Final Thoughts on Chemistry for C9H11NO

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Optimization of imidazole amide derivatives as cannabinoid-1 receptor antagonists for the treatment of obesity

Several imidazole-based cyclohexyl amides were identified as potent CB-1 antagonists, but they exhibited poor oral exposure in rodents. Incorporation of a hydroxyl moiety on the cyclohexyl ring provided a dramatic improvement in oral exposure, together with a ca. 10-fold decrease in potency. Further optimization provided the imidazole 2-hydroxy-cyclohexyl amide 45, which exhibited hCB-1 Ki = 3.7 nM, and caused significant appetite suppression and robust, dose-dependent reduction of body weight gain in industry-standard rat models.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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1-Aminoindan-2-ol, a suitable ligand for the synthesis of chiral, intramolecularly stabilized compounds of aluminum, gallium, and indium

The reactions of enantiomerically pure (1R,2S)-(+)-cis-1-aminoindan-2-ol, (1S,2R)-(-)-cis-1-aminoindan-2-ol, and racemic trans-1-aminoindan-2-ol with trimethylaluminum, -gallium, and -indium produce the intramolecularly stabilized, enantiomerically pure dimethylmetal-1-amino-2-indanolates (1R,2S)-(+)-cis-Me2-AlO-2-C*HC7H6-1- C*HNH2 (1), (1S,2R)-(-)-cis-Me2AlO-2-C*HC 7H6-1-C*HNH2 (2), (1R,2S)-(+)-cis-Me 2GaO-2-C*HC7H6-1-C*HNH2 (3), (1R,2S)-(+)-cis-Me2InO-2-C*HC7H 6-1-C*HNH2 (4), (1S,2R)-(-)-cis-Me 2InO-2-C*HC7H6-1-C*HNH2 (5), and racemic (+/-)-trans-Me2InO-2-C*HC7H 6-1-C*HNH2 (6). The compounds were characterized by 1H NMR, 13C NMR, 27Al NMR and mass spectra as well as 1 and 3 to 6 by determination of their crystal and molecular structures. The dynamic dissociation/association behavior of the coordinative metal-nitrogen bond was studied by low temperature 1H NMR spectroscopy.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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Design and synthesis of tridentate facially chelating ligands of the [2.n.1]-(2,6)-Pyridinophane family

Syntheses are reported for tripyridine macrocycles 2 and 3 and some of their alkyl derivatives. The macrocycles are designed to stabilize to various extents coordinated d8 metal precursors and d6 alkane oxidative addition products (ptIV), therefore allowing favorable kinetics and thermodynamics of (e.g., PtII) the cleavage of substrate H-C(sp3) bonds. Both the Chichibabin protocol and oxidative coupling of carbanions by copper(I) iodide were used for the macrocyclization step. Crystal structures of singly and doubly protonated 2 establish atom connectivity in the macrocycle, and reveal structural features which are obscured in solution NMR by rapid proton migration.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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Indinavir analogues with blocked metabolism sites as HIV protease inhibitors with improved pharmacological profiles and high potency against PI-resistant viral strains

Indinavir analogues with blocked metabolism sites show highly improved pharmacokinetic profiles in animals. The cis-aminochromanol substituted analogues exhibited excellent potency against both the wild-type (NL4-3) virus and protease inhibitor-resistant HIV strains.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

Brief introduction of C7H9N

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One pot synthesis of ureas and carbamates via oxidative carbonylation of aniline-type substrates by CO/O2 mixture catalyzed by Pd-complexes

Abstract Carbonylation of aromatic amines by direct insertion of carbon monoxide is catalyzed by PdCl2(XnPy)2 complexes (where Py = pyridine, X = -CH3, -Cl; n = 0-2) and gives, depending on the conditions, ethyl N-phenylcarbamates or N,N?-diphenylureas. For carbonylation of aniline, a proper choice of XnPy ligands in PdCl2(XnPy)2 catalyst and application of molecular oxygen instead of nitrobenzene (conventionally used oxidant for carbonylations) allow to carry out the process under mild conditions with high yield and selectivity. The best results (75% yield of the main product with selectivity of catalyst above 90%) were obtained for the process catalyzed by PdCl2(2,4-Cl2Py)2 complex at 100C and they were greatly improved in comparison to 41% yield and 68% selectivity obtained for CO/nitrobenzene used at 180C.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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Kinetic resolution by copper-catalyzed azide-alkyne cycloaddition

The use of chiral pybox ligands imparts enantioselectivity to the Cu I-catalyzed azide-alkyne cycloaddition reaction, in the form of kinetic resolution of alpha-chiral azides and desymmetrization of gem-diazides. While levels of selectivity are modest, the results show unequivocally that the process benefits from ligand-accelerated catalysis.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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Synthesis of potent C2-symmetric, diol-based HIV-1 protease inhibitors. Investigation of thioalkyl and thioaryl P1/P1? substituents

The synthesis of novel, potent diol-based HIV-1 protease inhibitors, having either -SAr, -SCH2Ar, or -SCH2R groups as P1/P1? substituents is described. They can be prepared using a straightforward synthesis involving a thiol nucleophilic ring opening of a diepoxide. Inhibitor 13 was found to be a potent inhibitor of HIV-1 PR, showing good antiviral activity in a cell-based assay.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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Tertiary Alcohols as Radical Precursors for the Introduction of Tertiary Substituents into Heteroarenes

Despite many recent advances in the radical alkylation of electron-deficient heteroarenes since the seminal reports by Minisci and co-workers, methods for the direct incorporation of tertiary alkyl substituents into nitrogen heteroarenes are limited. This report describes the use of tert-alkyl oxalate salts, derived from tertiary alcohols, to introduce tertiary substituents into a variety of heterocyclic substrates. This reaction has reasonably broad scope, proceeds rapidly under mild conditions, and is initiated by either photochemical or thermal activation. Insights into the underlying mechanism of the higher yielding visible-light initiated process were obtained by flash photolysis studies, whereas computational studies provided insight into the reaction scope.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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Preparation of N-chlorothio(methyl)carbamoyl halides

A process for the preparation of N-chlorothio(methyl)carbamoyl halides.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis

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The synthesis of beta-nitropyridine compounds

Pyridine and a number of substituted pyridines have been nitrated by reaction with N2O5 followed by reaction with an aqueous solution of SO2xH2O or NaHSO3. The dependence of the yields on the pH of the aqueous reaction medium, on the concentration of SO2xH2O-HSO3-, on addition of methanol to the aqueous phase, and on the reaction temperature were investigated. The yields obtained with NaHSO3 were: 3-nitropyridine 77%, 2-methyl-5-nitro-pyridine 36%, 3-methyl-5-nitropyridinc 24%, 3-acetyl-5-nitropyridine 18%, 5-nitropyridine-3-carboxylic acid 15%, 3-chloro-5-nitropyridine 11%, 4-methyl-3-nitropyridine 39%, 4-acetyl-3-nitropyridine 67%, 4-cyano-3-nitropyridine 45%, 4-phenyl-3-nitropyridine 68%, 4-formyl-3-nitropyridine 62% (from reaction in liquid SO2), 3-nitropyridine-4-carboxylic acid 48%, methyl 3-nitropyridine-4-carboxylate 75%, 2,3-dimethyl-5-nitropyridine 37%, 2,4-dimethyl-5-nitropyridine 64%, 3-nitroquinoline 10% and 4-nitroisoquinoline 42%.

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Reference:
Chiral nitrogen ligands in late transition metal-catalysed asymmetric synthesis—I. Addressing the problem of ligand lability in rhodium-catalysed hydrosilations,
Nitrogen-Containing Ligands for Asymmetric Homogeneous and Heterogeneous Catalysis