An efficient regioselective synthesis of highly functionalized 3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidines via an isocyanide-based three-component reaction

Article abstract of DOI:10.1016/j.tetlet.2012.01.005

We present a novel, convenient, and efficient method for synthesizing polysubstituted 3-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidines via a three-component reaction. The zwitterions generated from the reaction of isocyanides and dialkyl acetylenedica

Full text of DOI:10.1016/j.tetlet.2012.01.005

Tetrahedron Letters 53 (2012) 1351–1353
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An efficient regioselective synthesis of highly functionalized
3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidines via an
isocyanide-based three-component reaction
Abbas Ali Esmaeili a,b, , Mahdieh Zangouei a, Ali Reza Fakhari c, Azizollah Habibi d
⇑
a Chemistry Department, University of Birjand, Birjand, PO Box 97175/615, Iran
b Department of Chemistry, Ferdowsi University of Mashhad, Mashhad, Iran
c Department of Chemistry, Faculty of Sciences, Shahid Beheshti University, G.C., PO Box 19396-4716, Evin, Tehran, I.R., Iran
d Faculty of Chemistry, University of Tarbiatmoallem, 15719-14911 Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
We present a novel, convenient, and efficient method for synthesizing polysubstituted 3-oxo-2,3-dihy-
dro-5H-[1,3]thiazolo[3,2-a]pyrimidines via a three-component reaction. The zwitterions generated from
the reaction of isocyanides and dialkyl acetylenedicarboxylates react with 2-imino-1,3-thiazolidin-4-one
to produce the title compounds in good yields.
Received 28 July 2011
Revised 10 December 2011
Accepted 3 January 2012
Available online 10 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
2-Imino-1,3-thiazolidin-4-one
Dialkyl acetylenedicarboxylates, Alkyl
isocyanides
Thiazolo[3,2-a]pyrimidine
Multi-component reactions (MCRs) have gained significant
attention due to the advent of high-throughput screening tech-
niques that have enabled rapid identification of potential new
medicines among large collections of organic compounds.1–4 Of
pivotal importance in this area are the isocyanide-based multicom-
ponent reactions (IMCRs) such as the versatile Ugi and Passerini
reactions.5,6 IMCRs allow a dramatic increase of structural com-
plexity in just one step, introducing at the same time three or more
diversity inputs with a high degree of atom economy.2d These reac-
tions leading to interesting heterocyclic scaffolds, are particularly
useful for the construction of diverse chemical libraries of
drug-like molecules.2c
especially for the treatment of Alzheimer’s disease,16 while others
have been reported to be active as CDC25B phosphatase inhibitors
in the low-micromolar range (for the most potent), and show
cytotoxic activity toward tumor cell lines (for example, ethyl (2Z)-
5-(1,3-benzodioxol-5-yl)-2-(2,5-dihydroxybenzylidene)-7-methyl-
3-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxyl-
ate,17 Fig. 1). CDC25 phosphatases play important roles in cell-cycle
regulation and are attractive targets for anticancer therapies.17
Alam et al. reported the synthesis of
a new series of
thiazolo[3,2-a]pyrimidine derivatives with anti-inflammatory and
antinociceptive activities.18 Several synthetic methods have been
Thiazolo[3,2-a]pyrimidines and their derivatives possess
interesting biological activities such as anti-inflammatory,7
psychopharmacological,8 antihypertensive,9 antimicrobial,10 and
antibacterial.11 They also function as diacylglycerol (DG) kinase
O
O
inhibitors,12 calcium antagonists,13 group
2
metabotropic
glutamate receptor antagonists,14 and HIV-1 reverse transcriptase
inhibitors.15 Furthermore, some thiazolo[3,2-a]pyrimidines have
been assigned as new acetylcholinesterase (AChE) inhibitors,
O
O
N
OEt
S
HO
N
OH
⇑
Corresponding author.
E-mail addresses: aa_esmaeili@yahoo.com, abesmaeili@ferdowsi.um.ac.ir (A.A.
Figure 1. An example of a thiazolo[3,2-a]pyrimidine that exhibits cytotoxic
Esmaeili).
activity.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.005

1352
A. A. Esmaeili et al. / Tetrahedron Letters 53 (2012) 1351–1353
Table 1
Reaction of 2-imino-1,3-thiazolidin-4-one (3) with dialkyl acetylenedicarboxylates 2
and isocyanides 1
R1
N
C:
1
+
CO2R2
CO2R2
R2O2C
O
CO2R2
N
CH2Cl2
r.t.
2
R1
+
S
N
N
H
O
NH
NH
4
S
3
Product
R1
R2
Yielda (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
Cyclohexyl
Cyclohexyl
Cyclohexyl
t-Bu
t-Bu
t-Bu
1,1,3,3-Tetramethylbutyl
1,1,3,3-Tetramethylbutyl
1,1,3,3-Tetramethylbutyl
Me
Et
i-Pr
Me
Et
i-Pr
Me
Et
87
70
75
85
78
83
85
75
72
Figure 2. ORTEP representation of the structure of 4a.
i-Pr
a
Isolated yield.
methoxy protons at d 3.68 and d 3.72, and a NH broad singlet at
d 8.82. The methylene protons of the CH2S moiety in 4a are diaste-
reotopic and showed characteristic AB quartet systems (d 3.90, d
4.00, JAB = 16.50 Hz). The 1H decoupled 13C NMR spectrum of 4a
showed 14 distinct resonances that confirm the proposed struc-
ture. The mass spectrum of 4a displayed the molecular ion peak
at m/z = 367, which is consistent with the proposed 1:1:1 adduct
of cyclohexyl isocyanide, dimethyl acetylenedicarboxylate, and 2-
imino-1,3-thiazolidin-4-one. The IR spectrum of 4a showed strong
absorptions at 1750 and 1724 cmꢀ1 due to the ester carbonyls and
described for the synthesis of thiazolo[3,2-a]pyrimidine ring
systems. The most common synthetic routes include: (i) [3+2]
cycloaddition of pyrimidine-2-thiones with 1,2-dielectrophiles
such as 1-acyl-2-bromoacetylenes,19 bromomalononitrile,10,19
chloroacetic acid,11 chloroacetyl chloride20 or phenacyl
bromide,13,20 (ii) the [3+3] reaction of 2-aminothiazoles with
1,3-dielectrophiles such as 2-hydroxypolyfluoroalk-2-enoates,21
1-benzotriazol-1-yl-3-phenylpropynone,22 or Meldrum’s acid
derivatives,23 (iii) [3+1+1] condensations of pyrimidine-2-thiones,
chloroacetic acid and benzaldehydes,7 (iv) [4+2] ring closure of
for the amino group at 3234 cmꢀ1
.
Unambiguous evidence for the structure of 4a was obtained
from single-crystal X-ray analysis. The ORTEP diagram of 4a is
shown in Figure 2.34
N0-(4,5-dihydrothiazol-2-yl)-N,N-dimethylamidines with
a-halok-
etones or acrylic dienophiles,24 (v) cyclization of arenecarbonylm-
ethylthiopyrimidinones,25 and (vi) reaction of 3-isothiocyanato-
A mechanism for the reaction is given in Scheme 1. The initial
event is formation of the zwitterion 5 from the isocyanide 1 and
DMAD 2. Next, the zwitterion is protonated by 2-imino-1,3-thiaz-
olidin-4-one (3). The resulting positively charged nitrilium ion 6 is
attacked by the conjugate base of the NH-acid, 7 leading to 1:1:1
adduct 8. This ketenimine intermediate undergoes intramolecular
cyclization to give the bicyclic 3-oxo-2,3-dihydro-5H-thiazol-
o[3,2-a]pyrimidine product (Scheme 1).
2-propeniminium salts with
a
-aminocarbonyl compounds.26
Furthermore, Adib et al. described a three-component procedure
for the combinatorial synthesis of 5H-thiazolo[3,2-a]pyrimidines
under simple conditions.27
In continuation of our previous work on IMCRs,28–31 attempts
were made to develop a new route for the synthesis of highly
substituted
3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidines.
The products 4a–i were prepared via the one-pot, three-compo-
nent reaction of an isocyanide 1 with a dialkyl acetylenedicarbox-
ylate (DAAD) 2 and 2-imino-1,3-thiazolidin-4-one (3)32 in good
yields (Table 1).
In summary, we have demonstrated that the one-pot, three
component reaction between isocyanides 1, dialkyl acetylenedi-
carboxylates 2 and 2-imino-1,3-thiazolidin-4-one (3) provides a
simple method for the preparation of 3-oxo-2,3-dihydro-5H-thiaz-
olo[3,2-a]pyrimidines of potential synthetic and pharmacological
interest. Fairly high yields of the products, the ready availability
of the starting materials, the simplicity of the reaction and mild
conditions are the main advantages of this method. The present
method is performed under neutral conditions and requires no
prior activation.
The reactions were carried out by mixing the acetylenic ester 2
and 2-imino-1,3-thiazolidin-4-one (3) in anhydrous dichlorometh-
ane. Next, a solution of the isocyanide 1 in anhydrous dichloro-
methane was added slowly to the reaction mixture. The reaction
proceeded spontaneously at ambient temperature and was com-
plete within 24 h. After completion of the reaction as indicated
by TLC, the solvent was distilled in vacuo. The residue, on chro-
matographic purification, afforded the thiazolo[3,2-a]pyrimidines
4 in good yields33 (Table 1). The structures of compounds 4a–i
were deduced from their IR, 1H NMR, and 13C NMR spectra and
by mass spectrometry (see Supplementary data). For example,
the 1H NMR spectrum of 4a exhibited two singlets due to the
Acknowledgment
We gratefully acknowledge financial support from the Research
Council of the University of Birjand.

A. A. Esmaeili et al. / Tetrahedron Letters 53 (2012) 1351–1353
1353
H
N
O
CO2R2
R2O2C
NH
S
R1
N
1
C
R2O2C
C
3
CO2R2
N
R1
5
2
R1
N
CO2R2
N
O
C
R2O2C
R2O2C
H
NH
N
CO2R2
CO2R2
N
H
N
S
O
S
NH
R1
C
S
CO2R2
N
N
H
R1
O
8
7
6
4
Scheme 1. Proposed mechanism for the formation of compounds 4.
17. Kolb, S.; Mondésert, O.; Goddard, M.; Jullien, D.; Villoutreix, B. O.; Ducommun,
B.; Garbay, Ch.; Braud, E. ChemMedChem 2009, 4, 633.
Supplementary data
18. Alam, O.; Khan, S. A.; Siddiqui, N.; Ahsan, W. Med. Chem. Res. 2009,
9267.
19. Elokhina, V. N.; Nakhmanovich, A. S.; Stepanova, Z. V.; Lopyrev, V. A.;
Bannikova, O. B.; Struchkov, Y. T.; Shishkin, O. V. Russ. Chem. Bull. 1996, 45,
2189.
20. Sherif, S. M.; Youssef, M. M.; Mobarak, K. M.; Abdel-Fattah, A.-S. M. Tetrahedron
1993, 49, 9561.
21. Liu, Y. S.; Huang, W. Y. J. Chem. Soc., Perkin Trans. 1 1997, 981.
22. Katritzky, A. R.; Rogers, J. W.; Witek, R. M.; Nair, S. K. Arkivoc 2004, viii, 52.
23. Ye, F. C.; Chen, B. C.; Huang, X. Synthesis 1989, 317.
Supplementary data (experimental details and spectroscopic
characterization of all compounds along with 1H, 13C NMR, IR
and mass spectra and crystallographic data) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2012.01.005.
References and notes
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33. Typical procedure for the preparation of dimethyl 7-(cyclohexylamino)-3-oxo-
2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-5,6-dicarboxylate (4a): To a stirred
solution of dimethyl acetylenedicarboxylate (0.14 g, 1 mmol) and 2-imino-1,3-
thiazolidin-4-one (3) (0.118 g, 1 mmol) in anhydrous CH2Cl2 (5 mL) was added
dropwise a solution of cyclohexyl isocyanide (0.083 g, 1 mmol) in anhydrous
CH2Cl2 (3 mL) at rt over 10 min. The reaction mixture was then stirred for 24 h.
The solvent was removed under reduced pressure and the residue purified by
silica gel (Merck 230–240 mesh) column chromatography using hexane–EtOAc
as eluent to yield 4a: yellow powder; mp 137–138 °C, 0.32 g, yield 87%. IR
(KBr) (m
max/cmꢀ1): 3234 (NH), 1750, 1724, 1637 (3C@O), 1H NMR (300.13 MHz,
CDCl3): dH (ppm) 1.20–1.93 (10 H, m, 5CH2 of cyclohexyl), 3.68 (3H, s, OMe),
2
5. (a) Li-Rong, W.; Chem, J.; Ming, L.; Huai-Yuan, X. Tetrahedron 2009, 65, 1287;
(b) Shaabani, A.; Mahyari, M.; Seyyedhamzeh, M.; Keshipour, S.; Weng Ng, S.
Tetrahedron Lett. 2011, 52, 4388.
3.72 (3 H, s, OMe), 3.90 (1H, d, JH,H = 17.4 Hz, CH2–S) 4.00 (1H, d,
2JH,H = 17.4 Hz, CH2–S), 3.88–4.03 (1H, m, CH–NH), 5.67 (1H, s, CH–CO2Me),
8.82 (1 H, br s, NH). 13C NMR (75.46 MHz, CDCl3): dC (ppm): 24.52, 24.58, 32.34,
(5CH2 of cyclohexyl), 33.74 (CH2–S), 34.04 (CH–CO2Me), 50.64, (CH–NH), 52.88
52.96 (2OMe), 68.87 (@C–CO2Me), 155.40 (N@C–N), 164.61 (NH–C@C), 168.28,
170.21, 170.66 (3C@O). MS: (m/z, %) 367 (M, 4), 336 (3), 308 (100), 226 (28),
198 (33), 166 (24), 107 (8), 55 (9). Anal. Calcd for C16H21N3O5S: C, 52.30; H,
5.76; N, 11.44. Found: C, 52.22; H, 5.73; N, 11.38.
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34. Selected X-ray crystallographic data for compound 4a: C16H21N3O5S (CCDC
799933): MW = 367.43, monoclinic, space group P21, a = 13.787(3) Å,
10. Sayed, H. H.; Shamroukh, A. H.; Rashad, A. E. Acta Pharm. 2006, 56, 231.
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xiii, 266.
b = 11.190(2) Å,
V = 1889.5(7) Å3, Z = 4, Dc = 1.292 mg/m3, F(000) = 776.0, crystal dimension
0.25 ꢁ 0.2 ꢁ 0.1 mm, radiation, Mo (k = 0.71073 Å), 2.39 6 2h 6 29.24,
intensity data were collected at 298(2) K with a Bruker APEX area-detector
diffractometer, employing the /2h scanning technique, in the range of
ꢀ18 6 h 6 17, ꢀ13 6 k 6 15, ꢀ17 6 l 6 17; the structure was solved by a direct
method, all non-hydrogen atoms were positioned and anisotropic thermal
parameters refined from 3841 observed reflections with R(int) = 0.1851 by a
full-matrix least-squares technique converged to R = 0.1225 and Raw = 0.2163
c = 12.808(3) Å,
a
= 90°,
b = 107.03(3)°,
c = 90°,
Ka
x
[I > 2r(I)].