A synthesis of functionalized 2-imino-1,3-thiazoles from tetramethylguanidine, isothiocyanates, and 2-chloro-1,3-dicarbonyl compounds

Article abstract of DOI:10.1007/s13738-013-0299-0

The Hantzsch method for thiazole synthesis is modified via the reaction of 2-chloro-1,3-dicarbonyl compounds with 2-(amidosulfanylenemethyl)-1,1,3,3- tetramethylguanidines (prepared in situ from tetramethylguanidine and isothiocyanates), to afford functionalized 2-imino-1,3-thiazoles in good yields. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s13738-013-0299-0

J IRAN CHEM SOC
DOI 10.1007/s13738-013-0299-0
ORIGINAL PAPER
A synthesis of functionalized 2-imino-1,3-thiazoles
from tetramethylguanidine, isothiocyanates,
and 2-chloro-1,3-dicarbonyl compounds
•
Issa Yavari Alaleh Malekafzali Samereh Seyfi
•
Received: 27 March 2013 / Accepted: 12 June 2013
Ó Iranian Chemical Society 2013
Abstract The Hantzsch method for thiazole synthesis is
modified via the reaction of 2-chloro-1,3-dicarbonyl com-
pounds with 2-(amidosulfanylenemethyl)-1,1,3,3-tetrameth-
ylguanidines (prepared in situ from tetramethylguanidine and
isothiocyanates), to afford functionalized 2-imino-1,3-thia-
zoles in good yields.
1,3-Thiazoles occupy a prominent position among het-
erocycles. In nature, the thiazolium ring is the chemically
active center in the coenzyme derived from vitamin B
(thiamin). A large number of thiazoles obtained from
microbial and marine origins exhibit important biological
effects, such as antitumor, antifungal, antibiotic, and anti-
viral activities [5]. Synthetic thiazoles have also been
shown to exhibit a wide variety of biological activity [6],
while others have found application as liquid crystals [7]
and cosmetic sunscreens [8]. Among these class of com-
pounds, 2-iminothiazole, isoform of 2-aminothiazole, is an
advantaged and privileged structure. In some cases, alkyl
group of 2-alkyliminothiazoles is changed into other alkyl
groups by isothiocyanates [9]. There are several methods
for the synthesis of tiazole derivatives [10, 11]. The clas-
sical method for the synthesis of thiazoles is the Hantzsch
process, in which a-haloketones are condensed with thio-
amides [12].
Keywords 2-Imino-1,3-thiazole Á Tetramethylguanidine Á
Isothiocyanate Á 2-Chloro-1,3-dicarbonyls
Introduction
Multi-component reactions (MCRs) are economically and
environmentally advantageous. MCRs are perfectly suited
for combinatorial library syntheses; thus, are finding
increasing use in the discovery process for new drugs and
agrochemicals [1–3]. In recent years, the research into
novel active organic substances and into the design of
molecular electronic devices has attracted considerable
interest [4]. In this respect, there are several studies
involved sulfur-containing compounds because they pres-
ent good conduction in organic materials or are relevant
biologically.
Experimental
All purchased solvents and chemicals were of analytical
grade and used without further purification. Melting points
and IR spectra were measured on an Electrothermal 9100
apparatus and a Shimadzu IR-460 spectrometer, respec-
tively. The 1H and 13C spectra were obtained with a
BRUKER DRX-500 AVANCE instrument using CDCl3 as
applied solvent and TMS as internal standard at 500.1 and
125.7 MHz, respectively. Mass spectra were recorded on a
FINNIGAN-MAT 8430 mass spectrometer operating at an
ionization potential of 70 eV. Elemental analyses for C,
H, N were performed using a Heraeus CHN-O-Rapid
analyzer.
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-013-0299-0) contains supplementary
material, which is available to authorized users.
I. Yavari (&) Á A. Malekafzali Á S. Seyfi
Department of Chemistry, Tarbiat Modares University,
PO Box 14115-175, Tehran, Iran
e-mail: yavarisa@modares.ac.ir
A. Malekafzali
e-mail: alalehmalekafzali@yahoo.com
123

J IRAN CHEM SOC
3
3J = 8.4, 2CH), 6.89 (2H, t, J = 8.4, 2CH). 13C NMR
General procedure
(125 MHz, CDCl3): d = 14.9 (Me), 29.5 (Me), 40.5
2
To a stirred solution of the isothiocyanate 2 (2 mmol) in
acetone (10 mL) was added, at room temperature, 0.23 g
(2 mmol) of 1. The mixture was stirred at room tempera-
ture for 30 min. Then, the 1,3-dicarbonyl 3 (2 mmol) was
added to the reaction mixture. After completion of the
reaction [8–12 h; TLC (AcOEt/hexane 2:1)], the solvent
was evaporated, and the residue was purified by ether/n-
hexane.
(2Me2N), 116.8 (d, J = 22.6, CH), 118.5 (C), 130.1 (d,
3J = 9.0,CH), 144.1 (C), 162.5 (d,1J = 251.5, CF), 164.7
(C), 166.5 (C), 172.0 (C), 188.8 (C = O). MS (EI, 70 eV):
m/z (%) = 334 (93), 291 (29), 264 (31), 235 (33), 210 (48),
196 (30), 153 (32), 115 (33), 85 (35), 71 (100), 44 (69).
Anal. calcd for C17H22ClFN4OS (384.90): C, 53.05; H,
5.76; N, 14.56 %. Found: C, 53.44; H, 5.31; N, 13.97 %.
1-(2-(4-Nitrophenylimino)-3-(bis(dimethylamino)methyl)-
1-(3-(Bis(dimethylamino)methyl)-2,3-dihydro-4-methyl-2-
2,3-dihydro-4-methylthiazol-5-yl)ethanone chloride (4d)
(phenylimino)thiazol-5-yl)ethanone chloride (4a)
Yellow powder, m.p. 120–122 °C. Yield: 0.78 g (95 %).
IR (KBr): vꢀ = 1,595, 1,525, 1,407, 1,352, 1,276 cm-1. 1H
NMR (500 MHz, CDCl3): d = 2.38 (3H, s, Me), 2.52 (3H,
s, Me), 3.07 (12H, s, 2Me2N), 7.87 (2H, d, 3J = 8.9, 2CH),
8.42 (2H, d, 3J = 8.9, 2CH). 13C NMR (125 MHz,
CDCl3): d = 15.6 (Me), 30.1 (Me), 41.3 (2Me2N), 120.0
(C), 125.6 (2CH), 130.2 (2CH), 140.1 (C), 143.5 (C), 148.7
(C), 164.4 (C), 1696. (C), 188.8 (C = O). MS (EI, 70 eV):
m/z (%) = 361 (95), 318 (34), 291 (25), 262 (35), 236 (23),
210 (50), 196 (34), 180 (38), 115(33), 85(36), 71 (100), 44
(75). Anal. calcd for C17H22ClN5O3S (411.91): C, 49.57;
H, 5.38; N, 17.00 %. Found: C, 49.21; H, 5.83; N,
16.89 %.
Pale cream powder, m.p. 121–123 °C. Yield: 0.67 g
(92 %). IR (KBr): vꢀ = 1,637, 1,592, 1,525, 1,469, 1,407,
1
1,067 cm-1. H NMR (500 MHz, CDCl3): d = 2.14 (3H,
s, Me), 2.33 (3H, s, Me), 2.88 (12H, s, 2Me2N), 7.11 (2H, t,
3
3J = 7.4, 2CH), 7.36 (1H, t, J = 7.4, CH), 7.37 (2H, d,
3J = 7.4, 2CH). 13C NMR (125 MHz, CDCl3): d = 14.8
(Me), 29.5 (Me), 40.5 (2Me2N), 118.2 (C), 127.0 (2CH),
129.8 (2CH), 130.1 (CH), 134.1 (C), 143.7 (C), 163.8 (C),
166.1 (C), 188.3 (C = O). MS (EI, 70 eV): m/z (%) = 315
(100), 273 (26), 246 (31), 217 (33), 210 (41), 196 (29), 190
(27), 135 (31), 115(28), 85(30), 71 (97), 44 (73). Anal.
calcd for C17H23ClN4OS (366.91): C, 55.65; H, 6.32; N,
15.27 %. Found: C, 56.15; H, 6.21; N, 15.36 %.
1-[2-(2,4-Dichlorophenylimino)-3-
N(5-Acetyl-3-di(dimethylamino)methyl)-4-methyl-2-
phenylcarbonylimino-2,3-dihydro-1,3-thiazole chloride
(4b)
di(dimethylamino)methyl-4-methyl-2,3-dihydro-1,3-
thiazol-5-yl]-1-ethanone chloride (4e)
Pale cream powder, m.p. 214–217 °C. Yield: 0.84 g
(97 %). IR (KBr): vꢀ = 2,929, 2,168, 1,585, 1,553,
Pale cream powder, m.p. 147–150 °C. Yield: 0.51 g
(67 %). IR (KBr): vꢀ = 2,270, 1,651, 1,610, 1,410, 1,274,
1
1,267 cm-1. H NMR (500 MHz, CDCl3): d = 1.36 (3H,
s, Me), 2.41 (3H, s, Me), 2.98 (12H, s, 2Me2N), 7.40 (1H,
1
1,064 cm-1. H NMR (500 MHz, CDCl3): d = 2.55 (3H,
s, Me), 2.67 (3H, s, Me), 3.05 (12H, s, 2Me2N), 7.48 (2H, t,
3
3
d, J = 8.6, CH), 8.15(1H, d, J = 8.6, CH), 8.63 (1 H, s,
CH). 13C NMR (125 MHz, CDCl3): d = 21.5 (Me), 30.0
(Me), 41.3 (2Me2N), 96.4 (C), 128.5 (C), 129.8 (C), 132.2
(C), 133.5 (CH), 134.1 (CH), 134.8 (CH), 136.0 (C), 165.4
(C), 166.1 (C), 200.4 (C = O). MS (EI, 70 eV):
m/z (%) = 384 (100), 341 (30), 314 (20), 285 (38), 259
(29), 210 (39), 203 (30), 196 (31), 115(37), 85(32), 71 (89),
44 (68). Anal. calcd for C17H21Cl3N4OS (435.80): C,
46.85; H, 4.86; N, 12.86 %. Found: C, 46.25; H, 5.22; N,
12.46 %.
3
3J = 7.4, 2CH), 7.59 (1H, t, J = 7.4, CH), 8.15 (2H, d,
3J = 7.4, 2CH). 13C NMR (125 MHz, CDCl3): d = 13.8
(Me), 30.3 (Me), 40.3 (2Me2N), 121.6 (C), 128.6 (2CH),
129.5 (2CH), 133.3 (CH), 138.2 (C), 157.5 (C), 161.8 (C),
165.6 (C), 175.0 (C = O), 189.6 (C = O). MS (EI, 70 eV):
m/z (%) = 344 (100), 301 (26), 274 (33), 245 (28), 210
(38), 196 (36), 163 (39), 115 (25), 85 (34), 71 (94), 44 (61).
Anal. calcd for C18H23ClN4O2S (394.92): C, 54.74; H,
5.87; N, 14.19 %. Found: C, 54.23; H, 6.17; N, 15.02 %.
1-(2-(4-Fluorophenylimino)-3-(bis(dimethylamino)methyl)
1-(3-(Bis(dimethylamino)methyl)-2-(ethylimino)-2,3-
-2,3-dihydro-4-methylthiazol-5-yl)ethanone chloride (4c)
dihydro-4-methylthiazol-5-yl)ethanone chloride (4f)
Pale cream powder, m.p. 122–123 °C. Yield: 0.66 g
(86 %). IR (KBr): vꢀ = 2,926, 2,179, 1,598, 1,542,
Pale cream powder, m.p. 165–167 °C. Yield: 0.67 g
(73 %). IR (KBr): vꢀ = 2,987, 2,322, 1,459, 1,404,
1,274 cm-1. 1H NMR (500 MHz, CDCl3): d = 1.27 (3H, t,
3J = 7.2, Me), 2.43 (3H, s, Me), 2.69 (3H, s, Me), 3.09
1
1,277 cm-1. H NMR (500 MHz, CDCl3): d = 1.71 (3H,
s, Me), 1.87 (3H, s, Me), 2.43 (12H, s, 2Me2N), 6.64 (2H, t,
123

J IRAN CHEM SOC
(12H, s, 2Me2N), 4.14 (2H, 3J = 7.2, q, CH2O). 13C NMR
(125 MHz, CDCl3): d = 13.4 (Me), 13.9 (Me), 30.0 (Me),
41.1 (2Me2N), 41.7 (OCH2), 118.3 (C), 144.1 (C), 164.6
(C), 165.6 (C), 188.5 (C = O). MS (EI, 70 eV): m/z (%) =
268 (89), 225 (31), 210 (44), 198 (29), 169 (28), 143 (32),
87 (32), 115(27), 85(31), 71 (100), 44 (71), 29 (21). Anal.
calcd for C13H23ClN4OS (318.87): C, 48.97; H, 7.27; N,
17.57 %. Found: C, 48.25; H, 7.74; N, 17.21 %.
130.4 (2CH), 141.9 (C), 142.1 (C), 148.5 (C), 164.2 (C),
167.0 (C), 168.4 (C = O). MS (EI, 70 eV): m/z (%) = 390
(86), 293 (31), 236 (32), 227 (38), 210 (36), 180 (30), 115
(27), 85 (29), 71 (100), 44 (64). Anal. calcd for
C18H24ClN5O4S (441.93): C, 48.92; H, 5.47; N, 15.85 %.
Found: C, 48.54; H, 6.21; N, 15.37 %.
Results and discussion
Ethyl 3-(bis(dimethylamino)methyl)-2,3-dihydro-4-methyl-
2-(phenylimino)thiazol-5-carboxylate chloride (4 g)
As a part of our current studies on the development of new
routes in thiazole synthesis [13–15], we describe an effi-
cient one-pot method for the synthesis of functionalized
2-imino-1,3-thiazoles 4 using 1,1,3,3-tetramethylguanidine
(1) as a nucleophile. The reaction of 1 and isothiocyanates
2 in the presence of 3 in acetone at room temperature
produced 4 in good yields after purification (Scheme 1). In
this procedure, we have modified the Hantzsch method for
thiazole synthesis via the reaction of 2-(sulfanylenemeth-
yl)-1,1,3,3-tetramethylguanidines (5, see Scheme 2) with
2-chloro-1,3-dicarbonyl compounds. Thus, various thio-
urea derivatives were prepared from 1 and 2. Compounds 4
were obtained from the reaction of these thioureas with 3.
The structures of compounds 4a-h were deduced from
Yellow oil, yield: 0.56 g (68 %). IR (KBr): vꢀ = 1,637,
1,592, 1,525, 1,469, 1,407, 1,067 cm-1
.
1H NMR
3
(500 MHz, CDCl3): d = 1.31 (3H, t, J = 7.1, Me), 2.28
(3H, s, Me), 3.06 (12H, s, 2Me2N), 4.29 (2H, q, J = 7.1,
3
CH2O), 7.23 (2H, t, 3J = 8.7, 2CH), 7.54 (1H, t, 3J = 8.7,
3
CH), 7.56 (2H, d, J = 8.7, 2CH). 13C NMR (125 MHz,
CDCl3): d = 14.2 (Me), 23.2 (Me), 40.2 (2Me2N), 57.4
(CH2O), 107.9 (C), 127.5 (2CH), 129.4 (2CH), 134.8 (CH),
145.9 (C), 164.5 (C), 166.2 (C), 166.9 (C), 168.9 (C = O).
MS (EI, 70 eV):m/z (%) = 345 (100), 246 (26), 240 (38), 226
(39), 190 (35), 135 (24), 115 (31), 85 (21), 71 (88), 44 (68).
Anal. calcd for C18H25ClN4O2S (396.93): C, 54.47; H, 6.35;
N, 14.11 %. Found: C, 54.89; H, 5.93; N, 14.47 %.
1
their IR, H NMR, and 13C NMR. The mass spectra of
these compounds displayed molecular ion peaks at appro-
1
priate m/z values. The H NMR spectrum of 4a in CDCl3
Ethyl 3-(bis(dimethylamino)methyl)-2,3-dihydro-4-methyl-
2-(4-nitrophenylimino)thiazol-5-carboxylate chloride (4 h)
showed three singlets for methyl (d = 2.14 and 2.33) and
dimethylamino (d = 2.88) protons. The carbonyl group
resonances in the 13C NMR spectra of 4a appear at
188.3 ppm. The mass spectrum of 4a does not display the
molecular ion peak, but the fragmentation pattern confirms
the proposed structure. The 1H NMR and 13C NMR spectra
of 4b–h were similar to those for 4a except for the side
chains, which exhibited characteristic resonances in the
appropriate regions of the spectrum.
Yellow oil, yield: 0.56 g (68 %). IR (KBr): vꢀ = 1,637,
1,592, 1,525, 1,469, 1,407, 1,067 cm-1
.
1H NMR
3
(500 MHz, CDCl3): d = 1.08 (3H, t, J = 7.1, Me), 1.92
(3H, s, Me), 2.88 (12H, s, 2Me2N), 4.03 (2H, q, J = 7.1,
3
CH2O), 7.64 (2H, t, 3J = 7.8, 2CH), 8.04 (2H, d, 3J = 7.8,
2CH). 13C NMR (125 MHz, CDCl3): d = 13.7 (Me), 22.9
(Me), 40.7 (CH2O), 41.1 (2Me2N), 124.4 (C), 125.5 (2CH),
Scheme 1 Formation of
compounds 4 from
tetramethylguanidine,
isothiocyanates, and 2-chloro-
1,3-dicarbonyl compounds
R
N
NMe2
O
O
NH
S
acetone
r.t.
S
N
R
C
NMe2
Cl
R'
N
N
N
Cl
O
R'
3
4
2
1
Yield (%) of 4
R
R'
2-4
a
b
c
d
e
f
Ph
Me
Me
Me
Me
Me
Me
OEt
OEt
92
67
86
95
97
73
68
68
PhCO
4-F-C6H4
4-O2N-C6H4
2,4-Cl2-C6H3
Et
g
h
Ph
4-O2N-C6H4
123

J IRAN CHEM SOC
Scheme 2 Proposed
mechanism for the formation
of compounds 4
Cl
R
N
R'
NH
NMe2
S
O
O
Me2N
Me2N
3
1
2
S
R
Me2N
N
N
H
5
6
R
N
NMe2
Cl
S
H
N
- H2O
NMe2
O
4
OH
R'
7
3. T. Ziegler, H.J. Kaiser, R. Schlomer, C. Koch, Tetrahedron 55,
8397 (1999)
4. J.M. Lehn, in Supramolecular Chemistry-Concepts and Per-
spectives, Ch. 8 (VCH, Weinheim, 1995)
5. T. Jorgensen, T.K. Hansen, J. Becer, Chem. Soc. Rev. 23, 41
(1994)
6. J.V. Metzger, in Thiazole and its Derivatives, (Wiley & Sons,
New York, 1979)
7. A.A. Kiryanov, P. Sampson, A.J. Seed, J. Org. Chem. 66, 7925
(2001)
8. T. Bach, S. Heuser, Tetrahedron Lett. 41, 1707 (2000)
9. D. Shin, J. Lee, H.G. Hahn, Tetrahedron 66, 5707 (2010)
10. D.S. Millan, R.H. Prager, C. Brand, P.H. Hart, Tetrahedron 56,
811 (2000)
11. W.L. Wang, D.Y. Yao, M. Gu, M.Z. Fan, J.W. Li, Y.C. Xing, F.J.
Nan, Bioorg. Med. Chem. Lett. 15, 5284 (2005)
12. R.H. Wiley, D.C. England, L.C. Behr, In Organic Reactions, vol.
6 (Wiley & Sons, New York, 1951) p. 367
13. I. Yavari, S. Beheshti, J. Iran. Chem. Soc. 8, 1030 (2011)
14. I. Yavari, A. Aminkhani, S. Skoulika, J. Iran. Chem. Soc. 9, 0000
(2012)
Mechanistically, the reaction starts with the formation of
2-(sulfanylenemethyl)-1,1,3,3-tetramethylguanidines (5)
from 1 and 2. Subsequent nucleophilic alkylation of thio-
urea derivative 5 with 2-chloro-1,3-dicarbonyls 3 yields
intermediate 6. Cyclization of this intermediate leads to 7,
which is converted to 4 by the elimination of water
(Scheme 2).
In conclusion, we have described a convenient route to
functionalized 2-imino-1,3-thiazoles from tetramethyl-
guanidine and isothiocyanates in the presence of 2-chloro-
1,3-dicarbonyl compounds. The advantage of the present
procedure is that the reaction is performed under neutral
conditions by simple mixing of the starting materials.
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¨
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¨
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