Synthesis of Strained γ‐Lactams by Palladium(0)‐Catalyzed C(sp3)−H Alkenylation and Application to Alkaloid Synthesis

A variety of strained α‐alkylidene‐γ‐lactams were synthesized by palladium(0)‐catalyzed intramolecular C(sp³)?H alkenylation from easily accessible acyclic and monocyclic bromoalkene precursors. These lactams are valuable intermediates for accessing various classes of mono‐ and bicylic alkaloids containing a pyrrolidine ring, as illustrated with the synthesis of an advanced model of the marine natural product plakoridine A and of the indolizidine alkaloid δ‐coniceine.     

Highly Stereoselective Cobalt(III)‐Catalyzed Three‐Component C−H Bond Addition Cascade

A highly stereoselective three‐component C(sp²)?H bond addition across alkene and polarized π‐bonds is reported for which Co^III catalysis was shown to be much more effective than Rh^III. The reaction proceeds at ambient temperature with both aryl and alkyl enones employed as efficient coupling partners. Moreover, the reaction exhibits extremely broad scope with respect to the aldehyde input; electron rich and poor aromatic, alkenyl, and branched and unbranched alkyl aldehydes all couple in good yield and with high diastereoselectivity. Multiple directing groups participate in this transformation, including pyrazole, pyridine, and imine functional groups. Both aromatic and alkenyl C(sp²)?H bonds undergo the three‐component addition cascade, and the alkenyl addition product can readily be converted into diastereomerically pure five‐membered lactones. Additionally, the first asymmetric reactions with Co^III‐catalyzed C?H functionalization are demonstrated with three‐component C?H bond addition cascades employing N‐tert‐butanesulfinyl imines. These examples represent the first transition metal catalyzed C?H bond additions to N‐tert‐butanesulfinyl imines, which are versatile and extensively used intermediates for the asymmetric synthesis of amines.     

Enantioselective Access to 1H‐Isoindoles with Quaternary Stereogenic Centers by Palladium(0)‐Catalyzed C−H Functionalization

A catalytic enantioselective method for the synthesis of chiral 1H‐isoindoles bearing quaternary stereogenic centers is reported. Powered by readily accessible phosphordiamidite ligands, the presented palladium(0)‐catalyzed C?H functionalization uses trifluoroacetimidoyl chlorides as electrophilic components. It delivers previously inaccessible perfluoroalkylated 1H‐isoindoles in high yields and enantioselectivities. The subsequent diastereoselective addition of nucleophiles provides access to densely substituted and sterically hindered isoindolines.     

Domino Pd0‐Catalyzed C(sp3)–H Arylation/Electrocyclic Reactions via Benzazetidine Intermediates

The Pd⁰‐catalyzed C(sp³)‐H arylation of 2‐bromo‐N‐methylanilides leads to unstable benzazetidine intermediates that rearrange to benzoxazines through 4π electrocyclic ring‐opening and 6π electrocyclization. The introduction of a bulky, non‐activatable amide group on the nitrogen atom was key to favor the challenging reductive elimination step and disfavor undesired reaction pathways.     

Palladium‐Catalyzed Direct C2 Arylation of N‐Substituted Indoles with 1‐Aryltriazenes

A novel and efficient palladium‐catalyzed C2 arylation of N‐substituted indoles with 1‐aryltriazenes for the synthesis of 2‐arylindoles was developed. In the presence of BF₃ ? OEt₂ and palladium(II) acetate (Pd(OAc)₂), N‐substituted indoles reacted with 1‐aryltriazenes in N,N‐dimethylacetamide (DMAC) to afford the corresponding aryl–indole‐type products in good to excellent yields.     

Z‐Selective (Cross‐)Dimerization of Terminal Alkynes Catalyzed by an Iron Complex

Efficient iron‐catalyzed homocoupling of terminal alkynes and cross‐dimerization of aryl acetylenes with trimethylsilylacetylene is reported. The complex [Fe(H)(BH₄)(iPr‐PNP)] ( 1 ) catalyzed the (cross‐)dimerization of alkynes at room temperature, with no need for a base or other additives, to give the corresponding dimerized products with Z selectivity in excellent yields (79–99 %).     

Palladium(II)‐Catalyzed ortho‐Arylation of Aromatic Alcohols with a Readily Attachable and Cleavable Molecular Scaffold

A palladium(II)‐catalyzed C?H arylation process of alcohols has been developed. The strategy utilizes a novel quinoline‐based hemiacetal scaffold that can direct the selective C?H bond functionalization. This reaction provides a useful method to construct biaryl compounds of benzyl alcohols in good to excellent yields. The new molecular scaffold can be readily attached, removed, and recovered.     

Palladium‐Catalyzed C−H Alkynylation of Unactivated Alkenes

Palladium‐catalyzed regio‐ and diastereoselective C?H functionalization with bromoalkynes and electronically unbiased olefins is reported. The picolinamide directing group enables the formation of putative 5 and 6‐exo‐metallacycles as intermediates to afford monoalkynylated products in up to 91 % yield in a stereospecific fashion. The systematic study reveals that substrates with a wide range of substituents on the olefin and bromoalkyne coupling partners are tolerated. Chemoselective transformations were demonstrated for the obtained amides, olefins, and alkynes.     

Steric Effect of Carboxylate Ligands on Pd‐Catalyzed Intramolecular C(sp2)–H and C(sp3)–H Arylation Reactions

A bulky carboxylic acid bearing three cyclohexylmethyl substituents at the α‐position, namely, tri(cyclohexylmethyl)acetic acid, is demonstrated to act as an efficient ligand source in Pd‐catalyzed intramolecular C(sp²)?H and C(sp³)?H arylation reactions. The reactions proceed smoothly under mild reaction conditions, even at room temperature due to the steric bulk of the carboxylate ligands, which accelerates the rate‐determining C?H bond activation step in the catalytic cycle.     

Access to 2‐Arylindoles via Decarboxylative C−C Coupling in Aqueous Medium and to Heteroaryl Carboxylates under Base‐Free Conditions using Diaryliodonium Salts

Easily accessible heteroaromatic carboxylic acids and diaryliodonium salts were successfully employed to construct valuable 2‐arylindoles and heteroaryl carboxylates in a regioselective fashion. C2‐arylated indoles were produced using a Pd‐catalyzed decarboxylative strategy in water without any base, oxidant, or ligand. Heteroaryl carboxylates were prepared under metal and base‐free conditions. This protocol was successfully utilized to synthesize Paullone, a cyclin‐dependent kinase (CDK) inhibitor.     

Synthesis and Application of Tetrahydro‐2H‐fluorenes by a Pd(0)‐Catalyzed Benzylic C(sp3)−H Functionalization

A new method has been developed for the synthesis of tetrahydro‐2H‐fluorenes based on a Pd(0)‐catalyzed benzylic C(sp³)?H functionalization. Importantly, the success of the cyclization step was dependent on there being substituents at the two positions ortho to the benzylic group to avoid an undesired C(sp²)?H functionalization. This method was subsequently used to prepare the right‐hand fragment of the hexacyclic triterpenoid benzohopanes, and therefore represents a powerful tool for the construction of the related compounds.     

Axially Chiral Dibenzazepinones by a Palladium(0)‐Catalyzed Atropo‐enantioselective C−H Arylation

Atropo‐enantioselective C?H functionalization reactions are largely limited to the dynamic kinetic resolution of biaryl substrates through the introduction of steric bulk proximal to the axis of chirality. Reported herein is a highly atropo‐enantioselective palladium(0)‐catalyzed methodology that forges the axis of chirality during the C?H functionalization process, enabling the synthesis of axially chiral dibenzazepinones. Computational investigations support experimentally determined racemization barriers, while also indicating C?H functionalization proceeds by an enantio‐determining CMD to yield configurationally stable eight‐membered palladacycles.     

Palladium‐Catalyzed Cross‐Coupling of Alkenyl Carboxylates

Carboxylate esters have many desirable features as electrophiles for catalytic cross‐coupling: they are easy to access, robust during multistep synthesis, and mass‐efficient in coupling reactions. Alkenyl carboxylates, a class of readily prepared non‐aromatic electrophiles, remain difficult to functionalize through cross‐coupling. We demonstrate that Pd catalysis is effective for coupling electron‐deficient alkenyl carboxylates with arylboronic acids in the absence of base or oxidants. Furthermore, these reactions can proceed by two distinct mechanisms for C?O bond activation. A Pd^0/II catalytic cycle is viable when using a Pd⁰ precatalyst, with turnover‐limiting C?O oxidative addition; however, an alternative pathway that involves alkene carbopalladation and β‐carboxyl elimination is proposed for Pd^II precatalysts. This work provides a clear path toward engaging myriad oxygen‐based electrophiles in Pd‐catalyzed cross‐coupling.     

Chiral Bifunctional Phosphine‐Carboxylate Ligands for Palladium(0)‐Catalyzed Enantioselective C−H Arylation

Previous enantioselective Pd⁰‐catalyzed C?H activation reactions proceeding via the concerted metalation‐deprotonation mechanism employed either a chiral ancillary ligand, a chiral base, or a bimolecular mixture thereof. This study describes the development of new chiral bifunctional ligands based on a binaphthyl scaffold which incorporates both a phosphine and a carboxylic acid moiety. The optimal ligand provided high yields and enantioselectivities for a desymmetrizing C(sp²)?H arylation leading to 5,6‐dihydrophenanthridines, whereas the corresponding monofunctional ligands showed low enantioselectivities. The bifunctional system proved applicable to a range of substituted dihydrophenanthridines, and allowed the parallel kinetic resolution of racemic substrates.     

Microwave‐Assisted Palladium‐Catalyzed Direct Arylation of 1,4‐Disubstituted 1,2,3‐Triazoles with Aryl Chlorides

Treatment of 1,4‐disubstituted 1,2,3‐triazoles with aryl chlorides in the presence of potassium carbonate under palladium catalysis and microwave irradiation at 250 °C for 15 min leads to arylation of the triazole at the 5‐position. A variety of functional groups, including ester and hydroxy groups, are compatible. The procedure is suitable for the regioselective preparation of trisubstituted triazoles. Microwave irradiation accelerates the reaction, thus allowing the rapid synthesis of trisubstituted triazoles, which are difficult to synthesize selectively.     

A Modular Approach to Dibenzo‐fused ϵ‐Lactams: Palladium‐Catalyzed Bridging‐C−H Activation

Tricyclic ring systems possessing a dibenzo structure joined to a seven‐membered heterocyclic ring frequently show important biological activities. However, a modular approach to these molecules based on efficient intermolecular reaction of readily available chemicals is lacking. Herein, an unprecedented palladium‐catalyzed formal [4+3] annulation for modular construction of these tricyclic systems is described. This reaction features easily accessible reactants (o‐haloarylaldehydes and N‐tosylhydrazones), broad substrate scope, and excellent functional group compatibility. The synthetic potential is demonstrated by the easy scale‐up reactions, late‐stage modification of complex molecules, and collective synthesis of bioactive molecules and approved drugs.     

Palladium‐Catalyzed Defluorinative Coupling of 1‐Aryl‐2,2‐Difluoroalkenes and Boronic Acids: Stereoselective Synthesis of Monofluorostilbenes

The palladium‐catalyzed defluorinative coupling of 1‐aryl‐2,2‐difluoroalkenes with boronic acids is described. Broad functional‐group tolerance arises from a redox‐neutral process by a palladium(II) active species which is proposed to undergo a β‐fluoride elimination to afford the products. The monofluorostilbene products were formed with excellent diastereoselectivity (≥50:1) in all cases, and it is critical, as traditional chromatographic techniques often fail to separate monofluoroalkene isomers. As a demonstration of this method's unique combination of reactivity and functional‐group tolerance, a Gleevec® analogue, using a monofluorostilbene as an amide isostere, was synthesized.     

Palladium‐Catalyzed Asymmetric C(sp3)−H Allylation of 2‐Alkylpyridines

The palladium‐catalyzed asymmetric side‐chain C(α)‐allylation of 2‐alkylpyridines, without using an external base, was developed. The high linear selectivities and enantioselectivities were achieved using new chiral diamidophosphite monodentate ligands. Given that the reaction conditions do not require an external base, this catalyst system enabled chemoselective C(α)‐allylation of 2‐alkylpyridines containing α‐carbonyl C?H bonds, which are more acidic than α‐pyridyl C?H bonds.