Synthesis of New Tetrazole Derivatives of Spiro- and Bis-barbiturates

Article abstract of DOI:10.1002/jccs.201500257

This work described the synthesis of the first and unprecedented examples of 5-aryl-1H-tetrazoles including spiro- and bis-(thio)barbiturates, generated from the reaction between 4-(1H-tetrazol-5-yl)benzaldehyde with (thio)barbituric acids and cyanogen br

Full text of DOI:10.1002/jccs.201500257

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Synthesis of New Tetrazole Derivatives of Spiro- and Bis-barbiturates
Elmira Kashani,a Nader Noroozi Pesyana* and Ertan Ôahinb
aDepartment of Organic Chemistry, Faculty of Chemistry, Urmia University, 57159, Urmia, Iran
bDepartment of Chemistry, Faculty of Science, Atatürk University, 25240 Erzurum, Turkey
(Received: Jul. 1, 2015; Accepted: Sept. 16, 2015; Published Online: Oct. 8, 2015; DOI: 10.1002/jccs.201500257)
This work described the synthesis of the first and unprecedented examples of 5-aryl-1H-tetrazoles includ-
ing spiro- and bis-(thio)barbiturates, generated from the reaction between 4-(1H-tetrazol-5-yl)benzal-
dehyde with (thio)barbituric acids and cyanogen bromide (BrCN) in the presence of triethylamine, pro-
viding good overall yields. Tetrazoles based on bis-(thio) barbiturates were also obtained in the absence of
BrCN under the same conditions. The structures were characterized by IR, 1H NMR, 13C NMR, X-ray
crystallography and mass analysis techniques. The reaction mechanism was proposed. The hydrogen
bond strength (EHB) versus d (O1·····O7 (w)) distance (kcal.mol-1) and corresponding pKa value for the
proton of H3A (in water molecule) in 4b.H2O were estimated to be 13.8 kcal.mol-1 and 8.2, respectively.
Keywords: Tetrazole; Spiro-barbiturates; 4-(1H-Tetrazol-5-yl) benzaldehyde; Intramolecular hydrogen
bonding; Intermolecular hydrogen bonding; X-ray.
INTRODUCTION
On the other hand, in the realm of biological chemis-
try, works involving artificial hydrogen bonding receptor
for barbiturate drugs16 has inspired the preparation of bar-
biturate derivatives possessing specific host-guest recogni-
tion properties.17 Barbiturate groups are strongly elec-
tron-withdrawing because they gain aromatic stabilization
Since 1980s, the growth of tetrazole chemistry has
continued due to its popular functionality with a wide range
of applications. Tetrazole has been synthesized under vari-
ous conditions.1 The conventional synthesis of 5-substi-
tuted tetrazoles involves a [2+3] cycloaddition of an azide
and a nitrile. But the major drawbacks of this approach are
the in situ generation of hydrazoic acid which is highly
toxic and explosive, use of expensive and toxic metals, etc.
An alternate methodology to overcome these shortcomings
was developed for the first time by Sharpless et al.2
5-Substituted-tetrazoles are reported to possess anti-
bacterial, (17),3 antifungal (TAK-456, 18),4 antiviral (19),5
analgesic (20),6 anti-inflammatory (21),7 antiulcer8 and
antihypertensive activities.9 Some examples such as Irbe-
sartan (22), Valsartan (23), Tasosartan (24), and Losartan
(25) are shown in Fig. 1. Tetrazoles are metabolically sta-
ble.10 They are used as cis-peptide bond mimics, drugs in
pharmaceuticals and bioisosteres for carboxylic acids.11
This feature and close similarity between the acidic charac-
teristics of tetrazole and carboxylic acid groups12 have in-
spired medicinal chemists to synthesize substituted te-
trazoles as potential medicinal agents. Tetrazole function-
ality is getting increasingly important, not only as precur-
sors for a variety of nitrogen-containing heterocycles13 but
also as materials with applications in explosives14 and even
as increasive lubricants.15
Fig. 1. Structures of some tetrazolic drugs.
* Corresponding author. Email: n.noroozi@urmia.ac.ir; nnp403@gmail.com
Supporting information for this article is available on the www under http://dx.doi.org/10.1002/jccs.201500257
J. Chin. Chem. Soc. 2015, 62, 959-967
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Kashani et al.
upon reduction.18 This property of barbiturate has been ex-
ploited in the preparation of molecules which possess very
pronounced quadratic non liner optical (NLO) properties
of interest for potential applications in opto-electronic and
photonic technologies.19 The reaction of 1, 3-diethyl thio-
barbituric acid (DETBA) with 4-cyano benzaldehyde by
Knoevenagel condensation followed by Michael addition
via second molecule of DETBA gave 4-(bis (1,3-diethyl-
4,6-dioxo-2-thioxohexahydropyrimidin-5-yl)methyl)
benzonitrile.20 This unexpected reaction outcome encour-
aged us to engage in synthesis of other tetrazole derivatives
of barbiturates such as; barbituric (BA), 1,3-dimethyl bar-
bituric (DMBA), 1-methyl barbituric (MBA), thiobarbituri
acid (TBA) and dimedone derived from 4-(1H-tetrazol-
5-yl)benzaldehyde (2).
and BrCN in the presence of triethylamine gave 4b. In the
IR spectrum of 4b, the appearance of tetrazole NH absorp-
tion in the range of 2500-3500 cm-1 and the frequency of
carbonyl groups in 1718 and 1676 cm-1 were the best evi-
dences for the preparation of 4b (see experimental). The 1H
NMR spectrum of 4b showed four methyl groups at d 2.43,
3.12, 3.22 and 3.40 ppm, a singlet at d 5.23 ppm that corre-
sponded to spiro C-H proton and two doublets at d 7.41 and
7.93 ppm that corresponded to phenyl group. On the other
hand, the loss of proton peak in aldehyde group (CH=O) at
d 10.07 ppm was another evidence for the synthesis of 4b.
The 13C NMR spectrum of 4b showed eighteen distinct
peaks (see experimental and Supplementary data). The
X-ray analysis obviously supported and confirmed the
structure of 4b (see later).
While we searched in the literature, there was no
reference regarding the tetrazoles of spiro- and bis-(thio)
barbiturates. In this work, we aimed to synthesis new te-
trazole derivatives of spiro- and bis-barbiturates.
In parallel, our aim was to convert the nitrile group of
6 and 7 to the corresponding tetrazole functions via [2+3]
cycloaddition reaction with sodium azide. These reactions
failed in synthesizing tetrazoles 4 and 8, respectively
(Scheme 2). For this reason, first, we performed the reac-
tion of 1 with sodium azide in the presence of catalytic
amounts of montmorillonite K10 which gave 2 in good
yields (Scheme 1).
RESULTS AND DISCUSSION
This paper describes the synthesis of the new and un-
precedented type tetrazoles of spiro- and bis-barbiturates.
The reaction of 4-cyanobenzaldehyde (1) with sodium
azide in the presence of catalytic amounts of montmorillo-
nite K10 gave 4-(1H-tetrazol-5-yl)benzaldehyde (2) and
then its reaction with BrCN and some (thio)barbiturates
such as; 3a, 3b, 3c, 3d and 3e gave new class of 5-substi-
tuted tetrazoles including spiro barbiturates (4a-4e) in the
presence of triethylamine and/or L-(+)-TA as a basic and
acidic conditions, respectively (Scheme 1, paths a and b).
Reaction of 1 with (thio) barbiturates 3a-3e
in the presence (path a) and absence of
BrCN (path b)
Scheme 2
Syntheses of 4a-4e and 16
Scheme 1
Initially, we synthesized 6b as representative, from
the reaction of 1 and 3 in the presence of cyanogen bromide
through Knoevenagel adduct of 5. Then the reaction of 6b
with sodium azide failed in the synthesis of 4b (Scheme 2,
path a). Bis-barbiturates 7 were obtained from the reaction
of 1 and 3 in the absence of cyanogen bromide and the syn-
thesis of 8 was filed (Scheme 2, path b). These phenomena
resulted from the electron donor ability of the carbon atom
on spiro[furo[2,3-d]pyrimidine-6,5¢-pyrimidin] ring mo-
Representatively, the one-pot reaction of 3b with 2
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Synthesis of New Tetrazole Derivatives
iety on 6 and bis-geminal barbiturate rings upon methine
group on 7, respectively. Therefore, the electron donor
ability in the para-position on phenyl ring prevented the
formation of tetrazole ring.21
molecule of 4b was linked by one intermolecular H-bond to
one water molecule in ratio of 1:1 (assigned as 4b.H2O). In
other words, two molecules of 4b.H2O made centrosym-
metric 26-membered ring with four intermolecular H-
bonds (Fig. 3). [N(1)·····O(7)i = 2.710(6) Å, < N(1)—
H(1)·····O(7)i = 162°; O(7)·····O(1)ii = 2.739(9) Å, <
O(7)—H(3B)·····O(1)ii = 157°, (symmetry codes (i): x,
3/2-y, 1/2+z, (ii): 1-x, -1/2+y, 1/2-z)]. Furthermore, O7—
H(3B)·····p (tetrazole) interactions were effective in the
structure [< O(7)—H(3B)·····Cgi = 177°, X·····Cgi =
3.175(8) Å (symmetry code (i): 1-x, -3/2+y, 1/2-z] (Fig.
3a). The crystallographic data and selected bond length,
angles and torsion angles (both experimental and calcu-
lated) are summarized in Tables 1 and 2, respectively. Crys-
tallographic data were deposited in CSD under CCDC-
906935 registration number and are available free of
charge upon request from CCDC, 12 Union Road, Cam-
bridge CB2 1EZ, UK (fax: +44-1223-336033, e-mail: de-
posit@ccdc.cam.ac.uk).
For further investigation of compound 4b, the crystal
structure of 4b is shown in Fig. 2. For the crystal structure
determination, the single crystal of the compound 4b was
used for data collection on a four-circle Rigaku R-AXIS
RAPID-S diffractometer (equipped with a two dimensional
area IP detector). The graphite-monochromatised Mo Ka
radiation (l = 0.71073 Å) and oscillation scans technique
with Dw = 5° for one image were used for data collection.
The lattice parameters were determined by the least-
squares methods on the basis of all reflections with F2 > 2s
(F2). Integration of the intensities, correction for Lorentz
and polarization effects and cell refinement was performed
using CrystalClear (Rigaku/MSC Inc., 2005) software.22
The structures were solved by direct methods using
SHELXS-9723 and were refined by a full-matrix least-
squares procedure using the software SHELXL-97.23 H-
atoms were positioned geometrically and were refined us-
ing a riding model. Water H-atoms were determined from
difference Fourier maps. The final difference Fourier maps
showed no peaks of chemical significance.
The crystal packing diagram of 4b is shown in Fig.
3a. p-(CN4H)-C6H4 substituted stereogenic center possess
the R-configuration. The crystal structure showed that each
Fig. 3. (a) Unit cell with the intermolecular H-bonding
geometry in the crystal structure of 4b (Two
molecules are omitted for clarity of H-bond).
(b) Formation of the centrosymmetric (Ci) 26-
membered ring for 4b (Center of symmetry is
assigned with dense dot (l)).
Fig. 2. Molecular structure of the compound 4b.H2O.
Thermal ellipsoids are shown at 30% probabil-
ity level.
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Table 1. Crystallographic data for compound 4b.H2O
Crystal data
C20H20N8O7
Mr = 484.44
Crystal system, Space group: monoclinic, P 21/c
a = 15.510 (5) Å
b = 7.679 (5) Å
g = 90.000 (5)°
V = 2137.9 (17) Å3
Z = 4
F(000) = 1008
Dx = 1.505 Mg m- 3
Mo Ka radiation, l = 0.71073 Å
m = 0.12 mm- 1
c = 18.434 (5) Å
a = 90.000 (5)°
b = 103.157 (5)°
Data collection
T = 293 K
42792 measured reflections
1384 reflections with I > 2s (I)
qmax = 26.5°, qmin = 2.3°
Refinement
4389 independent reflections
Rint = 0.479
R[F2 > 2s (F2)] = 0.098
S = 1.00
wR(F2) = 0.275
Drmax = 0.22 e Å- 3
Drmin = - 0.22 e Å- 3
group of one (thio)barbituric acid ring moiety with hydro-
xyl group of the enolic form of geminal (thio)barbituric
acid ring moiety (Scheme 3, path a). Any of these types of
barbiturates having amidic (-CO-NH-) and/or thioamidic
protons (-CS-NH-) did not show eight-membered intra-
molecular H-bond. It seemed that this phenomenon was
arisen from tautomerization of (thio)barbituric acids (lac-
tam-thiolactam ƒ lactim-thiolactim and/or lactam ƒ lac-
tim forms) that occurred prior to formation of intramole-
cular H-bond. Therefore, among these compounds, only
mono N-alkylated and N, N¢-dialkylated (thio) barbiturates
showed this type of intramolecular H-bond. Another com-
pound consisting eight-membered intramolecular H-bond
has also been reported.24 The reaction of 2 with dimedone
(3f) gave 8f. Intramolecular condensation of 8f gave 9-
(4-(1H-tetrazol-5-yl)phenyl)-3,4,6,7-tetrahydro-3,3,6,6-
tetramethyl-2H-xanthene-1,8(5H,9H)-dione (9f) through
the loss of H2O under refluxing. This new compound is of
new tetrazole containing xanthene derivative (Scheme 3,
path b).
Table 2. The selected experimental bond lengths, angles and
torsion angles for 4b.H2O
Atom
Exp.
O3—C9
C10—C11
N2—N3
C8—C11
C8—C5
C1—C2
C9—C8
N1—N2
1.455 (7)
1.320 (8)
1.285 (9)
1.491 (9)
1.515 (9)
1.468 (10)
1.610 (9)
1.342 (8)
1.348 (9)
0.84 (14)
1.09 (16)
106.0 (5)
116.2 (6)
114.6 (5)
108.6
N1—C1
O7—H3A
O7—H3B
O3—C9—C8
C11—C8—C5
C5—C8—C9
C5—C8—H8
H3A—O7—H3B
N2—N1—C1—C2
O1—C12—C11—C8
C13—N8—C10—O3
O3—C9—C17—O5
C17—C9—C16—N6
C3—C4—C5—C8
O1—H3A—O7—H3B
O1—H3A—O7—H1
C3—C2—C1—N1
94 (9)
- 178.3 (6)
- 2.9 (12)
- 177.3 (5)
- 30.3 (8)
- 30.6 (8)
-176.9
147.80
63.09
1.97
All possible tautomeric forms of 7b, 7e and other
1
bis-(thio) barbiturates are shown in Scheme 4. The H
NMR spectrum of 7b showed two broad singlets at d 13.46
and 10.13 ppm that indicated the enol form was predomi-
nant. The chemical shifts of methyl protons appeared at d
3.46 and 3.37 ppm and a singlet appeared at d 5.64 ppm
which corresponded to methine CH proton. One of the
enolic protons formed eight-membered intramolecular
H-bond but the other exchangeable proton did not form
H-bond at the same time (Scheme 4). The existence of
eight-membered intramolecular H-bond in these molecules
We have synthesized new types of tetrazoles of bis-
barbiturates (8a-e). The reaction of 2 with 3a-3e produced
8a-e in the absence of BrCN and in the presence of tri-
ethylamine. The Michael adducts derived from 3b and 3e
(N,N¢-dialkylated (thio)barbituric acids) exclusively showed
eight-membered intramolecular H-bond between carbonyl
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Synthesis of New Tetrazole Derivatives
Reaction of 2 with (thio)barbiturates 3 for
Scheme 3
biturate ring moieties are equivalent. For instance, com-
pound 10b showed a singlet at d 3.27 ppm for NMe pro-
tons. For compounds 8b and/or 10b not in triethylam-
monioum salt form (only in enolic form), the NMe protons
would show two distinct singlets for four methyl groups in
1H NMR spectrum because of the restricted rotation about
C1-C5 and/or C1-C5¢ single bonds (Scheme 4 and see also
experimental and supplementary data). Instead, in the solu-
tion state, when these compounds were in salt form with the
positive charge located on the triethylammonioum cation
and the delocalized negative charge distributed almost
equally on both barbituric acids, the chemical shift value of
four NMe protons would be equivalent because of the free
rotation about mentioned single bonds, C1-C5 and/or
C1-C5¢ (Scheme 5).
formation of Michael adducts (8a-e) and 9f
and eight-membered intramolecular H-bond
in 8b and 8e
Possible eight-membered intramolecular
Scheme 4
H-bonds in 7b, 7e, 8b, 10b and 11e-14e
restricted the rotations around C1-C5 and/or C1-C5¢ single
bonds. Therefore, two substituents (methyl and/or ethyl
groups) on N1 and N3 atoms in the geminal (thio) barbitu-
rate ring moieties had nonequivalent chemical shifts. The
eight-membered intramolecular H-bond for other b-dicar-
bonyl bis-(thio) barbiturates have also been reported.25 In
7e, the methyl and methylene groups showed two triplets
and two quartets, respectively. Two exchangeable protons
in 7e appeared at d 13.90 and 8.50 ppm (see experimental
and Table 3). 1H NMR spectra of Michael adducts contain-
ing o-nitro substituted phenyl ring (10b and 10c) showed
extremely low field for intramolecular H-bonded proton. In
1
particular, in H NMR spectroscopy, the proton was in-
creasingly deshielded with increasing hydrogen bond
strength, which resulted in 1H downfield shifts that were
correlated with the length of the hydrogen bond.26 Thus,
NMR shift data could be used to estimate lengths of
H-bonds.26 For this reason we concluded that, in com-
Table 3. The chemical shifts of the exchangeable protons of Hb
(H-bonded) and Hf (H-free)
pounds 10b and 10c the donor-acceptor distances (dO·····O
)
Compd.
Hb
Hf
should be less than 2.50 (according to the extremely low
field proton chemical shift values at d 16.25 ppm for Hb in
intramolecular eight-membered H-bond in 10b and 10c as
shown in Scheme 5). The formed tetrazolyl bis-barbitu-
rates 8b and 8e were obtained as triethylammonium salt in
the presence of triethylamine (Scheme 3 and Table 3). An-
other evidence to support this data, was the existence of a
plane of symmetry in these molecules (8b, 8e, 10b and 10c)
from NMR point of view. The chemical shifts of proton and
carbon atoms of the same groups in the geminal (thio)bar-
7b
13.46
13.90
[a]
10.13
8.50
[b]
[b]
[b]
8.40
8.00
12.10
7e
8b
10b
10c
12e
13e
14e
16.25[c]
16.20[c]
14.00
14.00
13.90
[a] Presumably the peak of Hb is overlapped with the peak of
water. [b] The salt of triethylammonium is formed. [c] Formation
of resonance assisted strong H-bond.
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Resonance assisted intramolecular H-bond-
ing in 10b and 10c
Scheme 5
of a water molecule (for more information see experimen-
tal and Supplementary data).
1
The H NMR spectra of 4a-4e also confirmed the
sticking of a water molecule to these compounds via two
intermolecular hydrogen bonds. This phenomenon was
supported by X-ray crystal structure and 1H NMR spectrum
of 4b.H2O as representative (Figs. 2 and 6). The Mass
spectra of the compounds 4a-4e were also analyzed. These
compounds showed the existence of a water molecule and
also the aggregation of the mentioned adducts (see experi-
mental and Supplementary data).
In this work, comparison of the strength of the H-
bond in 4b.H2O with other carboxylic acids and flavone-
acid compounds which were reported by Wallet et al.27 and
methyl 2, 4-dimethoxysalicilate by which were reported
Dabbagh et al.28 allowed the estimation of the pKa of
4b.H2O. They used this method when the experimental
pKa determination was impractical. The estimated pKa
value for intermolecular H-bond of 4b.H2O (O7 (w)—
H3A·····O1) was equal to ~8.2 (Fig. 4A). According to the
correlation between hydrogen bond strength (EHB) and
d(O·····O) distance,29 the estimated EHB for intermolecular
H-bond for 4b.H2O was ~13.8 kcal/mol (Fig. 4B). Accord-
ing to Table 4, in 4b.H2O, the value of d (N1·····O7(w)) was
shorter than d (O1·····O7(w)) distance. In this case it acted
as an acceptor for the nitrogen donor forming N1—
H1·····O7(w) hydrogen bond.
Fig. 4. Correlation of d(O1·····O7(w)) distance (2.71
) in 4b.H2O with increasing pKa values of
trichloroacetic (A), chloroacetic (B), 2,6-di-
methoxybenzoic (C), propionic (D), acetic (E)
and formic acids (F)27,28 and estimation of the
pKa value for 4b.H2O (A). Hydrogen bond
strength (EHB) versus d(O1·····O7(w)) distance
(B).29 Estimation of the pKa and EHB (kcal/mol)
values for intermolecular H-bond of 4b.H2O
(- - - - -).
The mass spectrum of 4b.H2O is shown in Fig. 5. The
mass spectrum demonstrated the sticking of a water mole-
cule to 4b. The mass fragment of 4b.H2O was shown at m/z
484. The fragment at m/z 466 corresponded to 4b with loss
Table 4. Experimental donor-acceptor and hydrogen bonds distances in 4b.H2O
D–H·····A
d(D–H)
d(H·····A)
d(D·····A)
< (DHA)
Directionality
N1–H1·····O7(W[a])
O7(W)–H3A·····O1
0.861
0.844
1.880
1.940
2.710
2.739
161.58
157.47
Medium
Weak
[a] Water.
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CHEMICAL SOCIETY
Synthesis of New Tetrazole Derivatives
Fig. 5. Representatively, mass spectrum of 4b.H2O
(aliphatic region).
EXPERIMENTAL
General: The drawing and nomenclature of compounds
was done by ChemBioDraw Ultra 12.0 version software. Melting
points were measured with a digital melting point apparatus
(Electrothermal) and were uncorrected. IR spectra were deter-
mined in the region 4000-400 cm-1 on a NEXUS 670 FT IR spec-
trometer by preparing KBr pellets. The 1H and 13C-NMR spectra
were recorded on Bruker 300 FT-NMR at 300 and 75 MHz, re-
Fig. 6. Representatively, expanded 1H NMR spectrum
of 4b.H2O (aliphatic region).
of 1.0 mmol (0.13 g) 4-cyano benzaldehyde (1), 3.0 mmol (0.2 g)
sodium azide and 0.05 g montmorillonite K10 in 20 mL DMF and
refluxed for 24 h. The progression of reaction was monitored by
thin layer chromatography (TLC, EtOAc: AcOH/80:20 (v:v)).
The reaction mixture was stand and cooled to room temperature.
The solidified catalyst (montmorillonite K10) was filtered off,
and then washed with 20 mL deionized water and 5 mL acetone.
The mother liquid acidified with conc. HCl till the pH received to
2 (pH = 2). The acidic liquid washed by brine, stands at overnight,
concentrated, precipitated and filtered off then washed with few
mLs of water and dried. (0.12 g, 70% yield).
4-(1H-tetrazol-5-yl)benzaldehyde (2):30 Pale yellow so-
lid (70%); mp = 170-175 °C; FT IR (KBr) 2500-3500 (CN4H),
1669 (C=O), 1577 (C=C ar.), 1212, 830 cm-1; 1H NMR (DMSO-
d6, 300 MHz) d 8.10 (d, 2H, J = 7.5 Hz), 8.24 (d, 2H, J = 7.5 Hz),
10.07 (s, 1H); 13C NMR (DMSO-d6, 75 MHz) d: 193.1, 156.0,
1
spectively (Urmia University, Urmia, Iran). H and 13C-NMR
spectra were obtained on solution in CDCl3 as solvents using
TMS as internal standard. The data are reported as (s = singlet, d =
doublet, t = triplet, m = multiplet or unresolved, bs = broad sin-
glet, coupling constant(s) in Hz, integration). All reactions were
monitored by TLC with silica gel-coated plates. The mass analy-
sis performed using mass spectrometer (Agilent Technology (HP)
type, MS Model: 5973 network Mass selective detector Electron
Impact (EI) 70 eV), ion source temperature was 230 °C (Tehran
University, Tehran, Iran). Compounds 230 3c and 3d31 were syn-
thesized in our laboratory based on reported references. 4-Cyano
benzaldehyde 1, 3a, 3b, 3e, 3f and used solvents were purchased
from Merck and Aldrich without further purification.
General procedures for the preparation of 2: In a 50 mL
round bottom flask equipped with magnetically stirrer a mixture
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138.0, 130.8, 130.0, 128.0.
756 (7), 657 (15), 612 (7), 578 (20), 537 (55), 485 (20), 456 (12),
439 (M++1, 28), 401 (10), 368 (100), 313 (26), 272 (55), 238 (70),
191 (25), 149 (55), 107 (53), 73 (48), 41 (43).
General procedures for the preparation of 4a-4c: In a 50
mL round bottom flask equipped with magnetically stirrer and an
ice-bath 1.0 mmol (0.106 g) BrCN dissolved in 2 mL methanol.
The solution of 2.0 mmol ( 0.312 g) 1,3-dimethyl barbituric acid
3b, 1.0 mmol (0.174 g) 4-(1H-tetrazol-5-yl)benzaldehyde 2 and
1.1 mmol (0.2 mL) triethylamine and/or 1.1 mmol (0.15 g)
L-(+)-TAin 30 mL methanol added drop wise by a separatory fun-
nel. The reaction mixture was stirred for 0.5 h at 0 °C to room tem-
perature. The progression of reaction was monitored by thin layer
chromatography (tlc, EtOAc: AcOH/80:20 (v:v)). The crystalline
white solid precipitate, filtered off, washed with few mLs of
methanol and dried. (0.37 g, 80% yield).
General procedures for the preparation of 7b, 7e, 8b, 8e,
10b, 10c and 11e-14e: In a 50 mL round bottom flask equipped
with magnetic stirrer the solution of 2.0 mmol (0.312 g) 1,3-
dimethylbarbituric acid 3b and 1.0 mmol (0.174 g) 4-(1H-
tetrazol-5-yl)benzaldehyde 2 dissolved in 20 mL methanol, 1.1
mmol (0.2 mL) triethylamine in 10 mL methanol added drop wise
by a separatory funnel. The reaction mixture was stirred and
refluxed for 24 h at 60 °C. The reaction was monitored by thin
layer chromatography (TLC, EtOAc: AcOH/80:20 (v:v)). The
crystalline white solid precipitate, filtered off, washed with few
mL methanol and dried. (0.398 g, 70% yield).
5-(4-(1H-tetrazol-5-yl)phenyl)-1H,1¢H-spiro[furo[2,3-d
]pyrimidine-6,5¢-pyrimidine]-2,2¢,4,4¢,6¢(3H,3¢H,5H)-pen-
taone (4a): White solid (60%); mp = 292-294 °C (decomps.); FT
IR (KBr) 2844-3531 (CN4H), 1719 (C=O), 1675 (C=O), 1533
(C=C ar.), 1405, 1372, 1231, 771 cm-1; 1H NMR (DMSO-d6, 300
MHz) d 4.92 (s, 1H), 7.39, (d, 2H, J = 4.8 Hz), 7.94 (d, 2H, J = 4.8
Hz), 10.87 (s, 1H), 11.08 (s, 1H), 11.64 (s, 1H), 12.68 (bs, 1H);
13C NMR (DMSO-d6, 75 MHz) d: 167.2, 165.0, 164.2, 160.3,
151.2, 149.7, 138.6, 130.5, 127.2, 124.5, 89.5, 86.0, 55.4; MS:
m/z 790 (6), 549 (12), 508 (6), 462 (15), 440 (13), 412 (100, base
peak), 342 (14), 340 (67), 297 (98), 229 (30), 185 (12), 149 (18),
108 (24), 43 (32). 5-(4-(1H-tetrazol-5-yl)phenyl)-1,1¢,3,3¢-
tetramethyl-1H,1¢H-spiro[furo[2,3-d]pyrimidine-6,5¢-pyrim-
idine]-2,2¢,4,4¢,6¢(3H,3¢H,5H)-pentaone (4b): White solid
(80%); mp = 292-294 °C (decomps.); FT IR (KBr) 2500-3500
(CN4H), 1718 (C=O), 1676 (C=O), 1518 (C=C ar.), 1447, 1382,
1032, 749 cm-1; 1H NMR (DMSO-d6, 300 MHz) d 2.43 (s, 3H),
3.12 (s, 3H), 3.22 (s, 3H), 3.40 (s, 3H), 3.33 (bs, 1H, HOD, after
added D2O), 5.23 (s, 1H), 7.41 (d, 2H, J = 8.1 Hz), 7.93 (d, 2H, J =
8.1 Hz); 13C NMR (DMSO-d6, 75 MHz) d: 165.8, 163.4, 163.0,
158.6, 156.0, 151.3, 150.5, 138.4, 130.3, 127.0, 124.7, 90.3, 85.8,
55.7, 30.2, 29.5, 28.22, 28.19; MS: m/z 774 (8), 740 (5), 682 (4),
628 (15), 580 (30), 535 (13), 480 (6), 466 (M+, 40), 438 (100, base
peak), 403 (6), 351 (30), 295 (40), 262 (30), 227 (12), 190 (6), 156
(60), 107 (30), 71 (50), 43 (38). 5-(4-(1H-tetrazol-5-yl)phenyl)-
1¢,3-dimethyl-1H,1¢H-spiro[furo[2,3-d]pyrimidine-6,5¢-py-
rimidine]-2,2¢,4,4¢,6¢(3H,3¢H,5H)-pentaone (4c): White solid
(70%); mp = 244-246 °C (decomps.); FT IR (KBr) 2814-3738
(CN4H), 1733 (C=O), 1707 (C=O), 1644 (C=C ar.), 1522, 1437,
Triethylammonium 5-((4-(1H-tetrazol-5-yl)phenyl)(6-
hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-
5-yl)methyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-
4-olate (8b): White solid (70%); mp = 200-202 °C; FT IR (KBr)
2500-3500 (CN4H), 1693 (C=O), 1605 (C=C ar.), 1454, 1383,
1259, 797 cm-1; 1H NMR (DMSO-d6, 300 MHz) d 1.15 (t, 9H),
3.10 (q, 6H), 3.14 (s, 12H), 6.29 (s, 1H), 7.23 (d, 2H, J = 7.8 Hz),
7.80 (d, 2H, J = 7.8 Hz), 8.90 (bs, 1H); 13C NMR (DMSO-d6, 75
MHz) d: 163.1, 155.6, 151.9, 149.0, 128.1, 126.8, 120.8, 91.1,
46.3, 34.2, 28.4, 9.1. Triethylammonium 5-((6-hydroxy-1,3-
dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)(2-ni-
trophenyl)methyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-
pyrimidin-4-olate (10b): White solid (70%); mp = 128-130 °C
(decomps.); FT IR (KBr) 3474 (OH), 3097 (CH-ar.), 2984 (CH-
aliph.), 2947 (CH-aliph.), 1688 (C=O), 1615 (C=C ar.), 1526
(NO2), 1448, 1368, 1285, 1036, 797, 507 cm-1; 1H NMR (CDCl3,
300 MHz) d 1.33 (t, 9H), 3.40 (q, 6H), 3.27 (s, 12H), 6.40 (s, 1H),
7.24-7.44 (m, 4H), 9.62 (bs, 1H), 16.2 (bs, 1H); 13C NMR (CDCl3,
75 MHz) d: 163.8, 151.9, 149.9, 136.1, 131.2, 129.9, 126.5,
123.7, 91.2, 46.3, 32.0, 28.4, 8.7. Triethylammonium 5-((6-
hydroxy-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-
yl)(2-nitrophenyl)methyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahy-
dropyrimidin-4-olate (10c): White solid (70%), mp = 318-320
°C (decamps.); FT IR (KBr) 3450 (OH), 3068 (CH-ar.), 2993
(CH-aliph.), 1690 (C=O), 1610, 1527, 1461, 1363 cm-1; 1H NMR
(DMSO-d6, 300 MHz) d 1.15 (t, 9H, J = 7.2 Hz, 3 CH3CH2), 3.03
(s, 6H, 2 NCH3), 3.09 (q, 6H, J = 7.2 Hz, 3 -CH2CH3), 6.18 (s, 1H,
CH-aliph.), 7.23-7.42 (m, 4H, CH-ar.), 8.75 (bs, 1H, NH), 10.28
(s, 2H, NH-BA), 16.25 (bs, 1H, OH); 13C NMR (DMSO-d6, 75
MHz) d: 164.4, 162.6, 151.4, 150.3, 138.0, 131.1, 130.0, 126.5,
123.6, 90.4, 46.2, 30.9, 27.2, 9.1. Triethylammonium 5-((1,3-di-
ethyl-6-hydroxy-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidin-
5-yl)(2-nitrophenyl)methyl)-1,3-diethyl-6-oxo-2-thioxo-1,2,
1
1376, 1191, 1029, 756 cm-1; H NMR (DMSO-d6, 300 MHz) d
2.43 (s, 3H), 3.07 (s, 3H), 5.03 (s, 1H), 7.35 (d, 2H, J = 7.8 Hz),
7.94 (d, 2H, J = 7.8 Hz), 11.93 (s, 1H), 13.00 (bs, 1H); 13C NMR
(DMSO-d6, 75 MHz) d: 166.2, 164.2, 163.4, 159.6, 151.3, 150.0,
138.3, 130.2, 127.1, 90.0, 85.1, 56.0, 27.4, 27.3; MS: m/z 778 (4),
966
www.jccs.wiley-vch.de
© 2015 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2015, 62, 959-967

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis of New Tetrazole Derivatives
7. Dekhane, D. V.; Pawar, S. S., Gupta, S.; Shingare, M. S.;
Patil, C. R.; Thore, S. N. Bioorg. Med. Chem. Lett. 2011, 21,
6527-6532.
3,6-tetrahydropyrimidin-4-olate (11e): White solid (70%); mp
= 128-130 °C (decomps.); FT IR (KBr) 3083 (CH-ar.), 2979
(CH-aliph.), 2932 (CH-aliph.), 2871 (CH-aliph.), 1640 (C=O),
1614 (C=C ar.), 1526 (NO2), 1434, 1380, 1265, 1103, 781 cm-1;
1H NMR (CDCl3, 300 MHz) d 1.29 (m, 6H), 1.38 (t, 9H), 3.40 (m,
4H), 4.57 (q, 6H), 6.42 (s, 1H), 7.31 (d, 2H, J = 7.8 Hz), 7.46 (t,
1H, J = 8.1 Hz), 7.47 (t, 1H, J = 8.1 Hz), 9.69 (bs, 1H); 13C NMR
(CDCl3, 75 MHz) d: 175.0, 162.6, 162.3, 150.1, 131.3, 129.7,
126.8, 123.9, 121.0, 96.1, 46.3, 44.1, 43.7, 32.2, 12.4, 12.2, 8.7.
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CONCLUSIONS
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H. L.; Bome, C. A. Proc. Int. Pyrotech. Semin. 2000, 27,
3-14.
In summary, new tetrazole drivatives of spiro- and
bis-barbiturates and their sulfur analogs were made in re-
sults by the reaction between 4-(1H-tetrazol-5-yl)benzal-
dehyde with (thio)barbituric acids and BrCN in the pres-
ence of triethylamine and/or L-(+)-tartaric acid. The eight-
membered intramolecular H-bond was formed in N-
alkylated and N, N’-dialkylated bis-(thio)barbiturates. The
15. Li, J.; Ren, T.; Liu, H.; Wang, D.; Liu, W. Wear 2000, 246,
130-133.
16. Koike, T.; Takashige, M.; Kimura, E.; Fujioka, H.; Shiro, M.
Chem. Eur. J. 1996, 2, 617-623.
17. Chin, T.; Gao, Z.; Lelouche, I.; Shin, Y. K.; Purandare, A.;
Knapp, S.; Isied, S. S. J. Am. Chem. Soc. 1997, 119, 12849-
12858.
1
structure of all compounds was characterized by IR, H
NMR, 13C NMR spectroscopies and mass analysis tech-
nique. The structure of 4b.H2O was also characterized and
studied by X-ray crystallography. The hydrogen bond
strength (EHB) versus d(O1·····O7(w)) distance (kcal.
mol-1) and corresponding pKa value for the proton of H3A
(in water molecule) in 4b.H2O were estimated 13.8 kcal.
mol-1 and 8.2, respectively.
18. Marder, S. R.; Beratan, D. N.; Cheng, L. T. Science 1991,
252, 103-106.
19. Marder, S. R.; Cheng, L.-T.; Tiemann, B. G.; Friedli, A. C.;
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20. Adamson, J.; Coe, B. J.; Grassam, H. L.; Jeffery, J. C.; Coles,
S. J.; Hursthouse, M. B. J. Chem. Soc., Perk. Trans. 1 1999,
2483-2488.
ACKNOWLEDGEMENTS
21. Finnegan, W. G.; Henry, R. A.; Lofquist, R. J. Am. Chem.
Soc. 1958, 80(15), 3908-3911.
We gratefully acknowledge financial support by the
Research Council of Urmia University.
22. Rigaku/MSC, Inc.. 9009 New Trails Drive. The Woodlands,
TX 77381.
23. Sheldrick, G. M.; SHELXS97 and SHELXL97. University of
Göttingen: Germany, 1997.
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J. Chin. Chem. Soc. 2015, 62, 959-967
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