enantioselective PdꢀNHC catalyst for asymmetric catalytic
processes has not been well documented. Therefore, the
search for new chiral catalysts and catalytic systems invol-
ving chiral NHCꢀmetal complexes still remains challenging
and in high demand.
Meanwhile, much interest has been directed toward the
study of 3-hydroxyoxindoles possessing substituents at
their 3-positions due to their important biological activi-
ties.7 Compounds containing this structural unit have been
widely serving as targets for drug design and synthesis.
Several methods have been developed for the preparation
of 3-substituted oxindoles,8 but the asymmetric addition of
nucleophiles to isatins is still the most straightforward
approach to this structural scaffold. Even though asym-
metric additions of nucleophiles including arylboronic
acids to isatins catalyzed by transition metals have shown
promising progress,9 there has been a very limited number
of successful examples using the Pd catalytic complexes in
the literature.10 Previously, we have reported the synthesis
of a series of the chiral cationic NHCꢀPd2þ diaqua
complexes and their applications in catalytic enantioselec-
tive arylation reactions of imines with arylboronic acids.11
Herein, we would like to report our preliminary results on
the use of these chiral cationic NHCꢀPd2þ diaqua com-
plexes for the enantioselective arylation of isatins with
arylboronic acids.
Figure 1. Chiral cationic NHCꢀPd2þ diaqua complexes 1a and 1b.
adduct 3a in 71% yield and 50% ee in THF at room
temperature (Table 1, entry 1). Various bases were next
screened for this catalytic system; it was found that when
LiOH H2O was used as the base, the product 3a was
generated in 88% yield and 81% ee (Table 1, entries
2ꢀ14). We anticipated that the reactivity of isatin 2a would
3
be enhanced when Brønsted base LiOH H2O was added
3
into the reaction system leading to the formation of the
desired product in higher yield and enantioselectivity.12a
We then utilized the complex 1b to replace 1a as the
catalyst under identical conditions and found that the
Initially, we utilized the reaction of isatin 2a with
phenylboronic acid (2.0 equiv) as the model reaction in
the presence of 1.0 equiv of K2CO3 as the base and
NHCꢀPd complex 1a (Figure 1, 5 mol %) as the catalyst.
We found that the use of K2CO3 as the base led to the
Table 1. Optimization of the Reaction Condition for Catalytic
Enantioselective Addition of Arylboronic Acids to Isatins
(4) (a) Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C. Chem.
Commun. 2002, 2704. (b) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66,
3402. (c) Arao, T.; Kondo, K.; Aoyama, T. Tetrahedron Lett. 2006, 47,
1417. (d) Bertogg, A.; Camponovo, F.; Togni, A. Eur. J. Inorg. Chem.
2005, 347.
(5) (a) Bonnet, L. G.; Douthwaite, R. E.; Kariuki, B. M. Organome-
tallics 2003, 22, 4187. (b) Flahaut, A.; Baltaze, J. P.; Roland, S.;
Mangeney, P. J. Organomet. Chem. 2006, 691, 3498.
entry
base
K2CO3
solvent temp time yield (%)a ee (%)b
1
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
71
73
70
53
61
57
37
88
70
63
51
60
58
63
81
51
90
47
91
71
50 (R)c
51 (R)
43 (R)
42 (R)
54 (R)
51 (R)
48 (R)
81 (R)
51 (R)
57 (R)
74 (R)
57 (R)
61 (R)
43 (R)
73 (R)
65 (R)
71 (R)
70 (R)
54 (R)
57 (R)
2
K3PO4 3H2O
3
(6) (a) Sato, Y.; Imakuni, N.; Mori, M. Adv. Synth. Catal. 2003, 345,
488. (b) Sato, Y.; Imakuni, N.; Hirose, T.; Wakamatsu, H.; Mori, M.
J. Organomet. Chem. 2003, 687, 392.
3
KOH
4
Cs2CO3
KOtBu
Pyridine
Et3N
(7) (a) Nicolaou, K. C.; Hao, J.; Reddy, M. V.; Rao, P.; Rassias, G.;
Synder, S. A.;Huang, X.;Chen, D. Y.-K.;Brenzovich, W. E.;Giuseppone,
N.; Giannakakou, P.; O’Brate, A. J. Am. Chem. Soc. 2004, 126, 15316. (b)
Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209. (c) Rasmussen,
H. B.;MacLeod,J. K.J. Nat. Prod. 1997, 60, 1152. (d) Kohno, J.; Koguchi,
Y.; Nishio, M.; Nakao, K.; Kuroda, M.; Shimizu, R.; Ohnuki, T.;
Komatsubara, S. J. Org. Chem. 2000, 65, 990. (e) Hibino, S.; Choshi, T.
Nat. Prod. Rep. 2002, 19, 148.
5
6
7
8
LiOH H2O
3
9
Li2CO3
LiOAc
10
11
12
13
14
Ca(OH)2
Mg(OH)2
Al(OH)3
(8) (a) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402. (b)
Dounay, A. B.; Hatanaka, K.; Kodanko, J. J.; Oestreich, M.; Overman,
L. E.; Pfeifer, L. A.; Weiss, M. M. J. Am. Chem. Soc. 2003, 125, 6261. (c)
Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 3921. (d) Trost,
B. M.; Frederiksen, M. U. Angew. Chem., Int. Ed. 2005, 44, 308. (e) Jia,
Ba(OH)2 8H2O THF
3
15d LiOH H2O
THF
THF
THF
THF
THF
3
3
3
€
Y.-X.; Hillgren, J. M.; Watson, E. L.; Marsden, S. P.; Kundig, E. P.
16e LiOH H2O
€
Chem. Commun. 2008, 34, 4040. (f) Jia, Y.-X.; Kundig, E. P. Angew.
17f LiOH H2O
Chem., Int. Ed. 2009, 48, 1636.
(9) (a) Toullec, P. Y.; Jagt, R. B. C.; de Vries, J. G.; Feringa, B. L.;
Minnaard, A. J. Org. Lett. 2006, 8, 2715. (b) Shintani, R.; Inoue, M.;
Hayashi, T. Angew. Chem., Int. Ed. 2006, 45, 3353. (c) Shintani, R.;
Takatsu, K.; Hayashi, T. Chem. Commun. 2010, 46, 6822.
(10) Lai, H. S.; Huang, Z. Y.; Wu, Q.; Qin, Y. J. Org. Chem. 2009, 74,
283.
(11) (a) Chen, T.; Jiang, J. J.; Xu, Q.; Shi, M. Org. Lett. 2007, 9, 865.
(b) Ma, G. N.; Zhang, T.; Shi, M. Org. Lett. 2009, 11, 875. (c) Liu, Z.;
Shi, M. Organometallics 2010, 29, 2831. (d) Liu, Z.; Shi, M. Tetrahedron
2010, 66, 2619.
18
19
20
LiOH H2O
0 °C 72 h
45 °C 8 h
3
LiOH H2O
3
LiOH H2O
Dioxane rt
48 h
3
a Isolated yields. b Determined by chiral HPLC. c Determined by
comparison of the sign of optical rotation to the literature value.10
d Catalyst 1b was used. e 0.5 equiv base was used. f 2.0 equiv base were
used.
Org. Lett., Vol. 13, No. 9, 2011
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