Ketones addition-elimination

A number of compounds of the general type H2NZ react with aldehydes and ketones m a manner analogous to that of primary amines The carbonyl group (C=0) IS converted to C=NZ and a molecule of water is formed Table 17 4 presents exam pies of some of these reactions The mechanism by which each proceeds is similar to the nucleophilic addition-elimination mechanism described for the reaction of primary amines with aldehydes and ketones... 

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 mechanism of the Fiesselmann reaction between methylthioglycolate and a,P-acetylenic esters proceeds via consecutive base-catalyzed 1,4-conjugate addition reactions to form thioacetal Enolate formation, as a result of treatment with a stronger base, causes a Dieckmann condensation to occur providing ketone 8. Elimination of methylthioglycolate and tautomerization driven by aromaticity provides the 3-hydroxy thiophene dicarboxylate 9. 

Step 4 of Figure 29.11 Elimination of Thiamin Diphosphate The product of the HETPP reaction with lipoamide is a hemithioacetal, which eliminates thiamin diphosphate vlide. This elimination is the reverse of the ketone addition in step 1 and generates acetyl dihydrolipoamide. 

Acyloins (a-hydroxy ketones) are formed enzymatically by a mechanism similar to the classical benzoin condensation. The enzymes that can catalyze reactions of this type arc thiamine dependent. In this sense, the cofactor thiamine pyrophosphate may be regarded as a natural- equivalent of the cyanide catalyst needed for the umpolung step in benzoin condensations. Thus, a suitable carbonyl compound (a -synthon) reacts with thiamine pyrophosphate to form an enzyme-substrate complex that subsequently cleaves to the corresponding a-carbanion (d1-synthon). The latter adds to a carbonyl group resulting in an a-hydroxy ketone after elimination of thiamine pyrophosphate. Stereoselectivity of the addition step (i.e., addition to the Stand Re-face of the carbonyl group, respectively) is achieved by adjustment of a preferred active center conformation. A detailed discussion of the mechanisms involved in thiamine-dependent enzymes, as well as a comparison of the structural similarities, is found in references 1 -4. 

Ion 21 can either lose a proton or combine with chloride ion. If it loses a proton, the product is an unsaturated ketone the mechanism is similar to the tetrahedral mechanism of Chapter 10, but with the charges reversed. If it combines with chloride, the product is a 3-halo ketone, which can be isolated, so that the result is addition to the double bond (see 15-45). On the other hand, the p-halo ketone may, under the conditions of the reaction, lose HCl to give the unsaturated ketone, this time by an addition-elimination mechanism. In the case of unsymmetrical alkenes, the attacking ion prefers the position at which there are more hydrogens, following Markovnikov s rule (p. 984). Anhydrides and carboxylic acids (the latter with a proton acid such as anhydrous HF, H2SO4, or polyphosphoric acid as a catalyst) are sometimes used instead of acyl halides. With some substrates and catalysts double-bond migrations are occasionally encountered so that, for example, when 1 -methylcyclohexene was acylated with acetic anhydride and zinc chloride, the major product was 6-acetyl-1-methylcyclohexene. ... 

Addition-Elimination Mechanisms. In the reaction between a,p-unsaturated ketones and alkaline peroxide (15-48), the oxidizing agent adds to the substrate, and then part of it is lost ... 

Although the high reactivity of metal-chalcogen double bonds of isolated heavy ketones is somewhat suppressed by the steric protecting groups, Tbt-substituted heavy ketones allow the examination of their intermolecular reactions with relatively small substrates. The most important feature in the reactivity of a carbonyl functionality is reversibility in reactions across its carbon-oxygen double bond (addition-elimination mechanism via a tetracoordinate intermediate) as is observed, for example, in reactions with water and alcohols. The energetic basis... 

Attack of Grignard reagents on esters, e.g. (161), follows the general pathway indicated above, so that the initial product of addition/ elimination (eOR as leaving group) is a ketone (162) ... 

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... 

They have developed direct asymmetric synthesis of quaternary carbon centers via addition-elimination process. The reactions of chiral nitroenamines with zinc enolates of a-substituted-8-lactones afford a,a-disubstituted-6-lactones with a high ee through addition-elimination process, in which (5)-(+)-2-(methoxy methy l)pyrrolidine (SMP) is used as a chiral leaving group (Eq. 4.96).119 Application of this method to other substrates such as a-substituted ketones, esters, and amides has failed to yield high ee. 

It was found that treatment of a mixture of 120 and 121 with tris(diethylamino-sulfonium) trimethyldifluorosilicate [TASF(Et)] resulted in smooth addition-elimination to the naphthoquinone to form the y-alkylation product 125 (85 %). TASF(Et) is a convenient source of soluble, anhydrous fluoride ion [47]. It is believed that exposure of 121 to TASF(Et) results in fluoride transfer to generate a hypervalent silicate anion, as depicted in structure 124. The transfer of fluoride between TASF(Et) and 121 may be driven by stabilization of the anionic species 124 by delocalization of the carbon-silicon bond into the LUMO of the unsaturated ketone. 1,4-Addition-elimination of this species to the naphthoquinone 120 would then form the observed product. 

A somewhat related approach was followed by Molteni and coworkers, who have described the three-component, one-pot synthesis of fused pyrazoles by reacting cyclic 1,3-diketones with DMFDMA and a suitable bidentate nucleophile, such as a hydrazine derivative (Scheme 6.195) [357]. Again, the reaction proceeds by initial formation of an enamino ketone as the key intermediate from the 1,3-diketone and DMFDMA precursors, followed by a tandem addition-elimination/cydodehydration step. The details of this reaction, carried out in superheated water as solvent, have been described in Section 4.3.3.1. 

Aromatic halides react with crown ether-complexed K02 by an electron-transfer mechanism and not by nucleophilic attack, as was shown by Frimer and Rosenthal (1976) using esr spectroscopy. The corresponding phenol is the main reaction product (Yamaguchi and Van der Plas, 1977). Esters are saponified by the K02/18-crown-6 complex in benzene, presumably by an addition-elimination pathway (San Fillippo et al., 1976). The same complex has been used to cleave cr-keto-, or-hydroxy-, and or-halo-ketones, -esters, and -carboxylic acids into the corresponding carboxylic acids in synthetically useful quantities (San Fillippo et al., 1976). 

Acylation reactions can also be greatly improved in this way, with t-alkyl- or sec-alkyl-manganese reagents reacting with acid chlorides in excellent yields [123]. The related addition-elimination to 3-ethoxy-2-cyclohexenone is also improved, resulting after acidic aqueous workup in 3-methyl-2-cyclohexenone [125]. The perilla-ketone 126 was prepared in an improved yield using copper(I) catalysis (Scheme 2.58) [129]. 

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. 

C-3 as determined by mass spectral analysis.(55) In a mechanism involving ketone hydration prior to bindTrTg, incorporation in recovered inhibitor should be at least 50%, a value corresponding to that expected for a single cycle of nonstereospecific addition/nonstereospecific elimination of water to the ketone carbonyl. The actual results then indicate that addition-elimination is a highly stereospecific process and thus enzyme-catalyzed. 

Funabiki prepared a-fluoro-/ -phenylacrylaladehyde (92), a particularly useful synthetic intermediate, by an addition elimination strategy (Scheme 34) [81], Electrochemical fluorination of //-phenylsulfenyl-a, S-unsaturated ketones can form a-fluoro-a, S-unsaturated carbonyl compounds (Scheme 35) [82], a-Fluoro- S-thio-a, S-unsaturated ketone (93) was synthesized by the selective nucleophilic... 

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