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Article Cite This: J. Org. Chem. 2018, 83, 10281−10288

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Cascade Trisulfur Radical Anion (S3•−) Addition/Electron Detosylation Process for the Synthesis of 1,2,3-Thiadiazoles and Isothiazoles Bei-Bei Liu, Hui-Wen Bai, Huan Liu, Shun-Yi Wang,* and Shun-Jun Ji*

J. Org. Chem. 2018.83:10281-10288. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 09/08/18. For personal use only.

Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou 215123, People’s Republic of China S Supporting Information *

ABSTRACT: Trisulfur radical anion (S3•−) mediated reactions with in situ formed azoalkenes and α,β-usaturated N-sulfonylimines for the construction of 1,2,3-thiadiazoles and isothiazoles has been developed. S3•− is in situ generated from potassium sulfide in DMF. These two approaches provide a new, safe, and simple way to construct 4-subsituted 1,2,3-thiadiazoles, 5-subsituted 1,2,3-thiadiazoles, and isothiazole in good yields. The reactions include the formation of the new C−S and N−S bonds via S3•− addition and electron detosylation under mild conditions.

and elimination to olefin production.5 The Tuttle group developed a method using neutral organic super-electrondonor (S.E.D.) reagent reductive cleavage of sulfones and sulfonamides (Scheme 1a).6 In 2014, Zhao et al. reported a

1. INTRODUCTION Heterocycles, such as 1,2,3-thiadiazoles and isothiazoles, are of great importance on account of a large amount of biological activity compounds and pharmacological activity molecules. Fungicides and pesticide candidates include this scaffold (Figure 1).1 In addition, 1,2,3-thiadiazoles decomposed into

Scheme 1. Reactions toward the Detosylation Process

radical cascade cycloaddition/desulfonylation processes with N-Ts-2-alkynylaniline derivatives (Scheme 1b).7 Recently, inodine-catalyzed and flavin-iodine-catalyzed transannulations of N-tosylhydrazones with sulfur have been reported to give 1,2,3-thiadiazoles (Scheme 1c).8 Various approaches for the preparation of thiadiazoles were supplied, yet electron-catalytic radical cascade cycloaddition/desulfonylation processes still are an enormous challenge.

Figure 1. Representative bioactive 1,2,3-thiadiazole and isothiazole derivatives.

thioketenes in the presence of base, which could be exploited as intermediates for the construction of benzothiazoles, indols, and benzofurans.2 The sulfonyl group is involved in comprehensive applications in organic chemistry, popular as a good leaving group in amines3 and in sulfones.4 Further along the synthetic route, it can be more susceptible to undergo nucleophilic substitution © 2018 American Chemical Society

Received: June 7, 2018 Published: July 17, 2018 10281

DOI: 10.1021/acs.joc.8b01450 J. Org. Chem. 2018, 83, 10281−10288

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The Journal of Organic Chemistry

the temperature from 100 to 130 °C and reducing the amount of K2CO3 by half provided 5a in 66% yield (entry 13). On the basis of the above results, the combination of 0.3 mmol 3a, 0.6 mmol 4a, and 0.15 mmol K2CO3 in 1.5 mL of DMF was identified as the optimal reaction conditions. Because the α-chlorosulfonohydrazides 3 could be simply generated in the reaction with α-chloroketones and ptoluenesulfonohydrazide by removing the solvent, we employed a simple one-pot method to synthesize the desired compounds 5 directly from the crude substrates 3 without further purification. A mixture of 1a and 2a in diethyl ether (1.5 mL) was stirred at room temperature overnight to afford the crude intermediate 3a by removing the solvent. Then, K2S, K2CO3, and DMF were added and the mixture was stirred at 130 °C for 0.5 hour. To our delight, 5a was isolated in 65% yield, which is similar to the 66% yield of the two-step reaction. With this promising result in hand, variously substituted αchloroketones 1 were applied to the reaction with 2a under identical conditions (Table 2). Various electron-donating groups (−Me, −C(CH3)3, −OMe) at the aryl ring were tolerated, but the yield of the product decreased to 40% when the electron-donating group −OMe was employed. Next, we examined different halogen substituents on the aryl ring. The halogen groups (−F, −Cl, −Br) at the ortho-, para-, and meta-

Azoalkenes generated in situ from α-halogenohydrazones have normally played an important role in the synthesis of a variety of N-containing heterocyclic compounds.9−14 Recently, we reported the reaction of arylamines and α-halogenohydrazones to construct different substituented 1,2,3-triazoles.15 More recently, we demonstrated the synthesis of benzothiazines involving trisulfur radical anion (S3•−) addition and electron catalysis.16 To the best of our knowledge, the reactions involving S3•− species are very rare.16,17 It is still a great challenge to develop new reactions involving a trisulfur radical anion and electron catalysis. Herein, we report a cascade S3•− addition/electron detosylation process for the synthesis of 4-subsituted 1,2,3-thiadiazoles, 5-subsituted 1,2,3thiadiazoles, and isothiazole. S3•− is in situ generated from potassium sulfide in DMF with electron release at the same time.16 These reactions involve the formation of the new C−S and N−S bonds under transition metal-free conditions.

2. RESULTS AND DISCUSSION Initially, we investigated the reaction of N′-(2-chloro-1phenylethylidene)-4-methylbenzenesulfonohydrazide 3a with K2S and base K2CO3 at 100 °C in DMF. Fortunately, 4phenyl-1,2,3-thiadiazole 5a was observed in 52% yield (Table 1, entry 1). The yield of 5a was decresed without base (Table Table 1. Optimization of the Reaction Conditionsa

entry

base

1 2 3 4 5 6 7 8c 9d 10e 11f 12g 13h

K2CO3 DIPEA Cs2CO3 Li2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 S + KOH K2CO3

time

solvent

yieldb (%)

1.5 h 10 min 1h 7 min 1h 10 min 0.5 h 1.5 h 10 min 1h 17 min 0.5 h 0.5 h

DMF DMF DMF DMF DMF toluene DMSO DMF DMF DMF DMF DMF DMF

52 43 41 42 59 0 48 52 55 43 53 messy 66

Table 2. Substrate Scope of Reactiona

a

Reaction conditions: 3a (0.3 mmol), 4a sulfur reagent (K2S, 0.6 mmol), base (0.3 mmol), and solvent (1.5 mL) at 100 °C. The time of the reaction was monitored by TLC. bYields were determined by LC analysis using biphenyl as the internal standard. cBase (K2CO3 0.15 mmol). dBase (K2CO3, 0.6 mmol). eTemperature = 60 °C. f Temperature = 80 °C. gSulfur reagent (S, 0.9 mmol); base (KOH, 0.15 mmol). hBase (K2CO3, 0.15 mmol), 130 °C.

1, entry 2). Further investigations of various bases including inorganic and organic bases revealed that K2CO3 resulted in the best performance (Table 1, entries 3−5). Li2CO3 led to higher yield compared with K2CO3. By screening different solvents, we found DMF to be a suitable solvent for the reaction (Table 1, entries 6−7). Reducing or raising the amount of base does not effectively improve the yields (entries 8−9). Decreasing of the reaction temperature from 100 to 80 °C, 5a was obtained in similar yield with a longer time (entries 10−11). Unfortunately, the reaction system was messy when sulfur reagent was changed to S8 (entry 12). Gratifyingly, rising

a

Reactions with 1 (0.3 mmol) and 2a (0.3 mmol) were performed in 1 mL of Et2O at room temperature for 12 h. Then, removing the solvent, base (K2CO3 0.15 mmol), K2S (0.6 mmol), and DMF (1.5 mL) were added at room temperature. The mixture was stirred at 130 °C for 0.5 h. Isolated yield. 10282

DOI: 10.1021/acs.joc.8b01450 J. Org. Chem. 2018, 83, 10281−10288

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The Journal of Organic Chemistry Table 4. Substrate Scope of Reactiona

positions of the aryl ring were well-tolerated, furnishing the desired products 5e−5g and 5i−5l in 43%-68% yield. Methyl4-(2-chloroacetyl)benzoate reacted with 2a to generate the thiadiazole prouct 5h in 38% yield. Unfortunately, the reaction of 2-chloro-1-(3,4-dihydroxyphenyl)ethan-1-one 1m and 2chloro-1-(4-nitrophenyl)ethan-1-one 1n failed to give the desired products under the optimized conditions. Subsequently, we explored the reactions with various αtosylhydrazones derived from α-chloroaldehydes. In view of αchloroaldehydes being easily oxidized, we directly isolated the α-tosylhydrazonealdehydes and applied them to the next reaction (Table 3). α-Tosylhydrazones derived from αTable 3. Substrate Scope of Reactiona

a

Reaction conditions (unless otherwise noted): 3 (0.3 mmol), base (K2CO3, 0.15 mmol), K2S (0.6 mmol), and DMF (1.5 mL) were added at room temperature. The mixture was stirred at 130 °C for 0.5 h. Isolated yield.

a

Reaction conditions (unless otherwise noted): 6 (0.3 mmol), base (K2CO3, 0.5 mmol), K2S (0.6 mmol), and DMF (2 mL) were added at room temperature. The mixture was stirred at 130 °C for 0.5 h. Isolated yield.

chlorooctanal and α-chlorobenzenepropanal readily participated in this transformation, giving 1,2,3-thiadiazole products 5o and 5p in 56 and 77% yields, respectively. The reaction of N′-(2-chloro-2-phenylethylidene)-4-methylbenzenesulfonohydrazide 3r progressed well and gave the corresponding product 5r in 60% yield. While the cascade S3•− addition/electron detosylation reaction of in situ formed azoalkenes affords 1,2,3-thiadiazoles, we reason that a similar cascade S3•− addition/electron detosylation reaction of α,β-usaturated N-sulfonylimines can furnish isothiazole (Table 4). To our delight, the reaction of 6a with K2S afforded isothiazole 7a in 51% yield under identical conditions. With this promising result in hand, we further investigated the scope of α,β-ketimines. Various substituents with electron-donating (7b−7e) and electron-withdrawing (7f−7g) character, such as alkyl, halide, and nitrile groups at the para positions of the aryl ring on the substituted allylidenes, were also compatible, while allylidenes containing the thiophene motif were subjected to the reaction conditions (7h). The strategy was well adapted for gram-scale synthesis that the yield of 5a was improved in small increments (Scheme 2). It provided a simple and effective method to manufacture 1,2,3-thiadiazole on a large scale. In further study of the application of this method in the synthesis of 1,2,3thiadiazoles, we prepared the medicine intermediate15b 1q and applied it to the reaction under the optimized conditions. The reaction of 1q proceeded smoothly to furnish the desired compound 5q in 51% yield (Scheme 3). To gain more insights into the mechanism, a controlled experiment was conducted. When 2,2,4,4-tetramethyl-1-piperidinyloxy (TEMPO, 5 equiv) was added to the standard

Scheme 2. Gram-Scale Experiment

reaction (Scheme 4), it was found that the process was inhibited. Electron spin resonance (ESR) was carried out (see the Supporting Information for details). Gratifyingly, a strong single peak located at g = 2.02882 was observed. This result indicates that this reaction might proceed via radical processes, which matches with our previous work.16 According to the above results and reported literature, a plausible mechanism was proposed in Scheme 5. In the presence of the solvent DMF, the reagent K2S is activated to afford S3•− with electrons releasing at the same time.17,18 In process I, the azoalkene intermediate A is in situ generated from α-halogenohydrazine 3 in the presence of K2CO3. The addition of S3•− to A gives intermediate B, which is isomerized to afford intermediate radical C. The cleavage of the S−S bond and formation of the N−S bond provide intermediate D and S2•−, which can be further transformed to S3•− and continue to participate in the reaction.18 After electron detosylation of D with cleavage of the S−N bond by electron reductive transfer,19 the intermediate E is formed. Subsequently, going through aromatization of E furnishs the desired product 5. Alternatively, in process II, α,β-usaturated N-sulfonylimine undergoes a similar reaction process to afford different functionalized isothiazoles 7. 10283

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The Journal of Organic Chemistry Scheme 3. Reaction of 1q and K2S

performed on silica gel, visualized by irradiation with UV light. For column chromatography, 300−400 mesh silica gel was used. All reactions were carried out in air and using undistilled solvent, without the need for precautions to exclude air and moisture, unless otherwise noted. Melting points were recorded on an electrothermal digital melting point apparatus and were uncorrected. IR spectra were recorded on a BRUKER VERTEX 70 spectrophotometer. 1H NMR and 13C NMR spectra were recorded on a BRUKER 400 MHz (1H NMR) and 100 MHz (13C NMR) spectrometer using CDCl3 as the solvent and TMS as the internal standard. High-resolution mass spectra were obtained using a BRUKER micrOTOF-Q III instrument with an ESI source. ESR spectra were detected by a JES-X320 electron spin resonance instrument. Typical Procedure for the Construction of Chlorination of Ketones 1 (According to the Literature20). A flask was charged with the ketones (4 mmol), NCS (4 mmol, 1 equiv), and PTSA (0.4 mmol, 0.1 equiv). The reaction mixture was stirred overnight. The reaction was hydrolyzed and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over MgSO 4 and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography. Typical Procedure for the Construction of α-Chlorosulfonohydrazides 3 (According to the Literature21). Chlorination of ketones 1 (0.3 mmol) and p-TsNHNH2 2a (0.3 mmol) was performed in 1 mL of Et2O at room temperature. The mixture was stirred for 12 h, filtered, rinsed with cold (ice−water bath) Et2O, and evaporated under reduced pressure to give α-chlorosulfonohydrazides 3. Typical Procedure for the Construction of α,β-Usaturated N-Sulfonylimines 6 (According to the Literature22). To a solution of enone (4.8 mmol) and p-toluenesulfonamide (820 mg, 4.8 mmol) in dry dichloromethane (60 mL) at 0 °C under a nitrogen atmosphere was added via syringe Et3N (1.5 mL, 1.07 g, 10.6 mmol)

Scheme 4. Radical-Trapping Experiment

3. CONCLUSIONS In conclusion, we have developed a simple and facile method for the synthesis of 4-substituented and 5-substituented 1,2,3thiadiazole from in situ generated azoalkenes with S3•− via a cascade trisulfur radical anion addition and electron detosylation process. Our strategy employs mild conditions and avoids the employment of a diazo group and thionyl chloride. Not only are the aromaticity substrates suitable for the process, the aliphatic substrates can also work well. Studies along these lines are currently ongoing. 4. EXPERIMENTAL SECTION General Experimental Information. Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification. Analytical thin-layer chromatography (TLC) was

Scheme 5. Plausible Mechanism

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cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.61 (s, 1H), 8.02−7.98 (m, 2H), 7.18−7.14 (m, 2H). 13C NMR (100 MHz, chloroform-d) δ 164.6, 162.1, 161.9, 129.9, 129.3 (d, JC−F = 8.0 Hz), 127.1 (d, JC−F = 4.0 Hz), 116.3 (d, JC−F = 22.0 Hz) ppm. HRMS (ESI) m/z: calcd for C8H6FN2S+ [M + H]+, 181.0230; found, 181.0238. 4-(4-Chlorophenyl)-1,2,3-thiadiazole (5f). White solid (36 mg, 61%). Mp 135.8−138.3 °C. IR 2989, 1457, 1407, 908, 805 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.64 (s, 1H), 7.98 (d, J = 8.5 Hz, 3H), 7.47 (d, J = 8.5 Hz, 3H). 13C NMR (100 MHz, chloroform-d) δ 161.8, 135.5, 130.3, 129.5, 129.4, 128.7 ppm. HRMS (ESI) m/z: calcd for C8H6ClN2S+ [M + H]+, 196.9935; found, 196.9937. 4-(4-Bromophenyl)-1,2,3-thiadiazole (5g). White solid (49 mg, 68%). Mp 150.5−153.7 °C. IR 2902, 1592, 1453, 801, 789 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.65 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H). 13C NMR (100 MHz, chloroform-d) δ 161.8, 132.5, 130.4, 129.8, 129.0, 123.8 ppm. HRMS (ESI) m/z: calcd for C8H6BrN2S+ [M + H]+, 240.9430; found, 240.9442. Methyl 4-(1,2,3-thiadiazol-4-yl)benzoate (5h). Yellow solid (25 mg, 38%). Mp 144.2−149.7 °C. IR 3092, 2890, 1723, 1568, 989, 672, 1437, 766 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.77 (s, 1H), 8.17−8.11 (m, 4H), 3.94 (s, 3H). 13C NMR (100 MHz, chloroformd) δ 166.6, 161.8, 134.9, 131.6, 130.9, 127.4, 52.4 ppm. HRMS (ESI) m/z: calcd for C10H9N2O2S+ [M + H]+, 221.0379; found, 221.0378. 4-(2-Chlorophenyl)-1,2,3-thiadiazole (5i). Yellow solid (26 mg, 43%). Mp 134.5−136.7 °C. IR 1593, 1387, 1283, 894, 669 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.68 (s, 1H), 8.02 (s, 1H), 7.92− 7.89 (m, 1H), 7.44−7.39 (m, 1H). 13C NMR (100 MHz, chloroformd) δ 161.5, 135.2, 132.5, 131.0, 130.5, 129.5, 127.5, 125.5 ppm. HRMS (ESI) m/z: calcd for C8H6ClN2S+ [M + H]+, 196.9935; found, 196.9938. 4-(3-Fluorophenyl)-1,2,3-thiadiazole (5j). White solid (28 mg, 53%). Mp 185.5−187.3 °C. IR 2889, 1597, 1448, 1211, 837, 678 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.68 (s, 1H), 7.83−7.74 (m, 2H), 7.47 (td, J = 8.0, 5.8 Hz, 1H), 7.14 (td, J = 8.4, 2.5 Hz, 1H). 13 C NMR (101 MHz, chloroform-d) δ 164.5, 162.1, 161.7 (d, JC−F = 2.0 Hz), 132.9 (d, JC−F = 8.0 Hz), 130.9 (t, JC−F = 8.0 Hz), 123.1(d, JC−F = 3.0 Hz), 116.5 (d, JC−F = 21.0 Hz), 114.5 (d, JC−F = 24.0 Hz) ppm. HRMS (ESI) m/z: calcd for C8H6FN2S+ [M + H]+, 181.0230; found, 181.0228. 4-(2,5-Difluorophenyl)-1,2,3-thiadiazole (5k). Brown solid (32 mg, 54%). Mp 167.0−169.6 °C. IR 1598, 1494. 964, 943, 864,679 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.94 (d, J = 1.9 Hz, 1H), 8.17 (d, J = 9.0, 5.7, 3.2 Hz, 1H), 7.17 (td, J = 10.2, 9.6, 4.5 Hz, 1H), 7.12−7.04 (m, 1H). 13C NMR (100 MHz, chloroform-d) δ 158.6 (dd, JC−F = 324.5 Hz), 156.1 (dd, JC−F = 327.5 Hz), 155.2 (dd, JC−F = 2.0 Hz), 134.4 (d, JC−F = 14.0 Hz), 120.2 (dd, JC−F = 5.0 Hz), 117.6 (dd, JC−F = 9.0 Hz), 117.3 (dd, JC−F = 9.0 Hz), 116.5 (dd, JC−F = 26.0 Hz) ppm. HRMS (ESI) m/z: calcd for C8H5F2N2S+ [M + H]+, 199.0136; found, 199.0141. 4-(2,4-Difluorophenyl)-1,2,3-thiadiazole (5l). Brown solid (26 mg, 43%). Mp 187.0−189.6 °C. IR 2953, 1597, 1448, 1256, 1093, 836, 678 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.96 (d, J = 1.9 Hz, 1H), 8.25−8.21 (m, 2H), 7.24−7.21 (m, 1H), 7.15−7.09 (m, 1H). 13 C NMR (101 MHz, chloroform-d) δ 163.0 (dd, JC−F = 339.5 Hz), 160.4 (dd, JC−F = 339.0 Hz), 155.6 (d, JC−F = 4.0 Hz), 133.2 (q, JC−F = 13.0 Hz), 131.5 (dd, JC−F = 6.0 Hz), 115.6 (dd, JC−F = 12.0 Hz), 112.5 (dd, JC−F = 21.5 Hz), 104.8 (t, JC−F = 51.0 Hz) ppm. HRMS (ESI) m/z: calcd for C8H5F2N2S+ [M + H]+, 199.0136; found, 199.0151. 5-Hexyl-1,2,3-thiadiazole (5o). Yellow oil (29 mg, 56%). IR 2954, 2928, 2869, 1597, 1456, 1249, 1098, 893, 784 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.45 (s, 1H), 3.02−2.98 (m, 2H), 1.70 (p, J = 7.5 Hz, 2H), 1.35−1.25 (m, 6H), 0.88−0.84 (m, 3H). 13C NMR (100 MHz, chloroform-d) δ 158.2, 146.8, 31.5, 31.4, 28.7, 25.3, 22.5, 14.1 ppm. HRMS (ESI) m/z: calcd for C8H15N2S+ [M + H]+, 171.0950; found, 171.0955. 5-Benzyl-1,2,3-thiadiazole (5p). Yellow oil (41 mg, 77%). IR 2904, 1601, 1495, 1254, 1087, 789, 699 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.47 (s, 1H), 7.37−7.27 (m, 3H), 7.23−7.21 (m, 2H), 4.33 (s, 2H). 13C NMR (100 MHz, chloroform-d) δ 157.3,

followed by TiCl4 (0.58 mL, 1.0 g, 5.3 mmol). The reaction was heated at reflux temperature for 20 h. Then it was cooled to room temperature and quenched with water (50 mL). The two layers were separated, and the aqueous layer was extracted with dichloromethane (3 × 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with petroleum ether/ethyl acetate (v/v = 100:1−10:1) afforded the desired product imines 6 (70−85% yield). Typical Procedure for the Construction of 4-Disubstituted 1,2,3-Thiadiazole 5. p-TsNHNH2 (2a, 0.3 mmol) was added to a stirred solution of 2-chloroketone (1, 0.3 mmol) in Et2O (1 mL). The mixture was stirred overnight and evaporated under reduced pressure to give the crude products α-chlorotosylhydrazones 3. Followed by addition of K2CO3 (0.15 mmol), K2S (0.6 mmol), and DMF (1.5 mL) at room temperature, the mixture was stirred at 130 °C as monitored by TLC. The solution was then quenched by saturated salt solution and extracted with ethyl acetate; the combined organic layers were dried over Na2SO4, filtered, and evaporated under vacuum. The residue was purified by column chromatography on silica gel (eluent/ light petroleum ether/ethyl acetate, v/v = 100:1−10:1) to afford the desired product 5. Typical Procedure for the Construction of 5-Disubstituted 1,2,3-Thiadiazole 5. The α-chlorosulfonohydrazide 3 (0.3 mmol), K2CO3 (0.15 mmol), K2S (0.6 mmol), and DMF (1.5 mL) were added to a tube. The mixture was stirred at 130 °C as monitored by TLC. The solution was then quenched by saturated salt solution and extracted with ethyl acetate; the combined organic layers were dried over Na2SO4, filtered, and evaporated under vacuum. The residue was purified by column chromatography on silica gel (eluent/light petroleum ether/ethyl acetate, v/v = 100:1−10:1) to afford the desired product 5. Typical Procedure for the Construction of Isothiazole 7. The α,β-ketimine 6 (0.3 mmol), K2CO3 (0.5 mmol), K2S (0.6 mmol), and DMF (2.0 mL) were added to a tube. The mixture was stirred at 130 °C as monitored by TLC. The solution was then quenched by saturated salt solution and extracted with ethyl acetate; the combined organic layers were dried over Na2SO4, filtered, and evaporated under vacuum. The residue was purified by column chromatography on silica gel (eluent/light petroleum ether/ethyl acetate, v/v = 100:1− 10:1) to afford the desired product 7. 4-Phenyl-1,2,3-thiadiazole 4-(p-tolyl)-1,2,3-thiadiazole (5a). White solid (32 mg, 65%). Mp 75.5−77.8 °C. IR 3109, 2874, 1789, 1458, 1320, 1079, 807, 789 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.65 (s, 1H), 8.04 (d, J = 7.2 Hz, 2H), 7.53−7.42 (m, 3H). 13C NMR (100 MHz, chloroform-d) δ 162.9, 130.9, 130.2, 129.5, 129.3, 127.5 ppm. HRMS (ESI) m/z: calcd for C8H7N2S+ [M + H]+, 163.0324; found, 163.0327. 4-(p-Tolyl)-1,2,3-thiadiazole (5b). White solid (34 mg, 64%). Mp 74.5−76.3 °C. IR 3102, 1462, 1278, 895, 799 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.58 (s, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 2.42 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ 163.1, 139.6, 123.0, 129.4, 128.2, 127.4, 21.5 ppm. HRMS (ESI) m/z: calcd for C9H9N2S+ [M + H]+, 177.0481; found, 177.0485. 4-(4-Methoxyphenyl)-1,2,3-thiadiazole (5c). White solid (23 mg, 40%). Mp 89.5−93.3 °C. IR 3093, 2989, 1531, 1462, 1243, 879, 795 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.52 (s, 1H), 7.98 (d, J = 8.9 Hz, 2H), 7.03 (d, 8.9 Hz, 2H), 3.88 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ 162.8, 160.6, 128.9, 128.6, 123.7, 114.7, 55.5 ppm. HRMS (ESI) m/z: calcd for C9H9N2OS+ [M + H]+, 193.0430; found, 193.0428. 4-(4-(tert-Butyl)phenyl)-1,2,3-thiadiazole (5d). Yellow solid (46 mg, 48%). Mp 79.5−83.3 °C. IR 3093, 2962, 1463, 1362, 808 cm−1. 1 H NMR (400 MHz, chloroform-d) δ 8.59 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 1.36 (s, 9H). 13C NMR (100 MHz, chloroform-d) δ 152.7, 129.6, 128.1, 127.2, 126.2, 34.9, 31.3 ppm. HRMS (ESI) m/z: calcd for C12H15N2S+ [M + H]+, 219.0950; found, 219.0948. 4-(4-Fluorophenyl)-1,2,3-thiadiazole (5e). White solid (27 mg, 49%). Mp 184.5−186.3 °C. IR 3101, 2898, 1598, 1448, 837, 782 10285

DOI: 10.1021/acs.joc.8b01450 J. Org. Chem. 2018, 83, 10281−10288

Article

The Journal of Organic Chemistry

2H), 7.45−7.39 (m, 3H). 13C NMR (100 MHz, chloroform-d) δ 189.4, 145.3, 142.1, 137.0, 130.8, 129.4, 129.1, 128.6, 126.4, 121.7 ppm. HRMS (ESI) m/z: calcd for C15H11N2O2S+ [M + H]+, 283.0536; found, 283.0548. 5-(Thiophen-2-yl)-3-(p-tolyl)isothiazole (7h). Brown solid (11 mg, 14%). Mp 47.0−48.8 °C. IR 3032, 2915, 1725, 1662, 1579, 1443, 1267, 822, 655 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.08 (s, 1H), 7.92 (d, J = 5.5 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.43 (d, J = 5.5 Hz, 1H), 7.38−7.28 (m, 3H), 7.13−7.06 (m, 1H), 2.43 (d, J = 2.8 Hz, 3H). 13C NMR (100 MHz, chloroform-d) δ 136.0, 132.7, 131.4, 129.7, 128.8, 128.1, 126.8, 125.2, 120.4, 20.9 ppm. HRMS (ESI) m/z: calcd for C14H12NS2+ [M + H]+, 258.0406; found, 258.0410.

147,2, 137.9, 129.2, 128.5, 127.6, 31.3 ppm. HRMS (ESI) m/z: calcd for C9H9N2S+ [M + H]+, 177.0481; found, 177.0489. 4-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1,2,3-thiadiazole (5q). Yellow solid (56 mg, 51%). Mp 163.4−165.9 °C. IR 2956, 2922, 2851, 1456, 1278, 894, 783, 673 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.72 (s, 1H), 8.22 (d, J = 8.6 Hz, 2H), 7.78 (s, 1H), 7.64 (dd, J = 16.5, 7.8 Hz, 2H), 7.46 (d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, chloroform-d) δ 161.8, 144.53, 140.0 (t, JC−F = 50.0 Hz), 139.5 (t, JC−F = 9.0 Hz), 138.7 (t, JC−F = 9.0 Hz), 135.4, 131.8, 131.6, 130.7, 127.6, 123.1, 122.9, 122.2, 121.4 ppm. HRMS (ESI) m/z: calcd for C15H8BrF2N2S+ [M + H]+, 364.9554; found, 364.9553. 5-Phenyl-1,2,3-thiadiazole (5r). Brown oil (30 mg, 60%). IR 3091, 2958, 2924, 1464, 1444, 1247, 963, 758 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.85 (s, 1H), 7.65−7.54 (m, 2H), 7.52−7.41 (m, 3H). 13C NMR (100 MHz, chloroform-d) δ 157.1, 144.2, 130.5, 129.6, 128.2, 127.5 ppm. HRMS (ESI) m/z: calcd for C8H7N2S+ [M + H]+, 163.0324; found, 163.0327. 3,5-Diphenylisothiazole (7a). Yellow solid (36 mg, 51%). Mp 47.8−50.4 °C. IR 3052, 2922, 1950, 1663, 1482, 1446, 1046, 751, 669 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.05−7.94 (m, 2H), 7.75 (s, 1H), 7.69−7.62 (m, 2H), 7.51−7.38 (m, 6H). 13C NMR (100 MHz, chloroform-d) δ 168.5, 168.4, 135.0, 131.1, 129.7, 129.4, 129.0, 127.0, 126.8, 117.7 ppm. HRMS (ESI) m/z: calcd for C15H11NSNa+ [M + Na]+, 260.0504; found, 260.0490. 3-(4-(tert-Butyl)phenyl)-5-phenylisothiazole (7b). Brown solid (44 mg, 50%). Mp 58.8−59.6 °C. IR 3336, 3046, 2953, 2867, 1667, 1604, 1483, 1265, 1046, 822, 672 cm−1. 1H NMR (400 MHz, chloroform-d) δ 7.84 (d, J = 8.3 Hz, 2H), 7.64 (s, 1H), 7.56 (d, J = 6.9 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 7.34 (dd, J = 11.5, 7.2 Hz, 3H), 1.28 (s, 9H). 13C NMR (100 MHz, chloroform-d) δ 168.4, 152.6, 132.3, 131.2, 129.7, 129.4, 126.7, 125.9, 117.6, 34.9, 31.4 ppm. HRMS (ESI) m/z: calcd for C19H19NSNa+ [M + Na]+, 316.1130; found, 316.1125. 3-Phenyl-5-(p-tolyl)isothiazole (7c). Brown solid (23 mg, 30%). Mp 44.0−45.8 °C. IR 3358, 3179, 2918, 2849, 1899, 1733, 1646, 1366, 1071, 807, 697 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.01−7.96 (m, 2H), 7.72 (s, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.49−7.44 (m, 2H), 7.44−7.39 (m, 1H), 7.27 (s, 1H), 2.41 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ 168.5, 168.4, 140.0, 135.1, 130.1, 129.3, 128.9, 128.4, 127.0, 126.6, 21.5 ppm. HRMS (ESI) m/z: calcd for C16H13NSNa+ [M + Na]+, 274.0661; found, 274.0657. 3-(4-Pentylphenyl)-5-phenylisothiazole (7d). Brown solid (29 mg, 31%). Mp 45.0−47.5 °C. IR 3344, 3179, 2907, 2869, 1879, 1734, 1665, 1367, 1071, 807, 699 cm−1. 1H NMR (400 MHz, chloroform-d) δ 7.90 (d, J = 8.1 Hz, 2H), 7.72 (s, 1H), 7.65 (d, J = 6.8 Hz, 2H), 7.49−7.39 (m, 3H), 7.30−7.23 (m, 3H), 2.69−2.61 (m, 2H), 1.69− 1.61 (m, 2H), 1.34 (s, 4H), 0.89 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, chloroform-d) δ 129.7, 129.4, 129.0, 126.9, 126.7, 117.6, 35.9, 31.6, 31.2, 22.7, 14.2 ppm. HRMS (ESI) m/z: calcd for C20H21NSNa+ [M + Na]+, 330.1287; found, 330.1290. 3-Phenyl-5-(p-tolyl)isothiazole (7e). Brown solid (23 mg, 30%). Mp 46.7−47.9 °C. IR 3358, 3179, 2918, 2849, 1899, 1733, 1646, 1366, 1071, 807, 697 cm−1. 1H NMR (400 MHz, chloroform-d) δ 8.01−7.96 (m, 2H), 7.72 (s, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.49−7.44 (m, 2H), 7.44−7.39 (m, 1H), 7.27 (s, 1H), 2.41 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ 168.5, 168.4, 140.0, 135.1, 130.1, 129.3, 128.9, 128.4, 127.0, 126.6, 21.5 ppm. HRMS (ESI) m/z: calcd for C16H13NSNa+ [M + Na]+, 274.0661; found, 274.0657. 3-(4-Bromophenyl)-5-phenylisothiazole (7f). Brown solid (43 mg, 45%). Mp 114.3−115.4 °C. IR 3735, 2482, 2329, 2272, 1986, 1726, 792, 666 cm−1. 1H NMR (400 MHz, chloroform-d) δ 7.87 (d, J = 8.6 Hz, 2H), 7.72 (s, 1H), 7.63 (m, J = 18.4, 9.1, 2.0 Hz, 4H), 7.50−7.42 (m, 3H). 13C NMR (100 MHz, chloroform-d) δ 168.9, 167.2, 133.9, 132.1, 130.9, 129.9, 129.5, 128.5, 126.8, 123.7, 117.5 ppm. HRMS (ESI) m/z: calcd for C15H11BrNS+ [M + H]+, 315.9790; found, 315.9799. 3-(4-Nitrophenyl)-5-phenylisothiazole (7g). Brown solid (41 mg, 48%). Mp 119.0−121.4 °C. IR 2184, 2163, 2024, 1981, 573 cm−1. 1H NMR (400 MHz, chloroform-d) δ 7.99 (dd, J = 8.3, 4.0 Hz, 2H), 7.87−7.76 (m, 1H), 7.64 (dd, J = 6.5, 4.4 Hz, 3H), 7.54−7.46 (m,

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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.8b01450. Copies of 1H and 13C NMR spectra of the products (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Fax: 86-512-65880307 (S.Y.W.). *E-mail: [email protected]. Fax: 86-512-65880307 (S.J.J.). ORCID

Shun-Yi Wang: 0000-0002-8985-8753 Shun-Jun Ji: 0000-0002-4299-3528 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the National Natural Science Foundation of China (21772137, 21672157, 21372174), the Major Basic Research Project of the Natural Science Foundation of the Jiangsu Higher Education Institutions (No. 16KJA150002), the Ph.D. Programs Foundation of PAPD, the project of scientific and technologic infrastructure of Suzhou (SZS201708), and Soochow University for financial support. We thank Huan Liu in this group for reproducing the results of 5a, 5g, 5p, 7b, and 7d.

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REFERENCES

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