Org. Synth. 2002, 79, 35
DOI: 10.15227/orgsyn.079.0035
ETHYL 3-(p-CYANOPHENYL)PROPIONATE FROM ETHYL
3-IODOPROPIONATE AND p-CYANOPHENYLZINC BROMIDE
[
Benzenepropanoic acid, 4-cyano-, ethyl ester
]
Submitted by Anne Eeg Jensen, Florian Kneisel, and Paul Knochel
1
.
Checked by V. Girijavallabhan and Marvin J. Miller.
1. Procedure
A.
Ethyl 3-iodopropionate
. A 1-L, round-bottomed flask
equipped with a magnetic stirring bar and a reflux
condenser is charged with
ethyl 3-chloropropionate
(27.3 g, 0.2 mol)
(Note 1)
and
acetone (400 mL).
Sodium iodide
(300 g, 2 mol)
(Note 2) is added to the clear solution and the mixture is refluxed
for 16 hr. The resulting pale yellow reaction mixture is cooled to room temperature,
the stirring bar and reflux condenser are removed and the
acetone
is removed on a rotary
evaporator at 40°C/550 mbar (412 mm). The residue is taken up in
diethyl ether (300 mL)
and washed with a saturated aqueous solution of sodium
thiosulfate (3 × 100 mL). The ethereal phase
is dried over anhydrous
magnesium sulfate
,
filtered and the ether is removed by rotary evaporation at 40°C. The resulting yellow
oil is purified by distillation with a membrane pump 90°C/25
mbar (18.7 mm) yielding 36.8 g
of
ethyl 3-iodopropionate
as a clear oil (82%) (Note 3).
B.
4-Cyanophenylzinc bromide
.
A dry, 250-mL, three-necked flask equipped with an argon
inlet and a stirring bar is charged with
4-bromobenzonitrile
(9.1 g, 50 mmol)
(Note 4)
and evacuated for 5 min. The flask is flushed with argon, dry tetrahydrofuran (THF, 100 mL)
(Note 5) is added, and the flask is equipped with an internal
thermometer. The solution is cooled to −100°C in a diethyl
ether/liquid nitrogen bath and left for 5 min before slowly adding
butyllithium
(BuLi, 32 mL, 1.56 M in hexanes, 50 mmol)
(approx. 20 min). After complete addition the mixture is stirred at −100°C for
an additional 30 min before it is allowed to warm to −78°C. At this temperature,
a solution of
zinc bromide
(ZnBr2, 36.6
mL, 1.5 M in THF, 55 mmol)
(Note 6)
is slowly added (approx. 20 min). After complete addition, the reaction mixture is
kept at −78°C for 5 min, then the flask is warmed with an ice bath
to 0°C and left for 10 min at this temperature before allowing it to warm to room
temperature. The yield of the zinc reagent is checked by hydrolysis and iodolysis
(Note 7) before concentrating it under reduced pressure to 2.0-2.2
M (22-25 mL).
C.
Ethyl 3-(4-cyanophenyl)propionate
.
A dry, 100-mL, three-necked flask, equipped with an argon
inlet and a stirring bar, is charged with
nickel
acetylacetonate (Ni(acac)2, 520 mg, 2 mmol)
and evacuated for 10 min before flushing with argon. THF
(6.7 mL),
N-methylpyrrolidinone
(NMP, 3.3 mL)
(Note 8),
4-fluorostyrene (496 mg, 4
mmol)
(Note 9) and
ethyl
3-iodopropionate (4.56 g, 20 mmol)
are successively added and the flask is equipped with an internal thermometer.
The reaction mixture is cooled to −60°C before slowly adding the zinc reagent
with a syringe through a large diameter cannula. After complete
addition, the reaction mixture is allowed to warm to −14°C in a cryostat.
(The checkers used a dry ice/ethylene glycol bath). The conversion
is complete within 12-15 hr (Note 10), when it is quenched with
saturated aqueous ammonium chloride
solution (15 mL) and allowed to warm to room temperature.
The quenched reaction mixture is extracted with
diethyl
ether (7 × 150 mL), the ethereal extracts are
dried over
magnesium sulfate
,
filtered, and evaporated to dryness by rotary evaporation at 40°C. The resulting yellow
oil is purified by column chromatography (Note 11) affording
2.42 g (11.9 mmol) of
ethyl 3-(4-cyanophenyl)propionate
as a pale yellow oil (60%)
(Note 12).
2. Notes
1.
Ethyl 3-chloropropionate
from Aldrich Chemical Company, Inc.
, was used as obtained.
2.
Sodium iodide was
purchased from Acros Organics as water free, 99+%
.
3.
Spectral data are as follows: IR
(KBr) cm
−1: 2981 (m), 1372 (m), 1213
(s)
;
1H
NMR (300 MHz, CDCl
3) δ: 1.26 (t, 3 H, J = 7.1), 2.95
(t, 2 H, J = 7.5), 3.32 (t, 2 H, J = 7.5), 4.15 (q, 2 H,
J = 7.1)
;
13C
NMR (75 MHz, CDCl
3) δ: −3.3, 14.6,
39.0, 61.3, 171.4
. MS (EI, 70 eV): 228 (33), 183 (27), 155
(67), 101 (100), 73 (49)
. Anal. Calcd
for C
5H
9IO
2: C, 26.34; H, 3.98. Found: C, 26.27;
H, 3.96.
4.
4-Bromobenzonitrile
from ABCR Germany
is used as obtained.
5.
THF is dried by distillation under
argon
from
sodium/benzophenone
.
6.
Anhydrous ZnBr
2 is dried for 5 hr at 150°C under
oil
pump vacuum, then cooled to room temperature and flushed with
argon
before adding dry THF. The concentration is determined by transferring a 1-mL aliquot
to a
dry tared flask, then evaporating the THF.
7.
Hydrolysis: An aliquot of the reaction mixture is quenched with
saturated aqueous ammonium chloride
solution and extracted with ether, then injected on GC to verify that all
the
4-bromobenzonitrile
has been consumed. Iodolysis: An aliquot of the reaction mixture is added to a dry
vial containing
iodine; after 10 min ether is added and the ethereal
solution is washed with an
aqueous solution of sodium
thiosulfate
. The organic phase is injected on GC to verify the
formation of the zinc reagent. Decane was used as internal standard in the reaction.
8.
NMP is dried by stirring overnight with
calcium
hydride
, then refluxing for 5 hr followed by distillation under
argon from
calcium hydride
.
9.
4-Fluorostyrene
99% from Aldrich Chemical Company, Inc.
,
is used as obtained.
10.
The reaction is monitored by GC analysis of worked-up aliquots.
Tetradecane
is used as internal
standard for the cross-coupling reaction.
11.
The oil is taken up in
diethyl
ether
and absorbed onto approximately
15
g of flash silica (Merck silica gel 60 mesh 0.040-0.063
mm), then applied to a 10-cm diameter column packed with
500
g of flash silica eluting the product with
pentane/diethyl
ether 85:15. (The checkers used
10:1
hexanes/ether
for improved resolution.)
12.
Spectral data are as follows: IR
(KBr) cm
−1: 2983 (m), 2228 (m), 1732
(s), 1688 (m), 1186 (m)
.
1H NMR (300 MHz, CDCl
3) δ:
1.20 (t, 3 H, J = 7.1), 2.60 (t, 2 H J = 7.5), 3.00
(t, 2 H, J = 7.5), 4.10 (q, 2 H, J = 7.1), 7.30 (d, 2 H,
J = 7.8), 7.60 (d, 2 H, J = 7.8
;
13C NMR (75 MHz, CDCl
3) δ:
14.5, 31.3, 35.4, 61.0, 110.6,
119.2, 129.6, 132.6, 146.6, 172.5
.
MS (EI, 70 eV): 203 (26), 129
(100), 116 (39), 103 (12)
. Anal. Calcd.
for C
12H
13NO
2: C, 70.92; H, 6.45; N, 6.89. Found:
C, 70.61; H, 6.20; N, 6.74.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
The performance of cross-coupling reactions between aryl organometallics and alkyl
iodides is not well known. Only the reaction of diarylcuprates with alkyl iodides
may be considered for performing such cross-couplings.
2
The present procedure
3 describes
a convenient way for performing the cross-coupling between an arylzinc bromide and
an alkyl iodide. The reaction is catalyzed by Ni(acac)
2 (10 mol %) and
the addition of commercially available
4-fluorostyrene
(20 mol %). The role of
4-fluorostyrene
is to reduce the electron density of the nickel intermediate [(Ar)Ni(Alkyl)] by coordinating
to the nickel center and removing electron density, thereby favoring the reductive
elimination leading to Ar-Alkyl. The key role of several electron-poor styrenes such
as
m- or p-trifluoromethylstyrene
has been noticed in related cross-couplings between two Csp
3-centers.
4 The reaction tolerates a broad
range of functional groups such as ester, nitrile, amide, and halogen (Table 1).
The functionalized arylzinc reagents are best prepared either starting from an
aryllithium obtained by halogen-lithium exchange followed by a low-temperature (−80°C)
transmetalation
5
with ZnBr
2 or by performing an
iodine-
magnesium
exchange reaction. The latter reaction tolerates temperatures up to −30°C and
is more convenient for industrial applications.
6
Table 1
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
Ethyl 3-(4-cyanophenyl)propionate:
Benzenepropanoic
acid, 4-cyano-, ethyl ester (12); (116460-89-0)
Ethyl 3-iodopropionate:
Propanoic acid, 3-iodo-,
ethyl ester (9); (6414-69-3)
Ethyl 3-chloropropionate:
Propionic acid,
3-chloro-, ethyl ester (8);
Propanoic acid, 3-chloro-, ethyl
ester (9); (623-71-2)
Sodium iodide (8,9); (7681-82-5)
p-Cyanophenylzinc bromide:
Zinc, bromo(4-cyanophenyl)-
(12); (131379-14-1)
4-Bromobenzonitrile:
Benzonitrile, p-bromo-
(8);
Benzonitrile, 4-bromo- (9); (623-00-7)
Butyllithium:
Lithium, butyl-
(8,9); (109-72-8)
Zinc bromide (8,9); (7699-45-8)
Nickel acetylacetonate:
Nickel, bis(2,4-pentanedionato-)
(8);
Nickel, bis(2,4-pentanedionato-O, O')-, (sp-4-1)-
(9); (3264-82-2)
N-Methylpyrrolidinone:
2-Pyrrolidinone, 1-methyl-
(8,9); (872-50-4)
p-Fluorostyrene:
Styrene, p-fluoro-
(8);
Benzene, 1-ethenyl-4-fluoro- (9); (405-99-2)
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