Enolates acyl compounds

Coenzyme A is another adenine nucleotide derivative, with its primary functional group, a thiol, some distance away from the nucleotide end of the molecule. This thiol plays an important role in biochemistry via its ability to form thioesters with suitable acyl compounds (see Box 7.18). We have seen how thioesters are considerably more reactive than oxygen esters, with particular attention being paid to their improved ability to form enolate anions, coupled with thiolates being excellent leaving groups (see Box 10.8). 

Another important part of Organic 11 is carbonyl chemistry. We look at the basics of the carbonyls in Chapter 9. It s like a family reunion where 1 (John, one of your authors) grew up in North Carolina — everybody is related. You meet aldehydes, ketones, carboxylic acids, acyl chlorides, esters, cimides, and on and on. It s a quick peek, because later we go back and examine many of these in detail. For example, in Chapter 10 you study aldehydes and ketones, along with some of the amines, while in Chapter 11 we introduce you to other carbonyl compounds, enols and enolates, along with nitroalkanes and nitriles. 

We met ketenes in chapter 31 where they were intermediates in the Arndt-Eistert chain extension procedure. Now we are going to take a wider view of their value in synthesis. A ketene 1 is very electrophilic at the curious sp carbon atom (marked in 1) and combines with nucleophiles 2 to give enolates that are protonated at carbon 3 to give acylated compounds 4. 

Azetines 575, synthesized by the reaction of IV-acyl thiazolidinethione enolates with enolizable aldoxime ethers, have been successfully converted into the corresponding iV-acyl-substituted /3-aminocarbonyl compounds 576 by simple exposure to benzoyl chloride <2003JA3690>. The reactions presumably involved an acyliminium salt 577, which hydrolyzed to yield 576 (Scheme 74). 

A-factor is an optically active compound, but notice that one stereogenic centre is not specified in the structure (H with a wavy line). This is because it is a 1,3-dicarbonyl compound and is therefore in equilibrium with its stable enol which has a trigonal centre at that point. The obvious way to complete the synthesis is to acylate an enolate of the lactone with an acid chloride. 

An alternate approach to these useful 1,3-dicarbonyl substrates may be achieved through enolate orthoester acylation. Titanium enolates have been employed to effect this transformation (eq 19). Similarly, treatment of the titanium enolate of p-ketoimide with dioxolane orthoesters results in the formation of a masked tricarbonyl compound (eq 20). Trimethyl orthoacetate and Triethyl Orthoacetate are not appropriate partners in these coupling reactions. ... 

If the anodic oxidation of N-alkylanilines is performed in the presence of nucleophiles like enol ethers, nucleophilic substitution in the of-position to nitrogen by the enol ether can be observed in low yields. The electrophilic intermediate is the N-aryl iminium ion or the N-aryl imine after loss of two electrons and one or two protons. These intermediates add to the enol ether to give acetals (up to 26%) as addition products, or the first addition step is followed by an electrophilic aromatic substitution to form tetrahydroqui-nolines (13-39%) [47]. It should be noted at this point that better results for the nucleophilic a-substitution to nitrogen can be obtained with N,N-dialkylanilines (see next subsection). Optimum results, however, are obtained with N-acylated compounds via the intermediate N-acyl iminium ions (see Ref. 8). 

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... 

Complementary to the acylation of enolate anions is the acid-catalyzed acylation of the corresponding enols, where the regiochemistry of acylation can vary from that observed in base-catalyzed reactions. Although the reaction has been studied extensively in simple systems, it has not been widely used in the synthesis of complex molecules. The catalysts most frequently employed are boron trifluoride, aluminum chloride and some proton acids, and acid anhydrides are the most frequently used acylating agents. Reaction is thought to involve electrophilic attack on the enol of the ketone by a Lewis acid complex of the anhydride (Scheme 58). In the presence of a proton acid, the enol ester is probably the reactive nucleophile. In either case, the first formed 1,3-dicarbonyl compound is converted into its borofluoride complex, which may be decomposed to give the 3-d>ketone, sometimes isolated as its copper complex. 

Acylation Silyl enol ethers and ketene silyl acetals ate acylated to give 3-keto carbonyl compounds with CgFsNHsOTf as catalyst. 

FIGURE 19.24 A hydrogen at the a position of an acyl compound or nitrile is acidic and can he removed hy hase to give an enolate, or, in the case of nitriles, a resonance-stahUized species much like an enolate. 

Amides are the most resonance stabilized of acyl compounds and therefore the weakest acids. In an amide s polar resonance form it is the relatively electropositive nitrogen atom that bears the positive charge (Table 19.2 Fig. 19.25).Thus the polar form is relatively stable. There is no substantial chemistry of amide enolates. 

Enolates generated from iron acyl compounds such as 1 and 6 add readily to aldehydes. In order to achieve high levels of selectivity in these reactions it is necessary to exchange the lithium for another metal, such as aluminium(III), (which gives diastereoisomer 10) or tin(II) (which gives diastereoisomer 11) prior to addition of the aldehyde (Scheme 4.6). 

The most generally used carbonyl compounds for the acylation of enolate ions are esters. Here, nucleophilic addition of the anion to the carbonyl group is followed by loss of alkoxide from the tetrahedral intermediate. A classic example of this type of reaction is the Claisen condensation—the base-catalyzed self-condensation... 

Potassium Amides. The strong, extremely soluble, stable, and nonnucleophilic potassium amide base (42), potassium hexamethyldisilazane [40949-94-8] (KHMDS), KN [Si(CH2]2, pX = 28, has been developed and commercialized. KHMDS, ideal for regio/stereospecific deprotonation and enolization reactions for less acidic compounds, is available in both THF and toluene solutions. It has demonstrated benefits for reactions involving kinetic enolates (43), alkylation and acylation (44), Wittig reaction (45), epoxidation (46), Ireland-Claison rearrangement (47,48), isomerization (49,50), Darzen reaction (51), Dieckmann condensation (52), cyclization (53), chain and ring expansion (54,55), and elimination (56). 

The reaction of tnfluoromethyl-substituted A -acyl umnes toward nucleophiles in many aspects parallels that of the parent polyfluoro ketones Heteronucleophiles and carbon nucleophiles, such as enarmnes [37, 38], enol ethers [38, 39, 40], hydrogen cyanide [34], tnmethylsilylcarbomlnle [2,47], alkynes [42], electron-nch heterocycles [43], 1,3-dicarbonyl compounds [44], organolithium compounds [45, 46, 47, 48], and Gngnard compounds [49,50], readily undergo hydroxyalkylation with hexafluoroace-tone and amidoalkylation with acyl imines denved from hexafluoroacetone... 

Similarly, 1-alkylpyrroles, indoles, furans, thiophenes [60], a-picoline [61], enols, malonates [76], and organometallic compounds [56, 62] react with acyl imines of trifluoropyruvates to give derivatives of a-trifluoromethyl a-amino acids... 

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