Lanthanide amides [(Me3Si)2N]3Ln(μ-Cl) Li(THF)3 catalyzed hydrophosphonylation of aryl aldehydes

Article abstract of DOI:10.1021/jo101743e

A highly efficient method for the synthesis of α-hydroxy phosphonates via lanthanide amides [(Me₃Si)₂N]₃Ln(μ-Cl) Li(THF)₃ catalyzed hydrophosphonylation of aromatic aldehydes was developed. The reactions produce

Full text of DOI:10.1021/jo101743e

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methods such as reduction of keto phosphonates,2 R-hydrox-
Lanthanide Amides [(Me3Si)2N]3Ln( μ-Cl)Li(THF)3
Catalyzed Hydrophosphonylation of Aryl Aldehydes
ylation of alkyl phosphonates,3 and addition of trialkyl
phosphites to aldehydes4 have been utilized for the synthesis
of R-hydroxy phosphonates. Besides these pathways, the
addition of dialkyl phosphites to aldehydes, known as the
Pudovik reaction,5 is undoubtedly the most straightforward
and atom-economical one to R-hydroxy phosphonates. How-
ever, the Pudovik reaction cannot proceed spontaneously
without heating in the absence of catalyst. Many research
groups dedicated their efforts to develop highly active cata-
lysts for this reaction in recent years. As a consequence, some
catalysts or promoters, including metal oxides (such as MgO6
Qingmao Wu, Jun Zhou, Zhigang Yao, Fan Xu,* and
Qi Shen*
Key Laboratory of Organic Synthesis, College of Chemistry,
Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, China
*xufan@suda.edu.cn;qshen@suda.edu.cn
Received September 5, 2010
7
and Al2O3 ), Lewis bases8 (such as Et3N,9 pyridine,10 and
TMG11), Bronstedbases(suchasEtONa12 and Ti(OiPr)413,7b),
and some others (such as KF14 and MoO2Cl215), were found
to be effective for this transformation. In addition, several
examples of the reaction under thermal noncatalyzed
conditions16 were also reported. It came to our notice that
most of these systems require relatively harsh reaction condi-
tions, such as high temperature (above 100 °C), long time
(over 1 h), and/or high catalyst loading (more than 10 mol %).
Moreover, the yields were not always good and in some
instances the target products may cleave and regenerate
the starting raw materials.12,16b,17 More recently, to meet
the growing demand for enantiomerically pure materials,
the asymmetric synthesis of R-hydroxy phosphonates has
been greatly developed18 while the methods reported for the
A highly efficient method for the synthesis of R-hydroxy
phosphonates via lanthanide amides [(Me3Si)2N]3Ln-
( μ-Cl)Li(THF)3 catalyzed hydrophosphonylation of aro-
matic aldehydes was developed. The reactions produced
the products in excellent yields in the presence of 0.1 mol %
[(Me3Si)2N]3La( μ-Cl)Li(THF)3 at room temperature with-
in 5 min. The existence of LiCl in the catalyst was a key
factor affecting the catalytic activity. The mechanism for the
process of high efficiency was proposed.
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7498 J. Org. Chem. 2010, 75, 7498–7501
Published on Web 10/06/2010
DOI: 10.1021/jo101743e
r
2010 American Chemical Society

Wu et al.
JOCNote
stereoselective hydrophosphonylation of aldehydes usually
involve high catalyst loading. Therefore, the further develop-
ment of novel catalysts and relevant processes of high efficiency
for the synthesis of R-hydroxy phosphonate as valuable small
molecule still remains of great interest.
TABLE 1. Catalysts Screening for the Reaction of Benzaldehyde with
Diethyl Phosphitea
Homoleptic bis(trimethylsilyl)amides of lanthanides
19
Ln[N(SiMe3)2]3 have been found to be efficient catalysts
entry
catalyst
loading (mol %) time yield (%)
for a series of intermolecular or intramolecular reactions,
including the Tishchenko reaction,20 amidation,21 monoad-
dition of terminal alkynes to nitriles,22 coupling reaction of
isocyanides with terminal alkynes,23 and dimerization of
terminal alkynes.24 They also show high activity as catalysts
for versatile hydroelementation processes such as hydrosilyla-
tion,25 hydroboration,26 hydroamination,20b,27 hydrophos-
phination,28 and hydroalkoxylation.29 The tetracoordinate
1
2
3
4
5
6
7
8
9
LaCl3
2.0
2.0
2.0
2.0
0.5
0.1
0.5
0.1
0.05
1.0
12 h
12 h
12 h
6 h
5 min
5 min
5 min
5 min
5 min
48 h
0
0
0
0
63
0
96
92
43
0
LaBr3
LaI3
Yb(OTf)3
La[N(SiMe3)2]3
La[N(SiMe3)2]3
[(Me3Si)2N]3La(μ-Cl)Li(THF)3
[(Me3Si)2N]3La(μ-Cl)Li(THF)3
[(Me3Si)2N]3La(μ-Cl)Li(THF)3
10 LiCl
lanthanide amides [(Me3Si)2N]3Ln( μ-Cl)Li(THF)3,30
a
aReactions were performed with 1 mmol of PhCHO and 1.2 mmol of
chloride-bridged “ate” complex derived from Ln[N(SiMe3)2]3,
also work well as catalysts for aldol condensation,31 MMA
polymerization,30c,d aza-Henry reaction,32 and guanylation of
amines.33 Although [(Me3Si)2N]3Ln( μ-Cl)Li(THF)3 is more
readily available than Ln[N(SiMe3)2]3 from the viewpoint of
the synthetic method, the application of the former as an efficient
catalyst is comparatively limited. In some instances reported, the
catalytic activities of the tricoordinate Ln[N(SiMe3)2]3 and
tetracoordinate [(Me3Si)2N]3Ln( μ-Cl)Li(THF)3 were com-
pared with each other. The results indicated that the existence
HOP(OEt)2 in 1 mL of toluene at 25 °C.
of LiCl in [(Me3Si)2N]3Ln( μ-Cl)Li(THF)3 may sometimes31,32
improve the activity of Ln[N(SiMe3)2]3 while at other times33
produce the opposite effect.
In continuation of our previous studies on lanthanide-
catalyzed carbon-nitrogen bond-forming reactions,34 we
investigated the effectiveness of lanthanide amides as cata-
lysts for the carbon-phosphorus bond-forming reactions.
Herein, the paper presents a highly efficient process afford-
ing R-hydroxy phosphonates by the lanthanide amides-
catalyzed Pudovik reaction.
ꢀ
ꢀ
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The addition of diethyl phosphite to benzaldehyde to
afford diethyl [hydroxy(phenyl)methyl]phosphonate was
used as the model reaction in our initial screening of potential
lanthanide catalysts. As shown in Table 1, typical Lewis acid-
type compounds such as lanthanum trihalides (LaX3, X =
Cl, Br, I) and ytterbium triflate [Yb(OTf)3] cannot initiate
the reaction with the catalyst loading of 20 mol % (entries
1-4), indicating that the Lewis acidity of the lanthanide
compounds was not decisive in catalyzing this reaction. In
strong contrast, homoleptic lanthanum amide La[N(SiMe3)2]3
catalyzed the reaction with high efficiency. The product was
obtained in 63% yield with 0.5 mol % La[N(SiMe3)2]3 at 25 °C
for 5 min (entry 5). However, no desired product was observed
when the catalyst loading was decreased to 0.1 mol % (entry 6).
To our delight, the tetracoordinate lanthanum amide
[(Me3Si)2N]3La( μ-Cl)Li(THF)3 exhibited the catalytic activ-
ity that was still superior to that of tricoordinate lanthanum
amide La[N(SiMe3)2]3. The utility of 0.5 mol % of [(Me3Si)2-
N]3La( μ-Cl)Li(THF)3 gave the product in an excellent 96%
yield within 5 min (entry 7). Optimization studies revealed that
decreasing the catalyst loading to 0.1 mol % kept the yield at
92% (entry 8). Further decreased catalyst loading of 0.05 mol
% led to a dramatically lowered yield of 43% (entry 9).
Because [(Me3Si)2N]3La( μ-Cl)Li(THF)3 can be regarded as
a solvated adduct of La[N(SiMe3)2]3 and LiCl, anhydrous LiCl
was tried alone to verify whether it can act as a catalyst inde-
pendently. No product was detected after 48 h (entry 10).
Besides, the use of the mixture of La[N(SiMe3)2]3 and
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J. Org. Chem. Vol. 75, No. 21, 2010 7499

Wu et al.
JOCNote
TABLE 2. The Influence of Lanthanide Metal on the Reactiona
TABLE 4. [(Me3Si)2N]3La(μ-Cl)Li(THF)3-Catalyzed Reaction of
Aromatic Aldehydes with Dialkyl Phosphitesa
Ln =
Y
La
93
Nd
94
Sm
92
Er
90
Yb
82
entry
Ar
R
product
yield (%)
yield (%)
93
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Ph
1-naphthyl
2-furyl
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
i-Pr
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
92
97
94
92
91
92
94
96
92
93
96
94
94
94
94
95
94
91
aReactions were performed with 1 mmol of PhCHO and 1.2 mmol of
HOP(OEt)2 in 1 mL of toluene at 25 °C for 5 min.
2-Me2N-C6H4
4-Me2N-C6H4
2-CH3O-C6H4
3-CH3O-C6H4
4-CH3O-C6H4
2-CH3-C6H4
4-CH3-C6H4
2-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
4-F-C6H4
TABLE 3. The Influence of Alkali Metals and Halogens on the Reactiona
entry
M
X
yield (%)
1
2
3
4
5
Li
Li
Li
Na
Na
Cl
Br
I
Cl
I
94
91
14
18
0
3-NO2-C6H4
4-NO2-C6H4
Ph
Ph
aReactions were performed with 1 mmol of aldehyde and 1.2 mmol of
dialkyl phosphite in 1 mL of toluene at 25 °C for 5 min.
aReactions were performed with 1 mmol of PhCHO and 1.2 mmol of
HOP(OEt)2 in 1 mL of toluene at 25 °C for 5 min.
anhydrous LiCl in 1:1 ratio in THF as catalyst failed to
produce the same effect with [(Me3Si)2N]3La( μ-Cl)Li-
(THF)3. The result indicated that the combination manner
of La[N(SiMe3)2]3 with LiCl in crystalline [(Me3Si)2N]3-
La( μ-Cl)Li(THF)3 may be a key factor affecting its cata-
lytic ability. Then, the reaction conditions were selected as
0.1 mol % of [(Me3Si)2N]3Ln( μ-Cl)Li(THF)3 at 25 °C for
5 min for the following studies.
Next, a series of lanthanide amides were used to assess the
influence of central metal on the activity and the results are
shown in Table 2. It was found that the decrease in the Ln(III)
ionic radii from the light rare earth La to heavy rare earth
Er and Y has little influence on the reaction and the high yields
above 90% were obtained. When [(Me3Si)2N]3Yb( μ-Cl)-
Li(THF)3 was used, a slightly decreased yield of 82% was
observed. So, the amide complex of La, the largest metal among
those tested, was chosen as a representative lanthanide source
for carrying out the following studies.
Considering the obvious difference in the activity pre-
sented between La[N(SiMe3)2]3 and [(Me3Si)2N]3La( μ-Cl)-
Li(THF)3, a new question arose if LiCl is the best partner of
La[N(SiMe3)2]3 in improving the activity. It was known that
[(Me3Si)2N]3Ln( μ-Cl)Li(THF)3 can be formed in situ by the
metathesis reaction of LnCl3 with 3 equiv of LiN(SiMe3)2 in
THF.30c-e To learn more about the influence of alkali metal
ion and halide ion on the reaction, the model reaction with in
situ formed tetracoordinate lanthanum amides, generated by
the reaction of lanthanum trihalides with silylamides of
sodium or lithium, as catalysts was performed. The results
are presented in Table 3. As we expected, the in situ formed
[(Me3Si)2N]3La( μ-Cl)Li(THF)3 showed the same activity as
that of prepared [(Me3Si)2N]3La( μ-Cl)Li(THF)3 under the
standard reaction conditions. However, either changing
Cl to Br and I or changing Li to Na led to a decrease of the
yield. For example, the utility of LaI3 instead of LaCl3 gave a
yield of 14% (entry 3) while using NaN(SiMe3)2 instead of
LiN(SiMe3)2 provided an 18% yield (entry 4). The catalyst
generated from NaN(SiMe3)2 and LaI3 failed to give the
desired product (entry 5).
With the optimum reaction conditions in hand, the scope
of the reaction was explored to various aromatic aldehydes
and dialkyl phosphites. As shown in Table 4, all the reactions
proceeded smoothly and quickly affording the correspond-
ing R-hydroxy phosphonates in excellent yields (91-97%) at
room temperature within 5 min. The reaction was general for
aromatic aldehydes bearing substitutions at ortho-, meta-,
and para-positions and tolerates both electron-deficient
aldehydes and those that are electron rich. Heteroatoms
either in the functional groups of the benzene ring or in
heteroaromatics such as furan had no influence on the
reaction. Dialkyl phosphites with different steric hindrances
underwent the reaction giving the yields with little difference.
The results suggest that [(Me3Si)2N]3La( μ-Cl)Li(THF)3 is
highly active in catalyzing the hydrophosphonylation of
aromatic aldehydes, regardless of electronic effects or steric
effects of the substrates.
According to the distinctive properties of lanthanide
amides, the proposed mechanism (Scheme 1) for the Pudovik
reaction may involve rapid deprotonation of the dialkyl
phosphite, which may exist in its tautomeric form as the
phosphonate, releasing amine and forming the intermediate 5,
which is most probably the catalytically active species. 5 then
reacts as a nucleophile toward the carbonyl carbon atoms of
the aldehyde to generate the target R-hydroxy phosphonate.
The superiority in the catalytic ability of [(Me3Si)2N]3-
Ln( μ-Cl)Li(THF)3 over Ln[N(SiMe3)2]3 may be accounted
for by two possibilities. First, it has been found that the Ln-N
bond lengths in [(Me3Si)2N]3Ln( μ-Cl)Li(THF)3 are longer
than those found in Ln[N(SiMe3)2]3. For example, the average
30b
˚
Nd-N bond distance of 2.336 A
in [(Me3Si)2N]3Nd-
( μ-Cl)Li(THF)3 is longer than the Nd-N bond length of
2.29 A found in Nd[N(SiMe3)2]3, and the average Sm-N
19d
˚
7500 J. Org. Chem. Vol. 75, No. 21, 2010

Wu et al.
JOCNote
35
SCHEME 1. Proposed Mechanism for the Lanthanide Amide-
Catalyzed Pudovik Reaction
[(Me3Si)2N]3Ln( μ-Cl)Li(THF)3 is used, the aldehyde may
coordinate to the lithium to form the sterically less crowded
transition state B, wherein the Li moiety in the catalyst func-
tions as a Lewis acid instead of lanthanide. The stability of the
transition state B caused by the cooperation of lanthanide and
lithium may be an important factor resulting in the high
efficiency of [(Me3Si)2N]3Ln( μ-Cl)Li(THF)3.
In conclusion, we demonstrated here a highly efficient
method for the synthesis of R-hydroxy phosphonates via
hydrophosphonylation of aromatic aldehydes catalyzed by
the tetracoordinate lanthanide amides [(Me3Si)2N]3Ln-
( μ-Cl)Li(THF)3. The target products could be obtained in
excellent yields in the presence of 0.1 mol % of [(Me3Si)2N]3-
La( μ-Cl)Li(THF)3 at room temperature within 5 min. The
existence of LiCl in the catalyst was a key factor affecting the
catalytic activity. The further applications of this reaction for
the stereoselective synthesis of R-hydroxy phosphonates are
currently under investigation.
Experimental Section
Representative Procedure for Hydrophosphonylation of Aro-
matic Aldehydes. A mixture of [(Me3Si)2N]3La( μ-Cl)Li(THF)3
(8.8 mg, 0.01 mmol) and diethyl phosphite (1.66 g, 12 mmol) in
toluene (10 mL) was stirred for 10 min. Benzaldehyde (1.06 g,
10 mmol) was then added and the resulting mixture was allowed
to stir at 25 °C for 5 min. Water was added, and the mixture was
extracted with ethyl acetate (3 Â 10 mL). The combined organic
layer was dried over anhydrous Na2SO4, concentrated in vacuo,
and purified by chromatography on silica gel [eluent: acetone/
petroleum ether (60-90 °C) 1:5] to afford 3a (2.24 g, 92%) as
white crystals.
Diethyl (hydroxy(phenyl)methyl)phosphonate (3a): mp 82-83
°C (white crystals, lit.36 mp 83 °C); 1H NMR (400 MHz, CDCl3)
δ 7.50-7.48 (m, 2H), 7.39-7.30 (m, 3H), 5.03 (d, J = 10.8 Hz,
1H), 4.11-3.93 (m, 4H), 3.62 (br s, 1H), 1.27 (t, J = 7.2 Hz, 3H),
1.22 (t, J = 7.2 Hz, 3H).
bond distance of 2.319 A30c in [(Me3Si)2N]3Sm( μ-Cl)Li(THF)3
˚
is longer than the Sm-N bond length of 2.284 A19e found in
˚
Sm[N(SiMe3)2]3. These deviations of bond lengths may be
ascribed to the different steric hindrance around the lanthanide
metal center. The sterically more crowded [(Me3Si)2N]3Ln( μ-
Cl)Li(THF)3 may undergo the metathesis reaction with HOP-
(OR)2 more rapidly to form species 5. Besides, the extraordin-
ary activity that [(Me3Si)2N]3Ln( μ-Cl)Li(THF)3 displayed
may be rationalized by the cooperation of lanthanide and
lithium. In the case of using Ln[N(SiMe3)2]3 as catalyst, the
lanthanide center in species 5 may coordinate to the aldehyde
and lead to a close contact between the aldehyde and the
nucleophilic phosphorus atom via a transition state A, wherein
the lanthanide acts as a Bronsted base to deprotonate HOP-
(OR)2 as well as a Lewis acid to activate the aldehyde. However,
the formation of the transition state A may be suppressed
to a certain extent by the steric repulsive interactions of
the two substrates. When the sterically more flexible
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (20872106, 20972107) for finan-
cial support.
Supporting Information Available: General experimental
procedure, characterization data, and spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(35) Zhang, K.; Zhang, W.; Wang, S.; Sheng, E.; Yang, G.; Xie, M.;
Zhou, S.; Feng, Y.; Mao, L.; Huang, Z. Dalton Trans. 2004, 1029.
(36) Sekiguchi, A.; Ikeno, M.; Ando, W. Bull. Chem. Soc. Jpn. 1978, 51,
337.
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