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Synthesis of pyrazoles and indazoles

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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.

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.

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.

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 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.

CuI-catalyzed coupling of N-acyl-N′-substituted hydrazines with aryl iodides affords N-acyl-N′,N′-disubstituted hydrazines regioselectively. N-Acyl-N′-substituted hydrazines can also react with 2-bromoarylcarbonylic compounds in the presence of 4-hydroxy-L-proline as ligand to provide 1-aryl-1H-indazoles.
X. Xiong, Y. Jiang, D. Ma, Org. Lett., 2012, 14, 2552-2555.

An efficient synthesis of 2H-indazole derivatives in a one-pot three-component reaction of 2-chloro- and 2-bromobenzaldehydes, primary amines and sodium azide is catalyzed by copper(I) oxide nanoparticles (Cu2O-NP) under ligand-free conditions in polyethylene glycol (PEG 300) as a green solvent.
H. Sharghi, M. Aberi, Synlett, 2014, 25, 1111-1115.

2H-Indazoles are synthesized using a copper-catalyzed one-pot, three-component reaction of 2-bromobenzaldehydes, primary amines, and sodium azide. The catalyst plays the key role in the formation of C-N and N-N bonds. This method has a broad substrate scope with a high tolerance for various functional groups.
M. R. Kumar, A. Park, N. Park, S. Lee, Org. Lett., 2011, 13, 3542-3545.

In an operationally simple, mild and efficient one-pot synthesis of 2H-indazoles from commercially available reagents, ortho-imino-nitrobenzene substrates, generated via condensation, undergo reductive cyclization promoted by tri-n-butylphosophine to afford substituted 2H-indazoles. Various electronically diverse ortho-nitrobenzaldehydes and aromatic as well as aliphatic amines were examined.
N. E. Genung, L. Wei, G. E. Aspnes, Org. Lett., 2014, 16, 3114-3117.

Various N-aryl-1H-indazoles and benzimidazoles were synthesized from common arylamino oximes in good to excellent yields depending upon the base used in the reaction. Triethylamine promoted the formation of benzimidazoles, whereas 2-aminopyridine promoted the formation of N-arylindazoles.
B. C. Wray, J. P. Stambuli, Org. Lett., 2010, 12, 4576-4579.

A reductive cyclization of o-nitrobenzylidene amines under microwave conditions in the presence of MoO2Cl2(dmf)2 as catalyst and Ph3P as reducing agent delivers 2-aryl-2H-indazoles in good yields.
A. H. Moustafa, C. C. Malakar, N. Aljaar, E. Merisor, J. Conrad, U. Beifuss, Synlett, 2013, 24, 1573-1577.

1-Aryl-2-(2-nitrobenzylidene)hydrazines readily undergo intramolecular amination to afford 1-aryl-1H-indazole derivatives in good yields in the presence of potassium tert-butoxide in N,N-dimethylformamide at 100 °C. Displacement of the nitro group was achieved in the absence of significant electron-withdrawing substituents.
F. Esmaeili-Marandi, M. Saeedi, M. Mahdavi, I. Yavari, A. Foroumadi, A. Shafiee, Synlett, 2014, 25, 2605-2608.

Azobenzenes were readily acylated at the 2-position with aldehydes in good yields through a Pd-catalyzed C-H functionalization in the presence of TBHP. The obtained acylated azobenzenes could be efficiently converted into the corresponding indazole derivatives in nearly quantitative yields.
H. Li, P. Li, L. Wang, Org. Lett., 2013, 15, 620-623.

A rapid and efficient synthesis of 2H-indazoles, which involves a [3 + 2] dipolar cycloaddition of arynes and sydnones, proceeds under mild reaction conditions in good to excellent yields.
C. Wu, Y. Fang, R. C. Larock, F. Shi, Org. Lett., 2010, 12, 2171-2173.

The 1H-indazole skeleton can be constructed by a [3 + 2] annulation approach from arynes and hydrazones. Under different reaction conditions, both N-tosylhydrazones and N-aryl/alkylhydrazones can be used to afford various indazoles.
P. Li, C. Wu, J. Zhao, D. C. Rogness, F. Shi, J. Org. Chem., 2012, 77, 3127-3133.

Readily available, stable, and inexpensive N-tosylhydrazones react with arynes under mild reaction conditions to afford 3-substituted indazoles in good yields. The reaction involves a 1,3-dipolar cycloaddition of in situ generated diazo compounds and arynes.
P. Li, J. Zhao, C. Wu, R. C. Larock, F. Shi, Org. Lett., 2011, 13, 3340-3343.

The [3+2] cycloaddition of a variety of diazo compounds with o-(trimethylsilyl)aryl triflates in the presence of CsF or TBAF at room temperature provides a very direct, efficient approach to a wide range of potentially biologically and pharmaceutically interesting substituted indazoles in good to excellent yields under mild reaction conditions.
Z. Liu, F. Shi, P. D. G. Martinze, C. Raminelli, R. C. Larock, J. Org. Chem., 2008, 73, 219-226.

A general two-step synthesis of substituted 3-aminoindazoles from 2-bromobenzonitriles involves a palladium-catalyzed arylation of benzophenone hydrazone followed by an acidic deprotection/cyclization sequence. This procedure offers a general and efficient alternative to the typical SNAr reaction of hydrazine with o-fluorobenzonitriles.
V. Lefebvre, T. Cailly, F. Fabis, S. Rault, J. Org. Chem., 2010, 75, 2730-2732.

A Cu-catalyzed coupling reaction of 2-halobenzonitriles with hydrazine carboxylic esters and N′-arylbenzohydrazides proceed smoothly to provide substituted 3-aminoindazoles through a cascade coupling-(deacylation-)condensation process. A wide range of substituted 3-aminoindazoles can be prepared from the corresponding coupling partners.
L. Xu, Y. Peng, Q. Pan, Y. Jiang, D. Ma, J. Org. Chem., 2013, 78, 3400-3401.

A Cu-catalyzed coupling reaction of 2-halobenzonitriles with hydrazine carboxylic esters and N′-arylbenzohydrazides proceed smoothly to provide substituted 3-aminoindazoles through a cascade coupling-(deacylation-)condensation process. A wide range of substituted 3-aminoindazoles can be prepared from the corresponding coupling partners.
L. Xu, Y. Peng, Q. Pan, Y. Jiang, D. Ma, J. Org. Chem., 2013, 78, 3400-3401.

The reaction of β,γ-unsaturated γ-alkoxy-α-keto esters with 5-aminopyrazoles proceeds with high regioselectivity to yield new pyrazolo[1,5-a]pyrimidines bearing an ester function in the 7-position. The obtained drug-like compounds have a great potential for medicinal chemistry as they closely resemble the structure of several marketed pharmaceuticals.
O. O. Stepaniuk, V. O. Matviienko, I. S. Kontratov, I. V. Vitruk, A. O. Tolmachev, Synthesis, 2013, 45, 925-930.