Organocatalytic Stereoselective Mannich Reaction of 3-Substituted Oxindoles

Article abstract of DOI:10.1021/ol801351j

(Chemical Equation Presented) The asymmetric Mannich reaction of 3-substituted oxindoles and N-Boc (mines was investigated for the first time, employing bifunctional thiourea-tertiary amine organocatalysts based on OPEN scaffold. The novel transformations

Full text of DOI:10.1021/ol801351j

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3583-3586
Organocatalytic Stereoselective Mannich
Reaction of 3-Substituted Oxindoles
Xu Tian,† Kun Jiang,† Jing Peng,† Wei Du,† and Ying-Chun Chen*,†,‡
Key Laboratory of Drug-Targeting and Drug DeliVer System of Education Ministry,
Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan
UniVersity, Chengdu 610041, China, and State Key Laboratory of Biotherapy, West
China Hospital, Sichuan UniVersity, Chengdu, China
ycchenhuaxi@yahoo.com.cn
Received June 15, 2008
ABSTRACT
The asymmetric Mannich reaction of 3-substituted oxindoles and N-Boc imines was investigated for the first time, employing bifunctional
thiourea-tertiary amine organocatalysts based on DPEN scaffold. The novel transformations exhibited high diastereoselectivities, and the
Mannich adducts bearing adjacent quaternary and tertiary chiral centers were generally obtained in good to excellent enantioselectivities (up
to 95% ee).
The construction of a chiral quaternary center represents one
of the most challenging subjects in asymmetric synthesis and
has provoked continuing interest over the past decades.1
Among them, the application of prochiral 3-substititued
oxindoles as nucleophiles provides a very straightforward
approach to obtain a chiral quaternary center, and studies in
this field receive special attention because oxindoles bearing
C3-quaternary structures have been widely distributed in a
number of natural products and pharmaceutical molecules.2
A variety of catalytic asymmetric reactions of 3-substituted
oxindoles, including fluorination,3 hydroxylation,4 acyl mi-
gration,5 aldol reaction,6 and AAA reaction,7 have been well
presented. However, to the best of our knowledge, the
asymmetric Mannich reaction8 of 3-substituted oxindoles and
imines has not been investigated in the literature, as more
challenging molecular complexity with adjacent quaternary
and tertiary chiral centers must be created concurrently.9 Here
we would like to report the highly stereoselective Mannich
(3) (a) Hamashima, Y; Suzuki, T.; Takano, H.; Shimura, Y.; Sedeoka,
M. J. Am. Chem. Soc. 2005, 127, 10164. (b) Shibata, N.; Suzuki, E.; Asahi,
T.; Shiro, M. J. Am. Chem. Soc. 2001, 123, 7001. (c) Ishimaru, T.; Shibata,
N.; Horikawa, T.; Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M. Angew.
Chem., Int. Ed. 2008, 47, 4157.
† West China School of Pharmacy.
‡ West China Hospital.
(4) (a) Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.;
Kanemasa, S. J. Am. Chem. Soc. 2006, 128, 16488. (b) Sano, D.; Nagata,
K.; Itoh, T. Org. Lett. 2008, 10, 1593.
(1) For reviews of catalytic enantioselective construction of quaternary
chiral centers, see: (a) Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005,
347, 1473. (b) Peterson, E. A.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 11943. (c) Ramon, D. J.; Yus, M. Curr. Org. Chem. 2004, 8,
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Albrecht, B. K.; Williams, R. M. Org. Lett. 2003, 5, 197. (c) Reisman,
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Vedeis, E. J. Am. Chem. Soc. 2006, 128, 925. (c) Hills, I. D.; Fu, G. C.
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10.1021/ol801351j CCC: $40.75
Published on Web 07/19/2008
2008 American Chemical Society

reaction of 3-substituted oxindoles and N-Boc-imines cata-
lyzed by environmentally benign organocatalysts.
catalytic Mannich reaction generally exhibited high efficacy.
The starting materials were smoothly consumed after 10 h,
and the diastereomers 4a and 5a could be well separated
(Table 1, entries 1-4). Catalyst 1d possessing a chiral 1,2-
Recently thiourea-tertiary amine compounds have
demonstrated great success as bifunctional Brønsted
acid-Brønsted base catalysts for an array of 1,2- and 1,4-
addition reactions.10,11 It could be envisaged that nucleo-
philic oxindoles and electrophilic N-Boc imines should be
concertedly activated by such bifunctional catalysts, and the
corresponding Mannich products with dense substitutions
would be afforded stereoselectively. In addition, we proposed
that the use of an N-Boc-protected oxindole bearing a
bidentate motif would be more practicable since a double
hydrogen bonding interaction could be generated with the
protonated tertiary amine group.
Table 1. Screening Studies of Organocatalytic Mannich
Reaction of Oxindole 2a and N-Boc-benzaldimine 3aa
Based on these considerations, bifunctional thiourea-tertiary
amines 1a-d (10 mol %, Figure 1) with diversely structured
entry
cat. 1
yieldb (%)
drc
eed (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
1e
1e
1e
4a, 86/5a, 8
10.7:1
8.7:1
4.7:1
>18.4:1
>18.8:1
>18.4:1
>18.6:1
>18.0:1
1.7:1
69
82
80
93
95
63
91
92
<5
4a, 87/5a, 10
4a, 81/5a, 17
4a, 92/5a, <5
4a, 94/5a, <5
4a, 92/5a, <5
4a, 95/5a, <5
4b, 90/5b, <5
4c, 45/5c, 27
7e
8f
9g
a Unless noted otherwise, 2a was used as the nucleophile in m-xylene.
b Isolated yields of pure diastereomer 4 and 5. c Calculated from the isolated
yields of 4 and 5. d Determined by chiral HPLC analysis. e Toluene was
used. f 2b was used. g 2c was used.
Figure 1. Structures of thiourea-tertiary amine catalysts.
diphenylethylene-diamine (DPEN) skeleton demonstrated
to be the superior one in regard to both diastereo- and
enantioselectivity.12 The major isomer 4a was directly
isolated in 92% yield with 93% ee (entry 4). Subsequently,
other thiourea catalysts derived from DPEN were investi-
gated. Even slightly better results were attained by employing
catalyst 1e with a p-trifluoromethylphenyl substitution (entry
5), but considerably reduced enantioselectivity was observed
in the presence of catalyst 1f with a p-fluorophenyl group
(entry 6). A little lower ee value was gained when toluene
was used (entry 7). On the other hand, we further explored
the effects of N-protection group of oxindole catalyzed by
1e. Similar results could be achieved for 2b with an
N-ethoxycarbonyl group (entry 8, for 4b, 90% yield, 92%
ee). In contrast, N-methyloxindole 2c showed much lower
reactivity, and very poor stereoselectivity was obtained for
the corresponding Mannich adducts 4c and 5c (entry 9). This
indicates that the bidentate nature of N-protected oxindoles
is crucial for the stereocontrol.3a
scaffolds were screened in the Mannich reaction of 3-ben-
zyloxindole 2a and N-Boc-benzaldimine 3a at 5-10 °C in
m-xylene. Some 4 Å molecular sieves were added in order
to remove the trace amount of water. Gratifyingly, this
(9) For selected examples of catalytic construction of adjacent quaternary
and tertiary chiral centers, see: (a) Taylor, M. S.; Jacobsen, E. N. J. Am.
Chem. Soc. 2003, 125, 11204. (b) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu,
X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44,
105. (c) Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2005, 44, 2896. (d) Austin, J. F.; Kim, S.-G.;
Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5482. (e) Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 2896. (f) van Steenis,
D. J. V. C.; Marcelli, T.; Lutz, M.; Spek, A. L.; van Maarseveen, J. H.;
Hiemstra, H. AdV. Synth. Catal. 2007, 349, 281. (g) Lalonde, M. P.; Chen,
Y.; Jacobsen, E. N. Angew. Chem., Int. Ed 2006, 45, 6366
.
(10) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003,
125, 12672. (b) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org.
Lett. 2004, 6, 625. (c) Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding,
L.-S.; Wu, Y. Synlett 2005, 603. (d) Berkessel, A.; Cleemann, F.; Mukherjee,
S. Angew. Chem., Int. Ed. 2005, 44, 7466. (e) Vakulya, B.; Varga, S.;
Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967. (f) Ye, J.; Dixon, D. J.;
Hynes, P. S. Chem. Commun. 2005, 4481. (g) McCooey, S. H.; Connon,
S. J. Angew. Chem., Int. Ed. 2005, 44, 6367. (h) Song, J.; Wang, Y.; Deng,
L. J. Am. Chem. Soc. 2006, 128, 6048. (i) Inokuma, T.; Hoashi, Y.;
Takemoto, Y. J. Am. Chem. Soc. 2006, 128, 9413. (j) Liu, T.-Y.; Cui, H.-
L.; Long, J.; Li, B.-J.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. J. Am. Chem. Soc.
2007, 129, 1878. (k) Zu, L.; Wang, J.; Li, H.; Xie, H.; Jiang, W.; Wang,
W. J. Am. Chem. Soc. 2007, 129, 1036. (l) Zuend, S. J.; Jacobsen, E. N.
J. Am. Chem. Soc. 2007, 129, 15872. (m) Wang, J.; Xie, H.; Li, H.; Zu, L.;
Wang, W. Angew Chem., Int. Ed. 2008, 47, 4177
.
(11) For reviews on thiourea catalysis, see: (a) Takemoto, Y. Org.
Biomol. Chem. 2005, 3, 4299. (b) Connon, S. J. Chem.sEur. J. 2006, 12,
5418. (c) Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007, 107, 5713.
Figure 2. Structures of 3-substituted oxindoles.
3584
Org. Lett., Vol. 10, No. 16, 2008

With the optimal reaction conditions in hand, we then
examined a variety of oxindoles 2 (Figure 2) and imines 3
to establish the general utility of this novel asymmetric
transformation. The reaction scopes generally proved to be
broad with respect to both reactants. The major diastereomer
4 could be directly isolated, and the minor products 5 were
obtained in less than 10% yield for all the reactions tested.
As revealed in Table 2, in the reactions of N-Boc-benzaldi-
were attained for oxindoles 2k and 2l with electron-
withdrawing or -donating substituents on aryl ring (entries
10 and 11). On the other hand, some aryl and heteroaryl
imines were explored with oxindole 2a. The electronic nature
of the substituents has limited influences on the stereo
outcome, and satisfactory data were generally attained
(entries 12-16). However, alkyl imines exhibited quite low
reactivity toward 2a. Good yield could be delivered in the
reaction of more active 3-phenyloxindole 2j, but the enan-
tioselectivity could not be enforced (entry 17).
To determine the absolute configuration of the asymmetric
Mannich products, single crystals suitable for X-ray crystal-
lographic analysis were fortunately obtained from enan-
tiopure 4r that bears a sulfur atom. As shown in Figure 3, it
contains a (C2S,C16S) configuration.
Table 2. Asymmetric Mannich Reaction of 3-Substituted
Oxindoles 2 and N-Boc-imines 3
entry
2
R1
yielda (%)
drb
eec (%)
1
2
3
4
5
6
2a
2d
2e
2f
2g
2h
2i
2i
2j
2k
2l
2a
2a
2a
2a
2a
2j
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a, 94
4d, 95
4e, 85
4f, 90
4g, 83
4h, 76
4i, 40
>18.8:1
>19.0:1
>17.0:1
>18.0:1
17.0:1
>15.0:1
>8.0:1
12.0:1
12.4:1
>18.6:1
11.0:1
>19.0:1
11.3:1
>18.8:1
11.0:1
95
95
90
89
91
92
83
82
7d
8d,e
9
10
11
12
13
14
15
16
17
4j, 60
4k, 87 (80)f
4l, 93
3(11)f
88
84
91
93
88
4m, 88
4n, 95
4o, 90
4p, 94
4q, 89
4r, 90
4s, 75
p-F-Ph
Figure 3. X-ray crystallographic structure of enantiopure 4r.
m-Cl-Ph
o-Cl-Ph
p-Me-Ph
2-thienyl
i-propyl
85
On the basis of the observed absolute configuration of
enantiopure 4r, a plausible catalytic mechanism by concerted
activation was proposed. As illustrated in Scheme 1, a double
12.8:1
15.0:1
94g
<5
a Isolated yield of pure 4. b Calculated from the isolated yield of 4 and
5. c Determined by chiral HPLC analysis. d With 20 mol % of 1e for 72 h.
e N-Cbz-benzaldimine was used. f Data in parentheses were obtained at
-40 °C. g The absolute configuration of 4r was determined by X-ray
analysis (see Figure 3). The other products were assigned by analogy.
Scheme 1. Plausible Catalytic Mechanism for the Formation of
Chiral Mannich Adducts 4r by Concerted Activation
mine, excellent enantioselectivities were gained for variously
substituted 3-benzyloxindoles 2d-f (Table 2, entries 2-4).
Oxindole 2g bearing a 2-thienylmethyl group also afforded
a high ee value (entry 5). 3-n-Propyloxindole 2h showed
slower reactivity, while good yield could be obtained after
24 h in 91% ee (entry 6). Nevertheless, the Mannich reaction
of oxindole 2i bearing a bulky 3-isopropyl group was quite
sluggish. Moderate yield was isolated with 20 mol % of 1e
after 72 h (entry 7), while better yield with similar enanti-
oselectivity could be provided when less hindered N-Cbz-
benzaldimine was used (entry 8). Unfortunately, 3-pheny-
loxindole 2j gave rise to racemic product, and later it was
found that this reaction could proceed rapidly without any
catalyst (entry 9). Poor enantioselectivity was obtained even
at -40 °C (entry 9, data in parentheses). Good ee values
hydrogen bonding interaction might be formed between two
N-H of thiourea and the carbonyl of protected imine. On
the other hand, another double hydrogen bonding interaction
would be generated between the protonated tertiary amine
group and two carbonyls of the protected oxindole. Subse-
quently, si-face attack of the electrophilic imine through re-
face of the enolate would afford the desired Mannich adduct
4r with (S,S)-configuration.
(12) For the limited application of bifunctional thiourea-tertiary amine
from DPEN, see: Liu, T.-Y.; Long, J.; Li, B.-J.; Jiang, L.; Li, R.; Wu, Y.;
Ding, L.-S.; Chen, Y.-C. Org. Biomol. Chem. 2006, 4, 2097.
Org. Lett., Vol. 10, No. 16, 2008
3585

In conclusion, we have successfully presented the first
stereoselective Mannich reaction of 3-substituted oxindoles
and N-Boc-imines by employing bifunctional thiourea-tertiary
amine catalysts derived from chiral DPEN. In general,
excellent diastereo- and enantioselectivities could be obtained
for a spectrum of substrates. This novel methodology
provides facile access to densely substituted oxindole deriva-
tives with adjacent quaternary and tertiary chiral centers.
Current studies are underway to expand the synthetic utility
of this reaction.
Acknowledgment. We are grateful for the financial
support from National Natural Science Foundation of China
(20502018 and 20772084) and Ministry of Education (NCET-
05-0781).
Supporting Information Available: Experimental pro-
cedures, structural proofs including CIF file of enantiopure
4r, and NMR and HPLC spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL801351J
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Org. Lett., Vol. 10, No. 16, 2008