Unsymmetrical ferrocenylethylamine-derived monophosphoramidites: Highly efficient chiral ligands for Rh-catalyzed enantioselective hydrogenation of enamides and α-dehydroamino acid derivatives

Article abstract of DOI:10.1021/jo051912s

A new family of unsymmetrical ferrocenylethylamine-derived monophosphoramidites were synthesized and successfully applied in the Rh-catalyzed enantioselective hydrogenation of a range of enamides and α-dehydroamino acid esters, and ee values of up to 99.5% were obtained for both types of substrate. These results suggest that unsymmetrical amine-derived monophosphoramidites can also exhibit excellent enantioselectivity for a broad range of substrates, comparable to or higher than those of the most efficient symmetrical amine-derived monophosphoramidites reported thus far.

Full text of DOI:10.1021/jo051912s

Unsymmetrical Ferrocenylethylamine-Derived
Monophosphoramidites: Highly Efficient Chiral
Ligands for Rh-Catalyzed Enantioselective
Hydrogenation of Enamides and r-Dehydroamino
Acid Derivatives
sibility of a range of diverse ligand structures, and their often
lower cost when compared to bidentate ligands. Following the
2
a
2b
pioneering studies from the groups of Pringle, Reetz, and
2c
2d
2e
Feringa and more recently Chan and Zhou, a large number
of chiral monodentate phosphonite, phosphite, and phosphora-
midite ligands have been found to induce excellent enantiose-
lectivities in rhodium-catalyzed asymmetric hydrogenation
reactions, comparable to or exceeding those obtained with
Qing-Heng Zeng,†,‡ Xiang-Ping Hu, Zheng-Chao Duan,
†
†,‡
†
,†
3
Xin-Miao Liang, and Zhuo Zheng*
bidentate ligands. Among the chiral monodentate phosphorus
ligands developed to date, MonoPhos (1), the simplest member
Dalian Institute of Chemical Physics, Chinese Academy of
Sciences, 457 Zhongshan Road, Dalian 116023, China, and
Graduate School of the Chinese Academy of Sciences,
Beijing 100039, China
of the monodentate phosphoramidites based on axially chiral
4
2
,2′-binaphthol, has held an especially important position. In
addition to exhibiting high efficiency in the rhodium-catalyzed
hydrogenation of R-dehydroamino acids and esters, aromatic
enamides, and itaconic acid derivatives, the MonoPhos (1) ligand
architecture can be readily modified to optimize the hydrogena-
tion of substrates that do not give good results with Monophos
itself. Structural modification of the MonoPhos backbone can
be carried out either by introducing substituents onto the
binaphthyl moiety or by replacing the dimethylamino group with
other C2-symmetric amines. However, introduction of substit-
uents onto the binaphthyl moiety of MonoPhos has usually
resulted in diminished enantioselectivities and reaction rates.
In contrast, replacement of the dimethylamino group with other
C2-symmetrical amines has proven to be more successful. For
example, in the Rh-catalyzed enantioselective hydrogenation of
enamides, good enantioselectivity (96% ee) was obtained with
zhengz@dicp.ac.cn
ReceiVed September 13, 2005
(2) (a) Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D. J.;
Martorell, A.; Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 961. (b)
Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39, 3889. (c) van
den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van Esch, J.; de Vries, A.
H. M.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 11539.
(
2
d) Jia, X.; Li, X.; Xu, L.; Shi, Q.; Yao, X.; Chan, A. S. C. J. Org. Chem.
003, 68, 4539. (e) Hu, A.-G.; Fu, Y.; Xie, J.-H.; Zhou, H.; Wang, L.-X.;
A new family of unsymmetrical ferrocenylethylamine-
derived monophosphoramidites were synthesized and suc-
cessfully applied in the Rh-catalyzed enantioselective hy-
drogenation of a range of enamides and R-dehydroamino acid
esters, and ee values of up to 99.5% were obtained for both
types of substrate. These results suggest that unsymmetrical
amine-derived monophosphoramidites can also exhibit excel-
lent enantioselectivity for a broad range of substrates,
comparable to or higher than those of the most efficient
symmetrical amine-derived monophosphoramidites reported
thus far.
Zhou, Q.-L. Angew. Chem., Int. Ed. 2002, 41, 2348.
(3) For reviews of asymmetric hydrogenation with monophosphorus
ligands, see: (a) Lagasse, F.; Kagan, H. B. Chem. Pharm. Bull. 2000, 48,
3
15. (b) Komarov, I. V.; B o¨ rner, A. Angew. Chem., Int. Ed. 2001, 40, 1197.
(c) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer,
M. Adv. Synth. Catal. 2003, 345, 103. (d) Tang, W.; Zhang, X. Chem. Rev.
2
003, 103, 3029. (e) Jerphagnon, T.; Renaud, J.-L.; Bruneau, C. Tetrahe-
dron: Asymmetry 2004, 15, 2101. (f) Guo, H.; Ding, K. Chin. Sci. Bull.
2004, 49, 2003. For some recent examples of asymmetric hydrogenation
with monophosphorus ligands, see: (g) Fu, Y.; Guo, X.-X.; Zhu, S.-F.;
Hu, A.-G.; Xie, J.-H.; Zhou, Q.-L. J. Org. Chem. 2004, 69, 4648. (h) Fu,
Y.; Hou, G.-H.; Xie, J.-H.; Xing, L.; Wang, L.-X.; Zhou, Q.-L. J. Org.
Chem. 2004, 69, 8157. (i) Wu, S.; Zhang, W.; Zhang, Z.; Zhang, X. Org.
Lett. 2004, 6, 3565. (j) Botman, P. N. M.; Amore, A.; van Heerbeek, R.;
Back, J. W.; Hiemstra, H.; Reek, J. N. H.; van Maarseveen, J. H.
Tetrahedron Lett. 2004, 45, 5999. (k) Jerphagnon, T.; Renaud, J.-L.;
Demonchaux, P.; Ferreira, A.; Bruneau, C. AdV. Synth. Catal. 2004, 346,
33. (l) Reetz, M. T.; Li, X. Tetrahedron 2004, 60, 9709. (m) Huang, H.;
Zheng, Z.; Luo, H.; Bai, C.; Hu, X.; Chen, H. J. Org. Chem. 2004, 69,
Asymmetric hydrogenations catalyzed by chiral metal-ligand
complexes are among the most powerful tools for obtaining
1
enantiomerically enriched compounds. Despite the encouraging
2
2
2
355. (n) Reetz, M. T.; Ma, J.-A.; Goddard, R. Angew. Chem., Int. Ed.
005, 44, 412. (o) Reetz, M. T.; Li, X. Angew. Chem., Int. Ed. 2005, 44,
959. (p) Peng, H.-Y.; Lam, C.-K.; Mak, T. C. W.; Cai, Z.; Ma, W.-T.; Li,
performance of many bidentate P-chelate ligands, the past few
years have witnessed a renewed interest in the development of
chiral monodentate phosphorus-containing ligands for use in
rhodium-catalyzed asymmetric hydrogenation reactions. This
resurgence in monodentate ligands is due to the ready acces-
Y.-X.; Wong, H. N. C. J. Am. Chem. Soc. 2005, 127, 9603. (q) Reetz, M.
T.; Meiswinkel, A.; Mehler, G.; Angermund, K.; Graf, M.; Thiel, W.;
Mynott, R.; Blackmond, D. G. J. Am. Chem. Soc. 2005, 127, 10305. (r)
Liu, Y.; Ding, K. J. Am. Chem. Soc. 2005, 127, 10488. (s) 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. (t) Panella, L.; Feringa, B. L.; de Vries, J. G.;
Minnaard, A. J. Org. Lett. 2005, 7, 4177.
†
Chinese Academy of Sciences.
Graduate School of the Chinese Academy of Sciences
‡
(1) For reviews, see: (a) Brown, J. M. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
Germany, 1999; Vol. 1, Chapter 5.1. (b) Ohkuma, T.; Kitamura, M.; Noyori,
R. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH:
New York, 2000; Chapter 1.
(4) van den Berg, M.; Minnaard, A. J.; Haak, R. M.; Leeman, M.;
Schudde, E. P.; Meetsma, A.; Feringa, B. L.; de Vries, A. H. M.; Maljaars,
C. E. P.; Willans, C. E.; Hyett, D.; Boogers, J. A. F.; Henderickx, H. J.
W.; de Vries, J. G. AdV. Synth. Catal. 2003, 345, 308.
1
0.1021/jo051912s CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/25/2005
J. Org. Chem. 2006, 71, 393-396
393

SCHEME 1. Synthesis of Ferrocenylethylamine-Derived
R-dehydroamino acids esters and aromatic enamides. Further-
more, the hydrogenation reaction conditions used in this study
are much milder than those typically reported.
Monophosphoramidites 3a-fa
The synthesis of the monodentate ligands 3 is straightforward
as outlined in Scheme 1. R-Ferrocenylethylamines 5 can be
prepared from the corresponding N,N-dimethylamino precursor
a
Reagents and conditions: (a) MeI, acetone, 0 °C to room temperature;
2
(
°
b) R NH2, MeOH or CH3CN, room temperature; (c) 6, Et3N, toluene, 0
C to room temperature.
4
through a two-step transformation in high yields and with
10
retention of configuration at the stereogenic carbon center.
the use of MonoPhos only when the reaction was performed at
low temperature (-20 °C). Simply by replacing the dimethyl-
amino group of MonoPhos with a diethylamino group, the
enantioselectivity was increased to 99.6% ee at a higher
temperature (5 °C).2 When the dimethylamino group of
MonoPhos was replaced by a piperidyl or morpholine moiety,
the enantioselectivities for the hydrogenation of a broad range
of substrates could also be increased. Interestingly, replacement
of the dimethylamino group with an unsymmetrical amino
moiety has not been investigated as thoroughly, and has usually
The BINOL-derived chlorophosphite 6 was obtained in quan-
titative yield by heating (S)- or (R)-BINOL in neat PCl3 at reflux,
evaporation of excess reagents, azeotropic distillation of the
residue with toluene, and finally recrystallization from n-
5
e
11
hexane. Simple treatment of the chlorophosphite 6 with a series
of R-ferrocenylethylamines 5 in toluene at 0 to 25 °C in the
presence of triethylamine gave rise to the monophosphoramidite
ligands 3 in good to excellent yields. The resulting monophos-
phoramidites 3 are stable and can be kept under Ar atmosphere
for extended periods.
6
7
resulted in dramatically diminished enantioselectivity. To the
With these ferrocenylethylamine-derived monophosphora-
midites 3 in hand, we next proceeded to test their efficiency in
Rh-catalyzed asymmetric hydrogenation. In the first set of
experiments, N-(1-phenylethenyl)acetamide 7a was used as a
test substrate. Hydrogenation was conducted at room temper-
ature under a H2 pressure of 10 bar in the presence of 1 mol %
of catalyst prepared in situ from Rh(COD)2BF4 and 2.2 mol %
of chiral ligand, and the results are summarized in Table 1. As
a comparison, R-phenylethylamine-derived monophosphos-
phoramidites 2b and 2c were also evaluated in this test reaction.
Rh/(Sc,Sa)-2b complex showed no catalytic activity in this
reaction (entry 1), while its distereoisomer (Sc,Ra)-2c exhibited
good enantioselective induction, giving the hydrogenation
product in 93% ee (entry 2). Use of the corresponding
ferrocenylethylamine-derived ligand (Rc,Sa)-3a dramatically
improved the enantioselectivity and gave the product in 99%
best of our knowledge, with the exception of a recent report
showing that R-phenylethylamine-derived monophosphoramidite
2
a displayed excellent enantioselectivity in the Rh-catalyzed
8
asymmetric hydrogenation of â-dehydroamino acid esters, few
monodentate phosphoramidites with unsymmetrical amino
groups have exhibited high enantioselectivities in catalytic
asymmetric hydrogenation.
Prompted by our recent success in the development of
9
unsymmetrical ligands for asymmetric catalysis, we initiated
a study of the synthesis of a series of monodentate phosphora-
midites derived from unsymmetrical amines, and investigated
their efficiency in Rh-catalyzed asymmetric hydrogenation.
Herein, we report the results of this study, and describe the
development of R-ferrocenylethylamine-derived monophos-
phoramidites 3. We demonstrate that unsymmetrical amine
derived monophosphoramidites are also able to exhibit excellent
enantioselectivities for a broad range of substrates, including
(9) (a) Hu, X.; Dai, H.; Hu, X.; Chen, H.; Wang, J.; Bai, C.; Zheng, Z.
Tetrahedron: Asymmetry 2002, 13, 1687. (b) Hu, X.; Chen, H.; Hu, X.;
Dai, H.; Bai, C.; Wang, J.; Zheng, Z. Tetrahedron Lett. 2002, 43, 9179. (c)
Hu, X.; Chen, H.; Dai, H.; Hu, X.; Zheng, Z. Tetrahedron: Asymmetry 2003,
14, 2073. (d) Hu, X.; Dai, H.; Bai, C.; Chen, H.; Zheng, Z. Tetrahedron:
Asymmetry 2004, 15, 1065. (e) Hu, X.-P.; Zheng, Z. Org. Lett. 2004, 6,
3585. (f) Hu, X.-P.; Zheng, Z. Org. Lett. 2005, 7, 419. (g) Hu, X.-P.; Chen,
H.-L.; Zheng, Z. AdV. Synth. Catal. 2005, 347, 541. (h) Zeng, Q.-H.; Hu,
X.-P.; Duan, Z.-C.; Liang, X.-M.; Zheng, Z. Tetrahedron: Asymmetry 2005,
16, 1233.
(
5) Jia, X.; Guo, R.; Li, X.; Yao, X.; Chan, A. S. C. Tetrahedron Lett.
002, 43, 5541.
6) 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.
7) (a) Doherty, S.; Robins, E. G.; Pal, I.; Newman, C. R.; Hardacre, C.;
2
(
9
(
Rooney, D.; Mooney, D. A. Tetrahedron: Asymmetry 2003, 14, 1517. (b)
Zeng, Q. H.; Hu, X. P.; Liang, X. M.; Zheng, Z. Chin. Chem. Lett. 2005,
1
6, 1321.
8) (a) P e˜ na, D.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J. Am.
(10) Gokel, G. W.; Maequarding, D.; Ugi, I. K. J. Org. Chem. 1972,
37, 3052.
(
Chem. Soc. 2002, 124, 14552. (b) P e˜ na, D.; Minnaard, A. J.; de Vries, A.
H. M.; de Vries, J. G.; Feringa, B. L. Org. Lett. 2003, 5, 475.
(11) Franci o` , G.; Arena, C. G.; Faraone, F.; Graiff, C.; Lanfranchi, M.;
Tiripicchio, A. Eur. J. Inorg. Chem. 1999, 1219.
3
94 J. Org. Chem., Vol. 71, No. 1, 2006

TABLE 1. Rh-Catalyzed Asymmetric Hydrogenation of Enamides
TABLE 2. Rh-Catalyzed Asymmetric Hydrogenation of
a
r-Dehydroamino Acid Esters 9a
7
a-i
conv
R2 solvent (%) (config.)c
ee (%)b
ee (%)b
(config.)
entry ligand substrate
R1
R1
R2
c
entry
ligand
substrate
solvent
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
2b
2c
3a
3b
3c
3d
3e
3f
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7c
7d
7e
7f
H
H
H
H
H
H
H
H
H
H
H
4-CF3
4-Cl
4-Br
4-Me
4-OMe
3-OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH2Cl2 N.R. N.R.
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3b
3b
3b
3b
3b
3b
3b
9a
9a
9a
9a
9a
9a
9a
9a
9b
9c
9d
9e
9f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
H
H
H
H
H
H
H
4-OMe
2-OMe
4-Cl
2-Cl
H
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
EtOAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
98 (R)
91 (S)
85 (R)
60 (R)
98 (S)
70 (R)
97 (R)
94 (R)
>99 (R)
99.5 (R)
99 (R)
CH2Cl2 100
CH2Cl2 100
CH2Cl2 100
CH2Cl2 100
93 (S)
99 (R)
86 (S)
53 (R)
CH2Cl2 N.R. N.R.
CH2Cl2 100
CH2Cl2 100
MeOH 78
EtOAc 95
toluene 100
CH2Cl2 100
CH2Cl2 100
CH2Cl2 100
CH2Cl2 100
CH2Cl2 100
CH2Cl2 100
92 (R)
15 (S)
99 (R)
>99 (R)
63 (R)
99 (R)
99 (R)
99 (R)
>99 (R)
98 (R)
99.5 (R)
94 (R)
96 (R)
1
1
1
1
1
1
1
1
1
1
10
11
12
13
97 (R)
>99 (R)
a
Reactions were performed with 0.5 mmol of substrate and 1 mol % of
catalyst (L/Rh ) 2.2/1) in 3 mL of solvent at room temperature and with
an H2 pressure of 10 bar. Full conversions were achieved in all cases.
Enantiomeric excesses were determined by GC, using a CP-Chiralsil-L-
7g
7h
7i
b
Me CH2Cl2 100
Et CH2Cl2 100
c
H
Val capillary (0.25 mm × 30 m) column. Determined by comparing the
optical rotations with reported value.
a
Reactions were performed with 0.5 mmol of substrate and 1 mol % of
catalyst (L/Rh ) 2.2/1) in 3 mL of solvent at room temperature and with
an H2 pressure of 10 bar. b Enantiomeric excesses were determined by GC,
using a Chiral Select 1000 capillary (0.25 mm × 30 m) column.
Rh/(Rc,Sa)-3a complex also exhibited high efficiency in the
hydrogenation of E/Z mixtures of â-substituted enamides 7h-
i, giving the products with up to 96% ee (entries 18 and 19),
thereby demonstrating the wide scope of the present Rh/
monophosphoramidite catalyst in the hydrogenation of enam-
ides.
c
Determined by comparing the optical rotations with reported value.
ee, which is comparable to the best results obtained by those
monophosphoramidites containing a symmetrical amine moiety,
but under much milder conditions (entry 3). However, complex
To further show the synthetic utility of these unsymmetrical
ferrocenylethylamine-derived monophosphoramidites, we then
investigated their efficiency in the Rh-catalyzed asymmetric
hydrogenation of R-dehydroamino acid esters 9. Remarkable
enantioselectivities and catalytic activities were also observed
in this reaction, and the results were summarized in Table 2.
The most efficient catalyst was prepared in situ from Rh-
(COD)2BF4 and (Rc,Sa)-3a or (Rc,Rp,Sa)-3e, which provided the
products in 98% ee under standard conditions employed in the
hydrogenation of enamides 7 (entries 1 and 5). The reaction
was weakly solvent dependent and proceeded smoothly in all
of the solvents tested to give the product in good enantioselec-
tivities (entries 1, 7, and 8), with the best solvent being CH2Cl2
(entry 1). The rhodium complex of the ligand (Rc,Sa)-3a was
particularly effective for the hydrogenation of R-dehydroamino
acid esters. All of the substrates were hydrogenated in very high
enantioselectivities (entries 9-13), and the best results were
obtained in the hydrogenation of substrate 9c, which provided
ee values of up to 99.5% (entry 10).
(
Rc,Ra)-3b containing a (Ra)-binaphthyl moiety only gave the
product in 86% ee and with opposite absolute configuration
entry 4). These results indicated that the binaphthyl moiety in
(
the ligand controls the chirality of the hydrogenation product
and the matched stereogenic elements are (Rc)-central and (Sa)-
axial absolute configurations.
We next investigated the effect of amine moiety on the
reaction and found that the substitutent in the amine had a
dramatic influence on both the enantioselectivity and catalytic
activity. The results indicated that the rhodium complex of a
ligand containing a bulkier substituent in the amino moiety
tended to show lower catalytic activity and provided lower levels
of enantioselectivity (entries 3, 5, and 6). Thus, replacing the
methyl group of (Rc,Sa)-3a with an ethyl group dramatically
decreased the enantioselectivity to 53% ee (entry 5). The
rhodium catalyst derived from ligand 3d containing a benzyl
group surprisingly showed no catalytic activity in the reaction
(entry 6). The presence of planar chirality in the ferrocene ring
did not improve the enantioselectivity, and an ee of 92% was
obtained by the use of (Rc,Rp,Sa)-3e (entries 7 and 8). The nature
of the solvent had a significant effect, and CH2Cl2 proved to
be the best solvent for the reaction (entries 9-11). Under the
optimized conditions, the hydrogenation of a variety of aromatic
enamides with ligand (Rc,Sa)-3a was then performed. Excellent
enantioselectivities were obtained in each case regardless of the
electronic properties of the aryl group on the substrate (entries
Although the precise mode of stereoinduction for these
ferrocenylethylamine-derived monophosphoramidites is not
clear, the presence of additional central chirality should have
some impact on the enantiodiscrimination step. Compared with
C2-symmetrical monophosphoramidites such as Monophos (1),
chiral ferrocenylethylamine-derived monophosphoramidite (Rc,Sa)-
3a appears to provide a more effective chiral environment
around the Rh atom due to the presence of additional central
chirality, resulting in improved enantioselectivities. The mis-
matched central and axial chiralities in (Rc,Ra)-3b render the
12-17), and the best result was obtained for N-[1-(3-methoxy)-
phenylethyl]acetamide 7g (99.5% ee) (entry 17). Furthermore,
J. Org. Chem, Vol. 71, No. 1, 2006 395

chiral environment around the Rh atom less effective, resulting
in decreased enantioselectivities. The replacement of R groups
vacuo. The residue was purified by column chromatography to give
the crude product, which can be further purified by recrystallization
from hexane/dichloromethane.
2
on the nitrogen atom of ligands 3 from methyl (3a) to bulkier
ethyl (3c) and benzyl (3d) or by the introduction of a methyl
N-Methyl-N-[(R)-1-ferrocenylethyl]-(S)-1,1′-bi-2-naphthyl phos-
phoramidite (R
c
,S
); H NMR (400 MHz, CDCl
.00 (d, J ) 5.6 Hz, 3H), 4.01 (s, 4H), 4.13-4.15 (m, 2H), 4.22
a
)-3a: orange solid; [R]20
D
+17.5 (c 0.30,
1
group (R ) onto the ferrocenyl ring (3e and 3f) led to decreased
1
CHCl
3
3
) δ 1.47 (d, J ) 6.8 Hz, 3H),
enantioselectivities, which is possibly the result of steric effects
2
as reported by other groups.3
g,3t
13
(
s, 1H), 4.52 (s, 1H), 4.69-4.73 (q, 1H), 7.13-7.97 (m, 12H);
NMR δ 18.4, 26.7, 52.2, 52.6, 67.7, 67.9, 68.8, 69.4, 69.8, 77.4,
7.7, 78.0, 89.9, 122.7, 123.1, 124.6, 125.2, 125.4, 126.7, 127.5,
C
In summary, we have explored a new family of unsym-
metrical amine-derived monodentate phosphoramidites and
investigated their efficacy in Rh-catalyzed asymmetric hydro-
genation. Simply by changing the dimethylamino group of
Monophos (1) into an unsymmetrical ferrocenylethylamine
moiety, the selectivities in the hydrogenation of a broad range
of substrates could be increased dramatically. Thus, N-methyl
ferrocenylethamine-derived monophosphoramidite 3a is broadly
applicable and demonstrates extremely high selectivity in the
catalytic hydrogenation of both enamides and R-dehydroamino
acid esters, comparable to or exceeding those reached by
monophosphoramidites containing a symmetrical amine moiety
reported thus far. Furthermore, the air-stable ligands can be
readily prepared in three steps from readily available N,N-
dimethyl-1-ferrocenylethylamine and BINOL, which offers the
benefits of simple procedures and low cost. Further applications
of these ligands are in progress.
7
127.7, 128.8, 129.0, 130.4, 130.9, 131.2, 132.0, 133.2, 133.5, 150.2,
150.9; 31P NMR δ 148.0; HRMS(m/z) calcd for C33
H 558.1279, found 558.1254.
H29FeNO P +
2
General Procedure for Asymmetric Hydrogenation and
Determination of Enantiomeric Excesses. In a nitrogen-filled
glovebox, a stainless steel autoclave was charged with Rh-
-
2
(COD) BF
2 4
(2.0 mg, 0.5 × 10 mmol) and monophosphoramidite
-2
ligand 3 (1.1 × 10 mmol) in 1.5 mL of a degassed solvent. After
the solution was stirred for 10 min at room temperature, the
substrate (0.5 mmol) in 1.5 mL of the same solvent was added to
the reaction mixture. Hydrogenation was then performed under 10
bar of H pressure for 20 h at room temperature. The reaction
2
mixture was passed through a short silica gel column to remove
the catalyst. After evaporation of the solvent, the crude reaction
mixture was analyzed by chiral GC to determine the conversion
and enantiomeric excesses.
Acknowledgment. The authors thank the National Natural
Science Foundation of China (20472083) for financial support.
We thank Dr. Hon Wai Lam for his enthusiastic help in
preparing this paper.
Experimental Section
General Procedure for the Synthesis of Chiral Ferrocenyl-
ethylamine-Derived Monophosphoramidites. To a stirred solution
of ferrocenylethylamine (5a-d) (10 mmol) and triethylamine (50
mmol) in 100 mL of toluene was added dropwise a solution of
BINOL-based chlorophosphite (3.8 g, 11 mmol) in 30 mL of toluene
at 0 °C under a N atmosphere over 30 min. The resulting mixture
2
was allowed to stand at room temperature overnight. The precipitate
was removed by filtration, and the filtrate was concentrated in
Supporting Information Available: Experimental procedure,
characterization data, and spectroscopic data for all ligands.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO051912S
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96 J. Org. Chem., Vol. 71, No. 1, 2006