Baylis Hillman Adducts Research Articles

Choline Chloride–Urea Deep Eutectic Solvent/Cu–Mn Iminodiacetate Coordination Polymer as an Efficient Catalytic System for Synthesis of Morita–Baylis–Hillman Adducts with Antimicrobial Activity

Choline Chloride–Urea Deep Eutectic Solvent/Cu–Mn Iminodiacetate Coordination Polymer as an Efficient Catalytic System for Synthesis of Morita–Baylis–Hillman Adducts with Antimicrobial Activity

Atroposelective Arene‐Forming Wittig Reaction by Phosphorus PIII/PV=O Redox Catalysis

AbstractThe Wittig reaction is renowned as exceptionally versatile method for converting a diversity of aldehydes and ketones into alkenes. Recently, strategies for chiral phosphine catalysis under PIII/PV=O redox cycling emerged to render this venerable transformation stereoselective. Herein, we describe that phosphine redox catalysis enables the enantioselective synthesis of pertinent biaryl atropisomers by means of a stereocontrolled arene‐forming Wittig reaction. Key to the process is the release of an endogenous base from readily accessible tert‐butyloxycarbonylated Morita–Baylis–Hillman adducts triggered by catalyst intramolecularization, permitting mild phosphine redox catalysis for atroposelective Wittig reactions. By this strategy, a broad diversity of biaryl atropisomers is obtained with up to 94 : 6 enantioselectivity.

SYNTHESIS OF A FEW DERIVATIVES OF BAYLIS-HILLMAN ADDUCTS: BIO-EVALUATION AGAINST ASPERGILLUS NIGER AND CANDIDAALBICANS

A report of the synthesis of a few adducts of Baylis-Hillman adducts (BHA) using green protocol is established. The bioactivities of the adducts were evaluated against Aspergillus nigar and Candida albicans, two fungal pathogens.A few synthesized compounds were tested and found to have moderate to good anti-fungal activities against these two pathogens.

Pd/Zn Dual Catalysis for Site-, Enantio-, and Diastereo-Divergent 2-(Alkoxycarbonyl)allylation of α-Hydroxyketones with Morita–Baylis–Hillman Adducts

Pd/Zn Dual Catalysis for Site-, Enantio-, and Diastereo-Divergent 2-(Alkoxycarbonyl)allylation of α-Hydroxyketones with Morita–Baylis–Hillman Adducts

Aza-[4 + 2] annulations of α-vinyl Morita–Baylis–Hillman adducts for regiodivergent synthesis of exomethylene-bearing azatricyclic compounds

The regiodivergent synthesis of exomethylene-bearing azatricyclic products was achieved via aza-[4 + 2] annulations of cyclic imines with a single C4 synthon, the α-vinyl MBH adduct.

Utilizing Baylis–Hillman Adducts Followed by Michael Addition/Elimination Reaction for the Synthesis of Unusual Conformationally Stable Molecules Governed by Aromatic Interactions

AbstractThe compounds under investigation sought a new approach to synthesis via the Baylis‐Hillman (B−H) and Michael addition reactions. The product formation‘s legitimacy was tested using a repeat reaction with many different nucleophiles. The additional stability of the product via aromatic π⋅⋅⋅π and C−H⋅⋅⋅π interactions may result in unexpected product formation in diverse reactions undertaken utilizing different starting materials. This study suggests that weak interaction not only provides selectivity during reactions but also modifies the result.

Escape from Hydrofunctionalization: Palladium Hydride-Enabled Difunctionalization of Conjugated Dienes and Enynes.

Palladium hydrides are traditionally employed in hydrofunctionalization (i.e. monofunctionalization) of conjugated dienes and enynes, owning to its facile protic hydropalladation of electron-rich (or neutral) unsaturated bonds. Herein, we report a mild PdH-catalyzed difunctionalization of conjugated dienes and enynes. This protocol is enabled by the chemoselectivity switch of the initial hydropalladation step achieved by visible light enhancement of hydricity of PdH species. This method allows for cascade annulation of dienes and enynes with various easily available and abundant substrates, such as acrylic acids, acrylic amides, and Baylis-Hillman adducts, toward a wide range of alkenyl or alkynyl lactones, lactams, and tetrahydrofurans. This protocol also provides an easy access to complex spiro-fused tricyclic frameworks.

Palladium-Catalyzed Regioselective Asymmetric Chemodivergent Allylation of Oxazolones with Morita–Baylis–Hillman Adducts

Palladium-Catalyzed Regioselective Asymmetric Chemodivergent Allylation of Oxazolones with Morita–Baylis–Hillman Adducts

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.

Synthesis and discovery of Baylis-Hillman adducts as potent and selective thioredoxin reductase inhibitors for cancer treatment

The selenoprotein thioredoxin reductase (TrxR) is of paramount importance in maintaining cellular redox homeostasis, and aberrant upregulation of TrxR is frequently observed in various cancers due to their elevated oxidative stress in cells. Thus, it seems promising and feasible to target the ablation of intracellular TrxR for the treatment of cancers. We report herein the design and synthesis of a series of Baylis-Hillman adducts, and identified a typical adduct that possesses the superior cytotoxicity against HepG2 cells over other types of cancer cells. The biological investigation shows the selected typical adduct selectively targets TrxR in HepG2 cells, which thereafter results in the collapse of intracellular redox homeostasis. Further mechanistic studies reveal that the selected typical adduct arrests the cell cycle in G1/G0 phase. Importantly, the malignant metastasis of HepG2 cells is significantly restrained by the selected typical adduct. With well-defined molecular target and mechanism of action, the selected typical adduct, even other Baylis-Hillman skeleton-bearing compounds, merits further development as candidate or ancillary agent for the treatment of various cancers.

2H-Pyrano[3,2-c]chromene-2,5(6H)-diones: Synthesis, Characterization, Photophysical and Redox Studies for Potential Optoelectronic Applications.

Herein, we report the preparation of 2H-pyrano[3,2-c]chromene-2,5(6H)-diones 3a-x by reacting 4-hydroxycoumarins 1a-b with Baylis-Hillman adducts 2a-w having electron releasing or electron withdrawing groups on benzyl ring of the pyranochromene moiety and study of their photophysical properties. The study of optical and electrochemical properties of the prepared compounds reveals that the electron releasing and electron withdrawing groups has not much impact on ground and excited state electronic behavior on pyranochromene moiety. The density functional theory suggests the highest occupied molecular orbital and lowest unoccupied molecular orbitals spread on coumarin moiety of pyranochromene unit. Further, these compounds are thermally stable (up to 200°C) and lead to blue or green emission that should facilitate the development of organic light emitting diodes (OLEDs).

WITHDRAWN: Acetate derivative of Morita –Baylis-Hillman adducts (MBH): A powerful antifungal

In previous work, a new class of synthesized bioactive compounds of Morita –Baylis-Hillman adducts (MBH) showed an antioxidant and anti melanogensis activity. Accordingly, in the present work the relationship between antifungal activity and the responsible chemical function of MBH adducts and their derivatives (alcohols, acetates, phosphonates and hydrazono phosphonates) was investigated against plant pathogenic fungi Aspergillus niger, Fusarium oxysporum, Penicillium occitanis, Trichoderma reesei, Stachybotrys microspora, Fusarium solani, Trichoderma parceramosum, fusarium aethiopicum, Alternaria alternata and Aspergillus flavus using the agar diffusion method. Results showed acetates displayed varying degrees of antifungal activity against several fungi tested, while just one alcohol compound showed lower activity. The derivative with five carbon (2g) was the most powerful with an inhibitor growth zone diameter of 4.75÷0.21, 6.1±0.14, 4.35±0.21, 3.9±0.14, 4.54± 0.11, 3.55±0.07, 3±0, 3.2± 0.2, 5.36 ± 0.26 and 5.06± 0.5cm against; F. oxysporum, T. parceramosum, S. microspora, T. reesei, F. solani, P. occitanis, A. niger, F. aethiopicum, A. alternate and A. flavus respectively. Compared to the positive control the nystatin, most of the tested compounds exhibited moderate to strong inhibitory effects. The antifungal activity depended on the radical group. The novelty is that these adducts are evaluated for the first time for their antifungal effect. Antifungal activity is in general of linear or cyclic molecules coupled to six carbons. Here we show that the simple acetate six membered carbons are the most efficient molecule

Acceleration of Baylis-Hillman Reaction using Ionic Liquid Supported Organocatalyst

Background: Baylis-Hillman reaction requires cheap starting materials, easy reaction protocol, and possibility to create the chiral center in the reaction product has increased the synthetic efficacy of this reaction which also suffers from high catalyst loading, low reaction rate, and poor yield. Objective: The extensive use of various functional or non-functional ionic liquids (ILs) with organocatalyst acts not only as reaction medium but also as a support to anchor the catalysts to increase the reaction rate of various organic transformations. Methods: In this manuscript, we have demonstrated the synthesis of quinuclidine-supported trimethylamine-based functionalized ionic liquid as a catalyst for the Baylis-Hillman reaction. Results: We obtained the Baylis-Hillman adducts in good, isolated yield along with low catalyst loading, short reaction time, wide substrate scope, easy product, and catalyst recycling. N- ((E,3S,4R)-5-benzylidene-tetrahydro-4-hydroxy-6-oxo-2H-pyran-3-yl) palmitamide was also successfully synthesized using CATALYST-3 promoted Baylis-Hillman reaction. Conclusion: We successfully isolated the 25 types of Baylis-Hillman adducts using three different quinuclidine-supported ammonium-based ionic liquids such as Et3AmQ][BF4] (CATALYST-1), [Et3AmQ][PF6] (CATALYST-2), and [TMAAmEQ][NTf2](CATALYST-3) as new and efficient catalysts. Generally, all the reactions demonstrated higher activity and gave good to high yield in competition with various previously reported homogenous and heterogeneous catalytic systems. Easy catalyst and product recovery followed by 6 times of catalysts recycling were the added advantages of the prosed catalytic system. Tedious and highly active N-((E,3S,4R)-5-benzylidene-tetrahydro- 4-hydroxy-6-oxo-2H-pyran-3-yl) palmitamide derivative was also synthesized using CATALYST- 3 followed by Baylis-Hillman reaction.

Baylis–Hillman Adducts as a Versatile Module for Constructing Fluorogenic Release System

The controlled release of a molecule of interest (MOI) is useful in probe design, prodrug construction, and drug delivery. We report herein a versatile thiol-triggered fluorogenic release system using the Baylis-Hillman (BH) adducts as a module. Common functional groups (e.g., amino, hydroxyl, carboxylic, and sulfhydryl groups) in a MOI are readily integrated into the module. The MOI release is fast (∼10 min) with a nearly quantitative yield and a >250-fold fluorescence increment. We further prepared two prodrugs to release camptothecin and nitric oxide (NO) using the two-photon excitable template, and the activation of prodrugs was visualized in live cells and mouse tissues. The therapeutic potential of the NO prodrug was also validated in a stroke model. This BH adduct-based fluorogenic release features multiple advantages, such as easy preparation, compatibility of various functional groups, fast response, high release yield, and tunable emission spectra, and is expected to have broad applications.

Eco-friendly synthesis and structural determination of pyrene fused pyrroloquinolinone hybrid

Synthesis of a structurally complex hitherto unexplored novel class of pyrene fused pyrroloquinolinone was achieved in excellent yield via an environmental friendly solid-state melt reaction condition employing multicomponent cascade protocol which involves 1,3-dipolar cycloaddition and subsequent double annulation process. The 1,3-dipole component was derived in situ from diketone and α-amino acid, whereas the Baylis-Hillman adduct synthesized from pyrene-1-carbaldehyde was utilized as a dipolarophile. Structure of the compound was elucidated by 1H and 13C NMR spectroscopic analysis and further confirmed through single crystal X-ray diffraction and the molecular packing was described by using Hirshfeld surface analysis. The structure-reactivity descriptors of the synthesized compound were examined through DFT calculations. The pyrroloquinoline was evaluated for its antibacterial activity against three multi drug resistant bacterial and two fungal pathogens. The MIC value of the tested microbial pathogens were exhibited with minimum (0.156 mg/mL) and maximum (1.250 mg/mL). The antimicrobial results disclosed that compound 6 is considered as a potent candidate for effective therapeutic applications.

A formal [4 + 1] cycloaddition reaction of Baylis–Hillman bromides with sulfur ylides: facile access to α-alkenyl lactones

A formal [4 + 1] cycloaddition reaction of Baylis–Hillman adducts with sulfur ylides has been developed for the first time.

Environmentally friendly domino multicomponent strategy for the synthesis of pyrroloquinolinone hybrid heterocycles.

An efficient and elegant assembly of pyrene/aryl fused pyrrolo[2,3-b]quinolinone and pyrrolizino[3,2-b]quinolinone hybrid heterocycles was achieved via a domino multicomponent reaction strategy using a solid state melt reaction (SSMR) condition. The 1,3-dipole component was generated in situ from N-methylgylcine/l-proline and isatin, while the Baylis–Hillman adduct prepared from pyrene-1-carbaldehyde and various benzaldehydes is used as the dipolarophile. The domino protocol comprises 1,3-dipolar cycloaddition and a consequent double annulation reaction process. The advantages of this cascade protocol include environmentally friendly conditions, the avoidance of toxic organic solvents, simple work-up and good to excellent product yields.

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.

Synthesis, structure and biological evaluation of highly functionalized 2-azetidinone integrated spirooxindolopyrrolidine heterocyclic hybrid

Synthesis of structurally diverse novel class of azetidinone integrated spirooxindolopyrrolidine heterocyclic hybrid was achieved in excellent yield employing a single-pot intermolecular 1,3-dipolar cycloaddition cascade protocol. The highly functionalized dipolarophile, azetidinone Baylis-Hillman adduct, was prepared from 4-formyl azetidinone whereas the non-stabilized 1,3-dipole component was derived from trifluoromethoxyisatin and l-phenylalanine via decarboxylative condensation. The structure of the product was determined by X-ray diffraction on single crystal method. Further, the crystal structure was analyzed using Hirshfeld calculations. The packing of molecules is controlled by the O…H (19.2%), F…H (17.3%), C…C (3.2%) and N…H (14.8%) which are the most significant in cycloadduct. The electronic and reactivity descriptors of the cycloadduct were calculated on the basis of DFT calculations. The synthesized heterocyclic hybrid displayed significant activity against selected ESBL producing E. coli strains and the minimal MIC values was observed against E. coli WTP005.