Conversion of 2-methyl-4-styrylquinolines into 2,4-distyrylquinolines: synthesis, and spectroscopic and structural characterization of five examples.

Four new 2,4-distyrylquinolines and one 2-styryl-4-[2-(thiophen-2-yl)vinyl]quinoline have been synthesized using indium trichloride condensation reactions between aromatic aldehydes and the corresponding 2-methylquinolines, which were themselves prepared using Friedländer annulation reactions between mono- or diketones and (2-aminophenyl)chalcones: the products have all been fully characterized by spectroscopic and crystallographic methods. 2,4-Bis[(E)-styryl]quinoline, C25H19N, (IIa), and its dichloro analogue, 2-[(E)-2,4-dichlorostyryl]-4-[(E)-styryl]quinoline, C25H17Cl2N, (IIb), exhibit different orientations of the 2-styryl unit relative to the quinoline nucleus. In each of the 3-benzoyl analogues {2-[(E)-4-bromostyryl]-4-[(E)-styryl]quinolin-3-yl}(phenyl)methanone, C32H22BrNO, (IIc), {2-[(E)-4-bromostyryl]-4-[(E)-4-chlorostyryl]quinolin-3-yl}(phenyl)methanone, C32H21BrClNO, (IId), and {2-[(E)-4-bromostyryl]-4-[(E)-2-(thiophen-2-yl)vinyl]quinolin-3-yl}(phenyl)methanone, C30H20BrNOS, (IIe), the orientation of the 2-styryl unit is similar to that in (IIa), but the orientation of the 4-arylvinyl units show considerable variation. The thiophene unit in (IIe) is disordered over two sets of atomic sites having occupancies of 0.926 (3) and 0.074 (3). There are no hydrogen bonds of any kind in the structure of (IIa), but in (IId), a single C-H...O hydrogen bond links the molecules into cyclic centrosymmetric R22(20) dimers. A combination of C-H...N and C-H...π hydrogen bonds links the molecules of (IIb) into a three-dimensional framework structure. A combination of three C-H...π hydrogen bonds links the molecules of (IIc) into sheets, and a combination of C-H...O and C-H...π hydrogen bonds forms sheets in (IIe). Comparisons are made with the structures of some related compounds.

A three-step pathway from (2-aminophenyl)chalcones to novel styrylquinoline-chalcone hybrids: synthesis and spectroscopic and structural characterization of three examples.

Three new styrylquinoline-chalcone hybrids have been synthesized using a three-step pathway starting with Friedländer cyclocondensation between (2-aminophenyl)chalcones and acetone to give 2-methyl-4-styrylquinolines, followed by selective oxidation to the 2-formyl analogues, and finally Claisen-Schmidt condensation between the formyl intermediates and 1-acetylnaphthalene. All intermediates and the final products have been fully characterized by IR and 1H/13C NMR spectroscopy, and by high-resolution mass spectrometry, and the three products have been characterized by single-crystal X-ray diffraction. The molecular conformations of (E)-3-{4-[(E)-2-phenylethenyl]quinolin-2-yl}-1-(naphthalen-1-yl)prop-2-en-1-one, C30H21NO, (IVa), and (E)-3-{4-[(E)-2-(4-fluorophenyl)ethenyl]quinolin-2-yl}-1-(naphthalen-1-yl)prop-2-en-1-one, C30H20FNO, (IVb), are very similar. In each compound, the molecules are linked into a three-dimensional array by hydrogen bonds, of the C-H...O and C-H...N types in (IVa), and of the C-H...O and C-H...π types in (IVb), and by two independent π-π stacking interactions. By contrast, the conformation of the chalcone unit in (E)-3-{4-[(E)-2-(2-chlorophenyl)ethenyl]quinolin-2-yl}-1-(naphthalen-1-yl)prop-2-en-1-one, C30H20ClNO, (IVc), differs from those in (IVa) and (IVb). There are only weak hydrogen bonds in the structure of (IVc), but a single rather weak π-π stacking interaction links the molecules into chains. Comparisons are made with some related structures.

Synthesis, and spectroscopic and structural characterization of three new styrylquinoline-benzimidazole hybrids.

Three new 4-styrylquinoline-benzimidazole hybrids have been synthesized using a reaction sequence in which 2-methylquinoline precursors first undergo selective oxidation by selenium dioxide to form the corresponding 2-formylquinoline intermediates, followed by oxidative cyclocondensation reactions with benzene-1,2-diamine to yield the hybrid products. The formyl intermediates and the hybrid products have all been fully characterized using a combination of IR, 1H and 13C NMR spectroscopy, and high-resolution mass spectrometry, and the structures of the three hybrid products have been determined using single-crystal X-ray diffraction. Ethyl (E)-2-(1H-benzo[d]imidazol-2-yl)-4-(4-chlorostyryl)quinoline-3-carboxylate, C27H20ClN3O2, (IIIa), and ethyl (E)-2-(1H-benzo[d]imidazol-2-yl)-4-(2-methoxystyryl)quinoline-3-carboxylate, C28H23N3O3, (IIIb), both crystallize in the solvent-free form with Z' = 1, but ethyl (E)-2-(1H-benzo[d]imidazol-2-yl)-4-(4-methylstyryl)quinoline-3-carboxylate, C28H23N3O2, (IIIc), crystallizes as a partial hexane solvate with Z' = 3, and the ester group in one of the independent molecules is disordered over two sets of atomic sites having occupancies of 0.765 (7) and 0.235 (7). The molecules of (IIIc) enclose continuous channels which are occupied by disordered solvent molecules having partial occupancy. In all of the molecules of (IIIa)-(IIIc), the styrylquinoline fragment is markedly nonplanar. Different combinations of N-H...O and C-H...π hydrogen bonds generate supramolecular assemblies which are two-dimensional in (IIIb) and (IIIc), but three-dimensional in (IIIa). Comparisons are made with the structures of some related compounds.

Synthesis and spectroscopic and structural characterization of three new 2-methyl-4-styrylquinolines formed using Friedländer reactions between (2-aminophenyl)chalcones and acetone.

Three new 2-methyl-4-styrylquinoline derivatives have been synthesized in high yields using Friedländer reactions between chalcones [1-(2-aminophenyl)-3-arylprop-2-en-1-ones] and acetone, and characterized using IR, 1H and 13C NMR spectroscopy, and mass spectrometry, and by crystal structure analysis. In (E)-4-(4-fluorostyryl)-2-methylquinoline, C18H14FN, (I), the molecules are joined into cyclic centrosymmetric dimers by C-H...N hydrogen bonds and these dimers are linked into sheets by π-π stacking interactions. The molecules of (E)-2-methyl-4-[4-(trifluoromethyl)styryl]quinoline, C19H14F3N, (II), are linked into cyclic centrosymmetric dimers by C-H...π hydrogen bonds and these dimers are linked into chains by a single π-π stacking interaction. There are no significant hydrogen bonds in the structure of (E)-4-(2,6-dichlorostyryl)-2-methylquinoline, C18H13Cl2N, (III), but molecules related by translation along [010] form stacks with an intermolecular spacing of only 3.8628 (2) Å. Comparisons are made with the structures of some related compounds.

4-Styrylquinolines from cyclocondensation reactions between (2-aminophenyl)chalcones and 1,3-diketones: crystal structures and regiochemistry.

Structures are reported for two matched sets of substituted 4-styrylquinolines which were prepared by the formation of the heterocyclic ring in cyclocondensation reactions between 1-(2-aminophenyl)-3-arylprop-2-en-1-ones with 1,3-dicarbonyl compounds. (E)-3-Acetyl-4-[2-(4-methoxyphenyl)ethenyl]-2-methylquinoline, C21H19NO2, (I), (E)-3-acetyl-4-[2-(4-bromophenyl)ethenyl]-2-methylquinoline, C20H16BrNO, (II), and (E)-3-acetyl-2-methyl-4-{2-[4-(trifluoromethyl)phenyl]ethenyl}quinoline, C21H16F3NO, (III), are isomorphous and in each structure the molecules are linked by a single C-H...O hydrogen bond to form C(6) chains. In (I), but not in (II) or (III), this is augmented by a C-H...π(arene) hydrogen bond to form a chain of rings; hence, (I)-(III) are not strictly isostructural. By contrast with (I)-(III), no two of ethyl (E)-4-[2-(4-methoxyphenyl)ethenyl]-2-methylquinoline-3-carboxylate, C22H21NO3, (IV), ethyl (E)-4-[2-(4-bromophenyl)ethenyl]-2-methylquinoline-3-carboxylate, C21H18BrNO2, (V), and ethyl (E)-2-methyl-4-{2-[4-(trifluoromethyl)phenyl]ethenyl}quinoline-3-carboxylate, C22H18F3NO2, (VI), are isomorphous. The molecules of (IV) are linked by a single C-H...O hydrogen bond to form C(13) chains, but cyclic centrosymmetric dimers are formed in both (V) and (VI). The dimer in (V) contains a C-H...π(pyridyl) hydrogen bond, while that in (VI) contains two independent C-H...O hydrogen bonds. Comparisons are made with some related structures, and both the regiochemistry and the mechanism of the heterocyclic ring formation are discussed.

A concise and efficient concurrent synthesis of 6,11-dihydrodibenzo[b,e]azepines and 5,6,11,12-tetrahydrodibenzo[b,f]azocines and their conversion to 4-oxo-8,13-dihydro-4H-benzo[5,6]azepino[3,2,1-ij]quinoline-5-carboxylates and N-acetyl-5,6,11,12-tetrahydrodibenzo[b,f]azocines: synthetic sequence, spectroscopic characterization and the structures of two products.

Reaction of 2-allyl-N-benzyl-4-fluoroaniline or 2-allyl-N-benzyl-4-chloroaniline with 98% sulfuric acid leads to the concurrent formation of halogeno-substituted 11-ethyl-6,11-dihydrodibenzo[b,e]azepines, (II), and halogeno-substituted 11-methyl-5,6,11,12-tetrahydrodibenzo[b,f]azocines, (III), in each case in (II):(III) molar ratios of ca 2:1. Further reaction of (II) leads to ethyl 13-ethyl-2-halogeno-4-oxo-8,13-dihydro-4H-benzo[5,6]azepino[3,2,1-ij]quinoline-5-carboxylate, while acetylation of (III) gives the corresponding N-acetyl derivatives. The dibenzo[b,e]azepine and dibenzo[b,f]azocine ring systems are of importance in forming the core of a variety of bioactive compounds. In ethyl 13-ethyl-2-fluoro-4-oxo-8,13-dihydro-4H-benzo[5,6]azepino[3,2,1-ij]quinoline-5-carboxylate, C22H20FNO3, (IVa), the azepine ring adopts a conformation close to the twist-boat form, and the molecules are linked into a three-dimensional framework structure by a combination of C-H...O and C-H...π(arene) hydrogen bonds. The azocine ring in 5-acetyl-2-chloro-11-methyl-5,6,11,12-tetrahydrobenzo[b,f]azocine, C18H18ClNO, (Vb), adopts the boat-boat conformation and the molecules are again linked by C-H...O and C-H...π(arene) hydrogen bonds, but this time form a sheet structure.

Monoclinic and orthorhombic forms of (RS)-(E)-4-[2-(4-chlorobenzylidene)hydrazinyl]-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine: synthesis, concomitant polymorphism and supramolecular assembly mediated by C-H...N, C-H...π(arene) and C-Cl...π(arene) interactions.

The title compound, C21H20ClN5, has been synthesized in two steps from (RS)-4-chloro-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine and characterized by 1H and 13C NMR spectroscopy and by high-resolution mass spectrometry. Crystallization from hexane-ethyl acetate yields approximately equal quantities of a monoclinic polymorph in the space group Cc, (I), and an orthorhombic polymorph in the space group Pna21, (II). The molecules in polymorphs (I) and (II) show small differences in their molecular conformations, particularly in the shape of the azepine ring and the orientation of the chlorophenyl substituent. The molecules in polymorph (I) are linked by C-H...N and C-H...π(arene) hydrogen bonds to form sheets, which are linked into a three-dimensional framework structure by C-Cl...π(arene) interactions. There are no C-Cl...π(arene) interactions between the molecules in polymorph (II) and the supramolecular assembly takes the form of sheets built from C-H...N and C-H...π(arene) hydrogen bonds. Comparisons are made with some related structures.

A concise and versatile route to tetrahydro-1-benzazepines carrying [a]-fused heterocyclic units: synthetic sequence and spectroscopic characterization, and the molecular and supramolecular structures of one intermediate and two products.

A concise, efficient and versatile route from simple starting materials to tricyclic tetrahydro-1-benzazepines carrying [a]-fused heterocyclic units is reported. Thus, the easily accessible methyl 2-[(2-allyl-4-chlorophenyl)amino]acetate, (I), was converted, via (2RS,4SR)-7-chloro-2,3,4,5-tetrahydro-1,4-epoxy-1-benzo[b]azepine-2-carboxylate, (II), to the key intermediate methyl (2RS,4SR)-7-chloro-4-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine-2-carboxylate, (III). Chloroacetylation of (III) provided the two regioisomers methyl (2RS,4SR)-7-chloro-1-(2-chloroacetyl)-4-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine-2-carboxylate, (IVa), and methyl (2RS,4SR)-7-chloro-4-(2-chloroacetoxy)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-2-carboxylate, C14H15Cl2NO4, (IVb), as the major and minor products, respectively, and further reaction of (IVa) with aminoethanol gave the tricyclic target compound (4aRS,6SR)-9-chloro-6-hydroxy-3-(2-hydroxyethyl)-2,3,4a,5,6,7-hexahydrobenzo[f]pyrazino[1,2-a]azepine-1,4-dione, C15H17ClN2O4, (V). Reaction of ester (III) with hydrazine hydrate gave the corresponding carbohydrazide (VI), which, with trimethoxymethane, gave a second tricyclic target product, (4aRS,6SR)-9-chloro-6-hydroxy-4a,5,6,7-tetrahydrobenzo[f][1,2,4]triazino[4,5-a]azepin-4(3H)-one, C12H12ClN3O2, (VII). Full spectroscopic characterization (IR, 1H and 13C NMR, and mass spectrometry) is reported for each of compounds (I)-(III), (IVa), (IVb) and (V)-(VII), along with the molecular and supramolecular structures of (IVb), (V) and (VII). In each of (IVb), (V) and (VII), the azepine ring adopts a chair conformation and the six-membered heterocyclic rings in (V) and (VII) adopt approximate boat forms. The molecules in (IVb), (V) and (VII) are linked, in each case, into complex hydrogen-bonded sheets, but these sheets all contain a different range of hydrogen-bond types: N-H...O, C-H...O, C-H...N and C-H...π(arene) in (IVb), multiple C-H...O hydrogen bonds in (V), and N-H...N, O-H...O, C-H...N, C-H...O and C-H...π(arene) in (VII).

Synthesis and biological evaluation of sphingosine kinase 2 inhibitors with anti-inflammatory activity.

The synthesis of inhibitors of SphK2 with novel structural scaffolds is reported. These compounds were designed from a molecular modeling study, in which the molecular interactions stabilizing the different complexes were taken into account. Particularly interesting is that 7-bromo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine, which is a selective inhibitor of SphK2, does not exert any cytotoxic effects and has a potent anti-inflammatory effect. It was found to inhibit mononuclear cell adhesion to the dysfunctional endothelium with minimal impact on neutrophil-endothelial cell interactions. The information obtained from our theoretical and experimental study can be useful in the search for inhibitors of SphK2 that play a prominent role in different diseases, especially in inflammatory and cardiovascular disorders.

Observation of an infrequent enantiomer/conformer substitutional disorder in ethyl 13-ethyl-4-oxo-8,13-dihydro-4H-benzo[5,6]azepino[3,2,1-ij]quinoline-5-carboxylate heptane hemisolvate.

Considering the importance of quinolones due to their broad spectrum of biological activities, the crystal structure of the title compound, C22H21NO3·0.5C7H16, has been determined. Two enantiomers of the benzazepinoquinoline molecule and one molecule of heptane form the asymmetric unit of this centrosymmetric triclinic (P-1) crystal. All the molecules in the crystal present disorder. Substitutional disorder is observed for the benzazepine molecules, where a minority conformer of the R enantiomer replaces the main conformer of the S enantiomer and vice versa. Positional disorder is found for the heptane solvent molecule, which occupies a void left by the independent enantiomers of both conformers.

A concise, efficient and versatile synthesis of amino-substituted benzo[b]pyrimido[5,4-f]azepines: synthesis and spectroscopic characterization, together with the molecular and supramolecular structures of three products and one intermediate.

A concise, efficient and versatile synthesis of amino-substituted benzo[b]pyrimido[5,4-f]azepines is described: starting from a 5-allyl-4,6-dichloropyrimidine, the synthesis involves base-catalysed aminolysis followed by intramolecular Friedel-Crafts cyclization. Four new amino-substituted benzo[b]pyrimido[5,4-f]azepines are reported, and all the products and reaction intermediates have been fully characterized by IR, 1H and 13C NMR spectroscopy and mass spectrometry, and the molecular and supramolecular structures of three products and one intermediate have been determined. In each of N,2,6,11-tetramethyl-N-phenyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepin-4-amine, C22H24N5, (III), 4-(1H-benzo[d]imidazol-1-yl)-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, which crystallizes as a 0.374-hydrate, C21H19N5·0.374H2O, (VIIIa), and 6,7,9,11-tetramethyl-4-(5-methyl-1H-benzo[d]imidazol-1-yl)-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, C24H25N5, (VIIIc), the azepine ring adopts a boat conformation, but with a different configuration at the stereogenic centre in (VIIIc), as compared with (III) and (VIIIa). In the intermediate 5-allyl-6-(1H-benzo[d]imidazol-1-yl)-N-methyl-N-(4-methylphenyl)pyrimidin-4-amine, C22N21N5, (VIIb), the immediate precursor of 4-(1H-benzo[d]imidazol-1-yl)-6,8,11-trimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, (VIIIb), the allyl group is disordered over two sets of atomic sites having occupancies of 0.688 (5) and 0.312 (5). The molecules of (III) are linked into chains by a C-H...π(pyrimidine) hydrogen bond, and those of (VIIb) are linked into complex sheets by three hydrogen bonds, one of the C-H...N type and two of C-H...π(arene) type. The molecules of the organic component in (VIIIa) are linked into a chain of rings by two C-H...π(arene) hydrogen bonds, and these chains are linked into sheets by the water components; a single weak C-H...N hydrogen bond links molecules of (VIIIc) into centrosymmetric R22(10) dimers. Comparisons are made with some related compounds.

A versatile synthesis of cyclic dipeptides using the stepwise construction of the piperazine-2,5-dione ring from simple precursors: synthetic sequence and the structure of a representative product, (3RS)-4-(2-allyl-3,5-dimethylphenyl)-1-benzyl-3-phenylpiperazine-2,5-dione.

A versatile synthesis of multiply substituted cyclic dipeptides has been designed, based on the stepwise construction of the piperazine-2,5-dione ring using molecular fragments from four different precursor molecules. Starting from substituted 2-allylanilines, reaction with methyl 2-bromo-2-phenylacetate yields the corresponding methyl 2-(2-allylanilino)-2-phenylacetates, which react with haloacetyl chlorides to give methyl 2-[N-(2-allylphenyl)-2-haloacetamido]-2-phenylacetates, which then undergo ring closure with benzylamine to yield the corresponding cyclic dipeptides of type 4-(2-allylphenyl)-1-benzyl-3-phenylpiperazine-2,5-dione. (3RS)-4-(2-Allyl-3,5-dimethylphenyl)-1-benzyl-3-phenylpiperazine-2,5-dione, C28H28N2O2, (IIId), crystallizes with Z' = 2 in the space group P21/c; the allyl groups in the two independent molecules adopt different conformations and, in one of them, the allyl group is disordered over two sets of atomic sites having occupancies of 0.534 (4) and 0.466 (4). In both molecules, the piperazine-2,5-dione ring adopts a boat conformation, with the 3-phenyl ring in a quasi-axial site. The molecules of (IIId) are linked into a three-dimensional framework structure by a combination of three C-H...O hydrogen bonds and three C-H...π(arene) hydrogen bonds. Comparisons are made with some related structures.

An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors.

Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphingosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaffolds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1. Our study was carried out in different steps: virtual screening, synthesis, bioassays and molecular modelling. From our results, we propose a new dihydrobenzo[b]pyrimido[5,4-f]azepine and two alkyl{3-/4-[1-hydroxy-2-(4-arylpiperazin-1-yl)ethyl]phenyl}carbamates as initial structures for the development of new inhibitors. In addition, our molecular modelling study using QTAIM calculations, allowed us to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the different compounds must be refined in order to obtain an increase in the binding affinity of these ligands.

Three tetracyclic dibenzoazepine derivatives exhibiting different molecular conformations, different patterns of intermolecular hydrogen bonding and different modes of supramolecular aggregation.

The biological potential of compounds of the tricyclic dibenzo[b,e]azepine system has resulted in considerable synthetic efforts to develop efficient methods for the synthesis of new derivatives of this kind. (9RS,15RS)-9-Ethyl-11-methyl-9,13b-dihydrodibenzo[c,f]thiazolo[3,2-a]azepin-3(2H)-one, C19H19NOS, (I), crystallizes as a kryptoracemate with Z' = 2 in the space group P21, with one molecule each of the (9R,15R) and (9S,15S) configurations in the asymmetric unit, while (9RS,15RS)-9-ethyl-7,12-dimethyl-9,13b-dihydrodibenzo[c,f]thiazolo[3,2-a]azepin-3(2H)-one, C20H21NOS, (II), crystallizes with Z' = 1 in the space group C2/c. Ethyl (13RS)-2-chloro-13-ethyl-4-oxo-8,13-dihydro-4H-benzo[5,6]azepino[3,2,1-ij]quinoline-5-carboxylate, C22H20ClNO3, (III), exhibits enantiomeric disorder in the space group P-1 such that the reference site is occupied by the 13R and 13S enantiomers, with occupancies of 0.900 (6) and 0.100 (6). In each of the two independent molecules in (I), the five-membered ring adopts an envelope conformation, but the corresponding ring in (II) adopts a half-chair conformation, while the six-membered ring in the major form of (III) adopts a twist-boat conformation. The conformation of the seven-membered ring in each of (I), (II) and the major form of (III) approximates to the twist-boat form. The molecules of compound (I) are linked by two C-H...O hydrogen bonds to form two independent antiparallel C(5) chains, with each type containing only one enantiomer. These chains are linked into sheets by two C-H...π(arene) hydrogen bonds, in which the two donors are both provided by the (9R,15R) enantiomer and the two acceptor arene rings form part of a molecule of (9S,15S) configuration, precluding any additional crystallographic symmetry. The molecules of compound (II) are linked by inversion-related C-H...π(arene) hydrogen bonds to form isolated cyclic centrosymmetric dimers. The molecules of compound (III) are linked into cyclic centrosymmetric dimers by C-H...O hydrogen bonds and these dimers are linked into chains by a π-π stacking interaction. Comparisons are made with some related structures.

Unexpected ring-closure products derived from 3-(2-allylanilino)-3-phenylacrylate esters: crystal and molecular structures of 3-acetyl-8-allyl-6-methyl-2-phenylquinolin-4-yl acetate and (2RS)-2,8-dimethyl-4-phenyl-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinolin-6-one.

The reactions of two 3-(2-allylanilino)-3-phenylacrylate esters with acetic anhydride and with strong acids has revealed a richly diverse reactivity providing a number of unexpected products. Thus, acetylation of ethyl 3-(2-allylanilino)-3-phenylacrylate, (Ia), or ethyl 3-(2-allyl-4-methylanilino)-3-phenylacrylate, (Ib), with acetic anhydride yields not only the expected acetylated esters, (II), as the major products but also the unexpected polysubstituted quinolines 3-acetyl-8-allyl-2-phenylquinolin-4-yl acetate, (IIIa), and 3-acetyl-8-allyl-6-methyl-2-phenylquinolin-4-yl acetate, (IIIb), as minor products. Subsequent reaction of the major product ethyl 2-[(2-allyl-4-methylanilino)(phenyl)methylidene]-3-oxobutanoate, (IIb), with concentrated sulfuric acid did not provide the expected 3-acetylquinoline derivative, but instead two unexpected products, namely ethyl 4-ethyl-2-phenyl-1,4-dihydroquinoline-3-carboxylate, (IV), and ethyl 3-acetyl-4-ethyl-2-phenyl-3,4-dihydroquinoline-3-carboxylate, (V), in yields of 39 and 22%, respectively. The reaction of (Ib) with Eaton's reagent gave both the quinoline (Z)-6-methyl-2-phenyl-8-(prop-1-en-1-yl)quinolin-4(1H)-one, (VI), and the unexpected tricyclic product (2RS)-2,8-dimethyl-4-phenyl-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinolin-6-one, (VII), in yields of 71 and 12%, respectively. The products (II)-(VII) have all been fully characterized spectroscopically and the crystal structures of two of the unexpected products, i.e. (IIIb) (C23H21NO3) and (VII) (C19H17NO), are reported here. The formation of compounds (IV), (V) and (VII) all require an isomerization of the initial allyl substituent, with migration of the C=C double bond from the terminal site to the internal site. In (IIIb), the two acetyl substituents are oriented such that the intramolecular distance between the two carbonyl O atoms is only 3.243 (2) Å, and in (VII), the five-membered ring adopts a twisted half-chair conformation. The molecules of compound (IIIb) are linked by two independent hydrogen bonds to form sheets built from R4(3)(20) rings and the sheets are linked by a π-π stacking interaction to form a three-dimensional framework structure. The molecules of compound (VII) are linked by a single type of C-H...O hydrogen bond to form centrosymmetric R2(2)(14) dimers. The molecules of compound (V), which crystallizes with Z' = 2, are linked by two N-H...O and two C-H...O hydrogen bonds, forming a chain of rings.

Diastereoisomeric forms of 11-ethyl-6,11-dihydro-5H-dibenzo[b,e]azepine-6-carboxamide: syntheses and the molecular and supramolecular structure of the minor form (6RS,11RS)-11-ethyl-6,11-dihydro-5H-dibenzo[b,e]azepine-6-carboxamide.

Compounds containing the tricyclic dibenzo[b,e]azepine system have potential activity in the treatment of a number of diseases. Continuing with our studies on the synthesis of new small and potentially bioactive molecules, a synthetic route, involving acid-catalysed intramolecular Friedel-Crafts cyclization, to the readily separable diastereoisomers of 11-ethyl-6,11-dihydro-5H-dibenzo[b,e]azepine-6-carboxamide, a potentially useful precursor in the synthesis of analogues of some anti-allergenic, antidepressant and antihistaminic drugs currently in use, has been developed starting from 2-allylphenylamine and methyl 2-bromo-2-phenylacetate and proceeding via racemic methyl 2-[(2-allylphenyl)amino]-2-phenylacetate (A) and racemic 2-[(2-allylphenyl)amino]-2-phenylacetamide (B), to give the two diastereoisomers (I) and (II), C17H18N2O. Isomers (I) and (II), and their precursors (A) and (B), have all been fully characterized spectroscopically. Structure analysis of the minor isomer (I) shows that it has the (6RS,11RS) configuration, and that the azepine ring adopts a conformation intermediate between the boat and twist-boat forms, with the carboxamide and ethyl substituents both occupying quasi-equatorial sites. The molecules of (I) are linked by a combination of N-H...O, N-H...π(arene) and C-H...π(arene) hydrogen bonds to form complex sheets. Comparisons are made with the structures of some related compounds.

Crystal structures of five new substituted tetrahydro-1-benzazepines with potential antiparasitic activity.

Tetrahydro-1-benzazepines have been described as potential antiparasitic drugs for the treatment of chagas disease and leishmaniasis, two of the most important so-called `forgotten tropical diseases' affecting South and Central America, caused by Trypanosoma cruzi and Leishmania chagasi parasites, respectively. Continuing our extensive work describing the structural characteristics of some related compounds with interesting biological properties, the crystallographic features of three epoxy-1-benzazepines, namely (2SR,4RS)-6,8-dimethyl-2-(naphthalen-1-yl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, (1), (2SR,4RS)-6,9-dimethyl-2-(naphthalen-1-yl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, (2), and (2SR,4RS)-8,9-dimethyl-2-(naphthalen-1-yl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, (3), all C22H21NO, and two 1-benzazepin-4-ols, namely 7-fluoro-cis-2-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ol, C18H18FNO, (4), and 7-fluoro-cis-2-[(E)-pent-1-enyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ol, C15H20FNO, (5), are described. Some peculiarities in the crystallization behaviour were found, involving significant variations in the crystalline structures as a result of modest changes in the peripheral substituents in (1)-(3) and the occurrence of discrete disorder due to the molecular overlay of enantiomers with more than one conformation in (5). In particular, an interesting phase change on cooling was observed for compound (5), accompanied by an approximate fourfold increase of the unit-cell volume and a change of the Z' value from 1 to 4. This transition is a consequence of the partial ordering of the pentenyl chains in half of the molecules breaking half of the -3 symmetry axes observed in the room-temperature structure of (5). The structural assembly in all the title compounds is characterized by not only (N,O)-H...(O,N) hydrogen bonds, but also by unconventional C-H...O contacts, resulting in a wide diversity of packing.

Six polycyclic pyrimidoazepine derivatives: syntheses, molecular structures and supramolecular assembly.

A versatile synthetic method has been developed for the formation of variously substituted polycyclic pyrimidoazepine derivatives, formed by nucleophilic substitution reactions on the corresponding chloro-substituted compounds; the reactions can be promoted either by conventional heating in basic solutions or by microwave heating in solvent-free systems. Thus, (6RS)-6,11-dimethyl-3,5,6,11-tetrahydro-4H-benzo[b]pyrimido[5,4-f]azepin-4-one, C14H15N3O, (I), was isolated from a solution containing (6RS)-4-chloro-8-hydroxy-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine and benzene-1,2-diamine; (6RS)-4-butoxy-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepin-8-ol, C18H23N3O2, (II), was formed by reaction of the corresponding 6-chloro compound with butanol, and (RS)-4-dimethylamino-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepin-8-ol, C16H20N4O, (III), was formed by reaction of the chloro analogue with alkaline dimethylformamide. (6RS)-N-Benzyl-8-methoxy-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepin-4-amine, C22H24N4O, (IV), (6RS)-N-benzyl-6-methyl-1,2,6,7-tetrahydropyrimido[5',4':6,7]azepino[3,2,1-hi]indol-8-amine, C22H22N4, (V), and (7RS)-N-benzyl-7-methyl-2,3,7,8-tetrahydro-1H-pyrimido[5',4':6,7]azepino[3,2,1-ij]quinolin-9-amine, C23H24N4, (VI), were all formed by reaction of the corresponding chloro compounds with benzylamine under microwave irradiation. In each of compounds (I)-(IV) and (VI), the azepine ring adopts a conformation close to the boat form, with the C-methyl group in a quasi-equatorial site, whereas the corresponding ring in (V) adopts a conformation intermediate between the twist-boat and twist-chair forms, with the C-methyl group in a quasi-axial site. No two of the structures of (I)-(VI) exhibit the same range of intermolecular hydrogen bonds: different types of sheet are formed in each of (I), (II), (V) and (VI), and different types of chain in each of (III) and (IV).

Similar molecular constitutions but different conformations and different supramolecular assemblies in two related fused tetracyclic benzo[b]pyrimido[5,4-f]azepine derivatives.

A simple and effective two-step approach to tricyclic pyrimidine-fused benzazepines has been adapted to give the tetracyclic analogues. In (RS)-8-chloro-6-methyl-1,2,6,7-tetrahydropyrimido[5',4':6,7]azepino[3,2,1-hi]indole, C15H14ClN3, (I), the five-membered ring adopts an envelope conformation, as does the reduced pyridine ring in (RS)-9-chloro-7-methyl-2,3,7,8-tetrahydro-1H-pyrimido[5',4':6,7]azepino[3,2,1-ij]quinoline, C16H16ClN3, (II). However, the seven-membered rings in (I) and (II) adopt very different conformations, with the result that the methyl substituent occupies a quasi-axial site in (I) but a quasi-equatorial site in (II). The molecules of (I) are linked by C-H...N hydrogen bonds to form C(5) chains and inversion-related pairs of chains are linked by a π-π stacking interaction. A combination of a C-H...π hydrogen bond and two C-Cl...π interactions links the molecules of (II) into complex sheets. Comparisons are made with some similar fused heterocyclic compounds.

Five closely related 4-chloro-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepines: similar molecular structures but different supramolecular assemblies.

Dibenz[b,f]azepine (DBA) is a privileged 6-7-6 tricyclic ring system of importance in both organic and medicinal chemistry. Benzo[b]pyrimido[5,4-f]azepines (BPAs), which also contain a privileged 6-7-6 ring system, are less well investigated, probably because of a lack of straightforward and versatile methods for their synthesis. A simple and versatile synthetic approach to BPAs based on intramolecular Friedel-Crafts alkylation has been developed. A group of closely-related benzo[b]pyrimido[5,4-f]azepine derivatives, namely (6RS)-4-chloro-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, C14H14ClN3, (I), (6RS)-4-chloro-8-hydroxy-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, C14H14ClN3O, (II), (6RS)-4-chloro-8-methoxy-6,11-dimethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, C15H16ClN3O, (III), and (6RS)-4-chloro-8-methoxy-6,11-dimethyl-2-phenyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, C21H20ClN3O, (IV), has been prepared and their structures compared with the recently published structure [Acosta-Quintero et al. (2015). Eur. J. Org. Chem. pp. 5360-5369] of (6RS)-4-chloro-2,6,8,11-tetramethyl-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepine, (V). All five compounds crystallize as racemic mixtures and they have very similar molecular conformations, with the azepine ring adopting a boat-type conformation in each case, although the orientation of the methoxy substituent in each of (III) and (IV) is different. The supramolecular assemblies in (II) and (IV) depend upon hydrogen bonds of the O-H...N and C-H...π(arene) types, respectively, those in (I) and (V) depend upon π-π stacking interactions involving pairs of pyrimidine rings, and that in (III) depends upon a π-π stacking interaction involving pairs of phenyl rings. Short C-Cl...π(pyrimidine) contacts are present in (I), (II) and (IV) but not in (III) or (V).