Acylation of indoles via photoredox catalysis: A route to 3-acylindoles

Article abstract of DOI:10.1039/c5gc01931a

A visible-light-induced synthesis of 3-acylindoles from simple indoles and α-oxo acids at room temperature has been discovered. The reaction tolerates a wide range of functional groups and gives a variety of valuable 3-acylindoles in moderate to high yields under mild conditions.

Full text of DOI:10.1039/c5gc01931a

Green Chemistry
View Article Online
View Journal
COMMUNICATION
Acylation of indoles via photoredox catalysis:
a route to 3-acylindoles†
Cite this: DOI: 10.1039/c5gc01931a
Lijun Gu,*a,b Cheng Jin,c Jiyan Liu,a Hongtao Zhang,a Minglong Yuan*b and
Received 17th August 2015,
Accepted 2nd November 2015
Ganpeng Lia
DOI: 10.1039/c5gc01931a
www.rsc.org/greenchem
A visible-light-induced synthesis of 3-acylindoles from simple thesis of indol-3-yl aryl alkyl ketones is challenging under the
indoles and α-oxo acids at room temperature has been discovered. reaction conditions needed. Accordingly, a general, efficient
The reaction tolerates a wide range of functional groups and gives and operationally simple method for the synthesis of 3-acylin-
a variety of valuable 3-acylindoles in moderate to high yields doles is highly desirable.
under mild conditions.
Visible light is an environmentally friendly and sustainable
source of energy for activating chemical transformations.9
Although first proposed by Ciamician a century ago, there was
little interest in visible light as an energy source until 2008
when the reports describing visible light photoredox catalysis
as a powerful tool in organic synthesis and materials chemistry
began to appear.10 Many visible-light photoredox catalysts,
including ruthenium or iridium polypyridyl complexes,11 have
been used to improve visible light absorption efficiency.
Groups led by Yoon,12 MacMillan,13 Stephenson14 and
others15 have demonstrated the utility of photoredox catalysts
such as [Ir(bpy)2(dtbbpy)]PF6 and Ru(bpy)3Cl2. Notably, such
photocatalysts were used to functionalize C–H bonds. Recently,
MacMillan developed a radical decarboxylative coupling of
simple α-oxo acids and aryl halides for the synthesis of aryl
and alkyl ketones.16 This coupling reaction relies on the ability
of photoredox catalysts to simultaneously modulate the oxi-
dation states of organometallic intermediates and generate
open-shell organic species that can interface with Ni catalysts.
We questioned whether this synergistic catalytic pathway
might provide a direct and mild synthesis of 3-acylindoles by
the radical decarboxylative coupling of simple α-oxo acids and
indoles, a transformation that to our knowledge has not pre-
viously been described. Herein, we disclose our preliminary
results on visible-light-promoted transformation of α-oxo acids
and indoles for the synthesis of 3-acylindoles at room tempera-
ture without the requirement for CO, strong bases, or organo-
metallic reagents. This new method offers rapid access to
3-acylindoles from simple α-oxo acid precursors via an acyl
radical intermediate (Scheme 1).
3-Acylindoles and their derivatives are common motifs in
natural products, biologically active compounds and pharma-
ceuticals, and are also versatile precursors for the synthesis of
alkaloids and related heterocycles.1,2 The synthesis of 3-acylin-
doles has thus attracted considerable attention.3 Traditional
methods for the preparation of 3-acylindoles include Friedel–
Crafts reactions,4 Vilsmeier–Haack acylations,5 and Grignard
reactions.6 More recent methods involve the reaction of nitri-
lium salts with dialkyl carbenium ions and pyridinium salts.
All of these methods, however, have limitations, which include
the need for stoichiometric acid catalysts and harsh reaction
conditions. Regioselectivity is generally poor, and none of the
methods compatible with functional groups that are labile
under acidic conditions or sensitive to strong nucleophiles. As
a consequence, there is a strong demand for efficient alterna-
tive methods for the synthesis of 3-acylindoles. The formation
of new C–C bonds by direct transition-metal-catalyzed
functionalization of C–H bonds has emerged as a major topic
of research in organic chemistry and this methodology has
recently been applied to the synthesis of 3-acylindoles.7 Very
recently, we developed a synthesis of diaryl ketones that uses
visible-light-catalyzed carbonylation of indole C–H bonds
using CO and aryldiazonium salts.8 This reaction, however,
has several limitations. With the additional requirement for
CO, and aryldiazonium salts as starting materials, the syn-
aKey Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs
Commission & Ministry of Education, Yunnan Minzu University, Kunming, Yunnan
650500, China. E-mail: gulijun2005@126.com, yml@vip.163.com
To explore the decarboxylative acylation, the reaction of
2-oxo-2-phenylacetic acid 1a and N-methylindole 2a was con-
ducted as a model reaction. After surveying a series of reaction
parameters, we identified the reaction conditions for for-
mation of the desired product. Specifically, treatment of 1a
bEngineering Research Center of Biopolymer Functional Materials of Yunnan,
Yunnan Minzu University, Kunming, Yunnan 650500, China
cNew United Group Company Limited, Changzhou, Jiangsu 213166, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5gc01931a
This journal is © The Royal Society of Chemistry 2015
Green Chem.

View Article Online
Communication
Green Chemistry
these components (Table 1, entries 10 and 11). The replace-
ment of LiF with KF or CsF gave a worse result (Table 1,
entries 12 and 13). Without LiF, a significant drop in conver-
sion was observed (Table 1, entry 14). We found that the
amount of H2O had no influence on the reaction (Table 1,
entry 15).
Encouraged by these results, we applied the above visible-
light photocatalysis protocol to a range of both α-oxo acids 1
and indoles 2 to investigate the scope. The scope of α-oxo
acids 1 was initially explored in the presence of substrate 2a,
iodine, PC1, NiCl2·glyme, dtbbpy, Cs2CO3 and LiF under
irradiation with 35 W blue LED light in DMF at room tempera-
ture. 2-Oxo-2-phenylacetic acid derivatives with electron-donat-
ing groups in the para position performed well, giving the
desired products in good yields. 2-oxo-2-phenylacetic acids
bearing electron-withdrawing halogen and CF3 groups reacted
smoothly to give the corresponding products in good yields.
Furthermore, substituents at different positions on the phenyl
moiety (para, meta, and ortho positions) did not affect the reac-
tion efficiency (Table 2, entries 1–7). It is noteworthy that halo-
substituted α-oxo acids were tolerated well, thus leading to
halo-substituted products, which could be used for further
transformations (Table 2, entries 3 and 4). Importantly, the
polysubstituted α-oxo acid 1i gave the desired product 2i with a
moderate yield (Table 2, entry 8). Notably, indol-3-yl naphthyl
ketones have high affinity binding towards the cannabinoid
CB1 and CB2 receptors.17 The visible-light-induced acylation
process allowed the synthesis of indol-3-yl naphthyl ketones
3aj in 82% yield directly (Table 2, entry 9). Interestingly, the
introduction of heterocycles into this system made this metho-
dology more useful for the preparation of pharmaceuticals and
materials (Table 2, entry 10). Efforts were made to apply this
methodology for the synthesis of indol-3-yl aryl alkyl ketones.
It was found that the reactions with 1l and 1m proceeded
smoothly to give the aryl alkyl ketones 2m and 2l in good
yields (Table 2, entries 11 and 12).
Scheme 1 Evolution of photoredox and nickel catalysis for the syn-
thesis of 3-acylindoles.
with 2a in the presence of 3 mol% Ir[dF(CF3)ppy]2(dtbbpy)PF6
(PC1), 1 equivalent of iodine, 1 equivalent of LiF, 10 mol%
NiCl2·glyme,
15
mol%
4,4′-di-tert-butyl-2,2′-bipyridine
(dtbbpy), and 2 equivalents of Cs2CO3 in DMF under the
irradiation of a bulb of 35 W blue LED at room temperature
for 60 hours gave 3aa in 82% yield (Table 1, entry 1). A number
of other photocatalysts, including Ir(ppy)2(dtbbpy)(PF6)2,
Ru(bpy)3(PF6)2 and fac-Ir(ppy)3, were subsequently investigated
(Table 1, entries 2–4), and they were found to be less effective
than PC1. The yield of 3aa was lowered to 27% when the reac-
tion was irradiated with 36 W compact fluorescent light
(Table 1, entry 5). Of the solvents tested, DMF proved particu-
larly suitable (Table 1, entries 6–8). The yield decreased
sharply when Li2CO3 was used instead of Cs2CO3 (Table 1,
entry 9). No reaction was observed in the absence of any one of
Table 1 Optimization of the reaction conditionsa
To expand the scope of this visible-light-promoted acylation
reaction further, we next investigated the decarboxylative coup-
ling of 2-oxo-2-phenylacetic acid 1a with different indoles. The
variation of indole substituents gave the desired product in
moderate to excellent yield. Apart from 2a, 1-ethyl-2-methyl-
1H-indole 2b smoothly reacted with 1a and led to the corres-
ponding product 3ba in 83% yield. Electron-withdrawing-
group-substituted indole 2c could be used as a substrate to
produce the corresponding product 3ca in 74% yield (Table 3,
entry 2). N-Methylindoles bearing electron-donating groups,
such as methyl and methoxyl, proceeded smoothly in the reac-
tion to give the desired substituted indol-3-yl phenyl ketones
3da–3fa in moderate to good yields (Table 3, entries 3–5). In
addition, 1-methyl-1H-pyrrolo[2,3-b]pyridine 2g could also
provide the expected product 3ga in 67% yield. It was found
that the reactions of free NH-indoles 2h–2j with 1a proceeded
well and gave the desired 3-acylindoles 2ha, 2ia and 2ja in
57%, 52% and 48% yields, respectively (Table 3, entries 7–9).
To gain insight into the mechanism of the reaction, experi-
ments were carried out under the standard conditions. 3-Iodo-
Yieldb
(%)
Entry Variation from the “standard reaction conditions”
1
2
3
4
5
None
82
49
18
Ir(ppy)2(dtbbpy)(PF6)2 as a catalyst
Ru(bpy)3(PF6)2 as a catalyst
fac-Ir(ppy)3 as a catalyst
Trace
Irradiated with 36 W compact fluorescent light for 27
70 h
6
7
8
9
10
11
12
13
14
15
MeCN as a solvent for 70 h
CH2Cl2 as a solvent for 70 h
Toluene as a solvent for 70 h
Li2CO3 as the base
No PC1
No NiCl2·glyme
KF as the additive
CsF as the additive
Without LiF
0.4 mmol H2O was added
44
23
Trace
73
0
0
64
67
62
82
a Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), PC1 (3 mol%),
DMF (2.0 mL), dtbbpy (15 mol%), NiCl2·glyme (10 mol%), I2
(0.3 mmol), Cs2CO3 (0.6 mmol), LiF (0.3 mmol), room temperature,
35 W blue LED light for 60 h. b Isolated yield.
Green Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Green Chemistry
Communication
Table 2 Scope of α-oxo acids 1a
Table 3 Scope of indoles 2a
Yieldb (%)
78
Entry
1
Indoles 2
Product 3
Yieldb (%)
83
Entry
1
α-Oxo acid 1
Product 3
2
3
4
5
80
71
72
66
2
3
74
71
4
55
5
6
54
67
6
7
8
9
72
61
58
82
7
8
57
52
9
48
a Reaction conditions: 1a (0.3 mmol), 2 (0.3 mmol), PC1 (3 mol%),
DMF (2.0 mL), dtbbpy (15 mol%), NiCl2·glyme (10 mol%), I2
(0.3 mmol), Cs2CO3 (0.6 mmol), LiF (0.3 mmol), room temperature,
35 W blue LED light for 60 h. b Isolated yield.
10
79
11
12
75
69
a Reaction conditions: 1 (0.3 mmol), 2a (0.3 mmol), PC1 (3 mol%),
DMF (2.0 mL), dtbbpy (15 mol%), NiCl2·glyme (10 mol%), I2
(0.3 mmol), Cs2CO3 (0.6 mmol), LiF (0.3 mmol), room temperature,
35 W blue LED light for 60 h. b Isolated yield.
Scheme 2 Control experiment.
This journal is © The Royal Society of Chemistry 2015
Green Chem.

View Article Online
Communication
Green Chemistry
We are grateful for the financial support from Program for
Innovative Research Team (in Science and Technology) in Uni-
versity of Yunnan Province (IRTSTYN 2014-11) and the State
Ethnic Affairs Commission (12YNZ05).
Notes and references
1 For a few selected references, see: (a) G. La Regina,
T. Sarkar, R. Bai, M. C. Edler, R. Saletti, A. Coluccia,
F. Piscitelli, L. Minelli, V. Gatti and C. Mazzoccoli, J. Med.
Chem., 2009, 52, 7512; (b) I. Nicolaou and
V. J. Demopoulos, J. Med. Chem., 2003, 46, 417;
(c) P. M. Fresneda, P. Molina and M. A. Saez, Synlett, 1999,
1651; (d) J. Zhang, X. Xue, C. Xu, Y. Pan, G. Zhang, L. Xu,
H. Li and Z. Shi, ChemCatChem, 2014, 6, 3030;
(e) S. Kathiravan and I. A. Nicholls, Chem. Commun., 2014,
50, 14964; (f) M. Kim, N. K. Mishra, J. Park, S. Han,
Y. Shin, S. Sharma, Y. Lee, E. Lee, K. Kwak and I. Kim,
Chem. Commun., 2014, 50, 14249.
2 For selected examples, see: (a) J. E. Saxton, Nat. Prod. Rep.,
1997, 14, 55; (b) M. Toyota and N. Ihara, Nat. Prod. Rep.,
1998, 15, 327; (c) M. Bandini and A. Eichholzer, Angew.
Chem., Int. Ed., 2009, 48, 9608; (d) Q. Yang, C. Xiao, L. Lu;,
J. An, F. Tan, B. Li and W. Xiao, Angew. Chem., Int. Ed.,
2012, 51, 9137; (e) X. Zhang, Y. Li, H. Shi, L. Zhang,
S. Zhang, X. Xu and Q. Liu, Chem. Commun., 2014, 50,
7306; (f) M. Inman and C. J. Moody, Chem. Sci., 2013, 4, 29;
(g) G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106,
2875; (h) L. Gu, C. Jin, H. Zhang and L. Zhang, J. Org.
Chem., 2014, 79, 8453; (i) R. Leurs, P. L. Chazot,
F. C. Shenton, H. D. Lim and I. J. P. De Esch,
Br. J. Pharmacol., 2009, 157, 14; ( j) P. Sang, Z. Chen, J. Zou
and Y. Zhang, Green Chem., 2013, 15, 2096.
3 For selected examples, see: (a) M. M. Faul and
L. L. Winnerosk, Tetrahedron Lett., 1997, 38, 4749;
(b) S. K. Guchhait, M. Kashyap and H. Kamble, J. Org.
Chem., 2011, 76, 4753; (c) H. Johansson, A. Urruticoechea,
I. Larsen and D. S. Pedersen, J. Org. Chem., 2015, 80, 471;
(d) N. Wan, Y. Hui, Z. Xie and J. Wang, Chin. J. Chem., 2012,
30, 311; (e) P. Zhang, T. Xiao, S. Xiong, X. Dong and
L. Zhou, Org. Lett., 2014, 14, 3264; (f) L. Yu, P. Li and
L. Wang, Chem. Commun., 2013, 49, 2368.
4 For selected examples, see: (a) J. H. Wynne, C. T. Lloyd,
S. D. Jensen, S. Boson and W. M. Stalick, Synthesis, 2004,
2277; (b) K. Yeung, M. E. Farkas, Z. Qiu and Z. Yang, Tetra-
hedron Lett., 2002, 43, 5793; (c) T. Okauchi, M. Itonaga,
T. Minami, T. Owa, K. Kitoh and H. Yoshino, Org. Lett.,
2000, 2, 1485.
Scheme 3 Plausible mechanism.
1-methyl-indole 2a′ was obtained in 67% yield when the reac-
tion was performed in the absence of 1a. The reaction of
3-iodo-1-methyl-indole 2a′ with 1a in the presence of 3 mol%
PC1, iodine, LiF, NiCl2·glyme, dtbbpy, and Cs2CO3 in DMF
under the irradiation of a bulb of 35 W blue LED at room
temperature for 60 hours gave 3aa in 88% yield. The results
indicate that compound 2a′ may be involved in this process
(Scheme 2).
On the basis of these preliminary results and previous
studies,16 the catalytic cycle of this transformation was hypo-
thesized as shown in Scheme 3. IrIII photocatalyst PC1 is
known to undergo photoexcitation in the presence of visible
light to yield the long-lived photoexcited IrIII* (excited state
lifetime τ = 2.3 μs).18 This long-lived excited state possesses a
red
high oxidizing power (E [IrIII*/IrII] = 1.21 V versus the satu-
1/2
rated calomel electrode in MeCN) and should rapidly accept
an electron from 1a′ to produce the reduced photocatalyst IrII
and the corresponding carboxyl radical species. At this stage,
this open-shell dicarbonyl intermediate will rapidly extrude
CO2 to deliver the acyl radical species A. Within the same time
frame, the second catalytic cycle will be initiated by oxidative
addition of the Ni0 catalyst into 3-iodo-1-methyl-indole 2a′ to
produce complex B. The resulting electrophilic metal species B
will then rapidly trap the nucleophilic acyl radical A to
produce nickel acyl complex C. Reductive elimination of
complex C will give the desired product 3aa, while generating
the corresponding NiI–dtbbpy complex D. Single-electron
transfer (SET) from IrII species to the NiI–dtbbpy complex D
will return the metal catalyst to the required Ni0 in an exergo-
nic process. Notably, this second photoredox-mediated SET
event regenerates the ground-state IrIII catalyst while reconsti-
tuting the requisite Ni0, completing the photoredox and nickel
cycles simultaneously.
In conclusion, we have developed a novel and efficient
Ir/Ni-cocatalyzed acylation of simple indoles with α-oxo acids
for the direct synthesis of 3-acylindoles through C–C and C–H
bond activation. Readily available indoles without preactiva-
tion, broad substrate scope, and high-value products make
this protocol very practical and attractive. Mechanistic, scope,
and limitation studies of the reaction are in progress in our
laboratory.
5 W. Anthony, J. Org. Chem., 1960, 25, 2049.
6 J. Bergman and L. Venemalm, Tetrahedron Lett., 1987, 28,
3741.
7 For selected examples, see: (a) Y. Ma, J. You and F. Song,
Chem. – Eur. J., 2013, 19, 1189; (b) M. Zhao, L. Ran,
M. Chen, Z. Ren, Y. Wang and Z. Guan, ACS Catal., 2015, 5,
1210; (c) W. Wu and W. Su, J. Am. Chem. Soc., 2011, 133,
Green Chem.
This journal is © The Royal Society of Chemistry 2015

View Article Online
Green Chemistry
Communication
11924; (d) L. Gu, J. Liu, L. Zhang, Y. Xiong and R. Wang,
Chin. Chem. Lett., 2014, 25, 90; (e) T.-S. Jiang and
G.-W. Wang, Org. Lett., 2013, 15, 788.
8 L. Gu, C. Jin and J. Liu, Green Chem., 2015, 17, 3733.
9 For selected reviews on visible-light photoredox catalysis,
see: (a) J. Xuan and W. Xiao, Angew. Chem., Int. Ed., 2012,
and T. P. Yoon, Science, 2014, 344, 392; (c) D. M. Schultz
and T. P. Yoon, Science, 2014, 343, 1239176.
13 (a) H. Shih, M. N. V. Wal, R. L. Grange and
D. W. C. MacMillan, J. Am. Chem. Soc., 2010, 132, 13600;
(b) P. V. Pham, D. A. Nagib and D. W. C. MacMillan, Angew.
Chem., Int. Ed., 2011, 50, 6119.
51, 6828; (b) T. P. Yoon, M. A. Ischay and J. Du, Nat. Chem., 14 (a) L. Furst, J. M. R. Narayanam and C. R. J. Stephenson,
2010, 2, 527; (c) C. K. Prier, D. A. Rankic and
D. W. C. MacMillan, Chem. Rev., 2013, 113, 5322;
(d) K. Zeitler, Angew. Chem., Int. Ed., 2009, 48, 9785;
(e) L. Shi and W. Xia, Chem. Soc. Rev., 2012, 41, 7687;
(f) J. W. Tucker and C. R. J. Stephenson, J. Org. Chem.,
2012, 77, 1617; (g) G. Deng, Z. Wang, J. Xia, P. Qian,
Angew. Chem., Int. Ed., 2011, 50, 9655; (b) J. D. Nguyen,
J. W. Tucker, M. D. Konieczynska and C. R. J. Stephenson,
J. Am. Chem. Soc., 2011, 133, 4160; (c) J. D. Nguyen,
B. Reiss, C. Dai and C. R. J. Stephenson, Chem. Commun.,
2013, 49, 435; (d) C. Wallentin, J. D. Nguyen, P. Finkbeiner
and C. R. J. Stephenson, J. Am. Chem. Soc., 2012, 134, 8875.
R. Song, M. Hu, L. Gong and J. Li, Angew. Chem., Int. Ed., 15 (a) Y. Chen, A. S. Kamlet, J. B. Steinman and D. R. Liu, Nat.
2013, 52, 1535.
Chem., 2011, 3, 146; (b) Y. N. Cheng, X. Y. Gu and P. X. Li,
Org. Lett., 2013, 15, 2664; (c) V. S. Thoi, N. Kornienko,
C. G. Margarit, P. D. Yang and C. J. Chang, J. Am. Chem.
Soc., 2013, 135, 14413; (d) Y. Miyake, Y. Ashida,
K. Nakajima and Y. Nishibayashi, Chem. – Eur. J., 2014, 20,
6210.
10 G. A. Nicewicz and D. W. C. MacMillan, Science, 2008, 322, 77.
11 For recent selected examples for visible-light photoredox
catalysts such as ruthenium or iridium complexes, see:
(a) J. Du and T. P. Yoon, J. Am. Chem. Soc., 2009, 131,
14604; (b) D. Ravelli, D. Dondi, M. Fagnoni and A. Albini,
Chem. Soc. Rev., 2009, 38, 1999; (c) F. R. Petronijevic, 16 L. Chu, J. M. Lipshultz and D. W. C. MacMillan, Angew.
M. Nappi and D. W. C. MacMillan, J. Am. Chem. Soc., 2013, Chem., Int. Ed., 2015, 54, 7929.
135, 18323; (d) S. Ventre, F. R. Petronijevic, M. Nappi and 17 M. M. Aung, G. Griffin, J. W. Huffman, M. Wu, C. Keel,
D. W. C. MacMillan, J. Am. Chem. Soc., 2015, 137, 5654;
(e) X. Dai, D. Cheng, B. Guan, W. Mao, X. Xu and X. Li,
J. Org. Chem., 2014, 79, 7212.
B. Yang, V. M. Showalter, M. E. Abood and B. R. Martin,
Drug Alcohol Depend., 2000, 60, 133.
18 M. S. Lowry, J. I. Goldsmith, J. D. Slinker, R. Rohl,
R. A. Pascal Jr., G. G. Malliaras and S. Bernhard, Chem.
Mater., 2005, 17, 5712.
12 (a) L. Ruiz Espelt, E. M. Wiensch and T. P. Yoon, J. Org.
Chem., 2013, 78, 4107; (b) J. Du, K. L. Skubi, D. M. Schultz
This journal is © The Royal Society of Chemistry 2015
Green Chem.