A simple and practical method for the synthesis of 2-amino-5,6-dihydro-5,7- diarylquinazolin-4-ols

Article abstract of DOI:10.1002/jhet.229

(Chemical Equation Presented) We report an efficient and new method of synthesis of 2-amino-5,6-dihydro-5,7-diarylquinazolin-4-ols by the reaction of substituted cyclohexenones with guanidine hydrochloride in presence of NaOEt. The reactions are with 50-72% yield. All the synthesized compounds are characterized using IR, NMR and CHN analysis.

Full text of DOI:10.1002/jhet.229

1346
A Simple and Practical Method for the Synthesis of 2-Amino-5,6-
dihydro-5,7-diarylquinazolin-4-ols
Vol 46
S. Senguttuvan and Samuthira Nagarajan*
Department of Chemistry, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India
*E-mail: nagarajan.au@gmail.com
Received May 5, 2009
DOI 10.1002/jhet.229
Published online 11 November 2009 in Wiley InterScience (www.interscience.wiley.com).
We report an efficient and new method of synthesis of 2-amino-5,6-dihydro-5,7-diarylquinazolin-4-ols
by the reaction of substituted cyclohexenones with guanidine hydrochloride in presence of NaOEt. The
reactions are with 50–72% yield. All the synthesized compounds are characterized using IR, NMR and
CHN analysis.
J. Heterocyclic Chem., 46, 1346 (2009).
INTRODUCTION
RESULTS AND DISCUSSION
Quinazoline skeleton is an important pharmacophore
that occurs frequently in medicinal chemistry literature
[1]. Quinazolines are recently been the subject of deep
investigation due to their diverse pharmacological prop-
erties such as analgesic, narcotic, antimalarial, sedative,
hypoglycemic [2], anti-cancer [3] and anti-tubercular
activities[4]. It has been reported that quinazolines act
as potent [5] and highly selective inhibitors of epidermal
growth factor receptor tyrosine kinase and have been
employed as DNA binder [6]. Alkaloids with quinazo-
line ring system are known for natural compounds hav-
ing a wide spectrum of biological effects. The biological
activity of quinazolines strongly depends on the nature
and the position of the substituents in the quinazoline
ring. The 2-amino substituted quinazolines are reported
as potential histamine antagonists [7]. This large interest
in medicinal chemistry stimulated the development of
new and more efficient synthesis of amino substituted
heterocycles recently we have reported the synthesis and
antibacterial activity of naphthyl and thienyl substituted
2-aminopyrimidines [8]. In continuation of synthesis of
the biologically active heterocyclic compounds here we
report a simple synthesis for 2-amino-5,6-dihydro-5,7-
diarylquinazolin-4-ols.
Quinazolin-4-ols are synthesized in three steps
(Scheme 1) starting from easily available acetophenone
and benzaldehyde. Initialy, chalcones 1 were synthesized
by Claisen-Schmidt condensation between benzaldehyde
and acetophenone.
The chalcones on treatment with ethyl acetoacetate in
the presence of sodium ethoxide gave carbethoxycyclo-
hex-2-en-one derivatives 2. The structure of the carbe-
thoxycyclohex-2-en-one derivatives were conformed by
comparing with their reported IR and melting points.
Carbethoxycyclohex-2-en-one derivatives 2 on treat-
ment with guanidine hydrochloride in the presence of
sodium ethoxide under go condensation reaction and gave
2-amino-5,6-dihydro-5,7-diarylquinazolin-4-ols (3a–h).
1
The structures of 3a–h were elucidated by H and 13C
NMR, mass spectral analysis and elemental analysis. In
1
the H NMR spectra, the characteristic chemical shift of
the hydroxy protons of 3a–h were found at d ¼ 10.76–
10.81 ppm as a broad singlet. The two amino protons
were observed as a singlet at d ¼ 6.20–6.42 ppm. The
alkenic proton signal was observed at around 6.40 ppm.
To conclude, we have proposed an efficient method
for the preparation of 2-amino-5,6-dihydro-5,7-diarylqui-
nazoline-4-ols by reaction of guanidine hydrochloride
C
V
2009 HeteroCorporation

November 2009
A Simple and Practical Method for the Synthesis of 2-Amino-5,6-dihydro-
5,7-diarylquinazolin-4-ols
1347
Scheme 1. Synthesis of 2-amino-5,6-dihydro-5,7-diarylquinazoline-4-ols.
the mixture and refluxed for the 5 h. The reaction mixture was
kept aside for more than 1 h and the solid mass obtained was
collected and recrystallized from ethanol. The products were
confirmed from their reported IR spectra and melting points.
with carbethoxycyclohex-2-enone derivatives. These
compounds are known pharmacophores in several struc-
ture based drug design approaches.
2-Amino-5,6-dihydro-5,7-diarylquinazolin-4-ols
(3a–h).
EXPERIMENTAL
Appropriate diarylcyclohexenone (2a–h, 0.01 mole), guanidine
hydrochloride (0.01 mole) and sodium ethoxide (2 g in 30 mL etha-
nol) were refluxed for 28–32 h. The reaction mixture was cooled to
room temperature, poured into crushed ice and stirred. The sepa-
rated product was purified using column chromatography (silica
gel, 100–200 mesh, CHCl3-EtOAc, 6:4). All the compounds were
characterized using IR, 1H and 13C NMR and elemental analysis.
2-Amino-5,6-dihydro-5,7-diphenylquinazolin-4-ol (3a). This
compound was obtained as a yellow solid. mp 134–136ꢀC; yield
72.5%; IR (KBr) m cmꢁ1 3415 (NAH stretching), 2836 (CAH
stretching), 1649 (C¼¼C stretching) 1H NMR (DMSO-d6, 300
MHz), d ppm 2.94 (d, 1H, J ¼ 17.1 Hz), 3.12–3.22 (m, 1H), 4.21
(d, 1H, J ¼ 7.5 Hz), 6.42 (s, NH2), 6.46 (s, H-8), 7.09–7.49 (Ar-H),
10.76 (s, AOH). 13C NMR (DMSO-d6, 75 MHz) d ppm 34.3, 41.7,
110.1, 125.4, 125.9, 126.3, 126.9, 127.3, 127.8, 128.3, 128.5, 128.9,
129.1, 140.1, 145.2, 155.4, 161.5. Calc. for C20H17N3O: C 76.17;
H, 5.43; N, 13.32%. Observed were C, 76.12; H, 5.48; N, 13.48%.
2-Amino-5,6-dihydro-5-(4-flurophenyl)-7-phenylquinazolin-
4-ol (3b). This compound was obtained as white solid. mp
217–219ꢀC; yield 60.4%; IR (KBr) m cmꢁ1 3336 (NAH
Melting points are determined in open capillaries and are
uncorrected. The NMR spectra were recorded on 300 MHz spec-
trometer in DMSO-d6. Chemical shifts are expressed in parts per
million using residual solvent proton and carbon as internal
standards. The FT-IR spectra were recorded on NICOLET AVA-
TAR 360-FTIR instrument by using KBr pellets. Elemental anal-
yses were done on Vario EL. CHN elemental analyzer.
Preparation of chalcone (1a–h). About 0.5 g of sodium
hydroxide was dissolved in 50 mL of water. A mixture of ace-
tophenone (0.01 mole) and aromatic aldehyde (0.01 mole) in
50 mL of absolute ethanol was added. The mixture was stirred
at room temperature for 3 h and allow to stand for overnight.
The preceipitated solid was separated, washed with distilled
water and recrystallized from hot ethanol. The products were
confirmed from their reported IR spectra and melting points.
Ethyl-2-oxo-4,6-diarylcyclohex-2-en-carboxylate (2a-h). A
mixture of chalcone (0.01 mole) (1a-h) and ethyl acetoacetate
(0.01 mole) was dissolved in absolute ethanol (30 mL). So-
dium ethoxide (2 g sodium in 60 mL ethanol) was added to
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1348
S. Senguttuvan and S. Nagarajan
Vol 46
1
stretching), 2852 (CAH stretching), 1648 (C¼¼C stretching) H
NMR (DMSO-d6, 300 MHz) d ppm 2.92 (d, 1H, J ¼ 17.4
Hz), 3.21–3.11 (m, 1H), 4.21 (d, 1H, J ¼ 8.1 Hz), 6.38 (s,
NH2), 6.44 (s, 1H), 7.00–7.50 (Ar-H), 10.76 (s, AOH). 13C
NMR (DMSO-d6, 75 MHz) d ppm 34.2, C-6 (merged with
DMSO), 115.3, 125.3, 125.5,125.9, 127.8, 128.9, 129.0, 129.1,
129.2, 129.3, 130.0, 130.2, 132.0, 132.1, 132.5, 139.5, 143.9,
155.3, 169.7. Calc. for C20H16N3O C, 72.06; H, 4.84; N,
12.61%; Observed were C, 72.02; H, 4.86; N, 12.59%.
(Ar-H), 10.79 (s, OH). 13C NMR (DMSO-d6 75 MHz) 35.5,
40.8, 60.5, 110.8, 123.3, 126.8, 126.9, 128.8, 129.3, 130.1,
131.0, 132.1, 159.7, 169.6. Calc. for C21H19N3O2 C, 73.03; H,
5.54; N, 12.17%; observed were C, 73.10; H, 5.61; N, 12.15%.
2-Amino-5,6-dihydro-5-(3-nitrophenyl)-7-phenylquinazo-
lin-4-ol (3h). This compound was obtained as brownish yellow
solid. mp 262–265ꢀC; yield 65.3%; IR (KBr) m cmꢁ1 3448
(NAH stretching), 2923 CAH stretching, 1653 (C¼¼C stretching)
1H NMR (DMSO-d6, 300 MHz) d ppm 3.01 (d. 1H, J ¼ 17.4
Hz), 3.18–3.32 (m, 1H), 4.37 (d, 1H, J ¼ 8.1 Hz), 6.45 (s, NH2),
6.51 (s, 1H), 7.35–7.54 (Ar-H), 10.85 (s, AOH). 13C NMR
(DMSO-d6, 75 MHz) d ppm 34.4, C-6 (merged with DMSO),
113.5, 125.4, 125.9, 128.8, 129.2, 129.7, 131.4, 131.6, 139.5,
143.9, 144.0, 144.5, 155.5, 166.6. Calc. for C20H16N4O3 C,
66.66; H, 4.48; N, 15.55%; observed were C, 66.62; H, 4.45; N,
15.50%.
2-Amino-5-(4-chlorophenyl)-5,6-dihydro-7-phenylquinazo-
lin-4-ol (3c). This compound was obtained as white amorphous
solid. mp 196–198ꢀC; yield 70.1%; IR (KBr) m cmꢁ1 3437
(NAH stretching), 2858 (CAH stretching), 1647 (C¼¼C stretch-
1
ing) H NMR (DMSO-d6, 300 MHz) d ppm 2.93 (d, 1H, J ¼
17.6 Hz), 3.75–3.14 (m, 1H), 4.29 (d, 1H, J ¼ 8.4 Hz), 6.47 (s,
NH2), 6.54 (s. H-8), 7.13–7.51 (Ar-H), 10.78 (s, AOH). 13C
NMR (DMSO-d6, 300 MHz) d ppm 34.9, 43.1, 113.8, 120.1,
122.8, 125.2, 125.6, 126.4, 128.8, 129.9, 130.4, 130.5, 131.2,
137.2, 140.9, 159.1, 169.1. Calc. for C20H19N3ClO C, 68.67; H,
4.61; N, 12.01%; observed were C, 68.62; H, 4.64; N, 12.03%.
2-Amino-5-(3-bromophenyl)-5,6-dihydro-7-phenylquinazo-
lin-4-ol (3d). This compound is obtained as brown solid. mp
226–229ꢀC; yield 50.2%; IR (KBr) m cmꢁ1 3464 (NAH stretch-
Acknowledgment. The authors thank NMR Research Centre,
Indian Institute of Science, Bangalore for NMR spectral measure-
ments and S.S. Thank Cavinkare Research Centre, Chennai for
Research Fellowship.
1
REFERENCES AND NOTES
ing), 2920 (CAH stretching), 1638 (C¼¼C stretching) H NMR
(DMSO-d6, 300 MHz) d ppm 2.97 (d, 1H, J ¼ 17.2 Hz), 3.32–
3.12 (m, 1H), 4.21 (d, 1H, J ¼ 8.4 Hz), 6.41 (s, NH2), 6.47 (s,
H-8), 7.18–7.51 (Ar-H), 10.77 (s, AOH). 13C NMR (DMSO-d6,
75 MHz) d ppm 34.1, 41.5, 115.9, 121.0, 121.8, 123.9, 125.5,
125.9, 126.4, 127.8, 128.0, 129.2, 130.1, 139.4, 143.9, 147.9,
155.4, 170.9. Calc. for C20H16N3BrO C, 60.93; H, 4.09; N,
10.66%. Observed were C, 60.90; H, 4.05; N, 10.62%.
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2-Amino-5-(4-bromophenyl)-5-dihydro-7-phenylquinazolin-
4-ol (3e). This compound was obtained as a yellowish brown
colour solid. mp 184–186ꢀC; yield 55.1%; IR (KBr) m cmꢁ1
3377 (NAH stretching), 2853 (CAH stretching), 1630 (C¼¼C
stretching) 1H NMR (DMSO-d6, 300 MHz) d ppm 2.89 (d,
1H, J ¼ 17.7 Hz), 3.21–3.11 (m, 1H), 4.19 (d, 1H, J ¼ 8.4
Hz), 6.42 (s, NH2), 6.47 (s, HA), 7.13–7.49 (Ar-H), 10.83 (s,
AOH). 13C NMR (DMSO-d6, 75 MHz) d ppm 34.4, C-6
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144.0, 155.2, 170.0. Calc. for C20H16N3BrO C, 50.93; H, 4.09;
N, 10.66%, observed were C, 50.89; H, 4.10; N, 10.59%.
2-Amino-5,6-dihydro-5-(4-methylphenyl)-7-phenylquinazo-
lin-4-ol (3f). This compound was obtained as brownish red colour
solid. mp 174–178ꢀC; yield 45.7%; IR (KBr) m cmꢁ1 3331 (NAH
stretching), 2852 (CAH stretching), 1644 (C¼¼C stretching) 1H
NMR (DMSO-d6, 300 MHz) d ppm 1.23 (s, 3H, ACH3), 2.91 (d,
1H, J ¼ 17.4 Hz), 3.19–3.09 (m, 1H), 4.16 ( d, 1H, J ¼ 8.1 Hz),
6.35 (s, ANH2), 6.41 (s, 1H), 6.99–7.49 (Ar-H), 10.71, (s, AOH).
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129.0, 129.1, 129.2, 129.5, 131.5, 135.2, 136.2, 139.5, 140.2,
142.2, 155.2, 168.4. Calc. for C21H19N3O C, 76.57; H, 5.81; N,
12.76%; observed were C, 76.52; H, 5.79; N, 12.69%.
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3371 (NAH stretching), 2852 (CAH stretching), 1645 (C¼¼C
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet