Cyclization of enaminones derived from N-phenacylpyrrolidin-2-ones to pyrrolizines under acidic conditions

Abstract

Several N-phenacyl enaminones, prepared by Eschenmoser sulfide contraction between Nphenacylpyrrolidine-2-thiones and a range of substituted phenacyl halides, were transformed into 2,3dihydro-1H-pyrrolizines when treated with acetic acid or silica gel. Yields of the bicyclic products were in the range 57-100% depending on the route followed. Some further reactions of the newly formed pyrrole rings are also reported.

Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

“…A variety of N-(ethoxycarbonylmethyl) vinylogous amides prepared in three steps from pyrrolidin-2-one ( 16) or piperidin-2one (23) underwent cyclization to yield 2,3-dihydro-1H- The enaminone acted as an electrophile in these cyclization reactions rather than as a nucleophile, as had previously been found with N-phenacyl analogues [18]. The formation of products 19 occurred within minutes at 150 °C in xylene, while formation of products 26 occurred in ethanol at 100 °C in a few hours.…”

“…No apparent reaction occurred with dilute hydrochloric acid in ethanol (Table 1, entry 14) unless the solution was heated, in which case decomposition took place (Table 1, entry 15). Solutions of 15a in dichloromethane also decomposed rapidly when treated with aluminum trichloride or boron trifluoride at 50 °C, although no reaction was apparent at room temperature even after 18 hours (Table 1, entries [16][17][18][19]. When a solution of 15a in dichloromethane was treated with Amberlyst 15, an ion exchange resin with a strongly acidic sulfonic acid [40], it was rapidly adsorbed and presumably protonated, but it could be displaced from the resin upon treatment with aqueous sodium hydrogen carbonate (Table 1, entries 20 and 21).…”

“…In contrast to the corresponding N -phenacyl analogue 11 (Ar = Ar’ = Ph), the ester-containing enaminone 15a proved to be completely stable during chromatography on silica gel or upon dissolution in acetic acid at room temperature (conditions under which we had observed cyclization of vinylogous amides 11 [ 18 ]), and spontaneous cyclization to the expected pyrrolizinone 13a or tautomer 13a' did not take place ( Table 1 , entry 1). More vigorous conditions were therefore investigated.…”

“…The pyrrolizidine motif has up to now eluded us other than when it forms part of the tricyclic 2,3-dihydro-1 H -pyrrolo[1,2- a ]indole system [ 15 ], as in our route to aziridinomitosenes [ 16 – 17 ]. In the course of our attempts at the syntheses of aryl-bearing indolizidine alkaloids via N -phenacyl vinylogous amides such as 11 , however, we fortuitously found substituted 2,3-dihydro-1 H -pyrrolizines 12 as unexpected products when intermediates 11 were exposed to acidic conditions, including treatment with acetic acid or even during chromatography on silica gel ( Scheme 1 ) [ 18 ]. In these cyclizations the enaminone acts as an intramolecular nucleophile towards the phenacyl substituent, even though the nucleophilic character of the enamine component is expected to be suppressed by the “push–pull” effect arising from the electron-withdrawing carbonyl group [ 19 – 23 ].…”

“… Previous [ 18 ] and proposed routes to 2,3-dihydro-1 H -pyrrolizines from enaminones. Reagents and conditions: (i) AcOH–MeOH, rt, 18–24 h; (ii) SiO 2 , 90 °C, 1–2 h. …”