Enantioselective Amination of 3-Substituted-2-benzofuranones via Non-covalent N-Heterocyclic Carbene Catalysis.

Herein, an efficient method for asymmetric α-amination of 2-benzofuranones with N-heterocyclic carbene (NHC) catalysis is reported. The process is based on non-covalent interaction of NHC with substrate, facilitating the formation of a chiral ion-pair that encompasses enolate and azolium salt. The activated enolate adds to an electrophilic amine source with sufficient facial control to furnish an enantioenriched product having an amine substituted quaternary stereocenter. The process displays a broad substrate scope. A preparative scale synthesis has been achieved. Preliminary mechanistic investigations based on experimental and DFT studies suggest a reaction pathway that involves non-covalent substrate/NHC interactions and essentially implicate the role of π-π interaction in diastereomeric transition states for stereo-chemical discrimination.

Photocatalytic Synthesis of ß-Keto Primary Chlorides by Selective Chlorocarbonylation of Olefins.

Functionalized primary alkyl chlorides are precursors to a plethora of scaffolds but their access from chemical feedstocks remains challenging. Herein, we report a concise dual Ni/photoredox catalytic protocol for regioselective chlorocarbonylation of unactivated alkenes that enables rapid access to ß-keto primary chlorides. The catalytic process features an extensive substrate scope, scalability and functional group tolerance. The Ni/photocatalytic Cl⋅ generation and subsequent cross-coupling is implicated for the process based on the control experiments and DFT study. The synthetic utility of the protocol has been further corroborated through functionalization of complex substrates and modifications of the product.

Photochemical Oximesulfonylation of Alkenes Using Sulfonyl-Oxime-Ethers as Bifunctional Reagents.

Utilization of oxime ethers as bifunctional reagents remains unknown. Herein, we present a mechanistically distinct strategy that enables oximesulfonylation of olefins using sulfonyl-oxime-ethers as bifunctional reagents under metal-free photochemical conditions. Via concomitant C-S and C-C bond formation, the process permits incorporation of oxime and sulfonyl groups into olefins in a complete atom-economic fashion, providing rapid access to multi-functionalized ß-sulfonyl oxime ethers with good yields and stereoselectivity. The method is amenable to functionalization of complex bioactive molecules and is shown to be scalable. A radical chain mechanism initiated via photochemical Hydrogen Atom Transfer (HAT) mediated N-O bond cleavage is suggested for the process, based on our results on mechanistic investigations.

A General Approach to Intermolecular Olefin Hydroacylation through Light-Induced HAT Initiation: An Efficient Synthesis of Long-Chain Aliphatic Ketones and Functionalized Fatty Acids.

Herein, an operationally simple, environmentally benign and effective method for intermolecular radical hydroacylation of unactivated substrates by employing photo-induced hydrogen atom transfer (HAT) initiation is described. The use of commercially available and inexpensive photoinitiators (Ph2 CO and NHPI) makes the process attractive. The olefin hydroacylation protocol applies to a wide array of substrates bearing numerous functional groups and many complex structural units. The reaction proves to be scalable (up to 5 g). Different functionalized fatty acids, petrochemicals and naturally occurring alkanes can be synthesized with this protocol. A radical chain mechanism is implicated in the process.

Hydrogen-Bonding Assisted Catalytic Kinetic Resolution of Acyclic ß-Hydroxy Amides.

Enantioenriched acyclic α-substituted ß-hydroxy amides are valuable compounds in chemical, material and medicinal sciences, but their enantioselective synthesis remains challenging. A catalytic kinetic resolution (KR) of such amides with selectivity factor(s) up to >200 is developed via enantioselective acylation of primary alcohol with N-heterocyclic carbene. An enhanced selectivity for the catalytic KR process is realized using cyclic tertiary amine as base additive. Diastereomeric transition state models for the process are proposed to rationalize the origin of enantioselectivity.

Highly Enantioselective Synthesis of Functionalized Glutarimide Using Oxidative N-Heterocyclic Carbene Catalysis: A Formal Synthesis of (-)-Paroxetine.

A simple yet highly effective approach toward enantioselective synthesis of trans-3,4-disubstituted glutarimides from readily available starting materials is developed using oxidative N-heterocyclic carbene catalysis. The catalytic reaction involves a formal [3 + 3] annulation between enals and substituted malonamides enabling the production of glutarimide derivatives in a single chemical operation via concomitant formation of C-C and C-N bonds. The reaction offers easy access to a broad range of functionalized glutarimides with excellent enantioselectivity and good yield. Synthetic application of the method is demonstrated via formal synthesis of (-)-paroxetine and other bioactive molecules.

Molecular Oxygen Mediated Radical Dicarbofunctionalization of Olefin with Aldehyde.

Herein we present a metal- and peroxide-free method for the synthesis of sterically hindered amides bearing an all-carbon quaternary stereogenic center at the α-position via a one-pot alkylation/aryl-migration/desulfonylation radical cascade. The novel process is developed employing readily available and inexpensive aldehyde as an alkyl radical precursor and O2 as the sole oxidant. The method features a broad substrate scope, operational simplicity, convenient reagents, and scalability. A radical chain mechanism that is initiated by O2 is proposed for the process.

Aerobic Radical-Cascade Alkylation/Cyclization of α,ß-Unsaturated Amides: an Efficient Approach to Quaternary Oxindoles.

An efficient method for the aerobic radical-cascade alkylation/cyclization of α,ß-unsaturated amides to afford functionalized oxindoles with a C3 quaternary stereocenter is described. The process is based on the generation of valuable alkyl radicals through sustainable aerobic C-H activation of aldehydes followed by decarbonylation using O2 as the sole oxidant. This method features a broad substrate scope, inexpensive alkyl radical precursors, and convenient reagents. Finally, the method was successfully applied to the synthesis of alkyl analogues of tetrahydrofuranoindoline and (±)-esermethole.

Dioxygen-Mediated Decarbonylative C-H Alkylation of Heteroaromatic Bases with Aldehydes.

An operationally simple and economical method for the direct alkylation of heteroaromatic bases employing readily available aldehydes as alkyl radical precursors and molecular oxygen as a reagent is presented. This simple transformation demonstrates a broad substrate scope with respect to aldehydes and nitrogen heterocycles, enabling the introduction of several medicinally important yet challenging alkyl moieties, such as ethyl, isopropyl, tert-butyl, and cyclohexyl to the different classes of heterocyclic bases in good to excellent yields.

The catalytic asymmetric Abramov reaction.

The first catalytic enantioselective Abramov reaction is described. The process is based on the utilization of a chiral disulfonimide catalyst, which efficiently avoids the difficulties encountered with metal-based catalysts. Several functionalized α-hydroxy phosphonates were synthesized in good yields and with excellent enantiomeric ratios of up to >99:1. The process was shown to be scalable and up to 1 g of starting material could be employed under mild reaction conditions.

Catalytic asymmetric protonation of silyl ketene imines.

An efficient catalytic and highly enantioselective protonation of silyl ketene imines is described. The reaction is catalyzed by the chiral phosphoric acids TRIP or STRIP in the presence of a stoichiometric amount of methanol as the proton source and silyl acceptor. A variety of substituted racemic silyl ketene imines have been transformed into highly enantioenriched nitriles.

N-Heterocyclic carbene catalyzed desymmetrization of diols: access to enantioenriched oxindoles having a C3-quaternary stereocenter.

Herein, we describe an effective strategy for enantioselective synthesis of oxindoles having a C3-quaternary stereocenter via N-heterocyclic carbene (NHC) catalyzed desymmetrization of diols. The process is based on the catalytic asymmetric transfer acylation of primary alcohols using readily available aldehydes as an acylation agent. The reaction enables easy access to diversely functionalized C3-quaternary oxindoles with excellent enantioselectivity. The synthetic potential of the process is further demonstrated via the preparation of the key intermediate for (-)-esermethole and (-)-physostigmine.

Brønsted Acid-Promoted Intermolecular Dearomative Photocycloaddition of Bicyclic Azaarenes with Olefins under Aerobic Conditions.

Herein, we present a simplified reaction protocol for the dearomatization of bicyclic azaarenes via photochemical cycloaddition with alkenes using an Ir(III) photosensitizer, trifluoroacetic acid (TFA), dichloroethane, and a blue light-emitting diode. An efficient protonation of azaarenes with TFA enhances the reactivity of triplet azaarene toward olefins, enabling the photocycloaddition under aerobic conditions. The protocol applies to a broad range of substrates. Control experiments indicate a strong correlation between the degree of protonation of azaarene and the product yield.

Asymmetric Aminative Dearomatization of 2-Naphthols via Non-covalent N-Heterocyclic Carbene Catalysis.

Herein, successful utilization of non-covalent N-heterocyclic carbene (NHC) catalysis toward asymmetric aminative dearomatization of naphthols is presented. The NHC-catalyzed process offers enantioselective synthesis of cyclic enones possessing a nitrogen-containing α-quaternary stereocenter. The reaction applies to various functionalized substrates including acid-labile groups and is shown to be scalable. Substrate activation via an O-H···NHC hydrogen-bonding interaction is suggested based on the results obtained in mechanistic studies.

Photocatalytic Aerobic Coupling of Azaarenes and Alkanes via Nontraditional Cl• Generation.

Herein, we demonstrate a nonconventional photocatalytic generation of Cl• from a common chlorinated solvent, dichloroethane, under aerobic conditions and its successful utilization toward the cross-dehydrogenative coupling of alkanes and azaarenes via hydrogen atom transfer with Cl•. The process is free from chloride salt, toxic oxidant, and UV light. It is applicable to a broad spectrum of substrates. The proposed mechanism involving Cl• is supported by a series of mechanistic investigations.

Photocatalytic Incorporation of an Oxime Ether Functional Group at Inert C(sp3)-H Bonds via HAT.

Herein, we describe a photocatalytic method for the direct incorporation of an oxime functional group at inert C(sp3)-H bonds of ethers, amides, alcohols, amines, and alkanes via HAT with photoexcited eosin Y under mild conditions using air and a blue LED. Many useful functional groups are tolerated in this process, and the reaction is scalable. A series of mechanistic studies were carried out to support the radical pathway proposed for the process.

Heteroarylation of Ethers, Amides, and Alcohols with Light and O2.

An efficient protocol for the Cα-H heteroarylation of ethers, amides, and alcohols using air and light under mild conditions is described. The reaction is applicable to a wide spectrum of functional groups. The generation of C-radicals via photoinduced aerobic oxidation of ethers, amides, and alcohols is the key feature of the process. Control experiments suggest a radical pathway for the reaction.

Enantioselective α-Amination of Acyclic 1,3-Dicarbonyls Catalyzed by N-Heterocyclic Carbene.

Herein, we describe a method for the catalytic enantioselective α-amination of α-substituted acyclic 1,3-ketoamides and 1,3-amidoesters that affords the products possessing N-substituted quaternary stereocenters with a chiral N-heterocyclic carbene (NHC). The reaction is based on the utilization of an intrinsic Brønsted base characteristic of NHC that enables the catalytic formation of a chiral ion pair comprising the enolate and the azolium ion. A series of challenging open-chain α-substituted 1,3-dicarbonyls are aminated via this method with ee's of ≤99%.

Palladium-Catalyzed Decarboxylative ortho-C(sp2 )-H Aroylation of N-Sulfoximine Benzamides at Room Temperature.

A palladium-catalyzed method for the decarboxylative ortho C-H acylation of N-sulfoximine benzamides is developed at room temperature. The catalytic method enables easy access to various functionalized 2-aroylaromatic carboxylic acid derivatives in good isolated yields. Based on our mechanistic studies, a Pd(II)/Pd(IV) catalytic cycle that involves aroyl radical intermediate is proposed for the reaction.

Aerobic Acylarylation of α,ß-Unsaturated Amides with Aldehydes.

Herein, we illustrate that molecular oxygen (O2) is capable of promoting oxidative radical acylarylation of olefins with aliphatic aldehydes to afford acylated oxindoles in good yield (up to 97%). The key aspect of the process is the utilization of aldehyde auto-oxidation in developing aerobic radical olefin acylarylation. Kinetic studies confirm a lag phase for the reaction. Synthetic utility of the method is apparent via the preparation of biologically potent spirocyclic oxindoles and tetrahydrofuranoindolines.