Nickel-catalyzed heteroannulation of o-haloanilines with alkynes

Article abstract of DOI:10.1246/cl.2011.1067

A nickel-catalyzed heteroannulation has been developed where o-haloanilines react with alkynes to afford 2,3-disubstituted indoles. IPr (1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) was found to be an effective ligand for the reaction.

Full text of DOI:10.1246/cl.2011.1067

doi:10.1246/cl.2011.1067
Published on the web September 17, 2011
1067
Nickel-catalyzed Heteroannulation of o-Haloanilines with Alkynes
Yuji Yoshida, Takuya Kurahashi,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510
(Received June 9, 2011; CL-110482; E-mail: tkuraha@orgrxn.mbox.media.kyoto-u.ac.jp)
A nickel-catalyzed heteroannulation has been developed
where o-haloanilines react with alkynes to afford 2,3-disub-
stituted indoles. IPr (1,3-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene) was found to be an effective ligand for the reaction.
Table 1. Nickel-catalyzed heteroannulation of 1a with 2aa
Pr
[Ni(cod)2] (10 mol %)
X
ligand
+
Pr
Pr
Pr
base (1.2 equiv)
solvent, 100 °C, 12 h
N
H
NH2
2a
3a
1a; X = Br
Among various heterocyclic compounds, indoles are espe-
cially important because they are found in both natural products
and in pharmaceuticals.1,2 Therefore the development of new
synthetic methods to provide indoles is continuously in
demand.1b,2a,2b,3-5 Recently, we have developed cycloaddition
of readily available anthranilic acid derivatives with alkynes to
afford 2,3-disubstituted indoles.6 We found that the nickel-
catalyzed cycloaddition provides an opposite regioisomer to that
of palladium-catalyzed Larock heteroannulations: the nickel-
catalyzed reaction of anthranilic acid derivatives with unsym-
metrical substituted alkynes affords 2,3-disubstituted indoles
with bulky substituents on the 3 position (Scheme 1a), whereas
palladium-catalyzed reaction of o-haloaniline with the same
alkynes affords 2,3-disubstituted indoles with bulky substituents
on the 2 position.3 We assumed that such difference is ascribed
to differences in the intermediate for alkyne carbometallation
(i.e., cyclic or acyclic).3,6 To test our hypothesis, we became
intrigued by the development of nickel-catalyzed heteroannula-
tion of o-haloaniline with alkynes to afford 2,3-disubstituted
indoles and the observation of regioselectivity (Scheme 1b).
Herein, we wish to report the results.7
1b; X = I
1c; X = Cl
Cy
iPr
iPr
N
N
N
N
N
iPr
iPr
PPh2
IP
IMes
IPr
Cl
iPr
Cl
iPr
N
N
N
N
iPr
iPr
Cl-IPr
IBu
Entry 1 Ligand
Base
Solvent Yield/%b
1
2
3
4
5
6
7
8
9
1a PPh3 (40 mol %)
1a PCy3 (40 mol %)
1a PMePh2 (40 mol %)
1a PMe2Ph (40 mol %)
1a PMe3 (40 mol %)
1a PPr3 (40 mol %)
1a dppfc (20 mol %)
1a dpped (20 mol %)
1a IPr (10 mol %)
LiOt-Bu toluene 14
LiOt-Bu toluene
LiOt-Bu toluene 21
LiOt-Bu toluene 12
8
LiOt-Bu toluene
3
LiOt-Bu toluene 24
LiOt-Bu toluene
LiOt-Bu toluene
4
1
LiOt-Bu toluene 72
10 1a IMes¢HCl (10 mol %) LiOt-Bu toluene 72
11 1a IPr¢HCl (10 mol %) LiOt-Bu toluene 79 (76)
The results of optimization of reaction conditions for the
nickel-catalyzed heteroannulation of o-haloaniline 1 with 2a are
summarized in Table 1. It was found that the reaction with
phosphine ligands, such as PPh3, PCy3, and PMe3, proceeded
12 1a Cl-IPr¢HCl (10 mol %) LiOt-Bu toluene 25
13 1a IBu¢HCl (10 mol %) LiOt-Bu toluene 18
14 1a IPr¢HCl (20 mol %)
15 1a IPr¢HCl (10 mol %)
16 1a IPr¢HCl (10 mol %)
17 1a IPr¢HCl (10 mol %)
18 1a IPr¢HCl (10 mol %)
19 1a IPr¢HCl (10 mol %)
20 1a IPr¢HCl (10 mol %)
21 1a IPr¢HCl (10 mol %)
22 1a IPr¢HCl (10 mol %)
23 1b IPr¢HCl (10 mol %)
24 1c IPr¢HCl (10 mol %)
25 1a IPr¢HCl (10 mol %)
26 1a IPr¢HCl (10 mol %)
27 1a IPr¢HCl (5 mol %)
28 1a IPr¢HCl (10 mol %)
LiOt-Bu toluene 67
NaOt-Bu toluene
KOt-Bu toluene
5
6
6
5
4
Previous Report
NEt3
DBU
toluene
toluene
1) [Ni(cod)2] (10 mol %)
O
RL
PPr3 (40 mol %)
xylene, reflux, 24 h
O
RS
DABCO toluene
RL
RS
+
(a)
2) NaSMe, MeOH, 25 °C
N
N
R
LiOt-Bu benzene 74
LiOt-Bu xylene 67
H
RL
RS
LiOt-Bu dioxane 55
LiOt-Bu toluene 28
LiOt-Bu toluene 38
LiOt-Bu toluene 73e
LiOt-Bu toluene 74f
LiOt-Bu toluene 70g
LiOt-Bu toluene <1h
Ni
N
L
O
R
cyclic intermediate
Present Work
X
RS
Ni cat.
RL
RL
RS
(b)
aReactions were carried out using [Ni(cod)2] (10 mol %),
ligand, 1 (0.3 mmol), and 2a (0.45 mmol, 1.5 equiv) in 2 mL
+
NH2
N
RS
H
RL
b
of toluene at 100 °C for 12 h otherwise noted. NMR yields
based on 1. Isolated yield is given in parenthesis. cdppf:
1,1¤-bis(diphenylphosphino)ferrocene. ddppe: 1,2-bis(diphen-
NiX
NH2
acyclic intermediate
e
f
ylphosphino)ethane. 2a (1.0 mmol, 2 equiv). 2a (1.5 mmol,
g
h
Scheme 1. Cycloaddition and heteroannulation.
3 equiv). [Ni(cod)2] (5 mol %). AgSbF6 (100 mol %).
Chem. Lett. 2011, 40, 1067-1068
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1068
Table 2. Nickel-catalyzed heteroannulation of 1a with 2a
1) [Ni(cod)2] (10 mol %)
IPr·HCl (10 mol %)
LiOt-Bu (1.2 equiv)
toluene, 100 °C, 12 h
R2
Ph
Ph
[Ni(cod)2] (10 mol %)
IPr·HCl (10 mol %)
Br
Br
+
R1
H
R1
R2
(a)
(b)
+
2) TBAF, THF, r.t., 12 h
NH2
N
LiOt-Bu (1.2 equiv)
toluene, 100 °C, 12 h
N
NH2
SiMe3
2g
H
H
2
3
1a
1a
4 51%
Major
product
Entry
2
R1
R2
Yield/%
76
1) [Ni(cod)2] (10 mol %)
PPr3 (40 mol %)
xylene, reflux, 24 h
O
O
N
H
Ph
1
2
3
4
5
6
7
8
9
2a Pr
2b Ph
2c i-Pr
2d t-Bu Me
2e Ph Pr
2f SiMe3 C6H13
2g SiMe3 Ph
2h SiMe3 Me
2i SiMe3 CH2CH(OSit-BuMe2)Me
Pr
Ph
Me
3a
3b
3c
3d
3e
3f
3g
3h
3i
+
Ph
43
N
H
2) NaSMe, MeOH, 25 °C
tBu
SiMe3
85 (1/1)b
28 (10/1)b
51c,d
5
2g
6 74%
56c
Scheme 2. Cycloaddition and heteroannulation.
59c,d,e
67c
reaction. The nickel-catalyzed heteroannulation of o-haloaniline
with alkynes provides the same regioisomer as that of the
palladium-catalyzed Larock heteroannulations. Thus, as shown
in Scheme 2, the use of either nickel-catalyzed cycloaddition
or heteroannulation may allow one to prepare different re-
gioisomer of cycloadducts. Further efforts to elucidate an origin
of regioselectivity are underway with the aid of theoretical
calculations.10
49d (3/1)
aReactions were carried out using [Ni(cod)2] (10 mol %), IPr
(10 mol %), 1a (0.3 mmol), 2 (0.45 mmol, 1.5 equiv), and
LiOt-Bu (0.36 mmol, 1.2 equiv) in 2 mL of toluene at 100 °C
for 12 h otherwise noted. bRatio of regioisomers (3/3¤). cSingle
regioisomer. dReaction time; 24 h. eProtodesilylated cyclo-
adduct was obtained in 14% yield.
This work was supported by Grants-in-Aid from MEXT,
Japan. T.K. also acknowledges supports from Asahi Glass
Foundation and Kansai Research Foundation.
sluggishly to afforded indole 3a in low yields (Entries 1-6). The
use of bidentate phosphine ligands, such as dppf and dppe, gave
even lower yield of desired 3a (Entries 7 and 8). However, to our
delight, it was found that the use of carbene ligands improved
the yield of indole 3a drastically. That is, the reaction of 1a and
2a in the presence of [Ni(cod)2] (10 mol %), IPr (1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene) (10 mol %), and lithium
tert-butoxide (1.2 equiv) in toluene (100 °C) afforded 3a in 79%
yield (Entry 11). Among various carbene ligands examined,
IPr gave the best yield of 3a (Entries 9-13). The reaction
is sensitive toward base employed. The use of sodium tert-
butoxide or potassium tert-butoxide in place of lithium tert-
butoxide resulted in decreasing the yields of indole 3a to 5% and
6% respectively (Entries 15 and 16). It was also found that the
use of organic base, such as triethylamine, DBU, and DABCO,
afforded trace amounts of 3a (Entries 17-19). In other reaction
solvents, such as benzene, xylene, and 1,4-dioxane, yields of 3a
were slightly lower (Entries 20-22).
With the optimized reaction conditions, the scope of the
reaction was briefly examined and the results are summarized in
Table 2. The heteroannulation is also compatible with aryl-
substituted alkyne 2b and afforded 3b in 43% yield (Entry 2).
The reaction of 1a with unsymmetrical alkynes such as 2c and
2d also gave the indoles consisting of regioisomers in a range of
1/1 to 10/1 ratio (Entries 3 and 4). It was found that monoaryl-
substituted alkyne 2e reacted with 1a to provide 3e regioselec-
tively.3 The reaction of 1a with unsymmetrical alkynes,
containing sterically hindered substituents SiMe3, gave corre-
spondingly 2,3-disubstituted indoles regioselectivity (Entries
6-8). However, unsymmetrical alkynes 2i, containing sterically
hindered substituents on both ends, afforded 2,3-disubstituted
indole 3i with lower regioselectivity (Entry 9).8,9
References and Notes
1
For a general review, see: a) G. Zeni, R. C. Larock, Chem. Rev.
2004, 104, 2285. b) I. Nakamura, Y. Yamamoto, Chem. Rev.
2004, 104, 2127. c) M. Lautens, W. Klute, W. Tam, Chem. Rev.
1996, 96, 49. d) I. Ojima, M. Tzamarioudaki, Z. Li, R. J.
Donovan, Chem. Rev. 1996, 96, 635.
2
For some recent examples, see: a) D. R. Stuart, M. Bertrand-
Laperle, K. M. N. Burgess, K. Fagnou, J. Am. Chem. Soc. 2008,
130, 16474. b) R. Bernini, G. Fabrizi, A. Sferrazza, S. Cacchi,
Angew. Chem., Int. Ed. 2009, 48, 8078. c) T. Iwai, T. Fujihara, J.
Terao, Y. Tsuji, J. Am. Chem. Soc. 2010, 132, 9602.
For Larock heteroannulation, see: a) R. C. Larock, E. K. Yum,
M. D. Refvik, J. Org. Chem. 1998, 63, 7652. b) R. C. Larock,
E. K. Yum, J. Am. Chem. Soc. 1991, 113, 6689.
For recent reviews see: a) G. R. Humphrey, J. T. Kuethe, Chem.
Rev. 2006, 106, 2875. b) F. Alonso, I. P. Beletskaya, M. Yus,
Chem. Rev. 2004, 104, 3079.
For some recent transition-metal-catalyzed indole syntheses,
see: a) Z. Shi, C. Zhang, S. Li, D. Pan, S. Ding, Y. Cui, N. Jiao,
Angew. Chem., Int. Ed. 2009, 48, 4572. b) S. Kamijo, Y.
Yamamoto, J. Am. Chem. Soc. 2002, 124, 11940.
3
4
5
6
7
N. Maizuru, T. Inami, T. Kurahashi, S. Matsubara, Org. Lett.
2011, 13, 1206.
To the best of our knowledge, this is the first example of nickel-
catalyzed heteroannulation of haloanilines with alkynes to form
indoles.
8
9
Trace or lower amounts of indoles were obtained in the case
using o-bromoanilides, such as N-acyl-o-bromoaniline and N-
benzoyl-o-bromoaniline, in place of o-bromoaniline.
Terminal alkynes, such as triisopropylacetylene, 1-octyne, and
phenylacetylene, failed to participate in the reaction, presum-
ably due to rapid oligomerization of alkynes.
In conclusion, we have developed nickel-catalyzed hetero-
annulation of o-haloaniline with alkynes to afford substituted
indoles. It was found that IPr is an effective ligand for the
10 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Chem. Lett. 2011, 40, 1067-1068
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/