Michael addition tandem

Fusion of SIX membered nngs by reactnn of cyclanones with vinyl ketones (base or acd catalyzed), a tandem Michael addition aldol condensation... 

Unfortunately, much of Fiesselmann s work was documented only in patents and doctoral theses, allowing for the rediscovery of this classic reaction in recent years. In fact, as late as 1997, the Fiesselmann reaction of 5 with methylthioglycolate was rediscovered as a novel, tandem Michael addition/intramolecular Knoevenagel approach to thiophenes such as 6 ... 

The enolate of the 1,4-adduct, obtained after the stereoselective Michael addition step, as discussed in the previous sections, may be quenched in situ with various electrophiles. The fact that additional stereogenic centers may be formed via such tandem Michael addition/quench-ing procedures, giving products with high diastereoselectivity in many cases, extends the scope of these methods substantially. Furthermore these procedures occasionally offer the possibility of reversing the syn/anti diastereoselection. In the next sections pertinent examples of diastereoselective inter- and intramolecular quenching reactions will be discussed. 

In the case of nitronates possessing ester or nitrile moieties as terminal olefin substituents, tandem Michael addition to produce substituted furans 174,175 occurred faster than trapping of the nitronate anion by TMSCl (Eq. 17). 

However, when 2,6-dimethylbenzoquinone with sodium ( >3,5-hexadienoate (generated in situ) was reacted in water in the presence of a catalytic amount of sodium hydroxide, pentacyclic adducts were formed via deprotonation of the Diels-Alder adduct followed by tandem Michael-addition reactions with another molecule of 2,6-dimethylbenzoquinone (Eq. 12.25).83 Similar results were obtained with sodium ( >4,6-heptadienoate. 

Ley SV, Baxendale IR (2002b) New tools and concepts for modern organic synthesis. Nat Rev Drug Disc 1 573-586 Ley S V, Massi A (2000) J Comb Chem Polymer supported reagents in synthesis preparation of bicyclo[2.2.2]octane derivatives via tandem michael addition reactions and subsequent combinatorial decoration. 2 104—107 Ley SV, Schucht O, Thomas AW, Murray PJ (1999) Synthesis of the alkaloids ( )-oxomaritidine and ( )-epimaritidine using an orchestrated multi-step sequence of polymer supported reagents. J Chem Soc Perkin Trans 1 1251— 1252... 

A simple tandem Michael addition of cyanide ion with alkylation on Jt-deficient alkenes has been effected on diethyl l -methylpropylidenecyanoacetates and benzyl-idenemalonates using benzyltriethylammonium chloride to yield 2-alkyl-2,3-dicyanopropanoates and the analogous 2-ethoxycarbony derivatives [44]. 

Tandem Michael addition and alkylation of acrylic esters... 

Trimethyl aconitate can be cyclodimer-ized in 75% yield and a high stereoselectivity to a pentamethyl l-(2-methoxy-2-oxoethyl)- ,2,3,4,5-cyclopentane pentacar-boxylate. Product formation is initiated by an electrogenerated base that induces a catalytic cycle of two successive Michael additions. The most stable out of 16 possible diastereomers is formed, which indicates that the tandem Michael addition is thermodynamically controlled [282]. 

Electrophiles that have been used for the second alkylation of this tandem Michael addition -alkylation sequence are limited to primary iodoalkanes, (bromomethyl)benzenes and 3-bromo-propenes. Tables 9 and 10 provide details of the alkylations of enolate species prepared by 1,4-additions of -a,/j-unsaturated iron-acyl complexes by anionic carbon nucleophiles and anionic nitrogen nucleophiles, respectively. 

Related, achiral cc,/ -unsaturated molybdenum-( 2-acyl) complexes, such as 8, have been shown to undergo nucleophilic 1,4-conjugatc addition upon treatment with sodium borohy-dride or methyllithium to generate enolate species, such as 9 (produced by addition of hydride). Subsequent alkylation by iodomethane provides the a-alkylated product 1088. Extension of this tandem Michael addition-alkylation sequence to nonracemic molybdenum species has not yet been reported. 

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. 

Carbocyclization of m-alkcnyl-z-methoxybcnzy I lithiums to form five- or six-membered rings has been studied 101 the five-membered ring is formed with a cis-stereochemical relationship between the methoxy substituent and the adjacent methyl group. Intramolecular carbolithiation of vinyl sulfides at — 105°C in THF has been found to occur non-stereospecifically with regard to the newly formed C—Li centre.102. The stereochemistry of selective tandem Michael addition alkylation reactions of vinylphosphonates has been explored.103... 

Silyl enolates are useful carbon nucleophiles in the asymmetric tandem Michael addition and lactonization (Scheme 3.3). Mukaiyama recently reported that cinchona-derived ammonium phenoxides act as activators (nucleophilic catalysis), to give highly stereocontrolled products [18-20]. In a typical PTC manner, most of the... 

Scheme 3.3 Tandem Michael addition and lactonization using chiral ammonium phenoxide.

Zhang, J. Flippen-Anderson, J. L. Kozi-kowski, A. P. A tandem Michael addition ring-closure route to the metabotropic receptor ligand a-(hydroxymethyl) glutamic acid and its y-alkylated derivatives. J. Org. Chem. 2001, 66, 7555-7559. 

The ruthenium complex Cp Ru(bipyridyl)Cl has been developed as a catalyst for the first regioselective tandem Michael addition-allylic alkylation of activated Michael acceptors. The net outcome is the decarboxylative insertion of Michael acceptors into allyl /3-keto esters to produce (215). The reaction combines the generation of Ru-tt-allyl and enolate from (213) the enolate is first added to the Michael acceptor (214) and the resulting species is captured by the Ru-tt-allyl.254... 

The high diastereoselective synthesis of multifunctionalized 3,4-dihydro-coumarins bearing a quaternary stereocenter was developed through tandem Michael additions of indole and its derivatives (1-methyl, 2-methyl, 4-methoxy, 5-methoxy, 5-bromo, 6-benzyloxy) to 3-nitrocoumarines (3-nitro-chromen-2-one, 6- and 7-methyl-3-nitro-chromen-2-one) followed by methyl vinyl ketone in a one-pot step. For the tandem Michael additions, after the first Michael reaction of indole (2) with 3-nitrocoumarine (51) catalyzed... 

Recently, Mukaiyama and co-workers prepared cinchona alkaloid-derived chiral quaternary ammonium phenoxide-phenol complex 23 and used it as an efficient organocatalyst for the tandem Michael addition and lactonization between oc,f-unsaturated ketones and a ketene silyl acetal 24 derived from phenyl isobutyrate. This approach permits the highly enantioselective synthesis of a series of 3,4-dihydropyran-2-ones (25), as shown in Scheme 4.11 [17]. 

The best catalyst for this transformation was AgSbFg (10 mol%), and (3-ketoesters, malonates, and silyl enol ethers have been used for the nucleophilic addition on the pyridinium intermediate DD. The dihydroisoquinolines 48 have been further used in several reactions in order to assemble the framework of various alkaloids. One example is given in the formation of dihydroisoquinoline 49, bearing a pendent a, 3-unsaturated ketone. Compound 49 can rearrange to the tetracycle 50 (related to the core structure of karachine, Scheme 5.23), using TMSOTf, via a tandem Michael addition-Mannich reaction process (intermediates EE and FF). 

Ley SV, Mynett DM, Koot WJ, Solid phase synthesis of bicyclo[2,2,2]octane derivatives via tandem Michael addition reactions and subsequent reductive amination, Synlett., 1017-1020, 1995. 

In another study we have constructed a bicyclo[2.2.2]octane library using a tandem Michael addition of enolates of 2-cyclohexenones with various substituted acrylates.7 9 In this way it was possible to prepare a rigid scaffold, from readily available substrates, which could be further elaborated by transformation of the functional groups to give a large array of compounds (Scheme 6). This synthesis required minimal optimisation and... 

A tandem Michael addition/cyclization was also the key step in the synthesis of fura-none lignan derivatives recently described (Scheme 90). 

Tandem Michael addition and Homer olefination occur when a-phosphorylvinyl sulfoxides react with salicylaldehyde leading to a 3-sulfinyl-277-l-benzopyran. Any optical activity associated with the vinyl sulfoxide is retained in the product <06JOC8818>. 

The reaction proceeds via a tandem Michael addition-HBr elimination in which the carbanion (48) is the key intermediate to produce cyclopropanation. The success of the method depends from the correct addition of (46) to the basic solution of the alkenes (47). In fact, it is important to add bromonitromethane in several fractions in order to avoid its decomposition (that can happen under basic conditions). The cyclopropanation proceeds in good to excellent yields (75-96%) with a variety of substrates, but with moderate diastereoselectivity. The procedure works well even with cyclic alkenes, such as 7V-alkylmaleimides, with the exclusive formation of exocyclopropane derivatives. 

The very structure of the sulfone 134 dictated a convergent scheme for its preparation from the easily synthesized Cg, 138, and Cjo, 139, building blocks. Furthermore, the structure of 139 also suggested the utilization of a convergent route for its preparation, with the help of a tandem Michael addition/electro-philic alkylation sequence from cyclopentenone 140 via adduct 141. 

Lithiated A-protected SAMP can be used as an ammonia equivalent in Michael and tandem Michael additions to a,(3-unsaturated esters (eq 13). Furthermore, SAMP and RAMP... 

---