Aromatic as well as heteroaromatic acids were found to beexcellent catalysts for the Biginelli three component synthesisof dihydropyrimidinones. Benzoic acid, substituted benzoic acids, five- and six- membered heterocyclic acids can be used for this purpose

Adnan, Muhammad

Ain Khan, Misbahul

Ain, Quratul

Amina, Humaira

Kanwal, Fareeha

Lin, Whei-Oh

Naeem Khan, Muhammad

Nazeer, Areesha

Perveen, Saima

Uzzaman, Ashar

Revistes Catalanes amb Accés Obert

AFINIDAD LXXII, 569, Enero - Marzo 201560
RESUMEN
Se ha hallado que ácidos aromáticos y heteroaromáticos 
son catalizadores excelentes de la síntesis de dihidropi-
rimidonas mediante la reacción de tres componentes de 
Biginelli. Para este propósito pueden utilizarse ácido ben-
zoico, ácidos benzoicos substituidos, o ácidos heterocícli-
cos de 5 y 6 miembros. 
Palabras clave: Reacciones multicomponente, Pirimidi-
nas, Urea, Tiourea
SUMMARY
Aromatic as well as heteroaromatic acids were found to be 
excellent catalysts for the Biginelli three component syn-
thesis of dihydropyrimidinones. Benzoic acid, substituted 
benzoic acids, five- and six- membered heterocyclic acids 
can be used for this purpose.
Key words: Multiple component reactions, Pyrimidines, 
Urea, Thiourea.
RESUM
S’ha trobat que els àcids aromàtics i heteroaromàtics son 
excel·lents catalitzadors de la síntesis de dihidropirimido-
nes mitjançant la reacció de tres components de Biginelli. 
Amb aquest objectiu es poden utilitzar àcid benzoic, àcids 
benzoics substituïts, o àcids heterocíclics de 5 y 6 mem-
bres. 
Mots clau: Reaccions multicomponent, Pirimidines, Urea, 
Tiourea
Synthesis of pyrimidines, aromatic 
and heteroaromatic acids as 
Biginelli reaction catalysts
Areesha Nazeer*1,Quratul Ain1 , Muhammad Naeem Khan2 , Fareeha Kanwal1 ,Saima Perveen3 , 
Humaira Amina1, Whei-Oh Lin4, AsharUzzaman1, Muhammad Adnan3 and Misbahul Ain Khan1,3
1Institute of Chemistry, University of  the Punjab, Lahore, Pakistan. 2 Applied Chemistry Division, PCSIR 
Laboratories Complex, Lahore, Pakistan. 3 Department of Chemistry, The Islamia University of Bahawalpur, 
Bahawalpur, Pakistan. 4 Departmento de Quimica,Universidade de Grande Rio (UNIGRANRIO), Rua
Prof. Jose Hurdy, Duque de Caixias, RJ, Brasil.
Síntesis de pirimidinas y ácidos aromáticos y heteroaromáticos 
como catalizadores de la reacción de Biginelli
Síntesi de pirimidines i àcids aromàtics y heteroaromàtics com a catalitzadors de la reacció de Biginelli
Recibido: 4 de enero de 2014; revisado: 19 de marzo de 2014; aceptado: 20 de marzo de 2014
AFINIDAD LXXII, 569, Enero - Marzo 2015 61
INTRODUCTION
The Biginelli reaction is one of the important multicompo-
nent reactions (MCRs) which results in affording dihydro-
pyrimid-2-ones and 2-thiones(1,2).These pyrimidines are 
interesting potential scaffolds for the preparation of a large 
number of heterocyclic molecules with useful biological 
activities of which calcium channel blockers are already in 
clinical use(3).Biginelli reaction has recently been reviewed 
encompassing various aspects of the reaction(4). A number 
of catalysts have found to be effective in promoting the 
reaction and the list is ever expanding. Our own interest 
in this reaction has led us to the use of novel catalysts/
conditions in these reactions with competitive if not higher 
yields of the products. We have already reported the use 
of copper salts(5), high boiling alcohols(6) and amino acids(7), 
among others, under investigations. The original Biginelli 
reaction was conducted with acid catalysis 1.  The scope 
was increased by involving a series of aliphatic carboxylic 
acids(8). While contemplating to explore the usefulness of 
aromatic carboxylic acid as catalysts in this reaction, we 
were constrained to go ahead in view of the findings of 
Feng et al.(9) who reported  high enantioselectivity (up to 
98% in the cyclocondensation of various aldehydes, ethyl 
acetoacetate and urea by a “dual activation” using a com-
bination of a hydroxyproline and Bronsted acids (such as 
TFA and substituted  benzoic acids). However, the reaction 
yields were poor (8-22%).  Another publication of a similar 
nature(10) also mentions  use of  a few aromatic acids but 
with longer reaction period (72-98 hrs.). 
Some preliminary experiments in our laboratories using 
benzoic acids as catalysts were successful which encour-
aged us to follow this with other aromatic and heteroaro-
matic acids. The results are being reported in the present 
communication. 
MATERIAL AND METHODS
All the chemicals and reagents used in the present study 
were commercial products. These were purified by usual 
methods of distillation (for liquids) and crystallization from 
appropriate solvents (for solids). Melting points were de-
termined on a Gallenkamp melting point apparatus and 
are uncorrected. IR spectra were recorded on Perkin Elmer 
spectrum BX-1 and NMR on a Brucker 400 MHz spec-
trometer using tetramethylsilane as an internal reference.
Synthesis of 4-aryl-6-methyl-2-oxo (or thio)-1,2,3,4-tet-
rahydropyrimidine-5-carboxylates and 5-acetyl-4-aryl-
6-methyl-3, 4-dihydropyrimidin-2(1H)-ones (or thiones) 
( I and II )
General method
A mixture of 40 mmole of an aldehyde, 40mmol b-diketo 
compound, 45 mmole urea or thiourea and catalytic 
amount of the acid (10 mg) in 10 mL of ethanol or metha-
nol was heated under reflux for a 8-16 hours period. The 
reaction was monitored by TLC. After cooling the reaction 
mixture was diluted with water, kept for a few hours, the 
precipitates were filtered off, washed with water and dried. 
A portion was recrystallised from ethanol to give the ex-
pected dihydropyrimidinone (or thione) (I and II, Scheme 
1). The results are presented in Table 1.  
All the products of the reactions were compared with the 
authentic samples prepared by the literature methods and 
were found to be identical in all respects m.p., mixed m.p., 
FTIR or other spectra.  IR and 1HNMR spectra of some 
representative compounds are given below. 
Ethyl 6-methyl-2-oxo-4- phenyl-1, 2, 3, 4- tetrahydro-
pyrimidine -5-carboxylate (Ia)
FTIR (KBr) cm-1: 3414(NH), 3230, 3109, 2936, 1735(C=O, 
ester), 1680(C=O, Pyrimidine),        1620, 1490(Aromatic).
1H-NMR (DMSO-d6): d 9.17 (s, 1 H, NH), 7.72 (s, 1 H, NH), 
7.21–7.32 (m, 5H, Ar-H), 5.5 (s, 1 H, CH), 3.98 (q, J = 7.2 
Hz, 2H, OCH2CH3), 2.24 (s, 3 H, Me), 1.08 (t, J = 7.2 Hz, 3 
H, OCH2CH3).
13C-NMR (DMSO-d6): d 165.4, 152.2, 148.4, 144.9, 128.4, 
127.9, 127.8, 127.3, 126.3, 99.3, 59.2, 54.0, 17.8, 14.1.
Ethyl 4-(4’-hydroxyphenyl)-6-methyl-2-oxo-1, 2, 3, 
4-tetrahydropyrimidine-5-carboxylate (Ib)
FTIR (KBr) cm-1: 3417(NH), 3241(OH), 3120, 2984, 
1742(C=O, ester), 1687(C=O, Pyrimidine), 1612, 1485(Aro-
matic).
1H NMR (DMSO-d6): d  9.32 (s, 1 H,NH), 7.67 (s, 1 H,NH), 
6.69-7.02 (m, 4 H, Ar-H), 5.61 (s, 1H,OH), 5.04 (s, 1 H), 3.97 
(q, J = 7.2 Hz, 2 H, OCH2CH3), 2.23 (s, 3 H), 1.08 (t, J = 7.2 
Hz,3 H, OCH2CH3).   
13C NMR (DMSO-d6): d 165.4, 156.6, 152.2, 147.8, 135.5, 
128.9, 128.4 127.4, 115.0, 99.8, 59.1, 53.5, 17.8, 14.1.
Ethyl 6-methyl-4- phenyl-2-thioxo-1, 2, 3, 4- tetrahy-
dropyrimidine-5-carboxylate (IIa)
 FTIR (KBr) cm-1: 3327(NH), 3174, 3105, 2981, 1745(C=O, 
ester), 1622 ,1498(Aromatic), 1571 (C=C), 1465, 1326, 
1197, 759.
1H NMR (DMSO-d6): d 7.27-7.31 (m, 5H, Ph), 5.30 (s, 1H, 
CH, H- 4), 4.07 (q, 2H, OCH2CH3, J = 7.32 Hz), 2.44 (s, 
1H, NH), 2.34 (s, 3H, CH3), 2.15 (s, 1H, NH), 1.16 (t, 3H, 
OCH2CH3, J = 7.23 Hz). 
13C NMR (DMSO-d6): d 176.0, 166.9, 145.6, 144.5, 129.5, 
128.8, 127.6, 127.4, 126.2 102.8, 61.0, 56.1, 17.8, 14.5. 
RESULTS AND DISCUSSION
A condensation reaction for the preparation of dihyropy-
rimidinones  and thiones  (DHPM, X=O or S) was carried 
out. In this preliminary reaction of benzaldehyde, ethyl 
acetoacetate and urea in ethanol solvent, benzoic acid 
was used as a catalyst. DHPM was isolated in 28% yield 
with urea (Table 1) while with thiourea the product was iso-
lated in 17% yield (Table 2). However, when the reaction 
with thiourea was carried out in methanol over a period of 
16 hrs., the yield was somewhat improved (47%) (Table 3). 
Encouraged by these results other aromatic acids and 
some derivatives of heteroaromatic  acids were employed 
for these Biginelli reactions (Table 1-3).It was observed 
that benzoic acids with electron withdrawing groups and 
the heteroaromatic acids gave better results. In the case 
of nicotinic and isonicotinic acids, the pyridine ring has a 
similar influence (heteroaromatic acids such as pyridine 
carboxylic acids are slightly stronger acids than benzoic 
acid(11)). It is interesting to note that in these Biginelli con-
densations commercial pharmaceutical products such as 
mefenamic acid and nalidixic acid can also be used as 
catalysts. Furthermore change of solvent, from ethanol to 
AFINIDAD LXXII, 569, Enero - Marzo 201562
methanol, also somewhat improved the yields. Various other aspects of this reaction are continuously under exploration in 
our laboratories.
Table 1: Dihyropyrimidin-2-ones, aromatic and heteroaromatic acids catalysts in ethanol 
Catalyst Solvent Time (hr.) Product Yield m.p. Lit. m.p.
Benzoic acid EtOH 8 Ia 28 200 202-204(12)
2-Chlorobenzoic  acid EtOH 8 Ia 30 200 202-204(12)
2-Chloro-4-nitrobenzoic acid EtOH 8 Ia 39 200 202-204(12)
2-Chloro-4-nitrobenzoic acid EtOH 8 Ia 47 200 202-204(12)
Phenylacetic acid EtOH 8 Ia 50 200 202-204(12)
Mefenamic acid EtOH 8 Ia 31 200 202-204(12)
Nicotinic acid EtOH 8 Ia 79 200 202-204(12)
Isonicotinic acid EtOH 8 Ia 73 200 202-204(12)
Nalidixic acid EtOH 8 Ia 53 200 202-204(12)
Pyrazine-2-carboxylic acid EtOH 8 Ia 36 200 202-204(12)
1,3-diphenylpyrazole-4-carboxylic acid EtOH 8 Ia 59 200 202-204(12)
3,5-dimethyl-1-phenyl-pyra-
zole-4-carboxylic acid
EtOH 8 Ia 59 200 202-204(12)
3,5-dimethyl-1-(p-nitrophenyl-
pyrazole-4-carboxylic acid
EtOH 8 Ia 51 200 202-204(12)
2-Furoic acid EtOH 8 Ia 57 200 202-204(12)
Indole-2-carboxylic acid EtOH
EtOH
8
10
Ib
Ic
75
72
202
183
196-198(14)
206-208(16)
Indole-3-acetic acid EtOH
EtOH
8
15
Id
Ie
80
71
197
195
234-235(15)
186-189(17)
Table 2: Dihyropyrimidin-2-thiones, aromatic and heteroaromatic acids catalysts in ethanol
Catalyst Solvent Time (hr.) Product Yield m.p. Lit. m.p.
Benzoic acid EtOH 12 IIa 17 202 209-211(13)
2-Chlorobenzoic  acid EtOH 10 IIa 21 204 209-211(13)
2-Chloro-4-nitrobenzoic acid EtOH 10 IIa 23 203 209-211(13)
2-Chloro-4-nitrobenzoic acid EtOH 12 IIa 25 203 209-211(13)
Ar H
O
H2N NH2
X
+
Me R
O O
+
N
H
NH
Me
ROC
X
Ar
Acid
Ia Ar
 = Ph
Ib
 
Ar
 = 4-HOC6H4
Ic Ar
 =  4-HOC6H4
Id
 
Ar
 = Ph
Ie Ar
 = 3,4-O(CH2)2C6H3
R = OEt
R = OEt
R = Me
R = Me
R = OEt
Ia-Ie     X = O
IIa-IIb
  X = S
IIa Ar
 = Ph
IIb
 
Ar
 = 4-
 HOC6H4
R = OEt
R = Me
Scheme 1
AFINIDAD LXXII, 569, Enero - Marzo 2015 63
Phenylacetic acid EtOH 10 IIa 16 204 209-211(13)
Nicotinic acid EtOH 12 IIa 25 204 209-211(13)
3,5-dimethyl-1-phenyl-pyra-
zole-4-carboxylic acid
EtOH 12 IIa 21 203 209-211(13)
3,5-dimethyl-1-(p-nitrophenyl-
pyrazole-4-carboxylic acid
EtOH 12 IIa 22 203 209-211(13)
Indole-2-carboxylic acid EtOH 16 IIb 65 185 252-254(18)
Table 3: Dihyropyrimidin-2-thiones, aromatic and heteroaromatic acids as catalysts in  methanol 
Catalyst Solvent Time (hr.) Product Yield m.p. Lit. m.p.
Benzoic acid MeOH 16 IIa 49 202 209-211(13)
2-Chlorobenzoic  acid MeOH 12 IIa 45 204 209-211(13)
2-Chloro-4-nitrobenzoic acid MeOH 16 IIa 48 203 209-211(13)
2-Chloro-4-nitrobenzoic acid MeOH 12 IIa 59 203 209-211(13)
Phenylacetic acid MeOH 12 IIa 50 204 209-211(13)
Mefenamic acid MeOH 16 IIa 63 204 209-211(13)
Nicotinic acid MeOH 16 IIa 59 204 209-211(13)
Isonicotinic acid MeOH 16 IIa 61 203 209-211(13)
Nalidixic acid MeOH 16 IIa 66 204 209-211(13)
Pyrazine-2-carboxylic acid MeOH 16 IIa 58 205 209-211(13)
1,3-diphenylpyrazole-4-carboxylic acid MeOH 16 IIa 57 204 209-211(13)
3,5-dimethyl-1-phenyl-pyra-
zole-4-carboxylic acid
MeOH 16 IIa 51 203 209-211(13)
3,5-dimethyl-1-(p-nitrophenyl-
pyrazole-4-carboxylic acid
MeOH 16 IIa 47 203 209-211(13)
2-Furoic acid MeOH 12 IIa 44 202 209-211(13)
ACKNOWLEDGEMENTS
AN, QA,  and AU would like to thank HEC, Government of 
Pakistan for Indigenous Scholarships while MAK  is grate-
ful for HEC’s continuous support for analytical services.
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Synthesis of pyrimidines, aromatic and heteroaromatic acids as Biginelli reaction catalysts

Synthesis of pyrimidines, aromatic and heteroaromatic acids as Biginelli reaction catalysts

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