A Synthesis of Functionalized Thiazoles and Pyrimidine-4(3 H)-thiones from 1,1,3,3-Tetramethylguanidine, Acetylenic Esters, and Aryl Isothiocyanates

Article abstract of DOI:10.1055/s-0036-1590862

Aryl isothiocyanates react with dialkyl 2-{[bis(dimethylamino)methylene]amino}maleates, generated from 1,1,3,3-tetramethylguanidine and acetylenic esters, to afford 2-(dimethylamino)-1,3-thiazole derivatives, functionalized 2-(dimethylamino)-6-thioxo-1,6-dihydropyrimidines, and ethyl 2-(dimethylamino)-6-[(4-nitrophenyl)im ino]-4-phenyl-6 H -1,3-thiazine-5-carboxylate, in moderate to good yields.

Full text of DOI:10.1055/s-0036-1590862

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
de
Synlett
I. Yavari et al.
Letter
A Synthesis of Functionalized Thiazoles and Pyrimidine-4(3H)-
thiones from 1,1,3,3-Tetramethylguanidine, Acetylenic Esters,
and Aryl Isothiocyanates
Issa Yavari*a
Asiyeh Amirahmadia
Mohammad Reza Halvagarb
R2
R1
NH
S
R1
R2
Ar
C
N
N
MeCN
r.t.
N
R1
N
N
N
+
+
MeCN
reflux
R2
N
N
S
a
N
N
N
S
Department of Chemistry, Tarbiat Modares University,
R1
R2
Ar
PO Box 14115-175, Tehran, Iran
yavarisa@modares.ac.ir
Department of Inorganic Chemistry, Chemistry and
5
examples
0–61% yield
5 examples
34–45% yield
5
b
1
i
t
R
= Ph, CO2Me, CO2Et, CO2 Pr, CO2 Bu
Chemical Engineering Research Center of Iran,
PO Box 14335-186, Tehran, Iran
2
i
t
R
= CO2Me, CO2Et, CO2 Pr, CO2 Bu
Ar = Ph, 3-ClC6H4, 4-FC6H4, 4-BrC6H4,
-MeOC6H4
4
7
Received: 06.05.2017
Accepted after revision: 11.07.2017
Published online: 25.08.2017
sis of acetylcholine. Thiazoles are usually prepared by the
8
Hantzsch method, which suffers from long reaction times,
low yields, and harsh reaction conditions.9
DOI: 10.1055/s-0036-1590862; Art ID: st-2017-d0327-l
Here, we report a simple procedure for the synthesis of
-(dimethylamino)thiazole derivatives and functionalized
-(dimethylamino)-6-thioxo-1,6-dihydropyrimidine-5-car-
boxylate derivatives by a three-component coupling reac-
tion of 1,1,3,3-tetramethylguanidine (TMG), acetylenic es-
ters, and aryl isothiocyanates.
Initially, we chose TMG (1) and dimethyl acetylenedi-
carboxylate (DMAD; 2a) as model substrates to react with
isothiocyanatobenzene (3a). Various solvents (EtOH, THF,
and MeCN) were explored, and the results are summarized
in Table 1. The reactions performed in THF or MeCN at
room temperature for 48 hours gave 5a in low yields (Table
1, entries 1 and 2). When EtOH was used as the solvent,
only a reaction between EtOH and isothiocyanatobenzene
Abstract Aryl isothiocyanates react with dialkyl 2-{[bis(dimethylami-
no)methylene]amino}maleates, generated from 1,1,3,3-tetramethyl-
guanidine and acetylenic esters, to afford 2-(dimethylamino)-1,3-thi-
azole derivatives, functionalized 2-(dimethylamino)-6-thioxo-1,6-
dihydropyrimidines, and ethyl 2-(dimethylamino)-6-[(4-nitrophenyl)im-
ino]-4-phenyl-6H-1,3-thiazine-5-carboxylate, in moderate to good
yields.
2
2
Key words thiazolamines, alkynoate esters, pyrimidinethiones, te-
tramethylguanidine, aryl isothiocyanates
Heterocyclic compounds such as pyrimidines play im-
portant roles in the fields of drugs and agrochemicals, and
in many biological processes. In recent decades, many phar-
macological studies have been carried out on pyrimidine
1
and its derivatives, such as pyrimethamine. An important
derivative of pyrimidine is pyrimidine-2-thiol, also known
as 2-mercaptopyrimidine or (in its tautomeric form) 2-thi-
oxopyrimidine [pyrimidine-2(1H)-thione] (Figure 1).2
Table 1 Formation of Product 5a under Various Reaction Conditionsa
CO2Me
S
CO2Me
MeCN, r.t.
Ph
C
2
CO Me
NH
N
Cl
N
NH2
N
CO2Me
3a
S
N
+
N
N
N
MeCN
reflux
CO2Me
N
N
S
N
N
Cl
N
CO2Me
HO
SH
Pyrimethamine Pyrimidine-2-thiol
N
1
2a
4a
5a
H2N
N
NH2
N
Vitamin B1 (thiamine)
b
Entry
Solvent
Temp
Yield (%)
Figure 1 Examples of pharmaceuticals containing pyrimidine or thi-
azole moieties
1
2
3
THF
r.t.
trace
14
MeCN
EtOH
MeCN
r.t.
3
Thiazoles are interesting heterocyclic systems that ex-
hibit various biological properties, such as antimicrobial,
antihistaminic, and antiviral activities. Thiazole-contain-
ing vitamin B1 (thiamine) (Figure 1) helps in the normal
functioning of the nervous system by its role in the synthe-
reflux
reflux
–
4
4
52
5
6
a
Reaction conditions: 1 (0.115 g, 1 mmol), 2a (0.142 g, 1 mmol), 3a
(0.135 g, 1 mmol), solvent (5mL).
b
Isolated yield.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
Synlett
I. Yavari et al.
Letter
was observed (entry 3). Finally, reaction in MeCN at the re-
flux gave product 5a in 52% yield (entry 4).
The structures of products 5a–e and 6a–e were deduced
from their IR, H NMR, and C NMR spectra and their mass
spectrometric data. Unequivocal evidence for the structures
1
13
Therefore, the optimal reaction conditions are one
equivalent each of TMG (1), DMAD (2a), and isothiocyana-
tobenzene (3a) in refluxing MeCN. By using these opti-
mized reaction conditions and various dialkyl acetylenedi-
carboxylates 2, we prepared four derivatives of 2-(dime-
of 5e and 6c was obtained by single-crystal X-ray analy-
ses.1
3,14
The ORTEP diagrams of 5e and 6c are shown in Fig-
ure 2 and Figure 3, respectively.
10
thylamino)thiazole 5a–d (Table 2).
Table 2 Synthesis of Dialkyl 2-(dimethylamino)thiazole-4,5-dicarbox-
a
ylates 5a–d
CO2R
S
CO2R
CO2R
MeCN, r.t.
Ph
C
N
3a
N
N
CO2R
1
+
N
2
CO R
MeCN
reflux
S
N
N
CO2R
2
4
5
b
Entry
R
Product
Yield (%)
Figure 2 X-ray crystal structure (ORTEP) of 5e with thermal ellipsoids
1
2
3
Me
5a
5b
5c
5d
52
58
60
61
set at the 40% probability level14
Et
iPr
tBu
4
a
Reaction conditions: 1 (1 mmol), 2 (1 mmol), 3a (1 mmol), MeCN (5 mL),
reflux.
b
Isolated yield.
To extend the scope of this reaction, we used ethyl 3-
phenylpropiolate (2e) as the acetylenic ester (Table 3). The
reaction of TMG with 2e and isothiocyanatobenzene (3a)
gave ethyl 2-(dimethylamino)-4-phenylthiazole-5-carbox-
11
ylate (5e) together with ethyl 2-(dimethylamino)-1,4-di-
phenyl-6-thioxo-1,6-dihydropyrimidine-5-carboxylate
(
6a). By using a range of aryl isothiocyanates, a series of
Figure 3 X-ray crystal structure (ORTEP) of 6c with thermal ellipsoids
10
novel products 6b–e, were prepared (Table 3).
set at the 40% probability level14
Table 3 Synthesis of Compounds 5e and 6a–ea
CO2Et
Ar
S
Ph
CO2Et
C
N
3
Ph
CO2Et
S
MeCN, r.t.
N
Ph
N
N
1
+
+
MeCN
reflux
N
N
N
CO2Et
N
N
S
Ph
Ar
2e
4e
5e
6
Yield (%)b
Product
Yield (%)
b
Entry
Ar
Product
1
2
3
4
Ph
3-ClC
4-MeOC
5e
5e
5e
5e
5e
50
52
61
50
55
6a
6b
6c
6d
6e
45
36
34
40
35
6
H
4
6
H
4
4-FC
6
H
4
5
4-BrC
6
H
4
a
Reaction conditions: 1 (1 mmol), 2 (1 mmol), 3 (1 mmol), MeCN (5 mL), reflux.
Isolated yield.
b
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I. Yavari et al.
Letter
Ph
Ph
Ph
N
Ph
N
CO2Et
CO2Et
CO2Et
S
CO2Et
S
N
N
N
N
N
3
a + 4e
N
N
H
S
Ph
N
S
N
N
N
N
N
Ph
8
Ph
Ph
7
9
6a
Ph
Ph
Ph
Ph
CO2Et
H
N
S
N
Ph
N
N
N
N
N
N
N
CO2Et
NPh
2
CO Et
S
N
CO2Et
NPh
N
N
S
N
2
CO Et
S
NPh
S
NPh
NMe2
10
11
12
13
5e
Scheme 1 A plausible mechanism for the formation of products 5e and 6a
On account of their similar NMR spectra, the structures
Product 14 was readily identified from its NMR spectra.
5
a–d and of 6a, 6b, 6d, and 6e were assumed to be analo-
gous to those of 5e and 6c (as deduced from the crystallo-
graphic data), respectively.
In particular, in the 13C NMR spectrum of 14, there is no
peak for the C=S carbon. Unequivocal evidence for the
structure of 14 was obtained from single-crystal X-ray anal-
A plausible mechanism for the formation of products 5e
and 6a is shown in Scheme 1. It is conceivable that the reac-
tion between 4e and isothiocyanatobenzene (3a) affords in-
termediate 7, which converts into intermediate 8. This in-
termediate undergoes intramolecular nucleophilic attack
by nitrogen to generate pyrimidine derivative 9, which is
then converted into the dihydropyrimidine derivative 6a by
elimination of dimethylamine. Alternatively, intermediate 7
might undergo S-alkylation to afford the 1,3-thiazine deriv-
ative 10. This intermediate converts into the sulfur ylide 11
by 1,2-sulfur migration. The S-ylide 11 might then undergo
tautomerism to generate the more stable S-ylide 12, which
is converted into thiazole 5e via intermediate 13.
ysis.1
3,14
The ORTEP diagram of 14 is shown in Figure 4.
In the presence of 1-isothiocyanato-4-nitrobenzene
(
3f), ethyl 2-(dimethylamino)-6-[(4-nitrophenyl)imino]-4-
phenyl-6H-1,3-thiazine-5-carboxylate (14) was formed via
intermediate 16 (Scheme 2). This observation suggests that
the formation of product 14 is due to a lack of formation of
Figure 4 X-ray crystal structure (ORTEP) of 14 with thermal ellipsoids
set at the 40% probability level
14
5e, because the electron-withdrawing nature of the para-
nitro group stabilizes the imine structure 16.
In conclusion, we have developed a multicomponent re-
action of TMG, acetylenic esters, and aryl isothiocyanates as
a novel route to the synthesis of a series of 2-(dimethylami-
no)thiazole derivatives 5, functionalized 2-(dimethylami-
no)-6-thioxo-1,6-dihydropyrimidines 6, and ethyl 2-(dime-
thylamino)-6-[(4-nitrophenyl)imino]-4-phenyl-6H-1,3-thi-
azine-5-carboxylate (14) in moderate to good yields.
Ph
Ph
S
CO2Et
H
CO Et
2
N
N
N
S
N
N
N
3f
+ 4e
N
NO2
NO2
16
14
Supporting Information
Scheme 2 A plausible mechanism for the formation of product 14
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590862.
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Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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Letter
References and Notes
Ethyl (6Z)-2-(Dimethylamino)-6-[(4-nitrophenyl)imino]-4-
phenyl-6H-1,3-thiazine-5-carboxylate (14)
(1) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry; Wiley: Chiches-
Yellow solid; yield: 0.31 g (73%); mp 196–198 °C. IR (KBr): 3440
ter, 2010, 5th ed.. (b) Dhongade, H. J.; Dansena, H.; Chandrakar,
K. K. Asian J. Pharm. Clin. Res. 2015, 8,04 171. (c) Lagoja, I. M.
Chem. Biodiversity 2005, 2, 1.
–1
1
and 2930 (Me), 1721 (CO ), 1579 (C=N) cm
.
H NMR (500
2
MHz, CDCl ): δ = 1.07 (t, J = 7.1 Hz, 3 H), 3.25 (s, 6 H), 4.17 (q, J =
3
6
.9 Hz, 2 H), 7.12 (d, J = 8.9 Hz, 2 H), 7.49–7.50 (m, 3 H), 7.75 (d,
(
2) Cosimelli, B.; Greco, G.; Ehlardo, M.; Novellino, E.; Da Settimo,
F.; Taliani, S.; La Motta, C.; Bellandi, M.; Tuccinardi, T.;
Martinelli, A.; Ciampi, O.; Trincavelli, M. L.; Martini, C. J. Med.
Chem. 2008, 51, 1764.
13
J = 7.4 Hz, 2 H), 8.32 (d, J = 8.9 Hz, 2 H). C NMR (125.7 MHz,
CDCl ): δ = 13.8 (Me), 38.8 (Me N), 61.6 (CH O), 108.5 (C), 121.1
3
2
2
(
2 CH), 125.6 (2 CH), 128.2 (2 CH), 128.3 (2 CH), 129.7 (CH),
1
40.2 (C), 144.3 (C), 153.1 (C), 156.1 (C), 158.3 (C), 158.9 (C),
(
3) Metzger, J. V. In Comprehensive Heterocyclic Chemistry;C41.h9
Katritzky, A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984, 235.
4) Desai, N. C.; Joshi, V. V.; Rajpara, K. M.; Vaghani, H. V.; Satodiya,
H. M. J. Fluorine Chem. 2012, 142, 67.
a
p6., Vo.
l
+
168.1 (C=O). EI-MS: m/z (%) = 424.12 (M , 100), 380 (14), 322
(
34), 258 (21), 229 (31), 77 (23). Anal. Calcd for C21H20N O S
4 4
(
(
1
424.48): C, 59.42; H, 4.75; N, 13.20. Found: C, 59.73; H, 4.78; N,
3.23.
(
(
5) Brzezińska, E.; Kośka, G. Biomed. Chromatogr. 2006, 20, 1004.
6) Barradas, J. S.; Errea, M. I.; D’Accorso, N. B.; Sepúlveda, C. S.;
Damonte, E. B. Eur. J. Med. Chem. 2011, 46, 259.
(
12) Kaye, P. T.; Meakins, G. D.; Smith, A. K.; Tirel, M. D. J. Chem. Soc.,
Perkin Trans. 1 1983, 1677.
(
13) X-ray diffraction measurements were carried out on a STOE
IPDS 2T diffractometer with graphite-monochromated Mo-Kα
radiation. All single crystals were obtained from CH Cl –hexane
(7) Mishra, C. B.; Kumari, S.; Tiwari, M. Eur. J. Med. Chem. 2015, 92,
1.
2
2
(
8) (a) Souldozi, A.; Ramazani, A.; Dadrass, A. R.; Ślepokura, K.; Lis,
T. Helv. Chim. Acta 2012, 95, 339. (b) Nefzi, A.; Arutyunyan, S.;
Fenwick, J. E. J. Org. Chem. 2010, 75, 7939.
solutions and mounted on glass fibers. Cell constants and orien-
tation matrices for data collection were obtained by least-
square refinement of the diffraction data from 5045, 3838, and
(9) Zheng, H.; Mei, Y.-H.; Du, K.; Cao, X.-T.; Zhang, P.-F. Molecules
3762 reflections for compounds 5e, 6c, and 14, respectively. Dif-
2013, 18, 13425.
fraction data were collected in a series of ω scans in 1° oscilla-
tions, and integrated by using the STOE X-AREA software
package (see Ref. 15). Multiscan absorption corrections were
applied by using WinGX-2013.3 software. The structures were
solved by direct methods and subsequent difference Fourier
(10) Compounds 5, 6 and 14: General Procedure
TMG (1; 0.115 g, 1 mmol) and the appropriate acetylenic ester 2
(1 mmol) were dissolved in MeCN (5 mL), and the solution was
stirred for 1 h at r.t. Aryl isothiocyanate 3 (1 mmol) was added,
and the mixture was stirred at the reflux until the reaction was
complete [~48 h; TLC (EtOAc–hexane, 1:4)]. The mixture was
then filtered and the precipitate was purified by flash column
chromatography [silica gel, EtOAc–hexane (1:4)].
2
maps, and then refined on F by a full-matrix least-squares pro-
cedure using anisotropic displacement parameters. Atomic
factors are from the International Tables for X-ray Crystallogra-
phy. All non-hydrogen atoms were refined with anisotropic dis-
placement parameters. Hydrogen atoms were placed in ideal
positions and refined as riding atoms with relative isotropic dis-
placement parameters. All refinements were performed by
using the X-STEP32, SHELXL-2014, and WinGX-2013.3 programs
(11) Ethyl 2-(Dimethylamino)-4-phenylthiazole-5-carboxylate (5e)
1
2
Yellow crystals; yield: 0.17 g (61%); mp 111–113 °C, (Lit. 115–
–
1
.
1H NMR (500
116 °C). IR (KBr): 3382, 2975, 1697, 1566 cm
MHz, CDCl ): δ = 1.25 (t, J = 7.1 Hz, 3 H), 3.15 (s, 6 H), 4.20 (q, J =
3
1
3
7.1 Hz, 2 H), 7.37–7.39 (m, 3 H), 7.76 (d, J = 7.7 Hz, 2 H). C NMR
(see ref. 16).
(
125.7 MHz, CDCl ): δ = 14.2 (Me), 40.2 (Me N), 60.6 (CH O),
3
2
2
(14) CCDC 1546425, 1530696, and 1530695 contain the supplemen-
tary crystallographic data for compounds 5e, 6c, and 14, respec-
tively. These data can be obtained free of charge from The Cam-
1
1
1
10.4 (C), 114.2 (C), 127.6 (2 CH), 128.9 (CH), 129.9 (2 CH),
34.6 (C), 161.9 (C=O), 170.7 (C). EI-MS: m/z (%) = 276/09 (M ,
00), 231 (47), 175 (50), 133 (47), 89 (65), 44 (19). Anal. Calcd
+
bridge
Crystallographic
Data
Centre
(CCDC)
via
for C14H16N O S (276.35): C, 60.85; H, 5.84; N, 10.14. Found: C,
2
2
www.ccdc.cam.ac.uk/data_request/cif.
61.13; H, 5.88; N, 10.17.
(
15) X-AREA: Program for the Acquisition and Analysis of Data,
Version 1.30; STOE & Cie GmbH: Darmstadt, 2005.
16) For details, see: (a) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32,
Ethyl 2-(Dimethylamino)-1-(4-methoxyphenyl)-4-phenyl-6-
thioxo-1,6-dihydropyrimidine-5-carboxylate (6c)
(
Yellow solid; yield: 0.14 g (34%); mp 116–118 °C. IR (KBr): 3438,
837. (b) Allen, F. H.; Johnson, O.; Shields, G. P.; Smith, B. R.;
–1 1
2
929, 1685, 1617 cm . H NMR (500 MHz, CDCl ): δ = 1.25 (t,
3
Towler, M. J. Appl. Crystallogr. 2004, 37, 335. (c) Edgington, P. R.;
McCabe, P.; Macrae, C. F.; Pidcock, E.; Shields, G. P.; Taylor, R.;
Towler, M.; van der Streek, J. J. Appl. Crystallogr. 2006, 39, 453.
(d) Burnett, M. N.; Johnson, C. K. ORTEP-III Report ORNL-6895;
Oak Ridge National Laboratory: Oak Ridge, 1996. (e) Spek, A. L.
J. Appl. Crystallogr. 2003, 36, 7. (f) Sheldrick, G. M. Acta Crystal-
logr., Sect. A 2008, 64, 112. (g) Coppens, P.; Leiserowitz, L.;
Rabinovich, D. Acta Crystallogr. 1965, 18, 1035.
J = 7.1 Hz, 3 H), 2.85 (s, 6 H), 3.94 (s, 3 H), 4.33 (q, J = 7.1 Hz, 2
H), 7.09 (d, J = 7.9 Hz, 2 H), 7.36 (d, J = 7.9 Hz, 2 H), 7.47–7.56 (m, 3
H), 8.89 (d, J = 6.7 Hz, 2 H). C NMR (125.7 MHz, CDCl ):
δ = 13.9 (Me), 41.6 (Me N), 55.6 (MeO), 61.8 (CH O), 114.4 (2
CH), 124.7 (C), 128.4 (2 CH), 128.5 (2 CH), 130.4 (CH), 130.7 (2 CH),
13
3
2
2
1
1
2
6
32.9 (C), 137.4 (C), 154.6 (C), 157.5 (C), 159.6 (C), 167.4 (C=O),
85.7 (C=S). EI-MS: m/z (%) = 409.15 (M , 100), 365 (15), 258 (22),
29 (30), 147 (28), 77 (23). Anal. Calcd for C22H23N O S (409.50): C,
4.53; H, 5.66; N, 10.26. Found: C, 64.84; H, 5.69; N, 10.29.
+
3
3
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D