Highly regioselective C2-alkenylation of indoles Uusing the N-benzoyl directing group: An efficient Ru-catalyzed coupling reaction

Article abstract of DOI:10.1021/ol4011486

A highly regioselective alkenylation of indole at the C2-position has been achieved using the Ru(II) catalyst by employing a directing group strategy. This strategy offers rare selectivity for the alkenylation N-benzoylindole at the C-2 position in the pr

Full text of DOI:10.1021/ol4011486

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Highly Regioselective C2-Alkenylation of
Indoles Using the N‑Benzoyl Directing
Group: An Efficient Ru-Catalyzed
Coupling Reaction
Veeranjaneyulu Lanke and Kandikere Ramaiah Prabhu*
Department of Organic Chemistry, Indian Institute of Science, Bangalore-560012,
Karnataka, India
prabhu@orgchem.iisc.ernet.in
Received April 24, 2013
ABSTRACT
A highly regioselective alkenylation of indole at the C2-position has been achieved using the Ru(II) catalyst by employing a directing group
strategy. This strategy offers rare selectivity for the alkenylation N-benzoylindole at the C-2 position in the presence of the more active C3- and C7-
position of indole and the ortho-positions of the benzoyl protecting group. A simple deprotection of the benzoyl group has also been exemplified,
and the resulting product serves as a useful synthon for natural product syntheses.
Formation of CÀC bonds using nonfunctionalized pre-
cursors is a challenging task due to the unfavorable
reactivity of CÀH bonds.1À4 To achieve such a distinction,
it is important to understand the relative reactivity of
various centers of the molecule.5 The idea of employing
directing groups (DGs) for the activation of CÀH bonds
has been conceived by de Vries and van Leeuwen for
coupling anilides with olefins.6 In designing a directing
group strategy, it is important to employ a suitable group
which can be readily installed and removed/transformed,
and the substitution itself should not occur on the directing
group.7 In this regard, Pd catalyzed CÀH functionaliza-
tion reactions are well explored.1a,7a,8,9 Indole is an integral
feature of several biologically active compounds and
natural products and an important constituent in pharma-
ceutical applications.10 Alkenylation of indole at the
C2-position is a challenging task due to the electrophilic
nature of the reaction;11 thus functionalization of indole at
(7) Selected reviews and examples for CÀH functionalization using
directing groups: (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110,
1147. (b) Alberico, D.;Scott, M. E.;Lautens, M.Chem. Rev. 2007, 107, 174.
(c)Mewald, M.;Schiffner, J. A.;Oestreich, M.Angew. Chem., Int. Ed. 2012,
51, 1763. (d) Yamashita, M.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2009, 11, 2337. (e) Wang, C.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009,
131, 4194. (f) Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130,
7534. (g) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154. (h) Pastine, S. J.; Gribkov, D. V.; Sames, D. J. Am. Chem.
Soc. 2006, 128, 14220. (i) Ihara, H.; Suginome, M. J. Am. Chem. Soc. 2009,
131, 7502. (j) Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.; Gao, G.;
You, J. Angew. Chem., Int. Ed. 2009, 48, 3296. (k) Tobisu, M.; Nakamura,
R.; Kita, Y.; Chatani, N. J. Am. Chem. Soc. 2009, 131, 3174.
(8) Recent review on arylations: (a) Ackermann, L.; Vincente, R.;
Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792.
(1) Selected reviews for CÀH activation: (a) Engle, K. M.; Mei, T.-S.;
Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (b) Ackermann, L.
Chem. Rev. 2011, 111, 1315. (c) McMurray, L.; OHara, F.; Gaunt, M. J.
Chem. Soc. Rev. 2011, 40, 1885. (d) Yamaguchi, J.; Yamaguchi, A. D.;
Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960. (e) Trost, B. M. Science
1991, 254, 1471. (f) Trost, B. M. Acc. Chem. Res. 2002, 35, 695.
(2) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529.
(3) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y.
Science 2000, 287, 1992.
(4) See review for metal mediated radical reactions: Yeung, C. S.;
Dong, V. M. Chem. Rev. 2011, 111, 1215.
(5) Review for site selectivity: Neufeldt, S. R.; Sanford, M. S. Acc.
(9) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172.
(10) (a) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev.
2010, 110, 4489 and references therein. (b) Cacchi, S.; Fabrizi, G. Chem.
Rev. 2011, 111, 215. (c) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J.
J. Am. Chem. Soc. 2008, 130, 8172.
(11) Maehara, A.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett. 2008,
10, 1159.
Chem. Res. 2012, 45, 936.
(6) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.;
Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem.
Soc. 2002, 124, 1586.
r
10.1021/ol4011486
XXXX American Chemical Society

Table 1. Screening Studies for Directing Groups
Scheme 1. Selective Alkenylation Using Directing Groups
3 (%)a
4 (%)b
entry
indole
(C2-product)
(C7-product)
1
2
3
4
5
6
7
R = ÀH
nd
nd
nd
nd
nd
nd
12
nd
R = ÀCH3
nd
R = ÀCOCH3
R = ÀCO(CH3)3
R = ÀCO(CH3)3
R = ÀCOPh
46
trace
trace
66
R = ÀSO2C7H8
trace
a Conversion based on 1H NMR data. b nd = not detected.
the C2-position is less addressed.12,13 Alkenylation of
1-acylindoles has been explored as early as 1983 by Itahara
and co-workers13a by using Pd(II), which led to sub-
stitution at the C3-position (Scheme 1a). Furthermore,
Gaunt et al. reported C2-alkenylation of indoles using
Pd catalysts by altering the solvent to obtain C2- or
C3-alkenylated products in low to moderate yields.13b
preliminary studies indicated the suitability of N-acetylin-
dole, as it reacted with methyl acrylate to furnish the C2-
coupled product 3ea in 46% yield (entry 3, Table 1). We
anticipated that increasing the electron-donating ability of
substrates may increase the reactivity and, therefore, used
N-tert-butoylindole and N-Boc-indole for the reaction
with methyl acrylate (2a) under identical reaction condi-
tions. However, these reactions furnished trace amounts of
the anticipated C2-alkenylated products (entries 4 and 5,
Table 1). Very gratifyingly, when N-benzoylindole was
treated with methyl acrylate, the expected C2-substituted
product 3aa was obtained in 66% yield (entry 6, Table 1). It
is notable that the reaction of anilides with methyl acrylates
in similar conditions resulted in the alkenylation of anilides
at the ortho-position (Scheme 1c),17 and it is well-known
that the reaction of N-benzoylindole with methyl acrylate
(2a) inthe presenceof Pd catalyst results in the formation of
the C3-alkenylated product (Scheme 1a).13a Furtherscreen-
ing studies revealed that a sulfonyl protecting group
and simple indole and N-methyl indole were not suitable
substrates, as no reaction occurred even after prolonged
reaction times (entries 1, 2, and 7, Table 1). We anticipated
that Pd also could mimic the role of Ru, and we explored
the same reaction with Pd(II) instead of Ru(II). However,
this substitution resulted in the mixture of C2- and
C3-alkenylated products in low yields (see Supporting
Information, SI-Table 1).
Recently, Arrayas, Carretero and co-workers13c employed
ꢀ
N-pyridylsulfonyl as a directing group to functionalize indole
at the C2-position using an excess of alkenes in the presence
of a Pd(II) catalyst (Scheme 1b). The concept was based
on the ability of Pd to form six-membered palladacycles.14
Other than the N-pyridylsulfonyl group, there have been no
attempts to use other directing groups to alkenylate indole at
the C2-position. With this background and previous reports
on Ru-based catalysts,15 we hypothesized that the Ru(II)
catalyst could perform a selective C2-alkenylation of indole
using a carbonyl oxygen as a directing group. Moreover, a
C2-directing ability of Ru(II) would be favorable, as there are
a number of reports on Ru(II) forming five-membered cyclic
intermediates.16
To test this hypothesis, we started an investigation to
find a suitable directing group, which could promote
selective alkenylation of indole at the C2-position. Our
(12) Capito, E.; Brown, J. M.; Ricci, A. Chem. Commun. 2005, 1854.
(13) (a) Itahara, T.; Ikeda, M.; Sakakibara, T. J. Chem. Soc., Perkin
Trans. 1 1983, 1361. (b) Grimster, N. P.; Gauntlett, C.; Godfrey,
C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125. (c)
ꢀ
ꢀ
Garcıa-Rubia, A.; Gomez Arrayas, R.; Carretero, J. C. Angew. Chem.,
Int. Ed. 2009, 48, 6511. (d) Kandukuri, S. R.; Schiffner, J. A.; Oestreich,
M. Angew. Chem., Int. Ed. 2012, 51, 1265.
With the benzoyl group as a suitable directing group,
we continued screening studies to determine the optimal
amounts of the catalyst (Ru), activator (Ag), and oxidant
(Cu) required for this reaction. N-Benzoyl indole (1a) and
methyl acrylate (2a) were used as model substrates in the
presenceof [Ru(p-cymene)Cl2]2 asa catalyst, AgSbF6 asan
ꢀ
ꢀ
(14) Garcıa-Rubia, A.; Urones, B.; Gomez Arrayas, R.; Carretero,
J. C. Chem.;Eur. J. 2010, 16, 9676.
(15) Reviews and selected publications of ruthenium catalyzed func-
tionalization: (a) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem.
Rev. 2012, 112, 5879. (b) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002,
35, 826. (c) Singh, K. S.; Dixneuf, P. H. Organometallics 2012, 31, 7320.
(d) Arockiam, P. B.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Green
Chem. 2011, 13, 3075.
(16) (a) Kozhushkov, S. I.; Ackermann, L. Chem. Sci. 2013, 4,
886. (b) Ackermann, L. Acc. Chem. Res. 201310.1021/ar3002798. (c)
Ackermann, L.; Pospech, J. Org. Lett. 2011, 13, 4153. (d) Ackermann, L.;
Wang, L.; Wolfram, R.; Lygin, A. V. Org. Lett. 2012, 14, 728. (e) Padala,
K.; Jeganmohan, M. Org. Lett. 2011, 13, 6144. (f) Padala, K.; Jeganmohan,
M. Org. Lett. 2012, 14, 1134. (g) Li, B.; Devaraj, K.; Darcel, C.; Dixneuf,
P. H. Green Chem. 2012, 14, 2706.
activator, and Cu(OAc)2 H2O as an oxidant in a variety
of solvents and different temperatures. The reaction of 1a
with 2a in the presence of Ru(II) (5 mol %), AgSbF6
3
(17) (a) Hashimoto, Y.; Ortloff, T.; Hirano, K.; Satoh, T.; Bolm, C.;
Miura, M. Chem. Lett. 2012, 41, 151. (b) Ackermann, L.; Wang, L.;
Wolfram, R.; Lygin, A. V. Org. Lett. 2012, 14, 728.
B
Org. Lett., Vol. XX, No. XX, XXXX

As expected, the reaction at 100 °C resulted in the regiose-
lective formation of the C2-alkenylated product 3aa as the
sole product in almost quantitative yield (97%, entry 12).
These reactions (entries 10À12) indicate that the regioselec-
tivity of the reaction is controlled by the temperature of the
reaction. As can be seen in entry 13, NaOAc is not useful as
an activator in these Ru catalyzed reactions.20 Solvents
screening studies indicated that CH3CN, toluene, dioxane,
and water were not suitable solvents. Based on these studies,
we arrived at the optimal conditions for this reaction, i.e. 1a
(1 equiv), 2a (1.2 equiv), Ru complex (5 mol %), Ag salt
(20 mol %), and Cu salt (1 equiv) in DCE at 100 °C in the
presence of air.
Next, we continued to explore the scope of the reaction
(Schemes 2 and 3). As can be seen in Scheme 2, 1a reacted
with methyl acrylate 2a to furnish the oxidative coupled
product 3aa in excellent yield as the sole product (97%,
Scheme 2). Similarly, N-benzoylated derivatives of 5-bro-
moindole (1b), 6-chloroindole (1c), and 5-methoxyindole
(1d) underwent a smooth reaction with 2a to provide the
Heck type coupled products 3ba, 3ca, and 3da in good to
excellent yields. Similarly, ethyl acrylate (2b) reacted well with
indole derivatives 1a, 1b, 1c, and 1d to furnish the coupled
products 3ab, 3bb, 3cb, and 3db in good to excellent yields.
Table 2. Screening Studies for Optimal Conditions
conversiona
Ru
Ag
Cu
entry
2a
(mol %)
(mol %)
(equiv)
3aa
4aa
SM
1
2
5
20
1.2
1.2
1.2
none
0.25
1
66
nd
nd
<10
<10
65
41
13
66
6
12
nd
nd
nd
nd
5
22
2
2
none
20
100
100
90
3
2
5
5
5
5
5
5
5
5
5
5
5
none
20
4
2
5
2
10
90
6
2
20
30
7
3
20
1
9
50
8
5
20
1
7
80
9
1.2
1.2
1.2
1.2
1.2
20
1
7
27
10b
11c
12d
13e
20
1
5
89
20
1
17
97
nd
6
79
20
100
1
nd
nd
nd
100
1
a Based on 1H NMR data. b Reaction at rt. c Reaction at 60 °C.
d Reaction at 100 °C. e NaOAc was used instead of AgSbF6.
Scheme 2. Scope of the Reactiona
(20 mol %), and Cu(OAc)2 H2O (1.2 equiv) in DCE at
3
80 °C resulted in the formation of C2-substituted product
3aa18 as the major product (66%) along with C7-alkeny-
lated product 4aa19 (12%) and unreacted starting material
(22%, entry 1, Table 2). As can be seen, in the absence
of either Ru or Ag, no reaction was observed, whereas
the absence of copper acetate resulted in the formation of
C2-substituted indole 3aa in trace amounts (entries 2À4,
Table 2). Further, it was found that a similar reaction using
a catalytic amount of copper forms the C2-alkenylated
product 3aa in trace amounts (entry 5), whereas 1 equiv of
copper salt produced the expected C2-alkenylated product
3aa (65%) along with C7-alkenylated product 4aa (5%)
and 1a (30%, entry 6). Increasing the stoichiometry of
methyl acrylate (2a) to 3 or 5 equiv and performing the
reaction in the presence of 5 mol % Ru and 1 equiv of Cu
resulted in lowering the yield of C2-alkenylated product
3aa (entries 7À8). Nevertheless, using 1.2 equiv of 2a and
5 mol % of Ru with 1 equiv of copper acetate resulted in
enhancing the yield of C2-alkenylated product 3aa to 66%
along with C7-alkenylated product 4aa and unreacted
N-benzoyl indole (1a) (7% and 30% respectively, entry 9).
The reaction at ambient temperature resulted in the forma-
tion of 3aa and 4aa in almost equal ratio (58:42) in an
overall yield of 10% (entry 10). An increase in the reaction
temperate to 60 °C resulted in the formation of a mixture
of products 3aa/4aa (75:25) in 22% overall yield (entry 11).
a Reaction conditions: N-Benzoylindole (1 equiv), [Ru(p-cymene)Cl2]2
(5 mol %), AgSbF6 (20 mol %), Cu(OAc)2 H2O (1 equiv), acrylate
3
b
(1.2 equiv), DCE (2 mL), 100 °C, 3 h. Conversion based on 1H NMR
data. c Isolated pure yields.
Further studies revealed that other alkyl acrylates such
as 2-phenylethylacrylate (2c) and cyclohexyl acrylate (2d)
alsounderwent smooth coupling tofurnish the C2-coupled
products 3ac and 3ad in good yields (99% and 81%
respectively). This coupling reaction turned out to be a
(18) The C2-alkenylated N-benzoylindole derivatives were character-
ized by spectral data and single crystal structural analysis of 3ba (see SI).
(19) C7-Alkenylated N-benzoylindole 4 is characterized by spectral
data, and the structure was resolved by COSY and j-resolved NMR
experiments (see SI for details).
(20) Muralirajan, K.; Parthasarathy, K.; Cheng, C. H. Org. Lett.
2012, 14, 4262.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Reaction with tert-Butyl Acrylatea
Scheme 5. Deprotection and Hydrolysis
The scope of this highly regioselective coupling reaction
was further explored by reacting N-benzoylindole (1a)
with diacrylates (Scheme 4) and found that the two indole
moieties can couple with diacrylate. Hence, N-benzoylin-
dole (1a) reacted with 1,4-phenylene diacrylate (2i) under
optimal reaction conditions.
a Reaction conditions: N-Benzoylindole derivative (1 equiv), [Ru(p-
cymene)Cl2]2 (5 mol %), AgSbF6 (20 mol %), Cu(OAc)2 H2O (1 equiv),
3
b
acrylate (1.2 equiv), DCE (2 mL), 100 °C, 6 h. Conversion based on
1H NMR data. c Isolated pure yields.
As expected, diacrylate 2i coupled with 2.5 equiv of
indole 1a to furnish the coupled product (3ai) in excellent
isolated yield (92%). Under identical conditions, ethane-
1,2-diyl diacrylate (2j) also reacted well with 1a to furnish
the coupled product (3aj) in 60% yield (Scheme 4).
Due to its importance for further functionalization of
the indole moiety, we attempted the facile deprotection of
the benzoyl group.
Scheme 4. Reaction of Diacrylatesa
As can be seen from Scheme 5, the deprotection was
readily achieved by heating 3aa with NaOH in H2O/CH3CN
solution for 45 min to furnish the debenzoylated indole
derivative of acrylic acid (5) in almost quantitative yield.21
This product 5 is a very useful intermediate, which can be
transformed into a variety of natural products.22 Further,
the utility of the alkenylation of N-benzoyl indole has
been demonstrated by performing the reaction at 4 mmol
scale.23
A novel Ru catalyzed versatile regioselective alkenylation
strategy for indole derivatives at the C2-position has been
demonstrated using the benzoyl group as a directing group.
To the best of our knowledge, this is the first report of C2-
alkenylation of N-benzoylindoles. Although Ru catalysts are
well-known catalysts for direct alkenylation of benzamides
at the ortho-poistion, such functionalization is not observed
in the present strategy. The deprotection of the benzoyl
group is also very facile thereby making the methodology
more useful. Further work to establish the mechanistic
reasons for selectivity and to further explore the synthetic
scope of this mode of catalytic activation is in progress.
a Reaction conditions: N-Benzoylindole (2.5 equiv), [Ru(p-cymene)Cl2]2
(5 mol %), AgSbF6 (20 mol %), Cu(OAc)2 H2O (1 equiv), acrylate
3
b
(1 equiv), DCE (2 mL), 100 °C, 6 h. Conversion based on 1H NMR
data. c Isolated pure yields.
versatile reaction, as the reaction of 1a with aryl acrylate such
as phenyl acrylate (2e), 4-methoxy-phenyl acrylate (2f) and
naphthyl acrylate (2g) in a reaction with indole 1a furnished
the expected coupled products 3ae, 3af, and 3ag in good to
excellent yields (72%, 99%, and 85% respectively). How-
ever, the reaction of N-acetylindole (1e) with methyl acrylate
(2a) resulted in a moderate yield of the coupled product 3ea
(46%). The reaction of indole derivatives with tert-butyla-
crylate (2h) was interesting. As can be seen in Scheme 3,
N-benzoyl indole (1a) reacted with tert-butylacrylate (2h) to
furnish the product 3ah in which the tert-butyl group was
deprotected under the reaction conditions. The generality
of this reaction was further established by reacting tert-
butylacrylate (2h) with a few more indole derivatives. Thus,
the reaction of tert-butylacrylate (2h) with N-benzoylated
derivatives of 5-bromoindole (1b), 6-chloroindole (1c), and
5-methoxyindole (1d) furnished the corresponding alkeny-
lated acids 3bh, 3ch, and 3dh in moderate yields.
Acknowledgment. This paper is dedicated to Prof.
Goverdhan Mehta, FNA, FRS, National Professor, School
of Chemistry, University of Hyderabad, Hyderabad, India
on the occasion of his 70th birthday. The authors thank IISc
and RL Fine Chem for financial support and Dr. A. R.
Ramesha (RL Fine Chem) for useful discussions. V.L.
thanks CSIR for a fellowship.
(21) Linda, P.; Stener, A.; Cipiciani, A.; Savelli, G. Heterocycl. Chem.
1983, 20, 247.
(22) (a) Hibino, S.; Sugino, E.; Kuwada, T.; Oguru, N.; Sato, K.;
Choshi, T. J. Org. Chem. 1992, 57, 5917. (b) Tsotinis, A.; Afroudakis,
P. A.; Davidson, K.; Prashar, A.; Sugden, D. J. Med. Chem. 2007, 50,
6436. (c) Winder, P. A.; Cooper, C. B. Tetrahedron 1986, 42, 2985.
(23) Scaling up experiment:
Supporting Information Available. Experimental pro-
cedures, characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX