Removal of triphenylphosphine oxide by precipitation with zinc chloride in polar solvents

Article abstract of DOI:10.1021/acs.joc.7b00459

While the use of triphenylphosphine as a reductant is common in organic synthesis, the resulting triphenylphosphine oxide (TPPO) waste can be difficult to separate from the reaction product. While a number of strategies to precipitate TPPO are available, none have been reported to work in more polar solvents. We report here that mixing ZnCl₂ with TPPO precipitates a TPPO?Zn complex in high yield in several common polar organic solvents. The solvent compatibility of this procedure and the reliability of the precipitation in the presence of polar functional groups were examined to show the utility and limitations of this method.

Full text of DOI:10.1021/acs.joc.7b00459

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Removal of Triphenylphosphine Oxide by Precipitation with Zinc
Chloride in Polar Solvents
Donald C. Batesky,† Matthew J. Goldfogel,‡ and Daniel J. Weix*,‡
†Department of Chemistry, University of Rochester, Rochester, New York 14627-0216, United States and
‡Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, United States
S
* Supporting Information
ABSTRACT: While the use of triphenylphosphine as a
reductant is common in organic synthesis, the resulting
triphenylphosphine oxide (TPPO) waste can be difficult to
separate from the reaction product. While a number of
strategies to precipitate TPPO are available, none have been
reported to work in more polar solvents. We report here that
mixing ZnCl2 with TPPO precipitates a TPPO−Zn complex in high yield in several common polar organic solvents. The solvent
compatibility of this procedure and the reliability of the precipitation in the presence of polar functional groups were examined to
show the utility and limitations of this method.
The separation of TPPO byproducts from reaction products
has generally been accomplished by chromatography, but this
can be tedious on a larger scale.1,6 Separation by distillation is
useful for cases where the reaction product is sufficiently stable
and low-boiling,7 but a liquid−liquid or liquid−solid phase
separation would be more generally useful. TPPO can be
precipitated in cases where the reaction product is soluble in
very nonpolar solvents, such as cold hexanes and diethyl ether
mixtures.8 Product precipitation or crystallization is also a
common strategy, but success depends greatly upon the
identity of the product.9
In cases where these strategies cannot be applied, several
groups have described methods to convert TPPO into a more
easily separated species. For example, Lipshutz demonstrated
the removal of TPPO by alkylative trapping on Merrifield
resin,10 and Gilheany described the use of oxalyl chloride to
convert TPPO to triphenylphosphonium chloride, which is
easily precipitated from cyclohexane.11
When direct precipitation cannot be used and reactive
conversion is not possible, addition of a co-crystallization agent
has been employed. TPPO has been demonstrated to co-
crystallize with a wide variety of organic molecules with acidic
protons in nonpolar solvents.12 For example, researchers at
Shin-Etsu Chemical Co. removed TPPO by adding acetic acid
to an n-hexane mixture of product and TPPO to form an
immiscible TPPO−AcOH fluid phase that was separated from
the product solution.13 As another example, chemists at Squibb
found that, in toluene, they could remove TPPO and
diisopropylurea as a 1:1 complex.14
INTRODUCTION
■
Triphenylphosphine is a versatile reagent in organic synthesis;
reactions that use it to reduce functional groups, convert
carbonyls to olefins, or effect substitution of an alcohol for
another nucleophile are among the most common in organic
chemistry.1 In transformations that employ triphenylphosphine
(TPP) as a reductant, the triphenylphosphine is converted to
triphenylphosphine oxide (TPPO). Although in some cases
separation of TPPO from the reaction product is easily
achieved, the difficulty of the separation is often cited as a
barrier to using TPP as a reductant or reagent. This has
inspired research on improved removal methods for TPPO, the
development of alternative phosphines whose oxides are easier
to remove, and reactions that are catalytic in phosphine.
Although substantial progress continues to be made using
insoluble phosphine reagents or catalytic strategies, triphenyl-
phosphine is unlikely to be completely replaced in the near
term. For this reason, additional methods for the removal of
TPPO are still needed. We report here that TPPO is efficiently
precipitated as ZnCl2(TPPO)2 in polar solvents and demon-
strate how this discovery can be used to precipitate TPPO from
reactions that would otherwise require purification by column
chromatography.
BACKGROUND
■
Reports on solutions to the problem of separating triphenyl-
phosphine oxide (TPPO) byproducts in organic reactions fall
into three broad categories: (1) improved methods for TPPO
removal; (2) avoiding TPPO by using alternative phosphines2
with more easily separated phosphine oxides,3 and (3) avoiding
stoichiometric phosphine oxide waste by developing reactions
that are catalytic in phosphine4 or do not require phosphine at
all.5 This report is focused on methods of TPPO removal, so
strategies (2) and (3) will not be discussed further.
Lewis acid TPPO adducts are also well-known and have been
used in the extraction of metal salts but have been less
frequently applied to the removal of TPPO. For example,
Received: February 25, 2017
© XXXX American Chemical Society
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crystals of ZnCl2(TPPO)2 have been known for over 100
years,15 yet we could only find one report where ZnCl2 was
used to precipitate TPPO from ethereal reaction mixtures16 and
one patent where precipitation was mentioned, without
examples, alongside more detailed methods using MgCl2.17
Although the magnesium chloride method has been utilized on
scale, it is notable that a switch to a less polar solvent was
required for efficient separation.17b
Table 1. Effect of ZnCl2 Equivalents on Precipitation
Efficiency
a
All of these physical separation strategies were described
using low-polarity solvents, such as hexanes, toluene, cyclo-
hexane, and diethyl ether. To our knowledge, there are no
methods for the precipitation of TPPO from more polar
solvents (i.e., ethanol, ethyl acetate, tetrahydrofuran, etc.) that
are commonly used in organic synthesis. Such a method would
provide an additional tool in complex molecule synthesis.
a
Experiments were performed with 1.0 g of TPPO (3.6 mmol)
solvated in 10 mL of ethanol. To this solution was added the listed
ratio of solid ZnCl2. A white precipitate formed immediately, and the
reaction was allowed to stand for 18 h at 22 °C before the solid was
separated by filtration and rinsed with 10 mL of ethanol. The filtrate
was analyzed to determine the amount of TPPO in solution.
RESULTS AND DISCUSSION
■
In the course of large-scale (>50 g) preparation of 2,7-
dibromocarbazole 2 from 4,4′-dibromo-2-nitrobiphenyl 1 by
reductive cyclization with triphenylphosphine,18 one of us
noted that triphenylphosphine could be conveniently separated
from the carbazole product by precipitation from ethanolic zinc
chloride (Scheme 1). This approach was inspired by the use of
b
Percentage of TPPO remaining in solution was determined by
corrected GC yield with dodecane as an internal standard.
TPPO precipitation; at a 3:1 ratio TPPO could no longer be
detected in the filtered solution. Considering the diminishing
returns on TPPO removal with higher equivalents of ZnCl2, a
2:1 ratio was selected as optimal for further studies. It should be
noted that this precipitation is robust and the ratio of ZnCl2 to
TPPO can be tuned to minimize TPPO or excess ZnCl2
depending on the requirements for reaction purification.
Elemental analysis of several different precipitates suggested
that the complex formed is ZnCl2(TPPO)215 but might contain
a small amount of additional TPPO. The stoichiometry and
literature precedent are consistent with ZnCl2(TPPO)2 as the
precipitate.
Scheme 1. Removal of Triphenylphosphine Oxide by ZnCl2
Next, a systematic investigation of polar solvents frequently
used in organic synthesis was undertaken to determine the
general utility of this procedure (Table 2). TPPO was dissolved
in each solvent and precipitated with a 2:1 ratio of ZnCl2 to
TPPO. After filtration, GC analysis demonstrated that
precipitation proceeds in solvents ranging from THF to
phosphine oxides to selectively extract metal ions from mixtures
during the enrichment of uranium ores.19 In addition, the
synthesis of pure crystals of ZnCl2(TPPO)2 from ethanol
solutions has been reported previously but never applied to
TPPO removal from reaction mixtures.15b,d
iPrOH. EtOAc, PrOAc, and PrOH stood out as excellent
solvents for this method (<5% TPPO), whereas THF, 2-
MeTHF, and methyl ethyl ketone were tolerated (<15%
TPPO). MeOH, MeCN, acetone, and DCM (no precipitate
formed) did not allow for efficient precipitation (>15% TPPO)
either due to increased solubility of the TPPO/ZnCl2 adducts
or increased solvation of ZnCl2 reducing the equilibrium
constant for adduct formation. Solvent mixtures were explored
to determine if combinations of solvents could improve
precipitation. Only the combination of DCM/iPrOH improved
TPPO removal. Finally, the addition of excess EtOH can assist
in precipitation of ZnCl2(TPPO)2 (vide infra).
i
i
The reaction procedure was simple: a 1.8 M solution of
ZnCl2 in warm ethanol was added to an ethanolic solution of
the product/TPPO mixture at room temperature. After stirring
and scraping to induce precipitation, the ZnCl2(TPPO)2 adduct
precipitated from solution. The solution was filtered to remove
the precipitate, and the filtrate concentrated to remove ethanol.
Finally, the residue was slurried with acetone to separate the
soluble product from any insoluble excess zinc chloride. The
filtered solution was completely free of triphenylphosphine
oxide by TLC analysis without the need for chromatography.
Given this promising initial result, we sought to examine the
molar amount of zinc chloride added and find the optimal ratio
of ZnCl2 to TPPO for complete precipitation of TPPO from
solution (Table 1). This study was accomplished by dissolving a
fixed quantity of commercial TPPO in ethanol and adding
various equivalents of ZnCl2 to promote precipitation. After
precipitation, the amount of TPPO remaining in solution was
quantitated by GC analysis. We found that 90% of the TPPO
was removed from solution with an equimolar ratio of ZnCl2
and TPPO. Increasing the ratio of ZnCl2 to TPPO increased
We next sought to assess the functional group compatibility
of the method. While no brief survey could reveal all potential
incompatibilities, we conducted several precipitations in the
presence of small molecules bearing a representative array of
functional groups (Table 3). We anticipated that some
functional groups would prevent efficient separation by either
solubilizing the ZnCl2 adduct or by co-precipitating with TPPO
and ZnCl2.12 Removal of TPPO occurred efficiently (<5%
TPPO) with alcohol, aldehyde, and amide functional groups in
iPrOH20 with only a slight decrease in the recovery of
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a
Table 2. Solvent Effect on TPPO Precipitation with ZnCl2
Table 3. Functional Group Compatibility of TPPO
a
Precipitation
a
See Table 1 for experimental details. TPPO was precipitated with
0.98 g of ZnCl2 (7.2 mmol) in 10 mL of the listed solvent. An
additional 10 mL of solvent was used to wash the solid precipitate.
b
Percentage of TPPO remaining in solution was determined by
corrected GC yield with dodecane as an internal standard. EtOH =
ethanol; iPrOH = 2-propanol; THF = tetrahydrofuran; 2-MeTHF = 2-
methyltetrahydrofuran; MeCN = acetonitrile; EtOAc = ethyl acetate;
iPrOAc = isopropyl acetate; MEK = methyl ethyl ketone; DCM =
dichloromethane.
benzaldehyde (78%) (entries 1, 3, and 4). A protected amino
acid, Boc-Gly-OMe (entry 9), was also tolerated with minimal
loss. Less positive results were obtained with substrates that
appeared to co-precipitate with TPPO and ZnCl2 through basic
nitrogen atoms: aniline, 4-methoxypyridine, and quinidine
(entries 2, 7, and 10).21 A more hindered pyridine, 2,6-lutidine,
worked well (entry 8), consistent with the coordination
hypothesis. It may be possible to avoid coprecipitation by
further modification of the conditions (solvent, amount of zinc
used), but this was not investigated further.
In addition to the initial carbazole-forming reaction (see
Scheme 1), two classic organic reactions, the Corey−Fuchs22
and the Mitsunobu reaction,23 were explored to examine the
new method in situations where TPPO separation often
requires column chromatography.24 In the Corey−Fuchs
reaction to synthesize 4 (Scheme 2), we found that
precipitation of TPPO worked well. The crude reaction
mixture was washed with H2O2 to convert any remaining
phosphine and phosphonium species to TPPO, allowing
efficient removal with a single precipitation with ZnCl2
(Scheme 2).25 Compound 4 could be obtained on multigram
scale in 82% yield without the need for column chromatog-
raphy.
a
See Table 1 for experimental details. The listed additive (3.6 mmol)
was added to the initial TPPO solution in iPrOH prior to the addition
of 0.98 g of ZnCl2 (7.2 mmol). After precipitation, the reactions were
filtered and washed, and the remaining solution was analyzed by GC.
b
The percentage of TPPO and additive remaining in solution was
determined by GC comparison of the solution prior to ZnCl2 addition
and after filtration using dodecane as an internal standard. Reaction
was run with double the solvent. Control reactions showed that
quinidine formed a precipitate with ZnCl2 in the absence of TPPO.
c
d
solvent evaporation followed by dilution with EtOH and
precipitation with ZnCl2 (twice) removed the majority of
TPPO and allowed for the crystallization of the product directly
from the ethanol solution with no further manipulation; 6 was
isolated in 68% yield without purification by column
chromatography.
While the procedure worked well for the synthesis of 2, 4,
and 6, we did find several limitations to the method. Besides
the potential for co-precipitation (vide supra), we also found, in
one case, that an acid-sensitive β-lactone26 reacted with solvent
under these Lewis acidic conditions. In addition, the use of an
excess of ZnCl2 means that, in cases where zinc contamination
The Mitsunobu reaction to form 6 from L-menthol and 5 was
similarly successful (Scheme 3).23 The crude reaction mixture
was washed with sodium bicarbonate and peroxide to remove
excess acid 5 and oxidize any remaining TPP to TPPO. Simple
C
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complex at reflux. The starting triphenylphosphine was recovered, and
no complex was detected.
Scheme 2. Corey−Fuchs Reaction with Removal of TPP and
TPPO by Oxidation and Precipitation
Trial Reaction of Triphenylphosphine Oxide with Magne-
sium Chloride in Ethanol. A final experiment was run to see if,
under the same conditions, triphenylphosphine oxide would form an
alcohol insoluble complex with magnesium chloride.17 No precip-
itation occurred and only triphenylphosphine oxide was recovered.
General Procedure for Table 1: Optimizing Equivalents of
ZnCl2. A 20 mL scintillation vial was charged with a stirbar,
triphenylphosphine oxide (1.0 g, 3.6 mmol, 1 equiv), and EtOH (10
mL). To this solution was added the listed equivalents of solid ZnCl2
accompanied by the immediate formation of a white precipitate. The
mixture was allowed to stir for 18 h at 22 °C before the solid was
separated by filtration and rinsed with EtOH (10 mL). The filtrate was
collected, and dodecane (100 uL, 0.44 mmol) was added as an internal
standard. The percentage of triphenylphosphine oxide remaining in
the solution was determined by GC analysis, corrected.
General Procedure for Table 2: Solvent Effect on TPPO
Precipitation. A 20 mL scintillation vial was charged with a stirbar,
triphenylphosphine oxide (1.0 g, 3.6 mmol, 1 equiv), and solvent(s)
(10 mL total). To this solution was added ZnCl2 (0.98 g, 7.2 mmol, 2
equiv). The mixture was allowed to stir for 18 h at 22 °C before any
precipitate was separated by filtration and rinsed with the listed solvent
(10 mL). The filtrate was collected, and dodecane (100 μL, 0.44
mmol) was added as an internal standard. The percentage of
triphenylphosphine oxide remaining in the solution was determined
by GC analysis, corrected.
Scheme 3. Mitsunobu Reaction with Precipitation of TPPO
by ZnCl2
General Procedure for Table 3: Functional Group Compat-
ibility. A 20 mL scintillation vial was charged with a stirbar,
triphenylphosphine oxide (1.0 g, 3.6 mmol, 1 equiv), and the listed
additive (1.0 equiv). The solids were dissolved in iPrOH (10 mL),
which was used because phase separation occurred when EtOH was
used to solvate 1-octyne. Following complete dissolution, dodecane
(100 μL, 0.44 mmol) was added to the homogeneous solution as an
internal standard. The solution was analyzed by GC to determine
baseline ratios of triphenylphosphine oxide and additive to dodecane.
ZnCl2 (0.98 g, 7.2 mmol, 2 equiv) was then added to the solution,
initiating the formation of a white precipitate. The mixture was allowed
to stir for 18 h at 22 °C before the precipitate was separated by
would be a concern, additional washes or manipulations could
be required (i.e., distillation, extraction with water).
In conclusion, we have discovered that triphenylphosphine
oxide can be conveniently removed from solution by
precipitation with ZnCl2 in ethanol. This precipitation
functions in several polar organic solvents, such as EtOAc,
i
filtration and rinsed with PrOH (10 mL). The filtrate was collected
and analyzed by GC to determine the ratios of triphenylphosphine
oxide and additive to dodecane. The percentage of triphenylphosphine
oxide and additive remaining in the solution was determined by
comparing the GC ratios before and after zinc addition.
i
iPrOAc, and PrOH, and is tolerant of many common
functional groups including alcohols, aldehydes, amides, and
some nitrogen heterocycles. The method was showcased in the
large-scale, chromatography-free isolation of products from
three reactions that generate TPPO byproducts. We anticipate
that this method will provide an additional purification tool for
many reactions that use triphenylphosphine as a reductant.
2,7-Dibromocarbazole (2).18 A 5-L, three-neck flask fitted with
an air-powered mechanical stirrer, reflux condenser, and thermometer
was set in an electric heating mantle. Into this flask was added 214 g
(0.600 mol) of 4,4′-dibromo-2-nitrobiphenyl,18 1.18 L of 1,2-
dichlorobenzene, and 388 g (1.48 mol) of triphenylphosphine. The
stirred mixture was heated to reflux (190 °C) under a blanket of argon
and held at this temperature for 6 h. The dark-colored mixture was
allowed to cool slowly to rt with stirring overnight. The mixture was
concentrated at reduced pressure on a rotary evaporator to remove
1,2-dichlorobenzene. The dark, viscous residue was poured into a
Pyrex glass tray, the residue remaining in the evaporating flask was
rinsed with 200−300 mL of petroleum ether, and this was added to
the main body of crude product in the Pyrex tray. The tray was placed
in a vacuum oven and warmed to remove the petroleum ether and any
remaining 1,2-dichlorobenzene. The tray was allowed to cool to room
temperature, whereupon the black material solidified. The crude solid,
containing the product and triphenylphosphine oxide, was powdered
using a mortar and pestle or a Waring blender. The triphenylphos-
phine oxide content was assumed to be equivalent to the molar
quantity of triphenylphosphine used.
EXPERIMENTAL SECTION
Zinc chloride was ACS grade. All other solvents and reagents used
were commercial, ACS grade, or better.
■
Trial Precipitation of the Zinc Chloride Complex of
Triphenylphosphine Oxide. In a blank experiment, 20.0 g (76.3
mmol) of triphenylphosphine was suspended in 200 mL of ethanol
with gentle refluxing. Air was bubbled through the solution overnight,
yielding a clear, colorless solution of triphenylphosphine oxide. To this
mixture was added a solution of 10.4 g (76.3 mmol) of zinc chloride in
100 mL of warm ethanol. The mixture was stirred and allowed to cool,
whereupon a heavy, white precipitate separated. After the mixture had
cooled to rt, the solid zinc chloride complex was collected by vacuum
filtration on a Buchner funnel. The solid was then washed with water
(100 mL), ethanol (100 mL), and ether (100 mL) before it was air-
dried at room temperature, yielding 23.8 g. This corresponds to a 90%
yield for Zn(OPPh3)2Cl2.
The solid was dissolved in 1.8−2.0 L of ethanol with warming
(about 35−40 °C) in a 5-L, three-neck flask equipped with a stirrer,
thermometer, and reflux condenser and set in an electric heating
mantle. A solution of 202 g (1.48 mol) of zinc chloride in 1.0 L of
ethanol was made by gently warming the mixture. The resulting
solution was poured rapidly into the stirred solution of the mixture of
Trial Reaction of Zinc Chloride with Triphenylphosphine. A
second experiment on the same scale was run to see if alcohol
solutions of triphenylphosphine and zinc chloride would also form a
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product and triphenylphosphine oxide in the 5-L flask, forming a clear
dark solution. Within minutes, a heavy white precipitate separated
from the dark solution. After filtration of the solids (presumed to be
Zn(OPPh3)2Cl2) and rinsing of the solids with fresh ethanol, the
filtrate was shown by TLC analysis to contain only the product and no
detectible triphenylphosphine or its oxide.
layer was isolated and dried over anhydrous sodium sulfate before
being filtered and concentrated to dryness by rotary evaporation. The
resulting slightly yellow solid was dissolved in 600 mL of ethanol in a
1-L Erlenmeyer flask with gentle warming and stirring. To the stirred
solution was added, in a single portion, a warm solution of anhydrous
zinc chloride (42.0 g, 310 mmol) in ethanol (200 mL). Stirring was
continued while the inner wall of the flask was scratched with a glass
rod to initiate the precipitation of the zinc chloride complex of
triphenylphosphine oxide. The precipitation was complete after
stirring for 1 h at rt, and the mixture was filtered to remove the
ZnCl2(TPPO)2. The white solid was rinsed with 50 mL of warm
ethanol, and the filtrate was treated with decolorizing carbon (500 mg)
before being filtered through a Whatman glass microfiber filter.
Analysis (GC with dodecane as an internal standard) showed that 30%
of the TPPO had been removed. A second precipitation with ZnCl2
resulted in 85% of the TPPO being removed. The product was
recrystallized directly from the second ethanol filtrate as a thick mat of
white crystalline needles. The product was isolated by filtration to give
7.9 g (68% yield) of the pure compound (1R,2S,5R)-2-isopropyl-5-
methylcyclohexyl 4-nitrobenzoate. Additional yield could be obtained
from concentration of the mother liquor and recrystallization but was
not combined with the initial recrystallization due to a slight
triphenylphosphine oxide impurity. 1H and 13C NMR matched
literature data.23
Following evaporation of the ethanol from the 2,7-dibromocarba-
zole, the pure product was recrystallized from methylcyclohexane/
toluene to yield 111 g of product (75% yield). NMR (1H) and mass
spectrometry of this material were consistent with the structure and
1
the H NMR in DMSO matched that obtained from a commercial
sample (Sigma-Aldrich, copies of both in the SI).18 1H NMR (400
MHz; DMSO-d6): δ 11.52 (s, 1H), 8.10 (d, J = 8.3 Hz, 2H), 7.71 (d, J
= 1.4 Hz, 2H), 7.33 (dd, J = 8.3, 1.5 Hz, 2H).
(4,4-Dibromobut-3-enyl)benzene (4).22 A 2-L, three-neck flask
was fitted with a stirbar, addition funnel, and septum before being
flame-dried under vacuum and backfilled with N2. To the dry flask
were added carbon tetrabromide (41.3 g, 0.249 mol, 2 equiv) and dry
dichloromethane (200 mL). The flask was cooled in an ice water bath
to 0 °C, and a solution of triphenylphosphine (65.2 g, 0.497 mol, 4
equiv) in anhydrous dichloromethane (200 mL) was added under N2
at 0 °C over 30 min using the addition funnel. The mixture was stirred
at 0 °C for 10 min before a solution of 3-phenylpropionaldehyde (8.2
mL, 0.124 mol, 1 equiv) in anhydrous dichloromethane (133 mL) was
added via the addition funnel over 10 min while holding the reaction
mixture at 0 °C. The mixture was further stirred at 0 °C for 1 h before
250 mL of water was added and the mixture was transferred to a 2-L
separatory funnel. The aqueous layer was separated and extracted with
dichloromethane (3 × 100 mL). The combined dichloromethane
extracts were washed with a 10% solution of hydrogen peroxide (2 ×
100 mL) to oxidize any remaining phosphorus species to TPPO. The
organic layer was then washed with a saturated solution of Na2SO3 (2
× 100 mL), brine (2 × 100 mL), and dried over sodium sulfate. The
resulting solution was filtered and concentrated on a rotary evaporator
to an orange residue.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00459.
1H NMR spectra used to establish purity (PDF)
Video of the reaction process (ZIP)
AUTHOR INFORMATION
Corresponding Author
*E-mail: daniel.weix@rochester.edu.
■
The residue was dissolved in 400 mL of absolute ethanol in a 2-L
Erlenmeyer flask, and a homogeneous solution of ZnCl2 (37.5 g, 0.275
mol, 2.2 equiv) dissolved in EtOH (150 mL) was prepared with
stirring and gentle warming. Both solutions were allowed to cool to
room temperature before the zinc chloride solution was poured into
the stirred solution of the product over a 1 min period. Stirring was
continued, and formation of a white precipitate was induced by
scratching the interior wall of the Erlenmeyer flask with a glass rod.
After being stirred for 30 min, the zinc complex was collected by
filtration and rinsed with additional EtOH (50 mL). Analysis of the
filtrate by GC with dodecane as an internal standard showed that <1%
triphenylphosphine oxide remained in solution. The filtrate was
concentrated under reduced pressure on a rotary evaporator to yield
an orange oil. The crude material was further purified by distillation to
yield 29.5 g (82% yield) of (4,4-dibromobut-3-enyl)benzene as a
ORCID
Daniel J. Weix: 0000-0002-9552-3378
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Research reported in this publication was supported in part by
the National Institute of General Medical Sciences of the
National Institutes of Health under Award No. R01GM097243.
We thank Jalil Shojae (University of Rochester) and Astrid
Olivares (University of Rochester) for assistance with
compound characterization. We also thank Stella Wu for
assistance with video editing.
1
colorless oil boiling at 90−92 °C at 0.3 mmHg. Analysis by H NMR
and TLC (10:1 hexanes/ethyl acetate) and comparison with authentic
samples of triphenylphosphine and triphenylphosphine oxide showed
the product to be pure and that no phosphine impurities were
present.22
REFERENCES
■
(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 4-Nitrobenzoate
(6).23 A 1-L, round-bottom, three-neck flask, equipped with a
thermometer, dropping funnel, argon inlet, and magnetic stirrer bar,
was charged with l-menthol (6.00 g, 38.4 mmol), TPP (40.1 g, 152.4
mmol), 4-nitrobenzoic acid (25.8 g, 154.4 mmol), and THF (300 mL).
While the mixture was stirred under an argon atmosphere, the solution
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mL, 154 mmol) was added slowly by addition funnel while
maintaining the temperature below 10 °C. Upon completion of the
addition, the cooling bath was removed, and the yellow solution was
allowed to warm to rt and stir for 18 h. The reaction mixture was
warmed to 35−40 °C for 3 h before being transferred to a 2-L
separatory funnel and diluted with EtOAc (400 mL). The solution was
washed with saturated sodium bicarbonate (2 × 200 mL), 6%
hydrogen peroxide (2 × 250 mL), and water (400 mL). The organic
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