Readily available phosphine-phosphoramidite ligands for highly efficient Rh-catalyzed enantioselective hydrogenations

Article abstract of DOI:10.1021/ol0617749

(Chemical Equation Presented) A new family of air- and moisture-stable phosphine-phosphoramidite ligands (PEAPhos) has been prepared from commercially available and inexpensive (S)-α-phenylethylamine through a two- or three-step transformation and success

Full text of DOI:10.1021/ol0617749

ORGANIC
LETTERS
2
006
Vol. 8, No. 19
367-4370
Readily Available
Phosphine Phosphoramidite Ligands for
4
−
Highly Efficient Rh-Catalyzed
Enantioselective Hydrogenations
†
,‡
,†
†,‡
†,‡
Jia-Di Huang, Xiang-Ping Hu,* Zheng-Chao Duan, Qing-Hen Zeng,
†,‡
†,‡
†,‡
,†
Sai-Bo Yu, Jun Deng, Dao-Yong Wang, and Zhuo Zheng*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences,
57 Zhongshan Road, Dalian 116023, China, and Graduate School of Chinese
4
Academy of Sciences, Beijing 100039, China
zhengz@dicp.ac.cn
Received July 19, 2006
ABSTRACT
A new family of air- and moisture-stable phosphine
inexpensive (S)- -phenylethylamine through a two- or three-step transformation and successfully applied in the rhodium-catalyzed enantioselective
hydrogenations of a variety of substrates, in which up to 99.9% ee was obtained for all of these kinds of substrates.
−phosphoramidite ligands (PEAPhos) has been prepared from commercially available and
r
The catalytic asymmetric hydrogenation is one of the most
powerful tools for obtaining a wide range of enantiomerically
pure or enriched compounds. Although great progress has
scope, (2) the ability to operate at low levels of catalyst for
a range of substrates, (3) the ability to operate under a low
H pressure, (4) and a direct and simple ligand synthesis,
2
1
been made by use of a variety of bidentate P-chelate ligands
in past decades and monodentate phosphorus ligands more
recently, the need to develop new and unique phosphorus-
containing ligands with properties superior to their predeces-
sors remains. The minimum criteria for an optimum Rh-
catalytic system include the following: (1) a broad substrate
with the starting material being inexpensive or readily
available from single step synthesis. Moreover, it is most
desirable to develop protocols for the whole process that do
not necessitate the use of a glovebox, including the ligand
synthesis. However, many bidentate P-chelate ligands re-
ported so far suffered from either a lengthy synthesis or the
use of an expensive chiral starting material, and some of
them have poor thermal and air stability. These shortcomings
have seriously prevented their practical application in asym-
metric catalysis. Therefore, exploring the new catalytic
system to overcome these drawbacks and fulfill the above
criteria is an important, but still difficult task for chemists.
In the present work, we report a new class of modular
phosphine-phosphoramidite ligands, which can be easily
2
†
Dalian Institute of Chemical Physics.
Graduate School of Chinese Academy of Sciences.
‡
(1) For recent reviews, see: (a) Brown, J. M. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, Germany, 1999; p 121. (b) Ohkuma, T.; Kitamura, M.;
Noyori, R. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-
Interscience: New York, 2000; p 1.
(2) For reviews, see: (a) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler,
F.; Steiner, H.; Studer, M. Adv. Synth. Catal. 2003, 345, 103. (b) Tang,
W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
1
0.1021/ol0617749 CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/22/2006

3
prepared through a two- or three-step transformation from
the commercially available and inexpensive chiral R-phen-
ylethylamine (R-PEA). These phosphine-phosphoramidite
ligands (abbreviated as PEAPhos, meaning PhenylEthyl-
Amine derived Phosphine) are air-stable and can be exposed
to the air for several months without any changes in their
chiral ligand precursor for many asymmetric reactions, its
o-diphenylphosphino-substituted derivative, (S)-1-[2-(diphen-
ylphosphino)phenyl]ethylamine [(S)-DPPNH 3], has never
2
been explored to construct chiral ligands, to the best of our
knowledge, probably due to its difficult synthesis. Since (S)-
DPPNH 3 is a key intermediate to prepare the targeted
2
phosphine-phosphoramidite ligands 1, developing an ef-
ficient and direct method from R-phenylethylamine to
1
31
H or P NMR spectra and any loss in the catalytic activity
and enantioselectivity. PEAPhos proved to be highly efficient
for the rhodium-catalyzed enantioselective hydrogenation of
a wide range of substrates, including R-dehydroamino acid
esters, enamides, and dimethyl itaconate, in which up to
manufacture (S)-DPPNH
objective. One of the most direct ways to prepare (S)-
DPPNH 3 would be based on the direct ortho-lithiation of
2
3 becomes a timely and important
2
9
9.9% ee was obtained for all of these kinds of substrates,
R-phenylethylamine, followed by diphenylphosphination.
Although the N,N-dimethylamino group is commonly used
as an ortho-directing group for metalation of aromatic rings,4
direct use of primary amines for such a transformation was
comparable to the most efficient ligands reported so far.
5
much less explored. Polniaszek et al. have reported 1-(2-
chlorophenyl)ethylamine or 1-(2,6-dichlorophenyl)ethylamine
could be prepared from R-phenylethylamine via ortho-
lithiation directed by the in situ-generated N-lithiosilylamine.6
On the basis of Polniaszek’s procedure, we successfully
prepared (S)-DPPNH 3 from R-phenylethylamine by a direct
2
and experimentally convenient one-pot protocol.
The treatment of (S)-R-phenylethylamine with n-BuLi at
35 °C, followed by slow addition of neat Me SiCl
3
-
generated the monosilylated product, N-(trimethylsilyl)-1-
7
phenylethylamine. The latter was dilithiated by further
addition of 3 equiv of n-BuLi at -35 °C and then ortho-
phosphinated with chlorodiphenylphosphine. Following work-
Figure 1. Readily available phosphine-phosphoramidite ligands,
PEAPhos 1a-d.
up and crystallization, (S)-DPPNH
overall yields. By the treatment with HCOOC
C and then followed by the reduction with LiAlH
S)-DPPNH 3 was monomethylated to form (S)-DPPNHMe
in 52% yields. The resulting (S)-DPPNH 3 and (S)-
2
3 was produced in 40%
at 40-50
in THF,
2 5
H
PEAPhos 1a-d were conveniently prepared in a short
synthetic procedure from the chiral R-phenylethylamine,
which is outlined in Scheme 1. R-Phenylethylamine is one
°
(
4
4
2
2
DPPNHMe 4 can be easily converted into the corresponding
phosphine-phosphoramidite ligands in good yields by the
reaction with (R)- or (S)-BINOL-derived chlorophosphite 5
Scheme 1. Synthesis of Key Intermediates (S)-DPPNH
S)-DPPNHMe 4 and Targeted PEAPhos 1a-d
2
3 and
(
3
in toluene at 0 °C in the presence of 3 equiv of Et N as a
scavenger for HCl eliminated. These PEAPhos ligands 1 are
air- and moisture-stable and can be used in open air, which
make these ligands highly practical for general laboratory
preparations as well as scale-up operations.
In the first set of experiments, we used the Rh-catalyzed
asymmetric hydrogenation of a variety of methyl (Z)-
acetamidocinnamates 6 to benchmark the potential of this
class of new phosphine-phosphoramidite ligands in the
2
asymmetric catalysis. Hydrogenation was conducted in CH -
(3) (a) Juaristi, E.; Escalante, J.; Le o´ n-Romo, J. L.; Reyes, A. Tetrahe-
dron: Asymmetry 1998, 9, 715. (b) Juaristi, E.; Le o´ n-Romo, J. L.; Reyes,
A.; Escalante, J. Tetrahedron: Asymmetry 1999, 10, 2441.
(
4) (a) Gschwend, H. W.; Rodriguez, H. R. Org. React. (N.Y.) 1979, 26,
1
. (b) Hayashi, T.; Mise, T.; Fukushima, M.; Kagotani, M.; Nagashima,
N.; Hamada, Y.; Matsumoto, A.; Kawakami, S.; Konishi, M.; Yamamoto,
K.; Kumada, M. Bull. Chem. Soc. Jpn. 1980, 53, 1138. (c) Almena Perea,
J. J.; B o¨ rner, A.; Knochel, P. Tetrahedron Lett. 1998, 39, 8073. (d) Ireland,
T.; Grossheimann, G.; Wieser-Jeunesse, C.; Knochel, P. Angew. Chem.,
Int. Ed. 1999, 38, 3212.
(5) (a) Liu, D.; Tang, W.; Zhang, X. Org. Lett. 2004, 6, 513. (b) Liu,
D.; Dai, Q.; Zhang, X. Tetrahedron 2005, 61, 6460.
of the most typical nonnatural-type chiral compounds, and
both its enantiomers are readily available commercially at a
low price. Although R-PEA has been extensively used as a
(6) (a) Polniaszek, R. P.; Kaufman, C. R. J. Am. Chem. Soc. 1989, 111,
4
859. (b) Polniaszek, R. P.; Lichti, C. F. Synth. Commun. 1992, 22, 171.
7) Burns, S. A.; Corriu, R. J. P.; Huynh, V.; Moreau, J. J. E. J.
Organomet. Chem. 1987, 333, 281.
(
4368
Org. Lett., Vol. 8, No. 19, 2006

Cl
the presence of 1.0 mol % of catalyst prepared in situ from
Rh(COD) BF and 1.1 equiv of PEAPhos 1. The results are
summarized in Table 1. (S ,R )-PEAPhos 1a and 1b with a
2
at room temperature under a H
2
pressure of 10 bar in
hydrogenation product.8,9 Solvent screening indicated that
the solvent had a great effect on the enantioselectivity and
CH Cl proved to be the best solvent in terms of enantiose-
2
4
2
2
4
c
a
lectivity (entries 4-7).
Hydrogenation of a series of substituted R-dehydroamino
acid esters 6b-e was then performed in CH Cl by use of
(S ,S )-PEAPhos 1d. The results revealed that there is no
2
2
Table 1. Rh-Catalyzed Asymmetric Hydrogenation of
R-Dehydroamino Acid Esters 6a
c
a
major effect on the substitution pattern of R-dehydroamino
acid derivatives, and all of the substrates were hydrogenated
in excellent enantioselectivity with full conversions (entries
8
-11). Thus, all of the tested substrates were hydrogenated
in over 99% ee and the best result was obtained in the
hydrogenation of 2-methoxy-substituted substrate 6d, af-
fording the hydrogenation product in over 99.9% ee (entry
c a
10). To demonstrate the efficiency of the catalyst Rh/(S ,S )-
PEAPhos 1d, the hydrogenation of 6a was also carried out
with the reduced catalyst loadings as low as 0.01 mol %
Rh
ee %b
(config)
entry
ligand
substrate solvent (mol %)
(S/C ) 10 000), affording the corresponding amino acid
1
2
3
4
5
6
7
8
9
0
1
2
3
(Sc,Ra)-1a
(Sc,Ra)-1b
(Sc,Sa)-1c
(Sc,Sa)-1d
(Sc,Sa)-1d
(Sc,Sa)-1d
(Sc,Sa)-1d
(Sc,Sa)-1d
(Sc,Sa)-1d
(Sc,Sa)-1d
(Sc,Sa)-1d
(Sc,Sa)-1d
(Sc,Sa)-1d
6a
6a
6a
6a
6a
6a
6a
6b
6c
6d
6e
6a
6a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
MeOH
EtOAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.02
0.01
17.3 (R)
48.5 (R)
98.1 (R)
99.1 (R)
80.1 (R)
93.5 (R)
92.3 (R)
99.6 (R)
99.0 (R)
>99.9 (R)
99.7 (R)
99.0 (R)
98.8 (R)
derivative 7a in full conversions without loss of enantiose-
lectivity (entry 13).
For the hydrogenation of enamide substrates 8, the Rh
catalyst composed of PEAPhos was also particularly effec-
tive, and the results are summarized in Table 2. With the
exception of (S
high enantioselectivity in the hydrogenation of N-(1-phen-
ylethenyl)acetamide 8a. It is very strange that (S ,R )-1a,
c a
,R )-1b, all of the PEAPhos ligands showed
c
a
1
1
1
1
which proved to have unmatched chiral elements and
displayed very low enantioselectivity in the hydrogenation
of R-dehydroamino acid esters, unexpectedly gave a hydro-
c a
genation product in 95.9% ee (entry 1). Again, (S ,S )-1d
a
Reactions were performed in 3 mL of solvent with 0.5 mmol of
exhibited the highest enantioselectivity in up to 99.5% ee
(entry 4). Under the optimized reaction conditions as used
in the hydrogenation of R-dehydroamino acid esters, various
enamide substrates could be hydrogenated with the catalysis
substrates and 1 mol % of catalyst prepared in situ from Rh(COD)2BF4
and 1.1 equiv of PEAPhos 1 at room temperature and a H2 pressure of 10
bar for 12 h. Full conversions were achieved in all reactions. Enantiomeric
excesses were determined by GC, using a CP-Chiralsil-L-Val capillary (0.25
mm × 30 m) column. The absolute configuration was determined by
comparing the GC retention times with GC data in the literature.
b
c a
of Rh/(S ,S )-1d to afford the corresponding R-phenylethyl-
amine derivatives with extremely high enantiomeric excess
values. The substituted group in the phenyl ring of enamide
substrates had little impact on the enantioselectivity of the
reaction, and all of the substituted N-(1-phenylethenyl)-
a
(R )-binaphthyl moiety proved to be inferior ligands and
induced a very low ee (17.3% ee and 48.5% ee, respectively)
in this transformation (entries 1 and 2). In sharp contrast,
c a a
(S ,S )-PEAPhos 1c with a (S )-binaphthyl moiety exhibited
(
8) For review of asymmetric hydrogenation with monophosphoramidite
a significantly high enantioselectivity in 98.1% ee (entry 3).
This result indicated that the absolute configuration of
PEAPhos strongly influenced the enantioselectivity of the
ligands, see: (a) Jerphagnon, T.; Renaud, J.-L.; Bruneau, C. Tetrahedron:
Asymmetry 2004, 15, 2101. For some recent examples of asymmetric
hydrogenation with monophosphoramidite ligands, see: (b) Peng, H.-Y.;
Lam, C.-K.; Mak, T. C. W.; Cai, Z.; Ma, W.-T.; Li, Y.-X.; Wong, H. N. C.
J. Am. Chem. Soc. 2005, 127, 9603. (c) Liu, Y.; Ding, K. J. Am. Chem.
Soc. 2005, 127, 10488. (d) Hoen, R.; Boogers, J. A. F.; Bernsmann, H.;
Minnaard, A. J.; Meetsma, A.; Tiemersma-Wegman, T. D.; de Vries, J. G.;
Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44, 1896. (e) Panella, L.;
Feringa, B. L.; de Vries, J. G.; Minnaard, A. J. Org. Lett. 2005, 7, 4177.
f) Bernsmann, H.; van den Berg, M.; Hoen, R.; Minnaard, A. J.; Mehler,
G.; Reetz, M. T.; de Vries, J. G.; Feringa, B. L. J. Org. Chem. 2005, 70,
43. (g) Zeng, Q.-H.; Hu, X.-P.; Liang, X.-M.; Zheng, Z. Chin. Chem. Lett.
2005, 16, 1321. (h) Zeng, Q.-H.; Hu, X.-P.; Duan, Z.-C.; Liang, X.-M.;
Zheng, Z. J. Org. Chem. 2006, 71, 393.
reaction and the matched stereogenic elements are (S
c
)-central
and (S )-axial chirality. The increase of the steric hindrance
a
at the nitrogen atom of the ligands proved to be favorable
for the enantioselectivity of the reaction. By use of the
N-methylated (S ,S )-PEAPhos 1d, the enantioselectivity was
c a
(
further increased to 99.1% ee (entry 4). Noticeably, all of
the hydrogenation products obtained in the above procedures
had a (R)-configuration no matter the chirality of the
binathphtyl moiety in these PEAPhos ligands, meaning that
the central chirality controls the absolute configuration of
the product. This result is entirely opposite from those
obtained by phosphoramidite-containing ligands in the Rh-
catalyzed asymmetric hydrogenation, in which the axial
chirality has the crucial role in determining the chirality of
9
(
9) For the bidentate phosphoramidite-containing ligands, see: (a)
Franci o` , G.; Faraone, F.; Leitner, W. Angew. Chem., Int. Ed. 2000, 39,
428. (b) Di e´ guez, M.; Ruiz, A.; Claver, C. Chem. Commun. 2001, 2702.
c) Hu, X.-P.; Zheng, Z. Org. Lett. 2004, 6, 3585. (d) Jia, X.; Li, X.; Lam,
1
(
W. S.; Kok, S. H. L.; Xu, L.; Lu, G.; Yeung, C.-H.; Chan, A. S. C.
Tetrahedron: Asymmetry 2004, 15, 2273. (e) Burk, S.; Franci o` , G.; Leitner,
W. Chem. Commun. 2005, 3460. (f) Zeng, Q.-H.; Hu, X.-P.; Duan, Z.-C.;
Liang, X.-M.; Zheng, Z. Tetrahedron: Asymmetry 2005, 16, 1233. (g) Hu,
X.-P.; Zheng, Z. Org. Lett. 2005, 7, 419.
Org. Lett., Vol. 8, No. 19, 2006
4369

Table 2. Rh-Catalyzed Asymmetric Hydrogenation of
Enamides 8a
Scheme 2. Rh-Catalyzed Asymmetric Hydrogenation of
Dimethyl Itaconate 10 with (S ,S )-PEAPhos 1d
c
a
In conclusion, we have developed a concise and practical
method for the preparation of a new class of unsymmetrical
hybrid phosphine-phosphoramidite ligand (PEAPhos) through
a two- and three-step transformation from commercially
available and inexpensive (S)-R-phenylethylamine. PEAPhos
is highly efficient for the Rh-catalyzed enantioselective
hydrogenation of a variety of substrates including R-dehy-
droamino acid esters, enamides, and dimethyl itaconate, in
which up to 99.9% ee was obtained for all of these kinds of
substrates. Most interestingly, the central chirality in the
phenylethylamine backbone decided the absolute configu-
ration of the hydrogenation product no matter the (R)- or
entry
ligand
substrate
ee % (config)b
1
2
3
4
5
6
7
8
9
(Sc,Ra)-1a
(Sc,Ra)-1b
(Sc,Sa)-1c
(Sc,Sa)-1d
(Sc,Sa)-1d
(Sc,Sa)-1d
(Sc,Sa)-1d
(Sc,Sa)-1d
(Sc,Sa)-1d
(Sc,Sa)-1d
8a
8a
8a
8a
8b
8c
8d
8e
8f
95.9 (R)
73.9 (R)
98.6 (R)
99.5 (R)
99.1 (R)
99.0 (R)
98.8 (R)
98.5 (R)
99.8 (R)
99.9 (R)
10
8g
a
Reactions conditions: 3 mL of CH2Cl2, 0.5 mmol of substrates, 1
(S)-configuration of binathphyl moiety, contrary to the results
mol % of catalyst prepared in situ from Rh(COD)2BF4 and 1.1 equiv of
PEAPhos 1, room temperature, 10 bar of H2 pressure, 12 h. Full conversions
were achieved in all reactions. Enantiomeric excesses were determined
by GC, using a Chiral select 1000 capillary (0.25 mm × 30 m) column.
The absolute configuration was determined by comparing the GC retention
times with GC data in the literature.
obtained by phosphoramidite-containing ligands reported so
far. Furthermore, these PEAPhos ligands are air- and
moisture-stable, and can be held in open air for several
months. All of these features make these PEAPhos ligands
highly practical for general laboratory preparations as well
as academic and industrial applications.
b
acetamides were hydrogenated in 98.5-99.9% ee (entries
4
-10).
Acknowledgment. We are grateful for financial support
from the Natural Sciences Foundation of China (20472083).
Remarkable enantioselectivity and catalytic reactivity were
also observed in the Rh-catalyzed asymmetric hydrogenation
of dimethyl itaconate 10. The most efficient catalyst was
prepared in situ from Rh(COD) BF and (S ,S )-1d, which
2 4 c a
provided the hydrogenation product in up to 99.9% ee under
the same conditions as the hydrogenation of R-dehydroamino
acid esters (Scheme 2).
Supporting Information Available: Experimental de-
tails, characterization data, and analytic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0617749
4370
Org. Lett., Vol. 8, No. 19, 2006