Active-methylene compounds, acylation

Alkyl- and arylmercury(II) halides are used for the ketone formation[402]. When active methylene compounds. such as /f-keto esters or malonates are used instead of alcohols, acylated / -keto esters and malonates 546 are produced, For this reaction, dppf is a good ligand[403]. The intramolecular version of the reaction proceeds by trapping the acylpalladium intermediate with eno-late to give five- and six-membered rings smoothly. Formation of 547 by intramolecular trapping with malonate is an example[404]. 

Another well-established process to generate fluoro ketones proceeds via acylation ofenolates [68, 69] or activated methylene compounds [70 71] as well as by Claisen type condensation reactions [72] Because of the electrophilic power of the acylating agents, there is usually no need tor a catalyst [68]... 

Although most acylations of active methylene compounds are base catalysed, the acylations of ketones carried out with acetic anhydride take place best in presence of BF3. Acetone is converted to acetylacetone. 

The enolate ions of acetoacetic ester and other active methylene compounds react with 0-propiolactone to give the ethoxycarbonyl derivative, but the yields are generally not high. Application of this reaction to 2-ethoxycarbonyldodecanone (equation 53) has been recently patented, with the product reported to be a useful perfume intermediate (77JAP(K)77133952). The reaction is used quite widely with diketene, which gives C-acylation rather than alkylation of the enolate ion, followed by cyclization (72CPB1574). 

Most other carboxylic acid derivatives can acylate only ketone enolates that are formed quantitatively. In these reactions, the acylation product is a /J-diketone, i.e., an active-methylene compound. As a consequence it is so acidic that it will be deprotonated quantitatively. This deprotonation will be effected by the ketone enolate. Therefore, a complete acylation of this type can be achieved only if two equivalents of the ketone enolate are reacted with one equivalent of the acylating agent. Of course, proceeding in that manner would mean an unacceptable waste in the case of a valuable ketone. 

When the enolate of an active-methylene compound undergoes acylation with a carboxylic acid chloride, an active-methyne compound is formed initially (Figure 13.65, 13.66). If the electron acceptors therein are solely acyl- or (alkoxycarbonyl) groups, the substructure mentioned suffers from steric hindrance and substantial electrostatic repulsion forces. Active-methyne compounds with such a substitution pattern will react to alleviate this destabilization. 

The active-methyne compounds, which derive from the acylation of the enolates of active-methylene compounds with carboxylic acid chlorides, eliminate the extra acceptor(s) in an additional step or immediately in situ. The defunctionalizations involved include one or two decaboxylations depending on the nature of the reactants and subsequent processing steps (Figures 13.66 and 13.67)... 

Dithiolylium cations (see Chapter 4.31) unsubstituted on the 3- or 5-position react with active methylene compounds, in most cases with simultaneous oxidation, as shown in equation (15). This reaction has been performed with a large variety of ketones, acylic or cyclic, /3-diketones, /3-keto dithioesters and a-cyano ketones (71AHC(13)161,pp. 174,188, 80AHC(27)151,p. 183). 

C-Acylation. C-Acylation of active methylene compounds is usually conducted under basic conditions. Masamune et al. have developed a new method for conducting this reaction under neutral conditions that is patterned on the enzymic synthesis of fatty acids. The acylating reagent is the imidazolide of a carboxylic acid (1) prepared in situ. The substrate is the neutral magnesium salt of a mono ester or thioester of a malonic acid (2), prepared with magnesium ethoxide. The reaction of 2 with 1 is conducted in THF at 25-35° for 18-24 hours the yield of products (3) is generally >85%. ... 

C-Acylation. Active methylene compounds can be C-acylated directly by carboxylic acids with diethyl phosphorocyanidate (1) in combination with tri-ethylamine. DMF is the preferred solvent TMEDA or DBU can replace tri-ethylamine. ... 

Japp-Klingemann reaction. Formation of hydrazones by coupling of aryldiazonium salts with active methylene compounds in which at least one of the activating groups is acyl or carboxyl. This group usually cleaves during the process. 

When active methine compounds were used instead of active methylene compounds, 1,2-dia-cylcyclopropanes 10 were obtained. The mechanism involves migration of an acyl group. 

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