A facile microwave-assisted synthesis of 8,9-cycloalkathieno[3,2-e] [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones

Article abstract of DOI:10.1007/s12039-011-0067-6

A new series of fused thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidinones was synthesized by condensation of ethyl-3-cyano-4,5,6,7-tetrahydrobenzo[b] thiophene-2-yl carbamate with aryl acid hydrazides in quantitative yields using a facile, one-pot procedure under microwave-assisted conditions. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-011-0067-6

J. Chem. Sci., Vol. 123, No. 1, January 2011, pp. 69–73. * Indian Academy of Sciences.
A facile microwave-assisted synthesis of 8,9-cycloalkathieno[3,2-e]
[1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones
RAJWINDER KAURa, D PRAN KISHOREa, B LAKSHMI NARAYANAa,
K VENKAT RAOa, C BALAKUMARb, V RAJKUMARc and A RAGHURAM RAOa*
aPharmaceutical Chemistry Division, University Institute of Pharmaceutical Sciences and
Centre of Advanced Study in Pharmaceutical Sciences (UGC-CAS), Panjab University,
Chandigarh 160014, India
bCentre with Potential for Excellence in Biomedical Sciences (CPEBS), Panjab University,
Chandigarh 160014, India
cDepartment of Chemistry and Centre of Advanced Study in Chemistry (UGC-CAS),
Panjab University, Chandigarh 160014, India
e-mail: rrakkinepally@pu.ac.in
MS received 22 July 2010; revised 22 November 2010; accepted 6 December 2010
Abstract.
A new series of fused thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidinones was synthesized by
condensation of ethyl-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl carbamate with aryl acid hydrazides
in quantitative yields using a facile, one-pot procedure under microwave-assisted conditions.
Keywords. Microwave-irradiation; pyrimidinones; 1,2,4-triazole; aryl hydrazides; condensation.
1. Introduction
different G-protein coupled receptors: A1, A2A, A2B
and A3 ARs. These receptors are implicated in a
Asthma and chronic obstructive pulmonary disease number of inflammatory cell types including mast
(COPD) are prevalent inflammatory disorders of the cells, eosinophils, lymphocytes, neutrophils and mac-
lung and are poorly managed.1 Available antiasthmatic rophages which are expressed in lungs and are found
agents such as anticholinergic agents, β2 selective to be important in the pathophysiology of asthma.5
adrenergic agonists, methyl xanthines, antihistamines, Hence they are considered to be important targets for
mast cell stabilizers and corticosteroids are inadequate- new drug development for asthma.
ly effective and some are suitable only for symptom-
Over the past decade, a number of potent and
atic relief and most of them exhibit undesirable side selective AR agonists and antagonists, of various
effects.2 This necessitates further investigations in this structures, including xanthines and non-xanthines,
field to develop potent clinical candidates. Recent have been developed6,7 but relatively few compounds
trends in the development of new antiasthmatic agents entered clinical trials1,8–10 (table 1). This could be due
include various agents such as adenosine receptor to their poor pharmacokinetic profile, including low
(ARs) antagonists, isoenzyme selective phosphodies- water solubility8 and/or low CNS penetration. As a
terase 4 (PDE4) inhibitors, inhibitors of the biosynthe- consequence, a lot of interest has been generated in
sis of interleukin-4 (IL-4) and IL-4 antagonists, recent years to find ligands of ARs with high degree of
lipoxygenase (LOX) and leukotriene (LT) inhibitors, selectivity. A large number of studies are aimed at
thromboxane (TX) A2 receptor antagonists, potassium designing new ligands which are free from undesirable
channel openers and monoclonal antibodies.3,4 It has side effects.11
been observed that adenosine plays an important role
Among the various classes of heterocyclic com-
in mediating bronchial constriction, pulmonary inflam- pounds, a wide variety of fused pyrimidines such as
mation and airway remodelling by interacting with its pyrazolo-triazolo-pyrimidine, triazolo[1,5-c]quinazo-
line, triazolo[4,3-a]quinoxaline and imidazo[4,5-c]
*For correspondence
quinoline derivatives have been reported as selective
69

70
Rajwinder Kaur et al
Table 1. Adenosine receptor agonists and antagonists in clinical development for asthma and/or COPD.
S. No.
1.
Drug name
Molecular targets
Clinical indication
Status
EPI-2010 (EpiGenesis Pharmaceuticals)
Antisense oligonucleotide
of A1 AR
A2A AR agonist
A2A AR agonist
A2B AR antagonist
Inhibition of BHR and
bronchodilatation
Anti-inflammation
Anti-inflammation
Inhibition of BHR and
anti-inflammation
Discontinued
2.
3.
4.
UK-432,097 (Pfizer)
GW328267 (GSK)
CVT-6883 (CV Therapeutics)
Discontinued
Discontinued
Phase 2
5.
QAF 805 (Novartis)
Mixed A2B/A3 AR
antagonist
Inhibition of BHR and
anti-inflammation
Phase 1b
antagonists for A2A ARs.12–17 Furthermore, inclusion CDCl3 or DMSO-d6 solutions with a Bruker Avance II
of thienopyrimidine nucleus within a tetracyclic system 400 MHz spectrometer and signals recorded in parts
afforded a large number of bioactive derivatives.18 per million (δ) downfield from tetramethylsilane as
Recently a new series of triazolothienopyrimidines has internal standard, and J values are given in Hz. IR
been reported11 from these laboratories as adenosine spectra were recorded on Perkin Elmer FT-IR Spec-
A1 receptor antagonists with micromolar potencies. trometer (Spectrum RX I) using KBr pellet technique.
The encouraging results prompted us to design and The elemental analyses were performed using Thermo
synthesize new derivatives of triazolothienopyrimi- EA 2110 series. Melting points were recorded in open
dines. Hence a facile method has been attempted using capillaries on LABINDIA melting point apparatus and
microwave-assisted synthesis of 8,9-cycloalkathieno were uncorrected. Mass spectra (ESI) were recorded on
[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones (4) Waters Micromass Q-TOF Micro.
by incorporating a substituted triazole ring with
tetrahydrobenzothienopyrimidine in one framework. 2.2 Preparation of ethyl 3-cyano-4,5,6,7-
To achieve the synthesis of designed molecules (4), tetrahydrobenzo[b]thiophen-2-ylcarbamate (2)
we adopted a route through an appropriate carba-
2.2a Method A: A suspension of 1 (5·28g, 29·7 mmol) in
ethyl chloroformate (14·1 ml, 148 mmol) was heated
under microwave irradiation at 560W for 5 min. The
excess ethyl chloroformate was distilled off and toluene
(9·6 ml) was added. Slow addition of cyclohexane in
cold conditions induced crystallization. The resulting
solid was collected by filtration and rinsed with
cyclohexane. Drying under vacuum afforded compound
mate (2). When we completed their synthesis suc-
cessfully, it was interesting to learn that an Ukrenian
group came out with a different approach for the
synthesis of related compounds.19 We ascertained our
data and interacted with them and it was observed that
our method is comparatively easier and facile. The
salient features of the investigated reaction under
microwave-assisted conditions are enhanced reaction
rates, greater selectivity, and ease of the experimental
manipulation leading to an efficient and cost effective
pathway to several synthetically useful compounds.
The synthesis of target compounds appears to be an
area of intense investigation as several related
molecules with a broad range of activities have been
reported recently.19–23
1
2; yield 90%; mp 109–110°C. H NMR (400 MHz,
CDCl3): δ = 1·32–1·36 (t, 3H, −CH3), 1·73–1·86 (m,
4H, −(CH2)2−), 2·55–2·62 (m, 4H, −(CH2)2−), 4·26–
4·32 (q, 2H, −OCH2−), 7·69 (br s, 1H, −NH−) ppm. IR
(KBr): 3398·6, 3232·5, 2931·2, 2214·7, 1734·1, 1560·0,
1234·7 cm−1. ESI-MS (m/z; %) = 273·5 (M++Na+; 15),
251·3 (M++1; 30). Anal. Calcd. (%) for C12H14N2O2S:
C, 57·58; H, 5·64; N, 11.19. Found (%): C, 57·36; H,
5·68; N, 11·37.
2. Experimental
2.1 Materials, methods and instruments
2.2b Method B: A suspension of 1 (5·28g, 29·7 mmol) in
ethyl chloroformate (14·1 ml, 148 mmol) was heated
Reactions were routinely monitored by thin layer under reflux for 5 h. The excess ethyl chloroformate
chromatography (TLC) on silica gel (pre-coated F254 was distilled off and toluene (9·6 ml) was added. Slow
Merck plates) and visualized the products under UV addition of cyclohexane in cold conditions induced
1
light (254 nm). H NMR spectra were determined in crystallization. The resulting solid was collected by

A facile microwave-assisted synthesis of fused thieno-triazolo-pyrimidinones
71
filtration and rinsed with cyclohexane. Drying under (m, 2H, −CH2−), 8·33–8·35 (d, 2H, J = 8·8 Hz,
vacuum afforded compound 2; yield 72%
Ar−H), 8·50–8·52 (d, 2H, J = 8·8 Hz, Ar−H), 13·10
(br s, 1H, −NH−) ppm. ESI-MS (m/z; %) = 390·4
(M++Na+; 9), 368·2 (M++1; 19). Anal. Calcd (%) for
C17H13N5O3S: C, 55·58; H, 3·57; N, 19·06. Found
(%): C, 55·45; H, 3·78; N, 19·26.
2.3 Preparation of 8,9-cycloalkathieno[3,2-e][1,2,4]
triazolo[1,5-c]pyrimidin-5(6H)-ones (4a–d)
2.3a Method A: Ethyl 3-cyano-4,5,6,7-tetrahydrobenzo
[b]thiophen-2-ylcarbamate (2) (15·0 mmol) and aryl
acid hydrazides (3) (15·0 mmol) were taken in DMF
(10·0 ml). The resulting mixture was heated under
microwave irradiation at 560W for 15–40 min. It was
cooled to temperature below 100°C and added slowly
to the crushed ice. The separated solid was collected by
filtration and washed with water and 2-propanol.
Drying in vacuum afforded the title compounds.
2.6 2-(2-Hydroxyphenyl)-8,9,10,11-tetrahydro[1]
benzothieno[3,2-e][1,2,4]triazolo[1,5-c] pyrimidin-5
(6H)-one (4c, table 2, entry 3)
1H NMR (400 MHz, DMSO-d6): δ = 1·94 (m, 4H,
−(CH2)2−), 2·77 (m, 2H, −CH2−), 3·36 (m, 2H,
−CH2−), 6·95–6·99 (t, 1H, J = 7·6, 7·2 Hz, Ar−H),
7·01–7·03 (d, 1H, J = 8·0 Hz, Ar−H), 7·35–7·39 (t, 1H,
J = 8·0, 7·2 Hz, Ar−H), 8·27–8·29 (d, 1H, J = 7·6 Hz,
Ar−H), 11·13 (s, 1H, −OH), 13·10 (br s, 1H, −NH−)
ppm. ESI-MS (m/z; %) = 361·3 (M++Na+; 11), 339·4
(M++1; 14). Anal. Calcd (%) for C17H14N4O2S: C,
60·34; H, 4·17; N, 16·56. Found (%): C, 60·56; H,
4·01; N, 16·79.
2.3b Method B: To a solution of ethyl 3-cyano-4,5,6,7-
tetrahydrobenzo[b]thiophen-2-ylcarbamate (2)
(15·0 mmol) in DMF (17·0 ml) was added aryl acid
hydrazides (3) (15·0 mmol). The resulting mixture was
heated at 120°C for 12–24h under nitrogen-atmosphere.
It was cooled to temperature below 100°C and added
slowly to the crushed ice. The solid was collected by
filtration and washed with water and 2-propanol.
Drying in vacuum afforded the title compounds.
2.7 2-(2-Chlorophenyl)-8,9,10,11-tetrahydro[1]
benzothieno[3,2-e][1,2,4]triazolo[1,5-c] pyrimidin-5
(6H)-one (4d, table 2, entry 4)
1H NMR (400 MHz, DMSO-d6): δ = 1·87–1·92
(m, 4H, −(CH2)2−), 2·74–2·75 (m, 2H, −CH2−),
3·01–3·02 (m, 2H, −CH2−), 7·41–7·49 (m, 2H, Ar
−H), 7·54–7·56 (dd, 1H, J = 7·6, 7·2 Hz, Ar−H), 7·98–
8·00 (dd, 1H, J = 7·6, 7·2 Hz, Ar−H), 13·01 (br s, 1H,
−NH−) ppm. ESI-MS (m/z; %) = 381·3 (M++Na++2; 29),
379·3(M++Na+; 78), 359·3 (M++2; 12), 357·3 (M++1;
30). Anal. Calcd (%) for C17H13ClN4OS: C, 57·22; H,
3·67; N, 15·70. Found (%): C, 57·52; H, 3·89; N, 15·95.
2.4 2-Phenyl-8,9,10,11-tetrahydro[1]benzothieno[3,2-e]
[1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one
(4a, table 2, entry 1)
1H NMR (400 MHz, DMSO-d6): δ = 1·85–1·86
(m, 4H, −(CH2)2−), 2·67–2·69 (m, 2H, −CH2−),
3·03–3·04 (m, 2H, −CH2−), 7·38–7·43 (m, 3H,
Ar−H), 8·25–8·28 (m, 2H, Ar−H ), 12·74 (br s, 1H,
−NH−) ppm. 13C NMR (100 MHz, DMSO-d6): δ =
22·11, 23·25, 24·56, 25·12, 110·16, 127·41, 128·71,
128·74, 129·38, 130·36, 130·38, 143·00, 144·55,
151·52, and 163·67 ppm. IR (KBr): 2934·4, 1713·2,
1600·7, 1523·2, 1443·8, 747·7 cm−1. ESI-MS
(m/z; %) = 345·4 (M++Na+; 11) 323·4 (M++1; 100).
Anal. Calcd. (%) for C17H14N4OS: C, 63·33; H, 4·38;
N, 17·38. Found (%): C, 63·0; H, 4·28; N, 17·58.
3. Results and discussion
The designed molecules fused thieno[3,2-e][1,2,4]
triazolo[1,5-c]pyrimidinone derivatives 4a–d were
synthesized (scheme 1) starting from 2-amino-4,5,6,7-
tetrahydrobenzo[b]thiophen-3-carbonitrile (1), which
in turn was prepared following the well-known Gewald
process.24 Heating of 1 in excess of ethyl chlorofor-
mate gave ethyl-3-cyano-4,5,6,7-tetrahydrobenzo[b]
thiophene-2-ylcarbamate (2) quantitatively.25 Com-
pound 2 was characterized based on a typical nitrile
(C≡N) absorption band at 2214·7 cm−1, a strong signal
at 1734·1 cm−1 of the carbonyl group and an absorp-
tion band at 1560·0 cm−1 may be due to the ν (N–H) of
ethyl carbamate. Further, prominent triplet signal at δ
2.5 2-(4-Nitrophenyl)-8,9,10,11-tetrahydro[1]
benzothieno[3,2-e][1,2,4]triazolo[1,5-c]pyri- midin-5
(6H)-one (4b, table 2, entry 2)
1H NMR (400 MHz, DMSO-d6): δ = 1·93–1·95
(m, 4H, −(CH2)2−), 2·77 (m, 2H, −CH2−), 3·08

72
Rajwinder Kaur et al
MW, 560W
reflux, 5 min
CN
CN
O
isotopic abundances in its mass spectrum. These
compounds were also synthesized by conventional
methods by treating 2 with aryl hydrazides (3) in
DMF under nitrogen-atmosphere at 120°C for a compar-
ativestudy.
O
N
OC2H5
NH2
S
S
H
Cl
OC2H5
(2)
(1)
Under classical heating conditions, these reactions
have certain disadvantages like long reaction times
(12–24 h), high energy consumption and the need
for large amounts of solvents for work up and
purification. The MW-assisted reactions were carried
out using a Catalyst Microwave Reactor, under
constant irradiation power and by varying the
temperature (the so-called ‘power control’). The
best results were obtained when we used 80% of
the full power of the magnetron (560W). The details of
the optimized conditions employed, under MW
irradiation as well as under classical heating are
presented in table 2. A comparative analysis of the
MW, 560W
DMF
ArCONHNH2
(3)
Ar
N
N
N
O
N
S
H
(4)
Scheme 1. Synthesis of 8,9-cycloalkathieno[3,2-e][1,2,4]
triazolo[1,5-c]pyrimidin-5(6H)-ones.
1·32–1·36 ppm and a quartet signal at δ 4·26–4·32 ppm data obtained leads to the conclusion that the use of
of ethoxy protons and a broad singlet of NH at δ MW resulted in a remarkable acceleration of the
1
7·69 ppm in H NMR confirmed the presence of ethyl reactions, with the reaction times decreasing dramat-
carbamate group as the expected absorption pattern of ically, from hours to minutes (15 to 40 min). While
carbamates.26 Title compounds (4a–d) were synthe- optimizing the conditions, it was interesting to note
sized in good yields by irradiating compounds that the reactions could be carried out at considerably
2 and 327,28 in dimethylformamide at 560W. The lower temperatures (in the most cases by 10 to 30°C).
disappearance of nitrile (C≡N) stretch and appearance It was also of interest that, in some cases, under MW
of absorption band at 1600·7 cm−1 related to the ν irradiation the yields were substantially higher
(C=N) stretch of triazole in IR and multiplet signals (by almost 30%).
corresponding to aromatic protons at δ 7·38–7·43 ppm
and 8·25–8·28 ppm and a broad singlet for NH proton 4. Conclusion
1
of cyclic amide at δ 12·74 ppm in H NMR confirmed
the formation of title compounds (4a–d). Being a A series of thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidi-
chlorinated compound 4d exhibited the molecular ion none derivatives 4a–d was synthesized by employing
or other halogenated fragments with the appropriate innovative synthetic methods. We report here a
Table 2 Comparative data of conventional and microwave-assited synthesis of compounds 4a–d.
Microwave-assisted
Conventional (method-B)
(method-A)
Entry
Ar
Product*
Time
(min) at
560 W
% Yield
72.8
Time (h)
19
% Yield
41.3
1
2
4a
4b
29
O2N
20
80.5
16
59.3
OH
3
4
4c
40
15
65.6
66.2
24
12
39.6
39.3
Cl
4d
*These compounds were found to have melting points above 290oC. The exact temperature
could not be recorded

A facile microwave-assisted synthesis of fused thieno-triazolo-pyrimidinones
73
10. http://clinicaltrials.gov/ct2/show/NCT00430300 (1 of 5)
[5/10/2010 11:45:34 PM], Safety and Efficacy of
UK-432,097 in Chronic Obstructive Pulmonary Disease
11. Prasad M R, Rao A R, Rao P S, Rajan K S, Meena S
and Madhavi K 2008 Eur. J. Med. Chem. 43 614
12. Francis J E, Cash W D, Psychoyos S, Ghai G, Wenk P,
Friedmann R C, Atkins C, Warren V, Furness P, Hyun J
L, Stone G A, Desai M and Williams M 1988 J. Med.
Chem. 31 1014
comparative study of their syntheses under microwave
irradiation and by classical heating in solvent. A fast,
general, environment-friendly, and facile method under
microwave irradiation is presented. The microwave
irradiation provided a remarkable rate of acceleration
for the reaction, and the reaction time decreased
dramatically and in some cases (under MW irradiation)
the yields are also substantially higher. Efforts are
currently underway to optimize the lead structure and
the results of which will be the basis of our future
research endeavour.
13. Poucher S M, Keddie J R, Singh P, Stoggal S M,
Caulkett P W R, Jones G and Collis M G 1995 Br. J.
Pharmacol. 115 1096
14. Zocchi C, Ongini E, Conti A, Monopoli A, Negretti A,
Baraldi P G and Dionisotti S 1996 J. Pharmacol. Exp.
Ther. 276 398
Acknowledgements
15. Ongini E, Dionisotti S, Gessi S, Irenius E and Fredholm
B B 1999 Naunyn-Schmied. Arch. Pharmacol. 359 7
16. Neustadt B R, Hao J, Lindo N, Greenlee W J, Stamford
A W, Tulshian D, Ongini E, Hunter J, Monopoli A,
Bertorelli R, Foster C, Arik L, Lachowicz J, Ng K and
Feng K-I 2007 Bioorg. Med. Chem. Lett. 17 1376
17. Baraldi P G, Tabrizi M A, Bovero A, Barbara A, Preti
D, Francesca F, Romeo R, Varani K and Borea P A 2003
Eur. J. Med. Chem. 38 367
18. Soliman R, Habib N S, El-Tombary A A, El-Hawash
S A M and Shaaban O G 2009 Sci. Pharm. 77 755
19. Chernyuk O M, Tolmachova V S and Vovk M V 2009
Ukrainskii Khimicheskii Zhurnal 75 121
One of the authors (RK) is thankful to University
Grants Commission [UGC-F.33-188/2007 (SR)] for
financial support. We thank Prof. M V Vovk of Nats.
Pedagog. Univ, Kiev, Ukraine for sharing the spectral
information and for sending the original research
publication. We are also thankful to the Chairperson,
University Institute of Pharmaceutical Sciences,
Panjab University, Chandigarh for providing necessary
facilities.
20. Guetzoyan L J, Spooner R A, Lord J M, Roberts L M
and Clarkson G J 2010 Eur. J. Med. Chem. 45 275
21. Rashad A E, Shamroukh A H, Abdel-Megeid R E,
Mostafa A, El-Shesheny R, Kandeil A, Ali M A and
Banert K 2010 Eur. J. Med. Chem. 45 5251
References
1. Polosa R and Blackburn M R 2009 Trends Pharmacol.
Sci. 30 528
2. Prasad M R, Bahekar R H and Rao A R 2000 Pharmazie
55 475
22. Pfeiffer W, Dollinger H and Langer P 2009 Phosphorus,
Sulfur and Silicon 184 626
3. Yasothan U and Kar S 2008 Nat. Rev. Drug Discov. 7
285
23. Shetty N S, Lamani R S and Khazi I A M 2009 J. Chem.
Sci. 121 301
4. Manjunath S and Sakhare P M 2009 Indian J.
Pharmacol. 41 97
24. Fondjo E S, Dopp D and Henkel G 2006 Tetrahedron 62
7121
5. Polosa R 2002 Eur. Respir. J. 22 488
6. Fredholm B B, Ijzerman A P, Jacobson K A, Klotz K N
and Linden J 2001 Pharmacol. Rev. 53 527
7. Yuzlenko O and Kiec-Kononowicz K 2006 Curr. Med.
Chem. 13 3609
25. Knust H and Thomas A W 2009 US007507728B2
26. Silverstein R M, Bassler G C and Morrill T C 1991
Spectrometric identification of organic compounds 5th
edition, Singapore: John Wiley & Sons, Inc. 3rd
Chapter, 186
8. Muller C E, Sandoval-Ramfrez J, Schobert U, Geis
U and Frobenius W K N 1998 Bioorg. Med. Chem. 6
707
9. Nadeem A and Mustafa S J 2006 Drug Discov. Today:
Therapeutic Strategies 3 269
27. Braslau R, Anderson M O, Rivera F, Jimenez A,
Haddad T and Axon 2002 Tetrahedron 58 5513
28. Khan K M, Rasheed M, Ullah Z, Hayat S, Kaukab F,
Choudhary M I, Rahman A and Perveen S 2003 Bioorg.
Med. Chem. 11 1381