Intramolecular Schmidt reaction of tert-butyl 3-(3-azidopropyl)-4-oxopiperidine-1-carboxylate as a synthetic route to saturated fused aza heterocycles

Abstract

Treatment of the title compound with trifluoroacetic acid induced intramolecular Schmidt reaction with formation of a saturated fused heterocyclic system, tert-butyl 5-oxo-2, 3,4,5,7,8,9,9a-octahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2-carboxylate. The latter was reduced with lithium tetrahydridoaluminate, and subsequent treatment with hydrogen chloride in dioxane gave 2, 3,4,5,7,8,9,9a-octahydro-1H-pyrrolo[1,2-a][1,4]-diazepine dihydrochloride which is a promising intermediate product for the synthesis of N-substituted diazepines with a fused pyrrole ring.The Schmidt reaction, i.e., the reaction of carbonyl compounds with hydrazoic acid underlies an important method of synthesis of amines from carboxylic acids, amides from ketones, and nitriles from aldehydes [1,2]. It was found that the Schmidt reaction of aromatic aldehydes and cyclohexanone can be performed with the use of alkyl azides in the presence of strong acids; as a result, substituted arenecarboxamides [3] or N-substituted lactams [4] were obtained. Aube and Milligan [5] were the first to report intramolecular Schmidt reaction of azido ketone I with trifluoroacetic acid, which produced 91% of tricyclic lactam II (Scheme 1). Subsequently, analogous intramolecular cyclizations of various cyclic and aromatic azido ketones were studied, and fused polycyclic N-substituted lactams [6,7] and N-aryl-substituted lactams [8] were thus obtained. Apart from trifluoroacetic acid, titanium(IV) chloride, trifluoromethanesulfonic acid, and boron trifluoride-diethyl ether complex were used as catalysts.In continuation of our studies on the Schmidt reaction in the series of nitrogen-containing heterocyclic ketones [9], in the present work we made an attempt to accomplish intramolecular version of this reaction, as reported for analogous carbocyclic azido ketones [6]. For this purpose, we have synthesized azido ester V by alkylation of dimethylhydrazone III with 1-chloro-3-iodopropane [10] and subsequent nucleophilic substitution of the chlorine atom in IV by azido group on heating with sodium azide in DMSO (Scheme 2). Treatment of azide V with trifluoroacetic acid induced intramolecular Schmidt reaction leading to the formation of a new heterocyclic system. The product,4,7,8,9,4]diazepine-2-carboxylate (VI) was isolated in 24% yield after chromatographic purification.The discovered reaction attracts interest from the practical viewpoint, taking into account that it leads to fused diazepine derivatives which are known as pharmacologically important heterocyclic systems. Examples are zolazepam [11] (anticonvulsant and anesthetic agent), anxiolytic ripazepam [12,13], and antidepressant zometapine [14].Compound VI was subjected to chemical transformations to obtain a series of fused diazepine heterocycles. In particular, the carbonyl group in VI was reduced according to the procedure described in [15],