New and efficient synthesis of N-(4-substituted phenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-amines

Article abstract of DOI:10.14233/ajchem.2014.18067

The reaction of 2-isonicotinoyl-N-arylhydrazinecarbothioamide (2a-c) with chloroacetic acid in presence of anhydrous sodium acetate in absolute ethanol yields, in each case, a single product. The single crystal X-ray analysis confirmed the structure of these products as N-(4- aryl)-5-(pyridine-4-yl)-1,3,4-oxadiazol-2-amines (4a-c).

Full text of DOI:10.14233/ajchem.2014.18067

Asian Journal of Chemistry; Vol. 26, No. 24 (2014), 8483-8487
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.18067
New and Efficient Synthesis of N-(4-Substituted phenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-amines
1,*
1
2
1,2
M.A. BHAT , H.A. GHABBOUR , C.S.C. KUMAR and H.K. FUN
1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
2X-Ray Crystallography Unit, School of Physics, Universiti Sains Malaysia, 11800 USM, Penang, Malaysia
*Corresponding author: Fax: +966 1 4676220; Tel: +966 14677343; E-mail: mashooqbhat@rediffmail.com
Received: 22 May 2014;
Accepted: 25 August 2014;
Published online: 1 December 2014;
AJC-16387
The reaction of 2-isonicotinoyl-N-arylhydrazinecarbothioamide (2a-c) with chloroacetic acid in presence of anhydrous sodium acetate in
absolute ethanol yields, in each case, a single product. The single crystal X-ray analysis confirmed the structure of these products as N-(4-
aryl)-5-(pyridine-4-yl)-1,3,4-oxadiazol-2-amines (4a-c).
Keywords: Isoniazid, 1,3,4-oxadiazole, X-ray diffraction, Crystal structure and packing.
12
as POCl3 or concentrated sulfuric acid13. Alternatively,
INTRODUCTION
phosphonium salts and Burgess-type reagents14 have been used
1,3,4-Oxadiazole heterocycles are useful for the deve-
to promote the cyclization. However, these reagents cause the
lopment of molecules of pharmaceutical interest. Substituted
formation of significant by-products and are only suitable for
1,3,4-oxadiazoles, have been the subject of extensive research
due to its pharmacological activities. Literature survey revealed
that minor modifications in the structure of 1,3,4-oxadiazole
can lead to quantitative as well as qualitative changes in the
solid phase synthetic strategies. The reported cyclization
protocols for thiosemicarbazides (2a-c) into 1,3,4-oxadiazoles
(4a-c) were investigated using several desulfurization reagents
including mercuric salts, lead oxide, I2/NaOH, TsCl, DCC,
biological activities. One of the most effective first-line anti-
EDC, polymer supported DCC, PS-carbodiimides, TBTU and
hypervalent iodine(V)15,16. Most of these cyclization methods
TB drugs is isoniazid (INH). Many analogues featuring the
structure of isoniazid have been synthesized and tested as anti-
have several disadvantages such as handling of harsh and toxic
mycobacterials. In a critical review published recently, the
reagents, elevated temperatures, long reaction time, etc. From
existence of more than 3000 compounds based on the isoniazid
literature survey, there is no report of using chloroacetic acid/
core was reported by Janin1. It has been reported by Wilder-
anhydrous sodium acetate as cyclodesulfurization agent for
Smith2 and Mamolo et al.3 that conversion of isoniazid to the
corresponding 5-substituted-3H-1,3,4-oxadiazol-2-thione and
3H-1,3,4-oxadiazol-2-one and their 3-alkyl or aryl/alkyl
derivatives, was characterized by their high activity against
the synthesis of 1,3,4-oxadiazoles.
Thus newer and mild protocols for this privileged class
of molecules are continuously sought. We have now focused
on a simple and efficient protocol for the synthesis of N-(4-
aryl)-5-(pyridine-4-yl)-1,3,4-oxadiazol-2-amines.
M. tuberculosis strain H37Rv. 1,3,4-Oxadiazoles conform to
an important class of heterocyclic compounds with a wide
range of biological activities such as antiviral4, tyrosinase
EXPERIMENTAL
inhibitors5, antimicrobial6,7, cathepsin K inhibitors8, fungicidal9
and antineoplastic properties10. In continuation of our interest
All the solvents were obtained from Merck. The homo-
in the chemistry of 1,3,4-oxadiazoles11, we aimed to study the
geneity of the compounds was checked by TLC performed on
reaction of isoniazid thiosemicarbazides (2a-c) with chloro-
acetic acid/anhydrous sodium acetate (3). This reaction did
not afford possible 1,3,5-thiadiazolidinone where choroacetic
acid acts as cyclodesulfurization agent for (2a-c) to produce
corresponding 1,3,4-oxadiazoles (4a-c) Scheme-I. The most
straightforward synthetic route involves the cyclodehydration
of semicarbazides, which typically requires harsh reagents such
Silica gel G coated plates (Merck). Iodine chamber was
used for visualization of TLC spots. The FT-IR spectra were
recorded in KBr pellets on a (Spectrum BX) Perkin Elmer FT-
IR spectrophotometer. Melting points were determined on a
Gallenkamp melting point apparatus and thermometer was
uncorrected. NMR Spectra were scanned in DMSO-d6 on a
Bruker NMR spectrophotometer operating at 500 MHz for 1H

8484 Bhat et al.
Asian J. Chem.
Equimolar mixture of isonicotinic hydrazide (0.01 mol) and
4-aryl isothiocyanate in absolute ethanol (25 mL) was heated
until a clear solution was obtained. The solution was refluxed
for 3 h on water bath. The precipitated solid was filtered off
and recrystallized from ethanol.
General procedure for the synthesis of N-(4-aryl)-5-
(pyridin-4-yl)-1,3,4-oxadiazol-2-amine (4a-c): To a suspen-
sion of appropriate thiosemicarbazide 2a-c (0.01 mol) in
absolute ethanol (25 mL), chloroacetic acid (0.01 mol) and
anhydrous sodium acetate (0.012 mol) was added. The mixture
was refluxed on a water bath for 3 h, then left to cool. The
separated solid was filtered off, washed with water and
recrystallized from EtOH/DMF to give compounds 4a-c,
respectively.
N-(4-Chlorophenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-
2-amine (4a): Yield: 76 %; m.p.: 310-312 °C (EtOH/DMF)
(Lit19. m.p.: 238-240 °C; IR (KBr, νmax, cm-1): 3250 (NH str.);
1H NMR (500 MHz, DMSO-d6) δ: 7.4 (2H, d, J = 8.5 Hz, Ar-
H), 7.6 (2H, d, J = 8.5 Hz, Ar-H), 7.8 (2H, d, J = 4.2 Hz,
pyridyl-H), 8.8 (2H, d, J = 4.2 Hz, pyridyl-H), 11.06 (s, D2O
exch., 1H, NH); 13C NMR (125 MHz, DMSO-d6) δ: 118.8,
119.2, 125.8, 129.0, 130.0, 137.3, 150.8, 156.3, 160.0; ESI
m/z =273 [M]+, 275 [M + 1]+; HR MS: 271.976820.
N-(4-Flourophenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-
2-amine (4b): Yield: 67 %; m.p.: 250-252 °C (EtOH/DMF);
IR (KBr, νmax, cm-1): 3279 (NH); 1H NMR (500 MHz, DMSO-
d6) δ: 7.1 (2H, d, J = 8.5 Hz, Ar-H), 7.6 (2H, d, J = 8.5 Hz, Ar-
H), 7.7 (2H, d, J = 4.2 Hz, pyridyl-H), 8.7 (2H, d, J = 4.2 Hz,
pyridyl-H), 11.06 (s, D2O exch., 1H, NH); 13C NMR (125 MHz,
DMSO-d6) δ: 115.5, 118.9, 119.8, 130.7, 134.7, 150.6, 156.1,
156.5, 158.4, 160.4; ESI m/z = 257.1 [M + 1]+; HR MS:
255.9877.
Scheme-I: Synthesis of compounds 4a-c
and 125.76 MHz for 13C at the Research Center, College of
Pharmacy, King Saud University, SaudiArabia. Chemical shifts
are expressed in δ-values (ppm) relative to TMS as an internal
standard and D2O was added to confirm the exchangeable
protons. Mass spectra were measured on Jeol-JMS-700 HR
MS. Crystals suitable for X-ray diffraction were mounted on
glass fibers and their crystal data were collected using either
Bruker SMART Apex II diffractometer. The data for these
compounds were processed with SAINT and corrected for
absorption using SADABS (Bruker17). The structures of the
compounds were solved by direct method using the program
SHELXTL (Sheldrick18) and were refined by full-matrix least
squares technique on F2 using anisotropic displacement
parameters. The non-hydrogen atoms were refined aniso-
tropically. In these compounds, all the H atoms were calculated
geometrically with isotropic displacement parameters set to
1.2 (1.5 for methyl groups) times the equivalent isotropic U
values of the parent carbon atoms. For methyl groups, a rotating
group model was applied. The crystallographic data for the
reported compounds are given in Table-1. H-bonding
interactions are listed in Table-2.
General procedure for the synthesis of N-(4-aryl)-2-
(pyridin-4-ylcarbonyl) hydrazinecarbothioamide (2a-c):
TABLE-1
CRYSTAL DATA AND PARAMETERS FOR STRUCTURE REFINEMENT OF 4a, 4b AND 4c
Compound
Molecular formula
Molecular weight
4a
C13H9N4OCl
272.69
4b
C13H9N4OF
256.24
4c
C13H9N4OBr
317.14
Crystal system
Space group
Monoclinic
P21/c
Monoclinic
P21/c
Monoclinic
P21/c
a/Å
b/Å
c/Å
α/°
7.0865 (2)
14.2650 (3)
13.3863 (4)
90
6.8862 (2)
14.2190
13.3656 (3)
90
7.1990 (2)
14.2364 (5)
13.5100 (5)
90
115.973 (2)
90
1216.53 (6)
4
116.577 (2)
90
1170.41 (5)
4
115.886 (3)
90
1245.69 (8)
4
β/°
γ/°
V/Å3
Z
Dcalc (g cm-3)
Crystal dimensions (mm)
µ/mm-1
1.489
0.90 × 0.62 × 0.34
2.77
1.454
0.12 × 0.14 × 0.66
0.91
1.691
0.17 × 0.12 × 0.10
4.49
1.54178
8459
-8, 6; -17, 13; -16, 16
4.8-70.0
2227
1.54178
8049
-7, 7; -17, 16; -16, 15
6.2-69.8
2145
1.54178
8578
-8, 8; -17, 15; -15, 16
4.8-69.8
2331
Radiation γ (Å)
Reflections measured
Ranges/indices (h, k, l)
θ limit (°)
Unique reflections
Observed reflections (I > 2σ(I))
Parameters
1965
173
1833
173
1651
172
Goodness of fit on F2
1.06
1.06
1.05
0.033, 0.096
0.038, 0.114
0.043, 0.120
R1, wR2 (I ≥ 2σ(I))

Vol. 26, No. 24 (2014)
D-H···A
New and Efficient Synthesis of N-(4-Substituted phenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-amines 8485
TABLE-2
HYDROGEN BOND GEOMETRIES FOR COMPOUNDS 4a, 4b AND 4c
d(D-H) (Å)
d(H···A) (Å)
d(D···A) (Å)
Angle (D-H···A) (°)
(4a)
2.05
2.53
2.29
N4-H1N···N1i
C12-H12A···N2ii
C13-H13A···N3
0.86
0.93
0.95
2.9056 (19)
3.376 (2)
2.925 (2)
174.00
151.00
125.00
(4b)
2.05
2.51
2.28
N4-H4N···N1iii
C12-H12A···N2iv
C13-H13A···N3
0.88
0.93
0.93
2.9235 (19)
3.316 (2)
2.918 (2)
174.00
145.00
125.00
(4c)
2.09
2.53
2.31
3.04
N1A-H1···N5Av
C2A-H3···N3Aii
C1A-H2···N2A
0.86
0.93
0.93
0.93
2.915 (4)
3.392 (5)
2.938 (5)
3.819(14)
162.00
155.00
125.00
142.90
C11A-H11A···Br1A
(i) -x + 3, y + 1/2, -z + 1/2; (ii) -x + 1, -y-1, -z; (iii) -x + 2, y + 1/2, -z-1/2; (iv) -x, -y-1, -z-1; (v) –x-1, y + 1/2, -z-1/2
N-(4-Bromophenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-
2-amine (4c): Yield: 70 %; m.p.: 290-292 °C; IR (KBr, νmax
hydrogen bonds (Table-2. 4a) are observed. These H-bond
patterns are of significance, in which rings are the most
prominent features. The N4 of the secondary amine group of
one molecule is linked to N1 of the pyridine ring of the other
molecule via N4-H1N···N1 (symmetry code: -x + 3, y + 1/2,
-z + 1/2) hydrogen bond. These head-to-tail arrangements of
hydrogen bonds link the molecules into a supramolecular chain
along the crystallographic axis b. Furthermore these chains
are interconnected into a two dimensional structure via a pair
of C12-H12A···N2 (symmetry code: -x + 1, -y-1, -z) inter-
molecular H-bonds generating R22(16) ring motif. The crystal
packing is, as expected, dominated by these hydrogen bonds.
In the molecule, an intramolecular C13-H13A···N3 hydrogen
bond forms a six-membered ring, producing an S(6) ring motif.
The observed C(11)-Cl(1) bond length is 1.7487 (17) Å. Bond
lengths and bond angles are within the normal ranges.
,
cm-1): 3190 (NH); 1H NMR (500 MHz, DMSO-d6) δ: 7.5 (2H,
d, J = 8.5 Hz, Ar-H), 7.6 (2H, d, J = 8.5 Hz, Ar-H), 7.8 (2H, d,
J = 4.2 Hz, pyridyl-H), 8.8 (2H, d, J = 4.2 Hz, pyridyl-H),
11.06 (s, D2O exch., 1H, NH); 13C NMR (125 MHz, DMSO-
d6) δ:168.4, 163.3, 160.2, 156.3, 152.7, 150.6, 146.6, 138.0,
132.0, 125.0, 129.9, 121.4, 119.4, 113.7, 56.0; HR MS:
315.9593 [M+], 317.9696 [M+].
RESULTS AND DISCUSSION
The reaction of isonicotinichydrazide (1) with aryl iso-
thiocyanates in absolute ethanol afforded thiosemicarbazides
2a-c which was then treated with chloroacetic acid in presence
of anhydrous sodium acetate 3 in absolute ethanol to yield, in
each case, a single product as examined by TLC. However,
the intermolecular cyclization of thiosemicarbazides similar
to 2a-c via losing of H2S molecule to give 1,3,4-oxadiazoles
were reported with different procedures21. The structures of
compounds N-4-aryl-5-(pyridine-4-yl)-1,3,4-oxadiazol-2-
amines 4a-c were confirmed by single crystal X-ray analysis.
Scheme-I illustrates the synthetic pathways used for the prepa-
ration of target compounds. Starting materials thiosemi-
carbazides (2a-c) were used to produce the final compounds
N-(4-aryl)-5-(pyridine-4-yl)-1,3,4-oxadiazol-2-amines (4a-c).
In IR spectra of all compounds NH stretching were observed
at about 3219-3190 cm-1. In the 1H NMR spectra of the com-
pounds 4a-c that are taken in DMSO-d6, D2O exchangeable
NH proton was seen as broad singlet at 11 ppm. The aromatic
protons appear as multiplet at 7.1-8.8 ppm. High resolution
mass (HR MS) of the compounds 4a, 4b and 4c showed
273.9650, 256.9855 and 315.9593 mass, respectively in
agreement with their molecular formula.
(4a)
(4b)
Crystal structure of compound 4a: The molecular
structure of 4a is depicted in (Fig. 1 4a). The oxadiazole ring
(N2/N3/C6-C7/O1) is planar with a maximum deviation of
-0.0033(12) Å for O1, forming the dihedral angle of 5.61(8)°
and 3.42(8)° with the pyridine ring system (N1/C1-C5) and to
that of the chloro-substituted phenyl ring (C8-C13), respec-
tively. In the crystal packing of 4a, occurrence of N-H···N,
C-H···N intermolecular and an intramolecular C-H···N
(4c)
Fig. 1. ORTEP diagram of (4a-c), 50 % probability ellipsoid

8486 Bhat et al.
Asian J. Chem.
(4a)
(4a)
Fig. 2. Crystal packing of compound 4a
Crystal structure of compound 4b: (Fig. 1. 4b) shows
the molecular structure of 4b. The oxadiazole ring (N2/N3/
C6-C7/O1), with the maximum deviation of 0.0023(16) Å for
C6, is planar. It forms the dihedral angle of 7.27(8) and 3.71(8)
with the pyridine ring system (C1/C2/N1/C3/C4/C5) and to
the fluoro-substituted phenyl ring (C8-C13) respectively. Bond
lengths and bond angles are within the normal ranges. The
crystal packing of 4b is shown in (Fig. 3). The intermolecular
N-H···N hydrogen bonds link the molecules into zig-zag chains
along the b axis (Table-2. 4b). These chains are further inter-
connected via pair of C-H···N intermolecular H-bonds gene-
rating R22(16) ring motif. In the molecule, an intramolecular
C13-H13A···N3 hydrogen bond forms a six-membered ring,
producing the ring motif with graph-set notation of S(6). The
observed C(11)-F(1) bond length is 1.366(2) Å.
Crystal structure of compound 4c: The molecular struc-
ture of 4c is depicted in (Fig. 4). The oxadiazole ring (C7A/
O1A/C8AN3A/N2A), with the r.m.s deviation of -0.0033(12)
Å for O1, is planar. It forms the dihedral angle of 5.61(8)° and
3.42(8)° with the pyridine ring system (C9A/C10A/C11A/
N5A/C12A/C13A) and to the bromo-substituted phenyl ring
(C1A-C6A) respectively, which is identical to that of comp-
ound 4a. Bond lengths and bond angles are within the normal
ranges. In the crystal packing of 4c, occurrence of N-H···N,
C-H···N intermolecular hydrogen bonds and C-H···N intra-
molecular hydrogen bonds are observed (Table-2. 4c). The
N1A of the secondary amine group of one molecule is linked
to N5A of the pyridine ring of the other molecule via N1A-
H1···N5A hydrogen bond. These hydrogen bonds link the
molecules into a zig-zag chain running parallel to the crysta-
llographic axis b. Further the molecules are held together via
pair of C-H···N intermolecular H-bonds generating R22(16)
ring motif (Fig. 1. 4a). In the molecule (Fig. 1. 4c), an intra-
molecular C1A-H2···N2A hydrogen bond forms a six-mem-
bered ring, producing an S(6) ring motif. Unlike the crystal
packing of 4a and 4b, for 4c in addition to the above, inter-
molecular C11A-H11A···Br1A and N1A-H1···N5A inter-
actions is observed (Fig. 1. 4b) generating an additional R22(20)
ring motif.
Conclusion
The reaction of thiosemicarbazides 2a-c with cholroacetic
acid/anhydrous sodium acetate yields, in each case, a single
product. The FT IR, 1H NMR, 13C NMR, HR MS and single
crystal X-ray crystallography analysis confirmed the structure
of these products as N-(4-aryl)-5-(pyridine-4-yl)-1,3,4-
oxadiazol-2-amines, 4a-c. In the crystal structure studies of
these reported compounds 4a-c, H-bond patterns are of
significance, in which rings are the most prominent features.
The ring motifs with the graph-set notation of S(6), R22(16) in
4a-c and R22(20) in 4c have been observed and discussed.
Fig. 3. Crystal packing of compound 4b

Vol. 26, No. 24 (2014)
New and Efficient Synthesis of N-(4-Substituted phenyl)-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-amines 8487
(4c)
(4c)
Fig. 4. Crystal packing of compound 4c
6. S.L. Gaonkar, K.M.L. Rai and B. Prabhuswamy, Eur. J. Med. Chem.,
41, 841 (2006).
Supplementary details
Cambridge Crystallographic Data Center (CCDC)
numbers 922285, 922286 and 924114 contains crystallogra-
phic data for the structures 4a, 4b and 4c, respectively. Copies
of the data can be obtained, free of charge, on application to
CCDC 12 Union Road, Cambridge CB2 1EZ, UK (Fax: +44-
1223-336033; e-mail: deposit@ccdc.cam.ac.uk/ http://
www.ccdc.cam.ac.uk).
7. V.L. Pachhamia andA.R. Parekh, J. Indian Chem. Soc., 66, 250 (1989).
8. J.T. Palmer, B.L. Hirschbein, H. Cheung, J. Mc Carter, J.W. Janc, Z.W.
Yu and G. Wesolowski, Bioorg. Med. Chem. Lett., 16, 2909 (2006).
9. Y. Li, J. Liu, H. Zhang, X. Yang and Z. Liu, Bioorg. Med. Chem. Lett.,
16, 2278 (2006).
10. A.S.Aboraia, H.M.Abdel-Rahman, N.M. Mahfouz and M.A. El-Gendy,
Bioorg. Med. Chem., 14, 1236 (2006).
11. H.A. Abdel-Aziz, M.A. Bhat, M. Ghazzali, Phosphorus, Sulphur Silicon
Rel. Elem., 189, 1328 (2014).
12. M.Al-Talib, H. Tashtoush and N. Odeh, Synth. Commun., 20, 1811 (1990).
13. S. Sharma, V.K. Srivastava and A. Kumar, Eur. J. Med. Chem., 37, 689
(2002).
14. C.T. Brain, J.M. Paul, Y. Loong and P.J. Oakley, Tetrahedron Lett., 40,
3275 (1999).
ACKNOWLEDGEMENTS
The authors are thankful to Deanship of Scientific Research
and Research Center, College of Pharmacy, King Saud Univer-
sity.
15. S. Maghari, S. Ramezanpour, F. Darvish, S. Balalaie, F. Rominger and
H.R. Bijanzadeh, Tetrahedron, 69, 2075 (2013).
16. G. Prabhu and V.V. Sureshbabu, Tetrahedron Lett., 53, 4232 (2012).
17. Bruker APEX2, SAINT and SADABS, Bruker AXS Inc., Madison,
Winconsin, USA (2009).
18. G.M. Sheldrick, Acta Crystallogr. A, 64, 112 (2008).
19. M.S. Yar and M.W. Akhtar, Acta Pol. Pharm., 66, 393 (2009).
20. X. Wang, W. Wang, H.X. Liu, M.Y. Tan and M. Li, Acta Crystallogr.
C, 51, 1585 (1995).
REFERENCES
1. Y.L. Janin, Bioorg. Med. Chem., 15, 2479 (2007).
2. A.E. Wilder-Smith, Arzneimittelforschung, 16, 1034 (1966).
3. M.G. Mamolo, D. Zampieri, L. Vio, M. Fermeglia, M. Ferrone, S. Pricl,
G. Scialino and E. Banfi, Bioorg. Med. Chem., 13, 3797 (2005).
4. T.M. Tan, Y. Chen, K.H. Kong, J. Bai, Y. Li, S.G. Lim, T.H. Ang and Y.
Lam, Antiviral Res., 71, 7 (2006).
21. C.S. de Oliveira, B.F. Lira, J.M. Barbosa-Filho, J.G.F. Lorenzo and
P.F. de Athayde-Filho, Molecules, 17, 10192 (2012).
5. M.T.H. Khan, M.I. Choudhary, K.M. Khan, M. Rani and Atta-ur-
Rahman, Bioorg. Med. Chem., 13, 3385 (2005).