2‐Amino‐2‐oxazolines, IV: Kurzmitteilung: Reactions with Bromo Esters, Synthesis of Some 3‐Carboxyalkyl‐2‐imino‐oxazolidines

Abstract

Heterocyclic systems having a five membered ring fused with another ring including a bridgehead N are widely described for their pharmacological activity A common method for the synthesis of these fused heterocyclic systems is the alkylation of heterocyclic amines having an amino group at the a-position in respect to the ring N-atom with a-halo carbonyl corn pound^^*^). In continuing our study on the reactivity of 2-amino-2-oxazolines8), we describe here the synthesis of 3-carboxyalkyl-2-imino-oxazolidines 3 by treatment of 5-substituted-2-arnino-2-oxazolines 1 with the bromo esters 2. The two N-atoms of 2-amino-2-oxazolines are potent nucleophilic centers. Depending on the experimental condin -0.1 BrCH2-(CH-CH),-COOEt 1 2 /CHZ-(CH=CH),-COOEt 3 RCHz-CHOH-CH2-NH-CHZ-COOH 4a 3a 3b 3c No 943tions, substitutive reactions take place either on the endo or on the exo N of the amidine system. As we have noticed9), in the 2-amino-2-oxazoline form the endo N is more reactive than the exo one. At ambient temp. nucleophilic substitution preferably occurs on the endo N-atom. Substitutions on position 5 of the heterocycle are without effect on the reactivity indices calculated for the two nitrogens. The condensation of 1 with ethyl bromoacetate or ethyl 4-bromocrotonate in acetone at O'C led to 3-carbethoxyalkyl-2imino-oxazolidines as hydrobromine salts, with a small quantity of corresponding acid. HPLC analysis on a C18 reversed phase column (mobile phase: methanol-phosphate buffer M/30 pH 5.4) gave an integral ratio of 99/1. The alkylation reaction is generally believed to proceed by initial displacement of the bromine atom by the oxazoline ring nitrogen atom followed by rearrangement of the resonance stabilized oxazolinium salt"). An attempt to convert the 5substituted-3-carboxymethyl-2-imino-oxazolidines to the corresponding imidazo[2,1 -b]oxazoline by POC13 was performed according to lit?*"): no cyclization occurred. A similar resistance to ring closure was observed with 3-phenacyl-2-imino-oxazolidines'2).The hydrolysis of reaction compounds can be performed in acidic or in basic conditions. With an excess of NaOH in boiling water, we observed the opening of the oxazolidine ring in 3a leading to the N-substituted glycine 4a after neutralization. This reaction might proceed via the corresponding 2-oxazolidinone 13). In acidic conditions (excess of HCl in boiling water), only 3a and 3b, respectively, were isolated as hydrochloride salts. 3c was obtained as sodium salt after treatment with Na2CO3.The structures of all new synthesized products were investigated by spectral analyses. In 'H-NMR spectra of 3 as hydrochlorides, an exchangeable singlet assigned to the N' H2 was found near 9.8 ppm. The imine function (free bases obtained at ambient temp. after treatment with NH3) was assigned on the basis of IR-data (sharp peak at 3340 cm-': v NH) and 'H-NMR (6 = 5.5 ppm for NH). As it was described 9*12), in 2-iminooxazolidines C-5-H and C-4-H of the heterocycle from an ABX system. In compounds 3, C-5-H appeared as a complex multi...