Rh-catalyzed oxidative C2-alkenylation of indoles with alkynes: Unexpected cleavage of directing group

Article abstract of DOI:10.1016/j.tetlet.2014.04.001

A rhodium-catalyzed oxidative C2-alkenylation of indoles containing a N-(p-tolyl)carboxamide group with substituted alkynes via C-C bond formation and subsequent C-N bond cleavage has been described. This protocol represents direct access to C-2-alkenylated free (NH)-indoles, which are important building blocks in the synthesis of natural and pharmacological compounds.

Full text of DOI:10.1016/j.tetlet.2014.04.001

Tetrahedron Letters 55 (2014) 3104–3107
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rh-catalyzed oxidative C2-alkenylation of indoles with alkynes:
unexpected cleavage of directing group
Satyasheel Sharma a, Sangil Han a, Youngmi Shin a, Neeraj Kumar Mishra a, Hyunji Oh a, Jihye Park a,
Jong Hwan Kwak a, Beom Soo Shin b, Young Hoon Jung a, In Su Kim a,
⇑
a School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
b College of Pharmacy, Catholic University of Daegu, Gyeongsan 712-702, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A rhodium-catalyzed oxidative C2-alkenylation of indoles containing a N-(p-tolyl)carboxamide group
with substituted alkynes via CAC bond formation and subsequent CAN bond cleavage has been
described. This protocol represents direct access to C2-alkenylated free (NH)-indoles, which are
important building blocks in the synthesis of natural and pharmacological compounds.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 6 February 2014
Revised 26 March 2014
Accepted 1 April 2014
Available online 8 April 2014
Keywords:
Alkynes
C–H functionalization
Indoles
Olefination
Rhodium
Transition-metal-catalyzed oxidative CAH functionalizations
significantly improve the atom and step economy in organic syn-
thesis by avoiding the preparation of prefunctionalized starting
materials.1 In particular, alkynes hydroarylation has received much
attention as it is a convenient route for the synthesis of tri-substi-
tuted alkenes in a highly regio- and stereoselective manners
directly from simple arenes and alkynes. The chelation-assisted
alkenylation of aryl ketones with alkynes was first reported by
Murai and co-workers by using a ruthenium catalyst.2 Since this
pioneering report, remarkable progress has been made on the che-
lation-assisted alkenylations of sp2 CAH bonds with alkynes by
using various directing groups and transition-metal catalysts.3
Undeniably, indole derivatives represent one of the most privi-
leged classes of heterocyclic compounds because of their extensive
abundance in biologically active compounds.4 Thus, the direct
functionalization of indole nucleus has been of considerable inter-
est in organic and medicinal chemistry.5 In particular, the highly
C2-selective olefination of 2,3-unsubstituted indoles is a challeng-
ing task due to the electrophilic property of the organometallic
species involved in the coupling reaction, as the reaction occurs
preferentially at the more electron-rich C3-position of the indole
ring.6 For instance, Gaunt and co-workers disclosed the Pd(II)-cat-
alyzed regioselective C2- or C3-olefinations of free (NH)-indoles by
employing different solvents and additives.6b Carretero and co-
workers described the Pd(II)-catalyzed oxidative coupling of
indoles containing a removable N-(2-pyridyl)sulfonyl group and
highly substituted olefins to afford C2-olefinated indoles
(Scheme 1).6e,f Recently, Prabhu and co-worker reported an effi-
cient example for Ru(II)-catalyzed oxidative C2-alkenylation of
indoles assisted by a N-benzoyl directing group.6i In addition, Li
and co-workers6j and Song and co-workers,6k respectively, demon-
strated Rh(III)- and Ru(II)-catalyzed oxidative couplings between
N,N-dimethylcarbamoyl-protected indoles and olefins to afford
C2-alkenylated indoles.
Although there have been great advancements in C2-selective
alkenylation of indoles with olefins, the C2-alkenylation of indoles
with alkynes has been much less explored. For example, Nakao
et al. reported nickel-catalyzed C2-alkenylation of C3-substituted
indoles with alkynes.3i,7 Schipper et al. have made a significant
contribution for the coupling of indoles and alkynes under cationic
rhodium catalysis, but this method does not allow the use of dial-
kylacetylenes.8 In addition, Yoshikai and co-workers reported an
efficient cobalt-catalyzed C2-alkenylation of indoles bearing a
removable N-pyrimidyl group under mild conditions.9 Recently,
we have disclosed the rhodium-catalyzed oxidative C2-olefination
of indoles and pyrroles containing N-arylcarboxamide directing
groups with a range of olefins to provide the di-substituted alkenes
linked with free (NH)-indoles and pyrroles.10 As part of an ongoing
research program directed at CAH bond functionalizations,11 we
⇑
Corresponding author. Tel.: +82 312907788; fax: +82 31 292 8800.
E-mail address: insukim@skku.edu (I.S. Kim).
http://dx.doi.org/10.1016/j.tetlet.2014.04.001
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

S. Sharma et al. / Tetrahedron Letters 55 (2014) 3104–3107
3105
Using Alkenes
Using Alkynes
R
N
R'
N
S
N
R
O
O
NMe2
[Rh]
[Pd]
Carretero (ACIE, 2009)
O
Schipper (JACS, 2010)
R
[Ru]
H
N
N
DG
O
R'
Prabhu (OL, 2013)
N
R
[Ru] or [Rh]
[Co]
N
R
N
N
Yoshikai (ACIE, 2012)
NMe2
O
Li and Wang (CEJ, 2013)
Song (CC, 2013)
Scheme 1. Representative C2-selective alkenylation protocol of indoles using alkenes or alkynes.
C-C bond formation
R'
cat. [Rh]
cat. [Rh]
R'
This work
R
H
N
N
H
R
N
H
R
R
O
ArHN
Our recent work
C-N bond cleavage
Scheme 2. C2-Selective alkenylation of indoles via CAC bond formation and subsequent CAN bond cleavage.
Table 1
Selected optimization of reaction conditionsa
H
Pr
N
[RhCp*Cl2]2 (2.5 mol %)
Pr
NH
N
H
Pr
O
oxidant, additive
solvent, 100 °C, 20 h
Pr
1a
2a
3a
Me
Entry
Oxidant (mol %)
Additive (mol %)
AgSbF6 (10)
Solvent
Yieldb (%)
1
2
3
4
Cu(OAc)2ÁH2O (200)
Cu(OAc)2ÁH2O (200)
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-BuOH
MeCN
65
67
N.R.
Trace
50
15
18
55
74
Ag2CO3 (200)
AgOAc (200)
5
6c
7
Cu(OAc)2ÁH2O (20)
Cu(OAc)2ÁH2O (20)
Cu(OAc)2ÁH2O (200)
Cu(OAc)2ÁH2O (200)
Cu(OAc)2ÁH2O (200)
Cu(OAc)2ÁH2O (200)
Cu(OAc)2ÁH2O (200)
Pivalic acid (100)
8
9
10
11
12
DMF
DCE
THF
Trace
Trace
42
Bold font is for emphasizing the best condition in optimization table.
a
Reaction conditions: 1a (0.15 mmol), 2a (0.3 mmol), [RhCpÃCl2]2 (2.5 mol %), oxidant (quantity noted), additive (quantity noted), solvent (1 mL) at 100 °C for 20 h under
air in pressure tubes.
b
Isolated yield by flash column chromatography.
O2 gas (1 atm) was used.
c
herein present the rhodium-catalyzed oxidative C2-alkenylation of
indoles containing a N-(p-tolyl)carboxamide directing group with
internal alkynes providing the tri-substituted alkenes linked with
free (NH)-indoles at C2-position with high regio- and stereoselec-
tivity via CAC bond formation and subsequent CAN bond cleavage
(Scheme 2).
In a recent report, a N-arylcarboxamide group was used as an
efficient directing group for the formation of C2-olefinated free
(NH)-indoles via one-pot CAC bond formation and CAN cleavage
process.10 Thus, N-p-tolyl-1H-indole-1-carboxamide (1a) was cho-
sen as a model substrate for the oxidative coupling with 4-octyne
(2a), and the selected optimization is summarized in Table 1. To

3106
S. Sharma et al. / Tetrahedron Letters 55 (2014) 3104–3107
Table 2
Substrate scopea
R
H
R1
N
R1
[RhCp*Cl2]2 (2.5 mol %)
R
NH
Cu(OAc)2.H2O (200 mol %)
R2
R2
O
N
H
MeCN, 100 o
C
1a-1j
2a-2e
3a-3n, %b
Me
Pr
MeO
Cl
Pr
Pr
Pr
N
H
N
H
N
H
Pr
Pr
Pr
3a
3b
3c
, 70%
, 74%
, 62%
NO2
Br
Pr
Pr
N
H
N
H
Pr
Pr
Pr
b
Cl
N
Pr
Pr
H
3d, 66%
3e, 57%
3f, 74%
Pr
Cl
Pr
N
H
N
H
N
H
F
Me
c
3i
3g, 73%
3h, 58%
, 74%
R
Cl
R
Cl
Pr
N
H
N
H
N
H
Me
Pr
R
3l, 62%
3m, 0% (R = Me)
3n
3j, 61 % (R = F)
, 0% (R = CO2Me)
3k, 68 % (R = CO2Et)
Isolated yield by flash column chromatography.
c
A diastereomeric mixture (E/Z = 4:1) was obtained.
Reaction conditions: 1a–1j (0.15 mmol), 2a–2e (0.3 mmol), [RhCpÃCl2]2 (2.5 mol %),
a
Cu(OAc)2ÁH2O (200 mol %), MeCN (1 mL) at 100 °C for 20 h under air in pressure tubes.
our delight, cationic rhodium complex, derived from [RhCpÃCl2]2
and AgSbF6, in the presence of Cu(OAc)2ÁH2O in tert-amyl alcohol
(t-AmOH) at 100 °C catalyzed the coupling of 1a and 2a to provide
the desired product 3a in 65% yield (Table 1, entry 1). In the
absence of AgSbF6 additive under otherwise identical conditions,
the formation of 3a was found to be improved to 67% yield (Table 1,
entry 2). However, in the absence of both AgSbF6 and Cu(OAc)2ÁH2-
O, no formation of 3a was observed (Table 1, entry 3). Next, our
study focused on the use of oxidants such as Ag2CO3 and AgOAc,
but the chemical yield was not improved, as shown in entries 4
and 5. In addition, a catalytic amount of Cu oxidant in the presence
of O2 gas or pivalic acid failed to effect any significant product for-
mation (Table 1, entries 6 and 7). Further screening of solvents
revealed that MeCN is unique in its ability to facilitate high levels
of conversion. After further optimization, the best result was
obtained using a treatment of 2.5 mol % of [RhCpÃCl2]2 and
200 mol % of Cu(OAc)2ÁH2O in MeCN solvent at 100 °C for 20 h,
affording the desired C2-alkenylated product 3a in high yield
(74%), as shown in entry 9.
With the optimized reaction conditions in hand, the scope of
indoles with a N-(p-tolyl)carboxamide directing group and alkynes
was investigated, as shown in Table 2. The coupling of 4-octyne
(2a) and indoles 1a–1h with electron-rich and electron-deficient
groups (OMe, Me, NO2, F, Cl, and Br), regardless of the substituent
position on the phenyl ring, was found to be favored in this reac-
tion to furnish the corresponding products 3a–3h in good to high
yields. Particularly noteworthy was the tolerance of the reaction
conditions to bromo and chloro moieties, which provides a versa-
tile synthetic handle for further elaboration of the products. To fur-
ther explore the substrate scope of this process, symmetric and
unsymmetric alkynes were screened to couple with 5-chloro-N-
p-tolyl-1H-indole-1-carboxamide (1c). The reaction of symmetric
diarylacetylenes 2b–2d and indole 1c was found to be favored in
the C2-olefination reaction, affording the corresponding products
Ph
N
O
O
Pr
Ph
N
i) BF3.Et2O, CH2Cl2, rt
ii) DDQ, toluene, 120 o
O
Pr
O
+
N
H
Pr
R
C
Pr
N
H
3a (R = H)
R
4
3g (R = F)
5a (64%, R = H)
5b
(69%, R = F)
Scheme 3. Synthetic transformation of C2-olefinated indoles.

S. Sharma et al. / Tetrahedron Letters 55 (2014) 3104–3107
3107
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This transformation also showed good tolerance toward unsym-
metric internal alkyne 2e in the present catalytic system to provide
the corresponding adduct 3l with excellent regio- and stereoselec-
tivity in 62% yield. However, indoles 1i and 1j with substituents
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sponding free (NH)-indoles without
directing group.
a N-(p-tolyl)carboxamide
Further investigation on the synthetic utility of this method was
conducted, as shown in Scheme 3. Olefinated compounds 3a and
3g underwent Diels–Alder reaction with N-phenylmaleimide (4)
in the presence of a catalytic amount of BF3ÁOEt2, and the subse-
quent oxidation using DDQ provided pyrrolocarbazole derivatives
5a and 5b in 64% and 69% yields, respectively.
In conclusion, a rhodium-catalyzed oxidative C2-alkenylation of
indoles containing a N-(p-tolyl)carboxamide group with alkynes
via CAC bond formation and subsequent CAN bond cleavage has
been developed, which is an effective approach to access various
C2-alkenylated free (NH)-indoles. This transformation has been
applied to a range of substrates, and typically proceeds with excel-
lent level of regio- and chemoselectivities as well as with high
functional group tolerance. Further applications of this method to
the synthesis of biologically active compounds and a more detailed
mechanistic investigation are in progress.
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Acknowledgments
10. Sharma, S.; Han, S.; Kim, M.; Mishra, N. K.; Shin, Y.; Ha, J.; Kwak, J. H.; Jung, Y.
H.; Kim, I. S. Org. Biomol. Chem. 2014, 12, 1703.
This research was supported by the Basic Science Research Pro-
gram through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science and Technology
(Nos. 2013R1A2A2A01005249 and 2013058800).
11. (a) Park, J.; Park, E.; Kim, A.; Lee, Y.; Chi, K.-W.; Kwak, J. H.; Jung, Y. H.; Kim, I. S.
Org. Lett. 2011, 13, 4390; (b) Sharma, S.; Park, E.; Park, J.; Kim, I. S. Org. Lett.
2012, 14, 906; (c) Sharma, S.; Park, J.; Park, E.; Kim, A.; Kim, M.; Kwak, J. H.;
Jung, Y. H.; Kim, I. S. Adv. Synth. Catal. 2013, 355, 332; (d) Kim, M.; Park, J.;
Sharma, S.; Kim, A.; Park, E.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. Chem. Commun.
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H.; Jung, Y. H.; Kim, I. S. Chem. Commun. 2013, 1654; (f) Sharma, S.; Kim, A.;
Park, E.; Park, J.; Kim, M.; Kwak, J. H.; Lee, S. H.; Jung, Y. H.; Kim, I. S. Adv. Synth.
Catal. 2013, 355, 667; (g) Park, J.; Kim, A.; Sharma, S.; Kim, M.; Park, E.; Jeon, Y.;
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Kim, M.; Park, J.; Sharma, S.; Han, S.; Han, S. H.; Kwak, J. H.; Jung, Y. H.; Kim, I. S.
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H.; Jung, Y. H.; Oh, J. S.; Lee, Y.; Kim, I. S. Eur. J. Org. Chem. 2013, 6656; (l) Han,
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Supplementary data
Supplementary data (experimental procedure and spectro-
scopic data for all products) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2014.04.001.
References and notes
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