Iridium‐Catalyzed Direct C4‐ and C7‐Selective Alkynylation of Indoles Using Sulfur‐Directing Groups

Abstract

Indoles and their analogues have been one of the most ubiquitous heterocycles during the past century,a nd extensive studies have been conducted to establish practical synthetic methods for their derivatives.I np articular,s elective functionalization of the poorly reactive benzenoid core over the pyrrole ring has been agreat challenge.Reported herein is an iridium-catalyzed direct alkynylation of the indole C4-and C7-positions with the assistance of sulfur directing groups.This transformation shows aw ide range of functional-group tolerance with exceptional site selectivity.T he directing group can be either easily removed or transformed after catalysis.The synthetic utility of the alkyne fragment is demonstrated by the derivatization into the core structure of natural indole alkaloids.Scheme 3. Effect of the directing groups for the C7-selectivealkynylation. DCM = dichloromethane.Scheme 4. Substrate scope for the C7-selectivea lkynylation.Scheme 5. Derivatization of the C4-alkynylated indole 3a.D MF = N,Ndimethylformamide.

Phosphorus(III)-assisted regioselective C–H silylation of heteroarenes

“…Treatment of indole 1a either with both Ag 2 CO 3 (entry 3) or Cu(OAc) 2 (entry 4) showed much less efficient for C7-silylation, along with large amount of the by-product 5. solvent to other nonpolar solvent like cyclohexane also provided product 2a efficiently (entry 9), and the use of polar solvents involving DMF and THF, only led to trace amount of product 2a (not shown in the table). The indole substrates bearing other directing groups like N-P(O) t Bu 2 (5), N-Ts (7), N-Piv (8) and N-SMe (9) 49 were failed to generate any C-H silylation products, and only a small amount of C2 silylation by-product was obtained with 1-(pyrimidin-2-yl)-1H-indole (10) (entry 10). These results confirm the importance of the N-P t Bu 2 group moiety for achieving both high reactivity and selectivity.…”

“…Usually, C7-selective C-H functionalization of indoles demands the installation of a functional group at the C2 position to block this possible site 41 . Notably, numerous research groups have recently made valuable progress on direct C-H functionalization of indoles at C7-position [42][43][44][45][46][47][48][49] . In 2010, the C7-selective C-H borylation of indole was uncovered through iridium catalysis with the assistance of N-silyl-directing group 50 .…”

Recent Development on Cp*Ir(III)‐Catalyzed C−H Bond Functionalization

“…In 2019, Nishii and Miura developed an Ir(III)‐catalyzed regio‐divergent alkynylation of indoles with TIPS‐EBX as the alkynylation reagent, using thioethers as the directing groups (Scheme ). For C3‐thioether indoles, selective C4−H alkynylated indole products were obtained; while C7−H alkynylation proceeded smoothly with the use of N −SMe indoles.…”

Recent Advances in Metal‐catalyzed Alkylation, Alkenylation and Alkynylation of Indole/indoline Benzenoid Nucleus

“…Miura group explored thioether directed C4‐selective functionalization of indoles employing TIPS‐EBX under Ir(III)‐catalysis (Scheme 18). [21a] The reaction tolerates a wide range of functional group across all the positions of indole. As above, the thioether group can either easily be detached or converted into different type of building blocks.…”

“…While Miura and co‐workers achieved a direct C7‐alkynylation of indoles with TIPS‐EBX by incorporating a SMe DG onto the indole N ‐atom under Ir(III)‐catalysis (Scheme 46). [21a] The N‐SMe indoles are deprotected under basic treatment in‐situ to deliver C7‐alkynylated indole with broad substrate scope and functional group diversity.…”