A Mild Method for the Direct Fluorination of Pyrroles by Using a Lipophilic Anionic Phase-Transfer Catalyst

Article abstract of DOI:10.1002/ejoc.201600570

A mild fluorination method for pyrroles, based on anionic phase-transfer catalysis by using Selectfluor, a lipophilic phosphoric acid, and a base in an apolar solvent is described. The thus obtained fluorinated pyrroles bearing a wide variety of functional groups are attractive building blocks for medicinal chemistry.

Full text of DOI:10.1002/ejoc.201600570

DOI: 10.1002/ejoc.201600570
Communication
Fluorination
A Mild Method for the Direct Fluorination of Pyrroles by Using
a Lipophilic Anionic Phase-Transfer Catalyst
Kenichi Hiramatsu[a] and Hirokazu Tamamura*[a]
Abstract: A mild fluorination method for pyrroles, based on The thus obtained fluorinated pyrroles bearing a wide variety
anionic phase-transfer catalysis by using Selectfluor, a lipophilic of functional groups are attractive building blocks for medicinal
phosphoric acid, and a base in an apolar solvent is described. chemistry.
Introduction
phase-transfer catalyst combined with Selectfluor could dis-
solve the resulting complex slowly into an apolar solvent, af-
fording a mild fluorinating reagent for electron-rich pyrroles
Pyrrole is a common structural motif in marine natural products
and drugs such as, for example, the frequently used Atorvas-
tatin[1] and Sunitinib.[2,3] On account of their electron-rich na-
ture, pyrrole-based pharmaceuticals often contain additional
electron-withdrawing and/or bulky substituents to minimize or
avoid enzymatic oxidation.[4] Accordingly, medicinal applica-
tions for fluorinated pyrroles can be expected.
The classical synthetic approach to fluorinated pyrroles uses
gaseous fluorine, which is extremely corrosive and toxic.[5]
Other conventional methods include electrophilic fluorination
of lithiated pyrroles or pyrrole magnesium compounds by using
N-fluorobenzenesulfonimide (NFSI),[6,7] ZrCl4-catalyzed fluorin-
ations,[8] fluorinations with XeF2,[9] the Balz–Schiemann reac-
tion,[10] and anodic fluorinations.[11] All these methods require
either moisture-sensitive reagents, strong acids, or special appa-
ratus. Although transition-metal-catalyzed arylfluorination
methods have been developed, their applications to five-mem-
bered heteroarenes such as pyrroles still remain limited.[12]
A
popular electrophilic fluorination reagent for a wide range of
organic compounds is 1-chloromethyl-4-fluoro-1,4-diazoniabi-
cyclo[2.2.2]octane bis(tetrafluoroborate), also known as Select-
fluor,[13] which has been used to fluorinate pyrroles, for exam-
ple, in fluoro-decarboxylations[14] and microwave-assisted fluor-
inations of unactivated 2-acylpyrroles.[15] However, few fluorin-
ations of this type have been reported, and this can be attrib-
uted to the high electron density and reactivity of pyrroles to-
wards the high electrophilic reactivity of the F+ reagent.
In 2011, Toste reported the asymmetric electrophilic fluorin-
ation of olefins by using a chiral anionic phase-transfer catalyst,
which delivers cationic Selectfluor from an insoluble solid phase
into an apolar solution to mediate the asymmetric reaction
(Scheme 1, part 1).[16] We envisioned that a lipophilic anionic
[a] Department of Medicinal Chemistry, Institute of Biomaterials and
Bioengineering, Tokyo Medical and Dental University
Chiyoda-ku, Tokyo, 101-0062, Japan
E-mail: tamamura.mr@tmd.ac.jp
http://www.tmd.ac.jp/i-mde/www/en/biomolecular/index.html
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600570.
Scheme 1. Anionic phase-transfer catalysis.
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Communication
(Scheme 1, part 2). Preliminary studies revealed, however, that 19). Heterogeneous fluorination in THF, in the absence of base
the treatment of pyrroles with Selectfluor under homogeneous and catalyst, was clean but slow (Table 2, entries 14 and 20),
conditions in polar solvents often results in the formation of and the addition of either a lipophilic catalyst or a base failed
complex product mixtures.
to increase the product yield (Table 2, entries 15, 16, 21, and
22). However, when a lipophilic catalyst and a base were added
simultaneously, the reaction was accelerated and afforded the
desired products in moderate yield (Table 2, entries 17, 23, and
24).[19] This increase in yield supports our hypothesis that a lipo-
philic anionic phase-transfer agent catalyzes this mild fluorin-
ation. Even though controlling the reactivity by cooling the ho-
mogeneous reaction mixture is difficult (Table 2, entries 18 and
19), conducting the reaction under heterogeneous conditions
affords a mean to control the reactivity. For some substrates,
the fluorinated products were obtained even in the absence of
a catalyst and a base, which indicates a significant level of a
background reaction.[19,20] This might be explained by the fact
that apolar ether-type solvents, as well as crown-ethers exhibit
phase-transfer properties,[21] which may facilitate the heteroge-
neous fluorination to some extent, even in the absence of a
lipophilic anionic catalyst. Fluorination of 2, 4, and 11 was con-
ducted at 50 °C, as the reactions proceeded sluggishly at room
temperature. For all heterogeneous reactions, a significant
amount (ca. 15–35 %) of the starting material was recovered,
although the combined yield of products and recovered start-
ing material (RSM) was less than 100 %. This result suggests
partial decomposition of the pyrroles, even under heterogene-
ous conditions. Increasing the stoichiometry of Selectfluor and
the catalyst loading accelerated the reaction, but the product
yields remained constant.[22] Superstoichiometric reaction con-
ditions may thus promote the reaction, but simultaneously they
also promote the partial decomposition of products and the
starting materials.
Results and Discussion
Therefore, we started our study of this reaction by examining
the fluorination of pyrrole-3-carbaldehyde 1 (Table 1). The ho-
mogeneous reaction of 1 with 1.5 equivalents of Selectfluor in
DMF afforded a complex mixture (CM; Table 1, entry 1), while
the reaction under heterogeneous conditions in THF proceeded
slowly (Table 1, entry 2). However, when the reaction was car-
ried out in diethyl ether in the presence of stearic acid and
Na2CO3, pyrrole-5-fluoro-3-carbaldehyde (1a) and pyrrole-2-
fluoro-3-carbaldehyde (1b) were obtained in 14 and 4 % yield,
respectively (Table 1, entry 3). Screening of various catalysts
and bases (Table 1, entries 4–8) revealed that a combination of
Na3PO4 and tBuPA[17] or (R)-PhDAP[18] (Scheme 1) in THF af-
forded the best results, generating 1a in 28–30 and 1b in 19 %
yield (Table 1, entries 6 and 7).
Table 1. Optimization of reaction conditions for the mild fluorination of pyr-
role.
The fluorination of monosubstituted pyrroles 2, 3, 8–12, 14
and 15 occurred at either the 2- or 5-position; the 5-fluorinated
pyrroles were obtained in higher yield than the 2-fluorinated
pyrroles. This result may be attributed to a combination of elec-
trostatic and steric effects.[24] The reaction with multisubsti-
tuted pyrroles 4–7 furnished the monofluorinated products 4a–
7a.
Entry Catalyst
Base
Solvent
1a
1b
RSM
[%][a]
[%][a]
[%][a]
1
2
3
4
5
6
7
8
–
–
–
–
DMF
THF
Et2O
Et2O
Et2O
THF
CM
trace
14
15
22
30
28
trace
CM
trace
4
7
8
19
19
trace
CM
89
28
49
46
35
37
92
stearic acid
(R)-TRIP
(R)-PhDAP
(R)-PhDAP
tBuPA
Na2CO3
Na2CO3
Na2CO3
Na3PO4
Na3PO4
Na3PO4
THF
hexane
Under homo- and heterogeneous conditions, the fluorin-
ation of 3-acetyl thiophene and furan 3-ethyl carboxylate was
slow, even at 50 °C, while the fluorination of 2,4-dimethyl
pyrrole afforded complex product mixtures, which indicates
that pyrroles bearing neutral or electron-donating substituents
are very reactive and may potentially be unstable under these
conditions. To fluorinate pyrroles with electron-withdrawing
groups at the 2-position, significant microwave irradiation in
DMF is required.[15]
(R)-PhDAP
[a] CM: complex mixture. RSM: recovered starting material. Isolated yield after
column chromatography on silica gel.
Having established the optimized conditions, we examined
the substrate scope of this mild fluorination reaction (Table 2).
A range of pyrroles containing electron-withdrawing groups,
such as acetyl, ketone, ester carboxylate, carboxamide, and sulf-
one at the 3-position, were well tolerated and resulted in mod-
erate product yields. Proton, methyl, or benzyl substituents on
the pyrrole nitrogen atom were also tolerated well, and even
N-methylpyrrole (13) could be fluorinated to afford 2-fluoro-N-
methylpyrrole (13a). Under homogeneous conditions in DMF,
most fluorinations, except that of 3-phenylsulfonyl pyrrole (11),
With the exception of 13a, all fluorinated compounds shown
in Table 1 and Table 2 are previously unreported but structurally
simple compounds. The design of novel building blocks for
pharmaceutical purposes represents a desirable research target
in medicinal chemistry,[25] and the mild fluorination method re-
ported in this study affords simple fluorinated pyrroles, bearing
afforded complex product mixtures or low yields (Table 2, en- synthetically tractable substituents. This method thus offers an
tries 13 and 18).[19] When the reaction was conducted in DMF attractive synthetic route to the aforementioned building
at –20 °C, the reaction proceeded only slowly (Table 2, entry blocks.
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Communication
Table 2. Substrate scope for the mild fluorination of pyrroles.
Entry
R1, R3, R4
Catalyst
Base
Solvent
a
b
RSM
[%][a]
[%][a]
[%][a]
1[b]
2
Me, Ac, H (2)
(R)-PhDAP
(R)-PhDAP
tBuPA
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
–
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
TBME[d]
DMF
THF
THF
THF
THF
DMF
DMF
THF
THF
THF
THF
THF
27
27
58
47
49
41
34
23
26
24
21
54[e]
CM
4
5
5
30
CM
5
8
16
8
32
34
18
25
–
–
–
37
22
34
13
27
18
30
22
24
51
20
38[e]
CM
89
54
88
29
CM
79
63
49
80
25
34
Bn, Ac, H (3)
3[b]
4
(4)[c]
H, CO2Et, Me (5)
(R)-PhDAP
(R)-PhDAP
(R)-PhDAP
(R)-PhDAP
(R)-PhDAP
(R)-PhDAP
(R)-PhDAP
(R)-PhDAP
tBuPA
5
6
7
8
(6)[c]
(7)[c]
–
H, CO2Bn, H (8)
Me, CONEt2, H (9)
Me, CONHiPr, H (10)
H, SO2Ph, H (11)
Me, CONHPh, H (12)
Me, H, H (13)
H, CO2tBu, H (14)
H, CO2tBu, H (14)
H, CO2tBu, H (14)
H, CO2tBu, H (14)
H, CO2tBu, H (14)
Bn, CO2Et, H (15)
Bn, CO2Et, H (15)
Bn, CO2Et, H (15)
Bn, CO2Et, H (15)
Bn, CO2Et, H (15)
Bn, CO2Et, H (15)
Bn, CO2Et, H (15)
15
21
23
13
20
–
CM
trace
3
trace
16
CM
trace
5
9
10[b]
11
12
13
14
15
16
17
18
19[f]
20
21
22
23
24
–
–
–
–
Na3PO4
–
Na3PO4
–
–
–
Na3PO4
–
Na3PO4
Na3PO4
(R)-PhDAP
(R)-PhDAP
–
–
–
–
4
6
9
14
(R)-PhDAP
tBuPA
(R)-PhDAP
[a] CM: complex mixture. RSM: recovered starting material. Isolated yield after column chromatography on silica gel. [b] Reaction conducted at 50 °C. [c] The
structures of 4, 6, and 7 are shown in ref.[23] [d] TBME: tert-butyl methyl ether.[e] Determined by 1H NMR spectroscopy by using 4-fluoro-nitrobenzene as an
internal standard. [f] Reaction conducted at –20 °C.
crude residue was purified by flash column chromatography eluting
with EtOAc and hexanes; see the Supporting Information for details.
Conclusions
In conclusion, we have established a mild and controlled fluor-
ination of pyrroles in a heterogeneous environment by using a
combination of Selectfluor, a lipophilic anionic phase-transfer
Acknowledgments
catalyst, and a base. Further studies on temperature-sensitive
reactions under such heterogeneous conditions in the presence
of a lipophilic phase-transfer catalyst are currently conducted
in our laboratory and will be reported in due course.
We thank Prof. F. Dean Toste and Dr. Jörg P. Hehn (University of
California, Berkeley) for helpful discussions, and Dr. Nami Ohashi
and Takuya Kobayakawa for measuring mass spectra. K. H. is
grateful for support from Asubio Pharma Co., Ltd. and Daiichi-
Sankyo Co., Ltd.
Experimental Section
Keywords: Phase-transfer catalysis · Heterogeneous catalysis ·
General Procedure for Fluorination: To
a one-dram vial
Halogenation · Pyrrole · Building blocks
(15 × 45 mm) equipped with an 8 mm magnetic stirrer bar, the
substrate (0.2 mmol, 1.0 equiv.), anhydrous Na3PO4 (39 mg,
0.24 mmol, 1.2 equiv.), Selectfluor (106 mg, 0.3 mmol, 1.5 equiv.),
and the specified catalyst (0.02 mmol, 0.1 equiv.) were added. THF
(2 mL) was added to the mixture and the vial was capped with a
screw cap. When heating, a Biotage microwave vial equipped with
a magnetic stir bar and fitted with a septum cap was used instead.
The reaction mixture was stirred vigorously for 24 h at the indicated
temperature. The mixture was poured into solution of saturated
NaHCO3, extracted with EtOAc (2 × 4 mL), and the combined or-
ganic layer was dried with Na2SO4 and concentrated in vacuo. The
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Communication
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Received: May 10, 2016
Published Online: ■
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Fluorination
K. Hiramatsu, H. Tamamura* ......... 1–5
A Mild Method for the Direct Fluor-
ination of Pyrroles by Using a Lipo-
philic Anionic Phase-Transfer Cata-
lyst
A mild fluorination method for pyrr- apolar solvent. The thus obtained
oles has been developed, which is fluorinated pyrroles, bearing func-
based on anionic phase-transfer catal- tional groups, are sought-after build-
ysis by using Selectfluor, a lipophilic ing blocks in medicinal chemistry.
phosphoric acid, and a base in an
DOI: 10.1002/ejoc.201600570
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim