Modular phosphine-aminophosphine ligands based on chiral 1,2,3,4-tetrahydro-1-naphthylamine backbone: A new class of practical ligands for enantioselective hydrogenations

Article abstract of DOI:10.1002/adsc.200800418

A series of new chiral phosphine-aminophosphine ligands [(R)-HW-Phos] has been prepared from (R)-1,2,3,4-tetrahydro-1-naphthylamine through a two-step procedure, and successfully applied in the rhodium-catalyzed asymmetric hydrogenation of various functionalized olefins such as α-enol ester phosphonates, α-enamido phosphonates, (Z)-β-(acylamino)acrylates and so on. Excellent enantioselectivities have been achieved in the hydrogenation of most substrates tested, demonstrating the high potential of these newly developed phosphine-aminophosphine ligands in asymmetric catalysis. The present research also discloses that these newly developed phosphine-aminophosphine ligands are more efficient than that derived from (S)-1-phenylethylamine, suggesting that the increased rigidity conferred by a cyclohexyl fragment in these phosphine-aminophosphine ligands has a positive effect in the asymmetric induction.

Full text of DOI:10.1002/adsc.200800418

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DOI: 10.1002/adsc.200800418
Modular Phosphine-Aminophosphine Ligands Based on Chiral
1,2,3,4-Tetrahydro-1-naphthylamine Backbone: A New Class of
Practical Ligands for Enantioselective Hydrogenations
Min Qiu,a,b Xiang-Ping Hu,a,* Jia-Di Huang,a,b Dao-Yong Wang,a,b Jun Deng,a,b
Sai-Bo Yu,a,b Zheng-Chao Duan,a,b and Zhuo Zhenga,*
a
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, Peopleꢀs
Republic of China
Fax : (+86)-411-8468-4746; e-mail: zhengz@dicp.ac.cn or xiangping@dicp.ac.cn
The Graduate School of Chinese Academy of Sciences, Beijing 100039, Peopleꢀs Republic of China
b
Received: July 7, 2008; Revised: September 27, 2008; Published online: November 19, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800418.
Abstract: A series of new chiral phosphine-amino-
phosphine ligands [(R)-HW-Phos] has been pre-
pared from (R)-1,2,3,4-tetrahydro-1-naphthylamine
through a two-step procedure, and successfully ap-
plied in the rhodium-catalyzed asymmetric hydroge-
nation of various functionalized olefins such as a-
enol ester phosphonates, a-enamido phosphonates,
(Z)-b-(acylamino)acrylates and so on. Excellent
enantioselectivities have been achieved in the hy-
drogenation of most substrates tested, demonstrat-
ing the high potential of these newly developed
phosphine-aminophosphine ligands in asymmetric
catalysis. The present research also discloses that
these newly developed phosphine-aminophosphine
ligands are more efficient than that derived from
(S)-1-phenylethylamine, suggesting that the in-
creased rigidity conferred by a cyclohexyl fragment
in these phosphine-aminophosphine ligands has a
positive effect in the asymmetric induction.
recent strategy in this area relies upon the use of un-
symmetrical hybrid bidentate phosphorus ligands.[2]
Because of holding two chemically distinct phospho-
rus binding sites, these ligands can offer the unique
electronic environment around the metal centre, dif-
ferent from that provided by the ubiquitous C2-sym-
metrical ligands. Among the various unsymmetrical
hybrid bidentate phosphorus ligands, a combination
of phosphine and aminophosphine fragments was
found to be an effective arrangement for the con-
struction of new unsymmetrical hybrid bidentate
phosphorus ligands.[3] The first successful phosphine-
aminophosphine ligand was known as BoPhoz, re-
ported by Boaz et al in 2002, which showed excellent
enantioselectivities in the Rh-catalyzed asymmetric
hydrogenation of a-dehydroamino acid derivatives,
itacontate derivatives and a-keto esters.[3a] However,
the results in the Rh-catalyzed asymmetric hydroge-
nation of a-enamides with these BoPhoz ligands were
less satisfactory. By use of the fluorinated BoPhoz-
type ligands, Yip and Chan et al. found that the enan-
tioselectivity for the hydrogenation of this substrate
class could be dramatically increased.[3d] Chen et al.
Keywords: asymmetric catalysis; hydrogenation;
phosphine-aminophosphine
ligands;
rhodium;
1,2,3,4-tetrahydro-1-naphthylamine
introduced
a stereogenic phosphorus atom into
Bophoz-type ligands, and the comparative results
demonstrate that P-chirality improves the enantiose-
lectivity when acting cooperatively with the planar
Catalytic asymmetric hydrogenation is one of the chirality and the chirality at the carbon centre.[3g] Al-
most powerful and practical tools to access optically though significant progress has been made in the past
active compounds in contemporary synthetic organic few years, it should be noted that all of these phos-
chemistry, in which the development of new chiral phine-aminophosphine ligands are based on a chiral
phosphorus-containing ligands has played a significant 1-ferrocenylethylamine backbone, and few other
role.[1] Although many excellent phosphorus-contain- phosphine-aminophosphine skeletons were found to
ing ligands have been reported for highly enantiose- be effective in asymmetric catalysis. Moreover, the
lective hydrogenations in the past decades, the quest substrate scope with these ligands in catalytic hydro-
for new efficient ligands remains a major challenge. A genation is still limited, whereby some of the more
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Min Qiu et al.
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challenging substrate classes such as b-dehydroamino tion than that derived from (S)-1-phenylethylamine.
acid esters could not be hydrogenated in satisfactory On the basis of this assumption, we therefore envi-
enantioselectivities. Therefore, the search for more sioned that chiral 1,2,3,4-tetrahydro-1-naphthylamine-
practical and efficient phosphine-aminophosphine li- derived phosphine-aminophosphine species might be
gands in terms of ease of preparation and wide sub- an excellent ligand class since the increased rigidity
strate scope remains an interesting and important conferred by a cyclohexyl fragment may result in high
goal.
enantioselectivities. Herein we report the synthesis of
Very recently, we have developed a readily accessi- this new phosphine-aminophosphine ligand class and
ble phosphine-aminophosphine ligand, (S)-HH-Phos, their applications in highly efficient rhodium-cata-
which was prepared through a two-step transforma- lyzed asymmetric hydrogenation of a-enol ester phos-
tion from inexpensive and commercially available (S)- phonates, a-enamido
phosphonates,
(Z)-b-
1-phenylethylamine (Figure 1).[4] Although ee values (acylamino)
ACHTUNGTERNaNUGN crylates and so on.
of 93–97% were achieved in the Rh-catalyzed asym-
metric hydrogenation of dimethyl a-benzoyloxy- can be easily prepared from commercially available,
ACHTUNGTRENNUNGethenephosphonates and N-benzyloxycarbonyl a-en- optically active 1,2,3,4-tetrahydro-1-naphthylamine 2
These new phosphine-aminophosphine ligands 1
amido phosphonates, the asymmetric induction of this through a two-step transformation, which is shown in
ligand class still needs to be improved. Moreover, (S)- Scheme 1. The key to the synthesis of these target
HH-Phos is less efficient for the hydrogenation of compounds is the direct ortho-functionalization of the
other functionalized olefins, normally giving the hy- primary amine, which can be easily carried out by a
drogenation products in ee values of <90%. We rea- direct and experimentally convenient one-pot proto-
soned that the flexible nature of the chiral phenyl- col. Thus, (R)-1,2,3,4-tetrahydro-1-naphthylamine 2
ethylamine backbone should be responsible for these was treated with n-BuLi at 08C, following by slow ad-
unsatisfactory results, and ligands with an appropriate dition of neat ClSiMe3, which in situ generated a
rigid structure might have a better asymmetric induc- monosilyated product, N-(trimethylsilyl)-1,2,3,4-tetra-
hydro-1-naphthylamine. The latter was further dilithi-
ated by addition of 3 equiv. of n-BuLi at À258C, and
then ortho-phosphinated with ClPPh2. After work-up
and crystallization from n-hexane, the key intermedi-
ate (R)-THNANH2 3 was obtained in 52% overall
yields. (R)-THNANH2 3 was then converted into the
corresponding phosphine-aminophosphine ligand (R)-
HW-Phos 1a in high yield by the reaction with ClPPh2
in CH2Cl2 at 08C in the presence of Et3N as a scav-
Figure 1. Structure of phosphine-aminophosphine ligands
(S)-HH-Phos and (R)-HW-Phos 1a.
Scheme 1. Synthesis of (R)-HW-Phos ligands 1a–d.
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Table 1. Rh-catalyzed asymmetric hydrogenation of a-enol ester phosphonates 4.[a]
Entry
Ligand
Substrate
Conversion [%]
ee [%] (Configuration)[b]
1
2
3
4
5
6
7
8
(S)-HH-Phos
4a: R=H
4a: R=H
4a: R=H
4a: R=H
4a: R=H
4b: R=Me
4c: R=Et
4d: R=Ph
4e: R=4-Cl-C6H4
4f: R=3-Cl-C6H4
4g: R=2-Cl-C6H4
4h: R=4-F-C6H4
4i: R=4-NO2-C6H4
4j: R=4-CH3O-C6H4
4k: R=3-CH3OC6H4
4l: R=O-i-Pr
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
93.1 (S)
96.5 (R)
97.7 (R)
98.7 (R)
99.4 (R)
99.2 (R)
99.6 (R)
99.2 (R)
99.0
99.1
98.5
99.8
98.7
1a
1b
1c
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
9
10
11
12
13
14
15
16
99.1
98.9
99.7
[a]
All reactions were performed with 0.25 mmol of substrate at room temperature under an H2 pressure of 10 atm in 2 mL
of CH2Cl2 for 24 h. Substrate/[Rh(COD)2]BF4/ligand=1/0.01/0.011. Full conversions were achieved in all reactions.
The ee values were determined by HPLC on a chiral column. The absolute configuration was determined by comparing
AHCTUNGTRENNUNG
[b]
the optical rotation with the reported data.
enger for the HCl eliminated. Because two phospho- Table 1), significantly higher than that obtained with
rus groups are introduced sequentially in two separate the phosphine-aminophosphine ligand [(S)-HH-Phos]
steps, the electronic and steric properties of these li- derived from (S)-1-phenylethylamine (entry 1,
gands can be easily varied by replacing the diphenyl- Table 1). These results suggested that the increased ri-
phosphino group in the aminophosphino moiety with gidity in these phosphine-aminophosphine ligands has
various diarylphosphino groups. Thus, a series of (R)- a positive effect in the asymmetric induction. As it is
HW-Phos 1b–d was prepared in good yields by a deduced from the data in Table 1, (R)-HW-Phos 1d,
same procedure.
bearing two CF3 groups in the 3,5-positions of the
As we have reported, the (S)-HH-Phos ligand de- phenyl ring of the aminophosphino moiety, was the
rived from (S)-phenylethylamine displayed 93–97% most efficient ligand with regard to asymmetric induc-
ee for the Rh-catalyzed asymmetric hydrogenation of tion and afforded the hydrogenation product with an
a-enol ester phosphonates 4. For a comparison in the ee value of 99.4% (entry 5, Table 1). With the optimal
asymmetric induction between (S)-HH-Phos and (R)- ligand 1d, we next examined the enantioselectivity of
HW-Phos, in the first set of experiments, we used the the hydrogenation of b-alkyl substituted a-benzoyl-
Rh-catalyzed asymmetric hydrogenation of a-enol
ACHTUNGTRENoNGNU xyethenephosphonates 4b and c. The results indicat-
ester phosphonates 4 to benchmark the potential of ed that the b-alkyl substituent in the substrate has
these newly developed phosphine-aminophosphine li- little effect on the enantioselectivity. Thus, 4b with a
gands 1 in asymmetric catalysis. The reaction was per- methyl group and 4c with an ethyl group were hydro-
formed in CH2Cl2 at room temperature under an H2 genated in 99.2% ee and 99.6% ee, respectively (en-
pressure of 10 atm in the presence of 1 mol% of cata- tries 6 and 7, Table 1). To further broaden the synthet-
lysts prepared in situ from [Rh
1.1 equiv. of chiral ligands, and the results are sum- set of structurally diverse b-aryl substituted substrates
marized in Table 1. 4d–k was submitted to the optimized Rh-catalyzed
ACHTUNGTREN(NGNU COD)2]BF4 and ic interest of this highly enantioselective procedure, a
To our delight, these newly developed phosphine- asymmetric hydrogenation. The catalytic asymmetric
aminophosphine ligands 1a–d displayed extraordinari- hydrogenation of b-aryl substituted a-enol ester phos-
ly high enantioselectivities (96.5–99.4% ee) in the rho- phonates remains a challenging task.[5] It is only very
dium-catalyzed asymmetric hydrogenation of dimeth- recently that some unsymmetrical hybrid bidentate
yl a-benzoyloxyethenephosphonate 4a (entries 2–5, phosphorus ligands have been found to show good to
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Table 2. Rh-catalyzed asymmetric hydrogenation of a-enamido phosphonates 6.[a]
Entry
Ligand
Substrate
Conversion [%]
ee [%] (Configuration)[b]
1
2
3
4
5
6
7
8
(S)-HH-Phos
6a: R1 =H, R2 =Cbz
6a: R1 =H, R2 =Cbz
6a: R1 =H, R2 =Cbz
6a: R1 =H, R2 =Cbz
6a: R1 =H, R2 =Cbz
6b: R1 =H, R2 =Ac
6c: R1 =Me, R2 =Cbz
6d: R1 =Ph, R2 =Cbz
100
100
100
100
100
100
96.2 (S)
98.7 (R)
99.5 (R)
99.5 (R)
99.6 (R)
99.9
1a
1b
1c
1d
1d
1d
1d
[c]
[c]
–
100
–
99.1 (R)
[a]
All reactions were performed with 0.25 mmol of substrate at room temperature under an H2 pressure of 10 atm in 2 mL
of CH2Cl2 for 24 h. Substrate/[Rh(COD)2]BF4/ligand=1/0.01/0.011. Full conversions were achieved in all reactions.
The ee values were determined by HPLC on a chiral column. The absolute configuration was determined by comparing
the optical rotation with the reported data.
AHCTUNGTRENNUNG
[b]
[c]
Not determined because of low conversion.
excellent enantioselectivities in this transformation.[6] phosphonates and amides as described in the litera-
Therefore, the search of new chiral ligands with the ture.[8] However, the synthesis of other substituted
properties superior to their predecessors for this substrates using the same method failed. The subse-
transformation is still highly desirable. Gratifyingly, quent hydrogenation was performed under the opti-
we found that all b-aryl substituted substrates 4d–k mized conditions (CH2Cl2 as the reaction media, H2
were hydrogenated in excellent enantioselectivity pressure of 10 atm, and room temperature for 24 h)
(98.5–99.8% ee) with the present catalytic system, re- as employed in the hydrogenation of a-enol ester
gardless of the substitution pattern and electronic phosphonates. The results in Table 2 disclose that
properties of the substituent in the phenyl ring of the these newly developed phosphine-aminophosphine li-
substrates (entries 8–15, Table 1). High enantioselec- gands [(R)-HW-Phos 1a–d] are also highly efficient
tivity was also observed in the hydrogenation of the for the hydrogenation of dimethyl a-benzyloxycarbo-
b-alkoxy-substituted substrate 4l, for which 99.7% ee nylaminoethenephosphonate (6a), providing higher
was obtained (entry 16, Table 1). These results dem- enantioselectivities than that obtained with (S)-HH-
onstrate that the present catalytic system is highly Phos. Again, (R)-HW-Phos 1d, bearing two CF3
enantioselective in the hydrogenation of a-enol ester groups in the 3,5-positions of the phenyl ring of the
phosphonates, comparable to the best results reported aminophosphino moiety, was found to be the most ef-
so far.[5,6] However, an attempt to lower the catalyst ficient ligand with regard to asymmetric induction
loadings to 0.1 mol% failed, under the optimized hy- and afforded the hydrogenation product with an ee
drogenation conditions, <50% conversions were value of 99.6% (entry 5, Table 2). Protective groups
achieved.
on the nitrogen had little impact on the enantioselec-
To further demonstrate the scope and flexibility of tivity, normally giving ee values of over 99% (entries 5
the present catalytic system, we decided to apply the and 6, Table 2). The b-substituent in the substrates
phosphine-aminophosphine ligands 1 to the hydroge- had an significant effect in the enantioselectivity. For
nation of a-enamido phosphonates 6. Although the the hydrogenation of the substrate 6c with a b-methyl
catalytic asymmetric hydrogenation of a-dehydroami- substituent, a low conversion was observed even in an
no acid derivatives is one of the most studied and elevated H2 pressure (entry 7, Table 2). In sharp con-
widely applied methods for the enantioselective prep- trast, the substrate 6d with a b-phenyl substituent was
aration of a-amino acids, there are only a few catalyt- hydrogenated in full conversion and 99.1% ee
ic hydrogenation methods available to access optically (entry 8, Table 2).
active a-aminophosphonic acid derivatives, partly due
We continued our investigation on the use of these
to the difficult accessibility of a variety of substituted new phosphine-aminophosphine ligands 1a–d in the
enamido phosphonates.[7] Some N-protected a-enami- hydrogenation of (Z)-b-aryl-b-(acylamino)acrylates
do phosphonates 6a–d were prepared in moderate 8a–h. The asymmetric hydrogenation of b-(acylami-
yields by the condensation reaction between acyl no)acrylates, in particular those bearing an aryl group
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Table 3. Rh-catalyzed asymmetric hydrogenation of (Z)-b-aryl-b-(acylamino)acrylates 8.[a]
Entry
Ligand
Substrate
Conversion [%]
ee [%] (Configuration)[b]
1
(S)-HH-Phos
8a: Ar=Ph, R=Et
0
–
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1c
1c
1c
1c
1c
1c
1c
8a: Ar=Ph, R=Et
8a: Ar=Ph, R=Et
8a: Ar=Ph, R=Et
8a: Ar=Ph, R=Et
8b: Ar=4-Me-C6H4, R=Me
8c: Ar=3-Me-C6H4, R=Me
8d: Ar=2-Me-C6H4, R=Me
8e: Ar=4-MeO-C6H4, R=Me
8f: Ar=4-MeO-C6H4, R=Et
8g: Ar=4-Me-C6H4, R=Et
8h: Ar=3-MeO-C6H4, R=Et
100
100
100
100
100
100
100
100
100
100
100
93.5 (R)
92.1 (R)
94.9 (R)
92.1 (R)
95.7
95.0
96.5
96.8
96.3
10
11
12
96.2
96.8
[a]
All reactions were performed with 0.25 mmol of substrate at room temperature under an H2 pressure of 10 atm in 2 mL
of MeOH for 24 h. Substrate/[Rh(COD)2]BF4/ligand=1/0.01/0.011.
The ee values were determined by GC or HPLC on a chiral column. The absolute configuration was determined by com-
AHCTUNGTRENNUNG
[b]
paring the optical rotation with the reported data.
at b-position, remains much less successful compared (94.9% ee, entry 4, Table 3). With the optimal ligand
to the hydrogenation of their a-analogues. Although 1c, a variety of (Z)-b-aryl-b-(acylamino)acrylates 8b–
some chiral monodentate and bidentate phosphorus- h were hydrogenated in excellent enantioselectivities
containing ligands have recently been reported to (95.0–96.8% ee, entries 6–12, Table 3), which repre-
show good to excellent enantioselectivities,[9] phos- sented the best result in the hydrogenation of b-(acyl-
phine-aminophosphine ligands have proved to be an
ACHTUNGTRENaNGNU mino)acrylates with phosphine-aminophosphine li-
inferior ligand for this transformation and displayed gands.
only low to moderate enantioselectivities.[10] Initially,
We also investigated the efficiency of these newly
we examined the influence of the ligand structure on developed phosphine-aminophosphine ligands 1 in
the reactivity and enantioselectivity. Hydrogenation the hydrogenation of some other functionalized ole-
was conducted in MeOH at room temperature under fins such as a-dehydroamino acid esters, a-enamides
an H2 pressure of 10 bar in the presence of 1.0 mol% and itaconate (Figure 2), and the results are summar-
catalysts prepared in situ from [Rh
1.1 equiv. of chiral ligand. As shown in Table 2, phe- no acid esters 10, (R)-HW-Phos 1d proved to be the
nylethylamine-derived phosphine-aminophosphine best ligand and provided the hydrogenation products
ACHTUNGTREN(NUNG COD)2]BF4 and ized in Table 4. For the hydrogenation a-dehydroami-
ligand [(S)-HH-Phos] surprisingly showed no activity in good enantioselectivities (entries 1–4, Table 4). Un-
in the hydrogenation of (Z)-b-phenyl-b-(acylamino)- expectedly, this kind of ligands was inefficient in the
ACHTUNGTRENNUNGacrylates 8a (entry 1, Table 3). In sharp contrast, the hydrogenation of dimethyl itaconate 11 in terms of
corresponding (R)-HW-Phos 1a exhibited satisfactory asymmetric induction, in which an ee value of only
results, providing the hydrogenation product in full
conversion with 93.5% ee (entry 2, Table 3). The sub-
sequent experiments disclosed that all of the chiral
1,2,3,4-tetrahydro-1-naphthylamine-derived
phos-
phine-aminophosphine ligands 1a–d were efficient for
the hydrogenation of (Z)-b-phenyl-b-(acylamino)acry-
lates 8a, giving the hydrogenation products in full
conversions with good enantioselectivities (92.1–
94.9% ee, entries 2–5, Table 3). However, different
from that in the hydrogenation of a-enol ester phos-
phonates, (R)-HW-Phos 1c with a CF3 group in the 4-
position of the phenyl ring of the aminophosphino
moiety exhibited the highest enantioselectivity Figure 2.
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Table 4. Rh-catalyzed asymmetric hydrogenation of func-
tionalized olefins and ketones 10-13.[a]
Experimental Section
General Procedure for the Synthesis of Phosphine-
Aminophosphine Derivatives (R)-HW-Phos 1
Entry Ligand Substrate
Conversion
[%]
ee
[%][b]
Chlorodiphenylphosphine (0.2 mL, 1.1 mmol, 1.1 equiv.) was
dissolved in 2.0 mL of dried CH2Cl2, which was cooled to
08C. A solution of amino-phosphine intermediate (R)-
1
1d
10a: R1 =H,
R2 =Me
100
95.2
2
3
1d
1d
10b: R1 =H, R2 =Et 100
95.4
95.6
THNANH2
3 (331 mg; 1.0 mmol) and Et3N (303 mg,
10c: R1 =OMe,
R2 =Me
100
3.0 mmol) in 2.0 mL of CH2Cl2 was added dropwise to
above solution during 30 min. The resulting mixture was left
standing at room temperature overnight. The residue was
purified by column chromatography, resulting in (R)-HW-
Phos 1a as white solid; yield: 440 mg (85%), mp 128–1298C;
4
1d
10d: R1 =Cl,
100
94.0
R2 =Me
5
6
7
8
1d
1b
1b
1b
1b
1b
1b
1d
11
100
100
100
100
100
100
100
55.0
93.4
96.4
95.8
97.0
96.3
96.4
12a: R=H
12b: R=4-Me
12c: R=4-Cl
12d: R=4-Br
12e: R=4-CF3
12f: R=3-OMe
13
1
[a]1D5: À118.2 (c 0.504, CHCl3); H NMR (400 MHz, CDCl3):
d=1.54–1.61 (m, 2H), 1.91–1.92 (m, 1H), 2.15–2.18 (m,
1H), 2.29–2.34 (m, 1H), 2.72–2.75 (m, 1H), 2.83–2.87 (m,
1H), 5.05 (m, 1H), 6.81 (m, 1H), 7.05–7.27 (m, 20H), 7.38
(m, 2H); 31P NMR (162 MHz, CDCl3): d=À16.5, 34.8;
13C NMR (100 MHz, CDCl3): d =16.5, 29.5, 30.0, 52.0, 127.4,
127.9, 128.2, 128.3, 128.4, 128.5, 130.7, 131.5, 131.7, 133.0,
133.4, 133.6, 133.8, 134.0, 137.2, 138.7; HR-MS: m/z=
516.1991, calcd. for C34H32NP2 [M+H]: 516.2010.
9
10
11
12
[c]
[c]
–
–
[a]
All reactions were performed with 0.25 mmol of sub-
strate at room temperature under an H2 pressure of 10
atm in 2 mL of CH2Cl2 for 24 h. Substrate/
[RhACHTUNGTRENNUNG(COD)2]BF4/ligand=1/0.01/0.011.
The ee values were determined by GC on a chiral
column.
(R)-HW-Phos 1b: mp 94–958C; [a]1D5: À94.3 (c 0.582,
CHCl3); 1H NMR (400 MHz, CDCl3): d = 1.65–1.73 (m,
2H), 1.91 (m, 1H), 2.08–2.12 (m, 1H), 2.32–2.37 (m, 1H),
2.79–2.83 (m, 1H), 2.88–2.90 (m, 1H), 4.97–4.98 (m, 1H),
6.83–6.86 (m, 6H), 7.08–7.72 (m, 13H); 31P NMR (162 MHz,
CDCl3): d=À16.2, 34.5; 13C NMR (100 MHz, CDCl3): d =
16.7, 29.5, 30.2, 52.0, 103.9, 104.2, 104.5, 104.7, 113.4, 113.7,
113.9, 127.8, 128.7, 130.9, 133.0, 133.5, 133.7, 133.8, 134.0,
136.8, 136.9, 137.1, 137.3, 138.0, 138.1, 161.7; HR-MS: m/z=
586.1483, calcd. for C34H26F4NP2 [MÀH]: 586.1477.
[b]
[c]
Not determined because of low conversion.
55% ee was achieved (entry 5, Table 4). Different
from that in the hydrogenation of a-dehydroamino
acid esters, (R)-HW-Phos 1b with two F-atoms in the
3,5-positions of the phenyl ring of the aminophosphi-
no moiety was found to be the most efficient ligand
for the hydrogenation of enamides 12. A variety of
enamides 12 was hydrogenated in good enantioselec-
tivities, regardless of the electronic properties of the
substrates (entries 6–11, Table 4). The hydrogenation
of functionalized ketone 13 with Rh and Ru catalysts
proved to be inefficient, only low conversions were
achieved (entry 12, Table 4).
In summary, we have developed a new class of
readily available, air-stable chiral phosphine-amino-
phosphine ligands [(R)-HW-Phos 1] and successfully
applied them to the enantioselective hydrogenation of
various functionalized olefins such as a-enol ester
phosphonates, a-enamido phosphonates and (Z)-b-
aryl-b-(acylamino)acrylates and so on. Excellent
enantioselectivities have been achieved in the hydro-
genation of most substrates tested, demonstrating the
high potential of these phosphine-aminophosphine li-
gands in the preparation of optically active a-hy-
(R)-HW-Phos 1c: mp 88–898C; [a]1D5: À90.8 (c 0.526,
CHCl3); 1H NMR (400 MHz, CDCl3): d = 1.63–1.71 (m,
2H), 1.95 (m, 1H), 2.07–2.11 (m, 1H), 2.39–2.44 (m, 1H),
2.78–2.82 (m, 1H), 2.88–2.89 (m, 1H), 4.96–4.97 (m, 1H),
6.76 (m, 1H), 7.00 (m, 2H), 7.09–7.29 (m, 13H), 7.43–8.03
(m, 5H); 31P NMR (162 MHz, CDCl3): d=À15.8, 34.2;
13C NMR (100 MHz, CDCl3): d = 16.7, 29.5, 30.4, 52.3,
125.5, 125.6, 127.7, 128.0, 128.6, 128.7, 128.9, 130.9, 132.9,
133.5, 133.7, 133.8, 134.0, 134.5, 134.7, 134.8, 138.2, 143.5;
HR-MS: m/z=650.1626, calcd. for C36H28F6NP2 [MÀH]:
650.1601.
(R)-HW-Phos 1d: mp 164–1658C; [a]1D5: À65.7 (c 0.504,
CHCl3); 1H NMR (400 MHz, CDCl3): d = 1.69–1.80 (m,
2H), 2.02–2.05 (m, 2H), 2.53–2.58 (m, 1H), 2.81–2.85 (m,
1H), 2.91–2.93 (m, 1H), 4.92–4.93 (m, 1H), 6.72 (m, 1H),
6.87–6.91 (m, 2H), 7.11–7.31 (m, 10H), 7.77–7.84 (m, 6H);
31P NMR (162 MHz, CDCl3): d=À15.1, 34.0; 13C NMR
(100 MHz, CDCl3): d = 16.8, 29.5, 30.7, 52.6, 123.0, 123.2,
124.7, 128.1, 128.5, 128.6, 128.7, 128.8, 129.0, 130.8, 131.0,
131.5, 131.7, 132.8, 133.5, 133.7, 133.8, 137.4, 144.8, 146.0,
146.2; HR-MS: m/z=786.1326, calcd. for C38H26F12NP2
[MÀH]: 786.1349.
ACHTUNGTRENNUNGdroxyphosphonates, a-aminophosphonates, b-aryl-b-
amino acid esters and so on. The present research
also indicated that the increased rigidity conferred by
a cyclohexyl fragment in these phosphine-aminophos-
phine ligands has a positive effect in the asymmetric
induction. Studies to further investigate the scope of
these ligands are currently in progress.
General Procedure for Asymmetric Hydrogenation
In a nitrogen-filled glove-box, [RhACHTUNRTGENUNG(COD)2]BF4 (1.0 mg,
0.0025 mmol) and (R)-1a (1.4 mg, 0.0028 mmol) were dis-
solved in degassed CH2Cl2 (1 mL) in a 5-mL vial. After stir-
ring at room temperature for 15 min, a solution of dimethyl
2688
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ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 2683 – 2689

Modular Phosphine-Aminophosphine Ligands
COMMUNICATIONS
a-benzoyloxyethenephosphonate 4a (64 mg, 0.25 mmol, S/C
100:1) in 1 mL of degassed CH2Cl2 was added. The resulting
mixture was transferred to an autoclave, which was then
charged with H2 (10 atm). The hydrogenation was per-
formed at room temperature for 24 h. After carefully releas-
ing the hydrogen gas, the reaction mixture was concentrated
under reduced pressure. The residue was purified through a
plug of silica gel (eluting with a mixture of hexanes/EtOAc,
2/1) to afford 5a. The enantiomeric excess was determined
by chiral GC.
rahedron Lett. 2006, 47, 4033–4035; g) W. Chen, W.
Mbafor, S. M. Roberts, J. Whittall, J. Am. Chem. Soc.
2006, 128, 3922–3923; h) J. Deng, Z.-C. Duan, J.-D.
Huang, X.-P. Hu, D.-Y. Wang, S.-B. Yu, X.-F. Xu, Z.
Zheng, Org. Lett. 2007, 9, 4825–4828; i) J. Deng, X.-P.
Hu, J.-D. Huang, S.-B. Yu, D.-Y. Wang, Z.-C. Duan, Z.
Zheng, J. Org. Chem. 2008, 73, 2015–2017; j) A. Zanot-
ti-Gerosa, W. A. Kinney, G. A. Grasa, J. Medlock, A.
Seger, S. Ghosh, C. A. Teleha, B. E. Maryanoff, Tetra-
hedron: Asymmetry 2008, 19, 938–944; k) D. Amoroso,
T. W. Graham, R. Guo, C.-W. Tsang, K. Abdur-Rashid,
Aldrichim. Acta 2008, 41, 15–26.
[4] D.-Y. Wang, J.-D. Huang, X.-P. Hu, J. Deng, S.-B. Yu,
Z.-C. Duan, Z. Zheng, J. Org. Chem. 2008, 73, 2011–
2014.
Acknowledgements
[5] a) M. J. Burk, T. A. Stammers, J. A. Straub, Org. Lett.
1999, 1, 387–390; b) I. D. Gridnev, N. Higashi, T. Ima-
moto, J. Am. Chem. Soc. 2001, 123, 4631–4632; c) I. D.
Gridnev, M. Yasutake, T. Imamoto, I. P. Beletskaya,
Proc. Natl. Acad. Sci. USA 2004, 101, 5385–5390; d) H.
Liu, Y.-G. Zhou, Z.-K. Yu, W.-J. Xiao, S.-H. Liu, H.-W.
He, Tetrahedron 2006, 62, 11207–11217.
[6] a) M. Rubio, A. Suꢂrez, E. ꢃlvarez, A. Pizzano, Chem.
Commun. 2005, 628–630; b) M. Rubio, S. Vargas, A.
Suꢂrez, E. ꢃlvarez, A. Pizzano, Chem. Eur. J. 2007, 13,
1821–1833; c) D.-Y. Wang, X.-P. Hu, J.-D. Huang, J.
Deng, S.-B. Yu, Z.-C. Duan, X.-F. Xu, Z. Zheng,
Angew. Chem. Int. Ed. 2007, 46, 7810–7813.
[7] a) U. Schçllkopf, I. Hoppe, A. Thiele, Liebigs Ann.
Chem. 1985, 555–559; b) M. Kitamura, M. Tokunaga,
T. Pham, W. D. Lubell, R. Noyori, Tetrahedron Lett.
1995, 36, 5769–5772; c) U. Schmidt, G. Oehme, H.
Krause, Synth. Commun. 1996, 26, 777–781; d) M. Ki-
tamura, M. Yoshimura, M. Tsukamoto, R. Noyori, En-
antiomer 1996, 1, 281–303; e) J. Holz, M. Quirmbach,
U. Schmidt, D. Heller, R. Stꢄrmer, A. Bçrner, J. Org.
Chem. 1998, 63, 8031–8034; f) I. Grassert, U. Schmidt,
S. Ziegler, C. Fischer, G. Oehme, Tetrahedron: Asym-
metry 1998, 9, 4193–4202; g) T. Dwars, U. Schmidt, C.
Fischer, I. Grassert, R. Kempe, R. Frçhlich, K. Drauz,
G. Oehme, Angew. Chem. Int. Ed. 1998, 37, 2851–2853.
[8] J. Zon, Synthesis 1981, 324.
We are grateful for financial support from the National Natu-
ral Science Foundation of China (20873145, 20802076) and
the Knowledge Innovation Program of the Chinese Academy
of Sciences (DICP-S200802).
References
[1] For reviews, see: a) J. M. Brown, in: Comprehensive
Asymmetric Catalysis, Vol. 1, (Eds.: E. N. Jacobsen, A.
Pfaltz, H. Yamamoto), Springer, Berlin, 1999, pp 121–
182; b) T. Ohkuma, M. Kitamura, R. Noyori, in: Cata-
lytic Asymmetric Synthesis, (Ed.: I. Ojima), Wiley-
VCH, New York, 2000, pp 1–110; c) H.-U. Blaser, C.
Malan, B. Pugin, F. Spindler, H. Steiner, M. Studer,
Adv. Synth. Catal. 2003, 345, 103–151; d) W. Tang, X.
Zhang, Chem. Rev. 2003, 103, 3029–3069.
[2] S. H. L. Kok, T. T.-L. Au-Yeung, H.-Y. Cheung, W. S.
Lam, S. S. Chan, A. S. C. Chan, in: The Handbook of
Homogeneous Hydrogenation, (Eds.: J. C. de Vries,
C. J. Elsevier), Wiley-VCH, Weinheim, 2007; Part IV,
Chapter 27.
[3] a) N. W. Boaz, S. D. Debenham, E. B. Mackenzie, S. E.
Large, Org. Lett. 2002, 4, 2421–2424; b) N. W. Boaz,
S. E. Large, J. A. Ponasik, Jr., M. K. Moore, T. Bar-
nette, W. D. Nottingham, Org. Process Res. Dev. 2005,
9, 472–478; c) N. W. Boaz, J. A. Ponasik, Jr., S. E.
Large, Tetrahedron: Asymmetry 2005, 16, 2063–2066;
d) X. Li, X. Jia, L. Xu, S. H. L. Kok, C. W. Yip, A. S. C.
Chan, Adv. Synth. Catal. 2005, 347, 1904–1908;
e) N. W. Boaz, E. B. Mackenzie, S. D. Debenham, S. E.
Large, J. A. Ponasik, Jr., J. Org. Chem. 2005, 70, 1872–
1880; f) N. W. Boaz, J. A. Ponasik, Jr., S. E. Large, Tet-
[9] For reviews, see: a) H.-J. Drexler, J. You, S. Zhang, C.
Fisher, W. Baumann, A. Spannenberg, D. Heller, Org.
Process Res. Dev. 2003, 7, 355–361; b) C. Bruneau, J.-
L. Renaud, T. Jerphagnon, Coord. Chem. Rev. 2008,
252, 532–544.
[10] X.-P. Hu, Z. Zheng, Org. Lett. 2005, 7, 419–422.
Adv. Synth. Catal. 2008, 350, 2683 – 2689
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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