Β-keto Esters Research Articles

One-Pot Synthesis and Characterization of 3,4-Dihydropyrimidin-2(1H)-one Derivatives using Sulphonated Reduced Graphene Oxide Nanoparticles via Biginelli Cyclocondensation and its Cytotoxic Studies

A facile one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones (4a-h) was performed in the presence of sulphonated reduced graphene oxide nanoparticles (SrGO NPs), using various substituted aromatic aldehydes (1a-h), β-keto ester (2) and urea (3). Methanol solvent mediated the reaction, under refluxing conditions. The synthesized SrGO NPs were characterized using XRD, SEM-EDS and Raman spectroscopic methods. The structural moieties of the organic compounds were confirmed by 1H NMR, 13C NMR, FTIR and Mass spectroscopic techniques. The in vitro anticancer activity of the synthesized derivatives (4a-h) was investigated using MTT (4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric assay as per American Type Culture Collection protocol. The cytotoxic studies were conducted against MCF-7, SKNSH human cells, using doxorubicin as the standard. Majority of the derivatives have exhibited superior anticancer activity.

Electroreductive 4-pyridylation of unsaturated compounds using gaseous ammonia as a hydrogen source

By using ammonia as a hydrogen source, electrochemical pyridylation of unsaturated compounds is achieved with more than 50 examples. In particular, the β-keto ester could be converted to the corresponding tertiary β-hydroxyl ester for the first time.

Asymmetric silane reduction of ketones and β-Keto esters catalyzed by a chiral azolium/iridium system in the presence of a base in methanol at room temperature

Asymmetric silane reduction of ketones catalyzed by a system comprising a chiral azolium salt 1 and [Ir(cod)2]BF4 (2) in the presence of a base in methanol was achieved at room temperature within 2 h. Implementing a “pre-mixing” experimental procedure improved the efficiency of the catalytic reaction. Specifically, after treating a mixture of 1 and 2 with (EtO)2MeSiH (3a) in THF, the ketone substrate was allowed to react in the presence of K2CO3 in methanol at room temperature to afford the corresponding optically active alcohol in high yield and enantioselectivity. The reaction parameters were fully evaluated. The presence of 3a in the pre-mixing step and that of a base in the reduction step were found to be essential for success. The developed method was applied to the stereoselective reduction of β-keto esters. Additionally, an iridium species derived from the reaction of 1 with [IrCl(cod)]2 and AgBF4 was investigated.

Biocatalytic dynamic reductive kinetic resolution of aryl α-chloro β-keto esters: divergent, stereocontrolled synthesis of diltiazem, clentiazem, and siratiazem.

The first systematic study of ketoreductase (KRED)-catalyzed dynamic reductive kinetic resolution (DYRKR) on aryl α-chloro β-keto esters was performed, and 15 structurally diverse chiral anti-aryl α-chloro β-hydroxy esters were synthesized in 74-98% isolated yields, along with moderate-to-excellent diastereoselectivity (up to >99 : 1 dr) and good-to-excellent enantioselectivity (mostly >99% ee). LfSDR1-catalyzed complete reduction of 100 g L-1 of substrate 6b at a ten-gram scale was achieved with a continuous fed-batch strategy, affording anti-(2S,3S)-1b, the key intermediate of diltiazem, in a record-breaking space-time yield of 96 g L-1 d-1. An eight-step synthesis of diltiazem, clentiazem, and siratiazem was accomplished in 32-45% overall yields, featuring this versatile biocatalytic reduction reaction as well as an efficient, green chlorination reaction in flow.

A Convenient Green Protocol for the Synthesis of 4-Arylmethylidene-3-substituted-isoxazol-5(4H)-ones catalysed by Dimethylaminopyridine (DMAP)

Isoxazolemotif containing heterocyclic compounds are important for their wide range of biological activities. Therefore, in the present article, I report a convenient and green protocol for the synthesis of 4-arylmethylidene-3-substituted-isoxazol-5(4H)-ones by the one pot three component reaction of aldehydes, β-keto ester and hydroxylamine hydrochloride catalyzed by Dimethylaminopyridine (DMAP). 1 (a-i) 2(a-b) 3 (4a-f), (5a-i) Scheme 1: Reagent and conditions:(i) Dimethylaminopyridine (DMAP), H2O (5 mL), 70- 800C, 6 to 25 min.

Ligand- and Substrate-Controlled Chemodivergent Pd-Catalyzed Annulations of Cyclic β-Keto Esters with 3-Aryl-2H-azirines.

Chemodivergent Pd-catalyzed annulations of cyclic β-keto esters with 3-aryl-2H-azirines have been developed to provide rapid access to eight-membered ring lactams, bicyclic 3,4-dihydro-2H-pyrrole derivatives, and (E)-methyl [2-(2-oxocyclohexylidene)-2-phenylethyl]carbamates with high efficiency. The chemoselectivity can be determined by tuning the mono- or bisphosphine ligands as well as the substrate structure of cyclic β-keto esters.

PPh3-catalyzed β-selective addition of α-fluoro β-dicarbonyl compounds to allenoates

A highly selective phosphine-catalyzed β-addition of α-fluoro β-dicarbonyl compounds to allenoates has been developed. Both α-fluoro β-diketones and α-fluoro β-keto esters prove to be competent fluorocarbon nucleophiles, giving a series of the β-addition products bearing a fluorinated quaternary carbon center in good to excellent yields and with excellent regioselectivities. A plausible reaction pathway is presented.

One-Pot and Solvent Free Synthesis of 3,4-Dihydropyrimidin-2(1H)-Ones Using Recyclable Resin Purolite CT275DR as a Heterogeneous Catalyst via Three-Component Biginelli-Like Reactions

The Biginelli reaction is a one pot multicomponent reaction involves aromatic aldehyde, β-keto ester, and urea or thiourea in presence cationic exchange resins Purolite CT275DR supplied by Purolite to afford the corresponding dihydropyrimidine-2-one and there sulfur analog 3,4-dihydropyrimidine-2-thione in solvent free condition gave high yield and catalyst could be recycle and reused without much decrease in the catalytic activity.

Phase-Transfer Catalyzed Asymmetric [4 + 1] Annulations for the Synthesis of Chiral 2,2-Disubstituted Tetrahydrothiophenes.

An efficient catalytic asymmetric [4 + 1] reaction, which features the use of simple β-keto esters as one-carbon nucleophiles and 5-succinimidothio-pent-2-enoates as four-atom bielectrophiles, has been developed in the presence of a bifunctional chiral phase-transfer catalyst. The new annulation provides a distinct protocol to access the functionalized 2-acyl-2-carboxyl tetrahydrothiophenes bearing consecutive quaternary and tertiary carbon stereocenters in high diastereoselectivities and enantioselectivities. Moreover, the prepared products could be readily transformed into the chiral 2-alkyl-2-carboxyl tetrahydrothiophenes via two steps of debenzoylation and alkylation reactions.

Conversion of 5-methyl-4H-benzo[d][1,3]dioxin-4-one derivatives into functionalized 8-hydroxyisochroman-1-one under basic conditions

Syntheses of 8-hydroxyisochroman-1-one derivatives are described, promoted via a base-induced anionic accelerated rearrangement reaction from dimethyl dioxinone protected resorcylates. A biomimetic polyketide aromatization strategy via selective C-acylation of a β-keto ester, Pd(0)-catalyzed allylic migration and base-promoted cyclization and aromatization furnished the arene core of the resorcylate precursors.

Recent Progress on Synthesis and Bio-activities of Tetrahydropyrimidine-2-one derivatives

This review covers up synthesis, characterization and Pharmacological activities of various derivatives of 1,2,3,4-Tetrahydropyrimidine-2-one, including recent mechanistic advances, new building blocks and new pharmacological disclosures. Tetrahydropyrimidines (THPs) are one of the most important systems among the heterocycles. These compounds reported to have less toxicity to human and animals. Various synthesis strategies have been reported for different derivatives of Tetrahydropyrimidines, mainly these involves Biginelli reaction (condensation) consisting of one pot synthesis of 1,2,3,4-Tetrahydropyrimidine derivatives using urea, β-keto ester and aldehyde. These derivatives also forms important part as intermediate in the manufacture of various Pharmaceuticals. Techniques such as infrared spectroscopy, liquid chromatography-mass spectrometry, 1H NMR and 13C NMR spectrometry along with single crystal X-ray diffraction has been reported for structural characterization of these derivatives. U.S. National Library of Medicines, NIH and European PMC have reported many these derivatives. Some of derivatives have reported to have promising anti-bacterial, cytotoxic, antifungal, anti-inflammatory activities. Recently Ultrasound and Microwave promoted synthesis has shown promising results in synthesis of these derivatives. Many exciting prospects await for its exploitation in this fields.

A New Scalable Synthesis of ELQ-300, ELQ-316, and other Antiparasitic Quinolones.

The Endochin-Like Quinolone (ELQ) compound class may yield effective, safe treatments for a range of important human and animal afflictions. However, to access the public health potential of this compound series, a synthetic route needed to be devised that lowers costs and is amenable to large scale production. In the new synthetic route described here, a substituted β-keto ester, formed by an Ullmann reaction and subsequent acylation, is reacted with an aniline via a Conrad-Limpach reaction to produce 3-substituted 4(1H)-quinolones such as ELQ-300 and ELQ-316. This synthetic route, the first described to be truly amenable to industrial scale production, is relatively short (5 reaction steps), does not require palladium, chromatographic separation or protecting group chemistry, and may be performed without high vacuum distillation.

Diastereoselective Reduction of Selected α-substituted β-keto Esters and the Assignment of the Relative Configuration by 1H-NMR Spectroscopy

Background:: Chiral β-hydroxy esters and α-substituted β-hydroxy esters represent versatile building blocks for pheromones, β-lactam antibiotics and 1,2- or 1,3-aminoalcohols. Objective:: Synthesis of versatile α-substituted β-keto esters and their diastereoselective reduction to the corresponding syn- or anti-α-substituted β-hydroxy esters. Assignment of the relative configuration by NMR-spectroscopy after a Curtius rearrangement of α-substituted β-keto esters to 4-substituted 5-methyloxazolidin-2-ones. Methods: Diastereoselective reduction was achieved by using different Lewis acids (zinc, titanium and cerium) in combination with complex borohydrides as reducing agents. Assignment of the relative configuration was verified by 1H-NMR spectroscopy after Curtius-rearrangement of α-substituted β-hydroxy esters to 4-substituted 5-methyloxazolidin-2-ones. Results:: For the syn-selective reduction, titanium tetrachloride (TiCl4) in combination with a pyridine-borane complex (py BH3) led to diastereoselectivities up to 99% dr. High anti-selective reduction was achieved by using cerium trichloride (CeCl3) and steric hindered reducing agents such as lithium triethylborohydride (LiEt3BH). After Curtius-rearrangement of each α-substituted β-hydroxy ester to the corresponding 4-substituted 5-methyloxazolidin-2-one, the relative configuration was confirmed by 1H NMR-spectroscopy. Conclusion:: We have expanded the procedure of Lewis acid-mediated diastereoselective reduction to bulky α-substituents such as the isopropyl group and the electron withdrawing phenyl ring.

Effect of organic solvents on asymmetric reduction of β-keto esters using cyanobacterium Synechocystis sp. PCC 6803

The asymmetric reduction of tert-butyl 3-oxobutanoate by cyanobacterium Synechocystis sp. PCC 6803 under illumination with red LED light at 25 °C for 24 h afforded the corresponding (R)-β-hydroxy ester in 79% enantiomeric excess (ee) (81% yield), while the addition of toluene (1% (v/v)) to the system gave the corresponding (S)-β-hydroxy ester in >99% ee (87% yield). Organic solvents such as chloroform, benzene, ethylbenzene, cyclohexane, and methylcyclohexane showed similar effects and afforded the corresponding (S)-β-hydroxy ester in >99% ee. However, polar organic solvents, such as DMSO, THF, and ethanol, as well as dodecane—a hydrophobic solvent with a straight long-chain—did not exhibit such effects.

Synthesis and Characterization of Novel Methyl (3)5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates.

Series of methyl 3- and 5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates were developed and regioselectively synthesized as novel heterocyclic amino acids in their N-Boc protected ester form for achiral and chiral building blocks. In the first stage of the synthesis, piperidine-4-carboxylic and (R)- and (S)-piperidine-3-carboxylic acids were converted to the corresponding β-keto esters, which were then treated with N,N-dimethylformamide dimethyl acetal. The subsequent reaction of β-enamine diketones with various N-mono-substituted hydrazines afforded the target 5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates as major products, and tautomeric NH-pyrazoles prepared from hydrazine hydrate were further N-alkylated with alkyl halides to give 3-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates. The structures of the novel heterocyclic compounds were confirmed by 1H-, 13C-, and 15N-NMR spectroscopy and HRMS investigation.

Reactions of CF3-Haloenones with 1,3-Dicarbonyl Compounds: Chemo- and Stereoselective Assembly of Fluorinated Dihydrofurans

The chemo- and stereoselective one-pot synthesis of functionalized trifluoromethylated 4,5-dihydrofurans was developed. It consists in the treatment of fluorinated 2-haloenones with 1,3-dicarbonyl compounds (1,3-diketones and β-keto esters). The reaction was generally found to proceed in moderate to good yield and excellent selectivity. The mechanism of the assembly of these heterocycles is discussed in terms of multi-step processes involving formation of Michael adduct followed by cyclization through the classical intramolecular halogen nucleophilic substitution at sp3 carbon atom.

Rh(III)-Catalyzed Cascade Nucleophilic Addition/Annulation of 2-Diazo-1,3-diketones with 1,3-Dicarbonyl Compounds To Access 6,7-Dihydrobenzofuran-4(5H)-ones.

A Rh(III)-catalyzed cascade nucleophilic addition/intramolecular annulation of 2-diazo-1,3-diketones with 1,3-dicarbonyl compounds (e.g., 1,3-diketones and β-keto esters) is achieved to afford 6,7-dihydrobenzofuran-4(5H)-ones in up to 91% yields. Notably, a wide range of substrates and functional groups were well-tolerated under the optimized reaction conditions to give desired products in moderate to excellent yields with release of N2 and H2O as byproducts. Moreover, the method described is scalable and adaptable to late-stage functionalization.

Highly Enantioselective Direct Asymmetric Reductive Amination of 2-Acetyl-6-Substituted Pyridines.

A highly direct asymmetric reductive amination of a variety of ketone substrates, including 2-acetyl-6-substituted pyridines, β-keto esters, β-keto amides, and 1-(6-methylpyridin-2-yl)propan-2-one, has been disclosed for the first time (94.6% to >99.9% ee). With ammonium trifluoroacetate as the nitrogen source, various chiral corresponding primary amines were prepared in excellent enantioselectivity and conversion in the presence of a commercially available and inexpensive chiral catalyst, Ru(OAc)2{(S)-binap}, under 0.8 MPa of hydrogen gas pressure.

Enantioselective Total Synthesis of (+)-EBC-23, a Potent Anticancer Agent from the Australian Rainforest.

We describe here an enantioselective synthesis of (+)-EBC-23, a potent anticancer agent from the Australian rainforest. Our convergent synthesis features a [3+2] dipolar cycloaddition of an olefin-bearing 1,3-syn diol unit and an oxime segment containing 1,2-syn diol functionality as the key step. The segments were synthesized in a highly enantioselective manner using Noyori asymmetric hydrogenation of a β-keto ester and Sharpless asymmetric dihydroxylation of an α,β-unsaturated ester. Cycloaddition provided isoxazoline derivative which upon hydrogenolysis furnished the β-hydroxy ketone expediently. A one-pot, acid-catalyzed reaction removed the isopropylidene group, promoted spirocyclization, constructed the complex spiroketal lactone core, and furnished EBC-23 and its C11 epimer. The C11 epimer was also converted to EBC-23 by chemoselective oxidation and reduction sequence. The present synthesis provides convenient access to this family of natural products in an efficient manner.

Synthesis and characterization of a high-purity chiral 5,5'-disulfonato-BINAP ligand and its application in asymmetric hydrogenation of β-keto esters

Abstract 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) is a widely used chiral phosphine ligand, and the sulfonated BINAP is one of the important water-soluble BINAP derivatives. In this article, we report an improved oleum sulfonation method for the synthesis of the high-purity 5,5′-disulfonato-(S)-BINAP ligand with an industrially acceptable high yield. By optimizing the sulfonation conditions and improving the workup process, the yield of 5,5′-disulfonated products was enhanced to 73 %. Furthermore, an acetonitrile extraction protocol was developed for the purification of sulfonated products by efficiently removing phosphine oxides, by which the content of phosphine oxide can be controlled below 3 %. The structure of 5,5′-disulfonato-(S)-BINAP was characterized with the elemental analysis, FT-IR, 1H NMR, 13C NMR, 31P NMR, 1H-1H COSY, 1H-13C HSQC, 1H-13C HMBC, and HR-MS, which unambiguously confirmed that the sulfo groups are introduced at the 5,5′-position of the binaphthyl ring skeleton in (S)-BINAP. The prepared high-purity 5,5′-disulfonato-(S)-BINAP was evaluated in the Ru-catalyzed asymmetric hydrogenation of β-keto esters, which exhibited high catalytic activity, enantioselectivity and excellent catalytic stability.