Enantioseletive Fluorination of 3-Functionalized Oxindoles Using Electron-rich Amino Urea Catalyst

Article abstract of DOI:10.1002/adsc.201801133

An enantioselective fluorination of 3-functionalized oxindoles using electron-rich amino urea catalyst is described. Various 3-functionalized 3-fluoro-2-oxindoles were obtained in good yields and enantio-selectivity. The resulting enantioenriched 3-methylene nitrile 3-fluoro-2-oxindole product was found to inhibit indoleamine 2,3-dioxygenase considerably. (Figure presented.).

Full text of DOI:10.1002/adsc.201801133

Title: Enantioseletive Fluorination of 3-Functionalized Oxindoles Using
Electron-rich Amino Urea Catalyst
Authors: Xiaojian Jiang, Haitao Wang, Haoquan He, Wei Wang,
Yuqiang Wang, Zhihai Ke, and Ying-Yeung Yeung
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801133
Link to VoR: http://dx.doi.org/10.1002/adsc.201801133

Advanced Synthesis & Catalysis
10.1002/adsc.201801133
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Enantioseletive Fluorination of 3-Functionalized Oxindoles
Using Electron-rich Amino Urea Catalyst
a,
a
a
a
a
Xiaojian Jiang, * Haitao Wang, Haoquan He, Wei Wang, Yuqiang Wang,
b
b,
Zhihai Ke, Ying-Yeung Yeung *
a
Jinan University College of Pharmacy, Institute of New Drug Research and Guangzhou Key Laboratory of Innovative
Chemical Drug Research in Cardiocerebrovascular Diseases, Guangzhou 510632 (China)
E-mail: chemjxj2015@jnu.edu.cn
Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong (China)
E-mail: yyyeung@cuhk.edu.hk
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. An enantioselective fluorination of 3- functionalities using electron-rich urea organocatalyst.
functionalized oxindoles using electron-rich amino urea Moreover, it was identified that some of the
catalyst is described. Various 3-functionalized 3-fluoro-2- fluorinated products exhibit significant anti-cancer
oxindoles were obtained in good yields and enantio- activity.
selectivity. The resulting enantioenriched 3-methylene
nitrile 3-fluoro-2-oxindole product was found to inhibit
indoleamine 2,3-dioxygenase considerably.
Nitrile moiety is useful in many pharmaceutical
[1d]
structures, including bioactive molecules
and
[2d]
natural products . Initially, the organocatalytic
fluorination was performed using substrate 3-alkyl-2-
oxindole 3a in the presence of potassium carbonate in
acetone. N-Fluorobenzenesulfonimide (F1, NFSI)
was used as the electrophilic fluorinating agent
Keywords: Asymmetric catalysis; Fluorination; 3-
Functionalized oxindoles; Catalyst; Anti-cancer agent
(
Table 1). While Shibata and co-workers reported
that DHQ
2
PHAL (5) and DHQ PYR (6) could
2
Oxindole motifs present in many biologically active
promote the 3-fluorination of 3-aryl-2-oxindoles in
compounds[ and natural products. Thanks to the
1]
[2]
[4d]
moderate enantioselectivity, they were found to be
[3]
unique features of organofluorine compounds,
ineffective in catalyzing the asymmetric fluorination
of 3-alkyl-2-oxindole 3a although satisfactory yield
of product 4a was obtained (entries 1 and 2). BINOL-
derived phosphoric acid catalyst 7, cinchonine (8a),
fluorinated indoles become a common modification
in improving the bioactivity of relevant
pharmaceutical products.[
1e,g]
In particular, it was
found that enantioenriched 3-substituted 3-fluoro-2-
oxindoles exhibit broad applications in medicinal
Table 1. Evaluation of Catalysts.
chemistry.[
1e,f]
Owing to the potential of medical
applications of 3-substituted 3-fluoro-2-oxindoles,
several groups have developed enantioselective
[4]
fluorination of 3-aryl and 3-alkyloxindoles. Other
relevant approaches include[ asymmetric aldol
5]
reaction with fluoroenolates
and palladium-
[6]
catalyzed cyclization were documented. However,
majority of these methods rely on transition metal
catalysis and require the protection of the N-H indole
moiety. While Shibata and co-workers reported that
cinchona alkaloid-derived organocatalysts could
promote the enantioselective fluorination of 2-
oxindoles, the scope is limited to 3-aryl-substituted
substrates.[
4d]
Therefore, new methods to devise
3-functionalized 3-fluoro-2-
enantioenriched
oxindoles is still highly desired. Herein, we describe
a novel synthetic strategy to produce diverse
enantioenriched 3-fluoro-2-oxindoles bearing cyano,
hydroxyl, amide, sulfonamide, ester, allyl and, alkyl
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201801133
a)
Entrya)
erc)
Reactions were carried out with substrate 3a (0.1 mmol),
F
Catalyst
Time (d) Yield
b)
catalyst (0.015 mmol), Na
mmol) in EtOAc (3 mL) at 25 C.
2 3
CO (0.12 mmol) and F1 (0.12
(
%)
o
1
2
3
4
5
6
7
8
9
F1
F1
F1
F2
F1
F2
F1
F2
F1
F1
F1
F2
5
6
7
7
8a
8a
8b
8b
9a
9b
9c
9b
2
2
4
4
4
4
4
4
4
1
1
4
73
76
50:50
5842
ND
ND
ND
ND
ND
ND
ND
electron-rich nor electron-deficient urea catalysts
11b-11f) could alter the er substantially. Nonetheless,
trace
trace
trace
trace
trace
trace
trace
34
(
further modification of the urea moiety leading us to
the discovery that catalyst 11g bearing an admantyl
substituent returned a 96:4 er. Increasing the
bulkiness of the quinoline moiety (11h vs 11e)
returned equal enantiomeric ratio (87:13 er).
After identifying the optimal catalyst, we
continued to investigate the substrate scope of this
reaction (Table 3). The catalytic fluorination protocol
was found to be compatible with a range of oxindoles
with different N-substituents such as methyl and ethyl
groups (entries 1-2). Unsaturated compounds are
sensitive towards electrophilic fluorination. None-
theless, olefinic (3c-3e) and propargyl (3f) substrates
were well-tolerated under the reaction conditions
1
1
0
1
2
35:65
61:39
ND
45
trace
1
a)
Reactions were carried out with substrate 3a (0.1 mmol),
CO (0.12 mmol) and fluorine
source (0.12 mmol) in acetone (3 mL) at 25 C. Isolated
catalyst (0.015 mmol), K
2
3
o
b)
c)
yield.
sulfonyl.
Determined by chiral HPLC. Ts = 4-toluene-
(
entries 3-6). N-Phenyl oxindole 3g also worked well
in the system (entry 7). A series of N-methyl
oxindoles with different electron-rich or electron-
deficient substitutions at the aryl system were also
examined and good yields and enantioselectivity
were generally observed (entries 8-16). The absolute
configuration of the product 4h was determined by
X-ray diffraction analysis on the single-crystal
amino-thiocarbamate (8b), and amino-thiourea (9a)
also failed in promoting the fluorination of 3a (entries
3
–9). To our delight, appreciable yields and
enantiomeric ratio (er) of the desired product 4a
could be obtained when cinchona alkaloid-derived
urea catalyst 9b or 9c was applied (entries 10 and 11).
The reaction was sluggish when changing the
fluorinating agent to selectfluor (F2) (entry 12).
[7]
sample. It’s noteworthy that substrates bearing an
ester, an amide or a hydroxyl group returned high
yield and enantio-control (entries 17-19). In addition,
the reaction was scable in excellent yield with equal
high er ratio (entry 20).
A brief survey on solvents and bases revealed the
superior performance of EtOAc with sodium
carbonate, providing 4a in 17:83 er when catalyst 9b
was used (Table 2).[ The use of catalyst 10a with a
quinidine skeleton increased the er to 15:85.
Switching the catalyst backbone to the quinine-
derived catalyst 11a further improved the
enantioselectivity to 88:12 er. Although it is well-
documented that electronic demand on the urea-
system is often a crucial factor in organocatalytic
enantioselective reaction,[ it was found that neither
7]
Table 3. Substrate Scope of Fluorination of N-Substituted
Oxindole 3.
8−9]
Table 2. Study on Effect of The Substituent on The Urea
a)
Catalysts.
Entrya) R1
R2
Time
h)
4
Yield ,
er
b)
c)
(
1
2
3
Me
Et
Allyl
H
H
H
16
16
16
4a
4b
4c
65, 96:4
68, 90:10
69, 90:10
4
5
H
H
20
20
4d
4e
70, 89:11
69, 92:8
6
7
8
9
1
1
Proparyl
Ph
Me
Me
Me
H
H
4-Me
5-Me
6-Me
7-Me
16
24
16
16
16
16
4f
67, 91:9
71, 95:5
85, 95:5
85, 96:4
86, 97:3
79, 94:6
4g
4h
4i
4j
4k
0
1
Me
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201801133
1
1
1
1
1
1
1
1
2
3
4
5
6
7
8
9
0
Me
Me
Me
Me
Me
-
-
-
-
6-F
24
24
20
20
4l
4m 68, 91:9
75, 95:5
revealed that the current method is compatible with
many functionalities at the C(3) position (Table 4).
High enantio-control was observed when cyano
group containing substrate was utilized (12a). Alkyl
and allyl containing oxindole substrates 12b-c were
capable of delivering high enantioselectivities,
though much longer time was required to obtain high
yields. Substrates possessing NHBoc, NHTs and ester
moiety provided products in excellent yields and high
enantioselectivities (12d-e, 12h-i). High er values
5-Cl
5-Br
6-Br
4n
4o
4p
4q
4r
4s
66, 96:4
62, 92:8
69, 92:8
93, 95:5
98, 95:5
96, 90:10
99, 95:5
5-OMe 18
-
-
-
-
168
24
168
36
d)
2
4r
a)
Reactions were carried out with 3 (0.2 mmol), catalyst
1g (0.03 mmol), Na CO
(0.24 mmol) and F1 (0.24 mmol) could also be acquired when hydroxyl-containing
1
2
3
o
b)
c)
in EtOAc (6 mL) at 25 C. Isolated yield. Determined
by chiral HPLC. The reaction was conducted on a 1
mmol scale.
oxindole substrates were used (12f-g). Unfortunately,
the current reaction conditions were not suitable for
3-aryl-substituted 2-oxindole substrate (12j).
d)
A brief investigation on the possible intermediate
1
9
It is worth-mentioning that N-protection-free 3-
fluoro-2-oxindoles could be useful in the preparation
of pharmaceutically important compounds without
going through the laborious protection/deprotection
procedures. To the best of our knowledge, however,
only one literature reported the enantioselective
fluorination of unprotected 3-substituted oxindoles
with substrate scope limited to 3-alkyl and 3-aryl
substitions.[
was conducted by F NMR experiment on a mixture
of the catalyst 11g and NSFI under basic condition.
The fluorine signal exhibited a downfield-shift from –
40.0 ppm (pure NSFI) to 42.4 ppm (the putative
complex 11g-F), which could be attributed to the
coordination of the quinuclidine’s nitrogen of 11g to
[4d]
the fluorine of NSFI. Since the N-protection-free
2-oxindoles 12 also worked well under the catalytic
protocol, we believe that the N-H in the oxindole
substrate does not play a crucial role in the enantio-
determining step. A proposed catalytic cycle is
depicted in Scheme 1. We speculate that catalyst 11g
might firstly react with NSFI to generate the putative
fluorinating species 11g-F. The 2-oxindole 3 or 12
could then hydrogen-bond to the urea moiety to give
intermediate A and subsequent fluorination to yield
product 4 or 13. Instead of an electron-withdrawing
group, we suspect that the bulky admantyl group in
4e]
Table 4. Substrate Scope of Fluorination of 12.a)
1
1g might offer optimal steric demand for the
effective asymmetric transformation.
a)
Reactions were carried out with 12 (0.2 mmol), catalyst
1
2 3
1g (0.03 mmol), Na CO (0.24 mmol) and F1 (0.24 mmol)
o
in EtOAc (6 mL) at 25 C. Isolated yields were recorded.
Er was determined by chiral HPLC.
Nonetheless, we are delighted to realize that the
catalytic protocol was also suitable to N-protection-
free 2-oxindoles. For instance, 3-methyl-2-oxindole
Scheme 1. Proposed Mechanism.
(
12b) could readily be converted to the corresponding
-fluorinated product 13b in good enantioselectivity
Table 4). 13b is the key advanced intermediate for
Small-molecule inhibitors of indoleamine 2,3-
dioxygenase (IDO) are currently being translated to
3
(
[10]
clinic for evaluation as cancer therapeutics.
[1g]
the preparation of the bioactive compound 14 and
our approach provides an easy access to such
compound. Further attempt in diversifying the scope
Recently, the indole-based compound Indoximod has
been identified as a selective IDO inhibitor and is
2
[10b-c]
currently under clinical trial for cancer treatment.
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201801133
Innovation and Technology Funding (Project code:
GHP/008/17GD) for financial support.
We also evaulated the IDO inhibition effect of the
2
newly synthesized 3-fluoro-2-oxindole derivatives.
The starting material 12a (table 5, entry 1) shown
very poor effect on IDO
2
, while 13a inhibited IDO
2
References
substantially, indicating that α-fluorination is of
critical importance to increase bioactivity. Compared
to Indoximod, product 13a was capable of inhibiting
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IDO
2
considerably (table 5, entry 2), while products
with moderate
1
3e, 13f and 13g could inhibit IDO
2
[7]
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anti-cancer agents. The resulting products bearing
diverse functional groups allow for a rapid synthesis
of fluorine-containing bioactive molecules.
2
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Table 5. Results of IDO
2
Inhibition Effect.
(µM)
Entry Compound IC50 of IDO
2
1
2
3
4
5
6
7
8
9
1
12a
13a
13c
13e
13f
13g
4q
>1000
16
>1000
102
278
81
>1000
>1000
>1000
4r
4s
0
Indoximod 465
In summary, we have developed an efficient and
highly enantioselective fluorination of 3-substituted
-oxindoles in the presence of chiral urea catalyst.
2
Various N-protected and N-unprotected tertiary 3-
oxindoles bearing diverse functionalities were
synthesized in excellent yields and high
enantioselectivities. The method herein substantially
broadens the scope of tertiary 3-fluoro-2-oxindoles,
which is beneficial to organic and medicinal
chemistry. Further studies to investigate the
bioactivities and elaboration of these products are
ongoing.
3
, 2014.
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Experimental Section
General Procedure for Enantioselevtive Fluorination.
To a EtOAc (6 mL) solution of 3-substituted oxindole
substrates 3 or 12 (0.2 mmol, 1.0 equiv) and catalyst 11g
(
15.0 mg, 0.03 mmol, 0.15 equiv) at room temperature,
was added Fluorobenzenesulfonimide (F1, NFSI) (75.6mg,
.24 mmol, 1.2 equiv). The resulting mixture was stirred at
0
room temperature and monitored by TLC. The solution
was diluted with water (5 mL) and extrated with EtOAc,
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dried over MgSO
was purified by flash column chromatography
hexane/EtOAc) to yield the corresponding 3-fluoro 3-
4
and concentrated in vacuo. The residue
(
functionalized oxindole products 4 or 13.
2
1
004, 104, 1; e) J.-A. Ma, D. Cahard, Chem. Rev. 2008,
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Province (Grant No. 2017B050506006), National Natural
Science Foundation of China (Grant No. 21502068), and
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201801133
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Advanced Synthesis & Catalysis
10.1002/adsc.201801133
COMMUNICATION
Enantioseletive Fluorination of 3-Functionalized
Oxindoles Using Electron-rich Amino Urea
Catalyst
Adv. Synth. Catal. Year, Volume, Page – Page
Xiaojian Jiang,* Haitao Wang, Haoquan He, Wei
Wang, Yuqiang Wang, Zhihai Ke, Ying-Yeung
Yeung*
6
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