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Novel, Efficient and Regiospecific Alkylation/Arylation/Heteroarylation of Unsymmetrical Azo Compounds
Abstract
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.
We report herein an innovative synthetic strategy for the generation of polysubstituted indoles from indolines, aryldia-zonium salts, and azoles. The methodology encompasses an electrophilic substitution reaction affording C5-indoline in-termediates, which...
From synthesized novel ligand (L) made of Malonic acid dihydrazide and 2-pyridine carboxaldehyde, new complexes have been created. Ni(II), Cu(II), and Zn(II) complexes were created as a result. FT-IR, UV-Vis, Mass, 1H-NMR, 13C-NMR, C.H.N., Chloride-containing, Molar Conductance, Magnetic Susceptibility, and Atomic Absorption have all been used to identify these compounds. For each Nickel, Copper, and Zinc complexes the characterization findings revealed complexes with hexadentate octahedral coordination geometry and tetradentate ligand. Two Gram-positive (Staphylococcus aureus and Bacillus subtitles) and two Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria, as well as candida fungus, were evaluated for the biological activities of the novel compounds. With the exception of the Nickel complex, which failed to produce any effective inhibitory effects against pseudomonas, their results in inhibition were good.
N‐Aryl‐ and N‐alkenylhydrazides, which include a C(sp²)‐N−N motif, have attracted considerable attention not only in biologically active molecules but also because of their extensive technical applications in organic synthesis. C(sp²)−N bond construction protocols using an N‐acylhydrazine or azocarboxylic ester as the hydrazide source provide a powerful route to these compounds. These protocols exhibit different selectivity manner for the C(sp²) moiety and the regioselectivity issue of the N−N bond. This Minireview documents the available methods that have been developed based on different starting materials. The features and drawbacks of each subdivisional methodology are demonstrated.
We describe a tert-butyl nitrite-catalyzed oxidative dehydrogenation of hydrazobenzenes for producing azobenzenes. This method proceeds at ambient temperature and under an atmospheric environment by employing eco-friendly EtOH as the medium, representing a mild, general route to the synthesis of various symmetrical and nonsymmetrical azobenzenes in excellent yields with broad functional group tolerance.
A tandem oxidative cyclization/1,2-carbon migration of hydrazides for the synthesis of otherwise inaccessible hindered or enantiopure triazolopyridinones has been developed. This protocol exhibits broad substrate scope and can be easily scaled up by continuous flow synthesis under mild conditions. Most importantly, this method demonstrates a rearrangement with retention of configuration and can be readily applied for the late-stage modification of carboxylic-acid-containing pharmaceuticals, amino acids, and natural products to access enantiopure triazolopyridinones.
Recently, various fruitful organic reactions such as a catalytic Mitsunobu reaction were reported by virtue of alkyl 2-phenylazocarboxylates, however, the synthesis of alkyl 2-phenylazocarboxylates largely depended on the stoichiometric use of toxic oxidants. In this manuscript, an environment-friendly aerobic oxidative transformation of alkyl 2-phenylhydrazinecarboxylates to alkyl 2-phenylazocarboxylates was disclosed. The use of CuCl and DMAP system efficiently catalyzed the aerobic oxidation of alkyl 2-phenylhydrazinecarboxylates under mild conditions. The reaction rate of the present Cu-catalysis was much faster than that of the previously reported Fe-catalysis, and a variety of azo products were synthesized within 3 hours. The present protocol was effective on larger scale. It was observed that the produced azo compound could undergo various reactions without isolation through one-pot sequential protocols.
A convenient method for the synthesis of 2‐arylazocarboxylates from 2‐arylhydrazinecarboxylates by aerobic oxidation with iron phthalocyanine is described. The reaction is applicable to oxidative activation of 1‐acyl‐2‐phenylhydrazines. Some preliminary experiments suggest Michaelis–Menten kinetics and participation of radical species in the reaction mechanism.
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Allylation and benzylation of phenylazocarboxylic tert-butyl esters have been achieved under Barbier-type reaction conditions and in very short reactions times using the corresponding allyl and benzyl bromides or iodides in combination with zinc powder. Whereas all reactions occurred exclusively at the β-nitrogen atom of the azocarboxylic esters, the linkage of allyl units was shown to depend on the substitution pattern at the double bond of the allyl halide. The hydrazines obtained are useful precursors for indoles or indazoles.
Aromatic-bridged bis(hydrazines) were found to be the main products in the reaction of hydrazine polyanions with α,α′-dibromo-o-xylene. It was confirmed that the reaction is driven by a metal–halogen exchange process. A three-step reaction mechanism is suggested.
Phenylazocarboxylic tert-butyl esters have recently been shown to be highly versatile building blocks due to their ability to undergo nucleophilic aromatic substitutions under mild conditions, particularly well with [18F]fluoride, and to act as precursors for aryl radicals. In this article, we now report first examples for cycloaddition reactions to phenylazocarboxylates. In a one-pot reaction with readily accessible glycine imines, a variety of highly substituted 1,2,4-triazoles could be obtained with an unexpected preference for one regioisomer.
A RhIII-catalyzed C–H activation/cyclative capture approach, involving a nucleophilic addition of C(sp3)–Rh species to polarized double bonds is reported. This constitutes the first intermolecular catalytic method to directly access 1-aminoindolines with a broad substituent scope under mild conditions.
Using N’-aryl acylhydrazines as aryl donors, a novel copper(II)-catalyzed homo-coupling reaction of N’-aryl acylhydrazines has been developed for the synthesis of N’,N’-diaryl acylhydrazines. We also provided a complementary procedure for the preparation of unsymmetrical diaryl acylhydrazines via cross-coupling reaction. These protocols featured mild reaction conditions, wide functional group tolerance and highly regioselective products. Control experiments indicated that this kind of coupling reaction might undergo a transient acyl diazene intermediate.
The data on transformations of dialkyl azodicarboxylates and their analogues involving various substrates are generalized. Nucleophilic addition and oxidation, pericyclic reactions and reactions occurring under the Mitsunobu reaction conditions are considered. Ample opportunities for application of these compounds in fine organic synthesis are shown.
The bibliography includes 245 references.
A new copper salt catalyzed C-N coupling is described. This smooth reaction between azo compounds and organobismuth reagents provides efficient and highly regioselective access to Boc-protected aryl hydrazines. The yields under optimized conditions are mostly excellent and the synthetic procedure is robust and simple.
The first total syntheses of two natural antitumor enehydrazide compounds (hydrazidomycins A and B) and a related positional isomer of hydrazidomycin B (elaiomycin B) have been accomplished in a rapid and stereocontrolled fashion using a Peterson elimination approach. A regioselective silyl epoxide ring opening reaction with Boc-carbazate followed by base-mediated Peterson siloxide elimination stereospecifically installed the key Z-enehydrazide functionality. The use of Boc-carbazate allowed for the differential functionalization of the hydrazide nitrogens.
A photocatalytic system involving [Ru(bpyrz)3](PF6)2·2H2O, visible light, and air has been developed for cleavage of the N-N bonds of hydrazines and hydrazides. This catalytic system is generally effective for N,N-disubstituted hydrazine and hydrazide derivatives, including arylhydrazides, N-alkyl-N-arylhydrazines, and N,N-diarylhydrazines. The utility of this cleavage reaction has been demonstrated by synthesizing a variety of secondary aromatic amines.
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.
In view of the growing demand for new compounds showing biological activity against pathogenic microorganisms, such as pathogenic and phytopathogenic fungi, the objective of this study was to synthesize a new group of aliphatic and aromatic derivatives of hydrazide. In consequence of the reactions observed during synthesis, the resulting compounds retained their linear structure. Their structure and lipophilicity, measured by high-performance liquid chromatography (HPLC), were analyzed. Correlations were determined between the compounds’ molecular parameters and biological activity against Fusarium solani and Fusarium oxysporum fungi. The investigated compounds were also examined for their antifungal activity against Aspergillus fumigatus. The obtained results indicate that compounds with fluorine-containing substituents penetrate the cell structure more effectively and are characterized by higher antifungal potential than analogues with different substituents.
tert-Butyl phenylazocarboxylates are versatile building blocks for synthetic organic chemistry. Nucleophilic substitutions of the benzene ring proceed with aromatic amines and alcohols under mild conditions. The attack of aliphatic amines may be directed to the aromatic core as well as to the carbonyl unit leading to azocarboxamides. The benzene ring can further be modified through radical reactions, in which the tert-butyloxycarbonylazo group enables the generation of aryl radicals at either elevated temperatures or under acidic conditions. Radical reactions include oxygenation, halogenation, carbohalogenation, carbohydroxylation, and aryl-aryl coupling.
A review about recent applications of metalated heterocycles. Spanish Ministerio de Educación y Ciencia, Generalitat Valenciana and Universidad de Alicante
Bromine–magnesium exchange using iPrMgCl in THF at room temperature on 2-, 3- and 4-bromopyridines allowed the synthesis of various functionalized pyridines. The methodology was successfully used for the synthesis of 4-azaxanthone. Moreover, single exchange reactions observed on 2,6-, 3,5-, 2,3- and 2,5-dibromopyridines, with complete regioselectivity in the case of 2,3- and 2,5-dibromopyridines, afforded substituted bromopyridines, which were then involved in a second exchange step to provide difunctionalized pyridines.
Five representative hydrazo compounds have been oxidized in high yield using Br2 and pyridine. Yields range from 80% to 93%. For the synthesis of dibenzyl azodicarboxylate, this process produced analytically pure material directly from the reaction mixture.
Acetal protected 4-formylphenylbismuthane was prepared and used for arylation of trisubstituted hydrazines. Formylphenylhydrazines. obtained after removal of acetal group, were used in coupling reaction to give diols containing two substituted hydrazino moieties and the coupling of corresponding phenylimide derivatives gave corresponding diamines.
Substituted hydrazines have found many technical and commercial applications and this is reflected in the immense number of such compounds synthesized to date. In this review an attempt has been made to supplement the existing comprehensive literature by presenting only a selection of synthetic methods, judged to be of particular principal or practical interest, together with some additional, recent approaches. The important steps in the development from simple substituted hydrazines to rational synthesis of multisubstituted derivatives are recapitulated.
The phthaloyl group can be efficiently converted in very mild conditions into bis-tert-butyloxycarbonyl group using MeNH2, then Boc2O/DMAP, in a one-flask protocol.
The reaction of several functionalized primary, secondary and tertiary organozinc bromides, benzylzinc bromide, functionalized arylzinc halides and one heteroarylzinc bromide with ditert-butyl azodicarboxylate is described. The reaction products, N,N′-ditert-butoxycarbonylhydrazino derivatives are obtained in excellent yields for most aliphatic substrates and good yields for aromatic substrates. These compounds are direct precursors of hydrazino and amino derivatives by deprotection. The process constitutes the first synthetically useful electrophilic amination of organozinc derivatives, and takes advantage of the broad functional group tolerance of the organozinc chemistry.
'Almost all possibilities have been exhausted', stated H. Wieland in 1913 in the preface to his monograph Die Hydrazine with regard to the synthesis of N,N'substituted hydrazines. Even today suitable reagents and methods are lacking for the preparation of these compounds, which are important as precursors of pharmaceuticals, agrochemicals, and dyestuffs. The readily available, protected hydrazine 1 is a new reagent that may fill this gap.
The scope of a set of recently reported hydrazine reagents has been explored with respect to arylation. Compounds of type R1NHNHCOR2 can be selectively arylated under very mild conditions using triarylbismuth diacetates.
[GRAPHICS] [Cu(S,S)-t-Bu-box](OTf)(2) (1) catalyzes the enantioselective amination of enolsilanes with azodicarboxylate derivatives. Isomerically pure enolsilanes of aryl ketones, acylpyrroles, and thioesters added to the azo imide in greater than 95% ee. The use of an alcohol additive was critical to achieving catalyst turnover.
Various hydrazine derivatives containing combinations of trifluoroacetyl, trifluoromethanesulfonyl, and 2,4-dinitrophenyl groups were prepared. Synthetic strategy is studied in terms of using protecting groups and direct acylation.
N-acyl- and N-alkoxycarbonylaminophthalimides are prepared using a convenient reaction and are efficiently used as acid partners in Mitsunobu reaction. This reaction allows them to be alkylated by primary, secondary or benzyl groups. Comparison of the reactivities and pKa values of these N-substituted aminophthalimides suggest that the success of the Mitsunobu reaction in this case seems to be governed more by steric than by electronic effects. A final dephthaloylation step results in an efficient method for the preparation of 1,1-substituted hydrazines.
Various arylhydrazones have been successfully synthesized via a highly efficient palladium-catalyzed cross-coupling reaction between aryl halides and benzophenone hydrazone. All the reaction parameters have been studied and coupling products were obtained with excellent yields from the corresponding bromides or chlorides.
[reaction in text] Protected pyridylhydrazine derivatives were prepared in a one-step palladium-catalyzed amination reaction using chelating phosphine ligands. 2-Pyridyl chlorides, bromides, and triflates were effective electrophiles in these reactions. Di-tert-butyl hydrazodiformate was an excellent hydrazine substrate, and the resulting products were deprotected under mild conditions. Catalytic amination provides a direct route to protected bifunctional hydrazinopyridine linkers that are suitable for metal-bioconjugate syntheses.
[structure: see text] A new reagent for the systematic synthesis of substituted hydrazines is reported. Unlike previously developed reagents, this one contains only two protecting groups, thus providing a faster approach to multisubstituted derivatives. The selective introduction of alkyl and acyl groups is illustrated by a few examples. Also a new fast method for the deprotection of the triphenylphosphonium group is presented.
[reaction--see text] A convenient method for intermolecular N-arylation of hydrazides with substituted aryl iodides in the presence of a copper catalyst and Cs(2)CO(3) is reported. The C-N coupling of N-Boc hydrazine with para- and meta-substituted aryl iodides afforded the N-arylated products A, regioselectively. A reversal in regioselectivity is observed for the arylation of benzoic hydrazide with ortho-substituted aryl iodides, providing the N'-arylated products B.
The electrophilic amination of 2-fluorophenol, 4-fluorophenol, and 2-chlorophenol was observed to occur as a result of their treatment with diazenes 1-4 under mild reaction conditions in the presence of ZrCl(4). The products originating from the 2-fluorophenol or 2-chlorophenol can be considered as "normal" products of amination. On the other hand, the 2-chloro-4-amino-substituted phenols obtained from the 4-fluorophenol seem to be formed in a process that involves an ipso amination, the complete removal of the fluorine atom, and the introduction of the chlorine atom.
The pK(a) values in DMSO for 22 di- and triprotected hydrazine NH acids and two monosubstituted hydrazines have been determined using potentiometric titration. The results of density functional theory calculations at the B3LYP/6-311+G level of gas-phase acidities of a representative selection of mono-, di-, and trisubstituted hydrazines are compared with both the relevant published and novel experimental titration data. In the course of this work, a rough estimation of the pK(a) value of hydrazine in DMSO (ca. 38.0) has been deduced. For typical triprotected compounds of this kind containing moderately electron-withdrawing carbamate and imidodicarbonate or arenesulfonylcarbamate functions the pK(a) values fall in the range 15.1-17.3, whereas for N,N'-diprotected hydrazines with a carbamate and an aromatic sulfonyl group the corresponding values are 12.7-14.5. Several of these triprotected derivatives have recently been applied preparatively in stepwise synthesis of substituted hydrazines using alkyl halides as electrophiles in the presence of a phase transfer catalyst, and a few of them, with varying success, have been examined in model experiments with benzyl alcohol, triphenylphosphine, and diethyl azodicarboxylate in the Mitsunobu reaction. The dependence of the reactivity on the intrinsic acidity of the hydrazines in this reaction is highlighted. Furthermore, the regioselective alkylation of an N,N'-diprotected hydrazine can be rationalized on the basis of the presented data.