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Substrates-Controlled Domino Reactions of CrotonateDerived Sulfur Ylides: Synthesis of Benzothiophene Derivatives Wenhuan Ding, Youquan Zhang, Aimin Yu, Lei Zhang, and Xiangtai Meng J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 29 Oct 2018 Downloaded from http://pubs.acs.org on October 29, 2018

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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

Substrates-Controlled Domino Reactions of Crotonate-Derived Sulfur Ylides: Synthesis of Benzothiophene Derivatives Wenhuan Ding,a,‡ Youquan Zhang,a,‡ Aimin Yu,a Lei Zhangb,c and Xiangtai Menga,* aTianjin

Key Laboratory of Organic Solar Cells and Photochemical Conversion, School of Chemistry

& Chemical Engineering, Tianjin University of Technology, Tianjin 300384, P. R. China. bTianjin

Engineering Technology Center of Chemical Wastewater Source Reduction and Recycling,

School of Science, Tianjin Chengjian University, Tianjin 300384, P. R. China cCollege

of Chemistry, Beijing Normal University, Beijing 100875, P. R. China

O Cs2CO3 o

CHCl3, 0 C

R1

O R



1

S

R2

S

+ Br





CO2Me

DIPEA CH2Cl2, rt



EtOH, rt

CO2Me

R2 S R2 = CO2Et, COAr S   O  CO2Me

R1

R1 S

  two-carbon synthon

R2

S R2 = Ar OH

Cs2CO3

 



CO2Me  O 

  two-carbon synthon

R2 = o-C6H4OH

ABSTRACT: Substrates-controlled domino reactions between thioaurones or their analogues and crotonate-derived sulfur ylides were developed, and producing a broad spectrum of benzothiophene fused pyran derivatives, substituted chromene derivatives. In these reactions, the crotonate-derived sulfur ylides acting as a two-carbon synthon (α and β carbons or β and γ carbons) in an annulation reaction is reported for the first time. These investigations nicely complement and expand previous studied reactions of crotonate-derived sulfur ylides. In addition, the reaction mechanisms for these

1

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domino reactions are proposed, one of which is supported by DFT calculations. INTRODUCTION Crotonate-derived sulfur ylides have received recent attention due to their versatile reaction modes.1-6 Their reactions described in the literature typically act as one or three carbon synthons.7-15 Analyzing the mechanisms reported in the literature, generally, the reactions are initiated by nucleophilic attack from a γ (I) or αposition (II) (Figure 1, blue arrows of I and II) and ended by an SN2 reaction at the γ position (Figure 1, red arrows of I and II). Simultaneously, dimethylsulfane is removed, which could potentially be the driving force for the reaction mechanisms. As seen here, the crotonate-derived sulfur ylides usually act as one or three carbon synthon.16-18 From the mechanistic perspective, it is challenging for crotonate-derived sulfur ylides to act as a two-carbon synthon (Figure 1III and IV),19-27 as dimethylsulfane cannot be released in such a reaction. During our ongoing investigation of domino reactions,28-32 we have successfully developed the first [4+3] annulation reaction of a crotonate-derived sulfur ylide.29 We think that the sulfur atom in thioaurones may play a critical role, which works to stabilize the adjacent carbon anion by its vacant 3d orbital.33 Following this approach, we modified the thioaurone and realized that the crotonate-derived sulfur ylide can act as a two-carbon synthon in domino reactions. Herein, we synthesized three types of thioaurones or their analogues, and studied reaction with crotonate-derived sulfur ylides. When the thioaurones bear ester or acyl group, a [4+2] annulation reaction was occurred (Scheme 1a). Furthermore, when Ar group was introduced into thioaurones, a new [4+2] annulation was developed, and sulfide was incorporated into product (Scheme 1b). In addition, when hydroxyl group was installed on the Ar at

2


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ortho-position, a new vinylcyclopropane rearrangement domino reaction took place, yielding a 3-benzothiophene-substituted chromene (Scheme 1c). The most important is the crotonate-derived sulfur ylides acting as a two-carbon synthon in these domino reactions. To the best of our knowledge, crotonate-derived sulfur ylides acting as a two-carbon synthon has not yet been reported. Previous work: one or three-carbon synthon one carbon synthon 

S

E

 

three carbon synthon   CO2Me S 

CO2Me

Nu

Nu

I

[2+1] or [4+1]

E

II

[3+n]/[2+1] or [4+3]

This work, New reaction mode: two-carbon synthon   two-carbon

  two-carbon

synthon

synthon



S  Nu

III

 CO2Me

S

E

E



 CO2Me



IV

Nu

Figure 1. Reaction modes of crotonate-derived sulfur ylides. Scheme 1. Reaction Modes of Thioaurones and Sulfur Ylides

O Cs2CO3 o

CHCl3, 0 C O R

1

R2

S +  S Br







 

CO2Me

R1

(a)

R2 S R2 = CO2Et, COAr S   two-carbon  synthon  O  CO2Me DIPEA (b) 1 CH2Cl2, rt R 2 R S R2 = Ar

CO2Me

OH Cs2CO3 EtOH, rt

R1

  two-carbon synthon

S



CO2Me  O  (c)

2

R = o-C6H4OH

RESULTS AND DISCUSSION We investigated the reaction between ethyl (Z)-2-(3-oxobenzo[b]thiophen-2(3H)-ylidene)acetate 3



and crotonate-derived sulfur ylides and

Page 4 of 48

selected 1a and 2a as model substrates (Table 1). The

reaction was performed in toluene with Table 1. Optimization of the Domino Reactiona O

O +

S

CO2Et

S

base solvent, t

CO2Me CO2Et

S

Br

1a

aUnless

CO2Me

3a

2a

entry

solvent

base

t/oC

time

yieldb/%

1

toluene

Cs2CO3

25

1.5 h

11

2

THF

Cs2CO3

25

10 min

29

3

MeOH

Cs2CO3

25

1.5 h

0

4

EtOH

Cs2CO3

25

1.5 h

0

5

CH2Cl2

Cs2CO3

25

30 min

57

6

CHCl3

Cs2CO3

25

10 min

85

7

CH3CN

Cs2CO3

25

20 min

63

8

DMSO

Cs2CO3

25

10 min

26

9

DMF

Cs2CO3

25

10 min

40

10

CHCl3

Na2CO3

25

4h

44

11

CHCl3

K2CO3

25

2h

54

12

CHCl3

NaOH

25

20 min

63

13

CHCl3

EtONa

25

2h

56

14

CHCl3

NaH

25

1h

46

15

CHCl3

DABCO

25

1.5 h

67

16

CHCl3

DBU

25

1h

59

17

CHCl3

DMAP

25

1.5 h

70

18c

CHCl3

Cs2CO3

25

2h

82

19d

CHCl3

Cs2CO3

25

2h

77

20e

CHCl3

Cs2CO3

0

4h

96

21f

CHCl3

Cs2CO3

-15

6.5 h

80

22g

CHCl3

Cs2CO3

61

9.5 h

13

otherwise noted, reactions of 1a (0.2 mmol) with 2a (0.3 mmol) were carried out in the

presence of a base (2.5 equiv.) in 2 mL solvent at 25 oC. bIsolated yields. c3.0 equiv Cs2CO3 was used. d2.0

equiv Cs2CO3 was used. eReaction temperature is 0 oC. fReaction temperature is -15 oC. gReaction 4


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temperature is 61 oC. Cs2CO3 as the base at 25 oC (entry 1). In the reaction, [4+2] annulation occurred and a benzothiophene fused derivative 3a was produced in 11% yield. The structure of 3a was confirmed using NMR, HRMS and X-ray crystallography.34 The reaction conditions were optimized to improve the product yield. The solvent was the first element that underwent optimization. When the reaction was carried out in a polar solvent, THF, the yield improved to 29% (entry 2). However, in an protic solvent, e.g. MeOH or EtOH, no product formed (entries 3 and 4). Only moderate yield was generated when CH2Cl2 was used as the solvent (entry 5). To our surprise, the yield was improved to 85% in CHCl3 (entry 6). Several other solvents, e.g. CH3CN, DMSO and DMF were tested, each of which gave unsuccessful results (entries 7-9). After the solvent was optimized, the base was investigated. Weak inorganic bases Na2CO3 and K2CO3 showed moderate reactivity, producing 3a in yields of 44% and 54%, respectively (entries 10 and 11). No improvement was observed with the application of stronger bases (i.e. NaOH, EtONa and NaH) (entries 12-14). Tertiary amines were also studied, and were found to produce similar yields to that using Cs2CO3 (entries 15-17). Finally, the amount of base and the reaction temperature were investigated. Increasing or decreasing the amount of Cs2CO3 gave no improvement in the product yield (entries 18 and 19). However, the yield of 3a significantly increased when the reaction was carried out at 0 oC (entry 20). Using the optimized conditions, the scope of 1 was studied, the results for which are shown in Table 2. The effect of the ester group was explored. 5-CH3-substituted substrates containing methyl (1a) and ethyl ester (1b) produced excellent yields (entries 1 and 2). In contrast, substrates containing bulky

5



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ester groups (1c and 1d) gave moderate yields (entries 3 and 4). For non-substituted substrates (1e-1g), similar results were obtained (entries 5-7). Halogen substituents at position C5 of 1 were also investigated, and produced 3h, 3i and 3j in 83-98% yields (entries 8-10). In addition, the C7 chloro-substituted substrate 1k was tested, in which the desired product 3k was produced in 81% yield (entry 11). Substrate 1 containing benzoyl groups was also studied, the results of which are displayed in Table 3. Electron-neutral (1l) and electron-donating (1m) substituents on the benzoyl ring facilitated the domino reaction, and the corresponding products 4a and 4b were produced in yields of 84% and 98%, respectively (entries 1 and 2). Substrate 1 containing chloro, bromo, and fluoro substituents, particularly at the ortho position of thebenzoyl ring, produced 4c-4f in excellent yields (entries 3-6). When a methoxyl group was substituted at the C6 position (R1) (1r), the corresponding product 4g was generated in 93% yield (entry 7). The structure of 4e was confirmed by X-ray crystal structure.34

Table 2. Substrates Scope of Product 3a O R

O

1

S

R2

+

S

CO2Me

Br

1

Cs2CO3

R CHCl3, 0 C o

CO2Me

1

R2

S 3

2a

entry

R1

R2

time/h

yieldb/%

1

5-CH3 (1a)

CO2Et

4

96 (3a)

2

5-CH3 (1b)

CO2Me

2

98 (3b)

3

5-CH3 (1c)

CO2Bn

1.5

78 (3c)

4

5-CH3 (1d)

CO2tBu

1

75 (3d)

5

H (1e)

CO2Me

2.5

84 (3e)

6

H (1f)

CO2Et

2.5

98 (3f)

7

H (1g)

CO2Bn

2.5

95 (3g)

6


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aReaction

bIsolated

8

5-F (1h)

CO2Et

2.5

83 (3h)

9

5-Cl (1i)

CO2Et

3.5

92 (3i)

10

5-Br (1j)

CO2Et

2.5

98 (3j)

11

7-Cl (1k)

CO2Et

2

81 (3k)

conducted on a 0.4 mmol scale of 1 in 4 mL of CHCl3 (molar ratio of 1/2a/Cs2CO3 is 1:1.5:2.5).

yields.

Table 3. Substrates Scope of Product 4a O

O

R1

+

S 1

aReaction

bIsolated

O

R2

S

CO2Me

Br

Cs2CO3 o

CHCl3, 0 C

R

CO2Me

1

S 4

2a

O

R2

entry

R1

R2

time/h

yieldb/%

1

5-CH3 (1l)

H

2

84 (4a)

2

5-CH3 (1m)

4-CH3

2

98 (4b)

3

5-CH3 (1n)

4-Cl

1

98 (4c)

4

5-CH3 (1o)

4-F

3

95 (4d)

5

5-CH3 (1p)

3-Br

2

98 (4e)

6

5-CH3 (1q)

2-Cl

2.5

89 (4f)

7

6-CH3O (1r)

H

1.5

93 (4g)

conducted on a 0.4 mmol scale of 1 in 4 mL of CHCl3 (molar ratio of 1/2a/Cs2CO3 is 1:1.5:2.5).

yields.

During optimization reaction conditions of the [4+3] annulation reaction of crotonate-derived sulfur ylides with thioaurones,29 we found that when the organic base DABCO was used, another two new products were formed besides the desired [4+3] product after prolonging the reaction time. We carefully purified them and carried out the NMR spectra. To our delight, another new [4+2] annulation occurred, and the products bearing a sulfide moiety (Table 4). We also optimized the reaction

7



Page 8 of 48

conditions via changing the solvent, base and the ratio of the starting materials. Ultimately, the best reaction condition used DIPEA as base in CH2Cl2, with good diastereoselectivity and moderate yields (details see supporting information, Table S1). With the best reaction conditions in hand, the substrates scope of the domino reaction was studied, and the results were shown in Table 4. C5 chloro substituents on the blue benzene ring of 5 were first examined. Electron-neutral (5a) and electrondonating (5b) substituents on the red benzene ring facilitated the domino reaction, and the desired products were obtained in 61% and 63% yields, with 7:1 and 9:1 diastereomeric ratio, respectively (entries 1 and 2). When a chloro was installed at C4 position of the red benzene ring, the reaction proceeded well and the desired product was obtained in 56% yield with 8:1 diastereomericratio (entry 3). The reaction was readily applicable to 3-OCH3 (red benzene) substituted substrate (5d), providing the desired products in 63% yields with 8:1 diastereomeric ratio (entry 4).

The efficiency of the

domino reaction was significantly affected by steric hindrance, only 32% expected product was obtained with 1:1 diastereomeric ratio (entry 5). As expected, the reaction of 2-thienyl substituted 5f also worked well, affording the desired product 6f and 7f in total 45% yield with 5:1 diastereomeric ratio (entry 6). Furthermore, C5 bromo-substituted on the blue benzene ring substrates were also used in the domino reaction. The desired products were obtained in 58% and 51% yields with10:1 and 5:1 diastereomeric ratio, Table 4. Substrates Scope of EtNiPr2 Promoted Reactiona S H O

O R1 S

5

+ R2

S

CO2Me

EtNiPr2

H CO2Me +

R1

CH2Cl2, rt

S

Br 2a

S H O

6

8


R1 S

H R

2

H CO2Me

H 7

R2

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entry

R1

R2

time/d

yield/%b

dr./(6/7)c

1

5-Cl (5a)

H

2

61

7:1 (6a:7a)

2

5-Cl (5b)

4-CH3

10

63

9:1 (6b:7b)

3

5-Cl (5c)

4-Cl

10

56

8:1 (6c:7c)

4

5-Cl (5d)

3-CH3O

12

63

8:1 (6d:7d)

5

5-Cl (5e)

2-Cl

12

32

1:1 (6e:7e)

6

5-Cl (5f)

2-thienyl

10

45

5:1 (6f:7f)

7

5-Br (5g)

4-CH3

10

58

10:1 (6g:7g)

8

5-Br (5h)

4-Br

16

51

5:1 (6h:7h)

9

5-F (5i)

H

12

96

8:1 (6i:7i)

10

5-F (5j)

4-CH3

4

63

8:1 (6j:7j)

11

5-CH3 (5k)

H

5

57

7:1 (6k:7k)

12

7-Cl (5l)

H

7

65

7:1 (6l:7l)

aReaction

bIsolated

conducted on a 0.3 mmol scale of 5 in 4 mL of CH2Cl2 (molar ratio of 5/2a/EtNiPr2 is 1:3.5:4).

yields 6 and 7. cThe ratios of 6/7 is determined by crude 1H NMR spectra.

respectively (entries 7 and 8). It is important to note that the tolerance of the bromo-group on the blue and red benzene ring was especially synthetically useful and this provides an opportunity for further functionalization. In addition, blue benzene ring of 5i and 5j bearing fluoro substituent reacted smoothly and provided the corresponding products in 96% and 63% yield with 8:1 diastereomeric ratio (entries 9 and 10). Electron-donating group also was installed at blue benzene ring of 5k and afforded the desired product 6k and 7k in total 57% yield with 7:1 diastereomeric ratio (entry 11). The C7 chloro-substituted (blue benzene) substrate (5l) also reacted with 2a to produce the corresponding products in 65% yield with 7:1 diastereomeric ratio (entry 12). The structures of 6e and 7j were confirmed by X-ray crystal structure.34 Inspired by our previous work,31 the thioaurones bearing an OH group at the ortho position also

9



reacted with the crotonate-derived sulfur ylide. In this experiment, a new vinylcyclopropane rearrangement domino reaction took place, yielding a 3-benzothiophene-substituted chromene. Importantly, the crotonate-derived sulfur ylide acts as another type two-carbon synthon in this process (β and γ carbons). The reaction conditions were then optimized as the following (see supporting information for details, Table S2): thioaurone (1.0 equiv), sulfur ylide (1.5 equiv), and Cs2CO3 (2.5 equiv) as the base in EtOH at room temperature (entry 1). Different substrates were also explored, the results of which are summarized in Table 5. The substitution of R2 was first examined when R1 is a chloride atom at the C-5 position. Both electron-donating and electron-withdrawing groups were screened. When methyl was installed at the C-5 position, the desired product yields were 87% (entry 2). When halogen group was placed in the C-5 position (R2), the desired products 9c was generated in 70% yield, respectively (entry 3). When a bromo group was installed at the C-5 position (R1), the domino reaction reached completion, and the corresponding products (9d-9f) were obtained in 53%-72% yields (entries 4-6). When a fluoride group was substituted at C-5 (R1), the domino reaction generated the corresponding products (9j-9k) in yields of 59%-93% (entries 7-11). Electron-donating R1 groups were also examined, for example, with methyl at the C-5 position, the desired product 9l was obtained in 82% yield (entry 12). The sulfur ylide’s ester group was modified from Et to iPr, producing 9m and 9n were in 75% and 74% yields, respectively. The structure of 9m was determined by X-ray crystal structure.34 Table 5. Substrate Scopes of Product 9a

10


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O R1

OH OH

S 8

Br

Cs2CO3 EtOH, rt

O R1

2b

R1

R2

1

5-Cl (8a)

H

2

5-Cl (8b)

3

S 9

yield/%b

Et

0.5

81 (9a)

5-CH3

Et

0.5

87 (9b)

5-Cl (8c)

5-Br

Et

1.5

70(9c)

4

5-Br (8d)

H

Et

1

53 (9d)

5

5-Br (8e)

5-CH3

Et

0.5

55 (9e)

6

5-Br (8f)

5-Br

Et

0.5

72 (9f)

7

5-F (8g)

H

Et

1

62 (9g)

8

5-F (8h)

5-CH3

Et

1

59 (9h)

9

5-F (8i)

5-Cl

Et

0.5

93 (9i)

10

5-F (8j)

5-Br

Et

1

64 (9j)

11

5-F (8k)

3,5-Br2

Et

0.5

90 (9k)

12

5-CH3 (8l)

5-Cl

Et

1

82 (9l)

H

iPr

0.5

75 (9m)

5-CH3

iPr

1

74(9n)

5-Cl (8a) 5-Br (8e)

R3

R2

time/h

14

bIsolated

R2

CO2R3

S

entry

13

aReaction

+

CO2R3

conducted on a 0.3 mmol scale of 8 in 4 mL of EtOH (molar ratio of 8/2b/Cs2CO3 is 1:1.5:2.5).

yields.

To test the large-scale utility of the Cs2CO3-promoted domino reactions, a gram-scale reaction was performed using 1 g of 1a. The product 3a was produced in a yield of 98% under the optimized reaction conditions. Furthermore, a gram-scale reaction of 8a (1g) and 2b also was performed, and 9a was obtained in 63% yield. Treatment of 3a with 2.2 equivalents of m-CPBA at room temperature in CH2Cl2 produced compound 10 in 70% yield (Scheme 2). The structure of 10 was determined by X-ray crystal structure.34

Scheme 2. Transformation of 3a 11



O

m-CPBA (2.2 equiv)

CO2Me

O

CH2Cl2, rt

CO2Et

S

Page 12 of 48

CO2Me

CO2Et S O O 10, 70%

3a

Scheme 3. Proposed Mechanism of Formation of 3 and 6 S Br

CO2Me 2a

S

S

S Cs2CO3

O

O

CO2Me

S

A

CO2Me

CO2Me

CO2Me

1a or 5a S

B

S D

R C

R

S

S O

S

CO2Me CO2Me

H

O base S

O

CO2Me CO2Me

CO2Me CO2Me

S

G

O

proton transfer R = CO2Me

CO2Me R

S E

F

R = Ph S

S O

S

O

O

CO2Me CO2Me

S

3a

CO2Me Ph

6 and 7

Br -MeBr

S

CO2Me Ph

I

Although the full mechanistic details of the two-carbon synthon domino reactions require further investigation, we propose two possible mechanisms based on our experimental results (Scheme 3 and 4). Deprotonation of the crotonate-derived sulfonium salt 2a by Cs2CO3 produces intermediate A, which is in resonance with intermediate B. Subsequently, α- addition of intermediate B to 1a generates intermediate C. Intermediate D, which is the resonance structure of C, transforms into intermediate E via an intramolecular O-Michael addition. When the esters or ketones group were placed on the double bond (blue path), intermediate F was formed via proton transfer. Releasing a Me2S moiety produces three-membered intermediate G, which subsequently transforms into 3a via intermediate H. On the other hand, when Ar groups were installed on the double bond (red path),

12


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intermediate E abstracts a proton from solvent to give intermediate I. The methyl group of the Me2S sulfonium would be attacked by Br- to yield the product 6 and 7. Scheme 4. Proposed Mechanism of Formation of 9 CO2Et

S Br

Cs2CO3

CO2Et 2b

Cl

Cl

CO2Et

S

O

CO2Et OH

-Me2S

O

Cl

OH

S

A'

O

S

S C'

B'

OH S 5a

CO2Et CO2Et

O

Cl

O

Cl

tautomerization

O S

S

OH

G'

Cl

OH

E'

CO2Et O

S

proton transfer

O

S

F'

Cl

CO2Et

O

proton transfer

Cl

OH

D'

CO2Et O

S

Cl

OH

CO2Et O

S H'

9a

A

mechanism for the domino reaction of formation of 9 was also proposed (Scheme 4). The crotonate-derived sulfonium salt 2b was treated with Cs2CO3 to give allylic ylide A. Subsequently, Michael addition of A to 8a generates intermediate B. Intermediate B is subsequently transformed into three-membered intermediate C via intramolecular SN2 nucleophilic substitution. Then Cs2CO3 promotes selective cleavage of the C-C bond of the cyclopropane framework in C to form the ion-pair D. Afterward, intermediate E forms via proton transfer. Next, intermediate E undergoes intramolecular O-Michael addition to afford F, which transforms into intermediate G via keto-enol tautomerization. Then intermediate Hforms via another proton transfer process. Finally, product 9a

13



forms from intermediate H. Figure 2 depicts the proposed reaction mechanisms of 3 using DFT calculations. Geometrical optimizations were carried out at the B3LYP/6-31+G* level of theory and single point computations were carried out at the M062x/6-311+G* level of theory (see Supporting Information for computational details). The ylide 2a is generated in situ from the treatment of the corresponding sulfonium precursor with Cs2CO3. Initially, 2a binds with 1e by nucleophilic addition, passing through the transition state TS-1 to form the intermediate INT-1. For this step, the compound is required to overcome a free-energy barrier of 13.6 kcal/mol and absorb

O

S

CO2Me

O

H

O

CO2Me

S

O

O

TS-3

S

TS-2

O

S

Cs TS-4

S

13.6 TS-1

S

S H CO2Me

CO2Me

O O

CO2Me

4.3 INT-1

Cs

1a

O

+

TS-4'

S(CH3)2

CO2Me

CO2Me

S

-35.3 INT-5

-46.5 6/7

S

S O S

S

INT-3 CO2Me CO2Me

O S

CsCO3 CO2Me CO2Me

S

INT-4

S

3 Prodcut

S

CO2Me CO2Me

O

CO2Me CO2Me

S O

INT-5

O

Cs2CO3

-40.3 3

-41.1 INT-6

O

CO2Me

INT-2

-24.2 TS-7

6/7 Byproduct

CO2Me CO2Me

CO2Me CO2Me

S

-26.3 TS-6

Br

O

TS-7

H

Cs2CO3

CsCO 3

S

Cs O

O

CH3Br

O

S

2.2 INT-4

-1.0 INT-3

O O

16.4 CsHCO3 TS-4 8.9 TS-5

CO2Me

S 2a

-0.3 INT-2

Cs TS-6 O

Cs

-

9.5 CsHCO 3 TS-2 5.0 TS-3

0.0 Reactants 1+2

S

S

Br

CO2Me CO2Me

INT-1

O

24.0 TS-4'

O S

CO2Me

S

TS-5

CO2Me

S

CO2Me

Cs

O H CO2Me

O

CO2Me

O

S

TS-1

Gibbs Free-energies in kcal/mol

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

Page 14 of 48

O S

14


S

CO2Me CO2Me

INT-6

CO2Me CO2Me

CO2Me CO2Me Cs2HCO3

Page 15 of 48 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


Figure 2. Proposed mechanisms and free-energy profiles for the reaction 1 + 2a, determined at the M062x/6-311+G*//B3LYP/6-31+G* level of theory. free-energies by 4.3 kcal/mol. Following this, the carbonyl oxygen attacks the olefinic carbon adjacent to the ester group to generate a six-member-ring framework. This involves the low-lying transition state TS-2, leading to the intermediate INT-2. A molecule of CsHCO3 protonates the carbanion center in INT-2 via the proton-transfer transition state TS-3, subsequently relaxing to the ion-pair. This step has a free-energy barrier of only 5.3 kcal/mol, which is indicative of a kinetically facile proton-transfer process. Then the [CsCO3]− moiety could abstract the proton on the adjacent carbon center to form the 1,4-dipole structure INT-4, involving a free-energy barrier of 17.4 kcal/mol. The next step, INT-4 → INT-5, is an intramolecular substitution process, which forms a three-member ring and expels S(CH3)2. A total free-energy of 37.7 kcal/mol is liberated during the loss of Me2S, since the dipolar structure becomes a neutral structure. The next step, INT-5 → INT-6, is a proton-abstraction process with the help of Cs2CO3, which forms an ion-pair intermediate bearing a [Cs2HCO3]+ cationic moiety. The final step is the cleavage of a C−C bond in the three-member ring, which is accompanied by the protonation and rearrangement of the double-bond. This step yields the desired product with a free-energy barrier of 16.9 kcal/mol that is readily accessible at the temperature of 273 K. The first step via TS-1 should be able to control the orientation of two CO2Me groups in 6a/7a, although 6a and 7a were not the main products. The bond-formation between two sp2-hybrid carbon centers would result in the trans orientation of two CO2Me groups in INT-1. Since the trans conformer 15



is more stable than the cis conformer, such an orientation can be frozen by the formation of the cyclic structure. This can be used to rationalize the trans orientation of CO2Me and Ph observed in the main products of the 5a reaction system. The previous experiments demonstrated that use of 1a and 5a as reactant materials resulted in the different main products. To understand the different selectivity results between 1a and 5a, further DFT calculations have been performed at the same level of theory. The destiny of the intermediate INT-3 (see Figure 2) appears to dictate the direction of the main reaction, in that proton-transfer from INT-3 via TS-4 should make the reaction proceed along the pathway leading to 3a while nucleophilic attack by Br via TS-4’ could furnish 6a/7a. For the compound 1a system, TS-4 has a free-energy barrier of 17.4 kcal/mol and TS-4 has a higher free-energy barrier of up to 25.0 kcal/mol, and hence the production of 3a is mainly a result of the kinetic discrimination. For the compound 5a system, the free-energy barrier associated with TS-4 increases to 23.3 kcal/mol. We found that the proton-acceptor Cs2CO3 could form the Cs···O attractive interaction with the CO2Me groups, which can stabilize the TS-4 transition structure. In contrast, the Ph group in 5a would cause the steric repulsion, as reflected by the structural arrangements of TS-4 (see Supporting Information for three-dimensional graphs). If a large amine is used as the base, the proton-transfer transition state for the 5a system becomes quite congested, which might further disfavor the proton-transfer and result in the formation of 6a/7a. CONCLUSION In summary, two novel reaction modes, two-carbon synthon, of crotonate-derived sulfur ylide were

16


Page 16 of 48

Page 17 of 48 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


developed and successfully applied to the preparation of benzothiophene derivatives. By adjustment the structure of the thioaurones, the crotonate-derived sulfur ylide could act as α and β carbons or β and γ carbons synthon, which never reported before. These investigations nicely complement and expand previous studied reactions of crotonate-derived sulfur ylides. EXPERIMENTAL SECTION General Information. Unless otherwise stated, all reactions were performed under Ar atmosphere in oven-dried glassware with magnetic stirring, all reagents were purchased from commercial suppliers (Aldrich, TCI or Alfa Aesar) and used without further purification. All solvents were purified and dried according to standard methods prior to use. TLC monitored all reactions with silica gel-coated plates. Flash column chromatography was performed using 200-300 mesh silica gel. 1H- and 13C-NMR

spectrum was recorded at ambient temperature on Bruker 400 instruments. All spectra were

referenced to CDCl3 (1H δ 7.26 ppm and 13C NMR δ 77.00 ppm) and DMSO-d6 (1H δ 2.50 ppm and 13C

NMR δ 39.52 ppm). HRMS were obtained on Waters Xevo Q-TOF MS with ESI resource.

Melting points were measured on a RY-I apparatus and were reported uncorrected. Starting materials 1, 5, and 8 were synthesized according to literature.28, 29, 31 General procedure for 3 and 4 3a as an example, under Ar atmosphere, to a CHCl3 (4 mL) solution of 1a (100 mg, 0.40 mmol) was added 2a (146 mg, 0.60 mmol) and Cs2CO3 (328.0 mg, 1.0 mmol). The resulting mixture was stirred for 4 h at 0 oC. After the reaction completed (monitored by TLC), the reaction was then quenched by NH4Cl solution and extracted with CH2Cl2. The organic layer was separated and washed with water, 17



Page 18 of 48

then the CH2Cl2 layer was dried over MgSO4, filtered and concentrated in reduced pressure. The crude product was purified by chromatography (ethyl acetate: petroleum ether = 1:10) to give the pure 3a. General procedure for 6 and 7 6a as an example, under Ar atmosphere, to a CH2Cl2 (4 mL) solution of 5a (76.4 mg, 0.3 mmol) was added 2a (236 mg, 1.05 mmol) and DIPEA (145 mg, 1.2 mmol). The resulting mixture was stirred for 2d at room temperature. After the reaction completed (monitored by TLC), the solvent was removed under reduced pressure and the residue was purified by chromatography (ethyl acetate: petroleum ether = 1:20) to give the pure 6a (67 mg, 53%) and 7a (10 mg, 8%). General procedure for 9 9a as an example, under Ar atmosphere, to a EtOH (4 mL) solution of 5a (100 mg, 0.3 mmol) was added 2b (133mg, 0.5 mmol) and Cs2CO3 (282mg, 0.8 mmol). The resulting mixture was stirred for 1 h at room temperature. After the reaction completed (monitored by TLC), the solvent was removed under reduced pressure and the residue was extracted with CH2Cl2. The organic layer was separated and washed with water, then the CH2Cl2 layer was dried over MgSO4, filtered and concentrated in reduced pressure. The crude product was purified by chromatography (ethyl acetate: petroleum ether = 1:5) to give the pure 6a (81%). (Z)-2-(2-(4-chlorophenyl)-2-oxoethylidene)-5-methylbenzo[b]thiophen-3(2H)-one (1n): red solid: 60 mg (Yield 63%); mp: 195-196 °C; IR(KBr): 1685, 1632, 1592, 1471, 1400 cm-1; 1H NMR (400 MHz, CDCl3) δ = 8.08 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.70 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.43 (dd, J = 8.0, 0.2 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 2.40 (s, 3H) ppm;

18


13C{1H}

NMR (100 MHz,

Page 19 of 48 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


CDCl3) δ = 189.4, 188.0, 148.6, 145.6, 140.1, 137.7, 136.6, 135.7, 129.8, 129.2, 129.0, 127.5, 124.2, 118.0, 20.8 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H12ClO2S 315.0241; Found 315.0249. (Z)-2-(2-(3-bromophenyl)-2-oxoethylidene)-5-methylbenzo[b]thiophen-3(2H)-one (1p): red solid: 59 mg Yield 54%; mp: 230-231 °C; IR(KBr): 1686, 1634, 1605, 1472 cm-1; 1H NMR (400 MHz, CDCl3) δ = 8.24 (t, J = 1.6 Hz, 1H), 8.07 (s, 1H), 8.03 (dt, J = 7.6, 1.2 Hz, 1H), 7.68 – 7.80 (m, 2H), 7.35 – 7.48 (m, 3H), 2.41 (s, 3H) ppm; A reasonable

13C

NMR spectrum could not be obtained

because of its quit low solubility; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H12O2SBr 360.9715; Found 360.9718. (Z)-2-(2-(2-chlorophenyl)-2-oxoethylidene)-5-methylbenzo[b]thiophen-3(2H)-one (1q): red solid: 78 mg (Yield 82%); mp: 142-144 °C; IR(KBr): 1696, 1641, 1596, 1471 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.90 (s, 1H), 7.69 (s, 1H), 7.63 – 7.68 (m, 1H), 7.44 – 7.51 (m, 2H), 7.41 – 7.44 (m, 1H), 7.35 – 7.40 (m, 2H), 2.39 (s, 3H) ppm;

13C{1H}

NMR (100 MHz, CDCl3) δ = 191.1, 189.3, 147.3,

145.4, 138.2, 137.6, 136.6, 132.6, 132.0, 130.7, 130.2, 129.0, 127.4, 127.1, 124.2, 122.0, 20.8 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H12O2SCl 315.0241; Found 315.0251. 4-ethyl 3-methyl 2,8-dimethyl-2H-benzo[4,5]thieno[3,2-b]pyran-3,4-dicarboxylate (3a): yellow solid: 133 mg (yield 96%); mp: 70-72 °C; IR(KBr): 1714, 1615, 1522, 1447, 1394, 1261, 1227, 1132, 1035 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.60 (d, J = 8.4 Hz, 1H), 7.54 – 7.58 (m, 1H), 7.22 (dd, J = 8.2, 1.4 Hz, 1H), 5.62 (q, J = 6.5 Hz, 1H), 4.41 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 2.46 (s, 3H), 1.47 (d, J = 6.4 Hz, 3H), 1.40 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 165.6, 164.3, 19



Page 20 of 48

148.5, 136.9, 134.6, 133.0, 130.2, 128.9, 122.7, 121.3, 118.7, 110.4, 73.0, 62.1, 52.2, 21.3, 18.0, 14.1 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H18O5SNa 369.0767; Found 369.0784. Dimethyl 2,8-dimethyl-2H-benzo[4,5]thieno[3,2-b]pyran-3,4-dicarboxylate (3b): yellow solid: 130 mg (yield 98%); mp: 95-96 °C; IR(KBr): 1712, 1613, 1522, 1434, 1376, 1260, 1230, 1053, 1036 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.60 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.22 (dd, J = 8.4, 1.2 Hz, 1H), 5.63 (q, J = 6.5 Hz, 1H), 3.93 (s, 3H), 3.81 (s, 3H), 2.46 (s, 3H), 1.47 (d, J = 6.6 Hz, 3H) ppm; 13C{1H}

NMR (100 MHz, CDCl3) δ = 166.2, 164.3, 148.6, 137.0, 134.7, 132.9, 130.3, 129.0, 122.7,

121.3, 118.9, 110.3, 73.1, 52.8, 52.3, 21.3, 18.0 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C17H16O5SNa 355.0611; Found 355.0618. 4-benzyl 3-methyl 2,8-dimethyl-2H-benzo[4,5]thieno[3,2-b]pyran-3,4-dicarboxylate (3c): yellow solid: 127 mg (yield 78%); mp: 82-83 °C; IR(KBr): 1739, 1703, 1604, 1515, 1434, 1382, 1348, 1278, 1220, 1187, 1139, 1036 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.60 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.43 – 7.50 (m, 2H), 7.33 – 7.42 (m, 3H), 7.22 (d, J = 8.4 Hz, 1H), 5.62 (q, J = 6.5 Hz, 1H), 5.37 (q, J = 8.9 Hz, 2H), 3.61 (s, 3H), 2.46 (s, 3H), 1.46 (d, J = 6.6 Hz, 3H) ppm;

13C{1H}

NMR (100 MHz,

CDCl3) δ = 165.51, 164.29, 148.55, 136.98, 134.93, 134.62, 132.46, 130.23, 128.90, 128.86, 128.58, 128.57, 122.71, 121.27, 119.09, 110.29, 73.09, 67.86, 52.06, 21.29, 17.97 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C23H20O5SNa 431.0924; Found 431.0940. 4-(tert-butyl) 3-methyl 2,8-dimethyl-2H-benzo[4,5]thieno[3,2-b]pyran-3,4-dicarboxylate (3d): yellow solid: 112 mg (yield 75%); mp: 95-96 °C; IR(KBr): 1733, 1697, 1609, 1519, 1434, 1386, 1368, 1347, 1279, 1234, 1159, 1080 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.61 (d, J = 8.4 Hz, 1H), 20


Page 21 of 48 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


7.56 (s, 1H), 7.22 (dd, J =8.4, 0.8 Hz, 1H), 5.62 (q, J = 6.5 Hz, 1H), 3.81 (s, 3H), 2.46 (s, 3H), 1.61 (s, 9H), 1.46 (d, J = 6.8 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 164.5, 164.4, 148.5, 136.9, 134.5, 133.9, 130.3, 128.7, 122.6, 121.2, 117.6, 110.7, 83.6, 73.1, 52.0, 28.0, 21.3, 18.0 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H22O5SNa 397.1080; Found 397.1089. Dimethyl 2-methyl-2H-benzo[4,5]thieno[3,2-b]pyran-3,4-dicarboxylate (3e): yellow solid: 112 mg (yield 84%); mp: 85-86 °C; IR(KBr): 1737, 1711, 1595, 1510, 1446, 1436, 1367, 1272, 1231, 1131, 1054 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.70 – 7.80 (m, 2H), 7.34 – 7.43 (m, 2H), 5.64 (q, J = 6.7 Hz, 1H), 3.94 (s, 3H), 3.82 (s, 3H), 1.48 (d, J = 6.4 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 166.1, 164.3, 148.9, 139.6, 132.6, 130.0, 127.1, 124.7, 123.1, 121.5, 119.3, 110.0, 73.1, 52.9, 52.3, 18.0 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C16H14O5SNa 341.0454;Found 341.0469. 4-ethyl 3-methyl 2-methyl-2H-benzo[4,5]thieno[3,2-b]pyran-3,4-dicarboxylate (3f): yellow solid: 130 mg (yield 98%); mp: 57-58 °C; IR(KBr): 1728, 1709, 1610, 1593, 1514, 1445, 1433, 1373, 1261, 1233, 1056, 1017 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.69 – 7.80 (m, 2H), 7.34 – 7.43 (m, 2H), 5.64 (q, J = 6.7 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H), 1.40 (t, J = 7.0 Hz, 3H) ppm;

13C{1H}

NMR (100 MHz, CDCl3) δ = 165.5, 164.4, 148.8, 139.6, 132.6, 130.0,

127.0, 124.6, 123.0, 121.5, 119.2, 110.2, 73.1, 62.2, 52.2, 18.0, 14.1 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C17H16O5SNa 355.0611; Found 355.0632. 4-benzyl 3-methyl 2-methyl-2H-benzo[4,5]thieno[3,2-b]pyran-3,4-dicarboxylate (3g): yellow solid: 150 mg (yield 95%); mp: 89-90 °C; IR(KBr): 1742, 1705, 1609, 1276, 1137, 1076 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.68 – 7.81 (m, 2H), 7.33 – 7.49 (m, 7H), 5.63 (q, J = 6.7 Hz, 1H), 5.33 21



– 5.42 (m, 2H), 3.62 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H) ppm;

13C{1H}

Page 22 of 48

NMR (100 MHz, CDCl3) δ =

165.4, 164.3, 148.8, 139.6, 134.9, 132.1, 130.0, 128.9, 128.6, 128.6, 127.0, 124.6, 123.1, 121.5, 119.7, 110.1, 73.2, 67.9, 52.1, 18.0 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H19O5S 395.0948; Found 395.0944. 4-ethyl 3-methyl 8-fluoro-2-methyl-2H-benzo[4,5]thieno[3,2-b]pyran-3,4-dicarboxylate (3h): yellow solid: 116 mg (yield 83%); mp: 76-77 °C; 1H NMR (400 MHz, CDCl3) δ = 7.65 (dd, J = 8.8, 4.8 Hz, 1H), 7.41 (dd, J = 8.8, 2.4 Hz, 1H), 7.14 (td, J = 8.8, 2.4 Hz, 1H), 5.61 (q, J = 6.7 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 1.48 (d, J = 6.4 Hz, 3H), 1.40 (t, J = 7.0 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 165.1, 164.4, 160.8 (d, J = 244.0 Hz), 147.9 (d, J = 4.5 Hz), 134.8 (d, J = 1.4 Hz), 131.7, 131.0 (d, J = 9.5 Hz), 124.3 (d, J = 9.0 Hz), 120.9, 115.9 (d, J = 25.4 Hz), 112.4, 107.0 (d, J = 23.9 Hz), 73.3, 62.2, 52.3, 18.0, 14.0 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C17H15O5SFNa 373.0516; Found 373.0520. 4-ethyl 3-methyl 8-chloro-2-methyl-2H-benzo[4,5]thieno[3,2-b]pyran-3,4-dicarboxylate (3i): yellow solid: 135 mg (yield 92%); mp: 139-141°C; IR(KBr): 1716, 1614, 1517, 1446, 1383, 1261, 1222, 1079, 1035 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.73 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.33 (dd, J = 8.8, 2.0 Hz, 1H), 5.61 (q, J = 6.7 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H), 1.39 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 165.1, 164.4, 147.5, 137.5, 131.4, 131.14, 131.08, 127.3, 124.1, 121.2, 121.0, 111.9, 73.4, 62.3, 52.3, 18.1, 14.1 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H16O5SCl 367.0401; Found 367.0399. 4-ethyl 3-methyl 8-bromo-2-methyl-2H-benzo[4,5]thieno[3,2-b]pyran-3,4-dicarboxylate (3j):

22


Page 23 of 48 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


yellow solid: 161 mg (yield 98%); mp: 99-100 °C; IR(KBr): 1715, 1614, 1515, 1444, 1434, 1381, 1262, 1222, 1133, 1066 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.90 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 8.6, 1.8 Hz, 1H), 5.60 (q, J = 6.7 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H), 1.39 (t, J = 7.0 Hz, 3H) ppm;

13C{1H}

NMR (100 MHz, CDCl3) δ =

165.1, 164.4, 147.4, 138.0, 131.5, 131.4, 129.8, 124.3, 124.1, 121.3, 118.7, 111.7, 73.4, 62.3, 52.3, 18.0, 14.1 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C17H15O5SBrNa 432.9716; Found 432.9728. 4-ethyl 3-methyl 6-chloro-2-methyl-2H-benzo[4,5]thieno[3,2-b]pyran-3,4-dicarboxylate (3k): yellow solid: 119 mg (yield 81%); mp: 112-113 °C; IR(KBr): 1728, 1715, 1609, 1513, 1461, 1435, 1413, 1388, 1374, 1272, 1235, 1154, 1135, 1039 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.67 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 5.61 (q, J = 6.7 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 1.48 (d, J = 6.4 Hz, 3H), 1.41 (t, J = 7.2 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 165.1, 164.4, 148.6, 138.4, 131.6, 131.5, 128.4, 126.4, 125.9, 121.1, 119.8, 111.4, 73.4, 62.3, 52.3, 18.0, 14.1 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H16O5SCl 367.0401; Found 367.0406. Methyl

4-benzoyl-2,8-dimethyl-2H-benzo[4,5]thieno[3,2-b]pyran-3-carboxylate

(4a):

yellow

solid: 127 mg (yield 84%); mp: 97-98 °C; IR(KBr): 1710, 1701, 1597, 1517, 1505, 1450, 1384, 1372, 1267, 1231, 1128, 1042 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.89 – 7.98 (m, 2H), 7.63 (s, 1H), 7.51 – 7.60 (m, 2H), 7.45 (t, J = 7.8 Hz, 2H), 7.21 (dd, J = 8.4, 1.2 Hz, 1H), 5.79 (q, J = 6.7 Hz, 1H), 3.53 (s, 3H), 2.47 (s, 3H), 1.56 (d, J = 6.4 Hz, 3H) ppm;

13C{1H}

NMR (100 MHz, CDCl3) δ = 193.7,

23



Page 24 of 48

163.9, 149.0, 140.8, 137.4, 135.2, 134.8, 133.8, 130.3, 129.1, 128.82, 128.78, 122.8, 121.5, 116.3, 111.3, 73.1, 51.8, 21.3, 18.2 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H19O4S 379.0999; Found 379.1012. Methyl 2,8-dimethyl-4-(4-methylbenzoyl)-2H-benzo[4,5]thieno[3,2-b]pyran-3-carboxylate (4b): yellow solid: 154 mg (yield 98%); mp: 116-117 °C; IR(KBr): 1701, 1669, 1603, 1516, 1433, 1382, 1273, 1231, 1137, 1044 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.83 (d, J = 8.0 Hz, 2H), 7.62 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.18 – 7.26 (m, 3H), 5.78 (q, J = 6.5 Hz, 1H), 3.54 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H), 1.56 (d, J = 6.4 Hz, 3H) ppm;

13C{1H}

NMR (100 MHz, CDCl3) δ = 193.3, 163.9, 148.8,

144.8, 140.9, 137.4, 134.7, 132.7, 130.2, 129.5, 129.02, 128.96, 122.8, 121.4, 116.1, 111.4, 73.1, 51.7, 21.7, 21.3, 18.2 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C23H20O4SNa 415.0975; Found 415.0983. Ethyl

4-(4-chlorobenzoyl)-2,8-dimethyl-2H-benzo[4,5]thieno[3,2-b]pyran-3-carboxylate

(4c):

yellow solid: 162 mg (yield 98%); mp: 138-139 °C; IR(KBr): 1699, 1676, 1602, 1583, 1516, 1434, 1382, 1276, 1227, 1088, 1044 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.83 – 7.92 (m, 2H), 7.63 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.38 – 7.47 (m, 2H), 7.22 (dd, J = 8.4, 1.2 Hz 1H), 5.77 (q, J = 6.5 Hz, 1H), 3.57 (s, 3H), 2.47 (s, 3H), 1.55 (d, J = 6.8 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 192.5, 163.8, 149.1, 140.5, 140.3, 137.4, 134.9, 133.6, 130.2, 130.1, 129.3, 129.2, 122.9, 121.5, 116.2, 111.0, 73.1, 51.9, 21.3, 18.1 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H18O4SCl 413.0609; Found 413.0614. Methyl 4-(4-fluorobenzoyl)-2,8-dimethyl-2H-benzo[4,5]thieno[3,2-b]pyran-3-carboxylate (4d):

24


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yellow solid: 151 mg (yield 95%); mp: 105-106 °C; IR(KBr): 1701, 1677, 1596, 1518, 1504, 1435, 1383, 1275, 1232, 1155, 1044 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.89 – 8.02 (m, 2H), 7.63 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.07 – 7.17 (m, 2H), 5.78 (q, J = 6.5 Hz, 1H), 3.57 (s, 3H), 2.47 (s, 3H), 1.56 (d, J = 6.4 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 192.2, 166.1 (d, J = 254.5 Hz), 163.8, 149.1, 140.6, 137.4, 134.8, 131.7 (d, J = 2.9 Hz), 131.5 (d, J = 9.5 Hz), 130.2, 129.2, 122.8, 121.5, 116.2, 116.0 (d, J = 22.0 Hz), 111.1, 73.1, 51.9, 21.3, 18.1 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H17O4SFNa 419.0724; Found 419.0726. Methyl 4-(3-bromobenzoyl)-2,8-dimethyl-2H-benzo[4,5]thieno[3,2-b]pyran-3-carboxylate (4e): yellow solid: 173 mg (yield 98%); mp: 147-148 °C; IR(KBr): 1705, 1674, 1599, 1515, 1471, 1435, 1376, 1270, 1225, 1133, 1040 cm-1; 1H NMR (400 MHz, CDCl3) δ = 8.10 (t, J = 1.8 Hz, 1H), 7.79 (dt, J = 7.7, 1.2 Hz, 1H), 7.69 (ddd, J = 8.1, 1.7, 0.9 Hz, 1H), 7.61 – 7.66 (m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.23 (dd, J = 8.4, 1.2 Hz 1H), 5.78 (q, J = 6.5 Hz, 1H), 3.58 (s, 3H), 2.47 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H) ppm;

13C{1H}

NMR (100 MHz, CDCl3) δ = 192.4, 163.7, 149.2,

140.3, 137.4, 137.0, 136.6, 134.9, 131.3, 130.3, 130.2, 129.3, 127.5, 123.2, 122.9, 121.6, 116.4, 110.9, 73.1, 52.0, 21.3, 18.1 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H18O4SBr 457.0104; Found 457.0112. Methyl4-(2-chlorobenzoyl)-2,8-dimethyl-2H-benzo[4,5]thieno[3,2-b]pyran-3-carboxylate

(4f):

yellow solid: 147 mg (yield 89%); mp: 89-90°C; IR(KBr): 1704, 1678, 1588, 1511, 1470, 1384, 1270, 1227, 1133, 1066 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.70 (dd, J = 7.6, 1.4 Hz, 1H), 7.61 – 7.64 (m, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 8.0, 1.2 Hz, 1H), 7.43 (td, J = 7.6, 1.6 Hz, 1H), 7.27 –

25



Page 26 of 48

7.31 (m, 1H), 7.23 (dd, J = 8.2, 1.4 Hz, 1H), 5.73 (q, J = 6.7 Hz, 1H), 3.57 (s, 3H), 2.48 (s, 3H), 1.51 (d, J = 6.8 Hz, 3H) ppm;

13C{1H}

NMR (100 MHz, CDCl3) δ = 192.2, 164.0, 149.1, 141.0, 137.5,

134.8, 134.6, 133.7, 133.3, 131.8, 131.6, 130.3, 129.1, 126.7, 122.9, 121.5, 116.6, 111.5, 73.2, 52.1, 21.4, 17.8 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H17O4SClNa 435.0428; Found 435.0423. Methyl

4-benzoyl-7-methoxy-2-methyl-2H-benzo[4,5]thieno[3,2-b]pyran-3-carboxylate

(4g):

yellow solid: 147 mg (yield 93%); mp: 136-137 °C; IR(KBr): 1704, 1673, 1594, 1498, 1450, 1393, 1351, 1317, 1279, 1263, 1244, 1226, 1139, 1044 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.93 (d, J = 7.2 Hz, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 7.09 (d, J = 2.4 Hz, 1H), 7.00 (dd, J = 8.8, 2.0 Hz, 1H), 5.78 (q, J = 6.5 Hz, 1H), 3.84 (s, 3H), 3.52 (s, 3H), 1.56 (d, J = 6.4 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 193.9, 163.9, 159.7, 149.5, 142.2, 140.9, 135.3, 133.7, 128.8, 128.7, 123.9, 122.6, 115.2, 114.7, 108.7, 105.4, 73.2, 55.6, 51.7, 18.1 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H18O5SNa 417.0767; Found 417.0763. Methyl (2R,3R,4S)-8-chloro-2-((methylthio)methyl)-4-phenyl-3,4-dihydro-2H-benzo[4,5]thieno[3,2-b]py ran-3-carboxylate (6a): white solid: 67 mg (yield 53%); mp: 144-146 °C; IR(KBr): 1734, 1587, 1497, 1455, 1429, 1349, 1191, 1161, 1074, 1021 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.67 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.29 – 7.37 (m, 3H), 7.24 – 7.28 (m, 1H), 7.17 – 7.24 (m, 2H), 4.54 – 4.64 (m, 2H), 3.59 (s, 3H), 3.18 (t, J = 10.2 Hz, 1H), 2.85 – 2.99 (m, 2H), 2.32 (s, 3H) ppm; 13C{1H}

NMR (100 MHz, CDCl3) δ = 172.1, 144.5, 140.3, 134.9, 132.1, 130.5, 128.7, 128.2, 128.0, 26


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125.3, 123.7, 120.0, 118.2, 78.7, 53.0, 52.1, 44.7, 37.3, 17.5 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H20O3S2Cl 419.0537; Found 419.0555. Methyl (2R,3R,4S)-8-chloro-2-((methylthio)methyl)-4-(p-tolyl)-3,4-dihydro-2H-benzo[4,5]thieno[3,2-b]p yran-3-carboxylate (6b): white solid: 74 mg (yield57%); mp: 110-111 °C; IR(KBr): 1733, 1588, 1515, 1430, 1340, 1187, 1159, 1075, 1020 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.66 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.22 – 7.26 (m, 1H), 7.13 (d, J = 8.0 Hz, 2H), 7.04 – 7.11 (m, 2H), 4.58 (ddd, J = 10.0, 5.8, 4.2 Hz, 1H), 4.54 (d, J = 10.4 Hz, 1H), 3.60 (s, 3H), 3.16 (t, J = 10.2 Hz, 1H), 2.85 – 2.97 (m, 2H), 2.34 (s, 3H), 2.32 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 172.2, 144.4, 137.7, 137.3, 134.8, 132.2, 130.4, 129.4, 128.0, 125.2, 123.7, 120.0, 118.6, 78.7, 53.1, 52.2, 44.3, 37.3, 21.2, 17.5 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H21O3S2ClNa 455.0513; Found 455.0520. Methyl (2S,3R,4S)-8-chloro-4-(4-chlorophenyl)-2-((methylthio)methyl)-3,4-dihydro-2H-benzo[4,5]thieno [3,2-b]pyran-3-carboxylate (6c): white solid: 58mg (yield 50%); mp: 116-117 °C; IR(KBr): 1723, 1593, 1489, 1434, 1347, 1296, 1159, 1075, 1013 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.66 (d, J = 1.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.23 – 7.33 (m, 3H), 7.15 (d, J = 8.4 Hz, 2H), 4.53 – 4.61 (m, 2H), 3.61 (s, 3H), 3.13 (t, J = 10.2 Hz, 1H), 2.85 – 2.97 (m, 2H), 2.31 (s, 3H) ppm;13C{1H} NMR (100 MHz, CDCl3) δ = 171.9, 144.7, 138.9, 134.7, 133.9, 132.0, 130.6, 129.5, 129.0, 125.5, 123.8, 120.0, 117.4, 78.6, 53.0, 52.3, 44.0, 37.2, 17.5 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for

27



Page 28 of 48

C21H18O3S2Cl2Na 474.9967; Found 474.9963. Methyl (2R,3R,4S)-8-chloro-4-(3-methoxyphenyl)-2-((methylthio)methyl)-3,4-dihydro-2H-benzo[4,5]thie no[3,2-b]pyran-3-carboxylate (6d): white solid: 76 mg (yield 63%); mp: 122-123 °C; IR(KBr): 1729, 1593, 1493, 1431, 1337, 1189, 1157, 1074, 1022 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.67 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.20 – 7.29 (m, 2H), 6.84 (dd, J = 8.0, 2.4 Hz, 1H), 6.80 (d, J = 7.2 Hz, 1H), 6.70 – 6.77 (m, 1H), 4.52 – 4.63 (m, 2H), 3.77 (s, 3H), 3.61 (s, 3H), 3.18 (t, J = 10.2 Hz, 1H), 2.86 – 2.97 (m, 2H), 2.32 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 172.1, 159.8, 144.5, 141.9, 134.9, 132.1, 130.4, 129.7, 125.3, 123.7, 120.5, 120.0, 118.1, 113.9, 113.3, 78.7, 55.2, 52.9, 52.2, 44.6, 37.3, 17.5 ppm; HRMS (ESI-TOF) m/z:[M + H]+ Calcd for C22H22O4S2Cl 449.0643; Found 449.0640. Methyl (2R,3R,4S)-8-chloro-4-(2-chlorophenyl)-2-((methylthio)methyl)-3,4-dihydro-2H-benzo[4,5]thien o[3,2-b]pyran-3-carboxylate (6e): white solid: 22 mg (yield 16%); mp: 98-99 °C; IR(KBr): 1738, 1588, 1476, 1432, 1346, 1193, 1159, 1072, 1015 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.68 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.35 – 7.46 (m, 1H), 7.16 – 7.29 (m, 4H), 5.25 (d, J = 10.0 Hz, 1H), 4.73 (s, 1H), 3.65 (s, 3H), 3.24 (t, J = 10.2 Hz, 1H), 2.86 – 3.02 (m, 2H), 2.30 (s, 3H) ppm;

13C{1H}

NMR

(100 MHz, CDCl3) δ = 171.4, 144.8, 138.3, 134.8, 133.9, 132.1, 130.5, 129.58, 129.56, 129.1, 127.4, 125.4, 123.7, 120.0, 117.3, 78.4, 52.4, 51.4, 39.6, 37.1, 17.4 ppm; HRMS (ESI-TOF) m/z:[M + H]+ Calcd for C21H19O3S2Cl2 453.0147; Found 453.0142. 28


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Methyl (2R,3R,4S)-8-chloro-2-((methylthio)methyl)-4-(thiophen-2-yl)-3,4-dihydro-2H-benzo[4,5]thieno[ 3,2-b]pyran-3-carboxylate (6f): white solid: 48 mg (yield 38%); mp: 113-114 °C; IR(KBr): 1736, 1587, 1434, 1354, 1192, 1161, 1073, 1022 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.66 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 8.4, 2.0 Hz, 1H), 7.26 – 7.29 (m, 1H), 7.24 – 7.26 (m, 1H), 6.98 – 7.03 (m, 1H), 6.91 – 6.98 (m, 1H), 4.94 (d, J = 10.4 Hz, 1H), 4.58 (ddd, J = 9.9, 5.5, 4.5 Hz, 1H), 3.66 (s, 3H), 3.24 (t, J = 10.2 Hz, 1H), 2.85 – 2.98 (m, 2H), 2.32 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 171.8, 144.0, 143.0, 134.7, 132.0, 130.5, 126.7, 126.5, 125.5, 125.3, 123.8, 120.1, 117.7, 78.8, 53.6, 52.4, 39.8, 37.2, 17.5 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H18O3S3Cl 425.0101; Found 425.0122. Methyl (2R,3R,4S)-8-bromo-2-((methylthio)methyl)-4-(p-tolyl)-3,4-dihydro-2H-benzo[4,5]thieno[3,2-b]p yran-3-carboxylate (6g): white solid: 76 mg (yield 53%); mp: 113-114 °C; IR(KBr): 1733, 1584, 1514, 1452, 1429, 1337, 1186, 1158, 1107, 1068 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.82 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.4, 0.8 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 4.51 – 4.61 (m, 2H), 3.60 (s, 3H), 3.15 (t, J = 10.2 Hz, 1H), 2.85 – 2.98 (m, 2H), 2.34 (s, 3H), 2.31 (s, 3H) ppm;

13C{1H}

NMR (100 MHz, CDCl3) δ = 172.1, 144.3, 137.7, 137.3, 135.4, 132.6,

129.4, 128.0, 127.8, 124.0, 123.0, 118.4, 118.1, 78.7, 53.1, 52.1, 44.3, 37.3, 21.1, 17.4 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H22O3S2Br 477.0188; Found 477.0181. Methyl

29



Page 30 of 48

(2R,3R,4S)-8-bromo-4-(4-bromophenyl)-2-((methylthio)methyl)-3,4-dihydro-2H-benzo[4,5]thien o[3,2-b]pyran-3-carboxylate (6h): white solid: 69mg (yield 43%); mp: 133-135 °C; IR(KBr): 1727, 1588, 1488, 1431, 1356, 1338, 1193, 1163, 1013 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.82 (d, J = 2.0 Hz, 1H), 7.42 – 7.52 (m, 3H), 7.40 (dd, J = 8.4, 2.0 Hz, 1H), 7.05 – 7.13 (m, 2H), 4.52 – 4.61 (m, 2H), 3.61 (s, 3H), 3.12 (t, J = 10.2 Hz, 1H), 2.85 – 2.97 (m, 2H), 2.31 (s, 3H) ppm;

13C{1H}

NMR

(100 MHz, CDCl3) δ = 171.8, 144.6, 139.4, 135.3, 132.4, 131.9, 129.9, 128.1, 124.0, 123.1, 122.0, 118.2, 117.1, 78.5, 52.9, 52.2, 44.0, 37.2, 17.4 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H19O3S2Br2 540.9137; Found 540.9131. Methyl (2R,3R,4S)-8-fluoro-2-((methylthio)methyl)-4-phenyl-3,4-dihydro-2H-benzo[4,5]thieno[3,2-b]py ran-3-carboxylate (6i): white solid: 103 mg (yield 85%); mp: 128-129 °C; IR(KBr): 1733, 1603, 1496, 1445, 1346, 1185, 1161, 1145, 1108, 1019 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.55 (dd, J = 8.8, 4.4 Hz, 1H), 7.29 – 7.38 (m, 4H), 7.18 – 7.25 (m, 2H), 7.05 (td, J = 8.8, 2.4 Hz, 1H), 4.54 – 4.65 (m, 2H), 3.59 (s, 3H), 3.19 (t, J = 10.2 Hz, 1H), 2.85 – 2.98 (m, 2H), 2.32 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 172.1 (d, J = 0.6 Hz), 160.8 (d, J = 240.8 Hz), 144.9 (d, J = 4.1 Hz), 140.4, 132.1 (d, J = 1.7 Hz), 132.0 (d, J = 6.0 Hz), 128.7, 128.2, 128.0, 123.9 (d, J = 9.2 Hz), 118.7, 113.6 (d, J = 25.0 Hz), 106.1 (d, J = 23.8 Hz), 78.7, 53.1, 52.1 (d, J = 1.5 Hz), 44.8, 37.3,17.4 (d, J = 1.2 Hz) ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H20O3S2F 403.0832; Found 403.0818. Methyl (2R,3R,4S)-8-fluoro-2-((methylthio)methyl)-4-(p-tolyl)-3,4-dihydro-2H-benzo[4,5]thieno[3,2-b]p

30


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yran-3-carboxylate (6j): white solid: 70 mg (yield 56%); mp: 125-126 °C; IR(KBr): 1739, 1598, 1514, 1445, 1354, 1239, 1196, 1164, 1107, 1020 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.54 (dd, J = 8.8, 4.8 Hz, 1H), 7.35 (dd, J = 9.1, 2.6 Hz, 1H), 7.08 – 7.16 (m, 4H), 7.04 (td, J = 8.8, 2.4 Hz, 1H), 4.59 (ddd, J = 10.0, 5.6, 4.4 Hz, 1H), 4.54 (d, J = 10.4 Hz, 1H), 3.60 (s, 3H), 3.16 (t, J = 10.2 Hz, 1H), 2.85 – 2.97 (m, 2H), 2.34 (s, 3H), 2.32 (s, 3H) ppm;

13C{1H}

NMR (100 MHz, CDCl3) δ = 172.2,

160.7 (d, J = 240.7 Hz), 144.8 (d, J = 4.2 Hz), 137.7, 137.3, 132.04 (d, J = 7.7 Hz), 131.98, 129.4, 128.0, 123.9 (d, J = 9.1 Hz), 119.0, 113.5 (d, J = 25.1 Hz), 106.1 (d, J = 23.8 Hz), 78.7, 53.1, 52.1, 44.3, 37.3, 21.1, 17.5 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H22O3S2F 417.0989; Found 417.0986. Methyl (2R,3R,4S)-8-methyl-2-((methylthio)methyl)-4-phenyl-3,4-dihydro-2H-benzo[4,5]thieno[3,2-b]py ran-3-carboxylate (6k): white solid: 60 mg (yield 50%); mp: 167-168 °C; IR(KBr): 1734, 1588, 1437, 1350, 1201, 1166, 1088, 1021 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.51 (d, J = 8.4 Hz, 2H), 7.28 – 7.35 (m, 3H), 7.18 – 7.25 (m, 2H), 7.13 (dd, J = 7.8, 1.4 Hz, 1H), 4.55 – 4.64 (m, 2H), 3.59 (s, 3H), 3.18 (t, J = 10.2 Hz, 1H), 2.87 – 2.99 (m, 2H), 2.47 (s, 3H), 2.33 (s, 3H) ppm;

13C{1H}

NMR

(100 MHz, CDCl3) δ = 172.3, 145.0, 140.7, 133.9, 133.9, 131.2, 128.6, 128.2, 127.8, 126.6, 122.4, 120.1, 116.1, 78.4, 53.3, 52.1, 44.7, 37.3, 21.4, 17.4 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H23O3S2 399.1083; Found 399.1077. Methyl (2R,3R,4S)-6-chloro-2-((methylthio)methyl)-4-phenyl-3,4-dihydro-2H-benzo[4,5]thieno[3,2-b]py

31



ran-3-carboxylate (6l): white solid: 72 mg (yield 57%); mp: 112-113 °C; IR(KBr): 1736, 1590, 1472, 1359, 1193, 1165, 1096, 1021 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.59 – 7.65 (m, 1H), 7.28 – 7.38 (m, 5H), 7.19 – 7.26 (m, 2H), 4.55 – 4.68 (m, 2H), 3.59 (s, 3H), 3.19 (t, J = 10.2 Hz, 1H), 2.85 – 2.98 (m, 2H) , 2.32 (s, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 172.1, 145.4, 140.2, 135.7, 132.6, 128.8, 128.2, 128.1, 128.0, 125.3, 124.5, 118.7, 117.6, 78.7, 53.1, 52.1, 44.6, 37.2, 17.4 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H20O3S2Cl 419.0537; Found 419.0542. Methyl (2S,3R,4S)-8-chloro-2-((methylthio)methyl)-4-phenyl-3,4-dihydro-2H-benzo[4,5]thieno[3,2-b]pyr an-3-carboxylate (7a): white solid: 10 mg (yield 8%); mp: 94-95 °C; IR(KBr): 1729, 1583, 1495, 1454, 1432, 1343, 1192, 1172, 1095, 1075 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.71 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.33 – 7.36 (m, 1H), 7.31 – 7.33 (m, 1H), 7.27 – 7.30 (m, 2H), 7.26 – 7.27 (m, 1H), 7.24 – 7.26 (m, 1H), 4.66 (ddd, J = 8.1, 4.9, 3.1 Hz, 1H), 4.60 (d, J = 6.4 Hz, 1H), 3.68 (s, 3H), 3.34 (dd, J = 6.4, 3.2 Hz, 1H), 3.02 (dd, J = 14.0, 8.4 Hz, 1H), 2.83 (dd, J = 14.2, 5.0 Hz, 1H), 2.12 (s, 3H) ppm;13C{1H} NMR (100 MHz, CDCl3) δ = 170.5, 143.9, 142.2, 135.0, 132.3, 130.5, 128.7, 128.4, 127.6, 125.4, 123.8, 120.1, 116.3, 75.5, 52.3, 50.2, 40.2, 34.5, 16.5 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H20O3S2Cl 419.0537; Found 419.0553. Methyl (2S,3R,4S)-8-chloro-2-((methylthio)methyl)-4-(p-tolyl)-3,4-dihydro-2H-benzo[4,5]thieno[3,2-b]p yran-3-carboxylate (7b): white solid: 8 mg (yield 6%); mp: 116-117 °C; IR(KBr): 1728, 1583, 1514, 1428, 1347, 1193, 1167, 1094, 1073 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.70 (d, J = 2.0 Hz, 1H), 32


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7.56 (d, J = 8.4 Hz, 1H), 7.26 (dd, J = 8.4, 2.0 Hz, 1H), 7.14 (s, 4H), 4.67 (ddd, J = 8.3, 4.9, 3.3 Hz, 1H), 4.56 (d, J= 6.4 Hz, 1H), 3.68 (s, 3H), 3.32 (dd, J = 6.4, 3.2 Hz, 1H), 3.01 (dd, J = 14.4, 8.4 Hz, 1H), 2.81 (dd, J = 14.0, 4.8 Hz, 1H), 2.33 (s, 3H), 2.13 (s, 3H) ppm;

13C{1H}

NMR (100 MHz,

CDCl3) δ = 170.6, 143.7, 139.2, 137.3, 135.0, 132.3, 130.4, 129.4, 128.2, 125.3, 123.7, 120.1, 116.7, 75.6, 52.2, 50.4, 39.8, 34.6, 21.1, 16.5 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H22O3S2Cl 433.0693; Found 433.0696. Methyl (2S,3R,4S)-8-chloro-4-(4-chlorophenyl)-2-((methylthio)methyl)-3,4-dihydro-2H-benzo[4,5]thieno [3,2-b]pyran-3-carboxylate (7c): white solid: 7 mg (yield 6%); mp: 120-121 °C; IR(KBr): 1737, 1585, 1488, 1432, 1344, 1222, 1161, 1092, 1061 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.71 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.26 – 7.32 (m, 3H), 7.18 – 7.22 (m, 2H), 4.67 (ddd, J = 8.2, 4.7, 3.5 Hz, 1H), 4.57 (d, J = 6.8 Hz, 1H), 3.69 (s, 3H), 3.30 (dd, J = 6.8, 3.4 Hz, 1H), 2.99 (dd, J = 14.2, 8.3 Hz, 1H), 2.80 (dd, J = 14.2, 5.0 Hz, 1H), 2.13 (s, 3H) ppm;

13C{1H}

NMR (100 MHz,

CDCl3) δ = 170.3, 143.9, 140.6, 135.0, 133.5, 132.2, 130.6, 129.8, 128.9, 125.6, 123.8, 120.2, 115.8, 75.6, 52.4, 50.3, 39.5, 34.3, 16.5ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H18O3S2Cl2Na 474.9967; Found 474.9967. Methyl (2S,3R,4S)-8-chloro-4-(2-chlorophenyl)-2-((methylthio)methyl)-3,4-dihydro-2H-benzo[4,5]thieno [3,2-b]pyran-3-carboxylate (7e): white solid: 22 mg (yield 16%); mp: 153-155 °C; IR(KBr): 1735, 1589, 1465, 1432, 1371, 1196, 1165, 1074 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.71 (d, J = 2.0 Hz, 33



1H), 7.60 (d, J = 8.4 Hz, 1H), 7.44 (dd, J = 7.6, 1.2 Hz, 1H), 7.29 (dd, J = 8.8, 2.0 Hz, 1H), 7.18 – 7.27 (m, 2H), 7.13 (dd, J = 7.6, 1.6 Hz, 1H), 5.05 (d, J = 2.8 Hz, 1H), 4.41 (ddd, J = 7.5, 5.4, 2.4 Hz, 1H), 3.73 (s, 3H), 3.31 (t, J = 2.4 Hz, 1H), 3.09 (dd, J = 14.0, 8.0 Hz, 1H), 2.91 (dd, J = 14.4, 5.6 Hz, 1H), 2.15 (s, 3H) ppm;

13C{1H}

NMR (100 MHz, CDCl3) δ = 170.3, 145.8, 139.7, 135.1, 133.3,

132.0, 130.7, 130.5, 130.0, 128.9, 127.0, 125.5, 123.8, 120.2, 114.2, 75.0, 52.3, 47.4, 38.4, 35.7, 16.6 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H19O3S2Cl2 453.0147; Found 453.0128. Methyl (2S,3R,4S)-8-chloro-2-((methylthio)methyl)-4-(thiophen-2-yl)-3,4-dihydro-2H-benzo[4,5]thieno[ 3,2-b]pyran-3-carboxylate (7f): brown solid: 10 mg (yield 7%); mp: 88-89 °C; IR(KBr): 1728, 1582, 1435, 1340, 1195, 1176, 1092, 1060 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.70 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.28 (dd, J = 8.4, 2.0 Hz, 1H), 7.24 (dd, J = 5.0, 1.4 Hz, 1H), 6.94 – 6.98 (m, 2H), 4.90 (d, J = 4.8 Hz, 1H), 4.69 (ddd, J = 7.9, 5.5, 2.7 Hz, 1H), 3.71 (s, 3H), 3.43 (dd, J = 4.8, 2.8 Hz, 1H), 3.05 (dd, J = 14.2, 7.8 Hz, 1H), 2.91 (dd, J = 14.2, 5.8 Hz, 1H), 2.15 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 170.1, 145.8, 143.9, 134.9, 132.1, 130.5, 126.8, 126.2, 125.5, 125.1, 123.8, 120.2, 116.1, 75.4, 52.3, 50.1, 36.1, 34.8, 16.4 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H17O3S3ClNa 446.9921; Found 446.9926. Methyl (2S,3R,4S)-8-bromo-2-((methylthio)methyl)-4-(p-tolyl)-3,4-dihydro-2H-benzo[4,5]thieno[3,2-b]p yran-3-carboxylate (7g): white solid: 7 mg (yield 5%); mp: 115-116 °C; IR(KBr): 1726, 1581, 1514, 1428, 1344, 1336, 1193, 1170, 1091, 1067 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.86 (d, J = 2.0 Hz, 34


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1H), 7.50 (d, J = 8.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.0 Hz, 1H), 7.13 (s, 4H), 4.67 (ddd, J = 8.3, 4.9, 3.3 Hz, 1H), 4.56 (d, J = 6.4 Hz, 1H), 3.68 (s, 3H), 3.31 (dd, J = 6.4, 3.2 Hz, 1H), 3.01 (dd, J = 14.0, 8.4 Hz, 1H), 2.81 (dd, J = 14.4, 4.8 Hz, 1H), 2.33 (s, 3H), 2.13 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 170.6, 143.6, 139.2, 137.3, 135.6, 132.8, 129.4, 128.2, 127.9, 124.0, 123.1, 118.1, 116.5, 75.6, 52.2, 50.4, 39.8, 34.6, 21.1, 16.5 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H22O3S2Br 477.0188; Found 477.0165. Methyl (2S,3R,4S)-8-bromo-4-(4-bromophenyl)-2-((methylthio)methyl)-3,4-dihydro-2H-benzo[4,5]thien o[3,2-b]pyran-3-carboxylate (7h): white solid: 14 mg (yield 8%); mp: 131-132 °C; IR(KBr): 1736, 1581, 1485, 1430, 1343, 1170, 1159, 1090, 1066 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.87 (d, J = 1.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.41 (dd, J = 8.4, 1.6 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 4.64 – 4.70 (m, 1H), 4.56 (d, J = 6.8 Hz, 1H), 3.69 (s, 3H), 3.29 (dd, J = 6.8, 3.2 Hz, 1H), 2.99 (dd, J = 14.4, 8.4 Hz, 1H), 2.80 (dd, J = 14.2, 5.0 Hz, 1H), 2.13 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 170.3, 143.8, 141.1, 135.5, 132.6, 131.8, 130.1, 128.2, 124.1, 123.2, 121.7, 118.2, 115.5, 75.6, 52.4, 50.2, 39.5, 34.3, 16.5 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H18O3S2Br2Na 562.8956; Found 562.8961. Methyl (2S,3R,4S)-8-fluoro-2-((methylthio)methyl)-4-phenyl-3,4-dihydro-2H-benzo[4,5]thieno[3,2-b]pyr an-3-carboxylate (7j): white solid: 13 mg (yield 11%); mp: 97-98 °C; IR(KBr): 1725, 1601, 1508, 1447, 1347, 1250, 1194, 1172, 1082, 1061 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.57 (dd, J = 8.8, 35



4.8 Hz, 1H), 7.39 (dd, J = 9.0, 2.6 Hz, 1H), 7.11 – 7.17 (m, 4H), 7.06 (td, J = 8.8, 2.8 Hz, 1H), 4.69 (ddd, J = 8.3, 4.7, 3.5 Hz, 1H), 4.57 (d, J = 6.4 Hz, 1H), 3.68 (s, 3H), 3.32 (dd, J = 6.4, 3.2 Hz, 1H), 3.02 (dd, J = 14.2, 8.6 Hz, 1H), 2.81 (dd, J = 14.2, 4.6 Hz, 1H), 2.32 – 2.35 (m, 3H), 2.14 (s, 3H) ppm; 13C{1H}

NMR (100 MHz, CDCl3) δ = 170.7, 160.7 (d, J = 240.7 Hz), 144.0 (d, J = 4.1 Hz), 139.2,

137.3, 132.23 (d, J = 5.1 Hz), 132.18 (d, J = 2.7 Hz), 129.4, 128.2, 123.9 (d, J = 9.1 Hz), 117.2, 113.6 (d, J = 25.0 Hz), 106.2 (d, J = 23.8 Hz), 75.8, 52.2, 50.5, 39.8, 34.5, 21.1, 16.5 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H22O3S2F 417.0989; Found 417.0981. Methyl (2S,3R,4S)-8-methyl-2-((methylthio)methyl)-4-phenyl-3,4-dihydro-2H-benzo[4,5]thieno[3,2-b]py ran-3-carboxylate (7k): white solid: 8 mg (yield 7%); mp: 127-128 °C; IR(KBr): 1724, 1584, 1497, 1440, 1345, 1206, 1177, 1095, 1066 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.51 – 7.58 (m, 2H), 7.30 – 7.34 (m, 2H), 7.24 – 7.29 (m, 3H), 7.14 (d, J = 8.4 Hz, 1H), 4.68 (ddd, J = 8.2, 4.5, 3.4 Hz, 1H), 4.60 (d, J = 6.4 Hz, 1H), 3.67 (s, 3H), 3.35 (dd, J = 6.4, 3.2 Hz, 1H), 3.04 (dd, J = 14.4, 8.4 Hz, 1H), 2.84 (dd, J = 14.4, 4.8 Hz, 1H), 2.47 (s, 3H), 2.12 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 170.7, 144.1, 142.5, 134.2, 133.9, 131.4, 128.6, 128.4, 127.4, 126.7, 122.4, 120.2, 114.4, 75.5, 52.2, 50.5, 40.2, 34.5, 21.4, 16.4 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H23O3S2 399.1083; Found 399.1073. Ethyl 2-(3-(5-chloro-3-hydroxybenzo[b]thiophen-2-yl)-2H-chromen-2-yl)acetate (9a): brown solid: 98 mg (yield 80.67%); mp: 100-102 °C; IR(KBr): 3371, 2981, 1703, 1178, 800, 750 cm-1; 1H NMR (400 MHz, DMSO-d6) δ = 8.00 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.40 (dd, J = 8.4, 36


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2.0 Hz, 1H), 7.25 (dd, J = 7.6, 1.2 Hz, 1H), 7.17 (td, J = 7.6, 1.6 Hz, 1H), 6.95 (t, J = 7.8 Hz, 1H), 6.87 (s, 1H),6.79 (d, J = 8.0 Hz, 1H), 6.18 (dd, J = 10.0, 3.2 Hz, 1H), 5.76 (s, 1H), 4.05 – 4.18 (m, 2H), 2.65 – 2.79 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H) ppm;

13C{1H}

NMR (100 MHz, DMSO-d6) δ =

169.6, 150.1, 145.5, 134.7, 133.2, 129.4, 129.4, 128.9, 127.0, 125.7, 124.5, 122.1, 121.9, 120.6,118.9, 116.3, 115.5, 71.8, 60.2, 38.0, 14.1ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H17ClO4SNa 423.0430; Found 423.0428. Ethyl 2-(3-(5-chloro-3-hydroxybenzo[b]thiophen-2-yl)-6-methyl-2H-chromen-2-yl)acetate (9b): brown solid: 109 mg (yield 87%); mp: 141-143 °C; IR(KBr): 3424, 2980, 1705, 1175, 799, 772 cm-1; 1H

NMR (400 MHz, DMSO-d6) δ = 10.59 (s, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H),

7.39 (dd, 1H), 7.05 (s, 1H), 6.97 (d, J = 8.1 Hz, 1H), 6.82 (s, 1H), 6.68 (d, J = 8.1 Hz, 1H), 6.13 (dd, J = 9.4, 3.6 Hz, 1H), 4.03 – 4.19 (m, 2H), 2.63 – 2.77 (m, 2H), 2.23 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ = 169.7, 147.9, 145.3, 134.7, 133.2, 130.6, 129.8, 129.4, 129.0, 127.2, 125.7, 124.5, 121.9, 120.5, 119.1, 116.1, 115.6, 71.8, 60.1, 37.8, 20.2, 14.1ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H19ClO4SNa 437.0598; Found 437.0585. Ethyl 2-(6-bromo-3-(5-chloro-3-hydroxybenzo[b]thiophen-2-yl)-2H-chromen-2-yl)acetate (9c): brown solid: 101 mg (yield 70%); mp: 171-173 °C; IR(KBr): 3402, 2995, 1711, 1166, 802, 768 cm-1; 1H


7.50 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 8.4, 2.0 Hz, 1H), 7.30 (dd, J = 8.6, 2.2 Hz, 1H), 6.86 (s, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.21 (dd, J = 10.0, 2.8 Hz, 1H), 4.04 – 4.19 (m, 2H), 2.66 – 2.82 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H) ppm;

13C{1H}

NMR (100 MHz, DMSO-d6) δ = 169.5, 149.3, 146.1, 134.5, 37



133.4, 131.4, 130.2, 129.4, 129.0, 126.0, 124.6, 124.4, 120.7, 118.4, 117.5, 115.0, 113.3, 72.0, 60.2, 38.1, 14.1ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H16ClBrO4SNa 500.9549; Found 500.9533. Ethyl 2-(3-(5-bromo-3-hydroxybenzo[b]thiophen-2-yl)-2H-chromen-2-yl)acetate (9d): brown solid: 71 mg (yield 53%); mp: 149-151 °C; IR(KBr): 3424, 2982, 1701, 1177, 799, 748 cm-1; 1H NMR (400 MHz, DMSO-d6) δ = 10.63 (s, 1H), 8.14 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.95 (t, J = 7.2 Hz, 1H), 6.87 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.17 (dd, J = 9.6, 2.8 Hz, 1H), 4.03 – 4.19 (m, 2H), 2.65 – 2.80 (m, 2H), 1.19 (t, J = 7.0 Hz, 3H) ppm;

13C{1H}

NMR (100 MHz, DMSO-d6) δ = 169.6, 150.1, 145.3, 135.1, 133.6, 129.4,

128.9, 128.3, 127.0, 124.8, 123.6, 122.1, 122.0, 118.9, 117.5, 116.3, 115.3, 71.8, 60.2, 38.0, 14.2 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H17BrO4SNa 466.9928; Found 466.9923. Ethyl 2-(3-(5-bromo-3-hydroxybenzo[b]thiophen-2-yl)-6-methyl-2H-chromen-2-yl)acetate (9e): brown solid: 76 mg (yield 55%); mp: 145-147 °C; IR(KBr): 3416, 2989, 1702, 1172, 858, 809 cm-1; 1H


7.50 (d, J = 8.5 Hz, 1H), 7.04 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.81 (s, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.13 (dd, J = 9.4, 3.8 Hz, 1H), 4.04 – 4.17 (m, 2H), 2.62 – 2.76 (m, 2H), 2.22 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H) ppm;

13C{1H}

NMR (100 MHz, DMSO-d6) δ =170.1, 148.4, 145.7, 135.6, 134.0, 131.1,

130.3, 129.4, 128.8, 127.7, 125.2, 124.0, 122.3, 119.5, 118.0, 116.6, 115.8, 72.2, 60.6, 38.3, 20.7, 14.6 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H20BrO4S 459.0276; Found 459.0260. Ethyl 2-(6-bromo-3-(5-bromo-3-hydroxybenzo[b]thiophen-2-yl)-2H-chromen-2-yl)acetate (9f):

38


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brown solid: 113 mg (yield 72%); mp: 151-153 °C; IR(KBr): 3441, 2979, 1700, 1176, 800, 737 cm-1; 1H

NMR (400 MHz, DMSO-d6) δ = 8.03 (s, 1H), 7.97 (s, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.45 (d, J =

8.4 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.1 Hz, 1H), 6.66 (s, 1H), 6.27 (t, J = 6.2 Hz, 1H), 4.19 – 4.32 (m, 1H), 4.07 – 4.19 (m, 1H), 2.91 (d, J = 6.3 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H) ppm; 13C{1H}

NMR (100 MHz, DMSO-d6) δ = 169.5, 149.3, 146.3, 135.1, 133.9, 131.4, 130.3, 129.0,

128.6, 124.9, 124.5, 123.8, 118.5, 117.5, 117.3, 114.6, 113.3, 72.1, 60.3, 38.1, 14.2 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H16Br2O4SNa 544.9034; Found 544.9028. Ethyl 2-(3-(5-fluoro-3-hydroxybenzo[b]thiophen-2-yl)-2H-chromen-2-yl)acetate(9g): brown solid: 72 mg (yield 62%); mp: 127-129 °C; IR (KBr): 3442, 2983, 1619, 1174, 755, 740 cm-1; 1H NMR (400 MHz, DMSO-d6) δ = 10.59 (s, 1H), 7.87 (dd, J = 8.7, 4.9 Hz, 1H), 7.73 (dd, J = 9.9, 2.1 Hz, 1H), 7.26 (td, J = 8.7, 2.4 Hz, 2H), 7.16 (t, J = 7.6 Hz, 1H), 6.95 (t, J = 7.3 Hz, 1H), 6.85 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.19 (dd, J = 9.9, 2.9 Hz, 1H), 4.04 – 4.19 (m, 2H), 2.73 (qd, J = 15.1, 6.6 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ = 170.1, 160.6 (d, J = 238.2 Hz), 150.6, 146.3 (d, J = 4.1 Hz), 134.9 (d, J = 9.1 Hz), 130.8, 129.8, 129.5, 127.4, 125.1 (d, J = 9.1 Hz), 122.6, 122.4, 119.2, 116.8, 116.3,114.7 (d, J = 24.8 Hz), 107.3 (d, J = 24.3 Hz), 72.3, 60.6, 38.5, 14.6 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H17FO4SNa 407.0737; Found 407.0724. Ethyl 2-(3-(5-fluoro-3-hydroxybenzo[b]thiophen-2-yl)-6-methyl-2H-chromen-2-yl)acetat (9h): brown solid: 71 mg (yield 59%); mp: 142-144 °C; IR (KBr): 3415, 2982, 1705, 1217, 801, 730 cm-1; 1H

NMR (400 MHz, DMSO-d6) δ = 10.55 (s, 1H), 7.87 (dd, J = 8.6, 5.0 Hz, 1H), 7.72 (dd, J = 10.0,

1.6 Hz,1H), 7.25 (t, J = 8.0 Hz, 1H), 7.05 (s, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.81 (s, 1H), 6.68 (d, J =

39



8.0 Hz, 1H), 6.14 (dd, J = 9.8, 3.4 Hz, 1H), 4.03 – 4.19 (m, 2H), 2.65 – 2.77 (m, 2H), 2.23 (s, 3H), 1.19 (t, J = 7.0 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ =170.1, 160.6 (d, J = 240.4 Hz), 154.7, 148.4 (d, J = 4.2 Hz), 146.2 (d, J = 3.7 Hz), 131.1, 130.8, 130.2, 129.6, 127.6, 125.1, 125.0, 122.4, 119.5, 116.5, 114.7 (d, J = 23.6 Hz), 107.2 (d, J = 24.5 Hz),72.3 (d, J = 5.5 Hz), 60.6, 38.4, 20.7, 14.6 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H19FO4SNa 421.0882; Found 421.0880. Ethyl 2-(6-chloro-3-(5-fluoro-3-hydroxybenzo[b]thiophen-2-yl)-2H-chromen-2-yl)acetate (9i): brown solid: 117 mg (yield 93%); mp: 151-153 °C; IR (KBr): 3415, 2983,1702,1213, 804, 724 cm-1; 1H

NMR (400 MHz, DMSO-d6) δ = 10.73 (s, 1H), 7.88 (dd, J = 8.8, 4.8 Hz, 1H), 7.74 (dd, J = 9.8, 1.8

Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.27 (td, J = 8.8, 2.0 Hz, 1H), 7.18 (dd, J = 8.4, 2.4 Hz, 1H), 6.82 (t,J = 9.4 Hz, 2H), 6.22 (dd, J = 10.0, 2.4Hz, 1H), 4.05 – 4.19 (m, 2H), 2.67 – 2.82 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ = 170.0, 160.6 (d, J = 238.6 Hz), 149.3, 147.0 (d, J = 4.1 Hz), 134.8 (d, J = 8.7 Hz), 131.1, 130.9, 129.0, 126.6, 126.0, 125.1 (d, J = 9.4 Hz), 124.4, 118.4, 117.9, 115.0 (d, J = 25.2 Hz), 114.9, 107.4 (d, J = 24.4 Hz), 72.6, 60.7, 38.5, 14.6 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H17FClO4S 419.0517; Found 419.0515. Ethyl 2-(6-bromo-3-(5-fluoro-3-hydroxybenzo[b]thiophen-2-yl)-2H-chromen-2-yl)acetate (9j): brown solid: 89 mg (yield 64%); mp: 152-154 °C; IR(KBr): 3420, 2984, 1700, 1212, 886, 867 cm-1; 1HNMR

(400 MHz, DMSO-d6) δ = 10.73 (s, 1H), 7.89 (dd, J = 8.7, 4.9 Hz, 1H), 7.74 (dd, J=10.0, 2.2

Hz, 1H), 7.50 (d, J = 2.2 Hz, 1H), 7.28 (ddd, 2H),6.85 (s, 1H), 6.77 (d, J = 8.5 Hz, 1H), 6.22 (dd, J = 10.1, 2.7 Hz, 1H), 4.04 – 4.18 (m, 2H), 2.65 – 2.81 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H) ppm; 13C{1H}

40


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NMR (100MHz,DMSO-d6) δ = 170.0, 160.6 (d, J = 237.6 Hz), 149.8, 147.0 (d,J=4.0Hz), 134.7 (d,J=9.1Hz), 131.9, 130.9 (d, J = 23.5 Hz), 129.4, 125.2, 125.1, 124.9, 118.9, 117.8, 115.0 (d, J = 25.2 Hz), 114.9, 113.8, 107.4 (d, J = 24.2 Hz), 72.5, 60.7, 38.5, 14.6 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H16BrFO4SNa 484.9838; Found 484.9829. Ethyl2-(6,8-dibromo-3-(5-fluoro-3-hydroxybenzo[b]thiophen-2-yl)-2H-chromen-2-yl)acetate (9k): brown solid: 146 mg (yield 90%); mp: 162-164 °C; IR (KBr): 3421, 2981, 1703, 1173, 861, 726 cm-1; 1H NMR (400 MHz, DMSO-d6) δ = 10.93 (s, 1H), 7.89 (dd, J = 8.6, 4.8 Hz, 1H), 7.76 (dd, J = 9.6, 1.6Hz, 1H), 7.61 (d, J = 1.2Hz, 1H), 7.54 (s, 1H), 7.29 (td, J = 8.8, 1.6Hz, 1H), 6.84 (s, 1H), 6.37 (dd, J = 10.4, 1.8Hz,1H), 4.13 (q, J = 7.0 Hz, 2H), 2.83 (dd, J = 15.4, 10.8 Hz, 1H), 2.66 (dd, J = 15.2, 10.9 Hz, 1H), 1.21 (t, J = 7.0 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ = 169.7, 160.6 (d, J = 238.6 Hz), 147.6 (d, J = 4.2 Hz), 146.7, 134.6 (d, J = 9.2 Hz), 133.7, 131.7, 131.3, 128.9, 126.0, 125.2 (d, J = 9.0 Hz), 117.0, 115.4, 115.1, 114.0, 111.4, 107.6 (d, J = 24.3 Hz), 73.6, 61.0, 38.7, 14.6 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H15Br2FO4SNa 562.8942; Found 562.8934. Ethyl 2-(6-chloro-3-(3-hydroxy-5-methylbenzo[b]thiophen-2-yl)-2H-chromen-2-yl)acetate (9l): brown solid: 102 mg (yield 82%); mp: 129-131 °C; IR (KBr): 3430, 2983, 1709, 1185, 802, 738 cm-1; 1H

NMR (400 MHz, DMSO-d6) δ = 10.55 (s, 1H), 7.76 (s, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.36 (d, J =

2.2 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.16 (dd, J = 8.6, 2.3 Hz, 1H), 6.80 (d, J = 7.0 Hz, 2H), 6.22 (dd, J = 10.0, 2.7 Hz, 1H), 4.04 – 4.18 (m, 2H), 2.65 – 2.80 (m, 2H), 2.40 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ = 169.6, 148.7, 146.8, 133.6, 132.2, 130.8, 128.2, 41



127.8, 125.9, 125.9, 125.5, 124.2, 122.5, 121.2, 117.9, 116.5, 113.0, 72.2, 60.2, 38.1, 21.2, 14.2 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C22H19ClO4SNa 437.0590; Found 437.0585. Isopropyl 2-(3-(5-chloro-3-hydroxybenzo[b]thiophen-2-yl)-2H-chromen-2-yl)acetate (9m): brown solid: 117 mg (yield 75%); mp: 87-89 °C; IR(KBr): 3690, 2980, 1690, 1103, 865, 751 cm-1; 1H NMR (400 MHz, CDCl3) δ = 8.07 (s, 1H), 7.88 (s, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.14 (t, J = 7.7 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.92 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.73 (s, 1H), 6.20 (t, 1H), 4.91 –5.16 (m, 1H), 2.87 (t, 2H), 1.26 (d, J = 6.2 Hz, 3H), 1.08 (d, J = 6.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ = 172.4, 151.1, 144.4, 134.9, 133.8, 130.5, 129.7, 127.8, 126.9, 126.0, 123.5, 122.1, 121.8, 121.8, 120.6, 116.7, 116.6, 72.9, 69.5, 39.5, 21.8, 21.4 ppm; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H20ClO4S 415.0765; Found 415.0773. Isopropyl

2-(3-(5-bromo-3-hydroxybenzo[b]thiophen-2-yl)-6-methyl-2H-chromen-2-yl)acetate

(9n): brown solid: 105 mg (yield 74%); mp: 90-92 °C; IR(KBr): 3423, 2982, 1697, 1175, 796, 738 cm-1; 1H NMR (400 MHz, DMSO-d6) δ = 10.60 (s, 1H), 8.14 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.03 (s, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.81 (s, 1H), 6.67 (d, J = 8.1 Hz, 1H), 6.11 (dd, J = 9.6, 3.2 Hz, 1H), 4.91 – 5.00 (m, 1H), 2.60 – 2.71 (m, 2H), 2.22 (s, 3H), 1.21 (d, J = 6.2 Hz, 3H), 1.16 (d, J = 6.2 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, DMSO-d6) δ = 169.2, 148.0, 145.2, 135.1, 133.6, 130.6, 129.8, 128.9, 128.3, 127.2, 124.7, 123.6, 121.9, 119.1, 117.5, 116.0, 115.4, 71.9, 67.5, 38.1, 21.7, 21.5, 20.2 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C23H21BrO4SNa 495.0236; Found 495.0251. 4-ethyl 3-methyl 2,8-dimethyl-2H-benzo[4,5]thieno[3,2-b]pyran-3,4-dicarboxylate 5,5-dioxide

42


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(10): yellow solid: 80 mg (yield 70%); mp: 113-114 °C; IR(KBr): 2993, 2964, 2940, 2906, 2873, 1733, 1714, 1594, 1556, 1434, 1392, 1305, 1274, 1163, 1046, 1018 cm-1; 1H NMR (400 MHz, CDCl3) δ = 7.63 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.40 (s, 1H), 5.73 (q, J = 6.7 Hz, 1H), 4.39 – 4.50 (m, 2H), 3.80 (s, 3H), 2.46 (s, 3H), 1.53 (d, J = 6.8 Hz, 3H), 1.41 (t, J = 7.2 Hz, 3H) ppm; 13C{1H}

NMR (100 MHz, CDCl3) δ = 163.6, 162.9, 158.0, 144.4, 138.0, 133.3, 129.1, 126.4, 122.2,

120.9, 118.7, 110.6, 76.0, 62.7, 52.6, 21.7, 18.7, 13.9 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H18O7SNa 401.0665; Found 401.0677. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. NMR spectra of all new compounds and computational details (PDF) Crystallographic data for compound 3a, 4e, 6j, 7e, 9m, 10 (CIF) AUTHOR INFORMATION Corresponding Author [email protected] Author Contributions W.D. and Y.Z. contributed equally. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT

43



This work was financially supported by the National Natural Science Foundation of China (Grant No. 21403154), the Natural Science Foundation of Tianjin (Grant No. 13JCYBJC38700), and the Tianjin Municipal Education Commission (Grant No. 20120502). X. M. is grateful for the support from the 131 Talents Program of Tianjin and Training Project of Innovation Team of Colleges and Universities in Tianjin (TD13-5020).

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Li,

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CCDC 3a (1816737), 4e (1816733), 6j (1816735), 7e (1816736), 9m (1841651), 10

(1816734).

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Substrate-Controlled Domino Reactions of ... - ACS Publications

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