Meldrum’s acids

Since allylation with allylic carbonates proceeds under mild neutral conditions, neutral allylation has a wide application to alkylation of labile compounds which are sensitive to acids or bases. As a typical example, successful C-allylation of the rather sensitive molecule of ascorbic acid (225) to give 226 is possible only with allyl carbonate[l 37]. Similarly, Meldrum s acid is allylated smoothly[138]. Pd-catalyzed reaction of carbon nucleophiles with isopropyl 2-methylene-3,5-dioxahexylcarbomite (227)[I39] followed by hydrolysis is a good method for acetonylation of carbon nucleophiles. 

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

Thionyl chloride (11.5g, 96.4 mmol) was added to 2-nitrophenylacetic acid (8.72g, 48.2mmol) and the suspension was warmed to 50°C and stirred until gas evolution was complete. The resulting solution was concentrated in vacuo and the residue dissolved in CHjClj (30 ml). This solution was added dropwise to a stirred solution of Meldrum s acid (6.94 g, 48.2 mmol) in CH2CI2 (200 ml) under nitrogen at 0 C. The solution was stirred at 0" C for 1 h after the addition was complete and then kept at room temperature for an additional hour. The reaction solution was then worked up by successively washing with dil. HC1, water and brine and dried (MgSOJ. The dried solution was concentrated in vacuo and abs. ethanol (200 ml) was added to the residue. The mixture was... 

Meldrum s Acid. Meldmm s acid [2033-24-1] (3) is commercially used for the production of monoesters of malonic acid and beta-keto acids (17). The chemistry of Meldmm s acid is extensively reviewed in Reference 18. 

Flash thermolysis of compounds of the type (120), derivatives of Meldrum s acid , is a fairly general synthesis of ketenes (Scheme 103). Brown and coworkers (77AJC179) found that the spirooxirane (121) gave ketene, possibly via the expected carbonyloxirane (122) and probably by isomerization of carbenaoxirane (Scheme 104). 

Meldrum s acid (3) To malonic acid 1 (52 g, 0 5 mol) in acetic anhydride (60 mL, 0 6 mol) was added cone HjSOa while stimng Acetone 2 (40 mL, 0 55 moO was added Cooling lor 24 h, filtration, washing the solid with ice water and recrystallization from acetone-water gave 3 (35 g, 49%), mp 94-95 C (dec)... 

Meldrum s acid, pK 7.4, is exceptionally acidic in comparison to an acyclic analog such as dimethyl malonate, pK 15.9. For comparison, 5,5-dimethyl-1,3-cyclohexane-dione is only moderately more acidic than 2,4-pentanedione (11.2 versus 13.43). The pK values are those for DMSO solution. It is also found that the enhanced acidity of Meldrum s acid derivatives decreases as the ring size is increased. Analyze factors that could contribute to the enhanced acidity of Meldrum s acid. 

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. 

The first reaction can be conducted using various derivatives of methylenemalonic ester, such as malononitriles 7, malonamides 8, P-keto-esters 9 or Meldrum s acid 10. Substitutions of the aryl ring (including fused rings) and within the aryl ring are well tolerated for this reaction. 

The preparation and use of derivatized Meldrum s acid has led to an alternative preparation of 2-substituted quinolines (49 and 50) and the preparation of pyridopyrimidines (52). When Meldrum s acid derivatives are used (as shown in this example) decarboxylation occurred under the cyclization conditions. Three component coupling has been used to readily assemble the desired 3-anilino-acrylate from reaction of Meldrum s acid, (EtO)3CH and an aniline (e.g. 54 or 55).< ... 

One year later, Tietze and co-workers (97BMC1303) presented a general and straightforward method for the synthesis of diverse polymer-bound -keto esters starting from acid chlorides and Meldrum s acid. One such resin-bound y3-keto ester, 43, was treated with hydrazine hydrate in THF to afford resin-ffee N-2-unsubstituted pyrazolone 44 in 84% yield (Scheme 13). In the same paper, the synthesis of a large number of 4,5-disubstituted 2-phenyl-2,4-dihydro-37/-pyrazol-3-ones was reported. 

To set the stage for the crucial carbene insertion reaction, the acetic acid side chain in 32 must be homologated. To this end, treatment of 32 with 1,l -carbonyldiimidazole furnishes imidazo-lide 33, a competent acylating agent, which subsequently reacts with the conjugate base of Meldrum s acid (34) to give 35. Solvolysis of this substance with para-nitrobenzyl alcohol in acetonitrile at reflux provides /Mceto ester 36 after loss of one molecule of ace-... 

Meerwein-Pondorff-Verley reduction 57, 59, 496 Meldrum s acid 258 menthol 343 ff. 

Coupling of 2-diazoimidazole 445 with meldrum s acid occurred instantaneously to give hydrazone derivative 446. Cyclization and decarboxylation could be carried out in one pot by heating in acetic acid to afford (88JOC887) imidazotriazine 447, which on further heating gave 448. Meth-ylation of 448 under basic conditions takes place exclusively on N-l and N-2. In the absence of base, a complex mixture may be obtained (Scheme 96). 

Oxa-tetrahydropyridines are interesting intermediates for the preparation of pharmaceuticals and natural product based alkaloid systems. A modified Hantzsch reaction was developed under microwave irradiation for the preparation of 2-oxa-tetrahydropyridines 173 by reaction of Meldrum s acid, a /3-ketoester and an aldehyde, using NH4OAC as the source of ammonia (Scheme 62). Yields ranged from 81 to 91% at temperatures of 100-130 °C depending on the substrate (the aldehyde) employed. All the products obtained have the same structure except for the aromatic substituent in position 4 [109]. 

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-... 

Since ketones are stronger acids than carboxylic esters (Table 8.1), we are not surprised that 9 is a stronger acid than 11. But cyclization of 9 to 10 increases the acidity by only 2.1 pAT units while cyclization of 11 to 12 increases it by 8.6 units. Indeed, it has long been known that 12 (called Meldrum s acid) is an unusually strong acid for a 1,3-diester. The work of two groups explained... 

As aldehydes, commercially available rac-citronellal and a synthesized aromatic aldehyde and also two commercially available 1,3-diketones, 1,3-dimethylbarbituric acid and Meldrum s acid, were selected [18]. By 2 x 2 combinations of these reactants, four different cycloadducts were generated ([OS 57]). 

The addition of terminal alkynes to carbon-carbon double bonds has not been explored until recently, possibly because C=C double bonds are not as good electrophiles as C=N or C=0. In 2003, Carreira et al. reported the first conjugate addition reaction of terminal alkynes to C=C catalyzed by copper in water. The reaction proceeded with derivatives of Meldrum s acid in water in the presence of Cu(OAc)2 and sodium ascorbate (Eq. 4.35).59 However, this method was limited to C=C double bonds with two electron withdrawing groups. 

Reaction of the enatiopure aldehyde 2-800, obtained from the corresponding imine by enantioselective hydrogenation, with Meldrum s acid (2-801) and the enol ether 2-802a (E/Z= 1 1) in the presence of a catalytic amount of ethylene diammonium diacetate for 4h gave 2-805 in 90 % yield with a 1,3 induction of >24 1. As intermediates, the Knoevenagel product 2-803 and the primarily produced cycloadduct 2-804 can be supposed the latter loses C02 and acetone by reaction with water formed during the condensation step (Scheme 2.178). 

The Knoevenagel-type condensation of salicylaldehydes with malonic acid [14, 27], malonic ester [28], cyanoacetic ester [29], or Meldrum s acid [30], is... 

Song A, Wang X, Lam KS (2003) A convenient synthesis of coumarin-3-carboxylic acids via Knoevenagel condensation of Meldrum s acid with ortho-hydroxyaryl aldehydes or ketones. Tetrahedron Lett 44 1755-1758... 

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