Preparation of Dicationic Palladium Catalysts for Asymmetric
Catalytic Reactions.
Andrey E. Sheshenev, Alexander M. R. Smith and King Kuok (Mimi)
Hii*
Department of Chemistry, Imperial College London, South
Kensington, London SW7 2AZ, U.K.
ABSTRACT
The synthesis of Pd(OTf)2∙2H2O is described. This was used to
generate two different types of chiral dicationic palladium
complexes for highly enantioselective addition of aromatic amines
to -unsaturated conjugate alkenes, furnishing optically active
N-arylated -amino acid derivatives, which are valuable synthetic
intermediates for the synthesis of biologically active molecules
and peptidomimetics. The use of these catalysts in the
enantioselective aza-Michael addition of aromatic amines is
demonstrated.
INTRODUCTION
Dicationic (diphosphine)palladium(II) complexes are widely used
in asymmetric catalysis, and have been shown particularly to have
broad generality for the functionalisation of chelating Michael
donors containing enolisable carbon pronucleophiles (e.g.
-ketoesters, malonate esters, silyl enol ethers), where stereogenic
C-C,1-12 C-N,13 C-F14-20 and C-O21,22 bonds can be constructed. On
the other hand, these dicationic palladium complexes are also one
of the most effective catalyst systems for the conjugate addition
of aromatic amines to chelating Michael acceptors.23-29 Utilisation
of these catalysts in other type of reactions (with more limited
reaction scope) includes hydroamination,30,31 Friedel-Crafts,32 as
well as [2+2]33 and [4+2]34 cycloaddition reactions. Compared with
other transition metal-based Lewis acid catalysts, the dicationic
palladium complexes are much more stable towards air and moisture,
and can generally be employed in lower catalytic loadings.
Figure 1. Mono- and dimeric forms of dicationic diphosphine
palladium(II) complexes.
The catalyst can be utilised in one of two forms (Figure 1),
either as a monomeric dicationic bis-solvate complex (I), which
acts primarily as a Lewis acid, or the dimeric hydroxyl-bridged
complex (II), which has dual Lewis acid-Bronsted base properties.
The bis(aqua) complex of the bis(trifluoromethanesulfonate) salt
(solv = H2O, X = CF3SO3) is, by far, the most typical example,
although the nature of the coordinated solvate (solv = CH3CN, or a
mixture of H2O and CH3CN) and counteranion (X = BF4,11 SbF633) can
be varied, and can be interchanged.34 The coordinated water
molecule can be easily deprotonated to form the dimeric complex II.
Complexes of other congeners of BINAP, such as tol-BINAP, SEGPhos,
etc., are also reported, and are known to be more effective for
certain catalytic reactions.8
A common route to dicationic palladium(II) complexes uses silver
salts to abstract halides from the corresponding
[(diphosphine)PdCl2] complex in wet acetone9 or acetonitrile,30 but
the method has drawbacks, namely, the preparation requires the
addition of at least two equivalents (often in excess) of the
silver salt to the corresponding [(diphosphine)PdX2] complex (where
X = Cl or Br). As a result, careful and/or repeated
recrystallisation of the resultant complex is required to remove
all traces of silver salt, which may also be catalytically active,
inducing a competitive formation of racemic products, compromising
the enantioselectivity of the reaction.
In 1994, the preparation of Pd(OTf)2∙2H2O was described by
Murata and Ido,35 by the reaction of palladium(II) salts with
trifluoromenthanesulfonic (triflic) acid, who also showed that they
can be used as effective catalyst precursors for the synthesis of
[(diphosphine)Pd(OTf)2] complexes. However, only achiral phosphine
ligands were used, and consequently, asymmetric catalysis was not
demonstrated. We have subsequently shown that this palladium salt
can be used to generate chiral catalyst from chiral diphosphines,
and demonstrated their utility in the asymmetric aza-Michael
reactions, either as a catalyst precursor, to generate the
complexes in situ, or isolated complexes.26 Herein, we will
describe the preparation of Pd(OTf)2∙2H2O (1) in detail, from
commercially available reagents; we will also describe how it can
be used to generate [(R-BINAP)Pd(OH2)2][OTf]2 (2) and
[(R-BINAP)Pd(µ-OH)]2[OTf]2 (3) complexes, and the examples of how
they can be employed to attain highly enantioselective Michael
addition of aromatic amines to N-alkenoyl carbamates.
__________________________________________________________________________________
BOX 1 REPRESENTATIVE EXAMPLE OF THE USE OF 2 AND 3 IN
AZA-MICHAEL ADDITION REACTIONS
Figure 2. Enantioselective addition of an aromatic amine to an
N-alkenoyl carbamate.
Catalyst 2 can be used in the addition of non-nucleophilic
aromatic amines to -unsaturated Michael acceptors containing
1,3-dicabonyl chelating moieties, such as N-alkenoyl
oxazolidinones,23 carbamates24 or imides36 (Protocol A). On the
other hand, for the addition of nucleophilic aromatic amines, the
reaction is more effective when the amine is employed as a salt, in
combination with catalyst 3 (Protocol B),25,28,29 to provide a
buffered environment, where catalyst deactivation by amine binding
to the Lewis acidic centre can be minimised.
Protocol A
1 Weigh out methyl (2E)-but-2-enoylcarbamate (0.20 g, 1.40 mmol)
and catalyst (2) (0.045 g, 0.042 mmol, 3 mol %), place them into a
reaction tube equipped with a magnetic stirring bar, and purge the
tube with nitrogen.
2 Add dry THF (3.5 mL) to the tube via syringe under nitrogen. A
yellow solution is formed.
3 Add a solution of aniline (0.13 g, 1.40 mmol) in dry THF (3.5
mL) using a syringe pump (addition speed 0.2 mL/h) under a nitrogen
atmosphere (ambient temperature). When the addition is complete,
the reaction mixture is stirred for a further 3 h. The colour of
the reaction mixture turns deep-orange by the end of the
reaction.
Fast addition of aniline can cause significant yield
deterioration due to the deactivation of the catalyst.
4 Transfer the reaction mixture into a round bottom flask (50
mL) and concentrated to dryness using a rotary evaporator.
Do not heat the water bath over 35 °C, to avoid possible
racemisation of the product.
5 Pack a chromatography column (D 35 mm, L 300 mm) with 25 g of
silica using a mixture of hexane/ethyl acetate (3:2 v/v) as
eluant.
6 Dissolve the crude product in the eluant and load it onto the
packed column.
7 Add a layer of quartz sand (5 mm) on top of the column to
prevent drying.
8 Elute the column under the atmospheric pressure; collect 5 mL
fractions.
9 Analyse the contents of the collected fractions by thin-layer
chromatography (using hexane:ethyl acetate 3:2 v/v), Rf of the
product is found at 0.30.
10 Combine fractions containing the product and evaporate using
the rotary evaporator.
11 Dry the product under high vacuum.
Protocol B
1 Weigh out methyl (2E)-but-2-enoylcarbamate (0.20 g, 1.40
mmol), aniline triflate (PhNH2∙HOTf, 0.51 g, 2.10 mmol) and
catalyst 2 (0.038 g, 0.021 mmol, 1.5 mol %). Place them into a
reaction tube equipped with a magnetic stirring bar, and purge it
with nitrogen.
2 Add dry THF (2.8 mL) to the reaction tube via a syringe. A
yellow solution is formed.
3 Stir the reaction mixture for 18 h at room temperature. The
colour of the reaction mixture turns orange by the end of the
reaction.
4 Quench the reaction mixture by the addition of cold saturated
aqueous NaHCO3 (5 mL) with ice bath cooling.
Quenching at room temperature result in a decrease in the
enantiomeric purity of the product.
5 Dilute the reaction mixture with ethyl acetate (10 mL),
separate the aqueous layer and extracted it with ethyl acetate (5
mL).
6 Successively wash the combined organic layers with brine (5
mL) and dry over MgSO4.
7 Filter the solution and remove the solvent using a rotary
evaporator.
Do not heat the bath over 35 °C to avoid possible racemisation
of the product.
8 Purify the residual orange solid by column chromatography on
silica gel as described above (steps 5-11).
As 1.5 equiv. of aniline triflate is used, unreacted aniline can
be recovered in approx. 80% yield.
(3-Phenylaminobutyryl)carbamic acid methyl ester prepared by
Protocol A: yield 76%, 93% ee; prepared by Protocol B: yield 94%,
97% ee. The physical properties of the aza-Michael adduct are
dependent upon its optical purity. Racemic samples are found to
have higher melting points than optically active samples.37 In this
case, the racemic and 93% ee samples appeared as solids (A and B,
figure 4), while the sample containing 97% ee is a colourless
viscous oil (C, Figure 4). The products may be hydrolysed to
furnish the corresponding N-aryl--amino acids or amides.24
Colourless gum-like solid, mp 89.5–91 °C, [α]D = –3.3 (c 3.62,
CHCl3, 93% ee) or colourless viscous oil, [α]D –4.9 (c 3.69, CHCl3,
97% ee). Chiral HPLC (Chiralpak AD-H column, 1.0 mL/min, hexane:IPA
95:5 v/v, 254 nm) tR (major) = 25.0 min, tR (minor) = 29.8 min
(Figure 3). 1H NMR (400 MHz, CDCl3) δ 7.86 (br s, 1H), 7.21–7.14
(m, 2H), 6.72 (m, 1H), 6.64 (m, 2H), 4.03 (m, 1H), 3.76 (s, 3H),
3.76 (s, 1H), 3.05 (dd, 1H, J = 15.9, 6.0 Hz), 2.89 (dd, 1H, J =
15.9, 6.0 Hz), 1.30 (d, 3H, J = 6.3 Hz). 13C-{1H} NMR (100 MHz,
CDCl3) δ 172.6, 152.2, 146.7, 129.3, 118.0, 113.9, 53.0, 46.0,
42.2, 20.8.
Figure 3. Chiral HPLC chromatograms of
(3-phenylaminobutyryl)carbamic acid methyl ester: (a) racemic
sample; (b) prepared by protocol A; (c) prepared by protocol B.
Figure 4. Visual appearances of the aza-Michael adduct: A =
racemic sample; B = 93% ee; C = 97% ee.
__________________________________________________________________________________
EXPERIMENTAL DESIGN
Figure 5. Reaction Scheme.
Due to the highly corrosive nature of nitric acid and
trifluoromethanesulfonic acid, added precaution is necessary to
avoid direct contact with these reagents during the preparation of
Pd(OTf)2∙2H2O. The triflate salt is isolated as a hygroscopic,
light purple/lilac powder, which will degrade within minutes into a
dark brown liquid if left exposed to moist air. Pd(OTf)2∙2H2O has
been prepared successfully several times in our laboratory on 1-10
g scale. When not used immediately, it can be kept in a sealed tube
over P2O5 in a desiccator for up to a year without any visible
degradation.
Use of acetonitrile as a coordinating solvent helps to stabilise
the product and avoid the formation of the 1:2 adduct,
[Pd(R-BINAP)2][OTf]2, which is observed as a side-product when the
reaction is performed in CH2Cl2.26 During the preparation of the
diphosphine complexes, exposure of Pd(OTf)2∙2H2O to acetonitrile in
the absence of ligands should be kept to a minimum to avoid
polymerisation of the solvent. Once prepared, the diphosphine
palladium complexes can be stored at room temperature in a sealed
vial, although exposure to light should be minimised. Samples
prepared >5 years ago in our laboratory has retained their
original effectiveness.
The procedure has been repeated numerous times by several
researchers of varying abilities (undergraduate, postgraduate and
postdoctoral researchers) in over 7 years in our laboratory, during
which the chemical precursors have been procured from different
sources. This did not cause noticeable differences in the
results.
MATERIALS
CAUTION: All synthetic operations must be carried out in a fume
cupboard. Personal protective clothing (nitrile gloves, laboratory
coat and safety glasses) must be donned at all times.
• Palladium(II) nitrate hydrate (CAS Number 11102-05-3)
Oxidizer, irritant
• Trifluoromethanesulfonic acid (CAS Number 1493-13-6) Highly
corrosive, toxic
• (R)-(+)-(1,1′-Binaphthalene-2,2′-diyl)bis(diphenylphosphine)
(CAS Number 76189-55-4)
• Potassium carbonate Toxic, irritant
• Sodium hydroxide Toxic, irritant
• Magnesium sulfate (anhydrous)
• Acetonitrile extra dry (CAS Number 75-05-8) Flammable, toxic,
irritant
• Diethyl ether (anhydrous) Highly flammable, toxic
• Dichloromethane (anhydrous) Suspected carcinogenity
• Celite® 512 Medium (CAS Number 91053-39-3) Irritant
EQUIPMENT
•5-digit analytical balance
•Thermally controlled magnetic stirring plate
•Dreschel bottle (250 mL)
•Schlenk tubes (50 mL, 100 mL)
•Tubing adapter with side arm (cone size19/26, socket size
19/26)
•Rubber septa (joint: ST/NS 14/20, 19/22, 24/40)
•PVC tubing (8 mm bore, 10 mm O.D.)
•Teflon-coated stirring bars
•Disposable syringes (5 mL, 10 mL, 20 mL)
•Stainless steel needle (170 mm in length, size 21 gauge)
•Pasteur pipettes
•Pyrex centrifuge tubes (20 mL)
•Erlenmeyer flasks (100 mL, 500 mL)
•Centrifuge machine
•Glass vacuum oven for sample drying
•High-vacuum pump
•Disposable needles (120 mm, 50 mm)
•Funnels (diameter 55 mm, 80 mm)
•Pump (max pressure 100 mmHg)
•Heavy wall flat bottomed filter flasks (500 mL)
•Filtration funnel (diameter 4.5 mm, porosity 2)
•Melting point apparatus
•Polarimeter
REAGENT SETUP
• Anhydrous solvents (dichloromethane and diethyl ether) were
obtained using a solvent purification apparatus, by passing them
through columns of activated molecular sieves under N2.
• Preparation of 0.07 M aq. NaOH: the title solution was
prepared by dissolving NaOH pellets (0.28 g, 7.00 mmol) in
distilled water (100 mL).
EQUIPMENT SETUP
Figure 6. Equipment setup for the preparation of Pd(OTf)2∙2H2O
(steps 1-4).
•Preparation of palladium triflate (Figure 6): the Schlenk tube
and stirring bar were oven-dried at 100 °C overnight. The Schlenk
tube is attached to a N2/vacuum double manifold via a side arm
adapter, placed on top of the Schlenk tube (labeled A). The top of
the adapter was then sealed with a rubber septum (closing the tap
on the side of the Schlenk tube then gives a sealed vessel which
can be purged). The hose connector on the side of the Schlenk tube
(labeled B) was connected via plastic tubing to a Dreschel bottle
containing a sat. aq. K2CO3 solution (labeled C). This acts as an
acid scrubber for the waste stream.
•The glass vacuum oven for drying was set up at 120 °C.
•The centrifuge was set up at 1500 g.
Procedure
Steps 1-7: Synthesis of palladium(II)
bis(trifluoromethansulfonate) dihydrate, Pd(OTf)2.2H2O, 1
1 Weigh out Pd(NO3)2.nH2O (1.00 g, 4.34 mmol, anhydrous basis)
and place it in a Schlenk tube equipped with a stirring bar. Seal
with a rubber septum. Close the tap (B) on the side arm of the
Schlenk tube.
2 Attach the flask to a Schlenk line via the tubing adapter (A),
and evacuate the flask by the application of vacuum for 10 min with
magnetic stirring, then fill it with nitrogen gas under a slightly
positive pressure.
3 The tap on the Schlenk tube’s side-arm (B) is then released,
such that a steady stream of nitrogen flows from the flask into the
Dreschel bottle containing a solution of sat. aq. K2CO3 (acid
scrubber). Flow rate ca. 3 bubbles/sec.
4 With the magnetic stir bar set to rotate at 400 rpm, add
triflic acid (7.30 mL, 83.00 mmol) dropwise to the flask using a
disposable plastic syringe. Fuming (nitric acid vapour) should be
immediate visible (Figure 7) Maintain a rate of addition such as to
allow for a slow but steady quench of the acid vapour by the acid
scrubber. After complete addition, allow the resultant mixture to
stir at room temperature for a further 2 h.
Maintain a steady flow of nitrogen through the apparatus
throughout the procedure to purge the nitric acid fumes, and to
ensure that K2CO3 solution cannot be drawn back into the reaction
vessel, risking violent reaction with triflic acid.
5 Using a wide pipette, transfer the lilac slurry in roughly
equal quantities to two centrifuge tubes (Figure 7), seal them with
rubber septa and centrifuge at 1500 g for 5 min.
6 Remove the supernatant using a pipette, and place the tubes in
a small vacuum oven to dry at 120 °C and 0.03 mmHg for 18 h.
Whist slurried in triflic acid, palladium (II) triflate is
stable enough to be handled briefly in air.
7 Flush the drying piston with dry nitrogen before retrieving
the tubes, which are immediately sealed with a rubber septum.
Palladium triflate dihydrate is a pale-lilac powder. It is
highly moisture sensitive and must be handled avoiding contact with
air and stored in a desiccator over P2O5. Other less powerful
desiccants are less effective.
Figure 7. (a) Step 4: the addition of triflic acid; (b) Step 5:
transfer of the suspension containing the lilac product.
Steps 8-14: Synthesis of [(R-BINAP)Pd(OH2)2][OTf]2, 2
8 Equip a Schlenk tube with a stirring bar and a rubber septum,
then purge with nitrogen via the side-arm. Close the tap and remove
the nitrogen line, record the tare weight of the flask.
9 Under an inverted funnel attached to a nitrogen line, add
Pd(OTf)2∙2H2O (1) (2.44 g, 5.54 mmol) to the flask.
In order to reduce exposure to air, the palladium salt should be
added in a single portion. Seal the flask immediately and weigh it
again to ascertain the exact quantity.
10 Re-attach the nitrogen line to the side-arm and add dry
acetonitrile (50 mL). The formation of an orange solution is
observed. The solution will look brown/black in the presence of
colloidal palladium.
11 Remove the rubber septum and add (R)-BINAP (3.45 g, 5.54
mmol) to the solution as a single portion (Figure 8). Reseal the
tube and stir the reaction mixture at room temperature for 30 min.
If a clear, yellow solution is obtained, step 12 can be
skipped.
12 Using a Buchner funnel, filter the solution through a short
plug of Celite (~2 cm) and rinse with 10 mL of acetonitrile (Figure
8).
13 Dilute the filtrate (yellow solution) with diethyl ether (300
mL). Leave the resulting solution for 30 min at room temperature to
let the product precipitate (Figure 9). Collect the precipitated
product using a frit, rubber ring and filtration funnel.
14 Allow the solid to dry under vacuum.
The desired product is a stable yellow crystalline solid, which
can be stored indefinitely at room temperature in a closed vial,
purged with nitrogen.
Figure 8. (a) Step 11: Addition of (R)-BINAP to the solution of
Pd(OTf)2.2H2O. (b) Step 12: Filtration of reaction mixture through
Celite.
Figure 9. Step 13: Precipitation of complex 2.
Steps 15-19: Synthesis of [(R-BINAP)Pd(µ-OH)]2[OTf]2, 3
15 Weigh [(R-BINAP)Pd(OH2)2][OTf]2 (1.30 g, 1.22 mmol) into a
100 mL Erlenmeyer flask containing a magnetic stirrer. Dissolve it
in dichloromethane (20 mL) to form a yellow solution.
16 Using a 20 mL syringe, add aq. NaOH (0.07 M, 17.5 mL) in one
portion (Figure 10, left). To stop the solvent from evaporating,
seal the top of the reaction flask with an inverted septum, with an
escape needle (Figure 10, middle). Stir the reaction mixture
vigorously for 2 h, whereupon the solution turns a deep burgundy
colour (Figure 10, right).
17 Separate the biphasic mixture in a separatory funnel; wash
the organic layer with water (3×15 mL), dry it over anhydrous
MgSO4.
18 Separate the solution from the desiccant by filtration, and
concentrate the filtrate using a rotary evaporator.
19 Recrystallize the crude product from dichloromethane/diethyl
ether mixture (1.5 mL/5.0 mL), collect the product by
filtration
20 Dry the product under high vacuum.
The desired product is a stable red-orange powder and can be
stored at room temperature in a closed vial purged with
nitrogen.
Figure 10. Step 16: Addition of aq. NaOH and colour change
observed during the reaction.
Figure 11. Appearance of: (a) Palladium salt 1; and (b)
complexes 2 (left) and 3 (right).
TIMING
• Synthesis of (1): Steps 1-3, 15 min; Step 4, 2 h 10 min; Step
5, 10 min; Steps 6-7, 18 h 15 min. Total time: 20 h 50 min.
• Synthesis of (2): Step 8, 10 min; Step 9, 5 min; Step 10, 10
min; Steps 11, 35 min; Step 12, 15 min; Step 13, 1 h; Step 14, 3 h.
Total time: 5 h 15 min.
• Synthesis of (3): Step 15, 10 min; Step 16, 2 h 5 min; Steps
17-18, 1 h; Step 19, 30 min; Step 20, 3 h. Total time: 6 h 45
min.
ANTICIPATED RESULTS
In general, yields are usually very good for these
reactions:
Palladium salt 1: 90–94 %; monomeric complex 2: 91–97%; dimeric
complex 3: 90–97%.
TROUBLESHOOTING
Step
Problem
Solution
7
Pd(OTf)2∙2H2O (1) appears brown
The colour change is due to exposure to moist air. In some
cases, it may still be used for the preparation of 2, albeit in a
lower yield.
14
Poor recovery of complex 2
The mother liquor (filtrate) obtained in step 13 can be
evaporated using the rotavap, and further crops of crystals
obtained by recyrstallisation from acetonitrile/ether or
dichloromethane/ether.
14
Impurity present in diphosphine complex 2
Purified by recrystallisation (above), or start the synthesis
again with a fresh sample of 1.
16
Colour change not observed
The colour change may not be observed if more dilute solutions
of NaOH is used (< 0.007 M). In this case, the reaction progress
can be monitored by diluting aliquots of the organic layer with
CDCl3and analysed by 31P NMR spectroscopy.
ANALYTICAL DATA
Palladium triflate dihydrate (1): yield 94 %, pale-lilac powder,
mp > 300 °C.
[(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]-diaquo-palladium(II)
bis(trifluoromethanesulfonate) (2): yield 97 %, yellow crystals, mp
182.0–184.0 °C, [α]20D = +367.2 (c 1.22, CH2Cl2).
1H NMR (400 MHz, CDCl3) δ 7.86–7.84 (m, 6H), 7.70–7.63 (m, 12H),
7.56–7.50 (4H, m), 7.22 (t, 2H, J = 6.6 Hz), 7.06–7.02 (m, 3H),
6.90 (br s, 3H), 6.73 (d, 2H, J = 8.6 Hz), 4.00–3.75 (br s, 4H),
1.91 (s, 3H).
13C-{1H} NMR (100 MHz, CDCl3) δ 139.6, 135.0, 134.9, 134.8,
134.5, 133.0, 132.9, 132.0, 130.4, 130.3, 129.4, 129.3, 129.1,
128.7, 128.5, 127.7, 127.6, 127.0, 124.5, 123.9, 123.0, 122.4,
122.0, 121.0, 118.9, 118.8, 118.3, 2.3
31P -{1H} NMR (162 MHz, CDCl3) δ +33.0 (s)
[bis{((R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)palladium(II)}bis(μ−hydroxo)]
bis(trifluoromethanesulfonate) (3): yield 97 %, red-orange powder,
mp 223.0–224.0 °C, [α]20D =+652.2 (c 1.15, CH2Cl2).
1H NMR (400 MHz, CDCl3) δ 7.73–7.70 (m, 6H), 7.66–7.64 (m, 6H),
7.55–7.47 (m, 16H), 7.44–7.40 (m, 6H), 7.23–7.21 (t, 10H, J = 7.0
Hz), 7.11–7.03 (m, 16H), 6.59 (d, 4H, J = 8.6 Hz), -2.85 (s,
2H).
13C-{1H} NMR (100 MHz, CDCl3) δ 138.6, 138.6, 138.5, 134.7,
134.4, 132.9, 131.7, 131.6, 130.1, 128.9, 128.9, 128.8, 128.5,
128.2, 127.0, 126.9, 124.8, 124.1, 123.4, 123.0, 122.8, 120.4,
119.9, 119.8
31P-{1H} NMR (162 MHz, CDCl3) δ +29.1 (s)
AFFILIATION
Department of Chemistry, Imperial College London, U.K.
ACKNOWLEDGMENTS
AES is supported by a Marie Curie Intra European Fellowship,
within the 7th European Community Framework Programme (Project
252247).
CONTRIBUTIONS
AMRS refined the original procedures for catalyst preparation,
AES carried out the experimental procedure and aza-Michael
reactions, and KKH assembled the manuscript.
COMPETING FINANCIAL INTERESTS
The authors declare no competing financial interests.
CORRESPONDING AUTHOR
Correspondence to: K. K. (Mimi) Hii, Department of Chemistry,
Imperial College London, South Kensington, London SW7 2AZ, U.K.
REFERENCES
1Hamashima, Y., Hotta, D. & Sodeoka, M. Direct generation of
nucleophilic chiral palladium enolate from 1,3-dicarbonyl
compounds: Catalytic enantioselective Michael reaction with enones.
J. Am. Chem. Soc. 124, 11240-11241 (2002),
doi:10.1021/ja027075i.
2Hamashima, Y., Hotta, D., Umebayashi, N., Tsuchiya, Y., Suzuki,
T. & Sodeoka, M. Catalytic enantioselective Michael reaction of
1,3-dicarbonyl compounds via formation of chiral palladium enolate.
Adv. Synth. Catal. 347, 1576-1586 (2005),
doi:10.1002/adsc.200505199.
3Hamashima, Y., Sasamoto, N., Hotta, D., Somei, H., Umebayashi,
N. & Sodeoka, M. Catalytic asymmetric addition of
beta-ketoesters to various Imines by using chiral palladium
complexes. Angew. Chem. Int. Ed. 44, 1525-1529 (2005),
doi:10.1002/anie.200462202.
4Sasamoto, N., Dubs, C., Hamashima, Y. & Sodeoka, M.
Pd(II)-catalyzed asymmetric addition of malonates to
dihydroisoquinolines. J. Am. Chem. Soc. 128, 14010-14011 (2006),
doi:10.1021/ja065646r.
5Fukuchi, I., Hamashima, Y. & Sodeoka, M. Catalytic
asymmetric aldol reactions of enolizable carbon pronucleophiles
with formaldehyde and ethyl glyoxylate. Adv. Synth. Catal. 349,
509-512 (2007), doi:10.1002/adsc.200600568.
6Umebayashi, N., Hamashima, Y., Hashizume, D. & Sodeoka, M.
Catalytic enantioselective aldol-type reaction of beta-ketosters
with acetals. Angew. Chem. Int. Ed. 47, 4196-4199 (2008),
doi:10.1002/anie.200705344.
7Hamashima, Y., Sasamoto, N., Umebayashi, N. & Sodeoka, M.
Pd-II-catalyzed asymmetric addition reactions of 1,3-dicarbonyl
compounds: Mannich-type reactions with N-Boc Imines and
three-component aminomethylation. Chemistry--Asian J. 3, 1443-1455
(2008), doi:10.1002/asia.200800120.
8Sodeoka, M. & Hamashima, Y. Chiral Pd aqua
complex-catalyzed asymmetric C-C bond-forming reactions: a Brønsted
acid-base cooperative system. Chem. Commun. 5787-5798 (2009),
doi:10.1039/b911015a.
9Sodeoka, M., Tokunoh, R., Miyazaki, F., Hagiwara, E. &
Shibasaki, M. Stable diaqua palladium(II) complexes of BINAP and
Tol-BINAP as highly efficient catalysts for asymmetric aldol
reactions. Synlett, 463 (1997).
10Hagiwara, E., Fujii, A. & Sodeoka, M. Enantioselective
addition of enol silyl ethers to imines catalyzed by palladium
complexes: A novel way to optically active acylalanine derivatives.
J. Am. Chem. Soc. 120, 2474-2475 (1998), doi:10.1021/ja973962n.
11Fujii, A., Hagiwara, E. & Sodeoka, M. Mechanism of
palladium complex-catalyzed enantioselective Mannich-type reaction:
Characterization of a novel binuclear palladium enolate complex. J.
Am. Chem. Soc.121, 5450-5458 (1999), doi:10.1021/ja9902827.
12Fujii, A., Hagiwara, E. & Sodeoka, M. Asymmetric
Mannich-type reaction catalyzed by palladium complexes. J. Synth.
Org. Chem. Jpn 58, 728-735 (2000).
13Kang, Y. K. & Kim, D. Y. Catalytic enantioselective
electrophilic α-amination of β-ketoesters catalyzed by chiral
palladium complexes. Tetrahedron Lett. 47, 4565-4568 (2006),
doi:10.1016/j.tetlet.2006.05.003.
14Hamashima, Y., Yagi, K., Takano, H., Tamas, L. & Sodeoka,
M. An efficient enantioselective fluorination of various
beta-ketoesters catalyzed chiral palladium complexes. J. Am. Chem.
Soc. 124, 14530-14531 (2002), doi:10.1021/ja028464f.
15Hamashima, Y., Suzuki, T., Takano, H., Shimura, Y. &
Sodeoka, M. Catalytic enantioselective fluorination of oxindoles.
J. Am. Chem. Soc. 127, 10164-10165 (2005),
doi:10.1021/ja0513077.
16Hamashima, Y., Suzuki, T., Shimura, Y., Shimizu, T.,
Umebayashi, N., Tamura, T., Sasamoto, N. & Sodeoka, M. An
efficient catalytic enantioselective fluorination of
beta-ketophosphonates using chiral palladium complexes. Tetrahedron
Lett. 46, 1447-1450 (2005), doi:10.1016/j.tetlet.2005.01.018.
17Hamashima, Y., Suzuki, T., Takano, H., Shimura, Y., Tsuchiya,
Y., Moriya, K.-i., Goto, T. & Sodeoka, M. Highly
enantioselective fluorination reactions of beta-ketoesters and
beta-ketophosphonates catalyzed by chiral palladium complexes.
Tetrahedron 62, 7168-7179 (2006),
doi:10.1016/j.tet.2005.12.070.
18Hamashima, Y. & Sodeoka, M. Enantioselective fluorination
reactions catalyzed by chiral palladium complexes. Synlett,
1467-1478 (2006), doi:10.1055/s-2006-941578.
19Moriya, K.-i., Harnashima, Y. & Sodeoka, M.
Pd(II)-catalyzed asymmetric fluorination of
alpha-aryl-alpha-cyanophosphonates with the aid of 2,6-lutidine.
Synlett, 1139-1142 (2007), doi:10.1055/s-2007-977437.
20Suzuki, T., Goto, T., Hamashima, Y. & Sodeoka, M.
Enantioselective fluorination of tert-butoxycarbonyl lactones and
lactams catalyzed by chiral Pd(II)-bisphosphine complexes. J. Org.
Chem. 72, 246-250 (2007), doi:10.1021/jo062048m.
21Smith, A. M. R., Billen, D. & Hii, K. K.
Palladium-catalysed enantioselective alpha-hydroxylation of
beta-ketoesters. Chem. Commun. 3925-3927 (2009),
doi:10.1039/b907151b.
22Smith, A. M. R., Rzepa, H. S., White, A. J. P., Billen, D.
& Hii, K. K. Delineating Origins of Stereocontrol in Asymmetric
Pd-Catalyzed alpha-Hydroxylation of 1,3-Ketoesters. J. Org. Chem.
75, 3085-3096 (2010), doi:10.1021/jo1002906.
23Li, K. L. & Hii, K. K. Dicationic
[(BINAP)Pd(solvent)2][TfO]2: enantioselective hydroamination
catalyst for alkenoyl-N-oxazolidinones. Chem. Commun., 1132-1133
(2003), doi:10.1039/b302246c.
24Li, K. L., Cheng, X. H. & Hii, K. K. Asymmetric synthesis
of beta-amino acid and amide derivatives by catalytic conjugate
addition of aromatic amines to N-alkenoylcarbamates. Eur. J. Org.
Chem., 959-964 (2004), doi:10.1002/ejoc.200300740.
25Hamashima, Y., Somei, H., Shimura, Y., Tamura, T. &
Sodeoka, M. Amine-salt-controlled, catalytic asymmetric conjugate
addition of various amines and asymmetric protonation. Org. Lett.
6, 1861-1864 (2004), doi:10.1021/ol0493711.
26Phua, P. H., White, A. J. P., de Vries, J. G. & Hii, K. K.
Enabling ligand screening for palladium-catalysed enantioselective
aza-Michael addition reactions. Adv. Synth. Catal. 348, 587-592
(2006), doi:10.1002/adsc.200505404.
27Phua, P. H., Mathew, S. P., White, A. J. P., de Vries, J. G.,
Blackmond, D. G. & Hii, K. K. Elucidating the mechanism of the
asymmetric aza-Michael reaction. Chemistry—Eur. J. 13, 4602-4613
(2007), doi:10.1002/chem.200601706.
28Hamashima, Y., Tamura, T., Suzuki, S. & Sodeoka, M.
Enantioselective protonation in the aza-Michael reaction using a
combination of chiral Pd-mu-hydroxo complex with an amine salt.
Synlett 1631-1634 (2009), doi:10.1055/s-0029-1217347.
29Hamashima, Y., Suzuki, S., Tamura, T., Somei, H. &
Sodeoka, M. Scope and mechanism of tandem aza-Michael
reaction/enantioselective protonation using a Pd-mu-hydroxo complex
under mild conditions buffered with amine salts. Chemistry--Asian
J. 6, 658-668 (2011), doi:10.1002/asia.201000740.
30Li, K. L., Horton, P. N., Hursthouse, M. B. & Hii, K. K.
Air- and moisture-stable cationic (diphosphine)palladium(II)
complexes as hydroamination catalysts X-ray crystal structures of
two [(diphosphine)Pd(NCMe)(OH2)][OTf]2 complexes. J. Organomet.
Chem. 665, 250-257 (2003), doi:10.1016/s0022-328x(02)02138-1.
31Kawatsura, M. & Hartwig, J. F. Palladium-catalyzed
intermolecular hydroamination of vinylarenes using arylamines. J.
Am. Chem. Soc. 122, 9546-9547, doi:10.1021/ja002284t (2000).
32Kang, Y. K., Kwon, B. K., Mang, J. Y. & Kim, D. Y. Chiral
Pd-catalyzed enantioselective Friedel-Crafts reaction of indoles
with gamma,delta-unsaturated beta-keto phosphonates. Tetrahedron
Letters 52, 3247-3249 (2011), doi:10.1016/j.tetlet.2011.04.084.
33Aikawa, K., Hioki, Y. t., Shimizu, N. & Mikami, K.
Catalytic asymmetric synthesis of stable oxetenes via Lewis
acid-promoted [2 + 2] cycloaddition. J. Am. Chem. Soc. 133,
20092-20095 (2011), doi:10.1021/ja2085299.
34Pignat, K., Vallotto, J., Pinna, F. & Strukul, G. Cationic
complexes of palladium(II) and platinum(II) as Lewis acid catalysts
for the Diels−Alder reaction. Organometallics 19, 5160-5167 (2000),
doi:10.1021/om0003943.
35Murata, S. & Ido, Y. Practical synthesis of palladium
bis(trifluoromethanesulfonate) and its application to the synthesis
of palladium complexes. Bull. Chem. Soc. Jpn. 67, 1746-1748 (1994),
doi:10.1246/bcsj.67.1746
36Phua, P. H., de Vries, J. G. & Hii, K. K.
Palladium-catalysed enantioselective conjugate addition of aromatic
amines to alpha,beta-unsaturated N-imides. Effect of the chelating
moiety. Adv. Synth. Catal. 347, 1775-1780 (2005),
doi:10.1002/adsc.200505126.
37Guino, M., Phua, P. H., Caille, J. C. & Hii, K. K. A
concise asymmetric synthesis of torcetrapib. J. Org. Chem. 72,
6290-6293 (2007), doi:10.1021/jo071031g.
Pd(NO
3
)
2
.nH
2
O+HOTf(excess)
Pd(OTf)
2
.2H
2
O+HNO
3
1
+(R)-BINAP
[(R)-(BINAP)Pd(OH
2
)
2
][TfO]
2
1
2
2
+NaOH(aq)
[(R)-(BINAP)Pd(-OH)]
2
[TfO]
2
3
PAr
2
PAr
2
Pd
solv
solv
2+
[X]
-
2
PAr
2
PAr
2
Pd
H
O
O
H
2+
[X]
-
2
Ar
2
P
Ar
2
P
Pd
III
O
NHCO
2
Me
NH
2
+
cat.2(3mol%)
0.2MTHF,RT,21h
O
NHCO
2
Me
NH
76%,93%ee
O
NHCO
2
Me
NH
3
+
OTf
-
+
O
NHCO
2
Me
NH
94%,97%ee
cat.3(1.5mol%)
0.5MTHF,RT,18h
S-
S-
ProtocolA
ProtocolB