Organocatalytic (1+4)-Annulations of MBH Adducts with Electron-Deficient Systems

Benefited from the rapid development of MBH reaction, the reaction of MBH adducts have been established as the most synthetically useful transformations. However, compared with the well-established allylic alkylations and (3+2)-annulations, the (1+4)-annulations of MBH adducts have not developed rapidly until recently. As a helpful complement to the (3+2)-annulations of MBH adducts, the (1+4)-annulations of MBH adducts opens a robust access to structurally diverse five-membered carbo- and heterocycles. This paper summarizes recent advances in organocatalytic (1+4)-annulations using MBH adducts as 1 C-synthons for the construction of functionalized five-membered carbo- and heterocycles.     

Organocatalytic asymmetric transformations of modified Morita-Baylis-Hillman adducts

Chiral Lewis basic tertiary amines or phosphines can enable properly modified Morita-Baylis-Hillman (MBH) adducts to undergo asymmetric allylic substitutions with a wide range of nucleophiles. In addition, assisted by a Br?nsted base, chiral Lewis bases can also catalytically convert modified MBH adducts into allylic ylides, which can be engaged in a variety of asymmetric annulation reactions. This tutorial review will focus on such chiral Lewis base-catalysed asymmetric transformations of MBH adducts, especially those developed over the past five years, allowing for the rapid construction of densely functionalised chiral molecules with high levels of regio- and stereoselectivities.     

Transformations of Modified Morita‐Baylis‐Hillman Adducts from Isatins Catalyzed by Lewis Bases

The development of synthetic protocols to access architectures with broad structural and functional diversity from readily available starting materials is very attractive in both organic and medicinal chemistry fields. Toward this objective, the multifunctional isatin‐derived Morita‐Baylis‐Hillman (MBH) adducts provide opportunities to construct a variety of complex scaffolds containing a “privileged” oxindole motif through several catalytic pathways. By forming the ammonium or phosphonium salts with Lewis bases, isatin‐derived MBH adducts can undergo allylic substitutions with a range of nucleophiles, usually in a S_N2′‐S_N2′ pattern. Besides, assisted by Brønsted bases, the corresponding onium salts can be converted into the allylic ylide intermediates, which can undergo various annulation reactions or even 1,3‐difunctionalizations. Moreover, recent cooperative catalysis of Lewis bases and transition metal complexes further puts forward the application of isatin‐derived MBH adducts. This tutorial review covers the significant transformations of isatin‐derived MBH adducts, mostly in an asymmetric version, catalyzed by various Lewis bases over the past decade.     

Thiourea-catalyzed Morita-Baylis-Hillman reaction

Here, we describe our studies on the thiourea-catalyzed Morita-Baylis-Hillman (MBH) reaction. Chemoselective activation of carbonyl compounds via hydrogen bonding to thiourea as a catalyst is the key to drastic rate acceleration of this reaction. The application of chiral bis-thiourea-type organocatalysts, which can form a chiral double hydrogen-bonding network, is effective for enantioselective MBH reaction. A cooperative system of bis-thiourea compounds, synthesized from 1,2-diaminocyclohexane, and a Lewis base effectively promotes the MBH reaction at lower temperature, affording the MBH adducts in 33-95% yield with 44-90% ee. A plausible transition state model of the enantioselective MBH reaction is presented.     

Intermolecular Morita-Baylis-Hillman reactions using dicobalthexacarbonyl complexed acetylenic acetals

An intermolecular Morita-Baylis-Hillman (MBH) reaction using dicobalthexacarbonyl complexed acetylenic acetals as the electrophile is reported. Employing BF₃-OEt₂ as the Lewis acid with a sulfide as the Lewis base MBH adducts were obtained.     

Enantioselective Morita-Baylis-Hillman reaction promoted by L-threonine-derived phosphine-thiourea catalysts

A series of bifunctional phosphine-thiourea organic catalysts based on natural amino acid scaffolds were designed and prepared. L-threonine-derived bifunctional phosphine catalysts were found to be very efficient in promoting asymmetric Morita-Baylis-Hillman (MBH) reaction of acrylates with aromatic aldehydes, affording the desired MBH adducts with up to 90% ee. To gain mechanistic insights into the reaction, the effects of adding various additives on the MBH reaction were investigated. We propose that the hydrogen bonding interactions between the thiourea moiety of the catalyst and the enolate intermediate are crucial for the stereochemical outcome of the reaction. The method described in this report may provide a practical solution to the enantioselective MBH reaction of simple acrylates.     

Morita–Baylis–Hillman (MBH) Reaction Derived Nitroallylic Alcohols,Acetates and Amines as Synthons in Organocatalysis and Heterocycle Synthesis

The Morita–Baylis–Hillman (MBH) reaction is one of the most useful and efficient protocols for constructing new carbon–carbon bonds between an activated olefin and electrophiles in the presence of a tertiary amine/phosphine. Herein, we present the use of MBH alcohols, which are obtained from the reaction of nitrostyrenes with aldehydes, as well as acetates and amines derived thereof in several organocatalytic transformations. Densely functionalised MBH adducts can also be used to synthesise substituted heteroaromatic compounds, such as furan, pyrrole, pyrazole and imidazole derivatives.     

Synthesis of multi‐functionalized carbonyl compounds by palladium–catalysed γ‐substitution of MBH adducts with activated amides

Catalytic allylic γ‐substitution with Morita‐Baylis‐Hillman (MBH) adducts for creating a new family of unsymmetrical dicarbonyl compounds was presented in this work, in which a variety of allylated amide products were achieved in good yields and high regioselectivity with excellent linear‐to‐branched ratios. Especially, it was found that the Pd/HZNU‐Phos complex exhibited remarkably high activity (with a TON up to 16800) in this transformation between dicarbonyl amides and MBH adducts. In addition, the possibly multisite interaction between multifunctional Pd/HZNU‐Phos catalyst system and substrates might responsible for its exceptionally high efficiency in this reaction.     

Synthesis of 1H-benzo[g]indazole derivatives: propargyl–allenyl isomerization and 6π-electrocyclization involving two aromatic π-bonds

An efficient synthesis of 1H-benzo[g]indazoles starting from Morita–Baylis–Hillman (MBH) adducts is disclosed. The synthesis was carried out from MBH bromide via a sequential copper-catalyzed alkynylation, one-pot synthesis of pyrazole, propargyl–allenyl isomerization, and a 6π-electrocyclization involving two aromatic π-bonds and an allenyl π-bond.     

Construction of highly functional quaternary carbon stereocenters via an organocatalytic tandem cyanation-allylic alkylation reaction

The first tertiary amine-catalyzed tandem cyanation-allyic alkylation (CAA) reaction of aldehydes, appropriate cyanide sources, and Morita-Baylis-Hillman (MBH) adducts has been developed, which provides a facile access to densely functionalized products containing O-substituted quaternary centers.     

Nucleophilic substitution reaction of Morita–Baylis–Hillman adducts of isatin with X,S, N,and O-nucleophiles: a facile and efficient synthesis of highly functionalized tetrasubstituted alkene appended oxindoles

The Morita–Baylis–Hillman adducts derived from isatins and maleimides have undergone a facile and efficient allylic nucleophilic substitution reaction with X, S, N, and O-nucleophiles to afford functionalized tetrasubstituted alkene appended oxindoles in very good yield. The MBH adducts and their acetates on treatment with halides, saturated and unsaturated amines, thiols, and trialkyl orthoformates afforded allyl halide, allyl amine, allyl thio-ether and allyl ether derivatives of oxindole, respectively.     

Multifunctional chiral phosphines-catalyzed highly diastereoselective and enantioselective substitution of Morita-Baylis-Hillman adducts with oxazolones

Multifunctional chiral phosphine (phosphine-thiourea type) L2-catalyzed allylic substitutions of MBH adducts 1 with oxazolones 2 produce the corresponding optically active adducts 3 in good to excellent yields and ee's as well as moderate to good de's under mild conditions. The synergistic interaction between hydrogen bond donor site and nucleophilic site has been discussed, indicating that finely tuning the active sites of the multifunctional phosphine organocatalysts is very important.     

The Morita-Baylis-Hillman adducts of beta-aryl nitroethylenes with other activated alkenes: synthesis and anticancer activity studies

The Morita-Baylis-Hillman (MBH) adducts of beta-aryl nitroethylenes with methyl vinyl ketone (MVK) and acrylate, formed in moderate to good yield when mediated by imidazole/LiCl in THF at room temperature, inhibit HeLa cell proliferation by binding to tubulin.     

Tandem three-component reactions of aldehyde, alkyl acrylate, and dialkylmalonate catalyzed by ethyl diphenylphosphine

A new highly efficient three-component reaction of alkyl acrylate, aldehyde and dialkyl malonate using ethyl diphenylphosphine as organocatalyst has been described. Various highly functional compounds bearing hydroxyl groups and the ester functions can be easily prepared in moderate to good yields according to our one-step procedure. The reactions are believed to proceed via Morita-Baylis-Hillman reactions of alkyl acrylate and aldehydes, followed by the Michael addition reactions of dialkyl malonates. Our reactions indicated that the intermediate species formed in the phosphine-catalyzed MBH reaction are an effective organic base to catalyze the Michael addition reactions of dialkyl malonates to the preformed MBH adducts.     

Hydroxyalkylation of conjugated nitroalkenes with activated nonenolizable carbonyl compounds

[reaction: see text] The Morita-Baylis-Hillman reaction of a variety of conjugated nitroalkenes with activated nonenolizable carbonyl compounds such as glyoxylate, trifluoropyruvate, pyruvaldehyde, and ninhydrin in the presence of 40-100 mol % of DMAP in acetonitrile or 100 mol % of imidazole in CHCl(3) or THF provided the adducts in decent to good yields. In most cases, the reactions catalyzed by DMAP in acetonitrile were faster and provided the desired MBH adducts in higher yields as compared to the imidazole catalyzed reactions.     

Mechanism and synthesis of pharmacologically active quinolones from Morita-Baylis-Hillman adducts

The synthesis of quinolones from Morita-Baylis-Hillman (MBH) adducts is reported. The quinolone skeleton is formed via a TFA-mediated cyclization of the MBH adduct, and a mechanism study using ESI(+)-MS(/MS) has indicated the role played by TFA in this key reaction step. The total syntheses of Norfloxacin and a benzyl quinolone carboxylic acid (BQCA) derivative are described. Norfloxacin is a fluoroquinolonic antibacterial drug whereas BQCA is M₁ receptor positive allosteric modulator and seem to provide access to new potential drugs for Alzheimer disease, pain, and sleep disorders. The syntheses of these two important quinolones exemplify the versatility and potentiality of the approach.     

A substrate controlled, very highly diastereoselective Morita-Baylis-Hillman reaction: a remote activation of the diastereofacial selectivity in the synthesis of C-3-branched deoxysugars

The Morita-Baylis-Hillman (MBH) reaction of p-nitrobenzaldehyde with C (6) acyl protected enuloside 1 in the presence of TiCl₄/TBAI yielded highly diastereoenriched C-3-branched deoxysugar derivative or MBH adduct 1′a in high yield, while reactions of unprotected enuloside 2a and C (6) alkyl protected enulosides 2d-e with p-nitrobenzaldehyde under the same conditions afforded the adducts 2′a and 2′d-e, respectively, in low yield with moderate selectivity. Several representative aromatic and aliphatic aldehydes were selected to undergo MBH reaction with 1 to give their respective adducts in very good yield with a very high diastereoselectivity. A plausible mechanism based on the assumption of a Zimmerman-Traxler-type transition state was proposed to explain the excellent selectivity observed with adducts derived from 1. The synthetic application of these adducts were shown by their stereoselective reduction to corresponding threo isomers in very good yield.     

L-threonine-derived novel bifunctional phosphine-sulfonamide catalyst-promoted enantioselective aza-Morita-Baylis-Hillman reaction

A series of novel bifunctional phosphine-sulfonamide organic catalysts were designed and readily prepared from natural amino acids, and they were utilized to promote enantioselective aza-Morita-Baylis-Hillman (MBH) reactions. L-threonine-derived phosphine-sulfonamide 9b was found to be the most efficient catalyst, affording the desired aza-MBH adducts in high yields and with excellent enantioselectivities.     

Base-catalyzed reaction between isatins and N-Boc-3-pyrrolin-2-one

The base-catalyzed reaction between isatins and N-Boc-3-pyrrolin-2-one yields Morita–Baylis–Hillman (MBH) adducts instead of the expected aldol products in good to high yields (up to 97%). Various organic and inorganic bases are efficient catalysts for this reaction. Our study excluded the Morita–Baylis–Hillman mechanism for the formation of the MBH-type products. The MBH products are most likely formed as a result of the subsequent isomerization of the original aldol products between isatins and N-Boc-3-pyrrolin-2-one.     

Chiral phosphine-catalyzed regio- and enantioselective allylic amination of Morita–Baylis–Hillman acetates

Enantioselective allylic substitution of Morita–Baylis–Hillman (MBH) acetates with phthalimide was realized in the presence of a novel l-proline-derived chiral trifunctional phosphine amide ligand to give the corresponding allylic amination adducts in good yields (70–95%) and in modest to good enantioselectivities (34–78% ee’s).