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Tuning Flavin‐Based Photocatalytic Systems for Application in the Mild Chemoselective Aerobic Oxidation of Benzylic Substrates

DOI:10.1002/ejoc.201901628

Abstract

Chemoselective oxidation of substituted benzyl alcohols and toluene derivatives has been developed using a flavin photocatalyst, visible light and a suitable additive. Depending on the flavin and the additive, oxidation takes place selectively to the corresponding aldehyde or carboxylic acid. The procedure is also useful for oxidation of secondary alcohols or benzylic methylene‐containing compounds to ketones.

New flavin‐based photocatalytic systems used for chemoselective aerobic visible‐light oxidations have been developed by tuning the flavin structure and reaction conditions. 1,3‐Dimethyl‐7‐trifluoromethylalloxazine (2) and 10‐butyl‐3‐methyl‐7‐trifluoromethylisoalloxazine (3) were shown to mediate the selective oxidation of benzyl alcohols to form aldehydes in the presence of Cs₂CO₃. Flavin 3 was superior in the oxidation of toluene derivatives to form aldehydes in the presence of trifluoroacetic acid. On the other hand, photooxidations provided by ethylene‐bridged quaternary flavinium salt 1 gave the corresponding carboxylic acids. The usefulness of the developed catalytic systems using 1–3 was also demonstrated in the oxidation of secondary benzylic and aliphatic alcohols, and benzylic methylene groups to form the corresponding ketones. The systems have the advantage of a broad substrate scope and metal‐free conditions, which distinguish them from the previously reported flavin photooxidation reactions.

Flavinium catalyzed photooxidation: Detection and characterization of elusive peroxyflavinium intermediates  

DOI:10.1002/anie.201906293  

Abstract

Flavin‐based catalysts are photoactive in the visible range which makes them useful in biology and chemistry. Herein, we present electrospray‐ionization mass‐spectrometry detection of short‐lived intermediates in photooxidation of toluene catalysed by flavinium ions (Fl⁺). Previous studies have shown that photoexcited flavins react with aromates by proton‐coupled electron transfer (PCET) on the microsecond time scale. For Fl⁺, PCET leads to FlH^.+ with the H‐atom bound to the N5 position. We show that the reaction continues by coupling between FlH^.+ and hydroperoxy or benzylperoxy radicals at the C4a position of FlH^.+. These results demonstrate that the N5‐blocking effect reported for alkylated flavins is also active after PCET in these photocatalytic reactions. Structures of all intermediates were fully characterised by isotopic labelling and by photodissociation spectroscopy. These tools provide a new way to study reaction intermediates in the sub‐second time range.

Flavin Catalysis Employing an N(5)-Adduct: An Application in the Aerobic Organocatalytic Mitsunobu Reaction

 DOI:10.1002/ejoc.201900397

Abstract

An N(5)‐flavin adduct was utilized in a catalytic Mitsunobu reaction with triphenylphosphane (triphenylphosphine), in which flavin acts as a Mitsunobu reagent instead of dialkyl azodicarboxylate. Flavin is used in a catalytic amount after regeneration by dioxygen.

An artificial flavin system has been firstly proved to employ an N(5)‐adduct for a catalytic transformation. This mode of catalysis occurs in some flavoenzymes but it is unknown in chemocatalysis, still exclusively using only C(4a)‐adducts. In our report, an ethylene‐bridged biomimetic flavin has been shown to participate in the Mitsunobu esterification reaction as an alternative to dialkyl azodicarboxylate. The reaction occurs via a flavin N(5)‐triphenylphosphane adduct and is catalytic from the point of view of the flavin, which is regenerated by oxygen. This approach distinguishes from other catalytic Mitsunobu reaction procedures which require an extra catalytic system.

Nitrosobenzene: Reagent for the Mitsunobu Esterification Reaction

DOI:10.1021/acsomega.8b03551

Abstract

Nitrosobenzene has been demonstrated to participate in the Mitsunobu reaction in an analogous manner to dialkyl azodicarboxylates. The protocol using nitrosobenzene and triphenylphosphine (1:1) under mild conditions (0 °C) provides the ester derivatives of aliphatic and aromatic acids using various alcohols in moderate yield and with good enantioselectivity, giving the desired products predominantly with an inversion of configuration. The proposed mechanism, which is analogous to that observed using dialkyl azodicarboxylates, involves a nitrosobenzene–triphenylphosphine adduct and an alkoxytriphenylphosphonium ion and was supported by density functional theory calculations, ³¹P NMR spectroscopy, and experiments conducted with isotopically labeled substrates.

Combining flavin photocatalysis and organocatalysis: metal-free aerobic oxidation of unactivated benzylic substrates 

DOI:10.1021/acs.orglett.8b03547

Abstract

We report a system with ethylene-bridged flavinium salt 2b which catalyzes the aerobic oxidation of toluenes and benzyl alcohols with high oxidation potential (E_ox > +2.5 V vs SCE) to give the corresponding benzoic acids under visible light irradiation. This is caused by the high oxidizing power of excited 2b (E(2b*) = +2.67 V vs SCE) involved in photooxidation and by the accompanying dark organocatalytic oxygenation provided by the in situ formed flavin hydroperoxide 2b-OOH.

Azodicarboxylate-free esterification with triphenylphosphine mediated by flavin and visible light: method development and stereoselectivity control

DOI: 10.1039/C8OB01822G

Abstract

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.

Enantioselective complexation of 1‐phenylethanol with chiral compounds bearing urea moiety

DOI:10.1002/chir.22855

Abstract

A detailed study of diastereomeric complexes of chiral ureido‐1,1′‐binaphthalene derivatives with chiral 1‐phenylethanol showed that a derivative bearing only one urea unit makes five times more stable complex with (S)‐enantiomer than with (R)‐enantiomer of the alcohol. This phenomenon could be used in chiral discrimination processes. The influence of individual parts of the structure on the complexation properties is shown. The probable structure of diastereomeric complexes based on experimental results and computational methods is proposed.

Flavin derivatives immobilized on mesoporous silica: a versatile tool in visible-light photooxidation reactions

DOI:10.1007/s00706-017-2127-1

Abstract

Anchoring riboflavin tetraacetate to mesoporous silica (MCM-41) provides a heterogenized flavin photocatalyst, which was proven to be an effective catalyst for chemoselective sulfoxidation, benzyl alcohol oxidation, and photoesterification reactions. Analogously heterogenized 1-butyl-7,8-dimethoxyalloxazine was shown to mediate sulfoxidation and benzylic oxidation reactions. This is the first application of an alloxazine photocatalyst in a redox reaction. The use of these heterogeneous catalysts allows simple operation and work-up of the reaction mixtures.

Flavin Photocatalysts for Visible Light [2+2] Cycloadditions: Structure, Reactivity and Reaction Mechanism

DOI:10.1002/cctc.201701490

Abstract

New photocatalysts from the flavin family were found to mediate the [2+2] photocycloaddition reaction. 3-Butyl-10-methyl-5-deazaflavin (3a) and 1-butyl-7,8-dimethoxy-3-methylalloxazine (2e), when irradiated by visible light, were shown to allow an efficient (Φ ~ 3-10%) intramolecular cyclization of various types of substrates including substituted styrene dienes and bis(aryl enones), considered as electron-rich and electron-poor substrates, respectively, without any additional reagent. The versatility of the procedure was also demonstrated by the cyclization of photosensitive cinnamyl (E)-3-iodoallyl ether. Structure vs. activity studies found alloxazine 2e was more active than 7-monosubstituted (R = Cl, Br and MeO) alloxazines. The introduction of chlorine and bromine atom on the deazaflavin skeleton did not enhance the catalytic efficiency of 3a. A detailed electrochemical and spectroscopic study explains the reaction mechanism proceeding through energy transfer from the flavin excited triplet state to the diene followed by its cyclization.

DOI:10.1039/C6OB02770A

Abstract

Visible Light [2+2] Photocycloaddition Mediated by Flavin Derivative Immobilized on Mesoporous Silica

DOI:10.1002/cctc.201601654