Methyl N-Benzylidenealaninate

D-(1; R = Me)

[112674-72-3]  · C11H13NO2  · Methyl N-Benzylidenealaninate  · (MW 191.25) L-(1)

[40216-71-5] DL-(2; R = Et)

[60930-36-1]  · C12H15NO2  · Ethyl N-Benzylidenealaninate  · (MW 205.28) L-(2)

[60855-77-8] L-(3; R = t-Bu)

[78688-64-9]  · C14H19NO2  · t-Butyl N-Benzylidenealaninate  · (MW 233.34) L-(4; R = PhCH2)

[81852-01-9]  · C17H17NO2  · Benzyl N-Benzylidenealaninate  · (MW 267.35)

(metalation generates azadienolate anions which undergo a-alkylation and cycloaddition with electron-deficient alkenes and alkynes; alkylation and hydrolysis gives a-alkyl-a-methyl amino acids; cycloaddition affords 3-pyrroline- and pyrrolidine-2-carboxylates; ketenes and 2-(ethoxycarbonyl)allylzinc bromide add to the imine to form b-lactams and a-methylene-g-lactams, respectively)

Physical Data: L-(1) bp 84 °C/0.04 mmHg. L-(2) bp 100 °C/0.3 mmHg.

Preparative Methods: prepared by condensation of benzaldehyde with the alkyl alaninate ester hydrochloride1,2 in the presence or absence of dehydrating agents (molecular sieves or Na2SO4).36,41 For example, a solution of triethylamine (30.3 g, 0.3 mol) in CH2Cl2 is added slowly to a suspension of alanine methyl ester hydrochloride (41.8 g, 0.3 mol) and freshly distilled benzaldehyde (31.8 g, 0.3 mol) in CH2Cl2 cooled to 0 °C. The reaction mixture is stirred overnight at rt. The product is isolated and distilled under reduced pressure to give 46 g (80%) of the imine.

Handling, Storage, and Precautions: although stable at rt, the compound is normally stored under argon at 0 °C.

a-Alkylation: Synthesis of a-Methyl a-Amino Acids.

Benzaldimine esters of alanine are versatile alanine anion synthons. The protected alaninates can be deprotonated with a variety of bases (typically Lithium Diisopropylamide, Lithium Hexamethyldisilazide, or Potassium t-Butoxide in THF at -78 °C, or Potassium Carbonate or Potassium Hydroxide at rt in the presence of PTC) (eq 1). The anion reacts regiospecifically with alkyl halides (low enantiometric excess of ~16-50% is obtained with asymmetric PTC),16 carbonyl derivatives, or Michael acceptors to yield, after deprotection, a-methyl a-amino acid analogs. Numerous examples of this methodology have been reported (Table 1). The adducts can be either purified by distillation in vacuo or directly hydrolyzed in acidic medium to the corresponding free amino acid analogs.

g-Alkylation.

An abnormal alkylation in the g-position is observed with hindered a-bromo esters (eq 2).

Preparation of 3-Pyrrolines and Pyrrolidines.

N-Benzylidenealaninate anions react with alkenes and alkynes bearing electron-withdrawing groups to give [2 + 3] adducts. The reaction proceeds in good yield through a Michael addition of the a-anion followed by cyclization on the imine to give the 3-pyrroline and pyrrolidine derivatives (eq 3).

Generally, the addition is carried out in refluxing toluene or xylene2-5,18-22,31 and the 5-endo-trig cyclization adducts26 are formed; the endo product is usually the major isomer. The endo:exo ratio varies from 2.3:1 to 6.9:1 for the monocyclic products. Only the endo isomer is observed for the bicyclic pyrrolidines.22 The use of more polar solvents (acetonitrile, THF, CH2Cl2)24,25,29 with nitrogen bases (Triethylamine, 1,8-Diazabicyclo[5.4.0]undec-7-ene)25 and metal ions (Ag, Li, Zn, Mg)16,23-25,29,33 increases the rate of the reaction and also the amount of endo adduct, which in some cases is the sole isomer formed.24,29,33 The use of stronger bases (Sodium Hydride,30 benzyltrimethylammonium methoxide26) yields mixtures of endo and exo adducts. Phenyl vinyl sulfone in DMSO containing NEt3-LiOAc28 gives a 3:10 mixture of endo and exo adducts. The TiIV salts (Chlorotitanium Triisopropoxide, Dichlorotitanium Diisopropoxide)27,32 of methyl N-benzylidenealaninate anions give a g-cycloaddition adduct with methyl acrylate (eq 4).

Preparation of 3-Substituted 4-Phenyl-2-azetidinones (b-Lactams).

N-Benzylidenealaninates react with ketenes (generated in situ by treatment of the corresponding acid chloride with triethylamine) to give diastereoisomeric mixtures of cis-b-lactams (eq 5).34-37

Preparation of g-Lactams.38

Addition of an excess of organozinc reagents derived from 2-(bromomethyl)acrylates to racemic N-benzylidenealaninate gives the corresponding a-methylene-g-lactams as racemic mixtures. If the pure (R) or (S) isomer of the imine is used, only one enantiomer (RR) or (SS) of the a-methylene-g-lactam is obtained with ee >95% (eq 6).

N-Oxidation: Synthesis of Oxaziridines and Nitrones.39

N-Oxidation of the imine by Monoperoxyphthalic Acid affords oxaziridines, which rearrange to nitrones by acid catalysis (eq 7).

Related Reagents.

Benzophenone Imine; 1-Benzoyl-2-t-butyl-3,5-dimethyl-4-imidazolidinone; Diethyl Acetamidomalonate; Ethyl N-Benzylideneglycinate; Ethyl N-(Diphenylmethylene)-2-acetoxyglycinate; Ethyl N-(Diphenylmethylene)glycinate; Ethyl N-Benzylideneglycinate; Methyl a-Phenylglycinate.


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Philippe Bey

Marion Merrell Dow, Cincinnati, OH, USA



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