Organocatalytic enantioselective conjugate addition of ketones to isatylidine malononitriles

Article abstract of DOI:10.1039/c2cc17067a

An enantioselective Michael addition of ketones to alkylidenemalononitriles catalyzed by chiral primary amine I with (R)-5c as a co-catalyst in good yields (>90%) and with good enantioselectivities (85-96% ee) has been developed. The strategy has also been extended to a three-component version through a domino Knoevenagel/Michael sequence with similar or better outcomes. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc17067a

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 1692–1694
www.rsc.org/chemcomm
COMMUNICATION
Organocatalytic enantioselective conjugate addition of ketones to
isatylidine malononitrilesw
Lu Liu,a Deyan Wu,a Xiangmin Li,a Sinan Wang,a Hao Li,a Jian Li*a and Wei Wang*ab
Received 14th November 2011, Accepted 6th December 2011
DOI: 10.1039/c2cc17067a
An enantioselective Michael addition of ketones to alkylidene-
malononitriles catalyzed by chiral primary amine I with (R)-5c
as a co-catalyst in good yields (>90%) and with good enantio-
selectivities (85–96% ee) has been developed. The strategy has
also been extended to a three-component version through a domino
Knoevenagel/Michael sequence with similar or better outcomes.
is efficiently promoted by a quinidine derived primary amine
and (R)-binol-phosphoric acid as a co-catalyst in high yields
(90–97%) and with high enantioselectivities (85–95% ee).
Notably, unsymmetrical ketones proceed exclusively at a less
substituted site. Moreover, significantly, the strategy has been
extended in a highly efficient 3-component version using readily
available malononitrile, isatins and ketones.
Inspired by the capacity6 and our experience7 in cinchona
alkaloid derived primary amines I–III in enamine catalysis
with ketones, we decided to explore them in the studies
(Table 1). A model reaction between isatylidine malononitrile
1a and acetone 2a under a neat condition was carried out in
initial investigations. It was found that the process took place
in good yields, but low enantioselectivities (entries 1–3).
Catalyst I gave a slightly lower yield while the ee value was
much higher than II and III. To further improve the enantio-
selectivity, we performed the reaction with I in a solvent
accordingly (entries 4–9). The best results (85% yield, 49% ee)
were obtained in THF (entries 4). We also examined other
factors such as reaction temperature and catalyst loadings,
but disappointingly no significant improvement in enantio-
selectivity was seen (entries 10 and 11). Then acidic additives
as co-catalysts were investigated in combination with catalyst I
(entries 12–15). Achiral 4-nitrobenzoic acid 5a led to a drop in
enantioselectivity (entry 12), while chiral phosphoric acid 5b
was beneficial (entry 13). Gratifyingly, the use of binaphthyl
derived phosphoric acids (R)-5c and (S)-5c gave significant
enhancement in enantioselectivities without diminishing the
yield and reaction time (entries 14 and 15). Interestingly, the
(S)-enantiomer gave a relatively low ee value (entry 15), while
92% ee was achieved with the (R)-5c enantiomer, but with an
opposite configuration (entry 14). This indicates that the chiral
counter anions play an important role in governing both the level
of enantioselectivity and the identity of the major enantiomer.8,9
Having established the optimal reaction parameters, we
then examined the generality of the conjugate addition process
(Table 2). It is shown that structurally varied isatylidene
malononitrile derivatives 1 can efficiently engage in the reaction
(entries 1–10). High enantioselectivities (85–96% ee) and high
yields (90–97%) were obtained, irrespective of the alternations
in electronic and steric properties of the substituents appending
to the aromatic rings of the oxindole framework. It appears that
the free ‘‘N’’ in the oxindole is critical for achieving high
enantioselectivity. Masking of the ‘‘N’’ (e.g., Bn, entry 11) led
The ‘privileged’ status of 3,30-disubstituted oxindoles bearing
functional diversity and complex molecular architectures1
while possessing a wide array of intriguing biological properties
has trigged considerable synthetic interest.2 Impressively,
significant progress has been made in the development of
organocatalytic enantioselective reactions.2,3 Among them,
organocatalytic asymmetric conjugate additions to oxindole
derived Michael receptors have been demonstrated as a viable
approach to the 3,30-disubstituted oxindole framework.4,5 1,3-
Diketones,4e,f aldehydes,4g and nitroalkenes4h have been employed
as nucleophiles in these processes. While simple ketones could
be used to generate structurally diverse oxindoles, implementing
it faces the daunting challenge of creating a quaternary
stereogenic center via conjugate addition of chiral enamines
derived from ketones to b,b0-disubstituted unsaturated systems.
The lower reactivity of ketones than aldehydes and active
carbon nucleophiles and difficulty in governing the enantio-
facial discrimination and regioselectivity of formed enamines
are important factors. Furthermore, organocatalytic enantio-
selective conjugate additions of ketones to highly functiona-
lized Michael acceptors in biologically important molecular
architectures are a largely untapped field. Successful realiza-
tion of the process affords a highly valuable tool for the
construction of structurally diverse molecules.
Toward this end, in this communication, we would like to
disclose an organocatalytic highly enantioselective conjugate
addition of ketones to isatylidine malononitriles. The process
a School of Pharmacy, East China University of Science and
Technology, 130 Meilong Road, Shanghai 200237, China.
E-mail: jianli@ecust.edu.cn; Fax: +86 21-64252584;
Tel: +86 21-64252584
b Department of Chemistry and Chemical Biology, University of New
Mexico, MSC03 2060, Albuquerque, NM 87131-0001, USA.
E-mail: wwang@unm.edu; Fax: +1 505-277-2609
w Electronic supplementary information (ESI) available: Experimental
details and spectroscopic data for compounds 3 and 7. CCDC 853177.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c2cc17067a
c
1692 Chem. Commun., 2012, 48, 1692–1694
This journal is The Royal Society of Chemistry 2012

View Article Online
Table 1 Optimization of the reaction conditionsa
Fig. 1 X-Ray structure of 3e.
Table 3 Scope for I and (R)-5c co-catalyzed asymmetric three
component Michael addition reactionsa
Entry
Cat.
Solvent
Additive
t/h
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
I
Neat
Neat
Neat
THF
MeCN
DMF
Dioxane
CHCl3
Toluene
THF
THF
THF
THF
THF
THF
None
None
None
None
None
None
None
None
None
None
None
5a
2
9
12
6
4
5
65
77
85
85
77
77
64
77
64
85
80
95
70
95
95
35
8
6
II
III
I
I
I
I
I
I
I
I
I
I
I
49
37
23
49
31
42
49
52
37
59
ꢀ92
78
Entry
X
3
t/h
Yieldb (%)
eec (%)
7
72
96
18
20
22
5
1
2
3
4
5
6
7
8
H
4-Cl
5-F
5-Cl
5-Br
5-NO2
5-Me
5-OMe
6-Cl
3a
3b
3c
3d
3e
3f
3g
3h
3i
10
6
5
5
6
6
8
6
8
92
92
94
92
93
94
95
96
93
91
85
90
97
95
97
96
95
94
93
95
95
96
86
93
>99
88
9
10d
11e
12
13
14
15
5b
(R)-5c
(S)-5c
9
9
I
a
9
Unless specified otherwise, the reaction was carried out with 1a
(0.03 mmol), 2a (0.3 mmol, 10.0 equiv.), additive (0.012 mmol,
0.4 equiv.) and cat (0.006 mmol, 0.2 equiv.) in 0.3 mL of solvent at rt.
10
11
12
13
7-Cl
3j
9
48
8
5,7-Me2
4-Br
4-F
3m
3n
3o
b
c
Isolated yield. Determined by HPLC analysis (Chiralpak AD-H).
e
15 mol% cat. used. Reaction run at ꢀ15 1C.
9
d
a
b
c
Unless stated otherwise, see ESI. Isolated yield. Determined by
HPLC analysis (Chiralpak AD-H or AS-H).
to dramatic decrease of the ee value (46%). The reaction
proceeded exclusively at a less substituted site for unsymme-
trical ketone 2-butanone with high enantioselectivity (92% ee)
and in high yield (97%) despite long reaction time (entry 12).
The absolute configuration of the Michael adducts is deter-
mined based on single X-ray structural analysis of compound
3e (Fig. 1).10
Table 2 Scope for I and (R)-5c co-catalyzed asymmetric Michael
addition reactiona
Trigged by the possibility of in situ formation of isatylidene
malononitriles 1 from corresponding isatins 6 and malono-
nitrile, we explored a more atom-economical, three compo-
nent process under the same reaction conditions (Table 3).
To our delight, the Knoevenagel–Michael cascade process
proceeded smoothly to afford desired adducts 3 using only
1.0 equiv. of malononitrile. Notably, even slightly higher
efficiencies in terms of reaction yields (85–97%) and enantio-
selectivities (86–>99% ee) were observed with significant
tolerance of structural demand of isatins 6.
Entry
X, Y, R
3
t/h
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
H, H, Me
3a
3b
3c
3d
3e
3f
3g
3h
3i
9
6
5
4.5
6
6
8
6
8
95
91
95
90
93
92
95
95
91
91
92
97
92
96
95
91
94
93
94
95
85
86
46
92
4-Cl, H, Me
5-F, H, Me
5-Cl, H, Me
5-Br, H, Me
5-NO2, H, Me
5-Me, H, Me
5-OMe, H, Me
6-Cl, H, Me
7-Cl, H, Me
H, Bn, Me
We also demonstrated that the Michael adducts 3 can be
conveniently transformed into spirooxindole derivatives
(Scheme 1). The reduction of 3a with NaBH4 in MeOH at
room temperature11 was followed by spontaneous cyclization
to afford the spirooxindole product 7 in 80% yield and with
91% ee and 9 : 1 dr.
9
10
11
12
3j
3k
3l
9
7
168
In conclusion, we have developed a new highly enantio-
selective asymmetric Michael reaction of ketones with alkyl-
idenemalononitriles. The processes are efficiently catalyzed
by primary aminocatalyst I in the presence of (R)-5c as a
H, H, Et
a
b
c
Unless stated otherwise, see ESI. Isolated yield. Determined by
HPLC analysis (Chiralpak AD-H or AS-H).
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1692–1694 1693

View Article Online
(k) K. Zheng, C. Yin, X. Liu, L. Lin and X. Feng, Angew. Chem.,
Int. Ed., 2011, 50, 2573; (l) Q. Guo, M. Bhanushali and
C.-G. Zhao, Angew. Chem., Int. Ed., 2010, 49, 9460;
(m) S. M. Hande, M. Nakajima, H. Kamisaki, C. Tsukano and
Y. Takemoto, Org. Lett., 2011, 13, 1828; (n) F. Pesciaioli, P. Righi,
A. Mazzanti, G. Bartoli and G. Bencivenni, Chem.–Eur. J., 2011,
17, 2842; (o) X. Li, Y.-M. Li, F.-Z. Peng, S.-T. Wu, Z.-Q. Li,
Z.-W. Sun, H.-B. Zhang and Z.-H. Shao, Org. Lett., 2011,
13, 6160; (p) A. Singh and G. P. Roth, Org. Lett., 2011,
13, 2118; (q) Y.-M. Li, X. Li, F.-Z. Peng, Z.-Q. Li, S.-T. Wu,
Z.-W. Sun, H.-B. Zhang and Z.-H. Shao, Org. Lett., 2011,
13, 6200; (r) Y.-L. Liu, B.-L. Wang, J.-J. Cao, L. Chen,
Y.-X. Zhang, C. Wang and J. Zhou, J. Am. Chem. Soc., 2010,
132, 15176; (s) N. V. Hanhan, A. H. Sahin, T. W. Chang,
J. C. Fettinger and A. K. Franz, Angew. Chem., Int. Ed., 2010,
49, 744.
4 Oxindole derivatives as electrophiles in organocatalysis:
(a) Y. Cao, X. Jiang, L. Liu, F. Shen, F. Zhang and R. Wang,
Angew. Chem., Int. Ed., 2011, 50, 9124; (b) X.-C. Zhang,
S.-H. Cao, Y. Wei and M. Shi, Org. Lett., 2011, 13, 1142;
(c) X.-C. Zhang, S.-H. Cao, Y. Wei and M. Shi, Chem. Commun.,
2011, 47, 1548; (d) H.-P. Deng, Y. Wei and M. Shi, Org. Lett.,
2011, 13, 3348; (e) S.-W. Duan, H.-H. Lu, F.-G. Zhang, J. Xuan,
J.-R. Chen and W.-J. Xiao, Synthesis, 2011, 1847; (f) W.-B. Chen,
Z.-J. Wu, Q.-L. Pei, L.-F. Cun, X.-M. Zhang and W.-C. Yuan,
Org. Lett., 2010, 12, 3132; (g) K. Jiang, Z.-J. Jia, S. Chen, L. Wu
and Y.-C. Chen, Chem.–Eur. J., 2010, 16, 2852; (h) F. Pesciaioli,
P. Righi, A. Mazzanti, G. Bartoli and G. Bencivenni, Chem.–Eur. J.,
2011, 17, 2842; (i) Y.-B. Lan, H. Zhao, Z.-M. Liu, G.-G. Liu,
J.-C. Tao and X.-W. Wang, Org. Lett., 2011, 13, 4866;
(j) C. Palumbo, G. Mazzeo, A. Mazziotta, A. Gambacorta,
M. A. Loreto, A. Migliorini, S. Superchi, D. Tofani and
T. Gasperi, Org. Lett., 2011, 13, 6248.
Scheme 1 Transformation of 3,30-disubstituted oxindole 3a to spiro-
oxindole 7.
co-catalyst under mild reaction conditions. Furthermore,
more atom-economical three-component processes through a
domino Knoevenagel/Michael sequence have been realized
while achieving similar or better efficiencies. The products
bearing dense functionalities can be conveniently elaborated
to generate structurally diverse molecular architectures for
biological studies; further efforts along this line are being
pursued in this laboratory.
We gratefully acknowledge the financial supports from the
111 Project (Grant B07023) and East China University of
Science & Technology.
Notes and references
1 For reviews of oxindole alkaloids, see: (a) J. J. Badillo,
N. V. Hanhan and A. K. Franz, Curr. Opin. Drug Discovery
Dev., 2010, 13, 758; (b) S. Peddibhotla, Curr. Bioact. Compd.,
2009, 5, 20; (c) C. V. Galliford and K. A. Scheidt, Angew. Chem.,
Int. Ed., 2007, 46, 8748; (d) C. Marti and E. M. Carreira, Eur. J.
Org. Chem., 2003, 2209; (e) R. M. Williams and R. J. Cox, Acc.
Chem. Res., 2003, 36, 127.
2 For recent reviews of synthetic method development, see:
(a) B. M. Trost and C. Jaing, Synthesis, 2006, 369; (b) F. Zhou,
Y.-L. Liu and J. Zhou, Adv. Synth. Catal., 2010, 352, 1381;
(c) J. S. Russel, Top. Heterocycl. Chem., 2010, 26, 397;
(d) J. J. Badillo, N. V. Hanhan and A. K. Franz, Curr. Opin. Drug
Discovery Dev., 2010, 13, 758; (e) A. Millemaggi and R. J. K.
Taylor, Eur. J. Org. Chem., 2010, 4527.
3 For recent selected examples of synthesis of 3,30-disubstituted
oxindoles, see: (a) T. Zhang, L. Cheng, S. Hameed, L. Liu,
D. Wang and Y.-J. Chen, Chem. Commun., 2011, 47, 6644;
(b) X.-L. Liu, Z.-J. Wu, X.-L. Du, X.-M. Zhang and
W.-C. Yuan, J. Org. Chem., 2011, 76, 4008; (c) M. H. Freund
and S. B. Tsogoeva, Synlett, 2011, 503; (d) S.-W. Duan, J. An,
J.-R. Chen and W.-J. Xiao, Org. Lett., 2011, 13, 2290; (e) Z. Liu,
P. Gu, M. Shi, P. McDowell and G. Li, Org. Lett., 2011, 13, 2314;
(f) Z. Zhang, W. Zheng and J. C. Antilla, Angew. Chem., Int. Ed.,
2011, 50, 1135; (g) X. Li, S.-Z. Luo and J.-P. Cheng, Chem.–Eur.
J., 2010, 16, 14290; (h) F. Zhong, G.-Y. Chen and Y.-X. Lu, Org.
Lett., 2011, 13, 82; (i) M. Ding, F. Zhou, C.-H. Liu, Y.-L. Wang,
X.-L. Zhao and J. Zhou, Chem. Sci., 2011, 2, 2035; (j) B. Tan,
N. R. Candeias and C. F. Barbas, III, Nat. Chem., 2011, 3, 473;
5 For a recent review, see: A. Cordova, Catalytic Asymmetric Conjugate
´
Addition Reactions, Wiley-VCH, Weinheim, Germany, 2010.
6 For reviews of primary amine catalysis, see: (a) Y.-C. Chen,
Synlett, 2008, 1919; (b) F. Peng and Z. Shao, J. Mol. Catal. A:
Chem., 2008, 285, 1; (c) L.-W. Xu, J. Luo and Y.-X. Lu, Chem.
Commun., 2009, 1807.
7 The results of primary amine catalyzed Michael addition of
ketones from our group: (a) J. Wang, H. Li, L. Zu and
W. Wang, Adv. Synth. Catal., 2006, 348, 425; (b) F. Xue,
S.-L. Zhang, W.-H. Duan and W. Wang, Adv. Synth. Catal.,
2008, 350, 2194; (c) K. Mei, M. Jin, S.-L. Zhang, P. Li,
W.-J. Liu, X.-B. Chen, F. Xue, W.-H. Duan and W. Wang, Org.
Lett., 2009, 11, 2864; (d) G. Luo, S. Zhang, W.-H. Duan and
W. Wang, Synthesis, 2009, 1564; (e) F. Xue, L. Liu, S. Zhang,
W.-H. Duan and W. Wang, Chem.–Eur. J., 2010, 16, 7979.
8 For leading references in asymmetric counter ion directed catalysis,
see: (a) N. J. A. Martin and B. List, J. Am. Chem. Soc., 2006,
128, 13368; (b) T. Mandal and C.-G. Zhao, Angew. Chem., Int. Ed.,
2008, 47, 7714; (c) O. Lifchits, C. M. Reisinger and B. List, J. Am.
Chem. Soc., 2010, 132, 10227; (d) G. Bergonzini, S. Vera and
P. Melchiorre, Angew. Chem., Int. Ed., 2010, 49, 9685; (e) C. Liu
and Y. Lu, Org. Lett., 2010, 12, 2278 and ref. 4i.
9 Transition state models are proposed in Fig. S1 in ESIw.
10 CCDC 853177w.
11 K. Higashiyama and H. Otomasu, Chem. Pharm. Bull., 1980,
28, 1540.
c
1694 Chem. Commun., 2012, 48, 1692–1694
This journal is The Royal Society of Chemistry 2012