A novel route to 5-substituted 3-isoxazolols. Cyclization of N, O-DiBoc beta-keto hydroxamic acids synthesized via acyl Meldrum's acids

3-Isoxazolols are most often synthesized from a beta-keto ester and hydroxylamine. This cyclization typically gives rise to a major byproduct, the corresponding 5-isoxazolone. We have found that N, O-diBoc-protected beta-keto hydroxamic acids can be synthesized and cyclized to 5-substituted 3-isoxazolols without formation of any byproduct. We present a novel and versatile three-step procedure in which carboxylic acid derivatives are converted into acyl Meldrum's acids which, upon aminolysis with N, O-bis(tert-butoxycarbonyl)hydroxylamine, lead to the N, O-diBoc-protected beta-keto hydroxamic acids. These hydroxamic acid analogues were then, upon treatment with hydrochloric acid, cyclized to the corresponding 5-substituted 3-isoxazolols.     

Method for the rapid synthesis of highly functionalized 2-hydroxy-1-naphthoates. Syntheses of the naphthoic acid components of neocarzinostatin chromophore and N1999A2

We describe a four-step sequence for the synthesis of complex 2-hydroxy-1-naphthoic acids involving Z-selective olefination of benzaldehyde derivatives with a novel dioxolenone-containing phenyl phosphonate reagent, followed by dioxolenone cleavage with alkaline trifluoroethanol and oxidative cyclization (Mn(OAc)(3)) of the resultant trifluoroethyl beta-keto esters. [reaction: see text]     

Zinc- and indium-mediated ring-expansion reaction of alpha-halomethyl cyclic beta-keto esters in aqueous alcohol

Radical ring-expansion reaction of various alpha-halomethyl cyclic beta-keto esters and alpha-halomethyl benzocyclic beta-keto esters and chain-extension reaction of alpha-halomethyl beta-keto esters with zinc powder and indium powder in refluxing aqueous alcohol were carried out to generate the corresponding ring-expansion and chain-extension products. As the results indicate, it was found zinc powder was more effective than indium powder to give the corresponding ring-expanded products in quite good yields. Moreover, the addition of zinc bromide as Lewis acid showed an increase of the yields, depending on the substrates. The present reaction conditions are highly effective, simple, and environmentally friendly.     

Formation of a quaternary carbon center through the Pd(0)/PhCOOH-catalyzed allylation of cyclic beta-keto esters and 1,3-diketones with alkynes

Formation of a quaternary carbon center through the allylation of beta-keto esters and 1,3-diketones with alkynes is accomplished by the use of Pd(0)/benzoic acid catalyst. Reactions of various cyclic beta-keto esters and 1,3-diketones with alkynes in the presence of Pd(2)dba(3).CHCl(3) (5 mol %), PPh(3) (40 mol %), and PhCOOH (10 mol %) proceeded at 100 degrees C in toluene (5 M) to give the corresponding allylation products in high yields in a regio- and stereoselective manner. The possibility of asymmetric allylation is also discussed.     

Zinc-mediated ring-expansion and chain-extension reactions of beta-keto esters

[Chemical reaction: see text] The reaction of cyclic beta-keto esters with CF3CO2ZnCH2I provided the corresponding ring-expanded products in moderate to good yields. Although alpha-substituted acyclic beta-keto esters reacted with much less efficient, chain-extension reaction of simple beta-keto esters also proceeded effectively to generate gamma-keto esters in high yields.     

Facile and efficient one-pot synthesis of highly functionalized thieno[2,3-b]thiopyran-4-ones from beta-keto epsilon-xanthyl phosphonates

The one-pot synthesis of various functionalized thieno[2,3- b]thiopyran-4-ones from readily available beta-keto epsilon-xanthyl phosphonates has been accomplished by combining a Horner-Wadsworth-Emmons olefination with a base-induced intramolecular domino cyclization/thio-Michael addition. The use of cyclic ketones in this transformation allowed a facile access to novel spiro-type thieno[2,3- b]thiopyran structures.     

Unexpected formation of tetrasubstituted 2,3-dihydrofurans from the reactions of beta-keto polyfluoroalkanesulfones with aldehydes

Catalyzed by piperidine, the reactions of beta-keto polyfluoroalkanesulfones with aromatic aldehydes afforded the unexpected tetrasubstituted 2,3-dihydrofurans in good yields, probably proceeding through the normal Knoevenagel condensation products. This reaction provided an efficient and novel method for the stereoselective synthesis of fluorine-containing tetrasubstituted trans-2,3-dihydrofurans.     

Reactions of N-hydroxysuccinimide esters of anthranilic acids with anions of beta-keto esters. A new route to 4-oxo-3-quinolinecarboxylic acid derivatives

A new approach for the synthesis of 4-oxo-3-quinolinecarboxylic acid derivatives is described. This methodology involves the C-acylation of the anions of appropriate beta-keto esters with novel N-hydroxysuccinimide esters of anthranilic acids. The intermediate C-acylation products 3 are spontaneously cyclized to afford 3-ethoxycarbonyl-4-oxoquinoline derivatives 4. The introduction of a variety of substituents at positions 1 and 2 of the quinoline ring is feasible with the selection of suitable anthranilic acids and beta-keto esters. The structure of the obtained 2-substituted 3-ethoxycarbonyl-4-oxoquinolines was confirmed by IR and NMR spectral data.     

New Fe(III)-mediated radical cascade reactions of cyclopropyl silyl ethers

[reaction: see text] Fe(III)-mediated ring opening of cyclopropyl ethers bearing a phenyl-substituted butenyl side chain leads to the generation of beta-keto radicals that undergo 5-exo cyclization followed by a novel cascade sequence resulting in the formation of tricyclic ethers.     

Manganese-catalyzed construction of tetrasubstituted benzenes from 1,3-dicarbonyl compounds and terminal acetylenes

Treatment of beta-keto esters with terminal acetylenes in the presence of a catalytic amount of a manganese complex, MnBr(CO)5, and molecular sieves, gave multisubstituted aromatic compounds in good to excellent yields. This reaction employs [2 + 2 + 2] cycloaddition of beta-keto esters and 2 equiv of terminal acetylenes with dehydration. In the case of a 1,3-diketone, the corresponding acetophenone derivative and its deacylated compound can be synthesized selectively.     

Enantioselective Michael addition of beta-keto esters to methyl vinyl ketone employing a chiral N,N'-dioxide-scandium trifluoromethanesulfonate complex as a catalyst

An enantioselective Michael addition of beta-keto esters to methyl vinyl ketone exploiting a chiral N,N'-dioxide-scandium trifluoromethanesulfonate complex as a catalyst affords the corresponding Michael adducts in high yields and with enantioselectivities of up to 80% ee.     

Diastereoselective Vinyl Phosphate/beta-Keto Phosphonate Rearrangements

Several nonracemic diols and amino alcohols have been tested for their utility as chiral auxiliaries in vinyl phosphate/beta-keto phosphonate rearrangements. When (2R,4R)- or (2S,4S)-pentane-2,4-diol were employed, the diastereomeric beta-keto phosphonates obtained from three prochiral cyclohexanones gave separate resonances in their respective (31)P NMR spectra, allowing estimation of diastereomeric excess (de) via straightforward integration. A crystalline enol form of the beta-keto phosphonate was obtained from one ketone (4-(1,1-(ethylenedioxy)ethyl)-4-methylcyclohexanone, 10), which allowed determination of its absolute stereochemistry by X-ray diffraction analysis. When LTMP was used to induce rearrangement of vinyl phosphates derived from ketone 10 and (2R,4R)- or (2S,4S)-pentane-2,4-diol, a de of 2.5:1 was obtained. In addition, de values of 2.0:1 and 1.4:1 were obtained with parallel rearrangements of 4-isopropyl- and 4-methylcyclohexanone, suggesting that this sequence may be more generally applicable to preparation of nonracemic materials from prochiral cyclohexanones.     

Catalytic enantioselective Michael addition of 1,3-dicarbonyl compounds to nitroalkenes catalyzed by well-defined chiral ru amido complexes

Well-defined chiral Ru amido complexes promoted asymmetric Michael addition of 1,3-dicarbonyl compounds including malonates, beta-keto esters, and 1,3-diketones to nitroalkenes to give the corresponding adducts with excellent ees and in excellent yields.     

Direct carbon-carbon bond formation via chemoselective soft enolization of thioesters: a remarkably simple and versatile crossed-Claisen reaction applied to the synthesis of LY294002

Thioesters undergo chemoselective soft enolization and acylation by N-acylbenzotriazoles on treatment with MgBr2 x OEt2 and i-Pr2NEt to give beta-keto thioesters. Prior enolate formation is not required, and the reaction is conducted using untreated CH2Cl2 open to the air. The coupled products are stable synthetic equivalents of beta-keto acids and can be converted directly into beta-keto esters, beta-keto amides, and beta-diketones under mild conditions. The utility of this carbon-carbon bond-forming method is shown through the synthesis of the PI3-K inhibitor LY294002.     

CuI-catalyzed domino process to 2,3-disubstituted benzofurans from 1-bromo-2-iodobenzenes and beta-keto esters

CuI-catalyzed coupling of 1-bromo-2-iodobenzenes with beta-keto esters in THF at 100 degrees C leads to 2,3-disubstituted benzofurans. This domino transformation involves an intermolecular C-C bond formation and a subsequent intramolecular C-O bond formation process. Benzofurans with different substituents at the 5- and 6-position are accessible by employing the corresponding 1-bromo-2-iodobenzenes.     

Synthesis of cyclic enol ethers from alkenyl-beta-dicarbonyl compounds

In this work we describe the cyclofunctionalization of eleven differently substituted alkenyl-beta-dicarbonyl compounds, employing three electrophilic reagents, namely, iodine, p-methoxyphenyltellurium trichloride, and phenylselenenyl bromide. The reactions occur through the enolic form of the substrates, to afford the corresponding iodo-, telluro-, or selenocyclic enol ethers. Substrates bearing trisubstituted double bonds failed in reacting with the selenium and tellurium reagents. In general, beta-diketones reacted faster than beta-keto esters with the three studied electrophiles.     

Catalytic enantioselective fluorination and amination of beta-keto phosphonates catalyzed by chiral palladium complexes

[reaction: see text] The catalytic enantioselective fluorination and amination of beta-keto phosphonates catalyzed by chiral palladium complexes is described. Treatment of beta-keto phosphonates with N-fluorobenzenesulfonimide (NFSI) as electrophilic fluorinating reagent and diethyl azodicarboxylate (DEAD) as electrophilic amination reagent under mild reaction conditions afforded the corresponding alpha-substituted beta-keto phosphonates in moderate to excellent yields with excellent enantiomeric excesses.     

Enantioselective alkylation of beta-keto esters by phase-transfer catalysis using chiral quaternary ammonium salts

Catalytic enantioselective alkylation promoted by a quaternary ammonium salt from cinchonine as a phase transfer catalyst is described. Treatment of cyclo beta-keto esters with alkyl halide under mild reaction conditions afforded the corresponding alpha-alkylated beta-keto esters in moderate to excellent yields with high enantiomeric excesses     

Diversity-oriented synthesis of privileged benzopyranyl heterocycles from s-cis-enones

A novel strategy for the construction of benzopyranyl heterocyclic series with maximized diversity in the polar surface area on rigid scaffolds has been developed through a divergent synthetic pathway with high efficiency. s-cis-Enones embedded in a benzopyran skeleton were identified as versatile key intermediates for the synthesis of four different heterocycle libraries fused with a benzopyran substructure. These four novel core skeletons were designed by a creative recombination of the privileged skeletons: benzopyran, pyridine, pyrazole, pyrazolopyrimidine, and pyrimidine. The regioselective synthesis of each core skeleton was achieved by the introduction of three s-cis enone intermediates. This paper also explores the regioselective formation of arylpyrazole through the condensation of beta-keto aldehyde with arylhydrazine under three different conditions and presents the mechanistic information that was obtained from the regioisomeric ratio of arylpyrazole based on the substituent's electronic effect and reaction temperature. It appears that the regioselective synthesis of arylpyrazole was achieved through the intriguing interplay of the nucleophilicity on arylhydrazine and the electrophilicity on dielectrophiles.     

A novel multicomponent reaction of arynes, beta-keto sulfones, and michael-type acceptors: a direct synthesis of polysubstituted naphthols and naphthalenes

A novel multicomponent reaction of arynes, beta-keto sulfones, and Michael-type acceptors is presented, providing an efficient method for the synthesis of polysubstituted naphthols and polysubstituted naphthalenes. Further investigation suggests that the tandem reaction may proceed via a sequential nucleophilic attack to arynes, intramolecular nucleophilic substitution followed by a Michael addition, and a ring closure-elimination process.