Combination of the Suzuki-Miyaura cross-coupling and nucleophilic aromatic substitution of hydrogen (SNH) reactions as a versatile route to pyrimidines bearing thiophene fragments

Article abstract of DOI:10.1016/j.tet.2012.04.095

It has been shown that combination of the Suzuki-Miyaura cross-coupling and nucleophilic aromatic substitution of hydrogen is a versatile method for the synthesis of 4-(thiophen-2-yl)-, 5-(thiophen-2-yl)-, and 4,5-di(thiophen-2-yl) substituted pyrimidines from the commercially available 5-bromopyrimidine. The S_N^H (AE)- and S_N^H (AO)-reactions of 5-bromopyrimidine with thiophene and 2-bromothiophene have been studied by gas-liquid chromatography/mass-spectrometry. The structures of intermediate σ^H-adducts, as well as thiophene-(thiophenyl)pyrimidine and bithiophene-(thiophenyl)pyrimidine dyads have first been established by X-ray crystallography analysis.

Full text of DOI:10.1016/j.tet.2012.04.095

Tetrahedron 68 (2012) 5445e5452
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Combination of the SuzukieMiyaura cross-coupling and nucleophilic aromatic
H
substitution of hydrogen (SN ) reactions as a versatile route to pyrimidines
bearing thiophene fragments
,
a
a
a
Egor V. Verbitskiy a , Ekaterina M. Cheprakova , Pavel A. Slepukhin , Mikhail I. Kodess ,
*
Marina A. Ezhikova a, Marina G. Pervova a, Gennady L. Rusinov a b, Oleg N. Chupakhin a
,
,
,b
Valery N. Charushin a
,
b
a I. Postovsky Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences, S. Kovalevskoy Str. 22, Ekaterinburg 620041, Russia
b Ural Federal University named after the First President of Russia, B.N. Eltsin, Mira St. 19, Ekaterinburg 620002, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
It has been shown that combination of the SuzukieMiyaura cross-coupling and nucleophilic aromatic
substitution of hydrogen is a versatile method for the synthesis of 4-(thiophen-2-yl)-, 5-(thiophen-2-yl)-,
and 4,5-di(thiophen-2-yl) substituted pyrimidines from the commercially available 5-bromopyrimidine.
Received 19 January 2012
Received in revised form 13 March 2012
Accepted 24 April 2012
H
H
The SN (AE)- and SN (AO)-reactions of 5-bromopyrimidine with thiophene and 2-bromothiophene
Available online 3 May 2012
have been studied by gaseliquid chromatography/mass-spectrometry. The structures of intermediate
s
H-adducts, as well as thiophene-(thiophenyl)pyrimidine and bithiophene-(thiophenyl)pyrimidine
Keywords:
dyads have first been established by X-ray crystallography analysis.
SuzukieMiyaura reaction
Nucleophilic aromatic substitution of
hydrogen
Ó 2012 Elsevier Ltd. All rights reserved.
Pyrimidines
Thiophenes
Microwave-assisted synthesis
1. Introduction
The reactions leading to the formation of new carbonecarbon
bonds are of great importance for synthetic organic chemistry. The
SuzukieMiyaura palladium-catalyzed cross-coupling reactions of
aryl halides with organoboronic acids proved to be a versatile ap-
proach for the selective formation of carbonecarbon bonds, which
is used in particular for the synthesis of biaryls.1 Another approach
to the formation of CeC and CeX (X is a heteroatom) bonds with an
aromatic ring is based on nucleophilic aromatic substitution of
hydrogen (SNH) (Scheme 1).2 The advantage of this method is that it
does require neither the presence of a halogen atom in aromatic
substrate nor an expensive metal catalyst.
Scheme 1.
Pyrimidines belong to an important class of heteroaromatic
compounds, which have found wide applications as effective
pharmaceuticals, agrochemicals, and organic materials.3 A number
of pyrimidines are known to exhibit antimicrobial and antitumor
activities. Besides that, pyrimidines possess interesting co-
ordinating characteristics as ligands for a variety of transition
metals and have proved to be useful for construction of supra-
molecules.4 Electron-deficient nature of the pyrimidine ring pro-
vides a highly electron-accepting properties for the pyrimidine-
conjugated monomers and polymers.5 Indeed, conjugated mole-
cules bearing pyrimidine units as the key fragments attract a con-
siderable attention of chemists and physicists as promising
candidates for light-emitting diodes.6
* Corresponding author. E-mail address: verbitsky@ios.uran.ru (E.V. Verbitskiy).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.095

5446
E.V. Verbitskiy et al. / Tetrahedron 68 (2012) 5445e5452
In this paper a new approach to the synthesis of (thiophen-2-yl)
substituted pyrimidines is described. These
p-conjugated hetero-
cyclic systems consisting of thiophene/bithiophene units, as
electron-donating fragments attached to the pyrimidine ring, as
electron acceptor, are rather interesting for elucidation of their
photophysical and electrochemical properties.7 One of the tradi-
tional methods for the synthesis of such compounds is the Suzu-
kieMiyaura cross-coupling reaction.7,8 In this communication we
wish to report a new convenient approach to (thiophen-2-yl)
substituted pyrimidines by using a combination of two CeC cou-
pling reactions, i.e., the SuzukieMiyaura palladium-catalyzed cross-
coupling and the nucleophilic aromatic substitution of hydrogen.
Fig. 2. X-ray structure of 3b.
2. Results and discussion
Attempts to react compounds 5a,b with thiophene 2a or 2-
bromothiophene 2b in CF3COOH to obtain the products of double
nucleophilic substitution of hydrogen have failed. No traces of 4,6-
disubstituted pyrimidines 6aec have been observed in the reaction
mixtures by GCeMS (Scheme 3). A low reactivity of 5a,b toward
thiophenes 2a,b is probably due to the presence of the electron-
donating thienyl group at C(4) of the pyrimidine ring.
Compounds 4a,b have further been involved in the Suzu-
kieMiyaura cross-coupling reaction with 2-thienylboronic acid (2c)
under microwave irradiation, thus resulting in the formation of 4,5-
di(thiophen-2-yl)pyrimidine (8a) and 4-([2,20]-bithiophenyl-5-yl)-
5-(thiophen-2-yl)pyrimidine (9) in good yields (Scheme 4, Table 2).
The structure of compounds 8a and 9 has unequivocally been
established by X-ray crystallography (Figs. 3 and 4).
It has been shown earlier that pyrimidine, 5-methylpyrimidine
and their benzoanneleted analogs react in the presence of tri-
fluoroacetic acid with a number of aromatic compounds, such as
phenols, pyrroles, indoles, and thiophenes, to form rather stable 4-
aryl substituted 3,4-dihydropyrimidinium salts.9
Indeed, when thiophene 2a or 2-bromothiophene 2b was added
to a solution of 5-bromopyrimidine 1 in CF3COOH, and the reaction
mixture was stirred at room temperature for 24 h, thiophenyl
substituted dihydropyrimidines 3a or 3b were obtained as white
crystalline products in high yields (65e80%) (Scheme 2).
It is worth noting that in the reaction of 5-bromo-4-(5-
bromothiophen-2-yl)pyrimidine (4b) with 2-thienylboronic acid
(2c) the compound (10) is formed as by-product. Molecular ion
[M]þ for 10 is m/z 244, and it coincides with the molecular weight
of 8a, however the difference in retention times for these com-
pounds is about 2 min. In order to distinguish these compounds,
the synthesis of 10 was carried out by reacting 4-(5-
bromothiophen-2-yl) pyrimidine (5b) with 2-thienylboronic acid
(2c) under the same reaction conditions. The retention time for the
obtained compound 10 proved to coincide with that for by-product
derived from the reaction of 4b with 2c. Moreover, the crystal
structure of 4-([2,20]-bithiophenyl-5-yl)pyrimidine (10) was con-
firmed by X-ray diffraction (see Fig. 5).
Scheme 2.
The structure of thiophenyl substituted dihydropyrimidines 3a,b
has been established by X-ray crystallography analysis (Figs.1 and 2).
Dihydropyrimidines 3a,b are considered to be intermediate sH
-
adducts and, indeed, they can be transformed into SNH-products 4
and 5. Use of KOH/K3Fe(CN)6 in water as the oxidative system en-
abled us to transform dihydropyrimidines 3a,b into the products of
nucleophilic aromatic substitution of hydrogen 4a,b. The reaction
proceeds via the classical two-step “AdditioneOxidation” pathway
The method for obtaining of 4,5-dithiophenyl substituted py-
rimidines described above is not unique one, and can be com-
H
plemented with the inverted sequence of the SN and cross-
coupling reactions. In order to realize it, we have obtained 5-(thi-
ophen-2-yl)pyrimidine (11), and its reactivity in the SNH-reactions
with thiophene 2a and 2-bromothiophene 2b in CF3COOH have
been investigated.
Compound 11 was obtained in 55% yield according to a similar
cross-coupling procedure under microwave activation at 150 ꢀC in
THF/H2O (3:4) (Scheme 5).
Pyrimidine 11 was dissolved in trifluoroacetic acid, the corre-
sponding thiophene 2a or 2b was added, and the reaction mixture
was stirred under room temperature for 24 h (Scheme 6). According
to GCeMS spectra the major components in these mixtures proved
to be the corresponding 1,2-dihydropyrimidines 12a,b. Besides
that, the presence of 4-(5-bromothiophen-2-yl)-5-(thiophen-2-yl)-
3,4-dihydropyrimidin-1-ium (12b) trifluoroacetate was confirmed
by 1H NMR spectroscopic analysis, as clearly indicated by the
characteristic signal at 6.13 ppm, which corresponds to the proton
resonance at sp3-carbon of C(4) atom of the pyrimidine ring. Re-
action mixtures containing 12a or 12b without additional purifi-
cation were oxidized with K3Fe(CN)6 (1.0 mmol) in 33% aqueous
solution KOH for 2 h (Scheme 6). These reaction mixtures have also
been analyzed by GLCeMS. Unfortunately, 4,5-dithiophenyl
H
SN (AO). On the contrary, in the presence of secondary amines
(diethylamine, piperidine or morpholine) aromatization of com-
pounds 3a,b takes place due to the elimination of HBr, thus yielding
4-(thiophen-2-yl) (5a) and 4-(5-bromothiophen-2-yl) substituted
pyrimidine (5b), as products of cine-substitution of hydrogen
(Table 1).
Fig. 1. X-ray structure of 3a.

E.V. Verbitskiy et al. / Tetrahedron 68 (2012) 5445e5452
5447
Table 1
Effects of reaction conditions on structure and yields of SNH-products (4a,b or 5a,b) derived from
s
H-adducts 3a,b
Entry
1
s
H-Adducts
Oxidative system
Time, h
1
SNH-Products
Isolated yields (%)
42
Reaction mixturesa GCeMS (%)
3a
KOHeK3Fe(CN)6eH2O
4a
4ad95
3ad5
d
2
3
3a
3b
KOHeK3Fe(CN)6eH2O
KOHeK3Fe(CN)6eH2O
2
1
4a
4b
75
39
4bd76
5bd7
3be17
d
4
5
3b
3b
KOHeK3Fe(CN)6eH2O
Oxygen of air/diethylamine
2
24
4b
5a
69
38
5ad55
4ad11
3ad34
6
7
8
3a
3a
3b
Oxygen of air/piperidine
Oxygen of air/morpholine
Oxygen of air/diethylamine
24
24
24
5a
5a
5b
75
82
67
5ad82
Impuritiesd18
5ad87
Impuritiesd13
5bd74
4bd17
3bd9
9
3b
3b
Oxygen of air/piperidine
Oxygen of air/morpholine
24
24
5b
5b
78
77
5bd98
Impuritiesd2
5bd96
Impuritiesd4
10
a
For the reaction mixtures to study the solvent was distilling off solvent and the residue was analyzed by GCeMS.
Scheme 3.
Fig. 3. X-ray structure of 8a.
substituted pyrimidines 8a,b were obtained in moderate yields
(30e70%). The results of the SNH-reactions performed are sum-
marized in Table 3.
3. Conclusion
A combination of the cross-coupling and SNH-reactions proved
to be a versatile tool for the synthesis of pyrimidines bearing
thiophene fragments. The X-ray crystallography data for a number
of mono- and di(thiophenyl) substituted pyrimidines support the
proposed structures.
Scheme 4.
Table 2
The microwave-assisted SuzukieMiyaura cross-coupling reaction of monothiophenyl substituted pyrimidines (4a,b and 5b) with 2-thienylboronic acid (2c)a
Entry
Monothiophenyl substituted pyrimidine
Isolated yields (%)
Reaction mixtures, according to the data of GCeMS (%)
1
4a
4b
8ad57
9d59
8ad63 Ph3POd37
9d62
2b
10d11
10d13
Ph3POd25
10d71
3
5b
10d68
Ph3POd29
Unless otherwise indicated, the reaction conditions were as follows: starting SNH-compound (0.5 mmol), 2c (0.6 mmol), Pd(PPh3)4 (5 mol %), and K2CO3 (2.5 equiv) in
a
a mixture of THF (3 mL) and H2O (4 mL) at 150 ꢀC.
The reaction conditions were as follows: starting SNH-compound (0.5 mmol), 2c (1.2 mmol), Pd(PPh3)4 (10 mol %), and K2CO3 (5.0 equiv) in a mixture of THF (3 mL) and
b
H2O (4 mL) at 150 ꢀC.

5448
E.V. Verbitskiy et al. / Tetrahedron 68 (2012) 5445e5452
m/z 20e1000 and
a
quartz capillary column HP-5MS
(30 mꢁ0.25 mm, film thickness 0.25 mm). Helium served as a car-
rier gas, the split ratio of the flow was 1:50, and the consumption
through the column was 1.0 mL minꢂ1; the initial temperature of
the column was 40 ꢀC (storage 3 min), programming rate was
10 ꢀC minꢂ1e290 ꢀ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 tempera-
ture of the transition chamber was 280 ꢀC. Solutions of the samples
with a concentration of 3e4 mg mLꢂ1 were prepared in acetonitrile.
Samples of 1 mL of the obtained solutions were analyzed.
Column chromatography was carried out using Lancaster silica
gel 0.040e0.063 mm (230e400 mesh), eluting with ethyl acetate/
hexane, 1:2. 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 (l 254 or 365 nm).
Fig. 4. X-ray structure of 9.
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 temperature of the reaction was monitored using an
inserted IR sensor by the external surface of the reaction vessel.
X-ray intensity data were collected with a Xcalibur CCD diffrac-
ꢀ
tometer using Mo-K
a
(
l
¼0.71069 A) radiation at T¼295(2) K. Crystal
data and data collection parameters are summarized in Table 4. Unit
cell parameters were refined using all collected spots after the in-
tegration process. For 3a and 10 multi-scan methods of absorption
data correction, and for 3b and 8a the analytical absorption data
correction were used.12 Structures were solved by direct methods
with SHELX97.13 All the structures were refined by full-matrix least
squares on F2 using SHELX97. All the non-hydrogen atoms were
refined with anisotropic temperature factors. The hydrogen atoms
were calculated with AFIX. The H atoms were included in the re-
finement with an isotropic temperature factor. The details of the
refinement and the final R indices are presented in Table 4. De-
position numbers CCDC 863232 for 3a, CCDC 863233 for 3b, CCDC
863235 for 8a, CCDC 863234 for 9, and CCDC 863236 for 10 contain
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Fig. 5. X-ray structure of 10.
4. Experimental section
4.1. General information
Solvents and reagents were dried and purified according to the
described procedures.10
Products 4a, 5a, 9 and 11 have previously7,8c,11 been character-
ized, and the data obtained corresponded satisfactorily with NMR
and MS data, and comparison with authentic samples.
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. All signals in the 1H and 13C NMR spectra were assigned
on the basis of 2D 1He1H COSY, 1He13C HSQC and HMBC experi-
ments. Elemental analysis was carried on a Eurovector EA 3000
automated analyzer. Melting points were determined on Boetius
combined heating stages and were not corrected.
4.2. General procedure for the synthesis of sH
-
adductsdtrifluoroacetate 5-bromo-4-(5-X-thiophen-2-yl)-
3,4-dihydropyrimidiniums (3a,b)
Thiophene (2a) (50
mL, 2.0 mmol) or 2-bromothiophene (2b)
The GCeMS analysis of all samples was carried out using an
Agilent GC 7890A MS 5975C Inert XL EI/CI GCeMS spectrometer
with a quadrupole mass-spectrometric detector with electron
ionization (70 eV) and scan over the total ionic current in the range
(64 L, 2.0 mmol) was added to a solution of 5-bromopyrimidine
m
(1) (159 mg, 1.0 mmol) in CF3COOH (4 mL). The reaction mixture
was stirred for 24 h, evaporated, and the residue was washed with
EtOAc (3ꢁ10 mL). The precipitate that formed was filtered off and
dried.
_
CF COO
3
6
H
Br
5
+
N
1
1'
4
2'
S
2
N
H
5'
3
Scheme 5.
H
3'
4'
3a
4.2.1. Trifluoroacetate 5-bromo-4-thiophen-2-yl-3,4-dihydropyrimi-
diniums (3a). Yield (286 mg, 80%), white crystal powder; mp
165e166 ꢀC. dH (500 MHz, CD3CN) 2.20e5.60 (br s, 2H, NH), 5.87
(m, 1H, H-4, J¼0.6 Hz), 6.84 (dd, 1H, H-6, J¼0.8, 0.6 Hz), 7.07 (dd, 1H,
Scheme 6.

E.V. Verbitskiy et al. / Tetrahedron 68 (2012) 5445e5452
5449
Table 3
Composition of the reaction mixtures for the reaction of 5-(thiophen-2-yl)pyrimidine (11) with thiophenes 2a,b and yields of 4,5-dithiophenyl substituted pyrimidines (4a,b)
Entry
1
Reactants
Reaction mixtures, GLCeMS (%)
Reaction mixtures after oxidation with K3Fe(CN)6, GLCeMS (%)
Isolated yields (%)
11þ2a
8ad5
8ad61
Impuritiesd39
8ad32
12ad43
Impuritiesd52
8bd9
2
11þ2b
8ad1
12bd9
8bd90
8bd73
12bd91
Table 4
Crystal data and structure refinement for compounds 3a,b, 8a, 9 and 10
Compound
3a
3b
8a
9
10
Crystal size, mm
Crystal color
0.24ꢁ0.19ꢁ0.15
Colorless
C10H8BrF3N2O2S
Monoclinic
P21/c
12.3961(6)
9.4931(12)
11.2026(10)
90
93.745(6)
90
1315.5(2), 4
3.318
0.30ꢁ0.19ꢁ0.03
Colorless
C10H7Br2F3N2O2S
Monoclinic
P21/c
14.2706(18)
9.8243(11)
11.0938(10)
90
111.888(9)
90
1443.2(3), 4
5.795
0.22ꢁ0.12ꢁ0.05
Colorless
C12H8N2S2
Monoclinic
P21/c
5.6728(4)
13.1845(8)
14.9097(9)
90
94.127(5)
90
1112.25(12), 4
0.448
0.24ꢁ0.19ꢁ0.08
Yellow
C16H10N2S3
Monoclinic
P21/n
7.5862(6)
5.9836(9)
32.368(4)
90
95.199(8)
90
0.25ꢁ0.15ꢁ0.05
Colorless
C12H8N2S2
Monoclinic
P21/c
9.7914(7)
5.7843(4)
19.7378(14)
90
95.026(6)
90
1113.58(14), 4
0.448
Empirical formula
Crystal system
Space group
ꢀ
a, A
ꢀ
b, A
ꢀ
c, A
a
b
g
3
ꢀ
Volume (A ), Z
1463.2(3), 4
0.499
m
, mmꢂ1
Reflections collected
7707
7276
5948
7802
5645
Independent reflections (Rint
Reflections with I>2s(I)
)
3132 (0.0287)
1424
2864 (0.0313)
1445
2250 (0.0304)
1264
2988 (0.0517)
1316
2716 (0.0241)
1392
S
1.000
1.001
1.001
1.000
1.000
R1 [I>2
s(I)]
0.0400
0.0430
0.0486
0.0450
0.0347
wR2 [I>2
s
(I)]
0.0781
0.0882
0.1218
0.0631
0.0584
R1 (all data)
0.1030
0.1025
0.0845
0.1235
0.0845
wR2 (all data)
Largest diff. peak and hole, e/A
Completeness to (deg.)
0.0827
0.0958
0.1288
0.0688
0.0618
3
ꢀ
ꢁ
0.521 and ꢂ0.595
0.717 and ꢂ0.718
0.471 and ꢂ0.294
0.271 and ꢂ0.295
0.248 and ꢂ0.185
q
98.0% (26.00)
97.5% (26.00)
99.1% (26.37)
98.9% (26.40
98.8% (26.00)
H-40, J¼5.1, 3.6 Hz), 7.22 (ddd, 1H, H-30, J¼3.6, 1.3, 0.5 Hz), 7.54 (ddd,
1H, H-50, J¼5.1, 1.3, 0.5 Hz), 8.13 (d, 1H, H-2, J¼0.8 Hz); dC (126 MHz,
27.55; H, 1.62; N, 6.42; S, 7.35. Found: C, 27.53; H, 1.41; N, 6.52;
S, 7.64.
1
CD3CN) 55.52 (C-4), 105.80 (C-5), 118.16 (q, CF3, JCF¼294.1 Hz),
123.73 (C-6), 128.51 (C-40), 129.22 (C-30), 129.36 (C-50), 143.82 (C-2),
161.95 (q, COO, 2JCF¼33.6 Hz); dF (470.5 MHz, CD3CN) 88.60 (s,
CF3); Anal. Calcd for C10H8BrF3N2O2S (357.15): C, 33.63; H, 2.26; N,
7.84; S, 8.98. Found: C, 33.82; H, 2.29; N, 8.00; S, 8.95.
4.3. General procedure for the synthesis of 5-bromo-4-(5-X-
thiophen-2-yl)-pyrimidines (4a,b)
Compound 3a (or 3b) (0.5 mmol) was added to 3 mL of 33% KOH
aqueous solution. After that a solution of K3Fe(CN)6 (329 mg,
1.0 mmol) in 2 mL water was added. The resulting mixture was
stirred for an appropriate time (see Table 1, entries 1e4). After all
starting material was consumed, the reaction mixture was poured
into CHCl3 (10 mL), washed with water, extracted with CHCl3
(2ꢁ5 mL), dried with anhydrous Na2SO4 and evaporated under
vacuum. The residue was purified by flash column chromatography
(hexane/ethyl acetate) to afford the desired SNH-products (4a,b).
_
CF COO
3
6
1
H
Br
5
+
N
1'
4
2'
S
2
N
H
Br
3
H
5'
3'
4'
3b
6
Br
1
N
5
1'
2'
S
2
4
N
3
5'
3'
4'
4a
4.2.2. Trifluoroacetate 5-bromo-4-(5-bromothiophen-2-yl)-3,4-
dihydropyrimidiniums (3b). Yield (283 mg, 65%), white crystal
powder; mp 163e165 ꢀC. dH (500 MHz, CD3CN) 2.20e5.50 (2H, br s,
NH), 5.82 (s, 1H, H-4), 6.84 (s, 1H, H-6), 7.03 (d, 1H, H-30, J¼3.9 Hz),
7.10 (d, 1H, H-40, J¼3.9 Hz), 8.11 (s, 1H, H-2); dC (126 MHz, CD3CN)
55.66 (C-4), 104.93 (C-5), 115.33 (C-50), 118.17 (q, CF3,
1JCF¼294.1 Hz), 124.22 (C-6), 129.96 (C-30) 131.76 (C-40), 145.57 (C-
4.3.1. 5-Bromo-4-thiophen-2-yl-pyrimidine (4a).11 Yield (see Table
1, entries 1e2), pale yellow powder; mp 50e52 ꢀC (lit.11
208e210 ꢀC). dH (500 MHz, CDCl3) 7.20 (dd, 1H, H-40, J¼5.0,
3.9 Hz), 7.63 (dd, 1H, H-50, J¼5.0, 1.0 Hz), 8.43 (dd, 1H, H-30, J¼3.9,
1.0 Hz), 8.84 (s, 1H, H-6), 9.02 (s, 1H, H-2); dC (126 MHz, CDCl3)
115.42 (C-5), 128.26 (C-40), 131.81 (C-30), 131.98 (C-50), 140.71 (C-20),
2
20), 148.43 (C-2), 161.89 (q, COO, JCF¼33.9 Hz); dF (470.5 MHz,
CD3CN) 88.56 (s, CF3); Anal. Calcd for C10H7Br2F3N2O2S (436.05): C,

5450
E.V. Verbitskiy et al. / Tetrahedron 68 (2012) 5445e5452
156.23 (C-2),156.30 (C-4),160.82 (C-6); GC tR 19.11 min; MS m/z (rel
intensity) 240 (Mþ,100) for 79Br, 242 (Mþ,100) for 81Br; Anal. Calcd
for C8H5BrN2S (241.11): C, 39.85; H, 2.09; N,11.62; S,13.30. Found: C,
39.94; H, 2.39; N, 11.51; S, 13.05.
C8H5BrN2S (241.11): C, 39.85; H, 2.09; N, 11.62; S, 13.30. Found: C,
39.77; H, 2.12; N, 11.36; S, 13.63.
4.5. General procedure for the microwave-assisted Suzuki
cross-coupling reactions
6
5
Br
1
N
1'
A solution of K2CO3 (346 mg, 2.5 mmol) in 4 mL H2O was added
to a mixture of bromo-substituted pyrimidine (1, 4a or 5b)
(0.5 mmol), 2-thienylboronic acid (77 mg, 0.6 mmol), and Pd(PPh3)4
(29 mg, 5 mol %) in 3 mL THF. The resulting mixture was irradiated
in a microwave apparatus at 150 ꢀC (250 W) for 15 min. After that
solvent was distilled off in vacuo, and the residue was purified by
flash column chromatography (hexane/ethyl acetate) to afford the
desired cross-coupling products (8a, 10 and 11).
2'
S
2
4
N
Br
3
5'
3'
4b
4'
4.3.2. 5-Bromo-4-(5-bromothiophen-2-yl)-pyrimidine
(4b). Yield
(see Table 1, entries 3e4), pale yellow powder; mp 132e133 ꢀC. dH
(500 MHz, CDCl3) 7.15 (d, 1H, H-40, J¼4.2 Hz), 8.18 (d, 1H, H-30,
J¼4.2 Hz), 8.83 (s, 1H, H-6), 8.98 (s, 1H, H-2); dC (126 MHz, CDCl3)
114.86 (C-5), 120.53 (C-50), 131.30 (C-40), 132.34 (C-30), 142.20 (C-20),
155.17 (C-4),156.20 (C-2),160.92 (C-6); GC tR 21.90 min; MS m/z (rel
intensity) 319 (Mþ,100) for both 79Br, 320 (Mþ, 50) for 79Br and 81Br,
321 (Mþ, 50) for both 81Br; Anal. Calcd for C8H4Br2N2S (320.01): C,
30.03; H, 1.26; N, 8.75; S, 10.02. Found: C, 30.28; H, 1.18; N, 8.67; S,
9.89.
4'
3'
2'
5'
6
1
S
S
N
5
1'
1''
2''
2
4
N
5''
3
3''
4''
8a
4.4. General procedure for the synthesis of 4-(5-X-thiophen-
2-yl)-pyrimidines (5a,b)
Compound 3a (or 3b) (0.5 mmol) was dissolved in 3 mL of the
corresponding secondary amine (diethylamine, piperidine or
morpholine). The resulting solution was stirred for 24 h at room
temperature, the solvent was distilled off in vacuo, and the residue
was purified by flash column chromatography (hexane/ethyl ace-
tate) to afford the desired SNH-cine-products (5a,b).
4.5.1. 4,5-Dithiophen-2-yl-pyrimidine (8a). It was obtained from
compound 4a. Yield (see Table 2, entry 1), beige powder; mp
100e103 ꢀC. dH (500 MHz, CDCl3) 6.94 (dd, 1H, H-400, J¼5.0, 3.9 Hz),
7.06 (dd, 1H, H-300, J¼3.9, 1.1 Hz), 7.14 (dd, 1H, H-30, J¼3.5, 1.3 Hz),
7.18 (dd, 1H, H-40, J1¼5.1, 3.5 Hz), 7.46 (dd, 1H, H-500, J¼5.0, 1.1 Hz),
7.52 (dd,1H, H-50, J¼5.1,1.3 Hz), 8.64 (s,1H, H-6), 9.11 (s,1H, H-2); dC
(126 MHz, CDCl3) 124.14 (C-5),127.74 (C-50),127.88 (C-40),128.11 (C-
400), 128.47 (C-30), 130.84 and 130.86 (C-500, C-300), 136.28 (C-20),
141.06 (C-200), 157.55 (C-4), 157.79 (C-2), 159.07 (C-6); GC tR
22.92 min; MS m/z (rel intensity) 244 (Mþ, 100); Anal. Calcd for
C12H8N2S2 (244.34): C, 58.99; H, 3.30; N, 11.46; S, 26.25. Found: C,
58.94; H, 3.39; N, 11.53; S, 26.14.
6
1
5
N
1'
2'
2
S
4
N
3
5'
3'
4'
5a
4.4.1. 4-Thiophen-2-yl-pyrimidine (5a).7 Yield (see Table 1, entries
5e7), pale yellow powder; mp 61e63 ꢀC (lit.7 54e56 ꢀC). dH
(400 MHz, CDCl3) 7.17 (dd, 1H, H-40, J¼5.0, 3.7 Hz), 7.55 (dd, 1H, H-
50, J¼5.0, 1.2 Hz), 7.58 (dd, 1H, H-5, J¼5.3, 1.4 Hz), 7.78 (dd, 1H, H-30,
J¼3.7, 1.2 Hz), 8.68 (d, 1H, H-6, J¼5.3 Hz), 9.14 (d, 1H, H-2, J¼1.4 Hz);
GC tR 16.40 min; MS m/z (rel intensity) 162 (Mþ, 100); Anal. Calcd
for C8H6N2S (162.21): C, 59.24; H, 3.73; N, 17.27; S, 19.77. Found: C,
59.14; H, 3.59; N, 17.40; S, 19.87.
6
5
1
N
1'
1''
2'
S
S
2
5''
4''
4
N
5'
3
2''
3'
4'
3''
10
6
1
5
N
1'
2'
S
2
4
5'
N
Br
4.5.2. 4-[2,20]-Bithiophenyl-5-yl-pyrimidine (10).7 It has been
obtained from compound 5b. Yield (see Table 2, entries 2 and 3),
bright yellow powder; mp 118e121 ꢀC (lit.7 113e115 ꢀC). dH
(500 MHz, CDCl3) 7.07 (dd, 1H, H-400, J¼5.1, 3.6 Hz), 7.23 (d, 1H, H-40,
J¼3.9 Hz), 7.30 (dd, 1H, H-500, J¼5.1, 1.1 Hz), 7.31 (dd, 1H, H-300, J¼3.6,
1.1 Hz), 7.55 (dd, 1H, H-5, J¼5.4, 1.4 Hz), 7.68 (d, 1H, H-30, J¼3.9 Hz),
8.67 (d, 1H, H-6, J¼5.4 Hz), 9.12 (d, 1H, H-2, J¼1.4 Hz); dC (126 MHz,
CDCl3) 114.82 (C-5), 124.71 (C-40), 124.92 (C-300), 125.74 (C-500),
128.15 (C-400), 128.43 (C-30), 136.72 (C-200), 140.03 (C-20), 142.37 (C-
50), 157.03 (C-6), 158.52 (C-4), 159.08 (C-2); GC tR 24.90 min; MS m/z
(rel intensity) 244 (Mþ, 100); Anal. Calcd for C12H8N2S2 (244.34): C,
58.99; H, 3.30; N, 11.46; S, 26.25. Found: C, 59.04; H, 3.27; N, 11.57;
S, 26.12.
3
3'
4'
5b
4.4.2. 4-(5-Bromothiophen-2-yl)-pyrimidine (5b). Yield (see Table
1, entries 8e10), beige powder; mp 149e151 ꢀC. dH (400 MHz,
CDCl3) 7.13 (d, 1H, H-30(40), J¼4.0 Hz), 7.50 (dd, 1H, H-5, J¼5.5,
1.4 Hz), 7.51 (d, 1H, H-40(30), J¼4.0 Hz), 8.69 (d, 1H, H-6, J¼5.5 Hz),
9.11 (d, 1H, H-2, J¼1.4 Hz); GC tR 19.47 min; MS m/z (rel intensity)
240 (Mþ, 100) for 79Br, 242 (Mþ, 100) for 81Br; Anal. Calcd for

E.V. Verbitskiy et al. / Tetrahedron 68 (2012) 5445e5452
5451
4'
vacuum. The residue was purified by flash column chromatography
and the desired compounds (8a or 8b) were obtained in the cor-
responding yields (see Table 2, entries 1 and 2).
3'
6
5'
5
1
2'
S
1'
N
2
4
N
3
_
4'
11
CF COO
3'
2'
3
5'
6
1
H
S
S
N
5
1'
+
1''
2''
2
N
H
4
Br
4.5.3. 5-Thiophen-2-yl-pyrimidine (11).8c It has been obtained from
compound 1. Yield (45 mg, 55%), pale yellow powder; mp 77e78 ꢀC
(lit.8c 77.2e78.0 ꢀC). dH (400 MHz, CDCl3) 7.18 (dd, 1H, H-40, J¼5.0,
3.6 Hz), 7.44 (dd, 1H, H-30, J¼3.6, 1.1 Hz), 7.47 (dd, 1H, H-50, J¼5.0,
1.1 Hz), 8.98 (s, 2H, H-4 and H-6), 9.13 (s, 1H, H-2); GC tR 16.04 min;
MS m/z (rel intensity) 162 (Mþ, 100); Anal. Calcd for C8H6N2S
(162.21): C, 59.24; H, 3.73; N, 17.27; S, 19.77. Found: C, 59.18; H,
3.63; N, 17.55; S, 19.64.
3
H
5''
3''
4''
12b
4.7.1. 4-(5-Bromothiophen-2-yl)-5-(thiophen-2-yl)-3,4-
dihydropyridin-1-ium (12b). It’s obtained as the reaction mixture
(brown oil). dH (400 MHz, CD3CN) 6.13 (s, 1H, H-4), 6.95 (s, 1H, H-6),
6.98 (dd, 1H, H-40, J¼5.0, 3.8 Hz) 7.04e7.07 (m, 3H, H-30, H-300, H-
400), 7.35 (dd, 1H, H-50 J¼5.0, 0.9 Hz), 8.08 (s, 1H, H-2), 11.3 (br s, 1H,
NH); GC tR 28.26 min; MS m/z (rel intensity) 324 (Mþ-CF3COOH,
100) for 79Br, 326 (Mþ-CF3COOH, 100) for 81Br.
4'
3'
6
5'
1
5
2'
S1'
N
1'''
5'''
S
1''
2''
S
2
2'''
5''
4
N
3
4'''
3'''
3''
4''
4'
3'
2'
9
5'
6
1
S
S
N
5
1'
1''
2''
2
4
N
Br
3
5''
4.6. Synthesis of 4-[2,20]-Bithiophenyl-5-yl-5-thiophen-2-yl-
pyrimidine (9)
3''
4''
8b
A solution of K2CO3 (691 mg, 5.0 mmol) in 4 mL H2O was added to
a mixture of 5-bromo-4-(5-bromothiophen-2-yl)-pyrimidine (4b)
(160 mg, 0.5 mmol), 2-thienylboronic acid (154 mg, 1.2 mmol) and
Pd(PPh3)4 (58 mg, 10 mol %) in 3 mL THF. The resulting mixture was
irradiated in a microwave apparatus at 150 ꢀC (250 W) for 15 min.
After that solvent was distilled off in vacuo, and the residue was
purified by flash column chromatography (hexane/ethyl acetate) to
afford the desired cross-coupling products 9. Compound 9 was
obtained as a bright yellow powder; yield (163 mg, 59%); mp
120e122 ꢀC. dH (500 MHz, CDCl3) 6.87 (d, 1H, H-300, J¼4.0 Hz), 6.99
(d,1H, H-400, J¼4.0 Hz), 7.03 (dd,1H, H-4000, J¼5.1, 3.7 Hz), 7.16 (dd,1H,
H-30, J¼3.5, 1.2 Hz), 7.19 (dd, 1H, H-40, J¼5.1, 3.5 Hz), 7.25 (dd, 1H, H-
3000, J¼3.7, 1.2 Hz), 7.26 (dd, 1H, H-5000, J¼5.1, 1.2 Hz), 7.53 (d, 1H, H-50,
J¼5.1,1.2 Hz), 8.61 (s,1H, H-6), 9.09 (s,1H, H-2); dC (126 MHz, CDCl3)
123.91 (C-5), 124.58 (C-400), 124.87 (C-3000), 125.66 (C-5000), 127.80 (C-
50), 127.97 (C-40), 128.08 (C-4000), 128.45 (C-30), 131.78 (C-300), 136.28
(C-20), 136.71 (C-2000), 139.50 (C-200), 142.53 (C-500), 157.19 (C-4),
157.84 (C-2), 159.07 (C-6); GC tR 29.99 min; MS m/z (rel intensity)
326 (Mþ,100); Anal. Calcd for C16H10N2S3 (326.46): C, 58.87; H, 3.09;
N, 8.58; S, 29.46. Found: C, 59.01; H, 3.23; N, 8.41; S, 29.35.
4.7.2. 4-(5-Bromothiophen-2-yl)-5-thiophen-2-yl-pyrimidine
(8b). Yield (see Table 3, entry 2), yellow crystal powder; mp
174e177 ꢀC. dH (500 MHz, CDCl3) 6.80 (d, 1H, H-300, J¼4.1 Hz), 6.89
(d, 1H, H-400, J¼4.1 Hz), 7.13 (dd, 1H, H-30, J¼3.5, 1.0 Hz), 7.18 (dd, 1H,
H-40, J¼5.1, 3.5 Hz), 7.54 (dd, 1H, H-50, J¼5.1, 1.0 Hz), 8.62 (s, 1H, H-
6), 9.07 (s, 1H, H-2); dC (126 MHz, CDCl3) 119.29 (C-500), 123.75 (C-5),
128.02 (2C, C-40, C-50), 128.62 (C-30), 131.10 (C-400), 131.15 (C-300),
135.67 (C-20), 142.60 (C-200), 156.50 (C-4), 157.83 (C-2), 159.28 (C-6);
GC tR 25.29 min; MS m/z (rel intensity) 321 (Mþ, 100) for 79Br, 323
(Mþ, 100) for 81Br; Anal. Calcd for C12H7BrN2S2 (323.23): C, 44.59;
H, 2.18; N, 8.67; S, 19.84. Found: C, 44.44; H, 2.39; N, 8.53; S, 19.92.
Acknowledgements
This work was supported by the Ural Division of the Russian
Academy of Sciences (Program of Support of Young Scientists and
Post-Graduates No. 11-3-NP-627; Grants 12-P-3-1014, 12-T-3-1025
and 12-T-3-1031), the State Program for Supporting of Leading
Scientific Schools of the Russian Federation (grant NSh
5505.2012.3) and the Russian Foundation for Basic Research (grant
No. 10-03-96078-r_ural_a). The authors would like to thank Ms.
Rashida K. Novikova for obtaining of the single-crystal X-ray dif-
fraction data.
4.7. General procedure for the synthesis of SNH-productsd4-
(5-X-thiophen-2-yl)-5-thiophen-2-yl-pyrimidines (8a,b)
Thiophene (2a) or 2-bromothiophene (2b) (2 mmol) was added
to a solution of 5-thiophen-2-yl-pyrimidine (11) (81 mg, 0.5 mmol)
in CF3COOH (2 mL). The resulting solution was stirred at room
temperature for 24 h. After removal of the solvent under reduced
pressure the residue was analyzed by GCeMS (and 1H NMR for
12b), and then residue was added to 3 mL of aqueous 33% KOH
solution. After that a solution of K3Fe(CN)6 (329 mg, 1.0 mmol) in
2 mL of water was added. The resulting mixture was stirred for 2 h.
After all starting material was consumed, the reaction mixture was
poured into CHCl3 (10 mL), washed with water, extracted with
CHCl3 (2ꢁ5 mL), dried by anhydrous Na2SO4 and evaporated under
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.04.095. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.

5452
E.V. Verbitskiy et al. / Tetrahedron 68 (2012) 5445e5452
Moller, M.; Lehn, J.-M.; Sell, B.; Schubert, D.; Weidl, C. H.; Schubert, U. S. Angew.
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