Synthesis of new pyrrole-pyridine-based ligands using an in situ Suzuki coupling method

Article abstract of DOI:10.3762/bjoc.8.116

The compounds 6-(pyrrol-2-yl)-2,2'-bipyridine, 2-(pyrrol-2-yl)-1,10- phenanthroline and 2-(2-(N-methylbenz[d,e]imidazole)-6- (pyrrol-2-yl)-pyridine were synthesized by using an in situ generated boronic acid for the Suzuki coupling. Crystals of the products could be grown and exhibited interesting structures by X-ray analysis, one of them showing a chain-like network with the adjacent molecules linked to each other via intermolecular N-H...N hydrogen bonds.

Full text of DOI:10.3762/bjoc.8.116

Synthesis of new pyrrole–pyridine-based ligands
using an in situ Suzuki coupling method
Matthias Böttger1, Björn Wiegmann1, Steffen Schaumburg1,
Peter G. Jones2, Wolfgang Kowalsky1 and Hans-Hermann Johannes*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1037–1047.
1Labor für Elektrooptik am Institut für Hochfrequenztechnik,
Technische Universität Braunschweig, Bienroder Weg 94, 38106
Braunschweig, Germany and 2Institut für Anorganische und
Analytische Chemie, Technische Universität Braunschweig,
Hagenring 30, 38106 Braunschweig, Germany
doi:10.3762/bjoc.8.116
Received: 04 April 2012
Accepted: 18 June 2012
Published: 09 July 2012
Email:
Associate Editor: I. Marek
Hans-Hermann Johannes* - h2.johannes@ihf.tu-bs.de
© 2012 Böttger et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
boronic acids; complex chemistry; in situ generation; pyrrole-pyridine;
Suzuki coupling
Abstract
The compounds 6-(pyrrol-2-yl)-2,2‘-bipyridine, 2-(pyrrol-2-yl)-1,10-phenanthroline and 2-(2-(N-methylbenz[d,e]imidazole)-6-
(pyrrol-2-yl)-pyridine were synthesized by using an in situ generated boronic acid for the Suzuki coupling. Crystals of the products
could be grown and exhibited interesting structures by X-ray analysis, one of them showing a chain-like network with the adjacent
molecules linked to each other via intermolecular N–H…N hydrogen bonds.
Introduction
Tridentate ligands have recently received attention in the area of tralized, respectively. In a recent development, the Bünzli group
rare-earth-metal complex chemistry [1-5]. Many rare-earth- has succeeded in synthesizing homoleptic complexes, in which
metal cations, such as europium(III), have the tendency to be only one type of ligand binds to the central europium(III) via
nine-coordinating species. Besides their triple positive charge, two neutral and one negatively charged atom (Scheme 1,
this coordination sphere must be saturated to achieve high middle) [2-4]. As three ligands bind to the rare-earth cation, the
quantum yields when the target is to optimize its luminescent resulting complex is neutral, and its coordination number is nine
properties [6]. In the “classic” complexes, i.e., the β-diketo- and thereby saturated.
nates [6,7], this is often achieved by combining three “satu-
rating ligands” that consist of negatively charged β-diketonates Our interest in this type of complex is driven by its potential
with a “neutral ligand”, which is often bidentate or tridentate analytical application for luminescence degradation measure-
(Scheme 1, left). The coordination sphere and the positive ments on photocatalytic surfaces [8]. Currently, β-diketonate
charge of the rare-earth metal cation are thus saturated and neu- complexes are in use for this analysis, but homoleptic
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Beilstein J. Org. Chem. 2012, 8, 1037–1047.
Scheme 1: β-diketonate complexes (left), homoleptic complexes (middle) and planned homoleptic complexes of europium(III) (right).
complexes may be advantageous in our opinion, because they [1-4]. The synthesis of the resulting complexes was to date
only consist of one type of ligand, which is then subjected to unsuccessful. We report here on the synthesis of the new struc-
photocatalytically produced radicals. Therefore, we tried to tures 1–3.
broaden the scope by synthesizing a new class of ligands for
homoleptic complexes, which should bind to europium(III) via Results and Discussion
a pyrrolate anion (Scheme 1, right). The decision to choose a Our first retrosynthetic approach included a Suzuki coupling of
negatively charged heterocycle as a binding unit was based on the alpha-substituted boronic acid of Boc-protected pyrrole 7
the idea to enlarge the π-system of the ligand, thereby making it with the heteroaryl bromides 8–10, as shown in Scheme 3.
possible to absorb longer wavelengths of light (λ > 350 nm).
The target structures are shown in Scheme 2.
Compound 7 is described in literature [10], but it could not be
purified by column chromatography and therefore was not
Structures 1 and 2 comprise substructures of common neutral isolated as a pure product. In addition, reports on the stability of
ligands used in europium complex chemistry [6,9]: 2,2’-bipyri- this boronic acid show that it is not suitable for long-term
dine and 1,10-phenanthroline. Compound 3 comprises a benz- storage [10]. We therefore applied a modification of the Suzuki
imidazole heterocycle, which was also used by the Bünzli group coupling that was also used to prepare [2.2]paracyclophane-
Scheme 2: Pyrrole–pyridine-based structures synthesized in this study.
Scheme 3: Retrosynthetic approach for structures 1–3.
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Beilstein J. Org. Chem. 2012, 8, 1037–1047.
derivatives [11]. This comprised the in situ reaction of the step, since a negative charge is located on the boron atom. In
freshly prepared boronic acid/ester with the heteroaryl bro- Scheme 6 the coupling reactions are shown; detailed informa-
mides 8–10. These starting compounds could be prepared by tion about the reaction conditions is given in Table 1.
using literature procedures, as shown in Scheme 4.
Reaction 1 of aryl bromide 8 to product 4 was repeated under
Substance 8 was synthesized by following the standard litera- the same conditions and with the same amounts of starting ma-
ture procedure [12]. Compound 9 was synthesized by princi- terial and catalyst. The workup procedure was changed, which
pally the same reaction path [12,13]. 2-Bromopyridine-6-benz- affected the yield only to a very small extent. In the original
imidazole 10 was published in a patent [14], and its preparation publication [11] the aryl bromide coupling partner was used in
was adapted from [4]. The following in situ Suzuki coupling excess. As 19 is by far easier to prepare in large quantities, we
uses Boc-protected pyrrole [15], which was subjected to freshly altered the protocol and used it in excess, which produced even
prepared LDA at −78 °C and quenched with trimethylborate. a slightly better yield than the other way round (Table 1).
This gave rise to the intermediate 21/22 (Scheme 5).
Finally, deprotection of 4 with hydrochloric acid after the
coupling gave 1 in 93% yield. Compound 2 was directly
Afterwards the heteroaryl bromides 8–10 were added along isolated as Boc-deprotected product, but in a much lower yield.
with the catalyst and base in aqueous media and the reaction We believe the lower yield is caused by the workup procedure,
mixture was heated under reflux for several hours. The reaction because TLC indicated nearly full consumption of 19. During
times were not minimized. In principal the ester can react with column purification with aluminium oxide or silica (both were
the boronic acid, starting with the addition of the aqueous base tried) we noticed smearing of the blue fluorescent product under
(K2CO3). Yet, structure 21 is already activated for the coupling UV irradiation. Even deactivated aluminium oxide provides
Scheme 4: Synthesis of the heteroaryl bromides used in the coupling reaction.
Scheme 5: Generation of the borate intermediate 21/22.
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Beilstein J. Org. Chem. 2012, 8, 1037–1047.
Scheme 6: In situ Suzuki coupling reactions of the heteroaryl bromides 8–10.
enough acidity to split the Boc-moiety, which probably causes of 19 and the base did not significantly enhance the resulting
the generated amine to partly remain on the column. In the case yield (Table 1). The total reaction time was not systematically
of 6, using an excess of 19 lead to better yields, but it has to be minimized. After 20 h under reflux 6 was isolated in 87% yield;
mentioned that the workup procedure was also adjusted, thus it a reaction time of 70 h delivered 85% of 6. Compound 3 was
cannot be directly compared. Further increasing the equivalents synthesized in 70% yield by deprotection of 6. In this case
Table 1: Reaction conditions used for coupling reactions.
stirring
timea
K2CO3
(1 M)
aryl bromide
19
LDA B(OMe)3
Pd(PPh3)Cl2
[mol %]
product
yield
[equiv] [equiv] [equiv] [equiv]
[equiv]
1.2
1.2
1.0
1.0
1.1
1.1
1.5
1.5
15 h
15 h
8
8
1.65
1.65
84%
87%
1.0
1.25
1.4
1.9
1.5 h
8
2.0
89%
4
2
6
8
1.1
1.1
1.0
1.0
1.1
1.1
1.5
1.5
1.5 h
16 h
8
8
1.65
1.65
41%
39%
9
1.1
1.0
1.0
1.3
1.1
1.5
1.3
0.5 h
0.5 h
5
5
1.65
1.6
52%
85%
1.25
1.0
1.5
1.55
1.6
1.2 h
5
2.0
87%
10
aStirring time: After addition of B(OMe)3 at 0 °C to RT.
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Beilstein J. Org. Chem. 2012, 8, 1037–1047.
another method using sodium methoxide was applied, because for 2,2'-pyrrolylpyridines revealed 20 hits, all with cis
reaction with hydrochloric acid did not take place and the geometry, discounting rigid fused-ring systems and one steri-
unprotected starting material was recovered. We noticed no cally hindered di-tert-butyl system; the corresponding absolute
definite influence on the product yield when using different torsion angles ranged from 0 to 25°, mean value 7.5°. The
scales (2 mmol to 12 mmol).
molecular packing of 1 (Figure 2) is determined by a classical
hydrogen bond N17–H17…N1 involving the peripheral rings,
which connects the molecules via the a-glide plane to form
X-Ray analysis
The molecular structure of compound 1 is shown in Figure 1. chains parallel to the a-axis.
The angles subtended to the central ring are 30° from the
pyridyl and 8° from the pyrrolyl substituent. The N…N The structure of the methanol solvate of compound 2 is shown
configurations are trans for the bipyridyl substructure in Figure 3. The 1,10-phenanthroline ring system is planar
(N–C–C–N torsion angle −155.8(1)°) but cis for the
pyrrolylpyridine substructure (torsion angle 3.8(2)°). The
former is well-known as a structural preference of 2,2'-bipyridyl
systems. A search of the Cambridge Structural Database [16]
Figure 3: The structure of compound 2·CH3OH in the crystal. Ellip-
soids correspond to 50% probability levels. Hydrogen bond details
Figure 1: The structure of compound 1 in the crystal. Ellipsoids corres-
pond to 50% probability levels.
(Å,°) for N19–H19…O99: H…O 1.96(2), N…O 2.839(1), N–H…O 174(1);
for O99–H99…N1: H…N 1.93(2), O…N 2.841(1), N–H…O 173(2).
Figure 2: Packing diagram of compound 1, viewed parallel to the y-axis in the range y ≈ 1/4. Hydrogen bonds are indicated by dashed lines.
Hydrogen atoms not involved in the hydrogen bonds are omitted for clarity. Hydrogen bond details (Å,°) for N17–H17…N1: H…N 0.88(2), N…N
2.861(2), N–H…N 158(2), operator 1/2 + x, 1 1/2 − y, z.
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Beilstein J. Org. Chem. 2012, 8, 1037–1047.
(mean deviation 0.01 Å), and the pyrrole ring subtends an inter-
planar angle of 9° to it. The methanol molecule fits neatly into
the “bay” region of the parent molecule, forming classical
hydrogen bonds N19–H19…O99 and O99–H99…N1. The mole-
cules associate into pairs by ring stacking across inversion
centres (Figure 4). The interplanar distance is ca. 3.35 Å.
The structure of the ethanol solvate of compound 3 is shown in
Figure 5. The central ring is almost coplanar with the pyrrole
ring (interplanar angle 9°), but subtends an angle of 38° with
the benzimidazole system. Ethanol forms one classical
hydrogen bond within the asymmetric unit, acting as a donor,
but it also acts as a hydrogen bond acceptor via the a-glide
plane. The overall effect is to form helical chains of alternating
residues of 3 and ethanol, parallel to the a-axis (Figure 6).
The crystallographic data of compounds 1 to 3 are summarized
in Table 2.
Figure 5: The structure of compound 3·C2H5OH in the crystal. Ellip-
soids correspond to 50% probability levels. Hydrogen bond details
(Å,°) for O99–H99…N17: H…N 1.91(2), O…N 2.813(1), O–H…N 174(2).
Conclusion
The new target structures 1–3 were successfully synthesized in
good to acceptable yields by applying an in situ variation of the cules via hydrogen bonds. The idea was to synthesize
Suzuki coupling as the main reaction step. The crystal struc- europium(III) complexes containing the new ligands. Since the
tures of these compounds could be obtained by X-ray analysis. pyrrole amine is a very weak acid (pKa = 23.0) [17] it can only
They exhibit interesting, but very different structural features: 1 be deprotonated by hard bases, such as n-butyllithium or
forms chains that consist of molecules directly interconnected sodium hydride [18]. Therefore we chose to work in water-free
by N–H…N hydrogen bonds, whereas 2 retains the solvent conditions with the europium precursors EuCl3 (no crystalliza-
molecule methanol in the “bay” region of the molecule to form tion water) or Eu[N(SiMe3)2]3, which are commercially avail-
stacked dimers. Structure 3 forms a chain-like structure, but able. To date we did not succeed in synthesizing the target
retains the solvent molecule ethanol, which connects the mole- complexes depicted on the right-hand side of Scheme 1. This
Figure 4: Packing diagram of compound 2·CH3OH showing the formation of inversion-symmetric "stacked" dimers. Hydrogen bonds are shown as
thin dashed lines. Hydrogen atoms are omitted for clarity.
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Beilstein J. Org. Chem. 2012, 8, 1037–1047.
Figure 6: Packing diagram of compound 3·C2H5OH. Hydrogen bonds are shown as thick dashed lines. Hydrogen atoms not involved in the hydrogen
bonds are omitted for clarity. Hydrogen bond details (Å,°) for N1–H01…O99: H…O 2.01(2), N…O 2.848(1), N–H…O 154(1), operator −1/2 + x, y,
1/2 − z.
Table 2: Crystallographic data for compounds 1, 2·CH3OH, 3·C2H5OH.
compound
1
2·CH3OH
3·C2H5OH
formula
C14H11N3
221.26
C17H15N3O
277.32
C19H20N4O
320.39
Mr
habit
colourless tablet
0.4 × 0.25 × 0.2
orthorhombic
Pna21
amber tablet
0.25 × 0.2 × 0.15
monoclinic
P21/c
colourless block
0.4 × 0.3 × 0.15
orthorhombic
Pbca
crystallite size (mm)
crystal system
space group
cell constants:
a [Å]
9.8842(4)
16.1917(6)
7.1501(3)
90
9.7060(3)
10.3442(3)
13.4884(4)
90
9.09323(15)
17.5182(3)
21.2257(4)
90
b [Å]
c [Å]
α [°]
β [°]
90
91.043(4)
90
90
γ [°]
90
90
V (Å3)
Z
1144.32
4
1354.04
4
3381.19
8
Dx (g·cm−3)
μ (mm−1)
F(000)
T (°C)
wavelength (Å)
2θmax
1.284
0.08
1.360
0.09
1.259
0.08
464
584
1360
−173
0.71073
60
−173
−173
0.71073
60
0.71073
60
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Beilstein J. Org. Chem. 2012, 8, 1037–1047.
Table 2: Crystallographic data for compounds 1, 2·CH3OH, 3·C2H5OH. (continued)
Refl. measured
Refl. indep.
Rint
34078
1791
0.029
158
50772
3936
0.028
100
125784
4949
0.034
240
parameters
wR(F2, all refl.)
R(F, >4σ(F))
S
0.084
0.031
1.01
0.111
0.039
1.03
0.104
0.0406
1.04
max. Δ/ρ (e·Å−3)
0.25
0.36
0.36
class of compounds may also be of interest for other areas of were modelled by using a riding model starting from calculated
chemistry. The pyrrole–pyridine structural motif is featured in positions. Exceptions and special features: Compound 1: in the
current studies, owing to its complexation properties towards absence of significant anomalous scattering, Friedel opposite
first-row transition metals (Fe, Co, Ni, Cu, Zn) [18] and ruthe- reflections were merged and the Flack parameter is thus mean-
nium [19]. The intramolecular proton transfer of these species is ingless. Compound 3·C2H5OH: the ethanol molecule is disor-
also of interest for vibrational spectroscopy measurements [20].
dered over two positions, but the minor component is occupied
only to the extent of 9%. Its OH hydrogen was not located.
Similarity restraints for both ethanol orientations were used to
improve the stability of refinement. Crystallographic data have
Experimental
General
Melting points: Stuart Melting Point SMP3 apparatus, uncorr. been deposited with the Cambridge Crystallographic Data
Elemental analyses: Vario EL (Elementar Co.). IR: Bruker Centre as supplementary publications no. CCDC-871428 (1),
Tensor 27 spectrometer with a Diamond ATR sampling CCDC-871429 (2·CH3OH), CCDC-871430 (3·C2H5OH).
element. UV–vis: Varian Cary 100 Bio, spectra taken of solu- Copies of the data can be obtained free of charge from
tions in spectroscopic grade solvents. NMR: 600 MHz (1H), http://www.ccdc.cam.ac.uk/data_request/cif.
151 MHz (13C): Bruker AV2-600 spectrometer. 200 MHz (1H),
50 MHz (13C): Varian Mercury Plus 200. 1H chemical shifts Synthesis and characterization of the heteroaryl bromides 8 and
were recorded with tetramethylsilane (TMS) as the internal 9 starting from 2,2’-bipyridine (11) and 1,10-phenanthroline
standard. 13C measurements were taken with the corresponding (14), as well as the synthesis of compound 10 and 19 are shown
solvent signal as the reference. J values are rounded to 0.1 Hz. in Supporting Information File 1. Absorption, excitation and
Mass spectrometry: Thermofinnigan MAT95XL (EI). TLC: emission spectra of compounds 1–3 are included as well.
Silica plates (Polygram SIL G/UV 254), aluminium oxide plates
(Polygram N/UV 254). Flash chromatography: Silica (Kieselgel Synthesis of 6-(1-tert-butoxycarbonylpyrrol-2-yl)-
60, Fluka), aluminium oxide (aluminium oxide 90 neutral, 2,2’-bipyridine (4)
Merck). Aluminium oxide, activity III, was made by adding 8%
water and shaking the mixture vigorously in a closed flask. All
reagents were purchased from Aldrich or Alfa Aesar and used
as received. Solvents were purified before use. Dry solvents
were purchased from Aldrich or Fluka. Reactions were
performed under nitrogen atmosphere unless otherwise stated.
X-Ray structure determination: Data collection and reduc-
tion: Crystals were mounted in inert oil on glass fibres and Diisopropylamine (0.36 g, 3.57 mmol, 1.4 equiv) was dissolved
transferred to the cold gas stream of the diffractometer (Oxford in THF (5 mL) and cooled to −80 °C. Whilst the temperature
Diffraction Xcalibur). Measurements were performed with was kept constant, n-butyllithium (2.25 mL, 1.6 M in hexane,
monochromated Mo Kα radiation (λ = 0.71073 Å). No absorp- 3.57 mmol, 1.4 equiv) was added dropwise, and the mixture
tion corrections were applied. Structure refinement: The struc- was stirred for 1 h. Compound 19 (0.55 g, 3.29 mmol,
tures were refined anisotropically against F2 (program 1.29 equiv) in THF (4 mL) was added dropwise at −80 °C, and
SHELXL-97 [21]). Hydrogen atoms: OH and NH hydrogens the reaction mixture was stirred for another 1 h after which the
were refined freely; methyl hydrogens as constituents of reaction was quenched with trimethylborate (0.50 g, 4.85 mmol,
idealised rigid groups were allowed to rotate but not tip; other H 1.9 equiv). The mixture was allowed to warm to 0 °C and was
1044

Beilstein J. Org. Chem. 2012, 8, 1037–1047.
stirred for 1.5 h. At room temperature 8 (0.6 g, 2.55 mmol) and colorless powder (0.96 g, 4.34 mmol, 93%). Crystals of 1 could
Pd(PPh3)2Cl2 (144 mg, 0.2 mmol, 8 mol %) were added. The be grown by recrystallization from ethanol. Mp 120–121.5 °C;
reaction mixture was heated under reflux and aq K2CO3 1H NMR (600 MHz, CDCl3) δ 8.68 (ddd, 3JH,H = 4.8 Hz, 4JH,H
(5.1 mL, 1 M, 5.1 mmol, 2 equiv) was added meanwhile. It was = 1.8 Hz, 5JH,H = 0.9 Hz, 1H, 1-H), 8.45 (pseudo-dt, 3JH,H =
kept at that temperature for 2 h, then cooled to room tempera- 8.0 Hz, J = 1.1 Hz, 1H, 4-H), 8.15 (dd, 3JH,H= 7.7 Hz, 4JH,H =
ture and diluted with diethyl ether. The organic phase was 1.0 Hz, 1H, 7-H), 7.80 (ddd, 3JH,H = 7.9 Hz, 3JH,H = 7.5 Hz,
washed with sat. aq NaCl and the aqueous phase was extracted 4JH,H = 1.8 Hz, 1H, 3-H), 7.75 (dd, 3JH,H= 7.9 Hz, 3JH,H =
two times with diethyl ether. The combined organic extracts 7.7 Hz, 1H, 8-H), 7.56 (dd, 3JH,H= 7.9 Hz, 4JH,H = 1.0 Hz, 1H,
were then dried over MgSO4, filtered and the solvent was 9-H), 7.30 (ddd, 3JH,H = 7.5 Hz, 3JH,H = 4.8 Hz, 4JH,H =
removed. The raw product was preadsorbed onto silica. Column 1.2 Hz, 1H, 2-H), 6.94 (pseudo-dt, J = 2.6 Hz, 4JH,H = 1.4 Hz,
chromatography (SiO2, hexane/ethyl acetate 3:1, Rf = 0.4) gave 1H, 14-H), 6.76 (ddd, 3JH,H = 3.7 Hz, J = 2.5 Hz, 4JH,H =
4 as a yellow resin (0.73 g, 2.27 mmol, 89%). 1H NMR 1.4 Hz, 1H, 12-H), 6.32 (pseudo-dt, 3JH,H = 3.6 Hz, J = 2.7 Hz,
(600 MHz, CDCl3) δ 8.67 (ddd, 3JH,H= 4.8 Hz, 4JH,H = 1.8 Hz, 1H, 13-H), 9.75 (br. s, 1H, N-H) ppm; 13C NMR (151 MHz,
5JH,H = 0.9 Hz, 1H, 1-H), 8.46 (pseudo-dt, 3JH,H = 8.0 Hz, J = CDCl3) δ 156.2 (s, C-5), 155.0 (s, C-6), 149.9 (s, C-10), 149.1
1.1 Hz, 1H, 4-H), 8.34 (dd, 3JH,H= 7.9 Hz, 4JH,H = 1.0 Hz, 1H, (d, C-1), 137.4 (d, C-8), 136.7 (d, C-3), 131.6 (s, C-11), 123.6
7-H), 7.81 (dd, 3JH,H = 7.9 Hz, 3JH,H = 7.7 Hz, 1H, 8-H), 7.76 (d, C-2), 121.0 (d, C-4), 119.7 (d, C-14), 118.2 (d, C-9), 117.9
(ddd, 3JH,H = 7.9 Hz, 3JH,H = 7.6 Hz, 4JH,H = 1.8 Hz, 1H, 3-H), (d, C-7), 110.3 (d, C-13), 107.3 (d, C-12) ppm; EIMS (70 eV)
7.43 (dd, 3JH,H= 7.7 Hz, 4JH,H = 1.0 Hz, 1H, 9-H), 7.41 (dd, m/z (% relative intensity): M+● 222/221/220 (18/100/16);
3JH,H= 3.3 Hz, 4JH,H = 1.8 Hz, 1H, 14-H), 7.28 (ddd, 3JH,H= UV–vis (CH2Cl) λmax, nm (log ε): 307 (4.26), 283 (4.24), 239
7.2 Hz, 3JH,H = 4.6 Hz, 4JH,H = 1.1 Hz, 1H, 2-H), 6.48 (dd, (4.23); UV–vis (CH3OH) λmax, nm (log ε): 309 (4.29), 283
3JH,H= 3.3 Hz, 4JH,H = 1.8 Hz, 1H, 12-H), 6.27 (dd, 3JH,H = (4.22), 237 (4.23); IR (ATR) : 3126 (m), 3071 (m), 3005 (m),
3.3 Hz, 3JH,H = 3.3 Hz, 1H, 13-H), 1.28 (s, 9H, 17-H) ppm; 13C 2970 (m), 2841 (m), 2685 (m), 2551 (m), 1582 (m), 1555 (s),
NMR (151 MHz, CDCl3) δ 156.0 (s, C-5), 155.0 (s, C-6), 152.1 1455 (s), 1428 (s), 1407 (m), 1328 (w), 1258 (m), 1159 (m),
(s, C-10), 149.4 (s, C-15), 149.0 (d, C-1), 136.7 (d, C-8), 136.7 1126 (s), 1098 (w), 1076 (w), 1061(w), 1033 (m), 1001 (w),
(d, C-3), 134.3 (s, C-11), 123.6 (d, C-2), 123.6 (d, C-14), 123.1 986 (w), 936 (w), 879 (m), 854 (m), 823 (m), 780 (s), 731 (s),
(d, C-9), 121.3 (d, C-4), 118.8 (d, C-7), 115.6 (d, C-12), 110.5 679 (m), 628 (m), 609 (m) cm−1; anal. calcd C14H11N3: C 76.00
(d, C-13), 83.5 (s, C-16), 27.4 (q, C-17) ppm; EIMS (70 eV) , H 5.01, N 18.99; found: C 76.20, H 4.75, N 19.18.
m/z (% relative intensity): M+● 321 (5), [M − Boc]+● 222/221/
220 (14/100/9); anal. calcd for C19H19N3O2: C 71.01, H 5.96, Synthesis of 2-(pyrrol-2-yl)-1,10-phenanthroline (2)
N 13.08; found: C 70.95, H 6.43, N 12.96.
Synthesis of 6-(pyrrol-2-yl)-2,2’-bipyridine (1)
Diisopropylamine (1.11 g, 11.0 mmol, 1.1 equiv) was dissolved
in THF (20 mL) and cooled to −80 °C. Whilst the temperature
was kept constant, n-butyllithium (7.5 mL, 1.6 M in hexane,
Compound 4 (1.5 g, 4.7 mmol) was dissolved in 12.0 mmol, 1.2 equiv) was added dropwise, and the mixture
dichloromethane (110 mL) and cooled to 0 °C. Aqueous was stirred for 1 h. Compound 19 (1.67 g, 10.0 mmol) in THF
hydrochloric acid (27.5 mL, 2 M) was added dropwise under (5 mL) was added dropwise at −80 °C and the reaction mixture
vigorous stirring, upon which the biphasic mixture turned was stirred for another 1 h, after which it was quenched with
yellow. The organic phase was separated, and the aqueous trimethylborate (1.56 g, 15.0 mmol, 1.5 equiv). The mixture
phase was neutralized with sodium carbonate and then extracted was allowed to warm to 0 °C and was stirred for 1.5 h. At room
three times with dichloromethane. The combined organic temperature 9 (2.85 g, 11.0 mmol, 1.1 equiv), Pd(PPh3)2Cl2
extracts were dried over MgSO4 and filtered, and the solution (555 mg, 0.8 mmol, 8 mol %) and THF (50 mL) were added.
was concentrated. Ethyl acetate (same volume as remaining The reaction mixture was heated under reflux and aq K2CO3
dichloromethane) was added and the solution was filtered (16.5 mL, 1 M, 16.5 mmol, 1.65 equiv) was added meanwhile.
through aluminium oxide. Removal of the solvent yielded 1 as a It was kept under reflux for 40 h, then cooled to room tempera-
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Beilstein J. Org. Chem. 2012, 8, 1037–1047.
ture and diluted with diethyl ether. The organic phase was 2.25 mmol, 1.3 equiv) was added dropwise and the mixture was
washed with sat. aq NaCl, and the aqueous phase was extracted stirred for 1 h. Compound 19 (0.38 g, 2.27 mmol, 1.3 equiv) in
two times with diethyl ether. The combined organic extracts THF (2 mL) was added dropwise at −80 °C and the reaction
were then dried over MgSO4 and filtered, and the solvent was mixture was stirred for another 1 h, after which it was quenched
removed. The raw product was preadsorbed onto aluminium with trimethylborate (0.23 g, 2.24 mmol, 1.3 equiv). The mix-
oxide, activity III. Column chromatography (Al2O3, activity III, ture was allowed to warm to 0 °C and was stirred for 0.5 h. At
dichloromethane/ethyl acetate/hexane 1:1:2
→
room temperature 10 (0.49 g, 1.70 mmol), Pd(PPh3)2Cl2
dichloromethane/ethyl acetate 1:1, Rf (Al2O3, dichloromethane/ (0.07 g, 0.1 mmol, 6 mol %) and THF (4 mL) were added. The
ethyl acetate/hexane 1:1:2) = 0.27) gave 2 as a pale yellow solid reaction mixture was heated under reflux, and aq K2CO3
(1.0 g, 4.1 mmol, 41%). Recrystallization from methanol gave (2.8 mL, 1 M, 2.8 mmol, 1.65 equiv) was added meanwhile. It
brown crystals of 2, which retained one solvent molecule as was kept under reflux for 70 h, then cooled to room tempera-
indicated by X-ray and elemental analysis. Mp 119 °C (release ture and diluted with diethyl ether. The organic phase was
of methanol), 137 °C (melting of the remaining solid); 1H NMR washed with sat. aq NaCl and the aqueous phase was extracted
(600 MHz, CDCl3) δ 12.12 (s, 1H, N-H), 8.98 (dd, 3JH,H = two times with diethyl ether. The combined organic extracts
4.4 Hz, 4JH,H = 1.7 Hz, 1H, 1-H), 8.22 (dd, 3JH,H= 8.1 Hz, were then dried over MgSO4 and filtered, and the solvent was
4JH,H = 1.6 Hz, 1H, 3-H), 8.10 (d, 3JH,H = 8.5 Hz, 1H, 8-H), removed. Column chromatography (SiO2, diethyl ether, Rf =
7.88 (d, 3JH,H= 8.5 Hz, 1H, 9-H), 7.71 (d, 3JH,H= 8.7 Hz, 1H, 0.55) gave 6 as a colorless solid (0.55 g, 1.47 mmol, 85%). mp
6-H), 7.64 (d, 3JH,H= 8.8 Hz, 1H, 5-H), 7.56 (dd, 3JH,H= 125–126 °C; 1H NMR (600 MHz, CDCl3) δ 8.32 (dd, 3JH,H=
8.0 Hz, 3JH,H = 4.4 Hz, 1H, 2-H), 7.04 (dt, 3JH,H= 2.6 Hz, 7.9 Hz, 4JH,H = 1.1 Hz, 1H, 11-H), 7.85 (dd, 3JH,H = 7.9 Hz,
4JH,H = 1.4 Hz, 1H, 14-H), 6.90 (ddd, 3JH,H = 3.7 Hz, J = 3JH,H = 7.8 Hz, 1H, 10-H), 7.83 (ddd, 3JH,H= 7.4 Hz, 4JH,H =
2.4 Hz, 4JH,H = 1.4 Hz, 1H, 15-H), 6.32 (pseudo-dt, 3JH,H= 1.6 Hz, 5JH,H = 0.7 Hz, 1H, 19-H), 7.46 (dd, 3JH,H= 7.8 Hz,
3.6 Hz, J = 2.5 Hz, 1H, 16-H) ppm; 13C NMR (151 MHz, 4JH,H = 1.0 Hz, 1H, 9-H), 7.43–7.41 (m, 1H, 16-H), 7.39 (dd,
CDCl3) δ 150.9 (s, C-10), 148.8 (d, C-1), 145.5 (s, C-11), 145.2 3JH,H= 3.3 Hz, 4JH,H = 1.8 Hz, 1H, 4-H), 7.33 (ddd, 3JH,H =
(s, C-12), 136.6 (d, C-3), 136.2 (d, C-8), 132.3 (s, C-13), 129.1 7.5 Hz, 3JH,H = 7.1 Hz, 4JH,H = 1.4 Hz, 1H, 17-H), 7.30 (ddd,
(s, C-4), 126.8 (d, C-6), 126.4 (s, C-7), 124.4 (d, C-5), 122.8 (d, 3JH,H = 7.4 Hz, 3JH,H = 7.1 Hz, 4JH,H = 1.3 Hz), 6.50 (dd, 3JH,H
C-2), 122.0 (d, C-14), 119.1 (d, C-9), 109.8 (d, C-16), 109.2 (d, = 3.3 Hz, 4JH,H = 1.7 Hz, 1H, 6-H), 6.28 (dd, 3JH,H = 3.3 Hz,
C-15) ppm; EIMS (70 eV) m/z (% relative intensity): [M]+● 3JH,H = 3.3 Hz, 1H, 5-H), 4.25 (s, 3H, 14-H), 1.33 (s, 9H, 1-H)
247/246/245/244/243 (2/16/100/12/4); UV–vis (CH2Cl2) λmax, ppm; 13C NMR (151 MHz, CDCl3) δ 151.6 (s, C-8), 150.1 (s,
nm (log εmax): 339 (4.24), 311 (4.31), 235 (3.46); UV–vis C-13), 149.7 (s, C-12), 149.3 (s, C-3), 142.5 (s, C-20), 137.2 (s,
(CH3OH) λmax, nm (log εmax): 345 (4.13), 312 (4.24), 237 C-15), 136.8 (d, C-10), 134.0 (s, C-7), 123.9 (d, C-4), 123.2 (d,
(4.32) IR (ATR) :3610 (w), 3185 (m), 3113 (m), 2927 (w), C-17), 123.1 (d, C-9), 122.6 (d, C-11), 122.5 (d, C-18), 120.0
2820 (w), 1617 (w), 1585 (m), 1554 (m), 1503 (m), 1459 (m), (d, C-19), 116.0 (d, C-6), 110.6 (d, C-5), 109.9 (d, C-16), 83.9
1423 (m), 1408 (m), 1378 (m), 1338 (w), 1262 (w), 1215 (w), (s, C-2), 32.8 (q, C-14), 27.5 (q, C-1) ppm; EIMS (70 eV) m/z
1145 (m), 1125 (s), 1080 (w), 1030 (s), 936 (w), 882 (w), 839 (% relative intensity): [M]+● 375/374 (2/6), [M – Boc +
(s), 779 (s), 728 (s), 679 (s), 626 (m), 606 (s), 569 (m) cm−1; methyl]+● 290/289/288/287/286 (10/65/100/67/93), [M −
anal. calcd. for C16H11N3·CH3OH: C 73.63, H 5.45, N 15.15; Boc]+● 275/274/273 (6/32/35), [M − Boc-pyrrole + H+]+● 209/
found: C 73.30, H 5.33, N 15.25.
208/207/206 (3/18/16/12), [N-methylbenzimidazole]+● 132/
131/130/129 (4/39/2/5); anal. calcd for C22 H22 N4 O2: C 70.57,
H 5.92, N 14.96; found: C 70.39, H 5.97,N 15.02.
Synthesis of 2-(N-methylbenz[d,e]imidazo-2-yl)-6-
(1-tert-butoxycarbonylpyrrol-2-yl)-pyridine (6)
Synthesis of 2-(N-methylbenz[d,e]imidazo-2-yl)-6-
(pyrrol-2-yl)-pyridine (3)
Diisopropylamine (0.22 g, 2.17 mmol, 1.3 equiv) was dissolved Compound 6 (0.43 g, 1.15 mmol) was dissolved in methanol
in THF (3 mL) and cooled to −80 °C. Whilst the temperature (35 mL). Sodium methanolate (0.13 g, 2.35 mmol, 2.0 equiv)
was kept constant, n-butyllithium (0.9 mL, 2.5 M in hexane, was added and the solution was stirred for 17 h under reflux.
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Beilstein J. Org. Chem. 2012, 8, 1037–1047.
5. Bortoluzzi, M.; Paolucci, G.; Polizzi, S.; Bellotto, L.; Enrichi, F.;
Ciorba, S.; Richards, B. S. Inorg. Chem. Commun. 2011, 14,
1762–1766. doi:10.1016/j.inoche.2011.08.004
The solvent was removed and the residue was taken up in
ethanol (10 mL) and heated again. The mother liquor was then
cooled to 0 °C leading to crystallization. Colorless crystals of 3
were collected (0.220 g, 0.802 mmol, 70%). mp 184–187 °C;
1H NMR (600 MHz, CDCl3) δ 9.83 (s, 1H, N-H), 7.97 (dd,
3JH,H = 7.7 Hz, 4JH,H = 1.0 Hz, 1H, 8-H), 7.85 (m, 1H, 16-H),
7.72 (dd, 3JH,H = 8.0 Hz, 3JH,H = 7.7 Hz, 1H, 7-H), 7.54 (dd,
3JH,H= 8.0 Hz, 4JH,H = 1.0 Hz, 1H, 6-H), 7.39–7.31 (m, 3H,
13-H, 14-H, 15-H), 7.00 (ddd, 3JH,H= 2.6 Hz, J = 2.6 Hz, 4JH,H
= 1.4 Hz, 1H, 3-H), 6.77 (ddd, 3JH,H= 3.7 Hz, J = 2.5 Hz, 4JH,H
= 1.4 Hz, 1H, 1-H), 6.35 (ddd, 3JH,H= 3.6 Hz, 3JH,H = 2.6 Hz, J
= 2.6 Hz, 1H, 2-H), 4.10 (s, 3H, 11-H) ppm; 13C NMR
(151 MHz, CDCl3) δ 150.8 (s, C-10), 149.7 (s, C-5), 149.3 (s,
C-9), 142.5 (s, C-17), 137.3 (d, C-7), 136.9 (s, C-12), 131.4 (s,
C-4), 123.2 (d, C-14), 122.6 (d, C-15), 121.7 (d, C-8), 120.2 (d,
C-3), 120.0 (d, C-16), 118.2 (d, C-6), 110.5 (d, C-2), 109.9
(C-1), 107.8 (d, C-13), 32.4 (q, C-11) ppm; EIMS (70 eV) m/z
(% relative intensity): [M]+● 276/275/274/273/272 (2/14/80/
100/2); UV–vis (CH2Cl2) λmax, nm (log εmax): 335 (sh 4.20),
301 (4.41), 230 (4.22); UV–vis (CH3OH) λmax, nm (log εmax):
335 (sh 4.11), 300 (4.41), 232 (4.20); IR (ATR) : 3170 (m),
3102(m), 2965 (m), 2903 (m), 2858 (m), 1591 (m), 1566 (s),
1473 (s), 1454 (s), 1435 (s), 1391 (m), 1373 (m), 1327 (m),
1250 (m), 1158 (m), 1122 (m), 1083 (m), 1035 (m), 990 (m),
940 (w), 879 (m), 836 (m), 812 (s), 745 (s), 724 (s), 653 (m),
607 (m), 586 (w), 543 (m) cm−1; anal. calcd for C17H14N4: C
74.43, H 5.14, N 20.42; found: C 74.31, H 4.86, N 20.33.
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Supporting Information File 1
Experimental details for known compounds and spectral
data for compounds 1–3.
21.Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112–122.
doi:10.1107/S0108767307043930
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-116-S1.pdf]
License and Terms
Acknowledgements
We would like to thank Daniela Cichosch for assistance during
the synthesis. We are grateful to the BMWi and BMBF for the
financial support from grants 2005001AB8 and 01FS10043.
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
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The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.8.116
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