Four-component reaction between trimethyl phosphite, aroyl chlorides and dialkyl acetylenedicarboxylate with benzoic acid hydrazide

Article abstract of DOI:10.3184/174751911X13148978312160

A four-component and one-pot reaction between trimethyl phosphite, a dialkyl acetylene dicarboxylate and an aroyl chloride with benzoic acid hydrazide is described as a simple and efficient route for the synthesis of functionalised pyrazoles in good yields.

Full text of DOI:10.3184/174751911X13148978312160

516 RESEARCH PAPER
SEPTEMBER, 516–518
JOURNAL OF CHEMICAL RESEARCH 2011
Four-component reaction between trimethyl phosphite, aroyl chlorides
and dialkyl acetylenedicarboxylate with benzoic acid hydrazide
Alireza Hassanabadia*, Mohammad H. Mossleminb, Mohammad Anary-Abbasinejadb,
Farzaneh Ghazvininejadb and Somayeh Koochekib
aDepartment of Chemistry, Islamic Azad University, Zahedan Branch, PO Box 98135-978, Zahedan, Iran
bDepartment of Chemistry, Islamic Azad University, Yazd Branch, PO Box 89195-155, Yazd, Iran
A four-component and one-pot reaction between trimethyl phosphite, a dialkyl acetylene dicarboxylate and an aroyl
chloride with benzoic acid hydrazide is described as a simple and efficient route for the synthesis of functionalised
pyrazoles in good yields.
Keywords: benzoic acid hydrazide, functionalised pyrazoles, dialkyl acetylene dicarboxylate, trimethyl phosphite, multi-
component reaction
Substituted pyrazoles are known to possess a wide variety of
biological activities including herbicidal,1 anti-microbial,2
anti-bacterial,3 anti-inflammatory,4 insecticidal,5 analgesic,6
and anti-pyretic7 activity. 1,3,5-Tri- and 1,3,4,5-tetrasubsti-
tuted pyrazoles, which constitute the key structural units of
major drugs, such as, Celebrex8 and Acomplia9 are of interest
to the medicinal chemist.
The first method of the synthesis is 1,3,5-trisubstituted pyr-
azoles goes back to nineteenth century when Knorr employed
1,3-diketones and hydrazines as starting materials.10 Since two
isomeric products were formed from the reaction of hydrazines
with unsymmetrical dicarbonyl compounds which were diffi-
cult to separate, efforts to replace the dicarbonyl compounds
with olefinic or acetylenic ketones have been reported to
develop regioselective syntheses of the pyrazole rings.11
Although α,β-unsaturated ketones have been used as building
blocks for the preparation of pyrazoles, vinylphosphonates
have also been important synthetic intermediates12 in these
heterocycle syntheses.
The diastereoselective synthesis of a novel series of dialkyl
(E)-2-(dialkoxyphosphoryl)-3-(aroyl)-2-butenedioate deriva-
tives (4) using the reaction of trialkyl phosphite and an acety-
lenic ester with various aroyl chlorides via one-pot MCRs was
reported in 2010.13
In continuation of our work on the reaction between
trivalent phosphorus nucleophiles and acetylenic esters in the
presence of organic NH, OH, or CH-acids,14–23 we wish to
report the results of our study on the reaction between tri-
methyl phosphite, dialkyl acetylenedicarboxylates and aroyl
chlorides in the presence of benzoic acid hydrazide.
methoxy groups (δ = 3.63 and 3.82 ppm). The protons of the
aromatic groups exhibited characteristic signals in the aro-
matic region of the spectrum. The 13C NMR spectrum of com-
pound 5a showed 16 signals in agreement with the proposed
structure. The IR spectrum of compound 5a also supported the
suggested structure. Strong absorption bands were observed
at 1734 and 1691 cm−1 respectively for the ester and amide
carbonyl groups.
A reasonable mechanism for the formation of compounds 5
is presented at Scheme 2.
On the basis of the well-established chemistry of acetylenic
esters,24–27 it is reasonable to assume that the functionalised
pyrazole derivatives 5 arises from the initial addition of the
phosphite 2 to the acetylenic ester 3 and subsequent attack
of the resulting zwitterion 6 on the aroyl chloride 1 to yield
the ion pair 7. Then, attack of the chloride ion would yield
the vinylphosphonate 4. A conjugate addition of benzoic acid
hydrazide to the reaction of unsaturated ketone 4 with takes
place and is then followed by an expulsion of the phosphate to
lead to the formation of intermediate 8 and 9. The intermediate
9 undergoes cyclisation followed by the loss of water to form
product 5.
In summary dialkyl 5-(aryl)-1-phenyl-1H-pyrazole-3,4-
dicarboxylates may be prepared by a simple, one-pot and
four-component reaction between trimethyl phosphite, dialkyl
acetylenedicarboxylates and aroyl chlorides with benzoic acid
hydrazide in good yields. The present method has the advan-
tage that the reaction is performed under neutral conditions
and starting materials can be mixed without any activation or
modification.
Experimental
Results and discussion
Elemental analyses were performed at the analytical laboratory of
Science and Research Unit of the Islamic Azad University. Mass spec-
tra were recorded on a FINNIGAN-MAT 8430 mass spectrometer
operating at an ionization potential of 70 eV. IR spectra were recorded
on a Shimadzu IR-470 spectrometer.1H and 13C NMR spectra were
recorded on Bruker DRX-500 Avance spectrometer in solution in
CDCl3 using TMS as an internal standard. The chemicals employed in
this work were purchased from Fluka (Buchs, Switzerland) and were
used without further purification.
Treatment of dialkyl acetylenedicarboxylates (3), trimethyl
phosphite (2) and an aroyl chloride (1) with benzoic acid
hydrazide in toluene under reflux and one-pot conditions leads
to the formation of dialkyl 5-(aryl)-1-phenyl-1H-pyrazole-3,4-
dicarboxylate (5) after 32 h in 63–80% yield. (Scheme 1)
Different aroyl chlorides were used to study the scope of the
reaction,. As shown in Scheme 1, the reaction is compatible
with aroyl chlorides substituted by electron-attracting groups
such as nitro and or weakly electron-withdrawing group such
as bromo. Using electron-releasing groups such as methoxy,
no product was isolated.
Preparation of compounds 5a–h: general procedure
To a magnetically stirred solution of dialkyl acetylenedicarboxylate
(1 mmol) and aroyl chloride (1 mmol) in toluene (5 mL) was added
dropwise a solution of trimethyl phosphite (1 mmol) in toluene (3 mL)
at room temperature over 10 min. The reaction mixture was then
stirred for 8 h under reflux. Finally a solution of benzoic acid hydra-
zide (1 mmol) in toluene (5 mL) was added and the mixture was
stirred for 24 h under reflux. Solvent was removed under reduced
pressure, and the residue was separated by silica gel (Merck 230–240
mesh) column chromatography using a hexane–eethyl acetate mixture
as eluent.
The structures of compounds 5a–h were deduced from their
1
elemental analyses and their IR, H NMR, 13C NMR spectra.
The mass spectrum of compound 5a showed the molecular ion
peak at 409. The 1H NMR spectrum of compound 5a exhibited
two single sharp lines readily recognised as arising from
* Correspondent. E-mail:ar_hasanabadi@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2011 517
Scheme 1 Four-component reaction between aroyl chlorides, dialkyl acetylenedicarboxylate and trimethyl phosphite in the
presence of benzoic acid hydrazide.
Scheme 2 Suggested mechanism for formation of compound 5.

518 JOURNAL OF CHEMICAL RESEARCH 2011
Dimethyl 5-(4-nitrophenyl)-1-phenyl-1H-pyrazole-3,4-dicarboxyl-
ate (5a): Yield: 77%; Yellow oil, IR (KBr) (νmax/cm−1): 1734 (C=O
ester) and 1691 (C=O amide). MS, m/z (%): 409 (M+., 4). Anal.Calcd
for C20H15N3O7: C, 58.68; H, 3.69; N, 10.27. Found: C, 58.82; H, 3.55;
1731 (C=O ester) and 1694 (C=O amide). MS, m/z (%): 443 (M+., 11).
Anal.Calcd for C20H14ClN3O7: C, 54.13; H, 3.18; N, 9.47. Found: C,
53.95; H, 3.02; N, 9.61%. 1H NMR (500 MHz, CDCl3, Me4Si): δ 3.56,
and 3.72 (6 H, 2 s, 2 OCH3), 7.74–8.33 (8 H, m, 8 CH aromatic) ppm.
13C NMR (125.8 MHz, CDCl3, Me4Si): δ 52.67 and 53.44 (2 OCH3),
118.85 (C-5), 144.16 (C-4), 146.93 (C-3), 123.62, 125.18, 127.60,
129.21, 129.76, 131.95, 140.00, 140.83, 147.36 and 150.65 (aro-
matic), 163.28, 164.32, 166.38 (3C=O).
Dimethyl 5-(3-methoxycarbonylphenyl)-1-phenyl-1H-pyrazole-
3,4-dicarboxylate (5h): Yield: 63%; Yellow oil, IR (KBr) (νmax/cm−1):
1728 (C=O ester) and 1687 (C=O amide). MS, m/z (%): 422 (M+., 3).
Anal.Calcd for C22H18N2O7: C, 62.56; H, 4.30; N, 6.63. Found: C,
62.71; H, 4.25; N, 6.50%. 1H NMR (500 MHz, CDCl3, Me4Si): δ 3.51,
3.63 and 3.82 (9 H, 3 s, 3 OCH3), 7.42–7.98 (9 H, m, 9 CH aromatic)
ppm. 13C NMR (125.8 MHz, CDCl3, Me4Si): δ 51.89, 52.79 and 53.50
(3 OCH3), 119.34 (C-5), 144.13 (C-4), 147.25 (C-3), 121.74, 123.55,
129.11, 129.65, 130.72, 132.88, 134.10, 143.63, 148.55 and 150.62
(aromatic), 162.80, 163.1, 166.25 (3C=O).
1
N, 10.34%. H NMR (500 MHz, CDCl3, Me4Si): δ 3.63, and 3.82
(6 H, 2 s, 2 OCH3), 7.12–7.20 (5 H, m, 5 CH aromatic), 8.06 (2 H, d,
3
3JHH = 8 Hz, 2 CH of C6H4NO2), 8.33 (2 H, d, JHH = 8 Hz, 2 CH of
C6H4NO2) ppm. 13C NMR (125.8 MHz, CDCl3, Me4Si): δ 52.79 and
53.50 (2 OCH3), 119.10 (C-5), 144.44 (C-4), 147.07 (C-3), 124.11,
127.66, 129.28, 129.57, 131.40, 132.91, 139.85 and 150.65 (aro-
matic), 162.98, 164.19, 166.17 (3C=O).
Di-t-butyl 5-(4-nitrophenyl)-1-phenyl-1H-pyrazole-3,4-dicarboxyl-
ate (5b): Yield: 68%; Yellow oil, IR (KBr) (νmax/cm−1): 1723 (C=O
ester) and 1685 (C=O amide). MS, m/z (%): 493 (M+., 3). Anal. Calcd
for C26H27N3O7: C, 63.28; H, 5.51; N, 8.51. Found: C, 63.13; H, 5.59;
N, 8.45%. 1H NMR (500 MHz, CDCl3, Me4Si): δ 0.85 and 1.42 (18 H,
3
2s, 6 CH3), 7.08–7.35 (5 H, m, 5 CH aromatic), 8.08 (2 H, d, JHH
=
8 Hz, 2 CH of C6H4NO2), 8.23 (2 H, d, 3JHH = 8 Hz, 2 CH of C6H4NO2)
ppm. 13C NMR (125.8 MHz, CDCl3, Me4Si): δ 28.65 and 28.67 (6 CH3
of t-butyl groups), 87.28 and 81.80 (2 C of t-butyl groups), 120.98
(C-5), 143.74 (C-4), 144.32 (C-3), 125.86, 127.72, 129.74, 129.87,
130.05, 130.31, 138.08 and 150.16 (aromatic), 162.78, 164.26, 165.93
(3C=O).
Received 19 July 2011; accepted 23 August 2011
Paper 1100779 doi: 10.3184/174751911X13148978312160
Published online: 30 September 2011
Dimethyl 5-(4-bromophenyl)-1-phenyl-1H-pyrazole-3,4-dicarboxyl-
ate (5c): Yield: 75%; Yellow oil, IR (KBr) (νmax/cm−1): 1726 (C=O
ester) and 1680 (C=O amide). MS, m/z (%): 442 (M+., 11). Anal. Calcd
for C20H15BrN2O5: C, 54.19; H, 3.41; N, 6.32. Found: C, 54.25; H,
3.57; N, 6.40%. 1H NMR (500 MHz, CDCl3, Me4Si): δ 3.75, and 3.87
(6 H, 2 s, 2 OCH3), 7.58–8.20 (5 H, m, 5 CH aromatic), 7.61 (2 H, d,
References
1
2
S. Sugai, S. Mio, T. Honma and T.U.S. Sakamato, Patent, 1995, 5, 424.
N.M. Abunada, H.M. Hassaneen, N.G. Kandile and O.A. Miqdad,
Molecules, 2008, 13, 1501.
3
A. Tanitame, Y. Oyamada, K. Ofuji, M. Fujimoto, K. Suzuki, T. Ueda, H.
Terauchi, M. Kawasaki, K. Nagai, M. Wachi and J.I. Yamagishi, Bioorg.
Med. Chem., 2004, 12, 5515.
3
3JHH = 8 HZ, 2 CH of C6H4Br), 8.21 (2 H, d, JHH = 8 HZ, 2 CH of
C6H4Br) ppm. 13C NMR (125.8 MHz, CDCl3, Me4Si): δ 51.52 and
52.86 (2 OCH3), 120.39 (C-5), 144.54 (C-4), 147.25 (C-3), 124.02,
126.39, 129.26, 129.60, 131.59, 132.54, 138.34 and 150.44 (aro-
matic), 160.72, 163.84, 165.29 (3C=O).
4
5
6
7
C. Selvam, S.M. Jachak, R. Thilagavathi and A.K. Chakraborti, Bioorg.
Med. Chem. Lett., 2005, 15, 1793.
R. Katoch-Rouse, L.A. Pavlova, T. Caulder, A.F. Hoffman, A.G. Mukhin
and A.G.Horti, J. Med. Chem., 2003, 46, 642.
E.V. Shchegol’kov, O.G. Khudina, L.V. Anikina, Y.V. Burgart and V.I.
Saloutin, Khim.-Farm. Zh., 2006, 40, 27.
T.D. Penning, J.J. Talley, S.R. Bertenshaw, J.S. Carter, P.W. Collins, S.
Docter, M.J. Graneto, L.F. Lee, J.W. Malecha, J.M. Miyashiro, R.S. Rogers,
D.J. Rogier, S.S. Yu, G.D. Anderson, E.G. Burton, J.N. Cogburn, S.A.
Gregory, C.M. Koboldt, W.E. Perkins, K. Seibert, A.W. Veenhuizen, Y.Y.
Zhang and P.C. Isakson, J. Med. Chem., 1997, 40, 1347.
T.Yoshioka, T. Fujita, T. Kanai,Y. Aizawa, T. Kurumada, K. Hasegawa and
H. Horikoshi, J. Med. Chem., 1989, 32, 421.
Diethyl 5-(4-bromophenyl)-1-phenyl-1H-pyrazole-3,4-dicarboxyl-
ate (5d): Yield: 72%; Yellow oil, IR (KBr) (νmax/cm−1): 1726 (C=O
ester) and 1687 (C=O amide). MS, m/z (%): 470 (M+., 5). Anal.Calcd
for C22H19BrN2O5: C, 56.07; H, 4.06; N, 5.94. Found: C, 56.18; H,
3.98; N, 6.14%. 1H NMR (500 MHz, CDCl3, Me4Si): δ 0.92 and 1.32
3
3
(6 H, 2 t, JHH = 7 HZ, 2CH3), 4.26 and 4.42 (4 H, 2 q, JHH = 7 HZ,
2OCH2), 7.16–7.60 (5 H, m, 5 CH aromatic), 7.58 (2 H, d, 3JHH = 8 HZ,
2 CH of C6H4Br), 8.19 (2 H, d, 3JHH = 8 HZ, 2 CH of C6H4Br) ppm. 13
C
8
9
NMR (125.8 MHz, CDCl3, Me4Si): δ 14.34 and 14.71 (2CH3), 58.82
and 62.00 (2OCH2), 119.81 (C-5), 144.28 (C-4), 147.08 (C-3),
125.88, 127.69, 128.99, 129.20, 132.26, 132.67, 138.64 and 150.21
(aromatic), 162.68, 163.17, 165.03 (3C=O).
L. Knorr, Ber. Dtsch. Chem. Ges ,1883, 16, 2597.
10 X.J. Wang, J. Tan and K. Grozinger, Tetrahedron Lett., 2000, 41, 4713.
11 T. Minami and J. Motoyoshiya, Synthesis 1992, 333.
12 R. Kouno, T. Okauchi, M. Nakamura, J. Ichikawa and T. Minami, J. Org.
Chem.,1998, 63, 6239.
13 S. Rostamnia, A. Alisadeh and L.G. Zhu, J. Comb. Chem., 2009, 11, 143.
14 A. Hassanabadi, M.R. Hosseini-Tabatabaei, M. Shahraki M. Anary-
Abbasinejad and S. Ghoroghchian, J. Chem. Res., 2011, 11.
15 I. Yavari, M. Anary-Abbasinejad and Z. Hossaini, Org. Biomol. Chem.,
2003, 3, 560.
16 M. Anary-abbasinejad aand N. Ascarrian, J. Chem. Res., 2007, 11.
17 M. Anary-Abbasinejad, N. Rostami, A. Parhami and A. Hassanabadi,
J. Chem. Res., 2007, 257.
18 M. Anary-Abbasinejad, A. Hassanabadi and H. Anaraki-Ardakani, J.
Chem. Res., 2007, 455.
Dimethyl 5-(3-nitrophenyl)-1-phenyl-1H-pyrazole-3,4-dicarboxyl-
ate (5e): Yield: 80%; Yellow oil, IR (KBr) (νmax/cm−1): 1734 (C=O
ester) and 1691 (C=O amide). MS, m/z (%): 409 (M+., 9). Anal.Calcd
for C20H15N3O7: C, 58.68; H, 3.69; N, 10.27. Found: C, 58.82; H, 3.55;
N, 10.34%. 1H NMR (500 MHz, CDCl3, Me4Si): δ 3.67, and 3.86 (6
H, 2 s, 2 OCH3), 7.62–8.14 (9 H, m, 9 CH aromatic) ppm. 13C NMR
(125.8 MHz, CDCl3, Me4Si): δ 52.85 and 53.57 (2 OCH3), 119.16
(C-5), 144.42 (C-4), 147.15 (C-3), 121.51, 123.24, 129.28, 129.89,
130.58, 132.71, 134.23, 143.50, 148.61 and 150.65 (aromatic), 163.05,
164.28, 166.29 (3C=O).
Dimethyl 5-(2-nitrophenyl)-1-phenyl-1H-pyrazole-3,4-dicarboxyl-
ate (5f): Yield: 75%; Yellow oil, IR (KBr) (νmax/cm−1): 1734 (C=O
ester) and 1691 (C=O amide). MS, m/z (%): 409 (M+., 6). Anal.Calcd
for C20H15N3O7: C, 58.68; H, 3.69; N, 10.27. Found: C, 58.82; H, 3.55;
N, 10.34%. 1H NMR (500 MHz, CDCl3, Me4Si): δ 3.59, and 3.75 (6
H, 2 s, 2 OCH3), 7.52–7.91 (9 H, m, 9 CH aromatic) ppm. 13C NMR
(125.8 MHz, CDCl3, Me4Si): δ 52.73 and 53.58 (2 OCH3), 119.03
(C-5), 144.31 (C-4), 147.02 (C-3), 125.19, 127.62, 129.24, 129.93,
132.02, 133.87, 134.95, 139.82, 149.28 and 150.65 (aromatic), 162.91,
164.27, 166.12 (3C=O).
19 M. Anary-Abbasinejad and A. Hassanabadi, J. Chem. Res., 2007, 475.
20 M. Anary-Abbasinejad, H. Anaraki-Ardakani, A. Dehghan, A. Hassanabadi
and M.R. Seyedmir, J. Chem. Res., 2007, 574.
21 M. Anary-Abbasinejad, A. Hassanabadi and M. Mazraeh-Seffid, J. Chem.
Res., 2007, 708.
22 M. Anary-Abbasinejad, K. Charkhati and A. Hassanabadi, J. Chem. Res.,
2009, 319.
23 M.H. Mosslemin, M. Anary-Abbasinejad, A. Hassanabadi and M.A.
Bagheri, J. Sulfur. Chem., 2010, 31, 135.
24 I. Ugi, Pure Appl. Chem., 2001, 77, 187.
25 M.C. Bagley, J.W. Cale and J. Bower, Chem. Commun., 2002, 1682.
26 U. Bora, A. Saikia and R.C. Boruah, Org. Lett., 2003, 5, 435.
27 I. Yavari, H. Djahaniani and F. Nasiri, Tetrahedron, 2003, 59, 9409.
Dimethyl 5-(2-chloro-5-nitrophenyl)-1-phenyl-1H-pyrazole-3,4-
dicarboxylate (5g): Yield: 75%; Yellow oil, IR (KBr) (νmax/cm−1):

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