Baylis Hillman Acetates Research Articles

A comprehensive investigation of ethyl 2-(3-methoxybenzyl) acrylate substituted pyrazolone analogue: Synthesis, computational and biological studies

In this study, we successfully synthesized ethyl 2-(3-methoxybenzyl) acrylate-substituted pyrazolones derivative (EMH) through the reaction of Baylis-Hillman acetate with pyrazolones. We conducted comprehensive screenings to evaluate its invitro antifungal, antibacterial, and antioxidant properties. The molecule demonstrated notable in vitro antifungal and antibacterial activities attributed to the presence of anisole, enhancing absorption rates through increased lipid solubility and improving pharmacological effects. Structure-activity relationship (SAR) studies supported these findings. Additionally, insilico studies delved into the molecular interactions of the synthesized molecule with DNA Gyrase, Lanosterol 14 alpha demethylase, and KEAP1-NRF2 proteins, revealing strong binding interactions at specific sites. Furthermore, we employed ab-initio techniques to theoretically estimate the photophysical properties of the compounds. Ground state optimization, dipole moment, and HOMO-LUMO energy levels were calculated using the DFT-B3LYP-6-31G(d) basis set. The theoretical HOMO-LUMO values indicated high electronegativity and electrophilicity index. NBO analysis confirmed the presence of intermolecular ON...H hydrogen bonds resulting from the interaction of the lone pair of oxygen with the anti-bonding orbital. Overall, our results suggest that anisole-substituted pyrazolones derivatives exhibit promising applications in both photophysical and biological domains.

Synthesis of allylamines from Baylis–Hillman acetates using DBU under solvent free condition

Synthesis of allylamines from Baylis–Hillman acetates using DBU under solvent free condition

Vitamin B6-Based Biomimetic Asymmetric Catalysis

One of the fundamental goals of chemists is to develop highly efficient methods for producing optically active compounds, given their wide range of applications in chemistry, pharmaceutical industry, chemical biology, and material science. Biomimetic asymmetric catalysis, which imitates the structures and functions of enzymes, has emerged as an extremely attractive strategy for producing chiral compounds. This field has drawn tremendous research interest and has led to various protocols for constructing complex molecular scaffolds. The Vitamin B6 family, including pyridoxal, pyridoxamine, pyridoxine, and the corresponding phosphorylated derivatives, serves as the cofactors to catalyze more than 200 enzymatic functions, accounting for ∼4% of all enzyme activities. Although significant progress has been made in simulating the biological roles of vitamin B6 during the past several decades, its extraordinary catalytic power has not yet been successfully applied into asymmetric synthesis. In recent years, our group has been devoted to developing vitamin B6-based biomimetic asymmetric catalysis using chiral pyridoxals/pyridoxamines as catalysts. We are particularly interested in mimicking the processes of enzymatic transamination and biological aldol reaction of glycine, respectively, developing asymmetric biomimetic transamination and carbonyl catalysis enabled α-C-H transformation of primary amines. Using a chiral α,α-diarylprolinol-derived pyridoxal as the catalyst, we reported the first chiral pyridoxal catalyzed asymmetric transamination of α-keto acids in 2015. A significant breakthrough in biomimetic transamination was achieved by using an axially chiral biaryl pyridoxamine catalyst that bears a lateral amine side arm. The amine side arm acts as an intramolecular base, accelerating the transamination and proving highly effective for transamination of α-keto acids and α-keto amides. In addition, we discovered the catalytic power of chiral pyridoxals as carbonyl catalysts for asymmetric biomimetic Mannich/aldol reactions of glycinates. These chiral pyridoxals also enabled more α-C-H conversions of glycinates, such as asymmetric 1,4-addition toward α,β-unsaturated esters and asymmetric α-allylation with Morita-Baylis-Hillman acetates. Moreover, carbonyl catalysis can be further applied to highly challenging primary amines with inert α-C-H bonds, such as propargylamines and benzylamines, which represents a powerful strategy for direct asymmetric α-C-H functionalization of various primary amines without protection of the NH2 group. These biomimetic/bioinspired transformations provide efficient new protocols for the synthesis of chiral amines. Herein, we summarize our recent efforts on the development of the vitamin B6-based biomimetic asymmetric catalysis.

Synthesis and Elimination Pathways of 1-Methanesulfonyl-1,2-dihydroquinoline Sulfonamides

A series of new Morita-Baylis-Hillman acetates were prepared and reacted with methanesulfonamide (K2CO3, DMF, 23 °C) to produce tertiary dihydroquinoline sulfonamides in high yields. Subsequent efforts to eliminate the methylsulfonyl group from these derivatives (K2CO3, DMF, 90 °C) as a route to quinolines were met with mixed results. Although dihydroquinoline sulfonamides prepared from ethyl acrylate and acrylonitrile generally underwent elimination to give excellent yields of quinolines, those generated from 3-buten-2-one failed to undergo elimination and instead decomposed. The failure of these ketone substrates to aromatize presumably derives from the enolizable methyl ketone at C-3. Finally, the attempted aromatization of the acrylate-derived 6,7-difluoro-1,2-dihydroquinoline sulfonamide demonstrated that other interesting processes could occur in preference to the desired elimination.

Catalyst- and Additive-Free Electrochemical CO2 Fixation into Morita–Baylis–Hillman Acetates

AbstractThe electrochemical carboxylation of Morita–Baylis–Hillman (MBH) acetates with CO2 is presented. The process proceeds in the absence of transition-metal catalysts and relies on the cathodic reduction of MBH acetates to generate nucleophilic anions that are able to trap low-pressure CO2. Valuable succinate derivatives are obtained (20 examples) in high yields (up to 90%) and with excellent functional group tolerance. A remarkable substrate-controlled (electronic nature) regioselectivity of the transformation is documented along with a mechanistic rationale based on control experiments.

Synthesis of differentiated sulfur-containing polymers by regiodivergent polymerization of Morita–Baylis–Hillman acetates and thiols

Regiodivergent polymerization of Morita–Baylis–Hillman acetates and thiols afforded two differentiated sulfur-containing polymers, and the γ-polymers could be transformed into the corresponding α-polymers under radical conditions.

Montmorillonite K10 catalyzed facile synthesis of N-substituted indoles from primary amines and Morita–Baylis–Hillman acetate of cyclohexenone

Transition metal- and base-free synthesis of N-substituted indoles from primary amines and MBH acetate of cyclohexenone is developed.

Computational and experimental investigation on biological and photophysical properties of high yielded novel aryl-substituted pyrazolone analogue

A series of new aryl-substituted pyrazolone derivatives 5(a-h) were synthesised via the Baylis-Hillman acetate reaction with pyrazolones and tested for antifungal, antibacterial, and antioxidant properties in vitro. Among the tested molecules 5d and 5e show good in vitro antifungal and antibacterial activities due to the presence of fluorine, which enhances the absorption rate by increasing lipid solubility and improves the pharmacological activity. It is also evident from the results obtained from structure-activity relationship (SAR) studies. Further, the photophysical properties of synthesized compounds were theoretically estimated using the ab-intio technique. The ground state optimization and HOMO–LUMO energy levels are calculated using the DFT-B3LYP-6-311 basis set. Using the theoretically estimated HOMO–LUMO value, global chemical reactivity descriptor parameters are estimated, and the result shows that compounds 5d and 5e have a higher electronegative and electrophilicity index than other molecules. Overall results suggest that, fluorine substituted pyrazolone derivatives show good photophysical, SAR, and biological properties.

A highly regio- and stereoselective Pd-catalyzed electrocarboxylation of Baylis-Hillman acetates: An interesting switchable regioselectivity based on electrode material

We developed a novel regio- and stereoselective palladium catalyzed electrocarboxylation of Baylis-Hillman acetates. We found an interesting unprecedented electrode material-controlled switchable regioselectivity. When Platinum was taken as cathode, benzylic carboxylation products were found to be the predominant regioisomers (condition A). Under similar reaction conditions when Nickel was taken as cathode, a complete reversal in regioselectivity was observed providing cinnamyl carboxylation products as the predominant regio isomers with exclusively (E)-stereochemistry (condition B). We proposed plausible mechanisms to explain the switch in regioselectivity which were further supported by TEMPO experiments.

3+2]-Annulation of oxindolinyl-malononitriles with Morita–Baylis–Hillman acetates of nitroalkenes for the regio- and diastereoselective synthesis of spirocyclopentane-indolinones

3-Oxindolinyl-malononitrile participates as a 1,2-binucleophile in a highly regio- and stereoselective [3 + 2] annulation with 1,3-bielectrophilic nitroallylic acetates leading to spirocyclopentane-indolinones. The reaction takes place in the presence of DABCO in THF at room temperature and affords the multi-functional spirocyclic compounds possessing three chiral centers, including a spiro-chiral center in good to excellent yields and short reaction time. The key role of the malononitrile moiety in controlling the reactivity and selectivity has also been demonstrated. An SN2′-intramolecular Michael addition pathway is proposed for the [3 + 2] annulation based on DFT calculation results.

Magnesium catalyzed [3 + 3] heteroannulation of α-enolic dithioesters with MBH acetate: access to functionalized 3,4-dihydro-2H-thiopyrans.

Magnesium catalysis proved to be efficient towards [3 + 3] chemo- and diastereoselective heteroannulation employing racemic Morita-Baylis-Hillman (MBH) acetate as the C3 unit and α-enolic dithioester as the C2S1 unit, leading to highly substituted 3,4-dihydro-2H-thiopyrans in excellent yields. The compatibility with a wide range of functional groups makes this domino formation of C-C and C-S bonds interesting. DFT analyses for the regioselective formation of the intermediate was performed.

Direct synthesis of N-aryl/alkyl 3-carbonylpyrroles from the Morita–Baylis–Hillman acetate of 2,2-dimethoxyacetaldehyde and a primary amine

A kalinite catalyzed direct synthesis of N-substituted 3-carbonylpyrroles from the Morita–Baylis–Hillman acetate of 2,2-dimethoxyacetaldehyde and a primary amine in ethanol was developed.

Unveiling the abnormal effect of temperature on enantioselectivity in the palladium-mediated decabonylative alkylation of MBH acetate

An unusual temperature–enantioselectivity relationship was observed in the newly developed palladium-catalysed enantioselective nucleophilic substitution of cyclic Morita–Baylis–Hillman acetate and 4,4,4-trifluoro-1-phenyl-1,3-butanedione.

Synergistic photoredox and tertiary amine catalysis: generation of allylic sulfones from Morita–Baylis–Hillman acetates and sulfur dioxide

The first example of the synthesis of allylic sulfones through synergistic photoredox and tertiary amine catalysis, starting from MBH acetates, DABCO·(SO2)2 and 4-substituted Hantzsch esters or potassium alkyltrifluoroborates via a radical pathway, is reported.

Visible-light-induced sulfonylation of Baylis–Hillman acetates under metal- and oxidant-free conditions

A visible-light-driven metal- and oxidant-free procedure for the sulfonylation of Baylis–Hillman acetates with sulfonyl hydrazides under open-air conditions at room temperature is reported. The methods provide a green and facile synthetic route to access allylic sulfones.

Phosphinic Dehydrodipeptides: Diversification of the P1′ Residue with the Morita–Baylis–Hillman Acetates and Inhibition of Alanyl Aminopeptidases

Activated allyl acetates (the Morita–Baylis–Hillman acetates) were confirmed as convenient electrophilic precursors of the P1′ fragment of phosphinic dehydrodipeptides, and then, their selected saturated analogs were obtained in the subsequent reduction. This approach is particularly appropriate for structurally complex side chains and thus is an alternative to the addition of α-substituted acrylates with aminoalkylphosphinic acids. While phosphinic dehydrodipeptides were found to be good inhibitors of two mammalian alanyl metalloaminopeptidases, the saturated compounds showed higher activities than their structurally constrained counterparts. Docking calculations and molecular modeling showed that conformational freedom allowed for the favorable binding of distinct stereoisomers of phosphinates, while the presence of the double bond was more restrictive.

Silver/palladium relay catalyzed 1,3-dipole annulation/allylation reactions to access fully substituted allyl imidazolidines.

A silver/palladium relay catalyzed 1,3-dipole annulation/allylation reaction of iminoesters and Baylis-Hillman acetates for the construction of fully substituted allyl imidazolidines is reported. The reaction of both iminoesters and Baylis-Hillman acetates affords the fully substituted allyl imidazolidines in high yields and regioselectivities. The three component reaction is triggered by silver-catalyzed 1,3-dipole annulation, followed by the sequential palladium catalyzed allylation. Mechanistic studies reveal that the dual catalytic system plays a key role in the reaction. The developed methodology provides straightforward access to allyl imidazolidines under simple reaction conditions.

Synthetic Approaches to Nitro-Substituted Isoxazoles

Nitro-substituted isoxazoles are of utmost interest both as versatile intermediates for targeted organic synthesis and as perspective bioactive compounds for drug development. Nevertheless, the existing approaches to them usually lack generality and strongly depend on the position of the nitro group and on the presence of other substituents in the isoxazole ring. This review provides the first systematization of all available data concerning synthetic approaches to 3-, 4-, and 5-nitroisoxazoles. There are a number of preparative approaches to 4-nitroisoxazoles based on classical heterocyclization reactions of nitro-substituted compounds and the nitration of isoxazoles. 3-Nitro- and, especially, 5-nitroisoxazoles are much less readily available. A few methods affording 3-nitroisoxazoles have been reported, often employing the heterocyclization of unsaturated compounds by treatment with sodium nitrite. The sole general preparative method for 5-nitroisoxazoles, containing a variety of functional groups, employs the heterocyclization of electrophilic alkenes by treatment with tetranitromethane activated with triethylamine.1 Introduction2 Synthesis of 4-Nitroisoxazoles2.1 Nitration of Isoxazoles2.2 Condensations of α-Nitro Ketones or Their Oximes2.3 1,3-Dipolar Cycloaddition of Nitrile Oxides to Acetylenes and Their Synthetic Equivalents2.4 Heterocyclization of Acetylene Derivatives by Treatment with Sodium Nitrite2.5 Heterocyclization of Nitro Derivatives of 1,3-Diketones and Their Synthetic Equivalents2.6 Miscellaneous Methods3 Synthesis of 3-Nitroisoxazoles3.1 Heterocyclization of Acetylene Derivatives or 1,3-Dihalogenoalkenes by Treatment with Sodium Nitrite3.2 Heterocyclization of Morita–Baylis–Hillman Acetates by Treatment with Sodium Nitrite3.3 1,3-Dipolar Cycloadditions4 Synthesis of 5-Nitroisoxazoles4.1 1,3-Dipolar Cycloadditions4.2 Synthesis Using Polynitro Compounds5 Conclusion

Visible light enabled γ-trifluoromethylation of Baylis–Hillman acetates: stereoselective synthesis of trisubstituted alkenes

Metal-free γ-trifluoromethylation of Baylis–Hillman acetates is reported using Langlois’ reagent under visible light photoredox catalysis.

Baylis-Hillman acetates in organic synthesis: A simple two-step strategy for oxindole-spiro-α-arylidene-γ-butyrolactone framework

A facile, convenient, and two step strategy for synthesis of spirooxindoles containing α-arylidene-γ-butyrolactone moiety has been developed via monoalkylation of 2-oxindoles with Baylis-Hillman acetates followed by the spirolactonization of the resulting cinnamic esters on treatment with phenyliodine (III) bistrifluoroacetate (PIFA).