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B. Zhou et al. / Tetrahedron Letters 46 (2005) 3977–3979
2
For demonstration purposes, phenyl boronic acid was
N
N
N
N
employed to complete the second Suzuki coupling under
the same condition described earlier. The desired selec-
tively substituted 4,6-diarylpyrimidine 11 was thus
obtained.
a
6
4
Cl
Cl
OMe
Cl
2
1
b
In summary, we have illustrated a general, versatile, and
high yielding method for synthesis of unsymmetrical 4,6-
diarylpyrimidines. Starting with 4,6-dichloropyrim-
idine, we have selectively masked the reactivity of one
of the chloro group by displacing it with a methoxyl
group. After introduction of the first aryl substituent by
Suzuki reaction, the reactivity of the pyrimidine ring is re-
stored by replacing the methoxyl group with a chloro
group. The second Suzuki reaction completes the synthe-
sis of the diarylpyrimidine in good to excellent overall
yields.
N
N
OMe
R
3 R=H, 90%
4 R=p-OMe, 80%
8 R=o, m-diF, 85%
9 R=m-NO2, 86%
10 R=5-pyrimidine, 77%
11 R=2-thiophen, 79%
12 R=2-furan, 81%
5 R=m-COOMe, 64%
6 R=m-F, 84%
7R= p-F, 91%
Scheme 1. Reagents and conditions: (a) 1equiv NaOMe (25%w/w in
MeOH), MeOH, rt, 10 min, 95%; (b) 1.4 equiv aryl-B(OH)2, 0.1equiv
Pd(PPh3)4, 2 equiv Na2CO3, toluene, 90 °C, 12 h.
Acknowledgements
We wish to thank Medicinal Chemistry Department at
Merck for the generous support, and Dr. Prasun K.
Chakravarty and Dr. Patrick Shao for their invaluable
discussion and advice.
Once the desymmetrization of 4,6-dichloropyrimidine
was accomplished, the remaining chlorine atom was uti-
lized to introduce the desired aromatic groups. The aryl-
ation of chloropyrimidines via Suzuki cross-coupling
reaction have been explored and documented.9 Among
many widely used methods, Pd(PPh3)4 mediated condi-
tion is known to be the most efficient and highest yield-
ing. Therefore, the coupling reactions were carried
out in toluene at 90 °C in the presence of 0.1equiv of
Pd(PPh3)4 and excess of 2 N Na2CO3 for 12 hours. As
shown in Scheme 1, all the examples including both
electron rich and deficient phenyl analogs, as well as
the heterocyclic analogs gave very good yields.10
References and notes
1. (a) Guan, A. W. Proc. Natl. Acad. Sci. 1992, 89, 11456; (b)
Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic
Chemistry: Tetrahedron Organic Chemistry series; Perg-
mon: Amsterdam, 2000; Vol. 20.
2. Pinner, E. L. Ber. 1893, 26, 2122.
3. Dodson, R. M.; Seyler, J. K. J. Org. Chem. 1952, 16, 461.
4. Muller, T. J. J.; Braun, R. Org. Lett. 2000, 2, 1967.
5. Goodman, A. J.; Stanforth, P. S.; Tarbit, B. Tetrahedron
1999, 55, 15067.
6. Schomaker, J. M.; Delia, T. J. J. Org. Chem. 2001, 66,
7125.
At this stage, the masked methoxyl group was converted
back to chloride by the treatment of HBr–AcOH and
POCl311 (see Scheme 2). It is worth noting that the con-
ditions used to restore the chloride are mild enough to
leave the methoxy group on the phenyl ring untouched.
In addition, this high yielding two-step sequence re-
quires no further purification since the aqueous work
up (saturated sodium bicarbonate, then brine) is suffi-
cient to provide fairly pure products (determined by
7. General procedure: To a stirred solution of 4,6-dichloro-
pyrimidine (2 g, 13.4 mmol) in anhydrous methanol
(20 mL) at room temperature was added a solution of
NaOMe (3.1mL, 25 w/w, 13.4 mmol). The sodium chlo-
ride precipitate was formed immediately. The resulting
white suspension was refluxed for 30 min. After cooling
down to room temperature, the reaction mixture was
concentrated and diluted with ether and filtered through a
CeliteÒ pad. The filtrate was concentrated to give a white
1
TLC, LCMS, and H NMR).
1
solid (1.8 g, 93%). H NMR (CDCl3, 500 MHz) d 8.54 (s,
1H), 6.73 (s, 1H), 3.96 (s, 3H); LC–MS m/z [M++1] 144.9.
8. Shepherd, R. G.; Taft, W. E.; Krazinski, H. M. J. Org.
Chem. 1961, 26, 2764.
N
N
N
N
N
NH
a
b
OMe
O
9. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457;
(b) Cooke, G.; Cremiers, H. A.; Rotello, V. M.; Tarbit, B.;
Vanderstraeten, P. E. Tetrahedron 2001, 57, 2787; (c)
Qing, F.-L.; Wang, R.; Li, B.; Zheng, X.; Meng, W.-D.
J. Fluro. Chem. 2003, 120, 21 .
10. General procedure: To a stirred solution of 4-chloro-6-
methoxypyrimidine (0.94 g, 6.5 mmol) in n-PrOH (20 mL)
at room temperature was added phenylboronic acid (1.1 g,
9.1mmol), Pd(PPh 3)4 (0.75 g, 0.65 mmol), and aqueous
Na2CO3 (9.75 mL, 2 N, 19.5 mmol). The resulting dark
suspension was stirred at 90 °C for 14 h. After cooling
down to room temperature, the reaction mixture was
concentrated and diluted with ethyl acetate and filtered
through a CeliteÒ pad. The filtrate was washed with
MeO
MeO
MeO
4
9
N
N
c
Cl
MeO
10
11
Scheme 2. Reagents and conditions: (a) HBr–AcOH (1:3), 80 °C, 1h,
then satd NaHCO3; (b) POCl3, 30 m, 1 00°C, then satd NaHCO3, 90%
over two steps; (c) 1.4 equiv PhB(OH)2, 0.1equiv Pd(PPh 3)4, 2 equiv
Na2CO3, toluene, 90 °C, 12 h, 80%.