Meldrum s acid adduct

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). 

Keto esters and amides are versatile intermediates in organic synthesis and often are prepared from acyl Meldrum s acid adducts. This method involves formation of acyl Meldrum s adducts by reaction of Meldrum s acid with activated carboxylic acids followed by decarboxylation in the presence of nucleophiles such as alcohols or amines (Scheme 21.2). The ability of readily available acyl Meldrum s acids to react with various nucleophiles allows quick access to a variety of functionalized compounds. Apphcation of this methodology in synthetic chemistry has been widely exploited. For example, acyl Meldrum s adducts can react with imines to prepare pyridinones or... 

Figure 2. Library Meldrum s Acid Adduct Inputs,...

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). 

The Knoevenagel reaction consists in the condensation of aldehydes or ketones with active methylene compounds usually performed in the presence of a weakly basic amine (Scheme 29) [116], It is well-known that aldehydes are much more reactive than ketones, and active methylene substrates employed are essentially those bearing two electron-withdrawing groups. Among them, 1,3-dicarbonyl derivatives are particularly common substrates, and substances such as malonates, acetoacetates, acyclic and cyclic 1,3-diketones, Meldrum s acid, barbituric acids, quinines, or 4-hydroxycoumarins are frequently involved. If Z and Z groups are different, the Knoevenagel adduct can be obtained as a mixture of isomers, but the reaction is thermodynamically controlled and the major product is usually the more stable one. 

C-5 substituent either a pyrimidine (98) (when = NR2) or an isothiazole (99) (when R = Ar) are finally obtained. Sodium hydride as base resulted in ring fragmentation to give the open-chain adduct (100). Multistep mechanisms are proposed for these transformations (89BCJ1086>. The behavior of methylthio and dialkylamino salts (5 R = SMe and NRj, respectively) is quite similar and both give with carbon nucleophiles (e.g. Meldrum s acid) the same alkylidene derivative (97) (X , = Meldrum s acid residue) <(85CC696,88JCS(P1)899>. 

Although the acidity of Meldrum s acid is quite similar to that of barbituric acids, the same reaction conducted with this dicarbonylic compound in aqueous medium gave a complex mixture instead of the expected adduct [107]. The reaction... 

With an improved synthesis of the triazole fragment in hand, which would allow for its introduction much earher in the synthesis, we started searching for a direct preparation of the P-keto amide intermediate from trifluorophenylacetic acid (9). This type of transformation has been accomplished in the past using acyl Mel-drum s acid adducts [16]. This methodology involves reaction of Meldrum s acid with activated carboxyhc acids followed by decarboxylation in the presence of nucleophiles such as alcohols or amines (Scheme 5.13). The abihty of readily avail-... 

Proof of concept for this route was established by activating acid 9 with N,N -carbonyldi-imidazole (CDl) and treating it with Meldrum s acid to afford adduct 24 (Scheme 5.14). Despite its relatively high instability, adduct 24 was isolated by crystallization after aqueous work-up. Isolated 24 was easily converted to 25 in moderate yield by treatment with triazole salt 3 and Hunig s base. Because of the limited stability of intermediate 24 and in order to maximize the efficiency of the... 

Cyclopropane and lactone functions can be prepared by the same double alkylation protocol as shown in Scheme 8E.12 [64], Both dibenzyl malonate and Meldrum s acid served well as nucleophiles to give excellent enantioselectivities. While subjecting the malonate adduct 95 to the second alkylation generated cyclopropane 96, the alkylation of the Meldrum s adduct 97 under similar conditions produced lactone 98 via an unusual O-alkylation. 

The three-component reaction of indole (2) with sugar hydroxyaldehyde 281 and Meldrum s acid 282, with a catalytic amount of D,L-proline, afforded the 3-substitution product 283 as a single isomer [203]. The substituent possesses the czs-fused furo [ 3,2- b ] pyranonc skeleton. The proline catalyzes the Knoevenagel condensation of the sugar aldehyde 281 and Meldrum s acid 282 to provide the alkylidene derivative 284 of Meldrum s acid. Then a diastereo-selective Michael addition of indole and an intramolecular cyclization of this adduct 285 with evolution of carbon dioxide and elimination of acetone furnish the furopyranone in one-pot (Scheme 62). 

A domino Knoevenagel/Diels-Alder epimerization sequence followed by Suzuki coupling provided a library of biphenyl and terphenyl spirocychc triones (Scheme 24) [58]. The initial Knoevenagel adducts 103 were formed from either 1,3-indandione or Meldrum s acid 101 and various bromosubstituted benzalde-hydes in the presence of catalytic (l)-5,5-dimethyl thiazolidinium-4-carboxylate (DMTC) in high yields. Diels-Alder cycloaddition of 103 with 104, formed in sim from 102 and (l)-DMTC, provided exclusively the cA-spiro compounds 105 due to epimerization of the minor trans isomer to the thermodynamically more stable cis. Subsequent Suzuki couplings of 105 with various boronic acids afforded the final compounds 106. 

The acidity of these products cannot be determined by means of direct pH determination. However, the virtual acidity constant, AT l, is accessible from optical and electrochemical measurements. Comparison of the pX i values of selected Knoevenagel products and the pX values of some typical carboxylic acids in methanol establishes that they exhibit comparable acidity (Scheme 7). Using the o -values, the pX i values of benzylidene derivatives of Meldrum s acid are in good accordance with the Hammett equation. The Lewis acidity of Knoevenagel products is due to the formation of labile pseudobase adducts, the so-called anbadons (10), upon reaction with nucleophiles. Structures of the anbadons have... 

The lower sensitivity to catalysis of thiolate compared to alkoxide ion departure has been observed in other reactions and is a general phenomenon a detailed discussion has been presented in connection with the study of the acid-catalyzed breakdown of alkoxide and thiolate ion adducts of benzylidene Meldrum s acid type adducts/ The main reason for this reduced sensitivity appears to be the lower basicity of RS compared to RO or OH ions. However, the mechanism for catalysis is probably the same for all leaving groups and most likely represents a concerted reaction with a transition state such as 117 or 118 (B = H2O). 

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