Copper‐Catalyzed Cascade Cyclization of Indolyl Homopropargyl Amides: Stereospecific Construction of Bridged Aza‐[n.2.1] Skeletons

Abstract

Catalytic cycloisomerization-initiated cascade cyclizations of terminal alkynes have received tremendous interest, and been widely used in the facile synthesis of adiverse arrayof valuable complex heterocycles.H owever,t hese tandem reactions have been mostly limited to noble-metal catalysis,and are initiated by an exo-cyclization pathway. Reported herein is an unprecedented copper-catalyzed endo-cyclization-initiated tandem reaction of indolyl homopropargyl amides,w here copper catalyzesb oth the hydroamination and Friedel-Crafts alkylation process.This method allows the practical and atomeconomical synthesis of valuable bridged aza-[n.2.1] skeletons (n = 3-6) with wide substrate scope,and excellent diastereoselectivity and enantioselectivity by ac hirality-transfer strategy. Moreover,t he mechanistic rationale for this novel cascade cyclization is also strongly supported by control experiments, and is distinctively different from the related gold catalysis.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

Copper‐Catalyzed Cascade Cyclization of Indolyl Homopropargyl Amides: Stereospecific Construction of Bridged Aza‐[n.2.1] Skeletons

“…Further screening of solvents such as toluene and chlorobenzene led to as lightly decreased yield (entries [14][15]. [20] Besides the formation of bridged aza-[3.2.1] skeletons,this copper-catalyzed cascade cyclization was also viable for the construction of other valuable bridged aza-[n.2.1] skeletons. [17] Thus,both the metal catalyst and protecting group of the substrate are the key to achieve the desired cascade cyclization.…”

“…Initial investigation of N-protecting groups of the amide moiety demonstrated that the reaction proceeded smoothly with different sulfonyl groups to furnish the desired aza-[3.2.1] skeletons 2a-d in 68-84 %yields (entries 1-4), and the Ts-protected homopropargyl amide 1a gave the best result (entry 1). [20] In addition, other heterocycle-tethered homopropargyl amides 7a-c,and even the alkoxy arene-substituted amide 7d were suitable substrates for such ac opper-catalyzed cascade cyclization, delivering the desired aza-[3.2.1] skeletons 8a-d in 56-86 %y ields [Eqs. In addition, amides containing different substituents on the indole ring also underwent smooth cascade cyclization,p roducing the corresponding 2f-n in good to excellent yields (entries [6][7][8][9][10][11][12][13][14], Finally,i tw as found that the reaction also occurred well with (S)-(+ +)-tert-butylsulfinamide-derived 1e' ',a nd thus the other enatiomer, 2e' ', was specifically produced (entry 15).…”

“…In addition, the N-Bs group in 4a,w hich could be prepared on ag ram scale in 89 %y ield, was easily converted into the corresponding N-Me group,a ffording the desired 4aa in 72 %yield (2 steps). [20] Finally,i tw as found that 6g could undergo deprotection of both sulfonyl groups,s elective methyl protection, and subsequent alkylation to produce 6gb,aknown inhibitor of histamine and imidazoline receptor. [22] Moreover, 4aacould also be selectively transformed into aza-[4.2.1] skeleton 4ad and chlorinated aza-[4.2.1] skeleton 4ae in 81 %a nd 88 %y ield, respectively.…”

Synthesis of Medium-Sized Heterocycles by Transition-Metal-Catalyzed Intramolecular Cyclization

“…Ye and co-workers disclosed the first copper-catalyzed tandem reaction of chiral indolyl homopropargyl amide 67 involving a 5- endo- dig hydroamination and a subsequent Friedel–Crafts alkylation [ 66 ]. This method afforded bridged aza-[ n .2.1]-indole-based tropanes in most examples, but was also extended to indole-fused medium-sized heterocycles 68 ( Scheme 25 ).…”

“…This approach was compatible with aliphatic, aryl, and heteroaryl aldehydes, allowing access to various 8-and 9-membered saturated N,N-and N,O-heterocycle 66 products (Scheme 24). Ye and co-workers disclosed the first copper-catalyzed tandem reaction of chiral indolyl homopropargyl amide 67 involving a 5-endo-dig hydroamination and a subsequent Friedel-Crafts alkylation [66]. This method afforded bridged aza-[n.2.1]-indole-based tropanes in most examples, but was also extended to indole-fused medium-sized heterocycles 68 (Scheme 25).…”