Decarboxylative acylation of indolines with α-keto acids under palladium catalysis: A facile strategy for the synthesis of 7-substituted indoles

Article abstract of DOI:10.1039/c4cc06929c

Palladium-catalyzed decarboxylative acylation of highly substituted indolines with α-keto acids via C-H bond activation is described. This protocol provides efficient access to C7-carbonylated indoles known to have diverse biological profiles. This journal is

Full text of DOI:10.1039/c4cc06929c

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DOI: 10.1039/C4CC06929C.
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Graphical Abstract
Decarboxylative acylation of indolines with αꢀketo acids under palladium
catalysis: facile strategy to 7ꢀsubstituted indoles
Minyoung Kim, Neeraj Kumar Mishra, Jihye Park, Sangil Han, Youngmi Shin, Satyasheel Sharma,
Youngil Lee, EuiꢀKyung Lee, Jong Hwan Kwak and In Su Kim*
H
cat. Pd(TFA)2
(NH4)2S2O8
oxidation
H
H
N
N
N
DCE, 80 oC
O
Ph
R
OO
Ph
H
R
OO
O
C7-acylated indoles
R
30 examples
up 85% yield
HO
H
O
The palladiumꢀcatalyzed decarboxylative acylation of highly substituted indolines with αꢀ
keto acids via C–H bond activation is described.

ChemComm
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DOI: 10.1039/C4CC06929C
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ARTICLE TYPE
Decarboxylative acylation of indolines with α-keto acids under
palladium catalysis: facile strategy to 7-substituted indoles
Minyoung Kim,a Neeraj Kumar Mishra,a Jihye Park,a Sangil Han,a Youngmi Shin,a Satyasheel Sharma,a
Youngil Lee,b Eui-Kyung Lee,a Jong Hwan Kwaka and In Su Kim*,a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The palladium-catalyzed decarboxylative acylation of highly
substituted indolines with α-keto acids via C–H bond
activation is described. This protocol provides efficient access
synthesis of 3-acylindoles are Friedel-Crafts reactions,12
Vilsmeier-Haack reactions,13 and the reaction of indoles with
nitrilium14 or N-(α-haloacyl)-pyridinium salts15 (Scheme 1). The
10 to C7-carbonylated indoles known to have diverse biological 50 other protocols include the Ru- or Fe-catalyzed C3-
profiles.
carbonylations of indoles with anilines as carbonyl equivalents,16
the Pd-catalyzed addition of indoles to nitriles,17 and the Cu-
mediated decarboxylative acylation of indolic C3-position with α-
oxocarboxylic acids.18 The common routes to 2-aroylindoles
55 involve the direct addition of acyl electrophiles into the 2-
lithioindole species19 or the Pd-catalyzed tandem cyclization
reactions.20 Recently, the directing group-assisted catalytic C2-
acylations of indoles using aldehydes21 or α-keto acids22 have
been an intensive research area to override the inherent selectivity
60 of indoles. However, to the best of our knowledge, there has been
no previous report on catalytic C–H acylation at the C7-position
of indoles. Herein, we described a facile approach for the C7-
selective decarboxylative C–H acylation of indolines with α-
oxocarboxylic acids.23 Notably, the formed C7-aroylated
65 indolines can be readily converted to C7-aroylated indoles under
the oxidative conditions.
Since the pioneering works of Myers1 and Goossen,2 the
transition-metal-catalyzed decarboxylative cross-coupling
reactions using carboxylic acids, such as aryl, alkenyl and alkynyl
15 surrogates, have emerged as one of the most attractive tools for
the formation of C–C and C–heteroatom bonds in organic
synthesis.3 Recently, the decarboxylative cross-coupling reactions
on a sp3-hybridized carbon were also reported.4 However,
decarboxylative acylations using α-keto acids are relatively less
20 explored. For instance, Goossen et al. first described the Pd/Cu-
catalyzed decarboxylative acylation reaction of aryl bromides
with α-keto carboxylate salts as acyl equivalents to afford diaryl
ketones.5 Shortly thereafter, Ge and coworkers demonstrated an
elegant result on the palladium-catalyzed decarboxylative
25 acylation of acetanilides6a and phenylpyridines6b with α-
oxocarboxylic acids as acyl sources via C–H bond activation.
Guo and Duan reported the palladium-catalyzed decarboxylative
coupling between cyclic enamides and α-oxocarboxylic acids to
afford β-keto enamides.7 Inspired by these works, our group has
30 developed the decarboxylative acylation reactions of aromatic C–
H bonds with various directing groups, e.g., ketoximes,8a
phenylacetamides,8b and O-phenylcarbamates,8c with α-keto acids.
Later, some literatures on the directing group-assisted
decarboxylative acylations of aldoximes,9a anilides,9b benzoic
35 acids,9c
azobenzenes,9d,e
azoxybenzenes,9f
and
phenoxypyridines9g were also reported. In addition, a mild silver-
catalyzed acylarylation of acrylamides with α-oxocarboxylic
acids was described via a tandem decarboxylative radical
cyclization strategy.10
Scheme 1 Pd-catalyzed C7-acylation of indolines.
Our investigation was initiated by exploring the coupling of 1-
70 (indolin-1-yl)ethanone (1a) and 2-oxo-2-phenylacetic acid (2a).
After extensive screening of reaction conditions, we found that
Pd(TFA)2 catalyst efficiently catalyzed the coupling of 1a and 2a
in the presence of (NH4)2S2O8 as an external oxidant in DCE
solvent at 80 oC to afford our desired product 3a in 65% yield, as
75 shown in Table 1 (see ESI for the details). However, pivaloyl or
40
The 7-acylated indoles are ubiquitous structural motifs found
in a number of natural and synthetic molecules.11 With the
development of catalytic C–H bond functionalization, it has
become the most straightforward protocol leading to acylated
indoles. In general, acylation of indoles occurs preferentially at
45 the more electron-rich C3-position due to the premier site for
electrophilic substitution. The traditional methods for the
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N,N-dimethylcarbamoyl directing groups were found to be far
noted that the bromo moiety of 3j remained intact during the
course of the reaction, providing the opportunity for further
transformation on the product. This reaction was also compatible
less effective in the C7-acylation of indolines under identical
reaction conditions. Moreover, pyrimidinyl-protected indoline 1d
did not deliver the corresponding product. Interestingly, N- 30 with C2- or C3-substituted indolines 1k–1p furnishing the
5
benzoylated indolines 1e–1g displayed high reactivity to afford
our desired C7-aroylated products 3e–3g. It is noteworthy to
mention that the ortho-C–H bonds in N-benzoyl groups were
untouched, although they were found to be reactive in C–H
corresponding products 3k–3p in high yields. In addition, N-
benzolylated carbazole 1q participated in the decarboxylative
acylation reaction to provide 3q with slightly decreased reactivity
under the present reaction conditions. We were pleased to
funtionalization protocols.24 The regioselectivity of this reaction 35 observe C7-acylation of C6-substituted indolines 1r and 1s,
10 was further confirmed by removing N-benzoyl units of 3e–3g in
ethanolic KOH solution to give C7-benzoylated free-(NH)-
indoline 5b.
which provided the corresponding products 3r and 3s in 49% and
34% yields, respectively.
Table 3 Scope of α-keto acidsa
Table 1 Screening of directing groupsa
O
Pd(TFA)2 (5 mol %)
R
+
N
N
HO
2b-2m
(NH4)2S2O8 (200 mol %)
DCE, 80 oC, 15 h
Ph
O
Ph
H
O
1e
R
OO
4b-4m, %b
N
N
N
Ph
Ph
Ph
OO
OO
OO
F3C
MeO
X
4b, 78%
4c, 68% (X = Br)
4d, 82% (X = F)
4e, 75%
N
N
N
OO
4j, 57%
a
Cl
Reaction conditions: 1a–1g (0.2 mmol), 2a (0.3 mmol), Pd(TFA)2 (5
o
15 mol %), (NH4)2S2O8 (200 mol %), DCE (1 mL), 80 C for 15 h in sealed
Ph
Ph
Ph
X
OO
OO
tubes. b Yield isolated by column chromatography.
4f, 85% (X = Me)
4g, 81% (X = F)
4h, 81% (X = NO2)
4i, 79%
With the optimized reaction conditions in hand, the scope and
limitations of N-benzoylated indolines were examined (Table 2).
Table 2 Scope of indolinesa
N
N
N
OO
4m, 15%
Ph
Ph
S
OO
Ph
OO
Me
4l, 30% (43%)c
4k, 66%
a
Reaction conditions: 1e (0.2 mmol), 2b–2m (0.3 mmol), Pd(TFA)2 (5
o
40 mol %), (NH4)2S2O8 (200 mol %), DCE (1 mL), 80 C for 15 h in sealed
b
tubes. Yield isolated by column chromatography. 2l (0.6 mmol),
c
(NH4)2S2O8 (300 mol %), 20 h.
To further explore the substrate scope and limitations of this
process, a broad range of α-keto acids under the standard reaction
45 conditions was screened, as shown in Table 3. The coupling of
indoline 1e and phenylglyoxylic acids 2b–2i with electron-
donating and electron-withdrawing groups (MeO, Me, Br, Cl, F,
CF3 and NO2), regardless of the position of the substituent on the
aromatic ring, affording the corresponding products 4b–4i in high
50 yields. The halogen moieties on phenylglyoxylic acids were all
tolerated under the present reaction conditions. This
transformation also showed good reactivity toward naphthalenyl
oxoacetic acids 2j and 2k. In addition, 2-oxo-2-(thiophen-2-
yl)acetic acid (2l) was also found to be favoured in the
55 decarboxylative acylation reaction to afford the desired product 4l
with slightly decreased reactivity. However, aliphatic α-keto acid
2m underwent the decarboxylative acylation in low yield.
20 a Reaction conditions: 1e and 1e–1s (0.2 mmol), 2a (0.3 mmol), Pd(TFA)2
(5 mol %), (NH4)2S2O8 (200 mol %), DCE (1 mL), 80 oC for 15 h in
sealed tubes. b Yield isolated by column chromatography.
Next, we investigated a large-scale experiment to highlight the
robustness and practicality of this transformation. Thus one-pot
60 transformation was performed to provide 7-acylated indole 5a in
62% isolated yield via the decarboxylative acylation followed by
oxidation using DDQ (Scheme 2).
Indolines 1h–1j with substitutents (OMe, Cl and Br) on
aromatic ring was found to be favoured in the decarboxylative
25 C7-acylation reaction to afford the desired products 3h–3j with
an excellent level of regioselectivity in high yields. It should be
2
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In conclusion, we disclosed the palladium-catalyzed
decarboxylative acylation of highly substituted indolines with α-
oxocarboxylic acids as acyl sources. These transformations have
been applied to a wide range of substrates, and allow the
35 generation of an array of C7-acylated indoles, which are known
to be crucial scaffolds of biologically active compounds. Further
applications of this method to the preparation of bioactive
compounds and a detailed mechanistic study are currently
underway.
Scheme 2 One-pot scale-up experiment for the formation of 7-acylated
indoles.
To demonstrate the further transformation of C7-acylated
indolines, a removal of N-benzoyl protection group of 3e under
standard hydrolysis conditions was first subjected to give free-
(NH)-indoline 5b in 81% yield (Scheme 3, Eq. 1). Finally, we
sought to explore the possibility of performing sequential C–H
functionalization, wherein a newly installed functional group
5
40
This research was supported by Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (No. 2013R1A2A2A01005249)
10 would serve as the directing group for an additional C–H
activation (Scheme 3, Eq. 2). Thus, we performed the olefination
of 3a with n-butyl acrylate under ruthenium catalysis25 to afford
product 5c in 45% isolated yield with a high regioselectivity. The
starting material 3a was recovered in 38% yield. Though the
15 conversion yield is low, a slower reaction rate can be expected
presumably due to the nonproductive multidentate coordination
of the substrate with Ru catalyst.
Notes and references
a
45
School of Pharmacy, Sungkyunkwan University, Suwon 440-746,
Republic of Korea. Fax: 82 31 292 8800; Tel: 82 31 290 7788; E-mail:
insukim@skku.edu
b Department of Chemistry, University of Ulsan, Ulsan 680-749, Republic
of Korea
50 † Electronic Supplementary Information (ESI) available: Experimental
procedures and spectroscopic data for all compounds. See
DOI: 10.1039/b000000x/
1
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Scheme 3 Synthetic transformations of C7-acylated indolines.
20
A plausible reaction mechanism is outlined in Scheme 4. First,
a coordination of 1e to Pd(II) catalyst and the subsequent
cyclopalladation at the indolinic C7-position provides a 6-
membered palladacycle I, which reacts with 2a to afford dimeric
Pd(III) or Pd(IV) intermediate II along with decarboxylation.9a,d,e
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and meanwhile a Pd(II) sepecies is regenerated to complete the
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Scheme 4 Plausible reaction mechanism.
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