Table 1. THP benzene boronic acid stabilitya
1
week stability (area %)
2 week stability (area %)
THP benzene boronic acid
THP BBA)
THP BBA
(Rt∼12.3 min)
decomposition product
THP BBA
(Rt∼12.3 min)
decomposition product
(
(Rt∼3.9 min)
(Rt∼3.9 min)
room temperature
98.8
98.2
3.2
0.6
1.1
76.2
98.5
97.5
57.8
0.7
2.0
40.4
4
6
0 °C
0 °C
a
The results show the level of decomposition product in the 60 °C stability samples is lower at 2 weeks than at 1 week. This indicates decomposition is not constant
and may be localised depending on the homogeneity, and local storage conditions of the sample.
product. It is possible for the boronic acid to eliminate water
on heating, forming anhydrides. The water thus generated
in the presence of the boronic acid functionality can provide
a pH low enough to remove the THP-protecting group. It
was found necessary to dry the organic extract over
magnesium sulfate before concentration for this reason. The
stability of the solid isolated product was measured as a
function of time and temperature as shown in Table 1.
At this point we decided to replace the triisopropyl borate
mixture stirred vigorously for 2 h. The mixture was separated
and the organic phase transferred to a 5 L flask fitted for
distillation. The flask was heated under a nitrogen atmo-
sphere, and 2 L of solvent was distilled at 40 °C. Absolute
ethanol (3 L) was added, and distillation was continued. After
a further 1 L of solvent had been removed, more absolute
ethanol was added (500 mL). Distillation and solvent addition
was continued until the head temperature reached 78 °C;
this required another 500 mL of absolute ethanol. The
mixture was cooled to room temperature, with stirring,
overnight. The cold solution was seeded (370 mg) whilst
stirring, and an exothermic crystallisation began that was
moderated by ice-cooling. When the temperature of the
mixture reached 4 °C, the product was vacuum-filtered and
washed with absolute ethanol (1 L). The crystalline product
was dried in a vacuum oven to give the title compound (1.225
2
with the trimethyl borate as used in the literature whilst
keeping the temperature cold (-70 °C). An improved yield
of 83% was achieved on 40 g scale. In addition it was noticed
that the hydrolysis of the boronic acid methyl ester groups
was much quicker than that for the isopropyl esters. Careful
concentration in vacuo without over-heating followed by the
ether:isohexane slurry, to remove the UV active impurity,
also helped to increase this yield.
The use of low temperature was ultimately found to be
unnecessary, and the reaction could be carried out at 0 °C.
Finally, the slurry solvent was changed from the highly
volatile ether:isohexane mixture to ethyl acetate:isooctane
which could be used more safely in a pilot plant.
2
1
kg, 80%): mp 53.5-56.5 °C (lit. mp 51-53 °C); H NMR
(300 MHz, CDCl ) δ 7.37 (dt, 2H), 6.94 (dt, 2H), 5.37 (t,
3
1H), 3.87 (td, 1H), 3.65-3.55 (m, 1H), 2.1-1.9 (m, 1H),
1.9-1.8 (m, 2H), 1.8-1.5 (m, 3H).
[4-(2-(2H)-Tetrahydropyranyloxy)phenyl]boronic acid
(1). Dry tetrahydrofuran (700 mL) was added to bromide 2
(400 g, 1.56mol). As the solid dissolved, the temperature
fell from 20 °C to 7 °C and generated approximately 1 L of
solution.
Experimental Section
General. Melting points were recorded on a capillary
melting point apparatus and are uncorrected. H NMR spectra
1
Magnesium metal turnings (38 g, 1.58mol) and dry
tetrahydrofuran (100 mL) followed by three crystals of iodine
were added, under a nitrogen atmosphere, to a 2 L flask fitted
with a condenser. After the solution stirred at room temper-
ature for 1 min, a portion ( ∼100 mL) of the bromide 2
solution was added. After 5 min the reaction initiated, and
within a further 5 min it reached reflux. At this point the
reaction frothed vigorously for 5 min. When the frothing
had ceased, the remainder of the bromide 2 solution was
added in 20-40 mL portions over 35 min. After complete
addition the solution was kept at reflux for 1 h and then
were recorded on a Bruker 300 MHz instrument. Chemical
1
shifts for H NMR are reported in ppm downfield relative
to TMS as an internal standard in CDCl
Reactions were monitored by HPLC analysis.
-(4-Bromophenoxy)-(2H)-tetrahydropyran (2). 4-Bro-
3 6
or DMSO-d .
6
7
2
mophenol (1.025 kg, 5.92 mol) and dichloromethane (2.5
L) were added to a 10 L flask fitted with a condenser, and
the mixture stirred under a nitrogen atmosphere; the tem-
perature fell to 6 °C as the 4-bromophenol dissolved. 3,4-
Dihydro-2H-pyran (580 mL, 6.85 mol) was added in one
portion, and the temperature rose to 14 °C. Pyridinium
p-toluenesulfonate (10.0 g, 40 mmol) was added in one
portion, and the temperature rose to reflux within 10 min.
After a further 10 min the temperature began to slowly fall,
and the mixture was left to stir for 19 h. A solution of
aqueous sodium hydroxide (2 M, 1 L) was added, and the
8
cooled to 35 °C.
Tetrahydrofuran (1 L) and trimethyl borate (500 mL,
4
.46mol) were added, under a nitrogen atmosphere, to a 10
L flask. The solution was initially cooled to -14 °C and the
Grignard reagent then added over 30 min at 0 °C (( 5 °C);
a gray-white precipitate formed. After the resulting suspen-
sion stirred for 40 min at 0 °C (( 5 °C), a solution of aqueous
ammonium chloride (10%, 2.5 L) was added, and the
(6) Details are available in the Supporting Information.
(
7) Synthesis of this compound is unoptimised. The order of addition of the
reactants would have to be addressed on a larger scale to avoid uncontrolled
exotherms. This could be done by slow addition of 3,4-dihydro-2H-pyran
to a solution of phenol and catalyst.
(8) The Grignard reagent does not deteriorate after 24 h standing at room
temperature although it does partly precipitate from solution at the
concentration used.
154
•
Vol. 4, No. 3, 2000 / Organic Process Research & Development
Cladingboel, David E.
