Asymmetric double Michael reaction catalyzed by simple primary amine catalysts: A straightforward approach to construct spirocyclic oxindoles

Article abstract of DOI:10.1002/cjoc.201100543

The enantioselective double Michael reaction of N-Boc-3-nonsubstitued oxindoles with dienones catalyzed by chiral monoimide protected cyclohexane-1,2-diamines was developed. A wide range of optically active spirocyclic oxindoles were obtained up to 98% yield and up to 89% ee.

Full text of DOI:10.1002/cjoc.201100543

NOTE
DOI: 10.1002/cjoc.201100543
Asymmetric Double Michael Reaction Catalyzed by Simple
Primary Amine Catalysts: A Straightforward Approach to
Construct Spirocyclic Oxindoles
Luo, Xiyaa,b(罗西娅)
Bai, Jianfeia,b(摆建飞)
Tian, Fanga(田芳)
Wang, Lianglianga,b(汪亮亮)
Peng, Lina(彭林)
Jia, Linaa,b(贾利娜)
He, Guangyuna(贺光云)
Wang, Lixin*,a(王立新)
Xu, Xiaoying*,a(徐小英)
a Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic
Chemistry, Chinese Academy of Sciences, Chengdu, Sichuan 610041, China
b Graduate University of Chinese Academy of Sciences, Beijing 10039, China
The enantioselective double Michael reaction of N-Boc-3-nonsubstitued oxindoles with dienones catalyzed by
chiral monoimide protected cyclohexane-1,2-diamines was developed. A wide range of optically active spirocyclic
oxindoles were obtained up to 98% yield and up to 89% ee.
Keywords double Michael reaction, spirocyclic oxindole, amine catalyst, organocatalysis
Introduction
indole with α,β-unsaturated ketones catalyzed by the
cinchonined primary amine to create spiro[cyclohex-2-
enone-oxindoles].[11a] Subsequently, we also reported a
highly enantioselective double Michael reaction of
3-nonsubstitued oxindoles and dienones promoted by
the cinchona-based primary amines to access spirocyclic
oxindoles in excellent results.[11b] To date, asymmetric
double Michael reaction of diversified donors with
dienones through organocatalysis has been considered
as a powerful strategy to access cyclic compouds.[12] For
the significance of spirocyclic oxindoles and further
expanding this useful transformation, it is still desirable
to develop new catalytic system to achieve this
conversion.
Oxindole scaffolds are versatile and useful building
blocks, and commonly present in a number of natural
products and biologically active molecules.[1]
Particularly, spirocyclic oxindoles are attractive
intermediates for the preparation of many bioactive
compounds, which are widely used as drug candidates
and clinical pharmaceuticals.[2] The development of
highly efficient synthetic methods to access those
compounds would be of great values for drug-lead
synthesis. Over the past years, enormous impressive
successes have been made for the preparation of those
interesting structrues.[3] Among them, organocatalysis
has drawn great attentions since Melchiorre disclosed
the first example of organocascade reaction for the
construction of spiro[4-cyclohexanone]-1,3-oxindo-
line.[4] And after that, Gong,[5] Chen,[6] Yuan,[7] Wang[8]
and Rios[9] respectively reported excellent studies to
access spirocyclic oxindoles with contiguous multiple
stereocenters via asymmetric organocatalysis. It is
worth mentioning that Barbas’s group[10] reported a
domino Michael-aldol reaction between 3-substituted
oxindoles and methyleneindolinones catalyzed by a
novel multifunctional organocatalyst with tertiary-
primary amine and thiourea moieties, providing
bispirooxindoles with over four stereocentres in good
results.[10a]
In the past decade, chiral amines have been widely
applied in asymmetric catalysis.[13] Particularly, 1,2-
diphenylethane-1,2-diamine
and
cyclohexane-1,2-
diamine are frequently used to make chiral reagents,
ligands and catalysts such as Jacobsen’s salen ligands,[14]
Trost’s ligand,[15] and some other organocatalysts.[16]
Imide monoprotected-1,2-diamines, the key interme-
diates in the preparation of those molecules, have been
less exploited.[17] As a part of our continuous interests in
chiral aminocatalysis,[18] we wish to report the double
Michael reaction of 3-nonsubstituted oxindoles with
dienones catalyzed by chiral monoimide-1,2-diamines.
Results and Discussion
Recently, our group has developed a Michael/ketone
aldol/dehydration domino process of 2-hydroxy-3-acetyl
To optimize the reaction conditions, the reaction of
*
E-mail: wlxioc@cioc.ac.cn; xuxy@cioc.ac.cn; Tel.: 0086-028-85255208; Fax: 0086-028-85255208
Received November 1, 2011; accepted December 11, 2011; published online April 10, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201100543 or from the author.
Chin. J. Chem. 2012, 30, 1185—1188
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1185

Luo et al.
NOTE
N-Boc-3-nonsubstituted oxindole 2a with dienone 3a
was used as a model reaction and a series of chiral
diamines were used (Figure 1). As anticipated, the
reaction proceeded at room temperature in toluene and
afforded the desired product in moderate yields (35%—
64%) and poor enantioselectivities (Table 1, Entries 1—
7). Catalysts 1f and 1g with diphenylethylenediamine
scaffolds showed very low reactivities and gave disap-
pointing results (Table 1, Entries 6 and 7). Catalysts
1a—1e with cyclohexanediamine scaffolds afforded
relatively better yields (Table 1, Entries 1—5). The re-
action temperature greatly affected the effect of the
catalysts (Table 1, Entries 8—12). When the reaction
temperature was lowered to 0 ℃, the results were
slightly improved in the presence of 1a and 1c. Further
lowering the reaction temperature to －30 ℃, good
yield and enantioselectivity were obtained (69% yield,
86% ee, Table 1, Entry 12).
Then a series of solvents, additives and substrate
loadings were examined to further optimize the reaction
conditions (Table 2). Solvents have significant effects
on the results. THF, CH3CN and halogenated hydro-
carbon solvents except CH2Cl2 afforded trace desired
products (Table 2, Entries 2, 3, 7, 8). Cyclohexane and
EtOAc gave only moderate yields (Table 2, Entries 9
and 10). While aromatic hydrocarbon solvents afforded
good results (69%—76% yield, 60—86% ee, Table 2,
Entries 4—6 ). Among the solvents, toluene was the
suitable one and gave 69% yield and 86% ee (Table 2,
Entry 4).
Cl
Cl
O
O
O
Cl
N
N
N
Cl
O
NH2
O
O
NH2
1b
NH2
1c
1a
O
N
O
N
O
NH2
O
NH2
1e
1d
Ph
Ph
N
O
Ph
H2N
Ph
O
H2N
N
O
O
1g
1f
Figure 1 Structures of the catalysts.
Table 1 Screening of the catalystsa
Table 2 Optimization of reaction conditionsa
O
O
O
Ph
1b (20 mol%)
O
O
Ph
+
N
Ph
O
Cat. (20 mol%)
r.t., Toluene
Ph
o
Boc
Ph
O
O
Ph
Ph
-30 C, Toluene
+
N
N
3a
72 h
Boc
Boc
Ph
2a
N
Boc
3a
4a
2a
4a
eec/%
Entry
Solvent
CH2Cl2
Ratio of 2a/3a
Yieldb/% eec/%
Entry
Cat.
Time/h
Yieldb/%
1
2
1∶1.2
1∶1.2
1∶1.2
1∶1.2
1∶1.2
1∶1.2
1∶1.2
1∶1.2
1∶1.2
1∶1.2
1∶1.5
1∶2
32
33
nd
nd
86
60
61
nd
nd
8
1
2
1a
1b
1c
1d
1e
1f
24
24
24
24
24
24
24
64
64
64
72
72
58
64
57
56
61
37
35
69
77
74
73
69
22
11
14
2
CHCl3
nd
3
ClCH2CH2Cl
Toluene
m-xylene
Mesitylene
THF
trace
69
3
4
4
5
76
5
1
6
75
6
4
7
trace
trace
41
7
1g
1a
1b
1c
1b
1b
2
8
CH3CN
8d
9d
10d
11e
12f
18
46
20
76
86
9
Cyclohexane
EtOAc
10
11
12
13
14
15d
36
4
Toluene
Toluene
Toluene
Toluene
Toluene
54
81
72
83
86
86
39
1.5∶1
2∶1
64
a
Unless otherwise noted, the reaction was conducted with 0.1
mmol 2a, 0.12 mmol 3a, 20 mol% catalyst in 0.5 mL toluene at
25 ℃. b Isolated yield. Measured by chiral HPLC and the con-
figuration was determined by comparison with the reported
data[11b] (see the supporting information). The reaction was
conducted at 0 ℃. The reaction was conducted at －20 ℃.
f The reaction was conducted at －30 ℃.
78
c
2∶1
84
a
Unless otherwise noted, the reaction was conducted with 0.1
mmol 2a, 0.12 mmol 3a, 20 mol% 1b in 0.5 mL toluene at －30
℃ for 72 h. Isolated yield. Measured by chiral HPLC. d The
d
b
c
e
reaction was conducted for 96 h.
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Chin. J. Chem. 2012, 30, 1185—1188

A Straightforward Approach to Construct Spirocyclic Oxindoles
tested. Electron-withdrawing substituents on para-
positions afforded better yields and enantioselectivities
than electron-donating one (Table 3, Entries 2, 6 vs. 8).
The electron-withdrawing substuents on para- and
mtea-positions gave good to excellent yields (68%—
98%). The asymmetric dienones were also tested (Table
3, Entries 9—15). Both electron-withdrawing (Table 3,
Entries 9—12, 15) and electron-donating (Table 3,
Entries 13—14) substituents on dienones were tolerated.
Good yields and moderate to good enantioselectivities
were obtained (72% —96% yield, 51% — 89% ee),
whereas low disastereoselectivities were attained except
para-nitro group substituted (Table 3, Entries 9—14 vs.
15).
By tuning the stoichiometry of 2a to 3a, a significant
improvement of conversion was observed (Table 2,
Entries 11—14). Excessive amounts of dienones 3a
were unfavorable (Table 2, Entries 4 vs. 11 and 12). By
contrast, excessive oxindole 2a gave better yields, and
slightly affected the enantioselectivties (Table 2, Entries
4 vs. 13—14). When the reaction was conducted with
the molecular ratio of 2/1 reactants 2a/3a in toluene at
－30 ℃ for 96 h, the best result was obtained (84%
yield and 86% ee, Table 2, Entry 15).
With the established reaction conditions, the scope
of the substrates was finally investigated (Table 3). The
symmetric dienones were first evaluated and afforded
the desired adducts in moderate to excellent yields and
enantioselectivities (up to 98% yield, up to 86% ee).
The position of substituents on phenyl ring of dienones
delivered significant influences on the enantioselec-
tivities and yields. Unsubstituted benzene ring afforded
better yield and enantioselectivity than the substituted
ones (Table 3, Entry 1 vs. Entries 2—8). ortho-
Substituent gave low yield and enantioselectivity (37%
yield and 36% ee, Table 3, Entry 5). para-Substituents
afforded better ee values than meta- and ortho-
substituted ones (Table 3, Entries 2 vs. 3, 4 vs. 5, 6 vs.
7). The electronic features of the substitutents were also
Conclusions
In summary, chiral monoimide protected cyclohex-
ane-1,2-diamines were first successfully applied to
catalyze enantioselective double Michael reaction of
N-Boc-3-nonsubstitued oxindoles and dienones and a
wide range of optically active spirocyclic oxindoles
were obtained up to 98% yield and up to 89% ee.
Further studying of the catalytic mechanism of those
special chiral monoimide-1,2-diamines is going on in
our laboratory.
Table 3 Scope of substratea
Acknowledgement
O
O
This work was supported by National Natural Sci-
ence Foundation of China (Nos. 20802075, 21042006).
R1
1b (20 mol%)
O +
R2
O
R2
R1
N
Boc
-30 oC, Toluene
96 h
2a
3
N
References and Note
Boc
4
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Entry
R1
R2
Ph
Yieldb/% drc eed/%
1
2
Ph
4a/84
4b/98
4c/97
4d/91
4e/37
4f/68
4g/86
4h/20
4i/85e
4j/83e
nd
nd
nd
nd
nd
nd
nd
nd
86
74
55
48
36
83
60
59
4-FC6H4
3-FC6H4
4-FC6H4
3
3-FC6H4
4
3-ClC6H4
2-ClC6H4
4-BrC6H4
3-BrC6H4
4-MeC6H4
Ph
3-ClC6H4
2-ClC6H4
4-BrC6H4
3-BrC6H4
4-MeC6H4
3-FC6H4
5
6
7
8
9
1.5/1 51/53
10
11
12
13
14
15
Ph
4-BrC6H4
3-BrC6H4
4-CF3C6H4
4-MeC6H4
3-MeC6H4
5.7/1 83/66
Ph
4k/89e 1.8/1 73/78
4l/74e
3.3/1 63/53
4m/72e 1.3/1 87/83
4n/96e 1.3/1 79/73
Ph
Ph
Ph
Ph
4-NO2C6H4 4o/93e 13/1 89/82
a
Unless otherwise noted, the reaction was conducted with 0.4
mmol 2a, 0. 2 mmol 3, 20 mol% 1b in 1.0 mL toluene at －30
℃ for 96 h. Isolated yield. Measured by chiral HPLC. The
corresponding ee value was measured by chiral HPLC. e The total
yield of isomers.
b
c
d
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Chin. J. Chem. 2012, 30, 1185—1188
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1187

Luo et al.
NOTE
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[19] General
procedure
for
double
Michael
reaction
of
N-Boc-3-nonsubstitued oxindoles with dienones: To a stirred solution of
catalyst (20 mol%) and dienones (0.2 mmol) in toluene (1.0 mL) was
added oxindoles (2.0 equiv.) at －30 ℃ for 96 h. The crude product
was purified by column chromatography (silica gel, petroleum
ether/ethyl acetate) to give the desired product. The ee value was de-
termined by HPLC analyses (for 4a—4d, 4g—4l, 4n and 4o, HPLC
condition: AD-H, 1.0 mL/min, V(hexane)∶V(i-PrOH)＝90∶10; for
4e, HPLC condition: AD-H, 1.0 mL/min, V(hexane)∶V(i-PrOH)＝
97∶3; for 4f, HPLC condition: AS-H, 1.0 mL/min, V(hexane)∶
V(i-PrOH)＝80∶20; for 4m, HPLC condition: IC-H, 1.0 mL/min,
V(hexane)∶V(i-PrOH)＝95∶5).
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Palucki, M.; Finney, N. S.; Pospisil, P. J.; Güler, M. L.; Ishida, T.;
Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 948; (c) Loy, R. N.;
Jacobsen, E. N. J. Am. Chem. Soc. 2009, 131, 2786.
(Pang, B.; Qin, X.)
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Chin. J. Chem. 2012, 30, 1185—1188