11.
(S)-2-Chloropropanoic acid. In a 4-L, three-necked, round-bottomed flask equipped
with a mechanical stirrer, a 500-mL dropping funnel, and a two-necked adapter fitted
with a thermometer and a reflux condenser (Note 1), 89.1 g (1 mol) of (S)-alanine (Note
2) is dissolved in 1300 mL of 5 N hydrochloric acid (Note 3). The mixture is cooled to 0°C
in an ice/sodium chloride bath (Note 4) and a precooled solution of 110 g (1.6 mol) of
sodium nitrite in 400 mL of water is added dropwise at a rate of about 2 mL/min under
vigorous stirring and efficient cooling so that the temperature of the reaction mixture is
kept below 5°C. After 5 hr, the bath is removed and the reaction is allowed to stand
overnight at room temperature (Note 5). The reflux condenser is connected with a water
aspirator and the flask is carefully evacuated with stirring for 3 hr to remove nitrogen
oxides, whereupon the color changes from yellowish brown to pale yellow. While the
mixture is stirred vigorously, 100 g of solid sodium carbonate is added carefully in small
portions so as to prevent excessive foaming. The reaction mixture is extracted with four
portions of 400 mL of diethyl ether. The combined ether layers are concentrated to ca.
300 mL using a rotary evaporator at atmospheric pressure. The solution is washed with
50 mL of saturated brine, which thereafter is reextracted with three portions of 100 mL
of diethyl ether. The combined ethereal solutions are dried for 10 hr over calcium
chloride. The ether is distilled off with a rotary evaporator at atmospheric pressure (bath
temperature 40–50°C). The oily residue is transferred into a distillation flask (rinsing the
remainder with small portions of ether) and then fractionally distilled at reduced
pressure, the main fraction boiling within a range of 2–3°C (i.e., bp 75–77°C at 10 mm)
(Note 6) to give 63–71 g (58–65%) of an oil. The colorless oil is sufficiently pure for most
purposes (Note 7) and (Note 8). On prolonged standing in a refrigerator, the oil tends to
solidify partially or totally, but the white crystals formed have no sharp melting point.
This procedure can be employed for other α-amino acids (see Table I and the
Discussion).
12.
Palladium acetate (1.12 g, 0.005 mol), benzoquinone (2.16 g, 0.02 mol), manganese
dioxide (10.44 g, 0.12 mol), and anhydrous acetic acid (250 mL) (Note 1) are placed in a
1-L, round-bottomed flask equipped with a reflux condenser and a magnetic stirring bar.
This heterogeneous mixture is equilibrated by efficient stirring for 30–60 min.
Cycloheptane (9.61 g, 0.1 mol) (Note 2) is added, and the stirring is continued at 60°C
for 28 hr (Note 3). After the solution is cooled to room temperature, 250 mL of
pentane/ether (1 : 1) is added and the mixture is stirred for another 30 min. The twophase mixture is filtered with suction through a Büchner funnel, which contains a layer of
Celite (5–10 mm). The Celite layer is washed successively with 250 mL of pentane/ether
(1 : 1), 250 mL of water, 100 mL of pentane/ether (1 : 1), and 250 mL of water. After
the organic phases are separated, the aqueous phase is extracted 3 times with 250 mL of
pentane/ether (1 : 1). The combined organic phases are washed successively with 250
mL of water, 250 mL and then 100 mL of aqueous sodium hydroxide (2 N) (Note 4), 250
mL of water, and finally dried over anhydrous magnesium sulfate. After evaporation or
distillation of the solvent, the product is purified by distillation (Note 5) to give 2cyclohepten-1-yl acetate (11.25 g, 73%), bp 61–62°C (5 mm), lit.3 bp 70°C (6 mm)
(Note 6).
2. Notes
1. All the reagents used are analytical-grade, commercially available products, which
are
used
without
further
purification.
Darkened
benzoquinone
was
purified
by
sublimation. Activated grade manganese dioxide was used; however, it was not shown
that "activation" of manganese dioxide is necessary for the reaction.
13.
A. Ethyl α-(hydroxymethyl)acrylate. (See (Note 1)). A 1000-mL, four-necked, roundbottomed flask is fitted with mechanical stirrer, 250-mL equalizing funnel, condenser,
and thermometer. Paraformaldehyde (48 g, 1.6 mol), 1 N phosphoric acid (4 mL), and
water (110 mL) are heated at 90°C for 1.5 hr to form a clear aqueous formaldehyde
solution. This solution is cooled to room temperature. Triethyl phosphonoacetate (89.6 g,
0.4 mol) is added to the flask and the solution is stirred at room temperature at 1000
rpm. A solution of potassium carbonate (60.7 g, 0.44 mol) in water (60 mL) is added at
room temperature (first slowly: 10 mL in 10 min) and then more rapidly (40 min). The
temperature reaches 35–40°C and must be maintained at this level (with a water bath if
necessary). Stirring is continued for 5 min at 40°C after the end of the addition; then the
mixture (liquid–liquid heterogenous mixture) must be cooled rapidly to room temperature
using an ice bath (Note 2) while diethyl ether (200 mL) and brine (150 mL) are added.
After decantation, the mixture is extracted with ether (three 100-mL portions). The
combined organic layers are washed with brine (two 100-mL portions) (Note 3) and dried
over magnesium sulfate; the solvents are evaporated under reduced pressure and the
remaining oil is distilled to give a fraction at 65–70°C (1 mm) that weighs 38.5–41.6 g
(74–80%), nD20 1.4494. The hydroxy ester is of high purity as shown by GLC analysis
(25-m silica capillary OV-1 column) and spectral data (Note 4) and (Note 5).
14.
4-(4-Methoxyphenyl)-2-phenyl-1H-imidazole. A 2-L, three-necked, round-bottomed flask
equipped with an addition funnel, reflux condenser, and mechanical stirrer is charged
with 500 mL of tetrahydrofuran (THF) and 125 mL of water. Benzamidine hydrochloride
monohydrate (50 g, 0.29 mol) (Note 1) is added, followed by the slow, portionwise
addition of potassium bicarbonate (54.4 g, 0.57 mol) (Note 2). The reaction mixture is
vigorously heated to reflux. A solution of 4-methoxyphenacyl bromide (65.3 g, 0.29 mol)
in 325 mL of THF is then added dropwise via the addition funnel over a period of 30 min
while the reaction is maintained at reflux. After completion of the addition, the mixture is
heated at reflux for 18-20 hr (Note 3), then cooled in an ice bath (Note 4), and THF is
removed under reduced pressure using a rotary evaporator. An additional 100 mL of
water is added, and the resulting suspension is stirred at 50-60°C for 30 min. The
mixture is cooled in an ice bath and the solids are collected by filtration. The filter cake is
rinsed with two 100-mL portions of water and air-dried in the filter funnel for 2 hr. The
crude product is transferred to a 500-mL flask and 150 mL of diisopropyl ether and 150
mL of hexanes are added. The mixture is stirred for 2 hr at room temperature, and the
solids are again collected by filtration. The filter cake is dried in a vacuum oven for 48 hr
(68°C/ca. 100 mm) to give 68.6 g (96%) of the desired imidazole as an off-white solid
(Notes 5, 6).
15.
A 1-l., three-necked, round-bottomed flask is fitted with a mechanical stirrer and a
thermometer; the third neck of the flask is fitted with a 50-ml., pressure-equalizing
addition funnel, carrying a drying tube attached to a gas trap. The flask is charged with
200 ml. of dry nitrobenzene (Note 1), followed by 43 g. (0.32 mole) of anhydrous
aluminum chloride. After the aluminum chloride has dissolved, 39.5 g. (0.250 mole) of
finely ground 2-methoxynaphthalene (nerolin, (Note 2)) is added. An ice bath is used to
cool the stirred solution to about 5° before 25 g. (23 ml., 0.32 mole) of redistilled acetyl
chloride (Note 3) is added dropwise over a 15–20 minute period, with stirring and at a
rate which holds the temperature between 10.5 and 13° (Note 4). After addition of the
acetyl chloride is complete, the flask is kept immersed in the ice water while stirring is
continued for 2 hours. The mixture is then allowed to stand at room temperature for at
least 12 hours.
The reaction mixture is cooled in an ice bath, poured with stirring into a 600-ml.
beaker containing 200 g. of crushed ice, and treated with 100 ml. of concentrated
hydrochloric acid. The resulting two-phase mixture and 50 ml. of chloroform are
transferred to a 1-l. separatory funnel (Note 5); the chloroform-nitrobenzene layer is
separated and washed with three 100-ml. portions of water. The organic layer is
transferred to a 2-l., round-bottomed flask, and steam-distilled. A fairly rapid flow of
steam is used, and the distillation flask is heated in an oil bath at about 120°. After about
3 hours (3–4 l. of water) the distillation is stopped, and the residue in the flask is allowed
to cool. Residual water in the flask is decanted from the solid organic material and
extracted with chloroform. The solid residue in the flask is dissolved in 100 ml. of
chloroform and separated from any water left in the flask, and the chloroform layers are
combined and dried over anhydrous magnesium sulfate. The chloroform is removed on a
rotary evaporator, and the solid residue, weighing 50–65 g. (still slightly wet with
chloroform), is distilled under vacuum (Note 6). The receiving flask should be immersed
in ice water, and the fraction boiling about 150–165° (0.02 mm.) is collected (Note 7).
The yellow distillate (ca. 40 g., m.p. 85–95°) is recrystallized from 75 ml. of methanol,
cooled in an ice bath (Note 8) and filtered, yielding 22.5–24 g. (45–48%) of white,
crystalline 2-acetyl-6-methoxynaphthalene (Note 9), m.p. 106.5–108° (lit. 104–105°).3
16.
A 500-mL, three-necked, round-bottomed flask (Note 1) equipped with an overhead
mechanical stirrer, is charged with powdered succinic anhydride (10.01 g, 0.1000 mol)
(Note 2) and bromobenzene (96.87 g, 0.6170 mol) (Note 2) under dry argon. The
resulting white mixture is cooled to 0°C before anhydrous aluminum chloride (26.67 g,
0.2000 mol) (Note 2) is added in one portion (Note 3). The reaction conditions are
maintained over a period of 4 hr before the reaction mixture is allowed to warm to room
temperature. The reaction mixture is stirred for 96 hr at room temperature (completion
of the reaction is indicated by cessation of the evolution of hydrogen chloride gas) and is
then poured into cooled (0°C), mechanically stirred hydrochloric acid (250 mL, 37%)
(Note 4) and stirred for 1 hr. The white precipitate is filtered off, washed well with water
(1 L) and dried overnight on a Büchner funnel. The crude product (24.81 g, 97%) is
crystallized from dry toluene (Note 5) and dried under reduced pressure (P2O5, CaCl2, 18
hr) to afford a white crystalline product (first fraction, 20.76 g, second fraction, 3.47 g);
yield is 24.23 g (94%) (Note 6).
2. Notes
1. The glassware was dried in an oven at 130°C, assembled while still hot, and
alternately evacuated and flushed with argon.
2. The checkers purchased succinic anhydride, bromobenzene and aluminum chloride
from Wako Pure Chemical Industries, Ltd, Tokyo Chemical Industry Co., and Kanto
Chemical Co. respectively, and used them as received.
3. Upon the addition of the aluminum chloride the reaction progressively turned from a
yellow suspension to a clear yellow to a clear orange-red solution.
4. The checkers used 35-37% hydrochloric acid (340 mL) purchased from Kokusan
Chemial Works, Ltd.
5. The toluene was dried over sodium metal.
17.
A. (S)-3-(tert-Butyloxycarbonylamino)-1-diazo-4-phenylbutan-2-one . A 1-L, threenecked, round-bottomed flask is equipped with a magnetic stirring bar, nitrogen gas
inlet, bubble counter and a rubber septum on the center neck. The apparatus is dried
under a rapid stream of nitrogen with a heat gun. After the flask is cooled to room
temperature, the rate of nitrogen flow is reduced and Boc-phenylalanine (25.0 g, 94.2
mmol, Note 1) and anhydrous tetrahydrofuran (250 mL, Note 2) are added. The flask is
immersed in an ice-water bath and triethylamine (13.1 mL, 94.0 mmol, Note 3) is added.
After 15 min ethyl chloroformate (9.45 mL, 94.0 mmol,Note 4) is added. The reaction
mixture is stirred for another 15 min, and a white precipitate of triethylammonium
chloride appears; the stirring is then stopped. The septum is replaced by a funnel Note
(Note 5). An ethereal solution of diazomethane (about 125 mL, Note 6) is added through
the funnel, stirring is resumed for about 5 seconds and the nitrogen stream is stopped.
After 45 min, the remainder of the diazomethane solution (about 85 mL) is added. The
cooling bath is removed and the solution is allowed to react for 3 hr without stirring. With
stirring, 75 mL of 0.5 N acetic acid is added carefully to destroy unreacted diazomethane
and saturated aqueous sodium bicarbonate solution (75 mL) is added carefully. The
aqueous layer is separated in a separatory funnel and the organic layer is washed with
saturated aqueous sodium chloride (75 mL). The organic layer is dried over magnesium
sulfate , filtered, and the solvents are removed under vacuum on a rotary evaporator.
The crude product is placed under high vacuum for 3 hr (Note 7). The crude material is
used directly in the next step (Notes 8, 9).
1. Boc-phenylalanine was obtained from Aldrich Chemical Co., Inc. (The submitters
obtained their sample from Bachem).
2. Tetrahydrofuran was dried over sodium/benzophenone and freshly distilled before
use.
3. Triethylamine was freshly distilled from calcium hydride .
4. Ethyl chloroformate was freshly distilled before use.
5. A short stem, flame-polished funnel of diameter ca. 12.5 cm, free of any scratches
or broken edges, was used to prevent spontaneous decomposition of diazomethane .
7. The crude diazo ketone is first obtained as a viscous yellow oil, which slowly
solidifies under high vacuum. The checkers always handled the solid material behind a
safety shield.
18. (skrót)
B. (S)-3-(tert-Butyloxycarbonylamino)-4-phenylbutanoic acid . A 500-mL, threenecked flask is equipped with a nitrogen gas inlet, bubble counter, septum and a
magnetic stirring bar. The flask is carefully wrapped in aluminum foil (to exclude light
during the reaction). The crude diazo ketone from the preceding step is dissolved in
tetrahydrofuran (380 mL, Note 10) and added to the flask under an atmosphere of
nitrogen. De-ionized water (38 mL) is added, the flask is immersed in a dry ice-acetone
bath, and the solution is cooled to −25°C (temperature of the acetone cooling bath) for
30 min. Silver trifluoroacetate (2.72 g, 12.3 mmol, Note 11) is placed in a 50-mL
Erlenmeyer flask and quickly dissolved in triethylamine (39 mL, 279 mmol, Note 3). The
resulting solution is added to the diazo ketone solution in one portion (via syringe). The
solution is allowed to warm to room temperature overnight. Evolution of nitrogen starts
at a bath temperature of about −15°C.
The solution is transferred to a 1-L, round-bottomed flask and the reaction vessel is
rinsed with ethyl acetate (2 × 10 mL). The solution is evaporated to dryness with a
rotary evaporator and the residue is stirred for 1 hr with saturated aqueous sodium
bicarbonate (NaHCO3) solution (100 mL, Note 12). The black mixture is transferred into a
1-L separatory funnel with water (150 mL) and ethyl acetate (200 mL), and the mixture
is shaken well. The clear aqueous layer is separated and put aside, leaving an organic
phase containing a suspension of black solid. Brine (30 mL) is added to the organic phase
and the resulting mixture is shaken vigorously. Saturated, aqueous NaHCO3 solution (30
mL) is added, the medium is shaken again, and the layers are separated. The organic
layer is washed with three additional portions of saturated aqueous NaHCO3 solution (30
mL each) and all the aqueous layers are combined. All the combined aqueous layers are
then transferred to a 2-L, round-bottomed flask equipped with a magnetic stirring bar
and about 10 drops of Congo Red indicator (Note 14) and ethyl acetate (100 mL) are
added. The flask is immersed in an ice-water bath, the solution is stirred and 5 N (17.5
wt %) hydrochloric acid is added dropwise through an addition funnel until the color of
the indicator changes from red to blue (Note 15). The solution is placed in a 1-L
separatory funnel and the organic layer is separated. The aqueous layer is additionally
extracted with three portions of ethyl acetate. The combined organic layers are dried
over magnesium sulfate and evaporated on a rotary evaporator. The product crystallizes
slowly to essentially pure material and can be recrystallized (diethyl ether/light
petroleum) to yield 12.1 g product.
19.
9,10-Diphenylphenanthrene . In a 250-mL, three-necked, round-bottomed flask
equipped with a magnetic stirrer, a thermometer, and a septum is suspended 10.0 g
(27.3 mmol) of benzopinacol (Note 1) in 40 mL of dry toluene (Note 2) under a nitrogen
atmosphere. The suspension is cooled to 0°C using an ice-acetone bath, and 40 mL of
freshly distilled trifluoromethanesulfonic acid (triflic acid) (Note 3) and (Note 4) is added
in one portion via syringe (Note 5). The cold bath is removed, and the mixture is stirred
for 24 hr at room temperature. The resulting heterogeneous mixture is poured over 100
g of ice, the organic layer is separated, and the aqueous layer is extracted with two 100mL portions of toluene . The organic layers are combined, and washed with water (50
mL) and with brine (50 mL). The original solution is dried with anhydrous magnesium
sulfate , filtered, and the filtrate is concentrated under reduced pressure to afford 9.2 g
of crude product (mp 227-231°C) as a pale yellow solid. The crude product is
recrystallized from 450 mL of toluene-ethanol (1:1) to give 6.7 g (74%) of pure 9,10diphenylphenanthrene as a white solid (Note 6). Concentration of the mother liquor and
recrystallization of the residue from 100 mL of toluene-ethanol (1:1) gives another 1.4 g
(16%) of product (mp 237-238°C).
2. Notes
1. Benzopinacol was purchased from Aldrich Chemical Company, Inc. , and used
without further purification.
2. Toluene was purchased from Fisher Scientific Company and distilled from sodium
prior to use. Benzene may be substituted for toluene with the following differences: (a)
The initial solution is cooled to only 10°C, otherwise the benzene layer freezes. (b) The
mixture is extracted with three 100-mL portions of benzene after pouring over ice. (c)
Recrystallization from 430 mL of benzene-ethanol (1:1) gives a first crop of pure product
in 80-90% yield. The submitters indicate that dichloromethane can be used as the
solvent for the reaction and extractions.
3. Triflic acid was obtained from 3M (99% purity). The triflic acid must be distilled
prior to its use, and the distillation should be performed under a dry, inert atmosphere.
Triflic acid may be recycled using a published procedure.2
20.
1-Bromo-2-fluoro-2-phenylpropane (Note 1). A magnetically stirred mixture of αmethylstyrene (7.1 g, 60 mmol) (Note 2), triethylamine trihydrofluoride (Note 3) and
(Note 4) (14.7 mL, 90 mmol) and dichloromethane (Note 5) (60 mL) contained in a 250
mL, single-necked, round-bottomed flask is treated with N-bromosuccinimide (11.8 g, 66
mmol) (Note 6) at 0°C. After 15 min, the bath is removed, and stirring is continued at
room temperature for 5 hr (Note 7). The reaction mixture is poured into ice water (1000
mL), made slightly basic with aqueous 28% ammonia (Note 8), and extracted with
dichloromethane (4 × 150 mL). The combined extracts are washed with 0.1 N
hydrochloric acid (2 × 150 mL) and 5% sodium hydrogen carbonate solution (2 × 150
mL) and then dried over magnesium sulfate . After removal of the solvent by rotary
evaporation, the crude product is distilled (Note 9) to give the product: 11.6 g (89%); bp
50-52°C (0.15 mm), n20 D 1.5370 (Note 10).
2. Notes
2. The submitters have scaled this procedure up to 100 mmol for several alkenes in
the Table and to a 400-mmol scale for 1-pentene.
3. Triethylamine trihydrofluoride is less corrosive than Olah's reagent5
6
or anhydrous
hydrogen fluoride itself, but all contact with the skin must still be avoided. The reagent
has been tested for laboratory use only. The experiments should be done under an
efficient hood.
4. Triethylamine trihydrofluoride
7
is an oily liquid that does not attack borosilicate
glassware. The checkers purchased it from Aldrich Chemical Company, Inc., but it is also
available from Fluka Chemical Corp. and other suppliers.
5. Dichloromethane was dried over calcium hydride and distilled.
6. N-Bromosuccinimide was purchased from Aldrich Chemical Company, Inc. , and
used without purification; the purity of the compound is about 90%.
7. The reaction times for other olefins are given in the Table.
8. About 25-30 mL of aqueous 28% ammonia is necessary to make the solution
slightly basic. If the aqueous layer is not made basic (pH 9-10), decomposition of the
product is observed during distillation.
9. The distillation was performed using a 5-cm Vigreux column; there was no forerun.
The product is somewhat sensitive to light and temperature.