Disubstituted Hydrazines Research Articles

Synthesis of N,N‐Disubstituted Hydrazines by Electrocatalytic Addition of Hydrazines to α,β‐Unsaturated Carbonyl Compounds

AbstractA strategy for the synthesis of N,N‐disubstituted hydrazines via the electrocatalytic addition of hydrazine to α,β‐unsaturated carbonyl compounds is reported. The reaction was carried out under constant current electrolytic conditions in an undivided cell. Using this methodology, various N,N‐disubstituted hydrazines were prepared in 57–94% yield in 40 minutes. By adding cyclohexanone and acetic acid to the reaction mixture of N,N‐disubstituted hydrazines and heating for 2 hours, a one‐pot synthesis of N‐substituted indoles was also developed. Furthermore, based on cyclic voltammetry and control experiments, a plausible mechanism involving a radical pathway is proposed.

From indole to pyrrole, furan, thiophene and pyridine: Search for novel small molecule inhibitors of bacterial transcription initiation complex formation

The search for small molecules capable of inhibiting transcription initiation in bacteria has resulted in the synthesis of N,N′-disubstituted hydrazines and imine-carbohydrazides comprised of indole, pyridine, pyrrole, furan and thiophene using the respective trichloroacetyl derivatives, carbohydrazides and aldehydes. Replacement of the indole moiety by smaller heterocycles linked by CONHNC linkers afforded a broad variety of compounds efficiently targeting the RNA polymerase–σ70/σA interaction as determined by ELISA and exhibiting increased inhibition of the growth of Escherichia coli compared to Bacillus subtilis in culture. The structural features of the synthesized transcription initiation inhibitors needed for antibacterial activity were identified employing molecular modelling and structure–activity relationship (SAR) studies.

Pd-Catalyzed Regioselective Allylation of Mono- and Disubstituted Hydrazines

Palladium-catalyzed allylation of hydrazines using allyl alcohols is reported. This highly efficient protocol furnishes monoallylated hydrazines selectively, in 27-99% yields. Following an optimization of the reaction conditions and of the Pd-ligands, the allylations of both mono- and disubstituted hydrazines were investigated, as well as the effects of C2-substitution on the allylating agent. Of particular interest, a novel method for the selective monoallylation of monosubstituted hydrazines is demonstrated.

Zirconium Hydrazinediido Complexes Derived from Cyclic Hydrazines and Their Role in the Catalytic Synthesis of 1,7-Annulated Indoles

Reaction of cyclic 1,1′-disubstituted hydrazines with the bis(dimethylamido)zirconium complex [Zr{(NXyl)2Npy} (NMe2)2] (1) in the presence of dmap yielded the hexacoordinate zirconium hydrazinediido complexes [Zr{(NXyl)2Npy}(═NNC9H10)(dmap)2] (2) and [Zr{(NXyl)2Npy}(═NNC12H8)(dmap)2] (3). Hydrazinediides are thought to be key intermediates in the zirconium-catalyzed reaction of cyclic 1,1′-disubstituted hydrazines and disubstituted alkynes to yield 1,7-annulated indoles. Their basic structural motif is found in 5-HT3 receptor antagonists such as Cilansetron.

Organocatalytic cascade aza-Michael/hemiacetal reaction between disubstituted hydrazines and α,β-unsaturated aldehydes: Highly diastereo- and enantioselective synthesis of pyrazolidine derivatives

The catalytic synthesis of nitrogen-containing heterocycles is of great importance to medicinal and synthetic chemists, and also a challenge for modern chemical methodology. In this paper, we report the synthesis of pyrazolidine derivatives through a domino aza-Michael/hemiacetal sequence with chiral or achiral secondary amines as organocatalysts. Thus, a series of achiral pyrazolidine derivatives were obtained with good yields (up to 90%) and high diastereoselectivities (>20:1) with pyrrolidine as an organocatalyst, and enantioenriched pyrazolidines are also achieved with good results (up to 86% yield, >10/1 regioselectivity, >20:1 dr, 99% ee) in the presence of (S)-diphenylprolinol trimethylsilyl ether catalyst.

ChemInform Abstract: Assembly of N,N‐Disubstituted Hydrazines and 1‐Aryl‐1H‐indazoles via Copper‐Catalyzed Coupling Reactions.

CuI-catalyzed coupling of N-acyl-N′-substituted hydrazines with aryl iodides takes place at 60–90 °C to afford N-acyl-N′,N′-disubstituted hydrazines regioselectively and thereby gives a facile method for assembling N,N-diaryl hydrazines. N-Acyl-N′-substituted hydrazines can also react with 2-bromoarylcarbonylic compounds at 60–125 °C under the catalysis of CuI/4-hydroxy-l-proline to provide 1-aryl-1H-indazoles.

Assembly of N,N-Disubstituted Hydrazines and 1-Aryl-1H-indazoles via Copper-Catalyzed Coupling Reactions

CuI-catalyzed coupling of N-acyl-N'-substituted hydrazines with aryl iodides takes place at 60-90 °C to afford N-acyl-N',N'-disubstituted hydrazines regioselectively and thereby gives a facile method for assembling N,N-diaryl hydrazines. N-Acyl-N'-substituted hydrazines can also react with 2-bromoarylcarbonylic compounds at 60-125 °C under the catalysis of CuI/4-hydroxy-l-proline to provide 1-aryl-1H-indazoles.

Gold-Catalyzed Three-Component Annulation: Efficient Synthesis of Highly Functionalized Dihydropyrazoles from Alkynes, Hydrazines, and Aldehydes or Ketones

Polysubstituted dihydropyrazoles were directly obtained by a gold-catalyzed three-component annulation. This reaction consists of a Mannich-type coupling of alkynes with N,N'-disubstituted hydrazines and aldehydes/ketones followed by intramolecular hydroamination. Cascade cyclization using 1,2-dialkynylbenzene derivatives as the alkyne component was also performed producing fused tricyclic dihydropyrazoles in good yields.

Arylation of Diversely Substituted Hydrazines by Tri‐ and Pentavalent Organobismuth Reagents.

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Arylation of diversely substituted hydrazines by tri- and pentavalent organobismuth reagents

Various hydrazine derivatives were studied with respect to arylation by triarylbismuthane and triarylbismuth diacetate reagents with emphasis on scope and limitations. Among these reagents, a few contained bulky substituents in their aromatic rings. The applied substrates spanned a range from simple hydrazides to triply protected hydrazines and included a large number of intermediates of principal synthetic interest. In the case of mono- and disubstituted hydrazines the results demonstrate apparent advantages of pentavalent over trivalent reagents, exemplified by fast, highly chemoselective monoarylation of acylhydrazines at the terminal nitrogen. In contrast, trisubstituted hydrazines are more efficiently substituted by trivalent reagents. With these substrates, a strong influence of steric factors was occasionally observed, as reflected in lower yields and even complete reaction inhibition. The introduction of two different aromatic substituents into disubstituted hydrazines using step-by-step or one-pot procedures was accomplished.

Sequential azomethine imine cycloaddition–palladium catalysed cyclisation processes

In situ generation of azomethine imines from aryl/heteroaryl aldehydes and N, N′-disubstituted hydrazines followed by cycloaddition to N-methylmaleimide generates pyrazolidines, which undergo Pd(0) catalysed cyclisation involving the aldehyde and hydrazine substituents, with formation of 6–8 membered rings in good yield. AMI calculations indicate the preferred configuration of the azomethine imines involved and identify the most likely cycloaddition transition states.

Highly selective arylation of disubstituted hydrazines by pentavalent organobismuth reagents

The scope of a set of recently reported hydrazine reagents has been explored with respect to arylation. Compounds of type R 1NHNHCOR 2 can be selectively arylated under very mild conditions using triarylbismuth diacetates.

Preparations of Trisubstituted Hydrazines and Pyrazolidines from N-(1-Benzotriazolylalkyl)hydrazines.

Reactions of N,N'-disubstituted hydrazines with benzotriazole and aldehydes give N-(alpha-benzotriazoylalkyl)-N,N'-disubstituted hydrazines which on treatment with organometallic reagents form N-alkyl-N,N'-disubstituted hydrazines in good yields. N-(Benzotriazolylalkyl)-N,N'-disubstituted hydrazines and electron-rich olefins, in the presence of zinc bromide catalyst, generate N,N'-disubstituted pyrazolidines in moderate to good yields.

Alkylation of purine bases by carbon-centered radicals.

Mono- and di-substituted hydrazines are found ubiquitously (1, 2). They are present in the environment since they are used as herbicides, chemical intermediates, and as high energy fuels for rockets. They are found in plants such as tobacco and mushrooms. They are also present in medicine. All substituted hydrazines tested for carcinogenicity in long-term animal studies have been found to be positive (1). 1, 2-dimethylhydrazine (DMH) is a well known carcinogen that induces tumors specifically in the colon of rodents (3). Since DMH-induced lesions have characteristics that are remarkably similar to those of human colon cancer, this carcinogen is widely used as a model in the study of colon cancer. The ethyl derivative of DMH, 1, 2-diethylhydrazine (DEH), is also a carcinogen. DEH produces cancer in the thymus, liver, and brain (4). The mechanism(s) by which these di-alkyl hydrazines induce tumors is not known. Kang et al. (5) have shown that in rats the metabolism of DMH and DEH produces methyl radicals (·CH3) and ethyl radicals (·CH2CH3), respectively. Therefore, this investigation was conducted to explore the nature of the chemical interaction(s) between alkyl radicals and biomolecules using CH3 and RNA as models.KeywordsAlkyl RadicalEthyl RadicalPurine BaseChemical IntermediateChemical CarcinogenesisThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Carbon-centered free radical formation during the metabolism of hydrazine derivatives by neutrophils

The neutrophil-catalyzed metabolism of hydrazine derivatives to carbon-centered radicals was investigated by the spin-trapping technique using α-(4-pyridyl-l-oxide)- N- tert-butylnitrone (POBN). Oxidation of methylhydrazine (MeH), dimethylhydrazine (DMH), phenylethylhydrazine or procarbazine by neutrophils from rat peritoneal exudates led to the formation of alkyl radicals. The monosubstituted hydrazine oxidation by phorbol ester (PMA)- or Zymocel-activated neutrophils generated, on average, 2- to 4-fold more POBN-alkyl adducts than di-substituted hydrazines. Supernatant from sonicated neutrophils generated similar yields of radicals. Azide, an inhibitor of myeloperoxidase, effectively reduced the neutrophil-catalyzed radical yield from the oxidation of MeH but not DMH. On the other hand, Superoxide dismutase and catalase effectively inhibited radical formation in DMH metabolism by PMA-activated neutrophils, in contrast to MeH metabolism. Our results show that neutrophils are able to metabolize hydrazine derivatives, the pathway depending on the hydrazine substitution. AlkyI radical production during the oxidation of mono-substituted derivatives, such as MeH, was mediated mainly by myeloperoxidase, and that of di-substituted derivatives, such as DMH, was mediated mainly by active oxygen species.

ChemInform Abstract: Nitrosamines and Hydrazones of Dinitroformaldehyde from N,N‐ Disubstituted Hydrazines, a Dialkyl Nitroxide, and Tetranitromethane.

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ChemInform Abstract: Formation of 3‐Amino‐1,5,6,7‐tetrahydro‐4H‐indol‐4‐ones from 2‐(2‐Oxo‐2‐arylethyl)‐1,3‐cyclohexanediones and N,N‐Disubstituted Hydrazines.

AbstractThe phenacyldimedones (I) react with the disubstituted hydrazines (II) forming the tetrahydroindolones (III).

ChemInform Abstract: New Organonitrogen‐Derivatized Polyoxomolybdate Anion Clusters. Syntheses and Characterization of Tetranuclear and Octanuclear Oxomolybdates Containing Coordinatively Bound Organohydrazido(2‐) Units: (Mo4O10(OCH3)2(NNPh2)2)2‐ and (Mo8O16(OCH3)6(NNMePh)6)2‐.

AbstractThe 1:6 molar reaction of the octamolybdate (I) with disubstituted hydrazines NH2NPhR at room temp. (24 h) affords the tetranuclear methoxo‐bridged bis(hydrazido) clusters (II).

Indoles, IV 9‐Substituted 4,9‐Dihydropyrano[3,4‐b]indol‐1(3H)‐ones ‐ Synthesis and Conversion into 2,3,4,9‐Tetrahydro‐ 1H‐pyrido‐[3,4‐b]indoles

AbstractPyrano[3,4‐b]indolones 3a‐d are available from α‐ethoxyalyllactones 1a, c and disubstituted hydrazines 2a, b without isolation of intermediates. In a two‐phase system, however, the intermediate hydrazones 4a, c can be isolated. Conversion of 3a‐d into β‐carbolines was not possible by lactamisation but via the amides 8 and 9.

α-(1-phenylhydrazino)-alkanone phenylhydrazones: The reaction with carbonyl compounds

The unsymmetrically disubstituted hydrazines 1 were condensed with carbonyl compounds. Some of the expected condensation products were isolated, but some were formed as unstable intermediates which underwent 1,4-elimination: The phenylhydrazone of the carbonyl compound used was obtained, together with the corresponding phenylazo-alkene 11 or alternatively, the 1,4-addition product of a different protic nucleophile to 11.