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Article

Copper-Catalyzed One-Pot Synthesis of N-Sulfonyl Amidines from Sulfonyl Hydrazine, Terminal Alkynes and Sulfonyl Azides

by
Yu Zhao
1,†,
Zitong Zhou
1,†,
Man Chen
1 and
Weiguang Yang
1,2,*
1
The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China
2
The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang 524023, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2021, 26(12), 3700; https://doi.org/10.3390/molecules26123700
Submission received: 25 May 2021 / Revised: 10 June 2021 / Accepted: 14 June 2021 / Published: 17 June 2021
(This article belongs to the Special Issue The Click Reaction: A Powerful and Widely Used Tool in Drug Discovery, Bioconjugation, and Materials Science)
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Abstract

:
N-Sulfonyl amidines are developed from a Cu-catalyzed three-component reaction from sulfonyl hydrazines, terminal alkynes and sulfonyl azides in toluene at room temperature. Particularly, the intermediate N-sulfonylketenimines was generated via a CuAAC/ring-opening procedure and took a nucleophilic addition with the weak nucleophile sulfonyl hydrazines. In addition, the stability of the product was tested by a HNMR spectrometer.

1. Introduction

Amidine derivatives are important privileged scaffolds in medicinal chemistry [1,2,3], synthetic chemistry [4] and an important pharmacophore in drug discovery [5,6]. One subset of such compounds is N-sulfonyl amidine derivatives that show a prolific set of biological activities, including antifungal (I) [7], anticancer (II) [8], antiresorptive (III and IV) [9,10,11], antiproliferative (V) [12], dopamine transporter inhibitors (VI) [13] (Figure 1), etc. [14,15]. Therefore, the establishment of robust synthetic approaches for the preparation of N-sulfonyl amidines and their functionalizations is highly required.
Classical types of reactions have focused on the preparation of N-sulfonyl amidines involved in the reaction of cyclic thioamides and thioacetamide derivatives with sulfonyl azides [14,16,17,18], the phosphite-mediated Beckmann-like coupling of oximes and p-toluenesulfonyl azide [19], sulfonamide derivatives condensation with DMF–DMA [20], the sulfonamide reaction with formamide [21] and the sulfonyl ynamide rearrangement [22]. The most efficient method is the Cu-catalyzed multicomponent reaction of terminal alkynes, sulfonyl azides and amines, which has been applied to synthesize numerous oxygen-containing and nitrogen-containing heterocyclic compounds [23,24,25,26,27,28,29,30,31]. The ketenimine intermediate generated by Cu-catalyzed alkynes and sulfonyl azides [31,32,33] could take a nucleophilic addition reaction with most amines, as show in Scheme 1, including aliphatic primary amines [34,35,36], aliphatic secondary amines [37,38], aliphatic tertiary amines [39,40], quaternary amine salts [41], imines [27], nitrogenous heterocyclic compounds [42,43,44,45], urea derivatives [46], oximes [47], sulfoximines [48] and enyl amine [49,50]. However, to our knowledge, there are few previous works that used the weak nucleophile sulfonyl hydrazines for this method. Herein, the Cu-catalyzed one-pot synthesis of N-sulfonyl amidines from sulfonyl hydrazine, terminal alkynes and sulfonyl azides was reported.

2. Results

We began our investigation by examining the synthesis of 4-methyl-N-(2-phenyl-1-(2-(1-phenylethylidene)-1-tosylhydrazinyl) ethylidene)benzenesulfonamide 4a via 4-methyl-N′-(1-phenylethylidene)benzenesulfonohydrazide 1a, ethynylbenzene 2a and p-tosyl azide 3a. The reaction was carried out in the presence of CuI and Et3N in CH2Cl2 at room temperature for 1 h, and 4a was isolated in a 78% yield (Table 1, entry 1). Based on this finding, the reaction conditions were screened. First, several catalysts were screened, and most Cu-catalysts exhibited a high catalytic reactivity in this reaction, whether CuI-catalysts or CuII-catalysts (Table 1, entries 2–6). Other catalysts such as AgTFA failed to produce the desired product (Table 1, entries 7). Then, the effects of different bases were evaluated, and the screening results revealed that the use of Et3N achieved a superior result compared to DMAP, DIPEA, pyridine and the other bases (Table 1, entries 8–12). Finally, the solvents were screened, and a lower or comparable yield was obtained when CHCl3, DCE, MeCN, THF, DMSO and DMF were used as solvents, while toluene gave 4a the highest yield of 84% (Table 1, entry 13–19). Encouraged by this promising result, we tracked the reaction by TLC and found that it could be completed in less than an hour at room temperature (Table 1, entry 20–23).
With the optimized reaction conditions obtained, the substrate diversity with the sulfonyl hydrazines 1 was tested first. As shown in Scheme 2, the R1 electron effects of the substituents 1 had slight influences. For example, substrates bearing 4-OMe-C6H4, 4–Me-C6H4, 2-naphthyl and 2-tetra-hydronaphthalyl were examined, and the 72–88% yields of 4a–4e were isolated. The R2 of substrates 1 bearing the 2,4,6-trimethylphenyl group also can obtain 4f in a good yield of 80%. However, when changing the substrates 1 to other sulfonyl hydrazines, such as 1g–1k, it could not obtain the desired products and give decomposed or complex compounds. Next, the scopes and limitations of terminal alkynes 2 and sulfonyl azides 3 were examined. An aryl-substituted, aliphatic or 2-thienyl terminal alkynes and aryl-substituted or aliphatic sulfonyl azides can smoothly obtain the corresponding products 4g–4m with yields of 73–89% and 4n–4q with yields of 78–86%, in which both the substituents led to high yields and were influenced slightly.
The structure of 4a was confirmed by X-ray crystallography (Figure 2, CCDC deposition number 2075031).
Curiously, we found that the separated products in the solvent were unstable and would decompose. Thus, the stability of product 4a was tested by a HNMR spectrometer. As shown in Figure 3, the products dissolved in DMSO were relatively stable in the first four days, and the decomposition complex could be observed starting from the fifth day; then, the concentration of byproducts became thicker day by day. After a month, the system was relatively stable, and the decomposition was slow. Therefore, it is recommended that products 4a–4q should be dried and stored at a low temperature.

3. Experimental

3.1. General Information

All melting points were determined on a Yanaco melting point apparatus and were uncorrected. IR spectra were recorded as KBr pellets on a Nicolet FT-IR 5DX spectrometer. All spectra of 1H NMR (400 MHz) and 13C NMR (100 MHz) were measured on a 400 MHz Bruker spectrometer using DMSO-d6 or CDCl3 as the solvent, with tetramethylsilane (TMS) as the internal standard, at room temperature. Chemical shifts are given in δ relative to TMS, and the coupling constants J are given in Hz. HRMS were obtained on a Bruker micrOTOF-Q II spectrometer. All commercially available reagents were purchased from Sigma-Aldrich, Acros, Aladdin, TCI, Alfa, Innochem in China and were used without further purification. All reactions were carried out in dried reaction tube (25 mL). The original 1H and 13C NMR spectra are available in supplementary material.

3.2. Compound Characterizations and Preparations

4-methyl-N-((E)-2-phenyl-1-(2-((E)-1-phenylethylidene)-1-osylhydrazineyl) ethylidene) benzenesulfonamide (4a). 4-methyl-N′-(1-phenylethylidene) benzenesulfonohydrazide (1a) (0.114 mg, 0.50 mmol) was mixed with CuI (9.5 mg, 0.05 mmol) in 1-mL toluene. Then, ethynylbenzene (2a) (76.5 mg, 0.75 mmol), TsN3 (147.8 mg, 0.75 mmol) and TEA (101 mg, 1.0 mmol) were mixed in toluene (2 mL). After stirring at room temperature for 1 h and concentrated under reduced pressure, the mix was purified a flash chromatography (petroleum ether/ethyl acetate: 7:1) to give product 4a as a white solid, mp 143–144 °C. IR (KBr) ν 3063, 1564, 1492, 1442, 1309, 1145, 1082 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 8.0 Hz, 2H), 7.62 (t, J = 8.0 Hz, 3H), 7.53–7.46 (m, 6H), 7.28–7.21 (m, 5H), 7.01 (d, J = 6.8 Hz, 2H), 4.14 (s, 2H), 2.48 (s, 3H), 2.42 (s, 3H), 1.73 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 182.7, 165.2, 145.6, 143.6, 138.6, 135.0, 134.0, 133.1, 132.4, 129.7 (2C), 129.6 (2C), 128.9 (2C), 128.8 (2C), 128.6, 128.5 (2C), 127.8 (2C), 127.2, 126.5 (3C), 21.3 (3C), 17.7; HRMS (ESI-TOF) (m/z). Calcd for C30H29N3O4S2, [M + H]+ 560.1672; found 560.1675.
The products 4b–4q were prepared by a similar procedure.
4-methyl-N-((E)-2-phenyl-1-(2-((E)-1-(p-tolyl)ethylidene)-1-tosylhydrazineyl) ethylidene)benzenesulfonamide (4b). White solid, mp 153–155 °C. IR (KBr) ν 3062, 1594, 1568, 1307, 1172, 1147, 1084 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 7.8 Hz, 4H), 7.31 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.24–7.19 (m, 3H), 7.00 (d, J = 6.8 Hz, 2H), 4.19 (s, 2H), 2.47 (s, 3H), 2.42 (s, 3H), 2.39 (s, 3H), 1.69 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 182.3, 165.3, 145.5, 143.5, 142.6, 138.6, 134.0, 133.1, 132.3, 129.7 (2C), 129.6 (2C), 129.3 (2C), 128.9 (2C), 128.6 (2C), 128.5 (2C), 127.8 (2C), 127.1, 126.5 (3C), 21.2 (3C), 17.7; HRMS (ESI-TOF) (m/z). Calcd for C31H31N3O4S2, [M + H]+ 574.1829; found 574.1831.
N-((E)-1-(2-((E)-1-(4-methoxyphenyl)ethylidene)-1-tosylhydrazineyl)-2-phenylethylidene)-4-methylbenzenesulfonamide (4c). White solid, mp 141–143 °C. IR (KBr) ν 3063, 1590, 1494, 1289, 1173, 1141, 1085 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 7.8 Hz, 4H), 7.27 (d, J = 8.0 Hz, 2H), 7.23–7.18 (m, 3H), 7.05–6.99 (m, 4H), 4.49 (s, 2H), 3.85 (s, 3H), 2.47 (s, 3H), 2.42 (s, 3H), 1.67 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 181.5, 165.3, 162.6, 145.5, 143.5, 138.7, 134.0, 133.1, 132.3, 129.7 (2C), 129.6 (2C), 129.5 (2C), 128.9 (2C), 128.6, 128.5 (2C), 127.3, 127.1, 126.5 (3C), 114.1, 55.6, 21.2 (3C), 17.2; HRMS (ESI-TOF) (m/z). Calcd for C31H31N3O5S2, [M + H]+ 590.1778; found 590.1782.
4-methyl-N-((E)-1-(2-((E)-1-(naphthalen-2-yl)ethylidene)-1-tosylhydrazineyl)-2-phenylethylidene)benzenesulfonamide (4d). White solid, mp 172–173 °C. IR (KBr) ν 3056, 1590, 1574, 1494, 1359, 1305, 1144, 1084 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 8.02 (t, J = 7.2 Hz, 3H), 7.68–7.61 (m, 4H), 7.53–7.46 (m, 4H), 7.29 (d, J = 8.0 Hz, 2H), 7.25–7.17 (m, 3H), 7.02 (d, = 7.2, 2H), 4.34 (s, 2H), 2.48 (s, 3H), 2.43 (s, 3H), 1.87 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 182.3, 165.3, 145.6, 143.6, 138.6, 134.7, 134.0, 133.1, 132.4 (2C), 129.6 (2C), 129.4 (2C), 129.3 (2C), 128.9 (2C), 128.6, 128.5 (2C), 128.3, 128.2, 127.7, 127.2, 127.0, 126.5 (3C), 123.7, 21.2 (3C), 17.6; HRMS (ESI-TOF) (m/z). Calcd for C34H31N3O4S2, [M + H]+ 610.1829; found 610.1832.
4-methyl-N-((E)-2-phenyl-1-(2-((E)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethylidene)-1-tosylhydrazineyl)ethylidene)benzenesulfonamide (4e). White solid, mp 173–174 °C. IR (KBr) ν 3062, 3030, 1590, 1494, 1370, 1176, 1145, 1083 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 6.4 Hz, 5H), 7.28–7.16 (m, 6H), 6.99 (d, J = 8.0, 2H), 4.02 (s, 2H), 2.78 (s, 4H), 2.47 (s, 3H), 2.42 (s, 3H), 1.76 (s, 4H), 1.69 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 182.6, 165.3, 145.6, 143.6, 141.8, 138.6, 137.2, 134.0, 133.1, 132.4, 129.7 (2C), 129.6 (2C), 129.3, 128.9 (2C), 128.7 (2C), 128.6 (2C), 128.4, 127.2, 126.5 (2C), 124.9, 28.9 (2C), 22.6, 22.5, 21.3, 21.2, 17.6 (2C); HRMS (ESI-TOF) (m/z). Calcd for C34H35N3O4S2, [M + H]+ 614.2142; found 614.2145.
N-(1-(1-(mesitylsulfonyl)-2-((E)-1-phenylethylidene)hydrazineyl)-2-phenylethylidene)-4-methylbenzenesulfonamide (4f). White solid, mp 181–183 °C. IR (KBr) ν 3062, 1600, 1551, 1354, 1304, 1141, 1088 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 7.2 Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H), 7.34–7.17 (m, 7H), 7.03 (d, J = 7.2 Hz, 2H), 6.93 (s, 2H), 4.58 (s, 2H), 2.43 (s, 6H), 2.34 (s, 3H), 2.32 (s, 3H), 1.82 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 181.3, 164.7, 143.9, 143.2, 140.3, 138.5, 135.0, 133.1, 132.4, 132.3, 132.0, 131.9, 129.4 (2C), 128.8, 128.7 (2C), 128.5 (2C), 127.9, 127.7 (2C), 127.1 (2C), 126.3 (2C), 21.8 (2C), 21.0 (2C), 20.7, 18.5; HRMS (ESI-TOF) (m/z). Calcd for C32H33N3O4S2, [M + H]+ 590.1985; found 590.1988.
4-methyl-N-((E)-1-(2-((E)-1-phenylethylidene)-1-tosylhydrazineyl)-2-(p-tolyl)ethylidene)benzenesulfonamide (4g). White solid, mp 159–160 °C. IR (KBr) ν 3062, 2920, 1596, 1566, 1367, 1174, 1142, 1085 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 7.6 Hz, 2H), 7.61 (d, J = 8.0 Hz, 3H), 7.54–7.45 (m, 6H), 7.26 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 7.6 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 4.19 (s, 2H), 2.47 (s, 3H), 2.41 (s, 3H), 2.26 (s, 3H), 1.74 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 182.7, 165.4, 145.5, 143.5, 143.2, 138.6, 136.4, 135.1, 134.0, 132.3, 130.0, 129.6 (2C), 129.5 (2C), 129.1 (2C), 128.8 (2C), 128.5 (2C), 127.8 (2C), 126.5 (3C), 21.2 (2C), 20.7 (2C), 17.8; HRMS (ESI-TOF) (m/z). Calcd for C31H31N3O4S2, [M + H]+ 574.1829; found 574.1832.
4-methyl-N-((E)-1-(2-((E)-1-phenylethylidene)-1-tosylhydrazineyl)-2-(m-tolyl)ethylidene)benzenesulfonamide (4h). White solid, mp 146–148 °C. IR (KBr) ν 3062, 2920, 1598, 1569, 1489, 1359, 1367, 1294, 1142, 1087 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 7.6 Hz, 2H), 7.62 (d, J = 8.0 Hz, 3H), 7.53–7.45 (m, 6H), 7.28 (d, J = 8.0 Hz, 2H), 7.11 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.66 (s, 1H), 4.21 (s, 2H), 2.47 (s, 3H), 2.42 (s, 3H), 1.99 (s, 3H), 1.74 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 182.6, 165.2, 145.6, 138.6, 137.7, 134.9, 134.0, 133.0, 132.4, 130.5 (2C), 129.6 (2C), 129.5 (2C), 128.7 (2C), 128.5 (2C), 127.8 (2C), 127.6, 126.5 (3C), 125.7, 21.2 (3C), 20.7, 17.6; HRMS (ESI-TOF) (m/z). Calcd for C31H31N3O4S2, [M + H]+ 574.1829; found574.1830.
N-((E)-2-(4-fluorophenyl)-1-(2-((E)-1-phenylethylidene)-1-tosylhydrazineyl) ethylidene)-4-methylbenzenesulfonamide (4i). White solid, mp 157–159 °C. IR (KBr) ν 3062, 1595, 1564, 1375, 1308, 1190, 1083 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 3H), 7.54–7.45 (m, 6H), 7.27 (d, J = 8.0 Hz, 2H), 7.09–7.05 (m, 4H), 4.20 (s, 2H), 2.47 (s, 3H), 2.42 (s, 3H), 1.86 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 182.5, 165.0, 161.2 (d, J = 256.7 Hz), 145.7, 143.6, 138.5, 135.0, 133.9, 132.4, 130.7 (2C), 129.7 (2C), 129.6 (2C), 129.2 (d, J = 3.1 Hz), 128.8 (2C), 128.5 (2C), 127.8 (2C), 126.5 (3C), 115.5 (d, J = 21.8 Hz), 21.1 (2C), 21.1 (d, J = 7.7 Hz), 17.9; HRMS (ESI-TOF) (m/z). Calcd for C30H28FN3O4S2, [M + H]+ 578.1578; found 578.1581.
N-((E)-2-(4-chlorophenyl)-1-(2-((E)-1-phenylethylidene)-1-tosylhydrazineyl) ethylidene)-4-methylbenzenesulfonamide (4j). White solid, mp 153–155 °C. IR (KBr) ν 3064, 1593, 1562, 1444, 1345, 1272, 1122, 1081 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.0 Hz, 3H), 7.53–7.45 (m, 6H), 7.30–7.27 (m, 4H), 7.02 (d, J = 8.8 Hz, 2H), 4.24 (s, 2H), 2.47 (s, 3H), 2.42 (s, 3H), 1.90 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 182.5, 164.8, 145.7, 143.7, 138.4, 135.0, 133.8, 132.4, 132.1, 132.0, 130.6 (2C), 129.7 (2C), 129.6 (2C), 128.8 (2C), 128.5 (2C), 127.8 (2C), 126.5 (3C), 38.0, 21.1 (2C), 21.1, 18.0; HRMS (ESI-TOF) (m/z). Calcd for C30H28ClN3O4S2, [M + H]+ 594.1283; found 594.1285.
N-((E)-2-(4-bromophenyl)-1-(2-((E)-1-phenylethylidene)-1-tosylhydrazineyl) ethylidene)-4-methylbenzenesulfonamide (4k). White solid, mp 158–160 °C. IR (KBr) ν 3062, 1592, 1560, 1486 1369, 1282, 1142, 1082 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 7.2 Hz, 2H), 7.62 (d, J = 8.0 Hz, 3H), 7.53–7.41 (m, 8H), 7.28 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 4.21 (s, 2H), 2.47 (s, 3H), 2.42 (s, 3H), 1.91 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 182.4, 164.7, 145.7, 143.6, 138.4, 135.0, 133.8, 132.5, 132.4, 131.5, 132.0, 130.8 (2C), 129.7 (2C), 129.6 (2C), 128.8 (2C), 128.5 (2C), 127.8 (2C), 126.5 (3C), 120.3, 21.1 (2C), 18.0; HRMS (ESI-TOF) (m/z). Calcd for C30H28BrN3O4S2, [M + H]+ 638.0778; found 638.0779.
4-methyl-N-((E)-1-(2-((E)-1-phenylethylidene)-1-tosylhydrazineyl)octylidene) benzenesulfonamide (4l). White solid, mp 103–105 °C. IR (KBr) ν 3063, 2864, 1595, 1338, 1264, 1155, 1076 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 7.2 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.57–7.53 (m, 6H), 7.40 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 2.75 (d, J = 7.6 Hz, 2H), 2.56 (s, 3H), 2.44 (s, 3H), 2.40 (s, 3H), 1.39 (s, 2H), 1.17–1.08 (m, 8H), 0.75 (t, J = 6.8Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 181.5, 167.9, 145.6, 143.3, 138.9, 135.4, 134.1, 132.4, 129.7 (2C), 129.6 (2C), 128.9 (2C), 128.4 (2C), 127.8 (2C), 126.3 (2C), 32.5, 30.9, 28.8, 27.8, 24.9, 21.9, 21.3, 21.1, 18.7, 13.9; HRMS (ESI-TOF) (m/z). Calcd for C30H37N3O4S2, [M + H]+ 568.2298; found 568.2231.
4-methyl-N-((E)-1-(2-((E)-1-phenylethylidene)-1-tosylhydrazineyl)-2-(thiophen-2-yl)ethylidene)benzenesulfonamide (4m). Yellow solid, mp 67–69 °C. IR (KBr) ν 3062, 2927, 2866, 1590, 1369, 1307, 1153, 1087 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.85 (t, J = 6.8 Hz, 4H), 7.65 (d, J = 9.2 Hz, 3H), 7.48 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.11 (d, J = 7.8 Hz, 3H), 6.86–6.82 (m, 2H), 4.58 (s, 2H), 2.50 (s, 3H), 2.41 (s, 3H), 2.00 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 183.3, 163.9, 145.4, 143.4, 139.2, 135.8, 134.4, 134.2, 132.2, 129.4 (2C), 129.3 (2C), 129.2 (2C), 128.8 (2C), 128.1, 127.9 (2C), 127.1 (2C), 127.0, 125.4, 33.8, 21.9, 21.8, 18.2; HRMS (ESI-TOF) (m/z). Calcd for C28H27N3O4S3, [M + H]+ 565.1237; found 565.1239.
N-(2-phenyl-1-(2-((E)-1-phenylethylidene)-1-tosylhydrazineyl)ethylidene) benzenesulfonamide (4n). White solid, mp 149–151 °C. IR (KBr) ν 3062, 1589, 1561, 1494, 1365, 1282, 1140, 1085 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 6.8 Hz, 3H), 7.70–7.60 (m, 3H), 7.53–7.46 (m, 4H), 7.27–7.20 (m, 5H), 7.02 (d, J = 6.8 Hz, 2H), 4.23 (s, 2H), 2.41 (s, 3H), 1.74 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 182.7, 165.7, 145.6, 141.3, 135.0, 133.9, 133.1, 133.0, 132.4, 129.6, 129.3 (2C), 128.9 (2C), 128.8 (2C), 128.6 (2C), 128.5 (2C), 127.8 (2C), 127.2, 126.4 (3C), 21.2 (2C), 17.7; HRMS (ESI-TOF) (m/z). Calcd for C29H27N3O4S2, [M + H]+ 546.1516; found 546.1519.
4-chloro-N-(2-phenyl-1-(2-((E)-1-phenylethylidene)-1-tosylhydrazineyl) ethylidene)benzenesulfonamide (4o). White solid, mp 141–143 °C. IR (KBr) ν 3067, 1592, 1554, 1493, 1341, 1308, 1146, 1081 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 8.0 Hz, 2H), 7.75 (t, J = 9.6 Hz, 4H), 7.62 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 8.0 Hz, 4H), 7.29–7.20 (m, 5H), 7.02 (t, J = 6.8 Hz, 2H), 4.15 (s, 2H), 2.42 (s, 3H), 1.77 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 182.8, 165.5, 145.7, 140.2, 138.0, 135.0, 134.0, 133.0, 132.4, 129.6 (2C), 129.4 (3C), 128.8, 128.7 (2C), 128.6 (2C), 128.4 (2C), 128.3 (2C), 127.8 (2C), 127.2, 21.2 (2C), 17.8; HRMS (ESI-TOF) (m/z). Calcd for C29H26ClN3O4S2, [M + H]+ 580.1126; found 580.1128.
4-bromo-N-(2-phenyl-1-(2-((E)-1-phenylethylidene)-1-tosylhydrazineyl) ethylidene)benzenesulfonamide (4p). White solid, mp 139–140 °C. IR (KBr) ν 3066, 1594, 1554, 1493, 1374, 1309, 1145, 1083 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 8.4 Hz, 2H), 7.83 (t, J = 7.6 Hz, 2H), 7.68 (t, J = 7.6 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.53–7.49 (m, 4H), 7.29–7.20 (m, 5H), 7.01 (t, J = 7.2 Hz, 2H), 4.23 (s, 2H), 2.42 (s, 3H), 1.76 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 182.8, 165.5, 145.7, 140.6, 135.0, 134.0, 133.0, 132.4 (3C), 129.6 (2C), 128.8 (4C), 128.7 (2C), 128.4 (3C), 128.3 (2C), 127.2 (2C), 127.0, 21.2 (2C), 17.8; HRMS (ESI-TOF) (m/z). Calcd for C29H26BrN3O4S2, [M + H]+ 624.0621; found 624.0622.
4-methoxy-N-(2-phenyl-1-(2-((E)-1-phenylethylidene)-1-tosylhydrazineyl) ethylidene)benzenesulfonamide (4q). White solid, mp 143–145 °C. IR (KBr) ν 3010, 1592, 1561, 1492, 1367, 1296, 1144, 1082 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J = 7.6 Hz, 2H), 7.69 (t, J = 8.4 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 8.0 Hz, 4H), 7.29 (d, J = 8.0 Hz, 2H), 7.24–7.17 (m, 5H), 7.01 (d, J = 6.8 Hz, 2H), 4.24 (s, 2H), 3.92 (s, 3H), 2.42 (s, 3H), 1.73 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 183.0, 165.4, 163.1, 146.0, 135.5, 134.4, 133.6, 132.7, 130.0, 129.3 (2C), 129.2 (3C), 129.1 (4C), 129.0 (2C), 128.9 (2C), 128.2 (2C), 127.5, 114.8, 56.3, 21.7 (2C), 18.1; HRMS (ESI-TOF) (m/z). Calcd for C30H29N3O5S2, [M + H]+ 576.1622; found 576.1621.
1-phenyl-N-(2-phenyl-1-(2-((E)-1-phenylethylidene)-1-tosylhydrazineyl) ethylidene)methanesulfonamide (4r). White solid, mp 125–127 °C. IR (KBr) ν 3063, 2972, 1590, 1576, 1493, 1365, 1293, 1173, 1086 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 7.85–7.79 (m, 4H), 7.62 (t, J = 7.2 Hz, 1H), 7.56–7.50 (m, 4H), 7.21 (t, J = 6.8 Hz, 3H), 7.01 (d, J = 7.2 Hz, 2H), 4.18 (s, 2H), 3.04(t, J = 7.6 Hz, 2H), 2.46 (s, 3H), 1.75 (s, 3H), 1.69 (s, 2H), 1.02 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 182.5, 165.5, 145.7, 135.1, 134.6, 133.1, 132.3, 129.9 (3C), 128.9 (2C), 128.8 (3C), 128.6 (2C), 128.3 (3C), 127.8 (3C), 127.1, 56.0 (2C), 21.2, 17.6, 16.8, 12.6; HRMS (ESI-TOF) (m/z). Calcd for C30H29N3O4S2, [M + H]+ 560.1672; found 560.1676.

4. Conclusions

We developed an effective copper-catalyzed three-component one-pot synthesis of N-sulfonyl amidines from terminal alkynes, sulfonyl azides and weak nucleophilic sulfonyl hydrazine. The synthetic pathway extended the applications of the CuAAC/ring-opening reaction, and we expect that this methodology and N-sulfonyl amidines products could be applied to organic synthesis.

Supplementary Materials

The following are available online, The original 1H and 13C NMR spectra are available in supplementary material.

Author Contributions

Conceptualization, methodology and supervision W.Y.; experiment, Y.Z., Z.Z. and M.C.; spectroscopic characterization Y.Z. and Z.Z. and writing—review and editing, Y.Z., Z.Z., M.C. and W.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Applied and Basic Research Fund of Guangdong Province (2019A1515110918), the Medical Scientific Research Foundation of Guangdong Province (A2020202 and A2021037), the Science and Technology Planning Program of Zhanjiang (2019A01018) for support and the funds provided, in 2019, for the PhD-level researchers of Guangdong Medical University.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data is contained within the article.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 4a–4r are available from the authors.

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Molecules 26 03700 g001 550
Figure 1. Part of the sulfonyl amidine drug candidates.
Figure 1. Part of the sulfonyl amidine drug candidates.
Molecules 26 03700 g001
Molecules 26 03700 sch001 550
Scheme 1. Copper-catalyzed tandem reactions of the terminal alkynes, sulfonyl azides and amines.
Scheme 1. Copper-catalyzed tandem reactions of the terminal alkynes, sulfonyl azides and amines.
Molecules 26 03700 sch001
Molecules 26 03700 sch002 550
Scheme 2. The synthesis of products 4a–4r.
Scheme 2. The synthesis of products 4a–4r.
Molecules 26 03700 sch002
Molecules 26 03700 g002 550
Figure 2. X-ray crystal structure of compound 4a.
Figure 2. X-ray crystal structure of compound 4a.
Molecules 26 03700 g002
Molecules 26 03700 g003 550
Figure 3. The stability of product 4a tested by a HNMR spectrometer.
Figure 3. The stability of product 4a tested by a HNMR spectrometer.
Molecules 26 03700 g003
Table
Table 1. Optimization of the catalytic conditions a.
Table 1. Optimization of the catalytic conditions a.
Molecules 26 03700 i001
EntryCat.
(10 mol%)		Base
(10 mol%)		Solvent
(10 mol%)		Temp.
(°C)		Time
(h)		Yield
(%) b
entry 1CuIEt3NCH2Cl2rt1.078
entry 2CuBrEt3NCH2Cl2rt1.076
entry 3CuClEt3NCH2Cl2rt1.072
entry 4CuBr2Et3NCH2Cl2rt1.064
entry 5Cu(OAc)2Et3NCH2Cl2rt1.052
entry 6Cu(OTf)2Et3NCH2Cl2rt1.021
entry 7AgTFAEt3NCH2Cl2rt1.00
entry 8CuIDMAPCH2Cl2rt1.026
entry 9CuIDIPEACH2Cl2rt1.075
entry 10CuIPyridineCH2Cl2rt1.032
entry 11CuIt-BuONaCH2Cl2rt1.010
entry 12CuIK2CO3CH2Cl2rt1.08
entry 13CuIEt3NCHCl3rt1.076
entry 14CuIEt3NDCErt1.075
entry 15CuIEt3NToluenert1.084
entry 16CuIEt3NMeCNrt1.052
entry 17CuIEt3NTHFrt1.080
entry 18CuIEt3NDMSOrt1.010
entry 19CuIEt3NDMFrt1.06
entry 20CuIEt3NToluene401.075
entry 21CuIEt3NToluenert0.580
entry 22CuIEt3NToluenert2.084
entry 23CuIEt3NToluenert3.084
a Reaction conditions: To 1a (0.5 mmol), Cat. 10 mol%, base 1.2 eq. in the solvent (3 mL) was added 2a (1.2 eq.) and 3a (1.2 eq.), stirred at specified temperatures and times. b Isolated yields.
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Zhao, Y.; Zhou, Z.; Chen, M.; Yang, W. Copper-Catalyzed One-Pot Synthesis of N-Sulfonyl Amidines from Sulfonyl Hydrazine, Terminal Alkynes and Sulfonyl Azides. Molecules 2021, 26, 3700. https://doi.org/10.3390/molecules26123700

AMA Style

Zhao Y, Zhou Z, Chen M, Yang W. Copper-Catalyzed One-Pot Synthesis of N-Sulfonyl Amidines from Sulfonyl Hydrazine, Terminal Alkynes and Sulfonyl Azides. Molecules. 2021; 26(12):3700. https://doi.org/10.3390/molecules26123700

Chicago/Turabian Style

Zhao, Yu, Zitong Zhou, Man Chen, and Weiguang Yang. 2021. "Copper-Catalyzed One-Pot Synthesis of N-Sulfonyl Amidines from Sulfonyl Hydrazine, Terminal Alkynes and Sulfonyl Azides" Molecules 26, no. 12: 3700. https://doi.org/10.3390/molecules26123700

APA Style

Zhao, Y., Zhou, Z., Chen, M., & Yang, W. (2021). Copper-Catalyzed One-Pot Synthesis of N-Sulfonyl Amidines from Sulfonyl Hydrazine, Terminal Alkynes and Sulfonyl Azides. Molecules, 26(12), 3700. https://doi.org/10.3390/molecules26123700

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