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Author(s): Zhe Dong [sup.1] , David W. C. MacMillan [sup.1] Author Affiliations: (1) Merck Center for Catalysis at Princeton University, Princeton, USA Main Over the past half century, advances in [...], 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.sup.1. However, alkyl cross-couplings using native sp.sup.3-hybridized functional groups such as alcohols remain relatively underdeveloped.sup.2. 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.sup.3, but would allow access to the vast collection of commercially available, structurally diverse alcohols as coupling partners.sup.4. 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. A metallaphotoredox-based cross-coupling platform is capable of activating a wide range of free alcohols using N-heterocyclic carbene salts, cleaving C-O bonds to form free carbon radicals that are then used to form new C-C bonds.

Author(s): Xiaheng Zhang [sup.1] , Russell T. Smith [sup.1] , Chip Le [sup.1] , Stefan J. McCarver [sup.2] , Brock T. Shireman [sup.2] , Nicholas I. Carruthers [sup.2] , David [...], Multicomponent reactions are relied on in both academic and industrial synthetic organic chemistry owing to their step- and atom-economy advantages over traditional synthetic sequences.sup.1. Recently, bicyclo[1.1.1]pentane (BCP) motifs have become valuable as pharmaceutical bioisosteres of benzene rings, and in particular 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para-phenyl ring replacements.sup.2. These structures are often generated from [1.1.1]propellane via opening of the internal C-C bond through the addition of either radicals or metal-based nucleophiles.sup.3-13. The resulting propellane-addition adducts are then transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. Although this approach has been effective so far, a multicomponent reaction that enables single-step access to complex and diverse polysubstituted drug-like BCP products would be more time efficient compared to current stepwise approaches. Here we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicyclopentanes using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. This copper-mediated reaction operates on short timescales (five minutes to one hour) across multiple (more than ten) nucleophile classes and can accommodate a diverse array of radical precursors, including those that generate alkyl, [alpha]-acyl, trifluoromethyl and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which is substantially more metabolically stable than its commercial progenitor. A one-step, three-component radical coupling of [1.1.1]propellane by a photoredox reaction mediated by a copper catalyst produces drug-like bicyclopentanes.

Author(s): Ian B. Perry [sup.1] , Thomas F. Brewer [sup.1] , Patrick J. Sarver [sup.1] , Danielle M. Schultz [sup.2] , Daniel A. DiRocco [sup.2] , David W. C. MacMillan [...], 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.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.

Author(s): Yufan Liang [sup.1] , Xiaheng Zhang [sup.1] , David W. C. MacMillan [sup.1] Author Affiliations: (1) Merck Center for Catalysis at Princeton University, Princeton, USA Main Within the field [...], Over the past three decades, considerable progress has been made in the development of methods to construct sp.sup.2 carbon-nitrogen (C-N) bonds using palladium, copper or nickel catalysis.sup.1,2. However, the incorporation of alkyl substrates to form sp.sup.3 C-N bonds remains one of the major challenges in the field of cross-coupling chemistry. Here we demonstrate that the synergistic combination of copper catalysis and photoredox catalysis can provide a general platform from which to address this challenge. This cross-coupling system uses naturally abundant alkyl carboxylic acids and commercially available nitrogen nucleophiles as coupling partners. It is applicable to a wide variety of primary, secondary and tertiary alkyl carboxylic acids (through iodonium activation), as well as a vast array of nitrogen nucleophiles: nitrogen heterocycles, amides, sulfonamides and anilines can undergo C-N coupling to provide N-alkyl products in good to excellent efficiency, at room temperature and on short timescales (five minutes to one hour). We demonstrate that this C-N coupling protocol proceeds with high regioselectivity using substrates that contain several amine groups, and can also be applied to complex drug molecules, enabling the rapid construction of molecular complexity and the late-stage functionalization of bioactive pharmaceuticals. The synergistic combination of copper catalysis and photoredox catalysis forms sp.sup.3 C-N bonds in a rapid, room-temperature coupling protocol with high efficiencies and regioselectivities and a broad substrate scope.

Author(s): Craig P. Johnston [1]; Russell T. Smith [1]; Simon Allmendinger [1]; David W. C. MacMillan (corresponding author) [1] In the past 50 years, cross-coupling reactions mediated by transition metals [...]