Nanotechnologies / Materials
Drug development, Process chemistry, Electroluminescence material

Sulfur-directed site-selective functionalization of indolederivatives
Department of Applied Chemistry, Graduate School of Engineering
Associate Professor Yuji Nishii

https://researchmap.jp/y_nishii

Institute for Open and Transdisciplinary Research Initiatives (OTRI)Specially Appointed Professor Masahiro Miura

Nanotechnologies / Materials

Abstract
Indoles and their analogues have been one of the most ubiquitous heterocycles during the past century, and extensive studies
have been conducted to establish practical synthetic methods
for their derivatives. In particular, selective functionalization of thepoorly reactive benzenoid core over the pyrrole ring has been agreat challenge. We have developed transition-metal-catalyzed
direct functionalization of the indole C4- and C7-positions with theassistance of sulfur directing groups. This transformation shows awide range of functional-group tolerance with exceptional site selectivity. The directing group can be either easily removed or transformed after the catalysis.

▍ Background & Results
The indole heteroaromatic scaffold has been one of the mostprivileged heterocycles due to its wide prevalence in a variety ofmarketed drugs, biologically active compounds, and functionalmolecules. Accordingly, significant research interest has been focused on the development of site-selective decollation methods forindole derivatives, and the transition-metal-catalyzed direct C–Hbond transformation has recently been recognized as an attractive
synthetic tool for the late-stage functionalization. The indole coreinherently offers the six distinctive reaction sites for the catalysis.
Among these, selective functionalization of the benzenoid fragment
over the highly reactive C2 and C3 positions (pyrrol ring) has remained as a big challenge for the synthetic community. To address
this thorny issue, various catalytic protocols have been developedwith the aid of appropriate directing groups during the past decade.

https://researchmap.jp/read0013936

In this regard, we have interested in utilizing sulfur-based directing groups for the site-selective functionalization of indole skeleton.
The sulfur functionality (thioether) could be readily installed at theindole N1 and C3 positions upon treatment indole derivatives withelectrophilic sulfur reagent such as N-sulfanyl phthalimide. Additionally, these directing groups were easily removable under appropriate reaction conditions: treatment with TBAF (tetrabutylammonium fluoride) for the N1-SR groups, Raney Ni reduction or oxidation
into Isatin (indole-2,3-dione) scaffold for the C3-SR groups. More
importantly, the C3-S bond could be subjected to the Ni-catalyzed
Kumada-type cross-coupling reaction with Grignard reagents togive C3-alkylated and C3-arylated indoles. With the aid of the sulfur directing group, we achieved C4- and C7-selective direct C-Hfunctionalization of indole derivatives: Rh(III)-catalyzed alkenylation
and acylmethylation, Ir(III)-catalyzed alkynylation.

▍ Significance of the research and Future perspective
As described above, selective functionalization of the indole
benzene ring has remained as a significant challenge, and limited
achievement has been accomplished to date. In this work, we havesuccessfully developed a series of catalytic direct functionalization
methods. After the catalysis and removal of the sulfur directing
group, the obtained substituted indole derivatives could be furthertransformed to synthetically valuable yet difficult to access ringfused indoles, which highlighting the substantial importance in medicinal and materials chemistry.

P a t e n t
Kona, Chandrababu Naidu; Nishii, Yuji; Miura, Masahiro. Iridium-Catalyzed Direct C4- and C7-Selective Alkynylation of Indoles Using Sulfur-Directing
Groups Angew. Chem. Int. Ed. 2019, 58, 9856-9860. doi: 10.1002/anie.201904709
T r e a t i s e Kona, Chandrababu Naidu; Nishii, Yuji; Miura, Masahiro. Thioether-Directed C4-Selective C-H Acylmethylation of Indoles Using α- Carbonyl Sulfoxonium
Ylides Org. Lett. 2020, 22, 4806-4811. doi: 10.1021/acs.orglett.0c01617
Kona, Chandrababu Naidu; Nishii, Yuji; Miura, Masahiro. Sulfur-Directed C7-Selective Alkenylation of Indoles under Rhodium Catalysis Org. Lett. 2021,23, 6252-6256. doi: 10.1021/acs.orglett.1c01990
UR
L https://www-chem.eng.osaka-u.ac.jp/hirano-lab/
K e y w o r d catalysis, coupling reaction, indole, transition metal