Benzylic Sites Research Articles

Dual NHC/HAT‐Promoted Esterification to Access α‐Aryl Glycines

α‐Aryl glycines are among the more important carbonyl compounds, particularly as nonproteinogenic α‐amino acids present in many pharmacophores. As such, many strategies have been developed to access this motif, but direct carboxylation methods remain underdeveloped. Herein, we employ a dual NHC/HAT catalysis strategy to access 2‐azaallyl radicals, which subsequently couple with in situ generated ester azolium radical intermediates. Base‐mediated collapse of the ensuing tetrahedral intermediate liberates the NHC catalyst and benzophenone protected aryl glycine. This methodology was employed to esterify obtain a variety of aryl substituted glycine derivatives, as well as allylic and benzylic sites. Mechanistic studies reveal that this radical process operates under both oxidative and reductive quenching cycles, while preliminary experiments employing a chiral NHC and Lewis acid additive demonstrate modest enantioselectivity.

C-H amination chemistry mediated by trinuclear Cu(I) sites supported by a ligand scaffold featuring an arene platform and tetramethylguanidinyl residues.

Tripodal ligands that can encapsulate single or multiple metal sites in C3-symmetric geometric configurations constitute valuable targets for novel catalysts. Of particular interest in ligand development are efforts toward incorporating apical elements that exhibit little if any electron donicity, to enhance the electrophilic nature of a trans positioned active oxidant (e.g., metal-oxo, -nitrene). The tripodal ligand TMG3trphen-Arene has been synthesized, featuring an arene platform 1,3,5-substituted with phenylene arms possessing tetramethylguanidinyl (TMG) residues. Compound [(TMG3trphen-Arene)Cu3(μ-Cl)3] has been subsequently synthesized by extracting a Cu3(μ-Cl)3 cluster from anhydrous CuCl and shown to encapsulate a crown-shaped Cu3(μ-Cl)3 fragment, supported by Cu-NTMG bonds and modest Cu3⋯arene long-range contacts. Energy decomposition analysis (EDA) indicates that electrostatic contributions to the total interaction energy far exceed those due to orbital interactions. The latter involve orbital pairings largely associated with the NTMG stabilization of the Cu3(μ-Cl)3 cluster. The independent gradient model based on the Hirshfeld partition (IGMH) corroborates that contacts between the arene platform and the Cu3 triangle are noncovalent in nature. Catalyst [(TMG3trphen-Arene)Cu3(μ-Cl)3] enables amination of sec-benzylic and tert-C-H bonds of a panel of substrates by pre-synthesized PhINTces in solvent matrices that incorporate small amounts of HFIP. The involvement of an electrophilic aminating agent is evidenced by the better yields obtained for electron-rich benzylic sites and is further supported by Hammett analysis that reveals the development of a small positive charge during C-H bond activation. A rather modest KIE effect (2.1) is obtained from intramolecular H(D) competition in the amination of ethylbenzene, at the borderline of reported values for concerted and stepwise C-H amination systems. DFT analysis of the putative copper-nitrene oxidant indicates that the nitrene N atom is bridging between two copper sites in closely spaced triplet (ground state) and broken-symmetry singlet electronic configurations.

Palladium‐Catalyzed Direct C(sp3)−H Arylation of 5H‐Imidazo[2,1‐a]isoindole Scaffolds With Arylbromides

AbstractThe study of Pd(0)‐catalyzed C−H bond arylation of methyl 5H‐imidazo[2,1‐a]isoindole‐3‐carboxylates with aryl bromides is reported. This methodology gives ready access to a wide range of methyl 5H‐imidazo[2,1‐a]isoindole‐3‐carboxylates that are monoarylated at their benzylic sites. The C(sp3)−H bond arylation methodology is driven by regioselectivity under weakly basic conditions avoiding remarkably side C(sp2)−H poly‐arylation of the (hetero)aromatic unit. The process was applied to the preparation of novel imidazo[2,1‐a]isoindole‐based neurotransmitter Neuropeptide S antagonist analog.

Photoinduced copper catalyzed nitrogen-to-alkyl radical relay Sonogashira-type coupling of o-alkylbenzamides with alkynes.

This report describes a copper-catalyzed, photoinduced N-to-alkyl radical relay Sonogashira-type reactions at benzylic sites in o-alkylbenzamides with alkynes. The process employs an N-to-alkyl radical mechanism, initiated through the copper-catalyzed reductive generation of nitrogen radicals. Radical translocation is facilitated by a 1,5-hydrogen atom transfer (1,5-HAT), leading to the formation of translocated carbon radicals. These radicals are then subjected to copper-catalyzed alkynylation. The methodology exhibits broad sub-strate scope and applicability to the synthesis of complex natural products.

Stereoselective benzylic C(sp3)-H alkenylation enabled by metallaphotoredox catalysis.

Selective activation of the benzylic C(sp3)-H bond is pivotal for the construction of complex organic frameworks. Achieving precise selectivity among C-H bonds with comparable energetic and steric profiles remains a profound synthetic challenge. Herein, we unveil a site- and stereoselective benzylic C(sp3)-H alkenylation utilizing metallaphotoredox catalysis. Various linear and cyclic (Z)-all-carbon tri- and tetrasubstituted olefins can be smoothly obtained. This strategy can be applied to complex substrates with multiple benzylic sites, previously deemed unsuitable due to the uncontrollable site-selectivity. In addition, sensitive functional groups such as terminal alkenyl and TMS groups are compatible under the mild conditions. The exceptional site-selectivity and broad substrate compatibility are attributed to the visible-light catalyzed relay electron transfer-proton transfer process. More importantly, we have extended this methodology to achieve enantioselective benzylic C(sp3)-H alkenylation, producing highly enantioenriched products. The applicability and scalability of our protocol are further validated through late-stage functionalization of complex structures and gram-scale operations, underscoring its practicality and robustness.

A Simple Access to γ- and ε-Keto Arenes via Enzymatic Divergent C─H Bond Oxyfunctionalization.

Performing divergent C─H bond functionalization on molecules with multiple reaction sites is a significant challenge in organic chemistry. Biocatalytic oxyfunctionalization reactions of these compounds to the corresponding ketones/aldehydes are typically hindered by selectivity issues. To address these challenges, the catalytic performance of oxidoreductases is explored. The results show that combining the peroxygenase-catalyzed propargylic C─H bond oxidation with the Old Yellow Enzyme-catalyzed reduction of conjugated C─C triple bonds in one-pot enables the regio- and chemoselective oxyfunctionalization of sp3 C─H bonds that are distant from benzylic sites. This enzymatic approach yielded a variety of γ-keto arenes with diverse structural and electronic properties in yields of up to 99% and regioselectivity of 100%, which are difficult to achieve using other chemocatalysis and enzymes. By adjusting the C─C triple bond, the carbonyl group's position can be further tuned to yield ε-keto arenes. This enzymatic approach can be combined with other biocatalysts to establish new synthetic pathways for accessing various challenging divergent C─H bond functionalization reactions.

Cu‐Catalyzed Site‐ and Enantioselective Borylcyanation of 1,2‐Disubstituted Aryl Alkenes

AbstractA catalytic chemo‐ and enantioselective generation of secondary benzylic copper complexes from Cu−B(pin) (pin=pinacolato) additions to 1,2‐disubstituted aryl alkenes followed by in situ site selective cyanation at either aryl group or benzylic position to construct multifunctional alkylboron compounds is presented. The method is distinguished by identification of chiral Cu complexes leading to not only high enantioselectivity but also better efficiency compared with achiral catalysts. In addition, an unprecedented mode of cyanation at benzylic site through dearomative isomerization was disclosed. Functionalization of multifunctional alkylboron products provides useful building blocks that are otherwise difficult to access.

Photoinduced Nitrogen-to-Alkyl Radical Relay Heck Reaction of o-Alkylbenzamides with Vinyl Arenes by Palladium Catalysis.

Here, a palladium-catalyzed photoinduced N-to-alkyl radical relay Heck reaction of o-alkylbenzamides at benzylic sites with vinyl arenes is described. The reaction employs neither exogeneous photosensitizers nor external oxidants. It is proposed to proceed via a N-to-alkyl hybrid palladium-radical mechanism which occurs under mild conditions that are compatible with a wide range of functional groups. The products are easily transformed to azepinone derivatives, which are prevalent in pharmaceuticals and natural products.

Poly(arylene alkylene)s with pendent benzyl-tethered ammonium cations for anion exchange membranes

Polymeric anion-exchange membranes (AEMs) with alkali-stable quaternary ammonium (QA) cations are essential components for the development of alkaline membrane fuel cells and water electrolyzers. Ionic loss by β-elimination reactions typically accelerates at low water contents, i.e., high alkali concentrations, which makes QA cations attached to polymer backbones via benzylic sites interesting alternatives. In the present study, we synthesized and studied a series of ether-free poly(biphenyl alkylene)s (PB) and poly(p-terphenyl alkylene)s (PT) functionalized with different mono- or di-QA groups placed in benzylic positions. By employing different synthetic strategies, we systematically varied both the polymer backbone and the cationic structure to investigate the effect on morphology, alkaline stability and hydroxide conductivity. Two precursor polymers were first synthesized via superacid-mediated polyhydroxyalkylations involving 4′-methyl-2,2,2-trifluoroacetophenone, and biphenyl and p-terphenyl, respectively. Next, these polymers were benzylbrominated to allow the introduction of trimetylammonium (TMA), quinuclidinium (Qui), piperidinium (Pip), and bis-piperidinium (bisPip) cations, respectively, through Menshutkin reactions. The ionic content was conveniently controlled by adjusting the degree of bromination through the efficient Wohl-Ziegler reaction. AEMs functionalized with bisPip groups efficiently formed ionic clusters to reach high hydroxide ion conductivities, up to 78 and 133 mS cm−1 at 20 and 80 °C, respectively, and only decomposed above 262 °C. After storage in 1 M aq. NaOH at 80 °C, AEMs functionalized with Qui, and bisPip cations showed less ionic losses in comparison to those carrying Pip and TMA cations, which may be due to the bulky structure of the cage-like Qui cation. Careful 1H NMR analysis indicated that at low alkaline concentration, loss by nucleophilic substitution at benzylic positions dominated, while ring opening by Hofmann β-elimination of the alicyclic QAs accelerated at higher alkali concentrations. The findings of the present study provided valuable insights into the influence of structure and position of QAs on the stability and degradation mechanisms of benzylic QA cations at different alkali concentrations.

Coordination‐Controlled Nickel‐Catalyzed Benzylic Allylation of Unactivated Electron‐Deficient Heterocycles

AbstractHeterocycles are widespread in pharmaceuticals but methods for their transition metal‐catalyzed functionalization remain limited. This report describes a general, mild, and effective nickel‐catalyzed benzylic allylation and benzylation of 14 types of heterocyclic aromatic compounds, including pyridines, pyrazines, pyrimidines, pyridazines, triazines, benzimidazoles, oxazoles, thiazoles, as well as 3,3‐dimethyl‐indoles. The exquisite selectivity for benzylic sites at the 2‐position is hypothesized to be controlled by coordination of a heterocyclic nitrogen to Zn(TMP)2 subverting generally presumed pKa’s of benzylic protons. Furthermore, the broad range of heterocyclic substrates, the diversity of electrophiles, and excellent functional group compatibility suggest its future application to synthesis of complex molecules and library diversification in drug discovery.

Coordination-Controlled Nickel-Catalyzed Benzylic Allylation of Unactivated Electron-Deficient Heterocycles.

Heterocycles are widespread in pharmaceuticals but methods for their transition metal-catalyzed functionalization remain limited. This report describes a general, mild, and effective nickel-catalyzed benzylic allylation and benzylation of 14 types of heterocyclic aromatic compounds, including pyridines, pyrazines, pyrimidines, pyridazines, triazines, benzimidazoles, oxazoles, thiazoles, as well as 3,3-dimethyl-indoles. The exquisite selectivity for benzylic sites at the 2-position is hypothesized to be controlled by coordination of a heterocyclic nitrogen to Zn(TMP)2 subverting generally presumed pKa 's of benzylic protons. Furthermore, the broad range of heterocyclic substrates, the diversity of electrophiles, and excellent functional group compatibility suggest its future application to synthesis of complex molecules and library diversification in drug discovery.

Mechanistically Guided Workflow for Relating Complex Reactive Site Topologies to Catalyst Performance in C-H Functionalization Reactions.

Leveraging congested catalyst scaffolds has emerged as a key strategy for altering innate substrate site-selectivity profiles in C-H functionalization reactions. Similar to enzyme active sites, optimal small molecule catalysts often feature reactive cavities tailored for controlling substrate approach trajectories. However, relating three-dimensional catalyst shape to reaction output remains a formidable challenge, in part due to the lack of molecular features capable of succinctly describing complex reactive site topologies in terms of numerical inputs for machine learning applications. Herein, we present a new set of descriptors, "Spatial Molding for Approachable Rigid Targets" (SMART), which we have applied to quantify reactive site spatial constraints for an expansive library of dirhodium catalysts and to predict site-selectivity for C-H functionalization of 1-bromo-4-pentylbenzene via donor/acceptor carbene intermediates. Optimal site-selectivity for the terminal methylene position was obtained with Rh2(S-2-Cl-5-MesTPCP)4 (30.9:1 rr, 14:1 dr, 87% ee), while C-H functionalization at the electronically activated benzylic site was increasingly favored for Rh2(TPCP)4 catalysts lacking an ortho-Cl, Rh2(S-PTAD)4, and Rh2(S-TCPTAD)4, respectively. Intuitive global site-selectivity models for 25 disparate dirhodium catalysts were developed via multivariate linear regression to explicitly assess the contributing roles of steric congestion and dirhodium-carbene electrophilicity in controlling the site of C-H functionalization. The workflow utilizes spatial classification to extract descriptors only for reactive catalyst conformers, a nuance that may be widely applicable for establishing close correspondence between ground-state model systems and transition states. Broader still, SMART descriptors are amenable for delineating salient reactive site features to predict reactivity in other chemical and biological contexts.

Methane assisted catalyst synthesis and catalytic conversion of oleic acid

CH4-assisted synthesis of ZSM-5 enhances deoxygenation of oleic acid with methane as a co-reactant. Synthesis under CH4 environment produces a potential memory effect, yielding benzylic site and CO2 incorporation of the CH4 species.

Catalytic Intermolecular C(sp3)-H Amination: Selective Functionalization of Tertiary C-H Bonds vs Activated Benzylic C-H Bonds.

A catalytic intermolecular amination of nonactivated tertiary C(sp3)-H bonds (BDE of 96 kcal·mol-1) is reported for substrates displaying an activated benzylic site (BDE of 85 kcal·mol-1). The tertiary C(sp3)-H bond is selectively functionalized to afford α,α,α-trisubstituted amides in high yields. This unusual site-selectivity results from the synergistic combination of Rh2(S-tfpttl)4, a rhodium(II) complex with a well-defined catalytic pocket, with tert-butylphenol sulfamate (TBPhsNH2), which leads to a discriminating rhodium-bound nitrene species under mild oxidative conditions. This catalytic system is very robust, and the reaction was performed on a 50 mmol scale with only 0.01 mol % of catalyst. The TBPhs group can be removed under mild conditions to afford the corresponding NH-free amines.

Structure–Property Relationship in Poly(Terphenylene)-Based Anion Exchange Membranes; The Impact of Backbone Structure for the Free Volume Control in Alkaline Fuel Cell Application

The commercial application of anion exchange membrane fuel cells (AEMFCs) has been impeded by the lack of high ion conductivity and mechanical/chemical stability of the currently used anion exchange membranes (AEMs). A new class of aromatic polymers, which contain conducting head groups directly onto the polymer backbone were developed to attain long-term stability along with high conductivity. Inspired from this, a series of poly(terphenylene)-based anion exchange membranes devoid of benzylic sites or aryl-ether bonds, that are vulnerable to attack by hydroxide ion, were synthesized and were investigated for their physicochemical properties for alkaline fuel cell applications. The polymer backbones having N,N-dimethylpiperidinium conducting head group were synthesized using acid-catalyzed Friedel-Crafts polycondensation reaction between N-methyl-4-piperidone and meta/para-terphenyl monomers. Along with meta-terphenyl homopolymer, another three sets of copolymers were synthesized by introducing the kink structured meta-terphenyl in different ratios with para-terphenyl to control the free volume. The copolymer membrane, m-p-CoP-50, prepared from meta/para terphenyl monomers with a 1:1 molar ratio displayed a well-balanced water uptake, dimensional stability and the highest conductivity. The experimental procedures and the results will be discussed in detail.

Poly(meta/para-Terphenylene-Methyl Piperidinium)-Based Anion Exchange Membranes: The Effect of Backbone Structure in AEMFC Application.

A series of poly(meta/para-terphenylene-methyl piperidinium)-based anion exchange membranes devoid of benzylic sites or aryl ether bonds, that are vulnerable to degradation by hydroxide ions, are synthesized and investigated for their application as novel anion exchange membranes. The copolymers are composed of both linear para-terphenyl units and kink-structured meta-terphenyl units. The meta-connectivity in terphenyl units permits the polymer backbones to fold back, maximizing the interactions among the hydrocarbon polymer chains and enhancing the peripheral formation of ion aggregates, due to the free volume generated by the kink structure. The effects of the copolymer composition between para-terphenyl and meta-terphenyl on the morphology and the electrochemical and physicochemical properties of the corresponding polymer membranes are investigated.

Multiple Mechanisms Mapped in Aryl Alkyl Ether Cleavage via Aqueous Electrocatalytic Hydrogenation over Skeletal Nickel.

We present here detailed mechanistic studies of electrocatalytic hydrogenation (ECH) in aqueous solution over skeletal nickel cathodes to probe the various paths of reductive catalytic C-O bond cleavage among functionalized aryl ethers relevant to energy science. Heterogeneous catalytic hydrogenolysis of aryl ethers is important both in hydrodeoxygenation of fossil fuels and in upgrading of lignin from biomass. The presence or absence of simple functionalities such as carbonyl, hydroxyl, methyl, or methoxyl groups is known to cause dramatic shifts in reactivity and cleavage selectivity between sp3 C-O and sp2 C-O bonds. Specifically, reported hydrogenolysis studies with Ni and other catalysts have hinted at different cleavage mechanisms for the C-O ether bonds in α-keto and α-hydroxy β-O-4 type aryl ether linkages of lignin. Our new rate, selectivity, and isotopic labeling results from ECH reactions confirm that these aryl ethers undergo C-O cleavage via distinct paths. For the simple 2-phenoxy-1-phenylethane or its alcohol congener, 2-phenoxy-1-phenylethanol, the benzylic site is activated via Ni C-H insertion, followed by beta elimination of the phenoxide leaving group. But in the case of the ketone, 2-phenoxyacetophenone, the polarized carbonyl π system apparently binds directly with the electron rich Ni cathode surface without breaking the aromaticity of the neighboring phenyl ring, leading to rapid cleavage. Substituent steric and electronic perturbations across a broad range of β-O-4 type ethers create a hierarchy of cleavage rates that supports these mechanistic ideas while offering guidance to allow rational design of the catalytic method. On the basis of the new insights, the usage of cosolvent acetone is shown to enable control of product selectivity.

New Perspectives in the Indole Ring Functionalization using 2‐Indolylmethanols

Abstract2‐Indolylmethanols have been recently involved in several processes dealing with indole functionalization. These compounds, upon activation by Brønsted or Lewis acids, generate a bidentate electrophilic system amenable to react at the 3‐position or at the benzylic site with a wide range of nucleophilic reagents. The functionalization pattern is affected by the nature of the substituents at the carbinol unit and also depends on the nature of the nucleophile used. Nucleophilic reactants bearing a remote electrophilic site in their structure can be involved in a further ring closure ultimately leading to polycyclic derivatives. This review article summarizes some fundamental aspects of the chemistry of 2‐indolylmethanols with particular attention to those related to asymmetric synthesis.magnified image

Late-stage trifluoromethylthiolation of benzylic C-H bonds

The benzylic positions in drugs are sites that readily react with cytochrome P450 oxidases via single-electron oxidation. New synthetic methodologies to incorporate a fluoroalkyl group at the benzylic site are continually being developed, and in this paper, we report a metal-free and site-selective organophotoredox-catalyzed trifluoromethylthiolation of benzylic C-H bonds for a wide variety of alkyl arenes and heteroarenes. The precise and predictive regioselectivity among various C(sp3)-H bonds originates from an inner-sphere benzylic radical initiation mechanism, and avoids the use of external oxidants or hydrogen atom abstractors. Its practicality stems from the trifluoromethylthiolation of a series of drugs and complex organic molecules, which is overwhelmingly selective for benzyl groups. This operationally simple protocol can provide a general and practical access to structurally diverse benzylic trifluoromethyl sulfides produced from ubiquitous benzylic C-H bonds. Large scale trifluoromethylthiolation can be achieved with continuous flow photoredox technology.

Remote, Diastereoselective Cobalt-Catalyzed Alkene Isomerization–Hydroboration: Access to Stereodefined 1,3-Difunctionalized Indanes

The remote, diastereoselective hydroboration of 2- and 3-substituted indenes with a 2,2′:6′,2″-terpyridine cobalt alkyl precatalyst is described that maintains high regio- and stereoselectivity independent of the starting position of the alkene. Several 1,2- and 1,3-disubstituted indanyl boronate esters were obtained with exclusive (>20:1 dr) selectivity for the trans diastereomer including synthetically versatile, stereodefined diboron derivatives. Alkene isomerization by a putative cobalt hydride intermediate precedes carbon–boron bond formation, leading to the observed regioselectivity for boron incorporation at the unsubstituted C(sp3)–H benzylic site. The regio- and diastereoselectivity of the transformation were maintained independent of the starting position of the alkene, as demonstrated by hydroboration of three isomers of methyl-substituted indene. Deuterium-labeling experiments support rapid and reversible insertion and β-hydride elimination to isomerize 3-methylindene and 1-exo-methylene-indane, accounting for the isotopic distribution observed in the products. Mechanistic studies, including stoichiometric experiments, density functional theory calculations, and kinetic analysis, support a mechanism in which 2,3-alkene insertion into a cobalt hydride intermediate determines both the regio- and diastereoselectivity of the catalytic reaction. Synthetic applications of the indanyl boronate esters were demonstrated through the elaboration of the products to several examples of 1,3-disubstituted indanes, important carbocyclic structural motifs in both pharmacological and bioactive molecules.