Double Michael Addition Reaction Research Articles

Anion Cascade Reactions. Part I: Synthesis of 3-Isoquinuclidones from a Nazarov-like Reagent.

A simple and atom-economical one-step protocol is described for the synthesis of biologically valuable 3-isoquinuclidones. The method proceeds from the simple starting materials, α-acyl N-arylcinnamamides, and can be performed under mild conditions in the presence of tBuOK. The key steps of this process are the double Michael addition reaction of a Nazarov-like reagent and the subsequent intramolecular hemiamination. These flexible intermolecular reactions could be performed on a gram scale.

Organocatalytic Asymmetric Dearomatization of 3-Nitroindoles and 3-Nitrobenzothiophenes via Thiol-Triggered Diastereo- and Enantioselective Double Michael Addition Reaction

Organocatalytic asymmetric dearomatization of 3-nitroindoles and 3-nitrobenzothiophenes by reaction with ethyl 4-mercapto-2-butenoate has been developed. A range of chiral tetrahydrothiopheneindolines and tetrahydrothiophenebenzothiophenes bearing three contiguous stereocenters are obtained in high yields with good diastereoselectivities and excellent enantioselectivities. This is the first example of thiol-triggered catalytic asymmetric dearomatization of 3-nitroindoles and 3-nitrobenzothiophenes.

Synthesis of Pyridine-Dicarboxamide-Cyclohexanone Derivatives: Anticancer and α-Glucosidase Inhibitory Activities and In Silico Study.

An efficient and practical method for the synthesis of 2,6-diaryl-4-oxo-N,N′-di(pyridin-2-yl)cyclohexane-1,1-dicarboxamide is described in this present study, which occurs through a double Michael addition reaction between diamide and various dibenzalacetones. The reaction was carried out in dichloromethane (DCM) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The anticancer activities of the synthesized compounds were evaluated in several cancer cell lines, including MCF-7, MDA-MB-231, SAS, PC-3, HCT-116, HuH-7 and HepG2 cells. From these experiments, we determined that MDA-MB-231 was the most sensitive cancer cell line to the compounds 3c, 3e, 3d, 3j and 3l, which exhibited variable anticancer activities (3l [IC50 = 5 ± 0.25 µM] > 3e [IC50 = 5 ± 0.5 µM] > 3c [IC50 = 7 ± 1.12 µM] > 3d [IC50 = 18 ± 0.87 µM] > 3j [IC50 = 45 ± 3 µM]). Of these, 3l (substituted p-trifluoromethylphenyl and chloropyridine) showed good potency (IC50 = 6 ± 0.78 µM) against HCT-116 colorectal cancer cells and exhibited high toxicity against HuH-7 liver cancer cells (IC50 = 4.5 ± 0.3 µM). These values were three times higher than the values reported for cisplatin (IC50 of 8 ± 0.76 and 14.7 ± 0.5 µM against HCT-116 and HuH-7 cells, respectively). The highest α-glucosidase inhibitory activity was detected for the 3d, 3i and 3j compounds. The details of the binding mode of the active compounds were clarified by molecular docking studies.

Organocatalytic Asymmetric Synthesis of Highly Substituted Tetrahydrofurans and Tetrahydropyrans via Double Michael Addition Strategy

AbstractAn efficient organocatalytic asymmetric synthesis of 2,3,4‐trisubstituted tetrahydrofurans and tetrahydropyrans has been developed using tandem iminium−enamine catalysis. The process comprises of a double Michael addition reaction between γ/δ‐hydroxy‐α,β‐unsaturated carbonyls and enals. The products of this reaction are obtained in high enantio‐ and diasteroselectivities and some further synthetic transformations have been performed.

An efficient and simple one-pot synthesis of 2-perfluoroalkylated benzo[1,3]dioxole derivatives via double–Michael reaction of fluorinated alkynes

An efficient, mild and very easy method for the synthesis of 2-fluoroalkylated 1,3-benzodioxole derivatives was developed through a double Michael-addition reaction on ethyl 4,4,4-trifluorobut-2-ynoate with corresponding catechols. The procedure does not require the use of expensive supplementary additives for the preparation of 2-fluoroalkylated benzo ketals.

Origin of the Base‐Dependent Facial Selectivity in Annulation Reactions of Nazarov‐Type Reagents with Unsaturated Indolo[2,3‐a]quinolizidine Lactams

Methyl‐substituted Nazarov reagent 4 reacts stereoselectively with Nind‐Boc indoloquinolizidine lactams to give the expected 3‐H/15‐H cis pentacyclic yohimbine‐type adducts when using 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) as the base. However, a dramatic change of the facial selectivity was observed when the reaction was performed in the presence of Cs2CO3, leading to the corresponding trans adducts. This annulation is the key step of a stereocontrolled synthesis of the 17a‐carba analogue of the heteroyohimbine alkaloid akuammigine. Theoretical calculations were used to rationalize the facial selectivity of these double Michael addition reactions.

An environmentally benign double Michael addition reaction of heterocyclic ketene aminals with quinone monoketals for diastereoselective synthesis of highly functionalized morphan derivatives in water

This effort involved an efficient and concise one-pot procedure for the synthesis of morphans based on quinone monoketals 1 reacting with HKAs 2.

ChemInform Abstract: Selective Michael Reaction Controlled by Supersilyl Protecting Group.

AbstractSelective single and double Michael addition reactions of lithium organyls to acrylates are achieved using —Si(SiEt3)3 (supersilyl) as a carboxyl protecting group.

Stereocontrolled Annulations of Indolo[2,3‐a]quinolizidine‐Derived Lactams with a Silylated Nazarov Reagent: Access to Allo and Epiallo Yohimbine‐Type Derivatives

The facial selectivity of double Michael addition reactions of the silylated Nazarov reagent 4 to unsaturated indolo[2,3-a]quinolizidine lactams 3 has been studied. Pentacyclic 3-H/15-H trans adducts 5 are generated from Nind -unsubstituted lactams, but the corresponding cis isomers 6 are formed when the indole nitrogen has a tert-butyloxycarbonyl (Boc) substituent. This reversal in the facial selectivity of the annulation has been rationalized by means of theoretical calculations, which indicate that the initial nucleophilic attack under stereoelectronic control is hampered by the presence of the bulky Boc group. The synthetic usefulness of the pentacyclic Nazarov-derived adducts is demonstrated by their conversion into allo and epiallo yohimbine-type targets.

Regioselective Synthesis of α-Perfluoroalkylated Ketals via Double Michael Addition of Alcohols to Activated Alkynes

An efficient method was developed for the synthesis of alkyl 3,3-dialkoxy-3-(perfluoroalkyl)propanoates from ethyl 3-(perfluoroalkyl)propynoates and alcohols using a base-catalyzed double Michael addition reaction (which was accompanied by transesterification in the case of MeOH, EtOH, PrOH, and BuOH). This method provides easy access to the product α-perfluoroalkyl ketals with reasonable to good yields with total regioselectivity. This procedure does not require the use of expensive supplementary additives for the preparation of α-perfluoroalkyl ketals which are very sensitive to acidic conditions.

Synthesis, molecular structure and spectroscopic investigations of novel fluorinated spiro heterocycles.

This paper describes an efficient and regioselective method for the synthesis of novel fluorinated spiro-heterocycles in excellent yield by cascade [5+1] double Michael addition reactions. The compounds 7,11-bis(4-fluorophenyl)-2,4-dimethyl- 2,4-diazaspiro[5.5] undecane-1,3,5,9-tetraone (3a) and 2,4-dimethyl-7,11-bis (4-(trifluoromethyl)phenyl)-2,4-diazaspiro[5.5]undecane-1,3,5,9-tetraone (3b) were characterized by single-crystal X-ray diffraction, FT-IR and NMR techniques. The optimized geometrical parameters, infrared vibrational frequencies and NMR chemical shifts of the studied compounds have also been calculated using the density functional theory (DFT) method, using Becke-3-Lee-Yang-Parr functional and the 6-311G(d,p) basis set. There is good agreement between the experimentally determined structural parameters, vibrational frequencies and NMR chemical shifts of the studied compounds and those predicted theoretically. The calculated natural atomic charges using NBO method showed higher polarity of 3a compared to 3b.The calculated electronic spectra are also discussed based on the TD-DFT calculations.

Stereoselective synthesis of diazaspiro[5.5]undecane derivatives via base promoted [5+1] double Michael addition of N,N-dimethylbarbituric acid to diaryliedene acetones

The nitrogen containing spiro-heterocycle is one of the privileged synthetic motif that constitutes various naturally occurring molecules and displays a broad range of pharmaceutical and biological activities. A new methodology was developed for the synthesis of 2,4-diazaspiro[5.5]undecane-1,3,5,9-tetraones spiro-heterocyclic derivatives via cascade cyclization of [5+1] double Michael addition reaction of N,N-dimethylbarbituric acid with the derivatives of diaryldivinylketones in the presence of diethylamine at ambient temperature. The developed protocol is highly capable of furnishing diazaspiro[5.5]undecane derivatives 3a–m in excellent yields (up to 98%), from easily accessible symmetric and non-symmetric divinylketones 2a–m, containing aryl and heteroaryl substituents. The diazaspiro-heterocyclic structure was mainly elucidated by NMR and X-ray crystallographic techniques. The single-crystal X-ray studies revealed that, the cyclohexanone unit of spirocycles often prefers a chair conformation rather than twisted conformation. The intermolecular hydrogen bonding and CArH⋯π, π–π stacking interactions driving forces are mainly responsible for the crystal packing.

One-pot synthesis of densely functionalized cyclic β-aminoesters containing four stereocenters, based on a Et3N-promoted pseudo five-component reaction.

An effective and practical method has been developed for the diversity-oriented synthesis of fully substituted cyclohexene β-aminoester via a pseudo five-component reaction between nitromethane, aromatic aldehydes, and substituted cyanoacetate for the generation of a wide range of structurally relevant and highly functionalized compounds. The attractive range and features of the method, which enables the facile preparation of highly substituted cyclohexenes, are its simple and straightforward procedure, mild reaction conditions, and ideal yields. The mechanism involves a double Michael addition reaction followed by intramolecular ring closure. The fully substituted cyclohexene β-aminoesters with potential bioactivities could be of impact in medical chemistry.

ChemInform Abstract: Double Michael Addition Reactions of the Nazarov Reagent with 2‐Cyano‐2‐cycloalkenones: An Alternative Approach to cis‐Fused Bicyclic Systems.

AbstractThe DBU‐catalyzed stereoselective annulation reaction of cycloalkenones with the Nazarov reagent delivers a range of bicyclic compounds possessing a high degree of oxygenated functionality.

An efficient catalyst free synthesis of nitrogen containing spiro heterocycles via [5 + 1] double Michael addition reaction

2,4-Diazaspiro[5.5]undecane-1,3,5,9-tetraones and 3-thioxo-2,4-diazaspiro[5.5]undecane-1,5,9-triones have been synthesized via double Michael addition of 1,5-diaryl-1,4-pentadien-3-one with active methylene compounds such as N,N-dimethyl barbituric acid, barbituric acid, thio-barbituric acid and N,N-diphenyl thiobarbituric acid in ethylene glycol at 100 °C in the absence of any catalyst to give high yields within a short reaction time. The structure has been confirmed by X-ray analysis. The single-crystal structure of the diazaspiro compound revealed that the CAr–H⋯π, π–π stacking and intermolecular hydrogen bonding interactions act as major driving forces for crystal packing.

Facile construction of densely functionalized thiopyrano[2,3-b]quinolines via three-component reactions catalyzed by l-proline

L-Proline catalyzed, three-component reactions of 2-mercaptoquinoline-3-carbaldehyde, malononitrile and thiol-based nucleophiles were developed for the first time, for the synthesis of various 4H-substituted thiopyrano[2,3-b]quinolines derivatives via a Knoevenagel condensation followed by inter-intramolecular double Michael addition reaction. This transformation leads to the generation of a 4-substituted thiopyran ring, together with one C–C and two C–S bonds in a single operation.

Double Michael Addition Reactions of the Nazarov Reagent with 2-Cyano-2-Cycloalkenones: An Alternative Approach to cis-Fused Bicyclic Systems

A highly stereoselective annulation reaction of 2-cyano-2-cycloalkenones with the Nazarov reagent catalyzed by 1,8-diaza­bicyclo[5.4.0]undec-7-ene (DBU), leading to densely functionalized bicyclic systems, is developed.

ChemInform Abstract: Preparation and Double Michael Addition Reactions of a Synthetic Equivalent of the Nazarov Reagent.

AbstractThe synthetic equivalent of the Nazarov reagent (II) is stable in storage at ‐20 °C under N2‐atmosphere for several months.

Asymmetric Domino Double Michael Addition of Nitroolefins and Aldehyde Esters with trans-Perhydroindolic Acid as an Organocatalyst

An asymmetric domino double Michael addition reaction was developed using accessible substrates to construct biologically important and synthetically challenging cyclopentanes with four contiguous stereocenters. The proline-like molecules, <i>trans</i>-perhydroindolic acids, proved to be efficient organocatalysts in this reaction. Under the optimal reaction conditions, the asymmetric domino double Michael addition provided good yields (up to 98%), and excellent diastereoselectivities (up to 100% dr) and enantioselectivities (up to 99% ee). The obtained polysubstituted aliphatic cyclopentanes not only exist in biologically active natural products and medicines, but can also be converted into many other useful scaffolds via a simple transformation, such as <i>cis</i>-fused bicyclic lactams. Our current methodology is suitable for the synthesis of polysubstituted aliphatic cyclopentanes with contiguous multiple stereocenters.

Preparation and Double Michael Addition Reactions of a Synthetic Equivalent of the Nazarov Reagent

A synthetic equivalent of the Nazarov reagent, the silyl derivative 2, able to undergo base-catalyzed double Michael addition reactions with α,β-unsaturated carbonyl compounds has been developed. The new reagent satisfactorily reacts with unsaturated indolo[2,3-a]quinolizidine lactams to give pentacyclic yohimbinone-type derivatives.