Fig. 1 Proposed mechanism.
21, 58–67; (d) Y. B. Zhao, B. Mariampillai, D. A. Candito,
B. Laleu, M. Z. Li and M. Lautens, Angew. Chem., Int. Ed.,
2009, 48, 1849–1852.
3 (a) L. G. Quan, V. Gevorgyan and Y. Yamamoto, J. Am. Chem.
Soc., 1999, 121, 3545–3546; (b) L. G. Quan, M. Lamrani and
Y. Yamamoto, J. Am. Chem. Soc., 2000, 122, 4827–4828;
(c) D. Sole, L. Vallverdu, X. Solans, M. Font-Bardia and
J. Bonjoch, J. Am. Chem. Soc., 2003, 125, 1587–1594.
4 (a) K. R. Roesch and R. C. Larock, Org. Lett., 1999, 1, 553–556;
(b) H. Ohno, A. Aso, Y. Kadoh, N. Fujii and T. Tanaka, Angew.
Chem., Int. Ed., 2007, 46, 6325–6328.
5 (a) D. Sole and O. Serrano, Angew. Chem., Int. Ed., 2007, 46,
7270–7272; (b) D. Sole and O. Serrano, J. Org. Chem., 2008, 73,
9372–9378.
6 S. Cacchi, G. Fabrizi, F. Gavazza and A. Goggiamani, Org. Lett.,
2003, 5, 289–291.
(4)
(5)
Based on the above, we propose the mechanism shown in
Fig. 1. The oxindole is formed by intramolecular addition of
the oxidative addition intermediate I to the ketone. Alkoxy-
ligand exchange II (cycle A) liberates product 2a and the Pd(0)
catalyst is regenerated by b-H elimination (aldehyde formation)
followed by base assisted reductive elimination. For the
hydrodehalogenation side product 3a we propose halide–
alcoholate ligand exchange in I to give III (cycle B).
b-Elimination followed by reductive elimination affords 3a
(cycle B). The observation of the deuterated side product
shown in eqn (5) supports this pathway.
7 (a) C. C. Yang, P. J. Sun and J. M. Fang, J. Chem. Soc., Chem.
Commun., 1994, 2629–2630; (b) R. C. Larock, Q. P. Tian and
A. A. Pletnev, J. Am. Chem. Soc., 1999, 121, 3238–3239;
(c) A. A. Pletnev and R. C. Larock, J. Org. Chem., 2002, 67,
9428–9438; (d) A. A. Pletnev, Q. P. Tian and R. C. Larock, J. Org.
Chem., 2002, 67, 9276–9287; (e) Q. P. Tian, A. A. Pletnev and
R. C. Larock, J. Org. Chem., 2003, 68, 339–347; (f) C. X. Zhou and
R. C. Larock, J. Org. Chem., 2006, 71, 3551–3558.
8 (a) E. P. Kundig, T. M. Seidel, Y.-X. Jia and G. Bernardinelli,
¨
Angew. Chem., Int. Ed., 2007, 46, 8484–8487; (b) Y.-X. Jia,
J. M. Hillgren, E. L. Watson, S. P. Marsden and E. P. Kundig,
¨
Chem. Commun., 2008, 4040–4042; (c) Y.-X. Jia and E. P. Kundig,
Angew. Chem., Int. Ed., 2009, 48, 1636–1639.
¨
9 3-Hydroxyoxindoles can be obtained by addition of aryl Grignard
reagents or aryl lithium reagents (both are prepared from aryl
halides) to isatin: (a) M. A. Sukari and J. M. Vernon, J. Chem.
Soc., Perkin Trans. 1, 1983, 2219–2223; (b) S. J. Angyal,
E. Bullock, W. G. Hanger, W. C. Howell and A. W. Johnson,
J. Chem. Soc., 1957, 1592–1602 and ref. cit. Catalytic asymmetric
synthesis of 3-hydroxyoxindole: Pd catalysed intramolecular aryla-
tion of amides; (c) ref. 8b; M-catalysed addition of aryl boronic
acids to isatin; (d) R. Shintani, M. Inoue and T. Hayashi, Angew.
Chem., Int. Ed., 2006, 45, 3353–3356; (e) H. S. Lai, Z. Y. Huang,
Q. Wu and Y. Qin, J. Org. Chem., 2009, 74, 283–288; Lewis acid-
catalysed asymmetric hydroxylation of oxindoles; (f) T. Ishimaru,
N. Shibata, J. Nagai, S. Nakamura, T. Toru and S. Kanemasa,
J. Am. Chem. Soc., 2006, 128, 16488–16489.
In summary, we have developed a new and efficient
procedure to synthesize 3-hydroxyoxindole compounds in
high yields by applying palladium-catalysed direct addition
of aryl halides to a-ketoamides. Both, electron-rich phosphine
ligands and a reductant (alcohol, H2) are crucial. The forma-
tion of a new stereogenic center in 2 is another important
aspect that is receiving attention in ongoing research.
Notes and references
1 J. Tsuji, Palladium Reagents and Catalysis—New Perspectives for
the 21st Century, Wiley, Weinheim, 2004.
2 (a) R. C. Larock, M. J. Doty and S. Cacchi, J. Org. Chem., 1993,
58, 4579–4583; (b) V. Gevorgyan, L. G. Quan and Y. Yamamoto,
Tetrahedron Lett., 1999, 40, 4089–4092; (c) J. Vicente, J. A. Abad,
B. Lopez-Pelaez and E. Martinez-Viviente, Organometallics, 2002,
10 Although PCy3 has been used as a ligand in a similar addition
reaction of simple ketone substrates (ref. 3b), no reaction took
place from 1a to 2a using the reported conditions (5 mol%
Pd(OAc)2, 10 mol% PCy3, 2 eq. Na2CO3, 5 eq. 1-hexanol in
DMF).
ꢁc
This journal is The Royal Society of Chemistry 2010
132 | Chem. Commun., 2010, 46, 130–132