Functionalization of Alkynes and Alkenes Using a Cascade Reaction Approach: Synthesis of ß-Keto Sulfones under Metal-free Conditions.

Here, we are reporting a multicomponent cascade reaction approach for the synthesis of ß-keto sulfones by exploiting differential reactivity pattern of substrates under open-atmosphere and metal-free conditions. The coupling partners are aryldiazonium salts, unsaturated compounds, and DABSO. The optimized conditions worked well with both alkenes and alkynes. Moreover, the reaction also works with metabisulfite for the source of sulfone. The controlled liquid chromatography-mass spectrometry and 18O-labelled experiments suggested that air is a source of the incoming oxygen atom of the keto group of ß-keto sulfones.

α-Angelica lactone catalyzed oxidation of benzylic sp3 C-H bonds of isochromans and phthalans.

A metal-free organocatalytic system has been developed for highly efficient benzylic C-H oxygenations of cyclic ethers using oxygen as an oxidant. This oxidation reaction utilizes α-angelica lactone as a low cost/low molecular weight catalyst. The optimized reaction conditions allow the synthesis of valued isocoumarins and phthalides from readily available precursors in good yields. Mechanistic studies indicate that the reaction pathway likely involves a radical process via a peroxide intermediate.

Metal free C-H functionalization of diazines and related heteroarenes with organoboron species and its application in the synthesis of a CDK inhibitor, meriolin 1.

Here, we report a metal-free cross-coupling reaction of diazines and related heteroarenes with organoboron species via C-H functionalization. The optimized conditions represent a metal-free method for the activation of aryl/heteroarylboronic acids, which undergo coupling with diazines and related heteroarenes. Optimized conditions also find application in the synthesis of a pyrimidine-based potent CDK inhibitor, meriolin1.

Cross-dehydrogenative coupling of α-C(sp(3))-H of ethers/alkanes with C(sp(2))-H of heteroarenes under metal-free conditions.

Here we have developed an effective metal-free dehydrogenative coupling method wherein α-oxyalkyl and alkyl radicals were generated from various ethers and alkanes to undergo coupling with a variety of electron-deficient heteroarenes such as un/substituted iso-quinolones, quinolines, pyridines, pyrazines and pyrimidines. The persulfate-acetone-water system was optimized for the dehydrogenative coupling with cyclic ethers which gave moderate to excellent yields of α-oxyalkyl containing heteroarenes. We have also optimized the conditions for coupling with cyclic alkanes and alicyclic ethers and demonstrated by conducting the reactions with a variety of electron-deficient heteroarenes. Further, the present method is also applicable to electron deficient arenes like naphthoquinones and moreover, it didn't require any external acid.

Cu-Mn spinel oxide catalyzed regioselective halogenation of phenols and N-heteroarenes.

A novel simple, mild chemo- and regioselective method has been developed for the halogenation of phenols using Cu-Mn spinel oxide as a catalyst and N-halosuccinimide as halogenating agent. In the presence of Cu-Mn spinel oxide B, both electron-withdrawing and electron-donating groups bearing phenols gave monohalogenated products in good to excellent yields with highest para-selectivity. The para-substituted phenol gave monohalogenated product with good yield and ortho-selectivity. N-Heteroarenes such as indoles and imidazoles also gave monohalogenated products with high selectivity. Unlike the copper-catalyzed halogenation, the present method works well with electron-withdrawing group bearing phenols and gives comparatively better yields and selectivity. The Cu-Mn spinel catalyst is robust and reused three times under optimized conditions without any loss in catalytic activity. Nonphenolics did not undergo this transformation.

α-Angelica Lactone in a New Role: Facile Access to N-Aryl Tetrahydroisoquinolinones and Isoindolinones via Organocatalytic α-CH2 Oxygenation.

A method for the direct oxidation of various N-aryl tetrahydroisoquinolines and isoindolines to the corresponding lactams using α-angelica lactone as a catalyst was developed. The utility of the method was further demonstrated by synthesis of indoprofen and indobufen.

1,6-Conjugate-Addition-Induced [2 + 1] Annulation of para-Quinone Methides and Pyrazolones: Synthesis of Bis-Spiro Compounds with Contiguous Quaternary Spiro-Centers.

A diastereoselective formal 1,6-conjugate-addition-mediated [2 + 1] annulation reaction using p-quinone methides and pyrazolones has been described. The corresponding bis-spiro[cyclohexadienone-cyclopropane-pyrazolone] compounds were obtained in very good yield under mild reaction conditions.

Determination of ZSTK474, a novel Pan PI3K inhibitor in mouse plasma by LC-MS/MS and its application to Pharmacokinetics.

ZSTK474, a promising novel anticancer molecule derived from s-triazine, found to have antitumor activities against different cancer cell lines. However, neither LCMS method nor pharmacokinetics of ZSTK474 has been reported till now. A sensitive, simple, short and specific liquid chromatography tandem mass spectrometry (LCMS/MS) method was developed for the quantification of ZSTK474 in mouse plasma accordance with the US Food and Drug Administration guidelines. Extraction of drug molecule was carried out using protein precipitation. Chromatographic analyte separation was achieved on Atlantis dC18 (4.6×50mm, 3µm). Composition of isocratic mobile phase consists of 90% acetonitrile and 0.2% formic acid, at 0.7mL/min flow rate, having short 2.5min run time. Method development was validated and found to be linear over a dynamic range between 1.9-1000ng/mL; having a correlation coefficient (r 2)≥0.9978. The analyte was found to be stable under short and long term storage conditions. LCMS/MS method developed was validated and found to be selective, reproducible, precise and accurate to quantify ZSTK474 in plasma samples, and first time successfully applied to pharmacokinetic studies. Pharmacokinetic data showed fast absorption attaining Cmax at 0.25h and half life (t1/2) 5.18h after oral administration of ZSTK474 at 20mg/kg in mouse.

Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model.

In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ∼33 in comparison to reported leads. In addition, the identified lead 4ab demonstrated a good solubility and an acceptable in vivo PK profile. The identified lead 4ab showed an in vivo efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models with a TGI (tumor growth inhibition) of 90% without any mortality growth inhibition in comparison to reported leads.