Rh-catalyzed oxidative C-C bond formation and C-N bond cleavage: Direct access to C2-olefinated free (NH)-indoles and pyrroles

Article abstract of DOI:10.1039/c3ob42605j

The rhodium-catalyzed oxidative C2-olefination of indoles and pyrroles containing N-arylcarboxamide directing groups with a range of alkenes and subsequent cleavage of directing groups is described. This method provides direct and efficient access to C2-functionalized free (NH)-heterocycles.

Full text of DOI:10.1039/c3ob42605j

Organic &
Biomolecular Chemistry
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Rh-catalyzed oxidative C–C bond formation and
C–N bond cleavage: direct access to C2-olefinated
free (NH)-indoles and pyrroles†
Cite this: Org. Biomol. Chem., 2014,
12, 1703
Received 11th December 2013,
Accepted 21st January 2014
Satyasheel Sharma, Sangil Han, Mirim Kim, Neeraj Kumar Mishra, Jihye Park,
Youngmi Shin, Jimin Ha, Jong Hwan Kwak, Young Hoon Jung and In Su Kim*
DOI: 10.1039/c3ob42605j
www.rsc.org/obc
The rhodium-catalyzed oxidative C2-olefination of indoles and removable N-(2-pyridyl)sulfonyl group.5k,l In contrast to the
pyrroles containing N-arylcarboxamide directing groups with a vast majority of documents on the palladium-catalyzed olefina-
range of alkenes and subsequent cleavage of directing groups is tions, the indolic C–H olefinations using rhodium or ruthe-
described. This method provides direct and efficient access to nium catalysts, which often allow higher selectivities and
C2-functionalized free (NH)-heterocycles.
broad substrate scope, have been much less explored. For
example, Glorius first reported a single example of Rh-cata-
lyzed C2-olefination of N-acetyl indoles.6 Prabhu demonstrated
Ru-catalyzed oxidative C2-alkenylation of indoles using the
N-benzoyl directing group.7 Recently, Li and Wang8 and Song,9
respectively, reported Rh(III)- and Ru(II)-catalyzed oxidative
couplings between indoles containing a N,N-dimethylcarba-
moyl group and olefins to afford C2-alkenylated indoles
(Scheme 1).
Our initial investigation focused on the construction of a
unique tricyclic framework, imidazo[1,5-a]indol-3-one 3aa,
through a tandem C2-alkenylation and intramolecular cycliza-
tion between indole 1a containing an N-arylcarboxamide
group with acrylate 2a.10 Interestingly, the coupling reaction of
1a and 2a in the presence of the cationic rhodium complex,
derived from [Cp*RhCl2]2 and AgSbF6, and Cu(OAc)2 oxidant
in DCE solvent at 100 °C provided the unexpected product 3a
in 62% yield (eqn (1)).
The indole nucleus is a ubiquitous structural motif found in
bioactive natural products, pharmaceuticals, functional
materials, and agrochemicals.1 Thus the efficient synthesis
and functionalization of indoles have been of considerable
interest in organic and medicinal chemistry.2 In particular,
transition-metal-catalyzed cross-coupling of indoles and aryl
halides is one of the most sustainable protocols for the
functionalization of indoles.3 Since the pioneering efforts of
Fujiwara and Moritani,4 remarkable progress has been made
on the oxidative Heck coupling between indoles and olefins
under palladium catalysis via a twofold C–H bond cleavage.5
Due to the electrophilic nature of the organometallic species
involved in the coupling reaction, the reaction occurs preferen-
tially at the more electron-rich C3 position of the indole ring.
Therefore, the highly selective C2-olefination of 2,3-unsubsti-
tuted indoles has been an intensive research area to override
the inherent selectivity of indoles. For instance, Gaunt
described the regioselective Pd-catalyzed intermolecular C2- or
C3-alkenylation of free (NH)-indoles by employing different
solvents and additives.5f Satoh and Miura disclosed the Pd(II)-
catalyzed C–H alkenylation and subsequent decarboxylation
protocol of indole-3-carboxylic acids to afford exclusively
C2-alkenylated indoles, where the carboxyl group blocks the
C3-position and acts as
a
removable directing group.5j
Recently, Carretero reported the highly efficient Pd-catalyzed
C2-selective olefinations of indoles and pyrroles assisted by a
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
E-mail: insukim@skku.edu; Fax: +82 31 292 8800; Tel: +82 31 290 7788
†Electronic supplementary information (ESI) available: Experimental details and
spectroscopic data for all compounds. See DOI: 10.1039/c3ob42605j
Scheme 1 Transition-metal-catalyzed oxidative C2-olefination proto-
cols of indoles with alkenes.
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Table 2 Scope of indolesa
ð1Þ
Encouraged by this unprecedented result, we herein report
the rhodium-catalyzed C2-selective olefination of N-arylcarba-
moyl indoles and subsequent cleavage of directing groups.
After extensive screening for the optimal reaction conditions,
the best results were obtained by the use of 2 equiv. of 2a,
2.5 mol% of [RhCp*Cl2]2 and 2 equiv. of Cu(OAc)2·H2O in tert-
amyl alcohol (t-AmOH) solvent at 100 °C for 20 h, affording
our desired product 3a in 78% yield (Table 1, entry 1) (see ESI†
for the detailed optimization table). Next, we examined the
influence of carbamoyl directing groups, as shown in Table 1.
Free (NH)-indole did not yield any coupling compound under
the present reaction conditions (data not shown).
Compounds 1b–1d, derived from indole and corresponding
isocyanates,11 were compatible with the optimal reaction con-
ditions to afford our desired product 3a (Table 1, entries 2–4),
whereas N,N-disubstituted indole 1e furnished the C2-alkenyl-
ated compound 3e without further removal of a N-protection
group (Table 1, entry 5).
a Reaction conditions: 1a and 1f–1p (0.3 mmol), 2a (0.6 mmol),
[RhCp*Cl2]2 (2.5 mol%), AgSbF6 (10 mol%), Cu(OAc)2·H2O (200 mol%),
t-AmOH (1 mL), 100 °C for 20 h in sealed tubes. b Yield isolated by column
chromatography. c 2a (0.9 mmol), 36 h.
under optimal reaction conditions (Table 3). To our delight,
olefins 2b–2i with electron-withdrawing groups proved to be
good substrates for this transformation, affording the corres-
ponding products 4b–4i. This reaction was also compatible
with 1,2-disubstituted alkenes, such as (E)-methyl crotonate 2j,
With the optimized reaction conditions in hand, the scope
and limitation of indoles 1f–1p with the N-(p-tolyl)carboxa-
mide directing group were investigated, as shown in Table 2.
The coupling of ethyl acrylate (2a) and indoles 1f–1n with elec-
tron-rich and electron-deficient groups (OMe, Me, NO2, CN, F,
Cl, and Br), regardless of the substituent position on the
phenyl ring, was found to be favored in this reaction to afford
the corresponding products 3f–3n in moderate to good yields.
Particularly noteworthy was the tolerance of the reaction con-
ditions to bromo and chloro moieties, which provide a versa-
tile synthetic handle for further elaboration of the products.
This protocol was also successfully applied for C3-substituted
indoles, furnishing the corresponding products 3o and 3p.
To further explore the substrate scope and limitations, a
range of olefins 2b–2l was screened to couple with indole 1j
Table 3 Scope of olefinsa
Table 1 Screening of directing groups
Entry
R1
R2
Substrate
Product
Yielda (%)
1
2
3
4
5
H
H
H
H
4-MeC6H4
C6H5
4-MeOC6H4
n-Bu
1a
1b
1c
1d
1e
3a
3a
3a
3a
3e
78
65
72
42
90
a Reaction conditions: 1j (0.3 mmol), 2b–2l (0.6 mmol), [RhCp*Cl2]2
(2.5 mol%), AgSbF6 (10 mol%), Cu(OAc)2·H2O (200 mol%), t-AmOH
(1 mL), 100 °C for 20 h in sealed tubes. b Yield isolated by column
chromatography.
Me
Me
a Isolated yields by column chromatography.
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Scheme 2 Expansion of substrate scope to pyrroles.
Scheme 4 Formation of tricyclic indolic compounds.
affording the desired products 4j with complete (E)-stereo-
selectivity.12 Interestingly, the coupling of norbornene 2k with
indole 1j yielded the alkylated product 4k in 69% yield instead
of the expected olefinated one. In contrast, styrene 2l displayed
a relatively decreased reactivity under the present reaction
conditions.
A small amount (15%) of 1qa was obtained without using
copper acetate (condition A), while a 53% yield of 1qa was iso-
lated in the absence of cationic Rh catalyst (condition B),
which could be rationalized by assuming that Cu(OAc)2 might
play a key role in the deprotection of the N-arylcarboxamide
group.
After successful investigation of the oxidative olefination
with indoles, we next tried to expand our method to pyrrole,
which is a useful building block and the core motif of various
natural products and medicinally relevant molecules.13 To our
delight, the coupling reactions between 5a with the N-(p-tolyl)-
carboxamide group and acrylates 2a, 2c and 2e were found to
be favored in the olefination and subsequent cleavage of the
directing group to afford the 2,5-bis-olefinated pyrroles 6a–6c
in good yields (Scheme 2).
To gain a mechanistic insight into in situ removal of a
directing group, the following experiments were conducted
(Scheme 3). First, the treatment of indole 1a in the absence of
acrylate 2a under the standard reaction conditions provided
the starting material 1a in 87% recovered yield, and a trace
amount of 1aa was observed (Scheme 3, eqn (1)). Interestingly,
the reaction of C2-substituted indole 1q and carbazole 1r with
olefin 2a, respectively, provided free (NH)-indole 1qa and free
(NH)-carbazole 1ra instead of C7- or C1-olefinated compounds
(Scheme 3, eqn (2) and (3)).14 These results indicated that the
C2-substituents on indoles with a N-(p-tolyl)carboxamide
group might be crucial to facilitate the C–N bond cleavage
under the standard reaction conditions. To further probe the
role of rhodium catalyst and copper salt, some control experi-
ments were performed (Scheme 3, eqn (4), conditions A and B).
Gratifyingly, while performing control experiments to
prepare compound 3ab, which can be derived from 3a and
p-tolyl isocyanate, our initial target compound imidazo[1,5-a]-
indol-3-one 3aa was isolated in 45% yield via tandem N-amida-
tion followed by intramolecular cyclization (Scheme 4). This
result potentially provides new opportunities to use our
method for the construction of bioactive tricyclic indolic
derivatives.
In conclusion, we developed a novel strategy for the for-
mation of C2-functionalized free (NH)-indoles and free (NH)-
pyrroles via the rhodium(III)-catalyzed oxidative alkenylation of
N-arylcarbamoyl indoles and pyrroles with olefins and sub-
sequent cleavage of a protection group. Further applications to
the synthesis of biologically active compounds and a more
detailed mechanistic investigation are in progress.
Acknowledgements
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and Tech-
nology (no. 2013R1A2A2A01005249).
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