Cascade Trisulfur Radical Anion (S3?-) Addition/Electron Detosylation Process for the Synthesis of 1,2,3-Thiadiazoles and Isothiazoles

Article abstract of DOI:10.1021/acs.joc.8b01450

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

Full text of DOI:10.1021/acs.joc.8b01450

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Article
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
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A cascade trisulfur radical anion (S3 ) addition / electron deꢀtosylation process for
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the synthesis of 1,2,3ꢀthiadiazoles and isothiazoles
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BeiꢀBei Liu, HuiꢀWen Bai, Huan Liu, ShunꢀYi Wang,* and ShunꢀJun Ji*
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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; Eꢀmail: shunyi@suda.edu.cn; shunjun@suda.edu.cn
RECEIVED DATE
*CORRESPONDING AUTHOR FAX: 86ꢀ512ꢀ65880307.
•−
ABSTRACT. Trisulfur radical anion (S3 ) mediated reactions with in situ formed azoalkenes and α,βꢀ
usaturated Nꢀsulfonylimines for the construction of 1,2,3ꢀthiadiazoles 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 4ꢀsubsituted 1,2,3ꢀthiadiazoles, 5ꢀsubsituted 1,2,3ꢀthiadiazoles and
•−
isothiazole in good yields. The reactions include the formation of the new CꢀS and NꢀS bonds via S3
addition and electron deꢀtosylation under mild conditions.
•−
KEYWORDS: Trisulfur radical anion (S3 ); 1,2,3ꢀthiadiazole, isothiazole, deꢀtosylation
1. INTRODUCTION
Heterocycles, such as 1,2,3ꢀthiadiazoles 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, 1,2,3ꢀthiadiazoles 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
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Figure 1. Representative bioactive 1,2,3ꢀthiadiazole 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 SuperꢀElectronꢀDonor (S.E.D.) reagent reductive cleavage of sulfones and sulfonamides
(Scheme 1a).6 In 2014, Zhao et al. reported a radical cascade cycloadditionꢀdesulfonylation processes
with NꢀTsꢀ2ꢀalkynylaniline derivatives (Scheme 1b).7 Recently, inodineꢀcatalyzed and flavinꢀ
iodinecatalyzed transannulation of Nꢀtosylhydrazones with sulfur have been reported to give 1,2,3ꢀ
thiadiazoles (Scheme 1c).8 Various approaches for the preparation of thiadiazoles were supplied, yet
electronꢀcatalytic radical cascade cycloadditionꢀdesulfonylation processes still is an enormous challenge.
Scheme 1. Reactions Toward Deꢀtosylation Process.
Azoalkenes generated in situ from αꢀhalogeno hydrazones have been normally played an important
role in the synthesis of a variety of Nꢀcontaining heterocyclic compounds.9ꢀ14 Recently, we reported the
reaction of arylamines and αꢀhalogeno hydrazones to construct different substituented 1,2,3ꢀtriazoles.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.16ꢀ17 It’s still great challenges to develop new reactions involving trisulfur radical anion and
•−
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electron catalysis. Herein, we report a cascade S3 addition / electron deꢀtosylation process for the
synthesis of 4ꢀsubsituted1,2,3ꢀthiadiazoles, 5ꢀsubsituted 1,2,3ꢀthiadiazoles and isothiazole. S3•− is in situ
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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 CꢀS and NꢀS bonds under transition metalꢀfree conditions.
2. RESULTS AND DISCUSSION
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Initially,
we
investigated
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reaction
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N'ꢀ(2ꢀchloroꢀ1ꢀphenylethylidene)ꢀ4ꢀ
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methylbenzenesulfonohydrazide 3a with K2S and base K2CO3 at 100 C in DMF. Fortunately, 4ꢀpheylꢀ
1,2,3ꢀthiadiazole 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 3ꢀ5). 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 6ꢀ7). Reducing or raising the amount of base do not effectively improve the
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yields (entries 8ꢀ9). Decreasing of the reaction temperature from 100 C to 80 C, 5a was obtained
similar yield with a longer time (entries 10ꢀ11). Unfortunately, the reaction system was messy when
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sulfur reagent was changed to S8 (entry 12). Gratifyingly, rising the temperature from 100 C to 130 C
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
1
base
K2CO3
ꢀ
time
1.5 h
10 min
1 h
solvent
DMF
DMF
DMF
DMF
DMF
toluene
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
yieldb (%)
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3
DIPEA
Cs2CO3
Li2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
S+KOH
K2CO3
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7 min
1 h
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10 min
0.5 h
1.5 h
10 min
1 h
0
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8c
9d
10e
11f
12g
13h
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17 min
0.5 h
0.5 h
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messy
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aReaction conditions: 3a (0.3 mmol), 4a Sulfur reagent (K2S, 0.6 mmol), base (0.3 mmol) and solvent (1.5mL) at 100 C.
o
b
The time of the reaction was monitored by TLC. Yields 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 αꢀchlorosulfonohydrazides 3 could be simply generated in the reaction with αꢀ
chloroketones and pꢀtoluenesulfonhydrazide by removing the solvent, we employed a simply oneꢀpot
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
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were added and the mixture was stirred at 130 C for half an hour. To our delight, 5a was isolated in
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65% yield, which is similar to the 66% yield of the twoꢀstep reaction. With this promising result in hand,
variously substituted αꢀchloroketones 1 were applied to the reaction with 2a under the identical
conditions (Table 2). Various electronꢀdonating groups (ꢀMe, ꢀC(CH3)3, ꢀOMe) at the aryl ring were
tolerated, but the yield of the product decreased to 40% when the electronꢀdonating group ꢀOMe was
employed. Next, we examined different halogen substituents on the aryl ring. The halogen groups (ꢀF, ꢀ
Cl, ꢀBr) at the orthoꢀ, paraꢀ and metaꢀpositions of the aryl ring were well tolerated, furnishing the
desired products 5eꢀ5g in 49% to 68% yields. Unfortunately, the reaction of 2ꢀchloroꢀ1ꢀ(3,4ꢀ
dihydroxyphenyl)ethanꢀ1ꢀone 1m and 2ꢀchloroꢀ1ꢀ(4ꢀnitrophenyl)ethanꢀ1ꢀone 1n failed to give the
desired products under the optimized conditions.
Table 2. Substrate Scope of Reactiona
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a1 (0.3 mmol) and 2a (0.3 mmol) was performed in 1mL Et2O at room temperature for 12h. Then removing the solvent, base
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(K2CO3 0.15 mmol), K2S (0.6 mmol) and DMF (1.5mL) were added at room temperature. The mixture was stirred at 130 C
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for 0.5 h. Isolated yield.
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Subsequently, we explored the reactions with various αꢀtosylhydrazones derived from αꢀ
chloroaldehydes. In view of αꢀchloroaldehydes were easily oxidized, we directly isolated the αꢀ
tosylhydrazonesaldehydes and applied them to the next reaction (Table 3). αꢀTosylhydrazones derived
from αꢀchlorooctanal and αꢀchlorobenzenepropanal readily participated in this transformation, giving
1,2,3ꢀ thiadiazole products 5o and 5p in 56% and 77% yields, respectively. The reaction of N'ꢀ(2ꢀchloroꢀ
2ꢀphenylethylidene)ꢀ4ꢀmethylbenzenesulfonohydrazide 3r progressed well and gave the corresponding
product 5r in 60% yield.
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Table 3. Substrate Scope of Reactiona
aReaction 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 deꢀtosylation reaction of in situ formed azoalkenes affords
1,2,3ꢀthiadiazoles, we reason that similar cascade S3•− addition / electron deꢀtosylation reaction of α,βꢀ
usaturated Nꢀsulfonylimines 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,βꢀketimines. Various substituents with electronꢀdonating
(7bꢀ7e) and electronꢀwithdrawing (7fꢀ7g) 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
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aReaction 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 gramꢀscale synthesis that the yield of 5a was improved in small
increments (Scheme 2). It provided a simple and effective method to manufacture 1,2,3ꢀthiadiazole on a
large scale. Further study the application of this method in the synthesis of 1,2,3ꢀthiadiazoles, 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 2,2,4,4ꢀ
tetramethylꢀ1ꢀpiperidinyloxy (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
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Scheme 4. The Radicalꢀtrapping Experiment.
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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.17ꢀ18 In process I, the azoalkene intermediate A is in situ generated from αꢀ
halogeno 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 SꢀS bond and formation of NꢀS bond
•−
provides intermediate D and S2 , which can be further transformed to S3•− and continue to participate in
the reaction.18 After electron deꢀtosylation of D with the cleavage of the SꢀN 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,βꢀusaturated Nꢀsulfonylimines undergoes the similar
reaction process to afford different functionalized isothiazoles 7.
Scheme 5. A Plausible Mechanism.
3. CONCLUSION
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In conclusion, we have developed a simple and facile method for the synthesis of 4ꢀsubstituented and
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5ꢀsubstituented 1,2,3ꢀthiadiazole from in situꢀgenerated azoalkenes with S3 via cascade trisulfur
radical anion addition and electron deꢀtosylation 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.
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4. EXPERIMENTAL SECTION
General Experimental Information. Unless otherwise stated, all reagents were purchased from commercial suppliers and used without
further purification. Analytical thinꢀlayer 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
1
point apparatus and were uncorrected. IR spectra were recorded on a BRUKER VERTEX 70 spectrophotometer. H 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. Highꢀresolution mass spectra were obtained using BRUKER micrOTOFꢀQ III instrument with ESI source. ESR spectra
were detected by JESꢀX320 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 αꢀchlorosulfonohydrazides 3: (according to the literature:21):
Chlorination of ketones 1 (0.3 mmol) and pꢀTsNHNH2 2a (0.3 mmol) was performed in 1mL Et2O at room temperature. The mixture was
stirred for 12 h, filtered, rinsed with cold (iceꢀwater bath) Et2O and evaporated under reduced pressure to give αꢀchlorosulfonohydrazides
3.
Typical procedure for the construction of α,βꢀusaturated Nꢀsulfonylimines 6:(according to the literature:22):
To a solution of enone (4.8 mmol) and pꢀtoluenesulfonamide (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 (70ꢀ85% yield).
Typical procedure for the construction of 4ꢀdisubstituted 1,2,3ꢀthiadiazole 5:
pꢀTsNHNH2 (2a, 0.3 mmol) was added to a stirred solution of 2ꢀchloroketone (1, 0.3 mmol) in Et2O (1 mL). The mixture was stirred
overnight and evaporated under reduced pressure to give the crud products αꢀchlorotosylhydrazones 3. Followed by addition of K2CO3
o
(0.15 mmol), K2S (0.6 mmol) and DMF (1.5 mL) at room temperature. The mixture was stirred at 130 C as monitored by TLC. The
solution was then quenched by saturated salt solution and extracted with ethyl acetate, the combined organic layers were dried over
Na2SO4, filtered, and evaporated under vacuum. The residue was purified by column chromatography on silica gel (eluent: light petroleum
ether : ethyl acetate, v:v = 100:1− 10:1) to afford the desired product 5.
Typical procedure for the construction of 5ꢀdisubstituted 1,2,3ꢀthiadiazole 5:
The αꢀchlorosulfonohydrazide 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,βꢀketimine 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
o
130 C as monitored by TLC. The solution was then quenched by saturated salt solution and extracted with ethyl acetate, the combined
organic layers were dried over Na2SO4, filtered, and evaporated under vacuum. The residue was purified by column chromatography on
silica gel (eluent: light petroleum ether : ethyl acetate, v:v = 100:1− 10:1) to afford the desired product 7.
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4ꢀphenylꢀ1,2,3ꢀthiadiazole 4ꢀ(pꢀtolyl)ꢀ1,2,3ꢀthiadiazole (5a) White solid (32 mg, 65%). Mp 75.5 – 77.8 °C. IR 3109, 2874, 1789, 1458,
1
1320, 1079, 807, 789 cmꢀ1. H NMR (400 MHz, Chloroformꢀd) δ 8.65 (s, 1H), 8.04 (d, J = 7.2 Hz, 2H), 7.53 – 7.42 (m, 3H). 13C NMR
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(100 MHz, Chloroformꢀd) 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.
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4ꢀ(pꢀtolyl)ꢀ1,2,3ꢀthiadiazole (5b) White solid (34 mg, 64%). Mp 74.5 – 76.3 °C. IR 3102, 1462, 1278, 895, 799 cmꢀ1. H NMR (400 MHz,
Chloroformꢀd) 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, Chloroformꢀd) 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.
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4ꢀ(4ꢀmethoxyphenyl)ꢀ1,2,3ꢀthiadiazole (5c) White solid (23 mg, 40%). Mp 89.5 – 93.3 °C. IR 3093, 2989, 1531, 1462, 1243, 879, 795 cmꢀ
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1. H NMR (400 MHz, Chloroformꢀd) 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,
Chloroformꢀd) 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:
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193.0428.
4ꢀ(4ꢀ(tertꢀbutyl)phenyl)ꢀ1,2,3ꢀthiadiazole (5d) Yellow solid (46 mg, 48%). Mp 79.5 – 83.3 °C. IR 3093, 2962, 1463, 1362, 808 cmꢀ1. 1H
NMR (400 MHz, Chloroformꢀd) 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,
Chloroformꢀd) 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.
4ꢀ(4ꢀfluorophenyl)ꢀ1,2,3ꢀthiadiazole (5e) White solid (27 mg, 49%). Mp 184.5 – 186.3 °C. IR 3101, 2898, 1598, 1448, 837, 782 cmꢀ1. 1H
NMR (400 MHz, Chloroformꢀd) δ 8.61 (s, 1H), 8.02ꢀ7.98 (m, 2H), 7.18ꢀ7.14 (m, 2H). 13C NMR (100 MHz, Chloroformꢀd) δ 164.6, 162.1,
161.9, 129.9, 129.3 (d, JCꢀF = 8.0 Hz), 127.1 (d, JCꢀF = 4.0 Hz), 116.3 (d, JCꢀF = 22.0 Hz) ppm. HRMS (ESI) m/z calcd for C8H6FN2S+ [M +
H]+: 181.0230, found: 181.0238.
4ꢀ(4ꢀchlorophenyl)ꢀ1,2,3ꢀthiadiazole (5f) White solid (36 mg, 61%). Mp 135.8 – 138.3 °C. IR 2989, 1457, 1407, 908, 805 cmꢀ1. 1H NMR
(400 MHz, Chloroformꢀd) 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, Chloroformꢀd) 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.
4ꢀ(4ꢀbromophenyl)ꢀ1,2,3ꢀthiadiazole (5g) White solid (49 mg, 68%). Mp 150.5 – 153.7 °C. IR 2902, 1592, 1453, 801, 789 cmꢀ1. 1H NMR
(400 MHz, Chloroformꢀd) 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, Chloroformꢀd) 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 4ꢀ(1,2,3ꢀthiadiazolꢀ4ꢀyl)benzoate (5h) Yellow solid (25 mg, 38%). Mp 144.2 – 149.7 °C. IR 3092, 2890, 1723,1568, 989,672 1437,
766 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 8.77 (s, 1H), 8.17ꢀ8.11 (m, 4H), 3.94 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) 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.
4ꢀ(2ꢀchlorophenyl)ꢀ1,2,3ꢀthiadiazole (5i) Yellow solid (26 mg, 43%). Mp 134.5 – 136.7 °C. IR 1593, 1387, 1283, 894, 669 cmꢀ1. 1H NMR
(400 MHz, Chloroformꢀd) 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, Chloroformꢀd) 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.
4ꢀ(3ꢀfluorophenyl)ꢀ1,2,3ꢀthiadiazole (5j) White solid (28 mg, 53%). Mp 185.5 – 187.3 °C. IR 2889, 1597, 1448, 1211, 837, 678 cmꢀ1. 1H
NMR (400 MHz, Chloroformꢀd) 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, Chloroformꢀd) δ 164.5, 162.1, 161.7 (d, JCꢀF = 2.0 Hz), 132.9 (d, JCꢀF = 8.0 Hz), 130.9 (t, JCꢀF = 8.0 Hz), 123.1(d, JCꢀF = 3.0 Hz),
116.5 (d, JCꢀF = 21.0 Hz), 114.5 (d, JCꢀF = 24.0 Hz) ppm. HRMS (ESI) m/z calcd for C8H6FN2S+ [M + H]+: 181.0230, found: 181.0228.
4ꢀ(2,5ꢀdifluorophenyl)ꢀ1,2,3ꢀthiadiazole (5k) Brown solid (32 mg, 54%). Mp 167.0 – 169.6 °C. IR 1598, 1494. 964, 943, 864,679 cmꢀ1. 1H
NMR (400 MHz, Chloroformꢀd) 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, Chloroformꢀd) δ 158.6 (dd, JCꢀF = 324.5 Hz), 156.1 (dd, JCꢀF = 327.5 Hz), 155.2 (dd, JCꢀF = 2.0 Hz),
134.4 (d, JCꢀF = 14.0 Hz), 120.2 (dd, JCꢀF = 5.0 Hz), 117.6 (dd, JCꢀF = 9.0 Hz), 117.3 (dd, JCꢀF = 9.0 Hz), 116.5 (dd, JCꢀF = 26.0 Hz) ppm.
HRMS (ESI) m/z calcd for C8H5F2N2S+ [M + H]+: 199.0136, found: 199.0141.
4ꢀ(2,4ꢀdifluorophenyl)ꢀ1,2,3ꢀthiadiazole (5l) Brown solid (26 mg, 43%). Mp 187.0 – 189.6 °C. IR 2953, 1597, 1448, 1256, 1093, 836, 678
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cmꢀ1. H NMR (400 MHz, Chloroformꢀd) δ 8.96 (d, J = 1.9 Hz, 1H), 8.25 – 8.21 (m, 2H), 7.24 – 7.21 (m, 1H), 7.15 – 7.09 (m, 1H). 13
C
NMR (101 MHz, Chloroformꢀd) δ 163.0 (dd, JCꢀF = 339.5 Hz), 160.4 (dd, JCꢀF = 339.0 Hz), 155.6 (d, JCꢀF = 4.0 Hz), 133.2 (q, JCꢀF = 13.0
Hz), 131.5 (dd, JCꢀF = 6.0 Hz), 115.6 (dd, JCꢀF = 12.0 Hz), 112.5 (dd, JCꢀF = 21.5 Hz), 104.8 (t, JCꢀF = 51.0 Hz) ppm. HRMS (ESI) m/z calcd
for C8H5F2N2S+ [M + H]+: 199.0136, found: 199.0151.
5ꢀhexylꢀ1,2,3ꢀthiadiazole (5o) Yellow oil (29 mg, 56%). IR 2954, 2928, 2869, 1597, 1456, 1249, 1098, 893, 784 cmꢀ1. 1H NMR (400 MHz,
Chloroformꢀd) 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,
Chloroformꢀd) 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.
5ꢀbenzylꢀ1,2,3ꢀthiadiazole (5p) Yellow oil (41 mg, 77%). IR 2904, 1601, 1495, 1254, 1087, 789, 699 cmꢀ1. 1H NMR (400 MHz,
Chloroformꢀd) 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, Chloroformꢀd) 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.
4ꢀ(7ꢀbromoꢀ9,9ꢀdifluoroꢀ9Hꢀfluorenꢀ2ꢀyl)ꢀ1,2,3ꢀthiadiazole (5q) Yellow solid (56 mg, 51%). Mp 163.4 – 165.9 °C. IR 2956, 2922, 2851,
1456, 1278, 894, 783, 673 cmꢀ1. H NMR (400 MHz, Chloroformꢀd) 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, Chloroformꢀd) δ 161.8, 144.53, 140.0 (t, JCꢀF = 50.0 Hz), 139.5 (t, JCꢀF
=
9.0 Hz), 138.7 (t, JCꢀF = 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
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C15H8BrF2N2S+ [M + H]+: 364.9554, found: 364.9553.
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5ꢀphenylꢀ1,2,3ꢀthiadiazole (5r) Brown oil (30 mg, 60%). IR 3091, 2958, 2924, 1464, 1444, 1247, 963, 758 cmꢀ1. H NMR (400 MHz,
Chloroformꢀd) δ 8.85 (s, 1H), 7.65 – 7.54 (m, 2H), 7.52 – 7.41 (m, 3H). 13C NMR (100 MHz, Chloroformꢀd) 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.
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3,5ꢀdiphenylisothiazole (7a) Yellow solid (36 mg, 51%). Mp 47.8 − 50.4 °C. IR 3052, 2922, 1950, 1663, 1482, 1446, 1046, 751, 669 cmꢀ1.
1H NMR (400 MHz, Chloroformꢀd) 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,
Chloroformꢀd) 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.
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3ꢀ(4ꢀ(tertꢀbutyl)phenyl)ꢀ5ꢀphenylisothiazole (7b) Brown solid (44 mg, 50%). Mp 58.8 – 59.6 °C. IR 3336, 3046, 2953, 2867, 1667, 1604,
1483, 1265, 1046, 822, 672 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) 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, Chloroformꢀd) 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.
3ꢀphenylꢀ5ꢀ(pꢀtolyl)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 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) 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, Chloroformꢀd) 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.
3ꢀ(4ꢀpentylphenyl)ꢀ5ꢀphenylisothiazole (7d) Brown solid (29 mg, 31%). Mp 45.0 – 47.5 °C. IR 3344, 3179, 2907, 2869, 1879, 1734, 1665,
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1367, 1071, 807, 699 cmꢀ1. H NMR (400 MHz, Chloroformꢀd) 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,
Chloroformꢀd) 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.
3ꢀphenylꢀ5ꢀ(pꢀtolyl)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 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) 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, Chloroformꢀd) 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.
3ꢀ(4ꢀbromophenyl)ꢀ5ꢀphenylisothiazole (7f) Brown solid (43 mg, 45%). Mp 114.3 – 115.4 °C. IR 3735, 2482, 2329, 2272, 1986, 1726,
792, 666 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) 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, Chloroformꢀd) 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.
3ꢀ(4ꢀnitrophenyl)ꢀ5ꢀphenylisothiazole (7g) Brown solid (41 mg, 48%). Mp 119.0 – 121.4 °C. IR 2184, 2163, 2024, 1981, 573 cmꢀ1. 1H
NMR (400 MHz, Chloroformꢀd) 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, Chloroformꢀd) 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.
5ꢀ(thiophenꢀ2ꢀyl)ꢀ3ꢀ(pꢀtolyl)isothiazole (7h) Brown solid (11 mg, 14%). Mp 47.0 – 48.8 °C. IR 3032, 2915, 1725, 1662, 1579, 1443, 1267,
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822, 655 cmꢀ1. H NMR (400 MHz, Chloroformꢀd) 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, Chloroformꢀd) 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
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Education Institutions (No. 16KJA150002), the Ph.D. Programs Foundation of PAPD, the project of
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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.
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REFERENCES
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60
(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 1,2,3ꢀthiadiazole as inhibitors of hepatitis B virus replication. Eur. J. Med. Chem
1919–1926. (b) Zhan, P.; Liu, X.; Fang, Z.; Li, Z.; Pannecouque, C.; Clercq, E. D. Synthesis and antiꢀHIV activity
evaluation of 2ꢀ(4ꢀ(naphthalenꢀ2ꢀyl)ꢀ1,2,3ꢀthiadiazolꢀ5ꢀylthio)ꢀ ꢀacetamides as novel nonꢀnucleoside HIVꢀ1
reverse transcriptase inhibitors. Eur. J. Med. Chem 2009 44, 4648–4653. (c) AbdelꢀMagid, A. F. Therapeutic
potential of GPR120 agonists for the treatment of type 2 diabetes. ACS Med. Chem. Lett. 2015 , 1097–1098.
(2) (a) Lyapunova, A. G.; Androsov, D. A.; Petrov, M. L. A convenient synthesis of benzo[ ]chalcogenophenes from
4ꢀ(2ꢀchloroꢀ5ꢀnitrophenyl)ꢀ1,2,3ꢀchalcogenadiazoles. Tetrahedron Lett. 2013 54, 3427–3430. (b) Androsov, D. A.
Synthesis of 1,1ꢀdialkylindoliumꢀ2ꢀthiolates via baseꢀinduced transformation of 4ꢀ(2ꢀChloroꢀ5ꢀnitrophenyl)ꢀ1,2,3ꢀ
thiadiazole in the presence of secondary amines. J. Org. Chem 2008 73, 8612–8614. (c) Androsov, D. A.;
Neckers, D. C. Synthesis and reactivity of 4ꢀ(2ꢀChloroꢀ5ꢀnitrophenyl)ꢀ1,2,3ꢀthiadiazole. A novel oneꢀpot synthesis
of ꢀsubstituted indoleꢀ2ꢀthiols. 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[ ]thiopheneꢀ2ꢀthiolates and their derivatives via baseꢀpromoted
transformation of 4ꢀ(2ꢀMercaptophenyl)ꢀ1,2,3ꢀthiadiazoles. Org. Lett 2013 15, 4038–4041. (e) Xu, F.; Chen, Y.;
Fan, E.; Sun, Z. Synthesis of 3ꢀsubstituted aryl[4,5]isothiazoles through an allꢀheteroatom wittigꢀequivalent process.
Org. Lett 2016 18, 2777–2779. (f) Shukla, G.; Srivastava, A.; Singh, M. S. Metalꢀ and catalystꢀfree, formal [4+1]
annulation via tandem C=O/C=S functionalization: Oneꢀpot access to 3,5ꢀdisubstituted/annulated isothiazoles. Org.
Lett 2016 18, 2451–2454.
(3) Klimczak, U. K.; Zambroń, B. K. Effective 1,5ꢀstereocontrol in Pd(0)/InI promoted reactions of chiral
vinylazetidinꢀ2ꢀones with aldehydes. An efficient entry into nonracemic semiꢀprotected (3Z)ꢀ2,6ꢀantiꢀenediols.
Chem. Commun 2015 51, 6796–6799.
(4) (a) Magnus, P. D. Recent developments in sulfone chemistry. Tetrahedron 1977
Deng, L.; Tan, P.; Ni, C.ꢀF.; Gu, Y.ꢀC.; Hu, J.ꢀB. Radical fluoroalkylation of isocyanides with fluorinated sulfones
by visibleꢀlight 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
. 2010, 45,
N
.
,
,
6
b
,
.
,
N
,
b
.
,
.
,
.
,
N
ꢀTsꢀ4ꢀ
.
,
,
33, 2019–2045. (b) Rong, J.;
.
,
allylation of alkyl iodides using alkenyl and allylic sulfones. Org. Lett
.
2018
,
20, 1078–1081. (b) Siddiki, S. M. A.
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
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
βꢀketo sulfones. Org. Lett 2015 17, 4890–4893. (d) Kan, T.; Fukuyama, T. Ns strategies: a highly versatile
synthetic method for amines. Chem. Commun 2004 , 353–359. (e) Fukuyama, T.; Jow, C. K.; Cheung, M. 2ꢀ and
4ꢀNitrobenzenesulfonamides: 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
tolueneꢀ ꢀsulphonylhydrazones by alkali. J. Chem. Soc 1952 , 4735–4740. (g) Sakai, K.; Hida, N.; Kondo, K.
Reactions of αꢀpolyhalo ketone tosylhydrazones with sulfide ion and primary amines. Cyclization to 1,2,3ꢀ
thiadiazoles and 1,2,3ꢀtriazoles. 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 superꢀelectronꢀdonor (S.E.D.) reagent. J. Am. Chem. Soc 2007 129
13368–13369. (b) O’Sullivan, S.; Doni, E.; Tuttle, T.; Murphy, J. A. Metalꢀfree reductive cleavage of CꢀN and SꢀN
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, PꢀB.; Zhang, L.ꢀL.; Tang, G.; Zhao, Y.ꢀF. cascade
2016,
Page 12 of 14
1
2
3
4
5
6
7
8
.
,
.
,
.
, 0
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
p
.
, 0
.
,
.
,
,
.
,
A
phosphinoylation/cyclization/desulfonylation process for the synthesis of 3ꢀPhosphinoylindoles. Org. Lett
18, 1242–1245.
.
(8) (a) Chen, J.ꢀF.; Jiang, Y.; Yu, J.ꢀT.; Cheng, J. TBAIꢀcatalyzed reaction between
procedure toward 1,2,3ꢀthiadiazole. J. Org. Chem 2016 81, 271–275. (b) Ishikawa, T.; Kimura, M.; Kumoi, T.;
Iida, H. Coupled flavinꢀiodine redox organocatalysts: Aerobic oxidative transformation from ꢀTosylhydrazones to
1,2,3ꢀthiadiazoles. ACS Catal 2017 , 4986–4989.
(9) Miles, D. H.; Guasch, J.; Toste, F. D. A nucleophilic strategy for enantioselective intermolecular αꢀamination:
Access to enantioenriched αꢀarylamino 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 situꢀderived
azoalkenes: An umpolung alkylation procedure applicable to the formation of up to three contiguous quaternary
centers. J. Am. Chem. Soc 2010 132, 4546–4547.
NꢀTosylhydrazones and sulfur: A
.
,
N
.
, 7
,
N
ꢀsulfonyl
.
,
(11) (a) Attanasi, O. A.; Crescentini, L. D.; Favi, G.; Mantellini, F.; Mantenuto, S.; Nicolini, S. Interceptive [4+1]
annulation of in situ generated 1,2ꢀdiazaꢀ1,3ꢀdienes with diazo dsters: Direct access to substituted monoꢀ, biꢀ, and
tricyclic 4,5ꢀdihydropyrazoles. J. Org. Chem
F.ꢀF.; Jçrres, M.; Bolm, C. Enantioselective synthesis of dihydropyrazoles by formal [4+1] cycloaddition of in situꢀ
derived azoalkenes and sulfur ylides. J. Am. Chem. Soc 2012 134, 6924–6927. (c) Guo, C.; Sahoo, B.; Daniliuc, C.
. 2014, 79, 8331–8338. (b) Chen, J.ꢀR.; Dong, W.ꢀR.; Candy, M.; Pan,
.
,
G.; Glorius, F. NꢀHeterocyclic carbene catalyzed switchable reactions of enals with azoalkenes: Formal [4+3] and
12
ACS Paragon Plus Environment

Page 13 of 14
The Journal of Organic Chemistry
[4+1] annulations for the synthesis of 1,2ꢀdiazepines and pyrazoles. J. Am. Chem. Soc. 2014, 136, 17402–17405.
1
2
(d) Tong, M.ꢀC.; Chen, X.; Li, J.; Huang, R.; Tai, H.ꢀY.; Wang, C.ꢀJ. Catalytic asymmetric synthesis of [2,3]ꢀfused
3
4
indoline heterocyclesthrough inverseꢀelectronꢀdemand azaꢀdiels–alder reaction ofIndoles with azoalkenes. Angew.
5
6
7
8
Chem., Int. Ed
Org. Lett 2015
tetrahydropyridazines via inverse electronꢀdemand azaꢀdiels–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,Nꢀcyclic 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 electronꢀdemand azaꢀDiels–Alder/nucleophilic addition/ringꢀopening
reaction involving 2ꢀmethoxyfurans as efficient dienophiles. J. Am. Chem. Soc 2016 138, 3998–4001.
.
2014
, 53, 4680–4684; Angew. Chem. 2014, 126, 4768–4772. (e) Zhong, X.ꢀR.; Lv, J.; Luo, S.ꢀZ.
.
,
17, 1561–1564. (f) Wei, L.; Wang, C.ꢀJ. The catalytic asymmetric synthesis of
9
10
11
12
13
14
15
16
17
18
19
20
21
.
,
.
,
.
,
(12) Li, J.; Huang, R.; Xing, Y.ꢀK.; Qiu, G.ꢀF.; Tao, H.ꢀY.; Wang, C.ꢀJ. Catalytic asymmetric cascade vinylogous
mukaiyama 1,6ꢀMichael/Michael addition of 2ꢀsilyloxyfurans with azoalkenes: Direct approach to fused
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
butyrolactones. J. Am. Chem. Soc
(13) Zhu, T.ꢀH.; Wei, T.ꢀQ.; Wang, S.ꢀY.; Ji, S.ꢀJ. NIS/CHPꢀmediated reaction of isocyanides with hydrazones: access
to aminopyrazoles. Org. Chem. Front 2015 , 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 ꢀTosylhydrazones with anilines: Practical construction of 1,4ꢀdisubstituted 1,2,3ꢀtriazoles under metalꢀ
free and azideꢀfree conditions. Org. Lett 2014 16, 5108–5111.
. 2015, 137, 10124–10127.
.
, 2
N
.
,
(15) (a) Bai, H.ꢀW.; Cai, Z.ꢀJ.; Wang, S.ꢀY.; Ji, S.ꢀJ. Aerobic oxidative cycloaddition of αꢀchlorotosylhydrazones with
arylamines: General chemoselective construction of 1,4ꢀdisubstituted and 1,5ꢀdisubstituted 1,2,3ꢀtriazoles under
metalꢀfree and azideꢀfree 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 (GSꢀ5885): A potent, onceꢀdaily 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 electronꢀcatalyzed
sulfur insertion reactions: facile synthesis of benzothiazine derivatives under transition metalꢀfree 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,
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 14
electrochemistry, analytical chemistry and geochemistry. Chem. Soc. Rev. 2013, 42, 5996–6005. (c) Chivers, T.
1
2
−·
Ubiquitous trisulphur radical ion S3
. Nature 1974, 252, 32–33.
3
4
5
6
7
8
9
(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 NaO Bu. Org. Lett 2014 16, 6156–6159.
(b) Studer, A.; Curran, D. P. The electron is a catalyst. Nat. Chem 2014 , 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 , 1709–1719.
(19) O'Sullivan, S.; Doni, E.; Tuttle, T.; Murphy, J. A. Metalꢀfree reductive cleavage of CꢀN and SꢀN 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 ꢀhalosuccinimides under solventꢀfree reaction
conditions. Tetrahedron 2008 64, 5191–5199. (b) Szymanski, W.; Postema, C. P.; Tarabiono, C.; Berthiol, F.;
CampbellꢀVerduyn, L.; Wildeman, S. de.; Vries, J. G. de.; Feringa, B. L.; Janssen, D. B. Combining designer cells
t
.
,
.
, 6
−
−
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
.
,
,
7
.
,
N
,
and click chemistry for a oneꢀpot fourꢀstep 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 situꢀderived
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,β
unsaturated ꢀsulfonyl imines: An expeditious route to chiral ꢀaminoesters and piperidones. Chem. Eur. J
19, 14861–14866.
Nꢀsulfonyl
.
,
ꢀ
N
δ
.
2013
,
14
ACS Paragon Plus Environment