Catalytic Access to Diastereometrically Pure Four- and Five-Membered Silyl-Heterocycles Using Transborylation.

Silyl-heterocycles offer a unique handle to expand and explore chemical space, reactivity, and functionality. The shortage of catalytic methods for the preparation of diverse and functionalized silyl-heterocycles however limits widespread exploration and exploitation. Herein the borane-catalyzed intramolecular 1,1-carboboration of silyl-alkynes has been developed for the synthesis of 2,3-dihydrosilolyl and silylcyclobut-2-enyl boronic esters. Successful, catalytic carboboration has been achieved on a variety of functionally diverse silyl-alkynes, using a borane catalyst and transborylation-enabled turnover. Mechanistic studies, including 13C-labelling, computational studies, and single-turnover experiments, suggest a reaction pathway proceeding by 1,2-hydroboration, 1,1-carboboration, and transborylation to release the alkenyl boronic ester product and regenerate the borane catalyst.

Transition Metal-Free Catalytic C-H Zincation and Alumination.

C-H metalation is the most efficient method to prepare aryl-zinc and -aluminium complexes that are ubiquitous nucleophiles. Virtually all C-H metalation routes to form Al/Zn organometallics require stoichiometric, strong Brønsted bases with no base-catalyzed reactions reported. Herein we present a catalytic in amine/ammonium salt (Et3N/[(Et3N)H]+) C-H metalation process to form aryl-zinc and aryl-aluminium complexes. Key to this approach is coupling an endergonic C-H metalation step with a sufficiently exergonic dehydrocoupling step between the ammonium salt by-product of C-H metalation ([(Et3N)H]+) and a Zn-H or Al-Me containing complex. This step, forming H2/MeH, makes the overall cycle exergonic while generating more of the reactive metal electrophile. Mechanistic studies supported by DFT calculations revealed metal-specific dehydrocoupling pathways, with the divergent reactivity due to the different metal valency (which impacts the accessibility of amine-free cationic metal complexes) and steric environment. Notably, dehydrocoupling in the zinc system proceeds through a ligand-mediated pathway involving protonation of the ß-diketiminate Cγ position. Given this process is applicable to two disparate metals (Zn and Al), other main group metals and ligand sets are expected to be amenable to this transition metal-free, catalytic C-H metalation.

Piers-Rubinsztajn reaction to unlock an 8-step synthesis of 7-hydroxy cannabidiol.

A scalable synthesis of 7-hydroxy cannabidiol (7-OH CBD), a primary metabolite of (-)-cannabidiol (CBD), is highly desirable, from an industrial point of view, to enable future clinical trials. A Piers-Rubinsztajn reaction was key to enable a mild deprotection and a concise synthesis of 7-OH CBD from commercially available CBD, in 31% overall yield.

Group 13 exchange and transborylation in catalysis.

Catalysis is dominated by the use of rare and potentially toxic transition metals. The main group offers a potentially sustainable alternative for catalysis, due to the generally higher abundance and lower toxicity of these elements. Group 13 elements have a rich catalogue of stoichiometric addition reactions to unsaturated bonds but cannot undergo the redox chemistry which underpins transition-metal catalysis. Group 13 exchange reactions transfer one or more groups from one group 13 element to another, through σ-bond metathesis; where boron is both of the group 13 elements, this is termed transborylation. These redox-neutral processes are increasingly being used to render traditionally stoichiometric group 13-mediated processes catalytic and develop new catalytic processes, examples of which are the focus of this review.

B-N/B-H Transborylation: borane-catalysed nitrile hydroboration.

The reduction of nitriles to primary amines is a useful transformation in organic synthesis, however, it often relies upon stoichiometric reagents or transition-metal catalysis. Herein, a borane-catalysed hydroboration of nitriles to give primary amines is reported. Good yields (48-95%) and chemoselectivity (e.g., ester, nitro, sulfone) were observed. DFT calculations and mechanistic studies support the proposal of a double B-N/B-H transborylation mechanism.

Iron-catalysed alkene and heteroarene H/D exchange by reversible protonation of iron-hydride intermediates.

C-H functionalisation reactions offer a sustainable method for molecular construction and diversification. These reactions however remain dominated by precious metal catalysis. While significant interest in iron-catalysed C-H activation reactions has emerged, the isolation, characterisation and mechanistic understanding of these processes remain lacking. Herein the iron-catalysed C(sp2)-H bond hydrogen/deuterium exchange reaction using CD3OD is reported for both heterocycles and, for the first time, alkenes (38 examples). Isolation and characterisation, including by single-crystal X-ray diffraction, of the key iron-aryl and iron-alkenyl C-H metallation intermediates provided evidence for a reversible protonation of the active iron hydride catalyst. Good chemoselectivity was observed for both substrate classes. The developed procedure is orthogonal to previous iron-catalysed H/D exchange methods which used C6D6, D2, or D2O as the deuterium source, and uses only bench-stable reagents, including the iron(ii) pre-catalyst. Further, a new mechanism of iron-hydride formation is reported in which ß-hydride elimination from an alcohol generates the iron hydride. The ability to produce, isolate and characterise the organometallic products arising from C-H activation presents a basis for future discovery and development.

Boron-Catalyzed, Diastereo- and Enantioselective Allylation of Ketones with Allenes.

The diastereo- and enantioselective allylation of ketones remains a synthetic challenge, with transition metal catalysis offering the most applied methods. Here, a boron-catalyzed allylation of ketones with allenes is presented. Excellent yield, regioselectivity, and diastereoselectivity were found across functionalized substrates. The reaction was further developed to accommodate an enantioenriched boron catalyst and thus gave asymmetric ketone allylation in good yield, diastereoselectivity, and enantioselectivity. Mechanistic studies supported a hydroboration-allylation-transborylation pathway.

Diastereoselective, Catalytic Access to Cross-Aldol Products Directly from Esters and Lactones.

High oxidation-state carbonyl coupling partners including esters and lactones were reacted with enones to give aldol-type products directly using two-fold organoborane catalysis. This new retrosynthetic disconnection to aldol-type products is compatible with enolisable coupling partners, without self-condensation, and couples the high reactivity of secondary dialkylboranes with the stability of pinacolboronic esters. Excellent chemoselectivity, substrate scope (including those containing reducible functionalities and free alcohols) and diastereocontrol were achieved to access both the syn- and anti-aldol-type products. Mechanistic studies confirmed the two-fold catalytic role of the single secondary borane catalyst for boron enolate formation and formation of an aldehyde surrogate from the ester or lactone coupling partner.

A boron-nitrogen transborylation enabled, borane-catalysed reductive cyanation of enones.

Cyanation offers a simple method for the introduction of a nitrile group into organic molecules and an orthogonal route for the installation of a wide array of functional groups using simple transformations. Cyanation methods are dominated by transition metal catalysis and the use of hydrogen cyanide gas. Here, the electrophilic cyanation of enones was achieved using a main-group catalyst and a non-toxic, electrophilic cyanide source. This protocol was applied across a broad substrate scope including those containing reducible functional groups. Mechanistic studies indicated an amino-borane intermediate which underwent B-N transborylation (B-N/B-H exchange) to achieve catalytic turnover.

Aluminium-Catalyzed C(sp)-H Borylation of Alkynes.

Historically used in stoichiometric hydroalumination chemistry, recent advances have transformed aluminium hydrides into versatile catalysts for the hydroboration of unsaturated multiple bonds. This catalytic ability is founded on the defining reactivity of aluminium hydrides with alkynes and alkenes: 1,2-hydroalumination of the unsaturated π-system. This manuscript reports the aluminium hydride catalyzed dehydroborylation of terminal alkynes. A tethered intramolecular amine ligand controls reactivity at the aluminium hydride centre, switching off hydroalumination and instead enabling selective reactions at the alkyne C-H σ-bond. Chemoselective C-H borylation was observed across a series of aryl- and alkyl-substituted alkynes (21 examples). On the basis of kinetic and density functional theory studies, a mechanism in which C-H borylation proceeds by σ-bond metathesis between pinacolborane (HBpin) and alkynyl aluminium intermediates is proposed.

Borane-Catalyzed, Chemoselective Reduction and Hydrofunctionalization of Enones Enabled by B-O Transborylation.

The use of stoichiometric organoborane reductants in organic synthesis is well established. Here these reagents have been rendered catalytic through an isodesmic B-O/B-H transborylation applied in the borane-catalyzed, chemoselective alkene reduction and formal hydrofunctionalization of enones. The reaction was found to proceed by a 1,4-hydroboration of the enone and B-O/B-H transborylation with HBpin, enabling catalyst turnover. Single-turnover and isotopic labeling experiments supported the proposed mechanism of catalysis with 1,4-hydroboration and B-O/B-H transborylation as key steps.

TMEDA in Iron-Catalyzed Hydromagnesiation: Formation of Iron(II)-Alkyl Species for Controlled Reduction to Alkene-Stabilized Iron(0).

N,N,N',N'-Tetramethylethylenediamine (TMEDA) has been one of the most prevalent and successful additives used in iron catalysis, finding application in reactions as diverse as cross-coupling, C-H activation, and borylation. However, the role that TMEDA plays in these reactions remains largely undefined. Herein, studying the iron-catalyzed hydromagnesiation of styrene derivatives using TMEDA has provided molecular-level insight into the role of TMEDA in achieving effective catalysis. The key is the initial formation of TMEDA-iron(II)-alkyl species which undergo a controlled reduction to selectively form catalytically active styrene-stabilized iron(0)-alkyl complexes. While TMEDA is not bound to the catalytically active species, these active iron(0) complexes cannot be accessed in the absence of TMEDA. This mode of action, allowing for controlled reduction and access to iron(0) species, represents a new paradigm for the role of this important reaction additive in iron catalysis.

Hidden Boron Catalysis: Nucleophile-Promoted Decomposition of HBpin.

Simple nucleophiles with structural similarities to known hydroboration catalysts can readily mediate the formation of BH3 and borohydride species from pinacolborane (HBpin). Alkyne and alkene hydroboration reactions were successfully mediated by nucleophiles through BH3 generation, with BH3-catalyzed hydroboration found to dominate catalysis. NMR spectroscopy and kinetic analyses showed that the nucleophiles NaOtBu, Na[N(SiMe3)2], nBu2Mg, and nBuLi only promoted the formation of BH3 and were not "true" hydroboration catalysts.

Characterization of the Zwitterionic Intermediate in 1,1-Carboboration of Alkynes.

The reaction of a Lewis acidic borane with an alkyne is a key step in a diverse range of main group transformations. Alkyne 1,1-carboboration, the Wrackmeyer reaction, is an archetypal transformation of this kind. 1,1-Carboboration has been proposed to proceed through a zwitterionic intermediate. We report the isolation and spectroscopic, structural and computational characterization of the zwitterionic intermediates generated by reaction of B(C6 F5 )3 with alkynes. The stepwise reactivity of the zwitterion provides new mechanistic insight for 1,1-carboboration and wider B(C6 F5 )3 catalysis. Making use of intramolecular stabilization by a ferrocene substituent, we have characterized the zwitterionic intermediate in the solid state and diverted reactivity towards alkyne cyclotrimerization.

Iron-Catalysed C(sp2)-H Borylation Enabled by Carboxylate Activation.

Arene C(sp2)-H bond borylation reactions provide rapid and efficient routes to synthetically versatile boronic esters. While iridium catalysts are well established for this reaction, the discovery and development of methods using Earth-abundant alternatives is limited to just a few examples. Applying an in situ catalyst activation method using air-stable and easily handed reagents, the iron-catalysed C(sp2)-H borylation reactions of furans and thiophenes under blue light irradiation have been developed. Key reaction intermediates have been prepared and characterised, and suggest two mechanistic pathways are in action involving both C-H metallation and the formation of an iron boryl species.

Synthesis and structures of anionic rhenium polyhydride complexes of boron-hydride ligands and their application in catalysis.

The rhenium complex, [K(DME)(18-c-6)][ReH4(Bpin)(η2-HBpin)(κ2-H2Bpin)] 1, comprising hydride and boron ligands only, has been synthesized by exhaustive deoxygenation of the commercially available perrhenate anion (ReO4 -) with pinacol borane (HBpin). The structure of 1 was analysed by X-ray crystallography, NMR spectroscopy, and DFT calculations. While no hydrides were located in the X-ray crystal structure, it revealed a trigonal arrangement of pinacol boron ligands. Variable-temperature NMR spectroscopy supported the presence of seven hydride ligands but further insight was hindered by the fluxionality of both hydride and boron ligands at low temperature. Further evaluation of the structure by Ab Initio Random Structure Searching (AIRSS) identified the presence of hydride, boryl, σ-borane, and dihydroborate ligands. This complex, either isolated or prepared in situ, is a catalyst for the 1,4-hydroboration of N-heteroaromatic substrates under simple operating procedures. It also acts as a reagent for the stoichiometric C-H borylation of toluene, displaying high meta regioselectivity in the borylated products. Reaction of 1 with 9-BBN resulted in HBpin substitution to form the new anionic tetra(dihydroborate) complex [K(DME)(18-c-6)][Re(κ2-H-9-BBN)4] 4 for which the hydride positions were clearly identified by X-ray crystallography. The method used to generate these isolable yet reactive boron-hydride complexes is direct and straightforward and has potential utility for the exploitation of other metal oxo compounds in operationally simple catalytic reactions.

Kinetics and Mechanism of the Arase-Hoshi R2BH-Catalyzed Alkyne Hydroboration: Alkenylboronate Generation via B-H/C-B Metathesis.

The mechanism of R2BH-catalyzed hydroboration of alkynes by 1,3,2-dioxaborolanes has been investigated by in situ 19F NMR spectroscopy, kinetic simulation, isotope entrainment, single-turnover labeling (10B/2H), and density functional theory (DFT) calculations. For the Cy2BH-catalyzed hydroboration 4-fluorophenylacetylene by pinacolborane, the resting state is the anti-Markovnikov addition product ArCH = CHBCy2. Irreversible and turnover-rate limiting reaction with pinacolborane (k ≈ 7 × 10-3 M-1 s-1) regenerates Cy2BH and releases E-Ar-CH═CHBpin. Two irreversible events proceed in concert with turnover. The first is a Markovnikov hydroboration leading to regioisomeric Ar-C(Bpin)═CH2. This is unreactive to pinacolborane at ambient temperature, resulting in catalyst inhibition every ∼102 turnovers. The second is hydroboration of the alkenylboronate to give ArCH2CH(BCy2)Bpin, again leading to catalyst inhibition. 9-BBN behaves analogously to Cy2BH, but with higher anti-Markovnikov selectivity, a lower barrier to secondary hydroboration, and overall lower efficiency. The key process for turnover is B-H/C-B metathesis, proceeding by stereospecific transfer of the E-alkenyl group within a transient, µ-B-H-B bridged, 2-electron-3-center bonded B-C-B intermediate.

Recent Advances in the Deoxydehydration of Vicinal Diols and Polyols.

Deoxydehydration (DODH) is one of the most promising tools to reduce the oxygen content of biomass (sugars and polyols) and provide analogues of platform chemicals that are derived from fossil resources. This reaction converts a vicinal diol into an alkene and is typically catalyzed by high-oxidation-state metal-oxo compounds in the presence of a stoichiometric reductant, with examples of both homogeneous and heterogeneous systems. This minireview will highlight the developments in this field over the past 5 years and focus on efforts to solve the problems that currently prevent DODH being performed on a commercial scale, including the nature of the reductant, substrate scope and selectivity, and catalyst recovery and expense.

Regiodivergent hydrosilylation, hydrogenation, [2π + 2π]-cycloaddition and C-H borylation using counterion activated earth-abundant metal catalysis.

The widespread adoption of earth-abundant metal catalysis lags behind that of the second- and third-row transition metals due to the often challenging practical requirements needed to generate the active low oxidation-state catalysts. Here we report the development of a single endogenous activation protocol across five reaction classes using both iron- and cobalt pre-catalysts. This simple catalytic manifold uses commercially available, bench-stable iron- or cobalt tetrafluoroborate salts to perform regiodivergent alkene and alkyne hydrosilylation, 1,3-diene hydrosilylation, hydrogenation, [2π + 2π]-cycloaddition and C-H borylation. The activation protocol proceeds by fluoride dissociation from the counterion, in situ formation of a hydridic activator and generation of a low oxidation-state catalyst.

Mechanism of the Bis(imino)pyridine-Iron-Catalyzed Hydromagnesiation of Styrene Derivatives.

Iron-catalyzed hydromagnesiation of styrene derivatives offers a rapid and efficient method to generate benzylic Grignard reagents, which can be applied in a range of transformations to provide products of formal hydrofunctionalization. While iron-catalyzed methodologies exist for the hydromagnesiation of terminal alkenes, internal alkynes, and styrene derivatives, the underlying mechanisms of catalysis remain largely undefined. To address this issue and determine the divergent reactivity from established cross-coupling and hydrofunctionalization reactions, a detailed study of the bis(imino)pyridine iron-catalyzed hydromagnesiation of styrene derivatives is reported. Using a combination of kinetic analysis, deuterium labeling, and reactivity studies as well as in situ 57Fe Mössbauer spectroscopy, key mechanistic features and species were established. A formally iron(0) ate complex [ iPrBIPFe(Et)(CH2═CH2)]- was identified as the principle resting state of the catalyst. Dissociation of ethene forms the catalytically active species which can reversibly coordinate the styrene derivative and mediate a direct and reversible ß-hydride transfer, negating the necessity of a discrete iron hydride intermediate. Finally, displacement of the tridentate bis(imino)pyridine ligand over the course of the reaction results in the formation of a tris-styrene-coordinated iron(0) complex, which is also a competent catalyst for hydromagnesiation.