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
β-Amino alcohols derived from (1R,2S)-norephedrine were synthesized and used as ligands in the catalytic enantioselective diethylzinc addition to benzaldehydes. N-alkylated (1R,2S)-norephedrine-based derivative 3a gave the highest enantioselectivity. The effects of different parameters on the enantioselectivity of the product were investigated.
A series of metal triflate-catalyzed addition reactions of pyrrole to C=C and C=N bonds have been investigated to access pyrrole-based heterocyclic compounds. The addition of pyrrole to different α,β-unsaturated compounds or N-tosyl imines afforded suitable structures for the construction of [5-5] bicyclic systems or porphyrins, respectively. Intramolecular cyclization reactions were applied for the synthesis of pyrrolizine derivatives. In the other reaction mode, intermolecular cyclization reactions gave A4- and trans-A2B2-meso-substituted porphyrins under mild reaction conditions with low scrambling.
Novel phosphonate compounds were synthesized via Michael addition of N-heteroaromatic compounds to aryl-and alkyl-substituted vinylphosphonates using scandium triflate as the catalyst. Intramolecular cyclization reaction of the Michael adducts obtained gives novel (dimethoxyphosphoryl)pyrrolizin-3-ones in high yields as a single diastereomer.Phosphonates 1 and pyrrolizines 2 have attracted interest because of their biologically important properties. Derivatives of phosphonates are active as insecticides, herbicides, fungicides, plant growth regulators, and drugs and they are also effective transition-state-analogue inhibitors for a variety of enzymes. 3 Many synthetic methods for phosphonate analogues utilize C-C, 4 C-P, 5 and C-N 6 bond-formation processes. Among these, Michael addition appears to be more successful, since vinylphosphonates containing electron-withdrawing groups at the α-position are potential Michael acceptors. 4c The Michael addition reactions of N-heteroaromatics, e.g. imidazole and pyridine to bis(phosphono)ethylenes, 4f nitroalkanes to ethyl 2-(diethoxyphosphoryl)acrylate, 4g,h indole to dicyclohexylammonium 2-(diethoxyphosphoryl)acrylate, 4i vinylidene bisphosphonates and vinylphosphonates 4j have been studied. However, to the best of our knowledge, direct addition of pyrrole to vinylphosphonates has not yet been reported.Pyrrolizin-3-ones are mainly isolated from plants, insects, animals, marine organisms, and microbes. 7 The biological activity of pyrrolizines has been attributed to their unique bridgehead nitrogen skeleton. 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 cyclization 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. The intramolecular Wittig reaction of N-substituted phosphorus ylides has been used for the synthesis of functionalized 1H-pyrrolizine derivatives. 2b,8a,9a Arylsubstituted pyrrolizine derivatives have been synthesized by the intramolecular cyclization of N-alkylpyrrole derivatives in the presence of boron tribromide. 7b In our previous studies we reported that the metal triflates are suitable catalysts for the addition reactions of pyrrole to α,β-unsaturated systems. 12 We obtained ester-and cyano-functionalized pyrrole addition products in high yields with metal triflates. Among the obtained products, the ester-functionalized dimethyl 2-[phenyl(1H-pyrrolyl)methyl]malonate, methyl 2-cyano-3-phenyl-3-(1H-pyrrol-2-yl)propanoate and their substituted derivatives gave pyrrolizin-3-one structures via intramolecular cyclization...
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