Fused ring construction around pyrrole, indole, and related compounds via palladium-catalyzed oxidative coupling with alkynes

Article abstract of DOI:10.1021/jo9016698

(Chemical Equation Presented) The selective synthesis of 1,2,3,4-tetrasubstituted carbazoles can be performed effectively through the palladium-catalyzed oxidative coupling reactions of N-substituted indoles or their carboxylic acid derivatives with alkyn

Full text of DOI:10.1021/jo9016698

pubs.acs.org/joc
Fused Ring Construction around Pyrrole, Indole, and Related Compounds
via Palladium-Catalyzed Oxidative Coupling with Alkynes
Mana Yamashita, Hakaru Horiguchi, Koji Hirano, 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 July 31, 2009
The selective synthesis of 1,2,3,4-tetrasubstituted carbazoles can be performed effectively through the
palladium-catalyzed oxidative coupling reactions of N-substituted indoles or their carboxylic acid
derivatives with alkynes. Unsymmetrically octasubstituted carbazoles can also be obtained by the
stepwise couplings of 1-methylpyrrole-2-carboxylic acid with two different alkynes. In addition, the
present coupling procedure is applicable to the synthesis of other various heteroarenes possessing di-,
tri-, and tetracyclic cores. Some of the products exhibit intense fluorescence in the solid state.
Introduction
selectively produce fused aromatic and heteroaromatic com-
pounds, which are widely seen in organic functional materi-
als.3 As such an example, we have demonstrated that the
oxidative coupling of benzoic acids with alkynes takes place
effectively,4 in which the carboxylic function acts as the
directing group4,5 to enable the regioselective annulation.
Thus, their 1:1 and 1:2 coupling products, isocoumarin and
naphthalene derivatives, can be selectively obtained under
rhodium and iridium catalyzes, respectively (Scheme 1). The
latter involves double alkyne incorporation with decarboxyl-
ation. These reactions seem to be of considerable synthetic
The intermolecular coupling of aromatic substrates with
internal alkynes by transition-metal catalysis is now recog-
nized to be a powerful tool to construct π-conjugated
molecules.1 In particular, the catalytic oxidative coupling
of these substrates via regioselective C-H bond cleavage
with the aid of a directing group is a versatile and attractive
way from atom- and step-economic points of view2 to
€
(1) For example, see: (a) Brase, S.; de Meijere, A. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-
Interscience: New York, 2002; Vol. 1, Chapter IV.3, pp 1369-1429. (b) Tsuji, J.
Palladium Reagents and Catalysts, 2nd ed.; John Wiley & Sons: Chichester, UK,
(3) Selected reviews: (a) Anthony, J. E. Angew. Chem., Int. Ed. 2008, 47,
€
€
452. (b) Watson, M. D.; Fethtenkotter, A.; Mullen, K. Chem. Rev. 2001, 101,
€
2004; pp 201-265. (c) Brase, S.; de Meijere, A. In Metal-Catalyzed Cross-
€
Coupling Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004; Vol. 1, pp 224-276. (d) Balme, G.; Bouyssi, D.; Monteiro, N. In Multi-
1267. (c) Mitschke, U.; Bauerle, P. J. Mater. Chem. 2000, 10, 1471. (d) Harvey,
R. G. Polycyclic Aromatic Hydrocarbons; Wiley-VCH: New York, 1996.
(4) (a) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009,
74, 6295. (b) Shimizu, M.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem.
2009, 74, 3478. (c) Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007, 72,
5362. (d) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407.
(5) For recent examples utilizing a carboxylic function as a directing
group, see: (a) Miyasaka, M.; Fukushima, A.; Satoh, T.; Hirano, K.; Miura
Chem.;Eur. J. 2009, 15, 3674. (b) Wang, C.; Piel, I.; Glorius, F. J. Am.
Chem. Soc. 2009, 131, 4194. (c) Wang, D.-H.; Mei, T.-S.; Yu, J.-Q. J. Am.
Chem. Soc. 2008, 130, 17676. (d) Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008,
130, 14082. (e) Chiong, H. A.; Pham, Q.-N.; Daugulis, O. J. Am. Chem. Soc.
2007, 129, 9879. (f) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano,
S. P.; Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129, 3510. (g)
Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.; White, M. C. J. Am. Chem.
Soc. 2006, 128, 9032. (h) Lee, J. M.; Chang, S. Tetrahedron Lett. 2006, 47,
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component Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim,
2005; pp 224-276.
(2) Selected reviews: (a) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013.
(b) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41,
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DOI: 10.1021/jo9016698
r
Published on Web 08/31/2009
J. Org. Chem. 2009, 74, 7481–7488 7481
2009 American Chemical Society

Yamashita et al.
JOCArticle
SCHEME 1. Oxidative Coupling of Benzoic Acid with Alkynes
known to be capable of occurring regioselectively even with-
out the aid of any directing groups. We have also succeeded
in conducting the oxidative coupling of 1-methylindole itself
with alkynes to furnish the 1,2,3,4-tetrasubstituted carba-
zoles.10 The detailed results of these new coupling reactions
on not only indole but also pyrrole, benzofuran, furan, and
benzothiophene rings are described herein.
SCHEME 2. Oxidative Coupling of 1-Methylindole-3-carboxylic
Acid with Alkynes
Results and Discussion
We recently reported that 1-methylindole-3-carboxylic acid
(1a) smoothly underwent the oxidative coupling with alkenes
in the presence of Pd(OAc)2, Cu(OAc)2 H2O, and LiOAc as
3
catalyst, oxidant, and additive, respectively.11 In an initial
attempt, 1a (0.8 mmol) was treated with diphenylacetylene
(2a) (0.8 mmol) under similar conditions, using Pd(OAc)2
(0.02 mmol), Cu(OAc)2 H2O (0.8 mmol), LiCl (1.2 mmol),
3
and molecular sieves (MS4A, 400 mg) in DMAc (2.5 mL) at
140 °C under N2 for 2 h. As a result, the corresponding 1:2
coupling product 3a was formed in 64% yield (entry 1 in
Table 1). At 120 °C, 3a was found to be obtained almost
quantitatively (entry 2), while the yield was significantly
reduced at 100 °C (entry 3). Decreasing the amount of 1a to
0.6 mmol did not affect the reaction efficiency (entry 4,
conditions A). Under similar conditions, 1-methylindole-2-
carboxylic acid (1c) also reacted with 2a, but the yield of 3a
was considerably lower (71%, entry 5). Meanwhile, 3a could
not be obtained at all from the reaction using 1-methylindole
(1b) in place of 1a and 1c with 2a (entry 6). With the addition
of benzoic acid (0.2 mmol) as promoter,12 however, a small
amount of 3a was formed using 1b (entry 7). The reaction with
1b and 2a in a ratio of 0.4:1.2 in mesitylene (4 mL) gave 3a in
33% yield (entry 9). Under the conditions using Ag2CO3/
PhCO2H as oxidant and additive, respectively, in place of
utility because of wide availability of the acids as aryl
sources.
During our further study of the scope of the reactions, it
has been found that heteroarene carboxylic acids such as
1-methylindole-3-carboxylic acid hardly undergo the decar-
boxylative 1:2 coupling with the Ir catalyst (Scheme 2,
path b), while the corresponding lactones can be obtained
as 1:1 coupling products under rhodium catalysis (path a).4b
To our delight, the 1:2 coupling has been observed to proceed
efficiently by the use of a palladium catalyst to produce the
corresponding 1,2,3,4-tetrasubstituted carbazole derivatives
selectively (path c).6 Highly substituted carbazoles have been
attractive synthetic targets in medicinal chemistry and ma-
terials fields because of their interesting biological activities
as well as photophysical and optoelectronic properties.7
Expectedly, some of the carbazoles obtained by this protocol
have been found to show solid-state fluorescence.
Cu(OAc)2 H2O/LiOAc/PhCO2H, 3a was obtained in 59%
3
yield (entry 10). In this case, a small amount (ca. 5%) of
1,2,3,4-tetraphenylnaphthalene, which may be formed by the
oxidative1:2 coupling of PhCO2Hwith2a,13 was also detected
by GC-MS analysis. Eliminating PhCO2H suppressed the
reaction completely (entry 11). Expectedly, the use of 2,6-
dimethylbenzoic acid in place of PhCO2H avoided the
naphthalene formation, and the yield of 3a was improved
upto 74%(entry 12, conditions B). However, theseconditions
were not suitable for the reactions of 1a and 1c with 2a. Thus,
the yields of 3a were lower than those under conditions A
(entries 13 and 14 versus entries 4 and 5, respectively).
Meanwhile, the palladium-catalyzed direct arylation8 and
vinylation9 of various heteroaromatics including indoles are
(6) Preliminary communication: Yamashita, M.; Hirano, K.; Satoh, T.;
Miura, M. Org. Lett. 2009, 11, 2337.
(7) For recent examples, see: (a) Adhikari, R. M.; Neckers, D. C.; Shah,
B. K. J. Org. Chem. 2009, 74, 3341. (b) Jordan-Hore, J. A.; Johansson, C. C.
C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184.
(c) Tsuchimoto, T.; Matsubayashi, H.; Kaneko, M.; Nagase, Y.; Miyamura,
T.; Shirakawa, E. J. Am. Chem. Soc. 2008, 130, 15823. (d) Janosik, T.;
Next, the reactions of 1a and 1b with various internal
alkynes were examined under conditions A and B, respec-
tively. Methyl- (2b), methoxy- (2c), and chloro-substituted
(2d) diphenylacetylenes smoothly underwent coupling with
1a and 1b to afford the corresponding 1,2,3,4-tetraaryl-9-
methylcarbazoles 3b-d (entries 1-6 in Table 2). The product
yields were slightly higher in the cases with 1a under conditions
€
Wahlstrom, N.; Bergman, J. Tetrahedron 2008, 64, 9159. (e) Song, Y.; Di, C.;
Wei, Z.; Zhao, T.; Xu, W.; Liu, Y.; Zhang, D.; Zhu, D. Chem.;Eur. J. 2008,
14, 4731. (f) Tsang, W. C. P.; Munday, R. H.; Brasche, G.; Zheng, N.;
ꢀ
Buchwald, S. L. J. Org. Chem. 2008, 73, 7603. (g) Liegault, B.; Lee, D.;
Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org. Chem. 2008, 73, 5022.
(h) Kuwahara, A.; Nakano, K.; Nozaki, K. J. Org. Chem. 2005, 70, 413.
(i) Qiao, X.; Ho, D. M.; Pascal, R. A., Jr. J. Org. Chem. 1996, 61, 6748. For a
€
review, see: (j) Knolker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303.
(8) Selected reviews: (a) Liegault, B.; Lapointe, D.; Caron, L.; Vlassova,
ꢀ
(10) It was recently reported that the palladium-catalyzed oxidative
annulation of monosubstituted benzenes with alkynes gave the correspond-
ing naphthalenes as mixtures of regioisomers: Wu, Y.-T.; Huang, K.-H.;
Shin, Wu, T.-C. Chem.;Eur. J. 2008, 14, 6697.
(11) Maehara, A.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett. 2008, 10,
1159.
(12) For recent examples, see: (a) Ackermann, L.; Vicente, R.;
Althammer, A. Org. Lett. 2008, 10, 2299. (b) Lafrance, M.; Lapointe, D.;
Fagnou, K. Tetrahedron 2008, 64, 6015. (c) Pascual, S.; de Mendoza, P.;
Braga, A. A. C.; Maseras, F.; Echavarren, A. M. Tetrahedron 2008, 64, 6021.
(13) For an Ir-catalyzed version, see ref 4c.
A.; Fagnou, K. J. Org. Chem. 2009, 74, 1826. (b) Mori, A.; Sugie, A. Bull.
Chem. Soc. Jpn. 2008, 81, 548. (c) Seregin, I. V.; Gevorgyan, V. Chem. Soc.
Rev. 2007, 36, 1173. (d) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200.
(9) (a) Maehara, A.; Satoh, T.; Miura, M. Tetrahedron 2008, 64, 5982.
(b) Beck, E. M.; Grimster, N. P.; Hatley, R. H.; Gaunt, M. J. J. Am. Chem.
Soc. 2006, 128, 2528. (c) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125. (d) Tani, M.; Sakaguchi,
S.; Ishii, Y. J. Org. Chem. 2004, 69, 1221. For reviews, see: (e) Fujiwara, Y.;
Jintoku, T.; Takaki, K. CHEMTECH 1990, 636. (f) Jia, C.; Kitamura, T.;
Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633.
7482 J. Org. Chem. Vol. 74, No. 19, 2009

Yamashita et al.
JOCArticle
TABLE 1. Synthesis of 9-Methyl-1,2,3,4-tetraphenylcarbazole (2a)a
entry
lc
1
Y
Z
l/2a (mmol)
oxidant
additive
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc/PhCO2H
LiOAc/PhCO2H
LiOAc/PhCO2H
PhCO2H
solvent
T (°C)
time (h)
% yield of 3ab
1a
1a
1a
1a
1c
1b
1b
1b
1b
1b
1b
1b
1a
1c
H
H
H
H
CO2H
CO2H
CO2H
CO2H
H
0.8/0.8
0.8/0.8
0.8/0.8
0.6/0.8
0.6/0.8
0.6/0.8
0.6/0.8
0.4/1.2
0.4/1.2
0.4/1.2
0.4/1.2
0.4/1.2
0.4/1.2
0.4/1.2
Cu(OAc)2 H2O
Cu(OAc)2 H2O
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
140
120
100
120
120
120
120
120
120
120
120
120
120
120
2
6
8
9
8
8
8
8
8
8
8
8
8
8
64 (60)
99 (80)
61
99
71
0
10
13
33
59
0
74 (70)
69
2
3
2c
3c
4c
5c
6
7
8
9
10
11
12
13
14
3
Cu(OAc)2 H2O
Cu(OAc)2 H2O
3
3
CO2H
H
Cu(OAc)2 H2O
Cu(OAc)2 H2O
3
H
H
H
H
H
H
H
3
H
H
H
H
H
H
Cu(OAc)2 H2O
Cu(OAc)2 H2O
Cu(OAc)2 H2O
3
3
3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
2,6-Me2C6H3CO2H
2,6-Me2C6H3CO2H
2,6-Me2C6H3CO2H
H
CO2H
CO2H
H
aReaction conditions: Pd(OAc)2 (0.02 mmol), oxidant (0.8 mmol), (LiOAc (1.2 mmol)), (ArCO2H (0.2 mmol)), MS4A (400 mg), DMAc (2.5 mL), or
mesitylene (4 mL) under N2. bGC yield. Value in parentheses indicates yield after purification. cMS4A (400 mg) was added.
TABLE 2. Synthesis of 1,2,3,4-Tetrasubstituted 9-Methylcarbazoles 3a
the establishment of conditions A0, which are suitable for the
reaction with dialkylacetylenes. Thus, when an excess amount
of 2g (1a/2g=1:4) in the presence of LiOH H2O (1.2 mmol)
3
was used as well as LiOAc (2.4 mmol) as additive at 100 °C
under air, 3g was obtained in 58% yield (entry 9). The reaction
of 1b with 2g under conditions B gave 3g in only 10% yield
(entry 10). The reaction of 1a with 8-hexadecyne (2h) under
conditions A0 proceeded effectively to give 1,2,3,4-tetraheptyl-
9-methylcarbazole (3h) in 55% yield (entry 11). On the other
hand, treatment of an electron-deficient alkyne, bis[4-(trifluor-
omethyl)phenyl]acetylene (2i), with 1a predominantly gave not
the desired carbazole 3i but an O-H adduct, (Z)-1-(1-methy-
lindole-3-carboxy)-1,2-bis[4-(trifluoromethyl)phenyl]ethene (4),
in 46% yield (entry 12). For producing 3i, the reaction with 1b
under conditions B gave a better result. Thus, in the latter case,
3i was obtained in 66% yield (entry 13). Even with a more
electron-deficient alkyne, diethyl acetylenedicarboxylate (2j),
the reaction of 1b took place similarly to form 3j in 45% yield
(entry 14).
entry
1
Z
2
R
conditions time (h) 3, % yield
1
2
3
4
5
6
7
8
9
1a CO2H 2b 4-MeC6H4
1b 2b 4-MeC6H4
1a CO2H 2c 4-MeOC6H4
1b 2c 4-MeOC6H4
1a CO2H 2d 4-ClC6H4
A
B
A
B
A
B
A
A
A0
B
A0
A
B
8
10
8
10
12
10
9
3b, 82
3b, 70
3c, 75
3c, 67
3d, 62
3d, 57
3e, 85
3f, 72
3g, 58
3g, 10b
3h, 55
3i, 12b,?c
3i, 66
H
H
1b
H
2d 4-ClC6H4
1a CO2H 2e 4-ButC6H4
1a CO2H 2f 4-FC6H4
1a CO2H 2g Pr
9
10
10
10
9
10
10
10 1b
11 1a CO2H 2h heptyl
12 1a CO2H 2i 4-CF3C6H4
13 1b
14 1b
aReaction conditions A: 1 (0.6 mmol), 2 (0.8 mmol), Pd(OAc)2
(0.02 mmol), Cu(OAc)2 H2O (0.8 mmol), LiOAc (1.2 mmol), MS4A
(400 mg), DMAc (2.5 mL) at 120 °C under N2. Reaction conditions B: 1
(0.3 mmol), 2 (0.9 mmol), Pd(OAc)2 (0.015 mmol), Ag2CO3 (0.6 mmol),
2,6-Me2C6H3CO2H (0.15 mmol), mesitylene (3 mL) at 120 °C under N2.
Reaction conditions A0: 1a (0.4 mmol), 2 (1.6 mmol), Pd(OAc)2
H
2g Pr
The reaction of 1a with 2 seems to be initiated via fundamen-
tally similar steps to those proposed for the oxidative coupling of
H
H
2i 4-CF3C6H4
2j CO2Et
B
3j, 45
0
1a with alkenes using the Pd(OAc)2/Cu(OAc)2 H2O/LiOAc
system.11 Thus, as depicted in Scheme 3, coordination of the
carboxyl oxygen to Pd(OAc)2 with liberation of AcOH gives a
palladium(II) carboxylate A, and directed palladation at the C2-
position forms a palladacycle intermediate B. Subsequent
alkyne insertion14 and decarboxylation occur to produce a
five-membered palladacycle intermediate D.15 Then, the second
alkyne insertion and reductive elimination steps take place to
3
(0.02 mmol), Cu(OAc)2 H2O (0.8 mmol), LiOAc (2.4 mmol),
3
LiOH H2O (1.2 mmol), MS4A (400 mg), DMAc (2.5 mL) at 100 °C
3
under air. bGC yield. c(Z)-1-(1-Methylindole-3-carboxy)-1,2-bis-
[4-(trifluoromethyl)phenyl]ethene (4) was also formed in 46% yield.
(14) For examples of the stoichiometric reactions of palladacycles with
alkynes, see: (a) Wu, G.; Rheingold, A. L.; Geib, S. J.; Heck, R. F.
Organometallics 1987, 6, 1941. (b) Wu, G.; Rheingold, A. L.; Heck, R. F.
Organometallics 1987, 6, 2386. For a review, see: (c) Vila, J. M.; Pereira, M. T.
In Palladacycles; Dupont, J., Pfeffer, M., Eds.; Wiley-VCH: Weinheim, 2008; pp
87-108.
(15) However, the participation of other sequences involving decarboxyl-
ation on A (Scheme 3) or a copper carboxylate cannot be excluded (see refs 5i
and 7k, respectively).
A than those in the cases with 1b under conditions B. The
reactions of tert-butyl- (2e) and fluoro-substituted (2f) alkynes
with 1a also proceeded efficiently to produce carbazoles 3e and
3f in good yields (entries 7 and 8). Compared to these diaryl-
acetylenes, 4-octyne (2g) was found to be less reactive. Some
screening experiments with respect to reaction conditions led to
J. Org. Chem. Vol. 74, No. 19, 2009 7483

Yamashita et al.
JOCArticle
SCHEME 3. Plausible Mechanism for the Oxidative Coupling
of 1-Methylindole-3-carboxylic Acid (1a) with Alkynes 2
lective palladation-deprotonation step, as suggested in the
ruthenium-catalyzed direct arylation of aromatic C-H bonds
using this cocatalyst.12a The parallel use of Ag2CO3 as oxidant
rather than Cu(OAc)2 H2O may facilitate the coordination of
3
the benzoate on the Pd center, although the details of the
operation mechanism are not clear at the present time.
Table 3 summarizes the results for the coupling reactions
of various heteroarenes and their carboxylic acid derivatives
with 2a. Under conditions A, 1-(methoxymethyl)indole-
3-carboxylic acid (1d) underwent the coupling with 2a to
produce the corresponding carbazole 3k selectively in 72%
yield (entry 1). The carbazole 3k was also obtained in 38%
yield by the reaction of the parent 1-(methoxymethyl)indole
(1e) with 2a under conditions B (entry 2). One of reasons for
the lower efficiency in the latter case is due to the deprotec-
tion of once produced 3k to form N-unsubstituted 1,2,3,4-
tetraphenyl-9H-carbazole (3l) under conditions B. The reac-
tion of 1-phenylindole-3-carboxylic acid (1f) with 2a gave a
mixture of 1:2 and 1:1 coupling products. Thus, when these
substrates were treated using Pd(OAc)2 (0.04 mmol) for 12 h,
not only the expected product, 1,2,3,4,9-pentaphenyl-9H-
carbazole (3m) (14%), but also a tetracyclic compound, 5,6-
diphenylindolo[1,2-a]quinoline (5a) (32%), was formed by a
vinyl bridging (entry 3). In contrast, only 3m was obtained in
the reaction of 1-phenylindole (1g) under conditions B albeit
with a low yield (entries 4 and 5). Imidazo[1,2-a]pyridine (1h)
(0.8 mmol) also reacted with 2a (0.4 mmol) in a ratio of 1:1
under modified conditions A using a mixture of pivalic acid
(2 mL) and DMAc (1 mL) as a solvent system to afford a
tricyclic product 6 (entry 6).19 The yield of 6 decreased to less
than 10% under conditions B or similar ones using silver
oxidants. From the reaction of 1-methylpyrrole-2-carboxylic
acid (7a), a highly substituted indole derivative 8a was
obtained in 61% yield (entry 7). In this case, increasing in
the amounts of the substrate 7a (0.8 mmol) and LiOAc (2.4
mmol) resulted in a better product yield. Expectedly, product
8a could undergo further oxidative coupling under condi-
tions B (vide infra).
SCHEME 4. Plausible Mechanism for the Oxidative Coupling
of 1-Methylindole (1b) with Alkynes 2
produce carbazole 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.16 One of
the possible roles of added LiOAc is to provide acetate anions as
ligand to prevent the deactivation of Pd(0) to metallic species.17
In the cases using dialkylacetylenes, the addition of
LiOH H2O in combination with LiOAc improved the reac-
3
tion efficiency. Without this base, the formation of 1:1
oxidative coupling products together with 3 was detected
by GC-MS. One of its possible roles appears to be the trap
of acids formed during the reaction, which may induce the
ring-opening of palladacycle intermediates such as C and D
to form the corresponding acyclic vinylpalladium species.
Such aliphatic vinylpalladium intermediates are known
to undergo β-hydrogen elimination to produce allene
derivatives.18
Meanwhile, the reactions of benzofuran- (7b) and furan-
2-carboxylic acids (7d) with 2a were found to proceed
effectively under air with the addition of an appropriate
acid. The reaction of 7b using LiOH H2O (1.2 mmol)
3
The reaction of 1b with 2 seems to proceed via a route
similar to those proposed for the palladium-catalyzed direct
arylation and vinylation reactions.2,8,9 As in the initial step of
these reactions, regioselective direct palladation on the in-
dole ring occurs at the 3-position to form an indol-3-ylpalla-
dium species E (Scheme 4). It was confirmed that the
oxidative coupling of 1b with butyl acrylate using a Pd-
and 2,2-dimethylsuccinic acid (2.4 mmol) as additives in
place of LiOAc afforded 1,2,3,4-tetraphenyldibenzofuran
(9a) in 72% yield (entry 8). In the reaction of 7d, once
produced 1,2,3,4-tetraphenylbenzofuran (9b) was decom-
posed under conditions A. Therefore, the amount of
Cu(OAc)2 H2O was decreased to 0.05 mmol under air,
3
and pivalic acid (2.4 mmol) was added in place of LiOAc.
Under such modified conditions, 9b was obtained with a
substantial yield (entry 10). The reaction of benzofuran
(7c) itself under conditions B hardly proceeded to give
only a trace amount of 9a (entry 9). The couplings of
benzothiophene-2-carboxylic acid (7e) as well as benzo-
thiophene (7f) were sluggish under the conditions exami-
ned (entries 11 and 12).
(OAc)2/Cu(OAc)2 H2O/LiOAc system gave 3-vinylated
3
product selectively.11 In the present coupling with 2, the
alkyne insertion into the Pd-C bond of E occurs to form a
vinylpalladium intermediate F. Subsequently, the second
alkyne insertion, cyclopalladation at the 2-position of the
indole ring, and final reductive elimination may take place to
produce 3. The use of 2,6-dimethylbenzoic acid as cocatalyst
in less polar mesitylene appears to promote the first regiose-
(19) For recent examples of the direct arylation and vinylation of 1h, see:
(a) Koubachi, J.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G.
Synthesis 2009, 271. (b) Koubachi, J.; Kazzouli, S. E.; Berteina-Raboin, S.;
Mouaddib, A.; Guillaumet, G. J. Org. Chem. 2007, 72, 7650. (c) Koubachi,
J.; Kazzouli, S. E.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G.
Synlett 2006, 3237.
(16) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400.
(17) Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 576, 254 and
references therein.
(18) For example, see: Pivsa-Art, S.; Satoh, T.; Miura, M.; Nomura, M.
Chem. Lett. 1997, 823.
7484 J. Org. Chem. Vol. 74, No. 19, 2009

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TABLE 3. Synthesis of Fused Heteroaromatic Compoundsa
aReaction conditions A: 1 or 7 (0.6 mmol), 2a (0.8 mmol), Pd(OAc)2 (0.02 mmol), Cu(OAc)2 H2O (0.8 mmol), LiOAc (1.2 mmol), MS4A (400 mg),
3
DMAc (2.5 mL) at 120 °C under N2. Reaction conditions B: 1 or 7 (0.3 mmol), 2a (0.9 mmol), Pd(OAc)2 (0.015 mmol), Ag2CO3 (0.6 mmol), 2,6-
Me2C6H3CO2H (0.15 mmol), mesitylene (3 mL) at 120 °C under N2. Reaction conditions C: 7d (0.8 mmol), 2a (0.8 mmol), Pd(OAc)2 (0.02 mmol),
Cu(OAc)2 H2O (0.05 mmol), pivalic acid (2.4 mmol), MS4A (400 mg), DMAc (2.5 mL) at 120 °C under air. bGC yield. cPd(OAc)2 (0.04 mmol) was used.
3
dIn DMAc. e1h (0.8 mmol) and 2a (0.4 mmol) were used in the absence of MS4A in pivalic acid (2 mL)/DMAc (1 mL). f7 (0.8 mmol) was used. gLiOAc
i
j
(2.4 mmol) was used. hLiOH H2O (1.2 mmol) and 2,2-dimethylsuccinic acid (2.4 mmol) were used in place of LiOAc. Under air. LiOH H2O
(1.2 mmol), 2,2-dimethylsuccinic acid (2.4 mmol), and ZnCl2 (0.8 mmol) were used in place of LiOAc.
3
3
Next, the stepwise synthesis of unsymmetrically substi-
tuted carbazole derivatives was examined. Thus, in the first
step, 7a (2.4 mmol) was treated with 2b (2.4 mmol) in
the presence of Pd(OAc)2 (0.06 mmol), Cu(OAc)2 H2O
3
(2.4 mmol), LiOAc (7.2 mmol), and MS4A (800 mg)
in DMAc (7.5 mL) at 120 °C under N2 for 6 h. Then, for-
J. Org. Chem. Vol. 74, No. 19, 2009 7485

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TABLE 4. Synthesis of Unsymmetrically Substituted Carbazoles 10a
aReaction conditions: (i) 7a (2.4 mmol), 2 (2.4 mmol), Pd(OAc)2 (0.06 mmol), Cu(OAc)2 H2O (2.4 mmol), LiOAc (7.2 mmol), MS4A (800 mg),
3
DMAc (7.5 mL) at 120 °C under N2 for 6 h; (ii) 8 (0.4 mmol), 20 (1.2 mmol), Pd(OAc)2 (0.02 mmol), Ag2CO3 (0.8 mmol), 2,6-Me2C6H3CO2H (0.2 mmol),
mesitylene (4 mL) at 120 °C under N2 for 8 h. bWith 7a (1.2 mmol) and 2 (4.8 mmol) at 100 °C for 10 h (for step i).
med 1-methyl-4,5,6,7-tetrakis(4-methylphenyl)indole (8b)
(0.4 mmol) was treated with 2a (1.2 mmol) as the second
alkyne in the presence of Pd(OAc)2 (0.02 mmol), Ag2CO3
(0.8 mmol), and 2,6-dimethylbenzoic acid (0.2 mmol) in
mesitylene (4 mL) at 120 °C under N2 for 8 h to afford
9-methyl-1,2,3,4-tetrakis(4-methylphenyl)-5,6,7,8-tetraphe-
nylcarbazole (10a) in 64% yield (entry 1 in Table 4). Treat-
ment of 8b with 2d in the second step gave the corresponding
octaarylcarbazole 10b in 77% yield (entry 2). The reaction
using 2g in the first step afforded 1-methyl-4,5,6,7-tetrapro-
pylindole (8c) in a moderate yield. This can be converted to
1,2,3,4-tetraalkyl-5,6,7,8-tetraarylcarbazoles 10c-e in 75-82%
yields (entries 3-5).
It was found that not only these carbazoles but also the
tetracyclic compound 5,6-diphenylindolo[1,2-a]quinoline
(5a), obtained as the major product in the reaction of
1f with 2a (entry 3 in Table 3), showed solid-state fluore-
scence. Therefore, we attempted the synthesis of variously
substituted indolo[1,2-a]quinoline derivatives by the 1:1
coupling of 1-arylindole-3-carboxylic acids with diaryl-
acetylenes. When 1f (0.3 mmol) was treated with 2a
(0.45 mmol) in the presence of Pd(OAc)2 (0.03 mmol),
Cu(OAc)2 H2O (0.6 mmol), LiCl (1.8 mmol), and molec-
3
ular sieves (MS4A, 200 mg) in DMAc (1.5 mL) at 120 °C
under N2 for 12 h, 5a was obtained in a somewhat improved
yield (entry 1 in Table 5). Under similar conditions, 1f was
also coupled with 2b-f and 2i to afford the corresponding
5,6-diarylindolo[1,2-a]quinolines 5b-g (entries 2-7).
Methoxy- (1i) and methyl-substituted (1j) 1-phenylindole-3-
carboxylic acids also underwent the 1:1 coupling with 2a and
2d to give 5h and 5i, respectively (entries 8 and 9).
Some carbazoles showed solid-state fluorescence in a
range of 380-450 nm (see Figure S1 in the Supporting
Information). Notably, 3b and 10c exhibited relatively
strong emissions compared to a typical emitter, anthracene,
by factors of 3.7 and 2.6, respectively.
7486 J. Org. Chem. Vol. 74, No. 19, 2009

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JOCArticle
TABLE 5. Synthesis of 5,6-Diarylindolo[1,2-a]quinolines 5a
their carboxylic acid derivatives, especially indole deriva-
tives, with alkynes proceeds efficiently via regioselec-
tive C-H bond cleavage to afford fused heteroaromatic
compounds. Some products multiply substituted around
the heteroaromatic cores show relatively strong solid-state
fluorescence.
Experimental Section
General Procedure for Oxidaitve Coupling of 1-Methylindole-
3-carboxylic Acid (1a) with Diarylacetylenes 2 under Conditions
A. To a 20 mL two-necked flask were added LiOAc (1.2 mmol,
79 mg) and MS4A (400 mg), which were dried at 150 °C in vacuo
for 1 h. Then, 1a (0.6 mmol, 105 mg), alkyne 2 (0.8 mmol),
entry
1
X
2
Y
5, % yield
1
2
3
4
5
6
7
8
9
1f
1f
1f
1f
1f
1f
1f
1i
1j
H
H
H
H
H
H
H
OMe
Me
2a
2b
2c
2d
2e
2f
2i
2a
2d
H
5a, 52
5b, 55
5c, 40
5d, 36
5e, 50
5f, 39
5g, 25
5h, 46
5i, 36
Me
OMe
Cl
Pd(OAc)2 (0.02 mmol, 4.5 mg), Cu(OAc)2 H2O (0.8 mmol,
3
160 mg), dibenzyl (ca. 40 mg) as internal standard, and DMAc
(2.5 mL) were added. The resulting mixture was stirred under N2
at 120 °C. GC and GC-MS analyses of the mixtures confirmed
formation of 3. After cooling, the reaction mixture was poured
into diluted HCl aq (50 mL) and extracted with Et2O (50 mL).
Then, the organic layer was washed with saturated NaCl aq
(50 mL, twice) and dried over Na2SO4. Product 3 was isolated
by column chromatography on silica gel using hexane-ethyl
acetate.
But
F
CF3
H
Cl
aReaction conditions: 1 (0.3 mmol), 2 (0.45 mmol), Pd(OAc)2
(0.03 mmol), Cu(OAc)2 H2O (0.6 mmol), LiOAc (1.8 mmol), MS4A
(200 mg), DMAc (1.5-2 mL) at 120 °C under N2 for 12 h.
3
9-Methyl-1,2,3,4-tetraphenyl-9H-carbazole (3a): mp 276-
278 °C; 1H NMR (400 MHz, CDCl3) δ 3.23 (s, 3H),
6.75-6.90 (m, 12H), 7.18-7.37 (m, 12H); 13C NMR (100
MHz, CDCl3) δ 32.3, 108.4, 118.8, 121.2, 122.4, 122.7, 123.9,
125.0, 125.1, 125.5, 126.3, 126.4, 126.7, 126.7, 127.2, 128.0,
130.3, 131.6, 131.8, 131.9, 132.7, 135.4, 137.9, 138.8, 139.7,
140.3, 140.4, 140.5, 142.9; HRMS m/z (Mþ) calcd for
C37H27N 485.2143, found 485.2141.
SCHEME 5. Plausible Mechanism for the Oxidative Coupling
of 1-Phenylindole-3-carboxylic Acid (1f) with Alkynes 2
General Procedure for Oxidative Coupling of 1-Methylindole
(1b) with Alkynes 2 under Conditions B. To a 20 mL two-necked
flask were added 1b (0.4 mmol, 52 mg), alkyne 2 (1.2 mmol),
Pd(OAc)2 (0.02 mmol, 4.5 mg), Ag2CO3 (0.8 mmol, 221 mg),
n-docosane (ca. 40 mg) as internal standard, and mesitylene
(4 mL). The resulting mixture was stirred under N2 at 120 °C.
GC and GC-MS analyses of the mixtures confirmed formation
of 3. After cooling, the reaction mixture was poured into H2O
(50 mL) and extracted with Et2O (50 mL). Then, the organic
layer was washed with saturated NaCl aq (50 mL, twice) and
dried over Na2SO4. Product 3 was isolated by column chroma-
tography on silica gel using hexane-ethyl acetate.
As depicted in Scheme 5, the 1:1 coupling of 1-phenylin-
dole-3-carboxylic acid (1f) with 2 seems to proceed via steps
similar to those for the 1:2 coupling of 1a with 2 to form an
intermediate D0, related to D in Scheme 3. Then, protonolysis
of the indolyl-Pd bond in D0 may occur,20 rather than the
second alkyne insertion, to form a vinylpalladium intermedi-
ate G. Subsequently, cyclopalladation on the phenyl group
to afford a seven-membered palladacycle H and reductive
elimination may take place to afford product 5.
Most 5,6-diarylindolo[1,2-a]quinolines 5 obtained above
showed solid-state fluorescence in a range of 470-560 nm
(see Figure S2 in the Supporting Information). Interestingly,
5e exhibited significantly intense luminescence (λemis 476 and
506 nm), and the intensity was at least seven times stronger
than that of a typical emitter, coumarin 153, in the pre-
liminary estimation. It is apparent that the introduction of
two bulky tert-butyl substituents on the parent molecule 5a
significantly enhances the intensity of solid-state fluore-
scence. Remarkably, the quantum efficiency (Φ) of the
solid-state fluorescence of 5e was measured at an absolute
value of 68 ( 2%.
General Procedure for Oxidative Coupling of 1-Methylindole-
3-carboxylic Acid (1a) with Dialkylacetylenes 2 under Conditions
A0. To a 20 mL two-necked flask were added LiOAc (2.4 mmol,
158 mg) and MS4A (400 mg), which were dried at 150 °C in
vacuo for 1 h. Then, 1-methylindole-3-carboxylic acid (1a)
(0.4 mmol, 70 mg), alkyne 2 (1.6 mmol), Pd(OAc)2 (0.02 mmol,
4.5 mg), Cu(OAc)2 H2O (0.8 mmol, 160 mg), LiOH H2O
3
3
(1.2 mmol, 50 mg), dibenzyl (ca. 40 mg) as internal standard,
and DMAc (2.5 mL) were added. The resulting mixture was
stirred under air at 100 °C for 10 h. GC and GC-MS analyses of
the mixtures confirmed formation of 3. After cooling, the
reaction mixture was poured into diluted HCl aq (50 mL) and
extracted with Et2O (50 mL). Then, the organic layer was
washed with saturated NaCl aq (50 mL, twice) and dried over
Na2SO4. Product 3 was isolated by thin-layer chromatography
on silica gel using hexane-toluene.
9-Methyl-1,2,3,4-tetrapropyl-9H-carbazole (3g): oil; 1H
NMR (400 MHz, CDCl3) δ 1.08-1.13 (m, 9H), 1.19 (t, J=7.3
Hz, 3H), 1.55-1.63 (m, 4H), 1.67-1.81 (m, 4H), 2.70-2.75
(m, 4H), 3.04-3.08 (m, 2H), 3.14-3.18 (m, 2H), 4.02 (s, 3H),
7.16-7.22 (m, 1H), 7.34-7.42 (m, 2H), 8.03 (d, J=8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 14.4, 14.8, 15.0, 15.1, 23.2, 25.4,
25.5, 25.8, 30.6, 31.6, 32.2, 32.5, 32.7, 108.4, 118.7, 120.7, 121.6,
In summary, we have demonstrated that the palla-
dium-catalyzed oxidative couplings of heteroarenes and
(20) For example, see: Larock, R. C.; Tian, Q. J. Org. Chem. 2001, 66,
7372.
J. Org. Chem. Vol. 74, No. 19, 2009 7487

Yamashita et al.
JOCArticle
122.2, 123.1, 124.4, 130.5, 134.0, 138.0, 138.9, 142.7; HRMS m/z
Sports, Science and Technology, Japan, and the Kurata
Memorial Hitachi Science and Technology Foundation.
(Mþ) calcd for C25H35N 349.2770, found 349.2766.
Acknowledgment. We thank Dr. N. Tohnai, Osaka Uni-
versity, for fluorescence quantum efficiency measurements
and helpful discussions. This work was partly supported
by Grants-in-Aid from the Ministry of Education, Culture,
Supporting Information Available: Characterization data of
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
7488 J. Org. Chem. Vol. 74, No. 19, 2009