1,3,5-Triazine as core for the preparation of dendrons

Article abstract of DOI:10.24820/ARK.5550190.P011.245

A unique property of 2,4,6-trichloro-1,3,5-triazine (TCT) is its ability to undergoes a nucleophilic aromatic substitution reaction (SNAr) under temperature-controlled conditions. Using a convenient and biologically friendly protocol, mono-substituted s-t

Full text of DOI:10.24820/ARK.5550190.P011.245

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1,3,5-Triazine as core for the preparation of dendrons
a
a,b
a,b
c,d
b,*
Rotimi Sheyi, Anamika Sharma, Ashish Kumar, Ayman El-Faham, Beatriz G. de la Torre, and
a,c,e,f*
Fernando Albericio
aPeptide Science Laboratory, School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South
Africa
b
KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine and
Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa
Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia
c
d
Department of Chemistry, Faculty of Science, Alexandria University, PO Box 426, Alexandria 21321, Egypt
e
Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain
f
CIBER-BBN (Networking Centre on Bioengineering, Biomaterials and Nanomedicine) and Department of
Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain
Corresponding authors. email: albericio@ukzn.ac.za; garciadelatorreb@ukzn.ac.za
*
Received mm-dd-yyyy
Dates to be inserted by editorial office
Abstract
Accepted mm-dd-yyyy
Published on line mm-dd-yyyy
A unique property of 2,4,6-trichloro-1,3,5-triazine (TCT) is its ability to undergoes a nucleophilic aromatic
substitution reaction (S Ar) under temperature-controlled conditions. Using a convenient and biologically
N
friendly protocol, mono-substituted s-triazines were treated with excess nucleophiles to obtain tri-substituted
triazines in 1 + 2 mode (one nucleophile as the first substitution followed by another nucleophile for the other
two positions). The nucleophiles used for this study were phenol, thiol and amine, and the best order of
incorporation was phenol or thiol for the first position followed by amine for the last two positions.
Keywords: s-Triazine, dendron, HPLC, 1+2 mode, nucleophiles
DOI: https://doi.org/10.24820/ark.5550190.p011.245
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Introduction
s-Triazine derivatives have found numerous applications due to their potential to show biological and
1
, 2
3
4
therapeutic activity. For example, triazine compounds have anticancer,
antimalarial, antitubercular,
5-9
10, 11
antimicrobial, and antiviral properties.
,4,6-Trichloro-1,3,5-triazine (TCT), the main reagent for the synthesis of these triazine derivatives, offers
2
a versatile synthetic route by undergoing sequential nucleophilic substitution reactions. The ability of various
nucleophiles to substitute the chlorine atoms in TCT makes this reagent suitable for the preparation of mono-,
di- and trisubstituted derivatives of 1,3,5-triazine in a controlled manner.1
2-16
The substitution of chlorine atoms in TCT by distinct nucleophiles is a temperature-dependent sequential
reaction. Thus, the general rule for the replacement of these chlorine atoms, which varies with the reactivity
of the nucleophile used, proposes that the first substitution occurs at 0 ℃, the second at room temperature
1
7
(rt) and the third under heating conditions (Scheme 1).
Scheme 1. Nucleophilic substitution reaction for TCT.
Of note, apart from being temperature-dependent, the substitution pattern also depends on the nature of
nucleophile (i.e. amines, thiols, alcohols), its basic strength, steric factors, and, more importantly, the
substituents already present on the TCT/triazine (TA) core. For instance, the presence of an amine nucleophile
on the TCT/TA core prevents the incorporation of nucleophiles other than amines.1
8-20
TCT chemistry also encompasses orthogonal chemoselective properties, two interchangeable concepts
2
1
used in chemistry. The concept of orthogonality was first introduced in 1977 by Barany and Merrifield to
explain an orthogonal protecting scheme, and it was later demonstrated by Barany and Albericio in 1985 in a
2
2
23
sequential triorthogonal protection scheme. Chemoselectivity, as used by Trost in 1983 , is the ability of a
chemical reagent to discriminate among reactive sites. Hence, in practice, the concept of orthogonal
1
8
chemoselectivity is the discrimination between reactive sites in any order in different chemical mechanisms.
2
4, 25
TCT has also found application in the synthesis of dendrimers.
The term “dendrimer” comes from the
Greek word meaning “tree”. In chemistry, dendrimers are repetitive branching molecules, formed by a nucleus
(
core) molecule, branching units, branches, and peripheral groups, which could be the main responsible for
2
6-29
the biological activity.
In 1985, Tomalia and co-workers introduced the concept of a dendrimer with the
3
0, 31
idea of it being used in many applications, ranging from catalysis to electronics and drug delivery.
of a dendrimer, the ramified branches without the nucleus is known as a dendron.
As part
In previous work, we studied the orthogonal chemoselective property of TCT using three nucleophiles
1
9
(
phenol, 3-methylbutane-1-thiol and 3-methylbutan-1-amine). The best order and condition for the
incorporation of these nucleophiles was found to be phenol (O) at 0 °C, thiol (S) at rt, and finally amine (N) at
1
9
3
5 ℃, the latter temperature compatible with biological systems. The incorporation was achieved through
the electron-withdrawing behavior of phenol, which in turn deactivates the ring, hence maintaining electron
delocalization for further incorporation of thiol or amine at ambient temperature. The nucleophiles chosen are
to mimic the reactivity of Lys for amine, Tyr for phenol and Cys for thiol.
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With the successful replacement of the third chlorine at 35 ℃ and taking advantage of the reactivity of the
TCT chlorine atoms into consideration, this study sought to test the ability of TCT to demonstrate 1+2 mode
where the core is first substituted with a nucleophile to afford mono-substituted derivative which with excess
of another nucleophile (different from the first one incorporated onto mono-substituted triazine) to give
trisubstituted triazine molecules under, if possible, ambient condition.
Results and Discussion
Scheme 2 shows the synthetic route used to obtain compounds 1-9. Using TCT as the starting material, the
derivatives were synthesized by sequentially substituting its chlorine atoms with an equivalent amount of the
three different nucleophile(s). As a solvent, ethyl acetate was used due to its higher boiling point in
comparison with CH
2
Cl
, which was used in previous work.18
2
Scheme 2. Synthetic route for obtaining compounds 1-9.
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Mono-substituted triazine derivatives were prepared by reacting 1 equivalent of nucleophile (thiol, amine
and phenol) with 1 equivalent of TCT at 0 ℃ (except phenol, which was achieved at -20 ℃, a condition
1
9
validating our previous work) in the presence of diisopropylethylenamine (DIEA) as base, as reported earlier
by our group.1
Figure 1).
With the successful synthesis of mono-substituted triazine, 2 equivalents of each successive nucleophile
8-20
The reaction was completed in 30 min, as monitored by TLC, affording compounds 1-3
(
were added in each case (1-3). For 1, no product formation was observed. This result is consistent with our
earlier findings showing that once an amine is incorporated, only another amine can be incorporated under
1
8, 19
the given reaction conditions.
Therefore, 4 and 5 could not be prepared via this route.
Figure 1. HPLC chromatogram of compounds 1, 2 and 3.
Similarly, 2 was treated with two equivalents of amine, and phenol nucleophiles were added in parallel,
forming 6 and 7. At first, the reactions were allowed to stir at room temperature for 3 h. New products were
formed; however, TLC showed that the reactions were not complete, so they were kept for 12 h at 35 ℃. TLC
showed the complete consumption of the starting material, affording the product (6 and 7), as monitored by
HPLC (Figure 2).
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Figure 2. Chromatogram of compounds 6 and 7, as monitored by HPLC.
In parallel, 3 was used to synthesize 8 and 9 by adding 2 equivalents of thiol and amine nucleophiles followed
by the addition of 2 equivalents of DIEA. The reaction was kept at 35 °C for 12 h. Completion of the reaction
was monitored by TLC, affording 8 and 9 (Figure 3).
Figure 3. Chromatogram of compounds 8 and 9, as monitored by HPLC.
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Conclusions
In conclusion, here we report the preparation of triazine derivatives/dendrons by sequential incorporation of
nucleophiles (phenol, amine and thiol) onto TCT. To this end, 2 equivalents of these nucleophiles was added to
a mono-substituted triazine at 35 °C, a temperature compatible with biological systems. The strategy works in
cases where thiol and phenol are first substituents. However, once amine is incorporated, no reaction with
other nucleophiles occurs. Replacement of the third chlorine atom at 35 °C extends the use of TCT beyond a
triorthogonal linker in the biological context, thereby paving the way for nucleophilic reactions involving
various peptides, antibodies, and drugs. The applications of this strategy for the preparation of dendrimers of
biological interest using Lys, Tyr and Cys amino acids bearing peptides are currently being carried out in our
laboratories and will be described elsewhere.
Experimental Section
General. HPLC-grade solvents were used for all the synthetic preparations. 2,4,6-Trichloro-1,3,5-triazine (TCT),
isopentylamine, 3-methylbutane-1-thiol, phenol, and diisopropylethylamine were purchased from Sigma-
1
13
Aldrich (Sigma-Aldrich, Germany). Magnetic resonance spectra ( H NMR and C NMR) were recorded on a
Bruker 400 MHz, and chemical shift values are reported in δ units (ppm) using TMS as internal standard (δ
1
13
0
.00) and CDCl as solvent (δ 7.2 for H and δ 77.20 for C). Follow-up of the reactions and checks of the
3
purity of the compound were done by TLC on silica-gel-protected aluminium sheets 60 F254 (Merck), and the
spots were detected by exposure to UV light at λ 254 nm. Analytical HPLC was performed on an Agilent 1100
system using a Phenomenex C18 column (3 µm, 4.6 × 50 mm) by dissolving the sample in CH
3
CN only.
CN
Chemstation software was used for data processing. Buffer A: 0.1% TFA in H O, buffer B: 0.1% TFA in CH
2
3
were used in HPLC. High-resolution mass spectrometry (HRMS) was performed using a Bruker ESI-QTOF mass
spectrometer in positive-ion mode.
Synthesis of 2,4-dichloro-6-substituted s-triazine (X-DCT)
Scheme 3. Synthetic scheme for the formation of mono-substituted triazine.
TCT (50 mg, 0.27 mmol) was dissolved in EtOAc (1 mL) and cooled to 0 °C for 5 min. Nucleophile (0.27 mmol;
3
1.3 μL amine or 33.7 μL thiol or 25.4 mg phenol) was then added to the above stirring solution, followed by
addition of DIEA (47 L, 0.27 mmol). The reaction was stirred at 0 °C for 30 min. The progress of the reaction
was monitored by TLC (EtOAc/hexane as mobile phase) until no starting material was observed. The reaction
mixture was diluted with DCM (5 mL) and washed several times with water to remove DIEA salts. The organic
layer was collected, dried over MgSO
4
, filtered, and concentrated to afford the pure product, which was used
for the next step without further purification.
4
,6-Dichloro-N-isopentyl-1,3,5-triazin-2-amine (1). Off-white semi-solid, 94% yield; HPLC [30-95 % of CH
3
CN
1
(0.1% TFA/ H
2
O (0.1%TFA) over 15 min] t
R
7.7 min; H NMR (400 MHz, CDCl
3
): 0.88 (d, J 6.6 Hz, 6H, -CH
3
), 1.43
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1
3
(
2
[
q, J 7.5 Hz, 2H, -CH
2
), 1.59 (m, 1H, CH), 3.42 (m, 2H, -CH
2
), 5.70 (brs, NH); C NMR (100 MHz, CDCl
3
): 22.4,
+
5.7, 37.9, 39.9, 165.8, 171.0; LCMS m/z: calcd. for C
8
H12Cl
2
N
4
: 234.0439; found: 235.1224 [M+H] , 278.1577
+
M+CH CN+H] .
3
2
,4-Dichloro-6-(isopentylthio)-1,3,5-triazine (2). Yellowish oil, 92% yield; HPLC [30-95% of CH
3
CN (0.1% TFA/
), 1.54 (m, 2H,
): 21.1, 26.4, 28.3, 36.2, 168.9, 185.6.
1
H
2
O (0.1 %TFA) over 15 min] t
CH ), 1.65 (m, 1H, -CH), 3.10 (m, 2H, CH
HRMS: m/z: calcd. for C
R
10.2 min; H NMR (400 MHz, CDCl
3
): 0.90 (d, J 6.5 Hz, 6H, -CH
3
1
3
2
2
); C NMR (100 MHz, CDCl
3
+
8
H11Cl
2
N
3
S: 252.0251 [M+H] ; found: 252.0246.
2
,4-Dichloro-6-phenoxy-1,3,5-triazine (3). Off-white solid, 95% yield; HPLC [30-95% of CH
3
CN (0.1% TFA/ H O
2
1
(0.1%TFA) over 15 min] t
R
6.9 min; H NMR (400 MHz, CDCl
3
): 7.14 (d, J 8.1 Hz, 2H, Ar-H), 7.26 (t, J 7.4 Hz, 1H,
): 121.2, 126.5, 129.7, 151.3, 172.4, 173.8. HRMS:
1
3
Ar-H), 7.38 (t, J 7.8 Hz, 1H, Ar-H); C NMR (100 MHz, CDCl
m/z: calcd. for C
3
+
9
H
5
Cl
2
N
3
O: 241.0904 [M+H] ; found: 241.0886.
Synthesis of 2,4,6-trisubstituted s-triazine (XYY-T)
Scheme 4. Synthetic scheme for the formation of tri-substituted-triazine.
The corresponding nucleophile (2 equivalents, 0.54 mmol; 62.6 μL amine or 67.4 μL thiol or 50.8 mg phenol)
was added to the mono-substituted triazine (X-DCT) (0.27 mmol) in EtOAc (1 mL), followed by addition of DIEA
(94 L, 0.54 mmol). The reaction was stirred at 35 °C for 12 h. The progress of the reaction was monitored by
TLC (EtOAc/hexane) until no starting material was observed. The reaction mixture was diluted with DCM (5
mL) and washed several times with water to remove DIEA salts. The organic layer was collected, dried over
MgSO
4
, filtered, and concentrated to afford the pure product.
2
-(Isopentylthio)-4,6-diphenoxy-1,3,5-triazine (6). The target compound was prepared from 2. Yellowish semi
1
solid, 90% yield; HPLC [30-95% of CH
3
CN (0.1% TFA/ H
), 1.35 (m, 2H, -CH
2
O (0.1%TFA) over 15 min] t
R
10.9 min; H NMR (400
), 7.08 (m, 4H,
MHz, CDCl
Ar-H), 7.16 (m, 2H, Ar-H), 7.30 (m, 4H, Ar-H); C NMR (100 MHz, CDCl
29.4, 151.8, 167.9, 183.3. HRMS: m/z: calcd. for C20
3
): 0.72 (d, J 6.4 Hz, 6H, -CH
3
2
), 1.38 (m, 1H, -CH), 2.81 (m, 2H, -CH
2
1
3
3
): 22.2, 27.5, 28.5, 37.9, 121.7, 125.8,
+
1
H
21
N
3
O
2
S: 368.1433 [M+H] ; found: 368.1745.
2
4
N , N -Diisopentyl-6-(isopentylthio)-1,3,5-triazine-2,4-diamine (7). The target compound was prepared from
1
2
. Creamy solid, 88% yield; HPLC [30-95% of CH
3
CN (0.1% TFA/ H
2
O (0.1%TFA) over 15 min] t
R
12.6 min; H
NMR (400 MHz, CDCl ): 0.90 (m, 18H, -CH ), 1.46 (m, 6H, -CH
3
3
2
), 1.65 (m, 3H, -CH), 3.00 (m, 4H, -CH
2
), 3.36 (m,
1
3
2
1
H, -CH
2
), 5.26 (brs, NH); C NMR (100 MHz, CDCl
3
): 21.2, 21.4, 24.8, 26.4, 26.6, 27.6, 36.9, 38.6, 163.1, 167.0,
+
82.5. HRMS: m/z: calcd. for C18
H
35
N
5
S: 354.2691 [M+H] ; found: 354.3031.
2
,4-Bis(isopentylthio)-6-phenoxy-1,3,5-triazine (8). The target compound was prepared from 3. Pale yellow
1
oil, 92% yield; HPLC [30-95% of CH
CDCl ): 0.77 (d, J 6.5 Hz, 12H, -CH
3
CN (0.1% TFA/ H
), 1.40 (m, 4H, CH
2
O (0.1%TFA) over 15 min] t
R
11.6 min; H NMR (400 MHz,
3
3
2
), 1.50 (m, 2H, -CH), 2.90 (m, 4H, -CH
2
), 7.08 (m, 2H, Ar-
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1
3
H), 7.21 (m, 1H, Ar-H), 7.31 (m, 2H, Ar-H); C NMR (100 MHz, CDCl
28.6, 150.5, 169.9, 185.6. LCMS: m/z: calcd. for C19 OS
3
): 21.1, 26.4, 27.9, 36.6, 120.3, 125.3,
: 377.1596 [M+H] ; found: 378.2227.
+
1
H
27
N
3
2
2
4
N , N -Diisopentyl-6-phenoxy-1,3,5-triazine-2,4-diamine (9). The target compound was prepared from 3. Off-
1
white solid, 90% yield; HPLC [30-95% of CH
400 MHz, CDCl ): 0.91 (m, 12H, -CH ), 1.26 (m, 2H, -CH), 1.44 (m, 4H, -CH
.10 (brs, NH), 7.12 (m, 3H, Ar-H), 7.36 (m, 2H, Ar-H); C NMR (100 MHz, CDCl
24.8, 128.3, 150.9, 166.0, 169.8. HRMS: m/z: calcd. for C19
3
CN (0.1% TFA/ H
2
O (0.1%TFA) over 15 min] t
R
8.9 min; H NMR
2
(
5
1
3
3
2
), 3.41 (m, 4H, -CH
), 4.93 (brs, -NH),
): 21.3, 24.6, 36.9, 38.6, 120.6,
O: 344.2450 [M+H] ; found: 344.2819.
1
3
3
+
H
29
N
5
Acknowledgements
The work was funded by: Researchers Supporting Project at King Saud University (RSP-2020/50) (Saudi Arabia);
National Research Foundation (NRF) and the University of KwaZulu-Natal (South Africa); the Spanish Ministry
of Economy, Industry, and Competitiveness (MINECO) (RTI2018-093831-B-100), CIBER-BBN, and the
Generalitat de Catalunya (2017 SGR 1439) (Spain). Rotimi Sheyi thanks to MINTEK for a predoctoral fellowship.
Supplementary Material
1
13
The supplementary information includes copies of HPLC, H NMR and C NMR spectra and HRMS.
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