Facile synthesis of 2-amino-5,6,7,8-tetrahydro-5,7-diarylpyrido[4,3-d] pyrimidin-4-ols

Article abstract of DOI:10.1080/00397910902767491

2-Amino-5,6,7,8-tetrahydro-5,7-diarylpyrido[4,3-d]pyrimidin-4-ols were synthesized from various ethyl 2,6-diaryl-4-oxopiperidin-3-carboxylates with guanidine hydrochloride in presence of sodium ethoxide. Copyright Taylor & Francis Group, LLC.

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Facile Synthesis of 2-
Amino-5,6,7,8-tetrahydro-5,7-
diarylpyrido[4,3-d]pyrimidin-4-
ols
P. Amutha a & S. Nagarajan a
a Department of Chemistry , Annamalai University ,
Annamalainagar, India
Published online: 12 Aug 2009.
To cite this article: P. Amutha & S. Nagarajan (2009) Facile Synthesis of 2-
Amino-5,6,7,8-tetrahydro-5,7-diarylpyrido[4,3-d]pyrimidin-4-ols, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:18, 3348-3356, DOI: 10.1080/00397910902767491
To link to this article: http://dx.doi.org/10.1080/00397910902767491
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Synthetic Communications1, 39: 3348–3356, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902767491
Facile Synthesis of 2-Amino-5,6,7,8-tetrahydro-
5,7-diarylpyrido[4,3-d]pyrimidin-4-ols
P. Amutha and S. Nagarajan
Department of Chemistry, Annamalai University,
Annamalainagar, India
Abstract: 2-Amino-5,6,7,8-tetrahydro-5,7-diarylpyrido[4,3-d]pyrimidin-4-ols were
synthesized from various ethyl 2,6-diaryl-4-oxopiperidin-3-carboxylates with guani-
dine hydrochloride in presence of sodium ethoxide.
Keywords: Aminopyrimidines, hydroxypyrimidines
INTRODUCTION
Pyrimidine is a widespread heterocyclic moiety present in numerous
natural products. Pyrimidines are important not only because they are
an integral part of genetic materials (viz., DNA and RNA as nucleotides
and nucleosides), but also they have important biodynamic properties
and biological activities such as antibacterial, antifungal, antitubercular,
antiviral, antimicrobial, dopaminergic, VEGF-RZ kinase inhibitory, and
central nervous system depressant activity.[1–6] Substituted pyrimidines,
particularly with an amino group at 2 or 4 positions, are known pharma-
cophores in several structure-based drug-design approaches in medicinal
chemistry.[7,8] For example, aryl-2-aminopyrimidines have been reported
for the treatment of diseases modulated by the adenosine receptor. The
anti-HIV=HBV drugs abacavir and anti-atherosclerotic drug arnoxil are
examples of aminopyrimidine drugs available on the market.[9,10] Drugs
Received November 3, 2008.
Address correspondence to S. Nagarajan, Department of Chemistry, Annama-
lai University, Annamalainagar 608 002, India. E-mail: nagarajan.au@gmail.com
3348

Synthesis of 2-Aminopyrimidin-4-ols
3349
containing a pyrimidine with a hydroxy group such as tetrahydrofolate
and 5-methyltetrahydrofolate possess high antioxidant activity.[11]
The unique structure and great potential of these compounds
inspired us to report the synthesis and antibacterial activity of naphthyl
and thienyl substituted 2-aminopyrimidines.[12,13] In continuation of
our interest in the synthesis of the biologically active heterocyclic com-
pounds, here we address the synthesis of 2-amino-5,6,7,8-tetrahydro-5,7-
diarylpyrido[4,3-d]pyrimidin-4-ols.
RESULTS AND DISCUSSION
The synthetic strategy adopted in this work to obtain the ethyl 2,6-diaryl-
4-oxopiperidin-3-carboxylates is presented in Scheme 1 and uses the
condensation of aromatic aldehyde with keto ester in the presence of
ammonium acetate to furnish ethyl 2,6-diaryl-4-oxopiperidin-3-carboxy-
late 1a–h.[14] Refluxing 1a–h with guanidine hydrochloride in sodium
Scheme 1. Synthesis of ethyl 4-oxopiperidin-3-carboxylate.

3350
P. Amutha and S. Nagarajan
ethanolate for about 16 h yielded the desired 2-amino-5,6,7,8-tetrahydro-
5,7-diarylpyrido[4,3-d]pyrimidin-4-ols 2a–h (Scheme 2).
After our initial success in the cyclization of ethyl 2,6-diaryl-4-oxopi-
peridin-3-carboxylate 1a–d to 2-amino-5,6,7,8-tetrahydro-5,7-diarylpyrido
[4,3-d]pyrimidin-4-ols, we extended the same protocol to the N-substituted
ethyl 2,6-diaryl-4-oxopiperidin-3-carboxylate 1e–h with guanidine hydro-
chloride in sodium ethanolate.
Ethyl-1-acetyl-2,6-diaryl-4-oxopiperidin-3-carboxylates 1e and 1f
were synthesized by treatment of 1a or 1b with acetic anhydride and
triethylamine (1:3:3 ratio) in dry toluene. Similarly, ethyl-1-methyl-2,6-
diaryl-4-oxopiperidin-3-carboxylates 1g and 1h were obtained by reflux-
ing 1a and 1d with methyl iodide and anhydrous potassium carbonate in
dry acetone (Scheme 1). Soldatenkov et al. reported that the acylation of
ethyl 4-oxopiperidin-3-carboxylate gave enol-form and acylation took
place at both nitrogen and hydroxyl groups, but we were not able to iso-
late the diacetylated product under our experimental conditions.
2-Amino-5,6,7,8-tetrahydro-5,7-diarylpyrido[4,3-d]pyrimidin-4-ols 2a–h
were obtained in moderate to good yields (Table 1). All the new com-
pounds were characterized on the basis of their analytical, one- and
two-dimensional NMR spectral data, which are in agreement with their
proposed structure.
To conclude, we have proposed an efficient method for the prepara-
tion of 2-amino-5,6,7,8-tetrahydro-5,7-diarylpyrido[4,3-d]pyrimidin-4-ols
by reaction of guanidine hydrochloride with ethyl 4-oxopiperidin-3-
carboxylate. These compounds are known pharmacophores in several
structure-based drug-design approaches.
Scheme 2. Synthesis of 2-aminopyrimidin-4-ols.

3351

3352
P. Amutha and S. Nagarajan
Figure 1. Biologically active aminopyrimidines.
EXPERIMENTAL
Melting points are determined in open capillaries and are uncorrected.
The 1H NMR and 13C NMR spectra were recorded on a Brucker
AMX-500 spectometer operating at 400 MHz using dimethylsulfoxide
(DMSO) as solvent. The (FT-IR) spectra were recorded on a Nicolet
Avatar 360-FT-IR instrument Fourier transform–infrared using KBr
pellets. Elemental analyses were done on a Vario EL CHNOS elemental
analyzer.
General Procedure for the Synthesis of Ethyl 2,6-Diaryl-4-oxopiperidin-
3-carboxylates 1a–d
Ammonium acetate (0.1 mol), bezaldehyde (0.2 mol), and ketoester
(0.1 mol) were dissolved in 95% ethanol (40 ml). The ether insoluble
matters were filtered off, and concentrated hydrochloric acid (14 ml)
was added to the filtrate. The precipitated piperidone hydrochloride
was collected by filtration. The hydrochloride was dispersed in acetone
(50 ml), and concentrated aqueous ammonia was added dropwise until
a clear solution was obtained. The clear solution was poured into cold
water (500 ml), and the precipitated solid was collected and crystallized
from hot ethanol.

Synthesis of 2-Aminopyrimidin-4-ols
3353
General Procedure for Synthesis of Ethyl-1-acetyl-2,6-diaryl-4-
oxopiperidin-3-carboxylates 1e–f
A mixture of appropriate piperidin-4-one (0.01 mol), acetic anhydride
(0.03 mol), and triethylamine (0.03 mol) in dry benzene was refluxed for
6–8 h to afford the N-acetyl piperidin-4-ones. The reaction mixture was
washed with sodium bicarbonate (10%) and water, and then the solvents
were removed at low pressure. The residue was recrystallized from
distilled ethanol.
General Procedure for Synthesis of Ethyl-1-methyl-2,6-diaryl-4-
oxopiperidin-3-carboxylate 1g–h
A mixture of piperidin-4-one (10 g), anhydrous potassium carbonate
(10 g), and methyl iodide (5 ml) in acetone (100 ml) was refluxed for
3 h. Removal of acetone by distillation, dilution with water, and treat-
ment with aqueous ammonia yielded the compound.
General Procedure for Synthesis of 2-amino-5,6,7,8-tetrahydro-
5,7-diarylpyrido[4,3-d]pyrimidin-4-ols 2a–h
A mixture of ethyl 4-oxopiperidine-3-carboxylate (0.01 mol, 1.0 eq.) and
guanidine hydrochloride (0.012 mol, 1.2 eq.) was added to the sodium
ethanolate solution (dry sodium 0.25 g in 30 ml of anhydrous ethanol)
and refluxed for 16 h. After cooling to room temperature, the slurry
was evaporated. The residue was taken up in a minimum of 95% ethanol,
and water was added until precipitation. The white solid was collected
and purified using column chromatography (silica gel): eluent CHCl3–
CH3OH (9:1).
Data
Compound 2a
1H NMR (CDCl3): d ¼ 10.79 (s, 1H, OH), 6.42 (s, 2H, NH2), 4.92 (s, 1H,
H-5), 3.72 (dd, 1H, H-7), 2.58 (dd, 1H, H-8ax), 2.49 (dd, 1H, H-8eq),
7.1–7.4 (Ar-H); 13C NMR (DMSO): d ¼ 161.08 (C-2), 162.04 (C-4),
53.81 (C-5), 50.49 (C-7), 126.39–128.15 (Ar-C).

3354
P. Amutha and S. Nagarajan
Compound 2b
1H NMR (CDCl3): d ¼ 10.82 (s, 1H, OH), 6.43 (s, 2H, NH2), 4.88 (s, 1H,
H-5), 2.54 (dd, 1H, H-8ax), 2.38 (dd, 1H, H-8eq), 6.8–7.3 (Ar-H), 3.69 (d,
6H, -OCH3); 13C NMR (DMSO): d ¼ 160.86 (C-2), 161.76 (C-4), 53.25
(C-5), 49.77 (C-7), 113.04–128.99 (Ar-C), 54.95 (-OCH3).
Compound 2c
1H NMR (CDCl3): d ¼ 10.53 (s, 1H, OH), 6.35 (s, 2H, NH2), 4.86 (s, 1H,
H-5), 3.96 (dd, 1H, H-7), 2.61 (dd, 1H, H-8ax), 2.44 (dd, 1H, H-8eq),
6.98–7.45 (Ar-H), 1.24 (s, 6H, -CH3); 13C NMR (DMSO): d ¼ 161.18 (C-2),
162.26 (C-4), 57.47 (C-5), 56.26 (C-7), 114.28–130.43 (Ar-C), 27.1 (CH3).
Compound 2d
1H NMR (CDCl3): d ¼ 10.56 (s, 1H, OH), 6.36 (s, 2H, NH2), 4.86 (s, 1H,
H-5), 3.97 (dd, 1H, H-7), 2.62 (dd, 1H, H-8ax), 2.42 (dd, 1H, H-8eq),
6.98–7.47 (Ar-H); 13C NMR (DMSO): d ¼ 161.22 (C-2), 162.28 (C-4),
57.47 (C-5), 56.25 (C-7), 115.21–130.42 (Ar-C).
Compound 2e
1H NMR (CDCl3): d ¼ 11.05 (s, 1H, OH), 6.70 (s, 2H, NH2), 5.21 (s, 1H,
H-5), 2.74 (dd, 1H, H-8ax), 2.66 (dd, 1H, H-8eq), 6.88–7.36 (Ar-H), 1.89 (s,
3H, -CO CH3); 13C NMR (DMSO): d ¼ 160.33 (C-2), 161.33 (C-4), 57.35
(C-5), 48.85 (C-7), 126.25–128.72 (Ar-C), 22.89 (CH3), 170.76 (-CO CH3).
Compound 2f
1H NMR (CDCl3): d ¼ 10.94 (s, 1H, OH), NH2-protons merged in aro-
matic region, 5.12 (s, 1H, H-5), 2.71 (dd, 1H, H-8ax), 2.6 (dd, 1H, H-8eq),
6.98–6.65 (Ar-H), 1.88 (s, 3H, -CO CH3), 3.63 (d, 6H, OCH3); 13C NMR
(DMSO): d ¼ 160.23 (C-2), 161.87 (C-4), 56.63 (C-5), 48.32 (C-7),
113.36–134.53 (Ar-C), 22.86 (CH3), 54.97 (OCH3), 170.59 (-CO CH3).
Compound 2g
1H NMR (CDCl3): d ¼ 10.50 (s, 1H, OH), 6.36 (s, 2H, NH2), 4.15 (s, 1H,
H-5), 3.53 (dd, 1H, H-7), 2.94 (dd, 1H, H-8ax), 2.36 (dd, 1H, H-8eq),

Synthesis of 2-Aminopyrimidin-4-ols
3355
7.12–7.40 (Ar-H), 1.82 (s, 3H, CH3); 13C NMR (DMSO): d ¼ 160.41
(C-2), 160.82 (C-4), 66.54 (C-5), 64.55 (C-7), 127.67–129.69 (Ar-C),
CH3–merged with DMSO.
Compound 2h
1H NMR (CDCl3): d ¼ 10.52 (s, 1H, OH), 6.37 (s, 2H, NH2), 4.15 (s, 1H,
H-5), 3.54 (dd, 1H, H-7), 2.92 (dd, 1H, H-8ax), 2.48 (dd, 1H, H-8eq),
6.99–7.44 (Ar-H), 1.78 (s, 3H, CH3); 13C NMR (DMSO): d ¼ 161.94
(C-2), 162.49 (C-4), 65.18 (C-5), 63.02 (C-7), 41.47 (C-8), 113.60–130.46
(Ar-C), CH3–merged with DMSO.
ACKNOWLEDGMENTS
We thank the NMR Research Center, Indian Institute of Science,
Bangalore, for NMR spectral measurements, and P. A. thanks
Annamalai University for providing a student research fellowship.
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