4684
F. Zhou et al. / Tetrahedron Letters 52 (2011) 4681–4685
Table 3 (continued)
Supplementary data
Entry
R3
Time (h)
Yieldb (%)
Supplementary data (experimental procedures and data for
products) associated with this Letter can be found, in the online
F
6
p-FC6H4
2.5
F
References and notes
+
N
MeO
O
1. (a) Saxton, J. E. In The Chemistry of Heterocyclic Compounds; Wiley: New York,
1983; vol. 25, Part IV,; (b) Sundberg, R J. Indoles; Academic Press: New York,
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Yamada, F. Nat. Prod. Rep. 2005, 22, 73; (e) Kawasaki, T.; Higuchi, K. Nat. Prod.
Rep. 2005, 22, 761; (f) Higuchi, K.; Kawasaki, T. Nat. Prod. Rep. 2007, 24, 843.
2. Potential antiallergy agents: (a) Unangst, P. C.; Connor, D. T.; Stabler, S. R.;
Weikert, R. J.; Carethers, M. E.; Kennedy, J. A.; Thueson, D. O.; Chestnut, J. C.;
Adolphson, R. L.; Conroy, M. C. J. Med. Chem. 1989, 32, 1360; Mitomycin
analogues: (b) Iyengar, B. S.; Remers, W. A.; Catino, J. J. J. Med. Chem. 1989, 32,
1866; Inverse agonists of the benzodiazepine receptor (c) Bianucci, A. M.;
Settimo, A. D.; Settimo, F. D.; Primofiore, G.; Martini, C.; Giannaccini, G.;
Lucacchini, A. J. Med. Chem. 1992, 35, 2214; 5-HT2 antagonists: (d) Andersen, K.;
Perregaard, J.; Arn, J.; Nielsen, J. B.; Begtrup, M. J. Med. Chem. 1992, 35, 4823;
Selective serotonin uptake inhibitors (e) Malleron, J. L.; Gueremy, C.; Mignani,
S.; Peyronel, J. F.; Truchon, A.; Blanchard, J. C.; Doble, A.; Laduron, P.; Piot, O.;
Zundel, J. L.; Betschart, J.; Canard, H.; Chaillou, P.; Ferris, O.; Huon, C.; Just, B.;
Kerphirique, R.; Martin, B.; Mouton, P.; Renaudon, A. J. Med. Chem. 1993, 36,
1194; Nonpeptide angiotensin II receptor antagonists (f) Dhanoa, D. S.; Bagley,
S. W.; Chang, R. S. L.; Lotti, V. J.; Chen, T. B.; Kivlighn, S. D.; Zingaro, G. J.; Siegl, P.
K. S.; Patchett, A. A.; Greenlee, W. J. J. Med. Chem. 1993, 36, 4230.
Me
3ag (58)f
a
Reaction conditions: 1a (0.4 mmol),
2 (0.6 mmol), Pd(OAc)2 (10 mol %),
Cu(OTf)2 (1.0 equiv), Ag2O (1.5 equiv) in DMA (3.0 mL) at 120 °C under N2.
b
Isolated yield.
1a (0.2 mmol), 2b (0.4 mmol).
c
d
The yields of the corresponding deacetyl products are below 5%.
e
The yield of the corresponding deacetyl product 3af’ is 20%.
The yield of the corresponding deacetyl product 3ag’ is 15%.
f
R3
O
R1
Pd(OAc)2
oxidation
Pd(0)
R3
R1
N
H
1
R2
N
O
R2
C-H activation
3
3. (a) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry; Clive, W. B.,
Cheeseman, G. W. H., Eds.; Pergamon: Oxford, 1984; Vol. 4, pp 313–368; (b)
Pindur, U.; Adam, R. J. Heterocycl. Chem 1988, 25, 1; (c) Humphrey, G. R.;
Kuethe, J. T. Chem. Rev. 2006, 106, 2875; (d) Cacchi, S.; Fabrizi, G. Chem. Rev.
2005, 105, 2873; (e) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127; (f)
Cui, S.; Wang, J.; Wang, Y. J. Am. Chem. Soc. 2008, 130, 13526; (g) Takaya, J.;
Udagawa, S.; Kusama, H.; Iwasawa, N. Angew. Chem. Int. Ed. 2008, 47, 4906; (h)
Shen, M.; Leslie, B. E.; Driver, T. G. Angew. Chem. Int. Ed. 2008, 47, 5056; (i) Pei,
T.; Chen, C.; Dormer, P. G.; Davies, I. W. Angew. Chem. Int. Ed. 2008, 47, 4231; (j)
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Fournier, P.-A. J. Org. Chem. 2010, 75, 7033.
R3
AcO
2
R3
PdL
Pd
O
R1
+ HOAc
HOAc
R1
+
N
H
I
R2
R3
N
R2
O
III
2
R3
R3
Pd
R3
R1
alkyne insertion
intramolecular
N-attack
N
OAc
H
R2
O
4. (a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry; Pergamon: Oxford,
II
´
´
U.K., 2000; (b) Barluenga, J.; Jimenez-Aquino, A.; Aznar, F.; Valdes, C. J. Am.
Chem. Soc. 2009, 131, 4031.
Scheme 2. Proposed mechanism for the indole synthesis via palladium catalyzed
5. (a) Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem. Int. Ed. 2005, 44, 403;
(b) Fletcher, A. J.; Bax, M. N.; Willis, M. C. Chem. Commun. 2007, 4764; (c)
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C–H activation.
aromatic palladation with the assistance of the acetamino group
generates the six-membered palladacycle I,11,14 which is inserted
by alkyne 2 to afford an vinylic palladium(II) intermediate II,15 fol-
lowed by intramolecular amide attack and subsequent deprotona-
tion to form the corresponding palladium amide intermediate III.9b
Reductive elimination of III affords the corresponding indole prod-
uct 3 as well as a Pd(0) complex, which can be reoxidized to the
Pd(II) species in the presence of Cu(OTf)2 and Ag2O (Scheme 2).
The prepared cyclopalladated complex I’ could stoichiometrically
transform to the corresponding product (Scheme 1), which
provided a further proof for this proposed reaction mechanism.
In summary, a novel and simple method for the synthesis of
indoles from N-aryl amides and alkynes via palladium-catalyzed
C–H activation was achieved. Both stoichiometric and catalytic
versions have been successfully developed. It is worth noting that
the reaction proceeds well without the formation of diketone when
Cu(OTf)2 was used as the oxidant instead of CuCl2. Further investi-
gation on the synthetic applications of this reaction is in progress.
6. (a) Meijere, A.; Diederich, F. In Metal Catalyzed Cross-Coupling Reactions; Wiley-
VCH: Weinheim, 2004; vols. 1–2,; (b) Dyker,
G In Handbook of C–H
Transformations; Wiley-VCH: Weinheim, 2005; vol. 1,; (c) Alberico, D; Scott,
M. E.; Lautens, M. Chem. Rev. 2007, 107, 174; (d) Dyker, G. Angew. Chem. Int. Ed.
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V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173; (g) Li, C.-J. Acc. Chem. Res.
2009, 42, 335.
7. (a) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K. J. Am. Chem.
Soc. 2008, 130, 16474; (b) Stuart, D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am.
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2009, 48, 4572; (b) Chen, J.; Pang, Q.; Sun, Y.; Li, X. J. Org. Chem. 2011, 76, 3523.
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Acknowledgments
The Major State Basic Research Program (2009CB825300) is
acknowledged. We also thank the National Natural Science Foun-
dation of China (20732005, 20872158) and Chinese Academy of
Sciences for financial support.