Synthesis of 5-(het)aryl- and 4,5-di(het)aryl-2-(thio)morpholinopyrimidines from 2-chloropyrimidine via SN H and cross-coupling reactions

Article abstract of DOI:10.1007/s11172-014-0602-y

It has been shown that various combinations of nucleophilic aromatic substitution of hydrogen (S_N ^H), S_N ^ipso and the microwave-assisted Suzuki cross-coupling reactions are a versatile method for the synthesis o

Full text of DOI:10.1007/s11172-014-0602-y

Russian Chemical Bulletin, International Edition, Vol. 63, No. 6, pp. 1350—1358, June, 2014
1350
Synthesis of 5ꢀ(het)arylꢀ and 4,5ꢀdi(het)arylꢀ2ꢀ(thio)morpholinopyrimidines
H
from 2ꢀchloropyrimidine via SN and crossꢀcoupling reactions*
E. M. Cheprakova,a E. V. Verbitskiy,a,b M. A. Ezhikova,a M. I. Kodess,a M. G. Pervova,a P. A. Slepukhin,a
M. S. Toporova,a M. A. Kravchenko,c I. D. Medvinskiy,c G. L. Rusinov,a,b and V. N. Charushina,b
aI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
20 ul. Akademicheskaya/22 ul. S. Kovalevskoy, 620990 Ekaterinburg, Russian Federation.
Eꢀmail: Verbitsky@ios.uran.ru
bUral Federal University named after the First President of Russia B. N. Yeltsin,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation
cUral Research Institute for Phthisiopulmonology,
50 ul. XXII Parts’ezda, 620039 Ekaterinburg, Russian Federation
It has been shown that various combinations of nucleophilic aromatic substitution of hydroꢀ
ipso
gen (SNH), SN
and the microwaveꢀassisted Suzuki crossꢀcoupling reactions are a versatile
method for the synthesis of 5ꢀ(het)arylꢀ2ꢀ(thio)morpholinopyrimidine and 4,5ꢀdi(het)arylꢀ2ꢀ
(thio)morpholinopyrimidine derivatives. All synthesized pyrimidines were found to be active in
micromolar concentrations in vitro against Mycobacterium tuberculosis H37Rv.
Key words: pyrimidines, morpholine, thiomorpholine, crossꢀcoupling, microwave irradiaꢀ
tion, nucleophilic aromatic substitution of hydrogen, antituberculosis activity.
Scheme 1
Pyrimidines belong to an important class of heteroꢀ
aromatic compounds that have found wide applications as
effective pharmaceuticals, agrochemicals, and organic maꢀ
terials.1 For instance, 5ꢀ(het)arylꢀ2ꢀdialkylaminoꢀ and
4,5ꢀdi(het)arylꢀ2ꢀdialkylaminopyrimidines bearing either
morpholine or thiomorpholine moiety at the C(2) atom
have attracted great interest due to the wide range of bioꢀ
logical activities, e.g., herbicidal2 and antimicrobic3 activꢀ
ities. These compounds can affect the activities of specific
proteins, e.g., the activity of atonal homolog 1 (ATOHꢀ1)4
regulating the DNAꢀtemplated transcription and neuron
differentiation, as well as the epidermal growth factor
(EGF),5 which promotes the cell growth and epidermal
cell differentiation. They also can be used in treatment of
heurodegenerative diseases, cognitive disorders, and Alzꢀ
heimer´s disease.6
Condensation of (thio)morpholinocarboxamidines 1
with 1,2ꢀdihetarylꢀ3ꢀdimethylaminopropenones 2 results
in 2ꢀmorpholineꢀsubstituted pyrimidines 3 and their thio
analogs (Scheme 1).6
It has been shown earlier that the combination of nucleoꢀ
philic aromatic substitution of hydrogen (SNH) and microꢀ
waveꢀassisted Suzuki crossꢀcoupling reactions is an effiꢀ
cient pathway to 4,5ꢀdi(het)arylꢀsubstituted pyrimidines.7,8
The aim of the present work was to investigate the new
synthetic procedures towards 5ꢀ(het)arylꢀ and 4,5ꢀdi(het)ꢀ
X = O, S, CH, NAlk
arylꢀ2ꢀ(thio)morpholinopyrimidines from available
2ꢀchloropyrimidine using various combinations of the
SNipso or SNH and Suzuki crossꢀcouplings reactions.
Initially, the replacement of chlorine in 2ꢀchloroꢀ
pyrimidine (4) by the morpholine (5a) and thioꢀ
morpholine (5b) moieties and subsequent mild bromꢀ
ination of thus obtained 2ꢀ(thio)morpholineꢀsubstitutꢀ
ed pyrimidines 6a,b with bromine (20—25 C, CH2Cl2)
gives 5ꢀbromoꢀ2ꢀ(thio)morpholinopyrimidines 7a,b
(Scheme 2). Structures of compounds 7a,b were unamꢀ
biguously established by NMR spectroscopy and elemenꢀ
* Dedicated to Academician of the Russian Academy of Sciences
O. N. Chupakhin on the occasion of his 80th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1350—1358, June, 2014.
1066ꢀ5285/14/6306ꢀ1350 © 2014 Springer Science+Business Media, Inc.

4,5ꢀDi(het)arylꢀ2ꢀ(thio)morpholinopyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
1351
Scheme 2
Scheme 3
tal analysis and confirmed by Xꢀray diffraction of comꢀ
pound 7a (Fig. 1).
5ꢀBromoꢀ2ꢀ(thio)morpholinopyrimidines 7a,b were
further involved in the Suzuki crossꢀcoupling reaction with
arylboronic acids 8—11. Reactions of compounds 7a,b
with 3ꢀnitrophenylboronic acid (8) result in 5ꢀ(3ꢀnitroꢀ
phenyl)ꢀ2ꢀ(thio)morpholinopyrimidines 12a,b in the
yields of ~10% (Scheme 3). Structures of compounds 12a,b
were confirmed by Xꢀray diffraction of 12a (Fig. 2).
The conditions of these crossꢀcouplings reactions were
optimized using different combinations of palladium catꢀ
alysts (Pd(PPh3)4 or Pd(OAc)2) and phosphine ligands
(PPh3 or PCy3, Cy is cyclohexyl) (Table 1). According to
data from Table 1, the use of Pd(PPh3)4 as a catalyst and a
THF—H2O mixture in a 3 : 4 ratio as a solvent are optimal
reaction conditions (see Table 1, entries 3 and 6). It should
be noted that the use of palladium(II) acetate in the presꢀ
ence of PPh3 or PCy3 gives the comparable yields but the
content of byꢀproducts is higher.
Reagents and conditions: catalyst (Pd(OAc)2—PPh3/PCy3 or
Pd(PPh3)4), K2CO3, solvent (DMF or THF—H2O), microwave
irradiation, 20 min.
Ar =
(8, 12),
(9, 13),
(10, 14),
(11, 15)
Similar reactions of 5ꢀbromoꢀ2ꢀ(thio)morpholinoꢀ
pyrimidines 7a,b with 2ꢀthienylboronic (9), 2ꢀbenzo[b]ꢀ
thienylboronic (10), and 3ꢀbenzo[b]thienylboronic (11)
acids carried out under optimal conditions led to novel
X = O (a), S (b)
5ꢀhetarylꢀ2ꢀ(thio)morpholinopyrimidines 13—15 in the
yields of 40—60% (Scheme 3, Table 2).
The possibility to involve the synthesized compounds
into the nucleophilic substitution of hydrogen was studied
on the example of compounds 12a,b (Scheme 4). Accordꢀ
ing to GC/MS data, reaction mixtures obtained by stirꢀ
ring of 5ꢀ(3ꢀnitrophenyl)ꢀ2ꢀ(thio)morpholinopyrimidꢀ
ines 12a,b with thiophene (16) in CF3COOH for 3 days
followed by oxidation with aqueous K3Fe(CN)6 (2 equiv.)
N(1)
C(6)
C(5)
C(1)
C(3)
O(1)
C(2)
N(2)
Br(1)
C(4)
C(7)
C(8)
N(3)
H
contain small amounts of the SN products, namely,
2ꢀmorpholinoꢀ5ꢀ(3ꢀnitrophenyl)ꢀ4ꢀ(2ꢀthienyl)pyrimidine
(17a, 14%) and 5ꢀ(3ꢀnitrophenyl)ꢀ4ꢀ(2ꢀthienyl)ꢀ2ꢀthioꢀ
morpholinopyrimidine (17b, 4%) (Table 3).
Fig. 2. Crystal structure of 7a.
Prolongation of the reaction time up to 1 month does
not result in the noticeable increase in content of the tarꢀ
get products 17a,b in the reaction mixture sufficient for
their preparative isolation (see Table 3). 2ꢀMorpholinoꢀ5ꢀ
(3ꢀnitrophenyl)ꢀ4ꢀ(2ꢀthienyl)pyrimidine (17a) was isolatꢀ
ed by preparative HPLC in 21% yield. Besides, the startꢀ
ing 2ꢀmorpholinoꢀ5ꢀ(3ꢀnitrophenyl)pyrimidine (12a) was
recovered in 55% yield from the reaction mixture.
O(2)
N(2)
C(13)
N(1)
C(14)
O(1)
C(6)
C(8)
C(9)
O(3)
C(2)
C(10)
N(4)
C(5)
C(7)
C(12)
H
C(3)
C(11)
C(4)
C(1)
Apparently, low yields of compounds 17a,b in SN
N(3)
reactions can be explained by electronꢀdonating character
of the (thio)morpholinyl substituent at the position 2 of
Fig. 2. Crystal structure of 12a.

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Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
Cheprakova et al.
Table 1. GCꢀMS data on compositions of the reaction mixtures obtained by the reactions of 3ꢀnitrophenylboronic acid
(8) with 5ꢀbromoꢀ2ꢀ(thio)morpholinopyrimidines 7a,b under different reaction conditions*
Entry
Reaction
Catalytic system
Solvent
DMF
Reaction mixture composition**
1
7a + 8
Pd(OAc)2/PPh3 (10 mol.%)
7a (20.11), 12a (32.10),
Ph3PO (30.65), impurities (17.14)
7a (3.15), 12a (26.12),
PCy3 (14.91), impurities (55.8)
7a (1.9), 12a (38.5),
Ph3PO (28.2), impurities (31.4)
7b (3.62), 12b (32.67),
Ph3PO (34.14), impurities (29.57)
7b (4.17), 12b (42.02),
2
3
4
5
6
7a + 8
7a + 8
7b + 8
7b + 8
7b + 8
Pd(OAc)2/PCy3 (10 mol.%)
Pd(PPh3)4
DMF
THF/H2O
DMF
Pd(OAc)2/PPh3 (10 mol.%)
Pd(OAc)2/PCy3 (10 mol.%)
Pd(PPh3)4
DMF
PCy3 (14.73), impurities (39.08)
7b (6.6), 12b (73.5),
THF/H2O
Ph3PO (9.5), impurities (10.4)
* Reaction time 20 min, temperature 185 C, content of the PdII derivative in the catalytic system 5 mol.%.
** Component contents (%) are given in parenthesis.
Scheme 4
Table 2. GCꢀMS data on compositions of the reaction mixtures
and yields of 5ꢀ(het)arylꢀ2ꢀ(thio)morpholinopyrimidines 13—15
Entry
Reaction
Product
(Yield (%))
Reaction mixture
composition*
1
7a + 9
13a (44)
14a (40)
15a (53)
13b (41)
14b (40)
15b (57)
7a (15.8),
Ph3PO (14.1),
13a (42.7),
impurities(27.4)
7a (2.9),
Ph3PO (21.1),
14a (52.3),
impurities (23.7)
7a (3.5),
Ph3PO (7.4),
15a (73.5),
impurities (15.6)
7b (12.3),
Ph3PO (18.9),
13b (49.1),
impurities (19.7)
7b (13.6),
2
3
4
5
6
7a + 10
7a + 11
7b + 9
Reagents: 1) CF3COOH, 2) K3Fe(CN)6, KOH, H2O.
X = O (a), S (b)
7b + 10
7b + 11
Ph3PO (15.9),
14b (54.1),
impurities (16.4)
7b (4.9),
the starting pyrimidines 12a,b. This leads to decrease in
electrophilicity of the pyrimidine cycle due to increase in
an impact of the resonance structure B deactivating the
pyrimidine cycle towards nucleophilic attack (Scheme 5).
Since attempts of acid activation of pyrimidines under
SNH reaction conditions failed, these reactions were studꢀ
ied under nucleophilic activation conditions (Scheme 6).
5ꢀBromoꢀ2ꢀ(thio)morpholinopyrimidines 7a,b were inꢀ
volved in the reaction with 2ꢀthienyllithium (18) generatꢀ
ed in situ by treatment of thiophene (16) with butyllithiꢀ
um. This reaction gave the intermediate H adducts 19a,b,
which further were oxidized with the K3Fe(CN)6/KOH
aqueous solution. Compositions of the reaction mixtures
Ph3PO (6.2),
15b (73.9),
impurities (15)
* Component contents (%) are given in parenthesis.
were determined by GCꢀMS (Table 4). Conversions of the
starting pyrimidines 7a,b in SNH reactions under described
conditions were nearly 100%. Note that along with target
5ꢀbromoꢀ4ꢀ(2ꢀthienyl)ꢀ2ꢀ(thio)morpholinopyrimidines
20a,b, the reaction involving 5ꢀbromoꢀ2ꢀmorpholinoꢀ
pyrimidine (7a) produced byꢀproduct, 5ꢀbromoꢀ4ꢀbutylꢀ

4,5ꢀDi(het)arylꢀ2ꢀ(thio)morpholinopyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
1353
Table 3. GCꢀMS data on compositions of the reaction mixtures
obtained by the reactions of 5ꢀ(3ꢀnitrophenyl)ꢀ2ꢀ(thio)morꢀ
pholinopyrimidines 12a,b with thiophene (16) at different duraꢀ
tion of treatment with TFA and subsequent oxidation
2ꢀmorpholinopyrimidine (21a), due to the reaction with
butyllithium; while in the reaction involving 5ꢀbromoꢀ2ꢀ
thiomorpholinopyrimidine (7b), elimination of HBr gave
rise to the product of kine substitution of hydrogen, 4ꢀ(2ꢀthiꢀ
enyl)ꢀ2ꢀthiomorpholinopyrimidine (22b) (see Table 4).
Moreover, GCꢀMS indicated that the reaction mixture
obtained by the reaction of 5ꢀbromoꢀ2ꢀmorpholinopyrꢀ
imidine (7a) with 2ꢀthienyllithium (18) contained comꢀ
pound 23 (m/z 489 [M]+) together with unidentified imꢀ
purities. Compound 23 was isolated by preparative HPLC
Entry
Reaction
Dutarion of
treatment
Reaction mixture
composition*
CF3COOH
1
2
3
4
12a + 16
12a + 16
12b + 16
12b + 16
3 days
1 month
3 days
12a (86), 17a (14)
12a (71), 17a (29)
12b (96), 17b (4)
12b (87), 17b (13)
1
in the yield of 3%. According to H, 13C, and 2D NMR
1 month
experiments, compound 23 was identified as bromoꢀ2,2´ꢀ
dimorpholinoꢀ4´ꢀ(2ꢀthienyl)ꢀ4,5´ꢀbipyrimidine.
* Component contents (%) are given in parenthesis.
On the next step of our research, bromoꢀsubstituted
pyrimidines 20a,b were involved in microwaveꢀassisted
Scheme 5
H
 ꢀAdduct
NuH is nucleophile.
HA is acid.
Scheme 6
Reagents and conditions: i. BuLi, Et2O, 0 C; ii. 7a,b, Et2O, –20 C; iii. K3Fe(CN)6, KOH, H2O.
X = O (a), S (b)

1354
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
Cheprakova et al.
Table 4. GCꢀMS data on compositions of the reaction mixtures
and product yields in the reactions of 5ꢀbromoꢀ2ꢀ(thio)morꢀ
pholinopyrimidines (7a,b) with 2ꢀthienyllithium (18) and subseꢀ
quent oxidation
Table 5. GCꢀMS data on compositions of the reaction mixtures
and product yields in the reactions of 5ꢀ(het)arylꢀ4ꢀ(2ꢀthienyl)ꢀ
2ꢀ(thio)morpholinopyrimidines 17a,b and 24a,b
Entry
Reaction
Product
(Yield (%))
Reaction mixture
composition*
ОEntry
Reaction
Product
(Yields (%))
Reaction mixture
composition*
1
20a + 8
17a (70)
24a (80)
17a (63.4),
1
7a + 16/BuLi
20a (51),
21a (19),
23 (3)
7a (1.2), 20a (67.0),
21a (23.2), 22a (0),
23 (4.0),
Ph3PO (31.6),
impurities (5.0)
24a (80.8),
Ph3PO (19.0),
impurities (0.2)
7b (40.8),
2
3
20a + 9
20b + 8
impurities (4.6)
2
7b + 16/BuLi
20b (69),
22b (3)
7b (0), 20b (90.3),
21b (0), 22b (5.1),
impurities (4.6)
17a (42),
22b (34)
22b (32.6),
Ph3PO (24.4),
impurities (2.2)
22b (2.1),
* Component contents (%) are given in parenthesis.
4
20b + 9
24b (73)
24b (71.4),
Ph3PO (22.3),
impurities (4.2)
Suzuki crossꢀcoupling reactions (155 C, 20 min) with
3ꢀnitrophenylboronic (8) and 2ꢀthienylboronic (9) acids
(Scheme 7). Yields of 5ꢀhetarylꢀ4ꢀ(2ꢀthienyl)ꢀ2ꢀ(thio)ꢀ
morpholinopyrimidines 17a,b and 24a,b (42—80%) deꢀ
pend on the starting arylboronic acid (Table 5).
* Component contents (%) are given in parenthesis.
Table 6. Tuberculostatic activity of substituted pyrimidines 12a,b,
14a, 15a,b, 17a,b, 23, and 24a,b against Mycobacterium tuberꢀ
culosis H37Rv in vitro
Scheme 7
Compound
MIC/g mL–1
Compound
MIC/g mL–1
12a
12b
14a
15a
15b
17a
17b
6.25
12.5
12.5
12.5
12.5
12.5
6.25
20a
20b
23
24a
24b
Pyrazinamide
Isoniazid
6.25
12.5
1.5
3.1
12.5
12.5
0.1
Reagents and conditions: Pd(PPh3)4, K3CO3, THF, H2O, microꢀ
wave irradiation, 20 min.
X = O (a), S (b)
gen (SNH, SNipso) and Suzuki crossꢀcoupling reactions are
effective strategy towards novel 2,5ꢀdisubstituted and
2,4,5ꢀtrisubstituted pyrimidines. Indeed, these compounds
can be regarded as promising potential candidates for the
further development of new antitubercular agents.
Ar =
(8, 17),
(9, 24)
Wide range of antibacterial activity1 exhibited by a seꢀ
ries of pyrimidine derivatives prompted us to study antituꢀ
berculosis activity of the synthesized compounds. Thus,
we determined tuberculostatic activity of some 5ꢀ(het)ꢀ
arylꢀ2ꢀ(thio)morpholinopyrimidines (12a,b, 14a, 15a,b),
5ꢀbromoꢀ4ꢀ(2ꢀthienyl)ꢀ2ꢀ(thio)morpholinoꢀ (20a,b) and
5ꢀ(het)arylꢀ4ꢀ(2ꢀthienyl)ꢀ2ꢀ(thio)morpholinopyrimidines
(17a,b and 24a,b), and 5ꢀbromoꢀ2,2´ꢀdimorpholinoꢀ4´ꢀ
(2ꢀthienyl)ꢀ4,5´ꢀbipyrimidine (23) against Mycobacterium
tuberculosis H37Rv in vitro. Isoniazid and Pyrazinamide
were used as positive controls (Table 6). All compounds
have a bacteriostatic effect comparable and even higher
than that of Pyrazinamide with minimum inhibiting conꢀ
Experimental
Solvents and reactants were purified and dried as earlier
described.9
1H and 13C NMR spectra were recorded on a Bruker AVANCE
III 500 spectrometer (working frequencies of 500 and 126 MHz,
respectively) in CDCl3 relative to Me4Si (internal standard). All
signals in 1H and 13C NMR spectra were ascribed using 2D NMR
experiments (1H—1H COSY, 1H—13C HSQC/HMBC). Elemenꢀ
tal analyses were performed with a Perkin—Elmer PEꢀ240 eleꢀ
mental analyzer. Melting points were determined on a Boetius
apparatus and are uncorrected.
centration (MIC) of 12.5 g mL–1
.
In summary, tandem and more complicated sequencꢀ
es of the reactions of nucleophilic substitution of hydroꢀ
The GCꢀMS analyses of all samples were carried out using
an Agilent GC 7890A MS 5975C Inert XL EI/CI GCꢀMS specꢀ

4,5ꢀDi(het)arylꢀ2ꢀ(thio)morpholinopyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
1355
trometer with a quadrupole massꢀspectrometric 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
HPꢀ5MS (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. Aliquots of 1 mL of the obtained soluꢀ
tions were analyzed.
cell parameters are as follows: a = 22.1710(15) Å, b = 4.1344(3) Å,
c = 14.2241(11) Å, V = 1303.83(16) Å3, Z = 4, dcalc
=
= 1.458 g cm–3. At angles of 2.86 <  < 28.32, 3175 reflections
(Rint = 0.0358) were measured (2540 reflections with I > 2(I)).
The structure was solved and refined using SHELXTL software10
by the fullꢀmatrix leastꢀsquares method on F2. Nonhydrogen
atoms were included in the model in anisotropic approximation.
Hydrogen atoms were located by peaks of the spatial distribution of
electron density; some Hꢀatoms were calculated independently and
refined in isotropic approximation, remained Hꢀatoms were refined
using a riding model with fixed isotropic thermal parameters of
the parent atoms. The final Rꢀfactors are as follows: R1 = 0.0325,
wR2 = 0.0706 (based on reflections with I > 2(I)), R1 = 0.0452,
wR2 = 0.0738 (based on all reflections) at Qꢀfactor of S = 1.003 and
number of the refined parameters of 214. The peaks of maximum
Preparative HPLC was performed with semiꢀpreparative
Agilent 1200 Series liquid chromatography system (Agilent Techꢀ
nologies, USA), equipped with autosampler (900 L), diode array
detector (analytical wavelength of 280 nm), and fraction colꢀ
lector. Column was ZORBAX Eclipse XDBꢀC18 PrepHT
21.2 mm×150 mm, particles size of 5 m (Agilent Technologies,
USA), ambient column temperature, isocratic elution with acetoꢀ
and minimum electron density are  = 0.141/–0.109 e Å–3
.
All Xꢀray analyses data (CIF files) were deposited with the
Cambridge Crystallographic Data Center under CCDC 978028
(compound 7a) and CCDC 978034 (compound 12a) and are
available free of charge at http://www.ccdc.cam.ac.uk/Communiꢀ
ty/Requestastructure/Pages/DataRequest.aspx?.
nitrile—water (65 : 35), flow rate was 20 mL min–1
.
Antimicrobial assay of compounds 12, 14, 15, 17, 20, 23, and
24 were carried out in vitro against the H37Rv strain of Mycobacꢀ
terium tuberculosis (MBT) by vertical diffusion technique using
solid culture medium Novaya. Culture medium (5 mL) was disꢀ
tributed into the test tubes in sloping positions leaving an 1/2 of
the test tube bottom free. The slopes were inoculated delivering
suspension of MBT, strain H37Rv (0.1 mL, turbidity standard of
100 millions of bacteria in 1 mL of suspension), and transferred to
incubator for growing. After 24 h, the test tubes were placed
in the upright positions and the solutions of the studied comꢀ
pounds (0.3 mL) with concentrations of 12.5, 6.25, 3.1, 1.5, and
0.75 g mL–1 were delivered dropwise by the side wall of the test
tube. The test tubes were incubated at 37 C for 10 days. Growth
of MBT was estimated following standard procedure11, e.g., apꢀ
pearance of the zones of growth inhibition (more than 10 mm in
size) indicated the tuberculostatic properties of the compound in
the tested concentration. The size of the growth inhibition zone
(in mm) is proportional to the degree of tuberculostatic activity
of the compound. The growth inhibition equal to 100 mm was
regarded as complete inhibition of the MBT growth. For studyꢀ
ing tuberculostatic activity of the synthesized compounds, three
slopes for each concentration were used. The data obtained are
summarized in Table 6.
Microwave experiments were carried out in a Discover uniꢀ
modal microwave system (CEM, USA) with a working frequenꢀ
cy 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 temperature of
the reaction was monitored using an inserted IR sensor by the
external surface of the reaction vessel.
Flash chromatography was performed using Kieselgel 60,
0.040—0.063 mm (230—400 mesh).
The progress of the reactions and purity of the products were
checked by TLC on Sorbfil plates (Russia), in which the spot
were visualized under UV light ( = 254 or 365 nm).
Xꢀray diffraction analyses were carried out on an Xcalibur S
automatized 4ꢀcircle diffractometer, equipped with a CCD deꢀ
tector following the standard procedure ((MoK), graphite
monochromator,  scanning mode, step 1, 295(2) K).
Xꢀray diffraction of compound 7a was performed for a colorꢀ
less crystal fragment of 0.24×0.18×0.10 mm in size. Correction
for absorption was done analytically using a multifaceted crystal
model ( = 4.310 mm–1 10. The crystals are monoclinic, space
)
group is P21/n. The unit cell parameters are as follows: a =
= 4.6316(6) Å, b = 13.496(2) Å, c = 15.184(2) Å,  = 94.864(12),
V = 945.7(2) Å3, Z = 4, dcalc = 1.714 g cm–3. At angles of
2.69    33.22 3233 reflections (Rint = 0.0358) were meaꢀ
sured (1372 reflections with I > 2(I)). The structure was solved
and refined using SHELXTL software10 by the fullꢀmatrix leastꢀ
squares method on F2. Nonhydrogen atoms were included in the
model in anisotropic approximation. Hydrogen atoms were locatꢀ
ed by peaks of the spatial distribution of electron density and
refined using a riding model in isotropic approximation. Final
Rꢀfactors: R1 = 0.0322, wR2 = 0.0560 (based on reflections with
I > 2(I)), R1 = 0.1041, wR2 = 0.0586 (based on all reflections)
at Qꢀfactor of S = 1.004 and number of refined parameters of
118. The peaks of maximum and minimum electron density are
2ꢀMorpholinopyrimidine (6a). To a solution of morpholine 5a
(3.63 mL, 42 mmol) in DMF (50 mL), K2CO3 (5.8 g, 42 mmol)
was added; after 20 min stirring, 2ꢀchloropyrimidine (4.0 g,
35 mmol) was added. The reaction mixture was stirred for 24 h,
the solvent was removed in vacuo, the residue was purified by
column chromatography (elution with ethyl acetate—hexane,
1
1 : 1). Yield 6.94 g (79%), colorless oil. H NMR, : 3.75—3.81
(m, 8 H, OCH2, NCH2); 6.52 (t, 1 H, H(5), J = 4.7 Hz); 8.32
(d, 2 H, H(4), H(6), J = 4.7 Hz). 13C NMR, : 44.11 (NCH2); 66.77
(OCH2); 110.21 (C(5)); 157.66 (C(4), C(6)); 161.73 (C(2)).
Found (%): C, 58.01; H, 6.67; N, 25.14. C8H11N3O. Calculatꢀ
ed (%): C, 58.17; H, 6.71; N, 25.44. GC: tR = 15.36 min. MS,
m/z (Irel (%)): 165 [M]+ (100).
 = 0.348/–0.560 e Å–3
.
Xꢀray diffraction of compound 12a was carried out for an
yellow crystal of 0.25×0.12×0.04 mm in size. Correction for abꢀ
sorption was very small ( = 0.106 mm–1) and was not introꢀ
duced. The crystal is rhombic, space group is Pca21. The unit
2ꢀThiomorpholinopyrimidine (6b). To a solution of thiomorꢀ
pholine 5b (247 mg, 2.2 mmol) in MeCN (25 mL), K2CO3 (332 mg,
2.2 mmol) was added; after 20 min stirring, 2ꢀchloropyrimiꢀ
dine (4) (229 mg, 2 mmol) was added and the mixture was reꢀ

1356
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
Cheprakova et al.
fluxed for 10 h. The solvent was removed in vacuo, the residue
was dissolved in water (150 mL) and extracted with CHCl3
(3×50 mL). Removal of the solvent and column chromatography
of the residue (elution with ethyl acetate—hexane, 1 : 2) affordꢀ
ed compound 6b in the yield of 399 mg (55%), white crystalline
powder, m.p. 59—60 C. 1H NMR, : 2.64 (m, 4 H, SCH2); 4.15
(m, 4 H, NCH2); 6.47 (t, 1 H, H(5), J = 4.7 Hz); 8.29 (d, 2 H,
H(4), H(6), J = 4.7 Hz). 13C NMR, : 26.15 (SCH2); 46.19
(NCH2); 109.65 (C(5)); 157.63 (C(4), C(6)); 161.06 (C(2)).
Found (%): C, 53.16; H, 6.02; N, 23.35. C8H11N3S. Calculatꢀ
ed (%): C, 53.01; H, 6.12; N, 23.18. GC: tR = 17.86 min. MS,
m/z (Irel (%)): 181 [M]+ (100).
Synthesis of 5ꢀbromoꢀ2ꢀ(thio)morpholinopyrimidines 7a,b
(general procedure). To a solution of compound 6a (or 6b)
(0.36 mmol) in CH2Cl2 (25 mL), Br2 (22 L, 0.43 mmol) was
added, the reaction mixture was stirred at room temperature for
1 h and then treated with aqueous Na2CO3 for 2 h. The organic
layer was separated, the solvent was removed in vacuo and the
residue was recrystallizes from hexane.
5ꢀBromoꢀ2ꢀmorpholinopyrimidine (7a), white crystalline
powder. Yield 89%, m.p. 91—92 C. 1H NMR, : 3.73—3.77
(m, 8 H, OCH2, NCH2); 8.30 (s, 2 H, H(4), H(6)). 13C NMR,
: 44.28 (NCH2); 66.62 (OCH2); 106.15 (C(5)); 157.85 (C(4),
C(6)); 159.91 (C(2)). Found (%): C, 39.40; H, 4.11; N, 17.06.
C8H10N3OBr. Calculated (%): C, 39.37; H, 4.13; N, 17.21.
GS: tR = 18.55 min. MS, m/z (Irel (%)): 243 [M]+ (100) for 79Br,
245 [M]+ (100) for 81Br.
5ꢀBromoꢀ2ꢀthiomorpholinopyrimidine (7b), white crystalline
powder. Yield 82%, m.p. 80—82 C. 1H NMR, : 2.64 (m, 4 H,
SCH2); 4.12 (m, 4 H, NCH2); 8.29 (s, 2 H, H(4), H(6)). 13C NMR,
: 26.77 (SCH2); 46.58 (NCH2); 105.70 (C(5)); 157.93 (C(4),
C(6)); 159.39 (C(2)). Found (%): C, 36.96; H, 3.75; N, 16.08.
C8H10BrN3S. Calculated (%): C, 36.94; H, 3.87; N, 16.15.
GS: tR = 20.92 min. MS, m/z (Irel (%)): 259 [M]+ (100) for 79Br,
261 [M]+ (100) for 81Br.
Synthesis of 5ꢀ(het)arylꢀ2ꢀ(thio)morpholinopyrimidines 12—15
(general procedure). A. To a mixture of compound 7a (or 7b)
(1 mmol), the corresponding (het)arylboronic acid 8 (9, 10 or 11)
(1.2 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol) in degassed THF
(3 mL), a solution of K2CO3 (346 mg, 2.5 mL) in water (4 mL)
were added. The reaction mixture was microwave irradiated at
155 C (250 W) for 20 min, then solvent was removed in vacuo.
Products were isolated by column chromatography (elution with
ethyl acetate—hexane, 1 : 2).
B. A mixture of K2CO3 (346 mg, 2.5 mmol), bromopyrimꢀ
idine 7a (or 7b) (1 mmol), 3ꢀnitrophenylboronic acid (8) (200 mg,
1.2 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), and PPh3 (26 mg,
0.1 mmol) was dissolved in degassed DMF (7 mL) and microꢀ
wave irradiated at 180 C (250 W) for 20 min. Solvent was reꢀ
moved in vacuo, products were isolated by column chromatoꢀ
graphy (elution with ethyl acetate—hexane, 1 : 2).
C. A mixture of K2CO3 (346 mg, 2.5 mmol), bromopyrimꢀ
idine 7a (or 7b) (1 mmol), 3ꢀnitrophenylboronic acid (8) (200 mg,
1.2 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), and PCy3 (28 mg,
0.1 mmol) was dissolved in degassed DMF (7 mL) and microꢀ
wave irradiated at 180 C (250 W) for 20 min. Solvent was reꢀ
moved in vacuo, products were isolated by column chromatoꢀ
graphy (elution with ethyl acetate—hexane, 1 : 2).
2ꢀMorpholinoꢀ5ꢀ(3ꢀnitrophenyl)pyrimidine (12a), yellow
crystalline powder. Yield 57%, m.p. 192—194 C. 1H NMR,
: 3.80 (m, 4 H, OCH2); 3.89 (m, 4 H, NCH2); 7.62 (t, 1 H, H(5´),
J = 7.9 Hz); 7.80 (d, 1 H, H(6´), J = 7.5 Hz); 8.19 (d, 1 H,
H(4´), J = 8.2 Hz); 8.34 (s, 1 H, H(2´)); 8.60 (s, 2 H, H(4),
H(6)). 13C NMR, : 44.31 (NCH2); 66.76 (OCH2); 120.40
(C(2´)); 120.86 (C(5)); 121.88 (C(4´)); 130.12 (C(5´)); 131.45
(C(6´)); 137.41 (C(1´)); 148.92 (C(3´)); 155.96 (C(4), C(6)); 161.32
(C(2)). Found (%): C, 58.31; H, 5.03; N, 19.00. C14H14N4O3.
Calculated (%): C, 58.74; H, 4.93; N, 19.57. HPLC: tR = 4.05 min.
GC: tR = 27.96 min. MS, m/z (Irel (%)): 286 [M]+ (100).
5ꢀ(3ꢀNitrophenyl)ꢀ2ꢀthiomorpholinopyrimidine (12b), yellow
crystalline powder. Yield 60%, m.p. 149—150 C. 1H NMR,
: 2.69 (m, 4 H, SCH2); 4.22 (m, 4 H, NCH2); 7.62 (t, 1 H, H(5´),
J = 8.0 Hz); 7.80 (ddd, 1 H, H(6´), J = 7.8 Hz, J = 1.7 Hz,
J = 1.0 Hz); 8.18 (ddd, 1 H, H(4´), J = 8.2 Hz, J = 2.2 Hz,
J = 1.0 Hz); 8.34 (t, 1 H, H(2´), J = 1.9 Hz); 8.59 (s, 2 H, H(4),
H(6)). 13C NMR, : 26.99 (SCH2); 46.60 (NCH2); 120.38
(C(2´)); 120.50 (C(5); 121.85 (C(4´)); 130.11 (C(5´)); 131.42
(C(6´)); 137.43 (C(1´)); 148.92 (C(3´)); 156.03 (C(4), C(6)); 160.87
(C(2)). Found (%): C, 55.89; H, 4.58; N, 18.71. C14H14N4O2S.
Calculated (%): C, 55.62; H, 4.67; N, 18.53. GC: tR = 30.28 min.
MS, m/z (Irel (%)): 302 [M]+ (100).
2ꢀMorpholinoꢀ5ꢀ(2ꢀthienyl)pyrimidine (13a), white crystalꢀ
line powder. Yield 43%, m.p. 118—124 C. 1H NMR, : 3.78
(m, 4 H, OCH2); 3.84 (m, 4 H, NCH2); 7.08 (dd, 1 H, H(4´),
J = 5.2 Hz, J = 3.6 Hz); 7.16 (dd, 1 H, H(3´), J = 3.6 Hz, J = 1.1 Hz);
7.26 (dd, 1 H, H(5´), J = 5.2 Hz, J = 1.1 Hz); 8.55 (s, 2 H, H(4),
H(6)). 13C NMR, : 44.34 (NCH2); 66.77 (OCH2); 117.97
(C(5)); 122.35 (C(3´)); 124.34 (C(5´)); 128.07 (C(4´)); 138.26
(C(2´)); 155.01 (C(4), C(6)); 160.86 (C(2)). Found (%): C, 58.03;
H, 5.12; N, 17.04. C12H13N3OS. Calculated (%): C, 58.28; H, 5.30;
N, 16.99. GC: tR = 23.99 min. MS, m/z (Irel (%)): 247 [M]+ (100).
5ꢀ(2ꢀThienyl)ꢀ2ꢀthiomorpholinopyrimidine (13b), white crysꢀ
talline powder. Yield 49%, m.p. 98—100 C. 1H NMR, : 2.67
(m, 4 H, SCH2); 4.19 (m, 4 H, NCH2); 7.08 (dd, 1 H, H(4´),
J= 5.1 Hz, J = 3.6 Hz); 7.16 (dd, 1 H, H(3´), J = 3.6 Hz, J = 1.1 Hz);
7.26 (dd, 1 H, H(5´), J = 5.1 Hz, J = 1.1 Hz); 8.54 (s, 2 H, H(4),
H(6)). 13C NMR, : 26.92 (SCH2); 46.59 (NCH2); 117.58 (C(5));
122.31 (C(3´)); 124.29 (C(5´)); 128.08 (C(4´)); 138.31 (C(2´));
155.12 (C(4), C(6)); 160.35 (C(2)). Found (%): C, 54.80; H, 4.74;
N, 16.13. C12H13N3S2. Calculated (%): C, 54.72; H, 4.98;
N, 15.95. GC: tR = 25.99 min. MS, m/z (Irel (%)): 263 [M]+ (100).
5ꢀ(2ꢀBenzo[b]thienyl)ꢀ2ꢀmorpholinopyrimidine (14a), white
crystalline powder. Yield 52%, m.p. 201—202 C. 1H NMR,
: 3.79 (m, 4 H, OCH2); 3.87 (m, 4 H, NCH2); 7.30 (ddd, 1 H,
H(6´), J = 8.2 Hz, J = 7.0 Hz, J = 1.2 Hz); 7.35 (ddd, 1 H,
H(5´), J = 8.0 Hz, J = 7.0 Hz, J = 1.1 Hz); 7.39 (s, 1 H, H(3´));
7.75 (d, 1 H, H(4´), J = 8.0 Hz); 7.81 (d, 1 H, H(7´), J = 8.2 Hz);
8.64 (s, 2 H, H(4), H(6)). 13C NMR, : 44.35 (NCH2); 66.77
(OCH2); 117.68 (C(5)); 118.19 (C(3´)); 122.20 (C(7´)); 123.26
(C(4´)); 124.28 (C(6´)); 124.71 (C(5´)); 138.31 (C(2´)); 138.92
(C(7´a)); 140.53 (C(3´a)); 155.35 (C(4), C(6)); 161.03 (C(2)).
Found (%): C, 64.60; H, 5.22; N, 14.10. C16H15N3OS. Calculatꢀ
ed (%): C, 64.62; H, 5.08; N, 14.13. GC: tR = 29.31 min. MS, m/z
(Irel (%)): 297 [M]+ (100).
5ꢀ(2ꢀBenzo[b]thienyl)ꢀ2ꢀthiomorpholinopyrimidine (14b) pale
yellow powder. Yield 54%, m.p. 197—198 C. 1H NMR, : 2.69
(m, 4 H, SCH2); 4.21 (m, 4 H, NCH2); 7.30 (ddd, 1 H, H(6´),
J = 8.0 Hz, J = 7.1 Hz, J = 1.1 Hz); 7.35 (ddd, 1 H, H(5´),
J = 8.0 Hz, J = 7.1 Hz, J = 1.0 Hz); 7.37 (s, 1 H, H(3´)); 7.75
(d, 1 H, H(4´), J = 8.0 Hz); 7.81 (d, 1 H, H(7´), J = 8.0 Hz);
8.62 (s, 2 H, H(4), H(6)). 13C NMR, : 26.96 (SCH2); 46.61
(OCH2); 117.28 (C(5)); 118.09 (C(3´)); 122.18 (C(7´)); 123.23

4,5ꢀDi(het)arylꢀ2ꢀ(thio)morpholinopyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
1357
(C(4´)); 124.24 (C(6´)); 124.68 (C(5´)); 138.33 (C(2´)); 138.87
(C(7´a)); 140.52 (C(3´a)); 155.41 (C(4), C(6)); 160.523 (C(2)).
Found (%): C, 61.10; H, 4.65; N, 13.23. C16H15N3S2. Calculatꢀ
ed (%): C, 61.31; H, 4.82; N, 13.41. GC: tR = 32.18 min. MS,
m/z (Irel (%)): 313 [M]+ (100).
Found (%): C, 42.01; H, 3.60; N, 12.09 C12H12BrN3S2. Calcuꢀ
lated (%): C, 42.11; H, 3.53; N, 12.28. GC: tR = 27.87 min. MS,
m/z (Irel (%)): 341 [M]+ (100) for 79Br, 343 [M]+ (100) for 81Br.
5ꢀBromoꢀ4ꢀbutylꢀ2ꢀmorpholinopyrimidine (21a), yellow crysꢀ
talline powder. Yield 23%, m.p. 96—98 C (decomp.). 1H NMR,
: 0.95 (t, 3 H, H (4´), J= 7.4 Hz); 1.41 (sext, 2 H, H(3´), J = 7.4 Hz);
1.67 (m, 2 H, H(2´)); 2.71 (m, 2 H, H(1´)); 3.72—3.77 (m, 8 H,
SCH2, NCH2); 8.22 (s, 1 H, H(6)). 13C NMR, : 13.73 (C(4´));
22.29 (C(3´)); 29.18 (C(2´)); 36.34 (C(1´)); 44.23 (NCH2); 66.58
(OCH2); 107.07 (C(5)); 158.19 (C(6)), 160.22 (C(2)); 168.47
(C(4)). Found (%): C, 47.86; H, 6.26; N, 14.24. C12H18BrN3O.
Calculated (%): C, 48.01; H, 6.04; N, 14.00. GC: tR = 21.73 min.
MS, m/z (Irel (%)): 299 [M]+ (100) for 79Br, 301 [M]+ (100) for 81Br.
4ꢀ(2ꢀThienyl)ꢀ2ꢀthiomorpholinopyrimidine (22b), yellow crysꢀ
talline powder. Yield 5%, m.p. 124—127 C. 1H NMR, : 2.81
(m, 2 H, SCHB); 2.86 (m, 2 H, SCHA); 4.25 (ddd, 2 H,
NCHB, J = 14.4 Hz, J = 10.4 Hz, J = 2.8 Hz); 4.60 (dt, 2 H,
NCHA, J = 14.4 Hz, J = 4.3 Hz); 6.90 (d, 1 H, H(5), J = 5.1 Hz);
7.13 (dd, 1 H, H(4´), J = 5.1 Hz, J = 3.8 Hz); 7.48 (dd, 1 H,
H(5´), J = 5.1 Hz, J = 1.1 Hz); 7.69 (dd, 1 H, H(3´), J = 3.8 Hz,
J = 1.1 Hz); 8.33 (d, 1 H, H(6), J = 5.1 Hz). 13C NMR, : 35.55
(NCH2); 45.43 (SCH2); 104.95 (C(5)); 127.06 (C(3´)); 128.18
(C(4´)); 129.52 (C(5´)); 143.18 (C(2´)); 158.34 (C(6)); 159.56
(C(4)); 160.93 (C(2)). Found (%): C, 54.63; H, 4.86; N, 15.82.
C12H13N3S2. Calculated (%): C, 54.72; H, 4.98; N, 15.95.
GC: tR = 25.60 min. MS, m/z (Irel (%)): 263 [M]+ (100).
5ꢀBromoꢀ2,2´ꢀdimorpholinoꢀ4´ꢀ(2ꢀthienyl)ꢀ[4,5´]bipyrimꢀ
idine (23), dark yellow powder. Yield 4%, m.p. 201—204 C.
1H NMR, : 3.74 (m, 4 H, OCH2); 3.78 (m, 4 H, NCH2); 3.81
(m, 4 H, O´CH2); 3.93 (m, 4 H, N´CH2); 6.93—6.96 (m, 2 H,
H(4"), H(5")); 7.42 (m, 1 H, H(3"); 8.28 (s, 1 H, H(6´)); 8.38
(s, 1 H, H(6)). 13C NMR, : 44.28 (N´CH2); 44.37 (NCH2); 66.65
(OCH2); 66.82 (O´CH2); 107.52 (C(5)); 117.72 (C(5´)); 127.90
and 129.13 (C(4"), C(5")); 129.80 (C(3")); 142.48 (C(2")); 156.75
(C(4´)); 158.84 (C(6´)); 159.79 (C(6)); 160.45 (C(2´)); 160.63
(C(2)); 163.30 (C(4)). Found (%): C, 49.05; H, 4.54; N, 17.07.
C20H21BrN6O2S. Calculated (%): C, 49.09; H, 4.33; N, 17.17.
GC: tR = 45.29 min. MS, m/z (Irel (%)): 488 [M]+ (5) for 79Br,
490 [M]+ (6) for 81Br, 409 [M – thienyl]+ (100) for 79Br, 410
[M – thienyl]+ (20) for 81Br.
5ꢀ(3ꢀBenzo[b]thienyl)ꢀ2ꢀmorpholinopyrimidine (15a), white
crystalline powder. Yield 73%, m.p. 136—137 C. 1H NMR,
: 3.81 (m, 4 H, OCH2); 3.88 (m, 4 H, NCH2); 7.35 (s, 1 H,
H(2´)); 7.41 (m, 2 H, H(5´), H(6´)); 7.81 (m, 1 H, H(4´)); 7.92
(m, 1 H, H(7´)); 8.56 (s, 2 H, H(4), H(6)). 13C NMR, : 44.33
(NCH2); 66.81 (OCH2); 118.70 (C(5)); 122.23 (C(4´)); 123.06
(C7´); 123.14 (C(2´)); 124.56 (C(5´)); 124.65 (C(6´)); 131.82
(C(3´)); 137.71 (C(3a´)); 140.57 (C(7´a)); 157.14 (C(4),
C(6)); 161.00 (C(2)). Found (%): C, 64.51; H, 5.20; N, 14.05.
C16H15N3OS. Calculated (%): C, 64.62; H, 5.08; N, 14.13.
GC: tR = 28.64 min. MS, m/z (Irel (%)): 297 [M]+ (100).
5ꢀ(3ꢀBenzo[b]thienyl)ꢀ2ꢀthiomorpholinopyrimidine (15b),
pale yellow powder. Yield 74%, m.p. 110—111 C. 1H NMR,
: 2.71 (m, 4 H, SCH2); 4.23 (m, 4 H, NCH2); 7.35 (s, 1 H, H(2´));
7.41 (m, 2 H, H(5´), H(6´)); 7.81 (m, 1 H, H(4´)); 7.92 (m, 1 H,
H(7´)); 8.54 (s, 2 H, H(4), H(6)). 13C NMR, : 26.96 (SCH2);
46.55 (NCH2); 118.29 (C(5)); 122.26 (C(4´)); 123.07, 123.09
(C(7´), C(2´)); 124.56 (C(5´)); 124.65 (C(6´)); 131.86 (C(3´));
137.73 (C(3a´)); 140.59 (C(7´a)); 157.22 (C(4), C(6)); 161.49
(C(2)). Found (%): C, 61.25; H, 4.77; N, 13.04. C16H15N3S2.
Calculated (%): C, 61.31; H, 4.82; N, 13.41. GC: tR = 31.10 min.
MS, m/z (Irel (%)): 313 [M]+ (100).
Synthesis of 5ꢀbromoꢀ4ꢀ(2ꢀthienyl)ꢀ2ꢀ(thio)morpholinopyrimꢀ
idines (20a,b) and byꢀproducts 21a, 22b, and 23 (general proceꢀ
dure). 2ꢀThienyllithium was generated by adding of BuLi in hexane
(1.6 M, 2.9 mL, 4.5 mmol) to thiophene (16) (430 L, 5.4 mmol)
in diethyl ether (20 mL) at 0 C followed by keeping
the resulting solution for 4 h. The obtained solution of 2ꢀthienylꢀ
lithium was chilled to –30 C and a solution of 7a (or 7b)
(3 mmol) in diethyl ether (40 mL) was slowly added. The reacꢀ
tion mixture was stirred at –20 C for 1 h, then cooling was
removed and stirring was continued at room temperature for 18 h.
Then a solution of K3Fe(CN)6 (1.975 g, 6 mmol) and KOH
(1.010 g, 18 mmol) in water (20 mL) was added and the mixture
was stirred for 4 h. Solvent was removed in vacuo, products were
isolated by column chromatography (elution with ethyl acetꢀ
ate—hexane, 1 : 3).
5ꢀBromoꢀ2ꢀmorpholinoꢀ4ꢀ(2ꢀthienyl)pyrimidine (20a), beige
powder. Yield 67%, m.p. 122—124 C. 1H NMR, : 3.77 (m, 4 H,
OCH2); 3.82 (m, 4 H, NCH2); 7.15 (dd, 1 H, H(4´), J = 5.1 Hz,
J = 3.9 Hz); 7.52 (dd, 1 H, H(5´), J = 5.1 Hz, J = 1.1 Hz); 8.33
(dd, 1 H, H(3´), J = 3.9 Hz, J = 1.1 Hz); 8.40 (s, 1 H, H(6)).
13C NMR, : 44.35 (NCH2); 66.73 (OCH2); 101.89 (C(5));
127.99 (C(4´)); 130.46 (C(5´)); 131.00 (C(3´)); 142.37 (C(2´));
155.72 (C(4)), 159.55 (C(2)); 161.38 (C(6)). Found (%): C, 44.11;
H, 3.70; N, 12.63. C12H12BrN3OS. Calculated (%): C, 44.18;
H, 3.71; N, 12.88. GC: tR = 26.01 min. MS, m/z (Irel (%)): 325
[M]+ (100) for 79Br, 327 [M]+ (100) for 81Br.
5ꢀBromoꢀ4ꢀ(2ꢀthienyl)ꢀ2ꢀthiomorpholinopyrimidine (20b),
yellow crystalline powder. Yield 90%, m.p. 105—107 C. 1H NMR,
: 2.67 (m, 4 H, SCH2); 4.16 (m, 4 H, NCH2); 7.15 (dd, 1 H,
H(4´), J = 5.1 Hz, J = 3.9 Hz); 7.52 (dd, 1 H, H(5´), J = 5.1 Hz,
J = 1.1 Hz); 8.33 (dd, 1 H, H(3´), J = 3.9 Hz, J = 1.1 Hz); 8.39
(s, 1 H, H(6)). 13C NMR, : 26.84 (SCH2); 46.64 (NCH2);
101.47 (C(5)); 128.00 (C(4´)); 130.43 (C(5´)); 130.95 (C(3´));
142.45 (C(2´)); 155.78 (C(4)), 159.05 (C(2)); 161.46 (C(6)).
Synthesis of 5ꢀ(het)arylꢀ4ꢀ(2ꢀthienyl)ꢀ2ꢀ(thio)morpholinoꢀ
pyrimidines (17a,b and 24a,b) (general procedure). A. Thiophene
(16) (160 L, 2 mmol) was added to a solution of the corresꢀ
ponding pyrimidine 12a (or 12b) (1 mmol) in TFA (10 mL). The
reaction mixture was stirred for 1 month and concentrated. To
the residue, a solution of K3Fe(CN)6 (658 mg, 2 mmol) and
KOH (224 mg, 4 mmol) in water (10 mL) was added and mixture
was stirred for 2 h. The precipitate formed was collected, washed
with water, dried and analyzed by GCꢀMS. Compound 17a was
isolated by preparative HPLC.
B. To a mixture of 20a (or 20b) (1 mmol), 3ꢀnitrophenylꢀ
boronic (8) (or 2ꢀthienylboronic (9)) acid (1.2 mmol), and
Pd(PPh3)4 (58 mg, 0.05 mmol) in degassed THF (3 mL), a solution
of K2CO3 (346 mg, 2.5 mmol) in water (4 mL) was added. The
reaction mixture was microwave irradiated at 155 C (250 W) for
20 min. Solvent was removed in vacuo, products were isolated by
column chromatography (elution with ethyl acetate—hexane, 1 : 2).
2ꢀMorpholinoꢀ5ꢀ(3ꢀnitrophenyl)ꢀ4ꢀ(2ꢀthienyl)pyrimidine (17a),
yellow powder. Yield 21% (method A) or 70% (method B), m.p.
1
172—174 C. H NMR, : 3.82 (m, 4 H, OCH2); 3.92 (m, 4 H,
NCH2); 6.71 (dd, 1 H, H(3´), J = 3.8 Hz, J = 1.0 Hz); 6.85

1358
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
Cheprakova et al.
(dd, 1 H, H(4´), J = 5.0 Hz, J = 3.8 Hz); 7.38 (dd, 1 H, H(5´),
J = 5.0 Hz, J = 1.0 Hz); 7.61 (t, 1 H, H(5"), J = 7.9 Hz); 7.66
(dt, 1 H, H(6"), J = 7.7 Hz, J = 1.5 Hz); 8.20 (s, 1 H, H(4)); 8.21
(t, 1 H, H(2"), J = 1.9 Hz); 8.27 (ddd, 1 H, H(4"), J = 8.1 Hz,
J = 2.1 Hz, J = 1.2 Hz). 13C NMR, : 44.28 (NCH2); 66.85
(OCH2); 118.25 (C(5)); 122.76 (C(4")); 124.67 (C(2")); 127.80
(C(4´)); 129.74 (C(5´)); 128.82, 129.86 (C(5"), C(3´)); 136.14
(C(6")); 139.42 (C(1")); 142.60 (C(2´)); 148.63 (C(3")); 156.51
(C(6)); 159.30 (C(4)); 160.46 (C(2)). Found (%): C, 58.75;
H, 4.28; N, 15.41. C18H16N4O3S. Calculated (%): C, 58.68;
H, 4.38; N, 15.21. HPLC: tR = 8.29 min. GC: tR = 33.99 min.
MS, m/z (Irel (%)): 368 [M]+ (100).
5ꢀ(3ꢀNitrophenyl)ꢀ4ꢀ(2ꢀthienyl)ꢀ2ꢀthiomorpholinopyrimidine
(17b) was not isolated from the reaction mixture obtained folꢀ
lowing method A due to low conversion of the starting material
(see Table 3) and the closeness of the retention times of the
product and the starting compound 12b. Following method B,
compound 17b was obtained in 67% yield, light yellow powder,
m.p. 163—164 C. 1H NMR, : 2.72 (m, 4 H, SCH2); 4.25 (m, 4 H,
NCH2); 6.70 (dd, 1 H, H(3´), J = 3.9 Hz, J = 1.1 Hz); 6.85 (dd,
1 H, H(4´), J = 5.1 Hz, J = 3.9 Hz); 7.37 (dd, 1 H, H(5´), J = 5.1 Hz,
J = 1.1 Hz); 7.60 (t, 1 H, H(5"), J = 7.9 Hz); 7.66 (dt, 1 H,
H(6"), J = 7.7 Hz, J = 1.5 Hz); 8.18 (s, 1 H, H(6)); 8.21 (t, 1 H,
H(2"), J = 1.9 Hz); 8.27 (ddd, 1 H, H(4"), J = 8.1 Hz, J = 2.2 Hz,
J = 1.2 Hz). 13C NMR, : 27.00 (SCH2); 46.52 (NCH2); 117.90
(C(5)); 122.73 (C(4")); 124.68 (C(2")); 127.80 (C(4´)); 129.70
(C(5´)); 129.79, 129.80 (C(3´), C(5")); 136.14 (C(6")); 139.43
(C(1")); 142.69 (C(2´)); 148.63 (C(3")); 156.57 (C(4)); 159.35
(C(6)); 160.28 (C(2)). Found (%): C, 56.17; H, 4.28; N, 14.49.
C18H16N4O2S2. Calculated (%): C, 56.23; H, 4.19; N, 14.57.
GC: tR = 39.13 min. MS, m/z (Irel (%)): 384 [M]+ (100).
2ꢀMorpholinoꢀ4,5ꢀdi(2ꢀthienyl)pyrimidine (24a), yellow powꢀ
der. Yield 80% (method B), m.p. 158—160 C. 1H NMR, : 3.81
(m, 4 H, OCH2); 3.90 (m, 4 H, NCH2); 6.89 (dd, 1 H, H(4´),
J = 4.9 Hz, J = 3.8 Hz); 6.91 (dd, 1 H, H(3´), J = 3.8 Hz,
J = 1.3 Hz); 7.02 (dd, 1 H, H(3"), J = 3.5 Hz, J = 1.2 Hz); 7.12
(dd, 1 H, H(4"), J = 5.2 Hz, J = 3.5 Hz); 7.36 (dd, 1 H, H(5´),
J = 4.9 Hz, J = 1.3 Hz); 7.43 (dd, 1 H, H(5"), J = 5.2 Hz, J = 1.2 Hz);
8.27 (s, 1 H, H(6)). 13C NMR, : 44.28 (NCH2); 66.86 (OCH2);
112.82 (C(5)); 126.85 (C(5")); 127.58 (C(4")); 127.84 (C(4´));
128.14 (C(3")); 129.58 (C(5´)); 129.95 (C(3´)); 138.20 (C(2"));
142.83 (C(2´)); 157.53 (C(4)); 160.31 (C(6)); 160.72 (C(2)).
Found (%): C, 58.45; H, 4.44; N, 12.79. C16H15N3OS2. Calcuꢀ
lated (%): C, 58.33; H, 4.59; N, 12.75. GC: tR = 28.72 min. MS,
m/z (Irel (%)): 329 [M]+ (100).
126.84 (C(5")); 127.59 (C(4")); 127.86 (C(4´)); 128.15 (C(3"));
129.57 (C(5´)); 129.91 (C(3´)); 138.24 (C(2")); 142.93 (C(2´));
157.59 (C(4)); 160.26 (C(2)); 160.39 (C(6)). Found (%): C, 55.41;
H, 4.45; N, 12.27. C16H15N3S3. Calculated (%): C, 55.62;
H, 4.38; N, 12.16. GC: tR = 31.03 min. MS, m/z (Irel (%)): 345
[M]+ (100).
This work was financially supported by the Ural Diviꢀ
sion of the Russian Academy of Sciences (Programs
12ꢀPꢀ3ꢀ1014, 12ꢀTꢀ3ꢀ1025, 12ꢀTꢀ3ꢀ1031, and 13ꢀ3ꢀ019ꢀ
UMA), the Russian Foundation for Basic Research (Projꢀ
ects Nos 13ꢀ03ꢀ96049ꢀp_ural_a, 13ꢀ03ꢀ90606ꢀArm_a,
and 14ꢀ03ꢀ31040ꢀmol_a), the Council on Grants of the
President of the Russian Federation (Program for the State
Support of the Leading Scientific Schools of RF, Grant
HShꢀ5505.2012.3, and Program for the State Support of
Young PhDꢀScientists, Grant MKꢀ3939.2014.3), Minisꢀ
try of Education and Science of RF (Agreement No. 8430),
and Government of the Sverdlovskaya region.
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4,5ꢀDi(2ꢀthienyl)ꢀ2ꢀthiomorpholinopyrimidine (24b), yellow
powder. Yield 73% (method B), m.p. 149—152 C. 1H NMR,
: 2.71 (m, 4 H, SCH2); 4.24 (m, 4 H, NCH2); 6.88—6.90 (m, 2 H,
H(3´), H(4´)); 7.02 (dd, 1 H, H(3"), J = 3.5 Hz, J = 1.1 Hz);
7.12 (dd, 1 H, H(4"), J = 5.1 Hz, J = 3.5 Hz); 7.36 (m, 1 H,
H(5´)); 7.43 (dd, 1 H, H(5"), J = 5.1 Hz, J = 1.1 Hz); 8.25 (s, 1 H,
H(6)). 13C NMR, : 26.98 (SCH2); 46.53 (NCH2); 112.45 (C(5));
Received December 23, 2013;
in revised form May, 5 2014