Theoretical Investigation on TMSOTf-Promoted Cascade Reaction of Propargyl Alcohol and Protected Tryptamine to Construct Hexahydropyrrolo-[2,3-b]Indoline

Abstract

The first theoretical investigation on TMSOTf-promoted cascade reaction of propargyl alcohol and protected tryptamine was provided by our DFT calculation. First, propargyl alcohol is activated by TMSOTf resulting in silyl ether accompanied by release of triflic acid. Then silyl ether undergoes Meyer-Schuster re-arrangement generating allenic intermediate and HOSiMe3. Hydroxyl is transferred from the latter to ter-minal alkyne carbon along with recovered TMSOTf. Subsequently, the regioselective C-3 nucleophilic addi-tion proceeds with indole ring of tryptamine furnishing four-membered ring. Next, 5-exo-trig cyclization occurs forming fused pyrrolo[2,3-b]indoline core with simultaneous opening of four-membered ring. At last, the keto enol tautomerization forges quaternary C-3 stereocenter through two times of proton transfer for product hexahydropyrrolo[2,3-b]indoline. Comparatively, SN 2 type 5-exo-trig cyclization forming five-membered ring is determined to be rate-limiting.

Keywords: TMSOTf; Meyer-Schuster Rearrangement; C-3 Nucleophilic Addition; 5-Exo-Trig Cyclization; Indole

Citation

Nan Lu. Theoretical Investigation on TMSOTf-Promoted Cascade Reaction of Propargyl Alcohol and Protected Tryptamine to Construct Hexahydropyrrolo-[2,3-b]Indoline. WebLog J Mol Cell Biol. wjmcb.2026. i1003. https://doi.org/10.5281/zenodo.22851575