Ir(I)-catalyzed C-H bond alkylation of C2-position of indole with alkenes: Selective synthesis of linear or branched 2-alkylindoles

Article abstract of DOI:10.1021/ja308742x

A cationic iridium-catalyzed C2-alkylation of N-substituted indole derivatives with various alkenes has been developed, which selectively gives linear or branched 2-alkylindoles in high to excellent selectivity. This protocol relies on the use of the carbonyl group on the nitrogen atom of indole as a directing group: a linear product was predominant when an acetyl group was used as a directing group, and a branched product was predominant with a benzoyl group.

Full text of DOI:10.1021/ja308742x

Communication
pubs.acs.org/JACS
Ir(I)-Catalyzed C−H Bond Alkylation of C2-Position of Indole with
Alkenes: Selective Synthesis of Linear or Branched 2‑Alkylindoles
Shiguang Pan, Naoto Ryu, and Takanori Shibata*
Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Shinjuku, Tokyo,
169-8555, Japan
S
* Supporting Information
appropriate directing group. To this end, free N−H indole
ABSTRACT: A cationic iridium-catalyzed C2-alkylation
of N-substituted indole derivatives with various alkenes has
been developed, which selectively gives linear or branched
2-alkylindoles in high to excellent selectivity. This protocol
relies on the use of the carbonyl group on the nitrogen
atom of indole as a directing group: a linear product was
predominant when an acetyl group was used as a directing
group, and a branched product was predominant with a
benzoyl group.
and a range of N-substituted indoles were subjected to the
reaction with styrene in dioxane in the presence of 10 mol % Ir-
rac-BINAP complex at 135 °C (bath temperature) (Scheme 1).
Scheme 1. Relative Reactivity of N-Substituted Indoles
ndole is an important structural unit and is widely found in
Iheterocyclic compounds with biological and medicinal
applications.1 Thus, the efficient functionalization of indole
derivatives has attracted much attention from both academia
and industry, especially with regard to C−H bond activation
based on transition-metal catalyses.2 In extensive studies using
various metal catalysts over the past decade, regioselective C−
H bond arylation and alkenylation of indole at the C2- and C3-
positions has been reported.3 Regarding the alkylation of indole
derivatives, the C3-alkylation of indole can be achieved by
catalytic methods, such as Friedel−Crafts alkylation, allylic
alkylation, and conjugated addition.4 However, there have been
relatively few studies on the C2-alkylation of indole.5 Although
C2-alkylation of indole can be achieved through C2-lithiation
of N-protected indoles,6 efficient methods for direct C2-
alkylation of indole are rare. Notably, 2-alkylindoles serve as
precursors for a variety of medicinally important alkaloids and
their analogs; for example, 2-(arylethyl)indoles have been used
to create indoleamine 2,3-dioxygenase (IDO) inhibitors.7
Examples of direct C2-alkylation via transition-metal catalyzed
C−H activation are still limited, and only a Pd-catalyzed
example has been recently reported, which underwent a
norbornene-mediated migration of the palladium species from
the C3- to C2-position via C−H bond activation of indole.8
Therefore, the direct C2-alkylation of indole is in high demand.
We report here a regioselective C−H bond alkylation of indole
with alkenes at the C2-position using a cationic Ir catalyst,
which gave linear and branched 2-alkylindoles, respectively, in
high to excellent selectivity depending on the choice of the
directing group and the ligand of the Ir catalyst.
We were delighted to obtain 2-alkylindoles using acetyl and
benzoyl groups as directing groups, which can be removed
under a variety of reaction conditions.10 Interestingly, in the
reaction of N-acetylindole (1b) with styrene, linear 2-
alkylindole was a major product, while, in the reaction of N-
benzoylindole (1d), branched 2-alkylindole was a major
product.11
With two effective directing groups in hand, we next focused
on improving linear/branched selectivity and examined several
diphosphine ligands (Table 1). Initially, an acetyl group was
used as a directing group for the selective formation of linear 2-
alkylindole (entries 1−6). Among the BINAP derivatives,
tolBINAP (L1) and xylylBINAP (L2) realized good yields with
good selectivity; in particular, the ratio reached 90:10 when L2
was used as a ligand (entries 1 and 2). A more bulky BINAP
ligand (L3) showed lower reactivity and worse selectivity (entry
3). When a high combined yield was achieved with SEGPHOS
(L4), the ratio was not improved (entry 4). When DM-
SEGPHOS (L5) was used, the desired products were obtained
in 81% yield in total with a promising ratio (entry 5). With
further optimization, DM-SEGPHOS (L5) gave the products in
92% yield in total and the ratio was improved to 95:5 when 1,2-
dimethoxyethane (DME) was used as a solvent at 75 °C, but a
longer reaction time was required (entry 6). We further used a
benzoyl group as a directing group for the selective formation
of branched 2-alkylindole (entries 7−11). While screening
We have developed cationic iridium-catalyzed reactions
initiated by C−H bond activation.9 Based on the reported
protocols, we studied a cationic Ir-catalyzed direct C2-
alkylation of indole via C−H bond activation. Our preliminary
studies in this area focused on the identification of an
Received: September 3, 2012
Published: October 9, 2012
© 2012 American Chemical Society
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Communication
a
a
Table 1. Optimization of Reaction Conditions
Table 2. Reaction of N-Acetylindoles 1 with Alkenes 2
a
Conditions: indole (0.1 mmol), styrene (0.4 mmol), catalyst (0.01
mmol), ligand (0.01 mmol), dioxane (0.2 mL), at 135 °C (bath
b
temperature), unless otherwise noted. The ratio of linear to branched
c
products was determined by 1H NMR. 1,2-Dimethoxylethane (DME)
a
d
Conditions: acetylindole 1 (0.1 mmol), alkene 2 (0.4 mmol),
was used as solvent, and the bath temperature was 75 °C. 1,1′-
b
e
[Ir(cod)2]BF4 (0.01 mmol), unless otherwise noted. Conditions: A:
(S)-DM-SEGPHOS (L5, 0.01 mmol), DME (0.2 mL), 75 °C (bath
temperature); B: rac-BINAP (0.01 mmol), dioxane (0.2 mL), 135 °C
(bath temperature). The ratio of linear to branched products was
Bis(diphenylphosphino)ferrocene (DPPF). BARF: tetrakis(3,5-bis-
(trifluoromethyl)phenyl)borate.
c
BINAP derivatives did not improve the branched/linear ratio,
DPPF (L6) gave the desired products in excellent yield in total
with good branched selectivity (entry 7). To our delight, SDP
(L7) gave the products in excellent selectivity, albeit in low
yield. As a result of counteranion screening, BARF dramatically
improved the yields, and the branched/linear ratio reached 98:2
(entries 8 and 9). SDP derivatives (L8, L9) were also tested,
but the selectivity did not exceed those with SDP (L7) (entries
10 and 11). Therefore, the reaction of N-acetylindole was
examined under the conditions of entry 6 for the selective
synthesis of linear 2-alkylindole, and that of N-benzoylindole
was examined under the conditions of entry 9 for the selective
synthesis of branched 2-alkylindole.
Subsequently, the scope of N-acetylindoles and styrene
derivatives was examined using an Ir-DM-SEGPHOS catalyst
(condition A) (Table 2). A wide range of substituents could be
used in the reaction, and moderate to good yields and high
selectivity were achieved (entries 1−9). In the reaction of
styrene derivatives with an electron-donating group, the
selectivity of linear to branched products was slightly decreased,
but still high (entries 1−6). The steric effect played an
important role in this reaction, and ortho-bromo-substituted
styrene gave the product 3i in low yield (entry 9). In the
reaction with acrylonitrile (condition B), the Ir-rac-BANAP
catalyst realized perfect linear selectivity along with acceptable
yields (entry 10). Methyl vinyl ketone was also a suitable
substrate for this reaction and afforded the corresponding linear
product 3k with perfect selectivity, albeit in low yield (entry
11). The reaction of ethyl acrylate proceeded smoothly to give
1
determined by H NMR.
the alkylated product 3l in excellent yield with perfect linear
selectivity (entry 12). The scope of substituted N-acetylindole
was investigated by the reaction with ethyl acrylate (entries 13−
16). Notably, perfect linear selectivity was achieved in all cases.
We next investigated the scope of N-benzoylindole and
alkenes (Table 3). A wide variety of substituted styrenes were
used for generation of the corresponding branched 2-
alkylindoles with excellent selectivity (entries 1−5).12 Styrene
that contained a strongly electron-donating group, such as a
methoxy group, gave the desired product in low yield, but the
selectivity was excellent. When DPPF was used as a ligand, the
same reaction gave the product 6b in good yield in 24 h, and
the ratio of branched to linear product reached 96:4 (entries 2
and 3).13 4-Methyl- and 4-chloro-substituted styrenes led to the
corresponding products in respective yields of 86% and 50% in
total, and the branched/linear ratio was excellent (entries 4 and
5). The results indicated that the electron effect plays an
important role in this reaction. The scope of substituted N-
benzoylindole was investigated in the presence of styrene
(entries 6−9). 3-Methyl-N-benzoylindole gave 6e and 7e in a
high combined yield; however, the selectivity of branched and
linear products was poor, probably due to a steric effect (entry
6). 6-Fluoro-N-benzoylindole gave branched product 6f in high
yield with excellent selectivity (entry 7). The reaction of 7-
methyl-N-benzoylindole gave branched product 6g in excellent
selectivity, and DPPF gave the better yield (entries 8 and 9).
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a
Table 3. Reaction of N-Benzoylindoles 5 with Alkenes 2
present conditions. Next, the reactions of 2-deuterated N-
acetylindole-d1 with acrylate and 4-bromostyrene were
examined (eqs 2 and 3). The D contents of the recovered
substrates were different. Moreover, the incorporation of
deuterium at both the α- and β-positions of recovered 4-
bromostyrene was ascertained. These results indicate that C−H
bond cleavage and alkene insertion are reversible.
a
Conditions: benzoylindole 5 (0.1 mmol), alkene 2 (0.4 mmol),
[Ir(cod)2]BARF (0.01 mmol), (R)-SDP (0.01 mmol), dioxane (0.2
b
mL), unless otherwise noted. The ratio of branch to linear product
was determined by H NMR. 1,1′-Bis(diphenylphosphino)ferrocene
(DPPF, 10 mol %) was used as a ligand. Isolated by GPC, the NMR
c
1
d
On the basis of the above labeling experiments, we propose
the following mechanism (Scheme 3). Cleavage of the C−H
yields were described in parentheses.
In the reaction of aliphatic alkenes, the branched product was
predominant regardless of the directing group and the ligand of
the Ir catalyst (Scheme 2). For example, the Ir-BINAP-
Scheme 3. Plausible Reaction Mechanism
Scheme 2. Reaction of N-Substituted Indoles with 1-Nonene
catalyzed reaction of N-acetylindole with 1-nonene (8) gave the
branched product 9 predominantly yet in low yield, because of
low conversion. When a benzoyl group was used as a directing
group, the products (9b/10b) were obtained in high yield with
excellent selectivity under the same reaction conditions. The Ir-
SDP catalyst realized almost perfect branched selectivity, but
the yield was low.
For a preliminary mechanistic study, we used 2-deuterated
N-acetylindole-d1: the reaction was examined in the absence of
alkenes, but in the presence of H2O (eq 1). As a result, the D
content of the recovered substrate was 80%, and H/D exchange
was ascertained. The present result implies that the sp2 C−H
bond at the C2-position of indole was cleaved under the
bond at the C2-position of N-substituted indole gives the
intermediate A.14 Subsequent hydroiridation to alkene provides
intermediates B and/or C.15 Finally, reductive elimination gives
alkylated branched and/or linear products. In the reaction of N-
acetylindole with alkenes, intermediate C is more favorable
than intermediate B. In contrast, with N-benzoylindole,
intermediate B is more favorable.
In conclusion, we have developed a cationic Ir(I)-catalyzed
direct C2-alkylation of N-substituted indoles with alkenes via
C−H bond functionalization, which selectively gives linear or
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intramolecular reaction, see: (b) Baran, P. S.; Corey, E. J. J. Am.
Chem. Soc. 2002, 124, 7904. (c) Baran, P. S.; Guerrero, C. A.; Corey,
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branched 2-alkylindole in high to excellent selectivity. The
selectivity of linear or branched product was controlled by the
directing group and ligand. The present results constitute a new
example of C2-alkylation of indoles. Further studies on the
scope of the substrates, applications, and the precise
mechanism are underway in our laboratory.
(6) The direct C2-functionalization of indole can be achieved
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P. C.; Lamb, P.; Forcier, P.; Bryan, R. F. J. Org. Chem. 1978, 43, 4859.
(c) Mohan, B.; Nagarathnam, D.; Vedachalam, M.; Srinivasan, P. C.
Synthesis 1985, 188. (d) Hashimato, C.; Husson, H.-P. Tetrahedron
ASSOCIATED CONTENT
* Supporting Information
■
S
The experimental procedure, NMR experiments, and physical
properties of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
tshibata@waseda.jp
■
Lett. 1988, 29, 4563. (e) Dolusi
F.; Norberg, B.; Moineaux, L.; Colette, D.; Stroobant, V.; Pilotte, L.;
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c, E.; Larrieu, P.; Blanc, S.; Sapunaric,
Notes
̀
The authors declare no competing financial interest.
́
́
ACKNOWLEDGMENTS
■
(8) (a) Jiao, L.; Bach, T. J. Am. Chem. Soc. 2011, 133, 12990. (b) Jiao,
L.; Herdtweck, E.; Bach, T. J. Am. Chem. Soc. 2012, 134, 14563.
(9) (a) Tsuchikama, K.; Kasagawa, M.; Hashimoto, Y.; Endo, K.;
Shibata, T. J. Organomet. Chem. 2008, 693, 3939. (b) Tsuchikama, K.;
Hashimoto, Y.; Endo, K.; Shibata, T. Adv. Synth. Catal. 2009, 351,
2850. (c) Tsuchikama, K.; Kasagawa, M.; Endo, K.; Shibata, T. Org.
Lett. 2009, 11, 1821. (d) Tsuchikama, K.; Kasagawa, M.; Endo, K.;
Shibata, T. Synlett 2010, 97. (e) Shibata, T.; Hashimoto, Y.; Otsuka,
M.; Tsuchikama, K.; Endo, K. Synlett 2011, 2075. (f) Shibata, T.;
Hirashima, H.; Kasagawa, M.; Tsuchikama, K.; Endo, K. Synlett 2011,
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(h) Takebayashi, S.; Shibata, T. Organometallics 2012, 31, 4114.
(i) Pan, S.; Matsuo, Y.; Endo, K.; Shibata, T. Tetrahedron 2012, 68,
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(10) The removal of acetyl group: (a) Hanessian, S. Tetrahedron. Lett.
1967, 8, 1549. (b) Dilbeck, G. A.; Field, L.; Gallo, A. A.; Gargiulo, R. J.
J. Org. Chem. 1978, 43, 4593. (c) Keith, D. D.; Tortora, J. A.; Yang, R.
J. Org. Chem. 1978, 43, 3711. The removal of benzoyl group: (d) Ben-
Ishai, D.; Altman, J.; Peled, N. Tetrahedron 1977, 33, 2715. (e) Hughes,
P.; Clardy, J. J. Org. Chem. 1988, 53, 4793. (f) Boger, D. L.; Machiya,
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(11) Further screening of N-substituted indole was shown in the
Supporting Information.
(12) The enantiomeric excess of the branched product 6a was
moderate (42%) by using (R)-SDP as a chiral ligand. Further
improvement of the selectivity is the next project.
(13) The Ir-DPPF catalyst generally realized a high yield and
branched selectivity. The results were listed in the Supporting
Information.
(14) By the stoichiometric reaction of N-acetylindole (1b) with Ir-
rac-BINAP in an NMR tube, a small peak for M−H (−20.13 ppm)
was observed by 1H NMR, but the intermediate could not be
characterized yet.
This work was supported by the Grant-in-Aid for Scientific
Research on Innovative Areas, “Molecular Activation Directed
toward Straightforward Synthesis,” MEXT, Japan, and Global
COE program “Practical Chemical Wisdom,” Waseda Uni-
versity, Japan.
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