A facile microwave assisted one-pot strategy for the synthesis of Bis-hexahydroquinazolin-5(6H)-ones

Article abstract of DOI:10.1155/2010/769137

A facile microwave assisted one-pot synthetic protocol has been devised for the synthesis of 3,3′-(alkanediyl) bis (1-phenyl-1,2,3,4,7,8- hexahydroquinazolin-5(6H)-ones (2a-c), 3,3′-(1,4-phenylene) bis (1-phenyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (2d),3,3′-(alkanediyl) bis (7,7- dimethyl-1-phenyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-ones (2e-g) and 3,3′-(1,4-phenylene) bis(7,7-dimethyl-1-phenyl-1,2,3,4,7,8-hexahydroquinazolin- 5(6H)-one (2h) by the cyclocondensation of cyclic enaminones 1a, b with diamines and formaldehyde.

Full text of DOI:10.1155/2010/769137

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2010, 7(1), 281-286
http://www.e-journals.net
A Facile Microwave Assisted One-pot Strategy for the
Synthesis of Bis-hexahydroquinazolin-5(6H)-ones
MILAN CH. DUTTA§, KAUSHIK CHANDA§,
R. L. NONGKHLAW and JAI N. VISHWAKARMA§*
§Organic Research Lab., Department of Chemistry,
St. Anthony’s College, Shillong-793 001, India.
Department of Chemistry,
North-Eastern Hill University, Shillong-793 022, India.
jnvishwakarma@rediffmail.com
Received 15 June 2009; Accepted 18 July 2009
Abstract: A facile microwave assisted one-pot synthetic protocol has been
devised for the synthesis of 3,3′-(alkanediyl) bis (1-phenyl-1,2,3,4,7,8-
hexahydroquinazolin-5(6H)-ones (2a-c), 3,3′-(1,4-phenylene) bis (1-phenyl-
1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (2d),3,3′-(alkanediyl) bis (7,7-
dimethyl-1-phenyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-ones (2e-g) and
3,3′-(1,4-phenylene) bis(7,7-dimethyl-1-phenyl-1,2,3,4,7,8-hexahydroquinazolin-
5(6H)-one (2h) by the cyclocondensation of cyclic enaminones 1a, b with
diamines and formaldehyde.
Keywords: Enaminones, Quinazolinones, Diamines, Cyclocondensation.
Introduction
Fused pyrimidines are found in a broad variety of natural products1, used in medicines2,
possess antimalarial activities3 and other important biological properties4. Recently,
1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-dione derivatives have been reported to exhibit
potent calcium antagonist activities5,6 and have also attracted considerable attention owing to
their potential antibacterial activity against Staphylococcus aureus, Escherichia coli,
Pseudomonas aeruginosa7,8. However, synthesis of 5-oxo-1,2,3,4,5,6,7,8-octahydroquinazolines9
is least attended to and to the best of our knowledge bis(5-oxo-1,2,3,4,5,6,7,8-
octahydroquinazolines) are unknown in the literature and hence their biological properties
remain unexplored. Prompted by the promising biological properties of 1,2,3,4,5,6,7,8-
octahydroquinazolines, we have recently reported10 a facile synthetic methodology for 1-
aralkyl/aryl-3-alkyl/aralkyl/aryl-5-oxo-1,2,3,4,5,6,7,8-octahydroquinazolines and 1-aralkyl/aryl-
3-alkyl/aralkyl/aryl-7,7-dimethyl-5-oxo-1,2,3,4,5,6,7,8-octahydroquinazolines. In continuation
with our efforts on the synthesis of tetrahydropyrimidines11-14, we now report herein a facile

282
JAI N. VISHWAKARMA et al.
one pot synthetic strategy for bis-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-ones in which the
two quinazoline rings are linked through flexible aliphatic chains or through rigid aromatic
ring (Scheme 1).
O
O
O
H2N-A-NH2/CH2O
MeOH/Reflux
N
A N
R
R
R
NHPh
N
N
R = H, Me
A = -(CH2)n-, -C6H4-
n = 2, 3, 4
R
R
R
Ph
Ph
1
2
Scheme 1
Experimental
Melting points were recorded by open capillary method and are uncorrected. The IR spectra
1
were recorded on a Perkin-Elmer 983 spectrometer. H NMR (90 MHz) spectra were
1
recorded on Varian EM-390 spectrometer. High resolution H NMR and 13C NMR (300
MHz) spectra were recorded on Bruker ACF-300 spectrometer. The chemical shifts (δ ppm)
and the coupling constants (Hz) are reported in the standard fashion with reference to TMS
as internal reference. FAB-mass spectra (MS) were measured on JEOL 3SX 102/DA-6000
Mass spectrometer using Argon as the FAB gas and m-nitrobenzylalcohol as the matrix.
Elemental analyses were performed on a Vario-EL III instrument. Microwave irradiation
was carried out in a domestic MW oven (Samsung CE2733G) operating at 2450 MHz.
Enaminones 1a and 1b were synthesized by our reported procedure15.
General procedure
A mixture of diamine (0.5 mmol) and formaldehyde (2 mmol, 40% solution) in 1.5 mL
methanol was shaken at room temperature for 5 minutes. To this a solution of enaminones 1
(1 mmol) was added in 5-6 mL methanol and the resulting mixture was irradiated in a domestic
microwave oven for specified period of time (Table 2). After the completion of the reaction
(monitored by TLC), methanol was removed under reduced pressure to give a gum, which on
trituration with hexane and subsequent recrystallization in appropriate solvent gave compounds
2a, 2e, 2g and 2h. In case of compounds 2b, 2c, 2d and 2f the gum was chromatographed using
neutral alumina and ethylacetate (eluant). Under thermal conditions these reactions took much
longer time for completion giving the desired products in comparatively lower yields.
3,3′-(Ethane-1,2-diyl)bis(1-phenyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (2a)
0
It was obtained as a pale yellow solid in 85% yield; mp 182-184 C (EtOAc); IR (KBr):
1
1493, 1566 cm-1; H NMR (CDCl3): δ 1.70 (m, 4H, 2 CH2), 2.12-2.28 (t, 4H, 2 CH2), 2.31-
2.60 (t, 4H, 2 CH2), 2.83 (s, 4H, 2 CH2), 3.73 (s, 4H, 2 CH2), 4.43 (s, 4H, 2 CH2), 7.07-7.87
(m, 10H); MS: m/z 483 (MH+). Anal. Calc. for C30H34N4O2 (482.27): C, 74.66; H, 7.10; N,
11.61. Found: C, 74.41; H, 7.07; N, 11.66%.
3,3′-(Propane-1,3-diyl)bis(1-phenyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (2b)
1
It was obtained as yellow gum in 76% yield; IR (CCl4): 1493, 1560 cm-1; H NMR
(CDCl3): δ 1.84-1.85 (m, 4H, 2 CH2), 1.86-1.88 (m, 2H), 2.18-2.20 (t, 4H, 2 CH2), 2.32-
2.36 (t, 4H, 2 CH2), 2.67-2.72 (t, 4H, 2 CH2), 3.64 (s, 4H, 2 CH2), 4.30 (s, 4H, 2 CH2),
7.11-7.13 (m, 4H), 7.27-7.43 (m, 6H); 13C NMR (CDCl3): δ 22.10, 26.07, 27.72, 36.55,
47.96, 50.95, 71.98, 104.83, 127.36, 127.50, 129.84, 143,02, 158.36, 194.94; MS: m/z,
497 (MH+). Anal. Calc. for C31H36N4O2 (496.28): C, 74.97; H, 7.31; N, 11.28. Found: C,
74.66; H, 7.33; N, 11.24%.

A Facile Microwave Assisted One-pot Strategy for the Synthesis
283
3,3′-(Butane-1,4-diyl)bis(1-phenyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (2c)
It was obtained as yellow gum in 77% yield; IR (CCl4): 1493, 1560 cm-1; 1H NMR (CDCl3):
δ 1.58 (m, 4H, 2 CH2), 1.85-1.88 (m, 4H, 2 CH2), 2.21 (t, 4H, 2 CH2), 2.33 (t, 4H, 2 CH2),
2.62 (t, 4H, 2 CH2), 3.64 (s, 4H, 2 CH2), 4.29 (s, 4H, 2 CH2), 7.12-7.14 (m, 4H), 7.30-7.43
(m, 6H); 13C NMR (CDCl3): δ 22.08, 25.59, 27.71, 30.51, 47.59, 52.59, 72.19, 104.76,
124.61, 127.37, 129.31, 143,05, 158.48, 195.03; MS: m/z, 511 (MH+). Anal. Calc. for
C32H38N4O2 (510.29): C, 75.26; H, 7.50; N, 10.97. Found: C, 75.50; H, 7.48; N, 10.92%.
3,3′-(1,4-Phenylene)bis(1-phenyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (2d)
0
It was obtained as yellow solid in 79% yield; mp 191-193 C; IR (KBr): 1427, 1507, 1566
cm-1; 1H NMR (CDCl3): δ 1.70-2.06 (m, 4H, 2 CH2), 2.10-2.30 (t, 4H, 2 CH2), 2.33-2.60 (t,
4H, 2 CH2), 4.56 (s, 4H, 2 CH2), 4.99 (s, 4H, 2 CH2), 6.96-7.93 (m, 14H); MS: m/z, 531
(MH+). Anal. Calc. for C34H34N4O2 (530.27): C, 76.95; H, 6.46; N, 10.56. Found: C, 76.70;
H, 6.45; N, 10.51%.
3,3′-(Ethane-1,2-diyl)bis(7,7-dimethyl-1-phenyl-1,2,3,4,7,8-hexahydroquinazolin-
5(6H)-one (2e)
0
It was obtained as yellow solid in 87% yield; mp 193-194 C (CHCl3/Hexane); IR (KBr):
1493, 1566, 1619 cm-1; 1H NMR (CDCl3): δ 1.03 (s, 12H, 4 CH3), 2.10 (s, 4H, 2 CH2), 2.23
(s, 4H, 2 CH2), 2.93 (s, 4H, 2 CH2), 3.80 (s, 4H, 2 CH2), 4.50 (s, 4H, 2 CH2), 7.03-7.76 (m,
10H); MS: m/z, 539 (MH+). Anal. Calc. for C34H42N4O2 (538.33): C, 75.80; H, 7.86; N,
10.40. Found: C, 76.05; H, 7.88; N, 10.44%.
3,3′-(Propane-1,3-diyl)bis(7,7-dimethyl-1-phenyl-1,2,3,4,7,8-hexahydroquinazolin-
5(6H)-one (2f)
1
It was obtained as yellow gum in 75% yield; IR (CCl4): 1427, 1493, 1566, cm-1; H NMR
(CDCl3): δ 0.90 (s, 12H, 4 CH3), 1.59-1.61 (m, 2H), 1.99 (s, 4H, 2 CH2), 2.13 (s, 4H, 2
CH2), 2.60-2.65 (m, 4H, 2 CH2) 3.58 (s, 4H, 2 CH2), 4.24 (s, 4H, 2 CH2), 7.01-7.08 (m, 4H),
7.25-7.41 (m, 6H); 13C NMR (CDCl3): δ 24.92, 27.28, 27.36, 31.64, 39.99, 46.40, 48.65,
48.96, 49.46, 70.92, 102.15, 126.38, 127.89, 129.39, 141.78, 155.62, 193.42. Anal. Calc. for
C35H44N4O2 (552.35): C, 76.05; H, 8.02; N, 10.15. Found: C, 76.31; H, 7.98; N, 10.11%.
3,3′-(Butane-1,4-diyl)bis(7,7-dimethyl-1-phenyl-1,2,3,4,7,8-hexahydroquinazolin-
5(6H)-one (2g)
0
It was obtained as a pale yellow solid in 90% yield; mp 168-169 C (EtOAc); IR (KBr):
1440, 1566, 1613 cm-1; 1H NMR (CDCl3): δ 1.03 (s, 12H, 4 CH3), 1.46-1.83 (m, 4H, 2 CH2),
2.13 (s, 4H, 2 CH2), 2.26 (s, 4H, 2 CH2), 2.56-2.90 (m, 4H, 2 CH2) 3.76 (s, 4H, 2 CH2), 4.45
(s, 4H, 2 CH2), 7.10-7.86 (m, 10H); MS: m/z, 567 (MH+). Anal. Calc. for C36H46N4O2
(566.36): C, 76.29; H, 8.18; N, 9.89. Found: C, 76.02; H, 8.21; N, 9.83%.
3,3′-(1,4-Phenylene)bis(7,7-dimethyl-1-phenyl-1,2,3,4,7,8-hexahydroquinazolin-
5(6H)-one (2h)
0
It was obtained as yellow solid in 89% yield; mp 126-128 C (MeOH/EtOAc); IR (KBr):
1507, 1566, 1610 cm-1; 1H NMR (CDCl3): δ 0.93 (s, 12H, 4 CH3), 2.00 (s, 4H, 2 CH2), 2.23
(s, 4H, 2 CH2), 4.27 (s, 4H, 2 CH2), 4.89 (s, 4H, 2 CH2), 6.91-6.96 (m, 8H), 7.27-7.36 (m,
6H); 13C NMR (CDCl3): δ 28.08, 28.52, 32.82, 41.24, 45.96, 50.21, 52.59, 71.21, 104.63,
119.13, 127.53, 127.62, 129.88, 142.84, 157.52, 194.22; MS: m/z, 587 (MH+). Anal. Calc.
for C38H42N4O2 (586.33): C, 77.78; H, 7.21; N, 9.55. Found: C, 77.52; H, 7.18; N, 9.61%.

284
JAI N. VISHWAKARMA et al.
Results and Discussion
Thus, when a mixture of 3-anilinocyclohex-2-en-1-one (1a), ethylenediamine and
formaldehyde (2:1:4) in methanol was subjected to MWI, work-up of the reaction mixture
followed by chromatographic purification yielded a solid in 85% yields, which was
characterized as 3,3′-(ethane-1,2-diyl)bis(1-phenyl-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-
one (2a). The reaction was found to be general with other diamines and with corresponding
1a-b to give the respective 2b-h in 77-90% overall yields (Table 1). These reactions were
also carried out under thermal conditions to give the expected products in comparatively
lower yields and in addition they took much longer time for completion (Table 2). The
structures of the Bis-quinazolines were assigned on the basis of spectral and analytical data.
Thus, the infrared spectra of 2a-h showed strong peaks in the range of 1427 to 1619 cm-1 due
to highly delocalised double bonds and carbonyl group stretching frequencies of enaminone
1
functionalities. In the H NMR spectra of 2a & 2e the NCH2 protons of ethylene chain
appeared as singlets at 2.83 ppm and 2.93 ppm respectively whereas the NCH2 protons of
propylene chain in 2b & 2f gave triplets in the range of 2.60-2.72 ppm. The protons at C2 of
propylene chain gave multiplets in the range of 1.59-1.88 ppm. Likewise in 2c & 2g the
protons at C1 & C2 of butylene chains gave multiplets in the range of 2.56-2.90 and 1.46-
1.88 ppm respectively. The protons at C2 and C4 of quinazoline ring resonated in the range
of 4.24-4.99 and 3.64-4.56 ppm respectively. In 2a-d the C8 protons of the parent ring
appeared as triplets between 2.10 & 2.30 ppm but in 2e-h they appeared as singlets between
1.99 & 2.10 ppm. The C6 protons of the parent ring in 2a-d appeared as triplets between
2.31 & 2.60 ppm but in 2e-h they appeared as singlets between 2.13 & 2.26 ppm. The C7
protons of the ring in 2a-d resonated giving multiplets in the range of 1.58-2.06 ppm. The
two-methyl protons at C7 in 2e-h gave singlets between 0.90 & 1.03 ppm. The aromatic
protons resonated in their usual range of 6.91-7.93 ppm. A plausible mechanism for the
formation of 2 from the cyclic enaminones 1 is worked out (Scheme 2).
HO
OH
2 CH2O
H2N
A
NH2
N
A
N
N
O
A
N
H
H
O
O
O
2 CH2O
N
H
A
N
H
N
A
N
N
N
H
NHR
RHN
R
R
H
O
O
O
O
N
A
N
N
A
N
N
N
N
H
O O
H H
N
R
R
R
R
H
H
H
O
O
N
A
N
N
N
R
R
2
Scheme 2.

A Facile Microwave Assisted One-pot Strategy for the Synthesis
285
Table 1. Synthesis of bis-quinazolinones (2a-h)
Entry Enaminones (1)
Conditions
Bis-quinazolinones (2)
O
O
O
1
H2N-(CH2)2-NH2, CH2O,
MeOH/180 W
3 minutes
N
N
NH
N
N
C6H5
C6H5
C6H5
1a
2a
2b
2c
2d
O
O
2
3
4
H2N-(CH2)3-NH2, CH2O,
MeOH/180 W
2 minutes
1a
1a
1a
N
N
N
N
C6H5
C6H5
O
O
H2N-(CH2)4-NH2, CH2O,
MeOH/180 W
2.5 minutes
N
N
N
N
C6H5
C6H5
O
O
H2N-C6H4-NH2, CH2O,
MeOH/180 W,
3 minutes
N
N
N
N
C6H5
C6H5
O
O
O
5
6
7
8
H2N-(CH2)2-NH2, CH2O,
MeOH/180 W,
2 minutes
N
N
NH
C6H5
N
N
C6H5
C6H5
1b
2e
2f
O
O
H2N-(CH2)3-NH2, CH2O,
MeOH/180 W,
4 minutes
1b
1b
1b
N
N
N
N
C6H5
C6H5
O
O
O
H2N-(CH2)4-NH2, CH2O,
MeOH/180 W,
1.5 minutes
N
N
N
N
C6H5
C6H5
2g
O
H2N-C6H4-NH2, CH2O,
MeOH/180 W,
2 minutes
N
N
N
N
C6H5
C6H5
2h
Table 2. Comparison of microwave irradiation and thermal condition results.
Microwave Irradiation (180 W)
Time, min
Thermal (Reflux)
Compound
Yield, %
85
76
Time, h
Yield, %
58
70
65
71
3
2
27
22
24
24
22
23
8
2a
2b
2c
2d
2e
2f
2.5
3
77
79
2
87
75
88
68
4
1.5
2
90
89
59
55
2g
2h
20

286
JAI N. VISHWAKARMA et al.
Acknowledgements
The authors wish to thank the Principal, Rev. Fr. Ioannis Warpakma, SDB for the facilities
and Rev. Fr. Stephen Mavely, SDB and Rev. Fr. Joseph Nellanatt, SDB for their
encouragement during the course of this investigation. The financial support from ICAR-
NATP-PIU and UGC-New Delhi is gratefully acknowledged. Authors (KC & MCD) thank
ICAR for Senior Research Fellowships. Thanks are also due to the Heads of RSIC-CDRI
(Lucknow) and RSIC-NEHU (Shillong) for recording spectra.
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