A photochemical dehydrogenative strategy for aniline synthesis.

Chemical reactions that reliably join two molecular fragments together (cross-couplings) are essential to the discovery and manufacture of pharmaceuticals and agrochemicals1,2. The introduction of amines onto functionalized aromatics at specific and pre-determined positions (ortho versus meta versus para) is currently achievable only in transition-metal-catalysed processes and requires halogen- or boron-containing substrates3-6. The introduction of these groups around the aromatic unit is dictated by the intrinsic reactivity profile of the method (electrophilic halogenation or C-H borylation) so selective targeting of all positions is often not possible. Here we report a non-canonical cross-coupling approach for the construction of anilines, exploiting saturated cyclohexanones as aryl electrophile surrogates. Condensation between amines and carbonyls, a process that frequently occurs in nature and is often used by (bio-)organic chemists7, enables a predetermined and site-selective carbon-nitrogen (C-N) bond formation, while a photoredox- and cobalt-based catalytic system progressively desaturates the cyclohexene ring en route to the aniline. Given that functionalized cyclohexanones are readily accessible with complete regiocontrol using the well established carbonyl reactivity, this approach bypasses some of the frequent selectivity issues of aromatic chemistry. We demonstrate the utility of this C-N coupling protocol by preparing commercial medicines and by the late-stage amination-aromatization of natural products, steroids and terpene feedstocks.

Iodine-Catalyzed Diazenylation with Arylhydrazine Hydrochlorides in Air.

A mild approach to diazenylation of active methylene compounds and N-heterocyclic compounds with arylhydrazine hydrochlorides in the presence of iodine under basic aerobic conditions was developed. The reaction could be executed either under heating or in the presence of blue LED light, though the latter condition was found to be relatively efficient. Presumably, the aryldiazene produced by oxidation of arylhydrazine hydrochloride acts as a nitrogen scavenger of the radical intermediate generated from the active methylene compound in the presence of iodine to produce the diazo compounds. The scope and limitations of the protocol are presented.

Synthesis of S-(-)-5,6-Dihydrocanthin-4-ones via a Triple Cooperative Catalysis-Mediated Domino Reaction.

An enantioselective synthesis of S-(-)-5,6-dihydrocanthin-4-ones via a triple cooperative catalysis-mediated domino reaction having a broad substrate scope is reported. The reaction between substituted 1-formyl-9H-ß-carbolines and terminal alkynes in the presence of catalytic amounts of Jorgensen-Hayashi catalyst, copper iodide, and Hunig base proceeded via a multicascade route, affording the title compounds in good yields and excellent ees with interesting mechanistic features. These compounds were assessed for in vitro antiplasmodial activity against P. falciparum strains. Additionally, 5,6-dihydrocanthin-4-ones are demonstrated to be a versatile precursor to different fused ß-carboline derivatives via simple synthetic transformations.

Regioselective Metal-Free Decarboxylative Multicomponent Coupling of α-Amino Acids, Aldehydes and Isonitriles Leading to N-Substituted Azacyclic-2-carboxamides with Antithrombotic Activity.

An atom-economical regioselective synthesis of N-substituted prolinamides or N-substituted piperidine-2-carboxamides via a metal-free decarboxylative multicomponent coupling between l-proline or pipecolic acid, aldehydes, and isonitriles is described. The cascade event involves sequential imine formation, decarboxylation, isonitrile insertion, and hydrolysis to afford the product in one-pot. Two of the prolinamides were found to display appreciable antithrombotic activity via inhibition of platelet aggregation.

Synthesis of 3,4,5-Trisubstituted Isoxazoles from Morita-Baylis-Hillman Acetates by an NaNO2 /I2 -Mediated Domino Reaction.

An efficient NaNO2 /I2 -mediated one-pot transformation of Morita-Baylis-Hillman (MBH) acetates into alkyl 3-nitro-5-(aryl/alkyl)isoxazole-4-carboxylates is described. In a cascade event, initial Michael addition of NaNO2 to the MBH acetate furnishes the allylnitro intermediate which undergoes I2 -catalyzed oxidative α-CH nitration of the nitromethyl subunit followed by [3+2] cycloaddition to afford the title compounds. Structural elaborations of these highly substituted isoxazoles by SN Ar reactions and hydrogenolysis allows access to useful products.

Efficient and chemoselective imine synthesis catalyzed by a well-defined PN3-manganese(II) pincer system.

The highly efficient reductive amination of aldehydes with ammonia (NH3) and hydrogen (H2) to form secondary imines is described, as well as the dehydrogenative homocoupling of benzyl amines. Using an air-stable, well-defined PN3-manganese(II) pincer complex as a catalyst precursor, various aldehydes are easily converted directly into secondary imines using NH3 as a nitrogen source under H2 in a one-pot reaction. Importantly, the same catalyst facilitates the dehydrogenative homocoupling of various benzylamines, exclusively forming imine products. These reactions are conducted under very mild conditions, without the addition of any additives, yielding excellent selectivities and high yields of secondary imines in a green manner by minimizing wastes.

Homogeneous Catalysis in N-formylation/N-methylation Utilizing Carbon Dioxide as the C1 Source.

The growing emphasis on sustainable chemistry has driven research into utilizing carbon dioxide (CO2) as a nontoxic, abundant, and cost-effective C1 building block. CO2 offers a promising avenue for direct conversion into valuable chemicals ranging from fuels to pharmaceuticals. This review focuses on the utilization of CO2 for reductive N-formylation/N-methylation reactions of various amines, providing advantages over conventional methods involving toxic CO and other methylating reagents. The approach employs readily available reductants such as silane, borane reagents, and hydrogen (H2). The discussion encompasses recent developments in transition metal and organocatalyst systems for these reactions, highlighting mechanistic interpretations and factors influencing product selectivity.

Decarboxylative/Oxidative Amidation of Aryl α-Ketocarboxylic Acids with Nitroarenes and Nitroso Compounds in Aqueous Medium.

The decarboxylative/oxidative amidation of aryl α-ketocarboxylic acids with 5-aryl-3-nitroisoxazole-4-carboxylates and substituted dinitrobenzenes under oxidative aqueous conditions to afford N-aryl amides is described. The reaction is suggested to proceed via a radical pathway in which a benzoyl nitroxyl radical, the key intermediate formed from reaction between nitroarene and benzoyl radical from glyoxalic acid, couples with hydroxyl radical from water to produce amide. Mechanistic insight allowed the scope of the strategy to be expanded to the synthesis of amides via reaction between aryl α-ketocarboxylic acids and nitroso compounds.

Correction: A dual photoredox-nickel strategy for remote functionalization via iminyl radicals: radical ring-opening-arylation, -vinylation and -alkylation cascades.

[This corrects the article DOI: 10.1039/C9SC02616A.].

ß-carboline-based turn-on fluorescence chemosensor for quantitative detection of fluoride at PPB level.

A novel ß-carboline-based chemosensor, having an acidic NH proton that leads to fluoride-induced deprotonation involving a vivid color change from colorless to yellow is described. The absorption spectrum of the chemosensor in acetonitrile has a peak at 375 nm, which changes to 428 nm with the gradual addition of only fluoride in the solution with a clear isosbestic points at 357 nm and 392 nm. More interestingly, the chemosensor gives a turn-on type of fluorescence at 554 nm in the presence of fluoride. Further it was found that the sensor is highly selective towards fluoride over other anions including chloride, bromide, iodide, nitrate, borate, perchlorate and can quantitatively detect fluoride at ppb level with a limit of detection of 0.02 mg/ L or 20 ppb. The chemosensor was successfully demonstrated to assess the fluoride concentration in the tap water.

A dual photoredox-nickel strategy for remote functionalization via iminyl radicals: radical ring-opening-arylation, -vinylation and -alkylation cascades.

A divergent strategy for the remote arylation, vinylation and alkylation of nitriles is described. These processes proceed through the photoredox generation of a cyclic iminyl radical and its following ring-opening reaction. The distal nitrile radical is then engaged in nickel-based catalytic cycles to form C-C bonds with aryl bromides, alkynes and alkyl bromides.

Metal-Free Oxidative Nitration of α-Carbon of Carbonyls Leads to One-Pot Synthesis of Thiohydroximic Acids from Acetophenones.

A metal-free nitration of the α-C-H to carbonyl in propiophenones was achieved with I2/NaNO2 in the presence of an oxidant in dimethyl sulfoxide (DMSO) as the medium. Conversely under similar conditions, reaction of acetophenones produced thiohydroximic acids via a radical-based cascade event which involves oxidative nitration of the α-carbon to a carbonyl followed by Michael addition of the thiomethyl group from DMSO and subsequent rearrangement. Besides DMSO, the scope of the reaction encompasses other symmetrical and unsymmetrical dialkylsulfoxides.

Intramolecular Csp2-Csp2 Friedel-Crafts Arylation: Substrate- and Condition-Controlled Divergent Synthesis of Fused-ß-carbolines.

A triple cooperative catalysis-mediated multicomponent reaction between 1-formyl-N-substituted-ß-carbolines, a terminal alkyne, and a secondary amine allows access to unprecedented polycyclic ß-carbolines via sequential A3-coupling and an intramolecular Csp2-Csp2 Friedel-Crafts arylation reaction. The reaction is successful in a dry inert atmosphere only with substrates bearing a methoxy-substituted benzyl group at the indole nitrogen. Conversely, treating 3-aminoindolizino[8,7-b]indoles (obtained after A3-coupling) with acid in the presence of H2O in air offers a general route to natural-alkaloid-like products.

Synthesis of ß-Carboline-Based N-Heterocyclic Carbenes and Their Antiproliferative and Antimetastatic Activities against Human Breast Cancer Cells.

A series of novel ß-carboline-based N-heterocyclic carbenes was prepared via Mannich reaction between methyl 1-(dimethoxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylate, formaldehyde, and primary amines. All compounds were evaluated for their antiproliferative activity using human breast cancer and lung cancer cell lines. Three compounds, 3c, 3j, and 3h, were discovered to display IC50 less than 10 µM against human breast cancer MDA-MB-231 cells at 24 h of treatment. Pharmacologically these compounds lead to G2/M phase cell cycle arrest and induction of cellular apoptosis by triggering intrinsic apoptotic pathway through depolarization of mitochondrial membrane potential and activation of caspases. At lower concentrations, these compounds also showed antimigratory and antiinvasive effects against highly metastatic human breast cancer MDA-MB-231 cells via aberration of MAP-kinase signaling and by the inhibition of matrix metalloproteinases. However, these analogues lack in vivo effect in mouse model which may be attributed to their strong affinity to HSA that was investigated spectroscopically with compound 3h.