Arylation of Halogenated Pyrimidines
J . Org. Chem., Vol. 66, No. 21, 2001 7127
The trichloropyrimidine 8a was treated with one
equivalent of 7 in the glyme/water solvent system using
Pd(OAc)2/PPh3 as catalyst. (Scheme 3) A dramatic im-
provement in selectivity was achieved as 2,4-dichloro-6-
phenylpyrimidine 17 was isolated in 88% yield, accom-
panied by small amounts of the di- and trisubstituted
products. Interestingly, the selectivity of the coupling led
almost exclusively to the 4-substituted isomer. 13C NMR
could readily confirm the position of substitution, where
the spectrum showed four distinct carbons for the pyri-
midine ring indicative of an unsymmetrical substitution
pattern. The 2-phenyl derivative would exhibit only three
signals in the 13C NMR spectrum for the pyrimidine ring.
When 8a was treated with 2 equiv of 7 under similar
conditions only the 4,6-disubstituted product 18 was
isolated in high yield (88%). This product arises by a
subsequent substitution of the 4-phenyl derivative 17 at
position 6 rather than at position 2. This result, in
addition to our earlier report with substitution of chlorine
by phenoxide anions,8b continues a growing list of un-
usual substitution patterns. Previous work by us8a and
others13 describes a more statistical ratio of 4-substitution
vs 2-substitution when small anionic or neutral nucleo-
philes are employed.
mercially, as well as less costly, this pathway is quite
desirable. We are currently examining the scope of the
Suzuki coupling reaction using substituted phenylboronic
acids.
Exp er im en ta l Section
Gen er a l. Melting points were measured in open capillary
tubes and are uncorrected. Proton and carbon magnetic
1
resonance spectra were recorded at 300 MHz for H NMR and
75 MHz for 13C NMR using DMSO-d6 or CDCl3 containing
tetramethylsilane as an internal standard. Reactions were
monitored by thin-layer chromatography on silica gel contain-
ing fluorescent indicator using various combinations of hexane/
ethyl acetate or chloroform/methanol as eluant. The plates
used were Eastman Kodak. All mass spectral data were
obtained by means of direct insertion probe (DIP) methods.
Elemental analyses were performed by Galbraith Laboratories
of Knoxville, Tennessee. Chemicals and reagents were pur-
chased from Fisher or Aldrich Chemical Companies and were
used without further purification.
2,4,6-Tr iiod op yr im id in e (8b). A 100 mL round-bottom
flask was charged with 2,4,6-trichloropyrimidine 8a (5.0 g, 27.3
mmol) and 40 mL of HI as a 57% solution in water. The orange-
colored bi-phasic system eventually changed to a thick, light
orange slurry. After stirring overnight, the slurry was diluted
with water, cooled in an ice/water bath and filtered. The
resulting solid was washed well with cold water and dried to
yield the crude product (11.3 g, 24.7 mmol, 90% yield) as a
cream solid. The crude material was recrystallized from
hexane to yield pure 8b as ivory-colored needles, mp 203-
Treatment of 8a with a slight excess of 3 equiv of 7
under identical conditions afforded the triphenyl deriva-
tive 12 in 93% yield.
Although aryl fluorides are very unreactive toward
oxidative addition of palladium, we were curious as to
whether the electron-deficient pyrimidine ring coupled
with the strong electron-withdrawing effect of fluorine
would allow 2,4,6-trifluoropyrimidine 8c to function as
a suitable partner in a Suzuki coupling process. Unfor-
tunately, when 8c was treated in a manner similar to
the other halogenated pyrimidines no arylation was
observed. The major reaction appeared to be hydrolysis
of one or more of the fluorine substituents under the
relatively forcing conditions employed. We did not pursue
further attempts to obtain the desired Suzuki coupled
products since the chloro compound gave a satisfactory
synthetic method for arylation of the pyrimidine ring.
1
205 °C (7.9 g, 70% recovery, 63% yield); H NMR (DMSO-d6)
δ 8.3 (s, 1H); 13C NMR (DMSO-d6) δ 127.2, 130.1, 141.6; MS
(DIP) m/z 458 (M+, 100), 331 (M-127, 80). Anal. Calcd for C4-
HN2I3: C, 10.50; H, 0.22; N, 6.12. Found: C, 10.59; H, <0.5;
N, 6.13.
2,4,6-Tr ip h en ylp yr im id in e (12) a n d 4,6-d ip h en yl-2-
iod op yr im id in e (11). To a solution of 1.0 g (2.2 mmol) of
2,4,6-triiodopyrimidine 8b in glyme was added phenylboronic
acid 7 (0.28 g, 2.3 mmol) and aqueous sodium carbonate (0.72
g, 6.8 mmol). Palladium acetate (2.5 mol %) and tri-
phenylphosphine (5.0 mol %) were used to generate the
catalyst. The reaction was heated to reflux for 48 h. Following
workup, the residue was chromatographed using a hexane/
ethyl acetate gradient as the mobile phase. The first fraction
(110.3 mg, 16%) was 12; mp 184-186 °C.14
The second fraction was identified as 11 (87.0 mg, 11%);
1
Con clu sion s
mp 148-150 °C; H NMR (CDCl3) δ 7.5 (m, 6H), 8.0 (s, 1H),
8.1 (m, 4H); 13C NMR (CDCl3) δ 111.7, 127.3, 128.3, 131.5,
135.5, 166.3, 167.6; MS (DIP) m/z 358 (M+, 30), 231 (M-127,
100). Anal.Calcd. for C16H11N2I: C, 53.65; H, 3.10; N, 7.82.
Found: C, 54.08; H, 3.22; N, 7.74.
We have synthesized or purchased a series of haloge-
nated pyrimidines and subjected them to the conditions
normally employed for Suzuki coupling reactions and
obtained C-phenyl pyrimidines. Due to the electron-
deficient nature of the pyrimidine ring, the typical iodo
and bromo substrates proved to be too reactive to exhibit
good selectivity where two or more halogens are present
on the pyrimidine. The fluorinated pyrimidine, on the
other hand, was completely unreactive toward coupling
under comparable conditions. The observations that the
halogen atoms (I, Br, Cl) attached at C-2 were replaced
last provides a clear order of reactivity, namely position
4 > position 6 > position 2. The chloro pyrimidines proved
to be excellent precursors for the synthesis of specific
C-aryl pyrimidines in very good yields. Furthermore,
since chloro compounds tend to be more available com-
The reaction was repeated using the less active Pd(PPh3)4
catalyst. Two fractions were obtained using the same workup
as described above. The first fraction (109.8 mg, 16%) was
again 12. The second fraction (83.5 mg, 11%) was 11.
2,4-Diiod op yr im id in e (9b). A 25 mL round-bottom flask
was charged with 0.50 g (3.34 mmol) of 2,4-dichloropyrimidine
9a . Hydrogen iodide (15 mL as a 57% solution in water) was
added and the slurry stirred overnight at room temperature.
The reaction mixture was neutralized carefully with cooling
using 10% sodium hydroxide. The resulting gold-colored solid
was filtered and washed with cold water (0.91 g, 82% yield).
A second crop (0.10 g, 9% yield) was also obtained. mp 125-
126 °C.15
2-Iod o-4-p h en ylp yr im id in e (13a ) a n d 2,4-Dip h en ylp y-
r im id in e (14). A 25 mL round-bottom flask was charged with
321.8 mg (0.97 mmol) of 2,4-diiodopyrimidine 9b, 130.0 mg
(1.07 mmol, 1.1 equivalent) of phenylboronic acid 7, 318.0 mg
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J . M.; Hall, E. D.; Houser, D. J .; Krook, M. A.; Runge, T. A. J . Med.
Chem. 1990, 27, 1145. (d) Mossini, F.; Maggiali, C.; Morini, G.;
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Asahina, Y.; Kuroda, K. Ber. Dtsch. Chem. Ges. 1914, 47, 1815.
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