Nickel-catalyzed cycloaddition of anthranilic acid derivatives to alkynes

Article abstract of DOI:10.1021/ol200090g

A nickel-catalyzed cycloaddition has been developed where readily available anthranilic acid derivatives react with alkynes to afford substituted indoles. The reaction involves oxidative addition of Ni(0) to an ester moiety, which allows intermolecular addition to alkynes via decarbonylation and 1,3-acyl migration.(Figure Presented)

Full text of DOI:10.1021/ol200090g

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1206–1209
Nickel-Catalyzed Cycloaddition of
Anthranilic Acid Derivatives to Alkynes
Nobuyoshi Maizuru, Tasuku Inami, Takuya Kurahashi,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyoto 615-8510, Japan
tkuraha@orgrxn.mbox.media.kyoto-u.ac.jp; matsub@orgrxn.mbox.media.kyoto-u.ac.jp
Received January 12, 2011
ABSTRACT
A nickel-catalyzed cycloaddition has been developed where readily available anthranilic acid derivatives react with alkynes to afford substituted
indoles. The reaction involves oxidative addition of Ni(0) to an ester moiety, which allows intermolecular addition to alkynes via decarbonylation
and 1,3-acyl migration.
Indoles are an important class of heterocyclic com-
pounds because they are among the most ubiquitous
compounds in both natural products and pharmaceuticals.
Scheme 1. Nickel-Catalyzed [5 - 1 þ 2] Cycloaddition
Although there are a large number of methodologies for
synthesis and structural transformation of an indole nu-
cleus, the development of alternative methodologies,
which would allow for straightforward access to structu-
rally diverse indoles, remains an important research topic.
In the past few decades, transition-metal-catalyzed reac-
tions, such as Larock heteroannulation,1 have emerged as
synthesis of a heterocyclic compound from the readily avail-
powerful methodologies for the synthesis of structurally
diverse indoles.2,3 Recently, we demonstrated nickel-cata-
able heterocyclic compound with cycloadditions prompted
lyzed decarbonylative cycloaddition of alkynes to five-
(3) For some recent transition-metal-catalyzed indole syntheses, see:
membered heterocyclic compounds via carboamination
to give six-membered heterocyclic compounds, namely
(a) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K.
J. Am. Chem. Soc. 2008, 130, 16474. (b) Shimada, T.; Nakamura, I.;
Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 10546. (c) Furstner, A.;
Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024. (d) Bernini, R.;
Fabrizi, G.; Sferrazza, A.; Cacchi, S. Angew. Chem., Int. Ed. 2009, 48,
8078. (e) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N.
[5 - 1 þ 2] cycloaddition (Scheme 1).4 Our success in
€
(1) For Larock heteroannulation, see: (a) Larock, R. C.; Yum, E. K.;
Refvik, M. D. J. Org. Chem. 1998, 63, 7652. (b) Larock, R. C.; Yum,
E. K. J. Am. Chem. Soc. 1991, 113, 6689.
ꢀ
Angew. Chem., Int. Ed. 2009, 48, 4572. (f) Barluenga, J.; Jimenez-
ꢀ
Aquino, A.; Aznar, F.; Valdes, C. J. Am. Chem. Soc. 2009, 131, 4031.
(2) For recent reviews, see: (a) Humphrey, G. R.; Kuethe, J. T. Chem.
Rev. 2006, 106, 2875. (b) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem.
Rev. 2004, 104, 3079. (c) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004,
104, 2127. (d) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 2001, 2491.
(e) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045. (f) Joule,
J. A. In Science of Synthesis, Vol. 10; Thomas, E. J., Ed.; Thieme:
Stuttgart, Germany, 2000; p 361. (g) Sundberg, R. J. Indoles; Academic
Press: San Diego, CA, 1996. (h) Kr€uger, K.; Tillack, A.; Beller, M. Adv.
Synth. Catal. 2008, 350, 2153.
(g) Cao, C.; Shi, Y.; Odom, A. L. Org. Lett. 2002, 4, 2853. (h) Tillack, A.;
Jiao, H.; Garcia Castro, I.; Hartung, C. G.; Beller, M. Chem.;Eur. J.
2004, 10, 2409. (i) Ackermann, L.; Born, R. Tetrahedron Lett. 2004, 45,
9541. (j) Zhang, Y.; Donahue, J. P.; Li, C.-J. Org. Lett. 2007, 9, 627.
(k) Siebeneicher, H.; Bytschkov, I.; Doye, S. Angew. Chem., Int. Ed.
2003, 42, 3042. (l) Khedkar, V.; Tillack, A.; Michalik, M.; Beller, M.
Tetrahedron 2005, 61, 7622. (m) Lu, B. Z.; Zhao, W.; Wei, H.-X.;
Dufour, M.; Farina, V.; Senanayake, C. H. Org. Lett. 2006, 8, 3271.
(n) Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 11940.
r
10.1021/ol200090g
Published on Web 02/04/2011
2011 American Chemical Society

us to investigate a new reaction, which would allow us to
prepare indoles from readily available heterocyclic com-
pounds and alkynes.5-7 Such a process enables the synthesis
of indoles with substitution in a five-membered ring; it may
find applications in drug discovery and development. Herein,
we report our results of nickel-catalyzed [6 - 3 þ 2]
cycloaddition to provide indoles 3 from readily available
anthranilic acid derivative 1 and alkyne 2,8 which may
proceed via oxidative addition, decarbonylation, alkyne in-
sertion, 1,3-acyl migration, and reductive elimination
(Scheme 2).
Scheme 3. Cycloaddition of 1a to 2a
1,2-bis(dimethylphosphino)ethane (dmpe), 1,2-bis(diphenyl-
phosphino)ethane (dpppe), 1,2-bis(dimethylphosphino)
ethane (dmpe), 1,3-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene (IPr), and 1,3-bis(2,4,6-trimethylphenyl)imidazol-
2-ylidene (IMes) (entries 10-13).
Scheme 2. Nickel-Catalyzed [6 - 3 þ 2] Cycloaddition
Table 1. Nickel-Catalyzed Decarbonylative Cycloadditionsa
Initially, it was found that 1a reacted with 4-octyne (2a)
in the presence of Ni(cod)2 (10 mol %) and PMe3 (40 mol %)
in refluxing xylene to afford N-pivaloyl-protected indole
3aa in 48% yield along with a small amount of deprotected
indole 3aa0 (Scheme 3). Deprotected indole 3aa0 was ob-
tained as the sole product in 52% yield when the reac-
tion crude mixture was treated with NaSMe in MeOH as
a workup procedure. With the optimized workup pro-
cedure in hand, reaction conditions were further exam-
ined (Table 1). It was found that anthranilic acid deri-
vative 1 with sterically hindered tert-butyl substituent R
on the C2-position gave the best yield of indole 3aa0
(entry 1), while 1 with phenyl or methyl substituents gave
inferior results (entries 2 and 3). Among the ligands exam-
ined, PPr3 gave the best result and the reaction afforded
3aa0 in 62% yield (entry 7). Trace or lower amounts of
3aa were obtained in the cases using ligands, such as
entry
R
ligand
yield (%)b
1
tBu
Ph
PMe3
PMe3
PMe3
PMe2Ph
PMePh2
PPh3
52
11
4
2
3
Me
4
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
47
26
<1
62
47
11
<1
3
5
6
7
PPr3
8
PBu3
PCy3
9
10
11
12
13
dppec
dmped
IPre
<1
<1
IMesf
a Reactions were carried out using Ni(cod)2 (10 mol %), ligand (40
mol %), 1(0.5 mmol), and 2a (1.0 mmol) in 2 mL of refluxing xylene (160 °C)
for 12 h . b Isolated yields. c 1,2-Bis(diphenylphosphino)ethane. d 1,2-
Bis(dimethylphosphino)ethane. e 1,3-Bis(2,6-diisopropylphenyl)imidazol-
2-ylidene. f 1,3-Bis(2,4,6-trimethylphenyl)imidazol-2-ylidene.
(4) (a) Kajita, Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc.
2008, 130, 6058. (b) Kajita, Y.; Kurahashi, T.; Matsubara, S. J. Am.
Chem. Soc. 2008, 130, 17226.
(5) (a) Yoshino, Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc.
2009, 131, 7494. (b) Ooguri, A.; Nakai, K.; Kurahashi, T.; Matsubara, S.
J. Am. Chem. Soc. 2009, 131, 13194.
(6) (a) Miura, T.; Yamauchi, M.; Murakami, M. Org. Lett. 2008, 10,
3085. (b) Yamauchi, M.; Morimoto, M.; Miura, T.; Murakami, M.
J. Am. Chem. Soc. 2010, 132, 54. (c) Miura, T.; Yamauchi, M.; Kosaka,
A.; Murakami, M. Angew. Chem., Int. Ed. 2010, 49, 4955. (4) Miura, T.;
Morimoto, M.; Yamauchi, M.; Murakami, M. J. Org. Chem. 2010, 75,
5359.
(7) (a) Shintani, R.; Murakami, M.; Hayashi, T. J. Am. Chem. Soc.
2007, 129, 12356. (b) Wang, C.; Tunge, J. A. J. Am. Chem. Soc. 2008,
130, 8118. (c) Shintani, R.; Park, S.; Shirozu, F.; Murakami, M.;
Hayashi, T. J. Am. Chem. Soc. 2008, 130, 16174. (d) Shintani, R.; Park,
S.; Hayashi, T. J. Am. Chem. Soc. 2007, 129, 14866. (e) Shintani, R.;
Tsuji, T.; Park, S.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 7508.
(f) Shintani, R.; Murakami, M.; Hayashi, T. Org. Lett. 2009, 11, 457.
(g) Shintani, R.; Hayashi, S.; Murakami, M.; Takeda, M.; Hayashi, T.
Org. Lett. 2009, 11, 3754.
We next investigated the scope of this cycloaddition with
the optimized reaction conditions and workup procedure
(Table 2). A range of electron-donating or -withdrawing
ring substitutents tolerated the reaction conditions well
enoughtofurnish the corresponding indoles. Deprotection
of 3ba resulted in formation of an unstable indole 3ba0 to
purify with silica gel chromatography, and thus the cy-
cloadduct was isolated as N-pivaloyl-protected form 3ba
in 68% isolated yield (entry 1). Similarly, 3ca was obtained
by the reaction of 1c and 2a (entry 2). While trifluoro-
methyl-substituted substrate 1d reacted with 2a to afford
indole 3da0 in 81% yield after the protocol (entry 3).
Fluoro-substituted compounds, such as 1e, 1f, and 1g also
participated in the reaction to provide correspondingly
(8) Krantz, A.; Spencer, R. W.; Tam, T. F.; Liak, T. J.; Copp, L. J.;
Thomas, E. M.; Rafferty, S. P. J. Med. Chem. 1990, 33, 464.
Org. Lett., Vol. 13, No. 5, 2011
1207

Table 2. Scope of the Cycloadditiona
Table 3. Cycloaddition of 1g to Various Alkynes 2a
a Reactions were carried out using Ni(cod)2 (10 mol %), ligand
(40 mol %), 1 (0.5 mmol), and 2a (1.0 mmol) in 2 mL of refluxing xylene
(160 °C) for 24 h . b Isolated yields.
a Reactions were carried out using Ni(cod)2 (10 mol %), ligand
(40 mol %), 1g (0.5 mmol), and 2 (1.0 mmol) in 2 mL of refluxing xylene
(160 °C) for 12 h . b Isolated yields. c Ratio of regioisomers.
fluoro-substituted indoles in good to moderate yields
(entries 4-6).
addition of an ester CO-O bond to a Ni(0) complex.9,10
Decarbonylation and coordination of alkyne 2 take place,
during which the steric repulsive interaction is minimal
between the bulkier RL and the PPr3 ligand on the nickel,
to give nickel(II) intermediate 6a. The alkyne would then
insert into the C-Ni bond to give nickelacycle 7.11 With its
To extend the application of this protocol, examination
of the alkynes was performed (Table 3). It was found that
the reaction is also compatible with diphenylacetylene (2b)
and afforded 3gb0 in 62% yield (entry 1). The reaction of 1g
with an unsymmetrical alkyne such as 2c, 2d, 2e, or 2f gave
the products consisting of regioisomers with a 1/1 ratio in
high yields (entries 2-5). Bulky trimethylsilyl-substituted
alkynes such as 2g and 2h reacted with 1g to provide
indoles with complete regiocontrol in excellent yields
(entries 6 and 7). Monoaryl-substituted internal alkyne 2i
also reacted with 1g to give 3gi0 regioselectively in 54%
yield (entry 8). However, terminal alkynes, such as 1-oc-
tyne and phenylacetylene, failed to participate in the reac-
tion, presumably due to rapid oligomerization of alkynes.
A plausible reaction pathway to account for the forma-
tion of indole 3 based on the observed results is outlined in
Scheme 4. It is reasonable to consider that the catalytic
cycle of the present reaction should consist of the oxidative
Scheme 4. Plausible Pathway
(9) (a) Trost, B. M.; Chen, F. Tetrahedron Lett. 1971, 12, 2603.
(b) Sano, K.; Yamamoto, T.; Yamamoto, A. Chem. Lett. 1984, 941.
(c) Sano, K.; Yamamoto, T.; Yamamoto, A. Bull. Chem. Soc. Jpn. 1984,
57, 2741. (d) Yamamoto, T.; Sano, K.; Yamamoto, A. J. Am. Chem. Soc.
1987, 109, 1092. (e) Fischer, R.; Walther, D.; Kempe, R.; Sieler, J.;
€
Schonecker, B. J. Organomet. Chem. 1993, 447, 131.
1208
Org. Lett., Vol. 13, No. 5, 2011

Larock heteroannulation. For example, the palladium-
catalyzed reaction of 2g with 2-iodoaniline gives indole
3ag00 regioselectively after protodesilylation,1 whereas the
nickel-catalyzed reaction of 2g with 1a gave regioisomer
3ag0 as a single product after deprotection of the nitrogen
group (Scheme 5). The reason is not clear at the moment;
however, we assumed that such a difference may be ascribed
to differences of intermediate for the carbometalation of
alkyne (i.e., cyclic or acyclic).
Scheme 5. Regioselectivity of the Cycloaddition
In conclusion, we have developed a nickel-catalyzed
[6 - 3 þ 2] cycloaddition and applied the reaction for
divergent syntheses of indoles from readily available
anthranilic acid derivatives with alkynes. Further efforts to
expand the scope of the chemistry and studies of the detailed
mechanism are currently underway in our laboratories.
Acknowledgment. This work was supported by Grants-
in-Aid from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan. T.K. also acknowledges
the Asahi Glass Foundation, Kansai Research Founda-
tion, and Mizuho Foundation.
Supporting Information Available. Experimental pro-
cedures including spectroscopic and analytical data of
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(11) For the formation of oxa-nickelacycles, see: (a) Karsch, H. H.;
Leithe, A. W.; Reisky, M.; Witt, E. Organometallics 1999, 18, 90.
(b) Ogoshi, S.; Oka, M.; Kurosawa, H. J. Am. Chem. Soc. 2004, 126,
11802. (c) Ogoshi, S.; Ueta, M.; Arai, T.; Kurosawa, H. J. Am. Chem.
Soc. 2005, 127, 12810. (d) Ogoshi, S.; Nagata, M.; Kurosawa, H. J. Am.
Chem. Soc. 2006, 128, 5350. (e) Ogoshi, S.; Tonomori, K.; Oka, M.;
Kurosawa, H. J. Am. Chem. Soc. 2006, 128, 7077. (f) Ogoshi, S.; Arai, T.;
Ohashi, M.; Kurosawa, H. Chem. Commun. 2008, 1347. (g) Hratchian,
H. P.; Chowdhury, S. K.; Gutierrez-Garcia, V. M.; Amarasinghe,
K. K. D.; Heeg, M. J.; Schlegel, H. B.; Montgomery, J. Organometallics
2004, 23, 4636. (h) Amarasinghe, K. K. D.; Chowdhury, S. K.; Heeg,
M. J.; Montgomery, J. Organometallics 2001, 20, 370. (i) Montgomery,
J.; Amarasinghe, K. K. D.; Chowdhury, S. K.; Oblinger, E.; Seo, J.;
Savchenko, A. V. Pure Appl. Chem. 2002, 74, 129.
eight-membered ring strain, the Ni-O bond can undergo a
facile 1,3-acyl migration to give thermodynamically more
stable six-membered nickelacycle 8. Subsequent reductive eli-
mination gives 3 and regenerates the starting Ni(0) complex.
Lastly, it should be noted that the nickel-catalyzed
reaction provides an opposite regioisomer to that of the
(10) (a) O’Brien, E. M.; Bercot, E. A.; Rovis, T. J. Am. Chem. Soc.
2003, 125, 10498. (b) Johnson, J. B.; Bercot, E. A.; Rowley, J. M.;
Coates, G. W.; Rovis, T. J. Am. Chem. Soc. 2007, 129, 2718.
Org. Lett., Vol. 13, No. 5, 2011
1209