Synthesis of bis-8-hydroxyquinolines via an imination or a Suzuki-Miyaura coupling approach

Article abstract of DOI:10.1016/j.tetlet.2017.08.039

Bis-8-hydroxyquinolines represent an important yet underexplored class of potential ligands for the preparation of various coordination polymers, which can be used in a plethora of applications. In this work, the synthesis of two types of bis-8-hydroxyqui

Full text of DOI:10.1016/j.tetlet.2017.08.039

Accepted Manuscript
Synthesis of bis-8-hydroxyquinolines via an imination or a Suzuki-Miyaura
coupling approach
Rob De Vreese, Koen Muylaert, Cedric Maton, Lise Dereu, Frederique Taillieu,
Thomas Harth, Rik Van Deun, Henk Vrielinck, Christian V. Stevens, Matthias
D'hooghe
PII:
S0040-4039(17)31037-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.08.039
TETL 49229
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 June 2017
11 August 2017
15 August 2017
Please cite this article as: De Vreese, R., Muylaert, K., Maton, C., Dereu, L., Taillieu, F., Harth, T., Van Deun, R.,
Vrielinck, H., Stevens, C.V., D'hooghe, M., Synthesis of bis-8-hydroxyquinolines via an imination or a Suzuki-
Miyaura coupling approach, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.08.039
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Graphical abstract
1

Synthesis of bis-8-hydroxyquinolines via an imination or a Suzuki-
Miyaura coupling approach
Rob De Vreesea, Koen Muylaerta, Cedric Matona, Lise Dereua, Frederique Taillieua, Thomas Hartha, Rik
Van Deunb, Henk Vrielinckc, Christian V. Stevensa,*, Matthias D'hooghea,*
a SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience
Engineering, Ghent University, Coupure Links 653, B-9000, Ghent, Belgium
b L3 – Luminescent Lanthanide Lab, Department of Inorganic and Physical Chemistry, Faculty of Sciences, Ghent
University, Krijgslaan 281-S3, B-9000 Ghent, Belgium
c Department of Solid State Sciences, Faculty of Sciences, Ghent University, Krijgslaan 281-S1, B-9000, Ghent,
Belgium
* matthias.dhooghe@UGent.be, chris.stevens@UGent.be, phone: +3292649379, fax: +3292646221
Abstract
Bis-8-hydroxyquinolines represent an important yet underexplored class of potential ligands for the
preparation of various coordination polymers, which can be used in a plethora of applications. In this work, the
synthesis of two types of bis-8-hydroxyquinolines, prepared via either an imination or a Suzuki-Miyaura
coupling approach, as well as their analysis is discussed. Imination was pursued through the condensation of
quinolinecarbaldehydes with diamines or aminoquinolines with dialdehydes, and the Suzuki-Miyaura coupling
reactions were evaluated using a bromoquinoline substrate and diboronic acids.
Keywords: 8-hydroxyquinoline, imination, Suzuki-Miyaura coupling, NMR, EPR
8-Hydroxyquinolines have attracted a lot of attention due to their excellent electroluminescent
properties upon coordination with metals.1 Elaborating further on the success of 8-hydroxyquinoline
complexes in OLED displays, significant effort has been devoted in the last decade to the generation
of novel derivatives with improved photometric and thermal properties.2-4 By designing and
developing bis-8-hydroxyquinolines, in which two 8-hydroxyquinoline systems are integrated into
one molecular framework, the construction of coordination polymers can be envisioned representing
an extended network of metal ions coordinated to multidentate organic molecules. These chemical
architectures could then be applied to various areas e.g. chemical catalysis, molecular separation, gas
storage, chemical sensing, ion exchange and drug delivery.5,6 Although not frequently studied, some
examples of bis-8-hydroxyquinolines have been described in the literature (Fig. 1).7-15 Compounds 1
and 2 were previously prepared from 5-chloromethyl-8-hydroxyquinoline via nucleophilic
substitution using an amine, whereas structures 3 and 4 were synthesized from 2- or 5-substituted 8-
2

hydroxyquinolinecarbaldehydes through a condensation reaction. This short communication reports
on our recent endeavours to prepare similar structures and to extend the list of known examples
with novel bis-8-hydroxyquinolines synthesized through imination or Suzuki-Miyaura cross-coupling
approaches using 8-hydroxyquinoline-2-carbaldehyde or 5-bromo-8-hydroxyquinoline, respectively.
Figure 1. Selected examples of bis-8-hydroxyquinolines 1-4 reported in the literature.7-15
The first set of bis-8-hydroxyquinolines 7a-d was synthesized via a condensation reaction between 8-
hydroxyquinoline-2-carbaldehyde 5a (R = H, Scheme 1) and diamines 6 (Table 1). It should be
mentioned that derivatives 7a and 7c have previously been synthesized,15,16 whereas structures 7b
and 7d represent new systems. These iminations took place in ethanol at reflux for 8-24 hours, after
which the reaction was cooled to room temperature to obtain bis-imines 7a-d as pure solids. Full
1
characterization of these compounds was attempted using H and 13C NMR spectroscopy (CDCl3 or
DMSO-d6). Surprisingly, for pyridine-containing scaffold 7d no signals were detected in the 1H and 13
C
NMR spectra, even though the compound completely dissolved in CDCl3 and DMSO-d6. To address
this problem, NMR spectra were recorded in other deuterated solvents ((CD3)2CO, ethanol-d6) and at
higher temperatures, however, once again no signals were detected. We suspect that the formation
of stabilized unpaired electrons provoked the problem of NMR-silence in molecule 7d, and therefore,
electron paramagnetic resonance (EPR) measurements were performed on all four bis-8-
hydroxyquinolines 7a-d. The obtained spectra revealed a signal at a g-factor of 2.0044 for
compounds 7b-d (Q-band, microwave frequency normalized to 34.09 GHz, Fig. 2). This is a typical
value for carbon-centered radicals, and this observation thus provides a possible explanation for the
NMR incompatibility of structure 7d.17 As the free phenolic group present in compounds 7a-d could
be the source of radical species formation, synthesis of the corresponding O-benzyl-protected
derivatives 7e-h was realized via the imination of 8-benzyloxyquinoline-2-carbaldehyde 5b.
3

Surprisingly, again only for analog 7h possessing a pyridine linker, no signals were detected in the
NMR spectra, pointing to the contribution of the pyridine ring fragment to the NMR-silence of these
molecules. Finally, 5-substituted bis-8-hydroxyquinoline 1018 was prepared via a ‘reversed’ imination
approach (Scheme 1, Table 1). This was accomplished by adding terephthalaldehyde 9 to 5-amino-8-
hydroxyquinoline 8 in EtOH in the presence of triethylamine (2.5 equiv.). The solubility of bis-imine
10 in organic solvents (EtOH, EtOAc, CHCl3, DMSO, DMF), however, proved to be low, which could
possibly hamper its utility for further applications.
Scheme 1. Synthesis of bis-8-hydroxyquinolines 7a-h and 10.
Table 1. Synthesis and solubility of bis-8-hydroxyquinolines 7a-h and 10.
Cmpd.
Diamine 6
R
Solubility
(DMSO, rt)
Possibility to
record 1H NMR
Yield
(%)
spectrum
yes
yes
7a
7b
7c
7d
7e
7f
p-phenylenediamine 6a
2,4-diaminotoluene 6b
4,4'-methylenedianiline 6c
2,6-diaminopyridine 6d
p-phenylenediamine 6a
2,4-diaminotoluene 6b
4,4'-methylenedianiline 6c
2,6-diaminopyridine 6d
-
H
H
H
yes
yes
yes
yes
90
75
72
85
86
75
73
75
98
yes
no
H
Bn
Bn
Bn
Bn
-
yes
yes
yes
yes
7g
7h
10
yes
yes
partial
yes
no
yes
4

Figure 2. EPR spectra of compounds 7a-d at 34.09 GHz, recorded at room temperature with 5 mW microwave
power (7a = black, 7b = blue, 7c = red, 7d = green).
In summary, five bis-8-hydroxyquinolines (7a-d and 10) and four bis-8-benzyloxyquinolines (7e-h)
were synthesized via an imination approach for further investigation as potential scaffolds.
In a second part of this study, the synthesis of bis-8-hydroxyquinolines 13a-c was contemplated
utilizing Suzuki-Miyaura cross coupling methodology (Scheme 2). To that end, the following three-
step strategy was applied. In a first step, (i) O-protection of 5-bromo-8-hydroxyquinoline 11 with a
suitable protecting group (PG) to allow an efficient Suzuki-Miyaura coupling, (ii) addition of a
diboronic acid and a palladium catalyst to synthesize the O-protected bis-8-hydroxyquinolines, and
(iii) deprotection of the aromatic alcohol group to give compounds 13.
OH
N
1)
B(OH)2
OH
Br
OPG
Br
Z
(HO)2B
Z
N
N
Pd catalyst
2) deprotection
N
OH
11
12
13a (Z = p-phenylene)
13b
(Z = bis-(p-phenylene))
13c
(Z = 2,5-thiophenylene)
Scheme 2. Synthesis outline en-route to bis-8-hydroxquinolines 13a-c.
5

In the literature, one method is available for the synthesis of bis-8-hydroxyquinoline 13b (Z = bis-(p-
phenylene)).19 In that approach, the 8-hydroxyquinoline moiety was first O-protected with a methyl
group, but the yield of the subsequent demethylation reaction was low despite many attempts
(yields not reported). Therefore, the methoxymethyl protecting group was introduced instead, which
resulted in the synthesis of 13b (Z = bis-(p-phenylene)) in good yields for both the Suzuki-Miyaura
coupling and the deprotection step (78% and 91%, respectively).
In our first attempt to obtain compound 13a (Z = 1,4-phenylene, Scheme 2), 5-bromo-8-
hydroxyquinoline 11 was efficiently protected with a benzyl group utilizing a previously described
method by adding a slight excess of benzyl chloride to 5-bromo-8-hydroxyquinoline 11 in the
presence of potassium carbonate and potassium iodide (Scheme 3).20 Then, the Suzuki-Miyaura
coupling reaction was accomplished utilizing 5-bromo-8-benzyloxyquinoline 14, benzene-1,4-
diboronic acid, sodium carbonate and tetrakis(triphenylphosphine)palladium(0), affording dimeric
compound 15 in 52% yield after column chromatographic purification (SiO2). Unfortunately, 5-
phenyl-8-benzyloxyquinoline was also formed as a minor side-product. To obtain target molecule
13a, several attempts were made to remove the benzyl protecting group, utilizing palladium on
carbon and 1,4-cyclohexadiene or hydrogen gas, but unfortunately no deprotection of the benzyl
group was achieved in these experiments.
Scheme 3. Synthesis of compound 15 via 8-benzyloxyquinoline 14.
This disappointing result led us to explore an alternative route and to instead synthesize tosyl-
protected derivative 16 (Scheme 4), since the tosyloxy group could enhance the reactivity of the
bromoquinoline in the Suzuki-Miyaura reaction due to its electron-withdrawing properties.21,22
Furthermore, this protecting group has been reported to be easily removed upon treatment with
aqueous sodium hydroxide.23 For the tosyl protection of 5-bromo-8-hydroxyquinoline 11, a slightly
modified literature procedure was employed.23,24 Sodium hydroxide was used as a base to abstract
the phenolic proton in 5-bromo-8-hydroxyquinoline 11, after which para-toluenesulfonyl chloride
was added to afford tosylate 16 in nearly quantitative yield (Scheme 4). The following Suzuki-Miyaura
reaction with 1,4-benzenediboronic acid furnished bis-8-tosyloxyquinoline 17a in 83% yield, which
6

was considerably better than the same reaction carried out with the benzyl-protected counterpart 14
(52%, Scheme 3). Since the reactions in this pathway proceeded well, this sequence was also used to
produce derivatives 17b and c possessing a bis-(p-phenylene) and a 2,5-thiophenylene linker,
respectively, in 50% and 13% yield after column chromatographic purification (SiO2). In the final
deprotection step, all three tosylates 17a-c were subjected to hydrolysis with sodium hydroxide,
generating bis-8-hydroxyquinolines 13a-c in 72-97% yield. These three final products 13a-c were
obtained by performing the protecting group removal in different solvent systems (DMSO/EtOH 1/1
for 13a and 13b or EtOH/Acetone 1/1 for 13c), which improved the solubility of the starting products
17a-c and of sodium hydroxide. In a paper by Cui and co-workers, it has been reported that the
solubility of bis-8-hydroxyquinolines such as structure 13b is very low in organic solvents (THF and
CH2Cl2).19 This was confirmed here, as bis-quinolines 13a and 13b were shown to be poorly soluble in
water and in several organic solvents (EtOAc, DMSO, CHCl3). As a consequence, no NMR spectra
could be recorded for these two compounds. Fortunately, thiophenylene-linked structure 13c was
somewhat more soluble and was completely characterized by NMR (DMSO-d6). To indirectly prove
that structure 13a was effectively formed after the tosyl deprotection step, a derivatisation approach
was proposed. This was achieved by adding benzyl bromide (2.4 equiv.) and potassium carbonate (10
equiv.) to hydroxyquinoline 13a, which generated O-benzylated compound 15 (48%, Scheme 4). High
temperatures, an extended reaction time and a polar solvent (DMF) were necessary to improve the
solubility of compound 13a. It should be noted that the same compound 15 was previously prepared
using the Suzuki-Miyaura coupling approach illustrated in Scheme 3. The 1H and 13C NMR spectra of
structures 15 obtained via both pathways (Schemes 3 and 4), were identical, indirectly proving that
structure 13a was formed after the deprotection of tosylate 17a.
7

Scheme 4. Synthesis of compounds 13a-c via 8-tosyloxyquinoline 16.
Overall, eight bis-8-hydroxyquinolines (7a-d, 10 and 13a-c) were synthesized via an imination or a
Suzuki-Miyaura cross coupling approach and represent valuable molecular scaffolds for further
studies with respect to metal complexation. Of these eight structures, four have not been reported in
the literature (7b, 7d, 13a and 13c). The solubility of the compounds obtained through imination of
8-hydroxyquinoline-2-carbaldehyde using diamines (7a-d) in organic solvents (EtOH, EtOAc, CHCl3,
DMSO, DMF) proved to be superior over the structures obtained via imination with
terephthalaldehyde and 5-amino-8-hydroxyquinoline (10) or via Suzuki-Miyaura coupling (13a-c). For
bis-8-hydroxyquinolines 7d and 13a,b, no signals were detected upon NMR spectroscopic analysis.
8

This NMR-silence could be explained by the paramagnetic properties of 7d, as observed via EPR
measurements, and by the insolubility of bis-8-hydroxyquinolines 13a,b in water and organic
solvents. In conclusion, soluble bis-8-hydroxyquinolines 7a-d are much easier to handle, and
therefore we suggest that further investigation into the possible applications of the more soluble
imines 7a-d should have priority. Moreover, imines 7a-d can be easily prepared in only one step in
good yields.
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Highlights
•
Bis-8-hydroxyquinolines concern underexplored ligands for the preparation of coordination
polymers
•
•
Few reports on the synthesis of bis-8-hydroxyquinolines are available
This work discloses the preparation of bis-8-hydroxyquinolines (via imination or Suzuki-
Miyaura coupling) and their analysis
10