C7-Indole Amidations and Alkenylations by Ruthenium(II) Catalysis

Article abstract of DOI:10.1002/anie.202006164

C7?H-functionalized indoles are ubiquitous structural units of biological and pharmaceutical compounds for numerous antiviral agents against SARS-CoV or HIV-1. Thus, achieving site-selective functionalizations of the C7?H position of indoles, while discri

Full text of DOI:10.1002/anie.202006164

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Accepted Article
Title: C7-Indole Amidations and Alkenylations by Ruthenium(II)
Catalysis
Authors: Isaac Choi, Antonis Messinis, and Lutz Ackermann
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Angewandte Chemie International Edition
10.1002/anie.202006164
RESEARCH ARTICLE
C7-Indole Amidations and Alkenylations by Ruthenium(II)
Catalysis
Isaac Choi, Antonis M. Messinis, and Lutz Ackermann*
[
a]
Isaac Choi, Dr. Antonis M. Messinis, and Prof. Dr. Lutz Ackermann
Institut für Organische und Biomolekulare Chemie and Wꢀhler Research Institute for Sustainable Chemistry (WISCh)
Georg-August-Universität
Tammanstraße 2, 37077 Göttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de/index.html
Supporting information for this article is given via a link at the end of the document.
Abstract: C7–H functionalized indoles are ubiquitous structural units
of biological and pharmaceutical compounds for numerous antiviral
agents against SARS-CoV or HIV-1. Thus, achieving site-selective
functionalizations of C7–H of indoles, while discriminating among
other bonds, is highly demand. Herein, we disclose site-selective C7–
H activations of indoles accomplished by ruthenium(II)biscarboxylate
catalysis under mild conditions. Base-assisted internal electrophilic-
type substitution C–H ruthenation by weak O-coordination enabled
the C7–H functionalizations of indoles, offering ample scope including
C–N and C–C bond formation. The versatile ruthenium-catalyzed C7–
H activations were characterized by gram-scale syntheses and the
traceless removal of directing group, providing easy access to
pharmaceutically relevant scaffolds. Detailed mechanistic studies
through spectroscopic and spectrometric analyses shed light on the
unique nature of robust ruthenium catalysis for C7–H indole
functionalizations.
Major advances in C–H activation have been witnessed in recent
years.[
4]
Especially,
carboxylate-assisted
[5]
ruthenium(II)
catalysis[6] has emerged as a robust tool for a broad variety of
C−H functionalizations, including alkylation,[7] alkenylation,[8]
arylations,[
9]
alkyne annulations,
[10]
amidation,[11] hydrogen-
isotope exchange,[ and meta-C–H functionalizations. Despite
the recent advances in versatile and cost-effective ruthenium
catalysis, challenging C7–H functionalizations[14] of indoles have
thus far remained elusive, which mainly stems from the formation
of unfavorable six-membered metallacycles,[ with pioneering
contributions in iridium, rhodium, and palladium catalysis by
Chang,[16] Ma,[17] and Shi,[18] among others.[19]
12]
[13]
15]
Within our program on sustainable C–H activation, we have now
developed the first ruthenium(II)biscarboxylate-catalyzed C7–H
bond activation of indoles by a weakly coordinating[20] pivaloyl
directing group via the formation of unfavorable six-membered
ruthenacycles. Notable features of our strategy include a)
unprecedented carboxylate-assisted ruthenium-catalyzed C7–H
activation of indoles, b) expedient C7–H activations enabling
amidations and alkenylations under exceedingly mild conditions,
Introduction
c) deep mechanistic insights, providing solid evidence for the site-
Indoles are key structural motifs in a plethora of bio-relevant
compounds, drugs, and pharmaceuticals.[1] Particularly, C7-
functionalized indole scaffolds exhibit a number of antiviral
activities such as inhibitors of SARS-CoV, HIV-1, influenza virus
A/Hanfang/359/95 (H3N2), and HSV II.[2] As a consequence,
there is a continued high demand for general strategies providing
easy access to C7-substituted indoles in a sustainable fashion.[3]
[21]
selective
formation of six-membered ruthenacycles which
outperforms common five-membered ruthenacycles, d) detailed
kinetic studies by spectroscopic and spectrometric techniques,
elucidating the formation of ruthenium amide as a key step prior
to C–H scission.
Figure 2. Ruthenium(II)biscarboxylate-catalyzed C7–H activations of indole.
Figure 1. Selected antiviral compounds bearing C7-functionalized indoles.
1
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
Results and Discussion
effects of the N-substituent for inducing the C7–H activation of
indoles.
We initiated our studies by probing various reaction conditions for
the envisioned ruthenium(II)-catalyzed C7–H activation of N-
pivaloyl indole 1a with tosyl azide 2a (Table 1 and Table S1 in the
Supporting Information). We were delighted to observe that the
desired C7–H nitrogenated product 3aa was exclusively obtained
in TFE as the solvent by using cationic ruthenium(II) complex
generated in-situ from Ru(OAc)
2
(p-cymene) and a silver salt
(
entry 1). Interestingly, the C7–H amidated product 3aa was
selectively formed as the sole product, while the C2–H bond
remained entirely unmodified. The commercially available
ruthenium(II) catalyst, [RuCl (p-cymene)] , fell short in providing
2 2
the desired product (entry 2), clearly highlighting the importance
of the ruthenium(II)biscarboxylate catalysis regime. We
additionally employed other well-defined ruthenium complexes,
sterically demanding ligands, proved to be less effective (entries
Scheme 1. Examination of N-substitution pattern.
3–5). Reactions conducted in HFIP or DCE as the solvent gave
unsatisfactory results (entries 6–7). Control experiments revealed
the essential role of the silver salt for solely forming a cationic
ruthenium(II) carboxylate (entries 8–10).
With the optimal reaction conditions in hand, we next explored the
versatility of the C7–H amidation with a set of representative
indoles 1 and azides 2 (Scheme 2). Differently substituted indoles
1
bearing alkyl, alkoxy, and halogen groups at the C3-, C4-, C5-,
Table 1. Optimization studies for C7–H activation of indole.[a]
and C6-position were site-selectively transformed into the desired
C7–H nitrogenated products. The ruthenium(II)-catalyzed C7–H
activation also tolerated various azides 2 bearing arenesulfonyl
and alkanesulfonyl groups.
Yield
Entry
Deviation from above
none
[
%]
1
2
3
4
5
6
7
8
9
78
0
[RuCl
2
(p-cymene)]
(p-cymene) instead of Ru(OAc)
CMes) (p-cymene) instead of Ru(OAc)
CAd) (p-cymene) instead of Ru(OAc)
2
instead of Ru(OAc)
2
(p-cymene)
Ru(OPiv)
2
2
(p-cymene)
60
52
48
63
25
56
7
Ru(O
2
2
2
2
(p-cymene)
Ru(O
2
2
(p-cymene)
HFIP instead of TFE
DCE instead of TFE
8 mol % instead of 20 mol % of AgSbF
6
6 6
NaSbF instead of AgSbF
10
AgCl instead of AgSbF
6
0
Scheme 2. Scope of C7–H amidation of indoles 1.
[
a] Reaction conditions: 1a (0.25 mmol), 2a (0.75 mmol), catalyst (10 mol %),
AgSbF (20 mol %), TFE (1.0 mL), 40 °C, 24 h, isolated yield.
6
The robustness of the ruthenium(II)biscarboxylate-catalyzed C7–
H activation was further reflected by the C7–H alkenylation of N-
pivaloyl indoles 1 with acrylates 4 through a redox-active process
(Scheme 3). Thus, the site-selective alkenylated products 5
proved to be viable. Instead, attempted fluorinations and
trifluoromethylations led thus far to less satisfactory results. Yet,
a variety of substituted indoles 1 and acrylates 4 was tolerated,
thus efficiently transforming into the desired indole-7-alkenyl
derivatives 5 with excellent site-selectivity.
Thereafter, we probed the effect exerted by changing the pattern
on the indole N-substituent in substrates 1 (Scheme 1). Hence, a
variety of ketones, amide, ester, phosphine oxide, sulfone, and
pyridine were subjected to the established reaction conditions for
the C7−H activation of indole. Interestingly, only the N-pivaloyl
indole 1a underwent the C7−H amidation process. Contrarily,
other groups fell short in delivering the corresponding amidated
products 3, illustrating the importance of steric and electronic
2
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
Indeed, the ruthenium(II)-catalyzed C7–H amidation and
alkenylation could be easily conducted on gram scale without
significant loss of catalytic efficacy, thereby highlighting the
robustness of the ruthenium(II)biscarboxylate catalysis (Scheme
5).
Scheme 5. Gram-scale reaction for C7–H activation of Indole.
Flow technology provides an avenue for the increase in the
capability of chemical transformations in terms of improved heat
and mass transfer.[22] Thus, the scalability of C7–H activation of
indoles 1 was substantiated in a flow set-up, giving the desired
Scheme 3. Scope of C7–H olefination of indoles 1.
amidated product 3aa without loss of efficiency or selectivity
(
The practical utility of the established carboxylate-assisted
ruthenium(II)-catalyzed C7–H activation was next substantiated
by the traceless removal of the N-pivaloyl motif at room
temperature (Scheme 4). It is noteworthy that the traceless
removal of N-pivaloyl directing group could also sequentially
proceed in a one-pot strategy.
Scheme 6).[
23]
Scheme 6. Scalable flow reaction for C7–H amidation of indole.
Given the unique features of the unprecedented carboxylate-
assisted ruthenium(II)-catalyzed C7–H activation, we became
intrigued to delineating its mode of action (Scheme 7). To this end,
intermolecular competition experiments with differently
substituted N-pivaloyl indoles 1 were conducted (Scheme 7a-I).[
Thus, electron-rich substrate possessed an inherent higher
reactivity, proposing concerted metalation/deprotonation (CMD)
less likely,[ while providing support for a base-assisted internal
electrophile-type substitution (BIES) manifold.[25] Additionally, a
Hammett correlation was found in electronically differentiated
substrates, which have a substituent in meta-position to the
reaction center, indicating that an electrophilic mechanism might
occur in the C–H bond scission step (Scheme 7a-II).[23]
Furthermore, we performed the C7–H activation in the presence
of isotopically labeled TFE (Scheme 7a-III).[23] H/D-scrambling in
the C7- and C2-position was observed in the absence of substrate
23]
24]
2a, indicating the reversible nature of the C–H bond cleavage
event. In sharp contrast, a H/D exchange experiment in the
presence of 2a provided evidence of facile and irreversible new
C–N bond formation, giving excellent site-selectivity of ruthenium-
catalyzed C7–H of indole activation.
Scheme 4. Traceless removal of N-pivaloyl group in a one-pot fashion.
3
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
log(k/k
.300
0
)
0
0
0
0
Me
.200
.100
.000
y = -1.2064x + 0.0438
R² = 0.9666
H
ρ = -1.2
σ
(m)
-
0.100
0.000
0.100
0.200
0.300
0.400
0.500
-
-
-
-
-
0.100
0.200
0.300
0.400
0.500
OMe
F
Br
Scheme 7. Detailed experimental and analytical mechanistic investigations.
4
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
Subsequently, a reaction performed with substrate 1a and Conclusion
isotopically labeled compound [D] -1a showed a primary kinetic
4
isotope effect (KIE) of k
H
/k
D
≈ 1.1, indicating support for a fast C7–
In summary, we have reported on the first well-defined
carboxylate-assisted ruthenium-catalyzed C7–H activation of
indoles via the formation of challenging six-membered
ruthenacycles. Thus, the ruthenium(II)biscarboxylate catalyst
enabled C–N and C–C bond formation with excellent levels of
site-selectivity under exceedingly mild conditions. The robustness
and selectivity of the ruthenium catalysis were reflected by the
traceless removal of directing group and gram-scale reactions.
Detailed kinetic studies, along with NMR spectroscopy and mass
spectrometry, highlighted the importance of ruthenium nitrenoid
intermediates for the unique C7 indole position-selectivity.
[
23]
H scission (Scheme 7a-IV). In good agreement with this finding,
detailed kinetic experiments unraveled a zero-order dependence
of the reaction rate on the N-pivaloyl indole 1a, but a first-order
dependence was observed for the concentration of the tosyl azide
2
a and Ru(OAc)
2
(p-cymene) (Scheme 7a-V).[23]
Furthermore, in-operando NMR studies revealed the
consumption of substrate 1a and 2a with concomitant formation
of the desired product 3aa, accompanied by a small induction
period (Scheme 7b-I).[23] The successive formation and
consumption of three ruthenium species were also observed in
the 1H NMR spectra during catalysis, one of which potentially
corresponds to the catalyst resting state. Therefore, the catalytic
experiment was also monitored by high-resolution-electrospray
ionization-mass spectrometry (EXI-MS) as an attempt to obtain
Acknowledgements
further insights towards the ruthenium speciation during catalysis
Generous support from the Kwanjeong Educational Foundation
Scheme 7b-II).[ Furthermore, ruthenium species Ru
23]
-I was
(
2
(
(
fellowship to IC) is gratefully acknowledged and the DFG
Gottfried-Wilhelm-Leibniz-Preis to LA and SPP1807).
found to be a dimeric ruthenium complex according to an X-ray
diffraction analysis which corresponded to the exact mass of
7
28.0533, likely being part of a deactivation pathway rather than
Keywords: Indoles • C–H activation • Ruthenium • Amidation •
[23]
a catalytic intermediate (Scheme 7b-III).
Alkenylation
On the basis of our experimental mechanistic studies, a plausible
catalytic cycle for the carboxylate-assisted ruthenium(II)-
catalyzed C7–H indole activation was proposed (Scheme 8). The
mechanism rationale commences with the coordination of
substrate 2a to active ruthenium catalyst A to form ruthenium
amide intermediate B,[26] which has been often described as the
latter step after C–H activation. Presumably, C–H activation
occurs through base-assisted internal electrophilic-type
substitution (BIES) mechanism, preferentially leading to
ruthenium(II) species D rather than D'. The intermediate D is
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5
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Angewandte Chemie International Edition
10.1002/anie.202006164
RESEARCH ARTICLE
Entry for the Table of Contents
Lucky Seven: Challenging C7−H activation of indoles was accomplished by ruthenium(II) catalysis. The versatile ruthenium catalysis
offered C–N and C–C bond formation, highlighted by scalable reactions and the traceless removal of directing group. Detailed
mechanistic investigation based on diverse analysis tools shed light on a novel mode of action.
Institute and/or researcher Twitter usernames: @uniGoettingen @ResearchWohler @aztul
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