Cobalt induced C-H bond activation and C8-arylation of caffeine with aryl bromides

Article abstract of DOI:10.1016/j.inoche.2013.01.025

The 8-caffeinyl cobalt(I) complex (C8-caffeinyl)Co(PMe₃) ₄ (1) was obtained by reaction of caffeine with cobalt(I) complex CoMe(PMe₃)₄ via CH bond activation with the escape of methane. The reaction of 1 with ar

Full text of DOI:10.1016/j.inoche.2013.01.025

Inorganic Chemistry Communications 30 (2013) 139–142
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Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
Cobalt induced C\H bond activation and C8-arylation of caffeine with aryl bromides
Tingting Zheng a,b, Hongjian Sun a, Faguan Lu a, Klaus Harms c, Xiaoyan Li a,
⁎
a
School of Chemistry and Chemical Engineering, Shandong University, Shanda Nanlu 27, 250100 Jinan, People's Republic of China
Department of Chemistry, Capital Normal University, 100037 Beijing, People's Republic of China
b
c
Department of Chemistry, University of Marburg, Hans-Meerwein-Strasse, 35032 Marburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The 8-caffeinyl cobalt(I) complex (C8-caffeinyl)Co(PMe3)4 (1) was obtained by reaction of caffeine with
cobalt(I) complex CoMe(PMe3)4 via C\H bond activation with the escape of methane. The reaction of 1
with arylbromide afforded cobalt(II) complex (C8-caffeinyl)Co(PMe3)3Br (2) and the C,C-coupling products
8-aryl caffeine (3 and 4), 8-phenyl caffeine and 8-(2′-pyridinayl)caffeine. The crystal structures of complexes
1 and 2 were determined by X-ray diffraction.
Received 7 December 2012
Accepted 29 January 2013
Available online 4 February 2013
Keywords:
Caffeine
© 2013 Elsevier B.V. All rights reserved.
C,C-coupling
Cobalt
Trimethylphosphine
In the past few years, C\H bond activation mediated by transition-
metal complexes in homogeneous systems has been the subject of
study due to its involvement in important industrial catalytic processes.
C\H bond activation has been an important strategy to directly build a
C\C bond, which shortens the reaction steps and expands the substrate
scope in comparison with traditional reactions, and has been applied as
an efficient method in the chemistry of natural products and drug
molecules.
There has been considerable current interest in the chemistry of
caffeine, largely because of its crucial performance as adenosine re-
ceptor antagonists in biological systems [1]. The replacement of the
8-position of caffeine is of particular interest with reference to the
bioavailability and high selectivity for different classes of adenosine
receptors [2–4]. The conventional methodology of this substitution
suffers from low yields and several steps. Transition metal-catalyzed
cross-coupling procedures have been represented as an effective al-
ternative to obtain the C8-derivative of caffeine [5–16]. In order to
provide more chemical information on this C,C-coupling reaction of
caffeine herein we report our progress in cobalt induced C\H bond
activation and C8-arylation of caffeine with aryl bromides.
The reaction of CoMe(PMe3)4 with equivalents of caffeine caused
the oxidative addition of the C\H bond at the C8 atom of caffeine
affording the intermediate of one cobalt(III) species. The end product
1 was formed through the escape of methane via reductive elimination
(Eq. (1)) [17].
Crystallization from diethyl ether at −27 °C afforded cubic crystal-
line of complex 1 in the yield of 52%. Complex 1 in solid state is stable
for several hours at room temperature. The resonances of the N\CH3
group in the 1H NMR spectra are registered at 3.34 ppm (3H),
3.47 ppm (3H) and 4.09 ppm (3H) in the integral ratio of 1:1:1. The sig-
nals of the protons of the trimethylphosphine lie at 1.50 ppm as multi-
plet corresponding to 36H (4×PMe3). In the 31P NMR spectra two
signals at 14.2 and 40.3 ppm were found in the integral ratio of 1:1.
This result shows that the four trimethylphosphine ligands can be di-
vided into two groups in the ratio of 2:2 with two different chemical
environments.
The molecular structure of complex 1 was determined by X-ray
single crystal diffraction analysis (Fig. 1) [18]. Complex 1 can be consid-
ered as either a strongly distorted tetragonal pyramid with P3 atom at
the apical position or a strongly distorted trigonal bipyramidal geome-
try with P1–Co1–P4 (154.06(5)°) in the axial position. The sum of the
four angles (C1–Co1–P1=84.31(9); C1–Co1–P4=85.23(10); P1–
Co1–P2=90.59(3) and P2–Co1–P4=90.89(4)°) around the cobalt cen-
ter is 351.09° while the sum of the three angles (C1–Co1–P2=
159.32(11); C1–Co1–P3=94.26(11) and P2–Co1–P3=106.42(5)°) is
360°. Because the caffeine plane is in the plane of [C1P2P3], angle C1–
Co1–P2 is much larger than angles C1–Co1–P3 and P2–Co1–P3.
⁎
Corresponding author. Tel.: +86 531 88361350; fax: +86 531 88564464.
E-mail address: xli63@sdu.edu.cn (X. Li).
1387-7003/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.inoche.2013.01.025

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T. Zheng et al. / Inorganic Chemistry Communications 30 (2013) 139–142
Fig. 1. Molecular structure of 1. Selected bond distances (Å) and angles (deg): Co1–C1 1.931(3), Co1–P1 2.1850(10), Co1–P2 2.2009(10), Co1–P3 2.2282(12), Co1–P4 2.2048(10);
C1–Co1–P1 84.31(9), P1–Co1–P2 90.59(3), P2–Co1–P4 90.89(4), C1–Co1–P4 85.23(10), C1–Co1–P3 94.26(11), P1–Co1–P3 103.74(4), P2–Co1–P3 106.42(5), P4–Co1–P3 100.66(4),
P1–Co1–P4 154.06(5), C1–Co1–P2 159.32(11).
The reaction of complex 1 with aryl bromides (phenyl bromide
and 2-pyridinylbromide) in pentane gave rise to cobalt(II) complex
2 and the corresponding C,C-coupling products 3 and 4, 8-aryl caf-
feine, according to Eq. (2) [19].
minutes under ambient conditions. The molecular structure of com-
plex 2 is shown in Fig. 2 with selected bond distances and angles [20].
As complex 1, complex 2 also belongs to tetragonal pyramid coordi-
nation geometry. One trimethylphosphine ligand (P1) is situated at
the vertex of the pyramid. The other two trimethylphosphine ligands
(P2 and P3) are located in trans-configuration. The sum (355.33°) of
the four angles (C1–Co1–P2=89.71(11); P2–Co1–Br1=87.54(3);
P3–Co1–Br1=88.73(3) and C1–Co1–P3=89.35(10)°) indicates the
deviation from the coplanarity of the square plane. The coordination
bonds Co1\Br1 and Co1\P1 are in the plane of caffeine. This plane is
perpendicular to the square underside of the pyramid. All of the co-
ordination bond lengths are in the normal range [21].
Compounds 3 and 4 were purified by re-crystallization from
CH2Cl2 and were obtained as white crystals. These two compounds
were spectroscopically verified through comparison with those of
literatures [9,13].
Complex 2 forms green crystals suitable for X-ray single crystal
diffraction. These green crystals are stable in the air for several
Fig. 2. Molecular structure of 2. Selected bond distances (Å) and angles (deg): C1–Co1 1.914(4), P1–Co1 2.3102(11), P2–Co1 2.2133(10), P3–Co1 2.2293(10), Co1–Br1 2.4327(6);
C1–Co1–P2 89.71(11), C1–Co1–P3 89.35(10), P3–Co1–Br1 88.73(3), P2–Co1–Br1 87.54(3), C1–Co1–P1 95.23(11), P2–Co1–P1 99.30(4), P3–Co1–P1 95.98(4), P1–Co1–Br1
102.49(3), P2–Co1–P3 164.71(4), C1–Co1–Br1 162.28(11).

T. Zheng et al. / Inorganic Chemistry Communications 30 (2013) 139–142
141
Me
N
Me
N
Me
PMe3
PMe3
Me3P
N
Me3P
N
O
O
O
N
O
N
N
Co PMe3
PMe3
Ar
Co Br
PMe3
ArBr
2
+
+
N
N
N
N
N
Me
Me
Me
Me
Me
Me
O
O
1
2
3 , 4
Me
Ar
Me3P
N
O
N
PMe3
PMe
+
3
Co PMe3
PMe3
N
Co(PMe3)4
N
Me
Me
O
3a / 4a
Scheme 1. Proposed mechanism of C,C-coupling reaction.
The possible reaction mechanism of Eq. (2) has been proposed in
Scheme 1. The single electron oxidative addition is the first step to afford
8-caffeinyl cobalt(II) bromide 2 and the intermediate 3a/4a, 8-caffeinyl
aryl cobalt(II) complex. The latter is not stable and transforms to 8-aryl
caffeine 3 and 4 through C,C-coupling via reductive elimination with the
formation of Co(PMe3)4. The existence of Co(PMe3)4 was verified through
IR spectrum.
In conclusion, the 8-caffeinyl cobalt(I) complex 1 was prepared
through C8\H bond activation with methyl tetrakis(trimethyphos-
phine)cobalt(I) complex with the escape of methane. The reactions of
complex 1 with aryl bromides afforded C,C-coupling products 3 and 4
(8-phenyl caffeine and 8-(2′-pyridinayl)caffeine) with the formation
of 8-caffeinyl cobalt(II) bromide 2. This stoichiometric cross-coupling
process was proposed as combination of single-electron oxidative addi-
tion and reductive elimination.
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Acknowledgment
We gratefully acknowledge the support by NSF China no. 20972087
and Karlsruhe Nano-Micro Facility (KNMF) from Prof. Dr. D. Fenske and
Dr. O. Fuhr.
[17] Synthesis of 1. A solution of caffeine 0.32 g (1.65 mmol) in 30 mL of diethyl
ether was combined with a solution of CoMe(PMe3)4 0.44 g (1.64 mmol) in
20 mL of diethyl ether at −78 °C. The reaction mixture was allowed to warm
to ambient temperature and stirred for 16 h. During this period the reaction
mixture turned red-brown in color. After filtering, the red solid residue was
extracted with diethyl ether (60 mL). Recrystallization from diethyl ether at
4 °C yielded red single crystals suitable for X-ray diffraction. decop. >120 °C.
Appendix A. Supplementary data
CCDC-873453 (1), CCDC-873454 (2) contain the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk/conts/retrieving.html.
Yield: 0.53 g (58%). Elemental analyses for
1 C20H45CoN4O2P4 (556.23),
[Found (calculated)]: C, 43.01 (43.18); H, 8.50 (8.15); N, 10.33 (10.07). IR
(Nujol mull, cm−1): 938, ν(PMe3). 1H NMR (300 MHz, CDCl3, 297 K): δ 3.34
(s, 3H, N-CH3),δ 3.37 (s, 3H, N-CH3), 4.09 (s, 3H, N-CH3), 1.51 (m, 36H, PCH3).
31P NMR (121 MHz, C6D6, 300 K): δ 14.2 (s br, PCH3), 40.3 (s br, PCH3).
References
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group P21/c, a=13.702(3) Å, b=13.609(3) Å, c=14.799(3) Å, β=106.02(3)°,
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A
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θ
max =26.00°, semi-empirical correction. R1 =0.0487 (for
4727 reflections with I >2σ(I)), wR2 =0.1284 (all data). The structure was
solved by direct methods and refined with full-matrix least-squares on all F2
(SHELXL-97) with non-hydrogen atoms anisotropic.
[19] Synthesis of 3 and 2. A solution of 1 (0.62 g, 1.11 mmol ) in 30 mL of pentane
was combined with a solution of bromobenzene (0.35 g, 2.23 mmol) in 20 mL
of pentane at −78 °C. The reaction mixture was allowed to warm to ambient
temperature and stirred for 18 h. During this period the red-brown mixture
turned yellow-brown, and a lot of white powder was obtained. Then the
solution was filtrated, freezing at 4 °C afforded 0.16 g of green crystals (2)
(51.6%). The white powder was purified by recrystallization from CH2Cl2,
giving white crystals (3). (0.09 g, 61%). m.p. >120 °C. Elemental analyses for 2
C
17H36BrCoN4O2P3 (560.25), [Found (calculated)]: C, 36.21 (36.44); H, 6.30
(6.48); N, 9.89 (10.00). Complex 2: IR (Nujol mull, cm−1): 938, ν(PMe3).

142
T. Zheng et al. / Inorganic Chemistry Communications 30 (2013) 139–142
decop. >120 °C. Compound 3 was confirmed by the comparison of the 1H NMR
θmax=25.00°, semi-empirical correction. R1=0.0261 (for 3976 reflections with
data with those of the literature [13]. Compound 4 was synthesized according to
the method of synthesis of 3. Compound 4 (yield 67.1%) as white crystals was
confirmed by comparison of the 1H NMR data with those of the literature [9]
and by MS (C13H13N5O2): 272 (M+1).
I >2σ(I)), wR2 =0.0571 (all data). The structure was solved by direct methods
and refined with full-matrix least-squares on all F2 (SHELXL-97) with non-hydrogen
atoms anisotropic.
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[20] Crystallographic Data for 2. C17H36BrCoN4O2P3, Mr=560.25, orthorhombic, space
group Pna21, a=17.0825(9) Å, b=14.3558(7) Å, c=10.1679(7) Å, β=90°,
V=2493.5(2) Å3, T=193(2) K, Z=4, Dc=1.492 g cm−3, μ=2.503 mm−1, STOE
IPDS. A total of 8042 reflections were collected, 3976 unique (Rint=0.0310),