Synthesis of 3-(1, 3-diphenyl-1H-pyrazol-4-yl) propanoic acids using diimide reduction

Article abstract of DOI:10.1155/2012/481682

Pyrazole-1H-4-yl-acrylic acids (3a-j) were prepared from pyrazole-1H-4-carbaldehydes which in turn were prepared by the Vilsmeier-Haack reaction of phenyl hydrazone derivatives (1a-j). The reaction of pyrazole-1H- 4-yl-acrylic acids to 3-(1, 3-diphenyl-1H

Full text of DOI:10.1155/2012/481682

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2012, 9(1), 420-424
http://www.e-journals.net
Synthesis of 3-(1, 3-Diphenyl-1H-pyrazol-4-yl)
Propanoic Acids Using Diimide Reduction
M. DEEPA, V. HARINADHA BABU,
R. PARAMESHWAR and B. MADHAVA REDDY
Department of Pharmaceutical Chemistry
G. Pulla reddy College of Pharmacy, Mehdipatnam, Hyderabad-500028, India
parmi_pharma@yahoo.com
Received 2 July 2011; Accepted 27 August 2011
Abstract: Pyrazole-1H-4-yl-acrylic acids (3a-j) were prepared from pyrazole-
1H-4-carbaldehydes which in turn were prepared by the Vilsmeier-Haack
reaction of phenyl hydrazone derivatives (1a-j). The reaction of pyrazole-1H-
4-yl-acrylic acids to 3-(1, 3-diphenyl-1H-pyrazol-4-yl) propanoic acids (4a-j)
was carried out using Pd-charcoal and diimide methods and % yields were
compared. Though the yields may be slightly less in diimide method, the
method was found to be economical, highly effective with simple operating
procedure.
Keywords: Pyrazole acrylic acids, Pyrazole propanoic acids, Diimide method
Introduction
In the last few years, considerable attention has been focused on pyrazole derivatives due
to their interesting biological activities such analgesic1,antipyretic2, antiinflammatory3,4
antimicrobial5, antiviral6,7, antidiabetic8, anticancer9,10, estrogenic11 etc. In continuation of
our work on pyrazole derivatives, in the present study, an attempt has been made to
synthesize some novel pyrazole propanoic acid derivatives (4a-j) as per Scheme 1 with high
purity and in reasonable yields. We predict that these pyrazole propanoic acids may be
useful bioactive compounds in view of their individual biological nature.
Experimental
Melting points were determined in open capillary tubes using Analab melting point
apparatus and are uncorrected. Purity of the compounds was verified by a single spot in TLC
using E- Merck silica Gel F254, 0.25 mm aluminum plates. Visualization was accomplished
with UV light (254 nm) and iodine chamber. The IR spectra were recorded on Schimadzu
FT-IR Spectrophotometer by using 1% potassium bromide discs.

Synthesis of 3-(1, 3-Diphenyl-1H-pyrazol-4-yl) Propanoic Acids
421
CH3
CH3
NH
O
NH
NH2
N
CH3OH
+
Reflux 1-2 hr
R
(1a-j)
R'
R
R'
DMF,POCl3
Reflux 4-5 hr
COOH
R
R
CHO
Malonic acid,Pyridine
Reflux 4-5 hr
N
N
N
N
(3a-j)
R'
R'
(2a-j)
Diimide/Pd-Charcoal
4f=R=4-CH3,R'=2-CH3
4g=R=4-CH3,R'=4-CH3
4h=R=4-OCH3,R'=2-Cl
4i=R=4-CH3,R'=4-Cl
4a=R=H,R'=H
COOH
4b=R=H,R'=2-CH3
4c=R=H,R'=4-CH3
4d=R=H,R'=2-Cl
4e=R=2-Cl,R'=4-Cl
R
N
N
4j=R=4-OCH3,R'=2-CH3
R'
(4a-j)
Scheme 1. Synthesis of pyrazole propanoic acid derivatives
Mass spectra of the compounds were recorded on mass spectrometer (Agilent 1100
1
series; EI/ESI-MS). All the H NMR spectra were recorded on Brucker 300 MHz
Spectrometer using CDCl3/DMSO as solvent and tetramethylsilane as an internal Standard.
Chemical shift values are listed in δ scale. Elemental analyses were carried out on a Carlo
Erba 106 and Perkin Elmer model 240 analyzers.
Results and Discussion
Substituted phenyl hydrazones were prepared by heating substituted acetophenones with
different hydrazines in methanol under reflux for 1-2 h. Vilsmeier-Haack reaction12 of
phenyl hydrazones using DMF and POCl3 afforded pyrazole-4-carbaldehydes in good yields
1
and in high purity. The structures were confirmed on the basis of IR, H NMR and mass
spectral data. The aldehydes were converted into 3-(1, 3-diphenyl-1H- pyrazol-4-yl) acrylic
acids (3a-j) by heating with malonic acid in pyridine and in the presence of catalytic
amounts of piperidine in good yields (about 80%).Usually, the reduction of double bond in
α,β-unsaturated acids is carried out using catalysts like Pd-charcoal, platinum, nickel,
rhodium, nickel borohydride etc, which are highly expensive and in some cases disposal is

422
R. PARAMESHWAR et al.
the major problem. In the present study, the percentage yields of resulting 3-(1, 3-diphenyl-
1H-pyrazol-4-yl) propanoic acids (4a-j) obtained in both the methods are compared and the
physical data including % yields are reported in Table 1.
Table 1. Physical data of 3-(1, 3-diphenyl-1H-pyrazol-4-yl) propanoic acids (4a-j)
Compd
4a
R
H
R1
m.p 0C % Yield diimide method % Yield Pd-charcoal
H
100
99
68
66
65
67
64
69
64
65
68
66
79
78
77
72
76
75
79
78
74
75
H
2 CH3
4 CH3
2-C
4b
4c
H
98
98
H
2-CI
4-CH3 2 CH3
4-CH3 4 CH3
4d
4e
4f
4g
4-C
97
102
100
98
4-CH3
4-CH3
2-C
4-C
4h
4i
99
101
4-OCH3 2 CH3
4j
General procedure13
1, 3-Diphenyl-1H-pyrazole-4-carbaldehyde (2a-j)
To a mixture of DMF (0.1 mole) and phosphorous oxychloride (0.02 mole), ice-cold
solution of phenyl hydrazone (0.01 mole) was added drop wise with stirring under ice-cold
0
conditions. After the addition, the reaction mixture was refluxed and stirred at 60-70 C for
4-5 h. Solution was cooled and poured into crushed ice and neutralized with NaHCO3
solution. The solid obtained was filtered under suction and recrystallised from methanol.
3-(1, 3-Diphenyl-1H-pyrazol-4yl) acrylic acid (3a-j)
Pyrazole-4-carbaldehyde (0.01 mole) was dissolved in pyridine (10 mL) containing
(0.05 mole) malonic acid and a catalytic amount of piperidine (0.5 mL) and the reaction
0
mixture was refluxed for 4-5 h on a water bath at 95-100 C. The resulting solution was
poured into crushed ice with stirring and acidified with conc. HCl to remove any traces of
pyridine. The resultant precipitate was filtered, washed with water and dilute HCl, dried and
recrystallized from glacial acetic acid or any appropriate solvent.
3-(1, 3-Diphenyl-1H-pyrazole-4-yl) propanoic acid (4a-j): Diimide method
3-(1,3-Diphenyl-1H–pyrazole-4-yl)acrylic acid (0.01 mole) was dissolved in hydrazine
hydrate (99%, 6 mL) in a 250 mL conical flask and to the clear solution 20 mL of water was
added. The flask was immersed in an ice bath and to which added few crystals of CuSO4
with stirring. To the cold solution, 10 mL of hydrogen peroxide (30%) was added slowly
0
such that the temperature remains below 30 C. After the addition was completed, the
reaction mixture was allowed to stand in ice bath for 30 min followed by 10 min at room
temperature. To the above mixture, a few mL of concentrated HCl was added with stirring.
An oily product was separated which on cooling gave crystalline compound.
Palladium-charcoal method
To a solution of 3–(1, 3-diphenyl-1H-pyrazole-4-yl) acrylic acids (0.01 mole, 2.99 g) in
ethyl acetate (30 mL), 20% palladium–charcoal (0.1 mole), ammonium formate (0.2 mole)
in ethyl acetate (30 mL) was added with stirring. The reaction mixture was stirred for
overnight and the excess ethyl acetate was distilled off under reduced pressure. The
precipitate was filtered, dried and recrystallized from appropriate solvent.

Synthesis of 3-(1, 3-Diphenyl-1H-pyrazol-4-yl) Propanoic Acids
423
4a:White solid: IR(KBr)cm-1: 3438(O-H), 3013(C-H of aromatic ring),1708(C=O of
COOH), 1596(C=N); 1H NMR(CDCl3+DMSO-d6): δ 12.06(OH, s,1H, D2O exchangeable), 7.52-
7.59 (Ar-H,m, 11H), 2.71(CH2CH2COOH, t, 2H), 2.48(CH2CH2COOH, t, 2H); MS: m/z 293
(M+1); Anal.Calcd for C18H16N2O2: C,73.95; H, 5.52; N, 9.58. Found: C, 73.97; H, 5.49; N, 9.61%.
4b: White solid: IR (KBr)cm-1: 3415(O-H), 3016(C-H of aromatic ring), 1712(C=O of
1
COOH), 1628(C=N); H NMR(CDCl3+DMSO-d6): δ12.09(OH, s,1H, D2O exchangeable),
7.52-7.59(Ar-H, m,10H), 3.14(CH3, s,3H), 2.69(CH2CH2COOH, t, 2H), 2.46
(CH2CH2COOH, t, 2H); MS: m/z 307 (M+1); Anal. Calcd for C19H18N2O2: C, 74.49; H,
5.92; N, 9.14. Found: C, 74.51; H, 5.87; N, 9.16 %.
4c: White solid: IR (KBr)cm-1: 3434(O-H), 3012(C-H of aromatic ring), 2927(C-H of CH3),
1
1718(C=O of COOH), 1627(C=N); H NMR(CDCl3+DMSO-d6): δ12.01(OH, s, 1H, D2O
exchangeable), 7.52-7.59 (Ar-H, m, 10H), 3.14(CH3, s, 3H), 2.68(CH2CH2COOH, t, 2H),
2.42(CH2 CH2COOH, t, 2H); MS: m/z 307(M+1); Anal.Calcd for C19H18N2O2: C, 74.49; H,
5.92; N, 9.14. Found :C, 74.52; H, 5.86; N, 9.18 %.
4d: Pale yellow solid: IR(KBr)cm-1: 3438(O-H), 3011(C-H of aromatic ring), 1706(C=O of
1
COOH), 1612(C=N), 754(C-Cl); H NMR(CDCl3+DMSO-d6): δ12.16(OH, s,1H,D2O exchang-
eable) ,7.15-7.67(Ar-H,m,10H), 2.62(CH2CH2COOH, t ,2H), 2.44(CH2CH2COOH, t, 2H); MS :m/z
327(M+1); Anal.Calcd for C18H15ClN2O2: C, 66.16; H, 4.63; N, 8.57. Found : C, 66.19; H,
4.59;N,8.60%.
4e: Pale yellow solid: IR(KBr)cm-1: 3408(O-H), 3013(C-H of aromatic ring ), 1708(C=O of COOH),
1620(C=N), 756(C-Cl); 1HNMR(CDCl3+DMSO-d6): δ12.18(OH, s, 1H, D2O exchangeable), 7.15-
7.67(Ar-H, m, 9H), 2.58(CH2CH2COOH, t, 2H), 2.41(CH2CH2COOH, t, 2H); MS: m/z 362(M+1);
Anal.Calcd for C18H14Cl2N2O2: C, 59.85; H, 3.91; N, 7.76. Found: C, 59.88; H, 3.88; N, 7.78.%.
4f: White solid:IR(KBr)cm-1: 3418(O-H),3018 (C-H of aromatic ring), 1710(C=O of
1
COOH), 1623(C=N); HNMR(CDCl3+DMSO-d6): δ12.09(OH, s,1H,D2O exchangeable),
7.57-7.59(Ar-H, m, 9H), 3.24(CH3, s, 3H), 3.19(CH3, s,3H), 2.71(CH2CH2COOH, t, 2H),
2.42(CH2CH2COOH, t, 2H); MS: m/z 321(M+1); Anal.Calcd for C20H20N2O2: C, 74.98; H,
6. 29; N, 8.74. Found: C, 75.02; H, 6.25; N, 8.76 %.
4g: White solid: IR(KBr)cm-1: 3405(O-H), 3016(C-H of aromatic ring), 2857(C-H of CH3),
1
1708(C=O of COOH), 1617(C=N); HNMR (CDCl3+DMSO- d6): δ 12.14 (OH, s,1H, D2O
exchangeable), 7.45-7.98(Ar-H, m, 9H), 3.22(CH3, s, 3H), 3.18(CH3, s, 3H), 2.63(CH2
CH2COOH, t, 2H) 2.39(CH2CH2COOH, t, 2H); MS: m/z 321(M+1); Anal.Calcd for C20H20
N2O2: C, 74.98; H, 6.29; N, 8.74.Found : C, 75.03; H, 6.26; N, 8.77 %.
4h: White solid: IR (KBr)cm-1: 3423(O-H), 3014(C-H of aromatic ring), 2930(C-H of CH3),
1
1710 (C=O of COOH),1623(C=N); HNMR (CDCl3+DMSO-d6): δ12.06(OH, s, 1H,D2O
exchangeable), 7.52-7.59(Ar-H, m, 9H), 3.08(OCH3, s, 3H), 2.64(CH2CH2COOH, t, 2H),
2.38(CH2CH2COOH, t, 2H); MS: m/z 358(M+1); Anal.Calcd for C19H17ClN2O3: C, 63. 96;
H, 4.80; N, 7.85. Found : C, 63.98; H, 4.78; N, 7.88%.
4i: White solid: IR (KBr)cm-1: 3426(O-H), 3012(C-H of aromatic ring), 2932(C-H of CH3),
1
1718 (C=O of COOH), 1619(C=N), 752(C-Cl); HNMR (CDCl3+DMSO- d6): δ12.12 (OH,
s,1H,D2O exchangeable), 7.48-7.58(Ar-H, m, 9H), 3.04(CH3, s,3H), 2.69 (CH2CH2 COOH,
t, 2H), 2.42(CH2CH2COOH, t, 2H); MS: m/z 342(M+1); Anal.Calcd for C19H17ClN2 O2: C,
66.96; H, 5.03; N, 8.22. Found : C, 66.98; H, 5.00; N, 8.26%.
4j: White solid: IR (KBr)cm-1: 3405(O-H), 3014 (C-H of aromatic ring), 2815(C-H of
CH3),1708(C=O of COOH),1617(C=N);1HNMR(CDCl3+DMSO- d6 ); δ12.11(OH, s,1H,

424
R. PARAMESHWAR et al.
D2O exchangeable),7.45-7.98 (Ar-H, m,9H), 3.15(OCH3, s,3H), 3.04(CH3, s,3H), 2.63
(CH2CH2COOH, t, 2H),2.40(CH2CH2COOH); MS : m/z 337(M+1);Anal.Calcd for C20H20N2
O3 :C,71.41;H,5.99;N,8.33.Found : C,71.43;H,5.97;N,8.36%.
Conclusion
The reduction of pyrazole acrylic acids to pyrazole propanoic acids using diimide method
was found to have some advantages over palladium-charcoal method. The advantages are
operational simplicity, reasonable yields, economical and easy work-up.
Acknowledgment
The authors are thankful to the management of G. Pulla Reddy College of Pharmacy,
Hyderabad for providing facilities. The authors are also grateful to Director, IICT,
Hyderabad and NACTO Pharma Limited, Hyderabad for providing spectral data.
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