Enantioselective synthesis of 3-fluoro-3-allyl-oxindoles via phosphine-catalyzed asymmetric γ-addition of 3-fluoro-oxindoles to 2,3-butadienoates

Article abstract of DOI:10.1039/c5cc03289j

The first phosphine-catalyzed enantioselective γ-addition of 3-fluoro-oxindoles to 2,3-butadienoates has been developed. A range of 3-fluoro-substituted oxindole substrates were employed, and oxindoles containing a 3-fluoro quaternary center were constructed in high yields and with excellent enantioselectivities. The γ-addition products could be converted readily to optically enriched 3-fluoro-3-allyl oxindole derivatives.

Full text of DOI:10.1039/c5cc03289j

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DOI: 10.1039/C5CC03289J
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Enantioselective Synthesis of 3‐Fluoro‐3‐allyl‐oxindoles via Phos‐
phine‐Catalyzed Asymmetric ‐addition of 3‐Fluoro‐Oxindoles to
2,3‐Butadienoates
Received 00th January 20xx,
Accepted 00th January 20xx
Tianli Wang,a Ding Long Hoon,a and Yixin Lu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The first phosphine‐catalyzed enantioselective ‐addition of 3‐fluoro‐ vinyl sulfone was the only example. Given the biological importance
oxindoles to 2,3‐butadienoates has been developed. A range of 3‐fluoro‐ of 3‐fluorinated oxindoles, development of an efficient method to
substituted oxindole substrates were employed, and oxindoles containing access this type of structural motifs seems to be highly desirable.
a 3‐fluoro quaternary center were constructed in high yields and with
Remarkable progress has been made in nucleophilic phosphine
excellent enantioselectivities. The ‐addition products could be converted catalysis in the past decade, and now phosphine‐catalyzed
readily to optically enriched 3‐fluoro‐3‐allyl oxindole derivatives.
organocatalytic reactions have been firmly established as powerful
tools to access structurally diverse chiral molecules in synthetic
organic chemistry.11 In this context, phosphine‐catalyzed ‐addition
reactions of ‐substituted allenoates/alkynoates have drawn much
attention.12,13 We recently disclosed14 the first utilization of 2,3‐
butadienoates in enantioselective ‐addition reactions catalyzed by
our amino acid‐based chiral phosphines.15 To further extend the
power of phosphine‐catalyzed ‐addition reactions, we became
interested in exploring 3‐fluoro‐substitued oxindoles as potential
partners for this type of reaction. Herein, we document a
phosphine‐catalyzed enantioselective ‐addition of 3‐fluoro‐
oxindoles to allenoates, leading to the formation of novel oxindole
derivatives containing a 3‐fluorinated quaternary center (Scheme 1).
Fluorine‐containing molecules have captured much attention from
synthetic chemists, due to their great importance in medicinal
chemistry and pharmaceutical industry.1 Thus, various synthetic
strategies have been devised for efficient preparation of fluorinated
compounds in the past years.2
Optically enriched 3,3’‐disubstituted oxindoles are important
structural motifs that commonly present in many natural products
and bioactive molecules. In particular, oxindoles bearing a 3‐fluoro
substituted quaternary stereogenic center are highly interesting.3
Enantioselective electrophilic fluorination of prochiral oxindoles is
the most common and efficient strategy for the construction of
such structural motifs.4 In 2000, Shibata and co‐workers first
employed cinchona alkaloids and Selectfluor as enantioselective
fluorinating reagents.5 Shortly after, similar strategy was disclosed
by the Cahard group.6 Many catalytic systems for enantioselective
fluorination of oxindoles were reported subsequently, including:
(S)‐DM‐BINAP‐Pd complex, chiral dbfox‐Ph‐Ni(II), N,N’‐dioxide‐Sc(III)
complex, chiral NHC‐Pd, and organo bis‐cinchona alkaloids.7,8 Our
group is interested in creating fluorinated chiral molecules,
particularly those with quaternary centers. We took indirect
approaches to access chiral fluorinated molecules via asymmetric
carbon‐carbon and carbon‐heteroatom bond formation by
employing prochiral fluorinated synthons.9 However, utilization of
3‐fluorinated oxindoles is rare, and our early report10 on amine‐
catalyzed conjugate addition of 3‐fluoro‐substituted oxindoles to a
Scheme 1 Synthesis of oxindoles containing a 3‐fluorinated
quaternary center.
We chose N‐Boc‐3‐fluoro‐oxindole (5a1) and allenoate (6c) as
model compounds to investigate ‐addition reaction. The catalytic
effects of a number of amino acid‐based bifunctional phosphines
were examined, and the results are summarized in Table 1. All the
phosphine catalysts were sufficiently effective to promote the
projected ‐reaction. L‐Valine‐derived phosphines containing either
a thiourea or sulfonamide functional group led to the formation of
the desired ‐addition products in excellent yields, but with poor to
moderate enantioselectivities (entries 1−4). Phosphineamide
catalysts were found to be very efficient, furnishing the desired
products in very good yields and excellent enantioselectivities
(entries 5−10). L‐Threonine‐derived phosphine‐amide 2g turned out
Department of Chemistry, National University of Singapore, 3 Science Drive 3,
Republic of Singapore 117543.
E‐mail: chmlyx@nus.edu.sg
a. These authors contributed equally to this work.
† Electronic Supplementary Information (ESI) available: Complete experimental
procedures and characterization data for the prepared compounds. See
DOI: 10.1039/x0xx00000x
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to be the best catalyst, affording the ‐addition product 7a in 95%
yield and with 93% ee (entry 11). The dipeptide phosphines,
however, were found to be ineffective (entries 12 and 13).
Employing catalyst 2g, we also examined oxindoles with different N‐
protective groups (entries 1416), and N‐Boc group remained the
best.
(entries 1−8). In addition,‐ and ‐substituted allenoates were also
View Article Online
16
examined, and shown to have limited reaDctOivI:it1y0.1a0n3d9/sCe5lCecCt0iv3i2t8y.9J
Subsequently, solvent screening was performed, and toluene
remained the best reaction medium (entries 9−13). Furthermore,
lowering the reaction temperature was not beneficial (entry 14).
With the optimal reaction conditions in hand, scope of the
reaction was then evaluated. Various 3‐fluorinated oxin‐doles with
different substituents and substitution patterns were tested, and
the results are summarized in Table 3. Different halide substitutions
on the aromatic ring were well tolerated, and the corresponding
adducts were obtained in high yields and with excellent
enantioselectivities (entries 1–4). The oxindoles with either
electron‐withdrawing or electron‐donating substituents were also
suitable substrates (entries 5–7). Moreover, bis‐substituted 3‐
fluoro‐oxindole could also be used (entry 8). The absolute
configurations of the ‐addition products were determined by
comparing the optical rotation of a derivative (9) with the value
reported in the literature.7f
Table 1 Screening of different phosphine catalysts for asymmetric
‐addition of 3‐fluoro‐oxindole 5a to 2,3‐butadienoate 6ca
Table 2 Optimization of reaction conditionsa
Entry
1
Cat.
1a
1b
1c
1d
2a
2b
2c
2d
2e
2f
R(5a
)
Time (h) Yield (%)b Ee (%)c
Boc(5a1
Boc(5a1
Boc(5a1
Boc(5a1
Boc(5a1
Boc(5a1
Boc(5a1
Boc(5a1
Boc(5a1
Boc(5a1
)
)
)
)
)
)
)
)
)
)
1
88
95
88
98
95
93
88
89
93
92
95
90
90
86
82
<5
32
55
41
77
90
90
88
64
93
92
93
6
2
0.5
1
3
4
0.5
1
Entry
R(
Me(6a
t‐Bu(6b
6
)
Solvent
7
Yield (%)b Ee (%)c
5
1
)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
Et2O
7a1‐1
7a1‐2
7a1‐3
7a1‐4
7a1‐5
7a1‐6
7a1‐7
7a1‐8
7a1‐3
7a1‐3
7a1‐3
7a1‐3
7a1‐3
7a1‐3
92
90
95
91
92
89
85
88
95
88
90
92
81
83
91
91
93
93
93
92
86
77
90
73
88
92
45
69
6
1
2
)
2
7
3
Bn (6c
)
2
8
4
6d
2
9
5
6e
2
10
11
12
13
14
15
16
6
6f
2
2g
3
Boc(5a1)
7
6g
2
Boc(5a1
Boc(5a1
)
)
8
Ph(6h)
2
‐9
4
9
Bn(6c
Bn(6c
Bn(6c
Bn(6c
Bn(6c
Bn(6c
)
2
93
83
‐‐
2g
2g
2g
Cbz(5a2
Ac(5a3
Me(5a4
)
10
11d
12d
13e
14f
)
4
)
)
)
)
)
CHCl3
4
)
CH2Cl2
EtOAc
a
Reactions were performed with 5a (0.05 mmol), 6c (0.06 mmol)
and catalyst (0.005 mmol) in toluene (0.5 mL) at room temperature.
b Isolated yield. c Determined by HPLC analysis on a chiral stationary
phase. TBDPS = tert‐butyldiphenylsilyl, TBS = tert‐butyldimethylsilyl,
TMS = trimethylsilyl, Ts = 4‐toluenesulfonyl. Cbz = carboxybenzyl, Ac
= acetyl.
toluene
a
Reactions were performed with 5a1 (0.05 mmol), 6 (0.06 mmol)
and 2g (0.005 mmol) in the solvent (0.2 mL) specified at room
temperature for 2 h. b Isolated yield. c Determined by HPLC analysis
on a chiral stationary phase. The reaction time was 4 h. e The
d
reaction time was 6 h. f Performed at 0 oC for 12 h.
Having identified the best catalyst (2g), we next attempted to
further improve the results by optimizing all the reaction
parameters (Table 2). Allenoate 6c with a benzyl ester group was
shown to be the best among all the different allenoates tested
2 | J. Name., 2012, 00, 1‐3
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Table 3 Scope of asymmetric ‐addition of 3‐fluoro‐oxindoles 5 to
allenoate 6ca
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DOI: 10.1039/C5CC03289J
Time
(h)
Yield
(%)b
Ee
Entry
1
7
(%)c
F
COOBn
7a1
O
2
95
93
93
83
N
Boc
0.5
2
3
Scheme 2 Elaboration of ‐addition products.
0.5
2
95
95
95
94
94
94
92
90
At this stage, we have not performed detailed mechanistic
studies17 to elucidate the origin of stereochemical outcome. It is
intuitive to correlate hydrogen bonding interactions between N‐Boc
of substrates and the amide moiety of the catalyst with observed
asymmetric induction. This hypothesis was supported
experimentally; employment of the methylated catalyst 2g’, or
utilizing oxindole 5a’ without N‐Boc group led to dramatically
decreased enantioselectivity (Table 4).
4
5
6
2
Table 4
Asymmetric ‐addition promoted by different
phosphines: investigating the importance of H‐bonda
2
2
2
92
88
94
90
7
8
a Reactions were performed with 5 (0.05 mmol), 6c (0.06 mmol) and
2g (0.005 mmol) in toluene (0.2 mL) at room temperature. b Isolated
yield. c Determined by HPLC analysis on a chiral stationary phase.
7
/Yield (%)b
Entry
Ee (%)c
5
2
t(h)
5a1
5a1
5a’
2g
2
4
2
7a/95
7a/85
7a’/81
93
37
43
1
2
3
2g’
Although the reactions were generally performed in small
scales, scale‐up could be done easily. When the reaction was
performed with 1 mmol of oxindole 5a1, the desired
quaternary 3‐fluoro‐oxindole 7a1 was obtained in essentially
2g
a Reaction conditions: oxindole (0.05 mmol), 6c (0.12 mmol), and
catalyst (0.005 mmol) in toluene (0.5 mL). Isolated yield.
b
c
same chemical yield and enantioselectivity. The
‐addition
Determined by HPLC analysis on a chiral stationary phase.
product could be converted to a 3‐allyl substituted oxindole
8
in high yield through a few trivial steps. Saturation of the
double bond yielded 3‐fluoro‐3‐alkyl substituted oxindole
derivative 9 in good yield (Scheme 2).
In conclusion, we have developed the phosphine‐catalyzed
asymmetric ‐addition of 3‐fluorinated oxindoles to allenoates
for the first time. The desired quaternary 3‐fluoro‐3‐

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8
9
For organocatalytic asymmetric synthesis of 3‐fluoro‐3‐aryl
substituted oxindoles were obtained in high yields and with
excellent enantioselectivities. Given the importance of
oxindole compounds and fluorinated molecules in medicinal
chemistry, the products derived via our method may be
biologically very useful. Evaluation of bioactivities of molecules
synthesized and theoretical studies to understand
stereochemical origin of the reaction are underway.
We thank the National University of Singapore (R‐143‐000‐
599‐112), the Ministry of Education (MOE) of Singapore (R‐
143‐000‐494‐112) and GSK‐EDB (R‐143‐000‐491‐592) for
financial support.
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16 See the ESI (Scheme S2) for details.
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8
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