First heterogeneously palladium-catalysed fully selective C3-arylation of free NH-indoles

Article abstract of DOI:10.1016/j.tetlet.2008.02.130

A simple heterogeneously palladium-catalysed procedure for the selective C3-arylation of indoles is reported. Under relatively standard reaction conditions (Pd-catalyst, K₂CO₃, dioxane, reflux), using only 1 mol % [Pd(NH₃)₄]/NaY as the catalyst, indoles substituted or not at position 2 gave up to 92% conversion (i.e., 85% isolated yield) towards the expected C3-arylated indole.

Full text of DOI:10.1016/j.tetlet.2008.02.130

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2499–2502
First heterogeneously palladium-catalysed fully
selective C3-arylation of free NH-indoles
Giuseppe Cusati, Laurent Djakovitch *
IRCELYON-Institut de recherches sur la catalyse et l’environnement de Lyon, UMR 5256 CNRS-Universit e´ Claude Bernard Lyon 1,
2
Avenue Albert Einstein, F-69626 Villeurbanne, France
Received 30 January 2008; revised 20 February 2008; accepted 22 February 2008
Available online 29 February 2008
Abstract
A simple heterogeneously palladium-catalysed procedure for the selective C3-arylation of indoles is reported. Under relatively
standard reaction conditions (Pd-catalyst, K CO , dioxane, reflux), using only 1 mol % [Pd(NH ) ]/NaY as the catalyst, indoles substi-
2
3
3 4
tuted or not at position 2 gave up to 92% conversion (i.e., 85% isolated yield) towards the expected C3-arylated indole.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Indoles; Selective C3-arylation; Palladium; Heterogeneous catalysis
The substituted indole nucleus is a structural fragment
found in numerous biologically active natural and syn-
oriented synthesis of multi-functional indoles, generally
1
7
substituted at position 2 and/or 3 of the indole ring. How-
ever, they remain limited when applied to the synthesis of 2-
substituted-3-aryl-indoles, an important feature of alka-
loids having antimicrobial properties against fungi and
Gram positive bacteria, due to the limited choice of reagents
to introduce directly the right substituent at position 3 and
since unprotected indoles lead often to the formation of a
mixture of N1- and C2- or C3-arylated indoles.
1
,2
thetic compounds.
The synthesis and the functionali-
sation of indoles have been the subject of many
3
,4
researches for over 100 years, leading to well-established
5
–8
syntheses.
In the last 40 years, alternative palladium-catalysed syn-
theses, generally tolerant to a wide range of substituents,
8
,9
have appeared in the literature. These methods include
the palladium-induced cycloadditions of 2-haloanilines
with alkynes and the intra- or intermolecular reactions of
Alternatively, some research groups developed the palla-
dium-catalysed direct arylation of the indole nucleus:
Sames and co-workers reported a procedure for selective
1
0,11
2
-alkynyl anilides with aryl- or alkylhalides.
Other
reac-
1
2,13
approaches are based on Heck-type cyclisations,
C2-arylation of N-substituted indoles using {[Pd(OAc) ],
2
1
4
18
tions of alkynes with imines
or on intramolecular
PPh } as the catalyst. Sanford and co-workers reported
3
cyclisations. Heteroannulation sequences achieved through
palladium-catalysed aryl amination reaction were also
reported.
Many of these methods have proven to be the most pow-
erful and are currently applied in the target- or the diversity-
a palladium-catalysed C2-arylation of indoles under mild
+
reaction conditions (25 °C, AcOH, 15–24 h) using [Ar I ,
2
1
5,16
À
BF ] as the arylating agent. If Sames supported an electro-
4
(0)
(II)
philic palladation mechanism based on a Pd /Pd cata-
lytic cycle, Sanford proposed that the palladium-catalysed
C2-arylation of N-methyl or NH-indoles resulted from a
(II)
(IV)
19
Pd /Pd
catalytic cycle.
Bellina and co-workers
*
reported selective palladium- and copper-mediated
C2-arylations of heterocycles including free (NH)-indoles
with aryl iodides under ligandless and base-free
Corresponding author. Tel.: +33 4 72 44 53 81; fax: +33 4 72 44 53 99.
E-mail address: laurent.djakovitch@ircelyon.univ-lyon1.fr (L. Djako-
vitch).
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.130

2500
G. Cusati, L. Djakovitch / Tetrahedron Letters 49 (2008) 2499–2502
2
0
conditions. Recently, Fagnou and co-workers described
palladium-catalysed selective oxidative C2-arylations of
Having these conditions (Pd-catalyst, K CO , dioxane,
2 3
reflux) in hand we evaluated the activity of the hetero-
2
1
2+
N-protected indole. In some cases, selective C3-arylation
was achieved by using re-oxidant (Cu(OAc)2 (3 equiv),
-nitropyridine (0.1 equiv), CsOPiv (0.4 equiv)) or a large
excess of palladium ‘catalysts’ (i.e., 300 mol %). In
previous studies we reported the selective N1- versus
C3-arylation of free NH-indole, those selectivities being
directed through the catalytic system. However, the
reported methodology was rather limited to the use of
geneous [Pd(NH ) ] /NaY. The heterogeneous catalyst
3
4
was prepared, according to procedure previously reported,
by ion exchange of a NaY zeolite using a 0.1 M aqueous
3
2
+
À
solution of [Pd(NH ) ] , 2Cl . After a period of 24 h,
3 4
the exchanged [Pd(NH ) ]/NaY catalyst was obtained.
3
4
The absolute palladium content of the catalyst was deter-
2
4
mined by ICP-AES as 1.0 wt % Pd.
The results obtained for the arylation of various
indoles using bromobenzene as the arylating agent and
22
activated aryl halides.
2
+
In this rather hot research area, Zhang, He and co-
workers reported an interesting contribution using
dinuclear palladium phosphinous acid complexes for the
direct palladium-catalysed C3-arylation of the indole
nucleus. While they observed generally high selectivity
towards the C3-arylated compound, the method suffers
from two limitations: the use of 5 mol % homogeneous
Pd-catalyst that is tedious to separate and recycle and the
scope limitation to the indole nucleus itself as generally
1 mol % [Pd(NH ) ] /NaY as the catalyst are reported
3 4
in Table 1.
As expected all substrates led to good to high conver-
sions under the reaction conditions. The results depend
mainly on the nature of the substituent at position 2 of
the indole nucleus: while the 2-phenylindole and the indole
gave 68% and 74% conversion, respectively, the 2-methyl-
2
3
indole bearing the more donating substituent (CH ) led
3
to the lowest conversion (47%). For comparison, under
the same reaction conditions, Zhang, He and co-workers
achieved 71% conversion for the Indole using 5 mol % of
the optimised Pd-catalyst ([Pd(P(tBu) OH) Cl ]), while
2
-substituted indoles did not react. Furthermore, except
for some cases, the isolated yields are limited (650%).
Following our interest to develop new simple, eco-
efficient and environmentally friendly procedures for the
synthesis of biologically and pharmaceutically relevant
molecules, including indole heterocycles, we explored the
Pd-catalysed selective C3-arylation of NH-free indoles
using homogeneous and heterogeneous palladium catalysts
under mild reaction conditions.
Initially, the reaction was studied using the indole, the
-methylindole and the 2-phenylindole as substrates and
bromobenzene as the arylating agent under similar reaction
conditions as those reported by Zhang, He and co-workers
K CO as the base, Pd(OAc) as the catalyst, 24 h in
2 3 2
2
2
2
we achieved 74% conversion but using only 1 mol % hetero-
geneous Pd-catalyst.
Attempting to improve this result by using the more
reactive iodobenzene as the arylating agent unexpectedly
led to lack of conversion. Zhang, He and co-workers
reported that in some cases, generally, when poor conver-
sions of the indole were achieved, they observed the forma-
tion of biphenyl derivatives due to homocoupling. In our
case, because we used heterogeneous catalysts, we did not
observe such a compound but rather the dehalogenation
product (i.e., nitrobenzene in this case) in relatively high
yield (>20%).
2
(
refluxing dioxane) (Scheme 1).
Whatever the substrate used, high conversions were
achieved under these conditions: 100% for the 3-phenyl-
indole, 90% for the 3-phenyl-2-methylindole and 95% for
the 2,3-diphenylindole. These conversions are close to the
best result reported by Zhang, He and co-workers for the
After demonstrating the applicability of the hetero-
geneous [Pd(NH ) ]/NaY catalyst for the selective C3-aryl-
ation of free NH-indoles, we extended the study to various
aryl bromides (Table 2).
As reported in Table 2, almost all evaluated aryl bro-
mides led to moderate to high conversions with some differ-
ences depending on the nature of the substituent at position
2 on the indole ring. Generally, both the indole and the 2-
phenylindole gave moderate to high conversions (13–92%
3
4
arylation of the indole (71%), given that the Pd(OAc) is
2
apparently not an optimum catalyst. Under these condi-
tions, decreasing the amount of catalyst from 5 mol % to
1
mol % affected considerably the performance of the reac-
tion as no conversion were achieved for all substrates. This
is attributed to the formation of inactive palladium black
as observed during the reaction.
Table 1
Arylation of various indoles using the bromobenzene as arylating agent
2
a
(Scheme 1: R = H)
1
b
Entry
R
Yields (%)
1
2
3
a
H
CH
Ph
74
47
68
3
R2
R2
Br
R1
Reaction conditions: 2 mmol of 2-substituted indole, 2.2 mmol of
N
H
2+
[
Pd]-catalyst
2 3 3 4
bromobenzene, 6 mmol of K CO , 1 mol % [Pd(NH ) ] /NaY, 4 mL of
HN
R1
2
dioxane, reflux, 24–48 h.
b
Yields were determined by GC based on the area of the product
compared to that of an internal standard (diethylene glycol di-n-butyl
ether) (Drel = ± 5%).
1
Scheme 1. C3-Arylation of the 2-substituted indoles.

G. Cusati, L. Djakovitch / Tetrahedron Letters 49 (2008) 2499–2502
2501
Table 2
Remarkably, when using the Indole as the substrate,
only the arylation towards the 3-substituted indole nucleus
was observed. In the case of C2-arylation a singlet signal
a,b
Arylation of indoles (Scheme 1)
1
2
c,d
Yields (%)
25
Entry
R
R
1
2
3
4
5
6
7
8
9
H
H
CN
NO
OCH
CH
Cl
H
CN
NO
OCH
CH
Cl
H
CN
NO
OCH
CH
Cl
74 (70)
13
18
42 (40)
14
81 (75)
47
0
86 (80)
0
0
47
68 (62)
19
34
0
would be expected at ca. 6.4 ppm for both compounds. N1-
arylation or C2-arylation that was often described in the
literature for this substrate was never observed under our
2
3
3
3
18–20
reaction conditions.
3
The case of the 2-methylindole is probably the most
instructive. According to the ES mechanism, some authors
reported that the generally observed lower reactivity of the
CH
3
2
2-methylindole can be explained by the presence of the 2-
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
a
methyl group adjacent to the reactive C-3 position of the
indole nucleus that causes steric hindrance and prevents
the ‘free’ approach of electrophile. Such an explanation
did not appear to be fully satisfactory when regarding the
high reactivity observed when using the 4-bromonitroben-
zene as the arylating agent.
In order to account for these results, we suggest that two
concurrent mechanisms could occur: the electrophilic sub-
stitution (ES) versus a SNAr mechanism (SNAr).
3
Ph
2
3
0
92 (85)
Reaction conditions: 2 mmol of 2-substituted indole, 2.2 mmol of
2+
2 3 3 4
bromobenzene, 6 mmol of K CO , 1 mol % [Pd(NH ) ] /NaY, 4 mL of
dioxane, reflux, 24–48 h.
For the first mechanism (ES) to occur the initial step is
the formation of Pd(II)-complexes [ArPdX] resulting from
the oxidative addition of the aryl halide on in situ gener-
ated Pd(0)-species from the palladium precursors. Follow-
ing this step, indole coordination occurs at the metallic
centre to give finally the expected arylated compound
b
All compounds were identified by GC–MS (Shimadzu GC–MS
QP2010S).
c
Yields were determined by GC based on the area of the product
compared to that of an internal standard (diethylene glycol di-n-butyl
ether) (Drel = ± 5%).
d
Isolated yields are reported in brackets.
(Fig. 2). In this mechanism, due to the relative hindrance
around the palladium centre, steric hindrance at the indole
C2 position would be a limitation to the reaction, as men-
tioned above. It is generally admitted that the Indole reacts
following this mechanism.
In the second mechanism (SNAr), the indole nucleus
would directly coordinate the Pd(II)-precursors to give by
intramolecular CH-activation a pallada-indole derivative
enhancing thus strongly the nucleophilicity of the indole
nucleus. This derivative reacts then with the arylhalide by
the well-documented SNAr mechanism to give then the
expected arylated indole (Fig. 1). Such a mechanism is
conversions) depending mainly on the nature of the substi-
tuent on the arylhalide: except some specific cases electron-
donating substituent gave the highest conversions, while
electron-withdrawing substituent gave low conversions.
This should be, however, moderated by the reactivity of
aryl halide towards the oxidative addition. This explana-
tion is in agreement with the generally accepted mechanism
for the indole arylation through an electrophilic substitu-
tion (ES) mechanism (Fig. 2), the rate being almost related
to the electron density at the metallic centre.
Ar
Pd(L)n
Ar
Pd(L)n
X
Pd(L)
H
Ar
electrophilic
substitution
reductive
elimination
X
Pd(0)
n
Base
R
R
R
oxidative
addition
N
N
H
N
H
H
R
R
R
Pd(0)
N
H
Ar Pd(L)n
X
Fig. 1.
X
R
Pd(II)X
Pd(II)X
R
Ar
SNAr
Pd(II)X , base
2
R
R
R
N
H
CH-activation
(palladation)
N
H
N
H
N
Pd(0)
H
Fig. 2. Proposed mechanisms for C3-arylation of 2-susbtituted indoles.

2502
G. Cusati, L. Djakovitch / Tetrahedron Letters 49 (2008) 2499–2502
supported by previous studies on the selective vinylation of
the indole nucleus, a reaction that occurs exclusively
through intramolecular CH-activation, for which we
remarked the exceptional high reactivity of the 2-methyl-
References and notes
1
. Joule, J. A. In Science of Synthesis; Thomas, E. J., Ed.; Thieme:
Stuttgart, 2001; pp 361–652.
2
3
4
. Sundberg, R. J. Indoles; Academic Press: London, 1996.
. Tois, J.; Franz e´ n, R.; Koskinen, A. Tetrahedron 2003, 59, 5395–5405.
. Pyrroles and their Benzo Derivatives: (III) Synthesis and Applications;
Sundberg, R. J., Ed.; Pergamon: Oxford, 1984; Vol. 4.
. Robinson, B. The Fischer Indole Synthesis; John Wiley and Sons:
Chichester, 1982.
2
6
indole (2-Me ꢀ 2-H > 2-Ph). In addition, such a mech-
anism would occur only when activated aryl halides, like
4
-bromonitrobenzene, are used.
5
In summary, according to these suggestions, the way the
arylation of the indole nucleus would occur depends
mainly on the reactivity of the indole nucleus towards the
Pd(II)-precursors initiating therefore the SNAr mecha-
nism; when too slow, the in situ reduction of the Pd(II)-pre-
cursors to Pd(0)-species occurs initiating then the ES
mechanism. In that case the overall reactivity would
depend on the rate of coordination of the indole nucleus
onto the Pd(II)-centre (which depends on the steric hin-
drance and the electron density on both the indole ring
and the metallic centre).
In conclusion, we reported in this communication an
efficient heterogeneously Pd-catalysed procedure for the
fully C3-selective arylation of various 2-susbtituted indoles.
Depending on the nature of the substituents on the indole
ring and on the aryl bromides, two ‘concurrent’ mecha-
nisms were proposed to account for the results observed.
Generally, indoles bearing donor groups led to lower con-
versions. Whatever, all evaluated substrates gave moderate
to high yields of target compounds (15–92% conversion,
6
7
8
. Hughes, D. L. Org. Prep. Proced. Int. 1993, 25, 607–632.
. Clark, R. D.; Repke, D. B. Heterocycles 1984, 22, 195–221.
. Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875–2911.
9. Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873–2920.
0. Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644–4680.
1. Cacchi, S.; Fabrizi, G.; Lamba, D.; Marinelli, F.; Parisi, L. M.
Synthesis 2003, 728–734.
1
1
1
2. Hegedus, S. L.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am.
Chem. Soc. 1978, 100, 5800–5807.
13. Larock, R. C.; Babu, S. Tetrahedron Lett. 1987, 28, 5291–5294.
1
1
1
4. Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122,
662–5663.
5. Watanabe, M.; Yamamoto, T.; Nishiyama, M. Angew. Chem., Int.
Ed. 2000, 39, 2501–2504.
5
6. Ackermann, L. Org. Lett. 2005, 7, 439–442.
17. Witulski, B.; Alayrac, C.; Tevzadze-Saeftel, L. Angew. Chem., Int. Ed.
003, 42, 4257–4260.
8. Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127,
050–8057.
2
1
1
8
9. Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem.
Soc. 2006, 128, 4972–4973.
20. Bellina, F.; Cauteruccio, S.; Rossi, R. Eur. J. Org. Chem. 2006, 2006,
379–1382.
1. Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129,
2072–12073.
2. Djakovitch, L.; Rouge, P.; Zaidi, R. Catal. Commun. 2007, 8, 1561–
566.
1
4
0–85% isolated yields on some selected compounds) that
2
2
can compete with the best procedures reported to date
using homogeneous non-recyclable catalysts.
Current investigations focus on improving the activity
of the heterogeneous catalyst and on implementing this
step in a one-pot synthesis of pharmaceutically relevant
indoles.
1
1
23. Zhang, Z.; Hu, Z.; Yu, Z.; Lei, P.; Chi, H.; Wang, Y.; He, R.
Tetrahedron Lett. 2007, 48, 2415–2419.
2
2
4. Djakovitch, L.; Koehler, K. J. Am. Chem. Soc. 2001, 123, 5990–5999.
5. The selectivity of the reaction was attributed through H NMR
1
analysis from isolated compounds. For example, proton NMR data
1
2
1
are provided for compounds 2 with R = H and R = Cl: H NMR
3
(
7
(
3
250 MHz, CDCl ); d ppm: 8.17 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H),
.52 (d, J = 8.5 Hz, 2H), 7.33 (dd, J = 8.0 Hz, 16.3, 4H), 7.24–7.08
m, 3H); and R = H and R = OMe: H NMR (250 MHz, CDCl
ppm: 8.09 (s, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 8.7 Hz, 2H),
.34 (d, J = 7.5 Hz, 1H), 7.24–7.06 (m, 4H), 6.93 (d, J = 8.7 Hz,
H), 3.79 (s, 3H). In the case of C2-arylation a singlet signal would
Acknowledgements
3
3
1
2
1
3
); d
3
3
G.C. thanks the ‘Minist e` re de l’Education Nationale, de
l’Enseignement Sup e´ rieur et de la Recherche’ for funding.
We gratefully acknowledge the ‘Programme interdiscipli-
naire: Chimie Pour le D e´ veloppement Durable—R e´ seau
de Recherche 2: Aller vers une Chimie Eco-compatible’
for funding.
3
3
7
2
2
7
be expected at ca. 6.4 ppm for both compounds.
6. Djakovitch, L.; Rouge, P. J. Mol. Catal. A: Chem. 2007, 273, 230–239.
27. Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P. Synlett 1997,
2
1363–1366.