Angewandte
Communications
Chemie
How to cite: Angew. Chem. Int. Ed. 2021, 60, 8772–8780
International Edition:
German Edition:
Iron Catalysis
Hot Paper
Iron-Catalyzed Radical Activation Mechanism for Denitrogenative
Rearrangement Over C(sp3)–H Amination
Satyajit Roy+, Sandip Kumar Das+, Hillol Khatua, Subrata Das, Krishna Nand Singh, and
Abstract: An iron-catalyzed denitrogenative rearrangement of
1,2,3,4-tetrazole is developed over the competitive C(sp3)–H
amination. This catalytic rearrangement reaction follows an
unprecedented metalloradical activation mechanism. Employ-
ing the developed method, a wide number of complex-N-
heterocyclic product classes have been accessed. The synthetic
utility of this radical activation method is showcased with the
short synthesis of a bioactive molecule. Collectively, this
discovery underlines the progress of radical activation strategy
that should find wide application in the perspective of
medicinal chemistry, drug discovery and natural product
synthesis research.
of organic azide) remained completely unexplored, although
extremely important to access a wide number of complex N-
heterocyclic scaffolds. Moreover, it would be highly intriguing
to see the employment of base metal complexes[10] as catalyst
candidates instead of the expensive noble metal complexes
for these types of rearrangement (migration and or ring
expansion) reactions via nitrene or carbene-transfer reac-
tions.[11,12] Thus, with these considerations in mind, we present
a concept exploiting an iron-porphyrin catalyst that found to
be highly selective and efficient for the rearrangement of
variously designed 1,2,3,4-tetrazoles offering quick access to
various complex N-heterocycles. Importantly, while the
denitrogenative annulation of 1,2,3-triazoles[13] explored
extensively, the 1,2,3,4-tetrazole remained almost unutilized
except Wentrupꢀs and Huisgen and Fraunbergꢀs pioneering
some early studies towards the reactivity of 1,2,3,4-tetra-
zoles.[14]
From the last few years, our group engaged with the
development of 1,2,3,4-tetrazole chemistry for the prepara-
tion of various N-containing heterocycles.[15–18] Notably, we
observed that the Ir-catalyzed electrocyclization concept[15] of
the C(sp2)–H amination/annulation, the nature of the sub-
stituent group of the alkene at the C8 position of the 1,2,3,4-
tetrazole played an important role. The electrocyclization
occurred only when the alkene is mono-substituted and no
reaction occurred if the alkene is di-substituted (Figure 2A).
I
n recent times, azaindoles have gained remarkable attention
as the bioisosteres of indoles.[1] Surprisingly, use of azaindoles
compared to the indoles in the area of drug discovery,
medicinal chemistry and related fields of research are
extremely rare, which is due to the lack of suitable synthetic
methods. While numerous preparative methods are now
available for the diversely substituted indoles, preparation of
2,3-disubstituted azaindoles are extremely difficult, which is
owing to the issue of one extra nitrogen atom that enormously
alters chemical properties[2] of the molecule and offer a huge
challenge towards the chemical community (Figure 1).
Over the past few decades, transition metal-catalyzed
intramolecular rearrangement reaction (such as, bond migra-
À
tion and ring expansion) that forms new C C bonds represent
Moreover, very recently, we have reported an iron-catalyzed
3
an efficient tool for the quick preparation of complex
molecular architecture.[3,4] Recently, several pioneering
groups (such as, Murakami,[5] Fokin,[6] Driver,[7] and Shi[8])
have successfully developed elegant transformations from
diazo precursors and organic azides using Rh-catalysis.
However, despite the remarkable progress of the rearrange-
ment chemistry of diazo-compounds and organic azides with
Rh-catalysts, the chemistry of 1,2,3,4-tetrazole (a surrogate[9]
amination[17] of strong aliphatic C(sp ) H bonds where the
À
tetrazole is featured with an amide functionality (Figure 2B).
Considering these two previous reports, we then became
[*] S. Roy,[+] S. K. Das,[+] H. Khatua, S. Das, Prof. Dr. B. Chattopadhyay
Division of Molecular Synthesis & Drug Discovery
Centre of Bio-Medical Research (CBMR), SGPGIMS Campus
Raebareli Road, Lucknow 226014, U.P. (India)
E-mail: buddhadeb.c@cbmr.res.in
S. Roy,[+] Prof. Dr. K. N. Singh
Department of Chemistry, Institute of Science
Banaras Hindu University
Varanasi 221005 (India)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
Figure 1. Bioactive molecules with an azaindole core.
Angew. Chem. Int. Ed. 2021, 60, 8772 –8780
8772
ꢀ 2021 Wiley-VCH GmbH