Efficient synthesis of α-aminophosphonates via one-pot reactions of aldehydes, amines, and phosphates in ionic liquid

Article abstract of DOI:10.1002/hc.20724

Ionic liquids such as 1,3-dialkylimidazolium bromides make excellent solvents for synthesis of α-aminophosphonates from aldehydes, amines, and phosphites. The ionic liquids are successfully regenerated and reused. Copyright

Full text of DOI:10.1002/hc.20724

Heteroatom Chemistry
Volume 22, Number 5, 2011
Efficient Synthesis of α-Aminophosphonates
via One-Pot Reactions of Aldehydes, Amines,
and Phosphates in Ionic Liquid
Rahimeh Hajinasiri,1 Zinatossadat Hossaini,1 and
Faramarz Rostami-Charati2
1Department of Chemistry, Islamic Azad University, Qaemshahr Branch, P.O. Box 163,
Mazandaran, Iran
2Department of Chemistry, Facualty of Science, Gonbad Kavous University, P.O.Box 163,
Gonbad, Iran
Received 24 November 2010; revised 25 February 2011
acids in biological systems [7–10]. The importance
ABSTRACT: Ionic liquids such as 1,3-
of this area is highlighted by an increasing number
of studies dedicated to the topic, and a large volume
of research on their synthesis and biological activ-
ities has been reported in recent years. A number
dialkylimidazolium bromides make excellent solvents
for synthesis of α-aminophosphonates from aldehy-
des, amines, and phosphites. The ionic liquids are
ꢀ
C
successfully regenerated and reused.
2011 Wiley
of potent antibiotics, enzyme inhibitors, and phar-
macological agents are α-aminophosphonic acids as
well as their derivatives, particularly peptides [11–
13]. Aminophosphonic acids are also found as con-
stituent of natural products. Several methods are
available for the preparation of α-aminophosphonic
acids [14–24]. Here, we describe an efficient method
for the synthesis of α-aminophosphonates through
the reaction of aldehydes 1, amines 2, and phos-
phites 3 in ethyl methyl imidazolium bromide.
Periodicals, Inc. Heteroatom Chem 22:625–629, 2011;
View this article online at wileyonlinelibrary.com. DOI
10.1002/hc.20724
INTRODUCTION
Ionic liquids (ILs) have gained great attention in re-
cent years [1–3]. ILs have a high polarity and low va-
por pressure. These characteristics combined with
immiscibility with most of the less polar organic sol-
vents led to their use as a solvent or cosolvent in
catalysis. ILs have shown great assurance as an al-
ternative to conventional solvents [3]. ILs have the
unique properties of high thermal stability, low va-
por pressure, immiscibility with a number of organic
solvents, nonflammability, and recyclability [4–6].
α-Aminophosphonic acids are probably the most
important substitutes for corresponding amino
RESULTS AND DISCUSSION
The reaction of aldehydes 1, amines 2, and phos-
phites 3 proceeds smoothly with ethyl methyl imi-
dazolium bromide as a solvent at room temperature
to produce α-aminophosphonates 4 in good yields
(Fig. 1, Table 1).
For optimizing the reaction conditions, a sam-
ple reaction between benzaldehyde, benzyl amine,
and triphenylphosphite was carried out with dif-
ferent ILs as solvents (Fig. 2, Table 2). The re-
sults indicated that IL ethyl methyl imidazolium
Correspondence to: Rahimeh Hajinasiri; e-mail: rhmhajinasiri@
yahoo.com.
c
ꢀ
2011 Wiley Periodicals, Inc.
625

626 Hajinasiri, Hossaini, and Rostami-Charati
H
N
O
P
H
N
O
P
[emim]Br
R-CHO
ILs
Ph
+
+ P(OPh)3
Ph
NH2
Ph-CHO
R'
+
R′
NH2
P(OR″)3
OR″
OR″
OPh
OPh
+
Ph
R
1
2
3
4
FIGURE 2 The reaction of benzaldehyde, benzyl amine, and
triphenylphosphite.
FIGURE 1 Synthesis of α-aminophosphonate derivatives.
In conclusion, ILs are proved to be useful
and novel reaction media for the synthesis of
α-aminophosphonates from simple starting mate-
rials, avoiding the use of highly polar organic sol-
vents. The effects of the type of IL used on the
activity and selectivity were investigated. The IL
[emim][Br] was found to be the most effective.
The use of imidazolium ILs at room temperature
bromide is an excellent solvent for these reactions
(see Table 2).
The products were characterized on the basis of
1
their IR, H NMR, and 13C NMR studies. The mass
spectra of compounds 4a–4i displayed molecular ion
peaks at appropriate m/z values.
TABLE 1 α-Aminophosphonate Derivatives
Entry
Aldehyde
Amine
Phosphite
Product
Yield (%)
H
N
O
P
Ph-CHO
Ph
NH2
NH2
P(OMe)3
1
Ph
Ph
4a
76
OMe
OMe
Ph
H
N
O
P
P(OPh)3
Ph
2
Ph-CHO
4b
OPh
OPh
70
Ph
Ph
H
N
O
P
OPh
OPh
NH2
NH
P(OPh)3
P(OPh)3
3
4
Ph-CHO
Ph-CHO
4c
75
68
O
P
4d
4e
N
OPh
OPh
Ph
Ph
H
N
O
P
OPh
OPh
5
Ph-CHO
NH2
P(OPh)3
P(OPh)3
65
66
H
N
O
P
Ph
OPh
OPh
6
4-ClC6H4-CHO
Ph
NH2
4f
Cl
H
N
O
P
Ph
Ph
NH2
4g
P(OMe)3
n-Pr-CHO
70
7
OMe
OMe
Heteroatom Chemistry DOI 10.1002/hc

Efficient Synthesis of α-Aminophosphonates via One-Pot Reactions of Aldehydes, Amines, and Phosphates 627
TABLE 2 Optimization of the Reaction with Different ILs
Dimethyl[(benzylamino)(phenyl)methyl]
phosphonate (4a, C16H20NO3P)
Entry
Ionic Liquids
Yield (%)
Yellow oil; yield: 0.44 g (76%). IR (KBr): ν¯ = 1246
(P O), 2953 (CH) cm−1. EI-MS: 305 (2, M+), 290 (5),
274 (35), 214 (38), 199 (38), 196 (80), 91 (100), 31 (86)
1
2
3
4
5
6
[C-mim]HSO4
[C-7mim]H2PO4
[bmim]Cl
[bmim]Br
[emim]Br
40
41
55
54
68
38
15 (70). 1H NMR: δ = 2.98 (bs, NH), 3.48 (d, 3 JP-H
10.5, OMe), 3.53 (d, 2 JHH = 13.5, NCH2), 3.73 (3 JHP
10.5, OMe), 3.80 (2 JHH = 13.5, NCH2), 4.06 (1 JHP
=
=
=
[bmim]CF3SO3
20.7, CH), 7.3–7.5 (m, 10CH). 13C NMR: δ = 51.1 (d,
3 JC-P = 17.4, NCH2), 52.8 (d, JCP = 6.8, OMe), 53.3
2
(d, 2 JCP = 6.8, OMe), 59.4 (d, 1 JCP = 152.0, CH), 127.3
5
(CH), 128.0 (d, JCP = 2.9, CH), 128.7 (4CH), 128.8
(d, 4 JCP = 2.3, 2CH), 129.1 (d, 3 JCP = 6.2, 2CH), 136.8
(C), 140.3 (C). 31P NMR: 27.06 [P(O)(OMe)2].
significantly enhanced the rate of formation of α-
aminophosphonates. Advantages of our work are as
follows: (1) The reactions were performed with IL
media as the green solvent. (2) The starting material
can be used without any activation or modification.
(3) This method is convenient for the synthesis of
dialkyl and diaryl esters.
Diphenyl[(benzylamino)(phenyl)methyl]
phosphonate (4b, C26H24NO3P)
White solid; mp: 136◦C, yield: 0.60 g (70%). IR (KBr):
ν¯ = 1262 (P O), 2949 (CH) cm−1. EI-MS: 429 (2, M+),
324 (25), 234 (98), 196 (98), 106 (70), 93 (95), 91
EXPERIMENTAL
1
2
(100). H NMR: δ = 2.91 (bs, NH), 3.65 (d, JHH
=
13.4, NCH2), 3.93 (d, 2 JHH = 13.4, NCH2), 4.36 (2 JHP
=
All chemicals and ionic liquids were obtained from
Fluka (Switzerland) and were used without fur-
ther purification. We used the following for the
measurement of mp, Electrothermal-9100 apparatus
(Labequip, Markham, Ontario, Canada); IR spectra,
21.2, CH), 7.3–7.5 (m, 20CH). 13C NMR: δ = 51.1 (d,
3 JCP = 17.0, NCH2), 59.4 (d, 1 JCP = 152.0, CH), 120.8
(d, 3 JCP = 4.0, CH), 121.1 (d, 3 JCP = 4.3, 2CH), 125.2
5
(CH), 125.3 (CH), 127.4 (CH), 128.4 (d, JCP = 3.1,
Shimadzu IR-460 spectrometer; H NMR and 13C
1
CH), 128.7 (4CH), 128.5 (d, 5 JCP = 2.4, CH), 128.8 (d,
3
4 JCP = 3.1, 2CH), 129.5 (d, JCP = 6.9, 2CH), 129.9
NMR spectra, Bruker DRX-300 AVANCE instru-
ment, in CDCl3 at 300 and 75 MHz, respectively;
δ in ppm, J in Hz. EI-MS (70 eV): Finnigan-MAT-
8430 mass spectrometer in m/z. Elemental analyses
(C, H, and N) were performed with a Heraeus CHN-
O-Rapid analyzer. The results agreed favorably with
the calculated values.
3
(4CH), 136.9 (C), 140 (C), 151.2 (d, JC-P = 9.6, C),
151.6 (d, 3 JCP = 9.6, C).31P NMR: 17.73 [P(O)(OPh)2].
Diphenyl[(cyclohexylamino)(phenyl)methyl]
phosphonate (4c, C25H28NO3P)
General Procedure for the Preparation of
Yellow oil; yield: 0.63 g (75%). IR (KBr): ν¯ = 1738
(C O), 1246 (P O), 2953 (CH) cm−1. EI-MS: 421 (2,
M+), 338 (25), 324 (35), 234 (100), 187 (85), (77),
93 (90), 91 (95), 83 (55). 1H NMR: δ = 1.12–1.18 (m,
3CH2), 1.65–1.67 (m, CH2), 1.73–1.78 (m, CH2), 2.46–
2.48 (m, CH), 2.94 (bs, NH), 4.67 (d, 2 JHP = 23.0, CH),
6.94–7.46 (m, 15CH). 13C NMR: δ = 24.6 (CH2), 24.9
(CH2), 26.3 (CH2), 32.1 (CH2), 34.4 (CH2), 54.0 (d,
Compounds 4
To a magnetically stirred solution of 1 (2 mmol) and
2 (2 mmol) in 1 mL of IL [emim][Br], 3 (2 mmol) was
added at room temperature. After completion of the
reaction (0.5–1 h), as indicated by TLC (EtOAc/n-
hexane, 2:1), the products were extracted with Et2O
(3 × 10 cm3). The solvent was evaporated under re-
duced pressure to leave the crude product, which
was purified by column chromatography on silica gel
and eluted with a mixture of n-hexane:EtOAc (3:1) to
afford pure title compounds. The IL was recovered
by addition of water (5 cm3), and collected and dried
under vacuum.
1
3 JCP = 16.9, CH), 57.7 (d, JCP = 156.5, CH), 120.8
(d, 3 JCP = 4.2, 2CH), 121.1 (d, 3 JCP = 4.1, 2CH), 125.1
(CH), 125.2 (CH), 128.3 (d, 5 JCP = 3.2, CH), 128.7 (d,
3
4 JCP = 2.3, 2CH), 129.3 (d, JCP = 6.7, 2CH), 129.8
3
(4CH), 136.9 (C), 151.1 (d, JCP = 9.6, C), 151.6 (d,
3 JCP = 9.6, C).31P NMR: 15.50 [P(O)(OPh)2].
Heteroatom Chemistry DOI 10.1002/hc

628 Hajinasiri, Hossaini, and Rostami-Charati
Diphenyl[phenyl(pipperidino)methyl]
phosphonate (4d, C24H26NO3P)
Dimethyl[1-(benzylamino)butyl]phosphonate
(4g, C13H22NO3P)
White solid, mp: 127◦C; yield: 0.55 g (68%). IR (KBr):
ν¯ = 1246 (P O), 2953 (CH) cm−1. EI-MS: 407 (2,
M+), 333 (25), 234 (100), 173 (65), 93 (75), 91 (95),
Yellow oil; yield: 0.38 g (70%). IR (KBr): ν¯ = 1246
(P O), 2953 (CH) cm−1. EI-MS: 271 (2, M+), 215
(25), 165 (35), 162 (68), 106 (70), 109 (86), 91 (100),
57(90).1H NMR: δ = 0.86 (t, 3 J = 7.3, Me), 1.29–1.67
(m, CH2), 1.39–1.51 (m, CH2), 3.5 (m, CH), 2.88 (bs,
NH), 3.74 (d, 3 JHP = 10.4, OMe), 3.75 (d, 3 JHP = 10.4,
1
74 (66). H NMR: δ = 1.42–1.49 (m, 3CH2), 2.80–
2.91 (m, 2NCH2), 2.94 (bs, NH), 4.48 (d, 2 JHP = 25.4,
CH), 6.94–7.62 (m, 15CH). 13C NMR: δ = 24.2 (CH2),
3
2
2
26.4 (2CH2), 52.3 (d, JCP = 9.6, 2NCH2), 68.1 (d,
OMe), 3.90 (d, JHH = 14.2, NCH2), 4.00 (d, JHH =
1 JCP = 165.4, CH), 121 (d, 3 JCP = 3.9, 2CH), 121.2 (d,
3 JCP = 4.2, 2CH), 125.1 (CH), 125.2 (CH), 128.2 (d,
5 JCP = 3.0, CH), 128.6 (d, 4 JCP = 2.4, 2CH), 128.8 (d,
3 JCP = 7.0, 2CH), 129.8 (4CH), 136.9 (C)), 150.8 (d,
3 JCP = 9.6, C), 152.3 (d, 3 JCP = 9.6, C). 31P NMR: 16.50
[P(O)(OPh)2].
13.3, NCH2), 7.22–7.4 (m, 5CH). 13C NMR: δ = 13.7
3
2
(Me), 19.4 (d, JCP = 11.0, CH2), 32.3 (d, JCP = 1.9,
CH2), 51.1 (d, 3 JCP = 15.0, NCH2), 51.9 (d, 2 JCP = 5.12,
OMe), 52.2 (d, 2 JCP = 6.9, OMe), 53.5 (d, 1 JCP = 148.0,
CH), 127.1 (CH), 128.6 (4CH), 141.2 (C). 31P NMR:
26.90 [P(O)(OMe)2].
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1
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3
32.0 (CH2), 47.7 (d, JCP = 17.1, NCH2), 60.9 (d,
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(P O), 2949 (CH) cm−1. EI-MS: 464 (2, M+), 434 (35),
359 (35), 234 (100), 231 (68), 106 (85), 93 (85), 91
1
(100), 35 (65). H NMR: δ = 2.91 (bs, NH), 3.66 (d,
2
2 JHH = 13.4, NCH2), 3.92 (d, JHH = 13.5, NCH2),
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=
=
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3
(4CH), 128.9 (d, JCP = 2.4, 2CH), 130.0 (d, JCP
=
6.2, 2CH), 131.1 (4CH), 134.9 (C), 135.0 (C), 151.0
3
3
(d, JCP = 10.7), 151.2 (d, JCP = 10.7, C).31P NMR:
17.0 [P(O)(OPh)2].
Heteroatom Chemistry DOI 10.1002/hc

Efficient Synthesis of α-Aminophosphonates via One-Pot Reactions of Aldehydes, Amines, and Phosphates 629
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