L-proline-catalyzed asymmetric michael addition of 2-oxindoles to enones: A convenient access to oxindoles with a quaternary stereocenter

Article abstract of DOI:10.1055/s-0030-1259527

A new organocatalytic approach for 1,4-conjugate addition of 2-oxindoles to α,β-unsaturated ketones using the combination of readily available and nonexpensive l-proline and achiral trans-2,5-dimethylpiperazine as catalytic system is provided. The reaction results in oxindole derivatives with vicinal quaternary and tertiary carbon centers in up to 99% yield and 91% ee. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259527

CLUSTER
503
L-Proline-Catalyzed Asymmetric Michael Addition of 2-Oxindoles to Enones:
A Convenient Access to Oxindoles with a Quaternary Stereocenter
C
onstruction of Quater
a
nary Carbo
t
n Cent
t
h
L
-
Proline
C
a
i
talysisas H. Freund, Svetlana B. Tsogoeva*
Department of Chemistry and Pharmacy, Chair of Organic Chemistry I, University of Erlangen-Nuremberg,
Henkestr. 42, 91054 Erlangen, Germany
Fax +49(9131)8526865; E-mail: tsogoeva@chemie.uni-erlangen.de
Received 30 November 2010
Cl
Abstract: A new organocatalytic approach for 1,4-conjugate addi-
tion of 2-oxindoles to a,b-unsaturated ketones using the combina-
tion of readily available and nonexpensive L-proline and achiral
trans-2,5-dimethylpiperazine as catalytic system is provided. The
reaction results in oxindole derivatives with vicinal quaternary and
N
O
H
H
O
N
CN
tertiary carbon centers in up to 99% yield and 91% ee.
O
O
N
N
Key words: L-proline, organocatalysis, 2-oxindoles, quaternary
stereocenters, Michael addition
H
H
welwitindolinone A
isonitrile
spirotryprostatine A
O
Quaternary carbon centers are a common feature in many
complex natural products and bioactive compounds, and
the development of solid methodologies for their enantio-
selective construction is of tremendous importance and
became an exceptionally vivid branch of synthetic organic
research and process development during the last years in-
cluding asymmetric organocatalysis.1
H
H
NH
O
H
N
H
Me
O
alstonisine
Figure 1 Natural products with a 3,3-disubstituted 2-oxindole motif
Among the numerous alkaloids bearing a quaternary ste-
reocenter, structures with a 3,3-disubstituted 2-oxindole
scaffold are a quite common motif (Figure 1) and attract-
ed the interest of many research groups, because of their
manifold bioactive properties. In order to gain synthetic
access to such compounds or derivatives thereof, several
methods for asymmetric syntheses of 3,3-disubstituted 2-
oxindoles have been developed,2 among them, numerous
organocatalytic approaches were elaborated very recent-
ly.3
EWG
EWG
R1
R1
R1
∗
EWG
O
O
O
R2
EWG
R2
∗
∗
NH
NH
NH
Scheme 1 Construction of quaternary carbon centers through 1,4-
conjugate additions of 3-substituted 2-oxindoles to electrophilic al-
kenes
In this context, several examples of organocatalytic asym-
metric 1,4-conjugate additions4 of 3-substituted 2-oxin-
doles to various electrophilic alkenes (Scheme 1) have
been reported.5 However, in all of these methodologies,
relatively complex organocatalysts are employed, which
have to be synthesized separately in a cost-producing and
time-consuming manner.
addition of nitroalkanes to a,b-unsatured ketones and re-
lies on iminium activation of the acceptor.8
To the best of our knowledge, however, no attempts to ap-
ply this readily available organocatalytic system to 1,4-
conjugate additions of 3-substituted 2-oxindoles are
known in the literature. Herein, we do want to present the
results of our studies concerning the catalytic system and
the compatibility of the catalysis with various substrates.
Following our previous work on asymmetric organocata-
lytic construction of quaternary carbon centers6 and 1,4-
conjugate additions7 we decided to study the 1,4-conju-
gate addition of 3-substituted 2-oxindoles to a,b-unsatur-
ed ketones, applying a nonexpensive organocatalyst,
namely proline, in combination with achiral trans-2,5-
dimethylpiperazine additive.11 Such catalytic system has
been reported first by Hanessian and co-workers for the
We first investigated a set of potentially iminium-forming
catalyst motifs (1–9, Figure 2) in the 1,4-conjugate addi-
tion of 3-methyl-2-oxindole (10) to cylohex-2-enone
(Table 1). At the beginning of our experiments, we found
a pronounced synergism between the catalyst L-proline
(1) and the basic additive 11 (entry 3). While L-proline it-
self showed moderate reactivity and enantioselectivity
(entry 2), the additive 11 alone was inactive in the cataly-
sis (entry 1). However, the combination of both catalytic
components resulted in a fairly active and efficient cata-
SYNLETT 2011, No. 4, pp 0503–0507
x
x.
x
x.
2
0
1
1
Advanced online publication: 02.02.2011
DOI: 10.1055/s-0030-1259527; Art ID: Y02110ST
© Georg Thieme Verlag Stuttgart · New York

504
M. H. Freund, S. B. Tsogoeva
CLUSTER
O
tivities (entries 5, 9–11, Table 1). With respect to stereo-
selectivity, L-proline was the most beneficial catalyst in
this series of experiments, providing two diastereomers
(dr 47:53) of Michael adduct with 91% ee and 60% ee, re-
spectively (entry 3).
O
O
O
OH
Ph
N
HN
N
N
OH
OH
H
H
H
1
2
3
TBDPSO
TBDPSO
N
O
O
N
N
In order to possibly improve the stereoselectivity of this
catalysis, we then studied a set of other chiral and achiral
basic additives (12–20, Figure 3, Table 2) in combination
with proline. But with all these investigated additives, the
stereoselectivity was decreased, in comparison to the orig-
inally applied achiral trans-2,5-dimethylpiperazine (11).
In the case of the chiral piperazine 12, a negligible influ-
ence of the additive’s chirality on the product enantio-
selectivity was found (entries 2 and 3, Table 2).
Furthermore, the diastereoselectivity was again only mod-
erate, except for additive 20 (dr 27:73, entry 11).
N
N
H
N
N
OH
OH
H
H
H
4
5
6
Me
CF3
F3C
O
O
N
CF3
+
N
OH
Bn
H
NH2
H
N
Cl–
OTMS
H
CF3
7
8
9
Figure 2 Screened catalysts in the 1,4-conjugate addition of 3-
methyl-2-oxindole to cyclohex-2-enone
H
N
H
N
Me
N
Table 1 Screening of Various Catalysts in the 1,4-Conjugate Addi-
tion of 3-Methyl-2-oxindole (10) to Cyclohex-2-enone
N
H
N
N
H
Me
N
O
O
11
12
13
catalyst (30 mol%)
11 (100 mol%)
O
n-Oct
n-Oct
NH
N
H
+
N
*
N
CHCl3, r.t.
HO
*
N
H
n-Oct
O
N
N
10
14
15
16
Entry Catalyst Time (h) Yield
(%)b
drc,d
ee (%) ee (%)
17
N
(1st pair)c(2nd pair)c
H
1
2a
3
4
5
6
7
8
9
–
1
1
2
3
4
5
6
7
8
9
168
192
30
traces
27
–
–
62
91
–82
19
84
86
91
–
–
–7
60
–53
–9
66
11
35
–
N
HO
H
H
36:64
47:53
36:64
34:66
40:60
52:48
48:52
–
N
N
O
O
99
N
N N
H
H
MeO
OMe
30
99
18
19
168
30
54
N
N
99
H
H
30
99
N
H
N
O
O
48
99
N
N
H
MeO
OMe
168
168
168
traces
n.r.e
22
20
N
N
10
11
–
–
–
Figure 3 Screened basic additives in the 1,4-conjugate addition
13:87
–14
58
a No additive was used.
After having inspected various iminium-forming catalysts
and basic additives, the originally applied combination of
L-proline and trans-2,5-dimethylpiperazine was again
confirmed as the optimal and was used for further studies
concerning the influence of solvents on the catalysis
(Table 3).9
b Yield of isolated product.
c Determined by chiral HPLC.
d Ratio of 1st pair/2nd pair.
e No reaction.
lytic system (entry 3) and was used in the following
screening experiments (entries 4–11, Table 1).
Regarding catalytic activity, almost all of the chosen sol-
vents were suitable (entries 1–7, 9, and 11, Table 3), as in
all these cases very good product yields (97–99%) were
obtained. Surprisingly, in ethyl acetate (entry 8), the reac-
tion was sluggish and even after seven days no complete
Among the catalyst structures screened, compounds 1, 2,
4–6 catalyzed the addition reaction in high yields (up to
99%, entries 3, 4, 6–8). In contrast, compounds 3, 7–9
were either inactive or showed only moderate catalytic ac-
Synlett 2011, No. 4, 503–507 © Thieme Stuttgart · New York

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Construction of Quaternary Carbon Centers via L-Proline Catalysis
505
Table 2 Screening of Various Basic Additives in the 1,4-Conjugate
Addition of 3-Methyl-2-oxindole (10) to Cyclohex-2-enone
Table 3 Various Solvents in the 1,4-Conjugate Addition of 3-Meth-
yl-2-oxindole (10) to Cyclohex-2-enone
O
O
O
O
L-proline (30 mol%)
L-proline (30 mol%)
additive (100 mol%)
O
O
11 (100 mol%)
NH
+
NH
(S)
*
solvent, r.t.
+
CHCl3, r.t.
N
*
(R)
N
H
O
H
O
10
10
Yield drc,d
(%)b
ee (%) ee (%)
(1st pair)c (2nd pair)c
Entry Solvent
Time (h)Yield drb,c
(%)a
ee (%) ee (%)
Entry Additive Time
(h)
(1st pair)c (2nd pair)c
1
2
toluene
dioxane
THF
96
144
144
48
99
99
99
97
99
99
99
78
99
65
99
45:55
48:52
44:56
44:56
47:53
38:62
39:61
41:59
34:66
36:64
24:76
84
83
82
75
91
79
77
82
20
19
1
53
74
79
18
60
51
45
72
7
1
2
3a
4
5
6
7
8
9
11
12
12
13
14
15
16
17
18
19
20
30
72
99
99
99
88
98
81
92
99
97
91
93
47:53
38:62
43:57
44:56
41:59
41:59
40:60
48:52
40:60
41:59
27:73
91
77
–79
60
60
36
40
81
75
55
52
60
48
–42
2
3
72
4
CCl4
164
95
5
CHCl3
CH2Cl2
DCE
30
14
3
6
24
25
7
48
18
4
8
EtOAc
2-PrOH
DMF
168
96
24
10
6
9
24
10
11
24
32
7
10
144
144
18
–44
H2O
168
11
a Yield of isolated product.
a
D-proline was used instead of L-proline.
b Yield of isolated product.
b The dr was determined by chiral HPLC.
c Ratio of 1st pair/2nd pair (minor/major).
c Determined by chiral HPLC.
d Ratio of 1st pair/2nd pair.
oselectivity was noted. Besides the six-membered cyclic
enone, also its five-membered lower homologue was ap-
plied in somewhat lower yield and enantioselectivity (en-
try 12). In the case of the three open-chain enones (entries
13–15), not all were compatible with this catalytic meth-
odology and remained inactive even after a prolonged re-
action time.
conversion was achieved. In DMF, the catalysis was not
clean, as several byproducts were observed (entry 10).
With respect to the enantioselectivity of the catalysis, sol-
vents with increased polarity decreased the ee significant-
ly, especially in the first enantiomeric pair. In water, an
almost racemic product was formed (entry 11). Unfortu-
nately, each of the chosen solvents with a useful level of
ee did not positively influence the diastereoselectivity.
Taking account of all these results, CHCl3 was again se-
lected as the optimal solvent in terms of rate and stereo-
selectivity of the catalysis.10
In summary, we have applied for the first time the readily
available and simple catalytic system, L-proline/trans-
2,5-dimethylpiperazine,8 for the construction of vicinal
quaternary and tertiary carbon centers through 1,4-conju-
gate additions of 3-substituted 2-oxindoles to a,b-unsatur-
ated ketones. The synthetic scope of the catalytic system
has been successfully demonstrated. High yields (up to
99%) and good to high enantioselectivities (up to 91% ee)
were obtained.
Following these experiments, the substrate compatibility
was analyzed by applying various 3-substituted 2-oxin-
doles and a,b-unsatured ketones in the asymmetric 1,4-
conjugate addition (Table 4). A variety of 2-oxindoles
was converted with cyclohex-2-enone to the correspond-
ing Michael adducts in yields up to quantitative (entries
1–11). The reactions of 3-benzylated and 3-methylated 2-
oxindoles with cyclohex-2-enone resulted in good to high
enantioselectivities (72–91%, entries 2, 4–7), especially
in the first enantiomeric pair. Surprisingly, the 3-pheny-
lated 2-oxindole furnished a perfectly racemic product
(entry 3). In the case of N-substituted 3-methyl 2-oxin-
doles (entries 9–11) a significant decrease in the enanti-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors gratefully acknowledge financial support from the
Deutsche Forschungsgemeinschaft through SPP 1179 ‘Organocata-
lysis’.
Synlett 2011, No. 4, 503–507 © Thieme Stuttgart · New York

506
M. H. Freund, S. B. Tsogoeva
CLUSTER
Table 4 Substrate Scope of the Proline/trans-2,5-Dimethylpiperazine-Catalyzed 1,4-Conjugate Addition
O
R3
O
R4
O
R1
L-proline (30 mol%)
11 (100 mol%)
N
R1
+
O
R2
CHCl3, r.t.
N
R2
R3
R4
Entry
1
R1, R2
R3
R4
H
Time (h) Yield (%)a drb (1st pair/2nd pair) eeb (1st pair) eeb (2nd pair)
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)3-
-(CH2)2-
Me, Ph
H
48
48
63
40:60
47:53
45:55
39:61c
38:62
38:62
39:61
37:63
50:50
49:51
39:61
40:60
52:48
–
33
91
1
32
60
1
2
Me
H
99
3
Ph
H
48
76
4
Bn
H
48
99
84
81
72
82
68
2
37
30
24
40
19
43
66
50
15
70
–
5
4-BrC6H4CH2
4-O2NC6H4CH2
H
48
99
6
H
48
99
7
4-MeOC6H4CH2
H
48
99
8
MeO2CCH2
H
48
99
9
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Cbz
H
192
72
75
10
11
12
13
14
15
96
18
14
55
72
–
24
81
48
76
H
48
83
Ph, Ph
H
168
168
n.r.
traces
Me, H
H
–
–
–
a Yield of isolated product.
b The dr was determined by chiral HPLC.
c The absolute configurations in the major diastereomer were assigned by comparison of the measured HPLC retention times with the ones
reported in literature (ref. 5e). The absolute configurations of all other products were determined by analogy.
C. V.; Scheidt, K. A. Angew. Chem. Int. Ed. 2007, 46, 8748.
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(3) (a) Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C. Org.
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Synlett 2011, No. 4, 503–507 © Thieme Stuttgart · New York

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Construction of Quaternary Carbon Centers via L-Proline Catalysis
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the enantioselectivity.
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To a suspension of L-proline (0.3 equiv) and trans-2,5-
dimethylpiperazine (1 equiv) in CHCl3 (cbase = 0.2 M) 2-
oxindole (1 equiv) was added, followed by the a,b-unsatured
ketone (1 equiv). The reaction mixture was stirred at ambient
temperature, until the conversion was judged complete by
TLC, and transferred directly to purification by column or
flash chromatography (over SiO2). For more details, see
Supporting Information.
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