Michael-Stork addition of cyclopentyl enamine to allenyl ketones and esters

[Chemical reaction: see text] We report the first examples of a Michael-Stork enamine addition to allenyl esters and ketones. Studies reveal that 2 equivalents of enamine are required for optimal yields. In the case of an allenyl methyl ketone, cyclopentyl enamine addition led to 8-oxobicyclo[3.2.1]octane formation, providing evidence for the in situ formation of an enamine intermediate following the initial Michael-Stork reaction.     

Unusual reaction of aryldiazoacetates with enamines: highly effective synthesis of γ-ketoesters

The reaction of aryldiazoacetates with enamines catalyzed by copper and rhodium complexes provided γ-ketoesters in good yields. Careful analysis of the crude reaction mixture revealed a substituted enamine as the primary product, which was hydrolyzed over silica gel to give a γ-ketoester as the final product. A reaction mechanism involving nucleophilic addition of an enamine to a metal carbene and subsequent hydrogen transfer was proposed.     

New reaction of enamines with aryldiazoacetates catalyzed by transition metal complexes

The reaction of aryldiazoacetates with enamines catalyzed by copper and rhodium complexes provided γ-keto esters in good yields. A full investigation of the effects of solvents, catalysts, enamines and aryldiazoacetates on the reaction was carried out. Careful analysis of the crude reaction mixture revealed a substituted enamine as the primary product, which was hydrolyzed over silica gel to give a γ-keto ester as the final product. A reaction mechanism involving nucleophilic addition of an enamine to a metal carbene and subsequent hydrogen transfer was proposed. Chiral dirhodium and copper catalysts were examined and found to provide γ-keto esters with no enantioselectivity. The result could be rationalized based on the proposed reaction mechanism. Attempts to trap the enamine intermediate with several electrophilic reagents were not successful.     

Mechanistic investigation of the 2,5-diphenylpyrrolidine-catalyzed enantioselective alpha-chlorination of aldehydes

The mechanism for the 2,5-diphenylpyrrolidine-catalyzed enantioselective alpha-chlorination of aldehydes with electrophilic halogenation reagents has been investigated by using experimental and computational methods. These studies have led us to propose a mechanism for the reaction that proceeds through an initial N-chlorination of the chiral catalyst-substrate complex, followed by a 1,3-sigmatropic shift of the chlorine atom to the enamine carbon atom. The suggested reaction course is different from previously proposed mechanisms for organocatalytic enamine reactions, in which the carbon-electrophile bond is formed directly. Furthermore, the rate-determining step in the overall reaction was determined and the presence of nonlinear effects was probed.     

Development and evaluation of conditions for the kinetic quantitation of acetoacetate in body fluids

This paper describes a detailed study of the kinetic behavior of reactions used in the quantitation of acetoacetate in body fluids. Reactions studied are those between acetoacetate and glycine to form a transiently stable enamine intermediate, reaction of the enamine intermediate with nitroprusside, and simultaneous reaction of acetoacetate, glycine, and nitroprusside (nitrosopentacyanoferrate(III). Variables studied include pH, temperature and concentrations of all reactants. The primary reaction between acetoacetate and glycine follows pseudo-first-order kinetics at high pH (ρ 8.6) at which the enamine is transiently stable; the other reactions deviate from first-order behavior at longer times because the reaction product is unstable. Several options involving nonlinear curve-fitting methods applied to all reaction sequences above and an initial-rate method applied to the combined reactions are evaluated. Also, the two-step and combined-reaction sequences are evaluated for quantitation of acetoacetate in urine and serum samples. For acetoacetate in the concentration range 0.5–4.25 mmol l^?1, the methods yield relative standard deviations in the range 1.0–1.8% with absolute standard deviations of 3.5–35 μmol l^?1.     

The oxidation of compounds capable of imine-enamine tautomerism with lead tetraacetate

Compounds capable of imine-enamine tautomerism react preferentially via their enamine tautomer giving a 2-acetoxyaldehyde which equilibrates with the starting imine. This derives from the extra nucleophilicity of the β-carbon of the enamine tautomer. The reaction of the imine isomer to form an aryl- or an alkylnitrenoid species is a minor pathway.     

Fluoroalkyl alpha,beta-unsaturated imines. Valuable synthetic intermediates from primary fluorinated enamine phosphonates

[reaction: see text] A simple method for the preparation of fluoroalkyl allylamines or alpha,beta-unsaturated ketones by an olefination reaction of primary enamine phosphonates and aldehydes, followed by selective reduction with hydrides or hydrolysis, is reported. Fluorinated beta-amino nitriles are also obtained by an olefination reaction of primary enamine phosphonates with aldehydes and subsequent addition of metalated acetonitrile.     

Catalytic Asymmetric Electrochemical α‐Arylation of Cyclic β‐Ketocarbonyls with Anodic Benzyne Intermediates

Asymmetric catalysis with benzyne remains elusive because of the highly fleeting and nonpolar nature of benzyne intermediates. Reported herein is an electrochemical approach for the oxidative generation of benzynes (cyclohexyne) and its successful merging with chiral primary aminocatalysis, formulating the first catalytic asymmetric enamine–benzyne (cyclohexyne) coupling reaction. Cobalt acetate was identified to stabilize the in situ generated arynes and facilitate its coupling with an enamine. This catalytic enamine‐benzyne protocol provides a concise method for the construction of diverse α‐aryl (α‐cyclohexenyl) quaternary carbon stereogenic centers with good stereoselectivities.     

Synthesis and Photo-oxygenation of Some Substituted 1-Benzyl-3,4-dihydroisoquinolines. Mechanism of Enamine Photo-oxygenation

The synthesis of a series of substituted 1-benzyl-3,4-dihydroisoquinolines by Bischler-Napieralski cyclization is described. Competitive methylene blue sensitized photo-oxygenation experiments allowed the determination of relative rates of photo-oxygenation of 1-benzyl-3,4-dihydroisoquinolines, Substituents were shown to affect both the equilibrium concentration of the tautomeric enamine and the overall photo-oxygenation rate. After correcting for differences in enamine concentration, the relative rate data provided a diagnostic probe of the reaction mechanism, which involves transfer of charge in the rate-limiting step.     

Biosynthetically Inspired Syntheses of Secu′amamine A and Fluvirosaones A and B

Presented here is a concise synthesis of secu′amamine A, and fluvirosaones A and B from readily available allosecurinine and viroallosecurinine. The key C2‐enamine derivative of (viro)allosecurinine, the presumed biosynthetic precursors of these natural products, was accessed, for the first time, by a VO(acac)₂‐mediated regioselective Polonovski reaction. Formal hydration and 1,2‐amine shift of this pluripotent enamine compound afforded secu′amamine A. Formal oxidative [3+2] cycloaddition reaction between this enamine and TMS‐substituted methallyl iodide reagent paved the way to the precursors of fluvirosaones A and B. The relative stereochemistry at the C2 position of these advanced intermediates governs the fate of 1,2‐amine shift leading to fluvirosaones A and B. The syntheses of potential biosynthetic precursors and investigations of their chemical reactivities have provided insights regarding the biogenesis of these natural products.     

New, general, and practical enamine cyclopropanation using dichloromethane

[reaction: see text] Dichloromethane serves as a novel electrophilic carbene equivalent which adds to an enamine double bond. The presence of other alkene moieties in the enamine partner is well tolerated. Even enamines derived from sterically hindered ketones react readily with dichloromethane promoted by TiCl(4)-Mg.     

Theoretical investigations on the stereoselectivity of the proline catalyzed Mannich reaction in DMSO

The stereocontrol steps of the (S)-proline catalyzed Mannich reaction of cyclohexanone, formaldehyde, and aniline were theoretically investigated. The geometries of reactants, products, and transition states were optimized using density functional theory using the B3LYP functional with the 6-31++G(d,p) basis set. The energies of these compounds were then more accurately determined at the MP2 level, and the effect of DMSO as the solvent was included using a polarizable continuum model (PCM). The reaction was modeled from the previously proposed mechanism that cyclohexanone reacts with (S)-proline to generate an enamine, while formaldehyde reacts with aniline to produce an imine, and that the conformation around the C-N bond of the enamine 1 is crucial for the further enantioselective step. The formation of two conformations of the enamine via a proton transfer process was examined, revealing activation barriers for syn- and anti-enamine proton transfer of 10.2 and 17.9 kcal/mol, respectively. The transformation of syn- to anti-enamine through C-N bond rotation, however, was predicted to require only 4.2 kcal/mol, while the (S)- and (R)-intermediates could be obtained from subsequent reactions between enamine and imine with energy barriers of 8.5 and 12.4 kcal/mol, respectively. The difference between these barriers, but not the C-N rotation energy, becomes larger at the MP2 level and when DMSO as a solvent is included. This predicted enantioselective reaction, through the kinetic and thermodynamic favoring of the (S)-pathway, is in agreement with experimental results, which have reported the (S)-configuration as the major product.     

A selective synthesis of enamines versus aziridines

The reaction of 10‐azidoacetyl‐10H‐phenothiazine with olefinic dipolarophiles depends on the reaction temperature. In refluxing toluene, a mixture of enamine and aziridine is formed in 3:1 ratio. The reaction mechanism appears to involve a Michael‐type addition of the nucleophilic N¹ azide atom to the olefinic double bond. In chloroform, a cycloaddition reaction takes place with the formation of a 4,5‐dihydro‐1,2,3‐triazole. The heating of dihydrotriazoles in toluene is accompanied by nitrogen elimination leading to a mixture of enamine and aziridine in 1:3 ratio. J. Heterocyclic Chem., 2011.     

Enantioselective Formal [3+3] Cycloadditions of Ketones and Cyclic 1‐Azadienes by Cascade Enamine–Enamine Catalysis

An asymmetric formal [3+3] cycloaddition process with diversely structured aliphatic ketones and electron‐deficient cyclic 1‐azadienes was developed by cascade enamine–enamine catalysis of a cinchona‐based primary amine. This sequence involved a domino Michael addition–Mannich reaction to afford spirocyclic architectures in excellent diastereo‐ and enantioselectivity. Importantly, high regioselectivity was realized for a number of unsymmetrical aliphatic ketone substrates.     

Formation and stability of prolinol and prolinol ether enamines by NMR: delicate selectivity and reactivity balances and parasitic equilibria

Enamine key intermediates in organocatalysis, derived from aldehydes and prolinol or J?rgensen-Hayashi-type prolinol ether catalysts, were generated in different solvents and investigated by NMR spectroscopy. Depending on the catalyst structure, trends for their formation and amounts are elucidated. For prolinol catalysts, the first enamine detection in situ is presented and the rapid cyclization of the enamine to the oxazolidine ("parasitic equilibrium") is monitored. In the case of diphenylprolinol, this equilibrium is fully shifted to the endo-oxazolidine ("dead end") by the two geminal phenyl rings, most probably because of the Thorpe-Ingold effect. With bulkier and electron-withdrawing aryl rings, however, the enamine is stabilized relative to the oxazolidine, allowing for the parallel detection of the enamine and the oxazolidine. In the case of prolinol ethers, the enamine amounts decrease with increasing sizes of the aryl meta-substituents and the O-protecting group. In addition, for small aldehyde alkyl chains, Z-configured enamines are observed for the first time in solution. Prolinol silyl ether enamines are evidenced to undergo slow desilylation and subsequent rapid oxazolidine formation in DMSO. For unfortunate combinations of aldehydes, catalysts, solvents, and additives, the enamine formation is drastically decelerated but can be screened for by a rapid and facile NMR approach. Altogether, especially by clarifying the delicate balances of catalyst selectivity and reactivity, our NMR spectroscopic findings can be expected to substantially aid synthetically working organic chemists in the optimization of organocatalytic reaction conditions and of prolinol (ether) substitution patterns for enamine catalysis.     

Experimental and Computational Studies on the CH Amination Mechanism of Tetrahydrocarbazoles via Hydroperoxides

The acid‐catalyzed reactions of photochemically generated tetrahydrocarbazole peroxides with anilines have been studied experimentally and computationally to identify the underlying reaction mechanism. The kinetic data indicate a reaction order of one in the hydroperoxide and zero in the aniline. Computational investigations using density functional theory support the experimental findings and predict an initial tautomerization between an imine and enamine substructure of the primarily generated tetrahydrocarbazole peroxide to be the rate controlling step. The enamine tautomer then loses hydrogen peroxide upon protonation, generating a stabilized allylic carbocation that is reversibly trapped by solvent or aniline to form the isolated products.     

Phosphorylation of Nitrogen-Bearing Unsaturated and Aromatic Compounds

Abstract

The enamine reaction provides a valuable method for the selective alkylation and acylation of aldehydes and keto-nes. Similar procedure of phosphorylation is not practically studied. Using 1,3,3-trimethyl-2-methyleneindoline (Fischer's base) as the model enamine we investigated conditions of phosphorylation as well as stereochemistry, and reactions of obtained products of type 1. It was found that properties of some compounds were similar to those of amides of phosphorus acids (vinilologie).     

Rapid analysis of solvent effects on enamine formation by fluorescence: how might enzymes facilitate enamine chemistry with primary amines?

In order to determine factors that facilitate the use of primary amines in biological chemistry, solvent effects on enamine formation with glycine were studied. Solvent effects were rapidly analyzed by monitoring the increase in fluorescence resulting from the reaction between a fluorogenic maleimide and in situ-generated enamine of acetone. These studies suggest that in addition to a simple hydrophobic microenvironment, a microenvironment that also affords for hydrogen bond formation facilitates enamine-based reactions involving primary amines.     

Rhodium-catalyzed cycloisomerization of N-propargyl enamine derivatives

A novel rhodium-catalyzed cycloisomerization has been developed which converts N-propargyl enamine derivatives to their isomeric six-membered azacycles in good yields under mild reaction conditions. The [Rh(C2H2)2Cl]2/P(4-F-C6H4)3 catalyst, in combination with DABCO as a base and DMF as a solvent, was found to be effective in promoting the cyclization process. The reaction is proposed to proceed through an intramolecular nucleophilic attack of the enamine to the rhodium vinylidene followed by a base-mediated proton-shunting process. The base was found to play a crucial role in the transformation, indicating the proton migration to be an integral component of the catalytic cycle. An aprotic polar solvent was required for high conversion, which points to the intermediacy of a zwitterionic intermediate. The present reaction should prove useful for the efficient synthesis of various six-membered azacycles that are important structural motifs of many natural isolates and medicinal agents.     

Pyrrolidine as an efficient organocatalyst for direct aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with ketones

Pyrrolidine-catalyzed aldol reaction of trifluoroacetaldehyde ethyl hemiacetal (1) with ketones or aldehydes was described. In the presence of 20 mol % of pyrrolidine, the reaction proceeded smoothly at room temperature to afford the aldol products in good to excellent yields (up to 95%). Pyrrolidine showed a much higher catalytic activity than piperidine in the reaction with less reactive ketones. GC analysis clearly indicated that the catalyst and the enamine intermediates were kept at extremely low concentration during the reaction. Based on these observations, we suggested that formation of the enamine would be a rate-determining step for the catalytic aldol reaction. In addition, the asymmetric aldol reaction of 1 with cyclohexanone catalyzed by l-proline derivatives was also discussed.