Synthesis of tertiary α-amino phosphonate by one-pot three-component coupling mediated by LPDE

Article abstract of DOI:10.1016/S0040-4020(03)00759-2

A very mild, efficient and simple method for the synthesis of tertiary α-amino phosphonates is reported by reaction of an aldehyde, a secondary amine and trialkylphosphite in ethereal solution of lithium perchlorate, LPDE, at ambient temperature with high

Full text of DOI:10.1016/S0040-4020(03)00759-2

Tetrahedron 59 (2003) 5329–5332
Synthesis of tertiary a-amino phosphonate by one-pot three-
component coupling mediated by LPDE
*
Najmedin Azizi and Mohammad R. Saidi
Department of Chemistry, Sharif University of Technology, P.O. Box 11365-9516 Tehran, Iran
Received 20 February 2003; revised 16 April 2003; accepted 8 May 2003
Abstract—A very mild, efficient and simple method for the synthesis of tertiary a-amino phosphonates is reported by reaction of an
aldehyde, a secondary amine and trialkylphosphite in ethereal solution of lithium perchlorate, LPDE, at ambient temperature with high
yields. q 2003 Elsevier Science Ltd. All rights reserved.
a-Amino phosphonates are an important class of com-
pounds in pharmaceutical chemistry. The potential of
a-amino phosphonates as peptide mimics,1 enzyme
inhibitors,2 antibiotics and pharmacological agents3 has
been proved. Thus a variety of synthetic approaches are
desirable to synthesize of a-amino phosphonate. Among the
available methods, the nucleophilic addition of phosphite to
imines is the most convenient and is usually activated by an
alkali metal alkoxide or by a Lewis acid.4
appeared, which indicated the formation of iminium ion 3.
The mixture of 1 and 2 in diethyl ether, in the absence of
lithium perchlorate, did not produce the iminium ion 3 (no
signal at 8.6 ppm). Upon addition of trialkylphosphite,
tertiary a-amino phosphonates 4 was prepared in good
yields after few minutes at room temperature, Scheme 1.
To show the generality of this method, a wide range of
aldehydes were subjected to this procedure and converted to
the corresponding tertiary a-amino phosphonates with high
yields. Both aromatic and aliphatic aldehydes reacted with
secondary amines such as pyrrolidine, morpholine,11
diethylamine (trimethylsilyl)dimethyamine and piperidine.
The results are shown in Table 1.
A direct one-pot synthesis of tertiary a-amino phosphonates
has been reported via the reaction of an aldehyde with an
amine and dialkyl phosphite.5–8 Recently, we have reported
a one-pot three-component, general method for the
aminoalkylation of aldehyde with different nucleophiles.9
In this paper we describe a mild, convenient and simple
procedure for a three-component reaction of an aldehyde, a
secondary amine and trialkylphosphite for the preparation
of tertiary a-amino phosphonates. One-pot reaction mild
working condition and absence of tedious procedure for the
preparation of the iminium salt in separate step is the
advantage of this method compare to those reported
before.4c In addition to this, in most cases, almost pure
products are obtained by a simple work up procedure.
Reaction of aldehyde 1, a secondary amine 2 in concen-
trated ethereal solution of lithium perchlorate, leads to the
iminium ion 3 as an intermediate. The intermediate 3 can be
detected by NMR spectroscopy in solution.10 Thus, by the
addition of benzaldehyde and amine to the 5 M ethereal
solution of LiClO4, the benzaldehyde proton signal
disappeared, and at the same time a signal at 8.6 ppm
In conclusion, we have developed a general and efficient
method for one-pot synthesis of tertiary a-amino phos-
phonates in concentrated LPDE solution. The notable
advantages of this procedure are (a) general applicability
to a wide range of aldehydes and amines, (b) operational
simplicity with using relatively cheap LiClO4, in com-
parison with many other Lewis acids used for these
transformations and preparation of iminium salt in separate
step, (c) simple procedure with easy work up and high yields
of the product.
Keywords: tertiary a-amino phosphonate; trialkylphosphite; lithium
perchlorate.
*
Corresponding author. Tel.: þ98-21-600-5718; fax: þ98-21-601-2983;
e-mail: saidi@sharif.edu
Scheme 1.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00759-2

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N. Azizi, M. R. Saidi / Tetrahedron 59 (2003) 5329–5332
Table 1. Synthesis of tertiary a-amino phosphonates from aldehyde mediated by LPDE
Aldehydes
PhCHO
Amines
Product
References
Yielda (%)
4a,8 R¼Me
98
4b,8 R¼Et
4c,8 R¼Me
96
90
4d,8 R¼Et
92
95
4e4c
4f12
95
95
Me2NsiMe3
4g4c
4h16
98
95
4i12
4j12
96
93
4k16
Me2NSiMe3
4m14
4n15
4o8
95
95
84
a
Isolated yields.
1. Experimental
were performed under argon. Chemicals were purchased
from Merck and Fluka.
1.1. General
1.2. General procedure for the preparation of tertiary
a-amino phosphonates 4
LiClO4 (Fluka) was dried at 1608C for 24 h. Ether was dried
over Na/benzophenone under argon. IR spectra were taken
on a Mattson 1000 Unicam FTIR. 1H and 13C NMR spectra
were recorded on Bruker AC 500 instruments. All reactions
The aldehyde (2 mmol) and 3 ml of 5 M solution of LiClO4
in diethyl ether were placed in a 50 ml flask under argon and

N. Azizi, M. R. Saidi / Tetrahedron 59 (2003) 5329–5332
5331
stirred for 2 min. Then a secondary amine (4 mmol) was
added via a syringe. After 10 min, trialkylphosphite
(3 mmol) was added and the mixture was stirred at room
temperature for 5 min. Water (15 mL) and dichloromethane
(15 ml) were added. The organic phase was separated, and
dried over Na2SO4 and the solvent was removed using a
rotary evaporator. In some cases (ca. 4a, 4b, 4h and 4j)
almost pure product was obtained. All compounds were
known and characterized by comparison of their IR and
NMR (1H and 13C) spectra with those reported in the
literature or with an authentic sample.
1.2.6. a-(N,N-Diethylamino) phosphonates 4i.12 Yield
95%; oil; 1H NMR (500 MHz, CDCl3): dH 0.98 (t,
J¼7.2 Hz, 6H), 2.38 (m, 2H), 2.89 (m, 2H), 3.44 (d,
J¼10.6 Hz, 3H), 3.84 (d, J¼10.6 Hz, 3H), 4.74 (d,
J¼24.7 Hz, 1H), 7.18 (m, 1H), 7.35 (m, 1H), 7.83 (m,
1H); 13C NMR (125 MHz, CDCl3): dC 13.5 (CH3), 48.1
(CH2), 52.8 (d, J¼7.2 Hz, CH3), 54.6 (d, J¼9.1 Hz, CH3),
58.8 (d, J¼152.1 Hz, CH), 126.1 (CH), 128.3 (CH), 131.3
(C), 132.8 (CH), 134.6 (C), 137.8 (C); IR nmax (KBr) 2880,
1499, 1240, 760 cm21
.
1.2.7. a-Pyrrolidino phosphonates 4j.13 Yield 96%;
1.2.1. a-Pyrrolidino phosphonates 4a.8 Yield 98%; oil; 1H
NMR (500 MHz, CDCl3): dH 1.66 (m, 4H), 2.55 (m, 4H),
3.34 (d, J¼10.4 Hz, 3H), 3.75 (d, J¼10.5 Hz, 3H), 3.72 (d,
J¼16.0 Hz, 1H), 7.22–7.24 (m, 5H); 13C NMR (125 MHz,
CDCl3): dC 24.1 (CH2), 52.8 (d, J¼9.1 Hz, CH3), 53.9 (d,
J¼6.6 Hz, CH3), 55.8 (CH2), 56.8 (d, J¼148.1 Hz, CH),
127.7 (CH), 129.3 (CH), 130.4 (CH), 133.1 (d, J¼2.2 Hz,
C); IR nmax (CH2Cl2), 2940, 2850, 1470, 1230, 1042,
yellow solid; mp, 93–948C; H NMR (500 MHz, CDCl3):
1
dH 1.68 (m, 4H), 2.64 (m, 4H), 3.46 (d, J¼10.4 Hz, 3H),
3.75 (d, J¼10.5 Hz, 3H), 3.85 (s, 3H), 4.65 (d, J¼18.0 Hz,
1H), 6.89–6.98 (m, 2H), 7.26–7.73 (m, 2H); 13C NMR
(125 MHz, CDCl3): dC 23.5 (CH2), 52.6 (d, J¼9.1 Hz,
CH3), 53.4 (d, J¼6.6 Hz, CH3), 55.9 (CH3), 56.1 (CH2),
56.8 (d, J¼145.1 Hz, CH), 111.0 (CH), 120.7 (d,
J¼2.25 Hz, CH), 122.9 (CH), 129.3 (d, J¼2.1 Hz, CH),
131.5 (d, J¼4.1 Hz, CH), 157.8 (d, J¼9.2 Hz, CH); IR nmax
(KBr) 2953, 2839, 1598, 1491, 1463, 1246, 1028,
770 cm21
.
1.2.2. a-(N,N-Diethylamino) phosphonates 4c.8 Yield
90%; oil; 1H NMR (500 MHz, CDCl3): dH 0.94(t,
J¼7.2 Hz, 6H), 2.22 (m, 2H), 2.89 (m, 2H), 3.37 (d,
J¼10.5 Hz, 3H), 3.77 (d, J¼10.4 Hz, 3H), 4.00 (d,
J¼24.9 Hz, 1H), 7.16–7.38 (m, 5H); 13C NMR
(125 MHz, CDCl3): dC 13.5 (CH3), 45.1 (d, J¼8.25 Hz,
CH2), 52.8 (d, J¼6.8 Hz, CH3), 54.5 (d, J¼7.2 Hz, CH3),
61.9 (d, J¼163.3 Hz, CH), 128.2 (CH), 128.4 (CH), 130.7
(d, J¼8.8 Hz, CH), 133.2 (d, J¼4.7 Hz, C); IR nmax (KBr),
760 cm21
.
1.2.8. a-(N,N-Dimethylamino) phosphonates 4m.14 Yield
95%; oil; 1H NMR (500 MHz, CDCl3): dH 2.22 (s, 6H), 3.34
(d, J¼9.8 Hz, 3H), 3.68 (d, J¼9.7 Hz, 3H), 3.70 (d,
J¼18.9 Hz, 1H), 7.49 (m, 1H), 7.87 (m, 1H), 8.12 (m,
1H), 8.41 (m, 1H); 13C NMR (125 MHz, CDCl3): dC 43.9
(d, J¼8.9 Hz, CH3), 52.8 (m, CH3), 69.7 (d, J¼161.4 Hz,
CH), 123.1 (C), 129.2 (CH), 134.3 (C), 136.8 (CH), 139.1
(CH), 148.5 (C); IR nmax (KBr) 2948, 2880, 1598, 1495,
2973, 2840, 1494, 1452, 1247, 1033, 829, 569 cm21
.
1350, 1090, 960 cm21
.
1.2.3. a-Piperidino phosphonates 4e.4c Yield 95%; white
solid; mp, 69–708C; 1H NMR (500 MHz, CDCl3): dH 1.34
(t, J¼6.2 Hz, 2H), 1.56–1.64 (m, 4H), 2.41 (m, 2H), 2.78
(m, 2H), 3.54 (d, J¼8.6 Hz, 3H), 3.92 (d, J¼8.7 Hz, 3H),
4.01 (d, J¼22.8 Hz, 1H), 7.20–7.61 (m, 5H); 13C NMR
(125 MHz, CDCl3): dC 24.3 (CH2), 26.2 (CH2), 51.3 (CH2),
53.8 (d, J¼6.8 Hz, CH3), 54.9 (d, J¼7.8 Hz, CH3), 61.9 (d,
J¼160.3 Hz, CH), 128.6 (CH), 128.9 (CH), 131.7 (d,
J¼8.8 Hz, CH), 134.2 (d, J¼4.7 Hz, C); IR nmax (CH2Cl2),
1.2.9. a-Pyrrolidino phosphonates 4n.15 Yield 95%; oil;
1H NMR (500 MHz, CDCl3): dH 1.67 (m, 4H), 2.66 (m, 4H),
3.41 (d, J¼9.4 Hz, 3H), 3.77 (d, J¼10.1 Hz, 3H), 3.86 (d,
J¼18.0 Hz, 1H), 7.23–7.35 (m, 4H); 13C NMR (125 MHz,
CDCl3): dC 23.5 (CH2), 52.6 (d, J¼9.1 Hz, CH3), 53.4 (d,
J¼6.6 Hz, CH3), 56.1 (CH2), 57.8 (d, J¼148.1 Hz, CH),
128.7 (d, J¼2.25 Hz, CH), 130.4 (C), 131.1 (d, J¼4.2 Hz,
CH), 132.7 (C); IR nmax (KBr) 2950, 2860, 1480, 1246,
2933, 2852, 1450, 1248, 1034, 557 cm21
.
1082, 986, 888 cm21
.
1.2.4. a-Morpholino phosphonates 4f.12 Yield 95%; oil;
1H NMR (500 MHz, CDCl3): dH 2.58 (t, J¼6.3 Hz, 2H),
2.79 (t, J¼6.1 Hz, 2H), 3.51 (m, 3H), 3.67–3.74 (m, 4H),
3.81–3.88 (m, 4H), 7.19–7.43 (m, 5H); 13C NMR
(125 MHz, CDCl3): dC 24.3 (CH2), 26.5 (CH2), 52.3
(CH2), 52.8 (CH2), 54.8 (d, J¼6.8 Hz, CH3), 54.9 (d,
J¼7.8 Hz, CH3), 63.9 (d, J¼161.3 Hz, CH), 128.1
(CH), 128.8 (CH), 131.2 (d, J¼5.6 Hz, CH), 134.8 (d,
J¼3.4 Hz, C); IR nmax (CH2Cl2), 2925, 2850, 1230, 1020,
Acknowledgements
We are grateful to the Research Council of Sharif University
of Technology for financial support. We also thank
‘Volkswagen-Stiftung, Federal Republic of Germany’ for
financial support towards the purchase of equipments and
chemicals.
760 cm21
.
1.2.5. a-(N,N-Dimethylamino) phosphonates 4g.4c Yield
95%; oil; 1H NMR (500 MHz, CDCl3): dH 2.13 (s, 6H), 3.20
(d, J¼10.5 Hz, 3H), 3.59 (d, J¼10.7 Hz, 3H), 3.61 (d,
J¼20.8 Hz, 1H), 7.12–7.26 (m, 5H); 13C NMR (125 MHz,
CDCl3): dC 43.8 (d, J¼9.3 Hz), 53.2 (m, CH3), 68.1 (d,
J¼160.4 Hz, CH), 128.4 (CH), 130.6 (CH), 130.7 (CH),
132.2 (C); IR nmax (CH2Cl2) 2937, 2860, 1480, 1213,
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