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J. R. Medina et al. / Tetrahedron Letters 47 (2006) 7363–7365
Table 1.
of the resulting boronic ester with 30% aqueous hydro-
gen peroxide under basic conditions.10,11 However, this
approach is not suitable for the synthesis of compounds
with functionality incompatible with organolithium
reagents, Grignard reagents, and/or the alkaline nature
of the standard oxidation conditions.
1) KOAc, Pd(OAc)2,
bis-(pinacolato)diboron
DMF
Br
OH
N
N
.
2) NaBO3 4H2O
R
N
R
N
THF/H2O
It occurred to us that the Pd catalyzed cross-coupling
reaction of bis-(pinacolato)diboron with arylhalides,
first reported by Miyaura and co-workers12 and subse-
quently modified by Zhang and co-workers,13 could
be a mild and convenient method for the synthesis of
5-pyrimidyl boronic esters. In addition, the use of
sodium perborate as the oxidizing agent is a viable alter-
native to the standard hydrogen peroxide/NaOH oxida-
tion procedure. Since the reagent is mildly basic
(pH ꢀ 9.5), the addition of external base such as sodium
hydroxide is not required.14 Therefore, the synthesis of
2-substituted-5-hydroxypyrimidines with acid or base
sensitive functionality can be accomplished from the
respective 2-substituted-5-bromopyrimidines under very
mild reaction conditions.
Entry
1
Structure (R=)
Yielda (%)
70
N
Boc
N
N
2
48
N
Boc
Boc
N
3b,e
96
62
Boc
Boc
Boc
N
4e
N
Boc
N
Boc
2-Substituted-5-bromopyrimidines were prepared from
commercially available 2-chloro-5-bromopyrimidine by
chloride displacement with the corresponding amines
or thiols. Following the method of Zhang and co-work-
ers, the 5-bromopyrimidines were subjected to a Miya-
ura-type aryl boronate synthesis. After isolation of the
boronic esters, reaction of the crude product with
sodium perborate using the method of Kabalka et al.14
afforded the desired 5-hydroxypyrimidines in good to
excellent yields (Table 1). Arylbromides having elec-
tron-donating groups, such as amines, usually couple
poorly with the diboron reagent under the reaction con-
ditions.13 In contrast, because pyrimidine ring systems
are electron poor relative to their benzene analogs, the
coupling works efficiently even in the presence of
dialkylamines in the 2-position of the pyrimidine ring.
Occasionally, the pyrimidylboronate products were
accompanied by a significant amount of the symmetric
biaryls in the reaction mixture (Table 1, entries 3 and
4), demonstrating the propensity of these pyrimidyl-
boronic esters to undergo Suzuki coupling under these
mild reaction conditions. Increasing the amount of bis-
(pinacolato)diboron to 3 equiv relative to the starting
bromide minimizes the biaryl formation. The presence
of relatively acidic protons was not tolerated in our sys-
tems, as observed in example 5 (Table 1) in which a sig-
nificant amount of reduction by-product (42%) was
obtained.
5
33c
N
H
6
7
48
S
61d
F3C
S
a Un-optimized; isolated yields.
b This compound was not made by chloride displacement; instead it
was made by di-protecting the commercially available 2-amino-5-
bromopyrimidine.
c The starting material was recovered in 13% yield and the corre-
sponding product where the starting bromide had been reduced to H
was obtained in 42% yield.
d The starting material was recovered in 31% yield.
e 3 equiv of bis-(pinacolato)diboron reagent were required.
2. Representative procedure (Table 1, entry 1)
(1,1-Dimethylethyl) [1-(5-bromo-2-pyrimidinyl)-3-aze-
tidinyl]methylcarbamate (94 mg, 0.27 mmol), bis-(pina-
colato)diboron (77 mg, 0.30 mmol), potassium acetate
(81 mg, 0.82 mmol), and palladium acetate (2 mg,
0.003 mmol) were combined in a single necked round
bottomed flask sealed with a rubber septum. The flask
was flushed with nitrogen gas for 15 min. DMF
(1 mL) was added and the reaction mixture was heated
to 85 ꢁC overnight. The dark suspension was diluted
with water and extracted (3·) with ethyl acetate. The
combined organic layers were washed with water and
brine, dried over magnesium sulfate, filtered, concen-
trated, and further dried in vacuo. The dark oil was dis-
solved in THF (2 mL) and water (2 mL). Sodium
perborate tetrahydrate (105 mg, 0.69 mmol) was added
and the reaction mixture was stirred overnight. Satu-
rated aqueous ammonium chloride solution was added
and the aqueous layer was extracted twice with ethyl
acetate. The combined organic layers were washed with
In conclusion, we have shown that the synthesis of 5-
hydroxypyrimidines can be accomplished through the
combination of the Pd catalyzed cross-coupling reaction
of bis-(pinacolato)diboron with 5-bromopyrimidines
followed by sodium perborate oxidation. It is a mild
and practical method that avoids the use of strong acids
or bases while providing the desired products in good
yields. We believe, this methodology could be applied
to other heterocyclic systems, especially those possessing
functionalities which are incompatible with metal/halo-
gen exchange processes.15
Medina, Jesus R.
