America n Journal of Analy tic al Chemistry, 2011, 2, 371-375
doi:4236/ajac.2011.23045 Published Online July 2011 (http://www.scirp.org/journal/ajac)
371
Synthesis, Spectroscopy and X-Ray Crystal Structu re of
9-Methyl-3-Thiophen-2-Yl-Thieno [3, 2-e] [1, 2, 4] Triazolo
[4, 3-c] Pyrimidine-8-Carboxyl ic Acid Et hy l Ester
Nikhath Fathima1, Mohamed Ziaulla1, Afshan Banu1, Shridhar Ishwar Panchamukhi2,
Imtiyaz Ahmed Khazi 2, Noor Shahina Begum1*
1Departmen t of Chemistry, Bangalore University, Bangalore, India
2Departmen t of Chemistry, Karnatak University, Dharwad, India
Received October 19, 2010; revised April 6, 2011; accepted May 20, 2011
Abstract
The Preparation of 9-Methyl-3-thiophen-2-yl-thieno [3, 2-e] [1, 2, 4] triazolo [4, 3-c] pyrimi-
dine-8-carboxylic acid ethyl ester is described. Elemental analysis, IR spectrum, 1H NMR, 13C NMR and
X-ray crystal structure analyses were carried out to determine the composition and molecular structure of the
title compound. There are two independent molecules in the asymmetric unit exhibiting intermolecular
C-H…N, C-H…O interactions with additional π-π interaction that further helps in stabilizing the supramo-
lecular structure. The results showed that the proposed method for synthesis is simple, precise and accurate
which was further confirmed by crystal structure analysis.
Keywords: Thieno-Triazolo-Pyrimidine Derivative, Characterization, X-Ray Crystallographic Analysis,
C-H…N, C-H…O and π-π Weak Interactions.
1. Introduction
Pyrimidine and thieno p yrimid ine der ivatives are found in
a variety of natural products (viz., purines, pyrrolopyri-
midines, pyridopyrimidines, pteridines), agrochemicals
and veterinary products [1,2]. Compounds containing
fused pyrimidine ring make up a broad class of heterocy-
cles that has attracted attention in the past fe w years o w-
ing to its wide range of biological act ivities s uch as ant i-
cancer [3], antiviral [4], antitumor [5] and anti-inflam-
matory activities [6]. Also, the rapid growth in the lit-
erature dealing with the synthesis and biological activity
of the thienopyrimidine derivatives [7] prompted us to
undertake the synthesis of novel fused thienopyridine
derivative.
The synthesis of the compound was followed by mea-
surement of the analytical data and subsequent spec-
trosc opic analysis u sing IR, 1H-NM R and 13C-NMR tech-
niques to confir m the presence of the supposed ring sys-
tem. The compound was subjected to single crystal X-ray
diffraction analysis so that its supramolecular structure
could be inve stigated in ter ms of po ssible inter molecular
interactions.
2. Experimental Section
2.1. Material s
All chemicals were obtained from a commercial source
and use d witho ut furthe r purif ication. Yello w colour sin-
gle-crystals suitable for X-ray diffraction were obtained
by slow evaporation of t he solvents.
2.2. Analytical Methods
Melting points were determined in open capillaries and
are uncorrected. The IR spectra were recorded on Nicolet
Impact 410 FT IR spectrophotometer using KBr pellets.
1H and 13C NMR were recorded on Bruker 300-MHz FT
NMR spectrometer in CDCl3 with TMS as internal stan-
dard. Mass spectra were recorded on Finnigan MAT
(Model MAT 8200) spectrometer and elemental analyses
were carried out using Heraus CHN rapid analyzer.
2.3. Preparation of 9-Meth y l-3-Thiophen-2-Yl-
Thieno [3, 2-e] [1, 2, 4] Tria zolo [4, 3-c] Py-
rimidine-8-Carboxylic Acid Ethyl Ester
A mixture of 2 (0.2667 g, 1 mmole) and thiophene-2-

N. FATHIMA ET AL. 372
carboxylic acid hydrazide (0.1421 g, 1 mmole) wa s stir-
red at room temperature in tol uene (5 ml) and acetic acid
(0.060 g, 1 mmole) were added and the resulting reaction
mixture was refluxed for 12 h. After the completion of
the reaction the reaction mixture was washed with water
and dried over sodium sulphate. Toluene was removed
under reduced pressure to obtain analytically pure com-
pound.
2.4. Physical Measuments: 9-Methyl-3-Thiophen
-2-Yl-Thieno[3, 2-e][1, 2, 4]Triazolo[4, 3-c]
Pyrimidine-8-Carboxylic Acid Ethyl Est er
Yield 75%, mp: 174˚C - 176˚C. IR (KBr) ν·cm–1: 3068,
2983, 2924, 1728, 1617, 1531. 1H NMR (300 MHz,
CDCl3): δ 1.42 (
t
, 3 H, CH3), 3.2 (
s
, 3 H, CH3), 4.47
(
q
, 2H, CH2), 7.29 - 7.94 (
m
, 3 H, ArH), 9.78 (
s
, 1H,
C5-H). 13C NMR (75 MHz, CDCl3): δ 14.7, 15.6, 62.0,
121.8, 128.2, 128.4, 129.3, 129.6, 132.7, 138.5, 140.6,
150.5, 156.3, 161.6, 162.6. Anal. calcd. for C15 H12 N4 O2
S: C, 52.31; H, 3.51; N, 16.27; S, 18.62 Found: C, 52.88;
H, 3.80; N, 16.32; S,18.42. MS m/z: 346.07 (
2m+
).
3. X-Ray Diffraction Analysis
The X-ray diffraction data for the compound 3 was col-
lected on a Bruker Smart CCD Area Detector System,
using MoK
α
(0.71073 Å) radiation for the crystal. In-
tensity data were collected up to a maximum of 29.41˚ in
the
- ωφ
scan mode. The data were reduced using
SAINTPLUS [8]. The structure was solved by direct
methods using SHELXS97 [9] and difference Fourier
synthesis using SHELXL97 [9]. The positions and ani-
sotropic displacement parameters of all non-hydrogen
atoms were included in the full-matrix least-square re-
finement using SHELXL97 [9] and the procedure were
carried out for a few cycles until convergence was
reached. A total of 34420 reflections were collected, re-
Reagent and Conditions: i) Triethylorthoformate, reflux ii)
RCONHNH2, AcOH, reflux 12 h.
Table 1. Crystal data and s tructure refinement
Empirical formula
C15 H12 N4 O2 S2
Formula weight
344.41
Temperature
293(2) K
Wavelength
0.71073 Å
Crystal system , space group
Triclinic, P-1
Unit cell dimensions
a (Å)
8.3986(5)
b (Å)
8.9813(6)
c (Å)
23.3149(12)
α
(Å)
83.888(5)
β (˚) 79.673(5)
γ
(˚) 62.904(7)
Volume Å3
1539.65(2)
Z
4
Calculat ed dens i ty (mg/m3)
1.486
Absorption coefficient (mm–1)
0.360
F(000) 712
Crystal size
0.4 mm × 0.35 mm × 0.3 mm
Thet a range for data collection
2.55 - 29.41
Limiting indices
–11 < = h < = 11
–12 < = k < = 12
–30 < = l < = 31
Reflections collected / unique
34420/7623 [R(int) = 0.0726]
Completeness to th eta
29.4 1 8 9 . 3 %
Refinement method
Ful l-matrix least-squares on F2
Data/restraints/parameters
7623/0/425
Goodness-of-fit on F
2
0.934
Fina l R indices [I > 2sigm a(I)]
R1 = 0.0821, wR2 = 0.213 6
R indices (all data)
R1 = 0.1341, wR2 = 0.238 3
Largest diff. peak and hole(e Å-3)
0.85 1 and –0.196
sulting in 7623 [R(int) = 0.0726] independent reflections
of which the number of reflections satisfying
( )
I2I σ >
criteria were 4579. These were treated as observed. The
H atoms were placed at calculated positions i n the riding
model approximation (C-H 0.93 Å), with their tem- pe-
rature factors were set to 1.2 times those of the equiva-
lent isotropic te mperature factors of the parent atoms. All
other non-H atoms were refined anisotropi- cally. The R
factor for observed data finally converged to R = 0.0821
with wR2 = 0.2136 in the compo und. T he maximu m and
minimum values of residual electron den- sity were
0.851 and –0.196 eÅ–3. Molecular diagrams were gener-
ated using ORTEP [10]. The mean plane cal- culation
was done using the program P ARST [11].
4. Results and Discussion
4.1. Chemistry
The required 5-amino-4-cyano-3-methylthiophene-2-car-
boxylic acid ethyl ester 1 was prepared by Gewald’s re-
action as reported in the literature [12] Formation of 5-
amino-4-cyano-3-methylthiophene-2-carboxylic acid e-
thyl ester 1 was characterized by the presence of band at
2210 cm–1 due to cyano group and N-H stretching bands
at 3339 and 3190 cm–1 in their IR spectrum. Further it
was also supported by the presence of D2 O exchangeable

N. FATHIMA ET AL. 373
Table 2. Bond lengths [Å].
Atoms
Leng th
C1-C2 1.494(7)/1.480(9)
C2-O1
1.461(6)/1.457(6)
C3-O2
1.202(6)/1.196(6)
C3-O1
1.330(6)/1.325(6)
C3-C4
1.475(7)/1.479(6)
C4-C5
1.378(6)/1.370(7)
C4-S1
1.737(4)/1.736(5)
C5-C7
1.417(6)/1.437(6)
C5-C6
1.502(6)/1.494(7)
C7-C8
1.395(6)/1.389(6)
C7-C9
1.427(6)/1.422(6)
C8-N1
1.387(6)/1.384(6)
C8-S1
1.704(5)/1.722(5)
C9-N4
1.328(6)/1.325(6)
C9-N2
1.381(6)/1.383(5)
C10-N1 1.280(6)/1.283(7)
C10-N2
1.374(6)/1.361(7)
C11-N3
1.345(6)/1.328(6)
C11-N4
1.364(6)/1.368(6)
C11-C12
1.452(6)/1.447(6)
C12-C15
1.443(8)/1.588(8)
C12-S2
1.713(5)/1.706(5)
C13-C14
1.454(9)/1.343(7)
C14-C15
1.338(8)/1.43(9)
C15-S2
1.679(6)/1.663(6)
N2-N3
1.374(5)/1.375(5)
*The values given a fter/corres pond to molecu le B
broad singlet at
δ
7.97 in 1H NMR spectrum due to
NH2 group.
Imidoformate 2 was prepared in excellent yield by
treating 1 with triethylorthoformate in refluxing tem-
perature (scheme 1). The structure of imidoformate 2
was established by the absence of
N-H
v
in IR and the
presence of a triplet at
δ
1.42 and a quartet at δ 4.47
corresponding to protons of the ethoxy group and peak
around
δ
8.47 due to N = CH in the 1H NMR spec-
trum, along with the expected signals. The reaction of
imido- formate ester 2 with thiophene-2-carboxylic acid
hy- drazide in refluxing toluene afforded the desired 9-
Methyl-3-thiophen-2-yl-thieno [3, 2-e] [1, 2, 4] triazolo
[4, 3-c] pyrimidine-8-carboxylicacid ethyl ester (3) in
moder ate yield.
The structure of the target compound was ascertained
by the analytical and spectral data. IR spectra of this
compound exhibited bands at 1617 and 1531 due to
A B
Figure 1. ORTEP diagram of compound (2), showing 50%
probability displacement ellipsoids and the atom-number-
ing scheme.
Table 3. Se lected bond angles [˚].
Atoms
Angle
O1-C2-C1 107.3(4)/108.2(5)
O2-C3-O1
124.1(5)/124.0(4)
O2-C3-C4
124.9(4)/124.2(5)
O1-C3-C4
111.0(4)/111.7(4)
C5-C4-C3
127.8(4)/127.3(4)
C5-C4-S1
113.8(3)/114.3(3)
C3-C4-S1
118.3(3)/118.4(4)
C4-C5-C7
110.1(4)/110.0(4)
C4-C5-C6
126.9(4)/126.8(4)
C7-C5-C6
123.1(4)/123.1(4)
C8-C7-C5
113.4(4)/113.2(4)
C8-C7-C9
115.4(4)/115.6(4)
N1-C8-C7
126.0(4)/127.0(4)
N1-C8a-S1
121.7(3)/120.8(3)
C7-C8-S1
112.3(3)/112.2(3)
N4-C9-N2 109.6(4)/109.9(4)
N4-C9-C7
134.3(4)/135.0(4)
N2-C9-C7
116.0(4)/115.1(4)
N1-C10-N2
122.2(4)/123.1(5)
N3-C 11-N4
115.9(4)/116.2(4)
N3-C 11-C12
122.8(4)/122.0(4)
N4-C 11-C12
121.3(4)/121.8(4)
C11-C12-S2
122.8(3)/122.0(4)
C13-C12-S2
113.1(4)/118.8(4)
C12-C13-C14
106.9(6)/107.9(6)
C15-C14-C13
114.2(6)/116.3(6)
C14-C15-S2
114.4(5)/114.7(5)
C3-O1-C2
116.0(4)/116.7(4)
C10-N1-C8
116.5(4)/114.8(4)
C10-N2-N3
126.1(4)/126.4(4)
C10-N2-C9 123.9(4)/124.4(4)
N3-N2-C9 A
110.0(3)/109.2(4)
C11-N3-N2
101.3(4)/101.9(3)
C9-N4-C 11
103.1(4)/102.8(4)
C8-S1-C4
90.5(2)/90.3(2)
C15-S2-C12
91.4(3)/91.9(3)
*The values given a fter/corres pond to molecu le B
C = N and C = C. 1H NMR spectra displayed the absence
of peaks due to ethoxy protons present in compounds 2
and presence of thiophenic protons substituent in 3. Fi-
nally the structures were confirmed by their mass spec-
tral data and sin gle crystal x-ray di ffrac tion analysis .
4.2. Crystallography
Summary of crystallographic data and other structure
refinement parameters of the title compound are shown
in Ta ble 1. The selected bond lengths and b o nd angle s o f
all the non-hydrogen atoms are given in Tables 2 and
Table 3. Table 4 shows the respective hydrogen bond
interactions of the compound. The ORTEP view of the
molecule with atomic labeling (thermal ellipsoids drawn
at 50% probability) is sho wn in Figure 1. Fig ur e s 2 and
3 show t he packi ng of mo lecule s in t he crystal structure.
Figure 4 shows π-π interaction.
The compound 3 consists of two independent mole-
cules A and B respectively in the asymmetric unit. The
tricyclic system including the c onde ns ed thiophene, pyri-

N. FATHIMA ET AL. 374
Table 4. Non-bonded interactions and possible hydrogen
bonds (Å, ˚) for compound 3. (D-donor; A-acceptor; H-
hydrogen).
D-H· · ·A D-H H· · ·A D· · ·A D-H· · ·A
C10a-H10a...O2a
C10b-H10b2...N1b
C6b-H6b...N2bi
C14a-H14a...O2aii
C6a-H6a…O2aii
0.960(5)
0.960(5)
0.885(5)
0.890(9)
0.885(5)
2.335(5)
2.572(5)
2.584(9)
2.728(1)
2.752(2)
3.052(7)
3.302(8)
3.374(9)
3.122(7)
3.248(8)
131
133
149
138
116
Symmetry code: 0) x, y, z; i) –x + 1, –y, –z – 1; ii) –x + 2, –y, –z.
midine, and triazole rings is virtually planar as reported
earlier [13]. The dihedral angle between the condensed
thiophene-triazolo -pyrimidine rings and thieno ring is
coplanar inclined at an angle 13.77˚ and 12.76˚ in the
molecules A and B resp ecti vel y. The methyl group is cis
to the carboxylic acid ethyl ester group and almost or-
thogonal to thiophene-triazo lo -pyrimidine rings at an
angle 85.89˚ and 85.21˚ respectively.
The intramolecular interaction is different in mole-
cules A and B. Molecule A shows C-H…O interaction
whereas it is C-H…N in molecule B. In the molecule A,
the carbonyl group has cis orientation with resp ect to the
C8a = C9a double bond leading to a strong intramolecu-
lar C10a-H10a …O 2a hydrogen bond [C10 a-H10a =
0.960(5) Å, H10a…O2a = 2.338(5) Å, C10a…O2a =
3.056(7) Å and the angle C10a-H10a…O2a = 131˚]. In
th e mo lecule B, the stro ng int ra mole cular h ydro gen b ond
is C10b-H10b2…N1b [C10b-H10b2 = 0.960(5) Å,
H10b2…N1b = 2.567(5) Å, C10b…N1b = 3.303(8) Å
and the angle C10a-H10b2…N1b = 133˚]. These two
Figure 2. C-H….N intermolecular interactions viewed
roughly along ‘a’ axis.
interactions i n molec ules A and B leads to the for mation
of a pseudo-seven-membered ring pattern with graph set
motif S(7) [14], thus locking the molecular conformation
and eliminating conformational flexibility. The orienta-
tion of the carboxylic acid ethyl ester group is character-
ized by the torsion angles S(1a)-C(8a)-C(11a)-O(1a)
[9.7(6)˚] in molecule A and S(1b)-C(8b)-C(11b)-O(1b)
[3.5(1)˚] in the molecule B respectively.
The crystal structure of molecules A and B are stabi-
lized by some interesting features that comprises of in-
termolecular interactions C-H…N and C-H…O. The
C-H…N interaction results in centrosymmetric head to
head dimers corresponding to graph set motif
2
2
R
(8)
(Bernstein, et al., 1995) as depicte d in [Figure 2]. There
are two C-H...O hydrogen bonds [Figure 3], linking the
molecules in a cohesive manner. One of the C-H…O
interaction forms bifurcated bond from two donors C6b
and C14b to the same acceptor O2b resulting in a zig-zag
pattern. The other C-H…O interaction forms centro-
symmetric head to head dimers corresponding to graph
Figure 3. Packing of the molecules in crystal of (3) viewed
along ‘a’ axis. Dotted lines indicate C-H...O intermolecular
interactions generating bif urcated b ond resul ting in dimers.
Figure 4. π-π stacking interactions betw een the two pyrimi -
dine rings.

N. FATHIMA ET AL. 375
set notation R22(24) (Bernstein et al., 1995). The π-π
stacking interaction [Figure 4] between the two pyrimi-
dine rings being separated by a distance of 3.424(1)Å
(symmetry code: 1 – x, 1 – y, –z) further strengthe ns the
supramolecular structure.
5. Conclusions
In this paper we report the synthesis of 9-Methyl-3- thi-
ophen-2-yl-thieno [3, 2-e] [1, 2, 4] triazolo [4, 3-c] py-
rimidine-8-carboxylic acid ethyl ester. The X-ray ana-
lysis was carried o ut in order to establish supramolecular
assembly in terms of possible intermolecular interac-
tions. In the present work the crystallographic studies
aims at highlighting the importance of hydrogen bond
interaction which is one of the most important of all di-
rectional in- termolecular interactions. Here several hy-
drogen bond- ing interactions of the triazolo-pyrimidine
groups and the interaction between carboxylic acid ester
and the pyrimi- dine group between the two different
molecule s have b een demonstrated.
6. Supplementary Material
Crystallograp hic data for the s tructure (3) repo rted in this
paper have been deposited with the Cambridge data cen-
tre. The deposition number is CCDC 787335.
7. Acknowledgements
N. S. B is thankf ul to the Uni versit y Gr ants Co mmissio n
(UGC), India for the financial a ssistance.
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