Hydrophilic pyrazine-based phosphane ligands: Synthesis and application in asymmetric hydride transfer and H2-hydrogenation of acetophenone

Article abstract of DOI:10.1016/j.tetlet.2013.01.108

Pyrazine-based hydrophilic phosphanes are useful ligands for the ruthenium- and rhodium-catalyzed hydrogenations of acetophenone under hydride transfer and dihydrogen conditions. The effect of alcohol additives on the catalytic, enantioselective aqueous h

Full text of DOI:10.1016/j.tetlet.2013.01.108

Tetrahedron Letters 54 (2013) 1857–1861
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Hydrophilic pyrazine-based phosphane ligands: synthesis and application in
asymmetric hydride transfer and H2-hydrogenation of acetophenone
⇑
Nicolai I. Nikishkin, Jurriaan Huskens, Willem Verboom
Laboratory of Molecular Nanofabrication, MESA+ Institute for Nanotechnology, University of Twente, PO Box 217, 7500 AE Enschede, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyrazine-based hydrophilic phosphanes are useful ligands for the ruthenium- and rhodium-catalyzed
hydrogenations of acetophenone under hydride transfer and dihydrogen conditions. The effect of alcohol
additives on the catalytic, enantioselective aqueous hydrogenation of acetophenone is examined with the
newly developed (R,R)-DAMPYPHOS as the ligand and Rh2(norbornadiene)2Cl2 as the catalyst precursor,
giving rise to higher conversions (up to quantitative) and improved enantiomeric excesses (up to 95%) of
the formed 1-phenylethanol.
Received 29 November 2012
Revised 14 January 2013
Accepted 24 January 2013
Available online 1 February 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Asymmetric catalysis
Hydrogenation
Phosphanes
Pyrazine
Reduction
The most frequently used methods for ketone reduction are
transfer hydrogenation,1 from a hydrogen donor molecule, usually
isopropanol, and direct H2-hydrogenation.2 Common catalysts, em-
ployed in the former method involve a variety of Ru, Rh, and Ir
complexes with polydentate phosphanes and amines.3
H2-hydrogenation was one of the first transition metal cata-
lyzed processes studied in aqueous medium and continues to at-
tract interest.4 Sulfonated triarylphosphanes were reported for
alkene hydrogenation in aqueous biphasic systems,5 however, typ-
ically revealing modest or low activities. In general, water-soluble
phosphanes, containing ionic substituents, have several disadvan-
tages, among which are their high pH sensitivity6 and the high
charge accumulation in the coordination sphere of the metal com-
plex that leads to a significant Coulombic interligand repulsion and
to lower stability of the catalyst.7
On the other hand, one of the major challenges in aqueous-
biphasic catalysis8 is to promote interactions of the water-soluble
catalyst and other reagents with the hydrophobic substrate. For
polar molecules, being slightly soluble in water, the reaction can
occur in the aqueous bulk, however, as the substrate becomes less
soluble in water, the rate of the reaction decreases due to the lower
concentration of the substrate in the aqueous phase. This problem
can be solved by the use of either water-miscible organic cosol-
vents9 or phase-transfer agents,10 but often phase separation prob-
lems are encountered. Therefore, the design of ligands resulting in
a catalyst which is able to operate in both phases, and that needs
no cosolvent or surfactant, is very important. Remarkable exam-
ples were reported of quantitative asymmetric hydrogenations
of various acrylic acid derivatives in aqueous medium using
highly air-sensitive carbohydrate-backboned phosphanes with
ees >99%.11 Conversely, achieving such high enantioselectivities
in ketone hydrogenation is much more difficult due to the poor
donor ability of the carbonyl group and the lack of additional
anchoring sites.12
An electron-attracting pyrazine backbone affects the electronic
properties of
p
a phosphane-containing ligand, enhancing its
-acceptor properties,13 as well as impacting on the catalytic activ-
ity.14 The operational convenience, due to the air stability of such
ligands, is another property potentially of use for various asym-
metric catalyzes.15 This has motivated us to design and prepare
neutral, hydrophilic pyrazine-containing ligands. Here we present
a simple and versatile synthesis of three novel, hydrophilic, and
non-ionic phosphane ligands with a pyrazine backbone, named
AMPYPHOS, AMPYMORPH, and DAMPYPHOS.16 The successful
application of these ligands in the hydride-transfer and aqueous bi-
phasic H2-hydrogenation of acetophenone, as a model substrate, is
reported.
Ligand synthesis
We previously reported a facile and high-yielding method for
the introduction of phosphorus-containing functional groups onto
pyrazine scaffolds.17,18 In particular, it was found that phosphano-
pyrazineswere readilyaccessible in excellentyields via a palladium-
catalyzed P-C cross-coupling reaction of various chloropyrazines
⇑
Corresponding author. Fax: +31 53 4894645.
E-mail address: w.verboom@utwente.nl (W. Verboom).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.108

1858
N. I. Nikishkin et al. / Tetrahedron Letters 54 (2013) 1857–1861
N
Cl
Cl
N
1
O
Et3N
CH2Cl2
H
N
NH2
H2N NH2
Et3N
CH2Cl2
4
O
2
N
Et3N
CH2Cl2
3
O
O
O
O
N
NH HN
N
N
O
H
N
N
N
N
N
N
Cl
N
Cl
N
Cl
Cl
6
7
5
O
O
quantitative
quantitative
quantitative
(i)
(i)
(i)
O
N
O
O
NH HN
N
N
O
H
N
N
N
N
N
N
N
Ph2P
N
Ph2P
O
O
92%
PPh2
91%
(R,R)-DAMPYPHOS
Ph2P
92%
AMPYPHOS
AMPYMORPH
Scheme 1. Synthesis of the pyrazine-based phosphanes: AMPYPHOS, AMPYMORPH, and (R,R)-DAMPYPHOS; (i) HPPh2, DBU, Pd(OAc)2, MeCN, reflux.
with secondary phosphanes. The novel phosphanopyrazines,
AMPYPHOS, AMPYMORPH, and (R,R)-DAMPYPHOS, were prepared
in two steps starting from simple amines, employing this methodol-
ogy. Starting amines 2–4 were acylated quantitatively with a stoi-
chiometric amount of 6-chloropyrazine-2-carbonyl chloride (1) in
the presence of 2 equiv of triethylamine in dichloromethane to give
amides 5–7, respectively, each bearing a 6-chloropyrazine moiety.
Subsequent palladium-catalyzed P-C cross-coupling with diphenyl-
phosphane using 1 mol % of Pd(OAc)2 as the catalyst in the presence
of DBU in refluxing acetonitrile afforded AMPYPHOS, AMPYMORPH,
and (R,R)-DAMPYPHOS, respectively, as oily or waxy air-stable
materials, in over 90% yields (Scheme 1). (For further details see
the Supplementary data).
catalyst/ligand
base/T(oC)
OH
O
OH
O
+
+
Ph
Ph
Scheme 2. Transfer hydrogenation of acetophenone.
showing an increase of conversion upon increasing the base
strength. Adding Cs2CO3 to the reaction mixture resulted in ꢀ20%
conversion (Table 1, entry 5). The effect of the base was even more
pronounced for DBU giving 70% conversion (Table 1, entry 7),
reaching a maximum for i-PrONa with 85% and 100% conversions
with the Ru and Rh catalysts, respectively (Table 1, entries 9 and
11). Thus the best system for ketone transfer hydrogenation was
found to be Rh2nbd2Cl2/AMPYPHOS in the presence of i-PrONa.
These conditions were used for the asymmetric transfer hydroge-
nation of acetophenone with Rh2nbd2Cl2 in the presence of chiral
(R,R)-DAMPYPHOS (Table 1, entries 13 and 16). Despite excellent
catalytic activity at 83 °C (reflux temperature of isopropanol), the
enantiomeric excess was only 70% (Table 1, entry 13). A decrease
of the reaction temperature to 50 °C only slightly improved the
optical yield providing an ee of 75%. A further decrease of the reac-
tion temperature resulted into considerably lower conversions.
Subsequently, the activity of rhodium catalysts with the newly
prepared ligands was investigated for the hydrogenation of aceto-
phenone, under 10 bar of H2 at room temperature, in a biphasic
system consisting of aqueous NaOH (1 M) and the substrate
(0.1 M) (Table 2). Experiments without any additive or cosolvent
only showed moderate conversions of acetophenone into 1-phen-
ylethanol (Table 2, entries 1 and 2). Grzybek19 observed a signifi-
cant effect of methanol used as a cosolvent in the aqueous
biphasic hydrogenation of olefins. Therefore it was of interest to
study the effect of various alcohols on the conversion, as well as
on the enantioselectivity, in the case of our catalytic system. A pre-
liminary experiment with benzyl alcohol as an additive revealed
not only an enhancement of the reaction rate, but also an increase
in the optical yield of the product, 1-phenylethanol (Table 2, entry
5). The addition of EtOH, PhCH2OH, i-PrOH, and t-BuOH gave rise to
In the 1H NMR spectra the signal for the pyrazine proton adja-
cent to the chlorine at 8.66 ppm in 5 was shifted to 8.43 ppm in
AMPYPHOS. The formation of AMPYMORPH and (R,R)-DAMPY-
PHOS was also confirmed by the shift of the characteristic pyrazine
proton singlets from 9.22 and 8.69 ppm in 6 and 9.18 and 8.70 ppm
in 7 to 9.15 and 8.38 ppm in AMPYMORPH and 8.92 and 8.39 ppm
in (R,R)-DAMPYPHOS, respectively. All the above phosphanes
revealed distinct signals in the 31P NMR spectra, being À7.42,
À8.06, and À8.02 ppm for AMPYPHOS, AMPYMORPH, and DAMPY-
PHOS. In addition to the NMR spectra, all the compounds exhibited
the requisite molecular ion peaks in electrospray mass spectra.
Catalytic activity
To evaluate the most active catalytic system with Ru(PPh3)3Cl2
and Rh2(norbornadiene)2Cl2 (Rh2nbd2Cl2) as catalyst precursors,
and using acetophenone as the model substrate, an initial study
was performed under transfer hydrogenation conditions in isopro-
panol in the presence, as well as absence, of a base with the non-
chiral ligands AMPYPHOS and AMPYMORPH (Scheme 2). The re-
sults are summarized in Table 1.
In the absence of a base none of the catalytic systems revealed
any significant activity (Table 1, entries 1–4). On the other hand,
the addition of 10 mol % of a base promoted efficiently the catalysis

N. I. Nikishkin et al. / Tetrahedron Letters 54 (2013) 1857–1861
1859
Table 1
Transfer hydrogenation of acetophenone in isopropanol in the presence of 1 mol % of Ru(PPh3)3Cl2 or 0.5 mol % of Rh2nbd2Cl2 as the catalyst precursor and 2% or 1% of the
monodentate or bidentate ligand, respectively, for 15 h
Entry
Catalyst precursor
Ligand
Base
T (°C)
Conversion (%), (ee, %)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ru(PPh3)3Cl2
Ru(PPh3)3Cl2
Rh2nbd2Cl2
Rh2nbd2Cl2
Ru(PPh3)3Cl2
Ru(PPh3)3Cl2
Ru(PPh3)3Cl2
Ru(PPh3)3Cl2
Ru(PPh3)3Cl2
Ru(PPh3)3Cl2
Rh2nbd2Cl2
Rh2nbd2Cl2
Rh2nbd2Cl2
Rh2nbd2Cl2
Rh2nbd2Cl2
Rh2nbd2Cl2
AMPYPHOS
AMPYMORPH
AMPYPHOS
AMPYMORPH
AMPYPHOS
AMPYMORPH
AMPYPHOS
AMPYMORPH
AMPYPHOS
AMPYMORPH
AMPYPHOS
AMPYMORPH
(R,R)-DAMPYPHOS
AMPYPHOS
AMPYMORPH
(R,R)-DAMPYPHOS
None
None
None
None
83
83
83
83
83
83
83
83
83
83
83
83
83
50
50
50
<2
<2
5
<2
20
15
70
57
Cs2CO3 (10%)
Cs2CO3 (10%)
DBU (10%)
DBU (10%)
i-PrONa (10%)
i-PrONa (10%)
i-PrONa (10%)
i-PrONa (10%)
i-PrONa (10%)
i-PrONa (10%)
i-PrONa (10%)
i-PrONa (10%)
85
0
100
75
100 (70) (R)
97
70
97 (75) (R)
Table 2
Hydrogenation of acetophenone under 10 bar of H2 at room temperature in an aqueous NaOH (1 M) biphasic system in the presence of Rh2nbd2Cl2/AMPYPHOS or
(R,R)-DAMPYPHOS for 15 h
Entry
Rh2nbd2Cl2 (%)
Ligand
Additive (equiv)
Conversion (%), (ee, %)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
1
1
1
AMPYPHOS
None
None
47
(R,R)-DAMPYPHOS
(R,R)-DAMPYPHOS
AMPYPHOS
73 (75) (R)
100 (79) (R)
40
EtOH (1 equiv)
PhCH2OH (1 equiv)
PhCH2OH (1 equiv)
PhCH2OH (1 equiv)
PhCH2OH (2 equiv)
PhCH2OH (3 equiv)
i-PrOH (1 equiv)
i-PrOH (2 equiv)
i-PrOH (2 equiv)
t-BuOH (1 equiv)
t-BuOH (2 equiv)
t-BuOH (2 equiv)
1
(R,R)-DAMPYPHOS
(R,R)-DAMPYPHOS
(R,R)-DAMPYPHOS
(R,R)-DAMPYPHOS
(R,R)-DAMPYPHOS
(R,R)-DAMPYPHOS
(R,R)-DAMPYPHOS
(R,R)-DAMPYPHOS
(R,R)-DAMPYPHOS
(R,R)-DAMPYPHOS
100 (93) (R)
40 (92) (R)
80 (93) (R)
100 (93) (R)
100 (95) (R)
33 (93) (R)
10 (90) (R)
61 (83) (R)
23 (80) (R)
8 (80) (R)
0.5
0.5
0.5
0.5
0.25
0.05
0.5
0.25
0.05
considerably higher conversions of 100%,20 40%, 100%, and 61%,
respectively (Table 2, entries 3, 6, 9, and 12). Furthermore, the
enantiomeric excess of the product was different, depending on
the alcohol used, being maximal for i-PrOH (Table 2, entry 9). Sub-
sequently, the effect of a reduced catalyst load was studied (Table 2,
entries 6–14). Halving the amount of Rh2nbd2Cl2 required the pres-
ence of 3 equiv. of PhCH2OH to accomplish full conversion (Table 2,
entries 5 and 8).
Kinetic study
To study the hydrogenation in more detail, the reaction was fol-
lowed over time, using the Rh2nbd2Cl2/(R,R)-DAMPYPHOS catalytic
system and water as the solvent, with i-PrOH as an additive under
a constant hydrogen pressure of 10 bar. Figure 1 shows a sigmoidal
conversion of acetophenone over time, and a drastic reaction rate
acceleration after an induction period of about 6 h. However, when
the catalyst was activated in advance under 10 bar of hydrogen for
6 h, a linear relationship was observed for the formation of 1-phen-
ylethanol; the reaction in this case was complete in 8 h, compared
to 15 h without prior activation. The catalyst activation can be
visualized as shown in Scheme 3. Rapid hydrogenation of the diene
ligand occurs upon exposure of the catalyst precursor solution to a
hydrogen atmosphere.
Figure 1. Conversion of acetophenone into 1-phenylethanol over time under
catalytic hydrogenation conditions: acetophenone (0.1 M) in aqueous NaOH (1 M)
with i-PrOH (0.1 M) at 20 °C in the presence of 0.5% of Rh2nbd2Cl2/(R,R)-DAMPY-
PHOS under 10 bar of H2, with and without catalyst activation.
Rh(III) complex unfavorable. This effect is also responsible for the
oxidative addition of dihydrogen being, most likely, the rate-limit-
ing step.
Reaction mechanism and origin of the increase in
enantioselectivity in the presence of an alcohol
The resulting tetracoordinated rhodium species reveals almost
no further hydrogen uptake due to the trans-effect of the bidentate
phosphane ligand, which makes the formation of a dihydride
When acetophenone was hydrogenated in D2O/d1-EtOD/NaOD
with H2 employing Rh2nbd2Cl2/(R,R)-DAMPYPHOS as the catalyst,

1860
N. I. Nikishkin et al. / Tetrahedron Letters 54 (2013) 1857–1861
assistance of a base, to abstract the remaining proton from the me-
(R,R)-DAMPYPHOS
P
P
Cl
Cl
tal center, and a proton donor to protonate the product alkoxide, in
order to eliminate the product alcohol and to form the initial tetra-
coordinated Rh(I) complex, thereby completing the catalytic cycle.
The amplification of enantioselectivity upon the addition of dif-
ferent alcohols to the reaction mixture can be explained by
replacement of the hydroxide ligand by the corresponding alkoxide
making the resulting complex more sterically demanding.24 From
several possible coordination modes of acetophenone to the cata-
lytically active tetracoordinate rhodium species, only those that
provide the lowest steric interactions of the acetophenone phenyl
group with the bulky alkoxide ligand, undergo dihydrogen oxida-
tive addition followed by the preferable formation of the (R)-enan-
tiomer of 1-phenylethanol. This is clearly reflected in the
enantiomeric excesses of 79%, 93%, and 95%, obtained for EtOH,
PhCH2OH, and i-PrOH, (Table 2, entries 3, 5 and 9), respectively,
having increasing bulkiness in this series of alcohols. The ligand
steric bulk finally shields the active site of the catalyst, preventing
it from substrate coordination when switching to tert-butanol,
resulting in lower conversions and an enantiomeric excess
close to the values obtained without any additive (Table 2, entries
12–14).
In conclusion, excellent ees, up to 95%, have been obtained in
the rhodium-catalyzed aqueous hydrogenation of acetophenone
using a simple and easy-to-make chiral bidentate pyrazinophos-
phane ligand. The enantioselectivity of the reaction, as well as
the catalyst activity were found to be significantly improved by
adding a small amount of an alcohol, indicating the enhancement
of the enantiocontrol of the reaction via binding of an alcohol mol-
ecule by the catalyst. The found enantiomeric excesses are as high
as those reported recently for chiral ruthenabicyclic com-
plexes,25,26 these being presently to our knowledge, the best cata-
lysts for acetophenone reduction. However, in our case, full
conversion is achieved at five times lower hydrogen pressure and
requires no decreased temperatures. The easy preparation, stability
toward air oxidation, and amphiphilic nature, that enables applica-
tion of the described ligands in aqueous organometallic catalysis,
should reduce strongly the environmental impact of large scale
catalytic processes.
Rh
Rh
Rh
H2 (10 bar)
H2O/ROH/NaOH
RO
P
H
P
P
H2 (10 bar)
H
Rh
Rh
OR
S
P
S
S = solvent
R = H or alkyl
Scheme 3. Proposed catalyst activation sequence.
the reaction product was characterized by 1H NMR spectroscopy to
be a mixture of isotopomers with a high degree of deuteration of
the methyl group of 1-phenylethanol, which mostly results from
enolization of the parent acetophenone under basic conditions in
the deuterated aqueous medium. However, deuteration at the
carbon adjacent to the hydroxyl group was almost negligible.
These results prove the absence of proton/deuteron exchange
between the catalytically active rhodium hydride species and the
deuterated (protic) reaction medium, excluding the possibility
of the heterolytic cleavage of dihydrogen, which is typical for
rhodium-amido21 and iridium-amidophosphane ambifunctional
catalysts.22 Furthermore, it supports the oxidative addition of dihy-
drogen to the rhodium metal center as the key step in the catalytic
cycle. Consistent with this, under comparable conditions, using
10 bar of Ar instead of H2 gas, no conversion of acetophenone
was observed after 15 h. This result rules out the possibility of
transfer hydrogenation by the alcohol introduced into the reaction
mixture.
Based on these data, a mechanism as summarized in Scheme 4,
is proposed. The reaction follows the classical Schrock–Osborn
dihydride mechanism23 involving substrate coordination and the
oxidative addition of dihydrogen with the formation of an
Rh(III) dihydride complex. Subsequent migratory insertion of a hy-
dride ligand into the C@O bond results in the formation of an
Rh(III) monohydride complex with the product alkoxide ligand.
This monohydride complex ultimately needs the simultaneous
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.01.
108.
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Scheme 4. Proposed mechanism of acetophenone hydrogenation by H2 catalyzed
by Rh2nbd2Cl2/(R,R)-DAMPYPHOS in water.

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enantioselective catalyst for acetophenone reduction, however, full conversion
was achieved at three times higher hydrogen pressure and in a longer reaction
time, than in our case. Jiang, Q.; Jiang, Y.; Xiao, D.; Cao, P.; Zhang, X. Angew.
Chem., Int. Ed. 1998, 37, 1100–1103.
16. The trivial names of the ligands are derived from the combination of chemical
names for the scaffold and substituents: AMPYPHOS = amidopyrazine