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Most organic molecules absorb little or no visible light. Consequently, conventional organic photochemistry has relied on excitation in the ultraviolet regime, with the drawback that the high energy involved can lead to undesirable by-products. Over the past several years, an alternative strategy has emerged involving the visible excitation of metal complexes (primarily ruthenium and iridium) that can then engage in electron or energy transfer with organic compounds. The ensuing reactivity patterns complement thermally accessible outcomes without introducing detrimental quantities of excess energy. Schultz and Yoon ( 10.1126/science.1239176 ) review developments in this rapidly advancing area of photoredox catalysis. Chemists have long aspired to synthesize molecules the way that plants do—using sunlight to facilitate the construction of complex molecular architectures. Nevertheless, the use of visible light in photochemical synthesis is fundamentally challenging because organic molecules tend not to interact with the wavelengths of visible light that are most strongly emitted in the solar spectrum. Recent research has begun to leverage the ability of visible light–absorbing transition metal complexes to catalyze a broad range of synthetically valuable reactions. In this review, we highlight how an understanding of the mechanisms of photocatalytic activation available to these transition metal complexes, and of the general reactivity patterns of the intermediates accessible via visible light photocatalysis, has accelerated the development of this diverse suite of reactions.

Despite the widespread success of transition-metal-catalysed cross-coupling methodologies, considerable limitations still exist in reactions at sp 3 -hybridized carbon atoms, with most approaches relying on prefunctionalized alkylmetal or bromide coupling partners 1 , 2 . 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 3 – 5 , 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( s p 3 )–heteroatom bonds from strong C–H bonds has been reported 6 , 7 . Additionally, valuable technologies have been developed for the formation of carbon–carbon bonds from the corresponding C( sp 3 )–H bonds via substrate-directed transition-metal C–H insertion 8 , undirected C–H insertion by captodative rhodium carbenoid complexes 9 , or hydrogen atom transfer from weak, hydridic C–H bonds by electrophilic open-shell species 10 – 14 . Despite these advances, a mild and general platform for the coupling of strong, neutral C( s p 3 )–H bonds with aryl electrophiles has not been realized. Here we describe a protocol for the direct C( sp 3 ) 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 3 )–C( sp 2 ) 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. Direct coupling of aliphatic C–H nucleophiles to aryl electrophiles is described, through the combination of light-driven polyoxometalate hydrogen atom transfer and nickel catalysis.

In contrast to the wealth of catalytic systems that are available to control the stereochemistry of thermally promoted cycloadditions, few similarly effective methods exist for the stereocontrol of photochemical cycloadditions. A major unsolved challenge in the design of enantioselective catalytic photocycloaddition reactions has been the difficulty of controlling racemic background reactions that occur by direct photoexcitation of substrates while unbound to catalyst. Here, we describe a strategy for eliminating the racemic background reaction in asymmetric [2 + 2] photocycloadditions of α,β-unsaturated ketones to the corresponding cyclobutanes by using a dual-catalyst system consisting of a visible light–absorbing transition-metal photocatalyst and a stereocontrolling Lewis acid cocatalyst. The independence of these two catalysts enables broader scope, greater stereochemical flexibility, and better efficiency than previously reported methods for enantioselective photochemical cycloadditions.

The introduction of a trifluoromethyl (CF3) group can dramatically improve a compound’s biological properties. Despite the well-established importance of trifluoromethylated compounds, general methods for the trifluoromethylation of alkyl C–H bonds remain elusive. Here we report the development of a dual-catalytic C(sp3)–H trifluoromethylation through the merger of light-driven, decatungstate-catalysed hydrogen atom transfer and copper catalysis. This metallaphotoredox methodology enables the direct conversion of both strong aliphatic and benzylic C–H bonds into the corresponding C(sp3)–CF3 products in a single step using a bench-stable, commercially available trifluoromethylation reagent. The reaction requires only a single equivalent of substrate and proceeds with excellent selectivity for positions distal to unprotected amines. To demonstrate the utility of this new methodology for late-stage functionalization, we have directly derivatized a broad range of approved drugs and natural products to generate valuable trifluoromethylated analogues. Preliminary mechanistic experiments reveal that a ‘Cu–CF3’ species is formed during this process and the critical C(sp3)–CF3 bond-forming step involves the copper catalyst.Despite the importance of trifluoromethylated compounds, direct catalytic methods for the conversion of C(sp3)–H bonds into the corresponding C(sp3)–CF3 analogues have remained elusive. This transformation has now been achieved by the merger of copper catalysis with decatungstate photocatalysis, enabling the C(sp3)–H trifluoromethylation of abundant feedstocks, natural products and pharmaceuticals.

The addition of a methyl group to a drug molecule can greatly alter the drug’s pharmacological properties. A catalyst has been developed that enables this ‘magic methyl effect’ to be rapidly explored for drug discovery. Late-stage functionalization of complex organic molecules.

Late-stage functionalization has therefore emerged as a desirable approach to accelerate drug discovery5,6: much as a construction crew saws through existing walls to insert new windows, chemists aspire to cut through existing chemical bonds to insert new functional groups into molecules. Feng and colleagues are part of a research group that has long been interested in making ligand molecules that mimic the CYP450-enzyme architecture, in the hope of broadening the ability of iron complexes to transform C-H bonds into C=O bonds in diverse substrates, using hydrogen peroxide as the source of oxygen9. Feng et at. hypothesized that a less-oxidizing manganese catalyst would target the C-H bonds that are most easily metabolized on drug-like molecules. [...]they thought that the oxidation reaction could be halted midway to produce a hemi-oxidized intermediate, into which a methyl group could be inserted (Fig. 1).

Adding a promoter to a catalytic reaction can dramatically alter the performance and reactivity of a chemical transformation. By incorporating a Brønsted acid promoter to a photocatalysed reaction, previously unreactive C–H bonds can be functionalized, enabling the discovery of drug molecules.

There has been a recent surge of interest in the use of transition metal polypyridyl complexes as visible light-absorbing photocatalysts for synthetic applications. Among the most attractive features of this approach is the availability of many known complexes with well-characterized photophysical and electrochemical properties. In particular, Ru(bpz) 3 2+ is a powerful photooxidant that has proven to be uniquely suited for oxidatively induced photoredox transformations. We present here a straightforward and high-yielding route to Ru(bpz) 3 (PF 6 ) 2 that features an improved Pd-catalyzed synthesis of the 2,2’-bipyrazine ligand that is amenable to gram-scale preparations.

Despite the widespread success of transition-metal-catalysed cross-coupling methodologies, considerable limitations still exist in reactions at sp.sup.3-hybridized carbon atoms, with most approaches relying on prefunctionalized alkylmetal or bromide coupling partners.sup.1,2. 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.sup.3-5, 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.sup.3)-heteroatom bonds from strong C-H bonds has been reported.sup.6,7. Additionally, valuable technologies have been developed for the formation of carbon-carbon bonds from the corresponding C(sp.sup.3)-H bonds via substrate-directed transition-metal C-H insertion.sup.8, undirected C-H insertion by captodative rhodium carbenoid complexes.sup.9, or hydrogen atom transfer from weak, hydridic C-H bonds by electrophilic open-shell species.sup.10-14. Despite these advances, a mild and general platform for the coupling of strong, neutral C(sp.sup.3)-H bonds with aryl electrophiles has not been realized. Here we describe a protocol for the direct C(sp.sup.3) 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.sup.3)-C(sp.sup.2) 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.