Titanocene dichloride as an efficient catalyst for one-pot synthesis of α-aminophosphonates

Article abstract of DOI:10.2174/157017811799304359

Commercially available titanocene dichloride was firstly used as an extremely efficient catalyst for a three-component one-pot reaction of an amine, an aldehyde (ketone), and a dialkyl phosphite to form α-aminophosphonates under solvent-free conditions at

Full text of DOI:10.2174/157017811799304359

674
Letters in Organic Chemistry, 2011, 8, 674-681
Titanocene Dichloride as an Efficient Catalyst for One-Pot Synthesis of
ꢀ-Aminophosphonates
Hong-Ying Niu*,a,b, Hui-Juan Lia, Jian-Ping Li*,a, Yu Huanga, Run-Ze Maoa, De-Yang Lia,
Gui-Rong Qua and Hai-Ming Guoa
aCollege of Chemistry and Environmental Science, Key Laboratory of Green Chemical Media and Reactions of Ministry
of Education, Henan Normal University, Xinxiang, 453007, P.R. China
bSchool of Chemistry and Chemical Engineering, Henan Institute of Science and Technology, Xinxiang 453003,
P.R.China
Received February 09, 2011: Revised June 13, 2011: Accepted June 13, 2011
Abstract: Commercially available titanocene dichloride was firstly used as an extremely efficient catalyst for a three-
component one-pot reaction of an amine, an aldehyde (ketone), and a dialkyl phosphite to form ꢀ-aminophosphonates
under solvent-free conditions at ambient temperature in good to high yields, providing a green, rapid and convenient
method for the synthesis of ꢀ-aminophosphonates.
Keywords: ꢀ-Aminophosphonates, multi-component reaction, titanocene dichloride.
INTRODUCTION
catalyst for the synthesis of ꢀ-aminophosphonates. At the
same time, titanocene dichloride is commercially available,
non-toxic, inexpensive, highly active, and easy to handle.
Herein, for the first time, titanocene dichloride is reported as
a new and efficient catalyst for the synthesis of ꢀ-
aminophosphonates under solvent-free conditions.
As a kind of natural amino analogues, ꢀ-aminophos-
phonates constitute an important class of compounds with
diverse biological activities [1]. ꢀ-Aminophosphonates are
used as peptidomimetics [2], enzyme inhibitors [3],
pharmacogenetical agents [4], inhibitors of serine hydrolases
[5] and antitumor agents [6-8]. Thus, the development of
synthetic methodologies for ꢀ-aminophosphonates has
attracted much attention of medicinal/organic chemists. A
large number of methods for the preparation of diverse ꢀ-
aminophosphonates have been published since the first
synthesis by Fields in 1952 [9-22]. However, one-pot
synthesis of ꢀ-aminophosphonates remains a favor due to its
simple procedure and excellent yields. Recently, three-
component synthesis starting from aldehydes, amines and
diethylphosphite or triethylphosphite have been reported by
using Lewis or Bronsted acid catalysts such as LiClO4 [23-
26], InCl3 [27], ZrCl4 [28], SbCl3/Al2O3 [29], TaCl5-SiO2
[30], amberlyst-15 [31], Al2O3-MW [32], CF3COOH [33],
sulfamic acid [34], BF3·Et2O [35], M(OTf)n [36], M(ClO4)n
[37] and TiO2 [38]. Unfortunately, many of these methods
suffer from some drawbacks such as long reaction times,
requirement of solvents, additional reagents, heating, costly
and moisture sensitive catalysts, or special apparatus.
Therefore, it is necessary to develop an efficient method to
construct such significant compounds.
RESULTS AND DISCUSSION
To optimize the experimental conditions, the reaction
between 4-chlorobenzaldehyde, p-methoxyaniline and
diethylphosphite was chosen as a model reaction (Table 1). It
was found that the reaction afforded medium yields with 10
mol% Tp2TiCl2 within longer reaction time when certain
solvent such as EtOH, CH2Cl2, CH3Cl, THF, EtOAc or
PhMe was employed (entries 1-6). While under solvent-free
condition, the reaction gave 95% isolated yield within 30
minutes at room temperature (entry 7). Reducing catalyst
amount (3 mol%) led to the formation of ꢀ-
aminophosphonates in lower yield (80%) even in 60 minute
(entry 9). When the reaction was conducted by using 5 mol
% of Cp2TiCl2 at room temperature for 50 min under
solvent-free condition, 95% isolated yield was obtained
(entry 8).
To evaluate the generality of the reaction, various
aldehydes/ketons and aniline were subjected to the one-pot
three-component reaction catalyzed by Cp2TiCl2 (Table 2).
First, various aromatic aldehydes with different functional
groups such as Cl, OMe, NO2, OH, NMe2, and CH3 were
checked (entries 1-10). Electronic or steric effects from
aromatic aldehydes seemed to have little impact on the
reaction. The reaction proceeded smoothly to give the
desired products in high yields. To our delight,
heteroaromatic aldehydes also gave high yields catalyzed by
Cp2TiCl2 under solvent-free conditions (entries 11-13). It is
noteworthy, product 3la and 3ma from heteroaromatic
Titanocene dichloride is a kind of Lewis acid, since ꢀ-
aminophosphonates could be synthesized through three-
component reactions catalyzed by Lewis acid, we had
predicted that titanocene dichloride could be used an active
*Address correspondence to these authors at the College of Chemistry and
Environmental Science, Key Laboratory of Green Chemical Media and
Reactions of Ministry of Education, Henan Normal University, Xinxiang,
453007, P.R. China; Tel: 86-373-3329255; Fax: 86-373-3379276;
E-mails: niu_hy@163.com; jplig@163.com
1875-6255/11 $58.00+.00
© 2011 Bentham Science Publishers

Titanocene Dichloride as an Efficient Catalyst
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
675
a
Table 1. Optimization of the Reaction Conditions for the Synthesis of ꢀ-Aminophosphonates 3 Catalyzed by Tp2TiCl2
O
OCH3
O
NH2
+
(EtO)2P
Cp2TiCl2
H
HPO(OEt)2
N
H
+
H3CO
Cl
Cl
1
2
3
Entry
Catalyst (mol%)
Solvent/Temp ( oC)
Time
Yield (%)b
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
5
EtOH/50
CH2Cl2/50
28 h
24 h
20 h
28 h
18 h
18 h
83
86
78
87
65
76
95
95
80
CHCl3/50
EtOAc/50
THF/50
PhCH3/50
Solvent-free/r.t.
Solvent-free/r.t.
Solvent-free/r.t.
30 min
50 min
60 min
3
aReaction conditions: diamine (0.5 mmol), aldehyde (0.5 mmol) and diethyl phosphite (1.5 mmol). bIsolated yields based on aldehydes.
Table 2. Synthesis of ꢀ-Aminophosphonates with Various Aldehydes/Ketons and Anilinea
NH2
O
O
Cp2TiCl2 (5 mol%)
r.t. neat
(EtO)2P
R1
+
R1
H
HPO(OEt)2
+
N
H
3
1
2a
Products b
Products b
Entry
Time (min)
Entry
Time (min)
O
O
(EtO)2P
(EtO)2P
N
N
H
1
30
11
60
H
O
3ka
90% yield
3aa
96% yield
O
(EtO)2P
O
(EtO)2P
N
Ph
N
H
N
H
2
30
12
60
N
Cl
3ba
96% yield
CH3
3la 96% yield
O
O
(EtO)2P
(EtO)2P
N
Ph
N
N
H
H
3
30
13
60
N
Cl
3ca
94% yield
Cl
3ma 97% yield

676 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Niu et al.
(Table 2). Contd…..
Products b
Products b
Entry
Time (min)
Entry
Time (min)
O
O
(EtO)2P
(EtO)2P
N
H
N
4
50
14
60
H
Cl
3na 86% yield
3da 90% yield
O
(EtO)2P
O
(EtO)2P
N
H
H3C
5
30
15
60
N
H
O2N
3oa
trace
3ea
98% yield
O
(EtO)2P
O
(EtO)2P
N
H
6
30
16
60
H3C
N
H
3pa
66% yield
NO2
3fa
88% yield
O
O
H
(EtO)2P
(EtO)2P
N
N
H
17c
60
CH3
CH3
7
60
(H3C)2N
H3C
3ga
86% yield
3qa
NR
O
(EtO)2P
O
H
N
P(OEt)2
N
H
8
70
18d
50
HO
OCH3
3ra
89% yield
3ha
96% yield
O
O
H
N
(EtO)2P
(EtO)2P
19c
120
N
H
CH3
9
50
H3CO
3ia
96% yield
3sa
NR
O
(EtO)2P
N
H
10
60
H3C
3ja
96% yield
aReaction conditions: diamine (0.5 mmol), aldehyde (0.5 mmol) and diethyl phosphite (1.5 mmol). bIsolated yields based on aldehydes. cNo Reaction, the reaction was carried out at
100ꢀoC. dThe reaction was performed at 50 oC.
aldehydes are important scaffolds with biochemical activities.
For aliphatic aldehydes, the reactions gave trace product or
lower yields (Table 2, entries 14-16). Futhermore, excellent
chemoselectivities were observed for ꢀ,ꢁ-unsaturated
carbonyl substrates (Table 2, entry 14) that no competitive
conjugate addition reaction occurred.

Titanocene Dichloride as an Efficient Catalyst
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
677
In addition to aldehydes, some ketones were also
screened to the three-component coupling reaction catalyzed
by Cp2TiCl2 under solvent-free conditions (Table 2, entries
17-19). Due to the lower reactivities than that of aldehydes,
both straight-chain aliphatic ketones like 4-methyl-2-
pentanone (entry 17) and aromatic ketones like 4-methoxy-
acetophenone (entry 19) gave no product even the reaction
was carried out at 100ꢀ oC. While cyclic ketones like
cyclohexanone (entry 18) smoothly gave the expected
product in 89 % yield at 50 oC.
To study the influence of amines, a series of aromatic and
aliphatic amines were employed as the substrates under the
optimized reaction conditions (Table 3). For aromatic amines,
Table 3. Synthesis of ꢀ-Aminophosphonates with p-Chlorobenzaldehyde and Various Aminesa
O
CHO
(EtO)2P
Cp2TiCl2 (5 mol%)
R2
R2 NH2
+
HPO(OEt)2
+
N
H
Cl
Time (min)
60
r.t. neat
Cl
1b
2
3
Productsb
Productsb
Entry
Entry
Time (min)
F
NO2
O
O
(EtO)2P
(EtO)2P
N
Cl
N
1
7
30
H
H
Cl
Cl
3bb
96% yield
3bh
85% yield
OCH3
O
O
(EtO)2P
(EtO)2P
N
H
NO2
N
2
3
4
5
60
60
30
30
8
9
50
30
60
60
H
Cl
Cl
3bc
96% yield
3bi
95% yield
O
CH3
O
(EtO)2P
(EtO)2P
N
N
H
H
NO2
Cl
Cl
3bd
92% yield
3bj
(EtO)2P
96% yield
Cl
O
O
(EtO)2P
10c
N
H
CH3
N
H
Cl
Cl
3bk
(EtO)2P
90% yield
3be
96% yield
O
Br
O
(EtO)2P
N
H
N
H
11
Cl
Cl
3bf
96% yield
3bl
85% yield
O
I
O
(EtO)2P
(EtO)2P
N
12d
60
N
H
6
50
Cl
Cl
3bg
87% yield
3bm
NR
b
o
d
aReaction conditions: diamine (0.5 mmol), aldehyde (0.5 mmol) and diethyl phosphite (1.5 mmol). Isolated yields based on aldehydes. cThe reaction was performed at 50 C. No
Reaction.

678 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Niu et al.
it was found there were no remarkable electronic and steric
effects on the three-component couplings, since anilines with
p-, o-, and m-substituents resulted in the corresponding ꢀ-
aminophosphonates in excellent yields (entries 1-9). Apart
from aromatic amines, aliphatic amines were also selected to
the three-component couplings. Primary amines, like n-butyl
amine, phenyl-methanamine (entries 10-11) could provide
the target products in reasonable yields, while secondary
amines like piperidine (entry 12) were ineffective partners
for such a reaction.
4.76 (1H, d, JHP 24.0 Hz), 6.59 (2H, d, J 8.4 Hz), 6.69 (1H, t,
J 7.6 Hz), 7.10 (2H, J 8.0 Hz), 7.25-7.28 (1H, m), 7.33 (2H,
t, J 7.6 Hz), 7.47 (2H, d, J 7.6 Hz).
3ba: White solid, mp 57-59 oC; 1H NMR (DMSO-d6, 400
MHz) ꢁ: 1.06 (3H, t, JHH 6.8 Hz), 1.71 (3H, t, JHH 6.8 Hz),
3.73-3.80 (1H, m), 3.87-3.93 (1H, m), 4.00-4.07 (2H, m)
5.06 (1H, d, JHP 24.8 Hz), 6.27-6.31 (2H, m), 6.51 (1H, br s),
6.75 (2H, d, J 8.4 Hz), 6.96-7.01 (2H, m), 7.36 (2H, d, J 8.4
Hz), 7.52 (2H, dd, J 8.4, 1.6 Hz).
3ca: White solid, mp 88-90 oC; 1H NMR (DMSO-d6, 400
MHz) ꢁ: 1.06 (3H, t, JHH 7.2 Hz), 1.17 (3H, t, JHH 6.8 Hz),
3.72-3.82 (1H, m), 3.87-3.94 (1H, m), 4.02-4.06 (2H, m)
5.03 (1H, 2d, JHP 27.6, 7.2 Hz), 6.27-6.30 (1H, m), 6.50-6.54
(1H, m), 6.74-6.76 (2H, m), 6.99 (2H, d, J 8.0 Hz), 7.45-7.51
(4H, m).
CONCLUSIONS
In conclusion, commercially available Cp2TiCl2 was
firstly found to be a new and extremely efficient catalyst for
the synthesis of ꢀ-aminophosphonates by a three-component
one-pot reaction. With the increasing concern for need of
green synthetic procedures, the advantages such as theꢀ
solvent-free reaction condition, ambient temperature, high
yields, excellent chemoselectivities,ꢀ theꢀ use of easily
available and safe catalyst, and low catalyst amount make
the present methodology attractive and environmentally
benign.
o
1
3da: White solid, mp 87-89 C; H NMR (CDCl3, 400
MHz) ꢁ: 1.06 (3H, t, JHH 8.0 Hz), 1.34 (3H, t, JHH 7.2 Hz),
3.64 (1H, t, JHH 7.6 Hz), 3.89-3.93 (1H, m), 4.18-4.25 (2H,
m), 5.06 (1H, 2d, JHP 24.0 Hz), 6.58 (2H, d, J 7.6 Hz), 6.69
(1H, t, J 7.2 Hz), 7.11 (2H, t, J 7.2 Hz), 7.20-7.26 (2H, m),
7.38 (1H, d, J 7.2 Hz), 7.52 (1H, d, J 7.2 Hz).
3ea: Yellow solid, mp 112-124 oC; 1H NMR (CDCl3, 400
MHz) ꢁ: 1.19 (3H, t, JHH 7.2 Hz), 1.30 (3H, t, JHH 7.2 Hz),
3.83-3.93 (1H, m), 3.99-4.06 (1H, m), 4.07-4.21 (2H, m),
4.86 (1H, d, JHP 24.8 Hz), 6.53 (2H, d, J 8.0 Hz), 6.74 (1H, t,
J 7.2 Hz), 7.12 (2H, t, J 7.6 Hz), 7.66 (2H, dd, J 8.8, 2.0 Hz),
8.20 (2H, d, J 8.4 Hz).
3fa: Yellow solid, mp 152-154 oC; 1H NMR (CDCl3, 400
MHz) ꢁ: 1.18 (3H, t, JHH 6.8 Hz), 1.30 (3H, t, JHH 6.8 Hz),
3.86-3.93 (1H, m), 3.94-4.06 (1H, m), 4.11-4.19 (2H, m),
4.86 (1H, d, JHP 26.8 Hz), 6.56 (2H, d, J 8.0 Hz), 6.74 (1H, t,
J 7.2 Hz), 7.13 (2H, t, J 7.2 Hz), 7.26 (1H, s), 7.52 (1H, t, J
8.0 Hz), 7.83 (1H, d, J 7.6 Hz), 8.14 (1H, d, J 7.6 Hz).
EXPERIMENTAL SECTION
General
Elemental analyses were performed on a PE-2400
elemental analyzer. Melting points were determined with a
XRC-1 micro melting point apparatus and were uncorrected.
NMR spectra were recorded with a 400 NMR spectrometer
for 1H-NMR, 100 MHz for 13C-NMR. Proton chemical shifts
ꢁ were given in ppm relative to tetramethylsilane (0.00 ppm)
in CDCl3 or to the residual proton signals of the deuterated
1
solvent DMSO-d6 (2.50 ppm) for H and 13C NMR. For
o
1
3ga: White solid, mp 72-74 C; H NMR (CDCl3, 400
MHz) ꢁ: 1.14 (3H, t, JHH 6.8 Hz), 1.28 (3H, t, JHH 7.2 Hz),
2.91 (6H, s), 3.63-3.72 (1H, m), 3.73-3.97 (1H, m), 4.03-
4.16 (2H, m), 4.67 (1H, d, JHP 24.0 Hz), 6.60 (2H, d, J 7.6
Hz), 6.67 (3H, t, J 8.4 Hz), 7.09 (2H, t, J 7.6 Hz), 7.30 (2H,
dd, J 8.8, 2.4 Hz).
column chromatography 200-300 mesh silica gel (GF254)
was used as the stationary phase. All reactions were
monitored by thin layer chromatography (TLC). All regents
were purchased from commercial sources and purified
commonly before used.
3ha: White solid, mp 86-88 oC; 1H NMR (DMSO-d6, 400
MHz) ꢁ: 1.05 (3H, t, JHH 6.8 Hz), 1.18 (3H, t, JHH 7.2 Hz),
3.57 (3H, s), 3.72-3.80 (1H, m), 3.84-3.92 (1H, m), 4.04
(2H, t, JHH 6.8 Hz), 5.00 (1H, d, JHP 24.0 Hz), 5.90 (1H, br
s), 6.61 (2H, d, J 9.2 Hz), 6.70 (2H, d, J 9.2 Hz), 7.35 (2H, d,
J 8.0 Hz), 7.50 (2H, d, J 6.8 Hz).
Typical Procedure
To a glass vial, the required carbonyl compound (0.5
mmol), an amine (0.5 mmol), diethyl phosphite (1.5 mmol),
and Cp2TiCl2 (5 mol %) were added and the mixture was
stirred at room temperature. The progress of the reaction was
monitored by TLC (eluent: EtOAc/petroleum ether, 20:80).
After the reaction was completed, EtOAc (20 mL) was added
to the reaction mixture and the catalyst was separated by
filtration. The organic solvent was removed under reduced
pressure. After purification by chromatography on silica gel
(EtOAc/petroleum ether, 20:80) the ꢀ-amino phosphonates
were obtained. All new products were characterized by NMR
and elemental analyses.
o
1
3ia: White solid, mp 96-98 C; H NMR (CDCl3, 400
MHz) ꢁ: 1.14 (3H, t, JHH 7.2 Hz), 1.28 (3H, t, JHH 6.8 Hz),
3.67-3.72 (1H, m), 3.77 (3H, s), 3.91-3.97 (1H, m), 4.08-
4.15 (2H, m), 4.71(1H, 2d, JHP 24.0 Hz), 6.59 (2H, d, J 7.6
Hz), 6.69 (1H, t, J 7.6 Hz), 6.86 (2H, d, J 8.0 Hz), 7.10 (2H,
t, J 7.6 Hz), 7.38 (2H, dd, J 8.4, 2.0 Hz).
o
1
3ja: White solid, mp 58-60 C; H NMR (CDCl3, 400
MHz) ꢁ: 1.14 (3H, t, JHH 6.8 Hz), 1.29 (3H, t, JHH 6.8 Hz),
2.31 (3H, s), 3.67-3.73 (1H, m), 3.92-3.97 (1H, m), 4.10-
4.16 (2H, m), 4.75 (1H, 2d, JHP 24.0 Hz), 6.61 (2H, d, J 7.2
Hz), 6.69 (1H, t, J 7.6 Hz), 7.12 (4H, t, J 8.0 Hz), 7.35 (2H,
d, J 6.8 Hz).
1H NMR Spectral Data for all the Products
o
1
3aa: White solid, mp 88-90 C; H NMR (CDCl3, 400
MHz) ꢁ: 1.11 (3H, t, JHH 7.2 Hz), 1.28 (3H, t, JHH 7.2 Hz),
3.62-3.72 (1H, m), 3.89-3.98 (1H, m), 4.06-4.17 (2H, m),

Titanocene Dichloride as an Efficient Catalyst
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
679
3ka: Viscous colourless oil; 1H NMR (CDCl3, 400 MHz)
ꢀ: 1.20 (3H, t, JHH 6.8 Hz), 1.29 (3H, t, JHH 7.2 Hz), 3.70-
3.74 (1H, m), 4.00-4.04 (1H, m), 4.15-4.21 (2H, m), 4.90
(1H, d, JHP 23.2 Hz), 6.35 (2H, d, J 24.0 Hz), 6.67 (2H, d, J
8.0 Hz), 6.74 (1H, t, J 7.2 Hz) , 7.15 (2H, t, J 7.6 Hz), 7.37
(1H, d, J 6.4 Hz).
3bd: Viscous colourless oil; 1H NMR (CDCl3, 400 MHz)
ꢀ: 1.18 (3H, t, JHH 6.8 Hz), 1.30 (3H, t, JHH 6.8 Hz), 3.86-
3.93 (1H, m), 3.94-4.06 (1H, m), 4.11-4.19 (2H, m), 4.86
(1H, d, JHP 26.8 Hz), 4.92 (1H,br s), 6.56 (2H, d, J 8.0 Hz),
6.74 (1H, t, J 7.2 Hz), 7.13 (2H, t, J 7.2 Hz), 7.26 (1H, s),
7.52 (1H, t, J 8.0 Hz), 7.83 (1H, d, J 7.6 Hz), 8.14 (1H, d, J
7.6 Hz).
o
1
3la: White solid, mp 178-180 C. H NMR (CDCl3, 400
MHz) ꢀ: 1.15 (3H, t, JHH 6.4 Hz), 1.25 (3H, t, JHH 6.0 Hz),
2.43 (3H, s), 3.87-3.93 (1H, m), 4.03-4.13 (2H, m), 4.17-
4.25 (1H, m), 4.89 (1H, d, JHP 20.4 Hz), 6.51 (2H, d, J 7.2
Hz), 6.69 (1H, t, J 7.2 Hz), 7.07 (2H, d, J 6.8 Hz), 7.27 (3H,
d, J 8.0 Hz), 7.42 (2H, t, J 7.2 Hz), 7.59 (2H, t, J 6.4 Hz),
o
1
3be: White solid, mp 114-116 C; H NMR (CDCl3, 400
MHz) ꢀ: 1.15 (3H, t, JHH 6.8 Hz), 1.30 (3H, t, JHH 7.2 Hz),
3.71-3.81 (1H, m), 3.94-4.00 (1H, m), 4.08-4.17 (2H, m),
4.66 (1H, d, JHP 24.0 Hz), 6.47 (2H, d, J 8.8 Hz), 7.04 (1H, t,
J 8.8 Hz), 7.31 (2H, d, J 8.4 Hz), 7.38 (2H, dd, J 8.4, 2.0
Hz).
1
7.73 (2H, t, J 7.2 Hz); C NMR (CDCl3, 100 MHz) ꢀ: 16.3,
16.5, 21.3, 46.8, 48.6 (d, JCP 180 Hz), 63.3, 63.4, 113.5,
113.8, 116.8, 117.2, 118.5, 118.9, 126.4, 128.4, 129.1, 129.4,
131.7, 138.1, 139.8, 147.6; elemental analysis, C27H30N3PO3
requires: C, 68.20; H, 6.36; N, 8.84 %.; Found: C, 68.18; H,
6.38; N, 8.85 %. LRMS (FAB) m/z (pos) 476.7 [M+1]+.
3bf: White solid, mp 124-126 oC; 1H NMR (DMSO, 400
MHz) ꢀ: 1.06 (3H, t, JHH 7.2 Hz), 1.17 (3H, t, JHH 7.2 Hz),
3.75-3.79 (1H, m), 3.87-3.91 (1H, m), 4.01-4.06 (2H, m),
5.07 (1H, d, JHP 24.0 Hz), 6.74 (1H, t, JNH 7.2 Hz, 7.13 (2H,
d, J 8.8 Hz), 7.38 (2H, t, JHH 8.6 Hz), 7.50 (2H, d, J 8.8 Hz),
7.52 (2H, d, J 8.8 Hz); 1C NMR (DMSO, 100 MHz) ꢀ: 16.5,
16.7, 52.3 (d, JCP 151.2 Hz), 62.7, 62.8, 63.1, 65.5, 113.6,
114.6, 116.9, 117.2, 119.6, 128.4, 130.5, 132.6, 136.0, 145.0,
148.9, 151.3. HRMS: calcd for C17H21BrClNO3P [M+H+]
432.0131, found 432.0131.
3bg: White solid, mp 136-138 oC; 1H NMR (CDCl3, 400
MHz) ꢀ: 1.05 (3H, t, JHH 7.2 Hz), 1.15 (3H, t, JHH 6.8 Hz),
3.72-3.78 (1H, m), 3.84-3.94 (1H, m), 4.02-4.05 (2H, m),
5.08 (1H, 2d, JHP 24.8 Hz), 6.63 (3H, t, J 8.4 Hz), 6.90 (1H,
2d, J 8.8Hz), 7.26 (1H, d, J 8.4 Hz), 7.37 (2H, d, J 8.0 Hz),
7.50 (2H, d, J 8.4 Hz). HRMS: calcd for C17H21ClINO3P
[M+H+] 479.9992, found 479.9995.
3ma: White solid, mp 148-150 oC. 1H NMR (CDCl3, 400
MHz) ꢀ: 1.15 (3H, t, JHH 6.8 Hz), 1.26 (3H, t, JHH 6.0 Hz),
3.89-3.95 (1H, m), 4.04-4.13 (2H, m), 4.17-4.23 (1H, m),
4.89 (1H, 2d, JHP 20.8 Hz), 6.50 (2H, d, J 8.0 Hz), 6.71 (1H,
t, J 6.4 Hz), 7.07-7.10 (2H, m), 7.25-7.30 (1H, m), 7.44 (4H,
1
t, J 2.4 Hz), 7.64-7.66 (2H, m), 7.72 (2H, t, J 3.0 Hz); C
NMR (CDCl3, 100 MHz) ꢀ: 16.2, 16.4, 45.9, 47.6 (d, JCP 170
Hz), 63.3, 63.6, 107.0, 113.8, 116.9, 118.8, 126.7, 127.7,
128.9, 129.2, 129.4, 129.8, 131.2, 134.4, 139.6, 145.7, 151.2;
elemental analysis, C26H27ClN3PO3 requires: C, 62.97; H, 5.
49; N, 8.47 %.; Found: C, 62.99; H, 5.50; N, 8.46 %. LRMS
(FAB) m/z (pos) 496.6 [M+1]+.
3na: White solid, mp 102-104 oC; 1H NMR (CDCl3, 400
MHz) ꢀ: 1.16 (3H, t, JHH 7.2 Hz), 1.24 (3H, t, JHH 6.8 Hz),
3.67-3.72 (1H, m), 3.91-3.97 (1H, m), 4.08-4.15 (2H, m),
4.81(1H, d, JHP 24.0 Hz), 5.48 (1H, m), 5.62 (H, m), 6.60
(2H, d, J 7.6 Hz), 6.69 (2H, d, J 7.6 Hz), 6.86 (2H, d, J 8.0
Hz), 7.12 (2H, t, J 7.6 Hz), 7.48 (2H, d, J 8.0 Hz).
o
1
3bh: White solid, mp 72-74 C; H NMR (DMSO, 400
MHz) ꢀ: 1.05 (3H, t, JHH 6.8 Hz), 1.17 (3H, t, JHH 6.8 Hz),
3.72-3.80 (1H, m), 3.86-3.92 (1H, m), 4.00-4.06 (2H, m),
5.14 (1H, 2d, JHP 24.8 Hz), 6.63 (1H, br s), 6.73-6.76 (1H,
m), 6.95 (1H, dd, J 6.4 2.8 Hz), 7.03 (1H, t, J 8.8 Hz), 7.38
1
(2H, d, J 8.4 Hz), 7.50 (2H, d, J 8.8 Hz). C NMR (DMSO,
3pa: Viscous colourless oil; 1H NMR (CDCl3, 400 MHz)
ꢀ: 0.84-1.66 (13H, m), 4.09-4.17 (4H, m), 5.92 (1H, d, JHP
23.2 Hz), 6.62-6.76 (2H, m) , 7.14 (2H, t, J 7.2 Hz), 7.66
(1H, s).
100 MHz) ꢀ: 16.5, 16.7, 53.5 (d, JCP 151.8 Hz), 62.7, 62.8,
63.1, 108.3, 115.9, 114.6, 124.3, 117.2, 124.8, 128.4, 130.5,
131.5, 132.6, 136.2, 146.8, 146.9. HRMS: calcd for
C17H20Cl2FNO3P [M+H+] 406.0542, found 406.0544.
o
1
1
3ra: White solid, mp 100-102 C; H NMR (CDCl3, 400
MHz) ꢀ: 1.23 (6H, t, JHH 6.8 Hz), 1.52 (4H, t, J 9.2 Hz), 1.65
(1H, d, J 9.2 Hz), 1.76-1.84 (2H, m), 2.17-2.22 (2H, m), 2.94
(2H, br s), 3.95-4.11(4H, m), 6.79 (1H, t, J 7.2 Hz), 7.02
(2H, t, J 7.6 Hz), 7.15 (2H, t, J 8.4 Hz).
3bi: Viscous colourless oil; H NMR (CDCl3, 400 MHz)
ꢀ: 1.16 (3H, t, JHH 6.8 Hz), 1.29 (3H, t, JHH 7.2 Hz), 3.69
(3H, s), 3.76-3.82 (1H, m), 3.95-4.02 (1H, m), 4.06-4.17
(2H, m), 4.65 (1H, d, JHP 23.6 Hz), 6.50 (2H, d, J 8.8 Hz),
6.69 (2H, d, J 8.8 Hz), 7.29 (2H, t, J 8.4 Hz), 7.39 (2H, dd, J
8.4, 1.5 Hz).
3bb: Yellow solid, mp 141-143 oC; 1H NMR (DMSO-d6,
400 MHz) ꢀ: 1.06 (3H, t, JHH=6.8 Hz), 1.15 (3H, t, JHH 6.8
Hz), 3.76-3.82 (1H, m), 3.89-3.95 (1H, m), 4.00-4.06 (2H,
m), 5.38 (1H, 2d, JHP 23.6 Hz), 6.93 (2H, J 9.2 Hz), 7.42
(2H, d, J 8.8 Hz), 7.54 (2H, dd, J 8.4, 1.6 Hz), 7.94 (3H, d, J
9.2 Hz).
o
1
3bj: White solid, mp 90-92 C; H NMR (CDCl3, 400
MHz) ꢀ: 1.16 (3H, t, JHH 6.8 Hz), 1.29 (3H, t, JHH 6.8 Hz),
2.19 (3H, s), 3.75-3.82 (1H, m), 3.94-4.00 (1H, m), 4.06-
4.18 (2H, m), 4.66 (1H, d, JHP 24.0 Hz), 6.43 (2H, d, J 7.6
Hz), 7.16-7.19 (2H, m), 7.30-7.32 (2H, m), 7.37 (2H, d, J 6.8
Hz).
3bk: Viscous colourless oil; 1H NMR (CDCl3, 400 MHz)
ꢀ: 0.78 (3H, t, JHH 7.2 Hz), 1.04 (3H, t, JHH 6.8 Hz), 1.17-
1.25 (3H, m), 1.71-1.83 (6H, m), 2.62-2.65 (2H, m), 3.46-
3.52 (1H, m), 3.59-3.67 (1H, m), 4.66 (1H, d, JHP 17.2 Hz),
7.36 (2H, d, J 8.4 Hz), 7.68 (2H, dd, J 6.8, 2.0 Hz). HRMS:
calcd for C15H26ClNO3P [M+H+] 334.1339, found 334.1341.
o
1
3bc: Yellow solid, mp 126-130 C; H NMR (CDCl3,
400 MHz) ꢀ: 1.17 (3H, t, JHH 6.8 Hz), 1.20 (3H, t, JHH 6.8
Hz), 3.66-3.78 (1H, m), 3.92-4.00 (1H, m), 4.05-4.21 (2H,
m), 4.78 (1H, d, JHP 24.8 Hz), 6.68 (2H, s), 6.89 (1H, d, J 8.0
Hz), 7.18 (1H, t, J 8.0 Hz), 7.29 (1H, d, J 8.4 Hz), 7.41-7.49
(3H, m).

680 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Niu et al.
1
Syntheses of ꢁ-Amino ꢁ-Alkyl Phosphonic Acids, Synthesis 1994,
1272-1274;
Schmidt, U.; Oehme, G.; Kraus, H. Catalytic stereoselective
synthesis of ꢁ-Amino phosphonic acid derivatives by asymmetric
hydrogenation, Synth. Commun. 1996, 26, 777-781;
3bl: Viscous colourless oil; H NMR (CDCl3, 400 MHz)
ꢀ: 1.25 (3H, t, JHH 7.0 Hz), 1.27 (3H, t, JHH 7.0 Hz), 3.50
(1H, d, J 13.2 Hz), 3.77 (1H, d, J 13.2 Hz), 3.97-4.10 (6H,
m), 7.23-7.37 (10H, m).
[16]
[17]
Schꢂllkopf, U.; Hoppe, I.; Thiele, A. Asymmetric synthesis of
aminophosphonic acids, I enantioselective synthesis of L-(1-
aminoethyl)phosphonic acid by asymmetric catalytic
-
ACKNOWLEDGEMENTS
hydrogenation of N-[1-(dimethoxyphosphoryl)ethenyl]formamide,
Liebigs Ann. Chem. 1985, 555-559;
We are grateful for financial support from the National
Nature Science Foundation of China (grants 20772024,
20802016, and 21072047), the Program for New Century
Excellent Talents in University of Ministry of Education
(NCET-09-0122), the Program for Innovative Research
Team in University of Henan Province (2008IRTSTHN002),
and Henan National Nature Science Foundation
(102300410253).
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