Imidazoles: Effective Catalysts for Baylis-Hillman Reaction in Aqueous Media

β-Substituted enones have been considered less reactive in Baylis-Hillman reaction. The reaction of cyclic enones is sluggish or does not occur at all under traditional conditions. Various catalysts have been developed to pro mote the reaction of cyclic enones but with limited success. In previous study, we found that imidazole can catalyze the Baylis-Hillman reaction involving cyclic enones in aqueous THF solution.[1] In our continued efforts, we screened a variety of imidazoles to develop superior catalyst, and we found that the reaction could be greatly accelerated by adjusting the pH value of the water solution.     

Azoles: Effective Catalysts for Baylis-Hillman Reaction in Aqueous Media

β-Substituted enones have been considered less reactive in Baylis-Hillman reaction. The reaction of cyclic enones is sluggish or does not occur at all under traditional conditions. Various catalysts have been developed to pro mote the reaction of cyclic enones but with limited success. In previous study, we found that imidazole can catalyze the Baylis-Hillman reaction involving cyclic enones in aqueous THF solution. [1] In our continued efforts, a variety of azole compounds were examined in Baylis-Hillman reaction. We found that the azoles act as effective catalysts in properly adjusted water solution.     

Baylis-Hillman Reaction Involving Substituted Cyclic Enones in Aqueous Media

β-Substituted enones have been considered less reactive in Baylis-Hillman reaction. The reaction of cyclicenones is sluggish or does not occur at all under traditional conditions. [1] Therefore, substituted cyclic enones havebeen less explored in Baylis-Hillman reaction due to the extremely low reactivity. In this communication, we reported Baylis-Hillman reaction of substituted cyclic enones using our previously developed conditions with imidazole as catalyst. The reaction proceeded smoothly in aqueous media affording the desired product with good yields and moderate diastereoselectivity.     

Design of a Combinational Magnesium Catalyst for the Stereocontrolled Cross Reaction of Enones

The first stereocontrolled cross reaction of enones has been realized. A novel combinational magnesium catalyst was designed to address the enantioselectivity problem between reaction partners with an intermolecular symmetric structure and bearing identical functional groups. This new catalytic strategy was proven to be effective to introduce high levels of enantioselectivity in the cross reaction of enones.     

Studies on K2CO3-catalyzed 1,4-addition of 1,2-allenic ketones with diethyl malonate: controlled selective synthesis of beta,gamma-unsaturated enones and alpha-pyrones

The K2CO3 (10 mol %)-catalyzed 1,4-addition reaction of diethyl malonate with various substituted 1,2-allenic ketones leading to polyfunctionalized beta,gamma-unsaturated enones 3 or 4 was studied. With 3-unsubstituted 1-substituted-1,2-allenyl ketones, the highly selective formation of beta,gamma-unsaturated enones 4 was observed; with 1,2-allenyl ketones bearing one or two 3-substituents in the allenyl group, only beta,gamma-unsaturated enones 3 with an unmigrated carbon-carbon double bond were produced; with 3-monosubstituted-1,2-allenyl ketones Z-beta,gamma-unsaturated enones 3 were formed with excellent stereoselectivity (E:Z > 96:4); with propadienyl ketones, mixtures of beta,gamma-unsaturated enones 3 and 4 were formed. alpha-Pyrone derivatives were synthesized via the K(2)CO(3)-catalyzed or -promoted reaction of 1,2-allenic ketones with diethyl malonate via a sequential Michael addition-carbon-carbon double bond migration-lactonization process.     

One-pot beta-substitution of enones with alkyl groups to beta-alkyl enones

Vinylic hydrogens at the beta-position of enones were effectively substituted with alkyl groups in a one-pot procedure to afford beta-alkyl enones in good to high isolated yields by conjugate addition of higher-order dialkyl cyanocuprates to enones, followed by a reaction with N-tert-butylbenzenesulfinimidoyl chloride at -78 degree C.     

Copper(II)-bis(oxazoline) catalyzed asymmetric Diels-Alder reaction with alpha'-arylsulfonyl enones as dienophiles

Alpha'-arylsulfonyl enones are efficient bidentate dienophiles for the Cu(II)-bis(oxazoline) catalyzed enantioselective Diels-Alder reaction with a number of dienes, affording the corresponding products with good to high enantiomeric excesses. The resulting products can be alkylated and the sulfone removed, so alpha'-arylsulfonyl enones can be regarded as surrogates of simple monodentate enones, which are poor dienophiles with this catalytic system.     

Synthesis of trifluoromethyl-/cyclopropyl-substituted 2-isoxazolines by DBU-promoted domino reaction

NTrifluoromethyl and cyclopropyl substituted 2-isoxazolines were synthesized via a DBU-promoted domino reaction of β-trifluoromethyl-/β-cyclopropyl-substituted enones with hydroxylamine. The domino reaction consists of a Michael addition and the followed cyclization. A wide range of 3-substituted 5-cyclopropyl-5-trifluoromethyl-2-isoxazolines were obtained in good to excellent yields under mild reaction conditions. The method could also apply to other trifluoromethyl-substituted enones.     

Bridgehead Substitution via Putative Norborn‐1‐en‐3‐ones: Application in the Synthesis of Complex Molecules

The base‐mediated formation of a bridgehead double bond in a bicyclo[2.2.1]heptane system (anit‐Bredt molecules) is described. The synthesis of exocyclic norbornyl enones by Wittig reaction of α‐diketones is reported. These enones and their Michael adducts are used as substrates for the generation of transient bridgehead enones and their trapping with MeOH and H₂O. Bridgehead alcohols are easily synthesized from norbornyl enones and are exploited for the diversity oriented synthesis of frameworks of natural and unnatural products.     

Palladium-catalyzed conjugate addition of terminal alkynes to enones

A practical protocol for the hydroalkynylation of enones using Pd catalysis is reported. The reaction proceeds efficiently with a variety of alkynes as well as with several cyclic and acyclic enones, providing synthetically relevant β-alkynyl ketones in good to excellent yields.     

Direct Umpolung Morita–Baylis–Hillman like α‐Functionalization of Enones via Enolonium Species

Herein we report on the umpolung of Morita–Baylis–Hillman type intermediates and application to the α‐functionalization of enone C?H bonds. This reaction gives direct access to α‐chloro‐enones, 1,2‐diketones and α‐tosyloxy‐enones. The latter are important intermediates for cross‐coupling reaction and, to the best of our knowledge, cannot be made in a single step from enones in any other way. The proposed mechanism is supported by spectroscopic studies. The key initial step involves conjugate attack of an amine (DABCO or pyridine), likely assisted by hypervalent iodine acting as a Lewis acid leading to formation of an electrophilic β‐ammonium‐enolonium species. Nucleophilic attack by acetate, tosylate, or chloride anion is followed by base induced elimination of the ammonium species to give the noted products. Hydrolysis of α‐acetoxy‐enones lead to formation of 1,2‐diketones. The α‐tosyl‐enones participate in Negishi coupling reactions under standard conditions.     

Regioselectivity switch achieved in the palladium catalyzed α-arylation of enones by employing the modified Kuwajima-Urabe conditions

A new regioselective approach to the synthesis of α-aryl enones is reported. This represents an important application of the Kuwajima-Urabe protocol toward the synthesis of this simple albeit complex functional array. Several α-aryl enones were synthesized by the palladium catalyzed arylation of triethylsilylenol ethers of enones with high regioselectivity and broad scope, utilizing sterically encumbered electron-rich phosphine ligands to drive the reaction.     

The intramolecular reductive cyclization of cyclic enones

The reductive cyclization (electrohydrocyclization reaction) of tethered cyclic enones has been investigated under electrochemical, metal-mediated, and photochemical conditions. The tricyclic products are generally formed with excellent stereoselectivity, particularly if at least one of the enones is β,β-disubstituted.     

Difluoro-lambda3-bromane-induced oxidative carbon-carbon bond-forming reactions: ethanol as an electrophilic partner and alkynes as nucleophiles

Reported here for the first time are the oxidative couplings of alkynes and primary alcohols yielding conjugated enones. Although the BF3-catalyzed reaction of terminal alkynes with p-trifluoromethylphenyl(difluoro)-lambda3-bromane results in the fluoro-lambda3-bromanation of triple bonds to afford (E)-beta-fluorovinyl-lambda3-bromanes, reaction of an alkyne with the difluoro-lambda3-bromane in the presence of an alcohol and BF3-Et2O affords directly conjugated enones in good yields. The reaction proceeds in a highly stereo- and regioselective manner under metal-free conditions. Interestingly, no formation of enones was detected, when difluoro-lambda3-iodane p-CF3C6H4IF2 was used instead of the lambda3-bromane. A mechanism involving a lambda3-bromane-induced oxidation of an alcohol to an aldehyde, [2 + 2] cyclization with alkynes yielding 2H-oxetes, and finally the electrocyclic ring opening is discussed.     

Oxidation of Enones for Regioselective [3+2] Cycloaddition through γ-Enone Radical Intermediates

Herein, an oxidization reaction of enones with a Cu^II complex that leads to a new type of regioselective [3+2] cycloaddition is reported. Highly functionalized cyclopentenes and spirocyclic compounds are obtained in moderate-to-good yields. This cycloaddition reaction occurred through the formation of γ-enone radicals, providing a rarely explored reactivity pattern for enones.     

γ′‐Selective Functionalization of Cyclic Enones: Construction of a Chiral Quaternary Carbon Center by [4+2] Cycloaddition/Retro‐Mannich Reaction with 3‐Substituted Maleimides

The first example of organocatalyzed γ′‐selective functionalization of cyclic enones with 3‐substituted maleimides results in the stereoselective construction quaternary carbon center is presented. The reactions provided γ′‐functionalized cyclic enones and β‐functionalized cyclopentenones in good to excellent yields with excellent diastereo‐ and enantioselectivities. DFT calculations indicated that the reaction might proceed as a [4+2] cycloaddition/retro‐Mannich reaction which could explain the unexpected product with a chiral quaternary carbon center and the excellent stereoselectivity.     

Asymmetric Michael addition of malonates to enones catalyzed by a primary β-amino acid and its lithium salt

Highly enantioselective Michael addition of malonates to enones was achieved using a mixed catalyst consisting of a primary β-amino acid, O-TBDPS (S)-β-homoserine, and its lithium salt. Various cyclic and acyclic enones were converted into 1,5-ketoesters in high yields (up to 92%) with high enantioselectivity (up to 97% ee) under mild reaction conditions. Details of synthesis of the catalyst, optimization of the reaction conditions for the Michael addition reaction, and a plausible reaction mechanism are described.     

Novel metal-free hydrogenation of the carbon-carbon double bond in azulenoid enones by use of cycloheptatriene and protic acid

[reaction: see text] An efficient method for the hydrogenation of the carbon-carbon double bond in azulenoid and aromatic fused azulenoid enones without the use of hydrogen and a metal catalyst is reported. Treatment of a variety of azulenoid enones with cycloheptatriene and a protic acid in acetonitrile gave the corresponding beta-azulenyl ketone derivatives in excellent to moderate yield. In this reaction, cycloheptatriene acts as a hydride donor.     

Preparation of alpha-sulfenyl enones by thermal fragmentation of beta-sulfenyl enol triflates

[reaction: see text] The synthetic scope and mechanism of the fragmentation of cyclic beta-sulfenyl enol triflates to give alpha-sulfenyl enones are described. This transformation is the central step in a mild, functional group-tolerant method for preparing alpha-sulfenyl enones.     

The reaction of β-amino conjugated enones with trimethylchlorosilane

By the reaction of β-amino conjugated enones with trimethylchloroailane, both amino acetophenone and pyridine derivatives were formed in good yield. The selectivity of the formation of the products depended on the bulkiness of the N-substituents of β-amino conjugated enones.