Ketones substituted side

With unsymmetrical ketones, having hydrogens at both a-carbons, a mixture of products can be formed. In general such ketones react preferentially at the less substituted side, to give the less sterically hindered product. 

In the case of unsymmetrical ketones, the attack usually comes from the less highly substituted side, so that CH3 is more reactive than RCH2, and the R2CH group rarely attacks. As in the case of 10-118, this reaction has been used to effect cycliza-tion, especially to prepare five- and six-membered rings. Nitriles are frequently used instead of ketones, the products being 3-keto nitriles. 

When enamines are treated with alkyl halides, an alkylation occurs that is analogous to the first step of 12-14. Hydrolysis of the imine salt gives a ketone. Since the enamine is normally formed from a ketone (16-12), the net result is alkylation of the ketone at the a position. The method, known as the Stork enamine reaction is an alternative to the ketone alkylation considered at 10-105. The Stork method has the advantage that it generally leads almost exclusively to monoalkylation of the ketone, while 10-105, when applied to ketones, is difficult to stop with the introduction of just one alkyl group. Alkylation usually takes place on the less substituted side of the original ketone. The most commonly used amines are the cyclic amines piperidine, morpholine, and pyrrolidine. 

A mild metal-free a-iodi nation of ketones uses molecular iodine in a neutral reaction medium.296 Aliphatic ketones react predominantly on the more substituted side, with... 

But will any of this happen We want the ketone 2 to form the enolate, but won t the aldehyde 3 form an enolate more easily We want the enolate to form on the less substituted side of the ketone, but won t the conjugated enolate be more stable We want the enolate to attack the... 

Further selectivity is needed if the enol component is an unsymmetrical ketone. Some selectivity can be achieved by choice of acid, favouring the more substituted enol, or base, favouring kinetic enolate formation on the less substituted side. The acid 32 was used at a very early stage of Woodward and Eschenmoser s synthesis5 of vitamin Bi2. Standard a -unsaturated carbonyl disconnection revealed unsymmetrical ketone 33 and unenolisable but very electrophilic glyoxylic acid 34 available as its hydrate. In acid solution reaction occurred very selectively indeed. 

Disconnection of the 1,3-diCO relationship 37a gave the unsymmetrical ketone 38 and the unenolisable, symmetrical, and very electrophilic (again two carbonyl groups joined together very electrophilic) oxalate 23 R = Me. Now enolate formation needs to occur on the methyl group rather than the more substituted side. The answer was to use base. 

Another important contribution is to the regioselectivity of enolate formation from unsym-metrical ketones. As we established in chapter 13, ketones, particularly methyl ketones, form lithium enolates on the less substituted side. These compounds are excellent at aldol reactions even with enolisable aldehydes.15 An application of both thermodynamic and kinetic control is in the synthesis of the-gingerols, the flavouring principles of ginger, by Whiting.16... 

ZnBr2 also is an effective catalyst for the carbonyl insertion (Equation (75)).290 The Zn-catalyzed reaction is applicable to various aldehydes and ketones including aliphatic compounds. In sharp contrast to the Cu-catalyzed reaction, the carbonyl insertion occurs on the less substituted side with high regioselectivity. ZnBr2 most likely serves as electrophilic activation of carbonyl compounds. 

The situation is similar with cyclic boronates, which are prepared by the following procedure. Steroid (10 pmol) and the respective substituted boric acid (10 jumol) are dissolved in ethyl acetate (1 ml) and the mixture is allowed to stand for 5 min at room temperature. Under these conditions, 17,20-diols, 20,21-diols and 17,20,21-triols are converted completely into boronates. Cyclic boronate was mainly produced from 17,21-dihydroxy-20-ketone, but side-products also appeared, the formation of which could be suppressed by adding a 10% excess of the reagent [387—389]. Different substituents on the boron atom, such as methyl, n-butyl, tert.-butyl, cyclohexyl and phenyl, are interesting from the viewpoint of GC—MS application. They are further suitable for converting isolated hydroxyl groups into TMS or acetyl derivatives. 

We can add a useful piece of evidence to this weak-sounding explanation. The halogenation of an unsymmetrical dialkyl ketone gives different results in acid and in base. In base halogenation occurs preferentially on a methyl group, that is, on the less highly substituted side. In acid solution by contrast, halogenation occurs on the more substituted side of the carbonyl... 

If the ketone is unsymmetrical, this reaction will occur on the more substituted side, for the same reason that acid-catalysed enol bromination gives the more substituted a-bromocarbonyl compound (see the box on p. 536). 

This procedure avoids the difficulties we outlined earlier in the direct halogenation of aldehydes and ketones. It allows the preparation of haloketones on the less substituted side of the carbonyl group, for instance. 

To alkylate unsymmetrical ketones on more substituted side Me3SiCI, Et3N —> silyl enol ether with Sfvi 1-reactive alkylating agents... 

To alkylate unsymmetrical ketones on less substituted side LDA - kinetic lithium enolate with SN2-reactive electrophiles... 

We might consider using the lithium enolate or the silyl enol ether. As we need the kinetic enolate (the enolate formed on the less substituted side of the ketone), we shall be using the lithium enolate to make the silyl enol ether, so it would make sense to try that first. 

Unsymmetrical ketones often give a single product, even without the use of a specific enol equivalent, as reaction usually occurs on the less substituted side. This is another consequence of the final enolization being the irreversible step. In this example, both possible products may form, but only one of them can enolize. Under the equilibrating conditions of the reaction, only the enolate is stable, and all the material ends up as the isomer shown. 

Aza-enolates also react cleanly at carbon with acid chlorides. Good examples come from dimethyl-hydrazones of ketones. When the ketone is unsymmetrical, the aza-enolate forms on the less substituted side, even when the distinction is between primary and secondary carbons. The best of our previous regioselective acylations have distinguished only methyl from more highly substituted carbon atoms. 

After the first alkylation, the enamine prefers to re-form on the less substituted side so that the second alkylation occurs on the other side of the ketone from the first. The spirocyclic compound is further disfavoured as it would have a four-membered ring in this case. 

An efficient single-step synthesis of isoquinolines was achieved by a three-component reaction of aromatic ketone with benzylamine and alkyne. Rhodium (I) is used as the catalyst and o-functionalization of the aromatic rings is not necessary, indicating an extended scope for this method <03OL2759>. The reaction is complicated by a sizable amount of phenethyl-substituted side product. 

The most obvious way is a halogenation in add solution (Chapter 21) on the more substituted side of the ketone and elimination of HX in base. The double bond uhll prefer to go inside the ring and there is no argument about its stereoehcmistn. Typical bases would he tertiary amines o hindered alkoxides (c.g. t-RuO ). 

---