Morita Baylis Hillman Adducts Research Articles

Renewable synthesis of novel acrylates from biomass‐derived 5‐substituted‐2‐furaldehydes by Morita‐Baylis‐Hillman reaction

AbstractBiomass‐derived furfurals are becoming increasingly popular as renewable chemical building blocks for synthesizing specialty chemicals. Morita‐Baylis‐Hillman (MBH) reaction is a classic carbon‐carbon bond‐forming transformation between the α‐position of an activated alkene and a carbon electrophile (e. g., aldehyde) using a nucleophilic catalyst, such as a tertiary amine or phosphine. The MBH reaction is highly atom economical, affords excellent yields of adducts under mild reaction conditions, introduces substantial molecular complexity, and enjoys broad substrate scope. In this work, several novel MBH adducts have been synthesized starting from biomass‐derived 5‐substituted‐2‐furaldehydes and acrylates using 1,4‐diazabicyclo[2.2.2]octane (DABCO) as the organocatalyst. This work reports the first systematic study of the MBH reaction of 5‐substituted‐2‐furaldehydes and acrylates. A general synthetic protocol for the high‐yielding synthesis of MBH adducts has been developed. The reactions were performed at room temperature under solvent‐free conditions, and the spectroscopically pure products were produced in good to excellent isolated yields. Moreover, DABCO was recovered from the reaction mixture and successfully recycled.

Comparison between Chemoenzymatic and Bienzymatic Cascades Leading to Morita–Baylis–Hillman Adducts

AbstractChemoenzymatic and bienzymatic cascades offer advantages including increasing diversity of reactions and saving time and operational costs. Herein the oxidation of benzylic alcohols to the corresponding aldehydes coupled with the Morita−Baylis−Hillman (MBH) reactions in biocatalytic compatible potentially ‘green’ conditions has been exemplarily evaluated. One‐pot cascades avoiding the use of reactive aldehyde intermediates are described and compared, including a sequential chemoenzymatic cascade with a variant of galactose oxidase (GOase M3–5) and 1,4‐Diazabicyclo [2.2.2] octane (DABCO), a concurrent dual‐enzyme cascade with GOase M3–5 and a variant of the computationally designed enzyme MBHase (BH32.14), and finally a whole cell biotransformation with the co‐expression modules of the two enzymes. All of the cascades were performed on a diverse range of substrates (12–19 examples), affording moderate to high conversions (up to 93 %) and isolated yields (up to 80 %). The bienzymatic cascades offer optically active products in up to 91 % ee. Key factors affecting the chemoenzymatic and the bienzymatic cascades were highlighted, and the advantages and challenges were compared.

Recent advances in the synthetic applications of Morita-Baylis-Hillman and Rauhut-Currier adducts of nitroalkenes.

The Morita-Baylis-Hillman (MBH) and Rauhut-Currier (RC) adducts of nitroalkenes are important synthetic intermediates in organic synthesis. This review discusses the applications of different MBH and RC adducts of nitroalkenes such as MBH alcohols, acetates, bromides and hydrazinonitroalkenes as well as ketoalkylnitroalkenes in the synthesis of complex molecules including carbocycles and heterocycles. It also covers the mechanistic aspects, including the key intermediates and the reaction pathways. Early reports on MBH and RC reactions of nitroalkenes and applications of the products were covered in previous reviews. The present review covers the reports that appeared in the timeline of 2015-2023.

Diisobutylaluminium hydride mediated efficient synthesis of Morita–Baylis–Hilman adducts through α‐functionalization of alkyl propiolates

AbstractGenerally, oxindole derivatives are biologically important molecules and valuable building blocks in organic synthesis. Herein, we report a diisobutylaluminium hydride mediated efficient one‐pot synthesis of oxindole derivatives using N‐substituted isatins with methyl or ethyl propiolates at lower temperature (−78°C) through Morita‐Baylis‐Hillman (MBH) reaction. Within a short reaction time, a wide range of N‐alkyl or N‐aryl 3‐hydroxy oxindole derivatives (MBH adducts) were easily accessed in excellent yields under mild reaction conditions.

A New MBH Adduct as an Efficient Ligand in the Synthesis of Metallodrugs: Characterization, Geometrical Optimization, XRD, Biological Activities, and Molecular Docking Studies.

This article reports the synthesis, characterization, geometrical optimization, and biological studies of new MBH-based organometallic compounds of medicinal significance. The ligand (MNHA) was prepared via the Morita-Baylis-Hillman (MBH) synthetic route, from aromatic aldehyde containing multiple functional groups. Metal complexes were prepared in an alkaline medium and under other suitable reaction conditions. Spectral and elemental analyses were used to identify the structural and molecular formulas of each compound. Optimized geometry was determined through density functional theory (DFT) B3LYP and 6-311++ G (d,p) basis set for the MBH adduct, whereas structures of novel complexes were optimized with the semi-empirical PM6 method. Powder XRD analysis furnished the crystal class of complexes, with Co3+, Cr3+, and Mn2+ being cubic, while Ni2+ was hexagonal, and Cu2+ was orthorhombic. Moreover, the ligand, along with Ni2+ and Co3+ complexes, showed profound antibacterial action against S. aureus, E. coli, B. pumilis, and S. typhi. Additionally, all of the complexes were shown to persist in the positive antioxidant potential of the ligand. Contrarily, not a single metal complex conserved the antifungal potentials of the ligand.

Lipase-Catalysed Enzymatic Kinetic Resolution of Aromatic Morita-Baylis-Hillman Derivatives by Hydrolysis and Transesterification.

Acylated Morita-Baylis-Hillman (MBH) adducts were synthesised and subjected to enzymatic kinetic resolution (EKR) by hydrolysis employing various lipase enzymes: from P. fluorescens, P. cepacia (PCL), C. antarctica A (CAL-A), C. antarctica B (CAL-B) and Novozyme 435. In a number of instances enantiopure Morita-Baylis-Hillman acetates or butyrates and their corresponding hydrolysed MBH adducts were obtained with ee values of >90 %, at ca. 50 % conversion, corresponding to enantiomeric ratio (E) values of >200. Enantioselective transesterification reactions on MBH adducts was achieved using acyl anhydrides in THF or the greener organic solvent 2-MeTHF in the presence of CAL-A. This is the first report of successful lipase-catalysed EKR of aromatic MBH adducts by transesterification in organic medium.

Synthesis, Characterization, Biological Activities and Ab-initio Study of Transition Metal Complexes of [Methyl 2-((4-chlorophenyl)(hydroxy)methyle) Acrylate

Taking cognizance of the medicinal significance and diverse functions of synthetic Morita-Baylis-Hillman adducts (MBHA), the title ligand was synthesized and purified through column chromatography. Cr+3, Mn+2, Co+3, Ni+2, Cu+2 complexes of the ligand were synthesized under basic conditions, subjected to characterization through spectral analyses and verified with the IR spectrum that was generated computationally by the DFT B3LYP method, with 6-311++ G (d,p) basis set and Hartree Fock (HF) B3LYP method in conjunction with 3-21G(d,p) basis set. Powder XRD helped to testify crystals of the complexes. Moreover, the antibacterial, and antioxidant characteristics of MBHA and its complexes were also established. All of them were found to be active antioxidants. The antibacterial activities, examined against S. aureus, E. coli, B. pumilis and S. typhi have revealed that its Cobalt complex has an excellent potential to act against all of them. Hence, these compounds maybe having potentialities for the discovery of new, cheaper and efficient drugs against various infectious diseases. The study also uncovers the first example of utilization of MBHA towards metal complex formation.

An Improved Protocol for the Morita‐Baylis‐Hillman Reaction Allows Unprecedented Broad Synthetic Scope

AbstractThe Morita‐Baylis‐Hillman (MBH) reaction has been stablished as an important C−C bond‐forming transformation between carbonyl‐containing compounds and activated olefins. However, the slow reaction rate usually observed with electron‐rich electrophilic partners hinders a more widespread use of this reaction. In order to overcome this drawback, the effects of several Brønsted acids on the rate of DABCO‐catalyzed MBH reactions were evaluated. The protocol is operationally simple, involving neat and open‐flask conditions, and is compatible with a wide range of reagents. We suggest a general acid catalysis mechanism to be responsible for the rate increase. The synthetic versatility of the MBH adducts is exemplified with a two‐steps diastereoselective synthesis of the natural product (±)‐sitophilure. We hope this acid‐mediated protocol to have potential use as a general methodology for the MBH reaction.

Leishmanicidal activity of Morita-Baylis-Hillman adducts.

Leishmaniasis is a neglected disease that affects millions of people, mostly in developing countries. Although this disease has a high impact on public health, there are few drug options to treat the different leishmaniasis forms. Additionally, these current therapies have various adverse effects, including gastrointestinal disturbances, headache, pancreatitis, and hepatotoxicity. Thus, it is essential to develop new drug prototypes to treat leishmaniasis. Accordingly, the present study aimed to evaluate the leishmanicidal activity of Morita-Baylis-Hillman adducts and their O-acetylates, carboxylic acid derivatives, and acid and ester derivatives of 2-methyl-phenylpropanoids against Leishmania chagasi. Initially, we evaluated the cytotoxicity of 16 derivatives (1-16G) against J774A.1 macrophages. Eight derivatives (2G, 4G, 5G, 7G, 9G, 10G, 13G, and 15G) showed no cytotoxicity at up to the maximum concentration tested (100μM). When evaluated for antileishmanial effect against promastigote forms, 1G, 6G, 8G, 10G, 11G, 13G, 14G, 15G, and 16G displayed significant toxicity compared to the control (0.1% DMSO). Additionally, the compounds 1G, 5G, 7G, 9G, 11G, 13G, 14G, and 16G reduced macrophage infection by amastigotes. Thus, we conclude that these derivatives have antileishmanial effects, particularly 1G, which showed activity against promastigotes and amastigotes, and low toxicity against macrophages.

An isatin aldol adduct as a precursor to α,α’-difunctionalized methyl vinyl ketones

Isatin-methyl vinyl ketone aldol adducts underwent efficient Morita–Baylis–Hillman (MBH) and Rauhut–Currier (RC) reactions under mild conditions to bring about a functionalization of the olefinic α-carbon, and thereby α,α’-difunctionalization of methyl vinyl ketone in the process. The MBH adducts were characterized by the presence of a 2-methylene-1,3,5-trioxygenated system, whereas the RC dimerization of the substrate furnished compounds that bore two oxindole moieties, each adorned with a tetrasubstituted carbon and a hydroxyl group.

Regio- and stereoselective synthesis of functionalized and fused heterocycles from Morita-Baylis-Hillman adducts of dicyclopentadienone.

An efficient protocol for the Morita-Baylis-Hillman (MBH) reaction of dicyclopentadienone using CTAB has been developed. The MBH adduct was subsequently transformed to its acetate and bromide derivatives. The 1,3-bielectrophilic character of the MBH acetate and bromide was further explored with various 1,3-binucleophiles to construct various oxa-, thia- and aza-heterocycles. These reactions proceed through a cascade double Michael addition of 1,3-binucleophiles to the MBH acetate/bromide under basic conditions. Amenability of these reactions to scale-up and applications of the products in the synthesis of cyclopentenone-fused chromenones and thiopyranoindoles have been demonstrated.

Synthesis of Acrylonitrile Derivatives via Visible Light‐induced Coupling Reaction of Morita‐Baylis‐Hillman Adducts with Tertiary Amines and α‐Trimethylsilyl Amines

AbstractRu‐catalyzed coupling reaction of Morita‐Baylis‐Hillman (MBH) adducts with tertiary amines and α‐trimethylsilyl amines under visible light is disclosed. Compared with the reported MBH adducts with ester as withdrawing‐electron groups, MBH adducts with cyano group in this paper show different chemical reaction characteristics. The universality of substrates has been extended. A series of structurally complementary acrylonitriles are obtained in satisfied yields under mild condition, which provides a good opportunity to discover new meaningful bioactive compounds.

The Application of Biocatalysis in the Preparation and Resolution of Morita-Baylis-Hillman Adducts and Their Derivatives.

The Morita-Baylis-Hillman (MBH) reaction affords highly functionalised allylic alcohols containing a new stereogenic centre. These MBH adducts are very versatile and have been transformed into a large range of products, some of which have medicinal potential. Several examples of asymmetric syntheses of MBH adducts have been reported, although a generally applicable method remains to be developed. Biocatalytic approaches for the synthesis and enzymatic kinetic resolution of MBH adducts have been reported, and are discussed in detail in this review. Enzymes able to catalyse the asymmetric MBH reaction have been identified, but selectivity and efficiency have generally been low. Lipases, esterases and nitrile-converting enzymes have all been successfully applied in the resolution of MBH adducts, with excellent selectivity being realised in most cases.

Enantioselective Radical SN2-Type Alkylation of Morita-Baylis-Hillman Adducts Using Dual Photoredox/Palladium Catalysis.

An enantioselective radical alkylation of 4-alkyl-1,4-dihydropyridines with Morita-Baylis-Hillman (MBH) adducts has been reported. The SN2-type products are predominant. This reaction is enabled by dual photoredox/palladium catalysis. The alkylation products are provided in good yields with good regio- and enantioselectivity. The use of Ding's spiroketal-based bis(phosphine) (SKP) ligand is crucial to achieving satisfactory regio- and enantioselectivity. The resultant α,β-unsaturated ester can be easily reduced to a synthetically useful chiral allyl alcohol.

Silver/ThioClickFerrophos-Catalyzed 1,3-Dipolar Cycloaddition and Tandem Addition-Elimination Reaction of Morita-Baylis-Hillman Adducts.

The asymmetric 1,3-dipolar cycloaddition of glycine imino esters to Morita-Baylis-Hillman (MBH) adducts or acetylated MBH adducts is described. The reaction was efficiently catalyzed by AgOAc/(R,Sp)-ThioClickFerrophos at room temperature to afford pyrrolidine derivatives bearing a quaternary carbon as a single diastereomer with excellent enantioselectivity. When a cyclic pyrroline ester was used as the nucleophile instead of a glycine imino ester, the enantioselective tandem addition-elimination reaction with an acetylated MBH adduct proceeded with an excellent yield and enantioselectivity, resulting in the formation of an exo-olefin. The wide substrate scope of these reactions and the transformability of the products enable expeditious access to divergent multifunctionalized pyrrolidines in an optically pure fashion.

Facile and innovative catalytic protocol for intramolecular Friedel-Crafts cyclization of Morita-Baylis-Hillman adducts: Synergistic combination of chiral (salen)chromium(III)/BF3·OEt2 catalysis.

The chiral (salen)Cr(III)/BF3·OEt2 catalytic combination was found to be an effective catalyst for intramolecular Friedel–Crafts cyclization of electron-deficient Morita–Baylis–Hillman adducts. In presence of mild reaction conditions the chiral (salen)Cr(III)/BF3·OEt2 complex affords 2-substituted-1H-indenes from unique substrates of Morita–Baylis–Hillman adducts via an easy operating practical procedure.

Antimicrobial effect of Morita-Baylis-Hillman adducts against oral pathogens and cellular viability in human leukocytes / Efeito antimicrobiano de adutos de Morita-Baylis-Hillman contra patógenos orais e viabilidade celular em leucócitos de humanos

The aim of this work was to evaluate Morita-Baylis-Hillman adduct (MBHA) antimicrobial effect against oral pathogens and related cell viability in human leukocytes. Minimum inhibitory concentration (MIC) was determined using microdilution method. Cell viability was assessed in human peripheral blood mononuclear cells (PBMCs) using the resazurin assay. For S. aureus (ATCC 15656) and S. mutans (UA 159) MIC values of 2,000 μg/mL were reported for the A 1 Morita-Baylis-Hillman adducts. The MICs of the A 2 and A 3 adducts were not found for the bacterial strains. MIC values for the A 1 adduct was 125 μg/mL, A 2 1,000 μg/mL and A 3 to 15.6μg/mL against the C. albicans strain (ATCC 11006). PBMCs showed cell viability greater than 50 % when in contact with concentrations 10x higher than MIC of MBHA. It is concluded that MBHA A 1 , A 2 and A 3 present potential antimicrobial effects against C. albicans without presenting substantial cytotoxic effects in human cells, highlighting adduct A 3 for future therapeutic applications.

Propylphosphonic acid anhydride–mediated amidation of Morita–Baylis–Hillman–derived indolizine-2-carboxylic acids

Propylphosphonic acid anhydride has been successfully used as a coupling agent in the synthesis of a series of indolizine-2-carboxamido derivatives from indolizine-2-carboxylic acid and its 3-acetylated analogue. The acid substrates were obtained by saponification of the corresponding methyl esters produced, in turn, selectively and efficiently, by time-controlled cyclisation of a single Morita–Baylis–Hillman adduct. Various amino and hydrazino compounds with medicinal potential have been used to prepare indolizine-2-carboxamido and hydrazido derivatives.

Ligand-Dependent Regiodivergent Enantioselective Allylic Alkylations of α-Trifluoromethylated Ketones.

The asymmetric introduction of the CF3 unit is a powerful tool for modifying pharmacokinetic properties and slowing metabolic degradation in medicinal chemistry. A catalytic and enantioselective addition of α-CF3 enolates allows for expeditious access to functionalized chiral building blocks with CF3-containing stereogenicity. The computational studies reveal that the choice of ligand in a designed palladium-complex system regulates the regioselectivity and stereoselectivity of the asymmetric allylic alkyation of α-CF3 ketones and Morita-Baylis-Hillman adducts.

Brucine Diol-Catalyzed Enantioselective Morita-Baylis-Hillman Reaction in the Presence of Brucine N-Oxide

Brucine diol (BD) catalyzed asymmetric Morita–Baylis–Hillman (MBH) reaction is observed for the first time. Brucine N-oxide (BNO) was found to not have an effective chiral catalyst. Faster reaction rate was obtained using unsaturated ester or aromatic aldehydes in the presence of BNO. 4-Nitrobenzaldehyde and α,β-unsaturated ketone/ester were converted to the MBH adduct in moderate yields (up to 74%) with 70% ee value by this catalytic system. The mechanism of BD catalysis is probably initiated by conjugating the vicinal diol of BD to the carbonyl group of the aromatic aldehyde through hydrogen bonding. The tertiary amine of BD acts as a nucleophile to activate vinyl ketone for coupling with the carbonyl of aldehyde through an intramolecular carbonylated reaction. Finally, the breakdown of the complex caused the formation of the MBH adduct (a benzyl-allyl alcohol). The chirality of the benzyl-allyl alcohol is likely affected by the interaction of the bulky asymmetric plane of BD.