LETTER
Regioselective Synthesis of Trisubstituted Pyrimidines
863
18
The availability of remaining halogen substituents al- palladacycle 7 and Pd(t-Bu3P)2 showed reasonable
lowed for further functionalisation of the pyrimidine levels of activity. Bedford catalyst 7 was subsequently
nucleus. For example, the regioisomeric pair of 4-meth- employed for Suzuki reactions of 15 (entries 4–7), which
oxyphenyl-substituted chloropyrimidines 8 and 15 could gave rise to fully functionalised compounds 24–26 in low
be readily transformed to the fully trisubstituted materials to moderate yields. The use of microwave heating for high
by further palladium-catalysed coupling. Suzuki reactions temperature reactions led to a modest improvement in the
of 8 using the Bedford catalyst 7 provided 21–23 in good yield of 24 (entry 5).
yields (Table 2, entries 1–3). The nature of the boron
In summary, we have explored a simple and flexible ap-
coupling partner and catalyst were critical for efficient
proach to the regioselective preparation of trisubstituted
coupling in the 3-pyridyl case. A series of low yielding
pyrimidines. This makes use of the predicted reactivity
reactions using boronic acid and cyclic boronate ester de-
profile of the polyhalopyrimidine precursors to achieve
rivatives eventually resulted in a much improved 60%
selective sequential transformations. These reactions
yield when diethyl-3-pyridylborane was employed as the
were shown to be of broad scope by using a variety of aryl
coupling partner (entry 3). Stille couplings using 8 and
and heteroaryl boronic acid derivatives. Further studies on
the application of these findings are ongoing in our
laboratories.
tributylphenyltin were significantly less efficient and
afforded 21 in only 5–12% yield.6
Table 2 Suzuki Coupling of 4-Methoxyphenyl-Substituted Chloro-
pyrimidines 8 and 15
Acknowledgment
This work was supported by Cancer Research UK [CUK] program-
MeO
MeO
me grant number C309/A2187. The provision of summer stu-
dentships by the Institute of Cancer Research (to MC and DMW) is
gratefully acknowledged. We also thank Dr. Alastair Donald and
Dr. Andrew Kalusa for helpful assistance and discussions, and Dr.
Amin Mirza and Mr. Meirion Richards for their help with NMR and
mass spectrometry.
N
N
N
N
Suzuki coupling
N
N
Cl
R2
8
21–23
N
N
N
N
R2
Suzuki coupling
Cl
N
N
References and Notes
(1) Metal-Catalysed Cross-Coupling Reactions, 2nd ed., Vol. 1
and 2; de Meijere, A.; Diederich, F., Eds.; Wiley-VCH:
Weinheim, 2004.
OMe
OMe
15
24–26
(2) (a) Collins, I. J. Chem. Soc., Perkin Trans. 1 2002, 1921.
(b) Collins, I. J. Chem. Soc., Perkin Trans. 1 2000, 2845.
(3) For selected recent examples, see: (a) Witulski, B.; Azcon,
J. R.; Alayrac, C.; Arnautu, A.; Collot, V.; Rault, S.
Synthesis 2005, 771. (b) Bourrain, S.; Ridgill, M.; Collins, I.
Synlett 2004, 795. (c) Gudmundsson, K. S.; Johns, B. A.
Org. Lett. 2003, 5, 1369. (d) Johns, B. A.; Gudmundsson, K.
S.; Turner, E. M.; Allen, S. H.; Jung, D. K.; Sexton, C. J.;
Boyd, F. L.; Peel, M. R. Tetrahedron 2003, 59, 9001.
(4) For an excellent recent review, see: Schröter, S.; Stock, C.;
Bach, T. Tetrahedron 2005, 61, 2245.
(5) For selected recent examples, see: (a) Schröter, S.; Bach, T.
Synlett 2005, 1957. (b) Wu, J.; Zhang, L.; Sun, X. Chem.
Lett. 2005, 34, 550. (c) Comins, D. L.; Nolan, J. M.; Bori, I.
D. Tetrahedron Lett. 2005, 46, 6697. (d) Bookser, B. C.;
Matelich, M. C.; Ollis, K.; Ugarkar, B. G. J. Med. Chem.
2005, 48, 3389.
(6) Solberg, J.; Undheim, K. Acta Chem. Scand. 1989, 43, 62.
(7) Simkovsky, N. M.; Ermann, M.; Roberts, S. M.; Parry, D.
M.; Baxter, A. D. J. Chem. Soc., Perkin Trans. 1 2002, 1847.
(8) Schomaker, J. M.; Delia, T. J. J. Org. Chem. 2001, 66, 7125.
(9) Hughes, G.; Wang, C.; Batsanov, A. S.; Fern, M.; Frank, S.;
Bryce, M. R.; Perepichka, I. F.; Monkman, A. P.; Lyons, B.
P. Org. Biomol. Chem. 2003, 3069.
Entry Substrate R2
Methoda Product and yield (%)b
1
2
3
4
5
6
7
8
8
Ph
A
A
A
A
B
A
A
21, 60
22, 85
23, 60
24, 39d
24, 50
25, 31
26, 43
3-MeOC6H4
3-Pyridylc
Ph
8
15
15
15
15
Ph
3-MeOC6H4
3-OHCC6H4
a Method A: 0.05 equiv 7, 3.0 equiv R2B(OH)2, 2.0 equiv Na2CO3
(aq), DME, reflux, 18 h. Method B: as method A but heating under
microwave conditions, 145 °C, 1 h.
b Yields are unoptimised and refer to isolated materials, homogeneous
by HPLC and NMR analysis.
c Diethyl-3-pyridylborane as coupling partner.
d 54% yield based on recovered starting material.
We anticipated that coupling of chloride 15 would be
more challenging, due to the nature of the sterically hin-
dered benzenoid chlorine atom. For the coupling of 15
with phenylboronic acid, a screen of three catalysts select-
ed for their reactivity with chloroarenes was conducted.
(10) Strekowski, L.; Dworniczak, M.; Kowalewski, A. Pol. J.
Chem. 1980, 54, 1557.
(11) (a) Bedford, R. B.; Cazin, C. S. J. Chem. Commun. 2001,
1540. (b) Bedford, R. B.; Cazin, C. S. J.; Coles, S. J.;
Gelbrich, T.; Horton, P. N.; Hursthouse, M. B.; Light, M. E.
Organometallics 2003, 22, 987.
17
While [Pd(t-Bu3P)Br]2 gave a poor conversion, both
Synlett 2006, No. 6, 861–864 © Thieme Stuttgart · New York