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.     

Syntheses and conformational analyses of new naphth[1,2-e][1,3]oxazino[3,2-c]quinazolin-13-ones

The syntheses of naphth[1,2-e][1,3]oxazino[3,2-c]quinazolin-13-one derivatives (3a–f) were achieved by the solvent-free heating of benzyloxycarbonyl-protected intermediates (2a–f) with MeONa. For intermediates 2a–f, prepared by the reactions of substituted aminonaphthols with benzyl N-(2-formylphenyl)carbamate, not only the expected trans ring form B and chain form A¹, but also the rearranged chain form A² as a new tautomer were detected in DMSO at room temperature. The quantity of A² in the tautomeric mixture was changed with time.Conformational analyses of the target heterocycles 3a–f by NMR spectroscopy and accompanying theoretical calculations at the DFT level of theory revealed that the oxazine ring preferred a twisted chair conformation and the quinazolone ring was planar. Besides the conformations, both the configurations at C-7a and C-15 and the preferred rotamers of the 1-naphthyl substituent at C-15 were assigned, which allowed evaluation of the aryl substituent-dependent steric hindrance in this part of the molecules. Configurational assignments were corroborated by quantifying the ring current effect of 15-aryl in terms of spatial NICS.     

A new strategy for the synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines

A series of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines were prepared via oxidative cyclization of aldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-4-yl)hydrazones. Dimroth rearrangement of such a series yielded pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines.     

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.     

Novel furan derivatives related to triphenylene: benzo[1,2-c:3,4-c′:5,6-c″]-trifuran,naphtho[1,2-c:3,4-c′]difuran and phenanthro[9,10-c]furan

The title compounds have been synthesised by sequences involving as the key step the trapping of arynes with furan.     

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.     

DNMR, DFT and preparative study on the conformation of (Z)-4,5,6,7-tetrahydropyrazolo[1,5-e]benzo[g][1,5]diazonin-8-ones and (Z)-4,5-dihydropyrazolo[1,5-d]benzo[f][1,4]diazocin-7(6H)-ones

By means of base-catalyzed ring enlargement of triazaindenoindenes and pentalenoindenes obtained from anhydride-induced ring transformation of 3,4-dihydro-2H-pyrimido- and 2,3-dihydroimidazo[2,1-a]phthalazinium-olates, respectively, a series of pyrazolo[1,5-e]benzo[g][1,5]diazonin-8-ones and pyrazolo[1,5-d]benzo[f][1,4]diazocin-7(6H)-ones were obtained. Alternative pathways and energetics for the ring inversion of symmetrically substituted medium-size ring systems were determined by combined use of DNMR measurements and B3LYP/6-31G(d,p) calculations using the IEFPCM solvent model. One pyrazolobenzodiazonine carrying hydrogen at the C1 position was found to undergo facile ring inversion by a two-step mechanism, while 1-Me and 1-Ph substituents rendered complete rigidity to this ring system. A three-step mechanism was revealed for the ring inversion of the two studied pyrazolobenzodiazocines with energetics practically invariant to the investigated C1-substituents (H and Me). The attempted RCM of the N,O-diallyl derivative of a selected rigid model effected by Grubbs II catalyst led to deallylation and olefin isomerization avoiding the formation of bridged products with enhanced skeletal strain. A tolerable degree of ring strain associated with negligible skeletal distortion could be introduced into the same benzodiazonine by N,O-dialkylation with 1,3-bis(bromomethyl)benzene.     

Synthesis of tricyclic isoindoles and thiazolo[3,2-c][1,3]benzoxazines

The thermolysis of (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylic acids in Ac₂O led to novel 3-methylene-2,5-dioxo-3H,9bH-oxazolo[2,3-a]isoindoles and chiral (9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindoles were obtained on FVP. Starting from l-cysteine methyl ester (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazines were obtained as single stereoisomers. The thermolysis of (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazine-3-carboxylic acid in Ac₂O gave 5-acetyl-2-phenyl-2,3-dihydrothiazole. The structures of methyl (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylate 1a and methyl (2R,4R)-N-chlorocarbonyl-2-(2-hydroxyphenyl)thiazolidine-4-carboxylate 9 were determined by X-ray crystallography.     

Structural studies of 4-aryloctahydro-pyrido[1,2-c]pyrimidine derivatives

¹³C cross-polarisation magic angle spinning NMR data have been reported for four derivatives of 4-aryl-octahydro-pyrido[1,2-c]pyrimidine-1,3-dione and the X-ray diffraction data for two (with 2′-Me and 2′-OMe). The crystal structures show the presence of centrosymmetric cyclic dimers with intermolecular C1O?H-N or C3O?H-N hydrogen bonds, the configuration at the chiral centres (C4 and C4_a) was determined as RR (SS). The twisting of aromatic ring at C4 with respect to the pyrido[1,2-c]pyrimidine skeleton is about 68-109°.     

An efficient catalyst-free synthesis of novel benzo[a][1,3]oxazino[6,5-c]phenazine derivatives via one pot four-component domino protocol in water

A catalyst-free multicomponent reaction (MCR) capable of affording a wide range of novel benzo[a][1,3]oxazino[6,5-c]phenazine derivatives via one pot two-step domino protocol, in water is reported. Catalyst-free conditions along with green solvent system make the process ecofriendly as well as economical. Simple reaction conditions, easy work-up isolation, and purification of products are the significant advantages of the present protocol.     

Synthesis of new pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines and related heterocycles

The reaction between 5-amino-4-imino-1(2)-substituted-1(2)H-4,5-dihydropyrazolo[3,4-d]pyrimidines and several commercially available reactants afforded new heterocycles with a conserved pyrazolo[3,4-d]pyrimidine nucleus. The key intermediates employed proved to be suitable compounds by virtue of their two vicinal amino and imino groups that were used to obtain five, six and seven-membered rings.     

Synthesis of pyridino[3′,2′:4,5]pyrrolo[3,2-g]pyrrolo[3,4-e]indolizin-1,3-dione and pyrrolo[3,2-c]pyrazole skeletons

A three step synthesis of an isogranulatimide analogue, in which the imidazole moiety is replaced by a pyrrole unit and the indole heterocycle is replaced by a 7-azaindole moiety is described. Moreover, a novel synthetic pathway to the pyrrolo[3,2-c]pyrazole skeleton is reported.     

Synthesis of dipyrrolo[3,4-a:3,4-c]carbazoles: new kinase inhibitors

Two dipyrrolo[3,4-a:3,4-c]carbazole stereoisomers were unexpectedly obtained by Diels–Alder dimerization of 3-indolylmaleimide. Three dimensional structures of both stereoisomers were confirmed by X-ray analysis. Moreover compound 4 inhibits protein kinases in vitro, especially Pim-3, in the sub-micromolar range.     

Synthesis and properties of 1,6-methano[10]annuleno[3,4-c]thiophene and its 1,3-dicyano derivative

New thiophene-annulated 1,6-methano[10]annulene 1 and 2 were synthesized. The anisotropic deshielding effect from the π-electron system, based on the chemical shift values of the bridged methylene protons, is reduced compared with that of 3, and their crystal structures show clear bond alternation.     

A DFT study for the formation of imidazo[1,2-c]pyrimidines through an intramolecular Michael addition

The formation of imidazo[1,2-c]pyrimidines through a ring closure of 2-(2-sulfonylimino-1,2-dihydro-1-pyrimidinyl) acetamides has been studied using DFT methods. Analysis of the energy results for the cyclization step shows the demand of almost an acid catalyst, which increases the electrophilicity of the dihydropyrimidine moiety, in order to make feasible the intramolecular Michael addition. The substitution on both dihydropyrimidine and amide moieties has also an influence on the cyclization step.     

A facile synthesis and highly atom economic 1,3-dipolar cycloaddition of hexahydropyrido[3,4-c][1,5]benzothiazepines with nitrile oxide: stereoselective formation of hexahydro[1,2,4]oxadiazolo[5,4-d]pyrido[3,4-c][1,5]benzothiazepines

A series of new 2-methyl-11-aryl-4-[(E)-arylmethylidene]-1,2,3,4,11,11a-hexahydropyrido[3,4-c][1,5]benzothiazepines were obtained by the reaction of o-aminothiophenol and (E)-1-methyl-3,5-bis(arylidene)-4-piperidones in the presence of a catalytic amount of acetic acid under solvent-free microwave irradiation. These dipolarophiles undergo a highly atom economic 1,3-dipolar cycloaddition with nitrile oxide to afford a series of novel 6-methyl-1-phenyl-8-aryl-4-[(E)-arylmethylidene]-4,5,6,7,7a,8-hexahydro[1,2,4]oxadiazolo[5,4-d]pyrido[3,4-c][1,5]benzothiazepines stereoselectively.     

Synthesis of pyrano[3,4-c]pyrazole and pyrazolo[3,4-d][1,2]diazepine derivatives

By the action of thionyl chloride on 3(5)-R-4-phenacylpyrazole-5(3)-carboxylic acid ( 3c,d ), 3-R-5-phenylpyrano[3,4-c]pyrazole-7-(1H)ones ( 4c,d ) were obtained. When 4c,d were treated with hydrazine hydrate followed by refluxing in ethanol containing acetic acid, 4,7-dihydro-3-R-5-phenylpyrazolo[3,4-d][1,2]-diazepin-8-(1H)ones ( 6c,d ) were formed. Compounds 6c,d , in turn, were refluxed in ethanol saturated with hydrochloric acid to yield 6-amino-1,6-dihydro-3-R-5-phenyl-7H-pyrazolo[3,4-c]pyridin-7-ones ( 7c,d ). Compounds 7c,d could be obtained directly from 5c,d. The starting materials 3c,d were prepared by hydrolysis of the oxime of 3(5)-R-4-phenacyl-5(3)carboalcoxypyrazoles ( 1a,b ). Structural assignments rested on correct elemental analysis, molecular weights determined by mass spectrometry, and spectroscopic evidence.     

Synthesis and reactivity of pyrrolo[3,2-d][1,3]oxazine-2,4-dione. Access to new pyrrolo[3,2-e][1,4]diazepine-2,5-diones

A convenient synthesis of pyrrolo[3,2-d][1,3]oxazine-2,4-dione 4 is described and its reactivity towards various nucleophiles studied. The regioselective ring opening of anhydride 4 or its N-alkylated analog 25 in the presence of alanine or proline afforded, respectively, imidazolidinedione 22 and N-protected pyrrolo[3,2-e][1,4]diazepines 30 and 31 in a one-pot process. In a last part of this study, an alternative route to produce a library of eight non protected pyrrolo[3,2-e][1,4]diazepine-2,5-diones 35a–h is described to overcome the limited reactivity of anhydride 4.     

Preparation of novel pyridine-fused tris-heterocycles; pyrido[4,3-e]pyrrolo-/pyrido[4,3-e]furano[2,3-c]pyridazines and pyrido[3,4-b]pyrrolo[3,2-d]pyrrole

Three novel pyrido-fused tris-heterocycles have been prepared based on a Suzuki coupling and subsequent cyclisation approach. Pyrido[4,3-e]pyrrolo[2,3-c]pyridazine (3b, 77%) and pyrido[4,3-e]furano[2,3-c]pyridazine (5b, 76%) were obtained by intramolecular diazocoupling. Successful diazocoupling of furan (5b) is thus reported for the first time by NOBF₄ generation of the diazonium intermediate. N-TIPS-pyrido[3,4-b]pyrrolo[3,2-d]pyrrole (TIPS-4b) was synthesised by thermal cyclisation of pyridyl nitrene in considerably higher yield (71%) than previously experienced from similar cyclisations, due to TIPS-activation.     

Synthesis of the new ring system 2-oxo-[1,4]oxazino[3,2-e]indole, heteroanalogue of Angelicin

A convenient synthesis of the 2-oxo-[1,4]oxazino[3,2-e]indole ring system, an heteroanalogue of Angelicin, is reported. Our synthetic approach consisted of the annelation of the oxazine ring on the indole moiety using 4-amino-5-hydroxy indoles as building blocks. The antiproliferative activity of the new compounds either in the dark or under UVA irradiation was investigated.