An Expeditious Synthesis of Substituted Pyrrolidines and Tetrahydrofurans Starting from Baylis-Hillman Adducts

Abstract

Suitably substituted pyrrolidines and tetrahydrofurans constitute important moieties of many biologically important natural and non-natural substances. Various synthetic methodologies for these compounds have been examined. Among them one of the expeditious route is the catalytic hydrogenation of the corresponding exoor endo-double bond-containing precursors. Recently, we reported the synthesis of 2,5-dihydropyrroles and furans via the ring-closing metathesis (RCM) reaction of suitably modified Baylis-Hillman adducts. In addition, we reported the synthesis of exo-methylene tetrahydropyrroles and furans by using the radical cyclization of suitably modified Baylis-Hillman adducts. With these endoand exo-methylene compounds we examined the feasibility for the synthesis of substituted pyrrolidines and tetrahydrofuran derivatives under various catalytic hydrogenation conditions (Scheme 1). Required starting materials, 1a-d, were synthesized according to the previous paper from the Baylis-Hillman adducts or aza-Baylis-Hillman adducts via the sequential allylation and RCM reaction with second generation Grubbs catalyst. With these compounds we examined the hydrogenation toward tetrahydrofuran 2a and pyrrolidines 2b-d under typical catalytic hydrogenation conditions (EtOH, Pd/C, H2 balloon) and we obtained the desired compounds 2a-d in good to excellent yields with complete stereocontrol at room temperature or at elevated temperature depending upon the substrates (entries 1-4, Table 1). The stereochemistry of products 2a and 2b is cis based on the references and NOE experimental results of 2a (vide infra, Figure 1). As a next trial we examined the hydrogenation of exomethylene compounds 1e and 1f, which were prepared via the radical cyclization from the suitably modified BaylisHillman adducts as reported. The hydrogenation of 1e under similar conditions (Pd/C, EtOH) at room temperature or at around 40-50 C did not produce the tetrahydrofuran derivative 2e in appreciable amounts. When we carried out the reaction at elevated temperature (Pd/C, EtOH, reflux, 20 h, entry 5) we could obtain the reduction product 2e in 63% yield as a diastereomeric mixture (3:1). In the reaction we isolated trace amounts of 2,3-dihydrofuran derivative 3 (2%) and recovered remaining starting material 1e in 25% yield. The yield and stereoselectivity of 2e was not improved with Adam’s catalyst (PtO2, EtOH, reflux, 30 h, entry 6). However, when we replaced the solvent to EtOAc and carried out the reaction at around 50 C we could isolate the compound 3 in an increased yield (15%, entry 7). It is interesting to note that the yield of 3 could be increased to 97% under the conditions of Pd/C in EtOAc at room temperature (entry 8). The reaction of 1f under typical conditions (Pd/C, EtOH, 50 C, 10 h) did not produce any new compounds in appreciable amounts and the starting material 1f was recovered in 87% yield. However, when we changed the conditions (PtO2, EtOAc, 50 C, 12 h) desired reduction product 2f was obtained in 70% yield (9:1 mixture). The major isomer was separated in pure state and the stereochemistry was determined by NOE experiments (Fig. 1). However, unfortunately, we could not synthesize the double bond-isomerized compound, 2,3-dihydropyrrole, in this case under various conditions. In summary, we disclosed an expeditious route for the synthesis of pyrrolidines and tetrahydrofurans starting from