Organic Syntheses, Vol. 79, pp. 35-42
Checked by V. Girijavallabhan and Marvin J. Miller.
1. Procedure
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
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.
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.
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.
All toxic materials were disposed of in accordance with "Prudent Practices in the
Laboratory"; National Academy Press; Washington, DC, 1995.
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).
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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