Azepine / Cyclization, electrophilic / Pyrrolidines The synthesis of nitrogen-containing heterocycles is of continuing interest since many compounds of this type show a strong biological activity. A valuable method for the preparation of N-heterocycles is the cyclization of unsaturated iminium salts'), which are usually produced in situ from an amine or carbamate and a reactive aldehyde, e.g. formaldehyde. To obtain useful results, vinyl2)-and allylsilanes3) as terminating groups have to be employed. However, using imines which are activated by two electron-withdrawing groups such as esters, even with nonactivated alkenes, good results are obtained. This reaction also allows a simple access to substituted cyclic nonproteinogenic a-amino acids. Thus, recently we described the cyclization of the imines 14), which leads to substituted piperidines 2 and annulated piperidine lactones 3 by initiation with Lewis acids like FeC13 or trialkylsilyl triflates. According to the reaction conditions employed either the a-amino dicarboxylic ester 2 or the a-amino lactone ester 3 is isolated as main product. 1 2 3
In this paper we describe the extension of this protocol to the synthesis of pyrrole and azepine derivatives.
For the synthesis of five-, seven-, and eight-membered heterocycles the iminomalonates 8 -10 with two, four, and five methylene units, respectively, in the chain between the n: systems were prepared. They are easily obtained in almost quantitative yield by condensation of the primary amines 4-6 and ethyl as well as isopropyl mesoxalate 7a and 7 b in benzene with azeotropic removal of water.
a: R= E t b: R= iPr Treatment of 8a with trimethylsilyl triflate (TMS-OTf) in dichloromethane or tert-butyl methyl ether afforded the pyrrolidines l l a and 12a in a total yield of 61 and 53%, respectively. 12a is only a minor product, which is presumably formed in a side reaction by alkylation of the product l l a (Table 1).