Problems with acylation at carbon

The main problem with the acylation of enolates is that reaction tends to occur at oxygen rather than at carbon. 

The product of acylation on oxygen is an enol ester. The tendency to attack through oxygen is most marked with reactive enolates and reactive acylating agents. The combination of a lithium enolate and an acid chloride, for example, is pretty certain to give an enol ester. 

You have seen reaction at oxygen before, Enolates react on oxygen with silicon electrophiles and we found the products, silyl enol ethers, useful in further reactions. Enol esters also have their uses—as precursors of lithium enolates, for example. You saw one being used like this on p. 683, 

We introduced this chapter with an example of the second type of reaction, and we shall continue with a more detailed consideration of the Claisen ester condensation and related reactions. 

In Chapter 27, we mentioned no trouble with reaction at oxygen in the aldol reaction. This may now seem surprising, in view of what we have said about esters, as the electrophiles were aldehydes and ketones—not so very different from esters. We can resolve this by looking at what would happen if an aldehyde did attack an enolate on the oxygen atom. 

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We should not leave the subject of acylation at carbon without considering a problem that affects all such reactions to some degree. It can be understood most easily if we imagine some functional group Z that is able to stabilize a carbanion, and the acylation of that car-banion with an acid chloride—something like this. 

Alkylation at carbon, problems with enamines Application to the synthesis oflipoic acid Alkylation with tertiary alkyl groups Acylation at Carbon... 

Acylation at carbon is always a difficult problem because the product (usually an aldehyde or ketone) may be more reactive than the acylating agents in two ways more electrophilic at the carbonyl group and more acidic because of enolisation. Nitriles often perform well in the acylation of RLi or RMgBr, and the reaction of lithium salts of carboxylic acids with RLi is a strategy already discussed in chapter 2. Both these methods rely on the product being released during the work-up after all RLi is quenched. One example is the cyclopropyl ketone 34 needed by... 

The reaction steps are reversible and isomerization of the olefin, alkyl, or acyl species can take place to allow the formation of isoaldehydes. The typical 4 1 prodnct distribntion of normal and isoaldehydes mnst be separated if the mixture cannot be nsed commercially. Efforts were therefore made to increase the proportion of nseful normal aldehydes during operation. Partial success was achieved by operating at lower temperatures with higher carbon monoxide partial presstrres, althongh this decreased conversion to aldehydes. A major problem with the cobalt catalyst was the tendency to decompose at high temperatrrre and to deposit metal onto the reactor walls. This led to loss of activity and low catalyst recovery. 

The tautomeric character of the pyrazolones is also illustrated by the mixture of products isolated after certain reactions. Thus alkylation normally takes place at C, but on occasion it is accompanied by alkylation on O and N. Similar problems can arise during acylation and carbamoylation reactions, which also favor C. Pyrazolones react with aldehydes and ketones at to form a carbon—carbon double bond, eg (41). Coupling takes place when pyrazolones react with diazonium salts to produce azo compounds, eg (42). 

Anions derived from malonates are ambident nucleophiles, which can react at the carbon or oxygen atom. Therefore, carbon-carbon bond-forming reactions by alkylation or acylation of enolates have been encountered with difficulties. Side reactions which may cause problems are the above-mentioned competiting O-reaction and dialkylation . 

In chapters 19 (1,3-diCO) and 21 (1,5-diCO) we were able to use an enol(ate) as the carbon nucleophile when we made our disconnection of a bond between the two carbonyl groups. Now we have moved to the even-numbered relationship 1,2-diCO this is not possible. In the simple cases of a 1,2-diketone 1 or an a-hydroxy-ketone 4, there is only one C-C bond between the functionalised carbons so, while we can use an acid derivative 3 or an aldehyde 5 for one half of the molecule, we are forced to use a synthon of unnatural polarity, the acyl anion 2 for the other half. We shall start this chapter with a look at acyl anion equivalents (d1 reagents) and progress to alternative strategies that avoid rather than solve the problem. 

Several alternative procedures have been proposed to address this serious problem, a very simple one being changes in the reaction conditions. In fact, the amount of side product is substantially reduced when a slight excess of amino acid over acylating agent (1.25 equiv) and sodium carbonate (4 equiv) are used with a minimum amount of dioxane and with vigorous stirring at room temperature. This procedure, however, cannot be applied with hydrophobic amino acids such as leucine or vahne.t l Acylation of amino acids with 9-fluorenylmethyl azidoformate (Fmoc-N3, 18, prepared from Fmoc-Cl and pre-... 

The nitrogen atom in a-ferrocenylalkylamines generally shows the same reaction pattern as that in other amines alkylation and acylation do not provide synthetic problems. Due to the high stability of the a-ferrocenylalkyl carbocations, ammonium salts readily lose amine and are, therefore, important synthetic intermediates. Acylation of primary amines with esters of formic acid gives the formamides, which can be dehydrated to isocyanides by the standard POClj/diisopropylamine technique (Fig. 4-16) [92]. Chiral isocyanides are obtained from chiral amines without any racemization during the reaction sequence. The isocyanides undergo normal a-addition at the isocyanide carbon, but could not be deprotonated at the a-carbon by even strong bases. This deviation from the normal reactivity of isocyanides prompted us to study the electrochemistry of these compounds, but no abnormal redox behaviour, compared with that of other ferrocene derivatives, was detected [93]. The isocyanides form chromium pentacarbonyl complexes on treatment with Cr(CO)s(THF) (Fig. 4-16) and electrochemistry demonstrated that there is no electronic interaction between the two metal centres. 

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