3-(Polyfluoroacyl)chromones and their hetero analogues as valuable substrates for syntheses of 4-(polyfluoroalkyl)pyrimidines

Article abstract of DOI:10.1055/s-0029-1216957

Reactions of 3-(polyfluoroacyl)chromones and their hetero analogues with a number of 1,3-NCN-dinucleophiles, such as amidines or guanidines, were studied in detail, and preparative access to a set of diverse 5-salicyloyl-4- (polyfluoroalkyl)pyrimidines wa

Full text of DOI:10.1055/s-0029-1216957

PAPER
3233
3-(Polyfluoroacyl)chromones and Their Hetero Analogues as Valuable
Substrates for Syntheses of 4-(Polyfluoroalkyl)pyrimidines
4
-(Polyfluoroalkyl
n
)
pyrimidine
s
ton Kotljarov,a,b Roman A. Irgashev,c Viktor O. Iaroshenko,*d,e Dmitri V. Sevenard,f
Vyacheslav Ya. Sosnovskikhc
a
Fachbereich Chemie, Universität Konstanz, Fach M-720, Universitätsstr. 10, 78457 Konstanz, Germany
Institute of Organic and Bioorganic Chemistry, University of Tartu, Jakobi 2, 51014 Tartu, Estonia
Department of Chemistry, Ural State University, pr. Lenina 51, 620083 Ekaterinburg, Russian Federation
Enamine Ltd, 23 A. Matrosova st., 01103 Kyiv, Ukraine
b
c
d
Fax +380(44)5373253; E-mail: yaroshenko@enamine.net
National Taras Shevchenko University, 62 Volodymyrska st., Kiev-33, 01033, Ukraine
Hansa Fine Chemicals GmbH, BITZ, Fahrenheitstr. 1, 28359 Bremen, Germany
e
f
Received 23 February 2009; revised 29 May 2009
Dedicated to Professor Yulian Volovenko on the occasion of his 55th birthday
The known methods for the synthesis of fluorinated pyri-
midines can be classified as belonging to one of three gen-
eral strategies. The first and most commonly used
approach involves a two-component reaction between a
Abstract: Reactions of 3-(polyfluoroacyl)chromones and their het-
ero analogues with a number of 1,3-NCN-dinucleophiles, such as
amidines or guanidines, were studied in detail, and preparative ac-
cess to a set of diverse 5-salicyloyl-4-(polyfluoroalkyl)pyrimidines
was elaborated. These compounds appear to be a suitable starting 1,3-NCN-dinucleophile (an amidine or guanidine) and a
1,3-CCC-dielectrophile bearing a fluorinated moiety.5
The second strategy is based on the direct insertion of a
substrates for the synthesis of 4-(polyfluoroalkyl)pyrimidine-5-car-
boxylic acids or pyrimidines containing a benzofuran-3-yl substitu-
ent in the 5-position.
fluorinated group, either from an organometallic
precursor6 or by the transformation of a specially intro-
Key words: chromones, thiochromones, fluorine, pyrimidine core
duced group into one containing fluorine.7 The third gen-
annulation, regioselectivity, heterocycles
eral strategy involves an inverse-electron-demand Diels–
Alder protocol;8 this is comparatively rare and has been
used only for the synthesis of condensed fluorinated pyri-
midines.
3-Acylchromones, and especially 3-formylchromones,
which can be considered as 1,3-dicarbonyl compounds
with a masked salicyloyl fragment at the 2-position, re-
present an important class of oxygen heterocycles. Mole-
cules of these chromones possess three electrophilic
centers, so their interaction with nucleophiles sometimes
is somewhat unpredictable.1 Previously, a number of pre-
parative methods leading to pyrimidines have been elabo-
rated on the basis of reactions of 3-acylchromones with
various amidines and guanidines.2
In continuing our previous work in this field,5b,g,h,8 we re-
port here the use of 3-(polyfluoroacyl)chromones 1 as
novel and versatile substrates for the assembly of a pyri-
midine core bearing a polyfluoroalkyl substituent. These
polyfluoroacylated compounds readily and reversibly
1
form covalent hydrates 2, as observed from their H and
19F NMR spectra, which contain two sets of signals.
Pyrimidines containing a polyfluoroalkyl group are well
known pharmacophores that occur in numerous bioactive
substrates. Fluorinated pyrimidines have been identified
as potent and specific inhibitors of prostaglandin-endo-
peroxide synthase 2 (PTGS2; COX-2),3a as well as being
useful in the treatment of some diseases, including neo-
plasms.3b Some representatives of the class are selective
agonists of cannabinoid receptor type 2 (CB2) and can be
used for treatment of inflammatory pain.4 However, the
range of preparative methods for incorporating a polyflu-
oroalkyl function in a pyrimidine moiety or for assem-
bling the pyrimidine framework with a fluoroalkyl
substituent remains limited.
O
O
O
RF
O
O
1
Me
route A
N
route B
OH
RF
Me
O
OH
O
O
OH
OH
3
4
RF
2
Scheme
1
Routes to 3-(polyfluoroacyl)chromones and their
hydrates
Chromones 1, as mixtures with their corresponding hy-
drates 2, are easily accessible compounds, and can be ob-
tained either by trifluoroacetylation of (2E)-3-
(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one
SYNTHESIS 2009, No. 19, pp 3233–3242
Advanced online publication: 21.08.2009
DOI: 10.1055/s-0029-1216957; Art ID: P03009SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
9

3234
A. Kotljarov et al.
PAPER
(3; route A)9 or by formylation of 2-hydroxy-2-(polyfluo-
roalkyl)chroman-4-ones 4 with diethoxymethyl acetate at
140–150 °C for 15 min (route B)10 (Scheme 1). The struc-
ture of the hydrate 2 (RF = CF3) was confirmed unambig-
uously by means of a single crystal X-ray analysis
(Figure 1).
Table 1 Synthesis of 4-(Polyfluoroalkyl)pyrimidines 5a–p by
Reaction of Chromones 1 with 1,3-NCN-Binucleophiles
Pyrimidine RF
R1
H
H
H
Me
Cl
H
H
H
H
H
H
H
H
H
H
H
R2
H
H
H
H
H
X
Yield (%)
87
5a
5b
5c
5d
5e
5f
CF3
H
CF3
Me
Ph
Ph
Ph
87
CF3
92
CF3
49
CF3
44
CF3
MeO Ph
58
5g
5h
5i
CF3
H
H
H
H
H
H
H
H
H
H
4-HOC6H4
94
CF3
4-H2NC6H4
NH2
92
Figure 1 Molecular structure of hydrate 2 (RF = CF3)
CF3
84
To develop a new synthesis of polyfluoroalkyl-containing
pyrimidines that could be used for the preparation of
more-complex molecules, we studied the reaction of 1
with a number of 1,3-NCN-dinucleophiles. We found that
treatment of chromones 1 with amidine or guanidine salts
in the presence of sodium acetate in dry N,N-dimethyl-
formamide at 80 °C for 12 h gave the corresponding 4-
(polyfluoroalkyl)pyrimidines 5a–p in 27–94% yields, af-
ter optimization. The first step of the reaction appears to
involve an attack at the C-2 atom of the chromone by the
amino function, with concomitant opening of the pyrone
ring (1,4-addition; intermediate A). Subsequent intramo-
lecular attack at the RFCO group by the second nitrogen
leads to 5-acylated 4-RF-pyrimidines 5a–p (Scheme 2,
Table 1). Given the actual interest in fluoroheteroaromat-
ics as pharmaceutical intermediates,11 this novel entry to
fluorinated pyrimidines is noteworthy and complements
the published synthetic methods.
5j
CF3
NMe2
morpholino
Ph
91
5k
5l
CF3
80
CF2H
(CF2)2H
CF2H
(CF2)2H
(CF2)2CF3
52
5m
5n
5o
5p
Ph
68
NH2
57
NH2
27
Me
86
The alternative cyclization of A involving the imino group
and the carbonyl carbon atom connected to the benzene
ring to give 5H-chromeno[4,3-d]pyrimidin-5-ols 6 does
not occur except in the case of morpholinoformamidine,
where this pathway was observed and compound 6k was
isolated in 18% yield, in addition to product 5k. Note that
phenyl chromone-3-sulfonate undergoes a ring transfor-
mation with amidines to give the corresponding benzoxa-
thiinopyrimidines.12
O
R1
R2
CORF
H2N
HN
The structure and composition of 4-RF-pyrimidines 5a–p
+
X
1
were confirmed by 1-dimensional (1D) H, 19F, and 13C
O
1
NMR spectroscopy, 2D NMR correlation spectroscopy
(COSY), 1H–13C heteronuclear multiple bond correlation
(HMBC) spectroscopy, atmospheric-pressure spray ion-
ization (APSI) mass spectrometry, and elemental analy-
sis. In the case of RF = CF3, the most convincing evidence
for the formation of 5 was the chemical shift of C-4
i
OH
R1
O
OH
O
RF
N
CORF
N
R2
NH
X
R2
X
2
(d = 150–154 ppm) with a coupling constant JC,F = 35–
R1
5a–p
A
37 Hz. In rotating-frame Overhauser effect spectroscopy
(ROESY), a correlation of the pyrimidine proton in the 6-
position (d = 8.4–9.2 ppm) with the protons of the salicyl-
ic moiety was clearly observed. The 13C NMR spectra of
5a–p displayed a low-field signal at d = 196–198 ppm in
CDCl3 and at d = 192–194 ppm in DMSO-d6 for the car-
bonyl group carbon. With regard to the structure of com-
pound 6k, the resonance of the sp3-carbon atom was
observed at 95.5 ppm with 2JC,F = 33 Hz.
HN
X
O
X
N
N
N
N
N
R1
R2
OH
RF
OH
O
O
CF3
6
6k
The 3-(polyfluoroacyl)thiochromones 7, which are thio
analogues of 1, are previously unknown compounds. We
Scheme 2 Reagents and conditions: (i) DMF, 80 °C, 12 h.
Synthesis 2009, No. 19, 3233–3242 © Thieme Stuttgart · New York

PAPER
4-(Polyfluoroalkyl)pyrimidines
3235
recently elaborated a method for preparing these mole- ly for aromatic amines10 (Scheme 5, Table 3). Note that
cules from easily available thiochroman-4-one (2,3-dihy- condensation of 3-formylchromones with sulfa-
dro-4H-1-benzothiopyran-4-one).13 Thiochromones 7 are guanidine16 results in the formation of the corresponding
less reactive than 1, but they are still able to react with Schiff’s bases, the 3-[(4-guanidinosulfonyl)phenylimi-
amidines and guanidines salts under harsher conditions nomethyl]chromones. This different behavior is not unex-
(N,N-dimethylformamide, 12 h, 100 °C) to give good pected, in that the presence of an RF group will tend to
yields of the corresponding pyrimidines 8a–e (Scheme 3 complicate the dehydration stage.
and Table 2).
The structures of adducts 11a–d were determined by us-
ing spectral data for related compounds.10 The IR spectra
O
S
SH
O
RF
N
of 11a–d showed absorption bands in the ranges 3450–
3220 and 1646–1594 cm–1 arising from the OH and NH
groups and the aminoenone fragment, respectively. A
characteristic feature of the 1H NMR spectra in DMSO-d6
solution is the appearance of one singlet at d = 8.5–9.2
ppm for the OH proton and two AX doublets (JAX = 12.7
Hz) at d = 7.9–8.0 and 12.5 ppm for the =CH and –NH
protons, respectively. In the 19F NMR spectrum, a singlet
for the CF3 group of 11b appeared at –84.9 ppm, thereby
confirming that this group is bonded to the sp3-hybridized
carbon atom.
H2N
CORF
X
N
HN
i
X
7
8a–e
Scheme 3 Reagents and conditions: (i) DMF, 100 °C, 12 h.
Table 2 Synthesis of 4-(Polyfluoroalkyl)pyrimidines 8a–e by
Reaction of Thiochromones 7 with 1,3-NCN-Binucleophiles
Pyrimidine
RF
X
Yield (%)
8a
8b
8c
8d
8e
CF3
Ph
43
57
61
58
52
In addition, to confirm the enamine structure of 11a–d, an
X-ray diffraction study was carried out on crystals of the
product 11e as a model compound prepared from 3-(tri-
fluoroacetyl)chromone and 2-aminophenol (Figure 2).
CF3
Me
CF3
NH2
CF3
morpholino
Me
O
R
CORF
CF2CF3
+
H2N
SO2NHCNH2
NH
O
The proposed reaction was also found to be suitable for 8-
aza-3-(polyfluoroacyl)chromones 9,14 which showed a
similar reactivity with benzamidine or O-methylisourea
as dinucleophiles. The reaction proceeds in refluxing eth-
anol in the presence of potassium hydroxide to give keto-
linked bis-heterocycles 10a and 10b, which both contain
a 2-pyridone ring and a pyrimidine ring (Scheme 4). Non-
fluorinated analogues of 10 have previously been reported
to be selective inhibitors of phosphodiesterase V.15
1
SO2NHCNH2
NH
H
O
N
R
OH
RF
O
11a–d
O
O
RF
H2N
HN
CORF
X
H
O
N
N
OH
N
O
N
O
N
X
OH
H
9
10a,b
O
CF3
a: RF = CF2H, X = Ph (36%)
b: RF = CF3, X = OMe (38%)
11e
Scheme 5 Synthesis of 2-Hydroxy-2-(polyfluoroalkyl)chroman-4-
ones 11a–d
Scheme 4 Synthesis of 3-{[4-(Fluoroalkyl)-pyrimidin-5-yl]carbo-
nyl}-4,6-dimethylpyridin-2(1H)-ones
Table 3 Synthesis of 2-Hydroxy-2-(polyfluoroalkyl)chroman-4-
ones 11a–d by Reaction of Chromones 1 with Sulfaguanidine
Reaction of chromones 1 with sulfaguanidine (4-amino-
N-carbamimidoylbenzenesulfonamide; sulginum) in re-
fluxing ethanol gave the chroman-4-one derivatives 11a–
d, and no formation of the corresponding pyrimidines was
detected at all. Obviously, the presence of the sulfonyl
group near the guanidino moiety strongly reduces the nu-
cleophilicity of the latter, and the reaction proceeds with
the participation of the amino group, as reported previous-
Chroman-4-one
RF
R
Yield (%)
11a
11b
11c
11d
CF3
H
77
86
74
72
CF3
Me
H
CF2H
(CF2)2H
H
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3236
A. Kotljarov et al.
PAPER
XH
O
CF3
XMe
O
CF3
Me2SO4
i
N
N
N
N
N
N
5k, 8d
12a: X = O
b: X = S
O
O
ii BrCH2CO2Et
O
EtO
O
CF3
O
O
CF3
N
N
iv
N
N
N
N
14
13
O
O
Figure 2 Molecular structure of compound 11e
iv
N
KOH
iii
Next, in view of the fact that the pyrimidine ring is an im-
portant structural fragment of many natural and biologi-
cally active substances, we investigated some properties
of compounds 5b, 5k, 5p, and 8d as representative exam-
ples. We found that 4-(trifluoromethyl)pyrimidines 5k
and 8d reacted with an excess of dimethyl sulfate (3
equivalents) in refluxing toluene to afford the correspond-
ing O- and S-methylated products 12a and 12b in high
yields (70–77%). A remarkable feature in the 13C NMR
spectra of these compounds was the appearance of a quar-
tet (JC,F = 2.6 Hz for 12a and JC,F = 2.2 Hz for 12b) as-
signed to the methyl group, showing that the methyl and
trifluoromethyl groups are spatially close to one another,
and confirming the structure of pyrimidines 12
(Scheme 6).
CO2H
O
CF3
OH
N
N
15
O
Scheme 6 Reagents and conditions: (i) NaOH, K2CO3, Bu4NHSO4,
Me2SO4, toluene, reflux, 20 h; (ii) K2CO3 (5 equiv), ethyl bromoace-
tate (1.5 equiv), acetone, r.t., 12 h; (iii) a) KOH, b) 2 M aq HCl; (iv)
glacial HOAc, reflux, 24 h.
O
RF
O
RF
i
O
N
NaO
N
5b,k,p
OH
N
X
N
X
Derivatives of ortho-acylated phenols and thiophenols
have recently been used in the synthesis of various
benzofurans17a and benzothiophenes.17b We therefore in-
vestigated the synthesis of a benzofuran starting from py-
rimidine 5k (Scheme 6). First, 5k was alkylated with ethyl
bromoacetate in acetone containing potassium carbonate
to give ether ester 13 as a colorless solid in a yield of 98%.
When 13 was refluxed in glacial acetic acid, cyclization,
hydrolysis, and decarboxylation took place to yield ben-
zofuran 14. However, when the reaction was conducted in
dioxane with potassium hydroxide as a basic catalyst, fol-
lowed by the addition of hydrochloric acid, the stable in-
termediate 15 could be isolated; this was easily converted
into benzofuran derivative 14 by refluxing in glacial ace-
tic acid.
16'
16a–c
16a: RF = CF3, X = Me
b: RF = CF3, X = morpholino
c: RF = C3F7, X = Me
Scheme 7 Reagents and conditions: (i) THF, NaH (60% dispersion
in mineral oil), H2O2 (35% aq).
Oxidation of a series of derivatives 5 by treatment with so-
dium hydride in tetrahydrofuran, followed by the addition
of 35% aqueous hydrogen peroxide presumably led to the
formation of the esters 16¢, which underwent hydrolysis
during the acidic workup to afford the corresponding salts
16a–c. The oxidation occurred slowly and was complete
only after 96 h. The esters 16¢ were detected by GC-MS as
reaction intermediates; however, all our attempts to iso-
late these compounds failed. Sodium salts 16 were suc-
cessfully isolated in high yields by column
chromatography. Thus, compounds 5 are novel and con-
venient precursors for 4-RF-pyrimidine-5-carboxylic ac-
ids.
In conclusion, the reactions of 3-RFCO-chromones and
their hetero analogues with amidines or guanidines were
investigated systematically to provide a new simple and
convenient synthetic route to 5-salicyloyl-4-(polyfluoro-
alkyl)pyrimidines. Oxidation of these compounds under
Dakin reaction conditions yielded the corresponding 4-
Finally, it is worth mentioning that 4-(trifluoromethyl)py-
rimidine-5-carboxylic acids and their derivatives are of
interest because of their cardiotonic,18a antiviral, and anti-
mycotic activities.18b Additionally, some members of this
family have been recognized as a new class of potent ry-
anodine receptor activators18c and as inhibitors of AP-1
and NF-kB mediated gene expression.18d,e For this reason,
the sodium salts of pyrimidine acids 16a–c were prepared
under Dakin reaction conditions as outlined in
Scheme 7.19
Synthesis 2009, No. 19, 3233–3242 © Thieme Stuttgart · New York

PAPER
4-(Polyfluoroalkyl)pyrimidines
3237
1H NMR (CDCl3): d = 6.88 (ddd, 3J = 8.0, 7.4 Hz, 4J = 0.9 Hz, 1 H,
RF-pyrimidine-5-carboxylic acids as their sodium salts.
The simple procedures and the high yields of the products
allow the synthesis of functionalized fluorinated pyrim-
idines, which are interesting objects for medicine chemis-
try and drug discovery.
3
4
H-5¢), 7.05 (dd, J = 8.0 Hz, J = 1.6 Hz, 1 H, H-6¢), 7.10 (dd,
4
3
3J = 8.4 Hz, J = 0.9 Hz, 1 H, H-3¢), 7.58 (ddd, J = 8.4, 7.4 Hz,
4J = 1.7 Hz, 1 H, H-4¢), 8.93 (s, 1 H, H-6), 9.51 (s, 1 H, H-2), 11.50
(s, 1 H, OH).
13C NMR (CDCl3): d = 119.0, 119.2 (q, 5JC,F = 0.8 Hz), 119.7, 120.1
(q, 1JC,F = 277.0 Hz), 129.6 (q, 3JC,F = 1.2 Hz), 132.6, 138.5, 152.1
(q, 2JC,F = 37.0 Hz), 157.4, 159.6, 163.4, 195.9.
IR spectra were recorded on a Perkin-Elmer Spectrum BX-II instru-
1
ment as KBr disks. H (400 MHz), 13C (100 MHz), and 19F (376
MS (EI, 70 eV): m/z (%) = 268 (68) [M]+, 199 (77) [M – CF3]+, 172
MHz) NMR spectra were recorded on a Bruker DRX-400 spectrom-
eter in CDCl3 or DMSO-d6 solutions with TMS and CFCl3 as inter-
nal standards, respectively. Mass spectra were obtained on a
Hewlett-Packard HPGC/MS 5890/5972 instrument (EI, 70 eV) by
GC inlet or on a MX-1321 instrument (EI, 70 eV) by direct inlet. El-
emental analyses were performed at the Microanalysis Services of
the Institute of Organic Synthesis, Ural Branch, Russian Academy
of Sciences. Melting points are uncorrected. All the solvents that
were used were dried and distilled according to standard proce-
dures. Column chromatography was performed on silica gel (63–
200 mesh, Merck). Silica gel Merck 60F254 plates were used for
TLC. Satisfactory microanalyses were obtained: C 0.33; H 0.45;
(16), 121 (100) [HOC6H4CO]+, 93 (18) [C6H4CO]+, 65 (23).
2-Methyl-5-salicyloyl-4-(trifluoromethyl)pyrimidine (5b)
Yield: 246 mg (87%); colorless solid; mp 87–89 °C; Rf = 0.29 (PE–
EtOAc, 2:1).
1H NMR (CDCl3): d = 2.91 (s, 3 H, Me), 6.86 (t, 3J = 7.8 Hz, 1 H,
H-5¢), 7.08 (d, 3J = 7.8 Hz, 2 H, H-3¢, H-6¢), 7.56 (t, 3J = 7.8 Hz, 1
H, H-4¢), 8.80 (s, 1 H, H-6), 11.57 (s, 1 H, OH).
13C NMR (CDCl3): d = 26.0, 118.9, 119.4 (q, 5JC,F = 0.8 Hz), 119.6,
120.0 (q, 1JC,F = 277.0 Hz), 126.5 (q, 3JC,F = 1.2 Hz), 132.6, 138.2,
152.1 (q, 2JC,F = 36.0 Hz), 157.3, 163.2, 170.2, 196.6.
19F NMR (CDCl3): d = –66.0 (s, CF3).
N
0.25.
MS (EI, 70 eV): m/z (%) = 282 (32) [M]+, 214 (15) [M + 1 – CF3]+,
213 (100) [M – CF3]+, 172 (21), 121 (81) [HOC6H4CO]+, 93 (13)
[HOC6H4]+, 65 (17).
Crystal Data for 2 and 11e
Crystallographic measurements were performed at room tempera-
ture on an Enraf-Nonius CAD4 diffractometer operating in the w-2q
scan mode (the scanning rate ratio w/2q = 1.2). The structure was
solved by direct methods, and refined by the full-matrix least-
squares technique in an anisotropic approximation using
SHELXS97 and SHELXL9722 program packages. Hydrogen at-
oms were placed at calculated positions and refined by means of a
‘riding’ model.
2-Phenyl-5-salicyloyl-4-(trifluoromethyl)pyrimidine (5c)
Yield: 317 mg (92%); colorless solid; mp 100–102 °C; Rf = 0.65
(Et2O).
3
1H NMR (CDCl3): d = 6.88 (t, J = 7.8 Hz, 1 H, H-5¢), 7.11 (d,
3J = 7.8 Hz, 1 H, H-6¢), 7.19 (d, 3J = 7.8 Hz, 1 H, H-3¢), 7.52–7.60
(m, 4 H, H-4¢, Ph), 8.55 (m, 2 H, Ph), 8.93 (s, 1 H, H-6), 11.63 (s, 1
H, OH).
Crystal data for 2: triclinic, P1, a = 7.7360(15), b = 7.9747(16),
c = 8.4549(17) Å, a = 106.02(3)°, b = 91.66(3)°, g = 103.63(3)°,
V = 484.74(17) Å3, Z = 2, m(Mo-Ka) = 0.171 mm–1. 7071 reflec-
tions collected, 2046 unique reflections, [Rint = 0.0448), Mo-Ka ra-
diation (l = 0.71073 Å), 163 parameters, R1 = 0.0341,
wR2 = 0.0879, S = 1.076 (1921 reflections with I > 2s(I)].
13C NMR (CDCl3): d = 118.9, 119.5 (q, 5JC,F = 0.8 Hz), 119.6, 120.3
(q, 1JC,F = 277.0 Hz), 126.7 (q, 3JC,F = 1.2 Hz), 129.0, 129.0, 132.6,
132.7, 135.3, 138.3, 152.7 (q, 2JC,F = 36.0 Hz), 157.9, 163.3, 165.9,
196.9.
Crystal data of 11e: triclinic, P1, a = 6.2331(12), b = 8.8727(18),
c = 13.966(3) Å, a = 100.15(3)°, b = 96.47(3)°, g = 104.92(3)°,
V = 724.4(2) Å3, Z = 2, m(Mo-Ka) = 0.140 mm–1. 9551 reflections
collected, 2726 unique reflections, [Rint = 0.0798), Mo-Ka radiation
(l = 0.71073 Å), 226 parameters, R1 = 0.0554, wR2 = 0.1097,
S = 1.074 (1981 reflections with I > 2s(I)].
19F NMR (CDCl3): d = –66.1 (s, CF3).
MS (EI, 70 eV): m/z (%) = 344 (29) [M]+, 276(19) [M + 1 – CF3]+ ,
275 (100) [M – CF3]+, 121 (47) [HOC6H4CO]+, 120 (28)
[OC6H4CO]+, 93 (10) [HOC6H4]+, 65 (11).
5-(2-Hydroxy-5-methylbenzoyl)-2-phenyl-4-(trifluorometh-
yl)pyrimidine (5d)
Yield: 176 mg (49%); colorless crystals; mp 133–134 °C.
IR (KBr): 1635, 1574, 1533, 1484 cm–1.
1H NMR (CDCl3): d = 2.22 (s, 3 H, Me), 6.94 (br d, 1 H, H-6¢), 7.02
(d, 3J = 8.6 Hz, 1 H, H-3¢), 7.40 (dd, 3J = 8.6, 4J = 2.1 Hz, 1 H, H-
4¢), 7.53–7.62 (m, 3 H, Ph), 8.57–8.61 (m, 2 H, Ph), 8.94 (s, 1 H, H-
6), 11.49 (s, 1 H, OH).
13C NMR (DMSO-d6): d = 19.7, 117.6, 120.5 (q, 1JC,F = 276.2 Hz),
121.5, 128.2, 128.5, 129.1, 130.8, 131.0, 132.2, 135.2, 138.0, 150.1
(q, 2JC,F = 35.3 Hz), 157.8, 158.4, 163.5, 191.9.
Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge
Crystallographic Data Center as Supplementary Publication No.
CCDC 720749 for 2 and CCDC 720808 for 11e, and can be ob-
tained free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44(1223)336033; e-mail: depos-
it@ccdc.cam.ac.uk].
Compounds 5a–p and 8a–e; General Procedure
A mixture of 1 or 7 (1 mmol), the dinucleophile in the form of a salt
(1 mmol), and NaOAc (1 mmol) in dry DMF (7 mL) was stirred at
80–100 °C overnight. The progress of the reaction was monitoring
by TLC. The solvent was removed in vacuo, and the residue was pu-
rified by flash chromatography (silica gel) or recrystallization (hep-
tane–toluene).
5-(5-Chloro-2-hydroxybenzoyl)-2-phenyl-4-(trifluorometh-
yl)pyrimidine (5e)
Yield: 167 mg (44%); yellow crystals; mp 117–118 °C.
IR (KBr): 1634, 1570, 1540, 1463 cm–1.
5-Salicyloyl-4-(trifluoromethyl)pyrimidine (5a)
Yield: 233 mg (87%); colorless solid; mp 109–111 °C; Rf = 0.37
(Et2O).
3
1H NMR (CDCl3): d = 7.09 (d, J = 9.0 Hz, 1 H, H-3¢), 7.16 (d,
4J = 2.5 Hz, 1 H, H-6¢), 7.54 (dd, 3J = 9.0 Hz, 4J = 2.5 Hz, 1 H, H-
4¢), 7.54–7.63 (m, 3 H, Ph), 8.57–8.61 (m, 2 H, Ph), 8.95 (s, 1 H, H-
6), 11.57 (s, 1 H, OH).
Synthesis 2009, No. 19, 3233–3242 © Thieme Stuttgart · New York

3238
A. Kotljarov et al.
PAPER
5-(2-Hydroxy-4-methoxybenzoyl)-2-phenyl-4-(trifluorometh-
yl)pyrimidine (5f)
Yield: 155 mg (58%); colorless crystals; mp 108–109 °C.
IR (KBr): 1620, 1606, 1572, 1533, 1512, 1500 cm–1.
1H NMR (CDCl3): d = 3.26 (s, 6 H, 2 Me), 6.83 (t, 3J = 7.8 Hz, 1 H,
H-5¢), 7.01 (d, 3J = 7.8 Hz, 1 H, H-3¢), 7.32 (d, 3J = 7.8 Hz, 1 H, H-
6¢), 7.48 (t, 3J = 7.8 Hz, 1 H, H-4¢), 8.41 (s, 1 H, H-6), 11.84 (s, 1 H,
OH).
13C NMR (CDCl3): d = 37.0, 116.6 (q, 3JC,F = 1.0 Hz), 118.5, 119.1,
3
1H NMR (CDCl3): d = 3.88 (s, 3 H, MeO), 6.42 (dd, J = 9.0 Hz,
1
119.9, 120.2 (q, JC,F = 276.0 Hz), 132.7, 137.4, 154.1 (q,
4
4J = 2.4 Hz, 1 H, H-5¢), 6.54 (d, J = 2.4 Hz, 1 H, H-3¢), 7.08 (d,
2JC,F = 36.0 Hz), 159.5, 161.4 (q, 4JC,F = 0.8 Hz), 163.1, 198.0.
3J = 9.0 Hz, 1 H, H-6¢), 7.52–7.61 (m, 3 H, Ph), 8.55–8.58 (m, 2 H,
Ph), 8.93 (s, 1 H, H-6), 12.14 (s, 1 H, OH).
19F NMR (CDCl3): d = –66.9 (s, CF3).
MS (EI, 70 eV): m/z (%) = 311 (21) [M]+, 242 (89) [M – CF3]+, 191
(100) [M + 1 – HOC6H4CO]+, 190 (34) [M – HOC6H4CO]+, 121
(51) [HOC6H4CO]+, 120 (13) [OC6H4CO]+, 93 (11) [HOC6H4]+.
2-(4-Hydroxyphenyl)-5-salicyloyl-4-(trifluoromethyl)pyrimi-
dine (5g)
Yield: 339 mg (94%); colorless solid; mp 182–184 °C; Rf = 0.59
(Et2O).
2-Morpholin-4-yl-5-salicyloyl-4-(trifluoromethyl)pyrimidine
(5k)
Yield: 263 mg (80%); colorless solid; mp 137–139 °C; Rf = 0.31
(PE–Et2O, 1:1).
1H NMR (DMSO-d6): d = 6.94–7.00 (m, 4 H, H-3¢, H-5¢, Ar), 7.56
(t, 3J = 7.8 Hz, 1 H, H-4¢), 7.73 (d, 3J = 7.8 Hz, 1 H, H-6¢), 8.30 (d,
3J = 8.1 Hz, 2 H, Ar), 9.11 (s, 1 H, H-6), 10.31 (s, 1 H, OH), 10.78
(s, 1 H, OH).
13C NMR (DMSO-d6): d = 115.8, 117.5, 119.5, 120.4 (q,
1JC,F = 275.0 Hz), 122.0, 126.1, 129.1, 130.2, 131.4, 136.7, 150.1
(q, 2JC,F = 35.0 Hz), 158.2, 159.6, 161.4, 163.8, 192.4.
19F NMR (DMSO-d6): d = –65.6 (s, CF3).
MS (EI, 70 eV): m/z (%) = 361 (20) [M + 1]+, 360 (90) [M]+, 292
(24) [M + 1 – CF3]+, 291 (95) [M – CF3]+, 240 (34), 121 (100)
[HOC6H4CO]+, 120 (36) [OC6H4CO]+, 93 (23) [HOC6H4]+, 65 (22).
1H NMR (CDCl3): d = 3.79 (dd, 3J = 5.1, 4.6 Hz, 4 H, morpholino),
3.94 (dd, 3J = 5.1, 4.6 Hz, 4 H, morpholino), 6.86 (td, 3J = 7.8 Hz,
4J = 0.8 Hz, 1 H, H-5¢), 7.05 (dd, 3J = 8.2 Hz, 4J = 0.8 Hz, 1 H, H-
3¢), 7.31 (dd, 3J = 7.8 Hz, 4J = 1.6 Hz, 1 H, H-6¢), 7.53 (td, 3J = 7.8
Hz, 4J = 1.6 Hz, 1 H, H-4¢), 8.43 (s, 1 H, H-6), 11.80 (s, 1 H, OH).
13C NMR (CDCl3): d = 44.2, 69.6, 117.7 (q, 3JC,F = 1.0 Hz), 118.7,
118.8, 119.2, 119.8 (q, 5JC,F = 0.6 Hz), 120.2 (q, 1JC,F = 277.0 Hz),
132.8, 137.5, 154.3 (q, 2JC,F = 36.0 Hz), 159.7, 160.8 (q, 4JC,F = 1.0
Hz), 163.2, 197.6.
MS (EI, 70 eV): m/z (%) = 353 (48) [M]+, 322 (15), 284 (61) [M –
CF3]+, 233 (42) [M + 1 – HOC6H4CO]+, 232 (48) [M –
HOC6H4CO]+, 226 (28), 203 (15), 202 (39), 176 (19), 121 (100)
[HOC6H4CO]+, 120 (60) [OC6H4CO]+, 93 (25) [HOC6H4]+, 92 (20),
57 (19), 56 (25), 43 (19).
2-(4-Aminophenyl)-5-salicyloyl-4-(trifluoromethyl)pyrimidine
(5h)
Yield: 331 mg (92%); colorless solid; mp 160–162 °C; Rf = 0.52
(Et2O).
2-Morpholin-4-yl-5-(trifluoromethyl)-5H-chromeno[4,3-d]py-
rimidin-5-ol (6k)
This substance was obtained as a byproduct in the synthesis of 5k.
1H NMR (DMSO-d6): d = 6.94–7.00 (m, 4 H, H-3¢, H-5¢, Ar), 7.56
3
3
(t, J = 7.8 Hz, 1 H, H-4¢), 7.62 (br s, 2 H, NH2), 7.73 (d, J = 7.8
3
Hz, 1 H, H-6¢), 8.14 (d, J = 8.1 Hz, 2 H, Ar), 8.98 (s, 1 H, H-6),
Yield: 61 mg (18%); colorless solid; mp 143–147 °C; Rf = 0.23
(PE–Et2O, 1:1).
10.78 (s, 1 H, OH).
13C NMR (DMSO-d6): d = 113.4, 117.5, 119.4, 120.4 (q,
1H NMR (CDCl3): d = 3.7–3.9 (br m, 8 H, morpholino), 5.19 (s, 1
1JC,F = 276.0 Hz), 122.0, 122.1, 127.6 (q, JC,F = 1.0 Hz), 130.1,
3
3
4
H, OH), 7.04 (dd, J = 8.0 Hz, J = 0.9 Hz, 1 H, H-7), 7.11 (td,
131.5, 136.5, 150.1 (q, 2JC,F = 35.0 Hz), 153.0, 158.1, 159.6, 163.3,
3J = 7.8 Hz, J = 0.9 Hz, 1 H, H-9), 7.43 (dt, J = 7.8 Hz, J = 1.7
Hz, 1 H, H-8), 8.13 (dd, 3J = 7.8 Hz, 4J = 1.7 Hz, 1 H, H-10), 8.42
(s, 1 H, H-4).
4
3
4
192.9.
19F NMR (DMSO-d6): d = –65.6 (s, CF3).
MS (EI, 70 eV): m/z (%) = 360 (30) [M + 1]+, 359 (89) [M]+, 290
(16), 290 (70) [M – CF3]+, 240 (15), 239 (100), 121 (40)
[HOC6H4CO]+, 118 (28), 93 (12) [HOC6H4]+, 65 (13).
13C NMR (DMSO-d6): d = 44.1 (2C), 66.6 (2C), 95.5 (q,
1
2JC,F = 33.0 Hz), 107.8, 117.7, 120.2, 122.4 (q, JC,F = 287.0 Hz),
122.8, 124.9, 133.8, 153.8, 155.4, 156.9, 157.0.
MS (EI, 70 eV): m/z (%) = 353 (48) [M]+, 322 (15), 284 (61) [M –
CF3]+, 233 (42) [M + 1 – HOC6H4CO]+, 232 (48) [M –
HOC6H4CO]+, 226 (28), 203 (15), 202 (39), 176 (19), 121 (100)
[HOC6H4CO]+, 120 (60) [OC6H4CO]+, 93 (25) [HOC6H4]+, 92 (20),
57 (19), 56 (25), 43 (19).
2-Amino-5-salicyloyl-4-(trifluoromethyl)pyrimidine (5i)
Yield: 238 mg, (84%); colorless solid; mp 206–208 °C; Rf = 0.58
(Et2O).
1H NMR (DMSO-d6): d = 6.95 (t, 3J = 7.8 Hz, 1 H, H-5¢), 6.97 (d,
3J = 8.2 Hz, 1 H, H-3¢), 7.50–7.56 (m, 2 H, H-4¢, H-6¢), 7.85 (br s, 2
H, NH2), 8.47 (s, 1 H, H-6), 10.82 (s, 1 H, OH).
4-(Difluoromethyl)-2-phenyl-5-salicyloylpyrimidine (5l)
Yield: 160 mg (52%); colorless crystals; mp 105–106 °C.
IR (KBr): 1618, 1570, 1541, 1483 cm–1.
1H NMR (DMSO-d6): d = 6.98–7.06 (m, 2 H, H-3¢, H-5¢), 7.19 (t,
2JH,F = 53.4 Hz, 1 H, CF2H), 7.58 (ddd, 3J = 8.3, 7.3 Hz, 4J = 1.7 Hz,
1 H, H-4¢), 7.59–7.65 (m, 3 H, Ph), 7.68 (dd, 3J = 8.2 Hz, 4J = 1.7
Hz, 1 H, H-6¢), 8.47–8.50 (m, 2 H, Ph), 9.12 (s, 1 H, H-6), 10.80 (s,
1 H, OH).
3
13C NMR (DMSO-d6): d = 117.4, 119.2, 119.7 (q, JC,F = 1.2 Hz),
1
120.2 (q, JC,F = 276.0 Hz), 122.3, 131.8, 135.9, 152.3 (q,
2JC,F = 35.0 Hz), 159.5, 160.5, 163.1, 194.2.
19F NMR (DMSO-d6): d = –65.6 (s, CF3).
MS (EI, 70 eV): m/z (%) = 283 (35) [M]+, 215 (13) [M + 1 – CF3]+,
214 (85) [M – CF3]+, 190 (35) [M – HOC6H4]+, 163 (13) [M + 1 –
HOC6H4CO]+, 121 (70) [HOC6H4CO]+, 120 (100) [OC6H4CO]+, 93
(25) [HOC6H4]+, 92 (41), 65 (33).
19F NMR (DMSO-d6): d = –118.9 (d, 2JF,H = 53.4 Hz, CF2H).
2-Phenyl-4-(1,1,2,2-tetrafluoroethyl)-5-salicyloylpyrimidine
(5m)
Yield: 256 mg (68%); yellow needles; mp 135–136 °C.
2-(Dimethylamino)-5-salicyloyl-4-(trifluoromethyl)pyrimidine
(5j)
Yield: 283 mg (91%); colorless solid; mp 119–120 °C; Rf = 0.23
(PE–Et2O, 1:1).
Synthesis 2009, No. 19, 3233–3242 © Thieme Stuttgart · New York

PAPER
4-(Polyfluoroalkyl)pyrimidines
3239
IR (KBr): 1625, 1605, 1569, 1529, 1489 cm–1.
13C NMR (DMSO-d6): d = 25.9, 115.0 (q, 3JC,F = 1.4 Hz), 120.3 (q,
1JC,F = 277.0 Hz), 122.1, 122.3, 128.3, 135.0, 139.1, 154.3 (q,
2JC,F = 36.0 Hz), 162.7, 160.7, 165.3, 189.4.
MS (EI, 70 eV): m/z (%) 298 (33) [M]+, 230 (17) [M + 1 – CF3]+,
229 (88) [M – CF3]+, 190 (100), 189 (71), 162 (55), 137 (31)
[HSC6H4CO]+, 136 (13) [SC6H4CO]+, 109 (10) [HSC6H4]+, 65 (14).
1H NMR (DMSO-d6): d = 6.95–7.02 (m, 2 H, H-3¢, H-5¢), 7.28 (tt,
2JH,F = 51.6 Hz, 3JH,F = 6.0 Hz, 1 H, CF2CF2H), 7.58 (ddd, 3J = 8.4,
4
7.3 Hz, J = 1.7 Hz, 1 H, H-4¢), 7.60–7.68 (m, 3 H, Ph), 7.75 (dd,
3J = 7.9 Hz, 4J = 1.7 Hz, 1 H, H-6¢), 8.51–8.54 (m, 2 H, Ph), 9.23 (s,
1 H, H-6), 10.80 (s, 1 H, OH).
2-Amino-4-(difluoromethyl)-5-salicyloylpyrimidine (5n)
Yield: 160 mg (57%); colorless shining crystals; mp 235–236 °C.
2-Amino-5-(2-sulfanylbenzoyl)-4-(trifluoromethyl)pyrimidine
(8c)
Yield: 183 mg (61%); colorless solid; mp 219–221 °C; Rf = 0.65
(Et2O).
1H NMR (DMSO-d6) d = 7.39–7.56 (m, 3 H, H-3¢, H-4¢, H-5¢), 7.93
(br s, 2 H, NH2), 8.50 (d, 3J = 7.5 Hz, 1 H, H-6¢), 9.10 (s, 1 H, H-6),
9.42 (br s, 1 H, SH).
IR (KBr): 3337, 3198, 1673, 1622, 1586, 1541, 1519, 1484 cm–1.
1H NMR (DMSO-d6): d = 6.93–6.99 (m, 2 H, H-3¢, H-5¢), 7.13 (t,
2JH,F = 53.7 Hz, 1 H, CF2H), 7.43 (dd, 3J = 7.7 Hz, 4J = 1.6 Hz, 1 H,
H-6¢), 7.47 (ddd, 3J = 8.4, 7.4 Hz, 4J = 1.7 Hz, 1 H, H-4¢), 7.88 (br
s, 2 H, NH2), 8.37 (s, 1 H, H-6), 10.51 (s, 1 H, OH).
3
13C NMR (CDCl3): d = 112.0 (q, JC,F = 1.2 Hz), 120.9 (q,
13C NMR (DMSO-d6): d = 110.1 (t, 1JC,F = 239.9 Hz), 117.0, 119.0
1JC,F = 277.0 Hz), 121.8, 122.5, 132.0, 136.1, 137.9, 153.7 (q,
2JC,F = 36.0 Hz), 160.9, 162.6, 164.2, 190.5.
3
(t, JC,F = 3.3 Hz), 119.4, 124.1, 131.1, 134.3, 157.3, 159.9 (t,
2JC,F = 22.1 Hz), 162.7, 163.5, 193.4.
MS (EI, 70 eV): m/z (%) 299 (100) [M]+, 231 (20) [M + 1 – CF3]+,
230 (49) [M – CF3]+, 191 (14), 163 (15), 137 (30) [HSC6H4CO]+,
136 (45) [SC6H4CO]+, 109 (10) [HSC6H4]+.
2-Amino-4-(1,1,2,2-tetrafluoroethyl)-5-salicyloylpyrimidine
(5o)
Yield: 110 mg (27%); colorless crystals; mp 168–169 °C.
2-(Morpholin-4-yl)-5-(2-sulfanylbenzoyl)-4-(trifluorometh-
yl)pyrimidine (8d)
Yield: 214 mg (58%); colorless solid; mp 147–150 °C; Rf = 0.47
IR (KBr): 3370, 3333, 3193, 3162, 1666, 1631, 1607, 1582, 1537,
1516, 1488 cm–1.
1H NMR (DMSO-d6): d = 6.85 (tt, 2JH,F = 52.4 Hz, 3JH,F = 6.0 Hz, 1
H, CF2CF2H), 6.93–7.00 (m, 2 H, H-3¢, H-5¢), 7.51 (dd, 3J = 7.9 Hz,
4J = 1.7 Hz, 1 H, H-6¢), 7.54 (ddd, 3J = 8.4, 7.3 Hz, 4J = 1.7 Hz, 1 H,
H-4¢), 7.75 (br s, 2 H, NH2), 8.46 (s, 1 H, H-6), 10.93 (s, 1 H, OH).
(PE–Et2O, 1:1).
1H NMR (DMSO-d6) d = 3.72 (dd, 3J = 5.0, 4.8 Hz, 4 H, morpholi-
no), 3.99 (dd, 3J = 5.0, 4.8 Hz, 4 H, morpholino), 7.41–7.56 (m, 3
H, H-3¢, H-4¢, H-5¢), 8.34 (d, 3J = 7.8 Hz, 1 H, H-6¢), 8.88 (s, 1 H,
H-6), 9.27 (br s, 1 H, SH).
2-Methyl-5-salicyloyl-4-(perfluoropropyl)pyrimidine (5p)
Yield: 329 mg (86%); colorless solid; mp 81–84 °C; Rf = 0.27 (PE–
Et2O, 2:1).
13C NMR (CDCl3): d = 41.3, 68.9, 112.7 (q, 3JC,F = 1.6 Hz), 120.2
1
(q, JC,F = 277.0 Hz), 122.1, 122.7, 129.1, 135.4, 137.4, 154.1 (q,
2JC,F = 36.0 Hz), 159.3, 162.2, 162.1, 190.1.
3
1H NMR (CDCl3): d = 2.90 (s, 3 H, Me), 6.84 (td, J = 7.8 Hz,
4J = 0.8 Hz, 1 H, H-5¢), 7.03 (dd, 3J = 7.8 Hz, 4J = 1.4 Hz, 1 H, H-
6¢), 7.07 (dd, 3J = 8.0 Hz, 4J = 0.8 Hz, 1 H, H-3¢), 7.55 (td, 3J = 7.8
Hz, 4J = 1.4 Hz, 1 H, H-4¢), 8.77 (s, 1 H, H-6), 11.56 (s, 1 H, OH).
MS (EI, 70 eV): m/z (%) 369 (100) [M]+, 301 (55) [M + 1 – CF3]+,
300 (100) [M – CF3]+, 261 (31), 233 (15), 137 [HSC6H4CO]+ (30),
136 [SC6H4CO]+ (45), 109 [HSC6H4]+ (10).
1
13C NMR (CDCl3): d = 25.8, 108.7 (tqt, JC,F = 269.0 Hz,
5-(2-Sulfanylphenyl)-2-methyl-4-(pentafluoroethyl)pyrimidine
(8e)
Yield: 177 mg (52%); pink crystals; mp 123–127 °C; Rf = 0.40
(Et2O).
1H NMR (CDCl3): d = 2.15 (s, 3 H, Me), 7.29 (t, 3J = 7.6 Hz, 1 H,
H-5¢), 7.35 (t, 3J = 7.8 Hz, 1 H, H-4¢), 7.93 (d, 3J = 8.2 Hz, 1 H, H-
3¢), 8.38 (d, 3J = 7.8 Hz, 1 H, H-6¢), 8.66 (s, 1 H, H-6).
1
2
2JC,F = 38.0, 36.0 Hz), 112.6 (tt, JC,F = 260.0 Hz, JC,F = 32.0 Hz),
117.6 (ttq, 1JC,F = 288.0 Hz, 2JC,F = 34.0 Hz, 3JC,F = 1.2 Hz), 118.9,
5
119.5, 119.7 (t, JC,F = 1.1 Hz), 128.2 (t, JC,F = 1.2 Hz), 132.7,
138.1, 152.4 (t, 2JC,F = 27.0 Hz), 157.4, 163.2, 169.8, 196.8.
MS (EI, 70 eV): m/z (%) = 382 (25) [M]+, 381 (72) [M–1]+, 214 (17)
[M + 1 – C3F7]+, 213 (100) [M – C3F7]+.
1
2
5-(2-Sulfanylbenzoyl)-2-phenyl-4-(trifluoromethyl)pyrimidine
(8a)
Yield: 155 mg (43%); colorless crystals; mp 192–193 °C.
13C NMR (CDCl3): d = 30.7, 108.3 (tq, JCF = 254 Hz, JCF = 38
1
2
Hz), 114.2, 117.6 (qt, JCF = 283 Hz, JCF = 36 Hz), 125.5, 126.4,
127.2, 127.9, 133.9, 141.8, 156.8 (t, JCF = 28 Hz), 160.5, 162.6,
2
192.3.
IR (KBr): 3068, 1589, 1578, 1566, 1533 cm–1.
MS (EI, 70 eV): m/z (%) = 348 (21) [M]+, 230 (33) [M – C2F5 + 1]+,
1H NMR (DMSO-d6) d = 7.46–7.58 (m, H-3¢, H-4¢, H-5¢, 3 H),
7.58–7.64 (m, 3 H, Ph), 8.56–8.60 (m, 2 H, Ph), 8.73 (d, 3J = 7.5 Hz,
1 H, H-6¢), 9.20 (s, 1 H, H-6), 9.28 (br s, 1 H, SH).
MS (EI, 70 eV): m/z (%) = 360 [M]+ (18), 292 [M + 1 – CF3]+ (10),
291 [M – CF3]+ (100), 224 (55), 223 (70), 137 [HSC6H4CO]+ (15),
136 [SC6H4CO]+ (28), 109 [HSC6H4]+ (10), 65 (11).
229 (100) [M – C2F5]+, 200 (22).
3-{[4-(Difluoromethyl)-2-phenylpyrimidin-5-yl]carbonyl}-4,6-
dimethylpyridin-2(1H)-one (10a)
A soln of azachromone 9 (RF = CF2H; 100 mg, 0.4 mmol) in EtOH
(7 mL) was added to a soln of benzamidine hydrochloride (150 mg,
0.79 mmol) and KOH (70 mg, 1.25 mmol) in EtOH (5 mL). The
mixture was refluxed for 3 h, concentrated to dryness, and purified
by chromatography on a short silica gel column using toluene as the
mobile phase. On cooling the soln, yellow crystals that formed were
filtered off and dried; yield: 50 mg (36%); mp 227–228 °C.
5-(2-Sulfanylbenzoyl)-2-methyl-4-(trifluoromethyl)pyrimidine
(8b)
Yield: 170 mg (57%); colorless solid; mp 179–181 °C; Rf = 0.78
(PE–Et2O, 1:1).
1H NMR (DMSO-d6): d = 2.30 (s, 3 H, Me), 7.49–7.66 (m, 3 H, H-
3¢, H-4¢, H-5¢), 8.57 (d, 3J = 7.5 Hz, 1 H, H-6¢), 9.00 (s, 1 H, H-6),
9.28 (br s, 1 H, SH).
1H NMR (DMSO-d6): d = 2.24 (d, J = 0.5 Hz, 3 H, Me), 2.32 (s, 3
2
H, Me), 6.19 (s, 1 H, H-5¢), 7.19 (t, JH,F = 53.3 Hz, 1 H, CF2H),
7.57–7.63 (m, 3 H Ph), 8.44–8.47 (m, 2 H, Ph), 9.03 (s, 1 H, H-6),
12.02 (s, 1 H, NH).
Synthesis 2009, No. 19, 3233–3242 © Thieme Stuttgart · New York

3240
A. Kotljarov et al.
PAPER
13C NMR (DMSO-d6): d = 18.7, 20.4, 109.3, 110.8 (t, 1JC,F = 240.6
N-Carbamimidoyl-4-({[2-hydroxy-4-oxo-2-(1,1,2,2-tetrafluoro-
ethyl)-2H-chromen-3(4H)-ylidene]methyl}amino)benzene-
sulfonamide (11d)
3
Hz, CF2H), 121.7, 128.2, 129.0, 130.5 (t, JC,F = 2.9 Hz), 132.0,
135.8, 150.7, 156.4 (t, 2JC,F = 23.3 Hz), 157.2, 159.1, 162.0, 163.5,
192.4.
Yield: 284 mg (72%); mp 212–213 °C.
IR (KBr): 3456, 3370, 3333, 3227, 1646, 1611, 1594, 1533, 1470
cm–1.
3-{[2-Methoxy-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}-
4,6-dimethylpyridin-2(1H)-one (10b)
1H NMR (DMSO-d6): d = 6.72 (tdd, 2JH,F = 52.0 Hz, 3JH,F = 7.9, 5.1
This compound was prepared from azachromone 9 (RF = CF3) and
O-methylurea in an analogous manner to 10a; yield: 124 mg (38%);
yellow crystals; mp 217–218 °C.
3
Hz, 1 H, CF2CF2H), 6.72 (br s, 4 H, 4NH), 7.02 (dd, J = 8.3 Hz,
4J = 0.8 Hz, 1 H, H-8), 7.13 (ddd, 3J = 7.9, 7.3 Hz, 4J = 1.0 Hz, 1 H,
3
H-6), 7.50–7.54 (m, 2 H, Ar), 7.55 (ddd, J = 8.3, 7.3 Hz, 4J = 1.7
IR (KBr): 3000–2660, 1670, 1656, 1624, 1584, 1550, 1537, 1479
cm–1.
1H NMR (CDCl3): d = 1.98 (d, J = 0.5 Hz, 3 H, 6-Me), 2.46 (s, 3 H,
4-Me), 4.09 (s, 3 H, MeO), 6.06 (s, 1 H, H-5¢), 8.63 (s, 1 H, H-6),
12.98 (s, 1 H, NH).
3
Hz, 1 H, H-7), 7.76–7.80 (m, 2 H, Ar), 7.82 (dd, J = 7.8 Hz,
5
4J = 1.7 Hz, 1 H, H-5), 7.96 (dd, J = 12.7, JH,F = 1.0 Hz, 1
H, = CH), 9.10 (d, 4JH,F = 4.0 Hz, 1 H, OH), 12.49 (d, J = 12.7 Hz,
1 H, NH).
2-Hydroxy-3-[(2-hydroxyphenylamino)methylene]-2-(trifluo-
romethyl)chroman-4-one (11e)
Yield: 309 mg (88%); mp 172–174 °C; Rf = 0.37 (PE–EtOAc, 2:1).
1H NMR (DMSO-d6): d = 6.84 (t, 3J = 7.6 Hz, 1 H), 6.90–6.98 (m,
2 H), 7.01 (d, 3J = 7.6 Hz, 1 H), 7.09 (t, 3J = 7.6 Hz, 1 H), 7.39 (d,
3J = 7.6 Hz, 1 H), 7.48 (t, 3J = 7.6 Hz, 1 H), 7.79 (d, 3J = 7.6 Hz, 1
H), 8.01 (d, J = 13.2 Hz, 1 H, = CH), 9.01 (s, 1 H), 10.37 (s, 1 H),
12.69 (d, J = 13.2 Hz, 1 H, NH).
Compounds 11a–d; General Procedure
A soln of chromone 1 (1.0 mmol) and sulfaguanidine (220 mg, 1.03
mmol) in EtOH (10 mL) was refluxed for 3 h and then left at r.t. for
2 d. The precipitate that formed was filtered off, washed with EtOH,
and recrystallized (EtOH) to give pure product 11 as yellow crys-
tals.
N-Carbamimidoyl-4-({[2-hydroxy-4-oxo-2-(trifluoromethyl)-
2H-chromen-3(4H)-ylidene]methyl}amino)benzenesulfon-
amide (11a)
2
13C NMR (DMSO-d6): d = 98.0 (q, JC,F = 33 Hz), 98.8, 114.8,
115.8, 116.5, 122.2, 122.9 (q, 1JC,F = 289 Hz), 125.3, 125.7, 127.4,
139.8, 145.9, 146.6, 155.7, 179.2.
19F NMR (DMSO-d6): d = –85.3.
MS (EI, 70 eV): m/z (%) = 351 (34) [M]+, 283 (27) [M + 1 – CF3]+,
282 (100) [M – CF3]+, 243 (15) [M – C6H6NO]+, 173 (31)
[C10H5O3]+, 121 (54) [HOC6H4CO]+, 120 (24) [C7H6NO]+, 109 (45)
[C6H7NO]+, 65 (16).
Yield: 255 mg (77%); mp 210–212 °C.
IR (KBr): 3460, 3412, 3367, 3227, 1646, 1617, 1596, 1550, 1470
cm–1.
1H NMR (DMSO-d6): d = 6.72 (br s, 4 H, 4NH), 7.08 (d, J = 8.3
3
Hz, 1 H, H-8), 7.16 (ddd, 3J = 7.9, 7.2 Hz, 4J = 0.8 Hz, 1 H, H-6),
7.52–7.55 (m, 2 H, Ar), 7.57 (ddd, 3J = 8.4, 7.3 Hz, 4J = 1.7 Hz, 1
H, H-7), 7.76–7.79 (m, 2 H, Ar), 7.84 (dd, 3J = 7.8 Hz, 4J = 1.6 Hz,
1 H, H-5), 8.04 (d, J = 12.7 Hz, 1 H, = CH), 9.19 (s, 1 H, OH), 12.51
(d, J = 12.7 Hz, 1 H, NH).
Compounds 12a and 12b; General Procedure
A mixture of 5k or 8d (0.6 mmol), NaOH (120 mg, 3 mmol), K2CO3
(690 mg, 5 mmol), Bu4NHSO4 (72 mg, 0.2 mmol), and Me2SO4
(170 mL, 1.8 mmol) in toluene (10 mL) was stirred for 20 h under
reflux. The solid phase was filtered off, the liquor was concentrated
in vacuo, and the residue was purified by flash chromatography (sil-
ica gel).
N-Carbamimidoyl-4-({[2-hydroxy-6-methyl-4-oxo-2-(trifluo-
romethyl)-2H-chromen-3(4H)-ylidene]methyl}amino)benzene-
sulfonamide (11b)
Yield: 340 mg (86%); mp 236–238 °C.
IR (KBr): 3449, 3423, 3367, 3332, 3232, 1642, 1622, 1594, 1547,
1535, 1490, 1462 cm–1.
5-(2-Methoxybenzoyl)-2-(morpholin-4-yl)-4-(trifluorometh-
yl)pyrimidine (12a)
Yield: 252 mg (77%); yellow oil; Rf = 0.52 (Et2O).
1H NMR (DMSO-d6): d = 2.31 (s, 3 H, Me), 6.71 (br s, 4 H, 4NH),
6.98 (d, 3J = 8.3 Hz, 1 H, H-8), 7.37 (ddq, 3J = 8.3 Hz, 4J = 2.3, 0.6
Hz, 1 H, H-7), 7.50–7.54 (m, 2 H, Ar), 7.62 (d, 4J = 2.3 Hz, 1 H, H-
5), 7.75–7.79 (m, 2 H, Ar), 8.02 (d, J = 12.7 Hz, 1 H, = CH), 9.12
(s, 1 H, OH), 12.49 (d, J = 12.7 Hz, 1 H, NH).
1H NMR (CDCl3): d = 3.66 (s, 3 H, MeO), 3.74 (t, 3J = 4.7 Hz, 4 H,
morpholino), 3.90 (t, 3J = 4.7 Hz, 4 H, morpholino), 6.91 (d,
3J = 8.5 Hz, 1 H, H-3¢), 7.01 (td, 3J = 7.6 Hz, 4J = 0.9 Hz, 1 H, H-
3
4
5¢), 7.48 (ddd, J = 8.5, 7.0 Hz, J = 1.8 Hz, 1 H, H-4¢), 7.61 (dd,
19F NMR (DMSO-d6): d = –84.9 (s, CF3).
3J = 7.6 Hz, 4J = 1.8 Hz, 1 H, H-6¢), 8.37 (s, 1 H, H-6).
13C NMR (CDCl3): d = 44.1, 55.5 (q, JC,F = 2.6 Hz), 66.5, 111.6 (q,
N-Carbamimidoyl-4-({[2-(difluoromethyl)-2-hydroxy-4-oxo-
2H-chromen-3(4H)-ylidene]methyl}amino)benzenesulfon-
amide (11c)
1
JC,F = 1.6 Hz), 120.3 (q, JC,F = 277.0 Hz), 120.8, 121.4, 127.1,
131.3, 153.8 (q, 2JC,F = 36.0 Hz), 134.4, 158.5, 160.4, 161.1, 191.1.
MS (EI, 70 eV): m/z (%) = 367 (100) [M]+, 299 (10) [M + 1 – CF3]+,
298 (34) [M – CF3]+, 261 (23), 260 (89), 234 (73), 233 (44), 136
(19), 135 (55), 112 (11), 111 (12).
Yield: 265 mg (74%); mp 174–176 °C.
IR (KBr): 3457, 3425, 3363, 3220, 1643, 1610, 1596, 1544, 1469
cm–1.
1H NMR (DMSO-d6): d = 6.10 (t, 2JH,F = 55.3 Hz, 1 H, CF2H), 6.71
5-(2-Methylsulfanylbenzoyl)-2-morpholino-4-(trifluorometh-
yl)pyrimidine (12b)
Yield: 268 mg (70%); yellow oil; Rf = 0.65 (Et2O).
1H NMR (CDCl3): d = 2.55 (s, 3 H, MeS), 3.70 (t, 3J = 4.7 Hz, 4 H,
morpholino), 4.07 (t, 3J = 4.7 Hz, 4 H, morpholino), 7.49–7.66 (m,
3 H, H-3¢, H-4¢, H-5¢), 7.99 (d, 3J = 7.8 Hz, 1 H, H-6¢), 8.81 (s, 1 H,
H-6).
(br s, 4 H, 4NH), 7.02 (dd, 3J = 8.3 Hz, 4J = 0.9 Hz, 1 H, H-8), 7.10
3
4
(ddd, J = 7.9, 7.2 Hz, J = 1.0 Hz, 1 H, H-6), 7.47–7.51 (m, 2 H,
Ar), 7.53 (ddd, 3J = 8.4, 7.2 Hz, J = 1.7 Hz, 1 H, H-7), 7.75–7.79
4
(m, 2 H, Ar), 7.81 (dd, 3J = 7.8 Hz, 4J = 1.7 Hz, 1 H, H-5), 7.94 (d,
J = 12.6 Hz, 1 H, = CH), 8.46 (s, 1 H, OH), 12.47 (d, J = 12.6 Hz, 1
H, NH).
Synthesis 2009, No. 19, 3233–3242 © Thieme Stuttgart · New York

PAPER
4-(Polyfluoroalkyl)pyrimidines
3241
13C NMR (CDCl3): d = 25.0 (q, JC,F = 2.2 Hz), 42.3, 68.1, 112.0 (q,
MS (EI, 70 eV): m/z (%) = 411 (10) [M]+, 393 (83) [M – H2O]+, 392
(59) [M – 1 – H2O]+, 349 (100) [M – H2O – CO2]+, 348 (11) [M –
1 – H2O – CO2]+, 281 (11) [M + 1 – H2O – CO2 – CF3]+, 280 (37)
[M – H2O – CO2 – CF3]+, 232 (21) [M – H2O – CO2 – C8H5O]+.
1
JC,F = 1.6 Hz), 120.2 (q, JC,F = 277.0 Hz), 122.2, 122.4, 129.7,
135.0, 137.4, 153.8 (q, 2JC,F = 36.0 Hz), 159.3, 162.0, 163.1, 191.1.
MS (EI, 70 eV): m/z (%) = 383 (100) [M]+, 315(89) [M + 1 – CF3]+
, 314 (14) [M – CF3]+.
Compounds 16a–c; General Procedure
A soln of 5 (0.81 mmol) in THF (5 mL) was added dropwise to a
stirred suspension of NaH (60% dispersion in mineral oil, 43 mg,
1.08 mmol) in dry THF (10 mL). H2O2 (35% aq soln, 100 mg, 1.03
mmol) was added to the resulting soln, and the mixture was stirred
for 4 d at r.t. The mixture was then adjusted to pH ~4 with 1 M aq
HCl and extracted with Et2O. The combined organic layers were
dried (MgSO4), and the dissolved material was settled on silica gel.
A grey crystalline product was obtained by flash chromatography
with CH2Cl2, Et2O, and MeOH sequentially.
Ethyl (2-{[2-(Morpholin-4-yl)-4-(trifluoromethyl)pyrimidin-5-
yl]carbonyl}phenoxy)acetate (13)
A mixture of 5k (353 mg, 1 mmol), K2CO3 (690 mg, 5 mmol), and
BrCH2CO2Et (175 mL, 1.5 mmol) in acetone (20 mL) was stirred at
r.t. overnight. The solid phase was filtered off and the liquor was
concentrated in vacuo providing the pure white crystalline product;
yield: 426 mg (97%); mp 150–153 °C.
3
1H NMR (CDCl3): d = 1.20 (t, J = 7.1 Hz, 3 H, Me), 3.75 (dd,
3J = 5.1, 4.6 Hz, 4 H, morpholino), 3.91 (dd, 3J = 5.1, 4.6 Hz, 4 H,
morpholino), 4.13 (q, 3J = 7.1 Hz, 2 H, OCH2), 4.47 (s, 2 H, CH2),
7.08 (d, 3J = 7.7 Hz, 1 H, H-3¢), 7.10 (t, 3J = 7.7 Hz, 1 H, H-5¢), 7.48
Sodium 2-Methyl-4-(trifluoromethyl)pyrimidine-5-carboxylate
(16a)
Yield: 138 mg (75%); mp 157–158 °C; Rf = 0.55 (MeOH).
1H NMR (DMSO-d6): d = 2.64 (s, 3 H, Me), 8.84 (s, 1 H, H-6).
3
4
3
(td, J = 7.7 Hz, J = 1.7 Hz, 1 H, H-4¢), 7.67 (dd, J = 7.7 Hz,
4J = 1.7 Hz, 1 H, H-6¢), 8.47 (s, 1 H, H-6).
13C NMR (CDCl3): d = 13.9, 44.3, 61.3, 65.4, 66.6, 112.2, 120.4 (q,
1JC,F = 277.0 Hz), 122.0, 127.89, 131.6, 134.2, 153.8 (q, 2JC,F = 36.0
Hz), 156.5, 160.6, 161.4, 167.7, 190.9.
13C NMR (DMSO-d6): d = 24.8, 120.9 (q, 1JC,F = 276.0 Hz), 131.0
(q, 3JC,F = 0.8 Hz), 148.4 (q, 2JC,F = 35.0 Hz), 159.1, 165.2.
MS (EI, 70 eV): m/z (%) = 228 (100) [M]+, 161 (77).
MS (EI, 70 eV): m/z (%) = 439 (11) [M]+, 370 (57), 260 (71), 232
(100).
Sodium 2-(Morpholin-4-yl)-4-(trifluoromethyl)pyrimidine-5-
carboxylate(16b)
Yield: 194 mg (80%); mp 181–183 °C; Rf = 0.35 (MeOH).
4-[5-(1-Benzofuran-3-yl)-4-(trifluoromethyl)pyrimidin-2-
yl]morpholine (14)
Glacial AcOH (30 mL) was added to a mixture of KCl (1.37 g) and
15, prepared from 13 (0.88 g, 2 mmol) (see below). The resulting
mixture was refluxed for 24 h then concentrated in vacuo. The res-
idue was purified by flash chromatography (PE–Et2O, 2:1) to give
14 as a colorless crystals; yield: 620 mg (89%); mp 125–129 °C;
Rf = 0.45.
1H NMR (DMSO-d6): d = 3.64 (dd, 3J = 5.0, 4.5 Hz, 4 H, morpholi-
no), 3.69 (dd, 3J = 5.0, 4.5 Hz, 4 H, morpholino), 8.70 (s, 1 H, H-6).
1
13C NMR (DMSO-d6): d = 43.8, 65.6, 120.8 (q, JC,F = 277.0 Hz),
3
2
120.9 (q, JC,F = 2.0 Hz), 151.1 (q, JC,F = 34.0 Hz), 159.7, 162.1,
168.6.
MS (EI, 70 eV): m/z (%) = 299 (38) [M]+, 232 (100).
1H NMR (CDCl3): d = 3.79 (dd, 3J = 5.2, 4.4 Hz, 4 H, morpholino)
3.91 (dd, 3J = 5.2, 4.4 Hz, 4 H, morpholino), 7.26 (t, 3J = 7.8 Hz, 1
Sodium 2-Methyl-4-(perfluoropropyl)pyrimidine-5-carboxy-
late (16c)
Yield: 207 mg (78%); mp 111–113 °C; Rf = 0.85 (MeOH).
1H NMR (DMSO-d6): d = 2.79 (s, 3 H, Me), 9.01 (s, 1 H, H-6).
3
4
H, H-5¢), 7.35 (td, J = 7.8 Hz, J = 1.2 Hz, 1 H, H-6¢), 7.40 (dd,
3J = 7.8 Hz, 4J = 1.2 Hz, 1 H, H-4¢), 7.54 (d, 3J = 7.8 Hz, 1 H, H-7¢),
7.63 (s, 1 H, H-2¢), 8.50 (s, 1 H, H-6).
13C NMR (CDCl3): d = 44.2, 66.7, 110.3, 111.8, 114.2, 119.7, 120.9
(q, 1JC,F = 277.0 Hz), 123.2, 124.9, 127.9, 143.5 (q, JC,F = 2.4 Hz),
154.0 (q, 2JC,F = 34.0 Hz), 155.0, 160.5 (q, 4JC,F = 1.0 Hz), 162.3.
1
13C NMR (DMSO-d6): d = 26.1, 108.9 (tqt, JC,F = 269.0 Hz,
1
2
2JC,F = 38.0, 36.0 Hz), 112.7 (tt, JC,F = 260.0 Hz, JC,F = 32.0 Hz),
117.0 (ttq, JC,F = 288.0 Hz, 2JC,F = 34.0 Hz, JC,F = 1.2 Hz), 132.3
1
3
MS (EI, 70 eV): m/z (%) = 350 (14) [M + 1]+, 349 (100) [M]+, 281
(q, 3JC,F = 1.3 Hz), 151.4 (q, 2JC,F = 27.0 Hz), 159.1, 165.2.
(19) [M + 1 – CF3]+, 280+ (98) [M – CF3], 232 (75) [M – C8H5O]+.
MS (EI, 70 eV): m/z (%) = 328 (23) [M+], 261 (85), 144 (14), 143
(100).
3-Hydroxy-3-[2-(morpholin-4-yl)-4-(trifluoromethyl)pyrimi-
din-5-yl]-2,3-dihydro-1-benzofuran-2-carboxylic Acid (15)
A mixture of 13 (415 mg, 0.95 mmol) and KOH (265 mg, 4.73
mmol) in dioxane (20 mL) was stirred for 1 h at 30 °C to give a red
soln to which was added 2 M aq HCl (2.37 mL). The resulting soln
was concentrated in vacuo to give a gray solid residue (760 mg)
consisting of the expected product and KCl. This mixture was used
for the synthesis of 14 without further purification.
Acknowledgment
This work was supported financially by the Russian Foundation for
Basic Research (grant 06-03-32388). The work of Anton Kotljarov
was supported by the German Academic Exchange Service
(DAAD).
Yield: 383 mg (98%); mp 172–175 °C.
1H NMR (DMSO-d6): d = 3.66 (dd, 3J = 5.1, 4.6 Hz, 4 H, morpholi-
no), 3.72 (dd, 3J = 5.1, 4.6 Hz, 4 H, morpholino), 4.53 (s, 1 H, CH),
6.81 (d, 3J = 7.7 Hz, 1 H, H-4¢), 6.83 (t, 3J = 7.7 Hz, 1 H, H-5¢), 6.97
(d, 3J = 7.7 Hz, 1 H, H-7¢), 7.19 (t, 3J = 7.7 Hz, 1 H, H-6¢), 8.48 (s,
1 H, H-6), 9.69 (s, 1 H, OH).
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Synthesis 2009, No. 19, 3233–3242 © Thieme Stuttgart · New York

3242
A. Kotljarov et al.
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