Morita-Baylis-Hillman Research Articles

Synthesis of Multi-substituted 1,4-Dihydroquinoline Derivatives from Morita-Baylis-Hillman (MBH) Carbonates

Synthesis of Multi-substituted 1,4-Dihydroquinoline Derivatives from Morita-Baylis-Hillman (MBH) Carbonates

Studying the reactivity of alkyl substituted BODIPYs: first enantioselective addition of BODIPY to MBH carbonates.

The first enantioselective addition of alkyl BODIPYs to Morita–Baylis–Hillman (MBH) carbonates is reported. This is the first reported enantioselective methodology using the methylene position of BODIPYs as a nucleophile. The reaction is efficiently catalyzed by cinchona alkaloids, achieving high enantioselectivities and total diastereoselectivity. The use of cinchona alkaloid pseudo enantiomers (chinine/cinchonine) allows us to obtain both pairs of enantiomers in similar yields and enantioselectivities, a common issue in this type of reaction. The photophysical study of these dyes (absorption and fluorescence) has been performed in order to determine their parameters and explore future possible application in bioimaging. In addition, electronic circular dichroism (ECD) studies supported by time-dependent density functional theory (TD-DFT) calculations were also performed.

An easy and practical approach to access multifunctional cylcopentadiene- and cyclopentene-spirooxindoles via [3 + 2] annulation.

A highly regioselective [3 + 2] annulation of Morita-Baylis-Hillman (MBH) carbonates of isatin with aurone/thioaurone is developed. Spiroheterocycles such as spirooxindole cyclopentadiene and spirooxindole fused hydroxy cyclopentene derivatives are constructed in one pot by exploring the reactivity of Lewis bases. Combined experimental and density functional theory (DFT) calculations offered an insight into the reaction mechanism.

Z‐Selective α‐Arylation of α,β‐Unsaturated Nitriles via [3,3]‐Sigmatropic Rearrangement

AbstractThe Morita‐Baylis–Hillman (MBH) reaction and [3, 3]‐sigmatropic rearrangement are two paradigms in organic synthesis. We have merged the two types of reactions to achieve [3,3]‐rearrangement of aryl sulfoxides with α,β‐unsaturated nitriles. The reaction was achieved by sequentially treating both coupling partners with electrophilic activator (Tf2O) and base, offering an effective approach to prepare synthetically versatile α‐aryl α,β‐unsaturated nitriles with Z‐selectivity through direct α‐C‐H arylation of unmodified α,β‐unsaturated nitriles. The control experiments and DFT calculations support a four‐stage reaction sequence, including the assembly of Tf2O activated aryl sulfoxide with α,β‐unsaturated nitrile, MBH‐like Lewis base addition, [3,3]‐rearrangement, and E1cB‐elimination. Among these stages, the Lewis base addition is diastereoselective and E1cB‐elimination is cis‐selective, which could account for the remarkable Z‐selectivity of the reaction.

Z-Selective α-Arylation of α,β-Unsaturated Nitriles via [3,3]-Sigmatropic Rearrangement.

The Morita-Baylis-Hillman (MBH) reaction and [3, 3]-sigmatropic rearrangement are two paradigms in organic synthesis. We have merged the two types of reactions to achieve [3,3]-rearrangement of aryl sulfoxides with α,β-unsaturated nitriles. The reaction was achieved by sequentially treating both coupling partners with electrophilic activator (Tf2 O) and base, offering an effective approach to prepare synthetically versatile α-aryl α,β-unsaturated nitriles with Z-selectivity through direct α-C-H arylation of unmodified α,β-unsaturated nitriles. The control experiments and DFT calculations support a four-stage reaction sequence, including the assembly of Tf2 O activated aryl sulfoxide with α,β-unsaturated nitrile, MBH-like Lewis base addition, [3,3]-rearrangement, and E1cB-elimination. Among these stages, the Lewis base addition is diastereoselective and E1cB-elimination is cis-selective, which could account for the remarkable Z-selectivity of the reaction.

Facile Synthesis of Dihydroquinolines via Palladium Catalyzed Sequential Amination and Cyclisation of Morita-Baylis-Hillman Alcohols.

Quinolines and its derivatives are significant class of heterocyclic compounds which are identified as the key component in many natural products and biologically important molecules. We describe herein a facile method for the synthesis of quinoline derivatives from Morita‐Baylis‐Hillman (MBH) Alcohols via Palladium Catalyzed intramolecular aryl amination followed by allylic amination pathway. The reaction between a series of MBH alcohols and amino compounds (Tosyl, aliphatic and aromatic amines) under optimized reaction conditions with Pd(PPh3)2Cl2/DPPP catalyst system, afforded the corresponding 1,2‐dihydroquinolines upto 95 % isolated yield.

Naphthalenes and Quinolines by Domino Reactions of Morita-Baylis-Hillman Acetates.

An efficient synthetic route to highly functionalized naphthalenes and quinolines has been developed using domino reactions between Morita–Baylis–Hillman (MBH) acetates and active methylene compounds (AMCs) promoted by anhydrous K2CO3 in dry N,N-dimethylformamide (DMF) at 23 °C. The substrates incorporate allylic acetates positioned adjacent to a Michael acceptor as well as an aromatic ring activated toward a SNAr ring closure. A control experiment indicated that the initial reaction was an SN2’-type displacement of a side chain acetoxy by the AMC anion to afford the alkene product bearing the added nucleophile trans to the SNAr aromatic ring acceptor. Thus, equilibration of the alkene geometry of the initial product was required prior to cyclization. Products were isolated in good to excellent yields. Numerous cases (24) are reported, and several mechanistic possibilities are discussed.

Synthesis of Chiral gem-Difluoromethylene Compounds by Enantioselective Ethoxycarbonyldifluoromethylation of MBH Fluorides via Silicon-Assisted C-F Bond Activation.

The enantioselective ethoxycarbonyldifluoromethylation of Morita-Baylis-Hillman (MBH) fluorides with Me3SiCF2CO2Et under organocatalysis is described. Moderately functionalized chiral gem-difluoromethylene compounds with a stereogenic "C-CF2-C*" unit were synthesized in high yields with high enantioselectivities. The initial C-F bond activation is assisted by the silicon atom via a dual SN2'-SN2' stepwise pathway. Dynamic kinetic resolution of the MBH-fluorides explained the high yields and high ee's of the products. The method was extended to the enantioselective introduction of "Het-CF2" units.

Stereoselective allylic 1,3-dienylation of Morita–Baylis–Hillman carbonates via an alkylation–denitration sequence

A two-step, metal-free process for stereoselective allylic 1,3-dienylation of Morita–Baylis–Hillman (MBH) carbonates under mild reaction conditions has been developed. Using cyclic allylic nitro compounds as potential dienylating reagents, the transformation proceeds through tertiary amine-catalyzed allylic alkylation with MBH carbonates (14 examples, up to 94% yield), followed by AcOH-mediated denitration (12 examples, up to 87% yield), affording allylic 1,3-dienyl MBH derivatives with exclusive (E)-selectivity.

Morita‐Baylis‐Hillman Reaction Accessing GABA Intermediates: Synthesis of New Lipophilic Hydroxylated γ‐Nitroesters

AbstractThe Morita‐Baylis‐Hillman (MBH) reaction has attracted great attention to generate densely functionalized adducts with promising synthetic utility and biological activities. In this work we demonstrate, for the first time, the synthesis of a series of new lipophilic hydroxylated α‐alkyl γ‐nitroesters, advanced γ‐aminobutyric acid (GABA) intermediates, using the Morita‐Baylis‐Hillman (MBH) reaction as key step. The results show that the long‐chain MBH adducts can be synthesized in good yields in a metal‐free organocatalytic system in the presence of aliphatic aldehydes and activated alkenes, acrylonitrile or methyl acrylate. Followed, the Michael addition of nitromethane to MBH adducts resulted in hydroxylated α‐alkyl γ‐nitroesters in good yields. Thus, the key MBH reaction led to new lipophilic GABA advanced intermediates in good overall yields from aliphatic aldehydes, demonstrating the potential of this reaction pathway towards the synthesis of new drug molecules for the treatment of psychiatric or neurodegenerative disorders.

Organocatalytic Asymmetric C(sp2)−H Allylic Alkylation: Enantioselective Synthesis of Tetrasubstituted Allenoates

AbstractHerein we describe the first organocatalytic asymmetric C(sp2)−H allylation of racemic trisubstituted allenoates with Morita–Baylis–Hillman (MBH) carbonates to access axially chiral tetrasubstituted allenoates. Various trisubstituted allenoates and MBH carbonates were well tolerated under mild reaction conditions, providing novel chiral tetrasubstituted allenoates with adjacent axial chirality and tertiary carbon stereocenters in high yields with good to excellent diastereoselectivities and enantioselectivities.

Organocatalytic Asymmetric C(sp2 )-H Allylic Alkylation: Enantioselective Synthesis of Tetrasubstituted Allenoates.

Herein we describe the first organocatalytic asymmetric C(sp2 )-H allylation of racemic trisubstituted allenoates with Morita-Baylis-Hillman (MBH) carbonates to access axially chiral tetrasubstituted allenoates. Various trisubstituted allenoates and MBH carbonates were well tolerated under mild reaction conditions, providing novel chiral tetrasubstituted allenoates with adjacent axial chirality and tertiary carbon stereocenters in high yields with good to excellent diastereoselectivities and enantioselectivities.

Unconventional Transformations of Morita–Baylis–Hillman Adducts

Morita–Baylis–Hillman (MBH) adducts are versatile starting materials widely employed in Lewis base catalysis. A myriad of different transformations have been reported based on either allylic alkylations with stabilised nucleophiles or annulations with diverse dipolarophiles. Apart from these two conventional types of reactivity, MBH adducts have recently been implemented in alternative and complementary catalytic strategies, including: (i) one-pot and cascade transformations, where additional chemical bonds are formed following the asymmetric allylic alkylation event in a single synthetic operation; (ii) regioselective α-allylations for the synthesis of trisubstituted alkenes; and (iii) dual activation strategies, involving Lewis base catalysis together with transition metal complexes or light, enabling allylic alkylations with nonstabilised nucleophiles and cascade processes. The present Short Review summarises the most significant unconventional catalytic transformations of racemic MBH adducts reported within the last decade.1 Introduction2 Multi-Step Single-Vessel Transformations (path iii)2.1 One-Pot Transformations2.2 Cascade Transformations3 α-Allylations (path iv)3.1 SN2′ Mechanism3.2 SN2′–SN2 Mechanism3.3 Miscellaneous Mechanisms4 Dual Activation (path v)4.1 MBH Adduct as Electrophile4.2 MBH Adduct as Nucleophile5 Summary and Outlook

Organocatalytic Regioselective [3+2] Annulation of Morita-Baylis-Hillman Carbonates with Azonaphthalenes: An Efficient Access to 3-Spiropyrazole- 2-oxindoles

Background: A cheap and commercially available organocatalyst, 4-dimethylaminopyridine was successfully employed in the regioselective [3+2] cycloaddition of isatin-derived Morita-Baylis- Hillman carbonates with azonaphthalenes for the construction of 3-spiropyrazole-2-oxindoles in excellent yields under mild conditions. Methods: In the presence of 4-dimethylaminopyridine with a loading of 10 mol%, a series of isatinderived Morita-Baylis-Hillman carbonates reacted smoothly with azonaphthalenes in dichloromethane at room temperature to furnish 3-spiropyrazole-2-oxindoles in 72-98% yield. Result and Conclusion: In summary, we have developed reasonably cheap and commercially available 4-dimethylaminopyridine-mediated regioselective [3+2] annulations between isatin-derived Morita- Baylis-Hillman carbonates and azonaphthalenes for the construction of 3-spiropyrazole-2-oxindoles under mild conditions.

Azidophosphonium salt-directed chemoselective synthesis of (E)/(Z)-cinnamyl-1H-triazoles and regiospecific access to bromomethylcoumarins from Morita-Baylis-Hillman adducts.

The direct transformation of Morita–Baylis–Hillman (MBH) adducts into molecules of interest is a crucial process wherein allylic hydroxy-protected or halogenated MBH adducts are commonly preferred. Herein, we report an azidophosphonium salt (AzPS)-catalysed straight forward protocol for synthesising structurally demanding (E)/(Z)-cinnamyl-1H-1,2,3-triazoles and halomethylcoumarins from MBH adducts. The novel methodology, efficient catalyst, and direct utilization of MBH adducts under mild reaction conditions qualify the reported procedures as powerful synthetic tools.

Concise Synthesis of (+)-[13 C4 ]-Anatoxin-a by Dynamic Kinetic Resolution of a Cyclic Iminium Ion.

An asymmetric total synthesis of [13 C4 ]-anatoxin-a ([13 C4 ]-1) has been developed from commercially available ethyl [13 C4 ]-acetoacetate ([13 C4 ]-15). The unique requirements associated with isotope incorporation inspired a new, robust, and highly scalable route, providing access to 0.110 g of this internal standard for use in the detection and precise quantification of anatoxin-a in freshwater. A highlight of the synthesis is a method that leverages a cyclic iminium ion racemization to achieve dynamic kinetic resolution in an enantioselective Morita-Baylis-Hillman (MBH) cyclization.

Concise Synthesis of (+)‐[13C4]‐Anatoxin‐a by Dynamic Kinetic Resolution of a Cyclic Iminium Ion

AbstractAn asymmetric total synthesis of [13C4]‐anatoxin‐a ([13C4]‐1) has been developed from commercially available ethyl [13C4]‐acetoacetate ([13C4]‐15). The unique requirements associated with isotope incorporation inspired a new, robust, and highly scalable route, providing access to 0.110 g of this internal standard for use in the detection and precise quantification of anatoxin‐a in freshwater. A highlight of the synthesis is a method that leverages a cyclic iminium ion racemization to achieve dynamic kinetic resolution in an enantioselective Morita–Baylis–Hillman (MBH) cyclization.

First Zinc Bromide Promoted Annulative Domino Reactions between Enamines and Cyclic Morita–Baylis–Hillman Alcohols: Synthesis of N,O-Ketals

A new efficient ZnBr2-mediated annulative domino reaction between enamines and cyclic Morita–Baylis–Hillman (MBH) alcohols is disclosed. The process involves a tandem sequence (intermolecular conjugate addition of enamines to MBH alcohols and intramolecular nucleophilic addition of the hydroxyl moiety to the transiently generated iminium ion), affording the corresponding N,O-ketals diastereoselectively in good yields.

The Enantioselective Synthesis of Chiral Carbocyclic Nucleosides via Palladium‐Catalyzed Asymmetric Allylic Amination of Alicyclic MBH Adducts with Purines

AbstractThe enantioselective synthesis of carbocyclic nucleosides through the palladium‐catalyzed asymmetric allylic amination of alicyclic Morita‐Baylis‐Hillman (MBH) adducts with purines was successfully developed. With a combination of Pd2(dba)3/L7 as catalyst, various optically active carbocyclic nucleosides featuring a C=C double bond in the carbocycle moiety were obtained in high yields (up to 97%) with excellent N9/N7‐selectivities (>95/5) and enantioselectivities (up to >99.6%). In addition, these nucleoside analogs allowed for rapid transformation to a variety of other interesting structurally diverse chiral carbocyclic nucleosides.magnified image

Catalyst-Free Conjugate Addition of Indolizines to In Situ-Generated Oxidized Morita-Baylis-Hillman Adducts.

Sequential one-pot 2-iodoxybenzoic acid (IBX) oxidation of Morita-Baylis-Hillman (MBH) adducts followed by catalyst-free indolizine conjugate addition was developed. The wide scopes of MBH adducts and indolizines were investigated, and densely functionalized adducts were obtained in yields of up to 94%. The conjugate addition step occurred in less than a minute at room temperature with total regioselectivity toward indolizine C3 carbon. Less nucleophilic C1 carbon was also alkylated when C3-substituted indolizines were employed as the substrate.