The problem with problems : fundamental to applied research using palladium

The studies are very grateful for the support we have received from the following sources for the chemistry described in this Account: EPSRC (EP/R025754/1), The Leverhulme Trust (RPG-2015-308), and GlaxoSmithKline and AstraZeneca for several CASE awards and iCASE studentships.This Account describes the development of our cross-coupling and medicinal chemistry research from its origins at the outset of my independent career through to the present day. Throughout, the decisions and motivations as well as the mistakes and pitfalls are discussed.Publisher PDFPeer reviewe

An alternative synthesis of cycloalkyl-substituted CPA catalysts and application in asymmetric protonation reactions

LAM thanks the EPSRC (grant number EP/S027165/1) for postdoctoral funding.An alternative synthesis of cycloalkyl-substituted CPA catalysts is reported. A Negishi coupling offers improved yields and purity of the necessary 1,3,5-tri(cycloalkyl)benzenes. Limitations in the use of commercial organozinc reagents have been identified and a robust procedure for the preparation of these reagents is detailed. Similarly, a robust procedure for the key Kumada coupling is also provided. The route is demonstrated by preparation of three different tri(cycloalkyl)aryl-substituted CPAs and the utility of these catalysts in asymmetric protonation reactions is shown.Publisher PDFPeer reviewe

Ni vs. Pd in Suzuki-Miyaura sp2-sp2 cross-coupling : a head-to-head study in a comparable precatalyst/ligand system

We thank the University of St Andrews for a PhD studentship (MJW).The Suzuki-Miyaura reaction is a cornerstone method for sp2-sp2 cross-coupling in industry. There has been a concerted effort to enable the use of Ni catalysis as an alternative to Pd in order to mitigate cost and improve sustainability. Despite significant advances, ligand development for Ni-catalyzed Suzuki-Miyaura cross-coupling remains underdeveloped when compared to Pd and, as a consequence, ligands for Ni-catalyzed processes are typically taken from the Pd arena. In this study we evaluate the effect of using a similar Ni and Pd precatalyst based on a common bidentate ligand (dppf) in a head-to-head format for the most common type of biaryl couplings, establishing the practical implications of direct replacement of Pd with Ni, and identifying the potential origins of these observations in a mechanistic context.PostprintPeer reviewe

Chemoselective Suzuki-Miyaura cross-coupling via kinetic transmetallation

Chemoselective Suzuki-Miyaura cross-coupling generally requires a designed deactivation of one nucleophile towards transmetallation. Here we show that boronic acids can be chemoselectively reacted in the presence of ostensibly equivalently reactive boronic acid pinacol (BPin) esters by kinetic discrimination during transmetallation. Simultaneous electrophile control allows sequential chemoselective cross-couplings in a single operation in the absence of protecting groups

A chemoselective polarity-mismatched photocatalytic C(sp3)–C(sp2) cross-coupling enabled by synergistic boron activation

Funding: J.B. thanks AstraZeneca and the Engineering and Physical Sciences Research Council (EPSRC) for a PhD studentship. A.J.B.W. thanks the Leverhulme Trust for a Research Fellowship (RF-2022-014) and the EPSRC Programme Grant “Boron: Beyond the Reagent” (EP/W007517) for support.We report the development of a C(sp3)–C(sp2) coupling reaction using styrene boronic acids and redox-active esters under photoredox catalysis. The reaction proceeds through an unusual polarity-mismatched radical addition mechanism that is orthogonal to established processes. Synergistic activation of the radical precursor and organoboron are critical mechanistic events. Activation of an N-hydroxyphthalimide (NHPI) ester by coordination to boron enables electron transfer, with decomposition leading to a nucleofuge rebound, activating the organoboron to radical addition. The unique mechanism enables chemoselective coupling of styrene boronic acids in the presence of other alkene radical acceptors. The scope and limitations of the reaction, and a detailed mechanistic investigation are presented.Publisher PDFPeer reviewe

Catalytic amidation of unactivated ester derivatives mediated by trifluoroethanol

A catalytic amidation method has been developed, employing 2,2,2-trifluoroethanol to facilitate condensation of unactivated esters and amines, enabling the synthesis of a range of amide products in good to excellent yields. Mechanistic studies indicate the reaction proceeds through a trifluoroethanol-derived active ester intermediate

Synthesis of oxindoles and benozfuranones via oxidation of 2-heterocyclic BMIDAs

The synthesis of functionalized oxindoles and benzofuranones via oxidation of 2-BMIDA indoles and benzofurans, respectively, is described. Interconversion of boron species (BMIDAàBF3K) was necessary to enable oxidation and overcome boronic acid stability issues associated with a difficult BMIDA hydrolysis. Overall, a robust process was developed that allowed access to a small library of oxindole and benzofuranone products and facilitated the step-efficient synthesis of biologically-active compounds containing the oxindole pharmacophore

Accessing rare α-heterocyclic aziridines via Brønsted acid-catalyzed Michael addition/annulation : scope, limitations, and mechanism

Funding: T.A.H. thanks the University of St Andrews for a PhD studentship. A.J.B.W. thanks the Leverhulme Trust for a Research Fellowship (RF-2022-014).We report an approach to the diastereoselective synthesis of 1,2-disubstituted heterocyclic aziridines. A Brønsted acid-catalyzed conjugate addition of anilines to trisubstituted heterocyclic chloroalkenes provides an intermediate 1,2-chloroamine. Diastereocontrol was found to vary significantly with solvent selection, with computational modelling confirming selective, spontaneous fragmentation in the presence of trace acids, proceeding through a pseudo-cyclic, protonated intermediate and transition state. These chloroamines can then be converted to the aziridine by treatment with LiHMDS with high stereochemical fidelity. This solvent-induced stereochemical enrichment thereby enables an efficient route to rare cis-aziridines with high dr. The scope, limitations, and mechanistic origins of selectivity are also presentedPeer reviewe

Ligand-enabled copper-mediated radioiodination of arenes

The discovery of a copper precatalyst that facilitates the key mechanistic steps of arene halodeboronation has allowed a step change in the synthesis of radioiodine-containing arenes. The active precatalyst [Cu(OAc)(phen)2]OAc was shown to perform room temperature radio-iododeboronation of aryl boronic acids with 1–2 mol % loadings and 10 min reaction times. These mild conditions enable particularly clean reactions, as demonstrated with the efficient preparation of the radiopharmaceutical and SPECT tracer, meta-iodobenzylguanidine (MIBG).Peer reviewe

Total synthesis of (±)-aspidospermidine, (±)-aspidofractinine, (±)-limaspermidine, and (±)-vincadifformine via a cascade and common intermediate strategy

D.L.C. thanks EPSRC and GSK for a Ph.D. studentship.A concise strategy for the total synthesis of several Aspidosperma alkaloids is reported. A Suzuki–Miyaura cross-coupling provides access to a 2-vinyl indole that undergoes a Diels–Alder cascade reaction with butyn-2-one to deliver a pyrroloindoline intermediate. This undergoes cascade amidation, reduction, skeletal rearrangement, and intramolecular Michael addition to provide a common intermediate containing the full framework of the Aspidosperma alkaloids. The utility of this intermediate is shown in the synthesis of four different natural products.Publisher PDFPeer reviewe