Baylis Hillman Reaction Research Articles

Morita–Baylis–Hillman reaction of pyridine-2, 3, and 4-carboxaldehydes and N-methyl isatin with mono and diacrylates: synthesis of highly functionalized pyridine ligands and isatin derivatives

Morita–Baylis–Hillman reaction of pyridine-2, 3, and 4-carboxaldehydes and N-methyl isatin with less explored activated alkenes such as 1,6-hexanediol diacrylate (HDDA) and acrylates of lauryl and isoboronyl has been carried out to provide diversely functionalized mono and bis MBH adduct of pyridine aldehydes and isatin in very good yields. Synthetic use of MBH adducts thus obtained has been demonstrated by preparing pyridine-N-oxide derivatives and [3+2]-azomethine ylide cycloaddition products.

Glucosyloxymethylfurfural (GMF): a creative renewable scaffold towards bioinspired architectures

Abstract Glucosyloxymethylfurfural (GMF) is the glucosylated analogue of hydroxymethylfurfural (HMF), and is obtained in one step from the very available disaccharide isomaltulose. This account gives an overview on the preparation and the uses of GMF towards architectures containing a carbohydrate moiety and shows that rather elaborated targets can be synthesized from GMF in very short sequences. A special focus is made on carbon–carbon formation on the aldehyde group leading to new biobased acrylic derivatives by the Baylis–Hillman reaction.

Rasta Resin-TBD-Catalyzed γ-Selective Morita–Baylis–Hillman Reactions of α,γ-Disubstituted Allenones

Rasta resin-TBD (RR-TBD) was found to be an efficient organocatalyst for γ-selective Morita–Baylis–Hillman reactions between α,γ-disubstituted allenones and aryl aldehydes. In these reactions the heterogeneous nature of RR-TBD greatly facilitated product isolation since the catalyst could be separated simply by filtration.

Morita–Baylis–Hillman Reactions with Nitroalkenes: A Case Study

AbstractWe report on the use of a highly reactive super‐DMAP catalyst in Morita–Baylis–Hillman (MBH) reactions of nitroalkenes with ethyl glyoxylate, which result in excellent conversions and short reaction times with, importantly, very low catalyst loading. An extensive study of this particular reaction is presented, which examines all mechanistic and experimental details. Several critical points were hence uncovered that include the correlation between reaction efficiency and Lewis basicity of the catalyst; the double role played by the promoter, primarily as a nucleophilic activator towards the nitroalkene, and as a Brønsted base that triggers glyoxylate depolymerisation. More generally, the limitations in the choice of electrophiles that can engage efficiently in MBH‐type transformations are rationalized by the competition between a productive pathway and a nitroalkene polymerization process. Other aspects of this transformation, used as a case study, are presented in the light of physical organic chemistry.

(±)Methanodibenzodiazocine tethered [C-H]δ+ functional site: Study towards benzoin condensation and Baylis-Hillman reactions

New heterocyclic ring systems consisting of (±) methanodibenzodiazocine and imidazolium/ benzimidazolium salts were synthesized in very good yield. Subsequently, these halide salts were subjected to the anion exchange reaction with KPF6 to yield the corresponding azolium salts in excellent yield. The possible applications of these newly prepared salts were investigated in homogeneous catalysis. Remarkable changes in the catalytic activity were observed by varying the bulkiness of N-substituent at imidazole. Catalytic activity of these newly prepared salts was tested for the benzoin condensation reaction. Exclusive formation of benzoin products were observed in good yield. Similarly, the dimerization of cyclohexen-1-one to Baylis-Hillman type product, 2-(3-oxocyclohexyl)-2-cyclohexen-1-one was studied. Synthesis and application of (±)methanodibenzo diazocine tethered azolium salts for bezoincondensation and baylis-hillman type reactions.

ChemInform Abstract: Formation of Cyclohepta[b]indole Scaffolds via Heck Cyclization: A Strategy for Structural Analogues of Ervatamine Group of Indole Alkaloid.

Ervatamine, silicine, methuenine, etc., are naturally occurring alkaloids that exhibit antimicrobial, anticancer, and anti-HIV activities. Indole fused with a seven-membered carbocyclic ring is a commonly observed structural feature among this series of bioactive compounds. This work describes a strategic approach for the synthesis of cyclohepta[b]indole structural scaffolds. The synthetic strategy consists of a solvent-free Baylis-Hillman reaction of 2-bromobenzaldehydes, followed by iodine-catalyzed C-alkylation of indole with the Baylis-Hillman adducts. Finally, intramolecular Heck coupling reaction using Pd(OAc)2 as catalyst in the presence of benzyltrimethylammonium bromide under microwave condition produced the desired cyclohepta[b]indole derivatives.

ChemInform Abstract: Hydrolase‐Catalyzed Asymmetric Carbon—Carbon Bond Formation in Organic Synthesis

AbstractReview: 86 refs.

Tunable Bifunctional Phosphine–Squaramide Promoted Morita–Baylis–Hillman Reaction of N‐Alkyl Isatins with Acrylates

AbstractA series of highly tunable bifunctional phosphine‐squaramide H‐bond donor organocatalysts 6 has been synthesized from inexpensive and commercially available β‐amino alcohols in moderate yields. Catalyst 6 f can efficiently promote the asymmetric Morita–Baylis–Hillman (MBH) reaction of N‐alkyl isatins with acrylate esters providing the chiral 3‐substituted 3‐hydroxy‐2‐oxindoles in good yields and enantioselectivities (up to 93 % yield and 95 % ee), in which the challenging substrate tert‐butyl acrylate 9 d, provided the best ee value to date. Moreover, this methodology was applied successfully in the synthesis of chiral cyclic spiropyrrolizidineoxindole and γ‐butyrolactone derivatives without enantioselectivity deterioration. The possible mechanism of this MBH reaction was also investigated by 31P NMR, ESI‐MS and KIE studies. The KIE experiments show that the electrophilic addition of N‐methyl isatin to the complex of acrylate ester and phophine‐squaramide is the rate‐determing step of the asymmetric MBH reaction.magnified image

A case study of the mechanism of alcohol-mediated Morita Baylis-Hillman reactions. The importance of experimental observations.

The mechanism of the Morita Baylis–Hillman reaction has been heavily studied in the literature, and a long series of computational studies have defined complete theoretical energy profiles in these reactions. We employ here a combination of mechanistic probes, including the observation of intermediates, the independent generation and partitioning of intermediates, thermodynamic and kinetic measurements on the main reaction and side reactions, isotopic incorporation from solvent, and kinetic isotope effects, to define the mechanism and an experimental mechanistic free-energy profile for a prototypical Morita Baylis–Hillman reaction in methanol. The results are then used to critically evaluate the ability of computations to predict the mechanism. The most notable prediction of the many computational studies, that of a proton-shuttle pathway, is refuted in favor of a simple but computationally intractable acid–base mechanism. Computational predictions vary vastly, and it is not clear that any significant accurate information that was not already apparent from experiment could have been garnered from computations. With care, entropy calculations are only a minor contributor to the larger computational error, while literature entropy-correction processes lead to absurd free-energy predictions. The computations aid in interpreting observations but fail utterly as a replacement for experiment.

ChemInform Abstract: Less Reactive Ketones as Electrophiles and Acrylamides as Activated Alkenes in Intramolecular Baylis—Hillman Reaction: Facile Synthesis of Functionalized γ‐Lactam Frameworks.

Abstract Less reactive ketones and acrylamides have been successfully employed as electrophiles and activated alkenes, respectively, in intramolecular Baylis–Hillman reaction, thus providing a facile protocol for obtaining functionalized α-methylene-γ-lactam derivatives.

ChemInform Abstract: Enantioselective Aza‐Morita—Baylis—Hillman Reaction Between Acrylates and N‐Boc Isatin Ketimines: Asymmetric Construction of Chiral 3‐Substituted‐3‐aminooxindoles.

AbstractThe first enantioselective aza‐Morita—Baylis—Hillman reaction of acrylates with ketimines derived from isatins is developed.

Unified synthesis of tirandamycins and streptolydigins.

The asymmetric total syntheses of tirandamycins A-D and tirandalydigin as well as the synthesis of the left-hand fragment of streptolydiginone and streptolydigin from a common intermediate are described. The comprehensive approach features the highly enantio- and diastereoselective assembly of the anti,anti,syn-stereotetrad unit which relies on a cinchona alkaloid-catalyzed asymmetric Morita-Baylis-Hillman reaction.

HyEtPy]Cl–H2O: an efficient and versatile solvent system for the DABCO-catalyzed Morita–Baylis–Hillman reaction

A very efficient and versatile solvent system, [HyEtPy]Cl–H2O, has been developed and used in the DABCO-catalyzed Morita–Baylis–Hillman reaction.

Insights into the Morita–Baylis–Hillman reaction of isomeric dibenzofuran carbaldehydes: a theoretical and mass spectral study

Systematic theoretical and mass spectral investigations on the faster Morita–Baylis–Hillman (MBH) reaction of dibenzofuran-4-carbaldehyde (2) compared to its isomer, dibenzofuran-2-carbaldehyde (1) are described.

Bio-based solvents for the Baylis–Hillman reaction of HMF

The Baylis–Hillman reaction of HMF was investigated in various bio-based solvent systems and in water.

Versatile O- and S-functionalized 1,2,3-triazoliums: ionic liquids for the Baylis–Hillman reaction and ligand precursors for stable MIC-transition metal complexes

A series of O- and S-functionalized triazolium salts display high performance in the Baylis–Hillman addition and allow the one-pot formation of MIC-transition metal complexes.

Maleimide as an efficient nucleophilic partner in the aza-Morita-Baylis-Hillman reaction: synthesis of chiral 3-substituted-3-aminooxindoles.

A highly enantioselective Morita-Baylis-Hillman reaction of maleimides with isatin derived ketimines has been developed to obtain enantiomerically enriched 3-substituted-3-aminooxindoles using β-isocupreidine as an organocatalyst. Maleimide acting as a nucleophile provides products with up to 99% ee.

An enantioselective organocatalyzed aza-Morita-Baylis-Hillman reaction of isatin-derived ketimines with acrolein.

A highly enantioselective aza-Morita-Baylis-Hillman (aza-MBH) reaction of isatin-derived ketimines with acrolein was established using β-isocupreidine (β-ICD) or α-isocupreine (α-ICPN) as a chiral acid-base organocatalyst. The present protocol readily furnished (S) or (R)-aza-MBH adducts with a chiral tetrasubstituted carbon stereogenic center in up to 98% ee.

Kinetic and mechanistic investigations of the Baylis–Hillman reaction in ionic liquids

We report here a quantitative study of the kinetics and mechanism of the Baylis–Hillman reaction in the presence of ionic liquids as solvent media.

Morita-Baylis-Hillman reaction of acrylamide with isatin derivatives.

The Morita–Baylis–Hillman reaction of acrylamide, as an activated alkene, has seen little development due to its low reactivity. We have developed the reaction using isatin derivatives with acrylamide, DABCO as a promoter and phenol as an additive in acetonitrile. The corresponding aza version with acrylate and acrylonitrile has also been developed resulting in high product yields.