1-Ethyl -2-methylsuccinate

The carbonylation of some alkyl halides such as iodocyclohexane (911) can be carried out under neutral conditions in the presence of N,N,N.N-tetre,-methylurea (TMU), which is a neutral compound, but catches generated hydrogen halide. Molecular sieves (MS-4A) are used for the same pur-pose[768]. Very reactive ethyl 3-iodobutyrate (912) is carbonylated to give ethyl methylsuccinate (913) in the presence of TMU. The expected elimination of HI to form crotonate, followed by carbonylation, does not occur. 

The reaction was then concentrated and the residue was passed through a short column of silica gel eluting with ethyl acetate-diethyl ether (1 1) to remove the catalyst. The (,S )-dimethyl methylsuccinate does not need any further purification (190 mg, 95%). 

Heating the reaction for shorter periods gave erratic results. At this point the semisolid mixture can be diluted with 200 ml. of water, extracted with benzene, and the benzene extract fractionally distilled to give ethyl 2,3-dicyano-3-methylpentanoate, b.p. 146.0-147.5° (2.5 mm.), m27d 1.4429 (highly purified ester has b.p. 138.5-141.5° (2 mm.), 25d 1.4432). The overall yield of a-ethyl-a-methylsuccinic acid is decreased by about 5% when the dicyano intermediate is isolated. 

Methylsuccinic anhydride is prepared by condensation of ethyl 2-bromopropionate with ethyl cyanoacetate followed by hydrolysis of the nitrile, decarboxylation of the resultant p-ketoacid, and dehydration. 

Scheme 2. Nonequivalence of optical purity (op) and enantiomeric excess (ee) for 1-ethyl-l-methylsuccinic acid in chloroform.

Butanone, conversion to a-ethyl-a-methylsuccinic acid, 44, 59 Butenolides from aryl aldehydes and y-keto adds, 43, 5 7-(-Butoxynorbornadifne, 44,12... 

The optical purity is usually, but not always, equal to enantiomer excess. In order for the two to be equal, it is necessary that there be no aggregation. It is possible, for example, that a homochiral or heterochiral dimer (see Glossary, Section 1.6, for definitions) would refract the circularly polarized light differently than the monomer (or each other). In 1968 [19] Krow and Hill showed that the specific rotation of (S)-2-ethyl-2-methylsuccinic acid (85% ee) varies markedly with concentration, and even changes from levorotatory to dextrorotatory upon dilution. In 1969 [20], Horeau followed up on Krow and Hill s observation, and showed that the optical purity (at constant concentration) and enantiomer excess of (5)-2-ethyl-2-methylsuccinic acid were unequal except when enantiomerically pure or completely racemic. This deviation from linearity is known as the Horeau effect, and its possible occurence should be remembered when determining enantiomeric purity by polarimetry. 

Active methylene groups undergo Mitsunobu reactions with alcohols. Thus, when ethyl cyanoacetate is reacted with ethyl L-lactate, diethyl 2-cyano-3-methylsuccinate (113) is formed in 61% yield [42]. Acidic hydrolysis furnishes (5)-( — )-methylsuccinic acid (114) in 29% yield with an optical purity of 99% [43]. 

The asymmetric center of 120b can be inverted with carbon nucleophiles, as demonstrated by the synthesis of 1-ethyl ( S)-( — )-2-methylsuccinate (145) [52]. The reaction of 120b with sodium di- r -butylmalonate gives triester 144 with total inversion of configuration. Hydrolysis and decarboxylation furnishes the monoacid 145 (99% ee) in 54% overall yield from ethyl L-lactate. 

Acetoxy-2-methylbutyric acid, A32.17 2-Acetoxy-2-methylbutyric acid, A33.8 2-Ethyl-2-methylsuccinic acid, A55.5 2-Ethyl-3-methylsuccinic acids, A31.12, A31.20 Lactic acid, O-acetyl, ethyl ester, A1.9 2-Propylsuccinic acid, A28.9, A"36 2-Ethylglutaric acid, A32.il... 

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