University of Groningen
Pd-NHC Catalyzed Conjugate Addition versus the Mizoroki-Heck Reaction
Gottumukkala, Aditya L.; de Vries, Johannes G.; Minnaard, Adriaan J.
Published in:
Chemistry
DOI:
10.1002/chem.201003643
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
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Publication date:
2011
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Gottumukkala, A. L., de Vries, J. G., & Minnaard, A. J. (2011). Pd-NHC Catalyzed Conjugate Addition
versus the Mizoroki-Heck Reaction.
Chemistry
,
17
(11), 3091-3095.
https://doi.org/10.1002/chem.201003643
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Supporting Information
Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 694 51 Weinheim, 2011
Pd–NHC Catalyzed Conjugate Addition versus the Mizoroki–Heck Reaction
Aditya L. Gottumukkala,
[a]
Johannes G. de Vries,*
[a, b]
and Adriaan J. Minnaard*
[a]
chem_201003643_sm_miscellaneous_information.pdf
S1
General Information:
Glassware and Handling:
All experiments were carried out in flame dried or oven dried (150
o
C) glassware, in an
atmosphere of nitrogen, unless specified otherwise, by standard Schlenk techniques. Schlenk
reaction tubes with screwcaps, and equipped with a Teflon-coated magnetic stirbar were
flame dried under vacuum and allowed to return to room temperature prior to being charged
with reactants. A manifold permitting switching between nitrogen atmosphere and vacuum
was used to control the atmosphere in the reaction vessel. Once charged with all the
reactants, the reaction vessel was cycled through at least 3 cycles of nitrogen-vacuum-
nitrogen to ensure the atmosphere was inert.
Reaction temperature refers to the temperature of the oil bath.
Flash Chromatography was performed using Merck silica gel type 9385 (230-400 mesh),
using the indicated solvents.
Microwave experiments were performed on a CEM Discover Microwave apparatus, in crimp-
sealable reaction tubes. The tubes were prepared similar to reactions in oil bath. The
reactions were performed under Constant-Temperature Mode (Temperature Max 80
o
C), 110
W, with air-cooling, for 30 min. Work up and analysis was similar to reactions performed in oil
bath.
Solvents and Reagents
All solvents used for extraction, filtration and chromatography were of commercial grade, and
used without further purification, except for pentane, which was distilled prior to use. Peptide
Synthesis grade DMF used for reaction was purchased from BIOSOLVE BV (The
Netherlands) and degassed by a freeze-pump-thaw procedure (repeated cycles of freezing
under vacuum with liquid nitrogen and thawing to room temperature) prior to use. The
degassing was performed regularly in small batches, and once degassed, the DMF was used
within a few days.
Reagents were purchased from Sigma-Aldrich, Strem or Acros and used without further
purification. Analytical grade tri-n-butylamine was purchased from Sigma-Aldrich and stored
in an atmosphere of nitrogen. Palladium complex Pd
II
-NHC was synthesized as described in
literature
[1]
and stored under ambient conditions. Palladium complex Pd
0
-NHC was purchased
from Sigma-Aldrich and stored in a nitrogen-filled glovebox, from which the requisite amounts
were weighed out.
S2
Analysis
TLC was performed on Merck silica gel 60, 0.25 mm plates and visualization was done by UV
and staining with Seebach’s reagent (a mixture of phosphomolybdic acid (25 g), cerium (IV)
sulfate (7.5 g), H
2
O (500 mL) and H
2
SO
4
(25 mL)).
1
H- and
13
C-NMR were recorded on a Varian AMX400 (400, 100.59 MHz, respectively) using
CDCl
3
as solvent, unless specified otherwise. Chemical shift values are reported in ppm with
the solvent resonance as the internal standard (CHCl
3
: δ7.26 for 1H, δ 77.0 for 13C). Data
are reported as follows: chemical shifts (δ), multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, br = broad, m = multiplet), coupling constants J (Hz), and integration.
GC-MS measurements were made using a HP 6890 Series Gas Chromatograph system
equipped with a HP 5973 Mass Sensitive Detector. GC measurements were made using a
Shimadzu GC 2014 gas chromatograph system bearing a AT5 column (Grace Alltech) and
FID detection. Whenever GC yield is reported, the quantification was done using cyclo-octane
as internal standard.
High Resolution Mass measurements were performed using a ThermoScientific LTQ Oribitrap
XL spectrometer.
S3
Experimental Procedure for Conjugate Addition:
A Schlenk tube equipped with screwcap and egg-shaped Teflon coated stirbar was flame
dried under vacuum and allowed to cool down to room temperature under vacuum. The tube
was backfilled with nitrogen prior to opening the cap. 4-Iodoanisole (2.72 mmol, 637 mg), and
benzalacetone (1.14 mmol, 166.4 mg) were charged under a stream of nitrogen. The tube
was capped with a rubber septum and subjected to 3 cycles of vacuum and nitrogen. Pd
0
-
NHC (1.5 mol%, 0.017 mmol) was weighed under nitrogen, dissolved in 1 mL of degassed
DMF and injected into the reaction tube. Tri-n-butylamine (5.1 mmol, 1.2 mL) was added via
syringe, and the septum was replaced by a screw cap. The reaction mixture is biphasic with
the DMF layer being colored and the tri-n-butylamine being nearly colorless or faint yellow.
The Schlenk tube was then alternated through 3 cycles of vacuum and nitrogen, and placed
into a pre-heated oil bath at 80
o
C.
Upon completion as judged by GC-MS and/or TLC, (sampled from the DMF layer) the
reaction was cooled to room temperature and poured into 10% HCl (v/v) solution (10 mL) and
extracted with ether (3 X 25 mL). The organic extracts were combined, dried over anhydrous
MgSO
4
and concentrated in vacuo. The concentrate was loaded directly or adsorbed onto
silica prior to loading onto a silica gel column and eluted
Experimental Procedure for the Mizoroki-Heck Reaction:
A Schlenk tube equipped with screwcap and egg-shaped Teflon coated stirbar was flame
dried under vacuum and allowed to cool down to room temperature under vacuum. The tube
was backfilled with nitrogen prior to opening the cap. 4-Iodoanisole (1 mmol, 234 mg),
benzalacetone (1.5 mmol, 219 mg), and cesium pivalate (2 mmol, 652 mg) were charged
under a stream of nitrogen. The tube was capped with a rubber septum and subjected to 3
cycles of vacuum and nitrogen. Pd
0
-NHC (1.5 mol%, 0.017 mmol) was weighed under
nitrogen, dissolved in 1 mL of degassed DMF and injected into the reaction tube. The Schlenk
tube was then alternated through 3 cycles of vacuum and nitrogen, and placed into a pre-
heated oil bath at 80
o
C.
Upon completion as judged by GC-MS and/or TLC, the reaction was cooled to room
temperature and poured into 10% HCl (v/v) solution (10 mL) and extracted with ether (3 X 25
mL). The organic extracts were combined, dried over anhydrous MgSO
4
and concentrated in
vacuo. The concentrate was loaded directly or adsorbed onto silica prior to loading onto a
silica gel column and eluted.