Quantum Computational Investigation of (E)-1-(4-methoxyphenyl)-5-methyl-N'-(3-phenoxybenzylidene)-1H-1,2,3-triazole-4-carbohydrazide.

The title compound was synthesized and structurally characterized. Theoretical IR, NMR (with the GIAO technique), UV, and nonlinear optical properties (NLO) in four different solvents were calculated for the compound. The calculated HOMO-LUMO energies using time-dependent (TD) DFT revealed that charge transfer occurs within the molecule, and probable transitions in the four solvents were identified. The in silico absorption, distribution, metabolism, and excretion (ADME) analysis was performed in order to determine some physicochemical, lipophilicity, water solubility, pharmacokinetics, drug-likeness, and medicinal properties of the molecule. Finally, molecular docking calculation was performed, and the results were evaluated in detail.

Synthesis and Characterization of Novel 2-(1,2,3-Triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazoles and 2-(4,5-Dihydro-1H-pyrazol-1-yl)-4-(1H-1,2,3-triazol-4-yl)thiazoles.

Reactions of 1-(5-methyl)-1H-1,2,3-triazol-4-yl)ethan-1-ones and benzaldehydes in ethanol under basic conditions gave the corresponding chalcones. Reactions of the chalcones combined with thiosemicarbazide in dry ethanol containing sodium hydroxide afforded the corresponding pyrazolin-N-thioamides. Reactions of the synthesized pyrazolin-N-thioamides and several ketones (namely, ethyl 2-chloro-3-oxobutanoate, 2-bromoacetylbenzofuran, and hydrazonoyl chloride) gave the corresponding novel 2-(1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazoles in high yields (77-90%). Additionally, 2-(4,5-dihydro-1H-pyrazol-1-yl)-4-(1H-1,2,3-triazol-4-yl)thiazoles were obtained in high yields (84-87%) from reactions with N-pyrazoline-thioamides and 4-bromoacetyl-1,2,3-triazoles under basic conditions. The structures of six of the newly synthesized heterocycles were confirmed by X-ray crystallography.

Synthesis of sulfur-containing heterocycles via ring enlargement.

The current review deals with the use of ring expansion reactions for the synthesis of sulfur-containing heterocycles. Ring enlargement offers by far a convenient method for the synthesis of 'medium-sized ring systems', which are usually difficult to obtain or even produced in low yields. These reactions are often catalytically processed starting from a single cyclic precursor and, therefore, are superior to alternative classical iterative synthetic approaches in terms of atomic and conversion efficiency. The current review aims to shed light on the synthetic approaches that exist to afford medium-sized sulfur heterocycles from preexisting smaller rings (e.g., three-, four-, five-, six- and seven-membered rings).

Groebke-Blackburn-Bienaymé multicomponent reaction: emerging chemistry for drug discovery.

The Groebke-Blackburn-Bienaymé reaction (GBBR) is used for the one-pot synthesis of therapeutically relevant fused imidazoles bridgehead nitrogen heterocyclic compounds from readily available aldehyde, isocyanide and amidine building blocks. The reaction is driven by a wide range of catalysts and can be performed either under solvent or solvent-free conditions, or under microwave irradiation as heat source. The GBBR products can be used for the synthesis of a variety of more complex scaffolds via postmodification reactions. These include cyclization and nucleophilic substitution as well as further MCRs. The GBBR reaction has seen diverse applications in combinatorial and medicinal chemistry and its products are of great use in drug discovery. In this review, we summarize the efforts of the chemistry community in the progress and applications of GBBR since 1998. This review also includes some biological profiles and synthetic scopes of GBBR products. The component variations, postmodifications and secondary transformations will also be discussed throughout this review.

2-[3-(4-Chloro-phen-yl)-5-(4-fluoro-phenyl)-4,5-dihydro-1H-pyrazol-1-yl]-4-phenyl-1,3-thia-zole.

In the title compound, C24H17ClFN3S, the pyrazole ring is almost planar (r.m.s. deviation = 0.030 Å). With the exception of the methine-bound benzene ring, which forms a dihedral angle of 85.77 (13)° with the pyrazole ring, the remaining non-C atoms lie in an approximate plane (r.m.s. deviation = 0.084 Å) so that overall the mol-ecule has a T-shape. In the crystal, centrosymmetrically related mol-ecules are connected via π-π inter-actions between pyrazole rings [centroid-centroid distance = 3.5370 (15) Å] and these stack along the a axis with no specific inter-actions between them.

4-[5-(4-Fluoro-phen-yl)-1-(4-phenyl-1,3-thia-zol-2-yl)-4,5-dihydro-1H-pyrazol-3-yl]-5-methyl-1-(4-methyl-phenyl)-1H-1,2,3-triazole.

In the title compound, C28H23FN6S, the pyrazole ring adopts an envelope conformation, with the methine C atom being the flap atom. With respect to this ring, the 2-thienyl, triazole and fluoro-benzene rings are approximately coplanar, coplanar and perpendicular, respectively [dihedral angles = 8.56 (17), 6.03 (19) and 73.1 (2)°, respectively] so that to a first approximation the mol-ecule has a T-shape. In the crystal, mol-ecules are consolidated into a three-dimensional architecture by C-H⋯F (involving a bifurcated F atom), C-H⋯S and C-H⋯π inter-actions.

5-(4-Fluoro-phen-yl)-3-[5-methyl-1-(4-methyl-phen-yl)-1H-1,2,3-triazol-4-yl]-N-phenyl-4,5-dihydro-1H-pyrazole-1-carbothio-amide.

In the title compound, C26H23FN6S, the pyrazole ring has an envelope conformation, with the methine C atom being the flap atom. The thio-urea group is close to being coplanar with the pyrazole N atoms [N-N-C-S torsion angle = 176.78 (15)°], which allows for an intra-molecular N-H⋯N hydrogen bond; the connected triazole ring is nearly coplanar with this ring [N-C-C-N = -172.65 (19)°]. There is a significant twist between the pyrazole ring and attached fluoro-benzene ring [N-C-C-C = -18.8 (3)°] and a greater twist between triazole and attached tolyl ring [dihedral angle = 58.25 (14)°]. In the crystal, supra-molecular chains aligned along [40,10] are consolidated by π-π inter-actions between the triazole and phenyl rings [centroid-centroid distance = 3.7053 (13) Å].

2-(2,4-Dichloro-phen-oxy-meth-yl)-5-(4-methyl-phen-yl)imidazo[2,1-b][1,3,4]thia-diazole.

In the title compound, C18H13Cl2N3OS, the eight atoms comprising the central imidazo/thia-diazo-lethia-diazole residue are coplanar (r.m.s. deviation = 0.009 Å). The dihedral angle of 8.72 (13)° between the dichloro-benzene and tolyl rings reflects a twist about the O-C(benzene) bond; the Cm-O-Cb-Cb torsion angle = -168.5 (2)° (m = methyl-ene C and b is benzene C). Supra-molecular tapes along the b axis are found in the crystal structure which are mediated by π-π inter-actions occurring between centrosymmetrically related thia-diazole rings [inter-ring centroid distance = 3.6907 (16) Å] and between the benzene and tolyl rings [inter-ring centroid distance = 3.7597 (16) Å].

2-[5-(4-Fluoro-phen-yl)-3-(4-methyl-phen-yl)-4,5-dihydro-1H-pyrazol-1-yl]-4-phenyl-1,3-thia-zole.

In the title compound, C25H20FN3S, two independent mol-ecules comprise the asymmetric unit, which differ in the relative orientation of the fluoro-benzene ring with respect to the pyrazole ring to which it is attached [dihedral angles = 89.39 (17) and 75.23 (16)° in the two mol-ecules]. Each pyrazole ring adopts an envelope conformation with the methine C atom being the flap atom. There are additional twists in the mol-ecules, e.g. between the five-membered rings [dihedral angles = 18.23 (16) and 17.84 (16)°] and between the thia-zole and attached phenyl ring [10.26 (16) and 20.87 (15)°]. Overall, each mol-ecule has a T-shape. In the crystal, mol-ecules are connected into a three-dimensional architecture by weak C-H⋯π inter-actions.

3-(4-Chloro-phen-yl)-5-(4-fluoro-phen-yl)-4,5-dihydro-1H-pyrazole-1-carbothio-amide.

In the title compound, C16H13ClFN3S, the pyrazole ring adopts an envelope conformation with the methine C atom being the flap atom. The chloro- and fluoro-benzene rings are twisted out of the plane of the pyrazole ring [dihedral angles = 15.12 (11) and 80.55 (10)°, respectively]. The amine group is orientated towards a ring N atom, forming an intra-molecular N-H⋯N hydrogen bond. This H atom also forms a hydrogen bond to the F atom, which along with N-H⋯S hydrogen bonding leads to a supra-molecular chain along the c axis. Connections between chains of the type Cl⋯π lead to a layer in the bc plane.

5-Methyl-N'-[(3Z)-2-oxo-2,3-dihydro-1H-indol-3-yl-idene]-1-phenyl-1H-1,2,3-triazole-4-carbohydrazide.

In the title compound, C18H14N6O2, the benzene ring is slightly twisted out of the plane of the 1,2,3-triazole ring (r.m.s. deviation = 0.010 Å), forming a dihedral angle of 6.20 (13)°. The nine non-H ring atoms of the fused five- and six-membered ring system are almost coplanar (r.m.s. deviation = 0.032 Å). The near coplanarity in the central residue is consolidated by an intra-molecular bifurcated N-H⋯(O,N) hydrogen bond. The conformation about the N=C bond is Z. In the crystal, supra-molecular chains along [101] are sustained by N-H⋯O hydrogen bonds and C-H⋯O inter-actions. These are consolidated into a three-dimensional architecture by C-H⋯π and π-π inter-actions; the latter occur between centrosymmetrically related 1,2,3-triazole rings [centroid-centroid distance = 3.6056 (14) Å].

(2E)-3-(4-Fluoro-phen-yl)-1-[5-methyl-1-(4-methyl-phen-yl)-1H-1,2,3-triazol-4-yl]prop-2-en-1-one.

With respect to the triazole ring in the title compound, C19H16FN3O, the p-tolyl ring is inclined [dihedral angle = 51.79 (11)°], whereas the chalcone residue is almost coplanar [O-C-C-N and C-C-C-C torsion angles = -178.71 (19) and 178.42 (18)°, respectively]. The conformation about the C=C bond [1.328 (3) Å] is E, and the triazole methyl group and the carbonyl O atom are syn. In the crystal, centrosymmetrically related mol-ecules are connected by π-π inter-actions between the triazole and p-tolyl rings [centroid-centroid distance = 3.6599 (12) Å] and these are linked into a three-dimensional architecture by C-H⋯N and C-H⋯π inter-actions.

(2E)-1-[5-Methyl-1-(4-methyl-phen-yl)-1H-1,2,3-triazol-4-yl]-3-[4-(piperidin-1-yl)phen-yl]prop-2-en-1-one.

Two independent mol-ecules comprise the asymmetric unit of the title compound, C24H26N4O. The major difference between them is found in the relative orientation of the triazole-bound p-tolyl group which have the opposite sense of twist [N-N-C-C torsion angles = 55.8 (3) and -49.8 (3)°]. The chalcone residue is almost coplanar with the triazole ring [N-C-C-O and C-C-C-C torsion angles = -178.9 (2) and -178.5 (2)°, respectively; cf. 177.9 (3) and 168.5 (3)°, respectively, in the second mol-ecule]. The conformation about each C=C double bond is E and in each case the triazole methyl group is syn to the carbonyl O atom. In the crystal, mol-ecules aggregate into layers parallel to (-113). The first independent mol-ecule self-associates into a layer via C-H⋯O and C-H⋯π inter-actions. By contrast, layers comprising the second independent mol-ecule do not feature specific inter-actions between mol-ecules. The global crystal packing comprises alternating layers.

2-[3-(4-Bromo-phenyl)-5-(4-fluoro-phenyl)-4,5-di-hydro-1H-pyrazol-1-yl]-4-phenyl-1,3-thia-zole.

In the title compound, C24H17BrFN3S, the pyrazole ring is almost planar (r.m.s. deviation = 0.043 Å), with all but the perpendicular fluoro-benzene ring substituents [dihedral angle = 77.9 (3)°] being very approximately coplanar [dihedral angle with the 2-thienyl ring = 19.4 (3)° and with the bromo-benzene ring = 20.3 (3)°; dihedral angle between the 2-thienyl and attached phenyl ring = 11.0 (4)°], so that the mol-ecule has a T-shape. In the crystal, supra-molecular chains along the b-axis direction are sustained by C-H⋯S and C-Br⋯π inter-actions.

5-(4-Fluoro-phen-yl)-3-(4-methyl-phen-yl)-4,5-dihydro-1H-pyrazole-1-carbothio-amide.

The central pyrazole ring in the title compound, C17H16FN3S, adopts an envelope conformation with the methine C atom bearing the 4-fluoro-phenyl substituent as the flap atom. Whereas the tolyl ring is slightly twisted out of the least-squares plane through the pyrazole ring [dihedral angle = 13.51 (11)°], the fluoro-benzene ring is almost perpendicular [dihedral angle = 80.21 (11)°]. The thio-amide group is almost coplanar with the N-N bond of the ring [N-N-C-N torsion angle = 1.2 (3)°] and the amine group forms an intra-molecular hydrogen bond with a ring N atom. In the crystal, supra-molecular double layers in the bc plane are formed via N-H⋯S, N-H⋯F and C-H⋯F inter-actions.

4-Dimethyl-amino-1-(4-meth-oxy-phen-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrole-3-carbonitrile.

In the title compound, C14H13N3O3, a twist occurs, as seen in the dihedral angle of 53.60 (12)° between the pyrrole and benzene rings. A three-dimensional architecture is formed in the crystal whereby layers of mol-ecules in the ac plane are connected by C-H⋯O and C-H⋯π inter-actions.

(E)-5-(4-Meth-oxy-phen-yl)-N'-(2-oxoindolin-3-yl-idene)-1-phenyl-1H-pyrazole-3-carbohydrazide.

The asymmetric unit of the title compound, C25H19N5O3, is composed of two independent mol-ecules with slightly different conformations. The extended structure features N-H⋯O hydrogen bonds as well as π-π inter-actions.

3-[5-Methyl-1-(4-methyl-phen-yl)-1H-1,2,3-triazol-4-yl]-N-phenyl-5-[4-(piperidin-1-yl)phen-yl]-4,5-dihydro-1H-pyrazole-1-carbothio-amide dimethyl-formamide hemisolvate.

The essentially planar pyrazole ring (r.m.s. deviation = 0.013 Å) in the title hemisolvate, C(31)H(33)N(7)S·0.5C(3)H(7)NO, is almost coplanar with the pendant thio-urea residue [N-N-C-S torsion angle = -173.2 (4)°] and slightly twisted with respect to the triazole ring [dihedral angle = 7.7 (3)°]. An intra-molecular thio-urea-pyrazole N-H⋯N hydrogen bond, via an S(5) loop, is formed. Supra-molecular chains along the c axis are formed in the crystal via piperidine-triazole C-H⋯N inter-actions. These are bridged into loosely associated double chains via C-H⋯O inter-actions involving the disordered (over two positions) dimethyl-formamide solvent mol-ecules. The thio-urea-bound phenyl ring is also disordered over two positions of equal occupancy.

5-(4-Fluoro-phen-yl)-3-[5-methyl-1-(4-methyl-phen-yl)-1H-1,2,3-triazol-4-yl]-4,5-dihydro-1H-pyrazole-1-carbothio-amide.

In the title compound, C(20)H(19)FN(6)S, the pyrazole ring has an envelope conformation, with the methine C atom being the flap atom. The dihedral angle between the least-squares plane through the pyrazole and triazole rings is 7.59 (9)°, and the triazole and attached benzene ring form a dihedral angle of 74.79 (9)°. The thio-urea group is coplanar with the pyrazole ring [N-N-C-S torsion angle = -179.93 (11)°], which enables the formation of an intra-molecular N-H⋯N hydrogen bond. In the crystal, inversion-related mol-ecules associate via N-H⋯S hydrogen bonds and eight-membered {⋯HNCS}(2) synthons feature in the crystal packing. These synthons are connected into supra-molecular chains along the a axis via N-H⋯F hydrogen bonds, and the chains are consolidated into layers in the ab plane via C-H⋯S and C-H⋯F contacts.

4-{1-[4-(4-Bromo-phen-yl)-1,3-thia-zol-2-yl]-5-(4-fluoro-phen-yl)-4,5-dihydro-1H-pyrazol-3-yl}-5-methyl-1-(4-methyl-phen-yl)-1H-1,2,3-triazole.

In the title compound, C(28)H(22)BrFN(6)S, the central pyrazole ring has an envelope conformation, with the methine C atom being the flap atom. The dihedral angles between the least-squares plane through this ring and the adjacent thia-zole [18.81 (15)°] and triazole [1.83 (16)°] rings indicate a twist in the mol-ecule. A further twist is evident by the dihedral angle of 64.48 (16)° between the triazole ring and the attached benzene ring. In the crystal, C-H⋯N, C-H⋯F, C-H⋯π and π-π inter-actions [occurring between the thia-zole and triazole rings, centroid-centroid distance = 3.571 (2) Å] link mol-ecules into a three-dimensional architecture. The sample studied was a non-merohedral twin; the minor twin component refined to 47.16 (7)%.