Ethyl N-(Diphenylmethylene)glycinate1-3

(R = Et)

[69555-14-2]  · C17H17NO2  · Ethyl N-(Diphenylmethylene)glycinate  · (MW 267.33) (R = Me)

[81167-39-7]  · C15H15NO2  · Methyl N-(Diphenylmethylene)glycinate  · (MW 253.30) (R = Bn)

[81477-91-0]  · C22H19NO2  · Benzyl N-(Diphenylmethylene)glycinate  · (MW 329.38) (R = t-Bu)

[81477-94-3]  · C19H21NO2  · t-Butyl N-(Diphenylmethylene)glycinate  · (MW 295.38)

(glycine anion equivalent for amino acid synthesis by phase transfer catalysis and other methods)

Alternate Names: ethyl glycinate benzophenone imine; O'Donnell's Schiff base.

Physical Data: R = Et, mp 51-52 °C; pKa (DMSO) 18.7;4 R = Me, mp 42.5-43 °C; R = Bn, mp 86.5-87 °C; R = t-Bu, mp 111-112 °C.

Form Supplied in: several are commercially available.

Preparative Methods: by transimination of Benzophenone Imine with alkyl glycinate hydrochloride (room temperature/CH2Cl2).5 The crude product can often be used or it can be purified by recrystallization or flash chromatography.

Handling, Storage, and Precautions: the compounds are stable at room temperature, but they should be protected from moisture and acidic conditions (stored under argon or nitrogen). The hydrolysis product, benzophenone, can be detected either by TLC (EtOAc/hexane) or by NMR.

Amino Acid Synthesis by Catalytic Enantioselective Alkylation using Phase Transfer Catalysis.

Optically active a-amino acids are prepared in up to 66% enantiomeric excess (83:17 mixture of enantiomers) by alkylation of the benzophenone imine of glycine t-butyl ester (R = t-Bu) under phase transfer catalysis (PTC) conditions using chiral catalysts derived from the Cinchona alkaloids. The ability to scale the reaction up and the possibility of preparing a-amino acids in high optical purity were demonstrated by the synthesis of 6.5 g of optically pure nonnatural 4-chloro-D-phenylalanine (eq 1) using the N-benzylated derivative of cinchonine. The enantiomeric L-amino acids are prepared by simply changing to pseudoenantiomeric catalysts derived from cinchonidine.1 Use of optically active crown ethers (29% ee)6 or optically active vic-diols as cocatalysts (4% ee)7 has been reported.

Other Preparations of Optically Active Amino Acid Derivatives.

Enzymatic resolution has been used to prepare optically pure a-amino acid derivatives following either enantioselective PTC alkylation8 or racemic alkylation.9-12

Asymmetric synthesis involving alkylation of these and related Schiff base esters in the presence of either a chiral leaving group (up to 76% ee) or a chiral proton source (deracemization) (up to 70% ee) have been reported.13

Palladium Catalysis.

Pd0 catalyzed alkylations of the anion of Schiff base esters leads to g,d-unsaturated,14 g-allenic,15 cyclopropyl-containing,16 or 1,3-diene-containing17 amino acid derivatives. A catalytic, enantioselective allylation has been achieved in up to 68% ee by using chiral ligands in conjunction with Pd0 catalysis (eq 2).18,19

Other Alkylation Chemistry.

The benzophenone imines of glycine alkyl esters can be alkylated by a variety of different classes of alkyl halides (methyl, benzylic, allylic, propargylic, a-halo ester, primary, secondary) using either PTC or anhydrous conditions (Table 1).20-22

Other Reactions.

Michael additions,44,52-55 aldol type reactions (eq 3),56-60 imine additions,61,62 acylation (both N-acylation63 and C-acylation64), reaction with difluorocarbene,65 and monoarylation66-68 have been reported.

Related Reagents.

Benzophenone Imine; 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; N,N-Diethylaminoacetonitrile; (2S)-(+)-2,5-Dihydro-2-isopropyl-3,6-dimethoxypyrazine; N-(Diphenylmethylene)aminoacetonitrile; Ethyl N-(Diphenylmethylene)-2-acetoxyglycinate; Methyl N-Benzylidenealaninate; Methyl a-Phenylglycinate.


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Martin J. O'Donnell

Indiana University-Purdue University at Indianapolis, IN, USA



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