5-Acyl meldrum acid

Thermal fragmentation of l,3-dioxin-4-ones or acylated Meldrum acids with generation of a-oxoketenes, hetero Diels-Alder reactions of the latter, and their transformations into lactones and lactams, among them macrocyclic 99YGK76. 

In 2000, an efficient three-step procedure for the synthesis of 5-substituted 3-isoxazolols (without formation of undesired 5-isoxazolone byproduct) was published. The method uses an activated carboxylic acid derivative to acylate Meldrum s acid, which is treated with A,0-bis(ten-butoxycarbonyl)hydroxylamine to provide the N,0-di-Boc-protected P-keto hydroxamic acids 14. Cyclization to the corresponding 5-substituted 3-isoxazolols 15 occurs upon treatment with hydrochloric acid in 76-99% yield. 

This method has been extended to include imines other than A -thia-zolines, hence enabling the synthesis of multi ring-fused 2-pyridones (28,30, and 33, Scheme 8). Thus, by reacting dihydroisoquinoUnes 27 or /1-carboUnes 29 with acyl Meldrum s acid derivatives 24, a set of new ring-fused heterocycles was prepared in moderate to excellent yields (a and b. Scheme 8). These systems were prepared by using trifluoro acetic acid (TFA) as a proton source instead of solutions saturated with HCl (g). The switch of acid proved to be advantageous since it reduced the formation of by-products and increased the isolated yields. From a practical point of view, TFA is also su-... 

Scheme 7 Synthesis of AT-(oxoacyl)-L-HSL via 5-acylated Meldrum s acid...

The acylated Meldrum s acid approach has also been used by Shaefer et al. [57] and recently by Reverchon and coworkers [53] to prepare novel synthetic AT-(3-oxoacyl)-L-HSL derivatives with their acyl side-chain modified by introducing unsaturation, ramified alkyl, cycloalkyl 18 or aryl 19 substituents at the C-4 position. 

Acyl Meldrum s acids (83TH1 87TH1), easily accessible from carboxylic acid chlorides and Meldrum s acid, may be viewed as protected 3-oxo-carboxylic acid esters (78JOC2087). The latter offer the advantage... 

With diketene, intermediates of type (III) were isolated and subsequently cyclized under basic conditions following step (b). In the case of 3-oxo-carboxylic acid esters or 3-acyl Meldrum s acids, cyclization step (b) immediately follows reaction step (a), if a slight excess of amine is employed (85TH1 87TH1). Note that conversion of (III) to (V) involves the (IH)-enol (Table I cf. 75BSF2731). The relatively low yield in the case of malonic acid ester, as well as the failure of the reaction with the non-enolizable diphenyl phosphinylacetic ester and cyanoacetate, points to the participation of an enol structure of (III). 

Nu = alcohol, amine Scheme 5.13 Preparation of P-keto esters and amides from acyl Meldrum s acids... 

At the time this work was carried out, the mechanistic basis for the conversion of acyl Meldrum s acid adducts to corresponding P-keto esters/amides such as 25 was not well understood [16] . The IR method used to determine the nature of the protonation state of 24 presented an excellent opportunity to perform kinetic studies. These studies [17] showed that the reaction of 24 with amine nucleophile 3 was pseudo zero order in the anionic form 24. The reaction kobs was almost the same in the one-pot process as when the isolated 24 was used. This was consistent with the rate-determining step being the formation of the a-oxoketene intermediate 26 (Scheme 5.15). 

The mechanism involving acyl Meldrum s acids in solution was never clarified. Several proposed reaction pathways are often found in the same publication. 

B. and C. 2-Methyl-4H-pyran-4-one. A 1000-mL, round-bottomed flask equipped with a stir bar and a reflux condenser is charged with the crude acylated Meldrum s acid, 80 mL of butyl vinyl ether and 287 mL of toluene (or benzene) (Note 6). The reaction mixture is heated to 80°C for 7 hr (Note 7). The volatile components are removed under reduced pressure to yield 31.81 g of product (Note 8). To the residue are added 765 mL of tetrahydofuran, 191 mL of water and 2.7 g of p-toluenesulfonic acid. The mixture is heated to reflux for 18 hr, then the reaction is quenched with 10 g of solid sodium bicarbonate and allowed to stir for 15 min at 25°C (Note 9). The mixture is filtered to remove the sodium bicarbonate and the volatile components are removed under reduced pressure. The residue is dissolved in 500 mL of methylene chloride, placed in a separatory funnel and washed with 200 mL of water and 200 mL of brine solution. The aqueous layers are collected and extracted with methylene chloride (2 x 200 mL). The organic layers are combined, dried over 20 g of sodium sulfate for 1 hr, filtered into a 1000-mL, round-bottomed flask, and concentrated under reduced pressure. The resulting red oil is purified by chromatography using a 6-cm diameter glass column packed with 400 g of silica gel... 

Reaction times vary depending on scale. For optimum results the consumption of the acylated Meldrum s acid is monitored by TLC. 

Acylated Meldrum s Acid Pyrandione Pyrone (Yield)... 

Heterocycles. Indoles can be prepared by reaction of phenylhydroxylamine with an acyl Meldrum s acid (1) in refluxing CH3CN to give a product (2), which forms a 2-substituted indole (3) on treatment with another acyl Meldrum s acid (1).1 Example ... 

Keto acids and 2-alkyl- or 2-arylmalonic acids readily decarboxylate, and acylations with these proceed satisfactorily only at low temperatures. An alternative to direct acylation with /3-keto acids is thermolysis of acyl Meldrum s add (to generate an acylketene) in the presence of a nucleophile (Scheme 7.7). Esters of /J-keto acids can also be conveniently prepared from other keto esters by transesterification [27, 28],... 

Enol ethers add to acylated Meldrum s acid derivatives 729 to form the intermediate 3-methylenedihydro-2//-pyran-2,4(3//)-diones 730, which are converted into pyran-4-ones upon treatment with />-TSA (Scheme 182) <1996TL6499>. Likewise, 3,4-dihydro-2//-pyran 731 reacts with the Meldrum s acid derivative 732 to afford 5-(3-hydroxypropyl)-2-imcthylM//-pyranM-onc (Scheme 183) <1996TL6499>. 

Fig. 6.26. Acylation of alcohols with an acyl Meldrum s acid (A). The reaction product obtained after in situ decarboxylation is a /l-keto carboxylic acid ester D.

The solid acyl Meldrum s acid, without purification, is refluxed 1n 250 mL of anhydrous methanol for 2.5 hr. The solvent is removed with a rotary evaporator, and the residual oil 1s distilled under reduced pressure to give 25.2 g (82 ) of methyl phenylacetylacetate as a colorless liquid, bp 126-128°C/(0.6 mm). 

Methanolysis or ethanolysls of an acyl Meldrum s acid is performed simply by refluxing in methanol or ethanol solution. The products are methyl or ethyl g-keto esters, and they can usually be purified by distillation. When a higher ester (such as benzyl, t-butyl, or trichloroethyl) is required, it is... 

Recently, Melillo et al.t applied this Meldrum s acid method with some modifications to the synthesis of thienamycin. A carboxylic acid was treated with carbonyldiimidazole, followed by treatment with Meldrum s acid to give an acyl Meldrum s acid, which was converted to a 0-keto p-nitrobenzyl ester by refluxing in acetonitrile containing p-nitrobenzyl alcohol. ... 

For the reaction of 5-acyl Meldrum s acid with allylic alcohols, see Y. Oikawa, K. Sugano and O. Yonemitsu, J. Org. Chem., 1978, 43, 2087. 

Resin capturing Acyl Meldrum s acid 22 (5 equiv.) was heated with the spacer-modified polystyrene resin 27 in THF at reflux for 4h to give the polymer-bound 3-keto ester 23. 

When N-acylation of the amino acid derivatives 111 was performed with acylated Meldrum s acid 22, the products were 3-acyl-tetramic acids 116. In this case, fhe optimal conditions for cleavage proved to be DIEA/dioxane (3 7) at 80 °C (Scheme 31) [47]. 

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