Stereoelectronic effects in ring-chain tautomerism of 1,3-diarylnaphth[1,2-e][1,3]oxazines and 3-alkyl-1-arylnaphth[1,2-e][1,3]oxazines

The disubstitution effects of X and Y in 1-(Y-phenyl)-3-(X-phenyl)-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines on the ring-chain tautomerism, the delocalization of the nitrogen lone pair (anomeric effect), and the (13)C NMR chemical shifts were analyzed by using multiple linear regression analysis. Study of the three-component equilibrium B<==>A<==>C revealed that the chain<==>trans (A<==>B) equilibrium constants are significantly influenced by the inductive effect (sigma(F)) of substituent Y on the 1-phenyl ring. In contrast, no significant substituent dependence on Y was observed for the chain<==>cis (A<==>C) equilibrium. There was an analogous dependence for the epimerization (C<==>B) constants of 1-(Y-phenyl)-3-alkyl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines. With these model compounds, significant overlapping energies of the nitrogen lone pair was observed by NBO analysis in the trans forms B (to sigma*(C1-C1'), sigma*(C1-C10b), and sigma*(C3-O4)) and in the cis forms C (to sigma*(C1-H), sigma*(C1-C10b), and sigma*(C3-O4)). The effects of disubstitution revealed some characteristic differences between the cis and trans isomers. However, the results do not suggest that the anomeric effect predominates in the preponderance of the trans over the cis isomer. When the (13)C chemical shift changes induced by substituents X and Y (SCS) were subjected to multiple linear regression analysis, negative rho(F)(Y) and rho(F)(X) values were observed at C-1 and C-3 for both the cis and trans isomers. In contrast, the positive rho(R)(Y) values at C-1 and the negative rho(R)(X) values at C-3 observed indicated the contribution of resonance structures f (rho(R) > 0) and g (rho(R) < 0), respectively. The classical double bond-no-bond resonance structures proved useful in explaining the substituent sensitivities of the donation energies and the behavior of the SCS values.     

Synthesis of novel pyrido[2,3-e][1,3]oxazines

The preparation of novel pyrido[2,3-e][1,3]oxazines starting from 3-hydroxy-pyridine-2-carbonitrile, N-aralkoxy-3-hydroxy-pyridine-2-carboxamides and 3-hydroxy-pyridine-2-carboxylic acid hydrazides is described.     

Substituent effects in the ring-chain tautomerism of 4-aryl-1,3,4,6,7,11b-hexahydro-2H-pyrimido[6,1-a]isoquinolines

By condensation of 1-(2′-aminoethyl)-1,2,3,4-tetrahydroisoquinoline derivatives with substituted benzaldehydes, 1,6-unsubstituted and diastereomers of 1-methyl- or 6-methyl-substituted 4-aryl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrimido[6,1-a]isoquinolines were prepared. The ring-chain tautomeric equilibria of most of these compounds in CDCl₃ at 300 K were found to be shifted nearly totally towards either the cyclic or the open tautomeric forms, while the (6R*,11bR*)-6-methyl substituted compounds proved to be three-component tautomeric mixtures, the equilibria of which could be characterized by a Hammett-type equation. The conformational equilibria of the cyclic forms turned out to be strongly influenced by the 1- and 6-methyl substituents and the configurations of the substituted carbons (C-1 or C-6 and C-4) relative to C-11b.     

Synthesis of new 1,3-disubstituted-2,3-dihydro-1H-naphth[1,2e][1,3]oxazines

1,3-Disubstituted-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines were prepared through the ring-closure reactions of the aminobenzylnaphthols with substituted aryl- and heteroarylaldehydes.     

Efficient highly diastereoselective synthesis of 1,8a-dihydro-7H-imidazo[2,1-b][1,3]oxazines

1-Alkyl imidazoles react smoothly with dialkyl acetylenedicarboxylates in the presence of pyridine carboxaldehydes to diastereoselectively produce 1,8a-dihydro-7H-imidazo[2,1-b][1,3]oxazine derivatives in excellent yields.     

Pyrolysis of perhydro[1,2-c][1,3]oxazines: a green method of synthesizing 2,3-dehydropiperidine enamines

Heat pyrolysis of the oxazines formed from 2-piperidineethanol produced 2,3-dehydropiperidine enamines. The same results were observed when these oxazines were irradiated with microwaves. Various 2-substituted perhydrooxazines were synthesized by allowing 2-piperidineethanol or 2-piperidinemethanol to react with aldehydes or ketones.     

Rearrangements of tetrahydroimidazo[1,5-b]isoxazole-2,3-dicarboxylates to pyrrolo[1,2-e]imidazol-6-ols, precursors of 2,5-dihydro-1H-pyrrole derivatives

Isoxazolines 2 from the cycloaddition of imidazoline 3-oxides 1 with DMAD rearrange in the presence of methoxide to give cis-3-methoxy-7-(methoxycarbonyl)-2,7a-diaryl-5-oxo-2,3,5,7a-tetrahydro-1H-pyrrolo[1,2-e]imidazol-6-olates 3 with 100% de. The acidic hydrolysis of 3 led to kinetically controlled formation of methyl 1-formyl-4-hydroxy-5-oxo-2-phenyl-2-((arylamino)methyl)-2,5-dihydro-1H-pyrrole-3-carboxylates 6a-e. The intramolecular transformylations of the latter to the corresponding (E)- and (Z)-methyl 4-hydroxy-2-((N-(aryl)formamido)methyl)-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylates 7a-e were shown to be substituent dependent (correlate with σ) and characterized by Hammett type equations. The effect of temperature was investigated and the ρ constants determined for the same reaction series at 50, 60 and 70 °C. The amide diastereomeric ratio [(E)-7]/[(Z)-7] is substituent dependent and can be described by the equation log[(E)]/[(Z)]_x=−ρσ_I+log[(E)]/[(Z)]_x=H.     

Indium-mediated regioselective mono-allylation of 1,5-dicarbonyl compounds and dehydrative cyclization to 2,3-dihydro-4H-pyran-4-ones and 3,4-dihydro-2H-[1,4]oxazines

An indium-mediated Barbier type mono-allylation of 1,5-dicarbonyl compounds and a subsequent acid-catalyzed dehydrative cyclization afforded 2,3-dihydro-4H-pyran-4-ones and 3,4-dihydro-2H-[1,4]oxazines.     

Synthesis and conformational analysis of new naphth[1,2-e][1,3]oxazino[3,4-c]quinazoline derivatives

A new highly functionalized aminonaphthol derivative, 1-(amino(2-aminophenyl)methyl)-2-naphthol (4), was synthesized by the reaction of 2-naphthol, 2-nitrobenzaldehyde and tert-butyl carbamate or benzyl carbamate, followed by reduction and/or removal of the protecting group. The aminonaphthol derivative thus obtained was converted in ring-closure reactions with formaldehyde, benzaldehyde and/or phosgene to the corresponding naphth[1,2-e][1,3]oxazino[3,4-c]quinazoline derivatives. The conformational analysis of some derivatives by NMR spectroscopy and accompanying molecular modelling are also reported.     

Galanthamine analogs: 6H-benzofuro[3a,3,2,-e,f][1]benzazepine and 6H-benzofuro[3a,3,2-e,f][3]benzazepine

The known cholinesterase inhibitory capability of the Amarylidaceae alkaloid galanthamine prompted preparation of analogs in which the position of the nitrogen within the azepine ring is altered. The analogs 6H-benzofuro[3a,3,2-e,f][1]benzazepine and 6H-benzofuro[3a,3,2-e,f][3]benzazepine were prepared in 19 and 2.5%, respectively, following Kametani and Shimizu approaches, respectively. The aniline derivative 6H-benzofuro[3a,3,2-e,f][1]benzazepine failed to undergo most of the reactions typical for galanthamine. Thus, it neither oxidized to the analogous narwedine, nor epimerized to the analogous epigalanthamine, nor reduced to the lycoramine analog, under the conditions used for galanthamine.     

Synthesis and conformational analysis of naphth[1′,2′:5,6][1,3]oxazino[3,2-c][1,3]benzoxazine and naphth[1′,2′:5,6][1,3]oxazino[3,4-c][1,3]benzoxazine derivatives

A new functional group, the hydroxy group, was inserted into a Betti base by reaction with salicylaldehyde, and the naphthoxazine derivatives thus obtained were converted by ring-closure reactions with formaldehyde, acetaldehyde, propionaldehyde or phosgene to the corresponding naphth[1′2′:5,6][1,3]oxazino[3,2-c][1,3]benzoxazine derivatives. Further, the conformational analysis of these polycyclic compounds by NMR spectroscopy and an accompanying molecular modelling are reported; especially, both quantitative anisotropic ring current effects of the aromatic moieties in these compounds and steric substituent effects were employed to determine the stereochemistry of the naphthoxazinobenzoxazine derivatives.     

Synthesis of 2,6-disubstituted pyrido[2,3-b][1,4]oxazines

A new preparative method for pyrido[2,3-b][1,4]oxazines from 6-substituted 3-nitro-2-pyridones is demonstrated. This method consists of two steps: O-alkylation and reductive cyclization. In the former step, the bulkiness of both starting nitropyridones and C2 reagents is found to be essential for avoiding N-alkylation, which undergoes O-alkylation efficiently. The subsequent reductive cyclization affords pyridoxazines with carbon substituents at both the 2- and the 6-positions that have not been available.     

A new “one pot” preparation of 2-n,n-dialkylamino-1,3-benzoxazines and naphth[ 1,2-e][ 1,3]oxazines from corresponding ortho hydroxynitriles and phosgeniminium salts

Phosgeniminium salts 2 react easily with ortho hydroxybenzonitriles 1 and 2-hydroxy-1-naphthonitriles 6 to give 1,3-benzoxazine and naphth[1,2-e][1,3]oxazine derivatives respectively with a very good yield.     

A convenient synthesis of new pyrido[3,2-e][1,4]diazepine-2,5-diones and pyrido[2,3-e][1,4]diazepine-2,5-diones

A convenient synthesis of a series of pyrido[3,2-e][1,4]-diazepine-2,5-diones 8 and pyrido[2,3-e][1,4]diazepine-2,5-diones 9, is reported using the condensation of α-amino acid methyl ester derivatives with 1H-pyrido[3,2-d][1,3]oxazine-2,4-dione and 1H-pyrido[2,3-d][1,3]oxazine-2,4-dione. Compounds 8 and 9 were also synthesized by peptide coupling of α-amino acid methyl ester derivatives with β-amino acids (2 or 3) followed by the cyclisation in tetrahydrofuran with sodium hydride (NaH).     

A one-pot synthesis of 2,3-dihydro-1H-pyrrolo[3,2-c]quinolines

A one-pot synthesis of the 2,3-dihydro-1H-pyrrolo[3,2-c]quinoline core from substituted 2-iodoanilines and 2,3-dihydro-1H-pyrrole was achieved using 10 mol % Pd(PPh₃)₄, and K₂CO₃ in 1,4-dioxane at 170 °C for 1 h in a microwave oven. This reaction can be carried out on a gram scale. The proposed mechanism involves a Heck-coupling reaction followed by intra-molecular Schiff base formation and double bond migration.     

Cyclopropanation of 3,4-dihydro-1 H-benzo[e][1,4]diazepine-2,5-diones

A two step parallel synthesis protocol for the preparation of 1N-substituted spirobenzodiazepineones is described. Treatment of 4-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione with a series of alkyl halides using a microwave-assisted heating protocol provided N-derivatized compounds, which were transformed to the corresponding cyclopropylamines employing modified Kulinkovich-type reaction conditions. X-ray structural analysis gave conclusive evidence of the newly created spiro centre and revealed a significant flattening of the seven-membered ring system compared with the benzodiazepinedione system providing a characteristically different pattern of bond exit vectors. The physicochemical parameters log D, pK_a, solubility and membrane permeability of both cyclopropanated and precursor compounds were assessed.     

Morita-Baylis-Hillman route to 4H-pyrrolo[1,2-a][1]benzazepine derivatives

A simple method for synthesizing substituted 4H-pyrrolo[1,2-a][1]benzazepines using acid-assisted cyclization of the Morita-Baylis-Hillman adducts of 2-(1H-pyrrol-1-yl)benzaldehydes with methyl acrylate or methyl vinyl ketone as a key step has been developed.     

Solution-phase parallel synthesis of new 2H-pyrimido-[4,5-e][1,2,4]triazin-3-ylidenecyanamides

A practical synthesis of 2H-pyrimido[4,5-e][1,2,4]triazin-3-ylidenecyanamides has been developed. The key step is the coupling reaction of an aryldiazonium salt with 1-cyano-3-(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-ylamino)-2-methylisothiourea followed by intramolecular cyclization. A library of 2H-pyrimido[4,5-e][1,2,4]triazin-3-ylidenecyanamides was prepared in two steps from 6-aminouracils using this method.     

Synthesis of unsaturated [1,2]oxazines by using sigmatropic rearrangements and the ring-closing metathesis reaction

Various substituted unsaturated [1,2]oxazines have been synthesized by using a [2,3]- or a [3,3]-sigmatropic rearrangement and a ring-closing metathesis reaction as key steps.