Novel orthogonal strategy toward solid-phase synthesis of 1,3,5-substituted triazines.

Article abstract of DOI:10.1021/ol027195v

[reaction: see text] To improve upon the previous orthogonal method for synthesis of a triazine library, an alternative strategy has been developed via oxidation-activation of the thioether to the sulfone. Through a comparison between these two methods, the sulfone strategy was demonstrated as an enhanced method in the generation of highly pure triazine library compounds.

Full text of DOI:10.1021/ol027195v

ORGANIC
LETTERS
2003
Vol. 5, No. 2
117-120
Novel Orthogonal Strategy toward
Solid-Phase Synthesis of
1,3,5-Substituted Triazines
Jacqueline T. Bork, Jae Wook Lee, Sonya M Khersonsky, Ho-Sang Moon, and
Young-Tae Chang*
Department of Chemistry, New York UniVersity, New York, New York 10003
yt.chang@nyu.edu
Received October 29, 2002
ABSTRACT
To improve upon the previous orthogonal method for synthesis of a triazine library, an alternative strategy has been developed via oxidation-
activation of the thioether to the sulfone. Through a comparison between these two methods, the sulfone strategy was demonstrated as an
enhanced method in the generation of highly pure triazine library compounds.
Triazine derivatives have demonstrated a broad range of
biological activities, including anti-angiogenesis,1 herbicidal
effects,2 anti-metastatic effects,3 Erm methyltransferase
inhibition,4and anti-microbial effects.5 With the advent of
combinatorial chemistry, several triazine libraries have been
published in the literature, both in solid6 and solution7 phase,
taking advantage of its easy manipulation and the low price
of starting material. However, all of the reported procedures
contain stepwise amination, which is difficult to generalize
for nucleophiles with varying reactivities, and thus each
reaction step may accumulate byproducts, yielding impure
library compounds.6,7
We have recently developed a unique orthogonal solid-
phase synthetic pathway for a highly pure trisubstituted
triazine library, in which certain members of the library
exhibited anti-tubulin activity.8 In this synthetic approach,
three types of building blocks were prepared separately and
assembled by chemically orthogonal reactions (Figure 1).
Although the strategy worked very nicely, giving highly pure
triazine library compounds, two problems were encountered.
(1) Ono, M.; Kawahara, N.; Goto, D.; Wakahayashi, Y.; Ushiro, S.;
Yoshida, S.; Izumi, H.; Kuwano, M.; Sato, Y. Cancer Res. 1996, 56, 1512-
1516.
(2) Draber, W.; Tietjen, K.; Kluth, J. F.; Trebst, A. Angew. Chem., Int.
Ed. Engl. 1991, 30, 1621-1633.
(3) Maeda, M.; Iogo, M.; Tsuda, H.; Fujita, H.; Yonemura, Y.; Nakagawa,
K.; Endo, Y.; Sasaki, T. Anti-Cancer Drug Des. 2000, 15, 217-223.
(4) Hajduk, P. J.; Dinges, J.; Schkeryantz, J. M.; Janowick, D.; Kaminski,
M.; Tufano, M.; Augeri, D. J.; Petros, A.; Nienaber, V.; Zhong, P.;
Hammond, R.; Coen, M.; Beutel, B.; Katz, L.; Fesik, S. W. J. Med. Chem.
1999. 42, 3852-3859.
(5) Silen, J. L.; Lu A. T.; Solas, D. W.; Gore, M. A.; MacLean, D.;
Shah, N. H.; Coffin, L. M.; Bhinderwala, N. S.; Wang, Y.; Tsutsui, K. T.;
Look, G. C.; Campbell, D. A.; Hale, R. L.; Navre, M.; Deluca-Flaherty, C.
R. Antimicrob. Agents Chemother. 1998, 42, 1447-1453.
(6) (a) Stankova, M.; Lebl, M. Mol. DiVersity 1996, 2, 75-80. (b) Scharn,
D.; Wenschuh, H.; Reineke, U.; Schneider-Mergener, J.; Germeroth, L. J.
Comb. Chem. 2000, 2, 361-369. (c) Teng, S. F.; Sproule, K.; Hussain, A.;
Lowe, C. R. J. Mol. Recognit. 1999, 12, 67-75. (d) Filippusson, H.;
Erlendsson, L. S.; Lowe, C. R. J. Mol. Recognit. 2000, 13, 370-381.
(7) (a) Gustafson, G. R.; Baldino, C. M.; O’Donnel, M. E.; Sheldon, A.;
Tarsa, R. J.; Verni, C. J.; Coffen, D. L. Tetrahedron 1998, 54, 4051-4065.
(b) Johnson, C. R.; Zhang, B.; Fantauzzi, P.; Hocker, M.; Yager, K. M.
Tetrahedron 1998, 54, 4097-4106. (c) Falorni, M.; Giacomelli, G.; Mameli,
L.; Pordheddu, A. Tetrahedron Lett. 1998, 39, 7607.
(8) Moon, H.; Jacobson, E.; Khersonsky, S. M.; Luzung, M.; Walsh,
D.; Xiong, W.; Lee, J. W.; Parikh, P.; Lam, J. C.; Kang, T. W.; Rosania,
G. F.; Schier, A.; Chang, Y. T. J. Am. Chem. Soc. 2002, 124, 11608-
11609.
10.1021/ol027195v CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/01/2003

reductive amination,9 2-benzylsulfanyl-4,6-dichloro-[1,3,5]-
triazine, synthesized in solution,10 was loaded on the solid
support to give the first building block, 1. A subsequent
amination reaction of 1 with primary or secondary amines
introduced a second building block to the chloride position
to provide intermediate 2.
The sulfide intermediate allows for the introduction of yet
another substituent, by m-CPBA oxidation of the thioether
linkage,11 thus, generating another good leaving group, a
heterocyclic sulfone. Generally, sulfone is a better leaving
group than chloride, a characteristic that will increase the
reactivity at that site.12 It was found to be important to keep
the pH of the reaction approximately at 4. Whereas a lower
pH induced the cleavage of the PAL linker, a basic condition
resulted in hydroxyl replacement of the sulfone group. It is
also recommended to make a fresh sulfone intermediate for
the next step, as extended time in storage of the reactive
intermediate evoked the hydrolysis of the sulfone. A fol-
lowing amination occurred smoothly to incorporate the third
building block amines at the new activated position to
generate a trisubstituted triazine 4. Mild acidic cleavage of
the resin bound molecule gave the trisubstituted triazine
product, 5. All products were analyzed for purity and identity
by LC-MS equipped with a diode array detector.
Benzenemethanethiol was chosen as the most promising
reagent, versus 4-methylbenzenethiol or benzenethiol, be-
cause of its great stability during the following amination
step. For example, when 4-methylbenzenethiol was tested
as a candidate, the following amination with piperidine
resulted in a 7% impurity consisting of a disubstituted
piperidine, suggesting a premature displacement of the thiol
compound.
Figure 1. Previous orthogonal strategy for 1,3,5-trisubstituted
triazines.
First of all, one out of the three building blocks should be
prepared by solution-phase chemistry and must be purified
either by crystallization or chromatography, which is a
cumbersome step for some functionalities. A second problem
was found in the extension of the diversity in the last
amination step; the low reactivity of the third chloride inhibits
the reaction with moderately weak nucleophilic amines.
Herein, we report a new orthogonal pathway that can improve
the problems of our previous strategy.
To surmount the impediments of the previous orthogonal
scheme, we designed a novel orthogonal pathway incorporat-
ing an oxidation-activation of a thioether group (Scheme 1).
After a primary amine was coupled to 4-formyl-3-dimethoxy-
phenoxymethyl-functionalized polystyrene resin (PAL) by
A thorough comparison of reactivity was assessed between
the three different amination reactions on the triazine scaffold
correlating to the previous and current orthogonal methods:
chlorine as a leaving group in reaction A, benzyl sulfone as
a leaving group in reaction B, and chlorine as a leaving group
with benzylsulfanyl as an adjacent substituent in reaction C
(Table 1). The scope of the two orthogonal combinatorial
schemes has been validated by testing 30 amines in each of
the three pathways. The same conditions in Scheme 1 were
applied to each case.
Scheme 1. New Orthogonal Approach toward
1,3,5-Trisubstituted Triazine Librarya
The following amines represented in Table 1 demonstrate
the effectiveness of the new sulfone chemistry. 4-Methoxy-
benzylamine, a strong nucleophile, displayed high purity in
all three reactions. Many of the previously observed weaker
nucleophiles showed heightened reactivity in reaction B.
However, those amines that exhibited products with lower
purities were generally secondary, sterically hindered amines,
such as dibenzylamine and N-butylbenzylamine, entries 11
and 12, respectively. Benzyl sulfone is a bulkier leaving
group than chlorine, which appears to create a barrier for
(9) Chang, Y. T.; Gray, N.; Rosania, G. R.; Sutherlin, D. P.; Kwon, S.;
Norman, T.; Sarohia, R.; Leost, M.; Schultz, P. G. Chem. Biol. 1999, 6,
361-375.
a Reagents and conditions: (a) NHR2R′2 (20 equiv), DIPEA (20
equiv), BuOH/NMP (1:1), 120 °C, 3 h. (b) m-CPBA (10 equiv), 1
N NaOH, 1,4-dioxane, at pH 4, shaken for 8 h. (c) NHR3R′3 (20.0
equiv), DIPEA (20 equiv), BuOH/NMP (1:1), 120 °C, 3 h. (d) 10%
TFA /DCM, shaken for 30 min at room temperature.
(10) See Supporting Information section for full procedure.
(11) Ding, S.; Gray, G. S.; Ding, Q.; Schultz, P. G. J. Org. Chem. 2002,
66, 8273-8276.
(12) Guillier, F.; Roussel, P.; Moser, H.; Kane, P.; Bradley, M. Chem.
Eur. J. 1999, 5, 3450-3458.
118
Org. Lett., Vol. 5, No. 2, 2003

Table 1. Reactivity Comparison between Three Substitution Reactions
more sterically hindered nucleophiles. The purities of the
benzylsulfanyl triazines from reaction C were generally
higher than those of the 4-methoxybenzylamine triazines
from reaction A, suggesting an increased reactivity at the
chloro position of the benzylsulfanyl triazine.13 For those
compounds containing hydroxyl groups (i.e., entry 3), a TFA
ester formed, which was hydrolyzed by 10% dimethylethyl-
amine in MeOH. The impurities resulting in the reaction are
mainly unreacted starting material.
The reactivity data, of which some are shown in Table 1,
will be a useful guideline for the selection of the library
building blocks for a highly pure triazine library. To
demonstrate the practical usefulness of the results and the
flexibility of the new orthogonal chemistry, a small library
of 96 compounds was constructed and analyzed. Amines
were chosen for the second and third aminations, NHR2R′2
and NHR3R′3, respectively, on the basis of their compared
purities, as illustrated in Table 1. The reaction followed the
conditions in Scheme 1, which involved (1) a replacement
of chlorine, followed by (2) oxidation and a replacement of
sulfone (Figure 2). The average purity of the 96 products
was 94%. This result clearly demonstrates the robustness of
this new strategy.
In summary, we report a new synthetic strategy toward
making 1,3,5-trisubstituted combinatorial triazine libraries.
Figure 2. Test synthesis of a small library using new orthogonal
chemistry.
(13) Barillari, C.; Barlocco, D.; Raveglia, L. F. Eur. J. Org. Chem. 2001,
4737-4341.
Org. Lett., Vol. 5, No. 2, 2003
119

The sulfone chemistry in the combinatorial triazine scheme
has the following merits: (1) the difficulty of substituting
more unreactive amines at the final step has been improved
by using benzylsulfanyl triazine as an intermediate and
benzyl sulfone as a leaving group; (2) the overall sulfone
scheme provides a more convergent strategy, as the depen-
dence of scaffold diversity on multiple resin-bound amines
and variability in solution chemistry has been eliminated;
and (3) the flexibility at each amination site gives rise to a
greater diversification, broadening the scope of different
combinations. The construction of large numbers of library
members and their biological screening are in progress.
Acknowledgment. Funding supports from Luminogene
(www.luminogene.com) is acknowledged.
Supporting Information Available: Experimental details
for the syntheses of the library compounds and representative
LC-MS data. This material is available free of charge via
the Internet at http://pubs.acs.org.
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