Copper-catalyzed dehydrogenation or lactonization of C(sp3)-H bonds.

Cytochrome P450 enzymes are known to catalyze bimodal oxidation of aliphatic acids via radical intermediates, which partition between pathways of hydroxylation and desaturation5,6. Developing analogous catalytic systems for remote C-H functionalization remains a significant challenge14,15,16. Here we report the development of Cu(I)-catalyzed bimodal dehydrogenation/lactonization reactions of synthetically common N-methoxyamides via radical abstractions of the γ-aliphatic C-H bonds. The feasibility of switching from dehydrogenation to lactonization has also been demonstrated by altering reaction conditions. The use of a readily available amide as both radical precursor and internal oxidant allowed for the development of a redox-neutral C-H functionalization reactions with methanol as the sole side product. These C-H functionalization reactions using Cu(I) catalyst of loading as low as 0.5 mol% have been applied to the diversification of a wide range of aliphatic acids including drug molecules and natural products. The exceptional compatibility of this catalytic system with a wide range of oxidatively sensitive functionality demonstrates the unique advantage of using simple amide substrate as the mild internal oxidant.

Palladium (II)-Catalyzed C-H Activation with Bifunctional Ligands: From Curiosity to Industrialization.

In 2001, our curiosity to understand the stereochemistry of C-H metalation with Pd prompted our first studies in Pd(II)-catalyzed asymmetric C-H activation (RSC Research appointment: 020 7451 2545, Grant: RG 36873, Dec. 2002). We identified four central challenges: 1. poor reactivity of simple Pd salts with native substrates; 2. few strategies to control site selectivity for remote C-H bonds; 3. the lack of chiral catalysts to achieve enantioselectivity via asymmetric C-H metalation, and 4. low practicality due to limited coupling partner scope and the use of specialized oxidants. These challenges necessitated new strategies in catalyst and reaction development. For reactivity, we developed approaches to enhance substrate-catalyst affinity together with novel bifunctional ligands which participate in and accelerate the C-H cleavage step. For site-selectivity, we introduced the concept of systematically modulating the distance and geometry between a directing template, catalyst, and substrate to selectively access remote C-H bonds. For enantioselectivity, we devised predictable stereomodels for catalyst-controlled enantioselective C-H activation based on the participation of bifunctional ligands. Finally, for practicality, we have developed varied catalytic manifolds for Pd(II) to accommodate diverse coupling partners while employing practical oxidants such as simple peroxides. These advances have culminated in numerous C-H activation reactions, setting the stage for broad industrial applications.

Cu-mediated enantioselective C-H alkynylation of ferrocenes with chiral BINOL ligands.

A wide range of Cu(II)-catalyzed C-H activation reactions have been realized since 2006, however, whether a C-H metalation mechanism similar to Pd(II)-catalyzed C-H activation reaction is operating remains an open question. To address this question and ultimately develop ligand accelerated Cu(II)-catalyzed C-H activation reactions, realizing the enantioselective version and investigating the mechanism is critically important. With a modified chiral BINOL ligand, we report the first example of Cu-mediated enantioselective C-H activation reaction for the construction of planar chiral ferrocenes with high yields and stereoinduction. The key to the success of this reaction is the discovery of a ligand acceleration effect with the BINOL-based diol ligand in the directed Cu-catalyzed C-H alkynylation of ferrocene derivatives bearing an oxazoline-aniline directing group. This transformation is compatible with terminal aryl and alkyl alkynes, which are incompatible with Pd-catalyzed C-H activation reactions. This finding provides an invaluable mechanistic information in determining whether Cu(II) cleaves C-H bonds via CMD pathway in analogous manner to Pd(II) catalysts.

Ligand-Enabled γ-C(sp3)-H Hydroxylation of Free Amines with Aqueous Hydrogen Peroxide.

Selective oxidation of the γ-C-H bonds from abundant amine feedstocks via palladium catalysis is a valuable transformation in synthesis and medicinal chemistry. Despite advances on this topic in the past decade, there remain two significant limitations: C-H activation of aliphatic amines requires an exogenous directing group except for sterically hindered α-tertiary amines, and a practical catalytic system for C(sp3)-H hydroxylation using a green oxidant, such as oxygen or aqueous hydrogen peroxide, has not been developed to date. Herein, we report a ligand-enabled selective γ-C(sp3)-H hydroxylation using sustainable aqueous hydrogen peroxide (7.5-10%, w/w). Enabled by a CarboxPyridone ligand, a series of primary amines (1°), piperidines, and morpholines (2°) were hydroxylated at the γ-position with excellent monoselectivity. This method provides an avenue for the synthesis of a wide range of amines, including γ-amino alcohols, ß-amino acids, and azetidines. The retention of chirality in the reaction allows rapid access to chiral amines starting from the abundant chiral amine pool.

Ligand-Enabled Double γ-C(sp3 )-H Functionalization of Aliphatic Acids: One-Step Synthesis of γ-Arylated γ-Lactones.

γ-methylene C(sp3 )-H functionalization of linear free carboxylic acids remains a significant challenge. Here in we report a Pd(II)-catalyzed tandem γ-arylation and γ-lactonization of aliphatic acids enabled by a L,X-type CarboxPyridone ligand. A wide range of γ-arylated γ-lactones are synthesized in a single step from aliphatic acids in moderate to good yield. Arylated lactones can readily be converted into disubstituted tetrahydrofurans, a prominent scaffold amongst bioactive molecules.

Hydrogen-bond-acceptor ligands enable distal C(sp3)-H arylation of free alcohols.

The functionalization of C-H bonds in organic molecules is one of the most direct approaches for chemical synthesis. Recent advances in catalysis have allowed native chemical groups such as carboxylic acids, ketones and amines to control and direct C(sp3)-H activation1-4. However, alcohols, among the most common functionalities in organic chemistry5, have remained intractable because of their low affinity for late transition-metal catalysts6,7. Here we describe ligands that enable alcohol-directed arylation of δ-C(sp3)-H bonds. We use charge balance and a secondary-coordination-sphere hydrogen-bonding interaction-evidenced by structure-activity relationship studies, computational modelling and crystallographic data-to stabilize L-type hydroxyl coordination to palladium, thereby facilitating the assembly of the key C-H cleavage transition state. In contrast to previous studies in C-H activation, in which secondary interactions were used to control selectivity in the context of established reactivity8-13, this report demonstrates the feasibility of using secondary interactions to enable challenging, previously unknown reactivity by enhancing substrate-catalyst affinity.

Synthesis of ß,γ-Unsaturated Aliphatic Acids via Ligand-Enabled Dehydrogenation.

α,ß-Dehydrogenation of aliphatic acids has been realized through both enolate and ß-C-H metalation pathways. However, the synthesis of isolated ß,γ-unsaturated aliphatic acids via dehydrogenation has not been achieved to date. Herein, we report the ligand-enabled ß,γ-dehydrogenation of abundant and inexpensive free aliphatic acids, which provides a new synthetic disconnection as well as a versatile platform for the downstream functionalization of complex molecules at remote γ-sites. A variety of free aliphatic acids, including acyclic and cyclic systems with ring sizes from five-membered to macrocyclic, undergo efficient dehydrogenation. Notably, this protocol features good chemoselectivity in the presence of more accessible α-C-H bonds and excellent regioselectivity in fused bicyclic scaffolds. The utility of this protocol has been demonstrated by the late-stage functionalization of a series of bioactive terpene natural products at the γ-sites. Further functionalization of the ß,γ-double bond allows for the installation of covalent warheads, including epoxides, aziridines, and ß-lactones, into complex natural product scaffolds, which are valuable for targeted covalent drug discovery.

Macrocyclization via remote meta-selective C-H olefination using a practical indolyl template.

The synthesis of macrocyclic compounds with different sizes and linkages remains a great challenge via transition metal-catalysed intramolecular C-H activation. Herein, we disclose an efficient macrocyclization strategy via Pd-catalysed remote meta-C-H olefination using a practical indolyl template. This approach was successfully employed to access macrolides and coumarins. In addition, the intermolecular meta-C-H olefination also worked well and was exemplified by the synthesis of antitumor drug belinostat from inexpensive and readily available benzenesulfonyl chloride. Notably, catalytic copper acetate and molecular oxygen were used in place of silver salts as oxidants. Furthermore, for the first time, the formation of a macrocyclophane cyclopalladated intermediate was detected through in situ Fourier-transform infrared monitoring experiments and ESI-MS.

Palladium-Catalyzed Stitching of 1,3-C(sp3)-H Bonds with Dihaloarenes: Short Synthesis of (±)-Echinolactone D.

Palladium-catalyzed C(sp3)-H functionalization presents an efficient strategy to construct a variety of carbon-carbon bonds. However, application of this approach toward the preparation of five-membered benzo-fused carbocycles via the most simplifying C-H activation logic has not been realized. In this Article, we report a palladium-catalyzed annulation reaction between gem-dimethyl-containing amides and 1-bromo-2-iodoarenes that effectively constructs two Calkyl-Caryl bonds and provides access to a variety of five-membered benzo-fused compounds. In this transformation, the dihaloarene is stitched to the gem-dimethyl moiety via two sequential ß-C(sp3)-H arylations utilizing the differential reactivity of the 1,2-difunctionalized electrophile. This annulation reaction is enabled by a dual-ligand system comprising of an N-acyl glycine and a pyridine-3-sulfonic acid that synergistically promotes the palladium stitching and provides the bicyclic products. This method displays a broad substrate scope and shows excellent amide compatibility. We also demonstrate the synthetic potential of this annulation by synthesizing echinolactone D.

C-H Glycosylation of Native Carboxylic Acids: Discovery of Antidiabetic SGLT-2 Inhibitors.

C-Glycosides are critical motifs embedded in many bioactive natural products. The inert C-glycosides are privileged structures for developing therapeutic agents owing to their high chemical and metabolic stability. Despite the comprehensive strategies and tactics established in the past few decades, highly efficient C-glycoside syntheses via C-C coupling with excellent regio-, chemo-, and stereoselectivity are still needed. Here, we report the efficient Pd-catalyzed glycosylation of C-H bonds promoted by weak coordination with native carboxylic acids without external directing groups to install various glycals to the structurally diverse aglycon parts. Mechanistic evidence points to the participation of a glycal radical donor in the C-H coupling reaction. The method has been applied to a wide range of substrates (over 60 examples), including many marketed drug molecules. Natural product- or drug-like scaffolds with compelling bioactivities have been constructed using a late-stage diversification strategy. Remarkably, a new potent sodium-glucose cotransporter-2 inhibitor with antidiabetic potential has been discovered, and the pharmacokinetic/pharmacodynamic profiles of drug molecules have been changed using our C-H glycosylation approach. The method developed here provides a powerful tool for efficiently synthesizing C-glycosides to facilitate drug discovery.

Remote C-H Olefination of Heterocyclic Biaryls Enabled by Reversibly Bound Templates.

Remote C-H functionalization of heterocyclic biaryls will be of great importance in synthesis and medicinal chemistry. Through adjusting the geometric relationship of the directing atom and target C-H bonds, two new catalytic templates have been developed to enable the functionalization of the more hindered ortho-C-H bonds of heterobiaryls bearing directing heteroatom at the meta- or para-positions, affording unprecedented site-selectivity. The use of template chaperone also overcomes product inhibition and renders the directing templates catalytic. The utility of this protocol was demonstrated by olefination of heterocyclic biaryls with various substituents, overriding conventional steric and electronic effects. These ortho-C-H olefinated heterobiaryls are sterically hindered and can often be challenging to prepare through aryl-aryl coupling reactions.

Enhancing Substrate-Metal Catalyst Affinity via Hydrogen Bonding: Pd(II)-Catalyzed ß-C(sp3)-H Bromination of Free Carboxylic Acids.

The achievement of sufficient substrate-metal catalyst affinity is a fundamental challenge for the development of synthetically useful C-H activation reactions of weakly coordinating native substrates. While hydrogen bonding has been harnessed to bias site selectivity in existing C(sp2)-H activation reactions, the potential for designing catalysts with hydrogen bond donors (HBDs) to enhance catalyst-substrate affinity and, thereby, facilitate otherwise unreactive C(sp3)-H activation remains to be demonstrated. Herein, we report the discovery of a ligand scaffold containing a remote amide motif that can form a favorable meta-macrocyclic hydrogen bonding interaction with the aliphatic acid substrate. The utility of this ligand scaffold is demonstrated through the development of an unprecedented C(sp3)-H bromination of α-tertiary and α-quaternary free carboxylic acids, which proceeds in exceedingly high mono-selectivity. The geometric relationship between the NHAc hydrogen bond donor and the coordinating quinoline ligand is crucial for forming the meta-macrocyclophane-like hydrogen bonding interaction, which provides a guideline for the future design of catalysts employing secondary interactions.

Synthesis of 1,3-Dienes via Ligand-Enabled Sequential Dehydrogenation of Aliphatic Acids.

1,3-Dienes are common scaffolds in biologically active natural products as well as building blocks for chemical synthesis. Developing efficient methods for the synthesis of diverse 1,3-dienes from simple starting materials is therefore highly desirable. Herein, we report a Pd(II)-catalyzed sequential dehydrogenation reaction of free aliphatic acids via ß-methylene C-H activation, which enables one-step synthesis of diverse E,E-1,3-dienes. Free aliphatic acids of varying complexities, including the antiasthmatic drug seratrodast, were found to be compatible with the reported protocol. Considering the high lability of 1,3-dienes and lack of protecting strategies, dehydrogenation of aliphatic acids to reveal 1,3-dienes at the late stage of synthesis offers an appealing strategy for the synthesis of complex molecules containing such motifs.

Synthesis of Highly Substituted Aminotetrahydropyrans Enabled by Stereospecific Multivector C-H Functionalization.

Highly substituted aminotetrahydropyrans were synthesized via sequential C-H functionalizations. The process was initiated with a Pd(II)-catalyzed stereoselective γ-methylene C-H arylation of aminotetrahydropyran, followed by α-alkylation or arylation of the corresponding primary amine. The initial γ-C-H (hetero)arylation was compatible with a range of aryl iodides containing various substituents and provided the corresponding products in moderate to good yields. The subsequent α-alkylation or arylation of the isolated arylated products proceeded with high diastereoselectivity to afford value-added disubstituted aminotetrahydropyrans.

Regio-controllable [2+2] benzannulation with two adjacent C(sp3)-H bonds.

Regiocontrol in traditional cycloaddition reactions between unsaturated carbon compounds is often challenging. The increasing focus in modern medicinal chemistry on benzocyclobutene (BCB) scaffolds indicates the need for alternative, more selective routes to diverse rigid carbocycles rich in C(sp3) character. Here, we report a palladium-catalyzed double C-H activation of two adjacent methylene units in carboxylic acids, enabled by bidentate amide-pyridone ligands, to achieve a regio-controllable synthesis of BCBs through a formal [2+2] cycloaddition involving σ bonds only (two C-H bonds and two aryl-halogen bonds). A wide range of cyclic and acyclic aliphatic acids, as well as dihaloheteroarenes, are compatible, generating diversely functionalized BCBs and hetero-BCBs present in drug molecules and bioactive natural products.

Transannular C-H functionalization of cycloalkane carboxylic acids.

Cyclic organic molecules are common among natural products and pharmaceuticals1,2. In fact, the overwhelming majority of small-molecule pharmaceuticals contain at least one ring system, as they provide control over molecular shape, often increasing oral bioavailability while providing enhanced control over the activity, specificity and physical properties of drug candidates3-5. Consequently, new methods for the direct site and diastereoselective synthesis of functionalized carbocycles are highly desirable. In principle, molecular editing by C-H activation offers an ideal route to these compounds. However, the site-selective C-H functionalization of cycloalkanes remains challenging because of the strain encountered in transannular C-H palladation. Here we report that two classes of ligands-quinuclidine-pyridones (L1, L2) and sulfonamide-pyridones (L3)-enable transannular γ-methylene C-H arylation of small- to medium-sized cycloalkane carboxylic acids, with ring sizes ranging from cyclobutane to cyclooctane. Excellent γ-regioselectivity was observed in the presence of multiple ß-C-H bonds. This advance marks a major step towards achieving molecular editing of saturated carbocycles: a class of scaffolds that are important in synthetic and medicinal chemistry3-5. The utility of this protocol is demonstrated by two-step formal syntheses of a series of patented biologically active small molecules, prior syntheses of which required up to 11 steps6.

Synthesis of planar chiral ferrocenes via enantioselective remote C-H activation.

Planar chiral ferrocenes are widely studied structures in asymmetric catalysis, materials science and medicinal chemistry. Although synthetic methods for 1,2-disubstituted planar chiral ferrocenes are well known, methods for the direct construction of 1,3-disubstituted planar chiral ferrocenes remain elusive. Here we report a modular platform for the construction of planar chirality in 1,3-disubstituted ferrocenes/ruthenocenes via an enantioselective relay remote C-H activation strategy. This method demonstrates a mechanism for remote enantiocontrol via enantiodetermining initial C‒H activation at the C2 position, enabled by a chiral mono-N-protected natural amino-acid ligand, and subsequent relay to the remote C3 position by a bridgehead-substituted norbornene mediator. A wide variety of 1,3-disubstituted planar chiral metallocenes are prepared with high enantioselectivity (96‒99% e.e.). The reaction shows good functional-group tolerance and high step-economy, and aryl iodides/bromides are compatible as coupling partners. The resulting metallocenes can be readily derivatized to yield planar chiral ligands and catalysts for asymmetric catalysis as well as building blocks for other applications.

Formal γ-C-H Functionalization of Cyclobutyl Ketones: Synthesis of cis-1,3-Difunctionalized Cyclobutanes.

1,3-Difunctionalized cyclobutanes are an emerging scaffold in medicinal chemistry that can confer beneficial pharmacological properties to small-molecule drug candidates. However, the diastereocontrolled synthesis of these compounds typically requires complicated synthetic routes, indicating a need for novel methods. Here, we report a sequential C-H/C-C functionalization strategy for the stereospecific synthesis of cis-γ-functionalized cyclobutyl ketones from readily available cyclobutyl aryl ketones. Specifically, a bicyclo[1.1.1]pentan-2-ol intermediate is generated from the parent cyclobutyl ketone via an optimized Norrish-Yang procedure. This intermediate then undergoes a ligand-enabled, palladium-catalyzed C-C cleavage/functionalization to produce valuable cis-γ-(hetero)arylated, alkenylated, and alkynylated cyclobutyl aryl ketones, the benzoyl moiety of which can subsequently be converted to a wide range of functional groups including amides and esters.

Dual-Ligand Catalyst for the Nondirected C-H Olefination of Heteroarenes.

Pd(II)-catalyzed nondirected C-H functionalization of heteroarenes is a significant challenge for the following reasons: poor reactivity of electron-deficient heterocycles and the unproductive coordination of Lewis basic nitrogen atoms. Existing methodologies using palladium catalysis often employ a large excess of heterocycle substrates to overcome these hurdles. Despite recent advances in nondirected functionalization of arenes that allow them to be used as limiting reagents, the reaction conditions are incompatible with electron-deficient heteroarenes. Herein we report a dual-ligand catalyst that enables Pd(II)-catalyzed nondirected C-H olefination of heteroarenes without using a large excess of substrate. In general, the use of 1-2 equiv of substrates was sufficient to obtain synthetically useful yields. The reactivity was rationalized by the synergy between two types of ligands: a bidentate pyridine-pyridone ligand promotes C-H cleavage; the monodentate heterocycle substrate acts as a second ligand to form a cationic Pd(II) complex that has high affinity for arenes. The proposed dual-ligand cooperation is supported by a combination of X-ray, kinetics, and control experiments.

ß- and γ-C(sp3 )-H Heteroarylation of Free Carboxylic Acids: A Modular Synthetic Platform for Diverse Quaternary Carbon Centers.

PdII -catalyzed C(sp3 )-H activation of free carboxylic acids represents a significant advance from conventional cyclopalladation initiated reactions. However, developing a modular synthetic platform for diverse quaternary and tertiary carbon centers based on this reactivity, two challenges remain to be addressed: mono-selectivity in each consecutive C-H functionalization step; compatibility with heteroatoms. While the exclusive mono-selectivity was achieved by ß-lactonization/nucleophilic attack, the latter limitation remains to be overcome. Herein, we report the PdII -catalyzed ß- and γ-C(sp3 )-H heteroarylation of free carboxylic acids using pyridine-pyridone ligands capable of overcoming these limitations. A sequence of three consecutive C(sp3 )-H activation reactions of pivalic acid provides an unique platform for constructing diverse quaternary carbon centers containing heteroaryls which could serve as an enabling tool for escaping the flat land in medicinal chemistry.