Electrophilic Acylation Research Articles

Direct Electrophilic Acylation of N-Substituted Pyrazoles by Anhydrides of Carboxylic Acids

A simple, convenient and scalable approach to 1-substituted 4-acylpyrazoles through direct acylation of pyrazoles by anhydrides of aliphatic, aromatic and fluorinated carboxylic acids in the presence of concentrated sulfuric acid as a catalyst is described. Target ketones were obtained in 41–86% isolated yields in high purity without laborious purification. The scope and limitations of the method are discussed.

ESTUDIO DE LA REACTIVIDAD EN MOLÉCULAS FENÓLICAS MEDIANTE LA FUNCIÓN DE FUKUI

En este trabajo analizamos la estructura más estable y la evolución de la reactividad local utilizando los índices de Fukui en sistemas fenólicos sustituidos en posición-para, conforme se modifica la función base en diferentes métodos. Los resultados explican las sustituciones: electrofílica y nucleofílica aromática y la acilación en los sistemas fenólicos. Los cálculos se llevaron a cabo a un nivel: HF/3-21G, B3LYP/3-21G, B3LYP/6-31G(d) y MP2/6-31+G(d); se estableció el nivel de cálculo adecuado para cada tipo de reacción estudiada.

Mass spectrometric characterization of circulating covalent protein adducts derived from a drug acyl glucuronide metabolite: multiple albumin adductions in diclofenac patients.

Covalent protein modifications by electrophilic acyl glucuronide (AG) metabolites are hypothetical causes of hypersensitivity reactions associated with certain carboxylate drugs. The complex rearrangements and reactivities of drug AG have been defined in great detail, and protein adducts of carboxylate drugs, such as diclofenac, have been found in liver and plasma of experimental animals and humans. However, in the absence of definitive molecular characterization, and specifically, identification of signature glycation conjugates retaining the glucuronyl and carboxyl residues, it cannot be assumed any of these adducts is derived uniquely or even fractionally from AG metabolites. We have therefore undertaken targeted mass spectrometric analyses of human serum albumin (HSA) isolated from diclofenac patients to characterize drug-: derived structures and, thereby, for the first time, have deconstructed conclusively the pathways of adduct formation from a drug AG and its isomeric rearrangement products in vivo. These analyses were informed by a thorough understanding of the reactions of HSA with diclofenac AG in vitro. HSA from six patients without drug-: related hypersensitivities had either a single drug-: derived adduct or one of five combinations of 2-8 adducts from among seven diclofenac N-acylations and three AG glycations on seven of the protein's 59 lysines. Only acylations were found in every patient. We present evidence that HSA modifications by diclofenac in vivo are complicated and variable, that at least a fraction of these modifications are derived from the drug's AG metabolite, and that albumin adduction is not inevitably a causation of hypersensitivity to carboxylate drugs or a coincidental association.

ChemInform Abstract: Direct Electrophilic Acylation of N‐Substituted Pyrazoles by Anhydrides of Carboxylic Acids.

AbstractThe regioselective direct acylation of N‐substituted pyrazoles (I) is reported.

Pd-catalyzed Fukuyama cross-coupling of secondary organozinc reagents for the direct synthesis of unsymmetrical ketones

The coupling of acyl electrophiles with organometallic reagents represents a convergent route toward complex and versatile ketone products. Despite the mild conditions and high functional group tolerance, the cross-coupling of carboxylic acid derivatives, such as thioesters, and secondary organometallic reagents is an underdeveloped transformation. Herein, we disclose a convenient and efficient protocol for the Pd-catalyzed Fukuyama cross-coupling of secondary organozinc reagents with thioester electrophiles. Under these mild conditions, a range of thioesters possessing sensitive functional groups can be coupled with either activated or unactivated secondary organozinc halides in good yields. This method was expanded to include an acid chloride substrate, generating an aryl alkyl ketone in high yield. In addition, a modest dynamic kinetic resolution of the organozinc reagent can be achieved using chiral phosphoramidite ligands to furnish enantioenriched ketone products.

Synthesis and properties of novel poly(aryl ether ketone)s containing both 2,6-naphthylene and 1,4-naphthylene units

A new monomer containing naphthalene, namely 4,4′-di(1-naphthoxy)benzophenone (DNOBN), was prepared by the condensation reaction of 4,4′-difluorobenzophenone with 1-naphthol in the presence of base in N-methylpyrrolidone (NMP). Novel poly(aryl ether ketone)s containing both 2,6-naphthylene and 1,4-naphthylene units were synthesized by the electrophilic Friedel-Crafts acylation polycondensation of terephthaloyl chloride with a mixture of 2,6-bis(4-phenoxybenzoyl)naphthalene (BPOBN) and DNOBN, over a wide range of BPOBN/DNOBN molar ratios, in the presence of anhydrous AlCl3 and NMP in 1,2-dichloroethane (DCE). The copolymers obtained were characterized by different physicochemical techniques. The copolymers with 10–20 mol% DNOBN are semicrystalline and had remarkably increased Tgs over commercially available poly(ether ether ketone) and poly(ether ketone ketone) due to the incorporation of 2,6-naphthylene and 1,4-naphthylene moieties in the main chains. The copolymer IV with 20 mol% DNOBN had not only high Tg of 189°C, but also moderate Tm of 338°C, having good potential for melt processing. The copolymer IV had tensile strength of 102.2 MPa, Young’s modulus of 3.25 GPa, and elongation at break of 18.5% and exhibited high thermal stability and excellent resistance to organic solvents.

Direct Electrophilic Acylation of N-Substituted Pyrazoles by Anhydrides of Carboxylic Acids

A simple, convenient and scalable approach to 1-substituted 4-acylpyrazoles through direct acylation of pyrazoles by anhydrides of aliphatic, aromatic and fluorinated carboxylic acids in the presence of concentrated sulfuric acid as a catalyst is described. Target ketones were obtained in 41–86% isolated yields in high purity without laborious purification. The scope and limitations of the method are discussed.

Preparation of Osmium η5-Phospholide Complexes and Their Reactions with Acyl Electrophiles: C═O Bond Cleavage and C−C Bond Formation within the Metal Coordination Sphere

Two diphosphaosmocene species have been pre pared in excellent yields by the reaction of a lithium 2,5-dialkylphospholide (alkyl = cyclohexyl, (−)-menthyl) and [(η6-cymene)OsCl2]2 in THF. These are the first examples of phosphametallocenes with an osmium core. For the success of the phosphaosmocene synthesis, the use of a sterically demanding phospholide is crucial. A treatment of the 2,2′,5,5′-Cy4-diphosphaosmocene with an AcCl/AlCl3 mixture in dichloromethane gives a novel (μ-vinylidene)osmium complex via activation of the acetyl C═O double bond. In the osmium complex, a μ-vinylidene moiety bridges between the osmium atom and a phosphorus of the η4-(P-oxophospholide). In the presence of excess acetyl electrophile, the μ-vinylidene complex is subjected to further acetylation at the CH2 terminus of the μ-vinylidene moiety to give a (μ-acetylvinylidene)osmium complex. A stepwise application of acetyl chloride and phenylacetyl chloride to this transformation enabled production of a [μ-(phenylacetyl)vinylide...

ChemInform Abstract: Electrophilic Acylation of Fluoro Olefins with Perfluorinated α,. beta.-Unsaturated Carboxylic Acid Fluorides.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A novel Brønsted acid catalyst for Friedel–Crafts acylation

Bis(trifluoroalkylsulfonylimino)trifluoromethanesulfonic acid has demonstrated remarkable catalytic ability in the electrophilic acylation of aromatic substrates. Various perfluoroalkyl substituted aroyl chlorides are employed in Friedel–Crafts acylation typically using 1 mol % of catalyst.

Crystal Structure of 2-{1-[(1-(2-Pyridinio)ethylidene)hydrazono]ethyl}pyridinium diperchlorate, the Product of Template Condensation in the Presence of Cr(III)

AbstractIn an attempt to synthesize a Cr(III) complex of 2′-[1-(2-pyridinyl)ethylidene]oxamohydrazide an azine product 2-{1-[(1-(2-pyridinio)ethylidene)hydrazono]ethyl}pyridinium diperchlorate was obtained by an electrophilic acyl substitution catalyzed by Cr(III). Its structure was determined by X-ray crystal analysis and showed significant changes in comparison to the corresponding unprotonated compound. The 2-{1-[(1-(2-pyridinio)ethylidene)hydrazono]ethyl}pyridinium diperchlorate crystallizes in the space group P2 1 /n of the monoclinic crystal system with unit cell parameters a = 14.3809(3) A, b = 24.1516(5) A, c = 15.4471(3) A, β = 99.930(2)°, V = 5284.74(19) A 3 and Z = 12, i.e. three molecules per asymmetric unit.Graphical AbstractIn the template condensation of the 2′-[1-(2-pyridinyl)ethylidene]oxamohydrazide in presence of the chromium(III) ion the 2-{1-[(1-(2-pyridinio)ethylidene)hydrazono]ethyl}pyridinium diperchlorate was obtained and characterized by NMR spectroscopy and X-ray crystallography.[IMAGE]

Synthesis and characterization of novel soluble poly(ether ketone sulfone)s with pendant polychloro groups

A novel monomer of tetrachloroterephthaloyl chloride (TCTPC) was prepared by the chlorination of terephthaloyl chloride catalyzed by ferric chloride at 175–180°C for 10 h and confirmed by FTIR, MS, and elemental analysis. Five new polychloro substituted poly(aryl ether ketone sulfone)s (PEKSs) with inherent viscosities of 0.68–0.75 dL/g have been prepared from 4,4′-diphenoxydiphenylsulfone, 4,4′-bis(2-methylphenoxy) diphenylsulfone, 4,4′-bis(3-methylph-enoxy)diphenylsulfone, 4,4′-bis(2,6-dimethylphenoxy)diphenylsulfone, and 4,4′-bis(1-naphthoxy)-diphenylsulfone with TCTPC by electrophilic Friedel-Crafts acylation in the presence of DMF with anhydrous AlCl3 as a catalyst in 1,2-dichloroethane, respectively. These polymers having weight–average molecular weight in the range of 76,600–83,900 are all amorphous and show high glass transition temperatures ranging from 213 to 250°C, the 5% weight loss temperature over 450°C, high char yields of 60–67% at 700°C in nitrogen and good solubility in CHCl3 and polar solvents such as DMF, DMSO, and NMP at room temperature. All the polymers formed transparent, strong, and flexible films, with tensile strengths of 85.1–90.8 MPa, Young's moduli of 2.52–3.24 GPa, and elongations at break of 21.2–27.2%. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008

Unprecedented Formation of μ-Vinylidene Complexes from Phospharuthenocene and Acyl Chloride via Activation of the C═O Double Bond

A novel reaction mode of phosphametallocenes was discovered. The phospharuthenocenes with cyclohexyl substituents at the α-positions of the η5-phospholide(s) reacted with acyl electrophiles by an initial electrophilic attack to the ruthenium to produce the μ-alkenylidene species with activation of the acyl C═O double bond and elimination of an α-hydrogen.

Enantioenriched Vinylic Diamines by Asymmetric Allylic Amination

Allylic alkylations and aminations are versatile methods to generate synthetically useful compounds. Racemic aziridines can be converted via dynamic kinetic resolution (DYKAT) into enantioenriched allylic diamines. In this work, the direct products of the asymmetric amination undergo subsequent acyl migration of the more electrophilic acyl group. Chiral diamines are produced with differentiated amines. The methodology is used in the synthesis of the protein kinase inhibitor balanol.

Novel Electrophilic ipso Acylation—Detosylation Reaction of Pyrroles.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Activation of Pyridinium Salts for Electrophilic Acylation: A Method for Conversion of Pyridines into 3‐Acylpyridines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Malononitrile as a Carbonyl Synthon: A One‐Pot Preparation of Heteroaryl Amide via a SNAr‐Oxidation—Displacement Strategy.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Malononitrile as a carbonyl synthon: a one-pot preparation of heteroaryl amide via a SNAr-oxidation–displacement strategy

Malononitrile could be utilized as a synthon for the carbonyl moiety via a one-pot process that was initiated via base-mediated SNAr substitution of a heteroaryl halide. Subsequent peracetic acid oxidation of the resultant anion delivered an electrophilic acyl nitrile in situ that readily reacted with added nucleophiles to afford heteroaryl carboxylic acid derivatives. The reaction of the sodium salt of malononitrile with a series of heteroaryl chlorides followed by the subsequent addition of an amine and peracetic acid provided the corresponding heteroaryl amides.

Activation of Pyridinium Salts for Electrophilic Acylation: a Method for Conversion of Pyridines into 3-Acylpyridines

Cyanide adducts of N-MOM pyridinium salts react with strong acylating reagents to provide 3-acyl-4-cyano-1,4-dihydropyridines that can be aromatized to 3-acylpyridines using ZnCl2 in refluxing ethanol.

Structural basis for imipenem inhibition of class C beta-lactamases.

To determine how imipenem inhibits the class C beta-lactamase AmpC, the X-ray crystal structure of the acyl-enzyme complex was determined to a resolution of 1.80 A. In the complex, the lactam carbonyl oxygen of imipenem has flipped by approximately 180 degrees compared to its expected position; the electrophilic acyl center is thus displaced from the point of hydrolytic attack. This conformation resembles that of imipenem bound to the class A enzyme TEM-1 but is different from that of moxalactam bound to AmpC.