Microwave-assisted atom transfer radical addition of polychlorinated compounds to olefins without addition of metal catalysts

A new operationally simple and robust protocol for the metal-free atom transfer radical reaction (ATRA) has been developed. Polychlorinated compounds were effectively reacted with unactivated terminal olefins to generate 1,3-dichlorinated adducts under microwave irradiation in the presence of silicon carbide (SiC) as a heating element. The present microwave-assisted ATRA proceeds under essentially neutral conditions; thus, polar functionalities are well tolerated. In addition, an oxygen or a nitrogen unit was introduced to the internal side of the carbon chain via nucleophilic cyclization of the 1,3-dichlorinated adducts, and single-step formation of the six-membered carbocycle was realized through cyclization of the intermediate radical. The present methodology provides an expeditious way to prepare synthetically useful molecules from simple and unactivated terminal olefins.     

Platinum complex catalyzed reaction of tributyltin cyanide with alkynes

In the presence of a catalytic amount (5 mol%) of a platinum complex, tributyltin cyanide (1) reacts with dimethyl- (2a) or diethyl acetylenedicarboxylate (2b) to afford cyanostannylation adducts (3a, b) in excellent yields. The reaction proceeds highly selectively affording only a (Z)-isomer. The compounds 3a, b are novel products which possess synthetically useful cyano, alkenylstannyl and alkoxycarbonyl functionalities in the same molecule. Two alkoxycarbonyl functionalities may be indispensable on each alkyne carbon to accomplish the cyanostannylation reaction. Reaction with terminal alkynes gave the stannylated product (6).     

Iron‐Catalyzed Radical Cleavage/C−C Bond Formation of Acetal‐Derived Alkylsilyl Peroxides

A novel radical‐based approach for the iron‐catalyzed selective cleavage of acetal‐derived alkylsilyl peroxides, followed by the formation of a carbon–carbon bond is reported. The reaction proceeds under mild reaction conditions and exhibits a broad substrate scope with respect to the acetal moiety and the carbon electrophile. Mechanistic studies suggest that the present reaction proceeds through a free‐radical process involving carbon radicals generated by the homolytic cleavage of a carbon–carbon bond within the acetal moiety. A synthetic application of this method to sugar‐derived alkylsilyl peroxides is also described.     

Catalytic Enantioselective and Diastereoselective Allylic Alkylation with Fluoroenolates: Efficient Access to C3‐Fluorinated and All‐Carbon Quaternary Oxindoles

Synthetically versatile 3,3‐disubstituted fluorooxindoles exhibiting vicinal chirality centers were obtained in high yields and with excellent enantio‐, diastereo‐, and regioselectivity through catalytic asymmetric fluoroenolate alkylation with allylic acetates. The reaction proceeds under mild conditions and can be scaled up without compromising the asymmetric induction. The unique synthetic usefulness of the products is highlighted by the incorporation of additional functionalities and the formation of 3‐fluorinated oxindoles exhibiting an array of four adjacent centers of chirality. A new C−F bond functionalization path that provides unprecedented possibilities for the stereoselective generation of a chiral quaternary carbon center in the alkaloid scaffold is introduced.     

Carbon-alkylation,arylation and vinylation of nitronate ions with organothallium(III) compounds: electron-transfer activation of the TlC bond

The reaction of alkyl, aryl and vinylthallium(III)_diacetates with nitronate ions gives moderate to good yields of the carboncarbon bonded products. The reaction of the alkyl and arylthallium(III) analogs proceeds through radical intermediates which are generated by electron-transfer activation of the thalliumcarbon bond.     

Amide Synthesis by Nickel/Photoredox-Catalyzed Direct Carbamoylation of (Hetero)Aryl Bromides

Herein, we report a one-electron strategy for catalytic amide synthesis that enables the direct carbamoylation of (hetero)aryl bromides. This radical cross-coupling approach, which is based on the combination of nickel and photoredox catalysis, proceeds at ambient temperature and uses readily available dihydropyridines as precursors of carbamoyl radicals. The method's mild reaction conditions make it tolerant of sensitive-functional-group-containing substrates and allow the installation of an amide scaffold within biologically relevant heterocycles. In addition, we installed amide functionalities bearing electron-poor and sterically hindered amine moieties, which would be difficult to prepare with classical dehydrative condensation methods.     

The first conversion of primary alkyl halides to nitroalkanes under aqueous medium

Primary nitroalkanes and alpha,omega-dinitroalkanes can be easily obtained in aqueous medium by reaction of the corresponding halo derivatives with silver nitrite. The procedure works well with both alkyl bomide and alkyl iodide and proceeds in satisfactory to good yields even in the presence of other functionalities, minimizing the formation of the undesired alkyl nitrites.     

Sulfanyl radical addition–cyclization and its synthetic application

This review summarizes a new efficient carbon–carbon bond-forming reaction based on sulfanyl radical addition–cyclization, which proceeds by the formation of a carbon-centered radical species generated by the addition of a sulfanyl radical to a multiple bond and then intramolecular addition of the resulting carbon-centered radical to a multiple bond. The synthetic potentiality was demonstrated by the syntheses of anantine, oxo-parabenzlactone, cispentacin, vitamin D, and α-kainic acid.     

Metal-Free Electrochemical Reduction of Carbon Dioxide Mediated by Cyclic(Alkyl)(Amino) Carbenes

Carbenes are known to activate carbon dioxide to form zwitterionic adducts. Their inherent metal-free redox activity remains understudied. Herein, we demonstrate that zwitterionic adducts of carbon dioxide formed with cyclic(alkyl)(amino) carbenes are not only redox active, but they can mediate the stoichiometric reductive disproportionation of carbon dioxide to carbon monoxide and carbonate. Infrared spectroelectrochemical experiments show that the reaction proceeds through an intermediate radical anion formed by one-electron reduction, ultimately generating a ketene product and carbonate in the absence of additional organic or inorganic reagents.     

Copper‐Catalyzed Intermolecular Carboetherification of Unactivated Alkenes by Alkyl Nitriles and Alcohols

A three‐component carboetherification of unactivated alkenes has been developed allowing the rapid building of complexity from simple starting materials. A wide range of α‐substituted styrenes underwent smooth reactions with unactivated alkyl nitriles and alcohols to afford γ‐alkoxy alkyl nitriles with concomitant generation of a quaternary carbon center. A radical clock experiment provided clear‐cut evidence that the reaction proceeds through a tertiary alkyl radical intermediate.     

Amide Synthesis by Nickel/Photoredox‐Catalyzed Direct Carbamoylation of (Hetero)Aryl Bromides

Herein, we report a one‐electron strategy for catalytic amide synthesis that enables the direct carbamoylation of (hetero)aryl bromides. This radical cross‐coupling approach, which is based on the combination of nickel and photoredox catalysis, proceeds at ambient temperature and uses readily available dihydropyridines as precursors of carbamoyl radicals. The method's mild reaction conditions make it tolerant of sensitive‐functional‐group‐containing substrates and allow the installation of an amide scaffold within biologically relevant heterocycles. In addition, we installed amide functionalities bearing electron‐poor and sterically hindered amine moieties, which would be difficult to prepare with classical dehydrative condensation methods.     

The radical mechanism of cobalt(II) porphyrin-catalyzed olefin aziridination and the importance of cooperative H-bonding

The mechanism of cobalt(II) porphyrin-mediated aziridination of styrene with PhSO(2)N(3) was studied by means of DFT calculations. The computations clearly indicate the involvement of a cobalt 'nitrene radical' intermediate in the Co(II)(por)-catalyzed alkene aziridination. The addition of styrene to this species proceeds in a stepwise fashion via radical addition of the 'nitrene radical'C to the C=C double bond of styrene to form a γ-alkyl radical intermediate D. The thus formed tri-radical species D easily collapses in an almost barrierless ring closure reaction (TS3) to form the aziridine, thereby regenerating the cobalt(II) porphyrin catalyst. The radical addition of the 'nitrene radical'C to the olefin (TS2) proceeds with a comparable barrier as its formation (TS1), thus providing a good explanation for the first order kinetics in both substrates and the catalyst observed experimentally. Formation of C is clearly accelerated by stabilization of C and TS1 via hydrogen bonding between the S=O and N-H units. The computed radical-type mechanism agrees well with all available mechanistic and kinetic information. The computed free energy profile readily explains the superior performance of the Co(II)(porAmide) system with H-bond donor functionalities over the non-functionalized Co(TPP).     

Intramolecular radical additions to pyridines

Intramolecular 6-exolendo-trig and 5-exo-trig cyclisations of aryl radical intermediates to the alpha-, beta- and gamma-carbons of pyridine have been shown to be facile processes at neutral pH. The tether conjoining the radical donor to the pyridine plays an important role in determining the outcome of the reaction. When a Z-alkene is used as a tether, ortho-cyclisation proceeds in good yield. A more complex course is followed when a saturated two carbon tether is employed, leading to products derived from hydrogen atom abstraction, ipso-cyclisation and ortho-cyclisation pathways. All attempts to effect 5-exolendo-trig cyclisations failed. Tributyltin hydride, tris(trimethylsilyl)silane, tris(trimethylsilyl)germane and, in part, samarium(II) iodide can each be employed as mediators of the reaction.     

Photocaging of Carboxylic Acids: A Modular Approach

Photocaged compounds are important tools for studying and regulating multiple processes, including biological functions. Reported herein is the use of the Passerini multicomponent reaction for modular preparation of photocaged carboxylic acids. The reaction is compatible with several functionalities and proceeds smoothly both in water and dichloromethane. The choice of aldehyde determines the wavelength used for deprotection and enables formation of orthogonally protected products. The isocyanide component can be used for introduction of reactive tags and photosensitizers, as well as for immobilization on a solid support.     

Aryl Triflates in On-Surface Chemistry

The reactivity of aryl triflates in on-surface C−C coupling is reported. It is shown that the triflate group in aryl triflates enables regioselective homo coupling with preceding or concomitant hydrodetriflation on Cu(111). Three different symmetrical π-systems with two and three triflate functionalities were used as monomers leading to oligomeric conjugated π-systems. The cascade, comprising different intermediates at different reaction temperatures as observed for one of the molecules, proceeds via initial removal of the trifluoromethyl sulfonyl group to give an aryloxy radical which in turn is deoxygenated to the corresponding aryl radical. Thermodynamically driven regioselective 1,2-hydrogen atom transfer leads to a translocated aryl radical which in turn undergoes coupling. For a sterically more hindered bistriflate, where one ortho position was blocked, dehydrogenative coupling occurred at remote position with good regioselectivity. Starting materials, intermediates as well as products were analyzed by scanning tunneling microscopy. Structures and suggested mechanism were further supported by DFT calculations.     

Structure and reactivity of benzoylnitrene radical anion in the gas phase

The open-shell benzoylnitrene radical anion, readily generated by electron ionization of benzoylazide, undergoes unique chemical reactivity with radical reagents and Lewis acids in the gas phase. Reaction with nitric oxide, NO, proceeds by loss of N2 and formation of benzoate ion. This novel reaction is also observed to occur with phenylnitrene anion, forming phenoxide. Similar reactivity was observed in the reaction between benzoylnitrene radical anion and NO2, forming benzoate ion and nitrous oxide. Electronic structure calculations indicate that the reaction has a high-energy barrier that is overcome by the energy released by bond formation. Benzoylnitrene radical anion also transfers oxygen anion to NO and NO2 as well as to CS2 and SO2. In contrast, phenylnitrene anion reacts with carbon disulfide by C+ or CS+ abstraction, forming S- or S2-. Electronic structure calculations indicate that benzoylnitrene in the ground state resembles a slightly polarized benzoate anion, but with a free radical localized on the nitrogen.     

Expanding Radical SAM Chemistry by Using Radical Addition Reactions and SAM Analogues

Radical S‐adenosyl‐l ‐methionine (SAM) enzymes utilize a [4Fe‐4S] cluster to bind SAM and reductively cleave its carbon–sulfur bond to produce a highly reactive 5′‐deoxyadenosyl (dAdo) radical. In almost all cases, the dAdo radical abstracts a hydrogen atom from the substrates or from enzymes, thereby initiating a highly diverse array of reactions. Herein, we report a change of the dAdo radical‐based chemistry from hydrogen abstraction to radical addition in the reaction of the radical SAM enzyme NosL. This change was achieved by using a substrate analogue containing an olefin moiety. We also showed that two SAM analogues containing different nucleoside functionalities initiate the radical‐based reactions with high efficiencies. The radical adduct with the olefin produced in the reaction was found to undergo two divergent reactions, and the mechanistic insights into this process were investigated in detail. Our study demonstrates a promising strategy in expanding radical SAM chemistry, providing an effective way to access nucleoside‐containing compounds by using radical SAM‐dependent reactions.     

Denitrohydrogenation of aliphatic nitro compounds and a new use of aliphatic nitro compounds as radical precursors

Aliphatic nitro groups are replaced by hydrogen on treatment with tributyltin hydride which proceeds via free radical chain processes. As the nitro group is selectively denitrated and other reducible groups are not affected with tributyltin hydride, this reaction can be used as a method for removing the nitro group from polyfunctional compounds. The radical intermediates generated via denitration can be also used for the carbon-carbon bond forming reactions.     

Photocatalytic Difunctionalization of Vinyl Ureas by Radical Addition Polar Truce–Smiles Rearrangement Cascades

We report tandem alkyl‐arylations and phosphonyl‐arylations of vinyl ureas by way of a photocatalytic radical‐polar crossover mechanism. Addition of photoredox‐generated radicals to the alkene forms a new C?C or C?P bond and generates a product radical adjacent to the urea function. Reductive termination of the photocatalytic cycle generates an anion that undergoes a polar Truce–Smiles rearrangement, forming a C?C bond. The reaction is successful with a range of α‐fluorinated alkyl sodium sulfinate salts and diarylphosphine oxides as radical precursors, and the conformationally accelerated Truce–Smiles rearrangement is not restricted by the electronic nature of the migrating aromatic ring. Formally the reaction constitutes an α,β‐difuctionalisation of a carbon–carbon double bond, and proceeds under mild conditions with visible light and a readily available organic photocatalyst. The products are α,α‐diaryl alkylureas typically functionalized with F or P substituents that may be readily converted into α,α‐diaryl alkylamines.     

Photochemically induced electron transfer (PET) catalyzed radical cyclization: a practical method for inducing structural changes in peptides by formation of cyclic amino acid derivatives

A new radical cyclization reaction of unsaturated amino acid derivatives is presented. The reaction is induced by photoelectron transfer (PET) catalysis and proceeds, in comparison to commonly applied methods, under mild, nonoxidizing, and nontoxic conditions in neutral medium. This type of radical cyclization reaction can be used in peptide chemistry for inducing structural changes in peptides.