Asymmetric Synthesis of Chiral 1,2-Bis(Boronic) Esters Featuring Acyclic, Non-Adjacent 1,3-Stereocenters.

The construction of acyclic, non-adjacent 1,3-stereogenic centers, prevalent motifs in drugs and bioactive molecules, has been a long-standing synthetic challenge due to acyclic nucleophiles being distant from the chiral environment. In this study, we successfully synthesized highly valuable 1,2-bis(boronic) esters featuring acyclic and nonadjacent 1,3-stereocenters. Notably, this reaction selectively produces migratory coupling products rather than alternative deborylative allylation or direct allylation byproducts. This approach introduces a new activation mode for selective transformations of gem-diborylmethane in asymmetric catalysis. Additionally, we found that other gem-diborylalkanes, previously challenging due to steric hindrance, also successfully participated in this reaction. The incorporation of 1,2-bis(boryl)alkenes facilitated the diversification of the alkenyl and two boron moieties in our target compounds, thereby enabling access to a broad array of versatile molecules. DFT calculations were performed to elucidate the reaction mechanism and shed light on the factors responsible for the observed excellent enantioselectivity and diastereoselectivity. These were determined to arise from ligand-substrate steric repulsions in the syn-addition transition state.

Ir-Catalyzed Enantioselective Synthesis of gem-Diborylalkenes Enabled by 1,2-Boron Shift.

Asymmetric cross-couplings based on 1,2-carbon migration from B-ate complexes have been developed efficiently to access valuable organoboronates. However, enantioselective reactions triggered by 1,2-boron shift have remained to be unaddressed synthetic challenge. Here, Ir-catalyzed asymmetric allylic alkylation enabled by 1,2-boron shift was developed. In this reaction, we disclosed that excellent enantioselectivities were achieved through an interesting dynamic kinetic resolution (DKR) process of allylic carbonates at the elevated temperature. Notably, the highly valuable (bis-boryl)alkenes have enabled an array of diversifications to access versatile molecules. Extensive experimental and computational studies were conducted to elucidate the reaction mechanism of DKR process and clarify the origin of excellent enantioselectivities.

Palladium-Catalyzed Difunctionalization of Norbornenes via Arylation and Alkynylation.

We report the first general and practical method for the addition of aryl halides and alkynes to norbornenes with palladium catalysis. Norbornenes have been used as the unsaturated acceptors of aryl and alkynyl groups to construct saturated bridged C-C bonds. The combination of Pd(OAc)2/PCy3HBF4 has been identified as the optimal system promoting difunctionalization of norbornenes via the C-X/C-H bond cleavage and highly selective C(sp3)-C(sp2)/C(sp3)-C(sp) bond formation. Broad substrate scope and excellent functional group tolerance have been achieved to show the high efficiency of this approach. Mechanism studies based on experiments and DFT have been performed to gain insights into the catalytic mechanism.

Thiol Reactivity of N-Aryl α-Methylene-γ-lactams: Influence of the Guaianolide Structure.

The α-methylene-γ-lactam offers promise as a complementary warhead for the development of targeted covalent inhibitors. However, an understanding of the factors governing its electrophilic reactivity is needed to promote the development of lead compounds utilizing this motif. Herein we synthesize a series of N-aryl-substituted α-methylene-γ-lactams installed within the framework of a bioactive guaianolide analog. To determine the effects of the guaianolide structure on the electrophilic reactivity, these compounds were reacted with glutathione under biomimetic conditions, and the rate constants were measured. A linear free-energy relationship was observed with the Hammett parameter of the N-aryl group within the cis- or trans-annulated isomeric series of compounds. However, the trans-annulated compounds exhibited a ca. 10-fold increase in reactivity relative to both the cis-annulated compounds and the corresponding N-arylated 3-methylene-2-pyrrolidinones. Density functional theory calculations revealed that the reactivity of the trans-annulated stereoisomers is promoted by the partial release of the ring strain of the fused seven-membered ring in the thio-Michael addition transition state.

Bimetallic Cooperative Catalysis for Decarbonylative Heteroarylation of Carboxylic Acids via C-O/C-H Coupling.

Cooperative bimetallic catalysis is a fundamental approach in modern synthetic chemistry. We report bimetallic cooperative catalysis for the direct decarbonylative heteroarylation of ubiquitous carboxylic acids via acyl C-O/C-H coupling. This novel catalytic system exploits the cooperative action of a copper catalyst and a palladium catalyst in decarbonylation, which enables highly chemoselective synthesis of important heterobiaryl motifs through the coupling of carboxylic acids with heteroarenes in the absence of prefunctionalization or directing groups. This cooperative decarbonylative method uses common carboxylic acids and shows a remarkably broad substrate scope (>70 examples), including late-stage modification of pharmaceuticals and streamlined synthesis of bioactive agents. Extensive mechanistic and computational studies were conducted to gain insight into the mechanism of the reaction. The key step involves intersection of the two catalytic cycles via transmetallation of the copper-aryl species with the palladium(II) intermediate generated by oxidative addition/decarbonylation.

Decarbonylative Suzuki-Miyaura Cross-Coupling of Aroyl Chlorides.

Herein, we report a catalyst system for Pd-catalyzed decarbonylative Suzuki-Miyaura cross-coupling of aroyl chlorides with boronic acids to furnish biaryls. This strategy is suitable for a broad range of common aroyl chlorides and boronic acids. The synthetic utility is highlighted in the direct late-stage functionalization of pharmaceuticals and natural products capitalizing on the presence of carboxylic acid moiety. Extensive mechanistic and DFT studies provide key insight into the reaction mechanism and high decarbonylative cross-coupling selectivity.

Decarbonylative Phosphorylation of Carboxylic Acids via Redox-Neutral Palladium Catalysis.

We describe the direct synthesis of organophosphorus compounds from ubiquitous aryl and vinyl carboxylic acids via decarbonylative palladium catalysis. The catalytic system shows excellent scope and tolerates a wide range of functional groups (>50 examples). The utility of this powerful methodology is highlighted in the late-stage derivatization directly exploiting the presence of the prevalent carboxylic acid functional group. DFT studies provided insight into the origin of high bond activation selectivity and P(O)-H isomerization pathway.

Synthesis of Biaryls via Decarbonylative Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling of Carboxylic Acids.

The biaryl motif is a building block in many drugs, agrochemicals, and materials, and as such it is highly desirable as a synthesis target. The state-of-the-art process for biaryl synthesis from ubiquitous carboxylic acids is decarboxylative cross-coupling involving loss of carbon dioxide (CO2). However, the scope of these methods is severely limited, mainly due to specific substitution required to promote decarboxylation. The present report implements a decarbonylative version with loss of carbon monoxide (CO) that enables to directly engage carboxylic acids in a Suzuki-Miyaura cross-coupling to produce biaryls as a general method with high cross-coupling selectivity using a well-defined Pd(0)/(II) catalytic cycle. This protocol shows a remarkably broad scope (>80 examples) and is performed in the absence of exogenous inorganic bases. In a broader context, the approach shows promise for routine applications in the synthesis of biaryls by carefully controlled decarbonylation of prevalent carboxylic acids.

Highly-chemoselective step-down reduction of carboxylic acids to aromatic hydrocarbons via palladium catalysis.

Aryl carboxylic acids are among the most abundant substrates in chemical synthesis and represent a perfect example of a traceless directing group that is central to many processes in the preparation of pharmaceuticals, natural products and polymers. Herein, we describe a highly selective method for the direct step-down reduction of carboxylic acids to arenes, proceeding via well-defined Pd(0)/(ii) catalytic cycle. The method shows a remarkably broad substrate scope, enabling to direct the classical acyl reduction towards selective decarbonylation by a redox-neutral mechanism. The utility of this reaction is highlighted in the direct defunctionalization of pharmaceuticals and natural products, and further emphasized in a range of traceless processes using removable carboxylic acids under mild, redox-neutral conditions orthogonal to protodecarboxylation. Extensive DFT computations were conducted to demonstrate preferred selectivity for the reversible oxidative addition and indicated that a versatile hydrogen atom transfer (HAT) pathway is operable.

Highly Chemoselective, Transition-Metal-Free Transamidation of Unactivated Amides and Direct Amidation of Alkyl Esters by N-C/O-C Cleavage.

The amide bond is one of the most fundamental functional groups in chemistry and biology and plays a central role in numerous processes harnessed to streamline the synthesis of key pharmaceutical and industrial molecules. Although the synthesis of amides is one of the most frequently performed reactions by academic and industrial scientists, the direct transamidation of tertiary amides is challenging due to unfavorable kinetic and thermodynamic contributions of the process. Herein, we report the first general, mild, and highly chemoselective method for transamidation of unactivated tertiary amides by a direct acyl N-C bond cleavage with non-nucleophilic amines. This operationally simple method is performed in the absence of transition metals and operates under unusually mild reaction conditions. In this context, we further describe the direct amidation of abundant alkyl esters to afford amide bonds with exquisite selectivity by acyl C-O bond cleavage. The utility of this process is showcased by a broad scope of the method, including various sensitive functional groups, late-stage modification, and the synthesis of drug molecules (>80 examples). Remarkable selectivity toward different functional groups and within different amide and ester electrophiles that is not feasible using existing methods was observed. Extensive experimental and computational studies were conducted to provide insight into the mechanism and the origins of high selectivity. We further present a series of guidelines to predict the reactivity of amides and esters in the synthesis of valuable amide bonds by this user-friendly process. In light of the importance of the amide bond in organic synthesis and major practical advantages of this method, the study opens up new opportunities in the synthesis of pivotal amide bonds in a broad range of chemical contexts.

Nickel-Catalyzed Kumada Coupling of Boc-Activated Aromatic Amines via Nondirected Selective Aryl C-N Bond Cleavage.

A nickel-catalyzed Kumada coupling of aniline derivatives was developed by selective cleavage of aryl C-N bonds under mild reaction conditions. Without preinstallation of an ortho directing group on anilines, the cross-coupling reactions of Boc-protected aromatic amines with aryl Grignard reagents afforded unsymmetric biaryls. Mechanistic studies by DFT calculations revealed that the nickel-mediated C-N bond cleavage is the rate-limiting step.

Palladium-catalyzed decarbonylative Suzuki-Miyaura cross-coupling of amides by carbon-nitrogen bond activation.

Palladium-catalyzed Suzuki-Miyaura cross-coupling or aryl halides is widely employed in the synthesis of many important molecules in synthetic chemistry, including pharmaceuticals, polymers and functional materials. Herein, we disclose the first palladium-catalyzed decarbonylative Suzuki-Miyaura cross-coupling of amides for the synthesis of biaryls through the selective activation of the N-C(O) bond of amides. This new method relies on the precise sequence engineering of the catalytic cycle, wherein decarbonylation occurs prior to the transmetallation step. The reaction is compatible with a wide range of boronic acids and amides, providing valuable biaryls in high yields (>60 examples). DFT studies support a mechanism involving oxidative addition, decarbonylation and transmetallation and provide insight into high N-C(O) bond activation selectivity. Most crucially, the reaction establishes the use of palladium catalysis in the biaryl Suzuki-Miyaura cross-coupling of the amide bond and should enable the design of a wide variety of cross-coupling methods in which palladium rivals the traditional biaryl synthesis from aryl halides and pseudohalides.

Computational Study of Mechanism and Thermodynamics of Ni/IPr-Catalyzed Amidation of Esters.

Nickel catalysis has shown remarkable potential in amide C⁻N bond activation and functionalization. Particularly for the transformation between ester and amide, nickel catalysis has realized both the forward (ester to amide) and reverse (amide to ester) reactions, allowing a powerful approach for the ester and amide synthesis. Based on density functional theory (DFT) calculations, we explored the mechanism and thermodynamics of Ni/IPr-catalyzed amidation with both aromatic and aliphatic esters. The reaction follows the general cross-coupling mechanism, involving sequential oxidative addition, proton transfer, and reductive elimination. The calculations indicated the reversible nature of amidation, which highlights the importance of reaction thermodynamics in related reaction designs. To shed light on the control of thermodynamics, we also investigated the thermodynamic free energy changes of amidation with a series of esters and amides.

Palladium-Catalyzed Decarbonylative Borylation of Carboxylic Acids: Tuning Reaction Selectivity by Computation.

Decarbonylative borylation of carboxylic acids is reported. Carbon electrophiles are generated directly after reagent-enabled decarbonylation of the in situ accessible sterically-hindered acyl derivative of a carboxylic acid under catalyst controlled conditions. The scope and the potential impact of this method are demonstrated in the selective borylation of a variety of aromatics (>50 examples). This strategy was used in the late-stage derivatization of pharmaceuticals and natural products. Computations reveal the mechanistic details of the unprecedented C-O bond activation of carboxylic acids. By circumventing the challenging decarboxylation, this strategy provides a general synthetic platform to access arylpalladium species for a wide array of bond formations from abundant carboxylic acids. The study shows a powerful combination of experiment and computation to predict decarbonylation selectivity.

Factors Controlling the Reactivity and Chemoselectivity of Resonance Destabilized Amides in Ni-Catalyzed Decarbonylative and Nondecarbonylative Suzuki-Miyaura Coupling.

N-Glutarimide amides have recently emerged as an exceptional group of compounds with unusually high reactivity in amide C-N bond activation. To understand the key factors that control the remarkable reactivity of these resonance destabilized amides, we explored the Ni-catalyzed decarbonylative and nondecarbonylative Suzuki-Miyaura coupling with N-glutarimide amides through density functional theory calculations. Two leading effects are responsible for the C-N cleavage activity of N-glutarimide amides, the coordinating N-substituents and the geometric twisting. The carbonyl substituent of the N-glutarimide amides provides crucial nickel-oxygen interaction, which essentially acts as a directing group to facilitate the formation of the reactive intermediate for the amide C-N bond cleavage. The geometric twisting weakens the resonance stability by removing the acyl-nitrogen conjugation, which lowers the energy penalty for the C-N bond stretch during oxidative addition. For the chemoselectivity of decarbonylation versus carbonyl retention, we found that the C-C reductive elimination for ketone formation is kinetically faster than that for biaryl formation, while ketone is thermodynamically less stable with respect to the decarbonylated biaryls. The computations also suggest that the nickel catalyst is able to promote the decarbonylation of biaryl ketones via an unexpected C-C bond activation.

Mechanism and Origins of Ligand-Controlled Stereoselectivity of Ni-Catalyzed Suzuki-Miyaura Coupling with Benzylic Esters: A Computational Study.

Nickel catalysts have shown unique ligand control of stereoselectivity in the Suzuki-Miyaura cross-coupling of boronates with benzylic pivalates and derivatives involving C(sp3)-O cleavage. The SIMes ligand (1,3-dimesityl-4,5-dihydroimidazol-2-ylidene) produces the stereochemically inverted C-C coupling product, while the tricyclohexylphosphine (PCy3) ligand delivers the retained stereochemistry. We have explored the mechanism and origins of the ligand-controlled stereoselectivity with density functional theory (DFT) calculations. The oxidative addition determines the stereoselectivity with two competing transition states, an SN2 back-side attack type transition state that inverts the benzylic stereogenic center and a concerted oxidative addition through a cyclic transition state, which provides stereoretention. The key difference between the two transition states is the substrate-nickel-ligand angle distortion; the ligand controls the selectivity by differentiating the ease of this angle distortion. For the PCy3 ligand, the nickel-ligand interaction involves mainly σ-donation, which does not require a significant energy penalty for the angle distortion. The facile angle distortion with PCy3 ligand allows the favorable cyclic oxidative addition transition state, leading to the stereoretention. For the SIMes ligand, the extra d-p back-donation from nickel to the coordinating carbene increases the rigidity of the nickel-ligand bond, and the corresponding angle distortion is more difficult. This makes the concerted cyclic oxidative addition unfavorable with SIMes ligand, and the back-side SN2-type oxidative addition delivers the stereoinversion.