C-acylation of enols and enolates

The danger we have to face is that acylation is inclined to occur on oxygen rather than on carbon. In the extreme case, naked enolates (those with completely non-coordinating cations) acylate cleanly on oxygen with anhydrides or acid chlorides. 

Hydrolysis and decarboxylation in the usual way lead to keto-esters or keto-acids. Of the more common metals used to form enolates, lithium is the most likely to give good C-acylation as it, like magnesium, forms a strong O-Li bond. It is possible to acylate simple lithium enolates with enoliz-able add chlorides. 

We shall describe two examples of this reaction being used as part of the synthesis of natural products. The first is pallescensin A, a metabolite of a sponge. 

It is quite a simple compound and some chemists in Milan conceived that it might be made from the chloro-diketone shown below by alkylation of the enolate and subsequent reduction and dehydration of the remaining ketone. 

To test this idea, the chloro-diketone must be made and the route chosen was to react the lithium enolate of 4-t-butyl cyclohexanone with the correct acid chloride. 

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The combination of fluoride ions and enol silyl ethers provides a useful method for the generation of enolate anions [9]. Watts, Haswell and coworkers applied a borosilicate glass microreactor, having channel dimensions of 100 pm x 50 pm and equipped with an electrosmotic flow (EOF) pumping system, to the C-acylation of enolate anions, which leads to 1,3-diketones [10,11]. A THF solution of tetrabutyl-ammonium fluoride (TBAF) was placed in reservoir A, a THF solution of benzoyl... 

Scheme 3.62 C-acylation of enolates by methyl cyanoformate examination of site- and stereoselectivity.

Undesirable intermolecular reactions can be avoided during certain synthetic conversions. Thus it is often useful to carry out C-alkylation and C-acylation of compounds that form enolate anions, for example, esters with a-hydrogens. Such reactions are often complicated by self-condensation since the enolate anion can attack the carbonyl group of a second ester molecule. Attachment of the enolizable ester to a polymer support at low loading levels allows the alkylation and acylation reactions (Eq. 9-79) to be performed under... 

A novel base-catalyzed Fries-like rearrangement of a 3-acetoxythiophene has been reported (Scheme 149) (79JOC3292). This has been explained as the result of iodide-induced deacylation and subsequent C-acylation of the intermediate enolate anion. Some transformations of 4-hydroxy-2-methylthiophene-3-carboxylic ester are shown in Scheme 150 (69KGS567,75KGS914,71KGS759). 

C-Acylations of C,H-acidic compounds have also been realized on insoluble supports. The few examples that have been reported include the C-acylation of support-bound ester enolates with acyl halides [9], Claisen condensations of polystyrene-bound ketones with benzoic acid esters, the C-acylation of nitriles with acyl nitriles or anhydrides, and the C-acylation of phosphonates with acyl halides (Entries 5-9, Table... 

Tsang, R, Fraser-Reid, B, O- and C-Acylation of some carbohydrate enolates, J. Chem. Soc., Chem. Commun., 60-62, 1984. 

Magnesium or lithium enolates of thiol carboxylic esters can be acylated with suitable reagents (c/ Volume 2, Part 1). Highly functionalized new derivatives are obtained. The example shown in equation (35)33,102 J5 closely related to the C-acylation of malonyl-CoA with acetyl-CoA, which plays an important role in the biosynthesis of polypeptides and fatty acids. (S)-4-Hydroxy-5-methyl-3-oxo-hexanoyl-L-leucine esters (41), 2-demethyl analogs of the Hip-Leu moiety of didemnin antibiotics, can be prepared via the 3-keto thiol carboxylic esters (40 equation 36). ° ... 

TRIFLUORO-2-BUTYNOATE. C-Acylation of an enolate using methyl cyanoformate provides a convenient source of the a-carbometh-oxyoctalone, METHYL (la,4Ap,8Aa)-2-OXO-DECAHYDRO-l-NAPH-THOATE and represents a good example of generating jS-keto esters under mild conditions. The nitrone functionality is featured in a procedure which makes it in a single step from secondary amines and 6-METHYL-2,3,4,5-TETRAHYDROPYRIDINE N-OXIDE is the example described. Finally, the synthesis of phospholes l-PHENYL-2,3,4,5-TETRAMETHYLPHOS-PHOLE is described as an example of the versatility of zirconocene chemistry. 

Alkylation of enolate anions usually gives C-alkylation and is therefore not suitable for the preparation of enol ethers. The exception is when triethyloxonium tetrafluoroborate is used as the alkylating agent in a dipolar aprotic solvent. 0-Alkylation can be regioselectiveiy achieved if the enolate anion is derived from acetoacetate or a similar compound. On the other hand, 0-acylation of enols or enolate anions is quite common. Enol esters can therefore be prepared readily from the parent carbonyl compounds. For... 

Formation of the unexpected oxazolidinone in G18 proved to be crucial because models showed that direct C-acylation of the C-9 enolate derived from G17 was sterically disfavored. However, treatment of G18 with sodium meth-oxide did afford lactone G20 in 70% yield. Enolate G19 is postulated as the intermediate, and as in the case of the actinobolin analogue (E8, Scheme 18), regioisomeric enolization at C-7 is of no consequence, since acylation at that site is a less favored reaction. 

The reaction of an enolate with an acylating reagent often leads to the formation of a mixture of O- and C-acylated products 4]. Therefore, a large amount of work has been undertaken to explore and understand the reaction conditions that promote the regioselective acylation of enolates [5,6]. Microflow reactors have also been used for selective O- and C-acylation. The reaction of the silyl enol ether of acetophenone with benzoyl fluoride using a microflow reactor under EOF conditions selectively gives the... 

Preparing a- and 3-ketimines is often not easy, and two new routes for their synthesis now add to the available methodology for the synthesis of these sometimes useful compounds. a-Ketimines were the unexpected products of the reaction between a,a-dibromo-ketones and primary amines, and P-ketimines result in good yield from the selective C-acylation of enaminosilanes (nitrogen analogues of silyl enol ethers) with simple acid chlorides in the presence of potassium fluoride (Scheme 48). ... 

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