Carbonyl compounds Keto acids, Ketones, «?, /?-Unsaturated

Most solid-phase syntheses of pyrazoles are based on the cyclocondensation of hydrazines with suitable 1,3-dielectrophiles. The reported examples include the reaction of hydrazines with support-bound a,(3-unsaturated ketones, 1,3-diketones, 3-keto esters, a-(cyano)carbonyl compounds, and a, 3-unsaturated nitriles (Table 15.19). Pyrazoles have also been prepared from polystyrene-bound 3-(hydrazino)esters, which are generated by the addition of ester enolates to hydrazones (Entry 7, Table 15.19 see also Section 10.3). Benzopyrazoles can be prepared from support-bound hydra-zones using the reaction sequence outlined in Figure 15.11. Oxidation of a polystyrene-bound benzophenone hydrazone yields an a-(acyloxy)azo compound. Upon treatment with a Lewis acid, this intermediate is converted into a 1,2-diazaallyl cation,... 

The most commonly used protected derivatives of aldehydes and ketones are 1,3-dioxolanes and 1,3-oxathiolanes. They are obtained from the carbonyl compounds and 1,2-ethanediol or 2-mercaptoethanol, respectively, in aprotic solvents and in the presence of catalysts, e.g. BF, (L.F. Fieser, 1954 G.E. Wilson, Jr., 1968), and water scavengers, e.g. orthoesters (P. Doyle. 1965). Acid-catalyzed exchange dioxolanation with dioxolanes of low boiling ketones, e.g. acetone, which are distilled during the reaction, can also be applied (H. J. Dauben, Jr., 1954). Selective monoketalization of diketones is often used with good success (C. Mercier, 1973). Even from diketones with two keto groups of very similar reactivity monoketals may be obtained by repeated acid-catalyzed equilibration (W.S. Johnson, 1962 A.G. Hortmann, 1969). Most aldehydes are easily converted into acetals. The ketalization of ketones is more difficult for sterical reasons and often requires long reaction times at elevated temperatures. a, -Unsaturated ketones react more slowly than saturated ketones. 2-Mercaptoethanol is more reactive than 1,2-ethanediol (J. Romo, 1951 C. Djerassi, 1952 G.E. Wilson, Jr., 1968). 

These reversible reactions are cataly2ed by bases or acids, such as 2iac chloride and aluminum isopropoxide, or by anion-exchange resias. Ultrasonic vibrations improve the reaction rate and yield. Reaction of aromatic aldehydes or ketones with nitroparaffins yields either the nitro alcohol or the nitro olefin, depending on the catalyst. Conjugated unsaturated aldehydes or ketones and nitroparaffins (Michael addition) yield nitro-substituted carbonyl compounds rather than nitro alcohols. Condensation with keto esters gives the substituted nitro alcohols (37) keto aldehydes react preferentially at the aldehyde function. 

The carbon alpha to the carbonyl of aldehydes and ketones can act as a nucleophile in reactions with other electrophilic compounds or intermolecu-larly with itself. The nucleophilic character is imparted via the keto-enol tau-tomerism. A classic example of this reactivity is seen in the aldol condensation (41), as shown in Figure 23. Note that the aldol condensation is potentially reversible (retro-aldol), and compounds containing a carbonyl with a hydroxyl at the (3-position will often undergo the retro-aldol reaction. The aldol condensation reaction is catalyzed by both acids and bases. Aldol products undergo a reversible dehydration reaction (Fig. 23) that is acid or base catalyzed. The dehydration proceeds through an enol intermediate to form the a,(3-unsaturated carbonyl containing compound. 

Horner-Wadsworth-Emmons reactions are C—C-forming condensation reactions between the Li, Na, or K salt of a /J-keto- or an -(alkoxycarbonyl)phosphonic acid dialkyl ester and a carbonyl compound (cf. Figure 4.41). These reactions furnish a,f)-unsaturated ketones or a j8-unsaturated esters, respectively, as the desired products and a phosphoric acid diester anion as a water-soluble by-product. In general, starting from aldehydes, the desired compounds are produced fraus-selectively or in the case of olefins with trisubstituted C—C double bonds -selectively. 

The oxidation of a, -unsaturated carbonyl compounds under the usual conditions in DMF using PdCl2/CuCl/02 is very slow. However, regioselective oxidation of a, -unsaturated esters to 3-keto esters (equation IS), and a,3-unsaturated ketones to 1,3-diketones (equation 16) proceeds with NazPdCU in solvents such as S0% acetic acid, isc ropyl alcohol, and NMP. r-Butyl hydroperoxide and hydrogen peroxide are used as the reoxidants of the reduced palladium. The reaction proceeds slowly at room temperature but smoothly between SO and 80 C. Some typical examples of this process are shown in Table 1. 

Carbonyl compounds are in a rapid equilibrium with their enols, a process called keto-enol tautomerism. Although enol tautomers are normally present to only a small extent at equilibrium and can t usually be isolated in pure form, they nevertheless contain a highly nucleophilic double bond and react with electrophiles, for example, aldehydes and ketones are rapidly halogenated at the a position by reaction with CI2 Br2, or I2 in acetic acid solution. Alpha bromination of carboxylic acids can be similarly accomplished by the Hell-Volhard-Zelinskii (HVZ) reaction, in which an acid is treated with Bi and PHr3. The a-halogenated products can then undergo base-induced E2 elimination to yield ,jS-unsaturated carbonyl compounds. 

More complex products are obtained from cyclizations in which the oxidizable functionality and the alkene are present in the same molecule. y9-Keto esters have been used extensively for Mn(III)-based oxidative cyclizations and react with Mn(OAc)3 at room temperature or slightly above [4, 10, 11, 15], They may be cyclic or acyclic and may be a-unsubstituted or may contain an a-alkyl or chloro substituent. Cycloalkanones are formed if the unsaturated chain is attached to the ketone. y-Lactones are formed from allylic acetoacetates [10, 11]. Less acidic /3-keto amides have recently been used for the formation of lactams or cycloalkanones [37]. Malonic esters have also been widely used and form radicals at 60-80 °C. Cycloalkanes are formed if an unsaturated chain is attached to the a-position. y-Lactones are formed from allylic malonates [10, 11]. yff-Diketones have been used with some success for cyclizations to both alkenes and aromatic rings [10, 11]. Other acidic carbonyl compounds such as fi-keto acids, /3-keto sulfoxides, j8-keto sulfones, and P-nitro ketones have seen limited use [10, 11]. We have recently found that oxidative cyclizations of unsaturated ketones can be carried out in high yield in acetic acid at 80 °C if the ketone selectively enolizes to one side and the product cannot enolize... 

A rise in free fatty acids may also cause changes in the flavour components. Increased P-oxidation of the free fatty acids leads to P-keto acids which are decarboxylated to methyl ketones. There are also increases in unsaturated aldehydes, especially 2-enals and 2,4-dienals, probably formed by oxidation of unsaturated fatty acids. This marked increase in carbonyls and unsaturated aldehydes may cause a significant alteration in the flavour, as these compounds have considerable organoleptic properties. 

In general, binol-derived phosphoric acids are not good catalysts for the activation of simple carbonyl compounds such as aromatic, aliphatic, or a,p-unsaturated aldehydes or ketones [159]. In order to overcome these limitations, Nakashima and Yamamoto in 2006 [160] synthesized binol-derived A-trifyl phosphoramides (Figure 2.37). These compounds are 10 times more acidic than the corresponding phosphoric acids [157], a fact that can account for their higher catalytic efficiencies in reactions involving unsaturated ketones[160] or (3-keto esters [161]. 

Base- and acid-catalyzed aldol reactions of aldehydes generally lead to useful amounts of aldol product, the p-keto alcohol, or the product of dehydration, the a,P-unsaturated carbonyl compound. Aldol reactions of ketones are less useful because equilibrium does not usually favor product. Special techniques can be used (Soxhlet extractor) to thwart thermodynamics. If dehydration to the a,P-unsaturated carbonyl compound occurs, as it often does in acid-catalyzed aldols, the reaction may be practically successful. 

Silylation Reactions. In the presence of a catalytic amount of tetra-n-butylammonium fluoride (TBAF), ester (1) is a very efficient silylating agent for a wide variety of substrates including carbonyl compounds, alcohols, phenols, carboxylic acids, and alkynes. With unsymmetrical ketones the kinetic enol ether is the preferred product. Indeed, the use of (1) can provide superior selectivity to the use of hindered bases forenolate formation. This is illustrated with a 8,y-epoxy ester which provides an entry to /-keto-a, 8-unsaturated esters (eq 2). These silylation reactions of (1) can also be catalyzed by TBAF supported on silica. ... 

Diethyl trimethylsilyloxycarbonylmethanephosphonate" and diethyl car-boxymethanephosphonate " are the preferred reagents for the two-carbon homologation of aldehydes and ketones to give a,/8-unsaturated carboxylic acids, while 2,2-difluoro-l-tosylvinyl-lithium is a novel effective reagent for the preparation of a-keto-acids from carbonyl compounds (Scheme 21). a-Methoxy-aliphatic acids have been prepared from aliphatic aldehydes and chloroform using... 

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