Synthesis and evaluation of antitubercular activity of fluorinated 5-aryl-4-(hetero)aryl substituted pyrimidines

Article abstract of DOI:10.1016/j.bmc.2016.06.020

Various 5-(fluoroaryl)-4-(hetero)aryl substituted pyrimidines have been synthesized based on the Suzuki cross-coupling and nucleophilic aromatic substitution of hydrogen (S_N^H) reactions starting from commercially available 5-bromopyr

Full text of DOI:10.1016/j.bmc.2016.06.020

Accepted Manuscript
Synthesis and evaluation of antitubercular activity of fluorinated 5-aryl-4-(het-
ero)aryl substituted pyrimidines
Egor V. Verbitskiy, Svetlana A. Baskakova, Marionella A. Kravchenko, Sergey
N. Skornyakov, Gennady L. Rusinov, Oleg N. Chupakhin, Valery N. Charushin
PII:
S0968-0896(16)30443-6
DOI:
http://dx.doi.org/10.1016/j.bmc.2016.06.020
BMC 13076
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 April 2016
9 June 2016
10 June 2016
Please cite this article as: Verbitskiy, E.V., Baskakova, S.A., Kravchenko, M.A., Skornyakov, S.N., Rusinov, G.L.,
Chupakhin, O.N., Charushin, V.N., Synthesis and evaluation of antitubercular activity of fluorinated 5-aryl-4-
(hetero)aryl substituted pyrimidines, Bioorganic & Medicinal Chemistry (2016), doi: http://dx.doi.org/10.1016/
j.bmc.2016.06.020
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Bioorganic & Medicinal Chemistry
Synthesis and evaluation of antitubercular activity of fluorinated 5-aryl-4-(hetero)aryl
substituted pyrimidines
Egor V. Verbitskiy,a,b* Svetlana A. Baskakova,a Marionella A. Kravchenko,c Sergey N. Skornyakov,c
Gennady L. Rusinov,a,b Oleg N. Chupakhin,a,b Valery N. Charushina,b
a Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, S. Kovalevskoy Str., 22, Ekaterinburg, 620990, Russia
bUral Federal University, Mira St. 19, Ekaterinburg, 620002, Russia
cUral Research Institute for Phthisiopulmonology, 22 Parts’ezda St., 50, Ekaterinburg, 620039, Russia
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Various 5-(fluoroaryl)-4-(hetero)aryl substituted pyrimidines have been synthesized based on
the Suzuki cross-coupling and nucleophilic aromatic substitution of hydrogen (SNH) reactions
starting from commercially available 5-bromopyrimidine and their antitubercular activity against
Mycobacterium tuberculosis H37Rv has been explored. The outcome of the study disclose that,
some of the compounds have showed promising activity in micromolar concentration against
Mycobacterium tuberculosis H37Rv, Mycobacterium avium, Mycobacterium terrae, and
multidrug-resistant strains isolated from tuberculosis patients in Ural region (Russia).The data
concerning the "structure - activity" relationship for fluorinated compounds have been discussed.
Keywords:
Pyrimidine
Antimicobacterial
Tuberculosis
2016 Elsevier Ltd. All rights reserved.
Cross-coupling
Nucleophilic aromatic substitution of hydrogen
1
1. Introduction
compounds [24-26], we wish to report the synthesis of new 5-
(fluoroaryl)-4-(hetero)aryl substituted pyrimidines. In this paper
Fluorine-containing compounds, especially of heterocyclic
nature, have gained attention as biologically actives, and, indeed,
many of them are well presented in pharmaceutical market [1-
11]. In particular, a great variety of effective antibacterial agents
have the structure of fluoroquinolones [1,2,7-14]. In fact, some of
the anti-microbial compounds have fluorine atom in their
structure [15]. The presence of a fluorine atom in the structure of
organic molecules has been shown to modulate their
stereoelectronic parameters [14,15]. Further incorporation of
fluorine atom not only alters their electronic environment, but
also affects pKa value of the neighboring Brønsted acid/base
centers, polarity, and lipophilicity, as expressed by the
distribution coefficient. Fluorine substituents in bioactive
molecules appear to improve often their pharmacological
properties, such as better membrane permeability, enhanced
hydrophobic binding, and a good stability towards metabolic
transformation. This is why development of new fluorine-
containing antimycobacterial agents is continued interest for
chemists and biologists [18-23].
we intend to discuss the effects a fluorine atom or CF3-group at
C(2) and/or C(4) positions on the phenyl substituent in 5-
(fluoroaryl)-4-(hetero)arylpyrimidines on their antibacterial
activity against M. tuberculosis, and other pathogenic strains,
such as M. avium, M. terrae.
2. Results and discussion
2.1. Chemistry
The
desired
5-(fluoroaryl)-4-(hetero)aryl
substituted
pyrimidines have been synthesized based on the palladium-
catalyzed Suzuki cross-coupling reaction and nucleophilic
aromatic substitution of hydrogen (the SNH reaction) [27,28].
Initially 5-(fluoro-aryl)pyrimidines (3b-k) were obtained by
reacting 5-bromopyrimidine (1) with various fluorinated
benzeneboronic acids (2b-k) by using the aerobic Suzuki cross-
coupling reaction conditions in the presence of a new catalyst,
namely
trans-bis(dicyclohexylamine)palladium(II)
acetate
(DAPCy) (Scheme 1, Table 1) [28]. Whereas 5-phenyl-
pyrimidine (3a) was obtained from unsubstituted phenylboronic
acid (2a) by using the method A, as a reference compound for
comparison of biological activity (Scheme 1).
In continuation of our previous studies in the field of
pyrimidine derivatives, as potential antimycobacterial
———
1 Corresponding author. Tel./fax: +7 343 3693058; e-mail
address: Verbitsky@ios.uran.ru (E.V. Verbitskiy).
Here, we would like to mention that, when the benzeneboronic
acid with fluorine substitution at C(2) position (e.g. 2-F-, 2,4-F-,
2-CF3- or 2,4-CF3-) reacted with 5-bromopyridine under

R2
aforesaid reaction condition, the yields of the target products
3b,e,g,j were found to be poor. However, they were prepared in
good yields, according to the procedure described in our previous
publication [29]. The starting 5-bromopyrimidine was coupled
with the corresponding boronic acid (2b,e,g,j) under microwave
irradiation, by using 1,4-dioxane-H2O (4:3) as solvent, and
K2CO3 and Pd(PPh3)4, as catalyst (Scheme 1, method B).
R1
R3
R4
CF3COOH
N
+
X
N
4 (X= S);
5 (X= O)
3d,i,j
R2
R2
R2
R1
R3
R4
R1
R3
R4
R1
R3
_
B(OH)2
R1
CF3COO
Br
+
R4
N
Methods A or B
N
H
N
K3Fe(CN)6-KOH
H2O
R4
N
+
N
1
R2
Suzuki cross-coupling
N
X
X
N
N
H
R3
3a-k
H
2a-k
6d,i,j (X= S);
7d,i,j (X= O)
H

adduct
a: R1= H, R2= H, R3= H, R4= H;
b: R1= F, R2= H, R3= H, R4= H;
c: R1= H, R2= F, R3= , R4= H;
d: R1= H, R2= H, R3= F, R4= H;
e: R1= F, R2= H, R3= F, R4= H;
f: R1= H, R2= F, R3= H, R4= F;
g: R1= CF3, R2= H, R3= H, R4= H;
Method A: DAPCy (5 mol.%), K PO4 (2,5 equiv.), EtOH, r.t., 24 h;
__________________________3____________________________
Scheme 2. Synthesis of 5-(fluoroaryl)-4-(hetero)aryl substituted pyrimidines
6d,i,j and 7d,i,j through the SNH-methodology.
Method B: Pd(PPh3)4 (5 mol.%), K2CO3 (2,5 equiv.),
1,4-dioxane - H2O (4:3), 165OC, MW, 20 min.
Table 2. Reaction of 5-(fluoroaryl)pyrimidines 3d,i,j with
thiophene (4) and furan (5). Composition of the reaction
mixtures and yields of 5-(fluoroaryl)-4-(hetero)aryl
substituted pyrimidines 6d,i,j and 7d,i,j.
h: R1= H, R2= CF3, R3= H, R4= H;
i: R1= H, R2= H, R3= CF3, R4= H;
j: R1= CF3, R2= H, R3= CF3, R4= H;
k: R1= H, R2= CF3, R3= H, R4= CF3
Scheme 1. Synthesis of 5-phenylpyrimidine (3a) and 5-(fluoroaryl)-
pyrimidines 3b-k.
Entry
Reactants
Reaction mixturesa
Isolated yield
3d – 0.3 %
Table 1. Yields of 5-phenylpyrimidine (3a) and 5-
(fluoroaryl)pyrimidines 3b-k under the Suzuki cross-coupling
reaction.
1
3d+4
σH-adduct – 0 %
6d – 99.7 %
3i – 0.6 %
6d – 80 %
Entry
Reactants
Conditions
Method A
Method A
Method B
Method A
Method A
Method A
Method B
Method A
Method A
Method B
Method A
Method A
Method A
Method B
Method A
Product –Isolated yield
3a – 92 %
3b– 37 %a
3b – 44 %
3c – 61 %
3d – 71 %
3e– 11 %a
3e – 57 %
3f – 79 %
n.d.
2
3
4
5
3i+4
3j+4
3d+5
3i+5
3j+5
σH-adduct – 57.5 % 6i – 36 %
1
1+2a
2
6i– 41.9 %
1+2b
3
3j – 41.1 %
3j – 21 %
σH-adduct – 1.4 %
6j – 39 %
4
1+2c
1+2d
6j – 57.5 %
5
3d – 1.7 %
6
1+2e
1+2f
1+2g
σH-adduct – 0 %
7d – 98.3 %
3i – 1.2 %
7d – 57 %
7
8
9
σH-adduct – 68.5 % 7i – 26 %
10
11
12
12
13
14
3g – 49 %
3h – 63 %
3i – 77 %
n.d.
7i – 30.3 %
1+2h
1+2i
3j – 41.5 %
3j – 19 %
6
σH-adduct – 11.7 %
7j– 11 %
1+2j
7j – 46.8 %
3g – 35 %
3k – 53%
a
Reaction mixtures were analyzed by GC-MS after oxidation with
K3Fe(CN)6.
1+2k
aQuantity of the target product in the reaction mixture according to the GC-
MS data.
We have suggested that an aryl substituent at C(5) causes a
significant steric hindrance for the SNH-reaction which has to be
proceeding at the neighboring C(4) position of the pyrimidine
ring. Therefore, we have decided to use the opposite sequence of
the Suzuki cross-coupling and nucleophilic aromatic substitution
of hydrogen for the syntheses of 5-(fluoroaryl)-4-(hetero)aryl-
pyrimidines 6b-k and 7b-k. It has previously been shown that 5-
bromopyrimidine (1) reacts with thiophene (4) and furan (5) in
CF3COOH with subsequent oxidation of the intermediate H-
adducts to afford the corresponding 5-bromo-4-(thien-2-yl)-
pyrimidine (8) and 5-bromo-4-(furan-2-yl)pyrimidine (9) in good
yields (Scheme 3) [25,27,30]. Also it is worth noting that use of
DAPCy in the aerobic Suzuki cross-coupling reaction of 5-
bromopyrimidines, bearing electron-donating thiophenyl
substituents at C-4, leads to the corresponding products in rather
bn.d. – not determined.
At the next stage we have tried to realize nucleophilic
substitution of hydrogen at C-4 (the SNH-reaction) in 5-aryl
substituted pyrimidines by action of thiophene (4) and furan (5)
H
resulted. It has been shown that the SN reactions of compounds
3d,i,j with thiophene (4) and furan (5) result in the formation of
5-(fluoroaryl)-4-(hetero)arylpyrimidines 6d and 7d in moderate
yields, whereas products 6i,j and 7i,j have been obtained in low
yields (Scheme 2, Table 2).

low yields [31]. For this reason 5-bromopyrimidines 8 and 9 have
been involved in the Suzuki reaction with arylboronic acids 2a-k
under microwave irradiation (165 ºC, 20 min). Under these
reaction conditions the corresponding cross-coupling products,
viz. 5-(fluoroaryl)-4-(thien-2-yl)pyrimidines (6b-k) and 5-
(fluoroaryl)-4-(furan-2-yl)pyrimidines (7b-k), have been
obtained in good yields (Scheme 3, Table 3).
2.2. Antimycobacterial in vitro activity
The series of 33 compounds were screened for their activity in
vitro against M. tuberculosis H37Rv, M. avium, M. terrae, and
multi-drug-resistant strains, and the data on the minimal
inhibitory concentrations (MICs) of these compounds are
presented in Table 4. All new pyrimidines were compared with
the commercially available drugs Isoniazid, Ofloxacine and
Pyrazinamide, tested under the same experimental conditions.
1)
, CF3COOH
Br
Br
N
N
X
It follows from the experimental results that many compounds
(3a,b,d,h-j, 6b-f,i,k and 7b,d,e,g,h,i) are active at a relatively
low MIC (12.5 μg/mL). Besides that, we have observed that
incorporation of a fluoro atom in the phenyl substituent at C(5) of
pyrimidines (3b-d, 6b-f and 7b,d-f) does not enhance their
antituberular activity, with the exception of compound 7c,
bearing a fluoro atom at C(3) of the phenyl group. The
exceptions are the presence of either one fluoro atom at C(5) of
the phenyl substituent (compound 7c, MIC = 1.5 μg/mL), or two
fluoro atoms at C(2) and C(4) of 5-aryl substituent in compound
3e (see Table 4, entry 5), or two fluoro atoms at C(3) and C(5) of
5-aryl substituent in compound 3f (see Table 4, entry 6). On the
contrary, 5-aryl substituted pyrimidines 3k, 6h, 7g and 7k,
bearing one or two CF3-groups, proved to exhibit a significant
level of inhibitory properties against Mycobacterium tuberculosis
H37Rv and other strains (MIC from 3.1 to 0.7 μg/mL). Non-
fluorinated 5-phenylpyrimidines 6a and 7a have also
demonstrated a high MIC 6.25 and 0.35 μg/mL, correspondingly.
X
2) K3Fe(CN)6 - KOH/ H2O
N
N
1
SHN-reaction
8 (X= S);
9 (X= O)
R2
R1
R3
R4
B(OH)2
MW, 165 oC, 20 min
Pd(PPh3)4, K2CO3
R1
N
8 (X= S);
9 (X= O)
+
1,4-Dioxane - H2O
X
R4
R2
N
Suzuki cross-coupling
R3
2a-k
6a-k (X= S);
7a-k (X= O)
a: R1= H, R2= H, R3= H, R4= H;
b: R1= F, R2= H, R3= H, R4= H;
c: R1= H, R2= F, R3= , R4= H;
d: R1= H, R2= H, R3= F, R4= H;
e: R1= F, R2= H, R3= F, R4= H;
f: R1= H, R2= F, R3= H, R4= F;
1
g: R = CF3, R2= H, R3= H, R4= H;
4
h: R1= H, R2= CF3, R3= H, R = H;
i: R1= H, R2= H, R3= CF3, R4= H;
j: R1= CF3, R2= H, R3= CF3, R4= H;
k: R1= H, R2= CF3, R3= H, R4= CF3
Scheme 3. Synthesis of 4-(hetero)aryl-5-phenylpyrimidines 6a and 7a 5-
(fluoroaryl)-4-(hetero)aryl substituted pyrimidines 6b-k and 7b-k through the
sequence of SNH and the Suzuki cross-coupling reactions.
It is noteworthy that in the series of both 5-phenyl substituted
(3a, 6a and 7a) and 5-(2,4-bis-thrifluoromethylphenyl)
substituted (3j, 6j and 7j) pyrimidines the antitubercular activity
is growing in the following sequence 3a,j < 6a,j < 7a,j: from
C(4) unsubstituted (3a,j) to 4-(furan-2-yl) substituted (7a,j)
pyrimidines (see Table 4, entries 1,10,12,21,23 and 32). This
sequence and the recently obtained data for 4-furanyl substituted
pyrimidines [25] make compounds 7a and 7j as promising leads
for further development of new antitubercular agents. In the
series of C(3) and C(5)-fluoro or trifluoromethyl substituted
pyrimidines such clear sequences are not available, but it should
be noted that pyrimidines bearing a fluoro substituent at C(3)
position of the phenyl group are commonly more active than
their analogues with the CF3-group (for example, compare 3c and
3h, 7c and 7h, 3f and 3k). Besides that, C(4) unsubstituted
pyrimidine 3f has a high MIC (0.7 μg/mL), and it can also be
regarded as a candidate for development of new antitubercular
agents.
Table 3. The microwave-assisted Suzuki cross-coupling
reaction of 5-bromo-4-(hetero)aryl substituted pyrimidines 8
and 9 with various arylboronic acids 2a-k.
Entry
Reactants
Product –Isolated yield
1
8+2a
8+2b
8+2c
8+2d
8+2e
8+2f
8+2g
8+2h
8+2i
8+2j
8+2k
9+2a
9+2b
9+2c
9+2d
9+2e
9+2f
9+2g
9+2h
9+2i
9+2j
9+2k
6a – 93 %
6b – 99 %
6c – 94 %
6d – 99 %
6e – 86 %
6f – 94 %
6g – 94 %
6h – 96 %
6i – 96 %
6j – 49 %
6k – 84 %
7a – 91 %
7b – 80 %
7c – 88 %
7d – 85 %
7e – 81 %
7f – 84 %
7g – 87 %
7h – 90 %
7i – 92 %
7j – 39 %
7k – 97 %
2
3
4
5
6
7
8
9
For the most active compounds 3f, 7a and 7j having MIC ≤0.7
μg/mL against M. tuberculosis H37Rv, the data on their acute
toxicities on white mice have been obtained (Table 1). All tested
pyrimidines 3f, 7a and 7j proved to be less toxic in experiments
with white mice than Isoniazid. It should be noted that in case of
non-fluorinated 4-furan-2-yl-5-phenylpyrimidine (7a) the acute
oral toxicity proved to be two and four times lower the
fluorinated derivatives 3f and 7j. The structure of these
compounds has to be modified substantially in order to reduce
their toxicity with retention of the existing level of activity.
10
11
12
13
14
15
16
17
18
19
20
21
22

Table 4. In vitro antituberculosis activity of 5-arylpyrimidines (3a-k) and 5-aryl-4-heteroarylpyrimidines (6a-k and 7a-k).
R2
Antimycobacterial activity against different strains of Mycobacterium (MIC),
μg/mL
R1
R3
R4
LD50
Molecular
Mass
mouse,
Entry
Compound
MDRa
N
H37Rv
M. avium
M. terrae
mg/kg
N
Het
Het
R1
R2
R3
R4
μg/mL μM
μg/mL μM
μg/mL μM
μg/mL
μM
1
3a
3b
3c
3d
3e
3f
H
H
H
H
F
H
H
H
H
H
H
F
156.19
174.18
174.18
174.18
192.17
192.17
224.19
224.19
224.19
292.19
292.19
238.31
256.30
256.30
256.30
274.29
274.29
306.31
306.31
306.31
374.31
374.31
222.25
240.24
240.24
240.24
12.5
12.5
6.25
12.5
3.1
80.03
12.5
12.5
6.25
12.5
3.1
80.03
12.5
12.5
6.25
12.5
3.1
80.03
12.5
12.5
6.25
12.5
3.1
80.03
71.76
35.88
71.76
16.13
3.64
n.d.
n.d.
n.d.
n.d.
n.d.
300
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
150
n.d.
n.d.
n.d.
2
H
F
H
71.76
35.88
71.76
16.13
3.64
71.76
35.88
71.76
16.13
3.64
71.76
35.88
71.76
16.13
3.64
3
H
H
H
4
H
H
H
H
F
F
5
H
F
F
6
H
H
H
0.7
0.7
0.7
0.7
7
3g
3h
3i
H
CF3
H
H
H
H
H
H
H
CF3
H
H
H
H
H
F
6.2
27.66
55.76
55.76
42.78
5.13
6.2
27.66
55.76
55.76
42.78
5.13
6.2
27.66
55.76
55.76
42.78
5.13
6.2
27.66
55.76
55.76
42.78
5.13
8
H
CF3
H
12.5
12.5
12.5
1.5
12.5
12.5
12.5
1.5
12.5
12.5
12.5
1.5
12.5
12.5
12.5
1.5
9
H
H
H
CF3
CF3
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
3j
H
CF3
H
H
3k
6a
6b
6c
6d
6e
6f
H
CF3
H
thien-2-yl
thien-2-yl
thien-2-yl
thien-2-yl
thien-2-yl
thien-2-yl
thien-2-yl
thien-2-yl
thien-2-yl
thien-2-yl
thien-2-yl
furan-2-yl
furan-2-yl
furan-2-yl
furan-2-yl
H
H
6.2
26.02
48.77
48.77
48.77
45.57
45.57
20.24
4.90
6.2
26.02
12.5
6.2
26.02
12.5
6.2
26.02
12.5
F
H
H
12.5
12.5
12.5
12.5
12.5
6.2
12.5
12.5
12.5
12.5
12.5
6.2
12.5
12.5
12.5
12.5
12.5
6.2
12.5
12.5
12.5
12.5
12.5
6.2
H
F
H
12.5
12.5
12.5
H
H
F
12.5
12.5
12.5
F
H
F
45.57
45.57
20.24
4.90
45.57
45.57
20.24
4.90
45.57
45.57
20.24
4.90
H
F
H
6g
6h
6i
CF3
H
H
H
H
H
H
H
CF3
H
H
H
H
CF3
H
H
1.5
1.5
1.5
1.5
H
CF3
CF3
H
12.5
6.2
40.81
16.56
33.39
1.57
12.5
6.2
40.81
16.56
33.39
1.57
12.5
6.2
40.81
16.56
33.39
1.57
12.5
6.2
40.81
16.56
33.39
1.57
6j
CF3
H
H
6k
7a
7b
7c
7d
CF3
H
12.5
0.35
12.5
1.5
12.5
0.35
12.5
1.5
12.5
0.35
12.5
1.5
12.5
0.35
12.5
1.5
H
H
F
H
H
52.03
6.24
52.03
6.24
52.03
6.24
52.03
6.24
H
F
H
H
H
F
12.5
52.03
12.5
52.03
12.5
52.03
12.5
52.03

27
28
29
30
31
32
33
7e
7f
furan-2-yl
furan-2-yl
furan-2-yl
furan-2-yl
furan-2-yl
furan-2-yl
furan-2-yl
F
H
F
H
258.23
258.23
290.25
290.25
290.25
358.25
358.25
12.5
6.2
48.41
24.01
43.07
43.07
43.07
1.95
12.5
6.2
48.41
24.01
43.07
43.07
43.07
1.95
12.5
6.2
48.41
24.01
43.07
43.07
43.07
0.98
12.5
6.2
48.41
24.01
43.07
43.07
43.07
1.95
n.d.
n.d.
n.d.
n.d.
n.d.
600
n.d.
H
F
H
F
7g
7h
7i
CF3
H
H
H
H
12.5
12.5
12.5
0.7
12.5
12.5
12.5
0.7
12.5
12.5
12.5
0.35
3.1
12.5
12.5
12.5
0.7
CF3
H
H
H
H
CF3
CF3
H
H
7j
CF3
H
H
H
7k
CF3
CF3
3.1
8.65
3.1
8.65
8.65
3.1
8.65
133b
151c
n.ab
INH
137.14
0.1
0.73
0.1
0.73
0.1
0.73
-
-
PZA
OFL
123.12
361.37
12.5
0.1
101.53
0.28
n.d.
0.1
n.d.
n.d.
0.1
n.d.
-
-
1680c
5450d
0.28
0.28
0.1
0.28
n.d. – not determined; n.a. – data not available; INH – Isoniazid; PZA – Pyrazinamide; OFL – Ofloxacine.
aMDR (multi-drug-resistant tuberculosis strain) – Rifampin and Isoniazid resistant Mycobacterium tuberculosis strain having Beijing genotype with a combination of mutations Ser 531 - Leu 315 and Ser-Thr in rpoB and katG
genes, respectively.
bLD50 Oral mouse [32].
cLD50 Intraperitoneal mouse [32].
dLD50 Oral mouse [33].

Method A: K3PO4 (531 mg, 2.5 mmol) was added to a
solution of 5-bromopyrimidine (1) (159 mg, 1.0 mmol),
phenylboronic (2a) [2-fluorobenzeneboronic acid (2b), 3-
fluorobenzeneboronic (2c), 4-fluorobenzeneboronic (2d), 2,4-
difluorobenzeneboronic (2e), 3,5-difluorobenzeneboronic (2f), 2-
3. Conclusions
In summary, a simple and efficient way for the synthesis of
new family of 5-(fluoroaryl)-4-(hetero)aryl substituted
pyrimidines from commercially available 5-bromopyrimidine has
been advanced by using the sequence of nucleophilic aromatic
substitution of hydrogen (SNH) and the Suzuki cross-coupling
reactions. In the series of pyrimidines screened, compounds
bearing two fluoro atoms at C(3) and C(5) or CF3-groups at C(2)
and C(4) positions of the phenyl substituent, and also containing
the furanyl substituent at C(4) of the pyrimidine ring have shown
the most promising antitubercular activity. Further studies are
needed to explore the mechanism of antimicobacterial activity of
these compounds in detail.
(trifluoromethyl)benzeneboronic
(trifluoromethyl)benzeneboronic
(trifluoromethyl)benzeneboronic
(2g),
(2h),
3-
4-
(2i),
or
2,4-bis(trifluoro-
3,5-bis(trifluoro-
methyl)benzeneboronic
(2j),
methyl)benzeneboronic (2k) acids] (1.2 mmol) and trans-
bis(dicyclohexylamine)palladium(II) acetate (29 mg, 0.05 mmol)
in EtOH (10 mL). The resulting suspension was stirred at
ambient temperature for 24 h. EtOH was evaporated under a
reduced pressure and the residue was suspended in CH2Cl2 (20
mL) and filtered from inorganic salts. After that solvent was
distilled off under a reduced pressure, and the residue was
purified by flash column chromatography on silica gel
(hexane/ethyl acetate, 1:3) to afford the desired cross-coupling
products (3a-k).
4. Experimental section
4.1. General information
All reagents and solvents were obtained from commercial
sources and dried by using the standard procedures before use. 5-
Bromopyrimidine (1) and all arylboronic acids were purchased
from Sigma-Aldrich. 5-Bromo-4-(thien-2-yl)pyrimidine (8)
[27,30] and 5-bromo-4-(furan-2-yl)pyrimidine (9) [25] were
synthesized as described previously. Solvents (1,4-dioxane and
H2O) for the microwave-assisted Suzuki cross-coupling reaction
were deoxygenated by bubbling argon for 1h.
The 1H, 19F, and 13C NMR spectra were recorded on a Bruker
DRX-400 and AVANCE-500 instruments using Me4Si and C6F6
as an internal standards. Elemental analysis was carried on a
Eurovector EA 3000 automated analyzer. Melting points were
determined on Boetius combined heating stages and were not
corrected.
Method B: A solution of K2CO3 (346 mg, 2.5 mmol) in H2O
(3 mL) was added to a mixture of а 5-bromopyrimidine (1) (159
mg, 1.0 mmol), the corresponding (hetero)arylboronic acid (2a-
k) (1.2 mmol) and Pd(PPh3)4 (58 mg, 5 mol %) in 1,4-dioxane (4
mL). The resulting mixture was irradiated in a microwave
apparatus at 165 °C (250 W) for 20 min. After that solvent was
distilled off in vacuo, and the residue was purified by flash
column chromatography (hexane/ethyl acetate, 1:3) to afford the
desired cross-coupling products (3a-k).
4.2.1. 5-Phenylpyrimidine (3a) [34].
It has been obtained by the reaction of 1 with phenylboronic
(2a) acid. Yield (see Table 1, entry 1), white solid; mp 38-40 °C.
1H NMR (400 MHz, CDCl3): δ = 7.45-7.49 (m, 1H, Ph), 7.51-
7.55 (m, 2H, Ph), 7.58-7.60 (m, 2H, Ph), 8.92 (s, 2H, H-4 and H-
6), 9.17 (s, 1H, H-2) ppm. GC tR 15.76 min; MS m/z (rel
intensity) 156 (M+, 100). Anal. Calcd for C10H8N2 (156.19): C,
76.90; H, 5.16; N, 17.94. Found: C, 59.18; H, 3.63; N, 17.55.
The GC-MS analysis of all samples was carried out using an
Agilent GC 7890A MS 5975C Inert XL EI/CI GC-MS
spectrometer with a quadrupole mass-spectrometric detector with
electron ionization (70 eV) and scan over the total ionic current
in the range m/z 20–1000 and a quartz capillary column HP-5MS
(30 m × 0.25 mm, film thickness 0.25 mm). Helium served as a
carrier gas, the split ratio of the flow was 1 : 50, and the
consumption through the column was 1.0 mL min–1; the initial
temperature of the column was 40 °C (storage 3 min),
programming rate was 10 °C min–1 to 290 °C (storage 20 min),
the temperature of the evaporator was 250 °C, the temperature of
the source was 230 °C, the temperature of the quadrupole was
150 °C, and the temperature of the transition chamber was 280
°C. Solutions of the samples with a concentration of 3-4 mg mL–1
were prepared in THF. Samples of 1 mL of the obtained solutions
were analyzed.
4.2.2. 5-(2-Fluorophenyl)pyrimidine (3b).
It has been obtained by the reaction of 1 with 2-
fluorobenzenboronic (2b) acid. Yield (see Table 1, entries 2 and
1
3), white solid; m.p. 75-78 °C. H NMR (500 MHz, CDCl3): δ =
7.21-7.32 (m, 2H, Ph), 7.43-7.47 (m, 2H, Ph), 8.94 (d, 2H, J =
1.2 Hz, H-4 and H-6), 9.22 (s, 1H, H-2) ppm. 13C NMR (126
2
2
MHz, CDCl3): δ = 116.52 (d, JC,F = 22.0 Hz), 122.14 (d, JC,F
=
4
4
13.8 Hz), 125.04 (d, JC,F = 3.8 Hz), 129.75 (d, JC,F = 1.8 Hz),
4
3
130.06 (d, JC,F = 3.0 Hz), 130.98 (d, JC,F = 8.3 Hz), 156.33 (d,
3JC,F = 3.9 Hz), 157.66, 158.82, 160.80 ppm. 19F NMR (470.5
MHz, CDCl3) 44.17-44.22 (m, 1F) ppm. GC tR 15.57 min; MS
m/z (rel intensity): 174 (М+, 100). Anal. Calcd for C10H7FN2
(174.18): C 68.96, H 4.05, N, 16.08. Found: C 68.93; H, 3.96; N,
15.82.
Column chromatography was carried out using Alfa Aesar
silica gel 0.040-0.063 mm (230–400 mesh), eluting with ethyl
acetate-hexane., 1:1 or 1:3. The progress of reactions and the
purity of compounds were checked by TLC on Sorbfil plates
(Russia), in which the spots were visualized with UV light (λ 254
or 365 nm).
4.2.3. 5-(3-Fluorophenyl)pyrimidine (3c).
It has been obtained by the reaction of 1 with 3-
fluorobenzenboronic (2c) acid. Yield (see Table 1, entry 4), pale
yellow solid; m.p. 63-64 °C. 1H NMR (500 MHz, DMSO-d6): δ =
7.33 (m, 1H, Ph), 7.59 (td, 1H, J = 8.0, 6.2 Hz, Ph), 7.69 (ddd,
1H, J = 7.7, 1.5, 0.9 Hz, Ph), 7.75 (ddd, 1H, J = 10.4, 2.4, 1.9 Hz,
Ph), 9.20 (s, 2H, H-4 and H-6), 9.22 (s, 1H, H-2) ppm. 13C NMR
(126 MHz, DMSO-d6): δ = 113.81 (d, 2JC,F = 22.8 Hz), 115.66 (d,
Microwave experiments were carried out in a Discover
unimodal microwave system (CEM, USA) with a working
frequency of 2.45 GHz and the power of microwave radiation
ranged from 0 to 300 W. The reactions were carried out in a 10
mL reaction tube with the hermetic Teflon cork. The reaction
temperature was monitored, using an inserted IR sensor by the
external surface of the reaction vessel.
4
3
2JC,F = 21.00 Hz), 123.04 (d, JC,F = 2.8 Hz), 131.28 (d, JC,F
=
4
3
6.8 Hz), 131.93 (d, JC,F = 2.4 Hz), 136.15 (d, JC,F = 8.2 Hz),
154.89, 157.67, 162.69 (d, JC,F = 244.0 Hz) ppm. 19F NMR
1
(470.5 MHz, DMSO-d6) 50.51 (ddd, J = 10.1, 9.1, 6.2 Hz) ppm.
GC tR 15.58 min; MS m/z (rel intensity): 174 (М+, 100). Anal.
4.2. Synthesis
of
5-phenylpyrimidine
(3a)
and
5-
(fluoroaryl)pyrimidines (3b-k).

Calcd for C10H7FN2 (174.18): C 68.96, H 4.05, N, 16.08. Found:
C 68.85; H, 3.91; N, 15.87.
Hz, Ph), 7.77 (d, 1H, J = 14.9 Hz, Ph), 7.84 (s, 1H, H-2'), 8.99 (s,
2H, H-4 and H-6), 9.28 (s, 1H, H-2) ppm. 13C NMR (126 MHz,
1
1
CDCl3): δ = 123.73 (d, JC,F = 272.5 Hz), 124.79 (dq, JC,F
=
4.2.4. 5-(4-Fluorophenyl)pyrimidine (3d) [34].
4
241.5 Hz , JC,F = 3.7 Hz), 130.05, 130.33, 131.87, 132.13,
133.16, 135.19, 154.98, 158.11 ppm. 19F NMR (470.5 MHz,
CDCl3) 98.96 (s, CF3) ppm. GC tR 15.56 min; MS m/z (rel
intensity): 224 (М+, 100). Anal. Calcd for C11H7F3N2 (224.19): C
58.93, H 3.15, N, 12.50. Found: C 59.03; H, 3.06; N, 12.55.
It has been obtained by the reaction of 1 with 4-
fluorobenzenboronic (2d) acid. Yield (see Table 1, entry 5),
1
white solid; m.p. 96-98 °C. H NMR (500 MHz, CDCl3): δ =
7.23 (m, 2H, H-2' and H-6'), 7.56 (m, 2H, H-3' and H-5'), 8.92 (s,
2H, H-4 and H-6), 9.21 (s, 1H, H-2) ppm. 13C NMR (126 MHz,
2
3
4.2.9. 5-(4-Trifluorometylphenyl)pyrimidine (3i).
CDCl3): δ = 116.54 (d, JC,F = 21.8 Hz), 128.78 (d, JC,F
=
4
8.4 Hz), 130.39 (d, JC,F = 3.4 Hz), 133.44, 154.72, 157.49,
162.40, 164.39 ppm. 19F NMR (470.5 MHz, CDCl3) 49.34 (tt, 1F,
J = 8.4, 5.1 Hz) ppm. GC tR 15.84 min; MS m/z (rel intensity):
174 (М+, 100). Anal. Calcd for C10H7FN2 (174.18): C 68.96, H
4.05, N, 16.08. Found: C 68.90; H, 3.89; N, 15.96.
It has been obtained by the reaction of 1 with 4-
(trifluoromethyl)benzeneboronic (2i) acid. Yield (see Table 1,
1
entry 12), white solid; m.p. 110-112 °C. H NMR (500 MHz,
CDCl3): δ = 7.72 (d, 2H, J = 8.1 Hz, H-2' and H-6'), 7.80 (d, 2H,
J = 8.1 Hz, H-3' and H-5'), 8.99 (s, 2H, H-4 and H-6), 9.28 (s,
1H, H-2) ppm. 13C NMR (126 MHz, CDCl3): δ = 123.84 (d, 1JC,F
4.2.5. 5-(2,4-Difluorophenyl)pyrimidine (3e) [35].
= 272.3 Hz), 126.40 (q, 4JC,F = 3.7 Hz), 127.41, 131.17 (q, 2JC,F
=
4
It has been obtained by the reaction of 1 with 2,4-
difluorobenzenboronic (2e) acid. Yield (see Table 1, entries 6 and
32.8 Hz), 133.10, 137.86 (d, JC,F = 0.8 Hz), 155.02, 158.24
ppm. 19F NMR (470.5 MHz, CDCl3) 98.98 (s, CF3) ppm. GC tR
15.89 min; MS m/z (rel intensity): 224 (М+, 100). Anal. Calcd for
C11H7F3N2 (224.19): C 58.93, H 3.15, N, 12.50. Found: C 58.72;
H, 3.13; N, 12.64.
1
7), white solid; m.p. 93-95 °C. H NMR (500 MHz, CDCl3): δ =
6.98-7.08 (m, 2H, H-5' and H-6'), 7.74 (td, 1H, J = 8.6, 6.2 Hz,
H-3'), 8.90 (d, 2H, J = 1.3 Hz, H-4 and H-6), 9.23 (s, 1H, H-2)
2
ppm. 13C NMR (126 MHz, CDCl3): δ = 105.02 (t, JC,F
=
25.7 Hz), 112.51 (dd, 2JC,F = 21.5 Hz, 4JC,F = 3.8 Hz), 113.46 (dd,
4.2.10. 5-(2,4-Bis-trifluoromethylphenyl)pyrimidine
(3j) [36].
2JC,F = 14.2 Hz, 3JC,F = 4.0 Hz), 129.01 (d, 3JC,F = 2.0 Hz), 130.95
2
3
4
It has been obtained by the reaction of 1 with 2,4-
bis(trifluoromethyl)benzeneboronic (2j) acid. Yield (see Table 1,
(dd, JC,F = 9.8 Hz, JC,F = 4.5 Hz), 156.20 (d, JC,F = 3.7 Hz),
157.75, 160.01 (dd, 1JC,F = 252.2 Hz, 2JC,F = 12.0 Hz), 163.45 (dd,
1
1JC,F = 252.2 Hz, JC,F = 12.0 Hz) ppm. 19F NMR (470.5 MHz,
2
entries 12 and 13), white solid; m.p. 58-59 °C. H NMR (500
MHz, CDCl3): δ = 7.52 (d, 1H, J = 8.0 Hz, H-6'), 7.95 (d, 1H, J =
8.0 Hz, H-5'), 8.10 (s, 1H, H-3'), 8.75 (s, 2H, H-4 and H-6), 9.32
(s, 1H, H-2) ppm. 13C NMR (126 MHz, CDCl3): δ = 121.89 (d,
CDCl3) 48.85 (td, 1F, J = 9.7, 1.1 Hz), 54.07 (qd, 1F, J = 8.3, 6.3
Hz) ppm. GC tR 15.15 min; MS m/z (rel intensity): 192 (М+,
100). Anal. Calcd for C10H6F2N2 (192.17): C 62.50, H 3.15, N,
14.58. Found: C 62.58; H, 3.20; N, 14.52.
3
3
2JC,F = 18.4 Hz), 123.87 (dt, JC,F = 8.8 Hz, JC,F = 3.9 Hz),
124.07 (d, 2JC,F = 17.0 Hz), 128.88 (d, 4JC,F = 3.3 Hz), 130.20 (d,
4.2.6. 5-(3,5-Difluorophenyl)pyrimidine (3f).
It has been obtained by the reaction of 1 with 3,5-
difluorobenzenboronic (2f) acid. Yield (see Table 1, entry 8),
2
2JC,F = 31.4 Hz), 131.82 (d, JC,F = 33.8 Hz), 132.31, 132.86,
137.45, 155.86, 158.65 ppm. 19F NMR (470.5 MHz, CDCl3)
98.72 (s, CF3), 104.47 (s, CF3) ppm. GC tR 14.13 min; MS m/z
(rel intensity): 292 (М+, 100). Anal. Calcd for C12H6F6N2
(292.19): C 49.33, H 2.07, N, 9.59. Found: C 49.18; H, 2.21; N,
9.52.
1
white solid; m.p. 150-151 °C. H NMR (500 MHz, CDCl3): δ =
6.93 (tt, 1H, J = 8.8, 2.3 Hz, H-4'), 7.13 (m, 2H, H-2' and H-6'),
8.94 (s, 2H, H-4 and H-6), 9.27 (s, 1H, H-2) ppm. 13C NMR (126
MHz, CDCl3): δ = 104.43 (t, 2JC,F = 25.2 Hz), 110.06 (dd, 2JC,F
=
3
3
4.2.11. 5-(3,5-Bis-trifluoromethylphenyl)pyrimidine
(3k).
20.0 Hz, JC,F = 6.6 Hz), 132.32, 137.44 (t, JC,F = 9.7 Hz),
1
2
154.82, 158.39, 163.62 (dd, JC,F = 250.5 Hz, JC,F = 12.9 Hz)
ppm. 19F NMR (470.5 MHz, CDCl3) 54.13-54.21 (m, 2F) ppm.
GC tR 14.95 min; MS m/z (rel intensity): 192 (М+, 100). Anal.
Calcd for C10H6F2N2 (192.17): C 62.50, H 3.15, N, 14.58. Found:
C 62.52; H, 3.27; N, 14.33.
It has been obtained by the reaction of 1 with 3,5-
bis(trifluoromethyl)benzeneboronic (2k) acid. Yield (see Table 1,
entry 14), off-white solid; m.p. 152-154 °C. 1H NMR (500 MHz,
CDCl3): δ = 8.01 (s, 1H, H-4'), 8.03 (s, 2H, H-2' and H-6'), 9.01
(s, 2H, H-4 and H-6), 9.33 (s, 1H, H-2) ppm. 13C NMR (126
3
4
4.2.7. 5-(2-Trifluorometylphenyl)pyrimidine (3g).
MHz, CDCl3): δ = 122.77 (dt, JC,F = 7.4 Hz, JC,F = 3.6 Hz),
1
4
It has been obtained by the reaction of 1 with 2-
(trifluoromethyl)benzeneboronic (2g) acid. Yield (see Table 1,
122.96 (d, JC,F = 273.0 Hz), 127.20 (d, JC,F = 2.9 Hz), 131.93,
2
133.10 (d, JC,F = 33.8 Hz), 136.70, 155.06, 158.87 ppm. 19F
1
entries 9 and 10), pale yellow oil. H NMR (500 MHz, CDCl3): δ
NMR (470.5 MHz, CDCl3) 98.81 (s, CF3) ppm. GC tR 14.31 min;
MS m/z (rel intensity): 292 (М+, 100). Anal. Calcd for C12H6F6N2
(292.19): C 49.33, H 2.07, N, 9.59. Found: C 49.44; H, 2.24; N,
9.57.
= 7.35 (d, 1H, J = 7.5 Hz, H-6'), 7.64 (dt, 2H, J = 15.0, 7.4 Hz,
H-4' and H-5'), 7.84 (d, 1H, J = 7.8 Hz, H-3'), 8.74 (s, 2H, H-4
and H-6), 9.27 (s, 1H, H-2) ppm. 13C NMR (126 MHz, CDCl3): δ
= 123.70 (d, 1JC,F = 252.2 Hz), 126.54 (q, 3JC,F = 5.2 Hz), 129.00,
4
4.3. Synthesis of 4-(hetero)aryl-5-phenylpyrimidines 6a and 7a 5-
(fluoroaryl)-4-(hetero)arylpyrimidines 6b-k and 7b-k.
129.06, 129.24, 131.93 (d, JC,F = 2.6 Hz), 133.56, 133.63 (d,
4JC,F = 1.7 Hz), 156.11 (q, 4JC,F = 1.6 Hz), 158.03 ppm. 19F NMR
(470.5 MHz, CDCl3) 104.91 (s, CF3) ppm. GC tR 15.03 min; MS
m/z (rel intensity): 224 (М+, 100). Anal. Calcd for C11H7F3N2
(224.19): C 58.93, H 3.15, N, 12.50. Found: C 58.86; H, 3.05; N,
12.70.
A solution of K2CO3 (346 mg, 2.5 mmol) in 3 mL H2O was
added to a mixture of 5-bromo-4-(thien-2-yl)pyrimidine (8) [or 5-
bromo-4-(furan-2-yl)pyrimidine
(9)]
(0.5
mmol),
the
corresponding arylboronic acid (2a-k) (0.6 mmol) and Pd(PPh3)4
(29 mg, 5 mol %) in 1,4-dioxane (4 mL). The resulting mixture
was irradiated in a microwave apparatus at 165 °C (250 W) for
20 min. After that solvent was distilled off in vacuo, and the
residue was purified by flash column chromatography
(hexane/ethyl acetate, 1:3) to afford the desired 5-aryl-4-
(hetero)arylpyrimidines 6a-k and 7a-k..
4.2.8. 5-(3-Trifluorometylphenyl)pyrimidine (3h).
It has been obtained by the reaction of 1 with 3-
(trifluoromethyl)benzeneboronic (2h) acid. Yield (see Table 1,
1
entry 11), white solid; m.p. 103-105 °C. H NMR (500 MHz,
CDCl3): δ = 7.68 (d, 1H, J = 7.8 Hz, H-4'), 7.76 (d, 1H, J = 15.1

4.3.5. 5-(2,4-Difluorophenyl)-4-(thien-2-
4.3.1. 5-Phenyl-4-(thien-2-yl)pyrimidine (6a).
yl)pyrimidine (6e).
It has been obtained by the reaction of 5-bromo-4-(thien-2-
It has been obtained by the reaction of 5-bromo-4-(thien-2-
yl)pyrimidine (8) with 2,4-difluorobenzenboronic (2e) acid.
Yield (see Table 3, entry 5), beige solid; m.p. 67-69 °C. 1H NMR
(500 MHz, CDCl3): δ = 6.94 (dd, 1H, J = 5.0, 3.8 Hz, H-4"),
6.95-7.01 (m, 2H, H-5' and H-3"), 7.06 (m, 1H, H-6'), 7.33 (td,
1H, J = 8.3, 6.4 Hz, H-3'), 7.45 (dd, 1H, J = 5.0, 0.9 Hz, H-5"),
8.55 (s, 1H, H-6), 9.16 (s, 1H, H-2) ppm. 13C NMR (126 MHz,
yl)pyrimidine (8) with phenylboronic (2a) acid. Yield (see Table
3, entry 1), pale yellow solid; mp 104-106 °C. H NMR (500
1
MHz, CDCl3): 6.81 (dd, 1H, J = 3.8, 0.7 Hz, H-3"), 6.86 (dd, 1H,
J = 5.0, 3.8 Hz, H-4"), 7.34-7.39 (m, 2H, Ph), 7.41 (dd, 1H, J =
5.0, 0.7 Hz, H-5"), 7.47-7.52 (m, 3H, Ph), 8.55 (s, 1H, H-6), 9.12
(s, 1H, H-2) ppm. 13C NMR (126 MHz, CDCl3): 128.02, 128.79,
129.12, 129.16, 130.29, 130.81, 130.91, 136.29, 141.78, 156.25,
157.35, 158.20 ppm. GC tR 22.74 min; MS m/z (rel intensity) 238
(M+, 100). Anal. Calcd for C14H10N2S (238.31): C, 70.56; H,
4.23; N, 11.75. Found: C, 70.36; H, 4.30; N, 11.71.
2
2
CDCl3): δ = 105.00 (t, JC,F = 25.7 Hz), 112.46 (dd, JC,F
=
=
=
3
2
3
21.4 Hz, JC,F = 3.9 Hz), 120.06 (dd, JC,F = 16.6 Hz, JC,F
2
4.0 Hz), 123.91, 128.18, 129.91, 130.75, 132.18 (dd, JC,F
4
9.6 Hz, JC,F = 4.1 Hz), 141.39, 157.16, 158.08, 158.81, 160.16
4.3.2. 5-(2-Fluorophenyl)-4-(thien-2-yl)pyrimidine
(6b).
1
2
1
(dd, JC,F = 251.2 Hz, JC,F = 12.1 Hz), 163.70 (dd, JC,F
=
252.2 Hz, 2JC,F = 11.5 Hz) ppm. 19F NMR (470.5 MHz, CDCl3)
52.70 (q, 1F, J = 8.7 Hz), 54.27 (qd, 1F, J = 8.3, 6.4 Hz) ppm.
GC tR 21.99 min; MS m/z (rel intensity): 274 (М+, 100). Anal.
Calcd for C14H8F2N2S (274.29): C 61.31, H 2.94, N, 10.21.
Found: C 61.34; H, 2.84; N, 10.09.
It has been obtained by the reaction of 5-bromo-4-(thien-2-
yl)pyrimidine (8) with 2-fluorobenzeneboronic (2b) acid. Yield
(see Table 3, entry 2), pale yellow solid; m.p. 90-92 °C. 1H NMR
(500 MHz, CDCl3): δ = 6.89-6.91 (m, 2H, H-3" and H-4"), 7.21
(t, 1H, J = 8.9 Hz, Ph), 7.28-7.38 (m, 2H, Ph), 7.43 (dd, 1H, J =
4.6, 1.5 Hz, H-5"), 7.51 (tdd, 1H, J = 7.2, 5.2, 2.0 Hz, H-3), 8.57
(s, 1H, H-6), 9.16 (s, 1H, H-2) ppm. 13C NMR (126 MHz,
4.3.6. 5-(3,5-Difluorophenyl)-4-(thien-2-
yl)pyrimidine (6f).
2
2
It has been obtained by the reaction of 5-bromo-4-(thien-2-
CDCl3): δ = 116.35 (d, JC,F = 21.3 Hz), 123.95 (d, JC,F
=
4
yl)pyrimidine (8) with 3,5-difluorobenzenboronic (2f) acid. Yield
16.3 Hz), 124.74, 125.00 (d, JC,F = 3.7 Hz), 128.15, 129.91,
1
3
4
(see Table 3, entry 6), pale yellow solid; m.p. 108-110 °C. H
130.56, 131.18 (d, JC,F = 7.9 Hz), 131.29 (d, JC,F = 2.6 Hz),
1
NMR (500 MHz, CDCl3): δ = 6.89-6.99 (m, 5H, H-3'', H-4'' and
Ph), 7.47 (dd, 1H, J = 4.9, 1.1 Hz, H-5"), 8.53 (s, 1H, H-6), 9.15
(s, 1H, H-2) ppm. 13C NMR (126 MHz, CDCl3): δ = 104.47 (t,
141.64, 156.95, 157.91, 158.68, 159.86 (d, JC,F = 248.5 Hz)
ppm. 19F NMR (470.5 MHz, CDCl3) 44.98 (dt, 1F, J = 9.2, 6.7
Hz) ppm. GC tR 22.53 min; MS m/z (rel intensity): 256 (М+,
100). Anal. Calcd for C14H9FN2S (256.30): C 65.61, H 3.54, N,
10.93. Found: C 65.32; H, 3.52; N, 10.65.
2
3
2JC,F = 25.1 Hz), 112.52 (dd, JC,F = 19.7 Hz, JC,F = 6.4 Hz),
3
128.24, 128.77, 130.88, 130.94, 139.42 (t, JC,F = 9.7 Hz),
1
140.94, 156.13, 157.78, 158.00, 163.40 (dd, JC,F = 251.2 Hz,
4.3.3. 5-(3-Fluorophenyl)-4-(thien-2-yl)pyrimidine
(6c).
2JC,F = 12.9 Hz) ppm. 19F NMR (470.5 MHz, CDCl3) 54.06-54.13
(m, 2F) ppm. GC tR 21.67 min; MS m/z (rel intensity): 274 (М+,
100). Anal. Calcd for C14H8F2N2S (274.29): C 61.31, H 2.94, N,
10.21. Found: C 61.30; H, 2.96; N, 10.15.
It has been obtained by the reaction of 5-bromo-4-(thien-2-
yl)pyrimidine (8) with 3-fluorobenzeneboronic (2c) acid. Yield
1
(see Table 3, entry 3), white solid; m.p. 60-61 °C. H NMR (500
4.3.7. 4-Thien-2-yl-5-(2-
trifluorometylphenyl)pyrimidine (6g).
MHz, CDCl3): δ = 6.86 (dd, 1H, J = 3.9, 1.1 Hz, H-3"), 6.90 (dd,
1H, J = 5.0, 3.9 Hz, H-4"), 7.10 (ddd, 1H, J = 9.2, 2.3, 1.7 Hz,
Ph), 7.16 (ddd, 1H, J = 7.6, 1.4, 1.0 Hz, Ph), 7.20 (tdd, 1H, J =
8.5, 2.6, 0.9 Hz, Ph), 7.44 (dd, 1H, J = 5.0, 1.1 Hz, H-5"), 7.48
It has been obtained by the reaction of 5-bromo-4-(thien-2-
yl)pyrimidine (8) with 2-(trifluoromethyl)benzeneboronic (2g)
1
acid. Yield (see Table 3, entry 7), beige solid; m.p. 97-99 °C. H
(td, 1H, J = 8.0, 5.9 Hz, Ph), 8.54 (s, 1H, H-6), 9.14 (s, 1H, H-2)
2
ppm. 13C NMR (126 MHz, CDCl3): δ = 115.87 (d, JC,F
=
NMR (500 MHz, CDCl3): δ = 6.59 (d, 1H, J = 3.6 Hz, H-3"),
6.86 (m, 1H, H-4"), 7.35 (dd, 1H, J = 6.3, 1.4 Hz, H-6'), 7.41 (d,
1H, J = 4.9 Hz, H-5"), 7.65-7.71 (m, 2H, H-4' and H-5'), 7.89
(dd, 1H, J = 6.6, 1.9 Hz, H-3'), 8.53 (s, 1H, H-6), 9.16 (s, 1H, H-
2) ppm. 13C NMR (126 MHz, CDCl3): δ = 120.29, 123.56 (d,
2
4
20.9 Hz), 116.35 (d, JC,F = 22.1 Hz), 125.02 (d, JC,F = 3.0 Hz),
3
128.12, 129.67, 130.61, 130.84, 130.92 (d, JC,F = 8.4 Hz),
3
138.37 (d, JC,F = 7.8 Hz), 141.37, 156.20, 157.69, 158.01,
163.04 (d, 1JC,F = 248.4 Hz) ppm. 19F NMR (470.5 MHz, CDCl3)
50.39 (dt, 1F, J = 8.9, 5.8 Hz) ppm. GC tR 22.38 min; MS m/z
(rel intensity): 256 (М+, 100). Anal. Calcd for C14H9FN2S
(256.30): C 65.61, H 3.54, N, 10.93. Found: C 65.50; H, 3.52; N,
10.90.
3
1JC,F = 274.1 Hz), 126.92 (q, JC,F = 5.0 Hz), 128.12, 129.13,
2
129.39, 129.61, 130.56 (q, JC,F = 30.5 Hz), 132.01, 132.49,
4
134.69, 141.74, 156.28, 157.94 (d, JC,F = 1.2 Hz), 159.97 ppm.
19F NMR (470.5 MHz, CDCl3) 102.59 (s, CF3) ppm. GC tR 22.10
min; MS m/z (rel intensity): 306 (М+, 100). Anal. Calcd for
C15H9F3N2S (306.31): C 58.82, H 2.96, N, 9.15. Found: C 58.86;
H, 2.84; N, 9.04.
4.3.4. 5-(4-Fluorophenyl)-4-(thien-2-yl)pyrimidine
(6d).
It has been obtained by the reaction of 5-bromo-4-(thien-2-
4.3.8. 4-Thien-2-yl-5-(3-
trifluorometylphenyl)pyrimidine (6h).
yl)pyrimidine (8) with 4-fluoro-benzeneboronic (2d) acid. Yield
1
(see Table 3, entry 4), pale yellow solid; m.p. 102-103 °C. H
It has been obtained by the reaction of 5-bromo-4-(thien-2-
NMR (500 MHz, CDCl3): δ = 6.86 (dd, 1H, J = 3.8, 1.0 Hz, H-
3"), 6.90 (dd, 1H, J = 5.0, 3.8 Hz, H-4"), 7.20 (m, 2H, H-2' and
H-6'), 7.34 (m, 2H, H-3' and H-5'), 7.43 (dd, 1H, J = 5.0, 1.0 Hz,
H-5"), 8.53 (s, H, H-4), 9.12 (s, 1H, H-2) ppm. 13C NMR (126
yl)pyrimidine (8) with 3-(trifluoromethyl)benzeneboronic (2h)
1
acid. Yield (see Table 3, entry 8), white solid; m.p. 73-74 °C. H
NMR (500 MHz, CDCl3): δ = 6.81 (dd, 1H, J = 3.9 , 1.0 Hz, H-
3"), 6.90 (dd, 1H, J = 5.1 , 3.9 Hz, H-4"), 7.45 (dd, 1H, J = 5.1,
1.0 Hz, H-5"), 7.58 (d, 1H, J = 7.7 Hz, Ph), 7.63-7.66 (m, 2H,
2
MHz, CDCl3): δ = 116.33 (d, JC,F = 21.6 Hz), 128.02, 129.93,
3
130.60 (d, 2JC,F = 33.1 Hz), 133.01 (d, JC,F = 8.2 Hz), 132.20 (d,
4JC,F = 3.5 Hz), 141.56, 156.40, 157.49, 158.23, 162.09, 164.07
ppm. 19F NMR (470.5 MHz, CDCl3) 49.39 (tt, 1F, J = 8.6, 5.3
Hz) ppm. GC tR 22.60 min; MS m/z (rel intensity): 256 (М+,
100). Anal. Calcd for C14H9FN2S (256.30): C 65.61, H 3.54, N,
10.93. Found: C 65.41; H, 3.53; N, 10.87.
Ph), 7.77 (d, 1H, J = 7.7 Hz, Ph), 8.56 (s, 1H, H-6), 9.16 (s, 1H,
1
H-2) ppm. 13C NMR (126 MHz, CDCl3): δ = 123.71 (d, JC,F
=
4
4
272.5 Hz), 125.68 (q, JC,F = 3.8 Hz), 126.13 (q, JC,F = 3.8 Hz),
4
126.96, 128.12, 129.46, 129.77, 130.79 (q, JC,F = 2.1 Hz),
2
131.78 (q, JC,F = 32.8 Hz), 132.73, 137.17, 141.24, 156.33,

157.89, 158.12 ppm. 19F NMR (470.5 MHz, CDCl3) 99.01 (s,
CF3) ppm. GC tR 21.91 min; MS m/z (rel intensity): 306 (М+,
100). Anal. Calcd for C15H9F3N2S (306.31): C 58.82, H 2.96, N,
9.15. Found: C 58.76; H, 3.02; N, 9.04.
MS m/z (rel intensity) 222 (M+, 100). Anal. Calcd for C14H10N2O
(222.25): C, 75.66; H, 4.54; N, 12.60. Found: C, 75.46; H, 4.34;
N, 12.47.
4.3.13. 5-(2-Fluorophenyl)-4-(furan-2-
yl)pyrimidine (7b).
4.3.9. 4-Thien-2-yl-5-(4-
trifluorometylphenyl)pyrimidine (6i).
It has been obtained by the reaction of 5-bromo-4-(furan-2-
It has been obtained by the reaction of 5-bromo-4-(thien-2-
yl)pyrimidine (8) with 4-(trifluoromethyl)benzeneboronic (2i)
acid. Yield (see Table 3, entry 9), white solid; m.p. 125-127 °C.
1H NMR (500 MHz, CDCl3): δ = 6.82 (dd, 1H, J = 3.8, 0.8 Hz,
H-3"), 6.92 (dd, 1H, J = 5.0, 3.8 Hz, H-4"), 7.46 (dd, 1H, J = 5.0,
0.8 Hz, H-5"), 7.54 (d, 2H, J = 8.1 Hz, H-2' and H-6'), 7.78 (d,
yl)pyrimidine (9) with 2-fluorobenzeneboronic (2b) acid. Yield
(see Table 3, entry 13), yellow oil. H NMR (500 MHz, CDCl3):
1
δ = 6.40 (br. s, 1H, H-3"), 6.56 (br. s, 1H, H-4"), 7.18-7.21 (br.
m, 1H, H-5"), 7.28-7.32 (m, 2H, Ph), 7.46-7.49 (m, 2H, Ph), 8.60
(s, 1H, H-6), 9.22 (s, 1H, H-2) ppm. 13C NMR (126 MHz,
2
CDCl3): δ = 112.12, 115.19, 115.92 (d, JC,F = 21.4 Hz), 123.92
2H, J = 8.1 Hz, H-3' and H-5'), 8.55 (s, 1H, H-6), 9.17 (s, 1H, H-
(d, 2JC,F = 16.4 Hz), 124.44, 124.62 (d, 4JC,F = 3.6 Hz), 130.82 (d,
1
4
2) ppm. 13C NMR (126 MHz, CDCl3): 123.89 (d, JC,F
=
3JC,F = 8.0 Hz), 131.01 (d, JC,F = 2.5 Hz), 145.22, 150.66,
4
1
272.5 Hz), 126.18 (q, JC,F = 3.7 Hz), 128.19, 129.60, 129.71,
152.99, 157.99, 158.76, 159.93 (d, JC,F = 248.2 Hz) ppm. 19F
2
130.76, 130.86, 131.11 (q, JC,F = 32.7 Hz), 140.12, 141.26,
NMR (470.5 MHz, CDCl3) 47.44 (br. m, 1F) ppm. GC tR 20.33
min; MS m/z (rel intensity): 240 (М+, 100). Anal. Calcd for
C14H9FN2O (240.24): C 70.00, H 3.78, N, 11.66. Found: C 70.18;
H, 3.67; N, 11.45.
156.21, 157.88, 158.01 ppm. 19F NMR (470.5 MHz, CDCl3)
99.10 (s, CF3) ppm. GC tR 22.14 min; MS m/z (rel intensity): 306
(М+, 100). Anal. Calcd for C15H9F3N2S (306.31): C 58.82, H
2.96, N, 9.15. Found: C 58.71; H, 2.90; N, 9.09.
4.3.14. 5-(2-Fluorophenyl)-4-(furan-2-
yl)pyrimidine (7c).
4.3.10. 5-(2,4-Bis-trifluoromethylphenyl)-4-(thien-
2-yl)pyrimidine (6j).
It has been obtained by the reaction of 5-bromo-4-(furan-2-
It has been obtained by the reaction of 5-bromo-4-(thien-2-
yl)pyrimidine (8) with 2,4-bis(trifluoromethyl)benzeneboronic
(2j) acid. Yield (see Table 3, entry 10), pale yellow solid; m.p.
117-120 °C. H NMR (500 MHz, CDCl3): δ = 6.65 (d, 1H, J =
3.5, H-3"), 6.90 (dd, 1H, J = 4.9, 3.5 Hz, H-4"), 7.45 (d, 1H, J =
yl)pyrimidine (9) with 3-fluorobenzeneboronic (2b) acid. Yield
(see Table 3, entry 14), yellow oil. H NMR (500 MHz, DMSO-
1
d6): δ = 6.60 (dd, 1H, J = 3.5, 1.7 Hz, H-4"), 6.74 (dd, 1H, J =
3.5, 0.9 Hz, H-3"), 7.24 (d, 1H, J = 7.7 Hz, Ph), 7.29-7.37 (m,
2H, Ph), 7.53-7.57 (m, 1H, Ph), 7.77 (dd, 1H, J = 1.7, 0.9 Hz, H-
5"), 8.71 (s, 1H, H-6), 9.19 (s, 1H, H-2) ppm. 13C NMR (126
MHz, DMSO-d6): δ = 112.29, 115.20 (d, 2JC,F = 20.9 Hz), 115.35,
1
4.9 Hz, H-5"), 7.55 (d, 1H, J = 8.0 Hz, H-6'), 7.95 (d, 1H, J = 8.0
Hz, H-5'), 8.16 (s, 1H, H-3'), 8.51 (s, 1H, H-6), 9.20 (s, 1H, H-2)
2
4
ppm. 13C NMR (126 MHz, CDCl3): δ = 121.86 (d, JC,F
=
115.98 (d, 2JC,F = 22.2 Hz), 125.27 (d, JC,F = 2.6 Hz), 128.76 (d,
3
3
3
3
38.9 Hz), 123.89, 124.24 (dd, JC,F = 9.4 Hz, JC,F = 4.8 Hz),
4JC,F = 1.8 Hz), 130.54 (d, JC,F = 8.5 Hz), 138.26 (d, JC,F
=
4
1
126.24, 128.27, 129.30 (d, JC,F = 3.3 Hz), 130.52, 130.67 (d,
8.3 Hz), 145.96, 150.37, 151.38, 157.39, 158.42, 162.05 (d, JC,F
= 244.3 Hz) ppm. 19F NMR (470.5 MHz, DMSO-d6) 49.70 (td,
1F, J = 9.4, 6.3 Hz) ppm. GC tR 20.26 min; MS m/z (rel
intensity): 240 (М+, 100). Anal. Calcd for C14H9FN2O (240.24):
C 70.00, H 3.78, N, 11.66. Found: C 69.88; H, 3.64; N, 11.46.
2JC,F = 31.3 Hz), 131.16, 132.08 (d, JC,F = 34.0 Hz), 133.13,
2
138.77, 141.26, 156.13, 157.62, 158.47 ppm. 19F NMR (470.5
MHz, CDCl3) 98.85 (s, CF3), 102.30 (s, CF3) ppm. GC tR 20.64
min; MS m/z (rel intensity): 374 (М+, 100). Anal. Calcd for
C16H8F6N2S (374.31): C 51.34, H 2.15, N, 7.48. Found: C 51.18;
H, 2.35; N, 7.32.
4.3.15. 5-(4-Fluorophenyl)-4-(furan-2-
yl)pyrimidine (7d).
4.3.11. 5-(3,5-Bis-trifluoromethylphenyl)-4-(thien-
2-yl)pyrimidine (6k).
It has been obtained by the reaction of 5-bromo-4-(furan-2-
yl)pyrimidine (9) with 4-fluorobenzeneboronic (2c) acid. Yield
1
It has been obtained by the reaction of 5-bromo-4-(thien-2-
yl)pyrimidine (8) with 3,5-bis(trifluoromethyl)benzeneboronic
(2k) acid. Yield (see Table 3, entry 11), white solid; m.p. 145-
(see Table 3, entry 15), yellow oil. H NMR (500 MHz, CDCl3):
δ = 6.35-6.42 (m, 2H, H-3" and H-4"), 7.16-7.22 (m, 2H, H-5"
and Ph), 7.29-7.35 (m, 2H, Ph), 7.47-7.50 (m, 1H, Ph), 8.57 (s,
H, H-4), 9.20 (s, 1H, H-2) ppm. 13C NMR (126 MHz, CDCl3): δ
1
147 °C. H NMR (500 MHz, CDCl3): δ = 6.85 (dd, 1H, J = 3.8 ,
4
3
0.8 Hz, H-3"), 6.94 (dd, 1H, J = 5.1 , 3.8 Hz, H-4"), 7.49 (dd, 1H,
J = 5.1, 0.8 Hz, H-5"), 7.87 (s, 2H, H-2' and H-6'), 8.03 (s, 1H,
H-4'), 8.58 (s, 1H, H-6), 9.20 (s, 1H, H-2) ppm. 13C NMR (126
= 112.06, 115.94 (d, JC,F = 3.3 Hz), 129.74, 130.80 (d, JC,F =
4
8.2 Hz), 132.08 (d, JC,F = 3.4 Hz), 145.10, 150.29, 152.47,
157.69, 158.32, 161.99, 163.97 ppm. 19F NMR (470.5 MHz,
CDCl3) 49.02 (tt, 1F, J = 8.6, 5.3 Hz) ppm. GC tR 20.41 min; MS
m/z (rel intensity): 240 (М+, 100). Anal. Calcd for C14H9FN2O
(240.24): C 70.00, H 3.78, N, 11.66. Found: C 70.05; H, 3.68; N,
11.68.
3
4
MHz, CDCl3): δ = 122.78 (dt, JC,F = 7.4 Hz, JC,F = 3.7 Hz),
1
4
122.91 (d, JC,F = 273.0 Hz), 128.04, 128.23, 129.74 (d, JC,F
=
2
3.0 Hz), 130.84, 131.36, 132.78 (d, JC,F = 33.8 Hz), 138.54,
140.60, 156.42, 158.02, 158.43 ppm. 19F NMR (470.5 MHz,
CDCl3) 98.82 (s, 6F, CF3) ppm. GC tR 20.21 min; MS m/z (rel
intensity): 374 (М+, 100). Anal. Calcd for C16H8F6N2S (374.31):
C 51.34, H 2.15, N, 7.48. Found: C 51.32; H, 1.92; N, 7.30.
4.3.16. 5-(2,4-Difluorophenyl)-4-(furan-2-
yl)pyrimidine (7e).
It has been obtained by the reaction of 5-bromo-4-(furan-2-
4.3.12. 4-Furan-2-yl-5-phenylpyrimidine (7a).
yl)pyrimidine (9) with 2,4-difluorobenzenboronic (2e) acid.
1
Yield (see Table 3, entry 16), beige solid; m.p. 83-85 °C. H
It has been obtained by the reaction of 5-bromo-4-(furan-2-
NMR (500 MHz, CDCl3): δ = 6.44 (dd, 1H, J = 3.5, 1.7 Hz, H-
4"), 6.72 (d, 1H, J = 3.5 Hz, H-3"), 6.96 (td, 1H, J = 9.2, 2.5 Hz,
H-6'), 7.04 (td, 1H, J = 8.0, 1.7 Hz, H-5'), 7.30 (td, 1H, J = 8.4,
1.7 Hz, H-5'), 7.45 (d, 1H, J = 1.0 Hz, H-4"), 8.58 (s, 1H, H-6),
9.21 (s, 1H, H-2) ppm. 13C NMR (126 MHz, CDCl3): δ = 104.45
yl)pyrimidine (9) with phenylboronic (2a) acid. Yield (see Table
3, entry 12), white solid; m.p. 64-66 °C. H NMR (500 MHz,
1
CDCl3): δ = 6.26 (d, 1H, H-3", J = 3.5 Hz), 6.35 (dd, 1H, H-4", J
= 3.5, 1.7 Hz), 7.33-7.35 (m, 2H, H-5"and Ph), 7.49-7.50 (m, 4H,
Ph), 8.58 (s, 1H, H-6), 9.21 (s, 1H, H-2) ppm. 13C NMR (126
MHz, CDCl3): 111.99, 116.04, 128.65, 128.91, 130.77, 136.09,
144.95, 150.18, 152.36, 157.56, 158.16 ppm. GC tR 20.53 min;
2
2
(t, JC,F = 25.5 Hz), 111.91 (dd, JC,F = 21.4 Hz, 4JC,F = 3.8 Hz),
2
3
112.19, 115.21, 120.14 (dd, JC,F = 16.6 Hz, JC,F = 4.0 Hz),

2
4
123.51, 131.83 (dd, JC,F = 9.6 Hz, JC,F = 4.3 Hz), 145.37,
H-4"), 6.56 (dd, 1H, J = 3.5 Hz, H-3"), 7.46 (dd, 1H, J = 1.7, 0.8
Hz, H-5"), 7.48 (d, 2H, J = 8.0 Hz, H-2' and H-6'), 7.76 (d, 2H, J
= 8.0 Hz, H-3' and H-5'), 8.58 (s, 1H, H-6), 9.22 (s, 1H, H-2)
ppm. 13C NMR (126 MHz, CDCl3): 112.18, 116.00, 123.94 (d,
1
150.83, 153.12, 158.13, 158.96, 160.25 (dd, JC,F = 250.8 Hz,
2JC,F = 12.1 Hz), 163.43 (dd, JC,F = 251.2 Hz, JC,F = 11.6 Hz)
ppm. 19F NMR (470.5 MHz, CDCl3) 52.06 (q, 1F, J = 8.8 Hz),
53.45 (qd, 1F, J = 8.2, 6.4 Hz) ppm. GC tR 19.83 min; MS m/z
(rel intensity): 258 (М+, 100). Anal. Calcd for C14H8F2N2O
(258.23): C 65.12, H 3.12, N, 10.85. Found: C 65.00; H, 3.01; N,
10.65.
1
2
4
1JC,F = 272.4 Hz), 125.73 (q, JC,F = 3.7 Hz), 129.24, 129.51,
2
130.80 (q, JC,F = 32.8 Hz), 139.98, 145.34, 150.33, 152.19,
158.00, 158.21 ppm. 19F NMR (470.5 MHz, CDCl3) 99.13 (s,
CF3) ppm. GC tR 20.07 min; MS m/z (rel intensity): 290 (М+,
100). Anal. Calcd for C15H9F3N2O (290.25): C 62.07, H 3.13, N,
9.65. Found: C 62.20; H, 3.28; N, 9.54.
4.3.17. 5-(3,5-Difluorophenyl)-4-(furan-2-
yl)pyrimidine (7f).
4.3.21. 5-(2,4-Bis-trifluoromethylphenyl)-4-(furan-
2-yl)pyrimidine (7j).
It has been obtained by the reaction of 5-bromo-4-(furan-2-
yl)pyrimidine (9) with 3,5-difluorobenzenboronic (2f) acid. Yield
(see Table 3, entry 17), white solid; m.p. 92-93 °C. 1H NMR (500
MHz, DMSO-d6): δ = 6.62 (dd, 1H, J = 3.5, 1.7 Hz, H-4"), 6.89
(d, 1H, J = 3.5 Hz, H-3"), 7.19-7.25 (m, 2H, Ph), 7.38 (tt, 1H, J =
9.5, 2.3 Hz, H-4'), 7.79 (d, 1H, J = 1.0 Hz, H-5"), 8.72 (s, 1H, H-
6), 9.19 (s, 1H, H-2) ppm. 13C NMR (126 MHz, DMSO-d6): δ =
It has been obtained by the reaction of 5-bromo-4-(furan-2-
yl)pyrimidine (9) with 2,4-bis(trifluoromethyl)benzeneboronic
(2j) acid. Yield (see Table 3, entry 21), beige solid; m.p. 102-105
1
°C. H NMR (500 MHz, CDCl3): δ = 6.42 (dd, 1H, J = 3.5, 1.7
Hz, H-4"), 6.74 (dd, 1H, J = 3.5 Hz, H-3"), 7.32 (dd, 1H, J = 1.0
Hz, H-5"), 7.49 (d, 1H, J = 8.0 Hz, H-6'), 7.92 (d, 1H, J = 8.0 Hz,
H-5'), 8.11 (s, 1H, H-3'), 8.53 (s, 1H, H-6), 9.24 (s, 1H, H-2)
ppm. 13C NMR (126 MHz, CDCl3): δ = 112.22, 115.73, 121.96
2
2
103.84 (t, JC,F = 25.8 Hz), 112.43, 112.70 (dd, JC,F = 20.0 Hz,
2
3JC,F = 6.3 Hz), 115.49, 127.81, 139.56 (t, JC,F = 10.5 Hz),
1
146.24, 150.32, 151.29, 157.65, 158.44, 162.22 (dd, JC,F
=
2
2
246.6 Hz, 2JC,F = 13.6 Hz) ppm. 19F NMR (470.5 MHz, DMSO-
d6) 52.90-52.97 (m, 2F) ppm. GC tR 19.56 min; MS m/z (rel
intensity): 258 (М+, 100). Anal. Calcd for C14H8F2N2O (258.23):
C 65.12, H 3.12, N, 10.85. Found: C 64.94; H, 2.94; N, 10.72.
(d, JC,F = 37.2 Hz), 124.14 (d, JC,F = 35.4 Hz), 123.65 (dd, 3JC,F
3
2
= 8.6 Hz, JC,F = 4.5 Hz), 125.74, 128.66, 130.33 (d, JC,F
=
2
31.2 Hz), 131.45 (d, JC,F = 33.8 Hz), 132.69, 138.89, 145.69,
150.78, 152.20, 157.75, 158.53 ppm. 19F NMR (470.5 MHz,
CDCl3) 98.89 (s, CF3), 102.33 (s, CF3) ppm. GC tR 18.40 min;
MS m/z (rel intensity): 358 (М+, 100). Anal. Calcd for
C16H8F6N2O (358.25): C 53.64, H 2.25, N, 7.82. Found: C 53.60;
H, 2.22; N, 7.75.
4.3.18. 4-Furan-2-yl-5-(2-
trifluorometylphenyl)pyrimidine (7g).
It has been obtained by the reaction of 5-bromo-4-(furan-2-
yl)pyrimidine (9) with 2-(trifluoromethyl)benzeneboronic (2g)
acid. Yield (see Table 3, entry 18), beige solid; m.p. 77-79 °C.
1H NMR (500 MHz, CDCl3): δ = 6.26 (dd, 1H, J = 3.5, 0.5 Hz,
H-3"), 6.34 (dd, 1H, J = 3.5, 1.7 Hz, H-4"), 7.32 (d, 1H, J = 6.9
Hz, H-6'), 7.40 (dd, 1H, J = 1.7, 0.5 Hz, H-5"), 7.65 (m, 2H, H-4'
and H-5'), 7.84-7.89 (m, 1H, H-3'), 8.55 (s, 1H, H-6), 9.23 (s, 1H,
H-2) ppm. 13C NMR (126 MHz, CDCl3): δ = 112.05, 115.69,
4.3.22. 5-(3,5-Bis-trifluoromethylphenyl)-4-(furan-
2-yl)pyrimidine (7k).
It has been obtained by the reaction of 5-bromo-4-(furan-2-
yl)pyrimidine (9) with 3,5-bis(trifluoromethyl)benzeneboronic
(2k) acid. Yield (see Table 3, entry 22), white solid; m.p. 102-
1
104 °C. H NMR (500 MHz, DMSO-d6): δ = 6.64 (dd, 1H, J =
1
3
123.62 (d, JC,F = 274.0 Hz), 126.55 (q, JC,F = 5.0 Hz), 127.33,
3.5, 1.7 Hz, H-4"), 7.06 (dd, 1H, J = 3.5, 0.7 Hz, H-3"), 7.69 (dd,
2
128.90, 129.26 (q, JC,F = 30.3 Hz), 131.68, 132.07, 134.68 (d,
1H, J = 1.7, 0.7 Hz, H-5"), 8.19 (s, 2H, H-2' and H-6'), 8.22 (s,
4JC,F = 2.0 Hz), 145.24, 150.48, 152.46, 157.91 (d, JC,F
=
1H, H-4'), 8.83 (s, 1H, H-6), 9.23 (s, 1H, H-2) ppm. 13C NMR
4
3
1.5 Hz), 158.14 ppm. 19F NMR (470.5 MHz, CDCl3) 102.65 (s,
CF3) ppm. GC tR 19.74 min; MS m/z (rel intensity): 290 (М+,
100). Anal. Calcd for C15H9F3N2O (290.25): C 62.07, H 3.13, N,
9.65. Found: C 62.23; H, 3.23; N, 9.60.
(126 MHz, DMSO-d6): δ = 112.51, 115.43, 121.86 (dt, JC,F
=
4
1
7.6 Hz, JC,F = 3.8 Hz), 123.23 (d, JC,F = 272.9 Hz), 126.89,
129.82-130.61 (m), 138.73, 146.23, 150.72, 151.38, 157.86,
159.04 ppm. 19F NMR (470.5 MHz, DMSO-d6) 101.38 (s, 6F,
CF3) ppm. GC tR 18.31 min; MS m/z (rel intensity): 358 (М+,
100). Anal. Calcd for C16H8F6N2O (358.25): C 53.64, H 2.25, N,
7.82. Found: C 53.51; H, 2.39; N, 7.74.
4.3.19. 4-Furan-2-yl-5-(3-
trifluorometylphenyl)pyrimidine (7h).
It has been obtained by the reaction of 5-bromo-4-(furan-2-
yl)pyrimidine (9) with 3-(trifluoromethyl)benzeneboronic (2h)
acid. Yield (see Table 3, entry 19), pale yellow solid; m.p. 67-67
°C. 1H NMR (500 MHz, DMSO-d6): δ = 6.61 (dd, 1H, J = 3.2,
1.5 Hz, H-4"), 6.82 (d, 1H, J = 3.2 Hz, H-3"), 7.73-7.86 (m, 4H,
H-5" and Ph), 7.85 (d, 1H, J = 7.3 Hz, Ph), 8.75 (s, 1H, H-6),
4.4. General SNH-procedure for the synthesis of 5-(fluoroaryl)-4-
(hetero)-arylpyrimidines 6d,i,j and 7 d,i,j.
Thiophene (4) (160 μL, 2.0 mmol) [or furan (5) (145 μL, 2.0
mmol)] was added to
a solution of corresponding 5-
(fluoroaryl)pyrimidine 3d [3i or 3j] (1.0 mmol) in CF3COOH (5
mL). The reaction mixture was stirred at room temperature for 24
h and the solvents evaporated. A solution of KOH (224 mg, 4.0
mmol, 4 equiv.) and K3[Fe(CN)6] (658 mg, 2.0 mmol, 2 equiv.)
in water (10 mL) was added to the residue. The resulting mixture
was stirred for 24 h at room temperature; the semisolid formed
was filtered off, washed with H2O and air dried. The semisolid
was extracted with EtOAc and the organic solution was
concentrated in vacuo. The crude residue was purified by flash
column chromatography on silica gel (hexane/ethyl acetate, 1:2)
to afford the desired SNH-products (6d,i,j or 7d,i,j).
9.21(s, 1H, H-2) ppm. 13C NMR (126 MHz, DMSO-d6)3: δ =
1
112.38, 115.29, 124.03 (d, JC,F = 272.4 Hz), 124.99 (dd, JC,F
=
7.2 Hz, 4JC,F = 3.5 Hz), 125.79 (q, 3JC,F = 3.7 Hz), 128.45, 129.27
2
(q, JC,F = 32.0 Hz), 129.55, 133.27, 137.04, 146.04, 150.56,
151.42, 157.53, 158.74 ppm. 19F NMR (470.5 MHz, DMSO-d6)
101.51 (s, CF3) ppm. GC tR 19.82 min; MS m/z (rel intensity):
290 (М+, 100). Anal. Calcd for C15H9F3N2O (290.25): C 62.07, H
3.13, N, 9.65. Found: C 62.05; H, 3.27; N, 9.81.
4.3.20. 4- Furan-2-yl-5-(4-
trifluorometylphenyl)pyrimidine (7i).
It has been obtained by the reaction of 5-bromo-4-(furan-2-
yl)pyrimidine (9) with 4-(trifluoromethyl)benzeneboronic (2f)
acid. Yield (see Table 3, entry 20), white solid; m.p. 100-102 °C.
1H NMR (500 MHz, CDCl3): δ = 6.42 (dd, 1H, J = 3.5, 1.7 Hz,
4.5. Antimycobacterial assay.
To evaluate the inhibitory efficiency of molecules on
Mycobacterium tuberculosis (MTB), M. tuberculosis H37Rv,

Nenajdenko (Ed.), Fluorine in Heterocyclic Chemistry, Springer
International Publishing, New York, 2014, p. 59-109.
V.N. Charushin, E.V., Nosova, G.N. Lipunova, O.N. Chupakhin,
O.N.. Fluoroquinolones: Synthesis and Application, Fizmatlit,
Moscow, 2013.
which is susceptible to all classical antituberculosis drugs, was
used. The minimal inhibitory concentration (MIC) for M.
tuberculosis H37Rv for each compound was determined by a
micro broth dilution method. All molecules tested were dissolved
in dimethylsulfoxide and their 1/2 dilutions were prepared in 5
mL tubes using Löwenstein-Jensen medium. A few colonies
from freshly grown M. tuberculosis H37Rv were suspended in
Löwenstein-Jensen medium to obtain 1.0 McFarland turbidity
and diluted ten times using the same medium and the tubes were
incubated at 37 °C medium with a different concentration of the
tested molecule and to a positive control tube containing only
clear growth medium. After 24 hours the tubes were placed in a
vertical position and the free edge of the buried 0.3 mL of the
substance in the test compounds concentrations: 12.5, 6.2, 3.1,
1.5, 0.7, 0.37, 0.15 μg/mL. The tubes were then placed in an
thermostat at a temperature of 37 °C and incubated for 10 days.
Growth estimate for the MTB were determined by standard
methods, where the appearance of zones of growth retardation
MTB (over 10 mm) indicated the presence of tuberculostatic
properties in concentration of the compounds under study.
Penetration size stunting MTB (in mm) is proportional to the
degree of tuberculostatic activity. Growth delay of 100 mm or
more is considered as a complete growth inhibition MTB. The
multi-drug-resistant (MDR) tuberculosis strain have been isolated
from tuberculosis patients in Ural Research Institute for
Phthisiopulmonology (Russia). The minimal inhibitory
concentrations against M. avium, M. terrae, and MDR
tuberculosis strains were evaluated similarly.
7.
8.
V.N. Charushin, G.N. Lipunova, E.V. Nosova, O.N. Chupakhin,
Fluoroquinolones: Synthesis and Application, in: V. Nenajdenko
(Ed.), Fluorine in Heterocyclic Chemistry, Springer International
Publishing, New York, 2014, p. 111-179.
9.
Ismail, F. M. D. J. Fluorine Chem. 2002, 118, 27-33.
10. Long, T. E.; Turos, E.; Konaklieva, M. I.; Blum, A. L.; Amry,
A.; Baker, E. A.; Suwandi, L. S.; McCain, M. D.; Rahman, M.
F.; Dickey, S.; Lim, D.V. Bioorg. Med. Chem. 2003, 11, 1859-
1863.
11. Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013-1029.
12. Kamal, A.; Azeeza, S.; Malik, M. S.; Shaik, A. A.; Rao, M. V. J.
Pharm. Pharmaceut. 2008, 11, 56s-80s.
13. Minovski, N.; Vračko, M.; Šolmajer, T. Mol. Divers. 2011, 15,
417-426.
14. Asif, M. Chemistry International 2015, 1, 134-163.
15. Cremades, R.; Rodrígues, J. C.; García-Pachón, E.; Galiana, A.;
Ruiz-Garcí, M.; López, P.; Royo, G. J. Antimicrob. Chemother.
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4.6. Evaluation of acute toxicity in vivo.
16. Smart, B. E. J. Fluorine Chem. 2001, 109, 3-11.
17. Bonacorso, H. G.; Wentz, A. P.; Lourega, R. V.; Cechinel, C. A.;
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1072.
All experimental protocols were carried out in accordance
with the standard protocol approved by the Committee of the
Ethical Use of Animals of the Ural Research Institute for
Phthisiopulmonology
(CEUA/URIP).
The
synthesized
compounds were evaluated for their approximate LD50 in white
healthy mice (17 - 20 g body weight) divided into 3 groups of 5
animals each for testing of each compound [37,38]. Toxicity tests
were carried out via a single peroral administration of compound
in a 1% starch aqueous solution. The volume introduced did not
exceed 0.5 mL for mice. The observation period was 14 days.
The median lethal doses LD50 were used as the criteria of
toxicity.
18. Nalavde, Y. M.; Joshi, V.; Indian J. Chem. 2000, 39B, 634-637.
19. El-Sharief, M. A. M. Sh.; Moussa, Z.; El-Sharief, A. M. Sh. J.
Fluorine Chem. 2011, 132, 596-611.
20. Lo, K.; Cornell, H.; Nicoletti, G.; Jackson, N.; Hügel, H. Appl.
Sci. 2012, 2, 114-128.
21. Makki, M. S. I. T.; Abdel-Rahman, R. M.; Faidallah, H. M.;
Khan, K.A. J. Chem. 2013, Article ID 819462, 8 pages.
22. Esfahanizadeh, M.; Omidi, K.; Kauffman, J.; Gudarzi, A.;
Zahedani, S. S.; Amidi, S.; Kobarfard, F. Iranian J. Pharm. Res.
2014, 13, 115-126.
Acknowledgments
The research was financially supported by the Russian
Science Foundation (Project No. 15-13-00077).
23. Romero, A. H.; Salazar, J.; López, S.E. J. Fluorine Chem. 2015,
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Synthesis and evaluation of antitubercular
activity of fluorinated 5-aryl-4-(hetero)aryl
substituted pyrimidines
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E. V. Verbitskiy, S.A. Baskakova, M. A. Kravchenko, S. N. Skornyakov,
G. L. Rusinov, O. N. Chupakhin, V. N. Charushin
I. Postovsky Institute of Organic Synthesis, S. Kovalevskoy Str., 22, 620990 Ekaterinburg, Russia