Organophotoredox-Catalyzed Synthesis of Unnatural α/ß Amino Acids and Peptides via Deaminative Three-Component Coupling.

Herein, we disclose an expedient visible-light-mediated, organophotoredox-catalyzed multicomponent synthesis of unnatural amino acids using a Katritzky salt, glyoxal derivatives, and substituted anilines. Mechanistically, an alkyl radical is generated from the Katritzky salt via a deaminative process that undergoes addition to the in situ-generated imine to furnish α-amino acids in a moderate diastereoisomeric ratio. For the first time, we have demonstrated this deaminative protocol to access substituted ß-amino acids from α-amino acid-derived Katritzky salts. Furthermore, α-amino amides are also generated from the corresponding 2-oxoacetamide derivatives.

Shining light on the nitro group: distinct reactivity and selectivity.

The nitro moiety is an indispensable functional group in organic synthesis due to its facile introduction and reduction to the corresponding amines for a plethora of organic transformations. Owing to its distinct electronegative and conventional properties, it has been used for activated aromatic nucleophilic substitution (SNAr) reactions, Smiles reactions, Henry reactions, acyl anion equivalents, etc. Recently, the excellent photochemical properties of nitroarenes have been rediscovered by several groups, and their untapped potential in organic synthesis under UV or visible light irradiation has been exploited. Photoexcited nitroarenes can undergo facile reduction to amines, azo-coupling, metal-free reductive C-N coupling with boronic acids via a 1,2-boronate shift, hydrogen atom transfer (HAT), oxygen atom transfer for anaerobic oxidation of organic molecules, molecular editing via nitrene intermediates, denitrative coupling of ß-nitrostyrene, radical α-alkylation of nitroalkanes, etc. They have also been used as a photolabile protecting group in medicinal chemistry and chemical biology applications. Here, we summarise the recent findings on visible-light-mediated transformations involving nitro-containing organic molecules.

Green light-mediated dual eosin Y/PdII-catalyzed C(sp2)-H arylation of N-H unprotected 2-arylquinazolinones.

We report herein an eosin Y/Pd(II) dual catalytic approach for regio- and chemoselective C(sp2)-H monoarylation of N-H unprotected 2-phenyl quinazolinone derivatives under green light irradiation with no necessity for any base/additive/external oxidant. The free N-H moiety was post-modified for quinazolinone scaffold diversification and C-H annulation.

An HFIP-assisted, cobalt-catalyzed three-component electrophilic C-H amination/cyclization/directing group removal cascade to naphtho[1,2-d]imidazoles.

A concise and efficient method has been developed herein for the synthesis of valuable naphtho[1,2-d]imidazole derivatives. It involves an earth-abundant cobalt-catalyzed electrophilic ortho C-H amination/cyclization/directing group removal cascade with O-benzoloxyamines using paraformaldehyde as a one carbon synthon. Picolinamide has been utilized as a traceless directing group. A boosting effect of HFIP is found in the whole process. The reaction conditions are very simple and allow easy handling, making this methodology valuable and appealing.

Palladium-Catalyzed Cross-Electrophile Coupling between Aryl Diazonium Salt and Aryl Iodide/Diaryliodonium Salt in H2O-EtOH.

We report herein a mild highly chemoselective palladium-catalyzed cross-electrophile coupling between readily accessible aromatic diazonium salt and aryl iodide or diaryliodonium salt in water-ethanol (2:1) medium. Mechanistic studies revealed that ethanol is crucial to generate an active Pd(0) catalyst, and the counterion of the diazonium salt renders a cationic Pd(II) species that facilitates subsequent oxidative addition to aryl iodide/diaryliodonium salt. Silver(I) salt was crucial to retain the catalytic activity of palladium, removing the iodide ion as a precipitate.

Protocol for chemo- and regioselective C(sp3)-H activation using a heterogeneous copper powder-catalyzed reaction.

Here, we present a protocol for the synthesis of dibenzo[c,e]oxepin-5(7H)-ones starting from 2'-alkyl-[1,1'-biphenyl]-2-carboxylic acids. This technique uses two copper(0)-catalyzed benzylic C(sp3)-H activation strategies taking either di-tertbutyl peroxide or gaseous oxygen as an oxidant. We detail a photocatalytic thermal approach for copper powder-catalyzed reaction with oxygen. We also describe a procedure for catalyst recycling in both the strategies. The product has been successfully synthesized both in mmol and gram scale. For complete details on the use and execution of this protocol, please refer to Nandi et al. (2022).

A directing group switch in copper-catalyzed electrophilic C-H amination/migratory annulation cascade: divergent access to benzimidazolone/benzimidazole.

We present here a copper-catalyzed electrophilic ortho C-H amination of protected naphthylamines with N-(benzoyloxy)amines, cyclization with the pendant amide, and carbon to nitrogen 1,2-directing group migration cascade to access N,N-disubstituted 2-benzimidazolinones. Remarkably, this highly atom-economic tandem reaction proceeds through a C-H and C-C bond cleavage and three new C-N bond formations in a single operation. Intriguingly, the reaction cascade was altered by the subtle tuning of the directing group from picolinamide to thiopicolinamide furnishing 2-heteroaryl-imidazoles via the extrusion of hydrogen sulfide. This strategy provided a series of benzimidazolones and benzimidazoles in moderate to high yields with low catalyst loading (66 substrates with yields up to 99%). From the control experiments, it was observed that after the C-H amination an incipient tetrahedral oxyanion or thiolate intermediate is formed via an intramolecular attack of the primary amine to the amide/thioamide carbonyl. It undergoes either a 1,2-pyridyl shift with the retention of the carbonyl moiety or H2S elimination for scaffold diversification. Remarkably, inspite of a positive influence of copper in the reaction outcome, from our preliminary investigations, the benzimidazolone product was obtained in good to moderate yields in two steps under metal-free conditions. The N-pyridyl moiety of the benzimidazolone was removed for further manipulation of the free NH group.

Chemo- and regioselective benzylic C(sp3)-H oxidation bridging the gap between hetero- and homogeneous copper catalysis.

Selective C‒H functionalization in a pool of proximal C‒H bonds, predictably altering their innate reactivity is a daunting challenge. We disclose here, an expedient synthesis of privileged seven-membered lactones, dibenzo[c,e]oxepin-5(7H)-one through a highly chemoselective benzylic C(sp3)‒H activation. Remarkably, the formation of widely explored six-membered lactone via C(sp2)‒H activation is suppressed under the present conditions. The reaction proceeds smoothly on use of inexpensive metallic copper catalyst and di-tert-butyl peroxide (DTBP). Owing to the hazards of stoichiometric DTBP, further, we have developed a sustainable metallic copper/rose bengal dual catalytic system coupled with molecular oxygen replacing DTBP. A 1,5-aryl migration through Smiles rearrangement was realized from the corresponding diaryl ether substrates instead of expected eight-membered lactones. The present methodology is scalable, applied to the total synthesis of cytotoxic and neuroprotective natural product alterlactone. The catalyst is recyclable and the reaction can be performed in a copper bottle without any added catalyst.

Aryldiazonium Salts and DABSO: A Versatile Combination for Three-Component Sulfonylative Cross-Coupling Reactions.

A combination of aryldiazonium salts and DABSO provides a unique opportunity for sulfonylative multicomponent cross-coupling reactions. Here, a copper-catalyzed three-component cross-coupling of aryldiazonium salts, DABSO with arylboronic acids to obtain medicinally relevant unsymmetrical diarylsulfones is disclosed. Interestingly, a catalyst-free approach for the synthesis of arylvinylsulfones from the corresponding vinyl boronic acids or vinyl halides is explored under basic condition. Tethered aryldiazonium salts provided the corresponding annulated alkylvinylsulfones via alkene difunctionalization under the same transition metal-free condition. Mechanistically, these multicomponent reactions proceed through a single electron pathway by the formation of arylsulfonyl radical as a key intermediate.

The emergence of the C-H functionalization strategy in medicinal chemistry and drug discovery.

Owing to the market competitiveness and urgent societal need, an optimum speed of drug discovery is an important criterion for successful implementation. Despite the rapid ascent of artificial intelligence and computational and bioanalytical techniques to accelerate drug discovery in big pharma, organic synthesis of privileged scaffolds predicted in silico for in vitro and in vivo studies is still considered as the rate-limiting step. C-H activation is the latest technology added into an organic chemist's toolbox for the rapid construction and late-stage modification of functional molecules to achieve the desired chemical and physical properties. Particularly, elimination of prefunctionalization steps, exceptional functional group tolerance, complexity-to-diversity oriented synthesis, and late-stage functionalization of privileged medicinal scaffolds expand the chemical space. It has immense potential for the rapid synthesis of a library of molecules, structural modification to achieve the required pharmacological properties such as absorption, distribution, metabolism, excretion, toxicology (ADMET) and attachment of chemical reporters for proteome profiling, metabolite synthesis, etc. for preclinical studies. Although heterocycle synthesis, late-stage drug modification, 18F labelling, methylation, etc. via C-H functionalization have been reviewed from the synthetic standpoint, a general overview of these protocols from medicinal and drug discovery aspects has not been reviewed. In this feature article, we will discuss the recent trends of C-H activation methodologies such as synthesis of medicinal scaffolds through C-H activation/annulation cascade; C-H arylation for sp2-sp2 and sp2-sp3 cross-coupling; C-H borylation/silylation to introduce a functional linchpin for further manipulation; C-H amination for N-heterocycles and hydrogen bond acceptors; C-H fluorination/fluoroalkylation to tune polarity and lipophilicity; C-H methylation: methyl magic in drug discovery; peptide modification and macrocyclization for therapeutics and biologics; fluorescent labelling and radiolabelling for bioimaging; bioconjugation for chemical biology studies; drug-metabolite synthesis for biodistribution and excretion studies; late-stage diversification of drug-molecules to increase efficacy and safety; cutting-edge DNA encoded library synthesis and improved synthesis of drug molecules via C-H activation in medicinal chemistry and drug discovery.

Visible-Light- and PPh3-Mediated Direct C-N Coupling of Nitroarenes and Boronic Acids at Ambient Temperature.

We present here a metal-free, visible-light- and triphenylphosphine-mediated intermolecular, reductive amination between nitroarenes and boronic acids at ambient temperature without any photocatalyst. Mechanistically, a slow reduction of nitroarenes to a nitroso and, finally, a nitrene intermediate occurs that leads to the amination product with concomitant 1,2-aryl/-alkyl migration from a boronate complex. A wide range of nitroarenes underwent C-N coupling with aryl-/alkylboronic acids providing high yields.

Overcoming the Deallylation Problem: Palladium(II)-Catalyzed Chemo-, Regio-, and Stereoselective Allylic Oxidation of Aryl Allyl Ether, Amine, and Amino Acids.

We report herein a Pd(II)/bis-sulfoxide-catalyzed intramolecular allylic C-H acetoxylation of aryl allyl ether, amine, and amino acids with the retention of a labile allyl moiety. Mechanistically, the reaction proceeds through a distinct double-bond isomerization from the allylic to the vinylic position followed by intramolecular carboxypalladation and the ß-hydride elimination pathway. For the first time, C-H oxidation of N-allyl-protected amino acids to furnish five-membered heterocycles through 1,3-syn-addition is established with excellent diastereoselectivity.

Carboxylation of Aryl Triflates with CO2 Merging Palladium and Visible-Light-Photoredox Catalysts.

We report herein a visible-light-promoted, highly practical carboxylation of readily accessible aryl triflates at ambient temperature and a balloon pressure of CO2 by the combined use of palladium and photoredox Ir(III) catalysts. Strikingly, the stoichiometric metallic reductant is replaced by a nonmetallic amine reductant providing an environmentally benign carboxylation process. In addition, one-pot synthesis of a carboxylic acid directly from phenol and modification of estrone and concise synthesis of pharmaceutical drugs adapalene and bexarotene have been accomplished via late-stage carboxylation reaction. Furthermore, a parallel decarboxylation-carboxylation reaction has been demonstrated in an H-type closed vessel that is an interesting concept for the strategic sector. Spectroscopic and spectroelectrochemical studies indicated electron transfer from the Ir(III)/DIPEA combination to generate aryl carboxylate and Pd(0) for catalytic turnover.

Copper-Catalyzed Electrophilic Ortho C(sp2)-H Amination of Aryl Amines: Dramatic Reactivity of Bicyclic System.

A practical copper-catalyzed, 2-picolinamide-directed ortho C-H amination of anilines with benzoyl-protected hydroxylamines has been disclosed that proceeds smoothly without any external stoichiometric oxidant or additives. Remarkably, besides anilines, bicyclic naphthyl or heterocyclic amines furnished amination products with five- and six-membered cyclic and acyclic amines at the ortho position selectively. This electrophilic C-H amination also proceeds smoothly in water under slightly modified reaction conditions.

Exceedingly Fast, Direct Access to Dihydroisoquinolino[1,2- b]quinazolinones through a Ruthenium(II)-Catalyzed Redox-Neutral C-H Allylation/Hydroamination Cascade.

A ruthenium(II)-catalyzed redox-neutral synthesis of dihydroisoquinoline-fused quinazolinone derivatives has been accomplished through the merger of C-H activation and alkene difunctionalization using quinazolinone as an inherent directing group. This intermolecular reaction proceeds rapidly and is complete within 10 min, providing the annulation product in high yields without any stoichiometric metal oxidant. Mechanistically, this tandem reaction proceeds through directed ortho C-H allylation followed by hydroamination with the proximal -CONH group, to furnish 6-methyl-5,6-dihydro-8 H-isoquinolino[1,2- b]quinazolin-8-ones in a single operation. The carboxylic acid additive has a dual role in the formation of active catalyst and protodemetalation.

Atom-economical selenation of electron-rich arenes and phosphonates with molecular oxygen at room temperature.

Organoselenium and selenophosphorus compounds are ubiquitously found in biologically active compounds, agrochemicals, functionalized materials etc. Although selenium is a micronutrient and an essential trace element, its contamination/consumption in higher concentrations is extremely dangerous. However, most of the previous selenation reactions generate toxic selenium waste as a by-product. Thus development of green synthetic protocols of these compounds is in high demand. We report herein a mild base-catalyzed cross-dehydrogenative coupling (CDC) between electron-rich arenes and phenylselenol to afford 3-selenylindole or selenylated phenols under air at room temperature. Interestingly, in the presence of a base and oxygen, the phenylselenol is converted into the diphenyldiselenide and provides almost quantitative yield. Similarly, a mild synthesis of selenophosphates was also achieved from the corresponding diorganyldiselenide or phenylselenols and nucleophilic phosphonates in a "dump and stir" manner under an oxygen balloon without a base or catalyst. From the preliminary mechanistic studies for selenation of indoles and phosphonates with TEMPO and EPR of the reaction mixture, it was evident that the reaction proceeds through the anionic pathway, which is in sharp contrast to the previous literature. The present reactions proceed smoothly under the mild conditions, furnishing high to almost quantitative yields in several cases. The reaction is easily scaled up to gram scale and has been demonstrated for the synthesis of an anti-HIV zidovudine (AZT) analogue.

Sterically Controlled Ru(II)-Catalyzed Divergent Synthesis of 2-Methylindoles and Indolines through a C-H Allylation/Cyclization Cascade.

A ruthenium-catalyzed synthesis of 2-methylindole was accomplished via a C-H allylation/oxidative cyclization cascade. Strategically, ß-hydride elimination from the σ-alkyl-Ru intermediate has been suppressed by steric hindrance from a remote position. Hence, 2-methylindolines from the corresponding ortho-substituted anilines were achieved via protodemetalation in lieu of ß-hydride elimination under a modified reaction condition. This mild intermolecular annulation cascade proceeds smoothly by a redox-neutral ruthenium catalyst without stoichiometric metal oxidants, such as silver(I) or copper(II) salts, providing excellent functional group tolerance.

Ligand-Promoted γ-C(sp3)-H Arylation and Unsymmetrical Diarylation to Access Unnatural Amino Acid Derivatives.

A palladium(II)-catalyzed arylation of a γ-C(sp3)-H bond of protected amino acid is explored. The monoarylation is promoted by the commercially available, inexpensive phenanthroline ligand, and toxic silver salt is replaced by earth-abundant Mn(III)acetate. Subsequently, a hitherto unknown unsymmetrical diarylation at the γ-position is accomplished under the modified reaction conditions. Ligands have a prominent influence in both mono- and unsymmetrical diarylations.

Palladium-Catalyzed Ortho C-H Arylation of Aniline Carbamates with Diazonium Salts under Mild Conditions: Expedient Synthesis of Carbazole Alkaloids.

Despite the significant progress, C-H arylation with aryldiazonium salts is a major challenge because of the faster rate of oxidative addition compared to the C-H insertion, leading to a deleterious homocoupling product. Recently, this limitation has been overcome by merging a photoredox catalyst with transition-metal catalysts which proceeds through a distinct single electron-transfer mechanism. However, we have observed that the photoredox catalyst is not necessary for the C-H arylation of aniline rather chemical reactivity can be controlled by tuning the electronic nature of the substrate. We report, herein, a palladium-catalyzed C-H arylation of aniline carbamates with aryldiazonium salts under external oxidant, acid, base free conditions at room temperature. Mechanistic studies suggest that the present reaction proceeds through a directed electrophilic metalation pathway which is the slowest step. However, the oxidative addition may take place through either ionic (2e-) or radical (1e-) pathway to generate hypervalent Pd(IV) or Pd(III) intermediate, respectively. A facile reductive elimination from the hypervalent palladium complex furnishes the C-H arylation product under mild conditions. The carbamate directing group is easily removed from the product to obtain the corresponding ortho-arylated aniline, which is a precursor for plethora of carbazole alkaloids and other biologically active molecules. The reaction is scaled-up to gram scale to furnish the desired product in comparable yields. Finally, we have applied this C-H arylation methodology for the synthesis of series of carbazole alkaloids such as clausine V, clauszoline K, O-methoxymahanine, and O-methylmurrayamine-D.

Dual visible-light photoredox and palladium(ii) catalysis for dehydrogenative C2-acylation of indoles at room temperature.

A highly regioselective direct C2-acylation of N-pyrimidine protected indoles with aldehydes is reported at room temperature through the merger of visible light photoredox and palladium(ii) catalysis. Late-stage acylation of tryptophan, selective mono-acylation of carbazole and the syntheses of tubulin inhibitors D-64131 and D-68144 are also demonstrated.