Co(III)-Catalyzed Regioselective Functionalization of Isoquinolones with Naphthoquinones.

A strategy for Co(III)-catalyzed C(sp2)-H alkenylation of N-protected isoquinolones with 1,4-naphthoquinones has been disclosed. The developed protocol was efficiently applied for diversely substituted isoquinolones. Preliminary mechanistic experiments revealed the involvement of a five-membered cobaltacycle as an intermediate. Deuterium labeling experiments suggested the reversible nature of the C-H activation step. The scale-up reaction was also carried out, and the product was utilized as a chemosensor to detect Fe3+ ions.

Experimental and Computational Studies on RuII -Catalyzed C7-Allylation of Indolines with Allyl Bromide.

The selective C7-allylation of indolines with allyl bromide under ruthenium catalysis has been revealed here. Under established reaction conditions, C7-allylation of various indolines, including drug compounds, was accomplished with good selectivity and yields. Based on combined experimental and density functional theory (DFT) studies, the olefin insertion route was energetically favorable among four possible pathways. Experimental and DFT studies further revealed that the C-H activation is a reversible rate-limiting step.

Photoredox Minisci-Type Hydroxyfluoroalkylation of Isoquinolines with N-Trifluoroethoxyphthalimide.

A straightforward photocatalytic approach has been demonstrated to incorporate a trifluoroethanol unit onto the isoquinolines. Herein, we report N-trifluoroethoxyphthalimide as a hydroxyfluoroalkyl radical precursor, enabling efficient synthesis of trifluoroethanol-substituted heteroarenes. Radical quenching experiments confirmed the involvement of a free-radical pathway under developed photocatalytic conditions. The DFT calculations confirmed the intramolecular 1,2-HAT reactivity of the O-centered trifluoroethoxy radical (generated from N-trifluoroethoxyphthalimide under photocatalytic condition) to the C-centered trifluoroethanol radical. Fluorescence quenching studies suggested that isoquinoline was responsible for the quenching of Ir-photocatalyst emission. A catalytic cycle involving trifluoroethanol radical reaction with isoquinolines has been proposed.

Predictable site-selective functionalization: Promoter group assisted para-halogenation of N-substituted (hetero)aromatics under metal-free condition.

Herein, regioselective para-C-H halogenation of N-pyrimidyl (hetero)aromatics through SEAr (electrophilic aromatic substitution) type reaction is disclosed. SEAr type reaction has been utilized for the C5-bromination of indolines (para-selective) with N-bromosuccinimide under metal and additive-free conditions in good to excellent yields. The developed methodology is also applicable for iodination and challenging chlorination. The pyrimidyl group is identified as a reactivity tuner that also controls the regioselectivity. The present method is also applicable for selective halogenation of aniline, pyridine, indole, oxindole, pyrazole, tetrahydroquinoline, isoquinoline, and carbazole. DFT studies such as Fukui nucleophilicity and natural charge maps also support the observed p-selectivity. Post-functionalization of the title compound into the corresponding arylated, olefinated, and dihalogenated products is achieved in a one-pot, two-step fashion. Late-stage C-H bromination was also executed on drug/natural molecules (harmine, etoricoxib, clonidine, and chlorzoxazone) to demonstrate the applicability of the developed protocol.

C70 Fullerene Catalyzed Photoinduced Aerobic Oxidation of Benzylamines to Imines and Aldehydes.

C70 fullerene catalyzed photoinduced oxidation of benzylic amines at ambient conditions has been explored here. The developed strategy's main feature includes the additive/oxidant-free conversion of benzylic amine to corresponding imine and aldehydes. The reaction manifests broad substrate scope with excellent function group leniency and is applicable up to the gram scale. Further, symmetrical secondary amines can also be synthesized from benzylic amine in a one-pot two-step process. Various experiments and density functional theory studies revealed that the current reaction involves the generation of reactive oxygen species, single electron transfer reaction, and benzyl radical formation as key steps under photocatalytic conditions.

In silico approach for identifying natural lead molecules against SARS-COV-2.

The life challenging COVID-19 disease caused by the SARS-CoV-2 virus has greatly impacted smooth survival worldwide since its discovery in December 2019. Currently, it is one of the major threats to humanity. Moreover, any specific drug or vaccine unavailability against COVID-19 forces to discover a new drug on an urgent basis. Viral cycle inhibition could be one possible way to prevent the further genesis of this viral disease, which can be contributed by drug repurposing techniques or screening of small bioactive natural molecules against already validated targets of COVID-19. The main protease (Mpro) responsible for producing functional proteins from polyprotein is an important key step for SARS-CoV-2 virion replication. Natural product or herbal based formulations are an important platform for potential therapeutics and lead compounds in the drug discovery process. Therefore, here we have screened >53,500 bioactive natural molecules from six different natural product databases against Mpro (PDB ID: 6LU7) of COVID-19 through computational study. Further, the top three molecules were subjected to pharmacokinetics evaluation, which is an important factor that reduces the drug failure rate. Moreover, the top three screened molecules (C00014803, C00006660, ANLT0001) were further validated by a molecular dynamics study under a condition similar to the physiological one. Relative binding energy analysis of three lead molecules indicated that C00014803 possess highest binding affinity among all three hits. These extensive studies can be a significant foundation for developing a therapeutic agent against COVID-19 through vet lab studies.

Regioselective Arylation of Quinoline N-Oxides (C8), Indolines (C7) and N-tert-Butylbenzamide with Arylboronic Acids.

Herein, we disclose Ru(II)-catalyzed regioselective distal C(sp2)-H arylation of quinoline N-oxide with arylboronic acids to 8-arylquinolines. In the developed method, the Ru(II)-catalyst shows dual activity, that is, distal C-H activation of quinoline N-oxides followed by in situ deoxygenation of arylated quinoline N-oxide in the same pot. The current catalytic method features use of Ru metal as the catalyst and arylboronic acids as the arylating source under mild reaction conditions. Use of the Rh(III)-catalyst in place of Ru(II) under the same conditions afforded 8-arylquinoline N-oxides with excellent regioselectivity. Furthermore, the developed Ru(II) catalytic system is also extended for the C(sp2)-H arylation of indolines, N-tert-butylbenzamide, and 6-(5H)-phenanthridinone. Formation of the quinoline N-oxide coordinated ruthenium adduct is found to be the key reaction intermediate, which has been characterized by single crystal X-ray diffraction and NMR spectroscopy.

Cp*RhIII -Catalyzed Sterically Controlled C(sp3 )-H Selective Mono- and Diarylation of 8-Methylquinolines with Organoborons.

Herein, the RhIII -catalyzed selective monoarylation and diarylation (symmetrical and unsymmetrical) of 8-methylquinolines with organoboron reagents are disclosed. The selective monoarylation of primary C(sp3 )-H bonds is achieved by using 7-substituted 8-methylquinolines or by changing the quantity of the aryl boronic acids. The method is also applicable for the arylation of 2-ethylpyridines, and the heteroarylation with thiophene-2-ylboronic acids. Symmetrical and unsymmetrical diarylation of 8-methylquinolines have been carried out in one-pot and sequential manner, respectively. Late-stage monoarylation of oxime derivatives and gram-scale synthesis of monoarylated products has also been carried out. A mechanistic study revealed that the current reaction is first order with respect to both reactants and a five-membered rhodacycle intermediate may be involved in the catalytic cycle.

Ru(II)/Rh(III)-Catalyzed C(sp3)-C(sp3) Bond Formation through C(sp3)-H Activation: Selective Linear Alkylation of 8-Methylquinolines and Ketoximes with Olefins.

Herein, [RuCl2(p-cymene)]2/[Cp*RhIIICl2]2-catalyzed direct alkylation of C(sp3)-H bond of 8-methylquinolines with olefins (acrylates, styrenes, and aliphatic) is reported. The alkylation also proceeds with other conjugated systems such as malemides and α,ß-unsaturated ketones. The reaction is highly regioselective, forms only a linear product, and tolerates a variety of functional groups on quinoline and olefin moieties. Control experiments, deuterium labeling, and kinetic studies have been carried out for preliminary understanding of the reaction pathway. The reaction possibly proceeds through five-membered metallacycle under redox-neutral condition. Diversification of alkylated product and late-stage functionalization of ketoxime derivatives of (-)-santonin have also been carried out to demonstrate the applicability of the developed method.

Rh(III)-Catalyzed C(8)-H Activation of Quinoline N-Oxides: Regioselective C-Br and C-N Bond Formation.

A highly efficient and regioselective Rh(III)-catalyzed protocol for C8-bromination and amidation of quinoline N-oxide was developed. The transformation was found to be successful up to gram scale with excellent functional group tolerance and wide substrate scope. The mechanistic study revealed five-membered rhodacycle with quinoline N-oxide as a key intermediate for regioselective C8-functionalization. In addition, NFSI (N-fluorobis(phenylsulfonyl)-imide) was explored as an amidating reagent for C8-amidation of quinoline N-oxide for the first time.