Mn-Mediated Alpha-Radical Addition of Carbonyls to Olefins: Systematic Study, Scope, and Electrocatalysis

A systematic study of the manganese-mediated alpha-radical addition of carbonyl groups to olefins is presented. After an in-depth investigation of the parameters that govern the reaction, a first round of optimization allowed the development of a unified stoichiometric set of conditions which was subsequently assessed during the exploration of the scope. Due to observed limitations, the knowledge accumulated during the initial study was reengaged to quickly optimize promising substrates that were so far inaccessible under previously reported conditions. Altogether these results led to the creation of a predictive model based on the pKa of the carbonyl compound and both the substitution and geometry of the alkene coupling partner. Finally, a departure from the use of stoichiometric manganese was enabled through the development of a robust and practical electrocatalytic version of the reaction.

Carbene and Photocatalyst-Catalyzed Decarboxylative Radical Coupling of Carboxylic Acids and Acyl Imidazoles to Form Ketones

The carbene and photocatalyst co-catalyzed radical coupling of acyl electrophile and a radical precursor is emerging as attractive method for ketone synthesis. However, previous reports mainly limited to prefunctionalized radical precursors and two-component coupling. Herein, an N-heterocyclic carbene and photocatalyst catalyzed decarboxylative radical coupling of carboxylic acids and acyl imidazoles is disclosed, in which the carboxylic acids were directly used as radical precursors. The acyl imidazoles could also be generated in situ by reaction of a carboxylic acid with CDI thus furnishing a formally decarboxylative coupling of two carboxylic acids. In addition, the reaction was successfully extended to three-component coupling by using alkene as a third coupling partner via a radical relay process. The mild conditions, operational simplicity, and use of carboxylic acids as the reacting partners make our method a powerful strategy for construction of complex ketones from readily available starting materials, and late-stage modification of natural products and medicines.

Cu(II)-Catalyzed [3+2] Annulation of Thioamides with AIBN: Facile Access to Highly Functionalized Thiazolidine-4-ones

An efficient and versatile copper-catalyzed unprecedented intermolecular radical [3 + 2] annulation of thioamides with azobisisobutyronitrile (AIBN) is described. This two-component one-pot copper(II)-catalyzed transformation has been achieved via cascade formation of C-S/C−N bonds through the cyclization of in situ generated N,S-acetal intermediate from β-ketothioamide. This operationally simple method allows direct access to synthetically demanding thiazolidin-4-ones in good to excellent yields containing diverse functional groups of different electronic and steric nature. Remarkably, the readily available reaction partners, avoidance of expensive/toxic reagents and the gram scale synthesis are additional attributes to this strategy. AIBN here plays a dual role as radical initiator and unusual source of two carbon coupling partner. Notably, the products possess Z-stereochemistry with regard to the exocyclic C=C double bond at the 2-position of the thiazolidine ring.

Hidden Reactivity of Barbituric and Meldrum’s Acids: Atom-Efficient Free Radical C–O Coupling with N-Hydroxy Compounds

The reactivity of CH-acidic and structurally related enol-containing heterocycles towards N-oxyl radicals was disclosed. Traditionally, these substrates were considered as reactants for ionic transformations. Highly selective and efficient N-oxyl radical mediated C–O coupling of substituted barbituric or Meldrum’s acids with N-hydroxy compounds (N-hydroxyimides, hydroxamic acids, oximes, and N-hydroxybenzotriazole) was achieved using inexpensive manganese-containing salts as oxidants. Metal-free C–O coupling was demonstrated using diacetyliminoxyl as both the oxidant (hydrogen atom acceptor) and the coupling partner.

Chemodivergent assembly of ortho-functionalized phenols with tunable selectivity via rhodium(III)-catalyzed and solvent-controlled C-H activation

Ortho-functionalized phenols and their derivatives represent prominent structural motifs and building blocks in medicinal and synthetic chemistry. While numerous synthetic approaches exist, the development of atom-/step-economic and practical methods for the chemodivergent assembly of diverse ortho-functionalized phenols based on fixed catalyst/substrates remains challenging. Here, by selectively controlling the reactivities of different sites in methylenecyclopropane core, Rh(III)-catalyzed redox-neutral and tunable C-H functionalizations of N-phenoxyacetamides are realized, providing access to both ortho-functionalized phenols bearing linear dienyl, cyclopropyl or allyl ether groups, and cyclic 3-ethylidene 2,3-dihydrobenzofuran frameworks under mild cross-coupling conditions. These divergent transformations feature broad substrate compatibility, synthetic applications and excellent site-/regio-/chemoselectivity. Experimental and computational mechanistic studies reveal that distinct catalytic modes involving selective β-C/β-H elimination, π-allylation, inter-/intramolecular nucleophilic substitution cascade and β-H’ elimination processes enabled by different solvent-mediated and coupling partner-controlled reaction conditions are crucial for achieving chemodivergence, among which a structurally distinct Rh(V) species derived from a five-membered rhodacycle is proposed as the corresponding active intermediates.

General α-Amino 1,3,4-Oxadiazole Synthesis via Late-Stage Reductive Functionalization of Tertiary Amides and Lactams

An iridium-catalyzed reductive three-component coupling reaction for the synthesis of medicinally relevant α-amino 1,3,4-oxadiazoles from abundant tertiary amides or lactams, carboxylic acids, and (N-isocyanimino) triphenylphosphorane, is described. Proceeding under mild conditions using (<1 mol%) Vaska’s complex (IrCl(CO)(PPh₃)₂) and tetramethyldisiloxane to access the key reactive iminium ion intermediates, a broad range of structurally complex α-amino 1,3,4-oxadiazole architectures were efficiently accessed from diverse carboxylic acid feedstock coupling partners. Extension to α-amino heterodiazole synthesis was readily achieved by exchanging the carboxylic acid coupling partner for C-, S-, or N-centered Brønsted acids, and provided rapid and modular access to these desirable, yet difficult-to-access, heterocycles. Furthermore, the high chemoselectivity of the catalytic reductive activation step allowed the late-stage functionalization of 10 drug molecules, including the synthesis of novel heterodiazole-fused drug-drug conjugates.<br>

General α-Amino 1,3,4-Oxadiazole Synthesis via Late-Stage Reductive Functionalization of Tertiary Amides and Lactams

An iridium-catalyzed reductive three-component coupling reaction for the synthesis of medicinally relevant α-amino 1,3,4-oxadiazoles from abundant tertiary amides or lactams, carboxylic acids, and (N-isocyanimino) triphenylphosphorane, is described. Proceeding under mild conditions using (<1 mol%) Vaska’s complex (IrCl(CO)(PPh₃)₂) and tetramethyldisiloxane to access the key reactive iminium ion intermediates, a broad range of structurally complex α-amino 1,3,4-oxadiazole architectures were efficiently accessed from diverse carboxylic acid feedstock coupling partners. Extension to α-amino heterodiazole synthesis was readily achieved by exchanging the carboxylic acid coupling partner for C-, S-, or N-centered Brønsted acids, and provided rapid and modular access to these desirable, yet difficult-to-access, heterocycles. Furthermore, the high chemoselectivity of the catalytic reductive activation step allowed the late-stage functionalization of 10 drug molecules, including the synthesis of novel heterodiazole-fused drug-drug conjugates.<br>

Organophotocatalytic dearomatization of indoles, pyrroles and benzo(thio)furans via a Giese-type transformation

Accessing fascinating organic and biological significant indolines via dearomatization of indoles represents one of the most efficient approaches. However, it has been difficult for the dearomatization of the electron deficient indoles. Here we report the studies leading to developing a photoredox mediated Giese-type transformation strategy for the dearomatization of the indoles. The reaction has been implemented for chemoselectively breaking indolyl C=C bonds embedded in the aromatic system. The synthetic power of this strategy has been demonstrated by using structurally diverse indoles bearing common electron-withdrawing groups including (thio)ester, amide, ketone, nitrile and even aromatics at either C2 or C3 positions and ubiquitous carboxylic acids as radical coupling partner with high trans-stereoselectivity (>20:1 dr). This manifold can also be applied to other aromatic heterocycles including pyrroles, benzofurans and benzothiophenes. Furthermore, enantioselective dearomatization of indoles has been achieved by a chiral camphorsultam auxiliary with high diastereoselectivity.

Rh(III)-Catalyzed Olefination and Alkylation of Arenes with Maleimides: A Tunable Strategy for C(sp2)–H Functionalization

We herein report a new nitrogen-directed Rh(III)-catalyzed C(sp2)–H bond functionalization of N-nitrosoanilines and azoxybenzenes with maleimides as a coupling partner, in which the olefination/alkylation process can be finely controlled at room temperature by variation of the reaction conditions. This method shows excellent functional group tolerance, and presents a mild access to the resulting olefination/alkylation products in moderate to good yields.

Nickel-Catalyzed Defluorinative Alkylation of C(sp2)-F Bonds

A direct conversion of a C(sp2)-F bond into the corresponding C(sp2)-C(sp3) bond using Al(alkyl)3 as the coupling partner under nickel catalysis is reported. Intriguingly, aryl fluorides, alkenyl monofluorides, and alkenyl...