Decarboxylative Fluorination of Electron-Rich Heteroaromatic Carboxylic Acids with Selectfluor

Article abstract of DOI:10.1021/acs.orglett.7b00335

A transition-metal-free decarboxylative fluorination of electron-rich five-membered heteroaromatics, including furan-, pyrazole-, isoxazole-, thiophene-, indole-, benzofuran- and indazolecarboxylic acids, with Selectfluor is reported. Fluorinated dimer products were observed for nitrogen-containing heteroaromatic carboxylic acids, such as indole and pyrazole. An effective method has been developed to synthesize the monomer of 2- and 3-fluoroindoles with Li₂CO₃ as base at low temperature.

Full text of DOI:10.1021/acs.orglett.7b00335

Letter
pubs.acs.org/OrgLett
Decarboxylative Fluorination of Electron-Rich Heteroaromatic
Carboxylic Acids with Selectfluor
Xi Yuan, Jian-Fei Yao, and Zhen-Yu Tang*
Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha
410083, China
S
* Supporting Information
ABSTRACT: A transition-metal-free decarboxylative fluorina-
tion of electron-rich five-membered heteroaromatics, including
furan-, pyrazole-, isoxazole-, thiophene-, indole-, benzofuran- and
indazolecarboxylic acids, with Selectfluor is reported. Fluorinated
dimer products were observed for nitrogen-containing hetero-
aromatic carboxylic acids, such as indole and pyrazole. An
effective method has been developed to synthesize the monomer of 2- and 3-fluoroindoles with Li2CO3 as base at low
temperature.
ncorporation of fluorine into a target molecule has a
considerable impact on the molecule’s reactivity, selectivity,
Scheme 1. Decarboxylative Fluorination Strategy of
Electron-Rich Heteroarenes
I
biological activity, and physical properties.1 This is especially
true in medicinal chemistry, where fluorine is often employed
as a bioisostere of hydrogen and where many important drug
compounds also feature heteroaromatic rings.2 Fluorine-
containing, electron-rich, five-membered heteroarenes have
been widely investigated in agrochemical, pharmaceutical, and
material sciences.3 For example, penflufen is 5-fluoropyrazole
with antifungal/antimicrobial properties in plant protection.4
Early development of decarboxylative fluorination of alkyl
carboxylic acids employed toxic F2 or XeF2.5 Recently, various
elegant examples of decarboxylative fluorination of Csp3
carboxylic acids have been developed as effective methods to
construct C−F bonds. For example, the groups of Sammis, Li,
Gouverneur, Groves, MacMillan, and Ye have developed
decarboxylative fluorination of alkyl or aryloxy carboxylic
acids by Hunsdiecker-type fluorination and photofluorina-
tion.6−8 The Hu and Hartwig groups greatly extended scope of
this reaction to generate trifluoromethyl aryl ethers.9 Our group
has developed a transition-metal-free decarboxylative fluorina-
tion of cinnamic acids.10 Despite these remarkable advances in
decarboxylative fluorination of Csp3 carboxylic acids, general
methods for Csp2, such as aryl and heteroaromatic, carboxylic
acids, remains less developed.
represents the first general method for decarboxylative
fluorination of aryl carboxylic acids.
Our study commenced with the model reaction between
benzofuran-2-carboxylic acid 1a and Selectfluor (Table 1).12,13
Transition-metal-catalyzed methods (entry 1), including those
of Li et al.,7a hardly resulted in formation of the desired product
2a, presumably because of Ag(I) or Cu(I) metal coordination
to the heteroatom and the neighboring carboxylic group to
form insoluble silver or copper carboxylate.8a We found that
simply mixing 1a with Selectfluor at 70 °C in acetonitrile
(MeCN) and water (2:1) afforded a 35% yield (entry 2).
Screening of solvents showed that hydrophobic solvents such as
ethyl acetate and cyclohexane were better than hydrophilic
solvents, such as THF and dioxane (entries 5−10 vs 2−4).
Neither pure organic solvent nor pure water as solvent
provided any desired product. Weak bases were better than
Selective introduction of fluorine to the different sites of
heteroarenes represents another challenge in synthesis. For
example, direct electrophilic fluorination of electron-rich
heteroarenes normally occurs at the β-position (Scheme 1).11
It is of great interest to develop a new strategy to install fluorine
at the α-position of five-membered heteroarenes, which cannot
be accessed by electrophilic substitution. Herein, we disclose a
general decarboxylative fluorination of a broad range of furan-,
pyrazole-, isoxazole-, thiophene-, indole-, benzofuran-, and
indazole-2- and 3-carboxylic acids with inexpensive, bench
stable, and commercially available Selectfluor under mild
conditions. This method, to the best of our knowledge,
Received: February 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00335
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of Decarboxylative Fluorination of
Benzofuran-2-carboxylic Acid
Scheme 2. Decarboxylative Fluorinations of Furan-,
Thiophene-, Benzofuran-, Isoxazole-, Pyrazole-, and
Indolecarboxylic Acids
a,b
a
entry
solvent
MeCN
base
none
yield (%)
c
1
0
34
57
39
46
48
63
67
75
79
52
37
4
2
MeCN
THF
KF
3
KF
4
dioxane
toluene
hexane
cyclohexane
ethyl acetate
CH2Cl2
DCE
KF
5
KF
6
KF
7
KF
8
KF
9
KF
10
11
12
13
14
15
16
17
18
19
20
KF
DCE
NaF
CsF
DCE
DCE
NaOH
LiOAc
Li2CO3
Li3PO4
NaHCO3
HCOONa
NaCl
none
KF
DCE
71
19
61
22
71
39
35
0
DCE
DCE
DCE
DCE
DCE
DCE
d
21
DCE
e
22
DCE
KF
72
77
f
23
DCE
KF
a
Conditions: 1a (0.2 mmol), Selectfluor (0.4 mmol), base (0.8 mmol),
b
solvent/H2O (0.6 mL:1.2 mL), 70 °C, 15 h. 19F NMR yield based on
4-fluorotoluene as internal standard. 10% AgNO3 as catalyst. NSFI
or NFPY as fluorinating reagent. 50 °C. 90 °C.
c
d
e
f
a
Conditions: 1 (1 mmol), Selectfluor (2 equiv), KF (4 equiv), DCE
b
3.3 mL, H2O 1.7 mL, 70 °C, 15 h, isolated yields. Cyclohexane as
c
solvent, rt, 7 h. Yields determined by 19F NMR with 4-fluorotoluene
strong bases such as sodium hydroxide, which led to Selectfluor
decomposition. Further optimization with different lithium,
sodium, and potassium bases revealed potassium fluoride
(entries 10−19) as the best base with 79% yield. Alternative
electrophilic fluorination reagents, such as N-fluorobenzene-
sulfonimide (NSFI) and 1-fluoropyridium tetrafluoroborate
(NFPY), produced no product for this transformation (entry
21). At last, reactions at different temperatures were tested, and
70 °C was proved to be the best temperature (entries 23 and
24) for substrate 1a. Overall, the optimal combination of base
and solvent was the key for this reaction.
With the optimized conditions in hand, we explored the
substrate scope with different combinations of base, solvent,
and temperature. As summarized in Scheme 2, a range of
electron-rich heteroarenes, such as furan-, pyrazole-, isoxazole-,
thiophene-, indole-, benzofuran-, and indazolecarboxylic acids,
successfully underwent decarboxylative fluorination with
Selectfluor. Benzofuran-2-carboxylic acids with both electron-
rich (1b) and electron-deficient (1c−e) substitutions were
readily fluorinated with satisfactory yields (40%−77%). 2-
Furancarboxylic acids (1f and 1g) were fluorinated smoothly as
seen, but the reaction of 1f reacted much faster than 1g, and the
reaction had to be limited to 7 h in cyclohexane at room
temperature. Either elongation of reaction time or increased
temperature reduced the yield. Both electron-donating (1h and
1i) and electron-withdrawing substrates (1j and 1k) of
thiophene-2-carboxylic acids underwent the fluorination with
modest yields in cyclohexane. Only one example of
d
e
f
as internal standard. Cyclohexane as solvent. LiOAc as base. LiOAc
g
as base, EtOAc as solvent. Minor product yields lower than 10%
determined by 19F NMR.
benzothiophene-2-carboxylic acid (1l) resulted in the formation
of desired product (2l, 65%). Methyl-protected indazole-3-
carboxylic acid 1m served as the sole example of pyrazole-3-
carboxylic acids to accomplish this transformation successfully.
Fully substituted pyrazole-5-carboxllic acids with different
protecting groups (1n−q) were tested. Substrates with
electron-rich protecting groups such as methyl and benzyl
groups provided slightly higher yields than unprotected ones.
However, the phenyl-protected substrate (1q) did not afford
any product. Fully substituted pyrazole-4-carboxylic acid (1r)
was fluorinated with satisfactory yield, although pyrazole-3-
carboxylic acids with similar structures did not work for this
strategy. In the meantime, the decarboxylative fluorination of
isoxazolecarboxylic acids only occurred on the 5-position (1s).
Decarboxylative fluorination of indole-3-carboxylic acids (1t
and 1u) resulted in multiple products with low yields due to the
thermal instability of 3-fluoroindole at 70 °C in the basic
solution.14 Various 3-substituted pyrazole-5-carboxylic acids,
including methyl-/ethyl-protected and phenyl-substituted,
formed 5-fluorinated dimer products (3x−z) as the only
products with a 4,4′-linkage in remarkable yields (70%−82%)
in cyclohexane. Decarboxylative fluorination of both unpro-
tected and methyl-protected indole-2-carboxylic acids (1aa−af)
B
DOI: 10.1021/acs.orglett.7b00335
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
resulted in primarily 3,3′-linked dimers (3aa−af, 40%−58%)
and less than 10% monomeric product (2aa−af) with LiOAc as
base. Substrates with an electron-donating group produced
slightly higher yields than the substrates with electron-deficient
groups.
Scheme 3. Mechanistic Insights
Although the decarboxylative fluorinations of indolecarbox-
ylic acids were successful, the major products, 3,3′-linked
fluoroindoles, have limited applications in the synthetic field. In
addition, the yields of sensitive 3-fluoroindoles are relatively
low under current conditions. We began efforts toward the
syntheses of monomeric 2-fluoroindole with indole-2-carboxylic
acid 1aa as the model compound (entry 1, Table 2). Different
Table 2. Syntheses of 2-Fluoroindole Monomers
yield (%)
entry
base
temp (°C)
2aa
3aa
ratio (2aa/3aa)
a
1
LiOAc
70
70
70
70
0
10
18
16
29
45
49
52
40
31
30
18
13
10
9
1:4.0
1:1.7
1:1.9
1.6:1
3.5:1
4.9:1
5.8:1
a
2
Li3PO4
NaF
a
3
a
4
NaHCO3
NaHCO3
Na2CO3
Li2CO3
b
conducted. Radical scavenger TEMPO did not significantly
affect the yield under standard conditions (Scheme 3B). This
result is contrary to our previously reported decarboxylative
fluorinations of cinnamic acids.10 Due to the biphasic nature of
our methods, TEMPO might stay in the organic phase, which is
a hydrophobic solvent. Selectfluor is liberated from the effect of
TEMPO with the deprotonated heteroaromatic acids in the
aqueous phase, where both decarboxylation and fluorination
occur. After the reaction, the fluorinated products were
extracted into the organic phase. 19F NMR studies revealed
no fluorinated intermediates except Selectfluor in the aqueous
phase and the desired products in the organic phase (see
Supporting Information). In the dimer formation control
experiment, the presence of 2-fluoroindole (2aa) did not
improve the dimer yield and was not consumed under standard
conditions (Scheme 3C), which implied that 2-fluoroindole was
unlikely the starting material for formation of dimer 3aa
through Friedel−Crafts-type dimerization. In addition, we
5
b
6
0
b
7
0
a
Standard conditions: 0.2 mmol scale, solvent/H2O (1.2 mL/0.6
b
mL), Selectfluor (0.4 mmol), base (0.8 mmol), 70 °C, 24 h. Li2CO3
as base, 0 °C. MeCN as solvent. EtOAc as solvent.
c
d
bases were extensively screened (see Table S3). Lithium and
sodium bases were identified as base choices to increase the
selectivity (entries 2−4). Lowering the temperature to 0 °C
with lithium carbonate afforded the best selectivity of 5.8:1
(entry 7) and higher combined yields (62% vs 50%, entry 7 vs
1). Various indole-2- or -3-carboxylic acids were tested with
Li2CO3 as base at 0 °C.
Electron-rich indole-2-carboxylic acids 1ab resulted in better
selectivity and combined yields than electron-deficient substrate
1ac. For the unstable 3-fluoroindole syntheses, the low-
temperature method greatly improved both the selectivities
and yields (2v, 2w, and 2ag). As an example, the
decarboxylative fluorination of benzyl group protected indole-
3-carboxylic acid produced the desired 2ag as the sole product
with 87% yield.
The ability to conduct the decarboxylative fluorination on a
gram scale was accessed. The fluorination of ethyl-protected
pyrazole 5-carboxylic acid 1y on a 1 g scale produced 627 mg of
4,4′-linked dimerized product 3y (76% yield, Scheme 3A).
Silver-catalyzed Hunsdiecker-type and photocatalyzed de-
carboxylative fluorinations of alkyl or aryloxy carboxylic acids
involve organic radical intermediates and electrophilic fluori-
nating reagents. However, it is not easy for aryl carboxylic acids
to generate aryl radicals through a decarboxylative strategy. To
investigate the mechanism, a series of control experiments were
1
isolated about 10% of oxindole as the byproduct. H NMR
studies demonstrated that the formation of oxindole was in
proportional to the formation of fluorinated dimer product,
which implied they might go through a similar reaction
pathway. From kinetic studies, oxindole was not consumed in
the reaction and cannot be intermediate. The literature
demonstrated that treatment of indole-2-carboxylic acid with
electrophilic chlorinating reagents afforded 3,3-dichloro-oxin-
dole after decarboxylation.15 Selectfluor acts not only as an
initiator of electrophilic decarboxylation but also as a
fluorinating agent for the decarboxylative fluorination. How-
ever, the mechanism of this transformation remains unknown
and requires further investigation.
In conclusion, we have developed the first general method
for decarboxylative fluorination of aryl carboxylic acids.
Selectfluor and the combination of base, solvent, and
temperature were the keys for the decarboxylative fluorination
of electron-rich heteroaromatic carboxylic acids such as furan-,
pyrazole-, isoxazole-, thiophene-, indole-, benzofuran-, and
indazolecarboxylic acids under mild conditions. Efforts to
C
DOI: 10.1021/acs.orglett.7b00335
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chem. Soc. 2015, 137, 5654. (c) Wu, X.; Meng, C.; Yuan, X.; Jia, X.;
Qian, X.; Ye, J. Chem. Commun. 2015, 51, 11864.
achieve other decarboxylative functionalizations of heteroar-
omatic carboxylic acids are ongoing.
(8) (a) Huang, X.; Liu, W.; Hooker, J. M.; Groves, J. T. Angew.
Chem., Int. Ed. 2015, 54, 5241. (b) Li, J.; Li, Y. L.; Jin, N.; Ma, A. L.;
Huang, Y. N.; Deng, J. Adv. Synth. Catal. 2015, 357, 2474. (c) Patel, N.
R.; Flowers, R. A., III J. Org. Chem. 2015, 80, 5834. (d) Mizuta, S.;
Stenhagen, I. S. R.; O'Duill, M.; Wolstenhulme, J.; Kirjavainen, A. K.;
Forsback, S. J.; Tredwell, M.; Sandford, G.; Moore, P. R.; Huiban, M.;
Luthra, S. K.; Passchier, J.; Solin, O.; Gouverneur, V. Org. Lett. 2013,
15, 2648. (e) Phae-nok, S.; Soorukram, D.; Kuhakarn, C.; Reutrakul,
V.; Pohmakotr, M. Eur. J. Org. Chem. 2015, 2015, 2879.
(9) (a) Zhou, M.; Ni, C.; He, Z.; Hu, J. Org. Lett. 2016, 18, 3754.
(b) Zhang, Q.-W.; Brusoe, A. T.; Mascitti, V.; Hesp, K. D.; Blakemore,
D. C.; Kohrt, J. T.; Hartwig, J. F. Angew. Chem., Int. Ed. 2016, 55, 9758.
(10) Li, C.-T.; Yuan, X.; Tang, Z.-Y. Tetrahedron Lett. 2016, 57, 5624.
(11) For reviews, see: (a) Janin, Y. L. Chem. Rev. 2012, 112, 3924.
(b) O’Leary, E. M.; Jones, D. J.; O’Donovan, F. P.; O’Sullivan, T. P. J.
Fluorine Chem. 2015, 176, 93. For electrophilic substitution, see:
(c) Makino, K.; Yoshioka, H. J. Fluorine Chem. 1988, 39, 435.
(d) Barton, D. H. R.; Hesse, R. H.; Jackman, G. P.; Pechet, M. M. J.
Chem. Soc., Perkin Trans. 1 1977, 2604. (e) Lin, R.; Ding, S.; Shi, Z.;
Jiao, N. Org. Lett. 2011, 13, 4498.
(12) (a) Forrest, A. K.; O’Hanlon, P. J. Tetrahedron Lett. 1995, 36,
2117. (b) Phillips, E.; Li, Y.; Chang, H.-F. US Pat. Appl.
US20050176745 A1, 2005.
(13) (a) Wang, J.; Scott, A. I. J. Chem. Soc., Chem. Commun. 1995,
2399. (b) Hu, J.; He, Z. Faming Zhuanli Shenqing (Chinese).
102219638, 2011.
(14) Torres, J. C.; Garden, S. J.; Pinto, A. C.; da Silva, F. S. Q.;
Boechat, N. Tetrahedron 1999, 55, 1881.
(15) (a) Foglia, T. A.; Swern, D. J. Org. Chem. 1968, 33, 4440.
(b) Bass, R. J. Tetrahedron 1971, 27, 3263.
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.7b00335.
Experimental procedures, mechanistic studies, com-
pound characterization,and spectroscopic data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zytang@csu.edu.cn.
ORCID
Zhen-Yu Tang: 0000-0002-3972-5047
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the National Natural Science
Foundation of China (21302231), Hunan Provincial Natural
Science Foundation of China (14JJ3021), and Ph.D. Programs
of the Foundation of Ministry of Education of China
(20130162120032). We thank the Open-End Fund for the
Valuable and Precision Instruments of Central South University
for NMR assistance. X.Y. thanks the Fundamental Research
Funds for the Central Universities of Central South University.
REFERENCES
■
(1) For reviews, see: (a) Liang, T.; Neumann, C.; Ritter, T. Angew.
Chem., Int. Ed. 2013, 52, 8214. (b) Champagne, P. A.; Desroches, J.;
Hamel, J. D.; Vandamme, M.; Paquin, J. F. Chem. Rev. 2015, 115,
9073. (c) Campbell, M. G.; Ritter, T. Chem. Rev. 2015, 115, 612.
(2) For reviews, see: (a) Park, B. K.; Kitteringham, N. R.; O’Neill, P.
M. Annu. Rev. Pharmacol. Toxicol. 2001, 41, 443. (b) Vulpetti, A.;
Dalvit, C. Drug Discovery Today 2012, 17, 890. (c) Gillis, E. P.;
Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med.
Chem. 2015, 58, 8315.
(3) For reviews, see: (a) Isanbor, C.; O’Hagan, D. J. Fluorine Chem.
2006, 127, 303. (b) Wang, J.; Sanchez -Rosello, M.; Acena, J. L.; del
Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H.
Chem. Rev. 2014, 114, 2432. (c) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.;
Zhu, W.; Acena, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Chem. Rev.
2016, 116, 422.
(4) For penflufen, see: Dunkel, R.; Elbe, H.-L.; Greul, J.; Hartmann,
B.; Gayer, H.; Seitz, T.; Wachendorff-Neumann, U.; Dahmen, P.;
Kuck, K.-H. Patent WO 2006061215, 2006.
(5) (a) Grakauskas, V. J. Org. Chem. 1969, 34, 2446. (b) Patrick, T.
B.; Johri, K. K.; White, D. H. J. Org. Chem. 1983, 48, 4158. (c) Patrick,
T. B.; Khazaeli, S.; Nadji, S.; Hering-Smith, K.; Reif, D. J. J. Org. Chem.
1993, 58, 705.
(6) (a) Leung, J. C. T.; Chatalova-Sazepin, C.; West, J. G.; Rueda-
Becerril, M.; Paquin, J. F.; Sammis, G. M. Angew. Chem., Int. Ed. 2012,
51, 10804. (b) Rueda-Becerril, M.; Chatalova-Sazepin, C.; Leung, J. C.
T.; Okbinoglu, T.; Kennepohl, P.; Paquin, J. F.; Sammis, G. M. J. Am.
Chem. Soc. 2012, 134, 4026. (c) Rueda-Becerril, M.; Mahe, O.; Drouin,
M.; Majewski, M. B.; West, J. G.; Wolf, M. O.; Sammis, G. M.; Paquin,
J. F. J. Am. Chem. Soc. 2014, 136, 2637. (d) Leung, J. C. T.; Sammis, G.
M. Eur. J. Org. Chem. 2015, 2015, 2197.
(7) (a) Yin, F.; Wang, Z.; Li, Z.; Li, C. J. Am. Chem. Soc. 2012, 134,
10401. (b) Ventre, S.; Petronijevic, F. R.; MacMillan, D. W. C. J. Am.
D
DOI: 10.1021/acs.orglett.7b00335
Org. Lett. XXXX, XXX, XXX−XXX