Selective C-H acylation of indoles with α-oxocarboxylic acids at the C4 position by palladium catalysis

Article abstract of DOI:10.1039/c9cc03893k

The first Pd-catalyzed direct C-H acylation of indoles at the C4 position with α-oxocarboxylic acids using a ketone directing group is described. This reaction exhibits high regioselectivity with the tolerance of a wide scope of functional groups to afford diverse acylated indoles in moderate-to-good yields. The control experiments evidence the generation of acyl radicals via K₂S₂O₈ promoted decarboxylation of α-oxocarboxylic acids and the involvement of a Pd^II/Pd^IV catalytic cycle. Importantly, the synthetically useful selectivity observed might be applied to prepare indole derivatives with anti-tumor activity as tubulin inhibitors.

Full text of DOI:10.1039/c9cc03893k

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DOI: 10.1039/C9CC03893K
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Selective C-H Acylation of Indoles with α-Oxocarboxylic Acids at
the C4 Position by Palladium Catalysis
Jitan Zhang*, Manyi Wu, Jian Fan, Qiaoqiao Xu, and Meihua Xie*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The first Pd-catalyzed direct C-H acylation of indoles at the C4 selective functionalization of C4 C-H bond is still on its early
position with α-oxocarboxylic acids using a ketone directing group stage,8 and the diverse transformations remain relatively
is described. This reaction exhibits high regioselectivity and unexplored. Therefore, the development of new protocols for
accomplishes with a wide scope and functional group tolerance to the direct and regioselective C4 C-H bond functionalization of
afford diverse acylated indoles in moderate to good yields. The indoles would be highly appealing.
control experiments evidence the generation of acyl radicals via
Previous work: Metal mediated/catalyzed C2, C3 and C7-acylation of indoles
O
K2S2O8 promoted decarboxylation of α-oxocarboxylic acids and the
H
R2
R1
R1
a
PdII/PdIV catalytic cycle. Importantly, the
"
"
O
Lewis acid, [Cu], [Fe]
[Ru], [Pd]
involvement of
+
R2
N
R
N
synthetically useful selectivity observed might be applied to
prepare the indole derivatives with anti-tumor activity as tubulin
inhibitors.
R
R1
R1
H
N
DG
R1
R2
O
[RhI]
DG = PtBu2
[Pd], [RhIII
]
N
DG
H
DG = pyrimidyl
N,N-dimethylcarbamoyl
N
DG
The past decade has witnessed the emergence of C-H
functionalizations as an attractive alternative to traditional
coupling protocols for the construction of functional molecules
which maintains the expediency associated with simple cross-
coupling reactions, yet with greater atom and step economy.1
However, modulating the regioselective outcome of catalytic
transformation with multiple C-H bonds remains a challenging
task. Especially, the subtle difference from each other in
activation barrier makes it appealing to be able to gain highly,
even completely, site or regioselectivity.2 In this context,
indoles that possess six C-H bonds have received significant
attention for the regioselective C-H bond functionalization for
the past several years.3 Generally, the natural reactivity of
indoles suggested that metalation would take place
preferentially at the C3 position.4 To overcome this inherent
selectivity, substrate modifications, such as installation of
directing groups, have been widely utilized to drive the
reaction to the desired regiochemical route. Seminal efforts
for this research topic revealed that diverse transformations of
indoles at C2,5 C66 and C77 positions could be achieved
successfully with the assistance of functional groups installed
on N atom. Despite extensive progress in this field, the
+
R2
O
"
"
O
R2
This work: Pd-catalyzed selective C4-acylation of indoles possessing multiple C-H bonds
PG
R1
R2
N
R = H, alkyl, phenyl
O
e
l
X
c
O
PG
N
y
R1
c
a
R
d
a
l
l
a
p
d
H
e
r
PG
N
e
R1
b
m
e
m
-
e
v
i
R
H
F
Six-membered
palladacycle
O
R = H, alkyl, phenyl
Pd
F
+
i
v
e
R
-
m
O
R2
R1
OO
PG
e
m
b
e
r
e
OH
d
R2
p
a
l
l
a
d
a
O
c
N
y
c
l
e
X
R = phenyl
O
O
R2
Fig. 1 Acylation of indoles via C-H bond activation.
Given the prevalence of acylated indoles in medicinal
chemistry and pharmaceutical industries,9 considerable
attention has been paid to the establishment of the synthetic
methodologies. By taking advantages of C-H activation
strategies, some precedent catalytic systems have been
disclosed in this research area (Fig. 1).10 For instance, Li and co-
workers reported a rhodium-catalyzed oxidative C2-acylation
of indoles with aldehydes via a selective C-H activation.11a
Subsequently, Zhu11b and Noël11c also demonstrated the C-H
acylation of indoles at the C2-position with different acylated
reagents by palladium and photoredox catalysis, respectively.
Key Laboratory of Functional Molecular Solids (Ministry of Education), Anhui Key
Laboratory of Molecular Based Materials, College of Chemistry and Materials
Science, Anhui Normal University, Wuhu 241002, China.
E-mail: zhangjt@ahnu.edu.cn; xiemh@mail.ahnu.edu.cn
Electronic Supplementary Information (ESI) available. Experimental procedures
and characterization data for new compounds. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2019, 00, 1-5 | 1
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Very recently, Shi group12 described a Rh(I)-catalyzed C7-
selective acylation with anhydrides by C-H activation. To the
best of our knowledge, there has been no example for the
catalytic C4 C-H acylation of indoles,13 although a series of C4-
acylated indoles exhibit excellent antiproliferative activity as
inhibitors of tubulin polymerization.14 Undoubtedly, the
installation of an auxiliary group at C3-position might be a
readily accessible and practical strategy to achieve C4 C-H
activation via a six-membered metallacycle. Nevertheless, the
potential cleavage of other C-H bonds involving five-
membered metallacycles makes this set a remarkable
challenge. Inspired by Yu’s work on the direct C−H acylation of
aromatic ketones15 and as our efforts to selective C-H
activation chemistry, we herein discuss the first Pd-catalyzed
straight-forward acylation of indoles at the inert C4 position
via decarboxylative C-H bond functionalization with readily
available α-oxocarboxylic acids16 as acylated reagents. This
process exhibits high regioselectivity among multiple C-H
bonds of the indole substrates and good tolerance of various
functional groups.
Ts
N
Ts
N
View Article Online
Pd(OAc)2 (10 mol%)
AgTFA (0.3 equiv), K2S2O8 (2.0 equiv)
TFA (3.0 equiv), HFIP (1.0 mL), 80 oC,48 h
O
OH
DOI: 10.1039/C9CC03893K
+
R2
O
Ph
Ph
Ts
H
R2
OO
O
1e
2
3
Ts
Ts
Ts
N
N
N
N
Ph
Ph
Ts
Ph
Ph
Ts
OO
OO
OO
OO
Cl
Br
3ed
3ea
3eb
3ec
3eg
3ek
, 77%
, 58%
, 75%
, 64%
Ts
N
Ts
N
N
N
Ph
Ph
Ph
O2
N
Ph
OO
OO
OO
OO
O
3ef
3eh
, 72%
, 72%
, 71%
3ee
, 60%
Ts
N
Ts
N
Ts
N
Ph
Ph
Ph
OO
OO
OO
Br
F
Cl
CCDC 1902832
3ej
, 80%
, 78%
3ei
, 73%
Ts
Ts
Ts
Ts
N
N
N
N
Ph
O
Ph
Ph
OO
Ph
OO
OO
OO
We commenced our investigations with the C4 C-H
acylation of 1-(1-tosyl-1H-indol-3-yl)ethanone (1a) using 2-oxo-
2-phenylacetic acid (2a) as a coupling partner (more details,
see Optimization of Reaction Conditions and Table S1 in the
Supporting Information). Gratifyingly, the C4-acylated product
3aa was obtained in 47% yield when the reaction underwent
with Pd(OAc)2 (10 mol%), AgOAc (0.2 equiv), K2S2O8 (2 equiv),
and TFA (3 equiv) using HFIP as the optimal solvent that always
has beneficial effect on C-H activation17 (Table S1, entry 1).
Various Ag salts were explored and superior catalytic efficiency
was obtained when AgTFA was utilized to the reaction mixture
(Table S1, entries 2-4, and Supporting Information). Other
oxidants such as Na2S2O8, (NH4)2S2O8, or Oxone were not able
to give a better result (Table S1, entries 5-7). The reactivity
could not be improved under argon atmosphere (Table S1,
entry 8). Additional optimization revealed that an increase of
AgTFA loading to 0.3 equiv could lead to a higher yield in 65%
(Table S1, entry 9). While MsOH and TsOH·H2O were not
effective to this reaction, AcOH and PivOH afforded the
desired product just in depressed yields (Table S1, entries 10-
13). We next examined the impact of the auxiliary groups on
the reaction efficiency (details in supporting information). We
found that the choice of the protecting group on indole was
crucial, as N-H indole could generate the desired product in
low yields. The extensive screening gave the best choice
O
O2N
F3C
O
3el
3em
, 67%
3en
, 36%
3eo
, 53%
, 28%
Ts
N
Ts
N
Ph
OO
Ph
Ph
OO
S
3eq
, trace
3ep
, 27%
aReaction conditions: 1e (0.2 mmol), 2 (0.3 mmol), Pd(OAc)2 (0.02 mmol),
AgTFA (0.06 mmol), K2S2O8 (0.4 mmol), TFA (3.0 equiv), HFIP (1.0 mL), Air, 80
oC, 48 h. b Isolated yield by flash column chromatography.
Scheme 1 Substrate scope of α-oxocarboxylic acids a,b
were tolerated, including methyl, methoxyl, halogen, nitro and
trifluoromethyl groups (3ea-3em). No obvious electronic and
steric effects were observed, albeit a low yield was obtained
with 2-(4-nitrophenyl)-2-oxoacetic acid (3el). Interestingly, 2-
oxo-2-(3,4,5-trimethoxyphenyl)acetic
acid
could
also
participate in this reaction to afford the corresponding product
(3en) which might further be transformed to the free (NH)-
indole with biological activities.14a Furthermore, 2-
(naphthalen-2-yl)-2-oxoacetic acid gave a moderate yield
(3eo). However, heteroaromatic carboxylic acids led to a lower
yield (3ep), whereas aliphatic carboxylic acid nearly had no
reactivity (3eq). Finally, X-ray crystallographic analysis of 3ba
(CCDC 1903234) and 3ek (CCDC 1902832) further confirmed
the structure of these C4-acylated indoles.
phenyl(1-tosyl-1H-indol-3-yl)methanone,
and
the
Next, the scope of indoles was also examined. As showed in
Scheme 2, a number of functional groups on the indoles could
be tolerated, rendering the desired products in moderate to
good yields (3ka-3oa, 3qa, 3sa and 3ta). However, 3-benzoyl-
1-tosyl-1H-indole-6-carbonitrile and (5-methyl-1-tosyl-1H-
indol-3-yl)(phenyl)methanone failed to give the acylated
product, indicating that the reactivity of indoles was sensitive
to the electronic characters and steric hindrance (3pa and 3ra).
In addition, it should be noted that the low yields obtained in
this catalytic system was mainly due to the incomplete
reaction.
corresponding product could be isolated in 77% yield. Notably,
all the reaction above gave high regioselectivity at the C4
position, even for the indole substrate with multiple reactive
sites on the heterocyclic and aromatic rings.
The reaction proved to be general for a variety of α-
oxocarboxylic acids to afford C4 C-H acylated indoles in
moderate to good yields, and the results were summarized in
Scheme 1. The regioselectivity of decarboxylative acylation
was consistent with that of the model reaction. A number of
functional groups on the aromatic ring of α-oxocarboxylic acids
2 | J. Name., 2019, 00, 1-5
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Ts
R1
outcome of radical control experiments (Scheme 4b and 4c).
Ts
N
R1
View Article Online
N
Pd(OAc)2 (10 mol%)
AgTFA (0.3 equiv), K2S2O8 (2.0 equiv)
TFA (3.0 equiv), HFIP (1.0 mL), 80 oC,48 h
O
The H/D exchange experiment was DOalIs:o10.1c0o3n9/dCu9cCtCe0d3,89b3Ky
suggesting the initial C-H cleavage irreversible (Scheme 4d).
In respect of the reason for the regioselectivity at the C4
position, we hypothesize that a six-membered palladacycle
might be helpful for reducing the chelate ring strain derived
from the two double bonds on the cycle, whereas a five-
membered palladacycle would experience greater ring strain.19
OH
+
Ph
O
OO
Ph
Ts
H
O
1
2a
3
Ts
N
Ts
N
Ts
N
O
F
Cl
Br
N
Ph
Ph
Ph
Ph
Ph
Ph
OO
OO
OO
OO
3ka
3oa
3sa
3la
, 81%
3ma
, 72%
3na
, 71%
, 53%
O
Ph
OO
H
Ph
Ph
O
Cl
Ts
N
Ts
N
Ts
N
Ts
Pd(OAc)2 (1.0 equiv)
OH
NC
+
(a)
N
TFA (3.0 equiv), HFIP (1.0 mL), 80 oC, 48 h
O
N
N
F
Ts
Ts
Ph
Ph
Ph
1e
2a
3ea
no reaction
no reaction
OO
OO
OO
OO
a) without Ag and K2S2O8
b) without K2S2O8
3pa
, 0%
3qa
, 71%
3ra
, 0%
, 73%
Ts
Ph
OO
O
Ph
H
H
H
Ph
Ph
Ph
O
O
Ts
N
standard condtions
OH
OH
+
N
N
+
(b)
(c)
(d)
O
Ph
Ph
TEMPO (3.0 equiv), 3 h
N
N
O
O
Ts
3ea, 0%
Ts
1e
2a
6, 56%
OO
OO
O
Ph
OO
Ph
O
3ta
, 40%
, 42%
standard condtions
BHT (2.0 equiv)
+
aReaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), Pd(OAc)2 (0.02 mmol), AgTFA
(0.06 mmol), K2S2O8 (0.4 mmol), TFA (3.0 equiv), HFIP (1.0 mL), Air, 80 oC, 48 h. b
Isolated yield by flash column chromatography.
N
N
Ts
Ts
no reaction
1e
2a
O
O
H/D
Ph
Scheme 2 Substrate scope of indoles a,b
standard condtions
N
Ts
N
Ts
In order to demonstrate the practical utility of the
developed protocol, firstly, a gram-scale experiment with
phenyl(1-tosyl-1H-indol-3-yl)methanone (1e) and 2-oxo-2-
phenylacetic acid (2a) was carried out. With the standard
conditions, 1.50 g (63%) of isolated product 3ea could be
obtained (Scheme 3a). And the Ts group could be removed
easily in the presence of potassium hydroxide to give the N-H
indole 4 in 86% yield (Scheme 3b). Besides, the sequential
treatment of 3ea with CH3MgBr and MgSO4 in mild reaction
conditions would realize the formation of a functional alkene 5,
which might be transformed furtherly to 1,1-diarylalkane with
simple operation (Scheme 3c).18 And the selective reaction of
one ketone over other with excess Grignard reagent might be
mainly due to the larger steric hindrance in aryl-aryl ketone
comparing with that in aryl-pyrrolyl ketone.
1e
a) D2O (10.0 equiv)
b) CD3COOD (10 equiv)
1e, 0% D
1e, 0% D
Scheme 4 Control experiments
On the basis of our observations and analogous literature
precedents,15,20 a plausible reaction mechanism was proposed
(see in the Supporting Information ). While the formation of a
six-membered palladacycle A (see Mechanistic Studies in the
Supporting Information), the decarboxylic process promoted
by Ag/K2S2O8 generated an acyl radical species B which was
trapped by TEMPO to form the compound 6. Then the
oxidative coupling of intermediate B and PdII complex A
resulted in the formation of intermediate C, which might be
further oxidized to PdIV complex D. Finally, a reductive
elimination took place, releasing the desired product 3 and
regenerating the PdII catalyst.
In summary, the first C4 C-H acylation of indoles by
palladium catalysis has been developed with the aid of a
carbonyl directing group. The reaction proceeds with high
regioselectivity for the indole coupling partner and is
compatible with a wide variety of functional groups.
Moreover, the synthetic value of this transformation is proved
by the straightforward access to analogues of bioactive indoles
and the easily accessible transformations of the product.
Additional mechanistic studies to fully rationalize the observed
selectivity and broad synthetic applications of this catalytic
system are currently pursued in our laboratory.
Ts
N
Ts
N
O
Pd(OAc)2 (10 mol%)
AgTFA (0.3 equiv), K2S2O8 (2.0 equiv)
OH
+
(a)
TFA (3.0 equiv), HFIP (10 mL), 80 oC, 48 h
Ph
O
Ph
OO
H
O
1e
2a
, 7.5 mmol
3ea
, 63%, 1.50 g
, 5.0 mmol
Ts
N
H
N
KOH (5.0 equiv)
(b)
CH3OH (2.0 mL), reflux
Ph
Ts
Ph
Ph
OO
Ph
3ea,
OO
4
0.2 mmol
, 86%
Ts
1) CH3MgBr (3.0 equiv)
THF, 0 oC, 30 min
N
N
(c)
2) MgSO4 (100 mg)
silica gel (100 mg)
DCM, rt
Ph
OO
3ea,
Ph
O
5,
0.2 mmol
72%
Funding from Natural Science Foundation of China (No. 21702237,
and 21272004) is acknowledged.
Scheme 3 Gram-scale reaction and transformation of product 3ea
To gain more insight into the reaction mechanism, some
control experiments were carried out. When the reaction was
performed with 1.0 equiv Pd(OAc)2 in the absence of K2S2O8,
no reaction took place at all (Scheme 4a). This result indicates
that K2S2O8 might serve as the promoter for the generation of
acyl radical intermediate, which has been evidenced by the
Conflicts of interest
There are no conflicts of interest to declare.
Notes and references
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This journal is © The Royal Society of Chemistry 20xx
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The first catalytic C-H acylation of indoles at the C4 position with α-oxocarboxylicDOacI:i1d0s.10b3Vy9i/eCw9ACrtCic0le3O8n9li3nKe
palladium catalysis is described.
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