A CARBON-13, NITROGEN-15 AND PROTON NUCLEAR MAGNETIC RESONANCE STUDY OF THE CYCLIZATION OF 1-(2-CHLOROETHYL)-3-ALKYLUREAS TO 2-ALKYLAMINO-2-OXAZOLINE HYDROCHLORIDES

1-(2-Chloroethyl)-3-alkyl-1-nitrosoureas (CENUs) are among the most active anticancer drugs used today. It is widely accepted that the antitumor activity of these compounds is not caused by the parent molecule but rather by their rapid nonenzymatic decomposition to unstable intermediates. Denitrosation of the CENU to form 1-(2-chloroethyl)-3-alkylurea (CEAU) is one of the four pathways that have been proposed for CENU decomposition. The CEAUs are reactive compounds which readily undergo a cycloelimination of chloride to form 2-alkylamino-2-oxazoline (AAO) hydrochlorides. This investigation employed ('13)C, ('15)N and ('1)H NMR techniques in order to (1) elucidate the stereochemistry of the AAO hydrochlorides in solution and (2) to understand the factors affecting the reactivity of CEAUs as well as the mechanism by which the cyclization occurs. Understanding the details of this cyclization is significant because a similar cyclization has recently been proposed as a CENU decomposition pathway. The stereochemistry of ten AAO hydrochlorides were studied in CDCl(,3) by ('13)C and ('15)N NMR. ('13)C spectra of AAO salts in CDCl(,3) showed that when the alkyl substituent was primary or secondary, two different stereochemical structures of the AAO salt were present in solution at ambient temperature. It was also observed that the equilibrium between the two stereoisomeric structures of a particular AAO hydrochloride was very concentration dependent. One of the stereoisomers was preferred at dilute concentration and AAO hydrochlorides with sterically larger alkyl groups exhibit a greater preference for this stereoisomer. ('15)N NMR showed that the endocyclic nitrogen of the AAO salts was protonated. It is proposed that protonation of the endocyclic nitrogen resulted in partial double bond character for the exocyclic carbon-nitrogen bond. Hindered internal rotation of the alkylamino group of AAO salts with primary or secondary alkyl groups was observed. It appears that ion pairing between the chloride and protonated AAO were responsible for the concentration dependence. The reactivity of CEAUs in CDCl(,3) was also investigated. Results support a mechanism involving nucleophilic attack by the carbonyl oxygen on the saturated carbon with the concomitant displacement of chloride.