Chiral N,N′-dioxide-Yb(III) complexes catalyzed enantioselective hydrophosphonylation of aldehydes

Article abstract of DOI:10.1016/j.tetlet.2010.05.137

Chiral N,N′-dioxide-Ytterbium(III) complexes promoted the asymmetric addition of diethyl phosphate to aldehydes, giving the corresponding products with good yields and enantioselectivities. The addition of pyridine favored both reactivity and enantioselec

Full text of DOI:10.1016/j.tetlet.2010.05.137

Tetrahedron Letters 51 (2010) 4175–4178
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Tetrahedron Letters
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Chiral N,N0-dioxide-Yb(III) complexes catalyzed enantioselective
hydrophosphonylation of aldehydes
*
Weiliang Chen, Yonghai Hui, Xin Zhou, Jun Jiang, Yunfei Cai, Xiaohua Liu, Lili Lin, Xiaoming Feng
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610 064, China
a r t i c l e i n f o
a b s t r a c t
Chiral N,N0-dioxide-Ytterbium(III) complexes promoted the asymmetric addition of diethyl phosphate to
aldehydes, giving the corresponding products with good yields and enantioselectivities. The addition of
pyridine favored both reactivity and enantioselectivity. A possible catalytic cycle was proposed to explain
the mechanism of the asymmetric hydrophosphonylation of aldehydes.
Article history:
Received 23 April 2010
Revised 25 May 2010
Accepted 28 May 2010
Available online 8 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric hydrophosphonylation
Aldehydes
N,N0-dioxides
Ytterbium
Hydroxy phosphonates
1. Introduction
Initially, benzaldehyde 1a and diethyl phosphate 2 were chosen
as model reaction to optimize the reaction conditions. A series of
The catalytic asymmetric hydrophosphonylation of aldehydes is
one of the most powerful strategies for the synthesis of -hydroxy
N,N0-dioxide L2-metal complexes were examined. However, only
poor enantioselectivities were obtained in the presence of Sc(OTf)3,
Y(OTf)3, La(OTf)3, and Sm(OTf)3 (Table 1, entries 1–4). Fortunately,
L2-Yb(OTf)3 showed great potential in this reaction, giving the
product 3a in 53% yield with 60% ee (Table 1, entry 5). Interest-
ingly, the opposite configuration was also obtained with 47% ee,
when Fe(BF4)2ꢀ6H2O was chosen as a central metal (Table 1, entry
6). Considering both the yield and the enantioselectivity, Yb(OTf)3
was chosen for the next investigation.
a
phosphonates, whose structure–activity relationship demonstrates
wide applications in modern pharmaceutical chemistry such as
antibiotics, antiviral, HIV protease, and anticancer.1,2 Since the pio-
neering study of Wynberg on enantioselective hydrophosphonyla-
tion of aldehydes with the use of cinchona alkaloids,3 various
catalytic systems, including organic molecules4 and chiral metal
complexes5, have been developed. Shibasaki group reported the
first highly enantioselective hydrophosphonylation of aldehydes
using heterobimetallic complexes as the catalysts.5d,f Subse-
quently, excellent results were also observed by Katsuki,5j–l
Yamamoto5o, and our group5n using chiral aluminum complexes,
respectively. Very recently, titanium-BINOL-cinchonidine complex
was also employed to the reaction with excellent results.5r How-
ever, chiral Ytterbium complexes have not been utilized for this
reaction so far. On the other hand, chiral N-oxides and their metal
complexes have been shown to be highly efficient in many asym-
metric reactions.6 Herein, we wish to present chiral N,N0-dioxide
L2-Ytterbium(III) complex-catalyzed asymmetric hydrophospho-
nylation of various aldehydes, giving the desired products in good
to excellent yields (up to 99%) with good enantioselectivities (up to
82% ee). Based on the previous reports and our experiments, the
mechanism of the reaction was carefully discussed.
Then, several N,N0-dioxide ligands (Fig. 1, L1–L9) were com-
plexed in situ with Yb(OTf)3 to catalyze the asymmetric hydro-
phosphonylation of benzaldehyde 1a. As shown in Table 2, the
chiral backbone and the steric hindrance of R group of amide moi-
ety exhibited their importance in the enantioselectivities. (S)-pipe-
colic acid-oriented N,N0-dioxide L2 was superior to
derived and -proline-based ones (Table 2, entry 2 vs entries 1 and
L-ramipril acid-
L
9). On the other hand, bulkier amine-substituted amide provided
better result (Table 2, entry 2 vs entries 3–8). Accordingly, L2-
Yb(OTf)3 complex has the highest capability.
To further improve the enantioselectivity, the reaction temper-
ature was lowered to 0 °C; the enantioselectivity increased to 68%
ee, but the yield was dramatically decreased (Table 2, entry 10).
When 4 Å molecular sieves was added to the reaction system,7
the yield was greatly improved without any loss in enantioselectiv-
ity (Table 2, entry 11). Inspired by previous reports, different bases
were tested.5l Na2CO3, K2CO3, iPr2NEt, and Et3N have little influ-
ence on the enantioselectivity, while pyridine improved the
* Corresponding author. Tel./fax: +86 28 85418249.
E-mail address: xmfeng@scu.edu.cn (X. Feng).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.137

4176
W. Chen et al. / Tetrahedron Letters 51 (2010) 4175–4178
Table 1
Table 2
Central metal effects on the hydrophosphonylation of aldehydesa
Ligand effects on the hydrophosphonylation of aldehydesa
OH
OH
CHO
CHO
10 mol% L2-Yb(OTf)3 (1:1)
10 mol% L2-metal (1:1)
CH2Cl2, 30 ºC, 48 h
O
O
*
+
+
P(OEt)2
* P(OEt)2
O
HP(OEt)2
HP(OEt)2
CH2Cl2, 48 h
O
1a
2
3a
1a
2
3a
Yieldb (%)
eec (%)
Entry
Ligand
Temp (°C)
Yieldb (%)
eec (%)
Entry
Metal
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L9
L2
L2
L2
L2
L2
30
30
30
30
30
30
30
30
30
0
70
53
83
45
61
80
70
53
70
34
90
99
10
90
20
60
11
55
2
30
41
29
21
68
68
71
78
78
1
2
3
4
5
6
Sc(OTf)3
La(OTf)3
Y(OTf)3
Sm(OTf)3
Yb(OTf)3
Fe(BF4)2ꢀ6H2O
53
58
43
50
53
54
22(R)
7(R)
27(R)
3(R)
60(R)
47(S)
a
All reactions were carried out under nitrogen, benzaldehyde (0.1 mmol), diethyl
phosphite (0.15 mmol), 10 mol % L2, and 10 mol % metal in 0.5 mL CH2Cl2 at 30 °C
for 48 h.
9
10
11d
12d,e
13d,e
14d,f
b
Isolated yield.
0
0
c
Determined by HPLC analysis, the absolute configurations of 3a was determined
by comparing specific rotation.5a,c,n
ꢁ20
ꢁ20
a
All reactions were carried out under nitrogen, benzaldehyde (0.1 mmol), diethyl
L1: R = 2,6-iPr2C6H3 n = 0
phosphite (0.15 mmol), 10 mol % ligand, and 10 mol % Yb(OTf)3 in 0.5 mL CH2Cl2 for
48 h.
( )n
N
L2: R = 2,6-iPr2C6H3
L3: R = Ph
( )n
N
n = 1
n = 1
n = 1
n = 1
n = 1
n = 1
b
Isolated yield.
Determined by HPLC analysis.
Molecular sieves (20 mg 4 Å) were added.
L4: R = tBu
O
O
c
L5: R = CH2Ph
d
O
O
N
N
N
N
L6: R = adam
H
H
e
R
R
Pyridine (0.8
Pyridine (16
l
L) was added.
L7: R = 2-tBuC6H4
L8: R = 2,6-Me2C6H3
f
lL) was added.
n = 1
O
L9: Ar = 2,6-iPr2C6H3
Table 3
O
N
O
N
O
Substrate scope for the catalytic asymmetric hydrophosphonylation of aldehydesa
H
H
Ar
10 mol% L2-Yb(OTf)3 (1:1)
20 mg 4 Å MS, 16 µL pyridine
Ar
OH
O
RCHO
+
*
Figure 1. Structure of ligands.
R
P(OEt)2
HP(OEt)2
º
0.5 mL CH2Cl2, -20 C
O
1
2
3
enantioselectivity slightly (Table 2, entry 12). Fortunately, when
the temperature was further decreased to ꢁ20 °C, an obvious in-
crease in the enantiomeric excess, from 71% to 78%, was achieved,
Entry
R
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
90
99
99
89
97
92
94
85
84
94
72
85
79
87
68
84
91
78(R)
76
80(R)
80
80
71
82(R)
73
74
71
71
71(R)
71
80(R)
70
74
73
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3-PhOC6H4
4-PhC6H4
4-FC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
2-Furyl
but the yield sharply decreased (Table 2, entry 13). When 16 lL of
pyridine was added, the yield was improved up to 90% without
reduction in enantioselectivity (Table 2, entry 14). Therefore, the
optimal reaction conditions were identified as follows: 0.1 mmol
benzaldehyde, 1.5 equiv diethyl phosphate, 20 mg 4 Å molecular
9
sieves, 10 mol % L2, 10 mol % Yb(OTf)3, 16
in CH2Cl2 (0.5 mL) at ꢁ20 °C.
lL pyridine as additive
10
11
12
13
14
15
16
17
Under the optimized conditions, a range of aldehydes were
investigated,8 giving the corresponding products in high yields
and good ee values. Aldehydes bearing electron-donating groups
gave slightly higher enantioselectivities and reactivities than the
electron-withdrawing ones (Table 3, entries 2–9 vs 10–13). Fural-
dehyde was also found to be suitable in the reaction, and good re-
(E)PhCH@CH
1-Naphthyl
2-Naphthyl
a
All reactions were carried out under nitrogen, aldehyde (0.1 mmol), diethyl
sult was obtained (Table 3, entry 14). The
a,b-unsaturated
phosphite (0.15 mmol), 10 mol % L2, 10 mol % Yb(OTf)3, 20 mg 4 Å MS, and 16
pyridine in 0.5 mL CH2Cl2 at ꢁ20 °C for 48 h.
lL
aldehyde worked well with diethyl phosphate, giving the desired
product in 99% yield and 70% ee (Table 3, entry 15). The con-
densed-ring aldehydes (1-naphthyl, 2-naphthyl) were also tested,
delivering the corresponding products with good yields and
enantioselectivities (Table 3, entries 16 and 17).
b
Isolated yield.
c
Determined by HPLC analysis and the absolute configurations were assigned by
comparing with reported results of the optical rotation.5a,c,n
To clarify the mechanism of the reaction, some control experi-
ments were carried out. When pyridine was used in the absence
of L2-Yb(III) complex, the reaction did not occur, which implied
that the weak base pyridine could not catalyze the reaction inde-
pendently.4,9 L2-Ytterbium(III) complex promoted the reaction
smoothly at 0 °C, and the addition of pyridine favored the yield,
while the catalyst did not catalyze the reaction without pyridine
at ꢁ20 °C.10 On the other hand, L2-Yb(III) complex could efficiently
catalyze the reaction using pyridine as an additive at ꢁ20 °C.11
Based on these facts, a possible mechanism of chiral N,N0-dioxide
L2-Ytterbium(III) complex-catalyzed asymmetric hydrophospho-
nylation was proposed in Scheme 1. As rare metals, Sc(III) and
Yb(III) have numerous similar properties, including high oxophilic-
ity and Lewis acidity.12 We suspected that N,N0-dioxide-Yb(III)

W. Chen et al. / Tetrahedron Letters 51 (2010) 4175–4178
4177
at ꢁ20 °C, and the reaction mixture was stirred for 48 h. The pure
-hydroxy phosphonate 3a was afforded by column chromatogra-
2OTf-
a
phy on silica gel (ethyl acetate/petroleum ether 1:1 ꢂ 5:1) in 90%
yield with 78% ee. The ee was determined by HPLC analysis using
a Chiral AS-H column (hexane/2-propanol 80:20, 1.0 mL/min,
UV = 210 nm; tmajor = 7.13 min, tminor = 8.92 min). White solid,
*
*
O
O
O
O
O
RCHO + HPO(OEt)2
Yb
*
*
½
a 2D0
= +27.4 (c 0.175, CHCl3).
ꢃ
Yb
*
*
O
O
O
O
O
OTf
OTf
R
CH PH(OEt)2
Acknowledgments
A
B
*
We appreciate the National Natural Science Foundation of Chi-
na (No. 20872096), PCSIRT (No. IRT0846), and National Basic Re-
search Program of China (973 Program) (No. 2010CB833300) for
financial support and Sichuan University Analytical & Testing Cen-
ter for NMR spectroscopic analysis.
2OTf-
O
O
O
OH
Yb
*
*
O
O
R
P(OEt)2
O
*
O
H
N
R
CH P(OEt)2
C
2OTf-
Supplementary data
*
*
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.137.
O
O
O
O
Yb
Yb
*
*
*
*
O
O
O
O
OH
O
References and notes
N
H
O
O
CH
P(OEt)2
R
CH P(OEt)2
R
1. (a)The Role of Phosphonates in Living Systems; Hilderbrand, R. L., Ed.; RCRC Press:
Boca Raton, FL, 1983; (b) Engel, R. Chem. Rev. 1977, 77, 349; (c)
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Lifshits, M. I.; Karpenko, M. P. Zh. Obshch. Khim. 1982, 52, 801; (b) Stowasser, B.;
Budt, K. H.; Li, J. Q.; Peyman, A.; Rrppert, D. Tetrahedron Lett. 1992, 33, 6625; (c)
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D
E
N
H
Scheme 1. Proposed mechanism of the hydrophosphonylatin of aldehydes.
generated a transition state similar to N,N0-dioxide-Sc(III), and all
the oxygens of N-oxides coordinated with Yb(III).13
3. Wynberg, H.; Smaardijk, A. A. Tetrahedron Lett. 1983, 24, 5899.
4. Uraguchi, D.; Ito, T.; Ooi, T. J. Am. Chem. Soc. 2009, 131, 3836.
As a high oxophilic Lewis acid, the L2-Ytterbium(III) complex
could coordinate with aldehyde and diethyl phosphate efficiently.
In addition, Lewis acid favored the conversion of the phosphonate
tautomer into the phosphite tautomer (active). After a tautomeric
arrangement, the phosphite moiety of intermediate C showed en-
ough nucleophilicity to undergo the hydrophosphonylation suc-
cessfully at 0 °C. However, the reactivity of C sharply decreased,
when the temperature was lowered to ꢁ20 °C. It is supposed that
pyridine could enhance the nucleophilicity of the phosphorus atom
by trapping the proton of phosphite tautomer,14 and higher reac-
tive intermediate D, E could form, in which C–P bond formation
could process smoothly at ꢁ20 °C. Accordingly, the reaction could
proceed in the route of A–B–C at 0 °C without pyridine,15 while the
reaction could proceed in the route of A–B–D–E in the presence of
pyridine.
In conclusion, we have developed an asymmetric hydrophos-
phonylation of aldehydes using N,N0-dioxide L2-Ytterbium(III)
complex as a catalyst with pyridine as an additive. The reaction
underwent smoothly to give the corresponding adducts in good
to excellent yields (up to 99%) with good enantioselectivities (up
to 82% ee). In addition, a proposed catalyst cycle was depicted.
This, along with the expansion of N,N0-dioxides to other classes
of nucleophiles and electrophiles, constitutes the subject of our
sustained efforts.
5. Chiral lanthanoid complexes: (a) Yokomatsu, T.; Yamagishi, T.; Shibuya, S.
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Lett. 1994, 35, 227; (c) Yokomatsu, T.; Yamagishi, T.; Shibuya, S. J. Chem. Soc.,
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Yamagishi, T.; Yokomatsu, T.; Suemune, K.; Shibuya, S. Tetrahedron 1999, 55,
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(o) Abell, J. P.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 10521; Chiral titanium
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7. Molecular sieves were added to remove the water that decreased reaction
yield, see 5(h).
8. Aliphatic aldehydes were also tested in the reaction, but only poor results were
obtained.
9. Benzaldehyde and phenylglyoxal did not react with diethyl phosphate in the
presence of 16
10. The catalyst promoted the reaction smoothly in 90% yield with 68% ee in the
presence of 10 mol % L2-Yb(III) complex, 20 mg 4 Å MS at 0 °C. When 0.8
lL pyridine, 20 mg 4 Å MS at ꢁ20 °C.
2. General procedure
lL
pyridine was added, the yield increased to 99%, but no product was detected at
all in the absence of pyridine at ꢁ20 °C.
Typical procedure for the enantioselective hydrophosphonylation of
aldehydes. The mixture of Yb(OTf)3 (6.2 mg), 4 Å molecular sieves
(20 mg), L2 (6.5 mg), and CH2Cl2 (0.5 mL) was stirred in a test tube
under nitrogen atmosphere at room temperature for 30 min. Then
aldehyde 1a (0.1 mmol) was added and stirred for 20 min. The
11. The reaction underwent smoothly, giving product in 90% yield with 78% ee in
the presence of 10 mol % L2-Yb(III) complex, 20 mg 4 Å MS, 16
ꢁ20 °C.
lL pyridine at
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13. Liu, Y. L.; Shang, D. J.; Zhou, X.; Liu, X. H.; Feng, X. M. Chem. Eur. J. 2009, 15,
2055.
diethyl phosphate (0.15 mmol) and pyridine (16 lL) were added

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W. Chen et al. / Tetrahedron Letters 51 (2010) 4175–4178
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