Synthesis and Fungicidal Activity of Simple Structural 1,3-Thiazolidine-2-Thione Derivatives

Article abstract of DOI:10.1080/10426507.2014.931399

A series of simple structural 1,3-thiazolidine-2-thione derivatives with various substituents on the S-, N-, 4-, and 5-positions was synthesized with high yields from various vicinal amino alcohols via two steps and screened for their antifungal activity. Bioassay results reveal that some thiazolidine-2-thione derivatives show strong antifungal activities against P. capsici, G. zeae, S. sclerotiorum, A. alternata, B. cinerea, or R. solani. The SAR analysis indicates that N-acyl substituted and 4-alkyl substituents can enhance the antifungal activity. Notably, 4-isopropyl-N-propionylthiazoldine-2-thione shows excellent activity against B. cinerea and G. zeae with IC₅₀ values at 3.7 g/mL and 6.5 g/mL, respectively, and 4-isobutyl-N-propionylthiazoldine-2-thione shows remarkable fungicidal activity against R. solani, S. sclerotiorum, and G. zeae with IC₅₀ values at 1.0 g/mL, 12.1 g/mL, and 11.0 g/mL, respectively. GRAPHICAL ABSTRACT.

Full text of DOI:10.1080/10426507.2014.931399

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis and Fungicidal Activity of Simple Structural
1,3-Thiazolidine-2-thione Derivatives.
Ning Chena, Hongguang Dua, Weidong Liub, Shanshan Wanga, Xinyao Lia & Jiaxi Xua
a State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry,
Faculty of Science, Beijing University of Chemical Technology, Beijing 100029, China
b Hunan Research Institute of Chemical Industry, Changsha, Hunan, 410007, China
Accepted author version posted online: 26 Jun 2014.
To cite this article: Ning Chen, Hongguang Du, Weidong Liu, Shanshan Wang, Xinyao Li & Jiaxi Xu (2014): Synthesis and
Fungicidal Activity of Simple Structural 1,3-Thiazolidine-2-thione Derivatives., Phosphorus, Sulfur, and Silicon and the Related
Elements, DOI: 10.1080/10426507.2014.931399
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SYNTHESIS AND FUNGICIDAL ACTIVITY OF SIMPLE STRUCTURAL 1,3-
THIAZOLIDINE-2-THIONE DERIVATIVES.
Ning Chena, Hongguang Dua, Weidong Liub, Shanshan Wanga, Xinyao Lia, and Jiaxi Xua
a State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry,
Faculty of Science, Beijing University of Chemical Technology, Beijing 100029, China
b Hunan Research Institute of Chemical Industry, Changsha, Hunan, 410007, China.
Corresponding author. e-mail: jxxu@mail.buct.edu.cn
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Abstract A series of simple structural 1,3-thiazolidine-2-thione derivatives with various
substituents on the S-, N-, 4-, and 5-positions was synthesized with high yields from various
vicinal amino alcohols via two steps and screened for their antifungal activity. Bioassay results
reveal that some thiazolidine-2-thione derivatives show strong antifungal activities against P.
capsici, G. zeae, S. sclerotiorum, A. alternate, B. cinerea, or R. solani. The SAR analysis
indicates that N-acyl substituted and 4-alkyl substituents can enhance the antifungal activity.
Notably, 4-isopropyl-N-propionylthiazoldine-2-thione shows excellent activity against B. cinerea
and G. zeae with IC50 values at 3.7 µg/mL and 6.5 µg/mL, respectively, and 4-isobutyl-N-
propionylthiazoldine-2-thione shows remarkable fungicidal activity against R. solani, S.
sclerotiorum, and G. zeae with IC50 values at 1.0 µg/mL, 12.1 µg/mL, and 11.0 µg/mL,
respectively.
S
S
O
O
N
S
N
S
(S)
(S)
4g
4h
µ
IC50 = 1.0 g/mL for R. solani
µ
IC50 = 3.7 g/mL for B.cinerea
µg
IC50 = 12.1 /mL for S. scler otiorum
µg
IC50 = 6.5 /mL for G.Zeae
µg
IC50 = 11.0 /mL for G. zeae
Keywords Thiazolidine-2-thione, Fungicidal, Heterocycle, Synthesis, Bioactivity
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INTRODUCTION
Plant pathogenic fungi are one of the main threats for the growth of crops. Developing new
fungicides for the control of plant pathogenic fungi is always an imperative demand for the
future crops production. Thiazolidines, as the representatives of five-membered heterocycles, are
of considerable interest in different areas of medicinal chemistry.1 As an important class of
thiazolidine derivatives, thiazolidine-2-thione derivatives have been widely used in
pharmaceuticals and agrochemicals. For example, 1,3-thiazolidine-2,4-diones, Rhodanine
derivatives, are well-known compounds which show diversified biological activities such as anti-
hyperlycaemics, aldose reductase inhibitors, anti-cancer, anti-inflammatory, anti-arthritics, and
anti-microbials.2 As structural analogs, 1,3-thiazolidine-2-thione derivatives, however, have been
seldom reported with their biological activity though they have been widely used as chiral
auxiliaries in catalytic asymmetric synthesis in organic chemistry.3 Previous research has shown
that a series of thiazolidine-2-thiones containing N-acyl4 and N-arylaminocarbonyl5 substituents
have some fungicidal and pesticide activities. Some S-benzylthiazolines, synthesized from
thiazolidine-2-thiones, showed moderate or poor activity against E. subtilis, E. coli, P.
aeruginosa, C. albicans, and A. niger.6 However, all these bioactive compounds were generated
from 1,3-thiazolidine-2-thione itself without any substituents on the 4- and/or 5-position(s) in the
five-membered ring. Recently, Sasson and Gruzman reported that 2-(benzo[d]thiazolin-2-
ylmethylthio)-6-ethoxybenzo[d]thiazole, an 2-alkylthio substituted thiazoline compound
generated from the corresponding benzothiazolidine-2-thione, showed a high fit value to a
pharmacophore model derived from the structure of 2-chloro-5-{(Z),(E)-5-[(5-(4,5-dimethyl-2-
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nitrophenyl)furan-2-yl]methylene-4-oxothiazolidin-2-ylideneamino}benzoic acid (PT-1).7 Their
results made us believe that introducing diverse substituents on the thiazolidine-2-thione ring
might enhance their various bioactivities. Herein, 32 compounds including 14 new compounds
and 20 optically active ones were synthesized and screened for the fungicidal activities against
six phytopathogenic fungi with Rhizoctonia solani, Botrytis cinerea, Sclerotonia sclerotiorum,
Gibberella zeae, Phytophythora capsici, and Alternaria alternate.
RESULTS AND DISCUSSION
Various 4-alkyl, 4-aryl, 5-alkyl, or 5-aryl-1,3-thiazolidine-2-thiones 2 were synthesized from
the corresponding vicinal amino alcohols 1 according to our previous work.8 Optically active
compounds were also generated from the corresponding chiral vicinal amino alcohols. 2-
Benzylthio-1,3-thiazolines 3 were generated from 2 and benzyl chloride in good to excellent
yields with potassium carbonate as base under reflux.9
3-Propionylthiazolidine-2-thiones 4a-c were synthesized with good yields from 2a-c and
propionyl chloride at room temperature in the presence of triethyl amine (Table 1, entries 9–
11).10 However, the 4-substituted 1,3-thiazolidine-2-thiones 2d and 2h gave rise to the
corresponding products with lower yields (35% and 27%, respectively) under the same
conditions due to steric hindrance (Table 1, entries 12 and 17). In order to improve the yields, we
applied the stronger base sodium hydride at 78°C instead of n-BuLi used in the literature,10 and
achieved the desired products with good to excellent yields (Table 1, entries 12–16).
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N-(4-Chlorophenyl)-2-thioxothiazolidine-3-carboxamides
5
were obtained from 1,3-
thiazolidine-2-thiones 2 and p-chlorophenyl isocyanate in the presence of triethyl amine at room
temperature and subsequent recrystallization from ethanol or a mixture of hexane and diethyl
ether. It should be paid attention to the formation of a small amount of ethyl p-
chlorophenylcarbamate as by-product when ethanol was used as the recrystallization solvent due
to alcoholysis.
The preliminary antifungal activities of all synthesized compounds against the
phytopathogenic fungi, Rhizoctonia solani, Botrytis cinerea, Sclerotonia sclerotiorum,
Gibberella zeae, Phytophythora capsici, Alternaria alternata, were evaluated at a concentration
of 25 µg/mL. Their inhibition rates are listed in Table 2. Compared with Azoxystrobin, a
commercially available fungicide with a broad spectrum of bioactivity, many compounds shows
good to excellent fungicidal activities. 4-Benzylthiazolidine-2-thione (2f) and 4-isobutyl-N-
propionylthiazolidine-2-thione (4h) possess high activities against Sclerotonia sclerotiorum. In
addition, 2f and 4-isopropyl-N-propionylthiazoldine-2-thione (4g) also show high antifungal
activities against Botrytis cinerea. Inspiringly, most N-propionyl thiazolidine-2-thiones 4 show
moderate to excellent inhibitive activities against the phytopathogenic fungi. Typically, both 4g
and 4h at 25 µg/mL exhibit a broad fungicidal activity. They especially inhibit the growth of
Gibberella zeae at 100%, and 4h at 90% against Rhizoctonia solani. In addition, N-p-
chlorophenyl-4-isobutyl-2-thioxothiazolidine-3-carboxamide (5h) also shows 90% inhibition to
Rhizoctonia solani. To analize the structure activity relationship (SARA), the 4-substituted 1,3-
thiazolidine-2-thiones 2 show some fungicidal activities against Sclerotonia sclerotiorum,
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Alternaria alternata, and Botrytis cinerea, especially compound 2e. Comparing with the non-
substituted thiazolidine-2-thione 1a, substituents at the 4- and 5-positions can improve the
fungicidal ability, especially 4-substituted compounds, such as 2e (R1 = Me), 2f (R1 = Bn), and
2h (R1 = i-Bu). However, all 2-benzylthio-1,3-thiazolines 3 did not show any good fungicidal
activity. We are delighted to find that all N-propionylthiazolidine-2-thiones 4 displayed moderate
to good fungicidal activities, especially 4-substituted ones, such as 4e (R1 = Me), 4g (R1 = i-Pr),
and 4h (R1 = i-Pr). Comparatively, all 4-substituted N-p-chlorophenyl-2-thioxothiazolidine-3-
carboxamides 5 show poor activities, except 5h. The SARA results demonstrate that N-acyl
substituents and substituent at the 4-position are preferable for improving the antifungal activity
of 1,3-thiazolidine-2-thiones. However, substituents at the 5-position of 1,3-thiazolidine-2-thione
and 1,3-thiazoline rings (such as 2b-c, 3b-c, 4b-c, and 5b-c) are not beneficial for the fungicidal
activity.
On the basis of previous bioassays, the IC50 values of some excellent fungicidal compounds
(2f, 4g, 4h, and 5h) are listed in Table 3. Notably, compound 4g exhibits wonderful activities
against Botrytis cinerea and Gibberella zeae with IC50 values of 3.7 and 6.5 µg/mL, and
compound 4h shows excellent antifungal activities with IC50 values against S. sclerotiorum, G.
zeae, and R. solani, at 12.1 µg/mL, 10.9 µg/mL, and 1.0 µg/mL, respectively.
CONCLUSIONS
In summary, a series of structural simple thiazolidine-2-thione derivatives was synthesized
with moderate to good yields and screened for their antifungal activity. A preliminary bioassay
shows that all thiazolidine-2-thione derivatives exhibited antifungal activities against P. capsici,
G. zeae, S. sclerotiorum, A. alternate, B. cinerea, or R. solani. The SAR analysis reveals that N-
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acyl substituted and bulky 4-substituents can enhance the antifungal activities. The further
antifungal assay demonstrates that two compounds 4g and 4h were identified as the most
promising candidates for further study. Compound 4g shows excellent activity against B. cinerea
and G. zeae with IC50 values at 3.7 µg/mL and 6.5 µg/mL, respectively, and compound 4h shows
remarkable fungicidal activities against R. solani, S. sclerotiorum, and G. zeae with IC50 values
from 1.0 to 12.1 µg/mL.
EXPERIMENTAL
Melting points were obtained on a Yanaco MP-500 melting point apparatus and are
uncorrected. Optical rotations were measured on a Perkin Elmer 341LC polarimeter or Anton
1
Paar MCP200 polarimeter. The H and 13C NMR spectra were recorded on a Varian Mercury
200, Varian Mercury 300 Plus, or Bruker 400 spectrometer with tetramethylsilane (TMS) as
internal standard in CDCl3 solution. Chemical shifts (δ) are reported in ppm. IR Spectra (CDCl3)
were taken on a Nicolet 5700 Fourier transform infrared (FT-IR) spectrometer. HRMS data were
determined using an Agilent LC/MSD TOF mass spectrometer. The Supplemental Materials
contains 1H and 13C NMR spectra for selected compounds 3, 4 and 5 (Figures S 1 – S 47)
Supplemental data for this article can be accessed on the publisher's website. <TQ> Please
make the words "publisher's website" a live DOI link. </TQ>
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General Procedure for the Preparation of 2-Benzylthio-1,3-thiazolines 3
Thiazolidine-2-thione 2 (2.5 mmol), benzyl chloride (317 mg, 2.5 mmol), and K2CO3 (691 mg, 5
mmol) were dissolved in 10 mL of acetone. The resulting solution was refluxed for 2-4 h under
TLC monitoring and then was allowed to cool to r.t. and filtered. After removal of the solvent,
the crude product was obtained and purified by silica-gel column chromatography with a mixture
of petroleum ether and EtOAc (10:1, v/v) as eluent.
2-Benzylthio-1,3-thiazoline (3a).6 Yield 89%, colorless crystals. M. p. 50-52°C. 1H NMR
(300 MHz): δ 7.46 – 7.24 (m, 5H, ArH), 4.36 (s, 2H, CH2Ph), 4.23 (t, J = 8.0 Hz, 2H, CH2N),
3.40 (t, J = 8.0 Hz, 2H, CH2S). 13C NMR (75 MHz): δ 165.2, 136.5, 129.0, 128.6, 127.5, 64.2,
36.9, 35.6.
()-2-Benzylthio-5-methyl-1,3-thiazoline (3b).11 Yield 87%, Pale yellow oil. 1H NMR (300
MHz): δ 7.38-7.26 (m, 5H, ArH), 4.37 (d, J = 13.2 Hz, 1H, CH2Ph), 4.33 (d, J = 13.2 Hz, 1H,
CH2Ph), 4.19 (dd, J = 6.6, 13.6 Hz, 1H, CH2N), 4.03 (ddq, J = 4.4, 6.6, 13.2 Hz, 1H, CHS), 3.96
(dd, J = 4.4, 13.6 Hz, 1H, CH2N), 1.37 (d, J = 6.6 Hz, 1H, CH3). 13C NMR (75.5 MHz): δ 164.5,
136.5, 129.0, 128.6, 127.4, 71.1, 48.2, 36.8, 21.4.
(R)-2-Benzylthio-5-phenyl-1,3-thiazoline (3c). Yield 89%, colorless crystals, M.p. 46-
49°C. [α]2D0 = +298.4 (c = 1.4, Me2CO). IR: 1561 (C=N). 1H NMR (200 MHz): δ 7.39-7.27 (m,
10H, ArH), 5.03 (dd, J = 8.3, 6.0 Hz, 1H, CHS), 4.52 (dd, J = 14.9, 8.3 Hz, 1H, CH2N), 4.38 (s,
2H, CH2Ph), 4.43 (dd, J = 14.9, 6.0 Hz, 1H, CH2N). 13C NMR (50 MHz): δ 164.4, 141.0, 136.4,
129.0, 128.7, 128.5, 127.8, 127.4, 127.0, 72.1, 56.7, 36.8. HRMS (ESI) m/z 286.0712. Calcd for
+
C16H16NS2 : 286.0719 [M+H]+.
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(S)-2-Benzylthio-4-phenyl-1,3-thiazoline (3d). Yield 92%. M. p. 59-60°C. [α]2D0 = +170.2
(c = 1.4, Me2CO). IR: 1566 (C=N). 1H NMR (300 MHz): δ 7.31 (m, 10H, ArH), 5.49 (dd, J =
8.3, 9.0 Hz, 1H, CHN), 4.45 (d, J = 13.2 Hz, 1H, CH2Ph), 4.36 (d, J = 13.2 Hz, 1H, CH2Ph),
3.75 (dd, J = 8.3, 10.8 Hz, 1H, CH2S), 3.26 (dd, J = 9.0, 10.8 Hz, 1H in CH2S). 13C NMR (75.5
MHz): δ 165.6, 141.5, 136.7, 129.1, 128.55, 128.50, 127.6, 127.4, 126.4, 79.5, 42.9, 37.0. HRMS
(ESI) m/z, 286.0714. Calcd. for C16H16NS2: 286.0719 [M+H]+.
(S)-2-Benzylthio-4-benzyl-1,3-thiazoline (3f). Yield 91%. Pale yellow oil. [α]2D0 = 34.0 (c
= 0.6, Me2CO). IR: 1564 (C=N). 1H NMR (300 MHz): δ 7.37–7.14 (m, 10H, ArH), 4.67 (dddd, J
= 8.7, 7.8, 6.7, 5.4 Hz, 1H, CHN), 4.38 (d, J = 13.2 Hz, 1H, CH2Ph), 4.29 (d, J = 13.2 Hz, 1H,
CH2Ph), 3.27 (dd, J = 10.9, 7.8 Hz, 1H, CH2S), 3.14 (dd, J = 13.6, 5.4 Hz, 1H, CH2Ph), 3.09 (dd,
J = 10.9, 6.7 Hz, 1H, CH2S), 2.73 (dd, J = 13.6, 8.7 Hz, 1H, CH2Ph). 13C NMR (75 MHz): δ
164.15, 138.34, 136.67, 129.17, 128.96, 128.40, 127.32, 126.38, 77.62, 39.98, 39.10, 36.86.
+
HRMS (ESI) m/z 300.0878. Calcd. for C17H18NS2 : 300.0875 [M+H]+.
(S)-2-Benzylthio-4-isopropyl-1,3-thiazoline (3g). Yield 90%. Pale yellow oil. [α]2D0 = 6.3
(c = 0.7, Me2CO). IR: 1564 (C=N). 1H NMR (300 MHz): δ 7.37-7.20 (m, 5H, ArH), 4.36 (d, J =
13.2 Hz, 1H, CH2Ph), 4.36 (d, J = 13.2 Hz, 1H, CH2Ph), 4.16 (ddd, J = 9.8, 8.4, 6.6 Hz, 1H,
CHN), 3.34 (dd, J = 10.2, 8.4 Hz, 1H in CH2S), 3.10 (dd, J = 10.2, 9.8 Hz, 1H in CH2S), 1.94
(dhept, J = 6.6, 6.6 Hz, 1H, CH in iPr), 1.04 (d, J = 6.6 Hz, 3H, CH3), 0.96 (d, J = 6.6 Hz, 3H,
CH3). 13C NMR (75 MHz): δ 162.4, 137.1, 129.0, 128.4, 127.2, 83.1, 37.5, 36.8, 33.1, 19.7, 19.1.
+
HRMS (ESI) m/z 252.0872. Calcd. for C13H18NS2 : 252.0875 [M+H]+.
(S)-2-Benzylthio-4-isobutyl-1,3-thiazoline (3h). Yield 91%. Pale yellow oil. [α]2D0 = 32.9
(c = 0.8, Me2CO). IR: 1567 (C=N). 1H NMR (300 MHz): δ 7.37-7.21 (m, 5H, ArH), 4.46 (m,
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1H, CHN), 4.35 (d, J = 13.2 Hz, 1H, CH2Ph), 4.30 (d, J = 13.2 Hz, 1H, CH2Ph), 3.44 (dd, J =
10.6, 7.8 Hz, 1H, CH2S), 3.01 (dd, J = 10.6, 7.9 Hz, 1H, CH2Ph), 1.83 (dt, J = 13.3, 6.6, 1H, CH2
at iBu), 1.69 (ddhept, J = 6.6, 6.6, 6.6 Hz, 1H, CH, iBu), 1.38 (dt, J = 13.7, 7.0 Hz, 1H, CH2 at
iBu), 0.99 (d, J = 6.6 Hz, 3H, CH3), 0.96 (d, J = 6.6 Hz, 3H, CH3). 13C NMR (75 MHz): δ 162.7,
136.9, 129.0, 128.4, 127.3, 75.1, 44.0, 40.4, 36.9, 25.9, 22.71, 22.65. HRMS (ESI) m/z 266.1038.
+
Calcd. for C14H20NS2 : 266.1032 [M+H]+.
General Procedure for the Preparation of 3-Propionyl-thioazolidine-2-thiones 4
Under N2 atmosphere, NaH (120 mg, 60% dispersion in mineral oil, 3 mmol) was added to a
solution of thiazolidine-2-thione 2 (2.5 mmol) in 5 mL of THF and the resulting solution was
cooled to 78°C by a dry-ice-acetone bath. Propionyl chloride (255 mg, 2.5 mmol, 480 µL) was
then dropped in. After removal of the solvent in vacuo, the residue was purified by column
chromatography with a mixture of petroleum ether (60-90°C)/EtOAc (5:1, v/v) as eluent.
N-Propionyl-thiazolidine-2-thione (4a).10 Yield 98%, yellow crystals. M.p. 47-48°C. 1H
NMR (300 MHz): δ 4.60 (t, J = 7.5 Hz, 2H, CH2N), 3.30 (t, J = 7.5 Hz, 2H, CH2S), 3.26 (d, J =
7.2 Hz, 2H, CH2), 1.18 (t, J = 7.2, 3H, CH3). 13C NMR (75 MHz): δ 201.5, 175.5, 56.0, 32.2,
28.3, 8.7.
()-5-Methyl-N-propionyl-thiazolidine-2-thione (4b). Yield, 90%, yellow crystals. M. p.
107-108°C (n-hexane/EtOAc). IR: 1701 (C=O), 1163 (C=S). 1H NMR (200 MHz): δ 4.62 (dd, J
= 12.2, 7.1 Hz, 1H, CH2N), 4.24 (dd, J = 12.2, 6.4 Hz, 1H, CH2N), 3.78 (ddq, J = 7.1, 6.4, 6.7
Hz, 1H, CHS), 3.27 (q, J = 7.2 Hz, 2H, CH2), 1.47 (d, J = 6.7 Hz, 3H, CH3), 1.18 (t, J = 7.2 Hz,
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3H, CH3). 13C NMR (50 MHz): δ 201.4, 175.7, 62.4, 39.0, 32.3, 19.5, 8.8. HRMS (ESI) m/z
+
190.0350. Calcd for C7H12NOS2 : 190.0355 [M+H]+.
(S)-5-Phenyl-N-propionyl-thiazolidine-2-thione (4c). Yield 95%, yellow oil. [α]2D0 =
+271.4 (c = 0.9, Me2CO). IR: 1699 (C=O), 1174 (C=S). 1H NMR (300 MHz): δ 7.44-7.30 (m,
5H, ArH), 4.91 (dd, J = 7.6, 3.0 Hz, 1H, CH2S), 4.87 (dd, J = 7.6, 1.4 Hz, 1H), 4.57 (dd, J =
15.0, 10.6 Hz, 1H, CHS), 3.33 (dq, J = 18.1, 7.2 Hz, 1H, CH2CO), 3.24 (dq, J = 18.1, 7.2 Hz,
1H, CH2CO), 1.19 (t, J = 7.2, 3H). 13C NMR (75 MHz): δ 200.7, 175.4, 136.6, 129.2, 128.7,
+
127.3, 62.6, 47.9, 32.3, 8.8. HRMS (ESI) m/z 252.0517. Calcd for C12H14NOS2 : 252.0511
[M+H]+.
(S)-N-Propionyl-4-phenyl-thiazolidine-2-thione (4d).10 Yield 98%, sticky yellow oil. [α]2D0
= +289.9 (c. 0.8, Me2CO). 1H NMR (300 MHz):  7.43-7.28 (m, 5H, ArH), 6.25 (dd, J = 1.5, 8.2
Hz, 1H, CHN), 3.94 (dd, J = 8.2, 11.2 Hz, 1H, CH2S), 3.38 (dq, J = 18.2, 7.2 Hz, 1H, CH2CO),
3.20 (dq, J = 18.2, 7.2 Hz, 1H, CH2CO), 3.08 (dd, J = 1.5, 11.2 Hz, 1H, CH2S), 1.13 (t, J = 7.2
Hz, 3H, CH3). 13C NMR (75 MHz) δ: 202.1, 174.7, 139.2, 129.0, 128.4, 125.4, 69.8, 36.6, 32.5,
8.7.
(S)-4-Methyl-N-propionyl-thiazolidine-2-thione (4e). Yield: 98%. Sticky yellow oil. [α]D20
= +258.0 (c = 1.2, Me2CO). IR: 1697 (C=O), 1173 (C=S). 1H NMR (300 MHz): δ 5.34 (ddd, J =
7.3, 6.4, 0.9, 1H, CHN), 3.64 (dd, J = 11.2, 7.4 Hz, 1H, CH2S), 3.37 (dq, J = 18.0, 7.3 Hz, 1H,
CH2CO), 3.09 (dq, J = 18.0, 7.2 Hz, 1H, CH2CO), 2.80 (dd, J = 11.2, 0.9 Hz, 1H, CH2S), 1.51
(d, J = 6.4 Hz, 3H, CH3), 1.17 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (50 MHz): δ 200.8, 174.8,
+
63.5, 35.5, 32.2, 18.1, 8.7. HRMS (ESI) m/z, 190.0350, Calcd. for C7H12NOS2 : 190.0355
[M+H]+.
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(S)-4-Benzyl-N-propionyl-thiazolidine-2-thione (4f).10 Yield 98%, yellow crystals, M. p.
112-113°C (n-hexane/EtOAc). [α]D20 = +184.2 (c. 1.3, Me2CO). 1H NMR (300 MHz): δ 7.38 –
7.22 (m, 5H, ArH), 5.38 (ddd, J = 10.5, 7.2, 3.9, 1H, CHN), 3.42 (dq, J = 18.2, 7.2 Hz, 1H,
CH2CO), 3.38 (ddd, J = 11.5, 7.2, 1.6 Hz, 1H, CH2Ph), 3.21 (dd, J = 13.1, 3.9 Hz, 1H, CH2S),
3.11 (dq, J = 18.2, 7.2 Hz, 1H, CH2CO), 3.04(d, J = 13.1, 10.5 Hz, 1H, CH2S), 2.87 (d, J = 11.6
Hz, 1H, CH2Ph), 1.19 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (50 MHz): δ 201.0, 174.8, 136.5,
129.4, 128.8, 127.1, 68.6, 36.7, 32.3, 31.9, 8.8.
(S)-4-Isopropyl-N-propionyl -thiazolidine-2-thione (4g).10 Yield 96%, sticky yellow oil,
[α]2D0 = +409.1 (c. 1.2, Me2CO). H NMR (300 MHz): δ 5.17 (ddd, J = 8.1, 6.4, 1.3 Hz, 1H,
1
CHN), 3.52 (dd, J = 11.5, 8.1 Hz, 1H, CH2S), 3.36 (dq, J = 18.0, 7.2 Hz, 1H, CH2CO), 3.15 (dq,
J = 18.0, 7.2 Hz, 1H, CH2CO), 3.03 (dd, J = 11.5, 1.3 Hz, 1H, CH2S), 2.37 (dhept, J = 6.3, 6.9
Hz, 1H, CH), 1.17 (t, J = 7.2 Hz, 3H, CH3), 1.06 (d, J = 6.9 Hz, 3H, CH3), 0.98 (d, J = 6.9 Hz,
3H, CH3). 13C NMR (50 MHz): δ 202.6, 174.8, 71.6, 32.0, 30.7, 30.4, 19.0, 17.6, 8.9.
(S)-4-Isobutyl-N-propionyl-thiazolidine-2-thione (4h).10 Yield 66%, sticky yellow oil. 1H
NMR (300 MHz): δ 5.29 (ddd, J = 10.3, 7.2, 3.4 Hz, 1H, CHN), 3.56 (ddd, J = 11.3, 7.2, 1.1 Hz,
1H, CH2S), 3.37 (dq, J = 18.2, 7.2 Hz, 1H, CH2CO), 3.10 (dq, J = 18.2, 7.2 Hz, 1H, CH2CO),
2.91 (d, J = 11.3 Hz, 1H, CH2S), 1.93 (ddd, J = 13.2, 10.3, 3.9 Hz, 1H, CH2), 1.66 (ddhept, J =
9.8, 3.9, 6.4 Hz, 1H, CH), 1.55 (dddd, J = 13.2, 9.8, 3.4, 1.1 Hz, 1H, CH2), 1.17 (t, J = 7.2, 3H,
CH3), 1.01 (d, J = 6.4 Hz, 3H, CH3), 1.00 (d, J = 6.4 Hz, 3H, CH3). 13C NMR (50 MHz): δ 201.4,
174.7, 66.1, 39.6, 33.0, 32.2, 25.4, 23.5, 21.3, 8.8.
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General Procedure for the Preparation of N-(4-Chlorophenyl)-2-thioxothiazolidine-
3-carboxamides 5
To a solution of thiazolidine-2-thione (2 mmol) in 10 mL of anhydrous THF was added
anhydrous Et3N (202 mg, 2 mmol, 278 µL) and p-chlorophenylisocyanoate (306 mg, 2 mmol).
The resulting solution was stirred for 0.5~2 h under TLC monitoring. After removal of the
solvent in vacuo, the white solid was collected and further purified via recrystallization from
EtOH or a mixture of hexanes and diethyl ether, or by column chromatography with a mixture of
petroleum ether (60-90°C)/EtOAc (5:1, v/v) as eluent.
N-(4-Chlorophenyl)-2-thioxothiazolidine-3-carboxamide (5a).5 Yield 99%, colorless
crystals. M. p. 137-138°C (EtOH). 1H NMR (200 MHz): δ 12.12 (br s, 1H, NH), 7.46 (d, J = 8.9
Hz, 2H, ArH), 7.29 (d, J = 8.9 Hz, 2H, ArH), 4.77 (t, J = 7.9 Hz, 2H, CH2N), 3.30 (t, J = 7.8 Hz,
2H, CH2N). 13C NMR (50 MHz): δ 200.9, 149.5, 135.5, 129.7, 129.1, 121.5, 56.1, 26.7.
()-N-(4-Chlorophenyl)-4-methyl-2-thioxothiazolidine-3-carboxamide (5b). Yield
92%, colorless crystals. M. p. 143–144°C (EtOH). IR: 1711(C=O). 1H NMR (300 MHz): δ 12.14
(br s, 1H, NH), 7.46 (d, J = 8.8 Hz, 2H, ArH), 7.29 (d, J = 8.8 Hz, 2H, ArH), 4.76 (dd, J = 12.3,
7.3 Hz, 1H, CH2N), 4.44 (dd, J = 12.3, 6.0 Hz, 1H, CH2N), 3.92 – 3.63 (ddq, J = 7.3, 6.0, 6.8 Hz,
1H, CHS), 1.51 (d, J = 6.8 Hz, 3H, CH3). 13C NMR (75 MHz): δ 200.6, 149.6, 135.5, 129.6,
+
129.0, 121.5, 62.5, 37.6, 19.9. HRMS (ESI) m/z, 287.0078. Calcd. for C11H12ClN2OS2 :
287.0074 [M+H]+.
(R)-N-(4-Chlorophenyl)-5-phenyl-2-thioxothiazolidine-3-carboxamide (5c). Yield
95%, colorless crystals. M. p. 121–122°C (diethyl ether). [α]2D0 = +238.5 (c = 1.3, Me2CO). IR:
1712 (C=O). 1H NMR (300 MHz): δ 12.15 (br s, 1H, NH), 7.47 (d, J = 8.8 Hz, 2H, ArH), 7.39-
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7.31(m, 5H, ArH), 7.30 (d, J = 8.8 Hz, 2H, ArH), 5.06 (dd, J = 11.8, 7.4 Hz, 1H, CH2N), 4.88
(dd, J = 7.4, 7.4 Hz, 1H, CHS), 4.79 (dd, J = 11.8, 7.4 Hz, 1H, CH2N). 13C NMR (50 MHz): δ
200.0, 149.4, 136.7, 135.4, 129.8, 129.3, 129.1, 129.0, 127.3, 121.5, 62.7, 46.3. HRMS (ESI)
+
m/z, 349.0230. Calcd. for C16H14ClN2OS2 : 349.0231 [M+H]+.
(S)-N-(4-Chlorophenyl)-4-phenyl-2-thioxothiazolidine-3-carboxamide (5d). Yield
91%, colorless crystals. M. p. 136–137°C (EtOH). [α]2D0 = +489.7 (c = 0.7, Me2CO). IR: 1710
(C=O). 1H NMR (300 MHz): δ 12.25 (br s, 1H, NH), 7.43-7.26 (m, 8H, ArH), 7.24 (d, J = 8.7
Hz, 2H, ArH, AA’BB’ system), 6.48 (d, J = 8.7, 1.0 Hz, 1H, CHN), 3.96 (dd, J = 11.2, 8.7 Hz,
1H, CH2S), 3.03 (dd, J = 11.2, 1.0 Hz, 1H, CH2S). 13C NMR (75 MHz): δ 201.3, 148.8, 138.9,
135.4, 129.6, 129.1, 129.0, 128.7, 125.3, 121.4, 69.9, 35.0. HRMS (ESI) m/z, 349.0233. Calcd.
+
for C16H14ClN2OS2 : 349.0231 [M+H]+.
(S)-N-(4-Chlorophenyl)-4-methyl-2-thioxothiazolidine-3-carboxamide (5e). Yield
96%, colorless crystals. M. p. 108–110°C (n-hexane/EtOAc). [α]2D0 = +89.0 (c = 0.9, Me2CO). IR:
1710 (C=O). 1H NMR (300 MHz): δ 12.21 (s, 1H, NH), 7.47 (d, J = 8.9 Hz, 2H, ArH), 7.30 (d, J
= 8.9 Hz, 2H, ArH), 5.58 (ddq, J = 7.8, 0.6, 6.4 Hz, 1H, CHN), 3.68 (dd, J = 11.2, 7.8 Hz, 1H,
CH2S), 2.80 (dd, J = 11.2, 0.6 Hz, 1H, CH2S), 1.58 (d, J = 6.4, 3H, CH3). 13C NMR (75 MHz): δ
199.8, 149.0, 135.5, 129.6, 129.0, 121.5, 63.8, 33.9, 18.4. HRMS (ESI) m/z, 287.0072 Calcd. for
+
C11H12ClN2OS2 : 287.0074 [M+H]+.
(S)-4-Benzyl-N-(4-chlorophenyl)-2-thioxothiazolidine-3-carboxamide (5f). Yield
72%, colorless crystals. M. p. 131–132°C (CH2Cl2). [α]2D0 = +91.5 (c = 0.9, Me2CO). IR: 1707
(C=O). 1H NMR (300 MHz): δ 12.25 (s, 1H, NH), 7.48 (d, J = 8.9 Hz, 2H, ArH), 7.32 (m, 7H,
ArH), 5.61 (ddd, J = 10.7, 7.3, 3.7 Hz, 1H, CHN), 3.43 (ddd, J = 11.6, 7.7, 0.8 Hz, 1H, CH2Ph),
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3.30 (dd, J = 13.1, 3.6 Hz, 1H, CH2S ), 3.09 (dd, J = 13.1, 10.5 Hz, 1H, CH2S), 2.89 (d, J = 11.6
Hz, 1H, CH2Ph). 13C NMR (75 MHz): δ 200.5 149.3, 136.2, 135.5, 129.8, 129.4, 129.1, 128.9,
+
127.3, 121.7, 68.9, 36.9, 30.4. HRMS (ESI) m/z, 363.0381, Calcd. for C17H16ClN2OS2 :
363.0387 [M+H]+.
(S)-N-(4-Chlorophenyl)-4-isopropyl-2-thioxothiazolidine-3-carboxamide (5g). Yield
80%, colorless crystals. M. p. 118–120°C (EtOH). [α]2D0 = +262.1 (c = 0.7, Me2CO). IR: 1709
(C=O). 1H NMR (300 MHz): δ 12.28 (br s, 1H, NH), 7.47 (d, J = 8.9 Hz, 2H, ArH), 7.30 (d, J =
8.9 Hz, 2H, ArH), 5.40 (ddd, J = 8.8, 5.4, 1.2, 1H, CHN), 3.56 (dd, J = 11.5, 8.8 Hz, 1H, CH2S),
3.00 (dd, J = 11.5, 1.2 Hz, 1H, CH2S), 2.63–2.22 (dhept, J = 5.4, 6.9 Hz, 1H, CH), 1.08 (d, J =
6.9 Hz, 3H, CH3), 1.03 (d, J = 6.9 Hz, 3H, CH3). 13C NMR (75 MHz): δ 201.2, 149.4, 135.6,
129.6, 129.0, 121.5, 72.2, 31.2, 28.2, 18.9, 17.2. HRMS (ESI) m/z, 315.0383, Calcd. for
+
C13H16ClN2OS2 : 315.0387 [M+H]+.
(S)-N-(4-Chlorophenyl)-4-isobutyl-2-thioxothiazolidine-3-carboxamide (5h). Yield
90%, colorless crystals. M. p. 106–108°C (EtOH). [α]2D0 = +116.6 (c = 1.0, Me2CO). IR: 1710
(C=O). 1H NMR (300 MHz): δ 12.22 (br s, 1H, NH), 7.46 (d, J = 8.9 Hz, 2H, ArH), 7.29 (d, J =
8.9 Hz, 2H, ArH), 5.56 – 5.45 (m, 1H, CHN), 3.60 (dd, J = 11.3, 7.7 Hz, 1H, CH2S), 2.92 (d, J =
11.3 Hz, 1H, CH2S), 2.01-1.94 (m, 1H, CH2), 1.74 – 1.60 (m, 2H, CH and 1H, CH2 at iBu), 1.03
(d, J = 6.2 Hz, 3H, CH3). 1.01 (d, J = 6.2 Hz, 3H, CH3). 13C NMR (75 MHz): δ 200.2, 149.1,
135.5, 129.6, 129.0, 121.6, 66.5, 39.7, 31.5, 25.5, 23.6, 21.2. HRMS (ESI) m/z, 329.0549, Calcd.
+
for C14H18ClN2OS2 : 329.0544 [M+H]+.
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ACKNOWLEDGMENT
We thank the researchers, Manxiang Lei, Hui Pei, Zhenghua Yi, Lian He, in Hunan Research
Institute of Chemical Industry for their nice work on the antifungal bioassay.
FUNDING
This work was supported in part by The National Basic Research Program of China (No.
2013CB328905), the National Natural Science Foundation of China (Nos. 21372025 and
21172017), and the Fundamental Research Funds for the Central Universities (No ZY1216).
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REFERENCES
- Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Chem. Rev. 1997, 97, 449-472.
- a) Jain, V. S.; Vora, D. K.; Ramaa, C. S. Bioorg. Med. Chem. 2013, 21, 1599-1620. b)
Devinyak, O.; Zemenkovsky, B.; Lesyk, R. Curr. Top. Med. Chem. 2012, 12, 2763–2784.
c) Bhatti, R. S.; Shah, S.; Suresh; Krishan, P.; Sandhu, J. S. Int. J. Med. Chem. 2013, 1-
13.
- a) Shamszad, M.; Crimmins, M. T. Comprehensive Chirality. 2012, (3), 19-41. b)
Francisco, V.; Horacio F., O. Curr. Org. Chem. 2002, 6, 303-340.
- Weng, J. Q.; Shen, D. L.; Tan, C. X. Chin. J. Org. Chem. 2007, 27, 126-130.
- Weng, J. Q.; Shen, D. L. Tan, C. X.; Ou, X. M. Chin. J. Org. Chem. 2006, 26, 1106-1110.
- Kumar, R. V.; Kumar, K. V. S. R. J. Heterocycl. Chem. 2005, 42, 1191-1192.
- Meltzer-Mats, E.; Babai-Shani, G.; Pasternak, L.; Uritsky, N.; Getter, T.; Viskind, O.;
Eckel, J.; Cerasi, E.; Senderowitz, H.; Sasson, S.; Gruzman, A. J. Med. Chem. 2013, 56,
5335-5350.
- Chen, N.; Jia, W. Y.; Xu, J. X. Eur. J. Org. Chem. 2009, 5841-5846.
- Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775–777.
- Baiget, J.; Cosp, A.; Galvez, E.; Gomez-Pinal, L.; Romea, P.; Urpi, F. Tetrahedron, 2008,
64, 5637-5644.
- Cranham, J. E.; Cummings, W. A. W.; Johnston, A. M.; Stevenson, H. A. J. Agric. Food
Chem. 1961, 9, 143–146.
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Scheme 1 Synthesis of thiazolidine-2-thione derivatives
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Table 1 Physical and analytical data of 3a–5h.
Entry
1
Compd.
3a
Yield/%a
89
M.p./°C
50–52
oil
Specific Rotation
–
2
87
–
3b
3
89
46–49
59–60
oil
+298.4 (c. 1.4, Me2CO)
+170.2 (c. 0.9, Me2CO)
–55.2 (c. 1.1, Me2CO)
–34.0 (c. 0.6, Me2CO)
–6.3 (c. 0.7, Me2CO)
–32.9 (c. 0.8, Me2CO)
–
3c
4
92
3d
5
92
3e
6
91
oil
3f
7
90
oil
3g
8
94
oil
3h
9
98 b
90 b
95 b
25 b
98 c
98 c
98 c
47–48
107–108
oil
4a
10
11
12
13
14
15
–
4b
+271.4 (c. 0.9, Me2CO)
4c
oil
+289.9 (c. 0.8, Me2CO)
4d
oil
+258.0 (c. 1.2, Me2CO)
+184.2 (c. 1.3, Me2CO)
4e
4f
112-113
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16
17
18
19
20
21
22
23
24
25
26
96 c
27 b
66 c
99
oil
oil
+409.1 (c. 1.2, Me2CO)
+292.9 (c. 1.3, Me2CO)
4g
4h
137–138
143–144
121–122
136–137
108–110
131–132
118–120
106–108
–
5a
5b
5c
5d
5e
5f
92
–
95
+238.5 (c. 1.3, Me2CO)
+489.7 (c. 0.7, Me2CO)
+89.0 (c. 0.9, Me2CO)
+91.5 (c. 0.9, Me2CO)
+262.1 (c. 0.7, Me2CO)
+116.6 (c. 1.0, Me2CO)
91
96
72
80
5g
5h
90
a Isolated yield generated from 2. b Yield from Et3N as the base. c Yield from NaH as the
base.
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Table 2. Fungicidal activities of all synthesized compounds 2a–5h at concentrations of 25
µg/mL.
Inhibition rate a(%)
Entry
Compd
P. C.
G. Z.
S. S
0
A. A.
13.79
17.24
55.17
44.83
37.93
48.28
31.03
44.83
24.14
20.69
B. C.
20.41
20.41
51.02
85.71
100
R. S.
1
2
0
0
0
80.0
0
2a
2b
2c
2d
2e
2f
0
0
67.57
0
3
0
0
4
0
0
40.54
90.54
89.19
27.03
87.84
0
0
5
0
0
0
0
80.0
0
6
57.14
10.2
7
0
0
0
2g
2h
3a
3b
8
0
0
30.61
36.73
40.82
0
9
14.29
21.43
36.36
40.91
0
10
0
0
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
0
0
31.82
38.64
34.09
11.36
22.73
38.64
25.00
20.45
34.09
54.55
97.73
54.55
100
75.68
27.03
0
34.48
27.59
17.24
31.03
41.38
24.14
24.14
34.48
51.72
55.17
48.28
48.28
48.28
44.83
10.34
17.24
27.59
31.03
46.94
44.90
26.53
16.33
36.73
40.82
36.73
46.94
81.63
55.10
87.76
30.61
95.92
71.43
6.12
80.0
3c
3d
3e
3f
0
0
21.43
3.57
0
75.68
0
0
0
3g
3h
4a
4b
4c
4d
4e
4f
0
0
0
17.86
25
0
0
0
0
10.71
32.14
89.29
7.14
78.57
32.14
0
47.30
40.54
67.57
27.03
77.03
97.3
0
0
0
0
0
80.0
90.0
0
4g
4h
5a
5b
5c
5d
100
18.18
11.36
9.09
0
0
10.20
51.02
20.41
0
0
33.78
70.27
0
0
6.82
0
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29
30
31
32
33
0
18.18
20.45
15.91
27.27
81.82
0
60.81
0
31.03
34.48
20.69
13.79
55.17
30.61
30.61
30.61
28.57
42.86
0
0
5e
5f
0
0
0
5g
0
0
90.0
30.0
5h
Azob
42.86
64.86
a RS, Rhizoctonia solani; BC, Botrytis cinerea; SS, Sclerotonia sclerotiorum; GZ,
Gibberella zeae; PC, Phytophythora capsici; and AA, Alternaria alternate. bAzo, abbr.
for azoxystrobin.
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Table 3. In-vitro IC50 values of 2e, 4g, 4h, and 5h.
IC50
(µg/mL)
16.51
20.02
3.75
Entry Compd.
Phytopathogenic fungi
1
2
3
4
5
6
7
Botrytis cinerea
Sclerotonia sclerotiorum
Botrytis cinerea
2e
2e
4g
4g
4h
4h
4h
Gibberella zeae
6.51
Sclerotonia sclerotiorum
Gibberella zeae
12.10
10.97
1.01
Rhizoctonia solani
8
Rhizoctonia solani
20.41
5h
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