Acylation of active-methylene compounds

Complications often arise when an acyl group is introduced into a compound containing an active methylene group this is because the acylated products are more acidic than the starting materials so that their further reaction is easier than that of the starting materials this problem has been discussed by Claisen.426 

The following procedure for preparation of ethyl oe-benzoylacetoacetate illustrates Claisen s technique 426 

Sodium (35.4 g) is dissolved in ethanol and the solution is made up to a known volume (600 ml). Half of this sodium ethoxide solution is mixed in the cold with ethyl acetoacetate (100 g) this mixture is cooled to 5° and stirred while benzoyl chloride (45 ml) is then added during about 15 min and the temperature is not allowed to exceed 10°. The solution is next set aside for 30 min, after which half of the residual sodium ethoxide solution (i.e., 150 ml) is added in one portion, followed, gradually this time, by benzoyl chloride (22.5 ml), and again the mixture is set aside for a short time. This procedure is repeated, each time with half the previous amounts of ethoxide and benzoyl chloride, until all the material has been added. Meanwhile a mixture of sodium chloride and ethyl sodiobenzoylacetoacetate has separated from the alcoholic solution. The final mixture is set aside for a further ca. 12 h in the cold, then the solids are filtered off and washed with ether. The wash-ether precipitates a further amount of sodium enolate from the filtrate and this is added to the main fraction of solids. The crude sodium enolate is briefly dried, then dissolved in a three-fold amount of water and treated, with ice-cooling, with acetic acid until no more oil is precipitated. This oily product is taken up in ether, dried over calcium chloride, and fractionated the desired ester has b.p. 175-176°/12 mm. 

Benzoylacetone can also be benzoylated by the method just detailed but the product, acetyldibenzoylmethane, is more conveniently obtained by another method due to Claisen 426 this second method can also be used for benzoylation of acetoacetic and malonic esters though the yields are there not as good the procedure is to treat a mixture of benzoyl chloride and benzoylacetone in boiling ether with anhydrous sodium carbonate, as follows  

Acetyldibenzoylmethane (2-benzoyl-l-phenyl-l,3-butanedione) Benzoylacetone (16.2 g) and benzoyl chloride (14 g) are dissolved in anhydrous ether (100 ml), finely powdered anhydrous sodium carbonate (32 g) is added, and the mixture is set aside in a flask fitted with a reflux condenser and protected from moisture. The ether begins to boil in a short time. The mixture is set aside at room temperature for about 16 h, then the mixture of sodium chloride,sodium carbonate, and sodium enolate is filtered off, washed with ether, and whilst still moist with ether is dissolved in water. The ether is removed in a current of air, and precipitation by acetic acid then affords very pure acetyldibenzoylmethane (10 g). A further amount of enolate can be extracted from the ethereal mother-liquor by 10 % sodium carbonate solution, the total yield amounting to 87% (14 g). The pure product melts at about 110° 427 

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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. 

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 of Active Methylene Compounds. Treatment of an acylimidazole, derived from a carboxylic acid and (1), with the magnesium salt of a malonic or methyhnalonic half thiol ester results in C-acylation under neutral conditions (eq 7)7 The presence of secondary hydroxyl functionality in the carboxylic acid is tolerated, but primary alcohols require protection. Magnesium salts of malonic esters may be used equally effectively. Intramolecular C-acylation of ketones has also been reported. ... 

Kobayashi, T. and Tanaka, M. (1986) Acylation of active methylene compounds via palladium complexcarbonylative cross-coupling of organic halides. Tetrahedron Letters, 27,4745-4748. 

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)... 

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. 

A substituent which appears to be even more readily displaced by nucleophiles than alkylsulfonyl groups is 0-mesyl (OSO CH ). Conversion of a cyclic lactam to its 0-mesyl derivative is accomplished by treatment with methanesulfonyl chloride/Et N in methylene chloride solution displacement takes place readily with dlmethylamine (15 min at 20 in dioxane). This may prove to be a generally useful procedure for replacement of lactam oxygen by other nucleophiles without resorting to intermediate chloro compounds. Note that 2-trlfluoromethanesulfonyloxypyridlne (from 2(lH)-pyridone, NaH, and trifluoromethanesulfonyl chloride) is an effective reagent for cile acylation of activated aromatic compounds with carboxylic acids. 

DEPC in combination with NEtj has proved to be a new efficient reagent for the direct C-formylation of active methylene compounds with carboxylic acids and also for the iV-acylation (peptide bond formation), 5-acylation (thioester formation) and O-acylation (esterification).4,5 Reaction of DEPC with carboxylic acids 11 in the presence of triethylamine produces transient acyl cyanides, which in the presence of alcohols or thiols results in the formation of the corresponding esters (12) or thioesters (13). 

The concept of naked anions, i.e. anions solubilized in non-solvating media by the crown complexation of their counter-cations, has been applied further this year. Naked fluoride ion has been used as a catalyst for Michael additions,such as the cyanoethylation of active methylene compounds, and also as a base to mediate the acylation (and protection) of the indole nitrogen of tryptophan in peptides. The selective cleavage of protected amino-acids from oxyacyl resins [equation (18)] is a... 

Cottrell et al. at Merck Sharp and Dohme Research Laboratories reported a mild procedure that used potassium carbonate in dimethyl sulfoxide. These conditions were compatible with highly functionalized benzyl azides, and extended the substrate scope of active methylene compounds to acetoacetone and benzoylacetone. This extension provided access to acyl-1,2,3-triazoles 21 for the first time via the Dimroth triazole synthesis. 

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]... 

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. 

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). 

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