Rh-Catalyzed oxidative C-H activation/annulation: Converting anilines to indoles using molecular oxygen as the sole oxidant

Article abstract of DOI:10.1039/c3cc49751h

A practical and efficient Rh(iii)-catalyzed aerobic C-H activation has been developed for the facile synthesis of a broad range of indoles from simple anilines and alkynes. The protocol could be conducted under mild conditions and used environmentally friendly oxygen as the sole clear oxidant.

Full text of DOI:10.1039/c3cc49751h

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Rh-Catalyzed oxidative C–H activation/
annulation: converting anilines to indoles using
molecular oxygen as the sole oxidant†
Cite this: Chem. Commun., 2014,
50, 4331
Received 24th December 2013,
Accepted 28th February 2014
Guoying Zhang, Hui Yu, Guiping Qin and Hanmin Huang*
DOI: 10.1039/c3cc49751h
www.rsc.org/chemcomm
A practical and efficient Rh(III)-catalyzed aerobic C–H activation has
been developed for the facile synthesis of a broad range of indoles
from simple anilines and alkynes. The protocol could be conducted
under mild conditions and used environmentally friendly oxygen as
the sole clear oxidant.
Substituted indoles exist widely in pharmaceuticals, agrochemicals,
natural products, and organic functional materials and are also
useful intermediates in synthetic organic chemistry.1 As a result,
recently, considerable effort has been focused on the development
of new synthetic methods for the generation of indole motifs.2
Scheme 1 Methods for conversion of anilines to indoles by using molecular
oxygen as the sole oxidant.
Among them, transition-metal-catalyzed direct oxidative coupling of and a broad range of alkynes via rhodium catalyzed aerobic C–H
commercially available arylamines and alkynes via C–H activation is activation using oxygen as the sole oxidant (Scheme 1, eqn (2)).
of particular interest due to its sustainable and environmentally
Our initial investigation focused on the direct synthesis of indole
friendly features.3 However, stoichiometric oxidants, such as 3aa from the reaction of aniline 1a and 1,2-diphenylethyne 2a under
Cu(OAc)2, AgOAc, PhI(OAc)2, and TBHP, are generally required to 1 atm of O2 using t-AmOH as a solvent at 40 1C. On the basis of
maintain the catalytic cycle, resulting in the generation of undesired our experience with Rh-catalyzed aerobic oxidative C–H activation/
waste.4 One attractive method to solve this problem is using O2 as annulation,6 we chose Cp*Rh(H2O)3(OTf)2 as a catalyst and Ac2O as
the sole oxidant, in which only water is produced as a by-product.5 an additive, since one mol amount of HOAc (which can facilitate the
Indeed, by using O2 as the sole oxidant, Jiao and co-workers have oxidation of Rh(I) to Rh(III)) would be simultaneously produced in
successfully developed an elegant process for synthesis of indoles the reaction of Ac2O with aniline 1a. Under these conditions, the
from anilines and alkynes using Pd(OAc)2 as a catalyst.3d However, desired product 2,3-diphenylindole 3aa was isolated in 70% yield
only electron-deficient alkynes (dialkyl acetylenedicarboxylate) could after hydrolysis in situ in the presence of NaOH (Table 1, entry 1).
be tolerated in this system (Scheme 1, eqn (1)), thereby limiting the Other solvents, such as t-BuOH, CH3OH, DMF and acetone, did
potential scope of this environmentally benign transformation.
not improve the reactivity (Table 1, entries 2–5). Further inves-
We have recently demonstrated that molecular oxygen has tigation of the rhodium catalyst precursors revealed that the
enough ability to oxidize Rh(I) to Rh(III) in the presence of acid. reactivity was affected by the nature of the cationic counterion,
Based on this discovery, our group successfully developed an and the best result was achieved with Cp*Rh(H2O)3(OTf)2 as the
efficient Rh/O2 catalytic system for highly efficient oxidative C–H catalyst precursor. The best yield of 3aa was obtained when the
activation.6 Inspired by these results and in connection with our reaction was conducted at 100 1C whereas no appreciable
interest in the aerobic C–H activation, herein we report a practical increase in yield was obtained at higher temperatures. It is worth
and efficient approach to synthesize indoles from simple arylamines noting that the reaction still worked well even at room tempera-
ture and 3aa was obtained in moderate yield under other
identical reaction conditions (Table 1, entry 13). Finally, control
reactions demonstrated that only a trace amount of annulation
product 3aa was obtained under a nitrogen atmosphere. Taken
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute
of Chemical Physics, Chinese Academy of Sciences, Lanzhou, 730000, China.
E-mail: hmhuang@licp.cas.cn; Fax: +86 931-496-8129
together, we can conclude that the annulation was carried out by
† Electronic supplementary information (ESI) available. CCDC 974194. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc49751h stirring the t-AmOH solution of aniline, 1,2-diphenylethyne,
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Table 1 Optimization of the reaction conditionsa
1k vs. 1l. Besides, when a meta-substituent is present, the
reaction is preferred at the more sterically accessible position
(3ca, 3ea, 3ha and 3la). It is worth noting that the tolerance of
halogen, cyano and ester groups on the aromatic ring in this
protocol offers an opportunity for subsequent transformations,
which facilitates expedient synthesis of complex indoles. In
addition to substituted anilines, the naphthyl-substituted amine
was also compatible with this process, furnishing the desired
product 3pa in good yield. Notably, some arylamines could be
transformed into the corresponding indoles at 40 1C in moderate
to good yields, which could increase the practicality of our
reaction process dramatically (3aa, 3ba, 3fa, 3ka and 3ma).
Furthermore, the scope of the alkynes was also explored and the
results are shown in Table 3. Symmetrical diarylalkynes containing
electron-rich or -deficient functional groups reacted smoothly to give
the corresponding products in high yields. The unsymmetrical
alkynes, such as 2f and 2g were also successfully transformed into
the corresponding products in high yields with lower regioselectivity.
However, when 2h was employed as the coupling partner, only
isomer 3ah was obtained in 77% yield. The observed excellent
regioselectivity for this substrate may stem from the strong
electron-withdrawing ability of the trifluoromethyl group attached
here. Although dimethyl acetylenedicarboxylate and dialkyl alkynes
did not react with amines under these conditions, the aryl alkyl
alkynes such as 2i and 2j were found to be suitable for this reaction,
affording the corresponding products 3ai and 3aj in moderate yields
with high regioselectivities, respectively.
Entry
[Rh]
T/1C
Solvent
Yield (%)
1
2
3
4
5
6
7
8
Cp*Rh(H2O)3(OTf)2
Cp*Rh(H2O)3(OTf)2
Cp*Rh(H2O)3(OTf)2
Cp*Rh(H2O)3(OTf)2
Cp*Rh(H2O)3(OTf)2
Cp*Rh(H2O)(OAc)2
Cp*Rh(CH3CN)3(SbF6)2
[Cp*RhCl2]2
40
40
40
40
40
40
40
40
t-AmOH
t-BuOH
CH3OH
DMF
Acetone
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
70
18
o5
o5
49
o5
o5
0
80
79
84
81
9
Cp*Rh(H2O)3(OTf)2
Cp*Rh(H2O)3(OTf)2
Cp*Rh(H2O)3(OTf)2
Cp*Rh(H2O)3(OTf)2
Cp*Rh(H2O)3(OTf)2
Cp*Rh(H2O)3(OTf)2
60
80
100
120
25
10
11
12
13
14b
44
o5
100
a
General conditions: 1a (0.6 mmol), 2a (0.4 mmol), [Rh] (0.02 mmol),
Ac2O (0.6 mmol), solvent (2.0 mL), O2 (1 atm), for 24 h. Then NaOH
(1.2 mmol), CH3OH (2.0 mL), at RT for 1 h. Isolated yield, unless
b
otherwise noted. Under nitrogen.
5 mol% of Cp*Rh(H2O)3(OTf)2, and 1.5 equiv. of Ac2O at 100 1C
under 1 atm of O2 for 24 h to give the product in the best yield.
With the optimized conditions in hand, the scope of this
reaction with various arylamines was investigated. As shown in
Table 2, the reactions of arylamines 1 bearing an electron-
donating or electron-withdrawing group at the ortho, meta, or
para position of the phenyl ring proceeded smoothly to give the
corresponding products 3aa–3oa in 31–93% yields.7 An obvious
steric hindrance effect on the reactivity was observed, which
was demonstrated by the reactivities of 1b vs. 1c, 1d vs. 1e and
To gain insight into the reaction mechanism, several control
experiments were conducted under the standard conditions
(Scheme 2). Initially, acetanilide served as a substrate to react with 2a
under the modified conditions, the product 3aa was obtained in
85% yield. However, aniline could not be transformed into the
product at all under the same reaction conditions. These results
indicated that the acetanilide might be involved in the present
reaction (eqn (1) and (2)). Then intermolecular competition experi-
ments were carried out between arylamine 1b (4-CH3) and 1k (4-Cl).
Table 2 Substrate scope of anilinesa
Table 3 Substrate scope of alkynesa
Entry
R
Yield (%)
1
2
3
H
4-CH3
3-CH3
3aa, 84 (70)b
3ba, 93 (76)b
3ca, 71
4
5
6
7
8
9
10
11
12
13
14
15
16
4-t-Bu
3-t-Bu
4-CH3O
3,5-(CH3O)2
3,4-(CH3O)2
4-CF3O
4-F
4-Cl
3-Cl
4-Br
4-CN
3da, 92
Entry
R1
R2
Yield (%)
3ea, 84
3fa, 90 (61)b
3ga, 61
1
2
3
4
5
6
7
8
9
10
4-CH3C6H4
4-CH3OC6H4
4-FC6H4
4-BrC6H4
4-CH3C6H4
4-BrC6H4
3,5-(CF3)2C6H4
C6H5
C6H5
4-CH3C6H4
4-CH3OC6H4
4-FC6H4
4-BrC6H4
C6H5
3ab, 81 (58)b
3ac, 85
3ha, 76
3ia, 78
3ad, 76
3ae, 75 (37)b
3af, 79 (1.14 : 1)c (65)b
3ag, 62 (1 : 1)c
3ja, 76
3ka, 90 (80)b
3la, 49c
C6H5
3ah, 77 (56)b
3ai, 52
3ma, 90 (71)b
3na, 31
C6H5
CH3
Bn
3aj, 50 (12 : 1)c
3ak, 0
4-COOCH3
1-Naphthyl
3oa, 60
3pa, 62
n-Bu
n-Bu
a
a
General conditions: 1a (0.6 mmol), 2 (0.4 mmol), Ac2O (0.6 mmol),
Cp*Rh(H2O)3(OTf)2 (5 mol%), t-AmOH (2.0 mL), O2 (1 atm), at 100 1C
for 24 h. Then NaOH (1.2 mmol), CH3OH (2.0 mL), RT for 1 h. Isolated
General conditions: 1 (0.6 mmol), 2a (0.4 mmol), Ac2O (0.6 mmol),
Cp*Rh(H2O)3(OTf)2 (5 mol%), t-AmOH (2.0 mL), O2 (1 atm), at 100 1C
for 24 h. Then NaOH (1.2 mmol), CH3OH (2.0 mL), at RT for 1 h.
b
c
yield. At 40 1C. Ratios of regioisomers were determined by 1H NMR
b
c
Isolated yield. At 40 1C. Ratios of regioisomers were determined by
1H NMR analysis (1.08 : 1).
analysis. Major isomers are shown.
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In summary, we have developed an efficient Rh/O2 catalytic
system that allows the direct formation of indoles from commercially
available anilines and alkynes via C–H activation under the aerobic
conditions. The method is compatible with a variety of functional
groups and can be used to prepare a range of 1,2-disubstitued
indoles. This study together with our previous studies provides
strong evidence that the molecular oxygen has enough ability to
oxidize the Rh(I) to Rh(III) species in the presence of appropriate acid.
Further investigations to gain a detailed mechanistic understanding
as well as application of this aerobic oxidative catalytic system to
other oxidative C–H activation reactions are currently in progress.
This research was financially supported by the Chinese
Academy of Sciences and the National Natural Science Founda-
tion of China (21222203, 21372231 and 21133011).
Scheme 2 Preliminary mechanistic studies.
Notes and references
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