Radical addition approach to asymmetric amine synthesis: design, implementation, and comparison of chiral N-acylhydrazones

Intermolecular radical addition to C=N bonds with acyclic stereocontrol offers excellent potential as a mild, nonbasic carbon-carbon bond construction approach to chiral amines. Here, complete details of the first radical additions to chiral N-acylhydrazones as an approach to asymmetric amine synthesis are disclosed. Novel N-acylhydrazones were designed as chiral C=N radical acceptors with Lewis acid activation, restriction of conformational mobility, and commercial availability of precursors. Amination of 4-alkyl-2-oxazolidinones with O-(mesitylenesulfonyl)hydroxylamine or O-(p-nitrobenzoyl)hydroxylamine afforded N-aminooxazolidinones which were condensed with aldehydes to afford N-acylhydrazones 3-8. Three synthetic methods were developed, implementing these N-acylhydrazones in Lewis acid-promoted intermolecular radical additions to C=N bonds. First, additions of various secondary and tertiary alkyl iodides to propionaldehyde and benzaldehyde hydrazones (3 and 7) under tin hydride radical chain conditions in the presence of ZnCl2 gave N-acylhydrazine adducts with diastereomeric ratios ranging from 93:7 to 99:1. Radical additions to a series of N-acylhydrazones with different substituents on the oxazolidinone revealed that benzyl and diphenylmethyl were more effective stereocontrol elements than those with the aromatic ring directly attached to the oxazolidinone. Second, a tin-free method, exploiting dual functions of triethylborane for both initiation and chain propagation, enabled improved yields in addition of secondary alkyl iodides. Third, under photolytic conditions with hexamethylditin, primary radical addition could be achieved with ethyl iodide in the presence of diethyl ether as cosolvent; the 1-ethoxyethyl adduct was observed as a minor product. Chloromethyl addition was achieved under both the tin-free and photolytic conditions; in this case, the adduct bears alkyl chloride functionality with potential for further elaboration.     

Mn-mediated coupling of alkyl iodides and chiral N-acylhydrazones: optimization, scope, and evidence for a radical mechanism

Stereoselective radical additions have excellent potential as mild, nonbasic carbon-carbon bond constructions for direct asymmetric amine synthesis. Efficient intermolecular radical addition to C=N bonds with acyclic stereocontrol has previously been limited mainly to secondary and tertiary radicals, a serious limitation from the perspective of synthetic applications. Here, we provide full details of the use of photolysis with manganese carbonyl to mediate stereoselective intermolecular radical addition to N-acylhydrazones. Photolysis (300 nm) of alkyl halides and hydrazones in the presence of Mn2(CO)10 and InCl(3) as a Lewis acid led to reductive radical addition; diastereomer ratios ranged from 93:7 to 98:2 at ca. 35 degrees C. The reaction tolerates additional functionality in either reactant, enabling subsequent transformations as shown in an efficient asymmetric synthesis of coniine. A series of hydrazones bearing different substituents on the oxazolidinone auxiliary were compared; consistently high diastereocontrol revealed that the identity of the substituent had little practical effect on the diastereoselectivity. Further mechanistic control experiments confirmed the intermediacy of radicals and showed that independently prepared alkyl- or acylmanganese pentacarbonyl compounds do not undergo efficient addition to the N-acylhydrazones under thermal or photolytic (300 nm) conditions. These Mn-mediated conditions avoid toxic tin reagents and enable stereoselective intermolecular radical additions to C=N bonds with the broadest range of alkyl halides yet reported, including previously ineffective primary alkyl halides.     

Unprecedented cyclization of α-diazo hydrazones upon N-H functionalization: A Et3N base promoted one-step synthetic approach for the synthesis of N-amino-1,2,3-triazole derivatives from α-diazo hydrazone

In this communication, for the first time, we are reporting α-diazo hydrazone synthesis from hydrazones derived from β-keto esters and 2,4-dinitro phenyl hydrazine via diazo transfer reaction. We also report an unexpected cyclization of the α-diazo hydrazones upon N-H functionalization to give highly functionalized N-amino-1,2,3-triazole derivatives under metal-free condition. This one-step synthetic protocol can serve as a general tool to access nitrogen rich 5- and 6-membered heterocycles in excellent yields.     

Organocatalytic conjugate addition of formaldehyde N,N-dialkylhydrazones to beta,gamma-unsaturated alpha-keto esters

(1S,2R)-1-Aminoindan-2-ol-derived thioureas behave as efficient H-bonding organocatalysts for the nucleophilic conjugate addition of formaldehyde hydrazones to beta,gamma-unsaturated alpha-keto esters as enoate surrogates, affording the corresponding adducts in good yields and enantioselectivities.     

Novel method for synthesis of aryl hydrazones from α-diazo esters: scope and limitations of nucleophiles

Aryl hydrazones, the precursor of Fischer indole synthesis, were easily obtained by nucleophilic addition of aryllithium reagents to diazo esters. The aryl hydrazones were converted into indoles in good yields by heating with thionyl chloride in alcohol. Grignard reagent was also a good nucleophile, whereas organozinc reagent did not react with diazo esters. Aryllithium reagents were prepared by reacting aryl bromides having various substitutions at 2-, 3-, 4-, or multi positions with n-BuLi. The addition of nucleophiles derived from bromopyridines to diazo esters also gave hydrazones.     

Synthesis of 1-phenyl-3-methyl-4-alkyl-4-[N-methylbutyro(capro)lactyl]-5-pyrazolones

The corresponding hydrazones, which on heating are cyclized to give 1-phenyl-3-methyl-4-alkyl-(benzyl)-4-(2-oxopyrrolidinomethyl)- and 1-phenyl-3-methyl-4-alkyl(benzyl)-4-(N-methylcaprolactyl)pyrazolones, are formed in the reaction of alkyl(benzyl) (2-oxopyrrolidinomethyl)- and alkyl-(benzyl) (N-methylcaprolactyl)acetoacetic esters with phenylhydrazine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1546–1548, November, 1976.     

Highly diastereoselective mannich-type reactions of chiral N-acylhydrazones

The Lewis acid-mediated addition of silyl enolates to easily accessible homochiral N-acylhydrazones derived from 3-amino-2-oxazolidinones proceeded in yields up to 71% and diastereomeric ratios of 99:1. In most cases, optimal reaction conditions entailed the simple use of ZnCl(2) in acetonitrile at room temperature. Hydrazones derived from phenyl-, isopropyl-, and benzyl-substituted 2-oxazolidinones were examined in the reaction in terms of yield and diastereoselectivity. The facile SmI(2)-mediated N-N bond cleavage of the formed hydrazines was demonstrated yielding a beta-amino acid derivative. Hence, the overall reaction sequence constitutes an efficient asymmetric Mannich-type reaction. The sense of diastereoselectivity was explained by a preferential attack on the less shielded Si face of the chiral hydrazones and confirmed by means of X-ray crystallography.     

Reactions of Isomeric Arylchloropyruvates and Glycidates with Hydrazines

Reactions of arylchloropyruvic acids esters with aryl- and hetarylhydrazines give rise to pyrazolinedione hydrazones as a result of a tandem condensation of the substituted hydrazines with arylchloropyruvates. In contrast to this process in reaction with hydrazine hydrate a ready reduction unexpectedly occurs by Kizhner-Wolff mechanism affording 3-hydroxydihydrocinnamic acid hydrazide as the principal product. The isomeric arylglycidate reacts along the same pattern.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 5, 2005, pp. 710–717.Original Russian Text Copyright © 2005 by Mamedov, Mustakimova, Gubaidullin, Litvinov, Levin.     

Dual activation in asymmetric allylsilane addition to chiral N-acylhydrazones: method development, mechanistic studies, and elaboration of homoallylic amine adducts

[reaction: see text] Chiral N-acylhydrazones derived from commercially available 4-benzyl-2-oxazolidinone provide a rigid, conformationally restricted template to impart facial selectivity in additions to C=N bonds. In the presence of indium(III) trifluoromethanesulfonate [In(OTf)3], N-acylhydrazones undergo highly diastereoselective fluoride-initiated additions of allylsilanes (aza-Sakurai reaction). Mechanistic studies including control experiments and comparisons with allyltributylstannane, allylmagnesium bromide, and allylindium species implicate a dual activation mechanism involving addition of an allylfluorosilicate species to a chelate formed from In(OTf)3 and the chiral N-acylhydrazone. The N-N bonds of the adducts are readily cleaved in a two-step protocol to provide synthetically useful homoallylic N-trifluoroacetamides. Further elaboration of the latter compounds through Wacker oxidation and olefin metathesis provides diversely functionalized building blocks and expands the potential applications of this C-C bond construction approach to asymmetric amine synthesis.     

Synthesis, molecular properties prediction, and anti-staphylococcal activity of N-acylhydrazones and new 1,3,4-oxadiazole derivatives

Five new 1-(2-(5-nitrofuran-2-yl)-5-(aryl)-1,3,4-oxadiazol-3-(2H)-yl) ethanone compounds 5a-e were synthesized by cyclization of N-acylhydrazones 4a-e with acetic anhydride under reflux conditions. Their structures were fully characterized by IR, 1H-NMR, and 13C-NMR. Furthermore, evaluations of the antibacterial activity of the 1,3,4-oxadiazoles 5a-e and N-acylhydrazones 4a-e showed strong activity against several strains of Staphylococcus aureus, with MICs between 4 μg/mL to 32 μg/mL. In silico studies of the parameters of Lipinski's Rule of Five, as well as the topological polar surface area (TPSA), absorption percentage (% ABS), drug likeness and drug score indicate that these compounds, especially 4a and 5d, have potential to be new drug candidates.     

Configurational and constitutional information storage: multiple dynamics in systems based on pyridyl and acyl hydrazones

The C=N group of hydrazones can undergo E/Z isomerization both photochemically and thermally, allowing the generation of a closed process that can be tuned by either of these two physical stimuli. On the other hand, hydrazine-exchange reactions enable a constitutional change in a given hydrazone. The two classes of processes: 1) configurational (physically stimulated) and 2) constitutional (chemically stimulated) give access to short-term and long-term information storage, respectively. Such transformations are reported herein for two hydrazones (bis-pyridyl hydrazone and 2-pyridinecarboxaldehyde phenylhydrazone) that undergo a closed, chemically or physically driven process, and, in addition, can be locked or unlocked at will by metal-ion coordination or removal. These features also extend to acyl hydrazones derived from 2-pyridinecarboxaldehyde. Similarly to the terpydine-like hydrazones, such acyl hydrazones can undergo both constitutional and configurational changes, as well as metal-ion coordination. All these types of hydrazones represent dynamic systems capable of acting as multiple state molecular devices, in which the presence of coordination sites furthermore allows the metal ion-controlled locking and unlocking of the interconversion of the different states.     

[6π+4π] Cycloadditions of 5-azoniafulvene ions with nitrones and azomethine imines.

Nitrones as well as azomethine imines generated by the prototropic route from hydrazones are shown to add readily to the title iminium ions to give pyrrolo-annellated oxadiazine and triazine derivatives.     

New multi-1,2,3-selenadiazole aromatic derivatives

The aromatic polyketones 3a-d are versatile compounds for the synthesis of the multi-1,2,3-selenadiazole aromatic derivatives 1a-d. The preparation starts with the reaction between the multi-bromomethylene benzene derivatives 2a-d and 4-hydroxy- acetophenone to give compounds 3a-d which are transformed through the reaction with semicarbazide hydrochloride or ethyl hydrazine carboxylate into the corresponding semicarbazones derivatives 4a-d or hydrazones 5a-d. The reaction with selenium dioxide leads to regiospecific ring closure of semicarbazones or hydrazones to give the multi- 1,2,3-selenadiazole aromatic derivatives in high yield.     

The preparation of N-carboalkoxypyrazoles and N-phenylpyrazoles from C(α)-dianions of carboalkoxyhydrazones and phenylhydrazones

The 1,4-dianions of C(α),N-carboalkoxyhydrazones and C(α),N-phenylhydrazones were prepared in an excess of lithium diisopropylamide (LDA). These dilithiated intermediates resulted from metalation of substituted hydrazones of several all-aliphatic cyclic ketones, aliphatic-aromatic cyclic ketones phenylacetaldehyde, and several substituted propiophenones or acetophenones. The esters utilized for Claisen-type condensations of these dianion intermediates included methyl salicylate, methyl p-hydroxybenzoate, methyl nicotinate and related materials. The condensations were followed by acid-cyclizations to give a variety of N-phenylpyrazoles and N-carboalkoxypyrazoles, most of which are new.     

Zinc-mediated carbon radical addition to glyoxylic imines in aqueous media for the synthesis of alpha-amino acids

The addition of carbon radicals to glyoxylic imines was studied using zinc dust as a radical initiator. The zinc-mediated radical reaction of glyoxylic oxime ethers and hydrazones proceeded smoothly to give the alkylated products via a carbon-carbon bond-forming process in aqueous media. The reaction of the oxime ethers and hydrazones having an Oppolzer's camphorsultam group provided the corresponding alkylated products, which could be converted into enantiomerically pure alpha-amino acids. The diastereoselectivities observed in the reaction of hydrazones were better than those obtained in the reaction of oxime ethers.     

Pyridazines with heteroatom substituents in position 3 and 5. 3. 2-aryl-5-hydroxypyridazin-3(2H)-ones as potential herbicides: Synthesis and some reactions

The coupling of dimethyl acetonedicarboxylate 1 with a variety of aryldiazonium salts 2a-i produces the hydrazones 3a-i which can be cyclized in boiling dichlorobenzene to yield the pyridazone esters 4a-i , or in sodium hydroxide solution to give the pyridazone acids 5a-f,h,i , which can be decarboxylated at elevated temperatures. The hydroxy group in 4a,d can be acylated, sulfonated or alkylated yielding compounds 8a-n . Condensation of 4a,d with magic malonates 9a-d produces the pyronopyridazinones 10a-f . The reaction of 4a with hydrazine yields the hydrazide 12 via the salt 11 , and with ammonia the amide 14 .     

Ruthenium- and Copper-Catalyzed Propargylic Substitution Reactions of Propargylic Alcohol Derivatives with Hydrazones

Ruthenium- and copper-catalyzed propargylic substitution reactions of propargylic alcohol derivatives with N-monosubstituted hydrazones as ambident nucleophiles are achieved in which N-monosubstituted hydrazones exhibit impressive different reactivities depending on different catalytic systems, behaving as carbon-centered nucleophiles to give the corresponding propargylic alkylated products in ruthenium catalysis, or as nitrogen-centered nucleophiles to afford the corresponding propargylic aminated products in copper catalysis. DFT calculations were carried out to investigate the detailed reaction pathways of these two systems. Further transformation of propargylic substituted products affords the corresponding multisubstituted pyrazoles as cyclization products in good to high yields.     

Intramolecular and intermolecular diels-alder reactions of acylhydrazones derived from methacrolein and ethylacrolein

The intramolecular Diels-Alder reactions of hydrazones derived from methacrolein or ethylacrolein and terminally unsaturated N-acyl-N-methylhydrazines have been investigated. The hydrazones 7b and 7c derived from N-methyl-N-pent-4-enoylhydrazine 3b were found to undergo intramolecular [4 + 2] cycloaddition above 140 °C and the pyridopyridazines 12 were isolated. The corresponding hydrazones 8b and 8c from N-methyl N-pent-4-ynoylhydrazone 4a reacted similarly and gave as the final products the pyridines 13. The scope of the reaction is limited, as was shown by the failure of several other terminally unsaturated hydrazones of β-unsaturated aldehydes to undergo intramolecular cycloaddition. These hydrazones did, however, undergo intermolecular [4 + 2] cyctoaddition to N-phenylmaleimide. Other hydraiones 15 of methacrolein. including the benzoylhydrazone and the phenylhydrazone, also reacted with N-phenylmaleimide to give the pyridine 14b by way of an isolable dihydropyridine 16.     

The Chemistry of α-Carbonyl Azo Compounds

α-Carbonyl azo compounds such as diesters of azodicarboxylic acids, diacylazo compounds, and esters of arylazocarboxylic acids are highly reactive. They add e.g. to amines, aromatic compounds, olefins, CH acids, Grignard and diazo compounds, aldehydes, ketones, and ketenes. These reactions can be used for the preparation of triazanes, hydrazones, oxa-diazoline, azomethinimine, and diazetidine derivatives, etc. α,α′-Dicarbonyl azo compounds are among the strongest dienophiles known.     

Diastereo‐Divergent Synthesis of Saturated Azaheterocycles Enabled by tBuOK‐Mediated Hydroamination of Alkenyl Hydrazones

Diastereo‐divergent synthesis of saturated azaheterocycles has been achieved by tBuOK‐mediated hydroamination of alkenyl hydrazones. DFT calculations suggested that the cation–π interactions between a potassium cation and aryl substituents on hydrazones give rise to 2,5‐cis selectivity in pyrrolidines, which were synthesized by the reaction of γ,δ‐unsaturated N‐benzyl hydrazones. By contrast, 2,5‐trans selectivity was observed when an isopropyl group was used as the substituent on hydrazones. An unusual 2,6‐trans selectivity in piperidine formation was also realized using the present strategy.