A mechanism that enables direct aldehyde C-H functionalization has been achieved via the synergistic merger of photoredox, nickel, and hydrogen atom transfer catalysis. This mild, operationally ...simple protocol transforms a wide variety of commercially available aldehydes, along with aryl or alkyl bromides, into the corresponding ketones in excellent yield. This C-H abstraction coupling technology has been successfully applied to the expedient synthesis of the medicinal agent haloperidol.
A strategy for cross-electrophile coupling has been developed via the merger of photoredox and transition metal catalysis. In this report, we demonstrate the use of commercially available ...tris(trimethylsilyl)silane with metallaphotoredox catalysis to efficiently couple alkyl bromides with aryl or heteroaryl bromides in excellent yields. We hypothesize that a photocatalytically generated silyl radical species can perform halogen-atom abstraction to activate alkyl halides as nucleophilic cross-coupling partners. This protocol allows the use of mild yet robust conditions to construct Csp(3)-Csp(2) bonds generically via a unique cross-coupling pathway.
Modern drug discovery relies on the continual development of synthetic methodology to address the many challenges associated with the design of new pharmaceutical agents. One such challenge arises ...from the enzymatic metabolism of drugs in vivo by cytochrome P450 oxidases, which use single-electron oxidative mechanisms to rapidly modify small molecules to facilitate their excretion. A commonly used synthetic strategy to protect against in vivo metabolism involves the incorporation of electron-withdrawing functionality, such as the trifluoromethyl (CF(3)) group, into drug candidates. The CF(3) group enjoys a privileged role in the realm of medicinal chemistry because its incorporation into small molecules often enhances efficacy by promoting electrostatic interactions with targets, improving cellular membrane permeability, and increasing robustness towards oxidative metabolism of the drug. Although common pharmacophores often bear CF(3) motifs in an aromatic system, access to such analogues typically requires the incorporation of the CF(3) group, or a surrogate moiety, at the start of a multi-step synthetic sequence. Here we report a mild, operationally simple strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes through a radical-mediated mechanism using commercial photocatalysts and a household light bulb. We demonstrate the broad utility of this transformation through addition of CF(3) to a number of heteroaromatic and aromatic systems. The benefit to medicinal chemistry and applicability to late-stage drug development is also shown through examples of the direct trifluoromethylation of widely prescribed pharmaceutical agents.
Metal-catalysed cross-couplings are a mainstay of organic synthesis and are widely used for the formation of C-C bonds, particularly in the production of unsaturated scaffolds
. However, alkyl ...cross-couplings using native sp
-hybridized functional groups such as alcohols remain relatively underdeveloped
. In particular, a robust and general method for the direct deoxygenative coupling of alcohols would have major implications for the field of organic synthesis. A general method for the direct deoxygenative cross-coupling of free alcohols must overcome several challenges, most notably the in situ cleavage of strong C-O bonds
, but would allow access to the vast collection of commercially available, structurally diverse alcohols as coupling partners
. We report herein a metallaphotoredox-based cross-coupling platform in which free alcohols are activated in situ by N-heterocyclic carbene salts for carbon-carbon bond formation with aryl halide coupling partners. This method is mild, robust, selective and most importantly, capable of accommodating a wide range of primary, secondary and tertiary alcohols as well as pharmaceutically relevant aryl and heteroaryl bromides and chlorides. The power of the transformation has been demonstrated in a number of complex settings, including the late-stage functionalization of Taxol and a modular synthesis of Januvia, an antidiabetic medication. This technology represents a general strategy for the merger of in situ alcohol activation with transition metal catalysis.
Decarboxylative cross-coupling of alkyl carboxylic acids with vinyl halides has been accomplished through the synergistic merger of photoredox and nickel catalysis. This new methodology has been ...successfully applied to a variety of α-oxy and α-amino acids, as well as simple hydrocarbon-substituted acids. Diverse vinyl iodides and bromides give rise to vinylation products in high efficiency under mild, operationally simple reaction conditions.
Despite the widespread success of transition-metal-catalysed cross-coupling methodologies, considerable limitations still exist in reactions at sp
-hybridized carbon atoms, with most approaches ...relying on prefunctionalized alkylmetal or bromide coupling partners
. Although the use of native functional groups (for example, carboxylic acids, alkenes and alcohols) has improved the overall efficiency of such transformations by expanding the range of potential feedstocks
, the direct functionalization of carbon-hydrogen (C-H) bonds-the most abundant moiety in organic molecules-represents a more ideal approach to molecular construction. In recent years, an impressive range of reactions that form C(sp
)-heteroatom bonds from strong C-H bonds has been reported
. Additionally, valuable technologies have been developed for the formation of carbon-carbon bonds from the corresponding C(sp
)-H bonds via substrate-directed transition-metal C-H insertion
, undirected C-H insertion by captodative rhodium carbenoid complexes
, or hydrogen atom transfer from weak, hydridic C-H bonds by electrophilic open-shell species
. Despite these advances, a mild and general platform for the coupling of strong, neutral C(sp
)-H bonds with aryl electrophiles has not been realized. Here we describe a protocol for the direct C(sp
) arylation of a diverse set of aliphatic, C-H bond-containing organic frameworks through the combination of light-driven, polyoxometalate-facilitated hydrogen atom transfer and nickel catalysis. This dual-catalytic manifold enables the generation of carbon-centred radicals from strong, neutral C-H bonds, which thereafter act as nucleophiles in nickel-mediated cross-coupling with aryl bromides to afford C(sp
)-C(sp
) cross-coupled products. This technology enables unprecedented, single-step access to a broad array of complex, medicinally relevant molecules directly from natural products and chemical feedstocks through functionalization at sites that are unreactive under traditional methods.
The direct decarboxylative arylation of α-amino acids has been achieved via visible light-mediated photoredox catalysis. This method offers rapid entry to prevalent benzylic amine architectures from ...an abundant biomass, specifically α-amino acid precursors. Significant substrate scope is observed with respect to both the amino acid and arene components.
A new coupling protocol has been developed that allows the union of vinyl sulfones with photoredox-generated α-amino radicals to provide allylic amines of broad diversity. Direct C–H vinylations of ...N-aryl tertiary amines, as well as decarboxylative vinylations of N-Boc α-amino acids, proceed in high yield and with excellent olefin geometry control. The utility of this new allyl amine forming reaction has been demonstrated via the syntheses of several natural products and a number of established pharmacophores.
Transition metal catalysis has traditionally relied on organometallic complexes that can cycle through a series of ground-state oxidation levels to achieve a series of discrete yet fundamental ...fragment-coupling steps. The viability of excited-state organometallic catalysis via direct photoexcitation has been demonstrated. Although the utility of triplet sensitization by energy transfer has long been known as a powerful activation mode in organic photochemistry, it is surprising to recognize that photosensitization mechanisms to access excited-state organometallic catalysts have lagged far behind. Here, we demonstrate excited-state organometallic catalysis via such an activation pathway: Energy transfer from an iridium sensitizer produces an excited-state nickel complex that couples aryl halides with carboxylic acids. Detailed mechanistic studies confirm the role of photosensitization via energy transfer.
Deuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in drug discovery research, providing vital information about the biological fate of drugs and drug metabolites. ...Herein we demonstrate that a photoredox-mediated hydrogen atom transfer protocol can efficiently and selectively install deuterium (D) and tritium (T) at α-amino sp³ carbon-hydrogen bonds in a single step, using isotopically labeled water (D₂O or T₂O) as the source of hydrogen isotope. In this context, we also report a convenient synthesis of T₂O from T₂, providing access to high-specific-activity T₂O. This protocol has been successfully applied to the high incorporation of deuterium and tritium in 18 drug molecules, which meet the requirements for use in ligand-binding assays and absorption, distribution, metabolism, and excretion studies.
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