Highly enantioselective Rh-catalyzed hydrogenation of β,γ- unsaturated phosphonates with chiral ferrocene-based monophosphoramidite ligands

Article abstract of DOI:10.1021/jo901619c

(Chemical Equation Presented) An enantioselective synthesis of chiral alkylphosphonates bearing a β-stereogenic center, based on the Rh-catalyzed asymmetric hydrogenation of corresponding β-substituted β,γ-unsaturated phosphonates with a ferrocene-based monophosphoramidite ligand under the mild hydrogenation conditions, was developed, in which an ee value of up to 98% was obtained.

Full text of DOI:10.1021/jo901619c

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particular those bearing a β-stereogenic center, is still rare,
Highly Enantioselective Rh-Catalyzed
Hydrogenation of β,γ-Unsaturated Phosphonates
with Chiral Ferrocene-Based Monophosphoramidite
Ligands
although such a process holds the potential of providing
chiral alkylphosphonic acid derivatives with high efficiency.
Therefore, the development of new catalytic methods for the
enantioselective synthesis of these compounds is highly
desirable. We envision that the catalytic asymmetric hydro-
genation of the corresponding prostereogenic 2-arylallyl-
phosphonates should be one of the most effective methods
for the construction of these moieties because of its inherent
efficiency and atom economy. Although significant progress
has been made in the catalytic asymmetric hydrogenation of
R-arylethenylphosphonates3 and other R,β-unsaturated
phosphonates4 with various Rh, Ru, or Ir complexes, the
asymmetric hydrogenation of β,γ-unsaturated phospho-
nates remains unexplored. Herein we report for the first time
a highly enantioselective rhodium-catalyzed hydrogenation
of β-substituted β,γ-unsaturated phosphonates with a
1-ferrocenylethylamine-derived monodentate phosphorami-
dite ligand, with which a variety of chiral β-aryl-substituted
propylphosphonates were prepared in 90-98% ee.
Zheng-Chao Duan,†,‡ Xiang-Ping Hu,*,† Cheng Zhang,†,‡
Dao-Yong Wang,†,‡ Sai-Bo Yu,†,‡ and Zhuo Zheng*,†
†Dalian Institute of Chemical physics, Chinese Academy
of Sciences, 457 Zhongshan Road, Dalian 116023, China, and
‡The Graduate School of Chinese Academy of Sciences,
Beijing 100039, China
xiangping@dicp.ac.cn; zhengz@dicp.ac.cn
Received July 25, 2009
A family of prostereogenic β-substituted β,γ-unsaturated
phosphonates 4 was prepared from propargyl alcohol 1
through a simple and versatile synthetic method as shown
in Scheme 1. Initially, propargyl alcohol 1 underwent
^
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An enantioselective synthesis of chiral alkylphosphonates
bearing a β-stereogenic center, based on the Rh-catalyzed
asymmetric hydrogenation of corresponding β-substi-
tuted β,γ-unsaturated phosphonates with a ferrocene-
based monophosphoramidite ligand under the mild hy-
drogenation conditions, was developed, in which an ee
value of up to 98% was obtained.
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DOI: 10.1021/jo901619c
r
Published on Web 10/30/2009
J. Org. Chem. 2009, 74, 9191–9194 9191
2009 American Chemical Society

Duan et al.
JOCNote
SCHEME 1. Synthesis of β-Substituted β,γ-Unsaturated
Phosphonates 4
TABLE 1. Rh-Catalyzed Asymmetric Hydrogenation of Diethyl 2-
Phenylallylphosphonate 4aa
entry
ligand
BoPhoz
BINAP
TaniaPhos
WalPhos
solvent H2 (bar) conversion (%)b ee (%)c
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
40
40
40
40
40
40
40
40
40
40
40
40
40
40
10
100
63
100
100
92
69
23
26
78
41
42
52
90
94
78
81
85
region-specific additions of Grignard reagents in the presence
of CuI to yield allylic alcohols 2.5 By treatment with PPh3/Br2 in
CH2Cl2, alcohols 2 were transformed into allylic bromides 3 in
high yields. The reaction of allylic bromides 3 with various
trialkyl phosphites at refluxing temperature gave the target
2-substituted allylphosphonates 4 in good yields.
Me-DuPHOS CH2Cl2
PPFAPhos
(Rc,Sa)-5a
(Rc,Sa)-5b
(Rc,Sa)-5c
(Rc,Ra)-5d
(Rc,Sa)-5c
(Rc,Sa)-5c
(Rc,Sa)-5c
(Rc,Sa)-5c
(Rc,Sa)-5c
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
i-PrOH
THF
100
100
100
100
100
82
95
52
29
100
9
10
11
12
13
14
15
With easy access to the substrates 4, the key to achieving
high enantioselectivities for this asymmetric hydrogenation
therefore is to find an efficient catalyst. We initiated our
studies on the Rh-catalyzed asymmetric hydrogenation of
diethyl 2-phenylallylphosphonate 4a by briefly screening
several chiral phosphorus ligands. Hydrogenations were
performed in CH2Cl2 at room temperature under a H2
pressure of 40 bar in the presence of 1 mol % of catalysts
prepared in situ from [Rh(COD)2]BF4 and chiral ligand. The
preliminary results in Table 1 revealed that most of the highly
efficient and extensively used ligands in the Rh-catalyzed
asymmetric hydrogenation such as BoPhoz,8 BINAP,9 Tania-
Phos,10 WalPhos,11 DuPHOS,12 and PPFAPhos13 are not
effective for this hydrogenation in term of enantioselectivity
or reactivity (Table 1, entries 1-6). Interestingly, (Rc,Sa)-
FAPhos 5 (Figure 1), a new class of monophosphoramidite
ligands recently developed by us for the Rh-catalyzed asym-
metric hydrogenation of a variety of prochiral CdC bonds,
displayed promising results. The results disclosed that the
substituent in the amino moiety of FAPhos had a dramatic
effect on the enantioselectivity, and a ligand containing a
bulkier substituent in the amino moiety tended to provide
higher levels of enantioselectivity. Thus, replacing the methyl
group of (Rc,Sa)-FAPhos 5a with an ethyl group led to the
enantioselectivity dramatically rising from 52% ee to 90% ee
(Table 1, entries 7 and 8). Using (Rc,Sa)-FAPhos 5c contain-
ing a benzyl group further increased the enantioselectivity to
94% ee (Table 1, entry 9). A comparison of the results
d
d
PhMe
CH2Cl2
93
aHydrogenations were performed with 0.25 mmol of substrate 4a at
room temperature under a H2 pressure of 40 bar in 2 mL of solvent for 24
h unless otherwise specified. Substrate/[Rh(COD)2]BF4/ligand = 1/
0.01/0.011-0.022. bConversions were determined by GC. cThe ee values
were determined by HPLC on a chiral column. dNot determined.
FIGURE 1. Ferrocene-based monophosphoramidite ligands, FA-
Phos 5, for asymmetric hydrogenation.
obtained with (Rc,Sa)-FAPhos 5b and (Rc,Ra)-FAPhos 5d
revealed that the binaphthyl moiety in these ligands controls
the chirality of the hydrogenation product and the matched
stereogenic elements are (Rc)-central and (Sa)-axial absolute
configurations (Table 1, entries 8 and 10). Subsequent inves-
tigation on the optimization of the hydrogenation condition
disclosed that the nature of the solvent had a significant effect
in this hydrogenation. However, no result surpassed that
obtained in CH2Cl2 (Table 1, entries 11-14). Lowering H2
pressure to 10 bar also provided good enantioselectivity
(Table 1, entry 15).
(5) Duboudin, J. G.; Jousseaume, B. J. Organomet. Chem. 1979, 168, 1–
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Angew. Chem., Int. Ed. 1999, 38, 3212–3215.
Having established (Rc,Sa)-FAPhos 5c as the optimal
ligand, we next investigated the effect of the ester functional
group of β,γ-unsaturated phosphonates on enantioselecti-
vity. The results are summarized in Table 2. It is very
interesting that a modest change from a methyl ester (4b)
to an ethyl ester (4a) led to the dramatically increased
enantioselectivity (Table 2, entries 1 and 2). The introduction
of a bulkier i-Pr ester functional group further increased the
enantioselectivity to 97% ee (Table 2, entry 3). These results
(11) Sturm, T.; Weissensteiner, W.; Spindler, F. Adv. Synth. Catal. 2003,
345, 160–164.
(12) Burk, M. J. Acc. Chem. Res. 2000, 33, 363–372.
(13) Hu, X.-P.; Zheng, Z. Org. Lett. 2004, 6, 3585–3588.
(14) (a) Zeng, Q.-H.; Hu, X.-P.; Duan, Z.-C.; Liang, X.-M.; Zheng, Z.
J. Org. Chem. 2006, 71, 393–396. (b) Duan, Z.-C.; Hu, X.-P.; Deng, J.; Yu,
S.-B.; Wang, D.-Y.; Zheng, Z. Tetrahedron: Asymmetry 2009, 20, 588–592.
9192 J. Org. Chem. Vol. 74, No. 23, 2009

Duan et al.
JOCNote
TABLE 2. Effect of Ester Functional Group of 2-Phenylallylphospho-
nates on Enantioselectivitya
TABLE 3. Rh-Catalyzed Asymmetric Hydrogenation of Di-isopropyl
2-Substituted Allylphosphonates 4c-o with (Rc,Sa)-FAPhos 5c a
entry
substrate (R)
yield (%)
ee (%)b
1
2
3
4
5
6
7
8
4c (R1 = Ph, R2 = H)
98
98
98
99
96
97
93
95
91
96
99
98
97
97 (S);
95 (-);
97 (-);
98 (-);
97 (-);
97 (-);
95 (-);
96 (-);
97 (þ);
90 (-);
96 (-);
96 (S);
61 (-)c
4d (R1 = 2-MeOC6H4, R2 = H)
4e (R1 = 3-MeOC6H4, R2 = H)
4f (R1 = 4-MeOC6H4, R2 = H)
4g (R1 = 4-MeC6H4, R2 = H)
4h (R1 = 3-CF3C6H4, R2 = H)
4i (R1 = 4-CF3C6H4, R2 = H)
4j (R1 = 4-FC6H4, R2 = H)
4k (R1 = 1-naphthyl, R2 = H)
4l (R1 = 2-thienyl, R2 = H)
4m (R1 = PhCH2, R2 = H)
4n (R1 = n-C4H9, R2 = H)
(Z)-4o (R1 = Ph, R2 = Me)
entry
substrate (R)
conversion (%)b
ee (%)c
1
2
3
4
4b (R = Me)
4a (R = Et)
4c (R = i-Pr)
4c (R = i-Pr)
100
100
100
100
54
92
97
96d
aHydrogenations were performed with 0.25 mmol of substrate at
room temperature under a H2 pressure of 10 bar in 2 mL of CH2Cl2 for
24 h unless otherwise specified. Substrate/[Rh(COD)2]BF4/(Rc,Sa)-5c =
1/0.01/0.011. bConversions were determined by GC. cThe ee values were
determined by HPLC on a chiral column. dReaction was performed at a
catalyst loading of 0.2 mol % under a H2 pressure of 20 bar.
9
10
11
12
13
aHydrogenations were carried out with 0.25 mmol of substrate at
room temperature under a H2 pressure of 10 bar in 2 mL of CH2Cl2 for
24 h unless otherwise specified. Substrate/[Rh(COD)2]BF4/(Rc,Sa)-5c =
1/0.01/0.022. Full conversions were achieved in all cases. bThe ee values
were determined by HPLC on a chiral column. cHydrogenation was
performed at a catalyst loading of 5 mol % under a H2 pressure of 60 bar.
suggested that the ester functional group of β,γ-unsaturated
phosphonates has a significant influence on the enantios-
electivity, and the substrate with a bulkier ester group tended
to give higher enantioselectivity. Reducing the catalyst load-
ing to 0.2 mol % did not impact enantioselectivity but
required an elevated H2 pressure of 20 bar to complete the
hydrogenation (Table 2, entry 4). Further decrease of the
catalyst loading under the same hydrogenation condition
resulted in incomplete conversion.
catalytic system gave only low conversion. Full conversion
and moderate enantioselectivity were achieved under a H2
pressure of 60 bar in the presence of 5 mol % of catalyst
(entry 13).
Catalytic asymmetric synthesis of chiral β-substituted
propylphosphonates is still rarely explored. The first exam-
ple, based on the Rh-catalyzed asymmetric 1,4-addition to
1-alkenylphosphonates using arylboroxines as arylating re-
agents, was reported by Hayashi et al. in 1999, in which a
variety of chiral β-arylalkylphosphonates were achieved in
good enantioselectivities.2a However, this method has the
disadvantages of the use of the expensive reagent and high
catalyst loadings. To demonstrate the potential of the pre-
sent catalytic system, a series of β,γ-unsaturated phospho-
nates with a i-Pr ester functional group were then prepared
and subjected to this hydrogenation under the optimized
conditions (1 mol % of catalyst loading prepared in situ from
[Rh(COD)2]BF4 and 2.2 equiv of (Rc,Sa)-FAPhos 5c, per-
formed under 10 bar of H2 pressure in CH2Cl2 at room
temperature for 24 h). As shown in Table 3, full conversions
and high yields were achieved in all cases. The results
indicated that the electronic nature and the substitution
pattern of the substituent on the phenyl ring of substrates
had no major effect on the enantioselectivities. All of the
substrates with the different substituent in the phenyl ring
were hydrogenated with high enantioselectivities (Table 3,
entries 2-8). In the hydrogenation of the substrate 4k with a
β-1-naphthyl substituent, an ee value of 97% was obtained
(entry 9). The hydrogenation of β-heteroaromatic thienyl
and β-alkyl substituted substrates 4l-n also led to good
enantioselectivities (Table 3, entries 10-12). These results
demonstrate the high efficiency of the present catalytic
system in the catalytic hydrogenation of this new substrate
class. However, for the hydrogenation of trisubstituted
olefin (Z)-4o under the optimized conditions, the present
In conclusion, we have found that a series of chiral
β-substituted 1-propylphosphonates could be synthesized
in high enantioselectivities (90-98% ee) by a Rh-catalyzed
asymmetric hydrogenation of β-substituted β,γ-unsaturated
phosphonates using a ferrocene-based monophosphorami-
dite ligand, (Rc,Sa)-FAPhos 5c under the mild conditions
(10 bar of H2 pressure and room temperature). The research
suggested that the ester functional group of β,γ-unsaturated
phosphonates has a significant influence on the enantios-
electivity, and the substrate with a bulkier ester group tended
to give higher enantioselectivity. It is our hope that the
present work will provide a new and practical method to
prepare chiral 2-substituted alkylphosphonate derivatives.
Experimental Section
General Procedure for the Preparation of 2-Substituted Allyl-
phosphonates. To a solution of RMgBr (50 mmol) in 120 mL of
Et2O was added CuI (0.57 g, 3.0 mmol). The mixture was stirred
at room temperature for 0.5 h, and then a solution of propargyl
alcohol (1.12 g, 20 mmol) in 20 mL of Et2O was added slowly.
After the addition was complete, the reaction mixture was
refluxed for 24 h. After cooling to room temperature, an
aqueous solution of saturated NH4Cl was added slowly. The
organic layer was separated, and the aqueous layer was ex-
tracted with Et2O. The organic layer was combined and dried
over anhydrous Na2SO4. After removal of the volatiles, the
residue was purified by column chromatography (silica gel,
AcOEt/n-hexane, 10/1) to give allylic alcohols 2.
Bromine (1.76 g, 11 mmol) was added to a solution of PPh3
(3.14 g, 12 mmol) in 15 mL of CH2Cl2 over 10 min, maintaining
the temperature below -10 °C. A solution of allylic alcohols
2 (10 mmol) in 5 mL of CH2Cl2 was added, and the mixture was
J. Org. Chem. Vol. 74, No. 23, 2009 9193

Duan et al.
JOCNote
allowed to warm to 10 °C over 20 min. The mixture was diluted
with pentane (50 mL) and filtered through a plug composed
of silica (25 g) layered over neutral alumina (25 g). The plug
was washed with pentane/ether (30:1), and the combined
filtrates were evaporated to provide the crude allylic bromides
3, which can be used directly for the next step without further
purification.
10 bar was maintained. The hydrogenation was performed at
room temperature for 24 h. After carefully releasing the hydrogen,
the solvent was removed. The residue was filtered through a short
SiO2 column to remove the catalyst. The filtrate was concentrated
under reduced pressure, and the enantiomeric excess was deter-
mined by HPLC on a chiral column.
Di-isopropyl 2-Phenyl-1-propylphosphonate (6c). 97% ee.
A solution of allylic bromides 3 (5 mol) in trialkyl phosphites
(15 mol) was heated to reflux and stirred at the same temperature
for 3 h. Excess trialkyl phosphite and the side product were
removed in vacuo. Flash chromatography of the residue on silica
gel (AcOEt/hexane, 1:1) gave the target allylphosphonates 4.
[R]25 = -14.4 (c 1.2, CHCl3). HPLC conditions: chiralcel
D
AD-H, 40 °C, n-hexane/isopropyl alcohol = 98/2, flow rate =
1.0 mL/min, t1 = 13.8 min; t2 = 12.7 min. 1H NMR (400 MHz,
CDCl3): δ 1.19 (d, J = 6.2 Hz, 3H), 1.24 (d, J = 6.2 Hz, 3H),
1.27 (d, J = 6.2 Hz, 3H), 1.28 (d, J = 6.2 Hz, 3H), 1.39 (d, J =
7.2 Hz, 3H), 1.97-2.07 (m, 2H), 3.17-3.21 (m, 1H), 4.59-4.67
(m, 2H), 7.17-7.23 (m, 3H), 7.27-7.31 (m, 2H). 13C NMR (100
MHz, CDCl3): δ 23.4 (d, J = 8.0 Hz), 23.9 (d, J = 5.0 Hz), 24.0
(d, J = 5.0 Hz), 34.8, 35.7 (d, J = 139.0 Hz), 69.9 (d, J =
7.0 Hz), 70.0 (d, J = 7.0 Hz), 126.3, 126.7, 128.5, 147.1 (d, J =
13.0 Hz). 31P NMR (162 MHz, CDCl3): δ 28.6. HRMS calcd for
C15H25O3P: 284.1541, found 284.1548.
1
Di-isopropyl 2-Phenylallylphosphonate (4c). Yield: 50%. H
NMR (400 MHz, CDCl3): δ 1.17 (d, J = 5.7 Hz, 6H), 1.25 (d,
J = 5.7 Hz, 6H), 3.01 (d, J = 22.2 Hz, 2H), 4.60-4.67 (m, 2H),
5.35 (d, J = 5.2 Hz, 1H), 5.50 (d, J = 5.2 Hz, 1H), 7.24-7.33 (m,
3H), 7.45-7.47 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 23.7
(d, J = 5.0 Hz), 24.0 (d, J = 3.0 Hz), 34.0 (d, J = 140.0 Hz), 70.5
(d, J = 6.0 Hz), 117.0 (d, J = 11.0 Hz), 126.4, 127.6, 128.2, 139.0
(d, J = 10.0 Hz), 140.9 (d, J = 4.0 Hz). 31P NMR (162 MHz,
CDCl3): δ 24.9. HRMS calcd for C15H23O3NaP [M þ Na]:
305.1283, found 305.1290.
Acknowledgment. We thank the National Natural Science
Foundation of China (20802076) and the Knowledge
Innovation Program of the Chinese Academy of Sciences
(DICP-S200802) for financial support.
General Hydrogenation Procedure. To
a solution of
[Rh(COD)2]BF4 (1.0 mg, 0.0025 mmol) in 1 mL of CH2Cl2, which
was placed in a nitrogen-filled glovebox, was added 2.2 equiv of
ligand (Rc,Sa)-FAPhos 5c. The mixture was stirred at room
temperature for 30 min, and then was added a solution of a
substrate (0.25 mmol) in 1 mL of CH2Cl2. The reaction mixture
was transferred to a Parr stainless autoclave. The autoclave was
purged three times with hydrogen, and a hydrogen pressure of
Supporting Information Available: 1H, 31P and 13C NMR
spectra of 4c-o and 6c-o, and analysis of ee values of the
hydrogenation products 6a-o. This material is available free of
charge via the Internet at http://pubs.acs.org.
9194 J. Org. Chem. Vol. 74, No. 23, 2009