Enoates protonation

An interesting result has been observed when 4-formylantipyrine 89 was converted into the corresponding pyridinium salt 90 and reacted with alkyl 3-aminobut-2-enoates. Tire expected 1,4-dihydropyridines 91 are transient species in these syntheses and readily lose the 4-substituent (antipyrine, 93) so that dialkyl 2,6-dimethylpyridine-3,5-dicarboxylates 92 are obtained (85-95%) (94H815). Protonation of the pyrazole ring by the evolved hydrochloric acid accounts for this particular behavior (Scheme 29). 

The intramolecular asymmetric Stetter reaction of aliphatic aldehydes is generally more difficult to achieve due to the presence of acidic a-protons. Rovis and co-workers have demonstrated that the NHC derived from pre-catalyst 130 promotes the intramolecular Stetter cyclisation with enoate and alkyhdene malonate Michael acceptors 133. Cyclopentanones are generally accessed in excellent yields and enantioselectivities, however cyclohexanones are obtained in significantly lower yields unless very electron-deficient Michael acceptors are employed... 

Similarly, the lithium salt of a-iminyl carboxylate 485 can attack the /3-position of 2,3-alkadienoates to provide /i,y-unsaturated enoates 486, which upon protonation or hydrolysis afforded 487 and 488 [222],... 

Scheme 3.6. Diastereoselectivity in silylcuprate conjugate addition-alkylation (alkyl halides) or protonation reactions with a,/S-enoates [46],...

The Morita-Baylis-Hillman (MBH) reaction is the formation of a-methylene-/ -hydroxycarbonyl compounds X by addition of aldehydes IX to a,/ -unsaturated carbonyl compounds VIII, for example vinyl ketones, acrylonitriles or acrylic esters (Scheme 6.58) [143-148]. For the reaction to occur the presence of catalytically active nucleophiles ( Nu , Scheme 6.58) is required. It is now commonly accepted that the MBH reaction is initiated by addition of the catalytically active nucleophile to the enone/enoate VIII. The resulting enolate adds to the aldehyde IX, establishing the new stereogenic center at the aldehydic carbonyl carbon atom. Formation of the product X is completed by proton transfer from the a-position of the carbonyl moiety to the alcoholate oxygen atom with concomitant elimination of the nucleophile. Thus Nu is available for the next catalytic cycle. 

One report has indicated the potential of this mild reagent for a-oxidation of silyl ketoie acetals. Once again the usefulness is restricted by competition between the required silatropic ene process and the prototropic ene reaction giving rise to the enoate. For substrates lacking -protons the a-hydroperoxy ester is readily obtained in good yield. In one case where p-protons were present (methyl grotq)) an 80% yield of the silatropic product was obtained by carefully optimizing the reaction conditions. This may not however always be possible. 

Preparation of Derivatives. Enoate derivatives are prepared from the corresponding chiral alcohol by treatment with acry-loyl chloride in the presence of Triethylamine and catalytic 4-Dimethylaminopyridine or the appropriate carboxylic acid chloride and Silveril) Cyanide. Alkynyl ethers are readily available from the potassium alkoxide by treating with Trichloroethylene, in situ dechlorination with n-Butyllithium, and electrophilic trapping. Trapping the intermediate anion with a proton source or lodomethane followed by Lindlar reduction of the alkynyl ether affords the corresponding vinyl and l-(Z)-propenyl ether, respectively, while reduction of the alkynyl ether with Lithium Aluminum Hydride affords the l-( )-propenyl ether. 

Spin decoupling has been useful in identifying coupled pairs of nuclei. Figure 5-5 provides such an example for the molecule ethyl traw5-crotonate (ethyl fran.v-but-2-enoate). The alkenic protons split each other, and both are split by the allylic methyl group to form an ABX3 spin system. Irradiation at the methyl resonance frequency produces the upper spectrum in the inset for the alkenic protons, which have become a simple AB quartet. A more... 

Dehydrogenations, racemizations, exchange of a-protons and rearrangements of aldehydes catalysed by enoate reductase. Depending on the rate of reaction different amounts of enzyme have been used. The racemizations have been studied at pH 7.0, the H/ H-exchange and the dehydrogenations at pH 8.0 (18). 

Similarly, /-acetoxy-o, -enoates are reduced by samarium diodide to generate dienolates which are kinetically trapped at the a-position by electrophiles (proton, aldehydes, or ketones). (Z)-Alkenylsilanes are obtained in high diastereoselectivities if 0-acetyl-l-chloro-l-trimethylsilyIalkan-2-ols are treated with samarium iodide (eq 43). The stereochemical outcome is independent from the relative stereochemistry of the starting material. ... 

Retrosynthesis (i) in Scheme 10.9 identifies stereoselective formation of a carbon-hydrogen bond as a route to the chiral methyl branch. This could he accomplished, for instance, by asymmetric protonation of a prochiral eno-late, by asymmetric hydride transfer to a prochiral enoate (Scheme 10.10) [13], by transfer of a hydrogen atom to a prochiral carbon-centered radical, or by hydrogenation of a prochiral carbon-carbon double bond. The latter might sueeeed with the aid of chiral catalysts [14, 15]. Otherwise, one has to resort to the attachment of ehiral auxiliaries [16, 17]. 

More recent advances in intermolecular [3+2] reductive cycloadditions have involved combinations of enals or enoates with alkynes (Scheme 3-34).l 2 l The initially developed cycloadditions of enals and alkynes likely proceeds by initial formation of a metallacyclic enolate derivative, followed by enolate protonation and addition of the vinyl nickel unit to the resulting carbonyl to produce the boron alkoxide of the observed cyclopentenol product (Scheme 3-35). The analogous transformation with enoates may also proceed by this mechanism, depicted below by the sequence of initial generation of metallacycle 20, followed by enolate protonation to form 21 en route to product generation. Alternatively, the collapse of the metallacycle 20 to a ketene intermediate 22 may occur in the enoate variant. The precise pathway followed likely depends on whether protic or aprotic media are used. 

A TFA-promoted regioselective hydroarylation of 2,3-allenoates R C=C=C (R )C02Et with N-Ts- or A-Ac-indoles has been reported to occur at the electron-rich C=C bond, giving rise to 4-indolyl-4-arylbut-2-enoates. The E Z selectivity was found to be dependent on the reaction temperature and time. A mechanism involving the formation of ( )- and (Z)-allylic carbocations generated in situ on protonation of the allenoate with TEA, followed by Friedel-Crafts attack at the 3-position of the indoles, was proposed. ... 

It is known that silicon with bulky substituents can serve as an efficient stereo-directing functional element. In addition, silicon is a synthetic equivalent for an aUcoxy substituent, which opens a straightforward approach to the stereocontroUed aldol addition of acyclic molecules (Scheme 3.65). The protocol by Fleming ti al. starts with 1,4-addition of a silylcuprate to enoate 325 to give enolate (Z)-326 selectively under kinetic control, probably due to a chelating effect of the metals. On re-protonation and subsequent deprotonation with LDA, the enolate... 

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