Asymmetric one-pot sequential mannich/hydroamination reaction by organo- and gold catalysts: Synthesis of spiro[pyrrolidin-3,2′-oxindole] derivatives

Article abstract of DOI:10.1021/ol4004542

An asymmetric organo- and gold-catalyzed one-pot sequential Mannich/hydroamination reaction has been developed. Using this protocol, spiro[pyrrolidin-3,2′-oxindole] derivatives were synthesized in good yields (up to 91%) and excellent enantioselectivities

Full text of DOI:10.1021/ol4004542

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Asymmetric One-Pot Sequential Mannich/
Hydroamination Reaction by Organo-
and Gold Catalysts: Synthesis of
Spiro[pyrrolidin-3,20-oxindole] Derivatives
Xianjie Chen,†,‡ Hui Chen,‡ Xun Ji,‡ Hualiang Jiang,*,†,‡ Zhu-Jun Yao,† and Hong Liu*,‡
School of Chemistry and Chemical Engineering, Nanjing National Laboratory of
Microstructures, Nanjing University, 22 Hankou Road, Nanjing 210093, P. R. China,
and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 555 Zu Chong
Zhi Road, Shanghai, P. R. China
hljiang@mail.shcnc.ac.cn; hliu@mail.shcnc.ac.cn
Received February 19, 2013
ABSTRACT
An asymmetric organo- and gold-catalyzed one-pot sequential Mannich/hydroamination reaction has been developed. Using this protocol,
spiro[pyrrolidin-3,20-oxindole] derivatives were synthesized in good yields (up to 91%) and excellent enantioselectivities (up to 97% ee).
The spiro[pyrrolidin-3,20-oxindoles] are privileged struc-
tural motifs found in many biologically active natural and
unnatural compounds (Figure 1).1 For example, the spiro-
indolones including NITD609 have emerged as a novel
class of antimalarial drug candidates.1a Spirooxindole deriv-
atives have also shown antitumor,1d anti-inflammatory,1g
and antitubercular1f activities. However, synthesis of spiro-
[pyrrolidin-3,20-oxindoles], for a long time, has primarily
been limited to traditional cycloaddition synthetic methods,
which produce racemic diastereomeric mixtures.1bꢀg To
date, only a few asymmetric synthetic methods have been
reported, such as those applying transition-metal catalysts,
organocatalysts, and N-heterocyclic carbene catalysts.2
† Nanjing University.
‡ Shanghai Institute of Materia Medica.
(1) (a) Rottmann, M.; McNamara, C.; Yeung, B. K. S.; Lee, M. C. S.;
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Suwanarusk, R.; Jegla, T.; Schmitt, E. K.; Beck, H.-P.; Brun, R.; Nosten, F.;
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r
10.1021/ol4004542
XXXX American Chemical Society

Owing to its importance for the discovery of new bioactive
compounds, development of new efficient methods for
asymmetric synthesis of spiro[pyrrolidin-3,20-oxindole] de-
rivatives is of high demand.
Initially, a variety of organocatalysts (Figure 3) were
evaluated for the first Mannich reaction step, and the
results are summarized in Table 1. It was found that the
reaction was completed smoothly in toluene at room
temperature with the bifunctional thiourea catalyst 3a in
high yields but in racemic form (entry 1).5 The enantio-
meric excesses (ees) of the products were greatly improved
at lower temperatures (entries 2 and 3). Change of the
solvent did not affect the eesignificantly (entry 4). Cinchona
Figure 1. Examples of bioactive spiro[pyrrolidin-3,20-oxindole]
derivatives.
To achieve high efficiency in the synthesis of complex
compounds, multistep sequential reactions are often em-
ployed. Inspired by recent combined uses of organo- and
gold catalysts in one-pot sequential reactions,3 we designed
a new organo- and gold-catalyzed cascade protocol for the
condensation of oxindole imine derivatives 1 and pro-
gargylated malononitrile 2a (Figure 2).4 As a result,
combination of Mannich reaction and hydroamination
would produce various enantiopure spiro[pyrrolidin-3,20-
oxindole] derivatives.
Figure 3. Screened catalysts for the Mannich reaction.
Table 1. Optimization of the Organocatalysts for the
Enantioselective Addition of 2a to 1aa
Figure 2. Designed new approach to spiro[pyrrolidin-3,20-
oxindole] derivatives.
entry catalyst solvent temp (°C) time (h) yieldb (%) eec (%)
1
3a
3a
3a
3a
3b
3c
3d
3e
3f
toluene
toluene
toluene
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
rt
ꢀ40
ꢀ70
ꢀ70
ꢀ70
ꢀ70
ꢀ70
ꢀ70
ꢀ70
ꢀ70
ꢀ70
ꢀ70
ꢀ70
ꢀ70
ꢀ70
5 min
1
>99
>99
98
0
ꢀ6
ꢀ42
ꢀ2
ꢀ19
ꢀ10
ꢀ24
14
(3) For a recent review for one-pot reactions with organo- and gold
catalysts, see: (a) Loh, C. C. J.; Enders, D. Chem.;Eur. J. 2012, 18,
10212–10225. (b) Han, Z.-Y.; Chen, D.-F.; Wang, Y.-Y.; Guo, R.;
Wang, P.-S.; Wang, C.; Gong, L.-Z. J. Am. Chem. Soc. 2012, 134,
6532. (c) Wu, H.; He, Y.-P.; Gong, L.-Z. Org. Lett. 2013, 15, 460. For
selected examples of one-pot reactions using organo- and gold catalysts,
see: (d) Monge, D.; Jensen, K. L.; Franke, P. T.; Lykke, L.; Jørgensen,
K. A. Chem.;Eur. J. 2010, 16, 9478–9484. (e) Loh, C. C. J.; Badorrek,
J.; Raabe, G.; Enders, D. Chem.;Eur. J. 2011, 16, 13409–13414. (f)
Belot, S.; Vogt, K. A.; Besnard, C.; Krause, N.; Alexakis, A. Angew.
Chem., Int. Ed. 2009, 48, 8923–8926. (g) Jensen, K. L.; Franke, P. T.;
2
3
12
12
12
12
12
12
12
12
24
12
18
12
24
4
54
5
>99
75
6
7
36
8
>99
75
9
35
10
11
12
13
14
15d
3g
3h
3i
90
44
ꢀ
Arroniz, C.; Kobbelgaard, S.; Jørgensen, K. A. Chem.;Eur. J. 2010, 16,
1750–1753. (h) Barber, D. M.; Sanganee, H. J.; Dixon, D. J. Org. Lett.
2012, 14, 5290–5293.
90
75
85
83
(4) For recent examples of asymmetric reactions using N-Boc-protected
oxindole imine 1a derivatives, see: (a) Yan, W.; Wang, D.; Feng, J.; Li, P.;
Zhao,D.;Wang,R.Org. Lett. 2012,14, 2512–2515. (b) Hara, N.; Nakamura,
S.; Sano, M.; Tamura, R.; Funahashi, Y.; Shibata, N. Chem.;Eur. J. 2012,
18, 9276–9280. (c) Liu, Y.L.; Zhou, J. Chem. Commun. 2012, 10.1039/
C2CC36665G. For recent examples of asymmetric reactions using progargylated
malononitrile 2a, see: (d) Worgull, D.; Dickmeiss, G.; Jensen, K. L.; Franke,
P. T.; Holub, N.; Jørgensen, K. A. Chem.;Eur. J. 2011, 17, 4076–4080.
(e) Zweifel, T.; Hollmann, D.; Nielsen, M.; Jørgensen, K. A. Tetrahedron:
Asymmetry 2010, 21, 1624–1629.
3j
90
95
3k
3j
95
ꢀ51
95
89
a Unless otherwise noted, reactions were performed with 1a
(0.1 mmol) and 2a (1.2 equiv) in the presence of 10 mol %of catalyst 3
in 2 mL of solvent. b Isolated yields. c Determined by chiral HPLC anal-
ysis. d Catalyst loading (5 mol %).
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Optimization for the One-Pot Synthesis of
Spirooxindole 5aa
Scheme 1. Substrate Scope of One-Pot Sequential Reaction
between 1 and 2aa
temp time yieldb
(°C) (h) (%)
exo/endo
eed
(%)
entry
additive
none
(5a/5a0)c
1
2
3
4
5
6
7
8
rt
rt
60
rt
rt
rt
rt
rt
24
24
12
24
24
24
8
NR
PhCO2H (10%)
PhCO2H (20%)
p-TsOH (10%)
DPP (10%)
tracec
22
3:1
95
95
32
3.5:1
tracec
36
BF3 OEt2 (10%)
>20:1
>20:1
>20:1
>20:1
1:3.5
95
95
95
95
95
3
BF3 OEt2 (20%)
53
3
BF3 OEt2 (40%)
8
46
3
3
3
9e BF3 OEt2 (20%) rt
8
64
10 BF3 OEt2 (20%)
60
1
50
a Unless otherwise noted, reactions were performed with 1a
(0.1 mmol) and 2a (1.2 equiv) in the presence of 10 mol % of catalyst
3 in 2 mL of toluene. b Isolated yields. c Determined by 1H NMR with
crude products. d Determined by chiral HPLC analysis for major isomer.
e 1a (1.2 equiv) and 2a (0.1 mmol) was carried out under standard
conditions. DPP = diphenyl phosphate.
alkaloid catalyst 3b and Takemoto catalyst 3c,d6 were also
tested; however, poor enantioselectivities were obtained
(entries 5ꢀ7). Other Cinchona alkaloids such as quinidine
(3e) and quinidine derivatives (3fꢀj) were also investi-
gated.7 Catalysts 3eꢀg gave products in good yields,
though no improvement was achieved for the enantio-
selectivities (entries 8ꢀ10). Benzyl-substituted catalysts 3h
and 3i gave 75% and 83% ee, respectively (entries 11
and 12). To our delight, the bulky 9-anthracenmethoxy-
substituted catalyst 3j gave excellent enantioselectivity
(95% ee) (entry 13).8 Thiourea phenol catalyst 3k was also
(5) For selective examples of Mannich type reactions using Cinchona
alkaloid thiourea catalysts, see: (a) Song, J.; Wang, Y.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 6048–6049. (b) Song, J.; Shih, H. ꢀW.; Deng, L.
Org. Lett. 2007, 9, 603–606. (c) Bai, S.; Liang, X.; Song, B.; Bhadury,
P. S.; Hu, D.; Yang, S. Tetrahedron: Asymmetry 2011, 22, 518–523. (d)
Nakamura, S.; Maeno, Y.; Ohara, M.; Yamaura, A.; Funahashi, Y.;
Shibata, N. Org. Lett. 2012, 14, 2960–2963.
(6) For selective examples of Mannich type reactions using takemoto
derivatives catalysts, see: (a) Yamaoka, Y.; Miyabe, H.; Yasui, Y.;
Takemoto, Y. Synthesis 2007, 16, 2571–2575. (b) Lee, J. H.; Kim, Y.
a Reactions condtions: 1 (1.2 equiv) and 2 (0.1 mmol) in toluene
(2 mL), method A or method B. The exo/endo ratio of all products is
>20:1. The isolated yields were given after column chromatography.
The ee’s were determined by chiral HPLC analysis. The absolute
configuration was determined by X-ray analysis of product 5g (see the
Supporting Information), and the others were assigned accordingly.
examined, but the ee was relatively low (ꢀ51% ee)
(entry 14).9 Lower catalyst loading (5 mol %) did not
affect the yield or ee of product (entry 15).
€
ꢁ
Synthesis 2010, 11, 1860–1864. (c) Enders, D.; Goddertz, D. P.; Beceno,
C.; Raabe, G. Adv. Synth. Catal. 2010, 352, 2863–2868. (d) Zhao, D.;
Yang, D.; Wang, Y.; Wang, Y.; Wang, L.; Mao, L.; Wang, R. Chem. Sci.
2011, 2, 1918–1921.
(7) For selective examples of Mannich type reactions using quinidine
derivatives catalysts, see: (a) Shi, Z.; Yu, P.; Chua, P. J.; Zhong, G. Adv.
Synth. Catal. 2009, 351, 2797–2800. (b) Li, L.; Ganesh, M.; Seidel, D.
J. Am. Chem. Soc. 2009, 131, 11648–11649. (c) Cheng, L.; Liu, L.; Jia, H.;
Wang, D.; Chen, Y.-J. J. Org. Chem. 2009, 74, 4650–4653. (d) Liu, X.;
Deng, L.; Jiang, X.; Yan, W.; Liu, C.; Wang, R. Org. Lett. 2010, 12, 876–
879. (e) Liu, X.; Deng, L.; Song, H.; Jia, H.; Wang, R. Org. Lett. 2011,
13, 1494–1497.
(8) Albertshofer, K.; Tan, B.; Barbas, C. F., III. Org. Lett. 2012, 14,
1834–1837.
(9) Zhang, T.; Cheng, L.; Hameed, S.; Liu, L.; Wang, D.; Chen, Y.-J.
Chem. Commun. 2011, 47, 6644–6646.
We next examined the transformation of product 4a into
final spiro product 5a using various metal salt catalysts,
such as AuCl3, AuBr3, PPh3AuCl, PPh3AuNTf2, Cu(OTf)2,
andsoon.10 The respective yields and selectivities (endo/exo)
(10) For selective reviews of hydroamination reactions, see: (a)
€
Severin, R.; Doye, S. Chem. Soc. Rev. 2007, 36, 1407–1420. (b) Muller,
T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008,
108, 3795–3892. (c) Dion, I.; Beauchemin, A. M. Angew. Chem., Int. Ed.
2011, 50, 8233.
Org. Lett., Vol. XX, No. XX, XXXX
C

are summarized and discussed in detail in Table S1 of
the Supporting Information. Fortunately, XPhosAuNTf2
(XPhos =2-(dicyclohexylphosphino)-20,40,60-triisopropyl-
biphenyl, NTf2 = bis(trifluoromethylsulfonyl)imide) pro-
duced 5a in good yield (82%) with excellent selectivity
(exo/endo > 20:1).11
representative product 5g was determined as R by single-
crystal X-ray analysis (see the Supporting Information).12
As a further demonstration of the efficiency of this pro-
tocol, deprotection of 5a, produced the spiro[pyrrolidin-
3,20-oxindole] derivative 6a in 75% yield and 95% ee
(Scheme 2).
We further investigated whether the spirooxindole prod-
uct could be obtained by a one-pot sequential manner
with combined use of organo- and gold catalysts. The
results are summarized in Table 2. The initial reac-
tion conditions did not give the derised product without
any additives (entry 1). The literature mentioned that
the activity of Au(I) catalyst could be inhibited by the
bifunctional organocatalysts.3bꢀe Therefore, a variety of
Brønsted acids were considered to be applied as the
additives, including PhCO2H, p-TsOH, DPP. When
PhCO2H (10 mol %) or DPP (10 mol %) was applied at
room temperature, a trace amount of product was ob-
tained (entries 2 and 5). Higher temperature (entry 3) or
use of p-TsOH (entry 4) gave the desired product but as a
mixture of isomers in low yields. To our delight, product5a
was obtained in 36% yield and 95% ee with 10 mol % of
BF3 OEt2 (entry 6). When the amount of BF3 OEt2 was
Scheme 2. N-Boc Removal of Product 5a
In conclusion, we have successfully developed a highly
efficient one-pot sequential Mannich/hydroamination re-
action between oxindole imine and progargylated malo-
nonitrile by a combined use of organo- and gold catalysts.
Excellent enantioselectivities (up to 97% ee) and good
overall yields (up to 91%) were achieved using a quinidine
phenol derivative as the organocatalyst, XPhosAuNTf2 as
3
3
increased to 20 mol %, the yield of 5a was improved to
64% yield (95% ee) (entries 7ꢀ9). Under heating condi-
tions, a mixture of isomers(exo/endo1:3.5) was obtainedat
moderate yields (entry 10).
the metal catalyst, and BF3 OEt2 as the additive. This
3
newly developed strategy has been proven to be useful for
the efficient construction of biologically active spirooxin-
dole derivatives and may be applicable to other asym-
metric catalytic systems.
With the optimized conditions in hand, the substrate
scope was investigated (Scheme 1). Generally, moderate
yields and good enantioselectivities were obtained in the
presence of various substituents on the aromatic ring of
oxindole imine 1, including electron-donating groups
(5bꢀd), withdrawing group (5l), and halogen substituents
at various positions (5eꢀk). Several N-protecting groups
were also examined. N-Ethyl and N-benzyl groups gave
products 5m,n in acceptable yields with excellent enantio-
selectivities. However, the N-Cbz group of imine, instead
of the N-Boc group, gave a negative effect on the stereo-
selectivity (64% ee, 5o). The absolute configuration of
Acknowledgment. We gratefully acknowledge financial
support from the National Basic Research Program of
China (Grant Nos. 2009CB940903, 2009CB918502, and
2012CB518005), NSFC (21021063, 91229204, and
81025017), National S&T Major Projects (2012ZX09103-
101-072), China-EU Science and Technology Cooperation
Project (1109), and Silver Project (260644).
Supporting Information Available. Experimental pro-
cedures and compound characterizations (1H NMR, 13
NMR, HPLC) including X-ray data (CIF). This material
is available free of charge via the Internet at http://pubs.
acs.org.
(11) For selective examples of hydroamination reactions using
XPhosAuNTf2, see: (a) Kothandaraman, P.; Mothe, S. R.; Toh,
S. S. M.; Chan, P. W. H. J. Org. Chem. 2011, 76, 7633–7640. (b) Istrate,
C
ꢀ~
F. M.; Gagosz, F. Org. Lett. 2007, 9, 3181–3184. (c) Fustero, S.; Ibanez,
ꢀ
I.; Barrio, P.; Maestro, M. A.; Catalan, S. Org. Lett. 2013, 15, 832.
(12) CCDC 920347 contains the supplementary crystallographic data
for 5g. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX