Heterogeneous palladium catalysts applied to the synthesis of 2- and 2,3-functionalised indoles

Article abstract of DOI:10.1002/adsc.200505283

Heterogeneous palladium catalysts ([Pd(NH₃)₄] ²⁺/NaY and [Pd]/SBA-15) were applied to the synthesis of 2-functionalised indoles, giving generally high conversions and selectivities (>89% yield) using only 1 mol % [Pd]-catalyst under standard reaction conditions (polar solvent, 80°C). For the synthesis of 2,3-functionalised indoles by cross-coupling arylation, the [Pd]/SBA-15 catalyst was found to be particularly interesting, producing the expected compound with =35% yield after 12 days of reaction, which is comparable to the homogeneous catalyst, Pd(OAc)₂ (= 48% yield). In the course of the study, the dual reactivity of the indole nucleus was demonstrated: aryl bromides gave clean C-C coupling while aryl iodides led to a clean C-N coupling.

Full text of DOI:10.1002/adsc.200505283

FULL PAPERS
DOI: 10.1002/adsc.200505283
Heterogeneous Palladium Catalysts Applied to the Synthesis of
2- and 2,3-Functionalised Indoles
a,
b
a
´
Laurent Djakovitch, * Veronique Dufaud, Rabah Zaidi
a
Institut de Recherches sur la Catalyse, UPR-CNRS 5401, 2 Avenue Albert Einstein, 69626 Villeurbanne, France
Phone: (þ33)-472-44-53-81, Fax: (þ33)-472-44-53-99, e-mail: laurent.djakovitch@catalyse.cnrs.fr
b
´
´
Laboratoire de Chimie, UMR 5182, Ecole Normale Superieure de Lyon, 46 Allee dꢀItalie, 69364 Lyon Cedex 07, France
Received: July 20, 2005; Accepted: January 31, 2006
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract:
Heterogeneous
palladium
catalysts reaction, which is comparable to the homogeneous
([Pd(NH3)4]2þ/NaY and [Pd]/SBA-15) were applied catalyst, Pd(OAc)2 (¼48% yield). In the course of
to the synthesis of 2-functionalised indoles, giving the study, the dual reactivity of the indole nucleus
generally high conversions and selectivities (>89% was demonstrated: aryl bromides gave clean C C
yield) using only 1 mol % [Pd]-catalyst under stand- coupling while aryl iodides led to a clean C N cou-
ard reaction conditions (polar solvent, 808C). For pling.
ꢀ
ꢀ
the synthesis of 2,3-functionalised indoles by cross-
coupling arylation, the [Pd]/SBA-15 catalyst was Keywords: C N coupling reactions; cross-coupling ar-
found to be particularly interesting, producing the ex- ylation; heterogeneous palladium catalysts; immobili-
ꢀ
pected compound with ¼35% yield after 12 days of sation; indole synthesis; one-pot synthesis,
Introduction
ides to give either 2-, or 2,3-functionalised indoles (route
4, disconnections b & e).[19–22] Other approaches are
The indole nucleus is an important substructure found in based on Heck-type cyclization reactions (route 2, dis-
numerous natural or synthetic alkaloids.[1,2] The diversi- connection a),[23,24] on reactions of alkynes with imines
ty of the structures encountered, as well as their biolog- (route 5, disconnection c)[25] or on heteroannulation se-
ical and pharmaceutical relevance, have motivated re- quences achieved through palladium-catalysed arylami-
search aimed at the development of new economical, ef- nation reactions (disconnection f, not represented).[26–29]
ficient and selective synthetic strategies, particularly for Some of these methods have proven to be most powerful
the synthesis of functionalised indole rings.[3,4] Several and are currently applied in the target- or the diversity-
classical methods have been reported, including the oriented synthesis of indoles. Recently, a new disconnec-
Fischer indole synthesis from arylhydrazones,[5,6] the tion pathway based on the intramolecular cyclisation of
ꢀ
Batcho–Limgruber synthesis from o-nitrotoluenes and N-alkynyl-2-haloanilides followed by a C N coupling
dimethylformamide acetals,[7] the Gassman synthesis reaction with primary or secondary amines has been
from N-haloanilines,[8,9] the Madelung cyclisation of N- reported by Witulski et al. (route 3, disconnection
acyl-o-toluidines[10–12] and the reductive cyclization of a & d).[30]
o-nitrobenzyl ketones.[3] While these procedures have
Another commonly used procedure for the synthesis
contributed to this important area, some remain limited of 2-functionalised indole rings was from 2-iodoaniline
when the synthesis of functionalised indoles is required. and alkynes.[31–33] This procedure usually requires two
Recently, transition-metal-catalysed transformations, steps: the introduction of the ethynyl group onto the
ꢀ
and particularly palladium-catalysed reactions (Fig- benzene ring, usually known as a Sonogashira C C cou-
ure 1), have been developed, providing increased toler- pling reaction, followed by a heteroannulation, both of
ance towards functional groups, and leading generally to which are efficiently catalysed by Pd species. This proce-
higher reaction yields.[13,14] These methods include the dure appeared particularly convenient for the synthesis
palladium-induced cycloadditions of 2-haloanilines of richly functionalised indoles regarding the high toler-
with terminal or internal alkynes (route 1, retrosynthetic ance of the Sonogashira reaction and the heteroannula-
disconnections a & e),[15–18] and the intra- or intermolec- tion step towards functional groups present in the sub-
ular reactions of 2-alkynylanilides with aryl or alkyl hal- strates, arguments that probably contributed to its
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Laurent Djakovitch et al.
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strong development using homogeneous catalysts. Fur- Results and Discussion
thermore, it was found to be efficient for the solid-phase
synthesis of the indole nucleus,[34–36] a strategy generally
Catalysts
applied for the generation of indole-based combinatori-
al libraries.
However, all of these methods rely on the use of solu- The heterogeneous catalysts were prepared according
ble palladium catalysts, and only very few reports con- to procedures already reported in the literature. The
cern the use of heterogeneous catalytic systems, and al- [Pd(NH3)4]2þ/NaY (4.8% wt Pd) material was obtained
most none concern the use of heterogeneous palladium simply by ion exchange of NaY zeolite using a 0.1 M
catalysts.
aqueous solution of [Pd(NH3)4]2þ 2 Clꢀ.[41] The [Pd]/
Indeed, heterogeneous catalysts present several im- SBA-15 catalyst (2.1% wt Pd) was made by grafting
portant potential advantages over homogeneous cata- the [PdCl2{PPh2-(CH2)2-SiCH3(OCH2CH3)2}2] complex
lysts including easy handling, easy separation of the cat- via the condensation of ligand alkoxide moieties with
alytic species from the reaction mixture, which leads to surface silanols inside the pores of a calcined SBA-15
the added advantage of catalyst recycling.[37–40] These mesoporous silica.[42] The hexagonal ordering of the pal-
features lead to a lower cost synthetic process for fine ladium-functionalised material was confirmed by X-ray
chemicals and to a greener synthesis. Thus, a great deal diffractometry and the integrity of the molecular metal
of effort has been devoted to the creation of recoverable precursor, in particular the phosphine ligand arrange-
catalysts which mimic the high selectivity of the homo- ment at the palladium atom, was indicated by CP-
geneous systems. A typical approach is to immobilise a MAS 31PNMR which exhibits the two resonances of
homogeneous catalyst with well known catalytic proper- trans- and cis-isomers of the grafted complex (see Sup-
ties onto a solid support with high inorganic surface area porting Information) as well as by elemental analysis
which offers the possibility of generating a great number (molar ratio P/Pd around 2).
of active sites. Mesostructured porous silicas (e.g.,
Heterogeneous [Pd(NH3)4]2þ/NaY and [Pd]/SBA-15
MCM-41, MCM-48, SBA-15) are attractive materials catalysts were then evaluated and compared to homoge-
and attracted our attention as catalytic supports due to neous catalysts, Pd(OAc)2 and the “palladacycle”
their specific surface area (which can reach 1000 m2/g) {Pd[P(o-C6H4CH3)2-(o-C6H4CH2)(CH3CO2)]}2, for the
and the possibility of tuning the pore size between 2– one-pot synthesis of 2- or 2,3-functionalised indoles.
10 nm, properties which are also accompanied by very
high thermal and mechanical stability.
In this contribution, we described the applicability of Reactivity
two heterogeneous palladium catalysts, one micropo-
rous, [Pd(NH3)4]2þ/NaY, the other mesoporous, [Pd]/ As a part of our development of heterogeneously cata-
SBA-15, to the one-pot synthesis of 2-functionalised in- lysed Sonogashira cross-coupling reactions, we descri-
doles and the first results concerning the arylation at the bed the synthesis of 2-phenylindole (3) from 2-iodoani-
3 position by a cross-coupling reaction.
line and phenylacetylene catalysed by a [Pd(NH3)4]2þ
/
(NH4)Y species in goodyields.[43] However, this example
was rather limited and did not focus on the real potential
Figure 1. Retro-synthetic approaches toward the synthesis of indole nucleus catalysed by palladium.
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Heterogeneous Pd Catalysts in the Synthesis of 2- and 2,3-Functionalised Indoles
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of heterogeneous catalysts for the synthesis of fine
chemicals. Therefore, we were interested in applying
this method to the synthesis of other indole nuclei, par-
ticularly those having an alkyl group at the 2-position of
the ring, such as fluvastatin,[44] as this substructure has
been linked to the bioactivity of several molecules.
With this objective, we initiated a project exploring the
applicability of heterogeneous palladium catalysts
Scheme 1. Palladium-catalysed one-pot synthesis of 2-func-
tionalised indoles.
based on micro-(NaY) as well as ordered mesoporous
supports (SBA-15) with the aim of synthesising 2- and
2,3-functionalised indoles.
Initially, we examined the catalytic activity of the Pd that reactivity of 2-iodoaniline is higher than that of N-
catalysts for the synthesis of 2-functionalised indoles tosyl-2-iodoaniline, which was not expected given previ-
starting from 2-iodoaniline or, alternatively, N-tosyl-2- ous reports in the literature.[1,3] For example, for the re-
iodoaniline and a variety of terminal alkynes (Scheme action with phenylacetylene the full conversion of N-to-
1). The heterogeneous [Pd(NH3)4]2þ/NaY and [Pd]/ syl-2-iodoaniline requires up to 6 days, while that of 2-io-
SBA-15 catalysts were compared to classical homogene- doaniline takes generally only 1 day. The contrast is
ous catalysts [i.e., Pd(OAc)2, Herrmannꢀs “palladacy- much higher when using the 2-methylbut-3-yn-2-ol as
cle”]. The same reaction conditions {5 mmol aryl halide, the alkyne. These results contrast strongly with those
7 mmol alkyne, 1 mol % [Pd], 10 mL DMF/H2O (4:1), generally reported in the literature for which the modi-
808C} were applied for all substrates. The results are re- fication of the amino substituent on the aromatic sub-
ported in Table 1.
strate to an N-tosyl or an N-acetyl derivative leads to
In all cases, high conversions and high selectivities are higher conversion. This observation is often related to
observed, with isolated yields up to 76%. It was found higher rate of the heteroannulation step that is catalysed
Table 1. Palladium-catalysed, one-pot synthesis of 2-functionalised indoles (Scheme 1).
Product
R1
R2
Catalyst
P
Time [days]
Conversion [%][a]
GC Yield [%][a]
3a
H
P
h
d(OAc)2
89
100
93
75
30
91
95 (72)
76 (42)
45
2
Palladacycle[b]
3
[Pd(NH )4]/NaY
0.4
0.1
2
3
6
6
2
1
1
4
1
1
2
1
1
7
8
3
[Pd]/SBA-15
Pd(OAc)2
100
100
100
100
100
100
100
100
100
100
100
100
100
100
40
3b
Ts
Palladacycle[b]
[Pd(NH )4]/NaY
[Pd]/SBA-15
Pd(OAc)2
[Pd(NH )4]/NaY
[Pd]/SBA-15
Pd(OAc)2
[Pd(NH )4]/NaY
[Pd]/SBA-15
Pd(OAc)2
[Pd(NH )4]/NaY
[Pd]/SBA-15
Pd(OAc)2
[Pd(NH )4]/NaY
[Pd]/SBA-15
Pd(OAc)2
[Pd(NH )4]/NaY
[Pd]/SBA-15
Pd(OAc)2
91 (76)
89 (65)
93 (55)
89 (70)
93 (62)
52 (47)
92 (52)
93 (48)
78
94 (64)
93
35
74 (56)
91 (67)
80
91 (51)
89
3
3c
3d
3e
3f
H
n-Bu
3
[b]
Ts
H
3
[b]
C(CH3)2OH
3
Ts
H
80
3
7
2
1
1
100
100
100
100
82
[b]
3g
3h
(CH2)3CO2CH3
3
Ts
3
76
[Pd(NH )4]/NaY
[Pd]/SBA-15
1
1
100
100
91
90 (61)
3
Reaction conditions: 5 mmol aryl halide, 7 mmol alkyne, 8 mmol Et3N, 1 mol % [Pd] catalyst, 10 mL DMF/H2O (4: 1), 808C.
[a]
Conversions based on unreacted aryl halide and yields were determined by GC with an internal standard (diethylene glycol
di-n-butyl ether) (Drel ¼ ꢁ5%). Values in parentheses correspond to isolated product yields.
[b]
The mass balance between conversions and yields is related to the relatively high formation of aniline in these reactions.
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Laurent Djakovitch et al.
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by Pd(II) complexes.[13,14] From our results, it seems that reaction conditions {5 mmol 2-iodoaniline, 7 mmol phe-
such a conclusion is not applicable when heterogeneous nylacetylene, 1 mol % [Pd], 10 mL DMF/H2O (4:1),
catalysts are involved. This behaviour could be related 808C} over 6 h. The method used corresponds to the fol-
to a change in mechanism or, more likely, to the different lowing procedure: after the first run of the catalyst, the
nature of the active palladium species that catalyses the reaction mixture was allowed to cool to room tempera-
heteroannulation, which implies different transition ture and the catalyst was separated by centrifugation
states.
and washed twice with DMF/H2O (4:1) and allowed
Curiously, under our reaction conditions, the homoge- to “dry” at room temperature for 12 h. The recycled pal-
neous Pd(OAc)2 and the “palladacycle” show lower ac- ladium catalyst was then used without any regeneration
tivities than the heterogeneous catalysts. We attributed as the fresh catalyst under the same reaction conditions.
this observation to a lack of stability of the homogene- The procedure was repeated up to 5 recycles and the re-
ous complexes. Alone, these results justify the develop- sults obtained for the [Pd(NH3)4]2þ/NaYand [Pd]/SBA-
ment of heterogeneous catalysts in which the active pal- 15 are reported in Table 2. The apparent loss of activity
ladium centres are well dispersed and isolated prevent- could have several sources, including mechanical mass
ing thus a deactivation by sintering or palladium ag- loss during the recycling protocol (centrifuge, decanta-
glomeration.
tion) or real catalytic site deactivation. Nevertheless,
At this stage, it was interesting to compare the initial the activity of the recycled catalysts remained reasona-
activities of heterogeneous catalysts. This was done ble over the 2nd and 3rd runs before dramatically decreas-
through the synthesis of 2-phenylindole under standard ing for the [Pd(NH3)4]2þ/NaY while that of the [Pd]/
reaction conditions {5 mmol 2-iodoaniline, 7 mmol phe- SBA-15 catalyst led to good conversions up to the 5th
nylacetylene, 1 mol % [Pd], 10 mL DMF/H2O (4:1), run showing definitively a better behaviour for potential
808C, 6 h, Figure 2}. As depicted in Figure 2a, when us- applications in the fine chemical industry. Interestingly,
ing the [Pd(NH3)4]2þ/NaY catalyst, an induction period the AAS analyses realised on the liquid phase at the end
of about 7 min is observed before the reaction starts. of each run showed <0.5 ppm palladium. More rigorous
This period is probably due to the delay required to gen- attempts to detect catalytically active palladium were
erate in the bulk solution the catalytically active Pd spe- performed in an independent series of experiments
cies through a dissolution process (see “Recycling and (vide infra).
Leaching”below). After this period, an apparent “initial
Leaching was examined for the coupling reaction of 2-
activity” of 18.4 mmol/gPd ·min is observed for the iodoaniline and phenylacetylene under optimised reac-
[Pd(NH3)4]2þ/NaY catalyst, somewhat less than that of tion conditions using the hot filtration method: a catalyt-
43.1 mmol/gPd ·min observed for the mesoporous based ic run was started as for a standard reaction, and after
[Pd]/SBA-15 catalyst (Figure 2b).
10 min of reaction corresponding to ca. 34% yield using
Interestingly, for the [Pd]/SBA-15 catalyst no induc- the [Pd]/SBA-15 catalyst (or alternatively, 20 min of re-
tion period was observed, indicating that the grafted action, ca. 22% yield for the [Pd(NH3)4]2þ/NaY), the re-
Pd complexes are probably the active species, or effi- action mixture was filtered through a celite pad to afford
cient precursors, that are easily accessible to the re- a clear filtrate. The clear filtrate was then treated as the
agents due to the larger pore aperture of the mesopo-
rous supports (54 Š versus 7 Š for the NaY).
Generally, the reaction of less hindered alkynes,
namely the hex-1-yne and methyl hex-5-ynoate, re- Table 2. Recycling studies of the heterogeneous palladium
catalysts for the one-pot synthesis of 2-phenylindoles
(Scheme 1).
quired shorter reaction times than with phenylacetylene
when using heterogeneous catalysts, which was expect-
ed concerning the microporous nature of the zeolite sup-
ports (i.e., less limitation of the diffusion of the smaller
substrate molecules).
Run
Conversion [%][a]
[Pd(NH )4]/NaY
[Pd]/SBA-15
3
1
2
3
4
5
6
100
87
72
20
100
93
87
68
48
24
Recycling and Leaching
<5
After demonstrating the applicability of heterogeneous
palladium catalysts ([Pd(NH3)4]2þ/NaY and [Pd]/SBA-
15) for the synthesis of various 2-functionalised indoles,
the questions regarding the recyclability and the leach-
ing of active Pd species in solution for these heterogene-
ous catalysts were addressed.
Not evaluated
Reaction conditions: 5 mmol 2-iodoaniline, 7 mmol phenyl-
acetylene, 8 mmol Et3N, 1 mol % [Pd] catalyst, 10 mL
DMF/H2O (4: 1), 808C, 6 h.
[a]
Conversions based on unreacted aryl halide. The selectiv-
The recycling was examined for the coupling reaction
of 2-iodoaniline and phenylacetylene under optimised
ity of the reaction is>95%, i.e., in the error range of the
analytical method.
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Heterogeneous Pd Catalysts in the Synthesis of 2- and 2,3-Functionalised Indoles
FULL PAPERS
that the activity observed for that mesoporous based
catalyst is really due to the heterogeneous catalyst.
AAS analyses of the clear filtrates obtained by hot fil-
tration are in good agreement with these results: a Pd
content of 1150 ppm was determined for the catalytical-
ly active filtrate recovered from the [Pd(NH3)4]2þ/NaY-
catalysed reaction which can be compared to that of
<0.5 ppm for the filtrate recovered from the [Pd]/
SBA-15-catalysed reaction (which was shown to be inac-
tive).
Extended Applications
Having demonstrated the potential of the heterogene-
ous [Pd(NH3)4]2þ/NaY and [Pd]/SBA-15 catalysts for
the synthesis of 2-functionalised indoles 3, we were in-
terested in examining the possibility of arylating 2-sub-
stituted indoles at the 3-position of the ring (Scheme 2,
Table 3). Initially, we chose to study the arylation of 2-
phenylindole under standard cross-coupling conditions
(5 mmol 2-phenylindole, 7 mmol aryl halide, 7 mmol
NaOAc, 1 mol % [Pd], 10 mL NMP, 1408C).
Figure 2. Leaching of active Pd species in solution: [a] using
[Pd(NH3)4]/NaY and [b] using [Pd]/SBA-15 catalyst. Reaction
conditions: 5 mmol 2-iodoaniline, 7 mmol phenylacetylene,
8 mmol Et3N, 1 mol % [Pd] catalyst, 10 mL DMF/H2O
(4:1), 808C.
Scheme 2. Cross-coupling arylation at the 3-position of the 2-
phenylindole.
usual catalytic test, and its composition was followed by
GC and compared to that of a standard catalytic run.
Figure 2 shows clearly that the catalytic activity ob-
As reported in Table 3, the arylation of 2-phenylin-
served using the [Pd(NH3)4]2þ/NaY catalyst is mainly dole (3a) catalysed by the homogeneous Pd(OAc)2,
due to dissolved active Pd species since the conversion while being possible, is a very slow reaction requiring
of the 2-iodoaniline after the hot filtration increased up to 12 days for the half conversion of the 2-phenylin-
from 22% to 50%. However, one should note that the dole into the expected arylated compound 4, independ-
overall activity observed for the clear filtrate is not as ently of the aryl halide used. However, this reaction was
high as that observed in the presence of the heterogene- limited to the use of highly reactive electron-deficient
ous catalyst that can be seen as a “continuous” source of aryl bromidesthat are reputed togive high reactionrates
active Pd species. This result contrasts with that ob- in related Heck coupling reactions. Surprisingly, the ho-
tained from AAS analyses of the clear supernatant sol- mogeneous palladacyle gave almost no conversion (only
utions while evaluating the recycling, attesting clearly 3% after 6 days for the reaction with 4-bromofluoroben-
that dissolution-redeposition equilibrium occurs during zene) which was attributed to steric hindrance in the co-
such coupling reactions, as has often been suggested in ordination sphere of the palladium(II) transition state.
the literature. This equilibrium is therefore clearly de- Interestingly, the use of the heterogeneous [Pd]/SBA-
pendent on the reaction temperature, and strongly dis- 15 catalyst did not significantly decrease the reaction
placed towards the redeposition at low (ambient) tem- rate, which remains in an acceptable range. On the other
peratures.
hand, the [Pd(NH3)4]2þ/NaY catalyst gave only low con-
On the contrary, the results obtained using the [Pd]/ versions, probably due to diffusion limitations or to the
SBA-15 catalyst clearly showed that no leaching of ac- formation of less active palladium agglomerates into the
tive Pd species in the bulk solution occurred indicating bulk solution (leaching).
Adv. Synth. Catal. 2006, 348, 715 – 724
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Laurent Djakovitch et al.
GC Yield [%][a]
FULL PAPERS
Table 3. Palladium-catalysed, one-pot synthesis of 2,3-functionalised indoles (Scheme 2).
Product
R
F
Catalyst
P
Time [days]
Conversion [%][a]
4a
d(OAc)
12
6
50
3
48 (40)
–
2
Palladacycle[b]
[Pd(NH )4]/NaY
[Pd]/SBA-15
Pd(OAc)2
12
12
12
12
12
8
7
35
55 (39)
7
3
38
55
7
4b
NO2
[Pd(NH )4]/NaY
3
[Pd]/SBA-15
41
36
Reaction conditions: 2 mmol indole, 2.2 mmol aryl halide, 2.2 mmol NaOAc, 1 mol % [Pd] catalyst, 8 mL NMP, 1408C.
[a]
Conversions based on unreacted aryl halide and yields were determined by GC with an internal standard (diethylene glycol
di-n-butyl ether) (Drel ¼ ꢁ5%). Values in parentheses correspond to isolated product yields.
[b]
Given the very low activity of this catalyst, it was not further evaluated for this reaction.
ꢀ
ꢀ
Scheme 3. Dual reactivity in the 2-phenylindole: C C versus C N coupling reactions.
The reactivity of the aryl halides in the Heck reaction pounds in the arylation of the 2-phenylindole is to con-
being well established to follow the order I>Br, we de- sider the electrophilic substitution mechanism previous-
cided to use the more reactive 4-iodonitrobenzene. Un- ly reported by Gevorgyan et al.[50] and Sames et al.[48] for
expectedly, using the iodo derivative, we did not observe heteroaromatic compounds (Scheme 4). The first step
ꢀ
the C C coupling reaction as with the 4-bromonitroben- involves an oxidative addition between palladium(0)
zene or the 4-bromofluorobenzene to give 4a, b, but species and the aryl halide which leads to an aryl-palla-
ꢀ
rather a clean C N coupling reaction between the 2- dium(II) intermediate. Depending on the nature of the
phenylindole (3a) and the aryl iodide to give the com- halide, the palladium centre could be seen as a “hard”
pound 5 (Scheme 3).
(case of the bromide) or a “soft” (case of the iodide)
Similar arylation reactions of indole derivatives cata- electrophile. In the former the electrophilic substitution
lysed by homogeneous palladium complexes were re- of the bromide would involve the olefinic position lead-
cently reported by Sames et al.[45–48] Under their reac- ing to arylation at the C3-position whereas in the case of
tion conditions [Pd(OAc)2, P P 3h, MgO, PhI, polar sol- the iodide the electrophilic substitution would imply the
vent, 125–1508C, 24 h], exclusively C2-arylation of nitrogen atom giving rise to arylation at the N1-position.
NH-“free” indoles was observed. The authors explained The last steps involve a deprotonation and a reductive
this selectivity by the in situ formation of an indole-mag- elimination of palladium(0) species.
nesium salt (N-MgX) which acts as a protecting group of
Given these encouraging results, we undertook the
the nitrogen site. In some cases, C3-arylation was also evaluation of a one-pot synthesis of the 2,3-functional-
shown depending on the magnesium source and the sol- ised indole, 4, from 2-iodoaniline based on these hetero-
vent.
geneous catalysts (Scheme 4). The first reaction in-
In our case (Pd catalyst, NaOAc, ArX, polar solvent, volves the condensation with phenylacetylene, which
1408C), since the C2-position is already blocked by a was fully achieved after 24 h using 5 mol % [Pd]/SBA-
phenyl substituent, two sites of arylation could be con- 15 catalyst under the previously defined reaction condi-
ꢀ
sidered: the C3-postion of the azole ring (C C coupling) tions. The second step was then initiated without any
and the N1-position (C N coupling)[49] since no N-pro- separation of the intermediates, that is by the addition
ꢀ
tecting group (i.e., alkyl susbtituent...) or agent (i.e., into the reaction mixture of the corresponding amounts
magnesium source...) is used leaving this site accessible of 4-bromofluorobenzene and sodium acetate. The re-
to the arylation reaction.
sult was disappointing as only 8% conversion of the in-
The best explanation to account for the observed se- termediate 2-phenylindole (3a) was achieved within 8
lectivity between aryl iodide and aryl bromide com- days to give the expected compound 4b, after which no
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Heterogeneous Pd Catalysts in the Synthesis of 2- and 2,3-Functionalised Indoles
FULL PAPERS
Scheme 4. Proposed pathways to account the selectivity observed in the Pd-catalysed arylation of 2-phenylindole by aryl bro-
mides or iodides.
dictably, very slow. While trying to improve this step
by using a more reactive aryl iodide, we discovered a du-
ality of reactivity in the indole nucleus: using aryl bro-
ꢀ
mides a clean C C coupling reaction was observed while
using the corresponding aryl iodide led to a clean C N
ꢀ
coupling reaction.
Further studies are concentrating on the optimisation
all reaction steps (reaction conditions, catalysts...) and to
develop a direct one-pot synthesis of 2,3-funtionalised
indoles starting from simple 2-iodoaniline, alkynes and
aryl halides.
Scheme 5. Direct one-pot synthesis of 2,3-substituted indoles.
Experimental Section
evolution was observed. However, we should mention
that the reaction used here, and particularly the solvent
used (DMF/H2O, 4:1), did not correspond to optimised
cross-coupling conditions.
General Remarks
All manipulations were conducted under a strict inert atmos-
phere or vacuum conditions using Schlenk techniques includ-
ing the transfer of the catalysts to the reaction vessel. All glass-
ware was base- and acid-washed and oven-dried.
The solvents used for the synthesis of the molecular palladi-
um precursors and catalysts were dried using standard methods
and stored over activated 4 Š molecular sieves. All other
Conclusions
In summary, we have demonstrated the efficiency of het-
erogeneous palladium catalysts ([Pd(NH3)4]2þ/NaYand chemicals (organic reagents and solvents) were deaerated by
an argon flow before they were used.
[Pd]/SBA-15) for the synthesis of 2-functionalised in-
doles, 3. Generally high conversions and selectivities
are observed, leading to moderate to high isolated yields
using 1 mol % [Pd] catalyst. Standard reaction condi-
tions were defined in order to be independent of the sub-
strate; however, some of these reactions were found to
be quite slow (up to 2 days) and require further optimi-
sation. We also demonstrated that the arylation of 2-
phenylindole under classical cross-coupling reaction
Tetraethoxysilane (TEOS), poly(ethylene oxide)-poly(pro-
pylene oxide)-poly(ethyleneoxide) block copolymer (Pluronic
123, Mw: 5000) and diethoxymethylvinylsilane were purchased
from Aldrich Chemical and used without further purification.
PdCl2 and PdCl2(PPh3)2 were obtained, respectively, from Alfa
and Strem Chemicals. Diphenylphosphine was supplied by
Fluka.
2-(Diphenylphosphino)ethyldiethoxymethylsilane,
PPh2-(CH2)2-SiCH3(OCH2CH3)2, was synthesised by adapting
the procedure reported by Schmid et al.[51] Equimolar quanti-
conditions was possible, but these reactions were, pre- ties of HPPh2 and diethoxymethylvinylsilane were irradiated
Adv. Synth. Catal. 2006, 348, 715 – 724
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Laurent Djakovitch et al.
FULL PAPERS
for 4 days using a UV light (high pressure Hg lamp) and a wa-
ter-cooled quartz reactor; the product was purified by distilla-
tion under vacuum (bp 170–1808C/0.1 Torr, 85% yield). The
NaY zeolite (LZ-Z-52) was purchased from Sigma-Aldrich
Chemicals. The N-tosyl-2-idodoaniline was prepared accord-
ing a procedure reported in the literature.[30]
Catalyst Preparation
The homogeneous “palladacycle” {Pd[P(o-C6H4CH3)2-
(C6H4CH2)[OCOCH3]}2 catalyst was prepared from Pd(OAc)2
and tri(o-tolyl)phosphine following the procedure reported by
W. A. Herrmann et al.[52] The PdCl2(PhCN)2 used as palladium
precursor for the preparation of the [Pd]/SBA-15 catalyst was
prepared according to procedures previously described in the
literature.[53] The PdCl2{PPh2-(CH2)2-SiCH3(OCH2CH3)2}2
was synthesized by reacting 2 equivalents of PPh2-(CH2)2-
SiCH3(OCH2CH3)2 with bis(benzonitrile)palladium dichlor-
ide at room temperature in dichloromethane by adapting a
procedure reported elsewhere.[54]
Characterisation
All solid-state NMR spectra were recorded on a Bruker DSX-
300 or Avance-500 spectrometer equipped with a standard
4 mm probehead. The spinning rate was typically 10 kHz. 13C,
29Si and 31PNMR spectra were obtained by use of cross-polar-
isation (contact time 5 ms). To achieve a good polarisation
transfer, a ramp was used on the X channel. Recycle delays
Preparation of [Pd(NH3)4]2þ/NaY[41]
A 0.1 M ammonia solution of [Pd(NH3)4]Cl2 – prepared from
PdCl2 and a commercial ammonia solution – was added drop-
wise (4 mL/g zeolite, corresponding to ca. 5% wt Pd in the final
catalyst) to a suspension of the zeolite NaY in bidistilled water
(100 mL/g zeolite). The mixture was stirred for 24 h at room
temperature and the exchanged zeolite was filtered off and
washed until no trace of chloride was detected in the filtrate
(AgNO3 test). Then the zeolite was allowed to dry at room tem-
perature to give the entrapped [Pd(NH3)4]2þ/NaY catalyst as
slightly yellow material. ICP-AES analysis: 4.8% wt Pd.
1
were typically 1 s (a study on the H nucleus showed that it
1
was sufficient to allow all protons to fully relax). H, 13C and
29Si MAS spectra were referenced to tetramethylsilane. 31P
MAS spectra were referenced to 85% H3PO4.
X-ray powder diffraction (XRD) data were acquired on a
Bruker D5005 diffractometer using Cu Ka radiation (l¼
1.54184 E). A TA Instruments thermoanalyser 2950 HR
V5.3. was used for simultaneous thermal analysis combining
thermogravimetric (TGA) and differential thermoanalysis
(DTA) at a heating rate of 58C/min in air. Nitrogen adsorption
and desorption isotherms were measured at 77 K. The organo-
metallic-inorganic hybrids were evacuated at 1608C for 24
hours before the measurements. Specific surface areas were
calculated following the BET procedure. Pore size distribution
was obtained by using the BJH pore analysis applied to the de-
sorption branch of the nitrogen adsorption/desorption iso-
therm.
Preparation of [Pd]/SBA-15[42]
Mesoporous SBA-15 type silica was used as support and was
prepared by the acid-catalysed, non-ionic assembly pathway
described by Margolese et al.[55] The structure directing agent
(Pluronic 123) was removed by calcination under air at
5008C and the surfactant-free mesoporoussilica was rigorously
dried under a flow of nitrogen at 2008C prior to the grafting re-
action. Typically, PdCl2{PPh2-(CH2)2-SiCH3(OCH2CH3)2}2
(~500 mg) dissolved in dry toluene was added dropwise to a
suspension of calcined SBA-15 (1 g) in toluene and stirred at
258C for two hours to allow the diffusion of the molecular pre-
cursor into the channels of the pores. The reaction mixture was
then heated at 858C overnight. After filtration of the solid, the
unreacted palladium precursor was removed by a Soxhlet ex-
traction with CH2Cl2 during 10 hours. Finally, the resulting sol-
id was dried in vacuum at 258C. The organometallic-inorganic
hybrid material, denoted [Pd]/SBA-15, has been characterised
by several analytical, physical and spectroscopic techniques in-
cluding small-angle X-ray powder diffraction, nitrogen sorp-
tion isotherms, solid-state 1H, 13C, 31Pand 29Si NMR spectrosco-
py and TG-analyses (see Supporting Information). ICP-AES
The palladium content determinations of the heterogeneous
catalysts {[Pd(NH3)4]2þ/NaY and [Pd]/SBA-15} were per-
formed by ICP-AES from a solution obtained by treatment
of the catalysts with a mixture of HBF4, HNO3 and HCl in aTef-
lon reactor at 1808C.
Liquid NMR spectra were recorded on a Bruker AC-250
spectrometer. All chemical shifts were measured relative to re-
1
sidual H or 13C NMR resonances in the deuterated solvents:
CDCl3, d¼7.25 ppm for 1H, 77 ppm for 13C. Flash chromatog-
raphy was performed at a pressure slightly greater than atmos-
pheric pressure using silica (Merck Silica Gel 60, 230–400
mesh). Thin layer chromatography was performed on Fluka
Silica Gel 60 F254
.
High resolution mass spectra (HR-MS) were recorded on a
Thermo Finnigan MAT 95 XL spectrometer, with isobutane as
reactant gas for CI.
GC analyses were performed on an HP4890 chromatograph
equipped with an FID detector, an HP6890 autosampler and
an HP-5 column (cross-linked 5% phenyl-methylsiloxane,
30 mꢂ0.25 mm i.d.ꢂ0.25 mm film thickness). Nitrogen was
used as carrier gas. The mass spectra were obtained on an HP
6890 gas chromatograph equipped with an HP5973 mass de-
tector and an HP-5 MS column (cross-linked 5% phenyl-meth-
ylsiloxane, 30 mꢂ0.25 mm i.d.ꢂ0.25 mm film thickness). Heli-
um was used as carrier gas. The experimental error was esti-
mated to be Drel ¼ ꢁ5%.
1
analysis: 2.1% wt Pd and 1.3% wt P; MAS H NMR: d¼0.6
ꢀ
ꢀ
ꢀ
ꢀ
( SiCH3, SiCH2CH2P, OCH2CH3), 3.3 ( SiCH2CH2P,
OCH2CH3), 6.7 (phenyl ring); CP-MAS 13C NMR: d¼ ꢀ4.6
ꢀ
ꢀ
ꢀ
ꢀ
( SiCH3), 10.5 ( SiCH2CH2P), 18.7 and 20.1 ( OCH2CH3
ꢀ
ꢀ
and SiCH2CH2P, respectively), 58.2 ( OCH2CH3), 129.7–
137.8 (phenyl ring); CP-MAS 29Si NMR: d¼ ꢀ12.6 (D1 and
D2 sites), ꢀ91.6 (Q2 sites), ꢀ101.4 (Q3 sites), ꢀ108.2 ppm
(Q4 sites); CP-MAS 31PNMR: d¼20.7 (trans isomer), 30.9
(cis isomer).
722
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Heterogeneous Pd Catalysts in the Synthesis of 2- and 2,3-Functionalised Indoles
FULL PAPERS
Catalytic Tests
Acknowledgements
Thecatalytic reactions were carriedout ina three-necked flask,
or alternatively in pressure-sealed tubes, under argon. The
qualitative and quantitative analysis of the reactants and the
products was made by gas chromatography. Conversion and
yields were determined by GC based on the relative area of
GC signals referred to an internal standard (diethylene glycol
di-n-butyl ether) calibrated to the corresponding pure com-
pound. All catalysts were handled and transferred under ar-
gon.
´
ˆ
Financial support provided by the Region Rhone-Alpes, France
(Contract “NAHMOVCA” Number 301439201/E038131747/
ENS006) is gratefully acknowledged.
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