Synthesis and structural characterization of a highly substituted triazine ring comprising a sterically flexible methylene linker and coordinating substituents

Article abstract of DOI:10.1016/j.tetlet.2017.05.083

The efficient multi-step, large-scale synthesis, spectroscopic characterization and solid-state molecular structure of a new type of three-fold functionalized, sterically demanding triazine is reported. The aromatic heterocycle 6,6′,6′'-((1,3,5-triazine-2,4,6-triyl)tris(methylene))tris(2,4-di-tert-butylphenol) possesses three 2,4-di-tert-butylphenol synthons bound to the 1,3,5-triazine ring via synthetically challenging methylene linkages in the 2,4,6 positions. The key to success was found in the generation of a highly reactive imidate hydrochloride salt, namely ethyl 2-(3,5-di-tert-butyl-2-methoxyphenyl)acetimidate hydrochloride, that readily undergoes cyclotrimerization. The reported preparation opens new perspectives in the design and synthesis of novel triazine molecules bearing flexible and sterically demanding functionalized groups for various applications.

Full text of DOI:10.1016/j.tetlet.2017.05.083

Accepted Manuscript
Synthesis and Structural Characterization of a Highly Substituted Triazine Ring
Comprising a Sterically Flexible Methylene Linker and Coordinating Substitu-
ents
Christophe Werlé, Chih-Juo Madeline Yin, Frank W. Heinemann, Christina
Hauser, Karsten Meyer
PII:
S0040-4039(17)30675-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.083
TETL 48976
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 April 2017
19 May 2017
23 May 2017
Please cite this article as: Werlé, C., Yin, C.M., Heinemann, F.W., Hauser, C., Meyer, K., Synthesis and Structural
Characterization of a Highly Substituted Triazine Ring Comprising a Sterically Flexible Methylene Linker and
Coordinating Substituents, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.05.083
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Synthesis and Structural Characterization of a Highly Substituted
Triazine Ring Comprising a Sterically Flexible Methylene Linker and
Coordinating Substituents
Christophe Werlé*1, Chih-Juo Madeline Yin1, Frank W. Heinemann1, Christina Hauser1, Karsten
Meyer*1
Address: 1 Department of Chemistry and Pharmacy, Inorganic Chemistry, Friedrich-Alexander-University
Erlangen-Nürnberg, Egerlandstrasse 1, 91058 Erlangen, Germany.
* Corresponding authors
Email: Christophe Werlé – christophe.werle@fau.de; Phone: +49 (0)9131 8527362.
Email: Karsten Meyer – karsten.meyer@fau.de; Phone: +49 (0)9131 8527360.
Abstract
The efficient multi-step, large-scale synthesis, spectroscopic characterization and solid-state
molecular structure of a new type of three-fold functionalized, sterically demanding triazine is
reported. The aromatic heterocycle 6,6',6''-((1,3,5-triazine-2,4,6-triyl)tris(methylene))tris(2,4-di-tert-
butylphenol) possesses three 2,4-di-tert-butylphenol synthons bound to the 1,3,5-triazine ring via
synthetically challenging methylene linkages in the 2,4,6 positions. The key to success was found in
the generation of a highly reactive imidate hydrochloride salt, namely ethyl 2-(3,5-di-tert-butyl-2-
methoxyphenyl)acetimidate hydrochloride, that readily undergoes cyclotrimerization. The reported
preparation opens new perspectives in the design and synthesis of novel triazine molecules bearing
flexible and sterically demanding functionalized groups for various applications.
Keywords
Triazine; Heterocycles; Cyclotrimerization; Imidates
1

Introduction
Among the broad family of heterocycles,1 N-containing congeners,2 such as 1,3,5-triazines (s-
triazine), have gained importance in several different fields. The applications are certainly too
numerous to be listed here, but cover a very broad area ranging from pharmaceuticals,3 materials,4
supramolecular building blocks,5 and ligands6 to reagents for chemical transformations.7 Intrinsic to
this growing interest are the development of new synthetic methodologies for the efficient
preparation of more elaborate and sophisticated polyfunctional 1,3,5-triazines.8 In the course of our
ligand design program towards potential new ligands capable of coordinating large, oxophilic metal
centers, such as f-block metal ions,9 s-triazine derivatives such as 1 (Scheme 1) were found to be of
particular interest. This functionalized molecular platform constitutes a very interesting architecture
incorporating a methylene linkage connecting the heteroaromatic ring and the phenol groups at
alternating carbon atoms. Incorporation of an sp3-hybridized carbon linker is thought to provide
sufficient structural flexibility to properly accommodate the coordination of a metal ion through the
sterically shielding and chelating phenol arms. Most importantly, the anchoring triazine unit,
specifically the doubly degenerate set of triazine π* orbitals, ought to provide an efficient platform
for δ-backbonding with the symmetry-equivalent metal f-orbitals.9d, 10 This allows the synthesis of
electron-rich, low-valent coordination complexes for the reductive activation of small molecules of
biological and industrial importance, for example H2, CO, CO2, O2, and H2O.11
2

Scheme 1. Structure of triazine 1 and two attempted synthetic approaches.
To our surprise, literature procedures for the envisioned methylene linker on such heterocycles are
extremely scarce. This undoubtedly transpires from an inherent difficulty in constructing this very
specific linkage on triazine molecules. Recent developments in synthetic methodologies, particularly
in cross-coupling reactions involving various transition metal catalysts, e.g. Suzuki, Kumada, or
Negishi coupling, have allowed for the construction of arylmethylheteroaromatic molecules.12
Nevertheless, only a handful of triazine molecules displaying this interesting skeleton are reported,
but with rather simple motifs and without functional groups in the ortho-position of the linked
phenol group capable of coordinating metal ions.13 For our purposes, it was therefore necessary to
establish a facile and efficient entry into this elusive class of molecules, sufficiently robust and
flexible to enable further derivatization.
Results and Discussion
Our initial synthetic approach for introduction of the methylene linkage focused on coupling
reactions following the above-mentioned recent developments. For example, the Suzuki coupling
reaction12g, 14 of aryltrifluoroborate 2a with triazine 3 in the presence of PdCl2(dppf)·CH2Cl2 (with dppf
= 1,1'-bis(diphenylphosphino)ferrocene), and triethylamine in a mixture of iPrOH-H2O at reflux or,
3

alternatively, the Negishi coupling reaction12j, 15 of 3 with zinc reagent 2b using Pd(OAc)2 and S-Phos
(with S-Phos = 2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl) in THF at reflux (Scheme 2).
Scheme 2. Coupling routes investigated for the synthesis of triazine 1-OMe.
Unfortunately, these reaction pathways to the desired triazine 1-OMe were unsuccessful in our
hands as evidenced by mostly slow decomposition of the starting materials. In our attempts toward
the heterocycle synthesis, we therefore considered the cyclotrimerization of nitrile derivatives
(Scheme 1). The cyclization of three identical (or different) RCN groups constitutes a well-established
method that has previously allowed for the isolation of a number of 1,3,5-triazines.16 However,
depending on the nature of the substrate, the catalyst (i.e. Lewis acids, basic compounds or
lanthanides),16f, 16i-k, 17 or the reaction conditions (i.e. temperature, pressure, solvent),18 fluctuating
yields have been reported. In order to investigate the viability of this route, 2-(3,5-di-tert-butyl-2-
methoxyphenyl)acetonitrile 9 was readily synthesized following a five-step procedure, starting from
commercially available 2,4-di-tert-butylphenol 4 (Scheme 3). The first step involved the formylation
of phenol 4 using tin(IV) chloride, paraformaldehyde (PFA), and triethylamine.19 The resulting
aldehyde was then O-methylated via deprotonation of the alcohol with sodium hydroxide and
subsequent quench with methyl iodide leading to 3,5-di-tert-butyl-2-methoxybenzaldehyde 5 which
4

was then reduced with NaBH4 to afford the corresponding benzyl alcohol 7. The succeeding reaction
with phosphorus tribromide in CH2Cl2 afforded the desired benzyl bromide (8).9e Bromide 8, without
further purification, was treated with NaCN in an ethanol/water mixture to yield the targeted nitrile
derivative 9 on gram-scale with an overall yield of 68%. The solid-state molecular structure of key
compound 9 was unambiguously established by single-crystal X-ray diffraction analysis of colorless
needles (see ESI).
O
H
O
H
HO
a)
b)
HO
O
4
5
6
Br
HO
NC
c)
d)
e)
O
O
O
7
8
9
Scheme 3. Reagents and conditions: a) SnCl4, PFA, NEt3, toluene, 80 ºC, 12 h, 88%; b) MeI, NaOH,
THF/DMSO (10:1), RT, 12 h, 98%; c) NaBH4, ethanol, RT, 2 h, 95%; d) PBr3, 0 ºC → RT, 1 h, 89%, e)
NaCN, ethanol/H2O (10:1), 90%.
Our first cyclotrimerization attempts of nitrile 9 were guided by reported procedures for the
synthesis of other analogues.16 Thus, several catalysts such as triflic acid (TfOH), triflic anhydride
(Tf2O), trifluoroacetic acid (TFA), or samarium(II) iodide were investigated. Reaction times spanning
from 30 min to 24 h, at temperatures ranging from 40 ºC to 120 ºC, in commonly used solvents (ie.
toluene, n-hexane, dichloromethane) were considered. Unfortunately, none of these procedures
were successful; In most attempts starting material 9 was recovered unreacted. When catalysts,
such as Tf2O or TfOH were used, a complex mixture of products with no traces of triazine 1-OMe was
5

obtained, as evidenced by GC-MS and 1H NMR analysis. Clearly, the persistence of starting material 9
in the resulting reaction mixtures points to a lack of reactivity of the involved nitrile toward
cyclotrimerization. Therefore, an alternative pathway with drastically increased reactivity for 9 had
to be found. This difficulty was circumvented by generating the corresponding imidate hydrochloride
salt following a modified Pinner type reaction.20 This highly reactive imidate salt 10 exhibits the
increased reactivity required to overcome the electronic and steric constraints and undergo
cyclotrimerization.13e, 13g, 21 Imidate salt 10 was readily obtained by passing anhydrous hydrogen
chloride gas through a solution of nitrile 9 in a diethyl ether-ethanol mixture, leading to precipitation
of the salt in almost quantitative yield (Scheme 4). The isolated imidate 10 is moisture sensitive22 but
can be stored in the freezer under an inert gas atmosphere. Following our synthetic route (Scheme
4), imidate salt 10 was then converted to the conjugated ethyl imino ester 11 under basic conditions.
The reaction of 10 with 11 in a 1:5 ratio at 80 ºC smoothly furnished the expected triazine 1-OMe in
relatively good yield (66%) after 20 h. Finally, removal of the protecting groups using boron
tribromide in dichloromethane led to the targeted triazine 1 with an overall yield of 36% over 9
steps. The purity of 9 was confirmed by CHN elemental combustion analysis and its molecular
structure was determined by single-crystal X-ray diffraction analysis.
6

Scheme 4. Reagents and conditions: a) HCl(g), Et2O/EtOH (10:1), 0 ºC to RT, 12 h, 97%; b) NEt3,
Et2O/CH2Cl2 (1:1), 2 h, 87%; c) 10, neat, 80 ºC, 20 h, 66%; d) BBr3, CH2Cl2, 0 ºC to RT, 12 h, 98%.
Spectroscopic characterizations and structural analysis
1
The molecular structure of triazine 1 in solution was confirmed by H NMR and 13C NMR spectral
1
analyses. The H NMR spectrum of 1 in CDCl3 displayed the expected characteristic peaks of the
molecule (see ESI). Since the triazine core does not possess any hydrogen atoms, the hydrogen
peaks of the phenyl groups were investigated instead and their number was confirmed by peak
integration. Furthermore, 1H NMR spectroscopy showed a single set of sharp signals for the different
protons of the molecule; thus, suggesting freely rotating phenyl groups in solution. The 13C NMR
displayed the characteristic carbon atoms of the triazine core at high chemical shifts (i.e. 178.5 ppm),
which likely is caused by the proximity of two strongly electronegative N atoms. This chemical shift
was also in accordance with other reported literature examples.4a, 8f, 23 The highly shifted signals of
the other characteristic groups in the molecule, such as the C atom of the methylene linker (43 ppm)
or the aromatic C atoms (152 ppm) directly attached to the OH group, can be explained based on the
same rationale.
7

Compound 1 was analysed by IR vibrational spectroscopy; all signals were in line with the vibrational
spectra of reported 1,3,5-triazines.24 The most notable and characteristic feature was the strong
signal at 1533 cm–1 ascribed to the C=N stretching vibrations of the s-triazine ring. Several other
bands in the range of 2900-3000 cm–1 were assigned to the characteristic absorptions of the C–H
bending and stretching vibration modes of the aromatic hydrogen atoms. The characteristic O–H
group vibrations are known to be more sensitive to the environment and the absorption band
positions dependent on the strength of the hydrogen bond. In case of 1, intramolecular hydrogen
bonding occurs (see Fig. 1) and the resulting hydroxyl group stretching band appears at 3250 cm–1.
Figure 1. Molecular structure of triazine 1 in crystals of 1 • CH3CN (left), and a schematic
representation displaying the up/down orientation of the phenyl groups (right),
thermal ellipsoids are drawn at 50 % probability.
The solid-state molecular structure of 1 in single-crystals of 1 • CH3CN (Fig. 1) was unambiguously
established by single crystal X-ray structural analysis of colorless crystals obtained by diffusion of a
water/HCl mixture into an acetonitrile solution of the triazine. According to this XRD analyses, 1
crystallizes in the centrosymmetric, monoclinic space group P21/c. All non-hydrogen atoms were
refined anisotropically. The compound crystallized with two independent molecules of the triazine
8

derivative and two independent molecules of CH3CN in its asymmetric unit. The crystal packing
displayed a shifted orientation between the triazine cores with alternating electronegative N and
electropositive C atoms (ESI; Fig. S3, S4). The angles and bond lengths are similar to those reported
in the literature for structural analogues and thus the observed angles and bond lengths can be
confirmed (ESI; Table S2, S3).13b, 23-24, 25
Conclusion
In the course of this project, we discovered that, although important synthetic methodologies have
been developed in the past, the efficient synthesis of polyfunctional triazine rings still holds synthetic
challenges to be tackled. Overall, the synthesis of triazine 1 described herein is robust, facile, and
provides a platform for structural modifications. Although more steps are required than for the
direct cyclotrimerization of nitriles, or by applying coupling methods, this synthetic strategy is
considerably more flexible toward functionalization while incorporating the desired methylene
linkage and a potentially coordinating group, such as a phenol. This synthesis illustrates the power of
hydrochloride salts to undergo cyclotrimerization when elaborate and highly substituted target
molecules are sought. The new molecule described here displays an interesting architecture for
diverse applications; notably as a potential ligand in metal coordination for small molecule activation
and functionalization chemistry as well as in electrocatalysis. Initial forays in these areas are
currently being pursued.
Supporting Information
Spectroscopic data of 1, 1-OMe, 9-11. CCDC-1543709 (1) and CCDC-1543710 (9) contain the
supplementary crystallographic data for this paper.
Acknowledgement
9

We thank the Friedrich-Alexander-University of Erlangen-Nürnberg for financial support of this work.
Mrs. C. Wronna and Mrs. S. Hoffmann for conducting the elemental and HRMS analysis respectively.
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13

Highlights
•
•
•
An efficient synthesis of a novel three-fold functionalized, sterically demanding triazine ring
is presented.
Three 2,4-di-tert-butylphenol synthons are bound to the 1,3,5-triazine ring via a challenging
methylene linkage.
Cyclotrimerization of imidate salts constitutes a powerful method for the generation of
highly functionalized 1,3,5-triazine rings.
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Graphical abstract
15