Showing papers on "Hydrazone published in 2007"

Primary tert‐ and sec‐Allylamines via Palladium‐Catalyzed Hydroamination and Allylic Substitution with Hydrazine and Hydroxylamine Derivatives

Abstract: The challenge of controlling the regiochemistry of palladium-catalyzed allylic substitution by choice of ancillary ligand has a long history. Much attention has been focused on controlling regiochemistry because formation of the more substituted product could be developed into a mild route to sec- and even tert-alkylamines (Scheme 1). Akermark and co-workers reported that attack can occur at the more substituted position of a prenyl complex, but that the reversibility of this attack ultimately leads to formation of the less substituted amine in many cases.[1] More recently, Hou and co-workers reported a ligand for palladium that causes benzylamine to add irreversibly to form secondary and tertiary N-alkyl sec-butylamines,[2] and Yudin and co-workers have shown that the attack by aziridine is irreversible and that tert-alkyl-substituted aziridines can be prepared by allylic substitution.[3,4] Scheme 1 During studies to develop the scope of the hydroamination of dienes,[5–7] we found that the reactions of hydrazine and hydroxylamine derivatives occur irreversibly at the more substituted position of both prenyl and crotyl palladium intermediates. We explored this transformation further because, unlike the products from additions of aziridines,[3,4] the products from addition of hydrazine and hydroxylamine derivatives could be readily transformed into primary tert-alkylamines or sec-alkylamines. The synthesis of primary amines containing tertiary alkyl groups is challenging because many of the conventional methods, such as nucleophilic substitution and additions to imines, are difficult to conduct at tertiary electrophiles and at ketimines,[8, 9] and few catalytic reactions have been developed that form tert-alkyl-substituted amines.[10, 11] Herein we report our studies on the reactions of hydrazine and hydroxylamine derivatives to form allylamine products from reaction at the more hindered site of aliphatic dienes or allylic esters. This regioselectivity was observed in the presence of palladium catalysts bearing a range of bisphosphine ligands. Thus, this regioselectivity is controlled by the reagent and provides a versatile synthesis of sec- and tert-allylamines by palladium-catalyzed additions or substitutions, with subsequent N–N or N–O bond cleavage. While studying the reactions of hydrazine derivatives with isoprene as an avenue to expand the scope of the hydroamination of dienes,[5–7] we found that these reactions formed the product in which the C–N bond is formed between the hydrazone group and the most substituted carbon atom of the diene. Table 1 shows these reactions catalyzed by palladium complexes containing a series of bidentate phosphine ligands. Analysis of the crude reaction mixtures by 1H NMR spectroscopy revealed that the less substituted N-prenyl regioisomer was typically formed in less than 3% yield, regardless of the identity of the ligand in the catalyst. This regioselectivity contrasts that obtained from reactions of arylamines, even with the same catalyst.[5] Table 1 Effect of catalyst components on the hydroamination of isoprene with benzophenone hydrazone.[a] Consistent with the high activity of palladium–xantphos complexes as catalyst for the hydroamination of 1,3-dienes with arylamines,[5] the reaction of benzophenone hydrazone with isoprene occurred in the highest yields when catalyzed by the combination of [{Pd(allyl)Cl}2] and xantphos. Nevertheless, this reaction catalyzed by palladium complexes of several other bisphosphines or generated from alternative precursors formed the hydroamination product in substantial yields. The addition of HCl as an acid cocatalyst had no significant impact on the activity or regioselectivity of the reaction.[12] Studies on the scope of the hydroamination of dienes with benzophenone hydrazone and related nitrogen nucleophiles are summarized in Table 2. A variety of nucleophiles containing an N–N or N–O bond underwent addition to 1,3-dienes to produce the branched addition product in excellent yields. Benzophenone hydrazone, fluorenone hydrazone, 1-aminobenzotriazole, and phenylhydrazine all reacted with acyclic 1,3-dienes to yield the corresponding branched monoallylation products in excellent yields. O-benzylhydroxylamine also reacted with isoprene to yield the branched monoallylation product. Reactions of this hydroxylamine conducted in dichloromethane or toluene yielded predominantly the diallylation product, but reactions in tetrahydrofuran occurred with excellent selectivity for the branched, monoallylation product. Because the catalyst generated from xantphos was poorly soluble in tetrahydrofuran, these reactions were conducted with the catalyst generated from 2,7-di-tert-butyl-9,9-dimethyl-4,5-bis(diphenylphosphino)xanthenes (dtBu-xantphos). Table 2 Palladium-catalyzed hydroamination of acyclic and cyclic 1,3-dienes with H2NX (X=N, O) nucleophiles.[a] Because catalytic amination of allylic esters is likely to occur through the same η3-allylpalladium complexes as the hydroamination of dienes, we examined the addition of benzophenone hydrazone to ethyl 3-methylbut-2-enyl carbonate (Table 3). This substitution reaction formed only the branched regioisomer after 12 h at room temperature in the presence of the catalyst generated from xantphos and [{Pd-(allyl)Cl}2]. Like the hydroamination of isoprene, this allylic substitution favored the branched isomer with catalysts generated from all ligands tested (dpephos, binap, dppf, dpppent, and xantphos; see the Supporting Information). The identity of the leaving group of the allylic ester did affect the regioselectivity. A comparison of the reactions of the two regioisomers of prenyl ethyl carbonate revealed some memory effect,[13, 14] and significant amounts of linear product were observed from reactions of prenyl acetates and phosphates. Nevertheless, reactions of allylic carbonates formed the branched products selectively. Table 3 Palladium-catalyzed addition of H2NX nucleophiles to allylic esters.[a] Table 3 shows the reactions of benzophenone hydrazone, O-benzylhydroxylamine, and O-tritylhydroxylamine with a selection of alkyl-substituted allylic carbonates to form the branched substitution products. Additions of all three nucleophiles to prenyl ethyl carbonate yielded the branched regioisomer in good to excellent yield of isolated product (Table 3, entries 1, 3, 4). Reactions of O-tritylhydroxylamine with phenyl ethyl carbonate, but-2-enyl ethyl carbonate, and geraniol ethyl carbonate also yielded the branched regioisomer in good yield (Table 3, entries 4–6). Like the published reactions of aziridines, the regioselectivities of the reactions in Table 3 were independent of the reaction time.[4] By comparison, these reactions with morpholine formed the opposite regioisomeric products that result from substitution at the less hindered position of the allyl intermediate, just as reported with related bisphosphine ligands.[4] Reactions with cinnamyl carbonate catalyzed by [{Pd(η3-allyl)Cl}2] and xantphos in dichloromethane also formed the linear product. Although hydroxylamine and hydrazine derivatives can be valuable for certain applications, we sought to exploit the regioselectivity from these N-allylations of hydrazine and hydroxylamine derivatives to generate the more common amine functionality. The reactions in Equation (1) show that (1) N-prenyl-O-benzylhydroxylamine, N-3-crotyl-O-tritylhydroxylamine, and N-prenyl benzophenone hydrazone all undergo cleavage to the primary amine with powdered Zn in acetic acid. The volatile amine products were isolated as the HCl salts.[15] Although cleavage of hydroxylamines and hydrazides by zinc is well-known,[16, 17] cleavage of hydrazones under these conditions is less established. In summary, we have demonstrated that the regioselectivity for the hydroamination of dienes and the amination of allylic esters with hydrazine and hydroxylamine derivatives favors formation of the branched N-allyl products. This process gains particular synthetic value because the benzophenone hydrazone and hydroxylamine products form secondary and tertiary carbinamines after N–X bond cleavage with zinc. Because the regioselectivity occurs for a wide variety of bisphosphines, this sequence provides opportunities to develop new classes of enantioselective amination, and studies on this process are ongoing.

Controlled Release of Volatile Aldehydes and Ketones from Dynamic Mixtures Generated by Reversible Hydrazone Formation

Abstract: Delivery systems generated by reversible hydrazone formation from hydrazine derivatives (see Fig. 1) and carbonyl compounds in H2O efficiently increase the long-lastingness of volatile aldehydes and ketones (R1R2CO) in various perfumery applications. The hydrazones are usually obtained in an (E) configuration at the imine double bond (NHNC) and, in the case of aliphatic acylhydrazones R′CONHNCR1R2 (R′=alkyl), as syn and anti conformers with respect to the amide bond (CONHN). An average free-energy barrier of ca. 78 kJ/mol was determined for the amide-bond rotation by variable-temperature 1H-NMR measurements (Fig. 2). In the presence of H2O, the hydrazone formation is entirely reversible, reaching an equilibrium composed of the hydrazine derivative, the carbonyl compound, and the corresponding hydrazone. Kinetic measurements carried out by UV/VIS spectroscopy showed that the same equilibrium was reached for the formation and hydrolysis of the hydrazone. Rate constants are strongly pH-dependent and increase with decreasing pH (Table 1). The influence of the hydrazine structure on the rate constants is less pronounced than the pH effect, and the presence of surfactants reduces the rate of equilibration (Tables 1 and 3). The full reversibility of the hydrazone formation allows to prepare dynamic mixtures by simple addition of a hydrazine derivative to several carbonyl compounds. Dynamic headspace analysis on dry cotton showed that the presence of a hydrazine derivative significantly increased the headspace concentrations of the different carbonyl compounds as compared to the reference sample without hydrazine (Table 4). The release of the volatiles was found to be efficient for fragrances with high vapor pressures and low H2O solubility. Furthermore, a special long-lasting effect was obtained for the release of ketones. The simplicity of generating dynamic mixtures combined with the high efficiency for the release of volatiles makes these systems particularly interesting for practical applications and will certainly influence the development of delivery systems in other areas such as the pharmaceutical or agrochemical industry.

Tuning the antiproliferative activity of biologically active iron chelators: characterization of the coordination chemistry and biological efficacy of 2-acetylpyridine and 2-benzoylpyridine hydrazone ligands

Abstract: 2-Pyridinecarbaldehyde isonicotinoyl hydrazone (HPCIH) and di-2-pyridylketone isonicotinoyl hydrazone (HPKIH) are two Fe chelators with contrasting biological behavior. HPCIH is a well-tolerated Fe chelator with limited antiproliferative activity that has potential applications in the treatment of Fe-overload disease. In contrast, the structurally related HPKIH ligand possesses significant antiproliferative activity against cancer cells. The current work has focused on understanding the mechanisms of the Fe mobilization and antiproliferative activity of these hydrazone chelators by synthesizing new analogs (based on 2-acetylpyridine and 2-benzoylpyridine) that resemble both series and examining their Fe coordination and redox chemistry. The Fe mobilization activity of these compounds is strongly dependent on the hydrophobicity and solution isomeric form of the hydrazone (E or Z). Also, the antiproliferative activity of the hydrazone ligands was shown to be influenced by the redox properties of the Fe complexes. This indicated that toxic Fenton-derived free radicals are important for the antiproliferative activity for some hydrazone chelators. In fact, we show that any substitution of the H atom present at the imine C atom of the parent HPCIH analogs leads to an increase in antiproliferative efficacy owing to an increase in redox activity. These substituents may deactivate the imine R-C=N-Fe (R is Me, Ph, pyridyl) bond relative to when a H atom is present at this position preventing nucleophilic attack of hydroxide anion, leading to a reversible redox couple. This investigation describes novel structure-activity relationships of aroylhydrazone chelators that will be useful in designing new ligands or fine-tuning the activity of others.

Effect of Cooperative Hydrogen Bonding in Azo−Hydrazone Tautomerism of Azo Dyes

Abstract: Azo−hydrazone tautomerism in azo dyes has been modeled by using density functional theory (DFT) at the B3LYP/6-31+G(d,p) level of theory. The most stable tautomer was determined both for model compounds and for azo dyes Acid Orange 7 and Solvent Yellow 14. The effects of the sulfonate group substitution and the replacement of the phenyl group with naphthyl on the tautomer stability and on the behavior in solvent have been discussed. Intramolecular hydrogen bond energies have been estimated for the azo and hydrazone tautomers to derive a relationship between the tautomer stability and the hydrogen bond strength. The transition structures for proton transfer displayed resonance assisted strong hydrogen bonding properties within the framework of the electrostatic-covalent hydrogen bond model (ECHBM). Evolution of the intramolecular hydrogen bond with changing structural and environmental factors during the tautomeric conversion process has been studied extensively by means of the atoms-in-molecules (AIM) ana...

Synthesis, Structural Characterization and Electrochemical Studies of a Nicotinamide‐bridged Dinuclear Copper Complex derived from a Tridentate Hydrazone Schiff Base Ligand

Abstract: The in-situ formed hydrazone Schiff base ligand (E)-N′-(2-hydroxy-3-methoxybenzylidene)benzohydrazide (H2L1) and nicotinamide (L2) give the copper(II) complex [CuL1L2] on reaction with copper(II) acetate. In the solid state two copper atoms are linked by nicotinamide through coordination with its pyridyl nitrogen atom and its amide-C=O group to the dicopper(II) complex [CuL1(μ-L2)CuL1L2]. The coordination polyhedra are a CuO2N2 square and a CuO3N2 square pyramide. Cyclic voltammetric experiments of the solution species [CuL1L2] in DMF reveal reduction of the L1 ligand at three potentials with a reduction at −0.5 V resulting in decomposition of the complex.

Versatility of 2,6-diacetylpyridine (dap) hydrazones in generating varied molecular architectures: synthesis and structural characterization of a binuclear double helical Zn(II) complex and a Mn(II) coordination polymer.

Abstract: A binuclear complex of Zn(II) with formula [Zn(dap(A)2)]2·2.25DMF (2·2.25DMF) and a Mn(II) coordination polymer with formula [Mn3(dap(In)2)3(H2O)2·2DMSO]n (3·2DMSO)n have been prepared and structurally characterized [dap(A)2 = dideprotonated form of 2,6-diacetylpyridine bis(anthraniloyl hydrazone); dap(In)2 = doubly deprotonated form of 2,6-diacetylpyridine bis(isonicotinoyl hydrazone)]. In the Zn(II) complex the molecular units are double helical, with the Zn(II) ions in a square pyramidal environment. The Mn(II) complex on the other hand is a coordination polymer containing two different types of hepta-coordinated Mn(II) ions, which differ in their axial ligands. The magnetic properties of the Mn(II) complex, along with those of a double helical pyridine bridged binuclear Ni(II) complex, earlier synthesized by us, are also reported. The ability of the 2,6-diacetylpyridine bis(aroyl hydrazone) ligands to form double helical complexes is analyzed in terms of the conformational flexibility of the ligands. The differences in the magnetic properties of the µ-N bridged binuclear complexes formed by 1,1 azido N-bridging ligands, and pyridine N-bridging ligands, is analyzed with the help of EHMO calculations.

The first aza Diels–Alder reaction involving an α,β-unsaturated hydrazone as the dienophile: stereoselective synthesis of C-4 functionalized 1,2,3,4-tetrahydroquinolines containing a quaternary stereocenter

Abstract: The reaction between aromatic imines and methacrolein dimethylhydrazone in the presence of 10% indium trichloride affords in good to excellent yields biologically and synthetically relevant 1,2,3,4-tetrahydroquinolines bearing a hydrazone function at C-4 in a one-pot process that involves the formation of two C–C bonds and the stereoselective generation of two stereocenters, one of them quaternary, and this constitutes the first example of an α,β-unsaturated dimethylhydrazone behaving as a dienophile in a hetero Diels–Alder reaction and the first vinylogous aza-Povarov reaction.

Synthesis, Characterization and Antioxidant Activity of Naringenin Schiff Base and Its Cu(II), Ni(II), Zn(II) Complexes

Abstract: A new ligand, naringenin-2-hydroxy benzoyl hydrazone (11,L), was prepared by condensation of naringenin with 2-hydroxy benzoyl hydrazine. Its Cu(II), Ni(II), Zn(II) complexes have also been synthesized and characterized on the basis of H-1-NMR, IR, UV-Vis spectra, elemental analyses, molar conductivity and thermal analyses. The general formula of these complexes was M(H3L) [M=Cu(II), Ni(II) and Zn(II)]. In addition, the antioxidant activities (superoxide and hydroxyl radical) of the free ligand and its complexes were determined in vitro. These compounds were found to possess potent antioxidant activity and be better than standard antioxidants like vitamin C and mannitol. In particular, the Cu(II) complex displayed excellent activity on the superoxide radical.

An efficient synthesis and reactions of novel indolylpyridazinone derivatives with expected biological activity.

Abstract: Reaction of 4-anthracen-9-yl-4-oxo-but-2-enoic acid (1) with indole gave the corresponding butanoic acid 2. Cyclocondensation of 2 with hydrazine hydrate, phenyl hydrazine, semicarbazide and thiosemicarbazide gave the pyridazinone derivatives 3a-d. Reaction of 3a with POCl(3) for 30 min gave the chloropyridazine derivative 4a, which was used to prepare the corresponding carbohydrate hydrazone derivatives 5a-d. Reaction of chloropyridazine 4a with some aliphatic or aromatic amines and anthranilic acid gave 6a-f and 7, respectively. When the reaction of the pyridazinone derivative 3a with POCl(3) was carried out for 3 hr an unexpected product 4b was obtained. The structure of 4b was confirmed by its reaction with hydrazine hydrate to give hydrazopyridazine derivative 9, which reacted in turn with acetyl acetone to afford 10. Reaction of 4b with methylamine gave 11, which reacted with methyl iodide to give the trimethylammonium iodide derivative 12. The pyridazinone 3a also reacted with benzene- or 4-toluenesulphonyl chloride to give 13a-b and with aliphatic or aromatic aldehydes to give 14a-g. All proposed structures were supported by IR, (1)H-NMR, (13)C-NMR, and MS spectroscopic data. Some of the new products showed antibacterial activity.

Autoxidation of hydrazones. Some new insights.

Abstract: Autoxidation of hydrazones is a generally occurring reaction, leading mostly to the formation of α-azohydroperoxides. All structural kinds of hydrazones, having at least one hydrogen atom on nitrogen, are prone to autoxidation; however, there are marked differences in the rate of the reaction. Hydrazones of aliphatic ketones are 1−2 orders of magnitude more reactive than analogous derivatives of aromatic ketones. Even less reactive are the hydrazones of chalcones, which function also as efficient inhibitors of autoxidation of other hydrazones. These differences can be attributed to the reduction of the rate of the addition of oxygen to a hydrazonyl radical, which is a reversible reaction. In the case of conjugated ketones, it becomes endothermic, making this elementary step slow down and the chain termination reactions become important. Substituents influence the stability of hydrazonyl radicals and, consequently, the bond dissociation energies of the N−H bonds. In acetophenone phenylhydrazones, the subst...

Synthesis and Spectral Characterization of Hydrazone Schiff Bases Derived from 2,4-Dinitrophenylhydrazine. Crystal Structure of Salicylaldehyde-2,4-Dinitrophenylhydrazone

Abstract: 717–720; received November 12, 2006Reactions of 2,4-dinitrophenylhydrazine with salicylaldehyde, pyridine-2-carbaldehyde and 2-aminobenzophenone in methanol result in the hydrazone Schiff base ligands salicylaldehyde-, pyr-idine-2-carbaldehyde-, and 2-aminobenzophenone-2,4-dinitrophenylhydrazone, respectively. Crys-talsofsalicylaldehyde-2,4-dinitrophenylhydrazone aremonoclinic,spacegroup