Ketones addition-elimination reactions

Scheme 8.2. Addition-Elimination Reactions of Aldehydes and Ketones...

A polyfluorinated P,y-unsaturated ketone is formed m situ from tributylamine and 3,4-bis(tnfluoromethyl)-3-(pentafluoroethyl)-5,5,6,6,6-pentafluoro-2-hex-anone. The enol form of the unsaturated ketone cyclizes via an intermolecular addition-elimination reaction that involves exclusive attack by oxygen rather than by carbon. This reaction demonstrates the hardness of a F-C= site toward... 

The enamino ketone (49) was reported to give no identifiable products on reaction with N,N-dimethyl carbamoyl chloride 63). However, reaction of (49) with N,N-diethyl carbamoyl chloride in refluxing chlorobenzene gave the N-(3-diethyl-amino-5,5-dimethylcyclohex-2-en-1 -ylidene)pyrrolidinium salt, isolated as the perchlorate. The latter must have been formed as outlined in Scheme I, involving initial O carbamoylation followed by an addition-elimination reaction to give 138 cation which can react with diethylamino anion by a further addition-elimination displacement to give the product 46). 

The nitro-aldol approach is impractical for the synthesis of 2,2-disubstituted 1-nitroalkenes due to the reversibility of the reaction when ketones are employed as substrates. Addition-elimination reactions are used for the preparation of such nitroalkenes (see Chapter 4). 

The addition-elimination reaction of hetero-atom-substituted nitroalkenes provides functionalized derivatives of unsaturated nitro compounds.26 Nitroenamines are generally prepared from a-nitro ketones and amines (see Chapter 5 regarding acylation of nitro compounds).26... 

In Section 7.7.2 we met enamines as products from addition-elimination reactions of secondary amines with aldehydes or ketones. Enamines are formed instead of imines because no protons are available on nitrogen for the final deprotonation step, and the nearest proton that can be lost from the iminium ion is that at the P-position. 

Another more efficient catalytic version of the reaction consists of the interaction of ketones with chiral amines [6] to form enolate-like intermediates that are able to react with electrophilic imines. It has been postulated that this reaction takes place via the catalytic cycle depicted in Scheme 33. The chiral amine (130) attacks the sp-hybridized carbon atom of ketene (2) to yield intermediate (131). The Mannich-like reaction between (131) and the imine (2) yields the intermediate (132), whose intramolecular addition-elimination reaction yields the (5-lactam (1) and regenerates the catalyst (130). In spite of the practical interest in this reaction, little work on its mechanism has been reported [104, 105]. Thus, Lectka et al. have performed several MM and B3LYP/6-31G calculations on structures such as (131a-c) in order to ascertain the nature of the intermediates and the origins of the stereocontrol (Scheme 33). According to their results, conformations like those depicted in Scheme 33 for intermediates (131) account for the chiral induction observed in the final cycloadducts. 

As illustrated using arrow pushing, the first methyl anion drives an addition-elimination reaction forming a ketone. The second methyl anion then adds to the carbonyl in a 1,2-addition, generating the final alcohol. 

Replacement in vinylic derivatives is, however, facilitated by electron-withdrawing groups to the site of substitution and addition-elimination reactions of this type have been reviewed by Rappoport and by Patai and Rappoport Such reactions have been applied in the direct synthesis of vinyl azides. For example the synthesis in 81 % yield of the )5-azidovinyl ketone (25), of unspecified stereochemistry, from the chloro derivative and azide ion in dimethylformamide at 40° has been described by Maiorana . 

Table 7-2 summarizes kinetic data for the reaction of O2 with esters, diketones, and carbon dioxide.35,37-39 Esters react with superoxide ion to form diacyl peroxides or the carboxylate and the alcohol. Initial reaction occurs via a reversible addition-elimination reaction at the carbonyl carbon (Scheme 7-9). This conclusion is supported by the products that are observed in the gas-phase reaction of O2 with phenyl acetate and phenyl benzoate, which has been studied by Fourier-transform mass spectrometry.40 in effect, there is a competition between loss of O2 and loss of the leaving group. Carbanions are poor leaving groups, so that simple ketones without acidic a-hydrogen atoms are unreactive. The KC(O)OO- radical should be a reactive intermediate for the initiation of the autoxidation of allylic hydrogens (see Chapter 5). 

Little precise mechanistic studies have been undertaken with these inhibitors with the exception of the time-dependent inhibition of SAH hydrolase by 176. Stoichiometric loss of fluoride was observed by 19F-NMR during the inactivation process. However, there is only circumstantial evidence to support the addition-elimination mechanism proposed in Figure 1 all attempts to isolate an enzyme fragment covalently bound to an inhibitor have so far been unsuccessful. If the rate-determining step in the enzyme inhibition process is an attack of an enzyme nucleophilic residue on a 0-fluoro-a, 0-unsaturated imine or ketone, kinetic analysis of addition-elimination reactions to similar systems indicate that the ( )-isomer is the more active isomer (73) this could explain in part the isomeric preference seen with MAO and SAH hydrolase inhibitors. 

Aldehydes and ketones undergo nucleophilic addition-elimination reactions with oxygen and nitrogen nucleophiles. 

Overall, the addition of a nitrogen nucleophile to an aldehyde or a ketone is a nucleophilic addition-elimination reaction nucleophilic addition of an amine to form an unstable tetrahedral intermediate, followed by elimination of water. The tetrahedral intermediates are unstable because the newly formed sp carbon is bonded to an oxygen and to a nitrogen—another electronegative atom. Water is eliminated, and loss of a proton from the resulting protonated imine forms a stable imine. 

In contrast, the reaction of an aldehyde or a ketone with a carbon or hydrogen nucleophile forms a stable tetrahedral compound because the newly formed sp carbon is not bonded to a second electronegative atom. Thus, aldehydes and ketones undergo nucleophilic addition reactions with carbon and hydrogen nucleophiles, whereas they undergo nucleophilic addition-elimination reactions with nitrogen nucleophiles. 

SECTION 8.2. ADDITION-ELIMINATION REACTIONS OF KETONES AND ALDEHYDES... 

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