Rhodium(III)-catalyzed direct regioselective synthesis of 7-substituted indoles

Article abstract of DOI:10.1021/ol402626t

An efficient, atom-economic one-pot method was developed for the preparation of 7-substituted indoles via rhodium(III)-catalyzed oxidative cross-coupling. Regioselective olefination of indoline derivatives followed by one-pot subsequent oxidation provided the desired products in good to excellent yields.

Full text of DOI:10.1021/ol402626t

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rhodium(III)-Catalyzed Direct
Regioselective Synthesis
of 7‑Substituted Indoles
Zengqiang Song,†,‡ Rajarshi Samanta,§,† and Andrey P. Antonchick*,†,‡
Max-Planck-Institut fu€r Molekulare Physiologie, Abteilung Chemische Biologie,
€
Otto-Hahn-Strasse 11, 44227 Dortmund, Germany, and Technische Universitat
€
Dortmund, Fakultat Chemie und Chemische Biologie, Chemische Biologie,
Otto-Hahn-Strasse 6, 44227 Dortmund, Germany
andrey.antonchick@mpi-dortmund.mpg.de
Received September 11, 2013
ABSTRACT
An efficient, atom-economic one-pot method was developed for the preparation of 7-substituted indoles via rhodium(III)-catalyzed oxidative cross-
coupling. Regioselective olefination of indoline derivatives followed by one-pot subsequent oxidation provided the desired products in good to
excellent yields.
Many natural products with a broad spectrum of bio-
activity are based on indole. Moreover, indole has been
identified as a privileged scaffold for the design of bio-
logical probes and medicinal drugs.1 The synthesis of
substituted indole derivatives has received considerable
attention in organic chemistry. Many practical and effi-
cient methods have been developed for the construction
of an indole core in recent decades.2 Nevertheless, efficient
protocols for direct regioselective functionalization of
indole derivatives in order to get fast access to a variety
ofindolederivativesare inhigh demand.3 Extensivestudies
have been carried out over the past decades targeting
transition-metal-catalyzed CÀH bond activations at the
C-2 and C-3 positions of indole (Scheme 1).4 It has been
shown that 2- or 3-alkenylated indole derivatives can be
obtained via intermolecular oxidative coupling with cor-
responding nonfunctionalized coupling partners using
transition-metal catalysis.4À6 Recently, an elegant method
for preparation of 4-substituted tryptophans has been re-
ported (Scheme 1).7 7-Substituted indole derivatives are
very important due to their ubiquitous presence in numer-
ous natural products and pharmaceutically important
compounds (Figure 1).8 Regioselective oxidative CÀH
functionalization of indole derivatives at the C-7 position
has limited reports.9
† Max-Planck-Institut f€ur Molekulare Physiologie.
‡
€
Technische Universitat Dortmund.
§ Indian Institute of Technology Kharagpur, 721302 Kharagpur, India.
(1) (a) Huffman, J. W.; Padgett, L. W. Curr. Med. Chem. 2005, 12,
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1730.
r
10.1021/ol402626t
XXXX American Chemical Society

Scheme 1. Regioselective Functionalization of Indoles
Figure 1. Bioactive compounds based on 7-substituted indoles.
Our proposal is based on the functionalization of indo-
line derivatives, which are widely available from corre-
sponding indoles by reduction and following protection
(Scheme 1). In the initial study, we first examined the
coupling reaction between N-acetylindoline (1a) and styr-
ene (2a) using [Ru(SbF6)2(p-cymene)]2 as catalyst and
anhydrous Cu(OAc)2 as oxidant in DCE at 120 °C
(Table 1, entry 1). We obtained the desired product 3a in
24% isolated yield. Further screening of solvents with
DMF, t-AmOH, CH3CN, or 1,4-dioxane did not improve
the yield of our desired product (Table 1, entries 2À5).
Several oxidants such as AgOAc or benzoquinone were
As part of our studies on the direct functionalization
of unactivated CÀH bonds,10 we were interested in the
development of a transition-metal-catalyzed regioselective
method for 7-substituted indoles (Scheme 1). Here we
report an one-pot general approach for functionalization
of indole derivatives at the C-7 position.
(5) For Pd-catalyzed indole C-2 alkenylation, see: (a) Garcı
´
ꢀ
a-Rubia,
A.; Arrayas, R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2009, 48,
ꢀ
6511. (b) Garcıa-Rubia, A.; Arrayas, R. G.; Carretero, J. C. Chem.;
´
Eur. J. 2010, 16, 9676. (c) Maehara, A.; Tsurugi, H.; Satoh, T.; Miura,
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M. J. Angew. Chem., Int. Ed. 2005, 44, 3125. For rhodium(III)-catalyzed
indole C-2 alkenylation, see: (g) Patureau, F. W.; Glorius, F. J. Am.
Chem. Soc. 2010, 132, 9982. (h) Li, B.; Ma, J.; Xie, W.; Song, H.; Xu, S.;
Wang, B. Chem.;Eur. J. 2013, 19, 11863. (i) Ueyama, T.; Mochida, S.;
Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 706.
For Ru(II)-catalyzed indole C-2 alkenylation, see: (j) Lanke, V.; Prabhu,
K. R. Org. Lett. 2013, 15, 2818.
(6) For C-3 alkenylation, see: (a) Yokoyama, Y.; Matsumoto, T.;
Murakami, Y. J. Org. Chem. 1995, 60, 1486. (b) Itahara, T.; Kawasaki,
K.; Ouseto, F. Synthesis 1984, 236. (c) Chen, W.-L.; Gao, Y.-R.; Mao,
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(d) Huang, Q.; Song, Q.; Cai, J.; Zhang, X.; Lin, S. Adv. Synth. Catal.
2013, 355, 1512.
Table 1. Optimization of Reaction Conditionsa
entry
PG
Ac (1a)
solvent
oxidant
time (h) yieldc (%)
1
DCE
DMF
Cu(OAc)2
Cu(OAc)2
24
24
24
24
24
24
24
24
24
24
24
36
16
48
36
8
24
20
2
Ac (1a)
Ac (1a)
Ac (1a)
Ac (1a)
Ac (1a)
Ac (1a)
Piv (1b)
3
t-AmOH Cu(OAc)2
CH3CN Cu(OAc)2
dioxane Cu(OAc)2
14
4
<14
<14
trace
trace
n.d.d
n.d.d
53
(7) Liu, Q.; Li, Q.; Ma, Y.; Jia, Y. Org. Lett. 2013, 15, 4528.
5
(8) (a) Monache, F. D.; Dibenedetto, R.; Demoraesesouza, M. A.;
Sandor, P. Gazz. Chim. Ital. 1990, 120, 387. (b) Vougogiannopoulou, K.;
Fokialakis, N.; Aligiannis, N.; Cantrell, C.; Skaltsounis, A. L. Org. Lett.
2010, 12, 1908. (c) Asai, T.; Yamamoto, T.; Oshima, Y. Tetrahedron
Lett. 2011, 52, 7042. (d) Ishikura, M.; Abe, T.; Choshi, T.; Hibino, S.
Nat. Prod. Rep. 2013, 30, 694. (e) Yeung, K. S.; Qiu, Z. L.; Xue, Q. F.;
Fang, H. Q.; Yang, Z.; Zadjura, L.; D’Arienzo, C. J.; Eggers, B. J.;
Riccardi, K.; Shi, P. Y.; Gong, Y. F.; Browning, M. R.; Gao, Q.; Hansel,
S.; Santone, K.; Lin, P. F.; Meanwell, N. A.; Kadow, J. F. Bioorg. Med.
Chem. Lett. 2013, 23, 198. (f) Yeung, K. S.; Qiu, Z. L.; Yin, Z. W.;
Trehan, A.; Fang, H. Q.; Pearce, B.; Yang, Z.; Zadjura, L.; D’Arienzo,
C. J.; Riccardi, K.; Shi, P. Y.; Spicer, T. P.; Gong, Y. F.; Browning,
M. R.; Hansel, S.; Santone, K.; Barker, J.; Coulter, T.; Lin, P. F.;
Meanwell, N. A.; Kadow, J. F. Bioorg. Med. Chem. Lett. 2013, 23, 203.
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2003, 5, 1899. (b) Fanton, G.; Coles, N. M.; Cowley, A. R.; Flemming,
6
DCE
DCE
DCE
AgOAc
7
BQ
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
9
CO-2Py (1c) DCE
CONEt2 (1d) DCE
SO2-2Py (1e) DCE
10
11
n.d.d
96
12b CONEt2 (1d) DCE
13b CONEt2 (1d) dioxane Cu(OAc)2
51
14b CONEt2 (1d) toluene
15b Ac (1a)
DCE
Cu(OAc)2
31
Cu(OAc)2
99
16b CONEt2 (1d) t-AmOH Cu(OAc)2
17b CONEt2 (1d) t-AmOH Ag2CO3
18b CONEt2 (1d) t-AmOH Ag2O
19b CONEt2 (1d) t-AmOH PhI(OAc)2
20b CONEt2 (1d) t-AmOH NFSI
90
20
36
36
36
45
58
ꢀ
J. P.; Brown, J. M. Heterocycles 2010, 80, 895. (c) Urones, B.; Arrayas,
trace
trace
R. G.;Carretero, J. C. Org. Lett. 2013, 15, 1120. For indolineC-7position
arylations: (d) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S.
J. Am. Chem. Soc. 2005, 127, 7330. (e) Shi, Z.; Li, B.; Wan, X.; Cheng, J.;
Fang, Z.; Cao, B.; Qin, C.; Wang, Y. Angew. Chem., Int. Ed. 2007, 46,
5554. (f) Nishikata, T.; Abela, A. R.; Huang, S.; Lipshutz, B. H. J. Am.
Chem. Soc. 2010, 132, 4978. (g) Jiao, L.-Y.; Oestreich, M. Chem.;Eur. J.
2013, 19, 10845. (h) Jiao, L.-Y.; Oestreich, M. Org. Lett. 2013, 15, 5374.
(10) (a) Samanta, R.; Antonchick, A. P. Angew. Chem., Int. Ed. 2011,
50, 5217. (b) Samanta, R.; Narayan, R.; Antonchick, A. P. Org. Lett.
2012, 14, 6108.
a Reaction conditions: 1 (0.2 mmol), 2a (1.0 mmol), [RuCl2(p-
cymene)]2 (10 mol %), AgSbF6 (40 mol %), oxidant (2.5 equiv), 0.2 M
at 120 °C (the internal temperature of vial was 105 °C). b Reaction
conditions: 1 (0.1 mmol), 2a (0.5 mmol), [Cp*Rh(III)Cl2]2 (5 mol %),
AgSbF6 (20 mol %), oxidant (2.5 equiv), 0.1 M at 120 °C. c Isolatedyield.
d The formation of product was not detected.
B
Org. Lett., Vol. XX, No. XX, XXXX

tested to improve the yield of the desired product. Un-
fortunately, only formation of trace amount of 3a was
detected (Table 1, entries 6 and 7). Various directing
groups were tested to improve the yield of the product.
We found that N,N-diethylcarbamoyl-protected indoline
provided the desired alkenylated product 3d with 53%
yield (Table 1, entry 10). Other protecting groups like
pivolyl, 2-pyridylcarbonyl, or 2-pyridylsulfonyl did not
work (Table 1, entries 8, 9, and 11). After various experi-
ments with [Ru(SbF6)2(p-cymene)]2 we decided to switch
to [RhCp*(SbF6)2]2 as catalyst. Our initial attempt for
coupling of styrene with N,N-diethylcarbamoyl-protected
indoline in 1,2-dicholoroethane provided a very impressive
96% yield of the product (Table 1, entry 12) in 36 h when
5 mol % of rhodium(III) catalyst was used. Others solvents
such as 1,4-dioxane or toluene did not provide better yields
(Table 1, entries 13 and 14). When t-AmOH was used as
solvent, the desired product was obtained in excellent
yield and shorter reaction time (Table 1, entry 16). Other
oxidants like Ag2CO3 or Ag2O provided moderate yields,
whereas PhI(OAc)2 or NFSI gave almost no conversion
(Table 1, entries 17À20). In control experiment, the cou-
pling of styrene with the N,N-diethylcarbamoyl-protected
indole was tested and resulted in a mixture of pro-
ducts. On the other hand, the coupling of styrene with
N,N-diethylcarbamoyl-protected 2-methylindole or N,N-
diethylcarbamoyl 2,3,4,9-tetrahydro-1H-carbazole under
rhodium(III)-catalyzed conditions did not give any desired
product, and only starting material was remained (see the
Supporting Information for details).
followed by oxidation. In initial trials, acetyl-protected
indoline was used for olefination followed by oxidation.
Although the first step finished efficiently, the oxidation
of 7-alkenylated indoline to its indole derivative did not
provide a good yield (Table 2, entries 1À3) under different
oxidation conditions.11 However, changing of the acetyl
protection group to the N,N-diethylcarbamoyl group
led to 4d in satisfactory yield (80% for two steps) using
oxidation with MnO2 (Table 2, entry 5). Furthermore,
product 4d was obtained with 86% yield from 1d perform-
ing the reaction at 1 mmol scale. Other oxidants such
as DDQ, Mn(OAc)3 2H2O or TBHP did not provide
3
improvement of yield.
Scheme 2. Scope of 7-Substituted Indolesa
Table 2. Optimization of One-Pot Reaction Conditionsa
oxidant
(equiv)
time
(h)
yieldb
(%)
entry
PG
Ac (1a)
Ac (1a)
Ac (1a)
CONEt2 (1d)
CONEt2 (1d) t-AmOH
CONEt2 (1d)
CONEt2 (1d)
solvent
1c
2c
3c,d
4c
5
DCE
DCE
DCE
DCE
MnO2 (20)
DDQ (3)
TBHP (4)
MnO2 (20)
MnO2 (20)
DDQ (3)
24
24
24
24
8
38
11
trace
76
80
57
a Reaction conditions: indoline (0.1 mmol), alkene (0.5 mmol),
(Cp*RhCl2)2 (5 mol %), AgSbF6 (20 mol %), and anhydrous Cu(OAc)2
(2.5 equiv) with t-AmOH (0.1 M) at 120 °C (the internal temperature of
vial is 105 °C), after indolines completely disappeared, MnO2 was added
(30 equiv) to the reaction system, continue stirring at 120 °C for 8 h, total
reaction times are given in Scheme 2. b 40 equiv MnO2 used. c 20 equiv of
MnO2 used. PG = CONEt2.
6
7
t-AmOH
t-AmOH
4
24
Mn(OAc)3
22
3
2H2O (1.5)
TBHP (4)
chloranil (3)
8d
9
CONEt2 (1d)
CONEt2 (1d)
t-AmOH
t-AmOH
24
24
trace
36
a Reaction conditions: 1 (0.1 mmol), 2a (0.5 mmol), (Cp*RhCl2)2
(5 mol %), AgSbF6 (20 mol %), and anhydrous Cu(OAc)2 (2.5 equiv),
t-AmOH (0.1M) at 120 °C (the internal temperature of vial is 105 °C),
after 1 completely disappeared (8 h), oxidant was added to the reaction
system, continued stirring at 120 °C. b Isolated yield. c After 36 h, 1
completely diasppeared. d TBHP 5.5 M in decane.
Having the optimized conditions in hand, we explored
the scope and generality of this transformation. Initially,
we checkedthe generalityofalkenes. Coupling withmethyl
(11) For oxidation of indoline to indole using MnO2, see: (a) Lo,
Y. S.; Walsh, D. A.; Welstead, W. J., Jr.; Mays, R. P.; Rose, E. K.;
Causey, D. H.; Duncan, R. L. J. Heterocycl. Chem. 1980, 17, 1663. (b)
Kametani, T.; Ohsawa, T.; Ihara, M. J. Chem. Soc., Perkin Trans. 1
1981, 290.
Afterward, we explored the one-pot reaction conditions
for selective 7-functionalized indole synthesis, which is based
on the coupling of an indoline derivative with a styrene,
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Proposed Mechanism
Scheme 4. Application of 7-Substituted Indoles
memberedrhodacycleB. Insertion of olefin tothe carbonÀ
rhodium bond of B generated the seven-membered
rhodacycle C. β-Hydride elimination of the intermediate
C provided the desired product D with a rhodium(I) com-
plex which could be further oxidized to the rhodium(III)
complex by Cu(OAc)2 to continue the catalytic cycle.
Moreover, copper acetate could be the source of an acetate
ligand for the active rhodium species.12 In situ oxidation of
D via addition of external oxidant afforded the crucial
7-substituted indoles.
After developing the synthetic approach for synthesis of
7-substituted indoles, we tried to modify our product to
demonstrate its further synthetic utility. Using a known
method,5j we were able to alkenylate at the C-2 position of
4d with a different olefin in 63% isolated yield (Scheme 4,
5a). Hydrolysis of the directing group provided the
7-substituted indole 5b in 88% isolated yield. After the
hydrogenation of 4d over palladium on charcoal, we ob-
tained the 7-alkylated indole with 72% yield (Scheme 4, 5c).
In summary, a novel, rhodium(III)-catalyzed, versatile
regioselective olefination and its subsequent MnO2-
mediatedone-pot oxidation strategyto access 7-substituted
indoles has been developed. The desired products were
formed in a highly regioselective manner. This methodol-
ogy provides a broad substrate scope for 7-substituted
indole scaffolds with good to excellent yield.
acrylate (Scheme 2, 4e) proceeds quickly under the
developed reaction conditions and the desired indole was
isolated with 54% yield. Then we examined the effect of
substituents in different positions of the styrene. Halogen-
containing styrenes provided the products in moderate to
good yield (Scheme 2, 4fÀj). Electron-rich methoxystyrene
provided the product in moderate yield (Scheme 2, 4k).
Coupling with o-methyl-substituted styrene gave the
desired product with satisfactory yield (Scheme 2, 4l). For
phenyl-1,3-butadiene derivatives (Scheme 2, 4m,n) we ob-
tained the products with excellent regioselectivity and yield.
Investigation on vinyl-substituted naphthalene provided
excellent yield from 1-vinylnaphthalene (Scheme 2, 4p),
compared to the yield of 2-vinylnaphthalene (Scheme 2,
4o). The scope of the reaction with respect to the indoline
reactant has been also explored. Both electron-rich and
-poor indoline substrates bearing various groups at differ-
ent positions of the indoline ring participated well in the
reaction, providing the corresponding 7-substituted indoles
(Scheme 2, 4qÀu) with moderate to good yield.
A plausible mechanistic pathway for the synthesis of
7-substituted indoles was proposed via catalytic dehydro-
genative cross-coupling and its subsequent oxidation (see
Scheme 3). It has been postulated that [Rh(III)Cp*Cl2]2
reacts with AgSbF6 to generate a more active cationic
species A. This active rhodium species could contain
ligands such as acetate or solvent in addition to penta-
methylcyclopentadienyl (Cp*) ligands. Rhodium species
coordinate to the carbonyl oxygen of the diethyl carba-
moyl group, and subsequent C(sp2)ÀH bond activation
via concerted metalation/deprotonation provided the five
Acknowledgment. We gratefully acknowledge the China
Scholarship Council (CSC) for a doctoral fellowship and
€
Prof. Dr. H. Waldmann (MPI fur Molekulare Physiologie
and TU Dortmund) for his generous support.
Supporting Information Available. Experimental proce-
dures, full characterization of new compounds, and copies
of 1H and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
(12) (a) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc.
2010, 132, 6908. (b) Hyster, T. K.; Rovis, T. J. Am. Chem. Soc. 2010, 132,
10565.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX