Enol ethers Michael addition

In another example, addition of phenyl vinyl selenoxide into a mixture of an indanedione, hexamethyldisilazane, and TMSCl in dichloromethane affords the a-trimethylsiloxyselenide in 70% yield (eq 67). The reaction proceeds through a sequence of in situ formation of TMS silyl enol ether, Michael addition onto the phenyl vinyl selenoxide, and seleno Pummerer rearrangement of the resulting selenoxide. Trifluoroacetic anhydride and various other trialkylchlorosilanes give the same product for this reaction, but in much lower yields. 

Reagent 1 also undergoes asymmetric Michael additions with enolate ions. Michael additions with disubstituted lithium eno-lates proceed with almost complete tt-facial diastereoselectivity. Starting with these Michael additions, (—)-methyl jasmonate (eq 4) and (—)-estrone methyl ether (eq 5) can be obtained in high enantiomeric purities. 

The synthetic problem is now reduced to cyclopentanone 16. This substance possesses two stereocenters, one of which is quaternary, and its constitution permits a productive retrosynthetic maneuver. Retrosynthetic disassembly of 16 by cleavage of the indicated bond furnishes compounds 17 and 18 as potential precursors. In the synthetic direction, a diastereoselective alkylation of the thermodynamic (more substituted) enolate derived from 18 with alkyl iodide 17 could afford intermediate 16. While trimethylsilyl enol ether 18 could arise through silylation of the enolate oxygen produced by a Michael addition of a divinyl cuprate reagent to 2-methylcyclopentenone (19), iodide 17 can be traced to the simple and readily available building blocks 7 and 20. The application of this basic plan to a synthesis of racemic estrone [( >1] is described below. 

The highest enantioselectivities in the base-catalyzed Michael additions have so far been obtained using achiral bases complexed to chiral crown ethers. The addition of methyl 2,3-dihydro-l-oxo-1//-indene-2-carboxylate (1) to 3-buten-2-one using 4 mol% of a [l,T-binaphthalcnc]-2,2 -diol derived optically active crown ether 3 in combination with potassium AY/-butoxide as the base illustrates this successful method 259 260 It is assumed that the actual Michael donor is the potassium enolate complex of 1 and crown ether 3. 

For those substrates more susceptible to nucleophilic attack (e.g., polyhalo alkenes and alkenes of the type C=C—Z), it is better to carry out the reaction in basic solution, where the attacking species is RO . The reactions with C=C—Z are of the Michael type, and OR goes to the side away from the Z. Since triple bonds are more susceptible to nucleophilic attack than double bonds, it might be expected that bases would catalyze addition to triple bonds particularly well. This is the case, and enol ethers and acetals can be produced by this reaction. Because enol ethers are more susceptible than triple bonds to electrophilic attack, the addition of alcohols to enol ethers can also be catalyzed by acids. " One utilization of this reaction involves the compound dihydropyran... 

Conditions for effecting conjugate addition of neutral enolate equivalents such as silyl enol ethers in the presence of Lewis acids have been developed and are called Mukaiyama-Michael reactions. Trimethylsilyl enol ethers can be caused to react with electrophilic alkenes by use of TiCl4. These reactions proceed rapidly even at -78° C.308... 

Nitroalkenes are also reactive Michael acceptors under Lewis acid-catalyzed conditions. Titanium tetrachloride or stannic tetrachloride can induce addition of silyl enol ethers. The initial adduct is trapped in a cyclic form by trimethylsilylation.316 Hydrolysis of this intermediate regenerates the carbonyl group and also converts the ad-nitro group to a carbonyl.317... 

Twofold Michael additions have been utilized by the groups of Spitzner [2] and Hagiwara [3] to construct substituted bicyclo[2.2.2]octane frameworks. In Hagiwara s approach towards valeriananoid A (2-6) [4], treatment of trimethylsily-enol ether 2-2, prepared from the corresponding oxophorone 2-1, and methyl acrylate (2-3) with diethylaluminum chloride at room temperature (r.t.) afforded the bicyclic compound 2-4 (Scheme 2.2). Its subsequent acetalization allowed the selective protection of the less-hindered ketone moiety to provide 2-5, which could be further transformed into valeriananoid A (2-6). 

Under classical Mukaiyama conditions, silyl enol ether 2-372 and the Michael acceptors 2-373 and 2-374 underwent a twofold 1,4-addition to form an enolate in which an ideal set-up exists for an intramolecular aldol reaction. This led to 2-375 with the desired structural core of 2-376 in an overall yield of 42%. 

The use of oxygen-containing dienophiles such as enol ethers, silyl enol ethers, or ketene acetals has received considerable attention. Yoshikoshi and coworkers have developed the simple addition of silyl enol ethers to nitroalkenes. Many Lewis acids are effective in promoting the reaction, and the products are converted into 1,4-dicarbonyl compounds after hydrolysis of the adducts (see Section 4.1.3 Michael addition).156 The trimethylsilyl enol ether of cyclohexanone reacts with nitrostyrenes in the presence of titanium dichloride diisopropoxide [Ti(Oi-Pr)2Cl2], as shown in Eq. 8.99.157 Endo approach (with respect to the carbocyclic ring) is favored in the presence of Ti(Oi-Pr)2Cl2. Titanium tetrachloride affords the nitronates nonselectively. 

Titanium tetrachloride-catalysed Michael additions of trimethylsilyl enol ethers to artemisitene afforded a neat route to 14-substituted artemisinin derivatives of type 125 (eg. R = allyl) and to 9-epiartemisinin derivatives 126 some of these compounds were more active against Plasmodium falciparum than artemisinin <00BMCL1601>. A series of 11-azaartemisinins also have better activity than artemisinin <00BMC1111>. On the other hand, epiartemisinin, prepared by base-catalysed epimerisation of artemisinin, has been shown to have poor antimalarial activity <00HCA1239>. 

Oare, D. A., Stereochemistry of the Base-Promoted Michael Addition Reaction, 19, 227 Acyclic Stereocontrol in Michael Addition Reactions of Enamines and Enol Ethers, 20, 87 Okamoto, Yoshio, Optically Active Polymers with Chiral Recognition Ability, 24, 157. 

Michael addition of various a,fi-unsaturated carbonyl compounds to silyl enol ether catalyzed by Ti-beta and TS-1... 

The utilization of copper complexes (47) based on bisisoxazolines allows various silyl enol ethers to be added to aldehydes and ketones which possess an adjacent heteroatom e.g. pyruvate esters. An example is shown is Scheme 43[126]. C2-Symmetric Cu(II) complexes have also been used as chiral Lewis acids for the catalysis of enantioselective Michael additions of silylketene acetals to alkylidene malonates[127]. 

L. Toke, P. Bako, G. M. Keserii, M. Albert, L. Fenichel, Asymmetric Michael Addition and Deracemization of Enolate by Chiral Crown Ether , Tetrahedron 1998, 54, 213-222. 

Michael additions to quinones. In the presence of TrC104, enol silyl ethers undergo 1,4-addition to benzoquinone to give adducts that cyclize to benzofurans.1 A similar reaction with diimidoquinones produces indole derivatives. 

Donor- and acceptor-substituted allenes with general structures 1 or 2 (Scheme 8.1) have the most obvious synthetic potential among functionalized allene derivatives and therefore they serve as versatile building blocks in many synthetic endeavors [1], As expected, the reactivity of the double bonds of 1 or 2, which are directly connected to the activating substituents, are strongly influenced by these groups. Hence there is enol ether or enamine reactivity of 1 and Michael acceptor type chemistry of 2. In addition, the terminal double bonds are also influenced by these functional groups. 

Selective formation of 1,5-dicarbonyl compounds by 1,4-addition (Michael addition) of enolates to enones is facilitated by the use of enol silyl ethers as enolate equivalents [37]. The reaction is catalyzed by... 

Lewis acid-catalyzed Michael addition of silyl enol ether to a,P-unsaturated system. 

The asymmetric allylic C-H activation of cyclic and acyclic silyl enol ethers furnishes 1,5-dicarbonyl compounds and represents a surrogate of the Michael reaction [136]. When sufficient size discrimination is possible the C-H insertion is highly diastereoselective, as in the case of acyclic silyl enol ether 193 (Eq. 22). Reaction of aryldia-zoacetate 192 with 193 catalyzed by Rh2(S-DOSP)4 gives the C-H insertion product 194 (>90% de) in 84% enantiomeric excess. A second example is the reaction of the silyl enol ether 195 with 192 to form 196, a product that could not be formed from the usual Michael addition because the necessary enone would be in its tautomeric naphthol form (Eq. 23). 

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