CuO/SiO2 as a simple, effective and recoverable catalyst for alkylation of indole derivatives with diazo compounds

Article abstract of DOI:10.1039/c3ob40264a

The purely inorganic copper oxide on silica catalyzes the reaction of methyl phenyldiazoacetate with N-methyl indole under mild reaction conditions, giving the alkylation (formally a C-H insertion) in position 3, and the catalyst can be recovered and reused at least in 5 consecutive runs with only minor loss in activity. The scope of the reaction includes various diazo compounds and indole or pyrrole derivatives leading to alkylation or cyclopropanation depending on the heterocycle structure. An alternative mechanism, without reduction of Cu(ii) to Cu(i), is proposed on the basis of the obtained results. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40264a

Organic&
BiomolecularChemistry
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Volume 11 | Number 26 | 14 July 2013 | Pages 4273–4420
ISSN 1477-0520
PAPER
José M. Fraile et al.
CuO/SiO2 as a simple, effective and recoverable catalyst for alkylation of indole
derivatives with diazo compounds

Organic &
Biomolecular Chemistry
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PAPER
CuO/SiO2 as a simple, effective and recoverable catalyst
for alkylation of indole derivatives with diazo
compounds†
Cite this: Org. Biomol. Chem., 2013, 11,
4327
José M. Fraile,*a Karel Le Jeune,‡a José A. Mayoral,a Nicoletta Ravasiob and
Federica Zaccheriab
The purely inorganic copper oxide on silica catalyzes the reaction of methyl phenyldiazoacetate with
N-methyl indole under mild reaction conditions, giving the alkylation (formally a C–H insertion) in posi-
tion 3, and the catalyst can be recovered and reused at least in 5 consecutive runs with only minor loss in
activity. The scope of the reaction includes various diazo compounds and indole or pyrrole derivatives
leading to alkylation or cyclopropanation depending on the heterocycle structure. An alternative mech-
anism, without reduction of Cu(II) to Cu(I), is proposed on the basis of the obtained results.
Received 5th February 2013,
Accepted 12th April 2013
DOI: 10.1039/c3ob40264a
www.rsc.org/obc
knowledge the only example described with a heterogeneous
catalyst is the seminal work of Wenker et al. with copper-
1 Introduction
The indole structure is one of the most ubiquitous hetero- bronze.30 Frequently selectivity or even activity of metal cata-
cycles in nature. Owing to their presence in many natural bio- lysts depends on the oxidation state of this metal. In solution
active alkaloids,1–4 the synthesis of indole derivatives became redox processes together with a controlled atmosphere are fre-
the subject of intensive investigations.5–7 Among them, the quently used to adapt the catalyst to the mechanistic require-
direct functionalization of preformed indoles appears to be a ments of the reaction, but these changes are not so easy with
remarkably efficient and versatile route to complex indole heterogeneous catalysts. Furthermore the use of ambient con-
derivatives.8–11 For this purpose, insertion of carbenoids, ditions increases the practical applicability of the catalysts. For
resulting from the metal catalyzed degradation of diazo these reasons the development of catalysts able to stabilize the
compounds,12–15 represents a powerful and attractive tool required oxidation state of the metal under ambient con-
whose result depends on both the nature of the indole and the ditions is an interesting task.
diazo compound.16 Reaction of indole itself or N-alkyl indoles
In the course of our study on the preparation of hetero-
usually leads to C–H insertion with any type of diazo geneous copper catalysts for the C–H insertion into cyclic
compound and different catalysts, such as rhodium ethers,31,32 we described the use of a very simple and purely in-
carboxylates,17–21 copper salts,22–24 InBr3,22 and iron com- organic CuOx/silica–alumina catalyst for the insertion of phe-
plexes.25 Recently, it was shown that selective insertion in posi- nyldiazoacetate into the C–H bond of THF33 showing that
tion 2 of indole can be obtained using ruthenium catalysts.26 catalysts that stabilize Cu(I) are more active for this reaction, in
In contrast, N-acyl indoles are prone to undergo cyclopropana- agreement with the accepted mechanism. As a continuation of
tion in either the pyrrole ring23,27,28 with Cu catalysts or even our study, we report herein the extension of the use of this
in the benzene moiety29 with Rh. In spite of the versatility and type of catalyst to indole functionalization. Furthermore the
the efficiency of this methodology, to the best of our results allow us to obtain new mechanistic insights and
reinforce the importance of adapting the catalyst even for
apparently related reactions. On the other hand the develop-
aISQCH – Instituto de Síntesis Química y Catálisis Homogénea, Universidad de
ment of cheap, easily obtained and reusable catalysts is necess-
Zaragoza-CSIC, C/ Pedro Cerbuna, 12, E-50009 Zaragoza, Spain.
ary to increase the practical application of these reactions.
E-mail: jmfraile@unizar.es
bIstituto di Scienze e Tecnologie Molecolari, Consiglio Nazionale delle Ricerche, via
Golgi 19, I-20133 Milano, Italy
†Electronic supplementary information (ESI) available: Experimental methods
2 Experimental
(catalyst preparation, synthesis of indole derivatives, synthesis of diazo com-
pounds) and identification of all the reaction products. See DOI: 10.1039/
Typical conditions for the alkylation of indole derivatives
c3ob40264a
A solution of indole derivative (0.75 mmol) in DCM (3 mL) was
added to a dried powder of CuO/SiO2 (copper content 4% wt,
‡Current address: Institut des Sciences Moléculaires de Marseille, Université
Aix-Marseille, Campus Saint Jérôme, 13397 Marseille Cedex 20, France.
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Table 1 Optimization of reaction conditionsa
5 mol%). To the resulting suspension was added a solution of
diazo compound (0.5 mmol) in DCM (2 mL) in 2 hours with a
syringe pump. The reaction mixture was stirred at room temp-
erature for 15 hours. Then, concentration and direct purifi-
cation with flash chromatography afforded the desired
product. Methyl 2-(1-methyl-1H-indol-3-yl)-2-phenylacetate
(3a). Chemical yield: 89%; colorless oil; Rf (Hex–AcOEt 80/20)
Entry
Catalyst (% mol)
Run
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Cu(OTf)2 (5)
CuOx/SiAl (5)
CuO/SiO2 (5)
CuO/TiO2 (5)
CuO/SiO2 (2)
CuO/SiO2 (5)
1
1
1
1
1
2
3
4
5
1
15
15
4
15
15
4
70
75
89
8
79
84
80
84
92
<1
1
0.44; H NMR: 7.41–7.47 (m, 3H), 7.19–7.35 (m, 5H), 7.04–7.10
4
(m, 2H), 5.27 (s, 1H), 3.76 (s, 3H), 3.75 (s, 3H); 13C NMR: 173.6,
138.8, 137.1, 128.7, 128.5, 128.0, 127.3, 127.1, 122.0, 119.4,
119.1, 112.2, 109.5, 52.4, 48.9, 32.9; HRMS (ESI-MS) m/z:
15
15
48
10
None
[M + H]+, calcd for C18H18NO2 , 280.1332, found 280.1328.
+
a Conditions: Catalyst (2–5% mol) and 1a (0.75 mmol) in CH2Cl2
(3 mL) at rt, addition of 2a (0.5 mmol in CH2Cl2, 2 mL) in 2 h.
b Determined by GC, eicosane as the internal standard.
3 Results and discussion
3.1 Reaction between N-methylindole (1a) and methyl
support improved these results leading to 89% yield in only
4 hours (entry 3). In contrast, titania as the support provides
very poor yield (8%, entry 4), although it has some catalytic
effect, as shown in the control experiment (entry 10). Finally, a
lower amount of catalysts can be used but longer reaction
times are required to reach similar yields (79% in 15 h, entry
5). The heterogeneous nature of the catalyst was tested by fil-
tration experiments. As the reaction did not proceed in solu-
tion, degradation of the heterogeneous catalyst, leading to
catalytically active copper in solution, can be excluded as the
catalysis mechanism. Additionally the catalyst exhibited a
great hardiness, illustrated by its behaviour upon recovery
(Table 1). The yield remains almost the same during 5 cycles
(entries 6–9), and the longer reaction time required from cycle
4 is probably due to the unavoidable loss of the catalyst in the
filtration process.
phenyldiazoacetate (2a)
The catalysts were prepared by the chemisorption–hydrolysis
method,34–38 on three different supports, silica gel (surface
area: SA = 300 m2 g−1), SiO2–AlO3 (13% alumina, SA = 485 m2
g
−1) and TiO2 (Degussa P-25 80% anatase, 20% rutile, SA
=
50 m2 g−1). The support is added to a solution of [Cu(NH3)4]2+
at pH = 9, the copper precursor is hydrolyzed at 273 K, and the
solid is filtered, dried, and calcined in air at 673 K. This prepa-
ration method exploits the electrostatic interaction taking
place well above the point of zero charge of silica and titania
between the support surface and the [Cu(NH3)4]2+ complex
solution.39 This ensures a very high dispersion of the CuO
phase on the two supports, particularly on the one having a
higher surface area, namely silica.34,35 In contrast, the number
of strong acid sites of silica alumina determined by adsorption
calorimetry is close to that determined for an H-Beta zeolite
sample.36 This favours an ionic exchange reaction with the
[Cu(NH3)4]2+ solution that generates isolated Cuδ+ (1 ≤ δ ≤ 2)
species.37,38 A Cu loading of 4% was used in all cases.
3.2 Scope of the reaction: indole structure
Once the optimization of the conditions is accomplished, the
scope of the reaction was explored. First of all the structure of
the indole substrate was modified (Table 2). Regarding N-sub-
stitution (entries 1–5), the N-unprotected indole 1b is compati-
ble with this method, and no N–H insertion was observed
(entry 2).40 The presence of a bulky substituent such as TMS
(1c) seems to make the approach of the indole to the surface
metal-carbenoid more difficult. Thus, a gentle warming is
necessary to reach a moderate yield (61% overall yield), but
accompanied by some nitrogen deprotection (14%, entry 3).
The reactivity of N-benzylindole (1d, entry 4) is nearly the same
as that of N-methylindole. The presence of an electron-with-
drawing substituent in N-Boc-indole leads to a high yield of
the cyclopropanation product 3e, as a mixture of two diastereo-
mers (1 : 1 ratio), the same chemoselectivity described with Cu-
(OTf)2,23 and in contrast with the double cyclopropanation in
the benzenoid ring obtained with Rh2(DOSP)4.29 The insertion
product was not observed even when the reaction was carried
out at 80 °C. Neither the presence of bromo or methoxy substi-
tuents in position 5 (entries 6 and 7) nor that of a methyl
group in position 2 (entries 8 and 9) had any significant
influence on the results, and high yields of the insertion
The reaction test was performed with N-methylindole 1a
and methyl phenyldiazoacetate 2a (Scheme 1) in dichloro-
methane. The results are gathered in Table 1. The diazo com-
pound was added in two hours to minimize the formation of
dimerization products (dimethyl 2,3-diphenylmaleate and
fumarate). The best catalyst for THF insertion,33 Cu/SiO2–AlO3,
affords 75% yield within 15 h (entry 2), similar to that
obtained with Cu(OTf)2 (entry 1). However in the case of the
homogeneous catalyst an important amount of dimers was
detected, in contrast with the lack of these by-products with
the heterogeneous catalyst. Interestingly the use of silica as a
Scheme 1 Reaction between N-methylindole (1a) and methyl phenyldiazoace-
tate (2a).
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Table 2 Reactions of methyl phenyldiazoacetate (2a) with indole derivativesa
products were obtained. In contrast, the presence of an
electron-withdrawing group in position 2 leads to a drastic
drop in reactivity, as described in the case of insertions with
diazomalonate,24 and only a moderate yield at higher temp-
erature can be obtained (entry 11). However, the lower
electron density of the indole ring does not promote in this
case the cyclopropanation. When position 3 is already substi-
tuted, the insertion takes place at position 2, but again with
lower reactivity (entry 10).
Yieldb
(%)
Entry Indole
1
Temp. Product
rt
89
2
rt
75
3.3 Scope of the reaction: diazo compounds
In a second set of experiments, the scope with regard to the
diazo compound was studied (Table 3). Modification of the
aryl moiety of the donor–acceptor diazo compound41 with Br
or methoxy groups does not bring about significant modifi-
cation of the yield (entries 1 and 2). Other donor–acceptor
diazo compounds undergo side reactions instead of insertion.
With tert-butyl 2-diazohydrocinnamate (2d) only the cinna-
mates (Z–E mixture) from β-hydride migration are detected
(entry 3).42,43 In the case of the vinyl diazo compound 2e an
intramolecular 1,5-electrocyclization gives rise to the corres-
ponding pyrazole derivative (entry 4).44–47 To avoid the cycliza-
tion, the unsaturated diazolactone 2f, with a forced s-trans
conformation, was considered (entry 5).48,49 In this case, the
yield is lower than usual, and the expected product 4fa (27%
yield) is obtained together with the vinylogous isomer 4fb
(11% yield). This vinylogous reactivity had not been observed
in other reactions with this diazolactone.50 At higher tempera-
ture more complex reaction mixtures are obtained, without
increasing the yield.
3c
50 °C
47 (14)d
4
rt
82
5
6
rt
rt
86
78
An acceptor diazo compound, such as tert-butyl diazoace-
tate (2g), leads to the corresponding insertion product with
moderate yield (39%, entry 6) at 50 °C. The reaction performed
with the acceptor–acceptor dimethyl diazomalonate (2h) needs
to be heated at 80 °C to obtain good yield of the insertion
product (85%, entry 6).
7
8
rt
rt
83
70
3.4 Reaction with pyrroles
Finally, the reaction of methyl phenyldiazoacetate (1a) with
pyrrole derivatives (Scheme 2) was tested. With pyrrole itself
(5a), high conversion of the diazo compound (83%) was
obtained to the insertion products, only in position 2 as
obtained with other catalysts26 and diazo compounds,51–53 and
with a significant amount of double insertion product (7a). In
the case of the N-Boc-pyrrole, as expected, instead of C–H
insertion cyclopropanation occurs in good yield (90% conver-
sion of phenyldiazoacetate, eqn (2)). In this case, both mono-
cyclopropane 6b (two rotamers) and dicyclopropane 7b (one
single compound) are obtained. The latter is the only product
obtained with Rh under conditions close to the stoichiometric
ones,29 whereas the analogous monocyclopropane can be
obtained with Cu catalysts and diazoacetate.54,55
9
rt
90
10c
11c
50 °C
50 °C
41
50
a Conditions: CuO/SiO2 (5% mol) and 1 (0.75 mmol) in CH2Cl2 (3 mL),
addition of 2a (0.5 mmol in CH2Cl2, 2 mL) in 2 h. b Isolated yield.
c Reactions performed in 1,2-dichloroethane. d In brackets yield of 3b.
3.5 Reaction mechanism
The mechanism of this kind of reaction is still a matter of
debate. It has been proposed that insertion takes place
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Table 3 Reactions of different diazo compounds with N-methylindole (1a)a
Yieldb
(%)
Entry Diazo compound
1
Temp. Product
rt
79
85
—
2
rt
3
rt
Scheme 2 Reactions of pyrroles with methyl phenyldiazoacetate (1a) cata-
lyzed by CuO/silica.
4
5
rt
rt
—
proposed for these33 and related catalysts,60 although its mech-
anism is not fully understood. It can be assumed that this is
the mechanism involved in the cyclopropanation of N-Boc-
indole and N-Boc-pyrrole (Scheme 3).
27
However, some of our results seem to indicate that another
mechanism may be responsible, at least in part, for the inser-
tion reaction on the heterogeneous catalyst (Scheme 3). Silica–
alumina is able to stabilize Cu(I) species much better than
silica,37,38 which is in agreement with its better behaviour of
CuOx/SiO2–Al2O3 than CuO/SiO2 in the carbene insertion into
THF,33 a behaviour not observed in the case of the insertion
into N-methylindane. On the other hand CuO/SiO2 has been
recently shown to be an effective Lewis acid catalyst.61 The
origin of this acidity, well evident from the IR spectra of
adsorbed pyridine, traces back to the high dispersion of the
copper oxide phase in this catalyst, making its particles coordi-
natively unsaturated.62 Moreover, it has already been reported
that the nature of the catalyst support has a marked influence
on the reaction outcome of other heterogeneous Cu catalyzed
C–C bond forming reactions.63
6c
50 °C
80 °C
11
39
7c
The lack of dimerization products (2,3-diphenylmaleate and
fumarate), typical of carbene chemistry, may be due to the
slow addition of diazo compound, which minimizes this side
reaction. However, the addition of methyl phenyldiazoacetate
in one pot leads to the same result, showing that insertion is
a Conditions: CuO/SiO2 (5% mol) and 1a (0.75 mmol) in CH2Cl2
(3 mL), addition of 2 (0.5 mmol in CH2Cl2, 2 mL) in 2 h. b Isolated
yield. c Reactions performed in 1,2-dichloroethane.
through the opening of a transient cyclopropane in the case of very fast, without any induction period coming from the Cu(II)
N-alkyl and unprotected indoles18 and pyrroles22 (Scheme 3). to Cu(I) reduction,58,59 which has shown to be the rate limiting
This opening would not take place in the case of N-acylindoles step in some heterogeneously catalyzed cyclopropanations.64
A
and cyclopropane would be obtained as the main (or only) last piece of evidence for a Lewis acid mechanism is the
product. Other authors have proposed the formation of an different behaviour against the presence of ligands. Whereas
ylide by attack of the indole on Rh-carbene intermediates.17,56 the insertions through carbene intermediates are accelerated
This mechanism has been supported by DFT calculations for by bis(oxazoline) ligands,31–33 in this case the addition of a
reactions with alkyldiazoacetates20 (Scheme 3), and it has also ligand leads to the deactivation of the catalyst for indole inser-
been proposed for the case of Cu catalysts.18 However, Cu(I) tion. Thus a mechanism in which Cu(II) acts as a Lewis acid
has been recognized as the truly catalytic species in reactions, and is not reduced to Cu(I) may operate in this case, with N2 as
such as cyclopropanation,57 proceeding through Cu-carbene a leaving group in an aromatic electrophilic substitution and a
intermediates, and those Cu(I)-carbene intermediates can be final migration of a proton to recover the aromaticity of indole
obtained from Cu(II) precursors by in situ reduction with the or pyrrole (Scheme 3). In fact this mechanism would also
diazo compound.58,59 This kind of reduction has been agree with the substitution pattern observed, C3 for indole and
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Scheme 3 Proposed mechanisms for insertion and cyclopropanation of indoles.
C2 for pyrrole. It is important to note that the reaction is for-
mally and mechanistically similar to a Friedel–Crafts alkylation
but with N2 as the only concomitant byproduct and using an
easily separable and reusable catalyst.
Notes and references
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Financial support from the Spanish Ministerio de Economía y
Competitividad (project CTQ2011-28124) and the European
Commission (NANO-HOST programme no. PITN-GA-2008-
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