Γ-keto Carboxylic Acids Research Articles

Electrophilic 1,4-Addition of Carbon Dioxide and Aldehydes to Enones.

An umpoled electrophilic 1,4-addition to enones was achieved under photocatalytic conditions. Various enones reacted with CO2 in the presence of an iridium photocatalyst and a benzimidazoline reductant under blue-light irradiation to give the corresponding γ-keto carboxylic acids. Aldehydes also coupled with enones under similar photocatalytic conditions to afford γ-keto alcohols (homoaldols) that were transformed into dihydrofurans and tetrahydrofurans through azeotropic posttreatments. Regioselective deuterium incorporation from D2O at the β-position demonstrated that 1,4-addition takes place via homoenolate anions.

Magnesium-Promoted Reductive Carboxylation of Aryl Vinyl Ketones: Synthesis of γ-Keto Carboxylic Acids.

Direct reductive carboxylation of easily prepared aryl vinyl ketones under the atmosphere of carbon dioxide led to the selective formation of γ-keto carboxylic acids in 38-86% yields. The reaction is characterized by the carbon-carbon bond formation of carbon dioxide at the β-position of enone, with the use of magnesium turnings that can be easily handled as the reducing agent and the eco-friendly reaction conditions such as no pressuring, no lower or higher reaction temperature, and short reaction time. This protocol showed a wide substrate scope and provided a useful and convenient alternative to access biologically important γ-keto carboxylic acids.

Palladium/Zinc Co-Catalyzed Asymmetric Hydrogenation of γ-Keto Carboxylic Acids.

A palladium-catalyzed asymmetric hydrogenation of levulinic acid has been successful developed by using Zn(OTf)2 as co-catalyst. The present method not only has provided a strategy in the palladium-catalyzed asymmetric hydrogenation of ketone, but also allowed the preparation of a wide range of chiral γ-valerolactones in good yields with excellent enantioselectivities.

Enantioselective synthesis of chiral multicyclic γ-lactones via dynamic kinetic resolution of racemic γ-keto carboxylic acids

Ru-Catalyzed asymmetric transfer hydrogenation of γ-keto carboxylic acids has been achieved, affording chiral multicyclic γ-lactones in high yields with excellent diastereo- and enantioselectivities.

Palladium(II)-Catalyzed C(sp3)–H Activation of N,O-Ketals towards a Method for the β-Functionalization of Ketones

A method for the formal β-functionalization of aliphatic ketones via a palladium-catalyzed sp3 C–H activation pathway is reported. An N,O-ketal directs an aliphatic C–H carbonylation to form γ-lactams which upon hydrolysis generate γ-keto carboxylic acids. This C–C bond-forming reaction is tolerant of a range of functional groups, enabling the synthesis of a range of synthetically important building blocks. Furthermore, the concepts underlying this transformation have also enabled the development of a related C–H alkenylation process to highly functionalised heterocycles.

Rhodium-Catalyzed Asymmetric Synthesis of γ-Keto Carboxylic Acids

Key words rhodium catalysis - enantioselectivity - asymmetric catalysis - hydrogenation - methylene keto acids - keto acids

ChemInform Abstract: Gallium‐Catalyzed Reductive Lactonization of γ‐keto Acids with a Hydrosilane.

Described herein is the GaCl3-catalyzed lactonization of γ-keto carboxylic acids in the presence of PhSiH3 leading to the direct preparation of γ-lactone derivatives. This reducing system showed a relatively wide functional group tolerance.

Gallium-catalyzed reductive lactonization of γ-keto acids with a hydrosilane

Gallium chloride efficiently catalyzes cyclization of γ-keto carboxylic acids in the presence of PhSiH3 to produce the corresponding γ-lactone derivatives.

Boc-protected 1-(3-oxocycloalkyl)ureas via a one-step Curtius rearrangement: mechanism and scope

1-(3-Oxocyclobutyl) carboxylic acid (4a) was converted into N-Boc-protected 1-(3-oxocyclobutyl) urea (5a), a key intermediate for the preparation of agonists of metabotropic glutamate receptor 5, in one-step when treated with diphenyl phosphoryl azide and triethylamine in tert-butanol. The mechanism of the reaction involves a nucleophilic addition of the in situ generated tert-butyl carbamate to the isocyanate intermediate. This reaction is applicable to other 1-(3-oxocycloalkyl) carboxylic acids but not to linear γ-keto carboxylic acids.

New route to the 5-((arylthio- and heteroarylthio)methylene)-3-(2,2,2-trifluoroethyl)-furan-2(5H)-ones—Key intermediates in the synthesis of 4-aminoquinoline γ-lactams as potent antimalarial compounds

In this Letter we report on a multi-step synthesis of 5-((arylthio- and heteroarylthio)-methylene)-3-(2,2,2-trifluoroethyl)furan-2(5H)-ones starting from γ-keto thiolester or γ-keto carboxylic acid. The key intermediate γ-lactones were then reacted with 4-aminoquinoline-derived amines via ring opening—ring closure (RORC) process affording the corresponding γ-hydroxy-γ-lactams in moderate to good yields. In vitro antimalarial activity of the resulting new 4-aminoquinoline γ-lactams were evaluated against Plasmodium falciparum clones of variable sensitivity (3D7 and W2) and were found to be active in the range of 89–1600nM with good resistance index and did not show cytotoxicity in vitro when tested against human umbilical vein endothelial cells (HUVEC) up to concentration of 50μM.

Copper-catalyzed electrochemical synthesis of alkylidene lactones from carbon dioxide and 1,4-diarylbuta-1,3-diynes

The novel synthesis of alkylidene lactones from carbon dioxide with 1,4-diarylbuta-1,3-diynes via copper-catalyzed electrochemical route is described. The procedure was smoothly performed in an undivided electrochemical cell fitted with Ni cathode and Al anode, containing n-Bu4NBr–DMF electrolyte with a constant current under 4 MPa pressure of CO2. The corresponding alkylidene lactones could be obtained in moderate to good yields in the presence of catalyst CuI, while the γ-keto carboxylic acids as main products were obtained without any catalysts. A reaction mechanism was also briefly discussed.

A mild and efficient synthesis of a chiral pyridazinone derivative

We found a mild and efficient reaction condition for construction of a chiral 5-methyl-4,5-dihydropyridazin-3(2H)-one from a chiral β-methyl γ-ketocarboxylic acid via the corresponding acid hydrazide without racemization. Furthermore, we demonstrated that this two-step reaction can be attained by one-pot reaction. This method could be applied to various kinds of substrates because of the mild reaction conditions.

The Preferred Ring-Tautomeric Form of a Bicyclic γ-Ketocarboxylic Acid: An Equilibrium Driven by Relief of Angular Hybridization Strain

(±)-2-exo-Carboxy-2-endo-methyl-7-oxobicyclo[2.2.1]heptane exists preferentially in its closed, ringtautomer form, the tricyclic lactol (C9H12O3), which aggregates catemerically by forming hydroxyl-to-carbonyl hydrogen bonds [O O = 2.7667(16)A, O-H O = 170o] among molecules screw related in b. This ring-chain equilibrium is driven by relief of angular strain at the 7-ketone, whose origin is the ketone’s sp hybridization vs. the angle enforced by the bicyclic system. In the analogous compound with transposed functional groups, the equilibrium favors the keto acid, which

Selective Inhibition of Matrix Metalloproteinase Isozymes and in Vivo Protection against Emphysema by Substituted γ-Keto Carboxylic Acids

The synthesis and matrix metalloproteinase (MMP) inhibitory activity of a series of gamma-keto carboxylic acids are described. Among nine MMP isozymes tested, compound 1j displays selective inhibition of MMP-2, -9, and -12 with IC(50) values between 0.20 and 1.51 microuM, and in male golden Syrian hamsters, it shows protection against PPE-induced emphysema.

Chemospecificity in Arylations of δ‐ and γ‐Ketocarboxylic Acids with P2O5—MsOH, TfOH, and Related Acidic Media.

AbstractFor Abstract see ChemInform Abstract in Full Text.

CHEMOSPECIFICITY IN ARYLATIONS OF δ- AND γ-KETOCARBOXYLIC ACIDS WITH P2O5–MsOH, TfOH, AND RELATED ACIDIC MEDIA

ABSTRACT Remarkable contrast between chemospecificities in acid-mediated arylation of δ- and γ-ketocarboxylic acids was revealed: in the presence of P2O5–MsOH, TfOH, PPA, and MsOH, arylation of δ-ketocarboxylic acid 1A with arenes takes place at the carboxycarbonyl carbon, while that of γ-ketocarboxylic acid 1B takes place at the ketone carbonyl carbon, specifically.

Synthesis of γ-ketocarboxylic acids via reduction of γ-keto-α-hydroxycarboxylic acids with carbon monoxide catalyzed by a PdHCl system

A PdHCl catalytic system is highly active in the synthesis of γ-ketoacids of type ArCOCH 2CH 2COOH via reduction with CO of the ketohydroxy acids ArCOCH 2CHOHCOOH. Typical reaction conditions are: P CO: 20–30 atm; Pd/ substrate/H 2O/HCl = 1/400–1000/800–3000/ 100–1000 (mol); temperature: 100–110°C; [Pd]: 10 −3 to 10 −2 M; solvent: dioxane; reaction time: 1–2 h. The reaction occurs in high yield only when the palladium precursor is used in combination with HCl and in the presence of H 2O. Under the reaction conditions employed, the palladium(II) complex used as catalyst precursor decomposes to palladium metal. Pd/C is also highly active. It is proposed that the catalytic cycle proceeds through the following steps: (i) The chloride ArCOCH 2CHClCOOH, which forms in situ from the starting substrate and HCl, undergoes oxidative addition to reduced palladium with formation of a catalytic intermediate having a Pd-[CH(COOH)CH 2COPh] moiety. (ii) Interaction of H 2O and CO on the metal yields an intermediate having also a carbohydroxy ligand, (HOOC)-Pd-[CH(COOH)CH 2COPh]. (iii) This intermediate, after β-hydride abstraction from the carbohydroxy ligand, gives off CO 2 and reductive elimination gives product PhCOCH 2CH 2COOH. Alternatively, HCl may react with the intermediate proposed in step (i), yielding directly the product and a Pd(II) species, which is reduced by CO to a Pd(0) species, which starts another catalytic cycle.

Metallacyclische acyl-carboxylate des nickels: Reaktivität der acylgruppe und synthesepotential bei kreuzkopplungsreaktionen mit alkylhalogeniden

2-Cyclohexene-1,2-dicarboxylic acid-anhydride reacts with electron-rich nickel(0) centres to form nickel(0) complexes, whereas the isomeric 4-cyclohexene-1,2-dicarboxylic acid-anhydride reacts with ring opening of the anhydride to yield thermally stable acyl-carboxylato-nickel(II) compounds. The structure of a typical compound with (TMED)Ni 0 as a complex fragment was determined by single crystal X-ray structural analysis, the crystal also containing the product of CO-elimination, the nickelalactone. The cross-coupling reaction of metallacyclic acyl-carboxylato complexes of Ni with RX can be used for the formation of side chains of steroids containing γ-ketocarboxylic acids. These compounds are interesting precursors for the preparation of a analogues of vitamin D3 metabolises.

Synthesis of γ-keto carboxylic acids from γ-keto-α-chloro carboxylic acids via carbonylation—decarboxylation reactions catalysed by a palladium system

A palladium-based catalytic system is highly active in the synthesis of γ-keto acids of type ArCOCH 2CH 2COOH via carbonylation-decarboxylation of the corresponding α-chloride. Typical reaction conditions are: P(CO) = 20–30 atm; substrate/H 2O/Pd = 100–400/800–1000/1 (mol); temperature: 100–110 °C; [Pd]=0.25 × 10 −2−1 × 1O −2 M; solvent: acetone; reaction time: 1–2 h. A palladium(II) complex can be used as catalyst precursor. Under the reaction conditions above, reduction of the precursor to palladium metal occurs to a variable extent. High catalytic activity is observed when the precursor undergoes extensive decomposition to the metal. Pd/C is also highly active. Slightly higher yields are obtainable when the catalytic system is used in combination with a ligand such as PPh 3. A mechanism for the catalytic cycle is proposed: (i) The starting keto chloride undergoes oxidative addition to reduced palladium with formation of a catalytic intermediate having a Pd-[CH(COOH)CH 2COPh] moiety. The reduced palladium may be the metal coordinated by other atoms of palladium and/or by carbon monoxide and/or by a PPh 3 ligand when catalysis is carried out in the presence of this ligand. It is also proposed that the keto group in the β-position with respect to the carbon atom bonded to chlorine weakens the CCl bond, easing the oxidative addition step and enhancing the activity of the catalyst. (ii) Carbon monoxide ‘inserts’ into the PdC bond of the above intermediate to give an acyl catalytic intermediate having a Pd-[COCH(COOH)CH 2COPh] moiety. (iii) Nucleophilic attack of H 2O to the carbon atom of the carbonyl group bonded to the metal of the acyl intermediate yields a malonic acid derivative as product intermediate. This, upon decarboxylation, gives the final product. Alternatively, the desired product may form without the malonic acid derivative intermediate, through the following reaction pathway: the acyl intermediate undergoes decarboxylation with formation of a different acyl intermediate, having a Pd-[CO-CH 2CH 2COPh] moiety, which, upon nucleophilic attack of H 2O on the carbon atom of the carbonyl group bonded to the metal, yields the final product.

Model studies of the reduction of 3‐phenyl‐6H‐1,2‐oxazines, chemo‐ and stereoselectivity: synthesis of amino alcohols, amino acids, and related compounds

AbstractWhile palladium‐catalyzed hydrogenation of 3‐phenyl‐6H‐1,2‐oxazine 1 produces primary amine 5 in a nitrogen‐transposition reaction, the reductions of the related 1,2‐oxazines 2, 10, and the 1,2‐oxazin‐6‐one 3 afford the expected amino alcohols 4, 11, and the γ‐amino acid 6, respectively, with low diastereoselectivites. In the presence of acetic acid 3 is reductively converted into γ‐keto carboxylic acid 9 and 1 into the γ‐lactam derivative 12 probably by a ring contraction to a nitrone intermediate. Raney nickel as the catalyst is able to transform 1,2‐oxazine 7 bearing an exo‐methylene unit into 3,4‐dihydro‐2H‐pyrrole 13. The reaction of 6H‐1,2‐oxazine 1 with aluminium amalgam produces pyrrole 14 in moderate yield. Treatment of 1 with sodium in 2‐propanol brings about its transformation into pyrrolidine derivative 15 together with pyrrole 14 and amino alcohol 4 as minor products. The chemoselectivity and stereoselectivity of these reductions are discussed including mechanistic proposals for the multistep processes involved.