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.     

Baylis-Hillman adducts between pyridine carboxaldehyde derivatives and cyclic enones

Baylis-Hillman (BH) adducts were synthesized using pyridinecarboxaldehyde derivatives and cyclic enones. The Baylis-Hillman reaction was examined by employing various organic tertiary bases and solvents. It was observed that DBU in MeOH as well as imidazole and N-methylimidazole in aqueous MeOH are very effective. These pyridinecarboxaldehydes were reactive and efficient towards the Baylis-Hillman reaction and the resulting adducts are highly stable. The crystal structure for one of the BH adducts was determined.     

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.     

Switching the reactivity of dihydrothiopyran-4-one with aldehydes by aqueous organocatalysis: Baylis-Hillman, aldol, or aldol condensation reactions

An aqueous medium containing catalytic amounts of a tertiary amine was employed to direct the chemoselectivity of the reaction of aldehydes with 1a. With DBU, 2 was formed at room temperature as a rare exemplary of Baylis-Hillman reactions in heterocyclic enones. DABCO alternated the pathway toward an aldol reaction to form syn/anti mixtures of 3 with the syn isomers being the major products. With Et(3)N, aldol condensation dominated.     

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.     

Organocatalytic transfer hydrogenation of cyclic enones

The first enantioselective organocatalytic transfer hydrogenation of cyclic enones has been accomplished. The use of iminium catalysis has provided a new organocatalytic strategy for the enantioselective reduction of beta,beta-substituted alpha,beta-unsaturated cycloalkenones, to generate beta-stereogenic cyclic ketones. The use of imidazolidinone 4 as the asymmetric catalyst has been found to mediate the hydrogenation of a large class of enone substrates with tert-butyl Hantzsch ester serving as an inexpensive source of hydrogen. The capacity of catalyst 4 to enable enantioselective transfer hydrogenation of cycloalkenones has been extended to five-, six-, and seven-membered ring systems. The sense of asymmetric induction is in complete accord with the stereochemical model first reported in conjunction with the use of catalyst 4 for enantioselective ketone Diels-Alder reactions.     

Synthesis of β-Fluoroalkyl-β,β-dimethoxy Ketones and β-Fluoroalkyl-β-methoxy-α,β-enones

α-Bromo-β-fluoroalkyl-α,β-enones react with sodium methoxide in methanol to give the corresponding β-fluoroalkyl-β,β-dimethoxy ketones which eliminate methanol molecule to produce a mixture of E/Z-isomeric β-fluoroalkyl-β-methoxyvinyl ketones, the Z isomer prevailing.     

Toward understanding the scope of Baylis-Hillman reaction: synthesis of 3-(2- hydroxyphenyl)indolin-2-ones and polycyclic fused furans

A facile one-pot synthesis of 3-(2-hydroxyphenyl)indolin-2-ones has been developed via the TiCl₄-mediated Baylis-Hillman (B-H) reaction of N-substituted isatins and cyclohex-2-enone, followed by treatment of the in situ generated B-H alcohols with aq HBr. Baylis-Hillman reaction of aromatic cyclic 1,2-diones with cycloalk-2-enones under the influence of TiCl₄ has been successfully performed and the resulting Baylis-Hillman adducts have been conveniently transformed into pentacyclic and hexacyclic fused furan derivatives.     

Remarkable rate acceleration of imidazole-promoted Baylis-Hillman reaction involving cyclic enones in basic water solution

The Baylis-Hillman reaction of cyclic enones was greatly accelerated in basic water solution with imidazoles as catalysts, which resulted in short reaction time, high yields, and expanding substrate scopes. Bicarbonate solution was shown to be the optimal reaction medium for the reaction in this study. The apparent "enhanced basicity" of imidazoles accounted for the rate increase in alkaline solution.     

New chiral ferrocenyl P,S-ligands for highly diastereo-/enantioselective catalytic [3 + 2] cycloaddition of azomethine ylides with cyclic and acyclic enones

A new family of chiral ferrocenyl P,S-ligands has been developed and successfully applied in a highly endo-selective catalytic asymmetric cycloaddition of azomethine ylides with various enones, including cyclic and acyclic α-enones. For cyclic α-enones, a [Cu(CH(3)CN)(4)]ClO(4)/(R(c),S(Fc))-2f complex catalyzed the cycloaddition to give the sole endo-cycloadducts in perfect enantioselectivities (normally 99% ee), while an AgOAc/(R(c),S(Fc))-2f catalytic system exhibited good endo/exo selectivities (endo/exo = 91/9 to 96/4) and high enantiocontrol (up to 98% ee) for acyclic α-enones.     

Copper-catalyzed asymmetric conjugate addition of trialkylaluminium reagents to trisubstituted enones: construction of chiral quaternary centers

Me3Al, Et3Al, and vinylalane species undergo enantioselective conjugate addition to a wide range of 2- or 3-substituted enones (cyclopent-2-enones, cyclohex-2-enones, 3-methyl cyclohept-2-enone) in the presence of catalytic amount of copper salt (copper thiophene carboxylate, [Cu(CH3CN)4]BF4 or [CuOTf]2C6H6) and tropos-phosphoramidite-based ligand. Thus, chiral quaternary centers can be built, with up to 98% ee after rigorous optimization of experimental conditions. It was shown that the main important parameter was the order of the introduction of the reagents. Then, the generated enantioenriched aluminium enolates and the chiral conjugate adducts were functionalized and used for subsequent reactions.     

Acrylamide in the Baylis-Hillman reaction: expanded reaction scope and the unexpected superiority of DABCO over more basic tertiary amine catalysts

DMAP, DBU, and quinuclidine efficiently promote novel hydroalkoxylation reactions of acrylamide in primary alcohol solvents. DABCO is a comparatively poor hydroalkoxylation promoter and can effect clean, selective Baylis-Hillman reactions between acrylamide and aldehydes in alcoholic/aqueous media in which more basic nucleophilic catalysts promote hydroalkoxylation preferentially. Optimization of the reaction conditions has allowed acrylamide to be reacted with a range of aromatic aldehydes in moderate to excellent yields, including the first examples involving deactivated, electron-rich substrates such as p-tolualdehyde and o-anisaldehyde.     

The azoles: effective catalysts for Baylis-Hillman reaction in basic water solution

The azoles, which were inactive in neutral aqueous media, could be activated in alkaline solution and effectively catalyze the Baylis-Hillman reaction involving cyclic enones.     

Regioselective 1–4 addition of acyl and equivalents to α-enones

2-lithio-1,3-dithianes, bis(phenylthio)alkyllithiums and bis(methylseleno)alkyllithiums add 1–4 to α-enones if HMPT is present in the medium prior to the addition of enones. Most of the reactions occur under kinetic control.     

Asymmetric 1,4-addition of alkenylzirconium reagents to α,β-unsaturated ketones catalyzed by chiral rhodium complexes

Highly enantioselective 1,4-addition of alkenylzirconocene chlorides to α,β-enones was found to be catalyzed by a chiral rhodium complex generated from [Rh(cod)(MeCN)₂]BF₄ and (S)-BINAP. The reaction can be applied to either cyclic or acyclic enones and the optical yield was up to 99% ee. The reaction mechanism would involve the transmetalation between the alkenylzirconocene chloride and the rhodium complex to give the alkenylrhodium species as a key intermediate.     

Divergence in photoinduced electron transfer (PET) reactions: a useful strategy towards identifying route-selectivity in mixed ketones

The work utilized photoinduced electron transfer (PET) reactions to identify the preferred photoreaction route in molecules having juxtaposed α,β and β,γ-enones. Such process directly converted 2-hydroxyimino derivatives of 5-benzoylbicyclo[2.2.2]octenones to the corresponding bicyclo[3.2.1]octane derivatives. First evidence of Type B rearrangement in α,β-enones having acyl substitution at Cγ-position has been depicted in this work. In rigid mixed enones, this has been found to be generally the preferred photoreaction route.     

First example of electrophile induced Baylis-Hillman reaction: a novel facile one-pot synthesis of indolizine derivatives

Treatment of pyridine-2-carboxaldehyde with activated alkenes such as alkyl vinyl ketones and cyclic enones in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) provides a novel facile one-pot synthesis of indolizine derivatives, thus for the first time describing an electrophile induced Baylis-Hillman reaction.     

Catalyst Deactivation in Low Temperature Slurry Methanol Synthesis C Process

A catalyst system composed of Cu-based catalyst and alkaline methoxide for low temperature methanol synthesis have high activity and high methanol selectivity, but long run results show that catalyst deactivation has restricted the commercial application of the process. The experimental results showed that the deactivation rate of carbonylation catalysts is much more faster than that of hydrogenolysis catalysts, and the detailed studies including chemical analysis, gas chromatograph, FTIR and XRD demonstrated that most part of sodium methoxide is transformed to sodium formate after long time run.     

Water-promoted highly regio- and stereoselective synthesis of α-dehydro-β-amino esters and nitriles from Baylis-Hillman acetates

The nucleophilic addition of amines to Baylis-Hillman acetates has been efficiently carried out in water at room temperature in the absence of any base, acid, or metal catalyst to produce α-dehydro-β-amino esters and nitriles. This procedure addresses a variety of aliphatic open-chain and cyclic amines and anilines. All the reactions are highly regio- and stereoselective, fast and high yielding.     

Fast diastereoselective Baylis-Hillman reaction by nitroalkenes: synthesis of di- and triene derivatives

The Baylis-Hillman reaction is performed using nitroalkenes as activated alkenes, ethyl-2-bromomethylacrylate as electrophilic acceptor and DBU as catalyst base. Nitro dienes are obtained in good yields and very short reaction times. Moreover, starting from appropriate nitroalkenes it is possible to realize one pot the synthesis of trienic systems.