Powerful Electrophile Research Articles

Role of Cinchona Alkaloids in the Enantio- and Diastereoselective Synthesis of Axially Chiral Compounds.

ConspectusAsymmetric synthesis using organic catalysts has evolved since it was first realized and defined. Nowadays, it can be considered a valid alternative to transition metal catalysis for synthesizing chiral molecules. According to the literature, the number of asymmetric organocatalytic processes associated with atropisomer synthesis has rapidly increased over the past 10 years because organocatalysis addresses the challenges posed by the most widespread strategies used for preparing axially chiral molecules with satisfactory results.These strategies, useful to prepare a wide range of C-C, C-heteroatom, and N-N atropisomers, vary from kinetic resolution to direct arylation, desymmetrization, and central-to-axial chirality conversion. In this field, our contribution focuses on determining novel methods for synthesizing atropisomers, during which, in most cases, the construction of one or more stereogenic centers other than the stereogenic axis occurred. To efficiently address this challenge, we exploited the ability of catalysts based on a cinchona alkaloid scaffold to realize enantioselective organic transformations. Desymmetrization of N-(2-tert-butylphenyl) maleimides was one of the first strategies that we pursued for preparing C-N atropisomers. The main principle is based on the presence of a rotationally hindered C-N single bond owing to the presence of a large tert-butyl group. Following the peculiar reactivity of this type of substrate as a powerful electrophile and dienophile, we realized several transformations.First, we investigated the vinylogous Michael addition of 3-substituted cyclohexenones, where a stereogenic axis and two contiguous stereocenters were concomitantly and remotely formed and stereocontrolled using a primary amine catalyst. Subsequently, we realized desymmetrization via an organocatalytic Diels-Alder reaction of activated unsaturated ketones that enabled highly atropselective transformation with efficient diastereoselectivity, thereby simultaneously controlling four stereogenic elements. Employing chiral organic bases allowed us to realize efficient desymmetrizations using carbon nucleophiles, such as 1,3-dicarbonyl compounds, cyanoacetates, and oxindoles. These reactions, performed with different types of catalysts, highlighted the versatility of organocatalysis as a powerful strategy for atropselective desymmetrization of pro-axially chiral maleimides.Hereafter, we studied the Friedel-Crafts alkylation of naphthols with indenones, a powerful method for enantioselective synthesis of conformationally restricted diastereoisomeric indanones. We realized the first axially chiral selective Knoevenagel condensation using cinchona alkaloid primary amine as the catalyst. This reaction provided a powerful method to access enantioenriched olefins containing the oxindole core. Subsequently, we initiated an intense program for the computational investigation of the reaction mechanism of our atropselective processes. An understanding of the catalytic activity for vinylogous atropselective desymmetrization as well as of the role played by the acidic cocatalyst used for the experimental work was achieved.Recently, we have garnered interest in the novel frontiers of atropselective synthesis. As observed in recent publications, there is considerable interest in the development of methods for preparing N-N atropisomers, an emerging topic in the field of atropselective synthesis. We focused on the synthesis of hydrazide atropisomers by developing a one-pot sequential catalysis protocol based on two sequential organocatalytic reactions that provided high stereocontrol of two contiguous stereogenic elements.

Novel Electrophilic Warhead Targeting a Triple-Negative Breast Cancer Driver in Live Cells Revealed by "Inverse Drug Discovery".

The "inverse drug discovery" strategy is a potent means of exploring the cellular targets of latent electrophiles not typically used in medicinal chemistry. Cyclopropenone, a powerful electrophile, is generally used in bio-orthogonal reactions mediated by triarylphosphine or in photo-triggered cycloaddition reactions. Here, we have studied, for the first time, the proteome reactivity of cyclopropenones in live cells and discovered that the cyclopropenone warhead can specifically and efficiently modify a triple-negative breast cancer driver, glutathione S-transferase pi-1 (GSTP1), by covalently binding at the catalytic active site. Further structure optimization and signaling pathway validation have led to the discovery of potent inhibitors of GSTP1.

A 3D electropolymerized thin film based on an isoporphyrin and on a pyridine end-decorated molybdenum(II) halide cluster: Photoelectrochemical and impedance properties

Herein, the first example of formation of a 3D hybrid organic-inorganic copolymer based on an isoporphyrin and on a pyridine end-decorated molybdenum(II) halide cluster. The isoporphyrin copolymer thin film was obtained by electropolymerization of zinc-5,15-bis(p-tolyl)porphyrin in the presence of polyiodometalate with 6 pendant pyridyl ligands (((Bu4N)2[{Mo6I8}(OOC-C5H4N)6]). Electrogenerated porphyrin radical cation is a powerful electrophile which can rapidly react with the pyridine end-decorated Mo(II) halide cluster as nucleophile to form 3D copolymer containing stable isoporphyrin.The electropolymerization was monitored by electrochemical quartz crystal microbalance (EQCM). The copolymer was characterized by UV-Vis-NIR spectroscopy, X-ray photoelectron spectroscopy (XPS), electrochemistry, and atomic force microscopy (AFM). The existence of the radical of the isoporphyrin copolymer was proved by electron spin resonance spectroscopy (EPR).Interestingly, the UV-Vis-NIR spectra of the copolymer exhibited broadening and splitting of the Soret band as well as one additional band in the NIR between 750 nm and 1000 nm.The photoelectrochemical properties have been studied by electrochemical impedance spectroscopy and by photocurrent transient measurements under visible-NIR light irradiation.The 3D copolymer containing stable isoporphyrin radical exhibits interesting photocurrent response even under only NIR illumination.In the solid state, the 3D copolymer could be stored for over several months and even one year without any degradation under ambient conditions in air.

Ninhydrin Adducts as Valid Synthon in Organic Synthesis: A Review

AbstractNinhydrin (1,2,3‐indanetrione hydrate) is a powerful electrophile having enormousapplications in organic and bio‐organic sciences. In the last few years, reactivity of various ninhydrin adducts have been exploited extensively for the development of diverse organic scaffolds. The present review focuses on the applications of readily accessible ninhydrin adducts as building block towards the synthesis of a variety of compounds including N‐inserted compounds, spiro‐heterocycles, medium ring compounds, polycyclic molecules, propellanes, cycloadducts, allylic anions, axially chiral molecules etc. Interestingly, some of the compounds have profound biological activities and a few display important photophysical properties. Most of the reactions described here are simple and carried out with easily available starting materials under green conditions.

Benziodoxole-Derived Organosulfonates: The Strongest Hypervalent Iodine Electrophiles and Oxidants

This account describes the development of organosulfonyloxy-substituted iodine(III) and iodine(V) benziodoxole derived reagents, which are thermally stable compounds with useful reactivity patterns. Iodine(III) benziodoxoles and pseudobenziodoxoles are powerful electrophiles and mild oxidants toward various unsaturated compounds. In particular, pseudocyclic benziodoxole-derived triflate (IBA-OTf) is an efficient reagent for oxidative heteroannulation reactions. Aldoximes react with nitriles in the presence of IBA-OTf at room temperature to give 1,2,4-oxadiazoles in high yields. Moreover, IBA-triflate is used as a catalyst in oxidative heteroannulations with m-chloroperoxybenzoic acid as the terminal oxidant. The iodine(V) benziodoxole derived tosylates, DMP-tosylate and IBX-tosylate, are superior oxidants for the oxidation of structurally diverse, synthetically useful alcohols, utilized as key precursors in the total syntheses of polyketide antibiotics and terpenes. And finally, the most powerful hypervalent iodine(V) oxidant, 2-iodoxybenzoic acid ditriflate (IBX·2HOTf), is prepared by treatment of IBX with trifluoromethanesulfonic acid. According to the X-ray data, the I–OTf bonds in IBX-ditriflate have ionic character, leading to the high reactivity of this reagent in various oxidations. In particular, IBX-ditriflate can oxidize polyfluorinated primary alcohols, which are generally extremely resistant to oxidation.1 Introduction2 Iodine(III) Benziodoxole Based Organosulfonates3 Pseudocyclic Iodine(III) Benziodoxole Triflate (IBA-triflate)4 Pseudocyclic Iodine(III) Benziodoxole Tosylates5 Iodine(V) Benziodoxole Derived Tosylates6 Iodine(V) Benziodoxole Derived Triflate (IBX-ditriflate)7 Conclusions

Stable isoporphyrin copolymer: Electrochemical mechanism and behavior and photovoltaic properties

Two types of porphyrin copolymer thin films were obtained by electropolymerization of zinc-5,15-bis(p-tolyl)porphyrin. Electrogenerated porphyrin radical cation and dication are powerful electrophiles which can rapidly react with 1,1″-(1,3-propanediyl)bis-4,4′-bipyridinium hexafluorophosphate salt (bpy+–(CH2)3–+bpy·2PF6−) as nucleophiles to form copolymers containing stable isoporphyrin radicals or porphyrins, depending of the applied upper potential limit (1.0 V versus 1.6 V). Electrochemical routes leading to these electroactive copolymers are discussed and the unusual redox properties of copolymers containing stable isoporphyrin radicals are studied. The electropolymerization of the two copolymers was monitored by electrochemical quartz crystal microbalance (EQCM). The copolymers were characterized by UV–Vis–NIR spectroscopy, X-ray photoelectron spectroscopy (XPS), electrochemistry, electron spin resonance (ESR) and atomic force microscopy (AFM). Their electrical properties have been studied by electrochemical impedance spectroscopy and their photovoltaic performances have been investigated by photocurrent transient measurements under visible-NIR light irradiation. The isoporphyrin radical copolymer exhibited considerably better photocurrent generation when compared to the porphyrin copolymer.

Transition-Metal-Free Intermolecular α-Arylation of Ketones via Enolonium Species

Herein it is shown, for the first time, that enolonium species are powerful electrophiles capable of reacting with aromatic compounds in an intermolecular manner to afford α-arylated ketones. The reaction is compatible with a variety of functional groups, is of wide scope with respect to aromatic compounds and ketone, and even works for polymerization-prone substrates such as substituted pyrroles, thiophenes, and furans. Only 1.6 to 5 equiv of the commodity aromatic substrates is needed.

Direct Detection of the Open-Shell Singlet Phenyloxenium Ion: An Atom-Centered Diradical Reacts as an Electrophile.

A new photoprecursor to the phenyloxenium ion, 4-methoxyphenoxypyridinium tetrafluoroborate, was investigated using trapping studies, product analysis, computational investigations, and laser flash photolysis experiments ranging from the femtosecond to the millisecond time scale. These experiments allowed us to trace the complete arc of the photophysics and photochemistry of this photoprecursor beginning with the initially populated excited states to its sequential formation of transient intermediates and ultimate formation of stable photoproducts. We find that the excited state of the photoprecursor undergoes heterolysis to generate the phenyloxenium ion in ∼2 ps but surprisingly generates the ion in its open-shell singlet diradical configuration (1A2), permitting an unexpected look at the reactivity of an atom-centered open-shell singlet diradical. The open-shell phenyloxenium ion (1A2) has a much shorter lifetime (τ ∼ 0.2 ns) in acetonitrile than the previously observed closed-shell singlet (1A1) phenyloxenium ion (τ ∼ 5 ns). Remarkably, despite possessing no empty valence orbitals, this open-shell singlet oxenium ion behaves as an even more powerful electrophile than the closed-shell singlet oxenium ion, undergoing solvent trapping by weakly nucleophilic solvents such as water and acetonitrile or externally added nucleophiles (e.g., azide) rather than engaging in typical diradical chemistry, such as H atom abstraction, which we have previously observed for a triplet oxenium ion. In acetonitrile, the open-shell singlet oxenium ion is trapped to generate ortho and para Ritter intermediates, one of which (para) is directly observed as a longer-lived species (τ ∼ 0.1 ms) in time-resolved resonance Raman experiments. The Ritter intermediates are ultimately trapped by either the 4-methoxypyridine leaving group (in the case of para addition) or trapped internally via an essentially barrierless rearrangement (in the case of ortho addition) to generate a cyclized product. The expectation that singlet diradicals react similarly to triplet or uncoupled diradicals needs to be reconsidered, as a recent study by Perrin and Reyes-Rodríguez (J. Am. Chem. Soc. 2014, 136, 15263) suggested the unsettling possibility that singlet p-benzyne could suffer nucleophilic attack to generate a naked phenyl anion. Now, this study provides direct spectroscopic observation of this phenomenon, with an atom-centered open-shell singlet diradical reacting as a powerful electrophile. To the question of whether a nucleophile can attack a singly occupied molecular orbital, the answer is apparently yes, at least if another partially occupied orbital is available to avoid violation of the rules of valence.

ChemInform Abstract: Hypervalent Iodine: A Powerful Electrophile for Asymmetric α‐Functionalization of Carbonyl Compounds

AbstractReview: [45 refs.

Alternative synthetic routes to N-methyl-1,2,4-triazoline-3,5-dione (MeTAD) and other triazolinedione derivatives

N-Methyl-1,2,4-triazoline-3,5-dione (MeTAD) is a powerful electrophile and a versatile synthetic reagent. In this Letter we describe two methods for the synthesis of N-methylurazole, the direct precursor to MeTAD, on gram scales and in good yields. Both methods provide pure urazole while avoiding the necessity of large scale purification via column chromatography or recrystallization. One of the methods proved to be amenable for the synthesis of derivatives other than N-methyl.

Solvent-dependent release of bromine from bromoquercetins

Quercetin, 6-bromoquercetin (3), and 8-bromoquercetin (4) undergo H/D exchange at 6- and 8-positions, in acetone-d6 and methanol-d4, catalyzed by acids and bases. The base-catalyzed process is faster, and in acetone-d6 the half-lives of H-8 and H-6 are 56.5 and 48.6h, respectively. A high regioselectivity at the position 8 of quercetin is observed under acid-catalysis in both solvents but in methanol-d4 regioselectivity is retained even under base-catalysis. On the other hand, 6,8-dibromoquercetin (2), 4 and 6,8-dibromo-2′-hydroxyquercetin (5) manifest the ability of exchanging bromine with hydrogen (or deuterium) under acid-catalysis in acetone and other enolizable ketones (e.g., methyl ethyl ketone, acetylacetone, and isophorone). These bromophenols release bromine from their 8-position only, in a slow bromination process that likely involves their protonated form (arenium ion I) as brominating agent and the enol of the above ketones as Br-acceptor. The arenium ion I of these bromophenols is expected to be a powerful electrophile and its formation is most likely to be rate-determining.

Hypervalent iodine: a powerful electrophile for asymmetric α-functionalization of carbonyl compounds.

Environmentally friendly hypervalent iodine reagents are unusually effective promoters of asymmetric α-functionalization of carbonyl compounds. By using hypervalent iodine reagents, various substituents can be introduced into the α-position of carbonyl compounds. In the present review, we briefly survey the asymmetric α-functionalization of carbonyl compound reactions catalyzed by these hypervalent iodine reagents.

ChemInform Abstract: Hypervalent Iodine Reagents as Powerful Electrophiles

AbstractReview: ca. 100 refs.

Hypervalent Iodine Reagents as Powerful Electrophiles

Hypervalent iodine reagents have been investigated as very powerful electrophiles in many different reactions. Efficient formation of new carbon-heteroatom bonds as well as carbon-­carbon bonds can be achieved typically under mild reaction conditions with these metal-free reagents. Enantiomerically pure reagents provide the potential for stereoselective reactions and this aspect is highlighted in this account.

Methyliminopropadienone CH3–N═C═C═C═O: Photoelectron Spectrum and Electronic Structure

N-Methyliminopropadienone MeN═C═C═C═O 1a was generated by flash vacuum thermolysis of three 5-(aminomethylene)-1,3-dioxane-4,6-diones (Meldrum's acid derivatives). Online monitoring of the reactions permitted the recording of the UV-photoelectron spectra and the determination of the first two ionization energies of 1a as 9.0 and 12.4 eV. The first ionization energy (and the calculated highest occupied molecular orbital energy) of 1a are more comparable with those of N-methylketenimine than with ketene. In contrast, the calculated lowest unoccupied molecular orbital energy is significantly lower than those of both ketene and N-methylketenimine, thereby making iminopropadienones powerful electrophiles. Calculated charge densities indicate that electrophiles should attack at C3 or O and nucleophiles at C2 or C4 in broad agreement with experimental observations.

ChemInform Abstract: (1-(Trimethylsiloxy)alkyl)triphenylphosphonium Salts: Syntheses and Utilization. Comparisons with Analogous Pyridinium Salts.

Three-component reactions with aldehydes, trimethylsilyl trifluoro- methanesulfonate or iodide. and triphenylphosphine (TPP) yield the title compounds. The X-ray structure of the cationic part of a representative product, the (4-methylphenyl)[(trimethylsiloxy) methyl]TPP + , shows an interesting lengthening of the P + -C(α) bond compared with reported values for methyl(TPP) + and benzyl(TPP) + cations (C(α) represents the P-bonded carbon atom of the various alkyl groups). The behavior of the title compounds towards charged nucleophilic reagents and a powerful electrophile (trifluoromethanesulfonic anhydride) is similar to that of analogous pyridinium salts

Abstract A64: Ester-protected hydroxybenzyl phosphates (EHBP) inhibit the growth of various cultured human cancer cells: Evidence of a tissue type-independent effect

Abstract A64 Introduction Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NO-NSAIDs) consisting of a conventional NSAID to which an NO releasing moiety -ONO2 is covalently attached through a spacer have emerged as a new class of pharmaceutical agents. For several years we have been exploring the mechanism of action of NO-NSAIDs and in particular NO-aspirin (NO-ASA), with emphasis on their application to cancer. Our structure-activity studies with NO-ASA indicated that NO was pivotal for biological activity. However, careful re-examination regarding the contribution to the overall biological effect of each of the three structural components of NO-ASA, led to the surprising conclusion that the NO-releasing moiety was not required for the observed biological effects. Rather, it was the spacer that was responsible for the biological actions of NO-ASA. The NO-releasing moiety was acting as a leaving group leading to the generation of a reactive quinone methide (QM) intermediate which behaved as a powerful electrophile. The ASA component made no biological contribution (BBRC 2007:358, 1096-1101). We therefore synthesized a series of ortho, para, and meta EHBPs, in which the -ONO2 leaving group was replaced by a substituted phosphate as the leaving group and the ASA was replaced by an acetate. We also incorporated electron donating/withdrawing groups about the aromatic spacer in order to evaluate the effect of substitution on QM formation/stability and biological activity. Methods EHBPs as potential drugs: para-, ortho-, and meta-acetyloxybenzyl diethyl phosphate (Agents 1-3 respectively), p-acetyloxy-3-methylbenzyl diethyl phosphate (Agent 4), and p-acetyloxy-2-chlorobenzyl diethyl phosphate (Agent 5) were synthesized and purified at our lab with 1H-NMR verifying the structures. In some experiments we also used NO-ASA for comparison. Cell lines: Human colon, breast, leukemia, and pancreatic cancers. Growth inhibition: colorimetric MTT assay kit. Cell cycle phase distribution: flow cytometry. Apoptosis: subdiploid (sub-G0/G1) peak in DNA content histograms. Results Agent 1 was very effective in inhibiting the growth of all cell lines with IC50s of 0.6-0.8 µM, in contrast, p-NO-ASA had significantly higher IC50s, 10-20 µM. Agent 2 was less potent than agent 1 in all cell lines with IC50s of 63-155 µM, presumably because of steric interference between the diethyl phosphate and the acetyloxy groups making it difficult for the QM to form. Agent 3 was the least effective, with IC50s of 162-451 µM, this agent is comparable in potency to m-NO-ASA, both of which do not form QMs. Agent 4 containing an electron donating group, was extremely potent, IC50s being 0.3-0.5 µM. Agent 5 containing an electron withdrawing group had slightly higher IC50s, 0.5-1.0 µM. Agent 1 induced dose-dependent apoptosis, which was significantly higher compared to p-NO-ASA. Agent 1 dose-dependently altered the distribution of the cells in the cell cycle, causing an arrest in G0/G1. Conclusions EHBPs inhibited the growth of various human cancer cells, indicating a tissue type independent effect. They exercise pleiotropic effects involving cell death as well as cell cycle phase transitions. These results raise the possibility that EHBPs possess chemotherapeutic activity against a wide variety of human cancers. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A64.

Evidence of Reversibility in Azo-Coupling Reactions between 1,3,5-Tris(N,N-dialkylamino)benzenes and Arenediazonium Salts

The reactions between strongly electron-rich aromatic substrates (1,3,5-tris(N,N-dialkylamino)benzenes, neutral carbon super nucleophiles) and diazonium salts produce moderately stable sigma complexes (Wheland complexes). The reactivity of Wheland complexes with electrophiles (other diazonium salts, or 4,7-dinitrobenzofuroxan) produces exchange reactions in the electrophilic part: the better electrophile replaces the less powerful electrophile. In the same way, in Wheland complexes with the 1,3,5-tris(morpholinyl)benzene, the 1,3,5-tris(piperidinyl)benzene replaces the less powerful nucleophile 1,3,5-tris(morpholinyl)benzene. Evidence is reported here indicating that for the title system the reaction of the attack of the electrophilic reagent producing Wheland complexes is a reversible process. The final products of the diazo-coupling reactions undergo a further attack of some diazonium salts. From the final products of the double diazo-coupling reactions (diazo compounds), we collected evidence that is a clear instance of complete reversibility of the diazo-coupling reaction.

What a Difference One Electron Makes! Generating Low‐Coordinate Ti–C and V–C Multiply Bonded Frameworks through One Electron Oxidatively Induced α‐Hydrogen Abstractions

AbstractLow‐coordinate, high oxidation state titanium and vanadium complexes containing terminal metal–carbon multiply bonded functionalities have been prepared directly or indirectly through one electron oxidatively induced α‐hydrogen abstraction reactions. This synthetic approach offers a mild entry to reactive M=C and M≡C motifs, and does not depend on external stimulants such as heat, light or base to promote the α‐hydrogen‐abstraction step. In addition, this strategic protocol avoids the use of powerful electrophiles, thus generating terminal and nucleophilic M–C multiple bonds in low‐coordination environments. In some cases terminal alkylidenes containing β‐hydrogen atoms can also be introduced through this route. This microreview surveys the synthesis and chemistry surrounding isolable titanium and vanadium complexes bearing terminal alkylidene and alkylidyne ligands. Particular emphasis will be placed on the synthesis of the high oxidation state M–C multiple bond. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Synthesis of highly hindered polyanionic chelating ligands

Practical and efficient protocols to obtain highly hindered polyanionic chelating ligands based on bis-(3,5-di- tert-butyl-2-hydroxybenzamido) compounds are reported here. N-3,5-di- tert-Butylsalicyloyloxysuccinimide was treated with aliphatic diamines to form aliphatic hydrocarbon-linked bis-amides 4a– 4g . Aromatic diamines required more powerful electrophile, thus the corresponding benzylated acid chloride was used to form aromatic hydrocarbon-linked bis-amides 8a– 8d . The yields ranged from good to very good and showed that choosing the right acylating agent is a key point in this synthesis. All the compounds were characterized by elemental analysis, IR, MS and NMR.