Zn(OTf)2-catalyzed three component, one-pot cyclocondensation reaction of some new octahydroquinazolinone derivatives and access their bio-potential

Article abstract of DOI:10.1007/s00044-011-9628-y

An efficient synthesis of some new octahydroquinazolinone derivatives 4a-x by the cyclocondensation reaction of corresponding 2-thi(oxo)-1,2- dihydroquinoline-3-carbaldehyde 1a-e, 1,3-dicarbonyl compounds 2a-b, and substituted urea 3a-c using zinc triflat

Full text of DOI:10.1007/s00044-011-9628-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1188–1198
DOI 10.1007/s00044-011-9628-y
ORIGINAL RESEARCH
Zn(OTf)2-catalyzed three component, one-pot cyclocondensation
reaction of some new octahydroquinazolinone derivatives
and access their bio-potential
•
Pushpak M. Shah Manish P. Patel
Received: 23 August 2010 / Accepted: 18 March 2011 / Published online: 1 April 2011
Ó Springer Science+Business Media, LLC 2011
Abstract An efficient synthesis of some new octahydro-
quinazolinone derivatives 4a–x by the cyclocondensation
reaction of corresponding 2-thi(oxo)-1,2-dihydroquinoline-
3-carbaldehyde 1a–e, 1,3-dicarbonyl compounds 2a–b, and
substituted urea 3a–c using zinc triflate as a catalyst in
refluxing ethanol in high yield is described. The structures
of new compounds have been characterized on the basis of
isolated marine alkaloids with interesting biological
activities were also found to contain the DHPMs core
(Snider and Shi, 1993). Most notably among them are
batzelladine alkaloids, which were found to be potent HIV
gp-120-CD4 inhibitors (Patil et al., 1995; Sinder et al.,
1996). Thus, synthesis of the heterocyclic nucleus con-
tained in such compounds is of much current interest. The
classical Biginelli synthesis is a one-pot cyclocondensation
of 1,3-dicarbonyl compounds with aldehydes and urea or
thiourea in ethanol solution containing catalytic amounts of
acid. This method, however, involves long reaction time
period, harsh reaction conditions, and unsatisfactory yields,
especially in the case of substituted aromatic and aliphatic
aldehydes (Folkers et al., 1932; Wipf and Cunningham,
1995; Folkers and Johnson, 1934). Therefore, the discovery
of milder and practical routes for synthesis of DHPMs by
the Biginelli reaction continues to attract the attention of
researchers. More recently, strontium(II) nitrate (Chenjiang
et al., 2006), Zn(ClO4)2Á6H2O (Bose and Idrees, 2007),
tungstate sulfuric acid (Esfahani et al., 2008), chloroacetic
acid (Yang et al., 2007), iodine (Zalavadiya et al., 2009),
KSF montmorillonite (Bigi et al., 1999) have been found to
be effective for this transformation. However, many of
these one-pot procedures require strong protic or Lewis
acids, prolonged reaction time and high temperature.
Consequently, there is scope for further improvement
toward milder reaction conditions and better yields. In
recent years, zinc triflate is a unique Lewis acid that is
currently of great research interest (Ishimaru and Kojima,
2000). Octahydroquinazolinone derivatives have attracted
considerable attention since they exhibit potent antibacte-
rial activity against Staphylococcus aureus, Escherichia
coli, Pseudomonas aeruginosa (Kidwai et al., 2005) and
calcium antagonist activity (Yarim et al., 2003). Literature
survey reveals that number of octahydroquinazolinone
1
elemental analysis, FT- IR, H NMR, 13C NMR, and mass
spectral data. All the synthesized compounds were evalu-
ated for their antimicrobial activities against various
microbes. Minimum inhibitory concentration values of all
the 24 synthesized compounds were also determined. Some
of the synthesized compounds exhibited excellent antimi-
crobial activity.
Keywords Octahydroquinazolinone Á Zinc triflate Á
Cyclocondensation Á Bio-potential
Introduction
Dihydropyrimidones (DHPMs) are an important class of
the compounds and gaining increasingly importance due to
their therapeutic and pharmacological properties (Kappe,
1993). In recent years, properly functionalized DHPMs
have been developed as calcium channel modulators,
antihypertensive agents, a1a-adrenergic antagonists, neu-
ropeptide Y (NPY) antagonists, and compounds that target
the mammalian mitotic machinery (Atwal et al., 1991;
Grover et al., 1995; Kappe, 2000). Furthermore, several
P. M. Shah Á M. P. Patel (&)
Department of Chemistry, Sardar Patel University,
Vallabh Vidhyanagar 388120, Gujarat, India
e-mail: patelmanish1069@yahoo.com
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Med Chem Res (2012) 21:1188–1198
1189
(Kantevari et al., 2006; Lin et al., 2007) derivatives have
been synthesized by Biginelli reaction conditions using
various aldehydes but not a single reference has been found
where 2-thi(oxo)-1,2-dihydroquinoline-3-carbaldehyde is
used. In view of the above observation and in continuation
of our study on biologically active heterocyclic compounds
(Patel et al., 2005, 2008; Ladani et al., 2009), We wish to
report here 2-thi(oxo)-1,2-dihydroquinoline-3-carbalde-
hyde which is biologically active (Nandeshwarappa et al.,
2006; Nityadevi et al., 2004) with a view to obtain more
active heterocyclic systems containing two biologically
active moieties 2-thi(oxo)-1,2-dihydroquinoline-3-carbal-
dehyde (Lamani et al., 2010) and octahydroquinazolinone
(Abdel-Gawad et al., 2000; Minu et al., 2008).
compound 4a showed signals at d 21.28, 26.52, 36.79,
48.65 for aliphatic carbon, d 105.57, 115.26, 119.40,
122.29, 128.61, 130.58, 133.27 for aromatic carbon and
carbonyl carbons were observed at d 156.60, 161.73, and
193.66. The structure was further confirmed by its mass
spectral studies. It gave molecular ion peak at m/z 310
(M ? 1) corresponding to molecular formula C17H15N3O3
(Scheme 2). Similarly, all these compounds were charac-
terized on the basis of spectral studies. All the compounds
were screened for their antibacterial and antifungal
activities using gentamycin, ampicillin, chloramphenicol,
ciprofloxacin, norfloxacin, nystatin, and griseofulvin as
standard drugs. According to the reports by Folkers and
Johnson (1933) and Kappe (1997) for Biginelli reaction,
the formation of product 4a–x involves an imine interme-
diate (Int-1), formation of iminium ion (Int-2) by proton-
ation of imine intermediate with Lewis acid (Zn(OTf)2),
and addition of cyclic b-diketone to the iminium ion (Int-
3), and subsequent cyclodehydration (Scheme 3).
Results and discussion
Chemistry
The octahydroquinazolinones 4a–x were synthesized by
zinc triflate catalyzed condensation of 6-(un)sub.2-(thi)
oxo-1,2-dihydroquinoline-3-carbaldehyde 1a–e, cyclohexane-
1,3-dione or dimedone 2a–b, urea or thiourea or phenyl
thiourea 3a–c in ethanol by modification of the Biginelli
reaction in good yield (65–85%). The 6-(un)sub.2-(thi)oxo-
1,2-dihydroquinoline-3-carbaldehyde 1a–e were prepared
from literature procedure (Sriyastava and Singh, 2005)
(Scheme 1).
Antimicrobial screening
All the glass apparatus used were sterilized before use.
Antimicrobial activity of all the synthesized compounds
was carried out by broth microdilution method (NCCLS,
2002). Mueller–Hinton broth was used as nutrient medium
to grow and dilute the compound suspension for the test
bacteria and Sabouraud Dextrose broth used for fungal
nutrition. Inoculum size for test strain was adjusted to
108 CFU [colony forming unit] per milliliter by comparing
the turbidity. The strains used for the activity were pro-
cured from [MTCC—microbial type culture collection]
Institute of Microbial Technology, Chandigarh. Each syn-
thesized compound was diluted obtaining 2000 lg/ml
concentration, as a stock solution. The results are recorded
in the form of primary and secondary screenings. The
compounds 4a–x were screened for their antibacterial
The structures of compounds 4a–x were confirmed by
IR, 1H NMR, 13C NMR, and mass spectra. IR spectra of 4a
exhibited absorptions at 3395, 3206, and 3107 cm-1 for
1
(NH), 1711, 1657, and 1644 for (carbonyl group). The H
NMR of compound 4a showed singlet at d 11.86, 9.51, and
7.70 ppm for (NH) proton, it also showed multiplate at d
1.97–2.58 for (3CH2). Aromatic protons resonate as mul-
tiplates at d 7.04–7.68 ppm. The 13C NMR spectrum of
Scheme 1 Synthetic pathway
for the intermediates 1a–e
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Med Chem Res (2012) 21:1188–1198
Scheme 2 Synthetic pathway
for the compounds 4a–x
Scheme 3 Possible mechanism
for compounds
4a–x
activity against Bacillus subtilis (MTCC 441), Clostridium
tetani (MTCC 449), Streptococcus pneumoniae (MTCC
1936), E. coli (MTCC 443), Salmonella typhi (MTCC 98),
Vibrio cholerae (MTCC 3906) as well as for antifungal
activity against Aspergillus fumigatus (MTCC 3008) and
Candida albicans (MTCC 227) at concentrations of 1000,
500, and 250 lg/ml as primary screening. DMSO was used
as vehicle to get desired concentrations of compounds to
test upon microbial strains. The compounds found to be
active in the primary screening were further screened in a
second set of dilution at concentrations of 200, 100, 62.5,
50, 25, 12.5, and 6.25 lg/ml. Ten microliters suspension
from each well was further inoculated and growth was
noted after 24 and 48 h. The lowest concentration which
showed no visible growth (turbidity) after spot subculture
was considered as MIC for each compound. The standard
drugs used for comparison in this study were ampicillin,
chloramphenicol, ciprofloxacin, norfloxacin, and genta-
mycin for evaluating antibacterial activity and griseofulvin
and nystatin for antifungal activity.
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Med Chem Res (2012) 21:1188–1198
1191
From the screening results (Table 1), compound 4k
(R1 = OCH3, R2 = R3 = R4 = H, X = O, Y = S) shows
excellent antibacterial activity against E. coli when com-
pared with ampicillin and equivalent to chloramphenicol;
compounds 4c (R1 = OCH3, R2 = R3 = R4 = H, X =
Y=O), 4e (R1 = H, R2 = R3 = CH3, R4 = H, X = Y=O),
4f (R1 = R2 = R3 = CH3, R4 = H, X = Y=O), 4g (R1 =
OCH3, R2 = R3 = CH3, R4 = H, X = Y=O), 4h (R1 =
Cl, R2 = R3 = CH3, R4 = H, X = Y=O), 4i (R1 = R2 =
R3 = R4 = H, X = O, Y = S), 4l (R1 = Cl, R2 = R3 =
R4 = H, X = O, Y = S), and 4t (R1 = H, R2 = R3 =
CH3, R4 = H, X = Y=S) show comparable antibacterial
activity against E. coli when compared with ampicillin;
compound 4p (R1 = Cl, R2 = R3 = CH3, R4 = H, X = O,
Y = S) shows excellent antibacterial activity against S. typhi,
S. pneumoniae, V. cholerae, B. subtilis when compared with
chloramphenicol and ampicillin; compounds 4t and 4u
(R1 = R2 = R3 = H, R4 = Ph, X = O, Y = S) show
excellent antibacterial activity against S. typhi when com-
pared with ampicillin; compounds 4d (R1 = Cl, R2 = R3 =
R4 = H, X = Y=O) and 4n (R1 = R2 = R3 = CH3, R4 =
H, X = O, Y = S) show excellent antibacterial activity
against V. cholera when compared with ampicillin; com-
pounds 4a (R1 = R2 = R3 = R4 = H, X = Y=O), 4b (R1 =
CH3, R2 = R3 = R4 = H, X = Y=O), 4f, and 4n show
excellent antibacterial activity against S. pneumoniae when
Table 1 Antimicrobial activity of compounds 4a–x
Compounds
Minimum inhibitory concentration (MIC, lg/ml)
Gram-negative bacteria
Gram-positive bacteria
Fungi
E. coli
S. typhi
V. cholerae
S. pneumoniae
B. subtilis
C. tetani
C. albicans
A. fumigates
4a
250
500
100
200
100
100
100
100
100
500
50
250
500
250
250
250
250
150
200
500
500
125
200
150
150
250
25
500
200
500
100
250
1000
50
100
100
250
500
250
100
250
500
200
500
200
250
500
100
200
50
200
500
250
250
500
100
250
200
200
500
200
250
500
100
200
50
100
200
500
500
200
100
100
100
200
500
200
250
500
100
200
250
500
250
500
200
100
250
250
250
5
500
1000
500
1000
500
500
500
500
100
200
500
500
500
[1000
500
500
1000
250
100
250
500
250
1000
1000
–
[1000
1000
1000
1000
500
4b
4c
4d
4e
4f
1000
1000
[1000
200
4g
4h
500
500
500
200
250
500
100
200
50
4i
4j
500
4k
[1000
1000
500
4l
100
125
250
500
125
500
250
500
100
150
250
500
1000
4m
4n
[1000
[1000
1000
500
4o
4p
4q
200
200
500
100
100
200
250
500
5
500
250
200
250
200
500
500
250
5
500
500
250
500
150
500
500
1000
0.5
500
250
500
250
250
500
500
250
1
4r
[1000
100
4s
4t
500
4u
250
4v
1000
500
4w
4x
500
Gentamycin
Ampicillin
Chloramphenicol
Ciprofloxacin
Norfloxacin
Nystatin
Griseofulvin
0.05
–
100
50
25
10
–
100
50
100
50
100
50
250
50
250
50
–
–
–
–
25
25
50
50
100
50
–
–
10
10
10
100
–
–
–
–
–
–
–
100
500
100
–
–
–
–
–
–
100
Bold values indicate the values of excellent antimicrobial activity compared to standard drugs used
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Med Chem Res (2012) 21:1188–1198
compared with ampicillin; compounds 4a, 4c–d, 4f–i, 4k,
4l, 4n, 4o (R1 = OCH3, R2 = R3 = CH3, R4 = H, X = O,
Y = S), 4r (R1 = R2 = R3 = R4 = H, X = Y=S), 4t–u,
and 4x (R1 = R2 = R3 = CH3, R4 = Ph, X = O, Y = S)
show excellent antibacterial activity against B. subtilis
when compared with ampicillin; compounds 4a–b, 4e,
4g–i, 4k–l, 4n, 4p, 4r, 4t–u, 4v (R1 = H, R2 = R3 = CH3,
R4 = Ph, X = O, Y = S), 4w (R1 = CH3, R2 = R3 = H,
R4 = Ph, X = O, Y = S), and 4x show excellent anti-
bacterial activity against C. tetani when compared with
ampicillin; compound 4g shows excellent antibacterial
activity against V. cholera when compared with ampicillin
and chloramphenicol. The remaining compounds show
moderate to poor activity against all six bacterial species.
Antifungal screening data show that compounds 4i and 4s
(R1 = H, R2 = R3 = CH3, R4 = H, X = S, Y = O) show
excellent antifungal activity against C. albicans when
compared with nystatin and griseofulvin; compound 4s also
shows excellent antifungal activity against A. fumigates
when compared with nystatin and griseofulvin; compounds
4a, 4c, 4e–h, 4j (R1 = CH3, R2 = R3 = R4 = H, X = O,
Y = S), 4k–l, 4m (R1 = H, R2 = R3 = CH3, R4 = H,
X = O, Y = S), 4o–p, 4r, 4t, and 4v show excellent
antifungal activity against C. albicans when compared with
griseofulvin. The remaining compounds of entire series
showed only moderate to poor activity against both fungal
species.
compounds. Presence of phenyl group at 1st position of
quinazolinone does not improve the antimicrobial activity
of parent analog 4a. Majority of the compounds which
showed excellent antimicrobial activity when compared to
the standard drug ampicillin are active against E. coli,
B. subtilis, C. tetani, and C. albicans.
Conclusion
In connection with our on-going study on multi-component
synthesis of biologically active heterocyclic compounds,
our interests lie in zinc triflate catalyzed reactions at reflux
temperature and to access their bio-potential. We now wish
to report on a convenient and rapid one-pot three-compo-
nent synthesis of 7,7-dimethyl-4-(2-oxo-1,2-dihydroquin-
olin-3-yl)-3,4,7,8-tetrahydroquinazoline-2,5(1H,6H)-diones
(4a–x) with 5 mol% zinc triflate as a catalyst. These het-
erocyclic compounds containing both quinazoline and
quinoline ring systems are prepared by the reaction
of 2-thi(oxo)-1,2-dihydroquinoline-3-carbaldehyde 1a–e,
1,3-dicarbonyl compounds 2a–b, and substituted urea
3a–c in presence of zinc triflate. Zinc triflate may play
crucial role in accelerating the dehydrative steps. It can be
concluded from antimicrobial screening (Table 1), against
panel of human pathogens that most of the synthesized
octahydroquinazolinone derivatives were found to be
highly active, compared to standard drugs, against bacterial
pathogens. Among them, many compounds were found to
be the most active against B. subtilis and C. tetani when
compared to rest of the employed species. Antifungal
activity of the compounds shows that most of the com-
pounds found to be potent against C. albicans when com-
pared to A. fumigatus. It is worth mentioning that
combination of two biologically active moieties 2-thi(oxo)-
1,2-dihydroquinoline-3-carbaldehyde and octahydroqui-
nazolinone profoundly influences the biological activity.
Structure activity relationship (SAR) study
Analysis of structure–activity relationship shows that the
different substituents at positions R1, R2, R3, R4, X, and
Y affect the antimicrobial properties of studied substances.
Concerning the quinolone containing octahydroquinazoli-
none derivatives, substitution at R1 position of quinolone
ring, such as a lipophilic methyl group, does not improve
the antimicrobial activity, but hydrophilic methoxy group
improves the antimicrobial activity of parent analog 4a
against tested bacterial as well as fungal pathogens.
Compounds having electron-withdrawing chlorine group at
position R1 improve the antimicrobial activity, i.e., com-
pound 4p possessed the highest antimicrobial effectiveness
of the tested compounds. The electronic influence on the
antimicrobial activity of the selected substituents of
4a–x can be seen from the favorable effect of electron-
withdrawing effect of chlorine (4d, 4h, 4l, and 4p) and,
conversely, the detrimental action of the electron-donating
methyl and methoxy groups.
Experimental
Chemistry
General procedures
All the reagents were commercially available and used
without further purification. Solvents used were of analyt-
ical grade. Melting points were determined by open tube
capillary method (using silicon oil 350 cst) and are
The structure–activity relationship analysis of the data
reported in Table 1 further showed that the replacement of
oxygen with sulfur atom at C-2 position of quinolone in
compounds 4q, 4r, and 4s (expect compound 4t) does not
improve the antimicrobial effectiveness of the tested
uncorrected. Thin-layer chromatography (TLC, on alumi-
60
num plates precoated with silica gel,
F
, 0.25-mm
254
thickness) (Merck, Darmstadt, Germany) was used for
monitoring the progress of all reactions, purity and
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Med Chem Res (2012) 21:1188–1198
1193
homogeneity of the synthesized compounds; eluent
n-hexane:ethyl acetate::1:1. UV radiation and/or iodine
were used as the visualizing agents. Elemental analysis (% C,
H, N) was carried out by Perkin-Elmer 2400 series-II ele-
mental analyzer (Perkin-Elmer, USA) and all compounds
were within 0.4% of theory specified. The IR spectra were
recorded in KBr on a Perkin-Elmer Spectrum GX FT-IR
Spectrophotometer (Perkin-Elmer, USA) and only the char-
acteristic peaks are reported in cm-1. 1H NMR and 13C NMR
spectra were recorded in DMSO-d6 on a Bruker Avance 400F
(MHz) spectrometer (Bruker Scientific Corporation Ltd.,
Switzerland) using solvent peak as internal standard at 400
and 100 MHz, respectively. Chemical shifts are reported in
parts per million (ppm). Mass spectra were scanned on a
Shimadzu LCMS 2010 spectrometer (Shimadzu, Tokyo,
Japan).
Zn(OTf)2 (0.0005 mol) and ethanol (15 ml) were charged
in 100-ml round-bottomed flask with mechanical stirrer
and condenser. The reaction mixture was slowly heated and
refluxed for 4–5 h. On completion of reaction, monitored
by TLC using 1:1 n-hexane/ethyl acetate as eluent, the
reaction mixture was cooled to room temperature and solid
separated was filtered and washed with mixture of chlo-
roform and methanol (1:1) to obtain the pure compounds
4a–x. Analytical and spectroscopic characterization data of
the synthesized compounds 4a–x are given below:
4-(2-Oxo-1,2-dihydroquinolin-3-yl)-3,4,7,8-tetrahydro-
quinazoline-2,5(1H,6H)-dione (4a): yield: 85%; melting
range: 281–283°C; IR (KBr): 3395, 3206, 3107 (N–H str.),
1
1711, 1657, 1644 (–C=O str.) cm-1; H NMR (400 MHz,
DMSO-d6): d 1.97–2.58 (m, 6H, 3CH2), 5.32 (s, 1H, qui-
nazolinone H4), 7.04 (s, 1H, NH), 7.15–7.70 (m, 5H,
Ar–H), 9.51 (s, 1H, NH), 11.86 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6): d 21.28 (CH2), 26.52 (CH2), 36.79
(CH2–CO), 48.65 (quinazolinone C4), 105.57, 115.26,
119.40, 122.29, 128.61, 130.58, 133.27, 135.49, 138.60,
152.05 (Ar–C), 156.60 (C=O), 161.73 (C=O), 193.66
(C=O); ms: m/z 310 [M ? 1]?; Anal. Calcd. for C17H15
N3O3 (309.33 g/mol): C, 66.01; H, 4.89; N, 13.58%.
Found: C, 65.83; H, 4.77; N, 13.74%.
General procedure for the synthesis of 2-oxo-1,2-dihy-
droquinoline-3-carbaldehyde (1a–e) 2-(thi)oxo-1,2-dihy-
droquinoline-3-carbaldehyde 1a–e were prepared, according
to literature procedure (Sriyastava and Singh 2005):
dimethylformamide (0.250 mol) was cooled in a three-
necked round-bottomed flask at 0°C, to it phosphorous oxy-
chloride (0.70 mol) was added dropwise with stirring at
0–10°C. In this mixture, 4-substituted acetanilide (0.10 mol)
was added and the mixture was heated under reflux for 6 h at
75°C. Thereaction mass then cooled to room temperature and
poured in crushed ice with mechanical stirring. The product
isolated was filtered and washed with water till neutral. The
solid was crystallized from ethyl acetate to give pure
2-chloro-3-formyl quinoline.
4-(6-Methyl-2-oxo-1,2-dihydroquinolin-3-yl)-3,4,7,
8-tetrahydroquinazoline-2,5(1H,6H)-dione (4b): yield: 82%;
melting range: 286–288°C; IR (KBr): 3389, 3209, 3112
1
(N–H str.), 1705, 1666, 1649 (–C=O str.) cm-1; H NMR
(400 MHz, DMSO-d6): d 1.89–2.51 (m, 6H, 3CH2), 2.34
(s, 3H, CH3), 5.39 (s, 1H, quinazolinone H4), 7.11 (s, 1H,
NH), 7.18–7.63 (m, 4H, Ar–H), 9.47 (s, 1H, NH), 11.81
(s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): d 20.78
(CH3), 21.61 (CH2), 27.01 (CH2), 36.21 (CH2–CO), 49.07
(quinazolinone C4), 106.08, 115.66, 118.89, 122.87, 129.64,
131.43, 133.71, 135.18, 137.89, 152.57 (Ar–C), 157.06
(C=O), 162.34 (C=O), 194.01 (C=O); ms: m/z 324 [M ? 1]?;
Anal. Calcd. for C18H17N3O3 (323.35 g/mol): C, 66.86; H,
5.30; N, 13.00%. Found: C, 66.71; H, 5.12; N, 13.19%.
4-(6-Methoxy-2-oxo-1,2-dihydroquinolin-3-yl)-3,4,7,
8-tetrahydroquinazoline-2,5(1H,6H)-dione (4c): yield:
79%; melting range: 291–293°C; IR (KBr): 3392, 3209,
For the synthesis compounds 1(a–d), 2-chloro-3-formyl
quinolone (0.005 mol) and 70% glacial acetic acid were
charged in round-bottomed flask with mechanical stirrer and
condenser. The reaction mixture was slowly heated and
reflux for 5–6 h. After the completion of reaction (check by
TLC), the product was filtered and washed with ethanol. The
crude product was purified by leaching in (10:10 v/v) mix-
ture of methanol and chloroform to obtain pure solid sample.
Compound 1e prepared by stirred 2-chloro-3-formyl
quinolone (0.5 mol), sodium sulfide (0.0075 mol) in
dimethyl formamide. On completion of reaction (moni-
tored by TLC), the reaction mixture was poured on ice-
water and made acidic with acetic acid. The product was
filtered off, washed well with water. The crude product was
purified by leaching in (10:10 v/v) mixture of methanol and
chloroform to obtain pure solid sample (Scheme 1).
1
3118 (N–H str.), 1719, 1669, 1648 (–C=O str.) cm-1; H
NMR (400 MHz, DMSO-d6): d 1.81–2.43 (m, 6H, 3CH2),
3.83 (s, 3H, OCH3), 5.41 (s, 1H, quinazolinone H4), 7.09
(s, 1H, NH), 7.23–7.51 (m, 4H, Ar–H), 9.41 (s, 1H, NH),
11.73 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6):
d 21.53 (CH2), 27.13 (CH2), 36.29 (CH2–CO), 48.93
(quinazolinone C4), 55.81 (OCH3), 105.97, 115.31, 119.09,
122.75, 129.32, 131.11, 133.44, 134.53, 137.31, 152.65
(Ar–C), 156.95 (C=O), 161.98 (C=O), 194.15 (C=O); ms:
m/z 340 [M ? 1]?; Anal. Calcd. for C18H17N3O4
(339.35 g/mol): C, 63.71; H, 5.05; N, 12.38%. Found: C,
63.54; H, 4.91; N, 12.58%.
General procedure for the synthesis of 7,7-dimethyl-4-(2-
oxo-1,2-dihydroquinolin-3-yl)-3,4,7,8-tetrahydroquinazoline-2,
5(1H,6H)-dione (4a–x) 2-(thi)oxo-1,2-dihydroquinoline-
3-carbaldehyde (0.0025 mol), dimedone or cyclohexane-1,3-
dione (0.0025 mol), urea/thiourea/phenylthiourea (0.0025 mol),
123

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Med Chem Res (2012) 21:1188–1198
4-(6-Chloro-2-oxo-1,2-dihydroquinolin-3-yl)-3,4,7,
NMR (100 MHz, DMSO-d6): d 27.31 (CH3), 29.87 (CH3),
32.06 (C(CH3)2), 39.01 (CH2), 48.45 (CH2–CO), 50.29
(quinazolinone C4), 56.92 (OCH3), 106.08, 115.81, 118.43,
127.67, 131.19, 132.75, 132.89, 136.58, 136.23, 150.46
(Ar–C), 156.98 (C=O), 161.52 (C=O), 193.79 (C=O); ms:
m/z 368 [M ? 1]?; Anal. Calcd. for C20H21N3O4 (367.41
g/mol): C, 65.38; H, 5.76; N, 11.44%. Found: C, 65.62; H,
5.57; N, 11.26%.
8-tetrahydroquinazoline-2,5(1H,6H)-dione (4d): yield:
83%; melting range: 294–296°C; IR (KBr): 3398, 3214,
1
3145 (N–H str.), 1703, 1659, 1651 (–C=O str.) cm-1; H
NMR (400 MHz, DMSO-d6): d 1.75–2.41 (m, 6H, 3CH2),
5.33 (s, 1H, quinazolinone H4), 7.15 (s, 1H, NH),
7.27–7.59 (m, 4H, Ar–H), 9.46 (s, 1H, NH), 11.64 (s, 1H,
NH). 13C NMR (100 MHz, DMSO-d6): d 21.07 (CH2),
26.91 (CH2), 36.78 (CH2–CO), 49.11 (quinazolinone C4),
106.08, 115.78, 119.81, 123.04, 129.57, 130.92, 133.76,
134.91, 137.89, 153.01 (Ar–C), 157.11 (C=O), 162.08
(C=O), 194.37 (C=O); ms: m/z 344 [M ? 1]?; Anal.
Calcd. for C17H14ClN3O3 (343.77 g/mol): C, 59.40; H,
4.10; N, 12.22%. Found: C, 59.18; H, 4.23; N, 12.41%.
7,7-Dimethyl-4-(2-oxo-1,2-dihydroquinolin-3-yl)-3,4,7,8-
tetrahydroquinazoline-2,5(1H,6H)-dione (4e): yield: 84%;
melting range: 284–286°C; IR (KBr): 3390, 3208, 3114
4-(6-Chloro-2-oxo-1,2-dihydroquinolin-3-yl)-7,7-dime-
thyl-3,4,7,8-tetrahydroquinazoline-2,5(1H,6H)-dione (4h):
yield: 75%; melting range: 296–298°C; IR (KBr): 3398,
3221, 3139 (N–H str.), 1701, 1655, 1648 (–C=O str.)
cm-1 1H NMR (400 MHz, DMSO-d6): d 1.01 (s, 3H,
;
CH3), 1.06 (s, 3H, CH3), 2.05–2.31 (m, 4H, 2CH2), 5.39 (s,
1H, quinazolinone H4), 7.10 (s, 1H, NH), 7.18–7.69 (m,
4H, Ar–H), 9.53 (s, 1H, NH), 11.72 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6): d 27.13 (CH3), 29.71 (CH3), 32.44
(C(CH3)2), 39.57 (CH2), 48.21 (CH2–CO), 50.78 (quinaz-
olinone C4), 106.08, 115.81, 118.43, 127.67, 131.19,
132.75, 132.89, 136.58, 136.23, 150.46 (Ar–C), 156.98
(C=O), 161.52 (C=O), 193.79 (C=O); ms: m/z 372
[M ? 1]?; Anal. Calcd. for C19H18ClN3O3 (371.83
g/mol): C, 61.38; H, 4.88; N, 11.30%. Found: C, 61.65; H,
4.71; N, 11.53%.
1
(N–H str.), 1707, 1666, 1645 (–C=O str.) cm-1; H NMR
(400 MHz, DMSO-d6): d 1.04 (s, 3H, CH3), 1.06 (s, 3H,
CH3), 2.08–2.43 (m, 4H, 2CH2), 5.30 (s, 1H, quinazolinone
H4), 7.01 (s, 1H, NH), 7.04–7.68 (m, 5H, Ar–H), 9.47 (s, 1H,
NH), 11.82 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): d
27.81 (CH3), 29.04 (CH3), 32.76 (C(CH3)2), 39.08 (CH2),
48.66 (CH2–CO), 50.12 (quinazolinone C4), 105.61, 115.59,
119.05, 128.11, 131.85, 132.71, 132.93, 136.35, 136.75,
150.54 (10C, Ar–C), 156.58 (C=O), 161.66 (C=O), 193.64
(C=O); ms: m/z 338 [M ? 1]?; Anal. Calcd. for C19H19N3O3
(337.38 g/mol): C, 67.64; H, 5.68; N, 12.45%. Found: C,
67.85; H, 5.47; N, 12.63%.
4-(2-Oxo-1,2-dihydroquinolin-3-yl)-2-thioxo-1,2,3,4,7,
8-hexahydroquinazolin-5(6H)-one (4i): yield: 81%;
melting range: 306–308°C; IR (KBr): 3390, 3201, 3111
(N–H str.), 1657, 1638 (–C=O str.), 1189 (–C=S str.)
cm-1 1H NMR (400 MHz, DMSO-d6): d 1.91–2.53
;
7,7-Dimethyl-4-(6-methyl-2-oxo-1,2-dihydroquinolin-3-
yl)-3,4,7,8-tetrahydroquinazoline-2,5(1H,6H)-dione (4f):
yield: 81%; melting range: 293–295°C; IR (KBr): 3384,
(m, 6H, 3CH2), 5.41 (s, 1H, quinazolinone H4), 7.12–7.71
(m, 5H, Ar–H), 9.08 (s, 1H, NH), 10.91 (s, 1H, NH),
11.89 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6):
d 21.23 (CH2), 26.41 (CH2), 36.71 (CH2–CO), 48.13 (qui-
nazolinone C4), 105.06, 115.77, 119.87, 122.71, 128.18,
130.07, 132.97, 135.90, 139.01, 153.11 (Ar–C), 156.94
(C=O), 176.03 (C=S), 194.09 (C=O); ms: m/z 326 [M ? 1]?;
Anal. Calcd. for C17H15N3O2S (325.39 g/mol): C, 62.75; H,
4.65; N, 12.91%. Found: C, 62.49; H, 4.89; N, 13.18%.
4-(6-Methyl-2-oxo-1,2-dihydroquinolin-3-yl)-2-thioxo-
1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (4j): yield:
77%; melting range: 313–315°C; IR (KBr): 3388, 3203,
3114 (N–H str.), 1651, 1644 (–C=O str.), 1183 (–C=S str.)
3212, 3109 (N–H str.), 1701, 1669, 1641 (–C=O str.) cm-1
;
1H NMR (400 MHz, DMSO-d6): d 1.07 (s, 3H, CH3), 1.09
(s, 3H, CH3), 2.05–2.41 (m, 4H, 2CH2), 2.27 (s, 3H, CH3),
5.37 (s, 1H, quinazolinone H4), 7.07 (s, 1H, NH),
7.11–7.59 (m, 4H, Ar–H), 9.42 (s, 1H, NH), 11.77 (s, 1H,
NH). 13C NMR (100 MHz, DMSO-d6): d 20.56 (CH3),
27.37 (CH3), 29.53 (CH3), 32.37 (C(CH3)2), 38.97 (CH2),
50.61 (CH2–CO), 51.22 (quinazolinone C4), 105.93,
115.39, 118.92, 127.90, 131.52, 132.29, 132.73, 136.01,
136.66, 150.61 (Ar–C), 156.27 (C=O), 161.88 (C=O),
193.31 (C=O); ms: m/z 352 [M ? 1]?; Anal. Calcd. for
C20H21N3O3 (351.41 g/mol): C, 68.36; H, 6.02; N, 11.96%.
Found: C, 68.12; H, 5.87; N, 12.19%.
1
cm-1; H NMR (400 MHz, DMSO-d6): d 1.87–2.46 (m,
6H, 3CH2), 3.32 (3H, CH3), 5.33 (s, 1H, quinazolinone
H4), 7.04–7.73 (m, 4H, Ar–H), 9.72 (s, 1H, NH), 10.85
(s, 1H, NH), 11.91 (s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6): d 21.13 (CH3), 21.37 (CH2), 26.43 (CH2),
36.77 (CH2–CO), 48.28 (quinazolinone C4), 105.23,
115.41, 119.73, 122.67, 128.43, 130.18, 133.04, 136.11,
139.13, 153.62 (Ar–C), 156.38 (C=O), 175.94 (C=S),
194.47 (C=O); ms: m/z 340 [M ? 1]?; Anal. Calcd. for
C18H17N3O2S (339.42 g/mol): C, 63.70; H, 5.05; N,
12.38%. Found: C, 63.93; H, 5.26; N, 12.14%.
4-(6-Methoxy-2-oxo-1,2-dihydroquinolin-3-yl)-7,7-dime-
thyl-3,4,7,8-tetrahydroquinazoline-2,5(1H,6H)-dione (4g):
yield: 78%; melting range: 294–296°C; IR (KBr): 3395,
3213, 3118 (N–H str.), 1714, 1665, 1651 (–C=O str.) cm-1
;
1H NMR (400 MHz, DMSO-d6): d 1.05 (s, 3H, CH3), 1.07
(s, 3H, CH3), 2.01–2.37 (m, 4H, 2CH2), 3.89 (s, 3H, OCH3),
5.35 (s, 1H, quinazolinone H4), 7.02 (s, 1H, NH), 7.13–7.74
(m, 4H, Ar–H), 9.47 (s, 1H, NH), 11.67 (s, 1H, NH). 13C
123

Med Chem Res (2012) 21:1188–1198
1195
4-(6-Methoxy-2-oxo-1,2-dihydroquinolin-3-yl)-2-thioxo-
1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (4k): yield:
75%; melting range: 304–306°C; IR (KBr): 3391, 3207,
3105 (N–H str.), 1656, 1649 (–C=O str.), 1188 (–C=S str.)
NH), 11.75 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6):
d 20.81 (CH3), 27.82 (CH3), 29.06 (CH3), 32.78 (C(CH3)2),
39.11 (CH2), 50.14 (CH2–CO), 50.40 (quinazolinone C4),
105.67, 115.18, 119.17, 128.03, 131.35, 132.08, 132.46,
136.82, 136.97, 150.53 (Ar–C), 161.11 (C=O), 175.21
(C=S), 193.92 (C=O); ms: m/z 368 [M ? 1]?; Anal. Calcd.
for C20H21N3O2S (367.47 g/mol): C, 65.37; H, 5.76; N,
11.43%. Found: C, 65.21; H, 5.93; N, 11.28%.
1
cm-1; H NMR (400 MHz, DMSO-d6): d 1.89–2.49 (m,
6H, 3CH2), 3.92 (3H, OCH3), 5.37 (s, 1H, quinazolinone
H4), 7.07–7.75 (m, 4H, Ar–H), 9.67 (s, 1H, NH), 10.79
(s, 1H, NH), 11.94 (s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6): d 21.41 (CH2), 26.51 (CH2), 36.92 (CH2–CO),
48.18 (quinazolinone C4), 55.61 (3H, OCH3), 104.97,
115.56, 119.94, 122.81, 128.79, 130.11, 132.95, 136.22,
139.19, 153.92 (Ar–C), 155.87 (C=O), 175.72 (C=S),
194.73 (C=O); ms: m/z 356 [M ? 1]?; Anal. Calcd. for
C18H17N3O3S (355.42 g/mol): C, 60.83; H, 4.82; N,
11.82%. Found: C, 60.72; H, 4.98; N, 11.61%.
4-(6-Methoxy-2-oxo-1,2-dihydroquinolin-3-yl)-7,7-dime-
thyl-2-thioxo-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (4o):
yield: 80%; melting range: 319–321°C; IR (KBr): 3394, 3216,
3121 (N–H str.), 1654, 1633 (–C=O str.), 1197 (–C=S str.)
1
cm-1; H NMR (400 MHz, DMSO-d6): d 1.04 (s, 3H, CH3),
1.06 (s, 3H, CH3), 2.08- 2.46 (m, 4H, 2CH2), 3.89 (s, 3H,
OCH3), 5.36 (s, 1H, quinazolinone H4), 7.14–7.47 (m, 4H, Ar–
H), 9.11 (s, 1H, NH), 10.52 (s, 1H, NH), 11.78 (s, 1H, NH).
13C NMR (100 MHz, DMSO-d6): d 27.78 (CH3), 29.11 (CH3),
32.72 (C(CH3)2), 39.09 (CH2), 50.27 (CH2–CO), 50.31 (qui-
nazolinone C4), 55.19 (OCH3), 105.36, 115.53, 119.29, 128.57,
131.19, 132.22, 132.13, 136.70, 136.43, 150.93 (Ar–C), 161.48
(C=O), 175.44 (C=S), 194.13 (C=O); ms: m/z 384 [M ? 1]?;
Anal. Calcd. for C20H21N3O3S (383.47 g/mol): C, 62.64; H,
5.52; N, 10.96%. Found: C, 62.51; H, 5.33; N, 11.12%.
4-(6-Chloro-2-oxo-1,2-dihydroquinolin-3-yl)-7,7-dime-
thyl-2-thioxo-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one
(4p): yield: 75%; melting range: 312–314°C; IR (KBr):
3390, 3208, 3102 (N–H str.), 1663, 1658 (–C=O str.),
4-(6-Chloro-2-oxo-1,2-dihydroquinolin-3-yl)-2-thioxo-
1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (4l): yield:
77%; melting range: 307–309°C; IR (KBr): 3394, 3211,
3107 (N–H str.), 1658, 1646 (–C=O str.), 1179 (–C=S str.)
cm-1 1H NMR (400 MHz, DMSO-d6): d 1.81–2.44
;
(m, 6H, 3CH2), 5.42 (s, 1H, quinazolinone H4), 7.11–7.69
(m, 4H, Ar–H), 9.64 (s, 1H, NH), 10.73 (s, 1H, NH),
11.85 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6):
d 21.32 (CH2), 26.43 (CH2), 36.76 (CH2–CO), 48.49
(quinazolinone C4), 104.76, 115.31, 119.82, 122.47,
128.92, 130.34, 132.78, 136.44, 139.25, 154.12 (Ar–C),
155.32 (C=O), 176.02 (C=S), 194.43 (C=O); ms: m/z 360
[M ? 1]?; Anal. Calcd. for C17H14ClN3O2S (359.84
g/mol): C, 56.75; H, 3.92; N, 11.68%. Found: C, 56.57; H,
4.05; N, 11.84%.
1
1181 (–C=S str.) cm-1; H NMR (400 MHz, DMSO-d6):
d 1.03 (s, 3H, CH3), 1.07 (s. 3H, CH3), 1.78–2.47 (m, 4H,
2CH2), 5.38 (s, 1H, quinazolinone H4), 7.14–7.73 (m, 4H,
Ar–H), 9.61 (s, 1H, NH), 10.78 (s, 1H, NH), 11.89 (s, 1H,
NH). 13C NMR (100 MHz, DMSO-d6): d 27.56 (CH3),
29.29 (CH3), 32.70 (C(CH3)2), 39.51 (CH2), 49.88 (CH2–
CO), 51.23 (quinazolinone C4), 105.22, 115.73, 119.24,
122.38, 128.69, 130.81, 132.68, 136.53, 139.67, 154.46
(Ar–C), 155.18 (C=O), 175.92 (C=S), 194.21 (C=O); ms:
m/z 388 [M ? 1]?; Anal. Calcd. for C19H18ClN3O2S
(387.89 g/mol): C, 58.83; H, 4.68; N, 10.83%. Found: C,
58.66; H, 4.54; N, 10.98%.
7,7-Dimethyl-4-(2-oxo-1,2-dihydroquinolin-3-yl)-2-thi-
oxo-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (4m): yield:
84%; melting range: 314–316°C; IR (KBr): 3387, 3208,
3102 (N–H str.), 1663, 1661 (–C=O str.), 1193 (–C=S str.)
cm-1; 1H NMR (400 MHz, DMSO-d6): d 1.04 (s, 3H, CH3),
1.10 (s, 3H, CH3), 2.11–2.39 (m, 4H, 2CH2), 5.35
(s, 1H, quinazolinone H4), 7.03–7.61 (m, 5H, Ar–H), 9.68
(s, 1H, NH), 9.81 (s, 1H, NH), 11.73 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6): d 27.29 (CH3), 29.78 (CH3), 32.21
(C(CH3)2), 38.82 (CH2), 50.43 (CH2–CO), 51.22 (quinazoli-
none C4), 104.91, 115.28, 119.11, 127.72, 131.09, 132.61,
132.39, 136.52, 136.23, 151.04 (Ar–C), 156.88 (C=O),
176.12 (C=S), 194.19 (C=O); ms: m/z 354 [M ? 1]?; Anal.
Calcd. for C19H19N3O2S (353.45 g/mol): C, 64.57; H, 5.42;
N, 11.89%. Found: C, 64.43; H, 5.58; N, 11.71%.
4-(2-Thioxo-1,2-dihydroquinolin-3-yl)-3,4,7,8-tetra-
hydroquinazoline-2,5(1H,6H)-dione (4q): yield: 77%;
melting range: 305–307°C; IR (KBr): 3383, 3211, 3108
(N–H str.), 1661, 1653 (–C=O str.), 1176 (–C=S str.) cm-1
;
1H NMR (400 MHz, DMSO-d6): d 1.90–2.51 (m, 6H,
3CH2), 5.37 (s, 1H, quinazolinone H4), 7.09–7.87 (m, 5H,
Ar–H), 9.74 (s, 1H, NH), 10.85 (s, 1H, NH), 11.93 (s, 1H,
NH). 13C NMR (100 MHz, DMSO-d6): d 21.42 (CH2),
26.53 (CH2), 36.49 (CH2–CO), 48.22 (quinazolinone C4),
105.13, 115.71, 119.92, 122.86, 128.24, 130.13, 132.85,
135.80, 139.17, 153.23 (Ar–C), 156.72 (C=O), 188.20
(C=S), 194.14 (C=O); ms: m/z 326 [M ? 1]?; Anal. Calcd.
for C17H15N3O2S (325.39 g/mol): C, 62.75; H, 4.65; N,
12.91%. Found: C, 62.61; H, 4.77; N, 13.04%.
7,7-Dimethyl-4-(6-methyl-2-oxo-1,2-dihydroquinolin-3-
yl)-2-thioxo-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (4n):
yield: 65%; melting range: 301–303°C; IR (KBr): 3390,
3211, 3160 (N–H str.), 1655, 1637 (–C=O str.), 1190
(–C=S str.) cm-1; 1H NMR (400 MHz, DMSO-d6): d 1.02
(s, 3H, CH3), 1.04 (s, 3H, CH3), 2.23 (s, 3H, CH3),
2.10- 2.45 (m, 4H, 2CH2), 5.32 (s, 1H, quinazolinone H4),
7.19–7.52 (m, 4H, Ar–H), 9.00 (s, 1H, NH), 10.49 (s, 1H,
123

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Med Chem Res (2012) 21:1188–1198
2-Thioxo-4-(2-thioxo-1,2-dihydroquinolin-3-yl)-1,2,3,4,
(CH2–CO), 51.32 (quinazolinone C4), 105.65, 115.29,
119.76, 127.32, 128.11, 129.31, 129.54, 131.86, 132.57,
132.98, 134.68, 136.42, 136.57, 151.73 (Ar–C), 161.21
(C=O), 177.34 (C=S), 194.43 (C=O); ms: m/z 402 [M ? 1]?;
Anal. Calcd. for C23H19N3O2S (401.49 g/mol): C, 68.81; H,
4.77; N, 10.47%. Found: C, 68.62; H,4.93; N, 10.23%.
7,7-Dimethyl-4-(2-oxo-1,2-dihydroquinolin-3-yl)-
1-phenyl-2-thioxo-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-
one (4v): yield: 72%; melting range: 315–317°C; IR (KBr):
3359, 3261 (N–H str.), 1705, 1661 (–C=O str.), 1171
(–C=S str.) cm-1; 1H NMR (400 MHz, DMSO-d6): d 0.82 (s,
3H, CH3), 0.90 (s, 3H, CH3), 1.78–2.23 (m, 4H, 2CH2), 5.32
(s, 1H, quinazolinone H4), 7.19–7.83 (m, 10H, Ar–H), 9.48 (s,
1H, NH), 11.94 (s, 1H, NH). 13C NMR (100 MHz, DMSO-
d6): d 27.14 (CH3), 29.21 (CH3), 32.72 (C(CH3)2), 41.49
(CH2), 49.51 (CH2–CO), 51.12 (quinazolinone C4), 107.93,
115.20, 119.25, 122.43, 128.78, 130.05, 130.94, 131.37,
131.75, 138.49, 138.95, 139.32, 141.09, 151.61 (Ar–C),
161.26 (C=O), 178.42 (C=S), 194.77 (C=O); ms: m/z 430
[M ? 1]?; Anal. Calcd. for C25H23N3O2S (429.54 g/mol): C,
69.91; H, 5.40; N, 9.78%. Found: C, 69.76; H,5.24; N, 9.89%.
4-(6-Methyl-2-oxo-1,2-dihydroquinolin-3-yl)-1-phenyl-
2-thioxo-1,2,3,4,7,8 hexahydroquinazolin-5(6H)-one (4w):
yield: 70%; melting range: 313–315°C; IR (KBr): 3357,
3267 (N–H str.), 1712, 1673 (–C=O str.), 1165 (–C=S str.)
7,8-hexahydroquinazolin-5(6H)-one (4r): yield: 75%;
melting range: 316–318°C; IR (KBr): 3379, 3208, 3115
(N–H str.), 1664 (–C=O str.), 1179, 1168 (–C=S str.)
1
cm-1; H NMR (400 MHz, DMSO-d6): d 1.86–2.48 (m,
6H, 3CH2), 5.42 (s, 1H, quinazolinone H4), 7.07–7.81
(m, 5H, Ar–H), 9.72 (s, 1H, NH), 10.82 (s, 1H, NH),
11.90 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): d
21.31 (CH2), 26.48 (CH2), 36.32 (CH2–CO), 48.27 (qui-
nazolinone C4), 105.32, 115.54, 119.68, 122.73, 128.37,
130.19, 132.75, 135.69, 139.23, 153.45 (Ar–C), 174.72
(C=S), 188.12 (C=S), 194.31 (C=O); ms: m/z 342
[M ? 1]?; Anal. Calcd. for C17H15N3OS2 (341.46
g/mol): C, 59.80; H, 4.43; N, 12.31%. Found: C, 59.62;
H, 4.28; N, 12.43%.
7,7-Dimethyl-4-(2-thioxo-1,2-dihydroquinolin-3-yl)-3,4,7,
8-tetrahydroquinazoline-2,5(1H,6H)-dione (4s): yield: 78%;
melting range: 310–312°C; IR (KBr): 3388, 3213, 3110
(N–H str.), 1669, 1651 (–C=O str.), 1172 (–C=S str.) cm-1
;
1H NMR (400 MHz, DMSO-d6): d 1.08 (s, 3H, CH3), 1.09 (s,
3H, CH3), 2.13–2.35 (m, 4H, 2CH2), 5.39 (s, 1H, quinaz-
olinone H4), 7.01–7.64 (m, 5H, Ar–H), 9.65 (s, 1H, NH),
9.84 (s, 1H, NH), 11.76 (s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6): d 27.33 (CH3), 29.74 (CH3), 32.25 (C(CH3)2),
38.91 (CH2), 50.41 (CH2–CO), 51.32 (quinazolinone C4),
105.13, 115.44, 119.21, 127.84, 131.17, 132.70, 132.52,
136.65, 136.19, 151.13 (Ar–C), 156.81 (C=O), 188.53 (C=S),
194.27 (C=O); ms: m/z 354 [M ? 1]?; Anal. Calcd. for
C19H19N3O2S (353.45 g/mol): C, 64.57; H, 5.42; N, 11.89%.
Found: C, 64.42; H,5.59; N, 11.70%.
1
cm-1; H NMR (400 MHz, DMSO-d6): d 1.78–2.39 (m,
6H, 3CH2), 2.42 (s, 3H, CH3), 5.41 (s, 1H, quinazolinone
H4), 7.03–7.65 (m, 9H, Ar–H), 9.82 (s, 1H, NH), 11.73
(s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): d 20.81
(CH3), 21.32 (CH2), 26.51 (CH2), 36.47 (CH2–CO), 51.45
(quinazolinone C4), 105.56, 115.20, 119.65, 127.41,
128.24, 129.35, 129.76, 131.91, 132.64, 132.95, 134.63,
136.76, 136.94, 151.85 (Ar–C), 155.32 (C=O), 178.19
(C=S), 194.28 (C=O); ms: m/z 416 [M ? 1]?; Anal. Calcd.
for C24H21N3O2S (415.52 g/mol): C, 69.38; H, 5.09; N,
10.11%. Found: C, 69.21; H,5.18; N,10.29%.
7,7-Dimethyl-2-thioxo-4-(2-thioxo-1,2-dihydroquinolin-
3-yl)-1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (4t): yield:
74%; melting range: 322–324°C; IR (KBr): 3382, 3218, 3107
(N–H str.), 1670 (–C=O str.), 1173, 1169 (–C=S str.) cm-1
;
1H NMR (400 MHz, DMSO-d6): d 1.03 (s, 3H, CH3), 1.07
(s, 3H, CH3), 2.11–2.36 (m, 4H, 2CH2), 5.34 (s, 1H, qui-
nazolinone H4), 7.08–7.67 (m, 5H, Ar–H), 9.63 (s, 1H, NH),
9.89 (s, 1H, NH), 11.73 (s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6): d 27.41 (CH3), 29.72 (CH3), 32.23 (C(CH3)2),
38.87 (CH2), 50.38 (CH2–CO), 51.43 (quinazolinone C4),
105.65, 115.29, 119.76, 127.32, 131.86, 132.57, 132.98,
136.23, 136.45, 151.78 (Ar–C), 176.72 (C=S), 188.49 (C=S),
194.22 (C=O); ms: m/z 370 [M ? 1]?; Anal. Calcd. for
C19H19N3OS2 (369.51 g/mol): C, 61.76; H, 5.18; N, 11.37%.
Found: C, 61.59; H,5.32; N, 11.21%.
7,7-Dimethyl-4-(6-methyl-2-oxo-1,2-dihydroquinolin-
3-yl)-1-phenyl-2-thioxo-1,2,3,4,7,8-hexahydroquinazo-
lin-5(6H)-one (4x): yield: 71%; melting range: 309–311°C;
IR (KBr): 3354, 3264 (N–H str.), 1708, 1669 (–C=O str.),
1176 (–C=S str.) cm-1; 1H NMR (400 MHz, DMSO-d6): d
0.79 (s, 3H, CH3), 0.92 (s, 3H, CH3), 1.74–2.37 (m, 4H,
2CH2), 2.31 (s, 3H, CH3), 5.39 (s, 1H, quinazolinone H4),
7.05–7.79 (m, 9H, Ar–H), 9.77 (s, 1H, NH), 11.79 (s, 1H,
NH). 13C NMR (100 MHz, DMSO-d6): d 20.44 (CH3),
27.26 (CH3), 29.71 (CH3), 32.45 (C(CH3)2), 39.81 (CH2),
50.56 (CH2–CO), 51.57 (quinazolinone C4), 105.37,
115.16, 119.68, 127.25, 128.54, 129.26, 129.87, 131.91,
132.67, 132.94, 134.74, 136.82, 137.13, 151.68 (Ar–C),
155.23 (C=O), 176.57 (C=S), 194.82 (C=O); ms: m/z 444
[M ? 1]?; Anal. Calcd. for C26H25N3O2S (443.57 g/mol):
C, 70.40; H, 5.68; N, 9.47%. Found: C, 70.27; H, 5.81; N,
9.30%.
4-(2-Oxo-1,2-dihydroquinolin-3-yl)-1-phenyl-2-thioxo-
1,2,3,4,7,8-hexahydroquinazolin-5(6H)-one (4u): yield:
75%; melting range: 303–305°C; IR (KBr): 3353, 3259
(N–H str.), 1701, 1666 (–C=O str.), 1167 (–C=S str.) cm-1
;
1H NMR (400 MHz, DMSO-d6): d 1.81–2.43 (m, 6H,
3CH2), 5.38 (s, 1H, quinazolinone H4), 7.08–7.67 (m, 10H,
Ar–H), 9.85 (s, 1H, NH), 11.79 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6): d 21.44 (CH2), 26.62 (CH2), 36.41
123

Med Chem Res (2012) 21:1188–1198
1197
Acknowledgments The authors are thankful to Professor & Head,
Department of Chemistry, Sardar Patel University for providing 1H
NMR, 13C NMR spectroscopy and research facilities. We are also
thankful to Oxygen Healthcare Research Pvt. Ltd., Ahmedabad, for
providing mass spectroscopy facilities, SICART, Vallabh Vidhyana-
gar, for the elemental and FT-IR analysis and Dhanji P. Rajani,
Microcare Laboratory, Surat, for antimicrobial screening of the
compounds reported herein. One of the authors, Pushpak M. Shah is
grateful to UGC, New Delhi for Research Fellowship in Sciences for
Meritorious Students.
Kappe CO (1993) 100 years of the biginelli dihydropyrimidine
synthesis. Tetrahedron 49(32):6937–6963. doi:10.1016/S0040-
4020(01)87971-0
Kappe CO (1997) A reexamination of the mechanism of the biginelli
dihydropyrimidine synthesis. Support for an N-acyliminium ion
intermediate. J Org Chem 62(21):7201–7204. doi:10.1021/jo97
1010u
Kappe CO (2000) Biologically active dihydropyrimidones of the
biginelli-type—a literature survey. Eur J Med Chem 35(12):
1043–1052. doi:10.1016/S0223-5234(00)01189-2
Kidwai M, Saxena S, Khan MKR, Thukral SS (2005) Synthesis of
4-aryl-7,7-dimethyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2-one/
thione-5-one derivatives and evaluation as antibacterials. Eur
J Med Chem 40(8):816–819. doi:10.1016/j.ejmech.2005.02.009
Ladani NK, Patel MP, Patel RG (2009) An efficient three component
one-pot synthesis of some new octahydroquinazolinone deriva-
tives and investigation of their antimicrobial activities. Arkivoc
vii:292–302
Lamani DS, Venugopala KR, Bhojya Naik HS, Naik AB, Naik P (2010)
Synthesis, DNA binding, and antimicrobial activity of base-
catalyzed 2-phenyl-3-pyrido[3,2][1,3,4] thiadiazolo [3,2]quinoline
derivatives. Phosphorus Sulfur Silicon 185(1):1–11. doi:10.1080/
10426500802705354
Lin H, Zhao Q, Xu B, Wang X (2007) Nafion-H catalyzed cyclocon-
densation reaction for the synthesis of octahydroquinazolinone
derivatives. J Mol Catal 268(1–2):221–226. doi:10.1016/j.molcata.
2006.12.020
Minu M, Thangadurai A, Wakode SR, Agrawal SS, Narasimhan B
(2008) Arch Pharm Chem Life Sci 341(4):231–239. doi:10.1002/
ardp.200700153
References
Abdel-Gawad SM, El-Gaby MSA, Ghorab MM (2000) Synthesis and
evaluation of some new fluorinated hydroquinazoline derivatives
as antifungal agents II. Farmaco 55(4):249–255. doi:10.1016/S0014-
827X(00)00029-X
Atwal KS, Swanson BN, Unger SE, Floyd DM, Moreland S, Hedberg
A, O’Reilly BC (1991) Dihydropyrimidine calcium channel
blockers. 3. 3-carbamoyl-4-aryl-1, 2, 3, 4-tetrahydro-6-methyl-5-
pyrimidinecarboxylic acid esters as orally effective antihyper-
tensive agents. J Med Chem 34(2):806–811. doi:10.1021/jm0010
6a048
Bigi F, Carloni S, Frullanti B, Muggi R, Sartori G (1999) A revision
of the biginelli reaction under solid acid catalysis solvent-free
synthesis of dihydropyrimidines over montmorillonite KSF.
Tetrahedron Lett 40(17):3465–3468. doi:10.1016/S0040-4039
(99)00424-4
Bose DS, Idrees M (2007) An efficient and high yielding protocol for
the synthesis of substituted dihydropyrimidin-2(1 h)-ones and
spiro-fused heterocycles by involving tandem reactions. J Het-
erocyclic Chem 44(1):211–214. doi:10.1002/jhet.5570440133
Chenjiang L, Wang J, Yanping L (2006) One-pot synthesis of 3,4-
dihydropyrimidin-2(1H)-(thio)ones using strontium(II) nitrate as
a catalyst. J Mol Catal A 258(1–2):367–370. doi:10.1016/j.molcata.
2006.07.037
Esfahani MN, Karami B, Montazerozohori M, Abdi K (2008) An
efficient and clean one-pot synthesis of 3,4-dihydropyrimidine-
2(1H)-ones catalyzed by tungstate sulfuric acid in solvent-free
conditions. J Heterocyclic Chem 45(4):1183–1185. doi:10.1002/jhet.
5570450438
Folkers K, Johnson TB (1933) Researches on pyrimidines. CXXXVI.
The mechanism of formation of tetrahydropyrimidines by the
biginelli reaction. J Am Chem Soc 55(9):3784–3791. doi:10.1021/
ja01336a054
Folkers K, Johnson TB (1934) Hydrogenation of cyclic ureides under
elevated temperatures and pressures. I1 2-keto-1,2,3,4-tetrahy-
dropyrimidines. J Am Chem Soc 56(5):1180–1185. doi:10.1021/
ja01320a058
Nandeshwarappa B, Aruna Kumar DB, Kumaraswamy MN, Raviku-
mar YS, Bhojya Naik H, Mahadevan KM (2006) Microwave
assisted synthesis of some novel thiopyrano[2, 3-b]quinolines as
a new class of antimicrobial agent. Phosphorus Sulfur Silicon
181(7):1545–1556. doi:10.1080/10426500500366285
National Committee for Clinical Laboratory Standards (NCCLS)
(2002) West Valley Road, Suite 1400, Wayne, Pennsylvania
19087-1898, USA. Performance Standards for Antimicrobial
Susceptibility Testing; Twelfth Informational Supplement ISBN
1-56238-454-6, M100-S12 (M7)
Nityadevi V, Selvi P, Rajendran S (2004) An efficient synthesis of
dihydro selenolo (2, 3-b)quinoline-2-carboxylic ethyl esters and
2-selenoxo-1, 2-dihydro-3-carbethoxy ethyl quinolines-their anti-
bacterial studies. Phosphorus Sulfur Silicon 179(11):2355–2364.
doi:10.1080/10426500490485101
Patel RD, Patel MP, Patel RG (2005) Synthesis, characterization and
anti-bacterial activity of some new 2,3,6-trisubstituted quina-
zolin-4(3H)-ones. Indian J Chem 44B(9):1944–1946
Patel NA, Surti SC, Patel RG, Patel MP (2008) Synthesis, charac-
terization, and biological activity of some new benzoic acid and
thiazoloacridine derivatives. Phosphorus Sulfur Silicon 183(9):
2191–2203. doi:10.1080/10426500701852687
Patil AD, Kumar NV, Kokke WC, Bean MF, Freyer AJ, Brosse CD, Mai
S, Trunch A, Faulkner DJ, Carte B, Breen AL, Hertzberg RP,
Johnson RK, Westley JW, Ports BCM (1995) Novel Alkaloids
from the Sponge Batzella sp.: Inhibitors of HIV gpl2O-Human
CD4 Binding. J Org Chem 60(5):1182–1188. doi:10.1021/jo001
10a021
Folkers K, Harwood HJ, Johnson TB (1932) Researches on pyrim-
idines. Cxxx. Synthesis of 2-keto-1,2,3,4-tetrahydropyrimidines.
J Am Chem Soc 54(9):3751–3758. doi:10.1021/ja01348a040
Grover GJ, Dzwonczyk S, McMullen DM, Normandin DE, Parham
CS, Sleph PG, Moreland S (1995) Pharmacologic profile of the
dihydropyrimidine calcium channel blockers SQ 32, 547 and SQ
32, 946. J Cardiovasc Pharmacol 26(2):289–294
Ishimaru K, Kojima T (2000) A novel approach for mannich-type
bases having a terminal olefin: zinc triflate and water-promoted
cyclization/C–N bond cleavage process. J Org Chem 65(24):
8395–8398. doi:10.1021/jo0011888
Sinder B, Chen J, Patil AD, Freyer A (1996) Synthesis of the tricyclic
portions of batzelladines A,
B and D. Revision of the
stereochemistry of batzelladines A and D. Tetrahedron Lett
37(39): 6977–6980. doi:10.1016/0040-4039(96)01575-4
Kantevari S, Bantu R, Nagarapu L (2006) TMSCl mediated highly
efficient one-pot synthesis of octahydroquinazolinone and 1,8-
dioxo-octahydroxanthene derivatives. Arkivoc xvi:136–148
Snider BB, Shi Z (1993) Biomimetic synthesis of (.?-.)-crambines
A, B, C1, and C2. Revision of the structure of crambines B and
C1. J Org Chem 58(15):3828–3839. doi:10.1021/jo00067a014
123

1198
Med Chem Res (2012) 21:1188–1198
Sriyastava A, Singh RM (2005) Vilsmeier-Haack reagent: a facile
synthesis of 2-chloro-3-formylquinolines from N-arylacetamides
and transformation into different functionalities. Indian J Chem
44B(9):1868–1875
Wipf P, Cunningham A (1995) A solid phase protocol of the biginelli
dihydropyrimidine synthesis suitable for combinatorial chemis-
try. Tetrahedron Lett 36(43):7819–7822. doi:10.1016/0040-4039
(95)01660-A
Yang Y, Liu D, Liu C, Luo G (2007) One-pot synthesis of 3,4-
dihydropyrimidin-2(1H)-ones using chloroacetic acid as catalyst.
Bioorg Med Chem Lett 17(12):3508–3510. doi:10.1016/j.bmcl.
2006.12.068
Yarim M, Sarac S, Kilic FS, Erol K (2003) Synthesis and in vitro
calcium antagonist activity of 4-aryl-7,7-dimethyl/1,7,7-tri-
methyl-1,2,3,4,5,6,7,8-octahydroquinazoline-2,5-dione deriva-
tives. II Farmaco 58(1):17–24. doi:10.1016/S0014-827X(02)
00009-5
Zalavadiya P, Tala S, Akbari J, Joshi H (2009) Multi-component
synthesis of dihydropyrimidines by iodine catalyst at ambient
temperature and in vitro antimycobacterial activity. Arch Pharm
Chem Life Sci 342(8):469–475. doi:10.1002/ardp.200800224
123