Palladium(II)‐Catalyzed Enantioselective Arylation of Unbiased Methylene C(sp3)−H Bonds Enabled by a 2‐Pyridinylisopropyl Auxiliary and Chiral Phosphoric Acids

Enantioselective functionalizations of unbiased methylene C(sp³)?H bonds of linear systems by metal insertion are intrinsically challenging and remain a largely unsolved problem. Herein, we report a palladium(II)‐catalyzed enantioselective arylation of unbiased methylene β‐C(sp³)?H bonds enabled by the combination of a strongly coordinating bidentate PIP auxiliary with a monodentate chiral phosphoric acid (CPA). The synergistic effect between the PIP auxiliary and the non‐C₂‐symmetric CPA is crucial for effective stereocontrol. A broad range of aliphatic carboxylic acids and aryl bromides can be used, providing β‐arylated aliphatic carboxylic acid derivatives in high yields (up to 96 %) with good enantioselectivities (up to 95:5 e.r.). Notably, this reaction also represents the first palladium(II)‐catalyzed enantioselective C?H activation with less reactive and cost‐effective aryl bromides as the arylating reagents. Mechanistic studies suggest that a single CPA is involved in the stereodetermining C?H palladation step.     

Triiodide‐Mediated δ‐Amination of Secondary C−H Bonds

The C_δ?H amination of unactivated, secondary C?H bonds to form a broad range of functionalized pyrrolidines has been developed by a triiodide (I₃^?)‐mediated strategy. By in situ 1) oxidation of sodium iodide and 2) sequestration of the transiently generated iodine (I₂) as I₃^?, this approach precludes undesired I₂‐mediated decomposition which can otherwise limit synthetic utility to only weak C(sp³)?H bonds. The mechanism of this triiodide‐mediated cyclization of unbiased, secondary C(sp³)?H bonds, by either thermal or photolytic initiation, is supported by NMR and UV/Vis data, as well as intercepted intermediates.     

Copper‐Catalyzed Site‐Selective Intramolecular Amidation of Unactivated C(sp3)H Bonds

The intramolecular dehydrogenative amidation of aliphatic amides, directed by a bidentate ligand, was developed using a copper‐catalyzed sp³ C? H bond functionalization process. The reaction favors predominantly the C? H bonds of β‐methyl groups over the unactivated methylene C? H bonds. Moreover, a preference for activating sp³ C? H bonds of β‐methyl groups, via a five‐membered ring intermediate, over the aromatic sp² C? H bonds was also observed in the cyclometalation step. Additionally, sp³ C? H bonds of unactivated secondary sp³ C? H bonds could be functionalized by favoring the ring carbon atoms over the linear carbon atoms.     

Copper‐Catalyzed Bromination of C(sp3)−H Bonds Distal to Functional Groups

Selective bromination of γ‐methylene C(sp³)−H bonds of aliphatic amides and δ‐methylene C(sp³)−H bonds of nosyl‐protected alkyl amines are developed using NBS as the brominating reagent and catalytic amount of Cu^II/phenanthroline complexes as the catalyst. Aryl and benzylic C−H bonds at other locations remain intact during this directed radical abstraction reaction.     

Ligand‐Enabled Alkynylation of C(sp3)−H Bonds with Palladium(II) Catalysts

The palladium(II)‐catalyzed β‐ and γ‐alkynylation of amide C(sp³)−H bonds is enabled by pyridine‐based ligands. This alkynylation reaction is compatible with substrates containing α‐tertiary or α‐quaternary carbon centers. The β‐methylene C(sp³)−H bonds of various carbocyclic rings were also successfully alkynylated.     

Practical Synthesis of anti‐β‐Hydroxy‐α‐Amino Acids by PdII‐Catalyzed Sequential C(sp3)H Functionalization

An improved and practical procedure for the stereoselective synthesis of anti‐β‐hydroxy‐α‐amino acids (anti‐βhAAs), by palladium‐catalyzed sequential C(sp³)?H functionalization directed by 8‐aminoquinoline auxiliary, is described. followed by a previously established monoarylation and/or alkylation of the β‐methyl C(sp³)?H of alanine derivative, β‐acetoxylation of both alkylic and benzylic methylene C(sp³)?H bonds affords various anti‐β‐hydroxy‐α‐amino acid derivatives. As an example, the synthesis of β‐mercapto‐α‐amino acids, which are highly important to the extension of native chemical ligation chemistry beyond cysteine, is described. The synthetic potential of this protocol is further demonstrated by the synthesis of diverse β‐branched α‐amino acids. The observed diastereoselectivities are strongly influenced by electronic effects of aromatic AAs and steric effects of the linear side‐chain AAs, which could be explained by the competition of intramolecular C?OAc bond reductive elimination from Pd^IV intermediates vs. intermolecular attack by an external nucleophile (AcO^?) in an S_N2‐type process.     

Nickel‐Catalyzed Site‐Selective Amidation of Unactivated C(sp3)H Bonds

Intramolecular dehydrogenative cyclization of aliphatic amides was achieved on unactivated sp³ carbon atoms by a nickel‐catalyzed C?H bond functionalization process with the assistance of a bidentate directing group. The reaction favors the C?H bonds of β‐methyl groups over the γ‐methyl or β‐methylene groups. Additionally, a predominant preference for the β‐methyl C?H bonds over the aromatic sp² C?H bonds was observed. Moreover, this process also allows for the effective functionalization of benzylic secondary sp³ C?H bonds.     

Palladium‐Catalyzed Arylation of Unactivated γ‐Methylene C(sp3)H and δ‐CH Bonds with an Oxazoline‐Carboxylate Auxiliary

A palladium‐catalyzed arylation of unactivated γ‐methylene C(sp³)?H and remote δ‐C?H bonds by using an oxazoline‐carboxylate directing group has been developed. Arylation occurs with a broad substrate scope and high tolerance of functional groups (i.e., halogen, nitro, cyano, ether, trifluoromethyl, amine, and ester). The oxazoline‐type auxiliary can be removed under acidic conditions.     

Distal γ‐C(sp3)−H Olefination of Ketone Derivatives and Free Carboxylic Acids

Reported herein is the distal γ‐C(sp³)?H olefination of ketone derivatives and free carboxylic acids. Fine tuning of a previously reported imino‐acid directing group and using the ligand combination of a mono‐N‐protected amino acid (MPAA) and an electron‐deficient 2‐pyridone were critical for the γ‐C(sp³)?H olefination of ketone substrates. In addition, MPAAs enabled the γ‐C(sp³)?H olefination of free carboxylic acids to form diverse six‐membered lactones. Besides alkyl carboxylic acids, benzylic C(sp³)?H bonds also could be functionalized to form 3,4‐dihydroisocoumarin structures in a single step from 2‐methyl benzoic acid derivatives. The utility of these protocols was demonstrated in large scale reactions and diversification of the γ‐C(sp³)?H olefinated products.     

Site‐Selective δ‐C(sp3)−H Alkylation of Amino Acids and Peptides with Maleimides via a Six‐Membered Palladacycle

The site‐selective functionalization of unactivated C(sp³)?H bonds remains one of the greatest challenges in organic synthesis. Herein, we report on the site‐selective δ‐C(sp³)?H alkylation of amino acids and peptides with maleimides via a kinetically less favored six‐membered palladacycle in the presence of more accessible γ‐C(sp³)?H bonds. Experimental studies revealed that C?H bond cleavage occurs reversibly and preferentially at γ‐methyl over δ‐methyl C?H bonds while the subsequent alkylation proceeds exclusively at the six‐membered palladacycle that is generated by δ‐C?H activation. The selectivity can be explained by the Curtin–Hammett principle. The exceptional compatibility of this alkylation with various oligopeptides renders this procedure valuable for late‐stage peptide modifications. Notably, this process is also the first palladium(II)‐catalyzed Michael‐type alkylation reaction that proceeds through C(sp³)?H activation.     

Catalytic Enantioselective Methylene C(sp3)−H Amidation of 8‐Alkylquinolines Using a Cp*RhIII/Chiral Carboxylic Acid System

Catalytic enantioselective directed methylene C(sp³)?H amidation reactions of 8‐alkylquinolines using a Cp*Rh^III/chiral carboxylic acid (CCA) hybrid catalytic system are described. A binaphthyl‐based chiral carboxylic acid efficiently differentiates between the enantiotopic methylene C?H bonds, which leads to the formation of C?N bonds with good enantioselectivity.     

γ‐Functionalizations of Amines through Visible‐Light‐Mediated,Redox‐Neutral C−C Bond Cleavage

Cleavage of unstrained C−C bonds under mild, redox‐neutral conditions represents a challenging endeavor which is accomplished here in the context of a flexible, visible‐light‐mediated, γ‐functionalization of amines. In situ generated C‐centered radicals are harvested in the presence of Michael acceptors, thiols and alkyl halides to efficiently form new C(sp³)−C(sp³), C(sp³)−H and C(sp³)−Br bonds, respectively.     

γ‐Functionalizations of Amines through Visible‐Light‐Mediated,Redox‐Neutral C−C Bond Cleavage

Cleavage of unstrained C−C bonds under mild, redox‐neutral conditions represents a challenging endeavor which is accomplished here in the context of a flexible, visible‐light‐mediated, γ‐functionalization of amines. In situ generated C‐centered radicals are harvested in the presence of Michael acceptors, thiols and alkyl halides to efficiently form new C(sp³)−C(sp³), C(sp³)−H and C(sp³)−Br bonds, respectively.     

Selective Functionalization of Aromatic C(sp2)−H Bonds in the Presence of Benzylic C(sp3)−H Bonds by Electron‐Deficient Carbenoids Generated from 4‐Acyl‐1‐Sulfonyl‐1,2,3‐Triazoles

A rhodium(II)‐catalyzed reaction of newly prepared 4‐acyl‐1‐sulfonyl‐1,2,3‐triazoles with benzene, and its derivatives, is investigated. Acceptor/acceptor carbenoids generated from 4‐acyltriazoles undergo selective insertion at aromatic C(sp²)−H bonds in the presence of benzylic C(sp³)−H bonds to produce N ‐sulfonylenaminones.     

(2S,3S)‐2,6‐Dimethylheptane‐1,3‐diol,the oxygenated side chain of 22(S)‐hydroxycholestrol,and its synthetic precursor (R)‐4‐benzyl‐3‐[(2R,3S)‐3‐hydroxy‐2,6‐dimethylheptanoyl]‐1,3‐oxazolidin‐2‐one

(2S,3S)‐2,6‐Dimethylheptane‐1,3‐diol, C₉H₂₀O₂, (I), was synthesized from the ketone (R)‐4‐benzyl‐3‐[(2R,3S)‐3‐hydroxy‐2,6‐dimethylheptanoyl]‐1,3‐oxazolidin‐2‐one, C₁₉H₂₇NO₄, (II), containing C atoms of known chirality. In both structures, strong hydrogen bonds between the hydroxy groups form tape motifs. The contribution from weaker C—H...O hydrogen bonds is much more evident in the structure of (II), which furthermore contains an example of a direct short Osp³...Csp² contact that represents a usually unrecognized type of intermolecular interaction.     

Merging Photochemistry with Electrochemistry: Functional‐Group Tolerant Electrochemical Amination of C(sp3)−H Bonds

Direct amination of C(sp³)?H bonds is of broad interest in the realm of C?H functionalization because of the prevalence of nitrogen heterocycles and amines in pharmaceuticals and natural products. Reported here is a combined electrochemical/photochemical method for dehydrogenative C(sp³)?H/N?H coupling that exhibits good reactivity with both sp² and sp³ N?H bonds. The results show how use of iodide as an electrochemical mediator, in combination with light‐induced cleavage of intermediate N?I bonds, enables the electrochemical process to proceed at low electrode potentials. This approach significantly improves the functional‐group compatibility of electrochemical C?H amination, for example, tolerating electron‐rich aromatic groups that undergo deleterious side reactions in the presence of high electrode potentials.     

Ligand‐Enabled β‐Methylene C(sp3)−H Arylation of Masked Aliphatic Alcohols

Despite recent advances, reactivity and site‐selectivity remain significant obstacles for the practical application of C(sp³)?H bond functionalization methods. Here, we describe a system that combines a salicylic‐aldehyde‐derived L,X‐type directing group with an electron‐deficient 2‐pyridone ligand to enable the β‐methylene C(sp³)?H arylation of aliphatic alcohols, which has not been possible previously. Notably, this protocol is compatible with heterocycles embedded in both alcohol substrates and aryl coupling partners. A site‐ and stereo‐specific annulation of dihydrocholesterol and the synthesis of a key intermediate of englitazone illustrate the practicality of this method.     

Redox‐Neutral Coupling between Two C(sp3)−H Bonds Enabled by 1,4‐Palladium Shift for the Synthesis of Fused Heterocycles

The intramolecular coupling of two C(sp³)?H bonds to forge a C(sp³)?C(sp³) bond is enabled by 1,4‐Pd shift from a trisubstituted aryl bromide. Contrary to most C(sp³)?C(sp³) cross‐dehydrogenative couplings, this reaction operates under redox‐neutral conditions, with the C?Br bond acting as an internal oxidant. Furthermore, it allows the coupling between two moderately acidic primary or secondary C?H bonds, which are adjacent to an oxygen or nitrogen atom on one side, and benzylic or adjacent to a carbonyl group on the other side. A variety of valuable fused heterocycles were obtained from easily accessible ortho‐bromophenol and aniline precursors. The second C?H bond cleavage was successfully replaced with carbonyl insertion to generate other types of C(sp³)‐C(sp³) bonds.     

Synthesis of α‐Aryl Esters and Nitriles: Deaminative Coupling of α‐Aminoesters and α‐Aminoacetonitriles with Arylboronic Acids

Transition‐metal‐free synthesis of α‐aryl esters and nitriles using arylboronic acids with α‐aminoesters and α‐aminoacetonitriles, respectively, as the starting materials has been developed. The reaction represents a rare case of converting C(sp³)? N bonds into C(sp³)? C(sp²) bonds. The reaction conditions are mild, demonstrate good functional‐group tolerance, and can be scaled up.     

Palladium‐Catalyzed Intramolecular Carbene Insertion into C(sp3)−H Bonds

A palladium‐catalyzed carbene insertion into C(sp³)?H bonds leading to pyrrolidines was developed. The coupling reaction can be catalyzed by both Pd⁰ and Pd^II, is regioselective, and shows a broad functional group tolerance. This reaction is the first example of palladium‐catalyzed C(sp³)?C(sp³) bond assembly starting from diazocarbonyl compounds. DFT calculations revealed that this direct C(sp³)?H bond functionalization reaction involves an unprecedented concerted metalation–deprotonation step.