A Novel Sc(OTf)₃‐Catalyzed (2+2+1)‐Cycloannulation/Aza‐Friedel–Crafts Alkylation Sequence toward Multicyclic 2‐Pyrrolines

Abstract

The rapid assembly of molecular complexity continues to be at the forefront of novel reaction development. In the pursuit of that goal, we herein report a novel Sc(OTf) -catalyzed, one-pot multicomponent reaction that furnishes complex multicyclic 2-pyrrolines with excellent overall yields and perfect diastereocontrol. This process is based on our previously established (2+2+1)-cycloannulation of in situ generated 1-azaallyl cations, 1,3-dicarbonyls and primary amines. The newly formed and highly reactive aminal moiety is readily substituted with indoles and pyrroles both as external and internal π-nucleophiles to provide densely functionalized N-heterocycles with four new σ-bonds and two vicinal quaternary stereogenic centers. In addition, DFT calculations have been conducted to further characterize the intermediate 1-azaallyl cations.

Scandium(III)‐Triflate‐Catalyzed Multicomponent Reactions for the Synthesis of Nitrogen Heterocycles

“…Other Sc(OTf) 3 ‐catalyzed multicomponent cycloaddition approaches have been also applied to the construction of nitrogen‐containing heterocyclic structures [46–50] . Recently, Schlegel et al [46] . described an impressive [2+2+1] cycloannulation/aza‐Friedel‐Crafts alkylation multicomponent strategy for the synthesis of complex indolizine‐derived multicyclic compounds.…”

“…The 4‐CR model assembly was studied with 2‐hydroxy oxime ether 25 and methyl acetoacetate to furnish the intermediate 26 , which could be treated in situ with benzylamine and several electron‐rich substituted indoles (or pyrroles) to give cis ‐tetrahydroindeno[2,1‐ b ]pyrroles 27 (or 28 ) as single diastereomeric products (Scheme 10). [46] …”

Au(I)-Catalyzed Pictet–Spengler Reactions All around the Indole Ring

“…The synthesis of 2-(1 H -indol-2-yl)­ethan-1-amine was performed following procedures from the literature. , To a solution of indole-2-carboxylic acid (16.1 g, 1.00 equiv, 100 mmol) in THF (75 mL) was added LiAlH 4 (7.9 g, 2.07 equiv, 207 mmol) at 0 °C in a 15 min period; the mixture was then allowed to warm to room temperature slowly and stirred at room temperature for about 3 h. The reaction was quenched with 2 M NaOH under 0 °C and extracted with EtOAc, dried over MgSO 4 , and evaporated under a vacuum. The crude product was then purified by column chromatography to afford the corresponding (1 H -indol-2-yl)­methanol in 84% yield (12.4 g, 84 mmol).…”

Iron(III)-Catalyzed (4 + 2)-Cycloannulation of 2-Hydroxy Ketoxime Ethers with Indol-2-ylamides: Synthesis of Indole-Fused 2-Piperidinones

“…8 We have recently established various Lewis acid catalyzed transformations of 2-hydroxy ketoxime ethers 5 including highly versatile Friedel−Crafts reactions (FCRs) 9 as well as multicomponent reactions toward complex 2-pyrrolines. 10,11 We proposed that these reactions proceeded through putative 1-azaallyl cations and provided computational evidence for their intermediacy. 10 Based upon these studies, we envisioned novel (4 + 2)-cycloannulation reactions when 1,4-bisnucleophiles were employed to capture the intermediate 1-azaallyl cations.…”

“…10,11 We proposed that these reactions proceeded through putative 1-azaallyl cations and provided computational evidence for their intermediacy. 10 Based upon these studies, we envisioned novel (4 + 2)-cycloannulation reactions when 1,4-bisnucleophiles were employed to capture the intermediate 1-azaallyl cations. Regioselective addition of Nu 1 would form addition product A followed by cyclization via Nu 2 onto the ketoxime ether to generate the six-membered cycloannulation product B (Scheme 1).…”