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Cite This: J. Org. Chem. 2018, 83, 5410−5419

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*,† †

Tianjin Key Laboratory of Organic Solar Cells and Photochemical Conversion, School of Chemistry & Chemical Engineering, Tianjin University of Technology, Tianjin 300384, People’s Republic of China ‡ School of Science, Tianjin Chengjian University, Tianjin 300384, People’s Republic of China § College of Chemistry, Beijing Normal University, Beijing 100875, People’s Republic of China S Supporting Information *

ABSTRACT: The reaction of thioaurone derivatives with allenoate catalyzed by tris(4-methoxyphenyl)phosphane (P(4MeOC6H4)3) resulted in a domino annulation reaction to produce a benzothiophene-fused bridged bicyclic ring, with 40−91% 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.

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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 the 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-developed 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 the bridged dioxabicyclo[3.3.1]nonane skeleton via phosphine-catalyzed domino reaction of allenoate. To the best of our knowledge, only two bridge-ring structures obtained by using phosphine-catalyzed domino reaction of allenoates have been reported.21 During our ongoing investigation of domino reactions for the efficient construction of benzothiophene-fused heterocyclic

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 to have pharmacological activity against diabetes and liver disorders. 3 The oxaazabicyclo[3.3.1]nonane-containing alkaloid naucleamide E showed good antiproliferative, antiparasitic, and antimicrobial

Figure 1. Examples of compounds containing a dioxabicyclo[3.3.1]nonane or oxaazabicyclo[3.3.1]nonane subunit. © 2018 American Chemical Society

Received: January 17, 2018 Published: April 24, 2018 5410

DOI: 10.1021/acs.joc.8b00145 J. Org. Chem. 2018, 83, 5410−5419

Article

The Journal of Organic Chemistry Table 1. Optimization of the Domino Reactiona

compounds, we have synthesized a series of thioaurones and their analogues and studied their domino reactions.22 For example, a novel [4 + 3] annulation reaction of crotonatederived sulfur ylides using thioaurones was developed (Scheme 1a).22a Moreover, when the Ar groups on the thioaurones were Scheme 1. Versatile Reactivity of Thioaurone and Its Derivatives

entry

cat.

solvent

time/h

yieldb/%

1 2 3 4 5 6 7 8 9 10 11 12 13 14c 15d 16e

PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 P(4-FC6H4)3 P(4-MeOC6H4)3 P(4-MeOC6H4)3 P(4-MeOC6H4)3 P(4-MeOC6H4)3

THF EtOEt CH3OH C2H5OH i PrOH toluene CH3CN DMF DMSO CHCl3 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2

3.5 8.0 3.5 4.0 4.0 4.0 4.5 6.0 4.5 4.0 4.0 4.5 4.5 6.0 8.0 8.0

30 25 22 27 29 17 26 0 0 25 40 29 82 65 47 26

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 1a:2 = 1:2.0. dThe ratio 1a:2 = 1:1.5. eA 10 mol % concentration of P(4-MeOC6H4)3 was used as the catalyst.

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 toward the development of domino reactions for the efficient construction of benzothiophene-fused heterocyclic compounds, we started to develop a strategy for the fast and efficient construction of the benzothiophene-fused dioxabicyclo[3.3.1]nonane skeleton. As a result, we designed and synthesized a new series of thioaurones (1) bearing a 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.

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 2-propanol, there was no improvement in yields (entries 3−5). When toluene and acetonitrile were used as solvents, the yields remained low (only 17% and 26%, respectively) (entries 6 and 7). No products could be formed when the strong polar solvents DMSO and DMF were used (entries 8 and 9). When the reaction was performed in halogenated solvents, e.g., CHCl3 and CH2Cl2 (entries 10 and 11), the yield was improved, e.g., to 40% in CH2Cl2. As a result, CH2Cl2 was selected as the solvent of choice. Next, the effect of the 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 2 to 2.0 and 1.5 equiv resulted in a decrease in the yield of 3a (entries 14 and 15). Furthermore, decreasing the amount of PPh3 to 10 mol % resulted in a decrease in the yield (entry 16). Therefore, the optimal reaction conditions for this domino reaction were determined to be 20 mol % P(4MeOC6H4)3 as the catalyst, 2.5 equiv of 2, and the solvent CH2Cl2. The experiments were performed at room temperature. 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, methoxy, and nitro groups, 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 yields of 75%

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RESULTS AND DISCUSSION The reaction between thioaurone 1a (1.0 equiv) and allenoate 2 (2.5 equiv) catalyzed by PPh3 (20 mol %) in THF at room temperature resulted in a new compound (3a) produced in a yield of 30% (Table 1, entry 1). After purification by chromatography, 3a was characterized using NMR and HRMS, and the structure was solved using single-crystal Xray 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, a 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 5411

DOI: 10.1021/acs.joc.8b00145 J. Org. Chem. 2018, 83, 5410−5419

Article

The Journal of Organic Chemistry Table 2. Substrate Scope of the Domino Reactiona

methyl-substituted substrate 1z reacted with 2 to produce 3z in a yield of 52% (entry 26). 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 Scheme 2. Scale-up Reaction and Transformation

entry

R1

R2

time/h

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25c 26

5-Cl (1a) 5-Cl (1b) 5-Cl (1c) 5-Cl (1d) 5-Cl (1e) 5-Cl (1f) 5-Cl (1g) 5-Cl (1h) 5-Cl (1i) 5-Br (1j) 5-Br (1k) 5-Br (1l) 5-Br (1m) 5-Br (1n) 5-F (1o) 5-F (1p) 5-F (1q) 5-F (1r) 5-F (1s) 5-CH3 (1t) 5-CH3 (1u) 5-CH3 (1v) 5-CH3 (1w) 5-CH3 (1x) 5-Cl (1y) 7-CH3 (1z)

H 4′-CH3 4′-Cl 4′-Br 5′-F 4′-F 3′,4′-Br2 5′-CH3O 5′-NO2 H 4′-CH3 4′-Cl 4′-Br 3′,4′-Br2 H 4′-CH3 4′-Cl 4′-Br 3′,4′-Br2 H 4′-CH3 4′-Cl 4′-Br 3′,4′-Br2 H 4′-Br

4.5 3.5 8.0 5.0 4 4 16.5 8 10 6.0 2.5 5.5 6.5 16.5 4.5 3.0 6.5 2.5 15.5 6.5 2.5 6.5 4.5 14.5 6.5 5.0

yieldb/% 82 72 75 67 60 69 86 0 0 68 73 62 63 69 74 75 91 68 74 57 68 65 65 53 40 52

(3a) (3b) (3c) (3d) (3e) (3f) (3g) (3h) (3i) (3j) (3k) (3l) (3m) (3n) (3o) (3p) (3q) (3r) (3s) (3t) (3u) (3v) (3w) (3x) (3y) (3z)

in a yield of 64% when the reaction was scaled up to 1.02 g (1a, 3.54 mmol) under optimized reaction conditions. Moreover, the treatment of compound 3a with 2.2 equiv of m-CPBA at room temperature in CH2Cl2 led 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 materials 1a and 2 were consumed, and no desired product was obtained. To clarify the reaction mechanism, we synthesized a thioaurone (5)22a without the hydroxyl group. The reaction of 5 with 2 was performed under optimized reaction conditions. Benzo[4,5]thieno[3,2-b]pyran derivatives 6 and 7 were obtained in yields of 25% and 10%, respectively (Scheme 4).24 On the basis of the above observation and some related literature,16 a possible reaction mechanism is proposed in Scheme 5. Initially, the nucleophilic binding of P(4MeOC6H4)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. Subsequently, intermediate E is transformed into F. Finally, 3a forms by a H2O-assisted proton transfer and O-Michael addition reaction process. 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, resulting in the formation of a six-membered-ring structure and loss of the phosphine group. DFT calculations identify the location of the transition state

a

Unless otherwise indicated, the reaction was conducted on a 0.2 mmol scale of 1 in 2 mL of CH2Cl2 (molar ratio 1:2 is 1:2.5; X = OH). b Isolated yields. cX = NHTs.

and 67%, respectively (entries 3 and 4). In a similar manner, the reactions of fluorine-substituted substrates 1e and 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, with 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 group at 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 the 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 solvent (entry 25). The C-75412

DOI: 10.1021/acs.joc.8b00145 J. Org. Chem. 2018, 83, 5410−5419

Article

The Journal of Organic Chemistry Scheme 3. Asymmetric Domino Reactions

Scheme 4. Control Experiment

Scheme 5. Proposed Mechanism

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 5413

DOI: 10.1021/acs.joc.8b00145 J. Org. Chem. 2018, 83, 5410−5419

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The Journal of Organic Chemistry

Figure 2. Solvation Gibbs free energy profile for the domino reaction.

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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 diastereoselectivity. The proposed mechanism was investigated and supported by DFT calculations. Further study of the products’ bioactivities is currently under way, and the results will be reported in the future.

of up to 26.5 kcal/mol. Attempts to locate a tetravalent C2structure 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 C2structure 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 unfavorable 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 (the 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 tunneling effect could make the proton transfer more accessible at room temperature. In addition, the overall reaction releases a free energy of 36.7 kcal/mol, consistent with both the kinetic accessibility and thermodynamic spontaneity.

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EXPERIMENTAL SECTION

General Information. All reactions were performed under an Ar atmosphere 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 was used to monitor all reactions with silica gel-coated plates. Flash column chromatography was performed using 200−300 mesh silica gel. 1H and 13C NMR spectra were recorded at ambient temperature on Bruker 400 instruments. All spectra were referenced to CDCl3 (1H, δ 7.26 ppm; 13C NMR, δ 77.00 ppm) and DMSO-d6 (1H, δ 2.500; 13C NMR, δ 39.520). High-resolution mass spectra were obtained on a Waters Xevo Q-TOF mass spectrometer with an ESI resource. Melting points were measured on an RY-I apparatus and are reported uncorrected. General Procedure for the Syntheses of 1a−1z. Under an Ar atmosphere, to a solution of substituted benzo[b]thiophen-3(2H)-one (2 mmol) in toluene (10 mL) were added substituted salicylaldehyde (2.4 mol) and piperidine (2−3 drops). The resulting mixture was heated at 85 °C for 2−3 h. After the reaction was completed (monitored by TLC), the solvent was removed under reduced pressure. The crude product was recrystallized from EtOH to give the pure 1a−1z. Data for (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), 5414

DOI: 10.1021/acs.joc.8b00145 J. Org. Chem. 2018, 83, 5410−5419

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The Journal of Organic Chemistry

Data for (Z)-5-chloro-2-(2-hydroxy-5-nitrobenzylidene)benzo[b]thiophen-3(2H)-one (1i): yellow solid; 649.3 mg; mp 179−180 °C; 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) 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. Data for (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; 1H 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 = 8.4 Hz, 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. Data for (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; 13C 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. Data for (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. Data for (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. Data for (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. Data for (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), 7.58−7.61 (m, 3H), 7.30−7.39 (m, 1H), 6.98 (t, J = 7.8 Hz, 2H) ppm; 13C 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. Data for (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,

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 ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H10O2SCl 289.0085, found 289.0083. Data for (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, DMSOd6) 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. Data for (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. Data for (Z)-2-(5-bromo-2-hydroxybenzylidene)-5chlorobenzo[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, J = 8.4, 1.6 Hz, 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. Data for (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 °C; IR(KBr) 3215, 2943, 1657, 1553, 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. Data for (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 °C; 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. Data for (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. Data for (Z)-5-chloro-2-(2-hydroxy-5-methoxybenzylidene)benzo[b]thiophen-3(2H)-one (1h): brown solid; 667.8 mg; mp 154−155 °C; 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 (ESITOF) m/z [M + H]+ calcd for C16H12O3SCl 319.0190, found 319.0197. 5415

DOI: 10.1021/acs.joc.8b00145 J. Org. Chem. 2018, 83, 5410−5419

Article

The Journal of Organic Chemistry

Data for (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; 13C 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. Data for (Z)-2-(3,5-dibromo-2-hydroxybenzylidene)-5methylbenzo[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, 1H), 7.66−7.75 (m, 3H), 7.57 (d, J = 8.1 Hz, 1H), 2.38 (s, 3H) ppm; 13C NMR (100 MHz, DMSOd6) 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. Data for (Z)-N-(2-((5-chloro-3-oxobenzo[b]thiophen-2(3H)ylidene)methyl)phenyl)-4-methylbenzenesulfonamide (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. Data for (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; 13C 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. Data for benzyl 2-((6S,13R)-9-chloro-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-yl)acetate (3a): white solid; 75.8 mg; mp 136−137 °C; IR (KBr) 2959, 1730, 1209, 1175 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.29−7.35 (m, 5H), 7.21 (dd, J = 8.4, 2.0 Hz, 1H), 7.16 (dd, J = 7.6, 0.8 Hz, 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; 13C 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. Data for benzyl 2-((6S,13R)-9-chloro-2-methyl-13H-6,13methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-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 = 8.0, 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. Data for benzyl 2-((6S,13R)-2,9-dichloro-13H-6,13methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-yl)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

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. Data for (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. Data for (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, 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. Data for (Z)-2-(3, 5-dibromo-2-hydroxybenzylidene)-5fluorobenzo[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. Data for (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. Data for (Z)-2-(2-hydroxy-5-methylbenzylidene)-5methylbenzo[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, 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. Data for (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. 5416

DOI: 10.1021/acs.joc.8b00145 J. Org. Chem. 2018, 83, 5410−5419

Article

The Journal of Organic Chemistry = 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 = 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. Data for benzyl 2-((6S,13R)-2-bromo-9-chloro-13H-6,13methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-yl)acetate (3d): red solid; 72.4 mg; mp 165−166 °C; IR (KBr) 2993, 1725, 1203, 1174 cm−1; 1H 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. Data for benzyl 2-((6R,13R)-9-chloro-2-fluoro-13H-6,13methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-yl)acetate (3e): white solid; 57.6 mg; mp 153−154 °C; IR(KBr) 2959, 1724, 1216, 1185 cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.62 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.29−7.36 (m, 5H), 7.23 (dd, J = 8.6, 1.9 Hz, 1H), 6.89 (dd, J = 8.0, 2.7 Hz, 1H), 6.72−6.81 (m, 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. Data for benzyl 2-((6R,13R)-9-chloro-3-fluoro-13H-6,13methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-yl)acetate (3f): white solid; 66.2 mg; mp 217−218 °C; IR(KBr) 2951, 1724, 1213, 1175 cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.64 (d, J = 1.7 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.32−7.39 (m, 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. Data for benzyl 2-((6S,13R)-2,3-dibromo-9-chloro-13H-6,13methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-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), 7.30−7.34 (m, 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; 13C NMR (100 MHz, CDCl3) δ 167.8, 148.5, 141.1, 135.3, 134.10, 134.1, 131.7, 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 (ESITOF) m/z [M + H]+ calcd for C26H18O4SClBr2 618.8970, found 618.8969. Data for benzyl 2-((6S,13R)-9-bromo-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-yl)acetate (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. Data for benzyl 2-((6S,13R)-9-bromo-2-methyl-13H-6,13methanobenzo[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 (100 MHz, 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. Data for benzyl 2-((6S,13R)-9-bromo-2-chloro-13H-6,13methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-yl)acetate (3l): red solid; 67.0 mg; mp 128−129 °C; IR (KBr) 2961, 1732, 1199, 1079 cm−1; 1H 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; 13 C 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. Data for benzyl 2-((6S,13R)-2,9-dibromo-13H-6,13methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-yl)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; 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, 66.7, 44.3, 30.00, 29.9 ppm; HRMS (ESI-TOF) m/z [M + H]+ calcd for C26H19O4SBr2 584.9365, found 584.9378. Data for benzyl 2-((6S,13R)-2,3,9-tribromo-13H-6,13methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-yl)acetate (3n): red solid; 91.3 mg; mp 178−179 °C; IR (KBr) 2949, 1717, 1203, 1154 cm−1; 1H 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), 7.30−7.34 (m, 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. Data for benzyl 2-((6S,13R)-9-fluoro-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-yl)acetate (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), 3.28−3.37 (m, 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. Data for benzyl 2-((6S,13R)-9-fluoro-2-methyl-13H-6,13methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-yl)acetate (3p): white solid; 69.0 mg; mp 122−123 °C; IR (KBr) 2916, 5417

DOI: 10.1021/acs.joc.8b00145 J. Org. Chem. 2018, 83, 5410−5419

Article

The Journal of Organic Chemistry 1733, 1211, 1160 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 8.8, 4.6 Hz, 1H), 7.30−7.37 (m, 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. Data for benzyl 2-((6S,13R)-2-chloro-9-fluoro-13H-6,13methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-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. Data for benzyl 2-((6S,13R)-2-bromo-9-fluoro-13H-6,13methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-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; 13C 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. Data for benzyl 2-((6R,13R)-2,4-dibromo-9-fluoro-13H-6,13methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-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. Data for benzyl 2-((6S,13R)-9-methyl-13H-6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-yl)acetate (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. Data for benzyl 2-((6S,13R)-2,9-dimethyl-13H-6,13methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6-yl)acetate (3u): yellow solid; 62.0 mg; mp 119−120 °C; IR (KBr) 2947, 1727, 1210, 1160 cm−1; 1H 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. Data for benzyl 2-((6S,13R)-2-chloro-9-methyl-13H-6,13methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-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. Data for benzyl 2-((6S,13R)-2-bromo-9-methyl-13H-6,13methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-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. Data for benzyl 2-((6R,13R)-2,4-dibromo-9-methyl-13H6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6yl)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. Data for benzyl 2-((6S,13R)-9-chloro-5-tosyl-5,13-dihydro6H-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. Data for benzyl 2-((6S,13R)-2-bromo-11-methyl-13H-6,13methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-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), 7.28−7.35 (m, 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 an Ar atmosphere, to a solution of 3a (100 mg, 0.22 mmol) in CH2Cl2 (2 mL) was added m5418

DOI: 10.1021/acs.joc.8b00145 J. Org. Chem. 2018, 83, 5410−5419

The Journal of Organic Chemistry

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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%). Data for benzyl 2-((6S,13R)-9-chloro-12,12-dioxido-13H6,13-methanobenzo[d]benzo[4,5]thieno[2,3-g][1,3]dioxocin-6yl)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), 7.29−7.34 (m, 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. Data for benzyl (E)-2-(6-chloro-4-phenyl-3,4-dihydro-2Hbenzo[4,5]thieno[3,2-b]pyran-2-ylidene)acetate (6): white solid; 18.5 mg; mp 59−60 °C; 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. Data for 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 °C; 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.

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00145. NMR spectra of all new compounds and computational details (PDF) Crystallographic data for compound 3a (CIF)

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Article

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Lei Zhang: 0000-0003-0100-8357 Xiangtai Meng: 0000-0003-2713-0078 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS 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 thank Prof. Hongchao Guo and Prof. Zhengjie He for gifts of P5 and P6. 5419

DOI: 10.1021/acs.joc.8b00145 J. Org. Chem. 2018, 83, 5410−5419