10.1002/adsc.201701512
Advanced Synthesis & Catalysis
On the basis of the experimental evidence, a
chromatography on silica gel to afford the corresponding
plausible reaction mechanism is proposed (Scheme 7). products.
Pathway (a) involves a regioselective Wacker
oxidation followed by the spontaneous annulation to
Acknowledgements
hemiaminal F, which can quantitatively converted to
indole G (eq 4). The reductive elimination produces
the final indole product as well as the Pd(II) species
E, followed by the regeneration of catalytically active
Pd(II) via the oxidation with molecular oxygen
mediated by NOx. H2O2 is not observed and the final
product of O2 is H2O. In pathway (b) the direct C-H
activation affords the key intermediate C' from
complex B, however, the KIE and kinetic study do
not support it. Despite of the fact that the aza-Wacker
process via pathway (c) cannot be ruled out by far,
the slower reaction with more nucleophilic starting
material (N-Ph instead of N-Ts, eq 5) as well as the
first order dependence of the initial rate on [tBuOH]
does not support this pathway.
We thank the National Natural Science Foundation of China
(21672196, 21404096, 21602001, U1463202) for financial
support.
References
[1] a) A. J. Kochanowska-Karamyan, M. Hamann, T.
Chem. Rev. 2010, 110, 4489; b) T. Kawasaki, K.
Higuchi, Nat. Prod. Rep., 2005, 22, 761; c) R. J.
Sundberg, Indoles; 2nd ed. Academic Press: London,
1996; d) S. Cacchi, G. Fabrizi, Chem. Rev. 2011, 111,
PR215; e) M. Inman, C. J. Moody, Chem. Sci. 2013, 4,
29; f) T. Guo, F. Huang, L. Yu, Z. Yu, Tetrahedron
Lett. 2015, 56, 296.
[2] E. Fischer, F. Jourdan, Ber. Dtsch. Chem. Ges. 1883,
16, 2241.
[3] a) Indole Ring Synthesis: From Natural Products to
Drug Discovery; G. W. Gribble Ed. John Wiley &
Sons: Chichester, West Sussex, 2016; b) D. F. Taber,
Tirunahari, P. K. Tetrahedron 2011, 67, 7195.
[4] a) Z. Shi, C. Zhang, S. Li, D. Pan, S. Ding, Y. Cui, N.
Jiao, Angew. Chem. Int. Ed. 2009, 48, 4572; b) B. J.
Stokes, S. Liu, T. G. Driver, J. Am. Chem. Soc. 2011,
133, 4702; c) Q. Nguyen, T. Nguyen, T. G. Driver, J.
Am. Chem. Soc. 2013, 135, 620; d) Q.-Q. Yang, C.
Xiao, L.-Q. Lu, J. An, F. Tan, B.-J. Li, W.-J. Xiao,
Angew. Chem. Int. Ed. 2012, 51, 9137; e) M. Teders, L.
Pitzer, S. Buss, F. Glorius, ACS Catal. 2017, 7, 4053; f)
T. Watanabe, Y. Mutoh, S. Saito, J. Am. Chem. Soc.
2017, 139, 7749; g) R. C. Larock, E. K. Yum, J. Am.
Chem. Soc. 1991, 113, 6689; h) R. Nallagonda, M.
Rehan, P. Ghorai, Org. Lett. 2014, 16, 4786; i) Y. Wei,
I. Deb, N. Yoshikai, J. Am. Chem. Soc. 2012, 134, 9098.
[5] With stoichiometric Pd, a) L. S. Hegedus, G. F. Allen,
E. l. Waterman, J. Am. Chem. Soc. 1976, 98, 2674; b) L.
S. Hegedus, G. F. Allen, J. J. Bozell, E. L. Waterman, J.
Am. Chem. Soc. 1978, 100, 5800-5807. With catalytic
Pd: c) S. R. Fix, J. L. Brice, S. S. Stahl, Angew. Chem.
Int. Ed. 2002, 41, 164; d) R. Nallagonda, M. Rehan, P.
Ghorai, Org. Lett. 2014, 16, 4786.
Scheme 7. Proposed mechanism.
In conclusion, we have developed a general and
practical synthesis of functionalized indoles via an
aerobic intramolecular aza-Wacker of 2-vinylanilines
with molecular oxygen as terminal oxident which is
enabled by an organic redox cocatalyst and a bulky
alcohol solvent. This method has been evaluated in
the large scale synthesis of indomethacin and a
potential anti-breast cancer drug candidate 1 to
demonstrate its application potential.
[6]From 2-vinylanilines with Pd-cat BQ as oxidant: a) P. J.
Harrington, L. S. Hegedus, J. Org. Chem. 1984, 49,
2657; b) M. E. Krolski, A. F. Renaldo, D. E. Rudisill, J.
K. Still, J. Org. Chem. 1988, 53, 1170.
[7] L. Fra, A. Millá, J. A. Souto, K. Muñiz, Angew. Chem.
Int. Ed. 2014, 53, 7349.
Experimental Section
[8] a) Y. Yang, P. Gao, Y. Zhao, Z. Shi, Angew. Chem. Int.
Ed. 2017, 56, 3966; b) Y. Yang, X. Qiu, Y. Zhao, Y.
Mu, Z. Shi, J. Am. Chem. Soc. 2016, 138, 495; c) Y.
Yang, R. Li, Y. Zhao, D. Zhao, Z. Shi, J. Am. Chem.
Soc. 2016, 138, 8734.
[9] For aza-Wacker reactions: (a) G. Yang, C. Shen, W.
Zhang, Angew. Chem. Int. Ed. 2012, 51, 9141; b) X.
Kou, Y. Li, L. Wu, X. Zhang, G. Yang, W. Zhang, Org.
Lett. 2015, 17, 5566; d) G. Yang, W. Zhang, Org. Lett.
Pd(PhCN)2Cl2 (7.2 mg, 0.019 mmol) was weighed into a
25 mL Schlenk tube and dried under high vacuum for 15
t
t
min. Under O2 (1 atm balloon), BuOH (2 mL), BuONO
(5.2 mg, 0.05 mmol) and a vinylaniline (0.25 mmol) were
sequentially added. The resulting reaction mixture was
heated and stirred at 70 °C (monitored by TLC). The
reaction was quenched by the filtration through a thin silica
gel pad and washed with EtOAc. The filtrate was
concentrated and the residue was purified by
4
This article is protected by copyright. All rights reserved.