Morita-Baylis-Hillman Research Articles

Employing Small Polyfunctionalized Molecules for a Diastereoselective Synthesis of Highly Substituted Indolines

An efficient approach has been developed for the diastereoselective synthesis of 1,2,3‐trisubstituted indolines. The reaction sequence includes the highly diastereoselective reductive amination of 2‐oxo‐1,3‐propanediols, which are prepared by postfunctionalization of Morita–Baylis–Hillman (MBH) adducts, to give substituted 2‐amino‐1,3‐propanediols with an anti relative configuration. A subsequent intramolecular palladium‐catalyzed Buchwald coupling reaction provided the 1,2,3‐trisubstituted indolines in 47–82 % yield. The preference for the anti diastereomer was investigated by Gibbs free energy diagrams and applying theoretical calculations at the M06–2X/6‐31+G** level.

Harnessing Nucleophilicity of Allenol Ester with p-Quinone Methides via Gold Catalysis: Application to the Synthesis of Diarylmethine-Substituted Enones.

A gold(I)-catalyzed protocol for intermolecular 1,6-conjugate addition of nucleophilic allenol ester generated in situ through [3,3]-sigmatropic rearrangement with p-quinone methides ( p-QMs) has been developed. The gold catalyst plays a dual role by the π-acid-triggered activation of alkynes and at the same time as a Lewis acid for activation of p-QMs toward nucleophilic attack. This method enables rapid access to a wide range of densely functionalized diarylmethine-substituted enones, a Morita-Baylis-Hillman (MBH) product with high selectivity, excellent yields, and broad substrate scope.

Copper‐Catalyzed One‐Pot Borylative Aldolisation β‐Fluoride Elimination for the Formal Addition of Acrylates to Carbonyl Moieties

Herein, we report the copper-catalyzed domino borylation/aldolisation of methyl 2-fluoroacrylate with carbonyl compounds followed by an elimination to give Morita-Baylis-Hillman (MBH) analogues. The optimal conditions described were shown to be compatible with a wide range of aldehydes and ketones. Unprecedented MBH adducts derived from ketones were efficiently synthesized.

Morita-Baylis-Hillman enal-based triple cascade strategy for anti-selective synthesis of highly functionalized tetrahydropyridines using iminium-enamine catalysis

A novel and efficient three-component coupling strategy for stereoselective synthesis of highly substituted tetrahydropyridines (THP) is reported in high yield (83–94%) with excellent diastereoselectivity (95–99%) in favor of anti-isomer. The reaction proceeds via sequential iminium-iminium-enamine mediated formation of three consecutive CC, CC and CN bonds in one-pot through reaction of [E]-α-cyano/nitro unsaturated aldehyde, activated methylene and aldimine/phenyl-N-tosyl-methanimine and opens up a new aspect for the utility of Morita-Baylis-Hillman (MBH) adducts in THP synthesis.

Rhodium(II)-Catalyzed Reaction of 1-Tosyl-1,2,3-triazoles with Morita-Baylis-Hillman Adducts: Synthesis of 3,4-Fused Pyrroles.

A cascade reaction of rhodium azavinylcarbenes with Morita-Baylis-Hillman (MBH) adducts enables a novel synthetic approach to 3,4-fused pyrroles. The cascade reaction begins with the insertion of O-H bond into rhodium azavinylcarbenes, subsquent sigmatropic rearrangement provides substituted α,β-unsaturated cyclic ketone intermediates. Then the intramolecular aza Michael addition/oxidative aromatization sequence give rise to a wide range of 3,4-fused pyrroles in good yields, and with excellent functional group compatibility.

Can an Alcohol Act As an Acid/Base Catalyst in Water Solution? An Experimental and Theoretical Study of Imidazole Catalysis of the Aqueous Morita–Baylis–Hillman Reaction

The formation of carbon–carbon sigma bonds by the organocatalyzed Morita–Baylis–Hillman (MBH) reaction constitutes a convenient method for the synthesis of valuable, highly functionalized molecules. Its large-scale implementation is however hampered both by its poor performance with substrates such as α,β-unsaturated ketones and by the reduction of the nucleophilicity of the catalyst when using water as a solvent. Recent work from our laboratories has shown that a bicyclic imidazolyl alcohol (BIA) overcomes these limitations and is a much more efficient catalyst than imidazole for the aqueous MBH reactions of cyclic enones. The role of the hydroxyl group in the former catalyst is not easy to understand, however, since these reactions take place in water solution. We have studied the mechanism of the aqueous MBH reaction between 2-cyclohexenone and isatin, catalyzed either by imidazole or by the BIA catalyst, using a combined experimental and computational approach. The data allowed us to propose mechanist...

Enantioselective Synthesis of Carbocyclic Nucleosides via Asymmetric [3 + 2] Annulation of α-Purine-Substituted Acrylates with MBH Carbonates.

An efficient route to chiral carbocyclic nucleoside analogues containing a quaternary stereocenter and a C═C double bond has been established via a highly enantioselective [3 + 2] annulation of Morita-Baylis-Hillman (MBH) carbonates with α-purine-substituted acrylates. With 20 mol % (S)-SITCP as the catalyst, various chiral carbocyclic nucleoside analogues with a quaternary stereocenter and a C═C double bond were obtained in high yields (up to 92%) with good diastereoselectivities (up to 10:1 dr) and excellent enantioselectivities (up to 96% ee). Furthermore, the corresponding products were subjected to diverse transformations to afford interesting and potentially useful chiral carbocyclic nucleosides.

Amino acid ionic liquids as catalysts in a solvent-free Morita-Baylis-Hillman reaction.

In the present work, we describe the preparation of ten amino acid ionic liquids (AAILs) formed from ammonium salts as cations, derivatives of glycerol, and natural amino acids as anions. All of them are viscous oils, colorless or pale yellow, and hygroscopic at room temperature. They have appreciable solubility in many protic and aprotic polar solvents. The AAILs were used as catalysts in a Morita–Baylis–Hillman (MBH) reaction. The ionic liquids derivative from l-proline and l-histidine demonstrated the ability to catalyze the reaction between methyl vinyl ketone and aromatic aldehydes differently substituted in the absence of an additional co-catalyst under organic solvent-free conditions. The AAIL derivatives from l-valine, l-leucine, and l-tyrosine catalyzed the MBH reaction only in the presence of imidazole. The MBH adducts were obtained in moderate to good yields. Although the catalytic site in the ILs was in its enantiomerically pure form, all the MBH adducts were obtained in their racemic form.

A paramedic treatment for modeling explicitly solvated chemical reaction mechanisms.

We report a static quantum chemistry modeling treatment to study how solvent molecules affect chemical reaction mechanisms without dynamics simulations. This modeling scheme uses a global optimization procedure to identify low energy intermediate states with different numbers of explicit solvent molecules and then the growing string method to locate sequential transition states along a reaction pathway. Testing this approach on the acid-catalyzed Morita-Baylis-Hillman (MBH) reaction in methanol, we found a reaction mechanism that is consistent with both recent experiments and computationally intensive dynamics simulations with explicit solvation. In doing so, we explain unphysical pitfalls that obfuscate computational modeling that uses microsolvated reaction intermediates. This new paramedic approach can promisingly capture essential physical chemistry of the complicated and multistep MBH reaction mechanism, and the energy profiles found with this model appear reasonably insensitive to the level of theory used for energy calculations. Thus, it should be a useful and computationally cost-effective approach for modeling solvent mediated reaction mechanisms when dynamics simulations are not possible.

Recent advances in the annulation of Morita-Baylis-Hillman adducts.

In this review, we summarize some of the most recent advances in the construction of cyclic compounds from the annulation of Morita-Baylis-Hillman (MBH) adducts, which have demonstrated their importance by possessing diverse functional groups. Significant examples including [3 + 2], [3 + 3], [3 + 4] and other cyclizations described herein with MBH adducts were proven to be efficient approaches for the preparation of diverse cyclic structure motifs. However, most of the reported strategies are based on the use of non-chiral catalysts/ligands, whilst stereoselective reactions remain largely unexplored. This area is still in its infancy and future research on MBH adducts will definitely benefit the organic chemistry community, especially for the synthesis of drug candidates and other molecules that might draw attention to materials sciences.

Synthesis of 2-Benzazepines from Benzylamines and MBH Adducts Under Rhodium(III) Catalysis via C(sp2)–H Functionalization

The rhodium(III)-catalyzed cross-coupling reaction between commercially available benzylamines and Morita–Baylis–Hillman (MBH) adducts is described. This protocol provides a facile access to various 2-benzazepine derivatives via the C(sp2)–H activation of N-allylated benzylamines and subsequent intramolecular olefin insertion followed by N-allylation reaction. A range of substrates has been used, and a high level of chemoselectivity as well as functional group tolerance was observed. To gain mechanistic insight of this transformation, DFT calculations were also performed.

Regio- and Enantioselective Allylic Amination of Aliphatic MBH Adducts with N-Heteroaromatics.

Palladium-catalyzed regio- and enantioselective allylic amination of aliphatic Morita-Baylis-Hillman (MBH) adducts with N-heteroaromatic nucleophiles (e.g., benzimidazole, 4,5-diphenylimidazole, benzotriazole, and purines) was achieved by using a spiroketal-based diphosphine (SKP) ligand, and afforded a range of chiral, branched N-allyl products with high selectivity.

Organocatalyzed Decarboxylative Trichloromethylation of Morita-Baylis-Hillman Adducts in Batch and Continuous Flow.

Two protocols for the organocatalyzed decarboxylative trichloromethylation of Morita-Baylis-Hillman (MBH) substrates have been developed. Applying sodium trichloroacetate, as the trichloromethyl anion precursor, in combination with an organocatalyst and acetylated MBH-alcohols, the desired trichloromethylated products were obtained in good yields at room temperature in batch. The method was next extrapolated into a two-step continuous flow protocol, starting directly from the MBH alcohols, in combination with tributylamine acting both as base and catalyst. The flow process proved superior to the batch approach, reducing the reaction time from 16 hours to only 20 minutes, with increased yields for all investigated entries. Two examples were also taken to scale-up in flow producing more than 10 grams of both trichloromethylated targets. Finally, substitution of the organocatalyst to (DHQ)2 PHAL or (DHQD)2 PHAL induced chiral transfer to the generated stereocenter in the reaction attaining selectivities with nearly 90 % ee.

Synthesis of multi‐functionalized carbonyl compounds by palladium–catalysed γ‐substitution of MBH adducts with activated amides

Catalytic allylic γ‐substitution with Morita‐Baylis‐Hillman (MBH) adducts for creating a new family of unsymmetrical dicarbonyl compounds was presented in this work, in which a variety of allylated amide products were achieved in good yields and high regioselectivity with excellent linear‐to‐branched ratios. Especially, it was found that the Pd/HZNU‐Phos complex exhibited remarkably high activity (with a TON up to 16800) in this transformation between dicarbonyl amides and MBH adducts. In addition, the possibly multisite interaction between multifunctional Pd/HZNU‐Phos catalyst system and substrates might responsible for its exceptionally high efficiency in this reaction.

Amine‐Catalyzed Tandem Reactions of Morita–Baylis–Hillman Acetates with Isatins: Facile Synthesis of 3‐Hydroxyoxindoles

An amine‐catalyzed reaction between Morita–Baylis–Hillman (MBH) acetates and isatins to provide facile access to structurally interesting 3‐hydroxyoxindoles in moderate to good yields with diastereomeric ratios of 1:1 has been developed. A wide variety of isatin derivatives were tolerated under the conditions of this tandem reaction. Notably, the inert homoallylic methyl group of MBH acetate 1 was directly involved in the bond formation step, which was followed by a [4+2] annulation under mild conditions to lead to the desired products.

Controlled and Efficient Stereoselective Synthesis of Oxindole-Appended 1-Aza-1,3-butadiene Derivatives via a One-Pot Buchwald–Hartwig Amination/Elimination Strategy

The enamine-free, stereoselective synthesis of oxindole-appended­ 1-aza-1,3-butadienes with an electron-withdrawing-group at the 3-position has been achieved in good yields from (Z)-β-bromo-substituted Morita–Baylis–Hillman (MBH) adducts of oxindoles via a one-pot Buchwald–Hartwig amination/elimination strategy. The versatility of the (Z)-β-bromo MBH adducts of oxindoles was further demonstrated by the formation of π-conjugated oxindole derivatives in typical palladium­-catalysed coupling reactions.

Acrylamide in Rauhut-Currier reaction; intramolecular isomerization of activated alkenes for quinolone synthesis

Acrylamides are fundamental Michael acceptors which have been used profoundly in synthetic, medicinal and polymer chemistry. However, due to their lower reactivity they have been least used in Morita-Baylis-Hillman (MBH) reaction and have been out of its vinylogus version Rauhut Currier (RC) reaction. Herein, use of acrylamide in RC reaction is being presented. Intramolecular RC reaction followed by [1,3]-H shift led to the synthesis of quinolone moiety. DABCO catalyzed IRC reaction of acrylamide at 80 °C in presence of water, was found to work on a number of precursors. En route chemo selective, gram scale method for ambiphilic, versatile precursor 2-amino chalcone is also reported. Chemoselective and economical conversion of 2-nitro chalcone to 2-aryl quinoline has also been developed.

Short and Diastereoselective Total Synthesis of the Polyhydroxylated Pyrrolidine LAB-1: A Potent α-Glycosidase Inhibitor

We described herein a total synthesis of 1,4-dideoxy-1,4-imino-l-arabinitol [(2S,3S,4S)-2-(hydroxymethyl)pyrrolidine-3,4-diol, LAB-1], a polyhydroxylated pyrrolidine, which has been demonstrated to be a selective and potent α-glycosidase inhibitor. The main features of our approach are its shortness, efficiency, and simplicity. The total synthesis was accomplished in 6 steps with an overall yield of 12%, starting from a chiral optically active Morita–Baylis–Hillman (MBH) adduct prepared (without epimerization), from Garner’s aldehyde. As far as we know, this is the first report describing the total synthesis of this biologically active pyrrolidine by exploring the synthetic versatility of a MBH adduct.

Synthesis of Angularly Fused Pyrrolo[3,2‐c]quinoline Lactones and 4‐Carboxy‐3‐vinyl‐1,2‐dihydroquinolin‐2‐ones from Morita–Baylis–Hillman Adducts with Labile Acrylate Esters as Michael Acceptors by [3+2] Cycloaddition and Hoffmann‐Type Elimination

A number of highly functionalized Morita–Baylis–Hillman (MBH) adducts have been synthesized from N‐methylisatin and aryl and heteroaryl aldehydes as electrophiles and the less well‐known propargyl, allyl, and tert‐butyl acrylates as labile, activated alkenes in excellent yields. The MBH adducts thus obtained underwent azomethine ylide [3+2] cycloaddition reactions to yield unusual ring‐enlarged, angularly fused pyrrolo[3,2‐c]quinoline lactones in excellent yields. Subsequent reaction of the quinolin‐2‐one lactones under Hoffman elimination conditions (BnBr/KOH) afforded a lactone ring‐opened 4‐carboxy‐3‐vinyl‐1,2‐dihydroquinolin‐2‐one. A plausible mechanism and discussion of the stereochemical aspects of the cycloaddition reaction are provided.

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.