Three-component uncatalyzed eco-friendly reactions for one-pot synthesis of 4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine derivatives

Article abstract of DOI:10.1002/jhet.1771

A three-component system of one-pot synthesis of [1,2,4]triazolo[1,5-a] pyrimidine derivatives using condensation of 1,3-dicarbonyl compounds, aldehydes, and 5-amino[1,2,4]triazole in ethanol without any catalyst was reported in high yields via simple, efficient, and environmentally friendly process. The method reported herein considered a green process; this method has significant advantages of simple workup procedure, excellent yield, minimal environmental pollution, and short reaction time over classical reported methods.

Full text of DOI:10.1002/jhet.1771

Month 2014 Three-Component Uncatalyzed Eco-Friendly Reactions for One-Pot Synthesis
of 4,7-Dihydro[1,2,4]triazolo[1,5-a]pyrimidine Derivatives
*
Eman A. El Rady
Aswan University, Faculty of Science, Chemistry Department, Aswan 81528, Egypt
*
E-mail: emanelradi@hotmail.com
Received May 2, 2012
DOI 10.1002/jhet.1771
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
A three-component system of one-pot synthesis of [1,2,4]triazolo[1,5-a]pyrimidine derivatives using conden-
sation of 1,3-dicarbonyl compounds, aldehydes, and 5-amino[1,2,4]triazole in ethanol without any catalyst was
reported in high yields via simple, efficient, and environmentally friendly process. The method reported herein
considered a green process; this method has significant advantages of simple workup procedure, excellent yield,
minimal environmental pollution, and short reaction time over classical reported methods.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
dihydropyrimidinone due to its wide range of biological
activities [42–45]. The reactions described herein are
comparable intrinsically with the Biginelli reaction type,
using analogous amino azoles as alternative to urea/thiourea
in classical Biginelli reaction [38,39,46–48]. However,
work in this field has not lost current interest because of
varying reagents, catalysts, and conditions used in similar
reactions. Recently, the Biginelli reaction was developed
for the synthesis of [1,2,4]triazolo[1,5-a]pyrimidine and
its derivatives because of their remarkable diverse thera-
peutic and pharmacological activities such as analgesic,
anticonvulsant, anti-inflammatory, antimalarials, antimi-
crobial, and antifungal effects [49–52]. Owing to the
demand for an environmentally benign, green methodolo-
gies and continuing the interest for the synthesis of
heterocyclic compounds [53–58], the synthesis of [1,2,4]
triazolo[1,5-a]pyrimidine via a three-component system
under reflux without any catalyst have been reported
herein (Scheme 1).
Green chemistry has become a subject of intensive
research and important focuses within organic synthesis;
thus, it attracts more scientists and researchers to work in
this area. Also, green chemistry and its applications [1–7]
in synthetic organic chemistry are to reduce the use of
hazardous chemicals and formation of waste products that
concern the environment [8–11]. In recent years, most
researchers have been focusing on developing environ-
mentally benign reactions. The various methodologies
and routes have been developed for these purposes, from
the requirements of a green synthesis methodology is
the use of eco-friendly solvents, catalyst, and nontoxic
chemicals [12–17]. The environmentally benign synthetic
methods have received considerable attention, and some
uncatalyzed reactions have been developed [18]. In the
green chemistry, it is the marriage of economic and
environmental aspects for the new reactions. Thus, many
researchers tend to use multicomponent reaction strategy.
It has been found that the three-component condensation
constitutes an especially attractive synthetic strategy for
rapid efficient route because the products are formed in
single step without isolation of any intermediate, thus
reducing reaction time, energy, and material use [19–39].
The Biginelli reaction [40,41] is one of the most important
examples of multicomponent reaction for the synthesis of
RESULTS AND DISCUSSION
The general method for the synthesis of [1,2,4]triazolo
[1,5-a]pyrimidine involves cyclocondensation of amino-
triazole with a,b-unsaturated carbonyl compounds [59,60].
As a part of our interest in using the simple methods for
© 2013 HeteroCorporation

E. A. El Rady
Vol 000
Scheme 1. Synthesis of [1,2,4]triazolo[1,5-a]pyrimidine derivatives.
Scheme 2. (Route a) Plausible mechanism for the formation of 7-aryl/
alkyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine derivatives.
the synthesis of various heterocyclic compounds [61–64], a
very simple, green, and efficient method for the development
of a one-pot synthesis of [1,2,4]triazolo[1,5-a]pyrimidine deri-
vatives by three-component condensation of aliphatic, various
aromatic, and heterocyclic aldehydes with 1,3-dicarbonyl
compounds (ethyl acetoacetate, acetyl acetone, and diethyl
malonate) and 5-amino[1,2,4]triazole have been reported.
The reaction was carried out under reflux in ethanol without
any catalyst. The progress of the reaction was monitored by
TLC; after completion, the reaction mixture was cooled at
room temperature, and the solvent was concentrated under
vacuum. The obtained solid was filtered off, dried, and
recrystallized from proper solvent (see Experimental section).
The structure of the products was confirmed by IR, 1H NMR,
13C NMR, MS spectroscopy, and elemental analysis. The
previous method was examined by the use of several alde-
hydes with different 1,3-dicarbonyl compounds under the
same reaction conditions. It has been found that the reaction
proceeds very easy to give [1,2,4]triazolo[1,5-a]pyrimidine
derivatives in excellent high yields. A proposed mechanism
to account for the formation of [1,2,4]triazolo[1,5-a]pyrimi-
dine derivatives is shown in Schemes 2 and 3. Two possible
isomeric structures of 7-aryl/alkyl-4,7-dihydro[1,2,4]triazolo
[1,5-a]pyrimidine [8–10] and 5-aryl/alkyl-4,5-dihydro
[1,2,4]triazolo[1,5-a]pyrimidine [14] could be obtained
theoretically according to the plausible mechanism for the
synthesis of [1,2,4]triazolo[1,5-a]pyrimidine. A pyrimidine
ring could be formed with participation of NH or NH2
of 3-amino[1,2,4]triazole with arylidene dicarbonyl com-
pounds 3 to form two expected isomers 8–10 and/or 14.
As a start, the aldehyde is condensed with active methylene
of 1,3-dicarbonyl compounds forming a,b-unsaturated
carbonyl compounds 3 in situ via Knoevenagel reaction; this
is followed by Michael reaction of NH of 5-amino[1,2,4]-
triazole 4 with a, b-unsaturated carbonyl compounds 3
forming the intermediates 5–7 (Scheme 2) or by addition of
NH2 of 5-amino[1,2,4]triazole 4 with a,b-unsaturated
carbonyl compounds 3 to form the intermediates 11–13
(Scheme 3). Finally, after intramolecular cyclization, the
expected isomeric products 8–10 or 14 are formed.
Scheme 3. (Route b) Plausible mechanism for the formation of 5-aryl/
alkyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidine derivatives.
Regioselectivity of the reaction with participation of NH is
the subject of studies, and the preference was to produce
the isomers 8–10 referring to [36–39,46–48].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Three-Component One-Pot Synthesis of [1,2,4]Triazolo[1,5-a]pyrimidine
Ethyl 4,7-dihydro-5-methyl-7-phenyl-[1,2,4]triazolo[1,5-a]
pyrimidine-6-carboxylate 8b.
mp 190–192ꢀC (190–192ꢀC
CONCLUSION
In summary, the one-pot synthesis of three-component
reaction of aldehydes, 5-amino[1,2,4]triazole, and
1,3-dicarbonyl compounds that were refluxed in
ethanol for appropriate time afforded [1,2,4]triazolo
[1,5-a]pyrimidine derivatives in good to excellent
yields as well as an improved Biginelli reaction via
Knoevenagel and Michael reactions.
ref. [36]); Yield: 0.84 g, 96% (dioxane/H2O). IR (KBr): nmax
1
(in cmÀ1) 3289 (NH), 1713 (CO); H NMR (d ppm, DMSO-d6):
1.12 (t, 3H, CH3), 2.33 (s, 3H, CH3), 3.88 (q, 2H, CH2), 6.36
(s, 1H, C(7)H), 7.44 (m, 5H, Ph), 7.87 (s, 1H, C(2)H), 10.89
(s, 1H, NH). 13C NMR (d ppm, DMSO-d6): 8.44, 11.76, 31.49,
47.79, 112.55, 125.70, 128.34, 129.11, 137.32, 150.12, 150.21,
155.32, 199.86. MS (m/z %)= 284 (M+, 45%). Anal. Calcd for
C15H16N4O2 (284.31): C, 63.37%; H, 5.67%; N, 19.71%. Found:
C, 63.47%; H, 5.53%; N, 19.80%.
Ethyl 7-(4-chlorophenyl)-4,7-dihydro-5-methyl-[1,2,4]triazolo
[1,5-a]pyrimidine-6-carboxylate 8c.
EXPERIMENTAL
mp 260–262ꢀC; Yield:
Melting points were determined on a Gallenkamp electrothermal
melting point apparatus and are uncorrected, IR spectra were
recorded as potassium bromide pellets using an FTIR unit Bruker
Vector 22 spectrophotometer, 1H NMR spectra were obtained
in deuterated dimethyl sulfoxide as solvent at 300MHz and
75MHz, respectively, on a Varian Gemini NMR spectrometer
using TMS as internal standard. Chemical shifts are reported in d
units (ppm). Mass spectra were recorded on a Hewlett Packard
MS-5988 spectrometer at 70 eV. Elemental analysis was carried
out at the Microanalytical Center of Cairo University, Egypt.
General procedure for the synthesis of ethyl 4,7-dihydro-
7-substituted-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-6-
0.76 g, 87% (dioxane/H2O). IR (KBr): nmax (in cmÀ1) 3299
(NH), 1710 (CO); 1H NMR (d ppm, DMSO-d6): 1.31(t, 3H,
CH3), 2.30 (s, 3H, CH3), 4.19 (q, 2H, CH2), 5.88 (s, 1H, C(7)H),
7.44 (m, 4H, Ph), 8.22 (s, 1H, C(2)H), 9.56 (s, 1H, NH). 13C
NMR (d ppm, DMSO-d6): 8.43, 11.78, 31.46, 47.88, 112.54,
128.34, 129.11, 131.22, 137.32, 150.11, 150.21, 155.33, 199.84.
MS (m/z %) = 318 (M+, 55%). Anal. Calcd for C15H15ClN4O2
(318.76): C, 56.52%; H, 4.74%; N, 17.58%. Found: C, 56.59%;
H, 4.80%; N, 17.63%.
Ethyl 4,7-dihydro-7-(4-methoxyphenyl)-5-methyl-[1,2,4]triazolo
[1,5-a]pyrimidine-6-carboxylate 8d.
mp 240–242ꢀC; Yield:
0.84 g, 96% (dioxane). IR (KBr): nmax (in cmÀ1) 3287 (NH),
1705 (CO); 1H NMR (d ppm, DMSO-d6): 1.33 (t, 3H, CH3),
2.35 (s, 3H, CH3), 2.36 (s, 3H, OCH3), 4.17 (q, 2H, CH2), 5.86
(s, 1H, C(7)H), 7.43 (m, 4H, Ph), 8.20 (s, 1H, C(2)H), 9.58
(s, 1H, NH). 13C NMR (d ppm, DMSO-d6): 8.44, 11.76, 31.49,
47.79, 55.32, 112.55, 114.21, 130.34, 130.55, 150.12, 150.21,
155.32, 157.32, 199.86. MS (m/z %) = 314 (M+, 50%). Anal.
Calcd for C16H18N4O3 (314.34): C, 61.13%; H, 5.77%;
N, 17.82%. Found: C, 61.18%; H, 5.67%; N, 17.89%.
carboxylate 8a–i.
A mixture of aldehyde (1 mmol), ethyl
acetoacetate (1 mmol), and 5-amino[1,2,4]triazole (1 mmol) in
10-mL ethanol was refluxed; after 3 h, a precipitate was
separated during reflux. After completion of the reaction, the
precipitate was collected by filtration and recrystallized from a
proper solvent (Table 1).
Ethyl 4,7-dihydro-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-
6-carboxylate 8a.
mp 145–147ꢀC (150–152ꢀC ref. [36]);
Yield: 0.70 g, 80% (EtOH). IR (KBr): nmax (in cmÀ1) 3277 (NH),
1710 (CO); 1H NMR (d ppm, DMSO-d6): 1.19 (t, 3H, CH3),
1.43 (d, 3H, CH3), 1.63 (s, 3H, CH3), 3.99 (q, 2H, CH2), 5.46
(q, 1H, C(7)H), 7.77 (s, 1H, C(2)H), 10.59 (s, 1H, NH). 13C NMR
(d ppm, DMSO-d6): 8.21, 11.22, 21.62, 31.49, 47.77, 111.43,
150.11, 150.42, 151.23, 199.12. MS (m/z %)= 222 (M+, 40%).
Anal. Calcd for C10H14N4O2 (222.24): C, 54.04%; H, 6.35%; N,
25.21%. Found: C, 54.44%; H, 6.39%; N, 25.32%.
Ethyl 4,7-dihydro-7-(4-methylphenyl)-5-methyl-[1,2,4]triazolo
[1,5-a]pyrimidine-6-carboxylate 8e.
mp 235–237ꢀC; Yield:
0.67 g, 77% (dioxane/H2O). IR (KBr): nmax (in cmÀ1) 3290
(NH), 1709 (CO); 1H NMR (d ppm, DMSO-d6): 1.25 (t, 3H,
CH3), 2.37 (s, 3H, CH3), 2.38 (s, 3H, CH3), 4.19 (q, 2H, CH2),
5.88 (s, 1H, C(7)H), 7.49 (m, 4H, Ph), 8.29 (s, 1H, C(2)H), 9.68
(s, 1H, NH). 13C NMR (d ppm, DMSO-d6): 8.44, 11.78, 25.33,
31.49, 47.84, 112.54, 128.34, 129.11, 131.22, 137.36, 150.12,
Table 1
Ethyl acetoacetate as 1,3-dicarbonyl compounds with 3-amino triazole and aldehydesa for the synthesis of [1,2,4]triazolo[1,5-a]pyrimidine 8a–i in
refluxing ethanol.b
Entry
Productc
R
R1
R2
Time (h)
mp (ꢀC)
Yield (%)d
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8f
8g
8h
8i
CH3
C6H5
4-Cl-C6H4
4-CH3-C6H4
4-CH3O-C6H4
4-N(CH3)2C6H4
4-NO2-C6H4
2-NO2C6H4
2-Thienyl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
4
4
3
3
3
4
4
3
4
142
190
260
235
240
225
195
220
195
80
96
87
96
77
95
88
76
88
aVarious aldehydes (aliphatic, aromatic, and heterocyclic).
bThe reaction occurred in ethanol without any catalyst.
1
cStructural assignments of the products were based on their IR, HNMR, and MS.
dIsolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. A. El Rady
Vol 000
150.21, 155.32, 199.86. MS (m/z %) = 298 (M+, 55%). Anal. Calcd
for C16H18N4O2 (298.34): C, 64.41%; H, 6.08%; N, 18.78%.
Found: C, 64.49%; H, 6.78%; N, 18.85%.
(s, 1H, NH). 13C NMR (d ppm, DMSO-d6): 8.42, 11.73, 31.49,
47.75, 55.37, 40.21, 112.55, 122.21, 125.37, 125.57, 150.21,
155.32, 157.32, 199.86. MS (m/z %) = 291 (M + 1, 45%). Anal.
Calcd for C13H14N4O2S (290.34): C, 53.78%; H, 4.86%; N,
19.30%. Found: C, 53.89%; H, 4.99%; N, 19.45%.
Ethyl 7-(4-(dimethylamino)phenyl)-4,7-dihydro-5-methyl-[1,2,4]
triazolo[1,5-a]pyrimidine-6-carboxylate 8f.
mp 225–227ꢀC;
Yield: 0.83 g, 95% (EtOH). IR (KBr): nmax (in cmÀ1) 3298 (NH),
1710 (CO); 1H NMR (d ppm, DMSO-d6): 1.31 (t, 3H, CH3),
2.33 (s, 3H, CH3), 2.38 (s, 6H, 2CH3), 4.13 (q, 2H, CH2), 5.80
(s, 1H, C(7)H), 7.42 (m, 4H, Ph), 8.24 (s, 1H, C(2)H), 9.66
(s, 1H, NH). 13C NMR (d ppm, DMSO-d6): 8.44, 11.76, 31.49,
47.75, 55.37, 40.21, 112.55, 114.21, 130.37, 130.57, 150.12,
150.21, 155.32, 157.32, 199.86. MS (m/z %)= 327 (M+, 59%).
Anal. Calcd for C17H21N5O2 (327.38): C, 62.37%; H, 6.47%;
N, 21.39%. Found: C, 62.27%; H, 6.55%; N, 21.47%.
General procedure for the synthesis of 1-(4,7-dihydro-5-
methyl-7-substituted[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)ethanone
9a–h. Aldehyde (1mmol), aectylacetone (1 mmol) and 5-amino
[1,2,4]triazole (1 mmol) in 10 ml ethanol was heated at 90ꢀC for
the appropriate time as mentioned in Table 2. After the
completion of reaction, as indicated by TLC, the reaction
mixture was concentrated under reduced pressure, the resulting
solid product was triturated with methanol and filtered,
recrystallized from proper solvent.
Ethyl 4,7-dihydro-5-methyl-7-(4-nitrophenyl)-[1,2,4]triazolo
[1,5-a]pyrimidine-6-carboxylate 8g.
1-(5,7-Dimethyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-
6-yl)ethanone 9a.
mp 195–197ꢀC; Yield:
mp 170–172ꢀC; Yield: 0.70 g, 80%
0.77 g, 88% (dioxane/H2O). IR (KBr): nmax (in cmÀ1) 3298
(NH), 1707 (CO); 1H NMR (d ppm, DMSO-d6): 1.34 (t, 3H,
CH3), 2.15 (s, 3H, CH3), 4.10 (q, 2H, CH2), 5.84 (s, 1H, C(7)
H), 7.40 (m, 4H, Ph), 8.25 (s, 1H, C(2)H), 9.67 (s, 1H, NH). 13C
NMR (d ppm, DMSO-d6): 8.44, 11.78, 31.49, 47.79, 112.55,
114.22, 130.32, 130.57, 150.13, 150.21, 155.32, 157.32,
199.86. MS (m/z %) = 329 (M+, 50%). Anal. Calcd for
C15H15N5O4 (329.11): C, 54.71%; H, 4.59%; N, 21.27%.
Found: C, 54.78%; H, 4.65%; N, 21.35%.
(EtOH/H2O). IR (KBr): nmax (in cmÀ1) 3267 (NH); 1H
NMR (d ppm, DMSO-d6): 1.43 (s, 3H, CH3), 1.63 (d, 3H,
CH3), 2.24 (s, 3H, CH3), 5.40 (q, 1H, C(7)H), 7.79 (s, 1H,
C(2)H), 10.57 (s, 1H, NH). 13C NMR (d ppm, DMSO-d6):
8.43, 15.22, 21.62, 56.77, 106.32, 138.21, 150.11, 151.23.
MS (m/z %) = 164 (M+, 66%). Anal. Calcd for C8H12N4
(164.21): C, 58.51%; H, 7.37%; N, 34.12%. Found: C,
58.55%; H, 7.27%; N, 34.22%.
1-(4,7-Dihydro-5-methyl-7-phenyl-[1,2,4]triazolo[1,5-a]
Ethyl 4,7-dihydro-5-methyl-7-(2-nitrophenyl)-[1,2,4]triazolo
pyrimidin-6-yl)ethanone 9b.
mp 265–267ꢀC; Yield: 0.83 g,
[1,5-a]pyrimidine-6-carboxylate 8h.
mp 220–222ꢀC; Yield:
95% (EtOH). IR (KBr): nmax (in cmÀ1) 3280 (NH); 1H
NMR (d ppm, DMSO-d6): 1.40 (s, 3H, CH3), 1.61 (s, 3H,
CH3), 5.43 (s, 1H, C(7)H), 7.27 (s, 1H, C(2)H), 7.44
(m, 4H, Ph), 10.09 (s, 1H, NH). 13C NMR (d ppm, DMSO-d6):
8.44, 15.90, 56.77, 106.50, 125.70, 128.77, 129.11, 137.32,
138.32, 150.21, 151.54. MS (m/z %) = 226 (M+, 49%). Anal.
Calcd for C13H14N4 (226.12): C, 69.00%; H, 6.24%; N, 24.76%.
Found: C, 69.09%; H, 6.34%; N, 24.65%.
0.66 g, 76% (EtOH). IR (KBr): nmax (in cmÀ1) 3289 (NH), 1705
(CO); 1H NMR (d ppm, DMSO-d6): 1.37 (t, 3H, CH3), 2.16
(s, 3H, CH3), 4.10 (q, 2H, CH2), 5.85 (s, 1H, C(7)H), 7.42
(m, 4H, Ph), 8.25 (s, 1H, C(2)H), 9.68 (s, 1H, NH). 13C NMR
(d ppm, DMSO-d6): 8.43, 11.77, 31.49, 47.79, 112.55, 114.22,
130.32, 130.59, 150.13, 150.21, 155.32, 157.37, 199.89. MS
(m/z %) = 329 (M+, 50%). Anal. Calcd for C15H15N5O4
(329.11): C, 54.71%; H, 4.59%; N, 21.27%. Found: C, 54.77%;
H, 4.66%; N, 21.34%.
1-(7-(4-Chlorophenyl)-4,7-dihydro-5-methyl-[1,2,4]triazolo
[1,5-a]pyrimidin-6-yl)ethanone 9c.
mp 230–232ꢀC; Yield:
1
Ethyl 4,7-dihydro-5-methyl-7-(thiophene-2-yl)-[1,2,4]triazolo
0.83 g, 95% (EtOH). IR (KBr): nmax (in cmÀ1) 3298 (NH); H
NMR (d ppm, DMSO-d6): 1.28 (s, 3H, CH3), 1.66 (s, 3H,
CH3), 5.87 (s, 1H, C(7)H), 7.42 (m, 4H, Ph), 8.21 (s, 1H, C(2)
H), 9.56 (s, 1H, NH). 13C NMR (d ppm, DMSO-d6): 8.44,
15.90, 56.77, 106.50, 114.43, 129.11, 137.32, 138.32, 141.55,
150.21, 151.54. MS (m/z %) = 260 (M+, 67%). Anal. Calcd for
[1,5-a]pyrimidine-6-carboxylate 8i.
mp 195–197ꢀC; Yield:
0.77 g, 88% (EtOH). IR (KBr): nmax (in cmÀ1) 3269 (NH), 1708
(CO); 1H NMR (d ppm, DMSO-d6): 1.34 (s, 6H, 2CH3), 5.83
(s, 1H, C(7)H), 6.11 (d, 1H, C(3)H thienyl), 6.32 (d, 1H, C(4)
H
thienyl), 6.45 (d, 1H, C(5)H thienyl), 8.21 (s, 1H,C(2)H), 9.76
Table 2
Acetylacetone as 1,3-dicarbonyl compounds with 3-amino triazole and aldehydea for the synthesis of [1,2,4]triazolo[1,5-a]pyrimidine 9a–h in refluxing
ethanol.b
Entry
Productc
R
R1
R2
Time (h)
mp (ꢀC)
Yield (%)d
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
CH3
C6H5
4-Cl-C6H4
4-CH3-C6H4
4-CH3O-C6H4
4-N(CH3)2C6H4
2-NO2C6H4
2-Thienyl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
5
4
3
4
4
5
5
5
170
265
230
255
260
285
280
215
80
95
95
79
81
80
79
78
9g
9h
aVarious aldehydes (aliphatic, aromatic, and heterocyclic).
bThe reaction occurred in ethanol without any catalyst.
1
cStructural assignments of the products were based on their IR, HNMR, and MS.
dIsolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Three-Component One-Pot Synthesis of [1,2,4]Triazolo[1,5-a]pyrimidine
C13H13ClN4 (260.72): C, 59.89%; H, 5.03%; N, 21.49%.
Found: C, 59.77%; H, 5.12%; N, 21.37%.
1-(4,7-Dihydro-7-(4-methoxyphenyl)-5-methyl-[1,2,4]triazolo
1-(4,7-Dihydro-5-methyl-7-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]
pyrimidin-6-yl)ethanone 9h.
mp 215–217ꢀC; Yield: 0.68 g,
78% (EtOH). IR (KBr): nmax (in cmÀ1) 3269 (NH), 1708 (CO);
1H NMR (d ppm, DMSO-d6): 1.34 (s, 6H, 2CH3), 5.83 (s, 1H,
C(7)H), 6.11 (d, 1H, C(3)H thienyl), 6.32 (d, 1H, C(4)H thienyl),
6.45 (d, 1H, C(5)H thienyl), 8.21 (s, 1H,C(2)H), 9.76 (s, 1H, NH).
13C NMR (d ppm, DMSO-d6): 8.44, 15.90, 56.77, 106.50,
125.70, 126.77, 126.11, 137.32, 150.21, 151.54. MS (m/z %)
= 232 (M+, 45%). Anal. Calcd for C11H12N4S (232.30):
C, 56.87%; H, 5.21%; N, 24.12%. Found: C, 56.95%; H, 5.42%;
N, 24.42%.
[1,5-a]pyrimidin-6-yl)ethanone 9d.
mp 260–267ꢀC; Yield:
0.69 g, 79% (EtOH). IR (KBr): nmax (in cmÀ1) 3286 (NH); H
NMR (d ppm, DMSO-d6): 1.33(s, 3H, CH3), 2.34 (s, 3H, CH3),
2.37 (s, 3H, OCH3), 5.82 (s, 1H, C(7)H), 7.43 (m, 4H, Ph), 8.23
(s, 1H, C(2)H), 9.50 (s, 1H, NH). 13C NMR (d ppm, DMSO-d6):
8.44, 15.90, 32.22, 56.77, 106.50, 114.43, 129.12, 137.32,
138.32, 139.55, 150.21, 151.55. MS (m/z %) = 256 (M+, 62%).
Anal. Calcd for C14H16N4O (256.30): C, 65.61%; H, 6.29%;
N, 21.86%. Found: C, 65.55%; H, 6.34%; N, 21.98%.
1
General procedure for the synthesis of ethyl 5-ethoxy-
4,7-dihydro-7-substituted-[1,2,4]triazolo[1,5-a]pyrimidine-
1-(4,7-Dihydro-5-methyl-7-(p-tolyl)-[1,2,4]triazolo[1,5-a]
pyrimidin-6-yl)ethanone 9e.
mp 255–257ꢀC; Yield: 0.71 g,
6-carboxylate 10a–h.
Aldehyde (1 mmol), diethyl malonate
81% (dioxane). IR (KBr): nmax (in cmÀ1) 3290 (NH); H NMR
(d ppm, DMSO-d6): 1.25 (s, 3H, CH3), 1.97 (s, 3H, CH3), 2.11
(s, 3H, CH3), 5.86 (s, 1H, C(7)H), 7.42 (m, 4H, Ph), 8.25
(s, 1H, C(2)H), 9.67 (s, 1H, NH). 13C NMR (d ppm, DMSO-d6):
8.44, 15.90, 23.11, 56.73, 106.56, 114.43, 129.11, 137.32,
138.39, 141.55, 150.21, 151.59. MS (m/z %) = 240 (M+, 55%).
Anal. Calcd for C14H16N4 (240.30): C, 69.97%; H, 6.71%;
N, 23.32%. Found: C, 69.85%; H, 6.65%; N, 23.44%.
(1mmol), and 5-amino[1,2,4]triazole (1mmol) in ethanol were
heated at 90ꢀC for the appropriate time as mentioned in Table 3.
After the completion of the reaction, as indicated by TLC, the
reaction mixture was concentrated under reduced pressure, and
the resulting solid product was triturated with methanol and
filtered, and recrystallized from proper solvent.
1
Ethyl 5-ethoxy-4,7-dihydro-7-methyl-[1,2,4]triazolo[1,5-a]
pyrimidine-6-carboxylate 10a.
mp 160–162ꢀC; Yield: 0.68 g,
1-(7-(4-(Dimethylamino)phenyl)-4,7-dihydro-5-methyl-[1,2,4]
triazolo[1,5-a]pyrimidin-6-yl)ethanone 9f.
78% (MeOH/H2O). IR (KBr): nmax (in cmÀ1) 3267 (NH), 1713
(CO); 1H NMR (d ppm, DMSO-d6): 1.34 (t, 6H, 2CH3), 2.15
(d, 3H, CH3), 4.10 (q, 4H, 2CH2), 5.40 (q, 1H, C(7)H), 7.79
(s, 1H, C(2)H), 10.57 (s, 1H, NH). 13C NMR (d ppm, DMSO-d6):
8.21, 11.22, 21.62, 23.11, 31.49, 47.77, 112.43, 150.42, 150.90,
151.23, 155.23, 199.12. MS (m/z %) = 280 (M+, 64%). Anal.
Calcd for C12H16N4O4 (280.28): C, 51.42%; H, 5.75%;
N, 19.99%. Found: C, 51.49%; H, 5.88%; N, 19.87%.
mp 285–287ꢀC;
Yield: 0.70 g, 80% (dioxane). IR (KBr): nmax (in cmÀ1) 3287
(NH); 1H NMR (d ppm, DMSO-d6): 1.31 (s, 3H, CH3), 2.12
(s, 3H, CH3), 2.35 (s, 6H, 2CH3), 5.82 (s, 1H, C(7)H), 7.43
(m, 4H, Ph), 8.22 (s, 1H, C(2)H), 9.69 (s, 1H, NH). 13C NMR
(d ppm, DMSO-d6): 8.44, 15.90, 40.12, 56.77, 106.58, 114.43,
129.11, 137.33, 138.32, 141.59, 150.21, 151.86. MS (m/z %) = 269
(M+, 60%). Anal. Calcd for C15H19N5 (269.16): C, 66.89%;
H, 7.11%; N, 26.00%. Found: C, 66.78%; H, 7.24%; N, 26.21%.
1-(4,7-Dihydro-5-methyl-7-(2-nitrophenyl)-[1,2,4]triazolo[1,5-a]
pyrimidin-6-yl)ethanone 9g. mp 280–282ꢀC; Yield: 0.69 g, 79%
Ethyl 5-ethoxy-4,7-dihydro-7-phenyl-[1,2,4]triazolo[1,5-a]
pyrimidine-6-carboxylate 10b.
mp 230–235ꢀC; Yield: 0.84 g,
96% (EtOH). IR (KBr): nmax (in cmÀ1) 3280 (NH), 1707 (CO);
1H NMR (d ppm, DMSO-d6): 1.36 (t, 6H, 2CH3), 4.15
(q, 4H, 2CH2), 5.48 (s, 1H, C(7)H), 7.78 (s, 1H, C(2)H), 7.99
(m, 5H, Ph), 9.99 (s, 1H, NH). 13C NMR (d ppm, DMSO-d6):
8.21, 11.22, 23.11, 31.49, 47.77, 112.43, 125.23, 128.23,
129.13, 137.11, 150.42, 150.90, 151.21, 155.27, 199.12. MS
(m/z %) = 342 (M+, 45%). Anal. Calcd for C17H18N4O4
(342.13): C, 59.64%; H, 5.30%; N, 16.37%. Found: C,
59.77%; H, 5.45%; N, 16.45%.
1
(EtOH). IR (KBr): nmax (in cmÀ1) 3279 (NH); H NMR (d ppm,
DMSO-d6): 1.86 (s, 3H, CH3), 2.32 (s, 3H, CH3), 5.87 (s, 1H, C(7)
H), 7.42 (m, 4H, Ph), 8.23 (s, 1H, C(2)H), 9.67 (s, 1H, NH). 13C
NMR (d ppm, DMSO-d6): 8.44, 15.90, 47.77, 106.51, 128.43,
129.11, 137.32, 138.33, 141.55, 150.21, 151.57. MS (m/z %) = 271
(M+, 49%). Anal. Calcd for C13H13N5 (271.27): C, 57.56%;
H, 4.83%; N, 25.82%. Found: C, 57.64%; H, 4.99%; N, 25.96%.
Table 3
Diethyl malonate as 1,3-dicarbonyl compounds with 3-amino triazole and aldehydea for the synthesis of [1,2,4]triazolo[1,5-a]pyrimidine 10a–h in
refluxing ethanol.b
Entry
Productc
R
R1
R2
Time (h)
mp(ꢀC)
Yield (%)d
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10e
10f
CH3
C6H4
4-Cl-C6H4
4-CH3-C6H4
4-CH3O-C6H4
4-N(CH3)2C6H4
2-NO2C6H4
2-Thienyl
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
5
4
3
4
5
5
5
5
160
237
220
210
217
240
190
230
78
94
89
87
85
87
79
78
10g
10h
aVarious aldehydes (aliphatic, aromatic, and heterocyclic).
bThe reaction occurred in ethanol without any catalyst.
1
cStructural assignments of the products were based on their IR, HNMR, and MS.
dIsolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. A. El Rady
Vol 000
Ethyl 5-ethoxy-(4-chlorophenyl)-4,7-dihydro-[1,2,4]triazolo
[1,5-a]pyrimidine-6-carboxylate 10c. mp 220–222ꢀC; Yield:
0.78 g, 89% (EtOH). IR (KBr): nmax (in cmÀ1) 3288 (NH), 1712
(d ppm, DMSO-d6): 8.21, 11.22, 23.11, 31.49, 47.77, 112.43,
123.23, 126.13, 126.22, 139.11, 150.44, 150.90, 151.21,
155.27, 199.14. MS (m/z %) = 348 (M+, 41%). Anal. Calcd for
C15H16N4O4S (348.09): C, 51.71%; H, 4.63%; N, 16.08%.
Found: C, 51.88%; H, 4.76%; N, 16.22%.
1
(CO); H NMR (d ppm, DMSO-d6): 1.34 (t, 6H, 2CH3), 4.16
(q, 4H, 2CH2), 5.47 (s, 1H, C(7)H), 7.77 (s, 1H, C(2)H), 7.94
(m, 4H, Ph), 10.33 (s, 1H, NH). 13C NMR (d ppm, DMSO-d6):
8.21, 11.22, 23.11, 31.49, 47.77, 112.43, 114.23, 129.13,
138.11, 144.23, 150.44, 150.90, 151.21, 155.27, 199.14. MS
(m/z %) = 376 (M+, 66%). Anal. Calcd for C17H17ClN4O4
(376.79): C, 54.19%; H, 4.55%; N, 14.87%. Found: C,
54.27%; H, 4.76%; N, 14.97%.
REFERENCES AND NOTES
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Ethyl 5-ethoxy-4,7-dihydro-7-(4-methoxyphenyl)-[1,2,4]triazolo
[1,5-a]pyrimidine-6-carboxylate 10d.
mp 217–219ꢀC; Yield:
0.76g, 87% (EtOH). IR (KBr): nmax (in cmÀ1) 3285 (NH), 1709
(CO); 1H NMR (d ppm, DMSO-d6): 1.32 (s, 6H, 2CH3), 2.37
(s, 3H, OCH3), 4.17 (q, 4H, 2CH2), 5.80 (s, 1H, C(7)H), 7.43
(m, 4H, Ph), 8.23 (s, 1H,C(2)H), 9.55 (s, 1H, NH). 13C NMR
(d ppm, DMSO-d6): 8.21, 11.22, 23.11, 31.49, 40.12, 47.77,
112.43, 114.28, 129.11, 138.11, 144.23, 150.44, 150.88, 151.21,
155.27, 199.10. MS (m/z %)= 372 (M+, 64%). Anal. Calcd for
C18H20N4O5 (372.38): C, 58.06%; H, 5.41%; N, 15.05%. Found:
C, 58.26%; H, 5.61%; N, 15.25%.
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[1,5-a]pyrimidine-6-carboxylate 10e.
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mp 210–212ꢀC; Yield:
0.74g, 85% (dioxane/H2O). IR (KBr): nmax (in cmÀ1) 3290
(NH), 1709 (CO); 1H NMR (d ppm, DMSO-d6): 1.35 (t, 6H,
2CH3), 2.30 (s, 3H, CH3), 4.12 (q, 4H, 2CH2), 5.83 (s, 1H, C(7)
H), 7.45 (m, 4H, Ph), 8.24 (s, 1H,C(2)H), 9.56 (s, 1H, NH). 13C
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Calcd for C18H20N4O4 (356.38): C, 60.66%; H, 5.66%; N,
15.72%. Found: C, 60.56%; H, 5.77%; N, 15.84%.
Ethyl 5-ethoxy-7-(4-(dimethylamino)phenyl)-4,7-dihydro-[1,2,4]
triazolo[1,5-a] pyrimidine-6-carboxylate 10f.
mp 240–242ꢀC;
Yield: 0.76 g, 87% (EtOH). IR (KBr): nmax (in cmÀ1) 3287 (NH),
1
1707 (CO); H NMR (d ppm, DMSO-d6): 1.31 (t, 6H, 2CH3),
2.35 (s, 6H, 2CH3), 4.12 (q, 4H, 2CH2), 5.82 (s, 1H, C(7)H), 7.43
(m, 4H, Ph), 8.22 (s, 1H, C(2)H), 9.69 (s, 1H, NH). 13C NMR (d
ppm, DMSO-d6): 8.21, 11.22, 23.11, 31.49, 40.56, 47.77, 112.43,
114.23, 128.13, 140.11, 144.23, 150.44, 150.90, 151.21, 155.27,
199.19. MS (m/z %)= 385 (M+, 60%). Anal. Calcd for C15H19N5
(385.42): C, 59.21%; H, 6.01%; N, 18.17%. Found: C, 65.21%;
H, 6.21%; N, 18.31%.
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[1,5-a]pyrimidine-6-carboxylate 10g.
mp 190–192ꢀC; Yield:
0.69 g, 79% (EtOH). IR (KBr): nmax (in cmÀ1) 3279 (NH), 1709
(CO); 1H NMR (d ppm, DMSO-d6): 1.81 (t, 6H, 2CH3), 4.10
(q, 4H, 2CH2), 5.87 (s, 1H, C(7)H), 7.42 (m, 4H, Ph), 8.23
(s, 1H, C(2)H), 9.67 (s, 1H, NH). 13C NMR (d ppm, DMSO-d6):
8.21, 11.22, 23.13, 31.49, 47.70, 112.43, 114.23, 129.13,
138.19, 144.22, 150.44, 150.90, 151.11, 155.27, 199.21. MS
(m/z %) = 387 (M+, 48%). Anal. Calcd for C17H17N5O6
(387.35): C, 52.71%; H, 4.42%; N, 18.08%. Found: C, 52.66%;
H, 4.56%; N, 18.24%.
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0.68 g, 78% (MeOH). IR (KBr): nmax (in cmÀ1) 3279 (NH),
1
1709 (CO); H NMR (d ppm, DMSO-d6): 1.34 (t, 6H, 2CH3),
4.16 (q, 4H, 2CH2), 5.87 (s, 1H, C(7)H), 6.23 (d, 1H, C(3)
H
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H
thienyl), 8.11 (s, 1H,C(2)H), 9.69 (s, 1H, NH). 13C NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Three-Component One-Pot Synthesis of [1,2,4]Triazolo[1,5-a]pyrimidine
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet