A mild, organophotocatalytic N–O bond cleavage of Weinreb amides is disclosed, thereby expanding the chemistry of this venerable motif beyond acylation. This redox neutral process begins to reconcile the ubiquity of N–O bonds in contemporary synthesis with the disproportionately harsh, stoichiometric conditions that are often required for bond cleavage. The strategy is compatible with the parent alkyl derivatives (N–OMe, N–OAlkyl) thereby complementing tailored O-substituent approaches that require N–OAr groups (Ar = electron deficient). A broad range of acyclic and cyclic derivatives are dis-closed (>40 examples, up to 95%) and the synthetic utility of the method is demonstrated in a range of applications. In the case of cyclic Weinreb amide derivatives, this platform enables ambiphilic amide-aldehydes, of varying chain length, to be generated in a single transformation. Inspired by Emil Fischer´s seminal 1908 synthesis of aminoacetaldehyde using sodium amalgam, this method provides a milder route to access this important class of materials. Mechanistically-guided reaction development demonstrates the involvement of a photoinduced SET mechanism (PET), and this has been further advanced to a consecutive photoinduced electron transfer (ConPET) manifold: this has significantly expanded the scope of compatible substrates.

Geometrical E -> Z alkene isomerization is intimately entwined in the historical fabric of organic photochemistry and is enjoying a renaissance (Roth et al. Angew. Chem., Int. Ed. Engl. 1989 28, 1193-1207). This is a consequence of the fundamental stereochemical importance of Z-alkenes, juxtaposed with frustrations in thermal reactivity that are rooted in microscopic reversibility. Accessing excited state reactivity paradigms allow this latter obstacle to be circumnavigated by exploiting subtle differences in the photophysical behavior of the substrate and product chromophores: this provides a molecular basis for directionality. While direct irradiation is operationally simple, photosensitization via selective energy transfer enables augmentation of the alkene repertoire to include substrates that are not directly excited by photons. Through sustained innovation, an impressive portfolio of tailored small molecule catalysts with a range of triplet energies are now widely available to facilitate contra-thermodynamic and thermo-neutral isomerization reactions to generate Z-alkene fragments. This review is intended to serve as a practical guide covering the geometric isomerization of alkenes enabled by energy transfer catalysis from 2000 to 2020, and as a logical sequel to the excellent treatment by Dugave and Demange (Chem. Rev. 2003 103, 2475-2532). The mechanistic foundations underpinning isomerization selectivity are discussed together with induction models and rationales to explain the counterintuitive directionality of these processes in which very small energy differences distinguish substrate from product. Implications for subsequent stereospecific transformations, application in total synthesis, regioselective polyene isomerization, and spatiotemporal control of pre-existing alkene configuration in a broader sense are discussed.

Examples of geometric alkene isomerization in nature are often limited to the net exergonic direction (ΔG°<0), with the antipodal net endergonic processes (ΔG°>0) comparatively under-represented. Inspired by the expansiveness of the maleate to fumarate (Z→E) isomerization in biochemistry, we investigated the inverse E→Z variant to validate nO →πC=O * interactions as a driving force for contra-thermodynamic isomerization. A general protocol involving selective energy transfer catalysis with inexpensive thioxanthone as a sensitizer (λmax =402 nm) is disclosed. Whilst in the enzymatic process nO →πC=O * interactions commonly manifest themselves in the substrate, these same interactions are shown to underpin directionality in the antipodal reaction by shortening the product alkene chromophore. The process was validated with diverse fumarate derivatives (>30 examples, up to Z:E>99:1), including the first examples of tetrasubstituted alkenes, and the involvement of nO →πC=O * interactions was confirmed by X-ray crystallography.

A general strategy to enable the formal anti-hydrozirconation of arylacetylenes is reported that merges cis-hydrometallation using the Schwartz Reagent (Cp2ZrHCl) with a subsequent light-mediated geometric isomerization at λ = 400 nm.

Flavin-mediated photocatalytic oxidations are established in synthetic chemistry. In contrast, their use in reductive chemistry is rare. Deazaflavins with a much lower reduction potential are even better suited for reductive chemistry rendering also deazaflavin semiquinones as strong reductants. However, no direct evidence exists for the involvement of these radical species in reductive processes. Here, we synthesise deazaflavins with different substituents at C5 and demonstrate their photocatalytic activity in the dehalogenation of p -halogenanisoles with best performance under basic conditions. Mechanistic investigations reveal a consecutive photo-induced electron transfer via the semiquinone form of the deazaflavin as part of a triplet-correlated radical pair after electron transfer from a sacrificial electron donor to the triplet state. A second electron transfer from the excited semiquinone to p -halogenanisoles triggers the final product formation. This study provides first evidence that the reductive power of excited deazaflavin semiquinones can be used in photocatalytic reductive chemistry.

An operationally simple one-pot protocol has been developed to enable the conversion of diversely substituted cinnamic acid derivatives into angularly-fused dihydrocoumarins (up to 94%). Inspired by coumarin biosynthesis, this reaction cascade harnesses photochemical E → Z alkene isomerization enabled by energy transfer catalysis using inexpensive thioxanthen-9-one (TX) under irradiation at 402 nm. Subsequent lactonization generates the heterocyclic core prior to a second photosensitization event to induce a [2 + 2] cycloaddition, again mediated by TX. The tetracyclic products are generated efficiently, and proof of the structure was established by X-ray crystallography. Mechanistic investigations, including structural probes and NMR reaction monitoring, support the postulated order of events. The study underscores the synthetic value of inexpensive small-molecule organic photocatalysts in the generation of structural complexity via sequential π-bond activation.

Triphenylphosphine (Ph3P) activated by various electrophiles (e.g., alkyl diazocarboxylates) represents an effective mediator of esterification and other nucleophilic substitution reactions. We report herein an aza-reagent-free procedure using flavin catalyst (3-methyl riboflavin tetraacetate), triphenylphosphine, and visible light (448 nm), which allows effective esterification of aromatic and aliphatic carboxylic acids with alcohols. Mechanistic study confirmed that photoinduced electron transfer from triphenylphosphine to excited flavin with the formation of Ph3P˙+ is a crucial step in the catalytic cycle. This allows reactive alkoxyphosphonium species to be generated by reaction of an alcohol with Ph3P˙+ followed by single-electron oxidation. Unexpected stereoselectivity control by the solvent was observed, allowing switching from inversion to retention of configuration during esterification of (S)- or (R)-1-phenylethanol; for example with phenylacetic acid, the ratio shifting from 10 : 90 (retention : inversion) in trifluoromethylbenzene to 99.9 : 0.1 in acetonitrile. Our method uses nitrobenzene to regenerate the flavin photocatalyst. This new approach to flavin re-oxidation has also been successfully proved in benzyl alcohol oxidation, which is a "standard" process among flavin-mediated photooxidations.

The [2+2] photocycloaddition mediated by 1‐butyl‐3‐methyl‐7,8‐dimethoxyalloxazine ( 1 ) has been found to be an effective tool for cyclising ω‐phenyl‐ and ω,ω′‐diphenyl‐4‐aza‐1,6‐heptadienes, in which the nitrogen atom is protected by acylation or quaternisation, towards the synthesis of a variety of phenyl‐ and diphenyl‐3‐azabicyclo[3.2.0]heptanes and their corresponding quaternary salts. Thia derivatives, with the sulfur atom in the form of a sulfone group, underwent an analogous cyclisation. Advantageously, visible light (400 nm) was used for the cycloadditions in the presence of 1 , in contrast to the previously described procedures affording azabicyclo[3.2.0]heptanes by using UV irradiation. Practical applications are demonstrated through the synthesis of bicyclic quaternary ammonium salts, 6‐phenyl‐azabicyclo[3.2.0]heptanes known to exhibit biological activity or chiral spiro ammonium salts. Flavin 1 was also found to promote the efficient E → Z isomerisation of electron‐rich cinnamyl derivatives to produce mixtures enriched with the Z isomer (with Z/E ratios of up to 77:23).

We present enantioseparation of a series of racemic sulfoxides on three different amylose-based polysaccharide columns. Two of them have the amylose units modified with dimethylphenyl carbamoyl groups (Chiralpak AD-H and Chiralpak IA), while the third one possesses a carbamoyl moiety with an additional chiral centre (Chiralpak AS-H). The enantioseparation of selected analytes was achieved in high-performance liquid chromatography (HPLC) and the full analyte set was enantiomerically resolved using supercritical fluid chromatography (SFC). Comparing the results obtained in both modes, we show that enantioseparation under SFC conditions is superior to HPLC mode in terms of speed, while retaining excellent enantioselectivity and resolution. Faster elution of analytes was observed on increasing the polarity of the co-solvent (modifier) in the mobile phase. This trend is apparent in both chromatographic modes. Documenting the important role of the additional chiral centre, Chiralpak AS-H provided the best chromatographic parameters resulting in the enantioseparation of all analytes.

We have developed a metal-free process for the aerobic photooxygenation of sulfides to sulfoxides mediated by riboflavin tetraacetate or riboflavin (vitamin B2) photocatalysts and visible light (450 nm) in an acetonitrile-water (85:15 v/v) mixture. The optimised solvent system leads to both singlet-oxygen and electron-transfer pathways in photooxygenation, thus allowing oxidation of electron-poor and electron-rich thioanisoles, dialkyl sulfides and sterically hindered sulfides. Besides having a broad substrate scope, the method has very short reaction times and requires low catalyst loading (down to 0.1 mol%). These properties are due to the high photocatalyst stability and the extremely high quantum yields (1.3 for thioanisole oxygenation). Moreover, the method is chemoselective, producing only sulfoxides without overoxidation to sulfones. Taking into account the broad substrate scope, high selectivity and high efficiency, this method distinguishes itself from those previously reported. Other advantages include easy work-up of the reaction mixture, the availability and biodegradability of the photocatalysts and mild reaction conditions. We demonstrated, on a preparative scale, its practical application in the synthesis of the psychostimulant modafinil, in the selective oxidation of methionine derivatives, and in the detoxification of mustard gas.

A new application of flavin derivatives in visible light photocatalysis was found. 1-Butyl-7,8-dimethoxy-3-methylalloxazine, when irradiated by visible light, was shown to allow an efficient cyclobutane ring formation via an intramolecular [2+2] cycloaddition of both styrene dienes, considered as electron-rich substrates, and electron-poor bis(arylenones), presumably proceeding via an energy transfer mechanism.