I₂‐Catalyzed Cycloisomerization of Ynamides: Chemoselective and Divergent Access to Indole Derivatives

Abstract

Herein, an I 2 -catalyzed unprecedented cycloisomerization of ynamides is developed, furnishing various functionalized bis(indole) derivatives in generally good to excellent yields with wide substrate scope and excellent atom-economy. This protocol not only represents the first molecular-iodine-catalyzed tandem complex alkyne cycloisomerizations, but also constitutes the first chemoselective cycloisomerization of tryptamine-ynamides involving distinctively different C-(sp 3 )À C(sp 3 ) bond cleavage and rearrangement. Moreover, chiral tetrahydropyridine frameworks containing two stereocenters are obtained with moderate to excellent diastereoselectivities and excellent enantioselectivities. Meanwhile, cycloisomerization and aromatization of ynamides produce pyrrolyl indoles with high efficiency enabled by I 2 . Additionally, control experiments and theoretical calculations reveal that this reaction probably undergoes a tandem 5-exo-dig cyclization/rearrangement process.

Methodological Development and Applications of Tryptamine-Ynamide Cyclizations in Synthesizing Core Skeletons of Indole Alkaloids

“…In addition, some excellent examples on cyclizations of tryptamine-ynamides with different reaction pathways were also reported, which afforded facile access to the diverse skeletons of indole alkaloids.…”

Two-component symmetrical diarylation of ynamides

“…[11][12][13][14][15][16][17][18][19][20][21][22] On the other hand, ynamides, a special class of N-substituted alkynes, are of particular interest due to their unique reactivity arising from the polarization of N-lone pair electrons. [23][24][25][26][27][28][29][30][31][32][33][34][35] The intermediates involved in this process, such as keteniminium ions, and metal carbenoids, are crucial for metal-catalyzed dicarbofunctionalization reactions; the process allows making tetrasubstituted enamides. 36 Given the importance of such enamides, development of pathways for the synthesis of substituted enamides attracts attention.…”

Green and rapid acid-catalyzed ynamide skeletal rearrangement and stereospecific functionalization with anisole derivatives

“…1 However, there are many challenges and problems facing synthetic chemists due to its complementary reactivities under radical, 2 ionic or acidic, 2 f ,3 and transition-metal-catalyzed reactions 4 due to the biased carbon–carbon (α and β) triple bond directly bind to the nitrogen atom bearing an electron-withdrawing functionality, which results in higher reactivity, unwanted by-products, and issues with chemo-, regio-, and stereospecificity. 1–4 Various research groups (Sahoo, 1 c ,2 d , f ,5 Ye, 1 b , f ,2 b ,3 b , d ,4 a Evano, 2 a ,6 Hashmi, 7 and many others 8 ) have remarkably utilized ynamides in the construction of various heterocyclic compounds with the help of transition metals, Brønsted acids or additives, depending on the selection of the starting material and reaction conditions. 1–8 In particular, the key reaction intermediates generated in ynamide reactions are keteniminium 2 f ,3 with electrophilic reagents and ketenimine 4 c ,9 under thermal conditions or with nucleophilic reagents.…”