Meldrum’s acid derivative

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. 

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. 

An organocatalytic asymmetric hydroxylation was developed using spiro-Meldrum s acid derivatives, 20mol% proline, and nitrosobenzene. In fact, the heterocyclic moiety was necessary for a high-yielding asymmetric induction (Equation 67) <20050L1577, 2006OBC2685>. 

The structure of 4-oxa-l,2-dithia-3-aza-pentalene 26, obtained as the major product when diethylamine is reacted with Meldrum s acid derivative 25, has been solved (Equation 1) <2000J(P1)3107>. The S-S and S-C bond lengths were found to be 2.11 and 1.69 A, respectively. The S-S-C bond angle is 90.83°. 

Reaction of Meldrum s acid derivative 25 with secondary alkylamines in dichloromethane at room temperature afforded a mixture of compounds, including furo[2,3- -l,2,3-dithiazoles 26, the novel Meldmm s acid derivatives 79a-g, and sulfur (Scheme 8 and Table 1). Usually the reaction time is less than 6h with yields of approximately 20%. Of note is the fact that cyclic amines such as piperidine and pyrrolidine do not produce furo[2,3- / -l,2,3-dithiazoles in this way <2000J(P1)3107>. 

Solid-phase syntheses have become increasingly popular during the period of this review, with examples including the synthesis of 5,6,7,8-tetrahydro[l,6]naphthyridines from Meldrum s acids derived from /3-amino alcohols via Hantzsch condensation and cyclization with cyclative cleavage from the resin (using 70% trifluoroacetic acid (TFA)/dichloromethane (DCM) followed by 5% triethylamine/DCM) <1999S1951> and also of isoquinolinones and 5-oxo-5,6-dihydro-[l,6]naphthyridines <1995JOC5748>. 

In Delfourne and co-workers study toward the total synthesis of meridine, the Meldrum s acid derivative 91 was prepared. After several unsuccessful attempts to cyclize this material to the desired tricyclic compound 92, it was found that conversion into the quinone 93 was necessary for cyclization to occur (Scheme 4) <1997T1743>. Another approach to compounds with a central six-membered carbocyclic ring using Meldrum s acid derivatives has been... 

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