Cobalt-Catalyzed Regioselective Direct C-4 Alkenylation of 3-Acetylindole with Michael Acceptors Using a Weakly Coordinating Functional Group

Article abstract of DOI:10.1021/acs.orglett.9b03243

Herein, we disclosed the first report on the selective C(4)-H functionalization of 3-acetylindole derivatives using first-row transition metal cobalt where an acetyl group is acting as a weakly coordinating directing group. Selective C(4)-H functionalization has been achieved using diverse Michael acceptors (acrylate and maleimide) simply by switching the additive from copper acetate to silver carbonate. Further the formation of a cobaltacycle intermediate was also detected through HRMS for mechanistic insight.

Full text of DOI:10.1021/acs.orglett.9b03243

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cobalt-Catalyzed Regioselective Direct C‑4 Alkenylation of
3‑Acetylindole with Michael Acceptors Using a Weakly Coordinating
Functional Group
Shyam Kumar Banjare, Tanmayee Nanda, and P. C. Ravikumar*
National Institute of Science Education and Research (NISER), Bhubaneswar, HBNI, Jatani, Odisha 752050, India
S
* Supporting Information
ABSTRACT: Herein, we disclosed the first report on the selective C(4)−H functionalization of 3-acetylindole derivatives
using first-row transition metal cobalt where an acetyl group is acting as a weakly coordinating directing group. Selective C(4)−
H functionalization has been achieved using diverse Michael acceptors (acrylate and maleimide) simply by switching the
additive from copper acetate to silver carbonate. Further the formation of a cobaltacycle intermediate was also detected through
HRMS for mechanistic insight.
he heteroaromatic indole moiety is present in numerous
Tmarketed drugs such as Ondansetron (nausea), Suma-
triptan (migraine), and Indomethacin (anti-inflammatory). It
is considered as the fourth most commonly prevalent
heteroaromatic skeleton among the currently marketed
drugs.1 Owing to its biological significance, synthetic
modification of indole has been one of the frontline areas of
research for a long time. The C-2 and C-3 functionalizations of
indoles were well explored due to the inherent reactivity of N-
heterocycle.2 Traditionally functionalization at the benzenoid
(C-4 to C-7) ring of indole was performed through metal-
catalyzed coupling reaction using prefunctionalized substrates.3
A recent advancement in metal-catalyzed C−H activation/
functionalization reactions led to intense exploration of direct
C−H activation methods at the relatively less explored C-4 and
C-7 positions.4 Functionalization at the C-4 position of indole
is quite challenging due to the favorable five-membered
cyclometalation step at C-2 as compared to the high energy
six-membered cyclometalation step at C-4. During the past
decade several research groups have made phenomenal
progress on selective C-4 functionalization of indole via C−
H activation using second- and third-row transition metals
such as Rh, Ru, Ir, and Pd (Figure 1).5 However, there is no
report to date on the selective C-4 functionalization with first-
row transition metals. In recent years there has been an
Figure 1. C−H functionalization of 3-acylindole.
impetus for mimicking the reactivity of noble metals (Rh, Ru,
functionalized indole with a first-row transition metal using
Ir, and Pd) through a first-row transition metal due to its low
toxicity, easy availability, and low cost.6
simple and weakly coordinating directing groups, we envisaged
In addition, C−H activation reaction through weakly
coordinating directing groups is also gaining considerable
Received: September 13, 2019
attention recently. In continuation of our efforts to synthesize
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03243
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Organic Letters
Letter
synthesizing C-4 functionalized indole7 with commonly used
Michael acceptors such as acrylates8 and maleimides.9 We have
successfully achieved our desired cobalt-catalyzed C-4
functionalization of indoles with those Michael acceptors.
To test our hypothesis, we chose indole 1a and methyl
acrylate 2a as the model substrates, in the presence of Cp*Co
catalyst, silver hexafluoroantimonate (AgSbF6) additive, and
copper acetate as an oxidant.
For the optimization of C-4 alkenylation initially, we started
with a hydrocarbon and an oxygenated solvent such as toluene,
tetrahydrofuran, and 1,4-dioxane, but the reaction failed in
those solvents. However, when we used a chlorinated solvent
such as dichloromethane, 1,2-dichloroethane, and 1,2-dichlor-
obenzene for the reaction, it worked well producing a
moderate to good yield of the desired product 3aa (Table 1,
salt and HFIP as solvent proved to be the right conditions for
the C-4 alkenylation reaction (Table 1, entry 9). To
understand the influence of the Cp*Co catalyst on the titled
reaction, we carried out the reaction in the absence of the
catalyst which failed to give the adduct (Table 1, entry 16).
To further optimize the reaction in terms of directing
groups, we planned to examine the reaction with different
electron-rich and electron-poor directing groups, while
maintaining the same coupling partner 2a. We checked our
optimized reaction conditions with acetyl, trifluoroacetyl,
pivaloyl, carboxaldehyde, carboxylic acid, and acid derivative
substituted indoles (Table 2, entries 1−7). Among these
Table 2. Screening of Directing Groups for C-4
Alkenylation of Indole with Methyl Acrylates
a
Table 1. Optimization of the C-4 Alkenylation Reaction
entry
R
yield (%)
b
1
2
3
4
5
6
7
CH3
H
CF3
tBu
88 (3aa)
33 (3aa1)
52 (3aa2)
81 (3aa3)
0 (3aa4)
entry
solvent
toluene
THF
1,4-dioxane
DCM
DCE
1,2-DCB
TFE
Ag salt
yield (%)
1
2
3
4
5
6
7
8
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6, rt
−
0
0
0
OH
OMe
NH2CH3
55
62
41
69
22
88
56
24
44
80
38
16
0
23 (3aa5)
38 (3aa6)
TFT
substrates, acetyl- and pivaloyl-substituted indoles gave
excellent yields of 3aa and 3aa3 (Table 2, entries 1 and 4).
However, in the case of indole bearing carboxaldehyde and a
trifluoroacetyl directing group moderate yields were obtained
(Table 2, entries 2 and 3). Also, we screened acid and ester as a
directing group and the result was insignificant (Table 2,
entries 5 and 6). In the case of an amide directing group, both
C-4 and C-2 alkenylated adducts 3aa6 and 3aa7 were obtained
in a moderate yield (Table 2, entry 7). In contrast to the earlier
reports,5a,b an electron-rich directing group such as acetyl- and
pivaloyl-substituted indoles gave a C-4 regioselective adduct
with a cobalt catalyst. This complementary nature of cobalt
catalyst could be useful for selective synthesis of C-4
functionalized indoles containing electron-rich directing
groups.
With the optimized conditions in hand, we proceeded to
screen the generality of this catalytic reaction with various
indoles and acrylates to obtain an array of diversely
functionalized C-4 alkenylated indoles. The steric and
electronic influence of the alkyl substituent of acrylate for
the designed catalytic transformation was first tested with 1a. It
was observed that with increasing chain length of the alkyl
group, the yield of the corresponding alkenylated product
decreased (Scheme 1, 3aa−3ac). This indicates that the
presence of an electron-rich alkyl substituent on the ester
group of acrylates retards the catalytic reaction. In the case of
the bulkier tert-butyl (Scheme 1, 3ad) substituent, the reaction
failed under the optimized reaction conditions. Overall, it
implies that the reaction seems highly sensitive to the steric
and electronic nature of the alkyl substituents in acrylates.
However, it is encouraging to note that C-5 substituted indole
9
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
10
11
12
13
14
15
16
AgBF4
AgNTF2
Ag2O
AgSbF6, without Cu(OAc)·H2O
AgSbF6, without Cp*Co(CO)I2
a
Reaction conditions: 1a (0.1 mmol), 2a (4 equiv), CoCp*(CO)I2
(10 mol %), Ag salt (20 mol %), additive (1 equiv), hexafluoro-
b
isopropanol (0.1 M) as a solvent, 50 °C, 20 h. Isolated yields.
entries 4−6). In order to further improve the product yield, we
next focused on fluorinated solvents. When we performed the
reaction in trifluoroethanol (TFE), a slight enhancement of the
yield was observed (Table 1, entry 7). This result encouraged
us to check this transformation in other fluorinated solvents
such as hexafluoroisopropanol (HFIP) and trifluorotoluene
(TFT). Interestingly HFIP turned out to be the best solvent
for the titled transformation resulting in an 88% yield of 3aa
(Table 1, entry 9). To investigate the role of the silver additive,
we performed this reaction in the absence of AgSbF6 but the
reaction failed to give significant yield and we recovered the
starting material (Table 1, entry 11). This implies that AgSbF6
is playing crucial role in the alkenylation reaction. Motivated
by this outcome we envisioned that screening of the other
silver salts might improve the yield. Hence, different silver salts
such as AgBF4, Ag2O, and AgNTf2 were used, still no
improvement in the yield of 3aa was observed (Table 1,
entries 12−14). Thus, the combination of AgSbF6 as the silver
B
DOI: 10.1021/acs.orglett.9b03243
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Organic Letters
Letter
acetyl groups giving the product (Scheme 1, 3ha−3ma) in
moderate to excellent yields. It is worth mentioning that even
though, 3la and 3ma were obtained in diminished yields, 2-
alkylated indole derivatives were not obtained as side products.
Notably, the unprotected 3-acetyl indole showed good
reactivity for the present catalytic system (Scheme 1, 3ga).
Further, to show the diversity of the reaction, we utilized N-
methyl maleimide as a coupling partner and subjected it to the
same reaction conditions. Unfortunately, we observed only a
38% yield of desired product 5aa. Hence, to enhance the
product yield, we explored different additives and oxidants. A
better yield was obtained with Ag2CO3 (please see the
optimization table included in the Supporting Information). It
is noteworthy to mention here that with N-substituted
maleimides the reaction worked well (Scheme 2, 5aa, 5ac,
and 5ad).
Scheme 1. Scope of C-4 Alkenylation of Indole with
Acrylates
a b
,
Scheme 2. Scope of C-4 Alkenylation of Indole with
a b
,
Maleimides
a
Reaction conditions: 1a (0.1 mmol), 2a (4 equiv), CoCp*(CO)I2
(10 mol %), AgSbF6 (20 mol %), Ag2CO3 (1 equiv), hexafluoro-
b
isopropanol (0.1 M) as a solvent, 50 °C, 20 h. Isolated yields.
In the case of C-5 substituted indoles, a significant difference
of reactivity was observed. Fluoro-substituted indole 2b
reacted efficiently to give the desired adduct 5bd in 67%
yield while methoxy-substituted indoles 2d was less prone to
react under the same reaction conditions. To check the
feasibility of the transformation on large scale, we also
performed the reaction in 1 mmol scale and obtained an
excellent yield of 3aa.10 In the absence of the Michael acceptor,
both C(2)−H and C(4)−H of 3-acetyl indole under the same
reaction conditions became deuterated by 16% and 31%
respectively, with 10 equiv of D2O (Figure 2a).
The ratio of C(2)−H and C(4)−H deuteration did not
change notably after continuing the reaction for a longer time
which reveals that the first step might be a reversible step. In
addition, we also performed a competition study between an
electron-rich (1-(1-methyl-1H-indol-3-yl)ethanone) and an
electron-poor (2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)-
ethanone) substrate. We found that the catalytic C-4
alkenylation is selective to electron-rich indole leading to the
a
Reaction conditions: 1a (0.1 mmol), 2a (4 equiv), CoCp*(CO)I2
(10 mol %), AgSbF6 (20 mol %), Cu(OAc)2.H2O (1 equiv),
hexafluoroisopropanol (0.1 M) as a solvent, 50 °C, 20 h. Isolated
yields.
b
such as 5-fluoro indole reacted with different acrylates resulting
in excellent yields of desired products 3ba (96%), 3bb (77%),
and 3bc (70%). In contrast, bromo-substituted indole (1, 3ca)
did not react. It is possibly due to steric hindrance near the
reaction site. Indole bearing a methoxy group at the C-5
position also provided the desired products 3da and 3dc in
good yields.
However, electron-deficient indole (5-cyanoindole, 1e)
showed insignificant result (3ea). Besides C-5 substituted
indole, the C-2 substituted indole was also compatible with the
reaction conditions leading to the formation of respective
adduct 3fa in 81% yield. Moreover, many N-protected indoles
were found to be effective, including alkyl, benzyl, tosyl, and
C
DOI: 10.1021/acs.orglett.9b03243
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Organic Letters
Letter
Scheme 3. Proposed Catalytic Cycle
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03243.
General procedure and characterization data of all the
compounds (PDF)
Figure 2. Mechanistic studies.
Accession Codes
formation of the respective C-4 alkenylated adduct as the
exclusive product (Figure 2b). Likewise to examine the effect
of the N-protecting group in the catalytic reaction, another
competition study was accomplished between 1-(1H-indol-3-
yl)ethanone and 1-(1-methyl-1H-indol-3-yl)ethanone. The
catalytic C-4 alkenylation was found to be more facile with
the N-protected indole producing a higher yield of the
alkenylated compound (Figure 2c). Further we have
performed the stoichiometric reaction with a cobalt catalyst
to trap the cobaltacycle intermediate whereby the six-
membered intermediate has been detected through HRMS
for different derivatives of indole (Figure 2d).
CCDC 1944005−1944006 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pcr@niser.ac.in.
ORCID
Based on kinetic studies and literature precedents,11 we
proposed a plausible catalytic cycle (Scheme 3) where
Cp*Co(CO)I2 reacts with AgSbF6 to generate an active
catalyst I that forms a six-membered cyclometalated species II
in the presence of 1a which was detected in HRMS (Figure
2d). Then, the cationic cobalt(III) species undergoes π-
complexation with the Michael acceptor 2a followed by olefin
insertion to give intermediate IV. Then β-hydride elimination
followed by reductive elimination gives the desired product
3aa and cobalt(I) complex V, which is further oxidized by
copper acetate to regenerate the active cobalt(III) catalyst I for
the next catalytic cycle.
In summary, we developed cobalt-catalyzed regioselective C-
4 alkenylation of indole with activated olefins using a weakly
coordinating directing group. We also detected the six-
membered cobaltacycle through HRMS which supports our
proposed mechanism. The developed protocol works well with
various Michael acceptors and indoles. Further work regarding
the origin of C-4 selectivity is being carried out in our
laboratory.
P. C. Ravikumar: 0000-0002-5264-820X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful to NISER, Department of Atomic Energy
(DAE), Council for Scientific and Industrial Research (CSIR),
New Delhi (Grant 02(0256)/16/EMR II), and Science and
Engineering Research Board (SERB), New Delhi (Grant
EMRII/2017/001475) for the financial support. Shyam K.
Banjare and Tanmayee Nanda thank DAE for a research
fellowship. We are thankful to Dr. Asit Ghosh, NISER
Bhubaneswar for helpful discussions. We are thankful to Dr.
Aridham Ghosh, and Mr. Srinibas Sa, NISER Bhubaneswar, for
solving single-crystal X-ray data. We are thankful to summer
intern in our lab Mr. Rahul Kumar, Central University (GGV)
Bilaspur, CG, for experimental help. Special thanks to Dr. G.
Satyanatayana, IIT Hyderabad for his critical suggestions. We
are also thankful to the research groups of Dr. S. Nembenna,
D
DOI: 10.1021/acs.orglett.9b03243
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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