Tandem Michael Reaction Research Articles

A Diastereoselective Assembly of Tetralone Derivatives via a Tandem Michael Reaction and ipso-Substitution of the Nitro Group.

A highly diastereoselective tandem reaction of 2'-nitrochalcones is reported, involving Michael addition and a subsequent ipso-substitution of the nitro group to produce 1-tetralones with two contiguous chiral centers. A related annulation reaction of 2'-nitrochalcones with potassium cyanide affording 1-indanones with a C3-quaternary chiral center is also demonstrated.

Rhodanine‐Furan Bis‐Heterocyclic Frameworks Synthesis via Green One‐Pot Sequential Six‐Component Reactions: A Synthetic and Computational Study

AbstractCombinatorial construction of a drug‐like library of novel rhodanine‐furan bis‐heterocyclic scaffolds has been demonstrated through a novel one‐pot sequential six‐component reaction in water under ultrasound irradiation with 100% atom economy. The process is a sequence of tandem Michael reactions followed by domino cycloaddition/zwitterionic adduct formation/Mumm rearrangement/[1+4] cycloaddition processes, involving diverse primary amines, carbon disulfide, maleic anhydride, dialkyl acetylenedicarboxylates and various isocyanides. No catalyst was required, but the use of aqueous two‐phase (on water) conditions was critical. Docking and molecular dynamics calculations performed on human aldose reductase suggest that the bis‐heterocyclic frameworks formed may be useful inhibitors of this enzyme.

Synthesis of quinolin-2-ones from ortho-vinylcarbonylamino-substituted acylbenzenes by tandem Michael and Knoevenagel reactions

Consecutive Michael addition and Knoevenagel intramolecular condensation reactions provide 3-alkoxymethyl-, 3-aminomethyl-, and 3-benzylquinolin-2-ones from o-(vinylcarbonylamino)acyl-benzenes. The synthesis of 3-alkoxymethylquinolin-2-ones may be carried out in a one-pot procedure directly from o-(vinylcarbonylamino)acylbenzenes. Aminomethylquinolin-2-ones are formed in one-pot approach only from corresponding o-(vinylcarbonylamino)benzophenones. Their analogs with o-alkyl-carbonyl groups form Michael adducts under these conditions.

Diastereoselectivity in unusual intermolecular tandem Michael reactions

Highly stereoselective consecutive or tandem Michael (MIMI) reactions are reported. A variety of initial nucleophiles react with chiral acylated 1,3-oxazolidin-2-ones to generate a reactive enolate. The enolate then reacts stereoselectively with a second equivalent of the acylated 1,3-oxazolidin-2-one to afford ‘dimeric’ adducts. The adducts have three new contiguous stereogenic centers formed with a high level of control. Single crystal X-ray crystallographic analysis confirmed this controlled formation of novel tandem acyclic conjugate addition or MIMI products in several examples.

Cu-Catalyzed Asymmetric Tandem Dual Michael Reaction of Dialkylzinc to Enones

Cu-Catalyzed Asymmetric Tandem Dual Michael Reaction of Dialkylzinc to Enones

A synthetic study on gymnastatins F and Q: the tandem Michael and aldol reaction approach

Gymnastatins F ( 1) and Q ( 2) were successfully synthesized using the tandem Michael and aldol reaction of the corresponding spirodienones with hemiacetal functions. Inspection of the optical purities of the substrates suggested that undesired racemization does not proceed during the tandem reaction. Results of theoretical calculations agreed with the ratio of the reaction outcome.

A Rapid Synthesis of the Biotin Core through a Tandem Michael Reaction

A biotin core has been assembled in a short and efficient sequence utilizing a tandem intramolecular Michael reaction/fragmentation/Michael reaction from vinyl sulfoxide and sulfone alcohols (12 and 13).

Chemoselective Annulation of 1,3‐Dithiin, ‐Thiazine and ‐Oxathiin Rings on Thiazoles Using a Green Protocol.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Reaction of Nitroorganic Compounds Using Thiourea Catalysts Anchored to Polymer Support

Immobilization of chiral thiourea catalyst was studied. The PEG-bound thiourea showed better catalytic activity than those of the carboxypolystyrene HL resin-bound and TentaGel carboxy resin-bound thioureas. In the presence of PEG-bound thiourea, Michael and tandem Michael reactions of trans-β-nitrostyrene proceeded enantioselectively.

Polyacetylene Intermediate Bearing Reactive Benzylidene Malonate: Helix Induction, Inversion, and Recovery by Tandem Michael and Amidation Reactions with Chiral Nucleophiles and Water

A new polyacetylene bearing benzylidene malonate group, poly[4-{(diethyl-β-malonyl)vinyl}phenylacetylene], 1, was designed as a prochiral reacting polyacetylene intermediate to provide helix induction and inversion abilities with chiral nucleophiles. Polymer 1 underwent both Michael reaction and amidation in the presence of (R)-2-amino-1-propanol (R)-3 (and its (S)-form) to afford optically active polymers with extremely complicated and optically active sites in the side chains. UV-vis, circular dichroism, and NMR studies of 1 revealed the rapid coil-to-helix and subsequent slow helix-to-helix transitions of the resulting optically active polymers. Although the inverted helical conformation was fairly stabilized by intramolecular hydrogen bonds between the complicated and optically active side chains, the inverted helical sense was readily recovered to the initial screw sense by adding a very little amount of water. Polymer 1 is applicable to new chiroptical switching induced by various chiral nucleophiles and sensory systems to detect a trace amount of water. Polymer 1 may thus be a very useful prochiral precursor polymer for preparing various functional and biomimetic helical and higher ordered polymers in future.

Enantioselective tandem Michael reaction to nitroalkene catalyzed by bifunctional thiourea: total synthesis of (−)-epibatidine

Successive treatment of γ,δ-unsaturated β-ketoesters and nitroalkenes with a bifunctional thiourea and TMG promoted the tandem Michael addition, giving rise to highly functionalized cyclohexanones in good yields. The three contiguous stereogenic centers of the obtained products were constructed with high diastereo- and enantioselectivity (up to >99% de and 92% ee). The reaction was successfully applied to the asymmetric synthesis of (−)-epibatidine, which was synthesized from the cyclohexanone derivative in seven steps in 30% overall yield.

Stereoselective synthesis of new classes of atropisomeric compounds through a tandem Michael reaction–azacyclization process. Part 2

Three new classes of atropisomeric compounds, that is, 6-aryl-dihydro-pyridin-2-ones, 6-aryl-pyridin-2-ones and 2-aryl-pyrroles, have been prepared from chiral imines through an efficient stereoselective tandem Michael–azacyclization process. In all cases, a study has shown that the barrier to rotation of the chiral axis is remarkably high.

Electroreduction of β-hydroxy phenyl sulfones in acetonitrile

The electroreduction of β-hydroxy γ,δ-unsaturated sulfones did not lead to the formation of a double bond between the α and β carbons, but a certain β-hydroxy γ,δ-unsaturated sulfone ( 3bA) in the absence of proton donors gave a cyclohexenol derivative. This compound was derived from fission of a carbon–carbon bond between α- and β-positions followed by recombination of the two fragments in the tandem Michael and aldol reactions.

Total Synthesis of (R)- and (S)-semi-Vioxanthin

Compounds (R)- and (S)-semi-vioxanthin 2 were synthesized by a tandem Michael reaction of orsellinate 3 and the chiral Michael acceptors 4. The key step for the formation of lactone (R)-4 is a regio- and enantioselective, enzyme-catalyzed reduction of tert-butyl 3,5-dioxohexanoate (5) by an alcoholdehydrogenase from Lactobacillus brevis. Compound (S)-4 was synthesized by the Claisen condensation of tert-butyl acetate and ethyl (S)-3-hydroxy-butanoate (8). Cleavage of the benzyloxymethyl groups in the protected (R)- and (S)-semi-vioxanthins was achieved by hydrogenolysis to afford (R)-2 and (S)-2, respectively.

Solid-phase synthesis of indolizidine and quinolizidine derivatives.

An efficient method for the construction of simple indolizidine and quinolizidine derivatives on solid support has been developed. An intramolecular tandem Michael reaction initiated by the nucleophilic attack of a suitably placed amino group on the tethered Wittig condensation products between 4- or 5-aminoaldehydes attached to a trityl chloride resin and 4-[(4-methylphenyl)sulfonyl]-1-(triphenylphosphoranylidene)-2-b utanon e is the key step.

2,3-Bis(phenylsulfonyl)-1,3-butadiene: Substrate for Michael Donor/Acceptors in a Novel Synthesis of Fused Cyclopentenes.

The reaction of 2,3-bis(phenylsulfonyl)-1,3-butadiene with the anion of various 1-substituted dimethyl 1-pentenedioates has been investigated with the purpose of devising a tandem conjugate addition-[3 + 2]-anionic cyclization route for the synthesis of bicyclo[3.3.0]octenes. The reaction proceeds with complete stereospecificity as was evidenced by treating (E)- and (Z)-dimethyl (3-cyano-2-propenyl)propanedioate with NaH in the presence of the bis(phenylsulfonyl)diene. In both cases only a single cycloadduct was obtained with no detectable signs of the other diastereomer. The overall process involves a series of three sequential conjugate additions followed by benzenesulfinate ion ejection. The success of the method is dependent on the electrophilicity of the proximal pi-bond. When 2-((5-oxo-2,5-dihydrofuranyl)methyl)malonic acid dimethyl ester was used, a mixture of the tricyclic adduct as well as an allene was obtained. In this case, elimination of the benzenesulfinate group from the initially formed sulfone-stabilized carbanion is competitive with the intramolecular [3 + 2]-annulation process. The base-induced reaction of dimethyl 2-(methoxycarbonyl)-2-pentenedioate with the bis(phenylsulfonyl)diene was also studied. Even though the position of the acceptor moiety on the pi-bond was altered, the tandem Michael reaction sequence still occurs. The course of the reaction is dependent upon the length of the tether as well as the relative placement of the electron-withdrawing group on the olefin. Reaction with gamma-substituted beta,gamma-alkenyl derivatives leads to bicyclo[3.3.0]octenes, whereas beta-substituted beta,gamma-alkenyl reagents provide bicyclo[3.3.0]octenes derived from a novel alpha-elimination reaction.

Total synthesis of (±)-epibatidine

(±)-1α-Nitro-2β-[3-(6-chloropyridyl)]-cyclohexanone, a key intermediate for a stereocontrolled synthesis of the alkaloid epibatidine, possessing a 7-azanorbornane structure to which is attached, in an exo-orientation, a 5-(2-chloropyridyl) substituent, has been prepared either by Diels-Alder reaction or tandem Michael reaction by way of 5-(2-nitrovinyl)-2-chloropyridine as common starting material and 2-trimethylsilyloxy-1,3-butadiene or methyl 3-oxo-4-pentenoate as counterparts respectively.

Enantioselective synthesis of (−)-meroquinene through tandem Michael reaction methodology.

An enantioselective approach to the synthesis of non natural (−)-meroquinene 1 based on sequential inter- and intramolecular Michael reaction between (L)-menthyl N-benzyl-5-amino-2E-pentenoate 3 and 1-acetyloxy-4-methoxymethyloxy-2-nitrobutane 10b, acting as surrogate of 2-nitro-1,3-butadiene 4, is described. The heterocyclization process led to the formation of the piperidine ring system 12, obtained as an unseparable 80:20 mixture of diastereomers at the newly created chiral centres at C-3 and C-4, which became easily separable by column chromatography after transformation of the nitrogen protective benzyl group into the corresponding carbamates 14 and 15. Both compounds, after elaboration of the chain geminal to the nitro group into a vinyl appendage. underwent regio- and stereo-selective removal of the nitro group by palladium-catalyzed displacement with hydride generated by formate to give the precursor 19, easily converted by treatment with hydrochloric acid to 1, isolated as hydrochloride.

ChemInform Abstract: A New Approach to Kainoids Through Tandem Michael Reaction Methodology: Application to the Enantioselective Synthesis of (+)‐ and (‐)‐α‐ Allokainic Acid and to the Formal Synthesis of (‐)‐α‐Kainic Acid.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A new approach to kainoids through tandem Michael reaction methodology: application to the enantioselective synthesis of (+)- and (-)-.alpha.-allokainic acid and to the formal synthesis of (-)-.alpha.-kainic acid

A convergent, one-pot construction of functionalized pyrrolidine ring systemshas been developed. The method is based on a tandem Michael reaction initiated by an intermolecular conjugate addition of a nitrogen nucleophile to an electrophilic olefin followed by trapping of the generated enolate by a built-in α,β-unsaturated acceptor. After model studis verified the feasibility of the process and gave information about its stereochemical outcome, the strategy was successfully applied to kainoid synthesis