International Journal of ChemTech Research
CODEN( USA): IJCRGG
ISSN : 0974-4290
Vol.2, No.4, pp 1987-1991,
Oct-Dec 2010
Synthesis of N'-arylidenequinoxaline-2carbohydrazides, 3-Benzyl-5-(quinoxalin-3-yl)1,3,4-oxadiazole-2(3H)-thiones and 1-(2-Aryl5-(quinoxalin-3-yl)-1,3,4-oxadiazol-3(2H)yl)ethanones
Thirupathaiah T1, Kranthi kumar T2, Laxminarayana E2 and Thirumala Chary M1*
1Jawaharlal
Nehru Technological University College of Engineering, Jagityala,505 327 India
2Sreenidhi Institute of Science and Technology, Ghatkesar, HYDERABAD-501301(A.P.) India
*Corres.author:mtcharya@yahoo.com
Abstract: Ethyl quinoxaline-2-carboxylate (1), reacts with hydrazine to form Quinoxaline-2-carbohydrazide (2). This
compound cyclised with CNBr to offerd 5-(Quinoxalin-3-yl)-1,3,4-oxadiazol-2-amine (3). Compound 3 then converted N'arylidenequinoxaline-2-carbohydrazides (4a-f). The hydrzides (4a-f) are cyclised to form 3-aryl-5-(quinoxalin-3-yl)-1,3,4oxadiazole-2(3H)-thiones (5a-f) and 1-(2-Aryl-5-(quinoxalin-3-yl)-1,3,4-oxadiazol-3(2H)-yl)ethanones (6a-f) by reacting
with KOH/CS2 and Ac2O respectively.
Keywords: Oxadiazoles, quinoxolines, carbohydrazides, oxadiazathione.
Introduction
Quinoxaline derivatives are an important class of
nitrogencontaining heterocycles in medicinal chemistry13
. For example, quinoxaline is a part of various
antibiotics such as echinomycin, levomycin, and
actinoleutin that are known to inhibit growth of gram
positive bacteria2, and are active against various
transplantable tumors3. Several kinds of synthetic routes
toward quinoxalines have been developed, inclding the
condensation of aryl-1,2-diamines with a 1,2-diketones4,
Bi-catalyzed oxidative coupling of epoxides with ene1,2-diamines5, heteroannulation of nitroketene N,Saryliminoacetals with POCl36, cyclization of α-arylimino
oximes of α-dicarbonyl compounds7, and formation of
α-hydroxy ketones via a tandem oxidation process using
Pd(OAc)2 or RuCl2-(PPh3)3-TEMPO8 as well as MnO29.
Quinoxaline derivatives have been also reported to
possess a wide variety of biological activities10-12.
Notable among these are antioxidant, anti-inflammatory
antimicrobial, anticancer and antihistamic activities.
Drugs having nitrogen containing ring system13-15 are
well known for their anti-inflammatory, antioxidant,
antihistamic,
antimicrobial,
antidepressant,
hypoglycemic, hypotensive, anticarcenogenic activities
etc. 1,3,4-oxadiazoles are also known to have a broad
spectrum of biological activities16-18. In addition there
are some studies on electronic structures and thiol-thione
tautomeric equilibrium of heterocyclic thione
derivatives19-21. In view of the above facts, it was
contemplated to design and synthesize some oxadiazolo
quinoxaline derivatives.
M.Thirumala Chary et al /Int.J. ChemTech Res.2010,2(4)
1988
Scheme I
N
N
N
CNBr
N2H4
O
N
COOEt
N
1
NH2
N
CONHNH2
2
3
N
N
Ar-CHO
N
Ac2O
O
N
Ar
N
6a-e
N
N
KOH
CS2
N
N
5a-e
COCH3
S
N
Ar
4 a-e
O
N
CONHN
N
Ar
Ar = phenyl, 4-fluorophenyl, 2-fluorophenyl, 2-fluoro-4-methoxyphenyl, 4-hydroxyphenyl,
3-hydroxy-4-methoxyphenyl.
Experimental
Melting points were measured in a Sulphuric acid bath
and are uncorrected. The IR spectra were recorded on
Brucher-IFS-66 FTIR instrument. NMR spectra were
recorded on Varian Gemini 200 M Hz instrument using
tetramethylsilane as an internal standard in CDCl3.
Chemical shifts are expressed in ppm. The purity of the
compounds was checked by TLC and spots were
visualized in iodine vapour.
Quinoxaline-2-carbohydrazide (2)
To a solution of ethyl quinoxaline-2-carboxylate (1),
(0.01 mole) in methanol (15mL) was added 99%
hydrazine hydrate (0.05 mole) and refluxed for about 5
hr, reaction was monitored by TLC. After disappearance
of starting material reaction mass was cooled to room
temperature, and filtered the solid.
1
H NMR in DMSO-d6: 4.72 (brs, 2H), 7.97 (m, 2H),
8.17 (m, 2H), 9.42 (s, 1H), 10.27 (brs, 1H);
Mass: m/z 189 (M+1); C9H8N4O; C, 56.44; H, 3.38; N,
30.77;
5-(Quinoxalin-3-yl)-1,3,4-oxadiazol-2-amine (3)
To a solution of quinoxaline-2-carbohydrazide, (0.01
mole) in methanol (15mL) was added CNBr (0.01 mole)
and refluxed for about 4 hr, reaction was monitored by
TLC. After disappearance of starting material reaction
mass was cooled to room temperature, and filtered the
solid.
1
H NMR in DMSO-d6: 7.73 (brs, 2H), 7.93 (m, 2H),
8.15 (m, 2H), 9.47 (s, 1H);
Mass: m/z 214 (M+1); C10H7N5O; C, 57.34; H, 4.32; N,
33.75;
N'-arylidenequinoxaline-2-carbohydrazides (4a-f)
To a solution of quinoxaline-2-carbohydrazide (0.01
mole) in ethanol (60 ml), aldehyde (0.011 mole) and a
few drops of glacial acetic acid were added and the
mixture refluxed for 10 hours. It was then cooled
concentrated and poured into crushed ice and filtered.
The solid thus obtained was purified by recrystallization
from ethanol.
N'-benzylidenequinoxaline-2-carbohydrazide (4a)
1
H NMR in CDCl3: 7.45 (m, 3H), 7.87 (m, 4H), 8.16
(dd, 1H), 8.22 (dd, 1H), 8.46 (s, 1H), 9.78 (s, 1H), 10.88
(brs, 1H); Mass: m/z 277 (M+1); C16H12N4O; C, 70.25;
H, 5.38; N, 21.28;
N'-(4-fluorobenzylidene)quinoxaline-2-carbohydrazide
(4b)
1
H NMR in CDCl3: 7.45(m, 2H), 7.88 (m, 4H), 8.18 (dd,
1H), 8.23 (dd, 1H), 8.44 (s, 1H), 9.78 (s, 1H), 10.78 (brs,
1H); Mass: m/z 295 (M+1); C16H11FN4O; C, 65.30; H,
3.77; F, 6.46; N, 19.04; O, 5.44
N'-(2-fluorobenzylidene)quinoxaline-2-carbohydrazide
(4c)
1
H NMR in CDCl3: 7.43 (m, 2H), 7.82 (m, 4H), 8.12
(dd, 1H), 8.22 (dd,1H), 8.42 (s, 1H), 9.76 (s, 1H), 10.80
M.Thirumala Chary et al /Int.J. ChemTech Res.2010,2(4)
(brs, 1H); Mass: m/z 295 (M+1); C16H11FN4O; C, 65.30;
H, 3.77; F, 6.46; N, 19.04;
N'-(2-fluoro-4-methoxybenzylidene)quinoxaline-2carbohydrazide (4d)
1
H NMR in CDCl3: 3.74 (s, 3H), 7.44 (m, 2H), 7.81 (m,
3H), 8.13 (dd, 1H), 8.22 (dd, 1H), 8.43 (s, 1H), 9.80 (s,
1H), 10.82 (brs, 1H); Mass: m/z 325 (M+1);
C17H13FN4O2; C, 63.56; H, 3.44; N, 16.28
N'-(4-hydroxybenzylidene)quinoxaline-2-carbohydrazide
(4e)
1
H NMR in CDCl3: 7.35 (m, 3H), 7.81 (m, 3H), 8.13
(dd, 1H), 8.25 (dd, 1H), 8.45 (dd, 1H), 8.25 (dd, 1H),
8.45 (s, 1H), 9.78 (s, 1H), 10.85 (brs, 2H); Mass: m/z
293 (M+1); C16H12N4O2; C, 66.75; H, 5.24; N, 18.17
N'-(3-hydroxy-4-methoxybenzylidene)quinoxaline-2carbohydrazide (4f)
1
H NMR in CDCl3: 3.80(s, 3H), 7.38 (m, 3H), 7.80 (m,
3H), 8.15 (dd, 1H), 8.24 (dd, 1H), 8.43 (s, 1H), 9.75 (s,
1H), 10.80 (brs, 2H); C17H14N4O3; C, 64.55; H, 5.81; N,
16.38
3-Aryl-5-(quinoxalin-3-yl)-1,3,4-oxadiazole-2(3H)thiones (5a-f)
To a solution of N'-benzylidenequinoxaline-2carbohydrazide (0.01 mole) in EtOH, KOH (0.01 mole)
and CS2 were added and refluxed for overnight. It was
then cooled concentrated and poured into crushed ice
and filtered. The solid thus obtained was purified by
recrystallization from ethanol.
3-benzyl-5-(quinoxalin-3-yl)-1,3,4-oxadiazole-2(3H)thione (5a)
1
H NMR in DMSO-d6: 5.62(s, 2H), 7.25 (m, 5H), 7.85
(m, 2H), 8.22 (dd, 1H), 9.80 (s, 1H); Mass: m/z 321
(M+1)
3-(4-fluorobenzyl)-5-(quinoxalin-3-yl)-1,3,4-oxadiazole2(3H)-thione (5b)
1
H NMR in DMSO-d6: 5.64 (s, 2H), 7.26 (m, 4H), 7.85
(m, 2H), 8.24 (dd, 1H), 9.82 (s, 1H); Mass: m/z 339
(M+1)
3-(2-fluorobenzyl)-5-(quinoxalin-3-yl)-1,3,4-oxadiazole2(3H)-thione (5c)
1
H NMR in DMSO-d6: 5.58 (s, 2H), 7.24 (m, 4H), 7.80
(m, 2H), 8.23 (dd, 1H), 9.82 (s, 1H); Mass: m/z 339
(M+1)
3-(2-fluoro-4-methoxybenzyl)-5-(quinoxalin-3-yl)-1,3,4oxadiazole-2(3H)-thione (5d)
1
H NMR in DMSO-d6: 3.82 (s, 3H), 5.61 (s, 2H), 7.30
(m, 3H), 7.85 (m, 2H), 8.24 (dd, 1H), 9.80 (s, 1H);
Mass: m/z 369 (M+1)
1989
3-(4-hydroxybenzyl)-5-(quinoxalin-3-yl)-1,3,4oxadiazole-2(3H)-thione (5e)
1
H NMR in DMSO-d6: 5.60 (s, 2H), 7.28 (m, 4H), 7.80
(m, 2H), 8.25 (dd, 1H), 9.02 (brs, 1H), 9.80 (s, 1H);
Mass: m/z 337 (M+1)
3-(3-hydroxy-4-methoxybenzyl)-5-(quinoxalin-3-yl)1,3,4-oxadiazole-2(3H)-thione (5f)
1
H NMR in DMSO-d6: 3.81 (s, 3H), 5.62 (s, 2H), 7.29
(m, 3H), 7.79 (m, 2H), 8.22 (dd, 1H), 9.13 (brs, 1H),
9.82 (s, 1H); Mass: m/z 367 (M+1)
1-(2-Aryl-5-(quinoxalin-3-yl)-1,3,4-oxadiazol-3(2H)yl)ethanones (6a-f)
The
solution
of
N'-benzylidenequinoxaline-2carbohydrazide (0.01 mole) and Acetic anhydride (0.01
mole) were refluxed for overnight. It was then cooled
concentrated and poured into crushed ice and filtered.
The solid thus obtained was purified by recrystallization
from ethanol.
1-(2-Phenyl-5-(quinoxalin-3-yl)-1,3,4-oxadiazol-3(2H)yl)ethanones (6a)
1
H NMR in CDCl3: 2.41 (s, 3H), 6.62 (s, 1H), 7.23 (m,
2H), 7.42 (m, 2H), 7.52 (m, 1H), 7.85 (m, 2H), 8.22 (m,
2H), 9.45 (s, 1H); Mass: m/z 319 (M+1)
1-(2-(4-fluorophenyl)-5-(quinoxalin-3-yl)-1,3,4oxadiazol-3(2H)-yl)ethanones (6b)
1
H NMR in CDCl3: 2.40 (s, 3H), 6.60 (s, 1H), 7.24 (m,
2H), 7.43 (m, 2H), 7.65 (m, 2H), 8.22 (m, 2H), 8.45 (s,
1H); Mass: m/z 337 (M+1)
1-(2-(2-fluorophenyl)-5-(quinoxalin-3-yl)-1,3,4oxadiazol-3(2H)-yl)ethanones (6c)
1
H NMR in CDCl3: 2.42 (s, 3H), 6.61 (s, 1H), 7.25 (m,
2H), 7.44 (m, 2H), 7.64 (m, 2H), 8.23 (m, 2H), 9.40 (s,
1H); Mass: m/z 337 (M+1)
1-(2-(2-fluoro-4-methoxyphenyl)-5-(quinoxalin-3-yl)1,3,4-oxadiazol-3(2H)-yl)ethanones (6d)
1
H NMR in CDCl3: 2.39 (s, 3H), 3.78 (s, 3H), 6.60 (s,
1H), 7.13 (m, 2H), 7.44 (m, 2H), 7.65 (m, 2H), 8.22 (m,
1H), 9.39 (s, 1H); Mass: m/z 367 (M+1)
1-(2-(4-hydroxyphenyl)-5-(quinoxalin-3-yl)-1,3,4oxadiazol-3(2H)-yl)ethanones (6e)
1
H NMR in CDCl3: 2.40 (s, 3H), 6.61 (s, 1H), 7.12 (m,
2H), 7.45 (m, 2H), 7.65 (m, 3H), 8.25 (m, 2H), 9.42 (s,
1H); Mass: m/z 335 (M+1)
1-(2-(3-hydroxy-4-methoxyphenyl)-5-(quinoxalin-3-yl)1,3,4-oxadiazol-3(2H)-yl)ethanones (6f)
1
H NMR in CDCl3: 2.40 (s, 3H), 3.86 (s, 3H), 6.59 (s,
1H), 7.13 (m, 2H), 7.44 (m, 2H), 7.66 (m, 2H), 8.26 (m,
2H), 9.45 (s, 1H); Mass: m/z 365 (M+1)
M.Thirumala Chary et al /Int.J. ChemTech Res.2010,2(4)
1990
Table 1: Characterization data of compounds (5a-e), (7a-e) and (9a-e)
Compd
R*
Yield
m.p.
Mol.
(%)
(oC)
formula
5a
phenyl
69
222
C17H12N4OS
5b
4-fluorophenyl
71
222
C17H11FN4OS
5c
2-fluorophenyl
73
203
C17H11FN4OS
5d
2-fluoro-4-methoxyphenyl
78
210
C18H13FN4O2S
5e
4-hydroxyphenyl
79
245
C17H12N4O2S
5f
3-hydroxy-4-methoxyphenyl
71
260
C18H14N4O3S
6a
phenyl
68
225
C18H14N4O2
6b
4-fluorophenyl
81
232
C18H13FN4O2
6c
2-fluorophenyl
72
250
C18H13FN4O2
6d
2-fluoro-4-methoxyphenyl
75
222
C19H15FN4O3
6e
4-hydroxyphenyl
75
278
C18H14N4O3
6f
3-hydroxy-4-methoxyphenyl
68
242
C19H16N4O4
Conclusions
We have developed an efficient protocol synthesis of
new
3-benzyl-5-(quinoxalin-3-yl)-1,3,4-oxadiazole2(3H)-thiones (5a-f) and 1-(2-Aryl-5-(quinoxalin-3-yl)1,3,4-oxadiazol-3(2H)-yl)ethanones (6a-f). Operational
simplicity, cleaner reaction, easer work-up and are
environmentally co-friendly reactions. Moreover
quinoxaline derivatives are used as pharmaceutical
drugs.
References
1. Jaso A, Zarranz B, Aldana I and A. Monge, J. Med.
Chem. 2005, 48, 2019; b) Carta A, Paglietti G,.
Nikookar M.E.R, Sanna P, Sechi L and Zanetti S,
Eur. J. Med. Chem. 2002, 37, 355.
2. Dell, D.H. William, H.R. Morris, G.A. Smith,
J.Feeney, G.C.K. Roberts, J. Am. Chem. Soc. 1975,
97, 2497.
3. Bailly C, Echepare S, Gago F and Waring M.J, AntiCancer Drug Des. 1999, 15, 291.
4. a) Heravi M.M, Bakhtiari K, Tehrani M.H, N.M.
Javadi and H.A. Oskooie, ARKIVOC 2006, xvi, 16;
5.
6.
7.
8.
9.
b) H.R. Darabi, S. Mohandessi, K. Aghapoor and F.
Mohsenzadeh, Catal. Commun. 2007, 389;
Antoniotti S and Donach E, Tetrahedron Lett. 2002,
43, 3971.
Venkatesh C, Singh B, Mahata P.K and Junjapp H,
Org. Lett. 7 (2005) 2169.
Xekoukoulotakis N P, Hadjiantonious M C P and
Maroulis A J, Tetrahedron Lett. 2000, 41, 10299.
Robinson R S and Taylor R J K, Synlett (2005)
1003.
a) Raw S A Wilfred C D and Taylor R J K, Org.
Biomol. Chem, 2004, 2 788; b) Raw S A Wilfred C
D and Taylor R J K, Chem. Commun. 2003, 2286.
M.Thirumala Chary et al /Int.J. ChemTech Res.2010,2(4)
10. Sandeep K and Devender shinda B, Bioorg Med
Chem Lett., 2006, 16, 6181.
11. Dubey P K, Naidu A, Vijaya S and George Vineel
B, Indian J Chem., 2005, 44B, 573.
12. Ganapathy S, Ramalingam P and Babu Rao CH,
Indian J Heterocycl Chem., 2007, 16, 283.
13. Kumar A, Sharma S and Bajaj K, Indian J Chem.,
2003, 42B (8), 1979.
14. Ragabasawaraj B and Sangapure S S, Indian J
Heterocycl Chem., 2001, 11, 31.
15. Heas V, Roelof G and Cornelis A, Europ Pat Appl.,
1981, 21, 506.
*****
1991
16. Ram,V J and Vlietinck, A J, J Heterocycl. Chem.
1988, 25, 253.
17. Boschelli D H, Connor D T, Bornemeier D A, Dyer
R D, Kennedy J A, Kuipers P J, Okonkwo G C,
Svhrier D J and Wright C D J. Med. Chem. 1993,
36,1802.
18. Bahadur S and Pandey K K, J. Ind. Chem. Soc.
1980, 57, 447.
19. Aydogan F, Turgut Z Olcay N and Erdem S S, Turk.
J. Chem. 2002, 26, 159.
20. Charistos D A, Vagenes G V, Tzavellas L C,
Tsoleridis C A and Rodios N A, J. Heterocycl.
Chem. 1994, 31, 1593.
21. Tsoleridi C A, Charistos D A and Vagenes G V , J.
Heterocycl. Chem. 34, 1997, 1715.