Regioselective synthesis of 4-substituted indoles via C-H activation: A ruthenium catalyzed novel directing group strategy

Article abstract of DOI:10.1021/ol4031149

A highly regioselective functionalization of indole at the C-4 position by employing an aldehyde functional group as a directing group, and Ru as a catalyst, under mild reaction conditions (open flask) has been uncovered. This strategy to synthesize 4-substituted indoles is important, as this class of privileged molecules serves as a precursor for ergot alkaloids and related heterocyclic compounds.

Full text of DOI:10.1021/ol4031149

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Regioselective Synthesis of 4‑Substituted
Indoles via CÀH Activation: A Ruthenium
Catalyzed Novel Directing Group Strategy
Veeranjaneyulu Lanke and Kandikere Ramaiah Prabhu*
Department of Organic Chemistry, Indian Institute of Science, Bangalore-560012,
Karnataka, India
prabhu@orgchem.iisc.ernet.in
Received October 30, 2013
ABSTRACT
A highly regioselective functionalization of indole at the C-4 position by employing an aldehyde functional group as a directing group, and Ru as a
catalyst, under mild reaction conditions (open flask) has been uncovered. This strategy to synthesize 4-substituted indoles is important, as this
class of privileged molecules serves as a precursor for ergot alkaloids and related heterocyclic compounds.
Among indoles, 4-substituted indoles are known as
privileged frameworks that are attractive synthetic targets
in organic synthesis.1,2 This class of compounds are the
backbone of ergot alkaloids,3 which are biologically active
and promising drug candidates.4 Development of a short
synthetic route for 4-substituted indoles is a challenging
task, as the C-4 position of indole is less reactive and requires
a multistep sequence using 4-formylindole derivatives.5
Synthesis of 4-substituted indoles is crucial in developing
synthetic routes to ergot and related alkaloids, as it can be
transformed to a variety of natural products (Figure 1).6
Formation of CÀC bonds using unfunctionalized precursors
is cumbersome due to the unfavorable reactivity of CÀH
bonds,7 and selective functionalization is an even more
difficult task.8 A directing group (DG) strategy for CÀH
activation is a subject of research as it provides a simple,
short, and economical route to the target molecules.9 In
recent times, Ru-catalysts have emerged as highly efficient
and useful catalysts for the formation of CÀC bonds using a
DG strategy.10 However, there are only limited studies for
the alkenylation of indole derivatives by employing Ru
catalysts. The C-4 alkenylation of indoles has rarely been
addressed, except for a recent report on a Pd catalyzed
reaction of tryptophan,11 which is limited to only tryptophan
(1) (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (b)
Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010,
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A. P.; Ishida, H. J. Am. Chem. Soc. 1980, 102, 4265.
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Ponticello, G. S.; Baldwin, J. J. J. Org. Chem. 1979, 44, 4003. (c)
Kozikowski, A. P.; Ishida, H.; Chen, Y.-Y. J. Org. Chem. 1980, 45,
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r
10.1021/ol4031149
XXXX American Chemical Society

derivatives. Recently, Jeganmohan et al. reported Ru cata-
lyzed ortho-alkenylation of aromatic aldehydes.12e Based on
the literature precedence12 and in continuation of our quest
for the selective functionalization of indoles,13 we undertook
an investigation to functionalize indole at the C-4 position.
Scheme 1
The preliminary reaction of 1-benzyl-1H-indole-3-car-
baldehyde (1a) with methyl acrylate (2a) in the presence of
Ru(II) (5 mol %), AgSbF6 (20 mol %), and Cu(OAc)2
3
H2O (1.0 equiv) in ClCH2CH2Cl at 100 °C resulted in the
formation of C-4-substituted product 3aa in a major
amount (47%) along with a mixture of C-2 alkenylated
product 4aa (12%), 5aa (at C-2 and C-4 positions, 5%),
and 1a (34%, entry 1, Table 1). In the absence of either Ru
or Ag, no reaction was observed, whereas the absence of
copper acetate resulted in the formation of C-4 substituted
indole 3aa in trace amounts (entries 2À4, Table 1).
Further, enhancing the amount of Ru(II) to 10 mol %
resulted in the formation of a mixture of products 3aa, 4aa,
5aa, and 1a (45:20:13:22 ratio, entry 5, Table 1). Decreas-
ing the amount of the Cu catalyst to 0.5 equiv resulted in
the formation of the expected C-4 alkenylated product 3aa
in low yields (18%) along with unreacted aldehyde 1a
(82%, entry 6). Temperature control experiments revealed
the formation of 3aa in 17% yield when the reaction was
performed at 60 °C (entry 7). Increasing the temperature to
120 °C resulted in the formation of a mixture of 3aa, 4aa,
5aa, and starting material 1a in a ratio of 45:19:7:29,
respectively (entry 8, Table 1). Based on these observations
(entries5À8), we performed the reaction using Ru (10 mol %),
Cu (0.5 equiv) at 120 °Ctofindtheformationof3aa as a major
product (58% yield) along with 4aa, 5aa, and aldehyde 1a
(4%, 2%, 36% yields, entry 9). Further screening studies
revealed that AgSbF6 is a suitable activator, as the noncoor-
Figure 1. Biologically active compounds derived from C-4
substituted indoles.
Inthisstudy, wedescribe ourrecentfinding onthe highly
regioselective functionalization of indole at the C-4 posi-
tion by employing the aldehyde functional group as a
directing group, and Ru as a catalyst under mild reaction
conditions (open flask). An interesting observation is that,
unlike other known methods,12 in the present study it was
found that the reaction involves a six membered transition
state14 that leads to the expected product (Scheme 1). A
selective functionalization of indole at the C-4 position
using an aldehyde as a directing group provides advan-
tages of either removing the aldehyde group6a or further
functionalization.
(9) Review for directing group chemistry: (a) Engle, K. M.; Mei, T.-S.;
Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (b) Mewald, M.;
Schiffner, J. A.; Oestreich, M. Angew. Chem., Int. Ed. 2012, 51, 1763. (c)
Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (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) Tobisu, M.; Nakamura, R.; Kita, Y.; Chatani, N.
J. Am. Chem. Soc. 2009, 131, 3174. (k) Ritleng, V.; Sirlin, C.; Pfeffer, M.
Chem. Rev. 2002, 102, 1731. (l) Mousseau, J. J.; Charette, A. B. Acc.
Chem. Res. 2013, 46, 412.
(10) (a) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012,
112, 5879. (b) Kozhushkov, S. I.; Ackermann, L. Chem. Sci. 2013, 4, 886.
(11) Liu, Q.; Li, Q.; Ma, Y.; Jia, Y. Org. Lett. 2013, 15, 4528.
(12) (a) Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano, K.; Satoh, T.;
Miura, M. Org. Lett. 2011, 13, 706. (b) Ackermann, L.; Pospech, J. Org.
Lett. 2011, 13, 4153. (c) Arockiam, P. B.; Fischmeister, C.; Bruneau, C.;
Dixneuf, P. H. Green Chem. 2011, 13, 3075. (d) Padala, K.; Jeganmohan,
M. Org. Lett. 2011, 13, 6144. (e) Padala, K.; Jeganmohan, M. Org. Lett.
2012, 14, 1134. (f) Ackermann, L.; Wang, L.; Wolfram, R.; Lygin, A. V.
Org. Lett. 2012, 14, 728. (g) Kakiuchi, F.; Sato, T.; Igi, K.; Chatani, N.;
Murai, S. Chem. Lett. 2001, 386. (h) Ackermann, L. Acc. Chem. Res.
201310.1021/ar3002798.
À
dinating counterion SbF6 keeps the Ru coordination site
empty so that Ru can bind to the substrate. It was also found
that Cu(OAc)2 H2O is the most appropriate oxidant for the
3
reaction (entries 10À14). Increasing the stoichiometry of
methyl acrylate (2a) to 2.5 and 4 equiv in the presence of
10 mol % Ru(II) and 0.5 equiv of Cu(II) has enhanced the
yield of C-4 alkenylated product 3aa to 63% and 82%
respectively (entries 15À16). Based on these screening studies,
we arrived at the optimal conditions for this reaction, i.e., 1a
(1 equiv), 2a (4 equiv), [Ru(p-cymene)Cl2]2 (10 mol %), Ag
salt (20 mol %), and Cu(OAc)2 H2O (0.5 equiv) in
3
ClCH2CH2Cl at 120 °C in the presence of air.
Next, we continued to explore the scope of the reaction,
and the results are presented in Schemes 2 and 3. A variety
of 1-benzyl-1H-indole-3-carbaldehyde derivatives 1aÀ1e
reacted with methyl acrylate 2a to furnish C-4 alkenylated
products 3aa,3ba,3ca,3da,and3ea ingoodyields(80À95%).
(13) Lanke, V.; Prabhu, K. R. Org. Lett. 2013, 15, 2818.
(14) Li,J.;Kornhaab,C.;Ackermann,L.Chem. Commun. 2012,48, 11343.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Substrate Scope with Indole Derivativesa
Table 1. Screening Studies for Optimization
NMR conversiona
Ru
additive
(mol %)
oxidant
(equiv)
entry (mol %)
3aa 4aa 5aa sm
1b
2b
3b
4b
5b
6b
7c
5
AgSbF6 (20) Cu(II) (1)
47
nd
nd
12
5
34
none AgSbF6 (20) Cu(II) (1)
nd nd 100
nd nd 100
5
none
Cu(II) (1)
5
AgSbF6 (20) none
<10 nd nd 90
45 20 13 22
10
5
AgSbF6 (20) Cu(II) (1)
AgSbF6 (20) Cu(II) (0.5) 18
nd nd 82
nd nd 83
5
AgSbF6 (20) Cu(II) (1)
AgSbF6 (20) Cu(II) (1)
17
45
8
5
19
4
7
2
29
36
9
10
10
10
10
10
10
10
10
AgSbF6 (20) Cu(II) (0.5) 58
KPF6 (20) Cu(II) (0.5)
NH4PF6 (20) Cu(II) (0.5) 42
10
11
12
13
14
15d
16e
6
nd nd 94
nd nd 43
nd nd 100
nd nd 100
nd nd 100
AgSbF6 (20) PIDA
AgSbF6 (20) AgOAc
AgSbF6 (20) NaOAc
nd
nd
nd
AgSbF6 (20) Cu(II) (0.5) 63
7
5
25
a Reaction conditions: 1-benzyl-1H-indole-3-carbaldehyde (1 equiv),
[Ru(p-cymene)Cl2]2 (10 mol %), AgSbF6 (20 mol %), acrylate (2a)
(4 equiv), ClCH2CH2Cl (2 mL), 120 °C, 8À24 h. In the case of 2b,
AgSbF6 (20) Cu(II) (0.5) 82
5
2
11
b
Cu(OAc)2 H2O (1 equiv) was used. Conversion based on 1H NMR
a Based on 1H NMR data. b Reaction performed at 100 °C. c Reac-
tion performed at 60 °C. d 2.5 equiv of 2a. e 4.0 equiv of 2a. PIDA =
phenyliodine(III) diacetate.
3
data. c Isolated pure yields.
derivatives 3ac, 3ad, 3ae, 3af, 3ag, 3ah, and 3ai, in excellent
yields (70À87%, Scheme 3). This coupling reaction was a
versatile reaction, as the reaction of 1a with a variety of
R,β-unsaturated systems such as 2jÀ2o furnished the ex-
pected coupled products 3aj, 3ak, 3al, 3am, 3an, and 3ao in
moderate yields (Scheme 3).16
Similarly, the reaction of acrolein 2b with 1aÀ1e resulted in
the formation of products 3ab, 3bb, 3cb, 3db, and 3eb in
excellent yields (90À99%). As demonstrated by these exam-
ples, substrates with halogen substitution on the indole ring at
the C-6 (Cl and Br) position are well tolerated under the
reaction conditions to furnish the corresponding alkenylated
products (3ba, 3ca, 3bb, and 3cb), which are useful precursors
for further functionalization.15
Further, it was found that the alkenylation of 1-benzyl-
5-methoxy-1H-indole-3-carbaldehyde (1f) proceeds smoothly
with acrolein 2b to furnish the product 3fb in 83% yield.
Alkenylation of 1c with 4-bromostyrene resulted in the
formation of the product 3cm in moderate yield. Reaction
of 1-(4-methoxybenzyl)-1H-indole-3-carbaldehyde, which
is an N-protected PMB derivative of indole-3-carbaldehyde,
with 2a furnished the alkenylated product 4 in good
yield. Similarly, a reaction of N-benzoyl protected indole-
3-carbaldehyde with methyl acrylate (2a) under optimal
conditions yielded the product 6 in good yield. However,
the reactions to alkenylate benzofuran-3-carbaldehyde and
2-phenylacetaldehyde with acrolein were not successful.16
The scope of this highly regioselective coupling reaction
was further expanded by reacting 1a with a variety of
acrylates. Thus acrylates 2cÀ2i underwent a facile reaction
with 1a to afford the corresponding 4-substituted indole
Earlier, we demonstrated that using N-benzoyl as a
directing group on indole derivatives under a Ru catalyzed
reaction can lead to 2-alkenylated products 9.13 In light of
the present study, it would be appropriate to study the
regioselectivity and directing group abilities of formyl and
benzoyl directing groups, if they are present in the indole
moiety, as in compound 5 (Scheme 4). Therefore, when 5
was subjected to the present reaction conditions, the reac-
tion furnished a mixture of 4-alkenylated product 6 in a
major amount (68%) along with 2-alkenylated product 7
in a minor amount (7%, eq 1, Scheme 4). However, the
reaction of 1a (N-benzyl indole) with 2a under the optimal
reaction conditions furnished 3aa in 82% yield (Scheme 2).
To evaluate the steric factor involved in the above reaction
due to the presence of a formyl group at the third position
of indole, an independent reaction using a mixture of
3-formyl-N-benzyl indole (1a) and N-benzoyl indole (8)
was performed under the optimal conditions. This reaction
yielded a mixture of C-4 alkenylated product 3aa (46%) and
C-2 alkenylated product 9 (12%) in an 8:2 ratio along with
(15) (a) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot,
T. J.; Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062. (b) Kambe, N.;
Iwasaki, T.; Terao, J. Chem. Soc. Rev. 2011, 40, 4937.
(16) C-2 Alkenylated products were not observed with acrolein,
whereas in the remaining olefins, C-2 alkynylated products were
obtained in <7% yield (based on 1H NMR data).
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Substrate Scope with a Variety of Olefinsa
Scheme 4. Selective Alkenylation Reactions
a Conversion based on 1H NMR data. b Isolated pure yields.
Scheme 5. Synthetic Applications
a Reaction conditions: 1a (1 equiv), [Ru(p-cymene)Cl2]2 (10 mol %),
AgSbF6 (20 mol %), Cu(OAc)2 H2O (0.5 equiv), acrylate (2cÀ2i)
3
b
c
a Isolated, overall yields from 2 steps. Isolated pure yields.
(4 equiv), ClCH2CH2Cl (2 mL), 120 °C, 8À24 h. In the case of other
olefins (2jÀ2o), Cu(OAc)2 H2O (1 equiv) was used. b Conversion based
Conversion based on 1H NMR data.
3
on 1H NMR data. c Isolated pure yields.
product 126a obtained by removing the aldehyde group
from 3aa provides a unique opportunity for functionaliza-
tion at a third position, and this indole derivative provides
potential for the synthesis of a variety of indole hetero-
cyclic compounds.18
The CÀH functionalization using a directing group
strategy approach has been demonstrated for synthesizing
4-substituted indoles using the carbonyl oxygen of an
aldehyde as a directing group. This strategy to accomplish
4-substituted indoles isimportant, asthis class ofprivileged
molecules serves as a precursor for ergot alkaloids and related
heterocyclic compounds. To the best of our knowledge, this
is the first report of C-4 alkenylation of indoles using a Ru
catalyst and an aldehyde as a directing group. Further work
on the mechanism, reasons for selectivity, and exploration of
the synthetic scope of this strategy is in progress.
unreacted starting materials (eq 2, Scheme 4). These two
reactions indicate that the directing group ability of the
formyl group is more pronounced than the N-benzoyl group.
Bifunctional molecules such as 4-substituted indoles are
attractive synthetic targets, as they serve as precursors for
the synthesis of alkaloids that are related to the clavine
families and lysergic acid.2,3 One of the key intermediates
for the synthesis of this class of alkaloids is an appro-
priately substituted 1,3,4,5-tetrahydrobenzo[cd] indole
moiety, which is generally synthesized using a multiple
synthetic sequence.17 The potential of the present CÀH
activation strategy using an aldehyde as a directing group
has been demonstrated by synthesizing 10 in just two steps
by using a suitably substituted 1,3,4,5-tetrahydrobenzo[cd]
indole moiety with an overall yield of 68% (Scheme 5). The
reaction of 1-benzyl-1H-indole-3-carbaldehyde 1a with
methyl acrylate 2a was scaled up to the 750 mg scale under
standard reaction conditions to obtain the product 3aa in
68% isolated yield. Further, a selective reduction of the
olefin is also demonstrated using Pd/C at rt to obtain the
product 11 in quantitative yield (98%). Interestingly,
Acknowledgment. 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.
(17) (a) Somei, M.; Yamada, F.; Ohnishi, H.; Makita, Y.; Kuriki, M.
Heterocycl. Chem. 1987, 46, 2823. (b) Oppolzer, W.; Grayson, J .I. Helv.
Chim. Acta 1980, 63, 1706. (c) Kozikowski, A. P.; Chen, Y.-Y.; Wang, B. C.;
Xu, Z.-B. Tetrahedron 1984, 40, 2345. (d) Natsume, M.; Muratake, H.
Heterocycles 1980, 12, 445. (e) Anderson, A. G.; Ko, R. P., Jr. J. Org. Chem.
1984, 49, 4769. (f) Rebek, J.; Shue, H. J. Am. Chem. Soc. 1980, 102, 5426. (g)
Ninomiya, I.; Kiguchi, T.; Naito, T. J. Chem. Soc., Perkin Trans. 1 1980,
208. (h) Genet, J. P.; Grisoni, S. Tetrahedron Lett. 1986, 22, 4165.
(18) Shiri, M. Chem. Rev. 2012, 112, 3508.
Supporting Information Available. Experimental proce-
dures, 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