Phosphine-Catalyzed Domino Reaction of Thioaurones and Allenoate

Subscriber access provided by Kaohsiung Medical University

Phosphine-Catalyzed Domino Reaction of Thioaurones and Allenoate: Synthesis of Benzothiophene Fused Dioxabicyclo[3.3.1]nonane Derivatives Shanshan Ma, Aimin Yu, Lei Zhang, and Xiangtai Meng J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00145 • Publication Date (Web): 24 Apr 2018 Downloaded from http://pubs.acs.org on April 25, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

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.

Page 1 of 36 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

The Journal of Organic Chemistry

Phosphine-Catalyzed Domino Reaction of Thioaurones and Allenoate: Synthesis of Benzothiophene Fused Dioxabicyclo[3.3.1]nonane Derivatives Shanshan Ma†, Aimin Yu†, Lei Zhang‡, Xiangtai Meng*† †

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

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

School of Science, Tianjin Chengjian University, Tianjin 300384; College of Chemistry, Beijing

Normal University, Beijing 100875, P. R. China

ABSTRACT: The reaction of thioaurones derivatives with allenoate

catalyzed by

tris(4-methoxyphenyl)phosphane (P(4-MeOC6H4)3) resulted in a domino annulation reaction to produce a benzothiophene fused bridged bicyclic ring, with 40% to 91% yields. The advantages of the methodology include diastereoselective formation of a bridged bicyclic ring in a single step, very mild reaction conditions and success resulting from a broad functional group. The proposed mechanism was tested and supported by DFT calculations. INTRODUCTION Bridged dioxabicyclo[3.3.1]nonane and oxaazabicyclo[3.3.1]nonane skeletons have been found in various natural products and pharmaceuticals, some of them exhibit a wide range of significant bioactivities (Figure 1).1-2 For example, semburin, a bridged ketal derivative, was reported having pharmacological

activity

against

diabetes

and

liver

disorders.3

The

oxaazabicyclo[3.3.1]nonane-containing alkaloid Naucleamide E showed good antiproliferative,

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

antiparasitic, and antimicrobial activities.4 Ephedrannin B exhibited strong anti-inflammatory effects and effectively suppressed the transcription of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β).5 Owing to the promising biological properties and challenging synthesis of these compounds, considerable efforts have been devoted to the development of efficient methods to construct such skeletons,6-8 however, most of them require multistep synthesis or hashed reaction conditions. As a result, straightforward access to bridged dioxabicyclo[3.3.1]nonane skeleton from easily available starting materials under mild reaction conditions is highly desired.9-14 On the other hand, phosphine-catalyzed domino reaction of allenoate is a well-develop method for the synthesis of complex heterocyclic compounds. Since the pioneering [3+2] annulation developed by Lu,15 significant advances have been made in the phosphine-catalyzed [3+2] annulation of allenoates, and many types of carbo- and heterocyclic compounds have been synthesized.16-20 However, rare examples have been reported on the construction of bridged dioxabicyclo[3.3.1]nonane skeleton via phosphine-catalyzed domino reaction of allenoate. To the best of our knowledge, there are only two bridge-ring structures were reported by using phosphine-catalyzed domino reaction of allenoates.21

Figure 1. Examples of compounds containing dioxabicyclo[3.3.1]nonane or


Page 2 of 36

Page 3 of 36 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


oxaazabicyclo[3.3.1]nonane subunit.

Scheme 1. Versatile reactivity of thioaurones and its derivatives

During our ongoing investigation of domino reactions for the efficient construction of benzothiophene fused heterocyclic compounds. We have synthesized a series of thioaurones and its analogues and studied their domino reactions.22 For example, a novel [4+3] annulation reaction of crotonate-derived sulphur ylides using thioauroneswas developed (Scheme 1a).22a Moreover, when the Ar groups on the thioaurones were substituted for ester groups, the solvent-controlled switchable domino reactions with MBH (Morita-Baylis-Hillman) carbonate was reported, and three benzothiophene-fused compounds were synthesized (Scheme 1b).22b In line with our program aiming towards the development of domino reactions for the efficient construction of benzothiophene fused heterocyclic compounds, we started to develop an strategy for the fast and efficient construction of benzothiophene fused dioxabicyclo[3.3.1]nonane skeleton. As a result, we



designed and synthesized a new series of thioaurones (1) bearing an OH or NHTs moiety. A phosphine-catalyzed domino reaction between thioaurones (1) and allenoate was developed (Scheme 1c). To our surprise, a variety of benzothiophene-fused dioxabicyclo[3.3.1]nonane derivatives can be synthesized in a single step. Furthermore, this domino reaction proceeds under very mild conditions and produces the products in high yields and diastereoselectivity. RESULTS AND DISCUSSION The reaction between thioaurone 1a (1.0 equivalent) and allenoate 2 (2.5 equivalents) catalyzed by PPh3 (20 mol%) in THF at room temperature resulted in a new compound produced 3a in a yield of 30% (Table 1, entry 1). After purification by chromatography, 3a was characterised using NMR and HRMS, and the structure solved used single-crystal X-ray diffraction.23 A benzothiophene-fused bridged bicyclic ring was produced in a single step. In this reaction, multiple events occurred sequentially: (1) a bridged bicyclic ring, dioxabicyclo[3.3.1]nonane derivative, was formed in one step, (2) one C-C single bond and two C-O single bonds were formed, (3) the diastereoselectivity was very high, only one isomer was produced. In view of the above result, the domino reaction was optimized further to improve the reaction efficiency. The effect of the solvent on the reaction was studied. When diethyl ether was used as the solvent, only a yield of 25% of 3a was produced (entry 2). When the reaction was carried out in protic solvents, such as methanol, ethanol and isopropanol, there were no improved in yields (entries 3-5). When toluene and acetonitrile were used as solvents, the yields remained low (only 17% and 26%, respectively) (entries 6-7). No products could be formed when the strong polar solvents, DMSO and DMF, were used (entries 8-9). When the reaction was performed in halogenated solvents, e.g. CHCl3 and CH2Cl2 (entries 10-11), the yield was improved to 40% in CH2Cl2. As a result, CH2Cl2


Page 4 of 36

Page 5 of 36 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


was selected as the solvent of choice. Next, the effect of catalysts was studied. Tris(4-fluorophenyl)phosphane (P(4-FC6H4)3) showed low reactivity, producing product 3a with a yield of 29% (entry 12). However when tris(4-methoxyphenyl)phosphane (P(4-MeOC6H4)3) was used as the catalyst, 3a was obtained in a yield of 82% (entry 13). Reducing the amount of 2a to 2.0 and 1.5 equivalents, resulted in a decrease in yield of 3a (entries 14 and 15). Furthermore, decreasing the amount of PPh3 to 10 mol%, resulted in a decrease in yield (entry 16). Therefore, the optimal reaction conditions for this domino reaction was determined to be 20 mol% of P(4-MeOC6H4)3 as the catalyst, 2.5 equivalents of 2 and the solvent CH2Cl2. The experiments were performed at room temperature. Table 1. Optimization of the domino reactiona CO2Bn O Cl OH S

O

O

O

cat.

OBn

+

Cl

solvent, t S

1a

2

3a

entry

cat.

solvent

time/h

yieldb/%

1

PPh3

THF

3.5

30

2

PPh3

EtOEt

8.0

25

3

PPh3

CH3OH

3.5

22

4

PPh3

C2H5OH

4.0

27

5

PPh3

i

PrOH

4.0

29

6

PPh3

toluene

4.0

17

7

PPh3

CH3CN

4.5

26

8

PPh3

DMF

6.0

0

9

PPh3

DMSO

4.5

0

10

PPh3

CHCl3

4.0

25

11

PPh3

CH2Cl2

4.0

40

12

P(4-FC6H4)3

CH2Cl2

4.5

29

13

P(4-MeOC6H4)3

CH2Cl2

4.5

82

c

P(4-MeOC6H4)3

CH2Cl2

6.0

65

d

P(4-MeOC6H4)3

CH2Cl2

8.0

47

e

P(4-MeOC6H4)3

CH2Cl2

8.0

26

14 15 16 a

Unless otherwise indicated, the reaction was performed on a 0.2 mmol scale in solvent (2 mL),



1a/2 = 1:2.5. bIsolated yields. cThe ratio of 1a/2 = 1:2.0. dThe ratio of 1a/2 = 1:1.5. e10 mol% P(4-MeOC6H4)3 was used as catalyst. The scope of substrates with regard to a substitution at 1 was studied. The results are shown in Table 2. The substitution of R2 was determined when R1 was a chloride atom at the C-5 position. Various groups at R2, such as methyl, halogen groups, methoxy group and nitro group were studied (entries 1-9). The reaction of 1b with 2 produced the desired product 3b in a yield of 72% (entry 2). Substrates containing a halogen group, 1c and 1d gave the corresponding products in a yield of 75% and 67%, respectively (entries 3 and 4). In a similar manner, the reactions of fluorine-substituted substrates 1e or 1f with 2 also furnished the desired products 3e and 3f in 60% and 69% yields, respectively (entries 5 and 6). Furthermore, substrate 1e with one Br atom adjacent to a OH group produced the desired product 3e with a longer reaction time in a yield of 86% (entry 7). In addition, it was found that the substrates bearing strong electron-donating (1h, CH3O) or electron-withdrawing (1i, NO2) groups, the corresponding products were not obtained (entries 8 and 9). When the bromo group was substituted at the C-5 position (R1), the corresponding products were produced in good yields (62-73%) independent of the methyl or halogen groups at the R2 (entries 10-14). It is important to note that the substitution of the bromo-group on the phenyl ring is synthetically useful and provides an opportunity for further functionalization. When fluoride was substituted at C-5 position (R1), the reaction was efficient under optimized conditions, producing the corresponding products in yields of 68-91% (entries 15-19). When the electron-donating group (-CH3) was substituted at the C-5 position (R1), the corresponding products were produced in moderate yields (53-68%) (entries 20-24). The substrate 1y containing a NHTs group was also studied producing only a 39% yield with EtOH used as the


Page 6 of 36

Page 7 of 36 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


solvent (entry 25). The C-7 methyl substituted substrate 1z reacted with 2 to produce 3z in a yield of 52% yield (entry 26).

Table 2. Substrates Scope of the Domino Reactiona

entry

R1

R2

time/h

yieldb/%

1

5-Cl (1a)

H

4.5

82 (3a)

2

5-Cl (1b)

4′-CH3

3.5

72 (3b)

3

5-Cl (1c)

4′-Cl

8.0

75 (3c)

4

5-Cl (1d)

4′-Br

5.0

67 (3d)

5

5-Cl (1e)

5′-F

4

60 (3e)

6

5-Cl (1f)

4′-F

4

69 (3f)

7

5-Cl (1g)

3′,4′-Br2

16.5

86 (3g)

8

5-Cl (1h)

5′-CH3O

8

0 (3h)

9

5-Cl (1i)

5′-NO2

10

0 (3i)

10

5-Br (1j)

H

6.0

68 (3j)

11

5-Br (1k)

4’-CH3

2.5

73 (3k)

12

5-Br (1l)

4′-Cl

5.5

62 (3l)

13

5-Br (1m)

4′-Br

6.5

63 (3m)

14

5-Br (1n)

3′,4′-Br2

16.5

69 (3n)

15

5-F (1o)

H

4.5

74 (3o)

16

5-F (1p)

4′-CH3

3.0

75 (3p)

17

5-F (1q)

4′-Cl

6.5

91 (3q)

18

5-F (1r)

4′-Br

2.5

68 (3r)

19

5-F (1s)

3′,4′-Br2

15.5

74 (3s)

20

5-CH3 (1t)

H

6.5

57 (3t)

21

5-CH3 (1u)

4′-CH3

2.5

68 (3u)

22

5-CH3 (1v)

4′-Cl

6.5

65 (3v)

23

5-CH3 (1w)

4′-Br

4.5

65 (3w)

24

5-CH3 (1x)

3′,4′-Br2

14.5

53 (3x)

25

5-Cl (1y)

H

6.5

40 (3y)

26

7-CH3 (1z)

4′-Br

5.0

52 (3z)

c



a

Unless otherwise indicated, the reaction conducted on a 0.2 mmol scale of 1 in 2 mL of CH2Cl2

(molar ratio of 1/2 is 1:2.5, X = OH). bIsolated yields. cX = NHTs

Scheme 2. Scale up Reaction and Transformation

Scheme 3 Asymmetric Domino Reactions

To demonstrate the potential of this domino reaction for preparative purposes, we carried out a reaction of 1a and 2 on a gram-scale (Scheme 2a). The desired product 3a was produced in a yield of 64% when the reaction was scaled up to 1.02 g (1a, 3.54 mmol) under optimized reaction


Page 8 of 36

Page 9 of 36 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


conditions. Moreover, the treatment of compound 3a with 2.2 equivalents of m-CPBA at room temperature in CH2Cl2, lead to the production of compound 4 in a yield of 60% (Scheme 2b). The asymmetric reaction catalyzed by several chiral phosphines was attempted using 1a and 2 as model substrates (Scheme 3). The bifunctional chiral phosphine catalysts P1-P4 were first examined. The corresponding product 3a was obtained in 42%-65% yield, and only P1 gave 13% ee. Furthermore, a hydrid P-chiral phosphine oxide-phosphine P5 was also examined. However, the desired product 3a was not obtained and the starting material 1a was recovered. In addition, Kwon’s phosphine P6 was also screened. The starting material 1a and 2 were consumed and no desired product was obtained. To clarify the reaction mechanism, we synthesized a thioaurone 522a without the hydroxyl group. The reaction of 5 with 2 was performed under optimized reaction conditions. A benzo[4,5]thieno[3,2-b]pyran derivative 6 and 7 were obtained in a yield of 25% and 10%, respectively (Scheme 4).24 Based on the above observation and some related literature,16 a possible reaction mechanism was proposed in Scheme 5. Initially, the nucleophilic binding of P(4-MeOC6H4)3 on the β carbon of 2 generates the intermediate A. Intermediate B, which is the resonance structure of A, reacts with 1a to produce intermediate C. Intermediate D, which is the resonance structure of C, is transformed into intermediate E by an intramolecular O-Michael addition. And subsequently, Intermediate E transformed into F. Finally, 3a forms by a H2O assisted proton transfer and O-Michael addition reaction process. Scheme 4. Control Experiment



Scheme 5. Proposed Mechanism

The possible reaction mechanisms and corresponding free-energy variations determined by B3LYP/6-31+G* calculations are presented in Figure 2, with the atomic numbering. The reaction is initiated by the nucleophilic binding by the C1-atom of the allene-phosphine complex 2 onto the olefinic C4-atom of 1a via the transition state TS-1, which has a free-energy barrier of 17.9 kcal/mol. This elementary step produces an unstable intermediate (INT-1) which has a free-energy absorption of 5.4 kcal/mol. The carbonyl oxygen forms a C−O bond with the olefinic C2-atom,


Page 10 of 36

Page 11 of 36 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


resulting in the formation of a six-member-ring structure and loss of the phosphine group. DFT calculations identify the location of the transition state TS-2, suggesting a concerted nucleophilic substitution process occurring at the olefinic C2-atom involving a low free-energy barrier of 10.1 kcal/mol. A very stable intermediate (INT-2) is produced during the reaction with a free-energy exothermicity of up to 26.5 kcal/mol. Attempts to locate a tetravalent C2-structure as an intermediate, corresponding to the C2−O bond formation without the removal of the phosphine group failed, possibly due to the steric congestion of the tetravalent C2-structure containing a bulky phosphine group. The hydroxyl oxygen should form a C−O bond with the C2-atom and simultaneously the hydroxyl hydrogen needs to shift to the C3-atom to produce the desired product. The hydroxyl hydrogen had difficulty in transferring to the C3-atom directly, due to the geometrically unfavourable arrangements between the two proton-transfer termini. However, a water molecule could facilitate the proton-transfer by serving as a bridging group using hydrogen-bonding. Specifically, the hydroxyl hydrogen shifts to the water oxygen initially and the water hydrogen then shifts to the C3-atom, as reflected by the transition state TS-3 geometry.25 Calculations suggest that the C2−O bond-coupling occurs at this proton-transfer, resulting in these structural transformations occurring in a concerted manner. Relaxation of TS-3 along the forward reaction route could lead to the desired product 3a. Computationally using IRC calculations, the hydrogen-bond complexes INT-2-H2O and 3a-H2O have been located on the potential energy surfaces, which could bind to the transition state TS-3. Free-energy calculations demonstrate that the final step, INT-2-H2O → TS-3 → 3a-H2O, is the rate-determining step of the overall reaction and involves a free-energy



barrier of 28.4 kcal/mol, which appears to be slightly larger than that measured from the experimental temperature (free-energy barrier should be less than 25.0 kcal/mol at room temperature). Such an error could result from the uncertainty of DFT calculations, and the possible tunnelling effect could make the proton-transfer more accessible at room temperature. In addition, the overall reaction releases free-energy of 36.7 kcal/mol, consistent with both the kinetic accessibility and thermodynamic spontaneity.

Figure 2. Solvation Gibbs free energy profile for the domino reaction. CONCLUSION In conclusion, a phosphine-catalyzed sequential annulation domino reaction of allenoate and thioaurones was developed. A series of benzothiophene fused bridged bicyclic compounds were synthesized, with good yields and high diastereoselective. The proposed mechanism was


Page 12 of 36

Page 13 of 36 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


investigated and supported by DFT calculations. Further study of the products’ bioactivities is currently underway, and the results will be reported in the future. EXPERIMENTAL SECTION General Information. All reactions were performed under Ar atmospheres in oven-dried glassware with magnetic stirring. Unless otherwise stated, all reagents and solvents were purchased from commercial suppliers (Aldrich, TCI or Alfa Aesar) and used without further purification. TLC monitored all reactions with silica gel-coated plates. Flash column chromatography was performed using 200-300 mesh silica gel. 1H- and

13

C-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 2.500 and 13C NMR δ 39.520). HRMS were obtained on Waters Xevo Q-TOF MS with ESI resource. Melting points were measured on a RY-I apparatus and are reported uncorrected. General Procedure for the synthesis of 1a-1v. Under Ar atmosphere, to a solution of substituted benzo[b]thiophen-3(2H)-one (2 mmol) in toluene 10 mL was added substituted salicylaldehyde (2.4 mol) and piperidine (2-3 drops). The resulting mixture was heated at 85 oC for 2-3 h. After the reaction completed (monitored by TLC), the solvent was removed under reduced pressure. The crude product was recrystallized from EtOH to give the pure 1a-1v. (Z)-5-Chloro-2-(2-hydroxybenzylidene)benzo[b]thiophen-3(2H)-one (1a). Reaction time: 2.5 h; Brown solid; 529.9 mg (92%); mp: 217-218 °C; IR(KBr): 3436, 2993, 1656, 1534, 1188 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.29 (s, 1H), 7.70 – 8.00 (m, 3H), 7.63 (d, J = 7.2 Hz, 1H), 7.25 – 7.48; (m, 1H), 7.00 (d, J = 7.6 Hz, 2H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 186.4, 158.4, 143.8, 135.3, 132.9, 131.5, 131.0, 129.1, 129.0, 128.3, 126.2, 125.7, 120.5, 119.7, 116.3



Page 14 of 36

ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H10O2SCl 289.0085; Found 289.0083. (Z)-5-Chloro-2-(2-hydroxy-5-methylbenzylidene)benzo[b]thiophen-3(2H)-one (1b). Reaction time: 3.0 h; Red solid; 489.3 mg (81%); mp: 195-196 °C; IR (KBr): 3181, 3033, 1643, 1569, 1249 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.24 (s, 1H), 7.60 – 7.94 (m, 3H), 7.38 (s, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H) 2.26 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 186.3, 156.4, 143.8, 135.2, 133.6, 131.6, 131.0, 129.04, 128.95, 128.2, 128.0, 126.2, 125.6, 120.2, 116.2, 20.3 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H12O2SCl 303.0241; Found 303.0246. (Z)-5-Chloro-2-(5-chloro-2-hydroxybenzylidene)benzo[b]thiophen-3(2H)-one (1c). Reaction time: 3.0 h; Brown solid; 489.4 mg (76%); mp: 218-219 °C; IR (KBr): 3191, 3039, 1656, 1555, 1250 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.09 (s, 1H), 7.69 – 7.84 (m, 3H), 7.49 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 186.3, 157.0, 143.5, 135.4, 132.0, 131.24, 131.19, 129.7, 127.9, 127.1, 126.3, 125.7, 123.1, 122.1, 117.9 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H9O2SCl2 323.9773; Found 323.9777. (Z)-2-(5-Bromo-2-hydroxybenzylidene)-5-chlorobenzo[b]thiophen-3(2H)-one (1d). Reaction time: 2.5 h; Brown solid; 607.4 mg (83%); mp: 242-243 °C; IR (KBr): 3203, 2992, 1657, 1554, 1251 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.11 (s, 1H), 7.76 – 7.92 (m, 3H), 7.60 – 7.69 (m, 1H), 7.49 (dd, 1H), 6.95 (d, J = 8.7 Hz, 1H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 186.3, 157.4, 143.5, 135.5, 134.8, 131.3, 131.2, 130.8, 129.8, 127.0, 126.4, 125.7, 122.7, 118.3, 110.6 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H9O2SBrCl 367.9268; Found 367.9267. (Z)-5-chloro-2-(5-fluoro-2-hydroxybenzylidene)benzo[b]thiophen-3(2H)-one

(1e)

Reaction

time: 2.5 h; Brown solid; 596.7 mg (65%); mp 217-218 oC; IR(KBr): 3215, 2943, 1657, 1553,


Page 15 of 36 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


1252 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.16 (s, 1H), 7.71 – 7.93 (m, 3H), 7.18 – 7.36 (m, 2H), 6.99 (dd, J = 8.7, 4.7 Hz, 1H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 186.3, 156.3, 154.7, 154.0, 143.5, 135.5, 131.2 (d, J = 10.3 Hz), 129.7, 127.7, 126.3, 125.7, 121.1 (d, J = 7.8 Hz), 119.3 (d, J = 23.1 Hz), 117.4 (d, J = 7.9 Hz), 114.2 (d, J = 24.1 Hz) ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H9O2SClF 306.9990; Found 306.9989. (Z)-5-chloro-2-(4-fluoro-2-hydroxybenzylidene)benzo[b]thiophen-3(2H)-one

(1f)

Reaction

time: 2.5 h; Brown solid; 550.8 mg (60%); mp 259-260 oC; IR(KBr): 3158, 2972, 1652, 1552, 1255 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.20 (s, 1H), 7.73 – 7.91 (m, 3H), 7.56 – 7.71 (m, 1H), 6.72 – 6.93 (m, 2H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 186.7, 164.8 (d, J = 251.4 Hz), 160.7 (d, J = 11.8 Hz), 144.1, 135.8, 132.0, 131.53, 131.52, 131.4, 128.5, 126.7, 126.2, 118.1 (d, J = 2.7 Hz), 107.7 (d, J = 22.4 Hz), 103.7 (d, J = 24.0 Hz) ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H9O2SClF 306.9990; Found 306.9993. (Z)-5-Chloro-2-(3,5-dibromo-2-hydroxybenzylidene)benzo[b]thiophen-3(2H)-one

(1g).

Reaction time: 3.0 h; Brown solid; 692.4 mg (78%); mp: 249-250 °C; IR (KBr): 3307, 2993, 1663, 1556, 1250 cm-1; A reasonable 1H NMR and 13C NMR spectrum could not be obtained because of its quite low solubility. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H8ClBr2O2S 444.8295; Found 444.8304. (Z)-5-chloro-2-(2-hydroxy-5-methoxybenzylidene)benzo[b]thiophen-3(2H)-one (1h). Brown solid; 667.8 mg; mp 154-155 oC; IR(KBr): 3213, 1658, 1575, 1283 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.25 (s, 1H), 7.83 – 7.91 (m, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.14 (s, 1H), 7.02 (dd, J = 8.9, 2.2 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 3.78 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 186.2, 152.6, 152.2, 143.6, 135.2, 131.5, 131.0, 128.9, 128.5, 126.1, 125.6,



120.6, 119.5, 117.1, 112.5, 55.5 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H12O3SCl 319.0190; Found 319.0197. (Z)-5-chloro-2-(2-hydroxy-5-nitrobenzylidene)benzo[b]thiophen-3(2H)-one (1i). Yellow solid; 649.3 mg; mp 179-180 oC; IR(KBr): 3121, 2925, 1659, 1575, 1213 cm-1; 1H NMR (400 MHz, DMSO-d6) δ = 8.45 (s, 1H), 8.22 (d, J = 8.9 Hz, 1H), 8.12 (s, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.75 – 7.87 (m, 2H), 7.12 (d, J = 9.1 Hz, 1H), 1.22 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 186.2, 163.9, 143.3, 139.4, 135.6, 131.3, 131.0, 130.8, 127.7, 126.4, 126.1, 125.7, 124.7, 120.9, 116.6 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C15H8O4SClNNa 355.9755; Found 355.9758. (Z)-5-Bromo-2-(2-hydroxybenzylidene)benzo[b]thiophen-3(2H)-one (1j). Reaction time: 2.0 h; Brown solid; 491.3 mg (74%); mp: 216-217 °C; IR (KBr): 3220, 2946, 1651, 1550, 1252 cm-1; 1

H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.28 (s, 1H), 7.97 (s, 1H), 7.84 – 7.93 (m, 1H),

7.79 (d, J = 8.4Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 6.99 (dd, J = 7.6, 4.8 Hz, 2H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 186.3, 158.3, 144.3, 138.0, 132.9, 131.9, 129.1, 129.0, 128.7, 128.2, 126.6, 120.5, 119.8, 119.0, 116.3 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H10O2SBr 332.9579; Found 332.9592. (Z)-5-Bromo-2-(2-hydroxy-5-methylbenzylidene)benzo[b]thiophen-3(2H)-one (1k). Reaction time: 2.5 h; Red solid; 588.1 mg (85%); mp: 200-201 °C; IR (KBr): 3140, 3034, 1643, 1549, 1250 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.24 (s, 1H), 7.82 – 7.94 (m, 2H), 7.77 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 2.26 (s, 3H) ppm; 13

C NMR (100 MHz, DMSO-d6) δ 186.2, 156.3, 144.3, 137.9, 133.6, 131.9, 129.01, 128.94, 128.5,

128.2, 127.8, 126.5, 120.2, 118.90, 116.1, 20.3 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H12O2SBr 346.9736; Found 346.9753.


Page 16 of 36

Page 17 of 36 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


(Z)-5-Bromo-2-(5-chloro-2-hydroxybenzylidene)benzo[b]thiophen-3(2H)-one (1l). Reaction time: 2.5 h; Brown solid; 585.5 mg (80%); mp: 234-235 °C; IR (KBr): 3190, 2950, 1652, 1552, 1251 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.08 (s, 1H), 7.70 – 7.87 (m, 3H), 7.61 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 186.2, 157.0, 144.0, 138.2, 132.0, 131.6, 129.6, 128.7, 127.9, 127.1, 126.6, 123.1, 122.1, 119.2, 117.9 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H9O2SClBr 366.9190; Found 366.9209. (Z)-5-Bromo-2-(5-bromo-2-hydroxybenzylidene)benzo[b]thiophen-3(2H)-one

(1m).

Reaction time: 2.0 h; Brown solid; 623.0 mg (76%); mp: 229-230 °C; IR (KBr): 3161, 2947, 1652, 1551, 1251 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.10 (s, 1H), 7.70 – 7.96 (m, 3H), 7.63 (s, 1H), 7.47 (s, 1H), 6.94 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 186.2, 157.5, 144.0, 138.1, 134.8, 131.6, 130.8, 129.5, 128.6, 127.0, 126.6, 122.7, 119.1, 118.4, 110.5 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H9O2SBr2 410.8685; Found 410.8696. (Z)-5-Bromo-2-(3,

5-dibromo-2-hydroxybenzylidene)benzo[b]thiophen-3(2H)-one

(1n).

Reaction time: 2.0 h; Yellow solid; 761.0 mg (78%); mp: 249-250 °C; IR (KBr): 3173, 2947, 1644, 1549, 1250 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.11 (s, 1H), 7.82 – 8.02 (m, 4H), 7.69 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 186.1, 153.6, 144.0, 138.4, 136.5, 131.6, 131.5, 130.3, 128.8, 127.2, 126.7, 125.7, 119.2, 114.0, 111.5 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H8O2SBr3 488.7790; Found 488.7794. (Z)-5-Fluoro-2-(2-hydroxybenzylidene)benzo[b]thiophen-3(2H)-one (1o). Reaction time: 3.0 h; Red solid; 462.5 mg (85%); mp: 135-136 °C; IR (KBr): 3026, 2947, 1659, 1555, 1250 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.27 (s, 1H), 7.83 (dd, J = 8.0, 4.4 Hz, 1H), 7.62 (dd, J = 12.4, 7.6 Hz, 3H), 7.30 – 7.39 (m, 1H), 6.98 (t, J = 7.8 Hz, 2H) ppm;


13

C NMR (100 MHz,


DMSO-d6) δ 186.8 (d, J = 3.0 Hz), 160.8 (d, J = 244.6 Hz), 158.3, 141.0 (d, J = 1.8 Hz), 132.8, 131.5 (d, J = 7.3 Hz), 129.1, 128.8, 126.3 (d, J = 7.9 Hz), 123.4 (d, J = 24.3 Hz), 120.6, 119.8, 116.2, 112.5 (d, J = 23.1 Hz) ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H10O2SF 273.0380; Found 273.0386. (Z)-5-Fluoro-2-(2-hydroxy-5-methylbenzylidene)benzo[b]thiophen-3(2H)-one (1p). Reaction time: 3.0 h; Red solid; 463.4 mg (81%); mp: 136-137 °C; IR (KBr): 3039, 2948, 1651, 1553, 1258 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.23 (s, 1H), 7.81 (s, 1H), 7.59 (s, 2H), 7.36 (s, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 2.25 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 186.7 (d, J = 2.3 Hz), 160.8 (d, J = 246.0 Hz), 156.3, 140.6, 133.5, 131.6 (d, J = 7.2 Hz), 129.0, 128.9, 128.5, 128.2, 126.2 (d, J = 7.8 Hz), 123.3 (d, J = 24.1 Hz), 120.3, 116.1, 112.3 (d, J = 23.0 Hz), 20.3 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H12O2SF 287.0537; Found 287.0542. (Z)-2-(5-Chloro-2-hydroxybenzylidene)-5-fluorobenzo[b]thiophen-3(2H)-one (1q). Reaction time: 2.5 h; Yellow solid; 483.5 mg (79%); mp: 211-212 °C; IR (KBr): 3379, 2947, 1662, 1554, 1270 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.11 (s, 1H), 7.78 – 7.92 (m, 1H), 7.62 (t, J = 6.2 Hz, 3H), 7.36 (d, J = 8.8 Hz, 1H), 6.99 (dd, J = 8.8, 1.6 Hz, 1H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 186.7 (d, J = 2.9 Hz), 160.8 (d, J = 245.0 Hz), 157.0, 140.2 (d, J = 1.7 Hz), 131.9, 131.2 (d, J = 7.4 Hz), 130.3, 127.9, 126.9, 126.4 (d, J = 8.0 Hz), 123.6 (d, J = 24.3 Hz), 123.1, 122.2, 117.9, 112.5 (d, J = 23.2 Hz) ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H9O2SClF 306.9990; Found 307.0000. (Z)-2-(5-Bromo-2-hydroxybenzylidene)-5-fluorobenzo[b]thiophen-3(2H)-one (1r). Reaction time: 2.5 h; Orange solid; 609.0 mg (87%); mp: 212-213 °C; IR (KBr): 3449, 2950, 1656, 1544,


Page 18 of 36

Page 19 of 36 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


1261 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.11 (s, 1H), 7.88 (dd, J = 9.6, 4.4 Hz, 1H), 7.57 – 7.68 (m, 3H), 7.48 (dd, J = 8.8, 2.4 Hz, 1H) 6.95 (d, J = 8.8 Hz, 1H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 186.6 (d, J = 3.0 Hz), 160.8 (d, J = 244.8 Hz), 158.4, 140.2, (d, J = 2.0 Hz), 134.8, 131.4 (d, J = 7.6 Hz), 130.9, 129.7, 127.4, 126.4 (d, J = 7.7 Hz), 123.5 (d, J = 24.0 Hz), 122.8, 118.7, 112.5 (d, J = 23.1 Hz), 110.4 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H9O2SBrF 350.9485; Found 350.9495. (Z)-2-(3,

5-Dibromo-2-hydroxybenzylidene)-5-fluorobenzo[b]thiophen-3(2H)-one

(1s).

Reaction time: 2.5 h; Brown solid; 676.0 mg (79%); mp: 242-243 °C; IR (KBr): 3437, 2969, 1663, 1549, 1254 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.08 (s, 1H), 7.84 – 7.94 (m, 2H), 7.58 – 7.70 (m, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 186.6 (d, J = 3.0 Hz), 160.9 (d, J = 245.2 Hz), 153.5, 140.2 (d, J = 1.7 Hz), 136.5, 132.3, 131.1 (d, J = 7.3 Hz), 130.3, 127.0 (d, J = 2.6 Hz), 126.5 (d, J = 7.7 Hz), 125.8, 123.9 (d, J = 24.1 Hz), 114.0, 112.7 (d, J = 23.3 Hz) 111.7 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H8O2SBr2F 428.8590; Found 428.8605. (Z)-2-(2-Hydroxybenzylidene)-5-methylbenzo[b]thiophen-3(2H)-one (1t). Reaction time: 3.0 h; Red solid; 412.8 mg (77%); mp: 179-180 °C; IR (KBr): 3468, 3041, 1649, 1553, 1258 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.24 (s, 1H), 7.64 (dd, J = 16.6, 8.4 Hz, 3H), 7.52 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 6.98 (t, J = 7.9 Hz, 2H), 2.36 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 187.5, 158.1, 142.2, 136.8, 135.7, 132.4, 130.0, 129.0, 128.7, 127.7, 126.5, 124.1, 120.8, 119.7, 116.2, 20.3 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C16H12O2SNa 291.0450; Found 291.0453. (Z)-2-(2-Hydroxy-5-methylbenzylidene)-5-methylbenzo[b]thiophen-3(2H)-one

(1u).

Reaction time: 2.5 h; Brown solid; 451.3 mg (80%); mp: 242-243 °C; IR (KBr): 3450, 3044, 1656,



Page 20 of 36

1553, 1264 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.22 (s, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.14 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 2.36 (s, 3H), 2.27 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 187.4, 156.0, 142.1, 136.7, 135.6, 133.3, 130.0, 128.9, 128.4, 128.1, 127.77, 126.4, 124.1, 120.5, 116.0, 20.3, 20.2 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H15O2S 283.0787; Found 283.0795. (Z)-2-(5-Chloro-2-hydroxybenzylidene)-5-methylbenzo[b]thiophen-3(2H)-one (1v). Reaction time: 2.5 h; Yellow solid; 495.3 mg (80%); mp: 208-209 °C; IR (KBr): 3203, 2948, 1655, 1553, 1256 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.07 (s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.44 – 7.54 (m, 2H), 7.34 (dd, J = 8.4, 2.4 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 2.35 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 187.4, 156.8, 141.8, 137.0, 135.9, 131.5, 130.1, 129.7, 127.9, 126.5, 125.9, 124.3, 123.1, 122.4, 117.8, 20.3 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C16H11O2SClNa 325.0060; Found 325.0062. (Z)-2-(5-Bromo-2-hydroxybenzylidene)-5-methylbenzo[b]thiophen-3(2H)-one

(1w).

Reaction time: 3.0 h; Brown solid; 539.7 mg (78%); mp: 242-243 °C; IR (KBr): 3203, 2992, 1650, 1556, 1253 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.07 (s, 1H), 7.60 – 7.71 (m, 3H), 7.52 (d, J = 7.8 Hz, 1H), 7.46 (dd, J = 8.7, 2.3 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 2.35 (s, 3H) ppm;

13

C NMR (100 MHz, DMSO-d6) δ 187.4, 157.2, 141.8, 137.0, 135.9, 130.8, 130.1, 129.7,

128.9, 128.2, 126.5, 125.8, 124.3, 123.0, 118.2, 20.3 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H12O2SBr 346.9736; Found 346.9746. (Z)-2-(3,

5-Dibromo-2-hydroxybenzylidene)-5-methylbenzo[b]thiophen-3(2H)-one

(1x).

Reaction time: 2.0 h; Brown solid; 686.7 mg (81%); mp: 242-243 °C; IR (KBr): 3435, 3035, 1631, 1551, 1242 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.07 (s, 1H), 7.90 (d, J = 1.9 Hz,


Page 21 of 36 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


1H), 7.66 – 7.75 (m, 3H), 7.57 (d, J = 8.1 Hz, 1H), 2.38 (s, 3H) ppm;

13

C NMR (100 MHz,

DMSO-d6) δ 187.3, 153.3, 141.8, 137.3, 136.1, 132.3, 130.2, 129.5, 126.6, 126.0, 125.9, 124.4, 113.9, 111.6, 20.3 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H11SBr2O2 424.8841; Found 424.8845.

(Z)-N-(2-((5-Chloro-3-oxobenzo[b]thiophen-2(3H)-ylidene)methyl)phenyl)-4-methylbenzenes ulfonamide (1y). Reaction time: 2.0 h; Green solid; 652.7 mg (74%); mp: 197-198 °C; IR (KBr): 3194, 2948, 1667, 1556, 1259 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 7.71 – 7.97 (m, 4H), 7.60 (d, J = 7.2 Hz, 1H), 7.33 – 7.51 (m, 4H), 7.22 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 1.91 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 185.8, 144.2, 142.8, 136.7, 136.2, 135.5, 131.6, 131.4, 131.2, 131.2, 131.1, 130.8, 129.7, 129.0, 128.8, 127.5, 126.6, 126.2, 125.8, 20.4 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H17O3S2NCl 442.0333; Found 442.0349. (Z)-2-(5-Bromo-2-hydroxybenzylidene)-7-methylbenzo[b]thiophen-3(2H)-one (1z). Reaction time: 3.0 h; Red solid; 723.0 mg (72%); mp: 201-202 °C; IR (KBr): 3153, 2948, 1631, 1551, 1253 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.12 (s, 1H), 7.64 – 7.78 (m, 2H), 7.58 (d, J = 7.2 Hz, 1H), 7.49 (dd, J = 8.7, 2.2 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 2.38 (s, 3H) ppm;

13

C NMR (100 MHz, DMSO-d6) δ 187.8, 157.2, 144.4, 136.2, 134.6, 133.2,

130.7, 129.5, 126.3, 124.0, 122.9, 118.3, 110.5, 18.3 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H12O2SBr 346.9736; Found 346.9746. Benzyl 2-((6S,13R)-9-chloro-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-yl)ac etate (3a). White solid; 75.8 mg; mp: 136-137 °C; IR (KBr): 2959, 1730, 1209, 1175 cm-1; 1H



Page 22 of 36

NMR (400 MHz, CDCl3) δ 7.61 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.32 (dq, J = 7.2, 3.9 Hz, 5H), 7.21 (dd, J = 8.4, 2.0 Hz, 1H), 7.16 (dd, J = 7.6, 0.8Hz, 1H), 7.07 – 7.09 (m, 1H), 6.89 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 5.03 – 5.29 (m, 2H), 4.10 (t, J = 2.4 Hz, 1H), 3.22 – 3.47 (m, 2H), 2.70 (dd, J = 13.2, 3.2 Hz, 1H), 2.58 (dd, J = 13.2, 2.8 Hz, 1H) ppm;

13

C

NMR (100 MHz, CDCl3) δ 167.8, 151.7, 140.6, 135.2, 133.7, 131.7, 130.2, 128.2, 128.0, 127.9, 127.8, 126.2, 125.6, 124.8, 123.4, 121.2, 119.7, 118.5, 116.0, 98.1, 66.4, 44.2, 29.9, 29.8 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H20O4SCl 463.0765; Found 463.0779. Benzyl 2-((6S,13R)-9-chloro-2-methyl-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxoc in-6-yl)acetate (3b). White solid; 68.6 mg; mp: 134-135 °C; IR (KBr): 2951, 1723, 1208, 1192 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 2.0 Hz 1H), 7.54 (d, J =8.4 Hz 1H), 7.27 – 7.37 (m, 5H), 7.21 (dd, J = 8.8, 2.0 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 13.4, 1.6 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 5.14 – 5.24 (m, 2H), 4.04 (t, J = 3.0 Hz, 1H), 3.20 – 3.39 (m, 2H), 2.68 (dd, J = 13.4, 3.4 Hz, 1H), 2.56 (dd, J = 13.2, 2.8 Hz, 1H), 2.26 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.1, 149.8, 141.0, 135.6, 134.0, 132.0, 130.8, 130.5, 128.7, 128.5, 128.3, 128.1, 126.9, 125.6, 125.0, 123.7, 120.0, 118.8, 116.0, 98.4, 66.6, 44.6, 30.3, 30.2, 20.5 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C27H22O4SCl 477.0927; Found 477.0940. Benzyl 2-((6S,13R)-2,9-dichloro-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-y l)acetate (3c). Red solid; 74.4 mg; mp: 162-163 °C; IR (KBr): 2951, 1726, 1202, 1176 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 2.0 Hz, 2H), 7.56 (d, J = 2.4 Hz, 5H), 7.29 – 7.36 (m, 1H), 7.23 (dd, J = 8.8, 2.0 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 7.04 (dd, J = 8.6, 2.6 Hz, 1H), 6.72 (d, J =


Page 23 of 36 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


8.8 Hz, 1H), 5.18 (d, J = 2.0 Hz, 2H), 4.06 (t, J = 3.0 Hz, 1H), 3.32 (d, J = 2.0 Hz, 2H), 2.68 (dd, J = 13.4, 3.4 Hz, 1H), 2.57 (dd, J = 13.2, 2.8 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 167.9, 150.7, 141.1, 135.5, 134.1, 131.8, 130.7, 128.6, 128.4, 128.2, 128.1, 127.4, 126.2, 126.1, 125.3, 123.8, 120.0, 118.0, 117.6, 98.5, 77.3, 66.7, 44.3, 30.0, 29.9 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H18O4SCl2+H 497.0376; Found 497.0374. Benzyl 2-((6S,13R)-2-bromo-9-chloro-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxoci n-6-yl)acetate (3d). Red solid; 72.4 mg; mp: 165-166 °C; IR (KBr): 2993, 1725, 1203, 1174 cm-1; 1

H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.30 – 7.35 (m,

5H), 7.29 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 8.6, 2.2 Hz, 1H), 7.18 (dd, J = 8.4, 2.4 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 5.19 (d, J = 1.6 Hz, 2H), 4.05 (t, J = 3.0 Hz, 1H), 3.32 (d, J = 2.0 Hz, 2H), 2.68 (dd, J = 13.4, 3.4 Hz, 1H), 2.56 (dd, J = 13.2, 2.8 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 167.9, 151.2, 141.0, 135.4, 134.0, 131.8, 131.0, 130.7, 129.1, 128.6, 128.4, 128.2, 127.9, 125.3, 123.8, 120.0, 118.1, 118.0, 113.4, 98.5, 77.3, 66.7, 44.3, 29.9, 29.8 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H19O4SClBr 540.9870; Found 540.9868. Benzyl 2-((6R,13R)-9-chloro-2-fluoro-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxoci n-6-yl)acetate (3e). White solid; 57.6 mg; mp 153-154 oC; IR(KBr): 2959, 1724, 1216, 1185 cm-1; 1

H NMR (400 MHz, CDCl3) δ = 7.62 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.32 (t, J = 4.8

Hz, 5H), 7.23 (dd, J = 8.6, 1.9 Hz, 1H), 6.89 (dd, J = 8.0, 2.7 Hz, 1H), 6.76 (dtd, J = 16.8, 8.8, 3.8 Hz, 2H), 5.19 (d, J = 2.6 Hz, 2H), 4.06 (s, 1H), 3.32 (d, J = 2.9 Hz, 2H), 2.69 (dd, J = 13.3, 3.1 Hz, 1H), 2.58 (dd, J = 13.3, 2.8 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ = 168.0, 157.1 (d, J =



239.3 Hz), 148.0 (d, J = 2.2 Hz), 141.2, 135.5, 134.1, 131.9, 130.7, 128.6, 128.4, 128.2, 127.0 (d, J = 7.3 Hz), 125.3, 123.8, 120.1, 118.0, 117.2 (d, J = 8.1 Hz), 114.6 (d, J = 23.2 Hz), 112.9 (d, J = 23.7 Hz), 98.4, 66.7, 44.4, 30.2, 29.9 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C26H18O4SClFNa 503.0491; Found 503.0497. Benzyl 2-((6R,13R)-9-chloro-3-fluoro-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxoci n-6-yl)acetate (3f). White solid; 66.2 mg; mp 217-218 oC; IR(KBr): 2951, 1724, 1213, 1175 cm-1; 1

H NMR (400 MHz, CDCl3) δ = 7.64 (d, J = 1.7 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.35 (q, J = 7.2,

6.7 Hz, 5H), 7.25 (dd, J = 8.6, 1.9 Hz, 1H), 7.12 (dd, J = 8.2, 6.3 Hz, 1H), 6.63 (td, J = 8.4, 2.5 Hz, 1H), 6.54 (dd, J = 9.8, 2.5 Hz, 1H), 5.22 (s, 2H), 4.11 (d, J = 2.6 Hz, 1H), 3.35 (s, 2H), 2.71 (dd, J = 13.3, 3.2 Hz, 1H), 2.62 (dd, J = 13.3, 2.8 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ = 168.0, 162.3 (d, J = 245.0 Hz), 153.0 (d, J = 12.5 Hz), 140.7, 135.5, 134.0, 131.9, 130.7, 128.6, 128.4, 128.2, 127.1 (d, J = 9.8 Hz), 125.2, 123.8, 121.9 (d, J = 3.0 Hz), 112.0, 118.7, 108.3 (d, J = 21.9 Hz), 104.1 (d, J = 25.5 Hz), 98.4, 66.7, 44.3, 30.2, 29.6 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C26H18O4SClFNa 503.0491; Found 503.0494. Benzyl 2-((6S,13R)-2,3-dibromo-9-chloro-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dio xocin-6-yl)acetate (3g). Red solid; 106.3 mg; mp: 159-160 °C; IR (KBr): 2949, 1753, 1204, 1169 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.32 (s, 5H), 7.25 (s, 1H), 5.19 (q, J = 12.2 Hz, 2H), 4.08 (t, J = 3.0 Hz, 1H), 3.40 (d, J = 5.2 Hz, 2H), 2.68 (dd, J = 13.4, 3.4 Hz, 1H), 2.59 (dd, J = 13.2, 2.8 Hz, 1H), 1.21 (t, J = 7.0 Hz, 1H) ppm;

13

C NMR (100 MHz, CDCl3) δ 167.8, 148.5, 141.1, 135.3, 134.10, 134.1, 131.7,


Page 24 of 36

Page 25 of 36 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


130.8, 129.0, 128.6, 128.4, 128.2, 128.2, 125.6, 123.8, 120.2, 117.2, 113.4, 111.1, 99.3, 66.9, 44.0, 30.2, 29.9 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H18O4SClBr2 618.8970; Found 618.8969. Benzyl 2-((6S,13R)-9-bromo-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-yl)ac etate (3j). Red solid; 68.8 mg; mp: 128-129 °C; IR (KBr): 2960, 1732, 1208, 1160 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.28 – 7.38 (m, 6H), 7.16 (d, J = 7.6 Hz, 1H), 7.09 (td, J = 8.1, 1.4 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 6.83 (d, J = 4.0 Hz, 1H), 5.10 – 5.30 (m, 2H), 4.10 (t, J = 3.0 Hz, 1H), 3.20 – 3.45 (m, 2H), 2.70 (dd, J = 13.4, 3.4 Hz, 1H), 2.70 (dd, J = 13.2, 2.8 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.1, 152.0, 140.8, 135.5, 134.5, 132.4, 128.6, 128.3, 128.2, 128.1, 127.7, 126.5, 125.9, 124.1, 123.0, 121.5, 118.7, 118.2, 116.3, 98.4, 66.7, 44.6, 30.2, 30.1 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H20O4SBr 507.0266; Found 507.0272. Benzyl

2-((6S,13R)-9-bromo-2-methyl-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-

g][1,3]dioxocin-6-yl)acetate (3k). White solid; 76.0 mg; mp: 118-119 °C; IR (KBr): 2949, 1725, 1207, 1193 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.27 – 7.39 (m, 6 H), 6,96 (d, J = 1.2 Hz, 1H), 6.89 (dd, J = 8.2, 1.8 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 5.19 (d, J = 3.2 Hz, 2H), 4.04 (t, J = 3.0 Hz, 1H), 3.22 – 3.41 (m, 2H), 2.68 (dd, J = 13.4, 3.4 Hz, 1H), 2.56 (dd, J = 13.2, 2.8 Hz, 1H), 2.26 (s, 3H) ppm; 13C NMR (100MHz, CDCl3) δ 168.1, 149.8, 140.9, 135.6, 134.5, 132.5, 130.8, 128.7, 128.6, 128.3, 128.1, 127.6, 126.9, 125.6, 124.0, 123.0, 118.7, 118.2, 116.0, 98.4, 66.7, 44.6, 30.4, 30.2, 20.5 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C27H22O4SBr 521.0422; Found 521.0449.



Page 26 of 36

Benzyl 2-((6S,13R)-9-bromo-2-chloro-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxoci n-6-yl)acetate (3l). Red solid; 67.0 mg; mp: 128-129 °C; IR (KBr): 2961, 1732, 1199, 1079 cm-1; 1

H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.28 – 7.40 (m,

6H), 7.15 (d, J = 2.4 Hz, 1H), 7.03 (dd, J = 8.6, 2.6 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 5.21 – 5.15 (m, 2H), 4.06 (t, J = 3.0 Hz, 1H), 3.32 (d, J = 2.3 Hz, 2H), 2.68 (dd, J = 13.4, 3.2 Hz, 1H), 2.57 (dd, J = 13.2, 2.8 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 167.9, 150.7, 140.9, 135.5, 134.6, 132.2, 128.6, 128.4, 128.2, 128.1, 127.9, 127.4, 126.2, 126.1, 124.1, 123.1, 118.4, 117.9, 117.6, 98.5, 66.8, 44.3, 29.94, 29.88 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H19O4SClBr 540.9870; Found 540.9876. Benzyl 2-((6S,13R)-2,9-dibromo-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-y l)acetate (3m). Red solid; 73.6 mg; mp: 128-129 °C; IR (KBr): 2950, 1728, 1209, 1174 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.28 – 7.40 (m, 7H), 7.17 (dd, J = 8.6, 2.3 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 5.18 (s, 2H), 4.06 (d, J = 5.9 Hz, 1H), 3.31 (d, J = 2.1 Hz, 2H), 2.68 (dd, J = 13.3, 3.3 Hz, 1H), 2.56 (dd, J = 13.3, 2.9 Hz, 1H) ppm;

13

C NMR (100

MHz, CDCl3) δ 167.9, 150.7, 141.1, 135.5, 134.1, 131.8, 130.7, 128.6, 128.4, 128.2, 128.1, 127.4, 126.2, 126.1, 125.3, 123.8, 120.0, 118.0, 117.6, 98.5, 66.7, 44.3, 30.00, 29.9 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H19O4SBr2 584.9365; Found 584.9378. Benzyl 2-((6S,13R)-2,3,9-tribromo-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin6-yl)acetate (3n). Red solid; 91.3 mg; mp: 178-179 °C; IR (KBr): 2949, 1717, 1203, 1154 cm-1;


Page 27 of 36 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


1

H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 1.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 2.4

Hz, 1H), 7.38 (dd, J = 8.6, 1.8 Hz, 1H), 7.32 (s, 4H), 7.25 (s, 2H), 5.19 (q, J = 12.3 Hz, 2H), 4.08 (t, J = 3.0 Hz, 1H), 3.29 – 3.52 (m, 2H), 2.68 (dd, J = 13.4, 3.4 Hz, 1H), 2.59 (dd, J = 13.2, 2.8 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 167.8, 148.5, 140.9, 135.3, 134.6, 134.1, 132.1, 128.9, 128.6, 128.4, 128.2, 128.2, 128.2, 124.1, 123.2, 118.5, 117.1, 113.4, 111.1, 99.3, 66.9, 44.0, 30.2, 29.9 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H18O4SBr3 662.8476; Found 662.8452. Benzyl 2-((6S,13R)-9-fluoro-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-yl)ac etate (3o). Red solid; 66.0 mg; mp: 119-120 °C; IR (KBr): 2959, 1728, 1210, 1160 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 8.8, 4.8 Hz, 1H), 7.26 – 7.36 (m, 6H), 7.16 (d, J = 6.8 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 7.00 (td, J = 18.2, 3.4 Hz, 1H),6.89 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 5.19 (s, 2H), 4.06 (t, J = 3.0 Hz, 1H), 3.32 (s, 2H), 2.67 (dd, J = 13.4, 3.4 Hz, 1H), 2.58 (dd, J = 13.2, 2.8 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.1, 160.7 (d, J = 242.5 Hz), 152.0, 141.3 (d, J = 5.0 Hz), 135.6, 131.9 (d, J = 1.7 Hz), 131.2 (d, J = 1.7 Hz),128.5, 128.3, 128.2, 128.1, 126.6, 125.9, 123.9 (d, J = 9.3 Hz), 121.5, 119.3, 116.3, 113.4 (d, J = 25.3 Hz), 106.1 (d, J = 24.1 Hz) 98.4, 66.6, 44.6, 30.22, 30.19 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H20O4SF 447.1061; Found 447.1055. Benzyl 2-((6S,13R)-9-fluoro-2-methyl-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxoci n-6-yl)acetate (3p). White solid; 69.0 mg; mp: 122-123 °C; IR (KBr): 2916, 1733, 1211, 1160 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 8.8, 4.6 Hz, 1H), 7.33 (tq, J = 7.3, 3.3 Hz, 6H), 6.99 – 7.06 (m, 2H), 6.91 (dd, J = 7.8, 1.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 5.21 (s, 2H), 4.06 (t,



J = 3.0 Hz, 1H), 3.42 – 3.27 (m, 2H), 2.70 (dd, J = 13.4, 3.4 Hz, 1H), 2.59 (dd, J = 13.4, 2.8 Hz, 1H), 2.29 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.2, 160.8 (d, J = 240.6 Hz), 149.8, 141.4 (d, J = 4.2 Hz), 135.6, 132.0 (d, J = 9.0 Hz), 131.2 (d, J = 1.6 Hz), 130.8, 128.7, 128.6, 128.3, 128.2, 127.0, 125.6, 123.9 (d, J = 9.2 Hz), 119.3, 116.0, 113.3 (d, J = 25.1 Hz), 106.2 (d, J = 24.0 Hz), 98.4, 66.6, 44.6, 30.4, 30.2, 20.5 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C27H21O4SFNa 483.1037; Found 483.1049. Benzyl 2-((6S,13R)-2-chloro-9-fluoro-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxoci n-6-yl)acetate (3q). White solid; 87.4 mg; mp: 122-123 °C; IR (KBr): 2991, 1734, 1203, 1075 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 8.8, 4.4 Hz, 1H), 7.26 – 7.36 (m, 6H), 7.15 (d, J = 2.4 Hz, 1H), 7.02 (td, J = 8.7, 1.9 Hz, 2H), 6.72 (d, J = 8.8 Hz, 1H), 5.18 (s, 2H), 4.06 (t, J = 3.0 Hz, 1H), 3.32 (s, 2H), 2.67 (dd, J = 13.4, 3.4 Hz, 1H), 2.58 (dd, J = 13.4, 2.8 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.0, 160.8 (d, J = 241.0 Hz), 150.7, 141.4 (d, J = 4.2 Hz), 135.5, 131.8 (d, J = 9.6 Hz), 131.2 (d, J = 1.7 Hz), 128.6, 128.4, 128.2, 128.1, 127.5, 126.3, 126.1, 124.1 (d, J = 9.2 Hz) 118.5, 117.6, 113.7 (d, J = 25.1 Hz), 106.2 (d, J = 24.0 Hz), 98.5, 66.7, 44.4, 30.1, 29.9 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H19O4SClF 481.0671; Found 481.0668. Benzyl 2-((6S,13R)-2-bromo-9-fluoro-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxoci n-6-yl)acetate (3r). White solid; 71.3 mg; mp: 146-147 °C; IR (KBr): 2959, 1733, 1203, 1172 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 8.8, 4.4 Hz, 1H), 7.27 – 7.35 (m, 7H), 7.18 (dd, J = 8.4, 2.4 Hz, 1H), 7.03 (td, J = 8.8, 2.6 Hz, 1H), 6.67 (d, J = 8.8 Hz, 1H), 5.18 (s, 2H), 4.05 (t, J = 3.2 Hz, 1H), 3.32 (s, 2H), 2.67 (dd, J = 13.4, 3.4 Hz, 1H), 2.57 (dd, J = 13.4, 2.8 Hz, 1H) ppm;


Page 28 of 36

Page 29 of 36 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


13

C NMR (100 MHz, CDCl3) δ 168.0, 160.8 (d, J = 241.0 Hz), 151.3, 141.4 (d, J = 4.2 Hz), 135.5,

131.7 (d, J = 9.7 Hz), 131.2 (d, J = 1.5 Hz), 131.0, 129.1, 128.6, 128.4, 128.2, 128.0, 124.1 (d, J = 9.2 Hz), 118.5, 118.1, 113.7 (d, J = 25.1 Hz), 113.4, 106.2 (d, J = 24.0Z Hz), 98.5, 66.8, 44.3, 30.0, 29.9 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H19O4SBrF 525.0166; Found 525.0170. Benzyl 2-((6R,13R)-2,4-dibromo-9-fluoro-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dio xocin-6-yl)acetate (3s). Red solid; 89.1 mg; mp: 149-150 °C; IR (KBr): 2981, 1742, 1215, 1190 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 8.8, 4.6 Hz, 1H), 7.49 (d, J = 2.2 Hz, 1H), 7.39 – 7.30 (m, 7H), 7.07 (td, J = 8.8, 2.5 Hz, 1H), 5.46 – 5.02 (m, 2H), 4.20 – 3.91 (m, 1H), 3.58 – 3.31 (m, 2H), 2.66 (qd, J = 13.4, 3.1 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 167.8, 160.8 (d, J = 242.8 Hz), 148.5, 141.4 (d, J = 4.2 Hz), 135.3, 134.0, 131.6 (d, J = 9.7 Hz), 131.2 (d, J = 1.4 Hz), 129.0, 128.5, 128.4, 128.3, 128.2, 124.1 (d, J = 9.2 Hz), 117.7, 113.9 (d, J = 25.3 Hz), 113.3, 111.1, 106.3 (d, J = 24.2 Hz), 99.2, 66.9, 44.0, 30.2, 29.9 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H18O4SBr2F 602.9271; Found 602.9269. Benzyl 2-((6S,13R)-9-methyl-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-yl)ac etate (3t). White solid; 50.1 mg; mp: 118-119 °C; IR (KBr): 2951, 1720, 1194, 1084 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H) 7.27 – 7.38 (m, 5H), 7.18 (dd, J = 7.2, 1.6 Hz, 1H), 7.06 – 7.11 (m, 2H), 6.90 (t, J = 7.4, Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 5.21 (s, 2H), 4.09 (t, J = 3.0 Hz, 1H), 3.36 (d, J = 2.8 Hz, 2H), 2.70 (dd, J = 13.4, 3.4 Hz, 1H), 2.59 (dd, J = 13.4, 2.8 Hz, 1H), 2.43 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.2, 152.2, 141.2, 135.7, 133.1, 131.2, 128.5, 128.2, 128.1, 128.0, 126.5, 126.4, 126.3, 122.4, 121.4, 120.1, 117.0, 116.2,



98.3, 66.6, 44.8, 30.4, 30.2, 21.4 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C27H22O4SNa 465.1131; Found 465.1143. Benzyl 2-((6S,13R)-2,9-dimethyl-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-y l)acetate (3u). Yellow solid; 62.0 mg; mp: 119-120 °C; IR (KBr): 2947, 1727, 1210, 1160 cm-1; 1

H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.29 – 7.39 (m, 5H), 7.10 (d,

J = 8.0,Hz, 1H), 6.99 (d, J = 1.6 Hz, 1H), 6.89 (dd, J = 8.2, 1.8 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 5.21 (s, 2H), 4.05 (t, J = 3.0 Hz, 1H), 3.43 – 3.24 (m, 2H), 2.69 (dd, J = 13.4, 3.4 Hz, 1H), 2.58 (dd, J = 13.4, 2.8 Hz, 1H), 2.43 (s, 3H), 2.28 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.3, 149.9, 141.3, 135.7, 133.9, 133.1, 131.2, 130.7, 128.5, 128.2, 128.1, 126.9, 126.3, 126.0, 122.4, 120.1, 116.9, 115.9, 98.3, 66.6, 44.8, 30.5, 30.2, 21.4, 20.5 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C28H25O4S 457.1468; Found 457.1474. Benzyl 2-((6S,13R)-2-chloro-9-methyl-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxoc in-6-yl)acetate (3v). White solid; 61.9 mg; mp: 109-110 °C; IR (KBr): 2952, 1732, 1197, 1080 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.26 – 7.36 (m, 5H), 7.15 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.02 (dd, J = 8.6, 2.6 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 5.19 (s, 2H), 4.04 (t, J = 3.0 Hz, 1H), 3.33 (s, 2H), 2.66 (dd, J = 13.4, 3.4 Hz, 1H), 2.57 (dd, J = 13.4, 2.8 Hz, 1H), 2.42 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.1, 150.8, 141.3, 135.6, 134.1, 133.2, 131.0, 128.6, 128.3, 128.2, 127.9, 127.8, 126.6, 126.2, 125.9, 122.5, 120.2, 117.5, 116.1, 98.4, 66.7, 44.5, 30.1, 30.0, 21.4 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C27H22O4SCl 477.0922; Found 477.0921.


Page 30 of 36

Page 31 of 36 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


Benzyl 2-((6S,13R)-2-bromo-9-methyl-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxoc in-6-yl)acetate (3w). White solid; 67.6 mg; mp: 128-129 °C; IR (KBr): 2952, 1730, 1212, 1173 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.27 – 7.36 (m, 6H), 7.16 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 5.19 (s, 2H), 4.03 (s, 1H), 3.33 (s, 2H), 2.66 (dd, J = 13.4, 3.4 Hz, 1H), 2.56 (dd, J = 13.4, 2.8 Hz, 1H), 2.42 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.0, 151.4, 141.3, 135.6, 134.1, 133.2, 131.0, 130.8, 129.1, 128.6, 128.4, 128.3, 128.2, 126.6, 122.5, 120.2, 118.0, 116.1, 113.3, 98.4, 66.7, 44.5, 30.1, 30.0, 21.3 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C27H22O4SBr 521.0417; Found 521.0433. Benzyl 2-((6R,13R)-2,4-dibromo-9-methyl-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]di oxocin-6-yl)acetate (3x). White solid; 63.4 mg; mp: 136-137 °C; IR (KBr): 2949, 1725, 1207, 1193 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.4 Hz, 1H), 7.44 – 7.48 (m, 2H), 7.28 – 7.35 (m, 5H), 7.25 (s, 2H), 7.12 (d, J = 9.2 Hz, 1H), 5.11 – 5.25 (m, 2H), 4.06 (t, J = 3.0 Hz, 1H), 3.41 (q, J = 15.2 Hz, 2H), 2.65 (dd, J = 13.4, 3.4 Hz, 1H), 2.59 (dd, J = 13.4, 2.8 Hz, 1H), 2.42 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 167.9, 148.7, 141.4, 135.5, 134.2, 133.9, 133.27, 133.25, 130.9, 129.4, 128.5, 128.3, 128.2, 126.8, 122.5, 120.3, 115.3, 113.2, 111.0, 99.2, 66.9, 44.2, 30.3, 30.1, 21.3 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C27H22O4SBr2 598.9522; Found 598.9521. Benzyl 2-((6S,13R)-9-chloro-5-tosyl-5,13-dihydro-6H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][ 1,3]oxazocin-6-yl)acetate (3y). White solid; 49.2 mg; mp: 161-162 °C; IR (KBr): 3128, 1747,



1210, 1167 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.5 Hz, 1H), 7.28 – 7.46 (m, 7H), 7.12 – 7.25 (m, 4H), 6.79 (d, J = 8.1 Hz, 2H), 6.36 (d, J = 8.1 Hz, 2H), 5.19 (s, 2H), 4.28 (d, J = 15.8 Hz, 1H), 3.90 (s, 1H), 3.54 (d, J = 15.7 Hz, 1H), 2.60 (dd, 1H), 2.32 (dd, J = 13.4, 3.2 Hz, 1H), 1.83 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.8, 142.0, 140.6, 137.8, 136.1, 135.6, 134.4, 134.2, 131.2, 129.9, 128.5, 128.3, 128.21, 128.17, 128.0, 126.1, 125.4, 125.3, 125.0, 124.9, 123.2, 120.8, 115.2, 89.5, 66.7, 44.8, 38.0, 32.2, 21.1 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C33H27NO5S2Cl 616.1014; Found 616.1021. Benzyl 2-((6S,13R)-2-bromo-11-methyl-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxo cin-6-yl)acetate (3z). White solid; 54.1 mg; mp: 120-121 °C; IR (KBr): 2952, 1730, 1212, 1173 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.6 Hz, 1H), 7.31 (s, 6H), 7.24 (d, J = 8.0 Hz, 1H), 7.16 (dd, J = 8.8, 2.0 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 5.18 (s, 2H), 4.08 (s, 1H), 3.34 (s, 2H), 2.66 (dd, J = 13.2, 2.8 Hz, 1H), 2.59 (dd, J = 13.2, 2.4 Hz, 1H), 2.44 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.1, 151.4, 142.3, 136.0, 135.5, 132.1, 130.9, 130.6, 129.09, 129.06, 128.6, 128.3, 128.2, 125.3, 124.7, 118.0, 117.9, 115.7, 113.3, 98.4, 66.7, 44.4, 30.0, 29.9, 19.4 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C27H22O4SBr 521.0417; Found 521.0433. Synthetic procedure for 4: Under Ar atmosphere, to a solution of 3a (100 mg, 0.22 mmol) in CH2Cl2 2 mL was added m-CPBA (111.8 mg, 0.65 mmol). The resulting mixture was stirred at room temperature for 27 h. When the reaction was completed (monitored by TLC), the solvent was evaporated and the crude residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:5) with silica gel to obtain the product 4 (61 mg, yield: 60%).


Page 32 of 36

Page 33 of 36 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


Benzyl 2-((6S,13R)-9-chloro-12,12-dioxido-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]di oxocin-6-yl)acetate (4). White solid; mp: 155-156 °C; IR (KBr): 2937, 1733, 1219, 1164 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 6.4 Hz, 7H), 7.16 (t, J = 7.6 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 5.05 – 5.32 (m, 2H), 4.12 (s, 1H), 3.32 (q, J = 15.3 Hz, 2H), 2.57 (dd, J = 13.6, 2.8 Hz, 1H), 2.51 (dd, J = 13.6, 2.8 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 167.3, 150.9, 150.7, 139.5, 136.9, 135.3, 130.4, 129.6, 128.9, 128.7, 128.5, 128.3, 127.7, 123.7, 122.5, 121.9, 121.1 116.9, 116.4, 100.5, 67.0, 44.0, 29.7, 24.9 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H21O6SCl 495.0664; Found 495.0675. Benzyl (E)-2-(6-chloro-4-phenyl-3,4-dihydro-2H-benzo[4,5]thieno[3,2-b]pyran-2-ylidene)acetate (6). White solid; 18.5 mg; mp 59-60 oC; IR(KBr): 3030, 1701, 1643, 1122, 1075 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.69 (dq, J = 7.6, 4.3 Hz, 1H), 7.27 – 7.42 (m, 11H), 5.90 (s, 1H), 5.06 – 5.25 (m, 2H), 4.30 – 4.39 (m, 1H), 3.93 (dd, J = 15.4, 5.8 Hz, 1H), 3.62 (dd, J = 15.4, 7.8 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 166.6, 165.6, 142.0, 141.2, 136.2, 135.4, 131.6, 128.8, 128.5, 128.2, 128.1, 128.0, 127.7, 127.5, 125.7, 124.7, 119.4, 118.3, 100.7, 65.8, 37.6, 31.7 ppm; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H20O3SCl2 447.0816; Found 447.0828. Benzyl 2-(6-chloro-4-phenyl-4H-benzo[4,5]thieno[3,2-b]pyran-2-yl)acetate (7). White solid; 7.4 mg; mp 51-52 oC; IR(KBr): 2972, 1736, 1592, 1163, 1039 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.57 – 7.68 (m, 1H), 7.26 – 7.40 (m, 11H), 5.23 (s, 2H), 4.99 (dd, J = 36.7, 3.1 Hz, 2H), 3.43 (s, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 169.1, 144.5, 144.4, 141.3, 135.6, 135.3, 131.8, 128.8,



128.6, 128.3, 128.10, 128.05, 127.7, 127.4, 125.5, 124.6, 118.7, 118.3, 102.8, 66.9, 40.0, 39.4 ppm. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H20O3SCl2 447.0816; Found 447.0825. 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 (CIF) AUTHOR INFORMATION Corresponding Author [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENT 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. We thanks Prof. Hongchao Guo and Prof. Zhengjie He for gifts of P5 and P6. REFERENCES (1) Killday, K. B.; Davey, M. H.; Glinski, J. A.; Duan, P.; Veluri, R.; Proni, G.; Daugherty, F. J.; Tempesta M. S. J. Nat. Prod. 2011, 74, 1833.


Page 34 of 36

Page 35 of 36 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


(2) Shui, X.; Lu, X.; Gao, Y.; Liu, C.; Ren, F.; Jiang, Q.; Zhang, H.; Zhao, B.; Zheng, Z. Antiviral Res. 2011, 90, 54. (3) (a) Gao, F. J.; Carr, J. L.; Hoveyda, A. H. Am. Chem. Soc. 2014, 136, 2149. (b) Nagata, H.; Kawamura, M.; Ogasawara, K. Synthesis 2000, 13, 1825. (4) (a) Lamidi, M.; Gasquet, M.; Ollivier, E.; Ekekang, L. N.; Balansard, G. Pharm. Pharmacol. Lett. 1996, 6, 31. (b) Erdelmeier, C. A. J.; Regenass, U.; Rail, T.; Sticher, O. Planta Med. 1992, 58, 43. (5) Kim, I.-S.; Park, Y.-J.; Yoon, S.-J.; Lee, H.-B. Int. Immunopharmacol. 2010, 10, 1616. (6) Ruiz, M.; López-Alvarado, P.; Giorgi, G.; Menéndez, J. C. Chem. Soc. Rev. 2011, 40, 3445. (7) Zhao, W.-Y. Chem. Rev. 2010, 110, 1706. (8) Presset, M.; Coquerel, Y.; Rodriguez, J. Chem. Rev. 2013, 113, 525. (9) Wang, F.; Chen, F.; Qu, M.; Li, T.; Liu, Y.; Shi, M. Chem. Commun. 2013, 49, 3360. (10) Polat, M. F.; Hettmanczyk, L.; Zhang, W.; Szabo, Z.; Franzén, J. ChemCatChem 2013, 5, 1334. (11) Srinivas, V.; Koketsu, M. J. Org. Chem. 2013, 78, 11612. (12) Yin, G.; Ren, T.; Rao, Y.; Zhou, Y.; Li, Z.; Shu, W.; Wu, A.; J. Org. Chem. 2013, 78, 3132. (13) Rao, Y.; Yin, G. Org. Biomol. Chem. 2013, 11, 6029. (14) Guo, J.; Bai, X.; Wang, Q.; Bu, Z. J. Org. Chem. 2018, doi: 10.1021/acs.joc.8b00035. (15) (a) Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461. (b) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906. (16) Wei, Y.; Shi, M. Org. Chem. Front. 2017, 4, 1876, and references cited therein. (17) Cowen, B. J.; Miller, S. J. Chem. Soc. Rev. 2009, 38, 3102. (18) (a) Ni, C.; Chen, J.; Zhang, Y.; Hou, Y.; Wang, D.; Tong, X.; Zhu, S.-F.; Zhou, Q.-L. Org. Lett.



2017, 19, 3668. (b) Santos, B. S.; Pinho e Melo, T. M. V. D. Eur. J. Org. Chem. 2013, 3901. (c) Takizawa, S.; Kishi, K.; Yoshida, Y.; Mader, S.; Arteaga, F. A.; Lee, S.; Hoshino, M.; Rueping, M.; Fujita, M.; Sasai, H. Angew. Chem. Int. Ed. 2015, 54, 15511. (19) (a) Mao, B.; Shi, W.; Liao, J.; Liu, H.; Zhang, C.; Guo, H. Org. Lett. 2017, 19, 6340. (b) Xu, Y.; Hong, Y. J.; Tantillo, D. J.; Brown, M. K. Org. Lett. 2017, 19, 3703. (20) Takizawa, S.; Arteaga, F. A.; Yoshida, Y.; Suzuki, M.; Sasai, H. Org. Lett. 2013, 15, 4142. (b) Kramer, S.; Fu, G. C. J. Am. Chem. Soc. 2015, 137, 3803. (21) (a) Zhao, H.; Meng X.; Huang, Y. Chem. Commun. 2013, 49, 10513. (b) Gu, Y.; Hu, P.; Ni, C.; Tong, X. J. Am. Chem. Soc. 2015, 137, 6400. (22) (a) Zhang, Y.; Yu, A.; Jia, J.; Ma, S.; Li, K.; Wei, Y.; Meng, X. Chem. Commun. 2017, 53, 10672. (b) Jia, J.; Yu, A.; Ma, S.; Zhang, Y.; Li, K.; Meng, X. Org. Lett. 2017, 19, 6084. (23) CCDC 1814723 (3a) (24) The structures of 6 and 7 were determined by 1H,

13

C NMR, NOESY, HSQC and HRMS,

please see supporting information. (25) The solvent CH2Cl2 is commercial available, not dry CH2Cl2.


Page 36 of 36

Phosphine-Catalyzed Domino Reaction of Thioaurones and Allenoate

Recommend Documents