Common Electrophiles Research Articles

Reactivity of an Iron Carbonyl Dianion Dictated by a Lewis Basic Appendant

AbstractStudies toward transition metals in negative oxidation states are much less explored compared to those in zero or positive oxidation states. In this study, we present the synthesis and reactivity studies of an Fe(‐II) carbonyl dianion (3) featuring an appended Lewis base, [(L)Fe(CO)3]2− (L=Ph2PCH2CH2NMe2). Unlike the well‐known reactivity of [Fe(CO)4]2− with common electrophiles (E+) which typically forms [(E)2Fe(CO)4], 3 reacted with 2 equiv. of Ph3SnCl to afford a mixture of two products: one being an Fe(II) bis(triphenylstannyl) product (4), and the other an Fe stannylene product (5). Further insights into the reactivity of 3 was elucidated through its reactions with 2 equiv. of Cy3SnCl or Me3SiCl, producing an Fe(II) bis(tricyclohexylstannyl) product (8) and a zwitterionic complex (11), respectively, the latter emerging via THF ring‐opening. Intermediates generated from reactions of 3 with 1 equiv. of each electrophile were isolated to shed light on the reaction mechanisms, highlighting the influence of appended Lewis base on the reactivity of metal carbonyl dianions, especially the generation of the novel stannylene complex 5. The electronic structure of this paramagnetic stannylene complex was also investigated by computational studies.

Achiral Hydroxypyruvaldehyde Phosphate as a Platform for Multi-Aldolases Cascade Synthesis of Diuloses and for a Quadruple Acetaldehyde Addition Catalyzed by 2-Deoxyribose-5-Phosphate Aldolases

The 1,4-dicarbonyl unit is found in numerous molecules of biological interest, many of which are also polyhydroxylated. We developed a general, one-pot, multistep, stereoselective enzymatic method to prepare diuloses of structural diversity from achiral hydroxypyruvaldehyde phosphate (HPP) as the common electrophile for various aldolases. Surprisingly, for 2-deoxyribose-5-phosphate aldolases, HPP was an acceptor of choice for the multiple addition of acetaldehyde, widening the scope of longer-chain aldol adducts.

Nucleophile induced ligand rearrangement reactions of alkoxy- and arylsilanes

The ligand-redistribution reactions of aryl- and alkoxy-hydrosilanes can potentially cause the formation of gaseous hydrosilanes, which are flammable and pyrophoric. The ability of generic nucleophiles to initiate the ligand-redistribution reaction of commonly used hydrosilane reagents was investigated, alongside methods to hinder and halt the formation of hazardous hydrosilanes. Our results show that the ligand-redistribution reaction can be completely inhibited by common electrophiles and first-row transition metal pre-catalysts.

Development of Versatile Sulfone Electrophiles for Suzuki–Miyaura Cross-Coupling Reactions

The development of fluorinated sulfone derivatives as versatile electrophiles for Suzuki–Miyaura cross-coupling reactions is described. Introducing electron-withdrawing groups on the aryl ring of the sulfone facilitates the Pd-catalyzed activation of C–SO2 bonds. Cross-coupling reactions with fluorinated sulfone electrophiles are reported, leading to a variety of multiply arylated products in good yields. The reactivity of this unusual electrophile is benchmarked versus common electrophiles and its use in iterative cross-couplings for concise synthesis of biologically active molecules is described.

Aryl fluorosulfonates set new electrophile standard

Palladium-catalyzed amination in which an aryl halide or aryl triflate electrophile is coupled with an aryl or alkyl amine is one of the most popular reactions in organic chemistry. Streamlining this fundamental chemistry is hard to do, yet Patrick S. Hanley and coworkers at Dow Chemical have reported a breakthrough by developing an in situ method for generating aryl fluorosulfonates as alternative electrophiles in aminations (ACS Catal. 2016, DOI: 10.1021/acscatal.6b00865). The Dow team and other research groups previously reported using premade aryl fluorosulfonates for Suzuki couplings with aryl boronates. But the team’s one-pot amination method goes further. The researchers treated phenols with sulfuryl fluoride and a base at room temperature followed by addition of an amine coupling partner to create amination products. They found that aryl fluorosulfonates outperform other common electrophiles. In addition, the phenols can be sourced from biobased materials that are less expensive and more sustainab...

ChemInform Abstract: Lewis Acid‐Mediated β‐Selective Hydrocarboxylation of α,α‐Diaryl‐ and α‐Arylalkenes with R3SiH and CO2.

Abstract α,α-Diarylalkenes are successfully hydrocarboxylated with Et3SiH and CO2 with the aid of Et3SiB(C6F5)4 or EtAlCl2/Ph3SiCl to give carboxylic acids with a carboxy group at the β-position to the aryl groups. The EtAlCl2/Ph3SiCl-mediated reaction is also applicable to various α-arylalkenes. 1H NMR analysis of a mixture of EtAlCl2, Ph3SiCl, and Et3SiH strongly suggests the formation of a μ-H complex, [Ph3Si–H–SiEt3]+ AlEtCl3−, which is an equivalent of R3Si+ ions, while Et3SiB(C6F5)4 is an ion pair with a Et3Si+ ion. Therefore, in these reaction systems, a siloxycarbonylium, R3Si O C O+, is considered to be a common electrophile, the addition of which to the substrate, followed by trapping of the resulting cationic species with Et3SiH seems to afford the desired acid after aqueous workup.

ChemInform Abstract: Terminal Ynamides: Synthesis, Coupling Reactions, and Additions to Common Electrophiles

AbstractReview: [45 refs.

Lewis acid-mediated β-selective hydrocarboxylation of α,α-diaryl- and α-arylalkenes with R3SiH and CO2

α,α-Diarylalkenes are successfully hydrocarboxylated with Et3SiH and CO2 with the aid of Et3SiB(C6F5)4 or EtAlCl2/Ph3SiCl to give carboxylic acids with a carboxy group at the β-position to the aryl groups. The EtAlCl2/Ph3SiCl-mediated reaction is also applicable to various α-arylalkenes. 1H NMR analysis of a mixture of EtAlCl2, Ph3SiCl, and Et3SiH strongly suggests the formation of a μ-H complex, [Ph3Si–H–SiEt3]+ AlEtCl3−, which is an equivalent of R3Si+ ions, while Et3SiB(C6F5)4 is an ion pair with a Et3Si+ ion. Therefore, in these reaction systems, a siloxycarbonylium, R3SiOCO+, is considered to be a common electrophile, the addition of which to the substrate, followed by trapping of the resulting cationic species with Et3SiH seems to afford the desired acid after aqueous workup.

M‐Metallaphenol: Synthesis and Reactivity Studies

Treatment of the osmium complex [Os{CHC-(PPh3 )CH(OH)-η(2) -C≡CH}(PPh3 )2 (NCS)2 ] (1) with excess triethylamine produces the first m-metallaphenol complex [Os{CHC(PPh3 )CHC(OH)CH}(PPh3 )2 (NCS)2 ] (2). The NMR spectroscopic and structural data as well as the nucleus-independent chemical-shift (NICS) values suggest that osmaphenol 2 has aromatic character. The reactivity studies demonstrate that 2 can react with different isocyanates to form the annulation reaction products [Os{CHC(PPh3 )CHC(OCONR)C}(PPh3 )2 (NCS)2 ] (R=Ph (3), iPr (7), Bn (8)) via the carbamate intermediates [Os{CHC(PPh3 )CHC(O-CONHR)CH}(PPh3 )2 (NCS)2 ] (R=Ph (4), iPr (5), Bn (6)). In addition, the similar annulation reactions can be extended to other unsaturated compounds containing N-C multiple bonds, for example, isothiocyanates, pyridine, and sodium thiocyanate, which can produce the corresponding fused osmabenzene complexes. In contrast, the reactions of 2 with common electrophiles, such as NOBF4 , NO2 BF4 , N-bromosuccinimide, and N-chlorosuccinimide only led to the decomposition of the metallaphenol ring. The experimental results suggest that 2 is very electrophilic and readily reacts with nucleophiles, which is mainly due to the metal center and the strong electron-withdrawing phosphonium group.

Amidinate Salt of Hexafluoroacetone Hydrate for the Preparation of Fluorinated Compounds by the Release of Trifluoroacetate

A powerful, new reagent, an amidinate salt of hexafluoroacetone hydrate, is an air-stable salt that can be used for the preparation of fluorinated organic molecules. Nucleophilic trifluoromethylation reactions are demonstrated following the base-promoted release of trifluoroacetate. This reagent is soluble in many polar organic solvents and produces fluoroform, following the release of trifluoroacetate. Reactions with this reagent and common electrophiles provide excellent yields of trifluoromethylated products.

Mitochondria as a source and target of lipid peroxidation products in healthy and diseased heart

The heart is a highly oxidative organ in which cardiomyocyte turnover is virtually absent, making it particularly vulnerable to accumulation of lipid peroxidation products (LPP) formed as a result of oxidative damage. Reactive oxygen and nitrogen species are the most common electrophiles formed during lipid peroxidation and lead to the formation of both stable and unstable LPP. Of the LPP formed, highly reactive aldehydes are a well-recognized causative factor in ageing and age-associated diseases, including cardiovascular disease and diabetes. Recent studies have identified that the mitochondria are both a primary source and target of LPP, with specific emphasis on aldehydes in cardiomyocytes and how these affect the electron transport system and Ca(2+) balance. Numerous studies have found that there are functional consequences in the heart following exposure to specific aldehydes (acrolein, trans-2-hexanal, 4-hydroxynonenal and acetaldehyde). Because these LPP are known to form in heart failure, cardiac ischaemia-reperfusion injury and diabetes, they may have an underappreciated role in the pathophysiology of these disease processes. Lipid peroxidation products are involved in the transcriptional regulation of endogenous anti-oxidant systems. Recent evidence demonstrates that transient increases in LPP may be beneficial in cardioprotection by contributing to mitohormesis (i.e. induction of anti-oxidant systems) in cardiomyocytes. Thus, exploitation of the cardioprotective actions of the LPP may represent a novel therapeutic strategy for future treatment of heart disease.

Signaling pathways involved in phase II gene induction by α, β-unsaturated aldehydes

Phase II enzymes are induced primarily through the common electrophile response element (EpRE) signaling. Studies performed in different cell types and with different inducer appear to indicate variation in the upstream signaling pathways involved in the induction of these phase II genes. Nonetheless, whether variation in signaling among phase II genes in the same cell with the same inducer is unclear. This study is designed to answer this question using human bronchial epithelial cells (HBE1 cells) as a model and screening with a variety of protein kinase inhibitors with varying degrees of specificity. Two electrophiles, 4-hydroxynonenal (HNE) and acrolein, induced the expression of phase II genes (GCLC, GCLM, NQO1, NQO2, HO-1, and GSTM-1). Nrf2 silencing significantly decreased the induction of all of these genes, confirming the involvement of Nrf2-EpRE signaling. ERK and p38MAPK inhibitors had no effect, while a JNK inhibitor abrogated the GCLC and GCLM induction by HNE, but not that by acrolein. Among the PKC inhibitors used, one eliminated gene induction by HNE and acrolein, while two others showed no effects. One PI3K inhibitor decreased the induction of GCLM, NQO1, NQO2 and HO-1, but not GCLC and GST-M1; on the other hand, the inhibitory effects of another PI3K inhibitor on gene induction seems to be gene- and inducer- specific. In conclusion, our data suggest that although phase II genes are coordinately induced through Nrf2-EpRE signaling by electrophiles, the upstream signaling pathways involved are gene- and inducer- specific. It is also suggested that commercial kinase inhibitors may produce non-specific effects on phase II gene expression via mechanisms unrelated to their purported specificity.

Carbocupration−Functionalization of Arynes: Rapid Access to Variably Ortho-Substituted ((E)-3-Phenylprop-1-enyl)silanes

A consecutive three-component coupling reaction involving a lithium di[3-(prop-1-enyltrimethylsilyl)]cuprate, variably substituted ortho-arynes, and a selection of common electrophiles is described. The method affords readily functionalized homobenzylic vinylsilanes with exceptional E-diastereoselectivity and allows for in situ incorporation of carbon- or heteroatom-based electrophiles into the arene.

Electrophilic Aromatic Substitution. 13.(1) Kinetics and Spectroscopy of the Chloromethylation of Benzene and Toluene with Methoxyacetyl Chloride or Chloromethyl Methyl Ether and Aluminum Chloride in Nitromethane or Tin Tetrachloride in Dichloromethane. The Methoxymethyl Cation as a Remarkably Selective Common Electrophile.

Vacuum line kinetics studies have been made of the reaction in nitromethane between benzene and/or toluene, methoxyacetyl chloride (MAC), and AlCl(3) to produce benzyl or xylyl chlorides, CO, and a CH(3)OH(-)AlCl(3) complex. For both arenes, the rate law appears to be R = (k(3)/[AlCl(3)](0)) [AlCl(3)](2)[MAC]. When chloromethyl methyl ether (CMME) is substituted for MAC, a similar rate law is obtained. Both chloromethylation reactions yielded similar, large k(T)()/k(B)() ratios (500-600) and similar product isomer distributions with low meta percentages ( approximately 0.4) which suggest CH(3)OCH(2)(+) or the CH(3)OCH(2)(+)Al(2)Cl(7)(-) ion pair as a common, remarkably selective, electrophile. The kinetics of MAC decomposition to CMME and CO in the presence of AlCl(3) yielded the rate law R = k(2)[AlCl(3)](0)[MAC]. Here AlCl(3) is a catalyst (no CH(3)OH is formed), and thus the rate law is equivalent to the chloromethylation rate law. All three reactions have comparable reactivities, which is consistent with rate-determining production of the electrophile. Kinetics studies of benzene or toluene with SnCl(4) and MAC or CMME in dichloromethane were also completed. With MAC and benzene the rate law is R = k(3)[SnCl(4)](0)[MAC][benzene] and with toluene R = k(2)[SnCl(4)](0)[MAC]. MAC decomposition, again followed by CO production, was unaffected by the presence of either aromatic and obeyed the rate law R = k(2)' [SnCl(4)](0)[MAC] where k(2) approximately k(2)'. Chloromethylation with CMME followed the rate law R = k(3)[SnCl(4)](0)[CMME][arene] for benzene and toluene and produced a k(T)()/k(B)() ratio and product isomer distributions very similar to those determined with AlCl(3) in nitromethane, further supporting a common electrophile. Low-temperature (13)C and (119)Sn FT-NMR and Raman spectroscopic studies suggest the existence of a weak 1:1 adduct between MAC and SnCl(4) of the type RCXO --> SnCl(4), with electron donation to the metal through carboxy oxygen. Finally, an explanation is provided for the range of chloromethylation k(T)()/k(B)() values and product isomer percentages published in the literature.

Regioselective C-3 Alkylations of Oxindole Dianion

Abstract Oxindole is converted to its dianion by treatment with two equivalents each of n-BuLi and TMEDA. Alkylations with a number of common electrophiles define the scope of synthetically useful transformations leading to 3-monosubstituted and 3,3-disubstituted oxindoles.

The reactions of some common electrophiles, CH3 +, NO+, NO2 +, and O2NCH2 +, with monosubstituted benzenes in the gas phase

The reactions of CH3+, NO+, NO2+, and O2NCH2+ with monosubstituted benzenes (C6H5X where X = H, F, Cl, CF3, CH3, and CH3O) have been studied in the gas phase using a triple quadrupole mass spectrometer. Charge-exchange is the predominant process for all the ions with all the substituted benzenes. No adducts of the Wheland intermediate type were detected as major products but disproportionation products were observed with three of the primary ions [reactions (i)–(iii)]. In addition there were minor processes particular to one substituent with, CH3++ C6H5X → C7H6X (or C7H7)+ H2(or HX)(i) NO2++ C6H5X → C6H5XO+˙+ NO (ii) O2NCH2++ C6H5X → C6H5XNO++ CH2O (iii) one primary ion. The relevance of these gas-phase studies to the interpretation of solution-phase aromatic substitution is briefly discussed.