Pd(II)-catalyzed enantioselective oxidative tandem cyclization reactions. Synthesis of indolines through C-N and C-C bond formation

Article abstract of DOI:10.1021/ja060291x

We have developed an efficient Pd(II)-catalyzed enantioselective oxidative tandem cyclization strategy using molecular oxygen as a green oxidant for the double 5-exo-trig cyclizations of N-(2-allylaryl) amides to afford a variety of indolines in good yiel

Full text of DOI:10.1021/ja060291x

Published on Web 02/15/2006
Pd(II)-Catalyzed Enantioselective Oxidative Tandem Cyclization Reactions.
Synthesis of Indolines through C-N and C-C Bond Formation
Kai-Tai Yip, Min Yang, Ka-Lun Law, Nian-Yong Zhu, and Dan Yang*
Department of Chemistry, The UniVersity of Hong Kong, Pokfulam Road, Hong Kong, P. R. China
Received January 15, 2006; E-mail: yangdan@hku.hk
Table 1. Pd(II)-Catalyzed Oxidative Tandem Cyclization
Palladium-catalyzed tandem cyclization reactions are versatile
and powerful tools to construct complex polycyclic products
because multiple stereocenters can be established in one step under
mild conditions.1 In contrast to the well-developed asymmetric
tandem cyclization reactions catalyzed by chiral palladium(0)
complexes, asymmetric oxidative tandem cyclization reactions
involving palladium(II) complexes have received relatively little
attention, despite the fact that the latter reactions have an advantage
in that C-X bonds are formed to generate heterocyclic molecules,2
many of which are core structures of potent drugs and bioactive
natural products.3 The presence of cocatalysts (e.g., copper salts)
or organic oxidants (e.g., benzoquinone), which are used to
regenerate Pd(II) species, in oxidative Pd(II) catalysis complicates
the development of asymmetric transformation. Previously, the only
successful Pd(II)-catalyzed enantioselective oxidative tandem cy-
clization reactions were reported by Sasai,4 whose Wacker-type
tandem cyclization of alkenyl alcohols afforded bicyclic product
with excellent enantiomeric excess (up to 95%). Herein we de-
scribe the first enantioselective oxidative tandem cyclizations under
Pd(II) catalysis using nitrogen atom-based nucleophiles and mo-
lecular oxygen as the sole oxidant.
Reactionsa
Although an aza-Wacker-type tandem cyclization using a stoi-
chiometric amount of Pd(II) complex was reported previously by
Hegedus and co-workers (eq 1),5 that reaction required tandem relay
(using a 1,1-disubstituted alkene)6 and led to double-bond-isomer-
ized products. Initially, we chose the Pd(II)/pyridine catalyst system
for our studies of tandem cyclization reactions because it is effective
for a number of mechanistically distinct oxidative reactions,
including oxidation of alcohols, Wacker oxidation, oxidative C-C
bond cleavage, and oxidative cyclization.7 Indeed, successful
Pd(II)-catalyzed oxidative tandem cyclization of 1 occurred to afford
2 and/or 3 exclusively without the formation of any undesired
monocyclization products (Table 1).8 We evaluated substrates
1a-d, which bear different para-substituents, and observed a
general trend (entries 1-5) relating to the electronic effects that
the para-substituents have on reactivity (Cl ≈ H > Me > OMe);
for example, substrate 1b, which possesses an electron-withdrawing
group (X ) Cl), cyclized more efficiently than substrates 1c and
1d did, which bear electron-donating groups (X ) Me and OMe,
respectively). The product yield remained excellent even when the
catalyst loading was decreased to 5 mol % (entry 2). When pyridine
was employed as the ligand, incomplete conversions of substrates
1c and 1d occurred, even after prolonged heating. In contrast, the
cyclizations of 1c and 1d proceeded smoothly when using triphen-
a Unless otherwise indicated, all reactions were performed at 50 °C using
the substrate (0.3 mmol), pyridine (40 mol %), and Pd(OAc)2 (10 mol %)
in toluene (3 mL) under O2 (1 atm). b Yield of isolated product. c Pyridine
(20 mol %), Pd(OAc)2 (5 mol %). d PPh3 (40 mol %) was used instead of
pyridine. e Ratio of stereoisomers was not determined. f Ratio determined
from 1H NMR spectra; the major diastereomer is depicted. g Quinoline (40
mol %) was used instead of pyridine.
ylphosphine as the ligand (entries 4 and 5). Interestingly, substrates
1e-g, which exist in the E configuration, afforded exclusively the
products 2e-g in Z configurations in good yields (entries 6-8).
When the crotyl derivative 1h was employed, two different products
2h and 3h were isolated (entry 9). Unlike 2e-g, 2h existed as a
mixture of E and Z isomers. The major product 3h possesses two
stereogenic centers that were established in a single step from 1h.
Interestingly, 3i, which possesses an R-methyl substituent, was
obtained from 1i in excellent diastereoselectivity (entry 10). Similar
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C O M M U N I C A T I O N S
Table 2. Optimization of Reaction Conditionsa
promising ligand: it provided values of enantiomeric excess of up
to 54% (entry 7). Further optimization of the reaction conditionss
that is, adding activated 3 Å molecular sieves (entry 8), increasing
the reaction temperature to 80 °C (entry 9), and employing the bulky
tertiary amine diisopropylethylamine (DIPEA; entry 10)sled to
pronounced improvements in both the catalytic activity (yields of
up to 75%) and enantioselectivity (up to 86% ee).
Under the optimized conditions and using the chiral Pd(II)/
(-)-sparteine complex, a variety of chiral tandem cyclization
products 2 and 3 were obtained with good to excellent enantiose-
lectivities (Table 3). A comparably high enantiomeric excess of
2a was achieved even when the loading of the chiral Pd(II)/
(-)-sparteine catalyst was decreased to 5 mol % (entries 1-3).
The cyclization of 1b, which possesses a para-chloro substituent,
proceeded slower than that of 1a (entry 4 vs 1). Cyclization of
substrate 1f, which possesses a cinnamyl group, afforded 2f in the
S configuration, but without a significant improvement in the value
of the enantiomeric excess (80% ee, entry 5 vs 1); in contrast, the
presence of meta-methyl substituents on the aniline moiety (1k and
1l) enhanced the product enantioselectivity (2k, 91% ee, entry 7
vs 2; 2l, 87% ee, entry 8 vs 5). Relative to the Pd(OAc)2/pyridine
system, it is noteworthy that the Pd(TFA)2/(-)-sparteine complex
improved the diastereomeric ratio of product 3h from 1.8:1 to 8:1
(entry 9 of Table 1 vs entry 6 of Table 3).
a Unless otherwise indicated, all reactions were performed at 50 °C using
the substrate 1a (0.2 mmol), Pd(TFA)2 (20 mol %), and the ligand (80 mol
%) in toluene (2 mL) under O2 (1 atm). b For the structures of the different
chiral ligands, see the Supporting Information. c Determined from 1H NMR
spectra using nitrobenzene as the internal standard. d Determined through
HPLC analysis using a Chiralcel OD column. e Molecular sieves (3 Å) (500
mg/mmol substrate) were added. f Reaction temperature was 80 °C. g DIPEA
(2 equiv) was added.
Table 3. Pd(II)-Catalyzed Enantioselective Oxidative Tandem
Cyclization Reactionsa
In summary, we have developed a Pd(II)-catalyzed enantio-
selective oxidative tandem cyclization using readily available
(-)-sparteine as the chiral ligand and molecular oxygen as a green
oxidant. This methodology provides direct access to enantioenriched
and structurally versatile indolines. We are currently undertaking
mechanistic studies of this oxidative tandem cyclization, and the
results will be reported in due course.
Acknowledgment. This work was supported by the University
of Hong Kong and the Hong Kong Research Grants Council. D.Y.
acknowledges the Bristol-Myers Squibb Foundation for an Unre-
stricted Grant in Synthetic Organic Chemistry.
Supporting Information Available: Preparation and characteriza-
tion of 1-3; HPLC analysis of chiral products 2-3 and X-ray structures
of 2a and (+)-2f (PDF, CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
References
a Unless otherwise indicated, all reactions were performed at 80 °C using
the substrate (1 mmol), activated 3 Å molecular sieves (500 mg/mmol
substrate), DIPEA (2 equiv), Pd(TFA)2, and (-)-sparteine in toluene (10
mL) under O2 (1 atm). b Ratio of Pd(TFA)2 to (-)-sparteine was maintained
at 1:4. c Yield of isolated product. d Enantiomeric excess was determined
through HPLC analysis using a Chiralcel OD column. e Absolute config-
uration of the product 2f was determined to be S through X-ray analysis.
f Value of enantiomeric excess of the minor diastereomer of 3h.
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