Meldrum acid derivatives

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>. 

Synthetic applications of the pyrolysis of Meldrum acid derivatives 01S2059. 

Intramolecular Friedel-Crafts acylation of enolizable benzyl Meldrum acids 22 wifh scandium triflate (7%-12% mol) in refluxing nitromethane or acetonitrile is a powerful tool for the preparation of a variety of indan-l-ones 23 (Table Meldrum acid derivatives, mono- and dis-... 

FVP of the Meldrum acid derivatives (180) at 625°C (10 torr) proceeds cleanly and efficiently to give thiophenones (182) including the parent compound, which are often very unstable, air-sensitive, and acid-sensitive compounds (Scheme 45) <90CC375> see also <88TL5919>. The mechanism involving ketenes (181) as intermediates was proposed for this conversion. Meanwhile, benzo-... 

Another synthon to 4-oxocarboxylic acids has been recently described and utilized for the synthesis of pyridazinones of potential antihypertensive activity. Thus, arylmethylene Meldrum acid derivatives 97 (prepared by reacting Meldrum acid 96 with aldehydes and subsequent reduction of the formed arylidene derivative using triethylammonium formate, TEAF) could be alkylated with 4-bromophenacyl bromide 98 to yield 99 that then reacted with hydrazine hydrate to yield 100 (2004SC783 Scheme 17). 

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. 

Pyrolysis of the Meldrum acid derivative 458 produces the methylene ketene 459, which rearranges to the dienylketene 460 while the latter undergoes cyclization to give the /3-naphthol 461 . 

For compounds or papers dealing with tautomeric equilibria not mentioned above, see the following o-hydroxyazo dyes [74], 3-acyltetronic acids [75], a-heterocyclic ketones [76], P-diketones [77], Schiff bases [78-80], P-ketothioamides [81, 82], perylene quinones [83], meldrum acid derivatives [84], nitromalonamide [85], and piroxicam [36], For other, possibly older, data, see also reviews [2, 4-13]. 

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 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).< ... 

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-... 

Garreira and co-workers demonstrated the asymmetric conjugate addition reaction of Meldrum s acid-derived acceptors (Scheme 23).72 The adducts were obtained in good enantioselectivities (up to 94% ee). 

As mentioned in CHEC-II(1996) <1996CHEC-II(8)16>, 3//-pyrrolizin-3-one 2 and many other substituted analogues were synthesized by FVP of Meldrum s acid derivatives 189 via the in. ( ////-generated pyrrol-2-ylmethylidene ketenes 190 which cyclize by an intramolecular A-acylation (Scheme 43) <1997J(P1)2195, 2000J(P1)3584>. 

The ammonium catalyst (0.36 mmol) in dry THF (2 ml) is stirred with methanolic MeONa (20%, 0.11 ml) at room temperature. The mixture is stirred for 10 min and added to the Meldrum s acid derivative (0.3 mmol) in PhMe (13 ml) at -30°C. When the reaction is complete (ca. 5-10 min), as shown by GLC, it is quenched with aqueous citric acid (3%, 30 ml). The aqueous phase is separated, extracted with Et20 (3 x 20 ml), and the combined organic solutions are dried (MgS04) and evaporated at <50°C to yield the hemi-ester. 

C-alkylated Meldrum s acid derivatives are cleaved asymmetrically by alkoxide anions in the presence of quininium salts to yield chiral half esters (9.2.2) [11]. Thus, benzylquininium and cinchonidinium salts produce fl-hemi-esters and the cincho-nium and quinidinium salts produce the S-hemi-esters from, for example, 2,2,5-trimethyl-5-pheny 1-1,3-dioxane-4,6-dione. 

Stereoselective ring cleavage and monoesterification of chiral Meldrum s acid derivatives has been achieved in high yield with a 34% enantiomeric excess under phase-transfer catalytic conditions in the presence of A-benzylquininium chloride [29]. A similar asymmetric ring-opening of prochiral (meso) acid anhydrides with... 

Stereoselective cleavage and esterification of Meldrum s acid derivatives... 

Direct evidence has been reported for the formation of methoxyvinyl- and methylthiovinyl-(carboxy)ketenes (55c and 55d) upon flash vacuum thermolysis of Meldrum s acid derivatives (54c) and (54d), respectively " the intermediates decarboxylate readily to give (56c) and (56d), respectively, and are more transient than those obtained previously from (54a,b). 

Conformation of l,3-Dioxan-2-ones, l,3-Dioxan-4-ones, and Meldrum s Acid Derivatives... 

Ayras studied the stereochemistry of 2,5-di- and 2,2,5-tri-substituted 1,3-dioxane-4,6-diones (Meldrum s acid derivatives) in CCU (76MI1, 76MI2). 

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). 

In this chapter, the structures and chemistries of 1,3-dioxins, 1,3-oxathiins, and 1,3-dithiins are described, including both their fully saturated forms (1, 7, and 13) as well as their benzo analogs (6, 11, 12, and 17). The formally fully unsaturated monocyclic structures (4, 9, 10, and 16) contain only one endocyclic double bond with further unsaturation being accomodated by exocyclic double bonds (2, 3, 5, 8, 14, and 15), for example, by the introduction of a carbonyl group. Well known and intensively studied are the Meldrum s acid derivatives 18 and 19. In addition, 1,3-dioxane, 1,3-oxathiane, and 1,3-dithiane moieties can be part of spiro structures as well as hi- and tricyclic analogs. And finally, both the structures and chemistries of the corresponding sulfoxides and sulfones are also reported. 

Ground-state and excited-state reactions of chiral Meldrum s acid derivatives 39 with the enone function have been reviewed with an emphasis on the facial selectivity in the C=C bond (Figure 2) <1996H(42)861>. Top-face preference, even when it is sterically more hindered than bottom-face attack, is supported by hyperconjugation no —r c=c 39a, whereas bottom-face preference is dominated by steric effects in the sofa conformation of the molecule 39. The trajectory of the attacking reagent plays a balancing role. 

An enormous number of different 1,3-dioxane structures have been reported since 1996 in Figure 3, mono-, bicyclic and spiro variants are presented, while Figure 4 contains examples of tricyclic structures with the 1,3-dioxane moiety. The conformations, bond lengths, bond and dihedral angles of the 1,3-dioxane rings are determined by the ring fusion, the attached substituents, and the presence of exocyclic double bonds. Thus, published structures are classified as either monocyclic (mono), spiro-substituted (spiro), bicyclic (bi), or tricyclic (tri). The well-known Meldrum s acid derivatives (M) have been most intensively studied. 

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