Methylenespiro[2.3]hexanes via Nickel-Catalyzed Cyclopropanations with [1.1.1]Propellane.

[1.1.1]Propellane is a highly strained tricyclic hydrocarbon whose reactivity is dominated by addition reactions across the central inverted bond to provide bicyclo[1.1.1]pentane derivatives. These reactions proceed under both radical and two-electron pathways, hence, providing access to a diverse array of products. Conversely, transition metal-catalyzed reactions of [1.1.1]propellane are underdeveloped and lack synthetic utility, with reported examples generally yielding mixtures of ring-opened structural isomers, dimers, and trimers, often with poor selectivity. Herein, we report that nickel(0) catalysis enables the use of [1.1.1]propellane as a carbene precursor in cyclopropanations of a range of functionalized alkenes to give methylenespiro[2.3]hexane products. Computational studies provide support for initial formation of a Ni(0)-[1.1.1]propellane complex followed by concerted double C-C bond activation to give the key 3-methylenecyclobutylidene-nickel intermediate.

Isoindolinones via Copper-Catalyzed Intramolecular Benzylic C-H Sulfamidation.

2-Benzyl-N-tosylbenzamides and related substrates undergo copper-catalyzed intramolecular sulfamidation at the benzylic methylene to give N-arylsuflonyl-1-arylisoindolinones, which can be N-deprotected using samarium iodide to generate the free 1-arylisoindolinones. Preliminary mechanistic studies indicate that the rate-determining step is not C-H bond cleavage but are instead consistent with slow oxidation of a copper π-arene intermediate.

Cobalt-Catalyzed Suzuki Biaryl Coupling of Aryl Halides.

Readily accessed cobalt pre-catalysts with N-heterocyclic carbene ligands catalyze the Suzuki cross-coupling of aryl chlorides and bromides with alkyllithium-activated arylboronic pinacolate esters. Preliminary mechanistic studies indicate that the cobalt species is reduced to Co0 during the reaction.

How low does iron go? Chasing the active species in fe-catalyzed cross-coupling reactions.

The catalytic cross-coupling reactions of organic halides or related substrates with organometallic nucleophiles form the cornerstone of many carbon-carbon bond-forming processes. While palladium-based catalysts typically mediate such reactions, there are increasing concerns about the long-term sustainability of palladium in synthesis. This is due to the high cost of palladium, coupled with its low natural abundance, environmentally deleterious extraction (∼6 g of metal are produced per ton of ore), toxicity, and competition for its use from the automotive and consumer electronics sectors. Therefore, there is a growing interest in replacing palladium-based catalysts with those incorporating more earth-abundant elements. With its low cost, high natural abundance, and low toxicity, iron makes a particularly appealing alternative, and accordingly, the development of iron-catalyzed cross-coupling is undergoing explosive growth. However, our understanding of the mechanisms that underpin the iron-based catalytic cycles is still very much in its infancy. Mechanistic insight into catalytic reactions is not only academically important but also allows us to maximize the efficiency of processes or even to develop entirely new transformations. Key to the development of robust mechanistic models for cross-coupling is knowing the lowest oxidation state in the cycle. Once this is established, we can explore subsequent redox processes and build the catalytic manifold. Until we know with confidence what the lowest oxidation state is, any cycles proposed are largely just guesswork. To date, Fe(-II), Fe(-I), Fe(0), Fe(I), and Fe(II) have been proposed as contenders for the lowest-oxidation-state species in the cycle in iron-catalyzed cross-coupling; the aim of this Account is to pull together the various pieces of evidence in support, or otherwise, of each of these suggestions in turn. There currently exists no direct evidence that oxidation states below Fe(0) are active in the catalytic cycle. Meanwhile, the reactivity required of the lowest-oxidation-state species has been observed with model compounds in higher oxidation states, implying that there is no need to invoke such low oxidation states. While subzero-valent complexes do indeed act as effective precatalysts, it is important to recognize that this tells us that they are efficiently converted to an active catalyst but says nothing about the oxidation states of the species in the catalytic cycle. Zero-valent heterogeneous iron nanoparticles can be formed under typical catalytic conditions, but there is no evidence to suggest that homogeneous Fe(0) complexes can be produced under comparable conditions. It seems likely that the zero-valent nanoparticles act as a reservoir for soluble higher-oxidation-state species. Fe(II) complexes can certainly be formed under catalytically relevant conditions, and when bulky nucleophilic coupling partners are exploited, potential intermediates can be isolated. However, the bulky reagents act as poor proxies for most nucleophiles used in cross-coupling, as they give Fe(II) organometallic intermediates that are kinetically stabilized with respect to reductive elimination. When more realistic substrates are exploited, reduction or disproportionation to Fe(I) is widely observed, and while it still has not been conclusively proved, this oxidation state currently represents a likely candidate for the lowest one active in many iron-catalyzed cross-coupling processes.

Palladium-Catalyzed Ortho-Arylation of Carbamate-Protected Estrogens.

The palladium-catalyzed ortho-arylation of diethyl carbamate-protected estrone and estriol with aryl iodides gives the 2-arylated analogues. Subsequent removal of the carbamate directing group furnishes 2-arylated estrone, estradiol, or estriol depending on the method used.

Catalyst-Switchable Regiocontrol in the Direct Arylation of Remote C-H Groups in Pyrazolo[1,5-a]pyrimidines.

The regiodivergent palladium-catalyzed C-H arylation of pyrazolo[1,5-a]pyrimidine has been achieved, wherein the switch in regioselectivity between positions C3 and C7 is under complete catalyst control. A phosphine-containing palladium catalyst promotes the direct arylation at the most acidic position (C7), whereas a phosphine-free catalyst targets the most electron-rich position (C3).

Facile hydrolysis and alcoholysis of palladium acetate.

Palladium(II) acetate is readily converted into [Pd3 (µ(2) -OH)(OAc)5 ] (1) in the presence of water in a range of organic solvents and is also slowly converted in the solid state. Complex 1 can also be formed in nominally anhydrous solvents. Similarly, the analogous alkoxide complexes [Pd3 (µ(2) -OR)(OAc)5 ] (3) are easily formed in solutions of palladium(II) acetate containing a range of alcohols. An examination of a representative Wacker-type oxidation shows that the Pd-OH complex 1 and a related Pd-oxo complex 4 can be excluded as potential catalytic intermediates in the absence of exogenous water.

Expedient iron-catalyzed coupling of alkyl, benzyl and allyl halides with arylboronic esters.

While attractive, the iron-catalyzed coupling of arylboron reagents with alkyl halides typically requires expensive or synthetically challenging diphosphine ligands. Herein, we show that primary and secondary alkyl bromides and chlorides, as well as benzyl and allyl halides, can be coupled with arylboronic esters, activated with alkyllithium reagents, by using very simple iron-based catalysts. The catalysts used were either adducts of inexpensive and widely available diphosphines or, in a large number of cases, simply [Fe(acac)3] with no added co-ligands. In the former case, preliminary mechanistic studies highlight the likely involvement of iron(I)-phosphine intermediates.

TMEDA in iron-catalyzed Kumada coupling: amine adduct versus homoleptic "ate" complex formation.

The reactions of iron chlorides with mesityl Grignard reagents and tetramethylethylenediamine (TMEDA) under catalytically relevant conditions tend to yield the homoleptic "ate" complex [Fe(mes)3 ](-) (mes=mesityl) rather than adducts of the diamine, and it is this ate complex that accounts for the catalytic activity. Both [Fe(mes)3 ](-) and the related complex [Fe(Bn)3 ](-) (Bn=benzyl) react faster with representative electrophiles than the equivalent neutral [FeR2 (TMEDA)] complexes. Fe(I) species are observed under catalytically relevant conditions with both benzyl and smaller aryl Grignard reagents. The X-ray structures of [Fe(Bn)3 ](-) and [Fe(Bn)4 ](-) were determined; [Fe(Bn)4 ](-) is the first homoleptic σ-hydrocarbyl Fe(III) complex that has been structurally characterized.

Iron(I) in Negishi cross-coupling reactions.

Herein we demonstrate both the importance of Fe(I) in Negishi cross-coupling reactions with arylzinc reagents and the isolation of catalytically competent Fe(I) intermediates. These complexes, [FeX(dpbz)(2)] [X = 4-tolyl (7), Cl (8a), Br (8b); dpbz = 1,2-bis(diphenylphosphino)benzene], were characterized by crystallography and tested for activity in representative reactions. The complexes are low-spin with no significant spin density on the ligands. While complex 8b shows performance consistent with an on-cycle intermediate, it seems that 7 is an off-cycle species.

Community-based prehabilitation before elective major surgery: the PREP-WELL quality improvement project.

Optimising health and well-being before elective major surgery via prehabilitation initiatives is important for good postoperative outcomes. In a busy tertiary centre in North East England, the lack of a formal prehabilitation service meant that opportunities were being missed to optimise patients for surgery. This quality improvement project aimed to implement and evaluate a community-based prehabilitation service for people awaiting elective major surgery: PREP-WELL. A multidisciplinary, cross-sector team introduced PREP-WELL in January 2018. PREP-WELL provided comprehensive assessment and management of perioperative risk factors in the weeks before surgery. During a 12-month pilot, patients were referred from five surgical specialties at James Cook University Hospital. Data were collected on participant characteristics, behavioural and health outcomes, intervention acceptability and costs, and process-related factors. By December 2018, 159 referrals had been received, with 75 patients (47%) agreeing to participate. Most participants opted for a supervised programme (72%) and were awaiting vascular (43%) or orthopaedic (35%) surgery. Median programme duration was 8 weeks. The service was delivered as intended with participants providing positive feedback. Health-related quality of life (HRQoL; EuroQol 5D (EQ-5D) utility) and functional capacity (6 min walk distance) increased on average from service entry to exit, with mean (95% CI) changes of 0.108 (-0.023 to 0.240) and 35 m (-5 to 76 m), respectively. Further increases in EQ5D utility were observed at 3 months post surgery. Substantially more participants were achieving recommended physical activity levels at exit and 3 months post surgery compared with at entry. The mean cost of the intervention was £405 per patient; £52 per week. The service was successfully implemented within existing preoperative pathways. Most participants were very satisfied and improved their risk profile preoperatively. Funding has been obtained to support service development and expansion for at least 2 more years. During this period, alternative pathways will be developed to facilitate wider access and greater uptake.

Iron-catalysed Negishi coupling of benzyl halides and phosphates.

Iron-based catalysts containing either 1,2-bis(diphenylphosphino)benzene or 1,3-bis(diphenylphosphino)propane give excellent activity and good selectivity in the Negishi coupling of aryl zinc reagents with a range of benzyl halides and phosphates.

Palladium-catalysed ortho-arylation of carbamate-protected phenols.

The carbamate (-O2CNR2) function is an excellent directing group for palladium-catalysed direct arylation reactions giving both protected or free mono- or di-substituted phenols, as well as an example of a dibenzopyranone, depending on coupling partners (aryl iodides or diaryliodonium salts) and conditions.

The surprisingly facile formation of Pd(i)-phosphido complexes from ortho-biphenylphosphines and palladium acetate.

The widely-used ortho-biphenylphosphine ligands SPhos and RuPhos not only undergo facile orthometallation with palladium acetate, yielding strained, four-membered dimeric palladacycles but more surprisingly, in the presence of alcoholic solvents, along with the less encumbered analogue MePhos, yield unusual dinuclear Pd(i) complexes, in which the Pd-centers are bridged by both a phosphide ligand and by the arene of a coordinated phosphine donor.

Anion complexation via C-H...X interactions using a palladacyclic receptor.

A novel organometallic receptor binds anions in solution and in the solid state, with complexes stabilised through a series of C-HX interactions, as evidenced by 1H NMR spectroscopy, X-ray crystallography and computational models.

Simple rhodium-chlorophosphine pre-catalysts for the ortho-arylation of phenols.

Simple chlorodiisopropylphosphine adducts of rhodium, either pre-formed or formed in situ, prove to be highly effective catalysts for the ortho-arylation of phenols.

Iron nanoparticles in the coupling of alkyl halides with aryl Grignard reagents.

Iron nanoparticles, either formed in situ stabilized by 1,6-bis(diphenylphosphino)hexane or polyethylene glycol (PEG), or preformed stabilized by PEG, are excellent catalysts for the cross-coupling of aryl Grignard reagents with primary and secondary alkyl halides bearing beta-hydrogens and they also prove effective in a tandem cyclization/cross-coupling reaction.

Chiral palladium bis(phosphite)PCP-pincer complexes via ligand C-H activation.

The synthesis of a range of chiral palladium bis(phosphite) pincer complexes has been achieved via C-H activation of the parent ligands and one of the complexes formed shows good activity in the catalytic allylation of aldehydes.