Iridium-catalyzed asymmetric hydrogenation of imines in supercritical carbon dioxide using phosphite-type ligands

Article abstract of DOI:10.1016/j.tetlet.2011.01.104

A series of chiral phosphite-type ligands has been evaluated in the iridium-catalyzed asymmetric hydrogenation of acyclic arylimines in supercritical CO₂. High reactivities (100% conversion in 50-120 min) and enantioselectivities (up to 95%) we

Full text of DOI:10.1016/j.tetlet.2011.01.104

Tetrahedron Letters 52 (2011) 1395–1397
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Tetrahedron Letters
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Iridium-catalyzed asymmetric hydrogenation of imines in supercritical
carbon dioxide using phosphite-type ligands
⇑
Sergey E. Lyubimov , Eugenie A. Rastorguev, Pavel V. Petrovskii, Elena S. Kelbysheva, Nikolay M. Loim,
Vadim A. Davankov
A. N. Nesmeyanov-Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov Street 28, 119991 Moscow, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of chiral phosphite-type ligands has been evaluated in the iridium-catalyzed asymmetric hydro-
genation of acyclic arylimines in supercritical CO2. High reactivities (100% conversion in 50–120 min) and
enantioselectivities (up to 95%) were obtained.
Received 10 November 2010
Revised 15 January 2011
Accepted 25 January 2011
Available online 1 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Enantioselective hydrogenation
Supercritical carbon dioxide
Imines
Iridium
A major aim of modern synthetic chemistry is fast, economic
and environmentally friendly formation of fine chemicals, pharma-
ceutical intermediates and nutraceuticals. To achieve the highest
levels of reactivity in catalytic reactions, different parameters must
be explored and adjusted. In optimization strategies, careful selec-
tion of an efficient and inexpensive catalyst, and of the reaction
conditions including temperature and solvent are important.
Supercritical fluids are highly compressed gases which combine
the properties of gases and liquids in an intriguing manner.1,2
The fluids are completely miscible with permanent gases (e.g., N2
or H2), and this leads to much higher concentrations of dissolved
gases than can be achieved in conventional solvents.3 By perform-
ing the reaction in one, instead of two (gas/liquid) phases, the rate
of hydrogenation reactions can be increased by several orders. One
supercritical fluid of particular interest is carbon dioxide. It is non-
toxic, nonflammable, odorless, tasteless, inert, and inexpensive.
Moreover, after reaction, excess carbon dioxide in the product dis-
sipates into the atmosphere within a few minutes.
In asymmetric metallocomplex hydrogenation of C@C and C@N
containing substrates, bidentate phosphine ligands were long con-
sidered to be essential for obtaining high enantioselectivities.4–7
However, monodentate phosphites and phosphoramidites have
been shown to be excellent, and sometimes superior, alternatives
to bidentate ligands, in terms of enantioselectivity, simplicity of
synthesis and ease of structural variation.5,8–13 Recently, we
showed that monodentate phosphite-type ligands were also highly
effective in the Rh-catalyzed asymmetric hydrogenation of di-
methyl itaconate and enamides [up to 99% enantiomeric excess,
(ee)] in supercritical carbon dioxide (scCO2).14–18 It should be
emphasized, that 100% conversion can be achieved within 35–
180 min. Encouraged by these results we aimed to broaden the
technique of the asymmetric hydrogenation in scCO2 towards the
synthesis of chiral amines by the Ir-catalyzed reduction of prochi-
ral imines. Chiral amines are important synthetic intermediates for
the preparation of physiologically active compounds.7,19,20 In con-
trast to the recent progress made in the catalytic asymmetric
hydrogenation of olefins in scCO2,21,22 only Ir-catalysts with chiral
P,N-bidentate phosphinooxazolines have been investigated and
exhibited promising results (up to 81% ee) in the asymmetric
hydrogenation of imines in this medium.23,24 Here, we report a
successful application (up to 95% ee) of inexpensive phosphorami-
dites in Ir-catalyzed hydrogenations of acyclic arylimines in scCO2.
Our initial studies in supercritical CO2 were focused on the
enantioselective hydrogenation of N-(1-phenylethylidene)benzen-
amine (1) as a model substrate (Scheme 1).
Using (R)-PipPhos ligand (L1, Scheme 2) and [Ir(COD)2]BARF
(0.5 mol %) as a precatalyst at 40 atm of hydrogen, and high total
Ph
Ph
HN
*
H2
N
[Ir(COD)2]BARF (0.5% mol /L),
scCO2
Ph
Ph
1
2
⇑
Corresponding author. Tel.: +7 499 1352548; fax: +7 499 1356471.
E-mail address: lssp452@mail.ru (S.E. Lyubimov).
Scheme 1. Enantioselective hydrogenation of N-(1-phenylethylidene)aniline.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.104

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S. E. Lyubimov et al. / Tetrahedron Letters 52 (2011) 1395–1397
O
O
O
O
O
O
P
P
N
P
N
N
P
L2
L1
L3
H
O
O
O
O
P
O
O
O
P
O
O
H
L4
Scheme 2. Phosphorus ligands L1–L4.
Table 1
Enantioselective hydrogenation of imine 1
Entry
Catalyst
T (°C)
P, H2 (atm)
Total pressure (atm)
Time (min)
Conversion (%)
ee (%)
1
2
3
4
5
6
7
8
[Ir(COD)2]BARF/2L1
[Ir(COD)2]BARF/2L1
[Ir(COD)2]BARF/2L1
[Ir(COD)2]BARF/2L1
[Ir(COD)2]BARF/2L1
[Ir(COD)2]BARF/L2
[Ir(COD)2]BARF/2L3
[Ir(COD)2]BARF/L4
45
45
65
45
45
45
45
45
40
40
40
20
40
40
40
40
250
250
250
250
120
250
250
250
60
120
50
120
160
60
86
100
100
100
82
12
11
20
87 (S)
87 (S)
80 (S)
87 (S)
90 (S)
30 (S)
0
120
160
0
pressures (250 atm), gave the product 2 in very good enantioselec-
tivity (87% ee), and high conversion (86%) in 60 min (Table 1, entry
1).
Table 2
Asymmetric hydrogenation of imines 3a–ga
Entry
Substrate
R1
R2
Productb
ee (%)
Increasing the reaction time to 120 min led to complete conver-
sion of 1 into the desired amine 2. To evaluate the effect of temper-
ature and trying to increase the reaction rate, the temperature was
raised from 45 to 65 °C. In this case, the imine 1 was smoothly
hydrogenated in 50 min, but a small decrease in the enantioselec-
tivity was observed, compared to hydrogenation at 45 °C (Table 1,
entries 2 and 3). The hydrogen pressure showed no obvious effect
on the activity or enantioselectivity. Under 20 atm of H2, the reac-
tion reached completion within 120 min, and the ee remained the
same (Table 1, entries 2 and 4). Lowering the total pressure from
250 to 120 atm and using the same H2 pressure (40 atm) led to a
decrease in reaction rate (Table 1, entries 1, 2 and 5), but the ee
was increased slightly. It should be noted, that the catalytic system
[Ir(COD)2]BARF/2L1 in CH2Cl2 afforded 73–87% ee and complete
conversion in 19 h using 1 mol % of the catalyst.13 The use of scCO2
as the reaction medium allows lower catalytic loadings (0.5 mol %)
to be used leading to the same or better enantioselectivities. More-
over, the reaction rate in scCO2 was significantly better.
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
C6H5
C6H5
C6H5
C6H5
4-Br-C6H4
2-Naphthyl
Cymantrenyl
2-H3C–C6H4
2,3-(H3C)2–C6H3
4-H3C–C6H4
4-F–C6H4
C6H5
4a
4b
4c
4d
4e
4f
93
95
83
84
90
92
50
C6H5
C6H5
3g
4g
a
Reaction conditions: 0.5 mol % of [Ir(COD)2]BARF, 1 mol % of L1, 45 °C, 40 atm
H2, 250 atm total pressure, 120 min.
b
Conversion was 100% in each case.
R2
R2
HN
H2 (40 atm)
N
[Ir(COD)2]BARF (0.5% mol /2L1),
R1
*
R1
scCO2
4a-g
3a-g
Scheme 3. Enantioselective hydrogenation of imines.
Subsequently, a short series of phosphite-type ligands (Scheme
2) was screened under conditions that afforded high yields and
enantioselectivities (40 atm H2, 250 atm total pressure, 45 °C) in
the hydrogenation of 1. In contrast to amidophosphite L1, diam-
idophosphite L2 gave low enantioselectivity and conversion (Table
1, entry 6). Phosphite ligands L3 and L4 gave only racemic products
with poor conversions (Table 1, entries 7 and 8).
To explore the efficiency and the applicability of the Ir-PipPhos
catalyst in scCO2, the hydrogenation of a series of substituted aryli-
mines 3a–g (Table 2, Scheme 3) was studied. The hydrogenation of
imine 3a, containing a 2-methyl group on the N-aryl ring of the
substrate, gave a 93% ee (Table 2, entry 1). Introduction of an addi-
tional 3-methyl group to the imine (substrate 3b) led to a further
increase in enantioselectivity to 95% ee (Table 2, entry 2). Elec-
tron-donating (imine 3c) or electron-withdrawing (imine 3d)
groups at the para-position of the N-aryl ring had very limited ef-
fect on the enantioselectivity (Table 2, entries 3 and 4). Hydrogena-
tion of imine 3e, containing a 4-Br–C6H4 substituent on the
acetophenone unit, gave a 90% ee (Table 2, entry 5). In the presence
of the sterically hindered 2-naphthyl group, a 92% ee was achieved
(Table 2, entry 6). Asymmetric hydrogenation of substrate 3g con-
taining a bulky, but strongly electron-withdrawing cymantrenyl
group, under the same conditions gave the expected product with
50% ee.
The results illustrate the remarkable potential of supercritical
carbon dioxide as a reaction medium for the asymmetric Ir-cata-
lysed hydrogenation of imines using monodentate phosporamidite
ligands. Since complete conversion of the imines can be achieved
in 50–120 min using inexpensive amidophosphite ligands and
CO2 as the solvent, the process may constitute a viable ‘green’

S. E. Lyubimov et al. / Tetrahedron Letters 52 (2011) 1395–1397
1397
approach for the synthesis of valuable chiral amines with high
enantioselectivities.
2H). IR (CHCl3), m , m .
(C@O) 1944 and 2020 cmÀ1 (N–H) 3428 cmÀ1
Anal. Calcd for C16H12O3NMn: C, 59.45; H, 4.37; N, 4.33. Found:
C, 59.51; H, 4.43; N, 4.27.
Ligands L1–L413,25–27 [Ir(COD)2]BARF (BARF = {tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate}),28 were prepared according to
the literature. Imines 1, 3a and 3c–f were prepared following liter-
ature procedures.7,29 Imines 3b and 3g were prepared similarly to
1, 3a and 3c–f.
Acknowledgement
This work was supported by the RFBR Grant No. 09-03-12104-
ofi_m.
2,3-Dimethyl-N-(1-phenylethylidene)benzenamine (3b). Slightly
yellow solid. Mp 72–75 °C. 1H NMR (CDCl3, 400 MHz) d 2.06 (s,
3H), 2.16 (s, 3H), 2.31 (s, 3H), 6.51 (d, J = 7.8 Hz, 1H), 6.91 (d,
J = 7.4 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 7.45 (m, 3H), 8.01 (m, 2H).
References and notes
IR (CHCl3), m
(C@N) 1636 cmÀ1. Anal. Calcd for C16H17N: C, 86.05;
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H, 7.67; N, 6.27. Found: C, 86.15; H, 7.76; N, 6.18.
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N-(1-Cymantrenylethylidene)benzenamine (3g). Yellow solid. Mp
107–108 °C. 1H NMR (acetone-d6, 300 MHz) d 2.02 (s, 3H), 5.15 (m,
2H), 5.71 (m, 2H), 6.79 (d, J = 7.8 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H),
7.39 (t, J = 7.4 Hz, 2H). IR (CHCl3),
m , m(C@O)
(C@N) 1636 cmÀ1
1944 and 2024 cmÀ1. Anal. Calcd for C16H12O3NMn: C, 59.91; H,
3.76; N, 4.35. Found: C, 59.94; H, 3.75; N, 4.20.
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Hydrogenation procedure. The catalysts were prepared by adding
the corresponding ligand (0.0026 or 0.0052 mmol) to a solution of
[Ir(COD)2]BARF (3.3 mg, 0.0026 mmol) in CH2Cl2 (0.1 ml). The solu-
tion was stirred for 5 min before removing the solvent in vacuo.
The pre-formed catalysts (0.0026 mmol) and substrate
(0.52 mmol) were placed into a 10 ml autoclave open to air. The
vessel was pressurized with hydrogen and then filled with scCO2
by means of a syringe-press. The mixture was allowed to equili-
brate to the reaction temperature (10 min) and stirred for 50–
160 min. After stirring, the vessel was cooled to 10 °C and slowly
depressurized. The extent of conversion of the imines 1 and 3a–g
was determined by 1H NMR spectroscopy. Enantiomeric excesses
of the products 2 and 4a–g were determined by HPLC (Chiralcel
OD-H or Chiralcel OJ-H columns).
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2,3-Dimethyl-N-(1-phenylethyl)benzenamine (4b). Colorless oil.
1H NMR (CDCl3, 400 MHz) d 1.57 (d, J = 6.6 Hz, 3H), 2.16 (s, 3H),
2.30 (s, 3H), 3.37 (br s, 1H), 4.53 (q, J = 6.6 Hz, 1H), 6.28 (d,
J = 8.1 Hz, 1H), 6.55 (d, J = 7.4 Hz, 1H), 6.87 (t, J = 7.7 Hz, 1H),
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7.20–7.41 (m, 5H). IR (CHCl3),
16H19N: C, 85.28; H, 8.50; N, 6.22. Found: C, 85.36; H, 8.64; N,
m
(N–H) 3444 cmÀ1. Anal. Calcd for
C
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6.14.
N-(1-Cymantrenylethyl)benzenamine (4g). Yellow viscous oil. 1H
NMR (acetone-d6, 300 MHz) d 1.50 (d, J = 6.6 Hz, 3H), 4.01 (br s,
1H), 4.51 (q, J = 6.6 Hz, 1H), 4.84 (s, 2H), 5.10 (s, 1H), 5.18 (s, 1H),
6.66 (t, J = 7.2 Hz, 1H), 6.75 (d, J = 8.0 Hz, 2H), 7.16 (t, J = 7.8 Hz,