Sodium Enolate Research Articles

Scalable Preparation of the Masked Acyl Cyanide TBS-MAC.

This paper describes the three-step synthesis of TBS-MAC, a masked acyl cyanide (MAC) and a versatile one-carbon oxidation state three synthon. We have developed a scalable and detailed synthesis that involves: (1) acetylation of malononitrile to form the sodium enolate, (2) protonation of the enolate to form acetylmalononitrile, and (3) epoxidation of the enol, rearrangement to an unstable alcohol, and TBS-protection to form the title compound. Both the sodium enolate and acetylmalononitrile are bench-stable precursors to the intermediate hydroxymalononitrile, which can be converted to other MAC reagents beyond TBS by varying the protecting group (Ac, MOM, EE, etc.).

6,7‐Benzotropolone Syntheses Based on Ring‐Closing Metatheses and Four‐Electron Oxidations

Four homoallyl ortho‐vinylaryl ketones (10a‐d) – 1,8‐dienes of sorts – were prepared by several approaches. In the presence of 1–2 mol‐% Grubbs‐II catalyst, they ring‐closed to give 6,7‐dihydrobenzocyclohepten‐5‐ones (11a‐d) in 90–96 % yield. With SeO2 the parent compound (11a) delivered benzocyclohepten‐5‐one (13a) and/or selenium‐containing compounds (18–22) but no more than traces of 6,7‐benzotropolone (5a). However, 5a was accessible from compound 11a via the sodium enolate and allowing it to react with a stream of oxygen (43 % yield). The sodium enolates of the substituted 6,7‐dihydrobenzocyclohepten‐5‐ones 11b–d and oxygen underwent analogous 4‐electron oxidations. This furnished the substituted 6,7‐benzotropolones 11b‐d. In contrast, the corresponding lithium enolates were inert towards oxygen. The 6,7‐dihydrobenzocyclohepten‐5‐one 11d was also accessed differently, namely by a Grubbs‐II catalyst‐mediated RCM/C=C migration tandem reaction of the allyl ortho‐allylaryl ketone 73 – another 1,8‐diene of sorts (90 % yield).

DFT investigations of the unusual reactivity of 2‐pyridinecarboxaldehyde in base‐catalyzed aldol reactions with acetophenone

AbstractThe aldol reaction is recognized as an archetypal method to form carbon‐carbon bonds. Base‐catalyzed aldol reactions of aryl aldehydes with aryl methyl ketones typically produce condensation products (chalcones). However, 2‐pyridinecarboxaldehye, 2‐quinolinecarboxaldehyde, and 2‐ and 3‐fluorobenzaldehyde undergo tandem aldol‐Michael reactions with aryl enolates to yield conjugate addition products. To elucidate the different reactivities of aldol products formed in the reactions of benzaldehyde and 2‐pyridinecarboxaldehyde with the sodium enolate of acetophenone, density functional theory (DFT) calculations were performed to compare the energies of conformational isomers of the intermediates formed in the reaction, the energies of the corresponding condensation products, and the kinetic barriers to dehydration and conjugate addition. Computational results support the formation of the trans isomer of the condensation product in base‐catalyzed aldol reactions of either benzaldehyde or 2‐pyridinecarboxaldehyde with acetophenone. The susceptibility of the condensation product to conjugate addition is determined to result from the lower LUMO energy of trans‐1‐phenyl‐3‐(2‐pyridinyl)‐2‐propen‐1‐one. Consequently, the kinetic barrier for conjugate addition of a second equivalent of enolate with the condensation product of 2‐pyridinecarboxaldehyde is found to be significantly lower. Similar results were obtained for the reactions of fluorobenzaldehydes with aryl enolates.

Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives

A convenient two-step synthesis of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate derivatives has been developed starting from commercially available 2-aminobenzoic acids. In step 1, the anthranilic acids are smoothly converted to isatoic anhydrides using solid triphosgene in THF. In step 2, the anhydride electrophiles are reacted with the sodium enolate of ethyl acetoacetate, generated from sodium hydroxide, in warm N,N-dimethylacetamide resulting in the formation of substituted quinolines. A degradation–build-up strategy of the ethyl ester at the 3-position allowed for the construction of the α-hydroxyacetic acid residue required for the synthesis of key arylquinolines involved in an HIV integrase project.

Sodium Enolate Derived Reactions of N-Boc and N-benzyl-2-(S)- Pyroglutamates with Electrophiles: Synthesis of 4-Substituted and 2- Substituted Pyroglutamates

Sodium Enolate Derived Reactions of N-Boc and N-benzyl-2-(S)- Pyroglutamates with Electrophiles: Synthesis of 4-Substituted and 2- Substituted Pyroglutamates

Nucleophile-Mediated Ring Expansion of 5-Acyl-substituted 4-Mesyloxymethyl-1,2,3,4-tetrahydropyrimidin-2-ones in the Synthesis of 7-Membered Analogues of Biginelli Compounds and Related Heterocycles.

A general six-step approach to alkyl 2-oxo-2,3,6,7-tetrahydro-1H-1,3-diazepine-5-carboxylates and 5-acyl-2,3,6,7-tetrahydro-1H-1,3-diazepin-2-ones based on the nucleophile-mediated ring expansion reaction of 5-functionalized 4-mesyloxymethyl-1,2,3,4-tetrahydropyrimidin-2-ones has been developed. Synthesis of the latter involved nucleophilic substitution of tosyl group in readily available N-[(2-benzoyloxy-1-tosyl)ethyl]urea with sodium enolates of β-oxoesters or 1,3-diketones, followed by dehydration or heterocyclization-dehydration of resulting products, removal of benzoyl protection, and conversion of hydroxymethyl group into mesyloxymethyl group. Conformations of the obtained tetrahydro-1H-1,3-diazepin-2-ones in solid state and solutions were established using X-ray diffraction and NMR spectroscopy. A plausible mechanism of tetrahydropyrimidine ring expansion based on DFT calculation at B3LYP/6-31+G(d,p) level and NMR monitoring experiments was discussed. The ring contraction reaction of methoxy- or phenylthio-diazepinones under acidic conditions resulted in the corresponding 3-functionalized 1-carbamoyl-1H-pyrroles.

Thiocarbamate-Based Synthesis of 2,4,5,6-Tetrahydro-3H-1,2,4-Triazepine-3-Thiones

A five-step synthesis of 5,7-diaryl-substituted 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones starting from ethyl thiocarbamate was developed. The synthesis included a three-component condensation of ethyl thiocarbamate with aromatic aldehydes and p-toluenesulfinic acid to give O-ethyl[(aryl)(tosyl)methyl]thiocarbamates which were transformed into the corresponding O-ethyl (3-phenyl-3-oxopropyl) thiocarbamates by treatment with the sodium enolate of dibenzoylmethane followed by base-promoted retro-Claisen condensation. Reaction of the prepared thiocarbamates with hydrazine and subsequent acid-catalysed cyclisation of the derived 4-[(3-hydrazono-3-phenyl)prop-1-yl]semicarbazides gave the target triazepines.

SelectfluorTM on a PolyHIPE Material as Regenerative and Reusable Polymer‐Supported Electrophilic Fluorinating Agent

AbstractThe first recyclable polymer‐supported electrophilic fluorinating agent was prepared by reaction of molecular fluorine with the triethylenediamine motif that is grafted onto a poly(4‐vinylbenzyl chloride‐co‐divinylbenzene) polyHIPE material. The resulting polymeric SelectfluorTM‐type reagent demonstrated high efficiency in the fluorination of naphthol in the course of repeated sequences of fluorination and regeneration. It also reacted with the enol form and the sodium enolate of 1,3‐dicarbonyl compounds.magnified image

Different modes of acid-catalyzed cyclization of 4-(γ-oxoalkyl)semicarbazide hydrazones: 7-membered versus 14-membered cyclic semicarbazones formation

Acid-catalyzed cyclization of 4-(γ-oxoalkyl)semicarbazide hydrazones has been studied. 7-Membered cyclic semicarbazones, 2,4,5,6-tetrahydro-3H-1,2,4-triazepin-3-ones, were obtained from the γ-phenyl-substituted semicarbazides, while the cyclization of the γ-methyl-substituted semicarbazides involved two molecules of the starting material to result in 14-membered cyclic bis-semicarbazones, 1,2,4,8,9,11-hexaazacyclotetradeca-7,14-diene-3,10-diones. The 4-(γ-oxoalkyl)semicarbazide hydrazones were prepared according to a four-step synthesis based on amidoalkylation of the sodium enolates of 1,3-diketones with ethyl N-(1-tosylalk-1-yl)carbamates followed by base-promoted retro-Claisen reaction and treatment of the obtained ethyl N-(γ-oxoalkyl)carbamates with hydrazine.

Synthesis and structure of 2,6,7-trihydroxy-4,9-dioxodeca-2,5,7-trienoic acid esters

2,6,7-Trihydroxy-4,9-dioxodeca-2,5,7-trienoic acid esters and the corresponding sodium enolates were synthesized by condensation of acetone with dialkyl oxalates, and their structure was determined on the basis of IR, UV, and 1H NMR spectral data.

Reaction of 1-bromovinyl and 1-bromo-2-phenylvinyl sulfones with some CH acids

Benzyl, methyl, and phenyl α-bromovinyl sulfones reacted with malononitrile and dimethyl malonate sodium enolates in THF to give sulfonyl-substituted cyclopropanes. Reactions of the same sulfones with methyl acetoacetate sodium enolate afforded the corresponding sulfonyl-substituted cyclopropanes as mixtures of cis and trans isomers with a small impurity of 5-sulfonyl-4,5-dihydrofuran derivative. Phenyl and p-tolyl 1-bromo-2-phenylvinyl sulfones reacted with methyl acetoacetate sodium salt to produce a mixture of trans-isomeric 5-sulfonyl-4,5-dihydrofuran and Michael adduct of the CH acid with activated acetylene generated by concurrent 1,2-dehydrobromination of the initial α-bromovinyl sulfone.

Synthesis of novel 14-membered cyclic bis-semicarbazones

An efficient method for the stereoselective synthesis of novel 14-membered cyclic bis-semicarbazones based on acid-catalyzed cyclization of the hydrazones of 3-(3-oxobutyl)semicarbazides has been developed. The starting semicarbazides were prepared according to a four-step strategy involving amidoalkylation of the sodium enolate of acetylacetone with N-(α-tosylbenzyl)carbamates followed by base-promoted retro-Claisen reaction and treatment of the obtained N-(3-oxobutyl)carbamates with hydrazine.

ChemInform Abstract: Enantioselective Fluorination of β‐Ketoesters Catalyzed by Chiral Sodium Phosphate: Remarkable Enhancement of Reactivity by Simultaneous Utilization of Metal Enolate and Metal Phosphate.

A highly enantioselective fluorination of β-ketoesters catalyzed by chiral sodium phosphate is achieved. In this process, the simultaneous formation of sodium enolate and sodium phosphate under bas...

Method of continuous variation: characterization of alkali metal enolates using ¹H and ¹⁹F NMR spectroscopies.

The method of continuous variation in conjunction with 1H and 19F NMR spectroscopies was used to characterize lithium and sodium enolates solvated by N,N,N′,N′-tetramethylethyldiamine (TMEDA) and tetrahydrofuran (THF). A strategy developed using lithium enolates was then applied to the more challenging sodium enolates. A number of sodium enolates solvated by TMEDA or THF afford exclusively tetramers. Evidence suggests that TMEDA chelates sodium on cubic tetramers.

Nucleophilic addition/double cyclization cascade processes between enynyl Fischer carbene complexes and alkynyl malonates.

Two new selective cascade processes for enynyl Fischer carbene complexes 1 are described in their reaction with alkynyl malonates. When carbene complexes 1 react with the sodium enolate of homopropargyl malonates 3 a consecutive Michael-type addition/cyclopentannulation/6-exo cyclization takes place leading, in a regio- and stereoselective way, to n/5/6 angular tricyclic compounds 5. Furthermore, when propargylic malonates are used, a delayed protonation of the reaction mixture allows intermediate 1,4-addition adduct Ia to evolve through a 5-exo cyclization, consisting of an intramolecular nucleophilic attack from the central carbon of the allenylmetallate over the triple C-C bond. Further spontaneous cyclopentannulation of the resulting metallatriene gives rise to bicyclic and linear polycyclic compounds 6 and 7, some of them bearing a polyquinane framework.

Pd‐Catalyzed Carbonylative α‐Arylation of Aryl Bromides: Scope and Mechanistic Studies

Reaction conditions for the three-component synthesis of aryl 1,3-diketones are reported applying the palladium-catalyzed carbonylative α-arylation of ketones with aryl bromides. The optimal conditions were found by using a catalytic system derived from [Pd(dba)2] (dba=dibenzylideneacetone) as the palladium source and 1,3-bis(diphenylphosphino)propane (DPPP) as the bidentate ligand. These transformations were run in the two-chamber reactor, COware, applying only 1.5 equivalents of carbon monoxide generated from the CO-releasing compound, 9-methylfluorene-9-carbonyl chloride (COgen). The methodology proved adaptable to a wide variety of aryl and heteroaryl bromides leading to a diverse range of aryl 1,3-diketones. A mechanistic investigation of this transformation relying on 31P and 13C NMR spectroscopy was undertaken to determine the possible catalytic pathway. Our results revealed that the combination of [Pd(dba)2] and DPPP was only reactive towards 4-bromoanisole in the presence of the sodium enolate of propiophenone suggesting that a [Pd(dppp)(enolate)] anion was initially generated before the oxidative-addition step. Subsequent CO insertion into an [Pd(Ar)(dppp)(enolate)] species provided the 1,3-diketone. These results indicate that a catalytic cycle, different from the classical carbonylation mechanism proposed by Heck, is operating. To investigate the effect of the dba ligand, the Pd0 precursor, [Pd(η3-1-PhC3H4)(η5-C5H5)], was examined. In the presence of DPPP, and in contrast to [Pd(dba)2], its oxidative addition with 4-bromoanisole occurred smoothly providing the [PdBr(Ar)(dppp)] complex. After treatment with CO, the acyl complex [Pd(CO)Br(Ar)(dppp)] was generated, however, its treatment with the sodium enolate led exclusively to the acylated enol in high yield. Nevertheless, the carbonylative α-arylation of 4-bromoanisole with either catalytic or stoichiometric [Pd(η3-1-PhC3H4)(η5-C5H5)] over a short reaction time, led to the 1,3-diketone product. Because none of the acylated enol was detected, this implied that a similar mechanistic pathway is operating as that observed for the same transformation with [Pd(dba)2] as the Pd source.

Enantioselective Fluorination of β-Ketoesters Catalyzed by Chiral Sodium Phosphate: Remarkable Enhancement of Reactivity by Simultaneous Utilization of Metal Enolate and Metal Phosphate

Abstract A highly enantioselective fluorination of β-ketoesters catalyzed by chiral sodium phosphate is achieved. In this process, the simultaneous formation of sodium enolate and sodium phosphate under basic conditions is the key to achieving excellent selectivity. Indanone derivatives as well as benzofuranone derivatives could be employed in this reaction to afford the fluorinated adducts in good yields with good to excellent enantioselectivities.

ChemInform Abstract: Improved Synthesis of 3‐Aryl Isoxazoles Containing Fused Aromatic Rings.

A critical comparison of methods to prepare sterically hindered 3-aryl isoxazoles containing fused aromatic rings using the nitrile oxide cycloaddition (NOC) reveal that modification of the method of Bode, Hachisu, Matsuura, and Suzuki (BHMS), utilizing either triethylamine as base or sodium enolates of the diketone, ketoester, and ketoamide dipolarophiles, respectively, was the method of choice for this transformation.

Synthesis of γ-Azido-β-ureido Ketones and Their Transformation into Functionalized Pyrrolines and Pyrroles via Staudinger/aza-Wittig Reaction

A simple two-step procedure yielding γ-azido-β-ureido ketones or/and their cyclic isomers, 6-(1-azidoalkyl)-4-hydroxyhexahydropyrimidin-2-ones, has been developed. The synthesis includes three-component condensation of acetals of 2-azidoaldehydes with urea or methylurea and p-toluenesulfinic acid in aqueous formic acid followed by reaction of the obtained N-[(2-azido-1-tosyl)alkyl]ureas with sodium enolates of α-functionalized ketones. The azido ketones or their cyclic isomers are transformed into ureido-substituted Δ(1)- or/and Δ(2)-pyrrolines via Staudinger/aza-Wittig reaction promoted by PPh(3). The obtained pyrrolines are converted into 3-functionalized 1H-pyrroles via elimination of urea under acidic conditions. Convenient one-pot syntheses of 1H-pyrroles starting from N-[(2-azido-1-tosyl)alkyl]ureas or γ-azido-β-ureido ketones have been also developed.

UNUSUAL COURSE OF THE REACTION OF N-(TOSYLMETHYL)THIOUREA AND N-(AZIDOMETHYL)THIOUREA WITH SODIUM ENOLATE OF DIMEDONE

The end product of the reaction of N-(tosylmethyl)thiourea or N-(azidomethyl)thiourea with sodium enolate of dimedone is bis(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)methane (methylenebis-dimedone) instead of the expected 8a-hydroxy-7,7-dimethyl-2-thioxoperhydroquinazolin-5-one. Authors: A. D. Shutalev and E. A. Kishko. English Translation in Chemistry of Heterocyclic Compounds , 2000, 36 (1), pp 62-64 http://link.springer.com/article/10.1007/BF02256846