Palladium-catalyzed cross-coupling reaction of resin-bound chlorotriazines

Article abstract of DOI:10.1016/S0040-4039(03)01451-5

To introduce the biaryl structure as a triazine functionality, we have developed a new synthetic route via the Suzuki cross-coupling reaction of resin-bound chlorotriazines. The Suzuki cross-coupling reaction was achieved using various arylboronic acids, Pd(PPh₃)₄, Cs₂CO₃, and dioxane. With the integration of this chemistry and our previous orthogonal methodology, the triazine library is greatly expanded to a biaryl scaffold.

Full text of DOI:10.1016/S0040-4039(03)01451-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6141–6144
Palladium-catalyzed cross-coupling reaction of resin-bound
chlorotriazines
Jacqueline T. Bork, Jae Wook Lee and Young-Tae Chang*
Department of Chemistry, New York University, New York, NY 10003, USA
Received 29 April 2003; revised 3 June 2003; accepted 6 June 2003
Abstract—To introduce the biaryl structure as a triazine functionality, we have developed a new synthetic route via the Suzuki
cross-coupling reaction of resin-bound chlorotriazines. The Suzuki cross-coupling reaction was achieved using various arylboronic
acids, Pd(PPh ) , Cs CO , and dioxane. With the integration of this chemistry and our previous orthogonal methodology, the
3
4
2
3
triazine library is greatly expanded to a biaryl scaffold.
2003 Elsevier Ltd. All rights reserved.
©
The aryl–aryl bond formation has elicited much interest
in modern organic synthesis. This axially chiral bond is
often found in natural products such as alkaloids, and
tions. Herein, we report novel orthogonal reactions,
which can be expanded to incorporate the Suzuki reac-
tion (Scheme 1).
1
is prevalent in biologically active parts of
2
3
pharmaceutical and agrochemical specialties, as well
According to the orthogonal approach, a primary
amine was coupled to a 4-formyl-3-dimethoxyphen-
oxymethyl-functionalized polystyrene resin (PAL) by
4
as in the materials science. The development of syn-
thetic methods for assembling aryl–aryl structured com-
pounds has been aided by the advancement of
transition metal catalysis, namely Suzuki cross-coupling
reductive amination using NaBH(OAc) . A monosub-
3
stituted 4,6-dichloro-[1,3,5]triazine, which was synthe-
5
reactions.
Solution-phase Suzuki coupling reactions of aryl chlo-
6
rides, specifically heterocyclic chlorides, such as
7
,8
9
10
chloropyrimidines, chloropyridines, chloropurines,
8,11
and chlorotriazines,
have been reported in the litera-
ture. The Suzuki coupling was further extended to solid
1
2,13
phase both in chloropyrimidines
nes,
and chloropuri-
1
3,14
yet remained unexplored for the triazine scaf-
fold. Thus, we have developed a general method for
performing palladium-catalyzed cross-coupling of solid
supported chlorotriazines to provide a novel aryl–aryl
containing triazine library.
In our previous research, we developed a unique solid
phase synthetic pathway for a highly pure trisubstituted
1
5,16
triazine library.
Interestingly, a series of compounds
from the library, known as tubulyzines, demonstrated
significant biological activity by the inhibition of tubu-
lin polymerization. However, one of our limitations
was that triazine synthesis on solid support was
confined to simple amine or alcohol nucleophilic reac-
Scheme 1. Orthogonal strategy for 1,3,5-trisubstituted triazi-
nes. (a) (i) R NH , HOAc:THF (1:44), rt, 1 h. (ii) NaB-
1
2
16
H(OAc)3,
overnight.
(b)
benzenemethanethiol
or
p-methoxybenzylamine, DIEA, THF 0°C. (c) DIEA (4
equiv.), THF, 60°C, 3 h. (d) arylboronic acid, Pd(PPh ) ,
3
4
dioxane, 90°C, 15 h. (e) 10% TFA/DCM, rt, 30 min.
Purification was required via crystallization or column chro-
matography.
*
*
Corresponding author. Tel.: 1-212-998-8491; fax: 1-212-260-7905;
e-mail: yt.chang@nyu.edu
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01451-5

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J. T. Bork et al. / Tetrahedron Letters 44 (2003) 6141–6144
sized in solution, was loaded on the solid support to
give a chlorotriazine scaffold, through nucleophilic aro-
matic substitution in THF using DIEA (N,N-diiso-
propylethylamine) at 60°C. As the final derivatization
step, an arylboronic acid was coupled to the triazine
scaffold via the Suzuki reaction.
Table 2. Representative compounds with respective purity
To optimize the reaction conditions, several palladium
catalysts and bases with phenylboronic acid were first
studied (Table 1). Pd (dba) [tris(dibenzylideneacetone)
2
3
dipalladium] with carbene ligands, 1,3-bis-(2,4,6-
1
7
18
trimethyl-phenyl)-imidazolium chloride and Nolan,
yielded low product purity contaminated with unknown
byproducts and starting material. In addition to
Pd (dba) with carbene ligand or phosphine ligand,
2
3
Pd(PPh3)4 [tetrakis(triphenylphosphine)palladium] was
also tested as a catalyst–ligand complex. Although the
1
9
phosphine ligand with Pd (dba) allowed for the reac-
2
3
tion to proceed in comparable purity, commercially
available Pd(PPh ) with Cs CO was finally chosen for
3
4
2
3
our catalyst to avoid unnecessary material usage and an
extra preparation step. When weaker or stronger bases,
such as DIEA and t-BuOK, were chosen for the
replacement of Cs CO , unidentified impurities formed,
2
3
leading to the conclusion that proper strength of base is
necessary.
Using the optimal conditions, Pd(PPh ) and Cs CO in
3
4
2
3
dioxane solvent (entry 3), a variety of arylboronic acids,
20
represented in Table 2 (entries 1–7), were tested in the
Suzuki reaction. The catalyst was stored and dispensed
within a glove box to prevent oxidation of Pd(0). The
reactions were heated to 90°C for 15 h under argon.
Mild acidic cleavage of the resin-bound molecule by
using 10% TFA/DCM gave the final trisubstituted tria-
zine product 5. All products were analyzed for purity
and identity by LC-MS equipped with a diode array
detector (Table 2).
Our initial results from the Suzuki reaction, the final
Table 1. Optimization of Suzuki cross-coupling reaction
step in the orthogonal approach (Scheme 1, product
5
a), encouraged us to incorporate the coupling reaction
16
into our previously developed sulfone strategy. To
test the synthetic utility of Scheme 2, we applied the
Suzuki reaction, with the same optimal conditions to
each of the selected arylboronic acids in the following
pathway: (1) palladium-catalyzed coupling reaction
Scheme 2. Incorporation of Suzuki cross-coupling reaction
into the sulfone strategy. (a) m-CPBA (10 equiv.), 1N NaOH,
1
,4-dioxane, at pH 4, rt, 8 h. (b) p-Methoxybenzylamine (20
equiv.), DIEA (20 equiv.), BuOH:NMP (1:1), 120°C, 3 h. (c)
0% TFA/DCM, rt, 30 min.
1

J. T. Bork et al. / Tetrahedron Letters 44 (2003) 6141–6144
6143
with benzylsulfanyl as adjacent substituent (upon cleav-
age yields product 5b), (2) oxidation, (3) amine replace-
ment of sulfone and (4) cleavage, yielding product 5c.
Furuya, S.; Fujino, M. J. Med. Chem. 2003, 46, 113–
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Graeme, J.; Stevanovic, S.; Schimana, J.; Gebhardt, K.;
Fiedler, H. S.; Jung, G. J. Antibio. 2002, 55, 571–577.
3. (a) Ikegaya, K.; Ozaki, M.; Kawashima, T.; Miura, I.;
Muramatsu, N. Preparation of biarylalkylenecarbamic
acid derivatives as agricultural and horticultural fungi-
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Hatanaka, Y.; Hagiwara, E.; Gouda, K.; Hiyama, T.
Process of producing unsaturated organic compounds
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The purity data in Table 2 correlates to the three final
cleaved products of Scheme 1 and Scheme 2, 5a, 5b,
and 5c, with either 4-methoxybenzylamine or benzene-
methanethiol, as the X2 substituent. The R1 resin-
bound amine for all the reactions was 4-methoxybenzyl-
amine. The synthesis of 5c products required oxidation
with m-CPBA of the benzylsulfide, followed by replace-
ment of benzylsulfone with 4-methoxybenzylamine.
This served as a useful comparison for both pathways,
since 5a products and 5c products are identical com-
pounds.
4
. (a) Bringmann, G.; Stowasser, R.; Goebel, L. J.
Organomet. Chem. 1997, 544, 7–13; (b) Lee, D. H.; Im,
J. H.; Lee, J. H.; Hong, J. I. Tetrahedron Lett. 2002,
4
3, 9637–9640; (c) Messner, M.; Kozhushkov, S.; De
Generally, the 5b compounds demonstrated higher
purity than the 5a compounds. As a result, the final 5c
product exhibited high purity, as well, as it followed the
pathway of Scheme 2 with sulfide intermediate 4b.
Thus, the sulfone chemistry not only offers greater
accessibility for diversification, as the chemistry accom-
modates another site for nucleophilic amination, it also
allows for greater compound purity. As a further note,
the results illustrate the broad tolerance of the reaction
for arylboronic acids. Our final conditions allowed for
a wide variance of boronic acids with neutral, electron-
Meijere, A. Eur. J. Org. Chem. 2000, 1137–1155.
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In summary, we have developed two novel synthetic
strategies toward making 1,3,5-trisubstituted aryl-triazi-
nes that can be applied to combinatorial triazine
libraries. The previous orthogonal approach and the
sulfone chemistry, in combination with the Suzuki reac-
tion, will enable the generation of highly diversified and
pure aryl-triazines. We are now in the process of con-
structing an extensive aryl-triazine library with biologi-
cal screenings to follow.
2
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2