Beta-elimination Research Articles

Palladium-Catalyzed Ring-Closing Aminoalkylative Amination of Unactivated Aminoenynes.

An efficient strategy for preventing the β-hydride elimination of alkylpalladium species by ligation of the palladium with adjacent amino-group was developed, which enabled a novel palladium-catalyzed ring-closing aminoalkylative amination of unactivated aminoenynes. The reaction is amenable to aminals, as well as aliphatic aldehydes with secondary amines, which provides straightforward access to structurally diverse exocyclic allenic amines bearing 5 to 12-membered N-heterocycles. With chiral phosphoramidite-ligated palladium complex as the catalyst, an enantioselective variant was achieved with up to 93 % ee. Simultaneously, synthetic transformations of the chiral products were also conducted to afford structurally unique spirodiamines including one pharmaceutically active molecule via axial-to-central chirality transfer.

Cross-Coupling of Cyclobutenone N-Tosylhydrazones with Organohalides: Access to Conjugated Enynes and Enallenes via a Strained Allylpalladium Intermediate

A palladium-catalyzed cross-coupling reaction of cyclobutenone N-tosylhadrazones with organohalides is disclosed. The protocol involves the generation of a strained allylpalladium intermediate from readily available starting materials through palladium carbene migratory insertion, which undergoes electrocyclic ring opening and β-hydride elimination for the production of conjugated enynes and enallenes. The broad substrate scope, good to excellent yields, and tunable product diversity make the protocol potentially useful in organic synthesis.

Access to Substituted Indenol Ethers via a Regioselective Intermolecular Carbopalladation Cascade.

Alkyne carbopalladation reactions can rapidly generate multiple new C-C bonds; however, regioselectivity is challenging for intermolecular variants. Using ynol ethers, we observe complete regiocontrol of migratory insertion followed by a second migratory insertion with a pendant alkene to turn-over the catalytic cycle. The resulting products are oligosubstituted 1-indenol ethers with defined stereochemistry based on the initial alkene geometry. Blocking β-hydride elimination allowed for C-H and C-C reductive elimination steps for catalyst turnover.

Base-Induced Dehydrogenative and Dearomative Transformation of 1-Naphthylmethylamines to 1,4-Dihydronaphthalene-1-carbonitriles.

Solvothermal treatment of 1-naphthylmethylamine with potassium hydride (KH) or n-butyllithium (n-BuLi)-potassium t-butoxide (t-BuOK) in THF induces unusual two consecutive β-hydride eliminations to form 1-naphthonitrile and KH. The freshly generated KH is hydridic enough to undergo dearomative hydride addition to the resultant 1-naphthonitrile regioselectively at the C4 position to afford α-cyano benzylic carbanion, which could be functionalized by a series of electrophiles, liberating the corresponding 1,4-dihydronaphthalene-1-carbonitriles having a quaternary carbon center.

Cobalt-Catalyzed Hydrocyanation of Methylenecyclopropanes to Homoallylic Nitriles.

We describe herein a novel synthesis of various homoallylic nitriles via cobalt-catalyzed hydrocyanation of methylenecyclopropanes. Excellent selectivity, mild reaction conditions, good functional group compatibility, gram-scale reaction, and product transformations demonstrate the power of this protocol. This extraordinary selectivity can probably be attributed to the stronger aptitude of the alkyl-cobalt cyanide intermediate to undergo reductive elimination rather than β-hydride elimination.

Mechanistic Insights into Cobalt-Catalyzed Regioselective C4-Alkenylation of 3-Acetylindole: A Detailed Theoretical Study.

A detailed mechanistic study of Co(III)-catalyzed C4-alkenylation of 3-acetylindole (1a) was done based on calculations at density functional theory (DFT) and correlated wave function levels. The whole catalytic cycle consists of four steps: C-H activation, olefin insertion, β-hydride elimination, and regeneration of the catalyst. The theoretical results support olefin insertion as the rate-determining step leading to the experimentally observed regioselectivity of the C4 site over the C2 site. By the analysis of three-dimensional (3D) geometries and the NCl plot, the preference for the C4 site over the C2 site could be attributed to the weaker repulsive interaction between the indole moiety and olefin in the transition states of the olefin insertion step for the former. The reliability of the theoretical mechanistic results is further confirmed through the DFT calculation of other related indole derivatives and olefin substrates.

Base-Free Catalytic Hydrogen Production from Formic Acid Mediated by a Cubane-Type Mo3S4 Cluster Hydride.

Formic acid (FA) dehydrogenation is an attractive process in the implementation of a hydrogen economy. To make this process greener and less costly, the interest nowadays is moving toward non-noble metal catalysts and additive-free protocols. Efficient protocols using earth abundant first row transition metals, mostly iron, have been developed, but other metals, such as molybdenum, remain practically unexplored. Herein, we present the transformation of FA to form H2 and CO2 through a cluster catalysis mechanism mediated by a cuboidal [Mo3S4H3(dmpe)3]+ hydride cluster in the absence of base or any other additive. Our catalyst has proved to be more active and selective than the other molybdenum compounds reported to date for this purpose. Kinetic studies, reaction monitoring, and isolation of the [Mo3S4(OCHO)3(dmpe)3]+ formate reaction intermediate, in combination with DFT calculations, have allowed us to formulate an unambiguous mechanism of FA dehydrogenation. Kinetic studies indicate that the reaction at temperatures up to 60 °C ends at the triformate complex and occurs in a single kinetic step, which can be interpreted in terms of statistical kinetics at the three metal centers. The process starts with the formation of a dihydrogen-bonded species with Mo-H···HOOCH bonds, detected by NMR techniques, followed by hydrogen release and formate coordination. Whereas this process is favored at temperatures up to 60 °C, the subsequent β-hydride elimination that allows for the CO2 release and closes the catalytic cycle is only completed at higher temperatures. The cycle also operates starting from the [Mo3S4(OCHO)3(dmpe)3]+ formate intermediate, again with preservation of the cluster integrity, which adds our proposal to the list of the infrequent cluster catalysis reaction mechanisms.

Amine-functionalized hierarchically porous carbon supported Pd nanocatalysts for highly efficient H2 generation from formic acid with fast-diffusion channels

Formic acid (FA) has come to be considered a potential candidate for hydrogen storage, and the development of efficient catalysts for H2 releasing is crucial for realizing the sustainable process from FA. Herein, we have developed the ultrafine Pd nanoparticle (NPs) with amine-functionalized carbon as a support, which was found to show an excellent catalytic activity in H2 generation from FA dehydrogenation. The synergetic mechanism between amine-group and Pd active site was demonstrated to facilitate H2 generation by β-hydride elimination. Moreover, the texture of support for Pd NPs also plays an important role in determining the reactivity of FA, since the diffusion of gaseous products makes the kinetics of diffusion as a challenge in this high performance Pd catalysts. As a result, the as-prepared Pd/NH2-TPC catalyst with the small sized Pd nanoparticles and the hierarchically porous structures shows a turnover of frequency (TOF) value of 4312 h−1 for the additive-free FA dehydrogenation at room temperature, which is comparable to the most promising heterogeneous catalysts. Our results demonstrated that the intrinsic catalytic activities of active site as well as the porous structure of support are both important factors in determining catalytic performances in H2 generation from FA dehydrogenation, which is also helpful to develop high-activity catalysts for other advanced gas-liquid-solid reactions systems.

Dual Pd2+ and Pd0 sites on CeO2 for benzyl alcohol selective oxidation

Solvent-free aerobic oxidation of benzyl alcohol is a green approach for synthesizing fine chemicals. Pd-based catalysts are extensively investigated due to their excellent catalytic activity compared to other metal catalysts. Most researchers believe that metallic Pd species (Pd0) provide active centers. However, the critical role of active oxygen and the function of Pd2+ is neglected. Herein, supported Pd clusters on CeO2 (Pd/CeO2) with a stable high Pd2+/(Pd0 + Pd2+) ratio are prepared by atomic layer deposition (ALD). The turnover frequency (TOF) and activity on as-prepared Pd/CeO2 catalysts in solvent-free aerobic oxidation of benzyl alcohol reach 3.50 × 105 h−1 and 1.85 × 105 mol/(molPd·h), respectively, which are much superior to previously reported results. As the Pd loading increases, the TOFs exhibit a volcano relationship with the Pd2+/(Pd0 + Pd2+) ratio, pointing to a dual Pd0 and Pd2+ sites catalyzed mechanism. O2 kinetic isotopic effect and further evidence support a dual-site catalyzed oxygen-promoted β-hydride elimination mechanisms, in which benzyl alcohol is selectively adsorbed to Pd2+ sites and reacts with active oxygen species on nearby Pd0 sites during the reaction.

Single-Site Heterogeneous Organometallic Ir Catalysts Embedded on Graphdiyne: Structural Manipulation Beyond the Carbon Support.

Accurate control over the coordination circumstances of single-atom catalysts (SACs) is decisive to their intrinsic activity. Here, two single-site heterogeneous organometallic catalysts (SHOCs), Cp*Ir-L/GDY (L = OH- and Cl- ; Cp* = pentamethylcyclopentadienyl), with the fine-tuned local coordination and electronic structure of Ir sites, are constructed by anchoring Cp*Ir complexes on graphdiyne (GDY) matrix via a one-pot procedure. The spectroscopic studies and theoretical calculations indicate that the Ir atoms in Cp*Ir-Cl/GDY and Cp*Ir-OH/GDY have a much higher oxidation state than Ir in the SAC Ir/GDY. As a proof-of-principle demonstration, the GDY-supported SHOCs are used for formic acid dehydrogenation, which display a fivefold enhancement of catalytic activity compared with SAC Ir/GDY. The kinetic isotope effect and in situ Fourier-transform infrared studies reveal that the rate-limiting step is the β-hydride elimination process, and Cp* on the Ir site accelerates the β-hydride elimination reaction. The GDY-supported SHOCs integrate the merits of both SACs and molecular catalysts, wherein the isolated Ir anchored on GDY echoes with SACs' behavior, and the Cp* ligand enables precise structural and electronic regulation like molecular catalysts. The scheme of SHOCs adds a degree of freedom in accurate regulation of the local structure, the electronic property, and therefore the catalytic performance of single-atom catalysts.

DNA Stability in Biodosimetry, Pharmacy and DNA Based Data-Storage: Optimal Storage and Handling Conditions.

DNA long-term stability and integrity is of importance for applications in DNA based bio-dosimetry, data-storage, pharmaceutical quality-control, donor insemination and DNA based functional nanomaterials. Standard protocols for these applications involve repeated freeze-thaw cycles of the DNA, which can cause detrimental damage to the nucleobases, as well as the sugar-phosphate backbone and therefore the whole molecule. Throughout the literature three hypotheses can be found about the underlying mechanisms occurring during freeze-thaw cycles. It is hypothesized that DNA single-strand breaks during freezing can be induced by mechanical stress leading to shearing of the DNA molecule, by acidic pH causing damage through depurination and beta elimination or by the presence of metal ions catalyzing oxidative damage via reactive oxygen species (ROS). Here we test these hypotheses under well defined conditions with plasmid DNA pUC19 in high-purity buffer (1xPBS) at physiological salt and pH 7.4 conditions, under pH 6 and in the presence of metal ions in combination with the radical scavengers DMSO and Ectoine. The results show for the 2686 bp long plasmid DNA, that neither mechanical stress, nor pH 6 lead to degradation during repeated freeze-thaw cycles. In contrast, the presence of metal ions (Fe2+ ) leads to degradation of DNA via the production of radical species.

Mechanistically informed selection rules for competing β-hydride and β-heteroatom eliminations

Mechanistically informed selection rules for competing β-hydride and β-heteroatom eliminations

Iridium-Catalyzed Stereoselective Transfer Hydrogenation of 1,5-Benzodiazepines.

An iridium-catalyzed highly stereoselective transfer hydrogenation of N-protected 2,4-disubstituted-1,5-benzodiazepines as well as dibenzo[1,5]oxa/thiazepines is realized in an aqueous solvent under acidic conditions, with formic acid as the hydride donor. Only trans-products are obtained in all the cases where diastereoselective issues are associated. The catalyst efficiency is highly dependent on the electronic and steric properties of the substrates. Topologically analyzing the angle of attack for hydride delivering revealed, stereoelectronically, that the steric interaction between the N-protecting group and the sterically large iridium hydride intermediate constitutes the main contributor to the excellent stereochemical control. Highly deuterated products can also be accessible with DCO2D as the deuteride donor. The observed primary kinetic isotope effect (kH/kD = 4.24) suggests that the formation of iridium hydride through β-hydride elimination should be the rate-determining step (with C-H bond cleavage). The potential use of the chirally modified iridium catalysts in a chemical resolution of racemic 1,5-benzodiazepines is also conceptually demonstrated.

Synthesis of Bio-Inspired 1,3-Diarylpropene Derivatives via Heck Cross-Coupling and Cytotoxic Evaluation on Breast Cancer Cells.

The Heck cross-coupling reaction is a well-established chemical tool for the synthesis of unsaturated compounds by formation of a new C-C bond. In this study, 1,3-diarylpropene derivatives, designed as structural analogues of stilbenoids and dihydrostilbenoids, were synthesised by the palladium-catalysed reactions of 2-amidoiodobenzene derivatives with either estragole or eugenol. The products were obtained with high (E) stereoselectivity but as two regioisomers. The ratios of isomers were found to be dependent on the nature of the allylbenzene partner and were rationalised by electronic effects exercising a determining influence in the β-hydride elimination step. In addition, the cytotoxic effects of all the Heck reaction products were evaluated against MCF-7 and MDA-MB-231 human breast cancer cells, with unpromising results. Among all, compound 7d exhibited weak cytotoxic activity towards MCF-7 cell lines with IC50 values of 47.92 µM in comparison with tamoxifen and was considered to have general toxicity (SI value < 2).

Palladium-Catalyzed Intramolecular Heck Dearomative Alkenylation of Indoles with N-Tosylhydrazones.

An elegant Pd-catalyzed intramolecular Heck dearomative alkenylation of aryl iodides with functionalized N-tosylhydrazones proceeded through a sequential dearomative carbopalladation, migratory insertion, and β-hydride elimination in the presence of Pd(CF3COO)2 (10 mol %), PPh3 (30 mol %), and Cs2CO3 (2.0 equiv) in 1,4-dioxane (2.0 mL) at 120 °C for 14 h under an argon atmosphere. This cascade cycloaddition protocol provided a reliable and versatile approach to a sequence of structurally diverse indolines in moderate to good yields with good functional group compatibility. In addition, the synthetic robustness of the methodology is highlighted by a scaled-up experiment and derivatization of products via epoxidation and reduction reactions.

Pincer-Cobalt-Catalyzed Guerbet-Type β-Alkylation of Alcohols in Air under Microwave Conditions

Pincer complexes of the type (R2NNN)CoCl2 (R = iPr, tBu, Cy, Ph, p-F-C6H4) derived from the environmentally benign, earth-abundant, and inexpensive base metal cobalt have been synthesized that exist in equilibrium with [(R2NNN)2Co]CoCl4. Among these complexes, (iPr2NNN)CoCl2 has been found to be highly efficient for the catalytic β-alkylation of alcohols in air at 140 °C. While the pincer-Co (0.0025 mol %)-catalyzed β-alkylation in the presence of NaOtBu (2.5 mol %) took 24 h (85%, 34000 TON at 1417 TO/h) under conventional heating (140 °C), the corresponding reaction under microwave conditions (140 °C at 75 W) was complete in only 2 h with comparable yields (83%, 33200 TON), albeit with a better TOF (16600 TO/h). In contrast, CoCl2 (0.0025 mol %) under otherwise identical conditions leads to lower yields under both conventional (66%, 26400 TON at 1100 TO/h) and microwave heating (61%, 24400 TON at 12200 TO/h). The catalytic system has been successfully implemented (39 examples) to accomplish the β-alkylation of secondary alcohols with several primary alcohols. Well-defined molecular Co(II) species are involved during catalysis, as inferred from HRMS and hot-filtration experiments. EPR studies and magnetic moment measurements using the Evans method demonstrate that Co remains in its +2 state and in an octahedral geometry throughout the reaction. Pivotal evidence for the involvement of β-hydride elimination leading to acetophenone in the RDS of the pincer-Co catalyzed β-alkylation is obtained from competitive deuterium labeling experiments, which are indicative of a KIE of 6.14. The current report on base-metal catalysis in air under microwave conditions that leads to high yields of β-alkylation with unprecedented turnovers (33200 TON at 16600 TO/h) in a very short time (2 h) offers exciting atom-economical and greener possibilities for these class of synthetically valuable Guerbet-type reactions.

Out of Thin Air? Catalytic Oxidation of Trace Aqueous Aldehydes with Ambient Dissolved Oxygen.

Water reuse is expanding due to increased water scarcity. Water reuse facilities treat wastewater effluent to a very high purity level, typically resulting in a product water that is essentially deionized water, often containing less than 100 μg/L organic carbon. However, recent research has found that low-molecular-weight aldehydes, which are toxic electrophiles, comprise a significant fraction of the final organic carbon pool in recycled wastewater in certain treatment configurations. In this manuscript, we demonstrate oxidation of trace aqueous aldehydes to their corresponding acids using a heterogeneous catalyst (5% Pt on C), with ambient dissolved oxygen serving as the terminal electron acceptor. Mass balances are essentially quantitative across a range of aldehydes, and pseudo-first-order reaction kinetics are observed in batch reactors, with kobs varying from 0.6 h-1 for acetaldehyde to 4.6 h-1 for hexanal, while they are low for unsaturated aldehydes. Through kinetic and isotopic labeling experiments, we demonstrate that while oxygen is essential for the reaction to proceed, it is not involved in the rate-limiting step, and the reaction appears to proceed primarily through a base-promoted β-hydride elimination mechanism from the hydrated gem-diol form of the corresponding aldehyde. This is the first report we are aware of that demonstrates useful abiotic oxidation of a trace organic contaminant using dissolved oxygen.

Unveiling the mechanistic landscape of formic acid dehydrogenation catalyzed by Cp∗M(III) catalysts (M = Co or Rh or Ir) with bis(pyrazol-1-yl)methane ligand architecture: A DFT investigation

The production of dihydrogen via formic acid dehydrogenation (FAD) has been gaining remarkable attention and advancement as an alternative, sustainable and clean energy source. Density functional theory (DFT) calculations have been utilized to probe the reaction mechanism of FAD catalyzed by a Cp∗Rh(III) complex reported by Fink and Laurenczy with bis(pyrazol-1-yl)methane ligand system. The calculated energetics show that the rate-limiting step is the β-hydride elimination step and protonation by hydronium ion was calculated to be the most favourable route requiring relatively less activation energy than the conventional process which entails formic acid as the proton source. The Co and Ir congeners of the chosen Rh catalyst were computationally designed and they were also found to follow the same mechanism. Interestingly, the three metal centres (Co, Rh and Ir) were estimated to possess nearly the same activation barrier of c.a. 14 kcal/mol at the rate determining step. Thus, the proposed Co complex with such a small rate determining activation barrier, could be considered as a cheap and propitious earth-abundant transition metal-based catalyst for FAD.

Ni-Catalyzed Reductive 1,2-Cross-Dialkylation of Unactivated Alkenes with Two Alkyl Bromides.

Cross-dialkylation of unactivated alkenes represents a significant challenge due to competitive β-hydride elimination and associated selectivity issues. Herein, a Ni-catalyzed reductive 1,2-dialkylation of unactivated aliphatic alkenes has been developed using two different alkyl bromides. The reaction proceeds smoothly under mild conditions to install two Csp3-Csp3 bonds onto directed aliphatic alkenes, demonstrating excellent chemo- and regioselectivity with good functional group tolerance.

Impact of N-Aryl- and NHC Core-Substituents on the Coupling of Alkylzinc Nucleophiles: Is Bigger always Better?

Bulky Pd-N-heterocyclic carbene (NHC) catalysts (e. g., N-(di-2,6-(3-pentyl)phenyl), IPent) have been shown to have significantly higher reactivity in a wide variety of cross-coupling applications (i. e., C-C, C-S, C-N) than less hindered variants (e. g., N-(di-2,6-(isopropyl)phenyl), IPr). Further, chlorinating the backbone of the NHC ring sees an even greater increase in reactivity. In the cross-coupling of (hetero)aryl electrophiles to secondary alkyl nucleophiles, making the N-aryl groups larger reduces the amount of β-hydride elimination leading to alkene byproducts and chlorinating the NHC core had an even greater effect, all but eliminating alkene formation. In the present study involving the cross-coupling of primary alkyl electrophiles and nucleophiles, a sharp and surprising reversal of all of the above trends was observed. Bulkier catalysts had generally slower rate of reaction and β-hydride elimination worsened leading to extensive amounts of alkene byproducts.