allylic substitution reaction. Recently, we developed several
protocols to generate a chiral center on nucleophiles by the
Pd-catalyzed asymmetric allylic alkylation reaction.4 We
wondered whether we could take advantage of kinetic
resolution to resolve nucleophiles via Pd-catalyzed allylic
substitution reaction. In this paper, we address this question
and disclose our preliminary results on the kinetic resolution
of indolines via Pd-catalyzed allylic amination reaction.
Chiral indolines are found in a variety of natural and
biologically active products.7 Only a few examples of
catalytic asymmetric synthesis are described,8,9 and an
effective process still remains to be explored. Thus, indoline
1 was selected as the nucleophile in our investigation. At
first, 2-phenylindoline 1a was subjected to the reaction with
0.5 equiv of allyl acetate 2a in the presence of the ferrocene
ligand (S,R)-L1 at room temperature; allylated indoline 3a
was provided in 16% yield and in 6% ee while 1a was
recovered in 80% yield and in 3% ee (eq 1).
well as the structure of ligands, were investigated (eq 2, Table
1). By employing Et3N or K2CO3, the ee value of both 1a
Table 1. Optimization of Reaction Parametersa
3a or 4a
1a
yieldb
(%)
eec
(%)
yieldb
(%)
eec
(%)
entry
L
2
solvent base
1
2
3
4
5
6
7
8
L1 2a CH2Cl2
L1 2a CH2Cl2 Et3N
L1 2a CH2Cl2 K2CO3
16
49
49 26
6
8
80
3
46 10
46 51
46 56
50 50
50 ND
42 ND
L1 2a CH2Cl2 NaOAc 49 54
L1 2a DME
L2 2a DME
L3 2a DME
L4 2a DME
L5 2a DME
L6 2a DME
L6 2b DME
L6 2c DME
L7 2a DME
L8 2a DME
L9 2a DME
NaOAc 46 69
NaOAc 43 26
NaOAc 49 23
NaOAc 49 73 (-)d 50 70 (-)d
9
NaOAc 48 29 (-)d 47 ND
10
11
12
13
14
15
NaOAc 40 74
NaOAc 28 78
NaOAc 37 73
NaOAc 48 3.5
NaOAc 13
NaOAc 23
52 54
70 34
59 53
50 ND
80 ND
76 ND
47 47
49 77
50 83
48 82
1
7
16e L10 2a DME
NaOAc 39 53
17e L10 2c toluene NaOAc 45 92
18e L10 2c toluene
19e,f L10 2c toluene
42 89
45 91
To improve the efficiency of the reaction, the impact of
parameters, including bases, solvents, and allyl reagents as
a Molar ratio of 1a/2/[Pd(C3H5)Cl]2/L/base ) 100:50:1.25:2.5:100.
b Isolated yield. c Determined by chiral HPLC. d The reversed sequence of
peaks by HPLC. e 3.75 mol % of L10 was used. f Reaction was carried out
at 0 °C.
(4) (a) You, S. L.; Hou, X. L.; Dai, L. X.; Zhu, X. Z. Org. Lett. 2001,
3, 149. (b) Yan, X.-X.; Liang, C.-G.; Zhang, Y.; Hong, W.; Cao, B.-X.;
Dai, L.-X.; Hou, X.-L. Angew. Chem., Int. Ed. 2005, 44, 6544. (c) Zheng,
W. H.; Zheng, B. H.; Zhang, Y.; Hou, X. L. J. Am. Chem. Soc. 2007, 129,
7718. (d) Zhang, K.; Peng, Q.; Hou, X. L.; Wu, Y. D. Angew. Chem., Int.
Ed. 2008, 47, 1741.
and 3a increased (entries 2 and 3). The addition of NaOAc
improved the results further, providing 3a in 49% yield, 54%
ee and 1a in 46% yield, 51% ee (entry 4).10 Screening of
common solvents showed that DME was the best choice over
CH2Cl2, (entry 4) ether, THF, dioxane, hexane, and toluene
(not shown in Table 1). No significant changes were given
when cinnamyl carbonate 2b or branched allylic carbonate
2c was used (entry 10 vs entries 11 and 12).
The structure of the ferrocene ligands is critical in this
kinetic resolution. It is shown that the chiral elements in
ligand L4 are matched while those in ligands L3, L5, and
L6 are not; 49% yield of 3a with 73% ee and 50% recovery
of 1a with 70% ee were afforded by using L4 (entry 8 vs
entries 7, 9, and 10). It was also found that the configuration
of product was determined by that of the binol subunit
(entries 8 and 9 vs entries 7 and 10).4d Ligand L4 with i-Pr
at oxazoline ring gave better results than L1 and L2 with H
as substituent (entry 8 vs entries 5 and 6). The investigation
of ligands, including PHOX,11a,b FcPHOX,11c-e BINAP,11f
and Trost’s chiral ligand L10,11g-i revealed that better results
were obtained when L10 was the ligand (entry 16 vs entries
13-15). Even better results were provided if the reaction
proceeded in toluene and branched allylic carbonate 2c was
(5) For some reviews: (a) Kagan, H. B.; Fiaud, J. C. In Topics in
Stereochemistry; Eliel, E. L., Wilen, S. H., Eds.; Interscience: New York,
1988; Vol. 18, p 249. (b) Hoveyda, A. H.; Didiuk, M. T. Curr. Org. Chem.
1998, 2, 489. (c) Cook, G. R. Curr. Org. Chem. 2000, 4, 869. (d) Keith,
J. M.; Larrow, J. F.; Jacobsen, E. N. AdV. Synth. Catal. 2001, 343, 5. (e)
Reetz, M. T. Angew. Chem., Int. Ed. 2001, 40, 284. (f) Vedejs, E.; Jure,
M. Angew. Chem., Int. Ed. 2005, 44, 3974.
(6) (a) Hayashi, T.; Yamamoto, A.; Ito, Y. J. Chem. Soc., Chem.
Commun. 1986, 1090. (b) Choi, Y. K.; Suh, J. H.; Lee, D.; Lim, I. T.;
Jung, J. Y.; Kim, M. J. J. Org. Chem. 1999, 64, 8423. (c) Gais, H.-J.;
Spalthoff, N.; Jagusch, T.; Frank, M.; Raabe, G. Tetrahedron Lett. 2000,
41, 3809. (d) Reetz, M. T.; Sostmann, S. J. Organomet. Chem. 2000, 603,
105. (e) Longmire, J. M.; Wang, B.; Zhang, X. Tetrahedron Lett. 2000,
41, 5435. (f) Gilbertson, S. R.; Lan, P. Org. Lett. 2001, 3, 2237. (g) Hughes,
D. L.; Palucki, M.; Yasuda, N.; Reamer, R. A.; Reider, P. J. J. Org. Chem.
2002, 67, 2762. (h) Gais, H.-J.; Jagusch, T.; Spalthoff, N.; Gerhards, F.;
Frank, M.; Raabe, G. Chem.sEur. J. 2003, 9, 4202. (i) Lussem, B. J.; Gais,
H. J. J. Am. Chem. Soc. 2003, 125, 6066. (j) Faller, J. W.; Wilt, J. C.; Parr,
J. Org. Lett. 2004, 6, 1301. (k) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira,
E. M. J. Am. Chem. Soc. 2004, 126, 1628. (l) Onitsuka, K.; Matsushima,
Y.; Takahashi, S. Organometallics 2005, 24, 6472.
(7) (a) Gueritte, F.; Fahy, J., In Anticancer Agents from Natural Products;
Cragg, G. M., Kingston, D. G. I., Newman, D. J., Eds.; CRC Press: Boca
Raton, 2005; pp 123-135. (b) Bechle, B. M.; Didiuk, M. T.; Fritzen, E. L.;
Garigipati, R. S. WO2006032987-A1.
(8) (a) Orsat, B.; Alper, P. B.; Moree, W.; Mak, C. P.; Wong, C. H.
J. Am. Chem. Soc. 1996, 118, 712. (b) Kuwano, R.; Sato, K.; Kurokawa,
T.; Karube, D.; Ito, Y. J. Am. Chem. Soc. 2000, 122, 7614. (c) Kuwano,
R.; Kaneda, K.; Ito, T.; Sato, K.; Kurokawa, T.; Ito, Y. Org. Lett. 2004, 6,
2213. (d) Kuwano, R.; Kashiwabara, M. Org. Lett. 2006, 8, 2653. (e)
Kuwano, R.; Kashiwabara, M.; Sato, K.; Ito, T.; Kaneda, K.; Ito, Y.
Tetrahedron: Asymmetry 2006, 17, 521. (f) Arp, F. O.; Fu, G. C. J. Am.
Chem. Soc. 2006, 128, 14264
.
(10) (a) Grennberg, H.; Langer, V.; Backvall, J. E. J. Chem. Soc., Chem.
Commun. 1991, 1190. (b) Burckhardt, U.; Baumann, M.; Togni, A.
Tetrahedron: Asymmetry 1997, 8, 155. (c) Fagnou, K.; Lautens, M. Angew.
Chem., Int. Ed. 2002, 41, 26.
(9) For an example of enzymatic resolution of indolines, see: Gotor-
Fernandez, V.; Fernandez-Torres, P.; Gotor, V. Tetrahedron: Asymmetry
2006, 17, 2558
.
1790
Org. Lett., Vol. 11, No. 8, 2009