Synthesis of Hydrazine Derivatives (Hydrazides)

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An efficient method for the direct reductive alkylation of hydrazine derivatives with α-picoline-borane provided various N-alkylhydrazine derivatives upon fine-tuning of the substrates and the reagent equivalency in a one-pot manner. The method was applied to the synthesis of active pharmaceutical ingredients of therapeutic drugs such as isocarboxazid.
Y. Kawase, T. Yamagishi, J.-y. Kato, T. Kutsuma, T. Kataoka, T. Iwakuma, T. Yokomatsu, Synthesis, 2014, 46, 455-464.

Lewis base promoted direct reductive hydrazination enables a straightforward and facile synthesis of 1,1-disubstituted hydrazines with very good yields. Under the catalysis of hexamethylphosphoramide (HMPA) and N,N-dimethylacetamide (DMAc), respectively, various ketones and aldehydes reacted with phenylhdrazines.
T. Wang, X. Di, C. Wang, L. Zhou, J. Sun, Org. Lett., 2016, 18, 1900-1903.

A Ni(II)-bipyridine complex catalyzes a general and highly efficient photochemical C-N coupling reaction of challenging (hetero)aryl chlorides with hydrazides in the presence of an amine base without an external photosensitizer. This reaction provides a wide range of arylhydrazines with excellent functional group tolerance.
F. Lei, W. Xiong, G. Song, Y. Yan, G. Li, C. Wang, J. Xiao, D. Xue, Org. Lett., 2023, 25, 3287-3292.

A diaminocyclopentadienone ruthenium tricarbonyl complex catalyzes the synthesis of mono- or dialkylated acyl hydrazide compounds with primary and secondary alcohols as alkylating reagents using the borrowing hydrogen strategy. DFT calculations unveil the origin and the threshold between mono- and dialkylation.
N. Joly, L. Bettoni, S. Gaillard, A. Poater, J.-C. Renaud, J. Org. Chem., 2021, 86, 6818-6825.

[Cp*Ir(2,2'-bpyO)(H₂O)] catalyzes a transfer hydrogenation/N-methylation of acylhydrazones with methanol as both the hydrogen source and the methylating reagent to provide N',N'-methylaliphatic acylhydrazides in high yields. It was also confirmed that functional units in the bpy ligand of the catalyst are crucial for the catalytic activity of iridium complexes.
S. Luo, X. Xu, P. Zhang, Q. Shi, X. Yang, F. Li, Org. Lett., 2022, 24, 9081-9085.

N-acyl- and N-alkoxycarbonylaminophthalimides are efficiently used as acid partners in Mitsunobu reaction. This reaction allows them to be alkylated by primary, secondary or benzyl groups. A final dephthaloylation step results in an efficient method for the preparation of 1,1-substituted hydrazines.
N. Brosse, M.-F. Pinto, B. Jamart-Grégoire, J. Org. Chem., 2000, 65, 4370-4374.

A palladium-catalyzed C-N bond coupling reaction between arylhydrazines and aryl tosylates provides unsymmetrical N,N-diarylhydrazines in very good yields with good functional group compatibility.
Y. Huang, P. Y. Choy, J. Wang, M.-K. Tse, R. W.-Y. Sun, A. S.-C. Chan, F. Y. Kwong, J. Org. Chem., 2020, 85, 14664-14673.

Reactions of 4-alkyl-1,4-dihydropyridines as alkylation reagents with di-tert-butyl azodicarboxylate provide alkyl amine derivatives under heating conditions in the absence of catalysts and additives.
K. Nakajima, Y. Zhang, Y. Nishibayashi, Org. Lett., 2019, 21, 4642-4645.

CuI catalyzes a convenient intermolecular N-arylation of hydrazides with para- and meta-substituted aryl iodides in the presence Cs₂CO₃. A reversal in regioselectivity is observed for the arylation of benzoic hydrazide with ortho-substituted aryl iodides.
M. Wolter, A. Klapars, S. L. Buchwald, Org. Lett., 2001, 3, 3803-3805.

CuI/4-hydroxy-l-proline-catalyzed coupling of aryl bromides and N-Boc hydrazine takes place in DMSO to give N-aryl hydrazides. When aryl iodides are employed, no ligand is required. Under the catalysis of CuI/4-hydroxy-l-proline, the coupling reaction of aqueous ammonia with aryl bromides proceeds smoothly to afford primary arylamines.
L. Jiang, X. Lu, H. Zhang, Y. Jiang, D. Ma, J. Org. Chem., 2009, 74, 4542-4546.

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.

A catalytic one-pot synthesis of both symmetrical and unsymmetrical N,N-disubstituted acylhydrazides using an assortment of primary and secondary alcohols offers remarkable selectivity and excellent yields. The use of diols provides cyclic products with privileged structures.
S. Thiyagarajan, C. Gunanathan, Org. Lett., 2020, 22, 6617-6622.2.

The use of a catalytic amount of palladium, a MOP-type ligand, and Cs₂CO₃ enables a convenient method for the intermolecular N-arylation of hydrazides with aryl halides. The reaction gives coupled products in very good yields and tolerates a wide spectrum of functional groups.
F.-F. Ma, Z.-Y. Peng, W.-F. Li, X.-M. Xie, Z. Zhang, Synlett, 2011, 2555-2558.

A copper-catalyzed addition of arylboronic esters to di-tert-butyl azodicarboxylate affords Boc-protected arylated hydrazine derivatives in good yields under mild reaction conditions. The reaction tolerates various functional groups.
T. Uemura, M. Yamaguchi, N. Chatani, Synthesis, 2015, 47, 3746-3750.

Copper(I) oxide catalyzes an efficient intermolecular N-arylation of the anionic species derived from diisopropyl azodicarboxylate and sodium hydride with various aryl trifluoromethanesulfonates without ligand at 80 °C in N,N-dimethylformamide.
I. Yavari, M. Ghazanfarpour-Darjani, M. J. Bayat, A. Malekafzali, Synlett, 2015, 26, 942-944.

A gold(III) chloride catalyzed direct amination of arenes with azodicarboxylates allows the conversion of a broad range of substrates, including electron-deficient arenes, under mild conditions. This reaction provides an important approach for the synthesis of heterocyclic compounds in pharmaceutical and chemical industries.
L. Gu, B. S. Neo, Y. Zhang, Org. Lett., 2011, 13, 1872-1874.

Alkylation of hydrazine using a polyanion strategy provides a fast and convenient access to multialkylated hydrazine derivatives. Scope and limitations of the new method are also investigated.
A. Bredihhin, U. Mäeorg, Org. Lett., 2007, 9, 4975-4977.

A. Bredihhin, U. Mäeorg, Org. Lett., 2007, 9, 4975-4977.

Formation and use of a nitrogen dianion for selective hydrazine alkylation provides a fast and easy access to substituted hydrazines, which are widely used as drugs, pesticides, and precursors for a variety of compounds in organic synthesis.
A. Bredihhin, U. M. Groth, U. Mäeorg, Org. Lett., 2007, 9, 1097-1099.

A. Bredihhin, U. M. Groth, U. Mäeorg, Org. Lett., 2007, 9, 1097-1099.

A mild, copper-catalyzed addition of aryl- and heteroarylboronic acids to azo compounds is described. Excellent regioselectivity was observed in the addition to unsymmetrical azo compounds.
K. Kisseljova, O. Tšubrik, R. Sillard, S. Mäeorg, U. Mäeorg, Org. Lett., 2006, 8, 43-45.

K. Kisseljova, O. Tšubrik, R. Sillard, S. Mäeorg, U. Mäeorg, Org. Lett., 2006, 8, 43-45.

Excellent regioselectivity is observed in the addition of diverse organometallic nucleophiles to unsymmetrical azo compounds. Primary/secondary/tertiary alkyl, aryl and heteroaryl substituents were introduced this way in high yields.
O. Tšubrik, R. Sillard, U. Mäeorg, Synthesis, 2006, 843-846.

An efficient palladium-catalyzed allylic substitution of allyl acetates with arylhydrazines as nucleophiles provides N,N-disubstituted hydrazines in good yields under mild conditions. This method is highly regioselective and tolerates reactive groups such as Cl, Br, and I.
X. Wang, X. Wang, S. Shu, J. Liu, Q. Liu, T. Wang, Z. Zhang, Org. Lett., 2023, 25, 4880-4885.

The combination of cheap CuCl₂ with TMEDA catalyzes the reaction of terminal alkynes with dialkyl azodicarboxylates to provide ynehydrazides. The protocol offers high sustainability, good practicality, broad substrate scope, and wide functional group tolerance.
J. Lei, W. Sha, X. Xie, W.-T. Weng, Org. Lett., 2023, 25, 320-324.

An acid-mediated electrophilic hydrazinative halogenation of alkenes proceeds with readily available diethyl azodicarboxylate as a hydrazine source and low-cost potassium halides as nucleophilic halogen sources. A series of iodinated, brominated, and chlorinated hydrazines are facilely produced with a wide range of functional groups.
N. Huang, L. Liao, X. Zhao, Org. Lett., 2023, 25, 6587-6592.

The reaction of benzoyl acrylates, derived from Morita-Baylis-Hillman adducts, with hydrazines provides a range of N',N'-disubstituted benzohydrazides via a serendipitous carbon-carbon bond cleavage. The reaction features a regioselective formation of two carbon-nitrogen bonds.
A. K. Jha, R. Kumari, S. Easwar, Org. Lett., 2019, 21, 8149-8152.

A simple electrophilic amination of β-homoenolates derived from aryl- and alkyl-substituted cyclopropanols precursors with azodicarboxylates or azodicarboxamides provides bifunctional γ-keto hydrazine intermediates under mild conditions. The obtained products provide convenient synthetic access to γ-hydroxy hydrazide, γ-amino hydrazide, and heterocyclic derivatives.
T. Ramar, A. Ilangovan, N. A. Meanwell, M. A. M. Subbaiah, J. Org. Chem., 2022, 87, 14596-14608.

Using FeCl₃ as catalyst, a photoinduced ligand-to-metal charge transfer facilitates the generation of O-radicals from nonactivated cyclic alcohols, a subsequent β-scission, and finally a radical trapping. This mildly base-free system enables an amination of a broad substrate scope with high yields.
Z. Zhang, T. Xue, Z. Han, R. Zeng, Synthesis, 2023, 55, 433-442.

Catalytically generated boron enolates of carboxylic acids react with diisopropylazodicarboxylate as electrophilic aminating reagent to provide amino acid derivatives. The resulting α-aminocarboxylic acids can easily be converted to carboxylic acid derivatives. Extension to a catalytic asymmetric variant was possible by introducing a chiral ligand on the boron catalyst.
T. Morisawa, M. Sawamura, Y. Shimizu, Org. Lett., 2019, 21, 7466-7469.

A ligand-to-metal charge transfer (LMCT) excitation-homolysis process with an abundant and inexpensive cerium salt as the catalyst enables a direct catalytic generation of energetically challenging alkoxy radicals from alcohols. This catalytic manifold provides a simple and efficient way for versatile a δ-selective C-H bond functionalization under mild redox-neutral conditions.
A. Hu, J.-J. Guo, H. Pan, H. Tang, Z. Gao, Z. Zuo, J. Am. Chem. Soc., 2018, 140, 1612-1616.

In situ aerobic dual oxidation with asymmetric organocatalysis enables an enantioselective synthesis of α-hydrazino aldehydes from alcohols and N-Boc hydrazine instead of the conventional combination of aldehydes with azodicarboxylates. This reaction tolerates various substituents on the alcohol component and features excellent enantiocontrol, cheap starting materials, operational simplicity, and scalability.
Z. Cui, D.-M. Du, Org. Lett., 2016, 18, 5616-5619.

A regioselective intermolecular three-component reaction of styrenes with acetonitrile and azodicarboxylates provides vicinal diamination products in good yields via the Ritter reaction.
J. Cao, D. Lv, F. Yu, M.-F. Chiou, Y. Li, H. Bao, Org. Lett., 2021, 23, 3184-3189.

Mercuric triflate [Hg(OTf)₂] as a catalyst enables an efficient method for carbon-nitrogen bond formation between ally silyl ethers and N,N-acyltosylhydrazine under very mild conditions to yield various N-allylhydrazides in very good yields. This method does not require the use of any ligand system or supplementary additives.
M. Hayashi, M. Shibuya, Y. Iwabuchi, Synlett, 2012, 23, 1025-1030.

A highly chemo- and regioselective allylic amination of various hydrazones and hydrazides with allylic carbonates proceeds at ambient temperature in the presence of an [Ir(COD)Cl]₂/pyridine catalyst, ammonium iodide, and diethylzinc to afford the corresponding N-allylation products in high yields.
R. Matunas, A. J. Lai, C. Lee, Tetrahedron, 2005, 61, 6298-9308.

FeCl₃ mediates a propargylic substitution of tertiary propargylic alcohols with p-toluenesulfonyl hydrazide. A subsequent cyclization under mild conditions in the presence of iodine enables an efficient and rapid synthesis of iodo-3H-pyrazoles with a wide substrate scope and in high yields.
X.-T. Liu, Z.-C. Ding, L-C. Ju, Z.-N. Tang, F. Wu, Z.-P. Zhan, Synlett, 2017, 28, 620-624.

An efficient electrocatalytic aziridination of alkenes provides a structurally broad range of aziridines using an undivided cell operated at constant current and mediated by a catalytic quantity of n-Bu₄NI. The electrocatalytic reaction also proceeded in the absence of additional conducting salt.
J. Chen, W.-Q. Yan, C. M. Lam, C.-C. Zeng, L.-M. Hu, R. D. Little, Org. Lett., 2015, 17, 986-989.