Selective Fluorination of 4-Substituted 2-Aminopyridines and Pyridin-2(1 H)-ones in Aqueous Solution

Article abstract of DOI:10.1021/acs.orglett.8b02003

Fluorination of 2-aminopyridines and pyridin-2(1H)-ones in the presence of Selectfluor, water, and chloroform under mild conditions has been realized. This method gives fluorinated pyridines in good to high yields with high regioselectivities. The electro

Full text of DOI:10.1021/acs.orglett.8b02003

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Selective Fluorination of 4‑Substituted 2‑Aminopyridines and
Pyridin-2(1H)‑ones in Aqueous Solution
Gang Zhou, Yawei Tian, Xiaoming Zhao,* and Wenyan Dan
School of Chemical Technology and Engineering, State Key Laboratory of Pollution Control and Resource Reuse, Tongji University,
1239 Siping Road, Shanghai 200092, P. R. China
S
* Supporting Information
ABSTRACT: Fluorination of 2-aminopyridines and pyridin-
2(1H)-ones in the presence of Selectfluor, water, and
chloroform under mild conditions has been realized. This
method gives fluorinated pyridines in good to high yields with
high regioselectivities. The electron-deficient pyridine system
is activated by an amino or hydroxyl group at C2. The
regioselectivity of the fluorination reaction is strongly
dependent upon the substituent pattern in the 2-amino-
pyridine or pyridin-2(1H)-one. The transformation of the 3-
fluoro-substituted pyridine derivative into fluorinated zolimidine was achieved as well.
yridines are widely found in the scaffold of naturally
Poccurring compounds and popular drugs, such as nicotine,
pyridoxine, esomeprazole, and lansoprazole.1 Incorporating a
fluorine atom into organic compounds often leads to a
significant change in chemical, physical, and biological
properties.2 Accordingly, new methods for introducing a
fluorine atom into pyridine have been drawing great attention
in the past decade. In particular, the fluorine substituent
pattern on the pyridine ring has an extreme impact on the
chemical, physical, and biological activities.3 In fact, selective
fluorination of pyridines is a challenging task. Recently,
fluorination at C2 of the pyridine with silver(II) fluoride
(AgF2) by means of C−H bond activation fluorination was
developed.4 Some bioactive compounds such as gemifloxacin
and trovafloxacin mesylate show excellent biological activities
and contain a 3-fluoropyridine moiety.5 Fluorinated pyridine
derivatives are usually synthesized by alternative strategies,
including the Balz−Schiemann reaction and nucleophilic
aromatic substitution of chloro- or nitropyridines with
anhydrous fluoride (eq I in Scheme 1).6
3-Fluoro-2-aminopyridine derivatives are useful synthetic
intermediates.5 The known methods for the synthesis of 3-
fluoro-2-aminopyridines require the use of strong fluorinating
reagents, which are often unselective and difficult to handle, or
the utilization of less reactive reagents that attack only the
most activated arenes, which reduces the substrate scope. For
example, direct fluorination at C3 with F2 occurs to give 3-
fluoro-substituted pyridine derivatives in low yield with poor
regioselectivity.7 In connection with our previous work,8 we
speculated that the pyridine could be activated by a 2-amino
group and that selective fluorination could occur (eq II in
Scheme 1). In this paper, we describe the fluorination of 2-
aminopyridines and 2-hydroxypyridines with high regioselec-
tivities.
We began with the reaction of 4-phenyl-2-aminopyridine
(1a) with Selectfluor (2a)9 or AgF2 (2b)4 in the presence of
silver or palladium species that are effective catalysts for direct
fluorination of pyridines,4 pyrimidines,8 and arenes,10 but no
fluorinated pyridines were observed (Table 1, entries 1−3). To
our delight, in the absence of a metal catalyst, trace amounts of
fluorinated pyridine were detected with CH3CN as the solvent
(entry 4). The formation of 3-fluoro-4-phenyl-2-aminopyridine
(3a) (10%) and 5-fluoro-4-phenyl-2-aminopridine (3a′)
(trace) was observed when the reaction was conducted in
dichloromethane (DCM) at room temperature (entry 5).
Interestingly, the regioselective fluorination at C3 of the 2-
aminopyridine is not in agreement with the results of the well-
known electrophilic halogenation of 2-aminopyridines, which
generally occurs at C5.11 For instance, chlorination of 4-cyano-
2-aminopyridine at C5 is favored.12 Selectfluor (2a) worked as
not only an oxidizing agent but also a fluorine source in this
The Balz−Schiemann reaction involves strongly acidic and
oxidizing conditions to produce a diazonium salt. This key
intermediate is then heated in anhydrous HF or tetrafluor-
oborate salt to induce fluorination.
Scheme 1. Syntheses of Fluorinated Pyridines from
Aminopyridines
Received: June 27, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02003
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
yield (%)
entry
catalyst (20 mol %)
fluorine source 2
solvent
CH3CN
CH3CN
CH3CN
CH3CN
DCM
THF
toluene
DCM/H2O
3a
3a′
1
2
3
4
5
6
7
8
9
Ag2CO3
AgF2
[Pd(MeCN)4](BF4)2
Selectfluor
AgF2
−
−
−
−
−
−
−
trace
−
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
NFSI
−
−
−
−
−
−
−
−
−
−
−
−
trace
10
trace
trace
36
−
10
c
c
CHCl3/H2O
DCE/H2O
44
38
76
62
9
9
c
10
d
c
c
c
c
c
11
CHCl3/H2O
CHCl3/H2O
CHCl3/H2O
CHCl3/H2O
CHCl3/H2O
18
23
15 (9)
5
de
,
12
13
14
15
df
,
83 (73)
24
dg
,
d
−
−
a
b
Reaction conditions: 1a (0.10 mmol), 2 (0.12 mmol), and solvent (2 mL) at room temperature. Determined by 19F NMR analysis using 1-
c
d
fluoronaphthalene as an internal standard (isolated yields are given in parentheses). Organic solvent/H2O = 1/1. 1a (0.20 mmol) and 2 (0.10
e
f
g
mmol). 35 °C, 6 h. 15 °C, 24 h. 5 °C, 72 h.
case.9b,c Examination of solvents such as CH3CN, DCM,
toluene, and THF revealed that DCM led to a better yield than
others (entries 4−7). More significantly, the two-component
solvent containing water in a 1/1 ratio with the organic solvent
was beneficial for this fluorination, as the solubility of 2a was
improved. Further investigation of halogenated solvents
showed that CHCl3/H2O is suitable for this fluorination
(entries 8−10). The 1a/2a ratio has a large effect on the
results: for 1a/2a = 1/2, a trace amount of 3,5-difluoro-4-
phenyl-2-aminopyridine (3a″) and lower yield of 3a and 3a′
were obtained. To avoid the formation of the byproduct, an
excess of 1a was employed in further investigations (entry 11).
The reactions at temperatures ranging from 5 to 35 °C were
tested, and the one at 15 °C gave the best result (entries 12−
14). When 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO)
(0.4 mmol) was added to the reaction mixture under the
conditions of entry 13, neither 3a nor 3a′ was observed. These
results suggest that this fluorination reaction may pass through
a radical process.13 Next, the bench-stable fluorinating reagent
N-fluorobenzenesulfonimide (NFSI) (2c) was examined and
proved to be ineffective for this reaction (entry 15).
a b
,
Scheme 2. Scope of 2-Aminopyridine Substrates 1
Having established the optimized reaction conditions, we
next examined the scope of various 2-aminopyridines. 1a and
substrates 1b and 1c with an electron-donating group (p-MeO
and p-Me, respectively) on the phenyl ring gave the
corresponding products 3a−3c in good to high yields with
4/1 to 5/1 regioselectivity (Scheme 2). A single crystal of 3a
was obtained, and X-ray diffraction revealed that the
fluorination occurred at C3 of the pyridine. The 4-aryl-
substituted substrates 1d−f with an electron-withdrawing
group (p-F, p-CHO, and m-CHO, respectively) on the phenyl
ring produced the fluorinated products 3d−f in good yields
with 4/1 to 8/1 regioselectivity (Scheme 2). The substrates 1g
and 1h with a heteroaryl group (pyridinyl and quinolinyl,
respectively) gave rise to 3g and 3h14 in fair to good yields
with 6/1 to 8/1 regioselectivity; no other fluorinated
a
Reaction conditions: 2-aminopyridine 1 (0.20 mmol), 2a (0.10
b
mmol), and 1/1 CHCl3/H2O (2 mL) at 15 °C for 24 h. Yields were
determined by 19F NMR analysis using 1-fluoronaphthalene as an
c
internal standard (isolated yields are given in parentheses). Room
temperature, 24 h. 1i−k (0.40 mmol) and 2a (0.10 mmol) in 1/1
CHCl3/H2O (0.5 mL).
d
heterocyclic compounds were observed in these cases.
Furthermore, the substrates 1i−k with an aliphatic substituent
(Me or Et) or Cl at C4 of the pyridine afforded the
corresponding fluorinated products 3i−k in good yields with a
high level of regioselectivity (Scheme 2). Notably, no other
fluorinated 2-aminopyridines were observed in each case. It is
noteworthy that the fluorination of ethylpyridine derivatives
B
DOI: 10.1021/acs.orglett.8b02003
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
with Selectfluor (2a) occurred at the benzyl carbon rather than
at the pyridine ring through radical fluorination.15 The
formation of a benzyl carbon radical is key for this fluorination.
We extended this method to the other pyridine derivatives
such as amides 4, the isomers of 2-hydroxypyridines 4′
(Scheme 3). It is noteworthy that popular drugs16 such as
1/1 mixture of chloroform (7.5 mL) and water (7.5 mL) as the
solvent was conducted at 15 °C. After the completion of this
fluorination, 3i (208 mg, 55% yield, 3i/3i′ = 25/1) was
obtained (Scheme 4).
To demonstrate the potential utilization of 3i for the
synthesis of bioactive imidazo[1,2-a]pyridine compounds,17
a
[3 + 2] annulation reaction18 of 3i with ethynylbenzene (6a)
in the presence of Ag2CO3 at 110 °C selectively provided 8-
fluoro-7-methyl-3-phenylimidazo[1,2-a]pyridine (7a) in 73%
yield. Fluorinated zolimidine17 (7b) was obtained as well in
40% yield over the two steps (Scheme 4).
a b
,
Scheme 3. Scope of 2-Hydroxypyridine Substrates 4
On the basis of our observations and those of others,15
a
plausible mechanism is proposed in Scheme 5. Treatment of 4-
Scheme 5. Plausible Mechanism for This Fluorination
a
Reaction conditions: 4 (0.2 mmol), 2a (0.1 mmol), and CHCl3/
b
H2O (2 mL) at 35 °C for 24 h. Yields were determined by 19F NMR
analysis using 1-fluoronaphthalene as an internal standard (isolated
yields are given in parentheses).
pyridoxine (vitamin B6)16a and omeprazole (Prilosec)16b
contain a hydroxypyridine moiety, which is of great importance
in regard to medicinal chemistry. Thus, a range of amide
substrates 4 was examined under the optimal conditions at a
considerably higher reaction temperature than that of 2-
aminopyridines. The experimental results illustrate that (1) the
fluorination occurred only at C3 on the pyridine ring, and no
other fluorinated 2-hydroxypridines were observed; (2) the
fluorinated 4-aryl-substituted amides 5, the isomers of 4-
substituted 3-fluoro-2-hydroxypyridines 5′, were obtained in
good to high yields, except for 4e, which contains an electron-
withdrawing substituent on the 4-phenyl ring; (3) heteroaryl-
substituted amides such as 4-(thiophen-2-yl)pyridin-2(1H)-
one (4f) and aliphatic-substituted amides such as 4-
methylpyridin-2(1H)-one (4g) work very well; (4) no
fluorination occurred when a hydroxyl group on the pyridine
ring was replaced with a methoxy group. This outcome
indicated that the hydroxyl group is required for this
fluorination (Scheme 3). X-ray diffraction of 5b illustrated
that the fluorination occurred at C3.
substituted 2-aminopyridine 1 with 2a in CH3Cl/H2O at 15
°C initially gives Int A, which forms radical Int B, releasing a
proton through single electron transfer.15 Int B then isomerizes
to form resonance isomers Int C and Int D.13 Consequently,
the reaction of radical Int C with 2a followed by aromatization
of Int E affords 3-fluoro-2-aminopyridine 3 (Scheme 5).
In conclusion, we have developed a selective fluorination of
pyridines with Selectfluor in aqueous solution under mild
conditions. This method allows the use of 2-aminopyridines
and 2-hydroxypyridines as substrates, tolerates various func-
tional groups, and affords fluorinated pyridines in good to high
yields with high regioselectivities.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02003.
Experimental procedures, characterization data for all
new compounds, descriptions of stereochemical assign-
Scheme 4 demonstrates the large-scale synthesis of the
fluorinated pyridine 3i. The reaction of 4-methyl-2-amino-
pyridine (1i) (1.30 g, 12 mmol) with 2a (1.06 g, 3 mmol) in a
1
ments, and copies of H, 19F, and 13C NMR spectra for
all new compounds reported in the text (PDF)
Accession Codes
Scheme 4. Large-Scale Synthesis of 3i and Its Application
for the Synthesis of 7
CCDC 1842092−1842093 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
e-mailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xmzhao08@tongji.edu.cn
C
DOI: 10.1021/acs.orglett.8b02003
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
(12) Furuta, T.; Sawada, T.; Danjo, T.; Nakajima, T.; Uesaka, N.
WO 2012105594, 2012.
(13) Liang, D.; Li, Y.; Gao, S.; Li, R.; Li, X.; Wang, B.; Yang, H.
Green Chem. 2017, 19, 3344.
(14) Compounds containing 3h show excellent biological activities.
See: Zhang, X. WO 2017167150A1, 2017.
Xiaoming Zhao: 0000-0002-1447-128X
Notes
The authors declare no competing financial interest.
(15) Danahy, K. E.; Cooper, J. C.; Van Humbeck, J. F. Angew. Chem.,
Int. Ed. 2018, 57, 5134.
ACKNOWLEDGMENTS
■
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L.; Scirica, B. M.; Murphy, S. A.; Cannon, C. P. N. Engl. J. Med. 2010,
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The authors are grateful to the National Natural Science
Foundation of China (Grant 21272175) and the Fundamental
Research Funds for the Central Universities for financial
support of this research.
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