Rhodium-catalyzed oxidative coupling/cyclization of 2-phenylindoles with alkynes via C-H and N-H bond cleavages with air as the oxidant

Article abstract of DOI:10.1021/ol100560k

Figure presented The straightforward and efficient synthesis of indolo[2,1-a]isoquinoline derivatives has been achieved by the rhodium-catalyzed aerobic oxidative coupling/cyclization of 2-phenylindoles with alkynes. Some of the polycyclic products exhibit solid-state fluorescence.

Full text of DOI:10.1021/ol100560k

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2068-2071
Rhodium-Catalyzed Oxidative Coupling/
Cyclization of 2-Phenylindoles with
Alkynes via C-H and N-H Bond
Cleavages with Air as the Oxidant
Keisuke Morimoto, 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 March 7, 2010
ABSTRACT
The straightforward and efficient synthesis of indolo[2,1-a]isoquinoline derivatives has been achieved by the rhodium-catalyzed aerobic oxidative
coupling/cyclization of 2-phenylindoles with alkynes. Some of the polycyclic products exhibit solid-state fluorescence.
Nitrogen-containing polycyclic heteroarenes have attracted
considerable attention because of their biological and photo-
and electrochemical properties.1 Their construction usually
needs complicated multisteps with huge effort involving
high-volume byproducts.2 Recently, the oxidative coupling
of aromatic substrates with internal alkynes by transition
metal catalysis via regioselective C-H bond cleavage has
been developed for preparing fused polycyclic molecules.3
As such an example, we have reported the one-step synthesis
of 5,6-diarylindolo[1,2-a]quinoline derivatives by the pal-
ladium-catalyzed oxidative coupling of 1-phenylindole-3-
carboxylic acids with alkynes involving decarboxylation
(Scheme 1).4 The tetracyclic products have been found to
exhibit intense fluorescence in the solid state.
(3) Selected recent reviews for C-H functionalization: (a) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. ReV. 2010, 110, 624. (b) Sun, C.-L.;
Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677. (c) Chen, X.; Engle,
K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (d)
Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013. (e) Ferreira, E. M.; Zhang,
H.; Stoltz, B. M. Tetrahedron 2008, 64, 5987. (f) Park, Y. J.; Park, J.-W.;
Jun, C.-H. Acc. Chem. Res. 2008, 41, 222. (g) Herrerias, C. I.; Yao, X.; Li,
Z.; Li, C.-J. Chem. ReV. 2007, 107, 2546. (h) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. ReV. 2007, 107, 174. (i) Godula, K.; Sames, D. Science
2006, 312, 67. (j) Satoh, T.; Miura, M. J. Synth. Org. Chem. 2006, 64,
1199. (k) 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. (l)
Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077. (m) Ritleng,
V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731. (n) Kakiuchi, F.;
Murai, S. Acc. Chem. Res. 2002, 35, 826. (o) Dyker, G. Angew. Chem.,
Int. Ed. 1999, 38, 1698. (p) Shilov, A. E.; Shul’pin, G. B. Chem. ReV. 1997,
97, 2879.
(1) Selected examples: (a) Abet, V.; Nun˜ez, A.; Mendicuti, F.; Burgos,
C.; Alvarez-Builla, J. J. Org. Chem. 2008, 73, 8800. (b) Ahmed, E.; Briseno,
A. L.; Xia, Y.; Jenekhe, S. A. J. Am. Chem. Soc. 2008, 130, 1118. (c)
Parenty, A. D. C.; Song, Y.-F.; Richmond, C. J.; Cronin, L. Org. Lett. 2007,
9, 2253. (d) Gondek, E.; Kityk, I. V.; Danel, A.; Wisla, A.; Sanetra, J.
Synth. Met. 2006, 156, 1348. (e) Bersuker, I. B.; Bahceci, S.; Boggs, J. E.;
Pearlman, R. S. J. Comput.-Aided Mol. Des. 1999, 13, 419. (f) Tomoda,
H.; Hirano, T.; Saito, S.; Mutai, T.; Araki, K. Bull. Chem. Soc. Jpn. 1999,
72, 1327. (g) Barrio, J. R.; Sattsangi, P. D.; Gruber, B. A.; Dammann, L. G.;
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(2) Selected recent reviews: (a) Thansandote, P.; Lautens, M.
Chem.sEur. J. 2009, 15, 5874. (b) Gil, C.; Bra¨se, S. J. Comb. Chem. 2009,
11, 175. (c) Vincze, Z.; B´ıro´, B.; Cse´kei, M.; Tima´ri, G.; Kotschy, A.
Synthesis 2006, 1375.
10.1021/ol100560k  2010 American Chemical Society
Published on Web 04/08/2010

In an initial attempt, 2-phenylindole (1a) (0.5 mmol) was
treated with diphenylacetylene (2a) (0.5 mmol) in the
presence of [Cp*RhCl2]2 (0.01 mmol) and Ag2CO3 (0.5
mmol) as catalyst and oxidant, respectively, in o-xylene (3
mL)at100°CunderN2.Asaresult,5,6-diphenylindolo[2,1-a]-
isoquinoline (3a) was formed in 44% yield after 6 h (entry
1 in Table 1, Cp* ) pentamethylcyclopentadienyl). The
Scheme 1
Table 1. Reaction of 2-Phenylindole (1a) with
Diphenylacetylene (2a)a
During our further study of fused heteroaromatic construc-
tion,5 we have succeeded in building up an indolo[2,1-a]-
isoquinoline framework via the aerobic oxidative coupling
of 2-phenylindoles with alkynes under rhodium catalysis,
accompanied by C-H and N-H bond cleavages (Scheme
2).6 Note that this reaction proceeds smoothly with air as
entry
oxidant (mmol)
Ag2CO3 (0.5)
AgOAc (1)
AgOAc (1)
Cu(OAc)2·H2O (1)
Cu(OAc)2·H2O (0.05) + aird
aird
yield of 3ab
1c
2c
3
4
5
44
80
99 (96)
92
96 (96)
Scheme 2
6
21
a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), [(Cp*RhCl2)2]
(0.01 mmol), Na2CO3 (1 mmol), o-xylene (3 mL) at 100 °C for 6 h under
N2. b GC yield based on the amount of 1a used. The number in parentheses
indicates yield after purification. c Without Na2CO3. d Under N2-air (5:1,
900 mL).
terminal oxidant, in which no wastes are formed except for
water. The tetracyclic framework can be seen in various
natural products that exhibit a broad range of interesting
biological activity.7 Moreover, as are indolo[1,2-a]quinolines,
some of the indolo[2,1-a]isoquinoline derivatives obtained
have been found to show solid-state fluorescence. The results
obtained for the coupling are described herein.
product yield significantly increased to 80% by using
AgOAc (1 mmol) as the oxidant in place of Ag2CO3 (entry
2). The addition of Na2CO3 (1 mmol) enabled 3a to be
produced quantitatively (entry 3). An inexpensive oxidant,
Cu(OAc)2·H2O, was also effective for the present reaction
(entry 4). Furthermore, to our delight, a comparably good
yield was obtained even when the reaction was conducted
with a catalytic amount of Cu(OAc)2·H2O (0.05 mmol) under
N2-air (5:1) (entry 5).8 Without the copper cocatalyst, the
reaction was sluggish (entry 6).
Table 2 summarizes the results for the coupling of a series
of 2-arylindoles 1b-h with 2a under conditions with air as
terminal oxidant (entry 5 in Table 1). 2-(4-Substituted
phenyl)indoles 1b-e reacted with 2a smoothly to form the
corresponding 3-substituted 5,6-diphenylindolo[2,1-a]iso-
quinolines 3b-e in good yields (entries 1-4). 5-Methoxy-
and 5-chloro-2-phenylindoles, 1f and 1g, also underwent the
reaction with 2a to produce 10-substituted 5,6-diphenylin-
dolo[2,1-a]isoquinoline derivatives 3f and 3g, respectively
(entries 5 and 6). In the reaction of 2-(1-naphthyl)indole (1h)
with 2a, a pentacyclic product 3h was selectively obtained
in 74% yield (entry 7).
(4) (a) Yamashita, M.; Horiguchi, H.; Hirano, K.; Satoh, T.; Miura, M.
J. Org. Chem. 2009, 74, 7481. (b) Yamashita, M.; Hirano, K.; Satoh, T.;
Miura, M. Org. Lett. 2009, 11, 2337.
(5) (a) Fukutani, T.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Chem.
Commun. 2009, 5141. (b) Shimizu, M.; Hirano, K.; Satoh, T.; Miura, M. J.
Org. Chem. 2009, 74, 3478. (c) Yamashita, M.; Hirano, K.; Satoh, T.; Miura,
M. Org. Lett. 2009, 11, 2337. (d) Umeda, N.; Tsurugi, H.; Satoh, T.; Miura,
M. Angew. Chem., Int. Ed. 2008, 47, 4019. (e) Shimizu, M.; Tsurugi, H.;
Satoh, T.; Miura, M. Chem. Asian J. 2008, 3, 881. (f) Ueura, K.; Satoh, T.;
Miura, M. J. Org. Chem. 2007, 72, 5362. (g) Ueura, K.; Satoh, T.; Miura,
M. Org. Lett. 2005, 7, 2229.
(6) The heteroarene construction with transition metal catalysts has been
developed: (a) Verma, A. K.; Kesharwani, T.; Singh, J.; Tandon, V.; Larock,
R. C. Angew. Chem., Int. Ed. 2009, 48, 1138. (b) Lo¨tter, A. N. C.; Pathak,
R.; Sello, T. S.; Fernandes, M. A.; van Otterlo, W. A. L.; de Koning, C. B.
Tetrahedron 2007, 63, 2263. (c) de Koning, C. B.; Michael, J. P.; Pathak,
R.; van Otterlo, W. A. L. Tetrahedron Lett. 2004, 45, 1117.
(7) Selected examples: (a) Mamane, V.; Hannen, P.; Fu¨rstner, A.
Chem.sEur. J. 2004, 10, 4556. (b) Soldatenkov, A. T.; Soldatova, S. A.;
Ryashentseva, M. A.; Ntaganda, Zh.; Zvolinskii, O. V.; Smirnova, E. N.;
Kharlamova, M. D. Russ. Chem. Bull., Int. Ed. 2002, 51, 2116. (c) Orito,
K.; Harada, R.; Uchiito, S.; Tokuda, M. Org. Lett. 2000, 2, 1799. (d)
Ambros, R.; Schneider, M. R.; von Angerer, S. J. Med. Chem. 1990, 33,
153. (e) Ewing, J.; Hughes, G. K.; Ritchie, E.; Taylor, W. C. Nature 1952,
169, 618.
(8) Under air (1 atm), the yield of 3a slightly decreased to 78%.
(9) For related Cp*(1-pyrrolyl)Rh complexes, see: Jones, W. D.; Dong,
L.; Myers, A. W. Organometallics 1995, 14, 855.
(12) (a) Terao, Y.; Nomoto, M.; Satoh, T.; Miura, M.; Nomura, M. J.
Org. Chem. 2004, 69, 6942. (b) Terao, Y.; Wakui, H.; Nomoto, M.; Satoh,
T.; Miura, M.; Nomura, M. J. Org. Chem. 2003, 68, 5236. (c) Terao, Y.;
Wakui, H.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2001,
123, 10407. (d) Eisenbraun, E. J.; Harms, W. M.; Palaniswamy, V. A.;
Chen, H. H.; Porcaro, P. J.; Wood, T. F.; Chien, M. J. Org. Chem. 1982,
47, 342.
(10) Larock et al. reported copper-catalyzed addition of indole N-H to
diphenylacetylene.6a However, in our blank experiment in the absence of
the rhodium catalyst, any coupling products including 1-vinylindoles could
not be detected.
(11) Another possible pathway via aminorhodation of 2a by a indolyl-
rhodium intermediate and subsequent cyclorhodation to form B cannot be
excluded.
(13) It was confirmed that treatment of 4o under similar conditions to
those of entry 9 in Table 3 did not give 3o at all.
Org. Lett., Vol. 12, No. 9, 2010
2069

bond of A occurs to form seven-membered rhodacycle B or
C, respectively. In either case, the final reductive elimination
affords 3a. The resulting Cp*Rh(I) species seems to be
oxidized in the presence of the copper cocatalyst and air to
regenerate Cp*Rh(III)X2.
Table 2. Reaction of 2-Arylindoles 1 with Diphenylacetylene
(2a)a
The reactions of 1a with various internal alkynes 2b-i in
place of 2a were examined next. Methyl- (2b), tert-butyl-
(2c), methoxy- (2d), chloro- (2e), and trifluoromethyl- (2f)
substituted diphenylacetylenes underwent the coupling with
1a to afford the corresponding 5,6-diarylindolo[2,1-a]iso-
quinolines 3i-m in fair to good yields (entries 1-5 in Table
3). In the reaction of 2-methyl-4-phenyl-3-butyn-2-ol (2g)
Table 3. Reaction of 2-Phenylindole (1a) with Alkynes 2a
a Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), [(Cp*RhCl2)2] (0.01
mmol), Cu(OAc)2·H2O (0.05 mmol), Na2CO3 (1 mmol), o-xylene (3 mL)
at 100 °C for 6 h under N2-air (5:1, 900 mL). b GC yield based on the
amount of 1 used. The number in parentheses indicates yield after
purification. c For 10 h. d With
[(Cp*RhCl2)2] (0.005 mmol), Cu(OAc)2·H2O (0.025 mmol), Na2CO3 (0.5
mmol), and o-xylene (2 mL).
1 (0.25 mmol), 2a (0.25 mmol),
The oxidative coupling of 1a with 2a serves as an example
in a possible mechanism illustrated in Scheme 3, in which
Scheme 3
a Reaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), [(Cp*RhCl2)2] (0.01
mmol), Cu(OAc)2·H2O (0.05 mmol), Na2CO3 (1 mmol), o-xylene (3 mL)
at 100 °C for 6 h under N2-air (5:1, 900 mL). b GC yield based on the
amount of 1a used. The number in parentheses indicates yield after
purification. c Under N2 with AgOAc (1 mmol) in place of Cu(OAc)2·H2O.
d Under N2 with Ag2CO3 (0.5 mmol) in place of Cu(OAc)2·H2O and Na2CO3.
with 1a, although the yield of the corresponding product 3n
was somewhat low, no other regioisomers were formed (entry
6). The yield of 3n was significantly improved up to 94%
by using a stoichiometric amount of AgOAc as the oxidant
(entry 7). Note that the hydroxymethyl group can act as a
leaving group for further fucntionalization.12
Dialkylacetylenes such as 4-octyne (2h) and 8-octadecyne
(2i) also reacted smoothly with 1a under either aerobic
conditions (entries 8 and 10) or conditions with a silver salt
(entry 9) to efficiently afford the corresponding oxidative
coupling products. The major product in each case was,
neutral ligands are omitted. Initial coordination of the
nitrogen atom of 1a to Cp*Rh(III)X2 species9 and subsequent
cyclorhodation gives a five-membered rhodacycle intermedi-
ate A.10,11 Then, alkyne insertion into the N-Rh or C-Rh
2070
Org. Lett., Vol. 12, No. 9, 2010

unexpectedly, 6-alkyl-5-alkylidene-5,6-dihydroindolo[2,1-a]-
isoquinoline 4o or 4p, anticipated 5,6-dialkylindolo[2,1-a]-
isoquinoline 3o or 3p being produced in a minor amount.13
The product 4 seems to be constructed from 1a and a
dialkylacetylene through the steps depicted in Scheme 4. A
Scheme 4
Figure 1. Fluorescence spectra of 3f (A), 3j (B), and coumarin
153 (C) in the solid state upon excitation at 422 nm.
seven-membered rhodacycle intermediate B′ is generated in
a similar manner to that to B in Scheme 3. Since B′ has a
ꢀ-hydrogen, its elimination appears to occur in preference
to reductive elimination to form D.14 Then, D undergoes
intramolecular allene insertion into the C-Rh bond and
reductive elimination to produce 4.
Some of the indolo[2,1-a]isoquinolines obtained above
showed solid-state fluorescence in a range of 460-510 nm
(see the Supporting Information). Notably, 3f and 3j
exhibited relatively strong emissions compared to a typical
emitter, coumarin 153, by factors of 3.5 and 3.1, respectively
(λemis 470 (for 3f; A) and 476 nm (for 3j; B), Figure 1).
In summary, we have demonstrated that the rhodium-
catalyzed oxidative coupling of 2-phenylindoles with alkynes
proceeds efficiently under aerobic conditions through C-H
and N-H bond cleavages to give the corresponding in-
dolo[2,1-a]isoquinoline derivatives, some of which exhibit
solid-state fluorescence. Since 2-phenylindoles can be easily
prepared via the palladium-catalyzed direct arylation of
unsubstituted indole with arylboronic acids,15 the sequence
of the arylation and the present oxidative coupling provides
a simple synthetic pathway of the nitrogen-containing
polycyclic systems from readily available indole, arylboronic
acids, and alkynes.
Acknowledgment. This work was partly supported by
Grants-in-Aid from the Ministry of Education, Culture,
Sports, Science and Technology, Japan and the Kurata
Memorial Hitachi Science and Technology Foundation.
Supporting Information Available: Standard experimen-
tal procedure and characterization data of products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL100560K
(14) However, any byproducts possessing the allenyl moiety could not
be detected in the reaction mixture.
(15) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J.
Angew. Chem., Int. Ed. 2008, 47, 1473.
Org. Lett., Vol. 12, No. 9, 2010
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