Stereoselective Hydroxyallylation of Cyclopropenes with Cyclopropanols via NHC Catalysis of Transient Organozinc Species.

A stereoselective hydroxyallylation reaction of cyclopropenes with cyclopropanols is achieved under zinc-mediated conditions, affording densely functionalized cyclopropanes with excellent diastereocontrol over three contiguous stereocenters within and outside the cyclopropane ring. A racemic variant of the reaction is synergistically promoted by catalytic N-heterocyclic carbene (NHC) and organic base, whereas chiral amino alcohol-derived bifunctional NHC enables a catalytic enantioselective variant. The reaction likely involves the generation of enolized zinc homoenolate via ring-opening of zinc cyclopropoxide and enolization of the resulting homoenolate, followed by its addition to the cyclopropene as a prochiral allylzinc nucleophile. Our mechanistic investigations highlighted the transient nature of enolized homoenolate, which, once generated from thermodynamically predominant cyclopropoxide, immediately proceeds to allylzincation with cyclopropene. The NHC not only promotes the rate-determining generation of enolized homoenolate but also engages in the allylzincation process. The resulting cyclopropylzinc species undergoes partial in situ protonation while partially remaining intact, thereby leaving an opportunity for trapping with an external electrophile.

Hydrogenolysis of Cationic Half-Sandwich Zinc Complexes Containing a Chelating Amine: Facile Cleavage of Zinc-Carbon Bond by Dihydrogen to Give Zinc Hydride Cations.

Cationic half-sandwich zinc complexes containing chelating amines [Cp*Zn(Ln)][BAr4 F] (2 a, Cp*=η3-C5Me5, Ln=N,N,N',N'-tetramethylethylenediamine, TMEDA; 2 b, Ln=N,N,N',N'-tetraethylethylenediamine, TEEDA; 2 c, Cp*=η1-C5Me5, Ln=N,N,N',N'',N''-pentamethyldiethylenetriamine, PMDTA; Ar4 F=(3,5-(CF3)2C6H3)4) reacted with dihydrogen (ca. 2 bar) in THF at 80 °C to give molecular zinc hydride cations [(Ln)ZnH(thf)m][BAr4 F] (3 a,b, m=1; 3 c, m=0) previously reported along with Cp*H. Pseudo first-order kinetics with respect to the concentration of 2 b suggests heterolytic cleavage of dihydrogen by the Zn-Cp* bond, reminiscent of σ-bond metathesis. Hydrogenolysis of the zinc cation 2 b in the presence of benzophenone gave the zinc alkoxide [(TEEDA)Zn(OCHPh2)(thf)][BAr4 F] (5 b). Cation 2 b was shown to catalytically hydrogenate N-benzylideneaniline. The PMDTA complex 2 c underwent C-H bond activation in acetonitrile to give a dinuclear µ-κC,κN-cyanomethyl zinc complex [(PMDTA)Zn(CH2CN)]2[BAr4 F]2 (6 c).

Metal Activation Produces Different Reaction Environments for Intermediates during Oxidative Addition.

Commercial zinc metal powder requires activation for consistent and reliable use as a reductant in the formation of organozinc reagents from organohalides, and for the avoidance of supplier and batch-to-batch variability. However, the impact of activation methods on the reaction environments of subsequent intermediates has been unknown. Herein, a fluorescence lifetime imaging microscopy (FLIM) method is developed to bridge this knowledge gap, by imaging and examining reaction intermediates on zinc metal that has been activated by pretreatment through different common methods (i. e., by chemical activation with TMSCl, dibromoethane, or HCl; or by mechanical activation). The group of chemical activating agents, previously thought to act similarly by removing oxide layers, are here shown to produce markedly different reaction environments experienced by subsequent oxidative-addition intermediates from organohalides - data uniquely available through FLIM's ability to detect small quantities of intermediates in situ coupled with its microenvironmental sensitivity. These different microenvironments potentially give rise to different rates of formation, subsequent solubilization, and reactivity, despite the shared "[RZnX]" molecular structure of these intermediates. This information revises models for methods development for oxidative addition to currently sluggish metals beyond zinc by establishing diverse outcomes for pretreatment activation methods that were previously considered similar.

Early Organic Chemistry in Kyiv: Serhii Mykolayovych Reformatskyi (1860-1934) and his Name Reaction.

Serhiy Mykolayovych Reformatskyi, [Ukrainian: Рeφopмaтcьκий, Cepгiй Mиκoлaйoвич; Russian: Sergei Nikolaevich Reformatskii, РeΦopмaтcκий, Cepгeй Hиκoлaeвич (1860-1934)] was a product of Zaitsev's laboratory in Kazan Imperial University in Russia and one of the founding fathers of organic chemistry in Ukraine. He discovered his eponymous reaction while a graduate student in Kazan under Zaitsev, studying the synthesis of homoallylic alcohols. He modified this reaction by replacing the olefinic π bond of an allyl halide with a carbonyl group. In the prototype reaction, he treated ethyl haloacetates with zinc and aldehydes or ketones. The reaction gave the corresponding ß-hydroxyesters and remains an important synthetic method. Work on the reaction over the ensuing century and a quarter has led to the discovery of analogous reactions using a wide range of metals, and even permitting the use of water as a solvent.

Trimethylsilyl Chloride Aids in Solubilization of Oxidative Addition Intermediates from Zinc Metal.

Trimethylsilyl chloride (TMSCl) is commonly used to "activate" metal(0) powders toward oxidative addition of organohalides, but knowledge of its mechanism remains limited by the inability to characterize chemical intermediates under reaction conditions. Here, fluorescence lifetime imaging microscopy (FLIM) overcomes these prior limitations and shows that TMSCl aids in solubilization of the organozinc intermediate from zinc(0) metal after oxidative addition, a previously unknown mechanistic role. This mechanistic role is in contrast to previously known roles for TMSCl before the oxidative addition step. To achieve this understanding, FLIM, a tool traditionally used in biology, is developed to characterize intermediates during a chemical reaction-thus revealing mechanistic steps that are unobservable without fluorescence lifetime data. These findings impact organometallic reagent synthesis and catalysis by providing a previously uncharacterized mechanistic role for a widely used activating agent, an understanding of which is suitable for revising activation models and for developing strategies to activate currently unreactive metals.

Atroposelective NiII -Catalyzed Cross-Coupling Reactions Enable a Deeper Understanding of Negishi Couplings: Isolation and Application of Solid Aryl Higher-Order Zincates.

The Negishi cross-coupling reactions involves the application of organozinc reagents and is a highly versatile reaction in synthetic organic chemistry. The transmetallation step plays a pivotal role in the mechanism of these types of cross-coupling reactions. In this study, mechanistic investigations are presented indicating that higher-order zincates are the transmetallating active species in Pd- and Ni-catalyzed Negishi cross-coupling reactions. These findings are supported by halide salt addition experiments and by obtaining a single X-ray crystal structure of the solid monoaryl higher-order zincate [1-NaphthylZnX3 ]2- Mg(THF)2 2+ . The procedure developed in this work was further applied to the synthesis of various monoaryl higher-order zincates, after which their synthetic usefulness in terms of high reactivity towards transmetallation in Negishi cross-couplings, as well as stability, was exemplified in several reactions.

Transition-Metal Free Electrophilic Aminations of Polyfunctional O-2,4,6-Trimethylbenzoyl Hydroxylamines with Zinc and Magnesium Organometallics.

We reported a new electrophilic amination of various primary, secondary and tertiary alkyl, benzylic, allylic zinc and magnesium organometallics with O-2,4,6-trimethylbenzoyl hydroxylamines (O-TBHAs) in 52-99 % yield. These O-TBHAs displayed an excellent long-term stability and were readily prepared from various highly functionalized secondary amines via a convenient 3 step procedure. The amination reactions showed remarkable chemoselectivity proceeding without any transition-metal catalyst and were usually complete after 1-3 h reaction time at 25 °C. Furthermore, this electrophilic amination also provided access to enantioenriched tertiary amines (up to 88 % ee) by using optically enriched secondary alkylmagnesium reagents of the type s-AlkylMgCH2 SiMe3 .

Study on Flame Retardancy Behavior of Epoxy Resin with Phosphaphenanthrene Triazine Compound and Organic Zinc Complexes Based on Phosphonitrile.

A novel flame retardant phosphorus-containing organozinc complex (Zn-PDH) was prepared using zinc and iron as the metal center and 4-aminopyridine, with low steric hindrance, as the organic ligand, then using phosphazene to modify the organometallic complex (Zn-4APD). The flame retardant properties and mechanism of Zn-PDH/Tris-(3-DOPO-1-propyl)-triazinetrione (TAD) in epoxy resin (EP) were investigated. Flame inhibition behavior was studied by the vertical combustion test (UL94), while limiting oxygen index (LOI) measurement and flame retardant properties were studied by the cone calorimeter test (CONE). The flame retardant modes of action were explored by using the thermogravimetry-Fourier transform infrared (TG-FTIR) test, X-ray photoelectron spectrometer (XPS), and Raman spectroscopy (LRS). When TAD and Zn-PDH were added to the epoxy resin in the ratio of 3:1, the system achieved a balance between the gas-phase and condense-phase actions of the flame retardant effects, and the 3%TAD/1%Zn-PDH/EP composite system achieved not only good flame inhibition but also obtained good smoke and heat suppression performance, showing a comprehensive flame retardant performance. The gas phase and Zn-PDH mostly promoted charring with a barrier and protective effect in the condensed phase. As for the mechanism, TAD released the phosphorus-containing radicals and phenoxy radicals during decomposition and mainly exerted a gas-phase quenching effect. While in the condense phase, Zn-PDH promoted the decomposition of the polymer matrix to produce more aromatic structures and rapidly formed a complete and dense carbon layer rich in P-O-C crosslinked structures at high temperatures. Meanwhile, more N entered the gas phase in the form of inert gas, which diluted the concentration of the combustible fuel and helped to inhibit the combustion reaction.

Catalyst-Free Formal Conjugate Addition/Aldol or Mannich Multicomponent Reactions of Mixed Aliphatic Organozinc Reagents, π-Electrophiles and Michael Acceptors.

Catalyst-free multicomponent reactions of mixed alkylzinc reagents with Michael acceptors and aldehydes, ketones or activated imines are described. Primary, secondary and tertiary alkylzinc reagents, pre-generated in acetonitrile from the corresponding iodoalkanes, were used in the process, leading to the very efficient formation of a variety of ß-hydroxycarbonyl compounds. The imines showed more contrasting results, due to the direct addition of the organozinc compound to the C=N bond. Mechanistic assays involving TEMPO account for a polar instead of a radical character of the reaction.

3,3-Difluoroallyl Sulfonium Salts: Practical and Bench-Stable Reagents for Highly Regioselective gem-Difluoroallylations.

The site-selective introduction of the difluoromethylene group into organic molecules has important applications in producing pharmaceuticals and agrochemicals. However, the general and efficient methods that can construct both C(sp2 )-CF2 R and C(sp3 )-CF2 R bonds remain challenging. Here, we disclose a new type of practical and bench-stable difluoroalkylating reagent 3,3-difluoroallyl sulfonium salt (DFAS) that can be practically prepared from inexpensive and bulk chemical feedstock 3,3,3-trifluoropropene. This reagent allows highly regioselective gem-difluoroallylation of various organozinc reagents, including aryl, primary, secondary, and tertiary alkyl zinc reagents, via copper catalysis under mild reaction conditions with high efficiency. The reaction can also be extended to a series of substituted DFASs. Application of the approach leads to the short synthesis of complex analogs, showing the prospect of DFASs in medicinal chemistry.

Mechanochemical Pd-Catalyzed Cross-Coupling of Arylhalides and Organozinc Pivalates.

Cross-coupling reactions are essential tools in target molecule synthesis. However, the use of highly reactive organometallic reagents limits their applicability. Here, we present a mechanochemical Pd-catalyzed cross-coupling reaction between aryl halides and organozinc pivalates that can be carried out under ambient temperature and atmosphere. This operationally simple procedure affords a wide range of biaryl and aryl-heteroaryl derivatives in high yields and short times. The reaction tolerates various functional groups and can be realized on a synthetically useful scale. Its practical value was demonstrated in the short synthesis of the pharmaceutical diflunisal.

Recent Advances to Mediate Reductive Processes of Nitroarenes Using Single-Electron Transfer, Organomagnesium, or Organozinc Reagents.

Recent advances in the development of reductive reactions of nitroarenes using organomagnesium-, organozinc-, and single electron transfer reagents is discussed within this review. The review is divided into the following sections: IntroductionOrganomagnesium-mediated reductive reactionsOrganozinc- and zinc-mediated reductive reactionsIodine-catalyzed redox cyclizationsTitanium(III)-mediated reductive cyclizationsSulfur-mediated reductive reactionsAlkoxide-mediated reductive reactions4,4'-Bipyridine-mediated reductive reactionsVisible light-driven reductive amination reactionsElectrochemical reductive reactionsConclusion.

From a Well-Defined Organozinc Precursor to Diverse Luminescent Coordination Polymers Based on Zn(II)-Quinolinate Building Units Interconnected by Mixed Ligand Systems.

Introduction of photoactive building blocks into mixed-ligand coordination polymers appears to be a promising way to produce new advanced luminescent materials. However, rational design and self-assembly of the multi-component supramolecular systems is challenging from both a conceptual and synthetic perspective. Here, we report exploratory studies that investigate the potential of [Zn(q)2]2[tBuZn(OH)]2 complex (q = deprotonated 8-hydroxyquinoline) as an organozinc precursor as well as a mixed-ligand synthetic strategy for the preparation of new luminescent coordination polymers (CPs). As a result we present three new 2D mixed-ligand Zn(II)-quinolinate coordination polymers which are based on various zinc quinolinate secondary building units interconnected by two different organic linker types, i.e., deprotonated 4,4'-oxybisbenzoic acid (H2obc) as a flexible dicarboxylate linker and/or selected bipyridines (bipy). Remarkably, using the title organozinc precursors in a combination with H2obc and 4,4'-bipyridine, a novel molecular zinc quinolinate building unit, [Zn4(q)6(bipy)2(obc)2], was obtained which self-assembled into a chain-type hydrogen-bonded network. The application of the organometallic precursor allowed for its direct reaction with the selected ligands at ambient temperature, avoiding the use of both solvothermal conditions and additional base reagents. In turn, the reaction involving Zn(NO3)2, as a classical inorganic precursor, in a combination with H2obc and bipy led to a novel 1D coordination polymer [Zn2(q)2(NO3)2(bipy)]. While the presence of H2obc was essential for the formation of this coordination polymer, this ditopic linker was not incorporated into the isolated product, which indicates its templating behavior. The reported compounds were characterized by single-crystal and powder X-ray diffraction, elemental analysis as well as UV-Vis and photoluminescence spectroscopy.

Asymmetric Allylation Catalyzed by Chiral Phosphoric Acids: Stereoselective Synthesis of Tertiary Alcohols and a Reagent-Based Switch in Stereopreference.

The substrate scope of the asymmetric allylation with zinc organyls catalyzed by 3,3-bis(2,4,6-triisopropylphenyl)-1,1-binaphthyl-2,2-diyl hydrogenphosphate (TRIP) has been extended to non-cyclic ester organozinc reagents and ketones. Tertiary chiral alcohols are obtained with ee's up to 94% and two stereogenic centers can be created. Compared to the previous lactone reagent the stereopreference switches almost completely, proving the fact that the nature of the organometallic compound is of immense importance for the asymmetry of the product.

Chloroalkene dipeptide isosteres as peptidomimetics.

To date various biologically active peptides have been discovered, characterized and modified for drug discovery. However, the utilization of peptides as therapeutics involves some limitation due to several factors, including low metabolic stability owing to proteolysis and non-specific interactions with multiple off-target molecules. Hence, the development of "peptidomimetics," in which a part or whole of a molecule is modified, is a desirable strategy to enhance the stability or bioactivity of peptide-based drugs. In this situation, we have designed and developed a synthetic method for chloroalkene dipeptide isosteres (CADIs), which involves replacement of an amide bond in peptides with a chloroalkene structure and are classified as peptidomimetics. By a developed synthetic method, an N-tert-butylsulfonyl protected CADI can be obtained utilizing diastereoselective allylic alkylation with organocopper reagents as a key reaction. This CADI can be transformed into an N-fluorenylmethoxycarbonyl protected CADI in short steps. In addition, CADIs are used in Fmoc-based solid-phase peptide synthesis and introduced into a bioactive peptide. Protocols for practical preparation of some CADIs and peptide mimetics containing a CADI are described as detailed recipes.

Scalable Negishi Coupling between Organozinc Compounds and (Hetero)Aryl Bromides under Aerobic Conditions when using Bulk Water or Deep Eutectic Solvents with no Additional Ligands.

Pd-catalyzed Negishi cross-coupling reactions between organozinc compounds and (hetero)aryl bromides have been reported when using bulk water as the reaction medium in the presence of NaCl or the biodegradable choline chloride/urea eutectic mixture. Both C(sp3 )-C(sp2 ) and C(sp2 )-C(sp2 ) couplings have been found to proceed smoothly, with high chemoselectivity, under mild conditions (room temperature or 60 °C) in air, and in competition with protonolysis. Additional benefits include very short reaction times (20 s), good to excellent yields (up to 98 %), wide substrate scope, and the tolerance of a variety of functional groups. The proposed novel protocol is scalable, and the practicability of the method is further highlighted by an easy recycling of both the catalyst and the eutectic mixture or water.

Transition-Metal-Free Synthesis of Polyfunctional Triarylmethanes and 1,1-Diarylalkanes by Sequential Cross-Coupling of Benzal Diacetates with Organozinc Reagents.

A variety of functionalized triarylmethane and 1,1-diarylalkane derivatives were prepared via a transition-metal-free, one-pot and two-step procedure, involving the reaction of various benzal diacetates with organozinc reagents. A sequential cross-coupling is enabled by changing the solvent from THF to toluene, and a two-step SN 1-type mechanism was proposed and evidenced by experimental studies. The synthetic utility of the method is further demonstrated by the synthesis of several biologically relevant molecules, such as an anti-tuberculosis agent, an anti-breast cancer agent, a precursor of a sphingosine-1-phosphate (S1P) receptor modulator, and a FLAP inhibitor.

Salt to Taste: The Critical Roles Played by Inorganic Salts in Organozinc Formation and in the Negishi Reaction.

The first cross-coupling of organozinc nucleophiles with aryl halides was reported in 1977 by Negishi. Unknown to all at the time was the importance of salt additives that were often present as a byproduct from the organozinc preparation. For decades, these salt additives were overlooked until 2006 when it was discovered that two different, yet effective methods for preparing organozinc solutions (i.e. one with salt and one without) provided drastically different results. Since this finding, the exact role of salt additives in cross-coupling has been debated in the catalysis community. In this Review we highlight all the major discoveries regarding the influence of salt additives on the formation of organozinc reagents and their use in the Negishi reaction. These effects include solubilizing key intermediates, the formation of higher-order zincates, product inhibition, catalyst protection, and solvent effects.

Chiral N-tert-Butylsulfinyl Imines: New Discoveries.

In this account the reactions of chiral N-tert-butylsulfinyl imines with organometallic reagents such as organoalkaline (lithium, sodium, potassium and cesium derivatives), organomagnesium, organozinc, organoboron, organoaluminium, organoindium and organosilicon compounds is comprehensively described. The reactivity in all cases is derived to synthetic applications in order to prepare interesting organic nitrogenated molecules, especially in the field of alkaloid compounds.

Mechanism of an Elusive Solvent Effect in Organozinc Reagent Synthesis.

Solvent effects are often difficult to understand in cases where reaction intermediates, and thus their differential behavior in different solvents, are not directly observable by traditional ensemble analytical techniques. Herein, the sensitivity of single-particle fluorescence microscopy uniquely enables direct observation of organozinc intermediates and solvent effects on their build-up and persistence. When combined with NMR spectroscopy, these imaging data pinpoint the previously elusive mechanistic origin of solvent effects in the synthesis of widely used organozinc reagents. These findings characterize the acceleration of oxidative addition of the starting organoiodide to the surface of zinc metal in DMSO relative to THF, but once formed, surface intermediates display similar persistence in either solvent. The current studies are the first demonstration of a highly sensitive, single-particle fluorescence microscopy technique to pinpoint otherwise elusive solvent effects in synthetic chemistry.