Synthetic strategies to prepare 2-alkyl, 2-aryl and 2-acetylenyl substituted 4,6-diamino-1,3,5-triazines

Article abstract of DOI:10.1016/j.tetlet.2006.06.045

We have developed synthetic protocols to generate 2-alkyl, 2-aryl and 2-acetylenyl substituted 4,6-diamino-1,3,5-triazines from the corresponding 2-chloro compound.

Full text of DOI:10.1016/j.tetlet.2006.06.045

Tetrahedron Letters 47 (2006) 5973–5975
Synthetic strategies to prepare 2-alkyl, 2-aryl
and 2-acetylenyl substituted 4,6-diamino-1,3,5-triazines
Christian A. G. N. Montalbetti,a,* Thomas S. Coulter,a Muhammed K. Uddin,a
a
a
b
˚
Serge G. Reignier, Filippo Magaraci, Charlotta Grana¨s,
Christian Krog-Jensenb and Jakob Feldingb
aEvotec, 111 Milton Park, Abingdon, Oxon OX14 4RX, United Kingdom
bBioImage A/S Mørkhøj Bygade 28, DK-2860 Søborg, Denmark
Received 5 April 2006; revised 30 May 2006; accepted 7 June 2006
Available online 30 June 2006
Abstract—We have developed synthetic protocols to generate 2-alkyl, 2-aryl and 2-acetylenyl substituted 4,6-diamino-1,3,5-triazines
from the corresponding 2-chloro compound.
Ó 2006 Elsevier Ltd. All rights reserved.
The triazine scaffold is found in compounds presenting a
wide spectrum of biological activity. This core has been
utilised in diverse pharmaceutical applications such as
antiproliferative, antitubulin, antiangiogenic and anti-
depressive agents or in plant-protection applications
such as the triazine herbicides.1 Other factors which
have contributed to the widespread use of triazine
libraries in drug discovery are the ease of manipulation
and the availability of cheap starting materials used to
build this class of compounds.
assay.3 The screening campaign provided the substituted
triazine 2 as a 3 lM hit.
Trisubstituted 1,3,5-triazine derivatives can be generated
by stepwise replacement of the chlorine atoms of cyan-
uric chloride (2,4,6-trichloro-1,3,5-triazine) by amines,
alcohols or thiols. This strategy takes advantage of the
decrease in reactivity after introduction of each substi-
tuent. Derivatives containing three different substituents
are obtained in a reasonable yield and purity.4 The scaf-
fold is therefore well suited for combinatorial library
generation and solution phase4,5 or solid phase librar-
ies1b,c,6 have been reported.
In an anticancer project aiming to identify PI3 kinase
pathway inhibitors by monitoring FOXO1 transloca-
tion, a member of the Forkhead family of transcription
factors,2 we screened a library of 265,000 commercial
compounds using a cell based FOXO1 RedistributionÒ
Diverse methods for the introduction of alkyl substitu-
ents on cyanuric chloride are described in the literature,
Cl
Cl
N
Cl
N
Cl
(b)
(a)
N
N
N
N
N
N
N
N
Cl
Cl
Cl
N
N
H
O
O
1
2
Scheme 1. Reagents and conditions: (a) acetone, K2CO3, morpholine, 0 °C, 83% and (b) acetone–water (5:1), 3-chloroaniline, K2CO3, 40 °C, 94%.
Keywords: Triazine; Sonogashira; Suzuki; Nucleophilic substitution; PI3 Kinase pathway inhibitors; FOXO1 Translocation.
*
Corresponding author. Tel.: +44 1235 861561; e-mail: christian.montalbetti@evotec.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.045

5974
C. A. G. N. Montalbetti et al. / Tetrahedron Letters 47 (2006) 5973–5975
Ar
In order to establish a structure activity relationship at
the chlorine-substituted position on the triazine ring of
compound 2 we set out to prepare a selection of ana-
logues replacing the chlorine atom with malonyl, aryl
or alkynyl substituents.
N
N
N
N
NH
O
The original hit 2 was prepared, on a 20 g scale, via two
consecutive SNAr reactions, first reacting morpholine
with cyanuric chloride followed by addition of 3-chloro-
aniline, in 78% overall yield (Scheme 1).
Cl
(a)
(b)
O
N
O
N
OEt
NH
EtO
N
With compound 2 in hand, we investigated the replace-
ment of the final chlorine (Scheme 2). Aryl substituents
were successfully introduced by Suzuki and Miyaura10
coupling using the methodology developed by Cooke
et al.11 (Scheme 2a).
2
X
N
O
(c)
To our knowledge the use of a malonate derivative as a
soft nucleophile has not yet been described for either
cyanuric chloride or dichlorotriazines. The malonate
moiety also constitutes an advantageous handle for fur-
ther elaborations. However, introduction of malonate
on compound 2 proved unfruitful (Scheme 2b). We be-
lieve that this may be due to the malonate nucleophile
acting as a base and deprotonating the aniline nitrogen
on compound 2. The increased electron density on the
triazine ring resulting from this deprotonation would
then prevent any addition from taking place.
Ph
Cl
X
N
N
Cl
N
N
N
H
O
Scheme 2. Reagents and conditions: (a) DME, Pd(PPh3)4, K2CO3
(2 M), ArB(OH)2, 80 °C, 3 days (Ar (yield) = phenyl (62%), 2-thienyl
(44%), 3-furyl (55%), 3,4-dimethoxy (37%)); (b) THF or DMF, diethyl
malonate, NaH, room temperature to 60 °C, 14 h; only starting
material recovered and (c) toluene, DIPEA, CuI, Pd(PPh3)4,
PhC„CH or PhC„CMgBr, Et2O, 0 °C to room temperature or
100 °C; only starting material recovered.
To overcome this problem, we instead investigated the
malonate addition on 2,4-dichloro-6-morpholin-4-yl-
1,3,5-triazine 1. This change in order of addition now al-
lowed the successful introduction of the malonate group
to the triazine core (Scheme 3a). When 3-chloroaniline
was introduced in the final step under basic conditions
(Scheme 3c) the diester product was isolated. Alterna-
tively when the reaction was carried out under acidic
conditions (Scheme 3d) further decarboxylation was
observed and the mono ester was isolated as the
main product.
such as palladium mediated coupling of organozinc or
organotin reagents,7 addition of Grignard reagents8
and addition of silyl enol ethers.9
O
N
O
N
O
R
OEt
Cl
EtO
N
EtO
N
Cl
(c) or (d)
N
N
(a)
N
N
N
H
O
O
R= CO2Et for (c)
R= H for (d)
Ph
Ph
1
Cl
(b)
(e)
N
N
N
N
N
N
Cl
N
N
N
H
O
O
Scheme 3. Reagents and conditions: (a) THF, diethyl malonate (1.2 equiv), NaH (4 equiv), 0 °C to room temperature, 25%; (b) toluene, DIPEA,
CuI, Pd(PPh3)4, PhC„CH, room temperature, 48 h, 71%; (c) THF, K2CO3, 3-chloroaniline, 14%; (d) MeCN, TFA (2 equiv), 3-chloroaniline, 80 °C,
sealed tube, 18% and (e) THF, K2CO3, 3-chloroaniline, 33%.

C. A. G. N. Montalbetti et al. / Tetrahedron Letters 47 (2006) 5973–5975
5975
2. Kau, T. R.; Schroeder, F.; Ramaswamy, S.; Wojciechow-
ski, C. L.; Zhao, J. J.; Roberts, T. M.; Clardy, J.; Sellers,
W. R.; Silver, P. A. Cancer Cell 2003, 4, 463–476.
3. Lundholt, B. K.; Linde, V.; Loechel, F.; Pedersen, H. C.;
Møller, S.; Præstegaard, M.; Mikkelsen, I.; Scudder, K.;
Bjørn, S. P.; Heide, M.; Arkhammar, P. O.; Terry, R.;
Nielsen, S. J. J. Biomol. Screen 2005, 10, 20–29.
4. Henke, B. R.; Consler, T. G.; Go, N.; Hale, R. L.;
Hohman, D. R.; Jones, S. A.; Lu, A. T.; Moore, L. B.;
Moore, J. T.; Orband-Miller, L. A.; Robinett, R. G.;
Shearin, J.; Spearing, P. K.; Stewart, E. L.; Turnbull, P. S.;
Weaver, S. L.; Williams, S. P.; Wisely, G. B.; Lambert, M.
H. J. Med. Chem. 2002, 45, 5492–5505.
5. (a) Gustafson, G. R.; Baldino, C. M.; O’Donnel, M.-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.
6. Khersonsky, S. M.; Chang, Y.-T. J. Comb. Chem. 2004, 6,
474–477.
7. Xia, Y.; Mirzai, B.; Chackalamannil, S.; Czarniecki, M.;
Wang, S.; Clemmons, A.; Ahn, H. S.; Boykow, G. C.
Bioorg. Med. Chem. Lett. 1996, 6, 919–922.
8. (a) Hirt, R.; Nidecker, H.; Berchtold, R.; Scho¨nholzer, G.
Helv. Chim. Acta 1950, 33, 1365–1368; (b) Leroux, F.; van
Keulen, B. J.; Daliers, J.; Pommery, N.; Henichart, J. P.
Bioorg. Med. Chem. 1999, 7, 509–516; (c) Arvanitis, A. G.;
Gilligan, P. J.; Chorvat, R. J.; Cheeseman, R. S.; Christos,
T. E.; Bakthavatchalam, R.; Beck, J. P.; Cocuzza, A. J.;
Hobbs, F. W.; Wilde, R. G.; Arnold, C.; Chidester, D.;
Curry, M.; He, L.; Hollis, A.; Klaczkiewicz, J.; Krenitsky,
P. J.; Rescinito, J. P.; Scholfield, E.; Culp, S.; De Souza, E.
B.; Fitzgerald, L.; Grigoriadis, D.; Tam, S. W.; Wong, Y.
N.; Huang, S.-M.; Shen, H. L. J. Med. Chem. 1999, 42,
805–818.
The functionalisation of triazines by alkynes has been
described using Sonogashira coupling12,13 or Grignard14
addition methodologies on 2-chloro-4,6-dimethoxy-
1,3,5-triazine. In our case, the Sonogashira coupling
failed to give any product when carried out on com-
pound 2 or cyanuric chloride (Scheme 2c).
Using a similar strategy as described for the malonate
derivative, the coupling reaction with 2,4-dichloro-6-
morpholin-4-yl-1,3,5-triazine 1 afforded the alkyne
derivative in good yield (Scheme 3b). The final displace-
ment was achieved under basic conditions with 3-chloro-
aniline (Scheme 3e).
In conclusion, we have prepared a series of trisubstituted
triazines where one of the positions contains a carbon
substituent. In our hands, the order of synthetic steps
depends on the nature of the substituent. Whereas aryl
groups could be introduced during the last step via
Suzuki coupling on compound 2, introduction of the
malonyl and acetylenyl moieties is necessary at an
earlier stage on the dichlorotriazine 1, followed by the
final introduction of the aniline.
Acknowledgements
We would like to thank Dr. Richard Mears and Dr.
Steven Butcher for their useful suggestions during the
preparation of this manuscript.
References and notes
9. Shastin, A. V.; Rakitin, O. A.; Godovikova, T. I.;
Strelenko, Yu. A.; Dubovitskii, F. I.; Khmel’nitskii, L. I.
Bull. Acad. Sci. USSR Div. Chem. Sci. 1988, 37, 1282; Izv.
Akad. Nauk SSSR Ser. Khim. 1988, 6, 1447–1448.
10. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
11. Cooke, G.; de Cremier, H. A.; Rotello, V. M.; Tarbit,
B.; Vanderstraeten, P. E. Tetrahedron 2001, 57, 2787–
2789.
12. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 50, 4467–4470.
13. (a) Menicagli, R.; Samaritani, S.; Gori, S. Tetrahedron
Lett. 1999, 40, 8419–8422; (b) Samaritani, S.; Menicagli,
R. Tetrahedron 2002, 58, 1381–1386.
1. (a) Coon, M.; Ball, A.; Pound, J.; Ap, S.; Hollenback, D.;
White, T.; Tulinsky, J.; Bonham, L.; Morrison, D. K.;
Finney, R.; Singer, J. W. Mol. Cancer Ther. 2003, 2, 1067–
1078; (b) Moon, H.-S.; Jacobson, E. M.; Khersonsky, S.
M.; Luzung, M. R.; Walsh, D. P.; Xiong, W.; Lee, J. W.;
Parikh, P. B.; Lam, J. C.; Kang, T.-W.; Rosania, G. R.;
Schier, A. F.; Chang, Y.-T. J. Am. Chem. Soc. 2002, 124,
11608–11609; (c) Baindur, N.; Chadha, N.; Brandt, B. M.;
Asgari, D.; Patch, R. J.; Schalk-HiHi, C.; Carver, T. E.;
Petrounia, I. P.; Baumann, C. A.; Ott, H.; Manthey, C.;
Springer, B. A.; Player, M. R. J. Med. Chem. 2005, 48,
1717–1720; (d) Whitten, J. P.; Xie, Y. F.; Erickson, P. E.;
Webb, T. R.; De Souza, E. B.; Grigoriadis, D. E.;
McCarthy, J. R. J. Med. Chem. 2002, 39, 4354–4357; (e)
Tanabe, A.; Kawata, K. Anal. Sci. 2004, 20, 227–230.
14. (a) Menicagli, R.; Samaritani, S.; Zucchelli, V. Tetra-
hedron 2000, 56, 9705–9712; (b) Menicagli, R.; Samaritani,
S.; Signore, G.; Vaglini, F.; Dalla Via, L. J. Med. Chem.
2004, 47, 4649–4652.