An Efficient Synthetic Route for Pyrrolizinone Synthesis through Functionalized C-Alkylpyrroles

Abstract

Regioselective addition of pyrrole to methyl 3-aryl-2-cyanoacrylates was achieved, in high yields, with copper(II) triflate as the catalyst in toluene. C-Alkylated pyrroles afforded novel pyrrolizin-3-ones, in good to high yields and high diastereomeric ratio by an intramolecular cyclization reaction under mild reaction conditions.Bridgehead-nitrogen-containing heterocycles constitute a very large family of natural products. Pyrrolizine alkaloids are of interest among heterocyclic compounds since they have a wide range of biological activity. 1 Therefore, the development of efficient and simple synthetic methods for heterocyclic compounds occupy a broad area in organic synthesis.In several previously published works, different synthetic approaches have been used to construct the pyrrolizin-3-one structure (Scheme 1). Cyclization of the condensation product of pyrrole-2-carbaldehyde and malonic acid yielded pyrrolizin-3-one in very low yields. 2 It was reported that the reaction of 2-[(dimethylamino)methyl]pyrrole and diethyl acetamidomalonate in basic medium directly produced the bicyclic pyrrolizin-3-one structure (Scheme 1, eq. 1). 3 McNab was the first to generate 3H-pyrrolizin-3-one by flash vacuum pyrolysis (FVP) of the condensation product of pyrrole-2-carbaldehyde with Meldrum's acid (Scheme 1, eq. 2). 4 Pinho e Melo and co-workers later obtained pyrrolizin-3-ones by FVP of N-vinyl-and Cvinylpyrroles generated by the thermal extrusion of sulfur dioxide from pyrrolo[1,2-c]thiazole 2,2-dioxides (Scheme 1, eqs. 3 and 4). 5 Recently, pyrrolizin-3-one derivatives were synthesized from the alkylation products of pyrrole with a,b-unsaturated 2-acylimidazoles by Evans and Fandrick (Scheme 1, eq. 5) 6 and from the cyclization of the radical reaction product of pyrrole and a-halo esters by Byers and co-workers (Scheme 1, eq. 6). 7Despite the existence of different synthetic approaches for the synthesis of the pyrrolizin-3-one structure with different substituents, there remains a need for efficient and simple synthetic methods that provide substituted pyrrolizine structures under mild reaction conditions. We previously demonstrated that metal triflates are very efficient catalysts for the addition of pyrrole to a,b-unsaturated carbonyl compounds under mild reaction conditions. 8 This methodology allows direct alkylation of pyrroles in high yields. Alkylated products, especially with carbonyl or ester functionalities, have been demonstrated to be convenient precursors for the synthesis of pyrrolizine structures by their intramolecular cyclization. 9,10

Michael Addition of N-Heteroaromatics to Vinylphosphonates and Synthesis of Phosphoryl Pyrrolizones by Cyclization of Michael Adducts

“…Ar H R configuration if the vicinal coupling constant of the hydrogens was in the range 4.8-6.4 Hz and cis configuration if the vicinal coupling constant was in the range of 8.2-8.8 Hz. 10 In this work, the vicinal coupling constants of the hydrogens of 5a-j,l-p are between 4.0-4.4 Hz. As the vicinal coupling constants of 5a-j,l-p are in good agreement with the coupling constants previously correlated with trans configurations, the novel phosphorylpyrrolizones 5a-j,l-p are also assigned as trans.…”

“…8 They are used as antiinflammatory and analgesic drugs and as aromatase and tumor inhibitors. Current methods for the construction of the pyrrolizine skeleton involve intramolecular cycliza-tion of N-2b,7b,8a,9 or C-substituted 10,11 pyrrole derivatives. Base-catalyzed condensation 11c and intramolecular cyclization of C-alkylpyrrole derivatives in the presence of sodium carbonate 11d and sodium hydride 10 are effective methods for the synthesis of pyrrolizine ring structures.…”

“…Current methods for the construction of the pyrrolizine skeleton involve intramolecular cycliza-tion of N-2b,7b,8a,9 or C-substituted 10,11 pyrrole derivatives. Base-catalyzed condensation 11c and intramolecular cyclization of C-alkylpyrrole derivatives in the presence of sodium carbonate 11d and sodium hydride 10 are effective methods for the synthesis of pyrrolizine ring structures. Flash vacuum pyrolysis is also an applicable method for the cyclization of both N-alkyl-9b and C-alkylsubstituted 11a,b pyrrole derivatives to pyrrolizine ring structures.…”

Synthesis and styrene copolymerization of novel fluoro-iodo, trifluoromethyl, and trifluoromethoxy ring-substituted isobutyl phenylcyanoacrylates

“…Alkyl cyanoacrylates is family of vinyl monomers renowned for their high reactivity, instant adhesive properties, and wide-ranging applications [1][2][3]. Trisubstituted ethylenes (TSE), ring-functionalized (R 1 ) alkyl (R 2 ) phenylcyanoacrylates, R 1 PhCH = C(CN)CO2R 2 (PCA) continue to attract attention as compounds with variety of applications [4][5][6][7][8][9][10][11]. Thus, 2methoxy ring-substituted methyl PCA was used in pyrrolizinone synthesis through functionalized C-alkylpyrroles [4], as well as in molecular design for enhanced second-order nonlinear optical response [5,6].…”

“…Trisubstituted ethylenes (TSE), ring-functionalized (R 1 ) alkyl (R 2 ) phenylcyanoacrylates, R 1 PhCH = C(CN)CO2R 2 (PCA) continue to attract attention as compounds with variety of applications [4][5][6][7][8][9][10][11]. Thus, 2methoxy ring-substituted methyl PCA was used in pyrrolizinone synthesis through functionalized C-alkylpyrroles [4], as well as in molecular design for enhanced second-order nonlinear optical response [5,6]. 3-Methoxy ring-substituted methyl PCA was employed in diastereoselective syntheses of polysubstituted cyclohexanes and cyclopentenes via chemoselective phosphine-catalyzed cascade annulations [7] and in enhancement of the hyperpolarizability of styrene [8].…”