Novel orthogonal synthesis of a tagged combinatorial triazine library via grignard reaction

Article abstract of DOI:10.1071/CH09153

To expand the diversity of 1,3,5-triazine libraries to aryl and alkyl functionalities through the CC bond, we employed a novel orthogonal synthesis via Grignard monoalkylation or monoarylation of cyanuric chloride in solution to prepare aryl- or alkyl-substituted triazine building blocks. These aryl- or alkyl-substituted triazine building blocks were captured by a resin-bound amine, followed by amination and acidic cleavage with high purity. Herein, we demonstrate a novel orthogonal synthesis of a tagged aryl- and alkyl-triazine library on solid support, utilizing building blocks prepared via Grignard reaction in solution. Through incorporation of a triethylene glycol linker at one of the alternate sites on the triazine scaffold we explored an intrinsic tagged library approach. CSIRO 2009.

Full text of DOI:10.1071/CH09153

RESEARCH FRONT
Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2009, 62, 1000–1006
www.publish.csiro.au/journals/ajc
Novel Orthogonal Synthesis of a Tagged Combinatorial
Triazine Library via Grignard Reaction
Jae Wook Lee,A Jacqueline T. Bork,A Hyung-Ho Ha,B Animesh Samanta,B
and Young-Tae ChangB,C
ADepartment of Chemistry, New York University, New York, NY 10003, USA.
BDepartment of Chemistry, and NUS MedChem Program of Life Sciences Institute,
National University of Singapore, 117543, Singapore.
CCorresponding author. Email: chmcyt@nus.edu.sg
To expand the diversity of 1,3,5-triazine libraries to aryl and alkyl functionalities through the C–C bond, we employed
a novel orthogonal synthesis via Grignard monoalkylation or monoarylation of cyanuric chloride in solution to prepare
aryl- or alkyl-substituted triazine building blocks. These aryl- or alkyl-substituted triazine building blocks were captured
by a resin-bound amine, followed by amination and acidic cleavage with high purity. Herein, we demonstrate a novel
orthogonal synthesis of a tagged aryl- and alkyl-triazine library on solid support, utilizing building blocks prepared via
Grignard reaction in solution. Through incorporation of a triethylene glycol linker at one of the alternate sites on the
triazine scaffold we explored an intrinsic tagged library approach.
Manuscript received: 14 March 2009.
Manuscript accepted: 11 May 2009.
O
NH2
Introduction
HN
O
Combinatorial chemistry on solid support is a promising
methodology for the synthesis of a large number of molecules
with a high degree of diversity. More importantly, in con-
junction with high-throughput screening, this methodology
has become a powerful tool for the generation and optimiza-
tion of lead molecules in the drug discovery process.[1] The
1,3,5-triazine core, possessing three-fold symmetry, was cho-
sen as the scaffold for our libraries because it allows for
versatile modifications, uncomplicated by regiochemical con-
cerns and has proven a useful biological target.[2] The struc-
tural modification of these heterocycles at the 2-, 4-, and
6- positions has led to the development of several derivatives
with a broad range of biological properties; such as anticancer,[3]
antitrypanosomal,[4] antiretroviral,[5] antimicrobial,[6] CDK
inhibitors,[7] Erm methyltransferase inhibitors,[8] oestrogen
receptor modulators,[9] glucocerebrosidase inhibitiors,[10] and
p38MAPK inhibitors.[11] Moreover, we reported the tri-
azine analogue Tubulyzine as an inhibitor of tubulin
polymerization.[12,13] In addition, this class of triazines has been
described as chiral auxiliaries for NMR spectroscopy[14] and
as fluorescent molecules.[15] Recently, we carried out a high-
throughput screen of a series of triazine molecules that inhibit
β-amyloid aggregation.[16] One of the selected molecules, the
alkyltriazine G12 (Fig. 1),[17] exhibited an inhibitory effect
againstAβ42 peptide aggregation comparable to tannic acid and
dopamine, known inhibitors of this process.
N
N
N
N
H
G12
Fig. 1. The structure of G12 (Aβ42 peptide aggregation inhibitor).
(carba-analogues) on solid support utilizing building blocks
prepared via Grignard reaction in solution. Furthermore, in com-
parison to conventional triazine derivatives and conventional
carba-analogues of those compounds (Fig. 2), we will be able to
evaluate the role of heteroatoms, such as N(H), O, and S, and thus
provide valuable information for structure–activity relationship
analysis.
An aryl substitution on the triazine scaffold was previously
reported by our research group.[18c] However, this relied on
palladium-catalyzed reactions via solid support as a final deriva-
tization step, which did not support the synthesis of alkyl
derivatives. Although this previous method is satisfactory, we
have investigated other possibilities in order to expand the diver-
sity to both aryl- and alkyl-functional groups and to provide
an overall more efficient synthesis. Building on precedent for
the Grignard alkylation and Grignard arylation to efficiently
derivatize the triazine scaffold, we sought to expand compound
diversity by incorporating this orthogonally into our library
design.[18]
In continuation of our research on the development of novel
inhibitors against Aβ42 peptide aggregation and the general
development of molecular probes of biological function, we
designed a tagged aryl- and alkyl-substituted triazine library
Herein, we report the use of Grignard reactions in the solid
phase combinatorial synthesis of a library of aryl- and alkyl-
triazine compounds.
© CSIRO 2009
10.1071/CH09153
0004-9425/09/091000

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Synthesis of a Tagged Combinatorial Triazine Library
1001
O
NH2
O
NH2
HN
O
HN
O
N
N
N
N
R3
R3
N
N
X
N
N
R3Ј
R3Ј
X ϭ NH, O, S
Conventional triazine derivatives
Carba-analogues
Fig. 2. Structure of conventional triazine derivatives and carba-analogues.
Results and Discussion
Conclusions
As described above, an orthogonal synthetic strategy was used
in the synthesis of aryl and alkyl substituted-1,3,5-substituted
triazine libraries. Scheme 1 illustrates the orthogonal strategy
for the tagged triazine library, in which we constructed a library
of 588 triazines using entries A–L as alternate functionality for
building block I (Table 1). Resin-bound monosubstituted tri-
azine with triethylene glycol (TG) was used as a representative
linker. This was prepared according to conventional methods by
coupling TG-amine to a 4-formyl-3-dimethoxyphenoxymethyl-
functionalized polystyrene resin (PAL) by reductive amination
in the presence of NaBH(OAc)3 in DMF. To avoid a possible
side reaction of the triazine scaffold with the amine group on
the TG linker, one of the amine groups on the TG linker was
Boc-protected before the reductive amination step. Building
block I (2) was synthesized using the Grignard reaction, which
involved the coupling of various aryl- and alkyl-magnesium
halides with cyanuric chloride in THF/diethyl ether. General-
izing a previously described procedure from the literature,[19,20]
we tested various commercially available Grignard reagents
(Table 1, entries A–L) in the mono-alkylation and -arylation of
cyanuric chloride (building block I). In general, the compounds
containingalkylfunctionalities(entriesB, D, G), whencompared
to aryl functionalities (entries A, C, H), resulted in lower overall
yields. All alkyl-functionalized triazines were purified by col-
umn chromatography, while aryl functionalized triazines were
purified by recrystallization. The monoalkyl- and monoaryl-
substituted triazines were captured by the resin-bound amine 1
through nucleophilic substitution, resulting in a resin-bound tri-
azine 3. The chloride of resin-bound triazine 3 was displaced
with various amines 4 (building block II) by heating in a mixture
of n-BuOH:1-methyl-2-pyrrolidinone (NMP) (1:1) with N,N-
diisopropylethylamine (DIEA) at 120◦C. The advantage of this
approach over palladium-catalyzed coupling was that it allowed
displacement of the resin-bound triazine with secondary amines,
such as piperidine and di-(n-butyl)amine. Cleavage was accom-
plished by treatment of with 10% TFA/DCM, thus providing
compound 5. Analysis of products by LCMS showed that crude,
off-resin purity was >90%. The purity of the crude cleavage
products is summarized in Table 2. The purity of products was
dependent on the nature of the substituted group of building
blocks I and II. As we expected, decanyl triazine (Table 1,
entry G) showed relatively lower purity due to bulkiness of build-
ing block I. The relationship between the purity of product and
the reactivity of building block II was addressed in our previous
report.[18a] From these results, the use of amino acid derivatives
(building block II), gave lower crude purity and reduced reactiv-
ity, whereas higher yields were obtained with less bulky building
block I groups.
These results demonstrate an improvement in the combinato-
rial synthesis of aryl- and alkyl-functionalized triazine deriva-
tives relative to previous methods. In particular, the previous
Suzuki method only allowed for aryl substituents; whereas, this
improved method allows for both aryl and alkyl substitution.
Alkyl- and aryl-diverivatives were efficiently achieved via a
preparationofbuildingblockIinsolutionphase. Purificationand
isolationofaryl-andalkyl-triazinecompounds(buildingblockI)
relied on considerably simple methods; either recrystallization
or column chromatography was employed. Consequently, these
aryl- and alkyl-triazine compounds can be synthesized on large
scale, which allows for straight forward extension of chemical
libraries by varying building block II with different amines.
In conclusion, we have developed an enhanced method
for the synthesis of aryl/alkyl functionalized triazine libraries
on solid support. The further development and expansion of
triazine libraries to other functionalities, which includes the
extension of the Grignard derivatization to various aryl- and
alkyl-magnesium halides, is underway. Libraries prepared via
these methods will provide a structurally diverse pool of com-
pounds to probe biological function and identify potential leads
for further pharmacological development.
Experimental
General
Materials and solvents were obtained from commercial suppliers
and, unless otherwise noted, were used without further purifica-
tion. Anhydrous tetrahydrofuran (THF) and NMP from Acros
were used as reaction solvents without any previous purifica-
tion. PAL–aldehyde resin from Midwest Bio-Tech was used as
the solid support. For the synthesis of building block I, gen-
eral coupling reactions were performed through solution phase
chemistry and were purified by flash column chromatogra-
phy on Merck silica gel 60-PF245. All products were identi-
fied by LCMS from Agilent Technology using a C18 column
(20 × 4.0 mm), with a gradient of 5–95% CH3CN (containing
1% acetic acid)/H2O (containing 1% acetic acid) as eluant.
Equipment
Thermal reactions were performed using a standard heat block
from VWR scientific Products using 4 mL vials. Resin filtration
procedures were carried out using 70 µ PE frit cartridge from
Applied Separations.
Loading of Amine onto PAL Resin via Reductive
Amination (1)
To a suspension of 4-formyl-3,5-dimethoxyphenoxymethyl-
functionalized polystyrene resin (PAL) (1.0 g, 1.1 mmol) in

RESEARCH FRONT
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J. W. Lee et al.
OMe
TG-Boc
(a)
N
H
CHO
O
NH2
HN
O
TG-Boc
1
R2
N
OMe
(c)
HN
R2Ј
(d)
ϩ
N
N
N
N
ϩ
R2
R1
N
N
4
Cl
Cl
N
R1
Cl
R2Ј
Building block II
5
N
N
3
(b)
N
N
Cl
N
R1
Cl
N
Cl
2
O
NH2
TG ϭ
O
Building block I
Building block I – R
1
Cl
MeO
MeO
C
F
L
A
B
D
E
K
O
O
7
G
H
I
J
Building block II – NHR R؅
2
2
OMe
OMe
OMe
OMe
MeO
H N
OMe
MeO
OMe
OMe
OMe
O
H N
H N
2
H N
2
H N
H N
2
H N
H N
2
2
2
2
2
O
OMe
H N
H N
2
2
1
11
21
2
3
4
5
6
7
8
9
10
NO
2
O
H N
HN
O
HN
H N
2
H N
2
N
H
2
H N
2
N
N
H N
2
HN
HN
Cl
12
13
14
15
16
17
18
19
20
OCF
F
Cl
H N
2
3
N
N
HN
N
H N
2
N
H N
N
H N
H N
H N
2
H N
2
2
HN
2
2
H N
N
2
O
22
23
N
24
25
26
27
28
29
30
H
OH
O
O
N
N
O
N
N
N
N
N
H N
N
HN
2
N
NH
2
H N
N
H
2
H N
H N
2
2
H N
NH
2
2
31
32
33
34
35
36
37
O
38
39
40
O
O
O
Cl
OH
O
NH
2
NH
NH
2
2
OMe
OMe
OMe
OMe
OMe
H N
MeO
MeO
MeO
2
MeO
NH
NH
2
NH
NH
2
O
2
2
NH
O
O
O
2
41
42
43
44
45
46
47
48
49
Scheme 1. Orthogonal strategy for the tagged triazine library: Reagents and conditions: (a) (i) NH2-TG-Boc, 2% HOAc in THF, rt, 1 h. (ii) NaBH(OAc)3,
overnight. (b) R1MgX, THF, 0◦C to rt, 8 h. (c) DIEA, 60◦C, 3 h. (d) (i) NMP:BuOH (1:1), DIEA, 120◦C, 3 h. (ii) 10% TFA/DCM, rt, 0.5 h.
THF (40 mL) was added Boc-protected TG-amine (5.5 mmol),
followed by the addition of HOAc (0.9 mL). After shaking at
room temperature for 1 h, NaBH(OAc)3 (1.63 g, 7.7 mmol) was
added, and the reaction continued shaking at room temperature
for 8 h. Using a PE frit cartridge, the solvents and excess reagents
were filtered off and washed with DMF, dichloromethane (MC),
and MeOH (20 mL × 3), and a final wash with DCM and dried
under nitrogen gas.
cooled (0–5◦C), mechanically stirred solution of cyanuric chlo-
ride (10.93 mmol, 2 g) in benzene (125 mL); the mixture was
stirred at 0◦C for 4 h, subsequently warmed to room tem-
perature and stirred for a further 4 h. The reaction mixture
was quenched with 1 N HCl (40 mL), extracted with ethyl
acetate and washed with water. The organic layers were com-
bined and dried over MgSO4. The solvent was removed under
vacuum.
General Procedure for the Preparation of Building
Block I (2) via Grignard Alkylation (Table 1)
2,4-Dichloro-6-phenyl-[1,3,5]triazine (A)
A solution with THF/ether (1:1) (125 mL) of alkylmagne-
sium halide (Br or Cl) (13.0 mmol) was slowly added to a
Phenyl magnesium bromide, recrystallization with acetone, pale
yellow solid, 77%.

RESEARCH FRONT
Synthesis of a Tagged Combinatorial Triazine Library
1003
Table 1. Synthesis of mono-alkylated or arylated triazine intermediate (2) via Grignard reaction
Cl
Cl
R1MgX
N
N
N
N
THF/Et2O
Cl
N
Cl
Cl
N
R1
0–5°C
Entry
A
R1MgX
2 (% yield)
Entry
R1MgX
2 (% yield)
77
36
G
H
47
83
B
Cl
C
78
I
48
D
E
F
34
75
70
J
88
80
65
OMe
K
L
O
OMe
O
2,4-Dichloro-6-cyclohexyl-[1,3,5]triazine (B)
2,4-Dichloro-6-(2-mesityl)-[1,3,5]triazine (I)
Cyclohexyl magnesum chloride, methylenechloride/hexane
(1/100 v/v), white crystals, 36%.
2-Mesityl magnesium bromide, methylenechloride/hexane
(1/100 v/v), white solid, 48%.
2,4-Dichloro-6-benzyl-[1,3,5]triazine (J)
2,4-Dichloro-6-(4-chlorophenyl)-[1,3,5]triazine (C)
Benzyl magnesium chloride, recrystallization with acetone,
white solid, 88%.
4-Chlorophenyl magnesium bromide, recrystallization with
DCM, white solid, 78%.
2,4-Dichloro-6-phenethyl-[1,3,5]triazine (K)
2,4-Dichloro-6-isopropyl-[1,3,5]triazine (D)
Phenethyl magnesium chloride, recrystallization with acetone,
white solid, 80%.
Isopropyl magnesiumchloride, methylenechloride/hexane
(1/100 v/v), yellow oil, 34%.
2,4-Dichloro-6-[1,3]dioxolan-2-ylmethyl-[1,3,5]triazine (L)
1,3-Dioxlan-2-ylmethyl-magnesium
chloride/hexane (1/9 v/v), 65%.
bromide,
methylene
2,4-Dichloro-6-[2-(4-methoxy-phenyl)-ethyl]-
[1,3,5]triazine (E)
4-Methoxyphenethyl magnesium chloride, recrystallization
with acetone, orange solide, 75%.
Resin Capture of Triazine Scaffold via Amine
Substitution (3)
To a suspension of the PAL resin-bound amine (125 mg,
0.132 mmol) in THF (2.5 mL) was added 2,4-dichloro-
alkyl/aryl-[1,3,5]triazines (125 mg), followed by addition of
diisopropylethylamine (DIEA) (0.15 mL). The reaction was
placed in a heating block set at 60◦C for 2.5 h. Solvents and
excess reagent were filtered through a PE frit cartridge and
washed with DMF, DCM, MeOH (3 mL × 3) consecutively, with
a final wash with DCM (3 mL), and dried under nitrogen gas.
2,4-Dichloro-6-[2-(4-methoxy-phenyl)]-[1,3,5]triazine (F)
4-Methoxyphenyl magnesium bromide, recrystallization with
acetone, white crystals, 70%.
2,4-Dichloro-6-decyl-[1,3,5]triazine (G)
Decyl magnesium bromide, methylenechloride/hexane
(1/100 v/v), yellow oil, 47%.
Synthesis of Compound (5)
2,4-Dichloro-6-(p-tolylphenyl)-[1,3,5]triazine (H)
To a suspension of the resin (3, 10 mg, 11 µmol) in NMP
(0.25 mL) was added an amine (0.2 mmol), followed by the addi-
tion of n-butanol (0.25 mL) and diisopropylethylamine (DIEA)
p-tolyl magnesium bromide, recrystallization with DCM, white
crystals, 83%.

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1005
(30 µL, 0.22 mmol). The reaction was placed in a heating
block set at 120◦C for 3 h. The excess reagents were filtered
through a PE frit cartridge and washed with DMF, DCM, MeOH
(1 mL × 3) consecutively, with a final wash with DCM (1 mL).
The resin was dried under vacuum. The product cleavage reac-
tion was performed using 10% trifluoroacetic acid (TFA) in
dichloromethane (1 mL) for 30 min at room temperature and
washed with DCM (0.5 mL).
Accessory Publication
Representative tagged library compounds are available on the
Journal’s website.
Acknowledgements
This work was supported by a grant from National Institute of Health
(CA-96912). We thank Dr. Matthew S. Tremblay for critical reading of the
manuscript.
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