Asymmetric hydrogenation with the use of chiral carborane amidophosphite derivatives in supercritical carbon dioxide and CH2Cl2

Article abstract of DOI:10.1007/s11172-010-0321-y

New chiral carborane-containing amidophosphites containing the BINOL fragment (BINOL stands for 2,2′-dihydroxy-1,1′-binaphthyl) have been synthesized. The study of efficiency of these compounds as ligands in the Rh-catalyzed asymmetric hydrogenation of en

Full text of DOI:10.1007/s11172-010-0321-y

Russian Chemical Bulletin, International Edition, Vol. 59, No. 9, pp. 1836—1839, September, 2010
1836
Asymmetric hydrogenation with the use
of chiral carborane amidophosphite derivatives
in supercritical carbon dioxide and CH2Cl2
S. E. Lyubimov, V. A. Ol´shevskaya, P. V. Petrovskii, E. A. Rastorguev, T. A. Verbitskaya,
V. N. Kalinin, and V. A. Davankov
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 6471. Eꢀmail: lssp452@mail.ru
New chiral carboraneꢀcontaining amidophosphites containing the BINOL fragment
(BINOL stands for 2,2´ꢀdihydroxyꢀ1,1´ꢀbinaphthyl) have been synthesized. The study of efꢀ
ficiency of these compounds as ligands in the Rhꢀcatalyzed asymmetric hydrogenation of
enamides in supercritical carbon dioxide (scCO2) and CH2Cl2 showed that enantioselectivity of
the process is considerably higher in scCO2.
Key words: carboranes, asymmetric hydrogenation, amidophosphites, supercritical carbon
dioxide, rhodium complexes.
At present, significant amount of chemical reactions is
tion. One of the new trends in the development of efficient
chiral catalysts for hydrogenation processes in scCO2 is
incorporation of a bulky carborane group into the ligand
composition.10—12 In the present work, we demonstrate
results of testing of new amidophosphite ligands containꢀ
ing carborane substituents in the asymmetric Rhꢀcatalꢀ
yzed hydrogenation reaction of enamides in scCO2 and
CH2Cl2 to yield amino acid derivatives.
carried out in organic solvents, such as chlorinated hydroꢀ
carbons, methanol, acetone, which are significantly danꢀ
gerous for the environment, that stimulates a search for
the alternative, environmentally friendly media. Superꢀ
critical carbon dioxide (scCO2) is one of such media
because of availability of this compound and its environꢀ
mental and fire safety.1,2 In addition, carbon dioxide can
be easily and completely removed from the reaction prodꢀ
ucts within several minutes. Despite of this advantages, as
of this moment scCO2 is mainly used for extraction3 and
considerably less frequently as the medium for organic
synthesis.1 Note that scCO2 possesses excellent miscibiliꢀ
ty with gases, for example, with hydrogen, that makes it
easy to transport H2 to the reaction surface of catalysts.4
In addition, in the case of scCO2 no separation of gaseous
and liquid organic phases occurs, that is observed when
organic solvents are used in hydrogenation processes.
Therefore, the study of hydrogenation in scCO2 is an acꢀ
tual problem. At present, low attention is paid to the asymꢀ
metric metalꢀcomplex hydrogenation in scCO2, though
promising results have been obtained in this field. For
instance, the use of metalꢀcomplex catalysts with chiral
phosphine ligands demonstrated high enantioselectivity
in hydrogenation of a series of prochiral unsaturated subꢀ
strates. Usually, 12—48 h are required to reach the full
conversion, that is comparable with the results obtained in
organic solvents.5,6 Earlier,7—9 it has been shown that
chiral phosphites and amidophosphites are more promisꢀ
ing ligands for asymmetric hydrogenation in scCO2, which
provide the high rate and enantioselectivity of the reacꢀ
Results and Discussion
The reaction of orthoꢀcarboranylmethyl triflate (1) with
4ꢀfluoroaniline (2) or cyclopropylamine (3) led to carboꢀ
raneꢀcontaining amines 4 and 5 (Scheme 1).
Phosphorylation of amines 4 and 5 afforded new chiral
carboranyl amidophosphites L1 and L2 (Scheme 2).
Ligands L1 and L2 are well soluble in organic solvents,
such as CH2Cl2 and C6H6. The presence of the fluorine
atom in ligand L1 provides its good solubility also in the
nonpolar hexane. Fluorineꢀcontaining ligands, as comꢀ
pared to their analogs containing no fluorine atoms, are
characterized by better solubility in scCO2 as well, which
is a nonpolar enough medium.5
Amidophosphites L1 and L2 were tested in the Rhꢀcaꢀ
talyzed asymmetric hydrogenation of a series of enamides
7a—c — precursors of phenylalanine and its chlorineꢀ and
fluorineꢀcontaining analogs (Scheme 3, Table 1). Note
that Nꢀacetyl derivatives of 4ꢀchlorophenylalanine posꢀ
sess antiinflammatory properties, whereas the drugs based
on 4ꢀfluorophenylalanine exhibit antimicrobal properties.9
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1787—1790, September, 2010.
1066ꢀ5285/10/5909ꢀ1836 © 2010 Springer Science+Business Media, Inc.

Carboraneꢀtethered amidophosphite
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 9, September, 2010
1837
Scheme 1
Scheme 2
Scheme 3
tries 1 and 2). Application of the same catalytic system
[Rh(COD)2]BF4/2L1 in CH2Cl2 provided only 20% ee,
with the enantioselectivity remaining the same at both 15
and 40 atm of H2 (see Table 1, entries 3 and 4). When
amidophosphite L2 was used in hydrogenation of 7a at
15 atm of H2 in scCO2 and CH2Cl2 at 45 °C, the scCO2
also provided higher enantioselectivity (see Table 1, enꢀ
tries 5 and 6). In the hydrogenation of fluorineꢀcontaining
substrate 7b using the catalyst based on ligand L1 in scCO2,
48% ee at 40 atm of H2 and 52% ee at 15 atm of H2 were
achieved (see Table 1, entries 7 and 8). In CH2Cl2, 21% ee
at both high and low pressure of H2 was observed (entries 9
and 10). Ligand L2 in hydrogenation of 7b provides lower
enantioselectivity in both scCO2 and CH2Cl2, with the
enantiomeric excess of the reaction product 8b in scCO2
being higher (see Table 1, entries 11 and 12). Hydrogenaꢀ
tion of chlorineꢀcontaining enamide 7c with the use of
ligand L1 gave analogous results. For instance, applicaꢀ
tion of scCO2 provides higher enantioselectivity as comꢀ
pared to CH2Cl2 (see Table 1, entries 13—16). Hydrogeꢀ
nation of 7c using the catalytic system based on amiꢀ
dophosphite L2 in scCO2 showed that higher pressure of
H2 assists in the increase in conversion (entries 17—18).
*
i. H2, scCO2 or CH2Cl2, [Rh(COD)2]BF4/2L, 0.5 mol.%
R = H (a), F (b), Cl (c)
When the catalyst formed in situ starting from ligand
L1 and [Rh(COD)2]BF4 (COD stands for cyclooctꢀ1,5ꢀ
diene) was used in scCO2 at high (45 atm) hydrogen presꢀ
sure and molar ratio of the substrate to the catalyst 200/1,
the complete conversion of substrate 7a was reached in
2 h, and the product had 48% ee (see Table 1, entry 1).
A decrease in the pressure of H2 from 40 to 15 atm allowed
us to somewhat increase the enantioselectivity (cf. enꢀ

1838
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 9, September, 2010
Lyubimov et al.
Table 1. Hydrogenation of enamides 7a—c catalyzed by
[Rh(COD)2]BF4/2L (45 °C)
(10 mL) was refluxed for 4—8 h (TLC monitoring of conversion
of 1 using heptane—EtOAc (7 : 3) as an eluent). Water (20 mL)
was added to the reaction mixture, followed by extraction with
EtOAc (3×7 mL). A combined organic phase was washed with
water, dried with Na2SO4, and filtered, the solvent was evapoꢀ
rated in vacuo. The products were purified by column chromaꢀ
tography on silica gel (heptane—EtOAc (10 : 1) in the case of 4
and heptane in the case of 5).
a
Entry
L
R
PH
Medium t/h
Ptot
γ
eeb
2
/atm
/atm (%) (%)
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L2
L2
L1
L1
L1
L1
L2
L2
H
H
H
H
H
H
F
F
F
F
F
40
15
40
15
15
15
40
15
40
15
15
15
scCO2
scCO2
CH2Cl2
CH2Cl2
scCO2
CH2Cl2
scCO2
scCO2
CH2Cl2
CH2Cl2
scCO2
CH2Cl2
scCO2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
250
250
—
—
250
—
250
250
—
—
250
—
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
35
48
52
20
20
37
22
48
52
21
21
42
30
48
51
21
21
36
36
32
32
Nꢀ(oꢀCarboranylmethyl)ꢀNꢀ(4ꢀfluorophenyl)amine (4), white
powder. The yield was 1.07 g (65%), m.p. 82–83 °C. Found (%):
C, 40.56; H, 6.88; N, 5.16. C9H18B10FN. Calculated (%):
C, 40.43; H, 6.79; N, 5.24. 1H NMR (CDCl3), δ: 1.38—3.17
(m, 10 H); 3.76 (s, 1 H); 3.86 (s, 2 H); 3.92 (s, 1 H); 6.50—6.60
(m, 2 H); 6.90 (t, 2 H, J = 8.4 Hz). 11B {H} NMR (CDCl3), δ:
–14.00÷ –10.82 (m, 4 В); –11.52 (s, 2 В); –9.06 (s, 2 В); –5.14
9
(s, 1 В); –2.31 (s, 1 В). IR (CHCl3): νNH 3440 cm–1
.
10
11
12
13
14
15
16
17
18
19
20
Nꢀ(oꢀCarboranylmethyl)ꢀNꢀcyclopropylamine (5), viscous
colorless oil. The yield was 0.66 g (50%). Found (%): C, 33.84;
H, 8.94; N, 6.51. C6H19B10N. Calculated (%): C, 33.78; H, 8.98;
N, 6.57. 1H NMR (CDCl3), δ: 0.24—0.31 (m, 2 H); 0.41—0.49
(m, 2 H); 1.28—3.00 (m, 10 H); 2.14—2.21 (m, 1 H); 3.35 (s, 2 H);
3.94 (s, 1 H). 11B {H} NMR (CDCl3), δ: –14.32÷–14.30 (m, 4 В);
–11.41 (s, 2 В); –9.12 (s, 2 В); –5.55 (s, 1 В); –3.11 (s, 1 В). IR
F
L1 Cl 40
L1 Cl 15
L1 Cl 40
L1 Cl 15
L2 Cl 40
L2 Cl 15
L2 Cl 40
L2 Cl 15
250
250
—
scCO2
CH2Cl2
CH2Cl2
scCO2
scCO2
CH2Cl2
CH2Cl2
—
250
250
—
(CHCl3): νNH 3336 cm–1
.
8
100
100
Synthesis of ligands L1 and L2 (general procedure). Triethylꢀ
amine (0.14 mL, 1.0 mmol) and the corresponding carborane
amine 4 or 5 (1.0 mmol) were added to a solution of (Rax)ꢀ2ꢀ
chlorodinaphtho[2,1ꢀd:1´,2´ꢀf][1,3,2]dioxaphosphepane14 (6)
(0.35 g, 1.0 mmol) in C6H6 (15 mL) and the mixture was stirred
for 10 min at 20 °C, heated to the reflux, cooled to room temperꢀ
atures, a precipitate of HNEt3Cl was filtered off. The products
were purified by column flashꢀchromatography on silica gel
(benzene).
—
a
γ is the conversion.
b SꢀConfiguration of products in all the cases.
The full conversion was successfully reached within 3 h in
CH2Cl2, however, the enantioselectivity has proved someꢀ
what lower than in scCO2 (entries 19—20).
In conclusion, the asymmetric Rhꢀcatalyzed hydrogeꢀ
nation of enamides involving new carboraneꢀcontaining
chiral amidophosphites in scCO2 and CH2Cl2 allows one
to reach high conversions at low loading a Rhꢀcatalyst
within 2—3 h, with the ee values of the products being
higher in scCO2.
(Rax)ꢀ2ꢀ[Nꢀ(oꢀCarboranylmethyl)ꢀNꢀ(4ꢀfluorophenyl)amino]ꢀ
dinaphtho[2,1ꢀd:1´,2´ꢀf][1,3,2]dioxaphosphepane (L1), viscous
colorless oil. The yield was 0.49 g (85%). Found (%): C, 59.95;
H, 5.12; N, 2.50. C29H29B10FNO2P. Calculated (%): C, 59.89;
H, 5.03; N, 2.41. 31P NMR (CDCl3), δ: 136.61. 1H NMR
(CDCl3), δ: 1.36—3.18 (m, 10 H); 3.75 (s, 1 H); 3.84 (s, 2 H);
6.49—6.58 (m, 2 H); 6.90 (t, 2 H, J = 8.6 Hz); 7.21—8.00 (m, 12 H).
11B {H} NMR (CDCl3), δ: –14.18÷–12.16 (m, 4 В); –11.51
(s, 2 В); –9.06 (s, 2 В); –5.15 (s, 1 В); –2.32 (s, 1 В).
Experimental
(Rax)ꢀ2ꢀ[Nꢀ(oꢀCarboranylmethyl)ꢀNꢀcyclopropylamino]diꢀ
naphtho[2,1ꢀd:1´,2´ꢀf][1,3,2]dioxaphosphepane (L2), viscous
colorless oil. The yield was 0.42 g (80%). Found (%): C, 59.25;
H, 5.80; N, 2.59. C26H30NB10O2P. Calculated (%): C, 59.19;
H, 5.73; N, 2.65. 31P NMR (CDCl3), δ: 136.66. 1H NMR
(CDCl3), δ: 0.24—0.32 (m, 2 H); 0.41—0.49 (m, 2 H); 1.20—3.08
(m, 10 H); 2.14—2.21 (m, 1 H); 3.35 (s, 2 H); 3.95 (s, 1 H),
7.20—8.00 (m, 12 H). 11B {H} NMR (CDCl3), δ: –14.32÷–12.21
(m, 4 В); –11.40 (s, 2 В); –9.12 (s, 2 В); –5.52 (s, 1 В); –3.08 (s, 1 В).
Asymmetric hydrogenation of enamides in scCO2 and CH2Cl2.
The compound [Rh(COD)2]BF4 (2 mg, 0.005 mmol), the ligand
(0.01 mmol), and CH2Cl2 (0.3 mL) were placed in a 10ꢀmL
autoclave. The mixture was stirred for 2 min, the solvent was
evaporated in vacuo, followed by addition of the corresponding
enamide (7a—c) (1 mmol) and CH2Cl2 (4 mL), if the latter was
used as the solvent. The sealed autoclave was purged with CO2,
filled with hydrogen to the required pressure (see Table 1), then
carbon dioxide was added using a High Pressure Equipment to
250 atm. The reactor was heated to the corresponding temperaꢀ
31
Р, 1H, and 11B NMR spectra were recorded on an Avance
400 spectrometer (161.98, 400.13, and 128.4 MHz) relatively to
85% H3РO4 in D2O, Me4Si, and BF3•OEt2, respectively. Eleꢀ
mental analysis was performed in the Laboratory of Organic
Microanalysis of the A. N. Nesmeyanov Institute of Organoeleꢀ
ment Compounds, Russian Academy of Sciences.
All the reactions concerning preparation of catalysts were
performed in the atmosphere of dry argon in anhydrous solvents.
oꢀCarboranylmethyl triflate (1),13 (Ra)ꢀ2ꢀchlorodinaphthoꢀ
[2,1ꢀd:1´,2´ꢀf][1,3,2]dioxaphosphepane (6),14 [Rh(COD)2]BF4,15
methyl (Z)ꢀ2ꢀacetamidoꢀ3ꢀphenylacrylate (7a),16 methyl
(Z)ꢀ2ꢀacetamidoꢀ3ꢀ(4ꢀchlorophenyl)acrylate (7b),16 and methꢀ
yl (Z)ꢀ2ꢀacetamidoꢀ3ꢀ(4ꢀfluorophenyl)acrylate (7c)9 were obꢀ
tained according to the known procedures.
Synthesis of amines 4 and 5 (general procedure). A mixture of
oꢀcarboranylmethyl triflate 1 (1.9 g, 6.2 mmol), the correspondꢀ
ing amine (6.5 mmol), NaOAc (0.74 g, 9 mmol) and MeCN

Carboraneꢀtethered amidophosphite
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 9, September, 2010
1839
ture (45 °C) for 5 min and the process was performed with stirꢀ
ring using a magnetic stirrer. After the reaction was completed,
CO2 and H2 were slowly released, conversion was monitored by
1H NMR spectroscopy. Enantiomeric ratio of products 8a—c
was determined by HPLC on an Agilent HPꢀ1100 chromatoꢀ
graph using a Kromasil 5ꢀAmyCoat column according to the
procedure given in the literature.9
8. S. E. Lyubimov, V. A. Davankov, E. E. SaidꢀGaliev, A. R.
Khokhlov, Catalysis Commun., 2008, 9, 1851.
9. S. E. Lyubimov, I. V. Kuchurov, V. A. Davankov, S. G.
Zlotin, J. Supercritical Fluids, 2009, 50, 118.
10. S. E. Lyubimov, A. A. Tyutyunov, V. N. Kalinin, E. E. Saidꢀ
Galiev, A. R. Khokhlov, P. V. Petrovskii, V. A. Davankov,
Tetrahedron Lett., 2007, 48, 8217.
11. S. E. Lyubimov, I. V. Kuchurov, A. A. Tyutyunov, P. V.
Petrovskii, V. N. Kalinin, S. G. Zlotin, V. A. Davankov,
E. HeyꢀHawkins, Catalysis Commun., 2010, 11, 419.
12. S. E. Lyubimov, A. S. Safronov, A. A. Tyutyunov, V. N.
Kalinin, E. E. SaidꢀGaliev, A. R. Khokhlov, P. V. Petrovsꢀ
kii, P. M. Valetskii, V. A. Davankov. Izv. Akad. Nauk,
Ser. Khim., 2008, 57, 337 [Russ. Chem. Bull., Int. Ed., 2008,
57, 345].
This work was financially supported by the Russian
Foundation for Basic Research (Project Nos 09ꢀ03ꢀ12104ꢀ
ofi_m and 09ꢀ03ꢀ91345ꢀNNIO_a).
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Received July 14, 2010