Diindolylamine Preparation and Stability Investigations.

The synthesis of diindolylamines via the palladium-catalyzed cross-coupling of aminoindoles and bromoindoles has been investigated, and efficient coupling conditions using BrettPhos, Pd(OAc)2, K2CO3, and tBuOH have been identified. The diindolylamines were found to be unstable in ambient conditions. Blocking the reactive 3-position of the bromoindole coupling partner with a tert-butyl group results in a diindolylamine with improved air stability. NMR, CV, and UV-vis studies on an asymmetrically substituted 3-tert-butyl-3'H-diindolylamine indicate that the instability of the diindolylamine substrates is likely due to oxidative oligomerization. Literature conditions used for the preparation of 3-tert-butylindoles afforded only the indole tetramer. The presence of water during the alkylation reaction was identified as the cause of the formation of the tetramer. Replacing hygroscopic tBuOH with nonhygroscopic tBuCl as the alkylating reagent provided access to 7-bromo-3-tert-butyl indole.

Diastereomerically Differentiated Excited State Behavior in Ruthenium(II) Hexafluoroacetylacetonate Complexes of Diphenyl Thioindigo Diimine.

Mono- and diruthenium hexafluoroacetylacetonate (hfac) complexes of the thioindigo-N,N'-diphenyldiimine chelating ligand 3 have been prepared. The thioindigo diimine ligand binds to ruthenium in a bidentate fashion in the mononuclear compound 2 and serves as a bidentate chelating bridging ligand in the diruthenium complexes 1a and 1b. Compound 2 was isolated as a racemic mixture while the diruthenium complexes were isolated as the meso (ΔΛ) 1a and rac (ΔΔ and ΛΛ) 1b diastereomers. In-depth structural characterization of the compounds was performed, including X-ray crystallography, 1H, 13C, and 19F nuclear magnetic resonance (NMR) spectroscopy, and 2D NMR correlation experiments. Electrochemical properties were evaluated utilizing cyclic voltammetry. Ground state optical properties of the complexes were examined using UV-visible spectroscopy and spectroelectrochemistry. The excited state dynamics of the series were investigated by ultrafast transient absorption spectroscopy. Variable temperature NMR experiments demonstrated that the rac diruthenium compound 1b undergoes conformational exchange with a rate constant of 8700 s-1 at 298 K, a behavior that is not observed in the meso diastereomer 1a. The series of complexes possess metal-to-ligand charge transfer (MLCT) absorption bands in the near-infrared (λmax 689-783 nm). The compounds do not display photoluminescence in room temperature solution-phase experiments or in experiments at 77 K. Transient absorption spectroscopy measurements revealed excited states with picosecond lifetimes for 1a, 1b, and 2, and spectroelectrochemical experiments confirmed assignment of the transient species as arising from MLCT transitions. Unexpectedly, the transient absorption measurements revealed disparate time constants for the excited state decay of diastereomers 1a and 1b.

Synthesis and photophysics of thioindigo diimines and related compounds.

We report the synthesis and comprehensive characterization of diamine and diimine derivatives of the fluorescent compound thioindigo. Diamines 1 were obtained by metal-mediated amine condensation reaction with thioindigo. Oxidation of the products of the coupling reaction provided the diimines 2. X-ray crystal structures, cyclic voltammetry, and spectral and photophysical data of the compounds are presented. X-ray crystal structures demonstrate a planar structure for the diimine derivatives and a twisted conformation for the diamines. The diamine compounds 1 absorb in the UV (λmax 324-328 nm), significantly blue-shifted from the absorption spectrum of thioindigo. Diamines 1 exhibit moderate fluorescence (ΦF = 0.25, 0.045). A transient triplet state is observed in laser flash photolysis (LFP) experiments of 1, with lifetimes 1 order of magnitude longer than those of thioindigo. The diimine compounds 2 absorb at longer wavelengths (λmax 495-510 nm) than the diamines but are still slightly blue-shifted from thioindigo, with molar extinction coefficients 17-70% higher compared to thioindigo. The diimine compounds are not emissive, and LFP studies indicate transient species with microsecond lifetimes. Quenching experiments and transient absorption spectra are consistent with trans-cis isomerization.

Discovery of a novel series of 4-quinolone JNK inhibitors.

A novel series of highly selective JNK inhibitors based on the 4-quinolone scaffold was designed and synthesized. Structure based drug design was utilized to guide the compound design as well as improvements in the physicochemical properties of the series. Compound (13c) has an IC(50) of 62/170 nM for JNK1/2, excellent kinase selectivity and impressive efficacy in a rodent asthma model.

Direct N-acetyl enamine formation: lithium bromide mediated addition of methyllithium to nitriles.

An improved protocol for N-acetyl enamine formation is disclosed which involves LiBr-mediated addition of MeLi to substituted nitriles. The resulting enamides are isolated in high yields and excellent purity which permits subsequent hydrogenation at very low catalyst loading.

Synthesis of a tetrahydropyran NK1 receptor antagonist via asymmetric conjugate addition.

Two asymmetric syntheses of the NK(1) receptor antagonist 1-[2-(R)-{1-(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(R)-(3,4-difluorophenyl)-4-(R)-tetrahydro-2H-pyran-4-ylmethyl]-3-(R)-methylpiperidine-3-carboxylic acid (1) were developed. In both routes, the core tetrahydropyran stereochemistry was established by asymmetric conjugate addition to an alpha,beta-unsaturated ester (6), using an amide of the chiral auxiliary pseudoephedrine. Selective ester reduction then allowed formation of lactone 2 with the thermodynamically preferred trans geometry. The chiral ether side chain (3) was attached by stereoselective acetal substitution. In the first route, the chiral piperidine ester fragment was installed at the end by N-alkylation. In the shorter second synthesis, this piece was appended to the Michael acceptor at the beginning.

Direct synthesis of 4-arylpiperidines via palladium/copper(I)-cocatalyzed Negishi coupling of a 4-piperidylzinc iodide with aromatic halides and triflates.

A general procedure for the synthesis of 4-arylpiperidines via the coupling of 4-(N-BOC-piperidyl)zinc iodide with aryl halides and triflates is presented. The reaction requires cocatalysis with both Cl(2)Pd(dppf) and a copper(I) species. An improved, safer procedure for the activation of zinc dust is also presented.

Michael reactions of pseudoephedrine amide enolates: effect of LiCl on syn/anti selectivity.

The stereochemical outcome of the asymmetric Michael reaction of pseudoephedrine amide enolates changes dramatically in the presence of LiCl. Reaction of the enolate in the absence of LiCl results in formation of the anti Michael adduct with high selectivity, whereas in the presence of lithium chloride the syn adduct is favored. This method provides access to enantiomerically enriched trans-3,4-disubstituted delta-lactones from the anti Michael adducts by a two step reduction/lactonization sequence. Information obtained from NMR studies indicates that, under both enolization conditions, the (Z)-enolate is formed. A model to explain the turnover in selectivity based on NMR evidence is presented.

Pseudoephedrine as a chiral auxiliary for asymmetric Michael reactions: synthesis of 3-aryl-delta-lactones.

[reaction: see text] The asymmetric Michael reaction of pseudoephedrine amides is reported. The 1,5-dicarbonyl products are converted to 3-aryl-delta-lactones in a two-step reduction/lactonization sequence. This method provides access to enantiomerically enriched trans-3,4-disubstituted delta-lactones.