A General Synthesis of Cross-Conjugated Enynones through Pd Catalyzed Sonogashira Coupling with Triazine Esters.

The palladium-catalyzed Sonogashira coupling of α, ß-unsaturated acid derivatives offers a diversity-oriented synthetic strategy for cross-conjugated enynones. However, the susceptibility of the unsaturated C-C bonds adjacent to the carbonyl group toward Pd catalysts makes the direct conversion of α, ß-unsaturated derivatives as acyl electrophiles to cross-conjugated ketones rare. This work presents a highly selective C-O activation approach to prepare cross-conjugated enynones using α, ß-unsaturated triazine esters as acyl electrophiles. Under base and phosphine ligand-free conditions, NHC-Pd(II)-Allyl precatalyst alone catalyzed the cross-coupling of α, ß-unsaturated triazine esters with terminal alkynes efficiently, yielding 31 cross-conjugated enynones with diverse functional groups. This method demonstrates the potential of triazine-mediated C-O activation for preparing highly functionalized ketones.

Highly Chemoselective Transamidation of Unactivated Tertiary Amides by Electrophilic N-C(O) Activation by Amide-to-Acyl Iodide Re-routing.

The challenging transamidation of unactivated tertiary amides has been accomplished via cooperative acid/iodide catalysis. Most crucially, the method provides a novel manifold to re-route the reactivity of unactivated N,N-dialkyl amides through reactive acyl iodide intermediates, thus reverting the classical order of reactivity of carboxylic acid derivatives. This method provides a direct route to amide-to-amide bond interconversion with excellent chemoselectivity using equivalent amounts of amines. The combination of acid and iodide has been identified as the essential factor to activate the amide C-N bond through electrophilic catalytic activation, enabling the production of new desired transamidated products with wide substrate scope of both unactivated amides and amines, including late-stage functionalization of complex APIs (>80 examples). We anticipate that this powerful activation mode of unactivated amide bonds will find broad-ranging applications in chemical synthesis.

Iron-Catalyzed Cross-Coupling Reactions of Alkyl Grignards with Aryl Chlorobenzenesulfonates.

Aryl sulfonate esters are versatile synthetic intermediates in organic chemistry as well as attractive architectures due to their bioactive properties. Herein, we report the synthesis of alkyl-substituted benzenesulfonate esters by iron-catalyzed C(sp2)-C(sp3) cross-coupling of Grignard reagents with aryl chlorides. The method operates using an environmentally benign and sustainable iron catalytic system, employing benign urea ligands. A broad range of chlorobenzenesulfonates as well as challenging alkyl organometallics containing ß-hydrogens are compatible with these conditions, affording alkylated products in high to excellent yields. The study reveals that aryl sulfonate esters are the most reactive activating groups for iron-catalyzed alkylative C(sp2)-C(sp3) cross-coupling of aryl chlorides with Grignard reagents.

Electrophilicity Scale of Activated Amides: 17 O†NMR and 15 N†NMR Chemical Shifts of Acyclic Twisted Amides in N-C(O) Cross-Coupling.

The structure and properties of amides are of tremendous interest in organic synthesis and biochemistry. Traditional amides are planar and the carbonyl group non-electrophilic due to nN →π*C=O conjugation. In this study, we report electrophilicity scale by exploiting 17 O NMR and 15 N NMR chemical shifts of acyclic twisted and destabilized acyclic amides that have recently received major attention as precursors in N-C(O) cross-coupling by selective oxidative addition as well as precursors in electrophilic activation of N-C(O) bonds. Most crucially, we demonstrate that acyclic twisted amides feature electrophilicity of the carbonyl group that ranges between that of acid anhydrides and acid chlorides. Furthermore, a wide range of electrophilic amides is possible with gradually varying carbonyl electrophilicity by steric and electronic tuning of amide bond properties. Overall, the study quantifies for the first time that steric and electronic destabilization of the amide bond in common acyclic amides renders the amide bond as electrophilic as acid anhydrides and chlorides. These findings should have major implications on the fundamental properties of amide bonds.

Iron-Catalyzed C(sp2)-C(sp3) Cross-Coupling of Aryl Chlorobenzoates with Alkyl Grignard Reagents.

Aryl benzoates are compounds of high importance in organic synthesis. Herein, we report the iron-catalyzed C(sp2)-C(sp3) Kumada cross-coupling of aryl chlorobenzoates with alkyl Grignard reagents. The method is characterized by the use of environmentally benign and sustainable iron salts for cross-coupling in the catalytic system, employing benign urea ligands in the place of reprotoxic NMP (NMP = N-methyl-2-pyrrolidone). It is notable that high selectivity for the cross-coupling is achieved in the presence of hydrolytically-labile and prone to nucleophilic addition phenolic ester C(acyl)-O bonds. The reaction provides access to alkyl-functionalized aryl benzoates. The examination of various O-coordinating ligands demonstrates the high activity of urea ligands in promoting the cross-coupling versus nucleophilic addition to the ester C(acyl)-O bond. The method showcases the functional group tolerance of iron-catalyzed Kumada cross-couplings.

Characterization of Intermediate Oxidation States in CO2 Activation.

Redox chemistry during the activation of carbon dioxide involves changing the charge state in a CO2 molecular unit. However, such changes are usually not well described by integer formal charges, and one can think of COO functional units as being in intermediate oxidation states. In this article, we discuss the properties of CO2 and CO2-based functional units in various charge states. Besides covering isolated CO2 and its ions, we describe the CO2-based ionic species formate, oxalate, and carbonate. Finally, we provide an overview of CO2-based functional groups and ligands in clusters and metal-organic complexes.

Pd-Catalyzed Suzuki-Miyaura Cross-Coupling of Pentafluorophenyl Esters.

Although the palladium-catalyzed Suzuki-Miyaura cross-coupling of aryl esters has received significant attention, there is a lack of methods that utilize cheap and readily accessible Pd-phosphane catalysts, and can be routinely carried out with high cross-coupling selectivity. Herein, we report the first general method for the cross-coupling of pentafluorophenyl esters (pentafluorophenyl = pfp) by selective C⁻O acyl cleavage. The reaction proceeds efficiently using Pd(0)/phosphane catalyst systems. The unique characteristics of pentafluorophenyl esters are reflected in the fully selective cross-coupling vs. phenolic esters. Of broad synthetic interest, this report establishes pentafluorophenyl esters as new, highly reactive, bench-stable, economical, ester-based, electrophilic acylative reagents via acyl-metal intermediates. Mechanistic studies strongly support a unified reactivity scale of acyl electrophiles by C(O)⁻X (X = N, O) activation. The reactivity of pfp esters can be correlated with barriers to isomerization around the C(acyl)⁻O bond.