Alkyl Vinyl Ketones Research Articles

Development of an α'-hydroxy enone for the aminocatalytic asymmetric formal conjugate addition of aldehydes to acrylates, vinyl ketones and acrolein.

Aminocatalytic asymmetric conjugate addition of aldehydes to Michael acceptors is a well established C-C bond forming methodology. However, various acrylic-type acceptors, including acrylic acid derivatives and acrolein, remain reluctant. Here we demonstrate that the internal H-bonding self-activation in α'-hydroxy enones allows them to react smoothly with enolizable aldehydes using commercially available aminocatalysts to afford adducts in good yields and high enantioselectivity. Straightforward conversion of the ketol moiety of these adducts into aldehyde, ketone and carboxylic acid functionalities offers an indirect, unified entry to products derived from acrolein, alkyl-vinyl ketones and acrylates, respectively.

Fe(III)-catalyzed regioselective and faster synthesis of isocoumarins with 3-oxoalkyl moiety at C-4: Identification of new inhibitors of PDE4

In search of potent and new anti-inflammatory agents, we explored a new class of isocoumarin derivatives possessing the 3-oxoalkyl moiety at C-4 position. These compounds were synthesized via the FeCl3 catalyzed construction of isocoumarin ring. The methodology involved coupling of 2-alkynyl benzamides with alkyl vinyl ketone and proceeded via a regioselective cyclization to give the desired compound as a result of formation of CO and CC bonds. A large number of isocoumarins were synthesized and assessed against PDE4B in vitro. While isocoumarins containing an aminosulfonyl moiety attached to the C-3 aryl ring showed encouraging inhibition of PDE4B, some of the derivatives devoid of aminosulfonyl moiety also showed considerable inhibition. According to the SAR analysis the C6H4NHSO2R2-m moiety at C-3 position of the isocoumarin ring was favorable when the R2 was chosen as an aryl or 2-thienyl group whereas the presence of F or OMe substituent at C-7 of the isocoumarin ring was found to be beneficial. The compound 5f with IC50 values 0.125 ± 0.032 and 0.43 ± 0.013 µM against PDE4B and 4D, respectively was identified as an initial hit. It showed in silico interaction with the PHE678 residue in the CR3 region of PDE4B and relatively less number of interactions with PDE4D. Besides showing the PDE4 selectivity over other PDEs and TNF-α inhibition in vitro the compound 5f at an intraperitoneal dose of 30 mg/kg demonstrated the protective effects against the development of arthritis and potent immunomodulatory activity in adjuvant induced arthritic (AIA) rats. Furthermore, no significant adverse effects were observed for this compound when evaluated in a systematic toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) studies in zebrafish at various concentrations. Collectively, being a new, potent, moderately selective and safe inhibitor of PDE4B the isocoumarin 5f can be progressed into further pharmacological studies.

Synthesis of polymer microsphere‐supported chiral pyrrolidine catalysts by precipitation polymerization and their application to asymmetric Michael addition reactions

AbstractPolymer microsphere‐supported chiral pyrrolidine catalysts were successfully synthesized by a precipitation polymerization incorporating a methacrylate monomer bearing chiral N‐Boc‐pyrrolidine moiety, followed by removal of the N‐Boc groups. The resulting polymeric catalysts were applied to the asymmetric Michael addition reactions of aldehydes with alkyl vinyl ketones. The effects of the comonomer, the molar ratios within the catalyst, the catalyst loading, the temperature, and the solvent on the catalytic performance were investigated in detail. The reactions were found to proceed smoothly in the absence of a solvent. A hydrophobic polystyrene‐based chiral pyrrolidine catalyst exhibited high reactivity (up to 97% yield) and enantioselectivity (up to 95% ee) during these reactions. The catalyst could also be recovered and reused up to five times without significant loss of activity.

Synthesis of Benzo[a]quinolizidines via an Aza‐Michael/Oxidative Mannich Process

AbstractThe synthesis of substituted benzo[a]quinolizidines via aza‐Michael addition of tetrahydroisoquinolines to alkyl vinyl ketones, followed by oxidative Mannich cyclization, is described. Various Michael adducts are easily prepared, and subsequent DDQ‐mediated oxidations stereoselectively afford the corresponding azacycles efficiently. Furthermore, the one‐pot aza‐Michael/oxidative Mannich process gave benzo[a]quinolizidines, thus providing a metal‐free and practical synthetic route to N‐heterocyclic building blocks.

Synergistic Chemo/Biocatalytic Synthesis of Alkaloidal Tetrahydroquinolines

The power of complementary chemocatalytic and biocatalytic transformations is demonstrated in the asymmetric synthesis of 2-substituted tetrahydroquinolines. A series of racemic tetrahydroquinolines were synthesized through a convergent one-pot Rh(I)-catalyzed addition/condensation sequence of alkyl vinyl ketones and aminophenylboronic acids. The resulting tetrahydroquinolines were thereafter shown to be substrates for the flavin-dependent enzyme cyclohexylamine oxidase, and preparative-scale deracemizations have been demonstrated on these high-value targets.

Construction of 2‐Thiabicyclo[3.3.1]nonanes by Organocatalytic Asymmetric Formal [3+3] Cycloaddition

Powerful asymmetric desymmetrization of thiane‐3,5‐diones through formal [3+3] cycloaddition with alkyl vinyl ketones has been disclosed to access functionally rich 2‐thiabicyclo[3.3.1]nonanes in very good yields with excellent enantio‐ and diastereoselectivities by using organocatalysis.

Highly Substituted Cyclohexenes via Phosphine‐Catalyzed [4+2] Annulation of Electron‐deficient Dienes and Vinyl Ketones

AbstractA highly efficient phosphine‐catalyzed [4+2] annulation of electron‐deficient diene and alkyl vinyl ketone was developed for the first time, which provides an easy access to functionalized cyclohexenes. This method has the advantages of mild reaction conditions, widely functional group tolerance, high yields and transition metal free.magnified image

Organocatalytic Asymmetric Formal [3+2] Cycloaddition as a Versatile Platform to Access Methanobenzo[7]annulenes

Pharmaceutically and structurally important methanobenzo[7]annulenes were synthesized in very good yields with excellent enantio- and diastereoselectivities through an unprecedented organocatalytic formal [3+2] cycloaddition from readily available 2-alkyl-3-hydroxynaphthalene-1,4-diones and alkyl vinyl ketones.

Phosphine-Catalyzed Asymmetric Intermolecular Cross-Vinylogous Rauhut–Currier Reactions of Vinyl Ketones with para-Quinone Methides

A chiral amide-phosphine bifunctional catalyst was developed and successfully applied to the asymmetric intermolecular cross-vinylogous Rauhut–Currier of alkyl vinyl ketones with para-quinone methides, offering excellent regioselectivity and stereoselectivity (up to >99% enantiomeric excess (ee)). This method provides a facile access to structurally diverse widely existed diarylmethine stereogenic centers with excellent enantioselectivity. Density functional theory (DFT) calculations have been performed to understand the mechanism and enantioselectivity for this phosphine-catalyzed asymmetric transformation.

Planar chiral [2.2]paracyclophane-based phosphine-phenol catalysts: application to the aza-Morita-Baylis-Hillman reaction of N-sulfonated imines with various vinyl ketones

Several planar chiral [2.2]paracyclophane-based phosphine-phenol catalysts were prepared and applied to the aza-Morita-Baylis-Hillman reaction of aldimines with vinyl ketones. The pseudo-ortho-substituted aryl[2.2]paracyclophanol, in which the phosphino group was located at the meta-position of the aryl group, showed an exceptionally high reactivity and good enantioselectivity for the reaction of N-tosylated aldimines with various alkyl or aryl vinyl ketones.

Synthesis of C1–C15 of palmerolide A: tactical advances that can lead to better design strategies for polyketide synthesis

A streamlined synthesis of a C1–C15 fragment of palmerolide A is described. Key tactical advances (vis-à-vis previous reports from the Dudley laboratory) include diastereoselective reduction (>20:1 dr) of a C7 ketone using DIP chloride and a modified protecting group strategy that enables both improved step count and end-game efficiency. Asymmetric reduction of linear alkyl vinyl ketone derivatives is a largely unsolved problem in organic synthesis. DIP chloride has been uniquely effective for asymmetric reduction of the alkyl vinyl ketone derivatives in the present study.

When CMRP met alkyl vinyl ketone: visible light induced living radical polymerization (LRP) of ethyl vinyl ketone (EVK)

Photo responsive polyethyl vinyl ketone (PEVK) and various block copolymers were prepared through the visible light induced cobalt mediated radical polymerization (CMRP) process. The first order kinetics and linear increase in molecular weight with conversion demonstrated a well-behaved system. Chain extension experiments showed the retention of the living end of PEVK.

ChemInform Abstract: Ketones as Electrophiles in Two Component Baylis—Hillman Reaction: A Facile One‐Pot Synthesis of Substituted Indolizines.

Abstract2‐Alkanoyl(aroyl)‐pyridines (I) are used for Tms‐O‐Tf‐mediated coupling with alkyl vinyl ketones (II) and (V) providing a facile protocol for the synthesis of substituted indolizines (III)/(IV) and (VI), respectively.

Ketones as electrophiles in two component Baylis–Hillman reaction: a facile one-pot synthesis of substituted indolizines

2-Alkanoyl(aroyl)-pyridines have been successfully used for coupling with alkyl vinyl ketones under the influence of TMSOTf providing a facile protocol for the synthesis of substituted indolizines, thus demonstrating the application of ketones as electrophiles in a two component Baylis-Hillman reaction.

First biosynthetic pathway of 1-hepten-3-one in Iporangaia pustulosa (Opiliones).

Arthropods produce a great variety of natural compounds, many of which have unexplored biosynthesis. Among the armored harvestmen (Arachnida: Opiliones) of the suborder Laniatores, the defensive gland exudates contain vinyl ketones and other constituents of supposed polyketide origin. We have studied the biosynthesis of 1-hepten-3-one in the Neotropical harvestman Iporangaia pustulosa by feeding individuals with 13C-labeled precursors, demonstrating its mixed acetate/propionate origin. 13C NMR spectroscopy showed an unusual labeling pattern suggesting different propionate sources for starting and extender units. Our analysis also indicates the presence of methylmalonyl-CoA mutase, converting acetate into propionyl-CoA via succinyl-CoA, together with other C3 unit routes. This is the first biosynthetic study of alkyl vinyl ketones in arthropods. Our results shed light on the origin and diversification of chemical compounds in a major arthropod group.

Concise Synthesis of α-(Hydroxymethyl) Alkyl and Aryl Vinyl Ketones

2,4-Diketoesters 2 have first been reported as starting materials for the synthesis of a new class of α-hydroxymethyl-α,β-unsaturated ketones 3. Thus, under heterogeneous liquid–liquid medium in the presence of concentrated aqueous potassium carbonate as a base, both aliphatic and aromatic 2,4-dioxoalkanoates 2 react with aqueous formaldehyde to afford the corresponding ketones 3 in fair to good yields.

Efficient synthesis of substituted quinolines through intramolecular addition of aryl anion to carbonyl carbon

Substituted quinolines were synthesized in three steps from the Boc amides of substituted 2-iodoanilines and alkyl vinyl ketones. This method consists of (1) N-Michael addition of the Boc amide of 2-iodoaniline to alkyl vinyl ketone in the presence of Cs2CO3 in MeCN; (2) I–Mg exchange of the adduct with 3.5 equiv of i-PrMgCl·LiCl, and (3) acid-catalyzed reaction (excess AcCl in EtOH) of the resulting alcohol. Six examples are given with good yields.

L-proline and l-histidine co-catalyzed Baylis–Hillman reaction

Baylis–Hillman reaction between an aldehyde and an activated alkene, such as alkyl vinyl ketones, acrylates, acrylonitrile, and vinylsulfones, giving the β-hydroxy-α-methylene carbonyl compounds, is a versatile and atom-economical carbon–carbon bond-forming reaction. This reaction usually is catalyzed by strong Lewis bases such as tertiary amines and suffers from slow reaction rate. In this paper the Baylis–Hillman reaction between arylaldehydes and methyl vinyl ketone was successfully realized by a catalytic amount of l-proline and l-histidine system to give the corresponding normal Baylis–Hillman adducts in moderate to high yields for the first time. The effects of solvent and reagent electro property on the yields of this reaction were also investigated. Proline and histidine are naturally widely present amino acids in food system; furthermore, aldehydes and activated alkenes can also be easily produced in food processing, so proline and histidine co-catalyzed Baylis–Hillman reaction may find application in explaining some phenomena in food processing.

ChemInform Abstract: Organocatalytic Tandem Three‐Component Reaction of Imine, Alkyl Vinyl Ketone, and Imide via Aza‐Baylis—Hillman Reaction.

AbstractThe title reaction provides mild and diastereoselective approach to β‐amino ketones.

ChemInform Abstract: Tandem Michael Addition/Aldol Reaction of Allenic Ketones with Alkyl Vinyl Ketones: Versatile Synthesis of 2‐Alkynyl 1,5‐Diketones, 4‐Alkynyl‐3‐hydroxycyclohexanones and 4‐Alkynylcyclohexenones.

AbstractThe reaction leads to the 2‐alkynyl‐1,5‐diketones (III), when catalyzed by Bu4NF in THF at room temperature.