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.

Alternative and efficient one-pot three-component synthesis of substituted 2-aryl-4-styrylquinazolines/4-styrylquinazolines from synthetically available 1-(2-aminophenyl)-3-arylprop-2-en-1-ones: characterization and evaluation of their antiproliferative activities.

In this study, an alternative and efficient one-pot three-component synthesis approach to develop a new series of (E)-2-aryl-4-styrylquinazolines and (E)-4-styrylquinazolines is described. According to this approach, the target compounds were synthesized straightforward in high yields and in short reaction times from substituted 1-(2-aminophenyl)-3-arylprop-2-en-1-ones via its well-Cu(OAc)2-mediated cyclocondensation reactions with aromatic aldehydes or its well-catalyst-free cyclocondensation reactions with trimethoxy methane (trimethyl orthoformate), and ammonium acetate under aerobic conditions. This is an operationally simple, valuable, and direct method to synthesize 2-aryl- and non-C2-substituted quinazolines containing a styryl framework at C4 position from cheap and synthetically available starting materials. All the synthesized compounds were submitted to the US National Cancer Institute for in vitro screening. The bromo- and chloro-substituted quinazolines 5c and 5d displayed a potent antitumor activity against all the tested subpanel tumor cell lines with IC50 (MG-MID) values of 5.25 and 5.50 µM, and a low cytotoxic effect with LC50 (MG-MID) values of 91.20 and 84.67 µM, respectively, indicating a low toxicity of these compounds to normal human cell lines, as required for potential antitumor agents.

A hydrogen-bonded tetramer in (2RS,4SR)-7-bromo-2-(2-methylphenyl)-2,3,4,5-tetrahydro-1H-naphtho[1,2-b]azepin-4-ol and a three-dimensional hydrogen-bonded framework in (2RS,4SR)-2-(3-methylthiophen-2-yl)-2,3,4,5-tetrahydro-1H-naphtho[1,2-b]azepin-4-ol.

(2RS,4SR)-7-Bromo-2-(2-methylphenyl)-2,3,4,5-tetrahydro-1H-naphtho[1,2-b]azepin-4-ol, C21H20BrNO, (I), and (2RS,4SR)-2-(3-methylthiophen-2-yl)-2,3,4,5-tetrahydro-1H-naphtho[1,2-b]azepin-4-ol, C19H19NOS, (II), both crystallize with Z' = 2 in the space groups P2(1)/c and Cc, respectively; compound (II) crystallizes as a nonmerohedral twin, with twin fractions 0.183 (2) and 0.817 (2). The molecules of (I) are linked by O-H···O and O-H···N hydrogen bonds to form a cyclic centrosymmetric R4(4)(16) tetramer. The molecules of (II) are linked by O-H···O hydrogen bonds to form a C2(2)(4) chain and these chains are weakly linked by a single C-H···π(thienyl) interaction to form a three-dimensional array. Comparisons are made with some related compounds.

Three closely related thienyl-substituted 1,4-epoxynaphtho[1,2-b]azepines: hydrogen-bonded assembly in one, two and three dimensions.

(2R,4S)-2-(3-Methylthiophen-2-yl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine, C19H17NOS, (I), crystallizes with a single enantiomer in each crystal, whereas its geometrical isomer (2RS,4SR)-2-(5-methylthiophen-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-naphtho[1,2-b]azepine, (II), and (2RS,4SR)-2-(5-bromothiophen-2-yl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine, C18H14BrNOS, (III), both crystallize as racemic mixtures. A combination of one C-H...O hydrogen bond and two C-H...π(arene) hydrogen bonds links the molecules of (I) into a three-dimensional framework; the molecules of (II) are linked into a C(4)C(4)[R2(2)(7)] chain of rings by a combination of C-H...N and C-H...O hydrogen bonds; and in (III), where Z' = 2, a combination of four C-H...π(arene) hydrogen bonds and two C-H...π(thienyl) hydrogen bonds links the molecules into complex sheets. Comparisons are made with the assembly patterns in some aryl-substituted 1,4-epoxynaphtho[1,2-b]azepines.

Six closely related 4,6-disubstituted 2-amino-5-formylpyrimidines: different ring conformations, polarized electronic structures, and hydrogen-bonded assembly in zero, one, two and three dimensions.

In each of ethyl N-{2-amino-5-formyl-6-[methyl(phenyl)amino]pyrimidin-4-yl}glycinate, C(16)H(19)N(5)O(3), (I), N-{2-amino-5-formyl-6-[methyl(phenyl)amino]pyrimidin-4-yl}glycinamide, C(14)H(16)N(6)O(2), (II), and ethyl 3-amino-N-{2-amino-5-formyl-6-[methyl(phenyl)amino]pyrimidin-4-yl}propionate, C(17)H(21)N(5)O(3), (III), the pyrimidine ring is effectively planar, but in each of methyl N-{2-amino-6-[benzyl(methyl)amino]-5-formylpyrimidin-4-yl}glycinate, C(16)H(19)N(5)O(3), (IV), ethyl 3-amino-N-{2-amino-6-[benzyl(methyl)amino]-5-formylpyrimidin-4-yl}propionate, C(18)H(23)N(5)O(3), (V), and ethyl 3-amino-N-[2-amino-5-formyl-6-(piperidin-4-yl)pyrimidin-4-yl]propionate, C(15)H(23)N(5)O(3), (VI), the pyrimidine ring is folded into a boat conformation. The bond lengths in each of (I)-(VI) provide evidence for significant polarization of the electronic structure. The molecules of (I) are linked by paired N-H···N hydrogen bonds to form isolated dimeric aggregates, and those of (III) are linked by a combination of N-H···N and N-H···O hydrogen bonds into a chain of edge-fused rings. In the structure of (IV), molecules are linked into sheets by means of two hydrogen bonds, both of N-H···O type, in the structure of (V) by three hydrogen bonds, two of N-H···N type and one of C-H···O type, and in the structure of (VI) by four hydrogen bonds, all of N-H···O type. Molecules of (II) are linked into a three-dimensional framework structure by a combination of three N-H···O hydrogen bonds and one C-H···O hydrogen bond.

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.

(2RS,4SR)-7-bromo-2-exo-(2-chlorophenyl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine: sheets built by the π-stacking of hydrogen-bonded chains.

The molecules of the title compound, C(20)H(15)BrClNO, are linked into chains by a C-H...π(arene) hydrogen bond, in which the acceptor is the brominated ring of the naphthalene unit, and these chains are linked by an aromatic π-π stacking interaction, again involving the naphthalene unit, into a sheet structure.

Chain formation by disordered, but correlated, hydrogen bonds in cis-(2RS,4SR)-2-(thiophen-2-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ol and cis-(2RS,4SR)-2-(5-methylthiophen-2-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ol.

The closely related compounds cis-(2RS,4SR)-2-(thiophen-2-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ol, C(14)H(15)NOS, (I), and cis-(2RS,4SR)-2-(5-methylthiophen-2-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ol, C(15)H(17)NOS, (II), both crystallize with Z' = 2 in the space group P-1. In (I), the thienyl substituent in one of the two independent molecules is disordered over two sets of atomic sites having occupancies of 0.856 (2) and 0.144 (2). In both compounds, the two independent hydroxy O atoms are both within 2.8 Å of the hydroxy O atoms of two neighbouring molecules, and all of the hydroxy H atoms are disordered, each over two sites. The resulting O-H...O hydrogen bonds generate two similar but distinct C(4)(4)(8) chains, depending upon which hydroxy H-atom sites are occupied or vacant, with full correlation of the hydroxy H-atom occupancies within each chain. Comparisons are made with the supramolecular assembly in some related compounds.

Nine closely related tetrahydro-1,4-epoxy-1-benzazepines carrying pendant heterocyclic substituents: hydrogen-bonded supramolecular assembly in zero, one and two dimensions.

The structures are reported of nine closely related tetrahydro-1,4-epoxy-1-benzazepines carrying pendant heterocyclic substituents, namely: 2-exo-(5-nitrofuran-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-1H-1-benzazepine, C(14)H(12)N(2)O(4), (I), 7-fluoro-2-exo-(1-methyl-1H-pyrrol-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-1H-1-benzazepine, C(15)H(15)FN(2)O, (II), 7-fluoro-2-exo-(5-methylfuran-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-1H-1-benzazepine, C(15)H(14)FNO(2), (III), 7-fluoro-2-exo-(3-methylthiophen-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-1H-1-benzazepine, C(15)H(14)FNOS, (IV), 7-fluoro-2-exo-(5-methylthiophen-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-1H-1-benzazepine, C(15)H(14)FNOS, (V), 7-chloro-2-exo-(5-methylfuran-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-1H-1-benzazepine, C(15)H(14)ClNO(2), (VI), 2-exo-(5-methylfuran-2-yl)-7-trifluoromethoxy-2,3,4,5-tetrahydro-1,4-epoxy-1H-1-benzazepine, C(16)H(14)F(3)NO(3), (VII), 2-exo-(3-methylthiophen-2-yl)-7-trifluoromethoxy-2,3,4,5-tetrahydro-1,4-epoxy-1H-1-benzazepine, C(16)H(14)F(3)NO(2)S, (VIII), and 2-exo-(5-nitrofuran-2-yl)-7-trifluoromethoxy-2,3,4,5-tetrahydro-1,4-epoxy-1H-1-benzazepine, C(15)H(11)F(3)N(2)O(5), (IX). All nine compounds crystallize in centrosymmetric space groups as racemic mixtures with configuration (2RS,4SR). There are no direction-specific interactions between the molecules in (V). The molecules in (III), (IV), (VI) and (VII) are linked into simple chains, by means of a single C-H...O hydrogen bond in each of (III), (VI) and (VII), and by means of a single C-H...π(arene) hydrogen bond in (IV), while the molecules in (VIII) are linked into a chain of rings. In each of (I) and (II), a combination of one C-H...O hydrogen bond and one C-H...π(arene) hydrogen bond links the molecules into sheets, albeit of completely different construction in the two compounds. In (IX), the sheet structure is built from a combination of four independent C-H...O hydrogen bonds and one C-H...π(arene) hydrogen bond. Comparisons are made with some related compounds.

(2RS,4RS)-7-Fluoro-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine and (2RS,4RS)-7-chloro-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine are isomorphous but not strictly isostructural.

(2RS,4RS)-7-Fluoro-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(18)H(18)FNO, (I), and (2RS,4RS)-7-chloro-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(18)H(18)ClNO, (II), are isomorphous but not strictly isostructural, as the slight differences in the unit-cell dimensions and molecular conformations are sufficient to preclude, in the structure of (I), the direction-specific intermolecular interactions present in the structure of (II), where the molecules are linked into sheets by a combination of C-H···N and C-H···π(arene) hydrogen bonds.

2-Amino-6-methoxy-4-(4-methylanilino)-5-nitrosopyrimidine and ethyl N-[4-(adamantan-1-ylamino)-2-amino-5-nitrosopyrimidin-6-yl]-3-aminopropionate: polarized electronic structures and hydrogen-bonded supramolecular assembly in one and two dimensions.

In both 2-amino-6-methoxy-4-(4-methylanilino)-5-nitrosopyrimidine, C(12)H(13)N(5)O(2), (I), and ethyl N-[4-(1-adamantylamino)-2-amino-5-nitrosopyrimidin-6-yl]-3-aminopropionate, C(19)H(28)N(6)O(3), (II), the nitrosopyrimidine unit is planar and the bond distances provide evidence for significant polarization of the electronic structures. In (II), the ethoxycarbonyl fragment of the molecule is disordered over two sets of sites with occupancies of 0.910 (4) and 0.090 (4). In the molecules of both compounds, there is an intramolecular N-H···O hydrogen bond. The molecules of (I) are linked into a chain of rings by a combination of N-H···O and C-H···O hydrogen bonds, while the molecules of (II) are linked by a two-centre N-H···N hydrogen bond and a three-centre N-H···(N,O) hydrogen bond to form sheets containing four distinct types of ring.

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.

(2R*,4S*)-2-(pyridin-3-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ol: a three-dimensional framework built from O-H···N, C-H···O and C-H···π(arene) hydrogen bonds.

The title compound, C(15)H(16)N(2)O, crystallizes in the space group P2(1)2(1)2(1) with Z' = 1. The seven-membered ring adopts a chair-type conformation with the hydroxy and pyridyl substituents in equatorial sites. Molecules are linked into a three-dimensional framework structure by a combination of O-H···N, C-H···O and C-H···π(arene) hydrogen bonds, but N-H···O and N-H···π(arene) interactions are absent from the structure. Comparisons are made with some related compounds.

Synthesis, structural elucidation and in vitro antiparasitic activity against Trypanosoma cruzi and Leishmania chagasi parasites of novel tetrahydro-1-benzazepine derivatives.

Forty six new 1,4-epoxy-2-exo-aryl- and cis-2-aryl-4-hydroxytetrahydro-1-benzazepine derivatives were synthesized and fully characterized. All compounds were tested in vitro against both Trypanosoma cruzi and Leishmania chagasi parasites and also for cytotoxicity using Vero and THP-1 mammalian cell lines. Many of the evaluated compounds showed remarkable activity against the epimastigote and intracellular amastigote forms of T. cruzi, with IC50 values comparable with that of control drug nifurtimox, a nitrofuran derivative currently used in the treatment of Chagas' disease. Other derivatives were found to have good activity against L. chagasi promastigotes, with low toxicity against the mammalian cells, but neither of them was active on intracellular amastigotes of L. chagasi infecting THP-1 macrophages.

Five 2-aryl-substituted tetrahydro-1,4-epoxy-1-benzazepines: isolated molecules and hydrogen-bonded chains and sheets.

(2SR,4RS)-2-exo-Phenyl-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(16)H(15)NO, (I), (2SR,4RS)-2-exo-(4-chlorophenyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(16)H(14)ClNO, (II), and (2SR,4RS)-2-exo-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(17)H(17)NO, (III), all crystallize with Z' = 2, in the space groups Cc, P2(1)/n and P2(1)/c, respectively. In each of (II) and (III), the conformations of the two independent molecules are significantly different. The molecules in (I) are linked by C-H...pi(arene) hydrogen bonds to form two independent chains, each containing only one type of molecule. The molecules in (II) are linked into sheets by a combination of C-H...O, C-H...(N,O) and C-H...pi(arene) hydrogen bonds, all of which link pairs of molecules related by inversion, while in (III), the molecules are linked into sheets by a combination of C-H...N, C-H...O and C-H...pi(arene) hydrogen bonds. There are no direction-specific intermolecular interactions of any kind in the structure of (2SR,4RS)-7-bromo-2-exo-phenyl-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(16)H(14)BrNO, (IV), but in the structure of (2SR,4RS)-2-exo-(4-bromophenyl)-7-chloro-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(16)H(13)BrClNO, (V), a combination of one C-H...N hydrogen bond and one C-H...O hydrogen bond links the molecules into sheets of alternating centrosymmetric R(2)(2)(14) and R(6)(6)(22) rings. Comparisons are made with the structures of a number of related compounds.

A three-dimensional hydrogen-bonded framework in (2S*,4R*)-7-fluoro-2-exo-[(E)-styryl]-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine.

Molecules of the title compound, C(18)H(16)FNO, are linked into a three-dimensional framework structure by a combination of two C-H...O hydrogen bonds and three C-H...pi(arene) hydrogen bonds. Comparisons are made with the (2R,4R) diastereoisomer and with the corresponding pair of diastereoisomeric 7-chloro analogues.

Hydrogen-bonded dimers, chains and rings in six differently substituted 2-vinyltetrahydro-1,4-epoxy-1-benzazepines.

In (2SR,4RS)-2-exo-vinyl-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(12)H(13)NO, (I), the molecules are linked by two independent C-H...pi(arene) hydrogen bonds to form sheets, such that all of the molecules in a given sheet are of the same configuration. The molecules of (2SR,4RS)-7-chloro-2-exo-(2-methylprop-1-enyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(14)H(16)ClNO, (II), are linked by a C-H...O hydrogen bond into C(4) chains, where all the molecules in a given chain are of the same configuration, whereas the molecules of (2SR,4RS)-8-chloro-9-methyl-2-exo-(2-methylprop-1-enyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(15)H(18)ClNO, (III), are linked into centrosymmetric dimers by pairs of symmetry-related C-H...pi(arene) hydrogen bonds. (2RS,4RS)-8-Chloro-9-methyl-2-endo-(2-methylprop-1-enyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(15)H(18)ClNO, (IV), is a diastereoisomer of (III) and, as for (II), a single C-H...O hydrogen bond links the molecules into C(4) chains, each containing molecules of a single configuration. The structure of (2SR,4RS)-8-chloro-9-methyl-2-exo-(prop-1-en-2-yl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(14)H(16)ClNO, (V), contains a C-H...O hydrogen bond which links pairs of molecules into centrosymmetric R(2)(2)(6) dimers. (2SR,4RS)-7,9-Dichloro-2-exo-(prop-1-en-2-yl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(13)H(13)Cl(2)NO, (VI), is an inversion twin containing both the (2S,4R) and (2R,4S) enantiomers in the space group P2(1), and a C-H...O hydrogen bond links molecules of a given configuration into simple C(3) chains.

Four 1-naphthyl-substituted tetrahydro-1,4-epoxy-1-benzazepines: hydrogen-bonded structures in one, two and three dimensions.

(2S*,4R*)-2-exo-(1-Naphthyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(20)H(17)NO, (I), crystallizes with Z' = 2 in the space group P2(1); the two independent molecules have the same absolute configuration, although this configuration is indeterminate. The molecules of each type are linked by a combination of C-H...O and C-H...π(arene) hydrogen bonds to form two independent sheets, each containing only one type of molecule. (2SR,4RS)-7-Methyl-2-exo-(1-naphthyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(21)H(19)NO, (II), crystallizes as a true racemate in the space group P2(1)/c, and a combination of C-H...N, C-H...O and C-H...π(arene) hydrogen bonds links the molecules into sheets, each containing equal numbers of the two enantiomorphs. (2S*,4R*)-2-exo-(1-Naphthyl)-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(21)H(16)F(3)NO(2), (III), crystallizes as a single enantiomorph, as for (I), but now with Z' = 1 in the space group P2(1)2(1)2(1); again, the absolute configuration is indeterminate. A single C-H...π(arene) hydrogen bond links the molecules of (III) into simple chains. (2S,4R)-8-Chloro-9-methyl-2-exo-(1-naphthyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(21)H(18)ClNO, (IV), crystallizes as a single enantiomorph of well defined configuration, in the space group P2(1)2(1)2(1), where two independent C-H...π(arene) hydrogen bonds link the molecules into a single three-dimensional framework structure.