Synthesis of C4-Aminated Indoles via a Catellani and Retro-Diels–Alder Strategy

Abstract

Highly functionalized 4-aminoindoles were synthesized via the three-component cross-coupling of o-iodoaniline, N-benzoyloxyamines, and norbornadiene. The Catellani and retro-Diels–Alder strategy was used in this domino process. o-Iodoaniline, with electron-donating and sterically hindered protecting groups, made the reaction selective toward o-C–H amination. On the basis of density functional theory calculations, the intramolecular Buchwald coupling of this reaction underwent a dearomatization and a 1,3-palladium migration process. The reasons for the control of the chemical selectivity by the protecting groups are given. Moreover, synthetic applications toward 4-piperazinylindole and a GOT1 inhibitor were realized.

Recent Developments in the Palladium‐Catalyzed/Norbornene‐Mediated Synthesis of Carbo‐ and Heterocycles

“…[10] In 2019, Liang et al elegantly developed palladium catalyzed method for the synthesis of highly functionalized 4aminoindoles 16 from three-component cross coupling of ortho-iodoaniline 13, N-benzoyloxyamines 14, and norbornadiene 15 (Scheme 3). [11] Optimization studies revealed that use of Pd(OAc) 2 (10 mol%) as the catalyst, PPh 3 (20 mol%) as the ligand and Cs 2 CO 3 (4 equiv) as a base in toluene at 140 0 C for 36 h. In this reaction, strong electron withdrawing groups such as À NO 2 , À F and À Cl containing ortho-iodoanilines worked well and provided the desired products in excellent yields. The method was also found to be feasible for heterocyclic substrates such as 3iodopyridin-2-amine and 4-amino-7-azaindole afforded the corresponding products in good yields.…”

“…elegantly developed palladium catalyzed method for the synthesis of highly functionalized 4‐aminoindoles 16 from three‐component cross coupling of ortho ‐iodoaniline 13 , N ‐benzoyloxyamines 14 , and norbornadiene 15 (Scheme 3). [11] …”

Catellani Reaction: An Enabling Technology for Vicinal Functionalization of Aryl Halides by Palladium(0)/Norbornene Cooperative Catalysis

“…In 2019, Liang demonstrated such a strategy was compatible for the one‐step synthesis of highly functionalized 4‐aminoindoles 91 by combing o ‐iodoanilines with N‐ benzoyloxyamines (Scheme 35). [ 96 ] Importantly, electron‐donating group with large steric bulkiness on the nitrogen proved to be more beneficial, and the Catellani and retro‐Diels−Alder reactions could occur at the same time, thus enabling the one‐pot synthesis of 4‐aminoindoles.…”

Trifunctionalization of Aryl Iodides with Two Distinct Nitrogen and Carbon Electrophiles by Palladium/Norbornene Catalysis

“…If so, it would lead to highly valuable 1,2,3‐trifunctionalized arenes by the direct trifunctionalization of ortho ‐unsubstituted aryl halides at their three adjacent positions. [ 34‐38 ] However, the development of such a reaction is not a trivial task. According to the reactivity difference of electrophiles E a and E b that are involved, two main reaction modes could be envisioned.…”