Communication
Green Chemistry
solution (compare Table 3 with Table 5), with the exception of comparison with reported HPLC data on chiral stationary
substrate 1f, wherein a lower ee value is obtained with the phases (see ESI† for details).
resin as an additive.
Conclusions
Acknowledgements
In summary, a catalytic enantioselective synthesis of an array The authors thank the Spanish Ministerio de Economia y
of diversely substituted indolines has been developed and opti- Competitividad (CTQ2011-28512), the Generalitat de Catalunya
mised. It is based on asymmetric hydrogenation of indoles (2009SGR 00623) and the ICIQ Foundation for financial
using enantiomerically pure iridium complexes (derived from support.
P–OP ligand 4) as pre-catalysts and stoichiometric amounts of
sulfonic acids as additives. The best results were obtained
using the environmentally benign solvent 2-Me-THF. The
present study also provides an efficient method to transform
indoles into enantioenriched indolines by a greener hydrogen-
Notes and references
ation method that involves the use of reusable heterogeneous
additives (solid-supported sulfonic acids). Results are compar-
able to those obtained with the homogeneous catalyst.
To the best of the authors’ knowledge, the present work
constitutes the first example of the use of enantiomerically
pure iridium complexes in the asymmetric hydrogenation of
unprotected indoles. Furthermore, the disclosed method
enables a 50% reduction in the amount of required catalyst
relative to similar chemistry (use of enantiomerically pure pal-
ladium catalysts). This strategy is presently being extended for
the asymmetric hydrogenation of other types of CvN contain-
ing heterocycles.
1 (a) Modern Alkaloids: Structure, Isolation, Synthesis and
Biology, ed. E. Fattorusso and O. Taglialatela-Scafati, Wiley-
VCH Verlag GmbH
& Co. KGaA, Weinheim, 2008;
(b) P. M. Dewick, in Medicinal Natural Products: A Biosyn-
thetic Approach, John Wiley & Sons Ltd., 3rd edn, 2009, ch.
6, pp. 311–420; (c) F. Roussi, F. Guéritte and J. Fahy, in Anti-
cancer Agents from Natural Products, ed. D. J. Cragg,
G. M. Kingston and D. G. I. Newman, CRC Press, Boca
Raton, 2nd edn, 2011, ch. 7, pp. 177–198. For recent
examples on the biological and pharmaceutical utility of
indolines, see the following references and those cited
therein: (d) K. L. Marquis, A. L. Sabb, S. F. Logue,
J. A. Brennan, M. J. Piesla, T. A. Comery, S. M. Grauer,
C. R. Ashby Jr., H. Q. Nguyen, L. A. Dawson, J. E. Barrett,
G. Stack, H. Y. Meltzer, B. L. Harrison and S. Rosenzweig-
Lipson, J. Pharmacol. Exp. Ther., 2007, 320, 486;
Experimental section
General procedure for the Ir-mediated asymmetric
(
e) S. Samwel, J. O. Odalo, M. H. H. Nkunya, C. C. Joseph
hydrogenation
and N. A. Koorbanally, Phytochemistry, 2011, 72, 1826.
2 See the following selected synthetic methods: (a) F. O. Arp
and G. C. Fu, J. Am. Chem. Soc., 2006, 128, 14264;
(b) X. L. Hou and B. H. Zheng, Org. Lett., 2009, 11, 1789;
(c) S. Anas and H. B. Kagan, Tetrahedron: Asymmetry, 2009,
20, 2193; (d) D. Liu, G. Zhao and L. Xiang, Eur. J. Org.
Chem., 2010, 3975; (e) M. K. Ghorai and Y. Nanaji, J. Org.
Chem., 2013, 78, 3867; (f) Q.-Q. Yang, Q. Wang, J. An,
J.-R. Chen, L.-Q. Lu and W.-J. Xiao, Chem.–Eur. J., 2013, 19,
8401; (g) K. Saito, Y. Shibata, M. Yamanaka and
T. Akiyama, J. Am. Chem. Soc., 2013, 135, 11740.
3 (a) R. Kuwano, K. Sato, T. Kurokawa, D. Karube and Y. Ito,
J. Am. Chem. Soc., 2000, 122, 7614; (b) R. Kuwano,
K. Kaneda, T. Ito, K. Sato, T. Kurokawa and Y. Ito, Org. Lett.,
2004, 6, 2213; (c) R. Kuwano, M. Kashiwabara, K. Sato,
T. Ito, K. Kaneda and Y. Ito, Tetrahedron: Asymmetry, 2006,
17, 521; (d) N. Mrsic, T. Jerphagnon, A. J. Minnaard,
B. L. Feringa and J. G. de Vries, Tetrahedron: Asymmetry,
2010, 21, 7; (e) A. M. Maj, I. Suisse, C. Meliet and
F. Agbossou-Niedercorn, Tetrahedron: Asymmetry, 2010, 21,
2010.
A solution of the required amount of iridium precursor
([{Ir(μ-Cl)(cod)}
2
]) (0.00125 mmol) and the P–OP ligand 4
(0.00275 mmol) in the corresponding dry and deoxygenated
solvent (0.75 mL) was added under N into an autoclave con-
2
taining the substrate (0.25 mmol) and the additive
(0.25 mmol) in the deoxygenated solvent (0.5 mL). In all cases
the molar concentration of the substrate in the reaction
medium was adjusted to a final concentration of 0.20 M. The
autoclave was purged three times with H
did not exceed the selected one) and finally, the autoclave was
pressurised with H at the desired pressure. The reaction
2
(at a pressure that
2
mixture was stirred at the desired temperature for the stated
reaction time. After the hydrogen had been carefully released,
the resulting mixture was concentrated under vacuum and
then treated with saturated NaHCO
3
(4 mL). After stirring for
1
0 min, the mixture was extracted with EtOAc (2 × 4 mL), dried
4 2
over MgSO , filtered through a short pad of SiO and, finally,
concentrated in vacuo. Conversions were determined at this
1
point by H NMR analysis. The hydrogenation products were
2
isolated after chromatography on SiO . The enantioselectivities
were determined by HPLC analysis on chiral stationary phases
and the configuration of the products was established by
4 R. Kuwano and M. Kashiwabara, Org. Lett., 2006, 8, 2653.
5 A. Baeza and A. Pfaltz, Chem.–Eur. J., 2010, 16, 2036.
1156 | Green Chem., 2014, 16, 1153–1157
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