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Synthesis of pyrazoles

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An iron-catalyzed route for the regioselective synthesis of 1,3- and 1,3,5-substituted pyrazoles from the reaction of diarylhydrazones and vicinal diols allows the conversions of a broad range of substrates.
N. Panda, A. K. Jena, J. Org. Chem., 2012, 77, 9401-9406.

Ruthenium-catalyzed hydrogen transfer of 1,3-diols in the presence of alkyl hydrazines provides 1,4-disubstituted pyrazoles. A regioselective synthesis of unsymmetrical pyrazoles from β-hydroxy ketones can also be achieved.
D. C. Schmitt, A. P. Taylor, A. C. Flick, R. E. Kyne, Jr., Org. Lett., 2015, 17, 1405-1408.

An efficient, general, one-pot, three-component procedure for the preparation of 3,5-disubstituted 1H-pyrazoles includes condensation of substituted aromatic aldehydes and tosylhydrazine followed by cycloaddition with terminal alkynes. The reaction tolerates various functional groups and sterically hindered substrates to afford the desired pyrazoles in good yields.
L.-L. Wu, Y.-C. Ge, T. He, L. Zhang, X.-L. Fu, H.-Y. Fu, H. Chen, R.-X. Li, Synthesis, 2012, 44, 1577-1583

A copper-catalyzed sydnone-alkyne cycloaddition reaction offers a robust, straightforward and general method for constructing 1,4-pyrazoles from arylglycines using a three-step one-pot procedure.
S. Specklin, E. Decuypere, L. Plougastel, S. Aliani, F. Taran, J. Org. Chem., 2014, 79, 7772-7777.

A new and efficient metal-free, two-component, one-pot approach to a variety of 3,5-disubstituted 1H-pyrazoles from propargylic alcohols in good overall yields proceeds via an acid-catalyzed propargylation of N,N-diprotected hydrazines followed by base-mediated 5-endo-dig cyclization.
C. R. Reddy, J. Vijaykumar, R. Grée, Synthesis, 2013, 45, 830-836.

Visible light photoredox catalysis enables a selective and high yielding synthesis of polysubstituted pyrazoles in very good yields from hydrazine and various Michael acceptors under very mild reaction conditions in the presence of air as the terminal oxidant. The reaction is proposed to go through VLPC-promoted oxidation of hydrazine to diazene followed by its addition to Michael acceptors.
Y. Ding, T. Zhang, Q.-Y. Chen, C. Zhu, Org. Lett., 2016, 18, 4206-4209.

An I2-mediated metal-free oxidative C-N bond formation enables a regioselective pyrazole synthesis. This practical and eco-friendly one-pot protocol provides a facile access to various di-, tri-, and tetrasubstituted (aryl, alkyl, and/or vinyl) pyrazoles from readily available α,β-unsaturated aldehydes/ketones and hydrazine salts without isolation of the less stable intermediates hydrazones.
X. Zhang, J. Kang, P. Niu, J. Wu, W. Yu, J. Chang, J. Org. Chem., 2014, 79, 10170-10178.

Aluminum chloride mediated reactions of N-alkylated tosylhydrazones and terminal alkynes provide a series of 1,3,5-trisubstituted pyrazoles in very good yields with complete regioselectivity. The protocol is applied to a wide range of substrates and demonstrates excellent functional group tolerance.
M. Tang, Y. Wang, H. Wang, Y. Kong, Synthesis, 2016, 48, 3065-3076.

The reaction of terminal alkynes with n-BuLi, and then with aldehydes, followed by the treatment with molecular iodine, and subsequently hydrazines or hydroxylamine provided the corresponding 3,5-disubstituted pyrazoles or isoxazoles in good yields and with high regioselectivity.
R. Harigae, K. Moriyama, H. Togo, J. Org. Chem., 2014, 79, 2049-2058.

An efficient synthesis of 1,3,5-trisubstituted pyrazoles from N-alkylated tosylhydrazones and terminal alkynes converted a wide range of substrates. In comparison with common syntheses of substituted pyrazoles, this methodology offers complete regioselectivity, especially, if similar substituents are present.
Y. Kong, M. Tang, Y. Wang, Org. Lett., 2014, 16, 576-579.

A simple and straightforward multicomponent reaction of vinyl azide, aldehyde, and tosylhydrazine affords 3,4,5-trisubstituted 1H-pyrazoles regioselectively in good yields in the presence of a base. The reaction tolerates a range of functional groups.
G. Zhang, H. Ni, W. Chen, J. Shao, H. Liu, B. Chen, Y. Yu, Org. Lett., 2013, 15, 5967-5969.

1,3-Diketones, which were synthesized in situ from ketones and acid chlorides, were converted into pyrazoles by the addition of hydrazine. This method allows a fast and general synthesis of previously inaccessible pyrazoles and synthetically demanding pyrazole-containing fused rings.
S. T. Heller, S. R. Natarajan, Org. Lett., 2006, 8, 2675-2678.

A highly regioselective synthesis of 1-aryl-3,4,5-substituted pyrazoles based on the condensation of 1,3-diketones with arylhydrazines proceeds at room temperature in N,N-dimethylacetamide and furnishes pyrazoles in good yields.
F. Gosselin, P. D. O'Shea, R. A. Webster, R. A. Reamer, R. D. Tillyer, E. J. J. Grabowski, Synlett, 2006, 3267-3270.

Pyrazole or isoxazole derivatives are prepared by a palladium-catalyzed four-component coupling of a terminal alkyne, hydrazine (hydroxylamine), carbon monoxide under ambient pressure, and an aryl iodide.
M. S. M. Ahmed, K. Kobayashi, A. Mori, Org. Lett., 2005, 7, 4487-4489.

Visible light catalysis enables an efficient tandem reaction of hydrazones and α-bromo ketones to provide 1,3,5-trisubstituted pyrazoles. A radical addition followed by intramolecular cyclization affords the important pyrazole skeleton in good to excellent yields under mild conditions with wide group tolerance.
X.-W. Fan, T. Lei, C. Zhou, Q.-Y. Meng, B. Chen, C.-H. Tung, L-Z. Wu, J. Org. Chem., 2016, 81, 7127-7133.

Two highly regioselective routes enable the synthesis of unsymmetrically substituted pyrazoles with complementary regioselectivity from active methylene ketones. The reaction of the easily accessible 1,3-bisaryl-monothio-1,3-diketone or 3-(methylthio)-1,3-bisaryl-2-propenones with arylhydrazines furnished 1-aryl-3,5-bisarylpyrazoles with complementary regioselectivity at position 3 and 5.
S. V. Kumar, S. K. Yadav, B. Raghava, B. Saraiah, H. Ila, K. S. Ragappa, A. Hazra, J. Org. Chem., 2013, 78, 4960-4973.

A simple, highly efficient, 1,3-dipolar cycloaddition of diazo compounds and alkynyl bromides gives 3,5-diaryl-4-bromo-3H-pyrazoles or the isomerization products 3,5-diaryl-4-bromo-1H-pyrazoles in good yields. The diazo compounds and alkynyl bromides were generated in situ from tosylhydrazones and gem-dibromoalkenes, respectively. The reaction system exhibited high regioselectivity and good functional group tolerance.
Q. Sha, Y. Wei, Synthesis, 2013, 45, 413-420.

A simple one-pot method allows the synthesis of diversely functionalized N-arylpyrazoles from aryl nucleophiles, di-tert-butylazodicarboxlate, and 1,3-dicarbonyl or equivalent compounds.
B. S. Gerstenberger, M. R. Rauckhorst, J. T. Starr, Org. Lett., 2009, 11, 2097-2100.

M. S. M. Ahmed, K. Kobayashi, A. Mori, Org. Lett., 2005, 7, 4487-4489.

A regioselective synthesis of tri- or tetrasubstituted pyrazoles by the reaction of hydrazones with nitroolefins mediated with strong bases such as t-BuOK exhibits a reversed, exclusive 1,3,4-regioselectivity. Subsequent quenching with strong acids such as TFA is essential to achieve good yields. A stepwise cycloaddition reaction mechanism is proposed.
X. Deng, N. S. Mani, Org. Lett., 2008, 10, 1307-1310.

Two general protocols for the reaction of electron-deficient N-arylhydrazones with nitroolefins allow a regioselective synthesis of 1,3,5-tri- and 1,3,4,5-tetrasubstituted pyrazoles. Studies on the stereochemistry of the key pyrazolidine intermediate suggest a stepwise cycloaddition mechanism.
X. Deng, N. S. Mani, J. Org. Chem., 2008, 73, 2412-2415.

A regioselective one-pot synthesis of substituted pyrazoles from N-monosubstituted hydrazones and nitroolefins gives products in good yields. A key nitropyrazolidine intermediate is characterized and a plausible mechanism is proposed.
X. Deng, N. S. Mani, Org. Lett., 2006, 8, 3505-3508.

A highly efficient Pt-catalyzed [3,3] sigmatropic rearrangement/cyclization cascade of N-propargylhydrazones provides expedient access to various highly functionalized pyrazoles.
J.-J. Wen, H.-T. Tang, K. Xiong, Z.-C. Ding, Z.-P. Zhan, Org. Lett., 2014, 16, 5940-5943.

An unprecedented ruthenium(II)-catalyzed oxidative C-N coupling method enables a facile intramolecular synthesis of various synthetically challenging tri- and tetrasubstituted pyrazoles in the presence of oxygen as oxidant. The reaction demonstrates excellent reactivity, functional group tolerance, and high yields.
J. Hu, S. Chen, Y. Sun, J. Yang, Y. Rao, Org. Lett., 2012, 14, 5030-5033.

A general, highly flexible Cu-catalyzed domino C-N coupling/hydroamination reaction constitutes a straightforward alternative to existing methodology for the preparation of pyrroles and pyrazoles.
R. Martin, M. R. Rivero, S. L. Buchwald, Angew. Chem. Int. Ed., 2006, 45, 7079-7082.

Highly efficient nBu3P-catalyzed desulfonylative [3 + 2] cycloadditions of allylic carbonates with arylazosulfones enable the synthesis of pyrazole derivatives in very good yields under mild conditions.
Q. Zhang, L.-G. Meng, K. Wang, L. Wang, Org. Lett., 2015, 17, 872-875.

"One-Pot" Synthesis of 4-Substituted 1,5-Diaryl-1H-pyrazole-3-carboxylic Acids via a MeONa/LiCl-Mediated Sterically Hindered Claisen Condensation-Knorr Reaction-Hydrolysis Sequence
J.-A. Jiang, C.-Y. Du, C.-H. Gu, Y.-F. Ji, Synlett, 2012, 23, 2965-2968.

Alumino-heteroles are obtained from simple precursors in a fully chemo- and regioselective manner by a metalative cyclization. The carbon-aluminum bond is still able to react further with several electrophiles, without the need of transmetalation providing a straightforward access to 3,4,5-trisubstituted isoxazoles and 1,3,4,5-tetrasubstituted pyrazoles.
O. Jackowski, T. Lecourt, L. Micouin, Org. Lett., 2011, 13, 5664-5667.

Various 1-acyl-5-hydroxy-4,5-dihydro-1H-pyrazoles have been prepared in good yields from the corresponding 2-alkyn-1-ones. The resulting dihydropyrazoles undergo dehydration and iodination in the presence of ICl and Li2CO3 at room temperature to provide 1-acyl-4-iodo-1H-pyrazoles.
J. P. Waldo, S. Mehta, R. C. Larock, J. Org. Chem., 2008, 73, 6666-6670.

A rhodium-catalyzed addition-cyclization of hydrazines with alkynes affords highly substituted pyrazoles under mild conditions. The cascade reaction involves two transformations: addition of the C-N bond of hydrazines to alkynes via unexpected C-N bond cleavage and intramolecular dehydration cyclization.
D. Y. Li, X. F. Mao, H. J. Chen, G. Rong, P. N. Liu, Org. Lett., 2014, 16, 3476-3479.

A one-pot, three-component coupling of aldehydes, 1,3-dicarbonyls, and diazo compounds as well as tosyl hydrazones enables an operationally simple and high yielding synthesis of polyfunctional pyrazoles. The reaction proceeds through a tandem Knoevenagel condensation, 1,3-dipolar cycloaddition, and transition metal-free oxidative aromatization reaction sequence utilizing molecular oxygen as a green oxidant.
A. Kamal, K. N. V. Sastry, D. Chandrasekhar, G. S. Mani, P. R. Adiyala, J. B. Nanubolu, K.  J. Singarapu, R. A. Maurya, J. Org. Chem., 2015, 80, 4325-4335.

A tandem catalytic cross-coupling/electrocyclization allows the conversion of differentially substituted acyclic and cyclic enol triflates and an elaborated set of diazoacetates to provide the corresponding 3,4,5-trisubstituted pyrazoles with a high degree of structural complexity.
D. J. Babinski, H. R. Aguilar, R. Still, D. E. Frantz, J. Org. Chem., 2011, 76, 5915-5923.

A series of 4-substituted 1H-pyrazole-5-carboxylates was prepared from the cyclocondensation reaction of unsymmetrical enaminodiketones with tert-butylhydrazine hydrochloride or carboxymethylhydrazine. The compounds were obtained regiospecifically and in very good yields.
F. A. Rosa, P. Machado, P. S. Vargas, H. G. Bonacorso, N. Zanatta, M. A. P. Martins, Synlett, 2008, 1673-1678.

An easy and efficient copper-catalyzed reaction for the synthesis of polysubstituted pyrazoles from phenylhydrazones and dialkyl ethylenedicarboxylates tolerates a range of functionalities, and the corresponding adducts can be obtained in moderate to good yields.
C. Ma, Y. Li, P. Wen, R. Yan, Z. Ren, G. Huang, Synlett, 2011, 1321-1323.

The reaction of diazo(trimethylsilyl)methylmagnesium bromide with aldehydes or ketones gave 2-diazo-2-(trimethylsilyl)ethanols, which were applied to the synthesis of di- and trisubstituted pyrazoles via [3+2] cycloaddition reaction with ethyl propiolate or dimethyl acetylenedicarboxylate.
Y. Hari, S. Tsuchida, R. Sone, T. Aoyama, Synthesis, 2007, 3371-3375.

An I2-catalyzed oxidative cross coupling of N-sulfonyl hydrazones with isocyanides in the presence of TBHP as terminal oxidant enables the synthesis of 5-aminopyrazoles through formal [4 + 1] annulation via in situ azoalkene formation. Notable features are a metal/alkyne-free strategy, atom economy, catalytic I2, broad functional group tolerance, good reaction yields and short time.
G. C. Senadi, W.-P. Hu, T.-Y. Lu, A. M. Garkhedkar, J. K. Vandavasi, J.-J. Wang, Org. Lett., 2015, 17, 1521-1524.

In a single-step method for the synthesis of aminopyrazoles from isoxazoles, hydrazine serves to open the isoxazole to the unisolated ketonitrile intermediate and form the aminopyrazole. The two-step process involves ring opening of the isoxazole by deprotonation with hydroxide to generate the ketonitrile followed by the addition of acetic acid and hydrazine to form the aminopyrazole.
N. J. Kallman, K. P. Cole, T. M. Koenig, J. Y. Buser, A. D. McFarland, L. M. McNulty, D. Mitchell, Synthesis, 2016, 48, 3537-3543.

Visible light photoredox catalysis enables a selective and high yielding synthesis of polysubstituted pyrazoles in very good yields from hydrazine and various Michael acceptors under very mild reaction conditions in the presence of air as the terminal oxidant. The reaction is proposed to go through VLPC-promoted oxidation of hydrazine to diazene followed by its addition to Michael acceptors.
Y. Ding, T. Zhang, Q.-Y. Chen, C. Zhu, Org. Lett., 2016, 18, 4206-4209.

In the presence of activated carbon, Hantzsch 1,4-dihydropyridines and 1,3,5-trisubstituted pyrazolines were aromatized with molecular oxygen to the corresponding pyridines and pyrazoles in excellent yields.
N. Nakamichi, Y. Kawashita, M. Hayashi, Synthesis, 2004, 1015-1020.