27 (m, 3H), 6.87 (s, 2H), 5.44 (dd, J = 11.1, 3.8 Hz, 1H), 4.24 (dd, J = 14.0, 3.9 Hz, 1H), 3.88 (dd, J = 13.9, 11.1 Hz, 1H), 3.47 (s, 3H), 3.23 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.9, 143.1, 140.2, 136.2, 133.7, 132.1, 128.7, 128.5, 128.3, 60.0, 50.8, 45.0, 41.3, 23.0, 21.0; IR(KBr): 3357, 2959, 2921, 2851, 1734, 1633, 1496, 1376, 1314, 1261, 1135, 1047, 981, 769, 736, 698 cm-1; HRMS (ESI) calcd. for C20H26NO2S3: [M+H]+: 408.1126, found: 408.1127. 2-(Naphthalen-1-ylsulfonyl)-1-phenylethyl


(4o).

Purification by column chromatography on silica gel (Rf = 0.30, petroleum ether/ethyl acetate = 3:1) yielded 4o (23.2 mg, 56%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 8.17 (s, 1H), 7.85-7.80 (m, 3H), 7.70 (dd, J = 8.6, 1.8 Hz, 1H), 7.60-7.56 (m, 1H), 7.54-7.50 (m, 1H), 7.20-7.18 (m, 2H), 7.14-7.08 (m, 2H), 7.07-7.05 (m, 1H), 5.24 (dd, J = 10.8, 4.1 Hz, 1H), 4.31 (dd, J = 14.2, 4.1 Hz, 1H), 3.83 (dd, J = 14.2, 10.8 Hz, 1H), 3.35 (s, 3H), 3.09 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.7, 136.2, 135.9, 135.2, 132.0, 130.5, 129.5, 129.2, 129.1, 128.7, 128.5, 128.4, 127.9, 127.4, 123.0, 60.0, 50.9, 45.0, 41.2; IR(KBr): 3359, 3057, 2957, 2923, 2852, 1732, 1658, 1500, 1453, 1375, 1314, 1250, 1148, 1072, 979, 907, 864, 817, 753, 697, 638 cm-1; HRMS (ESI) calcd. for C21H22NO2S3: [M+H]+: 416.0813, found: 416.0812. 2-((6-Chloropyridin-3-yl)sulfonyl)-1-phenylethyl


(4p). Purification by column chromatography on silica gel (Rf = 0.30, petroleum ether/ethyl acetate = 3:1) yielded 4p (33.6 mg, 84%) as a white solid; m. p. 143-145 oC; 1H

NMR (400 MHz, CDCl3): δ 8.64 (d, J = 2.3 Hz, 1H), 7.86 (dd, J = 8.3, 2.5 Hz,

1H), 7.31-7.24 (m, 6H), 5.21 (dd, J = 11.4, 3.4 Hz, 1H), 4.39 (dd, J = 14.4, 3.5 Hz, 1H), 3.90 (dd, J = 14.4, 11.4 Hz, 1H), 3.48 (s, 3H), 3.24 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.4, 156.4, 149.7, 138.5, 134.9, 134.8, 129.1, 128.9, 128.6, 124.4, 60.4, 50.7, 45.2, 41.4; IR(KBr): 3356, 2959, 2921, 2851, 1566, 1498, 1449, 1379, 1325, 1251, 1156, 1109, 980, 907, 785, 745, 698 cm-1; HRMS (ESI) calcd. for C16H18ClN2O2S3: [M+H]+: 401.0219, found: 401.0220.



Page 22 of 47

2-(Ethylsulfonyl)-1-phenylethyl dimethylcarbamodithioate (4q). Purification by column chromatography on silica gel (Rf = 0.29, petroleum ether/ethyl acetate = 3:1) yielded 4q (21.9 mg, 69%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.46-7.44 (m, 2H), 7.40-7.36 (m, 2H), 7.35-7.32 (m, 1H), 5.45 (dd, J = 11.3, 3.5 Hz, 1H), 4.11 (dd, J = 14.4, 3.5 Hz, 1H), 3.66 (dd, J = 14.4, 11.3 Hz, 1H), 3.53 (s, 3H), 3.31 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.9, 136.5, 129.0, 128.7, 128.6, 57.1, 50.9, 48.3, 45.2, 41.4, 6.4; IR(KBr): 3360, 2957, 2921, 2851, 1658, 1496, 1454, 1378, 1314, 1255, 1124, 980, 908, 794, 699 cm-1; HRMS (ESI) calcd. for C13H20NO2S3: [M+H]+: 318.0656, found: 318.0657. 2-(Cyclopropylsulfonyl)-1-phenylethyl


(4r).

Purification by column chromatography on silica gel (Rf = 0.29, petroleum ether/ethyl acetate = 3:1) yielded 4r (22.3 mg, 68%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.40-7.38 (m, 2H), 7.33-7.29 (m, 2H), 7.28-7.24 (m, 1H), 5.48 (dd, J = 11.4, 3.6 Hz, 1H), 4.14 (dd, J = 14.3, 3.6 Hz, 1H), 3.68 (dd, J = 14.2, 11.4 Hz, 1H), 3.47 (s, 3H), 3.24 (s, 3H), 2.09-2.02 (m, 1H), 1.13-1.02 (m, 2H), 0.87-0.78 (m, 2H); 13C

{1H} NMR (100 MHz, CDCl3): δ 193.9, 136.3, 129.0, 128.7, 128.6, 58.7, 51.0,

45.2, 41.4, 30.6, 5.6, 4.7; IR(KBr): 3361, 2963, 2922, 2850, 1657, 1498, 1378, 1319, 1252, 1125, 980, 886, 773, 698, 544 cm-1; HRMS (ESI) calcd. for C14H20NO2S3: [M+H]+: 330.0656, found: 330.0657. 2-(Phenylsulfonyl)-1-(p-tolyl)ethyl dimethylcarbamodithioate (5a). Purification by column chromatography on silica gel (Rf = 0.28, petroleum ether/ethyl acetate = 3:1) yielded 5a (25.0 mg, 66%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.77-7.75 (m, 2H), 7.61-7.57 (m, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 7.9 Hz, 2H), 5.18 (dd, J = 11.3, 3.6 Hz, 1H), 4.28 (dd, J = 14.2, 3.6 Hz, 1H), 3.83 (dd, J = 14.1, 11.4 Hz, 1H), 3.45 (s, 3H), 3.21 (s, 3H), 2.32 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 194.0, 139.3, 138.4, 133.4, 132.6, 129.5, 128.9, 128.5, 60.0, 50.6, 45.0, 41.3, 21.2; IR(KBr): 3360, 2955, 2923, 2852, 1732, 1659, 1633, 1501, 1447, 1378, 1317, 1251, 1154, 1084, 982, 910, 789, 741, 688, 557 cm-1; HRMS (ESI) calcd. for C18H22NO2S3: [M+H]+: 380.0813, found: 380.0812.


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1-(4-Bromophenyl)-2-(phenylsulfonyl)ethyl


(5b).

Purification by column chromatography on silica gel (Rf = 0.31, petroleum ether/ethyl acetate = 3:1) yielded 5b (32.8 mg, 74%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.75-7.73 (m, 2H), 7.63-7.59 (m, 1H), 7.49-7.45 (m, 2H), 7.39-7.37 (m, 2H), 7.17-7.15 (m, 2H), 5.25 (dd, J = 11.2, 3.8 Hz, 1H), 4.24 (dd, J = 14.2, 3.8 Hz, 1H), 3.79 (dd, J = 14.2, 11.2 Hz, 1H), 3.46 (s, 3H), 3.23 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.2, 139.2, 135.0, 133.6, 131.9, 130.3, 129.1, 128.3, 122.6, 59.9, 50.2, 45.2, 41.3; IR(KBr): 3359, 2961, 2922, 2851, 1637, 1491, 1447, 1378, 1312, 1251, 1152, 1084, 981, 910, 794, 737, 688, 555, 527 cm-1; HRMS (ESI) calcd. for C17H19BrNO2S3: [M+H]+: 443.9761, found: 443.9760. 1-(4-Chlorophenyl)-2-(phenylsulfonyl)ethyl


(5c).

Purification by column chromatography on silica gel (Rf = 0.33, petroleum ether/ethyl acetate = 3:1) yielded 5c (27.1 mg, 68%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.76-7.74 (m, 2H), 7.63-7.59 (m, 1H), 7.50-7.46 (m, 2H), 7.25-7.21 (m, 4H), 5.25 (dd, J = 11.2, 3.8 Hz, 1H), 4.24 (dd, J = 14.2, 3.8 Hz, 1H), 3.79 (dd, J = 14.2, 11.2 Hz, 1H), 3.46 (s, 3H), 3.23 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.3, 139.2, 134.5, 134.4, 133.6, 130.0, 129.1, 129.0, 128.3, 60.0, 50.1, 45.3, 41.3; IR(KBr): 3359, 2959, 2921, 2851, 1732, 1658, 1494, 1447, 1379, 1312, 1252, 1153, 1088, 982, 910, 796, 738, 688, 581, 529 cm-1; HRMS (ESI) calcd. for C17H19ClNO2S3: [M+H]+: 400.0266, found: 400.0265. 1-(4-Fluorophenyl)-2-(phenylsulfonyl)ethyl


(5d).

Purification by column chromatography on silica gel (Rf = 0.30, petroleum ether/ethyl acetate = 3:1) yielded 5d (26.8 mg, 70%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.76-7.74 (m, 2H), 7.62-7.59 (m, 1H), 7.50-7.46 (m, 2H), 7.29-7.25 (m, 2H), 6.98-6.94 (m, 2H), 5.26 (dd, J = 11.2, 3.7 Hz, 1H), 4.26 (dd, J = 14.2, 3.8 Hz, 1H), 3.79 (dd, J = 14.2, 11.3 Hz, 1H), 3.46 (s, 3H), 3.23 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.5, 162.5 (d, J = 246.5 Hz), 139.3, 133.6, 131.7 (d, J = 3.4 Hz), 130.3 (d, J = 8.4 Hz), 129.0, 128.3, 115.7 (d, J = 21.5 Hz), 60.1, 50.1, 45.1, 41.3; IR(KBr): 3358, 2959, 2922, 2851, 1732, 1658, 1508, 1378, 1310, 1228, 1150, 1085,



Page 24 of 47

981, 910, 844, 766, 742, 557 cm-1; HRMS (ESI) calcd. for C17H19FNO2S3: [M+H]+: 384.0562, found: 384.0563. 1-(2-Chlorophenyl)-2-(phenylsulfonyl)ethyl


(5e).

Purification by column chromatography on silica gel (Rf = 0.30, petroleum ether/ethyl acetate = 3:1) yielded 5e (27.1 mg, 68%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.81-7.79 (m, 2H), 7.63-7.59 (m, 1H), 7.49 (t, J = 7.8 Hz, 2H), 7.45-7.42 (m, 1H), 7.35-7.32 (m, 1H), 7.25-7.20 (m, 2H), 5.66 (dd, J = 11.1, 3.7 Hz, 1H), 4.19 (dd, J = 14.4, 3.8 Hz, 1H), 4.09-4.03 (m, 1H), 3.45 (s, 3H), 3.23 (s, 3H);

13C

{1H}

NMR (100 MHz, CDCl3): δ 193.7, 138.7, 134.1, 133.7, 133.4, 130.4, 130.3, 129.6, 129.0, 128.6, 126.9, 58.5, 48.1, 45.3, 41.3; IR(KBr): 3360, 2957, 2922, 2851, 1732, 1501, 1477, 1445, 1378, 1315, 1252, 1145, 1085, 982, 909, 777, 751, 688, 553 cm-1; HRMS (ESI) calcd. for C17H19ClNO2S3: [M+H]+: 400.0266, found: 400.0266. 1-(3-Bromophenyl)-2-tosylethyl dimethylcarbamodithioate (5f). Purification by column chromatography on silica gel (Rf = 0.30, petroleum ether/ethyl acetate = 3:1) yielded 5f (27 mg, 59%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.2 Hz, 2H), 7.39-7.37 (m, 1H), 7.30-7.25 (m, 4H), 7.16 (t, J = 7.8 Hz, 1H), 5.28 (dd, J = 11.2, 3.8 Hz, 1H), 4.22 (dd, J = 14.3, 3.8 Hz, 1H), 3.79 (dd, J = 14.3, 11.2 Hz, 1H), 3.49 (s, 3H), 3.26 (s, 3H), 2.44 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.1, 144.7, 138.3, 136.2, 131.5, 131.4, 130.2, 129.6, 128.3, 127.5, 122.7, 59.9, 50.3, 45.2, 41.3, 21.7; IR(KBr): 3360, 2957, 2921, 2851, 1732, 1657, 1595, 1500, 1378, 1315, 1252, 1139, 1086, 980, 801, 771, 688, 555, 519 cm-1; HRMS (ESI) calcd. for C18H21BrNO2S3: [M+H]+: 457.9918, found: 457.9919. 1-(3-Chlorophenyl)-2-tosylethyl dimethylcarbamodithioate (5g). Purification by column chromatography on silica gel (Rf = 0.30, petroleum ether/ethyl acetate = 3:1) yielded 5g (21.9 mg, 53%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.2 Hz, 2H), 7.26-7.25 (m, 2H), 7.23-7.21 (m, 3H), 7.15 (s, 1H), 5.26 (dd, J = 11.1, 3.8 Hz, 1H), 4.21 (dd, J = 14.3, 3.8 Hz, 1H), 3.77 (dd, J = 14.3, 11.2 Hz, 1H), 3.47 (s, 3H), 3.24 (s, 3H), 2.42 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.2, 144.7, 138.1, 136.2, 134.5, 130.0, 129.6, 128.7, 128.5, 128.3, 127.0, 59.9, 50.3, 45.2,


Page 25 of 47 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


41.3, 21.6; IR(KBr): 3363, 2959, 2920, 2850, 1649, 1634, 1596, 1497, 1377, 1314, 1255, 1137, 1084, 982, 806, 774, 689, 550 cm-1; HRMS (ESI) calcd. for C18H21ClNO2S3: [M+H]+: 414.0423, found: 414.0424. 1-(2-Chlorophenyl)-2-tosylethyl dimethylcarbamodithioate (5h). Purification by column chromatography on silica gel (Rf = 0.29, petroleum ether/ethyl acetate = 3:1) yielded 5h (23.5 mg, 57%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.69 (d, J = 8.2 Hz, 2H), 7.47-7.45 (m, 1H), 7.37-7.35 (m, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.27-7.23 (m, 2H), 5.67 (dd, J = 11.1, 3.7 Hz, 1H), 4.20 (dd, J = 14.4, 3.8 Hz, 1H), 4.08-4.02 (m, 1H), 3.48 (s, 3H), 3.26 (s, 3H), 2.45 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.7, 144.6, 135.8, 134.1, 133.5, 130.4, 130.2, 129.6, 129.5, 128.6, 126.8, 58.6, 48.1, 45.2, 41.3, 21.7; IR(KBr): 3359, 2961, 2922, 2851, 1733. 1657, 1596, 1498, 1378, 1308, 1252, 1145, 1087, 1039, 980, 909, 813, 758, 556 cm-1; HRMS (ESI) calcd. for C18H21ClNO2S3: [M+H]+: 414.0423, found: 414.0422. 1-(p-Tolyl)-2-tosylethyl dimethylcarbamodithioate (5i). Purification by column chromatography on silica gel (Rf = 0.29, petroleum ether/ethyl acetate = 3:1) yielded 5i (20.8 mg, 53%) as a light yellow solid; m. p. 148-149 oC; 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 8.2 Hz, 2H), 7.26-7.24 (m, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 7.9 Hz, 2H), 5.16 (dd, J = 11.3, 3.6 Hz, 1H), 4.26 (dd, J = 14.1, 3.6 Hz, 1H), 3.80 (dd, J = 14.1, 11.3 Hz, 1H), 3.45 (s, 3H), 3.22 (s, 3H), 2.42 (s, 3H), 2.32 (s, 3H); 13C

{1H} NMR (100 MHz, CDCl3): δ 194.1, 144.4, 138.3, 136.4, 132.7, 129.5, 129.4,

128.5, 128.4, 60.0, 50.7, 45.0, 41.3, 21.7, 21.2; IR(KBr): 3358, 2955, 2921, 2851, 1658, 1498, 1377, 1317, 1252, 1152, 1137, 1086, 981, 910, 813, 778 cm-1; HRMS (ESI) calcd. for C19H24NO2S3: [M+H]+: 394.0969, found: 394.0968. 1-(4-(tert-Butyl)phenyl)-2-tosylethyl dimethylcarbamodithioate (5j). Purification by column chromatography on silica gel (Rf = 0.29, petroleum ether/ethyl acetate = 3:1) yielded 5j (22.6 mg, 52%) as a light yellow liquid; 1H NMR (400 MHz, CDCl3): δ 7.57 (d, J = 8.3 Hz, 2H), 7.26-7.22 (m, 2H), 7.20-7.16 (m, 4H), 5.26 (dd, J = 11.2, 3.7 Hz, 1H), 4.28 (dd, J = 14.2, 3.7 Hz, 1H), 3.84 (dd, J = 14.2, 11.2 Hz, 1H), 3.47 (s, 3H), 3.22 (s, 3H), 2.39 (s, 3H), 1.29 (s, 9H);

13C

{1H} NMR (100 MHz, CDCl3): δ



194.1, 151.3, 144.1, 136.6, 132.5, 129.4, 128.4, 128.2, 125.7, 60.1, 50.6, 45.0, 41.3, 34.6, 31.3, 21.6; IR(KBr): 3358, 3051, 3031, 2962, 2924, 2854, 1735, 1658, 1502, 1376, 1319, 1302, 1253, 1140, 1086, 983, 912, 812, 750, 559 cm-1; HRMS (ESI) calcd. for C22H30NO2S3: [M+H]+: 436.1439, found: 436.1440. 1-(4-Bromophenyl)-2-tosylethyl dimethylcarbamodithioate (5k). Purification by column chromatography on silica gel (Rf = 0.29, petroleum ether/ethyl acetate = 3:1) yielded 5k (35.2 mg, 77%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.2 Hz, 2H), 7.40-7.38 (m, 2H), 7.28-7.26 (m, 2H), 7.17-7.15 (m, 2H), 5.25 (dd, J = 11.2, 3.8 Hz, 1H), 4.24 (dd, J = 14.2, 3.8 Hz, 1H), 3.78 (dd, J = 14.2, 11.2 Hz, 1H), 3.48 (s, 3H), 3.25 (s, 3H), 2.46 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.2, 144.7, 136.3, 135.1, 131.8, 130.3, 129.6, 128.3, 122.5, 59.9, 50.2, 45.1, 41.3, 21.7; IR(KBr): 3360, 2963, 2921, 2850, 1652, 1634, 1595, 1490, 1406, 1378, 1315, 1253, 1138, 1086, 981, 910, 840, 803, 640, 556 cm-1; HRMS (ESI) calcd. for C18H21BrNO2S3: [M+H]+: 457.9918, found: 457.9919. 1-(4-Chlorophenyl)-2-tosylethyl dimethylcarbamodithioate (5l). Purification by column chromatography on silica gel (Rf = 0.29, petroleum ether/ethyl acetate = 3:1) yielded 5l (24 mg, 58%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 8.2 Hz, 2H), 7.26-7.24 (m, 2H), 7.23-7.19 (m, 4H), 5.24 (dd, J = 11.2, 3.8 Hz, 1H), 4.22 (dd, J = 14.2, 3.8 Hz, 1H), 3.76 (dd, J = 14.2, 11.2 Hz, 1H), 3.46 (s, 3H), 3.23 (s, 3H), 2.43 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.3, 144.7, 136.3, 134.6, 134.3, 130.0, 129.6, 128.9, 128.4, 60.0, 50.2, 45.1, 41.3, 21.7; IR(KBr): 3360, 3193, 2957, 2922, 2852, 1733, 1659, 1634, 1597, 1494, 1377, 1316, 1251, 1138, 1088, 98, 910, 814, 739, 654, 556 cm-1; HRMS (ESI) calcd. for C18H21ClNO2S3: [M+H]+: 414.0423, found: 414.0424. 1-(4-Fluorophenyl)-2-tosylethyl dimethylcarbamodithioate (5m). Purification by column chromatography on silica gel (Rf = 0.28, petroleum ether/ethyl acetate = 2:1) yielded 5m (19.9 mg, 50%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.64 (d, J = 8.3 Hz, 2H), 7.30-7.27 (m, 4H), 7.00-6.96 (m, 2H), 5.26 (dd, J = 11.2, 3.8 Hz, 1H), 4.26 (dd, J = 14.2, 3.8 Hz, 1H), 3.79 (dd, J = 14.2, 11.2 Hz, 1H), 3.48 (s, 3H),


Page 26 of 47

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3.25 (s, 3H), 2.45 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.5, 162.5 (d, J = 246.4 Hz), 144.6, 136.4, 131.8 (d, J = 3.4 Hz), 130.4 (d, J = 8.3 Hz), 129.6, 128.4, 115.7 (d, J = 21.6 Hz), 60.2, 50.1, 45.1, 41.3, 21.6; IR(KBr): 2957, 2921, 2851, 1600, 1509, 1378, 1316, 1228, 1152, 1086, 982, 803, 748 cm-1; HRMS (ESI) calcd. for C18H21FNO2S3: [M+H]+: 398.0718, found: 398.0719. 2-((6-Chloropyridin-3-yl)sulfonyl)-1-(p-tolyl)ethyl


(5n). Purification by column chromatography on silica gel (Rf = 0.34, petroleum ether/ethyl acetate = 3:1) yielded 5n (31.9 mg, 77%) as a white solid; m. p. 127-129 oC; 1H

NMR (400 MHz, CDCl3): δ 8.62 (d, J = 2.5 Hz, 1H), 7.85 (dd, J = 8.3, 2.5 Hz,

1H), 7.31 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H), 5.16 (dd, J = 11.5, 3.4 Hz, 1H), 4.39 (dd, J = 14.4, 3.4 Hz, 1H), 3.86 (dd, J = 14.4, 11.5 Hz, 1H), 3.48 (s, 3H), 3.24 (s, 3H), 2.34 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 193.6, 156.3, 149.7, 139.1, 138.5, 134.8, 131.7, 129.7, 128.5, 124.2, 60.4, 50.5, 45.1, 41.3, 21.2; IR(KBr): 3357, 2961, 2921, 2851, 1732, 1632, 1565, 1501, 1447, 1378, 1323, 1250, 1159, 1109, 981, 910, 832, 793, 740 cm-1; HRMS (ESI) calcd. for C17H20ClN2O2S3: [M+H]+: 415.0375, found: 415.0374. 1-(4-(tert-Butyl)phenyl)-2-((6-chloropyridin-3-yl)sulfonyl)ethyl dimethylcarbamodithioate (5o). Purification by column chromatography on silica gel (Rf = 0.28, petroleum ether/ethyl acetate = 3:1) yielded 5o (30.1 mg, 66%) as a light yellow liquid; 1H NMR (400 MHz, CDCl3): δ 8.59 (d, J = 2.4 Hz, 1H), 7.77 (dd, J = 8.4, 2.5 Hz, 1H), 7.25-7.21 (m, 3H), 7.12 (d, J = 8.3 Hz, 2H), 5.26 (dd, J = 11.4, 3.4 Hz, 1H), 4.43 (dd, J = 14.5, 3.4 Hz, 1H), 3.90 (dd, J = 14.5, 11.5 Hz, 1H), 3.49 (s, 3H), 3.24 (s, 3H), 1.30 (s, 9H);

13C

{1H} NMR (100 MHz, CDCl3): δ 193.6, 156.0,

152.2, 149.6, 138.3, 135.1, 131.6, 128.2, 126.0, 124.1, 60.5, 50.4, 45.1, 41.3, 34.6, 31.3; IR(KBr): 3357, 3032, 2961, 2921, 2851, 1658, 1566, 1503, 1447, 1376, 1323, 1251, 1156, 1109, 982, 911, 798 cm-1; HRMS (ESI) calcd. for C20H26ClN2O2S3: [M+H]+: 457.0845, found: 457.0845. 1-(4-Bromophenyl)-2-((6-chloropyridin-3-yl)sulfonyl)ethyl dimethylcarbamodithioate (5p). Purification by column chromatography on silica



Page 28 of 47

gel (Rf = 0.30, petroleum ether/ethyl acetate = 3:1) yielded 5p (34.4 mg, 72%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 8.73 (d, J = 2.2 Hz, 1H), 7.93 (dd, J = 8.4, 2.6 Hz, 1H), 7.44 (t, J = 8.5 Hz, 3H), 7.18 (d, J = 8.4 Hz, 2H), 5.19 (dd, J = 11.3, 3.6 Hz, 1H), 4.33 (dd, J = 14.5, 3.6 Hz, 1H), 3.86 (dd, J = 14.4, 11.3 Hz, 1H), 3.49 (s, 3H), 3.26 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 192.9, 156.7, 149.7, 138.5, 134.6, 134.3, 132.2, 130.2, 124.5, 123.0, 60.3, 50.0, 45.3, 41.4; IR(KBr): 3363, 2959, 2923, 2852, 1731, 1660, 1568, 1494, 1448, 1374, 1319, 1251, 1155, 1099, 981, 910,

837,

793,

738,

627,

572,

556

cm-1;

HRMS

(ESI)

calcd.

for

C16H16BrClN2NaO2S3: [M+Na]+: 500.9143, found: 500.9142. 1-(4-Bromophenyl)-2-((6-chloropyridin-3-yl)sulfonyl)ethyl dimethylcarbamodithioate (5q). Purification by column chromatography on silica gel (Rf = 0.29, petroleum ether/ethyl acetate = 3:1) yielded 5q (26.9 mg, 62%) as a white solid; m. p. 152-154 oC; 1H NMR (400 MHz, CDCl3): δ 8.72 (d, J = 2.4 Hz, 1H), 7.93 (dd, J = 8.4, 2.5 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.30-7.27 (m, 2H), 7.24-7.22 (m, 2H), 5.19 (dd, J = 11.3, 3.6 Hz, 1H), 4.32 (dd, J = 14.4, 3.6 Hz, 1H), 3.84 (dd, J = 14.4, 11.3 Hz, 1H), 3.47 (s, 3H), 3.24 (s, 3H);

13C

{1H} NMR (100

MHz, CDCl3): δ 192.9, 156.7, 149.8, 138.5, 134.9, 134.6, 133.7, 129.9, 129.3, 124.5, 60.3, 50.0, 45.3, 41.4; IR(KBr): 3358, 2959, 2921, 2850, 1731, 1658, 1565, 1494, 1378, 1322, 1250, 1157, 1139, 1108, 980, 797 cm-1; HRMS (ESI) calcd. for C16H17Cl2N2O2S3: [M+H]+: 434.9829, found: 434.9830. 2-((6-Chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)ethyl dimethylcarbamodithioate (5r). Purification by column chromatography on silica gel (Rf = 0.29, petroleum ether/ethyl acetate = 3:1) yielded 5r (28.8 mg, 69%) as a white solid; m. p. 136-138 oC; 1H NMR (400 MHz, CDCl3): δ 8.71 (d, J = 2.4 Hz, 1H), 7.95 (dd, J = 8.4, 2.5 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.29-7.26 (m, 2H), 7.01 (t, J = 8.5 Hz, 2H), 5.19 (dd, J = 11.3, 3.6 Hz, 1H), 4.34 (dd, J = 14.4, 3.6 Hz, 1H), 3.84 (dd, J = 14.4, 11.4 Hz, 1H), 3.47 (s, 3H), 3.24 (s, 3H);

13C

{1H} NMR (100

MHz, CDCl3): δ 193.1, 162.7 (d, J = 247.8 Hz), 156.7, 149.8, 138.5, 134.7, 131.0 (d, J = 3.4 Hz), 130.3 (d, J = 8.4 Hz), 124.5, 116.1 (d, J = 21.7 Hz), 60.5, 49.9, 45.2, 41.4; IR(KBr): 3395, 3355, 3186, 2958, 2922, 2850, 1732, 1646, 1566, 1509,1377,


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1322, 1251, 1159, 1109, 981, 910, 798, 738 cm-1; HRMS (ESI) calcd. for C16H17ClFN2O2S3: [M+H]+: 419.0125, found: 419.0126. 1-(3-Bromophenyl)-2-((6-chloropyridin-3-yl)sulfonyl)ethyl dimethylcarbamodithioate (5s). Purification by column chromatography on silica gel (Rf = 0.30, petroleum ether/ethyl acetate = 3:1) yielded 5s (34.4 mg, 72%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 8.66 (d, J = 2.2 Hz, 1H), 7.91 (dd, J = 8.3, 2.5 Hz, 1H), 7.44-7.39 (m, 2H), 7.34-7.33 (m, 1H), 7.25 (d, J = 8.5 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 5.23 (dd, J = 11.2, 3.7 Hz, 1H), 4.32 (dd, J = 14.6, 3.7 Hz, 1H), 3.84 (dd, J = 14.6, 11.3 Hz, 1H), 3.48 (s, 3H), 3.25 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 192.8, 156.7, 149.7, 138.4, 137.5, 134.7, 131.9, 131.5, 130.6, 127.4, 124.5, 123.0, 60.3, 50.1, 45.3, 41.4; IR(KBr): 3358, 3192, 2959, 2919, 2850, 1567, 1501, 1447, 1379, 1322, 1249, 1156, 1108, 979, 785, 637, 557 cm-1; HRMS (ESI) calcd. for C16H16BrClN2NaO2S3: [M+Na]+: 500.9143, found: 500.9144. 1-(3-Chlorophenyl)-2-((6-chloropyridin-3-yl)sulfonyl)ethyl dimethylcarbamodithioate (5t). Purification by column chromatography on silica gel (Rf = 0.30, petroleum ether/ethyl acetate = 3:1) yielded 5t (33 mg, 76%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 8.67 (d, J = 2.4 Hz, 1H), 7.93 (dd, J = 8.3, 2.5 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.29-7.25 (m, 2H), 7.23-7.19 (m, 2H), 5.23 (dd, J = 11.2, 3.6 Hz, 1H), 4.32 (dd, J = 14.6, 3.6 Hz, 1H), 3.86 (dd, J = 14.5, 11.3 Hz, 1H), 3.48 (s, 3H), 3.25 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 192.8, 156.7, 149.7, 138.4, 137.3, 134.9, 134.7, 130.4, 129.0, 128.7, 126.9, 124.5, 60.3, 50.1, 45.3, 41.4; IR(KBr): 3359, 2955, 2922, 2852, 1731, 1568, 1500, 1447, 1378, 1322, 1250, 1159, 1109, 980, 817, 786, 690 cm-1; HRMS (ESI) calcd. for C16H17Cl2N2O2S3: [M+H]+: 434.9829, found: 434.9828. 1-Phenyl-2-(phenylsulfonyl)ethyl diethylcarbamodithioate (6a). Purification by column chromatography on silica gel (Rf = 0.29, petroleum ether/ethyl acetate = 3:1) yielded 6a (25.9 mg, 66%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.77-7.75 (m, 2H), 7.60-7.56 (m, 1H), 7.46 (t, J = 7.9 Hz, 2H), 7.30-7.27 (m, 5H), 5.24 (dd, J = 11.3, 3.6 Hz, 1H), 4.33 (dd, J = 14.2, 3.6 Hz, 1H), 3.98-3.89 (m, 2H),



Page 30 of 47

3.85 (dd, J = 14.2, 11.3 Hz, 1H), 3.58 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.4 Hz, 3H), 1.18 (t, J = 7.4 Hz, 3H);

13C

{1H} NMR (100 MHz, CDCl3): δ 192.2, 139.3, 135.8,

133.5, 128.9, 128.8, 128.7, 128.5, 128.4, 60.1, 50.3, 49.2, 46.7, 12.5, 11.5; IR(KBr): 3360, 2976, 2921, 2851, 1681, 1491, 1448, 1420, 1319, 1305, 1269, 1205, 1141, 1084, 1005, 916, 779, 746, 691 cm-1; HRMS (ESI) calcd. for C19H24NO2S3: [M+H]+: 394.0969, found: 394.0968. 1-Phenyl-2-tosylethyl diethylcarbamodithioate (6b). Purification by column chromatography on silica gel (Rf = 0.35, petroleum ether/ethyl acetate = 4:1) yielded 6b (30.1 mg, 74%) as a light yellow liquid; 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 8.2 Hz, 2H), 7.28-7.26 (m, 5H), 7.26-7.24 (m, 2H), 5.22 (dd, J = 11.2, 3.6 Hz, 1H), 4.31 (dd, J = 14.2, 3.7 Hz, 1H), 3.98-3.88 (m, 2H), 3.82 (dd, J = 14.1, 11.3 Hz, 1H), 3.61-3.55 (m, 2H), 2.42 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 192.2, 144.4, 136.3, 135.9, 129.6, 128.7, 128.6, 128.5, 128.4, 60.1, 50.4, 49.2, 46.7, 21.7, 12.5, 11.5; IR(KBr): 3031, 2977, 2923, 1597, 1491, 1454, 1420, 1302, 1270, 1206, 1149, 1086, 1007, 984, 916, 752, 697 554 cm-1; HRMS (ESI) calcd. for C20H26NO2S3: [M+H]+: 408.1126, found: 408.1125. 2-((4-Fluorophenyl)sulfonyl)-1-phenylethyl

diethylcarbamodithioate

(6c).

Purification by column chromatography on silica gel (Rf = 0.35, petroleum ether/ethyl acetate = 4:1) yielded 6c (29.1 mg, 71%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.76-7.73 (m, 2H), 7.30-7.28 (m, 5H), 7.13-7.09 (m, 2H), 5.21 (dd, J = 11.4, 3.6 Hz, 1H), 4.35 (dd, J = 14.2, 3.6 Hz, 1H), 3.97-3.90 (m, 2H), 3.85 (dd, J = 14.2, 11.4 Hz, 1H), 3.62-3.56 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H);

13C

{1H} NMR (100 MHz, CDCl3): δ 192.1, 165.7 (d, J = 254.4 Hz), 135.6,

135.3 (d, J = 3.1 Hz), 131.3 (d, J = 9.7 Hz), 128.8, 128.7, 128.6, 116.2 (d, J = 22.5 Hz), 60.2, 50.3, 49.3, 46.7, 12.5, 11.5; IR(KBr): 3361, 2976, 2925, 2852, 1659, 1591, 1492, 1420, 1323, 1270, 1235, 1145, 1084, 1009, 916, 836, 755, 699, 555 cm-1; HRMS (ESI) calcd. for C19H23FNO2S3: [M+H]+: 412.0875, found: 412.0876. 2-((2-Chlorophenyl)sulfonyl)-1-phenylethyl

diethylcarbamodithioate

(6d).

Purification by column chromatography on silica gel (Rf = 0.33, petroleum ether/ethyl


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acetate = 4:1) yielded 6d (31.6 mg, 74%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.68-7.66 (m, 1H), 7.39-7.37 (m, 2H), 7.24-7.22 (m, 2H), 7.19-7.15 (m, 1H), 7.14-7.10 (m, 3H), 5.43 (dd, J = 11.1, 4.0 Hz, 1H), 4.51 (dd, J = 14.6, 3.9 Hz, 1H), 4.27 (dd, J = 14.6, 11.2 Hz, 1H), 3.95 (q, J = 7.0 Hz, 2H), 3.66-3.54 (m, 2H), 1.24 (t, J = 6.9 Hz, 3H), 1.20 (t, J = 7.6 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 191.9, 137.2, 135.8, 134.2, 132.6, 131.8, 131.4, 128.6, 128.5, 128.4, 127.1, 58.3, 50.4, 49.3, 46.7, 12.6, 11.5; IR(KBr): 3063, 2978, 2931, 2873, 1734, 1577, 1490, 1453, 1421, 1325, 1269, 1205, 1151, 1039, 916, 830, 761, 698, 555 cm-1; HRMS (ESI) calcd. for C19H23ClNO2S3: [M+H]+: 428.0579, found: 428.0580. 2-((6-Chloropyridin-3-yl)sulfonyl)-1-phenylethyl diethylcarbamodithioate (6e). Purification by column chromatography on silica gel (Rf = 0.35, petroleum ether/ethyl acetate = 3:1) yielded 6e (24 mg, 56%) as a light yellow liquid; 1H NMR (400 MHz, CDCl3): δ 8.65 (d, J = 2.3 Hz, 1H), 7.88 (dd, J = 8.4, 2.5 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.32-7.29 (m, 3H), 7.28-7.24 (m, 2H), 5.22 (dd, J = 11.4, 3.4 Hz, 1H), 4.44 (dd, J = 14.4, 3.4 Hz, 1H), 3.98-3.86 (m, 3H), 3.65-3.55 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H);

13C

{1H} NMR (100 MHz, CDCl3): δ 191.8, 156.4,

149.8, 138.5, 135.0, 134.8, 129.1, 128.8, 128.7, 124.3, 60.5, 50.2, 49.4, 46.8, 12.5, 11.5; IR(KBr): 2975, 2922, 2869, 2852, 1567, 1491, 1449, 1420, 1356, 1326, 1269, 1205, 1142, 1108, 1013, 915, 785 cm-1; HRMS (ESI) calcd. for C18H22ClN2O2S3: [M+H]+: 429.0532, found: 429.0533. 1-(4-(tert-Butyl)phenyl)-2-((6-chloropyridin-3-yl)sulfonyl)ethyl diethylcarbamodithioate (6f). Purification by column chromatography on silica gel (Rf = 0.32, petroleum ether/ethyl acetate = 3:1) yielded 6f (33.4 mg, 69%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 8.59 (d, J = 2.3 Hz, 1H), 7.78 (dd, J = 8.3, 2.5 Hz, 1H), 7.24-7.22 (m, 3H), 7.12 (d, J = 8.3 Hz, 2H), 5.28 (dd, J = 11.4, 3.4 Hz, 1H), 4.48 (dd, J = 14.5, 3.4 Hz, 1H), 3.98-3.95 (m, 2H), 3.90 (dd, J = 14.4, 11.5 Hz, 1H), 3.60 (ddd, J = 9.0, 7.5, 2.3 Hz, 2H), 1.30 (s, 9H), 1.25 (t, J = 6.9 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H);

13C

{1H} NMR (100 MHz, CDCl3): δ 191.9, 156.0,

152.1, 149.6, 138.4, 135.1, 131.5, 128.3, 125.9, 124.1, 60.6, 49.9, 49.4, 46.7, 34.6, 31.3, 12.6, 11.5; IR(KBr): 3360, 2963, 2923, 2853, 1567, 1490, 1447, 1420, 1357,



1324, 1268, 1206, 1144, 1107, 1014, 914, 831, 798, 564 cm-1; HRMS (ESI) calcd. for C22H30ClN2O2S3: [M+H]+: 485.1158, found: 485.1159. 1-(3-Bromophenyl)-2-((6-chloropyridin-3-yl)sulfonyl)ethyl diethylcarbamodithioate (6g). Purification by column chromatography on silica gel (Rf = 0.31, petroleum ether/ethyl acetate = 3:1) yielded 6g (38 mg, 77%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 8.66 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 8.4, 2.5 Hz, 1H), 7.44-7.39 (m, 2H), 7.34 (t, J = 1.7 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 5.24 (dd, J = 11.3, 3.6 Hz, 1H), 4.36 (dd, J = 14.6, 3.6 Hz, 1H), 4.01-3.89 (m, 2H), 3.84 (dd, J = 14.5, 11.3 Hz, 1H), 3.60 (dd, J = 14.4, 7.2 Hz, 2H), 1.25 (t, J = 4.8 Hz, 3H), 1.21 (t, J = 7.3 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 191.1, 156.7, 149.7, 138.4, 137.6, 134.7, 131.9, 131.6, 130.6, 127.4, 124.5, 123.0, 60.4, 49.6, 49.5, 46.9, 12.6, 11.5; IR(KBr): 3361, 2977, 2921, 2871, 2851, 1594, 1565. 1490, 1446, 1421, 1356, 1322, 1272, 1205, 1161, 1111, 1012, 982, 918, 786, 557 cm-1; HRMS (ESI) calcd. for C18H21BrClN2O2S3: [M+H]+: 506.9637, found: 506.9638. 1-(4-Bromophenyl)-2-((6-chloropyridin-3-yl)sulfonyl)ethyl dibutylcarbamodithioate (6h). Purification by column chromatography on silica gel (Rf = 0.33, petroleum ether/ethyl acetate = 8:1) yielded 6h (32.6 mg, 62%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.75-7.73 (m, 2H), 7.64-7.60 (m, 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.40-7.38 (m, 2H), 7.16 (d, J = 8.4 Hz, 2H), 5.23 (dd, J = 11.4, 3.6 Hz, 1H), 4.28 (dd, J = 14.2, 3.7 Hz, 1H), 3.91-3.75 (m, 3H), 3.50-3.46 (m, 2H), 1.67-1.62 (m, 2H), 1.58-1.53 (m, 2H), 1.34-1.30 (m, 2H), 1.29-1.22 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 191.9, 139.2, 135.0, 133.6, 131.9, 130.4, 129.0, 128.4, 122.5, 60.0, 54.9, 52.5, 49.7, 29.4, 28.2, 20.1, 20.0, 13.8, 13.7; IR(KBr): 3359, 2960, 2922, 2852, 1731, 1658, 1487, 1414, 1310, 1262, 1138, 1086, 1012, 909, 796, 736, 555 cm-1; HRMS (ESI) calcd. for C23H31BrNO2S3: [M+H]+: 528.0700, found: 528.069. 1-Phenyl-2-tosylethyl dibutylcarbamodithioate (6i). Purification by column chromatography on silica gel (Rf = 0.39, petroleum ether/ethyl acetate = 8:1) yielded


Page 32 of 47

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6i (25.9 mg, 56%) as a light yellow liquid; 1H NMR (400 MHz, CDCl3): δ 7.63 (d, J = 8.2 Hz, 2H), 7.28-7.26 (m, 5H), 7.25 (d, J = 8.6 Hz, 2H), 5.43 (dd, J = 11.3, 3.6 Hz, 1H), 4.31 (dd, J = 14.1, 3.6 Hz, 1H), 3.92-3.77 (m, 3H), 3.49 (dd, J = 9.0, 6.8 Hz, 2H), 2.42 (s, 3H), 1.68-1.60 (m, 2H), 1.58-1.53 (m, 2H), 1.37-1.22 (m, 4H), 0.94 (t, J = 7.3 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 192.5, 144.4, 136.3, 135.9, 129.5, 128.8, 128.7, 128.5, 128.3, 60.1, 54.8, 52.4, 50.5, 29.3, 28.3, 21.7, 20.1, 20.0, 13.8, 13.7; IR(KBr): 3393, 2958, 2924, 2871, 1647, 1488, 1454, 1416, 1319, 1219, 1147, 1087, 907, 812, 752, 697, 554 cm-1; HRMS (ESI) calcd. for C24H34NO2S3: [M+H]+: 464.1752, found: 464.1751. 1-(p-Tolyl)-2-tosylethyl dibutylcarbamodithioate (6j). Purification by column chromatography on silica gel (Rf = 0.39, petroleum ether/ethyl acetate = 8:1) yielded 6j (23.4 mg, 49%) as a light yellow liquid; 1H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 5.07 (dd, J = 11.4, 3.5 Hz, 1H), 4.24 (dd, J = 14.1, 3.6 Hz, 1H), 3.84-3.69 (m, 3H), 3.43-3.39 (m, 2H), 2.35 (s, 3H), 2.26 (s, 3H), 1.60-1.53 (m, 2H), 1.50-1.45 (m, 2H), 1.29-1.22 (m, 2H), 1.20-1.14 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H), 0.82 (t, J = 7.3 Hz, 3H);

13C

{1H} NMR (100 MHz, CDCl3): δ 192.7, 144.4, 138.3, 136.3, 132.6,

129.5, 129.4, 128.6, 128.5, 60.0, 54.7, 52.4, 50.2, 29.3, 28.3, 21.7, 21.2, 20.1, 20.0, 13.8, 13.7; IR(KBr): 3359, 3190, 2958, 2923, 2854, 1658, 1486, 1416, 1319, 1300, 1263, 1137, 1087, 910, 811, 779, 557 cm-1; HRMS (ESI) calcd. for C25H36NO2S3: [M+H]+: 478.1908, found: 478.1907. 1-(4-Bromophenyl)-2-tosylethyl dibutylcarbamodithioate (6k). Purification by column chromatography on silica gel (Rf = 0.38, petroleum ether/ethyl acetate = 8:1) yielded 6k (31.9 mg, 59%) as a colorless liquid; 1H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 5.25 (dd, J = 11.3, 3.7 Hz, 1H), 4.29 (dd, J = 14.2, 3.7 Hz, 1H), 3.93-3.75 (m, 3H), 3.53-3.49 (m, 2H), 2.46 (s, 3H), 1.70-1.62 (m, 2H), 1.61-1.54 (m, 2H), 1.39-1.30 (m, 2H), 1.28-1.36 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H), 0.92 (t, J = 7.3 Hz, 3H);

13C

{1H} NMR (100 MHz, CDCl3): δ 191.9, 144.7, 136.2, 135.1, 131.8,

130.4, 129.6, 128.4, 122.4, 60.0, 54.9, 52.5, 49.8, 29.4, 28.3, 21.7, 20.1, 20.0, 13.8,



Page 34 of 47

13.7; IR(KBr): 3359, 3188, 2959, 2923, 2853, 1658, 1633, 1596, 1487, 1415, 1316, 1263, 1219, 1138, 1087, 1011, 910, 803, 741, 556 cm-1; HRMS (ESI) calcd. for C24H33BrNO2S3: [M+H]+: 542.0857, found: 542.0858.

Supporting Information Available: X-ray data for 4b in CIF format; Experimental mechanistic studies. 1H and

13C

NMR spectra of all compounds. This material is

available free of charge via the Internet at http://pubs.acs.org. ACKNOWLEDGEMENTS The authors greatly acknowledge the financial support by Henan Agricultural University (30500567, 30500701).

REFERENCES (1) For reviews, see: (a) Haruki, H.; Pedersen, M. G.; Gorska, K. I.; Pojer, F.; Johnsson, K. Tetrahydrobiopterin Biosynthesis as an Off-target of Sulfa Drugs. Science 2013, 340, 987−991. (b) Feng, M.; Tang, B.; Liang, S.; Jiang, X. Sulfur Containing Scaffolds in Drugs: Synthesis and Application in Medicinal Chemistry. Yu,

Z.

Curr. Top. Med. Chem. 2016, 16, 1200−1216. (c) Wang, L.; Hea, W.;

Transition-metal

Mediated

Carbon-sulfur

Bond

Activation

and

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Alkene


Difunctionalization:


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Reactions

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(26)

(a)

Yoshida,

H.;

Kageyuki,

I.;

Takaki,

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K.

Copper-catalyzed

Three-component Carboboration of Alkynes and Alkenes. Org. Lett. 2013, 15, 952−955. (b) Kageyuki, I.; Osaka, I.; Takaki, K.; Yoshida, H. Copper-catalyzed B (dan)-Installing Carboboration of Alkenes. Org. Lett. 2017, 19, 830−833. (c) Kageyuki, I.; Yoshida, H.; Takaki, K. Three-Component Carboboration of Alkenes under Copper Catalysis. Synthesis 2014, 46, 1924−1932. (d) Gong, T.; Yu, S.; Li, K.; Su, W.; Lu, X.; Xiao, B.; Fu, Y. Copper-Catalyzed Alkynylboration of Alkenes with Diboron Reagents and Bromoalkynes. Chem. Asian J. 2017, 12, 2884−2888. (e) Xie, L.; Li, Y.; Qu, J.; Duan, Y.; Hu, J.; Liu, K.; Cao, Z.; He, W. A Base-free, Ultrasound Accelerated One-pot Synthesis of 2-Sulfonylquinolines in Water. Green Chem. 2017, 19, 5642−5646; (f) See ESI† for more details of the reaction mechanisms. (27) The active Cu(I) species can be initially formed through either the reduction of Cu(II) by the nucleophile or the disproportionation of Cu(II). For reduction, see: (a) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. Cu (II)-catalyzed Direct and Site-selective Arylation of Indoles under Mild Conditions. J. Am. Chem. Soc. 2008, 130, 8172−8174. (b) Ley, S. V.; Thomas, A. W. Modern Synthetic Methods for Copper − Mediated C(aryl)−O, C(aryl)−N, and C(aryl)−S Bond Formation. Angew. Chem. Int. Ed. 2003, 42, 5400−5449. For disproportionation, see: (c) Ribas, X.; Jackson, D. A.; Donnadieu, B.; Mahía, J.; Parella, T.; Xifra, R.; Hedman, B.; Hodgson, K. O.; Llobet, A.; Stack, T. D. P. Aryl C-H Activation by CuII To Form an Organometallic Aryl-CuIII Species: A Novel Twist on Copper Disproportionation. Angew. Chem. Int. Ed. 2002, 41, 2991−2994. (d) Yao, B.; Wang, D.; Huang, Z.; Wang, M. Room-temperature Aerobic Formation of A Stable Aryl-Cu(III) Complex and Its Reactions with Nucleophiles: Highly Efficient and Diverse Arene C-H Functionalizations of Azacalix[1] arene[3]pyridine. Chem. Commun. 2009, 2899−2901. (e) Ribas, X.; Calle, C.; Poater, A.; Casitas, A.; Gómez, L.; Xifra, R.; Parella, T.; Benet-Buchholz, J.; Schweiger, A.; Mitrikas, G.; Solà, M.; Llobet, A.; Stack, T. D. P. Facile C-H Bond Cleavage via a Proton-coupled Electron Transfer


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