Terminal alkyne-functionalized triazine by Sonogashira coupling: synthesis of a potential cell signalling inhibitor via click chemistry

Article abstract of DOI:10.1016/j.tetlet.2008.05.050

Introduction of the acetylene group on the 1,3,5-triazine scaffold was studied under various conditions. We describe here a new method to functionalize a triazine ring using Sonogashira coupling between 2-benzylsulfanyl-4,6-dichloro-1,3,5-triazine and tri

Full text of DOI:10.1016/j.tetlet.2008.05.050

Tetrahedron Letters 49 (2008) 4542–4545
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Tetrahedron Letters
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Terminal alkyne-functionalized triazine by Sonogashira coupling:
synthesis of a potential cell signalling inhibitor via click chemistry
Caroline Courme a,b, Sophie Gillon a,b, Nohad Gresh c,d, Michel Vidal c,d, Christiane Garbay c,d
,
Jean-Claude Florent a,b, Emmanuel Bertounesque a,b,
*
a CNRS UMR 176, 26 rue d’Ulm, 75005 Paris, France
b Institut Curie, Centre de Recherche, 26 rue d’Ulm, 75005 Paris, France
c INSERM U648, Laboratoire de Pharmacochimie Moléculaire et Cellulaire, Paris, France
d Université Paris Descartes, UFR Biomédicale, 45 rue des Saints-Pères, 75006 Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Introduction of the acetylene group on the 1,3,5-triazine scaffold was studied under various conditions.
We describe here a new method to functionalize a triazine ring using Sonogashira coupling between
2-benzylsulfanyl-4,6-dichloro-1,3,5-triazine and trimethylsilylacetylene to give the corresponding
2-benzylsulfanyl-4-chloro-6-(trimethylsilyl)ethynyl-1,3,5-triazine. The latter was then used to obtain
phosphoric acid mono-{4-[4-(4-amino-6-benzylsulfanyl-1,3,5-triazin-2-yl)-1,2,3-triazol-1-yl]-phenyl}
ester via click chemistry by Huisgen 1,3-dipolar cycloaddition reaction.
Received 14 March 2008
Revised 5 May 2008
Accepted 7 May 2008
Available online 14 May 2008
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Click chemistry
Privileged structures
Sonogashira coupling
1,3,5-Triazines
R2
1,2,3-Triazoles have gained increasing attention in medicinal
chemistry1 since the introduction of the so-called ‘click chemistry’
or Cu(I)-catalyzed 1,3-dipolar alkyne-azide coupling reaction,
which was pioneered by Sharpless.2 Protein tyrosine phosphatases
(PTPs) and protein tyrosine kinases (PTKs) have been the focus of
considerable drug discovery efforts in recent years, owing to their
implication in regulating cell-signalling pathways. In this context,
application of click chemistry recently led to the synthesis of
libraries of PTP inhibitors,3 and to the synthesis of the growth
R
N
R3
N
N
N
N
N
N
N
R1
R1
N
N
N
MeO
OMe
R1
R2
R1
R1
1 R = alkyl
4 R2 = alkyl, Ph
2 R1 = R2 = OMe, R3 = Cl
3 R1 = R2 = R3 = Cl
factor receptor-bound protein
2 (Grb2) SH2 domain-binding
Figure 1. Alkynylation of 1,3,5-triazine derivatives.
inhibitors designed to antagonize or modulate PTK signalling,4 in
addition to classical rational design of such inhibitors.5
4. Importantly, it appears that none of these papers mention the
synthesis of triazines possessing the terminal acetylene group,
required in our case for the Huisgen 1,3-dipolar cycloaddition reac-
tion. To our knowledge, the introduction of this functionality, via
Grignard alkynylation from cyanuric chloride 3, was only reported
in a patent in 1972.11
Exploiting the triazine privileged structure6,7 in medicinal
chemistry8 via click chemistry, which enables the construction of
libraries with asymmetric diversity, would be of great interest.
Alkynylation of 1,3,5-triazine derivatives has been reported under
various conditions. Menicagli and Samaritani9 described the
synthesis of 2-(alk-10-ynyl)-4,6-dimethoxy-1,3,5-triazines 1 by
Sonogashira cross-coupling between alk-1-ynes and 2-chloro-4,6-
dimethoxy-1,3,5-triazine 2 in the presence of different palladium
catalyst systems (Fig. 1). Furthermore, Grignard alkynylation of
2,4,6-trichloro-1,3,5-triazine 3 (cyanuric chloride) was revisited,10
allowing access to 2-(alk-10-ynyl)-4,6-dialkylamino-1,3,5-triazines
R3
N
N
N
N
N
R1
N
NHR4
H2O3PO
R2
5
* Corresponding author. Tel.: +33 156246659; fax: +33 156246631.
E-mail address: emmanuel.bertounesque@curie.fr (E. Bertounesque).
Figure 2. Triazine-functionalized, 1,4-disubstituted-1,2,3-triazoles 5.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.050

C. Courme et al. / Tetrahedron Letters 49 (2008) 4542–4545
4543
Thus, we have designed phosphate-containing 1,4-disubsti-
zylsulfanyl-1,3,5-triazin-2-yl)-1,2,3-triazol-1-yl]-phenyl} ester
(R1 = R2 = H, R3 = SBn, R4 = H) via click chemistry.
The introduction of the terminal acetylene functionality from 3
was demonstrated11 using [(trimethylsilyl)ethynyl]magnesium
bromide prepared from trimethylsilylacetylene (TMSA) and ethyl-
magnesium bromide (Table 1, entry 1). Addition of MeOH to the
5
tuted-1,2,3-triazoles 5 as potential cell signalling inhibitors3,12
using click chemistry strategy (Fig. 2). Herein, we present the pre-
liminary results of our investigation on the introduction of the
ethynyl functionality on substituted 1,3,5-triazine derivatives,
and the synthesis of phosphoric acid mono-{4-[4-(4-amino-6-ben-
Table 1
Introduction of the trimethysilylethynyl group on substituted 1,3,5-triazine derivativesa
Entry
Reaction conditions
Starting material triazine
Product yieldb
OMe
%
Cl
1. HCꢀC–TMS, EtMgBr
THF, then addition of MeOH
2. Hydrolysis
N
N
N
N
1
N
OMe
Cl
N
Cl
H
611
3
Cl
N
N
N
N
2
HCꢀC–MgBr (1 equiv)
Decomposition
Decomposition
THF, 0 °C, then addition of MeONa
Cl
Cl
Cl
Cl
N
3
Cl
3c
HCꢀC–MgBr (1 equiv)
Ni(acac)2, PPh3, THF, 0 °C
then addition of MeONa
N
3
Cl
N
Cl
HCꢀC–TMS (1 equiv)
PdCl2(PPh3)2, CuI, DIPEA
THF, rt, 20 h
N
N
N
N
4
5
Cl
N
Cl
TMS
TMS
7d 46%
3
Cl
N
N
HCꢀC–TMS (1.5 equiv)
Pd/C, PPh3, CuI, DIPEA
MeCN, 80 °C, 20 h, sealed tube
No reaction
Dmb
Dmb
Dmb
Dmb
N
H
N
N
H
8
Cl
N
N
6
HCꢀC–TMS (1.5 or 3 equiv)
Pd/C, PPh3, CuI, K2CO3,
MeCN, 80 °C, 20 h, sealed tube
No reaction
N
H
N
N
H
8
SBn
SBn
N
SBn
N
N
N
N
N
7e
HCꢀC–TMS (1.5 equiv)
Pd/C, PPh3, CuI, DIPEA
N
Cl
Cl
N
N
Cl
N
Cl
TMS
MeCN, 80 °C, 24 h, sealed tube
9
10 15%
11 25%
SBn
SBn
N
N
N
N
8f
HCꢀC–TMS (2 equiv)
PdCl2(PPh3)2, CuI, DIPEA
THF, rt, 20 h
N
Cl
Cl
N
Cl
TMS
9
10 38%
a
Unless otherwise specified, reactions were carried out with Pd catalyst 0.04 equiv, CuI 0.04 equiv, PPh3 0.16 equiv, base 2.5 equiv.
b
c
Yields were determined by 1H NMR analysis unless otherwise stated.
Ni(acac)2 0.01 equiv, PPh3 0.02 equiv.
Isolated yield.
d
e
Flash chromatography of the crude product gave two fractions: 4-benzylsulfanyl-6-chloro-N-ethyl-N-isopropyl-1,3,5-triazin-2-amine 11 (25%) and an inseparable
mixture of the starting material 9 and the desired cross-coupling product 10 (15%).
f
Scaled-up reaction (8 g of 9), 10 was inseparable from the starting triazine after flash chromatography.

4544
C. Courme et al. / Tetrahedron Letters 49 (2008) 4542–4545
SBn
N
SBn
N
SBn
N
a
N
N
N
+
+
9/10
H2N
N
NH2
H2N
N
H2N
N
TMS
b
H
12
13
14
Scheme 1. Synthesis of alkyne 14. Reagents and conditions: (a) NH3 (g), THF, rt, 20 h; (b) K2CO3, MeOH/THF (1:1), rt, 2 days, 80% (combined yield).
OH
OH
OPO(OBn)2
The required deprotection of trimethylsilylacetylene 10 existing
as a mixture with 9 was problematic, since the reaction under TBAF
conditions (TBAF, THF, rt) resulted in decomposition, and that the
treatment of 10 with potassium carbonate (K2CO3, MeOH/THF, rt)
not only yielded to the expected free acetylene group but also to
concomitant substitution by methoxide anion on the 6-Cl position.
We overcame this difficulty by a prior introduction of the required
NH2 group from the mixture containing 2-benzylsulfanyl-4,6-di-
chloro-1,3,5-triazine 9 and alkyne 10 (Scheme 1): thus, reaction
of ammonia with this mixture led to two fractions after flash chro-
matography, the less polar as an inseparable mixture of 12 and 13
(60% yield as determined by 1H NMR), and the more polar as pure
isolated compound 14 (20%). Treating the mixture of 12 and 13
with K2CO3 allowed the quantitative transformation of 13 into
14, in a combined yield of 80%.
With compound 14 in hand, we next turned out our attention to
the preparation of the desired 1,4-disubstituted-1,2,3-triazole
5.17,18 First, (4-azidophenyl)dibenzylphosphate 1719 was prepared
in an optimized two-step process. 4-Azidophenol 16 was obtained
from 4-aminophenol by diazotization followed by treatment of the
resulting diazonium salt with azide anion (89%). Phosphorylation
of 16 with dibenzylchlorophosphate20 (in situ prepared from
dibenzylphosphite) gave 17 in 81% yield (Scheme 2).
Finally, the 1,3-dipolar Huisgen cycloaddition of alkyne 14 and
aryl azide 17 was carried out to give triazole 18 in 54% yield
(Scheme 3). Deprotection of 18 led to triazinyl-triazole phosphate
5 (66%) which was purified by reversed-phase C18 chromato-
graphy (CH3CN/H2O).
In conclusion, we described a study on the introduction of the
ethynyl group on substituted 1,3,5-triazine derivatives via Sono-
gashira coupling. To the best of our knowledge, triazole 5 is the
first example of click chemistry by Huisgen cycloaddition reaction
applied to the privileged structure triazine.21 This method will be
optimized and used in the synthesis of triazine libraries. This
compound and analogues will be investigated as potential cell
signalling inhibitors.
a
b
NH2
N3
N3
15
16
17
Scheme 2. Synthesis of (4-azidophenyl)dibenzylphosphate 17. Reagents and con-
ditions: (a) 4-aminophenol 15 diluted in HCl aq (0.5 M HCl), 0 °C, then addition of
NaNO2 aq (1.5 equiv), 0 °C, then addition of NaN3 aq (1.5 equiv), 0 °C (dilution in
order to obtain a 0.2 M HCl final solution), 20 h, 89%; (b) (BnO)2P(O)H (2.5 equiv),
DIPEA (5 equiv), DMAP (0.5 equiv), CCl4/CH3CN (1:5), ꢁ15 °C, 3 h, 81%.
resulting alkynylated product followed by cleavage of the TMS pro-
tecting group led to 2-ethynyl-4,6-dimethoxy-1,3,5-triazine 6. By
contrast, treatment of 3 with ethynylmagnesium bromide only
resulted in decomposition of the starting material (entry 2). An
identical outcome was observed when Grignard alkynylation was
attempted with the Ni(acac)2-PPh3 system13 (entry 3). Next, we
examined the Sonogashira reaction14 of 3 with TMSA in the pres-
ence of PdCl2(PPh3)2 which gave 2-chloro-4,6-bis[(trimethyl-
silyl)ethynyl]-1,3,5-triazine 7 in 46% yield, with only traces of the
required monoethynylated product (entry 4). We then envisioned
the Sonogashira coupling of 6-chloro-N2,N4-bis(2,4-dimethoxyben-
zyl)-1,3,5-triazine-2,4-diamine 8—bearing two acid-labile dime-
thoxybenzyl (Dmb) protecting groups for the amines15—and
TMSA. Note that this triazine scaffold could lead to the synthesis
of triazoles 5 featuring two nitrogen functionalizations at C4
(NHR4) and C6 (R3). Unfortunately, with (Pd/C)/PPh3/CuI as the cat-
alytic system,9 no reactions occurred (entries 5 and 6). Finally, we
opted for 2-benzylsulfanyl-4,6-dichloro-1,3,5-triazine 916 as the
substrate, which allowed an orthogonal synthetic strategy, via the
sulfone chemistry (i.e., oxidative activation of the thioether), for
the generation of 1,3,5-trisubstituted combinatorial triazine
libraries.16 Under the previous reaction conditions with N,N0-diiso-
propylethylamine (DIPEA) as a base, triazine 9 gave rise to the
formation of the desired 2-benzylsulfanyl-4-chloro-6-(trimethyl-
silyl)ethynyl-1,3,5-triazine 10 in 15% yield, accompanied with 25%
yield of 4-benzylsulfanyl-6-chloro-N-ethyl-N-isopropyl-1,3,5-tria-
zin-2-amine 11 (entry 7). The latter results from the amination of
the starting material by DIPEA followed by the elimination of an iso-
propyl group.9b The same coupling reaction conducted at 25 °C for
24 h led to the recovery of triazine 9. However, replacement of the
catalyst (Pd/C)/PPh3 by PdCl2(PPh3)2 afforded the desired cross-cou-
pling product 10 in a synthetically useful 38% yield (entry 8).
Acknowledgments
We thank CNRS, Institut Curie and Ministère de la Recherche
(ACI ‘Molécules et Cibles Thérapeutiques’ 2002 No 02L0521) for
financial support. Fondation pour la Recherche Médicale (FRM) is
gratefully acknowledged for a fellowship granted to Caroline
Courme.
OPO(OBn)2
SBn
SBn
SBn
N
N
N
N
N
N
N
N
N
b
a
N
N
N
+
N
N
H2N
N
NH2
NH2
(BnO)2OPO
H2O3PO
H
N3
5
14
18
17
Scheme 3. Synthesis of triazinyl-triazole phosphate 5. Reagents and conditions: (a) ascorbic acid (0.1 equiv), CuSO4 (0.01 equiv), H2O/t-BuOH (1:1), 30 °C, 24 h, 54%; (b) TFA
95%, rt, 2 h, 66%.

C. Courme et al. / Tetrahedron Letters 49 (2008) 4542–4545
4545
10. Menicagli, R.; Samaritani, S.; Zucchelli, V. Tetrahedron 2000, 56, 9705–9711.
11. Burckhardt, U.; Zimmermann, M. Ger. Offen. 2,209,470, 1972; Chem. Abstr.
1972, 77, P164744.
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