Decarboxylative Fluorination of 2-Pyridylacetates

Article abstract of DOI:10.1002/chem.201900565

Syntheses of substituted pyridines and fluorinated compounds, which are often pharmaceutical targets, are important objectives in organic chemistry. Herein, we found that decarboxylative fluorination of lithium 2-pyridylacetates occur under catalyst-free conditions. The phenomenon can be applied to one-pot transformation of substituted methyl 2-pyridylacetate to 2-(fluoroalkyl)pyridine by decarboxylative fluorination of the intermediate lithium 2-pyridylacetate. This method was also applied to the syntheses of 2-(difluoroalkyl)pyridines.

Full text of DOI:10.1002/chem.201900565

DOI: 10.1002/chem.201900565
Communication
&
Organic Synthesis
Decarboxylative Fluorination of 2-Pyridylacetates
Ryouta Kawanishi, Lacksany Phongphane, Seiji Iwasa, and Kazutaka Shibatomi*[a]
Abstract: Syntheses of substituted pyridines and fluorinat-
ed compounds, which are often pharmaceutical targets,
are important objectives in organic chemistry. Herein, we
found that decarboxylative fluorination of lithium 2-pyri-
dylacetates occur under catalyst-free conditions. The phe-
nomenon can be applied to one-pot transformation of
substituted methyl 2-pyridylacetate to 2-(fluoroalkyl)pyri-
dine by decarboxylative fluorination of the intermediate
lithium 2-pyridylacetate. This method was also applied to
the syntheses of 2-(difluoroalkyl)pyridines.
The pyridine backbone is an important substructure found in
numerous medicinally relevant molecules.[1] Therefore, the de-
velopment of efficient methods for preparing substituted pyri-
dines is an important requirement in medicinal chemistry.
Hence, functionalizations of a carbon adjacent to the pyridine
ring have been studied intensively in recent years.[2,3] Since the
introduction of one or more fluorine atom into biologically
active compounds often improves their pharmacokinetics and/
or biological activities, the regio- and stereoselective fluorina-
tions of organic molecules are also important synthetic opera-
tions in drug discovery.[4] Therefore, development of methods
for fluorination on pyridylic carbon atoms have recently at-
tracted much attention. As noteworthy examples, Britton’s and
Humbeck’s research groups achieved monofluorination of het-
erobenzylic CÀH bonds in the absence of transition-metal cata-
lysts.[3] Meanwhile, decarboxylative halogenation of aliphatic
carboxylic acids is a useful method for the synthesis of various
alkyl halides because carboxylic acid is a fundamental and
easily available functional group.[5] Recently, excellent methods
for catalytic decarboxylative fluorination of aliphatic carboxylic
acids have been reported with a silver catalyst[6a] or Ru- or Ir-
based photoredox catalysts.[6b,c] However, these methods re-
quire the use of expensive transition-metal catalysts. On the
other hand, b-oxocarboxylic acids are known to easily undergo
decarboxylation without any transition-metal catalyst.[7] Using
this property, several decarboxylative functionalizations, includ-
ing fluorination reactions (Scheme 1a),[8] have been intensively
Scheme 1. Reaction design: the decarboxylative fluorination of 2-pyridylace-
tic acids.
studied.[9] Very recently, our research group also reported the
highly enantioselective decarboxylative chlorination of tertiary
b-ketocarboxylic acids using a chiral primary amine catalyst
and decarboxylative fluorination under catalyst-free condi-
tions.[8d,10] This easy release of carbon dioxide from b-oxocar-
boxylic acids can be attributed to resonance stabilization of
the resulting enolate. Considering this background, we envis-
aged 2-pyridylacetic acids 1 would produce a picolyl anion by
decarboxylation under mild conditions in a manner similar to
b-oxocarboxylic acids; the resulting carbanion is stabilized by a
resonance effect in which the negative charge is delocalized
on a nitrogen atom, and should react with an electrophilic flu-
orinating reagent to afford the corresponding 2-(fluoroalkyl)-
pyridine 2 (Scheme 1b). Indeed, some old research in the liter-
ature reported that 2-pyridylacetic acids undergo thermal de-
carboxylation to produce protonated products.[7e,11] However,
to our surprise, there are very few published studies on its ap-
plication to functionalization reactions,[12] except for examples
with transition-metal catalysts.[2a,13] Based on the above-men-
tioned hypothesis (Scheme 1b), we herein found that decar-
[a] R. Kawanishi, L. Phongphane, Prof. S. Iwasa, Prof. K. Shibatomi
Department of Applied Chemistry and Life Science
Toyohashi University of Technology
1-1 Hibarigaoka, Tempaku-cho, Toyohashi 441-8580 (Japan)
E-mail: shiba@chem.tut.ac.jp
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under:
https://doi.org/10.1002/chem.201900565.
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boxylative fluorination of lithium 2-pyridylacetates 3 yields 2-
(fluoroalkyl)pyridines 2. Furthermore, methyl esters 4 of 2-pyri-
dylacetic acids can be converted to 2 in a one-pot manner by
the decarboxylative fluorination of lithium salts 3 (Scheme 1c).
This method enables us to convert a methyl ester group into a
fluoride group in a one-pot manner without using expensive
transition-metal catalysts. Various starting compounds, methyl
2-pyridylacetates 4 with two alkyl substituents (R1 and R2), can
be prepared by simple SN2 alkylation of nonsubstituted 2-pyri-
dylacetate; which is also an advantage of the method.
Table 1. Optimization of the reaction conditions.[a]
Entry
[F+]
Solvent
Yield of 2a
[%][b]
Yield of 5a
[%][b]
1
2
3[c]
4[c,d]
5
6
7
8
Selectfluor
NFSI
–
DMF
DMF
DMF
DMF
toluene
MeCN
THF
90
71
0
0
0
16
17
30
0
6
0
68
18
65
0
We began by synthesizing the substituted 2-pyridylacetic
acid 1a by alkaline hydrolysis of the corresponding methyl
ester 4a and subsequent neutralization (Scheme 2). Although
1a was fluorinated to yield 2a, involving decarboxylation by
treatment with Selectfluor, even in the absence of a base,[14]
1a was difficult to handle because it slowly decomposed spon-
taneously, even at room temperature, to generate the proton-
ated product 5a (Scheme 2). During the above-mentioned in-
vestigation, we noticed that the lithium salt of 1a is more
stable toward decarboxylative protonation than 1a itself.[15]
–
Selectfluor
Selectfluor
Selectfluor
Selectfluor
MeOH
55
[a] Reactions were carried out with 3a and 3 equiv of fluorinating reagent
at room temperature for 8 h, unless otherwise noted. [b] Determined
after silica gel column purification. [c] No fluorinating reagent was em-
ployed. [d] Reaction was carried out at 1008C.
one-pot fashion. To that end, 4a was treated with lithium hy-
droxide in MeOH/H2O. Following hydrolysis, the solvent was
evaporated under reduced pressure. DMF and Selectfluor were
then added and the mixture was stirred at room temperature.
The reaction successfully afforded the desired product 2a in
85% yield over two steps (Table 2). Thus, we examined the
substrate scope of the sequential hydrolyses and decarboxyla-
tive fluorinations of methyl 2-pyridylacetates 4. As summarized
in Table 2, several methyl 2-pyridylacetates 4 were converted
to the corresponding fluorides 2 in good yields using the one-
pot procedure. The reaction tolerated several functional
groups such as alkenes, nitro groups, cyano groups, and alkyl
ethers. The reaction with quinoline and isoquinoline derivatives
also yielded the corresponding fluorides 2m and 2n, respec-
tively.
Scheme 2. Synthesis and decarboxylative fluorination of 1a. a) LiOH
(5 equiv), MeOH/H2O (3:1), 808C (bath temp.), 8 h, followed by neutralization
with HCl; b) Selectfluor (3 equiv), DMF, rt, 12 h.
Hence, we examined the reactivity of the lithium salt 3a to-
wards decarboxylative fluorination. Lithium salt 3a was ob-
tained in 90% yield by filtration of the precipitate following al-
kaline hydrolysis of 4a (Scheme 3). Treatment of 3a with Se-
Encouraged by the successful decarboxylative fluorinations
of a,a-disubstituted 2-pyridylacetates, we examined the reac-
tions of a-monosubstituted 2-pyridylacetates; 4o was reacted
using a procedure similar to that shown in Table 2. The difluori-
nated product 6o was obtained in 64% yield, along with the
monofluorinated product 2o in 22% yield (Table 3). The reac-
tion is supposed to proceed by base-mediated a-fluorination
of lithium 2-pyridylacetate and subsequent decarboxylative flu-
orination. The reactions of several a-monosubstituted 2-pyridy-
lacetates 4p–t afforded the corresponding 2-(difluoroalkyl)pyri-
dines 6p–t in one-pot processes, whereas the use of 4u–w af-
forded the monofluorinated products 2u–w in good yields.
Since electrophilic fluorinating reagents accelerate the de-
carboxylation of 3a, as indicated by the results shown in
Table 1, entries 1–3, we proposed the reaction mechanism
shown in Scheme 4. An electrophilic fluorine atom on Select-
fluor approaches the nitrogen atom on a pyridine ring to pro-
mote decarboxylation by forming N-fluoro-1,2-dihydropyridine
intermediate I, which would immediately isomerize to afford 2-
(fluoroalkyl)pyridines 2. Easy decarboxylation from 2-pyridyla-
cetates 4 can be explained by the resonance stabilization of
Scheme 3. Synthesis of lithium carboxylate 3a.
lectfluor in DMF successfully afforded the desired fluoride 2a
in 90% yield without generation of the protonated product 5a
(Table 1, entry 1). When N-fluorobenzenesulfonimide (NFSI) was
used as the fluorinating reagent, a slightly lower yield of 4a
was obtained (entry 2). Interestingly, decarboxylation did not
occur at room temperature in the absence of any electrophilic
fluorinating reagent (entry 3), whereas it occurred by heating
to 1008C (entry 4). These results indicate that the fluorinating
reagent accelerated the decarboxylation of 3a in some way.
Solvent screening revealed DMF as the optimum solvent (en-
tries 1, 5–8).
We also envisaged that hydrolysis of methyl ester 4 and sub-
sequent decarboxylative fluorination could be performed in a
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Table 2. Substrate scope.[a]
Table 3. Reaction of a-monosubstituted 2-pyridylacetates.[a]
[a] Hydrolysis of 4 was carried out with 1.5 equiv of LiOH in MeOH/H2O
(3/1) at 608C, and 5 equiv of Selectfluor was used in the fluorination.
Yield was determined after silica gel column purification. [b] Hydrolysis of
4 was carried out with 2.0 equiv of LiOH at 808C (bath temp.) for 45 h.
[a] Hydrolysis of 4 was carried out with 1.5 equiv of LiOH in MeOH/H2O
(3/1) under reflux conditions (bath temp. 1108C), and 3.0 equiv of Select-
fluor was used in the fluorination, unless otherwise noted. Yield was de-
termined after silica-gel column purification. [b] Hydrolysis of 4 was car-
ried out at 808C (bath temp.). [c] Hydrolysis of 4 was carried out for 23–
32 h. [d] LiOH (5 equiv) and Selectfluor (7 equiv) were used. [e] LiOH
(3 equiv) and Selectfluor (5 equiv) were used. [f] Fluorination was carried
out for 96 h (2j) or 40 h (2k). [g] Hydrolysis of 4 was carried out at 808C
(bath temp.), and 3.6 equiv of Selectfluor was used in the fluorination.
[h] Hydrolysis of 4 was carried out for 90 h.
the resulting carbanion by the delocalization of the negative
charge on a nitrogen atom (Scheme 1b). To support this hy-
pothesis, we examined the reaction with 3- and 4-pyridylace-
tates as the substrates (Scheme 5). The 3-pyridylacetate 7 did
not afford the fluorinated product at all under the same reac-
tion conditions, despite complete hydrolysis of the methyl
ester, whereas the 4-pyridylacetate 8 afforded the correspond-
ing fluorinated product 10 in 60% yield. These results imply a
correlation between the reactivity of pyridylacetates towards
decarboxylation and stability of the resulting carbanion; the
negative charge in a carbanion generated by decarboxylation
of 3-pyridylacetates can not be delocalized on a nitrogen atom
in contrast to the cases with 2- and 4-pyridylacetates.
Scheme 4. Proposed reaction pathway.
produce 2-(fluoroalkyl)pyridines in good yields. Alkaline hydrol-
ysis and subsequent decarboxylative fluorination can be per-
formed in a one-pot manner; as a result, the one-pot transfor-
mation of an ester group to a fluorine atom was achieved. The
method is also applicable to the synthesis of 2-(difluoroalkyl)-
pyridines. The resulting fluorides would be useful for the prep-
aration of medicinally relevant molecules that are important
pharmaceutical targets. We are currently investigating the ap-
plication of the method to other functionalizations, including
CÀC bond-forming reactions.
In conclusion, we found that the decarboxylative fluorination
of lithium 2-pyridylacetates, prepared by the alkaline hydroly-
ses of the corresponding methyl esters, proceeds smoothly to
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Scheme 5. Reaction of 3- and 4-pyridylacetates.
Experimental Section
General procedure for decarboxylative fluorination of 2-pyr-
idylacetates 4 (Table 2)
Lithium hydroxide was added to a solution of methyl 2-pyridylace-
tate 4 in MeOH/H2O (3:1, 0.2m), and the mixture was stirred until
the reaction completed. After all solvents were evaporated under
reduced pressure, Selectfluor and DMF were added to the mixture,
and the mixture was stirred until the reaction completed. The reac-
tion mixture was directly subjected to flash column chromatogra-
phy to give the corresponding fluorinated product 2. Detailed ex-
perimental procedures, characterization data, and traces of NMR
spectra are available in the Supporting Information
Acknowledgements
This study was supported by the Grants-in-Aid for Scientific Re-
search (B) (18H01974) and Daiko Foundation.
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Conflict of interest
The authors declare no conflict of interest.
[10] K. Shibatomi, K. Kitahara, N. Sasaki, Y. Kawasaki, I. Fujisawa, S. Iwasa,
Nat. Commun. 2017, 8, 15600.
Keywords: decarboxylation
·
difluoromethyl group
·
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Manuscript received: February 5, 2019
Revised manuscript received: April 1, 2019
Version of record online: && &&, 0000
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Communication
COMMUNICATION
&
Organic Synthesis
R. Kawanishi, L. Phongphane, S. Iwasa,
K. Shibatomi*
Substituted pyridines: Decarboxylative
fluorination of lithium 2-pyridylacetates
occur under catalyst-free conditions.
The phenomenon was applied to one-
pot transformation of a substituted
methyl 2-pyridylacetate into a 2-(fluo-
roalkyl)pyridine. The method was also
applied to the syntheses of 2-(difluor-
oalkyl)pyridines (see scheme).
&& – &&
Decarboxylative Fluorination of 2-
Pyridylacetates
Chem. Eur. J. 2019, 25, 1 – 5
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These are not the final page numbers! ÞÞ