Asymmetric hydrogenation of C=C double bonds using Rh-complex under homogeneous, heterogeneous and continuous mode conditions

Article abstract of DOI:10.1039/c2gc16447g

A green process for enantioselective hydrogenation of dehydroamino acid derivatives and dimethyl itaconate with a rhodium catalyst modified by a new phosphine-phosphoramidite has been developed providing 97.7-99.8% enantioselectivity in green solvents such as ethylene carbonate and propylene carbonate. The l-DOPA precursor was obtained by simple filtration in 71% yield with 99.5% ee. Dimethyl itaconate was hydrogenated under solvent-free condition at 50 °C with 98.7% ee. The new rhodium complex was heterogenized on a mesoporous Al₂O₃ support using phosphotungstic acid (PTA) as an anchoring agent and tested in heterogeneous batch and flow reaction modes. The supported catalyst was reused eight times in the batch mode with over 97% ee and used over 12 hours in the flow reaction mode with an average of 97% ee in the asymmetric hydrogenation reaction of (Z)-α-acetamidocinnamic acid methyl ester.

Full text of DOI:10.1039/c2gc16447g

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PAPER
Asymmetric hydrogenation of CvC double bonds using Rh-complex under
homogeneous, heterogeneous and continuous mode conditions†
Szabolcs Balogh,a Gergely Farkas,a József Madarász,a Áron Szöllősy,b József Kovács,c Ferenc Darvas,d
László Ürged and József Bakos*a
Received 12th November 2011, Accepted 23rd January 2012
DOI: 10.1039/c2gc16447g
A green process for enantioselective hydrogenation of dehydroamino acid derivatives and dimethyl
itaconate with a rhodium catalyst modified by a new phosphine–phosphoramidite has been developed
providing 97.7–99.8% enantioselectivity in green solvents such as ethylene carbonate and propylene
carbonate. The L-DOPA precursor was obtained by simple filtration in 71% yield with 99.5% ee.
Dimethyl itaconate was hydrogenated under solvent-free condition at 50 °C with 98.7% ee. The new
rhodium complex was heterogenized on a mesoporous Al2O3 support using phosphotungstic acid (PTA)
as an anchoring agent and tested in heterogeneous batch and flow reaction modes. The supported catalyst
was reused eight times in the batch mode with over 97% ee and used over 12 hours in the flow reaction
mode with an average of 97% ee in the asymmetric hydrogenation reaction of (Z)-α-acetamidocinnamic
acid methyl ester.
catalysts modified with hybrid bidentate ligands provide gener-
Introduction
ally better chiral induction with many of the substrates.6
Transition metal complexes containing chiral ligands are widely
used in industrial scale for asymmetric catalytic hydrogenation.
In particular, rhodium-based complexes modified with chiral
phosphine ligands have been found to be excellent catalysts.1
The discovery of novel and effective ligands is one of the key
challenges for the creation of more efficient catalysts. Several
hundreds of chiral ligands have been prepared and a few thou-
sand successful examples of asymmetric hydrogenation on lab-
scale have been published.2 Traditionally, chiral bidentate phos-
phine ligands2 have dominated this field until more recently
Feringa et al.,3 Reetz and Mehler4 and Pringle et al.,5 introduced
the use of monodentate phosphites and phosphoramidites.
Recently, it was shown that they are applicable for a wide range
of reactions, e.g. asymmetric hydrogenation, allylic alkylation
and hydroformylation.7 In addition to their excellent catalytic
properties, these ligands were found in some cases to be air and
moisture stable. However, so far only a limited number of these
compounds have been developed and characterized, such as Me-
AnilaPhos,8 THNAPhos and HY-Phos,9 ferrocenyl-containing
ligands,10 Indolphos,11 PEAPhos12 and QUINAPhos.13
Up to now organic cyclic carbonates have not played a role as
solvents for asymmetric hydrogenation. The few exceptions in
homogeneous catalysis include the platinum-catalyzed hydrosily-
lation of unsaturated fatty acids investigated by Behr et al.,14
regioselective rhodium-catalyzed hydroformylation,15 iridium-
and rhodium-catalyzed asymmetric hydrogenation by Börner
et al.,16 palladium-catalyzed Heck reaction by Reetz and
Lohmer,17 and rhodium-catalyzed intermolecular alkyne hydroa-
cylation.18 In catalytic processes it would be desirable to be able
to recover and to recycle the catalyst for economical and environ-
mental viability. A promising strategy is the heterogenization
of active metal complexes on an insoluble support. Many
approaches have been published to “heterogenize”, “immobilize”
or “anchor” a homogeneous catalyst19 by the use of polymer
supported catalysts20 and catalysts on inorganic carriers,21 or
both.22 Covalent binding is by far the most frequently used strat-
egy, however, a common and simple immobilization technique
of catalytically active metal complexes is ionic binding, which
is particularly useful for cationic rhodium23 and palladium
catalysts.24
Today, the most frequently used catalysts for asymmetric
hydrogenation contain phosphoramidite-type ligands. These
ligands3 are easy to prepare and they can be synthesized and
applied by high throughput screening methods, however,
aDepartment of Organic Chemistry, University of Pannonia, 8200
Veszprém, Egyetem u. 10, Hungary. E-mail: bakos@almos.vein.hu
bDepartment of Inorganic and Analytical Chemistry, University of
Technology and Economics, 1111 Budapest, Műegyetem rkp. 3-9,
Hungary
cInstitute of Environmental Engineering, University of Pannonia,
H-8201 Veszprém, P.O. Box 158, Hungary
dThalesNano Nanotechnology Inc., 1031 Budapest, Záhony u. 7,
Graphisoft Park, Hungary
†Electronic supplementary information (ESI) available: Supporting
information for this article contains the NMR spectra of the ligand and
its rhodium complex, hydrogenation experiments, preparation of [Rh
(COD)(4)]/PTA/Al2O3, textural characterization of support, the support
modified by PTA, and the immobilized complex, as well as HPLC analy-
sis of the chiral amino acid derivatives. See DOI: 10.1039/c2gc16447g
Besides easy separation, immobilization opens up new oppor-
tunities such as use of continuous flow reactors25 or further
1146 | Green Chem., 2012, 14, 1146–1151
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Table 1 Asymmetric hydrogenation of (Z)-α-acetamidocinnamic acid
methyl ester with [Rh(COD)(4)]BF4: effect of the solvent and pressurea
Pressure
Reaction time [h] [bar]
ee
[%]
Entry Solvent
b
1
2
3
4
5
6
CH2Cl2b
5.1
1.2
2.0
20.0
0.4
1.5
1
5
5
1
5
5
98.8
99.0
99.9
75.0
99.2
99.8
CH2Cl2
MeOH
MeOHc
EtOAc
Ethylene
carbonated,e
Propylene
carbonate
Propylene
carbonated
Glycerine
carbonated,e
EtOH (v/v = 96%)
7
2.8
2.9
5
5
5
5
99.2
99.6
72.0
99.8
Scheme 1 (i) Formation of lithium amide of 2 by Li metal or BuLi.
(ii) Addition of (S)-chlorodinaphthodioxaphosphepine to 3.
8
9
19.0 (conv. =
64%)
0.75
tuning of the catalyst environment, which in some cases can lead
to improved catalytic performance.26
10
a Reaction conditions: The catalyst was prepared in situ. 0.01 mmol [Rh
(COD)2]BF4 and 0.011 mmol ligand was stirred for 10 minutes in 5 mL
solvent. 1.25 mmol substrate was added and pressurized with H2. The
reaction was stirred at RT until full conversion. b Solvent: 10 mL.
c Result with MonoPhos.31 d The catalyst was prepared in MeOH.
e Reaction temperature: 50 °C.
In this paper, we present a detailed study demonstrating that
our novel hybrid phosphine–phosphoramidite ligand provides
high selectivity, even in green solvents, in the asymmetric hydro-
genation reaction. The green chemistry aspects27 of asymmetric
hydrogenation are represented by switching to environmentally
benign solvents and by solvent-free reactions, improved process
parameters (atom economy, high chemo- and enantioselectivity,
reaction efficiency, waste free workup) and continuous flow
processing.
only 1% of phosphine oxide was detected according to 31P
NMR spectroscopy.
Homogeneous asymmetric hydrogenation
Results and discussion
The new ligand (4) was tested in the typical Rh-catalyzed asym-
metric hydrogenation of (Z)-α-acetamidocinnamic acid methyl
ester (Table 1). All reactions were carried out at room tempera-
ture and were stirred and pressurized until full conversion. It
quickly became apparent that our ligand provides excellent
selectivity at ambient pressure in CH2Cl2, but deposition of Rh
metal was observed during the reaction (entries 1 and 2). By
switching to solvents with higher donor number the deposition
was eliminated, because solvents having better coordinating
properties might protect the complex from reduction if no sub-
strate is present. It is also important to note that the catalyst
exhibited the best performance in protic solvents like MeOH and
fine spirit (entries 3 and 10). The result achieved with MonoPhos
(entry 4) shows that our bidentate phosphorus ligand outper-
forms its monodentate analogue.
Synthesis
The novel ligand (4) was synthesized in three steps (Scheme 1).
At first, enantiomerically pure (4R,6R)-4,6-dimethyl-1,3,2-
dioxathiane 2,2-dioxide28 (1) and 2-propylamine were mixed
neat or in THF leading to the amino sulfate compound (2).29
The addition of (2) to three equivalents of LiPPh2 in THF pro-
vided the aminoalkyl phosphine (3). Ring opening reaction of
the cyclic sulfate with the amine and the second substitution
reaction take place with complete inversion at the stereogenic
centers providing a product with (2S,4S) configuration. Finally,
lithium amide of the secondary amine was formed by addition of
BuLi or Li metal.30 The amide was then treated with (S)-chloro-
dinaphtho[2,1-d:1′,2′-f]-1,3,2-dioxaphosphepine to give the
desired phosphine–phosphoramidite ligand (4).
The new compound exhibited two singlets at 153.48 ppm and
2.97 ppm in the 31P NMR spectrum. The Rh complex of the
ligand was synthesized by the addition of one equivalent of [Rh
(COD)2]BF4 to the ligand. The [Rh(COD)(4)]BF4 complex
showed two doublets of doublets: one at 137.28 ppm was
assigned to the amidite phosphorous with P–P coupling of 40.1
Hz and a Rh–P coupling of 242.8 Hz, the other one at
19.19 ppm was assigned to the phosphine phosphorous with
Rh–P coupling of 140.5 Hz.
One of the key principles of green chemistry is the elimination
of solvents in chemical processes or the replacement of hazar-
dous solvents with environmentally benign ones. Alkylene car-
bonates emerged recently as green solvents. The JEFFSOL®
carbonates can be used as safe and environmentally friendly
solvents replacing the commonly used harsh methylene chloride,
acetone, aromatic solvents, and other highly volatile and hazar-
dous solvents. They also have low vapor pressure which allows
their facile application at higher temperature. A review on the
application of organic carbonates as solvents in catalysis has
recently been published.32
The ligand showed remarkable air and moisture stability. A
small sample of compound (4) was left in air for one month and
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Table 2 Asymmetric hydrogenation of some substrates with [Rh
(COD)(4)]BF4
with ortho- or para-OMe electron donating groups resulted in
remarkable enantioselectivity (entries 7 and 8).
a
Our catalyst provided excellent enantioselectivity up to 99.0%
in propylene carbonate for the asymmetric hydrogenation of
L-DOPA precursor (entry 9). Notably, the DIPAMP33 (1,2-bis[(2-
methoxyphenyl)phenylphosphino]ethane) based catalyst has
been used for a long time by Monsanto in the technical pro-
duction of DOPA (a widely used drug for treating Parkinson’s
disease). It is interesting to note that enantioselective Rh-cata-
lyzed homogeneous hydrogenation of 3-methoxy-4-acetoxy-(Z)-
α-acetamidocinnamic acid with [Rh(COD)(R,R)-DIPAMP]BF4
gave 88.5% enantiomeric excess.34
Reaction
time [h]
ee
[%]
Entry Substrate
1
Solvent
Propylene
carbonate
MeOH
2.2
97.7
2
3
0.3
3.0
97.9
99.5
Propylene
carbonate
—
b
4
5
6
9.0
1.5
1.8
98.7
98.6
99.5
MeOH
MeOH
Another important aspect of green chemistry is the develop-
ment of more effective separation techniques. The workup of
propylene carbonate reactions can often be a problem due to its
high boiling point (242 °C) and solubility in water. The quick/
easy workup of the crude product with less solvent used is more
environmentally friendly. In our experiment the product of the
asymmetric hydrogenation of L-DOPA precursor could be easily
filtered from the reaction mixture at room temperature, washed
with ether, dried and then obtained with 71% yield and 99.6%
optical purity. This result was achieved without any optimization
of the process.
A highly desirable goal of green chemistry is to replace
organic solvents in chemical reactions with water. An alternative
is to carry out the reaction without any solvent. In our case
we were able to carry out the chemical transformation of
dimethyl itaconate without any solvent at elevated temperature
since our catalyst exhibited no temperature sensitivity.
The hydrogenated product was obtained at 50 °C with 98.7%
enantioselectivity at a substrate/catalyst molar ratio of 2500
(entry 4).
7
8
MeOH
MeOH
0.5
0.3
99.9
99.9
9
Propylene
carbonate
MeOH
3.0
99.0
96.7
10
∼7
11
12
Propylene
carbonate
MeOH
0.9
0.8
98.0
97.3
a Reaction conditions: see footnote in Table 1. b The catalyst was
prepared in MeOH. After evaporation of MeOH, 25 mmol substrate was
added to the catalyst. Reaction temperature: 50 °C.
A biologically active amino acid diphenylether derivative
could be readily obtained by the asymmetric hydrogenation of
the corresponding dehydroamino acid derivative (entries 11 and
12) with good selectivity in propylene carbonate and in MeOH.
Generally, the catalyst gave better performance in propylene car-
bonate than in MeOH except for methyl acetamido acrylate. In
this case the selectivity was approximately the same (entries 1
and 2).
Reactions carried out in propylene carbonate provided excel-
lent ee’s (entries 7 and 8). The reaction in pure ethylene carbon-
ate was carried out at 50 °C, but the ee remained over 99%
(entry 6). This result also indicates that the selectivity of our cat-
alyst is not sensitive to temperature increase. Glycerine carbonate
was not found to be a satisfactory solvent (entry 9). Low reactiv-
ity and enantioselectivity were obtained due to the low solubility
of H2 and/or the high viscosity of this solvent.
We have also investigated the application of the novel catalyst
for a variety of substrates. In every case outstanding activities
and enantioselectivities (Table 2) were obtained. The catalyst is
tolerant for acidic substrates: for example the benchmark sub-
strate (Z)-α-acetamidocinnamic acid and the L-DOPA precursor
were hydrogenated with enantioselectivities of 99.5% and
99.0%, respectively, at room temperature and only at 5 bar
pressure (entries 6, 9 and 10). These results underline the poten-
tial and stability of our catalytic system even in acidic reaction
conditions. In addition, we were able to eliminate the toxic
dichloromethane solvent from the process.
Heterogeneous asymmetric hydrogenation
An elegant heterogenization method of metal complexes was
introduced by Augustine et al. using rhodium complexes
immobilized on a mesoporous Al2O3 support with PTA as an
anchoring agent.35 Sheldon et al. developed a new aluminium
silicate with ideal characteristics for catalyst immobilization,
AlTUD-1, as a support for chiral rhodium catalysts used in
asymmetric hydrogenation.36
First, we anchored our catalyst on the commercially available
neutral gamma alumina support (Al2O3140, SBET = 140 m2 g−1
)
by means of PTA. The catalyst [Rh(COD)(4)]/PTA/Al2O3140 was
tested in heterogeneous batch mode (Table 3). The results show
that the system continuously lost its catalytic activity during
recycling, however, the enantioselectivity remained consistently
high, indicating a catalyst decomposition involving the formation
of a catalytically inactive oxo-species.
We have also investigated the structural variations on the sub-
strate, and found that substituent on the phenyl group has little
or no effect on the enantioselectivity of the reaction. Derivatives
1148 | Green Chem., 2012, 14, 1146–1151
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Table 3 Asymmetric hydrogenation of (Z)-α-acetamidocinnamic acid
methyl ester with [Rh(COD)(4)]/PTA/Al2O3140, batch systema
moisture, and tolerance of various hydrogenation conditions,
which make this ligand highly practical for general laboratory
preparations as well as scale-up operations. Screening of
substrates in different solvents showed that enantioselectivities
up to >99% can be reached in a range of green solvents like
ethylene- and propylene carbonate. We have also demonstrated
that propylene carbonate is a viable solvent for asymmetric
hydrogenation of dehydroamino acids.
No. of run
Conv. [%]
ee [%]
1
2
3
4
5
6
7
8
72.8
73.9
54.8
31.1
31.1
10.4
4.8
97.5
96.9
93.3
97.0
98.0
97.8
97.9
97.6
The in situ formed [Rh(COD)(4)]BF4 complex was immobi-
431
lized on mesoporous Al2O3 support using PTA as an anchor-
3.0
ing agent. A continuous-flow reaction system was applied using
a stationary-phase catalyst for the asymmetric hydrogenation of
(Z)-α-acetamidocinnamic acid methyl ester. It has been demon-
strated that the novel catalyst is applicable in flow-based enantio-
selective hydrogenation and can work continuously for 6 h with
over 99% conversion and with over 99% enantioselectivity, and
then another 6 h with over 90% conversion and an average of
97% enantioselectivity.
140
a Reaction conditions: [Rh(COD)(4)]/PTA/Al2O3
(85 mg) and
substrate (274 mg, 1.25 mmol) were stirred in 5 mL CH2Cl2 under 5 bar
of H2 pressure for 72 minutes. The reaction was stopped and after
settling of the catalyst the liquid phase was removed. A new charge of
substrate in 5 mL CH2Cl2 was added and the reaction was repeated.
Table 4 Asymmetric hydrogenation of (Z)-α-acetamidocinnamic acid
methyl ester with [Rh(COD)(4)]/PTA/Al2O3431, flow systema
Experimental
Time [min]
Conversion [%]
ee [%]
(2S,4R)-2-Isopropylamino-4-sulfatopentane (2)
80
>99
>99
>99
97.9
>99
90.3
98.8
99.3
99.4
99.3
99.0
93.1
130
175
220
360
740
A
solution of (4R,6R)-4,6-dimethyl-1,3,2-dioxathiane 2,2-
dioxide (3.27 g, 19.7 mmol) and isopropylamine (7.5 mL,
88.5 mmol) was stirred in 40 mL of THF for 48 hours mean-
while white precipitate formed. After that the solvent was evap-
orated and 60 mL of ether was added to the residue. The
suspension was stirred for 30 minutes and filtered. The solid was
washed two times with ether, dried with azeotropic distillation of
toluene. The solvent was evaporated by vacuum to give (2S,4R)-
2-isopropylamino-4-sulfatopentane as a white powder (4.33 g,
98.1%).
a Reaction conditions: The CatCart® contained 164.4 mg [Rh(COD)(4)]/
431
PTA/Al2O3
catalyst, solvent EtOAc, pressure 1 bar, substrate
concentration 0.05 mol L−1, temperature 25 °C, flow rate 0.1 mL min−1
.
To improve the productivity of the immobilized catalyst, the
140
microstructure of the support was changed from Al2O3
Al2O3
to
[α]2D0 = 0° (c 1.00 in DMSO), m.p.: 241–242 °C.
Elemental analysis:
431
with a larger surface area.37 Nitrogen adsorption–
desorption isotherms were measured for supports and immobi-
lized complexes (Rh-PTA/Al2O3), respectively (ESI†). In all
cases, these isotherms presented the characteristic form of meso-
porous materials. It can be easily remarked that the N2-adsorbed/
desorbed volume was higher in the case of pure carrier than in
the case of immobilized complexes.
Found: C, 42.69; H, 8.31; N, 6.28; S, 14.58. Calc. for
C8H19NO4S: C, 42.65; H, 8.50; N, 6.22; S, 14.23%.
1H NMR (500 MHz, DMSO): δ = 7.97 (s, 2H, NH2 ),
+
4.28–4.06 (m, 1H, CH), 3.46–3.13 (m, 2H, CH), 1.71–1.62 (m,
1H, CH2), 1.49–1.41 (m, 1H, CH2), 1.28–0.85 (m, 12H, CH3).
13C {1H} NMR (75 MHz, DMSO): δ = 70.99 (s), 49.31 (s),
46.67 (s), 22.59 (s), 19.85 (s), 18.53 (s), 16.80 (s).
Screening of the heterogenized catalyst [Rh(COD)(4)]/PTA/
431
Al2O3
was performed by filling the catalyst in CatCart®
cartridges and the reaction carried out using the H-Cube®
microfluid reactor (Table 4).38 This continuous flow system pro-
vides safe optimization of the reaction conditions (flow rate,
temperature, pressure, solvent, substrate concentration) in a short
period of time with only a small amount of catalyst and substrate
used. It has been demonstrated that the novel catalyst is appli-
cable in flow based enantioselective hydrogenation and can work
continuously for 6 h with over 99% conversion and over 99%
enantioselectivity, and another 6 h with over 90% conversion
and an average of 97% enantioselectivity.
(2S,4S)-2-Diphenylphosphino-4-isopropylaminopentane (3)
LiPPh2 in 1,4-dioxane (16.6 g, 59.3 mmol) was dissolved in
80 mL of abs. THF under argon atmosphere. (2S,4R)-2-Isopro-
pylamino-4-sulfatopentane (4.2 g, 18.7 mmol) was added drop-
wise to the red solution in small portions. The reaction mixture
was stirred for 3 hours. 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 was added to the residue
and the mixture was stirred until the two phases became clear
solutions. The pH was then adjusted to 1 with 10% solution of
oxygen-free HCl. The phases were then separated and the water
phase was washed three times with 30 mL portions of ether. The
pH was then set to around 9–10 with dropwise addition of
Na2CO3. The product was then extracted four times with 30 mL
portions of ether. After drying over MgSO4 the mixture was
Conclusions
The novel phosphine–phosphoramidite ligand (4) proved to be
highly active in rhodium-catalyzed asymmetric hydrogenation.
This ligand exhibits an extraordinary stability towards air and
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Asymmetric hydrogenation in flow system
filtered and evaporated. Purification was performed with flash
chromatography over silica gel with chloroform–methanol = 4 : 1
eluent to give (2S,4S)-2-diphenylphosphino-4-isopropylamino-
pentane as a clear transparent oil (3.40 g, 58.0%). The product
was dried with azeotropic distillation of toluene.
The H-Cube® system is designed for the hydrogenation of a
continuous flow of substrate which is flowed through the system
by the built in HPLC pump. Pure hydrogen gas is generated
by electrolytic water decomposition. The hydrogen gas and a
solution of the reactant are mixed, preheated (if needed), and
transferred to a disposable catalyst cartridge CatCart® that is pre-
loaded with the required heterogeneous catalysts. The product
then flows out of the cartridge and is collected in a vial or
flask. The CatCart® system is made up of a stainless steel tube
(normal size: 30 × 4 mm) packed with the heterogeneous cata-
lyst. A filter system at either end of the tube allows liquid to pass
through the column, but prevents solid particles leaving the car-
tridge. The columns contained 164.4 mg of [Rh(COD)(4)]/PTA/
Al2O3431. The instrument works in two modes: in full hydrogen
mode a large excess of hydrogen is generated at 1 bar (30 mL
min−1 hydrogen vs. 0.1 mL min−1 solution, Table 4) which
gives a gas–liquid mixture. In this condition the residence time
in the reactor is extremely low (approximately 1 sec at 0.1 mL
min−1 flow rate) and at the same time the reactor operates with a
H2/S/Rh molar ratio of 240/1/360.
[α]2D0 = −76.29° (c 0.97 in CH2Cl2).
Elemental analysis:
Found: C, 76.23; H, 8.87; N, 4.39. Calc. for C20H28NP: C,
76.64; H, 9.00; N, 4.47%.
1H NMR (500 MHz, CDCl3): δ = 7.52–7.48 (m, 4H, aro-
matic), 7.32–7.31 (d, 6H, aromatic), 2.98–2.81 (m, 2H, CH),
2.50–2.34 (m, 1H, CH), 1.59–1.43 (m, 1H, CH2), 1.40–1.23 (m,
1H, CH2), 1.14–0.95 (m, 12H, CH3). 31P {1H} NMR (121 MHz,
CDCl3): δ = 0.00 (s). 13C {1H} NMR (75 MHz, CDCl3): δ =
137.13 (d, J = 14.89 Hz), 137.13 (d, J = 14.27 Hz), 133.73 (dd,
J = 4.96, Hz J = 19.23 Hz), 128.73 (s), 128.34 (t, J = 6.51 Hz),
47.66 (d, J = 12.41 Hz), 45.24 (s), 40.97 (d, J = 16.75 Hz),
27.33 (d, J = 9.92 Hz), 23.34 (d, J = 26.67 Hz), 20.29 (s), 16.32
(d, J = 15.51 Hz).
N-((2S,4S)-4-(Diphenylphosphino)pentan-2-yl)-N-isopropyl-(S)-
dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepin-4-amine (4)
Acknowledgements
The authors thank the National Office for Research and Technol-
ogy (KMOP 1.1.4) for financial support as well as Huntsman
Corporation for providing samples of their green cyclic carbon-
ate solvents. This article was partly made under the project
TÁMOP-4.2.1/B-09/1/KONV-2010-0003 and TÁMOP-4.2.2/
B-10/1-2010-0025. These projects are supported by the
European Union and co-financed by the European Social Fund.
Special thanks are due to Béla Édes for the professional techni-
cal assistance.
(2S,4S)-2-Diphenylphosphino-4-isopropylaminopentane (1.0 g,
3.19 mmol) was dissolved in 20 mL of abs. THF and cooled to
0 °C. BuLi (2.48 mL, 3.51 mmol, 9.8 mg mL−1 Li in hexane)
was added dropwise. The color of the solution turned to yellow.
After stirring at 0 °C (S)-chlorodinaphtho[2,1-d:1′,2′-f]-1,3,2-
dioxaphosphepine (1.45 g, 4.15 mmol) in 10 mL of abs. THF
was fed to the reaction mixture. Formation of a white precipitate
was observed. The mixture was stirred for one hour. The reaction
mixture was filtrated through a short pad of silica and was evap-
orated to give yellow foam. Purification was performed with
flash chromatography on silica gel with the n-hexane : ethyl
acetate = 20 : 1. Rf.: 0.7 (0.67 g, 33.0%). The pure product is a
white solid.
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[α]2D0 = 176.12° (c 1.00 in CH2Cl2), m.p.: 133–150 °C.
Elemental analysis:
Found: C, 76.55; H, 6.21; N, 2.17. Calc. for C40H39NO2P2: C,
76.54; H, 6.26; N, 2.23%.
1H NMR (300 MHz, CDCl3): δ = 8.03–7.71 (m, 4H, aro-
matic), 7.59–7.14 (m, 18H, aromatic), 3.55–3.37 (m, 1H, CH),
3.37–3.23 (m, 1H, CH), 2.41–2.23 (m, 1H, CH), 1.98–1.80
(m, 1H, CH2), 1.77–1.60 (m, 1H, CH2), 1.29 (d, 3H, CH3), 1.07
(dd, 6H, CH3), 0.78 (dd, 3H, CH3). 31P {1H} NMR (121 MHz,
CDCl3): δ = 153.48 (s), 2.97 (s). 13C {1H} NMR (75 MHz,
CDCl3): δ = 150.14 (d, J = 4.44 Hz), 150.11 (s), 136,94 (d, J =
11.16 Hz), 136.75 (d, J = 12.41 Hz), 133.92 (d, J = 19.23 Hz),
133.44 (d, J = 17.98 Hz), 132.80 (d, J = 8.07 Hz), 131.35
(s), 130.71 (s), 129.96 (d, J = 37.21 Hz), 128.78 (d, J = 9.92
Hz), 128.39 (dd, J = 1.86 Hz, J = 6.82 Hz), 128.21 (s), 127.09
(d, J = 3.72 Hz), 125.90 (d, J = 9.92 Hz), 124.50 (d, J = 25.43
Hz), 124.01 (d, J = 5.58 Hz), 122.38 (d, J = 4.96 Hz), 121.92
(d, J = 2.48 Hz), 46.65 (d, J = 13.02 Hz), 46.43 (d, J = 13.03
Hz), 45.51 (d, J = 6.08 Hz), 27.40 (d, J = 10.88 Hz), 23.94
(d, J = 6.82 Hz), 21.83 (d, J = 10.54 Hz), 15.17 (d, J =
14.26 Hz).
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