1
000 ppm with respect to palladium. A 25+S flash cartridge
pooled and concentrated to 100 mL, and a sample was taken
for ICP analysis (26 ppm wt/wt with respect to palladium).
Concentration in vacuo gave the crude product (0.697 g).
The final 100-mL portion of the original reaction solution
was filtered through a bed of silica gel (60 Å), washed with
dichloromethane (100 mL), and evaporated back down to
100 mL. A sample was taken for ICP analysis (56 ppm wt/
wt with respect to palladium). Concentration in vacuo gave
the crude product (0.948 g).
filled with QuadraPure TU (13.0 g of resin, 24-mL column
volume) was fitted in a Biotage SP4 Flash Purification
System, with the palladium solution as the “strong solvent”
and THF as the “weak solvent”.
A gradient was programmed at a fixed flow rate of 2 mL/
min, starting with an initial 5 CV (120 mL) of THF to wet
the resin, then 20 CV (480 mL) of palladium solution, ending
with another 2 CV (48 mL) of THF. The programme was
set to collect all fractions (51 mL each) with the UV detector
collection wavelength set to 232 nm and the monitor
wavelength at 320 nm.
The Biotage unit was first primed, bypassing the column,
with a 50-mL portion of THF at a flow rate of 20 mL/min
to remove air from the lines. The programme was then run,
giving a breakthrough point at 12.5 CV (300 mL), depicted
by a sharp increase in gradient on the UV trace, and also by
the appearance of yellow-coloured fractions. The loading of
the cartridge equated to approximately 23 mg Pd/g of resin
15
Rosemund von-Braun Reaction. In a new, dry Biotage
2-5-mL microwave reaction tube were put 1-bromonaph-
thalene (2.2 g; 1.48 mL; 10.6 mmol), dry copper(I) cyanide
(1.05 g, 11.7 mmol), and pyridine (0.982 g; 1 mL; 10 mmol)
in the order stated. A small stirrer bar was added and the
top sealed with a crimper.
The mixture was heated at 250 °C in a microwave reactor
2
1
(
Biotage Initiator 60), and GC/MS analysis indicated
complete conversion in 30 min. The reaction mixture was a
dark-brown paste, which was slurried in dichloromethane
(800 mL). The brown slurry was filtered through Celite. ICP
(0.22 mmol/g).
analysis of the filtrate showed a copper content of 345 ppm
wt/wt.
Using a Biotage SP4 Flash Purification System, the crude
solution was passed through a QuadraPure IDA cartridge
Suzuki Reaction. 2-Bromopyridine (1.5 mL; 15.7 mmol),
4
-methoxybenzene boronic acid (2.96 g; 19.5 mmol), pal-
ladium(II) acetate (180 mg; 5 mol %), triphenylphosphine
780 mg, 20 mol %), potassium carbonate (13.0 g; 94 mmol),
(
(40+M). A gradient was run of 4 CV of dichloromethane
distilled water (15 mL), and isopropyl alcohol (150 mL) were
added successively to a 500-mL round-bottom flask. The
reaction mixture was heated under a nitrogen atmosphere at
reflux overnight. After this time GC/MS analysis indicated
that the reaction had gone to full conversion.
The cooled reaction mixture was partitioned between
dichloromethane (150 mL) and water (100 mL). The organic
layer was washed with brine solution, dried over magnesium
sulfate, and then filtered through Celite. The resulting
solution was diluted to 300 mL with dichloromethane and a
sample taken for ICP analysis (60 ppm wt/wt with respect
to palladium).
Using a Biotage SP4 Flash Purification System, 100 mL
of the crude solution was passed through a 12+M cartridge
of QuadraPure TU. A gradient was run consisting of initial
waste of 4 CV of dichloromethane (48 mL), with 25 CV for
the reaction mixture (300 mL, equating to the 100-mL portion
of reaction mixture and additional 200 mL of dichlo-
romethane) and 2 CV of dichloromethane (24 mL), at 1 mL/
min. Product-containing fractions (51 mL each, identified
by UV 232 and 254 nm, see Supporting Information) were
pooled and concentrated to 100 mL, and a sample was taken
for ICP analysis (<1 ppm wt/wt with respect to palladium).
Concentration in vacuo gave the crude product (0.967 g, 4
ppm wt/wt with respect to palladium).
(528 mL), with 7.6 CV for the reaction mixture (999 mL)
followed by 2 CV of dichloromethane (264 mL) at 8 mL/
min. The colourless product-containing fractions (51 mL
each, identified by UV) were pooled, and a sample was taken
for ICP analysis, which gave a result of less than 1 ppm of
copper in the final solution.
Sonogashira Reaction. Dichlorobis(triphenylphosphine)-
palladium(II) (175 mg; 5 mol %), copper(I) iodide (95 mg;
1
4
0 mol %), triethylamine (726 mg; 1.0 mL; 7.2 mmol),
-iodoacetophenone (1.23 g; 5.0 mmol), and phenyl acetylene
(0.82 mL; 7.5 mmol) were taken up in THF (100 mL) and
stirred at room temperature under a nitrogen atmosphere
overnight. After 18 h, GC/MS indicated complete conversion.
The reaction mixture was filtered through Celite, washing
with THF (150 mL).
The filtrate was concentrated in vacuo to 100 mL and
passed through a 25+S cartridge of QuadraPure TU using a
gradient of 4 CV of THF (96 mL), followed by 12.5 CV for
the reaction mixture and additional THF (300 mL), and
finally 1 CV of THF (24 mL) at 2 mL/min. The product-
containing fractions (51 mL each, identified by UV 232 and
2
54 nm, see Supporting Information) were pooled, and a
sample was taken for ICP analysis (<1 ppm wt/wt of
palladium).
Michael Addition. As per the literature procedure,18
methylvinylketone (5.0 mL, 60.7 mmol) was added dropwise
via syringe pump over 30 min to a stirred flask containing
ethyl 2-oxocyclohexane carboxylate (9.07 g, 53.3 mmol) and
iron(III) chloride (180 mg, 1.1 mmol, 2 mol %) immersed
in a water bath acting as a heat sink at room temperature
and then stirred overnight. After 18 h, GC/MS indicated
complete conversion. Volatiles were removed under reduced
Another 100-mL portion of the crude solution was passed
through a Biotage Flash AC 12+M cartridge containing
activated Nuchar carbon. A gradient was run consisting of
the initial waste of 4 CV of dichloromethane (48 mL), with
2
1
5 CV for the reaction mixture (300 mL, equating to the
00-mL portion of reaction mixture and an additional 200
mL of dichloromethane) and 8.2 CV of dichloromethane (99
mL), at 15 mL/min. Product-containing fractions (51 mL
each, identified by UV, see Supporting Information) were
(21) www.biotage.com/DynPage.aspx?id)22001 (accessed October 2006).
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Vol. 11, No. 3, 2007 / Organic Process Research & Development