Decarboxylative Fluorination of Arylcarboxylic Acids Promoted by ortho-Hydroxy and Amino Groups

Article abstract of DOI:10.1002/cjoc.201800016

A novel decarboxylative fluorination process has been developed for the synthesis of ortho-hydroxy/amino arylfluorides from salicylic acid analogs, in which the ortho-hydroxy/amino group plays an important role in the transformation. In addition, various arylfluorides are obtained in good to excellent yields under mild conditions.

Full text of DOI:10.1002/cjoc.201800016

Decarboxylative Fluorination of Arylcarboxylic Acids Promoted by
ortho-Hydroxy and Amino groups
†
a
†a
a
a
a
Dinghai Wang, Zheliang Yuan, Qilun Liu, Pinhong Chen, and Guosheng Liu*
ABSTRACT A novel decarboxylative fluorination process has been developed for the synthesis of ortho-hydroxy/amino arylfluorides from salicylic acid
analogs, in which the ortho-hydroxy/amino group plays an important role in the transformation. In addition, various arylfluorides are obtained in good to
excellent yields under mild conditions.
KEYWORDS metal-free, decarboxylative, fluorination, aryl carboxylic acids
Introduction
Organofluorine compounds have been widely used in
agrochemicals, pharmaceuticals, and materials, for introducing
fluorine atoms into organic molecules can significantly modify
their physical, chemical and biological properties. Traditional
approaches to aryl fluorides, such as Balz-Schiemann reaction
and Halex process , usually suffer from harsh conditions and
limited substrate scope. In recent years, transition-metal
catalyzed fluorination of aromatic compounds, has received much
attention (Scheme 1a). For instance, Buchwald and co-workers
reported a palladium-catalyzed cross-coupling reaction of aryl
triflates with CsF to afford fluoroarenes by using sterically
a) Transition metal-catalyzed cross-coupling fluorination
X
F
cat. Pd, Ag, Cu
Ar
Ar
X = OTf, halide, SnR3, Si(OR)3, B(OH)2
b) Decarboxylative fluorination of alkylcarboxylic acids
[
1]
[
2a]
[
2b]
[O]
- CO2
[F+]
R
R-F
R
COOH
R
COO
c) Decarboxylative fluorination of arylcarboxylic acids (this work)
[
3]
COOH
XH
COOH
F
+
[
F ]
X
R
[
4]
[4a]
[4b]
Ar
Ar
Ar
hindered phosphine ligands. Sanford
and Yu
described
1
int-I
2
direct oxidative fluorination of Aryl C-H bonds through a Pd(II/IV)
[5]
catalytic cycle. Ritter and coworkers reported a silver-catalyzed
Scheme 1. Synthesis of alkyl and aryl fluorides.
[
6]
fluorination of aryl stannanes with Selectfluor. In addition,
Hartwig, Sanford and our groups disclosed Cu-mediated or
catalyzed cross-coupling fluorination of aryl halides with AgF as a Results and Discussion
[
7]
nucleophilic fluorinating reagent.
Because carboxylic acids are very stable and readily available,
decarboxylative coupling reactions become a useful tool in
As part of our ongoing interest in transition metal-catalyzed
[14,15]
fluorination,
we set out to investigate the decarboxylative
fluorination of 2-hydroxy-1-naphthoic acid 1a under the catalysis
of metal catalysts, with Selectfluor as a strong electrophilic
fluorinating reagent (Table 1). As an efficient catalyst in
decarboxylative fluorination of aliphatic carboxylic acids, the
silver catalysts proved to be ineffective for the decarboxylation of
aryl carboxylic acids (entry 1). We were delighted to find that
trace the desired product 2a was obtained in the presence of a
[
8]
organic synthesis. Notably, recently radical fluorination has
been developed as a powerful method to construct C-F bonds.
Due to the thermodynamically favored radical decarboxylation
process, a series of decarboxylative fluorination reactions have
been developed, but substrates were limited to aliphatic
carboxylic acids (Scheme 1b). For instance, Sammis and
co-workers reported a photo-induced radical fluorination of alkyl
radicals which were generated from aliphatic carboxylic acids via
2
copper catalyst (Cu O), along with equal amounts of the
[
9 ]
difluorination product 2a' (entry 2). Further studies revealed that
addition of a base to our reaction could significantly improve the
yield, and different bases were examined for the decarboxylative
radical decarboxylation.
Li and co-workers developed a
silver-catalyzed decarboxylative fluorination of aliphatic
[
10]
carboxylic acids.
Despite these advances, compared to alkyl
3
fluorination (for details, see SI). Among them, NaHCO was
carboxylates, oxidative decarboxylative fluorination of aryl
carboxylic acids was extremely difficult, because of the much
higher oxidation potential of aryl carboxylates and their much
slower decarboxylation rate.
fluorination of aryl carboxylic acids, for the synthesis of aryl
fluorides, has never been reported. We speculated that, if an
ortho-hydroxy or amino group was introduced, aryl carboxylic
acid 1 would tautomerize to alkyl carboxylic acid int-I, which is
very prone to undergo oxidative decarboxylative fluorination to
give product 2 (Scheme 1c). Herein, we communicate the
oxidative decarboxylative fluorination of aryl carboxylic acids
promoted by ortho-hydroxy or amino groups under metal free
conditions.
proved to be the best choice and the reaction gave the desired
product 2a in 60% yield, along with trace amounts of the
difluorinated product 2a' (entry 3). Surprisingly, control
experiments showed that the reaction gave the desired product
2a in 85% yield in the absence of the metal catalyst (entry 4),
suggesting the C-F bond-forming is irrelevant with metal catalysts.
[
11 , 12 ]
Thus, the decarboxylative
[
13]
Further screening on the bases reveals that NaHCO
3
was the best
entries 4-9). While a worse result was obtained without the base
entry 10). Examining different electrophilic fluorinating reagents
(
(
indicated that NFSI, NFP-1, NFP-2 and NFP-3 were not suitable for
the reaction (entries 11-14). Either increasing or deceasing the
amount of the base and Selectfluor was not helpful to improve
the product yield (for details, see SI). Notably, the tethered
a
State Key Laboratory of Organometallic Chemistry, Center for Excellence in
E-mail: gliu@mail.sioc.ac.cn
Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences
†Webpage: http://guoshengliu.sioc.ac.cn
These authors contributed equally to this work.
Dedicated to Professor Xiyan Lu on the occasion of his 90 birthday
th
3
45 Lingling Road, Shanghai, 200032 (China)
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been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201800016
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ortho-hydroxy group is essential, and the decarboxylative reaction
of 1-naphthoic acid without ortho-hydroxy group didn't occur
under the optimized reaction conditions.
results, a series of 3-aminoquinoline-4-carboxylic acids 1t-1y were
tested under the standard reaction conditions. Excitingly, these
reactions proceeded smoothly to provide the fluorinated
aminoquinolines 2t-2y in good yields (52-75%). To demonstrate
the practicability of our reaction, a gram-scale reaction was
carried out, product 2l was obtained in an even higher yield
[
a]
Table 1. Optimization of reaction conditions.
(
93%). Unfortunately, the related acetamide substrates were
ineffective under the optimized reaction conditions.
[
a]
Table 2. Decarboxylative fluorination.
+
[
a] Reaction conditions: 1a (0.1 mmol), F (0.15 mmol), base (0.1
1
9
mmol) in THF (1 mL) at rt overnight. [b] FNMR yield using
3
N,N-dimethyltrifluoroacetamide (CF -DMA) as an internal
standard.
With the optimized conditions in hand, the substrate scope of
the decarboxylative fluorination reaction was then examined
(
Table 2). Firstly, various functional groups on the naphthalenyl
ring, such as methyl, bromide and methoxy, were compatible to
the reaction conditions and the corresponding products 2b-2d
were obtained in good to excellent yields. Lowering reaction
o
temperature to 0 C significantly inhibited the difluorination
[a] Reaction conditions: 1 (0.2 mmol), Selectfluor (0.3 mmol),
NaHCO (0.2 mmol) in THF (2 mL) at rt overnight, isolated yield.
[b] Reactions were conducted at 0 C. [c] The reaction was
conducted on a 2 g-scale.
reaction. For the substrate bearing both salicylic acid and simple
phenol, the reaction only underwent decarboxylative fluorination
to give the product 2e in 59% yield, and the phenol group was
intact. In addition, 1-hydroxy-2-naphthoic acid 1f was also
suitable for the decarboxylative fluorination reaction to give the
product 2f in 63% yield. Furthermore, electron-rich
3
o
Further transformations of these products were explored by
coupling reactions (Scheme 2). The triflated ester 3a derived from
the product 2l was selected. Under palladium-catalyzed
1
-hydroxy-2-benzoic acids can also be employed as substrates to
provide the corresponding products 2g-2h in moderate to good
yields. Unfortunately, the reactions of simple salicylic acids gave
trace decarboxylative fluorination products.
conditions,
3a
could
couple
with
phenylacetylene,
phenylmethanethiol and aryl boronic acids to deliver more
complex fluorinated quinolines 3b-3c in satisfied yields.
F
Ph
Inspired by the inherent interest of fluorinated heteroarenes
in drug discovery, next we focused on the decarboxylative
fluorination of quinoline-based aryl carboxylic acids with the
Ph
Pd(PPh ) /CuI, Et N
3
4
3
N
Ph
[
16
]
tethered ortho-hydroxy group.
As shown in Table 2,
3b 78%
3
-hydroxyquinoline -4-carboxylic acids 1i-1s were suitable
F
F
substrates for the decarboxylative fluorination reaction. The
reactions of substrates bearing alkyl or aryl groups at the
C2-position on the quinolinyl ring yielded the fluorinated products
OTf
Ph
HS
Ph
S
Ph
Pd2(dba)3/XantPhos
N
N
Ph
i-Pr2NEt
3a
3c 70%
2i-2n in excellent yields (75-90%). Meanwhile, various
CHO
F
substituents on the benzene ring, such as methyl, methoxy, and
chlorine, the reactions also proceeded smoothly to provide the
desired products 2o-2r in good yields (75-89%). In addition, a
thienyl group in quinolines can also be tolerated in the reaction,
giving the fluorinated product 2s in 70% yield. Based on these
OHC
B(OH)2
Pd(dppf)Cl2, Cs2CO3
N
Ph
3d 81%
Scheme 2. Further transformations of the product.
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To get some insight into the possible mechanism, some
preliminary experiments were performed. First, to demonstrate a
possible sequential decarboxylation and electrophilic fluorination
process, the substrate 4a was treated under standard conditions,
and the aromatization of int-IV to provide the desired product 2a.
For the two pathways, the oxidation of carboxylate ions to
carboxyl radicals exhibited much higher energy barrier than that
[
18]
of phenoxide, which supports the path b.
[
17]
no fluorinated product was observed (eq 1), which could rule
out this pathway. Meanwhile, the methylated substrate 4b also
failed to undergo decarboxylative fluorination, indicating that the
free hydroxy group is essential. Both reactions kept the substrates
remained. For an alternative tandem electrophilic fluorination
and decarboxylation process, the reaction rate of 4c was much
slower than that of 1a (Chart 1), and the product 5c was provided
O
O
O
O
F
O
O
OH
-
CO2
2
a
[F*]
int-IV
int-III
int-II
[
18 ]
in a low yield (eq 3).
These results suggested that the
Path A
COONa
OH
[
F*]
electrophilic fluorination is less likely. More importantly, we
found that addition of Tempo to our reaction completely
inhibited the decarboxylative fluorination process, suggesting a
possible radical pathway for the carboxylative fluorination.
NaHCO3
1
a-Na
Na
SelectFluor
COOH
OH
O
OH
O
O
H
O
NaHCO3
O
1
a
PCET
int-V
O
Cl
N
1
a-Na
Path B
F
N
2BF4
F
[F*]
OH
F
COOH
OH via int-IV
O
O
2a
int-VI
int-VII
Scheme 3. Proposed mechanism.
1
00
Conclusions
2
5
a (from 1a)
c (from 4c)
In conclusion, we have developed a novel protocol for the
synthesis of ortho-hydroxy/amino aromatic fluorides from
salicylic acid analogs through decarboxylative fluorination under
metal-free conditions. The reaction features excellent functional
group tolerance and a series of ortho-hydroxy/ amino (hetero)aryl
fluorides were synthesized in good to excellent yields.
80
60
40
20
0
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
0
33
66
100
133
Acknowledgement
Time (min)
We are grateful for the financial support from the National
Natural Science Foundation of China (24172219, 21532009,
21761142010 and 21790330), the National Basic Research
Program of China (973-2015CB856600), the strategic Priority
Research Program (XDB20000000), the Key Research Program of
Froniter Science (QYZDJSSW-SLH055), CAS, and the Science
Technology Commission of the Shanghai Municipality
(17XD140500 and 17JC1401200). This research was partially
supported by CAS Interdisciplinary Innovation Team.
Chart 1. The time course of the reactions of 1a (Table 2) and 4c
(eq 3) monitored by React-IR.
Based on these studies, two possible reaction pathways were
proposed for this decarboxylative fluorination. For the path a, the
substrate 1a would be deprotonated by a weak base to form the
carboxylate 1a-Na which might be oxidized by Selectfluor to
deliver the radical species int-II. Owing to the ortho-hydroxy or
amino group, the aryl carboxylate radical int-II could tautomerize
to a alkyl carboxylate radical int-III which then possibly undergoes
radical decarboxylation and fluorination to give species int-IV,
finally rearomatization of int-IV provides the desired product 2a.
Alternatively, in the presence of an oxidizing reagent, the
intermediate 1a-Na would undergo a proton-coupled electron
transfer (PECT) process to form phenoxy radical species int-V and
Selectfluor radical anions [F*]. After tautomerization, the radical
would delocalize from the oxygen to the α-carbon atom in
naphthols to give int-VI which proceeds radical Fluorination by
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1
19
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Accepted manuscript online: XXXX, 2017
Version of record online: XXXX, 2017
(
The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2017
Revised manuscript received: XXXX, 2017
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Entry for the Table of Contents
Page No.
Decarboxylative
Fluorination
of
Arylcarboxylic Acids Promoted by
ortho-Hydroxy and Amino groups
A novel decarboxylative fluorination process has been developed for the synthesis of
ortho-hydroxy/amino arylfluorides from salicylic acid analogs, in which the ortho-hydroxy/amino
groups play an important role in the transformation. In addition, various arylfluorides are obtained
in good to excellent yields under mild conditions.
Dinghai Wang, Zheliang Yuan, Qilun Liu,
Pinhong Chen, and Guosheng Liu*
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