- Nickel-catalysed conjugate addition to trimethylaluminum to sterically hindered α,β-unsaturated ketones
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Nickel acetylacetonate is an efficient catalyst for the 1,4-addition of trimethylaluminum to α,β-unsaturated ketones. The reaction is strongly solvent dependent and gives best results in tetrahydrofuran or ethyl acetate. The reaction is especially useful for the nucleophilic 1,4-methyl transfer to sterically hindered enones. A β-cuparenone synthesis via conjugate methyl group addition to an enone precursor is described.
- Flemming,Kabbara,Nickish,Neh,Westermann
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- STREIC EFFECTS ON REACTION RATES II: RATE AND EQUILIBRIUM CONSTANTS FOR OXIDATION OF BICYCLIC ALCOHOLS
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Equilibrium constants for oxidation of a series of bicyclic alcohols with cyclohexanone have been determined under Meerwein-Pondorf conditions.The data provide the thermodynamic background for interpretation of the mechanism of alcohol oxidation and ketone reductions.Free energies of the equilibrium (ΔGox) are compared with values calculated by molecular mechanics.
- Mueller, Paul,Blanc, Jacky
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- Enolate-Based Regioselective Anti-Beckmann C-C Bond Cleavage of Ketones
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The Baeyer-Villiger or Beckmann rearrangements are established methods for the cleavage of ketone derivatives under acidic conditions, proceeding for unsymmetrical precursors selectively at the more substituted site. However, the fragmentation regioselectivity cannot be switched and fragmentation at the less-substituted terminus is so far not possible. We report here that the reaction of ketone enolates with commercial alkyl nitrites provides a direct and regioselective way of fragmenting ketones into esters and oximes or ω-hydroxyimino esters, respectively. A comprehensive study of the scope of this reaction with respect to ketone classes and alkyl nitrites is presented. Control over the site of cleavage is gained through regioselective enolate formation by various bases. Oxidation of kinetic enolates of unsymmetrical ketones leads to the otherwise unavailable "anti-Beckmann"cleavage at the less-substituted side chain, while cleavage of thermodynamic enolates of the same ketones represents an alternative to the Baeyer-Villiger oxidation or the Beckmann rearrangement under basic conditions. The method is suited for the transformation of natural products and enables access to orthogonally reactive dicarbonyl compounds.
- Jahn, Ullrich,Ma?ek, Tomá?
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p. 11608 - 11632
(2021/09/02)
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- METHOD OF PREPARING 3,3,5,5-TETRAMETHYLCYCLOHEXANONE
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Method of preparing 3,3,5,5-tetramethylcyclohexanone comprising step (i): (i) converting isophorone to 3,3,5,5-tetramethylcyclohexanone in the presence of methylmagnesium chloride. The thus prepared 3,3,5,5-tetramethylcyclohexanone may be employed in a method of preparing 1-amino-1,3,3,5,5-pentamethylcyclohexane (Neramexane) or a pharmaceutically acceptable salt thereof.
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Paragraph 0111
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- METHOD OF PREPARING NERAMEXANE
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Method of producing a salt of 1-amino-1,3,3,5,5-pentamethylcyclohexane comprising steps (i) to (v): (i) converting isophorone to 3,3,5,5-tetramethylcyclohexanone; (ii) converting 3,3,5,5-tetramethylcyclohexanone obtained in step (i) to 1- hydroxy-1,3,3,5,5-pentamethylcyclohexane; (iii) converting 1-hydroxy-1,3,3,5,5-pentamethylcyclohexane obtained in step (ii) to 1-chloroacetamido-1,3,3,5,5-pentamethylcyclohexane; (iv) converting 1-chloroacetamido-1,3,3,5,5-pentamethylcyclohexane obtained in step (iii) to 1-amino-1,3,3,5,5-pentamethylcyclohexane; wherein at least one of 3,3,5,5-tetramethylcyclohexanone, 1-hydroxy-1,3,3,5,5- pentamethylcyclohexane, 1-chloroacetamido-1,3,3,5,5-pentamethylcyclohexane, is not subjected to a purification step.
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- METHOD OF PREPARING NERAMEXANE
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Method of preparing 1-amino-1,3,3,5,5-pentamethylcyclohexane or a pharmaceutically acceptable salt thereof, comprising at least two steps selected from the following steps (i) to (iv): (i) converting isophorone to 3,3,5,5-tetramethylcyclohexanone in the presence of methylmagnesium chloride; (N) converting 3,3,5,5-tetramethylcyclohexanone to 1-hydroxy-1,3,3,5,5- pentamethylcyclohexane in the presence of methylmagnesium chloride; (iii) converting 1-hydroxy-1,3,3,5,5-pentamethylcyclohexane to 1-chloroacetamido- 1,3,3,5,5-pentamethylcyclohexane in the presence of chloroacetonitrile in acidic solution; (iv) converting 1-chloroacetamido-1,3,3,5,5-pentamethylcyclohexane to 1-amino- 1,3,3,5,5-pentamethylcyclohexane in the presence of thiourea in water.
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- METHOD OF PREPARING 3,3,5,5-TETRAMETHYLCYCLOHEXANONE
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Method of preparing 3,3,5,5-tetramethylcyclohexanone comprising step (i): (i) converting isophorone to 3,3,5,5-tetramethylcyclohexanone in the presence of methylmagnesium chloride. The thus prepared 3,3,5,5-tetramethylcyclohexanone may be employed in a method of preparing 1-amino-1,3,3,5,5-pentamethylcyclohexane (Neramexane) or a pharmaceutically acceptable salt thereof.
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- Applications of diethoxymethane as a versatile process solvent and unique reagent in organic synthesis
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Diethoxymethane (DEM) has recently become available in commercial quantities. It has unique properties and is useful in a variety of applications in organic synthesis. It is low boiling (88 °C), azeotropes with water, and has a very low affinity for water. It is stable under basic conditions and as manufactured does not require drying for use as a solvent, even for organometallic reactions. DEM is useful as a process solvent especially for sodium hydride reactions, organolithium chemistry, copper-catalyzed conjugate additions, and phase-transfer reactions. As such, DEM is a potential replacement for tetrahydrofuran (THF), dichloromethane (CH2Cl2), glyme (1,2-dimethoxyethane), and methylal (1,1-dimethoxymethane). DEM is also useful as an ethoxymethylating agent, a formaldehyde equivalent, and a carbonylation substrate. Due to these unique properties and applications, DEM has exciting potential for widespread use both as a reagent and especially as a preferred solvent.
- Boaz, Neil W.,Venepalli, Bhaskar
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p. 127 - 131
(2013/09/07)
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- Methylation or ethylation agent and process for 1,4-addition of a methyl or ethyl group to an α, β-unsaturated keto compound
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This invention describes a new methylation or ethylation agent containing trimethyl aluminum or dimethyl zinc or triethyl aluminum as methyl or ethyl source, which additionally contains catalytic amounts of one or more copper(I) and/or copper(II) compounds as well as a process for the 1,4-addition of a methyl or ethyl group to an α,β-unsaturated or an α,β-double unsaturated ketone or an α,β-unsaturated aldehyde using the agent according to the invention. By using only catalytic amounts of copper and a CKW (chlorinatedhydrocarbon)-free reaction medium, the new methylation/ethylation agent/process is distinguished by its environmental compatibility and it is, for example, suitable for the production of initial products for the synthesis of biologically effective compounds.
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- The copper mediated Barbier reactions of α,β-unsaturated ketones: Regioselective conjugate and 1,2-addition
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The one-pot reaction of isophorone and other α,β-unsaturated ketones with alkyl and aryl halides in the presence of magnesium and a copper salt ('Barbier' conditions) leads to the regiospecific formation of 1,4-addition products; the use of lithium leads to regioselective 1,2-addition.
- Costello, Declan P.,Geraghty, Niall W. A.
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p. 3083 - 3096
(2007/10/03)
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- Envirocat EPZG as a New Heterogeneous Catalyst for the Regeneration of Ketones from Their Tosylhydrazones
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Envirocat EPZG represents a new heterogeneous catalyst for ketones regeneration from their tosylhydrazones. Aldehyde tosylhydrazones were less reactive under these conditions, allowing to perform a selective regeneration of ketone in the presence of both ketone and aldehyde tosylhydrazones.
- Ballini, Roberto,Bosica, Giovanna,Maggi, Raimondo,Sartori, Giovanni
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p. 795 - 796
(2007/10/03)
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- Some novel electron transfer mediated cascade ring-opening reactions of bicyclo[4.1.0]ketones
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The radical ring-opening reactions of cyclopropyl ketones, mediated by samarium (II) iodide and other electron transfer agents are described. This strategy allows tandem rearrangement cyclisation reactions and the trapping of the resultant samarium (III) enolates by a variety of electrophiles, for the construction of complex bicyclic systems.
- Batey, Robert A.,Harling, John D.,Motherwell, William B.
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p. 11421 - 11444
(2007/10/03)
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- Copper-Catalyzed Conjugate Addition of Trialkylaluminium to α,β-Unsaturated Carbonyl Compounds
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The Michael-type reaction of copper-catalyzed trialkylaluminium reagents with α,β-unsaturated carbonyl compounds is a useful and simple procedure for the transfer of hydrocarbon substituents.The scope of this process and the effect of chlorotrimethylsilane as additive were investigated.Preparatively useful results were generally obtainde from enones even with higher organoaluminium reagents, whereas the reaction with α,β-unsaturated aldehydes was limited to the use of trimethylaluminium.
- Kabbara, Jazid,Flemming, Steffen,Nickisch, Klaus,Neh, Harribert,Westermann, Juergen
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p. 743 - 754
(2007/10/02)
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- The Kharasch reaction revisited: CuX3Li2-catalyzed conjugate addition reactions of Grignard reagents
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The conjugate addition of Grignard reagents RMgX to α,β-unsaturated ketones and esters is effectively catalyzed by soluble copper ate-complexes of the type CuX3Li2, e.g.CuI*2LiCl.In the presence of Me3SiCl the corresponding ketone enolsilanes are formed in high yield and selectivity.Diastereoselectivity in the case of chiral ketones is similar to that observed by using stoichiometric amounts of cuprates R2CuLi.Thus CuX3Li2-catalyzed 1,4-additions of Grignard reagents may be an industrially viable process.Keywords: Copper; Magnesium; Lithium; Silicon; Ketone; Enolsilanes
- Reetz, Manfred T.,Kindler, Alois
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- Copper-Catalyzed Conjugate Addition of Trimethylaluminium to α,β-Unsaturated Ketones
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The conjugate methylation of α,β-unsaturated ketones with trimethylaluminium occurs smoothly in a very simple procedure under the catalytic CuI salts.Scope and limitations of this process as well as the influence of solvent and catalyst on the kinetics were studied.In addition, the effect of chlorotrimethylsilane as an additive was investigated.Attack on the carbonyl group in 1,2-fashion could not be observed under the reaction conditions.- Key Words: Conjugate alkylation / Trimethylaluminium / Copper catalysis
- Kabbara, Jazid,Flemming, Steffen,Nickisch, Klaus,Neh, Harribert,Westermann, Juergen
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p. 1489 - 1494
(2007/10/02)
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- The role of silanes on the copper-catalyzed conjugate alkylation of enones by organoaluminium reagents
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The effect of silanes as additives in the copper-catalyzed conjugate alkylation of enones by various organoaluminium reagents was investigated. TMSCl led to significant lower amounts of CuBr catalyst needed in the reaction of trimethylaluminium with enones, but was unsuccessful in the case of organoaluminium compounds of the formula Me2AlY (Y = Cl, OR). Me2AlOEt turned out to be a useful reagent for methylation without support of additives.
- Kabbara, Jazid,Flemming, Steffen,Nickisch, Klaus,Neh, Harribert,Westermann, Juergen
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p. 8591 - 8594
(2007/10/02)
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- Alkyliron and Alkylcobalt Reagents, VII. - On the Substitution of the Halogen of Alkenyl Chlorides, Alkenyl Fluorides, and Alkynyl Halides by Reagents of the Type R4MLi2 (M = Fe, Co)
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Me4FeLi2 and Me4CoLi2, which are favourable reagents for the substitution of Br in alkenyl bromides, also proved to be favourable for the substitution of the halogen in alkenyl chlorides (yields 68-99 percent; nearly complete retention of configuration in the case of Me4FeLi2), β-fluorostyrene (best yield 92 percent), and 1-fluoronaphthalene (best yield 47 percent).Me4FeLi2 differentiates between various alkenyl chlorides in 1:1 competition experiments better than Me4CoLi2 and is the optimal reagent for the substitution of halogen in 1-chloro-2-phenylethyne (12), 1-bromo-2-phenylethyne (13), and 1-chloro-3-phenoxypropyne (15) by methyl (yields 70, 46, and 80 percent, respectively).Substitution of the halogen in 12 by the n-butyl, n-octyl, and phenyl residue is better achieved by the catalytic systems RMgBr + 2.5 mol percent FeCl2 (R = nBu, nOct, Ph; yields 75, 63, and 96 percent, respectively) than by the reagents nBu4FeLi2, nBu4Fe(MgBr)2, nOct4Fe(MgBr)2, or Ph4Fe(MgBr)2 (yields 18-28 percent). Key Words: Iron, organo complexes / Cobalt, organo complexes
- Kauffmann, Thomas,Saelker, Reiner,Voss, Karl-Uwe
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p. 1447 - 1452
(2007/10/02)
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- Ene Reactions of Indane-1,2,3-trione (a Super-enophile) and Related Vicinal Tricarbonyl Systems
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Indane-1,2,3-trione 1 is conveniently prepared in quantitative yield by the azeotropic drying of ninhydrin 2 using chlorobenzene as solvent.The central C=O group of the trione is extremely electrophilic and ene addition occurs at this site with a wide range of alkenes and with terminal alkynes in aprotic solvents at moderate temperatures (70-130 deg C).The reactivity of trione 1 is somewhat attenuated by the solvent, and the ene additions are consistently faster in chloroform than in tetrahydrofuran.Stereoselectivity, when relevant, appears largely to be dictated bysteric factors.Regiochemical control can be exercised if the ene contains two reaction sites.Isoprene and 2,4-dimethylpenta-1,3-diene, however, react by Diels-Alder rather than by ene addition; the adducts are the expected regioisomers 18 and 20, respectively.Attempts to catalyse the ene reactions with Lewis acids were unsuccessful.The analogous ene reactions of 4,4,5,5-tetramethyl-cyclopentane-1,2,3-trione 44, 4,4,6,6-tetramethylcyclohexane-1,2,3-trione 45, and 2,2-dimethyl-1,3-dioxane-4,5,6-trione ('oxo-Meldrum's acid') 46 were also briefly investigated.
- Gill, G. Bryon,Idris, Muhammad S. Hj.,Kirollos, Kirollos S.
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p. 2355 - 2366
(2007/10/02)
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- SAMARIUM(II) IODIDE PROMOTED RADICAL RING OPENING REACTIONS OF CYCLOPROPYL KETONES
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Radical ring opening reactions of cyclopropyl ketones mediated by samarium(II) iodide-induced single electron transfer have permitted the elaboration of a tandem rearrangement cyclisation strategy.The resultant samarium enolates may be effectively quenched on oxygen or carbon by electrophiles.Key Words: Samarium(II) Iodide Reduction; Cyclopropylcarbinyl Radical Rearrangement; Cyclopropyl Ketone; Radical Cyclisation; Samarium Enolate.
- Batey, Robert A.,Motherwell, William B.
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p. 6649 - 6652
(2007/10/02)
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- Samarium(II) iodide promoted radical ring opening reactions of cyclopropyl ketones
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Radical ring opening reactions of cyclopropyl ketones mediated by samarium(II) iodide-induced single electron transfer have permitted the elaboration of a tandem rearrangement cyclisation strategy. The resultant samarium enolates may be effectively quenched on oxygen or carbon by electrophiles.
- Batey,Motherwell
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p. 6211 - 6214
(2007/10/02)
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- Reactions of Cyclohexane Derivatives in Superacids
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The reactions of menthol with FSO3H-SO2 and neomenthyl chloride with SbF5-SO2ClF follow different routes.The first yields a substituted cyclopentyl cation and the second a substituted cyclohexyl cation.Experiments on substituted cyclohexyl chlorides show that replacement of all the hydrogen atoms on the next but one carbon atom to the reaction centre blocks formation of a carbocation.It is suggested that ionisation of an equatorial chlorine atom takes place with assistance from an intramolecular electronic interaction, forming the methyl cyclopentyl carbocation in a synchronous process, rather than stepwise via the cyclohexyl carbocation.Reasons for contrasting behaviour in solvolytic reactions are discussed.
- Dean, Christopher,Whittaker, David
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p. 1541 - 1543
(2007/10/02)
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- Amberlyst 15, a Superior, Mild, and Selective Catalyst for Carbonyl Regeneration from Nitrogeneous Derivatives
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Various tosylhydrazones, oximes, 2,4-dinitrophenylhydrazones, and semicarbazones were converted into the corresponding carbonyl compounds, mostly in quantitive yields, via equilibrium exchange with aqueous acetone, by use of Amberlyst 15 as acidic catalyst.Good results were obtained also with aldehyde derivatives.Groups which are acid-sensitive survive under these reaction conditions.
- Ballini, Roberto,Petrini, Marino
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p. 2563 - 2566
(2007/10/02)
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- Organocuprates Containing Dimethyl Sulfoxide Anion as a Nontransferable Ligand
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Mixed homocuprates and in which the anion of dimethyl sulfoxide acts as a nontransferable ligand are readily prepared from MeSOCH2Li, alkyl- or aryllithium reagents, and Cu(I) salts.These novel cuprates are useful in the conversions of acid chlorides to ketones, conjugate additions to α,β-unsaturated ketones, SN2' reactions with allylic or propargylic acetates and epoxides, and coupling reactions with primary iodides and tosylates.All of these reactions proceed with selective transfer of the ligand R.From the points of view of cost, availability, and lack of interference with product isolation, the Me2SO anion is an ideal nontransferable ligand.
- Johnson, Carl R.,Dhanoa, Daljit S.
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p. 1885 - 1888
(2007/10/02)
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- 1,4-Addition of Triorganozincates and Silyldiorganozincates to α,β-Unsaturated Ketones
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Lithium and magnesium triorganozincates, prepared by combination of ZnCl2(TMEDA) with 3 molar equivalents of RLi or RMgX, or from dialkylzinc and 1 molar equivalent of RLi or RMgX, react with 2-cyclohexen-1-one (1) under mild conditions to produce moderate to good yields of the 1,4-addition products 2.The approximate reactivity order obtained from the product distribution using unsymmetrical zincates is tBuCH2 tBu, Me Me2PhSi.The latter groups are transferred with good selectivity from mixed reagents derived from Me2Zn.This sequence differs strikingly from that exhibited by unsymmetrical cuprates which transfer neopentyl very easily, and also tert-butyl more easily than the corresponding zincates.The methylation with Me3ZnLi is catalyzed by cobalt complexes.Other enones (7-13) generally give poor yields, and the cobalt-catalyzed methylation of isophorone (3) is complicated by a Kharasch-type deconjugation.Mixed silyldialkylzincates, Me2PhSiZnR2Li, produce the β-silyl ketones from a variety of unhindered or moderately hindered enones in practically useful yields; one example of an α,β-unsaturated ester (12) is also included.
- Tueckmantel, Werner,Oshima, Koichiro,Nozaki, Hitosi
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p. 1581 - 1593
(2007/10/02)
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- Ultrasound in Organic Synthesis. 7. Preparation of Organozinc Reagents and Their Nickel-Catalyzed Reactions with α,β-Unsaturated Carbonyl Compounds
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Diorganozinc compounds can be prepared with great ease and efficiency in a one-pot process, by sonication of lithium, an organic halide, and a zinc halide in THF or toluene mixtures.The reagents thus obtained give rise to clean and selective conjugate additions to α,β-unsaturated aldehydes and ketones in the presence of catalytic amounts of nickel acetylacetonate.
- Petrier, Christian,Barbosa, Jayne C. de Souza,Dupuy, Claude,Luche, Jean-Louis
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p. 5761 - 5765
(2007/10/02)
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- Cycloadditions of 1-(4-Methoxyphenyl)-2-methylvinyl Cation to Olefins. Stereochemistry and Structure of the Reaction Products
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(E)-1-Bromo-1-(4-methoxyphenyl)-1-propene (1a) reacts stereospecifically with (Z)-2-butene and silver tetrafluoroborate by cycloaddition of the intermediate vinyl cation 2a to give cis-1-(4-methoxyphenyl)-2,3,4-trimethyl-1-cyclobutene (3); with (E)-2-butene, 3 and trans-1-(4-methoxyphenyl)-2,3,4-trimethyl-1-cyclobutene (4) are formed in a ratio of 1:4.These results are in accord with a synchronous cycloaddition of the vinyl cation 2a to (Z)- and (E)-2-butene.Cyclohexene derivatives 14a, 14b, and 14c are obtained predominantly by the reaction of 1a and AgBF4 or AgSbF6 with vinylcyclopropane (11), ethyl vinyl ether (12), and isobutene (13), respectively.
- Bofinger, Klaus Rainer,Hanack, Michael
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p. 2993 - 3003
(2007/10/02)
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- Conjugate Addition Reactions of α,β-Unsaturated Ketones with Higher Order, Mixed Organocuprate Reagents, R2Cu(CN)Li2
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Conjugate reactions of mixed cuprates R2Cu(CN)Li2 with α,β-unsaturated ketones are reported.These reagents, in most cases, react extremely rapidly affording the corresponding alkylated ketones in high yields.Attempts at trapping the intermediate enolates appeared to be successful using MeI as electrophile; however, the method is not general and was, therefore, not pursued.The effects of solvent and ligand composition on R2Cu(CN)Li2 as well as on the more highly mixed species RTRRCu(CN)Li2 have been examined.The selectivity of ligand transfer in these latter,second generation organocuprates is also discussed.
- Lipshutz, Bruce H.,Wilhelm, Robert S.,Kozlowski, Joseph A.
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p. 3938 - 3942
(2007/10/02)
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- ULTRASOUND IN ORGANIC SYNTHESIS 6. AN EASY PREPARATION OF ORGANOZINC REAGENTS AND THEIR CONJUGATE ADDITION TO α-ENONES
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Sonication allows the efficient preparation of various organozinc reagents, which cleanly add in a conjugate fashion to α-enones in the presence of Ni(acac)2.
- Petrier, Christian,Luche, Jean-Louis,Dupuy, Claude
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p. 3463 - 3466
(2007/10/02)
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- Reaction of β-halo α,β-unsaturated ketons with cuprate reagents. Efficient syntheses of β,β-dialkyl ketones and β-alkyl α,β-unsaturated ketones. A synthesis of (Z)-jasmone
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Treatment of the 3-halo-2-cyclohexen-1-ones 11-15 and 17 with an excess of lithium dimethylcuprate provided good to excellent yields of the corresponding 3,3-dimethylcyclohexanones 21-24.Similar reactions involving the β-bromo cyclopentenones 19 and 20 stopped at the monoaddition stage, producing the cyclopentenones 40 and 43.Reaction of the β-bromo cyclohexenones 12 and 15 with 1.1 equiv. of lithium dimethylcuprate did not effect clean conversion of these substrates into the corresponding 3-methyl-2-cyclohexen-1-ones.When a series of β-bromo enones 12, 14-19were allowed to react with the lithium (phenylthio)(alkyl)cuprates 44-47, the correspondig β-alkyl enones were, in general, produced cleanly and efficiently.However, reaction of 3-bromo-2-methyl-2-cyclopenten-1-one (19) with the cuprate reagent 44 gave mainly the β-phenylthio enone 49.This undesired result could be avoided by employing, in the place of 19, The β-iodo cyclopentenone 50, which reacted smoothly with 44 to give a high yield of 2,3-dimethyl-2-cyclopenten-1-one (40).Reaction of 3-bromo-2-cyclohexen-1-one (14) with 3 equiv. of the mixed vinylcuprate reagent 48 gave 3-(3-butenyl)-2-cyclohexen-1-one (32).Alkylation of 1,3-cyclopentanedione with (Z)-1-chloro-2-pentene afforded compound 51, which was converted into the β-bromo enone 52.Treatment of the latter substance with lithium dimethylcuprate provided (Z)-jasmone (53).
- Piers, Edward,Cheng, Kin Fai,Nagakura, Isao
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p. 1256 - 1263
(2007/10/02)
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