[4 + 1] Cycloaddition Reaction of α,β-Alkynic ... - ACS Publications

Bei-Bei Liu , Wen-Bin Cao , Fei Wang , Shun-Yi Wang* , and Shun-Jun Ji*. Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry...
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Article Cite This: J. Org. Chem. 2018, 83, 11118−11124

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[4 + 1] Cycloaddition Reaction of α,β-Alkynic Hydrazones and KSCN under Transition-Metal-Free Conditions: Synthesis of N‑Iminoisothiazolium Ylides Bei-Bei Liu, Wen-Bin Cao, Fei Wang, Shun-Yi Wang,* and Shun-Jun Ji* 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, P. R. China

J. Org. Chem. 2018.83:11118-11124. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 09/21/18. For personal use only.

S Supporting Information *

ABSTRACT: A novel heteroannulation reaction between α,β-alkynic hydrazones and potassium thiocyanate has been developed for the synthesis of N-iminoisothiazolium ylides. The transformation features wide substrate scope, functional tolerance, and easy operation. This investigation involves a [4 + 1]-type cycloaddition reaction and C−S/S−N bond formation under transition-metal-free conditions. The application of this transformation to the gram-scale preparation of the N-imide ylide is also accomplished.

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INTRODUCTION Nitrogen-containing heterocycles are extensively found in pharmaceuticals,1,2 pesticides,3 natural products, and biomaterials.4 They also exhibit special antibacterial, anticancer, and bactericidal activities and widely used in industrial bactericides (Figure 1).5,6 Among of them, thiazoles and isothiazoles are important heterocycles and widely exist in drugs and natural products. During the past decade, more attention has been paid to the synthesis of N-ylides6 and their applications in arylation, alkenylation, alkylation,7,8 and cycloaddition reactions (Scheme 1a).9−16 However, there are limited reports for the construction of isothiazolium ylides such as N-arylsulfonylisothiazole-2-imines. The cyclcondensation of thiocyanatovinylaldehyde hydrazones from noncommercially available thiocyanatovinylaldehydes could afford N-arylsulfonylisothiazole-2imines over two steps (Scheme 1b).17,18 Therefore, it is more desirable to develop direct protocol for the construction of isothiazolium ylides from easily obtained starting materials under mild conditions. Herein, we report a tandem [4 + 1] cycloaddition reaction of α,β-alkynic hydrazones with KSCN for the regiospecific synthesis of substituted N-iminoisothiazolium ylides under transition-metal-free conditions (Scheme 1c). The transformation features wide substrate scope, functional tolerance, and easy operation. This investigation involves [4 + 1]-type cycloaddition reaction and C−S/S−N bond formation in one pot.

conditions. Gratifyingly, the desired product 3a was formed in 53% yield (Table 1, entry 1). The structure of 3a was unambiguously confirmed by X-ray crystallography (see the Supporting Information for details). Encouraged by this result, we further tried the reactions by increasing the reaction temperature, and the yield of 3a could be increased to 65% (Table 1, entries 2 and 3). Change of S-source from K2S to S8 led to diminished yields (Table 1, entries 4−6). Reducing or raising the amount of KSCN did not effectively improve the yields (entries 7 and 8). A 1:1 (V/V) blend of other solvents like EtOH, toluene, THF, 1,4-dioxane, and acetonitrile along with AcOH was used in the reactions (Table 1, entries 9−13). It was found that acetonitrile was better than other solvents. However, the yield was decreased when the ratio of mixed solvent was changed (Table 1, entries 14 and 15). With the optimization conditions in hand, we explored the scope of the alkynyl substrates to construct isothiazolium ylides (Table 2). For most substituted phenylacetylenes with electronically neutral or electron-withdrawing or electron-rich g groups at the meta or para position (3b−d and 3e−g), moderate to good yields of isothiazolium ylides were achieved. The reactions of 4-(cyanomethyl)phenyl derivative 1h and thiophene derivative 1i led to 3h and 3i in 50% and 35% yields, respectively. Functionalized terminal alkynes, such as 3bromoprop-1-yne derivative, failed to generate the corresponding isothiazolium ylide 3j. Use of substrates with propyl (1u) gave the corresponding products in 50% yields. Unfortunately, the reaction of 4-(chloromethyl)phenyl hydrazine only gave a

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RESULTS AND DISCUSSION Initially, we investigated the reaction of α,β-alkynic hydrazone 1a with KSCN in 3 mL of acetic acid at 60 °C under air © 2018 American Chemical Society

Received: July 9, 2018 Published: August 9, 2018 11118

DOI: 10.1021/acs.joc.8b01725 J. Org. Chem. 2018, 83, 11118−11124

Article

The Journal of Organic Chemistry

Figure 1. Pharmaceutically active isothiazolones and their derivatives.

Scheme 1. Different Strategies for the Synthesis of N-Ylides

hydrazides 1s and 1t with different substitution patterns were tested as well. Compound 3s was observed in 50% yield. Unfortunately, only a trace amount of 3t was detected. Next, we attempted the [4 + 1] cycloaddition of N′3-(1,3diphenylprop-2-yn-1-ylidene)-N′1-(1,3-diphenylprop-2-yn-1ylidene)isophthalohydrazide with KSCN. The disubstituted Niminoisothiazolium ylide was successfully obtained in 51% yield (Scheme 2). To evaluate the application of this tandem reaction, the gram-scale reaction was investigated with 1.50 g of 1a.

trace amount of the desired product 3k. It was found that 4nitro-, 4-chloro-, 4-trifluoromethyl-, and 4-methoxy-substituted aryl acetylenes could also apply to the reactions with KSCN to afford the desired products 3l−o in up to 73% yields. Heteroaryl and naphthyl groups were tolerated and resulted in N-iminoisothiazolium ylides 3p and 3q in 40% and 60% yield, respectively. It should be noted that the reaction of 4methyl-N′-(3-phenylprop-2-yn-1-ylidene)benzenesulfonohydrazide 1r could also lead to N-iminoisothiazolium ylide 3r in 70% yield. In addition, benzenesulfonyl 11119

DOI: 10.1021/acs.joc.8b01725 J. Org. Chem. 2018, 83, 11118−11124

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The Journal of Organic Chemistry Table 1. Optimization of the Reaction Conditionsa

Table 2. Substrate Scope of α,β-Alkynic Hydrazones (1)a

entry

temp (°C)

1a/2a

solvent

yieldb (%)

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

60 80 100 80 80 80 80 80 80 80 80 80 80 80 80

1:2 1:2 1:2 1:2 1:2 1:2 1:1.5 1:3 1:2 1:2 1:2 1:2 1:2 1:2 1:2

AcOH AcOH AcOH AcOH AcOH AcOH AcOH AcOH AcOH/EtOH (1:1) AcOH/toluene (1:1) AcOH/THF (1:1) AcOH/1,4-dioxane (1:1) AcOH/CH3CN (1:1) AcOH/CH3CN (1:2) AcOH/CH3CN (1:3)

53 65 63 0 0 48 64 63 40 64 trace 60 80 60 37

a

Conditions: 1a (0.3 mmol) and S-source (KSCN, 0.6 mmol) in solvent (3 mL). bIsolated yield. cS-Source: K2S. dS-source: Na2S2O3· 5H2O. eS-source: S8.

Interestingly, the N-iminoisothiazolium ylide 3a was isolated in 66% yield without further optimization of reaction conditions (Scheme 3). Meanwhile, to further illustrate the synthetic utility of this method (Scheme 4). We investigated the oxidation of 3a by hydrogen peroxide. It is worth noting that 3a was converted into 4,6-diphenyl-2-tosyl-2H-1,2,3-thiadiazine 1-oxide 7a in 82% yield. Moreover, the structure of 7a was confirmed by NMR, HRMS, IR, and X-ray analysis (see the Supporting Information for details). On the basis of the above results, a proposed mechanism for the tandem [4 + 1] cycloaddition reaction is outlined in Scheme 5. First, the addition of KSCN to α,β-alkynic hydrazine 1a gives the thiocyanative intermediate A, which undergoes proton transfer to afford the anion B. The following decyanative cyclization affords the N-iminoisothiazolium ylide 3a.

a

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NMR are reported relative to CDCl3 (δ 77.16). Data are reported in the following order: chemical shift (δ) in ppm; multiplicities are indicated s (singlet), bs (broad singlet), d (doublet), t (triplet), m (multiplet); coupling constants (J) are in hertz (Hz). Melting points were measured on an Electrothermal digital melting point apparatus and were uncorrected. IR spectra were recorded on a Bruker model ALPHA spectrophotometer and are reported in terms of frequency of absorption (cm−1). HRMS spectra were obtained using a Bruker micrOTOF-Q III instrument with ESI source. The starting materials were isolated by SepaBean machine flash chromatography, which was purchased from Santai Technologies, Inc. General Procedure for the Synthesis of Compounds 3. α,βAlkynic hyrazone 1 or 4 (0.3 mmol, 1.0 equiv) and potassium thiocyanate 2 (0.6 mmol, 2.0 equiv) were stirred at 80 °C (oil bath temperature) under air atmosphere in 3 mL of a mixed solvent of AcOH/acetonitrile (v/v = 1:1). Upon completion of the reaction (indicated by TLC), the mixture was cooled to room temperature, and ferrous chloride (2.5 equiv) was added to the reaction system. The reaction mixture was charged with silica gel and concentrated. The pure products were obtained after purification by column chromatography on silica gel with petroleum ether/ethyl acetate (v/v = 6:1−1:1) as the eluent.

CONCLUSION In conclusion, we have developed a novel [4 + 1] cycloaddition of α,β-alkynic hydrazine with KSCN under transition-metal-free conditions. This protocol provides a simple operation and economical, no inert gas atmosphere required strategy toward synthesis of N-iminoisothiazolium ylides.

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Standard conditions. Isolated yield.

EXPERIMENTAL SECTION

General Information. Unless otherwise noted, all commercially available compounds were used as provided without further purification. Solvents for chromatography were analytical grade and used without further purification. Analytical thin-layer chromatography (TLC) was performed on silica gel and visualized by irradiation with UV light. For column chromatography, 200−300 mesh silica gel was used. 1H NMR, 13C NMR, and 19F NMR were recorded on a Bruker 400 MHz spectrometer in CDCl3. Chemical shifts (δ) were reported referenced to an internal tetramethylsilane standard or the CDCl3 residual peak (δ 7.26) for 1H NMR. Chemical shifts of 13C 11120

DOI: 10.1021/acs.joc.8b01725 J. Org. Chem. 2018, 83, 11118−11124

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The Journal of Organic Chemistry Scheme 2. Reaction of α,β-Alkynic Hydrazones 4a with KSCN

(3,5-Diphenylisothiazol-2-ium-2-yl)(tosyl)amide (3a). Yellow solid (97 mg, 80%). Mp: 164.4−166.7 °C. IR: 3061, 2579, 1597, 1495, 1345, 1160, 879, 765 cm−1. 1H NMR (400 MHz, chloroform-d) δ: 7.67−7.62 (m, 2H), 7.59 (m, J = 7.8, 1.6 Hz, 2H), 7.56−7.49 (m, 3H), 7.43 (m, J = 7.8, 3.6 Hz, 3H), 7.35 (t, J = 7.5 Hz, 2H), 7.19 (s, 1H), 6.94 (d, J = 8.0 Hz, 2H), 2.28 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ: 160.9, 159.2, 141.5, 138.3, 132.1, 131.2, 130.0, 129.5, 129.1, 128.4, 127.0, 126.8, 115.4, 77.5, 21.4 ppm. HRMS (ESI) m/z: calcd for C22H19N2O2S2+ [M + H]+ 407.0882, found 407.0883. (5-(4-Chlorophenyl)-3-phenylisothiazol-2-ium-2-yl)(tosyl)amide (3b). Yellow solid (90 mg, 68%). Mp: 151.5−154.7 °C. IR: 3097, 2951, 2926, 2854, 1722, 1487, 1260, 1085, 794 cm−1. 1H NMR (400 MHz, chloroform-d) δ: 7.63 (d, J = 7.5 Hz, 2H), 7.56−7.46 (m, 4H), 7.42 (d, J = 7.8 Hz, 3H), 7.34 (t, J = 7.4 Hz, 2H), 7.21 (s, 1H), 6.95 (d, J = 7.8 Hz, 2H), 2.28 (s, 3H). 13C NMR (100 MHz, chloroformd) δ: 141.7, 138.3, 131.3, 130.3, 129.5, 129.1, 128.5, 128.3, 128.0, 127.0, 126.8, 115.8, 100.1, 21.5 ppm. HRMS (ESI) m/z: calcd for C22H18N2ClO2S2+ [M + H]+ 441.0493, found 441.0477. (5-(4-Fluorophenyl)-3-phenylisothiazol-2-ium-2-yl)(tosyl)amide (3c). Yellow solid (89 mg, 70%). Mp: 183.2−184.8 °C. IR: 3106, 2961, 2921, 2853, 1596, 1454, 1262, 1085, 1028, 762 cm−1. 1H NMR (400 MHz, chloroform-d) δ: 7.69−7.55 (m, 4H), 7.43 (d, J = 7.7 Hz, 3H), 7.34 (t, J = 7.5 Hz, 2H), 7.22 (t, J = 8.3 Hz, 2H), 7.16 (s, 1H), 6.95 (d, J = 7.8 Hz, 2H), 2.28 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ: 161.0, 158.0, 141.7, 138.3, 131.3, 129.5, 129.1, 129.0, 129.0, 128.5, 127.1, 124.7 (d, JC−F = 4.0 Hz), 117.4 (d, JC−F = 22.0 Hz), 115.5, 21.5 ppm. 19F NMR (376 MHz, CDCl3) δ: −106.2 ppm. HRMS (ESI) m/z: calcd for C22H18N2FO2S2+ [M + H]+ 425.0788, found 425.0786. (5-(3-Fluorophenyl)-3-phenylisothiazol-2-ium-2-yl)(tosyl)amide (3d). Yellow solid (55 mg, 43%). Mp: 167.2−169.7 °C. IR: 3108, 2962, 1919, 2853, 1596, 1478, 1260, 1138, 882, 653 cm−1. 1H NMR (400 MHz, chloroform-d) δ: 7.64 (d, J = 7.5 Hz, 2H), 7.55−7.47 (m, 1H), 7.46−7.40 (m, 3H), 7.35 (dt, J = 16.8, 8.8 Hz, 4H), 7.26 (d, J = 12.4 Hz, 2H), 6.95 (d, J = 7.9 Hz, 2H), 2.28 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ: 164.5, 162.0, 160.6, 157.1 (d, JC−F = 3.0 Hz), 141.7, 138.2, 131.8 (d, JC−F = 8.0 Hz), 131.3, 130.1 (d, JC−F = 8.0 Hz), 129.5, 129.1, 128.5, 128.3, 127.0, 122.8 (d, JC−F = 3.0 Hz), 118.9 (d, JC−F = 21.0 Hz), 116.2, 113.7 (d, JC−F = 23.0 Hz), 21.5 ppm. 19F NMR (376 MHz, CDCl3) δ: −109.7 ppm. HRMS (ESI) m/z: calcd for C22H18N2FO2S2+ [M + H]+ 425.0788, found 425.0773. (5-(4-Methoxyphenyl)-3-phenylisothiazol-2-ium-2-yl)(tosyl)amide (3e). Yellow solid (58 mg, 44%). Mp: 161.5−165.4 °C. IR: 3079, 2921, 2852, 1682, 1599, 1487, 1260, 1085, 794 cm−1. 1H NMR (400 MHz, chloroform-d) δ: 7.61 (d, J = 7.5 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 7.8 Hz, 3H), 7.32 (t, J = 7.4 Hz, 2H), 7.09 (s, 1H), 7.00 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 7.8 Hz, 2H), 3.88 (s, 3H), 2.27 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ: 162.8, 141.4, 138.5, 131.1, 129.5, 129.1, 128.2, 128.4, 127.1, 115.4, 114.1, 55.8, 21.5 ppm. HRMS (ESI) m/z: calcd for C23H21N2O3S2+ [M + H]+ 437.0988, found 437.0985. (3-Phenyl-5-(4-propylphenyl)isothiazol-2-ium-2-yl)(tosyl)amide (3f). Yellow solid (67 mg, 50%). Mp: 152.4−155.7 °C. IR 3086, 2957, 2928, 1598, 1487, 1274, 1133, 803, 689 cm−1. 1H NMR (400 MHz, chloroform-d) δ: 7.62 (d, J = 7.5 Hz, 2H), 7.50 (d, J = 7.9 Hz, 2H), 7.40 (d, J = 7.9 Hz, 3H), 7.31 (t, J = 8.5 Hz, 4H), 7.19 (s, 1H), 6.91 (d, J = 7.8 Hz, 2H), 2.64 (t, J = 7.5 Hz, 2H), 2.26 (s, 3H), 1.67 (h, J = 7.2 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz,

Scheme 3. Gram-Scale Reaction of 1a

Scheme 4. Oxidation of 3a

Scheme 5. Plausible Mechanism

General Procedure for the Synthesis of Compounds 5. α,βAlkynic hydrazone 4 (0.3 mmol, 1.0 equiv) and potassium thiocyanate 2 (1.2 mmol, 4.0 equiv) were stirred at 80 °C (oil bath temperature) under air atmosphere in 3 mL of mixed solvent of AcOH/acetonitrile (v/v = 1:1). Upon completion of the reaction (indicated by TLC), the mixture was cooled to room temperature, ferrous chloride (5.0 equiv) was added to the reaction system. The reaction mixture was charged with silica gel and concentrated. The pure products were obtained after purification by column chromatography on silica gel with petroleum ether/ethyl acetate (v/v = 6:1−1:1) as the eluent. Gram-Scale Reaction of 3a. α,β-Alkynic hyrazone 1a (4.0 mmol, 1.50g, 1.0 equiv) and potassium thiocyanate 2 (8.0 mmol, 0.78 g, 2.0 equiv) were stirred at 80 °C (oil bath temperature) under air atmosphere in 40 mL of mixed solvent of AcOH/acetonitrile (v/v = 1:1). Upon completion of the reaction (indicated by TLC), the mixture was cooled to room temperature, and ferrous chloride (2.5 equiv) was added to the reaction system. The reaction mixture was charged with silica gel and concentrated. The pure products were obtained after purification by column chromatography on silica gel with petroleum ether/ethyl acetate (v/v = 6:1−1:1) as the eluent. Caution! Excess ferrous chloride was added to the reaction system to remove cyanide ions. 11121

DOI: 10.1021/acs.joc.8b01725 J. Org. Chem. 2018, 83, 11118−11124

Article

The Journal of Organic Chemistry chloroform-d) δ: 159.6, 147.6, 141.4, 138.3, 131.0, 130.0, 129.5, 129.0, 128.4, 128.3, 126.9, 126.6, 125.6, 114.9, 37.9, 24.3, 21.4, 13.8 ppm. HRMS (ESI) m/z: calcd for C25H25N2O2S2+ [M + H]+ 449.1352, found 449.1344. (3-Phenyl-5-(m-tolyl)isothiazol-2-ium-2-yl)(tosyl)amide (3g). Yellow solid (81 mg, 64%). Mp: 174.5−177.4 °C. IR: 3088, 2961, 2920, 2852, 15981528, 1259, 1051, 791 cm−1. 1H NMR (400 MHz, chloroform-d) δ: 7.63 (d, J = 7.4 Hz, 2H), 7.39 (m, J = 17.7, 7.5 Hz, 9H), 7.18 (s, 1H), 6.94 (d, J = 7.6 Hz, 2H), 2.43 (s, 3H), 2.28 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ: 160.9 159.5, 138.4, 132.9, 131.1, 129.9, 129.5, 129.1, 128.4, 128.2, 127.4, 127.0, 123.9, 115.2, 29.8, 21.5, ppm. HRMS (ESI) m/z: calcd for C22H19N2O2S2+ [M + H]+ 407.0882, found 407.0871. (5-(4-(Cyanomethyl)phenyl)-3-phenylisothiazol-2-ium-2-yl)(tosyl)amide (3h). Yellow solid (67 mg, 50%). Mp: 169.2−172.3 °C. IR: 3113, 2960, 2920, 2851, 1597, 1532, 1260, 1136, 1048, 796 cm−1. 1 H NMR (400 MHz, chloroform-d) δ: 7.63 (t, J = 6.4 Hz, 4H), 7.50 (d, J = 7.5 Hz, 2H), 7.43 (d, J = 7.2 Hz, 3H), 7.39−7.31 (m, 2H), 7.26 (d, J = 11.1 Hz, 2H), 6.95 (d, J = 7.3 Hz, 2H), 3.85 (s, 2H), 2.28 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 141.9, 138.0, 134.2, 131.4, 129.6, 129.5, 129.2, 128.5, 128.2, 128.1, 127.6, 127.1, 117.0, 116.0, 23.7, 21.5 ppm. HRMS (ESI) m/z: calcd for C24H20N3O2S2+ [M + H]+ 446.0991, found 446.0972. (3-Phenyl-5-(thiophene-3-yl)isothiazol-2-ium-2-yl)(tosyl)amide (3i). Brown solid (43 mg, 35%). Mp: 158.2−160.7 °C. IR 3114, 2960, 2920, 1542, 1487, 1257, 1067, 792 cm−1. 1H NMR (400 MHz, chloroform-d) δ: 7.74 (s, 1H), 7.61 (d, J = 7.5 Hz, 2H), 7.56−7.48 (m, 1H), 7.41 (d, J = 7.7 Hz, 3H), 7.37−7.28 (m, 3H), 7.10 (s, 1H), 6.93 (d, J = 7.7 Hz, 2H), 2.27 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ: 161.0, 138.1, 131.2, 129.5, 129.1, 129.0, 128.8, 128.4, 128.3, 127.0, 126.5, 125.4, 115.3, 21.5 ppm. HRMS (ESI) m/z: calcd for C20H17N2O2S3+ [M + H]+ 413.0447, found 413.0439. (3-(4-(Chloromethyl)phenyl)-5-phenylisothiazol-2-ium-2-yl)(tosyl)amide (3k). Yellow solid (17 mg, 12%). Mp: 113.4−114.9 °C. IR 3193, 3061, 2920, 2851,1595, 1488, 1164, 1080, 754 cm−1. 1H NMR (400 MHz, chloroform-d) δ: 8.58 (s, 1H), 7.89 (d, J = 12.7, 8.2 Hz, 4H), 7.61 (d, J = 7.0 Hz, 2H), 7.46 (d, J = 25.5, 16.3, 7.9 Hz, 5H), 7.33 (d, J = 8.1 Hz, 2H), 4.60 (s, 2H), 2.42 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ: 144.6, 139.5, 135.5, 135.2, 134.2, 132.4, 130.7, 129.9, 128.9, 128.8, 128.1, 127.1, 45.8, 21.8 ppm. HRMS (ESI) m/z: calcd for C23H20ClN2O2S2+ [M + H]+ 455.0649, found 455.0646. (3-(4-Nitrophenyl)-5-phenylisothiazol-2-ium-2-yl)(tosyl)amide (3l). Yellow solid (99 mg, 73%). Mp: 153.7−155.7 °C. IR: 3062, 2922, 2852, 1600, 1487, 1108, 1027, 798, 663 cm−1 1H NMR (400 MHz, chloroform-d) δ: 8.28 (d, J = 8.6 Hz, 2H), 8.01 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.58−7.36 (m, 6H), 7.24 (s, 1H), 6.68 (s, 1H), 2.40 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ: 152.4, 146.0, 137.7, 134.7, 130.1, 129.9, 129.9, 129.1, 128.3, 128.1, 127.2, 124.2, 109.5, 21.9 ppm. HRMS (ESI) m/z: calcd for C22H18N3O4S2+ [M + H]+ 452.0733, found 452.0723. (3-(4-Chlorophenyl)-5-phenylisothiazol-2-ium-2-yl)(tosyl)amide (3m). Yellow solid (48 mg, 36%). Mp: 185.9−189.7 °C. IR: 2921, 2851, 1592, 1481, 1259, 1083, 762 cm−1. 1H NMR (400 MHz, chloroform-d) δ: 7.57 (m, J = 24.2, 12.5, 7.5 Hz, 8H), 7.43 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.21 (s, 1H), 6.98 (d, J = 7.9 Hz, 2H), 2.30 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ: 159.7, 159.6, 141.8, 137.5, 132.2, 130.9, 130.1, 129.2, 128.8, 128.2, 127.0, 126.8, 115.1, 21.5 ppm. HRMS (ESI) m/z: calcd for C22H18ClN2O2S2+ [M + H]+ 441.0493, found 441.0495. (5-Phenyl-3-(4-(trifluoromethyl)phenyl)isothiazol-2-ium-2-yl)(tosyl)amide (3n). Yellow solid (28 mg, 20%). Mp: 165.2−167.2 °C. IR 2961, 1534, 1487, 1295, 1112, 812, 760 cm−1. 1H NMR (400 MHz, chloroform-d) δ: 7.73 (d, J = 8.1 Hz, 2H), 7.57 (m, J = 14.2, 6.7 Hz, 7H), 7.38 (d, J = 8.1 Hz, 2H), 7.27 (s, 1H), 6.93 (s, 2H), 2.28 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ: 160.1, 159.4, 141.8, 138.2, 132.4, 131.6, 130.1, 130.0, 129.2, 128.0, 126.9, 126.9, 125.3 (q, JC−F = 3.0 Hz), 115.3, 21.4 ppm. 19F NMR (376 MHz, CDCl3) δ: −63.2 ppm. HRMS (ESI) m/z: calcd for C23H18F3N2O2S2+ [M + H]+ 475.0756, found 475.0746.

(3-(4-Methoxyphenyl)-5-phenylisothiazol-2-ium-2-yl)(tosyl)amide (3o). Yellow solid (68 mg, 52%). Mp: 183.5−185.9 °C. IR 2962, 1599, 1486, 1258, 1131, 1027, 765, 650 cm−1. 1H NMR (400 MHz, chloroform-d) δ: 7.76 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 6.9 Hz, 2H), 7.49 (m, J = 13.2, 7.8 Hz, 5H), 7.22 (s, 1H), 6.96 (d, J = 7.8 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 3.84 (s, 3H), 2.27 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ: 161.9, 160.5, 158.7, 141.5, 138.8, 131.9, 131.5, 129.9, 129.0, 128.4, 127.0, 126.7, 120.9, 115.1, 113.8, 55.6, 21.4 ppm. HRMS (ESI) m/z: calcd for C23H21N2O3S2+ [M + H]+ 437.0988, found 437.0987. (3-(Naphthalen-1-yl)-5-phenylisothiazol-2-ium-2-yl)(tosyl)amide (3p). Yellow solid (55 mg, 40%). Mp: 163.0−164.8 °C. IR: 3051, 2919, 1529, 1492, 1281, 1134, 762 cm−1. 1H NMR (400 MHz, chloroform-d) δ: 7.92 (d, J = 7.7 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 6.9 Hz, 2H), 7.48 (m, J = 21.7, 15.0, 8.1 Hz, 6H), 7.36− 7.15 (m, 5H), 6.65 (d, J = 7.7 Hz, 2H), 2.08 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ: 160.6, 159.2, 141.1, 138.6, 133.3, 132.1, 131.2, 130.4, 130.0, 129.3, 128.7, 128.6, 128.2, 127.2, 126.9, 126.8, 126.3, 125.7, 124.9, 124.2, 117.1, 21.3 ppm. HRMS (ESI) m/z: calcd for C26H21N2O2S2+ [M + H]+ 457.1039, found 457.1038. (3-(Furan-2-yl)-5-phenylisothiazol-2-ium-2-yl)(tosyl)amide (3q). Yellow solid (71 mg, 60%). Mp 154.3−155.8 °C. IR: 3091, 1591, 1496, 1283, 1140, 1062, 755 cm−1. 1H NMR (400 MHz, chloroformd) δ: 8.04 (d, J = 3.6 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.54 (m, J = 6.1, 1.8 Hz, 3H), 7.52−7.45 (m, 3H), 7.44 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.59 (m, J = 3.6, 1.7 Hz, 1H), 2.30 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ: 156.9, 145.3, 144.2, 142.0, 139.3, 131.7, 129.8, 129.3, 128.4, 127.0, 126.6, 119.6, 113.2, 111.3, 21.4 ppm. HRMS (ESI) m/z: calcd for C20H16N2O3S2Na+ [M + Na]+ 419.0495, found 419.0513. (5-Phenylisothiazol-2-ium-2-yl)(tosyl)amide (3r). Black solid (69 mg, 60%). Mp: 59.5−61.7 °C. IR 2923, 1607, 1510, 1488, 1161, 1027, 727, 689 cm−1. 1H NMR (400 MHz, chloroform-d) δ: 9.13 (s, 1H), 7.87−7.81 (m, 2H), 7.56−7.49 (m, 3H), 7.48−7.41 (m, 2H), 7.30 (d, J = 8.1 Hz, 2H), 6.52 (d, J = 4.5 Hz, 1H), 2.41 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ: 159.6, 143.9, 132.3, 129.7, 129.5, 127.9, 126.6, 110.5, 21.7 ppm. HRMS (ESI) m/z: calcd for C16H15N2O2S2+ [M + H]+ 331.0569, found331.0572. (3,5-Diphenylisothiazol-2-ium-2-yl)(phenylsulfonyl)amide (3s). Yellow solid (59 mg, 50%). Mp: 199.5−201.6 °C. IR: 2973, 2882, 1483, 1087, 1046, 721, 692 cm−1. 1H NMR (400 MHz, chloroform-d) δ: 7.66−7.57 (m, 4H), 7.57−7.49 (m, 5H), 7.42 (t, J = 7.4 Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.31−7.25 (m, 1H), 7.21 (s, 1H), 7.15 (t, J = 7.7 Hz, 2H). 13C NMR (100 MHz, chloroform-d) δ: 161.1, 141.5, 132.1, 131.2, 131.1, 130.0, 129.5, 128.6, 128.5, 128.4, 128.3, 127.0, 126.8, 115.4 ppm. HRMS (ESI) m/z: calcd for C21H16N2O2S2Na+ [M + Na]+ 415.0545, found 415.0545. (3-Phenyl-5-propylisothiazol-2-ium-2-yl)(tosyl)amide (3u). Yellow solid (56 mg, 50%). Mp: 114.1−116.6 °C. IR 3327, 2962, 1635, 1483, 1347, 1250, 757, 689 cm−1. 1H NMR (400 MHz, chloroform-d) δ: 7.24 (dd, J = 9.5, 2.6 Hz, 1H), 7.21−7.12 (m, 6H), 6.89 (d, J = 8.1 Hz, 2H), 6.76 (s, 1H), 3.04−2.95 (m, 2H), 2.31 (s, 3H), 1.77 (m, J = 14.9, 7.4 Hz, 2H), 1.08−1.02 (m, 3H). 13C NMR (100 MHz, chloroform-d) δ: 143.7, 135.6, 134.2, 129.4, 128.7, 128.3, 127.6, 127.0, 125.5, 29.5, 23.8, 21.6, 14.2 ppm. HRMS (ESI) m/z: calcd for C19H21N2O2S2+ [M + H]+ 373.1039, found 373.1052. Isophthaloylbis((3,5-diphenylisothiazol-2-ium-2-yl)amide) (5a). Yellow solid (97 mg, 51%). Mp: 129.5−131.7 °C. IR: 2962, 2861, 1686, 1483, 1256, 1022, 755, 690 cm−1 1H NMR (400 MHz, chloroform-d) δ: 7.57 (m, J = 28.1, 14.0, 7.1 Hz, 14H), 7.43 (t, J = 7.3 Hz, 2H), 7.31 (m, J = 23.2, 6.0 Hz, 5H), 7.23 (s, 2H), 7.16 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, chloroform-d) δ: 161.5, 160.0, 141.2, 132.2, 131.3, 131.3, 130.0, 129.5, 128.6, 128.5, 128.2, 127.1, 126.9, 115.5 ppm. HRMS (ESI) m/z: calcd for C38H27N4O2S2+ [M + H]+ 635.1570, found 635.1573. 4,6-Diphenyl-2-tosyl-2H-1,2,3-thiadiazine 1-oxide (7a). Yellow solid (105 mg, 82%). Mp: 154.3−155.2 °C. IR: 2962, 2919, 1259, 1009, 792, 662 cm−1 1H NMR (400 MHz, chloroform-d) δ: 8.11 (d, J = 8.2 Hz, 2H), 7.77 (s, 4H), 7.59−7.50 (m, 3H), 7.44 (d, J = 4.6 Hz, 3H), 7.36 (d, J = 8.1 Hz, 2H), 7.26 (s, 1H), 2.42 (s, 3H). 13C NMR 11122

DOI: 10.1021/acs.joc.8b01725 J. Org. Chem. 2018, 83, 11118−11124

Article

The Journal of Organic Chemistry (100 MHz, chloroform-d) δ: 145.9, 134.8, 134.6, 133.2, 131.2, 130.6, 129.9, 129.8, 129.2, 129.0, 127.3, 126.7, 113.2, 21.9 ppm. HRMS (ESI) m/z: calcd for C22H19N2O3S2+ [M + H]+ 423.0832, found 423.0841.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01725.

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Crystal data for 3a (CIF) Crystal data for 7a (CIF) 1H and 13C NMR spectra of the products and crystallographic data of 3a and 7a (PDF)

AUTHOR INFORMATION

Corresponding Authors

*Fax: 86-512-65880307. E-mail: [email protected]. *Fax: 86-512-65880307. E-mail: [email protected] 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 (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 Fei Wang in this group for reproducing the results for 3a, 3c, and 3q.

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REFERENCES

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The Journal of Organic Chemistry

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DOI: 10.1021/acs.joc.8b01725 J. Org. Chem. 2018, 83, 11118−11124