Copper-catalyzed decarboxylative C3-acylation of free (N-H) indoles with α-oxocarboxylic acids

Article abstract of DOI:10.1039/c3ob42171f

An efficient Cu-catalyzed decarboxylative C3-acylation of free (N-H) indoles using α-oxocarboxylic acids as acylating agents has been developed. This method was compatible with a variety of functional groups and provided an attractive alternative access to 3-acylindoles in moderate to high yields.

Full text of DOI:10.1039/c3ob42171f

Organic &
Biomolecular Chemistry
View Article Online
View Journal
COMMUNICATION
Copper-catalyzed decarboxylative C3-acylation of
free (N–H) indoles with α-oxocarboxylic acids†
Cite this: DOI: 10.1039/c3ob42171f
Cuiping Wang,a Shaoyan Wang,b Hua Li,c Jingbo Yan,b Haijun Chi,a Xichao Chenb
Received 2nd November 2013,
Accepted 19th January 2014
and Zhiqiang Zhang*a
DOI: 10.1039/c3ob42171f
www.rsc.org/obc
An efficient Cu-catalyzed decarboxylative C3-acylation of free considerable attention in recent years.6 Meanwhile, impressive
(N–H) indoles using α-oxocarboxylic acids as acylating agents has achievements have been made in direct C–H activation using
been developed. This method was compatible with a variety of various transition-metal catalysts such as Pd,7 Ru,8 Rh,9 or
functional groups and provided an attractive alternative access to Cu.10 Considering the atom- and step-economical features, the
3-acylindoles in moderate to high yields.
combination of decarboxylative coupling with C–H activation
could be considered the optimum strategy in the synthetic
application. In 2008, Crabtree reported the first Pd-catalyzed
decarboxylative C–H arylation.11 Subsequently, considerable
research on the decarboxylative C–H functionalization using
aromatic carboxylic acid as a substrate has been reported.12
Furthermore, α-oxocarboxylic acids were also used as decarboxy-
lative coupling partners for the direct acylation of the arene
C–H bond, which provided a new approach to ketones. Firstly,
the Ge group demonstrated several Pd-catalyzed decarboxy-
lative acylations including 2-phenylpyridines, acetanilides,
potassium aryltrifluoroborates and benzoic acids using α-oxo-
carboxylic acids as acylating agents.13 Duan and Guo also
reported a Pd-catalyzed decarboxylative acylation of cyclic
enamides with α-oxocarboxylic acids.14 Moreover, Kim et al.
also reported Pd-catalyzed decarboxylative acylation of o-methyl
ketoximes, phenylacetamides and o-phenyl carbamates with
α-oxocarboxylic acids.15 Most recently, Tan, Zhu and Zhang
developed three kinds of strategies of efficient Pd-catalyzed
decarboxylative acylations of o-methyl oximes, indoles and
2-aryloxypyridines with α-oxocarboxylic acids, respectively.16
Undoubtedly, the decarboxylative C–H functionalization has
emerged as a powerful tool for the construction of C–C bonds
in contemporary organic synthesis. Inspired by the recent
studies, we report a Cu-catalyzed decarboxylative C3-acylation of
free (N–H) indoles with α-oxocarboxylic acids to afford 3-acyl-
indoles in moderate to high yields.
The indole nucleus is one of the most important organic
structural motifs found in natural products, pharmaceutically
active compounds and agrochemicals.1 Particularly, 3-acylindoles
have been found to exhibit various pharmaceutical activities,
such as anticancer, HIV-1 integrase inhibition, and anti-
diabetic.2 Therefore, much effort has been devoted to the
preparation of 3-acylindoles. Traditionally, the most common
approach is Friedel–Crafts acylation of indole or indole
Grignard reagent with acyl chlorides.3 The other significant
approaches include Vilsmeier–Haack acylation of indole with
aryl acetamide,4a the reaction of indole with a nitrilium salt,4b
N-acylbenzotriazole,4c carboxylic acid,4d aniline,4e or nitrile.4f,g
Very recently, Wang described a novel and efficient Cu-promoted
decarboxylative direct C3-acylation of N-substituted indoles
with α-oxocarboxylic acids.5 Although significant advances
have been achieved, there are still some disadvantages, such
as strict exclusion of moisture, the use of a stoichiometric
Lewis acid promoter or expensive palladium catalyst, the intro-
duction of a protecting group at N-position of indole and a
long reaction time. Therefore, development of an efficient
approach to obtain 3-acylindoles is highly desirable.
Transition-metal-catalyzed decarboxylative C–C cross-coup-
ling reactions using carboxylic acids or carboxylates instead of
organometallic reagents as coupling partners have attracted
Our investigation started with decarboxylative coupling of
5-methoxyindole (1a) with phenylglyoxylic acid (2a) in the pres-
ence of 20 mol% Pd(II) with 2 equiv. of Ag2CO3 in DMF at
90 °C for 3 h. Unfortunately, both Pd(OAc)2 and PdCl2 gave
very low yields (Table 1, entries 1 and 2). Surprisingly, when
Cu(OAc)2·H2O co-catalyst was introduced into the Pd(OAc)2-
catalyzed reaction system, the yield was significantly enhanced
to 60% (Table 1, entry 3). Obviously, Cu(OAc)2·H2O plays a
aKey Laboratory for Functional Material, Educational Department of Liaoning
Province, University of Science and Technology Liaoning, Anshan, 114051,
P. R. China. E-mail: zhangzhiqiang@ustl.edu.cn; Fax: +86 421 592 8009;
Tel: +86 421 592 8009
bSchool of Chemical Engineering, University of Science and Technology Liaoning,
Anshan, 114051, P. R. China
cJiang Yin Amber Biopharmaceutical Co., Ltd, Wuxi, 214422, P. R. China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3ob42171f
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem.

View Article Online
Communication
Organic & Biomolecular Chemistry
Table 1 Optimization of reaction conditionsa
Table 2 Scope of Cu-catalyzed decarboxylative acylation of indolea
Oxidant
(equiv.)
Yieldb
(%)
Entry
Catalyst
Solvent
1
Pd(OAc)2
PdCl2
Pd(OAc)2/Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2
CuBr2
CuCl2·2H2O
CuO
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
—
Ag2CO3(2)
Ag2CO3(2)
Ag2CO3(2)
Ag2CO3(2)
Ag2CO3(2)
Ag2CO3(2)
Ag2CO3(2)
Ag2CO3(2)
Ag2CO3(2)
Ag2CO3(2)
Ag2CO3(2)
Ag2CO3(2)
—
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
NMP
DMAc
DMSO
DMSO
DMSO
8
22
60
71
70
65
59
66
71
70
68
64
<5
<5
2
3c
4
5
6
7
8
9
10
11
12d
13
14
Ag2CO3(2)
a Conditions: 1a (0.8 mmol), 2a (1.6 mmol), catalyst (20 mol%),
oxidant, solvent (4 mL), 90 °C, 3 h, under air. b Isolated yields.
c Cu(OAc)2·H2O (20 mol%) was added. d Cu(OAc)2·H2O (10 mol%) was
used.
crucial role in the reaction. A subsequent study indicated that
the acylation proceeded smoothly only in the presence of
Cu(OAc)2·H2O without Pd(OAc)2 to give the desired product 3a
in 71% yield (Table 1, entry 4). This result encouraged us to
find an appropriate copper catalyst. Further studies indicated
that Cu(OAc)2·H2O was superior to the other copper catalysts
(Table 1, entries 5–8). Further optimization of solvents demon-
strated that DMSO also promoted the reaction drastically
(Table 1, entries 9–11). However, the reaction in DMSO
resulted in a cleaner conversion into 3a compared to that in
DMF. The use of a reduced amount of catalyst gave rise to
slightly low reactivity (Table 1, entry 12). However, no desired
product was obtained in the absence of Cu(OAc)2·H2O or
Ag2CO3, which indicated that both the copper catalyst and the
silver oxidant were necessary for the formation of 3a (Table 1,
entries 13 and 14). Moreover, other silver oxidants, its loading
and the reaction temperature were also examined in the reac-
tion. The results are summarized in Table S1 (ESI†). Finally,
we found that the reaction proceeds most efficiently in the
presence of Cu(OAc)2·H2O (20 mol%) with 2 equiv. of Ag2CO3
in DMSO at 90 °C for 3 h (see Table S1, ESI† for details).
To explore the scope of the acylation reaction, the substi-
tuted indoles (1) were reacted with phenylglyoxylic acid under
the optimized conditions. The results are summarized in
Table 2. Notably, a variety of indoles underwent acylation with
phenylglyoxylic acid smoothly to afford the corresponding pro-
ducts in moderate to good yields (3a–g). It was noticed that
indoles with electron-rich groups (5-OCH3 and 5-CH3) were
found to be favored in the reaction to deliver the desired pro-
ducts in 71% and 77% yield, respectively (3a and 3b). However,
6-methoxyindole provided the target product only in 37% yield
a Conditions: 1 (0.8 mmol), 2 (1.6 mmol), Cu(OAc)2·H2O (20 mol%),
Ag2CO3 (2 equiv.), DMSO (4 mL), 90 °C, 1.5–8 h, under air, isolated
yields are given. b The reaction was carried out in DMF.
(3c). Additionally, 2-methylindole also afforded the product
albeit in a relatively low yield due to the steric effect (3d). Also
the acylation process is compatible with indoles bearing elec-
tron-deficient groups such as 5-Br and 5-NO2, although only
moderate yields were obtained (3f and 3g).
Subsequently, the scope of the α-oxocarboxylic acids (2) was
also investigated under the optimized conditions. Unexpect-
edly, the products were obtained as a mixture of isomers with
3h predominating besides C2-acylated product (4-nitrophenyl)-
(5-methoxy-1H-indol-2-yl)methanone determined a combination
1
of mixing H NMR and 13C NMR (see Fig. S1–S2, ESI†). Similar
results were also obtained using other substituted phenylglyoxylic
acids as acylating agents. However, the use of DMF instead of
DMSO leads to the exclusive acylation at C3-position of indole.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Communication
Although the detailed reason was not clear, other reactions without strict exclusion of moisture and exhibited good func-
were performed in DMF. A series of functional groups includ- tional group tolerance, which provides an attractive alternative
ing NO2, Br, Cl, CH3 and OCH3 on the phenyl ring were toler- to the existing synthetic methods of 3-acylindoles. Further
ated, and the desired products were obtained in moderate to investigation on the detailed reaction mechanism and studies
high yields (3h–m). It was observed that electron-deficient on transition-metal-catalyzed C–H functionalization using
groups such as p-NO2, p-Br and p-Cl exhibited high reactivity α-oxocarboxylic acids as coupling partners are ongoing in our
and gave high yields (3h–j), while electron-rich groups such as laboratory.
p-CH3 and p-OCH3 showed low reactivity and only gave 36%
and 38% yield, respectively (3l and 3m). ortho-Substituted phe-
nylglyoxylic acid also provided the target product in 44% yield
(3k). It is worth noting that the bromo and chloro groups on
Acknowledgements
both indole ring and phenyl ring remained untouched,
This work was financially supported by the Open Fund of Uni-
thereby providing an opportunity for further useful transform-
versity of Science and Technology Liaoning for Key Laboratory
ation. Gratifyingly, the electron-deficient phenylglyoxylic acids
of Functional Material (no. USTLKL2012-03) and the Youth
with p-NO2, p-Br, and p-Cl groups proved to be good substrates
Foundation of University of Science and Technology Liaoning
and were successfully reacted with indoles bearing 5-Br,
(no. 2012QN14).
5-CH3, 2-CH3 and 6-OCH3 groups under the optimized reaction
conditions, thus providing the corresponding products 3n–3u
in moderate to high yields.
To gain further insight into the reaction mechanism, the
precipitate was collected by centrifugation and filtration after
Notes and references
the reaction and was analyzed by XRD (X-ray powder diffrac-
tion). The significant diffraction peak was assigned to Ag0 (see
Fig. S3, ESI†), implying that Ag2CO3 additive can be considered
as the terminal oxidant in the reaction.
1 (a) R. J. Sundberg, Indoles, Academic Press, London, UK,
1996; (b) G. R. Humphrey and J. T. Kuethe, Chem. Rev.,
2006, 106, 2875.
2 (a) C.-C. Kuo, H.-P. Hsieh, W.-Y. Pan, C.-P. Chen, J.-P. Liou,
S.-J. Lee, Y.-L. Chang, L.-T. Chen, C.-T. Chen and
J.-Y. Chang, Cancer Res., 2004, 64, 4621; (b) M. L. Barreca,
S. Ferro, A. Rao, L. De Luca, M. Zappalà, A.-M. Monforte,
Z. Debyser, M. Witvrouw and A. Chimirri, J. Med. Chem.,
2005, 48, 7084; (c) I. Nicolaou and V. J. Demopoulos,
J. Med. Chem., 2003, 46, 417.
3 (a) C. Yang, H. H. Patel, Y.-Y. Ku, R. Shah and D. Sawick,
Synth. Commun., 1997, 27, 2125; (b) J. E. Taylor,
M. D. Jones, J. M. J. Williams and S. D. Bull, Org. Lett.,
2010, 12, 5740; (c) S. K. Guchhait, M. Kashyap and
H. Kamble, J. Org. Chem., 2011, 76, 4753; (d) J. Bergman
and L. Venemalm, Tetrahedron, 1990, 46, 6061.
Although the exact mechanism is still not clear, on the
basis of the above experimental results and the literature,13d,17
one plausible mechanism is proposed as shown in Scheme 1.
The electrophilic cupration first occurred at the C3-position of
indole forming the intermediate I, which subsequently under-
went a transmetalation step with the acylsilver species formed
by the silver-mediated decarboxylation of phenylglyoxylic acid,
to afford the Cu(III) intermediate II, followed by rearomatiza-
tion to generate the intermediate III. The subsequent reductive
elimination provided the desired product and a Cu(I), which
was reoxidized by AgI to regenerate a Cu(II) to finish the cataly-
tic cycle.
In summary, we have described an efficient Cu-catalyzed
decarboxylative C3-acylation of free (N–H) indoles with α-oxo-
carboxylic acids in combination with Ag2CO3 as the terminal
oxidant. The reaction can be performed smoothly under air
4 (a) W. Anthony, J. Org. Chem., 1960, 25, 2049; (b) S. C. Eyley,
R. G. Giles and H. Heaney, Tetrahedron Lett., 1985, 26,
4649; (c) A. R. Katritzky, K. Suzuki, S. K. Singh and
H.-Y. He, J. Org. Chem., 2003, 68, 5720; (d) K. P. Boroujeni,
Turk. J. Chem., 2010, 34, 621; (e) W. Wu and W. Su, J. Am.
Chem. Soc., 2011, 133, 11924; (f) T.-S. Jiang and
G.-W. Wang, Org. Lett., 2013, 15, 788; (g) Y. Ma, J. You and
F. Song, Chem.–Eur. J., 2013, 19, 1189.
5 L. Yu, P. Li and L. Wang, Chem. Commun., 2013, 49, 2368.
6 For selected examples, see: (a) L. J. Goossen, G. Deng and
L. M. Levy, Science, 2006, 313, 662; (b) L. J. Goossen,
N. Rodríguez and C. Linder, J. Am. Chem. Soc., 2008, 130,
15248; (c) J.-M. Becht and C. Le Drian, Org. Lett., 2008, 10,
3161; (d) R. Shang, Y. Fu, Y. Wang, Q. Xu, H. Z. Yu and
L. Liu, Angew. Chem., Int. Ed., 2009, 48, 9350.
7 C–H activation, Topics in Current Chemistry, ed. J.-Q. Yu and
Z. Shi, Springer, Berlin, Heidelberg, Germany, 2010, vol.
292.
Scheme 1 Plausible reaction mechanism.
8 W. Liu and L. Ackermann, Org. Lett., 2013, 15, 3484.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem.

View Article Online
Communication
Organic & Biomolecular Chemistry
9 D. A. Colby, A. S. Tsai, R. G. Bergman and J. A. Ellman, Acc.
Chem. Res., 2012, 45, 814.
2011, 13, 2062; (d) J. Miao and H. B. Ge, Org. Lett., 2013,
15, 2930.
10 (a) H.-Q. Do and O. Daugulis, J. Am. Chem. Soc., 2009, 131, 14 H. Wang, L.-N. Guo and X.-H. Duan, Org. Lett., 2012, 14,
17052; (b) G. Brasche and S. L. Buchwald, Angew. Chem.,
Int. Ed., 2008, 47, 1932.
11 A. Voutchokva, A. Coplin, N. E. Leadbeater and
R. H. Crabtree, Chem. Commun., 2008, 6312.
12 For selected examples, see: (a) J. Cornella, P. Lu and
I. Larrosa, Org. Lett., 2009, 11, 5506; (b) J. Zhou, P. Hu,
M. Zhang, S. Huang, M. Wang and W. Su, Chem.–Eur. J.,
2010, 16, 5876; (c) K. Xie, Z. Yang, X. Zhou, X. Li, S. Wang,
4358.
15 (a) M. Kim, J. Park, S. Sharma, A. Kim, E. Park, J. H. Kwak,
Y. H. Jung and I. S. Kim, Chem. Commun., 2013, 49, 925;
(b) J. Park, M. Kim, S. Sharma, E. Park, A. Kim, S. H. Lee,
J. H. Kwak, Y. H. Jung and I. S. Kim, Chem. Commun., 2013,
49, 1654; (c) S. Sharma, A. Kim, E. Park, J. Park, M. Kim,
J. H. Kwak, S. H. Lee, Y. H. Jung and I. S. Kim, Adv. Synth.
Catal., 2013, 355, 667.
Z. Tan, X. An and C.-C. Guo, Org. Lett., 2010, 12, 1564; 16 (a) Z. Yang, X. Chen, J. Liu, Q. Gui, K. Xie, M. Li and
(d) A. G. Myers, D. Tanaka and M. R. Mannion, J. Am.
Chem. Soc., 2002, 124, 11250; (e) Y. Zhao, Y. Zhang,
J. Wang, H. Li, L. Wu and Z. Liu, Synlett, 2010, 2352;
(f) M. Yamashita, K. Hirano, T. Satoh and M. Miura, Org.
Z. Tan, Chem. Commun., 2013, 49, 1560; (b) C. Pan, H. Jin,
X. Liu, Y. Cheng and C. Zhu, Chem. Commun., 2013, 49,
2933; (c) J. Yao, R. Feng, Z. Wu, Z. Liu and Y. Zhang, Adv.
Synth. Catal., 2013, 355, 1517.
Lett., 2009, 11, 2337; (g) C. Wang, S. Rakshit and F. Glorius, 17 (a) R. J. Phipps, N. P. Grimster and M. J. Gaunt, J. Am. Chem.
J. Am. Chem. Soc., 2010, 132, 14006.
Soc., 2008, 130, 8172; (b) K. Masui, H. Ikegami and A. Mori,
J. Am. Chem. Soc., 2004, 126, 5074; (c) M. Takahashi,
K. Masui, H. Sekiguchi, N. Kobayashi, A. Mori, M. Funahashi
and N. Tamaoki, J. Am. Chem. Soc., 2006, 128, 10930.
13 (a) M. Z. Li and H. B. Ge, Org. Lett., 2010, 12, 3464;
(b) P. Fang, M. Z. Li and H. B. Ge, J. Am. Chem. Soc., 2010,
132, 11898; (c) M. Z. Li, C. Wang and H. B. Ge, Org. Lett.,
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2014