Synthesis of N-alkoxycarbonyl ketimines derived from isatins and their application in enantioselective synthesis of 3-aminooxindoles

Article abstract of DOI:10.1021/ol3007953

A simple and general method in the synthesis of N-alkoxycarbonyl ketimines derived from isatins has been described first. Generally, the enantioselective addition of 1,3-dicarbonyl compounds to this kind of ketimine affords chiral 3-amino oxindoles in high yield and excellent ee.

Full text of DOI:10.1021/ol3007953

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of N-Alkoxycarbonyl Ketimines
Derived from Isatins and Their Application
in Enantioselective Synthesis of
3-Aminooxindoles
Wenjin Yan, Dong Wang, Jingchao Feng, Peng Li, Depeng Zhao, and Rui Wang*
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic
Medical Sciences, State Key Laboratory of Applied Organic Chemistry and Institute of
Biochemistry and Molecular Biology, Lanzhou University, Lanzhou, 730000, China
wangrui@lzu.edu.cn
Received March 28, 2012
ABSTRACT
A simple and general method in the synthesis of N-alkoxycarbonyl ketimines derived from isatins has been described first. Generally,
the enantioselective addition of 1,3-dicarbonyl compounds to this kind of ketimine affords chiral 3-amino oxindoles in high yield and
excellent ee.
Chiral R-tertiary amines are important building blocks
of naturally occurring and artificial biologically active
molecules.1 As one of the most important members,
optically active 3-aminooxindoles have been recog-
nized as the core structure in a variety of bioactive
molecules.2 Although there are catalytic asymmetric ami-
nation reactions to access these chiral compounds,3 the
asymmetric addition of carbon nucleophiles to ketimines,
which can simultaneously construct a carbon skeleton and
tetrasubstituted stereogenic center, is synthetically more
efficient. To achieve this goal, several diastereoselective
approaches could be found.4 In the case of the catalytic
enantioselective nucleophilic addition reaction using keti-
mines derived from isatins as substrates, there are only a
few examples established.5
(1) For review, see: Shibasaki, M.; Kanai, M. Chem. Rev. 2008, 108,
2853.
(2) For reviews, see: (a) Dounay, A. B.; Overman, L. E. Chem. Rev.
2003, 103, 2945. (b) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int.
Ed. 2007, 46, 8748. (c) Zhou, F.; Liu, Y. L.; Zhou, J. Adv. Synth. Catal.
2010, 352, 1381. (d) Shen, K.; Liu, X.; Lin, L.; Feng, X. Chem. Sci. 2012,
3, 327. (e) Klein, J. E. M. N.; Taylor, R. J. K. Eur. J. Org. Chem. 2011,
6821.
(3) (a) Cheng, L.; Liu, L.; Wang, D.; Chen, Y.-J. Org. Lett. 2009, 11,
3874. (b) Bui, T.; Borregan, M.; Barbas, C. F., III. J. Org. Chem. 2009,
74, 4537. (c) Qian, Z.-Q.; Zhou, F.; Du, T.-P.; Wang, B.-L.; Ding, M.;
ꢀ
Zhao, X.-L.; Zhou, J. Chem. Commun. 2009, 6753. (d) Bui, T.; Hernandez-
Torres, G.; Milite, C.; Barbas, C. F., III. Org. Lett. 2010, 12, 5696.
(e) Yang, Z.; Wang, Z.; Bai, S.; Shen, K.; Chen, D.; Liu, X.; Lin, L.;
Feng, X. Chem.;Eur. J. 2010, 16, 6632. (f) Mouri, S.; Chen, Z.;
Mitsunuma, H.; Furutachi, M.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2010, 132, 1255. (g) Shen, K.; Liu, X.; Wang, G.; Lin, L.;
Feng, X. Angew. Chem., Int. Ed. 2011, 50, 4684.
(4) (a) Lesma, G.; Landoni, N.; Pilati, T.; Sacchetti, A.; Silvani, A.
J. Org. Chem. 2009, 74, 4537. (b) Jung, H. H.; Buesking, A. W.; Ellman,
J. A. Org. Lett. 2011, 13, 3912. (c) Yan, W.; Wang, D.; Feng, J.; Li, P.;
Wang, R. J. Org. Chem. 2012, 77, 3311.
r
10.1021/ol3007953
XXXX American Chemical Society

The result in the absence of the enantioselective addition
of carbon nucleophiles to ketoimines derived from isatins
was caused by the lack of appropriate ketimines. Although
some N-aryl ketimines have been synthesized in the pre-
sence of an acid catalyst and water scavenger,6 the low
reactivity and tedious procedure of deprotection of the N-
aryl group from the corresponding product limit the
application of these known ketimines in synthesis. N-
Alkoxy carbonyl groups such as N-Boc and N-Cbz are
known as the most useful protecting groups in organic
synthesis. Although one sample has been achieved by Hu’s
group in the presence of Rh2(OAc)4 and DDQ with
moderate yield,7 to date, there is no general method for
the synthesis of N-alkoxycarbonyl ketimines derived from
isatins, especially for those with readily cleavable N-Boc
group.
As part of our ongoing interest in developing new
methods for the synthesis of optically active 3,30-disubsti-
tuted oxindoles,8 we herein report a general method for the
synthesis of N-alkoxycarbonyl ketimines derived from
isatins and their further application in the enantioselective
nucleophilic addition of 1,3-dicarbonyl compounds cata-
lyzed by a Cinchona alkaloid-derived thiourea.
in high yield. The results combining the structural
diversity of N-Boc ketimines with the further synthetic
ketimines of 2g and 2h proved that the application of the
aza-Witting process was a successful strategy in the
synthesis of N-alkoxycarbonyl ketimines derived from
isatins.
After obtaining the N-alkoxycarbonyl ketimines derived
from isatins, we focused on examining the synthetic utility
of these substrates. With the addition of pentane-2,4-dione
to the ketimine 2b as the model reaction, natural cinchona
alkaloids (L1ꢀL4) (Figure 1) were employed as the cata-
lysts initially. In all cases, although the ketimine 2b was
converted smoothly to the adduct 3b in high yield, poor
enantioselectivities were obtained (entries 1ꢀ4, Table 1).
Other representative catalysts derived from cinchona alka-
loids (L5ꢀL7) were used next (Figure 1).11
Experimentally, we began our investigation with the
synthesis of N-Boc ketimines derived from N-methyl isatin.
After a series of depressing failures using traditional
methods for the synthesis of N-alkoxycarbonyl ketimines,9
an exciting result emerged by the employment of the aza-
Wittig process, and the expected product was obtained in
95% yield (see Scheme 1).10 Subsequently, several isatins
with different substituted groups at the 1-position were
involved in the evaluation of the generality of this synthetic
method. As shown in Scheme 1, in general, the method was
carried out with ꢀH, ꢀCH3, ꢀCH2C6H5, ꢀCH2OCH3,
ꢀCOCH3, and ꢀBoc as the substituted group, respectively,
Figure 1. Catalysts for screening.
Scheme 1. Preparation of N-Alkoxycarbonyl Ketimines by Use
of Aza-Witting Reaction
Table 1. Catalyst Screening for Enantioselectivity Addition of
Pentane-2,4-dione to 2ba
entry
catalystb
time (h)
yield (%)
eec (%)
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
16
17
10
11
96
60
12
95
83
3
0
92
10
10
3
85
27
60
67
92
>99
a Reaction conditions: 2b (0.2 mmol), pentane-2,4-dione (0.22 mmol),
CH3C6H5 (1 mL), and at room temperature. b Catalyst loading (10 mol %).
c Determined by HPLC analysis.
B
Org. Lett., Vol. XX, No. XX, XXXX

Catalyst L5 was not suitable for this enantioselective
addition reaction, while L6 gave the product in moderate
ee (entries 5 and 6, Table 1). To our delight, the enantios-
electivity was dramatically improved to 92% ee when
quinineꢀthiourea L7 was used as the catalyst.
After the end of the reactivity assessment of ketimines
2aꢀh, we evaluated the different N-Boc ketimines derived
from various substituted N-methylisatins via a reaction
with malonates to define the scope of the reaction and the
further synthetic utility of this kind of ketimines. As
summarized in Scheme 2, the addition of dimethyl mal-
onate and diethyl malonate to ketimine 2b preceded
smoothly and gave the products both in 96% ee. Notably,
using dibenzyl malonate as the nucleophile the reaction
gave the adduct in quantitative yield and up to 98% ee. A
variety of 1-methyl N-Boc ketimines were then involved in
the following examination, and generally, high to excellent
enantioselectivities were obtained in the addition of di-
benzyl malonate to these ketimines. These results indi-
cated that the ketimines with the substituted group at the
With the satisfactory catalyst L7 in hand, we then assessed
the influence of solvents, temperature, and additives in the
addition of pentane-2,4-dione to the ketimine 2b. As
shown in the Supporting Information, the best result was
obtained in toluene at 0 °C and without the addition of
molecular sieves.
Having established the optimal reaction protocol, we
then evaluated the reactivities of different ketimines 2aꢀh
in this catalytic enantioselective nucleophilic addition re-
action. As shown in Table 2, the results revealed that the
substituted groups at ketimine 1-position had a significant
effect both on the enantioselectivity and the reactivity of
ketimines. The reactions preceded smoothly with ꢀCH3,
ꢀCH2C6H5 and ꢀCH2OCH3 as the substituted groups
at the ketimine 1-position and gave the products in
high yields and excellent enantioselectivities, respectively
(entries 2, 3, and 6, Table 2). It was noteworthy that the
ketimine without the substituted group at 1-position
showed good reactivity in this addition reaction and gave
the product 3a in 86% yield and 87% ee (entry 1, Table 2),
while lower reactivity was observed with the bulk-substi-
tuted Boc group and offered the product with no enantios-
electivity (entry 5, Table 2). Meanwhile, the ketimine with
acetyl at the 1-position lost reactivity in the addition
reaction (entry 4, Table 2). Furthermore, with results
similar to those for 3b, the enantimer 3b0 could also be
obtained under these conditions using quinidine-derived
thiourea L8 as the catalyst.
Scheme 2. Reaction Scope of Enantioselective Additionsa
Table 2. Reactivities Evoluation of Ketimines 2aꢀha
entry
ketimine
product
time (h)
yield (%)
eeb (%)
1
2a
2b
2b
2c
2d
2e
2f
3a
3b
3b0
3c
60
18
18
8
86
>99
>99
95
87
95
2
3
ꢀ95
94
4
5c
6d
7
3e
3f
80
24
24
24
95
95
84
90
0
97
90
97
8
2g
2h
3g
3h
a Reaction condition: ketimine (0.2 mmol), nucleophilic reagent (0.22
mmol), toluene (1 mL), at room temperature. The reaction time required
for each substrate is given. The ee’s were determined by HPLC analysis.
9
a Reaction condition: ketimine (0.2 mmol), pentane-2,4-dione (0.22
mmol), toluene (1 mL), at 0 °C. b Determined by HPLC analysis. c No
adduct was found. d At room temperature.
(6) For examples, see: (a) Rajopadhye, M.; Popp, F. D. J. Heterocycl.
Chem. 1987, 24, 1637. (b) Konkel, M. J.; Lagu, B.; Boteju, L. M.;
Jimenez, H.; Noble, S.; Walker, M. W.; Chandrasena, G.; Blackburn,
T. P.; Nikam, S. S.; Wright, J. L.; Kornberg, B. E.; Gregory, T.; Pugsley,
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Org. Lett., Vol. XX, No. XX, XXXX
C

5-position giving the products in lower yields than those
with the substituted group at the 6- and 7-position. In
addition, it turned out that this asymmetric addition of
dibenzyl malonates to disubstitued ketimine also followed
the same reaction pattern, which afforded the addition
product in 73% yield and 94% ee.
Furthermore, some other 1,3-dicarbonyl compounds
were also explored. The addition of 1,3-diphenylpro-
pane-1,3-dione to ketimine 2b offered the product 4n in
90% yield and 75% ee. With ethyl 2-oxocyclopentanecar-
boxylate as the nucleophile compound, 4o was obtained
with 76% yield, 1:1 dr, and 96% ee. Additionally, as
expected, the catalytic system also proved to be efficient
for prochiral cyclic β-ketoester, leading to 4p with >99%
yield, 3.5:1 dr, and in 92% ee and 98% ee respectively.
On the basis of X-ray crystal structure analysis of
product 4i (Supporting Information), a potential transi-
tion-state structure was proposed. As shown in Figure 2,
similar to the model suggested by Takemoto,12 catalyst
serves the dual function of activating both reaction part-
ners. The tertiary amine of catalyst deprotonates the
malonate and, through coordination, holds it in close
proximity, while the thiourea moiety binds and activates
the ketimine through hydrogen bonds.
Figure 2. Proposed transition state.
of 1,3-dicarbonyl compounds. In general, the correspond-
ing adducts were obtained in high yields and excellent ee.
Acknowledgment. We are grateful for the grants from
the National Natural Science Foundation of China (Nos.
20932003 and 90813012), the Key National S&T Program
“Major New Drug Development” of the Ministry of
Science and Technology of China (2012ZX09504-001-
003), and the Fundamental Research Funds for the Cen-
tral Universities (lzujbky-2010-126) for financial support.
In conclusion, we have described a general strategy for
the synthesis of N-alkoxycarbonyl ketimines derived from
isatins in high yield under very simple reaction conditions.
The reactivity has been demonstrated in the synthesis of
chiral 3-aminooxindoles by the enantioselective addition
Supporting Information Available. Experimental pro-
cedures and characterization of the products. Crystal-
lographic data for compound of 4i (CIF). This material
is available free of charge via the Internet at http://
pubs.acs.org.
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The authors declare no competing financial interest.
D
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