Iron-Mediated Dialkylation of Alkenylarenes with Benzyl Bromides.

We disclose a method for the dibenzylation of alkenylarenes with benzyl bromides using iron powder. This reaction generates branched alkyl scaffolds adorned with functionalized aryl rings through the formation of two new C(sp3)-C(sp3) bonds at the vicinal carbons of alkenes. This protocol tolerates electron-rich, electron-neutral, and electron-poor benzyl bromides and alkenylarenes. Mechanistic studies suggest the formation of benzylic radical intermediates as a result of single-electron transfer from the iron, which is intercepted by alkenylarenes.

Ni-Catalyzed Linearizable Cyclization/Coupling with Detachable Silicon-Oxygen Linker: Access to 1,2-Oxasilolanes, 3-Hydroxysilanes and 4-Arylalkanols.

We disclose a Ni-catalyzed cyclization/alkylmetal interception reaction in which products are readily linearized to permit regiodefined alkene dicarbofunctionalization. This method offers a convenient route to access 1,2-oxasilolane heterocycles, 3-hydroxysilanes and 4-arylalkanols with the formation of C(sp3)-C(sp3) bonds at primary and secondary alkyl carbon centers. In this reaction, a silicon-oxygen (Si-O) bond functions as a detachable linker that can be delinked with several hydride, alkyl, aryl and vinyl nucleophiles to create profusely functionalized 3-hydroxysilanes. A silicon motif in the cyclic C(sp3)-Si-O construct in 1,2-oxasilolane heterocycles can also be selectively deleted by Pd-catalyzed hydrodesilylation affording Si-ablated linear alcohol products reminiscent of vicinal ethylene dicarbofunctionalization with C(sp3) and C(sp2) carbon sources.

Interception and Synthetic Application of Diradical and Diene Forms of Dual-Nature Azabicyclic o-Quinodimethanes Generated by 6π-Azaelectrocyclization.

We demonstrate that 2-alkenylarylaldimines and ketimines undergo thermal 6π-azaelectrocyclization to generate a wide range of azabicyclic o-quinodimethanes (o-QDMs). These o-QDMs exist as a hybrid of a diene and a benzylic diradical. The diradical nature was confirmed by their ability to undergo dimerization and react with H-atom donor, 2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) and O2. In addition, the interception of the diradicaloid o-QDMs by H-atom transfer was used to synthesize five tetrahydroisoquinoline alkaloids and related bioactive molecules. The diene form can undergo [4+2] cycloaddition reactions with different dienophiles to generate bridged azabicycles in high endo:exo selectivity. The azabicyclic o-QDMs can be generated for [4+2] cycloaddition from a wide range of electronically and sterically varied 2-alkenylarylimines, including mono, di, tri and tetrasubstituted alkenes, and imines derived from arylamine, alkylamine (1°, 2°, 3°), benzylamine, benzylsulfonamide and Boc-amine.

Nickel-Catalyzed Alkene Difunctionalization as a Method for Polymerization.

Alkene dicarbofunctionalization is a rapidly emerging tool for complex molecule synthesis that installs two carbon fragments regioselectively across an alkene. This method has the potential to engineer stereodefined polymers, yet the application of difunctionalization reactions to polymer synthesis remains unexplored. Herein, we describe the first example of a Ni-catalyzed difunctionalization of alkenes with arylboronic esters and aryl bromides innate to the alkene. The polymerization reaction proceeds regioselectively with the addition of the aryl bromide to the terminal alkenyl carbon and arylboronic ester to the internal benzylic carbon. The resultant poly[arylene-α-(aryl)ethylene]s comprise aryl groups installed at regular intervals along the polymer backbone through chain propagation in two directions. Polymers with molecular weights generally ranging from 30 to 175 kDa were obtained after successful fractionation from oligomeric species. Thermal analysis of the poly[arylene α-(aryl)ethylene]s revealed stability up to ∼399 °C, with a Tg of 90 °C, both of which are similar in value to poly(styrene)s and poly(phenylene methylene)s.

Nickel-Catalyzed Regioselective Intermolecular Dialkylation of Alkenylarenes: Generation of Two Vicinal C(sp3 )-C(sp3 ) Bonds Across Alkenes.

We disclose a Ni-catalyzed regioselective dialkylation reaction of alkenylarenes with α-halocarbonyls and alkylzinc reagents. The reaction produces γ-arylated alkanecarbonyl compounds with the generation of two new C(sp3 )-C(sp3 ) bonds at the vicinal carbons of alkenes. This reaction is effective for the use of primary, secondary and tertiary α-halocarboxylic esters, amides and ketones in conjunction with primary and secondary alkylzinc reagents as the sources of two C(sp3 ) carbons for the dialkylation of terminal and cyclic internal alkenes.

Transition Metal (Ni, Cu, Pd)-Catalyzed Alkene Dicarbofunctionalization Reactions.

Recently, alkene dicarbofunctionalization, i.e., the powerful organic synthesis method of alkene difunctionalization with two carbon sources, emerged as a formidable reaction with immense promise to synthesize complex molecules expeditiously from simple chemicals. This reaction is generally achieved with transition metals (TMs) through interception by carbon sources of an alkylmetal [ß-H-C(sp3)-[M]] species, a key intermediate prone to undergo rapid ß-H elimination. Related prior reports, since Paolo Chiusoli and Catellani's work in 1982 [ Tetrahedron Lett. 1982, 23, 4517], have used bicyclic and disubstituted terminal alkenes, wherein ß-H elimination is avoided by geometric restriction or complete lack of ß-H's. With reasoning that ß-H-C(sp3)-[M] intermediates could be rendered amenable to interception with the use of first row late TMs and formation of coordination-assisted transient metallacycles, these two strategies were implemented to address the ß-H elimination problem in alkene dicarbofunctionalization reactions.Because first row late TMs catalyze C(sp3)-C(sp3) coupling, Cu and Ni were anticipated to impart sufficient stability to ß-H-C(sp3)-[M] intermediates, generated catalytically upon alkene carbometalation, for their subsequent interception by carbon electrophiles/nucleophiles in three-component reactions. Additionally, such an innate property could enable alkene difunctionalization with carbon coupling partners through entropically driven cyclization/coupling reactions. The cyclometalation concept to stabilize intractable ß-H-C(sp3)-[M] intermediates was hypothesized when three-component reactions were performed. The idea of cyclometalation to curtail ß-H elimination is founded upon Whitesides's [ J. Am. Chem. Soc. 1976, 98, 6521] observation that metallacycles undergo ß-H elimination much slower than acyclic alkylmetals.In this Account, examples of alkene dicarbofunctionalization reactions demonstrate that Cu and Ni catalysts could enable cyclization/coupling of alkenylzinc reagents, alkyl halides, and aryl halides to afford complex carbo- and heterocycles. In addition, forming coordination-assisted transient nickellacycles enabled regioselective performance of three-component dicarbofunctionalization of various alkenyl compounds. In situ reaction of [M]-H with alkenes generated after ß-H elimination induced an unprecedented metallacycle contraction process, in which six-membered metal-containing rings shrank to five-membered cycles, allowing creation of new carbon-carbon bonds at allylic (1,3) positions. Applications of these regioselective alkene dicarbofunctionalization reactions are discussed.

C-H Bond Functionalization under Electrochemical Flow Conditions.

Electrochemical C-H functionalization is a rapidly growing area of interest in organic synthesis. To achieve maximum atom economy, the flow electrolysis process is more sustainable. This allows shorter reaction times, safer working environments, and better selectivities. Using this technology, the problem of overoxidation can be reduced and less emergence of side products or no side products are possible. Flow electro-reactors provide high surface-to-volume ratios and contain electrodes that are closely spaced where the diffusion layers overlap to give the desired product, electrochemical processes can now be managed without the need for a deliberately added supporting electrolyte. Considering the importance of flow electrochemical C-H functionalization, a comprehensive review is presented. Herein, we summarize flow electrolysis for the construction of C-C and C-X (X=O, N, S, and I) bonds formation. Also, benzylic oxidation and access to biologically active molecules are discussed.

Backscatter multiple wavelength digital holography for color micro-particle imaging.

This work applies digital holography to image stationary micro-particles in color. The approach involves a Michelson interferometer to mix reference light with the weak intensity light backscattered from a distribution of particles. To enable color images, three wavelengths are used, 430, 532, and 633 nm, as primary light sources. Three separate backscattered holograms are recorded simultaneously, one for each wavelength, which are resolved without spectral cross talk using a three-CMOS prism sensor. Fresnel diffraction theory is used to render monochrome images from each hologram. The images are then combined via additive color mixing with red, green, and blue as the primary colors. The result is a color image similar in appearance to that obtained with a conventional microscope in white-light epi-illumination mode. A variety of colored polyethylene micro-spheres and nonspherical dust particles demonstrate the feasibility of the approach and illustrate the effect of simple speckle-noise suppression and white balance methods. Finally, a chromaticity analysis is applied that is capable of differentiating particles of different colors in a quantitative and objective manner.

Balanced forced-diuresis as a renal protective approach in cardiac surgery: Secondary outcomes of electrolyte changes.

OBJECTIVES: Forced-diuresis during cardiopulmonary bypass (CPB) can be associated with significant electrolyte shifts. This study reports on the serum electrolyte changes during balanced forced-diuresis with the RenalGuard® system (RG) during CPB. METHODS: Patients at risk of acute kidney injury (AKI)-(history of diabetes &/or anaemia, e-GFR 20-60 ml/min/1.73 m2 , anticipated CPB time >120 min, Log EuroScore >5)-were randomized to either RG (study group) or managed as per current practice (control group). RESULTS: The use of RG reduced AKI rate (10% for RG and 20.9% in control, p = .03). Mean urine output was significantly higher in the RG group during surgery (2366 ± 877 ml vs. 765 ± 549 ml, p < .001). The serum potassium levels were maintained between 3.96 and 4.97 mmol/L for the RG group and 4.02 and 5.23 mmol/L for the controls. Median potassium supplemental dose was 60 (0-220) mmol (RG group) as compared to 30 (0-190) mmol for control group over first 24 h (p < .001). On Day 1 post-op, there were no significant differences in the serum sodium, potassium, calcium, magnesium, phosphate, and chloride levels between the two groups. Otherwise, postoperative clinical recovery was also similar. CONCLUSIONS: Balanced forced-diuresis with the RG reduced AKI rates after on-pump cardiac surgery compared to controls. Although the RG group required higher doses of IV potassium replacement in the postoperative period, normal serum levels of potassium were maintained by appropriate intravenous potassium supplementation and the clinical outcomes between groups were similar.

Nickel-Catalyzed Regioselective Alkenylarylation of γ,δ-Alkenyl Ketones via Carbonyl Coordination.

We disclose a nickel-catalyzed reaction, which enabled us to difunctionalize unactivated γ,δ-alkenes in ketones with alkenyl triflates and arylboronic esters. The reaction was made feasible by the use of 5-chloro-8-hydroxyquinoline as a ligand along with NiBr2 ⋅DME as a catalyst and LiOtBu as base. The reaction proceeded with a wide range of cyclic, acyclic, endocyclic and exocyclic alkenyl ketones, and electron-rich and electron-deficient arylboronate esters. The reaction also worked with both cyclic and acyclic alkenyl triflates. Control experiments indicate that carbonyl coordination is required for the reaction to proceed.

Ni-Catalyzed Arylbenzylation of Alkenylarenes: Kinetic Studies Reveal Autocatalysis by ZnX2 *.

We report a Ni-catalyzed regioselective arylbenzylation of alkenylarenes with benzyl halides and arylzinc reagents. The reaction furnishes differently substituted 1,1,3-triarylpropyl structures that are reminiscent of the cores of oligoresveratrol natural products. The reaction is also compatible for the coupling of internal alkenes, secondary benzyl halides and variously substituted arylzinc reagents. Kinetic studies reveal that the reaction proceeds with a rate-limiting single-electron-transfer process and is autocatalyzed by in-situ-generated ZnX2 . The reaction rate is amplified by a factor of three through autocatalysis upon addition of ZnX2 .

Ni-Catalyzed Regioselective 1,2-Dialkylation of Alkenes Enabled by the Formation of Two C(sp3)-C(sp3) Bonds.

We disclose a Ni-catalyzed vicinal difunctionalization of alkenes with benzyl halides and alkylzinc reagents, which produces products with two new alkyl-alkyl bonds. This alkene dialkylation is effective in combining secondary benzyl halides and secondary alkylzinc reagents with internal alkenes, which furnishes products with three contiguous all-carbon secondary stereocenters. The products can be readily elaborated to access complex tetralene, benzosuberene, and bicyclodecene cores. The reaction also features as the most efficient alkene difunctionalization process to date with catalyst loadings down to 500 ppm and the catalytic turnover number (TON) and turnover frequency (TOF) registering up to 2 × 103 and 165 h-1 at rt, respectively.

An Expedient Route to 9-arylmethylanthracene Derivatives via Tandem Ni-catalyzed Alkene Dicarbofunctionalization and Acid-promoted Cyclization-aromatization.

We report a nickel-catalyzed one pot synthesis of 9-arylmethylanthracene motifs, which find applications in medicinal and material chemistry. In this synthesis, we apply three component alkene dicarbofunctionalization of 2-vinylaldimines with aryl iodides and arylzinc reagent to generate a 1,1,2-diarylethyl scaffold, which then undergoes an acidpromoted cyclization followed by aromatization to furnish 9-arylmethylanthracene cores. With the new method, a number of differently-substituted 9-arylmethylanthracene derivatives can be synthesized in good yields.

Nickel-Catalyzed α-Carbonylalkylarylation of Vinylarenes: Expedient Access to γ,γ-Diarylcarbonyl and Aryltetralone Derivatives.

We report a Ni-catalyzed regioselective α-carbonylalkylarylation of vinylarenes with α-halocarbonyl compounds and arylzinc reagents. The reaction works with primary, secondary, and tertiary α-halocarbonyl molecules, and electronically varied arylzinc reagents. The reaction generates γ,γ-diarylcarbonyl derivatives with α-secondary, tertiary, and quaternary carbon centers. The products can be readily converted to aryltetralones, including a precursor to Zoloft, an antidepressant drug.

Generation of aerosol-particle light-scattering patterns from digital holograms.

The similarity between the light-scattering pattern of a particle in the near-forward direction and diffraction from the particle's silhouette is investigated. Images of irregularly shaped free-flowing aerosol particles are obtained from digital hologram measurements, which are then binarized to yield a silhouette. Application of Huygens's principle to the silhouette generates an approximate scattering pattern, which when compared to the true measured pattern shows good agreement for particles much larger than the wavelength of light.

Synergistic Bimetallic Ni/Ag and Ni/Cu Catalysis for Regioselective γ,δ-Diarylation of Alkenyl Ketimines: Addressing ß-H Elimination by in Situ Generation of Cationic Ni(II) Catalysts.

We disclose unprecedented synergistic bimetallic Ni/Ag and Ni/Cu catalysts for regioselective γ,δ-diarylation of unactivated alkenes in simple ketimines with aryl halides and arylzinc reagents. The bimetallic synergy, which generates cationic Ni(II) species during reaction, promotes migratory insertion and transmetalation steps and suppresses ß-H elimination and cross-coupling, the major side reactions that cause serious problems during alkene difunctionalization. This diarylation reaction proceeds at remote locations to imines to afford, after simple H+ workup, diversely substituted γ,δ-diaryl ketones that are otherwise difficult to access readily with existing methods.

Mechanism of the Ullmann Biaryl Ether Synthesis Catalyzed by Complexes of Anionic Ligands: Evidence for the Reaction of Iodoarenes with Ligated Anionic CuI Intermediates.

A series of experimental studies, along with DFT calculations, are reported that provide a detailed view into the mechanism of Ullmann coupling of phenols with aryl halides in the presence of catalysts generated from Cu(I) and bidentate, anionic ligands. These studies encompass catalysts containing anionic ligands formed by deprotonation of 8-hydroxyquinoline, 2-pyridylmethyl tert-butyl ketone, and 2,2,6,6-tetramethylheptane-3,5-dione. Three-coordinate, heteroleptic species [Cu(LX)OAr]- were shown by experiment and DFT calculations to be the most stable complexes in catalytic systems containing 8-hydroxyquinoline or 2-pyridylmethyl tert-butyl ketone and to be generated reversibly in the system containing 2,2,6,6-tetramethylheptane-3,5-dione. These heteroleptic complexes were characterized by a combination of 19F NMR, 1H NMR, and UV-vis spectroscopy, as well as ESI-MS. The heteroleptic complexes generated in situ react with iodoarenes to form biaryl ethers in high yields without evidence for an aryl radical intermediate. Measurements of 13C/12C isotope effects showed that oxidative addition of the iodoarene occurs irreversibly. This information, in combination with the kinetic data, shows that oxidative addition occurs to the [Cu(LX)OAr]- complexes and is turnover-limiting. A Hammett analysis of the effect of phenoxide electronic properties on the rate of the reaction of [Cu(LX)OAr]- with iodotoluene also is consistent with oxidative addition of the iodoarene to an anionic phenoxide complex. Calculations by DFT suggest that this oxidative addition is followed by dissociation of I- and reductive elimination of the biaryl ether from the resulting neutral Cu(III) complex.

Ni-Catalyzed Regioselective Alkylarylation of Vinylarenes via C(sp3)-C(sp3)/C(sp3)-C(sp2) Bond Formation and Mechanistic Studies.

We report a Ni-catalyzed regioselective alkylarylation of vinylarenes with alkyl halides and arylzinc reagents to generate 1,1-diarylalkanes. The reaction proceeds well with primary, secondary and tertiary alkyl halides, and electronically diverse arylzinc reagents. Mechanistic investigations by radical probes, competition studies and quantitative kinetics reveal that the current reaction proceeds via a Ni(0)/Ni(I)/Ni(II) catalytic cycle by a rate-limiting direct halogen atom abstraction via single electron transfer to alkyl halides by a Ni(0)-catalyst.

Ni-Catalyzed Regioselective ß,δ-Diarylation of Unactivated Olefins in Ketimines via Ligand-Enabled Contraction of Transient Nickellacycles: Rapid Access to Remotely Diarylated Ketones.

We disclose a [(PhO)3P]/NiBr2-catalyzed regioselective ß,δ-diarylation of unactivated olefins in ketimines with aryl halides and arylzinc reagents. This diarylation proceeds at remote locations to the carbonyl group to afford, after simple H+ workup, diversely substituted ß,δ-diarylketones that are otherwise difficult to access readily with existing methods. Deuterium-labeling and crossover experiments indicate that diarylation proceeds by ligand-enabled contraction of transient nickellacycles.

Transition Metal-Catalyzed Dicarbofunctionalization of Unactivated Olefins.

Transition metal (TM)-catalyzed difunctionalization of unactivated olefins with two carbon-based entities is a powerful method to construct complex molecular architectures rapidly from simple and readily available feedstock chemicals. While dicarbofunctionalization of unactivated olefins has a long history typically with the use of either carbon monoxide to intercept C(sp3 )-[M] (alkyl-TM) species or substrates lacking in ß-hydrogen (ß-Hs), development of this class of reaction still remains seriously limited due to complications of ß-H elimination arising from the in situ-generated C(sp3 )-[M] intermediates. Over the years, different approaches have been harnessed to suppress ß-H elimination, which have led to the development of various types of olefin dicarbofunctionalization reactions even in substrates that generate C(sp3 )-[M] intermediates bearing ß-Hs with a wide range of electrophiles and nucleophiles. In this review, these developments will be discussed both through the lens of historical perspectives as well as the strategies scrutinized over the years to address the issue of ß-H elimination. However, this review article by no means is designed to be exhaustive in the field, and is merely presented to provide the readers an overview of the key reaction developments.