Organocatalytic Biomimetic Decarboxylative Aldol Reaction of Fluorinated β-Keto Acids with Unprotected Isatins

Article abstract of DOI:10.1002/adsc.201800831

A facile asymmetric synthesis of fluorinated 3-hydroxyoxindoles through the biomimetic decarboxylative aldol reaction of fluorinated β-keto acids with unprotected isatins catalyzed by quinine-derived urea catalyst has been achieved. One of the features of this work is that the easily available α, α-difluoro/α-monofluoro-β-keto acids have been first applied in the enantioselective synthesis of fluorinated compounds as the masked fluoroenolates. Furthermore, the utility of this method was demonstrated by its ability to access a series of difluorinated 3-hydroxyoxindoles with up to 95% ee and monofluorinated 3-hydroxyoxindoles with up to 90 : 10 d.r. and 94% ee. (Figure presented.).

Full text of DOI:10.1002/adsc.201800831

Title: Organocatalytic Biomimetic Decarboxylative Aldol Reaction of
Fluorinated β-Keto Acids with Unprotected Isatins
Authors: Jun Deng, Yin-Long Li, Xue-Lin Wang, Dan Xiao, Ming-Ying
Liu, and Yunfei Du
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800831
Link to VoR: http://dx.doi.org/10.1002/adsc.201800831

10.1002/adsc.201800831
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Organocatalytic Biomimetic Decarboxylative Aldol Reaction of
Fluorinated -Keto Acids with Unprotected Isatins
Yin-Long Li,a, b Xue-Lin Wang,b Dan Xiao,a Ming-Ying Liu,a Yunfei Dub and Jun
Denga, b,*
a
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Innovative Drug Research Centre,
School of Pharmaceutical Sciences, Chongqing University, 55 Daxuecheng South Road, Shapingba, Chongqing
401331, China. Fax: (+86)-23-65678460, E-mail: jdeng@cqu.edu.cn
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A facile asymmetric synthesis of fluorinated 3- utility of this method was demonstrated by its ability to
hydroxyoxindoles through the biomimetic decarboxylative access a series of difluorinated 3-hydroxyoxindoles with up
aldol reaction of fluorinated β-keto acids with unprotected to 95% ee and monofluorinated 3-hydroxyoxindoles with
isatins catalyzed by quinine-derived urea catalyst has been up to 90:10 d.r. and 94% ee.
achieved. One of the features of this work is that the easily
available α, α-difluoro/α-monofluoro-β-keto acids have been
first applied in the enantioselective synthesis of fluorinated
compounds as the masked fluoroenolates. Furthermore, the
Keywords: aldol reaction; fluorinated β-keto acids;
di/monofluorinated oxindoles; organocatalysis
Introduction
Organofluorine chemistry is one of the most
promising research fields because the introduction of
fluorine atom into molecules could result in beneficial
properties, and its application in modern life is
extensively exploited in materials, medicines and
agrochemicals.[1] Considering the fact that the
fluorine substituents are virtually absent in natural
products, the installation of fluoroalkyl groups relies
heavily on the development of selective and effective
fluorinating reagents.[2] Although numerous fluorine-
containing synthons have emerged during the past
decades, and the asymmetric synthesis of
organofluorine compounds has particularly been the
focus of intensive research efforts,[3] it is still
challenging to assemble fluoroalkyl groups in
enantioselective versions.
3-Hydroxy-2-oxindole is an appealing structural
motif exists in a large variety of biologically active
molecules (Figure 1).[4] Synthetically, isatins are the
prevalent candidates for constructing those attractive
frameworks, and the catalytic asymmetric aldol
reaction provide an efficient access to the
enantioenriched 3-hydroxy-2-oxindoles.[5] As the
fluorinated building blocks could exert positive
effects on evaluation of structure-activity
Figure 1. Biologically active 3-hydroxy-2- oxindoles.
relationships, several distinct strategies have been
advanced to achieve 3-hydroxy-2-oxindoles as
fluorinated versions in recent years. For example,
Zhou and co-workers reported the first example of
highly enantioselective synthesis of 3-difluoroalkyl
substituted 3-hydroxyoxindoles using difluoroenol
silyl ethers as nucleophiles. However, the acyclic
monofluorinated silyl enol ether for synthesis of
monofluorinated 3-hydroxyoxindole was realized
with lower enantioselectivity (Scheme 1, eq a).[6]
Afterwards, Fang and Wu et al. developed an
asymmetric aldol reaction of trifluoromethyl α-
fluorinated gem-diols with N-benzyl isatins, with the
reaction of the corresponding difluoroenolate
precursors being failed to provide difluorinated
oxindoles (Scheme 1, eq b).[7] More recently, Zhang
and Yi groups illustrated the aldol addition of
difluoroenlates derived from 2,2-difluoro-1,3-
diketones with N-benzyl isatins. Unfortunately, the
monofluorinated 3-hydroxyoxindole was afforded
with racemic mixture form (Scheme 1, eq c).[8]
1
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10.1002/adsc.201800831
Advanced Synthesis & Catalysis
Results and Discussion
At the outset of our work, the unprotected isatin 1a
and α,α-difluoro-β-keto acid 2a were selected as the
model substrates to evaluate various chiral
organocatalysts (Table 1). To our delight, using the
cinchona alkaloid-derived bifunctional thiourea A as
catalyst and THF as solvent, the desired product 3a
was obtained in 53% yield and 81% ee. Encouraged
by this result, the related H-bond donor quinine
derivatives were examined and the thiourea catalyst B
could afford 3a with enhanced yield (65%) and
similar enantioselectivity (80% ee). In the following,
the quinine-derived urea C was found to be the most
promising catalyst, furnishing the difluorinated 3-
hydroxy oxindole in 80% yield with excellent
enantioselectivity (92% ee). While the use of the
squaramide-based catalyst D and the Takemoto’s
catalyst E led to the decrease of yields and ee values.
Noteworthy, the dual H-bond donors of the catalyst
seemed to be important for realizing effective
enantiocontrol, due to the fact that catalysts F-H
possessing one or no H-bond donor, the
enantioselectivities of 3a dropped significantly.
Table 1. Representative results of the catalyst evaluation.a
Scheme 1. Enantioselective synthesis of fluorinated 3-
hydroxy-2-oxindoles.
Although the above mentioned methods have been
established, several challenging problems remain to
be solved. For example, these methods were
restricted to the syntheses of either difluorinated or
monofluorinated oxindoles, and N-protecting groups
were usually required in order to get high
enantioselectivities. Therefore, the further exploration
of novel fluorinating precursors in the stereoselective
synthesis of fluorinated oxindole analogues is still
desirable. On the other hand, inspired by the
polyketide biosynthesis via the activation of malonic
acid half thioesters (MAHTs) by polyketide synthases
(PKSs),
a
great number of organocatalytic
enantioselective decarboxylative aldol reactions have
been developed. Recently, Wennemers group
reported an enantioselective organocatalyzed aldol
reactions of fluoromalonic acid halfthioesters as a
masked fluorinated thioacetate enolate with
aldehyde.[9] In addition to being masked enolates, β-
keto acids are safe and readily available starting
materials, which largely enable their applications in
the area of asymmetric decarboxylative aldol reaction
as well as fluorination reaction.[10] But to the best of
our knowledge, the reports on using fluorinated β-
keto acids as fluorinating precursors remain very
limited, especially the further extension of fluorinated
β-keto acids in enantioselective synthesis was rarely
recognized.[11] In this regard, we wish to report herein
the asymmetric synthesis of di/mono-fluorinated 3-
hydroxyoxindoles via organocatalytic biomimetic
decarboxylative aldol reactions of α,α-difluoro/α-
monofluoro-β-keto acids with unprotected isatins
(Scheme 1, eq d).
aConditions: 1a (0.15 mmol), 2a (0.225 mmol), catalyst
(20 mol%), THF (1.5 mL), rt for 96 h, isolated yield, ee
was determined by HPLC analysis.
2
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10.1002/adsc.201800831
Advanced Synthesis & Catalysis
Table 2. Substitution effect of the nitrogen atom of isatin
After identified the suitable catalyst C, we set out
to further optimize the reaction conditions (Table 2).
The substitution effect of the nitrogen atom of isatin
was first investigated. In addition to the unprotected
isatin, N-methyl isatin and N-benzyl isatin also
afforded the desired products (3b and 3c) with good
yields and enantioselectivities (Table 2, entries 2 and
3). Moreover, screening of different solvents revealed
that CH2Cl2, toluene, CH3CN and MeOH resulted in
and optimization of the reaction conditions.a
Entry
R
H
Me
Bn
H
H
H
H
H
Solvent
THF
THF
Yield (%)b
80 (3a)
85 (3b)
71 (3c)
60 (3a)
35 (3a)
57 (3a)
47 (3a)
83 (3a)
67 (3a)
ee (%)c
92
91
88
40
14
20
0
74
1
2
3
4
5
6
7
8
9d
the
remarkable
decrease
of
yields
and
THF
enantioselectivies (Table 2, entries 4 to 7). The
employment of DMF has a negative impaction on the
enantioselectivity, albeit with the yield being
increased to 83% (Table 2, entry 8). By reducing the
catalyst loading to 10 mol%, the enantioselectivity
was maintained with 92% ee, but a diminished yield
was observed (67%, Table 2, entry 9).
Having established the optimal conditions, we then
studied the substrate scope of this newly established
method. The representative results are depicted in
Table 3. Generally, various isatins bearing both
electron-donating and electron-withdrawing groups
were employable, generating difluorinated oxindoles
in good to excellent yields and enantioselectivities
(Table 3, 3d to 3l). For instance, the methyl and
methoxy substituted isatins exhibited 55-65% yields
CH2Cl2
toluene
CH3CN
MeOH
DMF
H
THF
92
aConditions: 1 (0.15 mmol), 2a (0.225 mmol), catalyst C
b
(20 mol%), solvent (1.5 mL), rt for 96 h. Isolated yield.
cee was determined by HPLC analysis. d10 mol% of
catalyst C was used.
Table 3. Substrate scope of isatins and α,α-difluoro-β-keto acids.a
aConditions: 1 (0.15 mmol), 2 (0.225 mmol), catalyst C (20 mol%), THF (1.5 mL), rt for 96 h. Yields of isolated products
are given. ee was determined by HPLC analysis.
3
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10.1002/adsc.201800831
Advanced Synthesis & Catalysis
and 90-91% ee (3d to 3f). Meanwhile, a variety of
halogen-substituted isatins also furnished the desired
products in satisfactory enantioselectivities (86-89%
ee, 3g to 3j). The substrates with strong electron-
withdrawing groups (CF3, NO2) afforded high yields
of the corresponding products. However, lower
enantioselectivies were observed in these two cases
(78-79% ee, 3k and 3l). Subsequently, the scope of
α,α-difluoro-β-keto acids was investigated (Table 3,
3m to 3u). Difluoro-β-keto acids appended with
electron-rich groups (methyl and methoxy) were
proved competent in the decarboxylative reaction,
affording the desired products in 89-94% ee (3m to
3o). Substrates containing halogen substituents in the
ortho- and para-position of the aromatic ring were
also tolerated well in the reaction, with high yields
and enantioselectivities being obtained (78-93%
yields, 81-92% ee, 3p to 3r). Of note is that the
trifluoromethyl-substituted difluoro-β-keto acid could
afford the product with up to 90% yield and 95% ee.
(3s). In addition, naphthyl and heteroaryl substituents
also gave the corresponding difluorinated oxindoles
in 93% ee and 75% ee, respectively (3t and 3u).
Furthermore, the substituent at the 4-position of isatin
had no obvious effect on the yield and
enantioselectivity (Table 3, 3v).
To further demonstrate the versatility of the present
method, the exploration of the mono-fluorinated 3-
hydroxy oxindole synthesis was carried out (Table 4).
Under the established conditions, the organocatalytic
biomimetic decarboxylative aldol reaction of α-
fluoro-β-keto acid 4a with isatin delivered an
excellent yield with 82:18 d.r. and 87% ee after 2 h
(Table 4, entry 1). We were pleased to find that the
amount of catalyst C decreased to 10 mol% could
slightly enhance the steroselectivity (82:18 d.r., 90%
ee, Table 4, entry 2). Extensive screening of solvents
revealed CH2Cl2, DMF, toluene, MeOH and MTBE
failed to give superior results (Table 4, entries 3 to 7).
The subsequent investigation showed that 1,4-
dioxane was the more suitable solvent, 85:15 d.r. and
91% ee were obtained by running the reaction at the
temperature of 0 oC to 25 oC (Table 4, entry 10).
Table 5. Substrate scope of isatins and α-monofluoro-β-
keto acids.a
Table 4. Optimization of the mono-fluorinated 3-hydroxy
oxindole synthesis.a
Entry Solvent
T (oC) Yield
d.r.c
ee
(%)b
(%)c
1d
2
3
4
5
6
7
8
THF
25
25
25
25
25
25
25
25
95
93
42
84
35
88
78
93
82:18 87
82:18 90
54:46 37
81:19 88
63:37 50
69:31 62
69:31 62
85:15 90
THF
CH2Cl2
DMF
toluene
MeOH
MTBE
1,4-
dioxane
1,4-
dioxane
1,4-
9
10
92
93
82:18 90
85:15 91
10e
0 to
25
aConditions: 1 (0.15 mmol), 4 (0.75 mmol), catalyst C (10
dioxane
o
mol%), 1,4-dioxane (1.5 mL), 0 C for 10 min, and then
aConditions: 1a (0.15 mmol), 4a (0.75 mmol), catalyst C
o
warmed to 25 C. Yields of isolated products are given.
(10 mol%), solvent (1.5 mL), 2 h. Isolated yield. c d.r. and
b
Values in brackets refer to the ee of the minor isomer, d.r.
ee (major isomer) were determined by HPLC analysis. d 20
and ee were determined by HPLC analysis. bReacted for 12
h.
e
mol% of catalyst C was used. Reaction solution was
o
o
stirred at 0 C for 10 min, and then warmed to 25 C.
MTBE = methyl tert-butyl ether
4
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10.1002/adsc.201800831
Advanced Synthesis & Catalysis
(S)-3-(1,1-difluoro-2-oxo-2-phenylethyl)-3-
With the optimal conditions in hand, the substrate
hydroxyindolin-2-one (3a). Yield: 80%, 36 mg, white
scope of different isatins and α-fluoro-β-keto acids 4
was conducted and the results are illustrated in Table
5. Notably, the introductions of methyl and methoxy
groups to isatins were generally beneficial for the
diastereoselectivities, delivering the corresponding
products with excellent enantioselectivities (94% and
91% ee, 5b and 5c). Halogen atom and
trifluoromethyl group-modified isatins successfully
gave the mono-fluorinated 3-hydroxyoxindoles in
excellent yields (95%) and good steroselectivities
(80:20 and 78:22 d.r., 88% and 86% ee, 5d and 5e).
Additionally, other substituted α-fluoro-β-keto acids
also could be employed in the asymmetric
decarboxylative reaction without compromising the
enantioselectivities (88-93% ee, 5f to 5i). The present
reaction conditions were also compatible with the
naphthyl-substituted α-fluoro-β-keto acid and the
corresponding product could be isolated in 78% yield
along with good stereoselectivity (80:20 d.r. and 92%
ee, 5j).
o
solid, mp: 150-151 C, Rf = 0.29 (30% EtOAc/petroleum
ether); 92% ee, HPLC conditions: Daicel Chiralcel AD-H,
i-PrOH/hexane = 30/70, 1.5 mL/min, 254 nm; tr (major) =
5.005 min, tr (minor) = 8.963 min. Optical rotation: [α]D
15
= -353.7 (c = 0.41, MeOH). 1H NMR (600 MHz, Acetone-
d6) δ 6.20 (brs, 1H), 6.98 (d, J = 7.8 Hz, 1H), 7.01 (t, J =
7.6 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.43 (d, J = 7.5 Hz,
1H), 7.57 (t, J = 7.9 Hz, 2H), 7.73 (t, J = 7.4 Hz, 1H), 8.12
(d, J = 7.7 Hz, 2H), 9.65 (brs, 1H). 19F NMR (376 MHz,
Acetone-d6) δ -109.94 (s, 2F). 13C NMR (151 MHz,
Acetone-d6) δ 76.9 (t, J = 25.6 Hz), 111.0, 117.9 (t, J =
262.7 Hz), 122.9, 126.8, 127.2, 129.6, 131.1 (t, J = 3.3 Hz),
131.7, 133.8, 135.4, 144.12, 174.0, 188.9 (t, J = 29.1 Hz).
HRMS (ESI): m/z calcd for C16H11F2NNaO3 (M+Na)+
326.0605, found 326.0595.
General procedure for the asymmetric synthesis of 3-
fluoroalkyl-3-hydroxyoxindoles 5.
The solution of isatin 1 (0.15 mmol) and catalyst C (8.7
mg, 0.015 mmol) in 1,4-dioxane (0.5 mL) was stirred at
room temperature for 10 min. Then the reaction mixture
o
was cooled to 0 C, followed by the solution of freshly
prepared α-fluoro-β-keto acid 4 (4.0-5.0 equiv) in 1,4-
dioxane (1.0 mL) was added. After 10 min, the reaction
slowly warmed to room temperature and further stirred for
the reported time. The solvent was removed under reduced
pressure, the crude product was purified by flash column
chromatography (SiO2; gradient eluent: petroleum ether to
30% EtOAc in petroleum ether) to provide the 3-
fluoroalkyl-3-hydroxyoxindoles.
Conclusion
In summary, we have developed an asymmetric
biomimetic decarboxylative aldol reaction utilizing
fluorinated β-keto acids as the novel building blocks.
In the presence of quinine-derived urea catalyst,
various difluorinated 3-hydroxyoxindoles bearing a
fully substituted carbon were obtained in moderate to
good yields (45-93%) and good to excellent
enantioselectivities (75-95% ee). Particularly, the
present methodology also enables a highly efficient
and valuable access to the enantioenriched
monofluorinated 3-hydroxyoxindoles exhibiting
vicinal chiral centers, good diastereoselectivities (d.r.
up to 90:10) and excellent enantioselectivities (ee up
to 94%) were observed. We hope this protocol will
facilitate other applications of fluorinated β-keto
acids in the stereoselective synthesis of numerous
bioactive molecules.
(S)-3-((S)-1-fluoro-2-oxo-2-phenylethyl)-3-
hydroxyindolin-2-one (5a). Yield: 93%, 40 mg, colorless
oil, Rf = 0.38 (40% EtOAc/petroleum ether); d.r. 85:15,
91% ee (major isomer), HPLC conditions: Daicel Chiralcel
AD-H, i-PrOH/hexane = 30/70, 1.5 mL/min, 254 nm; tr
(major) = 4.795 min, tr (minor) = 6.637 min. Optical
15
1
rotation: [α]D = +25.6 (c = 0.43, MeOH). H NMR (600
MHz, CDCl3) δ 4.97 (brs, 1H), 5.96 (d, J = 46.2 Hz, 1H),
6.81 (d, J = 7.5 Hz, 1H), 6.92 (t, J = 7.2 Hz, 1H), 7.11 –
7.22 (m, 2H), 7.40 (t, J = 7.7 Hz, 2H), 7.54 (t, J = 7.1 Hz,
1H), 7.94 (d, J = 7.8 Hz, 2H), 9.07 (brs, 1H). 19F NMR
(376 MHz, CDCl3) δ -193.10 –193.35 (m, 1F). 13C NMR
(151 MHz, CDCl3) δ 76.7 (d, J = 25.2 Hz), 91.2 (d, J =
190.7 Hz), 111.1, 123.1, 125.8, 126.1, 128.7, 129.5 (d, J =
3.5 Hz), 130.8, 134.5, 135.2, 141.6, 177.1, 195.3 (d, J =
19.4 Hz). HRMS (ESI): m/z calcd for C16H12FNNaO3
(M+Na)+ 308.0699, found 308.0706.
Experimental Section
General procedure for the asymmetric synthesis of 3-
difluoroalkyl-3-hydroxyoxindoles 3.
Acknowledgements
To a solution of isatin 1 (0.15 mmol) in THF (1.5 mL) was
added catalyst C (17.3 mg, 0.03 mmol) and α,α-difluoro-β-
keto acid 2 (0.225 mmol) at room temperature. The
reaction mixture was stirred vigorously at room
temperature for 96 h, and the solvent was removed under
reduced pressure. The crude product was purified by flash
column chromatography (SiO2; gradient eluent: petroleum
ether to 30% EtOAc in petroleum ether) to provide the 3-
difluoroalkyl-3-hydroxyoxindole.
This work is financially supported by the National Natural
Science Foundation of China (21702023, 21572154), Chongqing
Science and Technology Commission (cstc2017zdcy-adyfx0022)
and Chongqing University (0903005203454).
5
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10.1002/adsc.201800831
Advanced Synthesis & Catalysis
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10.1002/adsc.201800831
Advanced Synthesis & Catalysis
FULL PAPER
Organocatalytic Biomimetic Decarboxylative Aldol
Reaction of Fluorinated -Keto Acids with
Unprotected Isatins
Adv. Synth. Catal. Year, Volume, Page – Page
Yin-Long Li,a, b Xue-Lin Wang,b Dan Xiao,b Ming-
Ying Liu,b Yunfei Dua and Jun Denga, b,*
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