A novel and effective approach to 4-fluoropyrimidines

Article abstract of DOI:10.1016/j.tetlet.2013.11.070

A series of 4-fluoropyrimidine 1-oxides, obtained via three-component heterocyclization, was studied under various reduction conditions. An effective preparative method for the synthesis of 4-fluoropyrimidines from readily available starting materials was elaborated. 4-Fluoro-substituted tetrahydroquinazolines and tetrahydroquinazoline N-oxides were demonstrated to be highly reactive in aromatic nucleophilic substitution.

Full text of DOI:10.1016/j.tetlet.2013.11.070

Accepted Manuscript
A novel and effective approach to 4-fluoropyrimidines
Kseniya N. Sedenkova, Elena B. Averina, Yuri K. Grishin, Tamara S.
Kuznetsova, Nikolay S. Zefirov
PII:
S0040-4039(13)02017-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.11.070
TETL 43865
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 October 2013
25 October 2013
14 November 2013
Please cite this article as: Sedenkova, K.N., Averina, E.B., Grishin, Y.K., Kuznetsova, T.S., Zefirov, N.S., A novel
and effective approach to 4-fluoropyrimidines, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.
2013.11.070
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Graphical Abstract
A novel and effective approach to 4-
fluoropyrimidines
Leave this area blank for abstract info.
Kseniya N. Sedenkova, Elena B. Averina, Yuri K. Grishin, Tamara S. Kuznetsova, Nikolay S. Zefirov
F
F
R1
R2
R1
R2
R1
R2
-
NO+BF4
RCN
F
N
N
PCl3
CHCl3
Br
N
O
R
N
R

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A novel and effective approach to 4-fluoropyrimidines
Kseniya N. Sedenkovaa, b, Elena B. Averinaa, b, , Yuri K. Grishina, Tamara S. Kuznetsovaa, b, Nikolay S.
Zefirov a, b
aLomonosov Moscow State University, Department of Chemistry, Leninskie Gory, 1-3, Moscow 119991, Russia
bIPhaC RAS, Severnyi Proezd, 1, Chernogolovka, Moscow Region, 142432, Russia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of 4-fluoropyrimidine 1-oxides, obtained via three-component heterocyclization, was
studied under various reduction conditions. An effective preparative method for the synthesis of
4-fluoropyrimidines from readily available starting materials was elaborated. 4-Fluoro-
substituted tetrahydroquinazolines and tetrahydroquinazoline N-oxides were demonstrated to be
highly reactive in aromatic nucleophilic substitution.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
4-fluoropyrimidine N-oxides
4-fluoropyrimidines
reduction
aromatic nucleophilic substitution
Fluorine-substituted organic molecules have found broad
application in the design of pharmaceuticals and agrochemicals,
and in most cases, they contain the fluorine atom connected to an
aryl or heteroaryl moiety.1 In particular, fluoro-substituted
pyrimidines are standard building blocks in the construction of
molecules with a wide range of biological activity, including
anticancer,2 antiviral,3 antifungal4 and herbicidal activities.5
Moreover, pyrimidines containing a fluorine atom at position 4 or
6 are highly reactive in SNAr processes and represent useful
synthetic intermediates as precursors of aminopyrimidines,6
pyrimidinones,7 aryloxy8 and heteroaryloxypyrimidines,9 and
heterocyclic10 and macrocyclic11 compounds with valuable
properties.
precursors for 4-fluoropyrimidines, and herein we report a novel,
convenient approach to substituted pyrimidines via reduction of
the corresponding pyrimidine N-oxides.
We synthesized a series of 4-fluoropyrimidine N-oxides 2a–g
(Table 1) and investigated them under various reduction
conditions, aiming to obtain 4-fluoropyrimidines. For this
purpose we chose several reducing agents, which have been
reported in reactions with heterocyclic N-oxides, namely,
F
R1
R2
R1
RCN
F
Br NO+BF4
N
-
R2
N
O
R
1
2
However, the number of synthetic routes to 4/6-
fluoropyrimidines remains quite limited. The only general
approach to these heterocycles is via nucleophilic substitution of
other halogen atoms or, rarely, an NMe3+ group on treatment with
sources of nucleophilic fluorine.12 There are several examples of
the synthesis of 4/6-fluoropyrimidines via cyclization and
recyclization, but all of them are based on polyfluorinated
starting compounds and lead to either polyfluoro or
trifluoromethyl-substituted pyrimidines, being therefore of quite
narrow application.13
R=Alk, Ph
-
R1=H, R2=Alk, Ar; -R1-R2- = -(CH2)4
Scheme 1. Synthesis of 4-fluoropyrimidine N-oxides via
heterocyclization of gem-bromofluorocyclopropanes.14
hydrogen,15 triethyl phosphite,16 phosphorus(III) chloride17 and
triphenylphosphine.18
Reduction of 4-fluorotetrahydroquinazoline N-oxide 2a by
hydrogen in methanol over 10% Pd/C led to a complex mixture
of products, and no trace of the desired 4-fluoro-5,6,7,8-
tetrahydro-2-methylquinazoline 3a was observed in the NMR
spectra of the reaction mixture. The same result was obtained
when we used P(OEt)3 under reflux in 1,2-dichloroethane:
We have previously elaborated an effective synthetic method
affording novel 4-fluoropyrimidine N-oxides 2 based on the
three-component
heterocyclization
of
gem-
bromofluorocyclopropanes 1 with NOBF4 in the presence of
organic nitriles (Scheme 1).14 Heterocycles 2 represent excellent
———
1
according to the H NMR spectrum of the reaction mixture, no
 Corresponding author. Tel.: +7-495-939-3969; fax: +7-495-939-3969; e-mail: elaver@org.chem.msu.ru

2
Tetrahedron
reduction proceeded, while the starting N-oxide 2a decomposed
significantly.
F
O
N
Al2O3
N
NH
The reaction of N-oxide 2a with triphenylphosphine, carried
N
R
R
out in acetonitrile under reflux, yielded a single product. To our
surprise,
3a,b
5a, 32%
5b, 38%
it
was
not
the
pyrimidine
3a,
but
triphenyl(heteroaryl)phosphonium salt 4, resulting from
nucleophilic attack of the phosphorus on the carbon atom of the
heterocycle (Scheme 2).19 Even on using a five-fold excess of
triphenylphosphine, we did not observe any trace of the
tetrahydroquinazoline 3a nor the reduced phosphonium salt. It
should be noted that similar processes leading to tetraaryl or
triaryl(heteroaryl)phosphonium salts, described in the literature,
require either harsh reaction conditions20 or transition metal
catalysts and reagents,21 while the above-mentioned reaction
taking place under mild conditions represents an example of the
extraordinary reactivity of 4-fluoropyrimidine N-oxide in SNAr
OH
OH
OH
OH
OH
OH
R
N
R
3
3
N
N
O
O
F
N
2
2
l
l
- F-
A
A
R
N
R
N
HN
HO
O
N
processes.22
F
N
3a
F
N
Scheme 3. Transformation of 4-fluorotetrahydroquinazolines 3a,b
on the surface of Al2O3.
PPh3
CH3CN
80 oC
N
N
O
2a
PPh3F
N
In conclusion, we have shown that 4-fluoropyrimidines can be
accessed by a two-step synthetic protocol, involving the
heterocyclization of gem-bromofluorocyclopropanes and
subsequent reduction of the resulting pyrimidine N-oxides with
PCl3. The methods employed are extremely mild and provide a
general route to this important class of heterocycles, which are of
potential synthetic and pharmacological interest.
4, 79%
N
O
Scheme 2. Substitution of fluorine in 4-fluoropyrimidine oxide 2a on
treatment with triphenylphosphine.
The reaction of N-oxide 2a with the phosphorus(III) reagent,
Acknowledgments
PCl3, in chloroform under reflux afforded the desired 4-
24
fluorotetrahydroquinazoline 3a (Table 1).23, We also used 4-
We thank the Russian Foundation for Basic Research (Project
11-03-01040-а) and the Presidium of RAS (Program N 8) for
financial support of this work. The research was facilitated using
an Agilent 400-MR NMR spectrometer, purchased under the
program of MSU development.
fluoropyrimidine N-oxides 2b–g in the reaction using the same
conditions and obtained a series of 4-fluoropyrimidines 3b–g in
good to excellent yields (Table 1).25 It should be noted that
compounds 3a–g were isolated with purities exceeding 95% after
work-up.
Table 1. Synthesis of 4-fluoropyrimidines 3a–g.
Supplementary data
F
F
R1
R1
-
NO+BF4
R1
R2
F
PCl3
N
Supplementary data
characterization data for compounds 3a–g, 4, 5a, b) associated
with this article can be found in the online version.
(experimental
procedures
and
N
CHCl3
60 oC
R2
N
O
Br
RCN
R
R2
N
3a-g
R
1a-g
2a-g
Compounds 1–3
Yield of 2 (%)14 Yield of 3 (%)a
References and notes
a
b
c
d
e
f
R1-R2 = -(CH2)4-, R=CH3
R1-R2 = -(CH2)4-, R=C2H5
R1-R2 = -(CH2)4-, R=t-Bu
R1-R2 = -(CH2)4-, R=Ph
R1=H, R2=Hex, R=CH3
R1=H, R2=Ph, R=CH3
47
46
60
20
57
39
53
68
88
90
93
90
95
89
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1032.
g
R1=H, R2=3-Cl-C6H4, R=CH3
5. Johnson, T. C.; Martin, T. P.; Mann, R. K.; Pobanz, M. A. Bioorg.
Med. Chem. 2009, 17, 4230.
a Isolated yields
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An attempt to perform column chromatography of 4-
fluorotetrahydroquinazolines 3a,b on commercial neutral Al2O3
unexpectedly led to the complete transformation of the starting
compounds into pyrimidinones 5a,b, apparently, resulting from
nucleophilic substitution of the highly reactive fluorine by
hydroxyl groups present on the surface of alumina (Scheme 3).26
Examples of nucleophilic reactions where the surface of alumina
functions as a reagent are known in the literature.27
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the corresponding phosphonium salt, (2-methyl-5,6,7,8-
tetrahydroquinazolin-4-yl)(triphenyl)phosphonium fluoride in
95% yield (see Supplementary data).
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Dominguez, C.; Falsey, J.; Gavva, N. R.; Katon, J.; Nixey, T.;
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Dehaen, W.; Maes, W. Org. Lett. 2011, 13, 126. (b) Ranjbar-
Karimi, R.; Sandford, G.; Yufit, D. S.; Howard J. A. K. J.
Fluorine Chem. 2008, 129, 307.
12. (a) Brown, D. J. In The Chemistry of Heterocyclic Compounds:
The Pyrimidines; Brown, D. J., Ed.; John Wiley & Sons: New
York, 1994, Vol. 52, pp. 345–347. (b) Gebhardt, P.; Saluz, H. P.
ARKIVOC, 2012, 159. (c) Bennett, B. K.; Harrison, R. G.;
Richmond, T. G. J. Am. Chem. Soc. 1994, 116, 11165. (d) Andres,
P.; Marhold, A. J. Fluorine Chem. 1996, 77, 93. (e) Yoneda, N.;
Fukuhara, T. Tetrahedron, 1996, 52, 23. (f) Darabantu, M.;
Lequeux, T.; Pommelet, J.-C.; Ple, N.; Turck, A. Tetrahedron,
2001, 57, 739.
23. General procedure for the reduction of pyrimidine N-oxides 2a–g:
PCl3 (27.4 mg, 0.017 ml, 0.2 mmol) was added dropwise to a
stirred solution of pyrimidine N-oxide 2a–g (0.1 mmol) in CHCl3
(1 ml) and the mixture was refluxed for 2 h. Then it was allowed
to cool to r.t. and quenched with an equal amount of ice–water.
The organic phase was separated and the water phase extracted
with CHCl3 (3×1 mL). The combined organic layers were washed
with a saturated solution of NaHCO3 (3 ml) and with H2O (3 ml)
and dried over MgSO4. The solvent was evaporated in vacuo, the
purities of compounds 3a–g was above 95%.
24. 4-Fluoro-5,6,7,8-tetrahydro-2-methylquinazoline (3a). Yield 68%
(11.3 mg) from 2a (18.2 mg), Rf=0.2 (petroleum ether:CHCl3,
1:1), colorless oil. 1H NMR (400.0 MHz, CDCl3) δ: 1.76–1.92 (m,
4H, 2CH2), 2.59 (s, 3H, CH3), 2.64 (br t, 2H, 3JHH 6.2 Hz, CH2),
2.83 (br t, 2H, 3JHH 6.3 Hz, CH2); 13C NMR (100.6 MHz, CDCl3)
δ: 20.6 (CH2), 21.4 (CH2), 21.9 (CH2), 25.2 (CH3), 31.7 (3JCF 5 Hz,
CH2), 112.8 (2JCF 27 Hz, C4a), 165.1 (3JCF 14 Hz, C2), 167.6 (1JCF
251 Hz, CF), 170.2 (3JCF 7 Hz, С8a); 19F NMR (376.3 MHz,
CDCl3) δ: -68.14 (s, 1F). HRMS (ESI): calcd for C9H11FN2
[M+H]+: 167.0979. Found: 167.0988.
25. 4-Fluoro-2-methyl-6-phenylpyrimidine (3f).Yield 95% (17.9 mg)
from 2f (20.4 mg), Rf=0.6 (CHCl3), colorless oil. 1H NMR (400.0
MHz, CDCl3) δ: 2.74 (s, 3H, CH3), 7.12 (br s, 1H, CH, Pyr), 7.49–
7.52 (m, 3H, 3CH, Ph), 8.03–8.07 (m, 2H, 2CH, Ph); 13C NMR
(100.6 MHz, CDCl3) δ: 25.9 (CH3), 99.1 (2JCF 31 Hz, C5), 127.3
(2CH, Ph), 129.0 (2CH, Ph), 131.3 (CH, Ph), 136.0 (4JCF 5 Hz, C,
Ph), 168.8 (3JCF 7 Hz, C6), 169.4 (3JCF 14 Hz, C2), 170.7 (1JCF 250
Hz, C4); 19F NMR (376.3 MHz, CDCl3) δ: -61.38 (s, 1F). HRMS
(ESI): calcd for C11H9FN2 [M+H]+: 189.0823. Found: 189.0823.
26. Column chromatography was performed on aluminum oxide
―Acros organics‖ (activated, neutral, 50–200 micron). Employing
aluminum oxide, previously dried at 400 oC, led to complete
decomposition of compound 3a.
27. See for example: (a) Varma, R. S.; Lamture, J. B.; Varma M.
Tetrahedron Lett. 1993, 34, 3029. (b) Hondrogiannis, G.; Tan, L.
Ch.; Pagni, R. M.; Kabalka, G. W.; Herold, S.; Ross, E.; Green, J.;
McGinnis M. Tetrahedron Lett. 1994, 35, 6211. (c) Wilgus, C. P.;
Downing, S.; Molitor, E.; Bains, S.; Pagni, R. M.; Kabalka, G. W.
Tetrahedron Lett. 1995, 36, 3469. (d) Debnath, K.; Pathak S.;
Pramanik, A. Tetrahedron Lett. 2013, 54, 896.
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Zhuzhgov, E. L. J. Fluorine Chem. 2000, 103, 105. (b) German,
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Chem. Bull. 1997, 46, 1920. (c) Inouye, Y.; Higuchij, Y. J.
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K. R.; Sargent, C. R. J. Chem. Soc., Perkin Trans. 1, 1981, 1071.
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Chem. 2012, 77, 9893.
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19. (2-Methyl-1-oxido-5,6,7,8-tetrahydroquinazolin-4-
yl)(triphenyl)phosphonium fluoride (4). PPh3 (350.0 mg, 1.32
mmol) was added to a solution of tetrahydroquinazoline N-oxide
2a (80.0 mg, 0.44 mmol) in MeCN (1 ml) and the reaction mixture
was refluxed for 48 h. After cooling to r.t., the solvent was
evaporated in vacuo. The solid residue was washed with Et2O (10
ml) to remove the excess of PPh3. Yield 79% (154.5 mg), white
amorphous solid, Rf=0.9 (CHCl3: CH3OH, 1:1). 1H NMR (400.0
MHz, CDCl3) δ: 1.56–1.64 (m, 2H, CH2(6)), 1.80–1.90 (m, 2H,
CH2(7)), 2.12 (br t, 2H, 3JHH 6.2 Hz, CH2(5)), 2.54 (s, 3H, CH3),
2.93 (br t, 2H, 3JHH 6.5 Hz, CH2(8)), 7.65-7.71 (m, 6H, 6CH, Ph),
7.72-7.80 (m, 6H, 6CH, Ph), 7.83-7.90 (m, 3H, 3CH, Ph); 13
C
NMR (100.6 MHz, CDCl3) δ: 19.7 (CH3), 20.1 (CH2(7)), 20.7
(CH2(6)), 25.3 (CH2(8)), 27.6 (CH2(5)), 116.8 (1JCP 89, 3C, Ph),
129.5 (1JCP 124 Hz, C4), 130.7 (JCP 13 Hz, 6CH, Ph), 134.5 (JCP
10 Hz, 6CH, Ph), 135.7 (4JCP 3 Hz, 3CH, Ph), 137.9 (2JCP 25 Hz,
C4a), 157.7 (3JCP 11 Hz, C8a), 158.7 (3JCP 23 Hz, C2); 31P NMR
(161.9 MHz, CDCl3) δ: 19.05 (s, 1P); 19F NMR (376.3 MHz,
CDCl3) δ: –152.87 (s, 1F). HRMS (ESI): calcd for [C27H26N2OP+]:
425.1777. Found: 425.1763.
20. (a) Egg, H.; Richter, W.; Bretschneider, H. Monash. Chem., 1969,
100, 518. (b) Okui, K.; Ito, K.; Kametani, T. J. Heterocycl. Chem.
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2008, 73, 590.
22. Obtained later in the course of this work, 4-fluorotetrahydroquina-
zoline 3a was found to be even more reactive in this process. The
reaction of 3a with PPh3 proceeded at r.t. in CHCl3 and afforded

Graphical Abstract
A novel and effective approach to 4-
fluoropyrimidines
Leave this area blank for abstract info.
Kseniya N. Sedenkova, Elena B. Averina, Yuri K. Grishin, Tamara S. Kuznetsova, Nikolay S. Zefirov
F
F
R1
R2
R1
R2
R1
R2
-
NO+BF4
RCN
F
N
N
PCl3
CHCl3
Br
N
O
R
N
R