Efficient ecofriendly synthesis of pyrazole acryloyl analogs by amino acid catalysis

Article abstract of DOI:10.1080/00397911.2016.1164863

An easy and effective green approach of Knoevenagel condensation and arylidene formation with the substrates involves pyrazole-3-carbaldehydes and active methylenes under catalytic action of glycine (the simplest amino acid) in dimethylsulfoxide. These re

Full text of DOI:10.1080/00397911.2016.1164863

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
An Efficient Eco-Friendly Synthesis of Pyrazole
Acryloyl Analogues by Amino Acid Catalysis
Faryal Chaudhry, Nadia Asif, Syed Salman Shafqat, Amir Azam Khan,
Munawar Ali Munawar & Misbahul Ain Khan
To cite this article: Faryal Chaudhry, Nadia Asif, Syed Salman Shafqat, Amir Azam Khan,
Munawar Ali Munawar & Misbahul Ain Khan (2016): An Efficient Eco-Friendly Synthesis
of Pyrazole Acryloyl Analogues by Amino Acid Catalysis, Synthetic Communications, DOI:
10.1080/00397911.2016.1164863
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1164863
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Date: 22 March 2016, At: 22:47

AN EFFICIENT ECO-FRIENDLY SYNTHESIS OF PYRAZOLE ACRYLOYL
ANALOGUES BY AMINO ACID CATALYSIS
Faryal Chaudhry1,4, Nadia Asif1, Syed Salman Shafqat3, Amir Azam Khan3, Munawar
Ali Munawar1,, Misbahul Ain Khan1,2
1Institute of Chemistry, University of the Punjab, Lahore, Pakistan,
2Department of Chemistry, the Islamia University of Bahawalpur, Bahawalpur, Pakistan,
3Department of Mechanical and Manufacturing Engineering, Faculty of Engineering,
Universiti Malaysia Sarawak, Sarawak, Malaysia,
4Department of Chemistry, Kinnaird College for Women, Lahore, Pakistan
Address correspondence to Munawar Ali Munawar, Institute of Chemistry, University of
the Punjab, Lahore 54590, Pakistan. E-mail: mamunawar.chem@pu.edu.pk
Abstract
An easy and effective green approach of Knoevenagel condensation and arylidene
formation with the substrates; pyrazole-3-carbaldehydes and active methylenes under
catalytic action of glycine (the simplest amino acid) in DMSO. These reactions were
successfully carried out at room temperature.
KEYWORDS: Active methylenes; Arylidenes; Glycine; Knoevenagel condensation;
Pyrazole-3-carbaldehyde
1

INTRODUCTION
One of the acknowledged pathways to develop a new C-C bond through exploitation of
an aldehydic or ketonic functionality and an active methylene group is Knoevenagel
condensation. Traditionally, these reactions were carried out in organic solvents with
basic catalysts and sometimes under acidic conditions also.[1,2] In recent times, various
modern homogeneous and heterogeneous catalysts have also been introduced for this
purpose, such as guanidine,[3] sodium benzoate,[4] I2-K2CO3,[5] ZnCl2,[6] phosphane,[7]
borate zirconia,[8] different ionic liquids,[9] Al2O3,[10] silica supported catalysts,[11]
zeolites,[12] calcite and fluorite.[13] But even though, expensive reagents, harmful reaction
conditions, undesired side products, tedious workups, prolonged reaction times and poor
yields are still existed limitations of these methodologies. To deal with these tangible
obstacles, more efficient yet facile reaction conditions are being sought.
Although some amino acids were used for condensation reactions [14-16] and there are
reports of green Knoevenagel reaction protocols,[17] to the best of our knowledge; this
amino acid catalysis was not explored to synthesize pyrazolyl acryloyl analogues or for
the condensation of arylaldehydes with pyrazolones. We had earlier explored this
possibility in some limited reactions.[18] With the benefit of foresight, we aimed to extend
this catalytic potentials of amino acids for synthesizing targeted molecules 3(a-r). The
present communication deals with the comparative studies of amino acids where glycine
found as the most influential catalyst.
2

RESULTS AND DISCUSSION
To evaluate the efficacy of easily accessible amino acids for condensations, Scheme 1
was designed to monitor their catalytic effect. Malonic acid, methyl or ethyl cyanoacetate
and a pyrazolone were used as active methylenes along with aryl/hetarylpyrazole
aldehydes. DMSO was used as a solvent to avoid any solubility problems. The reactions
were carried out at room temperature and glycine was the preferred amino acid catalyst.
The stirring of reaction mixture at room temperature afforded the required products 3(a-
r) within 3-15 hours, the catalytic effect of glycine augmenting the product yield. This
eco-friendly reaction conditions were employed throughout this project.
For the syntheses of precursors 1(a-f), previously reported procedures were followed.[19]
A typical synthetic pathway of cinnamic acids has involved condensation of aldehdyes
with malonic acids. It is to be noted that the usual Knoevenagel condensations with
malonic acid 2a produced often accompanied with decarboxylation and lead to acrylic
acids.[20] We had earlier reported that performing this reaction with pyridine/piperidine
with ethanol as a solvent prevented decarboxylation.[21] Here again mild reaction
conditions helped in retaining both carboxyl groups successfully in compounds 3(a-f) and
no decarboxylation was observed. Among all the absorption bands in IR spectrum, the
most convincing were of two carbonyl absorption bands which was the first indication of
the existence of dicarboxyl groups. Perhaps, one of the carbonyl group is involved in
strong intramolecular hydrogen bonding, hence appeared at low frequency. Some of the
derivatives were insoluble in common NMR solvents however MS results confirmed
their formation.
3

With methyl or ethyl cyanoacetate 2(b,c), the products 3(g-l) were isolated. As far as
stereochemical aspects are concerned, only a single isomer was obtained in all these
cases. Keeping in view the least steric hindrance, presumably, the trans configuration
was the most stable one in which smaller cyano group is on the same side to pyrazole
nucleus. In the IR spectrum the carbonyl stretching band of ester group above 1700 cm-1
and 1H NMR signals along with MS molecular ion peaks verified the targeted molecules.
The miscellaneous Knoevenagel reactions involved a pyrazolone 2d as a condensation
partner. Different arylidenes 3(m-r) were prepared and confirmed by the physical and
spectroscopic analyses. The details are given in the Table 1.
The model precursors; compound 1a and malonic acid were used for the initial studies.
The comparative studies (Table 2) were furnished between percentage yields of the
product 3a which indicated the catalytic efficiency of each amino acid (20 mol%). It
seemed that the bifunctional (basic and acidic) nature of amino acid has facilitated this
condensation reaction.
The pH is found to be the critical controlling factor of this reaction as also documented in
condensation reaction of furfural and malonic acid by using glycine as a catalyst.[22] In all
cases, good to excellent yields were obtained whereas nearly no condensation occured in
the absence of an amino acid. The basic amino acids (lysine and histidine) have resulted
in good yields however with an acidic glutamic acid, the product was obtained in 48%
4

yield. Surprisingly, the best results were achieved with glycine. Possibly due to smaller
size, glycine could easily participate in reaction mechanism. Therefore, glycine was used
as a catalyst of choice for the remaining reactions. Similarly, to see the effects of
different solvents, this model reaction was also carried out at room temperature in
different solvents (Table 3).
Among these, DMSO stands out as the best solvent and gave excellent yields. To
optimize the catalyst quantity, different catalytic amounts (10, 20 and 30 mol%) of
glycine were also used. 20 and 30 mol% of glycine gave the best result (Table 4).
Consequently, the optimium condition was equivalent amounts of substrates in DMSO,
add 20 mol% of glycine and stir at room temperature for the required timings.
Two general mechanistic pathways; Path A (Scheme 2) and Path B (Scheme 3) are
possible. Path A first involves the generation of carbanion from an active methylene by
glycine.
Whereas in Path B, with glycine and aldehyde, first of all an iminium ion is formed
which afterwards reacts with malonic acid.
CONCLUSION
The amino acid glycine was successfully employed as a progressive catalyst for the
Knoevenagel condensation of pyrazole-4-carbaldehydes 1(a-f) with active methylenes
and pyrazolone to give pyrazole acryloyl analogues 3(a-r) efficiently. These valuable
5

green reactions resulted in excellent yields of products in DMSO solvent at room
temperature.
EXPERIMENTAL
Some reagents and chemicals were purchased from the Sigma-Aldrich, Merck and used
without purification. The TLC was performed over DC-Alufolien Silica Gel 60 F254
Merck to monitor the reaction progress. The melting points were uncorrected. Agilent
Technologies Cary 630 FTIR was used for taking FTIR spectra. The 1H NMR spectra
were recorded on Bruker DPX-400 MHz Spectrometer in CDCl3. The MAT312 or JEOL
MS Route was used for MS spectra. The elemental analyses were determined on Perkin-
Elmer 2400 Series II CHN/S Analyzer.
General Procedure For The Synthesis Of Products 3(A-R)
To a mixture of an aldehyde 1(a-f) (2.0 mmol) and an active methylene 2(a-d) (2.0
mmol) dissolved in 5 mL of DMSO, 0.022 g of glycine (0.40 mmol, 20 mol%, 0.20
equiv) was added. The stirring was continued at room temperature for 3-15 hrs and then
quenched with ice water to obtain neat precipitates of pyrazole acryloyl compound 3(a-r)
which were further purified by recrystallization with ethanol.
(E)-Methyl 2-(Cyanocarbonyl)-3-(1,3-Diphenyl-1H-Pyrazol-4-Yl)Acrylate (3g)
From 1a (0.50 g), 3g was obtained as a white solid; mp 136-138 ºC; Yield: 0.54 g; 82%;
IR (νmax-cm-1; neat): 3143-2952 (C-H), 2215 (C≡N), 1726 (C=O), 1605 (C=N), 1591
(C=C); 1H NMR (CDCl3, 400 MHz), δ: 3.88 (s, 1H; -OCH3), 7.39 (t, 1H, J = 8.0 Hz; Ar-
6

1H), 7.48-7.53 (m, 5H; Ar-2H & Ar1-3H), 7.60 (dd, 2H, J = 8.0, 1.2 Hz; Ar1-2H), 7.82
(d, 2H, J = 8.0 Hz; Ar-2H), 8.29 (s, 1H; =CH), 9.13 (s, 1H; H-5 Pyr); MS (EI+): m/z (%)
329.0 (M+, 20.7); Anal. Calcd. For C20H15N3O2: C, 72.94; H, 4.59; N, 12.76%. Found: C,
73.03; H, 4.65; N, 12.84%.
FUNDING
The authors are highly obliged to the Higher Education Commission of Pakistan for
providing financial support.
SUPPLEMENTAL MATERIAL
The experimental details, characterization data and spectral data for this article can be
accessed on the publisher’s website.
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9

Table 1. Glycine catalysed Knoevenagel condensation for the synthesis of pyrazole
acryloyl derivatives 3(a-r) in DMSO at room temperature
Entry Carbaldehyde
Active
Product
Time
(h)
3
Yield
(%)
93
Methylene
1
2a
2a
2
4
84
3
4
3
86
82
2a
2a
3.5
5
4.5
81
2a
10

6
3.5
79
2a
7
8
5.5
89
84
2b
2b
6
9
5
91
89
2b
2b
10
4.5
11

11
12
6
5
84
81
2c
2b
13
14
12
13
85
78
2d
2d
15
16
11.5
87
84
2d
2d
12
12

17
18
15
14
74
78
2d
2d
13

Table 2. Preliminary screening of different amino acids as catalysts
Entry
Catalyst
Yield (%)
1
Without Catalyst
Glycine
11
93
48
70
83
63
72
69
66
68
85
2
3
Glutamic Acid
Asparagine
Lysine
4
5
6
Leucine
7
Tyrosine
8
Tryptophan
Methionine
Valine
9
10
11
Histidine
14

Table 3. Knoevenagel condensation of 1a and malonic acid with 20 mol% of glycine in
different solvents
Entry Solvent
Yield (%)
1
2
3
4
5
6
7
THF
29
35
56
22
72
93
34
CH2Cl2
CH3CN
H2O
DMF
DMSO
Solvent-free
15

Table 4. Knoevenagel condensation of 1a and malonic acid in DMSO with different
catalytic amounts (mol%) of glycine
Entry Glycine (mol%) Yield (%)
1
2
3
10
20
30
72
93
91
16

Scheme 1. Synthesis of pyrazole acryloyl analogues 3(a-r).
17

Scheme 2. Plausible Path A for the synthesis of 2-((1,3-diphenyl-1H-pyrazol-4-
yl)methylene)malonic acid 3a.
18

Scheme 3. Plausible Path B for the synthesis of 2-((1,3-diphenyl-1H-pyrazol-4-
yl)methylene)malonic acid 3a.
19