Organic Letters
Letter
ASSOCIATED CONTENT
* Supporting Information
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S
Experimental procedures and full spectroscopic data for all new
compounds are available free of charge via the Internet at http://
AUTHOR INFORMATION
Corresponding Author
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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Financial support from the NIGMS (R01 GM100985-01),
Princeton University, Eli Lilly, and Amgen is gratefully
acknowledged. We also thank Frontier Scientific and Sigma−
Aldrich for kind donations of chemicals and Dr. Kevin Sylvester
(current position: PPG Industries) for helpful discussions.
A.G.D. is a fellow of the Alfred P. Sloan Foundation and a
Camille Dreyfus Teacher−Scholar.
REFERENCES
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Figure 3. Electrophile scope. (a) Reactions run on a 0.5 mmol scale at
0.01 M under an N2 atmosphere. (b) Isolated yields (average of two
runs). (c) Enantiomeric excess determined by chiral HPLC (average of
two runs).
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caused a slight decrease in selectivity (1d). A variety of electron-
neutral nucleophiles performed well (1a−g), including an ester,
which would be incompatible with alternative approaches using
aryllithium reagents (1f). Electron-deficient nucleophiles
provided lower yield and enantioselectivity (1h), while
electron-rich nucleophiles were the most selective, although
they required double catalyst loading to achieve high yields (1i−
l). Notably, a thioether was tolerated, suggesting that the catalyst
is resistant to common poisons. Select heterocyclic boroxines
were also competent in the reaction (1k,l). However, sufficiently
electron-rich species such as 2-benzofurylboroxine were
nucleophilic enough to undergo racemic background reaction.24
The scope of the electrophile was also investigated (Figure 3).
Unfortunately, both yield and selectivity suffered relative to
reactions with unsubstituted EEDQ.25 Substitution on the
quinoline ring was tolerated to a moderate extent at the 5, 6,
and 7 positions (2a−c).26 Electron-withdrawing groups
enhanced selectivity (2d,e) while electron-donating groups
diminished it (2f). Lastly, the reaction can be run with different
carbamate protecting groups, although ethyl carbamate remained
superior (2g,h).27
(6) (a) Fotie, J.; Kaiser, M.; Delfin, D. A.; Manley, J.; Reid, C. S.; Paris,
J.-M.; Wenzler, T.; Maes, L.; Mahasenan, K. V.; Li, C.; Werbovetz, K. A.
J. Med. Chem. 2010, 53, 966. (b) Probst, G.; Aubele, D. L.; Bowers, S.;
Dressen, D.; Garofalo, A. W.; Hom, R. K.; Konradi, A. W.; Marugg, J. L.;
Mattson, M. N.; Neitzel, M. L.; Semko, C. M.; Sham, H. L.; Smith, J.;
Sun, M.; Truong, A. P.; Ye, X. M.; Xu, Y.; Dappen, M. S.; Jagodzinski, J.
J.; Keim, P. S.; Peterson, B.; Latimer, L. H.; Quincy, D.; Wu, J.;
Goldbach, E.; Ness, D. K.; Quinn, K. P.; Sauer, J.-M.; Wong, K.; Zhang,
H.; Zmolek, W.; Brigham, E. F.; Kholodenko, D.; Hu, K.; Kwong, G. T.;
Lee, M.; Liao, A.; Motter, R. N.; Sacayon, R.; Santiago, P.; Willits, C.;
Bard, F.; Bova, M. P.; Hemphill, S. S.; Nguyen, L.; Ruslim, L.; Tanaka,
K.; Tanaka, P.; Wallace, W.; Yednock, T. A.; Basi, G. S. J. Med. Chem.
2013, 56, 5261. (c) Cracknell, M.; Duriatti, A.; Kirby, N. World Patent
9,805,646, Feb 12, 1998.
(7) 2-Aryl-1,2-dihydroquinolines have also been incorporated in chiral
phosphoramidite ligands: Pullmann, T.; Engendahl, B.; Zhang, Z.;
Holscher, M.; Zanotti-Gerosa, A.; Dyke, A.; Francio, G.; Leitner, W.
Chem.Eur. J. 2010, 16, 7517.
(8) Ahamed, M.; Todd, M. H. Eur. J. Org. Chem. 2010, 5935.
(9) Asymmetric hydrogenation of quinolines is well-known; however,
such methods cannot terminate at the dihydroquinoline and instead
yield tetrahydroquinoline products. To the best of our knowledge, a
general and selective oxidation of tetrahydroquinolines to dihydroqui-
nolines is unknown. (a) Wang, T.; Zhuo, L.-G.; Li, Z.; Chen, F.; Ding,
Z.; He, Y.; Fan, Q.-H.; Xiang, J.; Yu, Z.-X.; Chan, A. S. C. J. Am. Chem.
Soc. 2011, 133, 9878. (b) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-
W.; Zhou, Y.-G. J. Am. Chem. Soc. 2003, 125, 10536. (c) Rueping, M.;
Antonchick, A. P.; Theissman, T. Angew. Chem., Int. Ed. 2006, 45, 3683.
(10) Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2000, 122, 6327.
In conclusion, the Ni−iminium activation mode has enabled
the development of an enantioselective arylation of quinolinium
ions. This method allows modular access to 2-aryl-1,2-
dihydroquinolines with moderate to high levels of selectivity.
Furthermore, we employ a Ni(II) precatalyst that delivers Ni(0)
under exceptionally mild conditions, an advance that may find
general utility in Ni catalysis.
(11) Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc. 2007,
129, 6686.
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dx.doi.org/10.1021/ol4031364 | Org. Lett. XXXX, XXX, XXX−XXX