Diethyl Acetamidomalonate

[1068-90-2]  · C9H15NO5  · Diethyl Acetamidomalonate  · (MW 217.22)

(glycine anion equivalent for amino acid synthesis)

Physical Data: mp 95-96 °C.

Form Supplied in: commercially available.1

Amino Acid Synthesis.

Diethyl acetamidomalonate is the starting material for the classical Sörensen synthesis of amino acids, first reported in 1903.2-4 The protected glycinate is deprotonated with base [typically Sodium Ethoxide/EtOH or Sodium Hydride in THF, DMF or DMSO; more recently by phase-transfer catalysis (PTC)5-13], reacted with an electrophile (generally an alkyl halide or Michael acceptor), hydrolyzed and then decarboxylated (eq 1).14 Although the second ester group acidifies the a-proton and avoids the common problem of dialkylation of an active methylene compound,15 it is not possible to induce chirality at the a-carbon of amino acid derivatives by carbon-carbon bond formation with diethyl acetamidomalonate.16

Numerous examples of this methodology exist and a brief listing of recent reports serves to highlight the possibilities in terms of reaction types (alkylations,5,6,9,13,17-54 1,2-carbonyl or imine additions,55,56 Michael additions,7,8,10-12,57,58 and an arylation59).

Amino acids with the following side chains have been produced by the Sörensen method: alkane,19,21,26,30,60 alkene,6,7,11,17,23,25,31,34,42,54,60-63 alkyne,6,39,51,53,60,62 aromatic,8,10,12,18,22,24,25,27,32,34,35,37,38,40,41,46,48,50,54,60 carbocycle,61 fluoro,6,35,52,57,58,64 halo (Cl, Br),5,9,13,22,23,43,48,52 heterocycle,17,20,28,29,37,43-45,49,52,55,57,59,60,64 iron,18 13C label,30,56 2H label,40,56 3H label,19,22 15N label,49 nitrogen,5,9-11,20,23,24,29,38,40-45,50,52,55-57,59,60,65,66 oxygen,5,7,8,10-13,17,20,22,24,27-29,31,33,35-38,43-46,48-50,52,55,57-60,62,64,66 phosphorus,5,48,50,52,60 platinum,65 pro(cyclic imino),5,9,37,42,47 sulfur,7,23,33,44,45 and tin.51

New synthetic methodologies, such as catalytic enantioselective synthesis, are of special interest. Examples include phase-transfer catalyzed Michael addition to give (1) in 68% ee,8,12 and palladium-catalyzed allylation to give (2) in up to 97% ee.17,25,34,54 The chiral catalysts are a quaternarized Ephedra alkaloid derivative and a chiral phosphine ligand, respectively. In both of these cases the enantioselective reaction occurs at the indicated b-carbon center. Palladium-catalyzed carbopalladation of allenes to form 1,3-diene-containing amino acid derivatives,63 conversion of the normally nucleophilic malonate into an electrophile by bromination followed by reaction as a glycine cation equivalent with a variety of nucleophiles,60,62,66 and the synthesis of either heterocycles67,68 or polymers69 using compounds prepared from the parent malonate have also been reported.

As noted above, the amino acid derivatives prepared by this methodology are achiral at the a-carbon. Recently, kinetic resolution by enantioselective hydrolysis with enzymes has been used for the direct preparation of the individual enantiomers.61,70-73

Related Reagents.

1-Benzoyl-2-t-butyl-3,5-dimethyl-4-imidazolidinone; (2S,4S)-3-Benzoyl-2-t-butyl-4-methyl-1,3-oxazolidin-5-one; t-Butyl 2-t-Butyl-3-methyl-4-oxo-1-imidazolidinecarboxylate; Diethyl Malonate.

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Martin J. O'Donnell

Indiana University-Purdue University at Indianapolis, IN, USA

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