Fluoro-phenyl Ring Research Articles

6-Chloro-3-[5-(4-fluorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl]-2-methyl-4-phenylquinoline

In the title compound, C31H23ClFN3, the pyrazole ring forms dihedral angles of 72.75 (7), 18.08 (9) and 86.26 (9)° with the quinoline ring system, the phenyl ring and the fluoro­phenyl ring, respectively. In the crystal, inter­molecular C—H⋯N hydrogen bonds link the mol­ecules into chains propagating along the c axis. The crystal structure is further stabilized by C—H⋯π inter­actions.

4-(4-Fluorophenyl)-2-oxo-1,2,5,6-tetrahydrobenzo[h]quinoline-3-carbonitrile

In the mol­ecule of the title compound, C20H13FN2O, the fluoro­phenyl ring is oriented at a dihedral angle of 72.76 (3)° with respect to the fused benzene ring. In the crystal structure, inter­molecular N—H⋯O, C—H⋯O and C—H⋯F inter­actions link the mol­ecules into chains. π–π contacts between the quinoline and benzene rings [centroid–centroid distance = 3.918 (3) Å] may further stabilize the structure. A weak C—H⋯π inter­action is also present. The O atom and two of the CH2 groups of the quinoline ring system are disordered over two positions. The O atom was refined with occupancies of 0.489 (17) and 0.511 (17), while C and H atoms were refined with occupancies of 0.435 (13) and 0.565 (13).

Regioselective lithiations of 2-(3,5-dichlorophenyl)-2-(4-fluorophenyl)-1,3-dioxolane

Dichlorophenyl)-2-(4-fluorophenyl)-1,3-dioxolane on treatment with butyllithium undergoes deprotonation at the 4-position flanked by the two chloro substituents. The corresponding 4-trimethylsilyl derivative was regioselectively lithiated with butyllithium at the 2-position of the dichlorophenyl ring. Deprotonation with butyllithium complexed with N,N,N',N,N-pentamethyldiethylenetriamine occurred at the site adjacent to the fluorine of the fluorophenyl ring.

6-(2-Fluorophenyl)-5,6-dihydrobenzimidazolo[1,2-c]quinazoline

In the title compound, C20H14FN3, the pyrimidine ring adopts a half-chair conformation. The dihedral angle between the benzimidazole ring system and the fluoro­phenyl ring is 84.18 (10)°. In the crystal structure, mol­ecules are linked into a two-dimensional network parallel to the bc plane by N—H⋯N and C—H⋯F hydrogen bonds.

2-[4-(2-Fluorophenyl)piperazin-1-ylmethyl]-4,6-dimethylisothiazolo[5,4-b]pyridin-3(2H)-one

In the title mol­ecule, C19H21FN4OS, the piperazine ring adopts a chair conformation. A conjugation effect of the lone pair of the tertiary N atom with the π-electron system of the fluorophenyl ring is diminished by the steric effect of the 2-F substituent. The crystal structure contains short inter­molecular C—H⋯X (X = N, O) contacts and π–π inter­actions [with a ring centroid-to-centroid separation of 3.5908 (18) Å].

TwoN-substituted 3,5-diphenyl-2-pyrazoline-1-thiocarboxamides

The structures of N-ethyl-3-(4-fluorophenyl)-5-(4-methoxyphenyl)-2-pyrazoline-1-thiocarboxamide, C19H20FN3OS, (I), and 3-(4-fluorophenyl)-N-methyl-5-(4-methylphenyl)-2-pyrazoline-1-thiocarboxamide, C18H18FN3S, (II), have similar geometric parameters. The methoxy/methyl-substituted phenyl groups are almost perpendicular to the pyrazoline (pyraz) ring [interplanar angles of 89.29 (8) and 80.39 (10) degrees for (I) and (II), respectively], which is coplanar with the fluorophenyl ring [interplanar angles of 5.72 (9) and 10.48 (10) degrees]. The pyrazoline ring approximates an envelope conformation in both structures, with the two-coordinate N atom involved in an intramolecular N-H...N(pyraz) interaction. In (I), N-H...O and C-H...S intermolecular hydrogen bonds are the primary interactions, whereas in (II), there are no intermolecular hydrogen bonds.

(R)-4-(4-fluorophenyl)-1-[2-hydroxy-2-(3-methyl-1-benzofuran-2-yl)ethyl]piperazinium chloride propan-1-ol solvate.

The title compound, C21H24FN2O2+.Cl-.C3H8O, is a potential drug designed as a hybrid compound with antihypertensive, antioxidant and beta-adrenolytic activity. The cation contains nearly planar benzofuran and fluorophenyl ring systems, as well as a piperazine ring adopting an almost perfect chair conformation. The benzofuran and piperazine moieties are connected by an ethyl chain, the moieties forming a dihedral angle of 163.12 (13) degrees. In the crystal structure, ions and propanol solvent molecules are linked via N-H...Cl and O-H...Cl bonds into linear (010) chains.

NMR studies of the inclusion complex between beta-cyclodextrin and paroxetine.

A 1H and 13C NMR study on the inclusion complex of paroxetine with beta-cyclodextrin was carried out in order to define the stoichiometry of the association and its strength. Proton and carbon chemical shift measurements of paroxetine and beta-cyclodextrin were performed at several molar ratios and temperatures, allowing the determination of a 1:1 stoichiometry and an association constant value of the order of 2 x 10(3) for the paroxetine-beta-cyclodextrin complex. Overhauser effects in the rotating frame were also measured, and the experimental interproton distance constraints have been used for molecular model building of the complex. The obtained model indicates that the benzodioxolyl moiety of paroxetine is deeply inserted in the cavity of the cylindrical structure of beta-cyclodextrin, while the fluoro-phenyl ring lays above the wider rim.

The structure of 1-(p-fluorophenylmethyl)-2-(4-methyl-1-piperazinyl)-1H-benzimidazole hydrogen fumarate

The crystal and molecular structure of the title compound has been determined by X-ray analysis. The 1-(p-fluorophenylmethyl)-2-(4-methyl-1-piperazinyl)-1H-benzimidazole ion cocrystallizes with fumaric acid, (C19H22N4F+·C4H3O4−), in space group P-1 with cell dimensions a = 9.938(1), b = 10.131(1), c = 12.712(1) A, α = 86.57(1), β = 69.41(2), and γ = 67.22(2)°. The piperazine N4 atom is protonated and contacts the deprotonated O atom of the fumarate anion through a hydrogen bond. The benzimidazole ring is nearly planar and makes a dihedral angle of 111.25(12)° with the fluorophenyl ring. The piperazine ring adopts a chair conformation.

1,2-Diarylpyrroles as Potent and Selective Inhibitors of Cyclooxygenase-2

Series of 1,2-diarylpyrroles has been synthesized and found to contain very potent and selective inhibitors of the human cyclooxygenase-2 (COX-2) enzyme. The paper describes short and practical syntheses of the target molecules utilizing the Paal-Knorr reaction. Electrophilic substitution on 1 proceeds in a regioselective fashion, and the method was used to generate a number of tetrasubstituted pyrroles. Detailed SAR on the series has been studied by modifications of the aryl rings and the substituents in the pyrrole ring. Diarylpyrrole 1 is a very potent (COX-2, IC50 = 60 nm) and selective (COX-1/COX-2 = > 1700) inhibitor whereas the isomeric 2 is completely inactive against COX-2. Modifications of the substituents on the fluorophenyl ring in 1 yields very potent inhibitors of COX-2 (IC50 = 40-80 nm) with excellent selectivity (1200 to > 2500) vs COX-1. Analog 20 containing a sulfonamide group is an excellent inhibitor of COX-2 with an IC50 of 14 nm. Tetrasubstituted pyrroles containing groups such as COCF3, SO2CF3, or CH2OAr at position 3 in the pyrrole ring give excellent inhibitors (COX-2, IC50 = 30-120 nm). In vivo testing in the carrageenan-induced paw edema model in the rat establishes that the 1,2-diarylpyrroles are orally active antiinflammatory agents. Compound 3 is the most potent inhibitor of edema with an ED50 of 4.7 mpk.

Dynamic behaviour of fluoro‐substituted 1,8‐diarylnaphthalenes: A 19F,19F and 1,1H 2D EXSY NMR and AM1 computational study

AbstractInteractions between polar groups and π systems were studied for stacked aryls in 1‐fluorophenyl‐8‐arylnaphthalenes, in which an ‘electron‐rich’ aryl ring is forced in a stacked geometry with an ‘electron‐poor’ fluorophenyl ring; the rotation process was examined using different NMR techniques (lineshape analysis, 2D EXSY). The ΔG≠S obtained when considering 1H and 19F nuclei were perfectly comparable. Semi‐empirical calculations (AM1) were performed to evaluate ΔG≠S for the rotation process, and the results are compared with the experimental NMR values.

Nonpeptide HIV Protease Inhibitors. Differential Introduction of Alkylamino Groups into the Two Aryl Rings of Haloperidol

In efforts to synthesize haloperidol analogues with improved properties as HIV protease inhibitors, methods were sought to introduce mono- and dialkylamino groups into the two aromatic rings of the parent structure. We report here that the reaction of haloperidol with alkylamines in the presence of a strong base (NaNH) regiospecifically introduces the alkylamino group into the chlorophenyl ring, whereas the same reaction in the presence of a weak base (KCO) results in exclusive replacement of the fluorine of the fluorophenyl ring. Different amine functions can be introduced at the two rings by sequential reactions in the presence of, respectively, a strong and a weak base. The reaction catalyzed by NaNH involves, at least in part, benzyne formation, whereas the reaction catalyzed by KCO involves direct nucleophilic addition to the aromatic ring. The regiospecificity of the reaction is due to conjugation of the fluorophenyl ring to a ketone group. The fluorophenyl ring is activated by the ketone towards nucleophilic aromatic substitution but is deactivated by the same function when it is converted by strong base to the enolate anion. Carbonyl conjugation of one of two haloaryl groups appears to be a general strategy for regiospecific introduction of alkylamino functions into complex aromatic molecules. The alkylamino derivatives actually prepared are comparable to haloperidol as inhibitors of the HIV-1 protease.

Structure and dynamics of α-chymotrypsin-N-trifluoroacetyl-4-fluorophenylalanine complexes

Fluorine NMR lineshape, relaxation and Overhauser effect data collected at 282 and 470 MHz have been used to obtain information about the nature of complexes formed between N-trifluoroacetyl-4-fluorophenylalanine and the enzyme chymotrypsin. Systems involving both enantiomers have been examined as well as derivatives of these in which the aromatic ring hydrogens have been replaced by deuterium. The enzyme-induced fluorine chemical shift effects and the dynamics of molecular motions of the fluorophenyl ring at the respective binding sites appear to be similar in both complexes and, where comparable, the results are in agreement with data obtained at lower frequencies that have been reported by other workers. The dynamics of the fluoroaromatic ring in these complexes are significantly different from those observed in a closely related acylated enzyme.

Haloperidol binding to monoclonal antibodies. Predictions of three-dimensional combining site structure via computer modeling.

The amino acid sequences of five monoclonal antibodies (designated mAbs A-E) which bind to the dopaminergic D-2 antagonist, haloperidol, with a variety of affinities (Kd = 4-810 nM), have been used to build theoretical, three-dimensional, computer models of the variable region combining sites. Physiocochemical interactions which have been previously determined from in vitro binding data have been used to orient the drug molecule within the combining site model. The results indicate that hydrophobic, aromatic, and ionic amino acids are involved in specific interactions with the antagonist molecule. For example, fluorescence quenching data suggests that a tryptophan residue is intimately involved in the binding of haloperidol by mAb A. Examination of the modeled structure reveals five tryptophans within the variable fragment, only one of which (H-50) is within the classical beta-barrel binding pocket and is readily accessible to the antigen. Haloperidol's relatively electron poor fluorophenyl ring system stacks with the electron-rich tryptophan ring system at a distance of 3.3 A and in so doing, places haloperidol's positively charged piperidinyl nitrogen atom within hydrogen bond distance of the negatively charged Glu-95 and Asp-100A residues of the H3 loop (Glu-H-95 and Asp-H-100A). This type of analysis for each antibody provides an interesting profile of changes in amino acid composition and hypervariable loop length which markedly effect binding affinity and specificity for a series of proteins which have similar combining site.