(Bromodimethyl)sulfonium bromide: An inexpensive reagent for the solvent-free, one-pot synthesis of α-aminophosphonates

Article abstract of DOI:10.1016/j.tetlet.2004.12.070

A novel solvent-free, one-pot synthesis of α-aminophosphonates in the presence of catalytic (bromodimethyl)sulfonium bromide at room temperature in high yields is reported.

Full text of DOI:10.1016/j.tetlet.2004.12.070

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1209–1210
(Bromodimethyl)sulfonium bromide: an inexpensive reagent for
the solvent-free, one-pot synthesis of a-aminophosphonatesI
Sucheta Kudrimoti and Vittal Rao Bommena*
Organic Division II, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 7 October 2004; revised 30 November 2004; accepted 10 December 2004
Available online 8 January 2005
Abstract—A novel solvent-free, one-pot synthesis of a-aminophosphonates in the presence of catalytic (bromodimethyl)sulfonium
bromide at room temperature in high yields is reported.
Ó 2004 Elsevier Ltd. All rights reserved.
Phosphonate-containing molecules are biologically po-
tent. Their diverse applications include inhibitors of syn-
thase,1 HIV protease,2 renin,3 and PTPases,4,6 and as
antibiotics,5 enzyme inhibitors,6 herbicides7 and as sur-
rogates of a-amino carboxylic acids.8 a-Aminophospho-
nates have attracted attention as substrates in the
synthesis of phosphonopeptides.9 As a result, a variety
of synthetic approaches has been developed for the syn-
thesis of a-aminophosphonates, for example the
Kabachnik–Fields10 synthesis in which the key step is
nucleophilic base- or acid- catalysed condensation of
an amine with a carbonyl compound followed by the
addition of phosphite to the resulting imine. Lewis
acids11,12 including lanthanide triflates12c are known to
catalyse these reactions. However, many of these proce-
dures require expensive reagents in stoichiometric
amounts, long reaction times and deliver low yields.
Some of these reactions cannot be carried out in one
step with a carbonyl compound, an amine and a dial-
kylphosphite because the amine and water present dur-
ing imine formation can decompose or deactivate the
Lewis acid.12a
using (bromodimethyl)sulfonium bromide13 under sol-
vent-free conditions.
The reaction of aldehyde, amine and trimethylphosphite
in the presence of 10 mol % of (bromodimethyl)sulfo-
nium bromide at room temperature resulted almost
instantaneously in the formation of a-aminophospho-
nates in excellent yields (Scheme 1). In all cases, and
with a variety of substrates, the reaction proceeded
smoothly at ambient temperature affording high yields
of the desired products within 15–30 min (Table 1).14
The reaction conditions are very mild and the a-amino-
phosphonates were formed without any undesired by-
products. The simplicity and mild reaction conditions
make it a viable method for a,b-unsaturated aldehydes.
Another feature of this method is the survival of olefin,
ether, hydroxy and halide groups and no bromination of
aromatic rings was observed. Compared to other acid
catalysts such as SnCl2, ZrCl4,15 AlCl3,16 triflates,12c
InCl3,12b etc., (bromodimethyl)sulfonium bromide was
found to be more effective in terms of environmental
compatibility, yields, simple work-up and a short reac-
tion time.
Hence, there is a need to develop a convenient, environ-
mentally benign and practicably feasible method for the
synthesis of a-aminophosphonates.
In summary we have developed a novel efficient solvent-
free protocol for the synthesis of a-aminophosphonates
using catalytic (bromodimethyl)sulfonium bromide. The
We report for the first time, a simple, one-pot, practical
protocol for the synthesis of a-aminophosphonates
Me2S+Br Br-
R.T., Neat
OCH3
OCH3
O
OCH3
OCH3
O
P
R-NH2
H3CO-P
+
+
R1
H
Keywords: a-Aminophosphonates; (Bromodimethyl)sulfonium; Bro-
mide; Imine.
q IICT Communication no: 041027.
R1
N R
H
*
Scheme 1.
Corresponding author. E-mail: raobommena@yahoo.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.070

1210
S. Kudrimoti, V. Rao Bommena / Tetrahedron Letters 46 (2005) 1209–1210
Table 1.
Product
Amines
Aldehyde
Time (min)
Yield (%)
Mp (°C)
4a
4b
4c
4d
4e
4f
C6H5NH2
C6H5NH2
4-MeOC6H4
4-CH3C6H4
3-PhOC6H4
15
15
25
20
25
20
25
20
15
20
20
20
25
20
95
90
87
89
89
89
88
90
92
90
89
91
91
92
123
114
125
130
138
220
242
110
125
138
135
127
192
148
C6H5NH2
C6H5NH2
C6H5NH2
2,5-(MeO)2C6H3
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
4-F-2-CF3C6H3
4-CH3C6H4
C6H5CH2NH2
C6H5CH2NH2
4-FC6H4NH2
4-FC6H4NH2
4-FC6H4NH2
4-FC6H4NH2
4-FC6H4NH2
4-FC6H4NH2
4-FC6H4NH2
4g
4h
4i
4-MeOC6H4
4j
4-F-2-CF3C6H3
4-NO2C6H4
4-FC6H4
4k
4l
4m
4n
C6H4CH@CH
2,5-(MeO)2C6H3
P.; Lejczak, B. Phosphorus Sulfur 1991, 63, 193–
215.
method is effective for aromatic as well as a,b-unsatu-
rated aldehydes and provides excellent yields of the
product in a very short time, which makes it a novel,
environmentally friendly and economically viable pro-
cess for the synthesis of a-aminophosphonates.
10. (a) Kabachnik, M. J.; Medved, T. Izv. Akad. Nauk. SSSR
1953, 1126–1128; (b) Kabachnik, M. J.; Medved, T. Izv.
Akad. Nauk. SSSR 1954, 1024–1032; (c) Fields, E. K. J.
Am. Chem. Soc. 1952, 74, 1528–1531; (d) Petrov, K. A.;
Chauzov, V. A.; Erkhina, T. S. Russ. Chem. Rev. (Engl.
Transl.) 1974, 43, 2045–2087; (e) Soroka, M. Pr. Nauk.
Inst. Chem. Org. Fiz. Potechn. Wroclaw 1987, 32, 3–92; (f)
Mastalrez, P. In Handbook of Organophosphorus Chemis-
try; Engel, R., Ed.; Marcel Dekker: New York, 1992,
Chapter 7.
11. Laschat, S.; Kunz, H. Synthesis 1992, 90–95.
12. (a) Zon, J. Pol. J. Chem. 1981, 55, 643–646; (b) Ranu, B.
C.; Hajra, A.; Jana, J. Org. Lett. 1999, 1, 1141–1143; (c)
Qian, C.; Huang, J. J. Org. Chem. 1998, 63, 4125–
4128.
Acknowledgements
S.K. thanks the CSIR, New Delhi for the award of
Research Associateship and is grateful to the Director,
IICT, for support.
References and notes
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14. Typical experimental procedure: The amine (5 mmol) and
aldehyde (5 mmol) were stirred for a few minutes at room
temperature and then trimethyl phosphite (5 mmol) and
(bromodimethyl)sulfonium bromide (10 mol %) were
added and the mixture stirred for the appropriate time
(see Table 1). After completion of the reaction, as
indicated by TLC, the mixture was quenched with water
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flash chromatography (hexane–ethyl acetate), 8:2 to afford
the pure a-aminophosphonate.
All products gave satisfactory spectral data in accord with
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the assigned structures.
Data for 4g as an example, 1H NMR (400 MHz) (CDCl3):
3.55 (3H, d, J = 10.98 Hz OCH3), 3.62 (3H, d,
J = 10.98 Hz, OCH3), 3.75 (3H, s, OCH3), 4.75 (1H, d,
J = 23.42 Hz, CH), 5.78 (1H, br, NH), 6.60 (2H, d,
J = 8.75 Hz, Ar–H), 6.75 (2H, d, J = 8.75 Hz, Ar–H), 6.90
(2H, d, J = 8.75 Hz, Ar–H), 7.30 (2H, d, J = 8.75 Hz, Ar–
H). Anal. Calcd For C16H19FNO4P: C, 56.64; H, 5.60; N,
4.12%. Found: C, 56.44; H, 5.88; N, 4.18%.
15. Yadav, J. S.; Reddy, B. V. S.; Sarita, R. K.; Bhaskar, R.;
Prasad, A. R. Synthesis 2001, 15, 2277–2280.
16. Manjula, A.; Vittal; Rao, B.; Parvathi, N. Synth. Commun.
2003, 33, 2963–2969.