Organic Process Research & Development
Article
of 2 m/s and unless otherwise stated a transmembrane pressure
of 10 bar.
Low-temperature NMR to confirm presence of water in the
complex.
1H NMR (CDCl3, 400 MHz, −40 °C): δ 8.5 (br, 2 H, H2O),
7.67−7.60 (m, 2 H), 7.48−7.41 (m, 4 H), 7.17 (s, 2 H), 2.70
(sept, J = 6.5 Hz, 4 H), 1.80 (s, 6 H), 1.31 (d, J = 6.1 Hz, 12
H), 1.09 (d, J = 6.6 Hz, 12 H).
4-Chlorotoluene, (4-methoxyphenyl)boronic acid, and po-
tassium−tert-butoxide were purchased from Sigma-Aldrich
(Belgium), Umicore cross coupling series catalysts, CX-31,
and Peppsi-IPr were donated by Umicore AG & Co. KG
(Hanau, Germany). All membrane experiments were per-
formed in an in-house made cross-flow nanofiltration unit on
lab scale.
Cross-coupling reactions were analyzed on a waters UPLC
with a UV/vis PDA detector. A Waters Acquity BEH C18
column with dimensions of 2.1 × 50 mm, 1.7 μm, and a
gradient of water and acetonitrile buffered with 0.1% formic
acid. The column temperature was 40 °C, and the detector was
used at a wavelength of 270 nm.
Synthesis of acac Complex IPr-Pd(acac)Cl (4). A 10 mL
flask was charged with 1,3-bis(2,6-diisopropylphenyl)-1H-
imidazol-3-ium chloride (1) (425 mg, 1.00 mmol, 1.00 equiv)
and Pd(acac)2 (308 mg, 1.00 mmol, 1.00 eq.; purity: 99%)
under argon. Then, 1,4-dioxane (5 mL) was added, and the
mixture was heated to 100 °C (preheated oil bath). A yellow
suspension resulted that after several minutes turned orange
and was stirred for 17 h giving a yellow-orange homogeneous
mixture. The reaction progress was monitored by TLC (50%
acetone/heptanes). Upon cooling a precipitate formed. Celite
was added, the solvent was evaporated, and the residue was
purified chromatographically on silica (20 g; stepwise gradient;
eluent: 5−10% acetone/heptanes). After drying under reduced
pressure a yellow solid (582 mg, 0.92 mmol, 92% yield) was
obtained.
Analysis of Pd species was carried out using inductively
coupled plasma atomic emission spectroscopy (ICP-AES).
After evaporation of the solvent from the sample the residue
was digested using aqua regia and diluted with deionized water
to the required concentration range. The samples were then
analyzed for metal content.
1H NMR (400 MHz) and 13C NMR (100 MHz) were
Mp = 220−222 °C (dec.). Rf (50% acetone/heptanes) =
1
1
0.56. H NMR (CDCl3, 400 MHz): δ 7.52−7.47 (m, 2 H),
recorded on a Bruker Avance 400 instrument. For H NMR
7.36−7.32 (m, 4 H), 7.10 (s, 2 H), 5.11 (s, 1 H), 2.95 (sept, J =
6.7 Hz, 4 H), 1.83 (s, 3 H), 1.81 (s, 3 H), 1.33 (d, J = 6.6 Hz,
12 H), 1.09 (d, J = 6.9 Hz, 12 H). 13C NMR (CDCl3, 100
MHz): δ 186.8 (Cquat), 183.6 (Cquat), 156.1 (Cquat), 146.7
(Cquat), 135.1 (Cquat), 130.5 (CH), 125.3 (CH), 124.2 (CH),
99.5 (CH), 28.6 (CH), 27.2 (CH3), 27.1 (CH3), 26.4 (CH3),
23.1 (CH3).
spectra, chemical shifts (δ) are given relative to external TMS
(0.00 ppm). For 13C NMR spectra, chemical shifts (δ) are
given relative to CDCl3 (77.0 ppm). Coupling constants (J) are
reported in Hz. The following abbreviations are used: s, singlet,
d, doublet, t, triplet, q, quartet, quint, quintuplet, sept,
septuplet, m, multiplet, br, broad.
Melting points were measured with a Buchi B-545 melting
̈
General Cross-Coupling Procedure Batch Process. A
flask equipped with a magnetic stirring bar was charged with a
Pd catalyst (0.025 mmol, 0.5 mol %), 4-methoxyphenylboronic
acid (6 mmol, 1.2 equiv), and potassium tert-butoxide (6.5
mmol, 1.3 equiv). The flask was sealed with septum, and
ethanol (4 mL,) was added via syringe. The mixture was
degassed for 3 min; the flask was filled with argon, and the
reaction mixture was stirred in a preheated bath at 30° for 30
min. A degassed solution of 4-chlorotoluene (5 mmol, 1 equiv)
in ethanol (2 mL) was added, and the reaction mixture was
stirred at 30 °C for 4 h. 100 μL samples of the reaction mixture
were taken every 15 min and quenched by adding the sample to
a vial containing 500 μL of an aqueous saturated ammonium
chloride solution.
General Cross-Coupling Procedure with Online
Membrane Assisted Processing. To the filtration apparatus
fitted with a 120 mm single tube ceramic membrane was added
450 mL of a solution of Pd complex CX-31 (65 mg, 0.1 mmol,
0.01 equiv) in ethanol, previously degassed by bubbling
nitrogen through for 10 min. The circulation pump was
switched on and the mixture circulated at atmospheric pressure
until the internal temperature was 30 °C. A sample was taken
for ICP-AES analysis. Connected to the filtration apparatus via
a pump and set up to perform constant volume diafiltration was
a 150 mL solution of 4-chlorotoluene (1.27 g, 10 mmol, 1.0
equiv), (4-methoxyphenyl)boronic acid (1.67 g, 11 mmol, 1.1
equiv), potassium formate (0.42 g, 5 mmol, 0.5 equiv), and
potassium−tert-butoxide (1.45 g, 13 mmol, 1.3 equiv) in
ethanol (diafiltration solution) also degassed. The system
brought under pressure (10 bar), the membrane flux was
continually monitored. The reaction was allowed to proceed in
such a manner for 5 h with regular sampling of the filtration
loop contents (retentate), diafiltration solution, and the
point apparatus. Thin layer chromatography (TLC) was carried
out on silica-gel plates (Merck F254). Spots were detected with
UV light and revealed with KMnO4 or ninhydrin solutions.
Synthesis of IPrPd(OAc)2OH2 (3). A 25 mL flask under an
atmosphere of argon was charged with 1,3-bis(2,6-diisopropyl-
phenyl)-1H-imidazol-3-ium chloride (1) (213 mg, 0.50 mmol,
1.00 equiv). Subsequently, 10 mL of THF (degassed with argon
by purging the gas through the solvent for 15 min) was added,
and the mixture degassed with argon for an additional 5 min.
To this suspension, potassium tert-butoxide (112 mg, 1.00
mmol, 2.00 equiv) was added in a single portion. The beige-
yellowish mixture was stirred for 4 h. It was then filtered, under
argon, through glass filter with 0.5 g of Celite and a pad of
cotton directly into a 25 mL flask and washed portion wise with
5 mL of degassed THF. Palladium(II) acetate (135 mg, 0.60
mmol, 1.20 equiv) was added in one portion to give an orange-
brown homogeneous mixture that was stirred o/n at room
temperature. Solvent was evaporated under reduced pressure,
and the residue dissolved in 10 mL of DCM and washed with
10 mL of water. The aq. phase was extracted with DCM (2 × 5
mL; org. phase became colorless). After evaporation, the
orange-brown solid was dissolved in 1 mL of DCM, and 10 mL
of pentane was added. The resulting precipitate was sonicated
in ultrasound bath, filtered, and rigorously washed with
pentane. After drying under reduced pressure, an orange-
brown solid was obtained (235 mg, 0.37 mmol, 74% yield).
1H NMR (CDCl3, 400 MHz): δ 7.61−7.55 (m, 2 H), 7.43−
7.39 (m, 4 H), 7.10 (s, 2 H), 2.76 (sept, J = 6.8 Hz, 4 H), 1.74
(s, 6 H), 1.34 (d, J = 6.7 Hz, 12 H), 1.09 (d, J = 6.9 Hz, 12 H).
13C NMR (CDCl3, 100 MHz): δ 182.2 (Cquat), 151.0 (Cquat),
146.4 (Cquat), 134.7 (Cquat), 131.0 (CH), 125.5 (CH), 124.5
(CH), 28.5 (CH), 26.3 (CH3), 24.7 (CH3), 23.1 (CH3).
H
Org. Process Res. Dev. XXXX, XXX, XXX−XXX