Solvent-free synthesis of 1-[3-alkyl-4-methyl-2-thioxo-2,3-dihydrothiazole- 5-yl]-ethanones in a multicomponent reaction

Article abstract of DOI:10.1080/17415993.2012.688829

A simple and efficient one-pot synthesis of 1-[3-alkyl-4-methyl-2-thioxo-2, 3-dihydrothiazole-5-yl]- ethanones from the reaction of primary alkylamines and carbon disulfide in the presence of 3-chloro acetylacetone is described. This protocol has several advantages such as lack of need for a solvent and catalyst, high yields, mild conditions and short reaction times.

Full text of DOI:10.1080/17415993.2012.688829

Journal of Sulfur Chemistry
Vol. 33, No. 3, June 2012, 279–284
Solvent-free synthesis of 1-[3-alkyl-4-methyl-2-thioxo-2,3-
dihydrothiazole-5-yl]-ethanones in a multicomponent
reaction
Nasir Iravania*, Bahador Karamib, Farideh Asadimoghaddama, Maryam Monfareda
and Nahid Karamia
aDepartment of Chemistry, Gachsaran Branch, Islamic Azad University, Gachsaran, Iran; bDepartment of
Chemistry, Yasouj University, PO Box 353, Yasouj 75918-74831, Iran
(Received 22 March 2012; final version received 22 April 2012)
A simple and efficient one-pot synthesis of 1-[3-alkyl-4-methyl-2-thioxo-2,3-dihydrothiazole-5-yl]-
ethanones from the reaction of primary alkylamines and carbon disulfide in the presence of 3-chloro
acetylacetone is described. This protocol has several advantages such as lack of need for a solvent and
catalyst, high yields, mild conditions and short reaction times.
S
R
NH2
solvent-free
r.t. , 2-4 hr
N
S
CS2
+
R
O
O
CH3
CH3
O
CH3
H3C
Cl
Keywords: 3-chloro acetylacetone; 2-thioxo-2,3-dihydrothiazole; carbon disulfide; primary alkylamines;
multicomponent reaction
1. Introduction
Thiazoles and their derivatives exhibit various biological activities such as antimicrobial,
anti-inflammatory, antiviral, antituberculosis and cytotoxic activities (1–6). For example, the
thiazolium ring present in vitamin B1 serves as an electron sink, and its coenzyme form is impor-
tant for the decarboxylation of α-keto-acids (7). Especially noteworthy is the observation that
some thiazolines show interesting anti-HIV or anticancer activities and can inhibit cell division
*Corresponding author. Email: iravani.nasir@yahoo.com
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2012 Taylor & Francis
http://dx.doi.org/10.1080/17415993.2012.688829
http://www.tandfonline.com

280 N. Iravani et al.
(8–10). In view of the importance of thiazoles and their derivatives, several methods for their syn-
theses have been developed. The most widely used method is Hantzsch synthesis involving the
reaction of α-halocarbonyl compounds with thioureas or thioamides (11–13). Recently, syntheses
ofthiazol-2-iminederivativesfrombenzoylphenylthioureasandinsitu generatedα-bromoketones
obtained by the reaction of enolizable ketones with 1,10-(ethane-1,2-diyl)dipyridinium bistribro-
mide have been reported (14, 15). Thiazole derivatives were also synthesized by using catalysts
such as ammonium 12-molybdo phosphate (16), cyclodextrin (17), iodine (18a), and silica chlo-
ride (18b) in organic solvents such as 1-methyl-2-pyrrolidinone (19) and with the use of microwave
irradiation (20). However, in spite of their potential utility, many of these methods suffer from
drawbacks, such as harsh reaction conditions, cumbersome product isolation procedures, and
expensive catalysts.
As a part of our current studies, on the synthesis of sulfur-containing organic compounds
(21, 22), in this article, we describe an efficient method for the synthesis of functionalized 2,3-
dihydrothiazoles under solvent-free conditions. This catalyst-free and one-pot synthetic method
is facile with an easy workup procedure that gives pure target compounds containing several
potential centers for further modification.
2. Results and discussion
The reactions of alkylamines 1 and carbon disulfide 2 in the presence of 3-chloro acety-
lacetone 3 proceed smoothly at room temperature to produce 1-[3-alkyl-4-methyl-2-thioxo-
2,3-dihydrothiazole-5-yl]-ethanones 4a–4j in good yields after purification (Scheme 1). In
this procedure, we report a simple method for thiazole synthesis via the reaction of alkyl-
dithiocarbamic acids (5; Scheme 2) with 3-chloro acetylacetone. The alkyl-dithiocarbamic acid
S
O
O
solvent-free
r.t., 2-4 hr
N
S
R
CS2
R
NH2
+
+
H3C
CH3
Cl
CH3
CH3
O
1
2
3
4
1, 4
R
Yield(%)
a
b
c
4-MeO-C6H4
4-Cl-C6H4
82
90
88
97
2-Cl-C6H4
d
e
4-Me-C6H4
2-MeO-C6H4
C6H5
96
94
f
g
4-F-C6H4
Me
85
h
i
84
93
Et
nPr
j
86
Scheme 1. The three-component one-pot synthesis of 2,3-dihydrothiazoles 4.

Journal of Sulfur Chemistry 281
S
S
Cl
SH
R
N
H
-HCl
1 + 2
+ 3
R
N
H
SH
H3C
COCH3
5
6
O
S
S
N
S
R
N
H
S
- H2O
R
4
H3C
H3C
COCH3
COCH3
OH
O
7
8
Scheme 2. Plausible mechanism for the formation of 2,3-dihydrothiazoles 4.
derivatives were prepared from the reaction of 1 and 2. Functionalized 2,3-dihydro thiazoles 4
were obtained from the reaction of these dithiocarbamic acids with 3.
The structures of compounds 4a–4j were deduced from their elemental analyses and their IR, 1H
NMR, and13CNMRspectraldata.The 1HNMRspectrumof 4e inCDCl3 showedsevensignalsfor
methyl(δ = 2.39and2.51 ppm), methoxy(δ = 3.90 ppm), andmethylene(δ = 5.56 ppm)protons
along with signals (δ = 6.78, 6.86–6.92, and 7.29 ppm) for the aromatic protons. The 13C NMR
spectrum of 4e showed 14 signals including methyl (δ = 15.3 and 22.7 ppm), methylene (δ =
45.3 ppm), and methoxy (δ = 55.4 ppm) carbons along with signals (δ = 110.46–147.6 ppm) for
the two olefinic and six aromatic carbons that are in agreement with the proposed structure. In
addition, 13C NMR peaks in the spectrum of 4e at 188.2 and 188.68 ppm are diagnostic for α, β-
carbonyl and thiocarbonyl groups, respectively. Partial assignments of these resonances are given
in Section 4.
A plausible mechanism for this reaction is given in Scheme 2 and is initiated by reaction of the
primary alkylamine and carbon disulfide to give the dithiocarbamic acid derivatives 5. Subsequent
nucleophilic alkylation of 5 with 3-chloro acetylacetone 3 yields intermediate 6. This intermediate
undergoes HCl elimination and subsequent intramolecular cyclization to form the heterocyclic
intermediate 8, which generates 4 by elimination of water (Scheme 2).
3. Conclusions
We have reported a convenient transformation involving carbon disulfide and primary alkyl
amines in the presence of 3-chloro acetylacetone, which affords 1-[3-alkyl-4-methyl-2-thioxo-
2,3-dihydrothiazole-5-yl]-ethanones. This new protocol has several advantages such as the lack
of need for a solvent and catalyst, high yields, short reaction times, simple experimental workup
procedure, and neutral reaction conditions performed at room temperature by simple mixing of the
starting materials. The procedure described here also provides an efficient one-pot methodology
for the preparation of functionalized 2,3-dihydrothiazoles.

282 N. Iravani et al.
4. Experimental
4.1. General
Amines, carbon disulfide, and 3-chloro acetylacetone were obtained from Fluka and were used
without further purification; IR spectra: Shimadzu IR-460 spectrometer with a KBr liquid cell; 1H
and 13C NMR spectra: Bruker DRX-400AVANC instrument; in CDCl3 at 400.13 and 100.61 MHz,
respectively, δ in ppm, and J in Hz; Elemental analyses (C, H, and N) were performed with
a Heraeus CHN-O-Rapid analyzer. The analyses data were in agreement with the proposed
structures.
4.2. General procedure for the preparation of compounds 4a–4j
A mixture of 0.175 g of carbon disulfide (2.3 mmol) and the primary alkylamine 1 (2 mmol) was
stirred at room temperature for 30 min. Then, 3-chloro acetylacetone (2 mmol) was added to the
reaction mixture and stirred at room temperature. After completion of the reaction [2–4 h; TLC
(n-hexane/AcOEt 3:1)], the reaction mixture was purified by column chromatography [silica gel
(230–240 mesh; Merck), n-hexane/AcOEt 4:1)] to afford the pure title compounds.
4.2.1. 1-[3-(4-Methoxybenzyl)-4-methyl-2-thioxo-2,3-dihydrothiazole-5-yl]-ethanone (4a)
Yellow oil; yield: 0.24 g (82%). IR (KBr liquid cell): 3050 (CH arom), 2910 (CH aliph), 1670
(C9O), 1510 (C9C), 1160 (C9S) cm−1. 1H NMR: δ 2.38 (3H, s, CH3), 2.57 (3H, s, CH3), 3.80
(3H, s, OCH3), 5.52 (2H, s, CH2), 6.87 (2H, d, 3JHH = 8.4 Hz, 2 CH), 7.18 (2H, d, 3JHH = 8.4 Hz,
2 CH) ppm.13C NMR: δ 15.3 (CH3), 25.6 (CH3), 49.9 (CH2), 55.3 (OCH3), 111.8 (C), 114.3 (2
CH), 126.3(C), 128.1 (2 CH), 140.4 (C), 159.3 (C), 187.6 (C9O), 189.7 (C9S) ppm. Anal. Calcd
for C14H15NO2S2 (293.4): C, 57.31; H, 5.15; N, 4.77. Found: C, 57.2; H 5.26; N, 4.8%.
4.2.2. 1-[3-(4-Chlorobenzyl)-4-methyl-2-thioxo-2,3-dihydrothiazole-5-yl]-ethanone (4b)
Yellow oil; Yield: 0.26 g (90%). IR (KBr liquid cell): 3100(CH arom), 2900 (CH aliph), 1680
(C9O), 1565 (C9C), 1170 (C9S) cm−1. 1H NMR: δ 2.45 (3H, s, CH3), 2.61 (3H, s, CH3), 5.23
3
3
(2H, s, CH2), 7.32 (2H, d, JHH = 8.3 Hz, 2 CH), 7.38(2H, d, JHH = 8.2 Hz, 2 CH) ppm. 13C
NMR: δ 15.6 (CH3), 28.4 (CH3), 47.78 (CH2), 99.8 (C), 128.1 (2 CH), 129.3 (2 CH), 132.5 (C),
134.6 (C), 161.2 (C), 188.4 (C9O), 189.5 (C9S) ppm. Anal. Calcd for C13H12ClNOS2 (291.83):
C, 51.44; H, 4.15; N, 4.8. Found: C, 51.2; H 4.1; N, 4.73%.
4.2.3. 1-[3-(2-Chlorobenzyl)-4-methyl-2-thioxo-2,3-dihydrothiazole-5-yl]-ethanone (4c)
Yellow oil; Yield: 0.27 g (88%). IR (KBr liquid cell): 3050 (CH arom), 2810 (CH aliph), 1675
(C9O), 1590 (C9C), 1165 (C9S) cm−1. 1H NMR: δ 2.41 (3H, s, CH3), 2.51 (3H, s, CH3), 5.66 (2H,
s, CH2), 6.80(1H, d,3JHH = 7.6 Hz, CH), 7.20–7.29 (2H, m, 2 CH), 7.44 (1H, d,3JHH = 7.6 Hz,
CH) ppm. 13C NMR: δ 14.7 (CH3), 30.4 (CH3), 47.7 (CH2), 112.1 (C), 126.5 (CH), 127.5 (CH),
129.2 (CH), 129.8 (CH), 131.4 (C), 132.3 (C), 148 (C), 188.18 (C9O), 188.73 (C9S) ppm. Anal.
Calcd for C13H12ClNOS2 (291.83): C, 51.44; H, 4.15; N, 4.8. Found: C, 51.2; H 4.1; N, 4.73%.

Journal of Sulfur Chemistry 283
4.2.4. 1-[3-(4-Methylbenzyl)-4-methyl-2-thioxo-2,3-dihydrothiazole-5-yl]-ethanone (4d)
Yellow oil; Yield: 0.27 g (97%). IR (KBr liquid cell): 3000 (CH arom), 2800 (CH aliph), 1660
(C9O), 1550 (C9C), 1158 (C9S) cm−1. 1H NMR: δ 2.33 (3H, s, CH3), 2.38 (3H, s, CH3), 2.55
(3H, s, CH3), 5.53 (2H, s, CH2), 7.09 (2H, d, 3JHH = 7.6 Hz, 2 CH), 7.15 (2H, d, 3JHH = 8 Hz, 2
CH) ppm. 13C NMR: δ 15.03 (CH3), 21.13 (CH3), 30.36 (CH3), 50.2 (CH2), 120.18 (C), 126.56
(2 CH), 129.72 (2 CH), 131 (C), 137.97 (C), 148.43 (C), 188.2 (C9O), 188.67 (C9S) ppm. Anal.
Calcd for C14H15NOS2 (277.4): C, 60.61; H, 8.52; N, 5.05. Found: C, 60.6; H 8.48; N, 5.1%.
4.2.5. 1-[3-(2-Methoxybenzyl)-4-methyl-2-thioxo-2,3-dihydrothiazole-5-yl]-ethanone (4e)
Yellow oil, Yield: 0.28 g (96%). IR (KBr liquid cell): 3050 (CH arom), 2900 (CH aliph), 1670
1
(C9O), 1558 (C9C),1160 (C9S) cm−1. H NMR: δ 2.39 (3H, s, CH3), 2.51 (3H, s, CH3), 3.90
(3H, s, OCH3), 5.56 (2H, s, CH2), 6.78 (1H, d, 3JHH = 7.2 Hz, CH), 6.86–6.93 (2H, m, 2 CH),
3
7.28 (1H, d, JHH = 8.8 Hz, CH) ppm. 13C NMR: δ 15.3 (CH3), 22.7 (CH3), 45.3 (CH2), 55.4
(OCH3), 110.46 (C), 120.19 (CH), 120.9 (2CH), 121.9 (CH), 126.2 (C), 129.1 (C), 147.6(C),
188.21 (C9O), 188.68 (C9S) ppm. Anal. Calcd for C14H15NO2S2 (293.4): C, 57.31; H, 5.15; N,
4.77. Found: C, 57.2; H 5.26; N, 4.8%.
4.2.6. 1-[3-Benzyl-4-methyl-2-thioxo-2,3-dihydrothiazole-5-yl]-ethanone (4f)
Yellow oil; yield: 0.25 g (94%). IR (KBr liquid cell): 3020 (CH arom), 2920 (CH aliph), 1670
(C9O), 1558 (C9C), 1180 (C9S) cm−1. 1H NMR: δ 2.39 (3H, s, CH3), 2.55 (3H, s, CH3), 5.58
3
(2H, s, CH2), 7.2 (2H, d, JHH = 6.8 Hz, 2 CH), 7.33–7.36 (3H, m, 3 CH) ppm. 13C NMR: δ
15 (CH3), 22.7 (CH3), 50.37 (CH2), 124.5 (C), 126.6 (CH), 128.2 (2CH), 129.1 (2CH), 134 (C),
147.4 (C), 188.21 (C9O), 188.72 (C9S) ppm. Anal. Calcd for C13H13NOS2 (263.4): C, 59.27; H,
4.97; N, 5.32. Found: C, 59.3; H 4.88; N, 5.3%.
4.2.7. 1-[3-(4-Fluorobenzyl)-4-methyl-2-thioxo-2,3-dihydrothiazole-5-yl]-ethanone (4g)
Yellow oil; yield: 0.24 g (85%). IR (KBr liquid cell): 3050 (CH arom), 2910 (CH aliph), 1670
(C9O), 1559 (C9C), 1160 (C9S) cm−1. 1H NMR: δ 2.37 (3H, s, CH3), 2.55 (3H, s, CH3), 5.53
(2H, s, CH2), 7.03–7.34 (4H, m, 4 CH) ppm. 13C NMR: δ 14.99 (CH3), 29.7 (CH3), 49.67 (CH2),
100.1 (C), 128.6 (2 CH), 129.9 (2 CH), 147.4 (C), 150.9 (C), 161.9 (C-F, 1JCF = 264.7 Hz), 188.5
(C9O), 189.7 (C9S) ppm. Anal. Calcd for C13H12FNOS2 (281.4): C, 55.48; H, 4.29; N, 4.99.
Found: C, 55.5; H 4.3; N, 5%.
4.2.8. 1-[3-Ethyl-4-methyl-2-thioxo-2,3-dihydrothiazole-5-yl]-ethanone (4h)
Colorless oil; yield: 0.17 g (84%). IR (KBr liquid cell): 3048 (CH arom), 2910–2980 (CH aliph),
1668 (C9O), 1558 (C9C), 1160 (C9S) cm−1. 1H NMR: δ 1.34 (3H, t, 3JHH = 7.2 Hz, CH3), 2.36
(3H, s, CH3), 2.69 (3H, s, CH3),4.31 (2H, q, 3JHH = 6.8 Hz, CH2) ppm. 13C NMR: δ 12.6 (CH3),
14.1 (CH3), 22.69 (CH3), 42.56 (CH2), 120.19 (C), 146.68 (C), 187.22 (C9O), 188.19 (C9S)
ppm. Anal. Calcd for C8H11NOS2 (201.31): C, 53.69; H, 5.51; N, 6.96. Found: C, 53.7; H 5.5;
N, 6.95%.

284 N. Iravani et al.
4.2.9. 1-[3-(nPropyl)-4-methyl-2-thioxo-2,3-dihydrothiazole-5-yl]-ethanone (4i)
Colorless oil; yield: 0.2 g (93%). IR (KBr liquid cell): 3040 (CH arom), 2950 (CH aliph), 1665
(C9O), 1550 (C9C), 1165 (C9S) cm−1. 1H NMR: δ 1.02 (3H, t, 3JHH = 7.2 Hz, CH3), 1.81 (2H,
six, 3JHH = 7.1 Hz, CH2), 2.37 (3H, s, CH3), 2.69 (3H, s, CH3), 4.21 (2H, q, 3JHH = 7.2 Hz, CH2)
ppm. 13C NMR: δ 11.18 (CH3), 14.1 (CH3), 14.2 (CH2), 22.7 (CH3), 48.86 (CH2), 121.8 (C),
147.8 (C), 187.51 (C9O), 188.27 (C9S) ppm. Anal. Calcd for C9H13NOS2 (215.33): C, 50.19; H,
6.08; N, 6.5. Found: C, 50.2; H 6.1; N, 6.51%.
4.2.10. 1-[3-(nButyl)-4-methyl-2-thioxo-2,3-dihydrothiazole-5-yl]-ethanone (4j)
Colorless oil; yield: 0.2 g (86%). IR (KBr liquid cell): 3050 (CH arom), 2960 (CH aliph), 1668
(C9O), 1556 (C9C), 1160 (C9S) cm−1. 1H NMR: δ 0.88 (3H, t, 3JHH = 6.8 Hz, CH3), .99 (3H, t,
3JHH = 7.6 Hz, CH3), 1.43 (2H, six, 3JHH = 7.6 Hz, CH2), 1.72 (2H, qui, 3JHH = 6.8 Hz, CH2),
2.37 (3H, s, CH3), 2.69 (3H, s, CH3), 4.22 (2H, t, 3JHH = 7.6 Hz, CH2) ppm. 13C NMR: δ 14.68
(CH3), 14.71 (CH3), 14.8 (CH2), 20.09 (CH3), 22.7 (CH2), 47.3 (CH2), 120.07 (C), 146.88 (C),
187.41 (C9O), 188.24 (C9S) ppm. Anal. Calcd for C10H15NOS2 (229.4): C, 52.35; H, 6.59; N,
6.1. Found: C, 52.4; H 6.61; N, 6.12%.
Acknowledgement
We are thankful to the Gachsaran branch, Islamic Azad University, for the partial support of this work.
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