Conjugate addition reactions Methyl vinyl ketone

This is an example of a Robinson annulation. The mechanism for the Robinson annulation involves a sequence of conjugate addition reactions and aldol condensations. As illustrated, the first step is deprotonation of cyclohexanedione with sodium hydride. The resulting anion then participates in a 1,4-addition to methyl vinyl ketone. The resulting enolate anion then tautomerizes through... 

The use of water as a solvent in the conjugate addition was first reported for 1,3-diketones [31] and then applied to p-unsubstituted enones [32], other conjugated enones [33], methyl vinyl ketone [34], a,P-unsaturated nitriles [35], and dehydroalanine amides [36]. Also a related reaction, the Bayhs-HiUman coupling, was found to be greatly accelerated in water compared with usual organic solvents [37]. 

The reaction of a cyclic ketone—e.g. cyclohexanone 1—with methyl vinyl ketone 2 resulting in a ring closure to yield a bicyclic a ,/3-unsaturated ketone 4, is called the Robinson annulation This reaction has found wide application in the synthesis of terpenes, and especially of steroids. Mechanistically the Robinson annulation consists of two consecutive reactions, a Michael addition followed by an Aldol reaction. Initially, upon treatment with a base, the cyclic ketone 1 is deprotonated to give an enolate, which undergoes a conjugate addition to the methyl vinyl ketone, i.e. a Michael addition, to give a 1,5-diketone 3 ... 

The reaction of crotonaldehyde and methyl vinyl ketone with thiophenol in the presence of anhydrous hydrogen chloride effects conjugate addition of thiophenol as well as acetal formation. The resulting j3-phenylthio thioacetals are converted to 1-phenylthio-and 2-phenylthio-1,3-butadiene, respectively, upon reaction with 2 equivalents of copper(I) trifluoromethanesulfonate (Table I). The copper(I)-induced heterolysis of carbon-sulfur bonds has also been used to effect pinacol-type rearrangements of bis(phenyl-thio)methyl carbinols. Thus the addition of bis(phenyl-thio)methyllithium to ketones and aldehydes followed by copper(I)-induced rearrangement results in a one-carbon ring expansion or chain-insertion transformation which gives a-phenylthio ketones. Monothioketals of 1,4-diketones are cyclized to 2,5-disubstituted furans by the action of copper(I) trifluoromethanesulfonate. ... 

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

Brown proposed a mechanism where the enolate radical resulting from the radical addition reacts with the trialkylborane to give a boron enolate and a new alkyl radical that can propagate the chain (Scheme 24) [61]. The formation of the intermediate boron enolate was confirmed by H NMR spectroscopy [66,67]. The role of water present in the system is to hydrolyze the boron enolate and to prevent its degradation by undesired free-radical processes. This hydrolysis step is essential when alkynones [68] and acrylonitrile [58] are used as radical traps since the resulting allenes or keteneimines respectively, react readily with radical species. Maillard and Walton have shown by nB NMR, ll NMR und IR spectroscopy, that tri-ethylborane does complex methyl vinyl ketone, acrolein and 3-methylbut-3-en-2-one. They proposed that the reaction of triethylborane with these traps involves complexation of the trap by the Lewis acidic borane prior to conjugate addition [69]. 

Several attempts to take advantage of the intermediate boron enolate to achieve tandem conjugate addition-aldol reaction have been proposed [71]. Recently, Chandrasekhar [72] reported the addition of triethylborane to methyl vinyl ketone followed by the in situ trapping of the enolate by aromatic aldehyde (Scheme 26). 

In 1998, the rhodium-catalyzed conjugate addition of organostannanes to a,/9-unsatu-rated ketones and esters was reported by Oi [29]. In the reaction, which was carried out in the presence of [Rh(COD)(MeCN)2]BF4 in THF at 60°C, a variety of a,/9-unsatu-rated ketones and esters were transformed into the corresponding conjugate addition products. It is noted that the yield was highly dependent on the substitution pattern of the substrates. For example, /9-substituted enone 40 afforded an 86% yield of 41, whereas methyl vinyl ketone 42 gave only an 18% yield of 43 (Scheme 3.14). The addition of water to the reaction mixture improved the reactivity for the formation of 41 (98%) and 43 (80%) [30]. 

A particularly important example is the Robinson annulation, a procedure which constructs a new six-membered ring from a ketone.83 84 The reaction sequence starts with conjugate addition of the enolate to methyl vinyl ketone or a similar enone. This is followed by cyclization involving an intramolecular aldol addition. Dehydration frequently occurs to give a cyclohexenone derivative. Scheme 2.10 shows some examples of Robinson annulation reactions. 

The copper-catalyzed conjugate addition of methyl magnesium iodide to cyclohexenone and trapping the enolate as its trimethylsilyl enol ether, followed by a trityl hexachloro-antinomate-catalyzed Mukaiyama reaction, is apphed to / -(—jcarvone. C-2, C-3 functionalized chiral cyclohexanones are converted into their a-cyano ketones, which are submitted to Robinson annulation with methyl vinyl ketone. Highly functionalized chiral decalones are obtained that can be used as starting compounds in the total synthesis of enantiomerically pure clerodanes (equation 70). 

Heteroatoms were also tolerated in the cuprate, as demonstrated by the reaction of methyl vinyl ketone with (13 equation 10).36 A good yield of the conjugate addition product was reported (85%), without evidence of competing side reactions. 

Figure 12.13 shows that the iso-A enols of the /3-diketones A react with an a,/3-unsaturated carboxonium ion C that acts as a C electrophile. This oxocarbenium ion is formed by reversible protonation of the oc,/3-unsaturated methyl vinyl ketone in acetic acid. However, the oxocarbenium ion C in this figure does not react with the iso-A enols at its carbonyl carbon atom—as the protonated acetone in Figure 12.12 does with the enol of acetone—but at the center C-/3 of the conjugated C=C double bond. Accordingly, an addition reaction takes place whose regioselectivity resembles that of a 1,4-addition of an organometallic compound to an 0C,/3-unsaturated carbonyl compound (see Section 10.6). 1,4-additions of enols (like in this case) or enolates (as in Section 13.6) to a,/3-unsaturated carbonyl and carboxyl compounds are referred to as Michael additions. 

Of the reagents listed in Table 8.1, dialkyllithiocuprates stand out because of their unique ability to participate in 1,4-addition reactions. Such reactions, also known as conjugate additions, are generally referred to as Michael additions. This name reaction is illustrated in Scheme 8.16 with the reaction of dimethyllithiocuprate with methyl vinyl ketone. 

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. 

Base-catalysed conjugate addition of nitropropane to methyl vinyl ketone occurred smoothly to give the nitroketone. Formation of the salt with sodium methoxide was followed by oxidative cleavage of the C-N linkage with ozone. The product was a 1,4-diketone which was isolated without further aldol reaction by this route. 

The tellurium-lithium exchange used in the case of acyllithiums58 was also assayed for carbamoyllithiums 118, prepared by reaction of dialkylcarbamoyl chlorides with lithium n-butyltellurate111, m. The corresponding dialkylcarbamoyllithiums were prepared with n-butyllithium at —78 °C and trapped with different electrophiles including acyl chlorides and methyl vinyl ketone, which suffered conjugate addition (Scheme 31). 

A change in the course of the reaction of methyl vinyl ketone with A1,8fl-2-octalones was observed38,39 when a carbonyl group was introduced at C-5. In this case no y,(5-annulation occurred but, in addition to [4 + 2] cycloaddition to the cross-conjugated... 

The reaction can be modihed to give additional products, as with the reaction of o-hydroxybenzaldehyde and methyl vinyl ketone with DABCO, where the initial Baylis-Hillman product cyclized via conjugate addition of the phenolic oxygen to the conjugated ketone (15-31). ° Aldehydes and conjugated esters can be coupled with a sulfonamide to give an allylic amine. 

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