Synthesis of highly functionalized chiral 3,3′-disubstituted oxindoles via an organocatalytic enantioselective Michael addition of nitroalkanes to indolylidenecyanoacetates

Article abstract of DOI:10.1021/ol202931e

An efficient bifunctional cinchona alkaloid derived thiourea-promoted enantioselective conjugate addition of nitroalkanes to indolylidenecyanoacetates has been developed under neat conditions. The process leads to synthetically interesting densely functionalized 3,3′-disubstituted oxindoles with creation of up to three stereogenic centers.

Full text of DOI:10.1021/ol202931e

ORGANIC
LETTERS
2012
Vol. 14, No. 1
134–137
Synthesis of Highly Functionalized Chiral
3,30-Disubstituted Oxindoles via an
Organocatalytic Enantioselective Michael
Addition of Nitroalkanes to
Indolylidenecyanoacetates
Lu Liu,† Deyan Wu,† Shu Zheng,† Tengfei Li,† Xiangmin Li,† Sinan Wang,† Jian Li,†
Hao Li,*,† and Wei Wang*,†,‡
Department of Pharmaceutical Science, School of Pharmacy, East China University of
Science & Technology, Shanghai 200237, People’s Republic of China, and Department of
Chemistry and Chemical Biology, University of New Mexico, Albuqueruqe, New Mexico
87131-0001, United States
lieehao@hotmail.com; wwang@unm.edu
Received October 30, 2011
ABSTRACT
An efficient bifunctional cinchona alkaloid derived thiourea-promoted enantioselective conjugate addition of nitroalkanes to indolylidenecyanoacetates
has been developed under neat conditions. The process leads to synthetically interesting densely functionalized 3,30-disubstituted oxindoles with creation
of up to three stereogenic centers.
Given the broad spectrum of attractive biological prop-
erties of oxindole alkaloids,1 their structures have been a
driving force for developing new synthetic reactions. No-
tably, a number of elegant synthetic strategies have been
developed recently, particularly organocatalyzed asym-
metric versions.2 Despite the significant advances made,
an organocatalytic enantioselective conjugate addition of
nitroalkanes to oxindole-derived Michael acceptors has
not been reported to our knowledge.3ꢀ5 The rich chemistry
of the resulting nitro-containing products6 enabled facile
elaboration to structures of interest, important aspects in
diversity-oriented synthesis (DOS).7
In continuation of our efforts to create structurally
diverse oxindole compounds with potentially interesting
biological properties8 and with a view to fashioning the
quaternary stereogenic center9 of a large array of oxindole
natural products,1 we envisioned studying the reaction
shown in Scheme 1. The successful realization of a catal-
ytic asymmetric process would enable the generation of
3,30-disubstituted oxindoles bearing three versatile nitro-,
nitrile, and ester functionalities, which could allow con-
venient synthetic elaboration.1 Moreover, up to three ste-
reogenic centers including one full carbon quaternary
chiral center could be potentially created in this operation.
In this paper, we disclose a new, efficient organocataly-
tic enantioselective Michael addition of nitroalkanes to
† East China University of Science & Technology.
‡ University of New Mexico.
(1) For reviews of oxindole alkaloids, see: (a) Badillo, J. J.; Hanhan,
N. V.; Franz, A. K. Curr. Opin. Drug Discovery Disc. 2010, 13, 758.
(b) Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20. (c) Galliford, C. V.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748. (d) Marti, C.;
Carreira, E. M. Eur. J. Org. Chem. 2003, 2209.
r
10.1021/ol202931e
Published on Web 12/12/2011
2011 American Chemical Society

temperature improved the enantioselectivity and diaster-
eoselectivity significantly, while still preserving high yields
and short reaction times (entries 17ꢀ19).
Scheme 1. Organocatalytic Enantioselective Michael Addition
of Nitroalkanes to R,β-Unsaturated Cyanoacetate Oxindoles
Having established an optimal reaction protocol, we
next probed a variety of indolylidenecyanoacetates
(1) with nitroalkanes (2) to determine the scope of the
IV-catalyzed enantioselective Michael addition transforma-
tion (Table 2). We found that the process served as a
general approach to enantioenriched 3,30-disubstituted
oxindoles 3 with a significant structural variation. Nota-
bly, in all cases, the processes proceeded efficiently (1.5ꢀ
8 h) in high yield (93ꢀ99%) and with good to high
enantioselectivity (85ꢀ98% ee) and diastereoselectiv-
ity (4:1 to >20:1 dr). It appeared that the electronic effect
was limited. The benzene ring of 1 bearing electron-neutral
(entry 1), electron-withdrawing (entries 2ꢀ6), electron-
donating groups (entry 7) gave 85ꢀ98% ee and diastereo-
selectivity (9:1 to >20:1). Nevertheless, it was found that
derivatization of the nitrogen moiety in 1 (entries 8ꢀ15)
had an influence on the diastereoselectivity of products; in
general, the dr was decreased while the reaction yields and
enantioselectivities were affected marginally. Finally, we
also probed the structural features of nitroalkanes that
included nitroethane and -propane (entries 16 and 17) as
Michael donors for the conjugate addition reaction. They
smoothly underwent the reaction with high efficiency, and
three stereogentic centers were generated.
indolylidenecyanoacetates to generate 3,30-disubstituted
chiral oxindoles in high yield and with good to high
enantioselectivity (85ꢀ98% ee) and good to high dr (1:4 to
>20:1 dr ratio) under neat conditions. Furthermore, as
demonstrated, the adducts can be readily transformed to
chiral spiro-oxindoles as potential CRTH2 (DP2) receptor
antagonists.10
In the initial study, a variety of bifunctional amine
thiourea catalysts (10 mol %)11,12 were screened for the
proposed catalytic enantioselective Michael addition of
nitromethane 2a to indolylidene-cyanoacetate 1a without
a solvent (Table 1). We found that the reaction proceeded
smoothly to afford the desired product 3a in high yields
(92ꢀ99%, entries 1ꢀ8) with moderate dr, but the enantio-
selectivities varied. Among the catalysts probed, catalyst
IV13 gave the highest ee value (77% ee, entry 4). Therefore,
it was selected for further optimization of the reaction
conditions. It appeared that when the reaction was carried
out in a solvent, regardless of polarity (entries 4 and 9ꢀ16),
they were detrimental to the enantioselectivity and longer
reaction times were required. Lowering the reaction
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Org. Lett., Vol. 14, No. 1, 2012
135

Table 1. Optimization of Reaction Conditionsa
Table 2. Generality of IV-Catalyzed Conjugate Addition of
Nitroalkanes 2 to Indolylidenecyanoacetates 1a
entry
X, R1, R2, 3
H, H, H, 3a
time (h) % yieldb % eec
drd
1
2
3
4
5
6
7
8
9
3.5
3
99
95
94
96
94
95
93
95
96
94
98
97
97
94
95
95
97
87
98
9:1
5-Br, H, H, 3b
5-Cl, H, H, 3c
7-Cl, H, H, 3d
5-NO2, H, H, 3e
5-I, H, H, 3f
12:1
3
85 >20:1
85 >20:1
5
1.5
3
92
89
12:1
11:1
entry
cat.
solvent
time (h)
% yieldb
% eec
drd
5-MeO, H, H, 3g
H, CH2CO2Me, H, 3h
H, Me, H, 3i
2
85 >20:1
4
88
97
96
92
85
85
91
4:1f
6:1g
6:1h
8:1
1
2
I
neat
1/3
0.5
1/3
5/6
5/6
3
93
92
90
99
95
90
93
94
96
95
94
96
95
92
91
90
97
99
98
95
69
69
62
77
75
70
46
60
70
28
52
62
72
65
48
51
82
87
88
87
2:1
2:1
3:1
3:1
3:1
2:1
2:1
2:1
3:1
3:1
3:1
3:1
3:1
4:1
3:1
3:1
9:1
9:1
9:1
9:1
4
II
neat
10 H, Ac, H, 3j
6
3
III
IV
V
neat
11 5-Br, Me, H, 3k
12 5-Br, CH2CO2Me, H, 3l
13 5-Br, Bn, H, 3m
14 5-I, Me, H, 3n
6
4
neat
6
10:1
4:1
5
neat
8
6
VI
VII
VIII
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
neat
6
10:1
7
neat
2
15 5-OMe, Me, H, 3o
16e H, H, Me, 3p
17e H H, Et, 3q
4
90 >20:1
8
neat
0.5
7
3
88
97
7:1i
6:1j
9
CH2Cl2
DMF
THF
3
10
11
12
13
14
15
16
17e
18f
19g
20h
14
24
3.5
8
a Reaction conditions: unless specified, see footnote a in Table 1.
b Isolated yields. c Determined by chiral HPLC analysis (Chiralpak AD-
H or AS-H). d Determined by 1H NMR. e Major isomer with R-config-
uration determined by NOESY (see the Supporting Information for
details). f 14% ee for minor isomer. g 84% ee for minor isomer. h 73% ee
for minor isomer. i 25% ee for minor isomer. j 98% ee for minor isomer.
toluene
MeCN
EtOAc
dioxane
MeOH
neat
6
6
8
2.5
3.5
7
neat
showed that, for example, product 3b could be readily
transformed into a spirooxindole 4 (Scheme 2). Selective
reduction of the nitro group by ferrous sulfate to an amine
was followed by spontaneous lactamization to give pro-
duct 4 in 85% yield whose diastereoselectivity was im-
proved (dr >20:1). It is noteworthy that the racemic
spirooxindoles have been reported as CRTH2 (DP2)
receptor antagonists of potential usefor the treatment of
allergic inflammatory diseases.10 The asymmetric method
reported here could be employed for the preparation of the
neat
neat
40
a Reaction conditions: unless specified, a mixture of 1a (121 mg,
0.5 mmol) and a catalyst (0.05 mmol) in nitromethane (1.0 mL) was stirred at
rt for a specified time. After concentration in vacuo, the residue was purified
by silica gel chromatography, eluting with EtOAc and hexanes (1/2 v/v ratio).
b Isolated yield. c Determined by chiral HPLC (Chiralpak AD-H). d Deter-
mined by 1H NMR e Reaction carried out at 0 °C. f Reaction carried out at
ꢀ10 °C. g Reaction carried out at ꢀ25 °C. h 5 mol % of catalyst used.
The Michael adducts 3 hold great potential in DOS
and therapeutic agent development. Toward this end, we
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136
Org. Lett., Vol. 14, No. 1, 2012

Scheme 2. Synthesis of Spirooxindole via Reduction-Lactami-
zation Cascade
enantiomers for biological studies. The absolute config-
uration of product 3b was determined by the single-crystal
X-ray analysis of compound 4 (Figure 1).14
Figure 1. X-ray structure of compound 4.
Efforts toward application of the densely functionalized
Michael adducts in DOS and expanding the strategy for
new organic transformations are being pursued in our
laboratory.
In summary, we have developed a new enantioselec-
tive Michael addition of nitroalkanes to indolylidenecya-
noacetates, catalyzed by a bifunctional cinchona alkaloid
thiourea IV under neat, mild reaction conditions. No-
tably, up to three stereogenic centers and one quaternary
chiral center are generated in good to high enantio- and
diastereoselectvity. The reaction provides alternative ac-
cess to synthetically and biologically interesting, structu-
rally diverse, enantioenriched 3,30-disubstituted oxindoles.
Acknowledgment. This research is financially supported
by East China University of Science & Technology and the
China 111 Project (Grant No. B07023).
Supporting Information Available. 1H and 13C NMR
and HRMS data and experimental procedures and char-
acterization of the products 3 and 4. X-ray data for
compound 4 (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) See the Supporting Information for the CIF. The structure of the
compound derived from molecule 4 was determined by X-ray crystal
analysis. CCDC-851133 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via www.
ccdc.cam.ac.uk and see the Supporting Information.
Org. Lett., Vol. 14, No. 1, 2012
137