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Synthetic Methods
NHC-Catalyzed Aldimine Umpolung/6π-Electrocyclization Cascade
to Access Tetracyclic Dihydrochromeno Indoles
Rohan Chandra Das, Priyanshu Gupta, Sukriyo Chakraborty, Garima Jindal,* and
Akkattu T. Biju*
Abstract: The umpolung of aldimines using N-hetero-
cyclic carbenes (NHCs) is less explored compared to the
established polarity reversal of aldehydes. Described
herein is an NHC-catalyzed imine umpolung /6π-electro-
cyclization cascade, which leads to the atom- and pot-
economic synthesis of biologically important dihydro-
chromeno indoles. For the first time, the nucleophilic
aza-Breslow intermediates have been intercepted with
unactivated alkynes. Preliminary mechanistic and DFT
studies shed light on the role of the phenolic OH
moiety in promoting the addition of the aza-Breslow
intermediate to the unactivated alkyne via an intra-
molecular proton transfer in a stepwise manner. DFT
studies also support the regioselectivity preference for
the 5-exo-dig cyclization pathway, leading to the exclu-
sive formation of the indole products. Moreover, a
comparison of Gibbs free energies provides insight into
a thermodynamically preferred 6π-electrocyclization
over a competing oxa-Michael pathway. Further, this
strategy is applied to the formal synthesis of a Hepatitis
C Virus (HCV) NS5A inhibitor in a step-economical
method.
Introduction
Functionalized 2H-chromenes are a significant class of
oxygen-containing heterocycles that have garnered substan-
tial interest due to their prevalence in natural products,[1]
bioactive molecules,[2] photochromic materials,[3] and various
biopolymers.[4] Additionally, 2H-chromenes fused with sub-
stituted indole moieties exhibit intriguing medicinal proper-
ties, including anti-cancer, anti-tumor, anti-inflammatory,
and analgesic effects (Figure 1A).[5] Specifically, when the
fusion occurs between the C2 and C3 positions of indoles,
these heterocycles have been studied for their potential to
inhibit the NS5A polymerase.[6] Consequently, significant
efforts have been devoted to developing synthetic strategies
for these compounds, which can be categorized into two
main approaches: the formation of the benzopyran ring
through cyclization reactions and the late-stage functionali-
zation of the parent 2H-chromenes.[7] However, these
strategies often suffer from the involvement of multiple
steps, the use of costly transition metals, and/or the require-
ment of pre-functionalized starting materials.[8] So, the
development of a pot- and atom-economic strategy employ-
ing easily synthesizable starting materials is highly desirable.
Intrigued by these facts, we envisioned the synthesis of
tetracyclic dihydrochromeno indole core using aldimines
(prepared in one-step) with an unactivated alkyne moiety
tethered to it by the N-heterocyclic carbene (NHC)-
catalyzed polarity reversal strategy.
NHCs have become highly versatile catalysts in the field
of organocatalysis, effectively facilitating the reversal of
electrophile polarity.[9] A wide range of reactivity has been
exploited using aldehydes as electrophiles, initiated by the
formation of the well-known Breslow intermediate.[10] Also,
NHCs are effective in reversing the polarity of Michael
acceptors,[11] alkyl halides,[12] and imines.[13] Although the
Douthwaite[14] and Rovis groups[15] demonstrated the addi-
tion of NHCs to imines leading to the generation of aza-
Breslow intermediates, the catalytic applications of imine
umpolung were not demonstrated until later. In 2017, our
group[16] and the Suresh group[17] independently reported an
NHC-catalyzed imine umpolung, followed by an intercep-
tion of the aza-Breslow intermediates with activated CC
double bonds for the synthesis of indoles (Figure 1B). Later,
Lupton’s[18] and our group[19] independently disclosed enan-
tioselective variants of NHC-catalyzed imine umpolung,
where the aza-Breslow intermediate was trapped with
Michael acceptors and aldimines, respectively. Very re-
cently, the trapping of aza-Breslow intermediates by
carbonyl electrophiles has also been reported.[20] Intrigu-
ingly, the interception of aza-Breslow intermediates with
unactivated CC triple bonds is hitherto unknown. The
reason could be attributed to the fact that the π-bonds of the
CC triple bond are stronger than their double bond
counterparts, such as C=O, C=N, and C=C.[21] While alkynes
can be activated using transition metals like Au, Pt, and Cu
due to their high alkynophilicity,[22] their compatibility with
NHCs is problematic because NHCs tend to form complexes
with metals irreversibly. (Figure 1C).[23] Moreover, the non-
classical activation of alkynes, such as through chalcogen
bonding or hydrogen bonding, necessitates the use of an
additional reagent that serves as a chalcogen bond donor or
[*] R. C. Das, P. Gupta, S. Chakraborty, Prof. Dr. G. Jindal,
Prof. Dr. A. T. Biju
Department of Organic Chemistry, Indian Institute of Science,
Bangalore-560012, India
E-mail: gjindal@iisc.ac.in
atbiju@iisc.ac.in
Homepage: https://orgchem.iisc.ac.in/garima-jindal/
https://orgchem.iisc.ac.in/atbiju/
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How to cite: Angew. Chem. Int. Ed. 2025,64, e202416519
doi.org/10.1002/anie.202416519
Angew. Chem. Int. Ed. 2025,64, e202416519 (1 of 9) © 2024 Wiley-VCH GmbH
