Iridium(III)-catalyzed ß-trifluoromethyl enone carbonyl-directed regioselective ortho-C(sp2)-H olefination.

Due to the lower LUMO energy level at the ß-position of α,ß-unsaturated-ß-trifluoromethyl enone than that of its non-fluorinated counterpart, there is a challenge to activate the sp2 C-H bond of aromatic rings. Herein, we have reported iridium(III)-catalyzed ß-trifluoromethyl enone carbonyl-directed regioselective aromatic C(sp2)-H olefination with acrylates under oxidative conditions. Furthermore, coupling with natural product-derived acrylates, scale-up and product diversification have also been performed.

Pyridine C(sp2)-H bond functionalization under transition-metal and rare earth metal catalysis.

Pyridine is a crucial heterocyclic scaffold that is widely found in organic chemistry, medicines, natural products, and functional materials. In spite of the discovery of several methods for the synthesis of functionalized pyridines or their integration into an organic molecule, new methodologies for the direct functionalization of pyridine scaffolds have been developed during the past two decades. In addition, transition-metal-catalyzed C-H functionalization and rare earth metal-catalyzed reactions have flourished over the past two decades in the development of functionalized organic molecules of concern. In this review, we discuss recent achievements in the transition-metal and rare earth metal-catalyzed C-H bond functionalization of pyridine and look into the mechanisms involved.

Catalytic and Chemodivergent Synthesis of 1-Substituted 9H-Pyrrolo[1,2-a]indoles via Annulation of ß-CF3 Enones with 3-Substituted Indoles.

Chemodivergent reactions are more advantageous in organic synthesis that yield diversely functionalized scaffolds from common starting materials. Herein, we report an efficient metal-free chemodivergent protocol for the synthesis of 1-substituted 9H-pyrrolo[1,2-a]indole derivatives in the presence of catalytic amounts of Lewis acid/Brønsted acid conditions using 3-substituted indoles and ß-trifluoromethyl-α,ß-unsaturated ketones. Fine-tuning of the catalyst and solvent system in the reaction conditions deliver the trifluoromethyl, trifluoroethylcarboxylate, or carboxylic acid substituents on the C1-position of 9H-pyrrolo[1,2-a]indole derivatives in situ. It is postulated that the solvent and LA/BA catalyst interaction was found to be crucial for the catalytic C-F activation in these transformations.

High resolution mass spectrometry-driven metabolite profiling of baricitinib to report its unknown metabolites and step-by-step reaction mechanism of metabolism.

RATIONALE: Metabolite profiling is an integral part of the drug development process for selecting candidates with high therapeutic efficacy and low risk. Baricitinib (BARI) was approved in 2018 by the US Food and Drug Administration to treat rheumatoid arthritis. According to the available literature, no systematic study has been reported on the metabolite profiling of BARI. The biotransformation pathway of the drug has also not been established until recently. This study aims to identify BARI metabolites generated in in vitro matrices. METHODS: The in vitro metabolism study was carried out using rat liver microsome, human liver microsomes, and human S9 fraction. Ultra high-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (U-HPLC-Q/TOF) and ultra-high-performance liquid chromatography/linear ion trap-Orbitrap mass spectrometry (U-HPLC/LTQ-Orbitrap-MS/MS) were used to identify and characterize the metabolites of BARI. The in silico toxicity of BARI and its metabolite was studied using ProTox-II toxicity predictor software. RESULTS: A total of five new metabolites have been identified amongst which two (M1 and M2) were detected on both U-HPLC/LTQ-Orbitrap-MS/MS and U-HPLC-Q/TOF and two additional metabolites (M4 and M5) were detected on U-HPLC/LTQ-Orbitrap-MS/MS. Moreover, one metabolite (M3) was only detected on LC-QTOF. CONCLUSIONS: The major metabolic changes were found to be N-dealkylation, demethylation, hydroxylation, and hydrolysis. Metabolites M3 and M4 were found to have the potential for carcinogenicity. The novelty of the study can be justified by the unavailability of any previous research on in vitro metabolite profiling of BARI. Furthermore, this is the first time the biotransformation pathway of BARI and the toxicity potential of its metabolites have been reported.

Degradation kinetics and characterization of major degradants of binimetinib employing liquid chromatography-high resolution mass spectrometry.

Binimetinib (BMT) has recently been approved by the USFDA for the treatment of melanomas. An extensive literature search revealed that degradation kinetics of BMT is not reported in any scientific report. Till date, no stability indicating analytical method (SIAM) is available for quantification of BMT in presence of its impurities. Moreover, information on degradation products (DPs) of BMT and the degradation pathway is not known. In this study, we have developed a SIAM for BMT and characterized its major DPs using LC-Q-TOF-MS/MS. The SIAM was validated according to the ICH guideline and subsequently used to study the degradation kinetics of BMT. The method was found to be useful for separating BMT and all its DPs formed during different stress conditions. Three new DPs have been identified and characterized. H1 (acid hydrolytic DP) and O1 (oxidative degradation product) were isolated and characterized by NMR (1H) spectroscopy. An in silico toxicity evaluation of the DPs was performed using ProTox-II toxicity prediction software. Data obtained from the degradation kinetic study revealed that BMT degradation follows first-order kinetics under acidic hydrolysis and oxidative stress conditions. The degradation kinetics mechanism and knowledge on the pathway of degradation established through this study can be useful to improve the stability profile of the drug and to propose a more appropriate storage condition. The degradation impurities we have identified and characterized can be useful in setting the quality control acceptance criteria of the drug after their required qualification. The quantitative assay method can be used for routine quality control and stability study analysis of BMT in pharmaceutical industries and research laboratories.

Rh(III)-Catalyzed [3 + 2] Annulation via C-H Activation: Direct Access to Trifluoromethyl-Substituted Indenamines and Aminoindanes.

The rhodium(III)-catalyzed direct C-H addition and annulation of benzimidates and aldimines with ß-(trifluoromethyl)-α,ß-unsaturated ketones is described. This protocol provides the facile and efficient formation of various trifluoromethyl-containing indenamines or aminoindanes in moderate to high yields.

Benzophenone: a ubiquitous scaffold in medicinal chemistry.

The benzophenone scaffold represents a ubiquitous structure in medicinal chemistry because it is found in several naturally occurring molecules which exhibit a variety of biological activities, such as anticancer, anti-inflammatory, antimicrobial, and antiviral. In addition, various synthetic benzophenone motifs are present in marketed drugs. They also represent important ingredients in perfumes and can act as photoinitiators. This review will provide an overview of benzophenone moieties with medicinal aspects synthesized in the last 15 years and will cover the most potent molecule in each report. In this review, only benzophenones with substitutions on their aryl rings, i.e. diphenyl ketone analogues, have been covered.

Rhodium-Catalyzed [3 + 2] Annulation of Cyclic N-Acyl Ketimines with Activated Olefins: Anticancer Activity of Spiroisoindolinones.

The rhodium(III)-catalyzed redox-neutral coupling reaction of N-acyl ketimines generated in situ from 3-hydroxyisoindolinones with various activated olefins is described. This approach leads to the synthesis of bioactive spiroisoindolinone derivatives in moderate to high yields. In the case of internal olefins such as maleimides, maleates, fumarates, and cinnamates, spiroindanes were obtained by the [3 + 2] annulations reaction. In sharp contrast, acrylates and quinones displayed the ß-H elimination followed by Prins-type cyclization furnishing spiroindenes. The synthetic compounds were evaluated for in vitro anticancer activity against androgen-sensitive human prostate adenocarcinoma cells (LNCaP), human prostate adenocarcinoma cells (DU145), human endometrial adenocarcinoma cells (Ishikawa), human breast cancer cell (MCF-7), and triple negative human breast cancer cells (MDA-MB-231). Notably, quinone-containing spiroindenes displayed potent anticancer activity about 2- to 3-fold stronger than that of anticancer agent doxorubicin.

Cp*Rh(iii)-catalyzed C(sp3)-H alkylation of 8-methylquinolines in aqueous media.

The rhodium(iii)-catalyzed cross-coupling reaction of 8-methylquinolines with a range of allylic alcohols in water is described. This approach leads to the synthesis of various γ-quinolinyl carbonyl compounds, which are synthetically useful precursors for the construction of bioactive tetrahydroquinoline and azasteroid derivatives.

Synthesis of Succinimide-Containing Chromones, Naphthoquinones, and Xanthones under Rh(III) Catalysis: Evaluation of Anticancer Activity.

The weakly coordinating ketone group directed C-H functionalizations of chromones, 1,4-naphthoquinones, and xanthones with various maleimides under rhodium(III) catalysis are described. These protocols efficiently provide a range of succinimide-containing chromones, naphthoquinones, and xanthones with excellent site selectivity and functional group compatibility. All synthetic compounds were screened for in vitro anticancer activity against human breast adenocarcinoma cell lines (MCF-7). In particular, compounds 7aa and 7ca with a naphthoquinone scaffold were found to be highly cytotoxic, with an activity competitive with anticancer agent doxorubicin.

Rhodium(III)-Catalyzed C(sp(3))-H Alkylation of 8-Methylquinolines with Maleimides.

The rhodium(III)-catalyzed cross-coupling reaction of 8-methylquinolines and maleimides is described. In contrast to the C(sp(2))-H functionalization, a first catalytic functionalization of sp(3) C-H bonds with maleimides is reported. This protocol provides a facile access to various succinimide scaffolds on 8-methylquinolines via a direct C-H cleavage approach.

Rh(III)-Catalyzed C-H Functionalization of Indolines with Readily Accessible Amidating Reagent: Synthesis and Anticancer Evaluation.

The rhodium(III)-catalyzed direct C-H functionalization of various indolines with 1,4,2-dioxazol-5-ones as new amidating agents is described. This transformation provides efficient preparation of C7-amidated indolines known to display potent anticancer activity. The synthetic compounds were evaluated for in vitro anticancer activity against human prostate adenocarcinoma cells (LNCaP), human endometrial adenocarcinoma cells (Ishikawa), and human ovarian carcinoma cells (SKOV3). Compound 4f was found to be highly cytotoxic, with activity competitive with that of anticancer agent doxorubicin.

Cross-Coupling of Acrylamides and Maleimides under Rhodium Catalysis: Controlled Olefin Migration.

The rhodium(III)-catalyzed direct cross-coupling reaction of electron-deficient acrylamides with maleimides is described. This protocol displays broad functional group tolerance and high efficiency, which offers a new opportunity to access highly substituted succinimides. Dependent on the substituent positions of acrylamides and reaction conditions, olefin migrated products were obtained with high regio- and stereoselectivity.

Trifluoromethylallylation of Heterocyclic C-H Bonds with Allylic Carbonates under Rhodium Catalysis.

The rhodium(III)-catalyzed γ-trifluoromethylallylation of various heterocyclic C-H bonds with CF3-substituted allylic carbonates is described. These reactions provide direct access to linear CF3-containing allyl frameworks with complete trans-selectivity via C-H bond activation followed by a formal SN-type reaction pathway.

Mild and Site-Selective Allylation of Enol Carbamates with Allylic Carbonates under Rhodium Catalysis.

The rhodium(III)-catalyzed mild and site-selective C-H allylation of enol carbamates with 4-vinyl-1,3-dioxolan-2-one and allylic carbonates affords allylic alcohols and terminal allylated products, respectively. The assistance of the carbamoyl directing group provides a straightforward preparation of biologically and synthetically important allylated enol carbamates.

Discovery and SAR of N-(1-((substituted piperidin-4-yl)methyl)-3-methoxypiperidin-4-yl)-2-methoxybenzamide derivatives: 5-Hydroxytryptamine receptor 4 agonist as a potent prokinetic agent.

A series of novel benzamide derivatives, altering the 4-fluorophenylalkyl moiety in cisapride, were synthesized as 5-HT4 receptor agonists, and SAR of these analogs was examined on in vitro and in vivo prokinetic activities. These compounds were synthesized for high 5-HT4 receptor binding affinities and low hERG affinities. Several types of analogs were obtained and screened for 5-HT4 binding, hERG blocking, agonism, and gastric emptying assessment. Among the analogues, compound 23g showed promising results compared with the other analogs with respect to gastric emptying rates in rats. Therefore, we suggest that it may be a clinical candidate for the development of a potent prokinetic agent to treat GI disorders.

Access to 3-Acyl-(2H)-indazoles via Rh(III)-Catalyzed C-H Addition and Cyclization of Azobenzenes with α-Keto Aldehydes.

The rhodium(III)-catalyzed direct C-H functionalization of azobenzenes with ethyl glyoxalate and aryl glyoxals is described. This protocol provides the facile and efficient formation of various C3-acylated-(2H)-indazoles in moderate to high yields.

Rhodium-Catalyzed C-H Alkylation of Indolines with Allylic Alcohols: Direct Access to ß-Aryl Carbonyl Compounds.

The rhodium(III)-catalyzed site-selective C-H alkylation of various N-heterocycles, such as indolines, carbazoles, and pyrroles with readily available allylic alcohols is described. This protocol allows the generation of a heterocyclic scaffold containing a ß-aryl carbonyl moiety, which is known to be a crucial structural unit of biologically active compounds.

Direct C-H alkylation and indole formation of anilines with diazo compounds under rhodium catalysis.

The rhodium(III)-catalyzed direct functionalization of aniline C-H bonds with α-diazo compounds is described. These transformations provide a facile construction of ortho-alkylated anilines with diazo malonates or highly substituted indoles with diazo acetoacetates.

Synthesis of N-Sulfonylamidated and Amidated Azobenzenes under Rhodium Catalysis.

The rhodium(III)-catalyzed ortho-C-H amidation of azobenzenes with arylsulfonyl and aryl and alkyl isocyanates is described. The N-sulfonyl amidation reaction using arylsulfonyl isocyanates is first reported in the C-H activation strategy. These transformations provide the facile and efficient construction of a range of amide moieties into azobenzenes.