metal-catalyzed asymmetric catalysis, we recently reported
the synthesis of diastereomerically pure palladium complexes
incorporating new chiral NHC ligands and their successful
application in the Pd-catalyzed intramolecular R-arylation
of amides to obtain enantiomerically enriched 3-aryl-3-
methyl oxindoles.5c While elegant as a methodology to obtain
chiral quaternary carbon centers, the intramolecular R-ary-
lation at present has the drawback of providing oxindoles
that are difficult to functionalize further. We therefore
wondered whether 3-allyl-3-aryl oxindoles, previously ac-
cessible only via a two-step procedure involving a Pd-
catalyzed intramolecular R-arylation followed by an asym-
metric Pd-catalyzed allylic alkylation,4a,9 could be obtained
directly. Herein we report the successful achievement of this
strategy by using a newly designed NHC ligand.
Table 1. Initial Screening of Pd-Complexes 1a-c
convn [%]a
3a:4ab
ee [%]c d
,
entry
NHC·Pd
t [°C]
1
2
3
4
5
6
7
Ra,Ra-1a
Ra,Sa-1a
Sa,Sa-1a
Ra,Ra-1b
Ra,Sa-1b
Ra,Ra-1c
Ra,Sa-1c
23
23
23
50
50
50
50
>99
>99
>99
>99
>99
>99
>99
5:1
4:1
5:1
4:1
4:1
6:1
4:1
-24 (S)
56 (R)
34 (R)
39 (R)
58 (R)
46 (R)
66 (R)
a Determined by GC-MS. b Determined by analysis of 1H NMR spectra
of product mixtures prior to purification. c Determined by HPLC for 3a.
d Configuration of 3a assigned according to ref 10.
Scheme 1. Previously Reported Palladium Complexes 1a-c
in enantioselectivity though were immediately apparent.
Diastereomers of catalyst 1a, which performed best in our
previous investigation, gave erratic results with inconsistent
absolute configurations of product 3a. Omitting the R2-
isopropyl group on the wingtips of the NHC (precatalysts
1b) gave more usable results (entries 4 and 5). Furthermore,
precatalyst 1c that incorporates a slightly bulkier R1-
cyclohexyl group resulted in better enantioselection (entries
6 and 7). Although both the chemoselectivity as well as the
enantioselectivity (66% ee) were still not practical, the simple
fact that representative chiral mono- and bidentate phospho-
rus ligands showed inferior results (see Supporting Informa-
tion) suggested that complexes 1a-c contained the more
promising overall catalyst motif.
The tendencies in selectivity observed in Table 1 were
subsequently implemented in the design of a modified chiral
NHC structure that lacks the R2 wingtip group and incor-
porates a bulkier, unstrained 3-pentyl moiety on the 2-posi-
tion of the naphthyl side chains. The precursor imidazolinium
salt was obtained relatively easily (see Supporting Infor-
mation), and subsequent deprotonation, reaction with
[Pd(cinnamyl)Cl]2, and chromatographic workup gave pre-
catalyst 1d in 82% yield as three separable diastereomers [Ra,Ra-
1d (37%), Ra,Sa-1d (32%) and Sa,Sa-1d (13%)] (Scheme 2).
The results with standard substrate 2a (Table 2, entries
1-3) were very encouraging and all three diastereomeric
precatalysts 1d proved superior to their congeners 1a-c both
in terms of their higher reactivity (room temperature)11 and
their enhanced selectivity. As an unexpected and extremely
welcome side effect, incorporation of the new ligand greatly
Our investigation commenced by examining the ability of
previously reported NHC·Pd complexes 1a-c (Scheme 1)5f
to promote the intramolecular R-arylation of the model
substrate 2a. At the outset, it was not clear whether such
R-arylations would be preferred over a reaction scenario
involving Heck cyclizations giving rise to 7-exo-trig (or
8-endo-trig) products. The results reported in Table 1 indeed
indicate that product 4a was formed in noticeable amounts
(15-20%) with all diastereomers of catalysts 1a-c. Trends
(5) (a) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402. (b) Glorius,
F.; Altenhoff, G.; Goddard, R.; Lehmann, C. Chem. Commun. 2002, 2704.
(c) Arao, T.; Sato, K.; Kondo, K.; Aoyama, T. Chem. Pharm. Bull. 2006,
54, 1576. (d) Arao, T.; Kondo, K.; Aoyama, T. Chem. Pharm. Bull. 2006,
54, 1743. (e) Ku¨ndig, E. P.; Seidel, T. M.; Jia, Y.; Bernardinelli, G. Angew.
Chem., Int. Ed. 2007, 46, 8484. (f) Luan, X.; Mariz, R.; Robert, C.; Gatti,
M.; Blumentritt, S.; Linden, A.; Dorta, R. Org. Lett. 2008, 10, 5569. (g)
Wu¨rtz, S.; Lohre, C.; Fro¨hlich, R.; Bergander, K.; Glorius, F. J. Am. Chem.
Soc. 2009, 131, 8344.
(6) Taylor, A. M.; Altman, R. A.; Buchwald, S. L. J. Am. Chem. Soc.
2009, 131, 9900.
(7) Yasui, Y.; Kamisaki, H.; Takemoto, Y. Org. Lett. 2008, 10, 3303.
(8) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2009, 48, 8037.
(9) For other metal-catalyzed reactions leading to similar oxindoles, see:
(a) Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka, M.
J. Am. Chem. Soc. 2005, 127, 10164. (b) Shintani, R.; Inoue, M.; Hayashi,
T. Angew. Chem., Int. Ed. 2006, 45, 3353. (c) Pinto, A.; Jia, Y.; Neuville,
L.; Zhu, J. Chem.sEur. J. 2007, 13, 961. (d) Jia, Y.-X.; Hillgren, J. M.;
Watson, E. L.; Marsden, S. P.; Kundig, E. P. Chem. Commun. 2008, 4040.
(e) Jia, Y.-X.; Katayev, D.; Kundig, E. P. Chem. Commun. 2010, 46, 130.
For asymmetric organocatalytic approaches leading to similar products with
quaternary carbon centers starting from preformed 3-aryloxindoles and
derivatives, see: (f) Hills, I. D.; Fu, G. Angew. Chem., Int. Ed. 2003, 42,
3921. (g) He, R.; Ding, C.; Maruoka, K. Angew. Chem., Int. Ed. 2009, 48,
4559. (h) Jiang, K.; Peng, J.; Cui, H.; Chen, Y. Chem. Commun. 2009,
3955.
(10) Duguet, N.; Slawin, A. M. Z.; Smith, A. D. Org. Lett. 2009, 11,
3858.
(11) Bulkier NHC side chains have been shown to enhance reactivity
in classical Pd-coupling reactions; see, for example: (a) Altenhoff, G.;
Goddard, R.; Lehmann, C. W.; Glorius, F. J. Am. Chem. Soc. 2004, 126,
15159. (b) Song, C.; Ma, Y.; Chai, Q.; Ma, C.; Jiang, W.; Andrus, M. B.
Tetrahedron 2005, 61, 7438. (c) Marion, N.; Navarro, O.; Mei, J.; Stevens,
E. D.; Scott, N. M.; Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101. (d)
Organ, M. G.; Calimsiz, S.; Sayah, M.; Hoi, K. H.; Lough, A. J. Angew.
Chem., Int. Ed. 2009, 48, 2383.
Org. Lett., Vol. 12, No. 9, 2010
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