Synthesis of isoxazolobenzoxepanes via Michael addition of indoles to nitroalkenes and sequential intramolecular nitrile oxide cycloaddition

Nitroalkenes derived from O-propargyl salicylaldehyde undergo facile Michael addition with indoles leading to indole-derived Michael adducts. Intramolecular nitrile oxide cycloaddition (INOC) of the Michael adducts results in isoxazolobenzoxepanes in good to excellent yields.     

Asymmetric intramolecular michael addition of alpha-sulfinyl vinylic carbanion to enoates

The first example of an asymmetric intramolecular Michael addition reaction with use of alpha-lithiated vinylic sulfoxide as a Michael donor is reported. Michael addition of the alpha-lithiated vinylic sulfoxide to (Z)-enoates proceeds with high diastereoselectivity to give the adducts with (R)-configuration at the beta-position of the ester in the five-membered-ring formation. The selectivity was reversed in the six-membered-ring formation. The resulting ester enolates were reacted with alkyl halides or benzaldehyde with high diastereoselectivity.     

Enantioselective organocatalytic Michael additions of aldehydes to enones with imidazolidinones: cocatalyst effects and evidence for an enamine intermediate

An enantioselective intermolecular Michael addition of aldehydes to enones catalyzed by imidazolidinones has been achieved. Chemoselectivity (Michael addition vs aldol) can be controlled through judicious choice of hydrogen-bond-donating cocatalysts. The optimal imidazolidinone/hydrogen-bond-donor pair affords Michael addition products in excess of 90% ee. Furthermore, we have isolated and characterized an enamine intermediate and demonstrated its efficacy as a nucleophile in the observed Michael addition reactions.     

Amine-catalyzed Michael reactions of an aminoaldehyde derivative to nitroolefins

Catalytic enantioselective Michael addition reactions of α-amino functionalized aldehydes to nitroolefins have been developed. The Michael product was obtained in up to 98% ee, but the enantiomeric purity of the Michael product was decreased during isolation of the product.     

Aromatic l-prolinamide-catalyzed asymmetric Michael addition of aldehydes to nitroalkenes

Two chiral aromatic l-prolinamides were synthesized in high overall yield (95%) from N-Boc-l-proline and served as organocatalysts in asymmetric Michael reactions of aldehydes to nitroalkenes. Under the optimized reaction conditions, (S)-N-tritylpyrrolidine-2-carboxamide 4 was found to be a highly efficient organocatalyst for the Michael addition, and the corresponding Michael adducts were obtained in good yields (up to 94%), with excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to 99:1 dr).     

Sulfamic acid-catalyzed Michael addition of indoles and pyrrole to electron-deficient nitroolefins under solvent-free condition

Sulfamic acid (SA) effectively catalyze the Michael addition of indoles and pyrrole to nitroolefins under solvent-free condition to afford the corresponding Michael adducts in good to excellent yields.     

Enantioselective Michael reaction of malonates to nitroolefins catalyzed by bifunctional organocatalysts

Michael reaction of malonates to nitroolefins with chiral bifunctional organocatalysts, bearing both a thiourea and tertiary amino group, afforded Michael adducts with high yields and enantioselectivities (up to 95%, up to 93% ee).     

Thiourea to bicyclic scaffolds: highly regio- and stereoselective routes to dithiazolopyrimidines

Microwave-activated solvent-free Michael addition of 3-imino-1,4,2-dithiazoles to 4-arylidene-5(4H)-oxazolones furnished isolable adducts regio- and diastereoselectively, which underwent ring transformation to yield the target dithiazolopyrimidines. Alternatively, the similar conjugate addition of methanesulfinylmethylisothioureas to 4-arylidene-5(4H)-oxazolones diastereoselectively afforded Michael adducts, which underwent ring transformation followed by heterocyclization via deoxygenative demethylation with thionyl chloride to yield the same products dithiazolopyrimidines regio- and diastereoselectively.     

Tandem Michael addition of amines to maleic anhydride and 1,3-prototropic shift: experimental and theoretical results

Amines, namely diethylamine, diphenylamine, benzylamine, and pyrrolidine react with maleic anhydride to form Michael adducts. The Michael adducts formed with the first three amines undergo tandem 1,3-prototropic shift to give the final products. Computational calculations at the DFT (B3LYP/6-31+G*) level reveal that a reactant-complex formed between the initially formed Michael adduct and the respective amine plays a crucial role in the 1,3-prototropic shift. In the reaction of pyrrolidine with maleic anhydride, Michael addition is not followed by 1,3-prototropic shift. The theoretical studies of the latter reaction show that a reactant-complex is not formed in this case. Dimethyl maleate and dimethyl fumarate react with pyrrolidine to give the same Michael addition product.     

Highly enantioselective Michael addition of malononitrile to alpha,beta-unsaturated ketones

The highly enantioselective Michael addition of malononitrile to acyclic and cyclic alpha,beta-unsaturated ketones has been developed. The Michael reaction catalyzed by a primary amine derived from quinidine proceeded smoothly and provided the desired adducts with excellent enantioselectivities (83-97% ee).     

Enantioselectively organocatalytic Michael addition of ketones to alkylidene malonates

An organocatalytic asymmetric Michael addition of ketones to alkylidene malonates has been developed. In the presence of 20 mol % of urea 1a or N-(pyrrolidin-2-ylmethyl)trifluoromethanesulfonamide 1j, the reactions of ketones with alkylidene malonates afford the desired Michael adducts in moderate to good yields with good to high enantioselectivities under mild conditions.     

Organocatalytic enantioselective conjugate addition of ketones to isatylidine malononitriles

An enantioselective Michael addition of ketones to alkylidenemalononitriles catalyzed by chiral primary amine I with (R)-5c as a co-catalyst in good yields (>90%) and with good enantioselectivities (85-96% ee) has been developed. The strategy has also been extended to a three-component version through a domino Knoevenagel/Michael sequence with similar or better outcomes.     

Relative rates of Michael reactions of 2'-(phenethyl)thiol with vinyl sulfones,vinyl sulfonate esters,and vinyl sulfonamides relevant to vinyl sulfonyl cysteine protease inhibitors

[reaction: see text] The relative rates of Michael additions of 2'-(phenethyl)thiol to representative vinyl sulfonyl Michael acceptors were measured. The dependence of the reactivity of the Michael acceptor on the nature of the sulfonyl R substituent was determined in order to evaluate the effect of these substituents on the inactivation kinetics of comparably substituted vinyl sulfonyl cysteine protease inhibitors. The rates of these Michael additions vary over 3 orders of magnitude, with phenyl vinyl sulfonate esters (R = OPh) being ca. 3000-fold more reactive than N-benzyl vinyl sulfonamides (R = NHBn).     

Double michael addition reactions to tetrakis sulfonyl activated olefins

A new class of bis Michael adducts are prepared from 1,3‐bis‐[2‐(2‐arylethenesulfonyl)‐vinyl]‐benzenes and 1,4‐bis‐[2‐(2‐arylethenesulfonyl)‐vinyl]‐benzenes by double Michael addition reaction with active methylene compounds.     

Aerobic Pd-catalyzed sp3 C-H olefination: a route to both N-heterocyclic scaffolds and alkenes

This communication describes a new method for the Pd/polyoxometalate-catalyzed aerobic olefination of unactivated sp(3) C-H bonds. Nitrogen heterocycles serve as directing groups, and air is used as the terminal oxidant. The products undergo reversible intramolecular Michael addition, which protects the monoalkenylated product from overfunctionalization. Hydrogenation of the Michael adducts provides access to bicyclic nitrogen-containing scaffolds that are prevalent in alkaloid natural products. Additionally, the cationic Michael adducts undergo facile elimination to release α,β-unsaturated olefins, which can be further elaborated via C-C and C-heteroatom bond-forming reactions.     

Enantioselective Michael addition of aldehydes to nitroolefins catalyzed by pyrrolidine-HOBt

The oxytriazole catalyst “pyrrolidine-HOBt” developed for asymmetric Michael addition of cyclohexanone to nitroolefins is now evaluated for the asymmetric Michael addition of aldehydes to nitroolefins under similar reaction conditions. The results of this study indicate that, the oxytriazole catalyst “pyrrolidine-HOBt” is equally effective in promoting the Michael addition of aldehydes to nitroolefins on employing benzoic acid as an additive. The desired products, γ-nitrocarbonyl compounds were obtained in good yields and high enantioselectivities.     

Organocatalytic highly enantioselective Michael addition of 2-hydroxy-1,4-naphthoquinones to nitroalkenes

The first organocatalytic enantioselective Michael addition of 2-hydroxy-1,4-naphthoquinones to nitroalkenes for the direct synthesis of chiral nitroalkylated naphthoquinone derivatives was investigated. Good yields and excellent enantioselectivities (up to >99% ee) could be achieved. This organocatalytic asymmetric Michael addition provides an efficient route toward the synthesis of optically active functionalized naphthoquinones.     

Enantio- and diastereoselective Michael reaction of 1,3-dicarbonyl compounds to nitroolefins catalyzed by a bifunctional thiourea

We synthesized a new class of bifunctional catalysts bearing a thiourea moiety and an amino group on a chiral scaffold. Among them, thiourea 1e bearing 3,5-bis(trifluoromethyl)benzene and dimethylamino groups was revealed to be highly efficient for the asymmetric Michael reaction of 1,3-dicarbonyl compounds to nitroolefins. Furthermore, we have developed a new synthetic route for (R)-(-)-baclofen and a chiral quaternary carbon center with high enantioselectivity by Michael reaction. In these reactions, we assumed that a thiourea moiety and an amino group of the catalyst activates a nitroolefin and a 1,3-dicarbonyl compound, respectively, to afford the Michael adduct with high enantio- and diastereoselectivity.     

Aza-Michael Addition of Isatin and Phthalimide to Symmetrical Fumaric Esters in Ionic Liquid Media

Highly efficient aza-Michael additions of isatin and phthalimide to symmetrical fumaric esters in ionic liquid media to produce the corresponding Michael adducts in excellent yields are described which were performed at 100 ℃ for 1—5 h. The results show that these aza-Michael additions are not effective with fumaric esters containing sterically hindered alkoxy groups.     

Asymmetric Michael Addition of Ketones to Alkylidene Malonates and Allylidene Malonates via Enamine-Metal Lewis Acid Bifunctional Catalysis

Novel enamine-metal Lewis acid bifunctional catalysts were successfully applied to the asymmetric Michael addition of ketones to alkylidene malonates, offering excellent stereoselectivity (up to >99% ee and >99:1 dr). The asymmetric Michael addition of ketones to allylidene malonates was also achieved.