Highly enantioselective hydrogenation of enamides catalyzed by rhodium-monodentate phosphoramidite complex

Article abstract of DOI:10.1016/S0040-4039(02)01142-5

The monodentate phosphoramidite ligand monophos was used in the Rh-catalyzed asymmetric hydrogenation of enamides to give high enantioselectivities (up to 96% ee).

Full text of DOI:10.1016/S0040-4039(02)01142-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5541–5544
Highly enantioselective hydrogenation of enamides catalyzed by
rhodium–monodentate phosphoramidite complex
Xian Jia,a,b Rongwei Guo,a Xingshu Li,a Xinsheng Yaob and Albert S. C. Chana,*
aOpen Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis† and
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
bShenyang Pharmaceutical University, Shenyang, China
Received 11 April 2002; revised 6 June 2002; accepted 13 June 2002
Abstract—The monodentate phosphoramidite ligand monophos was used in the Rh-catalyzed asymmetric hydrogenation of
enamides to give high enantioselectivities (up to 96% ee). © 2002 Published by Elsevier Science Ltd.
Optically active amines and amides are useful resolving
agents, chiral auxiliaries and intermediates for the syn-
thesis of biologically active compounds.1 Traditional
methods for the synthesis of these valuable compounds
include fermentation, optical resolution and the use of
chiral starting materials. From a practical standpoint,
the asymmetric catalytic hydrogenation of enamides is
a convenient and economical route for the preparation
of chiral amides or amine derivatives. However, com-
pared with the great success made in the synthesis of
chiral amino acids and their derivatives through asym-
metric hydrogenation in the past three decades, success-
ful examples of the asymmetric hydrogenation of
enamides without the carboxyl functionality are much
less abundant. For example, the well-known rhodium
and ruthenium chiral diphosphine complexes, such as
Rh(BINAP), Rh(chiraphos), Rh(DIOP) and Ru-
(BINAP) afforded poor enantioselectivities in the asym-
metric hydrogenation of enamides. In 1996, Burk et al.
reported an important advance in the enantioselective
hydrogenation of arylenamides with Rh catalysts con-
taining Duphos and BPE ligands.2a Recently, several
reports of effective systems for the enantioselective
hydrogenation of enamides have been published.2b–d In
this paper, we report a highly active and enantioselec-
tive catalyst for this useful reaction.
Many phosphorus compounds are important ligands
for the preparation of catalysts used in transition metal-
catalyzed reactions.2e–g A large number of chiral phos-
phorus ligands with excellent enantioselectivity have
been designed and applied in asymmetric hydrogena-
tion.3–16 Previous studies involved mostly chiral biden-
tate ligands because of the seemingly important
chelating effect. Recently, Reetz17 and Feringa18
described a highly enantioselective Rh catalyst contain-
ing chiral monodentate phosphoramidite ligands for the
asymmetric hydrogenation of dehydroamino acid and
itaconic acid derivatives. Pringle19 and co-workers
applied a monodentate phosphonite ligand in the Rh-
catalyzed hydrogenation of methyl 2-acetamidoacryl-
ate. Herein, we report the application of the
monodentate phoshoramidite ligand 2,2%-O,O%-(1,1%-
binaphthyl) - O,O% - dioxo - N,N - dimethylphospholidine
(monophos)18 in the Rh-catalyzed asymmetric hydro-
genation of enamides.
N-(1-Phenylethenyl)acetamide 1, an enamide easily pre-
pared by the reduction of the corresponding oxime with
iron powder in the presence of acetic anhydride,20 was
chosen as a model substrate in the initial study (Scheme
1). The preliminary results showed that the catalyst was
highly effective and quantitative conversions were
observed in all reactions.21 Changes in hydrogen pres-
sure had little effect on enantioselectivity (entries 6–8,
Table 1). However, changing the solvent from CH2Cl2
to THF, MeOH, EtOAc and acetone reduced the ee
value of the product from 87 to 75, 67, 70 and 72%,
respectively (entries 1–5). Temperature was also an
important factor. Using dichloromethane as solvent, a
significant increase in enantioselectivity was observed
when the reaction temperature was decreased. The ee
Keywords: asymmetric hydrogenation; enamides; rhodium complex;
monophos.
* Corresponding author. Tel.: +852-27665607; e-mail: bcachan@
polyu.edu.hk
† University Grants Committee Area of Excellence Scheme (Hong
Kong).
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01142-5

5542
X. Jia et al. / Tetrahedron Letters 43 (2002) 5541–5544
reached a plateau at a reaction temperature of −20°C.
Further decrease in temperature did not give any fur-
ther enhancement in enantioselectivity. Under optimum
conditions, 95% ee was obtained (entry 10).
A variety of substrates were investigated (Scheme 2)
and high enantioselectivities and good conversions were
achieved in most cases (entries 1–4, 8, Table 2). How-
ever, the conversion rates for substrates 5 and 6 were
Rh + L*
NHAc
O
NHAc
+
H2
P
N
O
1
L* = Monophos
Scheme 1.
Table 1. Asymmetric hydrogenation of enamide 1 catalyzed by rhodium–monophos complexa
Entry
Solvent
H2 (psi)
Temperature (°C)
t (h)
ee (%)b
1
2
3
4
5
6
7
8
THF
300
300
300
300
300
200
500
700
300
300
300
300
rt
rt
rt
rt
rt
rt
rt
rt
1
1
1
1
1
1
1
1
75
87
70
67
72
87
85
85
90
95
95
95
CH2Cl2
EtOAc
MeOH
Acetone
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9
0
1.5
3
6
10
11
12
−20
−30
−40
6
a A typical procedure for the catalytic reaction is shown at the end of this paper;21 quantitative yields were observed in all reactions.
b The ee’s were determined by chiral GC analysis using a Chrompack chiral fused silical 50 m×0.25 mm chirasil-L-VAL column. The S
configuration was assigned by comparing the experimental results with published data.
R
CH2R
[ Rh(S-monophos)(COD)]BF4
H2
Ar
NHCOCH3
Ar
NHCOCH3
1: Ar = C6H5
R = H
R = H
R = H
R = H
R = H
R = CH3
R = H
R = H
R = H
2: Ar = p-CH3-C6H4
3: Ar = p-CH3O-C6H4
4: Ar = p-CF3-C6H4
5: Ar = 1-naphthyl
6: Ar = C6H5
7: Ar = p-Br-C6H5
8: Ar = m-CH3OC6H5
9: Ar = m-CH3C6H5
NHAc
NHAc
[ Rh(S-monophos)(COD)]BF4
H2
10
Scheme 2.

X. Jia et al. / Tetrahedron Letters 43 (2002) 5541–5544
5543
Table 2. Asymmetric hydrogenation of enamides catalyzed by rhodium–monophosa
Entry
Substrate
S/C (mol/mol)
Temperature (°C)
t (h)
Yield (%)
ee (%)b
1
2
3
4
5
6
7
8
1
2
3
4
5
5
6
7
8
100
100
100
100
50
−20
−20
−20
−20
rt
−20
−20
−20
−20
−20
−20
rt
8
8
8
6
6
18
18
8
8
8
\99
\99
\99
\99
\99
20
95
92
90
96
55
70
89
96
96
93
84
57
50
100
100
100
100
100
100
25
\99
\99
\99
\99
\99
9
10
11
12
9
10
10
10
2
a Hydrogen pressure was 300 psi in all reactions.
b The ee’s were determined by chiral GC analysis using a Chrompack chiral fused silical 50 m×0.25 mm chirasil-
L
-VAL column.
low (entries 6–7), probably due to the steric hindrance
effect of the substituents. The results demonstrated that
by using this simple rhodium–monophos catalyst, a-
aryl enamides can be easily hydrogenated to give the
desired products in high ee’s. Electron-withdrawing
groups at the para position of the phenyl ring of the
substrate enhanced the enantioselectivity (entry 4);
while electron-donating groups gave a negative effect
(entries 2–3). A naphthyl group on the substrate caused
decreases in both the reaction rate and the enantioselec-
tivity, probably due to its size (entry 5).
Org. Lett. 1999, 1, 1679; (e) Claver, C.; Fernandez, E.;
Gillon, A.; Heslop, K.; Hyett, D. J.; Martorell, A.;
Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 961;
(f) Chaloner, P. A.; Esteruelas, M. A.; Joo´, F.; Oro, L. A.
Homogeneous Hydrogenation; Kluwer: Dordrecht, 1994;
(g) Brown, J. M. In Comprehensive Asymmetric Catalysis;
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Springer: Berlin, 1999; Vol. 1, Chapter 5.1.
3. (a) Dang, T.-P.; Kagan, H. B. J. Chem. Soc., Chem.
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Am. Chem. Soc. 1972, 94, 6429.
4. (a) Zhang, X. Enantiomer 1999, 4, 541; (b) Noyori, R.
Asymmetric Catalysis in Organic Synthesis; Wiley & Sons:
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In conclusion, chiral monophos ligand (S)-2,2%-O,O%-
(1,1%-binaphthyl)-O,O%-dioxo-N,N-dimethylphospho-
lidine was found to be an effective ligand for the
Rh-catalyzed asymmetric hydrogenation of enamides.
The preparation of other effective monodentate ligands
and their application in the asymmetric hydrogenation
of enamides are in progress.
5. (a) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.;
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Acknowledgements
We thank the Hong Kong Research Grants Council
(Project No. ERB03), The University Grants Commit-
tee of Hong Kong (Areas of Excellence Scheme, AOE
P/10-01) and the Hong Kong Polytechnic University
ASD Fund for the financial support of this study.
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