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C. R. Chimie 21 (2018) 831e834Contents lists avaiComptes Rendus Chimie
www.sciencedirect.comPreliminary communication/CommunicationBulky alkylaminophenol chelates with high potential for
functionalization
Monika Olesiejuk, Karolina Bakalorz, Tomasz Krawczyk, Nikodem Kuznik*
Faculty of Chemistry, Silesian University of Technology, B. Krzywoustego 4, 44-100, Gliwice, Polanda r t i c l e i n f o
Article history:
Received 4 April 2018
Accepted 10 July 2018
Available online 24 August 2018
Keywords:
N,O-ligands
Aliphatic amines
Phenol
Mannich reaction* Corresponding author.
E-mail address: nikodem.kuznik@polsl.pl (N. Ku
https://doi.org/10.1016/j.crci.2018.07.002
1631-0748/© 2018 Académie des sciences. Publishea b s t r a c t
Aminophenols are an important class of N,O-ligands, particularly for the coordination of
first-row transition metals. While their structural and electronic character and the addi-
tional possibility of bioactivation are well appreciated in coordination chemistry, particu-
larly of responsive systems, the synthesis of the more branched and structurally demanding
models is still a challenge. Therefore, the synthesis of bulky bis(hydroxybenzyl)-N’-(ami-
nopyridyl)propanamines is described here. It consists of the Mannich reaction of 2,4-
disubstituted phenols with 3-aminopropan-1-ol and paraformaldehyde to N,N-bis(2-
hydroxybenzyl)-3-aminopropan-1-ol. Substitution of the hydroxyl group with chlorine
followed by amination with 2-(aminomethyl)pyridine results in bulky pentadentate N,O-
ligands with a free site on the nitrogen atom for further functionalization. The method
features good yields and high selectivity, and the products are well identified by spectro-
scopic methods.
© 2018 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.1. Introduction
Alkylaminophenols constitute a principle group of N,O-
ligands [1]. They are vastly applied for coordination of first
row transition complexes, serving, for example, as catalysts
in oxidation [2e5], polymerization processes [6], or organic
carbonate synthesis from CO2 [7e9]. Their benefits come
from the tripod geometry of the alkylamine skeleton that
allows for the formation of a chelating structure [10,11].
The amine nitrogen atom opens up the possibility of
symmetry control [12]. Additionally, the electronic char-
acter of the nitrogen electron pair could be tuned and
therefore fitted to many hard acids, such as high-valent d-
block metals [13]. On the other hand, the presence of a
phenol moiety in close vicinity of the nitrogen atoms se-
cures the systems' high affinity to transition metals [14].
These features have attracted the attention of coordination
chemists, who often impose additional factors on theseznik).
d by Elsevier Masson SAS. Aligands. One such structural factor is bulkiness of the sub-
stituents which allows for selective interactions (or even
their elimination) with other molecules. Moreover, the
recent enthusiasm in the idea of responsive molecules has
launched the quest for systems which may be capable of
covalent bond formation and cleavage within the molecule
upon activation by an external stimulus [15]. This concept
has already been investigated among bioresponsive
contrast agents that belong to rapidly developed molecular
probes [16,17]. Alkylaminophenols perfectly fit the basic
elements of responsive molecules delivering a very tunable
skeleton with both electronic and structural features, as
has been demonstrated for magnetic resonance imaging
contrast agents based on iron complexes [18e20]. Despite
these benefits which arewell appreciated due to the above-
mentioned applications and despite some efficient
methods such as the one published by Kerton et al that
was carried out “on water” [21], synthetic approaches
are still often a barrier to obtaining systems with the
most desired features. For this reason, we present our
study on branched, bulky N,N-bis(hydroxybenzyl)-N’-ll rights reserved.
M. Olesiejuk et al. / C. R. Chimie 21 (2018) 831e834832(pyridylmethyl)propanediamines 3 with one free nitrogen
site for further substitution. This is an extended system
of simpler N,N-bis(hydroxybenzyl)-N-ethan-N’-(pyridyl-
methyl)diamines which has already gained reasonable
attention and has achieved most of the properties in
groups of magnetic resonance imaging contrast agents [18].
2. Results and discussion
The approach to the synthesis of N,N-bis(hydrox-
ybenzyl)-N’-(pyridylmethyl)propanediamines was initially
launched by a method our group published for their N-
ethyl counterparts [18] (Scheme 1). However, the major
product separated for the post-reaction mixture was
reduced salicylaldehyde. A plausible explanation for this
reaction's failure was lower nucleophilicity of 3-
aminopropan-1-ol due to internal H-bonding as
compared to 2-aminoethanol.
The alternative approach to the N,N-bis(hydrox-
ybenzyl)-N-propane skeleton is via the Mannich reaction,
analogous to ethyl derivatives [22]. There, due to the lowScheme 1. Synthesis of N,N-bis(hydroxybenzyl)-
Scheme 2. The Mannich reaction of 2,4-disubstituted phenols to N,N-bis(hydroxyregioselectivity of the benzene ring substitution in phenols,
it is favored to block one of the ortho and the only para
position with alkyl substituents. This was additionally
beneficial to our idea of constructing a molecule with bulky
substituents, thus, we used 2,4-dialkylphenols in the
Mannich reaction (Scheme 2).
We were surprised to note that the yields (up to 66% for
1b), although generally not high, weremuchmore elevated
than in our previous reductive amination approach (34%
[18]). The final yields refer to the pure product of an
apparently five-molecular, multistep, two-stage Mannich
reaction. Byproducts were easily separated from the post-
reaction mixture and identified as structures with a single
phenyl fragment (Scheme 3).
The next step consisted chlorination of hydroxyl groups
with thionyl chloride. The reaction proceeded through a
multiphase reaction mixture of N- and O-sulfonation in-
termediates and their salts. However, the final workup by
hydrolysis in aqueous bicarbonate led to crude product 2,
which is usually of sufficient quality for further trans-
formations. The stability of the 3-chloropropan-1-amineN-propanamines via reductive amination.
benzyl)-N-propanamines. Yields of pure products are given in parentheses.
Scheme 3. Byproducts formed in the Mannich reaction of 2,4-di(tert-butyl)phenol with 3-aminopropan-1-ol and paraformaldehyde.
Fig. 1. X-ray structure of 2a N,N-bis(2-hydroxy-3,5-dimethylbenzyl)-3-chloropropan-1-amine; 50% probability ellipsoids with hydrogen bonding presented by
dashed lines.
M. Olesiejuk et al. / C. R. Chimie 21 (2018) 831e834 833moiety was surprisingly good, even to obtain a fine crystal
for X-ray analysis (Fig. 1). We did not observe dealkylation
of the fragment during its synthesis or further trans-
formationdthis is not common since analogous com-
pounds without hydroxyl substituents on the benzene ring
are known to form intramolecular ammonium salts that
undergo decomposition by dealkylation processes (Scheme
4) [23,24].
The stability of our products could be explained by
diminished nucleophilicity of the nitrogen atom due to the
formation of hydrogen bonds. Such bonding is well iden-
tified in the X-ray structure (Fig. 1) with the N…HO dis-
tance equal to 1.884 Å, thus placing it in the classical H-
bonding range. This interaction has been observed for
related structurally characterized compounds [21,25,26].Scheme 4. Dealkylation of non-hydrogen-bonThe final step of merging the N,N-bis(hydroxybenzyl)-
N-propanamine fragment with two additional nitrogen
centers consisted in N-alkylation of 2-(aminomethyl)pyri-
dine with chloroderivative 2. Our previous studies revealed
that a large excess of 2-(aminomethyl)pyridine (at least 7-
fold) was necessary to avoid its multiple alkylations.
Moreover, adjusting the reaction conditions was important
to increase the yield of the final product 3. It was found that
the reaction time had to be adjusted to complete substrate
2 consumption (by thin-layer chromatography [TLC]).
Prolongation of the reaction time led to serious product
decomposition, thus diminishing its overall yield.
We also investigated the direct introduction of propane-
1,3-diamine to the bis(hydroxybenzyl) skeleton. In this
approach, we carried out the Mannich reaction betweended N,N-dibenzyl-N-chloroalkylamines.
Scheme 5. The Mannich reaction of 2,4-di(tert-butyl)phenol, propane-1,3-diamine, and paraformaldehyde.
M. Olesiejuk et al. / C. R. Chimie 21 (2018) 831e8348342,4-di(tert-butyl)phenol, propane-1,3-diamine, and para-
formaldehyde. While reductive elimination of salicylalde-
hyde and propane-1,3-diamine led to N,N0-
bis(hydroxybenzyl)propane-1,3-diamine [19], the Mannich
reaction led to cyclization and formation of N,N0-disubsti-
tuted 1,3-diazine 4, which was well identified by X-ray
analysis (Scheme 5) [27,28]. Therefore, the route as
described above from 3-aminopropan-1-ol via chlorination
is a reasonable alternative that successfully leads to the
desired N,N-bis(hydroxybenzyl)-N-propanamines.
We show a convenient and selective way of synthesis of
bulky alkylaminophenols as a promising skeleton with a
free site on the nitrogen atom for responsive systems and
coordination compounds.
Acknowledgments
The Silesian University of Technology is acknowledged
for the financial support.
Appendix A. Supplementary data
Supplementary data related to this article can be found
at https://doi.org/10.1016/j.crci.2018.07.002.
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