Photo-fluorodecarboxylation of 2-aryloxy and 2-aryl carboxylic acids

Article abstract of DOI:10.1002/anie.201206352

Coming to light: The title reaction simply requires an aqueous alkaline solution of Selectfluor and light. The method is inexpensive and effective for a wide range of neutral and electron-poor 2-aryloxy and 2-aryl acetic acids to provide fluoromethyl ethers (see scheme) and benzyl fluorides, respectively. The mechanism most likely proceeds through an initial aryl excitation with a subsequent single-electron transfer. Copyright

Full text of DOI:10.1002/anie.201206352

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DOI: 10.1002/anie.201206352
Synthetic Methods
Photo-fluorodecarboxylation of 2-Aryloxy and 2-Aryl Carboxylic
Acids**
Joe C. T. Leung, Claire Chatalova-Sazepin, Julian G. West, Montserrat Rueda-Becerril, Jean-
FranÅois Paquin, and Glenn M. Sammis*
The escalating importance of fluorinated compounds in the
pharmaceutical and agrochemical sectors has placed a pre-
mium on the development of novel synthetic methods for
fluorine incorporation.[1] In that respect, we have recently
demonstrated that the electrophilic fluorine sources N-
fluorobenzenesulfonimide (NFSI)[2] and Selectfluor[3] can
effectively fluorinate alkyl radicals.[4] Continuing research in
this direction motivated us to examine Hunsdiecker-type[5]
fluorodecarboxylation reactions. There are few methods for
the direct fluorodecarboxylation of carboxylic acids, including
xenon difluoride mediated fluorodecarboxylations,[6] and
a very recent method developed by Li and co-workers
It was rapidly established that optimal results were
obtained by irradiating the system with 300 nm[8] light
(Table 1, entry 2).[9] Minimal conversion into the fluorinated
Table 1: Wavelength optimization for the fluorodecarboxylation of 1a to
give product 2a.
Entry[a]
l [nm][8]
Yield [%][b]
1
2
3
4
5
254
300
350
25
94[c]
47
4
tungsten lamp
sunlight
42
detailing
a silver-catalyzed fluorodecarboxylation using
Selectfluor.[7] Studies centering on 2-aryloxyacetic acids,
such as 1a, led to the surprising observation that the
fluorodecarboxylated product 2a forms in the absence of
transition metals when an alkaline solution of 1a and
Selectfluor is irradiated (Scheme 1). A control experiment
revealed that no reaction occurs in the absence of light.
Preparative and mechanistic aspects of this unusual process
are detailed herein.
[a] Reaction conditions: NaOH (1.5 equiv) and Selectfluor (3.5 equiv ) in
H2O (0.1m) irradiated for 1 h at the indicated wavelength on a 0.1 mmol
scale. [b] The yields were obtained by NMR spectroscopy using
trimethoxybenzene as an internal standard. [c] The reported yield is an
average of 3 runs.
product 2a was observed when a visible-light source was
utilized (entry 4). The wide range of wavelengths which can
effectively promote this fluorodecarboxylation allows this
reaction to be run with direct sunlight (entry 5). As seen in
Table 2, replacement of Selectfluor with either the triflate or
the tetrafluoroborate N-fluoropyridinium (NFPY) salts
(entries 2 and 3) did not lead to the formation of 2a. When
water was utilized as the solvent, NFSI did not lead to the
formation of 2a, and is most likely a result of the poor
aqueous solubility of the fluorinating agent. Adding aceto-
nitrile as a cosolvent afforded trace amounts of the fluori-
nated product (entry 4). A 28% yield of 2a, as determined by
NMR spectroscopy, was observed with NFSI as the fluorine
source in a solution of acetonitrile using 2,6-di-tert-butylpyr-
idine as a base (entry 5). The product 2a was also observed
when acetonitrile was utilized with Selectfluor and 2,6-di-tert-
butylpyridine (entry 6), albeit in lower yield than under the
aqueous sodium hydroxide conditions (entry 1). Clearly,
Selectfluor is the best reagent for this new photo-decarbox-
ylation.
The reaction of carboxylate salts that are not highly
soluble in water are more conveniently carried out in a mixed
aqueous/organic system. To illustrate, the carboxylate salt of
1b (Table 2, R = tBu) precipitated out of solution upon the
addition of Selectfluor. However, the system remained
homogeneous when a 2:1 H2O/acetonitrile solvent mixture
was used, thus resulting in the smooth formation of 2b
(entry 7).[10] A slight decrease in conversion was observed
when acetone was used as a cosolvent, at least in the case of
substrate 1a (entries 8 and 9). The nature of the carboxylate
Scheme 1. Photo-fluorodecarboxylation of the a-aryloxy derivative 1a.
[*] J. C. T. Leung,[+] C. Chatalova-Sazepin,[+] J. G. West,
M. Rueda-Becerril, Prof. G. M. Sammis
Department of Chemistry, University of British Columbia
2036 Main Mall, Vancouver, BC V6T 1Z1 (Canada)
E-mail: gsammis@chem.ubc.ca
Prof. J.-F. Paquin
Canada Research Chair in Organic and Medicinal Chemistry
Dꢀpartement de chimie, Universitꢀ Laval
1045 avenue de la Mꢀdecine, Quꢀbec, QC G1V0A6 (Canada)
[+] These authors contributed equally to this work.
[**] This work was supported by the University of British Columbia
(UBC), the Universitꢀ Laval, NSERC, the Canadian Research Chair
program, a doctoral fellowship from the Consejo Nacional de
Ciencia y Tecnologꢁa (CONACyT) to M.R.-B., a doctoral fellowship
from UBC to C.C.S., and a doctoral fellowship NSERC to J.C.T.L.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206352.
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Table 2: Screen of fluorine sources for substrates 1a and 1b.
Entry
Fluorine
source[a]
1 (R)
Solvent
Yield [%]
1[a,b]
2[a,b]
3[a,b]
4[a,b]
5[b,c]
6[b,c]
7[a,d]
8[a,c]
9[a,c]
Selectfluor
NFPY (OTf)
NFPY (BF4)
NFSI
1a (F)
1a (F)
1a (F)
1a (F)
1a (F)
1a (F)
1b (tBu)
1a (F)
1a (F)
H2O
H2O
H2O
94[e]
0[e]
0[e]
CH3CN/H2O (1:2)
CH3CN
CH3CN
CH3CN/H2O (1:2)
CH3CN/H2O (1:2)
acetone/H2O (1:2)
<5[e]
28[f]
53[f]
66[e]
96[e]
82[e]
NFSI
Selectfluor
Selectfluor
Selectfluor
Selectfluor
[a] Reaction conditions: NaOH (1.5 equiv), fluorine source (3.5 equiv),
1 (1.0 equiv) at 0.1m in the solvent, irradiated at 300 nm for 1 h. [b] The
reaction was run on a 0.1 mmol scale. [c] Reaction conditions: 2,6-di-tert-
butylpyridine (1 equiv), fluorine source (3.5 equiv), 1 (1.0 equiv)at 0.1m
in the solvent, irradiated at 300 nm for 1 h. [d] The reaction was run on
a 0.05 mmol scale. [e] The yields were obtained by NMR spectroscopy
using trimethoxybenzene as an internal standard. [f] The yields were
obtained by NMR spectroscopy using ethyl trifluoracetate as an internal
standard. See the Supporting Information for details. Tf=trifluoro-
methanesulfonyl.
Scheme 3. Current working mechanistic model.[14]
ceeding through hypofluorite intermediates,[17] are not con-
sistent with both the lack of 19F NMR evidence for the
formation of hypofluorites[18] and the low amounts of product
observed under thermal conditions.[19,20]
counterion seemed to have no effect on the overall effi-
ciency.[11]
In addition to the a-aryloxy substrates 1a and 1b,
phenylacetic acid (3) was successfully fluorinated in quanti-
tative yield as determined by NMR spectroscopy, and was
isolated in 72% yield (Scheme 2). Notably, all substrates
Mechanistic investigations are all consistent with the
arene excitation/oxidation mechanism detailed in Scheme 3.
The UV/Vis spectra of each substrate[21] is within the range of
the light source utilized to promote the photofluorodecar-
boxylation. The wavelength optimization (Table 1) addition-
ally supports the fact that the substrate itself is being excited
as the absorption overlap between substrate 1a and the
350 nm light source (entry 3) is significantly less than the
overlap with the 300 nm light source (entry 2). The decrease
in yield at 350 nm suggests that the substrate is excited, rather
than one of the reagents or a reactive intermediate. Further-
more, this mechanism is consistent with the lack of reactivity
of alkyl carboxylic acids and the failure to achieve fluorode-
carboxylation under thermal conditions. Additional support
for this proposal is provided by the work of Chang et al., who
recently described the amination of benzylic positions using
hypervalent iodide and dibenzenesulfonamide.[22] Thus, it is
apparent that the photo-fluorodecarboxylation mechanism
constitutes a variation on the theme of SOMO catalysis,[23]
and that sagacious exploitation of this new form of reactivity
may lead to novel transformations in the aromatic series.
A practical application of the chemistry is the preparation
of aromatic fluoroethers, in particular, difluoroethers, which
are of current interest in medicinal and agricultural chemis-
try.[24] The unsubstituted aryloxy substrate 1c was cleanly
fluorinated in high yield as detrmined by NMR methods
(Table 3, entry 1). Halide-substituted aryl derivatives were all
fluorodecarboxylated in good to excellent yields (entries 2–
5), although the dichloro substrate 1e required the use of
acetonitrile as a cosolvent for enhanced solubility. The
substrate 1b, having a tert-butyl group, also underwent
fluorodecarboxylation in excellent yield using acetonitrile as
a cosolvent (entry 6). The 2-aryloxy substrate 1g afforded low
Scheme 2. Photo-fluorodecarboxylation of phenylacetic acid (3).
lacking either the 2-aryloxy or the 2-aryl substitutent were not
successfully fluorinated under the optimized photofluorode-
carboxylation conditions, and all that was observed after one
hour was minor amounts of nonselective fluorination prod-
ucts. Benzoic acid was also not a viable substrate under the
reaction conditions as no formation of fluorobenzene was
observed. These noteworthy observations suggest that the
reaction may proceed through the mechanism depicted in
Scheme 3. Excitation of the B band transition (p!p*) of the
benzenoid nucleus of 1 creates an excited state (5),[12] which in
all likelihood is a better electron donor than the ground-state
molecule. A single-electron transfer (SET) event involving 5
and Selectfluor[13] results in the oxidized species 6,[14] which
then undergoes a decarboxylation analogous to a Strecker
degradation.[15,16] Regardless of which species, 7–9, is the main
resonance contributor, fluorination with Selectfluor can
either proceed through a radical[4] or an anion[3b] to afford 2.
Alternative mechanisms, such as the decarboxylation pro-
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Table 3: Synthesis of monofluoromethyl ethers.
Table 4: Synthesis of difluoromethyl ethers.
Entry[a]
1
1
R1
R2
H
Solvent
H2O
Yield [%][b]
46 (84)
Entry[a]
1
10
R
Solvent
H2O
Yield [%][b]
25 (59)
1c
10a
2
3
1a
1d
H
H
H2O
H2O
60 (94)
60 (61)
2
10b
H2O
44 (79)
3
4
5
10c
10d
10e
H2O
H2O
64 (66)
44
CH3CN/H2O
(1:2)
4
5
6
1e
1 f
1b
H
H
H
76
CH3CN/H2O
(1:2)
H2O
57 (72)
83
77 (77)
CH3CN/H2O
(1:2)
[a] Reaction conditions: NaOH (1.5 equiv), Selectfluor (3.5 equiv), 10
(1.0 equiv) at 0.1m in the solvent, and irradiated at 300 nm for 2.5 h.
[b] Yield of product isolated after extraction and filtration through a silica
gel plug. All yields for isolated products were determined for reactions
run on a 0.5 mmol scale. The number in parentheses refers to the yield,
as determined by NMR methods, of the reaction run on a 0.1 mmol
scale. Trimethoxybenzene was used as an internal standard. See the
Supporting Information for details.
7
8
1g
1h
H
H
H2O
H2O
– (34)[c]
78
CH3CN/H2O
(1:2)
9[d]
10
1i
3
OAc
H
68 (78)
H2O
72 (>95%)
yield, as determined by NMR spectroscopy, and a lower
yield was determined upon isolation because of product
volatility (entry 1). While halogen-substituted aryl derivatives
were successfully fluorinated (entries 2–4), the yields were
lower than for the synthesis of the analogously substituted
monofluorinated products (Table 3, entries 2, 3, and 5). The
para-tert-butyl substrate 10e was successfully fluorinated in
77% yield (Table 4, entry 5). As with the analogous analo-
gous acid, an electron-rich para-methoxy derivative (R =
para-MeOAr) also did not undergo the desired fluorination
reaction.
This new fluorodecarboxyation has numerous procedural
advantages. The carboxylic acid substrates can readily be
synthesized from the corresponding phenol[27,28] and all of the
reagents required for the fluorodecarboxylation, including
Selectfluor, are inexpensive on bulk scale. One particular
benefit of this new methodology is the ease of product
purification. Under the optimized NaOH conditions, all of the
starting materials and reagents are readily soluble in the
reaction mixture. After irradiation, the fluorinated product is
insoluble, thus slowing the rate of hydrolysis and product
decomposition. The product can then be recovered by
extraction with an organic solvent, thereby leaving the
majority of the by-products in the aqueous layer.
[a] Reaction conditions: NaOH (1.5 equiv), Selectfluor (3.5 equiv), 1 or 3
(1.0 equiv) at 0.1m in the solvent, and irradiated at 300 nm for 1 h.
[b] Yield of product isolated after extraction and filtration through a silica
gel plug. All yields were determined for reactions run on a 0.5 mmol
scale. The number in parentheses refers in to the yield, determined by
NMR methods, for the reaction run on 0.1 mmol scale. The yields were
obtained using trimethoxybenzene as an internal standard. [c] The yield
of the isolated product was not determined. [d] 1.5 equiv of K2CO3 was
used instead of NaOH. Ms=methanesulfonyl.
yields of the desired fluorinated product 2g (entry 7).[25]
Substrates with strongly electron-rich aromatic rings, such as
the para-methoxyphenyl analogue of 1 (R1 = para-OMeAr),
also were not fluorinated effectively under the photoreaction
conditions, and is likely a result of a competing nonselective
aryl fluorination reaction (entry 8). Similar oxygenation
patterns can be accessed when the electron density is
diminished, such as with the para-mesyloxy substrate 1h
which was fluorinated in 78% yield. 2-Aryl acids, such as
acetylmandelic acid (1i) and phenyl acetic acid (3) were also
fluorinated in good to excellent yields (entries 9 and 10).
These facile reaction conditions also allow the reaction to be
readily scalable to millimole scale. To wit, when the photo-
fluorodecarboxylation of 1e was run on a 2 mmol scale, the
fluorinated product was afforded in 86% yield upon iso-
lation.[26]
In conclusion, this transition-metal-free photo-fluoro-
decarboxylation marks the first example of a direct and
ꢀ
selective photochemical formation of C F bonds, and it is
With the successful application of this new fluorodecarb-
oxylation to monofluoroethers, studies next focused on the
application of the method to the synthesis of difluoroethers
(11; Table 4). Gratifyingly, the unsubstituted a-fluoro acid
derivative 10a underwent fluorodecarboxylation in high
most likely proceeds through initial excitation of the initial
aryl group with subsequent SET. This approach works well for
a broad range of a-aryloxy substrates using very mild and
inexpensive reaction conditions. Current efforts are directed
towards further examination of the reaction mechanism for
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[12] The nature of the excited-state 5 will differ depending upon the
this photo-fluorodecarboxylation, as well as investigating
other reactions that exploit this new form of reactivity.
substitution at R. Only one excited state has been shown for
clarity.
[13] Selectfluor is known to be an effective single-electron oxidant.
For representative examples, see Ref. [3b].
[14] It is also possible that the reaction proceeds through a PET from
the carboxylate to Selectfluor.
[15] A. Strecker, Justus Liebigs Ann. Chem. 1862, 123, 363 – 365.
[16] For a review on the Strecker degradation, see: A. Schçnberg, R.
Moubasher, Chem. Rev. 1952, 50, 261 – 277.
Received: August 8, 2012
Published online: September 28, 2012
Keywords: fluorine · photochemistry · radical reactions ·
.
reaction mechanisms · synthetic methods
[17] For
a review on the reactivity of acyl hypofluorite and
[1] a) W. K. Hagmann, J. Med. Chem. 2008, 51, 4359 – 4369; b) K. L.
Kirk, Org. Process Res. Dev. 2008, 12, 305 – 321.
hypofluorite derivatives, see: S. Rozen, Chem. Rev. 1996, 96,
1717 – 1736.
[2] E. Differding, H. Ofner, Synlett 1991, 187 – 189.
[3] a) R. E. Banks, S. N. Mohialdin-Khaffa, G. S. Lal, I. Sharif, R. G.
Syvret, J. Chem. Soc. Chem. Commun. 1992, 595 – 596; b) P. T.
Nyffeler, S. G. Durꢀn, M. D. Burkart, S. P. Vincent, C. H. Wong,
Angew. Chem. 2005, 117, 196 – 217; Angew. Chem. Int. Ed. 2005,
44, 192 – 212.
[18] 19F NMR analysis of reaction mixtures, both before and after
irradiation, shows no evidence of hypofluorite formation.
[19] Heating an aqueous solution of sodium hydroxide, substrate 1a,
and Selectfluor at 1008C for 1 hour yielded complete conversion
of the starting material, but only trace amounts of the
fluoromethoxy ether.
[4] M. Rueda-Becerril, C. Chatalova Sazepin, J. C. T. Leung, T.
Okbinoglu, P. Kennepohl, J. F. Paquin, G. M. Sammis, J. Am.
Chem. Soc. 2012, 134, 4026 – 4029.
[20] See the Supporting Information for a discussion of all of the
evidence against the formation of either acyl hypofluorites or
other hypofluorite derivatives.
[5] For
a
general review on halodecarboxylations, see: R. G.
[21] All of the UV/Vis data is provided in the Supporting Informa-
tion.
[22] H. J. Kim, J. Kim, S. H. Cho, S. Chang, J. Am. Chem. Soc. 2011,
133, 16382 – 16385.
Johnson, R. K. Ingham, Chem. Rev. 1956, 56, 219 – 269.
[6] For a review on XeF2: M. A. Tius, Tetrahedron 1995, 51, 6605 –
6634.
[7] F. Yin, Z. Wang, Z. Li, C. Li, J. Am. Chem. Soc. 2012, 134, 10401 –
10404.
[8] All of the light sources utilized for these experiments are not
strictly monochromatic. The indicated wavelength refers to the
maximum light intensity emitted. See the Supporting Informa-
tion for details about emission profiles.
[23] For initial studies on SOMO catalysis, see: a) T. D. Beeson, A.
Mastracchio, J. B. Hong, K. Ashton, D. W. C. MacMillan, Science
2007, 316, 582 – 585; b) H. Jang, J. B. Hong, D. W. C. MacMillan,
J. Am. Chem. Soc. 2007, 129, 7004 – 7005.
[24] For a recent review, see: B. Manteau, S. Pazenok, J. P. Vors, F. R.
Leroux, J. Fluorine Chem. 2010, 131, 140 – 158.
[9] Increasing the wavelength to 350 nm afforded comparable
amounts of decomposition as was observed at 254 nm.
[10] Replacing the tetrafluoroborate salt of Selectfluor with the more
organic-soluble PF6 salt provided 2b in 38% yield as determined
by NMR methods.
[11] Comparable yields were observed when a variety of bases,
including K2CO3, KOH, and LiOH were used for both substrates
1a and 1b.
[25] Background aryl fluorination was observed for this substrate.
[26] The reaction conditions were slightly altered for the 2 mmol
scale. See the Supporting Information for details.
[27] For a representative example of the synthesis of an a-aryloxy
acid, see: K. Lee, J. Med. Chem. 2007, 50, 1675 – 1684.
[28] For a representative example of the synthesis of an a-fluoro-a-
aryloxy acid, see: C. C. Ciocoiu, Bioorg. Med. Chem. 2011, 19,
6982 – 6988.
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