Combinatorial solid-phase synthesis of 6-aryl-1,3,5-triazines via suzuki coupling

Article abstract of DOI:10.1071/CH11034

A synthetic methodology to prepare collections of trisubstituted aryl 1,3,5-triazines with broad structural diversity via Suzuki coupling has been developed. We first optimized the combinatorial derivatization of the triazine core using Suzuki cross-coupling. Second, in order to further expand the methodology for the preparation of negatively charged triazines, we adapted this approach to polymer-supported amino acids and prepared aryl triazines with different charge distribution. With a collection of 160 aryl triazine derivatives in good purities and without any purification step, we proved the viability of this orthogonal scheme for the preparation of triazine libraries using amine/amino acid-captured solid supports and Suzuki cross-coupling. CSIRO 2011.

Full text of DOI:10.1071/CH11034

RESEARCH FRONT
Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2011, 64, 540–544
www.publish.csiro.au/journals/ajc
Combinatorial Solid-Phase Synthesis of 6-Aryl-
1,3,5-triazines via Suzuki Coupling
A
B C
,
D
A
Jae Wook Lee, Hyung-Ho Ha, Marc Vendrell, Jacqueline T. Bork,
B D E
, ,
and Young-Tae Chang
A
Department of Chemistry, New York University, New York, NY 10003, USA.
Department of Chemistry and Medchem Program of Life Sciences Institute,
National University of Singapore, 117543, Singapore.
B
C
College of Pharmacy, Sunchon National University, Suncheon, 570-742, Korea.
D
Singapore Bioimaging Consortium, Agency for Science, Technology
and Research (A*STAR), Singapore, 138667, Singapore.
E
Corresponding author. Email: chmcyt@nus.edu.sg
A synthetic methodology to prepare collections of trisubstituted aryl 1,3,5-triazines with broad structural diversity via
Suzuki coupling has been developed. We first optimized the combinatorial derivatization of the triazine core using Suzuki
cross-coupling. Second, in order to further expand the methodology for the preparation of negatively charged triazines, we
adapted this approach to polymer-supported amino acids and prepared aryl triazines with different charge distribution.
With a collection of 160 aryl triazine derivatives in good purities and without any purification step, we proved the viability
of this orthogonal scheme for the preparation of triazine libraries using amine/amino acid-captured solid supports and
Suzuki cross-coupling.
Manuscript received: 20 January 2011.
Manuscript accepted: 17 February 2011.
Introduction
Whereas the activities of these molecules depend on the aro-
matic and aliphatic substituents of the triazine core, fine-tuning
their interaction with specific proteins may require the incor-
poration of wider chemical diversification. In order to broaden
the molecular diversity of triazine compounds, we envisioned
that the combinatorial adaptation of Suzuki coupling for the
derivatization of the triazine core would allow the construction
of libraries using infrequent boronic acids as building blocks
for the main diversity source. Furthermore, we considered the
introduction of negative charges in the substituents of the tria-
zines to increase the number of possible interactions with their
target proteins. For this purpose, amino acids are excellent
building blocks, mainly due to their bioavailability, structural
and charge diversity, and good accessibility. Since the imple-
mentation of boronic acids within the aryl triazine core required
the optimization of an orthogonal synthetic scheme, we
designed a solid-phase methodology for the preparation of
polyethyleneglycol (PEG)-tagged aryl triazines via Suzuki
coupling that was compatible with the incorporation of charge
distribution variability. The preparation of a collection of 160
PEG-tagged aryl triazines (Chart 1) in high purities and without
any purification demonstrates the adequacy of this approach for
combinatorial chemistry syntheses.
Combinatorial chemistry is a powerful method for the synthesis
of large and structurally distinct libraries with broad molecular
diversity.[1–4] In conjugation with high-throughput screenings,
combinatorial chemistry has demonstrated its value for the
generation and optimization of lead compounds in drug dis-
covery.[5] One of the most popular techniques for the rapid
production of combinatorial libraries is based on the use of
solid-phase organic synthesis (SPOS). Major advantages of
SOPS include the ease of product isolation by filtration and the
use of an excess of reagents to force reactions to completion,
leading to an overall reduction of the total time required for the
synthesis. The 1,3,5-triazine scaffold is of particular interest in
combinatorial chemistry approaches due to its synthetic acces-
sibility, high chemical stability, and drug-like hydrogen bonding
properties. Moreover, a broad range of biological activities
have been reported for these structures, such as anticancer,[6–9]
antimicrobial,[10] and antiretroviral compounds,[11] inhibitors
of cyclin-dependent kinases (CDKs) and p38 mitogen-activated
protein kinases (MAPKs),[12,13] oestrogen receptor modulators,[14]
or inosine monophosphate dehydrogenase,[15] and tubulin poly-
merization inhibitors.[16,17] Such a wide range of biological
activities has been the main driving force to put a considerable
effort into the synthesis of large libraries of triazine deriva-
tives.[18,19] Our research group has reported the synthesis of
combinatorial triazine libraries and proved their potent biological
activity for several applications, such as microtubule destabili-
zation[17] or inhibition of b-amyloid plaques aggregation.[20]
Results and Discussion
We first designed the synthesis of PEG-tagged triazines with
aryl diversity via Suzuki coupling according to Scheme 1. A set
of solid supports was prepared by coupling 10 amine building
Ó CSIRO 2011
10.1071/CH11034
0004-9425/11/050540

RESEARCH FRONT
Synthesis of 6-Aryl-1,3,5-triazines
541
blocks to a Peptide Amide Linker polystyrene (PAL-PS) resin
via reductive amination in the presence of NaBH(OAc)3.
PAL-PS resins are compatible with palladium-catalyzed cross-
coupling conditions, and have been reported for the solid-phase
preparation of triazine libraries.[21–23]
After derivatization of cyanuric chloride with N-Boc-2,20-
(ethylenedioxy)diethylamine in solution phase, the resulting
N-Boc-2-(ethylenedioxy)diethylamine-4,6-dichloro-1,3,5-triazine
was coupled to 10 different amine resins by nucleophilic
substitution in THF at 608C using N,N-Diisopropylethylamine
(DIEA) as a base. Afterwards, resin-bound chlorotriazines were
derivatized under Suzuki cross-coupling conditions with a set of
aryl boronic acids (Chart 2) to yield the trisubstituted aryl 1,3,5-
triazines.
alkylamino-6-aryl-1,3,5-triazines. While we observed that the
purity of some products showed dependency on the nature of the
substituents within the building blocks (e.g. boronic acids A, F,
and M, Chart 2) exhibited a relatively lower purity than the rest
of the library) most of the compounds could be isolated in very
good purities without any purification step (average purity:
88%, Table 1).
In view of the successful adaptation of the Suzuki cross-
coupling derivatization to a combinatorial triazine library
approach, we aimed to extend the structural and charge diversity
with the use of amino acids as building blocks. We prepared
eight different resins by loading amino acids with aliphatic
(alanine, valine, leucine, isoleucine) and aromatic (phenylala-
nine, tyrosine) side chains, as well as polar ones (serine,
asparagine). After attaching 2-(ethylenedioxy)diethylamine-
4,6-dichloro-1,3,5-triazine to the resins by nucleophilic substi-
tution and carrying out Suzuki coupling derivatization as above
mentioned, we obtained 80 negatively charged trisubstituted
triazines in very high purities without any purification (average
purity: 92%, Table 2). Remarkably, none of these synthetic steps
required the protection of the carboxylic acid groups of the
amino acids, which facilitated the optimization of a general
protocol and improved the overall synthetic yields.
Finally, the treatment of the resins with a TFA-DCM (1:9)
solution released 80 different 2-(ethylenedioxy)diethylamine-4-
PEG-amine spacer
O
NH2
HN
O
HO
R1
O
N
N
N
H
N
R2
Diversity and
charge distribution
Aryl diversity by
Suzuki coupling
Conclusions
In the present work, we optimized an orthogonal approach for
the solid-phase synthesis of PEG-tagged triazines with aryl
diversity via Suzuki coupling. A 160-member aryl triazine
Chart 1. General structure for the library of differently charged PEG-
tagged aryl 1,3,5-triazines.
O
O
NHBoc
O
NH2
HN
O
HN
O
O
H
(a)
(c)
(d)
N
N
N
N
HN R1
OH
B
R1-NH2
O
N
R1
N
Cl
HN
R1
N
R2
HO
R2
O
NHBoc
Cl
N
HN
O
(b)
N
N
N
N
Cl
Cl
Cl
N
Cl
Scheme 1. Synthesis of differently charged trisubstituted 1,3,5-triazines. Reagents and conditions: (a) (i) amino acid or amine building block, AcOH-THF
(2:98), rt, 1 h, (ii) NaBH(OAc)3, AcOH-THF (2:98), rt, 8 h; (b) N-Boc-2,20-(ethylenedioxy)diethylamine, DIEA, THF, 08C, 2 h; (c) DIEA, THF, 608C, 3 h;
(d) (i) boronic acid building blocks, Pd(PPh3)4, Cs2CO3, dioxane, 908C, 15 h, (ii) TFA-DCM (1:9), rt, 0.5 h.
OH
B
OH
B
OH
B
OH
B
O
OH
B
OH
B
OH
B
NO2
CHO
S
HO
HO
HO
HO
HO
HO
HO
SMe
(A)
(B)
(C)
(D)
(E)
(F)
(G)
OH
B
OH
B
OH Ph
B
OH
OH
B
OH
B
B
HO
HO
HO
HO
HO
HO
OMe
F
OCF3
(H)
(I)
(J)
(K)
(L)
(M)
Chart 2. Boronic acids used for the library synthesis.

RESEARCH FRONT
542
J. W. Lee et al.
library was designed in order to incorporate broad structural
diversity and different charge distribution by using different
amine and amino acid-captured solid supports. The optimized
synthetic strategy enabled the incorporation of several boronic
acids as building blocks and different charge distribution via
diverse amino acids and amines, and proved to be compatible
with a wide range of chemical functionalities, asserting its
application in combinatorial chemistry syntheses. In addition to
employing non-protected building blocks, with this approach we
isolated the final triazine compounds in very good purities,
without any purification steps. The screening of the biological
properties of this library is currently ongoing.
Experimental
Materials and Methods
Unless otherwise noted, materials and solvents were obtained
from commercial suppliers (Acros and Aldrich) and were
used without further purification. PAL-aldehyde (4-formyl-3,5-
dimethoxyphenoxymethyl) resin from Midwest Bio-Tech(Cat #:
20840, Lot #: SY03470, loading: 1.10 mmol g–1) was used for
the generation of library compounds. The scaffold N-Boc-2-
(ethylenedioxy)diethylamine-4,6-dichloro-1,3,5-triazine was
prepared by solution-phase chemistry and purified by normal-
phase flash column chromatography on Sorbent Technologies
˚
silica gel, 60 A (63–200 mesh). TLC was carried out on SAI
Table 1. Purities of isolated 6-aryl-1,3,5-triazines with amine-captured solid supports
Purities were determined by integration of absorbance peaks at 254 nm
R1
R2
A
B
K
E
F
G
L
M
MeO
85
88
90
97
80
87
90
83
HN
MeO
85
90
93
95
82
88
87
83
HN
85
85
90
82
92
93
95
98
89
71
95
90
90
90
85
83
HN
HN
O
85
85
82
85
94
90
97
97
90
85
92
88
91
89
86
80
HN
OH
HN
F
85
80
85
90
90
90
95
89
90
96
98
95
82
90
83
90
87
94
92
90
95
83
85
82
HN
HN
O
N
HN
88
93
83
91
75
95
93
82
NH

RESEARCH FRONT
Synthesis of 6-Aryl-1,3,5-triazines
543
F254 pre-coated silica gel plates (250 mm layer thickness).
All library products were characterized by HPLC-MS (Agilent
Technology, HP1100) using a C18 column (20 ꢀ 4.0 mm2) and a
gradient of 5–95% CH3CN-H2O (containing 0.1% AcOH) over
4 min. Condensation reactions were performed in a standard
heat block from VWR Scientific Products using 4-mL glass vials
with paper-lined caps purchased from Fisher Scientific. Resin
filtration procedures were carried out in 70-mm PE-frit car-
tridges from Applied Separations (Cat. #: 2449).
were washed with DMF, DCM, and MeOH (20 mL ꢀ 3) and
dried under nitrogen gas.
Resin Capture of Triazine Scaffold by Amine
or Amino Acid Substitution
To a suspension of the resin-bound amines or amino acids
(125 mg, 0.13 mmol) in THF (2.5 mL) was added N-
Boc-2-(ethylenedioxy)diethylamine-4,6-dichloro-1,3,5-triazine
(0.4 mmol, 3 equiv.), followed by addition of DIEA (0.8 mmol,
6 equiv.). The reaction vial was placed in a heating block at 608C
for 2.5 h, and afterwards the solvents and excess reagents were
filtered off through a PE-frit cartridge and washed with DMF,
DCM, and MeOH (3 mL ꢀ 3 for every solvent).
Loading of Amino Acids and Amines onto PAL Resin
via Reductive Amination
To a suspension of 4-formyl-3,5-dimethoxyphenoxymethyl-
functionalized polystyrene resin (PAL) (1.0 g, 1.1 mmol) in
THF (40 mL) were added the building blocks R1 (5.5 mmol),
followed by the addition of AcOH (0.9 mL). After shaking at
rt for 1 h, NaBH(OAc)3 (1.63 g, 7.7 mmol) was added, and the
reaction was further shaken at rt for 8 h. Using PE-frit cartridges,
the solvents and excess reagents were filtered off and the resins
Suzuki Cross-coupling Reactions
Pd(PPh3)4 (7 mg, 6.06 mmol) and Cs2CO3 (35 mg, 0.1 mmol)
were dispensed to the different resin-bound triazines (10 mg,
11 mmol) in a glove box. Dioxane (1 mL) and boronic acids were
distributed to each reaction vial, and the vials were shaken 908C
Table 2. Purities of isolated 6-aryl-1,3,5-triazines with amino acid-captured solid supports
Purities were determined by integration of absorbance peaks at 254 nm
R1
R2
A
B
C
D
E
F
G
H
I
J
HO
O
98
95
95
92
91
80
99
80
93
98
N
H
O
HO
N
H
99
97
95
95
99
80
95
90
95
90
OH
O
HO
95
99
98
99
96
99
92
88
95
99
99
92
99
99
90
70
99
95
95
96
N
H
OH
HO
O
N
H
HO
O
99
94
95
99
98
93
95
95
94
85
89
80
99
97
96
95
94
96
99
99
94
94
80
80
95
90
90
97
80
99
N
H
HO
HO
O
N
H
O
N
H
HO
O
N
H
99
96
92
90
91
99
98
99
65
65
H2N
O

RESEARCH FRONT
544
J. W. Lee et al.
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off, and the resins were washed with a solution of 0.05 M sodium
diethyldithiocarbamate in DMF (1 mL ꢀ 5), and DMF, DCM,
and MeOH (3 mL ꢀ 3 for every solvent).
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Resin Cleavage
A solution of TFA-DCM (1:9) was added to the resins, which
were shaken at rt for 30 min. The final compounds were filtered
from the resin, washed with DCM, and evaporated under
vacuum. An average recovery yield around 80% was estimated
for the final compounds on the basis of the intensities of their
HPLC absorbance peaks.
Accessory Publication
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A list of amino acids and amine building blocks used for the
library synthesis, representative HPLC-MS data for the library
of PEG-tagged trisubstituted triazines are available on the
Journal’s website.
Acknowledgements
The authors gratefully acknowledge the financial support from the National
Institute of Health (CA-96912) and the National University of Singapore
(NUS) (Young Investigator Award: R-143-000-353-123). The authors thank
Francis B. Peters for his critical reading of the manuscript.
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