Non-enolizable carbonyl compounds

Corey and Chaykovsky were the first to investigate the reaction of dimethyl sulphoxide anion (dimsyl anion) with aldehydes and ketones400,401. They found that the reaction with non-enolizable carbonyl compounds results in the formation of /1-hydroxyalkyl sulphoxides in good yields (e.g. Ph2CO—86%, PhCHO—50%). However, with enolizable carbonyl compounds, particularly with cycloalkanones, poor yields of hydroxyalkyl products are observed (e.g. camphor—28%, cyclohexanone—17%, but... 

Allyl vinyl ethers have been prepared using the ylide (101) but only from non-enolizable carbonyl compounds. The ethers rearrange on heating to give a-allyl aldehydes, e.g. (102). 

The mechanism of the Mannich reaction has been extensively investigated. The reaction can proceed under both acidic and basic conditions, but acidic conditions are more common. Under acidic conditions the first step is the reaction of the amine component with the protonated non-enolizable carbonyl compound to give a hemiaminal, which after proton transfer loses a molecule of water to give the electrophilic iminium ion.°° This iminium ion then reacts with the enolized carbonyl compound (nucleophile) at its a-carbon in an aldol-type reaction to give rise to the Mannich base. 

Mannich reaction The condensation of CH activated compound with a primary or secondary amine and a non-enolizable carbonyl compound to afford aminoalkylated derivatives. 274... 

Recently, the MBH reactions of various conjugated nitroalkenes with activated non-enolizable carbonyl compounds 157, such as glyoxylate, tri-ffuoropyruvate and pymvaldehyde, catalyzed by DMAP or imidazole have been developed. In most cases, the reactions catalyzed by DMAP in acetonitrile were faster and provided the desired MBH adducts 158 in higher yields than did the imidazole-catalyzed reactions (Scheme 1.68). ... 

Thermal decomposition of / -substituted sulphoxides of the type (426) leads to olefins by nucleophilic attack of phosphorus on sulphur. Compound (426) is conveniently prepared from lithiomethylsulphinyl carbanion and a non-enolizable carbonyl compound followed by treatment with phosphorochlorid-ite. A similar elimination takes place using phenylthiomethyl-lithium, PhSCHgLi, instead of (427). ... 

One-electron oxidation systems can also generate radical species in non-chain processes. The manganese(III)-induced oxidation of C-H bonds of enolizable carbonyl compounds [74], which leads to the generation of electrophilic radicals, has found some applications in multicomponent reactions involving carbon monoxide. In the first transformation given in Scheme 6.49, a one-electron oxidation of ethyl acetoacetate by manganese triacetate, yields a radical, which then consecutively adds to 1-decene and CO to form an acyl radical [75]. The subsequent one-electron oxidation of an acyl radical to an acyl cation leads to a carboxylic acid. The formation of a y-lactone is due to the further oxidation of a carboxylic acid having an active C-H bond. As shown in the second equation, alkynes can also be used as substrates for similar three-component reactions, in which further oxidation is not observed [76]. 

The classic direct Mannich reaction discovered in 1912 [192a] is an aminoalkylation of carbonylic compounds involving ammonia (or a primary or secondary amine derivative), a non-enolizable aldehyde (usually formaldehyde) or a ketone, and an enolizable carbonyl compound, leading to P-aminocarbonyl derivatives [192b-e]. The indirect version of the Mannich reaction is the corresponding two-component reaction of a preformed iminium salt [193] and an enolizable carbonyl compound. 

Mixed aldol reactions between different aldehydes or ketones are usually plagued by formation of a mixture of products, because each component can function as a CH-acidic and carbonyl-active compound. Whereas the directed aldol reaction [14-16] is a rather general solution to this problem, the traditional aldol addition of non-identical carbonyl compounds is only successful when applied within the framework of a limited substitution pattern. Thus, a fruitful combination in mixed aldol reactions is that of an aldehyde with an enolizable ketone. Obviously, the aldehyde, having higher carbonyl reactivity, reacts as the electrophilic component, whereas the ketone, with comparatively lower carbonyl reactivity, serves as the CH-acidic counterpart. Because the self-aldolization of ketones is endothermic, this type of side reaction does not occur to a significant extent, so the product of the mixed aldol condensation is obtained in fair yield, as illustrated by the formation of ketone 6 from citral 5 and acetone, a key step in the synthesis of j5-ionone (Eq. (7)) [17]. 

Apart from the Takai method and titanium reagents such as 15, silyl reagents 16 and 17 frequently find application in the synthesis of vinylic silanes from carbonyl compounds. Reagent 16 can be utilized with aldehydes and non-enolizable ketones in a reaction analogous to the Peterson olefination Reagent 17 also reacts successfully with enolizable ketones.6... 

The stereochemistries were established at the stage of the ketones 38 - 40. The enolizable P-ketoester was m-fused compound 28, and the non-enolizable one (keto-form) was tram-fused compound 24. Reduction of the carbonyl group, mesylation or benzoylation, and then base treatment yielded the corresponding a,P-unsaturated ester in each case. Further reduction afforded the allyl alcohols 29 and 30 (Scheme 6). 

An alternative method for the formation of an a,(3-unsaturated carbonyl compound is the elimination of an initially formed Mannich product. The procedure is particularly effective for the formation of (3,(3-bis(unsubstituted) a, -unsaturated carbonyl compounds. The Mannich product 11 can be formed in the presence of a secondary amine and a non-enolizable aldehyde such as formaldehyde (2.12). The Mannich reaction is a useful carbon-carbon bond-forming reaction and the products have found application in the synthesis of, in particular, alkaloid ring systems. The Mannich product may eliminate under the reaction conditions, or can be alkylated to form the quaternary ammonium salt in order to induce elimination. A convenient variation of this method is the use of Eschenmoser s salt, H2C=NMe2 X. For example, Nicolaou s synthesis of hemibrevetoxin B used this salt in order to introduce the required methylene unit a- to the aldehyde 12 (2.13). The same transformation with the corresponding methyl ester, which is less acidic, requires prior enolization with a strong base (e.g. NaN(SiMe3)2) and subsequent quatemization of the tertiary amine with iodomethane and elimination using DBU. 

Peterson reactions of the lithium enolate 124 derived from N,N-dimethyl-(trimethylsilyl)acetamide with carbonyl compounds furnish the corresponding ,/ -unsaturated amides (Scheme 2.75) [210]. Although the amides are obtained in good yields in the reactions with ketones and with non-enolizable aldehydes, the reactions with enoli2able aldehydes give only negligible yields with predominant recovery of the starting amides. There appears to be little stereoselectivity in the... 

The modification of the Peterson reaction using an N-trimethylsilylamide anion instead of an a-silyl carbanion offers a promising route to the corresponding imines. Treatment of N-(p-tolyl)-N-trimethylsilylamide anion with carbonyl compounds yields the corresponding ketimines [400]. In particular, LiHMDS has been utilized for the preparation of N-trimethylsilylimines, which are useful as masked imine derivatives in the synthesis of yS-lactam antibiotics [401-407]. Reactions of LiHMDS with non-enolizable aldehydes, enolizable aldehydes, ketones, a diketone, and a-keto esters give the respective imines (Scheme 2.153) [408-413]. Chloro-trimethylsilane is added to convert the generated lithium trimethylsilanolate into hexamethyldisiloxane. 

The carbonyl group is accepting electrons in both the enolization step and the nucleophilic attack. The same compounds that are the most electrophilic are also the most easily enolizable. This makes acyl chlorides very enoUzable. To avoid nucleophilic attack, we cannot use chloride ion as base since chloride is not basic, so we must use a non-nucleophilic base such as a tertiary amine. The resulting enolate is not stable as it can eliminate chloride ion, a good leaving group, to form a ketene. This works particularly well in making dichloro-ketene from dichloroacetyl chloride as the proton to be removed is very acidic. 

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