Ionic Liquid-Mediated Hydrofluorination of o-Azaxylylenes Derived from 3-Bromooxindoles

Article abstract of DOI:10.1021/acs.orglett.7b00887

The hydrofluorination reaction of 3-bromooxindole using mild HF reagents in an ionic liquid is described. This transformation can operate at room temperature to give a series of 3-substituted 3-fluorooxindole derivatives including racemic BMS 204352 (MaxiPost). The mechanistic study about interactions between HF and 3-butyl-1-methylimidazolium tetrafluoroborate [bmim][BF₄] is also discussed on the basis of energy calculations.

Full text of DOI:10.1021/acs.orglett.7b00887

Letter
pubs.acs.org/OrgLett
Ionic Liquid-Mediated Hydrofluorination of o‑Azaxylylenes Derived
from 3‑Bromooxindoles
Satoshi Mizuta,*,† Hiroki Otaki,† Ayako Kitagawa,† Kanami Kitamura,† Yuki Morii,† Jun Ishihara,†
Kodai Nishi,‡ Ryo Hashimoto,§ Toshiya Usui,§ and Kenya Chiba§
†Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo, Nagasaki 852-8521 Japan
‡Department of Radioisotope Medicine, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523,
Japan
§Nishiisahaya Hospital, 3015 Kaizu, Isahaya, Nagasaki 854-0063, Japan
S
* Supporting Information
ABSTRACT: The hydrofluorination reaction of 3-bromoox-
indole using mild HF reagents in an ionic liquid is described.
This transformation can operate at room temperature to give a
series of 3-substituted 3-fluorooxindole derivatives including
racemic BMS 204352 (MaxiPost). The mechanistic study
about interactions between HF and 3-butyl-1-methylimidazo-
lium tetrafluoroborate [bmim][BF4] is also discussed on the
basis of energy calculations.
ucleophilic fluorination reactions for the synthesis of
organofluorines are very important in agrochemical,1
method for hydrofluorination to yield tertiary alkyl−F bonds is
rare.15 Herein, we disclose an ionic liquid-mediated hydro-
fluorination of o-azaxylylene intermediates 2 generated in situ
from 3-bromooxindoles 1, giving the 3-fluorooxindole products
3 (Scheme 1). In this study, the mechanistic study of
N
pharmaceutical,2 and radiopharmaceutical industries.3 This
importance has driven research interest in the development
of a method for the incorporation of fluorine atoms into
organic molecules. Therefore, versatile methods for alkyl,4
allyl,5 and aryl fluoride synthesis6 have recently been developed.
In addition, deoxyfluorination of alcohols has also been
explored extensively.7Among them, SN2 fluorination reaction
of alkyl halide or tosylate using alkali fluorides in polar aprotic
solvents is the most general method for synthesizing primary
and secondary alkyl fluorides. Numerous approaches using the
phase-transfer system, alcohol additives,8 ionic liquids,9 crown
ethers,10 and bulky ammonium salts11 to promote the poor
nucleophilicity of fluoride ion have been reported. Despite
these advances, the tertiary alkyl−F bond, which is difficult to
form via the nucleophilic fluorination reactions, remains a
challenge. Fluoride is a small ion that has high electronegativity
with decreasing nucleophilicity. It also tightly solvates with
protic solvents to decrease the nucleophilicity. Therefore, the
nucleophilic fluorination reactions have significant limitations in
terms of high-temperature conditions, limited substrates, and
solvents. However, recently, progress in this research has been
seen in the development of methods for forming sp3 C−F
bonds. Gilmour and Jacobsen developed 1,2-difluorination of
alkenes by the combination system with nucleophilic fluorine
sources/an oxidant/an aryl iodide catalyst, independently.12
Nishikata disclosed site-selective tertiary alkyl−fluorine bond
formation of α-bromoamides using CsF under copper
catalysis.13 An iron(II)-catalyzed aminofluorination of inactive
olefins using a fluorine ion formed by a complex of Et3N·3HF
and XtalFluor-E to afford β-fluoro amino products was reported
by Xu.14 To the best of our knowledge, an operationally simple
Scheme 1. Hydrofluorination of 3-Bromooxindole
Derivatives
interactions between HF and 3-butyl-1-methylimidazolium
tetrafluoroborate [bmim][BF4] is also discussed on the basis
of energy calculations.
The oxindole scaffold can be found in a tremendous number
of natural compounds as well as in biological active
compounds.16 The incorporation of fluorine atom into the
oxindole nucleus is valuable in medicinal chemistry. Since the
potential of 3-bromooxindoles as precursors of highly reactive
electrophilic o-azaxylylenes was reported in 1964,17
a
tremendous number of reactions with C, O, N, and S
nucleophiles have been developed.18 Given nucleophiles for
hydrofluorination of o-azaxylylenes, hydrogen fluoride is the
classical nucleophilic fluorinating reagent, but it must be
Received: March 26, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00887
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Organic Letters
Letter
handled carefully due to its hazardous gas. Currently available
HF-based reagents such as Olar’s reagent (HF−pyridine),
Et3N−HF, and poly(hydrogenfluoride)complex are less toxic
and easier to handle. Accordingly, we envisaged that an
operationally simple electrophilic fluorination of o-azaxylylene
intermediates is enabled by the use of such HF-based reagents.
We initially examined the hydrofluorination of 3-benzyl-3-
bromooxindole (4a) as a model substrate employing HF-based
reagents as a fluorine source in the presence of base (Table 1).
Et3N·3HF and base (5.0 equiv) provided a higher yield of 5a
(52%, entry 8). The reaction scale was increased from 0.1 to 1.0
mmol to 58% yield. The absence of base resulted in no product,
which suggests that base is necessary for dehydrobromination
of 4a to generate o-azaxylylene intermediates (entry 9). Upon
screening of fluorine sources including alkali fluorides, we
found that Et3N·3HF is the most proper nucleophile in
comparison to HF reagents based on pyridine and DMPU
(entries 10 and 11). Moreover, KF and CsF were evaluated,
and use of them afforded the fluorinated product in 31% and
35% yield, respectively (entries 12 and 13).
Table 1. Optimization of Hydrofluorination of 5a
We next investigated the influence of counterions of ionic
liquids (entries 14 and 15). When [bmim][NTf2] was used, we
obtained a result similar to that using [bmim][BF4]. The
hydrofluorination reaction in [bmim][OTf] gave a lower yield
(21%). Subsequently, we executed the recycling of solvent with
the optimized conditions in hand. After the reaction was
completed, 5a and byproducts were extracted with diethyl ether
from the ionic liquid followed by filtration through a Millipore
millex-lg. After drying under vacuum, [bmim][BF4] could be
reused for this hydrofluorination reaction. We have performed
three runs and obtained similar yields.
a
entry
fluorine source
X (equiv)
solvent
THF
yield (%)
1
2
Et3N·3HF
Et3N·3HF
Et3N·3HF
Et3N·3HF
Et3N·3HF
Et3N·3HF
Et3N·3HF
Et3N·3HF
Et3N·3HF
Py·HF
2
2
2
2
2
5
2
5
5
3
3
2
2
5
5
ND
ND
ND
29
DMSO
b
3
MeOH
We investigated the scope of 3-bromooxindole derivatives
(Scheme 2). 3-Benzyl-3-bromooxindoles 4b−e bearing differ-
4
5
6
7
8
CH2Cl2
MeCN
31
MeCN
31
Scheme 2. Scope of Hydrofluorination of Various 3-
Bromooxindoles
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][NTf2]
[bmim][OTf]
41
c
52 (58)
d
9
ND
3
10
11
12
13
14
15
DMPU·HF
KF
13
31
35
53
21
CsF
Et3N·3HF
Et3N·3HF
a
Determined by 19F NMR with fluorobenzene as an internal standard.
b
3-Methoxyoxindole as a main product was obtained in 55% yield (see
c
the Supporting Information for details). Yield in parentheses for the
reaction performed on a 1 mmol scale. Conducted in absence of
d
K3PO4. ND = not determined, Py = pyridine, DMPU = N,N′-
dimethylpropyleneurea.
The mixture of 4a and 2 equiv of Et3N·3HF and K3PO4 in
various solvents at room temperature was stirred for 36 h.
Extensive experiments revealed that the yield of product 5a was
greatly affected by the used solvent. Neither THF nor DMSO
was effective (entries 1 and 2). A protic solvent, MeOH, was
employed as a nucleophile to predominantly give a
corresponding 3-methoxyoxindole in 55% isolated yield
(entry 3). The fluorination reactions in dichloromethane or
MeCN produced the product 5 in 29% or 31% yield (entries 4
and 5). In MeCN, the increased yield was not observed by
addition of a large excess amount of fluorine source and base
(entry 6). Ionic liquids containing imidazolium cations have
been widely recognized as a useful reaction media not only the
for an ecofriendly recyclable solvent to replace volatile organic
solvents but also the for acceleration of reaction rate and
improvement of selectivity. It has also been reported for various
ionic liquid-mediated chemical transformations including SN2
fluorination reactions and halofluorination of alkenes.9 There-
fore, an ionic liquid [bmim][BF4] as a reaction medium was
employed to this reaction. As expected, ionic liquid-mediated
hydrofluorination of 4a increased to 41% yield (entry 7). In
addition to use of [bmim][BF4], addition of excess amount of
a
MeCN was used instead of [bmim][BF4].
ent electronic substituents (R = Br, CN, CF3, OMe) and 3-
benzyl-3,5-dibromooxindoles bearing different electronic sub-
stituents (R = Me, Et, iPr, Cl) were tolerable, giving the
corresponding products in 44−71% yields. The reactions of
4j−m bearing naphthalene, benzothiophene, and furan moieties
provided the corresponding products 5j−m in 40−62% yields.
Compound 5n bearing a pyridine ring was not an efficient
substrate for this hydrofluorination reaction. Syntheses of
B
DOI: 10.1021/acs.orglett.7b00887
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
aliphatic substituted 3-fluorooxindoles 5o,p were successful.
The presence of a bulky tert-butyl group resulted in a slightly
lower yield of 5p (39%). The hydrofluorination of 3-bromo-3-
phenyloxindole (4q) favored MeCN as the reaction medium
over ionic liquid. The hydrofluorination of 4q in MeCN
proceeded and gave the desired product 5n in 49% yield. In the
case of [bmim][BF4], rapid decomposition of 4q was observed.
BMS 204352 (MaxiPost), a potassium channel opener for the
treatment of stork, was developed.19 The structure is
characterized by an important three-component aromatic
oxindole and a fluorine atom at the 3-position of oxindole. A
large number of synthetic methods of BMS 204352 have been
reported to date. Most of those approaches for the
incorporation of fluorine atom are the electrophilic fluorination
reactions with electrophilic reagents such as Selectfluor and
NFSI. We thus attempted an approach for synthesis of BMS
204352 through the nucleophilic fluorination reaction. The
hydrofluorination of 3-bromooxindole 4s and the an analogue
4r with Et3N·3HF in [bmim][BF4] proceeded smoothly to give
the corresponding product 5r and racemic BMS 204352 (5s) in
64 and 70% yield, respectively. When MeCN was used instead
of [bmim][BF4], the yield of 5s was decreased to 21%.
Scheme 4. Scope of Nucleophiles
a
Nucleophile 2,2,2-trifluoroethanol was used as a solvent.
In order to further understand this transformation, we also
carried out experiments as shown in Scheme 3. To examine in
Figure 1. Hydrogen bonds in optimized geometry of HF and
[bmim][BF4].
Scheme 3. Control Experiments with 4a and 7
Interestingly, the bond length of HF is enlarged at 0.95 Å from
0.91 Å. The reason is that a counterpart [BF4] of the
imidazolium cation plays a role as a Brønsted base in drawing
the hydrogen of HF. Relevant reports about DFT studies of the
chelation of CsF with ionic liquids suggest that a counteranion
of ionic liquids neutralizes the Coulombic influence of Cs+ on
F−, enhancing SN2 fluorination reactions. The argument is very
similar to that of our calculation results. Taken together, these
results support a mechanism including the formation of
electrophilic o-azaxylylenes from 3-bromooxindole derivatives
and ionic liquid-mediated H−F bond activation.
In summary, we have developed the ionic liquid-mediated
hydrofluorination of o-azaxylylenes in situ generated from 3-
bromooxindoles using mild HF-based reagents under mild
conditions. In these reactions, synthesis of fluorinated
compounds for industrial purposes with nucleophilic is
noteworthy in terms of cost and atom economy because the
nucleophilic reagents such as alkaline fluorides and HF-based
reagents are usually less expensive than electrophilic reagents.
This operationally simple method provides access to a series of
3-fluorooxindole compounds which would be biologically
relevant compounds. Moreover, the mechanistic study based
on energy calculations revealed the enlargement of the H−F
bond length. Applications with synergetic effects of HF/
[bmim][BF4] in nucleophilic fluorination reactions are under-
way.
situ generation of reactive o-azaxylylene intermediate 6, the
reaction of 4a in [bmim][BF4] or MeCN in the presence of
K3PO4 without HF reagents was performed. The intermediate
6 would be formed in situ, but the evident decomposition of 4a
was merely observed due to its instability. Additionally, the
reaction of N-(ethoxycarbonyl)-3-bromooxindole 7 as a
substrate under standard conditions was performed, it did not
proceed at all. To this end, when a variety of O, S, and N
nucleophiles were used instead of HF reagents, these reaction
without ionic liquids successfully provided access to the
corresponding products (Scheme 4). Overall, these results
show that the intermediate 6 plays an important role as an
electrophile to react with HF reagent. As illustrated in Table 1,
ionic liquids have effects on the hydrofluorination of 3-
bromooxindole derivatives, gaining the higher yield of
fluorinated products, in contrast to the corresponding reactions
in common organic solvents.
We thus hypothesized that ionic liquids aid H−F bond
cleavage to accelerate the reaction with o-azaxylylene. Hydro-
gen bonds associated with interaction between HF and
[bmim][BF4] in optimized geometry at the MPW1K/6-311+
+G** level of theory are calculated (Figure 1).20 The results
show that the C2-acidic proton of [bmim] binds to the fluoride
of HF, which seems to partially decrease its nucleophilicity.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00887.
General experimental procedures and characterization
date for new compounds (PDF)
C
DOI: 10.1021/acs.orglett.7b00887
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
10795. (d) Lee, E.; Hooker, J. M.; Ritter, T. J. Am. Chem. Soc. 2012,
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: s-mizuta@nagasaki-u.ac.jp.
ORCID
Satoshi Mizuta: 0000-0002-9023-7671
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was supported financially by Grants-in-Aid for
Scientific Research (No. 26713041) from the Japan Society for
Promotion of Science (JSPS) and the Program of the network-
type Joint Usage/Research Center for Radiation Disaster
Medical Science of Hiroshima University, Nagasaki University,
and Fukushima Medical University.
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