An expeditious synthesis of tetrahydro-1,2,4-triazolo[5,1- b ]quinazolin-8(4 H)-ones and dihydro-1,2,4-triazolo[1,5-a ]pyrimidines

Full text of DOI:10.1080/00304948.2012.715062

This article was downloaded by: [Stanford University Libraries]
On: 25 September 2012, At: 02:25
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Organic Preparations and Procedures
International: The New Journal for
Organic Synthesis
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/uopp20
An Expeditious Synthesis of
Tetrahydro-1,2,4-triazolo[5,1-
b]quinazolin-8(4H)-ones and
Dihydro-1,2,4-triazolo[1,5-a]pyrimidines
Kumkum Kumari a , D. S. Raghuvanshi a & Krishna Nand Singh a
a Department of Chemistry, Faculty of Science, Banaras Hindu
University, Varanasi, 221005, India
Version of record first published: 24 Sep 2012.
To cite this article: Kumkum Kumari, D. S. Raghuvanshi & Krishna Nand Singh (2012): An Expeditious
Synthesis of Tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-8(4H)-ones and Dihydro-1,2,4-triazolo[1,5-
a]pyrimidines, Organic Preparations and Procedures International: The New Journal for Organic
Synthesis, 44:5, 460-466
To link to this article: http://dx.doi.org/10.1080/00304948.2012.715062
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Organic Preparations and Procedures International, 44:460–466, 2012
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2012.715062
An Expeditious Synthesis of Tetrahydro-1,2,4-
triazolo[5,1-b]quinazolin-8(4H)-ones and
Dihydro-1,2,4-triazolo[1,5-a]pyrimidines
Kumkum Kumari, D. S. Raghuvanshi, and Krishna Nand Singh
Department of Chemistry, Faculty of Science, Banaras Hindu University,
Varanasi 221005, India
There is currently great interest in solid-state reactions as they offer potential reduction in
environmental contamination with the elimination of solvents.1,2 One practical approach
to achieve this goal is by grinding the solid reactants together using a mortar and pes-
tle, a technique adopted for a number of reactions.3,4 One-pot multi-component reactions
(MCRs) have been exploited as a powerful tool for the assembly of large libraries of biolog-
ically active compounds.5,6 Among heterocycles, quinazolinones and triazolo-pyrimidines
have attracted a great deal of attention due to their therapeutic and pharmacological
properties.7,8 Drugs such as fluconazole and itraconazole are notable examples of anti-
fungal molecules possessing the triazole nucleus. In view of the above and considering
the fact that ionic liquids have been used as eco-friendly catalysts as well as solvents in
organic synthesis,9–13 it was thought worthwhile to utilize the catalytic potential of 1-n-
butyl-3-methylimidazolium tetrafluoroborate ([Bmim]BF4) in the synthesis of tetrahydro-
1,2,4-triazolo[5,1-b]quinazolin-8(4H)-ones and dihydro-1,2,4-triazolo[1,5-a]pyrimidines.
Although different strategies have been employed for the synthesis of these compounds,14–18
these methods suffer from drawbacks such as long reaction times, cumbersome isolation
of the products and harsh reaction conditions. We now report a facile and efficient ionic
liquid-catalyzed multi-component synthesis of tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-
8(4H)-ones (3) and dihydro-1,2,4-triazolo[1,5-a]pyrimidines (4) in excellent yields from
3-amino-1,2,4-triazole, aldehydes and dimedone (or ethyl acetoacetate), respectively, by
simple grinding using a mortar and pestle at room temperature (Scheme 1).
In order to optimize the reaction conditions, test reactions of 3-amino-1,2,4-triazole
(1), benzaldehyde (2a) and dimedone were carried out in the presence of various ionic
liquid catalysts. While there was no observable product in the absence of the catalyst,
the addition of various [Bmim] salts, brought about a dramatic change in the reaction
profile, the best result being obtained using 15 mol% of [Bmim]BF4 at room temperature
in 12 min. Although it was also determined that heating at 70◦C in the presence of 15 mol%
Submitted January 12, 2012.
Address correspondence to Krishna Nand Singh, Department of Chemistry, Faculty of Science,
Banaras Hindu University, Varanasi 221005, India. E-mail: knsinghbhu@yahoo.co.in
460

Expeditious Synthesis of Tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-8(4H)-ones 461
Scheme 1
of [Bmim]BF4 led to the desired product in 92% yield in 12 min, grinding of the reactants
at room temperature with 15 mol% of [Bmim]BF4 is the better procedure.
The optimized set of conditions was used for the reaction of 3-amino-1,2,4-triazole
(1), with aldehydes (2) and dimedone (ethyl acetoacetate) to afford a number of quinazoli-
nones 3 and triazolo-pyrimidines 4 (Table 1). Aromatic aldehydes bearing both electron-
donating and electron-withdrawing substituents, including a heterocyclic aldehyde, under-
went smooth coupling to afford the desired products 3a-n and 4a-f in excellent yields.
Although the reaction of aliphatic aldehydes with dimedone did not occur (Table 1, En-
tries 15, 16), it worked well with ethyl acetoacetate, leading to relatively good yields
(Entries 23–25). In an attempt to further broaden the scope of process, 1,3-indandione was
treated with benzaldehyde and 3-amino-1,2,4-triazole (1). However, instead of the desired
products, Knoevenagel-type products were obtained.
It is worthwhile to mention that when the reaction is carried out on a large scale, using
40 mmol of benzaldehyde, 40 mmol of dimedone, 40 mmol of 3-amino-1,2,4-triazole and
6.0 mmol of [Bmim]BF4, the corresponding product 3a is obtained in the same yield (92%)
as on the small-scale reaction. During initial grinding of the reactants, complete melting
of the mixture occurs suggesting the release of heat. The generation of heat may be due to
the occurrence of ‘hot spots’.19 The formation of a liquid phase (called eutectic mixture)
prior to the reaction, results in uniform distribution of the reactants and brings the reacting
species into greater contact than does a solvent.4 This explains the shorter reaction time
and better yields under solvent-free conditions. The recovered catalyst may be reused four
times without any noticeable decrease in its activity and in yields.
Experimental Section
All the chemicals including ionic liquids were procured from Aldrich (USA) and E. Merck
(Germany) and used as received. IR spectra were recorded as KBr pellets on a Jasco FT/IR-
5300 spectrophotometer. 1H and 13C NMR spectra were carried out in DMSO-d6 and CDCl3
on a Jeol AL300 FTNMR spectrometer at 300 MHz and 75 MHz, respectively; chemical
shifts are given in δ, relative to TMS as an internal standard. Elemental analysis (C, H, N)
was performed using CHN Analyzer Model CE-440. Melting points were measured in open

462
Singh et al.
Table 1
Synthesis of Tetrahydro-1,2,4-triazolo[5,1-b]quinazolin8(4H)-ones (3) and of
Dihydro-1,2,4-triazolo[1,5-a]pyrimidines (4)
Entry Product
R
Time (min) Yielda (%)
mp. (◦C)
Found lit.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5
11
13
12
13
15
12
13
10
11
14
13
15
13
12
20
20
12
11
12
13
15
14
13
13
12
92
87
82
90
85
82
83
80
85
81
86
89
84
89
0
249–251 248–25015
278–280 280–28214
290–293 290–29214
287–288 284–28815
283–285 285–28814
4-MeC6H4
3-NO2C6H4
4-BrC6H4
4-ClC6H4
3-BrC6H4
3-ClC6H4
4-MeOC6H4
4-NO2C6H4
4-FC6H4
3,4,5-(MeO)3C6H2
4-Me2NC6H4
2,4-Cl2C6H3
2-Thienyl
Et
280–282
291–292
—
—
231–233 230–23314
>300
279–281
250–253
>30015
—
—
3j
3k
3l
285–287 290–29316
3m
3n
3o
3p
4a
4b
4c
4d
4e
4f
>300
254–257
—
>30016
—
—
H
C6H5
0
—
—
80
84
81
80
75
77
73
71
72
190–192 190–19218
4-MeOC6H4
4-MeC6H4
4-BrC6H4
4-NO2C6H4
4-FC6H4
H
220–223
246–248
221–225
263–264
218–220
—
—
—
—
—
4g
4h
4i
194–197 196–19818
151–153 150–15218
Me
Et
148–150
—
aIsolated yields based on 3-amino-1,2,4-triazole.
capillaries and are uncorrected. All the products were characterized based on their mp, IR,
1H NMR and 13C NMR. The data of the unknown products are given below in Table 2.
General Procedure for the Synthesis of Tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-8
(4H)-ones (3) and Dihydro-1,2,4-triazolo[1,5-a]pyrimidines (4)
A mixture of 3-amino-1,2,4-triazole (3.36 g, 40 mmol), aldehyde (40 mmol), dimedone
(5.60 g, 40 mmol)/ethyl acetoacetate (5.20 g, 40 mmol) and 6 mmol of [Bmim]BF4 (1.36 g)
was ground in an agate mortar and pestle set for the appropriate time (Table 1). Upon
completion of the reaction (as indicated on TLC), cold water (40 mL) was added to the

Expeditious Synthesis of Tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-8(4H)-ones 463
Table 2
IR, 1H NMR, 13C NMR Data and Combustion Analyses
Cmpd
IR (cm−1
)
1H NMR (δ)
13C NMR (δ)
Combustion Analyses
(Found)
C
H
N
3f 3451, 2963, 1645, 0.96 (s, 3H, CH3),
26.89, 28.30, 32.12, 54.70 4.59 15.01
1577, 1546, 1522
1.05 (s, 3H, CH3),
2.12–2.56 (m, 4H,
CH2), 6.25 (s, 1H,
CH), 7.16–7.65
(m, 5H, Ar, CH),
11.34 (br s, 1H,
NH)a
49.76, 57.44,
104.89, 124.42,
127.18, 130.23,
132.10, 135.84,
144.50, 146.18,
150.29, 155.45,
193.46 a
(54.53) (4.61) (14.89)
3g 3451, 2955, 1645, 0.97 (s, 3H, CH3),
26.92, 28.39, 32.27, 62.10 5.21 17.04
1577, 1549, 1525
1.04 (s, 3H, CH3),
2.13–2.56 (m, 4H,
CH2), 6.22 (s, 1H,
CH), 7.12–7.76
(m, 5H, Ar, CH),
11.21 (br s, 1H,
NH)a
49.75, 57.49,
104.94, 125.62,
127.08, 130.33,
133.10, 136.48,
144.51, 146.78,
150.27, 155.28,
193.06a
(61.96) (5.14) (16.92)
3j 3451, 2955, 1648, 0.96 (s, 3H, CH3),
27.58, 28.95, 39.67, 65.37 5.49 17.94
1577, 1486,
1420, 1367
1.04 (s, 3H, CH3),
2.11–2.54 (m, 4H,
CH2), 6.22 (s, 1H,
CH), 6.96–7.29
(m, 4H, Ar), 7.69
(s, 1H, CH), 11.16
(br s, 1H, NH)a
50.27, 57.88,
105.59, 128.65,
130.13, 132.76,
142.12, 143.21,
150.61, 150.86,
193.44a
(65.25) (5.38) (17.82)
3k 3451, 2960, 1652, 1.12 (s, 3H, CH3),
27.33, 28.49, 32.62, 62.49 6.29 14.57
1577, 1510, 1363
1.24 (s, 3H, CH3),
2.35–2.41 (m, 4H,
CH2), 3.75 (s, 6H,
OCH3), 3.81 (s,
3H, OCH3), 6.34
(s, 1H, CH), 7.25
(m, 2H, Ar), 7.68
(s, 1H, CH), 11.63
(br, s, 1H, NH)a
50.33, 55.49,
57.83, 60.81,
106.27, 114.06,
128.58, 134.29,
147.16, 150.34,
150.66, 157.29,
193.43a
(62.37) (6.21) (14.43)
3n 3451, 2963, 1648, 1.10 (s, 3H, CH3),
27.39, 28.86, 32.67, 59.98; 5.37 18.65
1577, 1540,
1453, 1363
1.22 (s, 3H, CH3),
2.27–2.45 (m, 4H,
CH2), 6.63 (s, 1H,
CH), 6.85–7.11
(m, 3H, Ar), 7.25
(s, 1H, CH), 11.68
(br, s, 1H, NH)a
50.24, 57.85,
105.69, 123.47,
124.53, 126.33,
143.64, 147.33,
150.50, 159.55,
193.44a
(59.81) (5.41) (18.57)
(Continued on next page)

464
Singh et al.
Table 2
IR, 1H NMR, 13C NMR Data and Combustion Analyses (Continued)
Cmpd
IR (cm−1
)
1H NMR (δ)
13C NMR (δ)
Combustion Analyses
(Found)
C
H
N
4b 3255, 3097, 2988,
1.11 (t, 3H, CH3, J = 14.09, 19.07, 55.21,
61.13 5.77 17.82
(60.96) (5.70) (17.69)
2905, 1695, 1253
7.2 Hz), 2.56 (s,
3H, CH3), 3.76 (s,
3H, CH3), 4.02 (q,
2H, CH2, J =
59.80, 60.04,
99.04, 113.87,
128.49, 133.65,
145.52, 147.23,
148.65, 159.44,
165.69b
7.2 Hz), 6.37 (s,
1H, CH), 6.81–7.60
(m, 5H, Ar), 11.00
(br s,1H, NH)b
4c 3260,3097, 2988,
1.12 (t, 3H, CH3, J = 14.09, 19.07, 22.07,
64.41 6.08 18.78
(64.27) (6.12) (18.69)
2900, 1699, 1253
7.2 Hz), 2.29 (s,
3H, CH3), 2.55 (s,
3H, CH3), 4.02 (q,
2H, CH2, J =
59.80, 60.04,
99.04, 113.87,
128.49, 133.65,
145.52, 147.23,
148.65, 159.44,
165.69b
7.2 Hz), 6.37 (s,
1H, CH), 7.09–7.59
(m, 5H, Ar), 10.13
(br s,1H, NH)b
4d 3255, 3095, 2900,
1.15 (t, 3H, CH3, J = 14.09, 19.07, 59.80,
49.60 4.16 15.43
(49.43) (4.10) (15.50)
2905, 1695, 1260
7.2 Hz), 2.58 (s,
3H, CH3), 4.06 (q,
2H, CH2, J =
60.04, 99.04,
100.92, 113.87,
128.49, 133.65,
145.52, 147.23,
148.65, 165.69b
7.2 Hz), 6.37 (s,
1H, CH), 7.42–7.96
(m, 5H, Ar), 11.13
(br s,1H, NH)b
4e 3255, 3097, 2988,
1.17 (t, 3H, CH3, J = 14.10, 19.34, 59.71,
54.71 4.59 21.27
(54.56) (4.51) (21.12)
2905, 1705, 1253
7.2 Hz), 2.62 (s,
3H, CH3), 4.05 (q,
2H, CH2, J =
60.43, 97.82,
113.36, 123.91,
128.36, 146.74,
147.31, 147.79,
148.99, 165.11b
7.2 Hz), 6.52 (s,
1H, CH), 7.26–8.20
(m, 5H, Ar), 11.43
(br s,1H, NH)b
4f 3255, 3097, 2988,
1.11 (t, 3H, CH3, J = 14.07, 19.16, 59.69,
59.60 5.00 18.53
(59.42) (5.09) (18.66)
2905, 1702, 1253
7.2 Hz), 2.58 (s,
3H, CH3), 4.04 (q,
2H, CH2, J =
60.14, 98.71,
115.35, 115.64,
129.01, 129.12,
145.95, 147.26,
148.76, 165.49b
7.2 Hz), 6.41 (s,
1H, CH), 6.96–7.61
(m, 5H, Ar), 11.16
(br s,1H, NH)b
(Continued on next page)

Expeditious Synthesis of Tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-8(4H)-ones 465
Table 2
IR, 1H NMR, 13C NMR Data and Combustion Analyses (Continued)
Cmpd
IR (cm−1
)
1H NMR (δ)
13C NMR (δ)
Combustion Analyses
(Found)
C
H
N
4i 3260, 3085, 2980, 0.70 (t, 3H, CH3, J 7.90, 14.32, 19.17,
55.92 6.83 23.71
(55.83) (6.71) (23.64)
2905, 1705, 1255
= 7.2 Hz),
28.55, 57.24,
60.04, 97.28,
113.78, 146.91,
148.53, 165.96b
1.25–2.02 (m, 5H,
CH3 & CH2), 2.49
(s, 3H, CH3), 4.20
(q, 2H, CH2, J =
7.2 Hz), 5.54 (s,
1H, CH), 7.65 (s,
1H, Ar), 10.60 (br
s,1H, NH)b
aIn DMSO-d6; bIn CDCl3.
reaction mixture and the precipitate formed was collected. With dimedone, the product 3
was purified further by washing with acetone, whereas in the case of ethyl acetoacetate, the
product 4 was purified by recrystallization from ethanol. The ionic liquid may be recovered
by the evaporation of water under vacuum, followed by washing with diethyl ether and
drying in an oven at 90◦C and reused four times.
References
1. A. L. Garay, A. Pichon and S. L. James, Chem. Soc. Rev., 36, 846 (2007).
2. D. Braga, D. D’Addario, S. L. Giaffreda, L. Maini, M. Polito and F. Grepioni, Top. Curr. Chem.,
254, 71 (2005).
3. T. Friscic and W. Jones, Cryst. Growth Des., 9, 1621 (2009).
4. G. Rothenberg, A. P. Downie, C. L. Raston and J. L. Scott, J. Am. Chem. Soc., 123, 8701 (2001).
5. M. Syamala, Org. Prep. Proced. Int., 41, 1 (2009).
6. M. Syamala, Org. Prep. Proced. Int., 37, 103 (2005).
7. S. K. Pandey, A. Singh, Nizamuddin and A. Singh, Eur. J. Med. Chem., 44, 1188 (2009).
8. G. F. Yang, R. F. Lu, X. N. Fei and H. Z. Yang, Chin. J. Chem., 18, 435 (2000); Chem. Abstr.,
133, 150512X (2000).
9. S. Flanagan, E. Hall, W. Bowie, J. W. Fuhs, R. Logan, F. Maniei and A. Hunt, Green Chem., 7,
333 (2005).
10. R. M. Lau, F. V. Rantwijk, K. R. Seddon and R. A. Sheldon, Org. Lett., 2, 4189 (2000).
11. X. He and T. H. Chan, Tetrahedron, 62, 3389 (2006).
12. L. Xu, W. Chen, J. Ross and J. Xiao, Org. Lett., 3, 295 (2001).
13. A. R. Hajipour and F. Rafiee, Org. Prep. Proced. Int., 42, 285 (2010).

466
Singh et al.
14. A. Shaabani, E. Farhangi and A. Rahmati, Comb. Chem. High Throughput Screen., 9, 771 (2006).
15. M. M. Heravi, F. Derikvand and L. Ranjbar, Synth. Commun., 40, 677 (2010).
16. V. V. Lipson, S. M. Desenko, V. V. Borodina and V. I. Musatov, Russ. J. Org. Chem., 41, 114
(2005).
17. R. B. Shankar and R. G. Pews, J. Heterocycl. Chem., 30, 169 (1993).
18. O. V. Fedorova, M. S. Zhidovinova, G. L. Rusinov, and I. G. Ovchinnikova, Russ. Chem. Bull.,
Int. Ed., 52, 1768 (2003).
19. G. W. V. Cave, C. L. Raston and J. L. Scott, Chem. Commun., 2159 (2001).