excess amount of phosphoric acid was used and the reaction
temperature was very high. Therefore, we investigated a
method for synthesizing phosphate monoesters by the direct
condensation of equimolar amounts of phosphoric acid and
alcohols.
We first investigated the reaction of equimolar amounts
of 4-phenyl-1-butanol (1) and phosphoric acid in the presence
of Bu3N (1 equiv) in various solvents (Table 1). Reactions
DMF, probably due to the increase in the reaction temper-
ature and the polarity of the solvent (entries 1, 2, 7, and 8).
Therefore, we decided to use a 1:1 (v/v) mixture of DMF
and nitroethane as the reaction solvent.
Next, we investigated the reaction of alcohol 1 with
phosphoric acid in the presence of various tertiary amines
(Table 2). Tertiary amines and phosphoric acid form am-
Table 2. Effects of Tertiary Amines on the Reaction of 1 with
a
Table 1. Optimization of the Solvents in the Reaction of 1
with H3PO4
H3PO4
a
entry
tertiary amine
none
Bu3N
Bu3N
Bu3N
Et3N
(n-C6H13)3N
(n-C8H17)3N
Me2NC8H17
(i-Pr)2N(3-pentyl)
equiv
conv (%)b
entry
solvent
bp (°C)
conv (%)b
1
2
3
4
5
6
7
8
9
0
0.5
1
2
1
1
1
1
1
8
36
58
55
37
62
60
45
44
1
2
3
4
5
6
7
8
9
DMF
EtNO2
MeNO2
i-PrCN
EtCN
o-xylene
DMF-EtNO2 (1:1)
DMF-EtNO2 (1:3)
DMF-o-xylene (1:1)
153
114
101
107
97
70
21
1
0
0
144
9
58
40
20
a Reactions were carried out with 2 mmol of 1 and 2 mmol of H3PO4 in
4 mL of DMF-EtNO2 (1:1) at azeotropic reflux with the removal of water
a Reactions were carried out with 2 mmol of 1, H3PO4 and Bu3N in 4
1
using MS 3A for 6 h. b Determined by RP-HPLC and H NMR.
mL of solvents at azeotropic reflux with the removal of water using MS
3A for 6 h. b Determined by RP-HPLC and H NMR.
1
monium phosphates. Lipophilic tertiary amines make phos-
phoric acid soluble in the solvent. The reaction in the absence
of tertiary amine afforded phosphate monoester 2 in 8% yield
(entry 1). The yield of 2 increased as the amount of Bu3N
increased (entries 1-3) and reached a plateau at 55-58%
when the reaction was conducted with more than 1 equiv of
Bu3N (entries 3 and 4). Triethylamine, which is a less
lipophilic tertiary amine than Bu3N, provided 2 in 37% yield
(entry 5), while tertiary amines such as trihexylamine and
trioctylamine, which were more lipophilic than Bu3N, gave
results similar to those with Bu3N (entries 6 and 7). Sterically
less hindered N,N-dimethyloctylamine and more hindered
N,N-diisopropyl-3-pentylamine provided 2 in respective
yields of 45 and 44% (entries 9 and 10). Therefore, we
decided to use 1 equiv of tributylamine as the tertiary amine.
We next examined catalysts for the reaction of alcohol 1
with phosphoric acid (Table 3). An extensive screening of
catalysts (10 mol %) showed that some nucleophilic bases
promoted the reaction. N-Methylimidazole (3a), 4-(N,N-
dimethylamino)pyridine (DMAP, 4a), and 4-pyrrolidinopyr-
idine (4b), which are known to be good nucleophilic
catalysts, slightly promoted the reaction and gave 2 in
respective yields of 63, 60, and 64% (entry 1 versus entries
2, 6, and 7). More lipophilic nucleophiles, including N-
butylimidazole (3b), N-phenylimidazole (3c), 4-(N,N-dibu-
tylamino)pyridine (4c), and 4-(N-hexyl-N-methyl)pyridine
(4d) showed better catalytic activities and gave 2 in respec-
tive yields of 67, 68, 67, and 69% because of the good
solubility in the reaction mixture (entries 3, 4, 8, and 9).
were conducted for 6 h under azeotropic reflux with the
removal of water (molecular sieves 3A in a Soxhlet thimble).
Based on the solubility of phosphoric acid, aprotic polar
solvents such as amides, nitroalkanes, and nitriles were
thought to be suitable for the reaction.2 DMF provided
phosphate monoester 2 in 70% yield (entry 1). When the
reaction was carried out in nitroethane (bp 114 °C), 2 was
obtained in 21% yield (entry 2). Nitromethane (bp 101 °C),
isobutyronitrile (bp 107 °C), and propionitrile (bp 97 °C)
provided 2 in <1% yield (entries 3-5). On the other hand,
a nonpolar solvent like o-xylene (bp 144 °C) provided 2 in
9% yield because of the low solubility of phosphoric acid
in o-xylene (entry 6). Our results showed that DMF was the
best solvent for the reaction. However, over a prolonged
reaction time, DMF decomposed slightly at its boiling point.
We therefore investigated the reaction in a mixed-solvent
system to lower the reaction temperature and to dehydrate
under azeotropic reflux conditions more efficiently. We
examined various lower boiling point solvents mixed with
DMF and found that a 1:1 (v/v) mixture of DMF-nitroethane
was effective, giving 2 in 58% yield (entry 7 versus entry
9). The yield of 2 increased in proportion to the amount of
(2) Honjo, M.; Furukawa, Y.; Kobayashi, K. Chem. Pharm. Bull. 1966,
14, 1061.
(3) Although the 5′-monophosphate of 2′,3′-O-isopropylidene uridine (9)
has been synthesized in 58% yield using the method of ref 2, 2′,3′-O-
isopropylidene adenosine (10), cytidine (11), and guanosine (12), which
are thermally unstable, have been converted to their 5′-monophosphates in
respective yields of 38, 39, and 46%.
2000
Org. Lett., Vol. 7, No. 10, 2005