Pd(II)/tBu-quinolineoxazoline: An Air-Stable and modular chiral catalyst system for enantioselective oxidative cascade cyclization

Article abstract of DOI:10.1021/ol902348t

[Chemical Equation Presented] An air-stable and structurally tunable chiral ^tBu-quinolineoxazoline/Pd(II) catalyst system has been developed for the enantioselective oxidative cascade cyclization of a variety of disubstituted olefinic substrates, with the apparent advantages of good yields and excellent enantioselectivities (up to 98% ee) and diastereoselectivities (dr >24:1). A transition-state model has also been proposed to account for the excellent stereocontrol.

Full text of DOI:10.1021/ol902348t

ORGANIC
LETTERS
Pd(II)/tBu-quinolineoxazoline: An
Air-Stable and Modular Chiral Catalyst
System for Enantioselective Oxidative
Cascade Cyclization
2009
Vol. 11, No. 24
5626-5628
Wei He,†,‡ Kai-Tai Yip,† Nian-Yong Zhu,† and Dan Yang*,†
Department of Chemistry, The UniVersity of Hong Kong, Pokfulam Road, Hong Kong
(P. R. China), Department of Chemistry, The Fourth Military Medical UniVersity,
Changle Road, Xi’an (P. R. China)
yangdan@hku.hk
Received October 11, 2009
ABSTRACT
An air-stable and structurally tunable chiral tBu-quinolineoxazoline/Pd(II) catalyst system has been developed for the enantioselective oxidative
cascade cyclization of a variety of disubstituted olefinic substrates, with the apparent advantages of good yields and excellent enantioselectivities
(up to 98% ee) and diastereoselectivities (dr >24:1). A transition-state model has also been proposed to account for the excellent stereocontrol.
As integral cores of many bioactive alkaloids, enantioenriched
N-heterocycles have attracted tremendous attention for develop-
ment of new approaches to construct those cyclic
skeletons.1Numerous examples rely on transition-metal-cata-
lyzed asymmetric C-N bond formations such as allylic
substitution2 and hydroamination.3 However, these methods are
restricted to single bond-forming events, and their cascade
variants for constructing several bonds in a single step remain
to be developed. We previously reported enantioselective C-N
bond and C-C bond tandem cyclization reactions of unsaturated
anilides under a (-)-sparteine/Pd(TFA)2 catalyst system.4
Despite this earlier system’s excellent enantioselectivities (up
to 91% ee) and easy availability of (-)-sparteine, a new chiral
catalyst system (in particular, one adept at oxidative transforma-
tions) remains highly desirable because: (1) sparteine is difficult
to be chemically engineered, restricting its reaction scope; (2)
(+)-sparteine5 is not naturally occurring, and the preparation
of its surrogates invariably requires multistep synthesis;6,7 and
(3) new chiral ligands for Pd(II) that can tolerate oxidizing
conditions remain of great demand.8 More recently, we
discovered that in our oxidative cascade cyclization9 quino-
† The University of Hong Kong.
‡ The Fourth Military Medical University.
(1) For comprehensive reviews, see: (a) Nicolaou, K. C.; Edmonds, D. J.;
Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (b) Tietze, L. F.
Chem. ReV. 1996, 96, 115. For a thematic issue on “Heterocycles”, see:
Katritzky, A. R. (Ed. ), Chem. ReV. 2004, 104.
(4) To the best of our knowledge, this is the only successful example
of enantioselective oxidative C-N bond-forming reaction. See: Yip, K.-
T.; Yang, M.; Law, K.-L.; Zhu, N.-Y.; Yang, D. J. Am. Chem. Soc. 2006,
128, 3130.
(2) (a) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921. (b)
Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395.
(3) Mu¨ller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem.
ReV. 2008, 108, 3795.
(5) For the first asymmetric synthesis of (+)-sparteine, see: Smith, B. T.;
Wendt, J. A.; Aube´, J. Org. Lett. 2002, 4, 2577.
10.1021/ol902348t  2009 American Chemical Society
Published on Web 11/11/2009

line as an N-ligand is superior to pyridine, a well-established
ligand being used extensively in a range of Pd-catalyzed
oxidative reactions.10 These findings prompted us to incor-
porate readily available chiral elements into the quinoline
moiety for the development of new chiral ligands for Pd
catalysis as a viable alternative to the (-)-sparteine/Pd(II)
system. In contrast to the well-developed asymmetric Pd(0)-
catalyzed cyclization reactions,11 much less attention has
been paid to investigate the origins of enantioselectivities in
Pd(II)-catalyzed asymmetric nucleopalladation of alkenes.12
Herein, we present a new chiral Pd catalyst system compris-
ing quinoline and chiral oxazoline units,13 which catalyzes
enantioselective oxidative cascade cyclization of unsaturated
anilides to afford enantioenriched indolines14 with excellent
diastereoselectivities (dr >24:1) and enantioselectivities (up
to 98% ee). Also, we propose a transition-state model to
account for the observed high enantioselectivity attained by
the new chiral Pd catalyst system.
Isoquinoline-oxazoline L6 and L7 were also examined,
and only modest enantioselectivities were observed. Interest-
i
ingly, the Pr-quinoline-oxazoline L8 allowed moderate
conversion and enantiomeric excess (72% ee). With these
encouraging results, we moved on to evaluate a series of
quinoline-oxazoline ligands (QUOX) with different R groups.
These air-stable QUOX ligands can be readily synthesized
in two steps from their parent carboxylic acids and enan-
tiopure amino alcohols, making this class of ligands structur-
ally versatile and highly modular. Although L10, L12, and
L13 led to poor enantioselectivities, Bn-QUOX (L11) gave
good yield (80%) and moderate product ee value (76%). By
using tBu-QUOX (L9),17 the product enantioselectivity was
improved further to 93% ee. The X-ray crystallographic
structure of Pd(L9)Cl2 showed the coplanarity of the quino-
line and oxazoline units upon chelation with Pd(II).
Further optimization of the reaction conditions led to an
improved catalyst system, which was then used to evaluate
the scope of a Pd(II)-catalyzed enantioselective cascade
cyclization for a number of unsaturated acrylanilides (Table
1). Modest to good product yields were achieved for both
Since (-)-sparteine has been previously identified as a
good ligand for the oxidative cascade cyclization of mono-
substituted olefinic substrates, the disubstituted olefin 1a was
first subjected to the cyclization (Scheme 1). However, this
Table 1. Pd(II)-Catalyzed Enantioselective Cascade Cyclizationa
Scheme 1.
Screening of Chiral Ligandsa
substrate 1
entry
R1
R2
R3
t (h) yield of 2 (%)b ee (%)c
1
2
3
4
5
6
7
8
9
Ph
p-FC6H4
H
H
H
H
H
H
H
H
H
H
Ph
H
H
H
H
H
H
H
H
Ph
48
48
48
48
40
48
40
48
60
75 (2a)
68 (2b)
75 (2c)
74 (2d)
82 (2e)
70 (2f)
73 (2g)
65 (2h)
55 (2i)
45 (2j)
73 (2k)
98
92
80
96
86
82d
83
91
90
85
80
p-ClC6H4
p-MeC6H4
p-MeOC6H4
m-ClC6H4
o-MeOC6H4
2-naphthyl
Ph
10 Ph
11
p-MeC6H4 60
H 60
H
a Reaction scale: 1 mmol of substrate 1a. b Isolated yield. c Determined
by HPLC analysis using a Chiralcel OD column.
a Unless otherwise indicated, all reactions were carried out at 75 °C
with substrate (1 mmol), 2,6-lutidine (1 equiv), Pd(OAc)2 (10 mol %),
t
HNTf2 (20 mol %), and Bu-QUOX L9 (40 mol %) over activated 3 Å
molecular sieves (500 mg/mmol substrate) in toluene (10 mL) under O2 (1
atm). b Isolated yield. c Determined by HPLC analysis using a Chiralcel
OD or OD-H column. d The absolute configuration of product 2f was
determined by X-ray crystallography.
resulted in a low observed ee value of only 14%. C2-
symmetric BOX ligands15 L1-L2 and PyBOX ligand16 L3
were not efficient for this reaction. Pyridine-oxazoline ligand
L4 afforded product 2a in moderate yield but low enanti-
oselectivity (3% ee). We anticipated that placing one more
carbon between the pyridine and the oxazoline ring would
presumably allow the formation of a six-membered ring
chelate with Pd(II) species, thereby creating a distinct chiral
environment. Indeed, pyridine-oxazoline L5 did improve the
conversion dramatically, albeit with poor chiral induction.
electron-rich and electron-poor substrates (entries 1-7), and
in particular, the cyclization of 1a resulted in enantiomeric
excesses of up to 98% (entry 1). In addition, X-ray
crystallographic analysis of chiral product 2f also reveals
the absolute configuration of the angular carbon center as R
and that of the chlorophenyl-bearing carbon center as S. More
bulky substrate 1h could also be cyclized with excellent
chiral induction (91% ee; entry 8). Substrates 1i and 1j with
a cinnamide group cyclized less efficiently, albeit with good
enantioselectivities (entries 9 and 10). Cyclization of cis-
(6) For recent efforts, see: O’Brien, P. Chem. Commun. 2008, 655.
(7) For recent applications of (+)-sparteine surrogates in asymmetric
catalysis, see: Ebner, D. C.; Trend, R. M.; Genet, C.; McGrath, M. J.;
O’Brien, P.; Stoltz, B. M. Angew. Chem, Int. Ed. 2008, 47, 6367.
Org. Lett., Vol. 11, No. 24, 2009
5627

Figure 1. Proposed transition-state model.
olefin-bearing substrate 1k proceeded to afford 2k with good
yield and enantiomeric excess (entry 11).
site a instead of site b to maximize the interaction of the
chiral element of the ligand with the aryl olefin in the
formation of the first chiral center. The additional benzene
ring of the quinoline moiety is crucial to offer steric bulkiness
that constrains the orientation of the Pd-bound substrate. Prior
to amidopalladation, site b would be released by dissociation
of the counterion and occupied by the aryl-substituted olefin
(substrate). Since cyclization proceeds through a syn-ami-
dopalladation, four different transition states (TS) originating
from intermediate I are considered. Si-face cyclization of I
leading to TS A is disfavored due to steric repulsion between
the cinnamyl moiety of substrate and the tert-butyl group of
L9. In contrast, formation of TS B is favored through Re-
face cyclization. In this case, the orientation of the cinnamyl
group of the substrate is sterically matched with the chiral
environment of L9. However, when the substrate is turned
upside down, the resulting TS C and D are disfavored and
nonproductive since the cinnamyl group of the substrate
would directly clash with the tert-butyl group of L9,
regardless of the orientation of cinnamyl olefin from one side
to another (i.e., TS C T TS D). As a result, only one (TS
B) out of the four possible transition states is favored,
affording the enantioenriched product.
It is noteworthy that the oxidative cascade cyclization of
all substrates essentially yielded only one diastereomer. A
comparison of the cyclizations of 1a and 1k revealed the
stereospecific nature of the enantioselective cascade cycliza-
tions, in which the olefin geometry of the substrate com-
pletely controls the relative stereochemistry of the product.
In addition, the stereochemical outcomes supported the syn-
amidopalladation as the only operating pathway in the
reaction mechanism.18
The absolute stereochemistry of 2f can be explained by
proposing a transition-state model as shown in Figure 1.
Owing to the observed high enantioselectivities, the acrylim-
ide nitrogen (substrate) bound to the Pd center should occupy
(8) (a) Tsujihara, T.; Takenaka, K.; Onitsuka, K.; Hatanaka, M.; Sasai,
H. J. Am. Chem. Soc. 2009, 131, 3452. (b) Zhang, Y.; Sigman, M. S. J. Am.
Chem. Soc. 2007, 129, 3076. (c) Tietze, L. F.; Sommer, K. M.; Zinngrebe,
J.; Stecker, F. Angew. Chem., Int. Ed. 2005, 44, 257. (d) Arai, M. A.;
Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907. (e)
Uozumi, Y.; Kato, K.; Hayashi, T. J. Am. Chem. Soc. 1997, 119, 5063.
(9) Yip, K.-T.; Zhu, N.-Y.; Yang, D. Org. Lett. 2009, 11, 1911.
(10) (a) Nishimura, T.; Uemura, S. Synlett 2004, 201. (b) Stahl, S. S.
Angew. Chem., Int. Ed. 2004, 43, 3400.
(11) (a) Shibasaki, M.; Vogl, E. M.; Ohshima, T. AdV. Synth. Catal.
2004, 346, 1533. (b) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003,
103, 2945.
In summary, a novel chiral tBu-QUOX (L9)/Pd(II) system
has been developed for enantioselective oxidative cascade
cyclizations. This catalyst system has the advantages of being
air stable, structurally tunable, and highly stereoselective for
a variety of disubstituted olefinic substrates. A transition-
state model has also been proposed to account for the
excellent stereocontrol, which provides the basis for design-
ing new asymmetric oxidative systems.
(12) (a) Tietze, L. F.; Ila, H.; Bell, H. P. Chem. ReV. 2004, 104, 3453.
(b) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328. (c) Trend,
R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778.
(13) McManus, H. A.; Guiry, P. J. Chem. ReV. 2004, 104, 4151.
(14) For recent approaches to enantioenriched indolines, see: (a)
Barluenga, J.; Tudela, E.; Ballesteros, A.; Toma´s, M. J. Am. Chem. Soc.
2009, 131, 2096. (b) Hyde, A. M.; Buchwald, S. L. Angew. Chem., Int. Ed.
2008, 47, 177. (c) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128,
6314. (d) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 14264. (e)
Sanz Gil, G.; Groth, U. M. J. Am. Chem. Soc. 2000, 122, 6789.
(15) (a) Desimoni, G.; Faita, G.; Jorgensen, K. A. Chem. ReV. 2006,
106, 3561. (b) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
(16) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. ReV. 2003, 103, 3119.
(17) Chelucci, G.; Medici, S.; Saba, A. Tetrahedron: Asymmetry 1999,
10, 543.
Acknowledgment. We thank the University of Hong Kong
and the Hong Kong Research Grants Council (HKU 705807P)
for financial support of this research.
(18) For examples of the syn-aminopalladation pathway, see: (a) Muniz,
K.; Hovelmann, C. H.; Streuff., J. J. Am. Chem. Soc. 2008, 130, 763. (b)
Desai, L. V.; Sanford, M. S. Angew. Chem., Int. Ed. 2007, 46, 5737. (c)
Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179. (d) Nakhla, J. S.;
Kampf, J. W.; Wolfe, J. P. J. Am. Chem. Soc. 2006, 128, 2893. (e) Ney,
J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 8644. (f) Brice, J. L.;
Harang, J. E.; Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem.
Soc. 2005, 127, 2868. (g) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed.
2004, 43, 3605.
Supporting Information Available: Preparation and
characterization of 1-2 and L9; HPLC analysis of chiral
products 2; and X-ray crystallographic data of product (-)-
2f and complex Pd(L9)Cl2. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL902348T
5628
Org. Lett., Vol. 11, No. 24, 2009