Synthesis of new N-substituted chiral phosphine-phosphoramidite ligands and their application in asymmetric hydrogenations and allylic alkylations

Article abstract of DOI:10.1016/j.tetasy.2015.05.001

Phosphine-phosphoramidite ligands containing a 2,4-pentanediyl backbone, BINOL moieties, and Me, Bn or Ph substituent on the nitrogen were synthesized and fully characterized. The electronic effect of the N-substituents was examined by ³¹P NMR of their corresponding seleno-phosphate-amide and phosphine-selenide derivatives. The new ligands together with their earlier reported derivatives were tested in the palladium catalyzed asymmetric allylic alkylation of rac-(E)-1,3-diphenylallyl acetate. Remarkably high activity (up to 1780 h^-1 turnover frequency) and first order kinetics were observed by facilitating nucleophile formation. The substituent at the nitrogen and the configuration of chiral moieties had a high impact on the enantioselectivity. The new ligands were also tested in the rhodium-catalyzed asymmetric hydrogenation of methyl (Z)-α-acetamidocinnammate, dimethyl itaconate (up to 99.9% ee's) and methyl 2-acetamidoacrylate (up to 99.5% ee).

Full text of DOI:10.1016/j.tetasy.2015.05.001

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of new N-substituted chiral phosphine–phosphoramidite
ligands and their application in asymmetric hydrogenations and
allylic alkylations
Szabolcs Balogh a, Gergely Farkas b, Imre Tóth b, József Bakos b,
⇑
a NMR Laboratory, University of Pannonia, H-8200 Veszprém, Egyetem u. 10, Hungary
b Department of Organic Chemistry, University of Pannonia, H-8200 Veszprém, Egyetem u. 10, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Phosphine–phosphoramidite ligands containing a 2,4-pentanediyl backbone, BINOL moieties, and Me,
Bn or Ph substituent on the nitrogen were synthesized and fully characterized. The electronic effect of
the N-substituents was examined by 31P NMR of their corresponding seleno-phosphate-amide and phos-
phine–selenide derivatives. The new ligands together with their earlier reported derivatives were tested
in the palladium catalyzed asymmetric allylic alkylation of rac-(E)-1,3-diphenylallyl acetate. Remarkably
high activity (up to 1780 hꢀ1 turnover frequency) and first order kinetics were observed by facilitating
nucleophile formation. The substituent at the nitrogen and the configuration of chiral moieties had a high
impact on the enantioselectivity. The new ligands were also tested in the rhodium-catalyzed asymmetric
Received 8 April 2015
Accepted 5 May 2015
Available online xxxx
hydrogenation of methyl (Z)-a-acetamidocinnammate, dimethyl itaconate (up to 99.9% ee’s) and methyl
2-acetamidoacrylate (up to 99.5% ee).
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
BINOL moieties are useful ligands.9 One such ligand, UPPhos10 1a
(Scheme 1) provided up to 99.9% ee in the asymmetric hydrogena-
tion of benchmark substrates containing carbon–carbon double
bond under mild reaction conditions. Even environmentally
friendly alkylene carbonates or protic solvents could be used as
reaction media under similar reaction conditions. It should be
noted that cyclic carbonates are non-toxic, non-flammable, non-
volatile organic compounds with high boiling point and polar apro-
tic properties, which makes them excellent reaction media for
chemical reactions.
Although, organic cyclic carbonates have not played a major
role as solvents for asymmetric transformations, the exceptions
include the platinum-catalyzed hydrosilylations of unsaturated
fatty acids investigated by Behr et al.;11 regioselective, rhodium-
catalyzed hydroformylations;12 iridium- and rhodium-catalyzed
Asymmetric catalysis is a powerful tool for the introduction of
chirality in chemical compounds such as pharmaceuticals,
herbicides, or other fine chemical intermediates.1 Transition metal
complexes of chiral phosphorus ligands proved to be particularly
efficient catalysts for a wide range of asymmetric reactions.2
Most of these catalytic systems utilize chelating bisphosphorus
ligands. Among them, chiral phosphine–phosphoramidites also
showed promising results in asymmetric syntheses such as
hydrogenations,3 hydroformylations,4 additions of diethylzinc to
enones,5 [3+2] cycloadditions of azomethine ylides,6 or conjugate
reductions of
a
,b-unsaturated esters.7 Until now, predominantly
phosphine–phosphoramidites containing rigid or semi-rigid
backbone were successfully applied.8 Crévisy et al. reported the
only exception, where a phosphine–phosphoramidite with a pure
aliphatic backbone provided good activity with up to 53% ee in
the asymmetric addition of diethylzinc to cyclohex-2-enone.5
Recently, we have demonstrated that phosphine–phospho-
ramidites containing aliphatic 2,4-pentanediyl backbone and
1a R = iPr (UPPhos)
R
1b R = Me
1c R = Bn
1d R = Ph
O
O
P
N
PPh2
⇑
Corresponding author. Fax: +36 (88) 624469.
E-mail address: bakos@almos.vein.hu (J. Bakos).
URL: http://szerves.mk.uni-pannon.hu/index.php?lang=en (J. Bakos).
Scheme 1. UPPhos and new N-substituted phosphine–phosphoramidite ligands.
http://dx.doi.org/10.1016/j.tetasy.2015.05.001
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
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2
S. Balogh et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
asymmetric hydrogenations and palladium-catalyzed asymmetric
allylic alkylations by Börner et al.;13 palladium-catalyzed Heck
reaction by Reetz et al.,14 and rhodium-catalyzed intermolecular
alkyne hydroacylations by Willis et al.15 It was concluded, that
the (Sa,Sc,Sc)-combination of the axial and the two central chiral
elements represents the matched configuration.16 Furthermore,
the enantioselectivity of the reaction was highly dependent on
the combination of the chiral elements in the applied
backbone.Phosphine–phosphoramidites have unique electronic
properties on the two coordinating P-atoms. The phosphine part
2.1.
Characterization
of
the
ligands
and
their
[Rh(COD)(phosphine–phosphoramidites)]BF4 complexes
The 31P NMR spectra of the new compounds showed a two
singlet pattern in the expected chemical shift range for the two
P-atoms. In addition, the signals of 1b and 1d in CDCl3 at room
temperature showed a coupling of 14.5 Hz and 2.2 Hz, respectively.
Scalar coupling through five bonds can be excluded; however, the
splitting was explicable by through-space 1JP–P coupling. In partic-
ular, it is a sign of forced overlapping of the phosphorus lone pairs
hence the distance between the two phosphorus is close to 3 Å or
less.20 The magnitude of phosphorus through-space coupling
constants can have the range from 1 to 10 Hz in the case of bispho-
sphites,21 74–76 Hz for tetraphosphine ferrocenyl derivatives22 or
even extremely high values of 131–209 Hz as observed in
Quinaphos derivatives.23 Szalontai et al. demonstrated that flexible
bisphosphites show a decreasing coupling with increasing temper-
ature.21 Our 31P{1H}-NMR measurements of 2 showed decreasing
coupling constant with increasing temperature. Further proofs
for the through-space coupling are provided by the facts that the
NMR spectra of the diselenide adducts of 1b and 1d (see
Section 4) showed no splitting and their Rh complexes (Table 1)
showed no indication for the presence of diastereomers,
respectively.
has a good sigma-donor, while the amidite has strong
p-acceptor
properties. Furthermore, heterobidentates with coordinating
atoms connected to sterically different groups also exert a desym-
metrization effect. It is known that significant electron donation
from the nitrogen lone pair to the amidite phosphorus occurs,
resulting in a nearly trigonal–planar molecular geometry of the
nitrogen, which is typical of an sp2 hybridization state—and of an
increased P–N bond order, thus the rotation around this bond is
restricted.17 Furthermore, the phosphorus basicity can be fine-
tuned by changing the substituents at the nitrogen, which may
have a significant influence on the coordination and steric proper-
ties of the ligand and the substrate complexes; hence the catalytic
properties can also be fine-tuned. These unique electronic proper-
ties prompted us to investigate the N-substituent effect of the
ligand in the Rh-catalyzed asymmetric hydrogenation and in the
Pd-catalyzed asymmetric allylic alkylation of benchmark sub-
strates. Monodentate phosphoramidites are widely tested in Pd-
catalyzed asymmetric allylic alkylations.18 Contrarily, only the
IndolPhos phosphine–phosphoramidite was inspected by Reek
and Wassenaar in this reaction.19
The
r
-donor ability of phosphorus atoms in phosphine–phos-
phoramidites 1a–d has been evaluated by measuring the magni-
tude of coupling constants (1JSe–PC and JSe–PN in the 77Se
)
1
isotopomer of the corresponding seleno-phosphate-amide and
phosphine–selenide (See Table 2). The magnitude of JSe–P is very
1
much dependent upon the nature of the organic groups bound to
the phosphorus with electron-withdrawing groups causing an
increase whereas electron-donating groups causing a decrease in
the coupling constant.24 The largest JSe–PN coupling (973.0 Hz)
1
2. Results and discussion
was measured in diselenide of ligand 1d and the smallest
(959.8 Hz) in the diselenides of UPPhos (1a). This is about 100 Hz
lower than in analogous phosphites. Thus the electronic desym-
metrization in phosphine–phosphoramidites is expected to be
weaker compared to similar phosphine–phosphite ligands.
However, the differences in coupling constants and thus in elec-
In our on-going research on the development of phosphine–
phosphoramidites with chiral aliphatic backbone, we synthesized
three new N-substituted derivatives of UPPhos 1b–d (Scheme 1)
starting from cyclic sulfates following the synthetic method
described in our previous works (Scheme 2).9,16
O
P
Cl
R
R
O
R
O
O
+H2N
HN
P
N
LiPPh2
R-NH2
O
O
S
-
OSO3
PPh2
PPh2
O
O
3a-d
4a-d
2
1a-d
Scheme 2. Synthesis of N-substituted UPPhos type phosphine–phosphoramidite ligands.
Table 1
31P NMR data of ligands 1a–d and the corresponding [Rh(COD)(phosphine–phosphoramidite)]BF4 complexesa
PP0
Phosphine–phosphoramidite
[Rh(COD)(phosphine–
phosphoramidite)]BF4
dligPN (ppm)
dligPC (ppm)
dPN (ppm)
dPC (ppm)
D
d PN (ppm)
Dd PC (ppm)
1ab
1b
1c
153.5
141.0
147.1
141.0
3.0
0.1
2.0
0.0
137.3
138.3
135.4
131.4
19.2
19.9
17.8
18.7
ꢀ16.2
ꢀ2.7
16.2
19.9
15.8
18.7
ꢀ11.7
ꢀ8.6
1d
a
Spectra were measured in CDCl3 at 20 °C. PN is related to the phosphoramidite group and PC is related to the phosphino group.
Data from Refs. 9,16 are included for the sake of comparison.
b
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S. Balogh et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
Table 2
31P–77Se coupling constants in diselenides of ligands 1a–da
Se
R
R
O
O
O
Se
P
N
P
N
toluene
Se
O
1h, 100 °C
PPh2
PPh2
Ligand
1JSe–P phosphoramidite (Hz)
1JSe–P phosphine (Hz)
1ab
1b
1c
959.8
964.5
972.3
973.0
732.8
729.5
730.4
735.0
1d
a
0.064 mmol of ligand and elemental selenium (25 mg, 0.32 mmol) in toluene (1 mL) was stirred for 24 h. The unreacted
selenium was left to settle and the required quantity of the solution was added into an NMR tube. All spectra measured in
toluene at 20 °C.
b
Data from Ref. 16 are included for comparison.
tronic properties of 1a–d were much smaller than expected. For
example, 1c (N-Bn) and 1d (N-Ph) gave almost identical couplings,
which is rather surprising as one is connected with an aliphatic and
the other with an aromatic carbon to the nitrogen.
The coordination chemistry of rhodium complexes of ligands
1a–d, was investigated because of its relevance to the asymmetric
hydrogenation described below. The products formed upon treat-
ment of chiral ligands with one equivalent of [Rh(COD)2]BF4 were
evaluated by 31P{1H} NMR spectroscopy (Table 1).
acetamidocinnammate, methyl 2-acetamidoacrylate and dimethyl
itaconate. Previously, methanol and propylene-carbonate as sol-
vents and 5 bar pressure of H2 at room temperature were found
to be the optimal conditions for ligand 1a.9,16 For the sake of com-
parability, the same reaction parameters were applied herein
(Table 3).
As can be seen, the activities with the new ligands 1b–d are
better than with UPPhos 1a, while the selectivities are just as
good as with UPPhos 1a. The new ligands give similarly very high
ee’s for substrates containing acetamido groups. It is worth not-
ing, that the hydrogenation product in the presence of ligand 1c
gave the same excellent enantioselectivity both in propylene-car-
bonate and methanol (99.5% and 99.7%, respectively), while
ligand 1a, 1b, and 1d led to better ee’s in propylene-carbonate
(compare entries 1–8 in Table 3). For dimethylitaconate the high-
est enantioselectivity (99.9%) was observed with ligand 1d. A
decrease in the enantioselectivity was observed with 1b and 1c.
The results indicated that bulky substituents at the nitrogen were
preferred.
At a 1:1 ligand to metal ratio, two double doublets were exhib-
ited in the spectra indicating the formation of a seven-membered
chelate ring of [Rh(COD)(phosphine–phosphoramidite)]BF4
complexes. The coordination chemical shift differences [Dd =
d(complex) ꢀ d(ligand)] were found to be negative for the PN and
positive for the PC moieties, as expected for a good
p-acceptor
and a good d-donor moiety, respectively.
2.2. Catalytic experiments
The new ligands were first tested in the Rh-catalyzed asymmet-
ric hydrogenation of benchmark substrates as methyl (Z)-a-
Since UPPhos type of ligands have not been used in Pd-cat-
alyzed asymmetric allylic alkylations, 1a–d together with the ear-
lier published analogues 5–7 (Scheme 3) were tested in the
substitution of a benchmark substrate rac-(E)-1,3-diphenylallyl
acetate with dimethyl malonate (Table 4). The reactions were car-
ried out under standard conditions in the presence of N,O-
bis(trimethylsylyl)acetamide and a pinch of KOAc.
Table 3
Asymmetric hydrogenation of benchmark substrates with Rh(I) complexes of chiral
phosphine–phosphoramidite ligandsa
Entry
Substrate
Ligand
Reaction time to full
conv. (h)
ee (%)
Complete conversion was measured at 30 min reaction time in
common solvents except in THF and in propylene-carbonate
(Table 4). This is in contrast to the experience that phosphorus con-
taining ligands tested in the common benchmark allylic alkylation
reaction tend to have a low turnover frequency.25 For example, Pd-
complexes of atropisomeric bipyrimidyl diphosphines providing
81–95% ee and up to 66 hꢀ1 turnover frequency were thought to
be very active catalysts.26 In contrast, Gouygou et al. reported that
by using 1-pyrrolidinphospholes in THF as solvent, complete con-
version could be achieved with only 0.5% catalyst loading in five
1c
2
1a
1b
2.8
99.2 (R)
99.8 (R)
COOMe
NHAc
0.6 (5.7 bar)
0.8
1.0
0.8
0.7 (5.7 bar)
1.0
3b
4
98.8 (R)
99.5 (R)
99.7 (R)
99.6 (R)
98.2 (R)
1c
5b
6
1d
7b
8c
9
10
11
1a
1b
1c
2.2
1.3
1.4
0.9
97.7 (S)
97.9 (S)
95.8 (S)
99.5 (S)
COOMe
NHAc
minutes, hence the turnover frequency was well over 2000 hꢀ1 27
.
1d
However, only moderate ee’s (28–29%) could be obtained in this
case.
12c
13
1a
1b
3.0
2.0
99.5 (R)
88.1 (R)
By using sensitive ligands (for example phosphites), the use of
an excess was necessary to maintain active catalyst concentration
for prolonged reaction time; examples show up to 3 ligand/Pd ratio
in the case of bidentates.28 However, by using UPPhos, no excess of
the ligand was necessary. Moreover, the best enantioselectivity
was measured with a phosphine–phosphoramidite/Pd ratio of 1
(entries 1 and 2). The catalytic system was also tested in some
MeOOC
COOMe
14
15
1c
1d
1.5
1.5
74.6 (R)
99.9 (R)
a
Hydrogenation test conditions: [Rh(COD)2]BF4 (0.01 mmol). Substrate/Rh = 125,
phosphine–phosphoramidite/Rh = 1.1. Solvent: 5 mL propylene carbonate.
Pressure: 5 bar H2, rt.
b
Solvent: methanol.
For comparison, data included from Ref. 9.
c
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S. Balogh et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
O
O
O
O
O
P
N
P
N
P
N
O
PPh2
PPh2
PPh2
1g
1f
1e
Scheme 3. Earlier reported phosphine–phosphoramidite ligands with aliphatic bridge.16
Table 4
Asymmetric allylic alkylation catalyzed by Pd complexes of ligands 1a–ga
dimethyl malonate
MeOOC
COOMe
N,O-bis(trimethylsylyl)acetamide,
OAc
Ph
KOAc
∗
Ph
Ph
Ph
[Pd(C3H5)Cl]2,
phosphine-phosphoramidite
Entry
Ligand
1a
Solvent
ee (%)
1b
2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Ether
Acetonitrile
1,4-Dioxane
Propylene-carbonate
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
59
64
60
43
59
32
51
25
53
40
61
26
28
41
21
35
58
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
3c
4d
5
6
Figure 1. Effect of different conditions on the reaction rate in asymmetric allylic
alkylation using UPPhos 1a ligand. (a) Standard conditions. (b) Without solvent. (c)
With preformed nucleophile. (d) Cs2CO3 base. (e) With potassium salt of dimethyl
malonate. (f) With Bu4N salt of dimethyl malonate.
7
8e
9
10f
11g
12
13
14
15
16h
17
Encouraged by the high activities, we decided to evaluate the
allylic alkylation reaction with UPPhos in detail. The reaction rate
showed an induction period when standard reaction parameters
were used (Fig. 1a) or the reaction was carried out neat (Fig. 1b).
It should be noted, that the formation of the nucleophile starts
after the addition of N,O-bis(trimethylsylyl)acetamide, thus sug-
gesting that the reaction rate was limited by the low nucleophile
concentration at the early stage of the reaction. In our next attempt
to increase the reaction rate N,O-bis(trimethylsilyl)acetamide,
dimethyl malonate, and KOAc were stirred for 20 min before being
added to the vessel containing standard amounts of catalyst and
substrate (Fig. 1c). The reaction showed clean first order kinetics
on the substrate (Fig. 2, k = 5.4 * 10ꢀ3 sꢀ1, R2 = 0.98) and high turn-
over frequency (1026 hꢀ1 at 3 min). It should be noted that the
substrate remained racemic through the course of the reaction
thus indicating that no kinetic resolution took place. Moreover,
the enantioselectivity remained practically unchanged (Fig. 3).
Next, other preformed nucleophiles were tested. The reaction
using the potassium salt of dimethyl malonate stopped at ꢁ20%
conversion after 5 min and gave only 26% ee (Fig. 1e). This can
1g
a
Allylic alkylation test conditions: (Pd(C3H5)Cl)2 (0.00625 mmol). Substrate/
Pd = 100, phosphine–phosphoramidite/Pd = 1, dimethyl malonate/substrate = 3,
N,O-bis(trimethylsylyl)acetamide/substrate = 3. Solvent: 10 mL, rt, 30 min, com-
plete conversion unless otherwise stated.
b
Phosphine–phosphoramidite/Pd = 1.5, major product has an (R)-configuration.
Dimethyl malonate/substrate = 1.
50% conversion.
32% conversion after 15 min.
0 °C.
50 °C.
c
d
e
f
g
h
The major product has an (S)-configuration.
common solvents. Complete conversion was measured in toluene,
1,4-dioxane, acetonitrile and in ether. The enantioselectivities
were lower to those in CH2Cl2 and only 50% conversion was mea-
sured in THF (entry 4) after 30 min. In propylene-carbonate (entry
8) both enantioselectivity (25%) and activity were much lower than
in the solvents mentioned above. Some reports indicated, that low-
ering the reaction temperature resulted in significantly higher
ee’s.29 We also found an opposite effect, as the enantioselectivity
was only 40% at 0 °C (entry 10), while increasing the reaction tem-
perature to 50 °C caused no change in ee (entry 11).
Reaction kinetics had little influence on the ee’s with this
system. By comparing the results with ligands of different N-R sub-
stituents, it can be concluded that the enantioselectivity cannot
simply be related to electronic effects. For example 1d with the less
basic Ph-substituent (1JSe–PN = 973 Hz) gave 40% ee (entry 14) and
the test applying 1b with the more basic but less bulky Me-group
(1JSe–PN = 965 Hz) resulted in only 26% ee.
In both reactions, (hydrogenation and allylic alkylation), ligand
1e without a chiral bridge gave the lowest ee and the mismatched
diastereomer of UPPhos 1f showed an excess of the opposite enan-
tiomer. Reasonably good (58%) ee was measured with the (S)-H8-
BINOL derivative of UPPhos 1g.
Figure 2. First order kinetics with preformed nucleophile in the asymmetric allylic
alkylation using UPPhos 1a.
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S. Balogh et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
0.05 m/m%). The substrates methyl (Z)-a-acetamidocinnamate
and methyl 2-acetamidoacrylate for asymmetric hydrogenation
were synthesized according to the literature procedure.30 All other
chemicals were obtained commercially. 31P{1H}, 13C{1H} and 1H
NMR spectra were recorded on a Bruker Avance 400 spectrometer
in the NMR Laboratory at University of Pannonia, or on a VARIAN
UNITY 300 or Bruker DRX-500 spectrometer at University of
Technology and Economics. The key starting materials cyclic sul-
fates and the ring opening step were made according to the
method described by Sharpless et al.31 The aminoalkyl phospines
were prepared according to the literature.9
Figure 3. Ee change through the course of the asymmetric allylic alkylation using
UPPhos 1a ligand and standard reaction conditions.
4.2. GC analyses
4.2.1. Methyl (Z)-acetamidocinnamate
CHIRASIL-L-VAL column (25 m ꢂ 0.25 mm, df = 0.12
lm).
be explained by the degradation of the catalyst. However, the reac-
tion did not stop using the softer Cs2CO3 base, although the rate
was very low due to the heterogeneous system. Trost described
the use of tetra-n-alkylammonium salt of dimethyl malonate in
the allylic alkylation of 3-(acyloxy)cycloalkenes.28b The excellent
solubility of such ion pair ensures high nucleophile concentration
at the point of addition even in apolar solvents. The catalytic
system with UPPhos 1a showed a high initial turnover frequency
(1780 hꢀ1 at 3 min reaction time) using the tetra-n-
butylammonium salt of dimethyl malonate in CH2Cl2.
Temperature program: 2 min at 140 °C; 2 °C/min from 140 °C to
180 °C; 40 min at 180 °C. Retention times were 12.3 min for (R),
13.2 min for (S)-product, and 22.1 min for (Z)-a-acetamidocin-
namic acid methyl ester.
4.2.2. Methyl 2-acetamidoacrylate
b-Dex 255 column (30 m ꢂ 0.25 mm, df = 0.25
lm). Retention
times at 140 °C isotherm were 6.7 min for (S), 7.4 min for (R)-pro-
duct, and 5.9 min for acetamidoacrilyc acid methyl ester.
4.2.3. Dimethyl itaconate
3. Conclusion
b-Dex 255 column (30 m ꢂ 0.25 mm, df = 0.25
lm). Retention
times at 85 °C isotherm were 18.8 min for (R), 20.0 min for (S)-pro-
We have synthesized three novel derivatives of UPPhos 1a,
which were tested in the asymmetric hydrogenation of different
substrates. The new ligands containing Me, Bn, or Ph sub-
stituents 1b–d gave excellent enantioselectivities with methyl
duct, and 27.6 min for dimethyl itaconate.
4.3. HPLC analysis
(Z)-a-acetamidocinnammate and dimethyl itaconate (up to
Retention times on Kromasil 3-AmyCoat column with n-hex-
ane/2-propanol = 85/15 eluent mixture at 0.3 mL minꢀ1 were
6.7 min for 1,3-diphenylallyl acetate, 11.4 min for the (S)-enan-
tiomer and 15.1 min for the (R)-enantiomer. UV detection was
set to 280 nm and the substrate/product = 1.03 response factor
was found based on NMR measurement.
99.9% ee’s) and methyl 2-acetamidoacrylate (up to 99.5% ee).
The new ligands, together with four already reported UPPhos
analogues were tested in palladium catalyzed asymmetric allylic
alkylations for the first time. By using rac-(E)-1,3-diphenylallyl
acetate as the substrate and dimethyl malonate as the nucle-
ophile, remarkably high activities and moderate enantioselectiv-
ities (up to 64% ee) were observed with all these ligands. When
the reaction profile of the UPPhos system was investigated, we
found that the reaction rate was limited by the slow formation
of the nucleophile. By using an equivalent amount of nucleophile
prepared in situ, prior to the alkylation, first order kinetics were
observed for the substrate with an increased initial turnover fre-
quency of 1026 hꢀ1. The reaction rate could be further enhanced
by applying of the tetra-n-butyl ammonium salt of dimethyl
malonate and an initial turnover frequency of 1780 hꢀ1 was
reached. Apparently, the N-substituent effect on the basicity of
the amidite P-atom is low, but the space filling of the sub-
stituents has a notable impact on the enantioselectivity. To show
clearly the N-substituent effect of the ligand family on the enan-
tioselectivity in the asymmetric allylic alkylation, we aim to
carry out the synthesis of some ligands with more bulky alipha-
tic substituent on N atom.
4.4. Synthesis of ligands and their diselenide derivative
4.4.1. (2S,4R)-2-Methylamino-4-sulfato-pentane 3b
At first, NaOH in water was added to methylamine hydrochlo-
ride in water. The formed methylamine gas was transferred into
a solution of (4R,6R)-4,6-dimethyl-2,2-dioxide-1,3,2-dioxathiane
2 (3 g, 18.1 mmol) in 20 mL of THF at ꢀ30 °C. The solvent was
evaporated and 60 mL of ether were added to the residue. The sus-
pension was stirred for 30 min and filtered. The solid was washed
two times with ether, dried with azeotropic distillation using
toluene. The solvent was evaporated in vacuum to give 3.29 g of
a white powder (Yield: 92.6%). [a]
20 = 0 (c 1, DMSO), mp: 170 °C.
D
Anal. Calcd for C6H15NO4S: C, 36.53; H, 7.66; N, 7.10; S, 16.26.
Found: C, 36.27; H, 7.61; N, 7.12; S, 16.11. 1H NMR (500 MHz,
DMSO) d = 8.29 (s, 2H, NH+2), 4.28 (m, 1H, CH), 3.33 (m, 1H, CH),
2.50 (m, 3H, CH3), 1.79 (m, 1H, CH2), 1.55 (m, 1H, CH2), 1.22 (d,
3H, CH3), 1.20 (d, 3H, CH3) ppm. 13C{1H} NMR (125 MHz,
DMSO) d = 70.70 (s), 52.92 (s), 40.15 (s), 29.45 (s), 22.49 (s),
16.11 (s) ppm.
4. Experimental
4.1. General
(2S,4S)-2-Diphenylphosphino-4-methylamino-pentane 4b. At
first, LiPPh2ꢃ1,4-dioxane complex (14.3 g, 50.9 mmol) was dis-
solved in 40 mL of abs. THF under an argon atmosphere and cooled
to about ꢀ10 °C. (2S,4R)-2-Methylamino-4-sulfato-pentane 3b
(3.2 g, 16.4 mmol) was added dropwise to the red solution over
10 min. The cooling bath was removed and the reaction mixture
All reactions and manipulations were carried out under an
argon atmosphere using standard Schlenk techniques. Methanol,
THF, and diethyl ether were distilled and dried before use.
JEFSOLÒ propylene carbonate was provided by Huntsman
Corporation and used without drying or degassing (H2O content:
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6
S. Balogh et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
was allowed to warm up to RT and let stirred for one hour. The
color of the reaction mixture remained red. After evaporation of
the solvent, 80 mL of distilled oxygen free water and 60 mL of ether
were added to the residue and the mixture was stirred until the
two phases became clear solutions. The pH was then set to 1 with
10% oxygen free solution of HCl. Subsequently, the phases where
separated and the water phase was washed three times with
30 mL portions of ether. The pH was set to 9–10 by the dropwise
addition of Na2CO3. The product was then extracted four times
with 30 mL portions of ether. After drying over MgSO4 the mixture
was filtered and evaporated to give 3.70 g of (2S,4S)-2-
diphenylphosphino-4-methylamino-pentane 4b as a pale yellow
oil (Yield: 78.9%). Anal. Calcd for C18H24NP: C, 75.76; H, 8.48; N,
4.91. Found: C, 75.85; H, 7.84; N, 4.96. 1H NMR (500 MHz,
CDCl3): d = 7.55–7.45 (m, 4H), 7.36–7.28 (m, 6H), 2.72–2.60 (m,
1H, CH), 2.47–2.35 (m, 1H, CH), 2.34 (s, 3H, CH3), 1.56–1.42 (m,
diastereotopic 1H, CH2), 139–125 (m, diastereotopic 1H, CH2),
Diselenide of 1b.
(d, JSe–P = 964.5 Hz), 51.5 ppm (d, JSe–P = 729.6 Hz).
31P{1H} NMR (121 MHz, toluene): d = 88.7
1
1
4.4.2. (2S,4R)-2-(Benzilamino)-4-sulfato-pentane 3c
(4R,6R)-4,6-Dimethyl-2,2-dioxide-1,3,2-dioxathiane
2
(5 g,
30.08 mmol) was stirred in benzylamine (10.0 mL, 95.1 mmol).
The temperature was increased to 45 °C in the first 15 min. After
4 h, 100 mL of ether was added to the reaction mixture and the
precipitate was filtered and washed with 20 mL portions of ether.
The remaining solid was dried with azeotropic distillation using
toluene. The product was 7.4 g of a white powder (Yield: 90.0%).
Mp: 225 °C. Anal. Calcd for C12H19NO4S: C, 52.73; H, 7.01; N,
5.12; S, 11.73. Found: C, 53.14; H, 6.73; N, 5.41; S, 10.88. 1H
NMR (400 MHz, DMSO): d = 7.48 (dd, 2H), 7.38 (m, 3H), 4.45–
4.19 (m, 1H, CH), 4.06 (q, 2H, benzyl CH2), 3.31 (s, 2H, NH+2), 3.34
(m, 1H, CH), 1.70 (m, 2H, CH2), 1.26 (d, 3H, CH3), 1.17 (d, 3H,
CH3) ppm. 13C{1H} NMR (75 MHz, DMSO): d = 132.79 (s), 130.46
(s), 129.39 (s), 129.19 (s), 70.93 (s), 52.55 (s), 47.36 (s), 22.54 (s),
16.67 (s) ppm.
3
1.07 (q, JP–H = 15.1 Hz, 3H, CH3), 1.02 (d, 3H, CH3) ppm. 31P{1H}
NMR (121 MHz, CDCl3): d = 0.09 (s), 13C{1H} NMR (75 MHz,
1
1
CDCl3) d = 137.07 (d, JP–C = 14.8 Hz), 137.05 (d, JP–C = 13.9 Hz),
2
2
133.76 (d, JP–C = 192 Hz), 133.67 (d, JP–C = 19.1 Hz), 128.75 (s),
(2S,4S)-2-Diphenylphosphino-4-benzylamino-pentane 4c. This
compound was prepared by following the procedure described
for the preparation of (2S,4S)-2-diphenylphosphino-4-methy-
lamino-pentane 4b. The product was 2.8 g of pale yellow oil
3
3
3
128.38 (d, JP–C = 4.9 Hz), 128.28 (d, JP–C = 4.9 Hz), 52.78 (d, JP–C
=
=
1
2
12.41 Hz), 40.50 (d, JP–C = 16.8 Hz), 33.83 (s), 27.22 (d, JP–C
2
9.9 Hz), 19.41 (s), 16.48 (d, JP–C = 15.5 Hz) ppm.
(Yield: 74.3%).
[
a
]
20 = ꢀ49.8 (c 1, CH2Cl2). Anal. Calcd for
D
(11bS)-N-((2S,4S)-4-(Diphenylphosphino)pentan-2-yl)-N-methyl-
{dinaphtho[2,1-d:10,20-f][1,3,2]dioxaphosphepin-2-yl}-4-amine
C24H28NP: C, 79.75; H, 7.81; N, 3.88. Found: C, 79.43; H, 7.78; N,
3.94. 1H NMR (300 MHz, CDCl3): d = 7.56–7.49 (m, 3H), 7.35–7.25
(m, 12), 3.81–3.69 (q, 2H, benzyl CH2), 2.92–2.81 (m, 1H, CH),
2.51–2.41 (m, 1H, CH), 1.64–1.38 (m, diastereotopic 2H, CH2),
1b. (2S,4S)-2-Diphenylphosphino-4-methylamino-pentane
(1.5 g, 5.25 mmol), Li metal (74.5 mg, 10.5 mmol), THF (362
4b
L,
l
3
4.5 mmol) and styrene (301
lL, 2.63 mmol) were stirred
1.09 (d, 3H, CH3), 1.05 (dd, JHP = 15.1 Hz, 3H, CH3) ppm. 31P{1H}
vigorously in 20 mL of hexane under argon for 3 h at room
temperature to form a yellow solution with Li metal pieces.
After filtration of the excess Li metal, the yellow filtrate was added
to (S)-chloro-binaphtho[2,1-d:10,20-f][1,3,2]dioxaphosphepine (1.86 g,
5.3 mmol) in 30 mL of ether solution, which was precooled to
approximately ꢀ10 °C for 10 min under argon. The cooling bath
was removed and the reaction mixture was stirred for two hours
at room temperature. The white precipitates formed were filtered
and washed with ether. The liquid phase was evaporated to give
2.95 g of white solid foam (Yield: 93.6%). Purification was per-
formed by flash chromatography on silica gel with the eluent
hexane/EtOAc = 6/1. Rf: 0.7. After purification 0.46 g of white
NMR (121 MHz, CDCl3): d = 0.00 (s) ppm. 13C{1H} NMR (75 MHz,
1
1
CDCl3): d = 137.13 (d, JP–C = 14.9 Hz), 137.05 (d, JP–C = 14.0 Hz),
2
2
133.76 (d, JP–C = 19.2 Hz), 133.70 (d, JP–C = 19.1 Hz), 128.76 (s),
3
3
128.43 (s), 128.39 (d, JP–C = 5.9 Hz), 128.30 (d, JP–C = 5.8 Hz),
128.20 (s), 126.93 (s), 67.13 (s), 51.34 (s), 50.62 (d, JP–C
3
=
1
2
12.2 Hz), 40.70 (d, JP–C = 17.1 Hz), 27.26 (d, JP–C = 9.8 Hz), 19.95
2
(s), 16.60 (d, JP–C = 15.6 Hz) ppm.
(11bS)-N-((2S,4S)-4-(Diphenylphosphino)pentan-2-yl)-N-ben-
zyl-{dinaphtho[2,1-d:10,20-f][1,3,2]dioxaphosphepin-2-yl}-4-
amine 1c. This compound was prepared by following the proce-
dure described for the preparation of 1d. The crude product was
recrystallized from methanol or can be purified by flash chro-
matography under ambient conditions with kieselgel as the sta-
tionary phase and commercial chloroform as the eluent (Rf: 0.9).
The product was 1.86 g white powder (Yield: 37.5%).
powder were obtained (Yield: 14.6%). [a]
20 = +244.2 (c 1, CH2Cl2),
D
mp: 150–152 °C. Anal. Calcd for C38H35NO2P2: C, 76.11; H, 5.88;
N, 2.34. Found: C, 76.18; H, 5.89; N, 2.05. 1H NMR (500 MHz,
CDCl3): d = 8.02–7.85 (m, 4H), 7.63–7.20 (m, 18H), 4.00–3.84
(m, 1H, CH), 2.46–2.31 (m, 1H, CH), 2.12 (d, 3H, CH3), 1.67–1.46
[a]
20 = +129.2 (c 1, CH2Cl2), mp: 168 °C. Anal. Calcd for
D
3
(m, 2H, CH2), 1.29 (d, JH–H = 6.59 Hz, 3H, CH3), 1.02 (dd,
C44H39NO2P2: C, 78.21; H, 5.82; N, 2.07. Found: C, 77.98; H, 6.28;
3JH–H = 6.97 Hz, 3JP–H = 12.43 Hz, 3H, CH3) ppm. 31P {1H}
NMR (121 MHz, CDCl3): d = 141.04 (d, JP–P = 14.48 Hz), ꢀ0.07
(d, JP–P = 14.47 Hz) ppm. 13C {1H} NMR (75 MHz, CDCl3): d = 150.41
(s) and 150.34 (s) are diastereotopic, 149.62 (s), 137.31
(d, 1JP–C = 13.9 Hz) and 136.39 (d, 1JP–C = 16.1 Hz) are diastereotopic,
134.29 (d, 2JP–C = 19.6 Hz) and 133.21 (d, 2JP–C = 17.8 Hz) are diaster-
eotopic, 132.84 (s) and 132.70 (s) are diastereotopic, 131.38 (s) and
130.70 (s) are diastereotopic, 130.22 (s) and 130.02 (s) are
diastereotopic, 128.95 (s) and 128.47 (s) are diastereotopic, 128.45
N, 2.02. 1H NMR (400 MHz, CDCl3): d = 7.95 (d, J = 8.8 Hz, 1H),
7.89 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 8.8 Hz,
1H), 7.53 (d, J = 8.7 Hz, 1H), 7.40–7.24 (m, 16H), 7.27–7.13 (m,
2
4
8H), 4.10 (dd, JP–H = 15.5 Hz, JH–H = 5.3 Hz, 1H), 3.46 (m, 2H,
N-CH2–), 2.15 (m, 1H, CH), 1.52 (m, 1H, CH2) and 1.35 (s, 1H, CH2)
3
3
are diastereotopic, 1.23 (d, JH–H = 6.7 Hz, 3H, CH3), 0.63 (dd, JP–H
=
3
14.5 Hz, JH–H = 6.8 Hz, 3H, CH3) ppm. 31P{1H} NMR (162 MHz,
CDCl3): d = 147.14 (s), 2.01 (s) ppm. 13C{1H} NMR (75 MHz,
CDCl3): d 149.91 (s) and 149.84 (s) are diastereotopic, 149.61 (s),
3
3
1
1
(d, JP–C = 6.2 Hz) and 128.30 (d, JP–C = 7.2 Hz) are diastereotopic,
127.05 (s) and 126.98 (s) are diastereotopic, 126.06 (s) and 126.04
(s) are diastereotopic, 124.74 (s) and 124.54 (s) are diastereotopic,
123.99 (s) and 123.92 (s) are diastereotopic, 122.61 (s) and 122.58
(s) are diastereotopic, 122.16 (s) and 122.15 (s) are diastereotopic,
136.70 (d, JP–C = 15.3 Hz) and 136.50 (d, JP–C = 14.8 Hz) are dia-
2
2
stereotopic, 133.84 (d, JP–C = 21.6 Hz) and 133.59 (d, JP–C
=
21.3 Hz) are diastereotopic, 132.87 (s) and 132.66 (s) are diastereo-
topic, 131.47 (s) and 130.73 (s) are diastereotopic, 130.28 (s) and
130.23 (s) are diastereotopic, 128.77 (s) and 128.62 (s) are diaster-
eotopic, 128.40 (d, JP–C = 5.1 Hz) and 128.31 (d, JP–C = 5.0 Hz) are
diastereotopic, 128.19 (s) and 128.16 (s) are diastereotopic,
127.09 (s) and 126.97 (s) are diastereotopic, 126.08 (s) and
126.07 (s) are diastereotopic, 124.82 (s) and 124.58 (s) are
2
3
3
3
122.03 (s), 51.11 (dd, JP–C = 44.5 Hz, JP–C = 121 Hz), 37.99
1
4
2
(dd, JP–C = 17.5 Hz, JP–C = 7.6 Hz), 27.20 (d, JP–C = 12.0 Hz), 25.61
2
3
2
(d, JP–C = 1.2 Hz), 19.73 (d, JP–C = 3.7 Hz), 16.75 (d, JP–C = 10.6 Hz)
ppm.
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S. Balogh et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
7
diastereotopic, 124.13 (s) and 124.06 (s) are diastereotopic, 122.50
(s) and 122.47 (s) are diastereotopic, 122.25 (s) and 122.23 (s) are
chromatography under ambient conditions with kieselgel as the
stationary phase and commercial chloroform as the eluent (Rf:
2
3
diastereotopic, 121.76 (s), 50.52 (dd, JP–C = 24.3, JP–C = 11.7 Hz),
0.9) to gain 0.97 g white powder (Yield: 52.54%). [a]
20 = 89.4 (c 1,
D
2
2
3
47.12 (d, JP–C = 8.9 Hz), 40.67 (dd, JP–C = 14.7, JP–C = 7.5 Hz),
CH2Cl2), mp: 199–202 °C. Anal. Calcd for C43H37NO2P2: C, 78.05;
H, 5.64; N, 2.12. Found: C, 77.79; H, 5.50; N, 2.27. 1H NMR
(300 MHz, CDCl3): d = 7.96 (d, 1H, JH–H = 9.06 Hz), 7.92 (d, 1H,
3
3
2
27.16 (d, JP–C = 11.6 Hz), 19.82 (d, JP–C = 10.2 Hz), 15.24 (d, JP–C
=
14.0 Hz) ppm.
JH–H
=
8.28 Hz), 7.79 (d, 1H, JH–H = 8.67 Hz), 7.59 (d, 1H,
Diselenide of 1c.
(d, JSe–P = 971.7 Hz), 48.2 ppm (d, JSe–P = 730.2 Hz).
31P{1H} NMR (121 MHz, toluene): d = 89.7
JH–H = 8.67 Hz), 7.55–7.14 (m, 23H), 3.91–3.73 (m, 1H, CH),
2.15–2.02 (m, 1H, CH), 1.40–1.26 (m, 2H, CH2), 1.13 (d, 3H, JH–H =
1
1
3
3
3
6.60 Hz, CH3), 0.38 (dd, 3H, JP–H = 13.75 Hz, JH–H = 6.96 Hz, CH3).
31P{1H} NMR (162 MHz, CDCl3): d = 140.03 (d, JP–P = 2.23 Hz), 0.01
(d, JP–P = 2.23 Hz). 13C{1H} NMR (75 MHz, CDCl3): d = 149.66 (s)
and 149.58 (s) are diastereotopic, 149.34 (s), 139.53 (s) and
139.30 (s) are diastereotopic, 137.10 (d, 1JP–C = 14.5 Hz)
4.4.3. (2R,4S)-2-Anilino-4-sulfato-pentane 3d
(4R,6R)-4,6-Dimethyl-2,2-dioxide-1,3,2-dioxathiane
2
(5 g,
30.08 mmol) and aniline (2.9 mL, 33.1 mmol) were stirred in
20 mL of THF for 48 h to form a white precipitate. The solvent
was evaporated and 60 mL of ether was added to the residue. The
suspension was stirred for 30 min and filtered. The solid was
washed two times with ether and dried with azeotropic distillation
using toluene. The solvent was evaporated in vacuum to give 7.00 g
of (2R,4S)-2-anilino-4-sulfato-pentane 3d as a white powder (Yield:
1
and 136.25 (d, JP–C = 15.4 Hz) are diastereotopic, 134.10
2
2
(d, JP–C = 19.2 Hz) and 133.21 (d, JP–C = 17.8 Hz) are diastereoto-
pic, 132.87 (s) and 132.59 (s) are diastereotopic, 131.84 (s) and
131.75 (s) are diastereotopic, 131.43 (s) and 130.62 (s) are diaster-
eotopic, 130.30 (s) and 129.96 (s) are diastereotopic, 128.86 (s),
128.48–128.12 (m), 127.11 (s) and 126.91 (s) are diastereotopic,
126.71 (s) and 126.69 (s) are diastereotopic, 126.05 (s) and 125.84
(s) are diastereotopic, 12.79 (s) and 124.43 (s) are diastereotopic,
124.15 (s) and 124.08 (s) are diastereotopic, 122.22 (s) and
122.20 (s) are diastereotopic, 122.00 (s), 121.93 (s)
89.7%). [
a
]
20 = ꢀ10.2 (c 1, CH2Cl2), mp: 223 °C. Anal. Calcd for
D
C11H17NO4S: C, 50.95; H, 6.61; N, 5.40; S, 12.36. Found: C, 51.13;
H, 6.69; N, 5.82; S, 12.56. 1H NMR (400 MHz, DMSO): d = 10.35 (s,
2H, NH+2), 7.54–7.39 (m, 5H), 4.39 (m, 1H, CH), 3.73 (m, 1H, CH),
1.73 (m, 2H, CH2), 1.18 (d, 3H, CH3), 1.12 (d, 3H, CH3) ppm.
13C{1H} NMR (101 MHz, DMSO): d = 135.80 (s), 131.45 (s), 130.40
(s), 124.93 (s), 71.78 (s), 57.54 (s), 41.54 (s), 23.44 (s), 17.63 (s) ppm.
3
2
and 121.90 (s) are diastereotopic, 50.48 (dd, JP–C = 13.5 Hz, JP–C
10.1 Hz), 38.59 (dd, JP–C = 1.1 Hz, JP–C = 17.8 Hz), 26.64 (d, JP–C
11.3 Hz), 20.94 (d, JP–C = 2.2 Hz), 14.82 (d, JP–C = 12.3 Hz) ppm.
=
=
4
1
2
3
2
(2S,4S)-2-Diphenylphosphino-4-anilino-pentane 4d.
This
compound was prepared by following the procedure described for
the preparation of (2S,4S)-2-diphenylphosphino-4-methylamino-
pentane 4b. The product was 4.1 g of pale yellow oil (Yield: 74.5%).
Diselenide of 1d.
(d, JSe–P = 973.1 Hz), 50.0 ppm (d, JSe–P = 735.0 Hz).
31P{1H} NMR (121 MHz, toluene): d = 81.6
1
1
[
a
]
20 = ꢀ80.6 (c 1, CH2Cl2). Anal. Calcd for C23H26NP: C, 79.51; H,
4.5. Typical procedure for the asymmetric hydrogenation
D
7.54; N, 4.03. Found: C, 79.47; H, 7.95; N, 4.32. 1H NMR (400 MHz,
CDCl3): d = 7.54–7.47 (m, 4H), 7.34–7.30 (m, 6H), 7.13 (dd, 2H),
6.65 (tt, 1H, Hz), 6.51 (d, 2H), 3.64–3.55 (m, 1H, CH), 3.53–2.80 (s,
1H, NH), 2.54–2.43 (m, 1H, CH), 1.71–1.60 (m, 1H, CH2), 1.49–1.39
(m, diastereotopic 1H, CH2), 1.14 (d, 3H, CH3), 1.10 (d, 3H, CH3)
ppm. 31P{1H} NMR (162 MHz, CDCl3): d = ꢀ0.27 (s) ppm. 13C{1H}
In a Schlenk tube, [Rh(COD)2]BF4 (4.1 mg, 0.01 mmol) and
ligands 1a–d (0.011 mmol) were dissolved in 5 mL of propylene-
carbonate under argon and stirred for 20 min. Methyl (Z)-acetami-
docinnamate (275 mg, 1.25 mmol) was added and the mixture was
transferred under argon into a stainless steel autoclave (100 mL
internal volume) equipped with a glass test tube and manometer.
The mixture was pressurized to 5 bar with H2 and stirred at
600 RPM until no further pressure drop was detected on a 15 bar
manometer (Full conversion was at ꢁ4.65 bar).
1
NMR (75 MHz, CDCl3): d = 147.20 (s), 137.09 (d, JP–C = 14.1 Hz),
1
2
136.96 (d, JP–C = 15.0 Hz), 133.82 (d, JP–C = 19.4 Hz), 133.65 (d,
2JP–C = 19.1 Hz), 129.34 (s), 128.88 (s), 128.85 (s), 128.48 (d, JP–C
=
3
3
6.8 Hz), 128.39 (d, JP–C = 7.0 Hz), 117.17 (s), 113.31 (s), 46.73 (d,
3JP–C = 11.8 Hz), 40.97 (d, JP–C = 17.4 Hz), 27.45 (d, JP–C = 9.9 Hz),
1
2
20.31 (s), 16.62 (d, 2JP–C = 15.5 Hz) ppm.
4.6. Typical procedure for asymmetric allylic alkylation
(11bS)-N-((2S,4S)-4-(Diphenylphosphino)pentan-2-yl)-N-phe-
nyl-{dinaphtho[2,1-d:10,20-f][1,3,2]dioxaphosphepin-2-yl}-4-
In a Schlenk tube, [Pd(C3H5)Cl]2 (2.3 mg, 0.00625 mmol) and 1g
(8.0 mg, 0.0125 mmol) were dissolved in 10 mL of CH2Cl2 under
argon and stirred for 20 min. Next, rac-(E)-1,3-diphenylallyl acet-
ate (315 mg, 1.25 mmol) was added and the mixture was stirred
amine 1d.
pentane 4d (0.97 g, 2.792 mmol) in 20 mL of abs. THF was added
dropwise to the stirred solution of PCl3 (365 L, 4.188 mmol) and
triethylamine (677 L, 4.88 mmol) in 5 mL of THF over 20 min at
(2S,4S)-Dimethyl-2-diphenylphosphino-4-anilino-
l
again for 20 min. Dimethyl-malonate (165
(10 mg) and N,O-bis(trimethylsylyl)acetamide
3.75 mmol) were added. After the given reaction time, a 100 lL
l
L, 3.75 mmol), KOAc
l
(0.91 mL,
ꢀ20 °C. The mixture was then allowed to warm up to room tem-
perature and stirred for an hour. The solvent was evaporated at
reduced pressure and the remaining white solid was suspended
in 60 mL of ether. After filtering of triethylamine-hydrochloride
and the excess amount of triethylamine–trichlorophosphine
adduct, the organic phase was evaporated to give a clear oil. This
was then dissolved in 20 mL of abs. THF. Triethylamine (1.35 mL,
portion of the reaction mixture was transferred to 3 mL of satu-
rated NH4Cl solution. The mixture was properly shaken and the
organic phase was extracted with 3 ꢂ 3 mL portions of ether. The
combined organic phases were dried over MgSO4. The catalyst
was removed from the sample by chromatography on a short layer
of silicagel by an ether eluent. The filtrate was evaporated and the
remaining sample was prepared for HPLC analysis by dissolving it
9.9 mmol) and
a
solution of (S)-1,10-binaphthalene-2,20-diol
(1.22 g, 4.26 mmol) in 10 mL of abs. THF was then added to the
reaction mixture over 10 min at ꢀ20 °C. The reaction mixture
was evaporated at reduced pressure. The remaining white solid
was dissolved in chloroform and the suspension was filtered off
on a short pad of Al2O3. The product precipitates in ether, is par-
tially soluble in toluene, and dissolves well in chloroform or
dichloromethane. Final purification can be performed with flash
in a mixture of 100 lL 2-propanol and 3 mL of n-hexane.
4.7. Typical procedure to obtain [Rh(COD)(1a–d)]BF4 NMR
samples
Compounds 1a-d (0.03 mmol) in CH2Cl2 (5 mL) was added
dropwise to a solution of [Rh(COD)2]BF4 (12.18 mg, 0.03 mmol)
Please cite this article in press as: Balogh, S.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.05.001

8
S. Balogh et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
13. (a) Bayardon, J.; Holz, J.; Schäffner, B.; Andrushko, V.; Verevkin, S.; Preetz, A.;
Börner, A. Angew. Chem., Int. Ed. 2007, 46, 5971; (b) Schäffner, B.; Holz, J.;
Verevkin, S. P.; Börner, A. ChemSusChem 2008, 1, 249.
in CH2Cl2 (5 mL). The resulting orange solution was stirred for
20 min, concentrated and dissolved in CDCl3 (0.6 mL).
14. Reetz, M. T.; Lohmer, G. Chem. Commun. 1996, 1921.
15. Lenden, P.; Ylioja, P. M.; González-Rodriguez, C.; Entwistle, D. A.; Willis, M. C.
Green Chem. 2011, 13, 1980.
16. Balogh, Sz.; Farkas, G.; Szöllosy, Á.; Darvas, F.; Ürge, L.; Bakos, J. Tetrahedron:
Acknowledgements
}
This work was supported by the Hungarian Government and
the European Union (TAMOP-4.2.2.A-11/1/KONV-2012-0071). The
authors thank for Huntsman Corporation for providing samples
of the green cyclic carbonate solvents. We thank Béla Édes for skill-
ful assistance in synthetic and catalytic experiments.
Asymmetry 2013, 24, 66.
17. Wodrich, M. D.; Vargas, A.; Morgantini, P.-Y.; Merinoc, G.; Corminboeuf, C. J.
Phys. Org. Chem. 2009, 22, 101.
18. (a) Alexakis, A.; Polet, D. Org. Lett. 2004, 6, 3529; (b) Mikhel, I. S.; Bernardinelli,
G.; Alexakis, A. Inorg. Chim. Acta 2006, 359, 1826; (c) Malda, H.; Zijl, A. W.;
Arnold, L. A.; Feringa, B. L. Org. Lett. 2001, 3, 1169; (d) Shi, W.-J.; Wang, L.-X.;
Fu, Y.; Zhu, S.-F.; Zhou, Q.-L. Tetrahedron: Asymmetry 2003, 14, 3867; (e) Boele,
M. D. K.; Kamer, P. C. J.; Lutz, M.; Spek, A. L.; de Vries, J. G.; van Leeuwen, P. W.
N. M.; van Strijdonck, G. P. F. Chem. Eur. J. 2004, 10, 6232; (f) Fañanás-Mastral,
M.; Pérez, M.; Bos, P. H.; Rudolph, A.; Harattyunyan, S. R.; Feringa, B. L. Angew.
Chem., Int. Ed. 2012, 51, 1922; (g) Liu, W.-B.; Reeves, C. M.; Stoltz, B. M. J. Am.
Chem. Soc. 2013, 135, 17298.
19. (a) Wassenaar, J.; van Zutphen, S.; Mora, G.; Le Floch, P.; Siegler, M. A.; Spek, A.
L.; Reek, J. N. H. Organometallics 2009, 28, 2724; (b) Wassenaar, J. Dissertation,
University of Amsterdam, 2010.; (c) Wassenaar, J.; Jansen, E.; van Zeist, W.-J.;
Bickelhaupt, F. M.; Siegler, M. A.; Spek, A. L.; Reek, J. N. H. Nat. Chem. 2010, 2,
417.
20. (a) Mallory, F. B. J. Am. Chem. Soc. 1973, 95, 7747; (b) Mallory, F. B.; Mallory, C.
W.; Ricker, W. M. J. Org. Chem. 1985, 50, 457; (c) Mallory, F. B.; Mallory, C. W. J.
Am. Chem. Soc. 1985, 107, 4816; (d) Mallory, F. B.; Mallory, C. W.; Baker, M. B. J.
Am. Chem. Soc. 1990, 112, 2577; (e) Mallory, F. B.; Luzik, E. D., Jr.; Mallory, C. W.;
Carroll, P. J. J. Org. Chem. 1992, 57, 366; (f) Mallory, F. B.; Mallory, C. W.; Butler,
K. E.; Lewis, M. B.; Xia, A. Q.; Luzik, E. D., Jr.; Fredenburgh, L. E.; Ramanjulu, M.
M.; Van, Q. N.; Francl, M. M.; Freed, D. A.; Wray, C. C.; Hann, C.; Nerz-Stormes,
M.; Carroll, P. J.; Chirlian, L. E. J. Am. Chem. Soc. 2000, 122, 4108.
21. Szalontai, G.; Bakos, J.; Tóth, I.; Heil, B. Magn. Reson. Chem. 1987, 25, 761.
22. Hierso, J.-C.; Fihri, A.; Ivanov, V. V.; Hanquet, H.; Pirio, N.; Donnadieu, B.;
Robiére, B.; Amardeil, R.; Meunier, P. J. Am. Chem. Soc. 2004, 126, 11077.
23. Pullmann, T.; Engendahl, B.; Zhang, Z.; Hölscher, M.; Zanotti-Gerosa, A.; Dyke,
A.; Franciò, G.; Leitner, W. Chem. Eur. J. 2010, 16, 7517.
24. (a) Pinell, R. P.; Megerle, C. A.; Manatt, S. L.; Kroon, P. A. J. Am. Chem. Soc. 1973,
95, 977; (b) Allen, D. W.; Taylor, B. F. J. Chem. Soc., Dalton 1982, 51.
25. Rios, I. G.; Rosas-Hernandez, A.; Martin, E. Molecules 2011, 16, 970.
26. Chan, A. S.; Chen, G.; Gou, R.; Wu, Jing. US Patent 7,713,900 B2, 2010.
27. Hydrio, J.; Gouygou, M.; Dallemer, F.; Daran, J.-C.; Balavoine, G. G. A.
Tetrahedron: Asymmetry 2002, 13, 1097.
References
1. (a) Ojima, I. Catalytic Asymmetric Synthesis; WILEY, 2010; (b) Noyori, A.
Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons Ltd, 1994; (c)
Brunner, H.; Zettlmeier, W. Handbook of Enantioselective Catalysis; VCH: New
York, 1993; (d) Jacobsen, E. N.; Pfalz, A.; Yamamoto, H. Comprehensive
Asymmetric Catalysis I–III; Springer: Berlin, 2000.
2. (a) van Leeuwen, P. W. N. M. Homogeneous Catalysis; Kluwer Academic
Publishers, 2004; (b) de Vries, J. G.; Elsevier, C. J. Handbook of Homogeneous
Hydrogenation; WILEY-VCH: Weinheim, 2007.
3. (a) Vallianatou, K. A.; Kostas, I. D.; Holz, J.; Börner, A. Tetrahedron Lett. 2006, 47,
7947; (b) Zeng, Q.-H.; Hu, X.-P.; Duan, Z.-C.; Liang, X.-M.; Zheng, Z. Tetrahedron:
Asymmetry 2005, 16, 1233; (c) Yu, S.-B.; Huang, J.-D.; Wang, D.-Y.; Hu, X.-P.;
Deng, J.; Duan, Z.-C.; Zheng, Z. Tetrahedron: Asymmetry 2008, 19, 1862; (d)
Eggenstein, M.; Thomas, A.; Theuerkauf, J.; Franció, G.; Leitner, W. Adv. Synth.
Catal. 2009, 351, 725; (e) Wassenaar, J.; Kuil, M.; Spek, A. L.; Reek, J. N. H. Chem.
Eur. J. 2010, 16, 6509; (f) Li, Q.; Hou, C.-J.; Liu, X.-N.; Huang, D.-Z.; Liu, Y.-J.; Rui-
Feng Yang, R.-F.; Xiang-Ping Hu, X.-P. RSC Adv. 2015, 5, 13702; (g) Hou, C.-J.;
Wang, Y.-H.; Zheng, Z.; Xu, J.; Hu, X.-P. Org. Lett. 2012, 14, 3554; (h) Konrad, T.
M.; Schmitz, P.; Leitner, W.; Franciò, G. Chem. Eur. J. 2013, 19, 13299.
4. (a) Zhang, X.; Yan, Y. J. Am. Chem. Soc. 2006, 128, 7198; (b) Diéguez, M.; Ruiz, A.;
Claver, C. Tetrahedron: Asymmetry 2001, 12, 2827; (c) Chikkali, S. H.; Bellini, R.;
de Bruin, B.; van der Vlugt, J. I.; Reek, J. N. H. J. Am. Chem. Soc. 2012, 134, 6607.
5. Boeda, F.; Rix, D.; Clavier, H.; Crévisy, C.; Mauduit, M. Tetrahedron: Asymmetry
2006, 17, 2726.
6. Yu, S.-B.; Hu, X.-P.; Deng, J.; Wang, D.-Y.; Duan, Z.-C.; Zheng, Z. Tetrahedron:
Asymmetry 2009, 20, 621.
7. Hou, C.-J.; Guo, W.-L.; Hu, X.-P.; Deng, J.; Zheng, Z. Tetrahedron: Asymmetry
2011, 22, 195.
28. (a) Arena, C. G.; Drommi, D.; Faraone, F. Tetrahedron: Asymmetry 2000, 11,
4753; (b) Trost, B. M.; Murphy, D. J. Organometallics 1985, 4, 1143.
29. Chen, J.; Lang, F.; Li, D.; Cun, L.; Zhu, J.; Deng, J.; Liao, J. Tetrahedron: Asymmetry
2009, 20, 1953.
30. Vinneyard, B. D.; Knowles, W. S.; Sabacky, M.; Bachman, G. L.; Weinkauff, D. J. J.
Am. Chem. Soc. 1977, 99, 5946.
31. (a) Richardson, P. F.; Nelson, L. T. J.; Sharpless, K. B. Tetrahedron Lett. 1995, 36,
9241; (b) Lohray, B. B.; Gao, Y.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 2623;
(c) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 655.
8. (a) Boeda, F.; Beneyton, T.; Crévisy, C. Mini-Rev. Org. Chem. 2008, 5, 96; (b)
Wassenaar, J.; Reek, J. N. H. Org. Biomol. Chem. 2011, 9, 1704.
}
9. Balogh, Sz.; Farkas, G.; Madarász, J.; Szöllosy, Á.; Kovács, J.; Darvas, F.; Ürge, L.;
Bakos, J. Green Chem. 2012, 14, 1146.
10. Abbreviation of ligand 1a is UPPhos (University of Pannonia’s Phosphine).
11. (a) Behr, A.; Naendrup, F.; Obst, D. Eur. Lipid Sci. Technol. 2002, 104, 161; (b)
Behr, A.; Tosly, N. Chem. Eng. Technol. 2000, 23, 122; (c) Behr, A.; Naendrup, F.;
Obst, D. Adv. Synth. Catal. 2002, 344, 1142.
12. (a) Behr, A.; Obst, D.; Schulte, C.; Schosser, T. J. Mol. Catal. A 2003, 197, 115; (b)
Behr, A.; Obst, D.; Turkowski, B. J. Mol. Catal. A 2005, 226, 215.
Please cite this article in press as: Balogh, S.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.05.001