Iron-catalysed radical cyclization to synthesize germanium-substituted indolo[2,1-a]isoquinolin-6(5H)-ones and indolin-2-ones

Article abstract of DOI:10.1039/d1cc03907e

A simple and efficient strategy for iron-catalysed cascade radical cyclization was developed, by which an array of germanium-substituted indolo[2,1-a]isoquinolin-6(5H)-ones and indolin-2-ones were obtained in one pot with germanium hydrides as radical precursors. A rapid intramolecular radical trapping mode enabled the selective arylgermylation of alkenes over the prevalent hydrogermylation reaction.

Full text of DOI:10.1039/d1cc03907e

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Iron-catalysed radical cyclization to synthesize
germanium-substituted indolo[2,1-a]
Cite this: DOI: 10.1039/d1cc03907e
isoquinolin-6(5H)-ones and indolin-2-ones†
Yani Luo,‡a Tian Tian,‡ab Yasushi Nishihara,b Leiyang Lv *a and Zhiping Li
Received 19th July 2021,
Accepted 11th August 2021
a
*
DOI: 10.1039/d1cc03907e
rsc.li/chemcomm
A simple and efficient strategy for iron-catalysed cascade radical
Difunctionalization of alkenes is a highly sought-after trans-
cyclization was developed, by which an array of germanium- formation due to its dramatic increase of molecular diversity in
substituted indolo[2,1-a]isoquinolin-6(5H)-ones and indolin-2-ones a single step.10 However, the simultaneous introduction of a
were obtained in one pot with germanium hydrides as radical germyl group and another functionality into the CQC bond
precursors. A rapid intramolecular radical trapping mode enabled the using germanium hydrides, either via the ionic or radical
selective arylgermylation of alkenes over the prevalent hydrogermyla- pathway, has been scarcely explored (Scheme 1a). The main
tion reaction.
challenge associated with this process is that since germanium
hydrides are intrinsically excellent hydrogen donors, intermolecu-
Germanium, one of the heavier group 14 elements, has been lar hydrogen atom transfer occurs rapidly (104 to 105 sÀ1 11
upon
)
identified as a unique building block of bioactive molecules incorporation of germyl groups, thereby exclusively forming advan-
and organic optoelectronic materials.1 Compared to their tageous hydrogermylation products.12 We envisioned that the
corresponding carbon analogous, germanium-containing mole-
cules display distinctive chemical and pharmacological proper-
ties due to enhanced hydrophobic interactions with target
molecules through electropositive characteristics and an
increased covalent radius.2 For example,
a ‘‘germanium
switch’’, that replaces carbon with germanium in certain mole-
cules, as found in the retinoic acid and estrogen receptors,
could significantly strengthen the biological activity of hydro-
phobic pharmacophores.3 Besides, organogermanium com-
pounds have recently emerged as prospective cross-coupling
partners to overcome the limitations (e.g., orthogonal selectiv-
ity) of conventional organometallic reagents.4–6 Consequently,
the development of catalytic methods for the selective incor-
poration of germanium into organic skeletons, especially into
bioactive nitrogen-containing heterocycles, is enthusiastically
pursued and expected. In this context, transition metal and/or
Lewis acid-catalysed hydrogermylation of alkenes7 or alkynes8
with commercially-available germanium hydrides has emerged
as one of the most convenient and atom-economical
approaches to construct organogermanes.9
a Department of Chemistry, Renmin University of China, Beijing 100872, China.
E-mail: lvleiyang2008@ruc.edu.cn, zhipingli@ruc.edu.cn
b Research Institute for Interdisciplinary Science, Okayama University, 3-1-1
Tsushimanaka, Kita-ku, Okayama 700-8530, Japan
† Electronic supplementary information (ESI) available: Copies of 1H NMR and
13C NMR spectra for new compounds. See DOI: 10.1039/d1cc03907e
‡ These two authors contributed equally.
Scheme 1 Strategies of germyl-functionalization of alkenes.
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Table 1 Optimization of the reaction conditionsa
chemoselectivity issues might be overcome by designing the
transformation to ensure that the capture of the germanium-
alkene adduct step took place intramolecularly. This hypothesis
was based on literature reports that state the rate of intramolecular
radical trapping was estimated to 107 to 108 sÀ1 in relevant kinetic
studies13 (Scheme 1b).
Over the past decade, amide-tethered alkenes have been
extensively studied as viable substrates for the facile synthesis
of fused polycyclic nitrogen-containing scaffolds via radical
addition/intramolecular cyclization strategies, especially in
the concise construction of diversely substituted indolo
[2,1-a]isoquinolines,14 benzo[4,5]imidazo[2,1-a]isoquinolines15
and indolin-2-ones,16 which are important classes of fused-
indole derivatives and widely exist in natural products, phar-
maceuticals and functional materials. Inspired by the merits of
radical cascade processes and as part of our continuing interest
in iron-catalysed alkene functionalizations,17 we anticipated
that the difunctionalization of tertiary amine-tethered alkenes
would provide a feasible platform for introducing germanium
via rapid intramolecular radical trapping to overcome the
prevalent hydrogermylation. Herein, we report an iron-
catalysed radical cyclization strategy, whereby an array of
germanium-substituted indolo[2,1-a]isoquinolin-6(5H)-ones and
indolin-2-ones could be efficiently prepared with germanium
hydrides as radical precursors (Scheme 1c). To the best of our
knowledge, this is the first example of constructing a wide range of
germanium-embedded biologically valuable, fused nitrogen-
containing heterocycles via the 1,2-difunctionalization of alkenes.
We initiated our hypothesis by first exploring the model
reaction of N-methacryloyl-2-phenylindole (1a) with Ph3GeH
(2a) under different reaction conditions (Table 1). After exten-
sive evaluation of various parameters, the desired germanium-
substituted indolo[2,1-a]isoquinolin-6(5H)-one product 3a was
obtained in 95% yield in an FeCl2–(t-BuO)2 catalytic system with
1a (0.2 mmol) and 2a (0.22 mmol) in PhCl at 120 1C for 3 h
(entry 1). Based on the optimal reaction conditions, a series of
control experiments were carried out to evaluate the factors that
influence the reaction efficiency. For example, when ferrous
salts such as Fe(acac)2 and Fe(OAc)2 were used instead of FeCl2,
the yields of 3a were reduced to 54% and 45%, respectively
(entries 2 and 3). Other metal catalysts including CoCl2, MnCl2
and CuCl could also facilitate this transformation, yet their
catalytic activity was inferior to that of FeCl2 (entries 4–6).
In addition, the effect of solvent was also explored: moderate
yields (71–79%) of 3a were afforded when the reaction was
performed in MeCN, DCE or PhMe (entries 7–9). Notably, TBHP
or BPO as an oxidant resulted in a significant decrease in
reaction efficiency (entries 10 and 11). The results of the control
experiments revealed that 3a could be obtained in 56% yield
without a metal catalyst (entry 12), while no desired product
was detected in the absence of an oxidant or at a reduced
reaction temperature (e.g., 80 1C), despite the almost quantita-
tive amount of starting materials remaining (entries 13 and 14),
which can possibly be ascribed to invalid radical initiation.
With the reaction conditions optimized, the substrate scope
for the iron-catalysed oxidative germanium radical cyclization
Entry
Variation of the standard conditions
Yield 3ab (%)
1
2
3
4
5
6
7
8
None
95
54
45
39
52
83
79
71
73
29
3
Fe(acac)2 instead of FeCl2
Fe(OAc)2 instead of FeCl2
CoCl2 instead of FeCl2
MnCl2 instead of FeCl2
CuCl instead of FeCl2
MeCN instead of PhCl
DCE instead of PhCl
PhMe instead of PhCl
TBHP instead of (t-BuO)2
BPO instead of (t-BuO)2
Without FeCl2
9
10
11
12
13
14
56
0
0
Without (t-BuO)2
80 1C instead of 120 1C
a
Reaction conditions: 1a (0.2 mmol), Ph3GeH 2a (0.22 mmol), FeCl2
(2.5 mol%), (t-BuO)2 (0.4 mmol), PhCl (1.0 mL), 120 1C, 3 h, in a sealed
b
tube under N2 unless otherwise noted. NMR yields were determined
using 1H NMR with CH2Br2 as an internal standard based on 1a. TBHP =
tert-butyl hydroperoxide (5.5 M in decane). BPO = dibenzoyl peroxide.
was investigated. As shown in Table 2, a wide range of functiona-
lized 2-arylindoles 1 reacted smoothly with 2a to form the corres-
ponding germanium-substituted indolo[2,1-a]isoquinoli-6(5H)-
ones in moderate to good yields. For example, indole rings with
different substitution patterns, such as H, Me and F, were all
compatible under the optimal conditions to give the corres-
ponding products 3a–3e in 55–90% yields. The reaction was
scalable, as the reaction was performed on a 1.0 mmol scale to
give 3a in 76% yield. N-Methacryloyl-2-arylindoles bearing electron-
donating (-Me and -t-Bu) or electron-withdrawing (-F, -Cl, -Br and
-CF3) groups at the para-position of the 2-aromatic ring were
suitable for this transformation to afford the difunctionalized
products 3f–3k in good yields (63–76%), with slightly higher
reactivity for those bearing electron-withdrawing groups. Sub-
strates assembled with methyl groups at the meta- and ortho-
positions of the 2-aryl ring were readily converted to the desired
products 3l and 3m in 95% and 89% yields, respectively, without
the interference of steric hinderance. As expected, other p-systems
such as naphthalene (3n) and thiophene (3o) were also amenable
to this reaction mode. Substrates containing a methyl or phenyl
group at the C3 position of the indole ring underwent a radical
tandem cyclization smoothly to give the desired indolo
[2,1-a]isoquinolin-6(5H)-one products 3p and 3q in 76% and
68% yields, respectively. In the case of the indole-tethered unac-
tivated alkene 1r tested, the difunctionalized product
3r was obtained in only 58% yield, despite a two-fold increase of
germanium hydride 2a and a prolonged reaction time, probably
due to the instability of the generated germanium-alkene adduct
radical intermediate. The reaction was messy and only trace
amounts of the desired product were detected when 1-(2-phenyl-
1H-indol-1-yl)prop-2-en-1-one or 2-phenyl-1-(2-phenyl-1H-indol-1-
yl)prop-2-en-1-one was tested accordingly. To our delight, the
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Table 2 Scope of 2-arylindoles and Ge–Ha
Table 3 Scope of N-arylacrylamides and Ge–Ha
a
Reaction conditions: 4 (0.2 mmol), Ge–H 2 (0.22 mmol), FeCl2 (2.5
mol%), (t-BuO)2 (0.4 mmol), PhCl (1.0 mL), 120 1C, 3 h, in a sealed tube
b
under N2 unless otherwise noted. Isolated yields. 2a (0.4 mmol), 12 h.
the reaction efficiency. Besides, structurally distorted substrates
such as tetrahydroquinoline and dihydrodibenzoazepine-linked
alkenes also reacted smoothly to give the corresponding
germanium-substituted polycyclic products 5g and 5h in 82%
and 75% yields, respectively. A moderate yield was obtained in
testing naphthalene-substituted alkene 4i. To our delight, the
pyridine ring was tolerated without erosive coordination by the
iron catalyst, affording the difunctionalized product 5j in 62%
yield. Furthermore, analogous germanium hydrides behaved suc-
cessfully (5k and 5l) with established protocols. Notably, germa-
nium could be efficiently incorporated into the bioactive
phenylalanine-derived indolin-2-one skeleton (5m).
To gain a preliminary insight into the mechanism of the
present reaction, a set of control experiments were implemen-
ted. The transformation was remarkably terminated when
radical inhibitors, 2,2,6,6-tetramethylpipedinyloxy (TEMPO)
and butylatedhydroxytoluene (BHT), were subjected to the
standard conditions. Notably, TEMPO-GePh3 adduct 6 was
detected using HRMS, supporting the germanium radical-
mediated pathway (see the ESI† for details).
Meanwhile, a radical clock experiment using a-cyclopro-
pylstyrene substrate 7 afforded the ring-opening hydrogermyla-
tion product 8 in 32% yield and dihydronaphthalene 9 in 25%
yield (Scheme 2a). All these results clearly revealed the radical
nature of this iron-catalysed cascade reaction. Notably, the
reaction of 2-H-substituted N-methacryloyl indole 1v with
Ph3GeH under the standard conditions afforded the corres-
a
Reaction conditions: 1 (0.2 mmol), Ge–H 2 (0.22 mmol), FeCl2
(2.5 mol%), (t-BuO)2 (0.4 mmol), PhCl (1.0 mL), 120 1C, 3 h, in a sealed
tube under N2 unless otherwise noted. Isolated yields. 1.0 mmol. 2a
(0.4 mmol), 12 h.
b
c
germanium-substituted benzo[4,5]imidazo[2,1-a]isoquinoline pro-
duct 3s was achieved in 85% yield when the N-benzimidazole
derived alkene was applied. It was also found that when other
germanium radical precursors such as Ph2GeH2 and (n-Bu)3GeH
were subjected to the standard conditions, the desired products 3t
and 3u could also be afforded smoothly.
Encouraged by this result, we further extended this iron-
catalysed cascade radical cyclization strategy to construct bio-
logically active germanium-substituted indolin-2-ones from
N-arylacrylamides (Table 3). The desired products 5a–5c were
attained in excellent yields regardless of the electronic effects;
exploration of the substituents R2 indicated that electron-rich
protecting groups (e.g., Ph and Bn) proceeded robustly (5d and
5e), while the electron-withdrawing acetyl substituent (5f) retarded
ponding hydrogermylation product 10 in
a 77% yield
(Scheme 2b), which indicates that rapid intramolecular trap-
ping by p-moieties is the key and indispensable factor in
enabling the selective alkene arylgermylation over hydrogermy-
lation reactions (see the ESI† for proposed mechanism).
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In summary, we have successfully developed an iron-
catalysed cascade radical cyclization strategy to obtain an array
of germanium-substituted indolo[2,1-a]isoquinolin-6(5H)-ones
in one pot with germanium hydrides as radical precursors. This
protocol employs the rapid intramolecular radical trapping that
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Renmin University of China (21XNLG04, 21XNH087).
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