Nickel-catalyzed decarbonylative and decarboxylative cycloaddition of isatoic anhydrides with alkynes

Article abstract of DOI:10.1246/cl.130578

We have developed a nickel-catalyzed cycloaddition of isatoic anhydrides with alkynes to afford 2,3-disubstituted indoles. The reaction proceeds via the elimination of carbon monoxide and carbon dioxide and the insertion of alkynes.

Full text of DOI:10.1246/cl.130578

doi:10.1246/cl.130578
1
238
Published on the web October 5, 2013
Nickel-catalyzed Decarbonylative and Decarboxylative Cycloaddition
of Isatoic Anhydrides with Alkynes
Kenichiro Nakai, Takuya Kurahashi,* and Seijiro Matsubara*1
1
1,2
1
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510
2
JST, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012
(
Received June 21, 2013; CL-130578; E-mail: kurahashi.takuya.2c@kyoto-u.ac.jp, matsubara.seijiro.2e@kyoto-u.ac.jp)
We have developed a nickel-catalyzed cycloaddition of
and 10 mol % methylaluminum bis(2,6-di-tert-butyl-4-methyl-
phenoxide) (MAD) in toluene at 80 °C for 12 h. This afforded
8
isatoic anhydrides with alkynes to afford 2,3-disubstituted
indoles. The reaction proceeds via the elimination of carbon
monoxide and carbon dioxide and the insertion of alkynes.
indole 3aa in 10% yield, and the formation of quinolones was
not detected. We next examined the reaction at an elevated
temperature (160 °C) and found that the reaction proceeded to
furnish indole 3aa in 84% yield (Table 1, Entry 1). Among
various nonpolar solvents such as benzene, xylene, and toluene
gave the best yield to afford indoles. More polar solvents such
as 1,4-dioxane, pyridine, or N,N-dimethylacetamide gave the
product in lower yields. When the reaction was performed
with PMe2Ph instead of PMe3, the product was obtained in
quantitative yield (Entry 2). The use of other monophosphines
(Entries 3­5), phosphite (Entry 6), diphosphine (Entry 7), or
N-heterocyclic carbene (Entry 8) as ligands resulted in lower
yields. It was also found that the cycloaddition proceeded even
with a reduced amount of nickel catalyst (5 mol %) to afford
indole 3aa in excellent yield (Entry 9). Other Lewis acids were
found to be less active than MAD (Entries 10­12).
The indole skeleton is one of the most ubiquitous structural
components in biologically active natural and unnatural com-
1
pounds, as well as in the field of materials science. Therefore,
numerous methods have been developed for the preparation of
2
,3
indoles. Among them, the intermolecular transition-metal-
catalyzed syntheses of indoles are of great significance because
the reactions allow divergent synthesis with multiple organic
4
components.
We have developed nickel-catalyzed cycloadditions to form
heterocyclic compounds from heterocyclic compounds via the
elimination of small molecules.5 During the course of our
study, we found that the nickel-catalyzed [4 + 2] cycloaddi-
tion of isatoic anhydrides with alkynes gave 4-quinolones
,6
With the optimal reaction conditions in hand, we explored
the substrate scope (Table 2). N-Arylisatoic anhydrides possess-
ing electron-donating or -withdrawing groups also participated
5
a
(
Scheme 1a). The [4 + 2] cycloaddition reaction proceeds via
the elimination of a carbon dioxide molecule. The results
prompted us to investigate a different type of cycloaddition of
isatoic anhydrides to give indole derivatives, that is, a [3 + 2]
Table 1. Optimization of the reaction conditionsa
cycloaddition with alkynes via the elimination of carbon
[
Ni(cod) ] (10 mol %)
O
2
monoxide and carbon dioxide (Scheme 1b).5c,5d,5g,5i,7
Pr
ligand
additive (10 mol %)
First, N-phenylisatoic anhydride (1a) was treated under
argon with 4-octyne (2a), 10 mol % [Ni(cod)2], 20 mol % PMe3,
O
+
O
Pr
Pr
Pr
N
N
toluene, 160 °C, 12 h
Ph
3aa
Ph
a
1
2a
Entry
Ligand
PMe3 (20 mol %)
PMe2Ph (20 mol %)
Additive
MADc
Yield/%b
1
2
3
4
5
6
7
8
9
0
84
99
30
7
40
25
5
MAD
MAD
MAD
MAD
MAD
MAD
MAD
MAD
AlMe3
BPh3
PMePh (20 mol %)
2
PPh3 (20 mol %)
PBu (20 mol %)
3
P(OEt)3 (20 mol %)
d
dmpe (10 mol %)
e
IPr (20 mol %)
1
99
f
PMe2Ph (20 mol %)
1
PMe Ph (20 mol %)
31
51
20
2
1
1
PMe2Ph (20 mol %)
1
2
PMe Ph (20 mol %)
B(C F )
6 5 3
2
aReactions were carried out using [Ni(cod)2] (10 mol %),
ligand, additive (10 mol %), 1a (0.2 mmol), and 2a (0.3 mmol,
1
.5 equiv) in 1 mL of refluxing toluene for 12 h otherwise
9
b
c
noted. NMR yields based on 1a. MAD: methylaluminum
bis(2,6-di-tert-butyl-4-methylphenoxide). dmpe: 1,2-bis(di-
methylphosphino)ethane. IPr: 1,3-bis(2,6-diisopropylphenyl)-
imidazol-2-ylidene. [Ni(cod) ] (5 mol %).
d
e
Scheme 1. Nickel-catalyzed [4 + 2] cycloaddition and [3 + 2]
cycloaddition.
f
2
Chem. Lett. 2013, 42, 1238­1240
© 2013 The Chemical Society of Japan
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Table 2. Nickel-catalyzed annulation via elimination of CO/
a,b
CO2
O
[Ni(cod)2] (5 mol %)
PMe2Ph (20 mol %)
MAD (10 mol %)
R4
R1
R1
R2
O
R4
R5
R5
+
R2
toluene, 160 °C, 12 h
N
R3
N
R3
O
1
2
3
Pr
ba (R3 = 4-MeOC H ), 83%
6 4
3
3
3
ca (R3 = 4-F CC H ), 48%
3
6 4
Pr
da (R3 = Me), 76%
N
R3
3ea (R3 = PhCH2), 71%
Pr
Pr
Pr
MeO
Pr
Pr
N
Ph
Pr
N
Ph
F3C
N
Ph
N
Scheme 2. Plausible reaction pathway.
3
fa, 81%
3
ga, 76%
3ha, 68%c
with the use of MAD (20 mol %). It was also found that enyne
g reacted with 1a to provide indole 3ag in a higher yield.
Terminal alkynes such as 1-octyne or phenylacetylene failed to
participate in the reaction because of the rapid oligomerization
of the alkynes.
2
Ph
Pr
t-Bu
Ph
Ph
Ph
N
N
N
Ph
Ph
Ph
Even though the mechanism of this reaction has not been
elucidated completely, we propose the reaction pathway as
3ac, 99%(14/1d)
d
3
ab, 93%
3ad, 65% (6/1 )
5
a,5b
c
d
shown in Scheme 2.
The key to the catalytic process is the
8
4% (11/1 )
decarbonylation of intermediate 4 to afford 5 prior to decarbox-
ylation; the sterically bulky MAD coordinates to the carbamate
moiety to form 4 and prevent decarboxylation. Subsequent
insertion of alkyne 2 into intermediate 5 affords the 8-membered
nickelacycle intermediate 6; the advantage of the 8-membered
ring strain relief would enhance the decarboxylation and
reductive elimination to furnish indole 3 and regenerate the
nickel catalyst.
In conclusion, we have developed the cycloaddition of
isatoic anhydrides with alkynes to provide 2,3-disubstituted
indoles. We found that the use of MAD was crucial for the
transformation in promoting decarbonylation prior to alkyne
insertion and decarboxylation. Further efforts to expand the
scope of the chemistry and detailed studies of the mechanism are
currently underway in our laboratories.
Me
Me
Et
i-Pr
t-Bu
N
Ph
N
Ph
N
Ph
c
d
c
d
c
d
3
ae, 80% (1/1 )
3af, 82% (2/1 )
3ag, 92% (4/1 )
aReactions were carried out using [Ni(cod)2] (5 mol %),
PMe2Ph (20 mol %), MAD (10 mol %), 1 (0.2 mmol), and 2
0.3 mmol, 1.5 equiv) in 1 mL of refluxing toluene (oil bath
60 °C) for 12 h.9 Isolated yield based on 1a was given.
(
b
1
c
d
MAD (20 mol %). Ratio of diastereomer.
in the reaction to give correspondingly substituted indoles in
8
3 (3ba) and 48% (3ca) yields, respectively. N-Alkylisatoic
This work was supported by JST, ACT-C, and Grants-in-Aid
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan. T.K. acknowledges the Asahi Glass Foun-
dation, The Uehara Memorial Foundation, Tokuyama Science
Foundation, and Kurata Memorial Hitachi Science and Tech-
nology Foundation. K.N. also acknowledges the Japan Society
for the Promotion of Science for Young Scientists for fellowship
support.
anhydrides also reacted with alkyne 2a to furnish the cyclo-
adducts 3da and 3ea in high yields (3da and 3ea). The
cycloaddition of 5-methoxy- or 4-trifluoromethylisatoic anhy-
dride derivatives with alkyne 2a gave the corresponding
products 3fa and 3ga. A nicotinic acid anhydride 1h also
participated in the reaction with alkyne 2a to afford azaindole
3
ha in moderate yield.
Next, we examined the scope of the alkynes. Diphenylace-
tylene and 1-phenyl-1-pentyne were also suitable for the reaction
and gave the cycloadducts 3ab and 3ac in almost quantitative
yields. Alkynes possessing sterically bulky substituents such as
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© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

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Supporting Information is available electronically on the
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