Efficient one-pot synthesis of α-aminophosphonates from aldehydes and ketones catalyzed by ytterbium(III) triflate

Article abstract of DOI:10.1016/j.tetlet.2012.05.068

An efficient three component one-pot synthesis of N-silylated α-aminophosphonates and α,α-disubstituted α- aminophosphonates was developed using Yb(OTf)₃ as a catalyst at room temperature under mild conditions.

Full text of DOI:10.1016/j.tetlet.2012.05.068

Tetrahedron Letters 53 (2012) 3897–3899
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient one-pot synthesis of
a-aminophosphonates from aldehydes
and ketones catalyzed by ytterbium(III) triflate
⇑
Yeon Heo, Dae Hyan Cho, Mithilesh Kumar Mishra, Doo Ok Jang
Department of Chemistry, Yonsei University, Wonju 220-710, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient three component one-pot synthesis of N-silylated
tuted -aminophosphonates was developed using Yb(OTf)3 as a catalyst at room temperature under mild
conditions.
a-aminophosphonates and a,a-disubsti-
Received 9 April 2012
Revised 8 May 2012
Accepted 14 May 2012
Available online 26 May 2012
a
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Aldehyde
Ketone
a-Aminophosphonate
Ytterbium(III) triflate
a
-Aminophosphonates and their derivatives represent an
methods. However, some Lewis acids such as ZnCl2 and MgBr2
are deactivated by water released at an intermediate stage.12
Due to its high reactivity, easy handling, and inertness toward
air and water, Yb(OTf)3 has been used as an efficient Lewis catalyst
in organic transformations.13 The reaction of N-silylated imines
generated in situ with phosphites has been thought to afford N-
important class of compounds that perform increasing applications
in chemical industries. Their synthesis has received great attention
due to their potent biological activities. Most mammalian cells
contain some enzymes that hydrolyze phosphate groups. Phospho-
nates are important because of their stability with such enzymes
and their negligible mammalian cell toxicity.1 Their use in medic-
inal chemistry as enzyme inhibitors,2 antitumors,3 antibacterials,4
and anti-HIV agents5 has been well documented. Phosphonates
also serve as building blocks in the synthesis of pharmaceutically
useful compounds.6
silylated
nophosphonates. In this Letter, we report an efficient one-pot syn-
thesis of N-silylated -aminophosphonates from aldehydes or
a-aminophosphonates, which readily deprotect to a-ami-
a
ketones using hexamethyldisilazane and diethyl phosphite in the
presence of Yb(OTf)3 (Scheme 1).
Different methodologies have been developed for preparing
phosphonates, including one-pot reaction from methyleneaziri-
dines,7a DDQ-mediated direct oxidative phosphonylation of
amines under metal-free conditions,7b and lithium amide-induced
phosphonyl migration from nitrogen to carbon in terminal aziri-
The study began with a three component reaction of benzalde-
hyde with 1,1,1,3,3,3-hexamethyldisilazane and diethyl phosphite
in CH2Cl2 in the presence of 10 mol % Yb(OTf)3. The reaction pro-
ceeded smoothly at room temperature affording the desired prod-
uct in excellent yield (Table 1, entry 1). A comparable product yield
in CH3CN (entry 3) was noted, while yield was slightly reduced
when the reaction was performed in THF (entry 2). The reaction
had relatively low yield and a longer reaction time in EtOAc and
CHCl3 (entries 4 and 5). For further studies, CH2Cl2 was selected
as the solvent. A reaction using Sc(OTf)3 was not as efficient as
using Yb(OTf)3 (entry 6). To study the effect of nucleophiles,
dines.7c One of the most important ways to synthesize
a-amino-
phosphonates involves nucleophilic addition of phosphites to
imines. This reaction can be promoted by several types of catalysts,
including non-ionic surfactant Triton X-100,8a Fe3O4, and CeO2
nanoparticles,8a,b b-cyclodextrin,8c NBS,8d base catalysts,9 hetero-
poly acids,10a heterogeneous catalysts,10b,c ion exchange resins
Amberlite-IR 120,10d solid acids montmorillonite KSF,10e Brønsted
acids,10f–h and Lewis acids.11
Lewis acid-catalyzed one-pot synthesis of
nates is the most simple and efficient of the reported synthesis
a-aminophospho-
Si
Yb(OTf)3
OEt (10 mol%)
O
O
P
HN
R2
R1
Si
Si
H
OEt
OEt
R1
R2
N
H
OEt
P
O
rt
⇑
Corresponding author.
E-mail address: dojang@yonsei.ac.kr (D.O. Jang).
Scheme 1. Synthesis of a-aminophosphonates.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.068

3898
Y. Heo et al. / Tetrahedron Letters 53 (2012) 3897–3899
Table 1
Synthesis of N-silylated
reaction conditions
plished by employing ketones in place of aldehydes. Both aromatic
a-aminophosphonates from benzaldehyde under various
and aliphatic ketones reacted well to produce the corresponding
phosphonates in good yields. However, longer reaction times were
required compared to aldehydes (entry 1 vs 8). Long chained nor-
Yb(OTf)3
(10 mol%)
Si
HN
Ph
mal and
reaction (entries 9 and 10), whereas the reactivity of a cyclic ke-
tone was low (entry 11). The reaction did not proceed with ,b-
a,b-unsaturated ketones were good substrates for the
O
P
R
R
Si
Si
R
R
H
PhCHO
N
P
O
rt
H
a
R = OEt, Ph or
unsaturated cyclic ketone and benzophenone (entries 12 and 13).
To investigate the catalyst loading effect, the amount of Yb(OTf)3
was increased from 0.1 to 1.0 equiv in the reaction with acetophe-
none. However, the reaction time and yield were almost the same.
Deprotection of the trimethyl silyl group from N-silylated
n-Bu
Entry
R
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6b
7
8
OEt
OEt
OEt
OEt
OEt
OEt
Ph
CH2Cl2
THF
2.5
2.5
2.5
4
12
2.5
2.5
2.5
96
90
96
89
77
43
90
92
CH3CN
EtOAc
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
a
-aminophosphonates was accomplished by treating the com-
pound with trifluoroacetic acid in CH2Cl2 at room temperature in
quantitative yield (Scheme 2). The -aminophosphonates obtained
a
can be further modified to produce useful biologically active
compounds.14
n-Bu
In conclusion, an efficient one-pot synthesis of N-silylated
-aminophosphonates and a,a-disubstituted a -aminophospho-
a
Isolated yield.
Sc(OTf)3 was used instead of Yb(OTf)3.
b
a
nates was developed from aldehydes/ketones, hexamethyldisilaz-
ane, and diethylphosphite in the presence of Yb(OTf)3 under mild
conditions. The protocol’s advantage is the formation of a-amino-
phosphonates with easily removable N-protecting groups.
diphenylphosphine oxide and dibutylphosphine oxide were also
investigated while maintaining other optimized conditions. In both
cases, the corresponding products were obtained in comparative
yields (entries 7 and 8).
Typical procedure for one-pot synthesis of N-silylated
aminophosphonates
a-
Due to the above observations, a range of aromatic and aliphatic
aldehydes and ketones were investigated to determine the
method’s scope and limitations. The results are summarized in
Table 2. A general trend was observed for different aromatic and
aliphatic aldehydes. Aromatic aldehydes with an electron-donating
group and a moderate electron-withdrawing group afforded high
yields (entries 1–3) while aromatic aldehydes with a strong elec-
tron-withdrawing group, such as a nitro functionality, gave the de-
sired product in poor yield (entry 4). Reactions with iso-
butyraldehyde required excess 1,1,1,3,3,3-hexamethyldisilazane
and diethyl phosphite to obtain a high yield of the product (entry
5 vs 6). Similarly, n-butyraldehyde was converted into the desired
product with 87% yield (entry 7). Next, the reactivity of ketones
was examined under the present reaction conditions. Successful
A solution of benzaldehyde (53 mg, 0.5 mmol), 1,1,1,3,3,3-hex-
amethyldisilazane (121 mg, 0.75 mmol), and diethylphosphite
(103 mg, 0.75 mmol) in the presence of Yb(OTf)3 (31 mg,
0.05 mmol) in CH2Cl2 (4 mL) was stirred at room temperature for
2.5 h. The reaction mixture was washed with a saturated aqueous
NaHCO3 solution, and the product was extracted into ethyl acetate
(3 Â 10 mL). The combined organic layers were dried over anhy-
drous MgSO4 and were evaporated under reduced pressure to afford
a residue which was purified by silica gel column chromatography
(ethyl acetate/hexane, 3:7) to afford the product (151 mg, 96%): 1H
NMR (CDCl3): d 7.45–7.27 (5H, m), 4.96 (1H, d, JPH = 15.0 Hz), 4.08–
3.93 (4H, m), 1.33–1.15 (6H, m), 0.09 (9H, s); 31P NMR (CDCl3): d
20.4.
synthesis of a,a-disubstituted a-amino phosphonates was accom-
Table 2
Synthesis of N-silylated
a
-aminophosphonates from aldehydes and ketones in the presence of Yb(OTf)3
Si
Yb(OTf)3
O
O
P
HN
R2
R1
OEt (10 mol%)
OEt
Si
Si
H
OEt
OEt
R1
R2
N
H
P
O
rt
Entry
Aldehyde/Ketone
((CH3)3Si)2NH (equiv)
(EtO)2P(O)H (equiv)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14b
p-Anisaldehyde
1.5
1.5
1.5
1.5
1.5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
1.5
1.5
1.5
1.5
1.5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
36
30
30
36
48
91
97
97
26
52
88
87
89
75
80
55
0
p-N-Acetylbenzaldehyde
p-Chlorobenzaldehyde
p-Nitrobenzaldehyde
iso-Butyraldehyde
iso-Butyraldehyde
n-Butyraldehyde
Acetophenone
2-Dodecanone
Methylvinylketone
Cyclohexanone
Cyclohexenone
Benzophenone
Acetophenone
48
36
0
87
a
Isolated yield.
1.0 equiv of Yb(OTf)3 was used.
b

Y. Heo et al. / Tetrahedron Letters 53 (2012) 3897–3899
3899
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To a solution of diethyl phenyl(trimethylsilylamino)methyl-
phosphonate (175 mg, 0.5 mmol) in CH2Cl2 (10 mL) was added tri-
fluoroacetic acid (2 mL) dropwise at 0 °C and the reaction mixture
was stirred for 2 h at room temperature. Solvent was removed un-
der reduced pressure and pH was adjusted to 8.0 with a saturated
aqueous NaHCO3 solution. The mixture was extracted into ethyl
acetate (3 Â 10 mL). The combined organic layers were dried over
anhydrous MgSO4 and were evaporated under reduced pressure
to afford a residue which was purified by silica gel column chroma-
tography (ethyl acetate/hexane, 6:4) to afford the product (134 mg,
99%): 1H NMR (CDCl3):
d
7.45–7.26 (5H, m), 5.01 (1H, d,
JPH = 15.0 Hz), 4.19–3.65 (4H, m), 1.24 (6H, t, J = 7.2 Hz); 31P NMR
(CDCl3): d 21.8.
Acknowledgment
M.K.M. is grateful for
University.
a research fellowship from Yonsei
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