Spatio-temporal detachment of homogeneous electron transfer in controlling selectivity in mediated organic electrosynthesis.

In electrosynthesis, electron transfer (ET) mediators are normally chosen such that they are more easily reduced (or oxidised) than the substrate for cathodic (or anodic) processes; setting the electrode potential to the mediator therefore ensures selective heterogeneous ET with the mediator at the electrode, rather than the substrate. The current work investigates the opposite, and counter intuitive, situation for a successful mediated electroreductive process where the mediator (phenanthrene) has a reduction potential that is negative to that of the substrate, and the cathode potential is set negative to both (Eele < EM < Es). Simulations reveal a complex interplay between mass transport, the relative concentrations of the mediator and substrate as well as the heterogeneous and homogeneous rate constants for multiple steps, which under suitable conditions, leads to separation of the homogeneous chemistry in a reaction layer detached from the electrode. Reaction layer detachment is a spatio-temporal effect arising due to opposing fluxes of the mediator radical anion M˙- and the substrate 1, which ultimately prevents 1 from reaching the electrode, thereby affording a different reaction pathway. Simulations representative of unstirred batch (1D) and flow (2D) electrolysis are presented, which qualitatively reproduce the experimental selectivity outcomes for mediated and unmediated electroreductive cyclisation of aryl iodide 1. The potential to use highly reducing homogeneous ET agents, possessing reduction potentials beyond those of the substrates, offers exciting opportunities in mediated electrosynthesis.

Cathodic Radical Cyclisation of Aryl Halides Using a Strongly-Reducing Catalytic Mediator in Flow.

Electro-reductive radical cyclisation of aryl halides affords the corresponding hetero- and carbo-cycles in an undivided flow reactor equipped with steel and carbon electrodes using an organic mediator. A dissolving metal anode is not needed, and the mediator can be employed in a sub-stoichiometric amount (0.05 equiv), increasing the practical utility of cathodic radical cyclisation. The methodology is applied to O-, N-, and C-tethers, yielding tricyclic fused and spiro systems. In the absence of mediator, the major pathway is hydrogenolysis of the C-X bond, a 2 e- process occurring at the cathode. Predominance of the radical pathway in presence of a strongly reducing mediator (M) is consistent with homogeneous electron-transfer in a reaction layer detached from the cathode surface, where the flux of M.- leaving the electrode is such that little aryl halide reaches the cathode.

The development of a short route to the API ropinirole hydrochloride.

A four-step, three-stage synthesis of the API ropinirole hydrochloride has been developed from a commercially available naphthalene derivative. The new route has half the step-count and twice the overall yield of the current manufacturing process. Key features of the synthesis are a regioselective Birch reduction and an ozonolysis with concomitant ring closure to induce the required ring contraction.

Generation and Trapping of Ketenes in Flow.

Ketenes were generated by the thermolysis of alkoxyalkynes under flow conditions, and then trapped with amines and alcohols to cleanly give amides and esters. For a 10 min reaction time, temperatures of 180, 160, and 140 °C were required for >95 % conversion of EtO, iPrO, and tBuO alkoxyalkynes, respectively. Variation of the temperature and flow rate with inline monitoring of the output by IR spectroscopy allowed the kinetic parameters for the conversion of 1-ethoxy-1-octyne to be easily estimated (Ea = 105.4 kJ/mol). Trapping of the in-situ-generated ketenes by alcohols to give esters required the addition of a tertiary amine catalyst to prevent competitive [2+2] addition of the ketene to the alkoxyalkyne precursor.

The profound effect of the ring size in the electrocyclic opening of cyclobutene-fused bicyclic systems.

Fused cyclobutenes, prepared by the photocycloaddition of propargyl alcohols to cyclic anhydride chromophores, undergo facile thermochemical ring opening to fused γ-lactones. The size of the fused ring profoundly influences the temperature that is required to facilitate the ring opening (from 50 °C to 180 °C) and the nature of the product that is formed. Our studies provide new insights into the mechanistic course of these reactions and have been extended to facilitate the preparation of lactams fused to medium-sized rings.

Exploring diradical chemistry: a carbon-centered radical may act as either an anion or electrophile through an orbital isomer.

Diradical intermediates, formed by thermolysis of alkynylcyclobutenones, can display radical, anion, or electrophilic character because of the existence of an orbital isomer with zwitterionic and cyclohexatrienone character. Our realization that water, alcohols, and certain substituents can induce the switch provides new opportunities in synthesis. For example, it can be used to shut down radical pathways and to give access to aryl carbonates and tetrasubstituted quinones.

Intra- and intermolecular alkylation of N,O-acetals and π-activated alcohols catalyzed by in situ generated acid.

Intramolecular and intermolecular alkylations of carbocation precursors of limited ionization ability, principally N,O-acetals, without the use of an exogenous reagent have been developed. The reactions are carried out in 1,1,2,2-tetrachloroethane (TCE) and take advantage of the ability of this solvent to continuously release small amounts of HCl by thermolytic elimination. A study of the reaction led to several improved protocols such as (1) preheated TCE, (2) microwave-assisted reactions, and (3) flow or sealed-tube conditions, which allow significant reaction rate enhancements and made possible some challenging reactions such as the α-amidoalkylation of ketones. Studies using flow chemistry confirmed not only that very low concentrations of HCl generated from the solvent were responsible for the reactivity but also that TCE had additional beneficial properties in comparison to other chlorinated solvents such as dichloroethane. The method can easily be extended to the alkylation using proelectrophiles such as π-activated alcohols, which are normally unreactive toward HCl catalysis. This work represents the first successful use of HCl, the simplest strong Brønsted acid, as an efficient alkylation catalyst.

Total Synthesis of (±)-Paroxetine by Diastereoconvergent Cobalt-Catalysed Arylation.

A total synthesis of paroxetine is reported, with a diastereoselective and diastereoconvergent cobalt-catalysed sp3-sp2 coupling reaction involving a 3-substituted 4-bromo-N-Boc-piperidine (Boc = tert-butoxycarbonyl) substrate as a key step. A 9:1 diastereoselectivity was obtained, while a control experiment involving a conformationally locked 3-substituted 4-bromo-tert-butyl cyclohexane ring proceeded with essentially complete stereoselectivity.

Organoytterbium ate complexes extend the value of cyclobutenediones as isoprene equivalents.

Changing course: While organolithium and Grignard reagents favor addition to C1 of A (R=Me), the corresponding organoytterbium reagents add to C2 (R=tBu). Computational studies provide insights into the nature of organoytterbium species and their reactivity, and a total synthesis of (-)-mansonone B illustrates the utility of the method in terpenoid synthesis. Tf=trifluoromethanesulfonyl.

A systematic study of the interplay between guest molecule structure and intermolecular interactions in crystalline sponges.

Utilization of the crystalline sponge {[(ZnI2)3(tpt)2·x(solvent)]n} method has enabled characterization of a novel family of synthetic organic oils. The systematic structural differences and diversity of functional groups offered by 13 related molecular adsorbates provide a detailed quantitative understanding of the relationship between the guest structure, its conformation, and the type of intermolecular interactions adopted with neighbouring guests and the host framework. This analysis is extended to assess the connection of these factors to the resulting quality indicators for a particular molecular structure elucidation.

Aryl-aryl cross-coupling reactions without reagents or catalysts: photocyclization of ortho-iodoaryl ethers and related compounds via triplet aryl cation intermediates.

Cyclisations of benzyl ortho-iodoaryl ethers to benzo[c]chromenes can be effected without reagents or catalysts by irradiation with UVC under flow. Reactions proceed via triplet aryl cation generation, 5-exo and 3-exo-cyclisations, and rearomatisation. They have wide scope, are easy to effect and extend to a myriad of related ring systems.

Macrocylic bisbibenzyl natural products and their chemical synthesis.

Covering: 1995 to June 2011. The macrocyclic bisbibenzyl family of natural products are commonly found in liverworts and other bryophytes, though the recent isolation of riccardin C from a primrose extract has demonstrated their existence in higher flowering plants. Each has a core comprising four aromatic rings and two ethano bridges, being derived in Nature from two molecules of lunularin. Sub-classes are distinguished by the connectivity between these lunularin units, while individual natural products are distinguished by the hydroxy- and/or alkoxy-substituents decorating the core structures. Further diversification results from halogenation and oxidation, which may lead to dimerization or the creation of additional rings. The review provides a timely update to a previous Natural Product Reports article by Keseru and Nógrádi (Nat. Prod. Rep. 1995, 12, 69-75) and largely focuses on new additions to the family and the strategies used to effect their chemical synthesis.

New approaches to ondansetron and alosetron inspire a versatile, flow photochemical method for indole synthesis.

An oxidative photocyclisation of N-arylenaminones to indoles is described, that mirrors the Fischer indole synthesis but uses anilines in place of arylhydrazines. Its value is exemplified with new approaches to the WHO-listed APIs ondansetron and alosetron.

Wavelength dependent photoextrusion and tandem photo-extrusion reactions of ninhydrin bis-acetals for the synthesis of 8-ring lactones, benzocyclobutenes and orthoanhydrides.

Ninhydrin bis-acetals give access to 8-ring lactones, benzocyclo-butenes and spirocyclic orthoanhydrides through photoextrusion and tandem photoextrusion reactions. Syntheses of fimbricalyxlactone B, isoshihunine and numerous biologically-relevant heterocycles show the value of the methods, while TA-spectroscopy and TD-DFT studies provide mechanistic insights on their wavelength dependence.

High-Productivity Single-Pass Electrochemical Birch Reduction of Naphthalenes in a Continuous Flow Electrochemical Taylor Vortex Reactor.

We report the development of a single-pass electrochemical Birch reduction carried out in a small footprint electrochemical Taylor vortex reactor with projected productivities of >80 g day-1 (based on 32.2 mmol h-1), using a modified version of our previously reported reactor [Org. Process Res. Dev. 2021, 25, 7, 1619-1627], consisting of a static outer electrode and a rapidly rotating cylindrical inner electrode. In this study, we used an aluminum tube as the sacrificial outer electrode and stainless steel as the rotating inner electrode. We have established the viability of using a sacrificial aluminum anode for the electrochemical reduction of naphthalene, and by varying the current, we can switch between high selectivity (>90%) for either the single ring reduction or double ring reduction with >80 g day-1 projected productivity for either product. The concentration of LiBr in solution changes the fluid dynamics of the reaction mixture investigated by computational fluid dynamics, and this affects equilibration time, monitored using Fourier transform infrared spectroscopy. We show that the concentrations of electrolyte (LiBr) and proton source (dimethylurea) can be reduced while maintaining high reaction efficiency. We also report the reduction of 1-aminonaphthalene, which has been used as a precursor to the API Ropinirole. We find that our methodology produces the corresponding dihydronaphthalene with excellent selectivity and 88% isolated yield in an uninterrupted run of >8 h with a projected productivity of >100 g day-1.

Unified syntheses of cavicularin and riccardin C: addressing the synthesis of an arene adopting a boat configuration.

Concise syntheses of the natural products cavicularin (ten steps) and riccardin C (seven steps) are reported. Key features of the new synthetic route are a convergent strategy to assemble acyclic precursors and a sequence of regioselective reduction and halogenation steps to facilitate Wittig macrocyclisation and transannular ring contraction reactions.

New insights into cyclobutenone rearrangements: a total synthesis of the natural ROS-generating anti-cancer agent cribrostatin 6.

Aryl- and heteroarylcyclobutenone rearrangements proceed in excellent yield under continuous-flow conditions. The former shows a Hammett correlation with σ(I) providing strong evidence that electrocyclisation is the rate-determining step and has a late transition state. The reaction has been modelled by using DFT and CCSD(T) methods, with the latter giving excellent correlation with the experimental rate constant. A short and efficient total synthesis of cribrostatin 6, an anti-neoplastic and anti-microbial agent, provides a topical demonstration of the value of this method.

CH activation and CH2 double activation of indolines by radical translocation: understanding the chemistry of the indolinyl radical.

CH activation and CH(2) double activation of indolines at C2 may be achieved efficiently through radical translocation. The fate of the C2 indolinyl radical is dictated by the substitution at C3. Fragmentation, cyclisation and tandem cyclisation reactions leading to indole, azaheterocycle and azapropellane formation, respectively, are reported.

A photochemical ring expansion of 6- to 8-membered nitrogen heterocycles by [1,3]-sigmatropic rearrangement.

A new route to azocines and benzoazocines from furopyridinones is described through a photochemically induced [1,3]-sigmatropic rearrangement. The method gives access to these 8-membered nitrogen heterocycles from dimethyl squarate in four stages and with excellent atom economy by sequencing thermal and photochemical ring expansion steps under continuous flow.

A new mode of cyclobutenedione ring opening for the synthesis of 2-oxobut-3-enamides and tetrasubstituted furans.

A dichotomy between the additions of organolithiums and lithium amides to cyclobutenediones is described wherein the former give carbonyl addition products while the latter induce ring opening by enone cleavage via O- to C-lithium transfer. This distinct mode of ring scission gives access to 2-oxobut-3-enamides and tetrasubstituted furans.