Late-stage Functionalization Research Articles

1,3-Difunctionalization of [1.1.1]propellane through iron-hydride catalyzed hydropyridylation

Current methodologies for the functionalization of [1.1.1]propellane primarily focus on achieving 1, 3-difunctionalized bicyclo[1.1.1]pentane or ring-opened cyclobutane moiety. Herein, we report an innovative approach for the 1, 3-difunctionalization of [1.1.1]propellane, enabling access to a diverse range of highly functionalized cyclobutanes via nucleophilic attack followed by ring opening and iron-hydride hydrogen atom transfer. To enable this method, we developed an efficient iron-catalyzed hydropyridylation of various alkenes for C − H alkylation of pyridines at the C4 position, eliminating the need for stoichiometric quantities of oxidants or reductants. Mechanistic investigations reveal that the resulting N-centered radical serves as an effective oxidizing agent, facilitating single-electron transfer oxidation of the reduced iron catalyst. This process efficiently sustains the catalytic cycle, offering significant advantages for substrates with oxidatively sensitive functionalities that are generally incompatible with alternative approaches. The strategy presented herein is not only mechanistically compelling but also demonstrates broad versatility, highlighting its potential for late-stage functionalization.

Calcium(II)-Mediated Three-Component Selenylation of gem-Difluoroalkenes: Access to α,α-Difluoroalkyl-β-selenides.

A calcium-mediated three-component selenylation of gem-difluoroalkenes using alcohols as nucleophiles and N-(phenylseleno)phthalimide as the selenylation agent has been developed for the efficient synthesis of various α,α-difluoroalkyl-β-selenides. This selenylation reaction exhibits broad substrate and functional group tolerance, along with high levels of chemo- and regioselectivity. Additionally, the synthetic utility of the developed transformation in the late-stage functionalization of drug molecules was demonstrated.

Cooperative Phosphine-Photoredox Catalysis Enables N-H Activation of Azoles for Intermolecular Olefin Hydroamination.

Catalytic intermolecular olefin hydroamination is an enabling synthetic strategy that offers direct and atom-economical access to a variety of nitrogen-containing compounds from abundant feedstocks. However, despite numerous advances in catalyst design and reaction development, hydroamination of N-H azoles with unactivated olefins remains an unsolved problem in synthesis. We report a dual phosphine and photoredox catalytic protocol for the hydroamination of numerous structurally diverse and medicinally relevant N-H azoles with unactivated olefins. Hydroamination proceeds with high anti-Markovnikov regioselectivity and N-site selectivity. The mild conditions and high functional group tolerance of the reaction permit the rapid construction of molecular complexity and late-stage functionalization of bioactive compounds. N-H bond activation is proposed to proceed via polar addition of the N-H azole to a phosphine radical cation, followed by P-N α-scission from a phosphoranyl radical intermediate. Reactivity and N-site selectivity are classified by azole N-H BDFE and nitrogen-centered radical spin density, respectively, which can serve as a useful predictive aid in extending the reaction to unseen azoles.

An organocatalytic domino annulation approach via C(sp2)-OMe cleavage to unlock the synthesis of pyranochromenones enabled by HFIP.

Fused pyranochromenone derivatives have extensive applications in medicinal chemistry. Herein, we report the first HFIP/TsOH catalyzed, one-pot domino reaction by cleavage of the C(sp2)-OMe bond. Control experiments reveal that 1,3,5-trimethoxybenzene is rapidly protonated in the presence of HFIP to yield a dearomatized cationic diene intermediate. The gram-scale reaction and late-stage functionalization of natural products justified the practicality of this protocol.

Nickel-Catalyzed Highly Selective Radical C-C Coupling from Carboxylic Acids with Photoredox Catalysis.

Controlling the cross-coupling reaction between two different radicals is a long-standing challenge due to the process occurring statistically, which would lead to three products, including two homocoupling products and one cross-coupling product. Generally, the cross-coupling selectivity is achieved by the persistent radical effect (PRE) that requires the presence of a persistent radical and a transient radical, thus resulting in limited radical precursors. In this paper, a highly selective cross-coupling of alkyl radicals with acyl radicals to construct C(sp2)-C(sp3) bonds, or with alkyl radicals to construct C(sp3)-C(sp3) bonds have been achieved with the readily available carboxylic acids and their derivatives (NHPI ester) as coupling partners. The success originates from the use of tridentate ligand (2,2' : 6',2''-terpyridine) to enable radical cross-coupling process to Ni-mediated organometallic mechanism. This protocol offers a facile and flexible access to structurally diverse ketones (up to 90 % yield), and also a new solution for the challenging double decarboxylative C(sp3)-C(sp3) coupling. The broad utility and functional group tolerance are further illustrated by the late-stage functionalization of natural-occurring carboxylic acids and drugs.

Radical-Chain Hydrosilylation of Alkenes Enabled by Triplet Energy Transfer.

Development of mild, robust and metal-free catalytic approach for the hydrosilylation of alkenes is critical to the advancement of modern organosilicon chemistry given their powerful capacity in the construction of various C-Si bonds. Herein, we wish to disclose a visible light-triggered organophotocatalytic strategy, which proceeds via a triplet energy transfer (EnT)-enabled radical chain pathway. Notably, this redox-neutral protocol is capable of accommodating a broad spectrum of electron-deficient and -rich alkenes with excellent functional group compatibility. Electron-deficient alkenes are more reactive and the reaction could be finished within a couple of minutes even in PBS solution with extremely low concentration, which suggests its click-like potential in organic synthesis. The preparative power of the transformations has been further highlighted in a number of complex settings, including the late-stage functionalization and scale-up experiments. Furthermore, although only highly reactive (TMS)3SiH is suitable hydrosilane substrate, our studies revealed the great reactivity and versatility of (TMS)3Si- group in diverse C-Si and Si-Si bond cleavage-based transformations, enabling the rapid introduction of diverse functional groups and the facile construction of valuable quaternary silicon architectures.

Modulation of the Meisenheimer complex metabolism of nitro-benzothiazinones by targeted C-6 substitution

Tuberculosis, caused by Mycobacterium tuberculosis, remains a major public health concern, demanding new antibiotics with innovative therapeutic principles due to the emergence of resistant strains. Benzothiazinones (BTZs) have been developed to address this problem. However, an unprecedented in vivo biotransformation of BTZs to hydride-Meisenheimer complexes has recently been discovered. Herein, we present a study of the influence of electron-withdrawing groups on the propensity of HMC formation in whole cells for a series of C-6-substituted BTZs obtained through reductive fluorocarbonylation as a late-stage functionalization key step. Gibbs free energy of reaction and Mulliken charges and Fukui indices on C-5 at quantum mechanics level were found as good indicators of in vitro HMC formation propensity. These results provide a first blueprint for the evaluation of HMC formation in drug development and set the stage for rational pharmacokinetic optimization of BTZs and similar drug candidates.

Nickel-catalyzed cross-electrophile couplings of aryl fluorosulfates with vinyl chlorosilanes

An efficient cross-electrophile couplings of aryl fluorosulfates with vinyl chlorosilanes by using nickel as transition metal catalyst and manganese as reductant has been achieved. The reactions proceeded smoothly at room temperature via C-O bond activation to give a series of structurally varied aryl silanes in moderate to good yields, displaying broad substrate generality and good functional group compatibility. In addition, the reaction could be subjected to scale-up synthesis and be applied to late-stage functionalization of biologically active molecules.

Catalyst Editing via Post-Synthetic Functionalization by Phosphonium Generation and Anion Exchange for Nickel-Catalyzed Ethylene/Acrylate Copolymerization.

Rapid, efficient development of homogeneous catalysts featuring desired performance is critical to numerous catalytic transformations but remains a key challenge. Typically, this task relies heavily on ligand design that is often based on trial and error. Herein, we demonstrate a "catalyst editing" strategy in Ni-catalyzed ethylene/acrylate copolymerization. Specifically, alkylation of a pendant phosphine followed by anion exchange provides a high yield strategy for a large number of cationic Ni phosphonium catalysts with varying electronic and steric profiles. These catalysts are highly active in ethylene/acrylate copolymerization, and their behaviors are correlated with the electrophile and the anion used in late-stage functionalization.

Photoactivation of Millimeters Thick Liquid Crystal Elastomers with Broadband Visible Light Using Donor-Acceptor Stenhouse Adducts.

Light-responsive liquid crystal elastomers (LCEs) are stimuli-responsive materials that facilitate the conversion of light energy into a mechanical response. In this work, a novel polysiloxane-based LCE with donor-acceptor Stenhouse adduct (DASA) side-chains is synthesized using a late-stage functionalization strategy. It is demonstrated that this approach does not compromise the molecular alignment observed in the traditional Finkelmann method. This easy, single-batch process provides a robust platform to access well-aligned, light-responsive LCE films with thickness ranging from 400µm to a 14-layer stack that is 5mm thick. Upon irradiation with low-intensity broadband visible light (100-200mW cm-2), these systems undergo 2D planar actuation and complete bleaching. Conversely, exposure to higher-intensity visible light induces bending followed by contraction (300mW cm-2). These processes are repeatable over several cycles. Finally, it is demonstrated how light intensity and the resulting heat generation influences the photothermal stationary state equilibrium of DASA, thereby controlling its photoresponsive properties. This work establishes the groundwork for advancement of LCE-based actuators beyond thin film and UV-light reliant systems.

Divergent synthesis of complex withanolides enabled by a scalable route and late-stage functionalization.

Withanolides are a group of naturally occurring C28 steroids based on an ergostane skeleton. They have a high degree of polyoxygenation, and the abundance of O-functional groups has enabled various natural alterations to both the carbocyclic skeleton and the side chain. Consequently, these molecules have intricate structural features that lead to their highly varied display of biological activities including anticancer, anti-inflammatory, and immunomodulating properties. Despite being intriguing leads for further discovery research, synthetic access to the withanolides remains highly challenging-compounds for current biological research are mainly isolated from plants, often inefficiently. Here, we report the divergent synthesis of 11 withanolides in 12 to 20 steps, enabled by a gram-scale route and a series of late-stage functionalizations, most notably a bioinspired photooxygenation-allylic hydroperoxide rearrangement sequence. This approach enables further biological research disconnected from a reliance on minute quantities of the parent natural products or their simple derivatives.

Unveiled reactivity of masked diformylmethane with enamines forming resonance-assisted hydrogen bonding leads to di-meta-substituted pyridines

Pyridine, an essential structure in drug development, shows a wide array of bioactivities according to its substitution patterns. Among the bioactive pyridines, meta-substituted pyridines suffer from limited synthetic approaches despite their significance. In this study, we present a condensation-based synthetic method enabling the facile incorporation of biologically relevant functional groups at the meta position of pyridine. This methodology unveiled the concealed reactivity of 3-formyl(aza)indoles as diformylmethane analogs for synthesizing dissymmetric di-meta-substituted pyridines without ortho and para substitutions. Furthermore, we uncovered resonance-assisted hydrogen bonding (RAHB) as the requirement for the in situ generation of enamines, the key intermediates of this transformation. Successful development of the designed methodology linked to wide applications—core remodeling of natural products, drug–natural product conjugation, late-stage functionalization of drug molecules, and synthesis of the regioisomeric CZC24832. Furthermore, we discovered anti-inflammatory agents through the functional evaluation of synthesized bi-heteroaryl analogs, signifying the utility of this methodology.

Copper-Catalyzed Regiodivergent Asymmetric Difunctionalization of Terminal Alkynes.

We herein describe the first example of ligand-controlled, copper-catalyzed regiodivergent asymmetric difunctionalization of terminal alkynes through a cascade hydroboration and hydroallylation process. The catalytic system, consisting of (R)-DTBM-Segphos and CuBr, could efficiently achieve asymmetric 1,1-difunctionalization of aryl terminal alkynes, while ligand switching to (S,S)-Ph-BPE could result in asymmetric 1,2-difunctionalization exclusively. In addition, alkyl substituted terminal alkynes, especially industrially relevant acetylene and propyne, were also valid feedstocks for asymmetric 1,1-difunctionalization. This protocol is characterized by good functional group tolerance, a broad scope of substrates (>150 examples), and mild reaction conditions. We also showcase the value of this method in the late-stage functionalization of complicated bioactive molecules and simplifying the synthetic routes toward the key intermediacy of natural product (bruguierol A). Mechanistic studies combined with DFT calculations provide insight into the mechanism and origins of this ligand-controlled regio- and stereoselectivity.

Photoredox- and Cobalt-Cocatalyzed Dehydrogenative Ring-Opening/Functionalization of Monodonor Cyclopropanes

AbstractCatalytic ring-opening/functionalization of unactive cyclopropanes has proven to be a significant but challenging task in organic synthesis. Herein, we disclose the photoredox and cobalt cocatalyzed ring-opening/acceptorless dehydrogenative functionalization of monodonor cyclopropanes, which provides a promising platform to achieve a sustainable and atom-economic approach to assemble allylic N-acyl-acetal derivatives. The reaction features mild conditions, broad substrate scopes, and excellent functional group compatibilities. The optimized conditions accommodate various cycloalkylamides and primary, secondary, and tertiary alcohols, with applications in late-stage functionalization of pharmaceutically relevant compounds, stimulating the further utility in medicinal chemistry. Selective nucleophilic substitutions and further transformations of desired products with various carbon nucleophiles were succeed in a one-pot fashion, thus offering diverse acyclic or cyclic derivatives.1 Introduction2 Cooperative Photoredox and Cobalt-Catalyzed Dehydrogenative Functionalization of Allylic N-Acyl-acetal Derivatives3 Mechanistic Study4 Preliminary Studies of Asymmetric Transformation5 Conclusion and Perspectives

Base-Promoted (5 + 2) Annulation between 2-(Alkynylaryl)acetonitriles and Arylalkynes for the Synthesis of Benzocycloheptene Derivatives.

Herein, we describe a novel approach to the synthesis of benzocycloheptene derivatives via base-promoted (5 + 2) annulation between 2-(alkynylaryl)acetonitriles and arylalkynes. In this chemistry, 2-(alkynylaryl)acetonitriles are employed as a new C5 synthon to construct various benzocycloheptene(s) derivatives by building two C-C bonds in one single step. This method features excellent regioselectivity, the use of readily available starting materials, and good functional group tolerance. The practicality of the strategy was further demonstrated by gram-scale synthesis, late-stage functionalizations, and the post-modification of natural products such as probenecid and tetrahydrofurfuryl alcohol.

1,2-Difunctionalization of Aryne with Sulfenamide and Organohalide: Mild and Metal-Free Access to S-(o-Halo)aryl Sulfilimine.

A mild and metal-free approach has been developed for 1,2-difunctionalization of aryne using sulfenamides as a nucleophile and a halogen source (CX4) as an electrophile to synthesize S-(o-halo)aryl sulfilimines. The late-stage functionalizations of halide handles via Suzuki-Miyaura and Buchwald-Hartwig reactions exhibit the synthetic utilities of the products. The chemoselectivity, regioselectivity, rapidity, and use of economical CCl4 are the advantages of this protocol.

Modular Access to Functionalized Oxetanes as Benzoyl Bioisosteres.

Bioisosterism is a valuable principle exploited in drug discovery to fine-tune physicochemical properties of bioactive compounds. Functionalized 3-aryl oxetanes, as an important class of bioisosteres for benzoyl groups (highly prevalent structures in approved drugs), have been rarely utilized in agrochemicals and pharmaceuticals due to significant synthetic challenges. Here, we present a modular synthetic strategy based on the unexplored yet readily available reagents, oxetanyl trichloroacetimidates, inspired by Schmidt glycosylation, enabling easy access to a library of functionalized oxetanes. This operationally simple protocol leverages the vast existing libraries of aryl halides and various nucleophiles. The power and generality of this approach is demonstrated by late-stage functionalization of complex molecules, as well as the rapid synthesis of oxetane analogues of bioactive molecules and marketed drugs. Preliminary mechanistic study suggests that the oxygen atom in the oxetane ring plays a crucial role in stabilizing the carbocation intermediates.

P,N-Coordinating Ylide-Functionalized Phosphines (NYPhos): A Ligand Platform for the Selective Monoarylation of Small Nucleophiles.

Palladium-catalyzed coupling reactions of small nucleophiles are of great interest, but challenging due to difficulties in selectivity control. Herein, we report the development of a new platform of P,N-ligands consisting of ylide-functionalized phosphines with aminophosphonium groups (NYPhos) to address this challenge. These phosphine ligands are easily accessible in a wide structural diversity with highly modular electronic and steric properties. Based on a family of 14 ligands the selective monoarylation of acetone as well as other challenging ketones and amides was accomplished with record-setting activities even for aryl chlorides at room temperature including late-stage functionalizations of drug molecules. Moreover, ammonia and other small primary amines could be coupled at mild conditions. Isolation and structure analyses of palladium complexes within the catalytic cycle confirmed that the P,N-coordination mode is necessary to achieve the observed selectivities. It also demonstrated the facile adjustability of the N-donor strength, which is beneficial for the targeted design of tailored P,N-ligands for future applications.

Electrosynthesis of Quinoxalines via Intermolecular Cyclization/Dehydrogenation of Ketones with o-Phenylenediamines

AbstractIn this study, we proposed a novel electrochemical dehydrogenative synthetic method for preparing 2-substituted quinoxalines by intermolecular cyclization of aryl alkyl ketones and o-phenylenediamines. This method gave various quinoxalines in yields ranging from 35% to 71%. This novel protocol employs mild reaction conditions and offers moderate to excellent yields, a wide substrate scope, and broad functional-group compatibility. Furthermore, a late-stage functionalization and the wide substrate scope demonstrated the synthetic utility of this protocol.

Sulfonamide-directed site-selective functionalization of unactivated C(sp3)−H enabled by photocatalytic sequential electron/proton transfer

The generation of alkyl radical from C(sp3)−H substrates via hydrogen atom abstraction represents a desirable yet underexplored strategy in alkylation reaction since involving common concerns remain adequately unaddressed, such as the harsh reaction conditions, limited substrate scope, and the employment of noble metal- or photo-catalysts and stoichiometric oxidants. Here, we utilize the synergistic strategy of photoredox and hydrogen atom transfer (HAT) catalysis to accomplish a general and practical functionalization of unactived C(sp3)−H centers with broad reaction scope, high functional group compatibility, and operational simplicity. A combination of validation experiments and density functional theory reveals that the N-centered radicals, generated from free N − H bond in a stepwise electron/proton transfer event, are the key intermediates that enable an intramolecular 1,5-HAT or intermolecular HAT process for nucleophilic carbon-centered radicals formation to achieve heteroarylation, alkylation, amination, cyanation, azidation, trifluoromethylthiolation, halogenation and deuteration. The practical value of this protocol is further demonstrated by the gram-scale synthesis and the late-stage functionalization of natural products and drug derivatives.