Karolina Bakalorz

Monika Olesiejuk

Nikodem Kuźnik

Tomasz Krawczyk

Comptes Rendus Chimie

lable at ScienceDirectC. R. Chimie 21 (2018) 831e834Contents lists avaiComptes Rendus Chimiewww.sciencedirect.comPreliminary communication/CommunicationBulky alkylaminophenol chelates with high potential forfunctionalizationMonika 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 oArticle history:Received 4 April 2018Accepted 10 July 2018Available online 24 August 2018Keywords:N,O-ligandsAliphatic aminesPhenolMannich reaction* Corresponding author.E-mail address: nikodem.kuznik@polsl.pl (N. Kuhttps://doi.org/10.1016/j.crci.2018.07.0021631-0748/© 2018 Académie des sciences. Publishea b s t r a c tAminophenols are an important class of N,O-ligands, particularly for the coordination offirst-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 demandingmodels 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 chlorinefollowed 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 methodfeatures 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. IntroductionAlkylaminophenols constitute a principle group of N,O-ligands [1]. They are vastly applied for coordination of firstrow transition complexes, serving, for example, as catalystsin oxidation [2e5], polymerization processes [6], or organiccarbonate synthesis from CO2 [7e9]. Their benefits comefrom the tripod geometry of the alkylamine skeleton thatallows for the formation of a chelating structure [10,11].The amine nitrogen atom opens up the possibility ofsymmetry control [12]. Additionally, the electronic char-acter of the nitrogen electron pair could be tuned andtherefore fitted to many hard acids, such as high-valent d-block metals [13]. On the other hand, the presence of aphenol 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 coordinationchemists, 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 eventheir elimination) with other molecules. Moreover, therecent enthusiasm in the idea of responsive molecules haslaunched the quest for systems which may be capable ofcovalent bond formation and cleavage within the moleculeupon activation by an external stimulus [15]. This concepthas already been investigated among bioresponsivecontrast agents that belong to rapidly developed molecularprobes [16,17]. Alkylaminophenols perfectly fit the basicelements of responsive molecules delivering a very tunableskeleton with both electronic and structural features, ashas been demonstrated for magnetic resonance imagingcontrast agents based on iron complexes [18e20]. Despitethese benefits which arewell appreciated due to the above-mentioned applications and despite some efficientmethods such as the one published by Kerton et al thatwas carried out “on water” [21], synthetic approachesare still often a barrier to obtaining systems with themost desired features. For this reason, we present ourstudy 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 nitrogensite for further substitution. This is an extended systemof simpler N,N-bis(hydroxybenzyl)-N-ethan-N’-(pyridyl-methyl)diamines which has already gained reasonableattention and has achieved most of the properties ingroups of magnetic resonance imaging contrast agents [18].2. Results and discussionThe approach to the synthesis of N,N-bis(hydrox-ybenzyl)-N’-(pyridylmethyl)propanediamines was initiallylaunched by a method our group published for their N-ethyl counterparts [18] (Scheme 1). However, the majorproduct separated for the post-reaction mixture wasreduced salicylaldehyde. A plausible explanation for thisreaction's failure was lower nucleophilicity of 3-aminopropan-1-ol due to internal H-bonding ascompared 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 paraposition with alkyl substituents. This was additionallybeneficial to our idea of constructing a molecule with bulkysubstituents, thus, we used 2,4-dialkylphenols in theMannich reaction (Scheme 2).We were surprised to note that the yields (up to 66% for1b), although generally not high, weremuchmore elevatedthan in our previous reductive amination approach (34%[18]). The final yields refer to the pure product of anapparently five-molecular, multistep, two-stage Mannichreaction. Byproducts were easily separated from the post-reaction mixture and identified as structures with a singlephenyl fragment (Scheme 3).The next step consisted chlorination of hydroxyl groupswith thionyl chloride. The reaction proceeded through amultiphase reaction mixture of N- and O-sulfonation in-termediates and their salts. However, the final workup byhydrolysis 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 bydashed lines.M. Olesiejuk et al. / C. R. Chimie 21 (2018) 831e834 833moiety was surprisingly good, even to obtain a fine crystalfor X-ray analysis (Fig. 1). We did not observe dealkylationof the fragment during its synthesis or further trans-formationdthis is not common since analogous com-pounds without hydroxyl substituents on the benzene ringare known to form intramolecular ammonium salts thatundergo decomposition by dealkylation processes (Scheme4) [23,24].The stability of our products could be explained bydiminished nucleophilicity of the nitrogen atom due to theformation 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 forrelated 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 nitrogencenters consisted in N-alkylation of 2-(aminomethyl)pyri-dine with chloroderivative 2. Our previous studies revealedthat a large excess of 2-(aminomethyl)pyridine (at least 7-fold) was necessary to avoid its multiple alkylations.Moreover, adjusting the reaction conditions was importantto increase the yield of the final product 3. It was found thatthe reaction time had to be adjusted to complete substrate2 consumption (by thin-layer chromatography [TLC]).Prolongation of the reaction time led to serious productdecomposition, thus diminishing its overall yield.We also investigated the direct introduction of propane-1,3-diamine to the bis(hydroxybenzyl) skeleton. In thisapproach, 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 Mannichreaction led to cyclization and formation of N,N0-disubsti-tuted 1,3-diazine 4, which was well identified by X-rayanalysis (Scheme 5) [27,28]. Therefore, the route asdescribed above from 3-aminopropan-1-ol via chlorinationis a reasonable alternative that successfully leads to thedesired N,N-bis(hydroxybenzyl)-N-propanamines.We show a convenient and selective way of synthesis ofbulky alkylaminophenols as a promising skeleton with afree site on the nitrogen atom for responsive systems andcoordination compounds.AcknowledgmentsThe Silesian University of Technology is acknowledgedfor the financial support.Appendix A. Supplementary dataSupplementary data related to this article can be foundat https://doi.org/10.1016/j.crci.2018.07.002.References[1] O. Wichmann, R. Sillanp€a€a, A. Lehtonen, Coord. Chem. Rev. 256(2012) 371e392.[2] M. Hossain, M. Haukka, R. 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Bulky alkylaminophenol chelates with high potential for functionalization

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Bulky alkylaminophenol chelates with high potential for functionalization

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