Kinetic resolution of 2,3-dihydro-2-substituted 4-quinolones by palladium-catalyzed asymmetric allylic alkylation

Article abstract of DOI:10.1021/ja9082717

(Chemical Equation Presented) The kinetic resolution of a carbon nucleophile is realized for the first time via Pd-catalyzed asymmetric allylic alkylation with "unstabilized" ketone enolates as the nucleophile, providing both allylated 2,3-disubstituted 2

Full text of DOI:10.1021/ja9082717

Published on Web 12/08/2009
Kinetic Resolution of 2,3-Dihydro-2-substituted 4-Quinolones by
Palladium-Catalyzed Asymmetric Allylic Alkylation
Bai-Lin Lei,† Chang-Hua Ding,† Xiao-Fei Yang,† Xiao-Long Wan,‡ and Xue-Long Hou*,†
State Key Laboratory of Organometallic Chemistry, Department of Analytic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received September 29, 2009; E-mail: xlhou@mail.sioc.ac.cn
Kinetic resolution as one of the most powerful tools in asym-
metric catalysis has found wide applications in both academies and
industry.1 Many procedures have been developed with a high ee
value and yield, for both products and recovered starting materials.
However, the reactions suitable for the kinetic resolution are still
limited. Only in a few examples, a new chiral center in addition to
that present in the starting material was created in products.2 There
is much yet to be explored in relation to kinetic resolution. On the
other hand, Pd-catalyzed asymmetric allylic alkylation reactions
have been widely recognized as a powerful protocol in organic
synthesis.3 Recent progress allows it to install a chiral center at
“hard” carbon nucleophiles.4,5 The Pd-catalyzed allylic substitution
reactions have also been applied successfully in the kinetic
resolution; however, the majority of studies focus on the resolution
of allyl substrates.6 The resolution of a nucleophile is still very
limited.7 Recently, we succeeded in the kinetic resolution of
dihydroindoles via Pd-catalyzed asymmetric allylic amination.7
Here, we report preliminary results on the highly efficient kinetic
resolution of “hard” carbon nucleophiles, 2,3-dihydro-2-substituted
4-quinolones, by Pd-catalyzed AAA reaction. The application of
the methodology in organic synthesis is also demonstrated.
used as prenucleophile. It is noteworthy that the adduct 4a
incorporates chiral centers at both R and ꢀ positions of ketone.
This procedure represents a novel route to such a structural motif
in contrast to the arduous asymmetric synthesis through conven-
tional processes.8 The recovered optically active 3a is also of interest
with its prominent feature as biologically active molecules.9
Table 1. Optimization of Parameters for the Reaction of 3a with 2a
3
4
entry
2
L
yield%b
ee%c
yield%b
ee%c
d.r.d
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2c
2c
2c
2c
2c
L3
L1
L2
L4
L5e
L6e
L7e
L8e
L4
L4
L4
L4
L4
L4
L4
40
53
32
40
40
42
19
35
26
32
26
37
45
51
46
71
5
47
83
11
9
46
27
26
41
34
39
23
49
24
45
24
49
48
41
47
73
27
79
71
13
10/1
13/1
8/1
17/1
50/1
9/1
20/1
11/1
18/1
8/1
17/1
>99/1
>99/1
>99/1
>99/1
13
5
0
13
-25f
49
9
59
93
95
99
99
77
87
10
11g
12h
13i
14i,j
15i,k
65
73
79
93
53
87
a Molar ratio of 3a/2/[Pd(C3H5)Cl]2/L/base
b Isolated yield. c Determined by chiral HPLC. d Determined by 1H
NMR. e L5
(R)-BINAP, L6 (S)-tert-BuPHOX, L7 (S,
Sp)-iso-PrFcPHOX, L8
) 200:100:6:12:200.
)
)
)
)
(R, R)-DACH-phenyl Trost ligand. f The
reversed sequence of peaks by HPLC. g Run at -5 °C. h Run at -30
°C. i Run at -50 °C. j Ac of 3a was replaced with H. k Ac of 3a was
replaced with Boc.
Encouraged by these results, the impact of the reaction parameters
on the efficiency of the reaction was investigated (Table 1). The choice
of substituent on the oxazoline ring and the combination of chiral
elements in ligands are important. Much lower ee was obtained in the
presence of (Sphos, R)-L1 rather than (Rphos, R)-L2 (entry 2 vs 3),
suggesting the chiralities in the latter is matched. We then probed the
influence of the substituent on the oxazoline ring in SiocPhox ligands
and found (S, Rphos, R)-L4 with Ph as the substituent gave the best
results, affording 4a with 71% ee in 41% yield, with recovered 3a in
83% ee and 40% yield (entry 4 vs 1). Several commercially available
chiral ligands including (R)-BINAP, (S)-tert-BuPHOX, (S, Sp)-iso-
PrFcPHOX, and (R, R)-DACH-phenyl Trost ligand were also exam-
ined; nevertheless, only low ee was acquired (entries 5-8). Evaluation
of the leaving group in allyl reagents 2 clarified that phosphate was
among the best as the ee value of the recovered 3a increased from
83% and 59% to 93% (entry 10 vs 4, 9). Gratifyingly, enantioselectivity
increased dramatically when the reaction proceeded at lower temper-
ature, providing 4a with 93% ee (48% yield) and 3a in 99% ee (45%
yield) at -50 °C, while lower ee value was obtained for both 4a and
3a at -30 °C (entry 13 vs 12). The substituent on the nitrogen of 3
To test our idea, ketones 1a and 1b were adopted as prenucleo-
phile in the reaction with allyl reagent 2a using [Pd(C3H5)Cl]2 and
(S, Rphos, R)-SiocPhox L3 as catalyst in the presence of LiHMDS
as base (eq 1). An allylation product with low yield and ee was
obtained for ketone 1a, while a retro-Michael addition reaction took
place for ketone 1b. Delightfully, the allylation product 4a in 46%
yield and 73% ee was afforded while 3a was recovered in 40%
yield and 71% ee when 2,3-dihydro-2-phenyl-4-quinolone 3a was
† State Key Laboratory of Organometallic Chemistry.
‡ Department of Analytic Chemistry.
9
18250 J. AM. CHEM. SOC. 2009, 131, 18250–18251
10.1021/ja9082717  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Transformation of Allylated Adduct 4a into Valuable
Compound
also played a role in the reaction. When the acetyl group of 3a was
replaced by H or Boc, the ee of both recovered substrates and allylated
products decreased greatly (entries 14, 15 vs 13). The screen of solvents
and bases revealed that THF and LiHMDS were the best choice (not
showed in Table 1 but see Supporting Information).
Table 2. Substrate Scope for the Kinetic Resolution of
2,3-Dihydro-2-substituted 4-Quinolonesa
3
4
entry
substrate
yield%b
ee (%)c
yield%b
ee (%)c
Sd
of Pd-catalyzed AAA in organic synthesis. Studies on the extension
of the protocol to other carbon nucleophiles and applications of the
aforementioned procedure in organic synthesis are in progress.
1
2
3
3a
3b
3c
3d
3e
3f
3g
3h
3i
45
43
44
44
46
42
47
46
46
41
37
99
99
96
98
99
99
99
99
99
93
87
48
38
47
42
38
48
49
49
46
37
46
93
83
91
93
90
91
93
91
90
89
87
145
56
83
127
99
111
145
111
99
4
5e
6
Acknowledgment. Financially supported by the Major Basic
Research Development Program (2006CB806100), National Natural
Science Foundation of China (20532050, 20872161, 20821002),
Chinese Academy of Sciences, Croucher Foundation of Hong Kong,
and Shanghai Committee of Science and Technology.
7
8
9
10
3j
3k
58
40
11f
Supporting Information Available: General procedure for kinetic
resolution, spectral data for 3a-3k and 4a-4k, and X-ray analysis
data of 4c and 6 (cif file). This material is available free of charge via
the Internet at http://pubs.acs.org.
a Reaction conditions: 3/2c/[Pd(C3H5)Cl]2/L4/base ) 100:200:6:12:200,
0.05 M of 3 in THF at -50 °C. b Isolated yield. c Determined by chiral
d
HPLC. Calculated by the method describe by Kagan.1a e d.r. of 4e is
13/1. f d.r. of 4k is 5/1.
The substrate scope was examined, and the results were compiled
in Table 2 under the above optimized conditions. Generally, the
reactions provided allylated products 4 with trans-stereoselectivity
in 37-49% yields and 83-93% ee accompanied with 37-47%
yields of recovered starting materials in 87-99% ee (S-factor is
40-145). The substituents on both the 2,3-dihydro-4-quinolone core
and 2-phenyl group had limited effect on the enantioselectivity of
recovered 3 as its ee was consistently excellent (entries 1-9). The
substituents on the 2-phenyl group exerted some impact on the
selectivity of allylated products 4. When the substituent was at
the ortho-position of the 2-phenyl group, the stereoselectivity is
slightly low, giving 4b in 83% ee and 38% yield, presumably due
to the steric hindrance (entry 2). While either an electron-donating
or -withdrawing group was at the meta- and para-position of the
2-phenyl group, allylated products 4 were furnished with excellent
ee (entries 3-9). Notably, the reaction of 2-alkyl-2,3-dihydro-4-
quinolones gave excellent enantioselectivity (entries 10 and 11),
while the diastereoselectivity of 4k decreased to 5/1 (entry 11).
This kinetic resolution proceeded even on gram-scale under mild
conditions with high efficiency. Treatment of 1.17 g of 3a with
0.43 g of 2c under the above conditions still furnished a 44% yield
of 4a in 93% ee and 46% yield of 3a in 99% ee.
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