Catalytic functionalization of indoles by copper-mediated carbene transfer

Article abstract of DOI:10.1002/cctc.201400097

The complex [Tp^Br3Cu(NCMe)] (Tp^Br3=hydrotris(3,4,5- tribromo)pyrazolylborate) efficiently catalyzes the C-H functionalization of indole derivatives at C3 by carbene transfer from different diazoesters in a high-yield transformation involving low catalyst loadings and short reaction times. This system has shown that the previously proposed dichotomy of carbene addition (to the double bond) vs carbene insertion (to the C-H bond) corresponds to two consecutive reaction steps: the cyclopropane intermediates, observed in the reaction mixtures, are the precursors of the final C-H functionalization derivatives in a ring-opening process involving acid catalysis. Those in situ generated cyclopropanes undergo nucleophilic ring opening with Me ₂CuLi to afford both C2 and C3 functionalized indoles.

Full text of DOI:10.1002/cctc.201400097

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DOI: 10.1002/cctc.201400097
Catalytic Functionalization of Indoles by Copper-Mediated
Carbene Transfer
Manuela Delgado-Rebollo,[a] Auxiliadora Prieto,*[b] and Pedro J. Pꢀrez*[a]
The complex [TpBr3Cu(NCMe)] (TpBr3 =hydrotris(3,4,5-tribromo)-
pyrazolylborate) efficiently catalyzes the CÀH functionalization
of indole derivatives at C3 by carbene transfer from different
diazoesters in a high-yield transformation involving low cata-
lyst loadings and short reaction times. This system has shown
that the previously proposed dichotomy of carbene addition
(to the double bond) vs carbene insertion (to the CÀH bond)
corresponds to two consecutive reaction steps: the cyclopro-
pane intermediates, observed in the reaction mixtures, are the
precursors of the final CÀH functionalization derivatives in
a ring-opening process involving acid catalysis. Those in situ
generated cyclopropanes undergo nucleophilic ring opening
with Me2CuLi to afford both C2 and C3 functionalized indoles.
Introduction
The metal-mediated transfer of carbene groups from diazo
compounds to organic substrates is nowadays considered
a common tool in synthesis.[1] Among the plethora of reactions
reported with this strategy, the olefin cyclopropanation and
the carbon–hydrogen bond functionalization are of great inter-
est (Scheme 1). Indoles are found within the many substrates
that have been considered to be functionalized with that
methodology. Because the indole structure appears in a large
number of pharmaceuticals and agrochemicals,[2] the develop-
ment of mild and efficient protocols for the synthesis of in-
doles derivatives remains a field of intensive research.[3] The
metal-catalyzed functionalization of indoles with diazo com-
pounds has been described mainly with use of copper-based[4]
and rhodium-based[5] catalysts and rarely with use of several
other compounds of iron, ruthenium, or indium.[6] The reported
reaction outcome of indoles reacting with diazo compounds is
shown in Scheme 2. For nitrogen-protected indoles, most of
the known catalytic systems have provided the products de-
Scheme 1. The strategy for functionalization of olefins or CÀH bonds on the
basis of metal-mediated carbene transfer from diazo compounds.
rived from the formal insertion of such a unit into the CÀH
bonds of C3 (route A).[4d–f,5a,c–g,6b,c] Derivatization at C2 has been
achieved if there was a substituent at C3 (route B),[4f,h,5a] except
in a case with ruthenium-based catalysts.[6a] If the protecting
group at nitrogen has been Boc (Boc=tert-butyloxycarbonyl)
or acetyl, the carbene moiety instead adds to the unsaturated
CÀC bond, which yields a cyclopropane derivative (route
C).[4a–d,g] For nonprotected indoles, the above pattern of func-
tionalization at C2 or C3 has been described, which can also
be accompanied by the insertion of the carbene group in the
NÀH bond.[4c,f,5a] Finally, the addition to the aromatic six-
member ring has also been reported.[5b]
A previous work from our laboratory has shown that [TpxCu-
(NCMe)] (Tpx =hydrotrispyrazolylborate ligand) and IPrCuCl
[IPr=1,3-bis(diisopropylphenyl)imidazol-2-ylidene] complexes
promote the transfer of carbene groups from diazo com-
pounds to saturated and unsaturated fragments.[7] On the
basis of this experience and the aforementioned interest in the
functionalization of indoles, we decided to test the catalytic ca-
pabilities of these complexes for indole derivatization. We
found that the complex [TpBr3Cu(NCMe)] (TpBr3 =hydrot-
ris(3,4,5-tribromo)pyrazolylborate) efficiently catalyzes the reac-
tion of ethyl diazoacetate (EDA) and several indoles. In all
[a] Dr. M. Delgado-Rebollo, Prof. P. J. Pꢀrez
Laboratorio de Catꢁlisis Homogꢀnea
Unidad Asociada al CSIC
CIQSO-Centro de Investigaciꢂn en Quꢃmica Sostenible
Departamento de Quꢃmica y Ciencia de los Materiales
Universidad de Huelva
Campus de El Carmen, 21007 Huelva (Spain)
Fax: (+34)959219942
E-mail: perez@dqcm.uhu.es
[b] Dr. A. Prieto
Laboratorio de Catꢁlisis Homogꢀnea
Unidad Asociada al CSIC
CIQSO-Centro de Investigaciꢂn en Quꢃmica Sostenible
Departamento de Ingenierꢃa Quꢃmica, Quꢃmica Fꢃsica y Quꢃmica Orgꢁnica
Universidad de Huelva
Campus de El Carmen, 21007 Huelva (Spain)
Fax: (+34)959219983
E-mail: maria.prieto@diq.uhu.es
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201400097.
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EDA consumption within just 1 min, which afforded
3a in 68% yield. Further optimization experiments in-
dicated that it was possible to reduce the catalyst
amount to 1 mol% but maintaining the product yield
(Table 1, entry 5). To minimize the formation of by-
products, the diazo compound was added over 1 h
by using a syringe pump, which afforded 3a in 83%
yield (Table 1, entry 6).
We found a second interesting feature of this
system after purifying compound 3a by using silica
gel column chromatography: a complete and clean
conversion into 4a, which was obtained as a pure
yellowish oil in variable yield that depends on the re-
action conditions. In those experiments involving
1 mol% of the catalyst and 1 h of slow addition of
EDA, 4a was obtained in 98% yield relative to the in-
itial indole (Table 1, entry 6).
The reaction of EDA was examined with various 1-
methylindole substrates under the optimal condi-
tions. Cyclopropane derivatives were obtained either
with indoles bearing electron-withdrawing groups or
those bearing electron-donating groups in the ben-
zenoid ring. All those compounds were straightfor-
ward and quantitatively converted into the corresponding C3-
substituted derivatives (Table 2, 4b–d) upon treatment with
silica gel. In the reactions with C2 and C3-substituted indoles,
Scheme 2. Functionalization of indoles by transition metal-catalyzed carbene transfer
from diazo compounds.
cases, the cyclopropane derivative was obtained with simple
methyl-protected indoles. Furthermore, treatment of such cy-
clopropanes with silica gel induces the quantitative conversion
into the corresponding C3 inser-
tion products, which demon-
strates that the cyclopropanes
are intermediates in the for-
mation of insertion products.[8]
This method also functionalizes
the cyclopropane intermediates
upon reaction with Me2CuLi,
which provides C2 and C3-di-
functionalized indoles.
Results and Discussion
We first investigated the catalytic
potential of a series of [TpxCu-
(NCMe)] complexes as well as
Scheme 3. Catalytic functionalization of 1-methylindole with EDA.
that of IPrCuCl complexes in the
reaction of 1-methylindole (1a)
with EDA (2a). A 5 mol% of the catalyst was used in an experi-
ment performed in CH2Cl2 at room temperature (Scheme 3 and
Table 1). The four complexes led to the formation of the cyclo-
Table 1. Screening of the catalytic potential of some copper complexes.[a]
Entry
Catalyst
t
Yield [%][b]
1
3a/4a
4a (treated with SiO2)
propanation product 3a, as inferred from the H NMR spectra
1[c]
2[c]
3[c]
4[c]
5[c]
6[d]
IPrCuCl+NaBArF
[Tp*Cu(NCMe)]
[Tp*,BrCu(NCMe)]
[TpBr3Cu(NCMe)]
[TpBr3Cu(NCMe)]
[TpBr3Cu(NCMe)]
12 h
12 h
25 min
1 min
15 min
1 h
36/10
42/6
59/9
68/15
63/16
83/15
46
48
68
79
79
98
of the reaction crude. This finding is at variance with the afore-
mentioned previous work by others who used copper-based
catalysts in which, to that purpose, the indole should be nitro-
gen-protected with groups such as Boc or acetyl.[4a–d,g] In our
case, the methyl-protected indole gave the corresponding cy-
clopropane along with minor amounts of the C3-functionalized
product 4a. Diethyl fumarate and diethyl maleate completed
the mass balance for the initial EDA. The [TpBr3Cu(NCMe)] com-
plex demonstrated the best catalytic behavior, with complete
4
[a] Reaction conditions: 1 mmol of indole, 0.5 mmol of EDA, 5 mol% cata-
lyst (entries 1–4) or 1 mol% catalyst (entries 5–6), 4 mL of CH2Cl2 at RT.
[b] Isolated yield after silica gel chromatography. [c] EDA was added in
one portion. [d] EDA was added slowly for 1 h by using a syringe pump.
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Table 2. Copper-mediated functionalization of 1-methylindole substrates
with EDA.[a–c]
Table 3. Copper-mediated functionalization of 1-methylindole substrates
with other diazo compounds.[a,b]
[a] Reaction conditions: 1 mmol of indole, 0.5 mmol of EDA, 1 mol% of
[TpBr3Cu(NCMe)], 4 mL of CH2Cl2 at RT. R1 =H, Me, Ph; R2 =Me; R3 =OCH3,
Br, Me. [b] Isolated yield obtained by using silica gel chromatography.
[c] EDA was added over 1 h by using a syringe pump.
[a] Reaction conditions: 1 mmol of indole, 0.5 mmol of the diazo com-
pound, 1 mol% of [TpBr3Cu(NCMe)], 4 mL of CH2Cl2 at RT. R1 =H, Me, Ph;
R3 =OCH3, Br, Me; R4 =H, Ph, Me, CO2Et. [b] Isolated yield obtained by
using silica gel chromatography. [c] The diazo compound was added over
1 h by using a syringe pump. [d] Reaction at 408C. [e] 2mol% of [TpBr3Cu-
(NCMe)].
cyclopropylindole intermediates were not observed. Thus, sub-
stitution at the C2 position of the indole with a methyl or even
with a phenyl group was well tolerated, which afforded the
corresponding products in 96 and 85% yields, respectively (4e
and f). In contrast, substitution at the C3 position of the indole
gave the C2 insertion product in moderate yield after 3 h (4g).
We have also investigated the use of other diazo com-
pounds. More sterically hindered tert-butyl diazoacetate also
demonstrated good reactivity, and the reaction reached com-
pletion in 1 h with 90% yield (4h). In contrast, ethyl a-diazo-
phenylacetate demonstrated high reactivity with different sub-
stituted indoles, which afforded the corresponding C3 insertion
products in excellent yields and short reactions times (4i–n). In
this case, NMR studies performed at the end of the reaction
(1 h) showed these products as the unique component of the
reaction crude and no cyclopropanation product was ob-
served. However, if the [Tp*Cu(NCMe)] complex (Tp*=tris(3,5-
dimethyl-pyrazolyl)borate) was employed as a catalyst, NMR
analysis revealed the presence of cyclopropylindole in the reac-
tion mixture in small amounts during the transformation, evi-
dencing the intermediacy of such species in the formation of
compounds 4i–n. In contrast, the reaction of the less reactive
ethyl a-diazomethylacetate afforded a highly stable cyclopro-
panation product, which remained unchanged after purifica-
tion by using silica gel column chromatography. It was neces-
sary to stir the reaction crude for 30 min and to add silica gel
to induce the formation of the C3 insertion product (4o). Final-
ly, the less reactive ethyl diazomalonate required 2 mol% of
the catalyst and longer reaction times to give the C3 insertion
product in 80% yield (4p; Table 3).
(Scheme 4). The reaction with EDA was performed under the
same reaction conditions used for N-alkyl indoles (1 mmol of
indole, 0.5 mmol of EDA, and 1 mol% of the catalyst). The
1H NMR spectrum of the reaction mixture indicated a mixture
of three compounds. Although some resonances attributable
to cyclopropane rings could be observed, the complexity of
the mixture prevented us from performing a complete spectro-
scopic characterization. However, after treatment with silica gel
and column separation, compounds 4q–s were obtained in 73,
9, and 15% yields, respectively (Scheme 4a). The reaction out-
come did not change with the use of equimolar amounts of
indole and EDA. We then studied the reaction with ethyl a-di-
azophenylacetate. In this case, the one-pot addition of ethyl a-
diazophenylacetate afforded a mixture of C3 and NÀH inser-
tion products in 50 and 40% isolated yields, respectively
(Scheme 4b). Fortunately, the slow addition of the diazo com-
pound over 2 h with a syringe pump improved the selectivity,
and compounds 4t and u were isolated in 62 and 28% yields,
respectively. Notably, the catalytic carbene insertion into NÀH
bonds was observed with amines in a previous work from our
laboratory.[9] The interaction of the metallocarbene intermedi-
ate with the NÀH bond probably occurs through the N-lone
pair. Therefore, we do not consider this byproduct in the
mechanistic studies.
Furthermore, we studied the functionalization of a nonpro-
tected indole with EDA and ethyl a-diazophenylacetate
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that insertion occurs before the
formation of the cyclopropane
ring (Scheme 5, route C). And
the last proposal is based on the
formation of the cyclopropane
ring that later converts into the
insertion products (Scheme 5,
route D). The results discussed in
the previous sections indicate
that route D in Scheme 5, which
contains the sequential cyclopro-
panation and ring-opening steps
in the reaction of indole and the
diazo compound, governs this
transformation with [TpBr3Cu-
Scheme 4. Reaction of nonprotected indole with EDA and ethyl a-diazophenylacetate.
Cyclopropane ring-opening reactions
The indoline subunit functionalized at C2 and C3 positions is
found in a range of natural products.[10] Bearing in mind that
the indole functionalization occurs via a cyclopropyl intermedi-
ate, we developed a selective ring-opening reaction to obtain
those compounds. After testing different nucleophilic reagents,
we observed that Me2CuLi could open the cyclopropyl ring
under mild reaction conditions and afforded products in excel-
lent yields (Table 4). The ring-opening reaction was performed
by adding the reaction crude of the diazo compound and
indole dissolved in diethyl ether to a solution of Me2CuLi,
which was prepared in situ in the same solvent, and this reac-
tion led to the formation of compounds 5a–c in excellent
yields (Table 4, entries 1–3).
Scheme 5. Reaction pathways proposed for the formation of compounds 3
and 4.
(NCMe)] as the catalyst precursor. Notably, this find-
ing could be applied to other systems, particularly to
those in which no NMR studies of the reaction crude
were performed, and the reaction outcome was eval-
uated after column purification. Moreover, in those
systems in which the N-Boc indole was used, no ring
opening was observed because electron-withdrawing
Table 4. Cyclopropane ring opening with Me2CuLi.[a]
Entry
R1
R2
Product
Yield[b] [%]
dr[c]
groups would not stabilize the zwitterionic inter-
mediate (see below).
1
2
3
H
H
OMe
Et
tBu
Et
5a
5b
5c
89
81
92
52:48
70:30
57:43
An explanation is required for the ring-opening re-
action that follows cyclopropane formation. To eluci-
date whether a proton migration from the C3 posi-
tion of the indole to the a position of the ester
occurs, 3-deutero-1-methylindole was synthesized by
using a slightly modified method described in the lit-
erature.[11] Upon reaction with EDA (Scheme 6a), no
deuterium was observed in the final product, which
[a] Reaction conditions: Indole (1 mmol), diazo compound (0.5 mmol), [TpBr3Cu(NCMe)]
(1 mol%), CH2Cl2 (4 mL), RT. Then, CuI (0.54 mmol), Et2O (3 mL), MeLi (1.078 mmol,
1.6m in ether), T=08C. [b] Isolated yield. [c] dr=Diastereomeric ratio.
Mechanistic considerations
indicated that elimination could occur from cyclopropane. To
confirm this hypothesis, in which the proton in the a position
of the final product should come from the reaction medium,
the ring opening of cyclopropylindole was performed in a 1:1
mixture of acetonitrile and deuterium oxide in the presence of
catalytic amounts of hydrochloric acid (Scheme 6b). After stir-
ring the mixture for 30 min, the deuterated product in the
a position was obtained selectively (see the Supporting Infor-
In spite of the number of catalytic systems described for this
transformation to date, mechanistic proposals supported with
experimental evidences are scarce. Some authors have pro-
posed independent pathways for the formation of the carbene
insertion products (Scheme 5, route A) or the addition prod-
ucts (Scheme 5, route B) on the basis of the attack of the me-
tallocarbene moiety on the substrate. Others have proposed
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mation for details). Moreover,
a competition experiment with
the deutero and protio deriva-
tives was performed and the
ratio of cyclopropanes was
42:58, which slightly favored (ki-
netic isotope effect=1.38) the
protio-containing cyclopropane.
Unfortunately, it is not possible
to obtain data on the final prod-
ucts because elimination from
C3 occurs and either deuterium
or hydrogen resulted in elimina-
tion.
On the basis of all data col-
lected, an overall catalytic cycle
is proposed in Scheme 7. The
first step is the copper-mediated
cyclopropyl ring formation. In
the presence of an acid catalyst
(silica gel), the cyclopropane ring
undergoes opening through the
acid-catalyzed hydrogen elimina-
tion followed by proton transfer
from the medium to the a posi-
tion of the ester, which leads to
the final product 4. This mecha-
nism also explains the poor sta-
bility of the cyclopropanation
product if ethyl a-diazophenyl-
acetate or ethyl diazomalonate
is used. In these cases, the zwit-
terionic intermediate is stabilized
by the electron-withdrawing
groups, phenyl or CO2Et, which
provides a rapid ring-opening re-
action. Such stabilization is not
possible with EDA or ethyl a-
diazomethylacetate. Notably, im-
portant differences exist be-
tween our observations and
those reported with rhodium-
based catalysts. It is quite likely
that both metals operate in a dis-
tinct manner regarding this
transformation.
Scheme 6. Selective deuteration experiments.
Scheme 7. Mechanistic proposal for the indole functionalization by copper-catalyzed carbene addition and subse-
quent ring opening.
Conclusions
1 mol% of the catalyst and in a short reaction time. In addi-
The [TpBr3Cu(NCMe)] complex has demonstrated high catalytic
activity for the functionalization of nitrogen-protected indoles
through the formal carbene insertion (from diazo compounds)
into the CÀH bond located at C3. The activity compares well
with that of the most active rhodium-based catalysts known to
date, and it can be considered superior to that of other cop-
per(II)-, indium- or iron-based catalysts reported earlier. The de-
sired products are obtained in excellent yields with only
tion, experimental data collected indicate that the reaction
proceeds via a cyclopropanation–ring-opening sequence. The
intermediacy of the cyclopropyl species has been used to ach-
ieve the C2 and C3 functionalization through consecutive cy-
clopropanation and cyclopropane nucleophilic ring-opening
reactions using Me2CuLi and affording excellent yields.
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J. W. Kelly, Comprehensive Natural Products Chemistry, Pergamon Press,
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Experimental Section
Insertion reactions
General procedure: [TpBr3Cu(NCMe)] (1–2 mol%) and the corre-
sponding indole (1 mmol) were dissolved in CH2Cl2 (4 mL) in
a Schlenk tube equipped with a magnetic stir bar under an N2 at-
mosphere. Then, the diazo compound (0.5 mmol) was added in
one portion or dissolved in CH2Cl2 (1 mL) and added over 1 h by
using a syringe pump. The reaction mixture was stirred at RT for
a given time (15 min to 16 h), and the volatiles were removed
under vacuum. The residue was purified by using silica gel column
chromatography (diethyl ether/petroleum ether=1:7 with 1% of
Et3N) to afford the desired product.
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Consecutive cyclopropanation–cyclopropane ring-opening
reactions
General procedure: [TpBr3Cu(NCMe)] (1 mol%) and the correspond-
ing indole (1 mmol) were dissolved in CH2Cl2 (4 mL) in a Schlenk
tube equipped with a magnetic stir bar. Then, the diazo compound
(0.5 mmol) was added slowly for 1 h at RT under an N2 atmos-
phere. The reaction mixture was stirred for 5 min; the volatiles
were removed under vacuum; and the residue was redissolved in
diethyl ether. In contrast, in another Schlenk tube equipped with
a magnetic stir bar, CuI (0.539 mmol) was dissolved in diethyl ether
(3 mL), methyllithium (1.078 mmol, 1.6m in diethyl ether) was
added, and the reaction mixture was stirred for 5 min at 08C. Then,
the reaction crude of indole and the diazo compound was redis-
solved in diethyl ether and added to the above mixture, which was
stirred for another 5 min at 08C before cooling to À788C. Tempera-
ture was maintained that low for 4 h, and then volatiles were re-
moved under vacuum at RT. The residue was dissolved in water
and extracted with CH2Cl2 (3ꢂ5 mL). The combined organic layers
were washed with brine and dried over Na2SO4, and volatiles were
evaporated in vacuo. The product was purified by using silica gel
column chromatography (petroleum ether/diethyl ether=20:1
with 1% Et3N).
Acknowledgements
We thank the MINECO (CTQ2011-28942-CO2-01 and CTQ2011-
24502) and the Junta de Andalucia (Proyecto P10-FQM-06292).
M.D.R. thanks the Ministerio de Educaciꢂn y Ciencia for an FPU
fellowship.
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Weinheim, Germany, 2008; b) D. Zhang, H. Song, Y. Qin, Acc. Chem. Res.
2011, 44, 447.
Keywords: carbenes · diazo compounds · indole · ligand
effects · reaction mechanisms
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Received: January 29, 2014
Revised: March 11, 2014
Published online on June 24, 2014
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 2014, 6, 2047 – 2052 2052