Synthesis of N -azolylindoles by copper-catalyzed C-H/N-H coupling-annulation sequence of o -alkynylanilines

Article abstract of DOI:10.1021/ol203392r

A wide range of o-alkynylanilines undergo a copper-catalyzed direct C-H/N-H coupling with azoles followed by benzannulation to form the corresponding N-azolylindoles in good yields. The domino reaction proceeds effectively with molecular oxygen as the sol

Full text of DOI:10.1021/ol203392r

ORGANIC
LETTERS
2012
Vol. 14, No. 2
664–667
Synthesis of N-Azolylindoles by Copper-
Catalyzed CꢀH/NꢀH CouplingꢀAnnulation
Sequence of o-Alkynylanilines
Yoshiro Oda, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita,
Osaka 565-0871, Japan
k_hirano@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.ac.jp
Received December 19, 2011
ABSTRACT
A wide range of o-alkynylanilines undergo a copper-catalyzed direct CꢀH/NꢀH coupling with azoles followed by benzannulation to form the
corresponding N-azolylindoles in good yields. The domino reaction proceeds effectively with molecular oxygen as the sole oxidant and provides a
new dehydrogenative access to the titled compounds of interest in pharmaceutical and material sciences.
In this letter, we report a copper-catalyzed CꢀH/NꢀH
couplingꢀannulation sequence of o-alkynylanilines for the
synthesis of N-azolylindoles.
The indole nucleus is found in many pharmaceuticals
and functional materials. In particular, N-heteroaryl deri-
vatives have received much attention due to their unique
biological and physical properties.1 The most common
approach to the target motifs is the palladium-2 and
copper-catalyzed3 CꢀN bond forming reaction of NꢀH
indoles with heteroaryl halides.
Meanwhile, recent developments in the metal-promoted
direct CꢀH functionalization chemistry enabled an oxida-
tive direct CꢀH/NꢀH coupling of some heteroarenes with
alkylamines, anilines, and amides.4 Our group also suc-
ceeded in the copper-mediated direct amination of azoles.5
In the course of this study, we attempted the direct
coupling of azoles with NꢀH indoles leading to the N-
azolylindoles (Scheme 1, route a). However, our prelimin-
ary experiments with 2-phenyl-1,3,4-oxadiazole (1a) and
some NꢀH indoles by using copper catalysts completely
failed: the reported successful systems containing Cu(OAc)2/
4m
PPh3/NaOAc4l and Cu(OAc)2/pyridine/Na2CO3
or
(1) Reviews: (a) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27,
1113. (b) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045. (c)
Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (d) Hamphrey, G. R.;
Kuethe, J. T. Chem. Rev. 2006, 106, 2857. Selected examples: (e) Hall,
A.; Billinton, A.; Brown, S. H.; Chowdhury, A.; Giblin, G. M. P.;
Goldsmith, P.; Hurst, D. N.; Naylor, A.; Patel, S.; Scoccitti, T.;
Theobald, P. J. Bioorg. Med. Chem. Lett. 2008, 18, 2684. (f) Lahser,
F. C.; Gu, Z. PCT Int. Appl. 2010, WO 2010117939, A120101014.
(g) Kim, C. S.; Cho, Y. J.; Kwon, H. J.; Kim, B. O.; Kim, S. M.; Yoon,
S. S. Int. Appl. 2010, WO 2010107244, A2 20100923.
our original conditions, Cu(OAc)2/1,10-phenanthroline
(phen)/K2CO3, resulted in no formation of the desired
products. Thus, we envisioned a new working scenario
with o-alkynylanilines, in which the first copper-catalyzed
intermolecular direct CꢀN formation would furnish the
corresponding N-azolylaniline intermediates, and the sub-
sequent benzannulation under the same copper catalysis6
could produce the N-azolylindoles in one synthetic opera-
tion (route b).
On the basis of the above hypothesis, treatment of
2-(phenylethynyl)aniline (2a) with 1a in the presence of
an excess of Cu(OAc)2 and K2CO3 under O2 (1 atm,
balloon) in refluxing toluene furnished the desired
N-azolylindole 3aa in 71% yield (Table 1, entry 1). While
(2) Selected publications: (a) Mann, G.; Hartwig, J. F.; Driver, M. S.;
ꢀ
Fernandez-Rivas, C. J. J. Am. Chem. Soc. 1998, 120, 827. (b) Old, D. W.;
Harris, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 1403. (c) Watanabe,
M.; Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. 2000, 41,
481. (d) Grasa, G. A.; Viciu, M. S.; Huang, J.; Nolan, S. P. J. Org. Chem.
2001, 66, 7729.
(3) (a) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 11684. Relevant ChanꢀLam coupling: (b) Mederski,
W. W. K. R.; Lefort, M.; Germann, M.; Kux, D. Tetrahedron 1999,
55, 12757. (c) Yu, S.; Saenz, J.; Srirangam Jayaram, K. J. Org. Chem.
2002, 67, 1699. (d) Bekolo, H. Can. J. Chem. 2007, 85, 42.
r
10.1021/ol203392r
Published on Web 01/11/2012
2012 American Chemical Society

Table 1. Optimization Studies for Copper-Catalyzed CꢀH/
NꢀH CouplingꢀAnnulation Sequence of 2-(Phenylethynyl)-
aniline (2a) with 2-Phenyl-1,3,4-oxadiazole (1a) for the Synthe-
sis of 3aaa
Scheme 1. Dehydrogenative Approaches to N-Azolylindoles
Cu(OAc)2
(mol %)
additive
(mol %)
3aa,
% yieldb
entry
1
200
20
none
(71)
46
2
none
3
20
pyridine (100)
bpyc (20)
65
4
20
53
5
20
phend (20)
bathophene (20)
none
85 (79)
75
6
20
7f
8f
200
20
19
phen (20)
2
a Reaction conditions: Cu(OAc)2, additive, K2CO3 (0.60 mmol), 1a
(0.60 mmol), 2a (0.30 mmol), toluene (2.0 mL), reflux, 3ꢀ10 h, O2 (1 atm,
balloon). b The yields are determined by 1H NMR. Yield of isolated
product is in parentheses. c 2,20-Bipyridine. d 1,10-Phenanthroline. e 4,7-
Diphenyl-1,10-phenanthroline. f Under N2.
stoichiometric in copper, our postulated process would be
operative. We then turned our attention to the catalytic
variant. Not surprisingly, a decrease in the amount of
Cu(OAc)2 to 20 mol % resulted in a lower yield of 3aa
(entry 2). Thus, we subsequently tested the addition of
some additives to support the copper center. Nitrogen-
based ligands generally improved the reaction efficiency
(entries 3ꢀ6), with phen proving to be optimal (entry 5).
Other reaction systems using CuCl2, Cu(OTf)2, Na2CO3,
Cs2CO3, DMF, or DMSO gave no positive effect on yield
(data not shown). In the absence of molecular oxygen, the
yield largely dropped under either stoichiometric or cata-
lytic conditions (entries 7 and 8).
With catalytic conditions employed for entry 5 in
Table 1, we performed the domino reaction of 2a with a
range of 1,3,4-oxadiazoles 1. The representative N-azoly-
lindole products are illustrated in Table 2. Oxadiazoles 1
containing electron-donating methoxy as well as electron-
withdrawing chloro and trifluoromethyl groups under-
went the reaction very smoothly to afford the correspond-
ing indoles 3baꢀda in good yields. A bulky naphthalene
motif could be employed without any difficulties (3ea).
While the alkyl-substituted oxadiazole showed somewhat
lower reactivity, the satisfactory yield was obtained under
stoichiometric conditions (3fa). The generality of o-alky-
nylanilines was also good. At the alkyne terminus, electro-
nically and sterically diverse functions such as methyl,
methoxy, chloro, trifluoromethyl, and 1-naphthyl groups
were equally tolerated (3abꢀaf and 3cbꢀcd). The thienyl-
substituted aniline was transformed to the indoleꢀthiophene
conjugation 3ag in a comparable yield. Moreover, the
copper catalysis could accommodate primary, secondary,
and tertiary alkyl substituents (3ahꢀaj). The C5-substi-
tuted indoles 3ak and 3al were also readily accessible under
standard conditions.
(4) With palladium, see: (a) Tsang, W. C. P.; Zheng, M.; Buchwald,
S. L. J. Am. Chem. Soc. 2005, 127, 14560. (b) Thu, H.-Y.; Yu, W.-Y.;
Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048. (c) Wasa, M.; Yu, J.-Q.
J. Am. Chem. Soc. 2008, 130, 14058. (d) Jordan-Hore, A. A.; Johansson,
C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008,
130, 16184. (e) Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009,
131, 10806. (f) Xiao, B.; Gong, T.-J.; Xu, J.; Liu, Z.-J.; Liu, L. J. Am.
Chem. Soc. 2011, 133, 1466. (g) Sun, K.; Li, Y.; Xiong, T.; Zhang, J.;
Zhang, Q. J. Am. Chem. Soc. 2011, 133, 1694. (h) Cho, S. H.; Yoon, J.;
Chang, S. J. Am. Chem. Soc. 2011, 133, 5996. (i) Youn, S. W.; Bihn, J. H.;
Kim, B. S. Org. Lett. 2011, 13, 3738. With copper, see: (j) Chen, X.; Hao,
X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790. (k)
Uemura, T.; Imoto, S.; Chatani, N. Chem. Lett. 2006, 35, 842. (l)
Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett. 2009,
11, 1607. (m) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11, 5178. (n)
Shuai, Q.; Deng, G.; Chua, Z.; Bohle, D. S.; Li, C.-J. Adv. Synth. Catal.
2010, 352, 632. (o) Zhao, H.; Wang, M.; Su, W.; Hong, M. Adv. Synth.
Catal. 2010, 352, 1301. (p) John, A.; Nicholas, K. M. J. Org. Chem. 2011,
76, 4158. With silver, see: (q) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S.
Angew. Chem., Int. Ed. 2009, 48, 9127. With cobalt and manganese, see:
(r) Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S. Angew. Chem., Int. Ed.
2010, 49, 9899. Metal-free processes: (s) Antonchick, A. P.; Samanta,
R.; Kulikov, K.; Lategahn, J. Angew. Chem., Int. Ed. 2011, 50, 8605.
(t) Froehr, T.; Sindkinger, C. P.; Kloeckner, U.; Finkbeiner, P.;
Nachtsheim, B. J. Org. Lett. 2011, 13, 3754. (u) Lamani, M.; Prabhu,
K. R. J. Org. Chem. 2011, 76, 7938. (v) Kim, H. J.; Kim, J.; Cho, S. H.;
Chang, S. J. Am. Chem. Soc. 2011, 133, 16382. (w) Wertz, S.; Kodama,
S.; Studer, A. Angew. Chem., Int. Ed. 2011, 50, 11511. (x) Kantak, A. A.;
Potavathri, S.; Barham, R. A.; Romano, K. M.; DeBoef, B. J. Am.
Chem. Soc. 2011, 133, 19960. Also see: (y) Armstrong, A.; Collins, J. C.
Angew. Chem., Int. Ed. 2010, 49, 2282. (z) Zhang, M. Synthesis 2011,
3408.
(5) (a) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem.
Soc. 2010, 132, 6900. (b) Miyasaka, M.; Hirano, K.; Satoh, T.; Kowalczyk,
R.; Bolm, C.; Miura, M. Org. Lett. 2011, 13, 359. (c) Matsuda, N.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 2860.
(6) Reviews: (a) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108,
3395. (b) Vicente, R. Org. Biomol. Chem. 2011, 9, 6469. Copper-based
systems: (c) Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69,
1126. (d) Swamy, N. K.; Yazici, A.; Pyne, S. G. J. Org. Chem. 2010, 75,
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2012, 77, 617.
Org. Lett., Vol. 14, No. 2, 2012
665

Table 2. Copper-Catalyzed CꢀH/NꢀH CouplingꢀAnnulation
Sequence for the Synthesis of Various N-Azolylindoles 3a
Scheme 2. Copper-Catalyzed CꢀH/NꢀH CouplingꢀAnnulation
Sequence of o-Alkynylanilines 2 with Benzoxazoles 4 and
Benzothiazole (6)
entry
R1, R2 2
R3 1
3, % yieldb
1
2
3
4
R1 = H, R2 = Ph (2a)
R3 = 4-MeOC6H4 (1b) 3ba, 79
2a
2a
2a
R3 = 4-ClC6H4 (1c)
3ca, 85
R3 = 4-CF3C6H4 (1d) 3da, 89
R3 = 1-naphthyl (1e)
3ea, 81
R3 = 2-phenethyl (1f) 3fa, 72
5c 2a
6
R1 = H, R2 = 4-MeC6H4 R3 = Ph (1a)
(2b)
3ab, 84
7
8
2b
1c
3cb, 83
3ac, 78
R1 = H, R2 = 4-MeOC6H4 1a
(2c)
9
2c
1c
1a
3cc, 87
3ad, 76
Tsuji and Nakamura,8 and Field.9 Pleasingly, when oxadiazole
1a and 8 were subjected to substoichiometric conditions
10 R1 = H, R2 = 4-ClC6H4
(2d)
11 2d
1c
3 cd, 81
3ae, 69
12 R1 = H, R2 = 4-CF3C6H4 1a
Scheme 3. A Double Cyclization Approach to N-Azolylbenzo-
dipyrrole
(2e)
13 R1 = H, R2 = 1-naphthyl 1a
(2f)
3af, 83
3ag, 83
14 R1 = H, R2 = 3-thienyl
(2g)
15 R1 = H, R2 = Bu (2h)
1a
1a
3ah, 83
3ai, 84
16 R1 = H, R2 = cyclohexyl 1a
(2i)
17 R1 = H, R2 = t-Bu (2j)
1a
18 R1 = 4-Me, R2 = Bu (2k) 1a
19 R1 = 4-Cl, R2 = Bu (2l)
1a
3aj, 90
3ak, 90
3al, 83
a Reaction conditions: Cu(OAc)2 (0.060 mmol), phen (0.060 mmol),
K2CO3 (0.60 mmol), 1a (0.60 mmol), 2a (0.30 mmol), toluene (2.0 mL),
reflux, 10 h, O2 (1 atm, balloon). b Isolated yield of products is shown.
c With 0.30 mmol of Cu(OAc)2 and without phen.
We next turned our attention to some 1,3-azoles
other than 1,3,4-oxadiazoles (Scheme 2). Under modified
conditions with KOAc and o-xylene as a base and a
solvent, respectively, benzoxazoles 4 and benzothiazole
(6) took part in the reaction to form the desired N-
azolylindoles 5 and 7 albeit with moderate efficiencies.
Attempts to apply benzimidazole and polyfluoroarenes
remained unsuccessful at this stage.
Finally, we applied the domino CꢀH/NꢀH couplingꢀ
annulation to the reaction of 2,5-dialkynylphenylenediamine
8 for the synthesis of the benzodipyrrole skeleton7 that bears
the azole group on nitrogen (Scheme 3). Synthetic utilities of
this double cyclization approach have been demonstrated by
(130 mol % Cu(OAc)2/phen to 8), the desired benzodipyrrole
core 9 was obtained in 43% yield.
Although the exact reaction mechanism still remains
unclear at the present stage, a Cu(II)/O2-catalyzed oxida-
tive CꢀN coupling of azole 1 with aniline 2 could initially
occur through a (heteroaryl)(ArNH)Cu species,10 forming
the N-azolylaniline intermediate.11 Given the necessity of
molecular oxygen (Table 1, entries 7 and 8), an O2-
promoted oxidation process of Cu(II) to Cu(III) might
(7) For unique lower ionization potential and electron affinities of
benzodipyrroles, see: Salzner, U.; Lagowski, J. B.; Pickup, P. G.; Poirier,
R. A. Synth. Met. 1998, 96, 177.
(9) Clentsmith, G. K. B.; Field, L. D.; Messerle, B. A.; Shasha, A.;
Turner, P. Tetrahedron Lett. 2009, 50, 1469.
(8) (a) Tsuji, H.; Yokoi, Y.; Mitsui, C.; Ilies, L.; Sato, Y.; Nakamura,
E. Chem.;Asian J. 2009, 4, 655. Also see: (b) Nakamura, M.; Ilies, L.;
Otsubo, S.; Nakamura, E. Angew. Chem., Int. Ed. 2006, 45, 944. (c) Tsuji,
H.; Mitsui, C.; Ilies, L.; Sato, Y.; Nakamura, E. J. Am. Chem. Soc. 2007,
129, 11902.
(10) Relevant reaction mechanism: (a) Hamada, T.; Ye, X.; Stahl,
S. S. J. Am. Chem. Soc. 2008, 130, 833. (b) Kitahara, M.; Hirano, K.;
Tsurugi, H.; Satoh, T.; Miura, M. Chem.ꢀEur. J. 2010, 16, 1772. (c) Wei,
Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M. J. Am. Chem. Soc. 2010, 132,
2522 and ref 4l, m, and o.
666
Org. Lett., Vol. 14, No. 2, 2012

be involved prior to the CꢀN bond formation.12 Subse-
quent annulation of this intermediate proceeds via an
electrophilic activation of the alkynyl moiety by the
π-acidic nature of a Cu(II) salt to afford the product 3.
In conclusion, we have developed a copper-catalyzed
oxidative CꢀH/NꢀH couplingꢀannulation sequence
between azoles and o-alkynylanilines. This domino reac-
tion provides a new dehydrogenative approach to N-azoly-
lindoles of biological and physical interest. Moreover, this
protocol can be applied to the synthesis of the π-extended
N-azolylbenzodipyrrole structure.
Acknowledgment. This work was partly supported by
Grants-in-Aid from MEXT and JSPS, Japan. K.H. ac-
knowledges Kansai Research Foundation for the Promo-
tion of Science.
(11) A copper-catalyzed oxidative CꢀH/NꢀH coupling of primary
anilines is not trivial. The reported successful examples are limited to
special anilines that bear electron-deficient groups such as NO2; see
ref 4o and 4p. Thus, we speculate that the o-alkynyl group can act as a
directing group for the efficient intermolecular CꢀN coupling. For a
related directing effect of alkynyl groups, see: Asao, N.; Asano, T.;
Ohishi, T.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 4817.
(12) (a) Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130,
9196. (b) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009,
131, 5044. (c) King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.;
Ribas, X.; Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 12068.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data of compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 14, No. 2, 2012
667