Synthesis, characterization, and crystal structures of aryl-substituted ferrocenylpyrimidines by site-selective stepwise couplings of 2,4,6-trichloropyrimidine

Article abstract of DOI:10.1007/s00706-013-1142-0

A new ferrocenylpyrimidine containing chlorine was conveniently prepared via the coupling reaction of chloromercuriferrocene and 2,4,6- trichloropyrimidine, and a monoaryl-substituted ferrocenyl-pyrimidine was also readily obtained from the Suzuki coupling of the former with phenylboronic acid. The following Suzuki coupling of the monoaryl-substituted derivative with arylboronic acids in the presence of Pd(OAc)₂/P(Cy) ₃·HBF₄ gave diaryl-substituted ferrocenylpyrimidines. These compounds were characterized by elemental analysis, IR, MS, ¹H and ¹³C NMR. Additionally, the structures of the three compounds were determined by single-crystal X-ray analysis. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-013-1142-0

Monatsh Chem
DOI 10.1007/s00706-013-1142-0
ORIGINAL PAPER
Synthesis, characterization, and crystal structures
of aryl-substituted ferrocenylpyrimidines by site-selective
stepwise couplings of 2,4,6-trichloropyrimidine
•
Chen Xu Hongmei Li Zhiqiang Wang
•
•
•
Xinhua Lou Weijun Fu
Received: 13 August 2013 / Accepted: 18 December 2013
Ó Springer-Verlag Wien 2014
Abstract A new ferrocenylpyrimidine containing chlo-
rine was conveniently prepared via the coupling reaction of
chloromercuriferrocene and 2,4,6-trichloropyrimidine, and
a monoaryl-substituted ferrocenyl-pyrimidine was also
readily obtained from the Suzuki coupling of the former
with phenylboronic acid. The following Suzuki coupling of
the monoaryl-substituted derivative with arylboronic acids
in the presence of Pd(OAc)2/P(Cy)3ÁHBF4 gave diaryl-
substituted ferrocenylpyrimidines. These compounds were
have therefore attracted extensive attention [6–8]. Most of
the syntheses known to date for the preparation of substituted
pyrimidines rely on the condensation of two or more building
blocks [9–11]. Compared to these conventional methods, the
direct arylation of halopyrimidine is an alternative approach
that does not involve the preparation of product-specific
intermediates. However, examples of this chemistry are
limited [12–15]. Pyrimidine halides are very reactive in
metal-catalyzed cross-couplings [16, 17], and 2,4,6-trichlo-
ropyrimidine represents an interesting substrate for multiple
coupling reactions because it has three halogenated carbon
atoms. To our knowledge, there have been no other reports
concerning diaryl-substituted ferrocenylpyrimidines.
1
characterized by elemental analysis, IR, MS, H and 13C
NMR. Additionally, the structures of the three compounds
were determined by single-crystal X-ray analysis.
Keywords Coupling reaction Á Pyrimidine Á Ferrocene Á
On the other hand, numerous ferrocene-containing het-
erocycles have also proven to be of pharmacological and
therapeutical interest [18, 19]. In recent years, part of our
research effort has focused on the synthesis and application
of ferrocene derivatives containing heterocyclic rings. We
have developed an efficient method for the synthesis of
ferrocenylpyrimidines by the coupling of chloromercuri-
ferrocene with mono- and dihalopyrimidine [20–22]. The
application of chloromercuriferrocene as a source of a ferr-
ocenyl group in Pd-catalyzed coupling reactions has some
advantages, including extra stability and easy availability by
a direct mercuration of ferrocene [23, 24]. Herein, we report
our results related to site-selective stepwise couplings of
2,4,6-trichloropyrimidine, and provide convenient access to
a variety of diaryl-substituted ferrocenylpyrimidines that are
not readily available by other methods.
Crystal structure
Introduction
Pyrimidines are widespread heterocyclic motifs found in
many natural products, pharmaceuticals, and agrochemicals
[1, 2]. In addition, some pyrimidines are used in supramo-
lecular chemistry, functional materials, and organometallic
catalysis [3–5]. The syntheses of these pyrimidine entities
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-013-1142-0) contains supplementary
material, which is available to authorized users.
C. Xu (&) Á Z. Wang Á X. Lou Á W. Fu
College of Chemistry and Chemical Engineering, Luoyang
Normal University, Luoyang 471022, Henan, China
e-mail: xubohan@163.com
Results and discussion
H. Li
Department of Life Science, Luoyang Normal University,
Luoyang 471022, Henan, China
Initially, the coupling of chloromercuriferrocene (1.1 equiv)
and 2,4,6-trichloropyrimidine was performed in the presence
123

C. Xu et al.
Scheme 1
Fig. 1 The dimeric structure of
1 showing the C–HÁÁÁN
hydrogen bonds and p-p
stacking interactions. Non-
hydrogen-bonding H atoms are
omitted for clarity
of 3 mol% of Pd(PPh3)4 (Scheme 1). As expected, the above
coupling product is monoferrocenylpyrimidine. Increasing
chloromercuriferrocene loading to 2.2 equiv, the reaction did
not afford the diferrocenylpyrimidine. The halogen atom at
the 2-position of pyrimidine is known to be less reactive for
the oxidative addition of palladium than positions 4 and 6
[25, 26]. In comparison with the corresponding signal of
2,4,6-trichloropyrimidine [27], the pyrimidine proton of the
product (appearing at d = 7.20 ppm) is obviously shifted
upfield. Moreover, the 13C NMR spectrum of 1 exhibited
four signals for the pyrimidine ring, indicating that the
product 1 was 4-ferrocenylpyrimidine. The structure of the
product has been confirmed by single-crystal X-ray diffrac-
tion. Figure 1 shows that compound 1 exists as a dimer in the
crystal due to intermolecular C–HÁÁÁN hydrogen bonds and
p-p stacking interactions [28, 29].
It is known that the palladium-catalyzed Suzuki reaction
is a versatile technique for the formation of asymmetrical
biaryls [30, 31]. In the following experiments, the Suzuki
coupling of 1 with phenylboronic acid was investigated
(Table 1). The use of Pd(PPh3)4 in the presence of Cs2CO3
in dioxane at 110 °C for 12 h afforded the coupled product
2 in 87 % yield (entry 1). However, the double-coupled
product 3 was not isolated. Other reaction conditions such
as K3PO4 in dioxane and K2CO3 in toluene also afforded
good yields (entries 2 and 3 yielded 84 and 80 %,
respectively). Increasing phenylboronic acid loading to 2.5
equiv did not give product 3 for the present catalytic
systems (entry 4). In order to obtain trisubstituted pyrimi-
dine, we employed Pd(OAc)2/P(Cy)3ÁHBF4 (3/6 mol%) as
a catalyst [32], and the reaction gave a mixture of products
with the trisubstituted pyrimidine 3 as a side product (entry
5). To our delight, under the same conditions, the coupling
of 1 with 2.5 instead of 1.2 equiv of phenylboronic acid
afforded 3 in a good yield (entry 6, 82 %). This protocol
provides an efficient access to a variety of symmetric
diaryl-ferrocenylpyrimidines.
The detailed structures of 2 and 3 were confirmed by
single-crystal X-ray diffraction analysis. Like 1, 2 also
exists as a dimer in the crystal due to p-p stacking inter-
actions between the pyrimidine rings and benzene rings
(Fig. 2). The molecular structure of 3 was shown in Fig. 3.
The pyrimidine rings and substituted cyclopentadienyl
rings are approximately coplanar (dihedral angles of 2.4°
and 1.3°) in the two independent molecules. However, one
of benzene rings and the pyrimidine rings are not coplanar,
with dihedral angles of 25.3° and 31.0°. It is worth noting
that the intermolecular C–HÁÁÁp and p-p stacking interac-
tions are present in the crystal of 3, resulting in a 2D
supramolecular architecture (Fig. 4).
Finally, this newly developed coupling protocol was
also successfully applied to the synthesis of asymmetric
diaryl-substituted ferrocenylpyrimidines via the Suzuki
coupling of 2. Other arylboronic acids could be coupled
efficiently under the same reaction conditions (Cs2CO3,
Pd(OAc)2/P(Cy)3ÁHBF4) (Table 2). Electron-donating
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Aryl-substituted ferrocenylpyrimidines
Table 1 Suzuki coupling reaction of 1 with phenylboronic acid
Entry
Conditions
Equiv. PhB(OH)2
Yields/%a
2
3
1b
2b
3b
4b
5c
6d
Cs2CO3, dioxane
1.2
1.2
1.2
2.5
1.2
2.5
87
Trace
Trace
Trace
Trace
15
K3PO4, dioxane
84
K2CO3, toluene
80
Cs2CO3 (3.0 equiv), dioxane
Pd(OAc)2/P(Cy)3ÁHBF4 (3/6 mol%)
Pd(OAc)2/P(Cy)3ÁHBF4 (3/6 mol%)
89
61
trace
82
Reaction conditions: 1 (1.0 mmol), base (1.5 equiv), 5 cm3 solvent, 110 °C, 12 h
a
Isolated yields
b
Pd(PPh3)4 (3 mol%)
Cs2CO3 (1.5 equiv), 5 cm3 dioxane
c
d
Cs2CO3 (3.0 equiv)
Fig. 2 The dimeric structure of
2 showing the p-p stacking
interactions. H atoms are
omitted for clarity
substrates 4-methylphenylboronic acid and 3-methoxy-
phenylboronic acid reacted with 2 to give the corresponding
products 4 and 5. Their yields (95 and 93 %) are slightly
higher than the yield (83 %) of the electron-withdrawing
substrate, 4-acetylphenylboronic acid (entries 1-3).
In summary, we have reported a convenient synthesis of
diaryl-substituted ferrocenylpyrimidines by site-selective
stepwise couplings of 2,4,6-trichloropyrimidine. The pro-
ducts reported herein are not readily available by other
methods.
123

C. Xu et al.
Fig. 3 Molecular structure of 3
H atoms are omitted for clarity
Fig. 4 Two-dimensional network structure of 3 formed by C–HÁÁÁp and p-p stacking interactions. Non-hydrogen bonding H atoms are omitted
for clarity
(2,6-Dichloropyrimidin-4-yl)ferrocene
Experimental
(1, C14H10Cl2FeN2)
In a flask equipped with a reflux condenser and gas inlet,
2,4,6-trichloropyrimidine (1 mmol), chloromercuriferro-
cene (1.1 mmol), NaI (2 mmol), Pd(PPh3)4 (0.03 mmol),
18 cm3 THF, and 12 cm3 Me2CO were placed under N2
atmosphere. The reaction mixture was then placed in an oil
bath and heated at 70 °C for 6 h. After removal of the
solvent, the residue was purified by column chromatogra-
phy on silica gel using CH2Cl2 as an eluent to give the red
solid 1. Yield: 203 mg (61 %); IR (KBr): v = 3,097, 1,549,
1,515, 1,479, 1,389, 1,257, 1,183, 1,147, 1,105, 864, 818,
All reactions were carried out under a dry nitrogen
atmosphere using standard Schlenk techniques. All other
chemicals were commercially available expect for
chloromercuriferrocene [33]. IR spectra were collected
on a Bruker VECTOR22 spectrophotometer using KBr
pellets. NMR spectra were recorded on a Bruker DPX-
400 spectrometer in CDCl3 with TMS as an internal
standard. The MS spectra were obtained on an LC-MSD-
Trap-XCT instrument at 70 eV. Elemental analyses were
determined with a Thermo Flash EA 1112 elemental
analyzer.
1
753 cm-1; H NMR (400 MHz, CDCl3): d = 7.20 (s, 1H,
123

Aryl-substituted ferrocenylpyrimidines
Table 2 Suzuki coupling reactions of 2 with arylboronic acids
Entry Arylboronic acid
Product
Yield /%a
1
95
4
5
2
3
93
83
6
Reaction conditions: 2 (1.0 mmol), arylboronic acid (1.2 mmol), Pd(OAc)2 (3 mol%), P(Cy)3ÁHBF4 (6 mol%), Cs2CO3 (1.5 mmol), 5 cm3
dioxane, 110 °C, 12 h
a
Isolated yields
PyH), 4.99 (s, 2H, C5H4), 4.61 (s, 2H, C5H4), 4.13 (s, 5H,
C5H5) ppm; 13C NMR (100 MHz, CDCl3): d = 173.6,
161.5, 160.8, 114.4, 78.3, 72.6, 70.6, 68.8 ppm; MS (EI):
m/z = 333.0 ([M ? H]?).
cooled, the mixture was extracted with ethyl acetate and
evaporated, the residue was purified by column chroma-
tography on silica gel using CH2Cl2 as an eluent to give
the red solid 2. Yield: 325 mg (87 %); IR (KBr):
v = 3,080, 1,569, 1,507, 1,496, 1,409, 1,355, 1,243,
1
1,189, 1,032, 853, 821, 754 cm-1; H NMR (400 MHz,
(2-Chloro-6-phenylpyrimidin-4-yl)ferrocene
(2, C20H15ClFeN2)
In a Schlenk tube, a mixture of 1 (1.0 mmol), PhB(OH)2
CDCl3): d = 8.12 (brs, 2H, ArH), 7.58 (s, 1H, PyH),
7.48 (brs, 3H, ArH), 5.06 (s, 2H, C5H4), 4.57 (s, 2H,
C5H4), 4.12 (s, 5H, C5H5) ppm; 13C NMR (100 MHz,
CDCl3): d = 172.4, 166.1, 136.0, 131.5, 129.2, 127.4,
110.5, 79.2, 72.0, 70.4, 68.6 ppm; MS (EI): m/z = 375.0
([M ? H]?).
(1.2 mmol),
Pd(PPh3)4(0.03 mmol),
and
Cs2CO3
(1.5 mmol) in 5 cm3 dioxane was evacuated and charged
with nitrogen. The reaction mixture was then placed in
an oil bath and heated at 110 °C for 12 h. After being
123

C. Xu et al.
1
General procedure for the synthesis of 3–6
821 cm-1; H NMR (400 MHz, CDCl3): d = 8.06–8.11
(m, 4H, ArH), 7.92–7.97 (m, 3H, ArH), 7.80 (s, 2H,
J = 8.4 Hz, ArH), 7.60 (s, 1H, PyH), 5.09 (s, 2H, C5H4),
4.50 (s, 2H, C5H4), 4.07 (s, 5H, C5H5), 2.65 (s, 3H, CH3)
ppm; 13C NMR (100 MHz, CDCl3): d = 197.8, 160.4,
148.2, 145.3, 136.8, 136.1, 135.8, 129.8, 129.2, 128.8,
127.5, 126.9, 126.0, 120.2, 83.8, 70.8, 69.9, 68.2 ppm; MS
(EI): m/z = 459.1 ([M ? H]?).
In a Schlenk tube, a mixture of 2 (1.0 mmol), arylboronic
acid (1.5 mmol), Pd(OAc)2(0.03 mmol), P(Cy)3ÁHBF4
(0.06 mmol), and Cs2CO3 (2.0 mmol) in 5 cm3 dioxane
was evacuated and charged with nitrogen. The reaction
mixture was then placed in an oil bath and heated at 110 °C
for 12 h. After being cooled, the mixture was extracted
with ethyl acetate and evaporated; the residue was purified
by column chromatography on silica gel using CH2Cl2 as
an eluent to give the red solid 3–6.
Crystal structure determination
Crystallographic data for compounds 1–3 were collected on
a Bruker SMART APEX-II CCD diffractometer equipped
with a graphite monochromator at 296 K using Mo–Ka
(2,6-Diphenylpyrimidin-4-yl)ferrocene (3, C26H20FeN2)
Yield: 383 mg (92 %); IR (KBr): v = 3,091, 1,587, 1,564,
1,524, 1,497, 1,372, 1,244, 1,105, 1,074, 863, 821,
;
752 cm-1 1H NMR (400 MHz, CDCl3): d = 8.70 (d,
˚
radiation (k = 0.071073 A). The data were corrected for
Lorentz polarization factors as well as for absorption. The
structures were solved by direct methods and refined by
full-matrix least-squares methods on F2 with the SHELX-
97 program [34]. All non-hydrogen atoms were refined
anisotropically, while hydrogen atoms were placed in
geometrically calculated positions. CCDC reference num-
bers are 939,184-939,186 for 1–3, respectively. These data
can be obtained free of charge from the Cambridge Crys-
tallographic Data Centre via http://www.ccdc.cam.ac.uk/
data_request/cif.
2H, J = 8.2 Hz, ArH), 8.27 (d, 2H, J = 7.8 Hz, ArH),
7.61 (s, 1H, PyH), 7.55 (m, 6H, ArH), 5.16 (s, 2H, C5H4),
4.53 (s, 2H, C5H4), 4.09 (s, 5H, C5H5) ppm; 13C NMR
(100 MHz, CDCl3): d = 168.7, 164.1, 163.4, 138.5, 137.8,
130.7, 130.6, 129.0, 128.5, 127.3, 110.0, 81.4, 71.1, 70.1,
68.3 ppm; MS (EI): m/z = 417.1 ([M ? H]?).
[6-Phenyl-2-(p-tolyl)pyrimidin-4-yl]ferrocene
(4, C27H22FeN2)
Yield: 409 mg (95 %); IR (KBr): v = 3,050, 1,567, 1,524,
1,488, 1,368, 1,237, 1,216, 1,105, 1,026, 818, 753, 943,
816, 769, 756 cm-1
;
1H NMR (400 MHz, CDCl3):
Acknowledgments We are grateful to the National Natural Science
Foundation of China (Nos. 21272110, U1204205) and the Aid Project
for the Leading Young Teachers in Henan Provincial Institutions of
Higher Education of China for financial support of this work.
d = 8.57 (d, 2H, J = 8.2 Hz, ArH), 8.24 (d, 2H,
J = 7.8 Hz, ArH), 7.53–7.57 (m, 4H, ArH ? PyH), 7.33
(d, 2H, J = 8.2 Hz, ArH), 5.14 (s, 2H, C5H4), 4.51 (s, 2H,
C5H4), 4.08 (s, 5H, C5H5), 2.45 (s, 3H, CH3) ppm; 13C
NMR (100 MHz, CDCl3): d = 168.5, 164.3, 163.4, 140.7,
138.0, 135.9, 130.6, 129.7, 129.3, 129.0, 128.5, 127.3,
121.7, 109.8, 81.6, 71.0, 70.1, 68.3, 21.6 ppm; MS (EI): m/
z = 431.1 ([M ? H]?).
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