3097-74-3

609-02-9

3097-74-3

Examples 38-53 demonstrate the broad scope of application of the described method to a variety of dialkyl malonates and their derivatives using aqueous NaOH or KOH as the base. The operation of Example 1 was repeated using the various diesters listed in Table 5, and the results are summarized in Table 5. Most of the diesters were commercially available, and some were prepared by the standard Fischer esterification method. Unlike conventional monosaponification reactions, which often produce complex yellow reaction mixtures, this reaction in all cases isolated only the pure half ester, the starting diester, and in very few cases the diacid (if present). In some cases, based on the percent yields of the diester and recovered diester, it was hypothesized that small amounts of diacid may have been produced, but these were not extracted when the reaction mixture was processed. The resulting semiesters were of excellent purity and the elemental analytical data were clear. No decarboxylation products were detected in any of the monohydrolysis reactions. Overall, KOH exhibited higher reactivity and selectivity compared to NaOH, as shown in Table 5. This trend was most evident in the monohydrolysis of diethyl phenylmalonate (Examples 50-51), where both reactivity and selectivity were better with KOH than previous results with NaOH. The data in Table 5 suggest that selectivity may increase with increasing molecular hydrophobicity. For example, as the hydrophobicity of the ester group increases, the yield of the half ester is enhanced relative to the monohydrolysis of the ester group (see Table 5, Examples 50-53). The semiester yield is further increased when additional methyl or phenyl groups are introduced (Examples 42-53). Although not confined to theory, it is believed that inter- and/or intramolecular hydrophobic attraction interactions may play a key role in the monohydrolysis of the same ester group during the monohydrolysis reaction, and this high selectivity may protect the aggregates from further hydrolysis. This trend might explain the observed hydrophobic interactions. The only exception is the monohydrolysis of dipropylphenylmalonate (Examples 52 and 53), where the results may be attributed to the prolongation of the reaction time, which sometimes allowed the isolation of visible amounts of the corresponding diacid. Here, the use of acetonitrile (a slightly miscible, slightly non-polar, non-protonic solvent with water) in place of THF as a co-solvent helped to accelerate the reaction, increasing the half ester yield by about 10%. Previous studies have explored the effect of co-solvents in this monohydrolysis and found that a slightly miscible micropolar non-protonic solvent with water was an effective co-solvent. The introduction of bulky groups may hinder the adoption of selectively preferred conformations. Example 57 describes in detail the synthesis of monomethyl methylmalonate: dimethyl methylmalonate (175 mg, 1.2 mmol) was dissolved in 2 mL of THF, 20 mL of water was added, and the reaction mixture was cooled to 0°C in an ice-water bath. 1.2 equivalents of 0.25 M NaOH or KOH aqueous solution was added dropwise with stirring, and after continued stirring for 1.5 h, the mixture was acidified with 1 M HCl at 0 °C, saturated with NaCl, extracted with ethyl acetate (four times), and dried over Na2SO4. The extract was concentrated in vacuum and purified by silica gel column chromatography, eluting first with hexane:ethyl acetate (3:1) and then with ethyl acetate to give monomethyl methylmalonate as an oil.1H NMR (300 MHz, CDCl3) δ=1.43 (3H, d, J=7.2), 3.47 (1H, q, J=7.2), 3.73 (3H, s), 9.42 (1H , br.s); 13C NMR (75MHz, CDCl3) δ=13.08, 45.45, 52.39, 170.16, 175.38; IR (neat, cm-1) 1721, 1739, 2956-3202; C5H8O4 Elemental Analysis Calculated: C, 45.46; H, 6.10; Measured: C, 45.65; H, 5.10; C5H8O4 Elemental Analysis 45.65; H, 5.94.