Meldrum acid method

FVP of the Meldrum acid derivatives 347 gave the 2-substituted l,3-oxazin-6-ones 348 (Scheme 64). This method proved to be an effective procedure for the preparation of both 2-aryl- and 2-alkyl-substituted derivatives. The yields were not significantly influenced by the increasing bulkiness of the alkyl groups R <1996T3163>. 

Cyclization of a variety of alkylideneketenes generated by the Meldrum s acid method has provided a number of useful syntheses of nitrogen heterocycles. Thus, for example, FVP of 382 leads to the azepinone 383177, and the indole compounds 384 may give... 

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. ... 

The synthetically important isopropylidene malonates (Meldrum acids) can be prepared in a one-pot procednre employing this method. 

The reaction can also be extended to quatemized benzyl Meldrum acids 24, affording products 25 with a different substitution on the cyclo-pentanone ring (Table 3.10). The method is also applied to the synthesis of... 

Suitable condensing agents for this reaction are acetic anhydride,259,260 hydrogen chloride and thionyl chloride,261 dicyclohexylcarbodiimide,262 and phosphorus pentaoxide.263 For example, barbituric acids, 2-hydroxy-1,4-naphthoquinone, and methylene di(phenyl sulfone),259 malonodinitrile,261 Meldrum acid and 2,3-indenedione,262 dinitromethane and dihydroresorcinol260 yield ylides by this method. 

The syntheses of /3-enamino esters and related compounds from cyclic and acyclic /3-enamino Meldrums acid derivatives have been described good yields in a range of cases are obtained. In the natural product area, unsaturated esters that are biologically active analogous of leukotriene A4, and a pheromone of the Comstock Mealybug have been synthesized using conventional methods. 

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. 

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. 

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. 

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-... 

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. 

An interesting entry to functionalized dihydropyrans has been intensively studied by Tietze in the 1990s using a three-component domino-Knoevenagel Hetero-Diels-Alder sequence. The overall transformation involves the transient formation of an activated heterodienophile by condensation of simple aldehydes with 1,3-dicarbonyls such as barbituric acids [127], Meldrum s acid [128], or activated carbonyls. In situ cycloaddition with electron-rich alkenes furnished the expected functionalized dihydropyrans. Two recent examples concern the reactivity of 1,4-benzoquinones and pyrazolones as 1,3-dicarbonyl equivalents under microwave irradiation. In the first case, a new three-component catalyst-free efficient one-pot transformation was proposed for the synthesis of pyrano-1,4-benzoquinone scaffolds [129]. In this synthetic method, 2,5-dihydroxy-3-undecyl-1,4-benzoquinone, paraformaldehyde, and alkenes were suspended in ethanol and placed under microwave irradiations to lead regioselectively the corresponding pyrano-l,4-benzoquinone derivatives (Scheme 38). The total regioselectivity was... 

Enaminone 128 (Scheme 33) is obtained, together with an isomeric indo-lizine derivative, by flash vacuum thermolysis of aminomethylene Meldrum s acid derivative through intermediate ketene and delocalized azomethine ylide (85TL833). The thermally induced cyclization of semi-cyclic dienamines to afford, for instance, tricyclic 129 is also believed to start with an azomethine ylide (97JOC7744) the p-chlorophenyl substituent is essential for the reaction. Unstabilized ylide 130, on the other hand, is generated from pipecolinic acid and /1-phenylcinnamaldehyde by the decarboxylation method target base 131 is formed by 1,7-electrocycliza-tion and [l,5]-hydrogen shift (99J(P1)2605). 

Methylbenzofuran-3-carbaldehydes undergo ready condensation with Meldrum s acid (isopropylidene malonate) to afford arylmethylene derivatives 83. These on flash vacuum pyrolysis at 500-600 C give 3-dibenzofuranols 84 (Scheme 21). The arylmethylene derivative, e.g., 85, presumably undergoes conversion to a methylene ketene (86, Scheme 22) on pyrolysis, which undergoes a [1,5-H] shift and subsequent cyclization and tautomerization, yielding the dibenzofuranol 87. The derived methyl ether 88 has been converted by mild acetylation with acetyl chloride and aluminum chloride and subsequent boron trichloride-induced demethylation to the natural product ruscodibenzofuran (8). A limitation is imposed on this method because 3-acetyl-2-methyldibenzofurans fail to condense with Meldrum s acid so that l-methyl-3-dibenzofuranols are not available by this method. ... 

IR spectroscopy has been applied to study the pyrolysis of isonitroso Meldrum s acid 126 <1997PCA3936> and the photodecomposition of diazo-Meldrum s acid 127 <1996JA1551, 1997MI43> in the latter case, the application of a new method, ultrafast IR spectroscopy, was necessitated because the reaction was complete within only 20 ps. 

This method has also been modified. For example, Meldrum s acid was acylated with a N-protected amino acid at position 3. The intermediate was then cyclized via intramolecular nucleophilic attack of the amino group on one carbonyl group of the ring [87JCS(P1)1177 90JCS(P1)611]. Further special methods will be mentioned below. 

A convenient method for generating and trapping reactive ketenes is the flash-vacuum pyrolysis (FVP) of substituted Meldrum s acid derivatives. The dispirocyclobutane-l,3-dione 9 is obtained from the transient ketene 8 generated by FVP of the diester precursor 7.56... 

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). 

Methyl ketones Methyl ketones are available by acylation of Meldrum s acid (I) followed by hydrolysis with aqueous acetic acid (equation I). The method fails when R = C6H5 because of hydrolysis to benzoic acid. 

The procedure described here offers a general route to a variety of unsymmetrically substituted y-pyrones from Meldrum s acid.2 Substitution at the 2-position depends on the acid chloride chosen, while substitution at the 5-position is derived from the vinyl ether. A variety of substituted y-pyrones have been synthesized by utilization of this method as illustrated in the Table. The intermediate pyrandione is believed to arise through the addition of the vinyl ether to an acyl ketene that results... 

An attractive method to generate C5-monoalkyl-substituted Meldrum s acids consists of a two-step synthesis (Scheme 10). In the first step, a Knoevenagel reaction between Meldrum s acid (22) and an aldehyde (or sometimes a ketone) yields the C5-alkylidene derivative 23. In the following step, the alkylidene derivative 23 is reduced, to generate the C5-monoalkyl-substituted Meldrum s acid 24.[43 71 104 1051 Alternatively, in the second step, Michael addition of a nucleophile to the conjugated C=C bond in the C5-alkylidene derivative generates a Meldrum s acid 25 monosubstituted on C5 by a more elaborated alkyl.t106 ... 

Verdini and co-workers 71,81 107 were able to silylate the amine with Af,0-bis(trimethylsilyl)-acetamide 108 (BTMSA) and to ring-open Meldrum s acid in a one-pot procedure without isolating the labile Af-silyl derivative. Additional, less frequently employed methods for the synthesis of C2-substituted malonic acids are summarized in a review. 73 ... 

N-Tfa- and iV-Fmoc-a-amino ketones have been synthesized56 by reaction of some N -heterocycles or benzene with chiral AM Tfa- and Fmoc-a-aminoacyl)benzotriazoles [e.g. (49)] in the presence of aluminium trichloride. Full preservation of chirality was reported. Aromatic side-chains in some of the (a-amineacyl)benzotriazole compounds gave a competitive intramolecular cyclization, again with retention of chirality [e.g. (49) to (50)]. A full report57 on the intramolecular acylation of aromatics with Meldrum s acid derivatives catalysed by metal trifluoromethanesulfonates under mild reaction conditions has appeared [e.g. (51) to (52)]. The method tolerates many functional groups and was extended to the synthesis of 1-tetralones, 1-benzosuberones and donepezil (53). 

Phenylation and arylation have also been performed in bifunctional compounds such as malonates, /1-diketones and /1-ketoesters (Table 8.4). Diethyl malonate was arylated at room temperature affording mixtures of mono- and bis-arylated products, whereas isopropylidene malonate (Meldrum s acid) underwent bis arylation directly. Dimedone, the all carbon analogue of Meldrum s acid, was also mono-and bis-phenylated, with some concomitant O-phenylation [33], Generally, / -diketones show often ambident reactivity but the O-arylated product is normally the minor one an exception was noted in the triketone (PhCO)2CHCOPh which underwent mainly O-phenylation (68%) [33], Several dianions from /1-diketones have been arylated in high yields at the a-position, in a procedure superior to other methods [35]. 

A well established procedure for the synthesis of methylenemalonate 2-111 is the thermolysis of the anthracene derivative 2-110 [134a]. Recently, also a new method for the preparation of the useful methylidene-Meldrum s acid has been described [134b]. 

A series of A-substimted 4-aryl-4,6,7,8-tetrahydroquinoline-2,5(l//,3/f)-diones 63 has been synthesized by Tu and co-workers [110] through a rapid one-pot four-component reaction of an aldehyde, Meldrum s acid, a 1,3-cyclohexanedione and an amine in ethanol under microwave irradiation. This method allows the introduction of substiments at the nitrogen of octahydroquinolones 63. The reaction has a wide scope as different aromatic aldehydes and a variety of amines (including aliphatic and aromatic) are well tolerated in this four-component condensation (Scheme 47). 

The reaction of azlactones or a Meldrum s acid derivative with 2-phenylbut-3-ene-2-yl acetate, in the presence of the racemic ligand and a palladium source has provided a new method for controlling alkene geometry. By varying the reaction conditions excellent selectivities for either or Z geometry could be obtained. " ... 

Common synthetic methods for the preparation of cyclic 8-enamino esters are the condensation between a lactim ether and benzyl cyanoacetate followed by hydrogenolytic decarboxylation, or the imino ester carbon-carbon condensation with tert-butyl cyanoacetate followed by a trifluoroacetic acid treatment. The use of a thiolactam condensed with ethyl bromoacetate gives, after sulfur extrusion by triphenylphosphine, cyclic 8-enamino esters. Compared with these methods, the Meldrum s acid condensation followed by the monodecarboxylating transesterification described here is more convenient and practical. An extension of this procedure permits preparation of smaller... 

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