Zinc‐Catalyzed Alkyne Oxidation/CH Functionalization: Highly Site‐Selective Synthesis of Versatile Isoquinolones and β‐Carbolines

Abstract

An efficient zinc(II)-catalyzed alkyne oxidation/C À Hf unctionalization sequence was developed, thus leading to highly site-selective synthesis of avariety of isoquinolones and b-carbolines.I mportantly,i nc ontrast to the well-established gold-catalyzed intermolecular alkyne oxidation, over-oxidation can be completely suppressed in this system and the reaction most likely proceeds by aF riedel-Crafts-type pathway.M echanistic studies and theoretical calculations are described.Scheme 1. Initial design.

Gold-catalyzed intermolecular reaction of ynamides with 3-indolyl azides via an unexpected 1,2-alkyl migration

“…Recently, the generation of a-imino gold carbenes [14][15][16][17][18][19][20][21][22] through gold-catalyzed alkyne amination has gained significant attention, because this strategy offers easy access to a variety of valuable complex nitrogen-containing molecules [23][24][25][26][27][28][29][30][31][32][33]. In our recent study on the ynamide chemistry [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48], we first disclosed that benzyl azides could serve as efficient nitrene transfer reagents to react with ynamides for the intermolecular generation of aimino gold carbenes. As a result, this chemistry has evolved into a robust and reliable method for the construction of versatile 2aminoindoles and 3-amino-b-carbolines (Scheme 2a) [49].…”

Brønsted Acid Catalyzed Oxygenative Bimolecular Friedel–Crafts‐type Coupling of Ynamides

“…[3] Yet, currently two shortcomings have become apparent, 1) the nature of the gold-carbene has been elusive [4] and 2) the reported procedures involve mostly intramolecular trapping by C-nucleophiles with afew exceptions. [5] In this context, several recent reports highlighted the possible use of Brønsted acids,b yw ay of intramolecular trapping of alkyne/pyridine-N-oxide adduct with tethered arenes or sp 3 CÀHb ond (Scheme 1B). [6] Foramore desirable intermolecular oxygenative CÀC coupling of alkynes with nucleophilic arenes,w ee nvisioned that ynamides,b yvirtue of easily polarized triple bonds, would be suitable precursors to keteniminium ions under Brønsted acid catalysis (Scheme 1C).…”

“…[11] Lowering the catalyst loading (2.5 mol %) still produced 75 %o f3a,a lthough it took 12 ha tR Tf or completion (entry 10). Notably,t hese optimized conditions are much milder as compared to the gold catalysis [5] or previous acidmediated conditions [6] that typically employ high temperature (80 8 8C) and/or stoichiometric amount of acids.Asaresult, we observed no over-oxidation or hydration that often prevail at higher temperatures. [5] With these optimized conditions,w ei nvestigated the scope of indole and pyrrole nucleophiles ( Table 2).…”

Brønsted Acid Catalyzed Oxygenative Bimolecular Friedel–Crafts‐type Coupling of Ynamides

“…Among various Brønsted acids tested, HNTf 2 was identified as the most suitable acid catalyst (entries 1-7). Notably,t hese optimized conditions are much milder as compared to the gold catalysis [5] or previous acidmediated conditions [6] that typically employ high temperature (80 8 8C) and/or stoichiometric amount of acids.Asaresult, we observed no over-oxidation or hydration that often prevail at higher temperatures. Increase in the concentration further reduced the reaction time,resulting in ahigher yield (89 %) after only 15 min at RT (entry 8).…”

“…Weaker acids required elevated temperature and longer time for conversion and extensively gave rise to competing hydration (4a)a nd hydrochlorination byproducts (5a). [5] With these optimized conditions,w ei nvestigated the scope of indole and pyrrole nucleophiles ( Table 2). Theefficiency was highly dependent on the structure of pyridine-N-oxides as well and among them, 2-Cl-pyridine-N-oxide 2a(2 equiv) was chosen as an optimal oxidant (Table S1 in the Supporting Information).…”