Reaction of Bromoenones with Amidines: A Simple Catalyst-Free Approach to Trifluoromethylated Pyrimidines

Article abstract of DOI:10.1055/s-0040-1707969

A facile one-pot synthesis of trifluoromethylated pyrimidines has been achieved by the treatment of fluorinated 2-bromoenones with aryl- and alkylamidines. The assembly of pyrimidine core proceeds by the cascade reactions via aza-Michael addition-intramolecular cyclization-dehydrohalogenation/dehydration sequence. This strategy is featured by high selectivity and mild reaction conditions giving the target heterocycles in high yields (up to 99%). The unique influence of trifluoromethyl group on the reaction path is demonstrated.

Full text of DOI:10.1055/s-0040-1707969

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–K
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en
A. R. Romanov et al.
Paper
Synthesis
Reaction of Bromoenones with Amidines: A Simple Catalyst-Free
Approach to Trifluoromethylated Pyrimidines
Alexey R. Romanov
very important!
R'
Alexander Yu. Rulev*
CF3
R =
N
N
Alexander V. Popov
Evgeniy V. Kondrashov
Sergey V. Zinchenko
Ar
34 examples
CF3
R'
O
base
isolated yields up to 99%
Ar
R
+
H2N
NH
•HCl
solvent
A. E. Favorsky Institute of Chemistry, Siberian Branch of the
Russian Academy of Sciences, 1, Favorsky St., Irkutsk 664033,
Russia
rulev@irioch.irk.ru
rulev-irk@yandex.ru
Br
R'
catalyst-free
mild conditions
high selectivity
N
HN
Ar
CF3
R
=
available starting materials
Ac
Received: 24.01.2020
Accepted after revision: 12.02.2020
Published online: 09.03.2020
component of chemotherapy for solid tumors.7 A number of
methods for the assembly of pyrimidine core has been de-
scribed so far.8 The most common and traditional approach
to the non-fluorinated pyrimidines involves cyclocondensa-
tion of 1,3-dicarbonyl compounds or their equivalents with
1,3-binucleophiles bearing N–C–N moiety such as ami-
dines, guanidines, ureas, and their derivatives. This proce-
dure is known as the ‘principal synthesis’ of pyrimidines.9
In contrast, only a very limited number of methods for the
synthesis of trifluoromethylated pyrimidines have been de-
scribed previously.10 All these methods are based on the use
of fluorinated building blocks such as 1,3-diketones,11
-alkoxyvinyl(perfluoroalkyl)ketones,12 enones,13 amino-
enones,14 and perfluoroalkyl -diketo phosphorus ylides.15
However, the majority of these methods suffer from one or
more disadvantages, which include harsh reaction condi-
tions (high temperatures, long reaction times, transition
metal usage as a catalyst), hard-to-reach starting materials,
and moderate yields. Very recently, we have developed an
efficient synthesis of 6-trifluoromethylated pyrimidines
from CF3-ynones and nitrogen 1,3-binucleophiles.16 The
emergence of new pharmaceutical drugs possessing broad
spectrum of activities stimulates the search for novel re-
agents for the synthesis of pyrimidine derivatives.
The trifluoromethyl(-bromalkenyl)ketones are valu-
able templates for the assembly of fluorinated aza-hetero-
cycles. Previously, we successfully used these bromoenones
in the preparation of trifluoromethylated piperazin-2-
ones,17 piperazines and morpholines condensed with aziri-
dines,18 unusual morpholines condensed with oxetanes or
oxiranes,19 bis-oxazines,20 and other heterocycles. The most
remarkable achievements of our research team in the syn-
thesis of fluorinated aza-heterocycles were recently re-
viewed.21 Because these enones are now readily available22
we decided to use them as starting materials in the synthe-
sis of trifluoromethylated pyrimidines.
DOI: 10.1055/s-0040-1707969; Art ID: ss-2020-z0051-op
Abstract A facile one-pot synthesis of trifluoromethylated pyrimidines
has been achieved by the treatment of fluorinated 2-bromoenones with
aryl- and alkylamidines. The assembly of pyrimidine core proceeds by
the cascade reactions via aza-Michael addition–intramolecular cyclization–
dehydrohalogenation/dehydration sequence. This strategy is featured
by high selectivity and mild reaction conditions giving the target het-
erocycles in high yields (up to 99%). The unique influence of trifluoro-
methyl group on the reaction path is demonstrated.
Key words CF3--bromoenones, amidines, fluorinated pyrimidines,
aza-MIRC methodology, catalyst-free, mild conditions
The development of new efficient approaches to biolog-
ically active compounds and drugs is one of the greatest
challenges of modern organic chemistry.1 Nowadays, the
considerable interest in the elaboration of versatile routes
to fluorinated aza-heterocycles is caused by their use in
materials science as well as in agricultural, biological, and
medicinal chemistry.2 After nitrogen, fluorine seems to be
the next most favorite heteroatom for incorporation into
small organic molecules in life science-oriented research.3
It is well known that incorporation of fluorine [usually CF3
group or fluorine atom(s)] into heterocyclic core has made
possible the discovery of new biologically active com-
pounds. In fact, about 30% of modern biopharmaceutical
products contain fluorine or fluorine-bearing groups.4 Py-
rimidines are important structural motifs, which are found
in many bioactive synthetic and natural products as well as
in several top-selling drugs. Moreover, being structural
fragments of nucleic acids, pyrimidines are recognized as
privileged pharmacophores and occupy a special place in
bioorganic and medicinal chemistry.5 Many pyrimidine de-
rived drugs are used mainly as anticancer, antiviral, anti-
HIV, antibacterial, and antifungal agents.6 Thus, since its
discovery in 1957, 5-fluorouracil remains a foundational
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
A. R. Romanov et al.
Paper
Synthesis
Previously, it was shown that the treatment of function-
alized 3-halosubstituted but-3-en-2-ones with amidine
salts or guanidine led to corresponding imidazoles rather
than pyrimidines.23 Very recently, the reaction of conjugat-
ed -bromoalkenones with guanidine as 1,3-binucleophile
was described as an excellent approach to aminoimidaz-
oles.24 We hypothesized that the replacement of methyl or
aryl moieties by trifluoromethyl group in carbonyl bearing
function could increase the electrophilicity of the carbonyl
carbon and as a result to favor the aza-Michael addition of
amidines and following nucleophilic attack on the carbonyl
group and formation of six-membered heterocycle. The
strategy toward assembly of these heterocycles is shown in
Scheme 1.
To emphasize the role of trifluoromethyl group in the
reaction direction, we treated ketone 5 with amidine 2a. In
contrast to fluorinated bromoenones their non-fluorinated
analogue reacts with the same nucleophile under the same
conditions leading exclusively to imidazole 6 in high yield.
Motivated by the importance of the development of
original approach to trifluoromethylated pyrimidines 3, we
next investigated the generality of this reaction and its de-
pendence on the reaction conditions. For this purpose, a va-
riety of bromoenones 1a–f with benzimidamide 2a was
tested (Scheme 3).
Ph
Ph
O
reaction conditions
reflux, 3–4 h
N
N
R
CF3
H2N
NH
•HCl
+
Br
R
CF3
R
2a
1a–i
3
a
a
N
N
reaction conditions: Et3N, CHCl3 (A); Et3N, MeCN (B): DABCO, MeCN (C)
NH
R
b
O
Ar
R'
R
NH
O
H2N
NH
Ph
Ph
Ar
R'
Ph
R
Ar
R'
Br
N
N
N
N
N
N
Br
N
HN
Ar
CF3
CF3
b
Ph
3aa (99%), A
Ph
CF3
R'
F3C
O2N
O
3ba (81%), C
3ca (81%), A
Scheme 1 Possible pathways of heterocycle assembly
Ph
Ph
N
N
N
N
N
N
We began our study by taking 3-bromo-1,1,1-trifluoro-
4-phenylbut-3-en-2-one (1a) and benzamidine hydrochlo-
ride (2a) as the model starting reagents. The reaction was
initially performed in refluxing THF in the presence of Et3N
following the usual procedure, which we often apply for the
assembly of trifluoromethylated aza-heterocycles. We have
found that in contrast to non-fluorinated chalcones25 this
reaction proceeded smoothly under catalyst-free condi-
tions and afforded a 1:2 mixture of pyrimidine 3aa and im-
idazole 4a, which can be easily separated by column chro-
matography (Scheme 2).
CF3
CF3
CF3
Cl
MeO
3da (64%), A
3ea (51%), A
3fa (76%), B
Ph
Ph
Ph
N
N
N
N
N
N
CF3
CF3
CF3
O
F
Br
3ga (75%), A
3ha (61%), B
3ia (56%), A
Scheme 3 Scope of reaction with benzamidine hydrochloride (2a)
Ph
Ph
We found that the reaction result is sensitive to the sol-
vent nature. Keeping in mind that THF gives a mixture of
products 3 and 4, we used different solvents. Thus, the py-
rimidines 3 were obtained as the only products in CHCl3 in
the presence of Et3N (conditions A) or in acetonitrile in the
presence of Et3N (conditions B) or DABCO (conditions C).
According to the literature data, non-fluorinated -bromo-
,-unsaturated compounds under the similar or even the
same conditions give only five-membered heterocycles –
imidazoles or imidazolines.24,26 It should be noted that py-
rimidine 3aa under conditions A was isolated as the sole
product in 99% yield. With the optimized reaction condi-
tions in hand, the scope of amidine salts 2 was evaluated
(Table 1). Thus, we involved the benzimidamides, bearing
either an electron-withdrawing (2b–d) or an electron-
donating (2e) substituent in benzene ring, as well as acet-
amidine hydrochloride 2f into the reaction.
N
HN
for 1a
Ph
3aa (28%)
Ph
N
N
+
CF3
CF3 Ph
O
Ph
O
Et3N
4a (49%)
Ph
R' + H2N
•HCl
NH
THF,
reflux
Br
2a
1a (R' = CF3)
5 (R' = Me)
N
HN
for 5
Ac
Ph
6 (82%)
Scheme 2 Reaction of fluorinated and non-fluorinated bromoenones
with benzamidine
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

C
A. R. Romanov et al.
Paper
Synthesis
Table 1 Scope of Trifluoromethylated Pyrimidinesa
R
O
R
DABCO, MeCN
reflux, 3 h
N
N
H2N
NH
•HCl
Ar
CF3
+
Br
Ar
CF3
2b–f
1a–f
3
Entry
-Bromoenone
Ar
Amidine·HCl
R
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Ph
2b
2c
2d
2e
2f
4-CF3C6H4
4-NO2C6H4
4-ClC6H4
4-MeOC6H4
Me
4-CF3C6H4
4-NO2C6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
CF3
CF3
CF3
CF3
CF3
CF3
N
N
N
N
N
N
N
N
N
N
N
N
CF3
CF3
CF3
CF3
CF3
O2N
CF3
CF3
Ph
CF3
Cl
MeO
F3C
3fb (85%)
3eb (85%)
NO2
3db (80%)
3bb (98%)
3ab (93%)
3cb (95%)
NO2
NO2
NO2
NO2
N
N
N
N
N
N
N
N
N
N
CF3
Cl
CF3
CF3
Ph
CF3
MeO
Cl
Cl
O2N
F3C
3ac (80%)
3cc (74%)
3dc (63%)
3fc (76%)
3bc (76%)
Cl
Cl
Cl
Cl
N
N
N
N
N
N
N
N
N
N
N
N
CF3
CF3
Cl
CF3
CF3
Ph
CF3
MeO
O2N
F3C
3dd (87%)
3fd (74%)
3cd (98%)
3ed (77%)
3bd (92%)
3ad (93%)
OMe
OMe
OMe
N
N
N
N
N
N
CF3
CF3
Ph
CF3
F3C
MeO
3ae (71%)
3be (79%)
3fe (64%)
N
N
N
N
N
N
N
N
N
Ph
N
CF3
CF3
CF3
CF3
CF3
MeO
O2N
F3C
3af (38%)
3bf (48%)
3cf (71%)
3ef (38%)
3ff (38%)
a All reactions were carried out using bromoenone 1 (1 mmol) and amidine salt 2 (1.5 mmol) in the presence of DABCO (4 mmol) in MeCN (5 mL) under reflux for
3 h. Isolated yields (silica gel column chromatography) are given.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

D
A. R. Romanov et al.
Paper
Synthesis
O
R
R
NH2
H
HO
Br
N
base
Ar
CF3
H2N
+
NH
NH•HCl
R
N
O
Ar
CF3
Br
2
Ar
CF3
1
Br
base
CF3
HO
CF3
R
N
R
O
2 (R = Me)
H
2
N
N
N
Ar
– H2O
– HBr
OH
CF3
base
base
N
N
Ar
Ar
CF3
Ar
7
3
Ar
CF3
Br
8
Scheme 4 Proposed reaction mechanism
In most cases, the results obtained were not affected
greatly by the electronic characteristics of the aryl moiety
of starting bromoenone 1. In fact, pyrimidines 3bc, 3cc, and
3fc were obtained in the same yield (74–76%) from 4-nitro-
benzimidamide 2c and bromoenones bearing either elec-
tron-withdrawing (1b,c) or -donating (1f) substituent in ar-
omatic moiety. Similarly, the bromoenones 1a–f reacted
smoothly with 4-(trifluoromethyl)benzimidamide 2b to af-
ford the target pyrimidines in high yields (80–98%). In con-
trast, the nature of substituent in the amidine showed a sig-
nificant effect. To our surprise, pyrimidines 3 were isolated
in a much better yield when amidines bearing electron-
withdrawing substituent in aromatic moiety were used. Fi-
nally, when acetamidine hydrochloride (2f) was used in-
stead of arylamidines in this reaction, the expected pyrimi-
dines were isolated only in moderate yields. Solvent or base
in this case did not show a significant influence on the reac-
tion course. Similar results were observed in the reaction of
acetamidine hydrochloride with CF3-ynones16 and -un-
substituted enones.13
Most likely, the assembly of the six-membered core is
initiated by the aza-Michael addition of amidine, generated
in situ from its salt, followed by the intramolecular cycliza-
tion (these transformations are known as the aza-MIRC
methodology27). In the case of fluorinated bromoenones
the nucleophilic attack of the second nitrogen occurs pref-
erentially on the carbonyl carbon. Finally, the elimination of
hydrogen bromide and water affords the target pyrimidines
3. The alternative reaction pathway that involves the inter-
mediate formation of CF3-ynones 7 can apparently be ruled
out because their reactions with amidines proceeded in the
presence of very strong bases (MeONa, EtONa, t-BuOK,
DBU).16 Moreover, when fluorinated bromoenones 1 were
treated with acetamidine hydrochloride (2f) in the pres-
ence of triethylamine, the unusual adduct 8, which was al-
ways formed as a major by-product from the reaction of
two molecules of CF3-ynone with one molecule of acetami-
dine,16 was not detected in this case.
In conclusion, we have developed a new one-pot proce-
dure for the selective assembly of trifluoromethylated py-
rimidines from available fluorinated unsaturated bromoke-
tones and amidines. The reaction proceeds as aza-MIRC pro-
cess via conjugate nucleophilic addition–cyclocondensation–
dehydrobromination sequence. In contrast to non-fluori-
nated analogues, CF3--bromoenones readily transform
into target pyrimidines in yields of 38 to 99% under mild
and catalyst-free conditions.
Both organic bases – Et3N and DABCO – were successful-
ly used in the reaction. Excess of the base was used in order
to generate in situ amidine from the corresponding salt and
to neutralize hydrogen bromide, which was eliminated in
the course of reaction.
It should be noted that bromoenones 1 are much more
reactive in the reaction with amidines 2 than their non-
fluorinated analogues. For example, the reaction of bromo-
enone 1a with amidine 2a proceeded under reflux in THF
for 3 hours while the reaction of non-fluorinated analogue
5 with the same nucleophile was finished only after 12
hours under the same reaction conditions. This observation
is in good agreement with our previous conclusion of very
high reactivity of bromoenones 1 as the Michael acceptors
and our hypothesis22 proposed in the current paper on the
higher electrophilicity of carbonyl carbon in bromoenones
1 than in their non-fluorinated analogues. In the light of
these results, the mechanism of the synthesis of pyrimi-
dines 3 is quite clear (Scheme 4).
1H (400.1 MHz), 13C (100.6 MHz), and 19F (376.5 MHz) NMR spectra
were recorded on a Bruker Avance 400 MHz spectrometer. Chemical
shifts () are given in ppm with the use of the residual CHCl3 (7.24 for
1H NMR and 77.2 for 13C NMR), acetone (2.09 for 1H NMR; 29.9 for 13
C
NMR), DMSO (2.50 for 1H NMR and 39.5 for 13C NMR) as internal ref-
erences. The coupling constants (J) are given in hertz (Hz). IR spectra
were recorded on a Bruker Vertex 70 FT-IR spectrometer and with a
portable Varian 3100 diamond ATR/FT-IR spectrometer. The GC/MS
analyses were performed with a Shimadzu GCMS-QP5050A instru-
ment (EI, 70 eV). Melting points were measured by Micro-Hot-Stage
PolyTherm A and are given without further correction. All the
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

E
A. R. Romanov et al.
Paper
Synthesis
solvents were dried according to standard procedures and freshly dis-
tilled prior to use. The silica gel used for column chromatography was
70–230 mesh. All reagents were of reagent grade and were used as
such or distilled prior to use. The starting -bromoenones 1a,c–i are
known compounds and were prepared according to the reported pro-
cedures.22
2-Phenyl-4-(trifluoromethyl)-6[4-(trifluoromethyl)phenyl]-
pyrimidine (3ba)
Pale yellow solid; yield: 302 mg (81%); mp 107–108 °C (CHCl3); Rf =
0.9 (CHCl3).
IR (KBr): 1573 (C4=N), 1554 (C2=N–C6=C5), 1157 cm–1 (C–F).
1H NMR (CDCl3):  = 8.63–8.56 (m, 2 H, C6H5), 8.32 (d, J = 8.1 Hz, 2 H,
Ar), 7.86 (s, 1 H, C5H), 7.80 (d, J = 8.1 Hz, 2 H, Ar), 7.56–7.49 (m, 3 H,
C6H5).
13C NMR (CDCl3):  = 165.8 (C2), 165.1 (C6), 157.4 (q, J = 35.8 Hz, C4),
139.3, 133.6 (q, J = 32.8 Hz), 136.3, 132.0, 129.0, 128.9 (C6H5), 128.0,
126.5 (q, J = 3.7 Hz) (Ar), 124.0 (q, J = 272.6 Hz, ArCF3), 120.9 (q, J =
275.4 Hz, C4CF3), 110.4 (q, J = 2.5 Hz, C5).
(Z)-3-Bromo-1,1,1-trifluoro-4-[4-(trifluoromethyl)phenyl]but-3-
en-2-one (1b)
Bromoenone 1b was synthesized from (E)-1,1,1-trifluoro-4-[4-(tri-
fluoromethyl)phenyl]but-3-en-2-one (CAS 1637638-59-5) by the re-
ported procedure.22
Light yellow solid; yield: 1.518 g (78%); mp 46–48 °C (CHCl3); Rf = 0.7
(CHCl3).
IR (film): 1714 (C=O), 1598, 1416, 1324, 1210, 1161, 1117 cm–1 (C–F).
1H NMR (CDCl3):  = 8.19 (s, 1 H, C4H), 7.99 (d, J = 8.2 Hz, 2 H, Ar), 7.73
(d, J = 8.2 Hz, 2 H, Ar).
13C NMR (CDCl3):  = 176.0 (q, J = 36.0 Hz, C=O), 145.5 (C4), 136.5,
133.2 (q, J = 33.0 Hz), 131.2, 125.9 (q, J = 3.5 Hz, Ar), 123.7 (q, J = 272.7
Hz, ArCF3), 119.3 (C3), 115.8 (q, J = 291.4 Hz, C1F3).
19F NMR (CDCl3):  = –62.7 (s, 3 F, ArCF3), –69.8 (s, 3 F, C4CF3).
MS (EI): m/z (%) = 368 (100, M+), 349 (12), 196 (32), 176 (23), 104
(95), 103 (41), 77 (18), 76 (17), 75 (13), 69 (11), 51 (13).
Anal. Calcd for C18H10F6N2: C, 58.70; H, 2.74; N, 7.61. Found: C, 58.64;
H, 2.72; N, 7.28.
4-(4-Nitrophenyl)-2-phenyl-6-(trifluoromethyl)pyrimidine (3ca)
Light orange solid; yield: 279 mg (81%); mp 155–156 °C (CHCl3); Rf =
0.95 (CHCl3–MeOH 97:3).
IR (KBr): 1582 (C6=N), 1551 (C2=N–C4=C5), 1179, 1154 cm–1 (C–F).
19F NMR (CDCl3):  = –63.0 (s, 3 F, ArCF3), –68.6 (s, 3 F, C1F3).
MS (EI): m/z (%) = 348 (8, M+ + 1), 346 (8, M+ – 1), 279 (48), 277 (52),
251 (19), 249 (22), 170 (100), 169 (24), 151 (23), 120 (17), 75 (23), 74
(14), 69 (26), 50 (14).
1H NMR (CDCl3):  = 8.63–8.57 (m, 2 H, C6H5), 8.44–8.37 (m, 4 H, Ar),
7.92 (s, 1 H, C5H), 7.58–7.50 (m, 3 H, C6H5).
Anal. Calcd for C11H5BrF6O: C, 38.07; H, 1.45. Found: C, 38.38; H, 1.79.
13C NMR (acetone-d6):  = 166.0 (C2), 165.5 (C4), 157.8 (q, J = 35.4 Hz,
C6), 150.9, 142.3, 129.9, 124.9 (Ar), 137.0, 132.9, 129.8, 129.4 (C6H5),
121.9 (q, J = 275.2 Hz, CF3), 112.5 (C5).
Amidine Salts 2a–e
The amidine salts 2a–e were prepared according to the reported pro-
cedures28 (for 2b–d) and29 (for 2a,e). Their purity estimation was car-
ried out by 1H NMR spectroscopy with mesitylene as internal stan-
dard. All amidine salts 2a–e were of 95+% purity except 4-chlorobenz-
imidamide hydrochloride 2d (~85% purity) and contained NH4Cl as an
admixture. Acetamidine hydrochloride (2f) (CAS 124-42-5) is a com-
mercially available reagent (Aldrich 159158, 95%).
19F NMR (acetone-d6):  = –70.2.
MS (EI): m/z (%) = 345 (100, M+), 299 (39), 139 (13), 115 (16), 104
(49), 103 (21), 77 (17), 76 (14), 75 (13), 51 (12).
Anal. Calcd for C17H10F3N3O: C, 59.14; H, 2.92; N, 12.17. Found: C,
58.91; H, 2.60; N, 11.95.
4-(4-Chlorophenyl)-2-phenyl-6-(trifluoromethyl)pyrimidine
(3da)
Pyrimidines 3; General Procedure
Argon was bubbled through a mixture of the appropriate base Et3N or
DABCO (4 mmol) and amidine salt 2 (1.3–1.7 mmol) in the appropri-
ate solvent CHCl3 or MeCN (3.5–4 mL) at ~40 °C for 30 min to remove
the ammonia formed after treatment of NH4Cl with the base and to
generate the free binucleophile. Next, the bromoenone 1 (1 mmol)
dissolved in the same solvent CHCl3 or MeCN (1–1.5 mL) was added
and the reaction mixture was refluxed for 3–4 h. After cooling, the
mixture was concentrated in vacuo, and the residue was purified by
column chromatography (using a short column) on silica gel to afford
the pure target product 3. The following pyrimidines were obtained
by this procedure: 3aa, 3ca, 3da, 3ea, 3ga, 3ia (Method A: Et3N,
CHCl3), 3fa, 3ha (Method B: Et3N, MeCN), 3ba, 3ab, 3bb, 3cb, 3db,
3eb, 3fb, 3ac, 3bc, 3cc, 3dc, 3fc, 3ad, 3bd, 3cd, 3dd, 3ed, 3fd, 3ae, 3be,
3fe, 3af, 3bf, 3cf, 3ef, 3ff (Method C: DABCO, MeCN).
Pale yellow solid; yield: 214 mg (64%); mp 126–128 °C; Rf = 0.95
(CHCl3–MeOH 97:3).
1H NMR (CDCl3):  = 8.62–8.57 (m, 2 H, C6H5), 8.20 (d, J = 8.6 Hz, 2 H,
Ar), 7.83 (s, 1 H, C5H), 7.56–7.49 (m, 5 H, C6H5, Ar).
The NMR data are in agreement with those in the literature.16
2-Phenyl-4-(p-tolyl)-6-(trifluoromethyl)pyrimidine (3ea)
Pale yellow solid; yield: 161 mg (51%); mp 72–73 °C (CHCl3); Rf = 0.9
(CHCl3–MeOH 97:3).
IR (KBr): 1585 (C6=N), 1548 (C2=N–C4=C5), 1182, 1152 cm–1 (C–F).
1H NMR (CDCl3):  = 8.66–8.60 (m, 2 H, C6H5), 8.11 (d, J = 7.9 Hz, 2 H,
Ar), 7.80 (s, 1 H, C5H), 7.56–7.50 (m, 3 H, C6H5), 7.32 (d, J = 7.9 Hz, 2 H,
Ar), 2.43 (s, 3 H, CH3).
2,4-Diphenyl-6-(trifluoromethyl)pyrimidine (3aa)
13C NMR (CDCl3):  = 166.5 (C2), 165.4 (C4), 156.7 (q, J = 35.4 Hz, C6),
142.7, 133.2, 128.8, 127.5 (Ar), 136.8, 131.6, 130.0, 128.9 (C6H5), 121.2
(q, J = 275.2 Hz, CF3), 109.6 (C5), 21.6 (CH3).
19F NMR (CDCl3):  = –69.7.
MS (EI); m/z (%) = 314 (100, M+), 211 (18), 142 (51), 116 (12), 115
White solid; yield: 298 mg (99%); mp 72–74 °C; Rf = 0.95 (CHCl3–
MeOH, 97:3).
1H NMR (CDCl3):  = 8.65–8.60 (m, 2 H, C6H5), 8.28–8.23 (m, 2 H,
C6H5), 7.88 (s, 1 H, C5H), 7.59–7.51 (m, 6 H, C6H5).
19F NMR (CDCl3):  = –69.8.
(26), 103 (14).
The NMR data are in agreement with those in the literature.13,15,16
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Anal. Calcd for C18H13F3N2: C, 68.78; H, 4.17; N, 8.91. Found: C, 68.60;
H, 3.92; N, 8.65.
13C NMR (CDCl3):  = 165.5 (C2), 165.4 (C4), 165.4 (d, J = 253.2 Hz),
132.2 (d, J = 3.2 Hz), 129.8 (d, J = 8.9 Hz), 116.7 (d, J = 21.9 Hz, Ar),
157.0 (q, J = 35.7 Hz, C6), 136.6, 131.8, 128.9, 128.8 (C6H5), 121.0 (q, J =
275.3 Hz, CF3), 109.6 (C5).
19F NMR (CDCl3):  = –107.4 (s, 1 F, FAr), –69.8 (s, 3 F, CF3).
15N NMR (CDCl3, 40.6 MHz):  = –97.6 (N3), –110.5 (N1).
MS (EI): m/z (%) = 318 (100, M+), 215 (33), 195 (15), 159 (15), 149
(16), 147 (15), 146 (95), 139 (27), 126 (40), 124 (12), 121 (20), 120
(27), 104 (75), 103 (56), 95 (15), 77 (21), 76 (21), 75 (19), 51 (15).
4-(4-Methoxyphenyl)-2-phenyl-6-(trifluoromethyl)pyrimidine
(3fa)
Light yellow solid; yield: 250 mg (76%); mp 114–115 °C; Rf = 0.9
(CHCl3–MeOH 97:3).
1H NMR (CDCl3):  = 8.63–8.58 (m, 2 H, C6H5), 8.21 (d, J = 8.9 Hz, 2 H,
Ar), 7.79 (s, 1 H, C5H), 7.54–7.49 (m, 3 H, C6H5), 7.05 (d, J = 8.9 Hz, 2 H,
Ar), 3.89 (s, 3 H, CH3).
Anal. Calcd for C17H10F4N2: C, 64.15; H, 3.17; N, 8.80. Found: C, 64.02;
H, 2.95; N, 8.59.
The NMR data are in agreement with those in the literature.13,16
2-Phenyl-4-(m-tolyl)-6-(trifluoromethyl)pyrimidine (3ga)
4-Phenyl-6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]-
pyrimidine (3ab)
Pale yellow solid; yield: 235 mg (75%); mp 56–57 °C (CHCl3); Rf = 0.9
(CHCl3–MeOH 97:3).
IR (KBr): 1589 (C6=N), 1549 (C2=N–C4=C5), 1174, 1148 cm–1 (C–F).
Pale yellow solid; yield: 342 mg (93%); mp 95–97 °C (CHCl3), Rf = 0.9
(CHCl3).
IR (KBr): 1593 (C6=N), 1550 (C2=N–C4=C5), 1155, 1126 cm–1 (C–F).
1H NMR (CDCl3):  = 8.65–8.60 (m, 2 H, C6H5), 8.04 (d, J = 10.1 Hz, 2 H,
Ar), 7.86 (s, 1 H, C5H), 7.55–7.51 (m, 3 H, C6H5), 7.44 (dd, J1 = J2 = 7.6
Hz, 1 H, Ar), 7.38 (d, J = 7.6 Hz, 1 H, Ar), 2.49 (s, 3 H, CH3).
13C NMR (CDCl3):  = 166.7 (C2), 165.4 (C4), 156.7 (q, J = 35.6 Hz, C6),
139.1, 136.0, 132.8, 129.2, 128.1, 124.8 (Ar), 136.7, 131.7, 128.9, 128.8
(C6H5), 121.1 (q, J = 275.5 Hz, CF3), 110.1 (C5), 21.6 (CH3).
1H NMR (CDCl3):  = 8.70 (d, J = 8.1 Hz, 2 H, C6H5), 8.26–8.20 (m, 2 H,
Ar), 7.91 (s, 1 H, C5H), 7.76 (d, J = 8.1 Hz, 2 H, Ar), 7.62–7.53 (m, 3 H,
C6H5).
13C NMR (CDCl3):  = 167.0 (C2), 164.2 (C4), 157.1 (q, J = 35.7 Hz, C6),
139.9, 133.3 (q, J = 32.5 Hz), 127.7, 125.8 (q, J = 3.8 Hz) (Ar), 135.8,
132.4, 129.4, 129.2 (C6H5), 124.2 (q, J = 272.4 Hz, ArCF3), 121.0 (q, J =
275.4 Hz, C6CF3), 110.9 (q, J = 3.0 Hz, C5).
19F NMR (CDCl3):  = –69.7.
MS (EI): m/z (%) = 314 (100, M+), 313 (10), 211 (20), 157 (11), 142
19F NMR (CDCl3):  = –62.6 (s, 3 F, ArCF3), –69.8 (s, 3 F, C6CF3).
(59), 140 (11), 122 (10), 116 (14), 115 (39), 104 (20), 103 (24), 77 (13).
MS (EI): m/z (%) = 368 (39, M+), 197 (16), 177 (10), 128 (100), 103
(13), 102 (21), 101 (13), 77 (22), 76 (11), 75 (11), 51 (12).
Anal. Calcd for C18H13F3N2: C 68.79; H 4.17; N 8.91. Found: C 68.64; H
4.16; N 8.58.
Anal. Calcd for C18H10F6N2: C, 58.70; H, 2.74; N, 7.61. Found: C, 58.62;
H, 2.82; N, 7.53.
4-(5-Bromofuran-2-yl)-2-phenyl-6-(trifluoromethyl)pyrimidine
(3ha)
Light yellow solid; yield: 224 mg (61%); mp 139–141 °C (CHCl3); Rf =
0.95 (CHCl3–MeOH 97:3).
4-(Trifluoromethyl)-2,6-bis[4-(trifluoromethyl)phenyl]pyrimi-
dine (3bb)
IR (film): 1599 (C6=N), 1566, 1540 (C2=N–C4=C5), 1184, 1140 cm–1 (C–F).
Pale yellow solid; yield: 425 mg (98%); mp 133–134 °C (CHCl3); Rf =
0.9 (CHCl3).
1H NMR (CDCl3):  = 8.54–8.50 (m, 2 H, C6H5), 7.73 (s, 1 H, C5H), 7.53–
7.48 (m, 3 H, C6H5), 7.46 (d, J = 3.5 Hz, 1 H, furyl), 6.58 (d, J = 3.5 Hz, 1
H, furyl).
13C NMR (CDCl3):  = 165.4 (C2), 157.0 (q, J = 36.0 Hz, C6), 156.6 (C4),
153.3, 126.9, 116.1, 107.9 (thienyl), 136.3, 131.8, 128.8, 128.8 (C6H5),
120.9 (q, J = 275.2 Hz, CF3), 115.1 (C5).
IR (KBr): 1592 (C4=N), 1557 (C2=N–C6=C5), 1164, 1122 cm–1 (C–F).
1H NMR (CDCl3):  = 8.67 (d, J = 8.5 Hz, 2 H, Ar), 8.32 (d, J = 8.5 Hz, 2 H,
Ar), 7.93 (s, 1 H, C5H), 7.83 (d, J = 8.5 Hz, 2 H, Ar), 7.75 (d, J = 8.0 Hz, 2
H, Ar).
13C NMR (CDCl3):  = 165.5 (C2), 164.4 (C6), 157.6 (q, J = 36.1 Hz, C4),
139.4, 139.0, 133.9 (q, J = 32.8 Hz), 133.5 (q, J = 32.4 Hz), 129.2, 128.0,
126.4 (q, J = 3.8 Hz), 125.8 (q, J = 3.8 Hz, Ar, Ar), 124.1 (q, J = 272.4 Hz,
ArCF3), 123.9 (q, J = 272.5 Hz, ArCF3), 120.8 (q, J = 275.4 Hz, C4CF3),
111.2 (q, J = 2.4 Hz, C5).
19F NMR (CDCl3):  = –70.0.
MS (EI): m/z (%) = 370 (97, M+ + 1), 369 (25), 368 (100, M+ – 1), 289
(67), 261 (22), 241 (16), 198 (22), 196 (23), 170 (25), 168 (18), 131
(16), 120 (20), 104 (16), 103 (28), 96 (13), 89 (14), 77 (27), 76 (21), 63
(31), 51 (21).
19F NMR (CDCl3):  = –62.7 (s, 3 F, ArCF3), –62.8 (s, 3 F, ArCF3), –69.8 (s,
3 F, C4CF3).
Anal. Calcd for C15H8F3N2O: C, 48.81; H, 2.18; N, 7.59. Found: C, 48.82;
H, 2.08; N, 7.48.
MS (EI): m/z (%) = 436 (100, M+), 417 (41), 367 (15), 265 (32), 245
(18), 197 (17), 196 (90), 176 (50), 172 (51), 171 (31), 170 (23), 169
(11), 152 (20), 145 (27), 121 (23), 95 (10), 75 (18), 69 (23).
4-(4-Fluorophenyl)-2-phenyl-6-(trifluoromethyl)pyrimidine (3ia)
Anal. Calcd for C19H9F9N2: C, 52.31; H, 2.08; N, 6.42. Found: C, 52.24;
H, 1.97; N, 6.15.
Pale yellow solid; yield: 176 mg (56%); mp 102–103 °C (CHCl3); Rf =
0.95 (CHCl3–MeOH 97:3).
IR (KBr): 1596 (C6=N), 1552 (C2=N–C4=C5), 1183, 1157 cm–1 (C–F).
4-(4-Nitrophenyl)-6-(trifluoromethyl)-2-[4-(trifluoromethyl)-
phenyl]pyrimidine (3cb)
1H NMR (CDCl3):  = 8.67–8.61 (m, 2 H, C6H5), 8.31–8.25 (m, 2 H, Ar),
7.81 (s, 1 H, C5H), 7.60–7.53 (m, 3 H, C6H5), 7.30–7.24 (m, 2 H, Ar).
White solid; yield: 392 mg (95%); mp 171–172 °C (CHCl3); Rf = 0.9
(CHCl3).
IR (KBr): 1556 (C2=N–C4=C5), 1157 cm–1 (C–F).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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1H NMR (CDCl3):  = 8.72 (d, J = 8.1 Hz, 2 H, Ar), 8.42 (s, 4 H, Ar), 8.01
(s, 1 H, C5H), 7.78 (d, J = 8.2 Hz, 2 H, Ar).
13C NMR (CDCl3):  = 164.8 (C2), 164.7 (C4), 157.9 (q, J = 36.6 Hz, C6),
150.2, 141.4, 139.3, 133.7 (q, J = 32.8 Hz), 129.3, 128.7, 125.9 (q, J = 4.1
Hz), 124.6 (Ar, Ar), 124.1 (q, J = 272.4 Hz, ArCF3), 120.7 (q, J = 275.5 Hz,
C6CF3), 111.6 (q, J = 1.6 Hz, C5).
1H NMR (CDCl3):  = 8.67 (d, J = 8.1 Hz, 2 H, Ar), 8.19 (d, J = 8.3 Hz, 2 H,
Ar), 7.80 (s, 1 H, C5H), 7.74 (d, J = 8.2 Hz, 2 H, Ar), 7.03 (d, J = 8.4 Hz, 2
H, Ar), 3.89 (s, 3 H, OCH3).
13C NMR (CDCl3):  = 166.3 (C2), 164.0 (C4), 156.7 (q, J = 35.6 Hz, C6),
163.2, 140.1, 133.1 (q, J = 32.4 Hz), 129.4, 129.1, 128.1, 125.7 (q, J = 3.5
Hz), 114.8 (Ar, Ar), 124.3 (q, J = 276.3 Hz, ArCF3), 121.1 (q, J = 275.2 Hz,
C6CF3), 109.8 (q, J = 2.0 Hz, C5), 55.7 (OCH3).
19F NMR (CDCl3):  = –62.7 (s, 3 F, ArCF3), –69.7 (s, 3 F, C6CF3).
19F NMR (CDCl3):  = –62.6 (s, 3 F, ArCF3), –69.8 (s, 3 F, C6CF3).
MS (EI): m/z (%) = 398 (100, M+), 158 (25), 132 (13).
MS (EI): m/z (%) = 413 (100, M+), 383 (14), 368 (13), 367 (59), 355
(11), 176 (22), 173 (18), 172 (17), 145 (11), 127 (12), 76 (11), 75 (22),
69 (12), 51 (11), 50 (12).
Anal. Calcd for C19H12F6N2O: C, 57.29; H, 3.04; N, 7.03. Found: C,
56.93; H, 2.80; N, 6.75.
Anal. Calcd for C18H9F6N3O2: C, 52.31; H, 2.20; N, 10.17. Found: C,
52.28; H, 2.11; N, 9.94.
2-(4-Nitrophenyl)-4-phenyl-6-(trifluoromethyl)pyrimidine (3ac)
4-(4-Chlorophenyl)-6-(trifluoromethyl)-2-[4-(trifluoromethyl)-
phenyl]pyrimidine (3db)
Light yellow solid; yield: 276 mg (80%); mp 141–143 °C (CHCl3); Rf =
0.9 (CHCl3).
White solid; yield: 320 mg (80%); mp 121–123 °C (CHCl3); Rf = 0.9
(CHCl3).
IR (KBr): 1589 (C6=N), 1546 (C2=N–C4=C5), 1185, 1149 cm–1 (C–F).
1H NMR (CDCl3):  = 8.68 (d, J = 8.1 Hz, 2 H, Ar), 8.18 (d, J = 8.5 Hz, 2 H,
Ar), 7.88 (s, 1 H, C5H), 7.76 (d, J = 8.2 Hz, 2 H, Ar), 7.53 (d, J = 8.6 Hz, 2
H, Ar).
IR (KBr): 1588 (C6=N), 1524 (C2=N–C4=C5), 1184, 1148 cm–1 (C–F).
1H NMR (CDCl3):  = 8.63–8.57 (m, 2 H, C6H5), 8.44–8.37 (m, 4 H, Ar),
7.92 (s, 1 H, C5H), 7.58–7.50 (m, 3 H, C6H5).
13C NMR (CDCl3):  = 167.2 (C2), 163.4 (C4), 157.2 (q, J = 35.9 Hz, C6),
149.9, 142.2, 127.7, 124.0 (Ar), 135.5, 132.6, 129.8, 129.5 (C6H5), 120.8
(q, J = 275.4 Hz, CF3), 111.2 (q, J = 1.9 Hz, C5).
13C NMR (CDCl3):  = 165.8 (C2), 164.3 (C4), 157.3 (q, J = 36.0 Hz, C6),
139.7, 138.8, 134.2, 133.4 (q, J = 32.5 Hz), 129.8, 129.2, 128.9, 125.8
(q, J = 3.7 Hz, Ar, Ar), 124.2 (q, J = 272.4 Hz, ArCF3), 120.9 (q, J = 275.3
Hz, C6CF3), 110.6 (q, J = 2.9 Hz, C5).
19F NMR (CDCl3):  = –69.7.
MS (EI): m/z (%) = 345 (100, M+), 315 (34), 300 (11), 299 (63), 287
(17), 229 (14), 197 (13), 128 (35), 115 (18), 103 (16), 102 (61), 101
(23), 77 (33), 76 (22), 75 (23), 69 (26), 51 (20), 50 (14).
19F NMR (CDCl3):  = –62.6 (s, 3 F, ArCF3), –69.8 (s, 3 F, C6CF3).
Anal. Calcd for C17H10F3N3O2: C, 59.14; H, 2.92; N, 12.17. Found: C,
59.21; H, 2.65; N, 12.10.
MS (EI): m/z (%) = 404 (32, M+ + 2), 403 (19, M+ + 1), 402 (100, M+),
231 (12), 171 (12), 164 (29), 162 (82), 137 (13), 136 (19), 127 (21),
126 (19), 121 (11), 75 (20), 69 (11).
2-(4-Nitrophenyl)-4-(trifluoromethyl)-6-[4-(trifluoromethyl)-
phenyl]pyrimidine (3bc)
Anal. Calcd for C18H9ClF6N2: C, 53.68; H, 2.25; N, 6.96. Found: C, 53.81;
H, 2.28; N, 6.69.
Pale yellow solid; yield: 312 mg (76%); mp 180–181 °C (CHCl3); Rf =
0.9 (CHCl3).
4-(p-Tolyl)-6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]-
pyrimidine (3eb)
IR (KBr): 1588 (C4=N), 1550 (C2=N–C6=C5), 1185, 1127 cm–1 (C–F).
1H NMR (CDCl3):  = 8.80 (d, J = 8.5 Hz, 2 H, Ar), 8.42–8.32 (m, 4 H, Ar),
8.02 (s, 1 H, C5H), 7.85 (d, J = 8.0 Hz, 2 H, Ar).
13C NMR (acetone-d6):  = 166.7 (C2), 164.0 (C6), 157.8 (q, J = 36.0 Hz,
C4), 150.9, 140.0, 129.6, 124.8 (ArNO2), 142.7, 133.9 (q, J = 32.5 Hz),
130.5, 127.0 (q, J = 3.8 Hz, ArCF3), 125.0 (q, J = 271.8 Hz, ArCF3), 121.8
(q, J = 274.7 Hz, C4CF3), 113.5 (q, J = 2.9 Hz, C5).
Light yellow solid; yield: 325 mg (85%); mp 134–136 °C (CHCl3), Rf =
0.9 (CHCl3).
IR (KBr): 1585 (C6=N), 1550 (C2=N–C4=C5), 1159, 1122 cm–1 (C–F).
1H NMR (CDCl3):  = 8.69 (d, J = 8.2 Hz, 2 H, Ar), 8.11 (d, J = 8.4 Hz, 2 H,
Ar), 7.86 (s, 1 H, C5H), 7.75 (d, J = 8.2 Hz, 2 H, Ar), 7.35 (d, J = 7.9 Hz, 2
H, Ar), 2.45 (s, 3 H, CH3).
13C NMR (CDCl3):  = 166.8 (C2), 164.1 (C4), 156.9 (q, J = 35.8 Hz, C6),
143.1, 140.0, 133.2 (q, J = 32.5 Hz), 133.0, 130.2, 129.1, 127.6, 125.7 (q,
J = 3.6 Hz, Ar, Ar), 124.3 (q, J = 272.4 Hz, ArCF3), 121.0 (q, J = 275.4 Hz,
C6CF3), 110.4 (q, J = 1.8 Hz, C5), 21.7 (CH3).
19F NMR (acetone-d6):  = –62.4 (s, 3 F, ArCF3), –69.3 (s, 3 F, C4CF3).
MS (EI): m/z (%) = 413 (100, M+), 394 (18), 384 (11), 383 (44), 368
(19), 367 (89), 355 (30), 197 (15), 196 (21), 176 (27), 151 (16), 149
(13), 145 (14), 102 (68), 101 (12), 76 (20), 75 (33), 69 (63), 51 (12), 50
(16).
19F NMR (CDCl3): –62.6 (s, 3 F, ArCF3), –69.8 (s, 3 F, C6CF3).
MS (EI): m/z (%) = 382 (100, M+), 211 (10), 191 (10), 142 (39), 116
Anal. Calcd for C18H9F6N3O2: C, 52.31; H, 2.20; N, 10.17. Found: C,
51.98; H, 2.09; N, 9.95.
(17), 91 (11).
Anal. Calcd for C19H12F6N2: C, 59.69; H, 3.16; N, 7.33. Found: C, 59.98;
H, 2.87; N, 7.28.
2,4-Bis(4-nitrophenyl)-6-(trifluoromethyl)pyrimidine (3cc)
White solid; yield 289 mg (74%); mp 270–271 °C (CHCl3); Rf = 0.9
(CHCl3).
4-(4-Methoxyphenyl)-6-(trifluoromethyl)-2-[4-(trifluoromethyl)-
phenyl]pyrimidine (3fb)
IR (KBr): 1582 (C6=N), 1552 (C2=N–C4=C5), 1186, 1156 cm–1 (C–F).
1H NMR (acetone-d6): 8.80 (d, J = 8.9 Hz, 2 H, Ar), 8.44 (s, 4 H, Ar), 8.39
(d, J = 8.9 Hz, 2 H, Ar), 8.05 (s, 1 H, C5H).
13C NMR (DMSO-d6):  = 164.5 (C2), 162.3 (C4), 156.0 (q, J = 35.6 Hz,
C6), 149.5, 149.4, 141.0, 140.3, 129.2, 129.0, 123.6, 123.6 (Ar, Ar),
120.3 (q, J = 275.5 Hz, CF3), 112.9 (q, J = 2.9 Hz, C5).
Pale yellow solid; yield: 338 mg (85%); mp 141–142 °C (CHCl3); Rf =
0.9 (CHCl3).
IR (KBr): 1596 (C6=N), 1547 (C2=N–C4=C5), 1185, 1153 cm–1 (C–F).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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19F NMR (DMSO-d6):  = –67.7.
19F NMR (CDCl3):  = –69.8.
MS (EI): m/z (%) = 390 (100, M+), 360 (37), 344 (19), 332 (19), 314
(14), 299 (12), 298 (61), 297 (37), 286 (22), 285 (12), 176 (11), 127
(10), 115 (14), 103 (10), 102 (36), 101 (20), 100 (13), 77 (15), 76 (36),
75 (33), 74 (14), 69 (33), 63 (11), 51 (24), 50 (24), 44 (48), 43 (14).
MS (EI): m/z (%) = 336 (29, M+ + 2), 335 (19, M+ + 1), 334 (74, M+), 197
(11), 139 (13), 138 (15), 137 (25), 129 (11), 128 (100), 103 (14), 102
(33), 101 (17), 77 (30), 76 (16), 75 (20), 51 (19).
Anal. Calcd for C17H10ClF3N2: C, 61.00; H, 3.01; N, 8.37. Found: C,
60.83; H, 2.71; N, 8.12.
Anal. Calcd for C17H9F3N4O4: C, 52.32; H, 2.32; N, 14.36. Found: C,
52.15; H, 2.10; N, 14.19.
2-(4-Chlorophenyl)-4-(trifluoromethyl)-6-[4-(trifluoromethyl)-
phenyl]pyrimidine (3bd)
4-(4-Chlorophenyl)-2-(4-nitrophenyl)-6-(trifluoromethyl)pyrim-
idine (3dc)
Pale yellow solid; yield: 370 mg (92%); mp 177–179 °C (CHCl3); Rf =
White solid; yield: 238 mg (63%); mp 178–180 °C (CHCl3); Rf = 0.9
0.9 (CHCl3).
(CHCl3).
IR (KBr): 1592 (C4=N), 1553 (C2=N–C6=C5), 1178, 1148 cm–1 (C–F).
IR (KBr): 1586 (C6=N), 1525 (C2=N–C4=C5), 1185, 1155 cm–1 (C–F).
1H NMR (CDCl3):  = 8.54 (d, J = 8.2 Hz, 2 H, Ar), 8.33 (d, J = 7.9 Hz, 2 H,
Ar), 7.90 (s, 1 H, C5H), 7.82 (d, J = 8.0 Hz, 2 H, Ar), 7.48 (d, J = 8.2 Hz, 2
H, Ar).
13C NMR (acetone-d6):  = 166.4 (C2), 165.0 (C6), 157.7 (q, J = 35.6 Hz,
C4), 140.3, 133.8 (q, J = 32.2 Hz), 131.0, 126.9 (q, J = 3.8 Hz, ArCF3),
138.6, 135.9, 130.0, 129.5 (ArCl), 125.1 (q, J = 271.7 Hz, ArCF3), 121.9
(q, J = 274.7 Hz, C4CF3), 112.5 (q, J = 2.1 Hz, C5).
1H NMR (CDCl3):  = 8.77 (d, J = 8.6 Hz, 2 H, Ar), 8.35 (d, J = 8.6 Hz, 2 H,
Ar), 8.20 (d, J = 8.3 Hz, 2 H, Ar), 7.94 (s, 1 H, C5H), 7.56 (d, J = 8.2 Hz, 2
H, Ar).
13C NMR (CDCl3):  = 166.1 (C2), 163.6 (C4), 157.5 (q, J = 36.2 Hz, C6),
150.1, 142.1, 139.1, 134.0, 129.9, 129.8, 129.0, 124.0 (Ar, Ar), 120.8 (q,
J = 275.7 Hz, CF3), 111.0 (q, J = 3.0 Hz, C5).
19F NMR (CDCl3):  = –69.7.
19F NMR (CDCl3):  = –62.8 (s, 3 F, ArCF3), –69.8 (s, 3 F, C4CF3).
MS (EI): m/z (%) = 381 (35, M+ + 2), 380 (19, M+ + 1), 379 (100, M+),
335 (17), 334 (10), 333 (45), 321 (16), 162 (19), 137 (10), 136 (18),
127 (17), 126 (17), 102 (56), 101 (20), 76 (19), 75 (36), 69 (35), 51
(15), 50 (14).
MS (EI): m/z (%) = 404 (35, M+ + 2), 402 (100, M+), 383 (10), 196 (56),
176 (35), 145 (14), 140 (18), 139 (19), 138 (57), 137 (44), 102 (23), 75
(27), 69 (20).
Anal. Calcd for C18H9ClF6N2: C, 53.68; H, 2.25; N, 6.96. Found: C, 53.42;
H, 2.09; N, 6.98.
Anal. Calcd for C17H9ClF3N3O2: C, 53.77; H, 2.39; N, 11.07. Found: C,
54.07; H, 2.21; N, 10.79.
2-(4-Chlorophenyl)-4-(4-nitrophenyl)-6-(trifluoromethyl)pyrim-
idine (3cd)
4-(4-Methoxyphenyl)-2-(4-nitrophenyl)-6-(trifluoromethyl)-
pyrimidine (3fc)
Pale yellow solid; yield: 372 mg (98%); mp 198–199 °C (CHCl3); Rf =
Pale yellow solid; yield: 285 mg (76%); mp 192–193 °C (CHCl3); Rf =
0.9 (CHCl3).
0.9 (CHCl3).
IR (KBr): 1590 (C6=N), 1554 (C2=N–C4=C5), 1185, 1151 cm–1 (C–F).
1H NMR (CDCl3):  = 8.54 (d, J = 8.7 Hz, 2 H, ArCl), 8.40 (s, 4 H, ArNO2),
7.93 (s, 1 H, C5H), 7.49 (d, J = 8.7 Hz, 2 H, ArCl).
13C NMR (DMSO-d6):  = 164.4 (C2), 163.3 (C4), 156.0 (q, J = 35.6 Hz,
C6), 149.5, 140.7, 136.9, 134.4, 129.8, 129.1, 129.0, 123.9 (Ar, Ar),
120.5 (q, J = 275.5 Hz, CF3), 112.2 (q, J = 2.9 Hz, C5).
IR (KBr): 1586 (C6=N), 1545 (C2=N–C4=C5), 1189, 1142 cm–1 (C–F).
1H NMR (CDCl3):  = 8.75 (d, J = 8.5 Hz, 2 H, Ar), 8.33 (d, J = 8.5 Hz, 2 H,
Ar), 8.22 (d, J = 8.6 Hz, 2 H, Ar), 7.87 (s, 1 H, C5H), 7.06 (d, J = 8.6 Hz, 2
H, Ar), 3.90 (s, 3 H, OCH3).
13C NMR (CDCl3):  = 166.5 (C2), 163.4 (C4), 163.2, 149.9, 142.5, 129.7,
129.4, 127.8, 123.9, 114.9 (Ar, Ar), 156.8 (q, J = 35.6 Hz, C6), 120.9 (q,
J = 275.2 Hz, CF3), 110.2 (q, J = 2.7 Hz, C5), 55.7 (OCH3).
19F NMR (CDCl3):  = –69.7.
MS (EI): m/z (%) = 381 (37, M+ + 2), 380 (19, M+ + 1), 379 (100, M+),
333 (30), 176 (21), 140 (12), 139 (25), 138 (35), 137 (34), 127 (18),
115 (10), 114 (10), 111 (11), 102 (29), 101 (17), 100 (18), 76 (23), 75
(46), 74 (16), 69 (14), 63 (10), 51 (23).
19F NMR (CDCl3):  = –69.8.
MS (EI): m/z (%) = 375 (100, M+), 329 (17), 286 (11), 165 (10), 102
(13).
Anal. Calcd for C18H12F3N3O3: C, 57.61; H, 3.22; N, 11.20. Found: C,
57.90; H, 2.98; N, 11.42.
Anal. Calcd for C17H9ClF3N3O2: C, 53.77; H, 2.39; N, 11.07. Found: C,
53.92; H, 2.17; N, 11.26.
2-(4-Chlorophenyl)-4-phenyl-6-(trifluoromethyl)pyrimidine
(3ad)
2,4-Bis(4-chlorophenyl)-6-(trifluoromethyl)pyrimidine (3dd)
Light brown solid; yield: 320 mg (87%); mp 123–125 °C (CHCl3); Rf =
Light yellow solid; yield: 312 mg (93%); mp 94–96 °C (CHCl3); Rf = 0.9
0.9 (CHCl3).
(CHCl3).
IR (KBr): 1589 (C6=N), 1545 (C2=N–C4=C5), 1185, 1149 cm–1 (C–F).
IR (KBr): 1592 (C6=N), 1551 (C2=N–C4=C5), 1183, 1131 cm–1 (C–F).
1H NMR (CDCl3):  = 8.52 (d, J = 8.4 Hz, 2 H, Ar), 8.17 (d, J = 8.5 Hz, 2 H,
Ar), 7.83 (s, 1 H, C5H), 7.53 (d, J = 8.4 Hz, 2 H, Ar), 7.47 (d, J = 8.4 Hz, 2
H, Ar).
13C NMR (CDCl3):  = 165.5 (C2), 164.6 (C4), 157.2 (q, J = 35.9 Hz, C6),
138.6, 138.2, 134.9, 134.3, 130.2, 129.7, 129.1, 128.9 (Ar, Ar), 120.9 (q,
J = 275.4 Hz, CF3), 109.9 (q, J = 3.0 Hz, C5).
1H NMR (CDCl3):  = 8.55 (d, J = 8.3 Hz, 2 H, Ar), 8.26–8.20 (m, 2 H,
C6H5), 7.87 (s, 1 H, C5H), 7.60–7.54 (m, 3 H, C6H5), 7.48 (d, J = 8.3 Hz, 2
H, Ar).
13C NMR (CDCl3):  = 166.8 (C2), 164.6 (C4), 157.0 (q, J = 35.7 Hz, C6),
138.1, 136.0, 135.2, 132.2, 130.2, 129.4, 129.1, 127.7 (C6H5, Ar), 121.0
(q, J = 275.3 Hz, CF3), 109.8 (q, J = 2.9 Hz, C5).
19F NMR (CDCl3):  = –69.8.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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A. R. Romanov et al.
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MS (EI): m/z (%) = 370 (69, M+ + 2), 368 (100, M+), 164 (35), 162 (94),
139 (27), 138 (33), 137 (53), 136 (21), 127 (26), 126 (23), 111 (17),
102 (26), 101 (15), 100 (14), 76 (14), 75 (43), 74 (13), 69 (10), 51 (20).
Anal. Calcd for C18H13F3N2O: C, 65.45; H, 3.97; N, 8.48. Found: C,
65.20; H, 3.80; N, 8.21.
2-(4-Methoxyphenyl)-4-(trifluoromethyl)-6-[4-(trifluoromethyl)-
phenyl]pyrimidine (3be)
Anal. Calcd for C17H9Cl2F3N2: C, 55.31; H, 2.46; N, 7.59. Found: C,
55.07; H, 2.48; N, 7.52.
Pale yellow solid; yield: 314 mg (79%); mp 174–176 °C (CHCl3); Rf =
0.65 (CHCl3).
2-(4-Chlorophenyl)-4-(p-tolyl)-6-(trifluoromethyl)pyrimidine
IR (KBr): 1591 (C4=N), 1552 (C2=N–C6=C5), 1184, 1146 cm–1 (C–F).
(3ed)
Light yellow solid; yield: 268 mg (77%); mp 116–118 °C (CHCl3); Rf =
0.9 (CHCl3).
IR (KBr): 1590 (C6=N), 1545 (C2=N–C4=C5), 1186, 1149 cm–1 (C–F).
1H NMR (acetone-d6):  = 8.67 (d, J = 8.2 Hz, 2 H, Ar), 8.59 (d, J = 9.0
Hz, 2 H, Ar), 8.33 (s, 1 H, C5H), 7.98 (d, J = 8.2 Hz, 2 H, Ar), 7.14 (d, J =
9.0 Hz, 2 H, Ar), 3.95 (s, 3 H, OCH3).
1H NMR (CDCl3):  = 8.52 (d, J = 8.7 Hz, 2 H, Ar), 8.09 (d, J =8.2 Hz, 2 H,
Ar), 7.80 (s, 1 H, C5H), 7.45 (d, J = 8.6 Hz, 2 H, Ar), 7.33 (d, J = 8.2 Hz, 2
H, Ar), 2.44 (s, 3 H, CH3).
13C NMR (CDCl3):  = 166.6 (C2), 164.4 (C4), 156.7 (q, J = 35.4 Hz, C6),
142.9, 137.9, 135.3, 133.1, 130.2, 130.1, 129.0, 127.5 (Ar, Ar), 121.1 (q,
J = 275.5 Hz, CF3), 109.8 (q, J = 1.9 Hz, C5), 21.7 (CH3).
13C NMR (acetone-d6):  = 166.3 (C2), 166.3 (C6), 157.9 (q, J = 35.6 Hz,
C4), 164.3, 140.9, 133.8 (q, J = 32.4 Hz), 131.4, 130.0, 129.5, 127.0 (q,
J = 3.9 Hz), 115.3 (Ar, Ar), 125.3 (q, J = 271.9 Hz, ArCF3), 122.2 (q, J =
274.7 Hz, C4CF3), 111.2 (q, J = 2.7 Hz, C5), 56.1 (OCH3).
19F NMR (acetone-d6):  = –62.3 (s, 3 F, ArCF3), –69.5 (s, 3 F, C4CF3).
MS (EI): m/z (%) = 398 (100, M+), 355 (8), 199 (10), 196 (10), 176 (10),
19F NMR (CDCl3):  = –69.8.
134 (34), 133 (13), 90 (10).
MS (EI): m/z (%) = 350 (31, M+ + 2), 349 (17, M+ + 1), 348 (100, M+),
142 (69), 140 (12), 139 (12), 137 (18), 116 (24), 115 (42), 102 (10), 91
(13), 75 (11).
Anal. Calcd for C19H12F6N2O: C, 57.29; H, 3.04; N, 7.03. Found: C,
56.99; H, 2.89; N, 6.85.
2,4-Bis(4-methoxyphenyl)-6-(trifluoromethyl)pyrimidine (3fe)
Anal. Calcd for C18H12ClF3N2: C, 61.99; H, 3.47; N, 8.03. Found: C,
61.71; H, 3.54; N, 7.98.
Pale yellow solid; yield: 231 mg (64%); mp 132–133 °C; Rf = 0.6
(CHCl3).
IR (film): 1590 (C6=N), 1543 (C2=N–C4=C5), 1183, 1157 cm–1 (C–F).
2-(4-Chlorophenyl)-4-(4-methoxyphenyl)-6-(trifluoromethyl)-
pyrimidine (3fd)
1H NMR (CDCl3):  = 8.51 (d, J = 8.8 Hz, 2 H, Ar), 8.16 (d, J = 8.8 Hz, 2 H,
Ar), 7.67 (s, 1 H, C5H), 7.00 (d, J = 8.8 Hz, 2 H, Ar), 6.99 (d, J = 8.8 Hz, 2
H, Ar).
13C NMR (CDCl3):  = 165.6 (C2), 165.0 (C4), 156.3 (q, J = 35.2 Hz, C6),
162.8, 162.5, 130.5, 129.6, 129.1, 128.6, 114.5, 114.0 (Ar), 121.2 (q, J =
275.3 Hz, CF3), 108.2 (q, J = 2.7 Hz, C5), 55.6 (OCH3), 55.5 (OCH3).
Light yellow solid; yield: 269 mg (74%); mp 102–104 °C (CHCl3); Rf =
0.9 (CHCl3).
IR (KBr): 1590 (C6=N), 1546 (C2=N–C4=C5), 1182, 1153 cm–1 (C–F).
1H NMR (CDCl3):  = 8.51 (d, J = 8.6 Hz, 2 H, Ar), 8.18 (d, J = 8.9 Hz, 2 H,
Ar), 7.77 (s, 1 H, C5H), 7.45 (d, J = 8.6 Hz, 2 H, Ar), 7.03 (d, J = 8.9 Hz, 2
H, Ar), 3.88 (s, 3 H, OCH3).
13C NMR (CDCl3):  = 166.1 (C2), 164.4 (C4), 163.1, 137.9, 135.4, 130.2,
129.3, 129.0, 128.3, 114.7 (Ar, Ar), 156.6 (q, J = 35.5 Hz, C6), 121.1 (q,
J = 275.4 Hz, CF3), 109.3 (q, J = 3.1 Hz, C5), 55.7 (OCH3).
19F NMR (CDCl3):  = –69.8.
MS (EI): m/z (%) = 360 (100, M+), 345 (8), 180 (15), 158 (32), 133 (12),
103 (5), 90 (6), 77 (4), 63 (5).
Anal. Calcd for C19H15F3N2O2: C, 63.33; H, 4.20; N, 7.77. Found: C
63.40; H, 4.13; N, 7.78.
19F NMR (CDCl3):  = –69.8.
MS (EI): m/z (%) = 366 (35, M+ + 2), 365 (21, M+ + 1), 364 (100, M+),
227 (9), 158 (46), 137 (19), 133 (9), 132 (18), 102 (12), 89 (11), 75
(12), 63 (10).
2-Methyl-4-phenyl-6-(trifluoromethyl)pyrimidine (3af)
Pale yellow oil; yield: 90 mg (38%); Rf = 0.45 (CHCl3).
Anal. Calcd for C18H12ClF3N2O: C, 59.27; H, 3.32; N, 7.68. Found: C,
59.36; H, 3.10; N, 7.70.
1H NMR (CDCl3):  = 8.11 (d, J = 7.1 Hz, 2 H, C6H5), 7.80 (s, 1 H, C5H),
7.48-7.56 (m, 3 H, C6H5), 2.86 (s, 3 H, CH3).
19F NMR (CDCl3): –69.8.
The NMR data are in agreement with those in the literature.15,16
2-(4-Methoxyphenyl)-4-phenyl-6-(trifluoromethyl)pyrimidine
(3ae)
White solid; yield: 235 mg (71%); mp 85–86 °C (hexane); Rf = 0.53
(hexane–Et2O 5:1).
IR (film): 1589 (C6=N), 1550 (C2=N–C4=C5), 1184, 1153 cm–1 (C–F).
1H NMR (CDCl3):  = 8.57 (d, J = 8.4 Hz, 2 H, Ar), 8.24–8.18 (m, 2 H,
C6H5), 7.78 (s, 1 H, C5H), 7.57–7.51 (m, 3 H, C6H5), 7.01 (d, J = 8.4 Hz, 2
H, Ar).
13C NMR (CDCl3):  = 166.4 (C2), 165.3 (C4), 156.8 (q, J = 35.8 Hz, C6),
136.3, 131.9, 130.6, 129.2 (C6H5), 162.7, 129.4, 127.6, 114.1 (Ar), 121.2
(q, J = 275.3 Hz, CF3), 109.2 (q, J = 1.6 Hz, C5), 55.5 (OCH3).
2-Methyl-4-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]-
pyrimidine (3bf)
Light yellow solid; yield: 146 mg (48%); mp 55–56 °C (CHCl3); Rf = 0.7
(CHCl3).
IR (KBr): 1594 (C4=N), 1560 (C2=N–C6=C5), 1119, 1164 cm–1 (C–F).
1H NMR (CDCl3):  = 8.24 (d, J = 7.8 Hz, 2 H, Ar), 7.84 (s, 1 H, C5H), 7.78
(d, J = 8.2 Hz, 2 H, Ar), 2.89 (s, 3 H, CH3).
13C NMR (CDCl3):  = 170.1 (C2), 165.2 (C6), 157.0 (q, J = 35.8 Hz, C4),
139.3 (q, J = 1.3 Hz), 133.6 (q, J = 32.9 Hz), 128.0, 126.3 (q, J = 3.8 Hz,
Ar), 123.9 (q, J = 272.5 Hz, CF3), 120.8 (q, J = 275.2 Hz, CF3), 110.1 (q, J =
3.0 Hz, C5), 26.3 (CH3).
19F NMR (CDCl3):  = –69.8.
MS (EI): m/z (%) = 330 (100, M+), 315 (9), 165 (10), 134 (27), 133 (14),
128 (28), 103 (10), 77 (14).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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A. R. Romanov et al.
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19F NMR (CDCl3):  = –62.7 (s, 3 F, ArCF3), –69.8 (s, 3 F, C4CF3).
1-[2,4(5)-Diphenyl-1H-imidazol-5(4)-yl]-2,2,2-trifluoroenthan-1-
one (4a)
MS (EI): m/z (%) = 306 (100, M+), 287 (19), 265 (35), 245 (15), 197
(10), 196 (88), 176 (28), 170 (15), 145 (12), 75 (14), 69 (12), 66 (27),
42 (34).
Pale yellow viscous oil; yield: 155 mg (49%); Rf = 0.4 (CHCl3–MeOH
95:5).
IR (film): 3207 (N–H), 1693 (C=O), 1564, 1533 (C6H5), 1200, 1154 cm–1
(C–F).
Anal. Calcd for C13H8F6N2: C 50.99; H 2.63; N 9.15. Found: C 51.37; H
2.33; N 9.01.
1H NMR (acetone-d6):  = 12.6 (br s, 1 H, NH), 8.20 (d, J = 7.4 Hz, 2 H,
C6H5), 7.97–7.87 (m, 2 H, C6H5), 7.61–7.49 (m, 6 H, C6H5, C6H5), 3.87 (s,
1 H, NH).
2-Methyl-4-(4-nitrophenyl)-6-(trifluoromethyl)pyrimidine (3cf)
Light brown solid; yield: 200 mg (71%); mp 96–97 °C (CHCl3); Rf =
13C NMR (acetone-d6):  = 175.9 (q, J = 33.6 Hz, C=O), 148.0 (C2, imid-
azolyl), 144.2 (C4, imidazolyl), 131.6 (C5, imidazolyl), 130.8, 130.6,
130.3, 130.3, 130.2, 129.8, 129.8, 129.2, 126.9 (C6H5, C6H5), 118.2 (q,
J = 291.6 Hz, CF3).
19F NMR (acetone-d6):  = –73.1.
MS (EI): m/z (%) = 316 (63, M+), 248 (19), 247 (100), 116 (24), 109
0.85 (CHCl3–MeOH 97:3).
IR (film): 1589 (C6=N), 1549 (C2=N–C4=C5), 1168, 1149 cm–1 (C–F).
1H NMR (CDCl3):  = 8.34 (dd, J = 22.3, J = 9.0 Hz, 2 H, Ar), 7.88 (s, 1 H,
C5H), 2.90 (s, 3 H, CH3).
13C NMR (CDCl3):  = 170.2 (C2), 164.2 (C4), 157.1 (q, J = 35.8 Hz, C6),
149.9, 141.6, 128.7, 124.4 (Ar), 120.7 (q, J = 275.3 Hz, CF3), 110.4 (C5),
26.2 (CH3).
(12), 96 (11), 89 (58), 77 (15), 63 (12).
19F NMR (CDCl3):  = –69.7.
MS (EI): m/z (%) = 283 (100, M+), 253 (18), 237 (50), 236 (12), 225
Anal. Calcd for C17H11F3N2O·H2O: C, 61.08; H, 3.92; N, 8.38. Found: C,
61.29; H, 3.83; N, 8.21.
(15), 176 (12), 173 (10), 75 (16), 66 (14).
1-[2,4(5)-Diphenyl-1H-imidazol-5(4)-yl]enthan-1-one (6)
Anal. Calcd for C12H8F3N3O2: C 50.89; H 2.85; N 14.84. Found: C 51.15;
H 2.79; N 14.64.
Pale yellow solid; yield: 216 mg (82%); mp 154–155 °C (CHCl3); Rf =
0.55 (CHCl3–MeOH 95:5).
IR (film): 3244 (N–H), 1649 (C=O), 1536 cm–1 (C6H5).
2-Methyl-4-(p-tolyl)-6-(trifluoromethyl)pyrimidine (3ef)
1H NMR (CDCl3):  = 11.43 (br s, 1 H, NH), 8.07–8.00 (m, 2 H, C6H5),
7.56–7.50 (m, 2 H, C6H5), 7.42–7.33 (m, 6 H, C6H5, C6H5), 2.27 (s, 3 H,
CH3).
MS (EI) m/z (%) = 263 (33, M+ + 1), 262 (96, M+), 261 (46), 248 (18),
247 (100), 131 (16), 116 (33), 90 (13), 89 (91), 77 (19), 63 (20), 51
(10).
Colorless crystals; yield: 97 mg (38%); mp 50–52 °C (CHCl3); Rf = 0.85
(CHCl3–MeOH 97:3).
IR (film): 1594 (C6=N), 1551 (C2=N–C4=C5), 1168, 1151 cm–1 (C–F).
1H NMR (CDCl3):  = 8.02 (d, J = 8.0 Hz, 2 H, Ar), 7.77 (s, 1 H, C5H), 7.31
(d, J = 7.9 Hz, 2 H, Ar), 2.85 (s, 3 H, C2CH3), 2.42 (s, 3 H, ArCH3).
13C NMR (CDCl3):  = 169.7 (C2), 166.6 (C4), 156.3 (q, J = 35.4 Hz, C6),
142.6, 133.2, 130.1, 127.5 (Ar), 121.0 (q, J = 275.0 Hz, CF3), 109.3 (C5),
26.4 (C2CH3), 21.7 (ArCH3).
Anal. Calcd for C17H14N2O: C 77.84; H 5.38; N 10.68. Found: C 77.62; H
5.33; N 10.61.
The data are in agreement with those in the literature.30
19F NMR (CDCl3):  = –69.8.
MS (EI): m/z (%) = 252 (100, M+), 251 (23), 211 (11), 142 (33), 116
(17), 115 (23), 91 (17), 66 (13).
Funding Information
Anal. Calcd for C13H11F3N2: C, 61.90; H, 4.40; N, 11.11. Found: C,
61.57; H, 4.60; N, 11.36.
The reported study was funded by the Russian Foundation for Basic
Research (RFBR, project number 19-03-00206).
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4-(4-Methoxyphenyl)-2-methyl-6-(trifluoromethyl)pyrimidine
(3ff)
Acknowledgment
Pale yellow solid; yield: 103 mg (38%); mp 75–77 °C; Rf = 0.8 (CHCl3–
MeOH, 97:3).
The spectral and analytical data were obtained using the equipment
of the Baikal analytical center for collective use SB RAS.
1H NMR (CDCl3):  = 8.10 (d, J = 8.9 Hz, 2 H, Ar), 7.72 (s, 1 H, C5H), 7.00
(d, J = 8.9 Hz, 2 H, Ar), 3.87 (s, 3 H, OCH3), 2.82 (s, 3 H, CH3).
19F NMR (CDCl3):  = –69.8.
The NMR data are in agreement with those in the literature.16
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707969.
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Imidazoles 4a and 6; General Procedure
A mixture of Et3N (4 mmol) and benzimidamide hydrochloride (2a;
1.5–1.7 mmol) in THF (3 mL) was stirred at ~40 °C for 30 min to gen-
erate the free binucleophile. Next, the solution of bromoeone 1a or 5
(1 mmol) in THF (1–1.5 mL) was added and the reaction mixture was
refluxed for 3 (for 4a) or 12 h (for 6). After cooling, the mixture was
concentrated in vacuo, and the residue was purified by column chro-
matography on silica gel (CHCl3–MeOH 95:5) to afford the pure imid-
azole 4a or 6.
References
(1) Ojima, I. Front. Chem. 2017, 5, 52.
(2) (a) Rulev, A. R.; Romanov, A. R. RSC Adv. 2016, 6, 1984.
(b) Meyer, F. Chem. Commun. 2016, 52, 3077. (c) Fluorine in Het-
erocyclic Chemistry, Vol. 1; Nenajdenko, V. G., Ed.; Springer:
Berlin, 2014, 681. (d) Fluorine in Heterocyclic Chemistry, Vol. 2;
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

K
A. R. Romanov et al.
Paper
Synthesis
Nenajdenko, V. G., Ed.; Springer: Berlin, 2014, 760.
(e) Fluorinated Heterocyclic Compounds: Synthesis, Chemistry,
and Applications; Petrov, V. A., Ed.; Wiley: New Jersey, 2009,
515. (f) Fluorinated Heterocycles; Gakh, A. A.; Kirk, K. L., Ed.; ACS
Symposium Series 1003, Oxford University Press/American
Chemical Society: Washington, DC, 2009, 360.
(16) Romanov, A. R.; Rulev, A. Yu.; Ushakov, I. A.; Muzalevskiy, V. M.;
Nenajdenko, V. G. Eur. J. Org. Chem. 2017, 4121.
(17) (a) Rulev, A. Yu.; Muzalevskiy, V. M.; Kondrashov, E. V.;
Ushakov, I. A.; Romanov, A. R.; Khrustalev, V. N.; Nenajdenko, V.
G. Org. Lett. 2013, 15, 2726. (b) Muzalevskiy, V. M.; Ustynyuk,
Yu. A.; Gloriosov, I. P.; Chertkov, V. A.; Rulev, A. Yu.; Kondrashov,
E. V.; Ushakov, I. A.; Romanov, A. R.; Nenajdenko, V. G. Chem.
Eur. J. 2015, 21, 16982. (c) Gloriozov, I. P.; Muzalevskiy, V. M.;
Rulev, A. Yu.; Kondrashov, E. V.; Nenajdenko, V. G.; Ustynyuk,
Yu. A. Russ. J. Org. Chem. 2016, 52, 1098.
(18) (a) Muzalevskiy, V. M.; Rulev, A. Yu.; Kondrashov, E. V.;
Romanov, A. R.; Ushakov, I. A.; Chertkov, V. A.; Nenajdenko, V. G.
Eur. J. Org. Chem. 2016, 1612. (b) Rulev, A. Yu.; Romanov, A. R.;
Kondrashov, E. V.; Ushakov, I. A.; Vashchenko, A. V.;
Muzalevskiy, V. M.; Nenajdenko, V. G. J. Org. Chem. 2016, 81,
10029.
(19) Rulev, A. Yu.; Romanov, A. R.; Kondrashov, E. V.; Ushakov, I. A.;
Muzalevskiy, V. M.; Nenajdenko, V. G. Eur. J. Org. Chem. 2018,
4202.
(20) Rulev, A. Yu.; Romanov, A. R.; Kondrashov, E. V.; Ushakov, I. A.;
Muzalevskiy, V. M.; Nenajdenko, V. G. J. Fluorine Chem. 2019,
227, 109366.
(3) Leroux, F. R.; Manteau, B.; Vors, J-P.; Pazenok, S. Beilstein J. Org.
Chem. 2008, 4, 13.
(4) (a) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J. L.;
Soloshonok, V. A.; Izawa, K.; Liu, H. Chem. Rev. 2016, 116, 422.
(b) Togni, A. Adv. Synth. Catal. 2010, 352, 2689. (c) Bégué, J.-P.;
Bonnet-Delpon, D.; Crousse, B.; Legros, J. Chem. Soc. Rev. 2005,
34, 562.
(5) For selected recent reviews, see: (a) Fischer, G. Adv. Heterocycl.
Chem. 2019, 128, 1. (b) Meguru, R.; Garimella, S.; Balla, D.;
Sambaru, K. Int. J. PharmTech. Res. 2015, 8, 88. (c) Yerragunta, V.;
Patil, P.; Anusha, V.; Kumara Swamy, T.; Suman, D.; Samhitha, T.
PharmaTutor 2013, 1, 39.
(6) Bégué, J.-P.; Bonnet-Delpon, D. In Bioorganic and Medicinal
Chemistry of Fluorine; Wiley: Hoboken, 2008.
(7) Wigle, T. J.; Tsvetkova, E. V.; Welch, S. A.; Kim, R. B. Pharmaceu-
tics 2019, 11, 199.
(8) (a) For a review on the strategies for the pyrimidine synthesis,
see: Hill, M. D.; Mavossaghi, M. Chem. Eur. J. 2008, 14, 6836; and
references therein. For selected recent papers, see: (b) Guo, W.;
Li, C.; Liao, J.; Ji, F.; Liu, D.; Wu, W.; Jiang, H. J. Org. Chem. 2016,
81, 5538. (c) Su, L.; Sun, K.; Liu, L.; Sun, M.; Dong, J.; Zhou, Y.;
Yin, S-F. Org. Lett. 2018, 20, 3399. (d) Zhan, J-L.; Wu, M-W.;
Chen, F.; Han, B. J. Org. Chem. 2016, 81, 11994. (e) Sasada, T.;
Kobayashi, F.; Sakai, N.; Konakahara, T. Org. Lett. 2009, 11, 2161.
(f) Jadhav, S. D.; Singh, A. Org. Lett. 2017, 19, 5673.
(9) Chorlton, A. P. In Ullmann's Encyclopedia of Industrial Chemis-
try; 2000, DOI:10.1002/14356007.a22_431.
(21) Rulev, A. Yu. Eur. J. Org. Chem. 2018, 3609.
(22) (a) Rulev, A. Yu.; Ushakov, I. A.; Nenajdenko, V. G.; Balenkova, E.
S.; Voronkov, M. G. Eur. J. Org. Chem. 2007, 6039. (b) Rulev, A.
Yu.; Ushakov, I. A.; Nenajdenko, V. G. Tetrahedron 2008, 64,
8073.
(23) (a) Lipinski, C. A.; Blizniak, T. E.; Craig, R. H. J. Org. Chem. 1984,
49, 566. (b) Reiter, L. A. J. Org. Chem. 1984, 49, 3494.
(24) Guchhait, S. K.; Hura, N.; Shah, A. P. J. Org. Chem. 2017, 82, 2745.
(25) Zhu, Y.; Li, C.; Zhang, J.; She, M.; Sun, W.; Wan, K.; Wang, Y.; Yin,
B.; Liu, P.; Li, J. Org. Lett. 2015, 17, 3872.
(26) (a) Marsura, A.; Luu-Duc, C.; Gellon, G. Synthesis 1985, 537.
(b) Shilcrat, S. C.; Mokhallalati, M. K.; Fortunak, J. M. D.; Pridgen,
L. N. J. Org. Chem. 1997, 62, 8449.
(10) Kotljarov, A.; Irgashev, R. A.; Iaroshenko, V. O.; Sevenard, D. V.;
Sosnovskikh, V. Ya. Synthesis 2009, 3233.
(11) Dalinger, I. L.; Vatsadse, I. A.; Shevelev, S. A.; Ivachtchenko, A. V.
J. Comb. Chem. 2005, 7, 236.
(12) Bonacorso, H. G.; Bortolotto, G. P.; Navarini, J.; Porte, L. M. F.;
Wiethan, C. W.; Zanatta, N.; Martins, M. A. P.; Flores, A. F. C.
J. Fluorine Chem. 2010, 131, 1297.
(13) Funabiki, K.; Nakamura, H.; Matsui, M.; Shibata, K. Synlett 1999,
756.
(14) Kawase, M.; Hirabayashi, M.; Saito, S.; Yamamoto, K. Tetrahe-
dron Lett. 1999, 40, 2541.
(27) Rulev, A. Yu. Russ. Chem. Rev. 2011, 80, 197.
(28) (a) Jung, K.-Y.; Kim, S.-K.; Gao, Z.-G.; Gross, A. S.; Melman, N.;
Jacobson, K. A.; Kin, Y.-C. Bioorg. Med. Chem. 2004, 12, 613.
(b) Lu, X.; Xin, X.; Wan, B. Tetrahedron Lett. 2018, 59, 361.
(29) (a) Morel, B.; Franck, P.; Bidange, J.; Sergeyev, S.; Smith, D. A.;
Moseley, J. D.; Maes, B. U. W. ChemSusChem 2017, 10, 624.
(b) Kolb, H. C.; Kanamarlapudi, R. C.; Richardson, P. F.; Khan, G.
(Lexicon Pharmaceuticals, Inc.) US 6806380 B2, 2002.
(30) Zhang, P.-F.; Chen, Z.-C. Synthesis 2001, 2075.
(15) Saijo, R.; Watanabe, G.; Kurihara, K.; Kawase, M. Heterocycles
2014, 89, 2334.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K