Enolates reaction, with acyl chlorides

Because of the contribution of structures such as the one on the right to the resonance hybrid, the a-carbon of an enamine is nucleophilic. However, an enamine is a much weaker nucleophile than an enolate anion. For it to react in the SN2 reaction, the alkyl halide electrophile must be very reactive (see Table 8.1). An enamine can also be used as a nucleophile in substitution reactions with acyl chlorides. The reactive electrophiles commonly used in reactions with enamines are ... 

In summary, reactions of nitronates with acid anhydrides or acyl chlorides give the O-acylated products, and reactions with acyl imidazoles, phenyl esters, acyl nitriles, and enol-lactones gives the C-acylated products, (see Eq. 5.13).25 The C/O selectivity of nitronate acylation by RCOX is qualitatively correlated with strength (pKJ of the acid HX conjugated to the leaving group X .25... 

Reactions of titanocene-methylidene generated from titanacyclobutanes with acyl chlorides 55 [46] or acid anhydrides 56 [47] lead initially to the titanium enolates 57 (Scheme 14.24), which then afford aldols upon treatment with the carbonyl compounds. On the other hand, five-membered cyclic anhydrides are methylenated with dimethyltitanocene (Table 14.5, entry 7) [45]. 

Scheme 14.24. Formation of titanium enolates by the reaction of titanacyclobutanes with acyl chlorides or acid anhyd rides.

Use of I was explored in a study of the reaction of enolates with acyl chlorides as a route to 1,3-diketones (equation I). 

Another important issue of this reaction is the variable stereochemical outcome obtained depending upon the solvent used, the temperature, and the sequence of addition of the reactants. These aspects have been carefully studied experimentally by Xu et al. [71-73] in a brilliant series of papers. In particular, since one method for the generation of ketenes consists of the reaction between acyl chlorides (12) and bases (usually tertiary bases such as triethylamine), the direct reaction between compounds (12) with imines (66) was investigated at the B3LYP/6-31G level of theory [52], Under these conditions, it was calculated that formation trans-fi-lactams (70) from enolates (69) is preferred, in agreement with the experimental results [74—76] and with the careful analysis of Xu et al. [72] (Scheme 16). 

Acyliron complexes have found many applications in organic synthesis [40]. Usually they are prepared by acylation of [CpFe(CO)2] with acyl chlorides or mixed anhydrides (Scheme 1.13). This procedure affords alkyl, aryl and a,P-unsaturated acyliron complexes. Alternatively, acyliron complexes can be obtained by treatment of [Fe(C5Me5)(CO)4]+ with organolithium reagents, a,P-Unsaturated acyliron complexes can be obtained by reaction of the same reagent with 2-alkyn-l-ols. Deprotonation of acyliron complexes with butyllithium generates the corresponding enolates, which can be functionalized by reaction with various electrophiles [40]. 

Silyl enolates react with acyl cation equivalents to give the C- and/or O-acylated products (Equation (90)).333 Fluoride-catalyzed reaction using acyl fluorides is valuable for O-acylation of silyl enolates derived from aldehydes and ketones.334 CuCl also promotes the 0-acylation with acyl chlorides.335 The CuCl-promoted reaction of ester silyl enolates results in exclusive (7-acylation. Combined use of BiCfl and Znl2 (or Nal) effects catalytic (7-acylation of ketone silyl enolates with acyl chlorides. 

We have spent some considerable time and effort in understanding the aldol reaction simply because it is one of the most important reactions in organic chemistry. In the next chapter you will see how these ideas can be extended with almost no addition of principles to the acylation of enolates—the reaction of enols, enolates, and specific enol equivalents with acid chlorides and esters. We hope that you will see that the ideas introduced in this chapter find immediate application in the next. 

Three reactions, which were known from the literature to be catalyzed by Lewis acids were selected as test reactions. A, was the Reetz alkylation of silyl enol ethers with -butyl chloride for which titanium tetrachloride is known to be useful [52]. B, was the Diels-Alder reaction between furan and acetylenedicarboxylic ester for which aluminium trichloride is a good catalyst [53]. C, was a Friedel-Crafts acylation for which aluminium trichloride is the preferred catalyst [54]. The reactions are summarized in Scheme 6. 

The escape route from this difficulty suggested in the chapter was to use a magnesium er Magnesium is chelated by the two oxygen atoms of the stable enolate and blocks reaction at C-Acylation occurs even with acyl chlorides. 

Owing to the active hydrogen atoms at C-4 in 3,5-pyrazolidinediones various substitutions at C-4 can be accomplished. Reaction with acid chlorides in the presence of aluminum chloride gives 4-acyl-3,5-pyrazolidinediones.919,976 However, if two groups are already present at C-4, the enolic form of the dione is acylated on the oxygen atom to give 3-acyloxy-2-pyrazolin-5-ones.998 Treatment of 3,5-pyrazolidinediones with nitrous acid gives nitrosation at C-4.976 The nitroso... 

Having streamlined the synthesis of acyl chloride 54, the indirect preparation of methyl enol ester 51a was addressed. As previously discussed, attempts to synthesize 53a from formyl Meldrum s acid 58 had proven unsuccessful. However, Cossy and coworkers have reported the preparation of 53a via the ozonolysis of alkene 82 and subsequent use of the crude aldehyde in the total synthesis of octalactin. Thus, methyl vinyl acetate (82) was subjected to ozonolysis at —78 °C, followed by a reductive quench to provide formyl acetate 53a (Scheme 24). The crude methyl formyl acetate was acylated with acyl chloride 54, using the previously optimized conditions, to afford methyl enol ester 51a in 74% yield over two steps. This modification to the synthesis removes a further two reactions from the sequence with a formal synthesis of (—)-7-deoxyloganin (24) now achieved in 10 steps, a length more in keeping with the complexity of this target. 

Anions obtained from acetoacetic esters undergo acylation when they are treated with acyl chlorides or acid anhydrides. Because both of these acylating agents react with alcohols, acylation reactions cannot be carried out in ethanol and must be carried out in aptotic solvents such as DMF or DMSO (Section 6.13C). (If the reaction were to be carried out in ethanol, using sodium ethoxide, for example, then the acyl chloride would be rapidly converted to an ethyl ester and the ethoxide ion would be neutralized.) Sodium hydride can be used to generate the enolate ion in an aptotic solvent ... 

Although the reaction of enol silyl ethers with acid chlorides and anhydrides provides jS-diketones in good yields, the reaction with acyl cyanides has now been reported to give jS-ketocyanohydrins (22), which can be further elaborated to -diketones or unsaturated ketonitriles (Scheme 24). 

Reaction with Acyl Derivatives. Enolate (1) does not react with ethyl acetate or iV,iV-dimethylacetamide, and gives a complicated mixture of products with acetyl chloride. However, (1) is acetylated with acetylimidazole to give the lithium enolate of f-butyl acetoacetate (eq 5). ... 

Monoprotected P-keto-aldehydes may be prepared by the a-dialkoxymethyl-ation of pre-formed enolates or enamines with trimethyl orthoformate and boron trifluoride diethyl etherate. Regiospecificity is maintained when the enolate is released from the silyl enol ether with methyl-lithium. P-Keto-acetals or P-diketones may also be formed by acylation of enol ethers with acid chlorides. High yields depended on the use of activated acid chlorides, such as a-halo- or a-cyano-acetyl chlorides. Enaminosilanes are acylated by a wide range of acid chlorides in the presence of potassium fluoride and a crown ether, giving very high yields of the enaminone [equation (46)]. Under the reaction conditions,... 

The Pd(PhCN)2Cl2-catalyzed reaction of silacyclobutanes with acyl chlorides afforded cyclic silyl enol ethers possibly via a... 

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