Enantioselective conjugate addition of 3-fluoro-oxindoles to vinyl sulfone: An organocatalytic access to chiral 3-fluoro-3-substituted oxindoles

Article abstract of DOI:10.1039/c3ob41267a

An organocatalytic conjugate addition of prochiral 3-fluorinated oxindoles to vinyl sulfones was described for the first time. In the presence of bifunctional tertiary amine-thiourea catalysts, 3-fluoro-3-substituted oxindole adducts were obtained in exce

Full text of DOI:10.1039/c3ob41267a

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Enantioselective conjugate addition of 3-fluoro-
oxindoles to vinyl sulfone: an organocatalytic access to
Cite this: Org. Biomol. Chem., 2013, 11,
5217
chiral 3-fluoro-3-substituted oxindoles†
Received 19th June 2013,
Accepted 27th June 2013
Xiaowei Dou and Yixin Lu*
DOI: 10.1039/c3ob41267a
www.rsc.org/obc
An organocatalytic conjugate addition of prochiral 3-fluorinated counterparts. To the best of our knowledge, there is only one
oxindoles to vinyl sulfones was described for the first time. In such report in the literature. Shibata and co-workers employed
the presence of bifunctional tertiary amine–thiourea catalysts, bis-cinchona alkaloid as the catalyst to achieve enantio-
3-fluoro-3-substituted oxindole adducts were obtained in excel- selective fluorination of oxindoles.11 The reported reaction,
lent yields and with high enantiomeric excesses.
however, suffered from a long reaction time, and there was
also room for improvement of enantioselectivity.
Fluorinated molecules are of great importance in the pharma-
ceutical industry, and their distinctive characteristics are
mainly due to the unique properties of the fluorine atom
and the resulting C–F bonds.1 Not surprisingly, asymmetric
synthesis of fluorinated molecules has drawn enormous atten-
tion from the synthetic community in recent years.2
Recently, organocatalytic synthetic methods utilizing fluori-
nated substrates for the C–C bond formation have been shown
to be a viable approach for the synthesis of chiral fluorine-
containing molecules. The true advantage of this approach is
that the challenging asymmetric construction of C–F bonds is
turned into C–C bond formation, which is very well studied
and is much easier to control in modern organic synthesis.
In this context, we and others have developed a range of
asymmetric reactions for the synthesis of fluorine-containing
stereogenic centers using fluorinated pronucleophiles.12 To
align with our interest in synthesizing biologically important
Oxindoles are widely present in natural products and bio-
active molecules, and oxindoles bearing
a 3-fluorinated
quaternary stereogenic center are structural motifs that have
important applications in the pharmaceutical industry.3
Various synthetic strategies have been devised to target this
important molecular structure over the years. In 2001, Shibata
et al. described an enantioselective fluorination strategy by
using a combination of stoichiometric amounts of cinchona
alkaloid and Selectfluor.4 Shortly afterwards, the Shibata group
and the Cahard group independently reported an asymmetric
synthesis of BMS-204352 by using a stoichiometric amount of
cinchona alkaloid-derived fluorinating reagent.5 Metal-based
catalytic systems have been developed recently for the asym-
metric fluorination of oxindoles, including: Shibata’s dbfoxPh/
Ni(II) complex,6 Sodeoka’s (S)-DM-BINAP-Pd complex,7 Gade’s
boxmi-Ni(II),8 Feng’s Sc(III)-N,N′-dioxide complex,9 and Dorta’s
chiral NHC-Pd complex.10 On the other hand, advances
in organocatalytic enantioselective fluorination methods
lagged well behind as compared with their transition metal
structural scaffolds containing
a quaternary stereogenic
center,13 we became interested in developing an efficient strat-
egy to access 3-fluoro-3-substituted oxindoles. Vinyl sulfones
are valuable acceptors for conjugate addition reactions, mainly
due to the high electron withdrawing ability of the sulfone
group and a variety of well-established post-synthetic manipu-
lations of the sulfone functionality.14 Our group has recently
developed a number of asymmetric conjugate additions by
utilizing vinyl sulfones as the acceptors.15 We envisioned
that a conjugate addition of 3-fluoro-substituted oxindoles to
1,1-bis(benzenesulfonyl)ethylene may represent
a straight-
forward method to access enantiomerically enriched 3-fluoro-
3-substituted oxindoles (Scheme 1). In this communication,
we document the first organocatalytic asymmetric conjugate
addition of 3-fluoro-substituted oxindoles to a vinyl sulfone.
To promote the projected conjugate addition, tertiary
amine catalysts with a Brønsted acid moiety are apparently
an excellent choice.16 We chose conjugate addition of
3-fluorinated oxindole 1a to vinyl sulfone 2a as a model reaction,
and examined the catalytic effects of a number of tertiary
amine–(thio)urea catalysts. The results are summarized in
Table 1.
Department of Chemistry & Medicinal Chemistry Program, Life Sciences Institute,
National University of Singapore, 3 Science Drive 3, Singapore 117543, Republic of
Singapore. E-mail: chmlyx@nus.edu.sg
†Electronic supplementary information (ESI) available: Representative experi-
mental procedures, X-ray crystallographic data, HPLC chromatogram, and
NMR spectral data for all the compounds are described. CCDC 929593. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob41267a
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Table 1 Conjugate addition of 3-fluorooxindole 1a to vinyl sulfone 2a cata-
lyzed by different organic catalystsa
Scheme 1 Catalytic asymmetric synthesis of 3-fluoro-3-substituted oxindoles.
Cinchonine-derived tertiary amine–thiourea catalyst 4 was
found to be very effective, affording the desired product in
excellent yield and with moderate ee (entry 1). Cinchonidine
and quinine-derived catalysts 5 and 6 were more efficient, and
the reactions proceeded faster and the desired adducts were
obtained with higher enantioselectivities (entries 2–3). When
our recently developed multifunctional catalysts17 were
employed, slightly higher ee values could be obtained; the
reaction, however, suffered from low yield (entries 4–5).
Quinine-derived tertiary amine–urea 9 proved to be inferior to
catalyst 6 (entry 6). Overall, catalyst 6 offered the best results.
Further optimizations using 6 as the catalyst of choice
were then performed. Dilution of the reaction mixture
was beneficial, and lowering the temperature turned out to be
detrimental (entries 7–8). A solvent screening revealed that
Entry
Catalyst
Solvent
t (min)
Yieldb (%)
eec (%)
1
2
3
4
5
6
4
5
6
7
8
9
6
6
6
6
6
6
6
6
6
6
6
6
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Xylene
THF
CH2Cl2
CHCl3
DCE
CHCl3
CHCl3
30
10
5
5
5
5
8
60
10
60
30
15
15
15
15
15
25
120
>95
>95
>95
54
−68
81
84
86
85
69
86
80
81
82
87
90
83
91
93
92
93
90
52
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
7d
8d,e
chloroform was the best solvent (entries 9–13). Additive study 9d
10d
led to further enhancement; 3a was obtained in >95% yield
and with 93% ee when 4 Å molecular sieves were added
(entries 14–16). Moreover, the catalyst loading could be 13d
11d
12d
14d, f
reduced to 5 mol% without sacrificing the enantioselectivity
15d,g
16d,h
(entries 17–18).
CHCl3
CHCl3
CHCl3
With the optimal reaction conditions in hand, the substrate 17d,g,i
18d,g, j
scope of this conjugate addition reaction was then investi-
a Reactions were performed with 1a (0.05 mmol), 2a (0.05 mmol) and
the catalyst (0.005 mmol) in the solvent (0.5 mL) at room temperature.
b Isolated yield. c Determined by HPLC analysis on a chiral stationary
phase. d 1.0 mL solvent was used. e The reaction was performed
at 0 °C. f 3 Å molecular sieves (10 mg) were added. g 4 Å molecular
sieves (10 mg) were added. h 5 Å molecular sieves (10 mg) were added.
i Catalyst loading was 5 mol%. j Catalyst loading was 2 mol%. DCE:
dichloroethane.
gated. As summarized in Table 2, fluorinated oxindoles with
diverse substitution groups at different positions were exam-
ined, and consistent high yields and enantioselectivities could
be obtained. Different halide substitutions on the aromatic
ring were well tolerated (entries 2–6), and oxindoles with elec-
tron donating substitution groups as well as bis-substituted
oxindole were also suitable substrates (entries 7–9). In general,
all the reactions went to completion within one hour,
affording the desired adducts in high yields and excellent ee
values. The absolute configurations of the 3-fluoro-3-substi-
tuted oxindoles were assigned on the basis of the X-ray crystal-
lographic analysis of 3e (Fig. 1).18
Different electrophiles were also tested. Olefin 2b with
mono-sulfone activation was found to be unsuitable for the
reaction (eqn (1)). Substituted vinyl sulfone 2c was a good sub-
strate. In the presence of multifunctional catalyst 7, the conju-
gate addition of 1a to 2b took place readily, affording the
desired product in high yield, with high dr and near perfect ee
values (eqn (2)). Nitroolefin 2d was found to be sufficiently
reactive and the corresponding Michael addition proceeded
smoothly in the presence of catalyst 6.19 The desired adduct
was obtained in excellent yield, with moderate diastereo-
selectivity and enantioselectivity (eqn (3)).20
ð1Þ
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Table 2 Substrate scope of the conjugate addition of 3-fluorooxindoles 1 to
vinyl sulfone 2aa
Entry
1
3
t (min)
Yieldb (%)
>95
eec (%)
93
25
Fig. 1 X-ray crystal structure of 3e.
2
3
20
25
>95
>95
93
91
ð2Þ
ð3Þ
4
5
30
20
>95
>95
93
89
In summary, we have developed the first asymmetric conju-
gate addition of 3-fluoro oxindoles to vinyl sulfones, promoted
by tertiary amine–thiourea bifunctional catalysts. The desired
3-fluoro-3-substituted oxindoles were prepared in excellent
chemical yields and with very high enantiomeric excesses. The
reported method is simple and efficient, representing a promi-
sing approach to access biologically important chiral oxindoles
containing a 3-fluoro-quaternary stereogenic center.
6
7
30
45
>95
>95
87
89
Acknowledgements
We gratefully acknowledge generous financial support from
the National University of Singapore (R-143-000-469-112),
GSK-EDB (R-143-000-491-592), the Singapore-Peking-Oxford
Research Enterprise (COY-15-EWI-RCFSA/N197-1), and the
Ministry of Education (MOE) of Singapore (R-143-000-494-112).
8
9
50
60
>95
>95
90
89
Notes and references
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This journal is © The Royal Society of Chemistry 2013
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