Cycloaddition Reaction of α,β-Alkynic Hydrazones and KSCN under Transition-Metal-Free Conditions: Synthesis of N-Iminoisothiazolium Ylides

Article abstract of DOI:10.1021/acs.joc.8b01725

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

Full text of DOI:10.1021/acs.joc.8b01725

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Article
[4+1] Cycloaddition Reaction of #,#-alkynic Hydrazones and KSCN under
Transition-Metal Free Conditions: Synthesis of N-Iminoisothiazolium Ylides
Bei-Bei Liu, Wen-Bin Cao, Fei Wang, Shun-Yi Wang, and Shunjun Ji
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01725 • Publication Date (Web): 09 Aug 2018
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The Journal of Organic Chemistry
[4+1] Cycloaddition Reaction of
α,β-alkynic Hydrazones and KSCN under
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Transition-Metal Free Conditions: Synthesis of N-Iminoisothiazolium Ylides
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BeiꢀBei Liu, WenꢀBin Cao, Fei Wang, 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
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RECEIVED DATE
*CORRESPONDING AUTHOR FAX: 86ꢀ512ꢀ65880307.
ABSTRACT. A novel heteroannulation reaction between α,βꢀalkynic hydrazones and potassium
thiocyanate (KSCN) has been developed for the synthesis of Nꢀiminoisothiazolium ylides. The
transformation features wide substrate scope, functional tolerance and easy operation. This investigation
involves [4+1]ꢀtype cycloaddition reaction and C−S/S−N bonds formation under transitionꢀmetal free
conditions. The application of this transformation to the gramꢀscale preparation of the Nꢀimide ylide is
also accomplished.
KEYWORDS: Nꢀiminoisothiazolium ylide, [4+1]ꢀtype cycloaddition, C−S/S−N bonds, transitionꢀmetal
free
1. INTRODUCTION
Nitrogenꢀcontaining heterocycles are extensively found in pharmaceuticals,1ꢀ2 pesticides,3 natural
products and biomaterials.4 They also exhibit special antibacterial, anticancer and bactericidal activities
and widely used in industrial bactericide (Figure 1).5ꢀ6 Among of them, thiazoles and isothiazoles are
important heterocycles and widely exist in drugs and natural products.
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Figure 1. Pharmaceutical active isothiazolones and their derivatives.
During the past decade, more attentions have been paid to the synthesis of Nꢀylides6 and their
applications in arylation, alkenylation, alkylation7ꢀ8 and cycloaddition reactions (Scheme 1a).9ꢀ16
However, there are limited reports for the construction of isothiazolium ylides such as Nꢀ
arylsulfonylisothiazoleꢀ2ꢀimines. The cyclcondensation of thiocyanatovinylaldehyde hydrazones from
nonꢀcommercial available thiocyanatovinylaldehydes could afford Nꢀarylsulfonylisothiazoleꢀ2ꢀimines
over two steps (Scheme 1b).17ꢀ18 Therefore, it is more desirable to develop direct protocol for the
construction of isothiazolium ylides from easily obtained starting materials under mild conditions.
Herein, we report a tandem [4+1] cycloaddition reaction of α,βꢀalkynic hydrazones with KSCN for the
regiospecific synthesis of substituted Nꢀiminoisothiazolium ylides under transition metalꢀfree conditions
(Scheme 1c). The transformation features wide substrate scope, functional tolerance and easy operation.
This investigation involves [4+1]ꢀtype cycloaddition reaction and C−S/S−N bonds formation in pot.
Scheme 1. Different Strategies for The Synthesis of N-Ylides
(a) Previous work
R'
O
M(CO)5
OEt
O
EtO
O
N
N
R'
HN NH
R
R
H
(OC)5M
O
R
N
N
O
O
R
O
N
R2
R3
X
N
CO2Et
N
N
H
R1
EtO2C
R
R
N
N
R1
R2
CHO
HPO(OEt)2
R
NHNH2
R3
Br
N
R1
N
O
P
OEt
OEt
R1
CO2Et
N
R1
N
NHTs
R1
R'
N
N
N
R'
CO2Et
(b) Limited reports for the construction of isothiazolium ylides
CH NNHR
SCN
CHO
SCN
R
(CH2)n
R
NHNH2
(CH2)n
(CH2)n
N
N
S
(c) This work
R2
R2
KSCN
NNH R3
R3
N
R1
N
R1
AcOH:CH3CN (1:1)
80 o
Nonmetallic catalyst
S
C
Air bengin, one-pot
2. RESULTS AND DISCUSSION
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Initially, we investigated the reaction of α,βꢀalkynic hydrazone 1a with KSCN in 3 mL acetic acid at
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60 oC under air condition. Gratifyingly, the desired product 3a was formed in 53% yield (Table 1, entry
1). The structure of 3a was unambiguously confirmed by Xꢀray crystallography (see Supporting
Information for details). Encouraged by this result, we further tried the reactions by increasing the
reaction temperature and the yield of 3a could be increased to 65% (Table 1, entries 2ꢀ3). Change of Sꢀ
source from K2S to S8 led to diminished yields (Table 1, entries 4ꢀ6). Reducing or raising the amount of
KSCN do not effectively improve the yields (entries 7ꢀ8). A 1:1 (V/V) blend of other solvents like
EtOH, toluene, THF, 1,4ꢀdioxane and acetonitrile along with AcOH were used in the reactions (Table 1,
entries 9ꢀ13). It was found that acetonitrile was better than other solvents. However, the yield was
decreased when the ratio of mixed solvent was changed (Table 1, entries 14ꢀ15).
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Table 1. Optimization of The Reaction Conditionsa
Entry
1
Temp.
60
1a:2a
1:2
1:2
1:2
1:2
1:2
1:2
1:1.5
1:3
1:2
1:2
1:2
1:2
1:2
1:2
1:2
Solvent
AcOH
Yield (%)b
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63
0
2
80
AcOH
3
100
80
AcOH
4c
5d
6e
7
AcOH
80
AcOH
0
80
AcOH
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40
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trace
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AcOH
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80
AcOH
9
80
AcOH : EtOH (1:1)
AcOH : toluene (1:1)
AcOH : THF (1:1)
AcOH : 1,4ꢀdioxane (1:1)
AcOH : CH3CN (1:1)
AcOH : CH3CN (1:2)
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AcOH : CH3CN (1:3)
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aConditions: 1a (0.3 mmol) and Sꢀsource (KSCN, 0.6 mmol) in solvent (3 mL). Isolated yield. SꢀSouce: K2S. Sꢀsouce:
Na2S2O3·5H2O. eSꢀsouce: S8.
With the optimization conditions in hand, we explored the scope of the alkynyl substrates to construct
isothiazolium ylides (Table 2). To most substituted phenylacetylenes with electronically neutral or
electronꢀwithdrawing or electronꢀrich g groups at the meta or para position (3b-d and 3e-g), moderate
to good yields of isothiazolium ylides were achieved. The reactions of 4ꢀ(cyanomethyl)phenyl
derivative 1h and thiophene derivative 1i led to 3h and 3i in 50% and 35% yields, respectively.
Functionalized terminal alkynes, such as 3ꢀbromopropꢀ1ꢀyne derivative, failed to generate the
corresponding isothiazolium ylide 3j. Use of substrates with propyl (1u) gave the corresponding
products in 50% yields. Unfortunately, the reaction of 4ꢀ(chloromethyl)phenyl hydrazine only gave a
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trace amount of the desired product 3k. It was found that 4ꢀnitroꢀ, 4ꢀchloroꢀ, 4ꢀtrifluoromethylꢀ, and 4ꢀ
methoxyꢀsubstituted aryl acetylenes could also apply to the reactions with KSCN to afford the desired
products 3l-o in up to 73% yields. Heteroaryl and naphthyl groups were tolerated and resulted in Nꢀ
iminoisothiazolium ylides 3p and 3q in 40% and 60% yield, respectively. It should be noted that the
reaction of 4ꢀmethylꢀN'ꢀ(3ꢀphenylpropꢀ2ꢀynꢀ1ꢀylidene)benzenesulfonohydrazide 1r could also lead to
Nꢀiminoisothiazolium ylide 3r in 70% yield. In addition, Benzenesulfonyl hydrazides 1s and 1t with
different substitution patterns were tested as well. 3s was observed in 50% yield. Unfortunately, only
trace amount of 3t was detected.
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Table 2. Substrate scope of α,β-alkynic hydrazones (1)a
aStandard condition. Isolated yield.
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Next, we tried the [4+1] cycloaddition of N'3ꢀ(1,3ꢀdiphenylpropꢀ2ꢀynꢀ1ꢀylidene)ꢀN'1ꢀ(1,3ꢀ
diphenylpropꢀ2ꢀynꢀ1ꢀylidene)isophthalohydrazide with KSCN. The diꢀsubstituted Nꢀiminoisothiazolium
ylide was successfully obtained in 51% yield (Scheme 2).
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Scheme 2. The reaction of α,β-alkynic hydrazones 4a with KSCN.
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To evaluate the application of this tandem reaction, the gram scale reaction was investigated with
1.50 g of 1a. Interestingly, the Nꢀiminoisothiazolium ylide 3a was isolated in 66% yield without further
optimization of reaction conditions (Scheme 3).
Scheme 3. Gram Scale Reaction of 1a.
Meanwhile, to further illustrate the synthetic utility of this method (Scheme 4). We investigated the
oxidation of 3a by hydrogen peroxide. It is worth noting that 3a was converted into 4,6ꢀdiphenylꢀ2ꢀ
tosylꢀ2Hꢀ1,2,3ꢀthiadiazineꢀ1ꢀoxide 7a in 82% yield. Moreover, the structure of 7a was confirmed by
NMR, HRMS, IR, and Xꢀray analysis (see Supporting Information for details).
Scheme 4. Oxidation of 3a.
Based on the above results, a proposed mechanism for the tandem [4+1] cycloaddition reaction is
outlined in Scheme 5. First, the addition of KSCN to α,βꢀalkynic hydrazine 1a gives the thiocyanative
intermediate A, which undergoes proton tranfer to afford the anion B. The following decyanative
cyclization a ords the Nꢀiminoisothiazolium ylide 3a.
Scheme 5. A Plausible Mechanism.
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3. CONCLUSION
In conclusion, we have developed a novel [4+1] cycloaddition of α,βꢀalkynic hydrazine with KSCN
under transitionꢀmetal free conditions. This protocol provides a simple operation and economical, no
inert gas atmosphere required strategy to synthesis of Nꢀiminoisothiazolium ylides.
4. EXPERIMENTAL SECTION
1. General Information. Unless otherwise noted, all commercially available compounds were used as provided without further
purification. Solvents for chromatography were analytical grade and used without further purification. Analytical thinꢀlayer
chromatography (TLC) was performed on silica gel, visualized by irradiation with UV light. For column chromatography, 200ꢀ300 mesh
silica gel was used. 1HꢀNMR, 13CꢀNMR and 19F NMR were recorded on a BRUKER 400 MHz spectrometer in CDCl3. Chemical shifts (δ)
were reported referenced to an internal tetramethylsilane standard or the CDCl3 residual peak (δ 7.26) for 1H NMR. Chemical shifts of 13
C
NMR are reported relative to CDCl3 (δ 77.16). Data are reported in the following order: chemical shift (δ) in ppm; multiplicities are
indicated s (singlet), bs (broad singlet), d (doublet), t (triplet), m (multiplet); coupling constants (J) are in Hertz (Hz). Melting points were
measured on an Electrothermal digital melting point apparatus and were uncorrected. IR spectra were recorded on a BRUKER MODEL
ALPHA spectrophotometer and are reported in terms of frequency of absorption (cmꢀ1). HRMS spectra were obtained by using BRUKER
MICROTOFꢀQ III instrument with ESI source. The starting materials were isolated by SepaBean machine Flash Chromatography, which
purchased from Santai Technologies Inc.
2.1. General procedure for the synthesis of compounds 3
α,βꢀalkynic hyrazone 1 or 4 (0.3 mmol, 1.0 equiv) and potassium thiocyanate 2 (0.6 mmol, 2.0 equiv) were stirred at 80 °C (oil bath
temperature) under air atmosphere in 3 mL of mixed solvent of AcOH/acetonitrile (v:v = 1:1). Upon completion of the reaction (indicated
by TLC), the mixture was cooled to room temperature, ferrous chloride (2.5 equiv) was added to the reaction system. The reaction mixture
was charged with silica gel and concentrated. The pure products were obtained after purification by column chromatography on silica gel
with petroleum ether/ethyl acetate (v:v = 6:1−1:1) as the eluent.
2.2. General procedure for the synthesis of compounds 5
α,βꢀalkynic hyrazone 4 (0.3 mmol, 1.0 equiv) and potassium thiocyanate 2 (1.2 mmol, 4.0 equiv) were stirred at 80 °C (oil bath
temperature) under air atmosphere in 3 mL of mixed solvent of AcOH/acetonitrile (v:v = 1:1). Upon completion of the reaction (indicated
by TLC), the mixture was cooled to room temperature, ferrous chloride (5.0 equiv) was added to the reaction system. The reaction mixture
was charged with silica gel and concentrated. The pure products were obtained after purification by column chromatography on silica gel
with petroleum ether/ethyl acetate (v:v = 6:1−1:1) as the eluent.
2.3. Gram scale reaction of 3a
α,βꢀalkynic hyrazone 1a (4.0 mmol, 1.50g, 1.0 equiv) and potassium thiocyanate 2 (8.0 mmol, 0.78g, 2.0 equiv) were stirred at 80 °C (oil
bath temperature) under air atmosphere in 40 mL of mixed solvent of AcOH/acetonitrile (v:v = 1:1). Upon completion of the reaction
(indicated by TLC), the mixture was cooled to room temperature, ferrous chloride (2.5 equiv) was added to the reaction system. The
reaction mixture was charged with silica gel and concentrated. The pure products were obtained after purification by column
chromatography on silica gel with petroleum ether/ethyl acetate (v:v = 6:1−1:1) as the eluent.
Cautious!
Excess ferrous chloride was added to the reaction system to remove cyanide ions.
(3,5ꢀdiphenylisothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3a) Yellow solid (97 mg, 80%). Mp 164.4 – 166.7 °C. IR 3061, 2579, 1597, 1495, 1345,
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1160, 879, 765 cmꢀ1. H NMR (400 MHz, Chloroformꢀd) δ 7.67 – 7.62 (m, 2H), 7.59 (m, J = 7.8, 1.6 Hz, 2H), 7.56 – 7.49 (m, 3H), 7.43
(m, J = 7.8, 3.6 Hz, 3H), 7.35 (t, J = 7.5 Hz, 2H), 7.19 (s, 1H), 6.94 (d, J = 8.0 Hz, 2H), 2.28 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd)
δ 160.9, 159.2, 141.5, 138.3, 132.1, 131.2, 130.0, 129.5, 129.1, 128.4, 127.0, 126.8, 115.4, 77.5, 21.4 ppm. HRMS (ESI) m/z: calcd for
C22H19N2O2S2+ [M + H]+: 407.0882, found: 407.0883.
(5ꢀ(4ꢀchlorophenyl)ꢀ3ꢀphenylisothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3b) Yellow solid (90 mg, 68%). Mp 151.5 – 154.7 °C. IR 3097, 2951,
2926, 2854, 1722, 1487, 1260, 1085, 794 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.63 (d, J = 7.5 Hz, 2H), 7.56 – 7.46 (m, 4H), 7.42 (d,
J = 7.8 Hz, 3H), 7.34 (t, J = 7.4 Hz, 2H), 7.21 (s, 1H), 6.95 (d, J = 7.8 Hz, 2H), 2.28 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 141.7,
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+
138.3, 131.3, 130.3, 129.5, 129.1, 128.5, 128.3, 128.0, 127.0, 126.8, 115.8, 100.1, 21.5 ppm. HRMS (ESI) m/z: calcd for C22H18N2ClO2S2
[M + H]+: 441.0493, found: 441.0477.
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(5ꢀ(4ꢀfluorophenyl)ꢀ3ꢀphenylisothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3c) Yellow solid (89 mg, 70%). Mp 183.2 – 184.8 °C. IR 3106, 2961,
2921, 2853, 1596, 1454, 1262, 1085, 1028, 762 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.69 – 7.55 (m, 4H), 7.43 (d, J = 7.7 Hz, 3H),
7.34 (t, J = 7.5 Hz, 2H), 7.22 (t, J = 8.3 Hz, 2H), 7.16 (s, 1H), 6.95 (d, J = 7.8 Hz, 2H), 2.28 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ
161.0 , 158.0, 141.7, 138.3, 131.3, 129.5, 129.1, 129.0, 129.0, 128.5, 127.1, 124.7 (d, JCꢀF = 4.0 Hz), 117.4 (d, JCꢀF = 22.0 Hz), 115.5, 21.5
ppm. 19F NMR (376 MHz, CDCl3) δ ꢀ106.2 ppm. HRMS (ESI) m/z: calcd for C22H18N2FO2S2+ [M + H]+: 425.0788, found: 425.0786.
(5ꢀ(3ꢀfluorophenyl)ꢀ3ꢀphenylisothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3d) Yellow solid (55 mg, 43%). Mp 167.2 – 169.7 °C. IR 3108, 2962,
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1919, 2853, 1596, 1478, 1260, 1138, 882, 653 cmꢀ1. H NMR (400 MHz, Chloroformꢀd) δ 7.64 (d, J = 7.5 Hz, 2H), 7.55 – 7.47 (m, 1H),
7.46 – 7.40 (m, 3H), 7.35 (dt, J = 16.8, 8.8 Hz, 4H), 7.26 (d, J = 12.4 Hz, 2H), 6.95 (d, J = 7.9 Hz, 2H), 2.28 (s, 3H). 13C NMR (100 MHz,
Chloroformꢀd) δ 164.5, 162.0, 160.6, 157.1 (d, JCꢀF = 3.0 Hz), 141.7, 138.2, 131.8 (d, JCꢀF = 8.0 Hz), 131.3, 130.1(d, JCꢀF = 8.0 Hz), 129.5,
129.1, 128.5, 128.3, 127.0, 122.8 (d, JCꢀF = 3.0 Hz), 118.9 (d, JCꢀF = 21.0 Hz), 116.2, 113.7 (d, JCꢀF = 23.0 Hz), 21.5 ppm. 19F NMR (376
MHz, CDCl3) δ ꢀ109.7 ppm. HRMS (ESI) m/z: calcd for C22H18N2FO2S2+ [M + H]+: 425.0788, found: 425.0773.
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(5ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀphenylisothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3e) Yellow solid (58 mg, 44%). Mp 161.5 – 165.4 °C. IR 3079, 2921,
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2852, 1682, 1599, 1487, 1260, 1085, 794 cmꢀ1. H NMR (400 MHz, Chloroformꢀd) δ 7.61 (d, J = 7.5 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H),
7.40 (d, J = 7.8 Hz, 3H), 7.32 (t, J = 7.4 Hz, 2H), 7.09 (s, 1H), 7.00 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 7.8 Hz, 2H), 3.88 (s, 3H), 2.27 (s, 3H).
13C NMR (100 MHz, Chloroformꢀd) δ 162.8, 141.4, 138.5, 131.1, 129.5, 129.1, 128.2, 128.4, 127.1, 115.4, 114.1, 55.8, 21.5 ppm. HRMS
(ESI) m/z: calcd for C23H21N2O3S2+ [M + H]+: 437.0988, found: 437.0985.
(3ꢀphenylꢀ5ꢀ(4ꢀpropylphenyl)isothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3f) Yellow solid (67 mg, 50%). Mp 152.4 – 155.7 °C. IR 3086, 2957,
2928, 1598, 1487, 1274, 1133, 803, 689 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.62 (d, J = 7.5 Hz, 2H), 7.50 (d, J = 7.9 Hz, 2H), 7.40
(d, J = 7.9 Hz, 3H), 7.31 (t, J = 8.5 Hz, 4H), 7.19 (s, 1H), 6.91 (d, J = 7.8 Hz, 2H), 2.64 (t, J = 7.5 Hz, 2H), 2.26 (s, 3H), 1.67 (h, J = 7.2
Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 159.6, 147.6, 141.4, 138.3, 131.0, 130.0, 129.5, 129.0, 128.4,
+
128.3, 126.9, 126.6, 125.6, 114.9, 37.9, 24.3, 21.4, 13.8 ppm. HRMS (ESI) m/z: calcd for C25H25N2O2S2 [M + H]+: 449.1352, found:
449.1344.
(3ꢀphenylꢀ5ꢀ(mꢀtolyl)isothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3g) Yellow solid (81 mg, 64%). Mp 174.5 – 177.4 °C. IR 3088, 29612920, 2852,
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15981528, 1259, 1051, 791 cmꢀ1. H NMR (400 MHz, Chloroformꢀd) δ 7.63 (d, J = 7.4 Hz, 2H), 7.39 (m, J = 17.7, 7.5 Hz, 9H), 7.18 (s,
1H), 6.94 (d, J = 7.6 Hz, 2H), 2.43 (s, 3H), 2.28 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 160.9 159.5, 138.4, 132.9, 131.1, 129.9,
+
129.5, 129.1, 128.4, 128.2, 127.4, 127.0, 123.9, 115.2, 29.8, 21.5, ppm. HRMS (ESI) m/z: calcd for C22H19N2O2S2 [M + H]+: 407.0882,
found: 407.0871.
(5ꢀ(4ꢀ(cyanomethyl)phenyl)ꢀ3ꢀphenylisothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3h) Yellow solid (67 mg, 50%). Mp 169.2 – 172.3 °C. IR 3113,
2960, 2920, 2851, 1597, 1532, 1260, 1136, 1048, 796 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.63 (t, J = 6.4 Hz, 4H), 7.50 (d, J = 7.5
Hz, 2H), 7.43 (d, J = 7.2 Hz, 3H), 7.39 – 7.31 (m, 2H), 7.26 (d, J = 11.1 Hz, 2H), 6.95 (d, J = 7.3 Hz, 2H), 3.85 (s, 2H), 2.28 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 141.9, 138.0, 134.2, 131.4, 129.6, 129.5, 129.2, 128.5, 128.2, 128.1, 127.6, 127.1, 117.0, 116.0, 23.7, 21.5 ppm.
HRMS (ESI) m/z: calcd for C24H20N3O2S2+ [M + H]+: 446.0991, found: 446.0972.
(3ꢀphenylꢀ5ꢀ(thiophenꢀ3ꢀyl)isothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3i) Brown solid (43 mg, 35%). Mp 158.2 – 160.7 °C. IR 3114, 2960, 2920,
1542, 1487, 1257, 1067, 792 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.74 (s, 1H), 7.61 (d, J = 7.5 Hz, 2H), 7.56 – 7.48 (m, 1H), 7.41
(d, J = 7.7 Hz, 3H), 7.37 – 7.28 (m, 3H), 7.10 (s, 1H), 6.93 (d, J = 7.7 Hz, 2H), 2.27 (s, 3H).13C NMR (100 MHz, Chloroformꢀd) δ 161.0,
+
138.1, 131.2, 129.5, 129.1, 129.0, 128.8, 128.4, 128.3, 127.0, 126.5, 125.4, 115.3, 21.5 ppm. HRMS (ESI) m/z: calcd for C20H17N2O2S3
[M + H]+: 413.0447, found: 413.0439.
(3ꢀ(4ꢀ(chloromethyl)phenyl)ꢀ5ꢀphenylisothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3k) Yellow solid (17 mg, 12%). Mp 113.4 – 114.9 °C. IR 3193,
3061, 2920, 2851,1595, 1488, 1164, 1080, 754 cmꢀ1 1H NMR (400 MHz, Chloroformꢀd) δ 8.58 (s, 1H), 7.89 (d, J = 12.7, 8.2 Hz, 4H), 7.61
(d, J = 7.0 Hz, 2H), 7.46 (d, J = 25.5, 16.3, 7.9 Hz, 5H), 7.33 (d, J = 8.1 Hz, 2H), 4.60 (s, 2H), 2.42 (s, 3H). 13C NMR (100 MHz,
Chloroformꢀd) δ 144.6, 139.5, 135.5, 135.2, 134.2, 132.4, 130.7, 129.9, 128.9, 128.8, 128.1, 127.1, 45.8, 21.8 ppm. HRMS (ESI) m/z:
calcd for C23H20ClN2O2S2+ [M + H]+: 455.0649, found: 455.0646.
(3ꢀ(4ꢀnitrophenyl)ꢀ5ꢀphenylisothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3l) Yellow solid (99 mg, 73%). Mp 153.7 – 155.7 °C. IR 3062, 2922,
2852, 1600, 1487, 1108, 1027, 798, 663 cmꢀ1 1H NMR (400 MHz, Chloroformꢀd) δ 8.28 (d, J = 8.6 Hz, 2H), 8.01 (d, J = 8.6 Hz, 2H), 7.66
(d, J = 8.2 Hz, 2H), 7.58 – 7.36 (m, 6H), 7.24 (s, 1H), 6.68 (s, 1H), 2.40 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 152.4, 146.0, 137.7,
+
134.7, 130.1, 129.9, 129.9, 129.1, 128.3, 128.1, 127.2, 124.2, 109.5, 21.9 ppm. HRMS (ESI) m/z: calcd for C22H18N3O4S2 [M + H]+:
452.0733, found: 452.0723.
(3ꢀ(4ꢀchlorophenyl)ꢀ5ꢀphenylisothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3m) Yellow solid (48 mg, 36%). Mp 185.9 – 189.7 °C. IR 2921, 2851,
1
1592, 1481, 1259, 1083, 762 cmꢀ1. H NMR (400 MHz, Chloroformꢀd) δ 7.57 (m, J = 24.2, 12.5, 7.5 Hz, 8H), 7.43 (d, J = 8.0 Hz, 2H),
7.31 (d, J = 8.4 Hz, 2H), 7.21 (s, 1H), 6.98 (d, J = 7.9 Hz, 2H), 2.30 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 159.7, 159.6, 141.8,
+
137.5, 132.2, 130.9, 130.1, 129.2, 128.8, 128.2, 127.0, 126.8, 115.1, 21.5 ppm. HRMS (ESI) m/z: calcd for C22H18ClN2O2S2 [M + H]+:
441.0493, found: 441.0495.
(5ꢀphenylꢀ3ꢀ(4ꢀ(trifluoromethyl)phenyl)isothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3n) Yellow solid (28 mg, 20%). Mp 165.2 – 167.2 °C. IR
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2961, 1534, 1487, 1295, 1112, 812, 760 cmꢀ1. H NMR (400 MHz, Chloroformꢀd) δ 7.73 (d, J = 8.1 Hz, 2H), 7.57 (m, J = 14.2, 6.7 Hz,
7H), 7.38 (d, J = 8.1 Hz, 2H), 7.27 (s, 1H), 6.93 (s, 2H), 2.28 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 160.1, 159.4, 141.8, 138.2,
132.4, 131.6, 130.1, 130.0, 129.2, 128.0, 126.9, 126.9, 125.3 (q, JCꢀF = 3.0 Hz), 115.3, 21.4 ppm. 19F NMR (376 MHz, CDCl3) δ ꢀ63.2 ppm.
HRMS (ESI) m/z: calcd for C23H18F3N2O2S2+ [M + H]+: 475.0756, found: 475.0746.
(3ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀphenylisothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3o) Yellow solid (68 mg, 52%). Mp 183.5 – 185.9 °C. IR 2962, 1599,
1486, 1258, 1131, 1027, 765, 650 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.76 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 6.9 Hz, 2H), 7.49 (m, J
= 13.2, 7.8 Hz, 5H), 7.22 (s, 1H), 6.96 (d, J = 7.8 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 3.84 (s, 3H), 2.27 (s, 3H). 13C NMR (100 MHz,
Chloroformꢀd) δ 161.9, 160.5, 158.7, 141.5, 138.8, 131.9, 131.5, 129.9, 129.0, 128.4, 127.0, 126.7, 120.9, 115.1, 113.8, 55.6, 21.4 ppm.
HRMS (ESI) m/z: calcd for C23H21N2O3S2+ [M + H]+: 437.0988, found: 437.0987.
(3ꢀ(naphthalenꢀ1ꢀyl)ꢀ5ꢀphenylisothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3p) Yellow solid (55 mg, 40%). Mp 163.0 – 164.8 °C. IR 3051, 2919,
1529, 1492, 1281, 1134, 762 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.92 (d, J = 7.7 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 6.9
Hz, 2H), 7.48 (m, J = 21.7, 15.0, 8.1 Hz, 6H), 7.36 – 7.15 (m, 5H), 6.65 (d, J = 7.7 Hz, 2H), 2.08 (s, 3H). 13C NMR (100 MHz,
Chloroformꢀd) δ 160.6, 159.2, 141.1, 138.6, 133.3, 132.1, 131.2, 130.4, 130.0, 129.3, 128.7, 128.6, 128.2, 127.2, 126.9, 126.8, 126.3,
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125.7, 124.9, 124.2, 117.1, 21.3 ppm. HRMS (ESI) m/z: calcd for C26H21N2O2S2+ [M + H]+: 457.1039, found: 457.1038.
(3ꢀ(furanꢀ2ꢀyl)ꢀ5ꢀphenylisothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3q) Yellow solid (71 mg, 60%). Mp 154.3 – 155.8 °C. IR 3091, 1591, 1496,
1283, 1140, 1062, 755 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 8.04 (d, J = 3.6 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.54 (m, J = 6.1, 1.8
Hz, 3H), 7.52 – 7.45 (m, 3H), 7.44 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.59 (m, J = 3.6, 1.7 Hz, 1H), 2.30 (s, 3H). 13C NMR (100 MHz,
Chloroformꢀd) δ 156.9, 145.3, 144.2, 142.0, 139.3, 131.7, 129.8, 129.3, 128.4, 127.0, 126.6, 119.6, 113.2, 111.3, 21.4 ppm. HRMS (ESI)
m/z: calcd for C20H16N2O3S2Na+ [M + Na]+: 419.0495, found: 419.0513.
(5ꢀphenylisothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3r) Black solid (69 mg, 60%). Mp 59.5 – 61.7 °C. IR 2923, 1607, 1510, 1488, 1161, 1027,
727, 689 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 9.13 (s, 1H), 7.87 – 7.81 (m, 2H), 7.56 – 7.49 (m, 3H), 7.48 – 7.41 (m, 2H), 7.30 (d, J
= 8.1 Hz, 2H), 6.52 (d, J = 4.5 Hz, 1H), 2.41 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 159.6, 143.9, 132.3, 129.7, 129.5, 127.9, 126.6,
110.5, 21.7 ppm. HRMS (ESI) m/z: calcd for C16H15N2O2S2+ [M + H]+: 331.0569, found:331.0572.
(3,5ꢀdiphenylisothiazolꢀ2ꢀiumꢀ2ꢀyl)(phenylsulfonyl)amide (3s) Yellow solid (59 mg, 50%). Mp 199.5 – 201.6 °C. IR 2973, 2882, 1483,
1087, 1046, 721, 692 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.66 – 7.57 (m, 4H), 7.57 – 7.49 (m, 5H), 7.42 (t, J = 7.4 Hz, 1H), 7.34 (t,
J = 7.6 Hz, 2H), 7.31 – 7.25 (m, 1H), 7.21 (s, 1H), 7.15 (t, J = 7.7 Hz, 2H). 13C NMR (100 MHz, Chloroformꢀd) δ 161.1, 141.5, 132.1,
131.2, 131.1, 130.0, 129.5, 128.6, 128.5, 128.4, 128.3, 127.0, 126.8, 115.4 ppm. HRMS (ESI) m/z: calcd for C21H16N2O2S2Na+ [M + Na]+:
415.0545, found: 415.0545.
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(3ꢀphenylꢀ5ꢀpropylisothiazolꢀ2ꢀiumꢀ2ꢀyl)(tosyl)amide (3u) Yellow solid (56 mg, 50%). Mp 114.1 – 116.6 °C. IR 3327, 2962, 1635, 1483,
1347, 1250, 757, 689 cmꢀ1. 1H NMR (400 MHz, Chloroformꢀd) δ 7.24 (dd, J = 9.5, 2.6 Hz, 1H), 7.21 – 7.12 (m, 6H), 6.89 (d, J = 8.1 Hz,
2H), 6.76 (s, 1H), 3.04 – 2.95 (m, 2H), 2.31 (s, 3H), 1.77 (m, J = 14.9, 7.4 Hz, 2H), 1.08 – 1.02 (m, 3H). 13C NMR (100 MHz, Chloroformꢀ
+
d) δ 143.7, 135.6, 134.2, 129.4, 128.7, 128.3, 127.6, 127.0, 125.5, 29.5, 23.8, 21.6, 14.2 ppm. HRMS (ESI) m/z: calcd for C19H21N2O2S2
[M + H]+: 373.1039, found: 373.1052.
isophthaloylbis((3,5ꢀdiphenylisothiazolꢀ2ꢀiumꢀ2ꢀyl)amide) (5a) Yellow solid (97 mg, 51%). Mp 129.5 – 131.7 °C. IR 2962, 2861, 1686,
1483, 1256, 1022, 755, 690 cmꢀ1 1H NMR (400 MHz, Chloroformꢀd) δ 7.57 (m, J = 28.1, 14.0, 7.1 Hz, 14H), 7.43 (t, J = 7.3 Hz, 2H), 7.31
(m, J = 23.2, 6.0 Hz, 5H), 7.23 (s, 2H), 7.16 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 161.5, 160.0, 141.2, 132.2, 131.3,
131.3, 130.0, 129.5, 128.6, 128.5, 128.2, 127.1, 126.9, 115.5 ppm. HRMS (ESI) m/z: calcd for C38H27N4O2S2+ [M + H]+: 635.1570, found:
635.1573.
4,6ꢀdiphenylꢀ2ꢀtosylꢀ2Hꢀ1,2,3ꢀthiadiazine 1ꢀoxide (7a) Yellow solid (105 mg, 82%). Mp 154.3 – 155.2 °C. IR 2962, 2919, 1259, 1009,
792, 662 cmꢀ1 1H NMR (400 MHz, Chloroformꢀd) δ 8.11 (d, J = 8.2 Hz, 2H), 7.77 (s, 4H), 7.59 – 7.50 (m, 3H), 7.44 (d, J = 4.6 Hz, 3H),
7.36 (d, J = 8.1 Hz, 2H), 7.26 (s, 1H), 2.42 (s, 3H). 13C NMR (100 MHz, Chloroformꢀd) δ 145.9, 134.8, 134.6, 133.2, 131.2, 130.6, 129.9,
129.8, 129.2, 129.0, 127.3, 126.7, 113.2, 21.9 ppm. HRMS (ESI) m/z: calcd for C22H19N2O3S2+ [M + H]+: 423.0832, found:423.0841.
ASSOCIATED CONTENT
Supporting Information Available.
The Supporting Information is available free of charge on the ACS Publications website at
http://pubs.acs.org.
Copies of 1H and 13C NMR spectra of the products and crystallographic data of 3a and 7a (PDF).
Crystal data for 3a (CIF).
Crystal data for 7a (CIF).
ACKNOWLEDGMENT
We gratefully acknowledge the National Natural Science Foundation of China (21772137, 21672157,
21372174), the Major Basic Research Project of the Natural Science Foundation of the Jiangsu Higher
Education Institutions (No. 16KJA150002), the Ph.D. Programs Foundation of PAPD, the project of
scientific and technologic infrastructure of Suzhou (SZS201708), and Soochow University for financial
support. We thank Fei Wang in this group for reproducing the result of 3a, 3c, and 3q.
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