Table of Contents
Research Letters in Organic Chemistry
Volume 2008, Article ID 810678, 3 pages
http://dx.doi.org/10.1155/2008/810678
Research Letter

A Novel and One-Pot Synthesis of 6-arylpyrimidin-4-ol

Drug Discovery Chemistry, Glenmark Research Centre, Glenmark Pharmaceuticals Limited, MIDC, Mahape, Navi Mumbai 400709, India

Received 25 June 2008; Accepted 2 November 2008

Academic Editor: William Ogilvie

Copyright © 2008 Jitendra M. Gajera et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

We have developed a novel and one-pot synthesis of 6-arylpyrimidine-4-ol by reacting commercially available alkyl 3-oxo-3-arylpropanoate with formamide in the presence of stoichiometric amount of ammonium acetate.

1. Introduction

Pyrimidine derivatives are very well known for their various therapeutic applications. Pyrimidine derivatives are used as anticancer [1], anti-HIV [2], antibacterial [3], antimalarial [4], antihypertensive [5], sedative, hypnotics [6], anticonvulsant [7], antithyroid [8], antihistaminic agents [9], and antibiotics [10]. A very recent review describes the significance of pyrimidine derivatives as anti-inflammatory agents [11]. 2-thiopyrimidine derivatives possess potent activity against inflammation and immune disorders [12]. Recently, various pyrimidine derivatives have been reported as vanilloid receptor antagonists [13].

After looking at the diverse properties of pyrimidine derivatives, we selected 4,6-disubstituted pyrimidines as a part of our pharmacophore to synthesize novel anti-inflammatory agents. Literature survey revealed that 4,6-disubstituted pyrimidines can be prepared using either Biginelli approach [14] or reaction of β-iminoesters with formamide [15] or reaction of 4,6-dichloropyrimidines with appropriate boronic acids [16]. The only competitive method similar to our approach described in the literature uses formamidine in DMF and affords the product in only 14% after a reaction time of 3 days [17]. During the course of our research work on synthesis on various 4,6-disubstituted pyrimidines, we developed a novel and one-pot method for the synthesis of 6-arylpyrimidine-4-ol using commercially available raw materials. The method comprises reaction between 3-oxo-3-arylpropanoate, stoichiometric amount of ammonium acetate, and formamide at elevated temperature.

2. Results and Discussion

Various 6-arylpyrimidin-4-ols 3a-h were prepared by reacting methyl-3-oxo-3-arylpropanoates 1a-h with formamide in the presence of ammonium acetate with a yield of 50–70%.

The reaction of methyl-3-oxo-3-arylpropanoates 1 with the in situ generated ammonia gives the intermediate methyl 3-amino-3-arylacrylate 2, which subsequently reacts with formamide to give 6-arylpyrimidin-4-ols 3 (Scheme 1). One of the intermediates methyl 3-amino-3-phenylacrylate was isolated in 80% yield and characterized. Isolation and characterization of 2a confirm the reaction pathway (Table 1). The procedure described in the experimental part provides a novel and one-pot approach for the synthesis of 6-arylpyrimidin-4-ol.

tab1
Table 1: Yield and melting point of compounds 3a-h and 2a.
810678.scheme.001
Scheme 1

3. Experimental

Commercial solvents and reagents were used without further purification. 1 H NMR spectra were recorded on a Varian 300 MHz spectrometer. Melting points are uncorrected. Elemental analysis was performed on a Perkin-Elmer analyzer. Mass spectra were recorded on Thermo Finnigan LCQ DECA XP MAX (ION TRAP) mass spectrometer using atmospheric pressure chemical ionization (APCI) source in positive/negative mode at capillary voltage 3.14 V and capillary temperature 250°C.

Methyl 3-Amino-3-Phenylacrylate (2a)
To a stirred solution of methyl 3-oxo-3-phenylpropanoate (1 mmol) in formamide (5.0 mL) was added ammonium acetate (5 mmol) at ambient temperature. Reaction mixture was then heated to 110–120°C over a period of 1 hour and then held at 110–120°C for 1 more hour. It was then cooled to room temperature; diluted with cold water; and extracted with diethyl ether. The residue obtained after removal of diethyl ether was purified through silica gel column using ethyl acetate: petroleum ether (8:2) as an eluent to give methyl 3-amino-3-arylacrylate 2a as thick oil. IR (KBr): 3445, 1622, 1491, 1320 c m 1 . 1 H NMR (DMSO- 𝑑 6 ): 𝛿 3.56 (S, 3H); 4.78 (s, 1H); 7.34–7.59 (m, 5H); 7.95 (brs, 2H). [M−1 ] :176.23. Anal. calcd for C 1 0 H 1 1 N O 2 : C, 67.78; H, 6.26; N, 7.90. Found: C, 67.65; H, 6.24; N, 7.91.

General Procedure for Preparation of 6-Arylpyrimidine-4-Ol (3a-h)
A stirred solution of appropriate methyl 3-oxo-3-arylpropanoate 1 (1 mmol) in formamide (50 mol) was added ammonium acetate (5 mmol) and heated to 100–120°C over a period of 1 hour and held at 110–120°C for 1 more hour. It was then stirred for 4-5 hours at 160–170°C. Reaction mixture was cooled to room temperature and diluted with cold water. The precipitated material was extracted with ethyl acetate. The solid product obtained after removal of ethyl acetate was washed with diethyl ether to get pure product.

6-Phenylpyrimidine-4-Ol (3a)
This compound was obtained as light yellow solid. IR (KBr): 3435, 1668, 1592, 1252, 1024 c m 1 . 1 H NMR (DMSO- 𝑑 6 ): 𝛿 6.87 (s, 1H); 7.45–7.47 (m, 3H); 8.02-8.03 (m, 2H); 8.25 (s, 1H); 12.51 (brs, 1H). MS [M + 1 ] + :172.32. Anal. calcd for C 1 0 H 8 N 2 O : C, 69.76; H, 4.68; N, 16.27. Found: C, 69.74; H, 4.69; N, 16.31.

6-(4-Chlorophenyl)pyrimidine-4-Ol (3b)
This compound was obtained as light yellow solid. IR (KBr): 3339, 1667, 1594, 1243, 1014 c m 1 . 1 H NMR (DMSO- 𝑑 6 ): 𝛿 6.91 (s, 1H); 7.52 (d, 2H, 𝐽 = 8 . 4  Hz); 8.05 (d, 2H, 𝐽 = 8 . 7  Hz); 8.26 (s, 1H); 12.54 (brs, 1H). MS [M + 1 ] + :207.39. Anal. calcd for C 1 0 H 7 Cl N 2 O: C, 58.13; H, 3.41; N, 13.58. Found: C, 58.20; H, 3.42; N, 13.61.

6-(4-Bromophenyl)pyrimidine-4-Ol (3c)
This compound was obtained as light yellow solid. IR (KBr) 3445, 1685, 1589, 1257, 1010 c m 1 . 1 H NMR (DMSO- 𝑑 6 ): 𝛿 6.91 (s, 1H); 7.66 (d, 2H, 𝐽 = 9  Hz); 7.98 (d, 2H, 𝐽 = 8 . 4  Hz); 8.26 (s, 1H); 12.54 (bs, 1H). MS [M + 1 ] + :251.39. Anal. calcd for C 1 0 H 7 Br N 2 O: C, 47.84; H, 2.81; N, 11.16. Found: C, 47.89; H, 2.80; N, 11.15.

6-(4-Fluorophenyl)pyrimidine-4-Ol (3d)
This compound was obtained as light yellow solid. IR (KBr) 3444, 1672, 1600, 1242, 1035 c m 1 . 1 H NMR (DMSO- 𝑑 6 ): 𝛿 6.88 (s, 1H); 7.26–7.31 (m, 2H); 8.07–8.11 (m, 2H); 8.25 (s, 1H); 12.52 (brs, 1H). [M + 1 ] + :190.97. Anal. calcd for C 1 0 H 7 F N 2 O: C, 63.16; H, 3.71; N, 14.73. Found: C, 63.12; H, 3.70; N 14.76.

6-(4-Methylphenyl)pyrimidine-4-Ol (3e)
This compound was obtained as light yellow solid. IR (KBr): 3422, 1664, 1592, 1254, 1175, 1037 c m 1 . 1 H NMR (DMSO- 𝑑 6 ): 𝛿 2.34 (s, 3H); 6.81 (s, 1H); 7.26 (d, 2H, 𝐽 = 7 . 8  Hz); 7.92 (d, 2H, 𝐽 = 7 . 8  Hz); 8.22 (s, 1H); 12.20 (brs, 1H). [M + 1 ] + :186.39. Anal. calcd for C 1 1 H 1 0 N 2 O : C, 70.95; H, 5.41; N, 15.04. Found: C, 71.11; H, 5.43; 15.00.

6-(4-Methoxyphenyl)pyrimidine-4-Ol (3f)
This compound was obtained as light yellow solid. IR (KBr) 3397, 1666, 1605, 1245, 1177 c m 1 . 1 H NMR (DMSO- 𝑑 6 ): 𝛿 3.80 (s, 3H); 6.77 (s, 1H); 7.00 (d, 2H, 𝐽 = 8 . 7  Hz); 8.00 (d, 2H, 𝐽 = 9  Hz); 8.21 (s, 1H); 12.42 (brs, 1H). [M + 1 ] + :203.37. Anal. calcd for C 1 1 H 1 0 N 2 O 2 : C, 65.34; H, 4.98; N, 13.85. Found: C, 65.38; H, 4.97; N, 13.88.

6-(2,4-Dimethoxyphenyl)pyrimidine-4-Ol (3g)
This compound was obtained as light yellow solid. IR (KBr) 3414, 1673, 1610, 1270, 1170 c m 1 . 1 H NMR (DMSO- 𝑑 6 ): 𝛿 3.81 (d, 6H, 𝐽 = 4 . 5  Hz); 6.84 (s, 1H); 7.02 (d, 1H, 𝐽 = 8 . 4  Hz); 7.58 (s, 1H); 7.65 (d, 1H, 𝐽 = 9  Hz); 8.20 (s, 1H); 12.32 (brs, 1H). [M + 1 ] + :233.36. Anal. calcd for C 1 2 H 1 2 N 2 O 3 : C, 62.06; H, 5.21; N, 12.06. Found: C, 62.20; H, 5.23; N, 12.04.

6-(2-(cyclopentyloxy)phenyl)pyrimidine-4-Ol (3h)
This compound was obtained as light yellow solid. IR (KBr): 3313, 1643, 1574, 1279, 1242 c m 1 . 1 H NMR (DMSO- 𝑑 6 ): 𝛿 1.63–1.76 (m, 6H); 1.90–1.99 (m, 2H); 4.95 (m, 1H); 6.93 (s, 1H); 7.00 (t, 1H, 𝐽 = 7 . 8  Hz); 7.11 (d, 1H, 𝐽 = 8 . 4  Hz); 7.38 (t, 1H, 𝐽 = 6 . 9  Hz); 7.93 (d, 1H, 𝐽 = 6 . 3  Hz); 8.20 (s, 1H); 12.42 (brs, 1H). [M + 1 ] + :257.13. Anal. calcd for C 1 5 H 1 6 N 2 O 2 : C, 70.29; H, 6.29; N, 10.93. Found: C, 70.19; H, 6.27; N, 10.91.

Acknowledgment

The authors are thankful to analytical department for analytical support.

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