Synthesis of 4-amino-5-fluoropyrimidines and 5-amino-4-fluoropyrazoles from a β-fluoroenolate salt

Article abstract of DOI:10.3762/bjoc.16.41

A synthesis of fluorinated pyrimidines under mild conditions from amidine hydrochlorides and the recently described potassium 2-cyano-2-fluoroethenolate was developed. A broad substrate scope was tested and mostly excellent yields were obtained. The synthesis of fluorinated aminopyrazoles from the same fluorinated precursor could be demonstrated but proceeded with lower efficiency.

Full text of DOI:10.3762/bjoc.16.41

Synthesis of 4-amino-5-fluoropyrimidines and 5-amino-
-fluoropyrazoles from a β-fluoroenolate salt
4
Tobias Lucas, Jule-Philipp Dietz and Till Opatz*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 445–450.
Institute of Organic Chemistry, Johannes Gutenberg-University,
Duesbergweg 10–14, 55128 Mainz, Germany
doi:10.3762/bjoc.16.41
Received: 20 December 2019
Accepted: 03 March 2020
Published: 20 March 2020
Email:
Till Opatz* - opatz@uni-mainz.de
*
Corresponding author
Associate Editor: J. Aubé
Keywords:
© 2020 Lucas et al.; licensee Beilstein-Institut.
License and terms: see end of document.
cyclization; fluorinated heterocycles; fluorine; pyrazoles; pyrimidines
Abstract
A synthesis of fluorinated pyrimidines under mild conditions from amidine hydrochlorides and the recently described potassium
2
-cyano-2-fluoroethenolate was developed. A broad substrate scope was tested and mostly excellent yields were obtained. The syn-
thesis of fluorinated aminopyrazoles from the same fluorinated precursor could be demonstrated but proceeded with lower effi-
ciency.
Introduction
Due to its extremely widespread application in virtually all as antimetabolites or as nucleoside reverse transcriptase inhibi-
areas of synthetic organic chemistry, fluorine is considered a tors (NRTIs). Two of the most common 5-fluoropyrimidines are
“
magic” element. It confers metabolic stability and other unique the cytostatic 5-fluorouracil (1) [27] and the antimycotic
properties to organic molecules and a large fraction of modern prodrug 5-fluorocytosine (2) [28,29], which is also part of the
pharmaceuticals [1-6] and agrochemicals [7] contain at least anti-HIV agents emtricitabine [30] (ingredient of Truvada®)
one fluorine atom [8-15]. One of the approaches for their syn- and capecitabine [31] (Xeloda®) (see Figure 1) [32,33].
thesis is the use of small fluorinated building blocks which
avoids the often cumbersome regioselective fluorination at a While the introduction of fluorine into preexisting heterocycles
later synthetic stage [15-19].
can require difficult-to-handle, expensive and highly corrosive
electrophilic fluorine species [16,34,35], the present approach
Fluorinated pyrimidines, pyrimidine analogues and pyrazoles employs a fluorinated C3 building block recently described and
20,21] play a prominent role in several clinically important used by our laboratory for the synthesis of 2 [36]. Herein, we
[
pharmaceuticals [22-25]. These compounds act against HIV or present the synthesis of fluorinated pyrimidines and pyrazoles
HIV-related diseases [26], such as opportunistic fungal infec- from the same precursor. Potassium (Z)-2-cyano-2-fluoro-
tions, and represent nucleoside analogues which can either act ethenolate (8) was synthesized in three steps starting from
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Beilstein J. Org. Chem. 2020, 16, 445–450.
Figure 1: The structures of 5-fluorouracil (1), 5-fluorocytosine (2), emtricitabine (3) and capecitabine (4).
chloroacetamide (5). First, a Finkelstein halogen exchange reac- As the fluorine atom is part of a building block, harsh condi-
tion and a dehydration reaction were combined to obtain tions for a late-stage fluorination can be avoided, and even
fluoroacetonitrile (7) in 82% yield [36]. The latter then under- products with sensitive functionalities are accessible.
went a Claisen condensation with ethyl formate to obtain 8 in
Results and Discussion
7
1
7% yield with a purity of 90%. The product contained about
0% (1H NMR) of potassium formate, which could not easily Synthesis of fluorinated pyrimidines
be removed without risking the decomposition of the enolate To synthesize 2-alkyl- and 2-aryl-substituted 5-fluoro-4-
salt (Scheme 1).
aminopyrimidines, the reaction of 8 with various amidines was
investigated. Different formamidinium and guanidinium salts
were tested (Table 1) to evaluate the effect of the counter ion.
The hydrochlorides furnished the highest yields and no unde-
sired byproducts were formed. In contrast to the related reac-
tion with guanidinium salts [36], the reactions with amidine
hydrochlorides did not require any basic additives.
Under these improved conditions, the scope of the reaction for
producing alkyl-substituted pyrimidine derivatives was investi-
gated (Scheme 2). Starting from formamidine hydrochloride,
compound 10a was synthesized in 85% yield. A variety of
amidines with different steric hindrance such as methyl, cyclo-
propyl and tert-butyl substitution was used, and all substituents
Scheme 1: Synthesis of potassium (Z)-2-cyano-2-fluoroethenolate (8)
by Dietz et al. [36].
Table 1: Testing of different counter ions.
Entry
Starting material
R
Counter ion
Yield
1
2
3
4
9a
9b
9c
9d
H
H
NH2
NH2
acetate
chloride
carbonate
chloride
78% (10a)
85% (10a)
90% (10b)
94% (10b)
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Beilstein J. Org. Chem. 2020, 16, 445–450.
Scheme 2: Scope of the cyclization reaction. All yields are those of the purified products. aNo further purification was required to obtain analytically
pure material. bUse of sodium methoxide. cUsing O-methylisourea hemisulfate. dReaction time of 24 h. eProduct detected by LC–MS.
were well tolerated, providing the corresponding fluorinated The 4-chloro and 4-bromo derivatives (10m and 10n) were also
aminoalkylpyrimidines (10d–f) in yields of 81–93%.
obtained in excellent yields of 93% and 97%, respectively, and
represent potential substrates for subsequent cross-coupling
In spite of its potential electrophilic reactivity, the chloro- reactions, which would provide structurally more complex
methyl derivative 10g was obtained in excellent yield (90%) products.
and could be used for further modifications to construct more
complex products. Subsequently, benzamidine derivatives with Amidines with heterocyclic substituents were also evaluated.
a broad variety of substituents on the benzenoid core were eval- While the pyridine-substituted derivative 10o furnished a yield
uated as the nucleophiles. Benzamidine hydrochloride itself of 86%, the pyrazolo derivative 10p could only be obtained in a
yielded compound 10h with an excellent yield of 93%. A moderate yield of 38%. This might be explained by the tenden-
variety of substituted products including electron-donating cy of the pyrazolo moiety to act as a leaving group and a
(
compounds 10i–k) and electron-withdrawing groups (com- following addition–elimination reaction with methanol can take
pound 10l) were formed in nearly quantitative yields (95–99%). place (the corresponding 2-methoxy-substituted product was
Only the 4-hydroxyphenyl derivative 10j was obtained in a detected by LC–MS). This side reaction could also be observed
moderate yield (69%) presumably due to competing polymeri- in the attempted synthesis of the triazolo derivative 10r, where
zation of the enolate.
the desired pyrimidine could only be detected in traces by
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Beilstein J. Org. Chem. 2020, 16, 445–450.
LC–MS. Another limitation of the substrate scope was ob- use of non-nucleophilic bases, but with DBU, polymerization of
served in the cyclization with an Nα-protected arginine, where the fluoroenolate took place.
the desired pyrimidine 10q was also only observed in trace
amounts while the majority of the starting material remained
unchanged.
Synthesis of fluorinated aminopyrazoles
As in the cyclocondensation with amidines, the reaction of 8
with other bifunctional nucleophiles could also result in the for-
mation of fluorinated heterocycles. While attempts to obtain an
aminooxazole upon reaction with hydroxylamine were unsuc-
cessful, substituted hydrazines turned out to provide moderate
yields of fluorinated pyrazoles. Phenylhydrazine (12a) was
chosen as the model substrate for optimization (Table 2).
Scheme 3: Cyclization with phenylhydrazine (12a) to obtain the
desired pyrazole 13a and the byproducts 13b and 13c (detected via
LC–MS).
In the first reactions, only traces of the desired compound 13a
were observed. Changing the temperature did not increase the When using aqueous sodium hydroxide as the base, a 19% yield
yield. Acidic conditions were tested next but phenylhydrazine could be achieved. Switching the solvent to water led to an
hydrochloride and acetic acid again gave only traces of 13a and improvement of the yield to 36% (Table 2). In water, but with-
polymerization of the enolate took place. To stabilize the out using a base, the N-methylpyrazole 13d and the N-(2-
starting material, basic conditions were tested as well and pyridyl)-substituted derivative 13e could be obtained in 41%
various bases were used. With sodium methoxide, only traces of and 21% yield, respectively.
compound 13a could be detected and in addition, the dehalo-
genated- and methoxy-substituted derivatives (13b and 13c) The formation of the other possible aminopyrazole regioisomer
were observed (Scheme 3). This prompted us to investigate the was not observed, which could be explained by the preferential
Table 2: Synthesis of fluorinated pyrazoles.
Entry
R
Solvent
T [°C]
Additive
Results
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Phb
Ph
Ph
Ph
Ph
Ph
Ph
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
H2O
H2O
H2O
H2O
H2O
rt
5–10
−10
−10
5–10
0–5
0–5
0–5
rt
rt
rt
rt
rt
–
–
–
–
traces of 13a and 13ba
polymerization
polymerization
polymerization
polymerization
13a–ca
AcOH
NaOMe
DBU
NaOHaq
–
AcOH
NaOHaq
–
polymerization
13a (19%)c
traces of 13aa
polymerization
13a (36%)c
1
1
1
1
0
1
2
3
Phb
Me
2-Py
13d (41%)c
13e (20%)c
–
aDetected by LC–MS. bThe corresponding hydrochloride was used. cIsolated yield.
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Beilstein J. Org. Chem. 2020, 16, 445–450.
7
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Conclusion
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In summary, a synthesis of fluorinated pyrimidines under mild
conditions using fluoroenolate 8 and amidines in a cyclocon-
densation was developed. A series of substrates carrying ali-
phatic and aromatic substituents was successfully tested and
various functional groups were tolerated. The products could be
mostly isolated in excellent yields. Furthermore, the synthesis
of fluorinated pyrazoles from the same fluorinated enolate was
demonstrated, albeit in only low to moderate yields. Neverthe-
less, the presented method provides a simple and short route to
hitherto unknown compounds of this type.
1
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Supporting Information
Supporting Information File 1
Chemical procedures and analytical data, including copies
of 1H NMR and 13C NMR spectra.
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