New synthesis of 3,5-disubstituted-5H-thiazolo[3,2-a]pyrimidine via ring annulation of 3,4-dihydropyrimidin-2(1H)-thione using alkynyl(aryl)iodonium salts

Article abstract of DOI:10.1016/j.tetlet.2012.11.098

A transition metal-free protocol for the synthesis of biologically active thiazolo[3,2-a]pyrimidine derivatives has been achieved by the cyclocondensation of 3,4-dihydropyrimidin-2(1H)-thiones with alkynyl(aryl)iodonium tosylates. This reaction demonstrat

Full text of DOI:10.1016/j.tetlet.2012.11.098

Tetrahedron Letters 54 (2013) 600–603
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New synthesis of 3,5-disubstituted-5H-thiazolo[3,2-a]pyrimidine
via ring annulation of 3,4-dihydropyrimidin-2(1H)-thione
using alkynyl(aryl)iodonium salts
⇑
Amol V. Shelke, Bhagyashree Y. Bhong, Nandkishor N. Karade
Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra 440 033, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A
transition metal-free protocol for the synthesis of biologically active thiazolo[3,2-a]pyrimidine
Received 1 November 2012
Revised 22 November 2012
Accepted 24 November 2012
Available online 1 December 2012
derivatives has been achieved by the cyclocondensation of 3,4-dihydropyrimidin-2(1H)-thiones with
alkynyl(aryl)iodonium tosylates. This reaction demonstrates another useful application of alky-
nyl(aryl)iodonium tosylates as synthon of alkynyl cation.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Biginelli reaction
Thiazolo[3,2-a]pyrimidine
Alkynyl(aryl)iodonium tosylates
Cyclocondensation
Hypervalent iodine
The Biginelli reaction is a simple one pot three-component con-
densation of an aldehyde, b-ketoester, and urea or thiourea in the
presence of a catalytic quantity of acid to produce 3,4-dihydropyr-
imidin-2-(1H)-ones (DHPMs).1 The dihydropyrimidinones and
their derivatives exhibit a wide range of biological activities such
as calcium channel modulators, mitotic kinesine inhibitors, adren-
ergic receptor antagonists, antibacterial, and antiviral agents.2 Sev-
eral biologically active marine alkaloids were also found to contain
the dihydropyrimidinone-5-carboxylate core.3 Most notable
among them are batezelladine alkaloids, which have been found
to be potent HIV gp-120-CD4 inhibitors.4 Owing to this remarkable
pharmacological profile, there is a considerable interest in the dec-
oration of all the six positions of DHPMs (N1, C2, N3, C4, C5, and
C6) to produce low molecular weight ‘drug like’ compounds.5
One of such structural post-modifications of 3,4-dihydropyrimi-
din-2(1H)-thiones is due to the presence of cyclic thiourea type
antimicrobial, and antibacterial.7,8 They also serve as diacylglycerol
(DG) kinase inhibitors, calcium antagonists, group 2 metabotropic
glutamate receptor antagonists, and HIV-1 reverse transcriptase
inhibitors.8 Furthermore, some thiazolo[3,2-a]pyrimidines have
been assigned as new acetylcholinesterase (AChE) inhibitors, espe-
cially for the treatment of Alzheimer’s disease.7a
A variety of synthetic methods for the preparation of thiazol-
o[3,2-a]pyrimidine derivatives have been reported. One of the
most common procedures involves the cyclization of 4-aryl-3,4-
dihydropyrimidin-2(1H)-thiones with halogen derived doubly
electrophilic building blocks such as 2-bromo-ketones,7 chloroace-
tic acid,8 chloroacetyl chloride,9 methyl chloroacetate,10 and 1,2-
dichloroethane11 to form the C2–N3 linked thiazolo[3,2-a]pyrimi-
dine derivatives (Fig. 1). Recently, an improved protocol involving
in situ generation of
a-bromo ketone from the reaction of ketone
with 2 equiv of Br2, followed by its subsequent trapping with
3,4-dihydropyrimidin-2(1H)-thiones has been reported to form
thiazolo[3,2-a]pyrimidine derivatives.6c Another synthetic route
for the preparation of these compounds is via C–S cross-coupling
and 5-endo-dig cyclization sequence of 3,4-dihydropyrimidin-
2(1H)-thiones with terminal alkynes.12 This method utilizes CuCl
(2 equiv), N,N0-dicyclohexylimidazolium chloride (2 equiv) as the
ligand and Et3N (5 equiv) for the condensation of terminal alkyne
(2 equiv) with 3,4-dihydropyrimidin-2(1H)-thiones under reflux
conditions in toluene. The above discussed methods for the synthe-
sis of thiazolo[3,2-a]pyrimidine derivatives utilize mainly halogen
derived doubly electrophilic building blocks and terminal alkynes
moiety, leading to form highly elaborated skeletons with
a
potential pharmacological action.6 In particular, when the reaction
of 3,4-dihydropyrimidin-2(1H)-thiones is carried out with
1,2-dielectrophiles, the formation of ring annulation product,
thiazolo[3,2-a]pyrimidine derivatives take place via C2–N3 linked
centers.7–11,6c The synthesis of thiazolo[3,2-a]pyrimidine has
recently gained importance due to diverse pharmacological
activities such as anti-inflammatory, antiviral, antihypertensive,
⇑
Corresponding author. Fax: +91 712 2532841.
E-mail address: nnkarade@gmail.com (N.N. Karade).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.098

A. V. Shelke et al. / Tetrahedron Letters 54 (2013) 600–603
601
O
Ar
Ph
R1
N
S
N
Et3N, Toluene,
110 °C for 24h
ref. 12
Ph
(2 eqiuv)
CuCl (2equiv),
ICy.HCl (2equiv
present work
O
Ar
N
R2
O
Ar
O
Ar
N
R2
IPh OTs
Cl(CH2)2Cl
ref. 11
R1
N
R1
NH
R1
N
THF, K2CO3
S
S
N
H
S
r. t. 24h
O
ClCH2COOH
ref. 8
Br
ref. 7 R2
O
O
Ar
R2
Ar
O
R1
N
R1
N
S
S
N
N
Figure 1. Methods of cyclocondensation of 3,4-dihydropyrimidin-2(1H)-thiones to form C2–N3 linked thiazolo[3,2-a]pyrimidine derivatives.
for cyclocondensation with 3,4-dihydropyrimidin-2(1H)-thiones.
Herein, we wish to report the utilization of the alkynyl(aryl)iodoni-
um salts as another source of building block for the ring annulation
of 3,4-dihydropyrimidin-2(1H)-thiones to form thiazolo[3,2-
a]pyrimidine derivatives under transition metal-free conditions.
The alkynyl(aryl)iodonium salts represent one of the useful and
important classes of hypervalent iodine reagents, which show a
wide range of applicability as a source of electrophilic acetylene
equivalents, a change from the usual nucleophilic characteristics
of acetylene.13 The strong electron withdrawing properties of the
iodonium group make alkynyl(aryl)iodonium salts to react via Mi-
chael-type conjugate addition reactions as well as Diels–Alder and
other cycloadditions.14 The good leaving group ability of iodoben-
zene moiety renders alkynyl(aryl)iodonium salts as powerful elec-
trophilic alkynylating reagents toward various organic
nucleophiles.15
In 1996, Wipf and Venkatraman reported a versatile method for
the synthesis of thiazole by cyclocondensation of thioamides and
alkynyl(aryl)iodonium mesylates under basic conditions.16 The
structural similarity of thioamides and 3,4-dihydropyrimidin-
2(1H)-thiones led us to envisage that the reaction of the latter with
doubly electrophilic alkynyl(aryl)iodonium tosylates could lead to
form C2–N3 linked thiazolo[3,2-a]pyrimidine derivatives (Fig. 1).
The requisite alkynyl(aryl)iodonium tosylates were easily pre-
pared from appropriate terminal alkynes and hydroxy(tosyl-
oxy)iodobenzene using the literature methods.17 We began our
investigation with the model reaction of 4-phenyl-3,4-dihydropyr-
imidin-2(1H)-thiones 1a with phenyl(phenylethyny1)iodonium
tosylate 2a using K2CO3 as the base in different solvents such as
CH2Cl2, CHCl3, THF, and acetonitrile (Table 1). To our delight, the
concept works nicely and the formation of 3a took place in all
the solvents. However, the maximum 74% yield of 3a took place
using 1.4 equiv of 2a in THF after stirring at room temperature
for 24 h (Table 1, entry 8).18 In the absence of K2CO3, no formation
of 3a took place.
After optimization of the reaction conditions, the efficiency of
the process was investigated with the cyclocondensation of 4-
aryl-3,4-dihydropyrimidin-2(1H)-thiones with different alky-
nyl(aryl)iodonium tosylates. As shown in Table 2, the presence of
electron-donating and withdrawing substituents at C-4 aryl group
of 3,4-dihydropyrimidin-2(1H)-thiones has little influence on the
yields of cyclocondensation products. The alkynyl(aryl)iodonium
Table 2
Synthesis of thiazolo[3,2-a]pyrimidine derivatives using alkynyl(aryl)iodonium tosy-
lates and 3,4-dihydropyrimidin-2(1H)-thionesa
O
Ar
R2
O
Ar
N
Table 1
R1
NH
R1
N
K2CO3
Optimization of reaction conditions
R2
IPh OTs
O
Ph
THF
r. t., 24 h
N
H
S
S
O
Ph
N
Ph
2(a-m)
K2CO3
EtO
NH
1(a-m)
3(a-m)
EtO
N
Ph
IPh OTs
solvent
r. t., 24h
N
H
S
S
2a
Entry
Ar
R1
R2
Product 3
Yielda (%)
1a
3a
a
b
c
d
e
f
g
h
i
C6H5
CH3CH2O
CH3CH2O
CH3CH2O
CH3CH2O
CH3CH2O
CH3CH2O
CH3CH2O
CH3CH2O
CH3CH2O
CH3
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C4H9
C5H11
C5H11
C6H5
C4H9
C4H9
C4H9
3a
3b
3c
3d
3e
3f
3g
3h
3i
74
79
76
78
80
71
77
73
78
71
74
69
67
4-CH3OC6H4
3-CH3OC6H4
4-CH3C6H4
3,4-(CH3O)2C6H3
4-ClC6H4
2,5-(CH3O)2C6H3
C6H5
4-ClC6H4
4-CH3C6H4
4-CH3C6H4
3-CH3OC6H4
C6H5
Entry
2a (mmol)
Solvent
Yield of 3aa,b (%)
1
2
3
4
5
6
7
8
9
1
1
1
1.2
1.2
1.2
1.4
1.4
1.4
CHCl3
CH2Cl2
THF
CHCl3
CH2Cl2
THF
CHCl3
CH2Cl2
THF
45
42
56
51
53
66
60
57
74
j
k
l
3j
3k
3l
CH3
CH3
CH3
m
3m
a
Isolated yield.
a
b
Isolated yields after column chromatography.
Reaction conditions: 1a (1 mmol), 2a, and K2CO3 (2.5 mmol).

602
A. V. Shelke et al. / Tetrahedron Letters 54 (2013) 600–603
R3
B
O
R1
R1
O
R1
O
R1
O
R3
R3
H
[3, 3]
R2
N
R2
N
R2
N
R2
N
PhI
R3
I
C
C
N
H
S
Ph
R3
N
H
S
N
H
1
S
2
N
H
S
IPh
IPh
4
5
O
R1
R1
O
R1
O
R3
R3
R2
N
R2
N
R2
N
- PhI
C
N
H
S
S
S
N
H
N
3
alkylidene carbene 6
Scheme 1. Mechanism of 3,5-disubstituted-5H-thiazolo[3,2-a]pyrimidine formation.
9, 1573; (d) Danel, K.; Pedersen, E. B.; Nielsen, C. J. Med. Chem. 1998, 41, 191; (e)
Balkan, A.; Ertan, M.; Burgemeister, T. Arch. Pharm. 1992, 325, 499; (f) Balkan,
A.; Uma, S.; Ertan, M.; Wiegrebe, W. Pharmazie 1992, 47, 687; (g) Kappe, C. O.;
Roschge, P. J. Heterocycl. Chem. 1989, 1, 55.
tosylates bearing an aromatic ring as well as alkyl substituents re-
acted very well to provide the cyclization products in good to high
yields. All the products were characterized by IR, NMR, (1H and
13C), and LCMS analysis (Supplementary data).19
The plausible reaction mechanism for the formation of thiazol-
o[3,2-a]pyrimidine derivatives is shown in Scheme 1.16a The nucle-
ophilic sulfur of 3,4-dihydropyrimidin-2(1H)-thiones 1 can attack
on electrophilic iodine of 2 to form 4 which undergoes [3,3]-het-
ero-Claisen rearrangement to furnish vinyliodonium ylide 5. The
tendency of 5 for the reductive elimination of iodobenzene may
lead to form alkilidene carbene 6 as the intermediate which finally
undergoes cyclization to yield 3.
In conclusion, we have developed a mild, efficient, and transi-
tion metal-free protocol for the cyclocondensation of 3,4-dihydro-
pyrimidin-2(1H)-thiones with alkynyl(aryl)iodonium tosylates to
form thiazolo[3,2-a]pyrimidine derivatives in good yields. This
transformation demonstrates other useful applications of alky-
nyl(phenyl)iodonium salts as synthon of alkynyl cation.
8. Chloroacetic acid: (a) Pan, B.; Huang, R.; Zheng, L.; Chen, C.; Han, S.; Qub, D.;
Zhu, M.; Wei, P. Eur. J. Med. Chem. 2011, 46, 819; (b) Mohamed, S. F.; Flefel, E.
M.; Amra, A. E.; Abd El-Shafy, D. N. Eur. J. Med. Chem. 2012, 45, 1494; (c) Rashad,
A. E.; Sayed, H. H.; Shamroukh, A. H.; Awad, H. M. Phosphorus, Sulfur Silicon
Relat. Elem. 2005, 180, 2767; (d) Tozkoparan, B.; Ertan, M.; Kelicen, P.;
Demirdamar, R. Farmaco 1999, 54, 588; (e) Tozkoparan, B.; Ertan, M.; Krebs,
B.; Läge, M.; Kelicen, P.; Demirdamar, R. Arch. Pharm. Med. Chem. 1998, 331,
201; (f) Ghorab, M. M.; Mohamad, Y. A.; Mohamed, S. A.; Ammar, Y. A.
Phosphorus, Sulfur Silicon Relat. Elem. 1996, 108, 249; (g) Akhtar, M. S.; Seth, M.;
Bhaduri, A. P. Indian J. Chem. 1987, 268, 556.
9. Chloroacetyl chloride: Kolb, S.; Mondesert, O.; Goddard, M.-L.; Jullien, D.;
Villoutreix, B. O.; Ducommun, B.; Garbay, C.; Braud, E. Chem. Med. Chem. 2009,
4, 633.
10. Methyl chloroacetate: (a) Kulakov, I. V.; Nurkenov, O. A.; Turdybekov, D. M.;
Issabaeva, G. M.; Mahmutova, A. S.; Turdybekov, K. M. Chem. Heterocycl. Compd.
2009, 45, 856; (b) Abu-Hashem, A. A.; Youssef, M. M.; Hussein, H. A. R. J. Chin.
Chem. Soc. 2011, 58, 41.
11. 1,2-Dichloroethane: (a) Ghorab, M. M.; Mohamad, Y. A.; Mohamed, S. A.;
Ammar, Y. A. Phosphorus, Sulfur Silicon Relat. Elem. 1996, 108, 249–256; 1,3-
dibromopropane: (b) Bózsing, D.; Sohár, P.; Gigler, G.; Kovács, G. Eur. J. Med.
Chem. 1996, 31, 663.
12. Xiao, D.; Han, L.; Sun, Q.; Chen, Q.; Gong, N.; Lv, Y.; Suzenet, F.; Guillaumet, G.;
Cheng, T.; Li, R. RSC Adv. 2012, 2, 5054.
Acknowledgments
13. Reviews: (a) Zhdankin, V. V.; Stang, P. J. Tetrahedron 1996, 54, 10927; (b)
Yusubov, M. S.; Maskaev, A. V.; Zhdankin, V. V. ARKIVOC 2011, i, 370.
14. Williamson, B. L.; Stang, P. J.; Arif, A. M. J. Am. Chem. Soc. 1993, 115, 2590.
15. (a) Stang, P. J.; Surber, B. W.; Chen, Z.-C.; Roberts, K. A.; Anderson, A. G. J. Am.
Chem. Soc. 1987, 109, 228; (b) Ochiai, M.; Ito, T.; Takaoka, Y.; Masaki, Y.;
Kunishima, M.; Tani, S.; Nagao, Y. J. Chem. Soc., Chem. Commun. 1990, 118; (c)
Bachi, M. D.; Bar-Ner, N.; Crittell, C. M.; Stang, P. J.; Williamson, B. L. J. Org.
Chem. 1991, 56, 3912; (d) Liu, Z.; Chen, Z.-C.; Zheng, Q.-G. J. Heteterocycl. Chem.
2003, 40, 909; (e) Liu, Z.; Chen, Z.-C.; Zheng, Q.-G. Synth. Commun. 2004, 34,
361.
The authors are thankful to the Department of Science and
Technology, New Delhi, India (No. SR/S1/OC-72/2009) for the
financial support. The authors are also grateful to SAIF, Punjab Uni-
versity, Chandigarh, India, for recording the NMR spectra.
Supplementary data
Supplementary data associated (copies of IR, 1H NMR, 13C NMR
spectra, and LCMS are provided for all the compounds synthesized)
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2012.11.098.
16. (a) Wipf, P.; Venkatraman, V. J. Org. Chem. 1996, 61, 8004; (b) Miyamoto, K.;
Nishi, Y.; Ochiai, M. Angew. Chem., Int. Ed. 2005, 44, 6896; (c) Liu, Zhi; Chen,
Zhen-Chu; Zheng, Qin-Guo J. Chem. Res. (S) 2003, 11, 715; (d) Zhang, P. F.; Chen,
Z. C. Synthesis 2001, 358.
17. Margida, A. J.; Koser, G. F. J. Org. Chem. 1984, 49, 4703.
18. General experimental procedure for the synthesis of thiazolo[3,2-a]pyrimidine: To
a stirred solution of appropriate 4-aryl-3,4-dihydropyrimidin-2(1H)-thiones
(2 mmol) in THF (10 mL), K2CO3 (6 mmol) and alkynyl(aryl)iodonium tosylates
(4.8 mmol) were added and the reaction mixture was allowed to stir at room
temperature for 24 h. The progress of reaction was monitored by TLC. After
completion of the reaction, THF was evaporated under reduced pressure.
Water (10 mL) was added to the solid mass and the product was extracted with
ethyl acetate (3 ꢀ 20 mL). The combined ethyl acetate layer was again washed
with 3 N HCl (4 ꢀ 10 mL). The resultant acidic aqueous layer was then
neutralized with saturated NaHCO3 and the product was extracted with
ethyl acetate (4 ꢀ 10 mL). The combined ethyl acetate layer was washed with
brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure
to afford crude product, which was purified by column chromatography using
silica gel (230–400 mesh) with petroleum ether and ethyl acetate (3:1) as
References and notes
1. Reviews: (a) Kappe, C. O. Tetrahedron 1993, 49, 6937; (b) Kappe, C. O. Acc. Chem.
Res. 2000, 33, 879; (c) Sandhu, S.; Sandhu, J. S. ARKIVOC 2012, i, 66.
2. Review: Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043.
3. Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer, A. J.; DeBrosse, C.;
Mai, S.; Truneh, A.; Faulkner, D. J. J. Org. Chem. 1995, 60, 1182.
4. Aron, Z. D.; Overman, L. E. Chem. Commun. 2004, 253.
5. (a) Dallinger, D.; Kappe, C. O. Pure Appl. Chem. 2005, 77, 155; (b) Wannberg, J.;
Dallinger, D.; Kappe, C. O.; Larhed, M. J. Comb. Chem. 2005, 7, 574; (c) Matloobi,
M.; Kappe, C. O. J. Comb. Chem. 2007, 9, 275; (d) Couto, I.; Tellitu, I.; Domínguez,
E. J. Org. Chem. 2010, 75, 7954; (e) Singh, K.; Singh, K.; Wan, B.; Franzblau, S.;
Chibale, K.; Balzarini, J. Eur. J. Med. Chem. 2011, 46, 2290.
6. (a) Lengar, A.; Kappe, C. O. Org. Lett. 2004, 5, 771; (b) Hayashi, M.; Okunaga, K.;
Nishida, S.; Kawamura, K.; Eda, K. Tetrahedron Lett. 2010, 51, 6734; (c) Singh, S.;
Schober, A.; Gebinoga, M.; Groß, G. A. Tetrahedron Lett. 2011, 52, 3814; (d) Sun,
Q.; Suzenet, F.; Guillaumet, G. Tetrahedron Lett. 2012, 53, 2694.
eluent to afford thiazolo[3,2-a]pyrimidine derivatives
product.
3 as yellow solid
19. Characterization data for all the products:
Ethyl 7-methyl-3,5-diphenyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate (3a):
Yellow solid; mp 110–112 °C, 1H NMR 400 MHz (CDCl3):
d
1.16 (t,
7. 2-Bromoketones: (a) Zhi, H.; Chen, L.-M.; Zhang, L.-L.; Liu, S.-J.; Wan, D. C. C.;
Lin, H.-Q.; Hu, C. ARKIVOC 2008, 13, 266; (b) Quan, Z.-J.; Zhang, Z.; Wang, J.-K.;
Wang, X.-C.; Liu, Y.-J.; Ji, P.-Y. Heteroat. Chem. 2008, 2, 149; (c) Wichmann, J.;
Adam, G.; Kolczewski, S.; Mutel, V.; Woltering, T. Bioorg. Med. Chem. Lett. 1999,
J = 7.12 Hz, 3H), 2.46 (s, 3H), 4.07 (q, J = 7.2 Hz, 2H), 6.18 (s, 1H), 6.21 (s, 1H),
6.76 (d, J = 7.32 Hz, 2H), 7.05 (t, J = 7.3 Hz, 2H), 7.11 (d, J = 8.32, 3H), 7.39 (t,
J = 7.36 Hz, 2H), 7.46 (t, J = 7.34 Hz, 1H); 13C NMR 100 MHz (CDCl3): d 14.25,
23.19, 29.71, 57.99, 59.86, 101.28, 103.37, 126.56, 128.22, 128.67, 128.87,

A. V. Shelke et al. / Tetrahedron Letters 54 (2013) 600–603
603
128.96, 129.39, 129.73, 139.85, 141.95, 166.20, 166.63; IR (cmꢁ1): 2970, 2917,
1737, 1673, 1567, 1455, 1362, 1225, 1078, 994, 698, 599; MS (ESI) m/z (M+H)+
Calcd for C22H20N2O2S: 76.12. Found: 377.05.
150.93, 152.76, 155.57, 166.82, 166.87; IR (cmꢁ1): 2970, 1737, 1665, 1571,
1454, 1365, 1318, 1263, 1217, 1079, 1014, 996, 922, 794, 716, 698, 606, 573;
MS (ESI) m/z (M+H)+ Calcd for C24H24N2O4S: 436.15. Found: 437.10.
Ethyl 5-(4-methoxyphenyl)-7-methyl-3-phenyl-5H-thiazolo[3,2-a]pyrimidine-6-
carboxylate (3b): Yellow solid; mp 122–124 °C, 1H NMR 400 MHz (CDCl3): d
1.09 (t, J = 7.10 Hz, 3H), 4.12.383 (s, 3H), 3.61 (s, 3H), 3.97 (q, J = 7.12 Hz, 2H),
6.05 (s, 1H), 6.09 (s, 1H), 6.49 (d, J = 8.72 Hz, 2H), 6.59 (d, J = 8.72 Hz, 2H) 7.07
(d, J = 6.96 Hz, 2H), 6.31–6.41(m, 3H); 13C NMR 100 MHz (CDCl3): d 14.28,
23.43, 55.13, 57.37, 59.77, 101.39, 102.89, 113.42, 127.93, 128.67, 128.92,
129.63, 134.64, 139.81, 155.29, 159.24, 166.29, 166.81; IR (cmꢁ1): 3005, 2988,
1685, 1482, 1371, 1317, 1275, 1258, 1176, 1032, 763, 749, 694, 600; MS (ESI)
m/z (M+H)+ Calcd for C23H22N2O3S: 406.14. Found: 407.10.
Ethyl
7-methyl-3-pentyl-5-phenyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate
0.87 (t,
(3h): Yellow solid; mp 102–104 °C, 1H NMR 400 MHz (CDCl3):
d
J = 7.64 Hz, 3H), 1.52–1.36 (m, 8H), 1.42–1.46 (m, 1H), 1.53–1.60 (m, 1H), 2.17–
2.26 (m, 1H), 3.37 (s, 3H), 4.15 (q, J = 7.46 Hz, 2H), 5.93 (s, 1H), 6.18 (s, 1H),
7.22–7.30 (m, 5H); 13C NMR 100 MHz (CDCl3): d 13.93, 14.45, 22.29, 23.85,
26.60, 27.34, 31.10, 57.50, 59.85, 99.56, 100.01, 126.28, 128.18, 128.73, 139.90,
143.02, 156.03, 166.92, 166.98; IR (cmꢁ1): 2955, 2926, 1737, 1693, 1665, 1591,
1474, 1369, 1321, 1242, 1207, 1007, 831, 756, 696, 669; MS (ESI) m/z (M+H)+
Calcd for C21H26N2O2S: 370.17. Found: 371.00.
Ethyl 5-(3-methoxyphenyl)-7-methyl-3-phenyl-5H-thiazolo[3,2-a]pyrimidine-6-
carboxylate (3c): Yellow solid; mp 116–118 °C, 1H NMR 400 MHz (CDCl3):
d 1.09 (t, J = 7.08 Hz, 3H), 2.37 (s, 3H), 3.48 (s, 3H), 3.99 (q, J = 7.04 Hz, 2H), 6.09
(s, 1H), 6.16 (s, 1H), 6.35 (d, J = 7.56 Hz, 1H), 6.57 (d, J = 8.04 Hz, 1H), 6.09 (t,
J = 7.92 Hz, 1H), 7.06 (d, J = 7.24 Hz, 2H), 7.30–7.39 (m, 4H); 13C NMR 100 MHz
(CDCl3): d 14.31, 23.51, 54.95, 57.78, 59.80, 100.98, 102.95, 111.61, 113.96,
118.87, 128.69, 128.91, 129.31, 129.61, 139.73, 143.54, 155.73, 159.18, 166.45,
166.75; IR (cmꢁ1): 2981, 2837, 1689, 1598, 1585, 1483, 1371, 1313, 1252,
1226, 1077, 1001, 765, 749, 694, 605; MS (ESI) m/z (M+H)+ Calcd for
Ethyl
5-(4-chlorophenyl)-7-methyl-3-pentyl-5H-thiazolo[3,2-a]pyrimidine-6-
carboxylate (3i): Yellow solid; mp 110–112 °C, 1H NMR 400 MHz (CDCl3):
d 0.88 (t, J = 7.0 Hz, 3H), 1.25–1.30 (m, 7H), 1.44–1.47 (m, 1H), 1.55–1.58 (m,
1H), 2.20–2.24 (m, 1H), 2.34–2.39 (m, 4H), 4.16 (q, J = 6.04 Hz, 2H), 5.96 (s, 1H),
6.16 (s, 1H), 7.24–7.28 (m, 4H); 13C NMR 100 MHz (CDCl3): d 13.90, 14.45,
22.29, 23.84, 26.55, 27.34, 29.71, 31.10, 56.94, 59.99, 99.79, 99.92, 127.70,
128.94, 134.02, 139.68, 141.41, 156.01, 166.80; IR (cmꢁ1): 2928, 2864, 1737,
1677, 1562, 1455, 1369, 1205, 1064, 1014, 973, 813, 729, 636, 588; MS (ESI)
m/z (M+H)+ Calcd for C21H25ClN2O2S: 404.13. Found: 405.05.
C
23H22N2O3S: 406.14. Found: 407.05.
Ethyl 7-methyl-3-phenyl-5-(p-tolyl)-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(3d): Yellow solid; mp 130–132 °C, 1H NMR 400 MHz (CDCl3):
1.17 (t,
1-(7-Methyl-3-phenyl-5-(p-tolyl)-5H-thiazolo[3,2-a]pyrimidin-6-yl)ethanone (3j):
Yellow solid; mp 126–128 °C, 1H NMR 400 MHz (CDCl3): d 2.20 (s, 3H), 2.31
(s, 3H), 2.47 (s, 3H), 6.24 (s, 1H), 6.30 (s, 1H), 6.67 (d, J = 8.04 Hz, 2H), 6.86 (d,
J = 7.92 Hz, 2H), 7.15 (d, J = 6.96 Hz, 2H), 7.41 (t, J = 7.32 Hz, 2H), 7.46 (d,
J = 7.24 Hz, 1H); 13C NMR 100 MHz (CDCl3): d 14.16, 21.10, 22.72, 24.76, 29.39,
29.72, 31.47, 31.95, 57.20, 103.59, 112.46, 126.40, 128.98, 129.95, 137.83,
138.90, 140.35, 194.76; IR (cmꢁ1): 2916, 2848, 1737, 1611, 1462, 1369, 1311,
1228, 1177, 1062, 989, 941, 822, 696, 596; MS (ESI) m/z (M+H)+ Calcd for
d
J = 7.12 Hz, 3H), 2.20 (s, 3H), 2.45 (s, 3H), 4.06 (q, J = 7.08 Hz, 2H), 6.14 (s, 1H),
6.15 (s, 1H), 6.65 (d, J = 8.08 Hz, 2H), 6.85 (d, 7.92 Hz, 2H), 7.14 (d, J = 6.88 Hz,
2H), 7.40 (t, 7.24 Hz, 2H), 7.46 (t, J = 6.66 Hz, 1H); 13C NMR 100 MHz (CDCl3): d
14.28, 21.12, 23.55, 57.56, 59.74, 101.29, 102.74, 126.44, 128.65, 128.86,
128.90, 129.60, 129.62, 137.79, 139.30, 139.80, 155.62, 166.47, 166.80; IR
(cmꢁ1): 3090, 2924, 1737, 1680, 1573, 1469, 1362, 1312, 1227, 1176, 1072,
998, 788, 697, 656, 598; MS (ESI) m/z (M+H)+ Calcd for C23H22N2O2S: 390.14.
Found: 391.05.
Ethyl 5-(3,4-dimethoxyphenyl)-7-methyl-3-phenyl-5H-thiazolo[3,2-a]pyrimidine-
6-carboxylate (3e): Yellow solid; mp 136–138 °C, 1H NMR 400 MHz (CDCl3):
d 1.18 (t, J = 7.12 Hz, 3H), 2.47 (s, 3H), 3.54 (s, 3H), 3.77 (s, 3H), 4.08 (q,
J = 8.56 Hz, 2H), 6.12 (d, J = 7.76 Hz, 2H), 6.17 (s, 1H), 6.49 (d, J = 8.32 Hz, 1H),
6.59 (d, J = 8.76 Hz, 1H), 7.18 (d, J = 6.56 Hz, 2H), 7.44 (m, 3H). 13C NMR
100 MHz (CDCl3): d 14.31, 23.58, 55.39, 55.70, 57.64, 59.77, 101.27, 102.84,
109.66, 110.77, 119.09, 128.70, 128.93, 129.50, 129.87, 134.99, 139.74, 148.01,
148.55, 155.49, 166.32, 166.87; IR (cmꢁ1): 2970, 1737, 1661, 1578, 1486, 1442,
1365, 1231, 1159, 1092, 1023, 809, 739, 697, 658, 610; MS (ESI) m/z (M+H)+
Calcd for C24H24N2O4S: 436.15. Found: 437.10.
C22H20N2OS: 360.13. Found: 361.05.
1-(3-Butyl-7-methyl-5-(p-tolyl)-5H-thiazolo[3,2-a]pyrimidin-6-yl)ethanone (3k):
Yellow solid; mp 106–108 °C, 1H NMR 400 MHz (CDCl3): d 0.88 (t, J = 7.26 Hz,
3H), 1.34 (q, J = 7.29 Hz, 2H), 1.40–1.44 (m, 1H), 1.52–1.55 (m, 1H), 2.27 (s, 3H),
2.29–2.31 (m, 1H), 2.37 (s, 3H), 2.38 (s, 3H), 2.42–2.46 (m, 1H), 6.03 (s, 1H),
6.39 (s, 1H), 7.05 (d, J = 7.96 Hz, 2H), 7.16 (d, J = 8.12 Hz, 2H); 13C NMR
100 MHz (CDCl3): d 13.71, 21.12, 22.09, 25.08, 27.06, 28.29, 29.71, 31.71, 56.40,
100.52, 112.04, 126.16, 129.37, 137.85, 139.70, 140.76, 166.73, 194.24; IR
(cmꢁ1): 2956, 2930, 1597, 1586, 1454, 1314, 1211, 1079, 1040, 957, 847, 759,
733, 694, 665; MS (ESI) m/z (M+H)+ Calcd for C20H24N2OS: 340.16. Found:
341.00.
1-(3-Butyl-5-(3-methoxyphenyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-6-yl)eth-
anone (3l): Yellow solid; mp 114–116 °C, 1H NMR 400 MHz (CDCl3):
d 0.88 (t, J = 7.26 Hz, 3H), 1.34 (p, J = 7.28 Hz, 2H), 1.43 (m, 1H), 1.54 (m, 1H),
2.30 (m, 1H), 2.38 (s, 3H), 2.39 (s, 3H), 2.44 (m, 1H), 3.74 (s, 1H), 6.04 (s, 1H),
6.44 (s, 1H), 6.75 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 7.76 Hz, 2H), 7.16 (t, J = 7.86 Hz,
1H); 13C NMR 100 MHz (CDCl3): d 13.70, 22.07, 25.21, 27.01, 28.89, 31.67,
55.18, 56.27, 100.42, 111.63, 111.79, 113.31, 118.32, 129.72, 140.70, 144.01,
156.07, 159.72, 166.98, 194.27; IR (cmꢁ1): 2956, 2930, 1737, 1586, 1455, 1369,
1315, 1212, 1080, 1041, 958, 849, 747, 734, 695, 663; MS (ESI) m/z (M+H)+
Calcd for C20H24N2O2S: 356.16. Found: 357.00.
Ethyl
5-(4-chlorophenyl)-7-methyl-3-phenyl-5H-thiazolo[3,2-a]pyrimidine-6-
carboxylate (3f): Yellow solid; mp 128–130 °C, 1H NMR 400 MHz (CDCl3): d
1.17 (s, 3H), 2.45 (s, 3H), 4.07 (q, J = 8.78 Hz, 2H), 6.15 (s, 1H), 6.20 (s, 1H), 6.68
(d, J = 8.48 Hz, 2H), 7.02 (d, J = 8.48 Hz, 2H), 7.13 (d, J = 7.0 Hz, 2H), 7.40 (t,
J = 7.3 Hz, 2H), 7.48 (t, J = 7.36 Hz, 1H); 13C NMR 100 MHz (CDCl3): d 14.28,
22.48, 29.72, 57.36, 59.94, 100.95, 103.20, 128.02, 128.40, 128.79, 128.92,
129.32, 129.83, 133.92, 139.64, 140.60, 166.29, 166.61; IR (cmꢁ1): 2970, 2925,
1737, 1698, 1575, 1475, 1369, 1312, 1225, 1178, 1078, 1014, 996, 824, 770,
697, 654, 598; MS (ESI) m/z (M+H)+ Calcd for C22H19ClN2O2S: 410.09. Found:
411.05.
1-(3-Butyl-7-methyl-5-phenyl-5H-thiazolo[3,2-a]pyrimidin-6-yl)ethanone (3m):
Yellow solid; mp 126–128 °C, 1H NMR 400 MHz (CDCl3):
d 0.87 (t,
Ethyl 5-(2,5-dimethoxyphenyl)-7-methyl-3-phenyl-5H-thiazolo[3,2-a]pyrimidine-
6-carboxylate (3g): Yellow solid; mp 144–146 °C, 1H NMR 400 MHz (CDCl3):
d 1.12 (t, J = 12.72 Hz, 3H), 2.43 (s, 3H), 3.33 (s, 3H), 3.51 (s, 3H), 4.02 (q,
J = 9.57 Hz, 2H), 6.03 (s, 1H), 6.35 (d, J = 2.96 Hz, 1H), 6.43 (s, 1H), 6.52 (d,
J = 8.92 Hz, 1H), 6.61 (d, J = 8.88 Hz), 1H), 7.08 (d, J = 7.08 Hz, 2H), 7.36 (m, 3H);
13C NMR 100 MHz (CDCl3): d 14.12, 23.52, 54.60, 55.40, 55.50, 59.44, 99.96,
102.04, 111.31, 114.65, 114.72, 128.29, 128.75, 129.12, 130.10, 130.79, 139.99,
J = 7.24 Hz, 3H), 1.33 (m, 2H), 1.41 (m, 1H), 1.54 (m, 1H), 2.28 (m, 1H), 2.38
(s, 6H), 2.43 (m, 1H), 6.03 (s, 1H), 6.44 (s, 1H), 7.26 (m, 5H); 13C NMR 100 MHz
(CDCl3): d 13.67, 22.04, 25.27, 27.01, 28.87, 31.67, 56.46, 100.35, 111.80,
126.16, 127.95, 128.67, 140.65, 142.61, 156.04, 167.02, 194.21; IR (cmꢁ1):
2956, 2929, 1607, 1552, 1458, 1369, 1315, 1211, 1083, 957, 827, 719, 695, 659,
612; MS (ESI) m/z (M+H)+ Calcd for C19H22N2OS: 326.15. Found: 326.90.