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

Authors: Jitendra M. Gajera; Shital N. Tondlekar; Laxmikant A. Gharat
Journal: Research Letters in Organic Chemistry
 (2008)

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## 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.


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## Body

## 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-ols3a-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-arylpropanoates1 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.Table 1
Yield and melting point of compounds3a-h and 2a.
CompoundR1R2Yield (%)M. P. (°C)3aHH65271-2723bClH70213–2153cBrH68311–3133dFH61313–3153eCH3H57291-2923fOCH3H53282–2843gOCH3OCH350252–2543hHCyclopentyloxy55260–2642aHH80—Scheme 1


## 3. Experimental

Commercial solvents and reagents were used without further purification.H1 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 cm−1. H1 NMR (DMSO- d6): 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 C10H11NO2:
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-arylpropanoate1 (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 cm−1. H1 NMR (DMSO- d6): 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 C10H8N2O: 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 cm−1. H1 NMR (DMSO- d6): 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 C10H7ClN2O: 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 cm−1. H1 NMR (DMSO- d6): 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 C10H7BrN2O: 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 cm−1. H1 NMR (DMSO- d6): 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 C10H7FN2O: 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 cm−1. H1 NMR (DMSO- d6): 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 C11H10N2O:
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 cm−1. H1 NMR (DMSO- d6): 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 C11H10N2O2:
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 cm−1. H1 NMR (DMSO- d6): 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 C12H12N2O3:
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 cm−1. H1 NMR (DMSO- d6): 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 C15H16N2O2:
C, 70.29; H, 6.29; N, 10.93. Found: C, 70.19; H, 6.27; N, 10.91.



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*Source: 810678-2008-12-04.xml*