Hillman Reaction Research Articles

DABCO/Amberlyst® 15-Cocatalysed One-Pot Three-Component Aza-Morita–Baylis–Hillman Reaction Under Green Conditions

The one-pot multicomponent aza-Morita–Baylis–Hillman (MBH) reaction was performed under green conditions using 1,4-diazabicyclo[2.2.2]octane (DABCO) and Amberlyst® 15 as a co-catalyst, at ambient temperature and under negligible amounts of non-hazardous solvent. A number of α-methylene-β-amino acid derivatives were produced in good to excellent yields from different arylaldehydes, p-toluenesulfonamide and α,β-unsaturated carbonyl compounds. The environmental benignity of the process is accounted by the low E-factor (0.7) and high atom economy (95%) values obtained.

Ionic Liquid@ HT- Clay Combination for Baylis -Hillman Reaction and Lactone Ceramide Analog Synthesis

Abstract: This study investigates the use of ionic liquids (ILs) immobilized on HT-clay as catalysts for the Baylis-Hillman reaction. The catalytic system comprised three different types of ILs ([HIM]Im, [BIM]Im, [EIM]Im) and exhibited high reactivity, and the B-H products were obtained in good yield, which is superior to previously reported catalytic systems, whether they were heterogeneous or homogeneous. The HT-clay immobilized with ILs also allowed for easy recovery from the reaction mass and could be recycled for up to 7 consecutive runs with only a slight decrease in activity. Moreover, the scope of our catalytic system was extended to synthesize biologically active lactone ceramide analogs using the Baylis-Hillman reaction at room temperature with (S-) Garner aldehyde and methyl acrylate. The synthesis was successful, and we obtained good yields of the desired products, highlighting the versatility of the ionic liquid immobilized HT-clay catalytic system. This study demonstrates the potential of ionic liquid immobilized HT-clay as a promising catalyst for various organic reactions. Our findings emphasize the importance of developing efficient and environmentally friendly methods for synthesizing valuable organic compounds. The results obtained from this study provide a significant contribution to the ongoing research in the field of catalysis and will be useful for developing new approaches to the synthesis of complex organic molecules.

Novel 1,2,4-Triazole- and Tetrazole-Containing 4H-Thiopyrano[2,3-b]quinolines: Synthesis Based on the Thio-Michael/aza-Morita–Baylis–Hillman Tandem Reaction and Investigation of Antiviral Activity

A novel method for synthesizing 1,2,4-triazole- and tetrazole-containing 4H-thiopyrano[2,3-b]quinolines using a new combination of the thio-Michael and aza-Morita–Baylis–Hillman reactions was developed. Target compounds were evaluated for their cytotoxicities and antiviral activities against influenza A/Puerto Rico/8/34 virus in MDCK cells. The compounds showed low toxicity and some exhibited moderate antiviral activity. Molecular docking identified the M2 channel and polymerase basic protein 2 as potential targets. We observed that the antiviral activity of thiopyrano[2,3-b]quinolines is notably affected by both the nature and position of the substituent within the tetrazole ring, as well as the substituent within the benzene moiety of quinoline. These findings contribute to the further search for new antiviral agents against influenza A viruses among derivatives of thiopyrano[2,3-b]quinoline.

N-Boc-Amino Acid Mediated Morita-Baylis Hillman reaction of methylphenyl glyoxylate

The organocatalyzed Morita-Baylis Hillman (MBH) reaction of α-keto esters is a challenging carbon-carbon bond-forming reaction. We developed a catalytic system for the MBH reaction of methylphenyl glyoxylate with methyl vinyl ketone in a polar aprotic solvent. We used N-Boc-L-pipecolinic acid as a proton transfer mediator and 4-dimethylaminopyridine as the tertiary amine catalyst. We obtained the MBH adduct with a 66% yield in 48h. We proposed a detailed reaction mechanism involving a transition state that includes the hydrogen transfer by the acid functional group of N-Boc-L-pipecolinic acid.

Palladium‐Catalyzed Inverse and Normal Dehydrogenative Aza‐Morita–Baylis–Hillman Reactions with γ,δ‐Unsaturated Compounds

Abstractσ‐Lewis base‐catalyzed regio‐ and enantioselective aza‐Morita–Baylis–Hillman (MBH) reaction of α,β,γ,δ‐unsaturated systems remains a challenge due to the intrinsic covalent activation mode. Here we demonstrate that a Pd0 complex can mediate the dehydrogenative reaction of γ,δ‐unsaturated compounds to give corresponding electron‐poor dienes, which further undergo δ‐regioselective umpolung Friedel–Crafts‐type addition to imines via auto‐tandem Pd0‐π‐Lewis base catalysis. After β‐H elimination of in situ formed PdII‐complexes, unprecedented and chemically inverse aza‐MBH‐type adducts are finally furnished with fair to outstanding enantioselectivity, and a diversity of functional groups and both ketimine and aldimine acceptors can be well tolerated. Moreover, switchable α‐regioselective normal aza‐MBH‐type reaction also can be realized by tuning catalytic conditions, whereas moderate to good enantioselectivity with low to excellent Z/E‐selectivity is attained.

Computational Evolution Of New Catalysts For The Morita-Baylis-Hillman Reaction.

We present a de novo discovery of an efficient catalyst of the Morita-Baylis-Hillman (MBH) reaction by searching chemical space for molecules that lower the estimated barrier of the rate-determining step using a genetic algorithm (GA) starting from randomly selected tertiary amines. We identify 435 candidates, virtually all of which contain an azetidine N as the catalytically active site, which is discovered by the GA. Two molecules are selected for further study based on their predicted synthetic accessibility and have predicted rate-determining barriers that are lower than that of a known catalyst. Azetidines have not been used as catalysts for the MBH reaction. One suggested azetidine is successfully synthesized and showed an eightfold increase in activity over a commonly used catalyst. We believe this is the first experimentally verified de novo discovery of an efficient catalyst using a generative model.

Computational Evolution Of New Catalysts For The Morita–Baylis–Hillman Reaction**

AbstractWe present a de novo discovery of an efficient catalyst of the Morita–Baylis–Hillman (MBH) reaction by searching chemical space for molecules that lower the estimated barrier of the rate‐determining step using a genetic algorithm (GA) starting from randomly selected tertiary amines. We identify 435 candidates, virtually all of which contain an azetidine N as the catalytically active site, which is discovered by the GA. Two molecules are selected for further study based on their predicted synthetic accessibility and have predicted rate‐determining barriers that are lower than that of a known catalyst. Azetidines have not been used as catalysts for the MBH reaction. One suggested azetidine is successfully synthesized and showed an eightfold increase in activity over a commonly used catalyst. We believe this is the first experimentally verified de novo discovery of an efficient catalyst using a generative model.

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 Catalytic Systems for the Mechanistically Complex Morita–Baylis–Hillman Reaction

Recent Advances in Catalytic Systems for the Mechanistically Complex Morita–Baylis–Hillman Reaction

2-Fluoroenones via an Umpolung Morita-Baylis-Hillman Reaction of Enones.

Several methods have been reported for the formation of 2-fluoroenones. However, all these methods involve laborious multiple-step sequences with resulting low overall yields. In this paper, we report the first formal enone-α-H to F substitution, leading to 2-fluoroenones in a single step from ubiquitous enones in 63-90% yield. The reaction is applicable to a wide range of aromatic and alkenyl enones and is carried out at room temperature using HF-pyridine complex as the fluoride source. Mechanistic investigations support that the reaction takes place through a rare umpolung Morita-Baylis-Hillman-type mechanism.

C(sp3)–H Alkenylation of Tetrahydroisoquinolines via Merging Electrochemistry and Organocatalysis

C(sp3)-H alkenylation of tetrahydroisoquinoline by merging Shono oxidation and the Morita-Baylis-Hillman reaction is developed, employing 4-dimethylaminopyridine as an organocatalyst and TEMPO/NaBr as an electrocatalyst. The reaction proceeds via the interception of an iminium cation intermediate, which is generated in situ from anodic oxidation, leading to aza-Morita-Baylis-Hillman reaction products. Additionally, the use of TEMPO and NaBr as mediators is crucial to avoid the decomposition of products by lowering the oxidation potential of the reaction.

Phosphine-catalyzed asymmetric aza-Morita–Baylis–Hillman reaction of endocyclic ketimines and activated alkenes

Asymmetric aza-Morita–Baylis–Hillman reaction involving endocyclic ketimines, tetra-substituted chiral carbon center was achieved.

Morita–Baylis–Hillman reaction: how do optimal enzyme active sites compare with organocatalysts

Theoretical active site models for the Morita–Baylis–Hillman reaction uncover the importance of cooperativity between the oxyanion hole and the acid–base catalyst in catalyzing multiple steps via minimal reorganization.

Quinuclidine-Immobilized Porous Polymeric Microparticles as a Compelling Catalyst for the Baylis–Hillman Reaction

Quinuclidine-Immobilized Porous Polymeric Microparticles as a Compelling Catalyst for the Baylis–Hillman Reaction

Engineering the simply asymmetric Morita–Baylis–Hillman reactions in a sodium phosphate buffer system: from enzyme‐ to proline‐catalyzed transformation

AbstractBACKGROUNDThe Morita–Baylis–Hillman (MBH) reaction is an important carbon–carbon bond‐forming reaction. However, most MBH reactions suffer disadvantages such as high amounts of catalyst and hazardous solvents, long reaction time, low reactivity and selectivity. In this study, simple, cost‐effective and eco‐friendly asymmetric MBH reactions are developed.RESULTSFollowing our previous study that the commercial Candida antarctica lipase B (lipase CalB)‐catalyzed MBH reaction can be activated by introducing an amide compound as a co‐catalyst, the recombinant lipase CalBs (rCalBs) with polyamino acid tails are first attempted to be used in the same MBH reaction, but unfortunately chiral MBH products are not obtained. Enoate reductase (ER) is found to give asymmetric transformation of the MBH reaction with a conversion of 36.9% and enantiomeric excess (e.e.p) of 6.8% when other enzyme resources are expanded. According to the observation that the surface amino acids of ER may be key factors in achieving the MBH reaction, single amino acids are subsequently selected to catalyze the MBH reactions, and the reverse configuration of (R)‐ and (S)‐MBH products with e.e.p of 63.9% and 62.1% for single l‐proline‐ and d‐proline‐catalyzed MBH reactions are reached only in 4 h, respectively.CONCLUSIONProline can afford the asymmetric MBH reaction in a sodium phosphate buffer only in 4 h without the help of the other co‐catalyst in our study, which is superior to those reported. The study aims to introduce a novel phenomenon observed from enzyme‐catalyzed to proline‐catalyzed MBH reactions. © 2022 Society of Chemical Industry (SCI).

Synthesis of isomeric 4-(N-methyltetrazolylamino)-2-phenyl-4H-thiopyrano[2,3-b]quinoline-3-carbaldehydes and 4-hydroxy-2-phenyl-4H-thiopyrano[2,3-b]quinoline-3-carbaldehyde based on tandem thiol-Michael and (aza)-Morita-Baylis-Hillman reactions and an in vitro study of the activity of the obtained compounds against influenza virus.

3-{[(1-Methyl-1H-tetrazol-5-yl)imino]methyl}quinoline-2-thiol and 3-{[(2-methyl-2H-tetrazol-5-yl)imino]methyl}quinoline-2-thiol were synthesized. The sequence of the thiol-Michael reaction and the (aza)-Morita–Baylis–Hillman reaction yielded 4-[(1-methyl-1H-tetrazol-5-yl)amino]-2-phenyl-4H-thiopyrano[2,3-b]quinoline-3-carbaldehyde, 4-[(2-methyl-2H-tetrazol-5-yl)amino]-2-phenyl-4H-thiopyrano[2,3-b]-quinoline-3-carbaldehyde, and 4-hydroxy-2-phenyl-4H-thiopyrano[2,3-b]quinoline-3-carbaldehyde. Cytotoxicity and antiviral activity against the A/Puerto Rico/8/34 (H1N1) influenza virus strain in MDCK cell culture were determined for the obtained compounds. The study showed that the replacement of the hydroxyl group in 4-hydroxy-2-phenyl-4H-thiopyrano[2,3-b]quinoline-3-carbaldehyde with a 1-methyl- or 5-amino-2-methyltetrazolyl fragment decreased antiviral activity. At the same time, 3-{[(1-methyl-1H-tetrazol-5-yl)imino]-methyl}quinoline-2-thiol has a higher activity than 3-{[(2-methyl-2H-tetrazol-5-yl)imino]methyl}quinoline-2-thiol. This fact indicates a possible relationship between the arrangement of substituents in the tetrazole ring and the antiviral activity of the tested heterocyclic system.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10593-022-03083-w.

Highly Efficient Asymmetric Morita–Baylis–Hillman Reaction Promoted by Chiral Aziridine-Phosphines

Continuing our research on the use of organophosphorus derivatives of aziridines in asymmetric synthesis and expanding the scope of their applicability, chiral aziridine-phosphines obtained earlier in our laboratory were used as chiral catalysts in the asymmetric Morita–Baylis–Hillman reaction of methyl vinyl ketone and methyl acrylate with various aromatic aldehydes. The desired chiral products were formed in moderate to high chemical yields and with enantiomeric excess reaching value of 98% ee in some cases. The use of catalysts being pairs of enantiomers led to the desired products with opposite absolute configurations.

Cover Feature: An Improved Protocol for the Morita‐Baylis‐Hillman Reaction Allows Unprecedented Broad Synthetic Scope (Eur. J. Org. Chem. 9/2022)

The Cover Feature illustrates the effect of acetic acid on the rate of the Morita–Baylis–Hillman reaction. The use of acetic acid as a fuel (additive) increases the reaction rate in all tested cases, with special emphasis on electron-rich electrophilic partners. We believe that a general acid catalysis mechanism is responsible for this increase in reaction rate. More information can be found in the Research Article by G. W. Amarante, F. Coelho et al.

Engineered Biocatalyst Permits Enantioselective Morita–Baylis–Hillman Reaction

Key words Morita–Baylis–Hillman reaction - MBHase - directed evolution - enzyme engineering - asymmetric catalysis

The Morita-Baylis-Hillman reaction for non-electron-deficient olefins enabled by photoredox catalysis.

A strategy for overcoming the limitation of the Morita–Baylis–Hillman (MBH) reaction, which is only applicable to electron-deficient olefins, has been achieved via visible-light induced photoredox catalysis in this report. A series of non-electron-deficient olefins underwent the MBH reaction smoothly via a novel photoredox-quinuclidine dual catalysis. The in situ formed key β-quinuclidinium radical intermediates, derived from the addition of olefins with quinuclidinium radical cations, are used to enable the MBH reaction of non-electron-deficient olefins. On the basis of previous reports, a plausible mechanism is suggested. Mechanistic studies, such as radical probe experiments and density functional theory (DFT) calculations, were also conducted to support our proposed reaction pathways.