Methyl vinyl ketone nucleophilic attack

A. Nucleophilic Attack on Carbon. —(/) Activated Olefins. A study of triarylphosphine-catalysed dimerization of acrylonitrile to 2-methylene-glutaronitrile (26) and 1,4-dicyano-l-butene (27) has established a balance between phosphine nucleophilicity and protolytic strength of the solvent. The reaction of methyl vinyl ketone with triphenylphosphine in triethyl-silanol gave only 3-methylene-2,6-heptadienone (28). 

Polymerizations of vinyl ketones such as methyl vinyl ketone are also complicated by nucleophilic attack of the initiator and propagating carbanion at the carbonyl group although few details have been established [Dotcheva and Tsvetanov, 1985 Hrdlovic et al., 1979 Nasrallah and Baylouzian, 1977]. Nucleophilic attack in these polymers results in addition, while that at the ester carbonyl of acrylates and methacrylates yields substitution. The major side reaction is an intramolecular aldol-type condensation. Abstraction of an a-hydrogen from a methyl group of the polymer by either initiator or propagating carbanion yields an a-carbanion that attacks the carbonyl group of the adjacent repeat unit. 

The t]2 complex 333 can be prepared in 98% yield by the reaction of anisole with Os(NH3)5(OTf)3 in the presence of Mg. Michael addition of methyl vinyl ketone to the complex at 20 °C using TfOH afforded 336, which was converted to 337 by deprotonation with tertiary amine [83]. The diketone 340 was obtained by the Michael addition of methyl vinyl ketone to C-4 of the 4-methylanisole complex 338 to generate 339, followed by intramolecular nucleophilic attack of the keto enolate in 339. 

An alternative mode of reactivity is observed for [Os]-naphthalene when the nucleophile for the tandem addition is built into the electrophile. The normal mode of reactivity results in the formation of cis-l,4-dihydronaphthalenes (vide supra), but when a solution of the methyl vinyl ketone Michael addition product 24 in methanol (Table 6, entry 1) and a catalytic amount of triflic acid are allowed to react, the complexed hydrophenanthrenone 25 is isolated in 89 % yield [18]. This reactivity results from the pendant ketone undergoing a tauto-merization to form an enol, which can then attack the allyl cation at C2. The stereochemistry of the nucleophilic addition is still anti to the face involved in the metal coordination, but the... 

Michael additions are useful in acetoacetic ester syntheses and malonic ester syntheses because the enolate ions of both of these esters are good Michael donors. As an example, let s consider the addition of the malonic ester enolate to methyl vinyl ketone (MVK). The crucial step is the nucleophilic attack by the enolate at the carbon. The resulting enolate is strongly basic, and it is quickly protonated. 

Base catalysis is not required for conjugate addition. If the nucleophile is sufficiently enolized under the reaction conditions then the enol form is perfectly able to attack the unsaturated carbonyl compound. Enols are neutral and thus soft nucleophiles favouring conjugate attack, and p-dicarbonyl compounds are enolized to a significant extent (Chapter 21). Under acidic conditions there can be absolutely no base present but conjugate addition proceeds very efficiently. In this way methyl vinyl ketone (butenone) reacts with the cyclic P-diketone promoted by acetic acid to form a quaternary centre. The yield is excellent and the triketone product is an important intermediate in steroid synthesis as you will see later in this chapter. 

Owing to this dichotomy, a, -unsaturated aldehydes, ketones, or esters can undergo a nucleophilic attack at either the carbonyl carbon or the )S-carbon atom (Scheme 2.29). The first of these reactions is a familiar addition to the carbonyl group (1,2-addition) which leads, in this case, to the valuable allylic alcohols. Even more intriguing synthetic options, however, are offered by the alternative pathway, the 1,4-addition generally known as the Michael reaction. The classic version of this reaction employed stable carbanions such as those generated in situ from malonic ester or nitromethane under the action of bases and in the presence of Michael acceptors, e.g. methyl vinyl ketone 90 ... 

In comparing the speed of the addition of bromine to 1-butene and methyl vinyl ketone, we realize that the double bond of 1-butene would be attacked more readily because it lacks the electron-withdrawing carbonyl group of methyl vinyl ketone. IThile methyl vinyl ketone is less reactive in electrophilic additions such as these, it is more reactive toward attack of nucleophiles. 

Polar monomers, like methyl methacrylate, acrylonitrile, or methyl vinyl ketone, contain substituents that react with nucleophiles. This can lead to terminations and side reactions that compete with both initiation and propagation. An example is a nucleophilic substitution by an intramolecular backbiting attack of a propagating carbanion ... 

The role of the trimethylsilyl group is to stabilize the intermediate carbanion formed by conjugate addition. The silyl group is removed under conditions similar to those required for the dehydration the removal occurs by nucleophilic attack on silicon, resulting in displacement of the ketone. The advantage of the substituted methyl vinyl ketone is that it permits the annelation reaction to be carried out in aprotic solvents under conditions where enolate equilibration does not take place. The annelation of unsymmetrical ketones can therefore be controlled by using specific enolates generated by the methods described in Chapter 1. 

The Robinson annulation involves two reactions occurring in tandem a Michael reaction followed by an aldol condensation (loss of water is normally expected in this reaction so the aldol product is typically dehydrated to give an a,P-unsaturated cyclohexenone product). The reaction of an enolate as a nucleophile attacking the beta carbon of methyl vinyl ketone as the electrophile (a Michael reaction) forms the first carbon-carbon bond in the Robinson annulation and results in a 1,5-dicarbonyl product. The methyl group from MVK serves as the nucleophile for the second part of the reaction when it finds a carbonyl electrophile six atoms away to undergo an intramolecular aldol reaction. After dehydration, an a,P-unsaturated cyclohexenone product is formed. Ultimately, two new carbon-carbon bonds are formed within the cyclohexenone moiety. 

The introduction of umpoled synthons 177 into aldehydes or prochiral ketones leads to the formation of a new stereogenic center. In contrast to the pendant of a-bromo-a-lithio alkenes, an efficient chiral a-lithiated vinyl ether has not been developed so far. Nevertheless, substantial diastereoselectivity is observed in the addition of lithiated vinyl ethers to several chiral carbonyl compounds, in particular cyclic ketones. In these cases, stereocontrol is exhibited by the chirality of the aldehyde or ketone in the sense of substrate-induced stereoselectivity. This is illustrated by the reaction of 1-methoxy-l-lithio ethene 56 with estrone methyl ether, which is attacked by the nucleophilic carbenoid exclusively from the a-face —the typical stereochemical outcome of the nucleophilic addition to H-ketosteroids . Representative examples of various acyclic and cyclic a-lithiated vinyl ethers, generated by deprotonation, and their reactions with electrophiles are given in Table 6. 

As expected from the depicted mechanism, early attempts to control the stereoselectivity of the MBH reaction was focused on the application of chiral amines (Fig. 4.48). Thus, using high pressure conditions (5 kbar) to accelerate the reaction and a C -symmetric DABCO derivative 245 (15 mol%), product 241a (R =Me, R sq-NO CgH ), was obtained in 45% yield and 47% ee (1 mol% hydroquinone, THF, 30°C) [318]. When used with pyrrolizidine derivative 246 (10 mol%, acetonitrile, 0°C) improved results (17-93% yield, 39-72% ee) were obtained in reactions between methyl or ethyl vinyl ketone (237a R =Me and 237b R =Et) and aromatic aldehydes. The presence of NaBF as co-catalyst was required to achieve these results, due to the coordination of aldehyde and hydroxy group of the catalyst to the alkali metal, which fixed the orientation for the attack of the nucleophile to the electrophile in the transition state [319]. 

Since an amide nitrogen is far less basic than that of an aliphatic amine, amides do not displace alkene from palladium. The N atom of an amide is thus able to attack alkenes coordinated to Pd(II) to give vinyl amides, according to Scheme 1. Given in Table 1 is an example of the amidation of alkenes. The amidation can be made catalytic by using a combination of CuCl and O2 in the presence or absence of hexamethylphosphoramide (HMPA). The use of O2 alone also makes the reaction catalytic. The amidation does not proceed well with simple alkenes however, electron-deficient alkenes such as methyl acrylate and vinyl ketones undergo an effective catalytic amidation. Note that cyclic carbamates, because of the higher nucleophilicity of the N atom, are more reactive than cyclic amides. 

A majority of reaction sequences rely on the use of nucleophilic (metalated) variants of 1. However, the electrophilic character of the sterically congested methine carbon has been successfully exploited via displacement reactions with sodium azide.Ogata and Shimizu have also reported that 1 undergoes nucleophilic attack by 1,2,4-tiiazole in the presence of potassium carbonate to provide l-[bis(trimethylsilyl)methyl]-1,2,4-triazole (3) (eq 2). Subsequent introduction of TBAF results in desilylation of 3 to afford an a-sUyl carbanion intermediate that provides 1-vinyl-1,2,4-triazole products upon condensations with aldehydes or ketones (eq 3). While high yields of the alkene products are generally obtained, mixtures of 7Z-isomers are observed in all cases. 

This combination of reagents h s been used to oxidize terminal vinyl groups to methyl ketones and is known as the Wacker oxidation. The nucleophile is simply water, which attacks the activated alkene at the more substituted end in an oxypalladation step. (3-Hydride elimination from the resulting a-alkyl palladium complex releases the enol, which is rapidly converted into the more stable keto form. Overall, the reaction is a hydration of a terminal alkene that can tolerate a range of functional groups. 

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