Iron-Catalyzed C(sp²)–H Alkylation of Indolines and Benzo[h]quinoline with Unactivated Alkyl Chlorides through Chelation Assistance

Abstract

Regioselective C–H bond alkylation of indolines and benzo­[h]­quinoline with a wide range of unactivated and highly demanded primary and secondary alkyl chlorides is accomplished using a low-cost iron catalyst. This reaction tolerates diverse functionalities, such as C­(sp2)–Cl, fluoro, alkenyl, silyl, ether, thioether, pyrrolyl, and carbazolyl groups including cyclic and acyclic alkyls as well as alkyl-bearing fatty-alcohol and polycyclic-steroid moieties. The demonstrated iron-catalyzed protocol proceeded via either a five-membered or a six-membered metallacycle. Intriguingly, the C-7-alkylated indolines can be readily functionalized into free-NH indolines/indoles and tryptamine derivatives. A detailed mechanistic investigation highlights the participation of an active Fe­(I) catalyst and the involvement of a halogen-atom transfer process via a single-electron-based mechanism. Deuterium labeling and kinetics analysis indicate that the C–H metalation of indoline is the probable turnover-limiting step. Overall, the experimental and theoretical studies supported an Fe­(I)/Fe­(III) pathway for the alkylation reaction comprising the two-step, one-electron oxidative addition of alkyl chloride.

Experimental and computational studies of the mechanism of iron-catalysed C–H activation/functionalisation with allyl electrophiles

“…[2][3][4][5] Recent efforts in C-H functionalisation methodologies have focused more heavily on the use of base metal catalysts in order to develop systems which utilise metals that have high natural abundance and low toxicity relative to their precious metal counterparts. [6][7][8] Of particular note are iron-catalysed systems for C-H activation/functionalisation which have rapidly expanded over the last decade to introduce a broad range of functionalities from C-C bond-forming arylation, [9][10][11][12][13][14][15] alkenylation, 12,16 and alkylation [17][18][19][20][21] to C-heteroatom forming amination, 22,23 borylation, 24,25 and halogenation 26,27 among many others [28][29][30][31][32][33][34] (Scheme 1). Central to many iron-catalysed C-H functionalisations, the selectivity and yields of these systems are reliant upon the incorporation of directing groups, with triazole and quinoline groups particularly widely used.…”

Advances in the Iron-Catalyzed Direct Functionalizations of ­Heterocycles

“…Very recently, Punji and co-workers demonstrated the regioselective C-7 alkylation of indolines with diverse unactivated primary and secondary alkyl chlorides (Scheme 10). 24 The use of a strong base LiHMDS and Fe(OTf)2/Xantphos catalyst system is crucial for the reaction. This alkylation proceeded via the 2-pyridinyl chelation assistance by forming a five-membered or six-membered metallacycle involving iron.…”

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

“…Iron‐catalyzed C7‐alkylation of indolines has been achieved with unactivated primary and secondary alkyl chlorides (Scheme 36). [39] The reaction tolerates diversely functionalized alkyl chlorides, and involves Fe(I)/Fe(III) redox cycle embedded with two‐step one‐electron oxidative addition of alkyl chlorides.…”