Synthesis of novel 2-methyl and 2-cyanomethyl-12-aryl-8,12-dihydro-9Hchromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-11(10H )-one derivatives

Article abstract of DOI:10.3184/174751915X14190040330104

2-Methyl and 2-cyanomethyl-12-aryl-8,12-dihydro-9H-chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-11(10H )-one derivatives were synthesised by the cyclisations of acetic anhydride or ethyl cyanoacetate with chromeno[2,3-d]pyrimidine derivatives, which wer

Full text of DOI:10.3184/174751915X14190040330104

30 RESEARCH PAPER
VOL. 39 JANUARY, 30–35
JOURNAL OF CHEMICAL RESEARCH 2015
Synthesis of novel 2‑methyl and 2‑cyanomethyl‑12‑aryl‑8,12‑dihydro‑9H‑
chromeno[3,2‑e][1,2,4]triazolo[1,5‑c]pyrimidin‑11(10H)‑one derivatives
Bei Lia, Zhong-Xia Wangb, Zheng Xingc, Li-Zhuang Chena and Guang-Fan Hana,c*
aDepartment of Applied Chemistry, School of Environmental and Chemical Engineering, Jiangsu University of Science &Technology, Zhenjiang,
Jiangsu 212003, P.R. China
bOrdered Matter Science Research Center, Southeast University, Nanjing 211189, P.R. China
cZhenjiang College, Zhenjiang, Jiangsu 212003, P.R. China
2-Methyl and 2-cyanomethyl-12-aryl-8,12-dihydro-9H-chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-11(10H )-one derivatives
were synthesised by the cyclisations of acetic anhydride or ethyl cyanoacetate with chromeno[2,3-d]pyrimidine derivatives,
which were obtained by the reactions of hydrazine monohydrate and formimidate derivatives. In addition, 2,9,9-trimethyl-
12-(p-tolyl)-8,12-dihydro-9H-chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-11(10H )-one and 2-cyanomethyl-12-phenyl-
8,12-dihydro-9H-chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-11(10H )-one were further determined by single-crystal X-ray
diffraction analysis.
Keywords: chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-11(10H)-one, formimidate, synthesis of triazolopyrimidines
Much attention has been paid to the synthesis of various
triazolopyrimidines1–4 due to their pharmacological properties
such as antibacterial, antioxidant and antimalarial activities.5–7
The antioxidants that scavenge reactive oxygen species may
be of great value in preventing the onset and propagation of
oxidative diseases like autoimmune diseases, cardiovascular
diseases, neurovascular diseases and neurodegenerative
changes associated with ageing.8 Chromene and its derivatives
are also biologically interesting molecules which have
antimicrobial, antifungal, antileishmanial, antitumour,
hypotensive, local anaesthetic, antiallergenic, central nervous
system activities, as well as being used in the treatment of
Alzheimer’s disease and bipolar disorder.9,10
Results and discussion
The synthetic route of the title compounds are shown in
Scheme 1. The ethyl N-(3-cyano-5-oxo-4-aryl-5,6,7,8-
tetrahydro-4H-chromen-2-yl)formimidate
derivatives
1
were prepared by the method reported in the literature.11
Cyclisation of 3-amino-5-aryl-4-imino-3,4,8,9-tetrahydro-5H-
chromeno[2,3-d]pyrimidin-6(7H)-one intermediates 2 with
acetic anhydride or ethyl cyanoacetate afforded 2-methyl-12-
aryl-8,12-dihydro-9H-chromeno[3,2-e][1,2,4]triazolo[1,5-c]
pyrimidin-11(10H)-one derivatives 3 or 2-cyanomethyl-12-
aryl-8,12-dihydro-9H-chromeno[3,2-e][1,2,4]triazolo[1,5-c]
pyrimidin-11(10H)-one derivatives 4, respectively. The key
intermediates 2 were synthesised by the reaction of compounds
1 with 99% hydrazine monohydrate in ethanol at 0–5 °C. The
melting points and yields of compounds 3 and 4 are shown in
Tables 1 and 2, respectively.
In continuation of our previous works, we synthesised a
series of novel analogues of 2-methyl and 2-cyanomethyl-12-
aryl-8,12-dihydro-9H-chromeno[3,2-e][1,2,4]triazolo[1,5-c]
pyrimidin-11(10H)-one derivatives.
R1
R1
H
C
O
O
O
CN
R
R
R
R
NC
CN
NH2
O
1'
O
C
H
R1
(
O
E
t
)
3
O
N
N
R1
R1
N
R
R
N
O
3
O
NH
O
O
c 2
NH2
A
N
C
NH2NH2
N
R1
R
R
R
R
N
O
2
N=CHOEt
O
1
N
C
C
H
CN
2 C
O
O
N
N
O
E
t
N
N
R
R
O
4
Scheme 1
* Correspondent. E-mail: gf552002@163.com

JOURNAL OF CHEMICAL RESEARCH 2015 31
Table 1 Synthesis of 2-methyl-12-aryl-8,12-dihydro-9H-chromeno[3,2-e]
[1,2,4]triazolo[1,5-c]pyrimidin-11(10H )-one derivatives 3a–ia
Table 2 Synthesis of 2-cyanomethyl-12-aryl-8,12-dihydro-9H-chromeno
[3,2-e] [1,2,4]triazolo[1,5-c]pyrimidin-11(10H )-one derivatives 4a–fa
Entry
R1
R
M.p./°C
Yield/%b
Entry
R1
R
M.p./°C
Yield/%b
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
210–212
214–216
158–160
206–208
230–232
172–174
162–164
246–248
206–208
70
73
80
65
81
67
65
60
70
4a
4b
4c
4d
4e
4f
H
CH3
CH3
CH3
CH3
CH3
H
200–202
180–182
196–198
174–176
196–198
198–200
70
68
76
72
77
65
4-OCH3
3,4-(OCH3)2
3-NO2
4-CH3
2,4-Cl2
2-Cl
4-OCH3
4-CH3
2,4-Cl2
2-Cl
H
aReaction conditions: 10 mL ethanol, 1 mmol compounds 2, 2 mmol ethyl
2,4-Cl2
H
cyanoacetate, reflux.
bIsolated yield.
H
aReaction conditions: 1 mmol compounds 2, 10 mL acetic anhydride, reflux.
bIsolated yield.
Iminoethers are known to react with compounds
containing –NH2 moiety such as hydrazides.12,13 Because there
are mainly two reactive sites of iminoethers 1, the cyano group
and the imidic group, these make them susceptible to react with
hydrazides in absolute ethanol to give the key intermediates.
As shown in Scheme 2, three plausible pathways and different
products are possible.
(1) Successive two nucleophilic additions of –NH2 group
on the imidic carbon and on the cyano function to yield
compounds 2.
(2) Compound 1 in absolute ethanol with 99% hydrazine
monohydrate at reflux afforded 4-hydrazinyl-5-aryl-8,9-
dihydro-5H-chromeno[2,3-d]pyrimidin-6(7H)-one derivatives
2′. In addition, compound 2 may also undergo Dimroth
rearrangement in absolute ethanol at reflux to give the more
stable isomer 2′. Because of the synthesis rate of compound 2
is higher than isomer 2′, iminoethers 1 react with hydrazine
monohydrate more easily to give intermediate 2 at a lower
temperature.14
(3) Upon hydrazinolysis of compounds 1 using excess 99%
hydrazine monohydrate instead of equimolar amounts, the
raw material 2-amino-5-oxo-4-aryl-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile derivatives 1′ was recovered. This
may be attributed to the reaction of one mole of hydrazine
monohydrate with the iminoether 1, followed by elimination
of ethyl formate hydrazone rather than cyclisation to give the
pyrimidine ring.15
For studying the optimal reaction for the synthesis of
compounds 3, we have selected 3-amino-5-phenyl-4-imino-
3,4,8,9-tetrahydro-5H-chromeno[2,3-d]pyrimidin-6(7H)-
one 2f as the raw material. First we examined the reaction
of the compound 2f and acetic anhydride at low temperature
in ethanol. However, no reaction was observed. When the
reaction was at reflux, compound 2f underwent Dimroth
rearrangement to give 4-hydrazinyl-5-phenyl-8,9-dihydro-
5H-chromeno[2,3-d]pyrimidin-6(7H)-one 2′f. The structure
of isomer 2′f was characterised by IR, 1H NMR and elemental
analysis. Finally we observed that by using acetic anhydride as
a solvent at reflux, the reaction gave a good yield.
Encouraged by these results, we tried using ethyl
cyanoacetate as the solvent to synthesise compound 4, but its
characteristics, such as its high boiling point, make it hard
to evaporate from the reaction, so we used ethanol instead.
By constantly experimenting with the mole ratio of ethyl
cyanoacetate, compound 2f and ethanol, we observed that
1:2:10 is the optimal mole ratio to yield compound 4f.
R1
NHNH2
N
O
R
R
N
O
2'
E
t
O
2
H
N
H
2
,
H
x
r
e
f
u
l
N
f
e
l
u
r
x
,
H
O
t
E
R1
R1
NH
O
O
NH2NH2
NH2
N
C
N
–
EtOH, 0 5 C
°
R
R
R
R
N
O
O
N=CHOEt
1
2
N
E
H
2 N
H
R1
2
(
e
x
c
t
O
e
s
s
H
)
O
CN
R
R
NH2
O
1'
Scheme 2

32 JOURNAL OF CHEMICAL RESEARCH 2015
Synthesis of 2-methyl-12-aryl-8,12-dihydro-9H-chromeno [3,2-e]
[1,2,4]triazolo[1,5-c]pyrimidin-11(10H)-one derivatives (3a–i);
general procedure
A mixture of compounds 2 (1 mmol) and acetic anhydride (10 mL) was
heated to reflux for 6 h. After cooling, the precipitate were filtered
off, washed with ethanol, and recrystallised from ethanol to afford
compound 3.
The structure of compound 2′f was confirmed by IR spectra
with characteristic absorption bands of 1665 cm–1 for (C=O),
3323, 3394 for (–NH, –NH2). The structure of this compound
was further confirmed by 1H NMR. In the 1H NMR spectrum
of compound 2′f, a sharp single proton peak at δ 4.72 attributes
to the characteristic absorption proton peak of 5-H.
1
The data of IR, H NMR, elemental analysis shown in the
experimental section are in accordance with the chemical
structures of the target compounds. The structure of compound
3h was confirmed by IR spectra with characteristic absorption
bands of 1663 cm–1 for C=O, 2873, 2957 cm–1 for –CH3, and
3073 cm–1 for aromatic-H. The structure of this compound was
further confirmed by H NMR. In the H NMR spectrum of
compound 3h, a sharp single proton peak at δ 5.67 is attributed
to the characteristic absorption proton peak of 12-H.
Synthesis of 2-cyanomethyl-12-aryl-8,12-dihydro-9H-chromeno [3,2-
e][1,2,4]triazolo[1,5-c]pyrimidin-11(10H)-one derivatives (4a–f);
general procedure
A mixture of compounds 2 (1 mmol) and ethyl cyanoacetate (2 mmol)
in absolute ethanol (10 mL) was heated to reflux for 4 h, the reaction
progress was monitored by TLC. After cooling, the solid formed
was collected, and then purified by silica gel flash chromatography
using ethyl acetate/petroleum ether (2:1) as eluent to obtain pure
2-cyanomethyl-12-aryl-8,12-dihydro-9H-chromeno[3,2-e][1,2,4]
triazolo[1,5-c]pyrimidin-11(10H)-one derivatives 4.
1
1
The structure of compound 4d was confirmed by IR spectra
which showed characteristic absorption bands of 1663 cm–1 for
(C=O), 2255 cm–1 for (C≡N), 2881, 2965 cm–1 for (–CH3), and
3065 cm–1 for (aromatic-H), and the structure of this compound
Single-crystal X-ray crystallography
1
1
X-ray diffraction experiments were carried out using Bruker
SMART APEX CCD with MoKα radiation (λ=0.71073 Å) at
291(2) K. Data collection, cell refinement, and data reduction were
performed by using the CrystalClear software package. Absorption
corrections were applied using SADABS.16 The structures were solved
by direct methods using SHELXS-9717–18 and refined by full-matrix
least-squares methods anisotropically for non-hydrogen atoms using
SHELXL-97. Calculations were performed on a personal computer
with the Siemens SHELXTL program package. Crystallographic
data (excluding structure factors) for the structures in this paper have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication CCDC Nos. 1022159 for 3e, 1022673 for 4f.
The single crystal structure of 3e was determined by single-crystal
X-ray diffraction analysis (Figs 1 and 2) and the crystal data and
structure refinement are summarised in Table 3. The dihedral angle
between the least-squares pyrimidine ring and the least-squares
plane of the triazole ring in complex 3e is 2.972(78)°. Furthermore,
the dihedral angle between the least-squares pyran ring and the least-
squares plane of the cyclohexane ring is 14.086(87)°. The molecular
packing of 3e is further stabilised by intermolecular H-bond between
O(2) atoms and C(10) atoms of the neighbouring molecule.
further determined by H NMR. In the H NMR spectrum of
compound 4d, a sharp single proton peak at δ 5.67 was the
characteristic absorption proton peak of 12-H.
Conclusion
The present study affords a series of novel 2-methyl-12-
aryl-8,12-dihydro-9H-chromeno[3,2-e][1,2,4]triazolo[1,5-c]
pyrimidin-11(10H)-one derivatives 3 and 2-cyanomethyl-12-
aryl-8,12-dihydro-9H-chromeno[3,2-e][1,2,4]triazolo[1,5-c]
pyrimidin-11(10H)-onederivatives4bythereactionof3-amino-
5-aryl-4-imino-3,4,8,9-tetrahydro-5H-chromeno[2,3-d]
pyrimidin-6(7H)-one derivatives 2 with acetic anhydride
and ethyl cyanoacetate respectively in good yields. This
methodology is of interest due to the use of acetic anhydride
as solvent without any other organic solvent nor toxic metals as
catalyst, thus minimising the cost, the operational hazards and
the environmental pollution.
Experimental
Melting points were determined by an electrothermal apparatus and
the temperature was uncorrected. Microanalysis was performed
by the PerkinElmer 2400 Microanalytical Service. IR spectra were
obtained on a PerkinElmer 1700 spectrophotometer. 1H NMR spectra
were recorded on a Bruker ARX-400 instrument. All reactions were
monitored by TLC, which carried out on 0.2 mm silica GF254 (Merck)
plates using UV light (254 and 365 nm) for detection.
Crystal data for 3e: C22H22N4O2, Mw =374.44, monoclinic P21,
a= 5.662(3) Å, b=16.271(10) Å, c= 10.324(6) Å, V = 942.6(10)
Table 3 Crystallographic data for compounds 3e and 4f
3e
4f
Empirical formula
Formula weight
Wavelength/nm
Crystal system
C22H22N4O2
374.44
0.71073
Monoclinic
P 21
C20H15N5O2
357.37
0.71073
Triclinic
P 1
Space group
a/Å
b/Å
5.662(3)
16.271(10)
10.324(6)
90.00
97.696(7)
90.00
7.143(2)
9.347(3)
13.445(5)
98.246(4)
104.990(4)
99.722(4)
838.0(5)
2
c/Å
α/(o)
β/(o)
γ/(o)
Volume/Å3
942.6(10)
2
Z
Calculated density/g·cm–3
Absorption coefficient/mm–1
F (000)
1.319
0.087
396
1.416
0.096
372
R1 =0.0372,
R1 =0.0442,
Final R indices [I>2sigma(I)]
R indices (all data)
wR2 =0.0798
wR2 = 0.1290
R1 =0.0500,
wR2 =0.0873
R1 =0.0647,
wR2 = 0.1481
Fig. 1 Molecular structure of compound 3e.

JOURNAL OF CHEMICAL RESEARCH 2015 33
Fig. 2 Packing diagram of compound 3e in unit-cell along a axis.
Å3, Z=2, Dc =1.319 g cm−3, R1 (I > 2σ) = 0.0372, wR 2 =0.0873,
μ = 0.087 m m−1, S=0.992.
The single crystal structure of 4f was determined by single-crystal
X-ray diffraction analysis (Figs 3 and 4) and the crystal data and
structure refinement are summarised in Table 3. The dihedral angle
between the least-squares pyrimidine ring and the least-squares plane
of the triazole in complex 4f is 1.085(59)°. Furthermore, the dihedral
angle between the least-squares pyran ring and the least-squares plane
of the cyclohexane ring is 5.273(61)°.
Crystal data for 4f: C20H15N5O2, Mw =357.37, Triclinic P1, a=7.143(2)
Å, b= 9.347(3) Å, c= 13.445(5) Å, V = 838.0(5) Å 3, Z=2, Dc =1.416 g
cm−3, R1 (I > 2σ) = 0.0442, wR 2 = 0.1481, μ = 0.096 m m−1, S=0.990;
4-Hydrazinyl-5-phenyl-8,9-dihydro-5H-chromeno[2,3-d]
pyrimidin-6(7H)-one (2′f): Yield 55%; m.p. 162–164 °C. IR (KBr, ν,
1
cm–1): 3394, 3323, 1665; H NMR (CDCl3, 400 MHz) δ 1.93–2.03 (m,
2H, C8-H), 2.32–2.36 (m, 2H, C9-H), 2.64–2.70 (m, 2H, C7-H), 4.72
(s, 1H, C5-H),4.76 (s, 2H, –NH2), 7.16–7.35 (m, 5H, PhH), 8.00 (s, 1H,
Fig. 3 Molecular structure of compound 4f.
Fig. 4 Packing diagram of compound 4f in unit-cell along b axis.

34 JOURNAL OF CHEMICAL RESEARCH 2015
C2-H). Anal. calcd for C17H16N4O2: C, 66.22; H, 5.23; N, 18.17; found:
C, 66.35; H, 5.14; N, 18.08%.
1H, 12‑6′‑H), 7.21–7.24 (m, 2H, 12‑(4′+5′)‑H), 7.61–7.63 (d, J=7.6 Hz,
1H, 12‑3′‑H), 8.99 (s, 1H, C5-H). Anal. calcd for C21H19ClN4O2: C,
63.88; H, 4.85; N, 14.19; found: C, 63.75; H, 4.81; N, 14.35%.
2,9,9-Trimethyl-12-phenyl-8,12-dihydro-9H-chromeno[3,2-e]
[1,2,4]triazolo[1,5-c]pyrimidin-11(10H)-one (3a): Yield
70%; m.p. 210–212 °C. IR (KBr, ν, cm–1): 3073, 2965, 2890, 1646;
1H NMR(CDCl3, 400 MHz) δ 1.09 (s, 3H, –CH3), 1.15 (s, 3H, –CH3),
2.24–2.35 (dd, J1 =16.2 Hz, J2 =24.3 Hz, 2H, C8-H), 2.53 (s, 3H, –CH3),
2.62–2.72 (dd, J1 =18.6 Hz, J2 =23.0 Hz, 2H, C10-H), 5.47 (s, 1H,
C12-H), 7.14–7.18 (t, J=7.3 Hz, 1H, 12‑4′‑H), 7.24–7.27 (m, 2H, 12‑
(2′+6′)‑H), 7.42–7.44 (d, J=7.3 Hz, 2H, 12‑(3′+5′)‑H), 8.97 (s, 1H,
C5-H). Anal. calcd for C21H20N4O2: C, 69.98; H, 5.59; N, 15.55; found:
C, 69.75; H, 5.68; N, 15.66%.
12- (2,4 - Dichlorophe nyl)-2- me thyl- 8 ,12- dihydro -9H-
chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-11(10H)-one
(3h):
Yield 60%; m.p. 246–248 °C. IR (KBr, ν, cm–1): 3073, 2957, 2873,
1663; 1H NMR(CDCl3, 400 MHz) δ 2.08–2.12 (m, 2H, C9-H)),
2.40–2.44 (m, 2H, C8-H)), 2.51 (s, 3H, –CH3), 2.75–2.85 (m, 2H,
C10-H), 5.67 (s, 1H, C12‑H), 7.20–7.23 (m, 1H, 12‑6′‑H), 7.25 (m, 1H,
12‑5′‑H), 7.57–7.59 (d, J=8.3 Hz, 1H, 12‑3′‑H), 9.00 (s, 1H, C5-H).
Anal. calcd for C19H14Cl2N4O2: C, 56.87; H, 3.52; N, 13.96; found: C,
56.98; H, 3.61; N, 13.81%.
12-(4-Methoxyphenyl)-2,9,9-trimethyl-8,12-dihydro-9H-
2-Methyl-12-phenyl-8,12-dihydro-9H-chromeno[3,2-e][1,2,4]
triazolo[1,5-c]pyrimidin-11(10H)-one (3i): Yield 70%; m.p. 206–208 °C.
IR (KBr, ν, cm–1): 3081, 2961, 2884, 1648; 1H NMR(CDCl3, 400 MHz)
δ 2.10–2.13 (m, 2H, C9-H)), 2.40–2.46 (m, 2H, C8-H)), 2.53 (s,
3H, –CH3), 2.77–2.89 (m, 2H, C10-H), 5.51 (s, 1H, C12-H), 7.14–7.18 (t,
J=7.3 Hz, 1H, 12‑4′‑H), 7.23–7.27 (m, 2H, 12‑(2′+6′)‑H), 7.42–7.44
(d, J=7.2 Hz, 2H, 12‑(3′+5′)‑H), 8.98 (s, 1H, C5-H). Anal. calcd for
C19H16N4O2: C, 68.66; H, 4.85; N, 16.86; found: C, 68.88; H, 4.79; N,
16.61%.
2-Cyanomethyl-9,9-dimethyl-12-phenyl-8,12-dihydro-9H-
chromeno[3,2-e][1,2,4]triazolo [1,5-c]pyrimidin-11(10H)-one (4a):
Yield 70%; m.p. 200–202 °C. IR (KBr, ν, cm–1): 2954, 2907, 2859,
2249, 1658; 1H NMR(CDCl3, 400 MHz) δ 1.11 (s, 3H, –CH3),
1.16 (s, 3H, –CH3), 2.26–2.36 (dd, J1 =16.4 Hz, J2 =22.8 Hz, 2H,
C8-H), 2.64–2.74 (dd, J1 =17.9 Hz, J2 =24.8 Hz, 2H, C10-H), 3.99 (s,
2H, –CH2CN), 5.46 (s, 1H, C12-H), 7.14–7.18 (t, J=7.3 Hz, 1H, 12‑4′‑
H), 7.24–7.28 (m, 2H, 12‑(2′+6′)‑H), 7.40–7.42 (d, J=7.3 Hz, 2H, 12-
(3′+5′)‑H), 9.06 (s, 1H, C5-H). Anal. calcd for C22H19N5O2: C, 68.56; H,
4.97; N, 18.17; found: C, 68.78; H, 4.87; N, 18.01%.
chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-11(10H)-one
(3b):
Yield 73%; m.p. 214–216 °C. IR (KBr, ν, cm–1): 3082, 2973, 2890, 1696;
1H NMR(CDCl3, 400 MHz) δ 1.09 (s, 3H, –CH3), 1.15 (s, 3H, –CH3),
2.24–2.34 (dd, J1 =16.4 Hz, J2 =24.0 Hz, 2H, C8-H), 2.54 (s, 3H, –CH3),
2.61–2.71 (dd, J1 =18.5 Hz, J2 =21.7 Hz, 2H, C10-H), 3.73 (s, 3H,
12-OCH3), 5.42 (s, 1H, C12-H), 6.77–6.79 (d, J=8.7 Hz, 2H, 12‑(3′+5′)‑
H), 7.33–7.35 (d, J=8.7 Hz, 2H, 12‑(2′+6′)‑H), 8.98 (s, 1H, C5-H).
Anal. calcd for C22H22N4O3: C, 67.68; H, 5.68; N, 14.35; found: C, 67.79;
H, 5.59; N, 14.21%.
12-(3,4-Dimethoxyphenyl)-2,9,9-trimethyl-8,12-dihydro-9H-
chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-11(10H)-one
(3c): Yield 80%; m.p. 158–160 °C. IR (KBr, ν, cm–1): 3073, 2965,
1
2840, 1688; H NMR(CDCl3, 400 MHz) δ 1.12 (s, 3H, –CH3), 1.16
(s, 3H, –CH3), 2.27–2.36 (dd, J1 =16.3 Hz, J2 =21.2 Hz, 2H, C8-H),
2.55 (s, 3H, –CH3), 2.63–2.72 (t, J=18.5 Hz, 2H, C10-H), 3.79 (s, 3H,
12-OCH3), 3.89 (s, 3H, 12-OCH3), 5.43 (s, 1H, C12-H), 6.71–6.74
(d, J=8.3 Hz, 1H, 12‑6′‑H), 6.82–6.84 (m, 1H, 12‑5′‑H), 7.14–7.15
(d, J=2.0 Hz, 1H, 12‑2′‑H), 8.97 (s, 1H, C5-H). Anal. calcd for
C23H24N4O4: C, 65.70; H, 5.75; N, 13.33; found: C, 65.95; H, 5.68; N,
13.19%.
12-(4-Methoxyphenyl)-2-cyanomethyl-9,9-dimethyl-8,12-dihydro-
9H-chromeno[3,2-e][1,2,4]triazolo [1,5-c]pyrimidin-11(10H)-one (4b):
Yield 68%; m.p. 180–182 °C. IR (KBr, ν, cm–1): 3077, 2920, 2827,
2,9,9-Trimethyl-12-(3-nit rophenyl)- 8,12- dihydro -9H-
chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-11(10H)-one
(3d): Yield 65%; m.p. 206–208 °C. IR (KBr, ν, cm–1): 3082, 2948,
1
2262, 1647; H NMR(CDCl3, 400 MHz) δ 1.11 (s, 3H, –CH3), 1.16
(s, 3H, –CH3), 2.25–2.35 (dd, J1 =16.3 Hz, J2 =22.1 Hz, 2H, C8-H),
2.63–2.73 (dd, J1 =17.8 Hz, J2 =23.6 Hz, 2H, C10-H), 3.73 (s, 3H,
12-OCH3), 3.99 (s, 2H, –CH2CN), 5.41 (s, 1H, C12-H), 6.77–6.80 (d,
J=8.7 Hz, 2H, 12‑(3′+5′)‑H), 7.31–7.33 (d, J=8.8 Hz, 2H, 12‑(2′+6′)‑
H), 9.05 (s, 1H, C5-H). Anal. calcd for C23H21N5O3: C, 66.49; H, 5.09; N,
16.86; found: C, 66.63; H, 5.01; N, 16.58%.
1
2823, 1688; H NMR(CDCl3, 400 MHz) δ 1.11 (s, 3H, –CH3), 1.17 (s,
3H, –CH3), 2.26–2.37 (dd, J1 =16.3 Hz, J2 =27.7 Hz, 2H, C8-H), 2.53
(s, 3H, –CH3), 2.66–2.78 (dd, J1 =17.8 Hz, J2 =28.9 Hz, 2H, C10-H),
5.57 (s, 1H, C12-H), 7.44–7.48 (t, J=7.9 Hz, 1H, 12‑5′‑H), 7.93–7.95 (d,
J=7.7 Hz, 1H, 12‑6′‑H), 8.03–8.05 (d, J=8.2 Hz, 1H, 12‑4′‑H), 8.17 (s,
1H, 12‑2′‑H), 9.02 (s, 1H, C5-H). Anal. calcd for C21H19N5O4: C, 62.22;
H, 4.72; N, 17.27; found: C, 62.48; H, 4.81; N, 17.05%.
2-Cyanomethyl-9,9-dimethyl-12-(p-tolyl)-8,12-dihydro-9H-
chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-11(10H)-one (4c):
Yield 76%; m.p. 196–198 °C. IR (KBr, ν, cm–1): 3056, 2920, 2877,
2,9,9-Trimethyl-12-(p-tolyl)-8,12-dihydro-9H-chromeno[3,2-e][1,2,4]
triazolo[1,5-c]pyrimidin-11(10H)-one (3e): Yield 81%; m.p. 230–232 °C.
IR (KBr, ν, cm–1): 3056, 2957, 2840, 1688; 1H NMR(CDCl3,
400 MHz) δ 1.09 (s, 3H, –CH3), 1.15 (s, 3H, –CH3), 2.24 (s, 3H,
12-CH3), 2.24–2.34 (dd, J1 =14.5 Hz, J2 =22.9 Hz, 2H, C8-H), 2.53 (s,
3H, –CH3), 2.62–2.72 (dd, J1 =18.4 Hz, J2 =22.3 Hz, 2H, C10-H), 5.44
(s, 1H, C12-H), 7.05–7.07 (d, J=7.9 Hz, 2H, 12‑(3′+5′)‑H), 7.31–7.33
(d, J=8.1 Hz, 2H, 12‑(2′+6′)‑H), 8.97 (s, 1H, C5-H). Anal. calcd for
C22H22N4O2: C, 70.57; H, 5.92; N, 14.96; found: C, 70.43; H, 5.87; N,
15.13%.
1
2262, 1654; H NMR(CDCl3, 400 MHz) δ 1.11 (s, 3H, –CH3), 1.16
(s, 3H, –CH3), 2.25 (s, 3H, 12-CH3), 2.25–2.35 (dd, J1 =18.0 Hz,
J2 =24.7 Hz, 2H, C8-H), 2.63–2.74 (dd, J1 =17.8 Hz, J2 =24.3 Hz,
2H, C10-H), 3.99 (s, 2H, –CH2CN), 5.42 (s, 1H, C12-H), 7.05–7.07 (d,
J=7.9 Hz, 2H, 12‑(3′+5′)‑H), 7.29–7.31 (d, J=8.1 Hz, 2H, 12‑(2′+6′)‑
H), 9.05 (s, 1H, C5-H). Anal. calcd for C23H21N5O2: C, 69.16; H, 5.30; N,
17.53; found: C, 69.43; H, 5.15; N, 17.32.
12-(2,4-Dichlorophenyl)-2-cyanomethyl-9,9-dimethyl-8,12-dihydro-
9H-chromeno[3,2-e][1,2,4]triazolo [1,5-c]pyrimidin-11(10H)-one (4d):
Yield 72%; m.p. 174–176 °C. IR (KBr, ν, cm–1): 3065, 2965, 2881,
12-(2,4-Dichlorophenyl)-2,9,9-trimethyl-8,12-dihydro-9H-
1
chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-11(10H)-one
(3f):
2255, 1663; H NMR(CDCl3, 400 MHz) δ 1.10 (s, 3H, –CH3), 1.16 (s,
Yield 67%; m.p. 172–174 °C. IR (KBr, ν, cm–1): 3073, 2981, 2890, 1646;
1H NMR(CDCl3, 400 MHz) δ 1.10 (s, 3H, –CH3), 1.15 (s, 3H, –CH3),
2.23–2.33 (dd, J1 =16.4 Hz, J2 =26.7 Hz, 2H, C8-H), 2.50 (s, 3H, –CH3),
2.64 (s, 2H, C10-H), 5.66 (s, 1H, C12‑H), 7.20–7.22 (m, 1H, 12‑6′‑H),
7.25–7.27 (m, 1H, 12‑5′‑H), 7.55–7.58 (d, J=8.2 Hz, 1H, 12‑3′‑H),
9.01 (s, 1H, C5-H). Anal. calcd for C21H18Cl2N4O2: C, 58.75; H, 4.23; N,
13.05; found: C, 58.45; H, 4.28; N, 13.40%.
3H, –CH3), 2.24–2.34 (dd, J1 =16.4 Hz, J2 =25.2 Hz, 2H, C8-H), 2.65 (s,
2H, C10-H), 3.96 (s, 2H, –CH2CN), 5.67 (s, 1H, C12-H), 7.19–7.22 (m,
1H, 12‑6′‑H), 7.26–7.27 (m, 1H, 12‑5′‑H), 7.50–7.52 (d, J=8.2 Hz, 1H,
12‑3′‑H), 9.10 (s, 1H, C5-H). Anal. calcd for C22H17Cl2N5O2: C, 58.16; H,
3.77; N, 15.42; found: C, 58.42; H, 3.68; N, 15.18%.
12-(2-Chlorophenyl)-2-cyanomethyl-9,9-dimethyl-8,12-dihydro-9H-
chromeno[3,2-e][1,2,4]triazolo [1,5-c]pyrimidin-11(10H)-one (4e):
Yield 77%; m.p. 196–198 °C. IR (KBr, ν, cm–1): 3332, 2994, 2838,
2010, 1665; 1H NMR(CDCl3, 400 MHz) δ 1.10 (s, 3H, –CH3),
1.16 (s, 3H, –CH3), 2.23–2.33 (dd, J1 =16.3 Hz, J2 =24.0 Hz, 2H,
C8-H), 2.61–2.70 (dd, J1 =18.7 Hz, J2 =20.6 Hz, 2H, C10-H), 3.95
(m, 2H, –CH2CN), 5.72 (s, 1H, C12‑H), 7.12–7.16 (m, 1H, 12‑6′‑H),
7.23–7.26 (m, 2H, 12‑(4′+5′)‑H), 7.56–7.58 (d, J=7.4 Hz, 1H, 12‑3′‑H),
12-(2-Chlorophenyl)-2,9,9-trimethyl-8,12-dihydro-9H-
chromeno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-11(10H)-one
(3g):
Yield 65%; m.p. 162–164 °C. IR (KBr, ν, cm–1): 3067, 2953, 2873, 1665;
1H NMR(CDCl3, 400 MHz) δ 1.10 (s, 3H, –CH3), 1.15 (s, 3H, –CH3),
2.22–2.33 (dd, J1 =16.3 Hz, J2 =26.2 Hz, 2H, C8-H), 2.49 (s, 3H, –CH3),
2.60–2.69 (t, J=19.1 Hz, 2H, C10-H), 5.71 (s, 1H, C12-H), 7.10–7.14 (m,

JOURNAL OF CHEMICAL RESEARCH 2015 35
9.08 (s, 1H, C5-H). Anal. calcd for C22H18ClN5O2: C, 62.93; H, 4.32; N,
16.68; found: C, 62.68; H, 4.39; N, 16.91%.
4
P.G. Baraldi, M.A. Tabrizi, R. Romagnoli, H. El-Kashef, D. Preti, A.
Bovero, F. Fruttarolo, M. Gordalisa and P.A. Borea, Curr. Org. Chem.,
2006, 10, 259.
A. Zarguil, S. Boukhris, M.L. El Efrit, A. Souizi and E.M. Essassi,
Tetrahedron Lett., 2008, 49, 5883.
T. Okamura, Y. Kurogi, K. Hashimoto, H. Nishikawa and Y. Nagao,
Bioorg. Med. Chem. Lett., 2004, 14, 2443.
A.V. Dolzhenko, G. Pastorin, A.V. Dolzhenko and W.K. Chui, Tetrahedron
Lett., 2009, 50, 5617.
2-Cyanomethyl-12-phenyl-8,12-dihydro-9H-chromeno[3,2-e][1,2,4]
triazolo[1,5-c]pyrimidin-11(10H)-one (4f): Yield 65%; m.p. 198–200 °C.
5
6
7
8
9
1
IR (KBr, ν, cm–1): 2965, 2923, 2823, 2255, 1645; H NMR(CDCl3,
400 MHz) δ 2.12–2.15 (m, 2H, C9-H)), 2.42–2.48 (m, 2H, C8-H)),
2.78–2.91 (m, 2H, C10-H), 3.99 (s, 2H, –CH2CN), 5.49 (s, 1H, C12-H),
7.14–7.18 (m, 1H, 12‑4′‑H), 7.24–7.27 (m, 2H, 12‑(2′+6′)‑H), 7.40–7.42
(d, J=7.1 Hz, 2H, 12‑(3′+5′)‑H), 9.06 (s, 1H, C5-H). Anal. calcd for
C20H15N5O2: C, 67.22; H, 4.23; N, 19.60; found: C, 67.48; H, 4.15; N,
19.31%.
A.E. Rashad, O.A. Heikal, A.O.H. Elnezhawy and F.M.E. Abdelmegeid,
Heteroatom Chem., 2005, 16, 226.
V. Jeso and K.C. Nicolaou, Tetrahedron Lett., 2009, 50, 1161.
10 Q.B. Han, N.Y. Yang, H.L. Tian, C.F. Qiao, J.Z. Song, D.C. Chang, S.L.
Chen, K.Q. Luo and H.X. Xu, Phytochemistry, 2008, 69, 2187.
11 Z.X. Wang, B. Li, Z. Xing, L.Z. Chen and G.F. Han, J. Chem. Res., 2014,
38, 480.
12 P.M. Luthra, C.B. Mishra, P.K. Jha and S.K. Barodia, Bioorg. Med. Chem.
Lett., 2010, 20, 1214.
Received 12 October 2014; accepted 10 December 2014
Paper 1402955 doi: 10.3184/174751915X14190040330104
Published online: 9 January 2015
13 M.R.D. Giudice, A. Borioni, C. Mustazza and F. Gatta, J. Heterocyclic
Chem., 1994, 31, 1503.
14 S.R. Kanth, G.V. Reddy, K.H. Kishore, P.S. Rao, B. Narsaiah and U.S.N.
Murthy, Eur. J. Med. Chem., 2006, 41, 1011.
15 M.M. Kandeel, A.M. Kamal. E.K.A. Abdelall and H.A.H. Elshemy, Eur. J.
Med. Chem., 2013, 59, 183.
16 G.M. Sheldrick, SADABS. University of Göttingen, Germany, 1996.
17 G.M. Sheldrick, SHELXS-97, Program for Crystal Structure Solution,
University of Göttingen, Germany, 1997.
18 G.M. Sheldrick, SHELXL-97, Program for Crystal Structure Refinement,
University of Göttingen, Germany, 1997.
References
1
2
3
C. Bolcato, C. Cusan, G. Pastorin, G. Spalluto, B. Cacciari, K.N. Klotz, E.
Morizzo and S. Moro, Purinerg. Signal., 2008, 4, 39.
A.S. Shawali, H.M. Hassaneen and N.K. Shurrab, Tetrahedron, 2008, 64,
10339.
P.G. Baraldi, F. Fruttarolo, M.A. Tabrizi, D. Preti, R. Romagnoli, H.
El-Kashef, A. Moorman, K. Varani, S. Gessi, S. Merighi and P.A. Borea,
J. Med. Chem., 2003, 46, 1229.

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