Sequential Pd0 - and PdII -Catalyzed Cyclizations: Enantioselective Heck and Nucleopalladation Reactions.

An enantioselective consecutive cyclization/coupling process, catalyzed by palladium is reported. Stereoinduction arises from an enantioselective carbopalladation, generating an intermediate which promotes a nucleopalladation step. The dual cyclization sequence was compatible with a variety of alkyne-tethered oxygen- and nitrogen-centered nucleophiles, and a variety of alkenyl-tethered aryl iodides, to forge numerous bisheterocycles in good yields and high regio- and enantioselectivities.

Cycloisomerization of Carbamoyl Chlorides in Hexafluoroisopropanol: Stereoselective Synthesis of Chlorinated Methylene Oxindoles and Quinolinones.

Hexafluoroisopropanol (HFIP) was employed as an additive for the generation of 3-(chloromethylene)oxindoles via the chloroacylation of alkyne-tethered carbamoyl chlorides. This reaction avoids the use of a metal catalyst and accesses products in high yields and stereoselectivities. Additionally, this reaction is scalable and proved amenable to a series of product derivatizations, including the synthesis of nintedanib. The reactivity of alkene-tethered carbamoyl chlorides with hexafluoroisopropanol (HFIP) was harnessed towards the synthesis of 2-quinolinones.

Enantioselective Cobalt-Catalyzed Intermolecular Hydroacylation of 1,6-Enynes.

We report a cobalt-catalyzed hydroacylation of 1,6-enynes with exogenous aldehydes in a domino sequence to construct enantioenriched ketones. The products were obtained in good yields with excellent regio-, diastereo-, and enantioselectivity. Furthermore, the chiral products served as valuable precursors to access complex spirocyclic scaffolds with three contiguous stereocenters. The asymmetric hydroacylation process exhibited no C-H crossover and no KIE, thus indicating that the C-H bond cleavage was not involved in the turnover-limiting step.

Rapid Assembly of Unsymmetrically Linked Bis-heterocycles via Palladium Domino Catalysis.

A palladium-catalyzed domino reaction of alkene-tethered oxime esters is reported. This transformation uses an air-stable palladium precatalyst that initiates a Narasaka-Heck reaction, that is interrupted with a Pd(II)-promoted cyclization. Through this methodology, a novel class of unsymmetrical alkyl-linked bis-heterocycles were synthesized in yields up to 99%. The reaction is scalable up to 1.0 mmol, with simplified purification steps. This transformation expands the scope of accessible bis-heterocycles available through Narasaka-Heck reactions beyond C-H activation and direct anionic capture termination steps.

Pd-Catalyzed Domino Narasaka-Heck/C-H Activation/Amination Reactions: Synthesis of Bis-heterocyclic Spirocycles.

The palladium-catalyzed synthesis of bis-heterocyclic spirocycles containing both pyrroline and indoline motifs is reported. Di-tert-butyldiaziridinone is used to functionalize palladacycles generated in situ via domino Narasaka-Heck/C-H activation reactions. The reaction is readily scalable, and the spirocyclic products can undergo deprotection, reduction, and (3 + 2) cycloadditions, highlighting their synthetic utility. Additionally, kinetic isotope effect experiments support a turnover-limiting C-H functionalization step in the catalytic cycle.

Palladium-Catalyzed Three-Component Dearomatization/Sulfonylation Cascade.

The diastereoselective synthesis of sulfonylated indolines is reported. A palladium-catalyzed dearomative sulfination of (aza)indole-tethered aryl iodides generates reactive benzylic sulfinates. These intermediates react with electrophiles in a one-pot, two-step process to generate sulfonylated products in good yields and excellent diastereoselectivity. This three-component sequence demonstrates good scalability and can be applied toward the synthesis of sulfonamides. Additionally, further derivatizations of aryl iodide containing products furnish spiro- and alkynylated indoline products.

Palladium-Catalyzed Domino Heck/Sulfination: Synthesis of Sulfonylated Hetero- and Carbocyclic Scaffolds Using DABCO-Bis(sulfur dioxide).

The synthesis of a broad variety of hetero- and carbocyclic scaffolds via a Pd-catalyzed domino Heck/SO2 insertion reaction is reported. This reaction utilizes DABSO, a safe and easy-to-handle alternative to SO2 gas. The reaction proceeds through a sulfinate intermediate, which can act as a lynchpin for the in situ generation of sulfones, sulfonamides, and sulfonyl fluorides. Good yields and scalability are demonstrated.

Stereoselective Construction of γ-Lactams via Copper-Catalyzed Borylacylation.

A versatile and highly stereoselective borylative cyclization to generate polyfunctionalized γ-lactams has been developed. The stereoselective synthesis of these key ring systems is crucial due to their ubiquity in natural products. We report the diastero- and enantioselective construction of di- and trisubstituted γ-lactam cores, with examples containing an enantioenriched quaternary carbon.

Palladium-Catalyzed Disilylation and Digermanylation of Alkene Tethered Aryl Halides: Direct Access to Versatile Silylated and Germanylated Heterocycles.

A method for the palladium-catalyzed disilylation and digermanylation of aryl halides bearing a tethered alkene has been developed. The mechanism is thought to proceed via Heck-type cyclization, followed by C-H activation, resulting in a reactive fused-palladacycle. A wide variety of disilylated and digermanylated heterocycles are obtained from readily available aryl halides in high yields with various functional groups. Moreover, the developed protocol proved to be highly diastereoselective.