electron de-tosylation

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A cascade trisulfur radical anion (S3•-) addition / electron de-tosylation 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., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01450 • Publication Date (Web): 17 Jul 2018 Downloaded from http://pubs.acs.org on July 17, 2018

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The Journal of Organic Chemistry

A cascade trisulfur radical anion (S3•−) addition / electron de-tosylation 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* 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. Trisulfur radical anion (S3•−) mediated reactions with in situ formed azoalkenes and α,βusaturated 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 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 de-tosylation under mild conditions. KEYWORDS: Trisulfur radical anion (S3•−); 1,2,3-thiadiazole, isothiazole, de-tosylation 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, pharmacological activity molecules. Fungicides and pesticide candidates including this scaffold (Fig. 1).1 In addition, 1,2,3-thiadiazoles decomposed into thioketenes

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in the presence of base, which could be exploited as intermediates for the construction of benzothiazoles, indols, and benzofurans.2

Figure 1. Representative bioactive 1,2,3-thiadiazole and isothiazole derivatives. The sulfonyl group plays comprehensive applications in organic chemistry, popular as a good leaving group in amines,3 and in sulfones.4 Further along the synthetic route can more susceptible to undergo nucleophilic substitution and elimination to olefin production.5 Tuttle group developed using neutral organic Super-Electron-Donor (S.E.D.) reagent reductive cleavage of sulfones and sulfonamides (Scheme 1a).6 In 2014, Zhao et al. reported a radical cascade cycloaddition-desulfonylation processes with N-Ts-2-alkynylaniline derivatives (Scheme 1b).7 Recently, inodine-catalyzed and flaviniodinecatalyzed transannulation of N-tosylhydrazones with sulfur have been reported to give 1,2,3thiadiazoles (Scheme 1c).8 Various approaches for the preparation of thiadiazoles were supplied, yet electron-catalytic radical cascade cycloaddition-desulfonylation processes still is an enormous challenge. Scheme 1. Reactions Toward De-tosylation Process.

Azoalkenes generated in situ from α-halogeno hydrazones have been 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-halogeno hydrazones to construct different substituented 1,2,3-triazoles.15a 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’s still great challenges to develop new reactions involving trisulfur radical anion and electron catalysis. Herein, we report a cascade S3•− addition / electron de-tosylation process for the synthesis of 4-subsituted1,2,3-thiadiazoles, 5-subsituted 1,2,3-thiadiazoles and isothiazole. S3•− is in situ ACS Paragon Plus Environment

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generated from potassium sulfide in DMF with electron releasing 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-1-phenylethylidene)-4-

methylbenzenesulfonohydrazide 3a with K2S and base K2CO3 at 100 oC in DMF. Fortunately, 4-pheyl1,2,3-thiadiazole 5a was observed in 52% yield (Table 1, entry 1). The yield of 5a was decresed without base (Table 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 do not effectively improve the yields (entries 8-9). Decreasing of the reaction temperature from 100 oC to 80 oC, 5a was obtained 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 the temperature from 100 oC to 130 oC and reduce the amount of K2CO3 by half provided 5a in 66% yield (entry 13). Based on the above results, the combination of 0.3 mmol 3a, 0.6 mmol 4a, and 0.15 mmol K2CO3 in 1.5 mL DMF was identified as the optimal reaction conditions. Table 1. Optimization of The Reaction Conditionsa

entry

base

time

solvent

yieldb (%)

1

K2CO3

1.5 h

DMF

52

2

-

10 min

DMF

43

3

DIPEA

1h

DMF

41

4

Cs2CO3

7 min

DMF

42

5

Li2CO3

1h

DMF

59

6

K2CO3

10 min

toluene

0

7

K2CO3

0.5 h

DMSO

48

8c

K2CO3

1.5 h

DMF

52

9

d

K2CO3

10 min

DMF

55

e

K2CO3

1h

DMF

43

f

K2CO3

17 min

DMF

53

12

g

S+KOH

0.5 h

DMF

messy

13

h

K2CO3

0.5 h

DMF

66

10

11

a

Reaction conditions: 3a (0.3 mmol), 4a Sulfur reagent (K2S, 0.6 mmol), base (0.3 mmol) and solvent (1.5mL) at 100 oC.

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 oC. fTemperature = 80 oC. gSulfur reagent (S, 0.9 mmol), base (KOH, 0.15 mmol). hBase (K2CO3, 0.15 mmol), 130 oC.


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Since the α-chlorosulfonohydrazides 3 could be simply generated in the reaction with αchloroketones and p-toluenesulfonhydrazide by removing the solvent, we employed a simply 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 for 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 oC for half an 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 α-chloroketones 1 were applied to the reaction with 2a under the 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-positions of the aryl ring were well tolerated, furnishing the desired products 5e-5g in 49% to 68% yields. Unfortunately, the reaction of 2-chloro-1-(3,4dihydroxyphenyl)ethan-1-one 1m and 2-chloro-1-(4-nitrophenyl)ethan-1-one 1n failed to give the desired products under the optimized conditions. Table 2. Substrate Scope of Reactiona


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1 (0.3 mmol) and 2a (0.3 mmol) was performed in 1mL Et2O at room temperature for 12h. Then removing the solvent, base

(K2CO3 0.15 mmol), K2S (0.6 mmol) and DMF (1.5mL) were added at room temperature. The mixture was stirred at 130 oC for 0.5 h. Isolated yield.

Subsequently, we explored the reactions with various α-tosylhydrazones derived from αchloroaldehydes. In view of α-chloroaldehydes were easily oxidized, we directly isolated the αtosylhydrazonesaldehydes and applied them to the next reaction (Table 3). α-Tosylhydrazones derived from α-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-chloro2-phenylethylidene)-4-methylbenzenesulfonohydrazide 3r progressed well and gave the corresponding product 5r in 60% yield. Table 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 (1.5mL)

were added at room temperature. The mixture was stirred at 130 oC for 0.5 h. Isolated yield.

While cascade S3•− addition / electron de-tosylation reaction of in situ formed azoalkenes affords 1,2,3-thiadiazoles, we reason that similar cascade S3•− addition / electron de-tosylation reaction of α,βusaturated N-sulfonylimines can furnish isothiazole (Table 4). To our delight, the reaction of 6a with K2S afforded isothiazole 7a in 51% yield under the 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 group, halide and nitrile groups at the para positions of the aryl ring on the substituted allylidenes were also compatible. While allylidenes containing thiophene motif is subjected to the reaction condition (7h). Table 4. Substrate Scope of Reactiona


5


a

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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 oC for 0.5 h. Isolated yield.

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. Further study the application of this method in the synthesis of 1,2,3-thiadiazoles, we prepared the medicine intermediate15b 1q and applied it to the reaction under the optimized conditions. The reaction of 1q underwent smoothly to furnish the desired compound 5q in 51% yield (Scheme 3). Scheme 2. Gram Scale Experiment.

Scheme 3. The Reaction of 1q and K2S.

To gain more insights into the mechanism, a controlled experiment was conducted. When 2,2,4,4tetramethyl-1-piperidinyloxy (TEMPO, 5 equiv) was added to the standard reaction (scheme 4), it was found that the process was inhibited. Electron Spin Resonance (ESR) was carried out (See supporting information for details). Gratifyingly, a strong single peak located at g =2.02882 was observed. This


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result indicate that this reaction might undergoes via radical processes, which is match with our previous work.16 Scheme 4. The Radical-trapping Experiment.

According to the above results and reported literatures, 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 αhalogeno hydrazine 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 S-S bond and formation of N-S bond provides intermediate D and S2•−, which can be further transformed to S3•− and continue to participate in the reaction.18 After electron de-tosylation of D with the cleavage of the S-N bond by electron reductive transfer,19 the intermediate E is formed. Subsequently, go through aromatization of E furnishs the desired product 5. Alternatively, in process II, α,β-usaturated N-sulfonylimines undergoes the similar reaction process to afford different functionalized isothiazoles 7. Scheme 5. A Plausible Mechanism.

e-

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In conclusion, we have developed a simple and facile method for the synthesis of 4-substituented and 5-substituented 1,2,3-thiadiazole from in situ-generated azoalkenes with S3•− via cascade trisulfur radical anion addition and electron de-tosylation process. Our strategy employs mild conditions and avoids the employment of diazo group and thionylchloride. Not only the aromaticity substrates are suitable for the process, the aliphatic substrates can also work well. Studies on 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 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 of 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) spectrumeter using CDCl3 as solvent and TMS as internal standard. High-resolution mass spectra were obtained using BRUKER micrOTOF-Q III instrument with ESI source. ESR spectra were detected by JES-X320 electron spinresonance instrument. Typical procedure for the construction of chlorination of ketones 1:(according to the literature:20): 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 (3x10 mL). The combined organic layers were dried over MgSO4 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 literature:21): Chlorination of ketones 1 (0.3 mmol) and p-TsNHNH2 2a (0.3 mmol) was performed in 1mL 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 literature:22): To a solution of enone (4.8 mmol) and p-toluenesulfonamide (820 mg, 4.8 mmol) in dry dichloromethane (60 mL) at 0 ºC under nitrogen atmosphere, was added via syringe Et3N (1.5 mL, 1.07 g, 10.6 mmol) 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 (3x50 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) to afford 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 crud 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 oC 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) was added to a tube. The mixture was stirred at 130 oC 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) was added to a tube. The mixture was stirred at 130 oC 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.


8

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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 cm1 1 . H 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. 1H 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 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, Chloroform-d) 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, Chloroform-d) 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). 13C 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). 13C 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, 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 =


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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. 1 H 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, 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.

ASSOCIATED CONTENT Supporting Information Available. The copies of 1H and 13C NMR spectra of the products. This material is available free of charge via the Internet at http://pubs.acs.org. 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 ACS Paragon Plus Environment

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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 result of 5a, 5g, 5p, 7b, and 7d.

REFERENCES (1) (a) Dong, W.-L.; Liu, Z.-X.; Liu, X.-H.; Li, Z.-M.; Zhao, W.-G. Synthesis and antiviral activity of new acrylamide derivatives containing 1,2,3-thiadiazole as inhibitors of hepatitis B virus replication. Eur. J. Med. Chem. 2010, 45, 1919–1926. (b) Zhan, P.; Liu, X.; Fang, Z.; Li, Z.; Pannecouque, C.; Clercq, E. D. Synthesis and anti-HIV activity evaluation of 2-(4-(naphthalen-2-yl)-1,2,3-thiadiazol-5-ylthio)-N-acetamides as novel non-nucleoside HIV-1 reverse transcriptase inhibitors. Eur. J. Med. Chem. 2009, 44, 4648–4653. (c) Abdel-Magid, A. F. Therapeutic potential of GPR120 agonists for the treatment of type 2 diabetes. ACS Med. Chem. Lett. 2015, 6, 1097–1098. (2) (a) Lyapunova, A. G.; Androsov, D. A.; Petrov, M. L. A convenient synthesis of benzo[b]chalcogenophenes from 4-(2-chloro-5-nitrophenyl)-1,2,3-chalcogenadiazoles. Tetrahedron Lett. 2013, 54, 3427–3430. (b) Androsov, D. A. Synthesis of 1,1-dialkylindolium-2-thiolates via base-induced transformation of 4-(2-Chloro-5-nitrophenyl)-1,2,3thiadiazole in the presence of secondary amines. J. Org. Chem. 2008, 73, 8612–8614. (c) Androsov, D. A.; Neckers, D. C. Synthesis and reactivity of 4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole. A novel one-pot synthesis of N-substituted indole-2-thiols. J. Org. Chem. 2007, 72, 5368–5373. (d) Teplyakov, F. S.; Vasileva, T. G.; Petrov, M. L.; Androsov, D. A. A new synthesis of benzo[b]thiophene-2-thiolates and their derivatives via base-promoted transformation of 4-(2-Mercaptophenyl)-1,2,3-thiadiazoles. Org. Lett. 2013, 15, 4038–4041. (e) Xu, F.; Chen, Y.; Fan, E.; Sun, Z. Synthesis of 3-substituted aryl[4,5]isothiazoles through an all-heteroatom wittig-equivalent process. Org. Lett. 2016, 18, 2777–2779. (f) Shukla, G.; Srivastava, A.; Singh, M. S. Metal- and catalyst-free, formal [4+1] annulation via tandem C=O/C=S functionalization: One-pot access to 3,5-disubstituted/annulated isothiazoles. Org. Lett. 2016, 18, 2451–2454. (3) Klimczak, U. K.; Zambroń, B. K. Effective 1,5-stereocontrol in Pd(0)/InI promoted reactions of chiral N-Ts-4vinylazetidin-2-ones with aldehydes. An efficient entry into nonracemic semi-protected (3Z)-2,6-anti-enediols. Chem. Commun. 2015, 51, 6796–6799. (4) (a) Magnus, P. D. Recent developments in sulfone chemistry. Tetrahedron 1977, 33, 2019–2045. (b) Rong, J.; Deng, L.; Tan, P.; Ni, C.-F.; Gu, Y.-C.; Hu, J.-B. Radical fluoroalkylation of isocyanides with fluorinated sulfones by visible-light photoredox catalysis. Angew. Chem., Int. Ed. 2016, 55, 2743–2747. (5) (a) Sumino, S.-H.; Uno, M.; Huang, H.-J.; Wu, Y.-K.; Ryu, I. Palladium/Light induced radical alkenylation and allylation of alkyl iodides using alkenyl and allylic sulfones. Org. Lett. 2018, 20, 1078–1081. (b) Siddiki, S. M. A.


11


Page 12 of 14

H.; Touchy, A. S.; Kon, K.; Shimizu, K. Direct olefination of alcohols with sulfones by using heterogeneous platinum catalysts. Chem. Eur. J. 2016, 22, 6111–6119. (c) Pandey, G.; Vaitla, J. Desulfonylative methenylation of β-keto sulfones. Org. Lett. 2015, 17, 4890–4893. (d) Kan, T.; Fukuyama, T. Ns strategies: a highly versatile synthetic method for amines. Chem. Commun. 2004, 0, 353–359. (e) Fukuyama, T.; Jow, C. K.; Cheung, M. 2- and 4-Nitrobenzenesulfonamides: Exceptionally versatile means for preparation of secondary amines and protection of amines. Tetrahedron Lett. 1995, 36, 6373–6374. (f) Bamford, W. R.; Stevens, T. S. 924. The decomposition of toluene-p-sulphonylhydrazones by alkali. J. Chem. Soc. 1952, 0, 4735–4740. (g) Sakai, K.; Hida, N.; Kondo, K. Reactions of α-polyhalo ketone tosylhydrazones with sulfide ion and primary amines. Cyclization to 1,2,3thiadiazoles and 1,2,3-triazoles. Bull. Chem. Soc. Jpn. 1986, 59, 179–183. (6) (a) Schoenebeck, F.; Murphy, J. A.; Zhou, S.-Z.; Uenoyama, Y.; Miclo, Y.; Tuttle, T. Reductive cleavage of sulfones and sulfonamides by a neutral organic super-electron-donor (S.E.D.) reagent. J. Am. Chem. Soc. 2007, 129, 13368–13369. (b) O’Sullivan, S.; Doni, E.; Tuttle, T.; Murphy, J. A. Metal-free reductive cleavage of C-N and S-N bonds by photoactivated electron transfer from a neutral organic donor. Angew. Chem., Int. Ed. 2014, 53, 474–478. (7)

Gao,

Y.-Z.;

Lu,

G.-Z.;

Zhang,

P-B.;

Zhang,

L.-L.;

Tang,

G.;

Zhao,

Y.-F.

A

cascade

phosphinoylation/cyclization/desulfonylation process for the synthesis of 3-Phosphinoylindoles. Org. Lett. 2016, 18, 1242–1245. (8) (a) Chen, J.-F.; Jiang, Y.; Yu, J.-T.; Cheng, J. TBAI-catalyzed reaction between N-Tosylhydrazones and sulfur: A procedure toward 1,2,3-thiadiazole. J. Org. Chem. 2016, 81, 271–275. (b) Ishikawa, T.; Kimura, M.; Kumoi, T.; Iida, H. Coupled flavin-iodine redox organocatalysts: Aerobic oxidative transformation from N-Tosylhydrazones to 1,2,3-thiadiazoles. ACS Catal. 2017, 7, 4986–4989. (9) Miles, D. H.; Guasch, J.; Toste, F. D. A nucleophilic strategy for enantioselective intermolecular α-amination: Access to enantioenriched α-arylamino ketones. J. Am. Chem. Soc. 2015, 137, 7632–7635. (10) Hatcher, J. M.; Coltart, D. M. Copper(I)-catalyzed addition of grignard reagents to in situ-derived N-sulfonyl azoalkenes: An umpolung alkylation procedure applicable to the formation of up to three contiguous quaternary centers. J. Am. Chem. Soc. 2010, 132, 4546–4547. (11) (a) Attanasi, O. A.; Crescentini, L. D.; Favi, G.; Mantellini, F.; Mantenuto, S.; Nicolini, S. Interceptive [4+1] annulation of in situ generated 1,2-diaza-1,3-dienes with diazo dsters: Direct access to substituted mono-, bi-, and tricyclic 4,5-dihydropyrazoles. J. Org. Chem. 2014, 79, 8331–8338. (b) Chen, J.-R.; Dong, W.-R.; Candy, M.; Pan, F.-F.; Jçrres, M.; Bolm, C. Enantioselective synthesis of dihydropyrazoles by formal [4+1] cycloaddition of in situderived azoalkenes and sulfur ylides. J. Am. Chem. Soc. 2012, 134, 6924–6927. (c) Guo, C.; Sahoo, B.; Daniliuc, C. G.; Glorius, F. N-Heterocyclic carbene catalyzed switchable reactions of enals with azoalkenes: Formal [4+3] and


12

Page 13 of 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry [4+1] annulations for the synthesis of 1,2-diazepines and pyrazoles. J. Am. Chem. Soc. 2014, 136, 17402–17405. (d) Tong, M.-C.; Chen, X.; Li, J.; Huang, R.; Tai, H.-Y.; Wang, C.-J. Catalytic asymmetric synthesis of [2,3]-fused indoline heterocyclesthrough inverse-electron-demand aza-diels–alder reaction ofIndoles with azoalkenes. Angew. Chem., Int. Ed. 2014, 53, 4680–4684; Angew. Chem. 2014, 126, 4768–4772. (e) Zhong, X.-R.; Lv, J.; Luo, S.-Z. Org. Lett. 2015, 17, 1561–1564. (f) Wei, L.; Wang, C.-J. The catalytic asymmetric synthesis of tetrahydropyridazines via inverse electron-demand aza-diels–alder reaction of enol ethers with azoalkenes. Chem. Commun. 2015, 51, 15374–15377. (g) Hu, X.-Q.; Chen, J.-R.; Gao, S.; Feng, B.; Lu, L.-Q.; Xiao, W.-J. [4+3] Cycloaddition of in situ generated azoalkenes with C,N-cyclic azomethine imines: efficient synthesis of tetrazepine derivatives. Chem. Commun. 2013, 49, 7905–7907. (h) Huang, R.; Chang, X.; Li, J.; Wang, C.-J. Cu(I)-catalyzed asymmetric multicomponent cascade inverse electron-demand aza-Diels–Alder/nucleophilic addition/ring-opening reaction involving 2-methoxyfurans as efficient dienophiles. J. Am. Chem. Soc. 2016, 138, 3998–4001.

(12) Li, J.; Huang, R.; Xing, Y.-K.; Qiu, G.-F.; Tao, H.-Y.; Wang, C.-J. Catalytic asymmetric cascade vinylogous mukaiyama 1,6-Michael/Michael addition of 2-silyloxyfurans with azoalkenes: Direct approach to fused butyrolactones. J. Am. Chem. Soc. 2015, 137, 10124–10127. (13) Zhu, T.-H.; Wei, T.-Q.; Wang, S.-Y.; Ji, S.-J. NIS/CHP-mediated reaction of isocyanides with hydrazones: access to aminopyrazoles. Org. Chem. Front. 2015, 2, 259–264. (14) Cai, Z.-J.; Lu, X.-M.; Zi, Y., Yang, C.; Shen, L.-J.; Li, J.; Wang, S.-Y.; Ji, S.-J. I2/TBPB mediated oxidative reaction of N-Tosylhydrazones with anilines: Practical construction of 1,4-disubstituted 1,2,3-triazoles under metalfree and azide-free conditions. Org. Lett. 2014, 16, 5108–5111. (15) (a) Bai, H.-W.; Cai, Z.-J.; Wang, S.-Y.; Ji, S.-J. Aerobic oxidative cycloaddition of α-chlorotosylhydrazones with arylamines: General chemoselective construction of 1,4-disubstituted and 1,5-disubstituted 1,2,3-triazoles under metal-free and azide-free conditions. Org. Lett. 2015, 17, 2898–2901. (b) Link, J. O.; Taylor, J. G.; Xu, L.; Mitchell, M.; Guo, H.; Liu, H.; Kato, D.; Kirschberg, T.; Sun, J.; Squires, N.; Parrish, J.; Keller, T.; Yang, Z.-Y.; Yang, C.; Matles, M.; Wang, Y.; Wang, K.; Cheng, G.; Tian, Y.; Mogalian, E.; Mondou, E.; Cornpropst, M.; Perry, J.; Desai, M. C. Discovery of ledipasvir (GS-5885): A potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection. J. Med. Chem. 2014, 57, 2033–2046. (16) Gu, Z.-Y.; Cao, J.-J.; Wang, S.-Y.; Ji, S.-J. The involvement of the trisulfur radical anion in electron-catalyzed sulfur insertion reactions: facile synthesis of benzothiazine derivatives under transition metal-free conditions. Chem. Sci. 2016, 7, 4067–4072. (17) (a) Shields, T. C.; Kurtz, A. N. Active sulfuration of norbornenes. J. Am. Chem. Soc. 1969, 91, 5415–5416. (b) Chivers, T.; Elder, P. J. W. Ubiquitous trisulfur radical anion: fundamentals and applications in materials science,


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electrochemistry, analytical chemistry and geochemistry. Chem. Soc. Rev. 2013, 42, 5996–6005. (c) Chivers, T. Ubiquitous trisulphur radical ion S3−·. Nature 1974, 252, 32–33. (18) (a) Zhang, G.; Yi, H.; Chen, H.; Bian, C.; Liu, C.; Lei, A. Trisulfur radical anion as the key intermediate for the synthesis of thiophene via the interaction between elemental sulfur and NaOtBu. Org. Lett. 2014, 16, 6156–6159. (b) Studer, A.; Curran, D. P. The electron is a catalyst. Nat. Chem. 2014, 6, 765–773. (c) Gaillard, F.; Levillain, E.; Lelieur, J. P. Polysulfides in dimethylformamide: Only the radical anions S3− and S4− are reducible. J. Electroanal. Chem. 1997, 432, 129–138. (d) Wu, H.-L.; Huff, L. A.; Gewirth, A. A. In situ raman spectroscopy of sulfur speciation in lithium–sulfur batteries. ACS Appl. Mater. Interfaces 2015, 7, 1709–1719. (19) O'Sullivan, S.; Doni, E.; Tuttle, T.; Murphy, J. A. Metal-free reductive cleavage of C-N and S-N bonds by photoactivated electron transfer from a neutral organic donor. Angew. Chem., Int. Ed. 2014, 53, 474–478. (20) (a) Pravst, I.; Zupan, M.; Stavber, S. Halogenation of ketones with N-halosuccinimides under solvent-free reaction conditions. Tetrahedron 2008, 64, 5191–5199. (b) Szymanski, W.; Postema, C. P.; Tarabiono, C.; Berthiol, F.; Campbell-Verduyn, L.; Wildeman, S. de.; Vries, J. G. de.; Feringa, B. L.; Janssen, D. B. Combining designer cells and click chemistry for a one-pot four-step preparation of enantiopure β-hydroxytriazoles. Adv. Synth. Catal. 2010, 352, 2111–2115. (21) Hatcher, J. M.; Coltart, D. M. Copper(I)-catalyzed addition of grignard reagents to in situ-derived N-sulfonyl azoalkenes: An umpolung alkylation procedure applicable to the formation of up to three contiguous quaternary centers. J. Am. Chem. Soc. 2010, 132, 4546–4547. (22) Espinosa, M.; Blay, G.; Cardona, L.; Pedro, J. R. Asymmetric conjugate addition of malonate esters to α,βunsaturated N-sulfonyl imines: An expeditious route to chiral δ-aminoesters and piperidones. Chem. Eur. J. 2013, 19, 14861–14866.


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electron de-tosylation

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