No abstract

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.

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 Csp3–Csp2 bonds generically via a unique cross-coupling pathway.

The functionalization of carbon–hydrogen (C–H) bonds is one of the most attractive strategies for molecular construction in organic chemistry. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in organic molecules and its availability for functionalization at almost any stage in a synthetic sequence1. Although many C–H functionalization reactions involve C(sp3)–C(sp2) coupling, there is a growing demand for C–H alkylation reactions, wherein sp3 C–H bonds are replaced with sp3 C–alkyl groups. Here we describe a polarity-match-based selective sp3 C–H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodology simultaneously uses three catalytic cycles to achieve hydridic C–H bond abstraction (enabled by polarity matching), alkyl halide oxidative addition, and reductive elimination to enable alkyl–alkyl fragment coupling. The sp3 C–H alkylation is highly selective for the α-C–H of amines, ethers and sulphides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chemistry.

Transition metal-catalyzed arene functionalization has been widely used for molecular synthesis over the past century. In this arena, copper catalysis has long been considered a privileged platform due to the propensity of high-valent copper to undergo reductive elimination with a wide variety of coupling fragments. However, the sluggish nature of oxidative addition has limited copper's capacity to broadly facilitate haloarene coupling protocols. Here, we demonstrate that this copper oxidative addition problem can be overcome with an aryl radical-capture mechanism, wherein the aryl radical is generated through a silyl radical halogen abstraction. This strategy was applied to a general trifluoromethylation of aryl bromides through dual copper-photoredox catalysis. Mechanistic studies support the formation of an open-shell aryl species.

Photocatalysis for organic synthesis has experienced an exponential growth in the past 10 years. However, the variety of experimental procedures that have been reported to perform photon-based catalyst excitation has hampered the establishment of general protocols to convert visible light into chemical energy. To address this issue, we have designed an integrated photoreactor for enhanced photon capture and catalyst excitation. Moreover, the evaluation of this new reactor in eight photocatalytic transformations that are widely employed in medicinal chemistry settings has confirmed significant performance advantages of this optimized design while enabling a standardized protocol.

Multicomponent reactions (MCRs) have become a mainstay in both academic and industrial synthetic organic chemistry due to their step- and atom-economy advantages over traditional synthetic sequences 1 . Recently, bicyclo[1.1.1]pentane (BCP) motifs have come to the fore as valuable 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 2 . Often these structures are generated from [1.1.1]propellane via opening of the internal C─C bond, either through the addition of radicals or metal-based nucleophiles 3 - 13 . The resulting propellane-addition adducts are subsequently transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. While this approach has been effective to date, it is clear that a multicomponent reaction that enables single-step access to complex and diverse polysubstituted BCP products would be synthetically advantageous over the current stepwise approaches. Herein we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicycles using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. The reaction operates on short time scales (five minutes to one hour) across multiple (>10) nucleophile classes and can accommodate a diverse array of radical precursors, including those which generate alkyl, α-acyl, trifluoromethyl, and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which has substantially different pharmacokinetic properties to those of its commercial progenitor.

Alkyl chlorides are bench-stable chemical feed-stocks that remain among the most underutilized electrophile classes in transition metal catalysis. Overcoming intrinsic limitations of C(sp 3 )-Cl bond activation, we report the development of a novel organosilane reagent that can participate in chlorine atom abstraction under mild photocatalytic conditions. In particular, we describe the application of this mechanism to a dual nickel/photoredox catalytic protocol that enables the first cross-electrophile coupling of unactivated alkyl chlorides and aryl chlorides. Employing these low toxicity, abundant, and commercially available organochloride building blocks, this methodology allows access to a broad array of highly functionalized C(sp 2 )-C(sp 3 ) coupled adducts, including numerous drug analogs.