Convenient Structural Diversity-Guided Synthesis of Functionalized Sulfur-Containing Heterocycles via α-Substituted Cyanoacetamides

Article abstract of DOI:10.1002/jhet.2792

A convenient molecular diversity-oriented synthesis of various functional sulfur-containing heterocyclic scaffolds mainly including isothiazole, 2H-1,3-thiazine, and thiazolidine via different methods from α-substituted cyanoacetamides is described. The target molecules have been identified on the basis of analytical spectral data, which may serve as useful structural subunits in the fields of drug discovery.

Full text of DOI:10.1002/jhet.2792

Month 2016
Convenient Structural Diversity-Guided Synthesis of Functionalized
Sulfur-Containing Heterocycles via α-Substituted Cyanoacetamides
*
Shaoyong Ke
National Biopesticide Engineering Research Center, Hubei Biopesticide Engineering Research Center, Hubei Academy of
Agricultural Sciences, Wuhan 430064, People’s Republic of China
*
E-mail: keshaoyong@163.com or shaoyong.ke@nberc.com
Received July 4, 2016
DOI 10.1002/jhet.2792
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
A convenient molecular diversity-oriented synthesis of various functional sulfur-containing heterocyclic
scaffolds mainly including isothiazole, 2H-1,3-thiazine, and thiazolidine via different methods from
α-substituted cyanoacetamides is described. The target molecules have been identified on the basis of analytical
spectral data, which may serve as useful structural subunits in the fields of drug discovery.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
diversity-oriented procedure for access to various
functional sulfur-containing heterocycles that exploit mild
ring-closure methods and easily available raw materials
(Fig. 2), and these heterocycles might serve as useful
structural subunits in the fields of drug discovery.
Sulfur is an essential element in the fields of life science
and organic chemistry [1]. Many sulfur-containing
building blocks play an important role in modern organic
synthesis and are also widely used in the pharmaceutical
industry, agrochemical chemistry, and materials science
[2–6]. Especially, many sulfur heterocyclic compounds
have been developed as drugs (such as penicillin [7],
sulfasomizole [8], saccharin [9], enzalutamide [10]; Fig. 1)
and agrochemicals (such as penthiopyrad [11], isotianil
[12], tiadinil [13], thiamethoxam [14], and fluensulfone
[15]; Fig. 1). In addition, some sulfur-containing
heterocycles and their derivatives can also be used as
important synthons for further transformation to related
heterocycles via diverse reaction conditions [16–19].
Up to now, organosulfur compounds have received
considerable attention because of their wide area of
application, so the development of novel functionalized
multi-substituted sulfur-containing heterocycles as
potential pharmaceuticals is still an important area of
interest in life science and the search for an efficient
method for the preparation of these heterocyclic
derivatives under mild conditions is not only highly
desirable but also necessary. In this short communication,
RESULTS AND DISCUSSION
Considering the convenient synthesis to construct the
structure diversity of sulfur-containing heterocyclic
derivatives, four different types of compounds (5, 6, 7, and
8) were investigated and obtained via α-substituted
cyanoacetamides 4. The general synthetic route for the
target compounds is outlined in Scheme 1.
For the sake of structural diversity, we attempted the
preparation of four different types of heterocyclic
compounds (5, 6, 7, and 8) using the key intermediates
α-substituted cyanoacetamides
4
as described in
Scheme 1. In order to explore these transformations, the
convenient preparation of intermediate heteroaryl-
isothiocyanates 3 is obviously important. Although the
substituted isothiocyanate can be prepared by several
methods [20–25], we desire to develop convenient and
effective methods for these heterocyclic isothiocyanates.
The representative compound 6-chloropyridin-3-amine
we would like to present
a convenient structural
© 2016 Wiley Periodicals, Inc.

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Vol 000
Figure 1. Representative structures of sulfur-containing heterocycles.
Figure 2. Construction strategy for various functional heterocycles.
Scheme 1. Synthetic route for sulfur-containing heterocyclic derivatives via α-substituted cyanoacetamides. Reagents and conditions: a. CS2, NaOH;
b. ClCOOEt; c. KOH, DMA; d. Br2, CH3COOEt; e. BrCH2COOEt, DMF; f. R3CHO, Cat. p-MeC6H4SO3H, EtOH. [Color figure can be viewed at
wileyonlinelibrary.com]
was chosen as a substrate for the optimization of the
reaction conditions, and four different methods have been
fully investigated (Scheme 2). The screened results
indicated that method C gives the best conversion and
yields (78%); however, the target intermediate can also be
obtained via methods A and B with very low yields (34%
and 28%, respectively). Especially, for Method B, the
reaction is very intense when the phosphorus oxychloride
is dropped, and this reaction is difficult to handle.
Furthermore, the transformation cannot be completed
according to method D, which just stay at the stage of
intermediate 1,3-bis(6-chloropyridin-3-yl)thiourea.
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Scheme 2. The optimization of the reaction conditions for heterocyclic isothiocyanate.
After the optimization of the conditions for
intermediates 3, various transformations for different
heterocyclic derivatives have been fully explored. The
key intermediates α-substituted cyanoacetamides 4 were
conveniently obtained via nucleophilic additional reaction
between compounds 3 and substituted cyanoacetamide
under the optimized alkaline conditions. In the process of
screening for the practical reaction conditions, the
different reaction systems mainly including Et3N/MeCN,
Et3N/DMF, and Et3N/DMA were tried, but did not work
for this procedure. Then, the strong inorganic base in polar
solvent was adopted to explore this transformation, and
the results demonstrated that this system can conveniently
prepare the target compounds under simple process.
Subsequently, the constructions of different sulfur
heterocyclic derivatives was explored via different
heterocyclization reactions. First, the intermediate 4 was
transformed into the corresponding substituted
isothiazole derivatives 5 via bromine oxidation reaction.
However, the separation and purification of the
products were obviously affected by different solvents.
When we adopted dichloromethane as solvent in this
heterocyclization reaction, the target compounds was not
easy to separate from the mixtures, but in the ethyl
acetate, it was easy to separate the products because of the
differences in the solubility of the raw materials and
products. Then, the substituted isothiazole derivatives 6
can also be conveniently prepared via a similar method
presence of ethanol. Irrespective of the fact whether
aromatic or aliphatic aldehydes were used, the cyclization
proceeded very smoothly in the same reaction conditions.
All target compounds gave satisfactory chemical analyses,
and the general procedures and spectral data were
described in the Experimental section.
CONCLUSIONS
In summary, a convenient structural diversity-oriented
synthesis of functionalized sulfur-containing heterocyclic
scaffolds is described. The target isothiazole, 2H-
1,3-thiazine, and thiazolidine heterocyclic derivatives have
been prepared from α-substituted cyanoacetamides, which
have been identified on the basis of analytical spectral data.
EXPERIMENTAL
Instrumentation and chemicals.
All melting points
(m.p.) were obtained using a digital model X-5 apparatus
(Gongyi Yuhua Instrument Co., LTD, Gongyi, China)
and are uncorrected. The infrared absorption spectra were
recorded on a Thermo Nicolet FT-IR Avatar 330
instrument (Thermo Electron Corporation, Waltham, MA)
1
in KBr discs and are reported in cmÀ1. H NMR spectra
were recorded on a Brucker spectrometer (Bruker,
Fallanden, Switzerland) at 400MHz with DMSO-d6 as
the solvent and TMS as the internal standard. 13C NMR
spectra were recorded on a Brucker spectrometer at
150 MHz with DMSO-d6 as solvent and TMS as the
internal standard. Chemical shifts are reported in δ (parts
to compound
5
from N-substituted α-substituted
cyanoacetamides 4. After this, according to the general
method for synthesis of thiazolidine heterocycles, the
ethyl 2-bromoacetate was used to construct the substituted
thiazolidine 7 via sequence electrophilic substitution and
intramolecular cyclization reactions. Furthermore, the
intermediates 4 were used to react with appropriate
aldehydes to give the corresponding heterocyclic 2H-
1,3-thiazine derivatives 8 via classic heterocyclization
reactions catalyzed by p-toluene sulfonic acid in the
n
per million) values. Coupling constants J are reported in
Hz. Mass spectra were performed on a MicroMass
Quattro microTM API instrument (Waters, Milford, MA).
Elemental analysis was performed on a Vario EL III
elemental analysis instrument (Elementar Analysensysteme
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GmbH, Germany). Analytical thin-layer chromatography
(TLC) was carried out on precoated plates, and spots were
visualized with ultraviolet light. All chemicals or reagents
were purchased from standard commercial supplies, which
were analytical grade and used directly without purification.
General synthetic procedure for the intermediate 3. To a
solution of sodium hydroxide (0.4g, 0.01mol) in water
(5mL) was added carbon disulfide (1.14g, 0.015mol)
under ice bath, and then substituted aromatic amine 1
(0.01mol) was slowly added for about 30min. After that,
the ice bath was removed, and the mixture was rose to
room temperature, and then the reaction mixture was
heated to 70–80°C and monitored by TLC. After
completion, the resulting mixture was cooled to room
temperature, and the excess carbon disulfide was removed
under vacuum distillation. Then, the residue was extracted
by toluene, and the aqueous phase was directly used for the
following transformation. To the obtained aqueous phase
was added dropwise ethyl chloroformate (0.011mol) under
30–35°C, and then the temperature of the mixture was
maintained and detected by TLC. On completion of the
reaction, the mixture was extracted with dichloromethane.
The organic layer was washed with water and brine and
dried over anhydrous sodium sulfate, and the solvent was
removed under reduced pressure to obtain the products.
General synthetic procedure for the intermediate 4. To a
stirring solution of cyanoacetamide (1.68 g, 0.02mol) in
20mL of N,N-dimethylacetamide was added 2.65g
(0.04mol) of KOH powder. After 20min, the newly
prepared substituted isothiocyanate (0.015mol) was added in
5mL of N,N-dimethylacetamide. The mixture was stirred
until the substituted isothiocyanate was disappeared, and
then the reaction mixture was poured into ice water, and the
pH value of the system was adjusted to 5–6. The mixture
was stirred for additional 30 min, and the solid was separated
after filtration, which were used directly without purification.
General synthetic procedure for substituted isothiazoles 5
5-((6-Chloropyridin-3-yl)amino)-3-hydroxyisothiazole-4-
carbonitrile 5b. White powder, yield 79%, m.p. >250°C;
IR (KBr, cmÀ1): υ 3316 (br, OH), 3150 (NH), 2172 (CN)
1
cmÀ1; H NMR (400MHz, DMSO-d6): δ= 10.82 (s, 1H,
NH), 8.41 (s, 1H, Py-H), 7.81 (dd, J= 8.4 Hz, 1H, Py-H),
7.57 (d, J =8.8 Hz, 1H, Py-H); 13C NMR (150MHz,
DMSO-d6): δ 161.3, 154.4, 145.2, 138.3, 134.5, 128.6,
126.4, 112.1, 89.6; MS (ESI) m/z 253.4 (M +H)+, calcd
for C9H5ClN4OS m/z= 252.0. Anal. Calcd for
C9H5ClN4OS: C, 42.78; H, 1.99; N, 22.17. Found: C,
42.52; H, 1.83; N, 22.33.
2-Cyclohexyl-3-oxo-5-(phenylamino)-2,3-dihydroisothiazole-
4-carbonitrile 6a. White powder, yield 86%, m.p. 207–
208°C; IR (KBr, cmÀ1): υ 3138 (NH), 2183 (CN), 1647
(CO) cmÀ1 1H NMR (400MHz, DMSO-d6): δ = 10.94
;
(s, 1H, NH), 7.45 (t, J= 8 Hz, 2H, Ph-H), 7.37–7.26 (m,
3H, Ph-H), 4.17–4.06 (m, 1H, N–CH), 1.83–1.65 (m, 4H,
Cy-H), 1.61–1.49 (m, 1H, Cy-H), 1.43–1.22 (m, 4H, Cy-
H), 1.15–1.01 (m, 1H, Cy-H); 13C NMR (150MHz,
DMSO-d6): δ 169.2, 161.5, 135.4, 132.3, 128.1, 124.7,
117.6, 86.2, 63.8, 37.5, 27.4, 23.3; MS (ESI) m/z 300.6
(M + H)+, calcd for C16H17N3OS m/z =299.1. Anal. Calcd
for C16H17N3OS: C, 64.19; H, 5.72; N, 14.04. Found: C,
63.98; H, 5.87; N, 14.18.
5-((6-Chloropyridin-3-yl)amino)-2-cyclohexyl-3-oxo-2,3-
dihydroisothiazole-4-carbonitrile 6b. White powder, yield
75%, m.p. 218–220°C; IR (KBr, cmÀ1): υ 3148 (NH), 2189
1
(CN), 1654 (CO) cmÀ1; H NMR (400MHz, DMSO-d6):
δ =11.04 (s, 1H, NH), 8.47 (s, 1H, Py-H), 7.90 (q,
J = 8.4 Hz, 1H, Py-H), 7.62 (d, J = 8.8 Hz, 1H, Py-H), 4.20–
4.10 (m, 1H, N-CH), 1.82–1.73 (m, 4H, Cy-H), 1.65–1.50
(m, 1H, Cy-H), 1.45–1.31 (m, 4H, Cy-H), 1.20–1.05 (m,
1H, Cy-H); 13C NMR (150MHz, DMSO-d6): δ 171.4,
165.2, 139.5, 136.4, 131.5, 127.5, 125.2, 116.3, 89.6, 67.2,
39.3, 28.1, 23.9; MS (ESI) m/z 335.6 (M+ H)+, calcd for
C15H15ClN4OS
m/z= 334.1.
Anal.
Calcd
for
C15H15ClN4OS: C, 53.81; H, 4.52; N, 16.73. Found: C,
53.64; H, 4.38; N, 16.81.
and 6.
The substituted isothiazole derivatives 5 and 6
General synthetic procedure for substituted thiazolidine
7. The prepared intermediate 4 (1 mmol) was dissolved
in dimethylformamide (8 mL), and the ethyl bromoacetate
(1.2 mmol) was added. The reaction mixture was heated
to 75–80°C for about 4–5 h, and the mixture was
neutralized with saturated sodium carbonate solution, and
ice water was added. The resulting precipitate was
were conveniently prepared via bromine oxidation reaction
of compound 4. The typical procedures are as follows: To
a stirring solution of compound 4 (1mmol) in 10mL of
ethyl acetate was added dropwise bromine (1.2mmol in
ethyl acetate). After 20min stirring at ambient temperature,
the solid was filtrated and washed with ethyl acetate.
3-Hydroxy-5-(phenylamino)isothiazole-4-carbonitrile 5a.
filtered off and recrystallized from ethanol.
White powder, yield 84%, m.p. 232–234°C; IR (KBr,
cmÀ1): υ 3284 (br, OH), 3125 (NH), 2158 (CN) cmÀ1; 1H
NMR (400 MHz, DMSO-d6): δ =10.67 (s, 1H, NH), 7.42
(t, J= 8 Hz, 2H, Ph-H), 7.30 (d, J = 8 Hz, 2H, Ph-H), 7.19
(t, J= 8 Hz, 1H, Ph-H); 13C NMR (150 MHz, DMSO-d6):
δ 168.5, 165.7, 137.2, 133.8, 130.3, 125.6, 115.5, 81.4;
MS (ESI) m/z 218.3 (M+ H)+, calcd for C10H7N3OS
m/z= 217.0. Anal. Calcd for C10H7N3OS: C, 55.29;
H, 3.25; N, 19.34. Found: C, 55.10; H, 3.08; N, 19.52.
2-Cyano-2-(4-oxo-3-phenylthiazolidin-2-ylidene)acetamide
7a. White powder, yield 77%, m.p. >250°C; IR (KBr,
cmÀ1): υ 3275, 3242 (NH), 2174 (CN), 1731, 1636 (CO)
1
cmÀ1; H NMR (400MHz, DMSO-d6): δ= 7.63–7.57 (m,
4H, Ph-H), 7.48 (bs, 1H, NH), 7.32–7.27 (m, 1H, Ph-H),
2
7.11 (bs, 1H, NH), 3.88 (d, J = 1.8 Hz, 2H, CH2); 13C
NMR (150 MHz, DMSO-d6): δ 166.5, 161.4, 142.6,
137.1, 132.4, 128.6, 118.5, 88.2, 71.4, 40.2; MS (ESI) m/z
260.3 (M+ H)+, calcd for C12H9N3O2S m/z= 259.0. Anal.
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Calcd for C12H9N3O2S: C, 55.59; H, 3.50; N, 16.21. Found:
C, 55.43; H, 3.36; N, 16.37.
2-(3-(6-Chloropyridin-3-yl)-4-oxothiazolidin-2-ylidene)-2-
S–CH), 2.35 (m, 2H, CH2), 1.08 (t, J = 8Hz, 3H, CH3);
13C NMR (150MHz, DMSO-d6): δ 171.3, 166.4, 158.6,
142.4, 138.6, 128.1, 125.7, 118.3, 86.8, 57.2, 38.6, 10.5;
MS (ESI) m/z 295.5 (M + H)+, calcd for C12H11ClN4OS
m/z= 294.0. Anal. Calcd for C12H11ClN4OS: C, 48.90; H,
cyanoacetamide 7b.
White powder, yield 73%, m.p.
>250°C; IR (KBr, cmÀ1): υ 3316, 3274 (NH), 2186
(CN), 1748, 1644 (CO) cmÀ1 1H NMR (400MHz,
;
3.76; N, 19.01. Found: C, 48.69; H, 3.62; N, 19.26.
DMSO-d6): δ= 8.53 (d, J = 4Hz, 1H, Py-H), 8.02
(q, J =8 Hz, 1H, Py-H), 7.75 (d, J = 8Hz, 1H, Py-H),
7.44 (bs, 1H, NH), 7.07 (bs, 1H, NH), 3.92 (d,
2J = 1.6Hz, 2H, CH2); 13C NMR (150 MHz, DMSO-d6):
δ 169.3, 164.5, 143.1, 140.2, 137.8, 133.5, 126.2,
120.4, 92.6, 73.5, 43.6; MS (ESI) m/z 295.4 (M+ H)+,
calcd for C11H7ClN4O2S m/z = 294.0. Anal. Calcd for
C11H7ClN4O2S: C, 44.83; H, 2.39; N, 19.01. Found: C,
44.58; H, 2.27; N, 19.32.
6-((6-Chloropyridin-3-yl)amino)-4-oxo-2-phenyl-3,4-
dihydro-2H-1,3-thiazine-5-carbonitrile 8d.
Pale yellowish
solid, yield 81%, m.p. >250°C; IR (KBr, cmÀ1): υ 3359,
3318 (NH), 2202 (CN), 1712, 1668 (CO) cmÀ1 1H
;
NMR (400 MHz, DMSO-d6): δ = 10.78 (s, 1H, NH), 8.67
(s, 1H, NH), 8.40 (s, 1H, Py-H), 7.85–7.62 (m, 6H, Py-H
and Ph-H), 7.56 (d, J = 8Hz, 1H, Py-H), 5.73 (s, 1H,
S–CH); 13C NMR (150MHz, DMSO-d6): δ 170.2, 167.5,
156.4, 144.6, 140.3, 137.4, 130.5, 128.4, 126.6, 122.4,
120.1, 116.8, 91.6, 65.7; MS (ESI) m/z 343.4 (M +H)+,
calcd for C16H11ClN4OS m/z= 342.0. Anal. Calcd for
C16H11ClN4OS: C, 56.06; H, 3.23; N, 16.34. Found: C,
49.83; H, 3.05; N, 16.52.
General synthetic procedure for 1,3-thiazine 8.
To a
solution of α-substituted cyanoacetamides 4 (1 mmol) in
anhydrous ethanol (15 mL) was added corresponding
aldehyde (1.1 mmol) and catalytic amount of
p-toluenesulfonic acid at room temperature, and then the
stirred mixture was refluxed for several hours, which was
monitored by TLC. Then the solution was concentrated,
and the heterocyclization products 8 separated out on
Acknowledgments. This work was supported in part by the
Applied Basic Research Program of Wuhan City
(2016020101010093) and Hubei Agricultural Science Innovation
Centre (2016-620-000-001-039). The authors also gratefully
acknowledge the partial support from the Key Laboratory
of Integrated Pest Management in Crops in Central China,
Ministry of Agriculture and Key Laboratory for Crop Diseases,
Insect Pests and Weeds Control in Hubei Province
(2015ZTSJJ9).
cooling and were recrystallized from aqueous ethanol.
2-Ethyl-4-oxo-6-(phenylamino)-3,4-dihydro-2H-1,3-thiazine-
5-carbonitrile 8a. Pale yellowish solid, yield 83%, m.p.
225–227°C; IR (KBr, cmÀ1): υ 3352, 3314 (NH), 2195
(CN), 1723, 1678 (CO) cmÀ1 1H NMR (400MHz,
;
DMSO-d6): δ =10.42 (s, 1H, NH), 8.56 (s, 1H, NH), 7.48
(t, J = 8 Hz, 2H, Ph-H), 7.38–7.27 (m, 3H, Ph-H), 4.81 (t,
J =8.4 Hz, 1H, S-CH), 2.38 (m, 2H, CH2), 1.14 (t, J = 8Hz,
3H, CH3); 13C NMR (150 MHz, DMSO-d6): δ 167.6,
164.3, 139.1, 130.2, 127.3, 125.4, 119.4, 82.7, 59.6, 37.5,
10.8; MS (ESI) m/z 260.6 (M +H)+, calcd for C13H13N3OS
m/z= 259.1. Anal. Calcd for C13H13N3OS: C, 60.21; H,
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4-Oxo-2-phenyl-6-(phenylamino)-3,4-dihydro-2H-1,3-
thiazine-5-carbonitrile 8b.
Pale yellowish solid, yield
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2210 (CN), 1704, 1658 (CO) cmÀ1; H NMR (400MHz,
1
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7.65–7.48 (m, 7H, Ph-H), 7.25–7.18 (m, 3H, Ph-H), 5.68
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6-((6-Chloropyridin-3-yl)amino)-2-ethyl-4-oxo-3,4-dihydro-
2H-1,3-thiazine-5-carbonitrile 8c.
Pale yellowish solid,
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3327 (NH), 2208 (CN), 1716, 1663 (CO) cmÀ1 1H
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet