Preparation of dihydrotetrazolo[1,5-a]pyrimidine derivatives from Biginelli 3,4-dihydropyrimidine-2-thiones

Article abstract of DOI:10.1016/j.tet.2014.09.069

Dihydropyrimidines (DHPM) with a fused tetrazole ring have been synthesized via a smooth and efficient three-step protocol involving N,S-dimethylated and 2-hydrazinyl-dihydropyrimidine intermediates, respectively. The described protocol is applicable to e

Full text of DOI:10.1016/j.tet.2014.09.069

Tetrahedron 70 (2014) 8582e8587
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preparation of dihydrotetrazolo[1,5-a]pyrimidine derivatives
from Biginelli 3,4-dihydropyrimidine-2-thiones
*
Jamshed Hashim , Nuzhat Arshad, Ijaz Khan, Sonia Nisar, Basharat Ali,
M. Iqbal Choudhary
H.E.J. Research Institute of Chemistry, ICCBS, University of Karachi, Karachi 75270, Pakistan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 March 2014
Received in revised form 4 September 2014
Accepted 22 September 2014
Available online 28 September 2014
Dihydropyrimidines (DHPM) with a fused tetrazole ring have been synthesized via a smooth and efficient
three-step protocol involving N,S-dimethylated and 2-hydrazinyl-dihydropyrimidine intermediates, re-
spectively. The described protocol is applicable to electron rich and electron poor DHPM precursors as
well. The insertion of tetrazole ring in monastrol type dihydropyrimidines makes it interesting for
pharmacological investigations.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Dihydropyrimidines
Tetrazole
DHPM scaffold
Monastrol
Biological activities
1. Introduction
Pyrimidines are an integral part of DNA and RNA, and have di-
verse pharmacological properties.1 In addition, other heterocycles,
in association with the pyrimidine nucleus, have shown an essen-
tial role in several biological processes and have a considerable
chemical and pharmacological importance (Fig. 1). Notably, py-
rimidines of the Biginelli type (DHPMs) represent one of the most
active classes of pyrimidine derivatives, possessing a wide spec-
trum of biological activities. For example, they show significant
in vitro activity against DNA and RNA viruses,2 including polio and
herpes viruses,2 and have diuretic,3 anti-HIV (1),4 and antitumor
activities (2).5 Furthermore, pyrimidines of this type are known
antihypertensive agents (3),6 have anti-epileptic (4),7 and antitu-
bercular activity (5),8 and are inhibitors for the propagation of the
malarial parasite (6)9 (Fig. 1). In search of more potent and effective
medicinally important molecules, numerous Biginelli dihydropyr-
imidines and related annulated or multi-functionalized pyrimi-
dines heterocycles have been investigated or tested against
different diseases.10
Fig. 1. Important drug molecules containing DHPM and tetrazole structural motifs.
On the other hand the tetrazole structural sub unit has been
identified as an active pharmaceutical scaffold and thus is an im-
portant structural descriptor in the methodology of new drug de-
sign. Compounds containing the tetrazole structural unit have
hypotensive, antimicrobial, antiviral, antiallergic, cytostatic, noo-
tropic, and other biological activities.11 The introduction of the
* Corresponding author. Tel.: þ92 21111222292x173; fax: þ92 2199261713; e-mail
addresses: jamshed.hashim@iccs.edu, jamshedhashim@yahoo.co.uk (J. Hashim).
URL: http://www.iccs.edu
http://dx.doi.org/10.1016/j.tet.2014.09.069
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

J. Hashim et al. / Tetrahedron 70 (2014) 8582e8587
8583
tetrazole ring into an organic substrate quite often leads not only to
an increase in the efficacy but also to an increase in the pro-
longation of drug action. Additionally 1,5-disubstituted tetrazoles
have a notable drug recognition,1a,b,12 for example, tetrazoloaze-
pine Cardiazol (7) has long been used as anticonvulsant and central
nervous system stimulant.1a,b Moreover, aminotetrazole analogues
of type 8 have been disclosed for the treatment/prevention of
a variety of pain states, e.g., chronic inflammatory pain, neuropathic
pain, spinal cord injury, neuro-degeneration, or depression.11
Therefore, the heterocyclic system of Biginelli DHPMs, linked to
another medicinally important substructure (i.e., the tetrazole
ring), is expected to exhibit interesting pharmacological properties.
In the view of the facts, mentioned above, and as part of our
initial efforts to discover potentially bioactive new compounds, we
have synthesized some new derivatives of dihydropyrimidines
annulated at the 1/2 position with a tetrazole ring of type 10
(Scheme 1). Herein, we describe a novel approach for the synthesis
of hitherto unknown dihydrotetrazolo[1,5-a]pyrimidine dihydro-
chloride derivatives of type 10 by utilizing Biginelli DHPMs 9 as
a precursor via a three-step sequence.
monastrol because of the medicinal importance of dihydropyr-
imidine (ꢀ)-2 (monastrol and its sub-derivatives) in human mitotic
kinesin, e.g., 5,14 good overall yields were observed.
As a first step in three-step sequence, the initially formed
dihydropyrimidine-2-thiones 9aef were subjected to double
methylation.15 For the desired double methylation at N-1 and
C(2)]S positions of the DHPM scaffold, we initially performed
model studies on phenyl-2-thione by employing microwave sealed
vessel conditions (100 ꢁC, 5 min).16 It was quickly realized that for
the required double methylation, K2CO3 as base is required along
with methyl iodide. However, with K2CO3 under microwave con-
ditions at 100 ꢁC a mixture of three products, identified as mono S-
methylated, double methylated at N-3 and S positions, and
a product with triple methylation on all available positions at N-1,
C-2, and N-3 was obtained. Ultimately, the reaction proceeded by
heating 1 equiv of thione, 2 equiv of K2CO3 with 5 equiv of methyl
iodide in acetonitrile as solvent under conventional oil bath reflux
heating at 80 ꢁC for 6 h under inert conditions. This provided 85% of
isolated yield of the desired product (11d) after flash chromatog-
raphy along with traces of the mono S-methylated product. With
the optimized conditions, successful double N,S-methylation was
achieved with the other four DHPMs with overall good yields along
with mono S-methylated product as minor byproduct (Table 1).
Table 1
N,S-Dimethylation step of DHPMsa,b
Scheme 1. Dihydrotetrazolo[1,5-a]pyrimidine dihydrochloride derivatives of type 10.
2. Results and discussion
According to the general strategy outlined in Scheme 1, our
synthesis of the required tetrazole-annulated DHPM commenced
with the preparation of DHPM precursors 9, which were synthe-
sized in good to excellent yields on 20 mmol scale by the cyclization
of three components, e.g., arylaldehydes, thiourea, and substituted
b
-ketoesters in acetonitrile via reflux or microwave heating fol-
lowing the literature (Biginelli reaction).13 The initially formed
dihydropyrimidine-2-thiones 9aef were subsequently converted
to dihydrotetrazolo[1,5-a]pyrimidine dihydrochloride 10aef by
a three-step sequence following dimethylation, hydrazination and
then cyclization (Scheme 2).
For the conversion of N,S-dimethylated dihydropyrimidines to
the corresponding hydrazino derivatives, different reaction con-
ditions were investigated involving, hydrazinating reagents, sol-
vent and temperature variations. In our hands the most suitable
protocol was the use of 4 equiv of hydrazinum dihydrochloride in
DMF as solvent under sealed vessel oil bath heating for 2 h at
120 ꢁC. All the dimethylated adducts 11aef were successfully
transformed to the corresponding hydrazine dihydrochloride de-
rivatives 12aef in excellent yields after flash column chromatog-
raphy (Table 2).
Scheme 2. Three-step synthetic sequence of 10.
We optimized reaction conditions for the three-step sequence
for the 4-phenyl DHPM precursor. Thereafter, on successful com-
pletion of the reaction sequence, the same strategy was applied to
other electron rich and electron poor DHPMs and as well as

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J. Hashim et al. / Tetrahedron 70 (2014) 8582e8587
Table 2
Table 3
Hydrazino derivatives of DHPMa,b
Tetrazolo derivatives of DHPM corea,b
The conversion of hydrazine derivatives 12aef to tetrazolo
dihydrochloride derivatives 10aef, as the final step in sequence,
was readily accomplished by using sodium nitrite as a reducing
agent under an inert atmosphere at 0 ꢁC. Acetic acid of 90% was
found to be the best solvent for this transformation while less than
90% acetic acid provided incomplete conversions due to poor sol-
ubility of hydrazine derivatives. The reaction needed 45 min to
completion and provided moderate to good yields of the tetrazolo
derivatives of DHPM 10 (Table 3).
compounds, the insertion of tetrazole ring in monastrol type
DHPMs makes it interesting for pharmacological investigations.
Our ongoing interest is to screen these potentially biological active
molecules and continue our efforts to design novel DHPM for drug
discovery.
4. Experimental section
DHPM compounds 10aef may exist in their azide and/or tetra-
zole forms, respectively.17 The proton NMR spectrums of 10aef
recorded in MeOD/CDCl3 displayed only single set of signals, which
indicates that only one tautomer of both is present. Since a strong
azido absorption band (2160e2120 cmꢂ1) in the IR spectrum is
absent, it appears evident that compounds 10aef are present in its
tetrazolo form.
The new derivatives were characterized by spectral data and
these compounds are currently under investigation for their anti-
oxidant, anti-inflammatory, antimicrobial, calcium channel block-
ing activity, anti-HIV, diabetes, and for treating and/or preventing
diseases of the lungs and cardiovascular system in our laboratories.
4.1. General experimental details
NMR spectra were recorded on Bruker AV-III, Bruker AV-500
and Bruker AV-600 instruments. One-dimensional (1D) 1H NMR
spectra were acquired using a 300 and 500 MHz spectrometers
while 13C NMR at 75, 100, 125, and 150 MHz. Chemical shifts (
d) are
reported in parts per million (ppm) relative to tetramethylsilane
(TMS) as an internal standard. The letters s, d, t, q, and m are used to
indicate singlet, doublet, triplet, quadruplet, and multiplet. Cou-
pling constants (J values) are quoted in hertz (Hz).
Electron ionization (EI), electrospray ionization (ESI), and fast
atom bombardment (FAB) were measured on JEOL (JMS-600H),
Applied Biosystems (QSTAR XL MS/MS System), and JEOL (JMS-
HX110), respectively. High-resolution mass spectra were obtained
by ESI method using time-of-flight (TOF) analyzer or FAB or EI
methods using high-resolution magnetic sector analyzer mass
spectrometer. FTIR spectra were recorded on Shimadzu (FTIR-8900)
and Bruker (Vector-22).
Analytical HPLC analysis was carried out on Shimadzu (LC-20)
using a C18 reversed-phase column (RP) (150ꢃ4.6 mm, particle
size 5 mm) at 25 ꢁC. Mobile phase A (water/acetonitrile 90:10 (v/
v)þ0.1% TFA) and B (MeCNþ0.1% TFA) at a flow rate of 1.0 mL/min
were used. The following gradient was applied: linear increase
from solution 30% B to 100% B in 8 min, hold at 100% solution B for
3. Conclusions
In conclusion, we have developed a smooth and efficient pro-
tocol for the synthesis of novel DHPM tetrazolo derivatives. The
conversion of Biginelli 3,4-dihydropyrimidine-2-thiones to dihy-
drotetrazolo[1,5-a]pyrimidine derivatives by the described protocol
is applicable for electron rich and electron poor DHPMs as well and
provides good overall yields for the tetrazolo adducts. These de-
rivatives were designed, inspired by highly potent bicyclic DHPM
derivatives, which have been described earlier in the literature. Due
to the fact that tetrazole is a component in different bioactive

J. Hashim et al. / Tetrahedron 70 (2014) 8582e8587
8585
7 min. The synthesized compounds were purified via flash chro-
matography on silica gel or Biotage SP-1 automated flash chro-
matography system using cartridges packed with KP-SIL, 60 A
Mꢂ73), 227 (100, Mꢂ93); HRMS (ESI-TOF) m/z calcd for
C
16H20N2O3S [MþH]þ¼321.1273, found 321.1274.
ꢀ
(32e63
m
m particle size). TLC analyses were performed on pre-
4.4.2. Methyl 1,4-dimethyl-2-(methylthio)-6-phenyl-1,6-
dihydropyrimidine-5-carboxylate (11b). Yellow solid; 50.5 mg
(70%); mp 100e102 ꢁC (ethanol); Rf (10% EtOAc/hexane) 0.39; IR
coated (silica gel 60 HF254) plates. All anhydrous solvents (stored
over molecular sieves) and chemicals were obtained from stan-
dard commercial vendors and were used without any further
purification.
(KBr) nmax 2924, 2854, 1699, 1621, 1363, 1161, 1067 cmꢂ1 1H NMR
;
(300 MHz, CDCl3)
1H), 3.77 (s, 3H), 3.55 (s, 3H), 3.47 (s, 3H), 2.45 (s, 3H); 13C NMR
(75 MHz, CDCl3) 179.7, 166.1, 147.7, 139.5, 128.9 (2C), 128.0, 125.8
d 7.24e7.29 (m, 3H), 7.10e7.13 (m, 2H), 5.57 (s,
d
4.2. Microwave irradiation experiments
(2C), 105.8, 61.3, 51.6, 43.0, 38.1, 16.9; MS (positive ESI) m/z 291 (5,
Mþ1), 290 (100, M); HRMS (ESI-TOF) m/z calcd for C15H18N2O2S
[MþH]þ¼291.1167, found 291.1187.
Microwave-assisted synthesis was carried out in an Initiator-8
single-mode microwave instrument producing controlled irradia-
tion at 2.450 GHz (Biotage AB, Uppsala), including proprietary
Workflow Manager Software (version 2.1). Experiments were car-
ried out in sealed microwave microwave (2e5 mL, 10e20 mL filling
volume) process vials utilizing the standard absorbance level
(400 W maximum power). Reaction times under microwave con-
ditions refer to hold times at the temperatures indicated, not to
total irradiation times. The temperature was measured with an IR
sensor on the outside of the reaction vessel.
4.4.3. Methyl 1,4-dimethyl-2-(methylthio)-6-(p-tolyl)-1,6-
dihydropyrimidine-5-carboxylate (11c). Yellow solid; 57.0 mg
(75%); mp 74e76 ꢁC; Rf (10% EtOAc/hexane) 0.43; IR (KBr) nmax 2925,
1697, 1599, 1506, 1233, 1100 cmꢂ1 1H NMR (300 MHz, CDCl3)
;
d
7.05e7.18 (m, 4H), 5.15 (s, 1H), 3.59 (s, 3H), 2.95 (s, 3H), 2.48 (s, 3H),
2.34(s, 3H), 2.27 (s, 3H);13CNMR(75 MHz,CDCl3)
d
167.2, 162.7, 154.5,
138.8, 137.6, 129.1 (2C), 126.8 (2C), 103.3, 63.0, 50.6, 36.4, 23.0, 21.0,
14.0; MS (positive ESI) m/z 305 (10, Mþ1), 304 (100, M); HRMS (ESI-
TOF) m/z calcd for C16H20N2O2S [MþH]þ¼305.1324, found 305.1322.
4.3. General procedure for the synthesis of dihydropyr-
imidines precursors (9aef)
4.4.4. Ethyl 1,4-dimethyl-2-(methylthio)-6-phenyl-1,6-
dihydropyrimidine-5-carboxylate (11d). Yellow solid; 57.0 mg
(75%); mp 90e92 ꢁC; Rf (10% EtOAc/hexane) 0.41; IR (KBr) nmax
A mixture containing 10 mmol of the corresponding benzalde-
hyde (1a), 15 mmol of corresponding methyl 2a or ethyl acetoa-
cetate 2b, 761 mg (10 mmol, 1.0 equiv) of thiourea 3a, and 620 mg
(1.0 mmol, 10 mol %) of Yb(OTf)3 or 1.27 mL (10 mmol, 1.0 equiv) of
TMSCl was suspended in 10 mL of anhydrous acetonitrile under
a nitrogen atmosphere in a 20 mL microwave vial (Pyrex) equipped
with a magnetic stirring bar. The vial was sealed and stirred for
2 min at room temperature to allow homogenization then the
mixture was heated for 40 min at 120 ꢁC by microwave irradiation.
After cooling the reaction mixture was poured onto 500 mL of ice
water and allowed to stir for 1 h in order to obtain maximum
precipitation. Filtration then delivers the pure DHPMs. Where
needed the product was directly purified by gradient dry flash
chromatography using appropriate solvents. The physical and
spectroscopic data of DHPM (9aef) were found in agreement with
the literature.13a,b
2989, 2503, 1757, 1615, 1381, 1160, 790 cmꢂ1 1H NMR (300 MHz,
;
CDCl3)
d 7.25e7.28 (m, 4H), 7.06e7.20 (m, 1H), 5.19 (s, 1H),
3.98e4.14 (m, 2H), 2.97 (s, 3H), 2.49 (s, 3H), 2.34 (s, 3H), 1.17 (t,
J¼7.1 Hz, 3H); 13C NMR (75 MHz, CD3OD)
d 168.3, 161.2, 155.8, 142.9,
129.6 (2C), 129.2, 128.1 (2C), 104.8, 64.2, 60.8, 43.5, 22.9, 14.5, 11.7;
MS (positive ESI) m/z 305 (5, Mþ1), 304 (100, M); HRMS (ESI-TOF)
m/z calcd for C16H20N2O2S [MþH]þ¼305.1324, found 305.1331.
4.4.5. Ethyl 1,4-dimethyl-2-(methylthio)-6-(p-tolyl)-1,6-
dihydropyrimidine-5-carboxylate (11e). Yellow solid; 61.0 mg
(77%); mp 92e94 ꢁC (ethanol); Rf (10% EtOAc/hexane) 0.48; IR (KBr)
nmax 2925, 1690, 1600, 1507, 1384, 1233, 1103 cmꢂ1 1H NMR
;
(500 MHz, CDCl3)
d
7.17 (d, J¼8.0 Hz, 2H), 7.07 (d, J¼7.9 Hz, 2H), 5.15
(s, 1H), 4.02e4.09 (m, 2H), 2.96 (s, 3H), 2.48 (s, 3H), 2.34 (s, 3H),
2.28 (s, 3H),1.18 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CD3OD)
d 168.4,
165.1, 155.7, 140.1, 139.2, 130.2 (2C), 128.1 (2C), 105.1, 64.2, 60.8, 37.1,
4.4. General procedure for the synthesis of dimethylated di-
30.7, 23.0, 21.1, 14.6; MS (direct probe, positive EI) m/z 318 (100, M),
hydropyrimidines (11aef)
317 (20, Mꢂ1); HRMS (ESI-TOF) m/z calcd for
C17H22N2O2S
[MþH]þ¼319.1480, found 319.1481.
A mixture of 0.25 mmol of the corresponding DHPMs 9aef,
69.17 mg (0.50 mmol, 2.0 equiv) of potassium carbonate, and 78
m
L
4.4.6. Ethyl 1,4-dimethyl-2-(methylthio)-6-(p-nitro)-1,6-
dihydropyrimidine-5-carboxylate (11f). Yellow solid; 48.0 mg
(55%); mp 176e178 ꢁC (ethanol); Rf (15% EtOAc/hexane) 0.37; IR
(KBr) nmax 3412, 2976, 2924, 1677, 1519, 1367, 1337, 1237, 1105,
(1.25 mmol, 5.0 equiv) of methyl iodide was suspended in 1.2 mL of
anhydrous acetonitrile in a 5 mL microwave vial equipped with
magnetic stirrer. The reaction vessel was sealed and flushed with
nitrogen then heated for 6 h at 80 ꢁC using a conventional oil bath.
Thereafter, the solvent was removed under reduced pressure. The
product was purified by automated flash chromatography (hexane/
ethyl acetate) to provide the desired 2-substituted dihydropyr-
imidines 11aef as yellow solids.
822 cmꢂ1; 1H NMR (500 MHz, CDCl3)
d
8.14 (d, J¼8.7 Hz, 2H), 7.46
(d, J¼8.7 Hz, 2H), 5.32 (s, 1H), 4.03e4.14 (m, 2H), 2.99 (s, 3H), 2.50
(s, 3H), 2.33 (s, 3H),1.20 (t, J¼7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
166.5, 163.3, 155.3, 148.8, 147.6, 127.8 (2C), 123.9 (2C), 102.9, 62.8,
59.9, 36.8, 23.2,14.3,14.2; MS (direct probe, positive EI) m/z 349 (10,
M), 320 (15, Mꢂ29), 227 (100, Mꢂ122); HRMS (EIþ) m/z calcd for
4.4.1. Ethyl 6-(3-hydroxyphenyl)-1,4-dimethyl-2-(methylthio)-1,6-
dihydropyrimidine-5-carboxylate (11a). Yellow solid; 68.0 mg
(85%); mp 150e152 ꢁC (ethanol); Rf (15% EtOAc/hexane) 0.24; IR
(KBr) nmax 3278, 1664, 1230, 1106 cmꢂ1; 1H NMR (300 MHz, CDCl3)
C
16H19N3O4S [M]þ¼349.1096, found 349.1095.
4.5. General procedure for the synthesis of hydrazinyl dihy-
dropyrimidines dihydrochloride (12aef)
d
7.14 (t, J¼7.8 Hz, 1H), 6.78e6.86 (m, 1H), 5.19 (s, 1H), 4.09 (q,
J¼5.2 Hz, 2H), 3.08 (s, 3H), 2.70 (s, 3H), 2.45 (s, 3H), 1.20 (t, J¼7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3)
165.1, 163.9, 158.8, 143.2, 138.0,
A mixture of 0.25 mmol of the corresponding N,S-dimethylated
DHPMs 11aef and 105 mg (1.0 mmol, 4.0 equiv) of NH2NH2$2HCl
was suspended in 3 mL of anhydrous DMF in a 5 mL microwave vial
equipped with magnetic stirrer. The reaction vessel was sealed and
d
129.9, 118.80, 118.0, 112.8, 107.5, 64.6, 61.4, 39.4, 17.7, 16.9, 14.1; MS
(positive EI) m/z 321 (5, Mþ1), 320 (29, M), 319 (3, Mꢂ1), 247 (16,

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J. Hashim et al. / Tetrahedron 70 (2014) 8582e8587
flushed with nitrogen then heated for 2 h at 120 ꢁC in a conven-
tional oil bath. Thereafter, the solvent was removed under reduced
pressure. The product was purified by automated flash chroma-
tography using (hexane and ethyl acetate) solvents to provide the
desired 2-substituted dihydropyrimidines dihydrochloride 12aef
as white solids.
(d, J¼8.6 Hz, 2H), 5.53 (s, 1H), 4.10e4.25 (m, 2H), 3.31 (s, 3H), 2.33
(s, 3H), 1.26 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CD Cl3)
d 175.4,
164.9, 147.8, 147.2, 143.2, 127.7 (2C), 124.2 (2C), 101.4, 62.5, 60.7,
40.6, 18.5, 14.2; MS (direct probe, positive EI) m/z 336 (15, Mþ1),
335 (60, M), 213 (100, Mꢂ122); HRMS (ESI-TOF) m/z calcd for
C
15H21N5O4 [MþH]þ¼336.1672, found 336.1646.
4.5.1. Ethyl 2-hydrazinyl-6-(3-hydroxyphenyl)-1,4-dimethyl-1,6-
dihydropyrimidine-5-carboxylate dihydrochloride (12a). White
solid; 61.0 mg (80%); mp 168e170 ꢁC; Rf (25% EtOAc/hexane) 0.50;
4.6. General procedure for the synthesis of tetrazolo dihy-
dropyrimidines dihydrochloride (10aef)
IR (KBr) nmax 3383, 3209, 1682, 1482, 1442, 1244, 1112 cmꢂ1
;
1H
A dry 5 mL microwave vial equipped with a magnetic stirrer was
flushed with nitrogen and then charged with 0.25 mmol of the cor-
responding hydrazinyl dihydropyrimidines dihydrochloride 12aef
and 69 mg (1.0 mmol, 4.0 equiv) of sodium nitrite (NaNO2). The re-
actionvessel was sealed and flushed withnitrogen and kept at 0 ꢁC in
a CaCl2 ice bath. Then 6 mL of 90% cold acetic acid is added slowly in
the dark and the reaction mixture was kept at 0 ꢁC for further 45 min
under N2 atmosphere with continuous stirring. Thereafter, the re-
action mixture was concentrated and co-evaporated with 3e4 mL of
toluene under reduced pressure at room temperature. The product
was purified by automated flash chromatography using (chloroform
and methanol) solvents to provide the desired 2-substituted dihy-
dropyrimidines dihydrochloride (10aef) as oils.
NMR (300 MHz, CDCl3)
d
7.17 (t, J¼7.9 Hz, 1H), 6.74e6.89 (m, 3H),
5.35 (s, 1H), 4.13 (q, J¼5.4 Hz, 2H), 3.31 (s, 3H), 2.30 (s, 3H), 1.24 (t,
J¼7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 175.1, 165.3, 156.1, 142.3,
142.0, 130.1, 119.3, 115.5, 113.6, 102.3, 62.9, 60.5, 40.5, 18.4, 14.2; MS
(positive ESI) m/z 307 (5, Mþ1), 306 (100, M), 233 (2, Mꢂ73); HRMS
(EIþ) m/z calcd for C15H22N4O3 [M]þ¼306.1692, found 306.1720.
4.5.2. Methyl 2-hydrazinyl-1,4-dimethyl-6-phenyl-1,6-dihydro-
pyrimidine-5-carboxylate dihydrochloride (12b). White solid;
51.5 mg (75%); mp 178e180 ꢁC; Rf (15% EtOAc/hexane) 0.39; IR
(KBr) nmax 3328, 3180, 2925, 1709, 1436, 1240, 1106, 699 cmꢂ1 1H
;
NMR (300 MHz, CDCl3)
d
7.28 (s, 5H), 5.39 (s, 1H), 3.66 (s, 3H), 3.29
175.1, 165.7, 142.7,
(s, 3H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
140.3, 128.9 (2C), 128.4, 126.8 (2C), 102.2, 63.2, 51.4, 40.5, 18.3; MS
(positive ESI) m/z 277 (5, Mþ1), 276 (100, M); HRMS (EIþ) m/z calcd
for C14H20N4O2 [M]þ¼276.1586, found 276.1612.
4.6.1. Ethyl 7-(3-hydroxyphenyl)-6,9-dimethyl-4,7-dihydrotetrazolo
[1,5-a]pyrimidine-6-carboxylate dihydrochloride (10a). Orange oil;
51.0 mg (65%); Rf (10% MeOH/CHCl3) 0.23; IR (KBr) nmax 3138, 2929,
1711, 1381, 1262, 767 cmꢂ1 1H NMR (300 MHz, CD3OH)
; d 7.23 (t,
4.5.3. Methyl 2-hydrazinyl-1,4-dimethyl-6-(p-tolyl)-1,6-
J¼7.7 Hz, 1H), 6.80e6.90 (m, 3H, m), 5.48 (s, 1H), 4.08 (q, J¼5.8 Hz,
dihydropyrimidine-5-carboxylate
dihydrochloride
(12c). White
2H), 3.16 (s, 3H), 2.39 (s, 3H), 1.14 (m, 3H); 13C NMR (75 MHz, CDCl3)
solid; 60.5 mg (84%); mp 154e156 ꢁC (ethanol); Rf (10% EtOAc/
hexane) 0.24; IR (KBr) nmax 3219, 2949, 1709, 1545, 1382, 1242, 1111,
d 165.1, 158.8, 150.8, 146.0, 140.5, 129.5, 119.0, 117.3, 113.8, 105.5,
61.0, 60.6, 39.6, 19.1, 14.1; MS (positive FAB) m/z 318 (10, Mþ1), 275
769 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
7.09e7.17 (m, 4H), 5.33 (s,
(100, Mꢂ42); HRMS (ESI-TOF) m/z calcd for
C15H19N5O3
1H), 3.66 (s, 3H), 3.28 (s, 3H), 2.30 (d, J¼3.4 Hz, 6H); 13C NMR
[MþH]þ¼318.1566, found 318.1587.
(150 MHz, CD3OD) d 176.8,167.5,145.1,139.4,139.3,130.3 (2C), 127.9
(2C), 102.8, 63.9, 51.6, 40.5, 21.1, 17.4; MS (positive ESI) m/z 291 (5,
Mþ1), 290 (100, M); HRMS (EIþ) m/z calcd for C15H22N4O2
[M]þ¼290.1743, found 290.1764.
4.6.2. Methyl 6,9-dimethyl-7-phenyl-6,7-dihydrotetrazolo[1,5-a]py-
rimidine-8-carboxylate dihydrochloride (10b). Orange oil; 45.5 mg
(64%); Rf (5% MeOH/CHCl3) 0.21; IR (KBr) nmax 2950, 2923, 1703,
1625, 1545, 1377, 1254, 1187, 1095, 762, 701 cmꢂ1 1H NMR
;
4. 5. 4. Ethyl 2-hydrazinyl-1, 4-dimethyl-6-phenyl-1, 6-
dihydropyrimidine-5-carboxylate dihydrochloride (12d). White
solid; 61.0 mg (85%); mp 136e138 ꢁC (ethanol); Rf (10% EtOAc/hex-
ane) 0.38; IR (KBr) nmax: 3436, 3185, 2922, 1707, 1552, 1485, 1239,
(300 MHz, CDCl3)
d
7.31e7.33 (m, 5H), 5.31 (s, 1H), 3.60 (s, 3H), 3.06
166.5, 151.9, 151.4,
(s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
140.9, 128.8 (2C), 128.7, 127.5 (2C), 104.4, 60.7, 51.1, 38.7, 21.6; MS
(positive FAB) m/z 288 (20, Mþ1), 245 (100, Mꢂ42); HRMS (FABþ)
m/z calcd for C14H17N5O2 [MþH]þ¼288.1461, found 288.1478.
1105, 699 cmꢂ1; 1H NMR (300 MHz, DMSOed6)
d 7.23e7.38 (m, 5H),
5.41 (s, 1H), 4.01 (q, J¼3.9 Hz, 2H), 3.16 (s, 3H), 2.25 (s, 3H), 1.12 (t,
J¼7.0, 3H); 13C NMR (75 MHz, CD3OD)
d
176.9, 167.0, 145.1, 142.5,
4.6.3. Methyl
6,9-dimethyl-7-(p-tolyl)-6,7-dihydrotetrazolo[1,5-a]
129.7 (2C), 129.3, 128.1 (2C), 102.9, 64.2, 61.3, 40.6, 17.4, 14.5; MS
(positive ESI) m/z 291 (5, Mþ1), 290 (100, M), 258 (6, Mꢂ32); HRMS
(EIþ) m/z calcd for C15H22N4O2 [M]þ¼290.1743, found 290.1731.
pyrimidine-8-carboxylate dihydrochloride (10c). Orange oil; 51.0 mg
(68%); Rf (5% MeOH/CHCl3) 0.22; 1H NMR (300 MHz, CD3OD)
d
7.15e7.25 (m, 4H), 5.31 (s,1H), 3.56 (s, 3H), 2.95 (s, 3H), 2.31 (s, 3H),
2.29 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
166.6, 152.0, 151.4, 138.5,
4.5.5. Ethyl 2-hydrazinyl-1,4-dimethyl-6-(p-tolyl)-1,6-
138.2, 129.4 (2C), 127.4 (2C), 104.4, 60.3, 51.0, 38.6, 21.7, 21.1; MS
(positive FAB) m/z 302 (10, Mþ1), 259 (100, Mꢂ42); HRMS (FABþ) m/
z calcd for C15H19N5O2 [MþH]þ¼302.1617, found 302.1645.
dihydropyrimidine-5-carboxylate
dihydrochloride (12e). White
solid; 60.5 mg (80%); mp 140e142 ꢁC (ethanol); Rf (10% EtOAc/
hexane) 0.28; IR (KBr) nmax: 3217, 2923,1701, 1638, 1554, 1477, 1234,
1102, 784 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
7.09e7.17 (m, 4H), 5.33
(s, 1H), 4.08e4.14 (m, 2H), 3.28 (s, 1H), 2.30 (d, 6H, 4.0 Hz),1.22-1.25
(m, 3H); 13C NMR (75 MHz, CD3OD)
176.8, 167.1, 144.9, 139.5,
4.6.4. Ethyl
6,9-dimethyl-7-phenyl-6,7-dihydrotetrazolo[1,5-a]py-
rimidine-8-carboxylate dihydrochloride (10d). Orange oil; 46.5 mg
d
(62%); Rf (6% MeOH/CHCl3) 0.28; 1H NMR (300 MHz, CDCl3)
139.3, 130.3 (2C), 128.1 (2C), 103.0, 64.0, 61.2, 40.5, 21.1, 17.4, 14.5;
MS (positive ESI) m/z 305 (5, Mþ1), 304 (100, M); HRMS (EIþ) m/z
calcd for C16H24N4O2 [M]þ¼304.1899, found 304.1930.
d
7.03e7.21 (m, 5H), 5.20 (s, 1H), 3.94 (q, J¼6.8 Hz, 2H), 2.89 (s, 3H),
2.29 (s, 3H), 1.05e1.09 (m, 3H); 13C NMR (75 MHz, CD3OD)
d
166.5,
152.5, 141.4, 138.3, 130.6, 130.0 (2C), 129.1 (2C), 106.6, 62.2, 61.5,
39.8, 19.5, 14.4; MS (positive FAB) m/z 302 (5, Mþ1), 259 (100,
Mꢂ42); HRMS (FABþ) m/z calcd for C15H19N5O2 [MþH]þ¼302.1617,
found 302.1638.
4.5.6. Ethyl 2-hydrazinyl-1,4-dimethyl-6-(p-nitro)-1,6-
dihydropyrimidine-5-carboxylate
dihydrochloride
(12f). White
solid; 77.0 mg (76%); mp 183e185 ꢁC (ethanol); Rf (25% EtOAc/
hexane) 0.52; IR (KBr) nmax: 3219,1699,1641,1522,1476,1349,1238,
4.6.5. Ethyl 6,9-dimethyl-7-(p-tolyl)-6,7-dihydrotetrazolo[1,5-a]py-
rimidine-8-carboxylate dihydrochloride (10e). Orange oil; 47.5 mg
1118 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
8.19 (d, J¼8.6 Hz, 2H), 7.48

J. Hashim et al. / Tetrahedron 70 (2014) 8582e8587
8587
(61%); Rf (5% MeOH/CHCl3) 0.26; 1H NMR (300 MHz, CDCl3)
References and notes
d
7.06e7.20 (m, 4H), 5.23 (s, 1H), 4.02 (q, J¼4.5 Hz, 3H), 3.00 (s, 3H),
2.37 (s, 3H), 2.29 (s, 3H), 1.13 (t, J¼7.1, 3H); 13C NMR (75 MHz,
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CD3OD)
d 166.5, 152.3, 147.1, 140.5, 138.4, 130.6 (2C), 129.1 (2C),
106.7, 61.9, 61.6, 39.7, 21.2, 19.4, 14.3; MS (positive FAB) m/z 316 (20,
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[MþH]þ¼316.1774, found 316.1803.
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4.6.6. Ethyl 6,9-dimethyl-7-(p-nitro)-6,7-dihydrotetrazolo[1,5-a]py-
rimidine-8-carboxylate dihydrochloride (10f). Orange oil; 85.5 mg
(82%); Rf (5% MeOH/CHCl3) 0.20; IR (KBr) nmax 2979, 2923, 1701,
1623, 1523, 1373, 1347, 1260, 1187, 1093, 825 cmꢂ1 1H NMR
;
(500 MHz, CDCl3)
d
8.16 (d, J¼8.5 Hz, 2H), 7.52 (d, J¼8.4 Hz, 2H),
5.38 (s, 1H), 3.98e4.08 (m, 2H), 2.91 (s, 3H), 2.33 (s, 3H), 1.15 (t,
J¼7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 175.4, 165.7, 152.8,
151.9, 147.7, 128.5 (2C), 124.0 (2C), 103.7, 60.3, 60.1, 38.9, 21.5, 14.1;
MS (positive ESI) m/z 347 (5, Mþ1), 304 (100, Mꢂ42); HRMS (ESI-
TOF) m/z calcd for C15H18N6O4 [MþHꢂN3]þ¼304.1297, found
304.1283.
Acknowledgements
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This work was supported by the Higher Education Commission
of Pakistan (Proposal No. 20-1160/R&D/09). J.H. thanks Mr. Yaqoob
John for HRMS analysis.
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Supplementary data
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These data include the copies of the 1H NMR and 13C NMR
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