Cerium(III)-catalyzed C3-acylation of indoles with nitroolefins

Article abstract of DOI:10.1016/j.tetlet.2016.01.029

A novel and efficient cerium(III)-catalyzed C3-selective acylation of N-H indoles using nitroolefins as acylating reagents was first developed. It was found that the use of CeCl₃ as a catalyst achieves an unexpected and highly efficient C-C bon

Full text of DOI:10.1016/j.tetlet.2016.01.029

Tetrahedron Letters xxx (2016) xxx–xxx
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Tetrahedron Letters
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Cerium(III)-catalyzed C3-acylation of indoles with nitroolefins
a
a
a
a
b,
Cheng-Tao Feng a, , Hui-Zhi Zhu , Zhong Li , Zaigang Luo , Song-Song Wu , Shi-Tang Ma
⇑
⇑
a Anhui University of Science & Technology, Huainan, Anhui 232001, PR China
b Anhui Science and Technology University, Fengyang, Anhui 233100, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient cerium(III)-catalyzed C3-selective acylation of N–H indoles using nitroolefins as acy-
lating reagents was first developed. It was found that the use of CeCl3 as a catalyst achieves an unex-
pected and highly efficient C–C bond cleavage.
Received 3 November 2015
Revised 5 January 2016
Accepted 8 January 2016
Available online xxxx
Ó 2016 Published by Elsevier Ltd.
Keywords:
Indoles
Nitroolefins
Acylation reaction
Ketone
The indole skeleton is present in many pharmaceuticals and
biologically active alkaloids, and a great deal of attention has been
paid to the synthesis of substituted indoles by either de novo
indole ring construction or modification of indole ring.1 Among
reports on indole rings, 3-acylindoles and their derivatives show
some special properties, and some of which serve as potent agents
to treat HIV, diabetes, and cancer.2 They are also used as valuable
intermediates in a variety of functional group transformations.3
Traditional strategies for the synthesis of 3-acylindoles typically
involved the use of acyl chlorides (Scheme 1, A) as acylated
reagents, which suffer from some limitations, including the use
of stoichiometric amounts of Lewis acid, the requirement of a pro-
tecting functional group on nitrogen and strict exclusion of mois-
ture. In addition, these reactions often have low selectivity, N1
acylation or N1/C3 diacylation were observed.4 The reactions of
indoles with nitrilium salts (Scheme 1, B)5 or N-(ahaloacyl)-
pyridinium salts (Scheme 1, C) were also demonstrated.6 Recently,
a series of new acylating reagents have been developed to construct
3-acylindoles. Wu and Su found that indoles could be acylated via
ruthenium- or ferrum-catalyzed oxidative coupling using anilines
as carbonyl equivalents (Scheme 1, D), whereas the use of organic
peroxides could cause explosion hazards.7 Nitriles were another
valuable acyl source for the acylation of indoles, but these reac-
tions required an expensive Pd salt as the catalyst (Scheme 1,
O
O
A
N
R
R1
C
N
R2
N
R
Cl
H
B
C
O
H
C
OH
R
C
R
Ar
N
H
O
F
D
E
Scheme 1. Representative acylating reagents.
for the success of the reactions.9 To address such issues, it is highly
desirable to develop new acylating reagents and reaction condi-
tions for the acylation of indoles with free N–H.
Nitroolefins, which are inexpensive and broadly available, are
widely used as Michael acceptors because of the high electrophilic-
ity of the double bond.10 They have been employed to synthesize a
variety of interesting heterocyclic or acyclic compounds.11 Our
group developed a cerium catalyzed cascade cyclization of 2-alky-
lazaarenes (1) with nitroolefins (2) to construct pyrrolo[1,2-a]
quinoline derivatives (3).12 Encouraged by the result, we then tried
to realize the cascade cyclization of 2-(pyridin-2-yl)-1H-indole
(4a) with nitroolefins (2) using cerium as catalyst (Scheme 2). Sur-
prisingly, the expected product 7-phenylindolo[2,3-a]quinolizine
(6) was not observed. Instead, we found that (E)-(2-nitrovinyl)ben-
zene (2a) reacted with 2-(pyridin-2-yl)-1H-indole (4a) to give an
unexpected C3 acylation product of phenyl(2-(pyridin-2-yl)-1H-
indol-3-yl)methanone (5a) with 90% isolated chemical yield.
E).8
(Scheme 1, F), Wang et al. reported a novel copper-promoted
decarboxylative acylation of indoles with -oxocarboxylic acids,
a-Oxocarboxylic acids were also used as acylating reagents
a
however stoichiometric amounts of copper salt were necessary
⇑
Corresponding authors.
http://dx.doi.org/10.1016/j.tetlet.2016.01.029
0040-4039/Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Feng, C.-T.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.01.029

2
C.-T. Feng et al. / Tetrahedron Letters xxx (2016) xxx–xxx
N
O
Ph
N
O
N
OEt
H
O
4a
1
N
NO2
N
Ph
OEt
7H2O. CeCl3 (10 mol %)
7H2O. CeCl3 (10 mol %)
N
2a
Ph
H
3
5a
our previous work
cascade cyclization
Ph
N
N
H
6
Scheme 2. Cascade cyclization and acylation.
The applications of cerium compounds to organic transforma-
group to 7-position of the indole ring marginally reduced the reac-
tion yield (Table 2, 5t).
tions have been extensively studied.13 They have attracted much
attention in organic synthesis because they are inexpensive, easy
to handle, and highly tolerant to air and moisture. Therefore, the
development of cerium-catalyzed methods would be of a great
value. Herein, we report a cerium-catalyzed C3-selective acylation
of N–H indoles using nitroolefins as acylating reagents. To our
knowledge, this is the first example of using the nitroolefins as
acylating reagents in acylation reactions.
To gain insight into the possible mechanism of the reaction, a
few control experiments were carried out. In the presence of the
radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO),
a negative influence on the yield was observed (Scheme 3, Eq. 1).
This implied that some radical intermediates should be involved
in the reaction. Next, instead of nitroolefin, benzaldehyde was used
to react with 2-(pyridin-2-yl)-1H-indole under the optimal reac-
tion conditions. Almost no desired product was obtained in this
case (Scheme 3, Eq. 2). When the reaction of 2-(pyridin-2-yl)-1H-
indole (4a) and trans-(Z)nitrostyrene (2a) was performed in the
cerium catalytic system under argon gas, the desired product
(5a) was obtained in 93% yield (Scheme 3, Eq. 3). This result indi-
cated that the nitro group might act as an internal oxidant. When
2-phenyl-1H-indole (Scheme 3, Eq. 4) or 2-(pyridin-4-yl)-1H-
indole (Scheme 3, Eq. 5) was used to react with nitroolefin (2a),
michael adducts were separated as major product. The above
results suggest that the existence of pyridin-2-yl group has an
unclear intramolecular effect on the product formation process.
To look into the prospect of this new acylation reaction, a model
reaction using easily available 2-(pyridin-2-yl)-1H-indole (4a) and
trans-(Z)nitrostyrene (2a) was investigated in detail by varying the
catalyst in order to develop appropriate conditions (Table 1). We
screened various Lewis acids and found that other Lewis acids,
including copper salt, iron salt, nickel salt, cobalt salt, are either
ineffective or less effective than CeCl3Á7H2O (Table 1, entries 1–
6). The reaction gave a poor yield in the absence of catalyst (Table 1,
entry 7). On the other hand, the organic solvent was also found to
play an important role in the reaction. Among various solvents
screened, ethanol was found to be the most suitable solvent. Other
solvents reduced the yield of this reaction (Table 1, entries 8–13).
The yield of 5a decreased to 72% when lowering the temperature
from 120 °C to 100 °C (Table 1, entry 14). In recent years, it has
been found that the CeCl3Á7H2O–NaI system as an efficient Lewis
acid activator has a wide range of interesting applications in
organic chemistry.13b However, the introduction of 0.1 equiv of
NaI into the reaction system significantly suppressed the reaction
(Table 1, entry 15).
Table 1
Optimization of the reaction conditionsa
O2N
10 mol% cat.
+
O
N
H
With the optimal conditions in hand, the substrate scope and
limitation of the reaction was explored. First of all, the substrate
scope of nitroolefins 2 was examined. As illustrated in Table 2, aro-
matic nitroalkenes with both electron-rich (4-Me, 4-OMe, 4-NMe2)
and electron-deficient (CF3) substituents on the aromatic ring par-
ticipated in this reaction smoothly to afford the expected products
in good to excellent yields. Generally, an electron-donating sub-
stituent on the aromatic ring has a negative effect on the yield.
Unprotected phenol functions were well tolerated under the opti-
mized conditions, when R1 was replaced by a 2-OH group, the reac-
tion gave a lower yield in comparison with that R1 was a 4-OH
group (Table 2, entries 5f and 5n). This implied that steric effect
had an influence on the reaction. The reaction of ring-fused (5o)
nitroalkene also afforded the corresponding product in good yields.
However, less-reactive alkyl substituted nitroalkenes did not give
the target products under the current reaction conditions.
Next, the effect of the substituents attached on the indole ring
was examined. The halogen, including fluoro, chloro, or bromo
group, had little influence on the reaction (Table 2, 5q–5s), thus pro-
viding the possibility to allow additional coupling reactions. The
electron-donating group at 5-position of the indole ring was also
well tolerated, affording the corresponding product in excellent
yield (Table 2, 5p). But the introduction of an electron-donating
N
N
N
H
4a
2a
5a
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuCl2Á2H2O
FeCl3Á6H2O
NiCl2Á6H2O
CoCl2Á6H2O
CeCl3Á7H2O
TsOHÁH2O
—
CeCl3Á7H2O
CeCl3Á7H2O
CeCl3Á7H2O
CeCl3Á7H2O
CeCl3Á7H2O
CeCl3Á7H2O
CeCl3Á7H2O
CeCl3Á7H2O
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
DMF
MeCN
THF
CH2Cl2
MeOH
EtOH
EtOH
32
25
38
Traces
90
29
36
Traces
Traces
21
Traces
Traces
85
9
10
11
12
13
14c
15d
72
43
a
Reaction conditions: 4a (0.20 mmol), 2a (0.30 mmol), catalyst (0.02 mmol),
solvent (2 ml), 120 °C, 12 h.
b
Isolated yield.
The reaction was at 100 °C.
0.02 mmol of NaI was used.
c
d
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C.-T. Feng et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
Table 2
Acylation of indoles with nitroolefinsa
Ar
O
10 mol% CeCl3 7H2O
EtOH, 120 °C
R
NO2
+
Ar
N
H
R
N
N
N
H
4
2
5
F
Cl
Br
O
O
N
O
O
N
N
N
N
N
N
N
N
N
N
H
5c
N
H
5d
H
H
5a
5b
, 90%
, 80%
, 83%
, 96%
O
HO
N
O
O
O
O
N
N
N
H
N
H
N
H
N
H
5e, 82%
5g
5f, 87%
, 75%
5h, 72%
F3C
Cl
Cl
O
Cl
O
O
O
O
N
N
N
H
N
H
N
N
H
H
5i
, 77%
5j, 93%
5k
, 75%
5l
, 82%
O
O
OH
O
O
Ph
O
O
O
N
N
N
N
O
N
N
N
H
N
H
N
H
N
H
5m, 62%
5n, 45%
5o, 53%
5p, 88%
Ph
O
Ph
Ph
Ph
O
O
F
Br
Cl
N
H
N
H
N
N
H
N
N
H
5q
, 98%
5r, 91%
5s, 72%
5t, 65%
a
Standard reaction conditions: 4 (0.20 mmol), 2 (0.30 mmol), CeCl3Á7H2O (0.02 mmol), 2 ml EtOH, 120 °C, 12 h, isolated
yield.
On the basis of the control experiments and literature
reports,10a,14 a plausible mechanism is outlined in Scheme 4. The
first step of the reaction is the Friedel–Crafts reaction of
2-pyridyl-indole I with nitroolefin II to form the intermediate III.
Ce(III) salt may accelerate the reaction by increasing the
electrophilicity of the nitroolefin. Subsequently, the intermediate
III is converted into intermediate IV by a Ce(III)-catalyzed Nef
reaction. The intermediate IV is converted to V by oxidation
reaction, further oxidation to the carbon–oxygen double bond VI
is occured via a carbon–carbon bond cleavage.
In conclusion, we have developed an unprecedented acyla-
tion reaction of indoles with nitroolefins through the cleavage
of C–C bonds. In the presence of 10 mol % cerium(III) chloride
heptahydrate, a range of aryl nitroolefins smoothly underwent
acylation with unprotected indoles to give
a wide range
of 3-acylindoles in moderate to excellent yields with extremely
high regioselectivity. The current research paves the way for
the use of nitroolefins as unique acylating reagent in chemical
synthesis.
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4
C.-T. Feng et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Ph
O
N
NO2
7H2O CeCl3, EtOH
TEMPO
(1)
N
+
N
H
(1.5 equiv)
120 °C
N
H
38%
Ph
O
O
N
N
7H2O CeCl3, EtOH
120 °C
N
N
(2)
(3)
(4)
+
H
N
H
N
H
0%
Ph
O
NO2
7H2O CeCl3, EtOH
120 °C, Ar.
+
N
H
N
H
93%
NO2
Ph
NO2
7H2O CeCl3, EtOH
120 °C
+
+
N
H
N
H
76%
NO2
Ph
NO2
7H2O CeCl3, EtOH
120 °C
N
(5)
N
H
N
N
H
68%
Scheme 3. The control experiments to prove the mechanism.
2. (a) Gribble, G. W. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon Press: New York, 1996; Vol. 2, p 207; (b)
Massa, S.; Santo, R. Di; Artico, M. J. Heterocycl. Chem. 1990, 27, 1131; (c) Pais, G.
C. G.; Zhang, X.; Marchand, C.; Neamati, N.; Cowansage, K.; Svarovskaia, E. S.;
Pathak, V. K.; Tang, Y.; Nicklaus, M.; Pommier, Y.; Burke, T. R. J. Med. Chem.
2002, 45, 3184; (d) Barreca, M. L.; Ferro, S.; Rao, A.; Luca, L. D.; Zappala, M.;
Monforte, A.-M.; Debyser, Z.; Witvrouw, M.; Chimirri, A. J. Med. Chem. 2005, 48,
7084; (e) Wu, Y.-S.; Coumar, M. S.; Chang, J.-Y.; Sun, H.-Y.; Kuo, F.-M.; Kuo, C.-
C.; Chen, Y.-J.; Chang, C.-Y.; Hsiao, C.-L.; Liou, J.-P.; Chen, C.-P.; Yao, H.-T.;
Chiang, Y.-K.; Tang, U.-K.; Chen, C.-T.; Chu, C.-Y.; Wu, S.-Y.; Yeh, T.-K.; Lin, C.-Y.;
Hsieh, H.-P. J. Med. Chem. 2009, 52, 4941.
NO2
N
Ph
Friedel-Crafts
reaction
NO2
+
N
H
N
N
II
I
H
III
Nef reaction
OH
O
Ph
3. (a) Lauchli, R.; Shea, K. J. Org. Lett. 2006, 8, 5287; (b) Coldham, I.; Dobson, B. C.;
Fletcher, S. R.; Franklin, A. I. Eur. J. Org. Chem. 2007, 16, 2676.
Ph
Ph
O
O
N
[O]
[O]
4. (a) Ketcha, D. M.; Gribble, G. W. J. Org. Chem. 1985, 50, 5451; (b) Bergman, J.;
Venemalm, L. Tetrahedron 1990, 46, 6061; (c) Faul, M. M.; Winneroski, L. L.
Tetrahedron Lett. 1997, 38, 4749; (d) Okauchi, T.; Itonaga, M.; Minami, T.; Owa,
T.; Kitoh, K.; Yoshino, H. Org. Lett. 2000, 2, 1485; (e) Ottoni, O.; Neder, A. de V.
F.; Dias, A. K. B.; Cruz, R. P. A.; Aquino, L. B. Org. Lett. 2001, 3, 1005; (f) Katritzky,
A. R.; Suzuki, K.; Singh, S. K.; He, H.-Y. J. Org. Chem. 2003, 68, 5720; (g) Wynne, J.
H.; Lloyd, C. T.; Jensen, S. D.; Boson, S.; Stalick, W. M. Synthesis 2004, 2277; (h)
Taylor, J. E.; Jones, M. D.; Williams, J. M. J.; Bull, S. D. Org. Lett. 2010, 12, 5740; (i)
Guchhait, S. K.; Kashyap, M.; Kamble, H. J. Org. Chem. 2011, 76, 4753.
5. Eyley, S. C.; Giles, R. G.; Heaney, H. Tetrahedron Lett. 1985, 26, 4649.
6. Bergman, J.; Backvall, J.-E. B.; Lindstrom, J.-O. Tetrahedron 1973, 29, 971.
7. Wu, W.; Su, W. J. Am. Chem. Soc. 2011, 133, 11924.
8. (a) Jiang, T. S.; Wang, G. W. Org. Lett. 2013, 15, 788; (b) Ma, Y. H.; You, J. S.; Song,
F. J. Chem. Eur. J. 2013, 19, 1189.
9. Yu, L.; Li, P.; Wang, L. Chem. Commun. 2013, 2368.
10. For selected examples, see: (a) Guo, F. F.; Lai, G. Y.; Xiong, S. S.; Wang, S. J.;
Wang, Z. Y. Chem. Eur. J. 2010, 16, 6438; (b) Guo, F. F.; Chang, D. L.; Lai, G. Y.;
Zhu, T.; Xiong, S. S.; Wang, S. J.; Wang, Z. Y. Chem. Eur. J. 2011, 17, 11127; (c) Xu,
K.; Zhang, S.; Hu, Y. B.; Zha, Z. G.; Wang, Z. Y. Chem. Eur. J. 2013, 19, 3573; (d)
Gao, M.; Tian, J.; Lei, A. W. Chem. Asian J. 2014, 9, 2068.
N
N
H
N
N
H
V
N
H
VI
IV
Scheme 4. Plausible reaction mechanism.
Acknowledgments
We gratefully thank the financial supports of the Natural
Science Foundation of China (81403268, 21102003), Scientific
Research Foundation for the Introduction of Talent and Young
Teachers and Scientific Research Foundation of Anhui University
of Science & Technology (QN201508).
Supplementary data
11. For selected examples, see: (a) Yan, R. L.; Yan, H.; Ma, C.; Ren, Z. Y.; Gao, X. A.;
Huang, G. S.; Liang, Y. M. J. Org. Chem. 2012, 77, 2024; (b) Fallan, C.; Lam, H. W.
Chem. Eur. J. 2012, 18, 11214; (c) Feng, C. T.; Su, J. H.; Yan, Y. Z.; Guo, F. F.;
Wang, Z. Y. Org. Biomol. Chem. 2013, 11, 6691; (d) Ghosh, M.; Mishra, S.; Hajra,
A. J. Org. Chem. 2015, 80, 5364.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.01.029.
12. Feng, C. T.; Yan, Y. Z.; Zhang, Z. L.; Xu, K.; Wang, Z. Y. Org. Biomol. Chem. 2014, 12, 4837.
13. (a) Sridharan, V.; Menéndez, J. C. Chem. Rev. 2010, 110, 3805; (b) Bartoli, G.;
Marcantoni, E.; Marcolini, M.; Sambri, L. Chem. Rev. 2010, 110, 6104; (c)
Properzi, R.; Marcantoni, E. Chem. Soc. Rev. 2014, 43, 779.
References and notes
1. For reviews, see: (a) Katritzky, A. R.; Ramsden, C. A.; Joule, J. A.; Zhdankin, V. V.
Handbook of Heterocyclic Chemistry, 3rd ed.; Elsevier: Oxford, 2010; (b)
Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
14. Noland, W. E. Chem. Rev. 1955, 55, 137.
Please cite this article in press as: Feng, C.-T.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.01.029