Microwave-assisted synthesis of α-aminophosphinic acids from hypophosphorus acid salts under solvent free conditions

Article abstract of DOI:10.1016/S0040-4039(03)00893-1

A simple, efficient, and general method has been developed for the synthesis of α-aminophosphinic acids from hypophosphorus salts under solvent-free conditions using microwave irradiation. α-Aminophosphinic acids were obtained in high yield under mild conditions by reaction of the amine salts of hypophosphorus acid with aldehydes in the presence of microwave irradiation.

Full text of DOI:10.1016/S0040-4039(03)00893-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4243–4245
Microwave-assisted synthesis of a-aminophosphinic acids from
hypophosphorus acid salts under solvent free conditions
Babak Kaboudin* and Nasser As-habei
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45195-159, Iran
Received 9 February 2003; revised 27 March 2003; accepted 4 April 2003
Abstract—A simple, efficient, and general method has been developed for the synthesis of a-aminophosphinic acids from
hypophosphorus salts under solvent-free conditions using microwave irradiation. a-Aminophosphinic acids were obtained in high
yield under mild conditions by reaction of the amine salts of hypophosphorus acid with aldehydes in the presence of microwave
irradiation. © 2003 Elsevier Science Ltd. All rights reserved.
Organophosphorus compounds have found a wide
range of application in the areas of industrial, agricul-
tural, and medicinal chemistry owing to their biological
and physical properties as well as their utility as syn-
thetic intermediates.1 a-Functionalized phosphinic acids
are valuable intermediates for the preparation of medic-
inal compounds and synthetic intermediates. a-
Aminophosphinic acids, the phosphinic acid analogues
of a-amino carboxylic acids, are an important class of
compounds that exhibit a variety of interesting and
useful properties. Compounds containing an a-
aminoalkylphosphinic acid functional group are of con-
siderable importance because of their anti-bacterial,2
herbicidal3 and fungicidal4 activities. In contrast to the
widely studied a-aminophosphonic acid derivatives,5–8
relatively few papers have been reported on the chem-
istry of a-aminophosphinic acids, although there is
evidence that a-aminophosphinic acids are pharmaceu-
tically active. Many effective methods for the prepara-
tion of a-aminoalkylphosphonic acids have been
developed, but few synthetic routes to a-aminophos-
phinic acids have been reported. These methods involve
prolonged heating of anhydrous hypophosphorus acid
with a Schiff’s base and Mannich-type reactions of
amines with aldehydes and anhydrous hypophosphorus
acid.9 However, both of these methods have problems,
including harsh reaction conditions, anaerobic and
anhydrous conditions, long reaction times and side
reactions.10 To avoid the problems associated with han-
dling anhydrous H3PO2, hypophosphorus salts (highly
crystalline, high-melting, cheap, and non-hygroscopic)
have been developed as safer and convenient reagents
for the synthesis of phosphinic acids. The application
11
of microwave energy to accelerate organic reactions is
of increasing interest and offers several advantages over
conventional techniques.12 Syntheses which normally
require lengthy periods, can be achieved conveniently
and very rapidly in a microwave oven. As part of
our efforts to explore the utility of microwave-assisted
reactions for the synthesis of organophosphorus
compounds,13–18 we report a new method for the
preparation of a-aminophosphinic acids from hypo-
phosphorus acid salts under solvent-free conditions,
using microwave irradiation producing high yields of
a-aminophosphinic acids (Scheme 1, Table 1).
As shown in Scheme 1 and Table 1, the reaction of a
mixture of anilinium hypophosphite19 with aromatic
and aliphatic aldehydes (2a–j) under microwave irradia-
tion, afforded the desired products in good yields (3a–
j). Cyclohexylammonium hypophosphite also reacted to
give the desired compounds in good yields (3k–l). The
reaction of (R)-(+)-phenylethylammonium hypophos-
phite with aldehydes gave the desired compounds in
good yields. The reactions were clean with no tar
formation.20
* Corresponding author. Tel.: +98 241 4242239; fax: +98 241
4249023; e-mail: kaboudin@iasbs.ac.ir
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00893-1

4244
B. Kaboudin, N. As-habei / Tetrahedron Letters 44 (2003) 4243–4245
Table 1. Reaction of a hypophosphorus acid salts with aldehydes under microwave irradiation
R 1
R% 2
Reaction time (min)
Yield (%)a
3
a
b
c
d
e
f
g
h
i
j
k
l
m
n
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
Cyclohexyl
Cyclohexyl
(R)-(+)-1-Phenylethyl-
(R)-(+)-1-Phenylethyl-
C6H5-
0.5
2
1.5
2
1
1
1.5
1
2
1
1
66
68
65
70
68
65
68
75
78
80
60
65
66b
78c
p-CH3C6H4-
p-CH3OC6H4-
p-(CH3)2CHC6H4-
m-BrC6H4-
m-ClC6H4-
m-CH3OC6H4-
o-ClC6H4-
1-C10H7-
C6H5-CHꢀCH-
C6H5-
C6H5-CHꢀCH-
C6H5-
C6H5-CHꢀCH-
1
1
1
a Isolated yields.
b Diastereomeric ratio is 55:45 based on 31P NMR.
c Diastereomeric ratio is 60:40 based on 31P NMR.
In summary, low consumption of solvent, fast reaction
rates, mild reaction conditions, good yields, the simple
work-up, and relatively clean reactions with no tar
formation make this method an attractive and a useful
contribution to the present methodologies. Indeed, a
wide range of aldehydes and amine salts were converted
to the corresponding a-aminophosphinic acids using
this method.
Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M. J. Med.
Chem. 1989, 32, 1652; (d) Hassal, C. H. In Antibiotics;
Hahn, F. E., Ed.; Springer Verlag: Berlin, 1983; Vol. VI,
pp. 1–11; (e) Hyun-Joon, H.; Gong-Sil, N. Synth. Com-
mun. 1992, 22, 1143; (f) Gancarz, R.; Wieczorek, J. S.
Synthesis 1978, 625; (g) Seyferth, D.; Marmor, R. S.;
Hilbert, P. J. Org. Chem. 1971, 36, 1379; (h) Worms, K.
H.; Schmidt-Dunker, M. In Organic Phosphorus Com-
pounds; Kosolapo, G. M.; Marier, L., Eds.; John Wiley &
Sons: New York, 1976; Vol. 7, p. 1.
Acknowledgements
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The Institute for Advanced Studies in Basic Sciences
(IASBS) is thanked for supporting this work.
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B. Kaboudin, N. As-habei / Tetrahedron Letters 44 (2003) 4243–4245
4245
20. This solvent-free reaction method is operationally simple.
10 mmol of hypophosphorus acid salt was added to 10
mmol of aldehyde and the mixture was irradiated with
microwaves for 0.5–2 min at 720 W (a kitchen-type
microwave was used in all experiments). Sodium hydrox-
ide (1.6 g, 50%) was added dropwise to the reaction
mixture and this was extracted with ether (3×20 ml) until
the ether layer appeared completely colorless. The
aqueous portion was freed from residual ether by heating.
After cooling, the aqueous solution was added dropwise,
with rapid stirring, to 20 ml of 3N hydrochloric acid.
The precipitated a-aminophosphinic acid was filtered
and redissolved in aqueous sodium hydroxide, the solu-
tion was extracted with ether, and the a-aminophos-
phonic acid reprecipitated by adding to aqueous hydro-
chloric acid as shown above. After filtration, washing
with water, and drying in vacuo over phosphorus
pentoxide a light yellow powder was obtained. All prod-
ucts gave satisfactory spectral data in accord with the
assigned structures. For 3m as an example 1H NMR
(CD3OD/TMS-500 MHz): 1.64 (3H, d, J=6.9 Hz), 3.76,
4.01 (1H, 2d, J=13.8 Hz, -CHP), 4.21, 4.70 (1H, 2q,
J=6.9 Hz), 6.94, 7.02 (1H, 2d, JH–P=500 Hz), 7.26–8.02
(10H, m); 31P NMR (D2O/H3PO4): 15.16, 16.44 (45:55);
IR (KBr): 3650–2120 (-NH3), 1201 (PꢀO), 1055–930
14. Kaboudin, B.; Nazari, R. Tetrahedron Lett. 2001, 42,
8211.
15. Kaboudin, B.; Nazari, R. Synth. Commun. 2001, 31,
2241.
16. Kaboudin, B.; Balakrishna, M. S. Synth. Commun. 2002,
31, 2773.
17. Kaboudin, B. Tetrahedron Lett. 2002, 43, 8713.
18. Kaboudin, B.; Nazari, R. J. Chem. Res. 2002, 291.
19. Procedure for the preparation of hypophosphorus acid
salts (1): The amine (0.1 mol) was added to stirred
anhydrous hypophosphorus acid (6.6 g, 0.1 mol, water
was removed under vacuum from a commercially avail-
able 50% solution, for the method used, see: Fitch, P. J.
J. Am. Chem. Soc. 1964, 86, 61) in ethanol with cooling
to prevent the temperature rising above 25°C. The precip-
itated salts were filtered off and washed with dry ethanol
and then with dry ether. All salts gave satisfactory spec-
tral data in accord with the assigned structures. For
(R)-(+)-1-phenylethylammonium hypophosphite as an
example: white crystals; mp 118–20°C; [h]D=+53.5 (c
1.87, CH3OH); 1H NMR (D2O/TMS/500 MHz): 1.44
(3H, d, J=6.9 Hz), 4.32 (1H, q, J=6.9 Hz), 6.86 (2H, d,
J
H–P=500 Hz), 7.32 (5H, m); 31P NMR (D2O/H3PO4):
6.87 ppm; IR (KBr): 3600–2015, 1201 (PꢀO), 1059, 970
(PꢁO) cm−1
(PꢁO) cm−1
.
.