Organocatalytic asymmetric Michael addition of unprotected 3-substituted oxindoles to 1,4-naphthoquinone

Article abstract of DOI:10.3762/bjoc.8.157

We reported the first example of organocatalytic Michael addition of unprotected 3-prochiral oxindoles 1 to 1,4-naphthoquinone. Quinidine derivative (DHQD)₂PYR was found to be able to catalyze this reaction in up to 83% ee, with moderate to exc

Full text of DOI:10.3762/bjoc.8.157

Organocatalytic asymmetric Michael addition of
unprotected 3-substituted oxindoles
to 1,4-naphthoquinone
Jin-Sheng Yu, Feng Zhou, Yun-Lin Liu and Jian Zhou*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1360–1365.
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry, East China Normal University,
3663 N. Zhongshan Road, Shanghai, 200062, P. R. China
doi:10.3762/bjoc.8.157
Received: 27 May 2012
Accepted: 25 July 2012
Published: 23 August 2012
Email:
Jian Zhou* - jzhou@chem.ecnu.edu.cn
This article is part of the Thematic Series "Organocatalysis".
Guest Editor: B. List
* Corresponding author
Keywords:
3,3-disubstituted oxindoles; Michael addition; organocatalysis;
quaternary stereogenic center; unprotected 3-substituted oxindoles
© 2012 Yu et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
We reported the first example of organocatalytic Michael addition of unprotected 3-prochiral oxindoles 1 to 1,4-naphthoquinone.
Quinidine derivative (DHQD)2PYR was found to be able to catalyze this reaction in up to 83% ee, with moderate to excellent
yields. This method could be used for the synthesis of enantioenriched 3,3-diaryloxindoles, and the catalytic synthesis of which was
unprecedented.
Introduction
The catalytic asymmetric synthesis of 3,3-disubstituted oxin- thesis of 3,3-diaryloxindoles has not been reported. This is
doles has recently received great attention because of the wide possibly due to the challenge in the construction of such
occurrence of this structural motif in natural products and congested quaternary stereogenic centers. Only Sammakia tried
pharmaceutically active compounds [1-3]. In addition, struc- the SNAr reaction of unprotected 3-phenyloxindole with chiral
ture–activity relationship studies have revealed that the absolute electron-deficient 5-halooxazoles, promoted by 1.0 equiv of
configuration and the substituent of the C3 position of oxindole Cs2CO3 [21], with ca. 1:1 diastereoselectivity obtained.
greatly influenced the biological activities [4]. Accordingly, the
development of efficient synthetic methods to enable the syn- In this context, we are interested in the catalytic economical
thesis of 3,3-disubstituted oxindoles in great structural diversity asymmetric diverse synthesis of 3,3-disubstituted oxindoles,
is of current interest, and much progress had been made in the using cheap and easily available starting materials and simple
catalytic enantioselective synthesis of 3-hydroxyoxindoles chiral catalysts to facilitate biological evaluation. We have
[5-10], 3-aminooxindoles [11-15] and 3-quaternary oxindoles developed the catalytic asymmetric addition of acrolein,
[16-20]. Despite achievements, the catalytic asymmetric syn- allyltrimethylsilane or difluoroenoxysilanes to isatins to furnish
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Beilstein J. Org. Chem. 2012, 8, 1360–1365.
differently substituted enantioenriched 3-hydroxyoxindoles [22- β-ketoesters and aldehydes. Inspired by their work, we antici-
24]. For the synthesis of chiral 3-aminooxindoles, we devel- pated that the catalytic asymmetric addition of 3-aryloxindoles
oped the first example of catalytic asymmetric addition of to quinones would possibly install a hydroquinone moiety at the
nucleophiles to isatin-derived ketoimines using TMSCN [25] C3 position of oxindole to furnish the desired chiral 3,3-diaryl-
and the amination of unprotected 3-prochiral oxindoles using oxindoles. It also came to our attention that, while the addition
di-tert-butyl azodicarboxylate [26,27]. To construct the C3 of 3-prochiral oxindole to a variety of Michael acceptors had
quaternary stereogenic carbon center, we have designed a novel been studied [32-46], the use of quinones as the Michael
cinchona alkaloid-based phosphoramide bifunctional catalyst to acceptor had not been realized. Therefore, in this letter we are
realize a highly enantioselective Michael addition of both going to report our initial results about the catalytic asymmetric
unprotected 3-alkyl- and 3-aryloxindoles to nitroolefins [28]. Michael addition of unprotected 3-prochiral oxindoles to 1,4-
Based on these results, together with our efforts in the synthesis naphthoquinone.
of unsymmetric 3,3-diaryloxindoles [29], we try to develop a
catalytic asymmetric method to enantioenriched 3,3-diaryl- Results and Discussion
oxindoles.
We began the reaction development by the evaluation of
different chiral catalysts derived from cinchona alkaloids in the
In 2007, Jørgensen and coworkers pioneered the organocat- reaction of 3-phenyloxindole 1a and 1,4-naphthoquinone (2a),
alytic asymmetric addition reactions to quinones [30,31] which with ethyl acetate (EtOAc) as the solvent at 0 °C (Table 1,
turned out to be a powerful strategy for the α-arylation of Figure 1). A variety of bifunctional cinchona alkaloid-derived
Table 1: Condition optimization for the reaction of 1a and 2a.
Entrya
Cat.
Solvent
Additive
Yield of 3a (%)b
ee (%)c
1
5
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
THF
–
52
61
40
34
14
60
64
51
50
61
32
21
31
43
29
50
50
33
36
43
65
43d
59
14
4
2
6
–
3
7
–
4
8
–
5
9
–
15
64d
73d
77
64
64
47
36
73
80
70
78
78
76
40
77
4
6
10
11
12
12
12
12
12
12
12
12
12
12
12
12
12
12
–
7
–
8
–
9
–
10
11
12
13
14
15
16
17
18
19
20
21
Acetone
CH3CN
DCM
–
–
–
Toluene
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
–
MS 4Å
MS 5Å
H2O (5.0 equiv)
H2O (10.0 equiv)
PhCO2He
(S)-BINOLe
(R)-BINOLe
LiCle
aReactions were run on a 0.10 mmol scale. bIsolated yield. cDetermined by chiral HPLC analysis. dOpposite enantiomer. e10 mol % used.
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Beilstein J. Org. Chem. 2012, 8, 1360–1365.
Figure 1: Cinchona alkaloid-derived catalysts screened for condition optimization (Table 1).
catalysts 5–9 were first tried, aiming to facilitate the reaction by 43% (Table 1, entry 8 versus 14). The use of MS 5Å had a
the dual activation of both reaction partners, with H-bonding negative effect on both the reactivity and the enantioselectivity
donor moiety of the catalyst to activate quinone 2a and the (Table 1, entry 15). Water had no obvious effect on the reaction
tertiary amine to deprotonatively activate oxindole 1. The reac- outcome (Table 1, entries 16 and 17). The addition of acids led
tion generally proceeded slowly, and only the oxidation prod- to diminished yield and enantioselectivity (Table 1, entries
uct, 1,4-naphthoquinone derivative 3a, was obtained in 18–20).
moderate yield after five days. No hydroquinone product 4 was
detected by TLC and NMR analysis of the crude reaction mix- Based on these screenings, we determined to examine the sub-
ture. While the simple quinine and quinidine as catalysts could strate scope by running the reaction at 0 °C in EtOAc, with
deliver product 3a in 59% ee (Table 1, entry 2), all other bifunc- 20 mol % of (DHQD)2PYR 12 to improve the reactivity.
tional catalysts turned out to be much less enantioselective Different substituted 3-prochiral oxindoles were first examined
(Table 1, entries 3–5). However, the dinuclear Brønsted base and the results are shown in Table 2. An electron-withdrawing
catalysts 10–12 could achieve higher ee for the desired product substituent at the C5 position of the oxindole had a positive
3a with comparable yields (Table 1, entries 6–8). When the effect on the reactivity and enantioselectivity of the reaction.
hydrogenated catalyst 12 was used, 77% ee for product 3a was The corresponding products 3a–d could be obtained in good to
obtained with 51% yield (Table 1, entry 8). In light of this, we excellent yields with up to 81% ee. Without an electron-with-
used catalyst 12 for the following screenings.
drawing group, products 3e and 3f were obtained in diminished
yields and enantioselectivities. Different aryl substituents at the
We further examined the solvent effects, and found that EtOAc C3 position were also investigated, the corresponding products
turned out to be the most suitable solvent which afforded prod- 3g–k were obtained in acceptable yields and up to 83% ee. We
uct 3a in highest ee (Table 1, entries 8–13). Since the reactivity also tried if this method could be extended to 3-alkyloxindoles
was unsatisfactory, we further tried the use of some additives to but had to find out that product 3l was obtained in only
improve the reaction rate. The use of MS 4Å could improve the moderate enantioselectivity and yield. The absolute configur-
enantioselectivity to 80%, but decreased the yield from 51% to ation of product 3f was determined to be (S) by chemical trans-
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Beilstein J. Org. Chem. 2012, 8, 1360–1365.
Table 2: Substrate scope of unprotected 3-prochiral oxindolesa–c.
Product, yield, enantioselectivity and reaction time
3a
3c
3d
3b
70% yield, 79% ee, 5 d
97% yield, 80% ee, 6 d
74% yield, 81% ee, 6 d
71% yield, 79% ee, 8 d
3h
3e
3f
3g
46% yield, 69% ee, 9 d
51% yield, 70% ee, 9 d
76% yield, 81% ee, 6 d
45% yield, 54% ee, 8 d
3k
3l
3i
3j
55% yield, 83% ee, 6 d
68% yield, 77% ee, 6 d
53% yield, 65% ee, 6 d
58% yield, 19% ee, 8 d
aRun on a 0.25 mmol scale. bIsolated yield. cDetermined by chiral HPLC analysis.
formation to the corresponding known compound [47]; all other corresponding hydroquinone product 4. The free hydroxy
products were tentatively assigned in analogy (for details, see groups were protected to prevent re-oxidation. For example,
Supporting Information File 1).
product 3i was reduced and converted to the desired 3,3-diaryl-
oxindole 13 in 57% yield without the loss of ee. We further
Other quinones such as 2,6-dichloro-1,4-benzoquinone and 1,4- checked if this protocol could be operated as a “one-pot”
benzoquinone were also examined, however, none of them sequential reaction. After the reaction of 1i and 2 was run at
could react with 3-phenyloxindole 1a to give the desired prod- 0 °C for five days a small amount of oxindole 1i still remained.
uct.
Then, the reaction was warmed to room temperature, followed
by the addition of Pd/C and ammonium formate. When TLC
While the oxidation product 3 was obtained as the only product analysis revealed that the hydrogenation of product 3i was
from the Michael addition, it could be hydrogenated to the completed, acetyl chloride and triethylamine were added. The
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Beilstein J. Org. Chem. 2012, 8, 1360–1365.
desired product 13 was obtained in 50% yield with 75% ee (10PJ1403100), Specialized Research Fund for the Doctoral
(Scheme 1). The diminished enantioselectivity was due to the Program of Higher Education (20090076120007), Innovation
fact that the remaining oxindole 1i continued to react with 2 at Program of SMEC (12ZZ046), and the Fundamental Research
room temperature during the following steps. Even if there is Funds for the Central Universities (East China Normal Univer-
much potential for further improvement in the ee, this sequen- sity 11043) are highly appreciated.
tial reaction represented the first example of catalytic asym-
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