Double Michael addition esters

Most aryl alkyl sulphones react with electron-deficient alkenes in the expected manner [e.g. 4-8] and a-(arenesulphonyl)acetic esters undergo a catalysed one-pot double Michael addition with Michael acceptors (Scheme 6.24) [8], The two Michael acceptors can be either identical or different. 

But there are many cases known where the (4+2) cycloaddition fails even with siloxy-activated dienes, e.g., methyl (E)-crotonate does not react with diene 1 at normal pressure and elevated temperature llO C), whereas the aprotic double Michael addition does give the desired bicyclo[2.2.2]octane in high yield. This reaction gives mainly (92%) bicyclic esters with the endo configuration. 

EXAMPLES OF CARBOCYCLIC ESTERS PREPARED BY THE APROTIC DOUBLE MICHAEL ADDITION... 

A route to bicyclic alkanes was published by Ley et al. [31], which involved a double Michael addition with a resin-bound unsaturated ester to afford the highly functionalized bicyclo[2.2.2]octane(Fig. 5). 

Different cyclic products are formed in the double Michael addition of malonic acid ethyl methyl ester to ( vE)-l,5-diphenylpenta-l,4-dien-3-one under basic conditions. Label the stereogenic units in the reaction products with the appropriate stereodescriptors. 

A double Michael addition on the trihydroxydienoate 5 leads to the bicyclic ester 6 with total stereoselectivity. After protection of the primary hydroxy function, the dienoate is treated at 20 C with potassium /cr/-butoxide in a mixture of ten-butyl alcohol/benzene. The desired bicyclic ester 6, containing both tetrahydrofuranyl and tetrahydro-2/f-pyrany] moieties, is obtained in about 50% yield. This compound is stereochemically pure and its structure is confirmed on the basis of the H-NMR spectrum51. 

Reaction of 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-dienecarhoxylic esters 1229 with 2-amino- or 2-aminomethyl-anilines 1230 produces r-5-(benzimidazol-2-yl)pyrroline-2-acetic acid esters 1231 from a double Michael addition process. Substituents on the nitrogen atoms or in the aromatic ring are tolerated as long as they do not strongly reduce the nucleophilicity of the nitrogen atoms (Scheme 307) <2005S2357>. 

M. ihara and co-workers utilized an intramolecular double Michael addition for the efficient and completely stereoselective construction of the tricyclo[6.3.0.0 ]undecan-10-one framework during the total synthesis of (+)-longiborneol. The substituted cyciopentenone precursor was exposed to several different reaction conditions, and the highest yield was obtained when LHMDS was used as the base. The first deprotonation took place at C11 the resulting enolate added to C9, and the ester enolate (negative charge located at CIO) in turn added to the cyciopentenone at C3. 

Methyl 3-(imidazolyl)acrylate (3) prepared earlier in a two step procedure" can be obtained in high yield from imidazole (1) and methyl propiolate (2) at ambient temperature. The presence of KIO montmorillonite speeds up the reaction but does not alter the E Z isomer ratio determined by H-NMR spectroscopy. The distribution of the addition products (3 and 4) depends on the molar ratio of the reactants. Double Michael addition is favored by the use of excess imidazole leading to alkyl 3,3-bis(l-imidazolyl)propionate (4) (Table 1). Remarkable acceleration can be achieved in the reaction of benzimidazoles (5) (R = H, Ph) with propiolic esters (2) by the use of KIO montmorillonite the reaction time can be decreased from 5-7 days to 1-7 hours (Table 2). 

On the other hand, Wang and co-workers [28, 29] made two important contributions to the synthesis of cyclopentene derivatives. Both reactions were initiated with a carbo-conjugated addition of malonates derivatives. The first one was a double Michael addition between enals and 7-malonate-a,(3-imsaturated esters catalyzed by XII rendering the final cyclopentanes with three stereogenic centers in good yields (87-92%) and excellent stereoselectivities (84—99% ee) [28]. As for the second one, Wang and co-workers focus on the synthesis of cyclopentenes. This reaction was based on a Michael-aldol sequence followed by dehydration, between aromatic enals and dimethyl 2-oxoethylmalonate [29]. A set of densely functionahzed chiral cyclopentenes were synthesized in high yields (63-89%) and excellent enantiose-lectivities (91-97% ee) (Scheme 10.13). 

The [l,4,2]-oxazaphosphinane naphthoquinones 51 were obtained from a short synthesis based on transformation of 2,3-dichloro-l,4-naphthoqui-none into 2-amino-3-hydroxy-1,4-naphthoquinone 50 by a double Michael addition of water and of nitrite, followed by the reduction of the nitro group into an amino group using sodium dithionite (Scheme 11). Then, a three component reaction, mixing various ketones, alkyl dichloro-phosphate, and quinone 50 furnished fused the quinonic systems 51 in yields ranging from 60% to 95%. The monoester derivative 52 is readily obtained by treatment of the ester 51 ((R = Et, = R = Me) with TMSBr in chloroform, followed by methanolysis of the sdyl ester intermediate. 

In efforts towards a synthesis of eremolactone, the dienolate (158) has been found to react with the cyano-ester (159) to give (160) (probable stereochemistry shown) most likely via a double Michael addition rather than a Diels-Alder reaction. Highly substituted cyclohexanes have been prepared by cycloadditions between cyclohexa-1,3-dienes and nitroso-compounds followed by N—O and olefinic bond cleavage (Scheme 12). ... 

SCHEME 1.59 Double Michael addition reactions with malonate a,P-unsaturated esters. 

The addition of active methylene compounds (ethyl malonate, ethyl aoeto-acetate, ethyl plienylacetate, nltromethane, acrylonitrile, etc.) to the aP-double bond of a conjugated unsaturated ketone, ester or nitrile In the presence of a basic catalyst (sodium ethoxide, piperidine, diethylamiiie, etc.) is known as the Michael reaction or Michael addition. The reaction may be illustrated by the addition of ethyl malonate to ethyl fumarate in the presence of sodium ethoxide hydrolysis and decarboxylation of the addendum (ethyl propane-1 1 2 3-tetracarboxylate) yields trlcarballylic acid ... 

The method was applied to the synthesis of (-t-)-l9-nortestosterone by the following sequence of reactions. Michael addition of the bisannulation reagent 124 to the optically active keto ester 129 and decarboxylation afforded 130, and subsequent aldol condensation gave 131. Selective Pd-catalyzed oxidation of the terminal double bond afforded the diketone 132 in 78% yield. Reduction of the double bond and aldol condensation gave ( + )-19-nortestosterone (133)[114]. 

In its original form, the Michael addition consisted on the addition of diethyl malonate across the double bond of ethyl cinnamate in the presence of sodium ethoxide to afford a substituted pentanedioic acid ester. Currently, all reactions that involve a 1,4-addition of stabilized carbon nucleophiles to activated 7i-systems are known as Michael additions. Among the various reactants, enolates derived from p-dicarbonyl compounds are substrates of choice due to their easy deprotonation under mild conditions. Recently, Michael addition-based MCRs emerged as highly potential methodologies for the synthesis of polysubstituted heterocycles in the five- to seven-membered series. 

Dimerization of methyl crotonate has been carried out with alkaline earth metal oxides as basic catalysts 15). The reaction proceeds by Michael addition, which is initiated by abstraction of an allylic hydrogen of methyl crotonate by the basic site to form the allylic carbanion, which attacks a second methyl crotonate molecule at the jS-position to form a methyl diester of 3-methyl-2-vinylglutaric acid. The diester undergoes a double bond migration to form the final E- and Z- isomers of 3-ethylidene-3-methylglutaric acid dimethyl ester (MEG) (Scheme 22). 

---