Parent Ketone Research Articles

Application of biocatalysis towards asymmetric reduction and hydrolytic desymmetrisation in the synthesis of a β-3 receptor agonist

Chemoenzymatic syntheses of two key intermediates in the preparation of a potent β-3 receptor agonist 1 are described. A lipase-catalysed hydrolytic desymmetrisation is employed in a new synthesis of intermediate 7, which avoids the use of alkyl-tin reagents. A second biotransformation delivers chiral chlorohydrin 5 from its parent ketone in greater enantiomeric excess than the previously-described Noyori-reduction process. A brief discussion of the enantioselectivity of a set of single-point mutants of Sporobolomyces salmonicoloraldehyde reductase in this bioreduction is also presented.

Novel Thiosemicarbazones of the ApT and DpT Series and Their Copper Complexes: Identification of Pronounced Redox Activity and Characterization of Their Antitumor Activity

The novel chelators 2-acetylpyridine-4,4-dimethyl-3-thiosemicarbazone (HAp44mT) and di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (HDp44mT) have been examined to elucidate the structure-activity relationships necessary to form copper (Cu) complexes with pronounced antitumor activity. Electrochemical studies demonstrated that the Cu complexes of these ligands had lower redox potentials than their iron complexes. Moreover, the Cu complexes where the ligand/metal ratio was 1:1 rather than 2:1 had significantly higher intracellular oxidative properties and antitumor efficacy. Interestingly, the 2:1 complex was shown to dissociate to give significant amounts of the 1:1 complex that could be the major cytotoxic effector. Both types of Cu complex showed significantly more antiproliferative activity than the ligand alone. We also demonstrate the importance of the inductive effects of substituents on the carbonyl group of the parent ketone, which influence the Cu(II/I) redox potentials because of their proximity to the metal center. The structure-activity relationships described are important for the design of potent thiosemicarbazone Cu complexes.

α-Telluration of 2,4,6-trimethylacetophenone under mild conditions: Role of steric factor in the solid state structures of Te(II and IV) compounds

Elemental tellurium inserts into the C sp3–Br bond of α-bromomesitylmethyl ketone and due to its strong carbophilic character affords the crystalline C-tellurated derivative of 2,4,6-trimethylacetophenone, (MesCOCH 2) 2TeBr 2, 1b in over 80% yield. Electrophilic substitution of the parent ketone with aryltellurium trichlorides, at room temperature, gives nearly quantitative yields of unsymmetrical alkylaryltellurium dichlorides (MesCOCH 2)ArTeCl 2 (Ar = mesityl, Mes, 2a; 1-naphthyl, Np, 3a; anisyl, Ans, 4a). Fairly stable mesitoylmethyltellurium(II) derivatives, (MesCOCH 2) 2Te, 1 and (MesCOCH 2)ArTe (Ar = Mes, 2; Np, 3 and Ans, 4) obtained as the reduction products of their dihalotellurium(IV) analogues, readily undergo oxidative addition of dihalogens to afford the corresponding (MesCOCH 2) 2TeX 2 (X = Cl, 1a; Br 1b; I, 1c) and (MesCOCH 2)ArTeX 2 (X = Cl, Br, I, Ar = Mes, 2a, 2b, 2c; Np, 3a, 3b, 3c and Ans, 4a, 4b, 4c). Crystallographic structural characterization of 1, 1b, 2, 2a, 2b, 2c, 3, 3a and 4c illustrates that the steric demand of mesityl group appreciably influences primary geometry around the 5-coordinate Te(IV) atom when it is bound directly to it. It also makes the Te atom inaccessible for the ubiquitous Te⋯X intermolecular secondary bonding interactions that result in supramolecular structures. In the crystal lattice of symmetrical telluroether 1, an interesting supramolecular synthon based upon reciprocatory weak C–H⋯O H-bonding interaction gives rise to chains via self-assembly.

Novel Application of an Electrooxidative Method for the Formation of a Tetrahydrofuran Ring from 5-Hydroxy-2-pentanone Phenylhydrazone

Various ketone phenylhydrazones that possess a hydroxy group on the parent ketone moiety were subjected to electrooxidation in methanol in the presence of KI and NaOMe. In the case of 4-hydroxy-2-butanone phenylhydrazone, the nucleophilic attack of the azomethine carbon by a methoxide ion affording the corresponding methoxy(phenylazo)alcohol was dominant. Interestingly, however, in the case of 5-hydroxy-2-pentanone phenylhydrazone, similar reaction conditions favored the intramolecular cyclization to afford a (phenylazo)tetrahydrofuran derivative.

Studies on the chemistry and reactivity of alpha-substituted ketones in isonitrile-based multicomponent reactions.

Using the Passerini and Ugi reactions as representative tests, the utility of several alpha-substituted ketones R-CO-CH(2)-X (X = sulfonyloxy, acyloxy, azido, halo, hydroxy, and sulfonyl) in isonitrile-based multicomponent reactions was explored. In a relative rate study (R = PhCH(2)CH(2)), each of the alpha-substituted ketones underwent Passerini condensation more rapidly than the parent ketone. Short, highly convergent routes to oxazoline, beta-lactam, di-O-acylglyceramides, and other molecular frameworks were developed.

A Mild and Efficient Method for Oxidative Deprotection of Trimethylsilyl Ethers to the Corresponding Carbonyl Compounds Using [PhCH2NMe2Ph]2S2O8

Deprotection of trimethylsilyl ethers to the parent aldehydes and ketones in high yields has been carried out under mild conditions using N-benzyl N,N-dimethyl anilinium peroxodisulfate.

Aldehyde N,N‐Dialkylhydrazones as Neutral Acyl Anion Equivalents: Umpolung of the Imine Reactivity

AbstractThe isoelectronic replacement of the α‐carbon of enamines by nitrogen leads to the corresponding hydrazones, and thus, they can be termed “aza‐enamines”. Hence, aldehyde N,N‐dialkylhydrazones enable analogous electrophilic substitutions at the imine carbon that corresponds to the β‐carbon of enamines. In addition, after hydrolysis of the product hydrazones to the parent ketones or aldehydes, these reactions constitute an umpolung of the classical carbonyl reactivity and overall a nucleophilic acylation or formylation. This review covers the aza‐enamine chemistry from its very beginning in the late 1960s up to this year. In the first part, reactions of aromatic, aliphatic, and heterocyclic aldehyde N,N‐dialkylhydrazones with highly reactive substrates such as the Vilsmeier and Mannich reagents, sulfonyl isocyanates, perfluoroacetic anhydride, and inorganic electrophiles such as halogens and phosphorus tribromide are described. The hydrazones of α,β‐unsaturated aldehydes react as vinylogous aza‐enamines at the terminal carbon providing unsaturated aldehydes. As electron‐rich dienes and dienophiles, they also form Diels–Alder adducts and thus interesting N‐heterocycles. The second part covers carbon–carbon bond formations of the sterically less‐demanding formaldehyde N,N‐dialkylhydrazones with synthetically very useful electrophiles such as various Michael acceptors and carbonyl compounds. Formaldehyde SAMP‐hydrazone and related derivatives generally give excellent asymmetric inductions. Finally, first organocatalytic versions of the aza‐enamine chemistry are presented. In summary, the rich chemistry of aldehyde N,N‐dialkylhydrazones as neutral acyl anion, formyl anion, and cyanide equivalents is demonstrated. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

The Effects of Ring Size and Substituents on the Rates of Acid‐Catalysed Hydrolysis of Five‐ and Six‐Membered Ring Cyclic Ketone Acetals

AbstractA series of sterically similar five‐ and six‐membered ring cyclic diol‐derived ketone acetals have been prepared and their rates of acid‐catalysed hydrolysis examined. The rates of hydrolysis are substantially affected by acetal ring conformational stereoelectronic effects and resonance effects depending upon the substituents on the parent ketone; an A1 mechanism of hydrolysis explains the observed effects.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Novel 1,5-difluoropenta-1,4-diyn-3-one, its sulfur and selenium analogues: MP2 and DFT gas phase study of their molecular structures and vibrational spectra

1,5-Difluoropenta-1,4-diyne-3-one, its sulfur and selenium analogues in C 2v symmetry have been studied in the gas phase by ab initio MP2 and B3LYP methods. The basis set employed for these methods is 6-311++G(d,p) for all atoms. Molecular parameters, namely bond lengths, bond angles, rotational constants, dipole moments and energies, and vibrational infrared spectra parameters, namely harmonic vibrational frequencies and absolute intensities are predicted for these difluoroketones. Atomisation energies and natural charges on the atoms have also been predicted. The molecular parameters and vibrational spectra of the parent ketone namely, penta-1,4-diyn-3-one [Y. Umar, J. Mol. Struct. (THEOCHEM) 728 (2005) 111–115], have been calculated at the same levels of theory and basis set employed in this study. The results obtained are in good agreement with available experimental literature data. Therefore, data from the present study are expected to be valid for the molecular structures and vibrational spectra of the novel difluoroketones. This work also compares the effect on molecular and vibrational parameters of penta-1,4-diyn-3-one, its sulfur and selenium analogues when hydrogen is substituted by fluorine.

Aqueous Media Deprotection of Ketoximes with Ammonium Persulfate.

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Aqueous Media Deprotection of Ketoximes with Ammonium Persulfate

Oximes are very useful for protecting groups in organic synthesis. These highly crystalline compounds can be prepared from carbonyl and non carbonyl compounds. The regeneration of carbonyl compound from oximes provides an alternative method for the preparation of these compounds. The classical method for regeneration of carbonyl compounds from oximes reqire strongly acidic conditions, which is not suitable for acid sensitive compounds. In order to avoid this, many oxidative deoximation methods have been developed in recent years. Ammonium persulfate is an inexpensive and readily accessible oxidizing agent. It is commonly used in industry for bleaching and for wastewater treatment. However, only sporadic literature is available that describes its applications in organic synthesis, the oxidations of alkenes, substituted aromatics, cyclization and deoximation under strenuous conditions using sulfuric acid. Synthetic chemists continue to explore new methods to carry out chemical transformations. One of these new methods is to run reactions in aqueous media. Organic reactions in water, without the use of any harmful organic solvents, are of great current interest, because water is an easily available, economical, safe and environmentally benign solvent. In continuation of our ongoing program to develop environmentally benign methods in the absence of organic solvent, we now wish to report that ammonium persulfate deoximates ketoximes to the parent ketones cleanly and in good yield in an aqueous media. This reagent oxidizes aldehydes to acids, so deoximation of aldoximes is unlikely to be useful. Dissolution of ammonium persulfate in water and subsequent reaction with ketoximes under stirring at room temperature or reflux gave the corresponding carbonyl compounds in good yields. Table 1 contains a summary of the results we have obtained for variety of ketoximes. The synthetic value of these results is apparent when it is noted that such reactions in the past have usually been achieved by the use of activated ammonium persulfate. Even the sterically hindered ketoximes were successfully deoximated in excellent yields (entries 1 and 9). This reaction does not require an activation procedure or the use of expensive equipment or materials.

2,6-Dicarboxypyridinium Fluorochromate: A Mild and Efficient Reagent for Oxidative Deprotection of Trimethylsilyl Ethers to Their Corresponding Carbonyl Compounds

Deprotection of trimethylsilyl ethers to their parent aldehydes and ketones in high yields has been carried out using 2,6-dicarboxypyridinium fluorochromate under mild conditions.

Enolate Structure and Electron Affinity

Photodetachment cross sections for a series of cyclic enolates were measured using a continuous wave (CW) ion cyclotron resonance instrument to generate and detect the ions. We report electron affinities for the radicals corresponding to the removal of the extra electron from the following anions: 2-methylcyclopent-1-enolate, 3-methylcyclopent-1-enolate, 4-methylcyclopent-1-enolate, 5-methylcyclopent-1-enolate, 2-methylcyclohex-1-enolate, 3-methylcyclohex-1-enolate, 4-methylcyclohex-1-enolate, 4-ethylcyclohex-1-enolate, 5-methylcyclohex-1-enolate, and 6-methylcyclohex-1-enolate. Some of these anions are mixed with their tautomers, derived from deprotonation of the parent ketone; the consequences of this are analyzed. The effect of alkylation on the electron affinities is discussed. The effect of vibrational modes on the lifetimes of the dipole-bound states of 4-methylcyclohex-1-enolate and 4-ethylcyclohex-1-enolate is discussed.

Synthesis of the (1 S,2 S)- and (1 R,2 S)-stereoisomers of the respective E- and Z-isomers of ethyl 4-[(2-hydroxycyclohexyl)methyl]phenoxy-3-methyl-2-butenoate using yeast whole cell bioreduction of the parent ketones

Saccharomyces cerevisiae, strain DBM 2115, was successfully employed in the reduction of the separated Z- and E-isomers of ethyl 4-[(2-oxocyclohexyl)methyl]phenoxy-3-methyl-2-butenoates 1 and 2, in order to prepare the (1 S,2 S)- and (1 R,2 S)-enantiomers of the corresponding ethyl 4-[(2-hydroxycyclohexyl)methyl]phenoxy-3-methyl-2-butenoates 3– 6. The products were obtained with the required absolute configuration: (1 S,2 S)- 3 (ee = 98%; yield 48%), (1 R,2 S)- 4 (ee = >99%; yield 45%), (1 S,2 S)- 5 (ee = 98.5%; yield 47%), and (1 R,2 S)- 6 (ee = >99%; chemical yield 44%).

Studies on the ketone‐catalyzed decomposition of caroate in aqueous alkaline medium

AbstractThe kinetics of ketone‐catalyzed decomposition of caroate (peroxomonosulfate) was studied in aqueous alkaline medium at 25°C. The rate follows simple second‐order kinetics, first order in each [Ketone] and [PMS]. The rate constant values are independent of hydroxide ion concentrations over the range from 0.05 M to 0.15 M. The experimental results suggest that the nucleophilic addition of SO ion at the carbonyl carbon leads to the formation of oxirane intermediate in the rate‐determining step. Oxirane reacts rapidly with another SO to give the parent ketone, oxygen, and SO. The observed substituent effect on the activation energy EA and Arrhenius (A) factor suggests that the electron‐donating substituents stabilize the activated state and make the entropy of activation more negative. This can be explained by the fact that the mechanism of oxirane formation shifts from concentric to nonconcentric process as we go from acetone to 3‐hexanone. © 2005 Wiley Periodicals, Inc. Int J Chem Kinet 37: 483–488, 2005

Michael Addition of Ketone Enolates to α,β‐Unsaturated Esters or Amides in a One‐Pot Procedure: Highly Efficient Effect of Lithium Salt Generated in situ on Organotin Enolate.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Influence of the nature of the substrate and of operative parameters in the electrocarboxylation of halogenated acetophenones and benzophenones

The electrocarboxylation of halogenated acetophenones and benzophenones to the corresponding hydroxycarboxylic acids has been carried out in undivided cell equipped with aluminium sacrificial anode and using 1-methyl-2-pyrrolidinone (NMP) as the solvent. The radical anion generated by the electro-reduction of the aromatic ketone is involved in several competitive reactions which lead to the formation of the target hydroxycarboxylic acid, the corresponding alcohol and pinacol and the de-halogenated parent ketone. If sufficiently negative working potentials are imposed, the latter is reduced to the corresponding carboxylate, pinacol and alcohol. Very different results in terms of selectivity and faradic efficiency in the target hydroxycarboxylic acids were obtained when the substrate was changed. Higher selectivities were obtained with chlorobenzophenones with respect to the homo-substituted chloroacetophenones as a result of a less relevant formation of dehalogenated compounds, alcohols and pinacols. The cleavage of the carbon–halogen bond was, moreover, more favoured by changing from meta to para to ortho isomer and from fluoro to chloro to bromo derivatives. The performances of the process have been found to be strongly dependent on the adopted values of temperature, substrate concentration and working potential.

Michael Addition of Ketone Enolates to α,β-Unsaturated Esters or Amides in a One-Pot Procedure: Highly Efficient Effect of Lithium Salt Generated in situ on Organotin Enolate

Michael addition of a metal ketone enolate to an α,β-unsaturated ester is thermodynamically disfavored, and thus, isolated metal enolates with an equimolar amount of Lewis acids or additives are usually required. This work describes the methodology of one-pot Michael addition from the parent ketones and unsaturated esters to the products directly. The treatment of a parent ketone with sec-butyllithium and Bu3SnBr gives a highly coordinated tin enolate that is complexed with LiBr generated in situ. The species is reactive and affords the Michael adducts, δ-keto esters and amides, in the reaction with α,β-unsaturated esters and amides, respectively.

Synthesis and rearrangement of [1,1′-bicyclobutyl]-1-ols and spiro[3.4]octan-5-ols: a general access to bicyclo[3.3.0]octenes (hexahydropentalenes)

Several new Grignard reagents based on substituted cyclobutanes have been generated and added to cyclobutanones to yield mono- to trimethylated [1,1′-bicyclobutyl]-1-ols. Mono- to trimethylated spiro[3.4]octan-5-ols have been prepared from the parent ketone via alkylation and/or addition reactions. Upon treatment with acid, all [1,1′-bicyclobutyl]-1-ols and spiro[3.4]octan-5-ols rearrange to yield a single bicyclo[3.3.0]octene.

6-Oxo-Morphinane Oximes: Pharmacology, Chemistry and Analytical Application

The permanent therapeutic importance of morphine derivatives in pain treatment has inspired continual synthetic efforts to modify the rigid pentacyclic systems in search for new selective analgesic agents. As a result, several morphinane oximes have been synthesized recently, which have the additional advantage of possessing an oxime group that can provide a method for selective determination of opiate alkaloids in biological matrices. The oximes of hydrocodone and oxycodone have stronger analgesic effect than the parent ketones and they also proved to be effective in preventing the respiratory depressant and hypotensive actions of fentanyl. In this work a review is given on the present status of oxime pharmacology, chemistry and analysis and also the oxime and O-methyl oxime formation of 6-oxo-morphinanes with therapeutic interest (codeinone, oxycodone, hydrocodone and 14-OH-codeinone). The oxime formation was monitored by reversed-phase HPLC and the chromatographic properties of oxime isomers have been characterized. The assignation of the individual isomers isolated by preparative HPLC was performed by (1)H NMR spectroscopy based on the chemical shift differences of the 5-H signals. In this way the isomeric ratio in the oxime products could also be determined. It was found that in the case of Delta(7)-6-oxo-morphinanes, depending on the substituents, the formation of the Z-isomer highly dominates (73-96%) over that of the E-isomer. However, for the saturated 7,8-(dihydro) derivatives the E-isomer is definitely preferred (>98%). In conclusion of a survey on the theoretical background of oxime isomerism, the conformational differences between the saturated and unsaturated morphinane systems were found responsible for the different E/Z ratios. On the basis of the isomeric ratio and the on-line CD and UV spectra of the pure isomers, the molar ellipticities and absorbancies of the isomers were calculated by a parameter estimation method.