Access to Perfluoroalkyl-Substituted Enones and Indolin-2-ones via Multicomponent Pd-Catalyzed Carbonylative Reactions

A simple method for accessing perfluoroalkyl-substituted enones is described applying a four-component palladium-catalyzed carbonylative coupling of aryl boronic acids together with terminal alkynes and perfluoroalkyl iodides in the presence of carbon monoxide. A wide range of highly functionalized enones can thus be prepared in a single operation in good yields. With 2-aminophenylalkynes, an intramolecular aminocarbonylation event overrules providing the indolin-2-one framework. Finally, adaptation of the two-chamber technology expands the method to the synthesis of the aforementioned structures with ¹³C-isotope labeling

Regioselective Rh(I)-Catalyzed Sequential Hydrosilylation toward the Assembly of Silicon-Based Peptidomimetic Analogues

A highly regioselective Rh­(I)-catalyzed hydrosilylation of enamides is presented. This mild protocol allows access to a wide variety of different arylsilanes with substitution at the β-position of the enamide and functionalization on the alkyl chain tethered to the silane. This protocol is extended to include a sequential one-pot hydrosilylation. Using diphenylsilane as the appendage point, hydrosilylation of a protected allyl alcohol followed by hydrosilylation of an enamide generates a complex organosilane in one step. This highly convergent strategy to synthesize these functionalized systems now provides a way for the rapid assembly of a diverse collection of silane-based peptidomimetic analogues

Effective Palladium-Catalyzed Hydroxycarbonylation of Aryl Halides with Substoichiometric Carbon Monoxide

A protocol for the Pd-catalyzed hydroxy­carbonylation of aryl iodides, bromides, and chlorides has been developed using only 1–5 mol % of CO, corresponding to a <i>p</i>_CO as low as 0.1 bar. Potassium formate is the only stoichiometric reagent, acting as a mildly basic nucleophile and a reservoir of CO. The substoichiometric CO could be delivered to the reaction from an acyl-Pd­(II) precatalyst, which provides both the CO and an active catalyst, and thereby obviates the need for handling a toxic gas

Palladium-Catalyzed <i>N</i>-Acylation of Monosubstituted Ureas Using Near-Stoichiometric Carbon Monoxide

The palladium-catalyzed carbonylation of urea derivatives with aryl iodides and bromides afforded <i>N</i>-benzoyl ureas (20 examples) in yields attaining quantitative via the application of near-stoichiometric amounts of carbon monoxide generated from the decarbonylation of the CO precursor, 9-methylfluorene-9-carbonyl chloride. The synthetic protocol displayed good functional group tolerance. The methodology is also highly suitable for ¹³C isotope labeling, which was demonstrated through the synthesis of three benzoyl ureas, including the insecticide triflumuron, whereby ¹³CO was incorporated into the core structure

Palladium-Catalyzed Synthesis of Aromatic Carboxylic Acids with Silacarboxylic Acids

Aryl iodides and bromides were easily converted to their corresponding aromatic carboxylic acids via a Pd-catalyzed carbonylation reaction using silacarboxylic acids as an <i>in situ</i> source of carbon monoxide. The reaction conditions were compatible with a wide range of functional groups, and with the aryl iodides, the carbonylation was complete within minutes. The method was adapted to the double and selective isotope labeling of tamibarotene

Toward a Practical Catalyst for Convenient Deaminative Hydrogenation of Amides under Mild Conditions

Amide bond reduction is a versatile transformation offering access to various alcohols and amines that could be used as valuable precursors in the chemical and pharmaceutical industries, e.g., for manufacturing plastics, textiles, dyes, agrochemicals, etc. Over the last two decades, catalytic amide hydrogenation employing homogeneous catalysis has gained more attention due to the atom efficiency and low environmental impact of this transformation. Owing to the inherent strength of amide bonds, amide hydrogenation procedures often involve high temperatures and pressures, which is why efforts are being channeled to finding protocols with lower-energy input. Here, we report a mild amide hydrogenation method involving commercially available precursors Ru(acac)3 and 1,2-bis(di-tert-butylphosphinomethyl)benzene (L4), which under basic conditions, at 80 °C and under 30 bar of H2, can selectively hydrogenate a series of 2°-benzamides to anilines and alcohols with yields of 36–98% and 29–92%, respectively. Additionally, 1°- and 3°-amides proved to be appropriate substrates; however, low to moderate yields were obtained. The catalyst is believed to operate via an inner-sphere mechanism with a hemiaminal being the likely intermediate during the hydrogenation process

Palladium-Catalyzed <i>N</i>-Acylation of Monosubstituted Ureas Using Near-Stoichiometric Carbon Monoxide

The palladium-catalyzed carbonylation of urea derivatives with aryl iodides and bromides afforded <i>N</i>-benzoyl ureas (20 examples) in yields attaining quantitative via the application of near-stoichiometric amounts of carbon monoxide generated from the decarbonylation of the CO precursor, 9-methylfluorene-9-carbonyl chloride. The synthetic protocol displayed good functional group tolerance. The methodology is also highly suitable for ¹³C isotope labeling, which was demonstrated through the synthesis of three benzoyl ureas, including the insecticide triflumuron, whereby ¹³CO was incorporated into the core structure

Palladium-Catalyzed Thiocarbonylation of Aryl, Vinyl, and Benzyl Bromides

A catalytic protocol for synthesis of thioesters from aryl, vinyl, and benzyl bromides as well as benzyl chlorides was developed using only stoichiometric amounts of carbon monoxide, produced from a solid CO precursor inside a two-chamber system. As a catalytic system, the combination of bis­(benzonitrile) palladium­(II) chloride and Xantphos furnished the highest yields of the desired compounds, along with the weak base, NaOAc, in anisole at 120 °C. The choice of catalytic system as well as solvent turned out to be important in order to ensure a high chemoselectivity in the reaction. Both electron-rich and electron-deficient aryl bromides worked well in this reaction. Addition of 1 equiv of sodium iodide to the reaction improved the chemoselectivity with the electron-deficient aryl bromides. The thiol scope included both aryl and alkyl thiols, including 2-mercaptobenzophenones, whereby a thiocarbonylation followed by a subsequent McMurry coupling yielded differently substituted benzothiophenes. It was demonstrated that the methodology could be applied for ¹³C introduction into the thiophene ring

Carbonylative Suzuki Couplings of Aryl Bromides with Boronic Acid Derivatives under Base-Free Conditions

The carbonylative Suzuki–Miyaura reaction between aryl bromides and arylboronic acid equivalents is herein reported, using base-free conditions and a limited excess of carbon monoxide generated <i>ex situ</i> from stable CO-precursors. Under these conditions, unsymmetrical biaryl ketones were obtained in modest to excellent yields. This method was adapted to the synthesis of the triglyceride and cholesterol regulator drug, fenofibrate, and its ¹³C-labeled derivative in good yields from the appropriate CO-precursor

Palladium Catalyzed Carbonylative Coupling of Alkyl Boron Reagents with Bromodifluoroacetamides

A catalytic protocol for the preparation of α,α-difluoro-β-alkyl-β-ketoamides is developed employing a Pd-mediated carbonylative Suzuki coupling between alkylboron reagents and bromodifluoroacetamides with COgen as the CO source. The reaction reveals good functional group tolerance providing a broad selection of α,α-difluoro-β-alkyl-β-ketoamides in moderate to good yields, which represent useful precursors for further synthetic manipulation. Finally, the methodology is amenable to ¹³C-isotope labeling at the ketone carbon applying ¹³C-COgen