Synthesis of 6- to 10-membered ring (E)-hydroxyiminohydroazaazoniabenzocycloalkenes derivative from cyclization of 2-nitromethylene-1-(ω-phenylalkyl)imidazolidine or 2-nitromethylene-1-(ω-phenylalkyl)hexahydropyrimidine in trifluoromethanesulfonic acid

In trifluoromethanesulfonic acid, 2-nitromethylene-1-(ω-phenylalkyl)imidazolidine or 2-nitromethylene-1-(ω-phenylalkyl)hexahydropyrimidine derivatives undergo an intramolecular cyclization to afford (E)-hydroxyiminohydroazaazoniabenzocycloalkenes, in their trifluoromethanesulfonate salt form. The reaction probably occurres via the formation of an electrophilic transient hydroxynitrilium ion (or O-protonated nitrile oxide). The yields are generally good, except for the higher-membered ring derivatives.     

Ring cleavage of dihydropyrimidine skeleton

The first observation of ring cleavage between positions 1 and 2 of a 1,4-dihydropyrimidine skeleton was reported upon the nucleophilic addition of 4,6-unsubstituted 1,4-dihydropyrimidine with 3 equiv of an aniline derivative or phenylhydrazine in the presence of 0.1 equiv of pyridinium p-toluenesulfonate (PPTS) in CH₂Cl₂; the nucleophilic reactions of 4-methyl-6-unsubstituted 1,6(3,4)-dihydropyrimidine with the same amines gave conventional substituted products at position 2. The effect of this ring opening was found to be due to the electron density of the benzene ring of a nucleophilic amine. On the other hand, aralkylamines, alkylamines, or heterocyclic amines did not cleave the skeleton. The ring-opening chemical structure was confirmed by X-ray crystallographic analysis. This characteristically different phenomenon may be due to the pattern of two CC double bonds of 1,4-DP and 1,6(3,4)-DP as well as to the effect of two substituted groups on the DP ring.     

Synthesis of 4-dialkylaminopyridine derivatives through ring-rearrangement of 3-nitro-2H-pyran-2-one acetamidines

A new synthesis of substituted 4-dialkylaminopyridines was developed, starting from 3-nitropyran-2-one N-functionalized amidines. Secondary amines were reacted with the amidines in a sealed tube and in ethanol as the solvent yielding exclusively 4-dialkylaminopyridine derivatives or a mixture with 4-methylpyridine derivative, depending on the C-α-linked substituents of the starting amidine. Structural elucidation of the 4-dialkylaminopyridines revealed their existence as two tautomeric forms, depending on the solvent.     

Conformational flexibility of 1,4-dihydroazine carbonyl derivatives

Summary The molecular geometry of 4-oxo derivatives of 1,4-dihydropyridine, 1,4-dihydropyrimidine, 1,4-dihydropyridazine, and 1,4-dihydro-1,3,5-triazine has been calculated by the semi-empirical quantum-chemical AM1 method. It could be shown that the dihydrocycle in these compounds is not conformationally rigid. Changing the angle between the endocyclic double bond planes ±15° causes less than 1 kcal/mol increase of energy.

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Konformative Flexibilität von 1,4-Dihydroazin-carbonyl-Derivaten (Kurze Mitt.)

Zusammenfassung Die molekulare Geometrie von 4-Oxo-Derivaten von 1,4-Dihydropyridin, 1,4-Dihydropyrimidin, 1,4-Dihydropyridazin und 1,4-Dihydro-1,3,5-triazin wurde mittels der semiempirischen quantenchemischen AM1-Methode berechnet. Es konnte gezeigt werden, daß der zweifach hydrierte Ring in diesen Verbindungen nicht starr ist. Eine Änderung des Winkels zwischen den Ebenen der endocyclischen Doppelbindungen um ±15° bewirkt eine Energieerhöhung von weniger als 1 kcal/mol.

     

Electronic structure and conformational flexibility of 1,4-dihydroazines and their 4-ylide derivatives

The conformational flexibility of 1,4-dihydropyridine, 1,4-dihydropyrimidine, 1,4-dihydropyridazine, 1,4-dihydro-1,3,5-triazine, and their 4-oxo, imino, and methylene derivatives was studied by the semiempirical quantum-chemical AM1 method. It was demonstrated that the replacement of the methylene group in the dihydroazine ring by the exocyclic double bond results only in an increase in the rigidity of the heterocycle rather than leading to a loss of its conformational flexibility. It was suggested that nonplanar conformations of rings in ylide derivatives are stabilized by the nonaromatic cyclic -system. Introduction of the exocyclic double bond does not cause a substantial change in the -electronic structure of the heterocycle. The aromaticity indicesI ₆ andI ₆() were calculated. The correlation between these indices and a change in the energy upon bending of the heterocycle was established.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No 8 pp 1938–1941, August, 1996.     

Monocyclic and Fused 4-Imino(4-Oxo)-1,3,2-Diazaphospholanes and - Phosphorinanes. Synthesis and Some Properties

Abstract

In contrast to the great variety of well known phosphorus heterocycles with exocyclic C=O double bond the number of ones containing exocyclic C=N bond is unusually modest. We elaborated the convenient method of preparation of various N,P,N-heterocycles with exocyclic C=N bond (1–4) from the readily available corresponding amino acid amidines and appropriated dichlorides or diamides of phosphorus (III) acids. Rings' 1–3 with P(III) are easily converted into (thio)phosphoryl derivatives, while the direct phosphorylation of amino amidines by RP(Y)Cl₂ is unusually ineffective. Tricycles 4 - derivatives of 2-(2-amino pheny1)imidazoline - mainly exist in the more conjugated hydrophosphazo tautomeric form 4b (>90 %).     

Stereoselective synthesis of hexahydroindoles and octahydrocyclohepta[b]pyrroles via gold(I)-catalyzed intramolecular 1,4-hydroamination of cyclic 1,3-dienes

The gold(I)-catalyzed intramolecular hydroamination of cyclohexa-1,3-dienes bearing an arylsulfonamide at the C-5 position proceeds in a 1,4-addition manner to afford hexahydroindole derivatives in a diastereoselective fashion and in good yields, whereas octahydrocyclohepta[b]pyrrole derivatives can be obtained from seven-membered ring substrates under the same reaction conditions. Coordination of the gold(I) species to the 1,3-diene at the double bond adjacent to the arylsulfonamide tether gave an η²-alkene gold complex. The anti-attack of the sulfonamide to the η²-alkene gold complex at the terminal position of the 1,3-diene resulted in the formation of the fused bicyclic ring with a newly formed Au-C bond at the allylic position. Allylic rearrangement of the η¹-allylgold complex followed by protodemetalation provided the fused heterobicyclic skeletons and regenerated the catalyst.     

A new and efficient one-pot synthesis of 2-hydroxy-1,4-dihydrobenzoxazines via a three-component Petasis reaction

The secondary amines synthesized by the reaction between 2-aminophenols and aromatic aldehydes, via the reduction of the corresponding imines, were employed in the synthesis of new 2-hydroxy-2H-1,4-benzoxazine derivatives through a one-pot Petasis multicomponent reaction in good to excellent yields.     

Novel porphyrin-quinazoline conjugates via the Diels-Alder reaction

Novel derivatives of meso-tetraphenylporphyrin with appended quinazoline moieties were synthesized, via the Diels-Alder reaction, between a 4-(porphyrinyl)pyrimidine ortho-quinodimethane and 1,4-benzoquinone, 1,4-naphthoquinone and N-(p-nitrophenyl)maleimide. The structure of one bis adduct was established by X-ray crystallography and mass spectrometry. We have unequivocally confirmed that the 2:1 adducts obtained from the reaction of pyrimidine-fused 3-sulfolenes with N-arylmaleimides have an open-chain structure and not a cyclooctapyrimidine structure, as previously published.     

Versatile synthesis of chiral 2-substituted-5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepines as novel scaffolds for peptidomimetic building

The stereocontrolled synthesis of phenylalanine and tryptophan derived 5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine derivatives is described. This new methodology involves a modified Strecker reaction of N-Boc protected amino aldehydes and methyl anthranilate, reduction of the resulting α-amino nitriles, and lactamization. The resulting 2-substituted-5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepines were further functionalized at position 4 by alkylation or acylation reactions. One of these new tryptophan-derived 1,4-benzodiazepines showed significant selective binding affinity at cholecystokinin CCK₁ receptors (IC₅₀=156.5±33.2 nM).     

Domino reactions in water for the stereoselective synthesis of novel spiro dihydro-2′H-[indene-2,3′-thiophen]-1(3H)-ones with three contiguous stereocenters

The domino reactions of (E)-2-(aryl)-2,3-dihydro-1H-inden-1-ones and 1,4-dithiane-2,5-diol in the presence of triethylamine in water stereoselectively afforded a library of 2′-(aryl)-4′-hydroxy-4′,5′-dihydro-2′H-spiro[indene-2,3′-thiophen]-1(3H)-ones. This transformation presumably proceeds via the generation of 2-mercaptoacetaldehyde from 1,4-dithiane-2,5-diol followed by Michael addition–intramolecular aldol sequence with C–C and C–S bond formations and creation of three contiguous stereocenters in a one-pot operation.     

A novel and convenient method for the synthesis of new derivatives of pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione

A novel methodology has been developed for the efficient synthesis of 1,4-pyridopyrrolodiazepine derivatives. The key reaction is the bromination under mild conditions by NBS of compounds resulting via peptide coupling of l-proline methyl ester with 3-aminopyridine-2-carboxylic acid 1, then intramolecular cyclization in the construction of 2-bromo-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione 4. This latter is then engaged in cross-coupling reactions to generate 1,4-pyridopyrrolodiazepines derivatives 5a-m, 6a-i, 7, and 8a-c. This strategy provides an efficient method to access a library of compounds based on privileged substructures that are of great interest in drug discovery.     

Microwave-assisted one-pot synthesis of benzo[b][1,4]thiazin-3(4H)-ones via Smiles rearrangement

The synthesis of benzo[b][1,4]thiazin-3(4H)-one derivatives in a simple and efficient method from the one-pot reaction of substituted 2-chlorobenzenthiols, chloroacetyl chloride, and primary amines via Smiles rearrangement under microwave irradiation gave high yields (65-92%) of the products with short reaction time (15-20 min).     

NBS-mediated practical cyclization of N-acyl amidines to 1,2,4-oxadiazoles via oxidative N‒O bond formation

A reaction involving an efficient NBS-mediated oxidative N?O bond formation has been established for the synthesis of 1,2,4-oxadiazoles from readily accessible N-acyl amidines. The features of this synthetic method include simplicity of operation, mild reaction conditions, short reaction times, high yields, and eco-friendliness. The reaction also works well with crude N-acyl amidines obtained by amidation of simple benzoic acids and amidines to produce biologically relevant 1,2,4-oxadiazoles in a scalable fashion.     

Nitrenic reactivity of diazirines

Butyl 3-bromo-3H-diazirine-3-carboxylate (7) and 3-bromo-3-phenyl-3H-diazirine (17) exhibit nitrenic reactivity with phenylmagnesium bromide or tetrabutylammonium cyanide. The formation of several N,N′-disubstituted amidines is attributed to the intermediacy of 1-phenyl or 1-cyano-1H-diazirines possessing a singlet imidoylnitrene character at the N2 atom. Most notably, the reaction of 7 with PhMgBr in diethyl ether affords 2-hydroxy-2,2,N-triphenylacetamidine (9) and 2-methyl-5,5-diphenyl-4-phenylamino-2,5-dihydrooxazole (10) as products derived from nitrene insertion to the ether α-C–H bond.     

Me3SiCl-promoted intramolecular cyclization of aromatic compounds tethered with N,O-acetals leading to the facile preparation of 1,4-benzodiazepine skeletons

The Me₃SiCl-promoted intramolecular aminomethylation of a novel type of N,O-acetals, which were prepared via a facile three-step synthesis from N-alkylaniline derivatives and N-alkyl-2-oxazolidinones that leads to the production of pharmaceutically useful 1,4-benzodiazepine skeletons with a variety of functional groups is described. This method was successfully applied to the facile preparation of both tricyclic benzodiazepine derivatives and a 1,4-benzoxazepine derivative via 7-exo-trig cyclization.     

2-Amidinylindole-3-carbaldehydes: synthesis of new tetracyclic compounds containing the pyrrolo[1,2-c]1,4-diazepine ring

2-Amidinylindol-3-carbaldehydes bearing an α-alkoxycarbonyl substituent on the cyclic-tertiary amine moiety were prepared. Pyrolysis of these amidines in diethylenglycol-monoethyl ether produced mainly a pyrrolo[1′,2′-1,2]-1,4-diazepino[5,6-b]indol-7,11-dione. A similar result was obtained starting from 2-amidinylbenzofuran-3-carbaldehyde.     

Cyclorhenated compounds derived from 1,4-diaryl-1-azabutadienes: preparation, structures and reactions

PhCH₂Re(CO)₅ reacted with 1,4-diaryl-1-azabutadienes to give cyclometallated (η²-(C,N)-azabutadiene)Re(CO)₄ (4) together with the substituted derivatives (η¹-(N)-azabutadiene)(η²-(C,N)-azabutadiene)Re(CO)₃ (6 and 7) The substituted product was shown by NMR and X-ray crystal structure analysis to be an inseparable mixture of isomers differing in the conformation of the η¹-ligand about the NC bond—trans for (6) and cis for (7). Reaction of the mixture of 6 and 7 from 1,4-diphenyl-1-azabutadiene with phenyl acetylene gave η⁵-(1,2,4-triphenyl-1-aza-cyclohexadienyl)Re(CO)₃.     

The molecular diversity of three-component reactions of 4-dimethylamino- or 4-methoxypyridine with acetylenedicarboxylates and arylidene cyanoacetates

The three-component reactions of 4-dimethylamino- or 4-methoxypyridine with acetylenedicarboxylates and arylidene cyanoacetates showed very interesting molecular diversity. The polysubstituted 1,8,9,9a-tetrahydro-4H-1,4-ethanoquinolizines, 2H-pyran-2,3-dicarboxylates, and buta-1,3-diene-1,2,4-tricarboxylates derivatives can be formed in high yields and with good diastereoselectivity depending on the substrates and reaction conditions.     

An improved synthesis and some reactions of diethyl 4-oxo-4H-pyran-2,5-dicarboxylate

The reaction of ethyl 2-(dimethylamino)methylene-3-oxobutanoate with diethyl oxalate in the presence of sodium hydride in THF gave diethyl 4-oxo-4H-pyran-2,5-dicarboxylate, from which 4-oxo-4H-pyran-2,5-dicarboxylic and 4-oxo-1-phenyl-1,4-dihydropyridine-2,5-dicarboxylic acids and their derivatives were obtained in good yields.