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Table 3 Ag-catalyzed one-pot two-step cyclization/difluoroalkoxylation
of N-methyl-2-alkynylanilinesa,b
fluorinating reagents in a single operation by employing inexpensive
and air-stable silver salts as the catalyst. The current protocol
conveniently affords structurally diverse fluorinated indole
derivatives including 3-fluoroindoles, 3,3-difluoro-3H-indoles,
2-hydroxy-3,3-difluoroindolines and 2-alkoxy-3,3-difluoroindolines.
We are thankful for the financial support from the National Basic
Research Program of China (973 Program, 2011CB808601), and the
National NSF of China (21202105, 21025205 and 21321061).
Notes and references
1 (a) R. J. Sundberg, Indoles, Academic, New York, 1996; (b) G. W. Gribble,
Heterocyclic Scaffolds II: Reactions and Applications of Indoles, Springer,
Berlin, 2010; (c) T. Kawasaki and K. Higuchi, Nat. Prod. Rep., 2005,
22, 761.
a
The reaction was run on a 0.3 mmol scale under N2. For details, see
b
c
the ESI. Isolated yield. NaHCO3 (1.0 equiv.) was added.
2 (a) K. Kru¨ger, A. Tillack and M. Beller, Adv. Synth. Catal., 2008, 350, 2153;
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48, 9608; (c) S. Cacchi and G. Fabrizi, Chem. Rev., 2011, 111, PR215.
Table 4 Ag-catalyzed one-pot synthesis of 3-fluoroindolesa,b
´
´
4 (a) J. P. Begue and D. Bonnet-Delpon, Bioorganic and Medicinal
Chemistry of Fluorine, John Wiley & Sons, Inc., New York, 2008;
(b) A. V. Petrov, Fluorinated Heterocyclic Compounds: Synthesis,
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F. Diederich, Science, 2007, 317, 1881; (e) S. Purser, P. R. Moore, S. Swallow
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6 For selected examples for the synthesis of monofluorinated indole
derivatives, see: (a) N. Shibata, T. Tarui, Y. Doi and K. L. Kirk, Angew.
Chem., Int. Ed., 2001, 40, 4461; (b) Y. Hamashima, T. Suzuki,
H. Takano, Y. Shimura and M. Sodeoka, J. Am. Chem. Soc., 2005,
127, 10164; (c) T. Fujiwara, B. Yin, M. Jin, K. L. Kirk and Y. Takeuchi,
J. Fluorine Chem., 2008, 129, 829; (d) T. Ishimaru, N. Shibata,
T. Horikawa, N. Yasuda, S. Nakamura, T. Toru and M. Shiro, Angew.
Chem., Int. Ed., 2008, 47, 4157; (e) T. Seki, T. Fujiwara and
Y. Takeuchi, J. Fluorine Chem., 2011, 132, 181.
a
The reaction was run on a 0.3 mmol scale under N2. For details,
b
c
see the ESI. Isolated yield. 1.3 equiv. of Selectfluor was used.
d
e
3,3-Difluoro-3H-indole 2d was also obtained in 25% yield. 1.0 equiv.
of NaHCO3 was added.
7 For selected examples for the synthesis of difluorinated indole
derivatives, see: (a) J. C. Torres, S. J. Garden, A. C. Pinto, F. S. Q.
da Silva and N. Boechat, Tetrahedron, 1999, 55, 1881; (b) R. P. Singh,
U. Majumder and J. M. Shreeve, J. Org. Chem., 2001, 66, 6263;
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Chem., 2010, 75, 5505; (d) O. Lozano, G. Blessley, T. M. del Campo,
A. L. Thompson, G. T. Giuffredi, M. Bettati, M. Walker, R. Borman
and V. Gouverneur, Angew. Chem., Int. Ed., 2011, 50, 8105; (e) R. Lin,
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8 A. Arcadi, E. Pietropaolo, A. Alvino and V. Michelet, Org. Lett., 2013,
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19, 1189; (c) L.-Q. Zhang, S. Yang, X. Huang, J. You and F. Song,
Chem. Commun., 2013, 49, 8830.
Scheme 2 Proposed mechanism.
10 For Ag-catalyzed cyclization of 2-alkynylanilines, see: (a) D. W.
Knight, WO, 2006100479 A1, 2006; (b) C. H. Oh, S. Karmakar,
H. Park, Y. Ahn and J. W. Kim, J. Am. Chem. Soc., 2010, 132, 1792;
(c) J. Liu, X. Xie and Y. Liu, Chem. Commun., 2013, 49, 11794.
11 (a) T. Furuya, A. E. Strom and T. Ritter, J. Am. Chem. Soc., 2009,
131, 1662; (b) P. Tang, T. Furuya and T. Ritter, J. Am. Chem. Soc.,
2010, 132, 12150; (c) C. Huang, T. Liang, S. Harada, E. Lee and
T. Ritter, J. Am. Chem. Soc., 2011, 133, 13308; (d) T. Xu, X. Mu,
H. Peng and G. Liu, Angew. Chem., Int. Ed., 2011, 50, 8176; (e) T. Xu
and G. Liu, Org. Lett., 2012, 14, 5416; ( f ) Q. Liu, Y. Wu, P. Chen and
G. Liu, Org. Lett., 2013, 15, 6210.
difluoroalkoxylation with NFSI or Selectfluor to form 3-fluoroindoles,
3,3-difluoro-3H-indoles, 2-hydroxy-3,3-difluoroindolines and
2-alkoxy-3,3-difluoroindolines, respectively.7e The oxidation of IM2
to Ag(II) species by NFSI and subsequent reductive elimination
and electrophilic fluorination is also a possible pathway to
obtain 3,3-difluoro-3H-indoles 2.11
In conclusion, we have developed a highly efficient cyclization/
fluorination reaction of 2-alkynylanilines with electrophilic
3026 | Chem. Commun., 2014, 50, 3024--3026
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