ABSTRACT
1-Allyl- and 1-(3-phenylallyl)-substituted 4-(2-bromo-1,1-dimethylethyl)azetidin-2-ones were transformed into 3-substituted 7-alkoxy-5,5-dimethyl-1-azabicyclo[4.2.0]octane-8-ones through radical cyclization by means of n-tributyltin hydride and AIBN in toluene with excellent diastereocontrol (>or=99%). The radical cyclization of 4-(2-bromo-1,1-dimethylethyl)-1-(2-methylallyl)azetidin-2-ones afforded 8-alkoxy-3,6,6-trimethyl-1-azabicyclo[5.2.0]nonan-9-ones in good diastereomeric excess (75-78%). The reductive ring opening of 1-azabicyclo[4.2.0]octane-8-ones and 1-azabicyclo[5.2.0]nonan-9-ones with lithium aluminum hydride resulted in novel 2-(1-alkoxy-2-hydroxyethyl)piperidines and -azepanes, which were isolated as single isomers.
Subject(s)
Azepines/chemistry , Bridged Bicyclo Compounds/chemical synthesis , Piperidines/chemistry , beta-Lactams/chemical synthesis , Cyclization , Magnetic Resonance Spectroscopy , Mass Spectrometry , Oxidation-Reduction , StereoisomerismABSTRACT
[reaction: see text] A new synthesis of stereodefined aziridines and azetidines, starting from 4-(1- or 2-haloalkyl)azetidin-2-ones, is described. Treatment of the latter compounds with LiAlH(4) gave 1,2-fission of the beta-lactam, followed by an intramolecular nucleophilic substitution of the halogen, giving rise to the formation of 2-(1-alkoxy-2-hydroxyethyl)aziridines in the case of 4-(1-haloalkyl)azetidin-2-ones and of 2-(1-alkoxy-2-hydroxyethyl)azetidines in the case of 4-(2-haloalkyl)azetidin-2-ones. The resulting 2-(1-alkoxy-2-hydroxyethyl)aziridines were transformed into the corresponding trans-3,4-substituted oxolanes via an intramolecular nucleophilic ring opening, triggered by AlCl(3).
ABSTRACT
The synthesis of 4-(1-haloalkyl)-2-azetidinones and 4-(2-haloalkyl)-2-azetidinones was investigated with use of the Staudinger reaction between in situ generated ketenes and alpha-haloimines or beta-haloimines. This new class of functionalized 2-azetidinones was further evaluated for its potential use as intermediates in the synthesis of highly functionalized compounds. The reaction of 4-(1-haloalkyl)-2-azetidinones and 4-(2-haloalkyl)-2-azetidinones with sodium methoxide in methanol yielded ring-opened products, i.e., methyl 2-alkoxy-4-(alkylamino)pentenoate and methyl 5-(alkylamino)pentenoate, respectively. Further attention was paid in detail to the reaction mechanism involved in this peculiar transformation. It was proven that these reactions proceeded via intermediate aziridines or azetidines.
ABSTRACT
An easy synthesis of 2-aryl-3,3-dichloroazetidines, a rather unexplored class of azaheterocycles, is described. The title compounds were easily obtained by reduction of the corresponding 4-aryl-3,3-dichloro-2-azetidinones with monochloroalane, which in turn were synthesized by a ketene-imine [2 + 2] cycloaddition. The reactivity of 3,3-dichloroazetidines with bases was investigated, yielding 2-[dimethoxy(aryl)methyl]aziridines by ring contraction when treated with sodium methoxide. Furthermore, reacting the 3,3-dichloroazetidines with sodium hydride in DMSO, followed by aqueous workup, afforded 1-alkyl-2-aroylaziridines, by hydrolysis of the intermediate 2-azetines and ring closure of the transient 3-amino-2-chloro-1-phenyl-1-propanone derivatives. Monitoring this reaction in an NMR tube, using sodium hydride in DMSO-d(6), allowed the characterization of the intermediate strained heterocyclic enamines, i.e., 2-azetines, by (1)H and (13)C NMR.