[4 + 1] Cycloaddition Reaction of Î±,Î²-Alkynic Hydrazones and KSCN

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[4+1] Cycloaddition Reaction of #,#-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 Shunjun Ji J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01725 • Publication Date (Web): 09 Aug 2018 Downloaded from http://pubs.acs.org on August 10, 2018

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The Journal of Organic Chemistry

[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; E-mail: [email protected]; [email protected] RECEIVED DATE *CORRESPONDING AUTHOR FAX: 86-512-65880307.

ABSTRACT. A novel heteroannulation reaction between α,β-alkynic hydrazones and potassium thiocyanate (KSCN) has been developed for the synthesis of N-iminoisothiazolium ylides. The transformation features wide substrate scope, functional tolerance and easy operation. This investigation involves [4+1]-type cycloaddition reaction and C−S/S−N bonds formation under transition-metal free conditions. The application of this transformation to the gram-scale preparation of the N-imide ylide is also accomplished. KEYWORDS: N-iminoisothiazolium ylide, [4+1]-type cycloaddition, C−S/S−N bonds, transition-metal free 1. 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 bactericide (Figure 1).5-6 Among of them, thiazoles and isothiazoles are important heterocycles and widely exist in drugs and natural products.

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Figure 1. Pharmaceutical active isothiazolones and their derivatives. During the past decade, more attentions have been paid to the synthesis of N-ylides6 and their applications in arylation, alkenylation, alkylation7-8 and cycloaddition reactions (Scheme 1a).9-16 However, there are limited reports for the construction of isothiazolium ylides such as Narylsulfonylisothiazole-2-imines. The cyclcondensation of thiocyanatovinylaldehyde hydrazones from non-commercial available thiocyanatovinylaldehydes could afford N-arylsulfonylisothiazole-2-imines 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 bonds formation in pot. Scheme 1. Different Strategies for The Synthesis of N-Ylides (a) Previous work R' O

M(CO)5

O

HN NH

R

OEt

H

R2

N

N N

R3

1

O

R CO2Et

R

1

R CHO

R NHNH 2

HPO(OEt)2 N

N NHTs

N

R

R

R3

R2

N N

EtO2C

O

N N

Br

N

R

R

O N H

N N

(OC)5M

O

X

O

EtO

R'

N O P OEt OEt

CO2Et

R1

R'

R1

R1 N N

R1

R' CO2Et

(b) Limited reports for the construction of isothiazolium ylides CH NNHR

CHO

R

(CH2)n

R NHNH 2

(CH2)n

(CH2)n S

SCN

SCN

N N

(c) This work R2

R2

KSCN NNH R3

R1

AcOH:CH3CN (1:1) 80 oC Nonmetallic catalyst

R1

S

N N

R3

Air bengin, one-pot

2. RESULTS AND DISCUSSION ACS Paragon Plus Environment

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Initially, we investigated the reaction of α,β-alkynic hydrazone 1a with KSCN in 3 mL acetic acid at 60 oC under air condition. 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 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 2-3). Change of Ssource from K2S to S8 led to diminished yields (Table 1, entries 4-6). Reducing or raising the amount of KSCN do not effectively improve the yields (entries 7-8). A 1:1 (V/V) blend of other solvents like EtOH, toluene, THF, 1,4-dioxane and acetonitrile along with AcOH were 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 14-15). Table 1. Optimization of The Reaction Conditionsa

Entry

Temp.

1a:2a

Solvent

Yield (%)b

1

60

1:2

AcOH

53

2

80

1:2

AcOH

65

3

100

1:2

AcOH

63

c

80

1:2

AcOH

0

5d

80

1:2

AcOH

0

4

e

80

1:2

AcOH

48

7

80

1:1.5

AcOH

64

8

80

1:3

AcOH

63

6

9

80

1:2

AcOH : EtOH (1:1)

40

10

80

1:2

AcOH : toluene (1:1)

64

11

80

1:2

AcOH : THF (1:1)

trace

12

80

1:2

AcOH : 1,4-dioxane (1:1)

60

13

80

1:2

AcOH : CH3CN (1:1)

80

14

80

1:2

AcOH : CH3CN (1:2)

60

15

80

1:2

AcOH : CH3CN (1:3)

37

a

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

With the optimization conditions in hand, we explored the scope of the alkynyl substrates to construct isothiazolium ylides (Table 2). To 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 3-bromoprop-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 ACS Paragon Plus Environment

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trace amount of the desired product 3k. It was found that 4-nitro-, 4-chloro-, 4-trifluoromethyl-, and 4methoxy-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 Niminoisothiazolium ylides 3p and 3q in 40% and 60% yield, respectively. It should be noted that the reaction of 4-methyl-N'-(3-phenylprop-2-yn-1-ylidene)benzenesulfonohydrazide 1r could also lead to N-iminoisothiazolium ylide 3r in 70% yield. In addition, Benzenesulfonyl hydrazides 1s and 1t with different substitution patterns were tested as well. 3s was observed in 50% yield. Unfortunately, only trace amount of 3t was detected. Table 2. Substrate scope of α,β-alkynic hydrazones (1)a

a

Standard condition. Isolated yield.


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Next, we tried the [4+1] cycloaddition of N'3-(1,3-diphenylprop-2-yn-1-ylidene)-N'1-(1,3diphenylprop-2-yn-1-ylidene)isophthalohydrazide with KSCN. The di-substituted N-iminoisothiazolium ylide was successfully obtained in 51% yield (Scheme 2). Scheme 2. The reaction of α,β-alkynic hydrazones 4a with KSCN.

To evaluate the application of this tandem reaction, the gram scale reaction was investigated with 1.50 g of 1a. Interestingly, the N-iminoisothiazolium ylide 3a was isolated in 66% yield without further optimization of reaction conditions (Scheme 3). Scheme 3. Gram Scale Reaction of 1a.

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-2tosyl-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 Supporting Information for details). Scheme 4. Oxidation of 3a.

Based on 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 tranfer to afford the anion B. The following decyanative cyclization affords the N-iminoisothiazolium ylide 3a. Scheme 5. A Plausible Mechanism. ACS Paragon Plus Environment

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3. 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 to synthesis of N-iminoisothiazolium ylides.

4. EXPERIMENTAL SECTION 1. 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, 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 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 by using BRUKER MICROTOF-Q III instrument with ESI source. The starting materials were isolated by SepaBean machine Flash Chromatography, which purchased from Santai Technologies Inc. 2.1. General procedure for the synthesis of compounds 3 α,β-alkynic 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 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 (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. 2.2. General procedure for the synthesis of compounds 5 α,β-alkynic hyrazone 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. 2.3. 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, 0.78g, 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, 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. Cautious! Excess ferrous chloride was added to the reaction system to remove cyanide ions. (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, Chloroform-d) δ 141.7,


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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). 13 C 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, 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, 29612920, 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. 1H 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-(thiophen-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,


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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, Chloroform-d) 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, found:331.0572. (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, Chloroformd) 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 (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.

ASSOCIATED CONTENT Supporting Information Available. The Supporting Information is available free of charge on the ACS Publications website at http://pubs.acs.org. Copies of 1H and 13C NMR spectra of the products and crystallographic data of 3a and 7a (PDF). Crystal data for 3a (CIF). Crystal data for 7a (CIF). ACKNOWLEDGMENT 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 Fei Wang in this group for reproducing the result of 3a, 3c, and 3q.

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[4 + 1] Cycloaddition Reaction of Î±,Î²-Alkynic Hydrazones and KSCN

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