Regioselective C-H functionalization directed by a removable carboxyl group: Palladium-catalyzed vinylation at the unusual position of indole and related heteroaromatic rings

Article abstract of DOI:10.1021/ol8000602

The palladium-catalyzed oxidative vinylation of indole-3-carboxylic acids with alkenes effectively proceeds via directed C-H functionalization and decarboxylation to produce the corresponding 2-vinylated indoles. Similarly, pyrrole-, furan-, and thiophenecarboxylic acids also undergo decarboxylative vinylation.

Full text of DOI:10.1021/ol8000602

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1159-1162
Regioselective C−H Functionalization
Directed by a Removable Carboxyl
Group: Palladium-Catalyzed Vinylation
at the Unusual Position of Indole and
Related Heteroaromatic Rings
Atsushi Maehara, Hayato Tsurugi, Tetsuya Satoh,* and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka UniVersity, Suita,
Osaka 565-0871, Japan
satoh@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.ac.jp
Received January 9, 2008
ABSTRACT
The palladium-catalyzed oxidative vinylation of indole-3-carboxylic acids with alkenes effectively proceeds via directed C−H functionalization
and decarboxylation to produce the corresponding 2-vinylated indoles. Similarly, pyrrole-, furan-, and thiophenecarboxylic acids also undergo
decarboxylative vinylation.
The indole nucleus is found in a great number of biologically
active natural and unnatural compounds, and the synthesis
of its derivatives is of considerable importance in organic
synthesis. Recently, various methods for its derivatization
by means of transition metal catalysis have been developed
in addition to the traditional ones.1 Among the effective,
straightforward strategies for the introduction of a side chain
into indoles is the palladium-catalyzed oxidative direct
vinylation with alkenes via C-H bond cleavage (Fujiwara
reaction).2 The vinylation usually occurs at the electron-rich
C3-position of indoles due to the electrophilic nature of the
reaction. Gaunt and co-workers reported the solvent-
controlled regioselective vinylation of indoles by palladium
catalysis.3 Thus, C3-vinylated products were produced almost
exclusively in DMF/DMSO, whereas C2-vinylation products
predominated in dioxane/acetic acid. However, the C2-
vinylation was performed for only a few sets of substrate
combinations with a relatively high palladium loading.
A general strategy for regioselective C-H functionaliza-
tion is to utilize the coordination of a functional group in a
given substrate to the metal center of a catalyst.4 Various
catalytic C-H alkylation and vinylation reactions of aromatic
substrates bearing such a metal-directing group have been
successfully developed. It was shown that an indole substrate
bearing 2-pyridylmethyl group on the N1-position as the
directing group undergoes C2-vinylation selectively.5
On the other hand, we demonstrated the oxidative coupling
of benzoic acids with alkenes and alkynes involving ortho-
vinylation under palladium-, rhodium-, and iridium cataly-
ses.6 Among them, the iridium-catalyzed reaction of car-
boxylic acids with alkynes is accompanied by decarboxylation
(1) For selected reviews, see: (a) Cacchi, S.; Fabrizi, G. Chem. ReV.
2005, 105, 2873. (b) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000,
1045. (c) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113.
(2) (a) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34,
633. (b) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem.
ReV. 2007, 107, 5318. (c) Tsuji, J. Palladium Reagents and Catalysts, 2nd
ed.; John Wiley & Sons: Chichester, U.K., 2004.
(3) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew.
Chem., Int. Ed. 2005, 44, 3125.
10.1021/ol8000602 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/16/2008

to form naphthalene derivatives as the 1:2 coupling products.6a,7
This indicates that the carboxyl function may act as a unique,
removable directing group. In the context of our further study
of catalytic C-H functionalization,6,8 it has been revealed
that the selective synthesis of 2-vinylindoles can be achieved
by the palladium-catalyzed oxidative coupling of indole-3-
carboxylic acids with alkenes via regioselective vinylation
directed by the carboxyl function and subsequent decar-
boxylation (Scheme 1, Het-CO2H ) indole-3-carboxylic
When 1-methylindole-3-carboxylic acid (1a) (0.4 mmol)
was treated with butyl acrylate (2a) (1.2 mmol) in the
presence of Pd(OAc)2 (0.02 mmol), Cu(OAc)2‚H2O (0.8
mmol), and molecular sieves (MS4A, 400 mg) in DMAc at
120 °C for 2 h under N2, butyl (E)-3-(1-methylindol-2-yl)-
2-propenoate (3a) was formed in 42% yield (entry 1 in Table
1). No 3-vinylated products could be detected by GC-MS
Table 1. Reaction of 1-Methylindole-3-carboxylic Acid (1a)
with Butyl Acrylate (2a)a
Scheme 1
entry
additive
temp (°C)
time (h)
% yield of 3ab
1
2
3
4c
5
6
7
8
120
140
160
140
140
140
140
140
2
2
1
1
2
4
4
4
42
48
42
34
82 (71)
68
46
acids). Furthermore, the protocol has been found to be
applicable to the vinylation of other five-membered het-
eroaromatic systems. These new findings are described
herein.
LiOAc
NaOAc
LiCl
Cs2CO3
52
(4) Reviews: (a) Kakiuchi, F. Top. Organomet. Chem. 2007, 24, 1. (b)
Ackermann, L. Top. Organomet. Chem. 2007, 24, 35. (c) Satoh, T.; Miura,
M. Top. Organomet. Chem. 2007, 24, 61. (d) Kalyani, D.; Sanford, M. S.
Top. Organomet. Chem. 2007, 24, 85. (e) Alberico, D.; Scott, M. E.; Lautens,
M. Chem. ReV. 2007, 107, 174. (f) Jun, C.-H.; Jo, E.-A.; Park, J.-W. Eur.
J. Org. Chem. 2007, 1869. (g) Godula, K.; Sames, D. Science 2006, 312,
67. (h) Satoh, T.; Miura, M. J. Synth. Org. Chem. 2006, 64, 1199. (i) Conley,
B. L.; Tenn, W. J., III; Young, K. J. H.; Ganesh, S. K.; Meier, S. K.;
Ziatdinov, V. R.; Mironov, O.; Oxgaard, J.; Gonzales, J.; Goddard, W. A.,
III; Periana, R. A. J. Mol. Catal. A 2006, 251, 8. (j) Miura, M.; Satoh, T.
Top. Organomet. Chem. 2005, 14, 55. (k) Kakiuchi, F.; Chatani, N. AdV.
Synth. Catal. 2003, 345, 1077. (l) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem.
ReV. 2002, 102, 1731. (m) Miura, M.; Nomura, M. Top. Curr. Chem. 2002,
219, 211. (n) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826. (o)
Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698. (p) Kakiuchi, F.; Murai,
S. Top. Organomet. Chem. 1999, 3, 47. (q) Shilov, A. E.; Shul’pin, G. B.
Chem. ReV. 1997, 97, 2879.
a Reaction conditions: [1a]:[2a]:[Pd(OAc)2]:[Cu(OAc)2‚H2O]:[additive]
) 0.4:1.2:0.02:0.8:1.2 (in mmol), MS4A (400 mg) in DMAc (10 mL) under
N2. b GC yield based on the amount of 1a used. Value in parentheses
indicates yield after purification. c AgOAc (0.8 mmol) was used in place
of Cu(OAc)2‚H2O.
analysis. The yield of 3a was somewhat enhanced at 140
°C (entry 2), while a further elevation of temperature showed
no positive effect (entry 3). As an oxidant, AgOAc was less
effective than the copper salt (entry 4). Fortunately, the yield
of 3a was almost doubled by addition of LiOAc (1.2 mmol)
(entry 5). Other alkali metal salts examined were less
effective than LiOAc (entries 6-8). It was confirmed that,
under similar conditions, 1-methylindole (4) reacted with 2a
to give C3-vinylated product 5 selectively in 62% yield
(Scheme 2).
(5) Capito, E.; Brown, J. M.; Ricci, A. Chem. Commun. 2005, 1854.
(6) (a) Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007, 72, 5362.
(b) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407. (c) Miura,
M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M. J. Org. Chem. 1998,
63, 5211.
(7) The catalytic decarboxylation7a,b,e,g as well as decarboxylative
arylation7c-h,l and vinylation reactions7i-k of carboxylic acids have recently
been reported: (a) Goossen, L. J.; Thiel, W. R.; Rodr´ıguez, N.; Linder, C.;
Melzer, B. AdV. Synth. Catal. 2007, 349, 2241. (b) Dickstein, J. S.;
Mulrooney, C. A.; O’Brien, E. M.; Morgan, B. J.; Kozlowski, M. C. Org.
Lett. 2007, 9, 2441. (c) Gribkov, D. V.; Pastine, S. J.; Schnu¨rch, M.; Sames,
D. J. Am. Chem. Soc. 2007, 129, 11750. (d) Goossen, L. J.; Melzer, B. J.
Org. Chem. 2007, 72, 7473. (e) Goossen, L. J.; Rodr´ıguez, N.; Melzer, B.;
Linder, C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824. (f)
Becht, J.-M.; Catala, C.; Le Drian, C.; Wagner, A. Org. Lett. 2007, 9, 1781.
(g) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662. (h)
Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.; Bailey, M. D.;
Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11350. (i) Tanaka, D.; Romeril,
S. P.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 10323. (j) Tanaka, D.;
Myers, A. G. Org. Lett. 2004, 6, 433. (k) Myers, A. G.; Tanaka, D.;
Mannion, M. R. J. Am. Chem. Soc. 2002, 124, 11250. (l) Okazawa, T.;
Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2002, 124, 5286.
(8) For example: (a) Uto, T.; Shimizu, M.; Ueura, K.; Tsurugi, H.; Satoh,
T.; Miura, M. J. Org. Chem. 2008, 73, 298. (b) Nakano, M.; Satoh, T.;
Miura, M. J. Org. Chem. 2006, 71, 8309. (c) Terao, Y.; Wakui, H.; Nomoto,
N.; Satoh, T.; Miura, M.; Nomura, M. J. Org. Chem. 2003, 68, 5236. (d)
Terao, Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem.
Soc. 2001, 123, 10407. (e) Nishinaka, Y.; Satoh, T.; Miura, M.; Nomura,
M.; Matsui, H.; Yamaguchi, C. Bull. Chem. Soc. Jpn. 2001, 74, 1727. (f)
Satoh, T.; Inoh, J.-I.; Kawamura, Y.; Kawamura, Y.; Miura, M.; Nomura,
M. Bull. Chem. Soc. Jpn. 1998, 71, 2239.
Scheme 2
a GC yield. Value in parentheses indicates yield after purification.
Table 2 summarizes the results for the coupling reactions
of a series of 1-substituted indole-3-carboxylic acids and
alkenes using the catalyst system of Pd(OAc)2/Cu(OAc)2‚
H2O/LiOAc. Acrylic acid derivatives 1b-d and styrene (1e)
underwent the coupling with 1a to produce the corresponding
1160
Org. Lett., Vol. 10, No. 6, 2008

possible roles of added LiOAc is to provide acetate anions
as ligand to prevent the deactivation of Pd(0) to metallic
species.10
Table 2. Reaction of Indole-3-carboxylic Acids 1a-d with
Alkenes 2a-ea
Next, the vinylation of other various heteroarene carbox-
ylic acids was examined under similar reaction conditions.
Expectedly, 1-methylindole-2-carboxylic acid (6a) reacted
with 2a via C3-vinylation and decarboxylation to form
compound 7a () 5) selectively in 85% yield (entry 1 in Table
3). Similarly, 3-vinylated pyrrole 7b could be obtained
time
(h)
product,
% yieldb
entry
1
R1
2
R2
1
2
3
4
5
6
7
1a Me
1a Me
1a Me
1a Me
1b MeOCH2
1c Ph
2b CO2Et
2c CO2Cyc
2d CO2(t-Bu)
2e Ph
2a CO2Bu
2a CO2Bu
8
4
8
1
8
8
4
3b, 71 (58)
3c, 68 (62)
3d, 61 (54)
3e, 58 (47)
3f, 55 (50)
3g, 51 (43)
3h, 48 (39)
Table 3. Reaction of Heteroarenecarboxylic Acids 6a-f with
2aa
1d 4-MeC6H4 2a CO2Bu
a Reaction conditions: [1]:[2]:[Pd(OAc)2]:[Cu(OAc)2‚H2O]:[LiOAc] )
0.4:1.2:0.02:0.8:1.2 (in mmol), MS4A (400 mg), in DMAc (10 mL) at 140
°C under N2. b GC yield based on the amount of 1a used. Value in
parentheses indicates yield after purification. c Cy ) cyclohexyl.
2-vinylindoles 3b-e selectively (entries 1-4). 1-(Meth-
oxymethyl)- and 1-arylindole-3-carboxylic acids 1b-d were
also coupled with 2a on their 2-position exclusively to give
3f-h (entries 5-7). The reaction of 1-unprotected indole-
3-carboxylic acid, however, did not proceed.
A plausible mechanism for the reaction of indole-3-
carboxylic acids 1 with alkenes 2 is illustrated in Scheme 3.
Scheme 3
a Reaction conditions: [6]:[2a]:[Pd(OAc)2]:[Cu(OAc)2‚H2O]:[LiOAc] )
0.4:1.2:0.02:0.8:1.2 (in mmol), MS4A (400 mg), in DMAc (10 mL) at 140
°C under N2. b GC yield based on the amount of 6 used. Value in parentheses
indicates yield after purification. c C3 ) 3-vinylated products; C2 )
2-vinylated products. d At 120 °C. e Benzothiophene was also formed (16%).
f Without LiOAc.
Coordination of the carboxyl oxygen to Pd(OAc)2 with
liberation of AcOH gives a palladium(II) carboxylate A.
Then, directed palladation at the C2-position forming a
palladacycle intermediate B, alkene insertion, and â-hydride
elimination successively occur to produce a hydridopalladium
carboxylate C. The subsequent steps involving decarbox-
ylation and reductive elimination take place to form 2-vi-
nylindole 3. The resulting Pd(0) species may be oxidized in
the presence of the copper(II) salt to regenerate Pd(OAc)2.
During palladium-catalyzed oxidative reactions, in general,
the regeneration of Pd(II) from Pd(0) is considered to be
the crucial step to determine catalyst efficiency.9 One of the
exclusively in 74% yield from 1-methylpyrrole-2-carboxylic
acid (6b) (entry 2). This is one of the rare examples of the
selective C3-vinylation of pyrroles. Usual electrophilic
substitution reactions are known to take place at the C2-
position predominantly. There is, to our knowledge, only one
example of C3-vinylation in which the reaction is sterically
controlled by the bulky 1-TIPS group on pyrrole.11 The C3-
(10) Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 576, 254 and
references therein.
(9) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400 and references
therein.
(11) Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem.
Soc. 2006, 128, 2528.
Org. Lett., Vol. 10, No. 6, 2008
1161

vinylation of benzofurans is also rare, because it is electrically
and sterically unfavorable. The present directed decarboxy-
lative vinylation method was found to be applicable to it.
Thus, the reaction of benzofuran-2-carboxylic acid (6c) with
2a gave C3-vinylated product 7c predominantly, while a trace
amount (less than 2% yield) of the C2-vinylated isomer was
formed (entry 3). On the other hand, in the reaction of
benzothiophene-2-carboxylic acid (6d) with 2a under similar
conditions, C3- and C2-vinylated products were obtained in
a ratio of 7:1, along with a considerable amount (16%) of
unsubstituted benzothiophene (entry 4). As with 1-methylin-
dole (Scheme 2), benzothiophene itself underwent C2-
vinylation predominantly under similar conditions (31%, C3:
C2 ) 1:9). Therefore, at least part of the C2-vinylated
product formed in the reaction of 6d seems to arise from
the sequence of the initial decarboxylation and subsequent
non-directed vinylation of the resulting benzothiophene.
From furan- and thiophene-2-carboxylic acids, 6e and 6f,
mixtures of the corresponding C3- and C2-vinylated products
were formed (entries 5 and 6).
with alkenes proceeds efficiently via directed C-H vinylation
and decarboxylation to exclusively give the corresponding
2-vinylindoles. Other related heteroarenecarboxylic acids also
undergo the vinylation. The selective C3-vinylation of
N-methylpyrrole-2- and benzofuran-2-carboxylic acids is
notable. In these reactions, the carboxyl function effectively
acts as a unique, removable directing group. Work is
underway toward further development of relevant reactions
around the key functional group.
Acknowledgment. This work was partly supported by
Grants-in-Aid from the Ministry of Education, Culture,
Sports, Science and Technology, Japan and the Sumitomo
Foundation.
Supporting Information Available: Standard experi-
mental procedure and characterization data of products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have demonstrated that the palladium-
catalyzed oxidative coupling of indole-3-carboxylic acids
OL8000602
1162
Org. Lett., Vol. 10, No. 6, 2008