Silver-catalyzed decarboxylative fluorination of aliphatic carboxylic acids in aqueous solution

Article abstract of DOI:10.1021/ja3048255

Although fluorinated compounds have found widespread applications in the chemical and materials industries, general and site-specific C(sp³)-F bond formations are still a challenging task. We report here that with the catalysis of AgNO₃, various aliphatic carboxylic acids undergo efficient decarboxylative fluorination with SELECTFLUOR reagent in aqueous solution, leading to the synthesis of the corresponding alkyl fluorides in satisfactory yields under mild conditions. This radical fluorination method is not only efficient and general but also chemoselective and functional-group- compatible, thus making it highly practical in the synthesis of fluorinated molecules. A mechanism involvinig Ag(III)-mediated single electron transfer followed by fluorine atom transfer is proposed for this catalytic fluorodecarboxylation.

Full text of DOI:10.1021/ja3048255

Communication
pubs.acs.org/JACS
Silver-Catalyzed Decarboxylative Fluorination of Aliphatic Carboxylic
Acids in Aqueous Solution
Feng Yin,‡,§ Zhentao Wang,‡,§ Zhaodong Li,† and Chaozhong Li*,†,‡
†Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. China
‡Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China
S
* Supporting Information
Products and Chemicals, Inc.)10 or N-fluorobis-
ABSTRACT: Although fluorinated compounds have
found widespread applications in the chemical and
materials industries, general and site-specific C(sp3)−F
bond formations are still a challenging task. We report here
that with the catalysis of AgNO3, various aliphatic
carboxylic acids undergo efficient decarboxylative fluorina-
tion with SELECTFLUOR® reagent in aqueous solution,
leading to the synthesis of the corresponding alkyl
fluorides in satisfactory yields under mild conditions.
This radical fluorination method is not only efficient and
general but also chemoselective and functional-group-
compatible, thus making it highly practical in the synthesis
of fluorinated molecules. A mechanism involvinig Ag(III)-
mediated single electron transfer followed by fluorine atom
transfer is proposed for this catalytic fluorodecarboxyla-
tion.
(benzenesulfonyl)imide (NFSI) provides a convenient entry to
site-selective monofluorination and can be highly enantioselec-
tive under transition-metal catalysis or organocatalysis.11,12
Nevertheless, the method is mainly restricted to the synthesis
of α-fluoro carbonyl compounds. The development of more
general and practical methods for site-specific C(sp3)−F bond
formation is certainly highly desirable.
In comparison with nucleophilic or electrophilic fluorination,
radical fluorination is far less explored. Not only its synthetic
potential but also the detailed mechanisms remain unclear. While
radical intermediates might be involved in the fluorodecarbox-
13
ylation of carboxylic acids with F2 or XeF2,14 these reactions
suffer from low efficiency and limited substrate scope.
Furthermore, the high toxicities and instabilities of these two
reagents prevented practical applications of these methods. Very
recently, Sammis and co-workers reported the fluorination of
alkyl radicals via the decomposition of tert-butyl peresters of
carboxylic acids with NFSI and SELECTFLUOR® reagent.15
However, this method requires the prior conversion of carboxylic
acids to peresters, and the reported efficiency for the fluorination
of primary alkyl radicals is low. In addition, the generality of this
method is unclear, and the simultaneous generation of highly
reactive tert-butoxyl radicals in this system is undesirable.
Herein we report that the silver-catalyzed decarboxylative
fluorination of aliphatic carboxylic acids with SELECTFLUOR®
reagent in aqueous solution provides a convenient, general, and
efficient method for site-specific C(sp3)−F bond formation. Our
extensive study using 2-ethyltetradecanoic acid (A-1) as the
model substrate revealed that with the catalysis of AgNO3 (20
mol %), the reaction of A-1 with SELECTFLUOR® reagent in
1:1 (v:v) acetone/H2O solution at refluxing temperature
(method A) for 3 h leads to the clean formation of the expected
product 3-fluoropentadecane (1) in 93% isolated yield (eq 1).
he introduction of fluorine atoms into organic molecules
T
significantly changes their physical, chemical, and biological
properties, and thus, fluorinated compounds have found
widespread applications in almost all aspects of the chemical
industry ranging from materials to agrochemicals and
pharmaceuticals.1 Moreover, 18F-labeled organic compounds
are clinically used as contrast agents for positron emission
tomography.2 However, despite fluorine’s importance, C−F
bond formation, especially site-specific monofluorination of
complex molecules, is still challenging.3,4 In particular, methods
for the general and site-specific formation of C(sp3)−F bonds are
limited, contrast to the recent significant progress in the
formation of aromatic C(sp2)−F bonds4,5 led by the Buchwald
group5a and the Ritter group.5b,c
Alkyl fluorides are mainly accessed by either nucleophilic or
electrophilic substitution reactions. However, the weak nucleo-
philicity of fluoride ions limits access to C−F bonds via direct
nucleophilic substitution reactions.6 The conversion of alkyl
alcohols to alkyl fluorides using (diethylamino)sulfur trifluoride
(DAST) or [bis(2-methoxyethyl)amino]sulfur trifluoride
(Deoxo-Fluor® reagent) is a common method for site-specific
monofluorination, but it often suffers from the competing
dehydration and rearrangement processes.7,8 The C(sp3)−F
reductive elimination from alkylgold(III) fluoride complexes also
proceeds via carbocation-like rearrangements, as reported by
Mankad and Toste.9 Electrophilic fluorination using fluorine
reagents such as 1-chloromethyl-4-fluorodiazoniabicyclo[2.2.2]-
octane bis(tetrafluoroborate) (SELECTFLUOR® reagent, Air
No decarboxylative hydrogenation or hydroxylation product
(pentadecane or pentadecan-3-ol) could be detected. Other
Ag(I) salts, such as AgBF4, AgOAc, and AgOTf, exhibited almost
the same catalytic behavior as AgNO3, while no reaction occurred
Received: May 17, 2012
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
without the presence of a Ag(I) salt. On the other hand,
bidentate silver complexes such as Ag(Phen)2OTf (Phen = 1,10-
phenanthroline) or Ag(BPy)2OTf (BPy = 2,2′-bipyridine) failed
to initiate the fluorodecarboxylation. Switching the fluorine
source from SELECTFLUOR® reagent to NFSI led to no
reaction at all. In addition to Ag(I) ions, water also proved to be
essential. No decarboxylation occurred in any of the anhydrous
organic solvents screened, including acetone, N,N-dimethylfor-
mamide, and dimethyl sulfoxide, even with the catalysis of
AgBF4, which has better solubility than AgNO3 in these solvents.
The fluorodecarboxylation was slightly slower in CH3CN/H2O
solution and did not proceed in biphasic systems such as C6H6/
H2O or ClCH2CH2Cl/H2O.
Table 1. AgNO3-Catalyzed Decarboxylative Fluorination of
Carboxylic Acids
With the optimized conditions (eq 1) in hand, we then set out
to explore the scope and limitations of the above method, and the
results are summarized in Table 1. Secondary alkyl carboxylic
acids underwent efficient decarboxylative fluorination to afford
the corresponding products 2−8. Both cis- and trans-2-
benzoylcyclohexanecarboxylic acid led to the formation of the
same fluoride 7 as a 1:1 mixture of two stereoisomers under the
same reaction conditions, implying that the two reactions
proceeded via the same intermediate. Tertiary alkyl carboxylic
acids were more reactive than secondary ones, and their reactions
proceeded smoothly even at room temperature, as exemplified
by the synthesis of fluorides 9−14 in high yields. In comparison,
primary alkyl carboxylic acids were less reactive. For example, the
reaction of stearic acid at refluxing temperature gave the expected
product 15 in only 20% yield, while about 70% of the stearic acid
was recovered. Nevertheless, increasing the amount of
SELECTFLUOR® reagent to 4 equiv increased the yield to
37%. Further adjustment of the water/acetone ratio allowed
fluoride 15 to be isolated in 56% yield, the major byproduct being
the decarboxylative hydrogenation product heptadecane, as
indicated by GC−MS. In a similar fashion, fluorides 16 and 17
were obtained in moderate yields. On the other hand, for
substrates having better solubility in water, the reaction could be
performed in pure water (method B). Thus, the reactions of N-
protected 3-aminopropanoic acid and 6-aminohexanoic acid with
SELECTFLUOR® reagent proceeded smoothly and cleanly in
warm water (∼55 °C), leading to the high-yield production of
functionalized primary alkyl fluorides 18 and 19, respectively. No
decarboxylative hydrogenation products could be observed in
these two cases. The use of water alone as the solvent also proved
advantageous in cases where the fluorinated products were
sensitive toward SELECTFLUOR® reagent.16 For example, the
fluorodecarboxylation of adamantane-1-carboxylic acid in water/
acetone solution at room temperature gave 1-fluoroadamantane
(21) in only 22% yield along with the formation of di- and
trifluorinated adamantanes in comparable amounts. However,
when the reaction was carried out in water, the expected product
21 was obtained in 67% yield. Similarly, α-heteroatom-
substituted alkyl fluorides 22−24 were synthesized in much
higher yields in water than in water/acetone. Presumably, the
poor water solubility of the product fluorides inhibits their
further reaction with SELECTFLUOR® reagent in water.
Unlike aliphatic carboxylic acids, aromatic acids such as
benzoic acid, 4-chlorobenzoic acid, and 2-nitrobenzoic acid failed
to give any desired products under the above experimental
conditions, with all of the starting acid being recovered in each
case.
a
Method A: acid (0.2 mmol), SELECTFLUOR® reagent (0.4 mmol),
AgNO3 (0.04 mmol), acetone (2 mL), H2O (2 mL), 10 h; reaction
temperature: reflux for 1−7 and 15−17, 45 °C for 8 and 14, rt for 9−
13. Method B: acid (0.2 mmol), SELECTFLUOR® reagent (0.4
b
mmol), AgNO3 (0.04 mmol), H2O (2 mL), 55 °C, 1−10 h. Isolated
c
yields based on the starting acid. Two stereoisomers in 72:28 ratio.
d
e
f
cis/trans = 50:50. 30 mol % AgNO3 was used. 4 equiv of
SELECTFLUOR® reagent was used, and the acetone/H2O ratio was
g
adjusted to 4:1. 1 equiv of SELECTFLUOR® reagent was used.
halide, ether, and aryl, which in turn encourages their application
to more complex organic molecules. For example, dehydroli-
thocholic acid derivatives A-25 and (+)-A-26 underwent
decarboxylative fluorination to give the corresponding products
25 and (+)-26 in high yields (eq 2).
It can also be inferred from Table 1 that the reactivity of
carboxylic acids decreases in the order tertiary > secondary >
primary ≫ aromatic. This reactivity pattern thus allows the
successful implementation of chemoselective fluorodecarbox-
ylation. For example, 2,2-dimethylpentanedioic acid (A-27)
underwent chemoselective decarboxylation to give the tertiary
alkyl fluoride 27 in almost quantitative yield (eq 3). Similarly, the
alkylic carboxyl groups in diacids A-28 and A-29 were selectively
The above results clearly demonstrate the generality of this
new method. The catalytic processes enjoy the tolerance of a
variety of functional groups, including amide, ester, carbonyl,
B
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Communication
Figure 1. Proposed Mechanism of Silver-Catalyzed Decarboxylative
Fluorination.
The Ag(II)- or Ag(III)-mediated decarboxylation of carboxylic
acids is well-documented.18,19 It is reasonable to assume that
Ag(III)−F has a reactivity similar to that of Ag(II) in
decarboxylation since the Ag−F bonding is substantially covalent
in Ag(III) and Ag(II) fluorides.20 While the fluorine atom
transfer from Ag(II)−F to an alkyl radical is unprecedented,
transition-metal-assisted halogen (Cl or Br) atom transfer, that is,
trapping of an alkyl radical by a complexed metal halide in a
higher oxidation state (Mn+1LmX) to give the alkyl halide and the
metal ion in a lower oxidation state (MnLm), is well-known.21 An
alternative explanation for the fluorine transfer would be an SET
mechanism involving oxidation of the alkyl radical to a
carbocation by Ag(II) with subsequent capture of the
carbocation by a fluoride anion. However, this is unlikely
because solvated F− is much less nucleophilic than H2O.
Another possibility for the fluorination would be fluorine
transfer from SELECTFLUOR® reagent to an alkyl radical. To
test this hypothesis, we designed the following experiments.
When 1-adamantanecarboxylic acid was treated with Ag-
(BPy)2S2O8 (200 mol %) and SELECTFLUOR® reagent (200
mol %) in acetone/H2O at room temperature, decarboxylation
occurred. However, only a trace amount of 1-fluoroadamantane
could be detected by GC−MS, as the major product was
adamantan-1-ol in 43% yield. This showed that the oxidation of
adamantyl radical by the Ag(II) complex is much faster than the
fluorine transfer to the adamantyl radical from SELECT-
FLUOR® reagent. In another set of experiments, tert-butyl 2-
ethyltetradecaneperoxoate (PE-1), the perester of acid A-1, was
used as the radical precursor (eq 7). The reaction of PE-1 with
removed while the benzoic carboxyl groups remained intact,
providing alkyl fluorides 28 and 29, respectively (eqs 4 and 5).
The above relative reactivities of carboxylic acids strongly
suggest that the reaction proceeds by an oxidative radical
decarboxylation mechanism. To provide further evidence of the
radical mechanism, cyclopropylacetic acid A-30 was designed as a
radical probe.17 The silver-catalyzed reaction of A-30 with
SELECTFLUOR® reagent in water afforded the ring-opening
product 30 in 40% yield as a 4:1 mixture of two stereoisomers
along with the recovery of A-30 in 21% yield (eq 6). No
corresponding fluoromethylcyclopropane derivative could be
detected by 1H NMR analysis. This result strongly supports the
involvement of a free radical mechanism in the silver-catalyzed
fluorodecarboxylation.
Although the detailed mechanism is still not clear, a tentative
one can be proposed (Figure 1). The oxidation of Ag(I) by
SELECTFLUOR® reagent generates an Ag(III)−F intermedi-
ate, presumably via oxidative insertion. The trivalent silver
species then undergoes single electron transfer (SET) with a
carboxylate anion to give the divalent silver intermediate Ag(II)−
F and a carboxyl radical. The fast decarboxylation of the carboxyl
radical provides the corresponding alkyl radical, which then
abstracts the fluorine atom of the adjacent Ag(II)−F to afford the
alkyl fluoride product and regenerate the Ag(I) catalyst. Thus,
the silver-catalyzed decarboxylative fluorination likely involves
SET followed by fluorine atom transfer. The inactiveness of
NFSI in the fluorodecarboxylation might be ascribed to its failure
to generate the high-valent silver species, as NFSI is a much
weaker oxidant than SELECTFLUOR® reagent.
SELECTFLUOR® reagent (200 mol %) in dry acetone was
carried out in a sealed tube at 120 °C. All of the PE-1 was
consumed within 2 h. The 1H NMR and GC-MS analyses of the
resulting mixture showed the formation of pentadecane (30%)
and fluoride 1 (22%) along with a number of unidentified
byproducts, implying that the rate of F abstraction from
SELECTFLUOR® reagent is comparable to that of H abstraction
from the solvent acetone for secondary alkyl radicals. When the
same reaction was carried out in the 1:1 (v:v) acetone/water
solution, pentadecane was obtained in 26% yield, but only a 4%
yield of fluoride 1 was observed. Instead, pentadecan-3-ol was
formed in 7% yield as determined by GC−MS (see the
C
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Journal of the American Chemical Society
Communication
(4) (a) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160. (b) Furuya, T.;
Klein, J. E. M. N.; Ritter, T. Synthesis 2010, 1804. (c) Furuya, T.; Kamlet,
A. S.; Ritter, T. Nature 2011, 473, 470.
(5) (a) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; García-
Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661.
(b) Tang, P.; Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2010, 132, 12150.
(c) Lee, E.; Kamlet, A. S.; Powers, D. C.; Neumann, C. N.; Boursalian, G.
B.; Furuya, T.; Choi, D. C.; Hooker, J. M.; Ritter, T. Science 2011, 334,
639.
(6) Selected examples: (a) Young, S. J. Chem. Soc. 1881, 39, 489.
(b) Kim, D. W.; Song, C. E.; Chi, D. Y. J. Am. Chem. Soc. 2002, 124,
10278. (c) Kim, K.-Y.; Kim, B. C.; Lee, H. B.; Shin, H. J. Org. Chem.
2008, 73, 8106.
(7) Middleton, W. J. J. Org. Chem. 1975, 40, 574.
(8) (a) Singh, R. P.; Shreeve, J. M. Synthesis 2002, 2561. (b) Sutherland,
A.; Vederas, J. C. Chem. Commun. 1999, 1739.
(9) Mankad, N. P.; Toste, F. D. Chem. Sci. 2012, 3, 72.
(10) (a) Singh, R. P.; Shreeve, J. M. Acc. Chem. Res. 2004, 37, 31.
́
(b) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent, S. P.; Wong,
C.-H. Angew. Chem., Int. Ed. 2005, 44, 192.
(11) Hamashima, Y.; Sodeoka, M. Synlett 2006, 1467.
(12) Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D. Science
2011, 334, 1681.
Supporting Information). These results are in sharp contrast to
the outcome depicted in eq 1, indicating that the mechanism of
fluorine transfer from SELECTFLUOR® reagent to alkyl radicals
is unlikely to be involved in the above silver-catalyzed processes.
Furthermore, the solvent effects in eq 7 strongly suggest the SET
mechanism for the reaction of alkyl radicals with SELECT-
FLUOR® reagent, which in turn supports our hypothesis of a
concerted fluorine atom transfer mechanism in the silver-
catalyzed fluorodecarboxylation.
An alternative mechanism for the fluorodecarboxylation would
be the involvement of divalent silver species such as Ag(II)−F−
Ag(II) rather than Ag(III)−F.22 To check on this possibility, a
mixture of acid A-1, AgNO3 (20 mol %), K2S2O8 (200 mol %)
and KF (100 mol %) in acetone/H2O was refluxed for 10 h. No
expected fluorinated product 1 could be detected, whereas the H-
abstraction product pentadecane was obtained in ∼80% yield.
The reaction of A-1a with AgF (100 mol %) and K2S2O8 (200
mol %) afforded the same result. It is known that the interaction
of AgNO3 with K2S2O8 results in the formation of Ag(II)
intermediates.18 Thus these experiments do not support Ag(II)
intermediacy. Further mechanistic investigations are certainly
required to reveal the nature of the high-valent silver
intermediates in the above decarboxylative fluorination.
(13) Grakauskas, V. J. Org. Chem. 1969, 34, 2446.
(14) (a) Patrick, T. B.; Johri, K. K.; White, D. H. J. Org. Chem. 1983, 48,
4158. (b) Patrick, T. B.; Johri, K. K.; White, D. H.; Bertrand, W. S.;
Mokhtar, R.; Kilbourn, M. R.; Welch, M. J. Can. J. Chem. 1986, 64, 138.
(c) Patrick, T. B.; Khazaeli, S.; Nadji, S.; Hering-Smith, K.; Reif, D. J.
Org. Chem. 1993, 58, 705. (d) Ramsden, C. A.; Shaw, M. M. Tetrahedron
Lett. 2009, 50, 3321.
(15) Rueda-Becerril, M.; Sazepin, C. C.; Leung, J. C. T.; Okbinoglu, T.;
Kennepohl, P.; Paquin, J.-F.; Sammis, G. M. J. Am. Chem. Soc. 2012, 134,
4026.
In conclusion, we have developed a novel decarboxylative
fluorination of aliphatic carboxylic acids that uses SELECT-
FLUOR® reagent as the fluorine source and AgNO3 as the
catalyst. The ready availability and low cost of the safe fluorine
reagent and catalyst, the mild experimental conditions, the
remarkable chemoselectivity, and the wide functional group
compatibility render this new radical fluorination method of
practical value in the synthesis of fluorinated molecules.
(16) Chambers, R. D.; Parsons, M.; Sanford, G.; Bowden, R. Chem.
Commun. 2000, 959.
(17) Newcomb, M. In Radicals in Organic Synthesis; Renaud, P., Sibi, M.
P., Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 1, pp 317−336.
(18) (a) Anderson, J. M.; Kochi, J. K. J. Am. Chem. Soc. 1970, 92, 1651.
(b) Anderson, J. M.; Kochi, J. K. J. Org. Chem. 1970, 35, 986.
(19) Kouadio, I.; Kirschenbaum, L. J.; Mehrotra, R. N.; Sun, Y. J. Chem.
Soc., Perkin Trans. 2 1990, 2123.
ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental details; characterizations of new compounds;
1
and copies of H, 13C and 19F NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) Grochala, W.; Hoffmann, R. Angew. Chem., Int. Ed. 2001, 40, 2742.
(21) (a) Clark, A. J. Chem. Soc. Rev. 2002, 31, 1. (b) Severin, K. Curr.
Org. Chem. 2006, 10, 217. (c) Pintauer, T. Eur. J. Inorg. Chem. 2010,
2449. (d) Li, C. In Encyclopedia of Radicals in Chemistry, Biology and
Materials; Chatgilialoglu, C., Studer, A., Eds.; Wiley: Chichester, U.K.,
2012; pp 943−964.
AUTHOR INFORMATION
■
Corresponding Author
clig@mail.sioc.ac.cn
Author Contributions
(22) Wang, Z.; Zhu, L.; Yin, F.; Su, Z.; Li, Z.; Li, C. J. Am. Chem. Soc.
2012, 134, 4258.
§F.Y. and Z.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by the National Natural Science
Foundation of China (Grants 20832006 and 21072211) and the
National Basic Research Program of China (973 Program)
(Grants 2011CB710805 and 2010CB833206).
REFERENCES
■
(1) (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
̈
(b) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (c) Purser, S.; Moore, P.
R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (d) Kirk,
K. L. Org. Process Res. Dev. 2008, 12, 305.
(2) Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A. D. Angew. Chem., Int. Ed.
2008, 47, 8998.
(3) Furuya, T.; Kuttruff, C. A.; Ritter, T. Curr. Opin. Drug Discovery Dev.
2008, 11, 803.
D
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