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The removal of boron-containing impurities requires oxidation of
the crude reaction mixture with H2O2. A neutral medium, such as
MeOH, at ambient temperature is sufficient for this purpose. The
oxidation of the boron-containing byproducts generates 2 equiv
cyclohexanol (b.p. 160–1618C) and an equivalent of boric acid.
Boric acid is easily removed by washing with aqueous acid or by
directly applying the concentrated reaction product to a silica-gel
column. The latter method can also be used to remove cyclohexa-
nol, which can also be removed by heating gently under high
vacuum (<0.1 torr) for a few minutes. If the oxidation step is not
conducted, the borinic acid side-products decompose during chro-
matography to give boron-containing impurities that tend to co-
elute with the desired product.
Scheme 7. Rationale for the unreactivity of acetates.
Methylation of the crude acid product with CH2N2 requires prior
workup and oxidation, along with a final aqueous wash to remove
boric acid. The omission of any of these steps gives rise to situa-
tions in which even a large excess of CH2N2 fails to effect methyla-
tion to any significant extent. This being said, methylation is not
required for efficient purification of these products provided that
a small amount of acetic acid is added to the eluent during chro-
matography.
Conclusion
Overall, our results suggest that the Ireland–Claisen rearrange-
ment of boron ketene acetals holds promise as a synthetically
applicable method. The nonbasic nature of the conditions for
promoting ketene acetal formation, as well as the generally
high levels of observed stereoselectivity, suggest that it should
prove to be a viable alternative to existing methods of pro-
moting this useful rearrangement.
Example procedure for optimization experiments using
cHx2BI
A solution of geranyl propionate (1, 52.6 mg, 0.250 mmol), an inter-
nal standard of 4,4’-di-tert-butylbiphenyl (8.3 mg, 0.0313 mmol),
and the appropriate base in the appropriate solvent was cooled to
ꢀ788C. To this solution was added cHx2BI (63 mL, 0.275 mmol)
dropwise. The solution was stirred at ꢀ788C for 1 h, allowed to
warm to room temperature, and stirred an additional 20 h. The re-
action was quenched by being poured into 4:1 sat. aq. NH4Cl/1m
Na2SO3 (25 mL) then acidified to pH 1 with 2m aq. HCl. This mix-
ture was extracted with Et2O (3ꢁ10 mL). The combined organic ex-
tracts were washed with brine (25 mL), dried with MgSO4, and con-
centrated. The resulting material was dissolved in CDCl3 (3.0 mL)
and analyzed by 1H NMR spectroscopy (300 MHz, 10 s relaxation
delay). The NMR spectrum was phase and baseline corrected. The
diastereoselectivity of the reaction was determined by the ratio of
the integrals of the peak centered at d=5.87 (dd, J=17.4, 10.8 Hz,
1H, major diastereomer) and 5.68 ppm (dd, J=11.0, 17.5 Hz, 1H,
minor diastereomer). The yield of the reaction was determined by
the ratio of the sum of the integrals of these two peaks to the inte-
gral of the aromatic protons of 4,4’-di-tert-butylbiphenyl at d=7.52
(ddd, J=8.5, 2.2, 1.9 Hz, 4H) and 7.44 ppm (ddd, J=8.5, 2.5, 1.7 Hz,
4H).
Experimental Section
Notes on handling cHx2BI
Dicyclohexyliodoborane, the borane reagent used for most of this
work, is a very water and oxygen sensitive compound that must at
all times be handled and stored under an inert atmosphere. The
pure reagent is a clear, colorless liquid at room temperature. Mate-
rial kept in septum-capped bottles, either neat or in solution, dis-
colors on the order of days to weeks, and strongly colored reagent
gives inferior results. After careful experimentation, we found the
following protocol to be useful: after synthesis of the reagent by
the method of Brown,[8] the crude material was distilled into
a Schlenk flask. On completion of the distillation, the product con-
taining flask was stoppered under an Ar purge and immediately
evacuated. The flask was taken into an N2 atmosphere glove-box,
transferred to a brown glass bottle, and stored at room tempera-
ture. Material stored in this way showed no evidence of decompo-
sition after several months had elapsed. The reagent was removed
from the glove-box in a syringe as needed and added to a reaction
mixture or diluted with hexanes to make a stock solution that was
used immediately.
General procedure A: rearrangement in CH2Cl2
To a stirred solution of the starting ester in CH2Cl2 (0.10m) was
added Et3N (5 equiv), and the solution was cooled to ꢀ788C. Neat
cHx2BI (1.1 equiv) was added dropwise, giving a cloudy colorless or
pale yellow solution. This solution was stirred at ꢀ788C for 1 h and
then allowed to warm to ambient temperature. The reaction was
stirred at room temperature until the starting ester was completely
consumed by TLC (eluent typically 19:1 hexanes/ethyl acetate,
KMnO4 stain solution) or until the reaction had ceased to progress
further, as judged qualitatively by TLC, to a maximum reaction
time of 24 h. The reaction was then quenched by being poured
into 4:1 sat. NH4Cl/1.0m Na2SO3, and the mixture was acidified
(pH 1) with 2m aq. HCl. The biphasic mixture was then extracted
with three portions of Et2O or EtOAc. The combined organic ex-
tracts were then washed with brine, dried with Na2SO4 and con-
centrated. The resulting residue was dissolved in MeOH (0.1m) and
Notes on workup and removal of boron-containing products
Once the crude reaction mixture is exposed to water, which imme-
diately hydrolyzes the acyloxyborane product, the free carboxylic
acid is generally sensitive to iodolactonization, which can occur
readily when the iodide containing reaction mixture is exposed to
air. Therefore, it is important to quench the reaction mixture with
a solution capable of reducing any free I2 to Iꢀ. We favored acidic
Na2SO3 for this purpose because the more commonly used
Na2S2O3 decomposes to insoluble S8 under the acidic conditions
necessary for carboxylic acid products to partition into the organic
layer.
Chem. Eur. J. 2014, 20, 4460 – 4468
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