Synthesis of 6-amino-5-cyano-1,4-disubstituted-2(1h)-pyrimidinones via copper-(i)-catalyzed alkyne-azide 'click chemistry' and their reactivity

Article abstract of DOI:10.3390/molecules1512884

In this paper we present the room temperature synthesis of a novel serie of 1,4-disubstituted-1,2,3-triazoles 4a-l by employing the (3 + 2) cycloaddition reaction of pyrimidinones containing alkyne functions with different model azides in the presence of

Full text of DOI:10.3390/molecules1512884

Molecules 2010, 15, 8841-8855; doi:10.3390/molecules15128841
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of 6-Amino-5-cyano-1,4-disubstituted-2(1H)-
Pyrimidinones via Copper-(I)-catalyzed Alkyne-azide ‘Click
Chemistry’ and Their Reactivity
Ennaji Najahi 1,2, Jan Sudor 2,3, Fakher Chabchoub 1, Françoise Nepveu 2,3,*, Fethi Zribi 1 and
,
Romain Duval 2 3
1
Laboratory of Applied Chemistry, Heterocycles, Fats and Polymers, Faculty of Science,
University of Sfax, 3000 Sfax, Tunisia; E-Mails: najahimco@yahoo.fr (E.N.);
fakher.chabchoub@yahoo.fr (F.C.); zfnfethi@yahoo.fr (F.Z.)
2
Laboratory of Medicinal Chemistry of Natural Substances and Redox Pharmacophores, University
of Toulouse, UPS, UMR 152, F-31062 Toulouse cedex 9, France; E-Mails: sudor@cict.fr (J.S.);
romain@cict.fr (R.D.)
3
IRD, UMR 152, F-31062 Toulouse cedex 9, France
* Author to whom correspondence should be addressed; E-Mail nepveu@cict.fr;
Tel.: +33562256869; Fax +3362259804.
Received: 15 October 2010; in revised form: 25 November 2010 / Accepted: 30 November 2010 /
Published: 3 December 2010
Abstract: In this paper we present the room temperature synthesis of a novel serie of 1,4-
disubstituted-1,2,3-triazoles 4a-l by employing the (3 + 2) cycloaddition reaction of
pyrimidinones containing alkyne functions with different model azides in the presence of
copper sulphate and sodium ascorbate. To obtain the final triazoles, we also synthesized
the major precursors 6-amino-5-cyano-1,4-disubstituted-2(1H)-pyrimidinones 3a-r from
ethyl 2,2-dicyanovinylcarbamate derivatives 2a-c and various primary aromatic amines
containing an alkyne group. The triazoles were prepared in good to very good yields.
Keywords: 2(1H)-pyrimidinones; 1,2,3-triazoles; (3 + 2) cycloaddition; alkynes; azides

Molecules 2010, 15
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Introduction
The copper-(I)-catalyzed Huisgen–Sharpless–Meldal 1,3-dipolar cycloaddition between alkynes
and azides (‘click’ chemistry) resulting in the formation of 1,4-disubstituted-1,2,3-triazoles has gained
significant importance because of its wide range of applications in various fields of drug discovery [1],
bioconjugation [2] and material or surface science [3,4]. Amongst the various classes of nitrogen
heterocycles, 1,2,3-triazoles and their derivatives deserve special recognition due to their wide usage
in industrial applications as dyes, photographic materials, corrosion inhibitors and as herbicidal,
fungicidal and antibacterial agrochemicals [5,6]. Several members of the 1,2,3-triazole family exhibit a
broad spectrum of antiinfectious properties such as antimicrobial [7], anti-HIV [8], anti-allergic [9]
and antimalarial activities [10]. On the other hand, 2(1H)-pyrimidinones also show significant
biological activities [11]. For instance, 2(1H)-pyrimidinones derivatives have been screened for
antihypertension [12], insulin-mimetic [13], anti-inflammatory [14] and anti-proliferative [15]
activities or as selective α1a-andrenergic receptor antagonists [16]. Interested by the wide variety of
pharmacological properties and potential applications of both 2(1H)-pyrimidinones and 1,2,3-triazoles
we have designed the synthesis of hybrid molecules consisting of both moieties. Our method is based
on the (3 + 2) cycloaddition reaction of 6-amino-5-cyano-1-(meta- or para-ethynylphenyl)-4-
substituted-2(1H)-pyrimidinones with different azides in the presence of copper sulphate and sodium
ascorbate at room temperatures that affords 1,4-disubstituted-1,2,3-triazoles.
Results and Discussion
Ethyl 2,2-dicyanovinylcarbamate derivatives 2a-c were prepared in good yields by action of
malononitrile with ethyl N-(ethoxycarbonyl)imidates 1a-c following a previously reported method [17]
(Scheme 1). The reaction of these compounds 2a-c with primary aromatic amines in chlorobenzene
under reflux yielded the 6-amino-5-cyano-1,4-disubstituted-2(1H)-pyrimidinones 3a-r in yields
ranging from 55 to 76% (Table 1). This synthetic method is more general and easier to implement than
the methods already described in the literature [18,19].
Scheme 1. Synthesis of 6-amino-5-cyano-1,4-disubstituted-2(1H)-pyrimidinones (3a-r).
Reagents and conditions: (i) primary aromatic amines, chlorobenzene, 110 °C, (2~4) h.
CN
5
O
R1
NH2
O
6
HN
N
4
N
ref-25
i
1
R2
OEt
R1
R1
OEt
N
3
CN
2
OEt
O
NC
2a-c
1a-c
3a-r
R1: C6H5; 4-CH3C6H4; C6H5-CH2
O
OCH3
OCH3
OCH3
R2:
;
;
;
;
;
O

Molecules 2010, 15
Table 1. Synthesis of 6-amino-5-cyano-1,4-disubstituted-2(1H)-pyrimidinones 3a-r.
8843
Entry Compound R1
R2
Phenyl
Naphthalen-1-yl
3,4,5-Trimethoxyphenyl
Yieldsa
75%
68%
71%
1
3a26
3b
3c
Ph
2
Ph
3
Ph
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
3d
3e
3f
Ph
Ph
Ph
2,3-Dihydrobenzo[b][1,4]dioxin-6-yl 74%
3-Ethynylphenyl
4-Ethynylphenyl
Phenyl
Naphthalen-1-yl
3,4,5-Trimethoxyphenyl
62%
60%
73%
67%
75%
3g26
3h
3i
4-CH3Ph
4-CH3Ph
4-CH3Ph
4-CH3Ph
4-CH3Ph
4-CH3Ph
Ph-CH2
Ph-CH2
Ph-CH2
Ph-CH2
Ph-CH2
Ph-CH2
3j
3k
3l
3m
3n
3o
3p
3q
3r
2,3-Dihydrobenzo[b][1,4]dioxin-6-yl 72%
3-Ethynylphenyl
4-Ethynylphenyl
Phenyl
Naphthalen-1-yl
3,4,5-Trimethoxyphenyl
70%
61%
76%
59%
65%
2,3-Dihydrobenzo[b][1,4]dioxin-6-yl 55%
3-Ethynylphenyl
4-Ethynylphenyl
a Isolated yield.
62%
58%
The (3 + 2) cycloaddition of 6-amino-5-cyano-1-(meta- or para-ethynylphenyl)-4-substituted-
2(1H)-pyrimidinones 3k, 3l, 3q and 3r with different azides A1, A2 and A3 (Figure 1) in the presence
of Na-ascorbate, THF/t-BuOH/H2O and CuSO4.5H2O, at room temperature resulted in the
corresponding 1,4-disubstituted-1,2,3-triazole compounds 4a-l (Scheme 2) in good yields (Table 2).
The structures of compounds 3a-r were in accordance with their spectroscopic data. The IR spectra of
the compounds in general exhibited an absorption band at 2,210 cm−1 indicating the presence of one
cyano group. The absorption band at around 3,265–3,275 cm−1 for the compounds 3e, 3f, 3k, 3l, 3q
and 3r indicated that the terminal alkyne C≡C-H was present in these compounds.
Scheme 2. Synthesis of 1,4-disubstituted-1,2,3-triazoles 4a-l. Reagents and conditions: (a)
Na-ascorbate (0.45 equiv), CuSO45H2O (0.1 equiv), THF/H2O/t-BuOH (3:1:1, v/v/v),
rt, 2d.
CN
CN
R1
R1
NH2
NH2
R3
N
N
N
N
N
N
i
N3 R3
+
O
O
N
(m, p)
(m, p)
3
4a-l
R1: 4-CH3C6H4; C6H5-CH2
R3: See A1, A2 and A3 in Figure 1.

Molecules 2010, 15
Figure 1. Structures of the three different azides used in this work.
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CO2Et
N
S
N
O
S
N
N
N
NH
S
N3
N3
N3
Azido methyl phenyl sulfide Aziprotryne
Azido-benzylidene-thiazolopyrimidine
(Azido-BTP)
(A1)
(A2)
(A3)
Table 2. Synthesis of 1,4-disubstituted-1,2,3-triazoles 4a-l.
Entry Compound Alkynes Azides Yieldsa
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
3k
3l
3q
3r
3k
3l
3q
3r
3k
3l
3q
3r
A1
A1
A1
A1
A2
A2
A2
A2
A3
A3
A3
A3
82%
72%
80%
75%
73%
94%
76%
71%
84%
72%
81%
88%
9
10
11
12
4j
4k
4l
a Isolated yield.
1
The mass spectra showed the respective [M + H]+ peaks. In the H-NMR spectra the most
significant information was the disappearance of triplet and quadruplet of ethoxy groups present in the
starting reagent 2a-c and the appearance of signals for the protons of the group R2 introduced by the
primary aromatic amines.
Structures of compounds 4a-l were established on the basis of their spectroscopic data. The IR
absorption band corresponding to a terminal C≡C-H group was not observed around 3,271 cm−1. The
1
mass spectra showed the respective [M + H]+ peaks. According to H-NMR spectra of the ‘click’
products the terminal triple bonded proton signal (δH = 4.3 ppm) of the alkynes 3 disappeared and the
newly formed triazole signal was observed at 8.5–9.5 ppm. The triazole ring formation was also
13
identified from the C-NMR spectra with the new signals of the ethylenic C atoms of the 1,2,3-
triazole moiety at δ = 120–122 ppm (CHar-triazole) and δ = 146–148 ppm (Cq-triazole).
X-ray crystal analysis of compounds 3b and 3g
To further confirm the structure of compounds 3, an X-ray crystallographic study of compounds 3b
and 3g was carried out (Figures 2 and 3). Crystals were obtained by slow evaporation from methanol

Molecules 2010, 15
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solution. Crystallographic data were collected at 180K with an Oxford-Diffraction XCALIBUR CCD
Diffractometer equipped with a Cryojet cooler device from Oxford Instruments. Structures were
solved by direct methods using SIR92 [20] and refined by full-matrix least-squares procedures on F
using the programs of the PC version of CRYSTALS [21]. Atomic scattering factors were taken from
the International Tables for X-ray Crystallography [22].
Figure 2. X-ray crystal analysis of compound 3b.
Figure 3. X-ray crystal analysis of compound 3g.
Data for 3b: C21H14N4O, CH4O, M = 370.41, colorless block crystal, 0.15 × 0.20 × 0.25 mm3,
monoclinic, space group P 21/c, a = 11.1402(4), b = 19.9585(6), c = 8.4770(3) Å,  = 105.839(4)°,
V = 1813.23(11) Å3, Z = 4, d = 1.36, µ(MoK) = 0.090, 253 parameters, 17,459 reflexions measured,
4,850 unique (R int = 0.030), 3,133 reflections used in the calculations (I > 3[I]), R = 0.0345,
wR = 0.0403, residual electronic density = - 0.17/0.32 (e.Å-3).
Data for 3g: C18H14N4O, CH4O, M = 334.38, colorless block crystal, 0.20 x 0.20 x 0.20 mm3,
monoclinic, space group P 21/c, a = 10.5511(3), b = 14.2950(5), c = 10.9120(4) Å,  = 93.184(3)°,
V = 1643.29(10) Å3, Z = 4, d = 1.35, µ(MoK) = 0.091, 226 parameters, 14,902 reflexions measured,
4,408 unique (R int = 0.030), 2,930 reflections used in the calculations (I > 3[I]), R = 0.0428,
wR = 0.0462, residual electronic density = - 0.22/0.39 (e.Å-3).

Molecules 2010, 15
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CCDC contain the supplementary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Conclusions
In summary, various 6-amino-5-cyano-1-(meta- or para-ethynylphenyl)-4-substituted-2(1H)-
pyrimidinones were synthesized and utilized as starting materials in the ‘click’ reaction to attach azido
residues. Consequently, we have employed these, in house synthesized precursors, to prepare a new
class of hybrid molecules 1,4-disubstituted-1,2,3-triazoles employing already known chemistry of (3 +
2) cycloaddition of azides and acetylenes in good to very good yields. All products that we have
obtained were hitherto unknown. A number of them are presently under pharmacological screening.
Experimental
Commercially available reagent grade chemicals were used as received without additional
purification. All reactions were followed by TLC (E. Merck Kieselgel 60 F-254), with detection by
UV light at 254 nm. Column chromatography was performed on silica gel (60–200 mesh E. Merck). IR
1
13
spectra were recorded on a Perkin-Elmer PARAGON 1000 FT-IR spectrometer. H- and C-NMR
spectra were recorded on an AC Bruker spectrometer at 300 MHz (1H) and 75 MHz (13C) using
(CD3)2SO as solvent with (CD3)2SO (δH 2.5) or (CD3)2SO (δC 39.5). Chemical shifts (δ) are reported in
parts per million (ppm) relative to tetramethylsilane (0 ppm) as internal reference and the following
multiplicity abbreviations were used: s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet; J in
hertz. The mass spectra were recorded on an ion trap mass spectrometer (Finnigan LCQ Deca XP
Max) using electrospray as an ionization source. Melting points were determined on an Electrothermal
9300 capillary melting point apparatus and are uncorrected. UV-visible spectra were recorded on a
Specord 205 Analytikjena spectrophotometer. The purity of all compounds was determined by LC-
PDA-MS methods and was found to be in the range between 96–99%.
General experimental procedure for preparation of 6-amino-5-cyano-1,4-disubstituted-2(1H)-pyrimid-
inones 3a-r
To a magnetically stirred solution of the ethyl 2,2-dicyanovinylcarbamate derivatives 2a-c (1 equiv)
in chlorobenzene (25 mL), a primary aromatic amine (1.2 equiv) added and reaction mixture was
stirred for 2~4 h at 110 °C. Reaction progress was monitored by TLC using the indicated eluents. The
resulting mixture was allowed to cool at room temperature. The formed precipitate was isolated by
filtration and washed with ethanol or with diethyl ether for 3e, 3f, 3k, 3l, 3q and 3r to give
pure products.
6-Amino-5-cyano-1,4-diphenyl-2(1H)-pyrimidinone (3a). White cristals, yield (75%), C17H12N4O, M =
288 gmol−1, mp 252–254 °C, Rf = 0.21 (ethyl acetate/dichloromethane, 70:30, v/v); UV (MeOH) λmax
nm (ε Lmol−1cm−1): 248 (32,400), 318 (11,232); IR (KBr) cm−1: 3,450–3,310 (NH2), 2,212 (CN),
1
13
1,665 (C=O), 1,616 (C=N); H-NMR: (DMSO-d6): δ = 7.34–7.82 (m, 12H, Ar-H + NH2); C-NMR

Molecules 2010, 15
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(DMSO-d6): δ = 72.9 (C-5), 117.1 (CN), 128.8, 128.9, 130, 130.7, 131.5, 135.1, 137.5, 154.1 (C-2),
160.5 (C-4), 172 (C-6); MS-(+)ESI: m/z (%): 599 ([2M+Na]+, 35), 311 ([M+Na]+, 4), 289 ([M+H]+, 100).
6-Amino-5-cyano-1-(naphthalen-1-yl)-4-phenyl-2(1H)-pyrimidinone (3b). Greyish white solid, yield
(68%), C21H14N4O, M = 338 gmol−1, mp 198–200 °C, Rf = 0.54 (ethyl acetate/dichloromethane,
70:30, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 248 (37,518), 318 (14,196); IR (KBr) cm−1:
3,450–3,310 (NH2), 2,211 (CN), 1,672 (C=O), 1,620 (C=N); 1H-NMR: (DMSO-d6): δ = 7.42–8.15 (m,
14H, Ar-H + NH2); 13C-NMR (DMSO-d6): δ = 73.1 (C-5), 117.2 (CN), 122, 127.1, 127.2, 127.8, 128,
128.8, 129, 129.2, 129.7, 130.7, 131.5, 131.6, 135.1, 137.6, 154.2 (C-2), 160.9 (C-4), 172.6 (C-6); MS-
(+)ESI: m/z (%): 699 ([2M+Na]+, 16), 339 ([M+H]+, 100).
6-Amino-5-cyano-1-(3,4,5-trimethoxyphenyl)-4-phenyl-2(1H)-pyrimidinone (3c). Yellowish white
solid, yield (71%), C20H18N4O4, M = 378 gmol−1, mp 255–257 °C, Rf = 0.21 (ethyl
acetate/dichloromethane, 70:30, v/v); UV (MeOH) λmax nm (ε L.mol−1cm−1): 249 (51,030), 320
1
(14,742); IR (KBr) cm−1: 3,450-3,310 (NH2), 2,209 (CN), 1,687 (C=O), 1,620 (C=N); H-NMR:
(DMSO-d6): δ = 3.74 (s, 6H, 2OCH3), 3.76 (s, 3H, OCH3), 7.39–7.60 (m, 9H, Ar-H + NH2); 13C-NMR
(DMSO-d6): δ = 56.5 (2C, 2OCH3), 60.4 (OCH3), 72.6 (C-5), 106.4, 117.1 (CN), 125.9, 128.6, 130.5,
136.9, 138, 138.4, 153.9, 154 (C-2), 160.7 (C-4), 172 (C-6); MS-(+)ESI: m/z (%): 779 ([2M+Na]+, 3),
379 ([M+H]+, 100).
6-Amino-5-cyano-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-phenyl-2(1H)-pyrimidinone (3d). Pale
brown solid, yield (74%), C19H14N4O3, M = 346 gmol−1, mp 283–285 °C, Rf = 0.49 (ethyl
acetate/dichloromethane, 70:30, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 248 (37887), 318
1
(12456); IR (KBr) cm−1: 3,450-3,310 (NH2), 2,210 (CN), 1,696 (C=O), 1,662 (C=N); H-NMR:
(DMSO-d6): δ = 4.30 (s, 4H, 2CH2), 6.80-7.59 (m, 10H, Ar-H + NH2); 13C-NMR (DMSO-d6): δ = 64.5
(CH2), 64.6 (CH2), 72.6 (C-5), 117.2 (CN), 118.5, 121.7, 125.7, 127.6, 129.2, 131.9, 137.7, 138.1,
144.5, 144.6, 154.1 (C-2), 160.7 (C-4), 171.8 (C-6); MS-(+)ESI: m/z (%): 715 ([2M+Na]+, 8), 347
([M+H]+, 100).
6-Amino-5-cyano-1-(3-ethynylphenyl)-4-phenyl-2(1H)-pyrimidinone (3e). Pale yellow solid, yield
(62%), C19H12N4O, M = 312 gmol−1, mp 237–239 °C, Rf = 0.52 (ethyl acetate/dichloromethane,
50:50, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 254 (36,972), 307 (14,508); IR (KBr) cm−1:
1
3,450–3,310 (NH2), 3,270 (≡C-H), 2,209 (CN), 1,665 (C=O), 1,636 (C=N); H-NMR: (DMSO-d6):
δ = 4.32 (s, 1H, C≡CH), 7.27–7.86 (m, 11H, Ar-H + NH2); 13C-NMR (DMSO-d6): δ = 73.7 (C-5), 82.4
(C≡CH), 83.2 (C≡CH), 117.2 (CN), 124.1, 128.6, 129.2, 129.9, 131.1, 132.4, 133.4, 134.5, 135.4,
141.5, 154 (C-2), 160.5 (C-4), 171.7 (C-6); MS-(+)ESI: m/z (%): 647 ([2M+Na]+, 21), 313 ([M+H]+, 100).
6-Amino-5-cyano-1-(4-ethynylphenyl)-4-phenyl-2(1H)-pyrimidinone (3f). White solid, yield (60%),
C19H12N4O, M = 312 gmol−1, mp 206–208 °C, Rf = 0.57 (ethyl acetate/dichloromethane, 50:50, v/v);
UV (MeOH) λmax nm (ε Lmol−1cm−1): 247 (38,844), 309 (13,572); IR (KBr) cm−1: 3,450-3,310
(NH2), 3,268 (≡C-H), 2,210 (CN), 1,676 (C=O), 1,635 (C=N); 1H-NMR: (DMSO-d6): δ = 4.31 (s, 1H,
13
C≡CH), 7.34–7.91 (m, 11H, Ar-H + NH2); C-NMR (DMSO-d6): δ = 73.7 (C-5), 82.3 (C≡CH), 83.2

Molecules 2010, 15
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(C≡CH), 117.2 (CN), 125, 128.5, 130.1, 131.2, 132.4, 133.4, 135.4, 141.3, 154 (C-2), 160 (C-4), 172.1
(C-6); MS-(+)ESI: m/z (%): 647 ([2M+Na]+, 10), 313 ([M+H]+, 100).
6-Amino-5-cyano-4-(4-methylphenyl)-1-phenyl-2(1H)-pyrimidinone (3g). White solid, yield (73%),
C18H14N4O, M = 302 gmol−1, mp 257–259 °C, Rf = 0.47 (ethyl acetate/dichloromethane, 70:30, v/v);
UV (MeOH) λmax nm (ε Lmol−1cm−1): 250 (26,727), 319 (11,325); IR (KBr) cm−1: 3,450–3,310
(NH2), 2,211 (CN), 1,674 (C=O), 1,619 (C=N); 1H-NMR: (DMSO-d6): δ = 2.52 (s, 3H, CH3), 7,45–7,9
13
(m, 11H, Ar-H + NH2); C-NMR (DMSO-d6): δ = 21.5 (CH3), 72.6 (C-5), 118.3 (CN), 128.8, 129,
130.1, 130.8, 131.5, 132.4, 135.1, 137.5, 154.3 (C-2), 160.8 (C-4), 172.5 (C-6); MS-(+)ESI: m/z (%):
627 ([2M+Na]+, 31), 325 ([M+Na]+, 3), 303 ([M+H]+, 100).
6-Amino-5-cyano-4-(4-methylphenyl)-1-(naphthalen-1-yl)-2(1H)-pyrimidinone (3h). Greyish green
solid, yield (67%), C22H16N4O, M = 352 gmol−1, mp 261–263 °C, Rf = 0.57 (ethyl acetate/
dichloromethane, 50:50, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 251 (26,928), 318 (12,672); IR
1
(KBr) cm−1: 3,450-3,310 (NH2), 2,209 (CN), 1,686 (C=O), 1,617 (C=N); H-NMR: (DMSO-d6):
13
δ = 2.43 (s, 3H, CH3), 7.38-8.15 (m, 13H, Ar-H + NH2); C-NMR (DMSO-d6): δ = 21.5 (CH3), 72.4
(C-5), 118.3 (CN), 122.5, 127, 127.2, 127.9, 128.1, 128.9, 129.1, 129.3, 129.8, 130.7, 131.4, 132.1,
135.6, 137.7, 154.6 (C-2), 161 (C-4), 172.8 (C-6); MS-(+)ESI: m/z (%): 727 ([2M+Na]+, 15), 353
([M+H]+, 100).
6-Amino-5-cyano-4-(4-methylphenyl)-1-(3,4,5-trimethoxyphenyl)-2(1H)-pyrimidinone
(3i).
Pale
yellow solid, yield (75%), C21H20N4O4, M = 392 gmol−1, mp 292–294 °C, Rf = 0.53 (ethyl acetate/
dichloromethane, 70:30, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 250 (52,920); IR (KBr) cm−1:
1
3,450-3,310 (NH2), 2,212 (CN), 1,671 (C=O), 1,625 (C=N); H-NMR: (DMSO-d6): δ = 2.41 (s, 3H,
13
CH3), 3.74 (s, 6H, 2OCH3), 3.77 (s, 3H, OCH3), 7.4–7.59 (m, 8H, Ar-H + NH2); C-NMR (DMSO-
d6): δ = 21.4 (CH3), 56.6 (2C, 2OCH3), 60.4 (OCH3), 72.6 (C-5), 106.4, 117.1 (CN), 125.8, 128.6,
130.5, 137.5, 138.1, 138.5, 154, 154.5 (C-2), 160.6 (C-4), 171.9 (C-6); MS-(+)ESI: m/z (%): 393
([M+H]+, 100).
6-Amino-5-cyano-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-(4-methylphenyl)-2(1H)-pyrimidinone
(3j). Yellow solid, yield (72%), C20H16N4O3, M = 360 gmol−1, mp 284–286 °C, Rf = 0.54 (ethyl
acetate/dichloromethane, 70:30, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 251 (32,940), 280
(19,980), 318 (13,500); IR (KBr) cm−1: 3,450–3,310 (NH2), 2,211 (CN), 1,658 (C=O), 1,634 (C=N);
1H-NMR: (DMSO-d6): δ = 2.40 (s, 3H, CH3), 4.30 (s, 4H, 2CH2), 6.79-7.60 (m, 9H, Ar-H + NH2);
13C- NMR (DMSO-d6): δ = 21.4 (CH3), 64.5 (CH2), 64.6 (CH2), 72.6 (C-5), 117.1 (CN), 117.9, 121.5,
125.8, 127.7, 128.5, 132, 137.4, 138, 144.8, 144.8, 154.1 (C-2), 160.7 (C-4), 171.8 (C-6); MS-(+)ESI:
m/z (%): 743 ([2M+Na]+, 9), 361 ([M+H]+, 100).
6-Amino-5-cyano-1-(3-ethynylphenyl)-4-(4-methylphenyl)-2(1H)-pyrimidinone (3k). Pale yellow solid,
yield (70%), C20H14N4O, M = 326 gmol−1, mp 247–249 °C, Rf = 0.61 (ethyl acetate/dichloromethane,
50:50, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 252 (24,339), 307 (16,137); IR (KBr) cm−1:
1
3,450–3,310 (NH2), 3,271 (≡C-H), 2,211 (CN), 1,671 (C=O), 1,640 (C=N); H-NMR: (DMSO-d6):
13
δ = 2.41 (s, 3H, CH3), 4.32 (s, 1H, C≡CH), 7.25–7.75 (m, 10H, Ar-H + NH2); C-NMR (DMSO-d6):

Molecules 2010, 15
8849
δ = 21.5 (CH3), 73.81 (C-5), 82.4 (C≡CH), 83.2 (C≡CH), 117.2 (CN), 124, 128.8, 129.3, 129.8, 131,
132.5, 133.3, 134.6, 135.6, 141.5, 153.9 (C-2), 160.5 (C-4), 171.8 (C-6); MS-(+)ESI: m/z (%): 675
([2M+Na]+, 19), 327 ([M+H]+, 100).
6-Amino-5-cyano-1-(4-ethynylphenyl)-4-(4-methylphenyl)-2(1H)-pyrimidinone (3l). Brownish yellow
solid, yield (61%), C20H14N4O, M = 326 gmol−1, mp 192–194 °C, Rf = 0.49 (ethyl acetate/
dichloromethane, 50:50, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 250 (28,851), 308 (15,159); IR
1
(KBr) cm−1: 3,450–3,310 (NH2), 3,270 (≡C-H), 2,209 (CN), 1,662 (C=O), 1,638 (C=N); H-NMR:
13
(DMSO-d6): δ = 2.41 (s, 3H, CH3), 4.30 (s, 1H, C≡CH), 7.27–7.94 (m, 10H, Ar-H + NH2); C-NMR
(DMSO-d6): δ = 21.5 (CH3), 72.9 (C-5), 82.3 (C≡CH), 83.3 (C≡CH), 117.2 (CN), 124.1, 128.9, 129.3,
131.1, 132.5, 134.4, 135.8, 141.3, 153.9 (C-2), 160.1 (C-4), 171.6 (C-6); MS-(+)ESI: m/z (%): 675
([2M+Na]+, 9), 327 ([M+H]+, 100).
6-Amino-4-benzyl-5-cyano-1-phenyl-2(1H)-pyrimidinone (3m). White solid, yield (76%), C18H14N4O,
M = 302 gmol−1, mp 276–278 °C, Rf = 0.31 (ethyl acetate/dichloromethane, 70:30, v/v); UV (MeOH)
λ
max nm (ε Lmol−1cm−1): 248 (22,197), 308 (14,043); IR (KBr) cm−1: 3,450-3,310 (NH2), 2,211 (CN),
1
1,680 (C=O), 1,614 (C=N); H-NMR: (DMSO-d6): δ = 3.9 (s, 2H, CH2), 7.3–7.53 (m, 12H, Ar-H +
NH2); 13C-NMR (DMSO-d6): δ = 43.4 (CH2), 73.7 (C-5), 116.7 (CN), 127.3, 128.9, 129, 129.4, 129.7,
130.7, 135, 137.1, 154.1 (C-2), 159.7 (C-4), 175.4 (C-6); MS-(+)ESI: m/z (%): 627 ([2M+Na]+, 20),
325 ([M+Na]+, 3), 303 ([M+H]+, 100).
6-Amino-4-benzyl-5-cyano-1-(naphthalen-1-yl)-2(1H)-pyrimidinone (3n). Pale violet solid, yield
(59%), C22H16N4O, M = 352 gmol−1, mp 252–254 °C, Rf = 0.47 (ethyl acetate/dichloromethane,
50:50, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 248 (24,288), 296 (17,952); IR (KBr) cm−1:
1
3,450–3,310 (NH2), 2,212 (CN), 1,678 (C=O), 1,618 (C=N); H-NMR: (DMSO-d6): δ = 3.97 (s, 2H,
13
CH2), 7.27–8.27 (m, 14H, Ar-H + NH2); C-NMR (DMSO-d6): δ = 43.6 (CH2), 73.7 (C-5), 116.6
(CN), 117.9, 121.7, 126.5, 126.9, 127.4, 127.8, 127.9, 129.1, 129.6, 129.7, 131.3, 134.3, 135, 137.1,
154.1 (C-2), 160 (C-4), 175.9 (C-6); MS-(+)ESI: m/z (%): 727 ([2M+Na]+, 10), 353 ([M+H]+, 100).
6-Amino-4-benzyl-5-cyano-1-(3,4,5-trimethoxyphenyl)-2(1H)-pyrimidinone (3o). Yellow solid, yield
(65%), C21H20N4O4, M = 392 gmol−1, mp 224–226 °C, Rf = 0.26 (ethyl acetate/dichloromethane,
70:30, v/v); UV (MeOH) λmax nm (ε L.mol−1cm−1): 247 (39,396), 307 (19,404); IR (KBr) cm−1:
1
3,450–3,310 (NH2), 2,208 (CN), 1,687 (C=O), 1,627 (C=N); H-NMR: (DMSO-d6): δ = 3.91 (s, 2H,
13
CH2), 3.75 (s, 6H, 2OCH3), 3.77 (s, 3H, OCH3), 7.47–8.62 (m, 9H, Ar-H + NH2); C-NMR (DMSO-
d6): δ = 43.4 (CH2), 56.6 (2C, 2OCH3), 60.4 (OCH3), 72.7 (C-5), 107.1, 116.9 (CN), 126, 128.6, 129.9,
137.1, 138.3, 138.5, 153.6, 154.4 (C-2), 160.7 (C-4), 175 (C-6); MS-(+)ESI: m/z (%): 393 ([M+H]+, 100).
6-Amino-4-benzyl-5-cyano-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2(1H)-pyrimidinone (3p). Dark
brown solid, yield (55%), C20H16N4O3, M = 360 gmol−1, mp 287–289 °C, Rf = 0.41 (ethyl acetate/
dichloromethane, 70:30, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 251 (31,320), 318 (15,120); IR
1
(KBr) cm−1: 3,450-3,310 (NH2), 2,210 (CN), 1,661 (C=O), 1,609 (C=N); H-NMR: (DMSO-d6):
13
δ = 3.9 (s, 2H, CH2), 4.32 (s, 4H, 2CH2), 6.79–8.05 (m, 10H, Ar-H + NH2); C-NMR (DMSO-d6):
δ = 43.4 (CH2), 64.5 (CH2), 64.8 (CH2), 72.6 (C-5), 116.9 (CN), 117.4, 121.7, 126, 127.5, 128.1,

Molecules 2010, 15
8850
131.5, 136.9, 138.1, 143.9, 144.2, 153.9 (C-2), 160.5 (C-4), 175.4 (C-6); MS-(+)ESI: m/z (%): 743
([2M+Na]+, 11), 361 ([M+H]+, 100).
6-Amino-4-benzyl-5-cyano-1-(3-ethynylphenyl)-2(1H)-pyrimidinone (3q). White solid, yield (62%),
C20H14N4O, M = 326 gmol−1, mp 224–226 °C, Rf = 0.47 (ethyl acetate/dichloromethane, 50:50, v/v);
UV (MeOH) λmax nm (ε Lmol−1cm−1): 248 (40,587), 308 (15,160); IR (KBr) cm−1: 3,450–3,310
1
(NH2), 3,271 (≡C-H), 2,209 (CN), 1,662 (C=O), 1,625 (C=N); H-NMR: (DMSO-d6): δ = 3.9 (s, 2H,
13
CH2), 4.3 (s, 1H, C≡CH), 7.32–7.83 (m, 11H, Ar-H + NH2); C-NMR (DMSO-d6): δ = 43.4 (CH2),
73.8 (C-5), 82.3 (C≡CH), 83.2 (C≡CH), 116.5 (CN), 123.9, 128.5, 129.2, 130.2, 131.4, 132.7, 132.9,
134.3, 136.4, 142.1, 154.1 (C-2), 160.8 (C-4), 174.9 (C-6); MS-(+)ESI: m/z (%): 675 ([2M+Na]+, 17),
327 ([M+H]+, 100).
6-Amino-4-benzyl-5-cyano-1-(4-ethynylphenyl)-2(1H)-pyrimidinone (3r). White solid, yield (58%),
C20H14N4O, M = 326 gmol−1, mp 252–254 °C, Rf = 0.56 (ethyl acetate/dichloromethane, 50:50, v/v);
UV (MeOH) λmax nm (ε Lmol−1cm−1): 250 (44,010), 318 (12,714); IR (KBr) cm−1: 3,450–3,310
(NH2), 3,269 (≡C-H), 2,211 (CN), 1,668 (C=O), 1,639 (C=N); 1H-NMR: (DMSO-d6): δ = 3.89 (s, 2H,
13
CH2), 4.31 (s, 1H, C≡CH), 7.27–7.63 (m, 11H, Ar-H + NH2); C-NMR (DMSO-d6): δ = 43.4 (CH2),
73.8 (C-5), 82.3 (C≡CH), 83.4 (C≡CH), 116.5 (CN), 123.4, 127.2, 128.9, 129.5, 129.6, 133.9, 135.5,
137, 153.9 (C-2), 159.6 (C-4), 175.5 (C-6); MS-(+)ESI: m/z (%): 675 ([2M+Na]+, 8), 327 ([M+H]+, 100).
General experimental procedure for preparation of 1,4-disubstituted-1,2,3-triazoles 4a-l
The mixture of alkyne 3 (1 mmol) and azides (1 mmol) was suspended in a mixture of THF/t-
BuOH/H2O (3:1:1, v/v/v, 6/2/2 mL). Sodium ascorbate (89 mg, 0.45 equiv) was added followed by
addition of CuSO45H2O (16 mg, 0.1 equiv). The heterogeneous mixture was stirred vigorously for 2
days, at which time TLC showed complete conversion. The reaction mixture was concentrated under
vacuum and the residue was treated with H2O (50 mL) and extracted with dichloromethane (3 × 15 mL).
The combined organic extracts were dried over anhydrous Na2SO4, filtered and evaporated under
reduced pressure to give a crude mass. Column chromatography purification using ethyl
acetate/dichloromethane as eluent gave the clicked product 4.
6-Amino-5-cyano-4-(4-methylphenyl)-1-(3-(1-(phenylthiomethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2(1H)-
pyrimidinone (4a). White solid, yield (82%), C27H21N7OS, M = 491 gmol−1, mp 220–222 °C,
Rf = 0.34 (ethyl acetate/dichloromethane, 70:30, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 253
(57,447), 319 (13,993); IR (KBr) cm−1: 3,450–3,310 (NH2), 2,225 (CN), 1,677 (C=O), 1,643 (C=N);
1H-NMR: (DMSO-d6): δ = 2.41 (s, 3H, CH3), 6.02 (s, 2H, CH2), 7.30–7.98 (m, 15H, Ar-H + NH2),
13
8.65 (s, 1H, CHar-triazole); C-NMR (DMSO-d6): δ = 21 (CH3), 52.1 (CH2), 72.1 (C-5), 116.7 (CN),
121.3 (CHar-triazole), 125.3, 125.9, 127.8, 127.9, 128.3, 128.8, 129.3, 130.6, 130.7, 132.2, 132.4, 134.1,
135.3, 141, 146 (Cq-triazole), 153.5 (C-2), 160 (C-4), 171.3 (C-6); MS-(+)ESI: m/z (%): 983 ([2M + H]+,
19), 514 ([M + Na]+, 7), 492 ([M+H]+, 100), MS-(-)ESI: m/z (%): 464 (26), 354 (8).
6-Amino-5-cyano-4-(4-methylphenyl)-1-(4-(1-(phenylthiomethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2(1H)-
pyrimidinone (4b). White solid, yield (72%), C27H21N7OS, M = 491 gmol−1, mp 259–261 °C,

Molecules 2010, 15
8851
Rf = 0.27 (ethyl acetate/dichloromethane, 70:30, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 251
(46,399), 318 (15,466); IR (KBr) cm−1: 3,450–3,310 (NH2), 2,226 (CN), 1,681 (C=O), 1,648 (C=N);
1H-NMR: (DMSO-d6): δ = 2.4 (s, 3H, CH3), 6.08 (s, 2H, CH2), 7.29–8.11 (m, 15H, Ar-H + NH2), 8.72
13
(s, 1H, CHar-triazole); C-NMR (DMSO-d6): δ = 21 (CH3), 52.3 (CH2), 72.7 (C-5), 116.5 (CN), 121.7
(CHar-triazole), 125.6, 127.4, 127.7, 128.6, 129.7, 130.5, 130.9, 132.1, 132.5, 133.9, 135.4, 140.9, 146.1
(Cq-triazole), 154 (C-2), 160.1 (C-4), 171.4 (C-6); MS-(+)ESI: m/z (%): 983 ([2M + H]+, 20), 514 ([M +
Na]+, 8), 492 ([M+H]+, 100), MS-(-)ESI: m/z (%): 464 (22), 354 (9).
6-Amino-4-benzyl-5-cyano-1-(3-(1-(phenylthiomethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2(1H)-pyrimidin-
one (4c). White solid, yield (80%), C27H21N7OS, M = 491 gmol−1, mp 235–237 °C, Rf = 0.36 (ethyl
acetate/dichloromethane, 70:30, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 250 (62,602), 318
1
(19,939); IR (KBr) cm−1: 3,450–3,310 (NH2), 2,208 (CN), 1,668 (C=O), 1,616 (C=N); H-NMR:
(DMSO-d6): δ = 3.90 (s, 2H, CH2), 6.13 (s, 2H, CH2), 7.27–7.65 (m, 16H, Ar-H + NH2), 8.85 (s, 1H,
13
CHar-triazole); C-NMR (DMSO-d6): δ = 43.4 (CH2), 52.2 (CH2), 73.4 (C-5), 117 (CN), 122.3 (CHar-
triazole), 124.9, 125.6, 126.9, 127.7, 128.3, 129.2, 129.6, 131.2, 131.8, 133.1, 133.4, 134.7, 136.5, 140.9,
147.3 (Cq-triazole), 154 (C-2), 159.6 (C-4), 175.7 (C-6); MS-(+)ESI: m/z (%): 983 ([2M + H]+, 19), 514
([M + Na]+, 7), 492 ([M+H]+, 100), MS-(-)ESI: m/z (%): 464 (2), 354 (8).
6-Amino-4-benzyl-5-cyano-1-(4-(1-(phenylthiomethyl)-1H-1,2,3-triazol-4-yl)phenyl)-2(1H)-pyrimidin-
one (4d). White solid, yield (75%), C27H21N7OS, M = 491 gmol−1, mp 262–264 °C, Rf = 0.30 (ethyl
acetate/dichloromethane, 70:30, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 248 (61,129), 319
1
(18,412); IR (KBr) cm−1: 3,450–3,310 (NH2), 2,226 (CN), 1,685 (C=O), 1,647 (C=N); H-NMR:
(DMSO-d6): δ = 3.9 (s, 2H, CH2), 6.23 (s, 2H, CH2), 7.2–7.91 (m, 16H, Ar-H + NH2), 8.64 (s, 1H,
13
CHar-triazole); C-NMR (DMSO-d6): δ = 43.5 (CH2), 51.9 (CH2), 73.7 (C-5), 116.5 (CN), 120.5 (CHar-
triazole), 126, 126.9, 127.2, 129.1, 129.9, 129.9, 129.9, 131.9, 132.2, 134.2, 136.4, 141.2, 146.7 (Cq-
triazole), 153.5 (C-2), 159.3 (C-4), 175.6 (C-6); MS-(+)ESI: m/z (%): 983 ([2M + H]+, 22), 514 ([M +
Na]+, 7), 492 ([M+H]+, 100), MS-(-)ESI: m/z (%): 464 (25), 354 (9).
6-Amino-5-cyano-1-(3-(1-(4-(isopropylamino)-6-(methylthio)-1,3,5-triazin-2-yl)-1H-1,2,3-triazol-4-
yl)-phenyl)-4-(4-methylphenyl)-2(1H)-pyrimidinone (4e). Pale yellow solid, yield (73%),
C27H25N11OS, M = 551 gmol−1, mp 230–232 °C, Rf = 0.39 (ethyl acetate/dichloromethane, 70:30,
v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 248 (71,905), 318 (19,009); IR (KBr) cm−1: 3,450–3,310
1
(NH2 + NH), 2,208 (CN), 1,671 (C=O), 1,627 (C=N); H-NMR: (DMSO-d6): δ = 1.21 (d, 3H,
J = 9 Hz, CH3), 1.23 (d, 3H, J = 9 Hz, CH3), 2.41 (s, 3H, CH3), 2.59 (s, 3H, -SCH3), 4.3 (m, 1H, CH),
13
7.25–7.77 (m, 11H, Ar-H + NH2 + NH), 8.1 (s, 1H, CHar-triazole); C-NMR (DMSO-d6): δ = 21.2
(SCH3), 21.5 (CH3), 22.3 (CH3), 22.6 (CH3), 42.8 (CH), 73.8 (C-5), 117.2 (CN), 120.7 (CHar-triazole),
126.3, 128.8, 129.3, 129.4, 131.3, 132.1, 132.1, 134.6, 135.9, 141.5, 146.4 (Cq-triazole), 154 (C-2), 160.5
(C-4), 164, 171.8 (C-6), 182.1, 183.1; MS-(+)ESI: m/z (%): 574 ([M + Na]+, 7), 552 ([M+H]+, 100),
MS-(-)ESI: m/z (%): 524 (64), 482 (7).
6-Amino-5-cyano-1-(4-(1-(4-(isopropylamino)-6-(methylthio)-1,3,5-triazin-2-yl)-1H-1,2,3-triazol-4-
yl)-phenyl)-4-(4-methylphenyl)-2(1H)-pyrimidinone (4f). white solid, yield (94%), C27H25N11OS,
M = 551 gmol−1, mp 253–255 °C, Rf = 0.31 (ethyl acetate/dichloromethane, 70:30, v/v); UV (MeOH)

Molecules 2010, 15
max nm (ε Lmol−1cm−1): 251 (64,467), 319 (15,703); IR (KBr) cm−1: 3,450–3,310 (NH2 + NH), 2,225
8852
λ
(CN), 1,663 (C=O), 1,638 (C=N); 1H-NMR: (DMSO-d6): δ = 1.21 (d, 3H, J = 9 Hz, CH3), 1.23 (d, 3H,
J = 9 Hz, CH3), 2.4 (s, 3H, CH3), 2.61 (s, 3H, -SCH3), 4.31 (m, 1H, CH), 7.21–7.75 (m, 11H, Ar-H +
NH2 + NH), 8.21 (s, 1H, CHar-triazole); 13C-NMR (DMSO-d6): δ = 21.1 (SCH3), 21.5 (CH3), 22.3 (CH3),
22.5 (CH3), 42.9 (CH), 73.8 (C-5), 116.9 (CN), 120.6 (CHar-triazole), 124.2, 128.8, 129.6, 131.4, 133.3,
134.6, 136, 141.3, 146.7 (Cq-triazole), 153.9 (C-2), 160.3 (C-4), 163.9, 171.7 (C-6), 182.1, 183.2; MS-
(+)ESI: m/z (%): 574 ([M + Na]+, 7), 552 ([M+H]+, 100), MS-(-)ESI: m/z (%): 524 (54), 482 (9).
6-Amino-4-benzyl-5-cyano-1-(3-(1-(4-(isopropylamino)-6-(methylthio)-1,3,5-triazin-2-yl)-1H-1,2,3-
triazol-4-yl)phenyl)-2(1H)-pyrimidinone (4g). Yellowish solid, yield (88%), C27H25N11OS,
M = 551 gmol−1, mp 241–243 °C, Rf = 0.37 (ethyl acetate/dichloromethane, 70:30, v/v); UV (MeOH)
λmax nm (ε Lmol−1cm−1): 249 (50,416), 307 (27,274); IR (KBr) cm−1: 3,450–3,310 (NH2), 2,206
(CN), 1,670 (C=O), 1,629 (C=N); 1H-NMR: (DMSO-d6): δ = 1.21 (d, 3H, J = 9 Hz, CH3), 1.23 (d, 3H,
J = 9 Hz, CH3), 2.59 (s, 3H, -SCH3), 3.9 (s, 2H, CH2), 4.3 (m, 1H, CH), 7.27–7.43 (m, 12H, Ar-H +
NH2 + NH), 8.29 (s, 1H, CHar-triazole); 13C-NMR (DMSO-d6): δ = 22.2 (SCH3), 22.3 (CH3), 22.5 (CH3),
42.8 (CH), 43.4 (CH2), 73.8 (C-5), 116.6 (CN), 120.8 (CHar-triazole), 127.4, 128, 128.3, 129, 129.8, 130,
131.3, 135.2, 137.3, 146.5 (Cq-triazole), 153.9 (C-2), 160.2 (C-4), 163.8, 164.2, 175.4 (C-6), 182.1, 183;
MS-(+)ESI: m/z (%): 574 ([M + Na]+, 9), 552 ([M+H]+, 100), MS-(-)ESI: m/z (%): 524 (61), 482 (7).
6-Amino-4-benzyl-5-cyano-1-(4-(1-(4-(isopropylamino)-6-(methylthio)-1,3,5-triazin-2-yl)-1H-1,2,3-
triazol-4-yl)phenyl)-2(1H)-pyrimidinone (4h). White solid, yield (71%), C27H25N11OS,
M = 551 gmol−1, mp 274–276 °C, Rf = 0.32 (ethyl acetate/dichloromethane, 70:30, v/v); UV (MeOH)
λmax nm (ε Lmol−1cm−1): 250 (52,069), 308 (25,621); IR (KBr) cm−1: 3,450–3,310 (NH2), 2,226
(CN), 1,685 (C=O), 1,642 (C=N); 1H-NMR: (DMSO-d6): δ = 1.21 (d, 3H, J = 9 Hz, CH3), 1.23 (d, 3H,
J = 9 Hz, CH3), 2.60 (s, 3H, -SCH3), 3.9 (s, 2H, CH2), 4.3 (m, 1H, CH), 7.36–7.47 (m, 12H, Ar-H +
13
NH2 + NH), 8.3 (s, 1H, CHar-triazole); C-NMR (DMSO-d6): δ = 21.5 (SCH3), 22.3 (CH3), 22.5 (CH3),
42.8 (CH), 43.4 (CH2), 73.8 (C-5), 116.5 (CN), 120.7 (CHar-triazole), 127.2, 127.8, 128.9, 129.6, 131.1,
135, 137.1, 146.5 (Cq-triazole), 154.1 (C-2), 159.7 (C-4), 163.6, 164, 175.4 (C-6), 182.1, 183.1; MS-
(+)ESI: m/z (%): 574 ([M + Na]+, 7), 552 ([M+H]+, 100), MS-(-)ESI: m/z (%): 524 (56), 482 (7).
(Z)-Ethyl-2-(4-(4-(3-(6-amino-5-cyano-4-(4-methylphenyl)-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-1-yl)benzylidene)-7-methyl-3-oxo-5-phenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-
carboxylate (4i). Golden yellow solid, yield (84%), C43H33N9O4S, M = 771 gmol−1, mp 285–287 °C,
Rf = 0.28 (ethyl acetate/dichloromethane, 50:50, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 248
(95,989), 308 (35,851); IR (KBr) cm−1: 3,450–3,310 (NH2), 2,211 (CN), 1,715 (C=O, ester), 1,677
1
(C=O); H-NMR: (DMSO-d6): δ = 1.13 (t, 3H, J = 6 Hz, CH3), 2.40 (s, 3H, CH3), 2.41 (s, 3H, CH3),
4.04 (q, 2H, J = 6 Hz, CH2), 6.06 (s, 1H, C-CH-N), 7.31–8.14 (m, 20H, Ar-H + NH2), 9.47 (s, 1H,
CHar-triazole); 13C-NMR (DMSO-d6): δ = 14.3 (CH3-CH2), 21.5 (CH3), 22.9 (CH3), 55.5 (C-CH-N), 60.7
(CH3-CH2), 72.6 (C-5), 109.4, 117.1 (CN), 120.4, 120.8 (CHar-triazole), 121.3, 125.9, 126.7, 127.9,
128.8, 129.1, 129.2, 129.3, 131.5, 131.9, 132.1, 132.5, 133.4, 134.6, 135.9, 137.7, 140.7, 141.5, 147.3
(Cq-triazole), 151.5, 154 (C-2), 155.7, 160.5 (C-4), 164.6 (C=O), 165.3, 171.9 (C-6); MS-(+)ESI: m/z
(%): 794 ([M + Na]+, 3), 772 ([M+H]+, 100), MS-(-)ESI: m/z (%): 744 (10).

Molecules 2010, 15
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(Z)-Ethyl-2-(4-(4-(4-(6-amino-5-cyano-4-(4-methylphenyl)-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-
1,2,3-triazol-1-yl)benzylidene)-7-methyl-3-oxo-5-phenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-
carboxylate (4j). Golden yellow solid, yield (72%), C43H33N9O4S, M = 771 gmol−1, mp 292–294 °C,
Rf = 0.25 (ethyl acetate/dichloromethane, 50:50, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 249
(84,424), 307 (38,164); IR (KBr) cm−1: 3,450–3,310 (NH2), 2,225 (CN), 1,727 (C=O, ester), 1,685
1
(C=O); H-NMR: (DMSO-d6): δ = 1.15 (t, 3H, J = 6 Hz, CH3), 2.41 (s, 3H, CH3), 2.43 (s, 3H, CH3),
4.11 (q, 2H, J = 6 Hz, CH2), 6.02 (s, 1H, C-CH-N), 7.29–8.20 (m, 20H, Ar-H + NH2), 9.32 (s, 1H,
CHar-triazole); 13C-NMR (DMSO-d6): δ = 14.3 (CH3-CH2), 21.5 (CH3), 22.9 (CH3), 55.5 (C-CH-N), 60.6
(CH3-CH2), 72.6 (C-5), 109.4, 117.4 (CN), 120.7, 120.8 (CHar-triazole), 122, 126.2, 126.7, 128.1, 129,
129.3, 131.6, 132, 132.2, 132.6, 133.6, 134.5, 136.1, 137.7, 140.6, 141.4, 147.5 (Cq-triazole), 151.7,
152.2 (C-2), 156.2, 161.2 (C-4), 165.1 (C=O), 165.6, 172.5 (C-6); MS-(+)ESI: m/z (%): 794 ([M +
Na]+, 3), 772 ([M+H]+, 100), MS-(-)ESI: m/z (%): 744 (7).
(Z)-Ethyl-2-(4-(4-(3-(6-amino-4-benzyl-5-cyano-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-1-
yl)benzylidene)-7-methyl-3-oxo-5-phenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(4k). Golden yellow solid, yield (81%), C43H33N9O4S, M = 771 gmol−1, mp 277–279 °C, Rf = 0.32
(ethyl acetate/dichloromethane, 50:50, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 250 (72,859), 318
(27,756); IR (KBr) cm−1: 3,450–3,310 (NH2), 2,212 (CN), 1,721 (C=O, ester), 1,671 (C=O); 1H-NMR:
(DMSO-d6): δ = 1.12 (t, 3H, J = 6 Hz, CH3), 2.40 (s, 3H, CH3), 3.9 (s, 2H, CH2), 4.09 (q, 2H, J = 6 Hz,
13
CH2), 5.98 (s, 1H, C-CH-N), 7.33–8.02 (m, 21H, Ar-H + NH2), 9.33 (s, 1H, CHar-triazole); C-NMR
(DMSO-d6): δ = 14.3 (CH3-CH2), 22.9 (CH3), 43.5 (CH2), 55.4 (C-CH-N), 60.7 (CH3-CH2), 73.4 (C-
5), 110.2, 116.5 (CN), 119.9, 121.2 (CHar-triazole), 122, 126, 126.6, 128.3, 128.9, 129, 129.8, 130.1,
131.5, 132, 132.4, 132.9, 134.2, 134.7, 136.1, 137.5, 139.9, 142, 146.7 (Cq-triazole), 150.9, 153.6 (C-2),
156.2, 159.6 (C-4), 164.5 (C=O), 166.2, 175.8 (C-6); MS-(+)ESI: m/z (%): 794 ([M + Na]+, 3), 772
([M+H]+, 100), MS-(-)ESI: m/z (%): 744 (9).
(Z)-ethyl-2-(4-(4-(4-(6-amino-4-benzyl-5-cyano-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-1-
yl)benzylidene)-7-methyl-3-oxo-5-phenyl-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(4l). Golden yellow solid, yield (68%), C43H33N9O4S, M = 771 gmol−1, mp 281–283 °C, Rf = 0.61
(ethyl acetate/dichloromethane, 50:50, v/v); UV (MeOH) λmax nm (ε Lmol−1cm−1): 253 (90,207), 319
(15,381); IR (KBr) cm−1: 3,450–3,310 (NH2), 2,226 (CN), 1,728 (C=O, ester), 1,676 (C=O); 1H-NMR:
(DMSO-d6): δ = 1.15 (t, 3H, J = 6 Hz, CH3), 2.41 (s, 3H, CH3), 3.89 (s, 2H, CH2), 4.12 (q, 2H,
J = 6 Hz, CH2), 6.00 (s, 1H, C-CH-N), 7.28–8.46 (m, 21H, Ar-H + NH2), 9.40 (s, 1H, CHar-triazole); 13C-
NMR (DMSO-d6): δ = 14.3 (CH3-CH2), 22.9 (CH3), 43.5 (CH2), 56.2 (C-CH-N), 60.7 (CH3-CH2), 73.8
(C-5), 112.5, 117.2 (CN), 120.3, 120.9 (CHar-triazole), 121.9, 126.3, 128.6, 129.4, 129.5, 129.9, 131.6,
131.8, 133.5, 133, 135.2, 135.4, 135.9, 137.6, 140.1, 142.2, 147.7 (Cq-triazole), 149.5, 153.9 (C-2), 157,
159.9 (C-4), 164.6 (C=O), 167.2, 174.9 (C-6); MS-(+)ESI: m/z (%): 794 ([M + Na]+, 3), 772 ([M+H]+,
100), MS-(-)ESI: m/z (%): 744 (6).
Acknowledgements
Thanks are due to the Ministry of Higher Education and Scientific Research of Tunisia for
awarding a fellowship to Ennaji Najahi. The Authors wish to thank R Duval for gift of the azide

Molecules 2010, 15
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derivative A3. We thank Dr. Carine Duhayon for providing the X-ray crystal analysis. Hany Ibrahim
and Pierre Perio for their help in the physico-chemical characterization of our compounds.
References
1. Kolb, H.C.; Sharpless, K.B. The growing impact of click chemistry on drug discovery. Drug
Discov. Today 2003, 8, 1128-1137.
2. Yi, L.; Shi, J.; Gao, S.; Li, S.; Niu, C.; Xi, Z. Sulfonium alkylation followed by ‘click’ chemistry
for facile surface modification of proteins and tobacco mosaic virus. Tetrahedron Lett. 2009, 50,
759-762.
3. Bock, V.D.; Hiemstra, H.; van Maarseveen, J.H. CuI-Catalyzed Alkyne-Azide “Click”
Cycloadditions from a Mechanistic and Synthetic Perspective. Eur. J. Org. Chem. 2006, 1, 51-68.
4. Fournier, D.; De Geest, B.G.; Du Prez, F.E. On-demand click functionalization of polyurethane
films and foams. Polymer 2009, 50, 5362-5367.
5. Fan, W.Q.; Katritzky. A.R. 1,2,3-Triazoles. Compr. Heterocycl. Chem. II 1996, 4, 1-126.
6. Kategaonkar, A.H.; Shinde, P.V.; Kategaonkar, A.H.; Pasale, S.K.; Shingate, B.B.; Shingare,
M.S. Synthesis and biological evaluation of new 2-chloro-3-((4-phenyl-1H-1,2,3-triazol-1-
yl)methyl)quinoline derivatives via click chemistry approach. Eur. J. Med. Chem. 2010, 45,
3142-3146.
7. Genin, M.J.; Allwine, D.A.; Anderson, D.J.; Barbachyn, M.R.; Emmert, D.E.; Garmon, S.A.;
Graber, D.R.; Grega, K.C.; Hester, J.B.; Hutchinson, D.K.; Morris, J.; Reischer, R.J.; Ford, C.W.;
Zurenko, G.E.; Hamel, J.C.; Schaadt, R.D.; Stapert, D.; Yagi, B.H. Substituent Effects on the
Antibacterial Activity of Nitrogen-Carbon-Linked (Azolylphenyl)oxazolidinones with Expanded
Activity Against the Fastidious Gram-Negative Organisms Haemophilus influenzae and
Moraxella catarrhalis. J. Med. Chem. 2000, 43, 953-970.
8. Alvarez, R.; Velázquez, S.; San-Félix, A.; Aquaro, S.; De Clercq, E.; Perno, C.F.; Karlsson, A.;
Balzarini, J.; Camarasa, M.J. 1,2,3-Triazole-[2,5-Bis-O-(tert butyldimethylsilyl)-.beta.-D-
ribofuranosyl]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole2'',2'' dioxide) (TSAO) Analogs: Synthesis
and Anti-HIV-1 Activity. J. Med. Chem. 1994, 37, 4185-4194.
9. Buckle, D.R.; Outred, D.J.; Rockell, C.J.M.; Smith, H.; Spicer, B.A. Studies on v-triazoles. 7.
Antiallergic 9-oxo-1H,9H-benzopyrano[2,3-d]-v-triazoles. J. Med. Chem. 1983, 26, 251-254.
10. Patil, V.; Guerrant, W.; Chen, P.C.; Gryder, B.; Benicewicz, D.B.; Khan, S.I.; Tekwani, B.L.;
Oyelere, A.K. Antimalarial and antileishmanial activities of histone deacetylase inhibitors with
triazole-linked cap group. Bioorg. Med. Chem. 2010, 18, 415-425.
11. Rovnyak, G.C.; Atwal, K.S.; Hedberg, A.; Kimball, S.D.; Moreland, S.; Gougoutas, J.Z.;
O’Reilly, B.C.; Schwartz, J.; Malley, M.F. Dihydropyrimidine calcium channel blockers. 4. Basic
3-substituted-4-aryl-1,4 dihydropyrimidine-5-carboxylic acid esters. Potent antihypertensive
agents. J. Med. Chem. 1992, 35, 3254-3263.
12. Atwal, K.S.; Rovnyak, G.C.; Schwartz, J.; Moreland, S.; Hedberg, A.; Gougoutas, J.Z.; Malley,
M.F.; David, M.F. Dihydropyrimidine calcium channel blockers: 2-heterosubstituted 4-aryl-1,4-
dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines. J.
Med. Chem. 1990, 33, 1510-1515.

Molecules 2010, 15
8855
13. Yamaguchi, M.; Wakasugi, K.; Saito, R.; Adachi, Y.; Yoshikawa, Y.; Sakurai, H.; Katoh, A.
Syntheses of vanadyl and zinc(II) complexes of 1-hydroxy-4,5,6-substituted 2(1H)-pyrimidinones
and their insulin–mimetic activities. J. Inorg. Biochem. 2006, 100, 260-269.
14. Sadanandam, Y.S.; Shetty, M.M.; Diwan, P.V. Synthesis and biological evaluation of new 3,4-
dihydro-6-methyl-5-N-methyl-carbamoyl-4-(substituted
pyrimidinethiones Eur. J. Med. Chem. 1992, 27, 87-92.
phenyl)-2(1H)pyrimidinones
and
15. Wright, C.M.; Chovatiya, R.J.; Jameson, N.E.; Turner, D.M.; Zhu, G.; Werner, S.; Huryn, D.M.;
Pipas, J.M.; Day, B.W.; Wipf, P.; Brodskya, J.L. Pyrimidinone-peptoid hybrid molecules with
distinct effects on molecular chaperone function and cell proliferation. Bioorg. Med. Chem. 2008,
16, 3291-3301.
16. Lagu, B.; Tian, D.; Chiu, G.; Nagarathnam, D.; Fang, J.; Shen, Q.; Forray, C.; Ransom, R.W.;
Raymond, S.L.C.; Kamlesh, P.V.; Zhang, K.; Gluchowski, C. Synthesis and evaluation of
furo[3,4-d]pyrimidinones as selective α1a-adrenergic receptor antagonists Bioorg. Med. Chem.
Lett. 2000, 10, 175-178.
17. Zribi, F.; Rekik, A.; Chabchoub, F.; Trabelsi, M.; Salem, M. Effect of malonates on simple imino
esters, N-acyls and N-ethoxycarbonyls in a basic medium. J. Tun. Chem. Soc. 2001, 4, 965-970.
18. Krechl, J.; Perez, M.A.; Cuadrado, F.J.; Soto, J.L. Pyrimidine-5-carbonitriles from Methyl N-
(Aminocarbonyl)-or N-(Aminothiocarbonyl)-imidates. Synthesis 1988, 2, 122-126. Our
compounds 3a and 3g were prepared according to the above cited reference by reaction of methyl
N-(phenyl or 4-methylphenylaminocarbonyl)imidates with malononitrile and sodium methoxide
in dry methanol.
19. Whitehead, C.W.; Traverso, J.J. Reactions of Orthoesters with Ureas. II. J. Am. Chem. Soc. 1955,
77, 5867-5872.
20. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A. Completion and refinement of
crystal structures with SIR92. J. Appl. Crystallogr. 1993, 26, 343-350.
21. Betteridge, P.W.; Carruthers, J.R.; Cooper, R.I.; Prout, K.; Watkin, D.J. CRYSTALS version 12:
Software for guided crystal structure analysis. J. Appl. Crystallogr. 2003, 36, 1487.
22. IBERS, J.A.; Hamilton, W.C. International Tables for X-ray Crystallography; Kynoch Press:
Birmingham, UK, 1974; Volume IV.
Sample Availability: Samples of the compounds are available from the authors.
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