Baylis Hillman Reaction Research Articles

Acryl Activation by Intramolecular Hydrogen Bond: Morita Baylis Hillman Reaction of Acrylamide with Broad Substrate Scope

Use of acrylamide as an activated alkene in largely recognized Morita Baylis Hillman (MBH) reaction has been least explored owing to less reactivity of acrylamide as Michael acceptor. Contrary acrylamide have profound applications in synthetic, medicinal and polymer chemistry. An intramolecular Hydrogen bond activated, MBH reaction of N-(2-hydroxyphenyl) acrylamide has been developed. With various control experiments, role of ortho hydroxy was found to be as an activator and was critical for success of reaction. Under the influence of DABCO, designed acrylamides gave wide substrate scope including a number of less reactive aldehydes and chemo selective MBH reactions. Such mode of activation can be helpful in design of other reactions too. An example has been presented by successful Michael addition reaction.

Recent Advances in the Chemistry of Masked Ortho‐Benzoquinones and Their Applications in Organic Synthesis

AbstractMasked ortho‐benzoquinones are important intermediates in organic synthesis that exhibit a rich and fascinating chemistry. Their functionally enriched structural skeleton makes them important scaffolds in organic synthesis. They undergo a variety of interesting reactions and have found wide applications, especially in the total synthesis of many natural products. The functionalities such as alkene, diene, carbonyl, enone, dienone and ketal inherent in their structure can interfere individually or collectively in chemical transformations, making their chemistry interesting as well as challenging. Here, the work on masked ortho‐benzoquinones is reviewed in terms of their reactions such as intermolecular and intramolecular Diels–Alder reactions, Michael additions, [3+2] cycloadditions, and Baylis–Hillman reactions; these reactions lead to the formation of highly functionalised heterocyclic and carbocyclic compounds that are otherwise difficult to access. This Focus Review summarises the developments in the chemistry of masked ortho‐benzoquinones and covers the literature from 2005 to 2016.

Some aspects of intramolecular carbocyclization of methyl (2E)-3-[(1S,2R,5R)-2-({[tert-butyl(dimethyl)-silyl]oxy}methyl)-5-(trimethylsilyl)cyclopent-3-en-1-yl]prop-2-enoate and its derivatives

Treatment of methyl (2E)-3-[(1S,2R,5R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-(trimethylsilyl) cyclopent-3-en-1-yl]prop-2-enoate with Bu4NF in THF resulted in intramolecular cyclization with formation of bicyclo[3.1.0]hexene structure. Possible ways of cyclopropane ring closure were discussed. Methyl (2E)-3-[(1R,4R,5S)-5-formyl-4-(trimethylsilyl)cyclopent-2-en-1-yl]prop-2-enoate failed to undergo intramolecular Baylis–Hillman reaction.

The application of Morita-Baylis-Hillman reaction: Synthetic studies on perophoramidine

A new concise methodology was developed for the synthesis of the two vicinal quaternary centers of the natural product perophoramidine. Key steps involved the Morita–Baylis–Hillman reaction, reductive cyclization and allylic alkylation. Moreover, most conditions are simple and convenient with good yields.

Stereoselective Construction of Entire Diastereomeric Stereotetrads Based on an Asymmetric Morita–Baylis–Hillman Reaction

A method for the enantio‐ and diastereoselective construction of all possible stereoisomers of a polypropionate stereotetrad having four contiguous stereogenic centers has been developed. The approach features an iterative sequence of cinchona‐alkaloid‐catalyzed Morita–Baylis–Hillman reaction and subsequent diastereoselective hydrogenation. By this method, benzaldehyde was successfully converted into eight diastereoisomeric 3,5‐dihydroxy‐2,4‐dimethyl‐5‐phenylpentanoic acid ester derivatives with high enantiomeric purities (99 % ee) in 25–67 % overall yield (eight steps) in a reagent‐controlled manner.

Palladium-Catalyzed Asymmetric Allylation of Allylic Acetates

Key words asymmetric allylic allylation - asymmetric palladium catalysis - Morita–Baylis–Hillman reaction

Analgesic and antiinflammatory evaluation of newer 2-amino nicotinate derivatives synthesized by baylis hillman reaction

Nicotine is an important class of heterocyclic compound, has been shown to exhibit diverse biological and pharmacological activities. In this study, a series of newer 2-amino nicotinate derivativeshave been synthesized by Baylis Hillman reaction. All the synthesized compounds have been characterized by using elemental analysis, FT-IR, 1 H NMR, 13 C NMR spectroscopy and further supported by mass spectroscopy. Purity of all the compounds has been checked on thin layer chromatographic plate and HPLC technique. All the synthesized compounds were tested for their analgesic and anti-inflammatory activities. The compounds exhibited significant analgesic and anti-inflammatory activities. These compounds can be further exploited to get the potent lead compounds. The detailed synthesis and the pharmacological screening of 2-amino nicotinate derivatives are reported.

Intermolecular Stetter Reactions on Morita‐Baylis‐Hillman Adducts: an Approach to Highly Functionalized 1,4‐Dicarbonyl Compounds

AbstractWe reported herein an N‐heterocyclic carbene (NHC)‐mediated intermolecular Stetter reaction between oxidized Morita‐Baylis‐Hillman (MBH) adducts and a variety of aldehydes. This protocol allows the synthesis of highly functionalized 1,4‐dicarbonyl compounds. The reaction is an alternative approach to these compounds using commercially available starting materials. This metal‐free process exhibits a wide substrate scope, excellent atom economy, compatibility with functionalized substrates and mild reaction conditions. The 1,4‐dicarbonyl compounds were prepared in two steps via MBH reactions with overall yields up to 99 %. This protocol is easily scalable. The synthetic usefulness of this method was demonstrated in a high yield synthesis of a tri‐substituted pyrrole used as an advanced intermediate in the total synthesis of kinase inhibitors as well as in the synthesis of another heterocycles.

Synthesis and biological evaluation of 2-alkoxycarbonylallyl esters as potential anticancer agents

The reaction of carboxylic acids with Baylis-Hillman reaction derived α-bromomethyl acrylic esters readily provide 2-(alkoxycarbonyl)allyl esters in good to excellent yields. These functionalized allyl esters have been evaluated for their cell proliferation inhibition properties against breast cancer (MDA-MB-231 and 4T1) and pancreatic cancer (MIAPaCa-2) cell lines to explore their potential as anticancer agents. Several of the synthesized derivatives exhibit good potency against all three cancer cell lines. Our structure activity relationship (SAR) studies on 2-carboxycarbonyl allyl esters indicate that substituted aromatic carboxylic acids provide enhanced activity compared to substituted aliphatic carboxylic acid analogs. Di- and tri-allyl esters derived from di-and tri-carboxylic acids exhibit higher inhibition of cell proliferation than mono esters. Further SAR studies indicate that the double bond in the 2-(alkoxycarbonyl)allyl ester is required for its activity, and there is no increase in activity with increased chain length of the alkoxy group. Two lead candidate compounds have been identified from the cell proliferation inhibition studies and their preliminary mechanism of action as DNA damaging agents has been evaluated using epifluorescence and western blot analysis. One of the lead compounds has been further evaluated for its systemic toxicity in healthy CD-1 mice followed by anticancer efficacy in a triple negative breast cancer MDA-MB-231 xenograft model in NOD-SCID mice. These two in vivo studies indicate that the lead compound is well tolerated in healthy CD-1 mice and exhibits good tumor growth inhibition compared to breast cancer drug doxorubicin.

Mechanism and reactivity in the Morita-Baylis-Hillman reaction: the challenge of accurate computations.

A systematic density functional theory exploration of various reactive steps together with benchmark coupled cluster results are used to propose an accurate model of the mechanism of the Morita-Baylis-Hillman (MBH) reaction in organic chemistry. This reaction has attracted considerable interest from the synthetic and mechanistic points of view in recent years, with both computational and experimental mechanistic studies. It has recently (R. E. Plata and D. A. Singleton, J. Am. Chem. Soc., 2015, 137, 3811-3826) been correctly pointed out that previous computational studies failed to reproduce known mechanistic features of the reaction. The same study argued that computation is simply not able at the present time to provide accurate models for such reactions. This second claim is shown by our present work to overstate the problem: by using current 'state of the art' methodology, our results are fully consistent with observed behavior within the expected error bars of 1-5 kcal mol-1, far smaller than the errors reported in Plata and Singleton's study. On the basis of exhaustive calculations reported here, we suggest that our proposed approaches for modeling electronic structure, solvation, and entropy should be able to provide accurate predictions for many more reactions. We also suggest that reactions like the MBH reaction, where solvation and entropy effects are particularly large, are among the hardest for computational mechanistic studies.

A computational investigation of the solvent-dependent enantioselective intramolecular Morita-Baylis-Hillman reaction of enones.

The intramolecular Morita-Baylis-Hillman reaction of β-mono and β,β-disubstituted enones shows high yields and stereo-selective products when the reaction is performed in the presence of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as a solvent. In this work, we carried out a computational study using the density functional Becke 3-(B3) parameter exchange and the Lee-Yang-Parr (LYP) correlation functional and 6-31+G* basis set. Two major steps i.e. C-C bond formation and proton transfer were analysed using different pathways. The calculations show a very low barrier (ΔG† = 0.23 kcal mol-1) for C-C bond formation in the case of an experimentally dominant product. For this pathway the subsequent proton transfer via the HFIP step has a barrier of 26.98 kcal mol-1. The same has been confirmed using a Molecular Electrostatic Potential (MESP), which shows a negative region in between CC in the transition state. In spite of high barriers for proton transfer, the intermediate products formed in this reaction pathway are thermodynamically more stable in comparison with other pathways. The thermodynamic stability of the final product in this pathway is observed to surpass all other effects in the presence of HFIP, thereby corroborating the experimentally observed enantioselectivity.

An efficient catalyst-free one-pot synthesis of primary amides from the aldehydes of the Baylis–Hillman reaction

Herein, a facile and efficient method for the preparation of allyl amides from the aldehydes of Baylis–Hillman adducts has been developed using a hydroxylamine/methanol system under a catalyst-free condition.

Expression of concern: Aza-Morita-Baylis-Hillman reactions catalyzed by a cyclopropenylidene.

Expression of concern for 'Aza-Morita-Baylis-Hillman reactions catalyzed by a cyclopropenylidene' by Xun Lu et al., Chem. Commun., 2016, 52, 12980-12983.

Highly diastereoselective synthesis of tertiary alcohols via intramolecular Baylis-Hillman reaction using less reactive acrylamides as activated alkenes and ketones as electrophiles

A simple and convenient protocol for highly diastereoselective intramolecular Baylis-Hillman (IBH) reaction of substrates containing less reactive acrylamides as activated alkene and ketones with α-chiral center (racemic) as electrophile components, thus producing α-methylene-γ-lactam frameworks having β-tertiary alcoholic functional group, has been developed.

Asymmetric Morita-Baylis-Hillman Reaction: Catalyst Development and Mechanistic Insights Based on Mass Spectrometric Back-Reaction Screening.

An efficient protocol for the evaluation of catalysts for the asymmetric Morita-Baylis-Hillman (MBH) reaction was developed. By mass spectrometric back-reaction screening of quasi-enantiomeric MBH products, an efficient bifunctional phosphine catalyst was identified that outperforms literature-known catalysts in the MBH reaction of methyl acrylate with aldehydes. The close match between the selectivities measured for the forward and back reaction and kinetic measurements provided strong evidence that the aldol step and not the subsequent proton transfer is rate- and enantioselectivity-determining.

One-Pot Synthesis of α-Ylidene δ-Lactones from Functionalized Allylic Bromides in a Water–Isopropanol Medium

The one-pot microwave-assisted synthesis of a series of α-ylidene δ-lactones from (Z)-2-(bromomethyl)-2-alkenoates (derived from Morita–Baylis–Hillman reaction) in an aqueous environment is reported. The protocol includes regioselective base-mediated allylation of ethyl acetoacetate with (Z)-2-(bromomethyl)-2-alkenoates followed by decarboxylative hydrolysis, carbonyl reduction of the keto carboxylate intermediate, and acid-mediated cyclization of the resulting δ-hydroxy acid to furnish the α-ylidene δ-lactones with good overall yields. The synthesis was also performed in the stepwise mode, which allowed the isolation and full characterization of each intermediate involved in the one-pot method. The main features of this efficient transformation include the fast reaction rates, the use of a benign aqueous medium, the use of inexpensive and readily available reagents, the production of nearly innocuous residues, and the requirement for a single work-up and purification stage at the end of the process.

ChemInform Abstract: Asymmetric Aza‐Morita—Baylis—Hillman Reactions of Chiral N‐Phosphonyl Imines with Acrylates via GAP Chemistry/Technology.

AbstractThe atom‐economical reaction proceeds with excellent diastereo and enantioselectivity.

Proline-Mediated Baylis–Hillman Reaction of Methyl Vinyl Ketone without a Co-catalyst under Solvent-Free Conditions

A proline-mediated Baylis–Hillman reaction of methyl vinyl ketone with aromatic aldehydes has been carried out without using any co-catalyst, under solvent-free conditions. The reaction works efficiently at 60 °C in the presence of a small amount of water to afford the Baylis–Hillman adducts in reasonable to very good yields over 8–48 h. The absence of a co-catalyst suggests that proline plays a role in the proton-transfer step of the reaction mechanism, in addition to its proposed involvement in the iminium ion formation and conjugate addition. This would, in principle, imply that proline acts as a trifunctional catalyst in the reaction, and mechanistic studies to gain a deeper understanding of this aspect should provide further insights in the future.

Chemoselectivity Improvement via Partial Shielding of an Imidazole Active Site in Branched/Dendritic Homogeneous Catalysts of the Baylis–Hillman Reaction

AbstractWhile comparing analogous polystyrene‐supported and homogeneous catalysts for the Baylis–Hillman reaction, we hypothesized that the hydrophobic envelopment of the imidazole catalytic sites of the former is responsible for the significantly better chemoselectivity exhibited by the heterogeneous catalysts compared to their homogeneous counterparts. In order to test this hypothesis, we prepared a series of branched/dendritic homogeneous catalysts, with an imidazole active site near the focal point and flexible tails of various lengths and polarities, capable of providing partial shielding of this site. The design of the catalysts was based on a 5‐hydroxyisophthalate scaffold, and they were prepared through a number of multistep synthetic pathways. The comparison of the catalysts under a variety of conditions in a model Baylis–Hillman reaction demonstrated that long hydrophobic tales enhance the chemoselectivity parameter of the catalysis, while reducing the rate of the consumption of the substrates, and that the chemoselectivity is further improved by the presence of a free phenolic moiety in the vicinity of the catalytic imidazole unit. Moreover, in second‐generation catalysts, the peripheral long tails could be either hydrophobic or polar, since the dendritic inner backbone itself presumably partially provides the necessary isolation of the catalytic site. Thus, experimental results support our hypothesis.magnified image

ChemInform Abstract: Catalytic Efficiency of Primary β‐Amino Alcohols and Their Derivatives in Organocatalysis

AbstractReview: [81 refs.