Michael addition-elimination

Michael addition/elimination 256 Mitsunobu glycosidation 543 ff. Mitsunobu reaction 259, 5291,... 

Two closely related reports of pyrazole generation by condensation of substituted hydrazines with enamino carbonyl compounds have appeared. In situ formation of an enaminoketone, by treatment of a diketone with dimethylformamide dimethyl acetal, was followed by tandem Michael addition-elimination/cyclodehydration under aqueous conditions in sealed microwave vessels (Scheme 3.12)17. Isoxazoles and pyrimidines were also prepared by replacing the substituted hydrazine with hydroxylamine or amidines, respectively (see Chapter 5, Section 5.3.2). The overall process may be regarded as another example of a multi-component coupling. In a similar fashion, enamino propenoates were condensed with substituted hydrazines to afford substituted pyrazoles (see Chapter 5, Section 5.3.2) (Scheme 3.12)18. 

Stiasni, N. and Kappe, C.O., A tandem intramolecular Michael-addition/elimination sequence in dihydropy-rimidone to quinoline rearrangements, ARKIVOC, 2002, 71-79. 

A brief exploration of annulations with nitro-free fluoro arene 37—readily prepared from ( )-methyl 3-methoxyacrylate (36) by a Michael addition elimination strategy with 2-(2-fluorophenyl)acetonitrile (35)—again revealed that direct SNAr cyclization was impeded under all conditions. Extended conjugation may have contributed however, the necessity for the conjugated sp2-hybridized aryl-propene anion to couple intramolecularly with another sp2-hybridized carbon atom imposed a highly strained reaction trajectory (Scheme 9). 

Benzyl bromides 15 derived from either salicylaldehydes or 2-methylphenols by reaction with alkyl propynoates afford 277-1 -benzopyrans on treatment with tetrahydrothiophene and K2CO3. A sulfonium ylide is proposed which initiates a Michael addition - elimination -substitution sequence. When CS2CO3 is used as the base, 477-1-benzopyrans result almost exclusively, presumably through isomerisation of the 277-1-benzopyran. The protocol thus offers access to both chromene isomers through simple variation of the reaction conditions <06OL3853>. The Cu-catalysed intramolecular O-arylation of a-(2-bromobenzyl)-P-keto esters in refluxing THF offers a useful route to 2-substituted 477-l-benzopyran-3-carboxylates <06JOC6427>. 

The related telluronium ylides also add to a,/3-unsaturated imines through a Michael addition-elimination to the olefin followed by a second equivalent of telluronium ylide addition to the imine, which subsequently eliminates to form aziridines 654 and 655 in a ratio of 13 1 (Scheme 159) <2005JA12222>. 

We next attempted to accomplish the annulation with snbstrates lacking the deactivating nitro gronp. A Michael addition elimination strategy was explored with readily available fluoro-derivative... 

Replacement of an unsaturated phenyliodo group. Formation of unsaturated sulfones by a tandem Michael addition-elimination is a highly efficient process that allows the synthesis of (Z)-l,2-bis(benzenesulfonyl)alkenes from (Z)-jS-(benzenesul-fonyl)alkenyliodonium salts. In S-ketoethynyl(phenyl)iodonium salts the electron-withdrawing power of the ketone group is weaker, the Michael addition is followed by carbene formation. Cyclopentenones are formed. A seemingly direct substitution of alkynyl(phenyl)iodonium salts gives alkynyl sulfones efficiently. ... 

A relatively rare example of the creation of chiral quaternary carbons has been uncovered in Michael addition-elimination reactions between lactone enolates [e.g. (444)] and a chiral nitro-alkene (445) ... 

Dicyanomethylene)indandione 254 reacted with a-amino acid esters to yield adducts 255 by Michael addition-elimination. 255 in turn underwent triethylamine-catalyzed cycloaddition with iV-methylmaleimide to give 256 . ... 

The discovery route to ivacaftor (1) was published in 2014. The left-hand fragment as 4-0X0-l,4-dihydroquinoline-3-carboxylic acid (14) was prepared according to literature procedures. Thus, condensation of aniline with diethyl ethoxymethylenanalonate (10) afforded the Michael addition/elimination of ethanol product as anilinyl-bis-ester 11. An intramolecular Friedel-Crafts acylation of 11 was accomplished by heating 11 in phenyl ether at 228-232 °C to furnish ester 12, which was readily hydrolyzed to produce acid 13. Acid 13 is a common building block for most of the synthetic routes toward ivacaftor (1). 

An unusual formation of furans 155 (together with the corresponding pyrroles 156) was observed when compound 154 was treated with two equivalents of primary amine. Ratio of products depends on amine properties. Thus, if the amine acts as a base, the reaction proceeds via the intermediate enolate and an intramolecular Michael addition/fluoride elimination sequence. Further nucleophilic displacement of the ethylsulfanyl group gives 3-carboxamide furans 155. If the amine acts as a nucleophile, a Michael addition/elimination followed by an intramolecular condensation leads to the corresponding pyrrole 156 via the enaminone [112, 113]. 

In principle, the heterocyclization between these p-substituted ketones and monosub-stitnted hydrazines proceeds by a Michael addition-elimination on the p-carbon atom by the more nncleophilic nitrogen of the hydrazine, followed by cyclodehydration to give mixtnres of 3-triflnoromelhyl and 5-trifluoromethylpyrazoles. In general, condensation reactions with melhylhydrazine lead to the 3-trifluoromethylpyrazole derivatives as only or major regioisomers, whereas with aryl or heterocyclic aromatic hydrazines, the formation of 5-trifluoromethylpyrazole prevails. 

Michael addition-elimination 243 rhodium-alkyl intermediates reductive elimination of Hg then oxidative addition of C—H... 

In contrast, the p-TsOH catalyzed reaction of the nitroviitylindole with 3-un-substituted and two 3-substituted indoles in solution by conventional method furnished both unsymmetrical and symmetrical bis(indolyl)nitroethanes (BINEs). The symmetrical bis(indolyl)nitroethanes results from novel tandem Michael addition-elimination-Michael addition reactions (Chakrabaity et al., 2004). 

Cope Elimination Corey-Winter Elimination Cycloaddition-Elimination Diels-Alder Elimination Hofmann Elimination Michael Addition-Elimination... 

Tang et al. reported an unexpected tetrahydrothiophene-catalyzed rearrangement/ annulation reaction via a tandem Michael addition/elimination/substitution for the synthesis of chromenes. The products are 27/-chromene- or 4f/-chromene-2-carboxylates, depending on the choice of the base. With K COj 2//-chromene is formed, with Cs COj, 47/-chromene is the major product (Scheme 7.40) [167]. 

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