Beta-elimination Research Articles

General alkyl fluoride functionalization via short-lived carbocation-organozincate ion pairs

Fluorinated organic compounds are frequently used across the chemical and life sciences. Although a large, structurally diverse pool of alkyl fluorides is nowadays available, synthetic applications trail behind the widely accepted utility of other halides. We envisioned that C(sp2)-C(sp3) cross-coupling reactions of alkyl fluorides with fluorophilic organozinc compounds should be possible through a heterolytic mechanism that involves short-lived ion pairs and uses the stability of the Zn-F bond as the thermodynamic driving force. This would be mechanistically different from previously reported radical reactions and overcome long-standing limitations of organometallic cross-coupling methodology, including competing β-hydride elimination, homodimerization and hydrodefluorination. Here, we show a practical Csp3-F bond functionalization method that expands the currently restricted synthetic space of unactivated primary, secondary and tertiary C(sp3)-F bonds but also uses benzylic, propargylic and acyl fluorides. Many functional groups and sterically demanding substrates are tolerated, which allows practical carbon-carbon bond formation and late-stage functionalization.

Comprehensive Mechanistic Analysis of Palladium- and Nickel-Catalyzed α,β-Dehydrogenation of Carbonyls via Organozinc Intermediates.

Introducing degrees of unsaturation into small molecules is a central transformation in organic synthesis. A strategically useful category of this reaction type is the conversion of alkanes into alkenes for substrates with an adjacent electron-withdrawing group. An efficient strategy for this conversion has been deprotonation to form a stabilized organozinc intermediate that can be subjected to α,β-dehydrogenation through palladium or nickel catalysis. This general reactivity blueprint presents a window to uncover and understand the reactivity of Pd- and Ni-enolates. Within this context, it was determined that β-hydride elimination is slow and proceeds via concerted syn-elimination. One interesting finding is that β-hydride elimination can be preferred to a greater extent than C-C bond formation for Ni, more so than with Pd, which defies the generally assumed trends that β-hydride elimination is more facile with Pd than Ni. The discussion of these findings is informed by KIE experiments, DFT calculations, stoichiometric reactions, and rate studies. Additionally, this report details an in-depth analysis of a methodological manifold for practical dehydrogenation and should enable its application to challenges in organic synthesis.

Kinetically-Controlled Ni-Catalyzed Direct Carboxylation of Unactivated Secondary Alkyl Bromides without Chain Walking.

Herein, we report the direct carboxylation of unactivated secondary alkyl bromides enabled by the merger of photoredox and nickel catalysis, a previously inaccessible endeavor in the carboxylation arena. Site-selectivity is dictated by a kinetically controlled insertion of CO2 at the initial C(sp3)-Br site by the rapid formation of Ni(I)-alkyl species, thus avoiding undesired β-hydride elimination and chain-walking processes. Preliminary mechanistic experiments reveal the subtleties of stereoelectronic effects for guiding the reactivity and site-selectivity.

Role of a cyclopentadienyl ligand in a heteroleptic alkoxide precursor in atomic layer deposition.

Alkoxide precursors have been highlighted for depositing carbon-free films, but their use in Atomic Layer Deposition (ALD) often exhibits a non-saturated growth. This indicates no self-limiting growth due to the chain reaction of hydrolysis or ligand decomposition caused by β-hydride elimination. In the previous study, we demonstrated that self-limiting growth of ALD can be achieved using our newly developed precursor, hafnium cyclopentadienyl tris(N-ethoxy-2,2-dimethyl propanamido) [HfCp(edpa)3]. To elucidate the growth mechanism and the role of cyclopentadienyl (Cp) ligand in a heteroleptic alkoxide precursor, herein, we compare homoleptic and heteroleptic Hf precursors consisting of N-ethoxy-2,2-dimethyl propanamido (edpa) ligands with and without cyclopentadienyl ligand-hafnium tetrakis(N-ethoxy-2,2-dimethyl propanamido) [Hf(edpa)4] and HfCp(edpa)3. We also investigate the role of a Cp ligand in growth characteristics. By substituting an alkoxide ligand with a Cp ligand, we could modify the surface reaction during ALD, preventing undesired reactions. The last remaining edpa after Hf(edpa)4 adsorption can undergo a hydride elimination reaction, resulting in surface O-H generation. In contrast, Cp remains after the HfCp(edpa)3 adsorption. Accordingly, we observe proper ALD growth with self-limiting properties. Thus, a comparative study of different ligands of the precursors can provide critical clues to the design of alkoxide precursors for obtaining typical ALD growth with a saturation behavior.

Vinyl-addition copolymerization of norbornene and 1-octene catalyzed by a non-bridged half-titanocene with a tetrazole-phenoxy ligand

A catalyst system comprising Cp*TiCl2(OPhTz) (Cp* = C5Me5, OPhTz = tetrazole-mono-ortho-substituted phenoxy anion), iBu3Al, and [Ph3C][B(C6F5)4] is employed in the vinyl-addition copolymerization of norbornene (NB) and 1-octene (OT) to understand the catalytic effects of the N-donor tetrazole substituent. Copolymerization is accompanied by significant β-hydride elimination, producing poly(norbornene-co-1-octene) (P(NB-co-OT)) with low yield and molecular weight. Although the incorporation of OT into the copolymer is less than expected, competitive incorporation of the two monomers is observed. Increasing the mole fraction of OT in the feed reduces both the yield and molecular weight of the copolymer. Spectroscopic analysis reveals that the catalyst system yields P(NB-co-OT)s that are terminated prior to complete monomer conversion, along with non-isolated cooligomers and OT-derived isomers. The cationic titanium(IV) center stabilized by the N-donor tetrazole substituent facilitates the highly regioselective 2,1-insertion of OT. This slows subsequent monomer insertion, thereby promoting β-hydride elimination.

Terahertz technology: A new frontier in Alzheimer’s disease therapy

<p>The vibrational and rotational energy levels of many biomacromolecules fall within the Terahertz (THz) frequency range, indicating that THz waves, under specific conditions, can interact with and affect the structure and functionality of various biological systems, including the brain. Increasing evidence suggests that the overproduction or inadequate elimination of amyloid beta (Aβ), leading to the accumulation of senile plaques (SPs) in the brain, is a key factor in the development of Alzheimer's disease (AD). The AD-affected brain exhibits several pathological hallmarks, such as hyperphosphorylation of tau protein, which leads to the formation of neurofibrillary tangles (NFTs), neuroinflammation, and degeneration of neurites and synapses. All of these may play important roles in the onset and progression of the disease. Current research primarily focuses on utilizing THz technology for biomonitoring and imaging, with less exploration into the biological effects of THz irradiation on AD. This review aims to examine the neurobiological effects of THz irradiation on AD pathology, including its impacts on neurons, mitochondria, blood vessels, and inflammation, and to provide an update on the current status of THz technology research in AD. It is designed to provide a new perspective for researchers in neuroscience, THz technology, and biomedicine.</p>

A mass spectrometrical surface chemistry study of aluminum nitride ALD from tris-dimethylamido aluminum and ammonia

We explored the surface chemistry in ALD of AlN from tris-dimethylamido aluminum (Al(NMe2)3) and ammonia using mass spectrometry. We suggest surface mechanisms involving β-hydride elimination and ligand decomposition, as well as ligand exchange.

CCC-NHC Au(iii) pincer complexes as a reliable platform for isolating elusive species.

The reactivity of unprecedented CCC-NHC Au(iii) pincer complexes has been investigated, employing a novel methodology for their preparation. Notably, this marks the inaugural case of CCC-NHC Au(iii) pincer complexes with a central aryl moiety where the two arms of the pincer ligand consist of N-heterocyclic carbenes (NHC). The stability conferred by the CCC-NHC ligand facilitated the isolation of elusive Au(iii) species, encompassing Au(iii)-formate, Au(iii)-F, Au(iii)-Me, and Au(iii)-alkynyl. Our study also unveiled the elusive Au(iii)-H species, offering valuable insights into its formation, stability, and reactivity. While the CCC-NHC Au(iii)-H complex remains stable at room temperature, its decomposition becomes conspicuous at elevated temperatures (>60 °C), exhibiting a more pronounced tendency under acidic conditions compared to basic ones. Through comprehensive experiments, we indirectly demonstrated the potential of Au(iii)-formate to undergo β-hydride elimination, becoming a key step in the dehydrogenation of formic acid. Theoretical calculations revealed variations in the reactivity of Au(iii)-H species towards sodium hydride and formic acid, highlighting a link between σ-donation from the pincer ligand and reaction energetics. Pincers with lower electron donation favored the reaction with sodium hydride but impeded the reaction with formic acid, whereas those with higher electron donation exhibited the opposite behavior. Additionally, the CCC-NHC Au(iii) pincer complex exhibited Lewis acid behavior, catalyzing the synthesis of phenols. In summary, the CCC-NHC Au(iii) pincer complex emerges as a versatile platform for isolating reactive species and unraveling elementary catalytic steps.

Ruthenium-catalyzed Heck coupling of 3-arylidene-oxindoles with alkenes: a facile synthesis of 3-allylidene-2(3H)-oxindoles.

A simple and efficient Ru(II)-catalyzed olefination of 3-(arylbenzylidene)indolin-2-ones with alkenes is described. This is an atom and step-economical strategy with a wide substrate scope, good functional group tolerance, and suitability for gram scale synthesis. A plausible mechanism is also proposed for this synthetic transformation involving the formation of a 5-membered ruthenacycle and insertion of the alkene followed by β-hydride elimination to deliver the desired product.

Pd(II)/LA-catalyzed acetanilide olefination with dioxygen.

Transition-metal-catalyzed aromatic olefination through direct C-H activation represents an atom and step-economic route for versatile pharmaceutical syntheses, and in many cases, different stoichiometric oxidants are frequently employed for achieving a reasonable catalytic efficiency of the transition metal ions. Herein, we report a Lewis acid promoted Pd(II)-catalyzed acetanilide olefination reaction with atmospheric dioxygen as the oxidant source. The linkage of the Lewis acid to the Pd(II) species through a diacetate bridge significantly improved its catalytic efficiency, and independent kinetic studies on the olefination step revealed that adding the Lewis acid significantly accelerated the olefination rate as well as the C-H activation step. A strong basicity of the internal base in the Pd(II) salt also benefited the olefination reaction plausibly through base-assisted β-hydride elimination.

A General Copper Catalytic System for Suzuki-Miyaura Cross-Coupling of Unactivated Secondary and Primary Alkyl Halides with Arylborons.

Suzuki-Miyaura cross-couplings (SMC) are powerful tools for the construction of carbon-carbon bonds. However, the couplings of sp3-hybridized alkyl halides with arylborons often encounter several problematic issues such as sluggish oxidation addition of alkyl halides and competitive β-hydride elimination side pathways of metal-alkyl species. In precedent reports, copper is mainly utilized for the coupling of sp2-aryl halides, and the cross-couplings with unactivated alkyl halides are far less reported. Herein, we demonstrate that a high-efficiency copper system enabled the coupling of arylborons with various unactivated secondary and primary alkyl halides including bromides, iodides, and even robust chlorides. The present system features broad scope, excellent functionality tolerance, scalability, and practicality. Moreover, the current system could be applied for the late-stage functionalization of complex molecules in moderate to high efficiency.

Ongoing Phase III Randomized Trial of Salvage DFP-10917 Vs. Non-Intensive Reinduction or Intensive Reinduction for Acute Myelogenous Leukemia (AML)

Background: DFP-10917 is a deoxycytidine analogue with a novel structure. It contains a side chain cyanide (CN) group at the 2 carbon of deoxyribose that induces DNA damage in a manner unique from structurally related nucleoside analogues (eg, cytarabine, decitabine, or gemcitabine). When administered at high doses, DFP-10917 inactivates deoxyribonucleic acid (DNA) polymerase leading to S-phase arrest similar to cytarabine. When administered at low concentrations by continuous infusion, it displays an alternative, potentially advantageous, mechanism of action - DNA strand breakage leading to G2/M phase arrest and ultimately cell apoptosis. The strand breakage occurs via a spontaneous beta elimination reaction that requires no additional enzymatic activity. There is no current standard treatment for patients with relapsed/refractory (R/R) AML. Results of a completed Phase I/II study in R/R AML (D11-11002; NCT01702155) demonstrated preliminary efficacy of DFP-10917 in this indication, with a ~50% complete response (CR) rate in Phase II. Five of 14 patients who achieved CR proceeded to stem cell transplantation. Based on completed studies, risks associated with DFP-10917 are predominantly hematological (eg, neutropenia, anemia, febrile neutropenia, leukopenia, lymphopenia, thrombocytopenia). Study Design and Methods: Based on promising Phase II results, the Sponsor initiated Study D18-11141 (NCT03926624), a Phase III, randomized, controlled study to compare the rate and duration of CR in patients with AML R/R to 2-4 prior induction regimens. Patients receive either DFP-10917 or non-intensive reinduction (low-dose cytarabine [LoDAC], azacitidine, decitabine, venetoclax + LoDAC or azacitidine or decitabine) or intensive reinduction (high and intermediate dose cytarabine regimens). Patients assigned to DFP-10917 receive 6 mg/m 2/day by continuous infusion for 14 days followed by a 14-day rest period. Control treatment is administered per physician's decision. Adults aged ≥18 years with histologically or pathologically confirmed diagnosis of AML based on World Health Organization classification and adequate performance status (≤2) and organ function are eligible. Study Status: The study is ongoing at 34 study centers in the United States. As of July 2023, 162 patients were enrolled, with 82 assigned to DFP-10917. A majority of the patients are male (57.4%) and aged <75 years (83.3%). Overall, 44% have AML with myelodysplasia-related changes; 36% have AML not otherwise specified; and <20% have AML with recurrent genetic abnormalities or therapy-related myeloid neoplasms. Enrollment and management of patients were affected from 2020 to 2021 by COVID-19 restrictions. A prospectively-planned interim analysis will occur after the 150 th patient randomized is followed for >2 months. Based on recruitment projections, this analysis is scheduled for 09/2023. At that time, the Data Safety Monitoring Board will review an unblinded estimate of the treatment effect for the primary endpoint of CR, with the study either stopped for superiority or futility or continuing to a final analysis. If continued, the number of patients required for the final analysis will range from 300 to 450, in increments of 50, with the number determined based on the size of the interim treatment effect for the primary endpoint of CR or the secondary endpoint of overall survival.

Kumada-Tamao-Corriu Type Reaction of Aromatic Bromo- and Iodoamines with Grignard Reagents.

The first example of the Kumada-Tamao-Corriu type reaction of unprotected bromoanilines with Grignard reagents is described. The method uses a palladium source and a newly designed Buchwald-type ligand as the catalytic system. Secondary and tertiary bromo- and iodoamines were also successfully coupled to alkyl Grignard reagents. The products of the competitive β-hydride elimination reaction were successfully reduced using a highly efficient electron-deficient phosphine ligand (BPhos). Mechanistic considerations allowed us to establish that the less electron-rich phosphine ligands stabilize the transition state much better than the electron-rich ones; hence, they increase the reaction yield and reduce the amount of β-hydride elimination products. The developed method proved to be tolerant of many functional groups and can be applied to many different aromatic bromo- and iodoamines. Multigram synthesis of p-toluidine from 4-bromoaniline was achieved with a palladium catalyst loading of only 0.03 mol%.

Palladium-Catalyzed Regiodivergent C-H Olefination of Imidazo[1,2a]pyridine Carboxamide and Unactivated Alkenes.

Despite remarkable successes in linear and branched vinyl (hetero) arene synthesis, regiodivergent C-H olefination with a single catalytic system has remained underdeveloped. Overcoming this limitation, a Pd/MPAA-catalyzed regiodivergent C-H olefination of imidazo[1,2a] pyridine carboxamides with unactivated terminal alkenes to generate branched and linear olefinated products depending upon the electronic nature of alkenes is reported herein. Moreover, this protocol can be applied for C-H deuteriation of the corresponding heteroarenes with D2 O as deuterium source. Preliminary experimental studies combined with computational investigations (DFT studies) suggest that regiodivergent olefination can be controlled by olefin insertion and β-hydride elimination steps.

Oxidative Addition and β-Hydride Elimination by a Macrocyclic Dinickel Complex: Observing Bimetallic Elementary Reactions.

The dinickel(I) complex Ni2 (tBu PONNOPONNO), featuring a planar macrocyclic diphosphoranide ligand tBu PONNOPONNO, offers a unique architectural platform for observing bimetallic elementary reactions. Oxidative addition reactions of alkyl halides produce dinickel(II) complexes of the type Ni2 (μ-R)(μ-X)(tBu PONNOPONNO). However, when R=Et β-hydride elimination is observed to form a dinickel monohydride, with the rate dependent on the nature of X. DFT studies suggest a new mechanism for bimetallic β-hydride elimination, where the rate dependence arises from the steric pressure imposed by the X group on the opposing trans face of the dinickel macrocycle. This work enhances understanding of bimetallic elementary reactions, particularly β-hydride elimination, which have not been well-explored for dinuclear systems.

Hemilabile P,N-Ligand-Assisted Gold-Catalyzed Heck Reaction of Aryl and Styryl Iodides with Styrenes.

A gold-catalyzed Heck reaction of aryl and styryl iodides with styrenes was developed. The hemilabile P,N-ligand-assisted gold-catalyzed C(sp2)-C(sp2) cross-coupling can synthesize stilbenes and bistyryl complexes, with good functional-group tolerance and mild conditions. The elementary organometallic steps of migratory insertion and β-hydride elimination might be involved in this ligand-enabled Au(I)/Au(III)-catalyzed Heck reaction with styrenes.

Palladium and Iron Cocatalyzed Aerobic Alkene Aminoboration.

Aminoboration of simple alkenes with nitrogen nucleophiles remains an unsolved problem in synthetic chemistry; this transformation can be catalyzed by palladium via aminopalladation followed by transmetalation with a diboron reagent. However, this catalytic process faces inherent challenges with instability of the alkylpalladium(II) intermediate toward β-hydride elimination. Herein, we report a palladium/iron cocatalyzed aminoboration, which enables this transformation. We demonstrate these conditions on a variety of alkenes and norbornenes with an array of common nitrogen nucleophiles. In the developed strategy, the iron cocatalyst is crucial to achieving the desired reactivity by serving as a halophilic Lewis acid to release the transmetalation-active cationic alkylpalladium intermediate. Furthermore, it serves as a redox shuttle in the regeneration of the Pd(II) catalyst by reactivation of nanoparticulate palladium.

Access to unsaturated bicyclic lactones by overriding conventional C(sp3)-H site selectivity.

Transition metal catalysis plays a pivotal role in transforming unreactive C-H bonds. However, regioselective activation of distal aliphatic C-H bonds poses a tremendous challenge, particularly in the absence of directing templates. Activation of a methylene C-H bond in the presence of methyl C-H is underexplored. Here we show activation of a methylene C-H bond in the presence of methyl C-H bonds to form unsaturated bicyclic lactones. The protocol allows the reversal of the general selectivity in aliphatic C-H bond activation. Computational studies suggest that reversible C-H activation is followed by β-hydride elimination to generate the Pd-coordinated cycloalkene that undergoes stereoselective C-O cyclization, and subsequent β-hydride elimination to provide bicyclic unsaturated lactones. The broad generality of this reaction has been highlighted via dehydrogenative lactonization of mid to macro ring containing acids along with the C-H olefination reaction with olefin and allyl alcohol. The method substantially simplifies the synthesis of important bicyclic lactones that are important features of natural products as well as pharmacoactive molecules.

C(sp3)–C(sp2) Reductive Elimination versus β-Hydride Elimination from Cobalt(III) Intermediates in Catalytic C–H Functionalization

The cationic bis(phosphine) cobalt(I) arene complex, [(depe)Co(η6-C7H8)][BAr4F] (depe = 1,2-bis(diethylphosphino)ethane; BAr4F = B[(3,5-(CF3)2)C6H3]4), was investigated as a precatalyst for three-component coupling of arenes, alkenes, and alkynes. Although a sterically attenuated catalyst was targeted with the goal of accelerating C–H functionalization, hydrovinylation derived from the alkene and alkyne was favored over three-component coupling. Remarkably, no catalytic hydrovinylation was observed in the absence of arene, demonstrating the role of C–H activation in the hydrovinylation process and ruling out a mechanism that involves β-H elimination from a cobalt(III) metallacycle. Deuterium labeling supported β-H elimination from a putative cobalt(III)–alkyl,aryl intermediate that forms after C–H activation by a cobalt(III) metallacycle. By varying the arene and alkene coupling partners, factors affecting the selectivity of C(sp3)–C(sp2) reductive elimination versus β-H elimination from the cobalt(III)–alkyl,aryl intermediate were determined.

Front Cover: Theoretical Investigations on the Agostic Interactions of the Molybdenum and Manganese Complexes (Eur. J. Inorg. Chem. 24/2023)

The Front Cover shows the gear set of “Homogeneous Catalysis” driven by an engine of “M−H−C Agostic Interaction”. The critical role of agostic interactions in homogeneous catalysis, such as polymerization, C−H bond activation, β-hydride elimination, and cyclometallation, is well-established. The Mo−H−C agostic interaction in the Mo β/γ-agostomers [CpMo(CO)2(PiPr3)]+ and the Mn−H−C agostic interaction in the Mn α/ϵ-agostomers [(C6H9]Mo(CO)3] were comprehensively investigated in this study. The findings on the agostic interactions presented here are believed to benefit the understanding of the agostic interactions involved in catalytic processes and to promote the development of new organometallic complexes. The cover was designed by the first author, Dr. Min Zhang. More information can be found in the Research Article by G. Liang and co-workers.