Lewis acid-catalyzed one-pot sequential reaction for the synthesis of α-halogenated β-keto esters

A Lewis acid-catalyzed one-pot sequential transformation of β-keto esters, aromatic aldehydes, and NCS/NBS was reported. The reaction proceeds by way of Knoevenagel condensation/Nazarov cyclization/halogenation to give α-chloro- and α-bromo-β-keto esters in moderate yields with high diastereoselectivities. However, several aromatic aldehydes with electron-withdrawing substituents afforded unexpected α,β′-dichloro-β-keto esters in good to high yields.     

SPANamine derivatives in the catalytic asymmetric α-fluorination of β-keto esters

The use of C₂-symmetric enantiopure nitrogen ligands in the asymmetric catalytic α-fluorination of β-ketoesters is described. SPANamine 1 in the presence of nickel salts gives up to 63% ee in the fluorination of tert-butyl 2-oxocyclopentanecarboxylate with N-fluorosuccinimide (NFSI). The same enantioselectivity is obtained when SPANamine 1 is used as an organocatalyst, although the reaction is much slower.     

Diastereoselectivity in the Carroll rearrangement of β-keto esters of tertiary allylic alcohols

Carroll rearrangement of β-keto esters derived from tertiary allylic alcohols, for example, 7, under basic conditions followed by decarboxylation of the resulting β-keto acids yielded the expected γ,δ-unsaturated methyl ketones 8 with a range of olefin geometries from 100:0 to 1:1.8 E/Z, depending on the relative steric requirements of the two groups at the allylic center.     

A mechanistic investigation into the zinc carbenoid-mediated homologation reaction by DFT methods: is a classical donor-acceptor cyclopropane intermediate involved?

An extensive density functional theory (DFT, M05-2X) investigation has been performed on the zinc carbenoid-mediated homologation reaction of β-keto esters. The mechanistic existence of a classical donor-acceptor cyclopropane intermediate was probed to test the traditional school of thought regarding these systems. Calculations of the carbenoid insertion step, following enolate formation, unmasked two possible pathways. Pathway B was shown to explain the proposed, but spectroscopically unobservable donor-acceptor cyclopropane intermediate, while the second (pathway A) reveals an alternative to the classical intermediate in that a cyclopropane transition state leads to product.     

Studies on the reaction of α-imino esters with organometallic compounds

Benzylzinc reagent reacted with α-imino ester (2) at the α-carbon exclusively, though other organometallic reagents such as Mg. Al, Cu, Tl, and B derivatives reacted at the nitrogen atom. Use of the (S)-amine as a chiral auxiliary of 2 created the R chirality at the imino carbon. Very high chiral Induction was realized In the reaction of prenylzinc reagent wlih α-imino 8-(-)phenylmenthyl ester (10). The reaction of 2 with heteroatom substituted allylic organometalic compounds (15) gave the corresponding α-heterostom substituted amino acid derivatives (16). Here again, the allylic zinc reagent gave the adduct in higher yield than the corresponding Tl, Al, and B reagents.     

NMR investigation on the interaction of β-cyclodextrin and ampicillin

The penetration of ampicillin molecule into the β-cyclodextrin cavity in aqueous solution is studied by ¹ H NMR, 2D COSY and ROESY spectroscopy. Obtained data suggest that the phenyl moiety of ampicillin is included inside the hydrophobic cavity of β-cyclodextrin molecule in the solution, and the mode and depth of this inclusion is confirmed on the basis of 2D ROESY spectral data.     

Tetramic acids and indole derivatives from amino acid β-keto esters. Fine-tuning the conditions of the key Cu-catalyzed reaction

1,3,5-Trisubstituted tetramic acids and 2,3-disubstituted indole derivatives were prepared from β-keto esters derived from amino acids by their reaction with iodophenyl-2-trifluoroacetylamine under Cu-catalysis. Both heterocyclic systems were generated from the same starting materials by choice of the appropriate reaction conditions.     

Transition-metal,organic solvent and base free α-hydroxylation of β-keto esters and β-keto amides with peroxides in water

Without employing any transition metal, organic solvent and base, a facile, economical and environmentally friendly strategy has been developed for the α-hydroxylation of β-keto esters and β-keto amides with peroxides via radical cross-coupling reaction in water under open-air conditions. This protocol allows a convenient access to various α-hydroxy-β-keto esters and α-hydroxy-β-keto amides with up to 92% yield (34 examples). Moreover, the reaction was successfully scaled up to gram quantity and mechanistic studies showed the radical pathway was involved in this hydroxylation.     

Inclusion of parabens in β-cyclodextrin: A solution NMR and X-ray structural investigation

A parallel study was conducted of the inclusion of alkyl parabens (guests) in the host β-cyclodextrin (β-CD). ¹H NMR data indicated an insertion of the guest phenyl ring into the β-CD cavity. The stoichiometry of each complex was 1:1, as determined by a continuous variation method that utilises the chemical shifts of the host protons. These chemical shifts were additionally used to determine the association constant yielding K values of 1631, 938, 460 and 2022 M^? 1 at 298 K for the methyl-, ethyl-, propyl- and butyl paraben solution state complexes, respectively. NOE experiments conducted on the methyl paraben solution complex indicated that the phenolic group of the guest was located at the secondary rim of the cyclodextrin cavity. Solid state structure analyses of the methyl and propyl paraben β-CD complexes were performed. Both complexes crystallised at ambient temperature in the space group C2, Z = 4 with a host to guest ratio of 1:1. Additionally, a second crystal structure between methyl paraben and β-CD is reported. This complex crystallised at 7^oC in the space group P1, Z = 2 with a 1:1 host–guest stoichiometry.

¹H NMR and solid state structure analyses were conducted on the inclusion of alkyl parabens in the host β-cyclodextrin. Both indicated an insertion of the guest phenyl ring into the β-CD cavity.     

A highly diastereoselective decarboxylative mannich reaction of β-keto acids with optically active N-sulfinyl α-imino esters

A range of protected γ-oxo-α-amino esters have been prepared in a highly regio- and stereoselective manner through the decarboxylative Mannich reaction of β-keto acids with optically active N-tert-butanesulfinyl α-imino esters in the presence of 3 mol % La(OTf)(3) or 5 mol % Y(OTf)(3) at 20 °C. Preliminary mechanistic studies indicate that the reaction proceeds through imine addition followed by decarboxylation.     

Synthesis of β-keto esters in-flow and rapid access to substituted pyrimidines

We have developed an in-flow process for the synthesis of β-keto esters via the BF(3)·OEt(2)-catalyzed formal C-H insertion of ethyl diazoacetate into aldehydes. The β-keto esters were then condensed with a range of amidines to give a variety of 2,6-substituted pyrimidin-4-ols.     

Recoverable Cinchona ammonium salts as organocatalysts in the enantioselective Michael addition of β-keto esters

Several dimeric Cinchona-alkaloid anthracenyldimethyl-derived ammonium salts, are used as organocatalysts in the enantioselective Michael addition reaction of cyclic β-keto esters to α,β-unsaturated carbonyl compounds, in the presence of diisopropylethylamine as a base (30 mol %), for the generation of enantiomerically enriched adducts bearing quaternary stereocenters. Quinine and quinidine-derived dimeric ammonium salts (1–10 mol %) afford the opposite and higher enantioselectivities of the corresponding adducts (up to 94% ee) in good yields (up to 98%). Substituted 2-alkoxycarbonyl-1-indanones are used as nucleophile precursors, as well as ethyl 2-oxocyclopentanecarboxylate and tert-butyl 2,5-dioxo-1-phenylpyrrolidine-3-carboxylate. These organocatalysts can be recovered at the end of the reaction by precipitation in ether and reused without any loss of activity.     

Photoinduced electron-transfer reaction of α-bromomethyl-substituted benzocyclic β-keto esters with amines: selective reaction pathways depending on the nature of the amine radical cations

Photoinduced electron-transfer reaction of α-bromomethyl-substituted benzocyclic β-keto esters with tertiary amines was investigated. Debrominated β-keto esters and ring-expanded γ-keto esters were obtained as major products. On the basis of mechanistic experiments it was concluded that these products are formed via a reaction sequence of selective carbon–bromine bond cleavage and subsequent competitive hydrogen abstraction and Dowd–Beckwith ring-expansion of the resulting primary alkyl radicals. The characteristic product distribution observed for the type of amine used is rationalized on the basis of selective reaction pathways of generated radical intermediates that depend on the nature of the amine radical cations.     

Rhodium-catalyzed cross-coupling reaction of arylboronates and diazoesters and tandem alkylation reaction for the synthesis of quaternary α,α-heterodiaryl carboxylic esters

A rhodium-catalyzed one-pot three-component coupling reaction was developed for the synthesis of quaternary α,α-heterodiaryl carboxylic esters. This reaction involves cross-coupling of the arylrhodium(I) complexes with α-aryldiazoacetates to form oxa-π-allylrhodium complexes. With KOtBu and alkyl halides, tandem alkylation of the allyl complex occurs to form a quaternary stereocenter at the carbenic carbon.     

A DFT investigation of the retro-ene reactions of β-hydroxyacetylenes: concerted or stepwise mechanism

Structural Chemistry - The retro-ene reactions of β-hydroxyacetylene and its 10 derivatives have been investigated theoretically at the B3LYP/6-31+G(d) level. The reactions are found to...     

Recent topics in the syntheses of β-keto carboxylic acids and the derivatives

β-Keto carboxylic acids are key intermediates in organic syntheses, used for the development of fine chemicals, natural products, and various biologically relevant molecules. Their utilities stem from the structural features and facile bond formations, e.g., asymmetric reduction of carbonyl groups for the synthesis of β-hydroxy carboxylic acids and conjugated addition reactions through decarboxylative enolate nucleophiles, which utilize the amphiphilic reactivity of β-keto carboxylic acids. Despite their versatility and utilities, development of efficient and straightforward synthetic methods for β-keto carboxylic acids has not attracted considerable attention owing to their instability. As efficient synthetic strategies for β-keto carboxylic acids and their derivatives, reactions of α-diazoesters, acylation of malonate anions, cross-coupling reactions, and CO₂ insertion reactions are summarized in this review.     

Catalytic asymmetric chloroamination reaction of α,β-unsaturated γ-keto esters and chalcones

Highly efficient catalytic chloroamination reaction of α,β-unsaturated γ-keto esters and chalcones has been developed via a chloronium-based mechanism to deliver anti-regioselective vicinal chloroamines instead of the aziridinium intermediates delivered aminochlorides. The combination of TsNCl(2) and TsNH(2) as reagents made the transformation highly efficient, delivering the γ-carbonyl-β-chloro-α-amino acid derivatives and α-chloro-β-amino-ketone derivatives in nearly quantitative yields with up to 99% ee and 99:1 dr under 0.05-0.5 mol % catalyst loading. TsNHCl was demonstrated to act as the key reactive species to form a bridged chloronium ion intermediate in the presence of a chiral scandium complex. The method might provide useful information for further realization of other haloamination reactions.     

Catalytic enantioselective chlorination of cyclic β-keto esters in the presence of chiral Pd(II) complexes

The catalytic enantioselective electrophilic chlorination promoted by chiral palladium complexes is described. The treatment of β-keto esters with 2,3,4,5,6,6-hexachlorocyclohex-2,4-dienone as chlorine source under mild reaction conditions afforded the corresponding α-chlorinated β-keto esters with excellent enantioselectivities (up to 94% ee).