Energy transfer photocatalysis: exciting modes of reactivity.

Excited (triplet) states offer a myriad of attractive synthetic pathways, including cycloadditions, selective homolytic bond cleavages and strain-release chemistry, isomerizations, deracemizations, or the fusion with metal catalysis. Recent years have seen enormous advantages in enabling these reactivity modes through visible-light-mediated triplet-triplet energy transfer catalysis (TTEnT). This tutorial review provides an overview of this emerging strategy for synthesizing sought-after organic motifs in a mild, selective, and sustainable manner. Building on the photophysical foundations of energy transfer, this review also discusses catalyst design, as well as the challenges and opportunities of energy transfer catalysis.

Double Strain-Release [2π+2σ]-Photocycloaddition.

In pursuit of potent pharmaceutical candidates and to further improve their chemical traits, small ring systems can serve as a potential starting point. Small ring units have the additional merit of loaded strain at their core, making them suitable reactants as they can capitalize on this intrinsic driving force. With the introduction of cyclobutenone as a strained precursor to ketene, the photocycloaddition with another strained unit, bicyclo[1.1.0]butane (BCB), enables the reactivity of both π-units in the transient ketene. This double strain-release driven [2π+2σ]-photocycloaddition promotes the synthesis of diverse heterobicyclo[2.1.1]hexane units, a pharmaceutically relevant bioisostere. The effective reactivity under catalyst-free conditions with a high functional group tolerance defines its synthetic utility. Experimental mechanistic studies and density functional theory (DFT) calculations suggest that the [2π+2σ]-photocycloaddition takes place via a triplet mechanism.

EnT-Mediated N-S Bond Homolysis of a Bifunctional Reagent Leading to Aliphatic Sulfonyl Fluorides.

Sulfur(VI) fluoride exchange (SuFEx) gives rise to a plethora of high-valent sulfur linkages; however, the availability of (aliphatic) sulfonyl fluoride manifolds lag behind, owing to the limited sources of introducing the SO2F moiety via a classical two-electron approach. Recently, radical-based methodologies have emerged as a complementary strategy to increase the diversity of accessible click partners. In this work, synthesis of a bench-stable sulfamoyl fluoride reagent is presented, which may undergo sigma-bond homolysis upon visible-light-induced sensitization to form protected ß-amino sulfonyl fluorides from alkene feedstocks. Notably, this offers an appealing strategy to access various building blocks for peptido sulfonyl fluorides, relevant in a medicinal chemistry context, as well as an intriguing entry to ß-ammonium sulfonates and ß-sultams, from alkenes. Densely functionalized 1,3-sultones were obtained by employing allyl alcohols as substrates. Surprisingly, allyl chloride-derived ß-imino sulfonyl fluoride underwent S-O bond formation and ring closure to yield rigid cyclopropyl ß-imino sulfonate ester under SuFEx conditions. Furthermore, by engaging a thiol-based hydrogen atom donor in the reaction, the reactivity of the same reagent can be tuned toward the direct synthesis of aliphatic sulfonyl fluorides. Mechanistic experiments indicate an energy transfer (EnT)-mediated process. The transient sulfonyl fluoride radical adds to the alkene and product formation occurs upon either radical-radical coupling or hydrogen atom transfer (HAT), respectively.

syn-Selective Difunctionalization of Bicyclobutanes Enabled by Photoredox-Mediated C-S σ-Bond Scission.

Given the importance of cyclic frameworks in molecular scaffolds and drug discovery, it is intriguing to precisely forge and manipulate ring systems in synthetic chemistry. In this field, the intermolecular synthesis of densely substituted cyclobutanes with precise diastereocontrol under simple reaction conditions remains a challenge. Herein, a photoredox strategy for the difunctionalization of bicyclo[1.1.0]butanes (BCBs) under high regio- and syn-selectivity is disclosed. C-S σ-bond cleavage of partially unsaturated sulfur-containing bifunctional reagents in an overall strain-release-driven process enables the thio-alkynylation, -alkenylation, and -allylation of BCBs under mild conditions and demonstrates the generality of this protocol. Mechanistic studies suggest that the intermediacy of cyclic distonic radical cations might be key for the efficient scission of C-S σ-bonds and the origin of diastereoselectivity.

Radical Carbonyl Umpolung Arylation via Dual Nickel Catalysis.

The formation of carbon-carbon bonds lies at the heart of synthetic organic chemistry and is widely applied to construct complex drugs, polymers, and materials. Despite its importance, catalytic carbonyl arylation remains comparatively underdeveloped, due to limited scope and functional group tolerance. Herein we disclose an umpolung strategy to achieve radical carbonyl arylation via dual catalysis. This redox-neutral approach provides a complementary method to construct Grignard-type products from (hetero)aryl bromides and aliphatic aldehydes, without the need for pre-functionalization. A sequential activation, hydrogen-atom transfer, and halogen atom transfer process could directly convert aldehydes to the corresponding ketyl-type radicals, which further react with aryl-nickel intermediates in an overall polarity-reversal process. This radical strategy tolerates─among others─acidic functional groups, heteroaryl motifs, and sterically hindered substrates and has been applied in the late-stage modification of drugs and natural products.

Chromium/Photoredox Dual Catalyzed Synthesis of α-Benzylic Alcohols, Isochromanones, 1,2-Oxy Alcohols and 1,2-Thio Alcohols.

Herein, a Cr/Photoredox-catalyzed general synthetic strategy to access α-benzylic alcohols, isochromanones, oxy alcohols and thio alcohols is unveiled. Alkylation of aldehydes being a crucial C-C bond forming reaction, designing competent catalytic systems would render an attractive and decorated set of diverse alcohol motifs. Considering the challenges associated with classical organometallic chemistry, the strategy of dual catalysis is applied here to generate diverse alcohol motifs in a mild and efficient manner. The amalgamation of photocatalysis with chromium chemistry is chosen for this purpose to generate an environment with low basicity and thus, high chemoselectivity. With alkyl silanes as preferred coupling partners, this catalytic setup produces a broad substrate scope with an excellent functional group tolerance and displays a facile scale-up as well. Its application towards biologically relevant molecules and product diversification contributes to the synthetic utility of this method.