A simple, convenient one-pot synthesis of [1,2,4]triazolo/benzimidazolo quinazolinone derivatives by using molecular iodine

Article abstract of DOI:10.1016/j.tetlet.2013.02.099

A wide variety of quinazolinone derivatives have been synthesized by condensation of 3-amino-1,2,4-triazole and 2-aminobenzimidazole as amine sources, with aromatic aldehydes and dimedone in the presence of 10 mol % of molecular iodine in acetonitrile und

Full text of DOI:10.1016/j.tetlet.2013.02.099

Tetrahedron Letters 54 (2013) 2480–2483
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A simple, convenient one-pot synthesis of [1,2,4]triazolo/benzimidazolo
quinazolinone derivatives by using molecular iodine
Ravinder Goud Puligoundla b, , Shuklachary Karnakanti a, , Rajashaker Bantu a, , Nagaiah Kommu b,
,
⇑
a,
Sudhakar Babu Kondra c, , Lingaiah Nagarapu
⇑
a Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad 500 607, India
b Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 607, India
c Department of Chemistry, Sri Krishnadevaraya University, Ananthapur 515 037, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A wide variety of quinazolinone derivatives have been synthesized by condensation of 3-amino-1,2,4-tri-
azole and 2-aminobenzimidazole as amine sources, with aromatic aldehydes and dimedone in the
presence of 10 mol % of molecular iodine in acetonitrile under reflux conditions through one-pot
reactions. Environmental acceptability, low cost, no need of chromatographic separation, and high yields
are the important features of this protocol.
Received 3 January 2013
Revised 26 February 2013
Accepted 28 February 2013
Available online 13 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Molecular iodine
3-Amino-1,2,4-triazole
2-Aminobenzimidazole
In the mainstream of current interest, multicomponent pro-
cesses have recently gained considerable economic and ecological
interest as they address fundamental principles of synthetic effi-
ciency and reaction design. Multi-component reactions (MCRs)
have been proven to be a very elegant and rapid way to access
complex structures in a single synthetic operation from simple
building blocks and show high selectivity.1
Nitrogen-containing heterocycles have always played a major
role in the pharmaceutical and agrochemical industries because
of their often potent physiological properties, which have resulted
in numerous applications.2 Triazolo quinazolinone derivatives are
an important class of natural products and exhibit a wide range
of spectrum of biological activities, such as antihypertensive,3 anti-
histaminic,4 analgesic, anti-inflammatory,5 anticancer,6 and anti-
HIV activities.7 Moreover, the triazoles, imidazoles, pyrazoles,
and tetrazoles are representing an important structural motif in
medicinal chemistry and can be found in the drugs containing aro-
matic five-membered nitrogen heterocycle, such as cholesterol-
reducing atorvastatin, anti-inflammatory celecoxib, anti-ulcerative
cimetidine, b-lactamase tazobactam, antifungal fluconazole, and
anti-hypertensive losartan (Fig. 1). These derivatives also have a
long history of application in agrochemicals and pharmaceutical
industry as herbicides and active pharmaceuticals. The prevalence
of triazolo quinazolinone cores in biologically active molecules has
stimulated the need for elegant and efficient ways to make these
heterocyclic lead.
Several different strategies for the synthesis of substituted triaz-
olo/benzimidazolo quinazolinones are known, the most common
protocol is the reaction of substituted aldehydes with 3-amino-
1,2,4-triazole and 2-aminobenzimidazole as amine sources and
dimedone in the presence of acid or basic catalysts. There are literary
data about the synthesis of 6,6-dimethyl-9-phen yl-5,6,7,9-tetrahy-
dro-[1,2,4]triazolo[5,1-b]quinazolin-8(4H)-one and 3,3-dimethyl-
12-phenyl-1,2,3,4,5,12-hexatrahydro-[4,5]imidazolo [2,1-b]quinaz
olin-1-one derivatives by treatment of 3-amino-1,2,4-triazolo or
2-aminobenzimidazole with aldehydes and dimedone.8 The cyclo-
condensation was realized by heating of the starting materials in
DMF under reflux conditions8a,b or in the presence of sulfamic acid
using acetonitrile as solvent under reflux conditions8c or in the pres-
ence of ionic liquids8d or in the presence of heteropolyacids.8e How-
ever, many of these methods are associated with various drawbacks
such as use of metal catalysts, harsh reaction conditions, tedious
experimental procedures, unsatisfactory yields, long reaction times,
and usage of expensive and moisture sensitive catalysts. Hence,
there is a need to develop a rapid, efficient, and environmentally be-
nign synthetic protocol for the synthesis of triazolo/benzimidazolo
quinazolinone derivatives.
⇑
Corresponding authors. Tel.: +91 40 27191509/10; fax: +91 40 27193382 (K.N.);
tel.: +91 40 27191509; fax: +91 40 27193382 (S.B.K.).
E-mail addresses: rajashakerbantu@yahoo.co.in (R. Bantu), nagaiah@iict.res.in
(K. Nagaiah), drksbabu@gmail.com (S.B. Kondra).
In recent years, the use of molecular iodine in organic synthesis
has received considerable attention as an inexpensive, non-toxic,
readily available agent affording the corresponding products with
Tel.: +91 40 27191509; fax: +91 40 27193382.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.099

R. G. Puligoundla et al. / Tetrahedron Letters 54 (2013) 2480–2483
2481
Me
OH
NH
O
OH
NH Me
CN
N
HN
COOH
N
S
Me
HN
N
CF3
N
O
H2N
S
N
F
O
Cimetidine
Celecoxib
Atorvastatin
N
N
N
O
H
O
N
OH
S
N
N
N
HN
N
N
N
N
N
N
Cl
N N
Me
COOH
O
F
F
HO
Losartan
Fluconazole
Tazobactam
Figure 1.
Table 1
high selectivity in excellent yields. The mild Lewis acidity associ-
ated with iodine enhanced its usage in organic synthesis to per-
form several organic transformations using stoichiometric levels
to catalytic amounts. Owing to advantages associated with this
eco-friendly catalyst, molecular iodine has been explored as a pow-
erful reagent in organic synthesis.9 Recently, we reported the use
of iodine for the synthesis of 1,2,3,6-tetrahydropyrimidines.10 In
this Letter, we report the synthesis of [1,2,4]triazolo[5,1-b]quinaz-
olin-8(4H)-one and 3,3-dimethyl-12-phenyl-3,4,5,12-tetrahydro
benzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one derivatives by the
iodine catalyzed cyclocondensation of 3-amino1,2,4-triazole 1/2-
aminobenzimidazole 5, aromatic aldehydes 2 and 3 in excellent
yields (Scheme 1 and Table 1).
Initially, the reaction of 3-amino-1,2,4 triazole (1) with 4-nitro
benzaldehyde (2) and dimedone (3) in the presence of 10 mol %
of iodine for 10–15 min. was refluxed in 5 mL of CH3CN. The reac-
tion mass was cooled to room temperature and filtered. The solid
was separated and washed with water, dried at reduced pressure
to afford the title compound 6,6-dimethyl-9-(4-nitrophenyl)-
5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-b]quinazolin-8(4H)-one (4d)
in 97.1% yield. Interestingly we did not obtain any product when
the experiment was done without catalyst under refluxing in ace-
tonitrile. All the [1,2,4]triazolo/benzimidazolo quinazolinone
derivatives were obtained in excellent yields with good purity.
The isolated products were completely characterized by IR, 1H
NMR, and mass spectroscopic analyses. The formation of com-
pound 4d was evident from the appearance of [M+H]+ peak at m/
z 340 in mass spectrum (ESI), –C@O stretching at 1646 cmÀ1 in
IR and the appearance of characteristic methine proton as a singlet
at d 6.35 in 1H NMR and the appearance of carbonyl carbon at d
Multicomponent reaction of aromatic aldehydes 2, 3-amino 1,2,4-triazole 1, and
dimedone 3 for the synthesis of 4a–n
Entry
R
Product
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
C6H5
2,4-diCl-C6H3
4-BrC6H4
4-NO2C6H4
4-FC6H4
4-ClC6H4
2,4,6-triOMe-C6H2
4-OCH3C6H4
4-CH3C6H4
4-OHC6H4
3-OHC6H4
2,4-OMeC6H3
2-NO2C6H4
2-OMeC6H4
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
10.0
10.0
10.0
10.0
10.0
10.0
15.0
10.0
10.0
15.0
15.0
15.0
15.0
15.0
81.2
92.2
84.4
97.1
82.4
96.1
84.3
89.9
85.8
88.5
83.1
85.7
91.0
88.0
9
10
11
12
13
14
a
Reaction conditions: benzaldehyde (1.0 mmol), dimedone (1.0 mmol), 3-amino
1,2,4-triazole (1.0 mmol), 10 mol % iodine, 10–15 min reflux.
b
Isolated yields.
170.25 ppm in 13C NMR spectrum was in agreement with the pro-
posed structure.
To explore the scope of this reaction for the synthesis of
[1,2,4]triazolo[5,1-b]quinazolin-8(4H)-one derivatives different
substituted aldehydes were reacted with 3-amino-1,2,4 triazole
and dimedone in the presence of molecular iodine and acetonitrile
as the reaction medium (Table 1). In general, all the reactions
were very clean, and the 1,2,4-triazolo[5,1-b]quinazolin-8(4H)-
one derivatives were obtained in high yields under these condi-
tions. Aldehyde bearing electron-donating groups (Me, OMe) and
O
CHO
O
Iodine (10 mol %)
N
HN
N
N
N
+
NH2
+
R
CH3CN,reflux,10-15 min
N
O
N
H
1
2
3
Scheme 1. Molecular iodine mediated synthesis of 1,2,4-triazolo[5,1-b]quinolin-8(4H)-one derivatives.

2482
R. G. Puligoundla et al. / Tetrahedron Letters 54 (2013) 2480–2483
R
N
O
O
CHO
H
N
N
Iodine (10 mol %)
+
NH2
R
+
N
H
CH3CN,reflux,10-15 min
O
N
5
2
3
6 a-e
Scheme 2. Molecular iodine mediated synthesis of 3,3-dimethyl-12-phenyl-3,4,5,12-tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolin-1(2H)-one derivatives.
6a–e in the presence of molecular iodine (Scheme 3). The hypothesis
supported the fact that initially the reaction was initiated by iodine,
Table 2
Multicomponent reaction of aromatic aldehydes 2, 2-amino benzimidazole 5, and
dimedone 3 for the synthesis of 6a–6e
which reacts with benzaldehyde and forms a complex A. Further
complex A reacts with amine sources, giving rise to complex B and
upon loss of water molecule, proton transformation takes place giv-
ing rise to the crucial intermediate C. Further complex C undergoes
intramolecular cyclization by loss of water molecule to give the tar-
get products (Scheme 3). The simplicity, together with the use of
inexpensive, non-toxic, and environmentally benign natured molec-
ular iodine under acetonitrile media is another remarkable feature
of the procedure. The reaction mixture was cooled to room temper-
ature, the precipitate formed was filtered, washed with water and
dried to give pure 3a–n and 6a–e in excellent yields.
Entry
R
Product
Time (min)
Yield (%)
1
2
3
4
5
C6H5
6a
6b
6c
6d
6e
10.0
10.0
10.0
10.0
10.0
84.6
82.2
84.4
69.1
72.4
2,4-diCl-C6H3
4-BrC6H4
4-NO2C6H4
4-ClC6H4
a
Reaction conditions: benzaldehyde (1.0 mmol), dimedone (1.0 mmol), 2-amino
benzimidazole (1.0 mmol), 10 mol % iodine, 10–15 min reflux.
b
Isolated yields
In conclusion, we have developed an efficient and facile method
for the synthesis of 1,2,4-triazolo[5,1-b]quinazolin-8(4H)-one
derivatives and 3,3-dimethyl-12-phenyl-3,4,5,12-tetrahydrobenzo
[4,5]imidazo[2,1-b]quinazolin-1(2H)-one derivatives by treatment
of the corresponding aldehydes with 3-amino-1,2,4-triazoles or
2-amino benzimidazole and dimedone by using iodine in the pres-
ence of acetonitrile at reflux conditions in 10–15 min. The mild
reaction conditions, less expensive reaction medium, operational
simplicity, and high yields are the advantages of this protocol.
Molecular iodine mediated reactions are very useful both from
economical and environmental points of view.
electron-withdrawing groups (NO2) gave the desired products in
quantitative yields in 10 min (Table 1, entries 4, 7, 8, 12, and 14).
Results show that the substituent groups did not play any signifi-
cant role in the reactivity of the substrate.
In order to explore the generality of the reaction, we extended
our study using 2-amino benzimidazole 5 as amino source, react-
ing with dimedone 3, iodine as catalyst in the presence of acetoni-
trile with different substituted aromatic aldehydes to prepare a
series of benzimidazole quinazolinone derivatives (Scheme 2 and
Table 2). Various aromatic aldehydes containing electron-with-
drawing and electron-donating substituents show equal ease
toward the product formation in good to high yields.
Acknowledgments
Molecular iodine showed remarkable reactivity as a ‘hard–soft’
reagent and considerably accelerated the reactions. On the basis of
all our experimental results, together with literature reports we
have proposed the plausible mechanism for the formation of
[1,2,4]triazolo/benzimidazolo quinazolinone derivatives 3a–n and
The authors gratefully acknowledge the Director IICT, Hyd. for
his constant encouragement and support. Authors thank New
Delhi for financial support through the program ORIGIN of XII
FVP (CSC0108).
O
OH
Ph
O
O
H
H
O
I-I
O
I
HO
Ph
Ph
O
O
A
Ph
O
O
HO
Ph
O
Ph
O
H
HO
N
HO
N
-H2O
N
HN
H N
HN
NH2
N
H
B
N
H
N
N
OH
N
C
-H2O
O
Ph
N
N
N
N
H
Scheme 3. A plausible mechanism for the synthesis of [1,2,4]triazolo/benzimidazolo quinazolinone derivatives by using molecular iodine.

R. G. Puligoundla et al. / Tetrahedron Letters 54 (2013) 2480–2483
2483
(75 MHz, CDCl3): d 192.9, 150.4, 150.0, 146.7, 137.7, 129.0, 128.8, 115.1,
114.8, 105.3, 57.2, 49.7, 32.1, 28.3, 26.8; MS m/z (ESI); 313 [M+H]+. 9-(4-
Chlorophenyl)-6,6-dimethyl-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-b]quinazol
in-8(4H)-one (Table 1, entry 6, 4f): Pale yellow solid; Yield 92%; mp 304–
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.02.
099.
306 °C; IR: 3091, 2963, 1649, 1578, 1366, 1254, 760 cmÀ1 1H NMR (300 MHz,
;
DMSO-d6): d 1.04 (s, 3H, CH3), 1.12 (s, 3H, CH3), 2.22 (q, J = 16.82, 17.90 Hz,
2H, –CH2), 2.54 (s, 2H, –CH2), 6.34 (s, 1H, –CH), 7.23 (q, J = 4.88, 8.68, 4H,
Ar-H), 7.43 (s, 1H, Ar-H), 10.77 (s, 1H, NH); MS m/z (ESI); 329 [M+H]+. 6,6-
Dimethyl-9-(2,4,6-trimethoxyphenyl)-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-b]qu
inazolin-8(4H)-one (Table 1, entry7, 4g): Pale yellow solid; Yield 92%; mp
References and notes
290–292 °C; IR: 3103, 2966, 1648, 1586, 1336, 1122, 1008 cmÀ1 1H NMR
;
1. (a) Weber, L. Curr. Med. Chem. 2002, 9, 2085–2093; (b) Hulme, C.; Gore, V. Curr.
Med. Chem. 2003, 10, 51–80; (c) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000,
39, 3168–3210.
2. Hagan, D. O. Nat. Prod. Rep. 2000, 17, 435.
3. Alagarsamy, V.; Solomon, V. R.; Murugan, M. Bioorg. Med. Chem. 2007, 15,
4009–4015.
4. Alagarsamy, V. Pharmazie 2004, 59, 3753–3755.
5. Alagarsamy, V.; Murugananthan, G.; Venkateshperumal, R. Biol. Pharm. Bull.
2003, 26, 1711–1714.
(300 MHz, DMSO-d6): d 1.15 (s, 3H, CH3), 1.18 (s, 3H, CH3), 2.31 (s, 2H, –CH2),
2.58 (q, J = 9.44, 16.61 Hz, 2H, –CH2), 3.79 (s, 3H, –OCH3), 3.82 (s, 6H, 2
 ÀOCH3), 6.37 (s, 1H, CH), 6.54 (s, 2H, Ar-H), 7.69 (s, 1H, Ar-H), 10.86 (s,
1H, NH); 13C NMR (75 MHz, CDCl3): d 193.0, 152.6, 150.6, 149.9, 146.6, 137.0,
105.2, 104.4, 59.8, 57.9, 55.7, 49.7, 32.0, 28.6, 26.5; MS m/z (ESI); 385 [M+H]+.
9-(4-Methoxyphenyl)-6,6-dimethyl-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-b]quin
azolin-8(4H)-one (Table 1, entry 8, 4h): Pale yellow solid; Yield 92%; mp 228–
230 °C; IR: 3092, 2966, 1647, 1582, 1367, 1248, 1176 cmÀ1
;
1H NMR
(300 MHz, DMSO-d6): d 1.10 (s, 3H, CH3), 1.17(s, 3H, CH3), 2.30 (s, 2H, –
CH2), 2.56 (s, 2H, –CH2), 3.76 (s, 3H, OCH3), 6.39 (s, 1H, –CH), 6.82 (d, J = 8.49
Hz, 2H, Ar-H), 7.25 (d, J = 7.55 Hz, 2H, Ar-H), 7.65 (s, 1H, Ar-H), 11.37 (s, 1H,
NH); MS m/z (ESI); 325 [M+H]+. 6,6-Dimethyl-9-p-tolyl-5,6,7,9-tetrahydro-
[1,2,4]tria zolo[5,1-b]quinazolin-8(4H)-one (Table 1, entry 9, 4i): Pale yellow
solid; Yield 92%; mp 266–268 °C; IR: 3091, 2924, 1649, 1581, 1368, 1253,
756 cmÀ1;1H NMR (300 MHz, DMSO-d6): dd 1.05 (s, 3H, CH3), 1.12 (s, 3H,
CH3), 2.20 (d, J = 11.52 Hz, 2H, –CH2), 2.27 (s, 3H, –CH3), 2.54 (s, 2H, –CH2),
6.28 (s, 1H, –CH), 7.07 (d, J = 7.93, 2H, Ar-H), 7.15 (d, J = 8.12, 2H, Ar-H), 7.54
(s, 1H, Ar-H), 10.81 (s, 1H, NH); 13C NMR (75 MHz, CDCl3): d 192.2, 148.9,
148.6, 145.8, 137.3, 136.0, 127.7, 125.7, 105.2, 56.9, 59.1, 31.2, 37.7, 26.0,
19.7; MS m/z (ESI); 309 [M+H]+. 9-(4-Hydroxyphenyl)-6,6-dimethyl-5,6,7,9-
tetrahydro-[1,2,4 ]triazolo[5,1-b]quinazolin-8(4H)-one (Table 1, entry 10, 4j):
Pale yellow solid; Yield 92%; mp >300 °C; IR: 3225, 2930, 1630, 1585, 1366,
6. Hour, M. J.; Huang, L. J.; Kuo, S. C.; Xia, Y.; Bastow, K.; Nakanishi, Y.; Hamel, E.;
Lee, K. H. J. Med. Chem. 2000, 43, 4479–4487.
7. Alagarsamy, V.; Revathi, R.; Meena, S.; Ramasheshu, K. V.; Rajashekarn, S.; De
Clercq, E. Indian J. Pharm. Sci. 2004, 66, 459–462.
8. (a) Lipson, V. V.; Desenko, S. M.; Shirobokova, M. G.; Borodina, V. V. Chem.
Heterocycl. Compd. 2003, 39, 1213; (b) Lipson, V. V.; Desenko, S. M.;
Shirobokova, M. G.; Shishkin, O. V.; Orlov, V. D. Chem. Heterocycl. Compd.
2003, 39, 1041; (c) Heravi, M. M.; Derikvand, F.; Ranjbar, L. Synth. Commun.
2010, 40, 677–685; (d) Kumari, K.; Raghuvanshi, D. S.; Sing, K. N. Org. Prep.
Proced. Int. 2012, 44, 460–466; (e) Heravi, M. M.; Ranjbar, L.; Derikvand, F.;
Alimadadi, B.; Oskooie, H. A.; Bamoharram, F. F. Mol. Divers. 2008, 12, 181–185.
9. (a) Yadav, J. S.; Reddy, B. V. S.; Premalatha, K.; Swamy, T. Tetrahedron Lett. 2005,
46, 2687; (b) Huang, G.; Isobe, M. Tetrahedron 2001, 57, 10241; (c) Tsukiyama,
T.; Peters, S. C.; Isobe, M. Synlett 1993, 413; (d) Hosokawa, S.; Kirschbaum, B.;
Isobe, M. Tetrahedron Lett. 1917, 1998, 39; (e) Tsukiyama, T.; Isobe, M.
Tetrahedron Lett. 1992, 33, 7911.
1268, 731 cmÀ1 1H NMR (300 MHz, DMSO-d6): d 1.06 (s, 3H, CH3), 1.12 (s, 3H,
;
CH3), 2.14–2.24 (m, 2H, –CH2), 2.52–2.64 (m, 2H, –CH2), 6.26 (s, 1H, –CH,
6.69-6.75 (m, 2H, Ar-H), 7.078 (d, J = 8.49, Hz, 2H, Ar-H), 7.54 (d, J = 10.38 Hz,
1H, Ar-H), 10.70 (s, 1H, NH); 13 C NMR (75 MHz, CDCl3) d 160.95, 138.61,
130.69, 125.72, 123.92, 112.44, 64.81, 63.18, 16.07, 14.1; MS m/z (ESI); 311
[M+H]+. 9-(3-Hydro xyphenyl)-6,6-dimethyl-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,
1-b]quinazolin-8(4 H)-one (Table 1, entry 11, 4k): Pale yellow solid; Yield 92%;
mp 289–290 °C; IR: 3090, 2962, 1650, 1579, 1366, 1254, 729 cmÀ1; IR: 3164,
10. (a) Nagarapu, L.; Hanmath Reddy, V.; Narshimahagi, C. H.; Rajashaker, B.;
Reddy, A. R. Synth. Commun. 2012, 42, 2131; (b) Rajashaker, B.; Mereyala, H. B.;
Nagarapu, L.; Kantevari, S. Tetrahedron Lett. 2011, 52, 4854.
Further reading
2955, 1624, 1563, 1362, 1249, 699 cmÀ1 1H NMR (300 MHz, DMSO-d6): d
;
1.06 (s, 3H, CH3), 1.11(s, 3H, CH3), 2.21 (q, J = 6.04, 16.43 Hz, 2H, –CH2), 2.53
(s, 2H, –CH2 ), 6.25 (s, 1H, –CH), 6.65-6.76 (m, 3H, Ar-H), 7.06 (t, J = 7.93,
8.12 Hz, 1H, Ar-H), 7.57 (d, J = 5.66, 1H, Ar-H), 8.91 (s, 1H, –OH), 10.78 (s, 1H,
NH); 13 C NMR (75 MHz, CDCl3) d 160.95, 138.61, 130.69, 125.72, 123.92,
112.44, 64.81, 63.18, 16.07, 14.1; MS m/z (ESI); 311 [M+H]. 9-(2,4-Dime
thoxyphenyl)-6,6-dimethyl-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-b]quinazolin-8
(4H)-one (Table 1, entry 12, 4l): Pale yellow solid; Yield 92%; mp 210–212 °C;
11. General procedure for the synthesis of [1,2,4]triazolo[5,1-b]quinazolin-8(4H)-ones
and hexahydro[4,5]benzimidazolo[2,1-b]quinazolinones by using molecular
iodine as the reaction medium:
A mixture of 3-amino-1,2,4-triazole or
benzimidazole (1.0 mmol), benzaldehyde (1.0 mmol), dimedone (1.0 mmol),
and acetonitrile (5 mL) was taken in a round bottom flask and added iodine
(10 mol %) and stirred at 80 °C for 10 min. After completion of the reaction, as
monitored by TLC, the reaction mass was cooled to room temperature and the
solid separated was filtered and washed with water and dried at reduced
pressure.
IR: 3092, 2932, 1651, 1580, 1367, 1262, 826 cmÀ1 1H NMR (300 MHz, DMSO-
;
d6): d 1.01 (s, 3H, CH3), 1.11 (s, 3H, CH3), 2.16 (q, J = 16.43, 17.94 Hz, 2H, –
CH2), 2.50 (d, J = 6.61 Hz, 2H, –CH2), 3.69 (s, 3H, –OCH3), 3.75 (s, 3H, –OCH3),
6.35-6.45 (m, 3H, –CH, Ar-H), 7.26 (d, J = 8.30 Hz, 1H, Ar-H), 7.63 (s, 1H, Ar-H),
10.68 (s, 1H, NH); 13C NMR (75 MHz, CDCl3) d 160.95, 138.61, 130.69, 125.72,
123.92, 112.44, 64.81, 63.18, 16.07, 14.1; MS m/z (ESI); 355 [M+H]+. 6,6-Di
methyl-9-(2-nitrophenyl)-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-b]quinazolin-8(4
H)-one (Table 1, entry 13, 4m): Pale yellow solid; Yield 92%; mp 290–292 °C;
Data of representative examples: 6,6-Dimethyl-9-phenyl-5,6,7,9-tetrahydro-
[1,2,4]triazolo[5,1-b]quinazolin-8(4H)-one (Table 1, entry 1, 4a): White solid;
Yield 92%; mp 250–252 °C; IR: 3090, 2962, 1650, 1579, 1366, 1254, 729 cmÀ1
;
1H NMR (300 MHz, DMSO-d6): d 1.05 (s, 3H, CH3), 1.11 (s, 3H, CH3), 2.21
(q, J = 10.19, 16.43 Hz, 2H, –CH2), 2.54 (s, 2H, –CH2), 6.33 (s, 1H, –CH), 7.25
(s, 4H, Ar-H), 7.56 (s, 2H, Ar-H), 10.82 (s, 1H, NH); MS m/z (ESI); 295 [M+H]+.
9-(2,4-Dichlorophenyl)-6,6-dimethyl-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-b
]quinazolin-8(4H)-one (Table 1, entry 2, 4b): Pale yellow solid; Yield 94.61%;
IR: 3094, 2924, 1645, 1586, 1356, 1264, 735 cmÀ1 1H NMR (300 MHz, DMSO-
;
d6): d 0.99 (s, 3H, CH3), 1.10 (s, 3H, CH3), 2.16 (q, J = 11.70, 16.43 Hz, 2H, –
CH2), 2.53 (s, 2H, –CH2), 7.15 (s, 1H, –CH), 7.19 (d, J = 7.74 Hz, 1H, Ar-H),
7.34–7.41 (m, 1H, Ar-H), 7.44–7.52 (m, 1H, Ar-H), 7.63 (s, 1H, Ar-H), 7.81 (d,
J = 8.12 Hz, 1H, Ar-H), 10.97 (s, 1H, NH); 13C NMR (75 MHz, CDCl3): d 192.9,
150.7, 150.1, 148.3, 146.9, 135.1, 133.0, 128.7, 123.7, 104.9, 52.7, 49.4, 32.1,
28.1, 26.9; MS m/z (ESI); 340 [M+H]+. 9-(2-Methoxyphenyl)-6,6-dimethyl-
5,6,7,9-tetrahydro-[1,2,4] triazolo[5,1-b]quinazolin-8(4H)-one (Table 1, entry 14,
4n): Pale yellow solid; Yield 92%; mp 240–243 °C; IR: 2930, 2837, 1648, 1583,
mp 323–325 °C; IR: 3089, 2964, 1650, 1585, 1368, 1269, 850 cmÀ1 1H NMR
;
(300 MHz, DMSO-d6): d 1.02 (s, 3H, CH3), 1.08 (s, 3H, CH3), 2.14 (q, J = 16.24,
24.36 Hz, 2H, –CH2), 2.53 (s, 2H, –CH2), 6.56 (s, 1H, –CH), 7.26–7.36 (m, 2H,
Ar-H), 7.43 (s, 1H, Ar-H), 7.62 (s, 1H, Ar-H), 11.23 (s, 1H, NH); MS m/z (ESI);
364 [M+H]+.9-(4-Bromophenyl)-6,6-dimethyl-5,6,7,9-tetrahydro-[1,2,4]triazo
lo[5,1-b]quinazolin-8(4H)-one (Table 1, entry 3, 4c): Pale yellow solid; Yield
93%; mp 286–288 °C; IR: 3091, 2962, 2919, 1649, 1584, 1367, 1255, 841
1368, 1246, 755 cmÀ1 1H NMR (300 MHz, DMSO-d6): d 1.01 (s, 3H, CH3), 1.11
;
cmÀ1 1H NMR (300 MHz, DMSO-d6): d 1.04 (s, 3H, CH3), 1.12 (s, 3H, CH3), 2.21
;
(s, 3H, CH3), 2.18 (q, J = 14.91, 16.43 Hz, 2H, –CH2), 2.51 (s, 2H, –CH2), 3.71 (s,
3H, –OCH3), 6.54 (s, 1H, –CH), 6.79–6.92 (m, 2H, Ar-H), 7.16-7.23 (m, 1H, Ar-
H), 7.37 (d, J = 7.36 Hz, 1H, Ar-H), 7.43-7.43 (m, 1H, Ar-H), 10.62 (s, 1H, NH);
MS m/z (ESI); 325 [M+H]+.3,3-Dimethyl-12-phenyl-1,2,3,4,5,12-hexatrahydro-
[4,5]imidazolo [2,1-b]quinazolin-1-one (Table 2, entry 6a): White solid; Yield
(q, J = 10.38, 16.43 Hz, 2H, –CH2), 2.54 (s, 2H, –CH2), 6.30 (s, 1H, –CH), 7.16 (d,
J = 8.30 Hz, 2H, Ar-H), 7.40 (d, J = 8.30 Hz, 2H, Ar-H), 7.58 (s, 1H, Ar-H), 10.94
(s, 1H, NH); MS m/z (ESI); 373 [M]+, 375 [M+2]+. 6,6-Dimethyl-9-(4-nitro
phenyl)-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-b]quinazolin-8(4H)-one (Table
1, entry 4, 4d): Pale yellow solid; Yield 93%; mp>300 °C; IR: 2965, 1646, 1579,
92%; mp >300 °C; IR: 3365, 2962, 1648, 1577 cmÀ1 1H NMR (300 MHz,
;
1352, 1253, 730 cmÀ1 1H NMR (300 MHz, DMSO-d6): d 1.04 (s, 3H, CH3), 1.12
;
DMSO-d6): d 1.01 (s, 3H, CH3), 1.11 (s, 3H, CH3), 2.11–2.22 (m, 2H, –CH2),
2.54–2.64 (m, 2H, –CH2), 6.42 (s, 1H, –CH), 6.85–7.25 (m, 9H, Ar-H), 10.84 (s,
1H, NH); MS m/z (ESI); 344 [M+H]+.
(s, 3H, CH3), 2.22 (q, J = 7.74, 16.99 Hz, 2H, –CH2), 2.54 (s, 2H, –CH2), 6.35 (s,
1H, –CH), 6.95 (t, J = 8.68, 2H, Ar-H), 7.22-7.29 (m, 2H, Ar-H), 7.47 (s, 1H, Ar-
H), 10.83 (s, 1H, NH). 13C NMR (75 MHz, CDCl3): d 170.25, 159.25, 136.29,
127.46, 122.00, 110.43, 71.79, 64.99, 29.68, 15.72; MS m/z (ESI); 340 [M+H]+.
9-(4-Fluorophenyl)-6,6-dimethyl-5,6,7,9-tetrahydro-[1,2,4]triazolo[5,1-b]qui
nazolin-8(4H)-one (Table 1, entry, 5, 4e): Orange oil liquid; Yield 92%; mp
12(4-Bromo-phenyl)-3,3-dimethyl-1,2,3,4,5,12-hexahydro benzo[4,5]imidazolo
[2,1,b] (Table 2, entry 6c): White solid; Yield 92%; mp >300 °C; IR: 3380, 2945,
1650, 1565 cmÀ1 1H NMR (300 MHz, DMSO-d6): d 1.04 (s, 3H, CH3), 1.11 (s,
;
301–303 °C; IR: 3091, 2962, 1648, 1579, 1365, 1216, 762 cmÀ1 1H NMR
;
3H, CH3), 2.10–2.24 (m, 2H, –CH2), 2.58–2.70 (m, 2H, –CH2), 6.44 (s, 1H, –CH),
6.85–7.35 (m, 8H, Ar-H), 10.84 (s, 1H, NH); MS m/z (ESI); 422 [M]+, 424
[M+2]+.
(300 MHz, DMSO-d6): d 1.04 (s, 3H, CH3), 1.12 (s, 3H, CH3), 2.22 (q, J = 7.74,
16.99 Hz, 2H, –CH2), 2.54 (s, 2H, –CH2), 6.35 (s, 1H, –CH), 6.95 (t, J = 8.68, 2H,
Ar-H), 7.22–7.29 (m, 2H, Ar-H), 7.47 (s, 1H, Ar-H), 10.83 (s, 1H, NH); 13C NMR