Organic Syntheses, Coll. Vol. 10, p.9 (2004); Vol. 77, p.135 (2000).
A 200-mL, flame-dried Schlenk flask
is purged with nitrogen
and charged with
10.0 g (40.6 mmol) of 4-iodoacetophenone
770 mg (4.1 mmol) of copper(I) iodide (CuI)
2.5 g (8.1 mmol) of triphenylarsine
150 mL of anhydrous 1-methyl-2-pyrrolidinone
. The dark solution is degassed for 15 min (nitrogen
sparge) and then
14.1 mL (44.7 mmol) of 2-(tributylstannyl)thiophene
is added. The reaction flask is immersed in a preheated oil bath
at 95°C and
215 mg (0.2 mmol) of 10% palladium on activated carbon
is added under a positive nitrogen
pressure. The mixture is kept at 95°C for 24 hr (Note 7)
and then allowed to cool to 25°C and diluted with
300 mL of ethyl acetate
. The dark mixture is poured into
200 mL of an aqueous saturated sodium fluoride
solution (Note 8)
and stirred vigorously for 30 min. The green-yellow heterogeneous mixture is passed through a sand pad contained in a medium-frit filter
, aided by a water aspirator
. The filtrate is partitioned in a separatory funnel
and the aqueous layer is extracted with two
100-mL portions of ethyl acetate
. The organic extracts are combined and stirred with
200 mL of fresh saturated aqueous sodium fluoride
solution for 30 min. The mixture is then passed through a sand pad as described above. The pad is rinsed with
50 mL of ethyl acetate
. The mixture is partitioned again and the aqueous layer is extracted with two
50-mL portions of ethyl acetate
. The organic extracts are combined and washed with five 100-mL portions of water and finally with
100 mL of brine
. The dark yellow solution is dried over anhydrous
) (Note 11)
and filtered. The used MgSO4
is washed with
50 mL of ethyl acetate
. The solvent is removed under reduced pressure to give a dark yellow solid that is dissolved in the minimum amount of dichloromethane
and adsorbed onto
20 g of silica gel
. The solvent is thoroughly removed under reduced pressure and the resulting solid is charged into a medium-pressure liquid chromatography column (silica gel, 3 × 15 cm)
. The product (6.6 g
) (Note 14)
is purified as described by Baeckström et al.4
4-Iodoacetophenone was purchased from Aldrich Chemical Company, Inc.
, and used without purification.
Copper(I) iodide was purchased from Aldrich Chemical Company, Inc.
, and purified according to a literature procedure.5
Caution: Triphenylarsine is highly toxic and must be handled with gloves in a well-ventilated hood.
It was purchased from Aldrich Chemical Company, Inc., and used as received.
1-methyl-2-pyrrolidinone was purchased from Aldrich Chemical Company, Inc.
, and used without further drying. The water content was determined to be 117 ppm using a Coulomatric K-F Titrimeter
The reaction can be monitored by quenching small aliquots with water and extracting with a small amount of diethyl ether
. The ethereal layer is spotted on an analytical silica gel TLC plate (0.25 mm thickness, from EM Separations Technology) (
in hexanes, using 254 nm UV light
to visualize the spots). The following are the Rf'
s of the components of the mixture: 2-(tributylstannyl)thiophene
(0.62), 4-iodoacetophenone (0.48), and
, (0.38 fluorescent). Trace amounts of 4-butylbenzophenone
, 0.52) were observed at the end of the reaction.
Caution: Sodium fluoride is highly toxic and should be handled with gloves in a well-ventilated hood.
It was purchased from Spectrum Chemical Mfg. Corp. and used without purification.
If crystallization underneath the frit occurs during the filtration process, the sand pad is washed with
20 mL of ethyl acetate
. The sand pad was changed three times during the filtration of the whole mixture to avoid clogging.
Silica gel 60, particle size 0.040-0.063 mm (230-400 mesh) was obtained from EM Separation Technology
The medium-pressure liquid chromatography system (MPLC) was purchased from Baeckström SEPARO AB.
The product (a golden flaky solid) exhibits the following properties: mp 118-119°C;
: 1680, 1601, 1270
H NMR (300 MHz, CDCl3
) δ: 2.6 (s, 3 H), 7.1 (m, 1 H), 7.3 (d, 1 H, J = 5), 7.4 (d, 1 H, J = 3.8), 7.7 (d, 2 H, J = 8), 8.0 (d, 2 H, J = 9)
C NMR (75.5 MHz, CDCl3
) δ: 26.5, 124.6, 125.6, 126.4, 128.3, 129.1, 135.7, 138.7, 142.9, 197.2
. Anal. Calcd for C12
OS: C, 71.30; H, 5.00; S, 15.90. Found: C, 71.14; H, 5.03; S, 15.77. (The material obtained by the checkers was a very pale yellow flaky solid.)
The purification was carried out using a hexanes/dichloromethane gradient (200 mL of each gradient solution). The gradient started with hexanes at a flow rate of 25 mL/min and the concentration of dichloromethane
was increased each time by 10%. A total of fifty 30-mL fractions were collected. Under these conditions, most of the triphenylarsine
used was recovered and recycled. (The checkers purified the material using conventional flash chromatography techniques. The crude product adsorbed on
20 g of flash silica gel
was dry packed on a 6-cm × 14-cm column of flash silica gel
. Elution with
750 mL of hexanes
500 mL each of a hexane/dichloromethane
gradient starting with
)/hexanes and finishing with 100% CH2
. A total of fifty 100-mL fractions were collected. The separation was monitored by analytical TLC as described in (Note 7)
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
The rate-enhancing influence of Cu(I) salts (the so-called "Copper Effect") in normally nonproductive and sluggish Stille couplings was first pointed out by Liebeskind et al.6
in 1990. A greater insight into this phenomenon was obtained later by Farina and co-workers.7
A number of modifications of the Stille reaction have since been reported. Among them are the cross-coupling of organostannanes with organic halides promoted by stoichiometric amounts of Cu(I) salts,8
and the Cu(I)- or Mn(II)-catalyzed cross-coupling of organostannanes with iodides in the presence of sodium chloride
It was also discovered that aryl and vinyl iodides, bromides, and triflates participated efficiently in cross-coupling reactions with organostannanes when catalyzed by palladium-on-carbon in the presence of Cu(I) as cocatalyst.1
The best conditions were found to be: Pd/C (0.5 mole%)
, Cu(I) (10 mole%)
, and AsPh3 (20 mole%)
. Besides the advantage of using a stable form of Pd(0), the yield of the products under these conditions was better than that obtained using tris(dibenzylideneacetone)palladium
] as the source of Pd(0). Similarly, a slightly lesser amount of the homocoupled product was observed using the Pd/C protocol. Although a significant amount of AsPh3
is necessary for cross-coupling to take place, it can be efficiently recovered (and recycled) at the end of the reaction by column chromatogaphy.
Other products prepared using the Pd/C protocol are:
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