Pyrroloindolone synthesis via a Cp*CoIII-catalyzed redox-neutral directed C-H alkenylation/annulation sequence

Article abstract of DOI:10.1021/ja5008432

A unique synthetic utility of a Cp*Co^III catalyst in comparison with related Cp*Rh^III catalysts is described. A C2-selective indole alkenylation/annulation sequence proceeded smoothly with catalytic amount of a [Cp*Co^III(C₆H ₆)](PF₆)₂ complex and KOAc. Intramolecular addition of an alkenyl-Cp*Co species to a carbamoyl moiety gave pyrroloindolones in 58-89% yield in one pot. Clear difference was observed between the catalytic activity of the Cp*Co^III complex and those of Cp*Rh^III complexes, highlighting the unique nucleophilic activity of the organocobalt species. The Cp*Co^III catalysis was also suitable for simple alkenylation process of N-carbamoyl indoles, and broad range of alkynes, including terminal alkynes, were applicable to give C2-alkenylated indoles in 50-99% yield. Mechanistic studies on C-H activation step under Cp*Co^III catalysis with the aid of an acetate unit as well as evaluation of the difference between organo-Co ^III species and organo-Rh^III species are also described.

Full text of DOI:10.1021/ja5008432

Article
pubs.acs.org/JACS
Pyrroloindolone Synthesis via a Cp*CoIII-Catalyzed Redox-Neutral
Directed C−H Alkenylation/Annulation Sequence
Hideya Ikemoto,† Tatsuhiko Yoshino,† Ken Sakata,‡,§ Shigeki Matsunaga,*,†,§ and Motomu Kanai*,†
†Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
‡Faculty of Pharmaceutical Sciences, Hoshi University, Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
§ACT-C, Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
ABSTRACT: A unique synthetic utility of a Cp*CoIII catalyst in
comparison with related Cp*RhIII catalysts is described. A C2-
selective indole alkenylation/annulation sequence proceeded
smoothly with catalytic amount of a [Cp*CoIII(C6H6)](PF6)2
complex and KOAc. Intramolecular addition of an alkenyl-
Cp*Co species to a carbamoyl moiety gave pyrroloindolones in
58−89% yield in one pot. Clear difference was observed between
the catalytic activity of the Cp*CoIII complex and those of
Cp*RhIII complexes, highlighting the unique nucleophilic activity
of the organocobalt species. The Cp*CoIII catalysis was also
suitable for simple alkenylation process of N-carbamoyl indoles,
and broad range of alkynes, including terminal alkynes, were applicable to give C2-alkenylated indoles in 50−99% yield.
Mechanistic studies on C−H activation step under Cp*CoIII catalysis with the aid of an acetate unit as well as evaluation of the
difference between organo-CoIII species and organo-RhIII species are also described.
1. INTRODUCTION
Transition metal-catalyzed direct C−H bond functionalization
has emerged as a powerful synthetic methodology.1 Catalytic
C−H bond functionalization processes do not require
preactivated substrates such as haloarenes and stoichiometric
amounts of organometallic reagents, and thus the process has
become an increasingly viable alternative to traditional cross-
coupling processes. The indole skeleton is an attractive
platform for developing regioselective C−H bond functional-
ization reactions because of its utility in the design and
synthesis of biologically active compounds.2 Tremendous
efforts have been focused on these reactions over the last
several years, leading to a variety of transition metal-catalyzed
direct C−H arylation,3 alkylation,4 oxidative alkenylation,5 and
redox-neutral direct alkenylation6−8 processes of indoles. On
the other hand, applications of the indole C−H functionaliza-
tion process to cascade reactions, providing access to more
functionalized N-fused indole cores, have been rare.9 Among N-
Figure 1. Biologically active natural and unnatural compounds bearing
a pyrrolo[1,2-a]indole core.
fused indole cores, a pyrrolo[1,2-a]indole bearing a 6−5−5
tricyclic skeleton is an important structural motif found in many
As a part of our ongoing research projects on first-row
biologically active natural products and pharmaceuticals, such
as antitumor mitomycin C, antimalarial flinderole B, anti-
transition metal catalysis,11,12 we recently demonstrated the
utility of a cationic high valent Cp*CoIII complex,
nociceptive melatonin analogues, and psychotropic compounds
[Cp*CoIII(C6H6)](PF6)2 (Cp*Co-1a), in C−H bond function-
alization processes.13 The nucleophilicity of the aryl-Co species
generated in situ via C−H bond activation featured the
(Figure 1).10 Thus, methods for efficiently providing a
pyrrolo[1,2-a]indole unit from readily available starting
materials via a C−H activation process are in great demand.
Here, we describe the C2-selective C−H alkenylation/
annulation cascade of N-carbamoyl indoles to afford
pyrroloindolones in one-pot.
Received: January 25, 2014
Published: March 20, 2014
© 2014 American Chemical Society
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Cp*CoIII catalysis, enabling nucleophilic addition to polar
electrophiles such as imines and enones. Previous reports from
our group, however, just demonstrated that the Cp*CoIII
catalyst could promote the reactions already established with
Cp*RhIII catalysts.14 To further expand the utility of the
Cp*CoIII catalysis, we explored a unique reaction in which only
the Cp*CoIII catalyst could efficiently promote the reaction. On
the basis of the large difference in electronegativity between Co
and Rh, we envisioned that the alkenyl-Cp*CoIII species,
generated via C2-selective C−H activation of indoles followed
by insertion to alkyne, would be nucleophilic enough to react
with an even less electrophilic N-carbamoyl directing
group,15,16 giving pyrroloindolones in one pot (Scheme 1;
this work). By adjusting the reaction conditions, Cp*CoIII also
successfully gave simply C2-alkenylated indoles from broad
range of alkynes, including terminal alkynes.
Table 1. Optimization of the Alkenylation/Annulation
Sequence
Scheme 1. (a) Previous Works: C2-Alkenylation of Indoles
and (b) This Work: C2-Alkenylation/Annulation Sequence
for Pyrroloindolone Synthesis
a
Determined by 1H NMR analysis of the crude reaction mixture using
1,1,2,2-tetrachloroethane as an internal standard unless otherwise
b
noted. Isolated yield after purification by silica gel column
c
chromatography. Regioisomeric ratio (rr) of 5 was 17:1. Number in
parentheses is the isolated yield of pure 4a (single regioisomer) after
purification by silica gel column chromatography.
2. RESULTS AND DISCUSSION
2.1. Cp*CoIII-Catalyzed Pyrroloindolone Synthesis.
Optimization studies toward pyrroloindolone synthesis are
summarized in Table 1. No reaction of N-dimethylcarbamoyl
indole 2a with alkyne 3a was promoted by 5 mol % of Cp*Co-
1a alone at 80 °C (entry 1), while simply alkenylated product
5aa was obtained in 90% yield in the presence of KOAc (10
mol %, entry 2). Desired pyrroloindolone 4a, however, was not
obtained at 80 °C. At 120 °C, the desired annulation proceeded
to give 4a in 22% yield (entry 3), together with 5aa (41%
yield). Increasing the amount of KOAc improved the yield of
4a (33%), but 5aa was still obtained as a major product (entry
4). As shown in eq 1, 4a was not obtained when treating 5aa
under identical reaction conditions (120 °C, with 5 mol % of
Cp*Co-1a, 20 mol % KOAc). The result suggested that 4a was
obtained directly from the alkenyl-Cp*CoIII intermediate via an
intramolecular nucleophilic addition, while 5aa was obtained
via irreversible proto-demetalation. The concentration of the
reaction was important to decelerate the intermolecular
protonation pathway (entries 4−6), and 4a was obtained in
61% yield at 0.1 M (entry 6). As shown in entries 7−9, Cp*Rh-
1b was not suitable for the desired alkenylation/annulation
sequence. Under the Fagnou’s conditions optimized for
alkenylation with 5 equiv of PivOH,6 5aa was obtained in
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a
Table 2. Pyrroloindolone Synthesis via Cp*Co-Catalyzed C−H Alkenylation/Annulation
b
entry
X
2
R1
R2
3
4
% yield
1
H
H
H
H
H
H
H
H
H
H
H
H
2e
2e
2e
2e
2e
2e
2e
2e
2e
2e
2e
2e
2f
Me
Me
Me
Me
Me
Me
Me
Me
Et
Ph
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
78
75
89
77
68
63
89
73
71
78
72
58
83
78
88
85
73
61
75
82
72
2
4-Me-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-Br-C6H4
4-CO2Et-C6H4
2-naphthyl
6-MeO-naphth-2-yl
Ph
3
4
5
6
7
3g
3h
3i
4g
4h
4i
8
9
10
11
12
13
14
15
16
17
18
n-Bu
Ph
1-thienyl
Ph
3j
4j
3k
3l
4k
4l
4-Br-C6H4
4-Br-C6H4
2-naphthyl
2-naphthyl
2-naphthyl
2-naphthyl
2-naphthyl
2-naphthyl
Ph
4-Me
5-Me
5-MeO
5-Cl
5-Br
5-CO2Me
H
Me
3g
3g
3g
3g
3g
3g
3m
3n
3o
3p
3q
4m
4n
4o
4p
4q
4r
2g
2h
2i
Me
Me
Me
2j
Me
2k
2e
2e
2e
2e
2e
Me
c
d
e
−
19
BnO2C(CH2)3
4s
4t
−
20
21
22
23
H
TBDPSO(CH2)3
Ph
H
Ph
Et
H
4-CO2Et-C6H4
Et
4u
4v
4w
f
H
0
f
H
4-Br-C6H4
0
a
Reaction was run using 2 (1.5 equiv), 3 (0.20 mmol), [Cp*Co(C6H6)](PF6)2 (5 mol %), KOAc (20 mol %) in 1,2-dichloroethane (0.1 M) under
b
c
Ar at 130 °C unless otherwise noted. Isolated yield of pure 4 (single regioisomer) after purification by silica gel column chromatography. Reaction
was run at 160 °C using [Cp*Co(C6H6)](PF6)2 (10 mol %) and KOAc (40 mol %). Isolated yield of 4s and its regioisomer (r.r. = 18:1). Isolated
yield of 4u and its regioisomer (r.r. = 1:1.2). Simply alkenylated products were obtained.
d
e
f
excellent yield, but annulation adduct 4a was obtained in less
than 1% (entry 7). We also attempted reactions with Cp*Rh-1b
in the presence of either KOAc or CsOPiv, but none of them
produced the desired 4a (entries 8−9). To further accelerate
the desired alkenylation/annulation pathway over the undesired
alkenylation/protonation pathway, the N-carbamoyl group was
modified (entries 10−13), and the best yield of 4a was obtained
with N-carbamoyl indole 2e bearing a morpholine unit (entry
13, 73%). To reconfirm that the present alkenylation/
annulation sequence is a characteristic process under the
Cp*CoIII catalysis, we again attempted the reaction of indole 2e
with Cp*Rh-1b, and only trace if any 4a was obtained (entries
14−16). To exclude the possible adverse effects of acetonitrile
in Cp*Rh-1b as well as different counterions, we additionally
attempted to use [Cp*RhCl2]2 with AgPF6 (Cp*Rh-1c), but
still desired 4a was not obtained (entries 17−19). Finally, 4a
was obtained in 82% (78% isolated yield) from 2e at 130 °C
after 20 h (entry 20) under Cp*Co-1a catalysis.
Both electron-donating and electron-withdrawing substituents
were compatible, and various 4- or 5-substituted indoles
showed good reactivity. In entries 1−10 and 13−18, each
annulation adduct was obtained as a single isomer. A minor
regioisomer of the alkenyl-Cp*CoIII intermediate was predom-
inantly protonated to afford alkenylated adduct 5 in each entry
(<10%). The alkenylation/annulation sequence proceeded
even with a functionalized alkyne 3m and 3n bearing either
an ester unit or a silyl ether unit, giving 4s and 4t in 75% yield
(18:1 regioisomeric ratio, entry 19) and 82% yield (single
isomer, entry 20). With unsymmetrical diaryl-alkyne 3o, the
annulation adduct 4u was obtained, but in poor regioisomeric
ratio (entry 21). Annulation adducts, however, were not
obtained from dialkyl-substituted alkynes and terminal alkynes,
because protonation of the alkenyl-Cp*CoIII intermediate
preferentially gave simply alkenylated products 5 (entries 22
and 23).
To demonstrate the synthetic utility of the present reaction,
we transformed pyrroloindolones, as summarized in Scheme 2.
Removal of the benzyl group in 4s (95%) followed by
activation of the carboxylic acid gave N-fused indole 6 bearing a
6−5−5−6 tetracyclic skeleton (57%). Hydrogenation of 4a
with Pt/C gave cis-substituted pyrroloindolone 7 in 79% yield.
The optimal reaction conditions were then applied to various
alkynes and indoles as summarized in Table 2. The
alkenylation/annulation sequence of indole 2e proceeded well
with various aryl/alkyl- and diaryl-substituted alkynes (entries
1−12). The scope of indole is summarized in entries 13−18.
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Ring-opening of the pyrroloindolone core was also readily
performed, and fully substituted α,β-unsaturated amide 8 was
obtained in 93% yield from 4a.
Scheme 2. Transformation of Pyrroloindolones
2.2. Cp*CoIII-Catalyzed C2-Alkenylation of Indoles.
Because simple C−H alkenylation also proceeded smoothly
under the reaction conditions in entry 2 of Table 1 (90% yield),
the substrate scope of the redox-neutral C−H alkenylation was
investigated in detail to compare the potential for Cp*CoIII
catalysis with previous examples using either the Cp*RhIII or
low valent Co-catalysis (see Scheme 1).6,7 As summarized in
Table 3, the scope of applicable alkynes was broad. Not only
aryl/alkyl- and diaryl-substituted alkynes (entries 1−8), but also
dialkyl-substituted alkynes (entries 9−16) gave the products in
good yield. Terminal alkynes are often rather difficult substrates
in hydroarylation reactions because of their relatively acidic
protons and problematic self-di- or trimerization under
transition metal catalysis. It is, therefore, noteworthy that
alkenylation proceeded even with terminal alkynes, giving
products in 68−78% yield with a >30:1 regioisomeric ratio
(entries 17−20).17 Limitations of the present system are shown
in entries 21−23. Sterically hinderd alkynes such as 3t and 3u
gave only trace, if any, products (entries 21 and 22).
a
Table 3. Cp*Co-Catalyzed C−H Alkenylation of Indoles
b
c
entry
X
2
R1
R2
3
5
r.r.
% yield
1
H
H
H
H
H
H
H
H
H
H
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2l
Me
Me
Me
Me
Me
Me
Et
Ph
3a
3b
3c
3d
3e
3f
5aa
5ab
5ac
5ad
5ae
5af
17:1
14:1
15:1
15:1
14:1
17:1
10:1
−
−
−
−
−
−
−
−
−
>30:1
>30:1
>30:1
>30:1
−
90
71
50
84
96
88
90
83
93
97
99
92
99
96
92
93
73
68
73
78
0
2
4-Me-C6H4
3
4-MeO-C6H4
4
4-Cl-C6H4
5
4-Br-C6H4
6
4-CO2Et-C6H4
7
Ph
3i
5ai
8
4-Br-C6H4
4-Br-C6H4
3l
5al
9
Et
Pr
Pr
Pr
Pr
Pr
Pr
Pr
H
Et
3p
3r
3r
3r
3r
3r
3r
3r
3q
3s
3q
3q
3t
5ap
5ar
5lr
10
11
12
13
14
15
16
Pr
5-Me
5-MeO
5-BnO
5-Cl
5-Br
5-CO2Me
H
Pr
2m
2n
2o
2p
2q
2a
2a
2l
Pr
5mr
5nr
5or
5pr
5qr
5aq
5as
5lq
5oq
5at
5au
5av
Pr
Pr
Pr
Pr
d
17
4-Br-C6H4
Ph
de
,
18
19
20
21
22
23
H
H
d
d
5-Me
5-Cl
H
H
4-Br-C6H4
4-Br-C6H4
Ph
2o
2a
2a
2a
H
TMS
iPr
Pr
H
Me
3u
3v
−
1.2:1
trace
90
H
Me
a
Reaction was run using 2 (1.5 equiv), 3 (0.30 mmol), [Cp*Co(C6H6)](PF6)2 1a (5 mol %), and KOAc (10 mol %) in 1,2-dichloroethane (0.5 M)
b
c
at 80 °C under Ar unless otherwise noted. Determined by 1H NMR analysis of the crude reaction mixture. Isolated yield after purification by silica
gel column chromatography was shown for each entry. Reaction was run at 130 °C in 0.15 M. Reaction was run using 2 equiv of 2a,
[Cp*Co(C6H6)](PF6)2 1a (10 mol %), and KOAc (20 mol %).
d
e
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Unsymmetrical dialkyl-alkyne 3v gave product in 90% yield, but
in poor regioisomeric ratio (1:1.2, entry 23).
Table 4. Negative Control Experiments
2.3. Mechanistic Studies. In the present reaction, the
Cp*CoIII-1a promoted the alkenylation/annulation sequence,
while the Cp*RhIII-1b and Cp*RhIII-1c promoted only the
alkenylation. We initially hypothesized that the carbon−metal
bond of the alkenyl-Cp*CoIII species would be more polarized
than that of the Cp*RhIII species, and thus be more
nucleophilic to react well, even with a poorly electrophilic
carbamoyl group.15 To evaluate the difference between the
postulated alkenyl-Cp*CoIII species and the alkenyl-Cp*RhIII
species, we tried to isolate the key intermediate but failed.
Thus, we instead isolated more stable cobaltacyclic aryl-
Cp*CoIII species derived from 2-phenylpyridine (Figure 2),
a
entry
cobalt source
additive
KOAc
% yield
1
2
3
4
5
6
7
8
none
0
CoII(OAc)2
none
0
CoIICl2
AgPF6 + KOAc
KOAc
0
CoIII(acac)3
0
[CoIII(NH3)6]Cl3
[Cp*CoIII(C6H6)](PF6)2
[Cp*CoIII(C6H6)](PF6)2
[Cp*CoIII(C6H6)](PF6)2
KOAc
0
LiOAc
0
NaOAc
57
CsOAc
66
a
Determined by 1H NMR analysis of the crude reaction mixture using
dibenzylether as an internal standard.
Scheme 3. H/D Exchange Experiments (a) with Cp*CoIII-1a
+ KOAc, (b) with Cp*CoIII-1a Alone, and (c) with Sc(OTf)3
Figure 2. ORTEP of cobaltacyclic compound derived from 2-
phenylpyridine.
because a corresponding aryl-Cp*RhIII species has already been
fully characterized.18 Each atomic charge was then estimated by
natural population analysis.19 As shown in Figure 3, the C−
catalysis in the presence of KOAc, the site-selective H/D
exchange occurred at the C2-position of the indole (41% D),
and no detectable deuterium incorporation was observed at the
C3-position (a). In contrast, the Cp*Co-1a alone selectively
promoted H/D exchange at the C3-position (b, 41% D). The
tendency in Scheme 3b was similar with that with a simple
Lewis acid, such as Sc(OTf)3, which also preferably promoted
H/D exchange at the C3-position (c, 60% D). These results
supported the mechanism that reversible C2-selective C−H
activation and metalation occurred under the Cp*CoIII catalysis
with the aid of acetate moiety.
The key role of an acetate unit in C−H activation step was
supported by DFT calculations with Gaussian0920 (B3LYP/6-
31G**)21 as shown in Figure 4. Previous theoretical studies
showed the importance of an acetate unit in the C−H
activation with IrIII, RhIII, and PdII complexes.22,23 Among some
conformations examined for the complex [Cp*CoIII(κ2-OAc)-
(2a)]+, the singlet-state structure 1A, in which the oxygen atom
of a carbamoyl group coordinates to the Co atom, is in the
Figure 3. Atomic charge of aryl-Cp*CoIII species and aryl-Cp*RhIII
species estimated by natural population analysis (B3LYP/6-31LAN).
CoIII bond in the cobaltacycle was more polarized than the C−
RhIII bond in the rhodacycle. Thus, we assume, by analogy, the
similar difference in carbon−metal bond between the alkenyl-
Cp*CoIII species and that of Cp*RhIII.
As to the alkenylation process, KOAc was important to
promote the reaction (Table 1, entry 1 vs entry 2). Several
negative control experiments either without cobalt salt or with
different cobalt sources (Table 4, entries 1−5) indicated that
the cationic CoIII was essential to promote the reaction. On the
other hand, potassium ion was not essential because other
metal acetates were somewhat effective to promote the
alkenylation (entries 6−8). To gain insight into the reaction
mechanism, H/D exchange experiments were performed in the
presence of CD3OD (Scheme 3a−c). Under the Cp*CoIII
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Figure 4. Relative Gibbs free-energy diagram (298.15 K) for acetate-assisted C−H activation pathways with the Cp*CoIII-catalyst (kcal/mol).
lowest Gibbs free energy at 298.15 K (see the Supporting
1
Information). The cleavage of a Co−O(acetate) bond in A
gives the structure of κ1-complex [Cp*CoIII(κ1-OAc)(2a)]+, 1B,
1
1
via the transition state TS(A−B). In B, weak interaction
between the C2 atom at indole and the Co atom exists (the
distance is 2.345 Å). After the transformation of 1B to the other
conformation of κ1-complex 1C, the abstraction of the hydrogen
atom at the C2-position by the oxygen atom at acetate and the
formation of the C−Co bond simultaneously occur through the
six-membered transition state 1TS(C−D) to afford the complex
1D. The bond distance between the C2 atom at indole and the
1
Co atom is 1.932 Å in D. Thus, there are three transition
1
1
states, TS(A−B) (ΔG = 18.9 kcal/mol), TS(B−C) (ΔG =
1
20.5 kcal/mol), and TS(C−D) (ΔG = 19.4 kcal/mol), and
1
1
two intermediates, B and C, along the singlet-state acetate-
assisted pathway from 1A to 1D, and the reaction step is
endothermic by 12.0 kcal/mol. The four-membered transition
1
state, TS(B−F), has much higher free energy (ΔG = 36.5
kcal/mol).22a,b
3
On the other hand, the triplet-state structure A is located
slightly higher, 1.0 kcal/mol, than the singlet structure A. In
1
the case of triplet state, the hydrogen atom at the C2-position
in 3A is directly transferred into the oxygen atom at acetate via
3
the six-membered transition state TS(A−D) to afford the
complex 3D. The relative free energy of 3TS(A−D) (20.9 kcal/
mol) is almost the same as those of the transition states in the
singlet-state pathway. The four-membered transition state
3TS(A−E) has also higher free energy (ΔG = 39.8 kcal/
mol), and the oxidative addition of Co−H bond in the complex
[Cp*CoIII(κ2-OAc)(2a)]+ was not found. Therefore, the
acetate-assisted C−H bond activation step goes through the
six-membered transition states in both singlet and triplet states.
A plausible catalytic cycle with a Cp*CoIII complex in the
presence of KOAc is shown in Figure 5. As the initial step,
thermal dissociation of the benzene ligand of [Cp*Co(C6H6)]-
(PF6)2 as well as ligand exchange to acetate (or substrate)
would generate catalytically active monocationic species I, in
equilibrium with a resting neutral diacetate complex. After
coordination of the carbamoyl group of indole 2 (II),
regioselective C−H metalation at the C2-position would
Figure 5. Postulated catalytic cycle.
occur via a concerted metalation−deprotonation mechanism23
to afford indolyl-Co species III. Insertion of alkyne 3 then
generates the key alkenyl-Co intermediate (IV). Annulation
(V) followed by release of morpholine gives product 4. On the
other hand, proto-demetalation of IV with AcOH gives product
5 and regenerates the active species I.
3. CONCLUSION
In summary, we demonstrated the characteristic reactivity of a
Cp*CoIII catalyst compared with related Cp*RhIII catalysts.
The C2-selective indole alkenylation/annulation sequence
proceeded smoothly in the presence of [Cp*CoIII(C6H6)]-
(PF6)2 and KOAc, giving pyrroloindolones in 58−89% yield.24
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(k) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008,
130, 8172. (l) Ackermann, L.; Lygin, A. V. Org. Lett. 2011, 13, 3332.
(m) Qin, X.; Liu, H.; Qin, D.; Wu, Q.; You, J.; Zhao, D.; Guo, Q.;
Huang, X.; Lan, J. Chem. Sci. 2013, 4, 1964.
(4) Alkylation using alkenes: (a) Pan, S.; Ryu, N.; Shibata, T. J. Am.
Chem. Soc. 2012, 134, 17474. Alkylation using alkyl halides: (b) Jiao,
L.; Bach, T. J. Am. Chem. Soc. 2011, 133, 12990. (c) Jiao, L.;
Herdtweck, E.; Bach, T. J. Am. Chem. Soc. 2012, 134, 14563. For
related C−C bond formation at C2-position, see: (d) Zhou, B.; Yang,
Y.; Li, Y. Chem. Commun. 2012, 48, 5163. (e) Zhou, B.; Yang, Y.; Lin,
S.; Li, Y. Adv. Synth. Catal. 2013, 355, 360.
The clear difference in the catalytic activity between the
Cp*CoIII complex and Cp*RhIII complexes highlighted the
unique nucleophilic activity of the organocobalt species. The
Cp*CoIII catalysis was also suitable for simple alkenylation
process, and broad range of alkynes including terminal alkynes
were applicable to give alkenylated products in 50−99% yield.
Further studies to apply the unique properties of first-row
transition metal catalysis to other reactions are ongoing.
ASSOCIATED CONTENT
■
(5) C2-selective oxidative Heck reactions of indoles: (a) Capito, E.;
Brown, J. M.; Ricci, A. Chem. Commun. 2005, 1854. (b) Grimster, N.
P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed.
2005, 44, 3125. (c) Maehara, A.; Tsurugi, H.; Satoh, T.; Miura, M.
S
* Supporting Information
Experimetal details, including procedures, syntheses and
characterization of new products, H and 13C NMR charts,
1
CIF, and computational details for supporting mechanism. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Org. Lett. 2008, 10, 1159. (d) García-Rubia, A.; Gom
Carretero, J. C. Angew. Chem., Int. Ed. 2009, 48, 6511. (e) García-
Rubia, A.; Urones, B.; Gomez Arrayas
́ ́
ez Arrayas, R.;
́
́
, R.; Carretero, J. C. Chem.Eur.
J. 2010, 16, 9676. (f) Lanke, V.; Ramaiah Prabhu, K. Org. Lett. 2013,
15, 2818. (g) Li, B.; Ma, J.; Xie, W.; Song, H.; Xu, S.; Wang, B.
Chem.Eur. J. 2013, 19, 11863. (h) Gong, B.; Shi, J.; Wang, X.; Yan,
Y.; Li, Q.; Meng, Y.; Xu, H. E.; Yi, W. Adv. Synth. Catal. 2014, 356,
137.
AUTHOR INFORMATION
Corresponding Author
smatsuna@mol.f.u-tokyo.ac.jp; kanai@mol.f.u-tokyo.ac.jp
■
(6) Cp*RhIII-catalyzed alkenylation using alkynes: Schipper, D. J.;
Hutchinson, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 6910.
(7) Low valent Co-catalyzed alkenylation using alkynes: Ding, Z.;
Yoshikai, N. Angew. Chem., Int. Ed. 2012, 51, 4698.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(8) For selected examples of C-2 alkenylation of 3-substituted
indoles, see: (a) Nakao, Y.; Kanyiva, K. S.; Oda, S.; Hiyama, T. J. Am.
Chem. Soc. 2006, 128, 8146. (b) Kuninobu, Y.; Kikuchi, K.; Tokunaga,
Y.; Nishina, Y.; Takai, K. Tetrahedron 2008, 64, 5974. (c) Gao, R.; Yi,
C. S. J. Org. Chem. 2010, 75, 3144.
(9) Transition metal-catalyzed N-fused indole synthesis via C−H
activation: (a) Lopez Suarez, L.; Greaney, M. F. Chem. Comm. 2011,
47, 7992. (b) Kandukuri, S. R.; Schiffner, J. A.; Oestreich, M. Angew.
Chem., Int. Ed. 2012, 51, 1265. (c) Davis, T. A.; Hyster, T. K.; Rovis, T.
Angew. Chem., Int. Ed. 2013, 52, 14181.
(10) (a) Galm, U.; Hager, M. H.; Van Lanen, S. G.; Ju, J.; Thorson, J.
S.; Shen, B. Chem. Rev. 2005, 105, 739. (b) Fernandez, L. S.;
Buchanan, M. S.; Carroll, A. R.; Feng, Y. J.; Quinn, R. J.; Avery, V. M.
Org. Lett. 2009, 11, 329. (c) Elmegeed, G. A.; Baiuomy, A. R.; Abdel-
Salam, O. M. E. Eur. J. Med. Chem. 2007, 42, 1285. (d) Protter, A. A.;
Chakravarty, S. Patent, WO2012/112961A1, 2012.
(11) Review on the first-row transition metal-catalyzed C−H bond
activation/C−C bond formation: (a) Kulkarni, A. A.; Daugulis, O.
Synthesis 2009, 4087. (b) Yoshikai, N. Synlett 2011, 1047.
We thank Dr. Sato at RIGAKU for assistance in X-ray analysis.
This work was supported in part by ACT-C program from JST
(K.S. & S.M.), Grant-in-Aid for Scientific Research on
Innovative Areas “Molecular Activation Directed toward
Straightforward Synthesis” from MEXT and Naito Foundation
(S.M.). T.Y. thanks JSPS for fellowships.
REFERENCES
■
(1) Recent reviews on C−H bond functionalization: (a) C−H
Activation. In Topics in Current Chemistry; Yu, J.-Q., Shi, Z.-J., Eds.;
Springer: Berlin, 2010; Vol. 292. (b) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. Rev. 2010, 110, 624. (c) Mkhalid, I. A. I.; Barnard,
J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010,
110, 890. (d) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(e) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev.
̈
2011, 40, 4740. (f) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem.
Soc. Rev. 2011, 40, 5068. (g) Ackermann, L. Chem. Rev. 2011, 111,
1315. (h) Zhu, C.; Wang, R.; Falck, J. R. Chem.Asian J. 2012, 7,
1502. (i) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F.
Angew. Chem., Int. Ed. 2012, 51, 10236. (j) Engle, K. M.; Mei, T.-S.;
Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (k) Yamaguchi, J.;
Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960.
(l) Li, B.-J.; Shi, Z.-J. Chem. Soc. Rev. 2012, 41, 5588. (m) Beatrice
Arockiam, P.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879.
(n) Wencel-Delord, J.; Glorius, F. Nature Chem. 2013, 5, 369.
(o) Rouquet, G.; Chatani, N. Angew. Chem., Int. Ed. 2013, 52, 11726.
(2) A review on C−H functionalization of indoles: Cacchi, S.; Fabrizi,
G. Chem. Rev. 2011, 111, PR215.
(12) Low-valent cobalt catalysts have been intensively investigated
for C−H functionalization reactions. For selected examples, see:
(a) Gao, K.; Lee, P.-S.; Fujita, T.; Yoshikai, N. J. Am. Chem. Soc. 2010,
132, 12249. (b) Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2011, 133, 400.
(c) Chen, Q.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2011, 133, 428.
(d) Li, B.; Wu, Z.-H.; Gu, Y.-F.; Sun, C.-L.; Wang, B.-Q.; Shi, Z.-J.
Angew. Chem., Int. Ed. 2011, 50, 1109. (e) Song, W.; Ackermann, L.
Angew. Chem., Int. Ed. 2012, 51, 8251. (f) Andou, T.; Saga, Y.; Komai,
H.; Matsunaga, S.; Kanai, M. Angew. Chem., Int. Ed. 2013, 52, 3213.
(13) (a) Yoshino, T.; Ikemoto, H.; Matsunaga, S.; Kanai, M. Angew.
Chem., Int. Ed. 2013, 52, 2207. (b) Yoshino, T.; Ikemoto, H.;
Matsunaga, S.; Kanai, M. Chem.Eur. J. 2013, 19, 9142.
(3) Reviews for C−H arylation of indoles: (a) Beck, E. M.; Gaunt, M.
J. In Topics in Current Chemistry; Yu, J.-Q., Shi, Z.-J., Eds.; Springer:
Berlin, 2010; Vol. 292, pp 85−121. (b) Seregin, I. V.; Gevorgyan, V.
Chem. Soc. Rev. 2007, 36, 1173. (c) Joucla, L.; Djakovitch, L. Adv.
Synth. Catal. 2009, 351, 673. Selected examples of C2-selective
arylation: (d) Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897.
(e) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127,
4996. (f) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005,
127, 8050. (g) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J.
(14) Reviews on Cp*RhIII catalysis: (a) Satoh, T.; Miura, M.
Chem.Eur. J. 2010, 16, 11212. (b) Patureau, F. W.; Wencel-Delord,
J.; Glorius, F. Aldrichimica Acta 2012, 45, 31. (c) Song, G.; Wang, F.;
Li, X. Chem. Soc. Rev. 2012, 41, 3651. (d) Chiba, S. Chem. Lett. 2012,
41, 1554.
(15) For Cp*RhIII-catalyzed nonoxidative alkenylation/annulation
sequence via C−N bond cleavage, substrates with better leaving
groups are required. Annulation via C−N bond cleavage of imide:
(a) Li, B.-J.; Wang, H.-Y.; Zhu, Q.-L.; Shi, Z.-J. Angew. Chem., Int. Ed.
2012, 51, 3948. In fact, transition metal-catalyzed C−N bond cleavage
of amides or imides is rare. For other examples, see the following with
́
Am. Chem. Soc. 2006, 128, 4972. (h) Toure, B. B.; Lane, B. S.; Sames,
D. Org. Lett. 2006, 8, 1979. (i) Stuart, D. R.; Villemure, E.; Fagnou, K.
J. Am. Chem. Soc. 2007, 129, 12072. (j) Yang, S.-D.; Sun, C.-L.; Fang,
Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1473.
5430
dx.doi.org/10.1021/ja5008432 | J. Am. Chem. Soc. 2014, 136, 5424−5431

Journal of the American Chemical Society
Article
Ni-catalysis: (b) Jenkins, A. D.; Herath, A.; Song, M.; Montgomery, J.
J. Am. Chem. Soc. 2011, 133, 14460. (c) Kajita, Y.; Matsubara, S.;
Kurahashi, T. J. Am. Chem. Soc. 2008, 130, 6058. Pd-catalysis:
́
(d) Sole, D.; Serrano, O. J. Org. Chem. 2008, 73, 9372.
(16) For selected leading works on Cp*RhIII-catalyzed alkenylation/
annulation via N−O bond cleavage (internal oxidant strategy):
(a) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. 2010,
132, 6908. (b) Too, P. C.; Wang, Y.-F.; Chiba, S. Org. Lett. 2010, 12,
5688. (c) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am.
Chem. Soc. 2011, 133, 2350. (d) Guimond, N.; Gorelsky, S. I.; Fagnou,
K. J. Am. Chem. Soc. 2011, 133, 6449. (e) Hyster, T. K.; Rovis, T.
Chem. Commun. 2011, 47, 11846. (f) Wang, H.; Grohmann, C.;
Nimphius, C.; Glorius, F. J. Am. Chem. Soc. 2012, 134, 19592. (g) Xu,
X.; Liu, Y.; Park, C.-M. Angew. Chem., Int. Ed. 2012, 51, 9372.
(h) Neely, J. M.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 66.
(i) Huckins, J. R.; Bercot, E. A.; Thiel, O. R.; Hwang, T.-L.; Bio, M. M.
J. Am. Chem. Soc. 2013, 135, 14492 and references therein. For
selected examples of alkenylation/annulation via redox-neutral
addition of alkenyl-Cp*RhIII species, see also: (j) Patureau, F. W.;
Besset, T.; Kuhl, N.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2154.
(k) Muralirajan, K.; Parthasarathy, K.; Cheng, C.-H. Angew. Chem., Int.
Ed. 2011, 50, 4169. (l) Qi, Z.; Wang, M.; Li, X. Org. Lett. 2013, 15,
5440. (m) Chen, Y.; Wang, F.; Zhen, W.; Li, X. Adv. Synth. Catal.
2013, 355, 353. (n) Dong, L.; Qu, C.-H.; Huang, J.-R.; Zhang, W.;
Zhang, Q.-R.; Deng, J.-G. Chem.Eur. J. 2013, 19, 16537. For other
examples including oxidative annulation, see reviews in ref 14.
(17) For Mn-catalyzed C−H alkenylation with terminal alkynes, see:
Zhou, B.; Chen, H.; Wang, C. J. Am. Chem. Soc. 2013, 135, 1264.
(18) Li, L.; Brennessel, W. W.; Jones, W. D. J. Am. Chem. Soc. 2008,
130, 12414.
(19) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys. 1985,
83, 735.
(20) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci,
B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.
P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,
N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;
̈
Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09,
Revision C.1; Gaussian, Inc.: Wallingford, CT, 2009.
(21) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens. Matter
Mater. Phys. 1988, 37, 785. (b) Stephens, P. J.; Devlin, F. J.;
Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98, 11623.
(c) Hehre, W. J.; Radom, L.; Schleyer, P. V. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; Wiley: New York, 1986. (d) Rassolov, V. A.;
Pople, J. A.; Ratner, M. A.; Windus, T. L. J. Chem. Phys. 1998, 109,
1223.
(22) (a) Davies, D. L.; Donald, S. M. A.; Al-Duaij, O.; Macgregor, S.
A.; Polleth, M. J. Am. Chem. Soc. 2006, 128, 4210. (b) Boutadla, Y.;
̈
Davies, D. L.; Macgregor, S. A.; Poblador-Bahamonde, A. I. Dalton
Trans. 2009, 5887. (c) Zhang, Q.; Yu, H.-Z.; Li, Y.-T.; Liu, L.; Huang,
Y.; Fu, Y. Dalton Trans. 2013, 42, 4175. (d) Davies, D. L.; Donald, S.
M. A.; Macgregor, S. A. J. Am. Chem. Soc. 2005, 127, 13754.
(23) Review on concerted metalation−deprotonation mechanism:
Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118.
(24) Under our standard conditions, pyrroles were not suitable
substrates for the synthesis of N-fused pyrrole cores.
5431
dx.doi.org/10.1021/ja5008432 | J. Am. Chem. Soc. 2014, 136, 5424−5431