Iridium-catalyzed hydrogenation of β-dehydroamino acid derivatives using monodentate phosphoramidites

Article abstract of DOI:10.1002/ejoc.200800241

The iridium-catalyzed asymmetric hydrogenation of 13 different β-dehydroamino acid derivatives to give optically active β-amino acid esters has been examined. Readily accessible monodentate octahydrobinaphthol- based phosphoramidites were used as chiral ligands. Good to excellent enantioselectivities and yields were obtained for the E isomers, whereas poorer catalyst performance was found for the Z isomers. Importantly, to obtain high enantioselectivity, substitution at the 3,3′-positions of the ligands was necessary. Enantioselectivities of up to 94% ee were achieved under optimized conditions. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800241

FULL PAPER
DOI: 10.1002/ejoc.200800241
Iridium-Catalyzed Hydrogenation of β-Dehydroamino Acid Derivatives Using
Monodentate Phosphoramidites
Stephan Enthaler,[a] Giulia Erre,[a] Kathrin Junge,[a] Kristin Schröder,[a] Daniele Addis,[a]
Dirk Michalik,[a] Marko Hapke,[a] Dmitry Redkin,[a] and Matthias Beller*[a]
Keywords: Asymmetric catalysis / Homogeneous catalysis / Hydrogenation / P ligands / Amino acids / Iridium
The iridium-catalyzed asymmetric hydrogenation of 13 dif-
ferent β-dehydroamino acid derivatives to give optically
active β-amino acid esters has been examined. Readily ac-
cessible monodentate octahydrobinaphthol-based phos-
phoramidites were used as chiral ligands. Good to excellent
enantioselectivities and yields were obtained for the E iso-
mers, whereas poorer catalyst performance was found for the
Z isomers. Importantly, to obtain high enantioselectivity, sub-
stitution at the 3,3Ј-positions of the ligands was necessary.
Enantioselectivities of up to 94% ee were achieved under
optimized conditions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
tions of β-dehydroamino acid derivatives with monodentate
ligands in the presence of iridium as the central metal.
Previously, de Vries and co-workers described the irid-
ium-catalyzed asymmetric hydrogenation of α-dehy-
droamino acid derivatives in the presence of monodentate
phosphoramidites with enantioselectivities of up to 98%
ee.[8] Following this work, we recently reported the im-
proved synthesis and application of monodentate octahyd-
robinaphthol-based phosphoramidites 5 (Scheme 1).[9]
Introduction
The discovery of novel peptide-based therapeutics is a
major target of research in medicinal chemistry. More re-
cently, significant attention has been devoted to non-natural
β-amino acids, which are useful building blocks in the syn-
thesis of biologically active compounds such as β-lactam
antibiotics, taxol derivatives and β-peptides.[1] Over the
years an increasing number of methods for the synthesis
of β-amino acids has been established.[1c,2] In this respect,
transition-metal-catalyzed asymmetric hydrogenation offers
an efficient and versatile strategy and represents a key tech-
nology for the advancement of “green chemistry”, specifi-
cally for waste prevention, achieving high atom efficiency
and advantageous economics.[3] By using rhodium or ruthe-
nium catalysts with chiral diphosphanes such as Me-
DuPhos, BINAP, BINAPO, BICP, TunaPhos, FerroTane,
JosiPhos, DIOP, BPPM, P-Phos and others in the asymmet-
ric hydrogenation of β-dehydroamino acid derivatives, good
to excellent enantioselectivities have been accomplished.[4]
Owing to the easier preparation and modification strategies
that have been developed more recently, efforts have been
dedicated to the application of systems based on mono-
dentate phosphorus ligands[5] such as phosphoramidites,
phosphites, phosphonites and phosphanes.[6] In the case of
monodentate ligands, so far rhodium has been the transi-
tion metal of choice. As a result of our ongoing research in
hydrogenation chemistry,[6j,7] we report herein for the first
time on highly selective asymmetric hydrogenation reac-
Results and Discussion
The synthesis of our phosphoramidite ligands 5 starts
with the selective hydrogenation of enantiomerically pure
1,1Ј-bi-2-naphthol (1)[10] in the presence of catalytic
amounts of Pd/C (Scheme 1).[11] The corresponding
5,5Ј,6,6Ј,7,7Ј,8,8Ј-octahydro-1,1Ј-bi-2-naphthol (2) was ob-
tained in excellent yield and subsequently selectively bromi-
nated at the 3,3Ј-positions with Br2.[11a,11g,12] Compound 3
was subjected to palladium-catalyzed coupling reactions
with several arylboronic acids.[13] The resulting diols 4 were
treated with P(NMe2)3 in refluxing toluene to obtain li-
gands 5 in moderate to good yields.[14] Ligand 5i was syn-
thesized by treating diol 3 with PCl2(NEt2) in the presence
of triethylamine.
Initial studies on the effect of reaction conditions were
carried out separately with ethyl (E)- and (Z)-3-acetamido-
3-phenyl-2-propenoate (E-6 and Z-6) as model substrates.
Typically, we used an in situ precatalytic mixture of 1 mol-
% of [Ir(cod)Cl]2 and 2 mol-% of the corresponding ligand.
All hydrogenation reactions were carried out in an eight-
fold parallel reactor array with a 3.0 mL reactor volume.[15]
At first we focused our attention on the effect of different
solvents such as dichloromethane, methanol, THF, toluene
[a] Leibniz-Institut für Katalyse an der Universität Rostock e.V.,
Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Fax: +49-381-12815000
E-mail: matthias.beller@catalysis.de
3352
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3352–3362

Iridium-Catalyzed Hydrogenation of β-Dehydroamino Acid Derivatives
Scheme 1. Synthesis of octahydrobinaphthol-based phosphoramidites 5.
and ethyl acetate combined with a variation of the initial whereas other solvents led to a somewhat lower selectivity.
hydrogen pressure (2.5, 10.0 and 25 bar). Selected results By increasing the hydrogen pressure up to 50 bar slight de-
are presented in Tables 1 and 2. In the case of the hydroge- creases in the enantioselectivity (78% ee) and yield were
nation of E-6 the best enantioselectivity of 88% ee was observed. Next, the in situ system was compared with the
achieved at a low hydrogen pressure (2.5 bar) in toluene, analogous isolated complex. Here, no significant differences
were observed (Table 1, Entries 8 and 9). By using standard
Table 1. Asymmetric hydrogenation of ethyl (E)-3-acetamido-3-
phenyl-2-propenoate (E-6) with variation of the solvent and pres-
sure.[a]
Table 2. Asymmetric hydrogenation of ethyl (Z)-3-acetamido-3-
phenyl-2-propenoate (Z-6) with variation of the solvent and pres-
sure.[a]
Entry
Solvent
Pressure [bar]
Conv. [%]
ee [%]
1
2
3
4
5
MeOH
MeOH
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
toluene
THF
THF
ethyl acetate
ethyl acetate
ethyl acetate
2.5
10
25
2.5
10
25
1.0
2.5
2.5
10
25
2.5
25
96
86
75
56
99
78 (S)
78 (S)
74 (S)
80 (S)
78 (S)
78 (S)
86 (S)
88 (S)
86 (S)
80 (S)
84 (S)
78 (S)
74 (S)
86 (S)
82 (S)
78 (S)
Entry
Solvent
Pressure [bar]
Conv. [%]
ee [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
MeOH
MeOH
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
THF
THF
2.5
10
25
2.5
10
25
2.5
10
25
2.5
10
25
2.5
10
25
6
Ͻ1
2
6
4
n.d.
n.d.
n.d.
rac.
rac.
6
83
7[b]
8
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
33
39
Ͼ99
76
9[c]
10
11
12
13
14
15
16
5
rac.
13
11
13
62
57
51
48
48
41
44 (S)
46 (S)
50 (S)
40 (S)
38 (S)
37 (S)
36 (S)
32 (S)
18 (S)
2.5
10
25
THF
83
ethyl acetate
ethyl acetate
ethyl acetate
[a] Reactions were carried out at 25 °C for 24 h with 0.0012 mmol
of [Ir(cod)Cl]2, 0.0024 mmol of ligand 5c and 0.12 mmol of sub-
strate in 2.0 mL of solvent. The conversion was determined by GC
(50 m Chiraldex β-PM, 110/30-4-180), and the ee was determined
by HPLC (Chiralpak AD-H, n-hexane/ethanol, 95:5, 1.0 mL/min).
[b] The reaction was carried out under isobaric conditions. [c] The
isolated complex was used as the catalyst.
[a] Reactions were carried out at 25 °C for 24 h with 0.0012 mmol
of [Ir(cod)Cl]2, 0.0024 mmol of ligand 5c and 0.12 mmol of sub-
strate in 2.0 mL of solvent. The conversions were determined by
GC (50 m Chiraldex β-PM, 110/30-4-180) and the ees by HPLC
(Chiralpak AD-H, n-hexane/ethanol, 95:5, 1.0 mL/min).
Eur. J. Org. Chem. 2008, 3352–3362
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3353

M. Beller et al.
FULL PAPER
chiral bidentate phosphorus ligands such as (–)-DIOP, (S)- corresponding sodium salts showed only a slight effect com-
BINAP, (S,S)-Ferrotane, (R,S)-JosiPhos and (S,S)-Me- pared with the chloride system. Notably a lower yield was
DuPhos under these conditions (dichloromethane with observed in the presence of sodium tetrakis[3,5-bis(trifluor-
5 bar hydrogen), only a racemic mixture of 6a was obtained. omethyl)phenyl]borate (NaBARF). Since the addition of io-
After that, the effect of reaction temperature was investi- dine proved to be beneficial in the iridium-catalyzed asym-
gated in more detail (Figure 1). In the presence of the model metric hydrogenation of imines, we decided to study the ef-
ligand 5c, the hydrogenation of the E isomer was not appre- fect of this additive as well.[16] However, the catalyst was
ciably influenced in the range of 10–110 °C (78–88% ee). completely inactive in the presence of iodine in this system
However, at 110 °C a significant amount (ca. 10%) of the (Table 3, Entry 2).
corresponding Z isomer was detected, probably caused by
thermal E/Z isomerization. The best catalyst performance sodium dodecylsulfonate (SDS)[7c] (Table 3, Entry 11). To
was found at 25 °C with an enantioselectivity of 88% ee.
stabilize the catalyst or mimic the Crabtree complex,[17]
No pronounced effect was observed in the presence of
On the other hand, the hydrogenation of Z-6 with an which is an excellent hydrogenation catalyst, pyridine was
iridium catalyst derived from [Ir(cod)Cl]2 and ligand 5c pro- added to the precatalyst, but no product at all was obtained
duced compound 6a in poor yield and poor enantio- (Table 3, Entry 12). In addition, the effect of a second
selectivity in all solvents (Table 2). Only in toluene was the equivalent of phosphorus ligand was studied (Table 3, En-
prevailing enantiomer isolated with selectivities of up to tries 14 and 15); no improvement in selectivity or activity
50% ee, accompanied by moderate conversion (Table 2, En- was observed in the presence of PPh3 or MonoPhos. Fi-
tries 7–9). Based on these results, toluene as the solvent and nally, it was possible to reduce the catalyst loading to
2.5 bar hydrogen pressure were selected for the hydrogena- 0.1 mol-% iridium maintaining the high level of enantio-
tion of the E isomer (conversion: Ͼ99%; enantioselectivity: selectivity.
88%) for further investigations.
Next we investigated the effect of different ligands on
To improve the reaction rate and the enantioselectivity, the selectivity of the model reaction. As shown in Table 4,
we decided to exchange the halide ligand with weaker coor- substitution in the 3,3Ј-positions of the binaphthyl core is
dinating ligands, for example, BF4– and ClO4– (Table 3, En- a prerequisite for obtaining reasonable enantioselectivity, as
tries 3–7). However, addition of the corresponding silver ligand 5a gave a much lower selectivity (Table 4, Entry 1).
salts led to diminished yields and selectivities, whereas the The best enantioselectivity (88% ee) was achieved with
Figure 1. Temperature dependency of the hydrogenation reactions {reactions were carried out for 24 h with 0.0012 mmol of [Ir(cod)Cl]2,
0.0024 mmol of ligand 5c and 0.12 mmol of substrate in 2.0 mL of toluene under 2.5 bar of hydrogen; the conversions were determined
by GC (50 m Chiraldex β-PM, 110/30-4-180) and the ees by HPLC (Chiralpak AD-H, n-hexane/ethanol, 95:5, 1.0 mL/min); experiments
carried out at 90 and 110 °C were run for 1 h}.
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Eur. J. Org. Chem. 2008, 3352–3362

Iridium-Catalyzed Hydrogenation of β-Dehydroamino Acid Derivatives
Table 3. Effect of additives and catalyst loading on the asymmetric
Table 4. Ligand screening in the asymmetric hydrogenation of 6.[a]
hydrogenation of E-6.[a]
Entry
Additive
Cat. [mol-%] Time [h] Conv. [%] ee [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
–
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
0.2
0.1
0.01
6
95
Ͻ1
10
17
84
99
6
89
63
48
97
Ͻ1
Ͼ99
70
25
99
52
27
Ͻ1
88 (S)
n.d.
I2 [10 mol-%]
16
16
16
24
24
24
24
24
24
16
16
16
24
24
24
24
24
24
AgBF4 [2 mol-%]
AgClO4 [2 mol-%]
NaBF4 [2 mol-%]
NaClO4 [2 mol-%]
NaBARF [2 mol-%]
NH4SO4 [10 mol-%]
nBu4Br [10 mol-%]
Me3SI [10 mol-%]
SDS [10 mol-%]
pyridine [5 mol-%]
CF3CH2OH [10 mol-%]
PPh3 [2 mol-%]
(S)-MonoPhos [2 mol-%]
–
50 (S)
68 (S)
87 (S)
88 (S)
64 (S)
88 (S)
69 (S)
82 (S)
88 (S)
n.d.
86 (S)
28 (S)
80 (S)
88 (S)
86 (S)
84 (S)
n.d.
–
–
–
[a] Reactions were carried out at 25 °C for 24 h with 0.0012 mmol
of [Ir(cod)Cl]2, 0.0024 mmol of ligand and 0.12 mmol of substrate
in 2.0 mL of toluene. The conversions were determined by GC
(50 m Chiraldex β-PM, 110/30-4-180) and the ees by HPLC (Chi-
ralpak AD-H, n-hexane/ethanol, 95:5, 1.0 mL/min). [b] Values per-
tain to the selenide of the corresponding ligand.
[a] Reactions were carried out with 0.0012 mmol of [Ir(cod)Cl]2,
0.0024 mmol of ligand 5 and 0.12 mmol of substrate in 2.0 mL of
toluene. The conversions were determined by GC (50 m Chiraldex
β-PM, 110/30-4-180) and the ees by HPLC (Chiralpak AD-H, n-
hexane/ethanol, 95:5, 1.0 mL/min).
para-substituted aryl groups in the 3,3Ј-positions, whereas cantly decreased the basicity, whereas aryl substituents led
phenyl and sterically demanding mesityl substituents gave to lower coupling constants. Except for mesityl substituents,
84 and 74% ee, respectively.
which strongly increase the basicity, no differences were de-
In order to obtain information on the electronic and ste- tected for the various aryl substituents.
ric properties of the presented ligands and to draw conclu-
In Figure 2 the 77Se–31P coupling constants are corre-
sions about possible structure–activity relationships, the lated to the enantioselectivity observed for the asymmetric
corresponding selenides 12 were synthesized by reaction of hydrogenation of E-6 (Table 4). There is no clear trend ob-
the phosphoramidites with an excess of selenium powder in served: 3,3Ј-disubstituted ligands with a 77Se–31P coupling
a sealed NMR tube. In most cases, the selenides were read- constant in the range of 965–971 Hz gave high enantiomeric
ily formed at room temperature, and rarely heating at 70°C excesses, whereas the electronically similar MonoPhos li-
for 2 h was necessary to obtain a sufficient amount of de- gand (J = 971 Hz) gave a significantly lower enantio-
sired product. The samples were analyzed by 31P NMR, selectivity. Steric factors apparently determine the enantio-
and the chemical shifts and coupling constants are pre- selectivity in the iridium-catalyzed hydrogenation of β-
sented in Table 4. The 77Se–31P coupling constants repre- amino acid derivatives.
sent a useful probe for the σ-donor properties and conse-
To explore the scope and limitation of the presented li-
quently for the metal–ligand interaction. The magnitude of gands, the asymmetric hydrogenation of a selection of β-
the 77Se–31P coupling constants reveal the σ character of dehydroamino acid derivatives was performed (Table 5).
the phosphorus lone-pair orbital. High magnitudes are ad- The β-acetamido acrylates were synthesized according to
junct to high σ character, hence the basicity of the phos- literature protocols.[4] In the case of the alkyl β-acet-
phorus atom is low.[19] In general, the values of the 77Se– amidoacrylates 13–17, the E/Z isomers were separated by
31P coupling constants (952–990 Hz) are in agreement with crystallization or column chromatography, whereas the syn-
the work of Murai et al., who reported values in the range theses of the aryl β-acetamidoacrylates and substrate 18
of 960–980 Hz for MonoPhos-based phosphoramidites.[20] produced mainly the Z isomers. The corresponding E iso-
A comparison of the 77Se–31P coupling constants of Mon- mers were accessible according to the procedure of Knowles
oPhos and octahydro-MonoPhos showed a more basic and co-workers by irradiation with light.[4b] A THF solu-
phosphorus atom for the saturated MonoPhos. The intro- tion of the crude mixture obtained by the acylation proto-
duction of bromo substituents at the 3,3Ј-positions signifi- col was stirred at room temperature and irradiated for
Eur. J. Org. Chem. 2008, 3352–3362
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3355

M. Beller et al.
FULL PAPER
Figure 2. 77Se–31P coupling constants of 12 versus the enantiomeric excesses obtained with ligands 5.
30–46 h and subsequently purified by crystallization or
column chromatography (Table 5). The E isomers were
obtained in good yields (60–83%). In the case of substrate
18, separation of the isomers was unsuccessful either by
crystallization or by column chromatography.
Table 5. Synthesis of E substrates by the light-induced isomeriza-
tion of Z substrates.
Asymmetric hydrogenation of those alkyl E substrates
showed the following trends: Changing the ester group from
a methyl to an isopropyl group resulted in a decrease in
enantioselectivity, accompanied by a slight decrease in the
yield (Table 6, Entries 1–3). The same tendency was ob-
served for the asymmetric hydrogenation of E-23. The effect
of R3 substitution was investigated on a set of eight dif-
ferent substrates. Improved selectivity was observed when
the bulkiness of the alkyl derivatives increased from methyl
to isopropyl (Table 6, Entries 3 and 5). In the case of the
aryl substituents, a slight negative effect on enantio-
selectivity was observed when an electron-withdrawing
group (Table 6, Entry 8) was positioned at the 4-position,
whereas an electron-donating group improved the enantio-
selectivity (Table 6, Entry 6). As good enantioselectivity was
detected for the 4-methoxy-substituted substrate, we syn-
thesized E-20 bearing a 2-methoxy substituent, which al-
lows for an additional coordination site to the metal atom.
Here, 94% ee was obtained (Table 6, Entry 7).
Yield of E
λmax
Entry Substrate R2
R3
R4
t [h]
[%]
[nm][e]
1[a,b]
2[a,b]
3[a,b]
4[a,b]
5[a,b]
6[d]
13
14
15
16
17
18
6
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Et
iPr
tBu
CH3
Et
iiPr
CH3
CH3
CH3
Et
Et
Et
Et
Et
–
–
–
–
–
30
30
32
30
46
30
46
11
10
11
12
14
29
80
83
67
83
83
60
312.0
312.5
323.5
311.5
327.0
–
352.9
360.5
354.7
336.5
346.5
337.9
7[d]
C6H5
8[c,d]
9[c,d]
10[d]
11[d]
12[d]
19
20
21
22
23
CH3 4-MeOC6H4
CH3 2-MeOC6H4
CH3
CH3 4-CH3C6H4
CH3 C6H5
4-FC6H4
CH3
[a] Acceptable amounts of the E isomer were formed during the
acylation process. [b] Separation of the E/Z mixture by crystalli-
zation (three times). [c] Separation of the E/Z mixture by column
chromatography. [d] A 460 W Phillips HPM 12 lamp, λ ≈ 420 nm,
was used as the light source. The yield was determined on the crude
mixture by 1H NMR spectroscopy. [e] λmax of the characteristic
shoulder from the Z isomer, calculated from the unified UV/Vis
spectra of the Z isomer minus the E isomer. All the measurements
were carried out in ethanol at 25 °C. λmax constitutes the energy of
Despite the fact that our initial attempts were unsuccess-
ful (Table 2), we examined the potential of our catalysts in
the asymmetric reduction of the corresponding Z deriva-
tives (Table 7). By using a higher pressure (25 bar) and THF isomerization of the Z to the E isomer.
3356 Eur. J. Org. Chem. 2008, 3352–3362
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Iridium-Catalyzed Hydrogenation of β-Dehydroamino Acid Derivatives
Table 6. Use of the octahydrobinaphthol-based phosphoramidites
Finally, we tested two examples of tetrasubstituted β-de-
hydroamino acid precursors. Unfortunately, for both 24[21]
and 25 only traces of the products were found
(Scheme 2).[22,23]
5 in the asymmetric hydrogenation of various E substrates.[a]
Entry Ligand Substrate R2
R3
R4 Conv. [%] ee [%]
1[b]
2[b]
3[b]
4[b]
5[b]
6[c]
7[c]
8[c]
9[c]
10[c]
5c
5c
5c
5c
5c
5c
5c
5c
5c
5c
E-13
E-14
E-15
E-16
E-17
E-19
E-20
E-21
E-22
E-23
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Et
CH3
Et
iPr
CH3
CH3
Et
Et
Et
Et
CH3
94
90
82
97
Ͼ99
49
62
79
Ͼ99
Ͼ99
50 (R)
32 (R)
6 (R)
62 (R)
80 (R)
90 (–)
94 (–)
84 (–)
88 (–)
90 (S)
iPr
CH3 4-MeOC6H4
CH3 2-MeOC6H4
CH3
CH3
CH3
4-FC6H4
4-CH3C6H4
C6H5
[a] Reactions were carried out at 25 °C for 24 h with 0.0012 mmol
of [Ir(cod)Cl]2, 0.0024 mmol of ligand 5 and 0.12 mmol of substrate
in 2.0 mL of toluene under an initial hydrogen pressure of 2.5 bar.
[b] Conversion determined by GC. [c] Conversion determined by
1H NMR spectroscopy.
Scheme 2. Asymmetric hydrogenation of tetrasubstituted amino
acid precursors.
Conclusion
as the solvent, reasonable amounts of product were ob-
tained with acceptable enantioselectivities. No detectable ef-
fect on the enantioselectivity of the ester functionality and
R3 substitution was observed as described for the corre-
sponding E-amino acid precursors (Table 7, Entries 1–5).
The best selectivity (75% ee) was observed with the bulky
tert-butyl derivative (Table 7, Entry 6). For aryl substrates,
in tendency lower enantioselectivities were achieved com-
pared with the alkyl derivatives (Table 7, Entries 7–11).
For the first time the iridium-catalyzed asymmetric hy-
drogenation of several β-amino acid precursors has been
examined in the presence of chiral monodentate octahydro-
binaphthol-based phosphoramidites. Separate studies for
the E and Z isomers showed crucial differences between
the two hydrogenation reactions. After optimization of the
reaction conditions, enantioselectivities of up to 94% ee
were achieved for the E isomers. Importantly, to obtain
high enantioselectivity, substitution at the 3,3Ј-positions of
the ligands was found to be necessary.
Table 7. Use of the octahydrobinaphthol-based phosphoramidites
5 in the asymmetric hydrogenation of various Z substrates.[a]
Experimental Section
General: All manipulations with oxygen- and moisture-sensitive
compounds were performed under argon using standard Schlenk
techniques. Toluene and THF were distilled from sodium/benzo-
phenone ketyl under argon. Methanol was distilled from Mg under
argon. Dichloromethane was distilled from CaH2 under argon.
Ethyl acetate (purchased from Fluka on molecular sieves) was used
without further manipulations. Ligands 5 were synthesized accord-
ing to our previously published protocols.[9] [Ir(cod)Cl]2 (Fluka and
Strem Chemicals) was used without further purification. 1H, 13C
and 31P NMR spectra were recorded with Bruker Avance 500, 400
and 300 spectrometers (1H: 500.13, 400.13 and 300.13 MHz; 13C:
125.8, 100.6 and 75.5 MHz; 31P: 121.5 MHz). Melting points were
determined with a melting point apparatus Stuart SMP3. IR spec-
tra were recorded with a Nicolet Magna 550 spectrometer. Mass
spectra were recorded with an AMD 402 spectrometer.
Entry Ligand Substrate R2
R3
R4 Conv. [%] ee [%]
1[b]
2[b]
3[b]
4[b]
5[b]
6[b]
7[c]
5c
5c
5c
5c
5c
5c
5c
5c
5c
5c
5c
Z-13
Z-14
Z-15
Z-16
Z-17
Z-18
Z-19
Z-20
Z-21
Z-22
Z-23
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Et
iPr
tBu
CH3
Et
iPr
CH3
CH3
CH3
Et
58
32
37
44
53
Ͼ99
59
10
58 (R)
50 (R)
62 (R)
48 (R)
60 (R)
75 (+)
46 (–)
–
CH3 4-MeOC6H4
CH3 2-MeOC6H4
CH3
CH3 4-CH3C6H4
CH3 C6H5
8[c]
Et
9[c]
4-FC6H4
Et
Et
CH3
78
53
70
37 (–)
45 (–)
67 (S)
10[c]
11[c]
General Synthesis of Alkyl β-Dehydroamino Acid Derivatives 13–17:
The corresponding β-oxo ester (0.07 mol) was added to a solution
of NH4OAc (0.36 mol) in methanol, ethanol or 2-propanol, de-
pending on the ester functionality (100 mL). After stirring at room
temperature for 60 h, the solvent was removed, and a mixture of
CHCl3 and water was added. The organic layer was washed with
[a] Reactions were carried out at 25 °C for 24 h with 0.0012 mmol
of [Ir(cod)Cl]2, 0.0024 mmol of ligand 5 and 0.12 mmol of substrate
in 2.0 mL of THF under an initial hydrogen pressure of 25 bar. [b]
Conversion determined by GC. [c] Conversion determined by 1H
NMR spectroscopy.
Eur. J. Org. Chem. 2008, 3352–3362
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3357

M. Beller et al.
FULL PAPER
water (3ϫ 50 mL) and brine (50 mL), and dried with Na2SO4.
The solvent was evaporated under reduced pressure to yield the
corresponding 3-amino-2-alkenoate. The 3-amino-2-alkenoate
(0.07 mol), pyridine (0.13 mol), and acetic anhydride (0.32 mol)
were dissolved in THF (50 mL), and the mixture was stirred at 70
(procedure A) or 95 °C (procedure B) for 12 h. The solution was
reduced to half of the volume, and ethyl acetate was added. After
washing with water, HCl, NaHCO3 and brine and drying with
Na2SO4, the solvent was removed.
59.7, 55.3, 25.0, 14.2 ppm. MS (ES, 70 eV): m/z (%) = 263 (28)
[M]+, 218 (5), 202 (3), 190 (100), 176 (23), 160 (3), 149 (45), 134
(30), 121 (4), 104 (3), 91 (4), 77 (6), 63 (3), 51 (2), 43 (15). HRMS:
calcd. for C14H17NO4 263.11521; found 163.115110. Crystallization
from ethanol.
Ethyl (Z)-3-Acetamido-3-(4-methoxyphenyl)acrylate (Z-19): M.p.
1
94–96 °C. H NMR (300 MHz, CDCl3): δ = 10.59 (br., 1 H, NH),
7.32–7.29 (m, 2 H, Ar), 6.90–6.83 (m, 2 H, Ar), 5.25 (s, 1 H, =CH),
4.20 (q, J = 7.1 Hz, 2 H, CH2CH3), 3.81 (s, 3 H, OCH3), 2.16 (s,
3 H, COCH3), 1.30 (t, J = 7.1 Hz, 3 H, CH2CH3) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 168.7, 168.6, 160.8, 154.2, 128.6, 127.9,
Procedure A (E Isomer Enriched Residue): Dissolving the residue in
ethyl acetate/n-hexane (1:1) and storing the solution overnight at
–20 °C yielded the E isomers of β-dehydroamino acid derivatives
13–17, which were recrystallized three times from ethyl acetate/n-
hexane (1:1) to give colorless crystals [yield of the main fraction
based on the β-oxo ester: E-13: 1.4 g (11%); E-14: 1.2 g (10%); E-
15: 1.5 g (11%); E-16: 1.4 g (12%); E-17: 1.8 g (14%)].
113.5, 100.0, 60.1, 55.3, 24.9, 14.3 ppm. IR (ATR): ν = 3261 (w),
˜
3103 (w), 3040 (w), 3020 (w), 2994 (w), 2950 (w), 2935 (w), 2910
(w), 2833 (w), 1724 (m), 1656 (m), 1607 (s), 1509 (m), 1486 (m),
1461 (m), 1369 (m), 1282 (s), 1241 (m), 1169 (s), 1101 (s), 1027 (s),
1003 (m), 994 (m), 967 (m), 876 (w), 837 (m), 824 (s), 777 (m), 740
(m), 729 (m), 702 (w), 681 (m) cm–1. MS (ES, 70 eV): m/z (%) =
263 (27) [M]+, 190 (100), 176 (23), 149 (44), 134 (30). HRMS: calcd.
for C14H17NO4 263.11521; found 263.115321. Rf = 0.48 (ethyl ace-
tate/n-hexane, 1:2).
Procedure B (Z Isomer Enriched Residue): The pure Z isomer was
obtained by column chromatography (eluent: ethyl acetate/n-hex-
ane, 1:1 or 1:2) [yield based on the β-oxo ester: Z-13: 4.3 g (39%);
Z-14: 1.2 g (35%) (0.035 mmol of β-oxo ester); Z-15: 6.0 g (46%);
Z-16: 1.6 g (26%) (0.035 mmol of β-oxo ester); Z-17: 4.0 g (31%)].
Ethyl (E)-3-Acetamido-3-(2-methoxyphenyl)acrylate (E-20): M.p.
1
130–132 °C. H NMR (300 MHz, CDCl3): δ = 7.43–7.36 (m, 1 H,
Methyl (Z)-3-Acetamido-4,4-dimethylpent-2-enoate (Z-18): Methyl
(Z)-3-acetamido-4,4-dimethylpent-2-enoate was synthesized ac-
cording to the general procedure A (see above), but the Z isomer
was exclusively formed. M.p. 60–63 °C. 1H NMR (400 MHz,
CDCl3): δ = 9.57 (br., 1 H, NH), 5.46 (s, 1 H, =CH), 3.71 (s, 3 H,
OCH3), 2.16 [s, 3 H, C(=O)CH3], 1.27 [s, 9 H, C(CH3)3] ppm. 13C
NMR (75.5 MHz, CDCl3): δ = 168.9, 167.9, 162.5, 101.1, 51.4,
Ar), 7.22–7.18 (m, 1 H, Ar), 7.15 (br., 1 H, CH), 7.03–6.93 (m, 2
H, Ar), 6.78 (br., 1 H, NH), 3.98 (q, J = 7.1 Hz, 2 H, CH2CH3),
3.82 (s, 3 H, OCH3), 2.09 (s, 3 H, COCH3), 1.10 (t, J = 7.1 Hz, 3
H, CH2CH3) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 168.8, 167.0,
156.2, 145.7, 130.7, 130.0, 125.3, 120.6, 111.1, 105.2, 59.4, 55.7,
25.0, 14.1 ppm. MS (ES, 70 eV): m/z (%) = 263 (30) [M]+, 190 (100),
176 (24), 149 (46), 134 (30) ppm. Rf = 0.1 (ethyl acetate/n-hexane,
1:2).
36.7, 28.5, 25.0 ppm. IR (ATR): ν = 3244 (w), 3156 (w), 3014 (w),
˜
2964 (w), 2909 (w), 2873 (w), 1724 (s), 1672 (m), 1650 (m), 1519
(m), 1480 (m), 1438 (m), 1393 (w), 1371 (m), 1348 (m), 1278 (m),
1260 (m), 1195 (s), 1174 (s), 1121 (m), 1035 (m), 1006 (m), 960 (w),
Ethyl (Z)-3-Acetamido-3-(2-methoxyphenyl)acrylate (Z-20): M.p.
1
59–62 °C. H NMR (300 MHz, CDCl3): δ = 10.95 (br., 1 H, NH),
928 (w), 890 (w), 850 (m), 799 (w), 732 (m), 696 (m) cm–1. MS (EI): 7.37–7.30 (m, 1 H, Ar), 7.19–7.14 (m, 1 H, Ar), 6.98–6.90 (m, 1 H,
m/z (%) = 199 (4) [M]+, 184 (2), 168 (6), 152 (8), 140 (100), 126 Ar), 6.86–6.81 (m, 1 H, Ar), 5.06 (s, 1 H, =CH), 4.20 (q, J = 7.1 Hz,
(18), 115 (14), 110 (30), 100 (18), 84 (12), 68 (30), 57 (10), 43 (62), 2 H, CH2CH3), 3.70 (s, 3 H, OCH3), 2.09 (s, 3 H, COCH3), 1.29
29 (6). HRMS: calcd. for C10H17NO3 199.12029; found
199.120440.
(t, J = 7.1 Hz, 3 H, CH2CH3) ppm. 13C NMR (75.5 MHz, CDCl3):
δ = 169.0, 167.4, 156.6, 152.4, 130.4, 128.7, 125.6, 120.3, 110.1,
99.2, 60.1, 55.5, 24.6, 14.2 ppm. IR (ATR): ν = 3254 (w), 3228 (w),
˜
General Synthesis of Aryl β-Dehydroamino Acid Derivatives: The
corresponding β-oxo ester (0.07 mol) was added to a solution of
NH4OAc (0.36 mol) in methanol or ethanol (100 mL), depending
on the ester group. After stirring at room temperature for 60 h, the
solvent was removed, and a mixture of CHCl3 and water was
added. The organic layer was washed with water (3ϫ 50 mL) and
brine (50 mL), and dried with Na2SO4. The solvent was evaporated
under reduced pressure to yield the corresponding 3-amino-2-phen-
ylacrylate. The 3-amino-2-phenylacrylate (0.07 mol), pyridine
(0.13 mol) and acetic anhydride (0.32 mol) were dissolved in THF
(50 mL), and the mixture was stirred at 90 °C for 12 h. The solution
was reduced to half of the volume, and ethyl acetate was added.
After washing with water, HCl, NaHCO3 and brine and drying
with Na2SO4, the solvent was removed. The oily residue was puri-
fied by column chromatography (eluent: ethyl acetate/n-hexane) to
yield the corresponding (Z)-3-acetamido-3-phenylacrylate. The E
isomers were accessible by subjecting a solution of the Z isomer in
THF to light irradiation (460 W Phillips HPM 12 lamp, λ ≈
420 nm) at room temperature for 2–3 d (Table 5).
3072 (w), 3033 (w), 3004 (w), 2986 (w), 2975 (w), 2936 (w), 2837
(w), 1723 (m), 1661 (m), 1619 (s), 1597 (m), 1491 (m), 1458 (m),
1435 (m), 1389 (w), 1368 (m), 1357 (m), 1294 (s), 1273 (s), 1247 (s),
1228 (m), 1172 (s), 1128 (m), 1090 (m), 1046 (m), 1017 (s), 983 (m),
951 (m), 937 (w), 866 (w), 854 (w), 838 (m), 810 (m), 780 (m), 754
(s), 731 (m), 681 (m) cm–1. MS (ES, 70 eV): m/z (%) = 263 (14)
[M]+, 190 (100), 176 (11), 134 (31). HRMS: calcd. for C14H17NO4
263.11521; found 163.115075. Rf = 0.25 (ethyl acetate/n-hexane,
1:2).
Ethyl (E)-3-Acetamido-3-(4-fluorophenyl)acrylate (E-21): M.p. 91–
1
92 °C. H NMR (300 MHz, CDCl3): δ = 7.33–7.28 (m, 2 H, Ar),
7.12–7.06 (m, 2 H, Ar), 7.04 (br., 1 H, CH), 6.84 (br., 1 H, NH),
3.98 (q, J = 7.2 Hz, 2 H, CH2CH3), 2.10 (s, 3 H, COCH3), 1.12 (t,
J = 7.2 Hz, 3 H, CH2CH3) ppm. 13C NMR (75.5 MHz, CDCl3): δ
= 168.9, 167.1, 163.2 (d, J = 249.5 Hz), 147.7, 132.4 (d, J = 3.5 Hz),
130.2 (d, J = 8.4 Hz), 115.4 (d, J = 21.8 Hz), 104.6, 59.8, 25.0,
14.1 ppm. MS (ES, 70 eV): m/z (%) = 251 (14) [M]+, 206 (5), 178
(100), 164 (37), 137 (56), 122 (26), 109 (8), 95 (6), 43 (20). HRMS:
calcd. for C13H14FNO3 251.09522; found 251.095163. Rf = 0.15
(ethyl acetate/n-hexane, 1:2).
Ethyl (E)-3-Acetamido-3-(4-methoxyphenyl)acrylate (E-19): M.p.
1
144–145 °C. H NMR (300 MHz, CDCl3): δ = 7.29–7.25 (m, 2 H,
Ar), 7.01 (br., 1 H, CH), 6.94–6.90 (m, 2 H, Ar), 6.69 (br., 1 H,
NH), 4.01 (q, J = 7.2 Hz, 2 H, CH2CH3), 3.83 (s, 3 H), 2.11 (s, 3
Ethyl (Z)-3-Acetamido-3-(4-fluorophenyl)acrylate (Z-21): M.p. 81–
84 °C. 1H NMR (300 MHz, CDCl3): δ = 10.66 (br., 1 H, NH),
H), 1.14 (t, J = 7.2 Hz, 3 H, CH2CH3) ppm. 13C NMR (75.5 MHz, 7.40–7.33 (m, 2 H, Ar), 7.09–7.05 (m, 2 H, Ar), 5.25 (s, 1 H, =CH),
CDCl3): δ = 168.8, 167.2, 160.5, 148.5, 129.6, 128.6, 113.8, 104.0,
4.23 (q, J = 7.1 Hz, 2 H, CH2CH3), 2.18 (s, 3 H, COCH3), 1.33 (t,
3358
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3352–3362

Iridium-Catalyzed Hydrogenation of β-Dehydroamino Acid Derivatives
J = 7.1 Hz, 3 H, CH2CH3) ppm. 13C NMR (75.5 MHz, CDCl3): δ
= 168.6, 168.5, 163.5 (d, J = 249 Hz), 153.4, 131.9 (d, J = 3.3 Hz),
129.0 (d, J = 8.5 Hz), 115.2 (d, J = 21.9 Hz), 101.0, 60.4, 24.8,
(12), 43 (100). HRMS: calcd. for C10H13NO5 227.07882; found
227.079149. Retention time (GC): 19.0 min (30 m HP 50-8-260/5-
8-280/5-8-300/5).
14.2 ppm. IR (ATR): ν = 3304 (w), 3060 (w), 2983 (w), 2935 (w),
˜
General Procedure for the Catalytic Hydrogenation of β-Dehy-
droamino Acid Derivatives: A solution of the β-dehydroamino acid
derivative (0.12 mmol) and the solvent (1.0 mL) was transferred by
syringe into an autoclave charged with argon. The catalyst was gen-
erated in situ by stirring [Ir(cod)Cl]2 (0.0012 mmol) and the corre-
sponding ligand (0.0024 mmol) in solvent (1.0 mL) for a period of
10 min and afterwards transferring the solution by syringe into the
autoclave. Then the autoclave was charged with hydrogen and the
mixture stirred at the required temperature. After the predeter-
mined time, the hydrogen was released and the reaction mixture
passed through a short plug of silica gel. The conversion was mea-
2909 (w), 2871 (w), 1687 (m), 1622 (m), 1606 (s), 1592 (m), 1505
(s), 1470 (w), 1449 (w), 1418 (w), 1365 (m), 1290 (m), 1279 (m),
1225 (m), 1158 (s), 1116 (m), 1103 (m), 1093 (m), 1034 (m), 1016
(m), 985 (m), 959 (m), 881 (w), 854 (m), 831 (s), 819 (m), 790 (m),
748 (w), 721 (w), 672 (m) cm–1. MS (ES, 70 eV): m/z (%) = 251
(16) [M]+, 206 (5), 178 (100), 164 (38), 137 (57), 122 (26), 109 (8),
95 (6), 43 (20). HRMS: calcd. for C13H14FNO3 251.09522; found
251.095593. Rf = 0.32 (ethyl acetate/n-hexane, 1:3).
Ethyl (E)-3-Acetamido-3-(4-methylphenyl)acrylate (E-22): M.p. 97–
1
100 °C. H NMR (300 MHz, CDCl3): δ = 7.19 (m, 4 H), 7.01 (s, 1
1
sured by GC or H NMR spectroscopy and the enantioselectivity
by GC or HPLC.
H, C=CH), 6.88 (br., 1 H, NH), 3.95 (q, J = 7.1 Hz, 2 H, CH2CH3),
2.37 (s, 3 H), 2.04 (s, 3 H), 1.11 (t, J = 7.1 Hz, 3 H, CH2CH3) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 168.9, 167.2, 148.9, 139.4,
133.5, 129.0, 128.0, 103.8, 59.6, 24.9, 21.4, 14.1 ppm. MS (ES,
70 eV): m/z (%) = 247 (15) [M]+, 174 (100), 160 (26), 133 (47), 118
(25).
Ethyl 3-Acetamido-3-phenylpropanoate (6a): Chiralpak AD-H; n-
hexane/ethanol, 95:5; flow rate 1.0 mL/min; retention time: (R)-6a
27.6 min, (S)-6a 29.3 min.
Methyl 3-Acetamidobutanoate (13a): 50 m Chiraldex β-PM; 130 °C;
retention time: (S)-13a 15.1 min, (R)-13a 16.4 min.
Ethyl (Z)-3-Acetamido-3-(4-methylphenyl)acrylate (Z-22): M.p. 40–
43 °C. 1H NMR (300 MHz, CDCl3): δ = 10.53 (br., 1 H, NH),
7.23–7.06 (m, 2 H, Ar), 7.11–7.06 (m, 2 H, Ar), 5.20 (s, 1 H,
C=CH), 4.14 (q, J = 7.1 Hz, 2 H, CH2CH3), 2.29 (s, 3 H), 2.08 (s, 3
H), 1.24 (t, J = 7.1 Hz, 3 H, CH2CH3) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 168.6, 168.4, 154.5, 139.7, 132.9, 128.7, 127.0, 100.5,
Ethyl 3-Acetamidobutanoate (14a): 25 m Lipodex E, 70/40-8-180;
retention time: (R)-14a 33.2 min, (S)-14a 33.4 min.
Isopropyl 3-Acetamidobutanoate (15a): 25 m Lipodex E, 70/25-10-
180; retention time: (R)-15a 33.2 min, (S)-15a 33.4 min.
60.2, 24.8, 21.3, 14.3 ppm. IR (ATR): ν = 3293 (w), 3208 (w), 3136
˜
Methyl 3-Acetamidopentanoate (16a): 25 m Lipodex E, 120/30; re-
tention time: (R)-16a 31.8 min, (S)-16a 32.2 min.
(w), 3054 (w), 3028 (w), 3005 (w), 2979 (w), 2934 (w), 2872 (w),
1903 (w), 1707 (m), 1686 (s), 1618 (s), 1568 (m), 1511 (m), 1470
(m), 1448 (m), 1412 (w), 1365 (m), 1290 (s), 1273 (s), 1219 (m),
1170 (s), 1115 (m), 1091 (m), 1033 (m), 1018 (m), 984 (m), 960 (w),
881 (w), 846 (m), 830 (m), 809 (s), 785 (w), 718 (m), 675 (m) cm–1.
MS (ES, 70 eV): m/z (%) = 247 (16) [M]+, 174 (100), 160 (26),
133 (46), 118 (26). HRMS: calcd. for C14H17NO3 247.12029; found
247.119734. Rf = 0.48 (ethyl acetate/n-hexane, 1:2).
Methyl 3-Acetamido-4-methylpentanoate (17a): 25 m Lipodex E,
130/20, retention time: (R)-17a 33.2 min, (S)-17a 33.4 min.
Methyl 3-Acetamido-4,4-dimethylpentanoate (18a): 25 m Lipodex
E, 70/40-8-200; retention time: (+)-17a 16.6 min, (–)-17a 18.9 min.
Ethyl 3-Acetamido-3-(4-methoxyphenyl)propanoate (19a): 1H NMR
(300 MHz, CDCl3): δ = 7.23–7.10 (m, 2 H, Ar), 6.86–6.71 (m, 3 H,
Ar and NH), 5.37–5.25 (m, 1 H, CHCH2), 3.94 (q, J = 7.1 Hz, 2
H, CH2CH3), 3.22 (s, 3 H, OCH3), 2.90–2.64 (m, 2 H, CHCH2),
1.92 (s, 3 H), 1.17 (t, J = 7.1 Hz, 3 H, CH2CH3) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 171.0, 169.0, 158.8, 132.6, 127.4, 113.8,
Synthesis of N-[1-(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-
ethyl]acetamide (25): A mixture of acetonitrile (18 mmol) and
methanol (18 mmol) was cooled to 0 °C, and a solution of HCl in
diethyl ether (c = 2 mol/L, 30 mmol, 15 mL) was added under ar-
gon. Colourless crystals were obtained at –30 °C after 2 d. The
crystals of methyl acetimidate hydrochloride were washed with di-
ethyl ether and dried in vacuo. Triethylamine (18.5 mmol) was
added to a well-stirred suspension of methyl acetimidate hydrochlo-
ride (9.12 mmol) in CH2Cl2 (20 mL) at room temperature. The mix-
ture was cooled to –15 °C, and acetyl chloride (9.12 mmol) in
CH2Cl2 (5 mL) was added dropwise. The solution was stirred at
room temperature for 20 h, then charged with an additional
amount of triethylamine (10 mmol) and cooled to 0 °C. A solution
of Meldrum’s acid (9.12 mmol) in CH2Cl2 (10 mL) was added, and
the mixture was heated at reflux for 20 h. The solution was washed
with water and brine, dried with Na2SO4, and the crude product
was purified by column chromatography (eluent: ethyl acetate/n-
hexane, 1:1 to 4:1). M.p. 119–120 °C. 1H NMR (300 MHz, CDCl3):
δ = 12.79 (br., 1 H, NH), 3.06 (s, 3 H), 2.30 (s, 3 H), 1.71 (s, 6 H)
60.5, 55.1, 49.1, 40.1, 23.1, 13.9 ppm. IR (ATR): ν = 3277 (w), 3066
˜
(w), 2981 (w), 2936 (w), 2837 (w), 1731 (m), 1646 (m), 1612 (m),
1586 (w), 1543 (m), 1512 (s), 1464 (w), 1443 (w), 1371 (m), 1296
(m), 1245 (s), 1176 (s), 1113 (m), 1094 (m), 1029 (s), 960 (w), 831
(m), 733 (w) cm–1. MS (ES, 70 eV): m/z (%) = 265 (3) [M]+, 222
(100), 178 (25), 136 (78), 132 (12), 91 (10). HRMS: calcd. for
C14H19NO4 265.13086; found 265.131602. Chiralpak AD-H; elu-
ent: n-heptane/ethanol, 90:10; flow rate 0.8 mL/min; retention time:
(+)-19a 13.4 min, (–)-19a 17.0 min.
Ethyl 3-Acetamido-3-(2-methoxyphenyl)propanoate (20a): M.p. 90–
1
96 °C. H NMR (300 MHz, CDCl3): δ = 7.23–7.11 (m, 2 H, Ar),
6.88–6.78 (m, 2 H, Ar), 6.74 (d, J = 8.8 Hz, 1 H, NH), 5.57–5.46
(m, 1 H, CHCH3), 3.92 (q, J = 7.1 Hz, 2 H, CH2CH3), 3.81 (s, 3
H, OCH3), 2.90–2.67 (m, 2 H, CHCH2), 1.92 (s, 3 H, COCH3),
1.07 (t, J = 7.1 Hz, 3 H, CH2CH3) ppm. 13C NMR (75.5 MHz,
ppm. 13C NMR (75.5 MHz, CDCl3): δ = 173.1, 169.7, 166.0, 161.4, CDCl3): δ = 171.2, 168.8, 156.8, 128.8, 128.6, 127.9, 120.6, 101.7,
103.5, 93.6, 26.8, 26.3, 19.6 ppm. IR (KBr): ν = 3432 (m), 3008
60.4, 55.3, 47.7, 39.3, 23.5, 14.0 ppm. IR (KBr): ν = 3285 (m), 3081
˜
˜
(m), 2994 (m), 2328 (w), 1750 (s), 1720 (s), 1677 (s), 1590 (s), 1458
(w), 2988 (w), 2963 (w), 2842 (w), 2160 (w), 2026 (w), 1976 (w),
(m), 1394 (m), 1385 (m), 1366 (m), 1349 (s), 1278 (s), 1246 (s), 1193 1732 (s), 1647 (s), 1601 (w), 1589 (w), 1553 (m), 1489 (m), 1466
(s), 1146 (m), 1072 (m), 1031 (m), 1009 (m), 945 (w), 927 (m), 897 (m), 1440 (m), 1390 (m), 1372 (m), 1298 (m), 1263 (m), 1239 (s),
(m), 862 (m), 799 (m), 728 (m), 650 (m), 614 (w), 600 (w), 572 (w), 1225 (m), 1175 (s), 1163 (s), 1134 (m), 1100 (m), 1072 (m), 1052
496 (m), 449 (m), 433 (m) cm–1. MS (ES, 70 eV): m/z (%) = 227 (2) (m), 1025 (s), 967 (w), 928 (w), 868 (m), 800 (m), 779 (m), 767 (s),
[M]+, 169 (80), 151 (20), 141 (24), 128 (43), 97 (45), 83 (47), 59 754 (m), 707 (m), 657 (m) cm–1. MS (ES, 70 eV): m/z (%) = 265 (7)
Eur. J. Org. Chem. 2008, 3352–3362
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3359

M. Beller et al.
FULL PAPER
[M]+, 222 (100), 178 (16), 136 (62). HRMS: calcd. for C14H19NO4
265.13086; found 265.131285. Chiralpak AD-H; eluent: n-heptane/
1.5 Hz, C-4,4Ј), 129.8 (C-1,1Ј or 3,3Ј or i,iЈ), 129.1 (C-1,1Ј or 3,3Ј
or i,iЈ), 129.1 (d, J = 1.5 Hz, C-1,1Ј or 3,3Ј or i,iЈ), 113.7 (m,mЈ),
ethanol, 95:5; flow rate 1.0 mL/min; retention time: (+)-20a 113.4 (m,mЈ), 101.5 (d, J = 19.0 Hz, cod-CH), 101.3 (d, J =
30.2 min, (–)-20a 41.3 min.
19.3 Hz, cod-CH), 55.4 (OCH3), 55.3 (OCH3), 52.5 (d, J = 1.9 Hz,
cod-CH), 52.0 (d, J = 2.2 Hz, cod-CH), 36.3 [d, J = 9.3 Hz,
N(CH3)2], 33.7 (d, J = 3.8 Hz, cod-CH2), 33.6 (d, J = 3.2 Hz, cod-
CH2), 29.3 (C-5,5Ј), 29.2 (C-5,5Ј), 28.7 (“t”, J = 2.5 Hz, cod-CH2),
27.6 (C-8,8Ј), 27.5 (C-8,8Ј), 22.9, 22.8, 22.8, 22.7 (C-6,6Ј,7,7Ј) ppm.
Ethyl 3-Acetamido-3-(4-fluorophenyl)propanoate (21a): 1H NMR
(400 MHz, CDCl3): δ = 7.29–7.24 (m, 2 H, Ar), 7.06–7.02 (m, 2 H,
Ar), 6.74 (d, J = 8.2 Hz, 1 H, NH), 5.44 (m, 1 H, CH), 4.11 (q, J
= 7.2 Hz, 2 H, CH2CH3), 2.87 (m, 2 H, CHCH2), 2.05 (s, 3 H,
COCH3), 1.21 (t, J = 7.2 Hz, 3 H, CH2CH3) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 171.1, 169.5, 162.1 (d, J = 246 Hz), 136.5
(d, J = 3.2 Hz), 128.1 (d, J = 8.0 Hz), 115.4 (d, J = 21.5 Hz), 60.8,
31P NMR (121.5 MHz, CDCl ): δ = 110.3 ppm. IR (ATR): ν =
˜
3
3033 (w), 3001 (w), 2930 (w), 2879 (w), 2833 (w), 1609 (m), 1514
(m), 1433 (m), 1399 (w), 1287 (m), 1245 (s), 1223 (m), 1176 (s),
1156 (m), 1135 (m), 1110 (w), 1063 (m), 1034 (m), 991 (s), 945 (s),
913 (w), 873 (w), 828 (s), 803 (s), 780 (m), 738 (m), 723 (m), 667
(m) cm–1. MS (EI): m/z (%) = 915 (8) [M]+, 807 (16), 579 (100),
536 (29), 518 (11), 267 (17), 246 (22), 97 (14), 83 (15), 69 (24), 57
(26). HRMS: calcd. for C44H50ClIrNO4P 915.27897; found
915.276327.
49.1, 40.1, 23.3, 14.0 ppm. IR (capillary film): ν = 3279 (s), 3069
˜
(m), 2983 (m), 2936 (m), 2873 (w), 1892 (w), 1732 (s), 1651 (s),
1606 (m), 1548 (s), 1512 (s), 1434 (m), 1373 (s), 1301 (s), 1225 (s),
1160 (s), 1097 (m), 1026 (m), 964 (w), 838 (s), 749 (w), 727 (m),
654 (w), 604 (m), 555 (m), 474 (m) cm–1. MS (ES, 70 eV): m/z (%)
= 253 (4) [M]+, 210 (100), 179 (10), 166 (17), 149 (20), 137 (23), 124
(65), 97 (7), 75 (5), 43 (20), 29 (7). HRMS: calcd. for C13H16FNO3
253.11087; found 253.111388. Chiralpak AD-H; eluent: n-hexane/
ethanol, 95:5; flow rate 1.0 mL/min; retention time: (+)-21a
32.8 min, (–)-21a 36.7 min.
Ethyl 3-Acetamido-3-(4-methylphenyl)propanoate (22a): 1H NMR
(300 MHz, CDCl3): δ = 7.20–7.07 (m, 4 H, Ar), 6.55 (d, J = 8.1 Hz,
1 H, NH), 5.37 (m, 1 H, CH), 4.19 (q, J = 7.1 Hz, 2 H, CH2CH3),
2.95 (m, 2 H, CHCH2), 2.30 (s, 3 H, ArCH3), 1.99 (s, 3 H, COCH3),
1.16 (t, J = 7.1 Hz, 3 H, CH2CH3) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 171.3, 169.2, 137.5, 137.2, 129.3, 128.6, 126.2, 60.7,
49.3, 39.9, 23.4, 21.0 ppm. IR (ATR): ν = 3276 (w), 3056 (w), 2981
˜
(w), 2930 (w), 2871 (w), 1733 (s), 1648 (s), 1542 (m), 1515 (m), 1444
(w), 1370 (m), 1293 (m), 1263 (m), 1162 (s), 1115 (m), 1095 (m),
1023 (m), 964 (w), 845 (w), 817 (m), 722 (m) cm–1. MS (ES, 70 eV):
m/z (%) = 249 (4) [M]+, 206 (100), 160 (14), 145 (10), 133 (17),
120 (52), 91 (15). HRMS: calcd. for C14H19NO3 249.13594; found
249.136208. Chiralpak AD-H; eluent: n-heptane/ethanol, 92:8, flow
rate 0.5 mL/min; retention time: (+)-22a 19.5 min, (–)-22a
23.9 min.
Acknowledgments
We thank Dr. R. Jackstell, Mrs. M. Heyken, Mrs. S. Buchholz,
Mrs. K. Reincke, Mrs. S. Schareina, Mrs. B. Friedrich and Dr. C.
Fischer (all Leibniz-Institut für Katalyse e.V. an der Universität
Rostock) for excellent technical and analytical assistance. In ad-
dition, we thank Dr. A. Köckritz, Dr. A. Pews-Davtyan and Dr.
N. Nemati (all Leibniz-Institut für Katalyse e.V. an der Universität
Rostock, Außenstelle Berlin) for general discussions. Generous fin-
ancial support from the state of Mecklenburg-Western Pomerania
and the Bundesministerium für Bildung und Forschung (BMBF)
as well as the Deutsche Forschungsgemeinschaft (Leibniz prize) is
gratefully acknowledged.
Methyl 3-Acetamido-3-phenylpropanoate (23a): Chiralcel OD-H; n-
heptane/ethanol, 95:5; flow rate 1.0 mL/min; retention time: (R)-
23a 15.5 min, (S)-23a 23.9 min.
Iridium Complex of Ligand 5c: [Ir(cod)Cl]2 (0.15 mmol) was dis-
solved in CH2Cl2 (1.0 mL) and the mixture stirred at room tem-
perature for 10 min. The solvent and all volatiles were removed in
vacuo. A solution of (S)-4-(dimethylamino)-2,6-bis(4-methoxy-
phenyl)-8,9,10,11,13,14,15-octahydrodinaphtho[2,1-d:1Ј,2Ј-f][1,3,2]-
dioxaphosphepine (5c) (0.15 mmol) was added, and the orange
mixture was stirred overnight. The solution was filtered, and the
solvent was removed in vacuo to afford an orange residue. Yield:
94%. [α]2D2 = 329.8 (c = 0.2, CH2Cl2). 1H NMR (300 MHz, CDCl3):
δ = 7.68 (m, 2 H, o-C6H4), 7.47 (m, 2 H, o-C6H4), 7.26 (br. s, 1 H,
4-H), 7.13 (br. s, 1 H, 4Ј-H), 6.97–6.89 (m, 4 H, m,mЈ-C6H4), 4.99
(m, 1 H, cod-CH), 4.90 (m, 1 H, cod-CH), 3.83 (s, 3 H, OCH3),
3.80 (s, 3 H, OCH3), 3.37 (m, 1 H, cod-CH), 2.86 (m, 4 H, 5,5Ј-
H), 2.70–2.66 (m, 2 H, 8,8Ј-H), 2.46–2.27 (m, 2 H, 8,8Ј-H; m, 1 H,
cod-CH), 2.12 [d, J = 10.8 Hz, 6 H, N(CH3)2], 2.12–2.00 (m, 3 H,
cod-CH2), 1.95–1.75 (m, 6 H, 6,6Ј,7,7Ј-H; m, 2 H, cod-CH2), 1.70–
1.55 (m, 2 H, 6,6Ј,7,7Ј-H; m, 2 H, cod-CH2) ppm. 13C NMR
(75.5 MHz, CDCl3): δ = 159.2 (p,pЈ), 158.8 (p,pЈ), 144.3 (d, J =
11.5 Hz, C-2,2Ј), 144.1 (d, J = 5.0 Hz, C-2,2Ј), 136.8 (d, J = 1.5 Hz,
C-8a,8aЈ), 136.23 (d, J = 1.8 Hz, C-8a,8aЈ), 134.3 (d, J = 1.5 Hz,
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(C-1,1Ј or 3,3Ј or i,iЈ), 130.0 (d, J = 1.2 Hz, C-4,4Ј), 129.8 (d, J =
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FULL PAPER
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DIOP or Ph-Binepine (2.0 mol-%) was utilized with 1.0 mol-%
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50 bar at 25 °C for 24 h. In the case of the ruthenium catalyst
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[23] Other bidentate ligands were tested in the hydrogenation of 26.
Use of 1.0 mol-% of [Ir(cod)Cl]2 and 2.0 mol-% of ligand (for
example: Me-DuPhos, BINAP, DIOP, BPPM, catASium M,
Ferrotane, ChiraPhos or Ph-Binepine) in CH2Cl2 (2.0 mL) un-
der a hydrogen pressure of 2.5 bar at 25 °C for 24 h showed
no activity. Also no reactivity was observed with rhodium or
ruthenium catalysts. Here, 1.0 mol-% of Me-DuPhos, BINAP,
Received: March 3, 2008
Published Online: May 13, 2008
3362
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Eur. J. Org. Chem. 2008, 3352–3362