1. science
2. chemistry
3. organic chemistry

Canadian Chemical Transactions
Year 2015 | Volume 3 | Issue 1 | Page 72-84
Ca
Research Article
DOI:10.13179/canchemtrans.2015.03.01.0169
Synthesis of Novel Pyrazolylmethylene-Pyrimidine
Heterocycles: Potential Synthons for Hybrid Β-Lactams
Aman Bhalla,* Shamsher S. Bari and Jitender Bhalla
Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh
160014, India
*
Corresponding Author: Email: [email protected] Phone: +91 172-253 4417/4405
Received: February 6, 2015
Revised: March 14, 2015 Accepted: March 18, 2015
Published: March 18, 2015
Abstract: Diversely substituted novel pyrazolylmethylene-pyrimidine heterocycles were synthesized via
Knoevenagel condensation between substituted formyl pyrazoles and barbituric acids without any base or
solid catalyst. All these thirteen novel heterocycles were characterized by FT-IR, NMR spectroscopy (1H,
13
C), 13C DEPT-135, 1H-13C HSQC, elemental analysis and mass spectrometry (in representative case).
Keywords: Pyrazole; barbituric acid; pyrazolylmethylene-pyrimidine; knoevenagel condensation; hybrid
β-lactams
1. INTRODUCTION
The problem of multidrug resistance by various microbial strains has perpetually instigated the
scientific community to explore newer, safer and effective chemotherapeutic agents. In this direction,
hybrid heterocycles [1] have attracted great interest of the researchers due to their promising leads in
producing new remedial outcomes. In recent years, various heterocycle based hybrid systems have shown
their importance due to various properties such as tumor growth inhibitory activity (indole, pyrazole and
pyrimidine based hybrids) [2], antimicrobial activity (glycoconjugates) [3] and cytotoxic activity (steroidanthraquinone based hybrids) [4]. The development of simple and greener synthetic methodologies using
readily available reagents for novel hybrid heterocycles which are biologically active in nature have
become the prime focus of organic chemists. It is well established that any modification or alteration in
the chemical structure of a compound or a drug may bring about mild or drastic changes in not only its
pharmacological activities but also its physico-chemical properties [5]. Hence, it was envisioned to
synthesize novel hybrid systems based on well acknowledged heterocycles viz. pyrazole and barbituric
acid.
Pyrazole and barbituric acid based hybrid systems constitute an elite category of heterocycles due
to their unique structural features along with their wide range of pharmacological activities such as
antitumor [2], antimicrobial [4], anticancer [6] etc. Pyrazole and its derivatives have remained as an active
area of research due to its extensive applications in agrochemical and pharmaceutical industries [7].
Pyrazole derivatives have expressed their importance, since they have been found as constituent of variety
of natural products such as withasomnine, pyrazofurin, formycin, fluviol and many others [8]. These have
also shown to exhibit various biological properties such as antimicrobial, antitumor, anti-inflammatory,
Borderless Science Publishing
72
Canadian Chemical Transactions
Year 2015 | Volume 3 | Issue 1 | Page 72-84
Ca
anti-depressive, anti-coagulant, anti-anxiety, anti HIV, antagonist of OPL1, inhibitors of BACE (useful in
treatment of Alzheimers disease), hepatitis C virus and hypoxia inducible factor [9]. On the other hand,
barbiturates are another class of N containing heterocycles popular as CNS depressants. By virtue of this,
barbiturates are extensively used as sedatives, hypnotics, anticonvulsants and anaesthetic agents [10-15].
Recently, barbiturates have also been reported to possess pharmacological potential as immunomodulators, analeptics, anti AIDS and anticancer [16-18].
Literature survey has revealed that Knoevenagel condensation [19] is generally carried out in the
presence of organic bases such as aliphatic amines, ethylene diamine, piperidine or their corresponding
ammonium salts and amino acids [20,21]. Apart from this, use of various other Lewis acid and base
catalysts such as ZnCl2, CdI2, Al2O3, KF/Al2O3, MgF has been reported in the literature [22-26]. Further,
solid phase catalyst [27], synthetic phosphates such as Na2CaP2O7 [28], NaY zeolites [29], cesium
modified mesoporous materials [30] have also been listed but still most of these suffered from significant
drawbacks such as toxic reagents, organic wastes, harsh reaction conditions, low yields or long reaction
times. In this paper, we are reporting the synthesis of novel pyrazolylmethylene-pyrimidine heterocycles
in the absence of any catalyst or organic bases.
In our earlier studies, we have demonstrated the synthesis of selenoalkanoic acids useful as βlactam precursors [31,32], novel 3-thio/seleno β-lactams and Lewis acid mediated functionalization [3339], stereoselective cis- and trans-3-alkoxy-β-lactams [40], spirocyclic β-lactams [35,41-42], (Z)- and
(E)-3-allylidene-β-lactams [43], 3-keto-β-lactams [44] and bicyclic-β-lactams [45]. Recently, hybrid βlactams I, II, III (Figure 1) with varied heterocyclic moieties have been shown to exhibit antimicrobial,
antiprotozoal, anti-inflammatory and analgesic activities [46-48]. So we envisaged the synthesis of
pyrazolylmethylene-pyrimidine substituted hybrid β-lactams. For this purpose, we explore the synthesis
of novel pyrazolylmethylene-pyrimidine heterocycles.
O
N
Cl
H2
C
Cl
N
N
O
N
O
N
O
O
N
H
N
N
O
N
HN
O
O
N
N N
N
O
O
I
II
III
Figure 1. Biologically active hybrid β-lactams
2. EXPERIMENTAL SECTION
2.1 Materials and Methods:
Melting points were determined in an open capillary on melting point apparatus and were
uncorrected. Fourier transform infrared spectra were recorded on a Thermo scientific Nicolet iS50 (FTIR) spectrophotometer (υmax in cm–1). 1H (400 MHz), 13C (100 MHz) NMR spectra were recorded on
Bruker Avance II (400 MHz) spectrometer. Chemical shifts are given in ppm relative to Me4Si as an
Borderless Science Publishing
73
Canadian Chemical Transactions
Year 2015 | Volume 3 | Issue 1 | Page 72-84
Ca
internal standard ( = 0 ppm) for 1H NMR, CDCl3 ( = 77.0 ppm) and CD3CN (δ = 1.3 ppm) for 13C
NMR spectra. The mass spectra (EI-MS) were obtained using Water’s Q-TOF Micromass (YB361)
spectrometer. The elemental analysis (C, H, N) were recorded on Flash 2000 Organic elemental analyzer.
Reactions were monitored by analytical thin-layer chromatography (TLC) using Merck Silica Gel G using
ethyl acetate-hexanes (10:90) as an eluant system. For visualization, TLC plates were stained with iodine
vapors or observed under UV light.
Phosphorus oxychloride (Merck), ethyl acetoacetate (Merck), phenyl hydrazine (Hi-media) and
all other commercially available compounds/reagents/solvents were of reagent grade quality and used
without any further purification. Dimethyl formamide was dried and distilled over anhydrous calcium
chloride (CaCl2) and phosphorus oxychloride (POCl3) was distilled and stored on molecular sieves (4Å).
2.2 General procedure for the synthesis of pyrazolylmethylene-pyrimidines 10a-m
Pyrazolecarbaldehyde 8a-e (1 mmol), 1,3-dimethyl barbituric acid 9a-c (1 mmol) and glacial
acetic acid (2-3 drops) were taken in absolute ethanol (30 ml). The mixture was refluxed for 4-5 h.
Completion of the reaction was checked by TLC. Disappearance of spot corresponding to reactants and
appearance of a new spot confirmed the completion of reaction. After the completion of reaction, the
reaction mixture was allowed to cool and a yellowish or orange solid was separated. Finally, the solid was
filtered, washed with cold ethanol and dried. It was purified by recrystallization from methylene chloride:
hexane to obtain the product as fluffy solid.
2.2.1
5-[(5'-Chloro-3'-methyl-1'-phenyl-1H-pyrazol-4'-yl)methylene]-1,3-dimethyl
2,4,6(1H,3H,5H)-trione 10a
pyrimidine-
Bright yellowish solid, mp: 174-175°C. IR (cm-1): 1725, 1660, 1570,
1427. 1H NMR (CDCl3, 400 MHz): δ 8.39 (s, 1H, =CH), 7.76-7.19 (m,
CH3
N
5H, ArH), 3.36 (s, 3H, NCH3), 3.33 (s, 3H, NCH3), 2.35 (s, 3H, CH3).
Ph N
13
C NMR (CDCl3, 100 MHz): δ 166.18, 162.88, 157.84, 155.27,
N
O
N
O
CH 3
150.70, 147.52, 137.07, 129.04, 127.46, 121.92, 105.28, 103.40, 29.09,
CH3
29.04, 13.07. 13C NMR (DEPT-135) (400 MHz, CDCl3): δC 147.43 (+),
129.01 (+), 127.40 (+), 121.83 (+), 29.07 (+), 29.01 (+), 13.06. Elemental Analysis for C17H15ClN4O3,
Found (Cacld.): C 56.81 (56.91), H 4.19 (4.21); N 15.58 (15.62).
Cl
O
2.2.2
5-[(5'-Chloro-3'-methyl-1'-phenyl-1H-pyrazol-4'-yl)methylene]-1,3-diphenylpyrimidine2,4,6(1H,3H,5H)-trione 10b
Bright yellowish solid, mp: 243-244°C. IR (cm-1): 1731, 1672, 1627,
O
Cl
1551, 1489. 1H NMR (CD3CN, 400 MHz): δ 8.49 (s, 1H, =CH), 7.79Ph
N
7.33 (m, 15H, ArH), 2.36 (s, 3H, CH3). 13C NMR (CD3CN, 75 MHz): δ
Ph N
166.48, 162.77, 158.01, 155.21, 149.84, 148.33, 137.19, 135.03, 134.59,
N
O
N
O
CH 3
129.29, 129.24, 129.08, 128.93, 128.58, 127.36, 121.77, 105.94, 103.33,
Ph
13.07. Elemental Analysis for C27H19ClN4O3, Found (Cacld.): C 67.04
(67.15), H 3.94 (3.97), N 11.55 (11.60).
Borderless Science Publishing
74
Canadian Chemical Transactions
Year 2015 | Volume 3 | Issue 1 | Page 72-84
Ca
2.2.3
5-[(5'-Chloro-3'-methyl-1'-phenyl-1H-pyrazol-4'-yl)methylene]-1,3-diphenyl-2thioxodihydropyrimidine-4,6(1H,5H)-dione 10c
Orange solid, mp: 234-235°C, IR (cm-1): 1687, 1629, 1567, 1490. 1H
O
Cl
NMR (CDCl3, 400 MHz): δ 8.46 (s, 1H, =CH), 7.71-7.16 (m, 15H,
Ph
N
ArH), 2.32 (s, 3H, CH3). 13C NMR (CDCl3, 100 MHz): δ 179.13,
Ph N
164.82, 161.99, 158.24, 155.63, 148.72, 139.91, 139.28, 136.81,
N
S
N
O
CH 3
129.60, 129.48, 129.07, 128.95, 128.83, 128.52, 128.38, 127.69,
Ph
121.87, 107.18, 104.38, 13.00. Elemental Analysis for C27H19ClN4O2S
Found (Cacld.): C 64.92 (64.99), H 3.81 (3.84), N 11.19 (11.23).
2.2.4
5-[(5'-Chloro-3'-methyl-1'-carbethoxymethyl-1H-pyrazol-4'-yl)methylene]-1,3dimethylpyrimidine-2,4,6(1H,3H,5H)-trione 10d
Yellowish fluffy solid and as a 53:47 mixture of rotamers, mp:
O
Cl
154-155°C; IR (cm-1): 1736, 1663, 1588, 1512. 1H NMR
CH 3
N
(CDCl3, 400 MHz): δ 8.23 (s, 1H, =CH), 4.62 (s, 2H, CH2CO),
EtOOCH2C N
4.16 (m, 2H, CH2CH3), 3.34 (s, 3H, NCH3), 3.29 (s, 3H,
N
O
O N
CH 3
NCH3), 2.18 (s, 3H, CH3), 1.18 (t, 3H, CH2CH3) (for one
CH 3
isomer) and 8.35 (s, 1H, =CH), 4.83 (s, 2H, CH2CO), 4.16 (m,
2H, CH2CH3), 3.35 (s, 3H, NCH3), 3.33 (s, 3H, NCH3), 2.28 (s, 3H, CH3), 1.18 (t, 3H, CH2CH3) (for other
isomer); the 1H NMR spectrum showed it to be a mixture of two rotamers; 13C NMR (CDCl3, 100 MHz):
δ 166.67, 166.25, 165.99, 162.90, 161.93, 159.64, 159.04, 154.98, 151.57, 151.31, 150.74, 147.78,
146.17, 132.83, 117.31, 113.79, 103.62, 103.57, 62.33, 62.15, 50.65, 47.88, 29.70, 29.07, 29.03, 28.88,
28.41, 14.50, 14.13, 14.10, 13.04. Elemental Analysis for C15H17ClN4O5, Found (Cacld.): C 48.76
(48.85), H 4.59 (4.65), N 15.02 (15.19).
2.2.5
5-[(5'-Chloro-3'-methyl-1'-carbethoxymethyl-1H-pyrazol-4'-yl)methylene]-1,3diphenylpyrimidine-2,4,6(1H,3H,5H)-trione 10e
Yellowish solid and as a 55:45 mixture of rotamers, mp: 240O
Cl
241 °C; IR (cm-1): 1738, 1683, 1593, 1518, 1492. 1H NMR
Ph
N
(CDCl3, 400 MHz): δ 8.44 (s, 1H, =CH), 7.49-7.25 (m, 10H,
EtOOCH2C N
ArH), 4.63 (s, 2H, CH2CO), 4.19 (m, 2H, CH2CH3), 2.27 (s,
N
O
O N
CH 3
3H, CH3), 1.24 (t, 3H, CH2CH3), (for one isomer) and 8.54 (s,
Ph
1H, =CH), 7.49-7.25 (m, 10H, ArH), 4.85 (s, 2H, CH2CO),
4.19 (m, 2H, CH2CH3), 2.33 (s, 3H, CH3), 1.24 (t, 3H, CH2CH3), (for other isomer); the 1H NMR
spectrum showed it to be a mixture of two rotamers; 13C NMR (CDCl3, 100 MHz): δ 166.53, 166.25,
166.15, 163.12, 161.89, 159.57, 159.18, 155.23, 151.91, 150.67, 150.15, 148.76, 147.79, 134.89, 134.62,
134.48, 134.43, 133.41, 129.36, 129.17, 129.07, 129.04, 128.99, 128.61, 128.50, 128.48, 128.42, 117.08,
113.96, 104.28, 103.46, 62.38, 62.21, 50.68, 47.96, 14.64, 14.13, 14.11, 13.04. Elemental Analysis for
C25H21ClN4O5, Found (Cacld.): C 60.79 (60.92), H 4.24 (4.29), N 11.28 (11.37).
Borderless Science Publishing
75
Canadian Chemical Transactions
Year 2015 | Volume 3 | Issue 1 | Page 72-84
Ca
2.2.6
5-[(1',3'-Diphenyl-1H-pyrazol-4'-yl)methylene]-1,3-dimethylpyrimidine-2,4,6-(1H,3H,5H)trione 10f
Bright yellowish solid, mp: 247-248°C, IR (cm-1): 1728, 1658, 1564,
O
H
1523, 1500. 1H NMR (CDCl3, 400 MHz): δ 9.78 (s, 1H, N–CH), 8.50
CH 3
N
(s, 1H, =CH), 7.81-7.18 (m, 10H, ArH), 3.33 (s, 3H, NCH3), 3.29 (s,
Ph N
3H, NCH3). 13C NMR (CDCl3, 100 MHz): δ 162.85, 161.67, 159.59,
N
O
N
O
151.43, 147.92, 138.98, 135.01, 130.85, 129.75, 129.63, 129.48,
CH3
128.95, 128.09, 120.01, 116.06, 112.54, 28.91, 28.26. EI-MS (m/z):
387 (M+H)+, 409 (M+Na)+. Elemental Analysis for C22H18N4O3, Found
(Cacld.): C 66.28 (68.38), H 4.34 (4.70), N 13.76 (14.50).
2.2.7 5-[(1',3'-Diphenyl-1H-pyrazol-4'-yl)methylene]-1,3-diphenylpyrimidine-2,4,6 (1H,3H,5H)trione 10g
Light yellowish solid, mp: 286-287°C. IR (cm-1): 1734, 1663, 1564,
O
H
1523, 1489. 1H NMR (CDCl3, 400 MHz): δ 9.87 (s, 1H, N–CH), 8.80 (s,
Ph
N
1H, =CH), 7.87-7.25 (m, 20H, ArH). 13C NMR (CDCl3, 100 MHz): δC
Ph N
162.98, 161.76, 160.11, 150.84, 149.73, 138.86, 135.66, 134.97, 134.82,
N
O
N
O
130.71, 129.82, 129.61, 129.56, 129.51, 129.37, 129.16, 129.04, 128.97,
Ph
128.84, 128.52, 128.32, 120.38, 116.38, 112.27, 100.02. Elemental
Analysis for C32H22N4O3, Found (Cacld.): C 75.18 (75.28), H 4.26
(4.34), N 10.89 (10.97).
2.2.8 5-[(1',3'-Diphenyl-1H-pyrazol-4'-yl)methylene]-1,3-diphenyl-2-thioxodihydro pyrimidine4,6(1H,5H)-dione 10h
Orange solid, mp: >300°C. IR (cm-1): 1703, 1672, 1563, 1523, 1496. 1H
O
H
NMR (CDCl3, 400 MHz): δ 9.79 (s, 1H, N–CH), 8.68 (s, 1H, =CH),
Ph
N
7.77-7.16 (m, 20H, ArH). 13C NMR (CDCl3, 100 MHz): δ 180.48,
Ph N
161.92, 160.29, 160.24, 150.53, 139.83, 139.67, 138.74, 135.79, 130.56,
N
S
N
O
129.78, 129.58, 129.50, 129.02, 128.93, 128.90, 128.76, 128.56, 128.40,
Ph
120.41, 116.79, 112.80. Elemental Analysis for C32H22N4O2S, Found
(Cacld.): C 72.80 (72.98), H 4.17 (4.21), N 10.55 (10.64).
2.2.9
1,3-Dimethyl-5-[(1'-phenyl-3'-p-tolyl-1H-pyrazol-4'-yl)methylene]pyrimidine-2,4,6
(1H,3H,5H)-trione 10i
Bright yellowish solid, mp: 239-240°C; IR (cm-1): 1724, 1659, 1566,
O
H
1533, 1501. 1H NMR (CDCl3, 400 MHz): δ 9.79 (s, 1H, N–CH), 8.52
CH 3
N
(s, 1H, =CH), 7.83-7.18 (m, 9H, ArH), 3.35 (s, 3H, NCH3), 3.31 (s, 3H,
Ph N
NCH3), 2.36 (s, 3H, CH3). 13C NMR (CDCl3, 100 MHz): δ 162.98,
N
O
O N
161.78, 159.84, 151.54, 148.29, 139.60, 139.09, 135.06, 129.73,
CH 3
129.68, 128.11, 127.96, 120.11, 116.17, 112.40, 28.96, 28.31, 21.47.
Elemental Analysis for C23H20N4O3, Found (Cacld.): C 68.78 (68.99),
CH3
H 4.95 (5.03), N 13.86 (13.99).
Borderless Science Publishing
76
Canadian Chemical Transactions
Year 2015 | Volume 3 | Issue 1 | Page 72-84
Ca
2.2.10
1,3-Diphenyl-5-[(1'-phenyl-3'-p-tolyl-1H-pyrazol-4'-yl)methylene)pyrimidine-2,4,6
(1H,3H,5H)-trione 10j
Light yellowish solid, mp: 283-284°C. IR (cm-1): 1735, 1664, 1561,
O
H
1531, 1498. 1H NMR (CDCl3, 400 MHz): δ 9.75 (s, 1H, N–CH), 8.70 (s,
Ph
N
1H, =CH), 7.77-7.16 (m, 19H, ArH), 2.31 (s, 3H, CH3). 13C NMR
Ph N
(CDCl3, 100 MHz): δ 163.01, 161.78, 160.27, 150.86, 149.95, 139.63,
N
O
O N
138.90, 135.59, 135.01, 134.85, 129.74, 129.70, 129.58, 129.49, 129.33,
Ph
129.13, 128.92, 128.85, 128.54, 128.25, 127.77, 120.37, 116.45, 112.07,
21.41. Elemental Analysis for C33H24N4O3, Found (Cacld.): C 75.39
CH3
(75.56), H 4.56 (4.61), N 10.59 (10.68).
2.2.11
1,3-Diphenyl-5-[(1'-phenyl-3'-p-tolyl-1H-pyrazol-4'-yl)methylene)-2-thioxodihydro
pyrimidine-4,6(1H,5H)-dione 10k
Orange solid, mp: >300°C. IR (cm-1): 1701, 1670, 1560, 1526, 1498. 1H
O
H
NMR (CDCl3, 400 MHz): δ 9.84 (s, 1H, N–CH), 8.75 (s, 1H, =CH),
Ph
N
7.84-7.25 (m, 19H, ArH), 2.35 (s, 3H, CH3). 13C NMR (CDCl3, 100
Ph N
MHz): δ 180.57, 162.01, 160.48, 160.37, 150.84, 139.91, 139.74, 138.82,
N
S
O N
135.79, 129.78, 129.71, 129.61, 129.52, 128.97, 128.93, 128.77, 128.62,
Ph
128.39, 127.65, 120.46, 116.92, 112.63, 21.41. Elemental Analysis for
C33H24N4O2S, Found (Cacld.): C 73.13 (73.31), H 4.41 (4.47), N 10.27
CH3
(10.36).
2.2.12
5-[(1'-Phenyl-3'-o-anisyl-1H-pyrazol-4'-yl)methylene]-1,3-dimethylpyrimidine-2,4,6
(1H,3H,5H)-trione 10l
Bright yellowish solid, mp: 238-239°C. IR (cm-1): 1724, 1656, 1602,
O
H
1557, 1500. 1H NMR (CDCl3, 400 MHz): δ 9.80 (s, 1H, N–CH), 8.29
CH3
N
(s, 1H, =CH), 7.82-6.98 (m, 9H, ArH), 3.73 (s, 3H, OCH3), 3.34 (s, 3H,
Ph N
OCH3), 3.28 (3H, s, OCH3). 13C NMR (CDCl3, 100 MHz): δC 162.94,
N
O
N
O
161.80, 157.77, 157.19, 151.58, 149.18, 139.17, 134.85, 132.02,
CH3
H3 CO
131.40, 129.60, 127.91, 121.18, 120.03, 119.91, 117.32, 111.80,
111.62, 55.65, 28.88, 28.27. Elemental Analysis for C23H20N4O4, Found
(Cacld.): C 66.15 (66.34), H 4.78 (4.84), N 13.34 (13.45).
2.2.13
5-[(3'-o-Anisyl-1'-phenyl-1H-pyrazol-4'-yl)methylene]-1,3-diphenylpyrimidine-2,4,6
(1H,3H,5H)-trione 10m
Yellowish solid, mp: 280-281°C. IR (cm-1): 1741, 1668, 1572, 1523,
O
H
1493. 1H NMR (CDCl3, 400 MHz): δ 9.75 (s, 1H, N–CH), 8.45 (s, 1H,
Ph
N
=CH), 7.76-6.93 (s, 19H, ArH), 3.73 (s, 3H, OCH3). 13C NMR (CDCl3,
Ph N
100 MHz): δ 162.97, 161.78, 158.23, 157.17, 150.91, 150.73, 138.98,
N
O
N
O
135.38, 135.06, 134.88, 132.00, 131.40, 129.51, 129.47, 129.32, 129.10,
Ph
H3 CO
128.91, 128.85, 128.52, 128.07, 121.14, 120.30, 119.70, 117.56, 111.62,
55.70. Elemental Analysis for C33H24N4O4, Found (Cacld.): C 73.19
(73.32), H 4.43 (4.48), N 10.21 (10.36).
Borderless Science Publishing
77
Canadian Chemical Transactions
Year 2015 | Volume 3 | Issue 1 | Page 72-84
Ca
3. RESULTS AND DISCUSSION
The synthesis of novel pyrazolylmethylene-pyrimidines 10a-m were achieved by the treatment of
diversely substituted formyl pyrazoles 8a-e with 1,3-disubstituted barbiturates 9a-c (Scheme 3).
Differently substituted formyl pyrazoles 8a-e have been prepared via three different reported strategies
[49-51] (Scheme 1). First strategy [49] involves the refluxing of phenyl hydrazine 1 and ethyl
acetoacetate 2 to give 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one 3 which upon Vilsmeier-Haack
formylation afforded 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde 8a (Scheme 1). In the
second strategy [50], hydrazine hydrate on reaction with ethyl acetoacetate 2 in absolute ethanol, results
in the formation of 3-methyl-1H-pyrazol-5(4H)-one 4. Pyrazolone 4 was then heated with ethyl
bromoacetate to give 3-methyl-1-carbethoxymethyl-1H-pyrazol-5(4H)-one 5 which on treatment with
phosphorous oxychloride and dimethyl formamide furnished 5-chloro-3-methyl-1-carbethoxymethyl-1Hpyrazole-4-carbaldehyde 8b (Scheme 1). In the third strategy [51], phenyl hydrazine 1 was treated with
various substituted acetophenones 6a-c in refluxing ethanol to yield different hydrazones 7a-c. These
hydrazones 7a-c underwent cyclization followed by formylation in the presence of phosphorus
oxychloride and dimethyl formamide to afford 1-phenyl-3-substitutedphenyl-1H-pyrazole-4carbaldehydes 8c-e (Scheme 1). All these compounds 8a-e were purified by crystallization using
dichloromethane: hexane as solvent system and characterized by melting point and 1H NMR
spectroscopy.
O
Strategy 1
PhNHNH 2 +
H3 C
1
Strategy 2
O
Ph
Ref lux
N N
OEt
O
2
NH 2NH 2.H2 O
O O
H3 C
OEt
C 2 H5 OH
CH3
3
Br
HN N
O
CH2 COOEt
O
OEt
CH3
N N
O
4
POCl3
CH 3
5
DMF
R2
N N
R3
R1
CHO
8a-e
Ph
Strategy 3
PhNHNH 2
+
1
1
O C R
CH 3
6a-c
C 2 H5 OH
Reflux
N N
H
H 3C
7a-c
R1
Strategy 1 R 1 = CH3 : R 2 = C6 H5 : R 3 = Cl;
Strategy 2 R 1 = CH3 : R 2 = CH 2COOC2 H5 : R 3 = Cl;
Strategy 3 R 1 = C 6H 5 , 4-CH 3C 6 H4 , 2-OMeC6 H4 : R 2 = C6 H5 : R 3 = H
Scheme 1. Synthesis of formyl pyrazoles 8a-e.
The second substrate 1,3-disubstituted barbituric/thiobarbituric acids 9a-c were synthesized by
the reaction of 1,3-disubstituted urea/thiourea with diethyl malonate and sodium in refluxing ethanol in
60-90% yields using reported procedure [52] (Scheme 2). The substrates 9a-c were purified by
crystallization in absolute ethanol and characterized by melting point and 1H NMR spectroscopy.
Borderless Science Publishing
78
Canadian Chemical Transactions
Year 2015 | Volume 3 | Issue 1 | Page 72-84
Ca
R4
N
H
C
O
O
X
N
H
R4
O
Na, C 2H 5OH
O
Reflux
+
R4
N
X
N
O
R
X = O, S;
R4 = CH3 , C 6H 5
O
4
9a-c
Scheme 2. Synthesis of barbituric acids 9a-c.
Finally, substrate 8 and 9 were subjected to Knoevenagel condensation to furnish novel
pyrazolylmethylene-pyrimidine derivatives 10a-m as the potential synthons for hybrid β-lactams. Initial
studies were carried out by treating the equimolar amount of formyl pyrazole 8a and 1,3-dimethyl
barbituric acid 9a in different solvents such as dichloromethane/chloroform/absolute ethanol at room
temperature but reaction fails to provide any target product. Next, we carried out the reaction in absolute
ethanol under sonication. The reaction results in the formation of target product 10a but the reaction did
not go to completion. The product was purified by crystallization and characterized using FT-IR, 1H
NMR and 13C NMR spectroscopy. Finally, the reaction was performed under optimized condition i.e. in
refluxing ethanol in the presence of 2-3 drops of glacial acetic acid (Scheme 3). This results in the
exclusive formation of the desired product 10a in high yield (Table 1, entry 1).
O
R2
N N
R3
N
R1
CHO
8a-e
+
O
N
R4
9a-c
C 2H 5OH
X
O
R3
R4
Ref lux
Glacial
acetic acid
(2-3 drops)
N
R2 N
N
R1 O
N
R4
R4
X
10a-m
Scheme 3. Synthesis of novel pyrazolylmethylene-pyrimidines 10a-m
To further explore the substrate scope and generality of the reaction, substrates 8a-e and 9a-c were
reacted with each other under similar conditions to afford the target pyrazolylmethylene-pyrimidine
heterocycles 10a-m. The reaction was found to be general with variety of substrates (Scheme 3, Table 3,
entries 2-13). The products were completely characterized on the basis of FT-IR, 1H NMR and 13C NMR
spectroscopy. The results were also corroborated by 1H-13C HSQC, elemental analysis and mass
spectrometry (in representative compound).
2D correlation spectroscopic study i.e. heteronuclear single quantum correlation (HSQC) was performed
on representative compound 10a to explain the assignment to different protons withrespect to carbon
atoms. The HSQC spectrum of 10a confirmed the assignment of CH3 (a; δ = 2.35 and 13.06 ppm), two
N–CH3 (b; δ = 3.33, 3.36 and 29.01, 29.07 ppm) and =CH (c; δ = 8.39 and 147.43 ppm) and all aromatic
protons.
Borderless Science Publishing
79
Canadian Chemical Transactions
Year 2015 | Volume 3 | Issue 1 | Page 72-84
Ca
Table 1. 1H-Pyrazolylmethylene-pyrimidines 10a-m
Sub. Sub. R1
R2
R3
R4
X
Mp
(°C)
8
9
1.
CH3
C6H5
Cl
CH3
O
174-175
8a
9a
2.
CH3
C6H5
Cl
C6H5
O
243-244
8a
9b
3.
CH3
C6H5
Cl
C6H5
S
234-235
8a
9c
4.
CH3
CH2COOEt
Cl
CH3
O
154-155
8b
9a
5.
CH3
CH2COOEt
Cl
C6H5
O
240-241
8b
9b
6.
C6H5
C6H5
H
CH3
O
247-248
8c
9a
7.
C6H5
C6H5
H
C6H5
O
286-287
8c
9b
8.
C6H5
C6H5
H
C6H5
S
>300
8c
9c
9.
4-CH3C6H4
C6H5
H
CH3
O
239-240
8d
9a
10.
4-CH3C6H4
C6H5
H
C6H5
O
283-284
8d
9b
11.
4-CH3C6H4
C6H5
H
C6H5
S
>300
8d
9c
12.
2-OCH3C6H4
C6H5
H
CH3
O
238-239
8e
9a
13.
2- OCH3C6H4
C6H5
H
C6H5
O
280-281
8e
9b
a
Yields of pure and isolated product.
b
Characterized by FT-IR, 1H NMR, 13C NMR spectroscopy, elemental analysis.
c
Also characterized by mass spectrometry.
d
Also characterized by DEPT 135 and 1H-13C HSQC.
Entry
Product
10
10ad
10b
10c
10d
10e
10fc
10g
10h
10i
10j
10k
10l
10m
Yielda,b
(%)
71
63
65
62
64
87
79
69
86
75
62
89
79
Figure 2. 1H-13C Heteronuclear Single Quantum Correlation (HSQC) of 10a
Borderless Science Publishing
80
Canadian Chemical Transactions
Year 2015 | Volume 3 | Issue 1 | Page 72-84
Ca
Literature study reveals that the Knoevenagel condensation usually occurs in the presence of a
base which abstracts a proton from active methylene group and generates a carbanion. This carbanion
further attacks the carbonyl carbon of aldehydic group and finally furnishes the target product with the
removal of water molecule. However, we performed Knoevenagel condensation reaction with our
substrate in the absence of a base. A plausible mechanism suggested that in barbituric acid, methylene
proton at C-5 is sufficiently acidic with pKa of 4.03 and hence can undergo keto-enol tautomerism [53]
easily as shown in scheme 4. Due to this, a nucleophilic centre has been generated which attacks the
carbonyl carbon of the formyl group of pyrazole 8. This leads to formation of intermediate I which
subsequently undergo dehydration to afford pyrazolylmethylene-pyrimidines 10a-m. Further, the kinetic
evidences of the Knoevenagel condensation using catalyst or without catalyst have already been
investigated [54].
O
R4
O
H
N
O
N
R4
R4
H
O
O
H
R1
O
H
N
N
N
+
N
R4
H
O
R3
9a-c
Keto-enol tautomerism
8a-e
R1
O
R4
H
N
O
N
R4
3
O R
10a-m
R2
R1
N
N
O HO H
-H 2O
R4
R2
O
N
N
R4
H 3
O R
N
N
R2
(I)
Scheme 4. Plausible mechanism for the synthesis of pyrazolylmethylene-pyrimidine derivatives.
4. CONCLUSION
A successful attempt has been made towards the synthesis of novel pyrazolylmethylenepyrimidines by combining various formyl pyrazoles with barbiturates as well thiobarbiturates. The
methodology involves the formation of carbon-carbon bond using highly simple, efficient and catalyst
free Knoevenagel condensation. The synthesized pyrazolylmethylene-pyrimidines 10a-m were
characterized using FT-IR, 1H NMR, 13C NMR, 1H-13C HSQC, elemental analysis and mass spectrometry.
Further studies on the incorporation of these pyrazolylmethylene-pyrimidine moieties in the β-lactam ring
system are ongoing in our laboratory.
ACKNOWLEDGEMENTS
We gratefully acknowledge the financial support for this work from Department of Science and
Technology (DST), New Delhi, Government of India, Project No. SR/FT/CS-037/2010 dated 28-10-2010
and University Grants Commission (UGC) vide sanction No. F.17-7(J) 2004 (SA-1) dated 03-10-2011.
SUPPLEMENTARY INFORMATION
1
H and 13C NMR spectra of pyrazolomethylene-pyrimidines 10a-m and EIMS spectra of β-lactam 10f.
Borderless Science Publishing
81
Canadian Chemical Transactions
Year 2015 | Volume 3 | Issue 1 | Page 72-84
Ca
REFERENCES AND NOTES
[1]
Mehta, G.; Singh V. Hybrid systems through natural product leads: An approach towards new molecular
entities. Chem. Soc. Rev. 2002, 31, 324-334.
[2]
Singh, P.; Kaur, M.; Holzer, W. Synthesis and evaluation of indole, pyrazole, chromone and pyrimidine
based conjugates for tumor growth inhibitory activities – Development of highly efficacious cytotoxic
agents. Eur. J. Med. Chem. 2010, 45, 4968-4982.
[3]
Ingle, V. N.; Gaidhane, P. K.; Hatzade, K. M.; Umare, V. D.; Taile, V. S. Synthesis and biological
activities of glycoconjugated spiro triones. Int. J. PharmTech Res. 2009, 1, 605-612.
[4]
Riccardis, F. D.; Izzo, I.; Filippo, M. D.; Sodano, G.; D’Acquisto, F.; Carnuccio, R. Synthesis and
cytotoxic activity of steroid-anthraquinone hybrids. Tetrahedron 1997, 53, 10871-10882.
[5]
Sharma, S. D.; Bhaduri, S. Synthesis of 2-azetidinones and other heterocycles from N-(3hydroxypropyl)imines. Indian J. Heterocycl. Chem. 2002, 11, 221-224.
[6]
Singh, P.; Kaur, M.; Verma, P. Design, synthesis and anticancer activities of hybrids of indole and
barbituric acids-Identification of highly promising leads. Bioorg. Med. Chem. Lett. 2009, 19, 3054-3058.
[7]
Kudo, N.; Furuta, S.; Taniguchi, M.; Endo, T.; Sato, K. Synthesis and herbicidal activity of 1,5diarylpyrazole derivatives. Chem. Pharm. Bull. 1999, 47, 857-868.
[8]
Kumar, V.; Kaur, K.; Gupta, G. K.; Sharma, A. K. Pyrazole containing natural products: synthetic
preview and biological significance. Eur. J. Med. Chem. 2013, 69, 735-753.
[9]
Perez-Fernandez, R.; Goya, P.; Elguero, J. A review of recent progress (2002-2012) on the biological
activities of pyrazoles. Arkivoc 2014, 2, 233-293.
[10] Brunton, L. L.; Lazo, J. S.; Keith, L. P. Goodman & Gilman’s the Pharmacological Basis of
Therapeutics, 11th Ed.; The McGraw-Hill Companies: New York, 2006.
[11] Johns, M. W. Sleep and hypnotic drugs. Drugs 1975, 9, 448-478.
[12] Whittle, S. R.; Turner, A. J. Differential effects of sedative and anticonvulsant barbiturates on specific
[3H]GABA binding to membrane preparations from rat brain cortex. Biochem. Pharmacol. 1982, 31,
2891-2895.
[13] Chen, X.; Tanaka, K.; Yoneda, F. Simple new method for the synthesis of 5-deaza-10-oxaflavin, a
potential organic oxidant. Chem. Pharm. Bull. 1990, 38, 307-311.
[14] Naquib, F. N. M.; Levesque, D. L.; Wang, E. C.; Panzica, P. P.; El Kouni, M. H. 5-Benzylbarbituric acid
derivatives, potent and specific inhibitors of uridine phosphorylase. Biochem. Pharmacol. 1993, 46, 12731278.
[15] Brunner, H.; Ittner, K. P.; Lunz, D.; Schmatloch, S.; Schmidt, T.; Zabel, M. Highly enriched mixtures of
methohexital stereoisomers by palladium-catalyzed allylation and their anaesthetic activity. Eur. J. Org.
Chem. 2003, 855-862.
[16] Grams, F.; Brandstetter, H.; D’Alo, S.; Gepperd, D.; Krell, H. W.; Leinert, H.; Livi, V.; Menta, E.; Oliva,
A.; Zimmermann, G. Pyrimidine-2,4,6-triones: a new effective and selective class of matrix
metalloproteinase inhibitors. Biol. Chem. 2001, 382, 1277-1285.
[17] Maquoi, E. N.; Sounni, E.; Devi, L.; Oliver, F.; Frankenne, F.; Krell, H. W.; Grams, F.; Foidart, J. M.;
Noel, A. Anti-invasive, antitumoral, and antiangiogenic efficacy of a pyrimidine-2,4,6-trione derivative,
an orally active and selective matrix metalloproteinases inhibitor. Clin. Cancer Res. 2004, 10, 4038-4047.
[18] Uhlmann, C.; Froscher, W. Low risk of development of substance dependence for barbiturates and
clobazam prescribed as antiepileptic drugs: results from a questionnaire study. CNS Neurosci. Ther. 2009,
15, 24-31.
[19] Laue, T.; Plagens, A. Named Organic Chemistry, John Wiley & Sons Ltd.: ISBN 0-470-01040-1
Wolfsburg, Germany.
Borderless Science Publishing
82
Canadian Chemical Transactions
Year 2015 | Volume 3 | Issue 1 | Page 72-84
Ca
[20] Kubota, Y.; Nishizaki, Y.; Sugi, Y. High catalytic activity of as-synthesized, ordered porous silicate
quaternary qmmonium composite for Knoevenagel condensation. Chem. Lett. 2000, 29, 998-999.
[21] Balalaie, S.; Sheikh-Ahmadi, M.; Bararjanian, M. Tetra-methyl ammonium hydroxide: An efficient and
versatile catalyst for the one-pot synthesis of tetrahydrobenzo[b]pyran derivatives in aqueous media.
Catal. Commun. 2007, 8, 1724-1728.
[22] Rao, P. S.; Venkataratnam, V. Zinc chloride as a new catalyst for Knoevenagel condensation.
Tetrahedron Lett. 1991, 32, 5821-5822.
[23] Prajapati, D.; Sandhu, J. S. Cadmium iodide as a new catalyst for Knoevenagel condensations. J. Chem.
Soc., Perkin Trans 1. 1993, 1, 739-740.
[24] Texier-Boullet, F.; Foucaud, A. Knoevenagel condensation catalysed by aluminium oxide. Tetrahedron
Lett. 1982, 23, 4927-4928.
[25] Dai, G.; Shi, D.; Zhou, L.; Huaxue, Y. Knoevenagel condensation catalyzed by potassium
fluoride/alumina. Chin. J. Appl. Chem. 1995, 12, 104-108.
[26] Kumbhare, R. M.; Sridhar, M. Magnesium fluoride catalyzed Knoevenagel reaction: An efficient
synthesis of electrophilic alkenes. Catal. Commun. 2008, 9, 403-405.
[27] Simpson, J.; Rathbone, D. L.; Billington, D. C. New solid phase Knoevenagel catalyst. Tetrahedron Lett.
1999, 40, 7031-7033.
[28] Bennazha, J.; Zahouily, M.; Sebti, S.; Boukhari, A.; Holt, E. M. Na2CaP2O7, a new catalyst for
Knoevenagel reaction. Catal. Commun. 2001, 2, 101-104.
[29] Reddy, T. I.; Varma, R. S. Rare-earth (RE) exchanged NaY zeolite promoted knoevenagel condensation.
Tetrahedron Lett. 1997, 38, 1721-1724.
[30] Ernst, S.; Bongers, T.; Casel, C.; Munsch, S. Cesium-modified mesoporous molecular sieves as basic
catalysts for Knoevenagel condensations. Stud. Surf. Sci. Catal. 1999, 125, 367-374.
[31] Bhalla, A.; Sharma, S.; Bhasin, K. K.; Bari, S. S. Convenient preparation of benzylseleno and
phenylselenoalkanoic acids: reagents for synthesis of organoselenium compounds. Synth. Commun. 2007,
37, 783-793.
[32] Bhalla, A.; Nagpal, Y.; Kumar, R.; Mehta, S. K.; Bhasin, K. K.; Bari, S. S. Synthesis and characterization
of novel pyridyl/naphthyl/(diphenyl)methylseleno substituted alkanoic acids: X-ray structure of 2pyridylselenoethanoic acid, 2-naphthylselenoethanoic acid and 2-(diphenyl)methylselenoethanoic acid. J.
Organomet. Chem. 2009, 694, 179-189.
[33] Bhalla, A.; Madan, S.; Venugopalan, P.; Bari, S. S. C-3 β-Lactam carbocation equivalents: versatile
synthons for C-3 substituted β-lactams. Tetrahedron 2006, 62, 5054-5063.
[34] Bhalla, A.; Rathee, S.; Madan, S.; Venugopalan, P.; Bari, S. S. Lewis acid mediated functionalization of
β-lactams: mechanistic study and synthesis of C-3 unsymmetrically disubstituted azetidin-2-ones.
Tetrahedron Lett. 2006, 47, 5255-5259.
[35] Bhalla, A.; Venugopalan, P.; Bhasin, K. K.; Bari, S. S. Seleno-β-lactams: synthesis of monocyclic and
spirocyclic selenoazetidin-2-ones Tetrahedron 2007, 63, 3195-3204.
[36] Bari, S. S.; Reshma; Bhalla, A.; Hundal, G. Stereoselective synthesis and Lewis acid mediated
functionalization of novel 3-methylthio-β-lactams. Tetrahedron 2009, 65, 10060-10068.
[37] Bari, S. S.; Bhalla, A.; Nagpal, Y.; Mehta, S. K.; Bhasin, K. K. Synthesis and characterization of novel
trans-3-benzyl/(diphenyl)methyl/naphthyl seleno substituted monocyclic β-lactams: X-ray structure of
trans-1-(4'-methoxyphenyl)-3-(diphenyl)methylseleno-4-(4'-methoxyphenyl)azetidin-2-one.
J.
Organomet. Chem. 2010, 695, 1979-1985.
[38] Bhalla, A.; Bari, S. S.; Vats, S.; Sharma, M. L. Facile and stereoselective synthesis of novel trans-3monosubstituted-3-benzylseleno-β-lactams. Res. J. Chem. Sci. 2012, 2, 59-64.
Borderless Science Publishing
83
Canadian Chemical Transactions
Year 2015 | Volume 3 | Issue 1 | Page 72-84
Ca
[39] Bari, S. S.; Bhalla, A.; Venugopalan, P.; Hundal, Q. Facile synthesis of novel C-3 monosubstituted 3phenylthio-β-lactams. Res. J. Chem. Sci. 2013, 3, 45-53.
[40] Bhalla, A.; Venugopalan, P.; Bari, S. S. Facile stereoselective synthesis of cis- and trans-3alkoxyazetidin-2-ones. Tetrahedron 2006, 62, 8291-8302.
[41] Bhalla, A.; Venugopalan, P.; Bari, S. S. A new synthetic approach to novel spiro-β-lactams. Eur. J. Org.
Chem. 2006, 4943-4950.
[42] Bari, S. S.; Bhalla, A. Spirocyclic-β-lactams: synthesis and biological evaluation of novel heterocycles. In
Topic in Heterocyclic Chemistry; Banik, B., Ed.; Springer: Berlin, Germany, 2010; p 49-99.
[43] Bari, S. S.; Arora, R.; Bhalla, A.; Venugopalan, P. Facile synthesis of (Z)- and (E)-3-allylidene-β-lactams
via thermal β-elimination of trans-3-allyl-3-sulfinyl-β-lactams. Tetrahedron Lett. 2010, 51, 1719-1722.
[44] Bari, S. S.; Magtoof, M. S.; Bhalla, A. Facile radical mediated synthesis of azetidin-2,3-diones: potential
synthons for biologically active compounds. Montash Chem. 2010, 141, 987-991.
[45] Bari, S. S.; Bhalla, A.; Reshma; Hundal, G. Facile synthesis of novel bicyclic β-lactams: analogues of Cfused penicillin type ring systems. Tetrahedron Lett. 2013, 54, 483-486.
[46] Singh, I.; Kaur, H.; Kumar, S.; Kumar, A.; Lata, S.; Kumar, A. Synthesis of new coumarin derivatives as
antibacterial agents. Int. J. ChemTech Res. 2010, 2(3), 1745-1752.
[47] Muralikrishna, S.; Raveendrareddy, P.; Ravindranath, L. K.; Harikrishna, S.; Raju, P. A. G. Synthesis
characterization and anti-inflammatory activity of indole derivatives bearing-4-oxazetidinone.
Chemical and Pharm. Res. 2013, 5(10), 280-288.
J.
[48] Raj, R.; Singh, P.; Haberkern, N. T.; Faucher, R. M.; Patel, N.; Land, K. M.; Kumar, V. Synthesis of 1H1,2,3-triazole linked β-lactam-isatin bi-functional hybrids and preliminary analysis of in vitro activity
against the protozoal parasite Trichomonas vaginalis. Eur. J. Med. Chem. 2013, 63, 897-906.
[49] Xu, C. -J.; Shi, Y. -Q. Synthesis and Crystal Structure of 5-Chloro-3-Methyl-1-Phenyl-1H-Pyrazole-4Carbaldehyde. J. Chem. Crystallogr. 2011, 41, 1816-1819.
[50] Wang, Z.; Ren, J.; Li, Z. A novel method for the synthesis of pyrazolo[5,1-b]thiazole. Synth. Commun.
2000, 30, 763-769.
[51] Parmar, K.; Sutaria, S.; Goswami, K.; Dabhi, Y. Synthesis of substituted 2-Azetidinones based on 1-Nphenyl-3-phenyl-4-formyl pyrazole (PFP). Der Chemica Sinica 2012, 3, 1153-1156.
[52] Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel's Textbook of Practical Organic
Chemistry, 5th Edn.; Longmann Group & Wiley & Sons: New York, 1989; p 1176.
[53] Mahmudov, K. T.; Kopylovich, M. N.; Maharramov, A. M.; Kurbanova, M. M.; Gurbanov, A. V.;
Pombeiro, A. J. L. Barbituric acids as a useful tool for the construction of coordination and
supramolecular compounds. Coord. Chem. Rev. 2014, 265, 1-37.
[54] Bednarz, S.; Bogdal, D. Kinetic study of the condensation of salicylaldehyde with diethyl malonate in a
nonpolar solvent catalyzed by secondary amines. Int. J. Chem. Kinet. 2009, 41, 589-598.
The authors declare no conflict of interest
© 2015 By the Authors; Licensee Borderless Science Publishing, Canada. This is an open access article distributed under
the terms and conditions of the Creative Commons Attribution license http://creativecommons.org/licenses/by/3.0
Borderless Science Publishing
84