Synthesis of Bicyclic Isothiazoles through an Intramolecular Rhodium

Sep 9, 2017 - Synthesis of Bicyclic Isothiazoles through an Intramolecular Rhodium-Catalyzed Transannulation of Cyanothiadiazoles. Boram Seo†, Hyuns...
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Synthesis of Bicyclic Isothiazoles through an Intramolecular Rhodium-Catalyzed Transannulation of Cyanothiadiazoles Boram Seo,† Hyunseok Kim,† Ya Gob Kim,† Yonghyeon Baek, Kyusik Um, and Phil Ho Lee* Department of Chemistry, Kangwon National University, Chuncheon 24341, Republic of Korea S Supporting Information *

ABSTRACT: An intramolecular rhodium-catalyzed transannulation of readily available cyanothiadiazoles containing an ester, amide, or ether as a linker is described. It provides a wide range of bicyclic isothiazoles in good to excellent yields together with the release of molecular nitrogen. These results indicate that the carbon atom in the α-thiavinyl carbene is nucleophilic and that the sulfur atom is electrophilic.

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contrast with earlier findings of Gevogyan and co-workers from the point of view of regioselectivity.4 Stimulated by these results and interested in the latent uses of bicyclic isothiazoles in medicinal chemistry, electronic material chemistry, and pharmaceuticals, we report an efficient intramolecular Rhcatalyzed transannulation of cyanothiadiazoles containing an ester, amide, or ether as a linker, leading to the straightforward preparation of bicyclic isothiazoles (Scheme 1).

INTRODUCTION Bicyclic isothiazole ring systems are privileged structural motifs found in many pharmaceutical compounds and functional materials.1 They have been widely used as significant privileged scaffolds in a myriad of areas such as organic electroluminescent materials, semiconductors, pesticides, anticancer drugs, and ligands (Figure 1).1 Thus, development of an efficient synthetic method for functionalized bicyclic isothiazoles is highly desired.

Scheme 1. Synthesis of Bicyclic Isothiazoles via Intramolecular Rh-Catalyzed Transannulation of Cyanothiadiazoles

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RESULTS AND DISCUSSION First, we investigated the intramolecular transannulation of cyanothiadiazole (1a) in the presence of a variety of transitionmetal catalysts and ligands (Table 1). A wide range of ligands, including 1,2-bis(diphenylphosphino)ethane (DPPE), 1,3-bis(diphenylphosphino)propane (DPPP), 1,4-bis(diphenylphosphino)butane (DPPB), bis[(2-diphenylphosphino)phenyl] ether (DPEPhos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), and bis(diphenylphosphino)biphenyl (BIPHEP) in the presence of [Rh(COD)Cl]2 were examined. To our delight, DPPE and DPPP gave the desired bicyclic isothiazole 2a in 59 and 43% yields, respectively (entries 1 and 2). The structure of 2a was confirmed by X-ray crystallography (see the Supporting Information).7 Although XantPhos is

Figure 1. Important compounds containing bicyclic isothiazole scaffolds.

In recent years, many metal-catalyzed transannulation reactions via metal−carbenoid intermediates from N-sulfonyl1,2,3-triazoles2 and pyridotriazoles3 have been reported. More recently, Gevorgyan and co-workers described the Rh-catalyzed transannulation of 1,2,3-thiadiazoles with alkynes for the synthesis of thiophenes via an α-thiavinyl carbene as a 1,3dipole equivalent.4 In addition, we developed the intermolecular Rh-catalyzed transannulation of 1,2,3-thiadiazoles with nitriles5 and alkenes6 to produce isothiazoles and 4-substituted dihydrothiophenes, respectively. These results are in obvious © 2017 American Chemical Society

Received: August 16, 2017 Published: September 9, 2017 10574

DOI: 10.1021/acs.joc.7b02077 J. Org. Chem. 2017, 82, 10574−10582

Article

The Journal of Organic Chemistry Table 1. Reaction Optimizationa

Scheme 2. Substrate Scope of Thiadiazoles Bearing a Cyanoethoxycarbonyl Groupa

entry

cat.

ligandb

time (h)

yield (%)c

1 2 3 4 5 6 7 8 9 10 11 12

[Rh(COD)Cl]2 [Rh(COD)Cl]2 [Rh(COD)Cl]2 [Rh(COD)Cl]2 [Rh(COD)Cl]2 [Rh(COD)Cl]2 [Rh(COD)Cl]2 Rh2(oct)4 [Cp*RhCl2]2 [Ir(COD)Cl]2 [Rh(COD)Cl]2

DPPE DPPP DPPB DPEPhos XantPhos BIPHEP DPPF DPPF DPPF DPPF

5 5 1 3 5 1 1 5 2 5 14 14

59 (34) 43 (45) 95 92 0 (52) 98 99 (92)d 0 (24) 93 0 (15) 0 (>99) 0 (>99)

DPPF

a

Reaction conditions: 1a (0.2 mmol) in the presence of 5.0 mol % catalyst and 12.0 mol % ligand in PhCl (1.0 mL) under a nitrogen atmosphere. bDPPE: 1,2-bis(diphenylphosphino)ethane. DPPP: 1,3bis(diphenylphosphino)propane. DPPB: 1,4-bis(diphenylphosphino)butane. DPEPhos: bis[(2-diphenylphosphino)phenyl] ether. Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. BIPHEP: bis(diphenylphosphino)biphenyl. DPPF: 1,1′-bis(diphenylphosphino)ferrocene. cYields were determined by NMR using CH2Br2 as an internal standard. Numbers in parentheses indicate the recovered yield of 1a. dIsolated yield of 2a.

inefficient, DPPB, DPEPhos, and BIPHEP provided 2a in 95, 92, and 98% yield, respectively (entries 3−6). DPPF was the ligand of choice, affording 2a in quantitative yield (99% NMR yield, 92% isolated yield, entry 7). Next, many catalysts, including Rh2(oct)4, [Cp*RhCl2]2, [Ir(COD)Cl]2, and [Rh(COD)Cl]2, were examined to disclose that [Rh(COD)Cl]2 (5.0 mol %) was the most effective catalyst (entries 7−10). Although Rh2(oct)4 and [Ir(COD)Cl]2 were not useful, the catalytic activity of [Cp*RhCl2]2 is comparable to that of [Rh(COD)Cl]2, leading to the formation of 2a in 93% yield. Control experiments without [Rh(COD)Cl]2 or DPPF did not proceed, indicating that this catalyst and ligand are essential for the intramolecular transannulation reaction (entries 11 and 12). With these optimized conditions in hand, we investigated the scope and limitation of the Rh-catalyzed intramolecular transannulation of many cyanothiadiazoles (1), which are readily accessed from the esterification of isothiazole-4carboxylic acid with 3-hydroxypropanenitrile (Scheme 2).4,8 The electronic variation of the substituents on the aryl group of 2-cyanoethyl 5-arylisothiazole-4-carboxylate did not influence the reaction efficiency. Electron-donating methyl, methoxy, and methylenedioxy groups gave the desired bicyclic isothiazoles in excellent yields, varying from 91 to 96%. The conditions of the Rh-catalyzed intramolecular transannulation reaction were compatible with bromo and nitro groups, providing 2e and 2f in 90 and 92% yields, respectively. 2-Furyl-substituted cyanothiadiazole 1g tolerated the optimized conditions and afforded the corresponding 2-furyl-substituted bicyclic isothiazole 2g in 91% yield. 2- or 3-Thiophenyl-substituted cyanothiadiazoles (1h and 1i) also provided the desired bicyclic isothiazoles (2h and 2i) in 80 to 90% yields, respectively. The present method worked equally well even with methyl- and cyclohexyl-substituted cyanothiadiazoles (1j and 1k), leading to

a

Reaction conditions: 1 (0.2 mmol) in the presence of 5.0 mol % [Rh(COD)Cl]2 and 12.0 mol % DPPF in PhCl (1.0 mL) under a nitrogen atmosphere at 130 °C for 1 h. bThe reaction was carried out at 80 °C.

the facile construction of bicyclic isothiazoles 2j (95%) and 2k (91%). Encouraged by these results, we examined the effect of the chain length and substituents on the cyanoalkyl group on the Rh-catalyzed transannulation (Scheme 3). Thiadiazoles (1l, 1m, and 1n) with cyanomethyl groups obtained from αhydroxynitriles, including 2-hydroxypropanenitrile, 2-hydroxy2-methylpropanenitrile, and 1-hydroxycyclohexanecarbonitrile, underwent the Rh-catalyzed transannulation, producing the desired bicyclic thiazoles (2l, 2m, and 2n) in excellent yields ranging from 91 to 93%. The structure of 2n was confirmed by X-ray crystallography (see the Supporting Information).7 Thiadiazoles (1o, 1p, and 1q) generated from the esterification reaction of 5-phenyl isothiazole-4-carboxylic acid with 3hydroxyheptanenitrile, 3-hydroxy-3-phenylpropanenitrile, and 3-hydroxy-3-p-tolylpropanenitrile were compatible with the reaction conditions to furnish the desired thiazoles (2o, 2p, and 2q) in quantitative yields. The present method worked equally well with thiadiazole 1r accessed from 2-hydroxycyclohexanecarbonitrile, resulting in the formation of tricyclic isothiazole 2r in 98% yield. We were pleased to obtain a tricyclic isothiazole (2s) in 90% yield from thiadiazole 1s derived from 2hydroxybenzonitrile. Variation of the substituents on the aryl group in the 2-hydroxybenzonitriles did not influence the efficiency in the syntheses of isothiazoles (2t and 2u), and 10575

DOI: 10.1021/acs.joc.7b02077 J. Org. Chem. 2017, 82, 10574−10582

Article

The Journal of Organic Chemistry Scheme 3. Substrate Scope of Thiadiazoles Bearing a Cyanoalkoxycarbonyl Groupa

Scheme 4. Substrate Scope of Cyanothiadiazoles Bearing Amide or Ether Linkersa

a

Reaction conditions: 3 (0.2 mmol) in the presence of 5.0 mol % [Rh(COD)Cl]2 and 12.0 mol % DPPF in PhCl (1.0 mL) under a nitrogen atmosphere. bDPPBz (12.0 mol %) was used as a ligand instead of DPPF. Reactions were carried out at 130 °C under microwave irradiation for 10 min in sealed microwave vial (SPS mode, 200 W).

yl)methanol and 3-bromopropanenitrile was applied to the present transformation, providing the corresponding bicyclic isothiazole 4c in 84% yield. Cyanothiadiazoles 3d and 3e with 4-bromobutanenitrile and 5-bromopentanenitrile moieties were subjected to the Rh catalyst, and the transannulation reaction occurred, producing the corresponding bicyclic isothiazoles 4d and 4e in 65 and 50% yields, respectively. A plausible reaction mechanism for the Rh-catalyzed intramolecular transannulation of cyanothiadiazoles is suggested in Scheme 5. First, a reversible ring−chain tautomerization of the thiadiazole moieties in cyanothiadiazoles 1 and 3 provides the cyano-substituted α-diazo thiocarbonyl A. The corresponding α-thiavinyl Rh-carbenoid B is then generated from the denitrogenation of A in the presence of the Rh calalyst.9 The [2 + 1] intramolecular cycloaddition of B affords the thiocarbonyl azirine intermediate C,10 which then cycloisomerizes to form bicyclic isothiazole 2 and 4 (path a). However, path a might be excluded in the catalytic cycle due to ring strain. On the other hand, the intermediate B might be subjected to intramolecular nucleophilic attack by the nitrile (path c) to furnish the nitrilium cation D, which subsequently cyclizes to afford the zwitterionic intermediate E. In the end, E regenerates the Rh catalyst to provide bicyclic isothiazoles 2 and 4. On the other hand, the zwitterionic intermediate E can be obtained through an intramolecular [3 + 2] cycloaddition of the nitrile group with the α-thiavinyl Rh-carbenoid B (path b). On the basis of the selective formation of the isothiazole (2 and 4), the nitrilium cation F is ruled out in the catalytic cycle due to an unfavorable geometry (path d). Confirmation of the comprehensive mechanism of the present method must wait for further investigation.

a Reaction conditions: 1 (0.2 mmol) in the presence of 5.0 mol % [Rh(COD)Cl]2 and 12.0 mol % DPPF in PhCl (1.0 mL) under a nitrogen atmosphere. bThe reaction was carried out at 80 °C.

therefore, methyl and bromo substituents were readily employed. Thiadiazole 1v generated from 2-hydroxy-1naphthonitrile took part in the Rh-catalyzed transannulation reaction to afford tetracyclic isothiazole 2v in 74% yield. Next, we investigated the Rh-catalyzed transannulation of cyanoalkyl 5-phenyl-1,2,3-thiodiazolyl-4-carboxylates (1) with an enlarged alkyl chain. Although thiadiazole 1w prepared from 4hydroxybutanenitrile was less reactive, the desired bicyclic thiazole 2w was obtained in acceptable yield. When thiadiazole 1x obtained from 2-(2-hydroxyphenyl)acetonitrile was treated with the Rh catalyst, tricyclic isothiazole 2x was obtained in 70% yield. Moreover, thiadiazole 1y bearing a 3-(2-hydroxynaphthalen-1-yl)propanenitrile moiety was compatible with the reaction conditions, resulting in the production of tetracyclic isothiazole 2y in 66% yield. To demonstrate the efficiency and scope of the present method, we next applied cyanothiadiazoles 3 bearing an amide or ether group as a linker between the thiadiazole ring and the nitrile group to the Rh-catalyzed transannulation (Scheme 4). Cyanothiadiazoles 3a and 3b with 2°- and 3°-amide group as a linker were smoothly converted to the corresponding bicyclic isothiazoles 4a and 4b in excellent yields. Cyanothiadiazole 3c with an ether linker obtained from (5-phenyl-1,2,3-thiadiazol-4-

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CONCLUSION In summary, we developed an intramolecular Rh(I)-catalyzed transannulation of readily available cyanothiadiazoles containing an ester, amide, or ether as a linker, serving as an efficient platform for the construction of a wide range of bi-, tri-, and tetracyclic isothiazoles in good to excellent yields together with 10576

DOI: 10.1021/acs.joc.7b02077 J. Org. Chem. 2017, 82, 10574−10582

Article

The Journal of Organic Chemistry Scheme 5. Plausible Mechanism

6.4 Hz, 2H), 2.78 (t, J = 6.4 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.2, 159.8, 147.4, 131.1, 129.8, 129.0, 125.9, 116.4, 60.1, 18.0; IR (film) 1731, 1623, 1324, 1173, 1002, 834, 751, 694 cm−1; HRMS (EI) m/z [M]+ Calcd for C12H9N3O2S: 259.0415, Found: 259.0413. 2-Cyanoethyl 5-(p-Tolyl)-1,2,3-thiadiazole-4-carboxylate (1b). White solid, 177.7 mg, 65%, mp: 98−100 °C, Rf = 0.3 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.44 (dt, J = 8.2, 1.8 Hz, 2H), 7.31 (dd, J = 8.4, 0.6 Hz, 2H), 4.58 (t, J = 6.5 Hz, 2H), 2.81 (t, J = 6.5 Hz, 2H), 2.44 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.6, 160.0, 147.0, 141.7, 129.78, 129.69, 122.8, 116.4, 60.1, 21.6, 18.0; IR (film) 2252, 1735, 1329, 1280, 1173 cm−1; HRMS (EI) m/z [M]+ Calcd for C13H11N3O2S: 273.0572, Found: 273.0569. 2-Cyanoethyl 5-(4-Methoxyophenyl)-1,2,3-thiadiazole-4-carboxylate (1c). White solid, 193.8 mg, 67%, mp: 87−89 °C, Rf = 0.2 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.52 (dt, J = 9.7,. 2.5 Hz, 2H), 7.01 (dt, J = 9.7, 2.5 Hz, 2H), 4.59 (t, J = 6.5 Hz, 2H), 3.88 (s, 3H), 2.84 (t, J = 6.5 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.5, 162.0, 160.2, 146.6, 131.6, 117.7, 116.5, 114.5, 60.1, 55.6, 18.1; IR (film) 2252, 1732, 1605, 1257, 1173 cm−1; HRMS (EI) m/z [M]+ Calcd for C13H11N3O3S: 289.0521, Found: 289.0522. 2-Cyanoethyl 5-(Benzo[d][1,3]dioxol-5-yl)-1,2,3-thiadiazole-4carboxylate (1d). Yellow oil, 88.0 mg, 29%, Rf = 0.2 (Et2O:DCM:Hx = 1:3:5); 1H NMR (400 MHz, CDCl3) δ 7.05−7.03 (m, 2H), 6.91 (d, J = 8.5 Hz, 1H), 6.08 (s, 2H), 4.60 (t, J = 6.5 Hz, 2H), 2.85 (t, J = 6.5 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.0, 160.0, 150.1, 148.1, 146.8, 124.6, 118.7, 116.5, 109.9, 108.7, 102.0, 80.0, 17.9; IR (film) 2915, 1731, 1624, 1471, 1320, 1141, 1036, 930, 783, 620 cm−1; HRMS (EI) m/z [M]+ Calcd for C13H9N3O4S: 303.0314, Found: 303.0312. 2-Cyanoethyl 5-(4-Bromophenyl)-1,2,3-thiadiazole-4-carboxylate (1e). White solid, 209.7 mg, 62%, mp: 116−118 °C, Rf = 0.3 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.65 (dt, J = 9.0, 2.2 Hz, 2H), 7.42 (dt, J = 9.0, 2.2 Hz, 2H), 4.58 (t, J = 6.4 Hz, 2H), 2.83 (t, J = 6.4 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.1, 159.7, 147.4, 132.3, 131.3, 125.8, 124.7, 116.4, 60.2, 18.0; IR (film) 2252, 1734, 1273, 1175, 1071 cm−1; HRMS (EI) m/z [M]+ Calcd for C12H879BrN3O2S: 336.9521, C12H881BrN3O2S: 338.9500, Found: 336.9519, 338.9507. 2-Cyanoethyl 5-(4-Nitrophenyl)-1,2,3-thiadiazole-4-carboxylate (1f). White solid, 200.8 mg, 66%, mp: 121−122 °C, Rf = 0.2 (Et2O:DCM:Hx = 1:3:5); 1H NMR (400 MHz, CDCl3) δ 8.37 (td, J = 9.1, 2.1 Hz, 2H), 7.73 (td, J = 9.1, 2.1 Hz, 2H), 4.59 (t, J = 6.3 Hz, 2H), 2.84 (t, J = 6.3 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.4, 159.4, 149.3, 148.1, 132.4, 131.0, 124.0, 116.4, 60.4, 18.1 cm−1; HRMS (EI) m/z [M]+ Calcd for C12H8N4O4S: 304.0266, Found: 304.0262.

the release of molecular nitrogen. These results suggest that the carbon atom in the α-thiavinyl carbene is nucleophilic and that the sulfur atom is electrophilic.

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EXPERIMENTAL SECTION

General. Reactions were carried out in oven-dried glassware under air atmosphere. [Rh(COD)Cl]2, Rh2(oct)4, [Cp*RhCl2]2, [Ir(COD)Cl]2, DPPF, DPPP, DPPE, Xantphos, DPEPhos, DPPB, and BIPHEP were purchased and was used as received. All commercially available reagents were used as received. Commercial available reagents were used without purification. Chlorobenzene was purified by distillation from CaCl2 under nitrogen. All reaction mixtures were stirred magnetically and monitored by thin-layer chromatography using silica gel precoated glass plates, which were visualized with UV light and then developed using either iodine or a solution of anisaldehyde. Flash column chromatography was carried out using silica gel (230−400 mesh). 1H NMR (400 MHz) and 13C{1H} NMR (100 MHz) spectra were recorded on an NMR spectrometer. Deuterated chloroform was used as the solvent, and chemical shift values (δ) are reported in parts per million relative to the residual signals of this solvent (δ 7.26 for 1H and δ 77.2 for 13C{1H}). Infrared spectra were recorded on an FT-IR spectrometer as either a thin film pressed between two sodium chloride plates or as a solid suspended in a potassium bromide disk. HRMS were obtained by fast atom bombardment (FAB) using a double focusing magnetic sector mass spectrometer and electron impact (EI) ionization technique (magnetic sector-electric sector double focusing mass analyzer) from the KBSI (Korea Basic Science Institute). Melting points were determined in an open capillary tube. The reaction temperature under microwave irradiation was monitored by an external surface sensor. Preparation of Cyanothiadiazoles 1 and 3a. To a solution of the alcohol or amine (6)11 (1.0 mmol), 4-dimethylaminopyridine (DMAP, 36.7 mg, 0.10 mmol), and thiadiazole-4-carboxylic acid (5)12 (822.8 mg, 1.3 mmol) in dry 1,2-dichloroethane (DCE, 10 mL) at 0 °C under a nitrogen atmosphere was added N,N′-dicyclohexylcarbodiimide (DCC, 823.3 mg, 1.3 mmol) in one portion. After being stirred for 30 min at the same temperature, the reaction mixture was allowed to warm to room temperature followed by stirring for an additional 3 h. Then, the reaction mixture was filtered by Celite and washed with dichloromethane (3 × 10 mL). The combined filtrate was evaporated under reduced pressure to give the crude product, which was purified by silica gel chromatography (EtOAc:hexane = 1:2) to provide the pure products 1 and 3a.13 2-Cyanoethyl 5-Phenyl-1,2,3-thiadiazole-4-carboxylate (1a). White solid, 212.6 mg, 82%, mp: 79−80 °C, Rf = 0.3 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.55−7.51 (m, 5H), 4.56 (t, J = 10577

DOI: 10.1021/acs.joc.7b02077 J. Org. Chem. 2017, 82, 10574−10582

Article

The Journal of Organic Chemistry 2-Cyanoethyl 5-(Furan-2-yl)-1,2,3-thiadiazole-4-carboxylate (1g). White solid, 59.8 mg, 24%, mp: 137−138 °C, Rf = 0.2 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 3.7, 0.6 Hz, 1H), 7.67−7.66 (m, 1H), 6.67 (q, J = 1.8 Hz, 1H), 4.71 (t, J = 6.6 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.4, 151.9, 147.1, 143.7. 142.9, 117.9, 116.5, 113.7, 60.1, 18.2; IR (film) 1725, 1575, 1484, 1277, 1177, 1146, 881, 767, 591 cm−1; HRMS (EI) m/z [M]+ Calcd for C10H7N3O3S: 249.0208, Found: 249.0207. 2-Cyanoethyl 5-(Thiophen-2-yl)-1,2,3-thiadiazole-4-carboxylate (1h). White solid, 217.6 mg, 82%, mp: 116−118 °C, Rf = 0.2 (Et2O:DCM:Hx = 1:3:5); 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 3.8, 1.2 Hz, 1H), 7.67 (dd, J = 5.1, 1.2 Hz, 1H), 7.20 (dd, J = 5.1, 3.8 Hz, 1H), 4.68 (t, J = 6.6, 2H), 2.93 (t, J = 6.6, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.3, 156.5, 145.2, 133.7, 132.5, 128.7, 125.8, 116.4, 60.3, 18.1; IR (film) 3106, 3062, 2251, 1726, 1167, 734 cm−1; HRMS (FAB) m/z [M + H]+ Calcd for C10H8N3O2S2: 266.0058, Found: 266.0060. 2-Cyanoethyl 5-(Thiophen-3-yl)-1,2,3-thiadiazole-4-carboxylate (1i). White solid, 212.2 mg, 80%, mp: 101−102 °C, Rf = 0.2 (Et2O:DCM:Hx = 1:3:5); 1H NMR (400 MHz, CDCl3) δ 8.07(dd, J = 3.0, 1.3 Hz, 1H), 7.48 (dd, J = 5.1, 3.0 Hz, 1H), 7.38 (dd, J = 5.1, 3.0 Hz, 1H), 4.65 (t, J = 6.5 Hz, 2H), 2.89 (t, J = 6.5 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.3, 157.6, 146.4, 129.8, 129.2, 127.3, 125.1, 116.5, 60.2, 18.1; IR (film) 3104, 1730, 1529, 1306, 1196, 1028, 947, 779, 627 cm−1; HRMS (EI) m/z [M]+ Calcd for C10H7N3O2S2: 264.9980, Found: 264.9981. 2-Cyanoethyl 5-Methyl-1,2,3-thiadiazole-4-carboxylate (1j). White solid, 195.2 mg, 99%, mp: 85−86 °C, Rf = 0.3 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 4.65 (t, J = 6.4 Hz, 2H), 2.93− 2.91 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.3, 160.3, 149.4, 116.6, 60.0, 18.2, 11.3; IR (film) 2969, 2253, 1729, 1497, 1385, 1212, 1183, 906, 862, 530 cm−1; HRMS (EI) m/z [M]+ Calcd for C7H7N3O2S: 197.0259, Found: 197.0257. 2-Cyanoethyl 5-Cyclohexyl-1,2,3-thiadiazole-4-carboxylate (1k). Yellow solid, 225.5 mg, 85%, mp: 94−95 °C, Rf = 0.1 (Et2O:DCM:Hx = 1:3:5); 1H NMR (400 MHz, CDCl3) δ 4.65 (t, J = 6.5 Hz, 2H), 3.73 (tt, J = 3.4, 17.5 Hz, 1H), 2.92 (t, J = 6.5 Hz, 2H), 2.13 (t, J = 6.2 Hz, 2H), 1.88−1.77 (m, 3H), 1.53−1.42 (m, 2H), 1.38−1.23 (m, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 174.0, 160.2, 147.4, 116.6, 59.9, 37.2, 36.2, 26.3, 25.5, 18.2; IR (film) 2931, 2853, 1730, 1488, 1316, 1132, 1005, 892, 847, 653 cm−1; HRMS (EI) m/z [M]+ Calcd for C12H15N3O2S: 265.0885, Found: 265.0887. 1-Cyanoethyl 5-Phenyl-1,2,3-thiadiazole-4-carboxylate (1l). White solid, 189.3 mg, 73%, mp: 82−83 °C, Rf = 0.5 (EtOAc:Hx = 1:3); 1H NMR (400 MHz, CDCl3) δ 7.58−7.52 (m, 5H), 5.61 (q, J = 6.9 Hz, 1H), 1.72 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.1, 158.8, 146.6, 131.3, 129.9, 129.0, 125.6, 116.9, 58.6, 18.8; IR (film) 1739, 1472, 1276, 1164, 1043, 845, 749, 692, 553 cm−1; HRMS (EI) m/z [M]+ Calcd for C12H9N3O2S: 259.0415, Found: 259.0417. 2-Cyanopropan-2-yl 5-Phenyl-1,2,3-thiadiazole-4-carboxylate (1m). Ivory solid, 96.7 mg, 35%, mp: 82−83 °C, Rf = 0.5 (EtOAc:Hx = 1:3); 1H NMR (400 MHz, CDCl3) δ 7.56−7.27(m, 5H), 1.82 (d, J = 0.4 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.3, 158.4, 147.4, 131.0, 129.8, 129.0, 125.8, 118.8, 70.2, 26.9; IR (film) 1743, 1470, 1389, 1348, 1179, 987, 848, 754, 695 cm−1; HRMS (EI) m/z [M]+ Calcd for C13H11N3O2S: 273.0572, Found: 273.0575. 1-Cyanocyclohexyl 5-Phenyl-1,2,3-thiadiazole-4-carboxylate (1n). Yellow solid, 150.4 mg, 48%, mp: 90−91 °C, Rf = 0.4 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.54−7.45(m, 5H), 2.31−2.28 (m, 2H), 1.91−1.85 (m, 2H), 1.72-, 1.57 (m, 5H), 1.35−1.29 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.0, 158.1, 147.5, 130.9, 129.7, 128.9, 125.8, 117.9, 74.5, 35.0, 24.4, 22.0; IR (film) 2941, 2863, 1742, 1470, 1334, 1279, 1028, 951, 844, 754 cm−1; HRMS (EI) m/z [M]+ Calcd for C16H15N3O2S: 313.0885, Found: 313.0882. 1-Cyanohexan-2-yl 5-Phenyl-1,2,3-thiadiazole-4-carboxylate (1o). Orange oil, 227.1 mg, 72%, Rf = 0.6 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.56−7.50 (m, 5H), 5.26 (dq, J = 8.1, 5.4

Hz, 1H), 2.74 (ddd, J = 48.1, 17.0, 5.5 Hz, 2H), 1.81−1.63 (m, 2H), 1.35−1.19 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.7, 159.7, 148.1, 130.9, 129.8, 128.8, 126.0, 116.1, 70.9, 33.0, 27.1, 23.0, 22.3, 13.9; IR (film) 2251, 1733, 1177 cm−1; HRMS (EI) m/z [M]+ Calcd for C16H17N3O2S: 315.1041, Found: 315.1044. 2-Cyano-1-phenylethyl 5-Phenyl-1,2,3-thiadiazole-4-carboxylate (1p). White solid, 218.0 mg, 65%, mp: 124−126 °C, Rf = 0.5 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.56−7.46 (m, 5H), 7.35−7.26 (m, 5H), 6.23 (t, J = 6.3 Hz, 1H), 2.94 (d, J = 6.4 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.0, 159.1, 147.8, 136.4, 130.9, 129.8, 129.6, 129.1, 128.0, 126.4, 126.0, 115.9, 72.4, 25.6; IR (film) 2252, 1736, 1172, 1002 cm−1; HRMS (EI) m/z [M]+ Calcd for C18H13N3O2S: 335.0728, Found: 335.0726. 2-Cyano-1-(p-tolyl)ethyl 5-Phenyl-1,2,3-thiadiazole-4-carboxylate (1q). Ivory solid, 223.6 mg, 64%, mp: 107−109 °C, Rf = 0.6 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.56−7.46 (m, 5H), 7.18−7.13 (m, 4H), 6.20 (t, J = 6.4 Hz, 1H), 2.93−2.91 (m, 2H), 2.33 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.9, 159.0, 147.8, 139.5, 133.4, 130.8, 129.8, 129.7, 128.9, 126.4, 126.0, 116.0, 72.3, 25.6, 21.3; IR (film) 2251, 1736, 1172 cm−1; HRMS (EI) m/z [M]+ Calcd for C19H15N3O2S: 349.0885, Found: 349.0883. 2-(Cyanomethyl)cyclohexyl 5-Phenyl-1,2,3-thiadiazole-4-carboxylate (1r). Orange oil, 188.0 mg, 60%, Rf = 0.4 (EtOAc:Hx = 1:4); 1H NMR (400 MHz, CDCl3) δ 7.56−7.48 (m, 5H), 5.20(dt, J = 3.9, 9.0 Hz, 1H), 2.68 (dt, J = 4.0, 9.7 Hz, 1H), 2.20−2.07 (m, 2H), 1.77−1.64 (m, 3H), 1.53−1.38 (m, 2H), 1.34−1.26 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.7, 159.2, 148.0, 130.8, 129.8, 128.8, 126.1, 119.8, 73.1, 33.5, 30.1, 27.8, 23.4, 22.7; IR (film) 2243, 1733, 1178 cm−1; HRMS (EI) m/z [M]+ Calcd for C16H15N3O2S: 313.0885, Found: 313.0883. 2-Cyanophenyl 5-Phenyl-1,2,3-thiadiazole-4-carboxylate (1s). White solid, 298.1 mg, 97%, Rf = 0.3 (EtOAc:Hx = 1:2), mp: 76− 77 °C, 1H NMR (400 MHz, CDCl3) δ 7.73−7.69 (m, 1H), 7.67−7.65 (m, 1H), 7.64−7.62 (m, 2H), 7.54- 7.46 (m, 3H), 7.42−7.38 (m, 2H); 13 C{1H} NMR (100 MHz, CDCl3) δ 165.0, 158.0, 151.8, 146.2, 134.4, 133.6, 131.2, 129.9, 129.0, 127.1, 125.4, 123.3, 115.1, 107.5; IR (film) 2233, 1756, 1449, 1324, 1224, 1136, 947, 845, 694 cm−1; HRMS (EI) m/z [M]+ Calcd for C16H9N3O2S: 307.0415, Found: 307.0417. 2-Cyano-4-methylphenyl 5-Phenyl-1,2,3-thiadiazole-4-carboxylate (1t). Light orange solid, 181.9 mg, 57%, mp: 124−126 °C Rf = 0.3 (EtOAc:Hx = 1:4); 1H NMR (400 MHz, CDCl3) δ 7.63−7.61 (m, 2H), 7.54−7.44 (m, 5H), 7.26 (d, J = 8.4 Hz, 1H), 2.40 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 164.9, 158.3, 149.7, 146.4, 137.4, 135.1, 133.7, 131.2, 130.0, 129.0, 125.5, 123.0, 115.3, 107.2, 20.8; IR (film) 2233, 1754, 1205, 1138 cm−1; HRMS (EI) m/z [M]+ Calcd for C17H11N3O2S: 321.0572, Found: 321.0569. 4-Bromo-2-cyanophenyl 5-Phenyl-1,2,3-thiadiazole-4-carboxylate (1u). Yellow solid, 77.2 mg, 20%, mp: 93−94 °C, Rf = 0.4 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 2.4 Hz, 1H), 7.77 (dd, J = 2.4, 8.8 Hz, 1H), 7.62−7.59 (m, 2H), 7.53−7.4 (m, 3H), 7.29 (d, J = 8.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.2, 157.6, 150.9, 145.9, 137.5, 135.9, 131.3, 129.9, 129.0, 125.3, 124.9, 119.8, 113.7, 109.3; IR (film) 2236, 1755, 1468, 1329, 1280, 1176, 1133, 854, 694 cm−1; HRMS (EI) m/z [M]+ Calcd for C16H879BrN3O2S: 384.9521, C16H881BrN3O2S: 386.9501, Found: 384.9521, 386.9494. 1-Cyanonaphthalen-2-yl 5-Phenyl-1,2,3-thiadiazole-4-carboxylate (1v). Orange solid, 164.4 mg, 46%, mp: 116−118 °C, Rf = 0.3 (EtOAc:Hx = 1:4); 1H NMR (400 MHz, CDCl3) δ 8.22, (d, J = 8.1 Hz, 1H), 8.13 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.74 (ddd, J = 7.0, 8.3, 1.2 Hz, 1H), 7.68−7.61 (m, 3H), 7.54−7.46 (m, 4H); 13 C{1H} NMR (100 MHz, CDCl3) δ 165.1, 158.1, 152.3, 146.4, 134.8, 132.9, 131.28, 131.22, 130.0, 129.6, 129.0, 128.8, 127.7, 125.5, 125.3, 121.0, 114.2, 103.6; IR (film) 2232, 1754, 1216, 1133 cm−1; HRMS (EI) m/z [M]+ Calcd for C20H11N3O2S: 357.0572, Found: 357.0569. 3-Cyanopropyl 5-Phenyl-1,2,3-thiadiazole-4-carboxylate (1w). Ivory solid, 153.1 mg, 56%, mp: 50−52 °C, Rf = 0.4 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.59−7.49 (m, 5H), 4.45 (t, J = 5.9 Hz, 2H), 2.29 (t, J = 7.2 Hz, 2H), 2.08−2.01 (m, 2H); 13C{1H} 10578

DOI: 10.1021/acs.joc.7b02077 J. Org. Chem. 2017, 82, 10574−10582

Article

The Journal of Organic Chemistry NMR (100 MHz, CDCl3) δ 162.4, 160.1, 148.2, 130.9, 129.7, 128.9, 126.2, 118.7, 63.5, 24.8, 14.2; IR (film) 2249, 1733, 1336, 1180 cm−1; HRMS (EI) m/z [M]+ Calcd for C13H11N3O2S: 273.0572, Found: 273.0572. 2-(Cyanomethyl) Phenyl-5-phenyl-1,2,3-thiadiazole-4-carboxylate (1x). White solid, 196.0 mg, 61%, mp: 96−98 °C, Rf = 0.4 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.62−7.59 (m, 2H), 7.56−7.47 (m, 4H), 7.43−7.39 (m, 1H), 7.35−7.30 (m, 2H), 3.67 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.3, 158.2, 148.2, 147.0, 131.2, 130.0, 129.8, 129.7, 129.0, 127.2, 125.6, 122.7, 122.6, 116.9, 19.1; IR (film) 2251, 1751, 1215, 1171, 1145 cm−1; HRMS (EI) m/z [M]+ Calcd for C17H11N3O2S: 321.0572, Found: 321.0574. 1-(2-Cyanoethyl)naphthalen-2-yl 5-phenyl-1,2,3-thiadiazole-4carboxylate (1y). Pink solid, 289.1 mg, 75%, mp: 112−113 °C, Rf = 0.4 (EtOAc:DCM:Hx = 1:2:5); 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.65−7.58 (m, 3H), 7.55−7.47 (m, 4H), 7.40 (d, J = 8.9 Hz, 1H), 3.39 (t, J = 8.0 Hz, 2H), 2.59 (t, J = 8.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.2, 159.1, 147.3, 146.4, 132.3, 132.0 131.2, 130.0, 129.4, 129.3, 129.0, 127.6, 126.1, 125.8, 124.7, 123.1, 121.2, 119.2, 22.3, 17.4; IR (film) 2247, 1745, 1207, 1146 cm−1; HRMS (FAB) m/z [M + H]+ Calcd for C22H16N3O2S: 386.0963, Found: 386.0964. N-(2-Cyanoethyl)-5-phenyl-1,2,3-thiadiazole-4-carboxamide (3a). White solid, 90.4 mg, 35%, mp: 87−89 °C, Rf = 0.1 (DCM); 1H NMR (400 MHz, CDCl3) δ 8.12 (br s, 1H), 7.65−7.62 (m, 2H), 7.54−7.46 (m, 3H), 3.75 (q, J = 6.5 Hz, 2H), 2.75 (t, J = 6.6 Hz, 2H); 13 C{1H} NMR (100 MHz, CDCl3) δ 161.3, 160.2, 149.0, 130.9, 130.2, 128.7, 125.8, 117.9, 36.0, 18.5; IR (film) 3347, 3061, 2932, 2250, 1672, 1535, 1503, 1075 cm−1; HRMS (EI) m/z [M]+ Calcd for C12H10N4OS: 258.0575, Found: 258.0577. Preparation of 3b.14 The solution of thiadiazole-4-carboxylic acid (5a)12 (412.44 mg, 2.0 mmol) and SOCl2 (2.0 mmol) was stirred at 60 °C for 3 h. After being stirred for 3 h, the redundant SOCl2 was evaporated under reduced pressure, and then amine in DCM (0.2 M) (6) was added dropwise and stirred at room temperature for 1 h. The organic phase was washed with aqueous HCl and aqueous K2CO3 and then dried by anhydrous MgSO4. After evaporating the DCM, the N(2-cyanoethyl)-N-methyl-5-phenyl-1,2,3-thiadiazole-4-carboxamide was obtained and used in the next step directly. N-(2-Cyanoethyl)-N-methyl-5-phenyl-1,2,3-thiadiazole-4-carboxamide (3b). White solid, 60 mg, 11%, mp: 104−105 °C, Rf = 0.2 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.57−7.47 (m, 5H), 3.85 (t, J = 6.5 Hz, 1.5 H), 3.61 (t, J = 7.0 Hz, 0.5 H), 3.26 (s, 1H), 3.04 (s, 2H), 2.80 (t, J = 6.5 Hz, 1.5 H), 2.72 (t, J = 7.0 Hz, 0.5 H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.6, 162.7, 157.8, 156.2, 151.5, 151.3, 131.1, 131.0, 129.7, 129.5, 129.4, 129.0, 126.2, 126.1, 117.9, 117.3, 47.3, 44.9, 38.1, 34.1, 17.7, 15.9; IR (film) 2233, 1756, 1471, 1449, 1329, 1136, 947, 845, 694 cm−1; HRMS (EI) m/z [M]+ Calcd for C13H12N4OS: 272.0732, Found: 272.0734. Preparation of 3c, 3d, and 3e. To an oven-dried round-bottom flask equipped with a magnetic stirring bar under a nitrogen atmosphere was added (1,2,3-thiadiazol-4-yl)methanol (7)15 (3.0 mmol) and DMF (9.0 mL). Dry sodium hydride (95%) (216 mg, 9.0 mmol) was added, and the mixture was stirred at room temperature for 30 min. 8 (15.0 mmol) was added, and the mixture was stirred at 100 °C for 2 h. All volatiles were removed in vacuo, and the resulting residue was partitioned between water and EtOAc. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and then dried over MgSO4. The solvent was removed in vacuo and purified by silica gel chromatography (EtOAc:hexane = 1:5) to provide the product 3.16 3-((5-Phenyl-1,2,3-thiadiazol-4-yl)methoxy)propanenitrile (3c). Yellow solid, 264.9 mg, 36%, mp: 54−56 °C, Rf = 0.5 (Et2O:Hx = 1:1); 1H NMR (400 MHz, CDCl3) δ 7.64−7.62 (m, 2H), 7.54−7.52 (m, 3H), 4.97 (s, 2H), 3.89 (t, J = 6.2 Hz, 2H), 2.67 (t, J = 6.2 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.6, 154.3, 130.5, 129.7, 129.6, 127.3, 117.8, 65.1, 64.2, 19.1; IR (film) 3061, 2918, 2873, 2251, 1245, 1100 cm−1; HRMS (FAB) m/z [M + H]+ Calcd for C12H12N3OS: 246.0701, Found: 246.0702.

4-((5-Phenyl-1,2,3-thiadiazol-4-yl)methoxy)butanenitrile (3d). Yellow oil, 116.7 mg, 15%, Rf = 0.3 (Et2O:DCM:Hx = 1:1:1); 1H NMR (400 MHz, CDCl3) δ 7.61−7.56 (m, 2H), 7.55−7.51 (m, 3H), 4.94 (s, 2H), 3.74 (t, J = 5.7 Hz, 2H), 2.44 (t, J = 7.1 Hz, 2H), 2.00− 1.93 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.9, 154.8, 130.4, 129.55, 129.51, 127.5, 119.4, 68.0, 64.3, 25.8, 14.2; IR (film) 3062, 2931, 2869, 2249, 1104, 697 cm−1; HRMS (FAB) m/z [M + H]+ Calcd for C13H14N3OS: 260.0858, Found: 260.0860. 5-((5-Phenyl-1,2,3-thiadiazol-4-yl)methoxy)pentanenitrile (3e). Yellow oil, 599 mg, 73%, Rf = 0.6 (Et2O:DCM:Hx = 1:1:1); 1H NMR (400 MHz, CDCl3) δ 7.61−7.58 (m, 2H), 7.58−7.50 (m, 3H), 4.91 (s, 2H), 3.66 (t, J = 5.7 Hz, 2H), 2.35 (t, J = 6.8 Hz, 2H), 1.82− 1.70 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.7, 155.1, 130.4, 129.6, 129.5, 127.6, 119.7, 69.5, 64.1, 28.7, 22.6, 17.1; IR (film) 3062, 2244, 1245, 1094, 834, 768, 697 cm−1; HRMS (FAB) m/z [M + H]+ Calcd for C14H16N3OS: 274.1014, Found: 274.1016. General Procedure for the Intramolecular Transannulation. To a test tube were added [Rh(COD)Cl]2 (4.9 mg, 0.01 mmol), DPPF (13.3 mg, 0.024 mmol), and cyanothiadiazoles (1) (0.2 mmol) in chlorobenzene (1.0 mL). The resulting mixture was stirred at 130 °C for 1 h under a nitrogen atmosphere. After Celite filtration and evaporation of the solvents in vacuo, the crude product was purified by silica gel column chromatography (EtOAc:hexane = 1:4) to provide the products 2 and 4. 3-Phenyl-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2a). White solid, 42 mg, 91%, mp: 70−71 °C, Rf = 0.3 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.71−7.69 (m, 2H), 7.50−7.46 (m, 3H), 4.60−4.57 (m, 2H), 3.24−3.21 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.6, 168.3, 161.0, 131.0, 129.3, 128.9, 128.7, 119.4, 67.0, 29.3; IR (film) 1729, 1533, 1274, 1082, 751, 601, 550, 514 cm−1; HRMS (EI) m/z [M]+ Calcd for C12H9NO2S: 231.0354, Found: 231.0354. 3-(p-Tolyl)-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2b). White solid, 47 mg, 96%, mp: 119−120 °C, Rf = 0.3 (EtOAc:Hx = 1:3); 1H NMR (400 MHz, CDCl3) δ 7.63−7.60 (m, 2H), 7.29 (d, J = 7.9 Hz, 2H), 4.58 (t, J = 6.0 Hz, 2H), 3.22 (t, J = 6.0 Hz, 2H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.9, 168.3, 161.2, 141.5, 129.6, 129.2, 125.9, 119.1, 67.0, 29.4, 21.6; IR (film) 1730, 1527, 1433, 1374, 1157, 1036, 808, 701 cm−1; HRMS (EI) m/z [M]+ Calcd for C13H11NO2S: 245.0510, Found: 245.0511. 3-(4-Methoxyphenyl)-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4one (2c). White solid, 50 mg, 96%, mp: 131−132 °C, Rf = 0.2 (EtOAc:Hx = 1:3); 1H NMR (400 MHz, CDCl3) δ 7.71 (td, J = 2.2, 9.7 Hz, 2H), 6.99 (dd, J = 1.6, 7.0 Hz, 2H), 4.57 (t, J = 6.0 Hz, 2H), 3.87 (s, 3H), 3.20 (t, J = 6.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.6, 168.4, 162.0, 161.4, 131.0, 121.1, 118.5, 114.4, 67.0, 55.6, 29.4; IR (film) 2929, 1729, 1536, 1433, 1254, 1083, 825, 702, 591 cm−1; HRMS (EI) m/z [M]+ Calcd for C13H11NO3S: 261.0460, Found: 261.0462. 3-(Benzo[d][1,3]dioxol-5-yl)-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2d). Yellow oil, 50 mg, 91%, Rf = 0.7 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.26−7.22 (m, 2H), 6.89 (d, J = 8.0 Hz, 1H), 6.05 (s, 2H), 4.57 (t, J = 6.0 Hz, 2H), 3.21 (t, J = 6.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.4, 168.3, 161.2, 150.2, 148.2, 124.1, 122.4, 118.9, 109.7, 108.7, 101.9, 67.0, 29.4; IR (film) 1728, 1534, 1487, 1234, 1109, 1036, 930, 864 cm−1; HRMS (EI) m/z [M]+ Calcd for C13H9NO4S: 275.0252, Found: 275.0250. 3-(4-Bromophenyl)-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4one (2e). White solid, 56 mg, 90%, mp: 143−144 °C, Rf = 0.3 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.63−7.58 (m, 4H), 4.60 (t, J = 6.0 Hz, 2H), 3.24 (t, J = 6.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 175.1, 168.4, 161.0, 132.2, 130.8, 127.6, 125.7, 119.6, 67.1, 29.3; IR (film) 1727, 1531, 1486, 1280, 1083, 1009, 812, 606, 522 cm−1; HRMS (EI) m/z [M]+ Calcd for C12H879BrNO2S: 308.9459, C12H881BrNO2S: 310.9439, Found: 308.9458, 310.9446. 3-(4-Nitrophenyl)-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2f). White solid, 51 mg, 92%, mp: 121−122 °C, Rf = 0.3 (EtOAc:Hx = 1:3); 1H NMR (400 MHz, CDCl3) δ 8.34 (dd, J = 2.1, 6.9 Hz, 2H), 7.88 (dd, J = 2.1, 6.9 Hz, 2H), 4.63 (t, J = 6.1 Hz, 2H), 3.28 (t, J = 6.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.1, 168.6, 160.7, 10579

DOI: 10.1021/acs.joc.7b02077 J. Org. Chem. 2017, 82, 10574−10582

Article

The Journal of Organic Chemistry

NMR (400 MHz, CDCl3) δ 7.73−7.68 (m, 2H), 7.51−7.44 (m, 3H), 4.62−4.56 (m, 1H), 3.20 (dd, J = 16.5, 3.2 Hz, 1H), 2.98 (dd, J = 16.5, 11.4 Hz, 1H), 1.97−1.88 (m, 1H), 1.80−1.72 (m, 1H), 1.62−1.52 (m, 1H), 1.51−1.34 (m, 3H), 0.94 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.0, 168.6, 161.0, 130.9, 129.3, 128.8, 128.7, 119.3, 78.9, 34.52, 34.46, 27.2, 22.5, 14.0; IR (film) 1731, 1536, 1286, 1170 cm−1; HRMS (EI) m/z [M]+ Calcd for C16H17NO2S: 287.0980, Found: 287.0981. 3,6-Diphenyl-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2p). Yellow solid, 61.1 mg, 99%, mp: 147−149 °C, Rf = 0.4 (EtOAc:Hx = 1:4); 1H NMR (400 MHz, CDCl3) δ 7.76−7.73 (m, 2H), 7.53−7.37 (m, 8H), 5.65 (dd, J = 11.2, 3.8 Hz, 1H), 3.46 (dd, J = 3.9, 16.8 Hz, 1H), 3.38 (dd, J = 16.6, 11.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.5, 168.2, 160.6, 137.8, 131.0, 129.4, 129.06, 128.98, 128.94, 128.7, 126.3, 119.4, 79.9, 36.6; IR (film) 1731, 1534, 1287, 1162 cm−1; HRMS (EI) m/z [M]+ Calcd for C18H13NO2S: 307.0667, Found: 307.0665. 3-Phenyl-6-(p-tolyl)-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4one (2q). White solid, 63.6 mg, 99%, mp: 148−150 °C, Rf = 0.4 (EtOAc:Hx = 1:4); 1H NMR (400 MHz, CDCl3) δ 7.75−7.73 (m, 2H), 7.53−7.47 (m, 3H), 7.37 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 5.62 (dd, J = 10.6, 4.2 Hz, 1H), 3.44 (dd, J = 16.7, 4.4 Hz, 1H), 3.38 (dd, J = 16.8, 10.8, 1H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.4, 168.4, 160.8, 139.0, 134.8, 131.0, 129.6, 129.4, 128.9, 128.7, 126.3, 119.5, 80.0, 36.5, 21.4; IR (film)1732, 1534, 1286, 1161 cm−1; HRMS (EI) m/z [M]+ Calcd for C19H15NO2S: 321.0823, Found: 321.0823. 3-Phenyl-5a,6,7,8,9,9a-hexahydro-4H-chromeno[4,3-c]isothiazol-4-one (2r). White solid, 55.9 mg, 98%, mp: 156−158 °C, Rf = 0.5 (EtOAc:Hx = 1:4); 1H NMR (400 MHz, CDCl3) δ 7.72−7.69 (m, 2H), 7.52−7.45 (m, 3H), 4.19 (td, J = 17.1, 4.3 Hz, 1H), 2.86 (td, J = 17.0, 4.1 Hz, 1H), 2.73−2.69 (m, 1H), 2.31−2.27 (m, 1H), 1.99− 1.90 (m, 2H), 1.80−1.70 (m, 1H), 1.53−1.38 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 176.2, 171.8, 161.0, 130.9, 129.3, 128.9, 128.8, 119.6, 81.8, 44.0, 31.4, 26.3, 24.7, 24.3; IR (film) 1728, 1533, 1274, 1173 cm−1; HRMS (EI) m/z [M]+ Calcd for C16H15NO2S: 285.0823, Found: 285.0822 3-Phenyl-4H-chromeno[4,3-c]isothiazol-4-one (2s).17 White solid, 46 mg, 84%, mp: 158−159 °C, Rf = 0.3 (EtOAc:Hx= 1:2); 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.2 Hz, 1H), 7.80−7.78 (m, 2H), 7.59−7.52 (m, 4H), 7.40−7.36 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.3, 162.8, 156.7, 152.7, 132.2, 131.2, 129.6, 129.0, 128.4, 125.0, 124.4, 117.5, 117.3, 117.1; IR (film) 1732, 1591, 1483, 1293, 1156, 896, 750, 639 cm−1. 8-Methyl-3-phenyl-4H-chromeno[4,3-c]isothiazol-4-one (2t). White solid, 58.1 mg, 99%, mp: 157−159 °C, Rf = 0.6 (EtOAc:Hx = 1:4); 1H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 1.4, 0.5 Hz, 1H), 7.80−7.78 (m, 2H), 7.56−7.52 (m, 3H), 7.36 (ddd, J = 8.4, 2.2, 0.5 Hz, 1H), 7.27 (d, J = 9.7 Hz, 1H), 2.47(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.3, 163.0, 156.9, 150.9, 134.8, 133.1, 131.2, 129.6, 129.0, 128.5, 117.2, 117.1, 21.0; IR (film) 1743, 1532, 1484, 1111 cm−1; HRMS (EI) m/z [M]+ Calcd for C17H11NO2S: 293.0510, Found: 293,0508. 8-Bromo-3-phenyl-4H-chromeno[4,3-c]isothiazol-4-one (2u). White solid, 64 mg, 90%, mp: 188−189 °C, Rf = 0.7 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 2.4 Hz, 1H), 7.80− 7.77 (m, 2H), 7.65 (dd, J = 8.8, 2.4 Hz, 1H), 7.58−7.53 (m, 3H), 7.28 (d, J = 8.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.7, 161.4, 156.0, 151.4, 134.8, 131.3, 129.4, 128.9, 128.0, 127.0, 119.0, 118.9, 117.7, 116.8; IR (film) 1755, 1583, 1458, 1274, 1250, 1003, 902, 855, 746, 536 cm−1; HRMS (EI) m/z [M]+ Calcd for C16H879BrNO2S: 356.9459, C16H881BrNO2S: 356.9439, Found: 356.9456, 356.9426. 3-Phenyl-4H-benzo[5,6]chromeno[4,3-c]isothiazol-4-one (2v). White solid, 59.3 mg, 90%, mp: 238−240 °C, Rf = 0.9 (Et2O:DCM:Hx = 1:3:3); 1H NMR (400 MHz, CDCl3) δ 10.10 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.82−7.76 (m, 3H), 7.62−7.50 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3) δ 177.2, 163.9, 156.8, 152.8, 133.5, 131.11, 131.06, 129.8, 129.7, 129.1, 129.0, 128.8, 128.5, 126.9, 126.2, 118.1, 117.4, 111.0; IR (film) 2919, 1730,

149.1, 134.8, 130.5, 124.0, 120.7, 67.3, 29.2; IR (film) 1735, 1514, 1348, 1279, 1348, 1279, 1084, 825, 746 cm−1; HRMS (EI) m/z [M]+ Calcd for C12H8N2O4S: 276.0205, Found: 276.0205. 3-(Furan-2-yl)-6,7-dihydro-4H-thieno[3,4-c]pyran-4-one (2g). White solid, 40 mg, 91%, mp: 150−151 °C, Rf = 0.5 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 3.6 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.27 (s, 1H), 4.56 (t, J = 6.1 Hz, 2H), 3.18 (t, J = 6.1 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.8, 163.0, 161.5, 145.4, 145.3, 117.0, 116.2, 113.5, 67.0, 29.0; IR (film) 1723, 1578, 1528, 1381, 1278, 1141, 1034, 870, 782, 700, 509 cm−1; HRMS (EI) m/z [M]+ Calcd for C10H7NO3S: 221.0147, Found: 221.0147. 3-(Thiophen-2-yl)-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2h). Yellow solid, 38.1 mg, 80%, mp: 72−74 °C, Rf = 0.4 (Et2O:DCM:Hx = 1:1:2); 1H NMR (400 MHz, CDCl3) δ 7.94 (dd, J = 3.8, 1.1 Hz, 1H), 7.60 (dd, J = 5.1, 1.1 Hz, 1H), 7.17 (dd, J = 5.1, 3.8 Hz, 1H), 4.56 (t, J = 6.0 Hz, 2H), 3.19 (t, J = 6.1 Hz, 2H); 13 C{1H} NMR (100 MHz, CDCl3) δ 168.4, 168.3, 161.4, 131.7, 131.4, 129.5, 128.3, 117.7, 66.9, 29.3; IR (film) 3104, 1725, 1536, 1278, 1220, 1153, 1084, 702 cm−1; HRMS (EI) m/z [M]+ Calcd for C10H7NO2S2: 236.9918, Found: 236.9915. 3-(Thiophen-3-yl)-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2i). White solid, 43 mg, 90%, mp: 126−127 °C, Rf = 0.4 (EtOAc:Hx = 1:2),1H NMR (400 MHz, CDCl3) δ 8.47 (dd, J = 1.3, 3.0 Hz, 1H), 7.52 (dd, J = 1.3, 5.1 Hz, 1H), 7.42 (dd, J = 3.0, 5.1 Hz, 1H), 4.56 (t, J = 6.0 Hz, 2H), 3.21 (t, J = 6.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.9, 168.5, 161.5, 129.4, 128.7, 128.0, 126.8, 118.5, 66.9, 29.3; IR (film) 1720, 1540, 1378, 1269, 1145, 1036, 982, 800, 780 cm−1; HRMS (EI) m/z [M]+ Calcd for C10H7NO2S2: 236.9918, Found: 236.9921. 3-Methyl-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2j). White solid, 32 mg, 95%, mp: 89−90 °C, Rf = 0.5 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 4.53 (t, J = 6.1 Hz, 2H), 3.15 (t, J = 6.1 Hz, 2H), 2.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.5, 167.4, 162.0, 121.5, 67.5, 29.0, 13.4; IR (film) 2919, 1725, 1540, 1264, 1074, 1053, 1009, 781, 701 cm−1; HRMS (EI) m/z [M]+ Calcd for C7H7NO2S: 169.0197, Found: 169.0199. 3-Cyclohexyl-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2k). White solid, 43 mg, 91%, mp: 101−102 °C, Rf = 0.7 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 4.52 (t, J = 6.1 Hz, 2H), 3.72 (tt, J = 3.4, 17.4 Hz, 1H), 3.15 (t, J = 6.1 Hz, 2H), 2.17−2.14 (m, 2H), 1.87−1.76 (m, 3H), 1.55−1.23 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3) δ 187.4, 167.3, 161.7, 119.6, 67.1, 38.6, 34.7, 28.9, 26.3, 25.8; IR (film) 2927, 1728, 1536, 1261, 1123, 1071, 1023, 786, 706 cm−1; HRMS (EI) m/z [M]+ Calcd for C12H15NO2S: 237.0823, Found: 237.0826. 6-Methyl-3-phenylfuro[3,4-c]isothiazol-4(6H)-one (2l). White solid, 42 mg, 91%, mp: 125−136 °C, Rf = 0.4 (EtOAc:Hx= 1:2); 1H NMR (400 MHz, CDCl3) δ 8.12−8.10 (m, 2H), 7.52−7.50 (m, 3H), 5.46 (q, J = 6.7 Hz, 1H), 1.72 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 182.7, 171.8, 161.9, 132.0, 130.0, 128.6, 128.4, 122.5, 76.1, 19.3; IR (film) 1757, 1551, 1466, 1303, 1117, 1048, 936, 759, 687 cm−1; HRMS (EI) m/z [M]+ Calcd for C12H9NO2S: 231.0354, Found: 231.0356. 6,6-Dimethyl-3-phenylfuro[3,4-c]isothiazol-4(6H)-one (2m). White solid, 45 mg, 92%, mp: 134−135 °C, Rf = 0.5 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 8.13−8.11 (m, 2H), 7.52−7.49 (m, 3H), 1.74 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.5, 171.8, 161.4, 131.9, 129.6, 128.6, 128.4, 122.0, 83.9, 26.1; IR (film) 1747, 1547, 1446, 1363, 1280, 1182, 1106, 900, 789, 686 cm−1; HRMS (EI) m/z [M]+ Calcd for C13H11NO2S: 245.0510, Found: 245.0512. 3′-Phenyl-4′H-spiro[cyclohexane-1,6′-furo[3,4-c]isothiazol]-4′one (2n). White solid, 53 mg, 93%, mp: 119−120 °C, Rf = 0.6 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 8.13−8.11 (m, 2H), 7.52−7.49 (m, 3H), 2.05−1.79 (m, 8H), 1.67−1.55 (m, 2H); 13 C{1H} NMR (100 MHz, CDCl3) δ 185.4, 171.3, 161.7, 131.8, 129.6, 128.7, 128.4, 122.4, 85.8, 35.2, 24.7, 22.1; IR (film) 2937, 1760, 1497, 1288, 1163, 1031, 943, 866, 711 cm−1; HRMS (EI) m/z [M]+ Calcd for C16H15NO2S: 285.0823, Found: 285.0821. 6-Butyl-3-phenyl-6,7-dihydro-4H-pyrano[4,3-c]isothiazol-4-one (2o). Colorless oil, 55.3 mg, 96%, Rf = 0.5 (EtOAc:Hx = 1:4); 1H 10580

DOI: 10.1021/acs.joc.7b02077 J. Org. Chem. 2017, 82, 10574−10582

The Journal of Organic Chemistry

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1273, 813, 747, 729, 691 cm−1; HRMS (EI) m/z [M]+ Calcd for C20H11NO2S: 329.0510, Found: 329.0511. 3-Phenyl-7,8-dihydro-4H,6H-oxepino[4,3-c]isothiazol-4-one (2w). Ivory solid, 20.6 mg, 40%, mp: 206−208 °C, Rf = 0.3 (EtOAc:Hx = 1:4); 1H NMR (400 MHz, CDCl3) δ 7.47−7.43 (m, 5H), 4.35 (dd, J = 5.3, 4.8 Hz, 2H), 3.32 (t, J = 8.08, 2H), 2.21−2.15 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.9, 170.2, 163.2, 130.2, 129.9, 129.0, 128.6, 125.6, 65.3, 31.6, 29.2; IR (film) 2956, 2921, 1712, 1522, 1481, 1193, 1033 cm−1; HRMS (EI) m/z [M]+ Calcd for C13H11NO2S: 245.0510, Found: 245.0512. 3-Phenylbenzo[6,7]oxepino[4,3-c]isothiazol-4(10H)-one (2x). White solid, 41 mg, 70%, mp: 119−120 °C, Rf = 0.8 (EtOAc:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.54−7.52 (m, 2H), 7.49−7.44 (m, 3H), 7.37−7.20 (m, 4H), 4.26 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 177.5, 168.8, 160.0, 151.0, 130.7, 129.6, 129.5, 129.0, 128.9, 126.6, 121.8, 121.6, 36.6; IR (film) 1734, 1525, 1485, 1276, 1221, 1060, 955, 800, 754, 692 cm−1; HRMS (EI) m/z [M]+ Calcd for C17H11NO2S: 293.0510, Found: 293.0512. 3-Phenyl-12,13-dihydro-4H-naphtho[2′,3′:7,8]oxocino[4,3-c]isothiazol-4-one (2y). White solid, 47.4 mg, 66%, mp: 195−196 °C, Rf = 0.5 (EtOAc:DCM:Hx = 1:2:5); 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.62−7.58 (m, 1H), 7.50−7.46 (m, 6H), 7.26 (d, J = 8.7 Hz, 1H), 3.65 (t, J = 7.2 Hz, 2H), 3.51 (t, J = 7.3 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.1, 165.8, 164.9, 148.1, 132.3, 131.8, 130.3, 129.4, 129.2, 129.0, 128.1, 127.6, 126.2, 126.1, 125.6, 123.5, 119.1, 32.5, 21.3; IR (film) 1747, 1265, 1214, 1162, 1066 cm−1; HRMS (EI) m/z [M]+ Calcd for C22H15NO2S: 357.0823, Found: 357.0820. 3-Phenyl-6,7-dihydroisothiazolo[4,3-c]pyridin-4(5H)-one (4a). Light brown solid, 43.9 mg, 95%, mp: 184−185 °C, Rf = 0.4 (acetone:Hx = 1:2); 1H NMR (400 MHz, CDCl3) δ 7.73−7.71 (m, 2H), 7.44−7.44 (m, 3H), 5.90 (s, 1H), 3.61 (dt, J = 2.7, 6.5 Hz, 2H), 3.15 (t, J = 6.5 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.8, 168.8, 163.2, 130.3, 129.6, 129.4, 128.6, 123.0, 40.2, 29.4; IR (film) 3189, 3064, 2917, 1671, 1546, 1330, 1063 cm−1; HRMS (EI) m/z [M]+ Calcd for C12H10N2OS: 230.0514, Found: 230.0512. 5-Methyl-3-phenyl-6,7-dihydroisothiazolo[4,3-c]pyridin-4(5H)one (4b). White solid, 46 mg, 94%, mp: 126−127 °C, Rf = 0.5 (EtOAc:Hx = 2:1); 1H NMR (400 MHz, CDCl3) δ 7.69−7.67 (m, 2H), 7.46−7.43 (m, 3H), 3.66 (t, J = 6.6 Hz, 2H), 3.11 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 172.2, 168.3, 161.7, 130.0, 129.6, 128.4, 123.5, 77.4, 48.3, 34.5, 29.0; IR (film) 1650, 1541, 1495, 1447, 1390, 1329, 1086, 816, 693 cm−1; HRMS (EI) m/z [M]+ Calcd for C13H12N2OS: 244.0670, Found: 244.0670. 3-Phenyl-6,7-dihydro-4H-pyrano[4,3-c]isothiazole (4c). White solid, 36.5 mg, 84%, mp: 54−56 °C, Rf = 0.4 (Et2O:Hx = 1:1); 1H NMR (400 MHz, CDCl3) δ 7.49−7.37 (m, 5H), 4.93 (s, 2H), 4.04 (t, J = 5.9 Hz, 2H), 3.04 (t, J = 5.9 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.5, 159.8, 130.9, 129.4, 129.3, 127.9, 127.8, 66.8, 65.3, 30.6; IR (film) 3057, 1397, 1227, 1095, 759, 720, 693 cm−1; HRMS (EI) m/z [M]+ Calcd for C12H11NOS: 217.0561, Found: 217.0560. 3-Phenyl-4,6,7,8-tetrahydrooxepino[4,3-c]isothiazole (4d). Yellow oil, 30.1 mg, 65%, Rf = 0.5 (Et2O:Hx = 1:1); 1H NMR (400 MHz, CDCl3) δ 7.48−7.40 (m, 3H), 7.36−7.33 (m, 2H), 4.64 (s, 2H), 4.07 (t, J = 5.1 Hz, 2H), 3.18−3.15 (m, 2H), 1.96−1.90 (m, 2H); 13 C{1H} NMR (100 MHz, CDCl3) δ 172.5, 163.0, 133.7, 130.8, 129.3, 129.15, 129.10, 75.7, 66.2, 34.0, 28.7; IR (film) 3058, 2943, 2846, 1252, 1108, 911, 697 cm−1; HRMS (EI) m/z [M]+ Calcd for C13H13NOS: 231.0718, Found: 231.0715. 3-Phenyl-6,7,8,9-tetrahydro-4H-oxocino[4,3-c]isothiazole (4e). Yellow oil, 24.5 mg, 50%, Rf = 0.4 (Et2O:Hx = 1:1); 1H NMR (400 MHz, CDCl3) δ 7.52−7.40 (m, 5H), 4.70 (s, 2H), 3.75 (t, J = 4.9, 2H), 3.19 (t, J = 6.3, 2H), 1.89−1.83 (m, 2H), 1.77−1.72 (m, 2H); 13 C{1H} NMR (100 MHz, CDCl3) δ 171.8, 164.0, 131.2, 130.8, 129.3, 129.2, 128.8, 69.9, 63.7, 32.1, 27.7, 27.6; IR (film) 3058, 2923, 2856, 1132, 1079, 750, 696 cm−1; HRMS (EI) m/z [M]+ Calcd for C14H15NOS: 245.0874, Found: 245.0872.

Article

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02077. Copies of the NMR spectra for all products (PDF) X-ray crystallographic data for 2a (CIF) X-ray crystallographic data for 2n (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Phil Ho Lee: 0000-0001-8377-1107 Author Contributions †

B.S., H.K., and Y.G.K. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (20110018355 and 2015H1C1A1035955) and BRL (2017R1A4A1015405). We thank Mr. Bongkeun Jeon (KNU) for his help in preliminary experiment.

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REFERENCES

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