One-pot synthesis of 4-(2,3-dihydro-2-hydroxy-1,3-dioxo-1H-inden-2-yl)- substituted 1-aryl-1H-pyrazole-3-carboxylates via a tandem three-component reaction

Article abstract of DOI:10.1002/hlca.201100317

The hitherto unreported, highly functionalized 1H-pyrazole-3-carboxylates 3 have been synthesized in good yields via a one-pot three-component domino reaction of phenylhydrazines, dialkyl acetylenedicarboxylates, and ninhydrin under mild conditions for the first time. No co-catalyst or activator is required for this multicomponent reaction, and the reaction is, from an experimental point of view, simple to perform (Scheme 1). The structures of compounds 3 were corroborated spectroscopically (IR, ¹H- and ¹³C-NMR, and EI-MS) and by elemental analyses. A plausible mechanism for this type of cyclization/addition reaction is proposed (Scheme 2). Copyright

Full text of DOI:10.1002/hlca.201100317

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Helvetica Chimica Acta – Vol. 95 (2012)
One-Pot Synthesis of 4-(2,3-Dihydro-2-hydroxy-1,3-dioxo-1H-inden-2-yl)-
Substituted 1-Aryl-1H-pyrazole-3-carboxylates via a Tandem Three-
Component Reaction
by Abdolali Alizadeh*, Ameneh Zarei, and Atieh Rezvanian
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115 – 175, Tehran, Iran
(phone: þ 98-21-88006631; fax: þ 98-21-88006544; e-mail: aalizadeh@Modares.ac.ir,
abdol_alizad@yahoo.com)
The hitherto unreported, highly functionalized 1H-pyrazole-3-carboxylates 3 have been synthesized
in good yields via
a one-pot three-component domino reaction of phenylhydrazines, dialkyl
acetylenedicarboxylates, and ninhydrin under mild conditions for the first time. No co-catalyst or
activator is required for this multicomponent reaction, and the reaction is, from an experimental point of
view, simple to perform (Scheme 1). The structures of compounds 3 were corroborated spectroscopically
(IR, 1H- and 13C-NMR, and EI-MS) and by elemental analyses. A plausible mechanism for this type of
cyclization/addition reaction is proposed (Scheme 2).
Introduction. – The synthesis of pyrazole derivatives has received considerable
attention due to their broad spectrum of biological activities [1]. Although there are
many reports related to the synthesis of pyrazoles in the literature, a search revealed
that the synthesis of pyrazole derivatives with an indene moiety have not been
described.
Results and Discussion. – As part of our program aimed at developing new routes
for the preparation of biologically active N-containing heterocylic compounds [2], we
describe an efficient synthesis of fully substituted 4-(1H-inden-2-yl)-1H-pyrazole-3-
carboxylates via a new one-pot three-component reaction. Thus, the reaction between
phenylhydrazines 1, dialkyl acetylenedicarboxylates 2, and ninhydrin in dry toluene at
reflux temperature leads to the formation of the 1H-pyrazole-3-carboxylates 3 in good
yields (Scheme 1).
The molecular structures of compounds 3 were elucidated using their elemental
1
analysis, MS, IR, and high-field H- and 13C-NMR spectra as described for 3a in the
Exper. Part. The mass spectrum of 3a exhibited the molecular-ion peak at m/z 378,
which is in agreement with the proposed structure. The IR spectrum of 3a showed
absorption bands at 3342 and 3200 cmꢀ1 due to stretching frequencies of two OH
groups. Absorption bands at 1727 and 1600 cmꢀ1 are due to the C¼O and COOMe
1
groups. The H-NMR spectrum of 3a showed three singlets for the MeO and the two
OH groups (d(H) 2.49, 3.34, and 8.93), and the aromatic moieties gave rise to several
1
signals in the aromatic region of the spectrum (d(H) 7.43 – 8.05). The H-decoupled
13C-NMR spectrum of 3a showed 14 distinct resonances in agreement with the
suggested structure.
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 95 (2012)
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Scheme 1. Synthesis of Highly Substituted 1H-Pyrazole-3-carboxylates 3
A tentative mechanistic rationale illustrating a probable route of the reaction is
shown in Scheme 2. We assume that the initial step is a nucleophilic addition of 1 to 2,
resulting in the formation of intermediate 4. Then, 4 cyclizes to the 4,5-dihydro-5-oxo-
1H-pyrazole-3-carboxylate 6 that undergoes successive keto-enol tautomerization,
followed by nucleophilic addition of the enol group to ninhydrin, resulting in the
formation of product 3 (Scheme 2).
In conclusion, we have designed a versatile, convenient, and efficient approach to
construct several 1H-pyrazole-3-carboxylates via a three-component one-pot reaction
of phenylhydrazines, dialkyl acetylenedicarboxylates, and ninhydrin for the first time.
The advantages of operational simplicity, economic viability, generality, atom-
economy, together with ecologically benign nature make this protocol a very efficient
alternative to literature methods, so that a wide range of compounds of type 3 could be
easily prepared for biological assays.
Scheme 2. A Plausible Mechanism for the Formation of 3

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Helvetica Chimica Acta – Vol. 95 (2012)
Experimental Part
General. Phenylhydrazine, 2,4-dinitrophenylhydrazine, dialkyl acetylenedicarboxylate, and ninhy-
drin were obtained from Merck (Germany) and Fluka (Switzerland), and were used without further
purification. M.p.: Electrothermal 9100 apparatus. IR Spectra: Shimadzu IR-460 spectrometer,
1
absorbances reported in cmꢀ1. H- and 13C-NMR spectra: in CDCl3 soln., Bruker DRX-500 AVANCE
spectrometer at 500.13 and 125.8 MHz, resp. EI-MS: FINNIGAN MATT-8430 mass spectrometer
operating at an ionization potential of 70 eV. Elemental analyses for C, H, and N: Heraeus CHN-O-
Rapid analyzer.
General Procedure. Formation of 3a. A soln. of phenylhydrazine (0.11 g, 1 mmol) and dimethyl
acetylenedicarboxylate (0.14 g, 1 mmol) in toluene (5 ml) was magnetically stirred for 4 h under reflux.
Then, a soln. of ninhydrin (0.16 g, 1 mmol) in toluene (3 ml) was added dropwise, and the mixture was
refluxed for 1 h. After completion, the mixture was filtered and the precipitate washed with cold toluene
to afford the pure product 3a.
Methyl 4-(2,3-Dihydro-2-hydroxy-1,3-dioxo-1H-inden-2-yl)-5-hydroxy-1-phenyl-1H-pyrazole-3-car-
boxylate (3a). Yield 0.30 g (80%). Yellow crystals. M.p. 2008. IR: 3342 (OH), 3200 (OH), 1727 (C¼O),
1600 (COOMe). 1H-NMR: 2.49 (s, OH); 3.34 (s, MeO); 7.43 (t, J ¼ 8.6, 1 arom. H); 7.53 – 7.57 (m, 2 arom.
H); 7.69 – 7.74 (m, 2 arom. H); 8.04 (d, J ¼ 8, 2 arom. H), 8.05 (d, J ¼ 8, 2 arom. H); 8.93 (s, OH).
13C-NMR: 51.3; 74.6; 98.6; 123.0; 123.8; 127.6; 129.1; 136.3; 137.5; 138.2; 140.1; 153.0; 162.2; 197.1. EI-MS:
378 (8, Mþ), 104 (67), 76 (100), 65 (25). Anal. calc. for C20H14N2O6 (378.34): C 63.49, H 3.73, N 7.40;
found: C 63.33, H 3.61, N 7.52.
Ethyl 4-(2,3-Dihydro-2-hydroxy-1,3-dioxo-1H-inden-2-yl)-5-hydroxy-1-phenyl-1H-pyrazole-3-car-
boxylate (3b). Yield 0.29 g (75%). Yellow crystals. M.p. 2708. IR: 3221 (OH), 3210 (OH), 1712
(C¼O), 1600 (COOEt). 1H-NMR: 0.95 (br. t, MeCH2); 2.28 (s, OH); 3.81 (br. q, MeCH2); 7.15 (s, OH);
7.55 (t, J ¼ 8.6, 1 arom. H); 7.69 – 7.71 (m, 2 arom. H); 7.70 – 7.73 (m, 2 arom. H); 8.04 (br. m, 4 arom. H).
13C-NMR: 13.7; 60.4; 74.6; 98.5; 123.1; 123.8; 127.6; 128.8; 129.1; 136.3; 137.5; 140.2; 153.0; 161.8; 197.1.
EI-MS: 232 (50), 132 (33), 104 (100), 76 (83), 50 (33). Anal. calc. for C21H16N2O6 (392.36): C 64.28, H
4.11, N 7.14; found: C 64.19, H 4.11, N 7.19.
1-Methylethyl-2-yl 4-(2,3-Dihydro-2-hydroxy-1,3-dioxo-1H-inden-2-yl)-5-hydroxy-1-phenyl-1H-pyr-
azole-3-carboxylate (3c). Yield 0.33 g (83%). Yellow crystals. M.p. 2928. IR: 3429 (OH), 3277 (OH),
1721 (C¼O), 1600 (COOPr). 1H-NMR: 1.23 (br. d, 2 Me); 2.9 (s, OH); 4.7 – 4.11 (m, Me2CH); 7.27 (br. q,
1 arom. H); 7.28 – 7.32 (m, 2 arom. H); 7.40 – 7.44 (m, 2 arom. H); 7.87 (s, OH); 7.99 – 8.03 (m, 4 arom. H).
13C-NMR: 21.6; 68.2; 69.6; 77.2; 122.1; 122.9; 125.3; 129.2; 130.3; 136.3; 137.4; 140.8; 143.1; 162.8; 196.6.
EI-MS: 132 (25), 104 (83), 76 (100), 61 (8). Anal. calc. for C22H18N2O6 (406.39): C 65.02, H 4.46, N 6.89;
found: C 65.09, H 4.39, N 6.71.
Methyl 4-(2,3-Dihydro-2-hydroxy-1,3-dioxo-1H-inden-2-yl)-1-(2,4-dinitrophenyl)-5-hydroxy-1H-
pyrazole-3-carboxylate (3d). Yield 0.36 g (78%). Yellow crystals. M.p. 2408. IR: 3399 (OH), 3236
(OH), 1724 (C¼O), 1600 (COOMe), 1506, 1330 (NO2). 1H-NMR: 2.27 (s, OH); 3.36 (s, MeO); 6.48 (s, 1
arom. H); 7.26 (br. d, 1 arom. H); 7.37 (br. d, 2 arom. H); 7.53 (d, J ¼ 5, 2 arom. H); 8.43 (br. d, 1 arom.
H); 8.75 (s, OH). 13C-NMR: 57.2; 84.2; 87.59; 122.8; 125.6; 128.1; 131.2; 137.0; 137.1; 137.2; 137.3; 139.8;
144.1; 149.4; 154.78; 196.9. EI-MS: 468 (4, Mþ), 368 (50), 83 (67), 57 (100). Anal. calc. for C20H12N4O10
(468.33): C 51.28, H 2.59, N 11.96; found: C 51.34, H 2.55, N 11.88.
Ethyl 4-(2,3-Dihydro-2-hydroxy-1,3-dioxo-1H-inden-2-yl)-1-(2,4-dinitrophenyl)-5-hydroxy-1H-pyra-
zole-3-carboxylate (3e). Yield 0.39 g (81%). Yellow crystals. M.p. 2508. IR: 3460 (OH), 3254 (OH), 1713
(C¼O), 1603 (COOMe), 1509, 1333 (NO2). 1H-NMR: 1.29 (s, MeCH2); 2.49 (s, OH); 3.31 (br. q,
MeCH2); 6.81 (s, 1 arom. H); 7.24 (br. d, 1 arom. H); 7.40 (br. d, 2 arom. H); 7.53 (br. d, 2 arom. H); 8.17
(br. d, 1 arom. H); 8.83 (s, OH). 13C-NMR: 13.9; 60.9; 81.0; 87.6; 123.1; 125.2; 128.1; 128.7; 128.8; 129.5;
129.9; 135.9; 137.4; 138.4; 138.6; 149.9; 196.9. EI-MS: 482 (9, Mþ), 368 (55), 83 (61), 57 (100). Anal. calc.
for C21H14N4O10 (482.36): C 52.29, H 2.93, N 11.62; found: C 52.33, H 11.5, N 11.52.

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Received August 9, 2011