TiCl4-catalyzed efficient one-pot synthesis of α α-amino phosphonates

Article abstract of DOI:10.1080/10426500600887461

α-Aminophosphonates are synthesized by three-component condensation of aldehydes, amines, and trimethylphosphite in acetonitrile by using TiCl ₄ as catalyst. Compared to conventional methods, this new method consistently has advantages, includi

Full text of DOI:10.1080/10426500600887461

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Phosphorus, Sulfur, and Silicon
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TiCl -Catalyzed Efficient One-
4
Pot Synthesis of α α-Amino
Phosphonates
a
a
Y. Thirupathi Reddy , P. Narsimha Reddy , B. Sunil
a
a
a
Kumar , Pradeep Rajput , N. Sreenivasulu & B.
a
Rajitha
a
Department of Chemistry , National Institute of
Technology , Warangal, India
Published online: 01 Feb 2007.
To cite this article: Y. Thirupathi Reddy , P. Narsimha Reddy , B. Sunil Kumar ,
Pradeep Rajput , N. Sreenivasulu & B. Rajitha (2007) TiCl -Catalyzed Efficient One-Pot
4
Synthesis of α α-Amino Phosphonates, Phosphorus, Sulfur, and Silicon and the Related
Elements, 182:1, 161-165, DOI: 10.1080/10426500600887461
To link to this article: http://dx.doi.org/10.1080/10426500600887461
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Phosphorus, Sulfur, and Silicon, 182:161–165, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600887461
TiCl -Catalyzed Efficient One-Pot Synthesis of α-Amino
4
Phosphonates
Y. Thirupathi Reddy
P. Narsimha Reddy
B. Sunil Kumar
Pradeep Rajput
N. Sreenivasulu
B. Rajitha
Department of Chemistry, National Institute of Technology, Warangal,
India
α-Aminophosphonates are synthesized by three-component condensation of alde-
hydes, amines, and trimethylphosphite in acetonitrile by using TiCl as catalyst.
4
Compared to conventional methods, this new method consistently has advantages,
including excellent yields, short reaction times, and mild reaction conditions.
Keywords α-aminophosphonates; aldehydes; amines; one-pot reaction; TiCl4
INTRODUCTION
Aminophosphates are an important class of biologically active
1
compounds, because of their structural analogy to α-aminoacids.
Hence, α-aminophosphonates continue to attract increased interest as
2
synthetic targets. Also, α-aminophosphonates act as peptide mimics,
3
4
5
enzyme inhibitors, antibiotics, crop protection agents, and catalytic
6
7
antibodies. As a result, a variety of synthetic approaches have been
developed for the synthesis of α-aminophosphonates. Of these meth-
ods, the nucleophilic addition of phosphates with imines, catalyzed by
an acid or a base, is one of the most convenient methods. It is interest-
ing to note that the Lewis acids catalyze the reaction in much milder
8
conditions. Among these, Lewis acids-such as SnCl2, SnCl4, BF3.OEt2,
9
,10
and ZnCl2/MgBr2, have been used for this transformation.
How-
ever, these reactions cannot be carried out in a one-pot operation
starting from aldehydes.10 Recent reagents include ZrCl4, lanthanide
11
Received April 7, 2006; accepted June 6, 2006.
Address correspondence to B. Rajitha, Department of Chemistry, National Institute
of Technology, Warangal, India. E-mail: rajitabharagavi@yahoo.com
161

1
62
Y. Thirupathi Reddy et al.
O
R-NH
TiCl , CH CN
4
3
OCH3
+
+ P(OCH3)3
R-NH2
R1
P
R1
r.t.
H
OCH3
1
2
3
O
4
SCHEME 1
triflates,12 InCl3,13 LiClO4-TMSCl14 and Montimorllonite-KSF15 were
used for this transformation. Very recently, a solvent-free reaction be-
tween aldehydes, ammonium formate, and dialkylphosphite catalyzed
1
6
by alumina under microwave conditions was also reported. Most of
the previously mentioned procedures employ dimethylphospite as the
reagent, with a view to see the migration of a methyl carbonium ion
1
7
to that of using a dimethyl (trimethyl silyl) phosphite. The present
study also aims at the development of a cheaper alternative reagent.
Herein we report an efficient and inexpensive protocol for the synthesis
of α-aminophosphonates using a catalytic amount of TiCl4 under mild
reaction conditions (Scheme 1).
The treatment of benzaldehyde, aniline, and trimethylphosphite in
the presence of 10 mole percent of TiCl4 in acetonitrile medium at r.t.
resulted in corresponding α-aminophosphonate. Similarly, various alde-
hydes and amines were treated with trimethylphosphite to afford cor-
responding α-aminophosphonates at an ambient temperature within
10–25 min in high yields 88–93% (Table I). The reaction conditions were
very mild, and the α-aminophosphonates were exclusively formed with-
out the formation of any undesired side products. The present method
does not require any additives or promoters1 for the reaction to proceed.
0
General Experimental Procedure
To a stirred solution of benzaldehyde (1.06 g, 10 mmol) and aniline
(
0.93 g, 10 mmol) in acetonitrile (25 mL) was added trimethylphos-
phite (1.40 g, 10 mmol) and TiCl4 (0.189 g, 10 mol%). The reaction
mixture was stirred at r.t. (Table I) until completion of the reaction as
indicated by TLC. The reaction mixture was quenched with cold water
and extracted with dichloromethane (2 × 50 mL), dried over anhydrous
Na2SO4, concentrated in vacuum, and purified by column chromatog-
raphy (hexane:ethyl acetate, 80:20) to afford correspondingly pure
α-aminophosphonates in a 93% (0.80 g) yield.
−
1
1
Selected spectral data of 4a. IR (KBr): 3302 cm (NH). H NMR
(
1
CDCl3, 300 MHz): δ = 3.42 (d, 3H, CH3), 3.75 (d, 3H, CH3), 4.53 (brs,
H, NH), 4.80 (d, 1H, CH), 6.69–7.45 (m, 10H, Ar-H).

One-Pot Synthesis of α-Amino Phosphonates
163
TABLE I TiCl
α-Aminophosphonates
4
-Catalyzed Efficient Synthesis of
a
Entry Aldehyde
Amine
Reaction Time (min)
10
Yield (%)b
93
NH2
4
4
a
b
CHO
NH2
NH2
NH2
OH
15
89
CHO
4
4
c
10
15
91
90
H C
CHO
3
d
MeO
CHO
NH2
Cl
Cl
CHO
4
4
e
f
15
15
88
90
NH2
N
CHO
NH2
CH3
4
4
4
g
h
i
15
25
10
91
89
90
CHO
NH2
CHO
CHO
CH3
NH2
Cl
NH2
4
4
j
15
15
92
90
CHO
CHO
NH2
Br
k
(
Continued on next page)

1
64
Y. Thirupathi Reddy et al.
TABLE I TiCl
α-Aminophosphonates (Continued)
4
-Catalyzed Efficient Synthesis of
a
Entry
Aldehyde
Amine
Reaction Time (min)
15
Yield (%)b
91
NH2
4
4
l
CHO
O
NH2
m
15
92
CHO
O
aYields refer to pure products, and all products were characterized by comparison of
their physical and spectral data with those of authentic samples.
b
All α-aminophosphonates are known compounds.
d. IR (KBr): 3316 cm 1 (NH). H NMR (CDCl3, 300 MHz): δ = 3.45
−
1
4
(
d, 3H, CH3), δ = 3.64 (d, 3H, CH3), 3.78 (d, 3H, OCH3), 4.72 (brs, 1H,
NH), 6.59 (d, 1H, CH), 6.54–7.11 (m, 9H, Ar-H).
−1
1
4
e. IR (KBr): 3322 cm (NH). H NMR (CDCl3, 300 MHz): δ = 3.54
d, 3H, CH3), δ = 3.72 (d, 3H, CH3), 5.27 (brs, 1H, NH), 5.83 (d, 1H, CH),
.54–6.63 (d, 2H), 6.65–6.78 (t, 1H), 7.05–7.42 (m, 5H).
(
6
CONCLUSION
We have demonstrated a novel and efficient protocol for the synthesis
of α-aminophosphonates using a catalytic amount of titanium tetra-
chloride. The method offers several advantages, including high yields
of product, very short reaction times, and an inexpensive catalyst, and
does not involve any additives to promote the reaction.
REFERENCES
[
1] (a) S. C. Fileds, Tetrahedron, 55, 1237 (1999); (b) E. K. Fields, J. Am. Chem. Soc.,
4, 1528 (1952); (c) C. Yuan and S. Chen, Synthesis, 1124, (1992); (d) D. R. More,
7
J. Org. Chem., 43, 992 (1978); (e) T. Yokomatsu, Y. Yoshida, and S. Shibuya, J. Org.
Chem., 59, 7930 (1994).
[
[
2] P. Kafarski and B. Lejczak, Phosphorous, Sulfur, and Silicon, 63, 1993 (1991).
3] (a) M. C. Allen, W. Fuhrer, B. Tuck, R. Wade, and J. M. Wood, J. Med. Chem., 32,
1652 (1989); (b) P. P. Giannousis and P. A. Bartlet, J. Med. Chem., 30, 1603 (1987).
[
[
4] F. R. Atherton, C. H. Hassall, and R. W. Lambert, J. Med. Chem., 29, 29 (1986).
5] (a) P. Wieczorek, B. Lejczak, M. Kaczanowska, and P. Kafarski, Pestic. Sci., 30, 43
(
1990); (b) I. A. Nachev, Liebigs Ann. Chem., 861 (1988).
[
6] R. Hirschmann, A. B. Smith III, C. M. Taylor, P. A. Benkovic, S. D. Taylor, K. M.
Yager, P. A. Sprengler, and S. J. Venkovic, Science, 265, 234 (1994).

One-Pot Synthesis of α-Amino Phosphonates
165
[
7] (a) V. P. Kukhar and V. A. Solodenko, Rus. Chem. Rev. (Engl. Trans.), 56, 859 (1987);
b) D. Redmore, Topics in Phosphorous Chemistry, Vol. 8, ed. E. J. Griffith and M.
(
Grayson, p. 515. (Wiley: New York, 1976).
[
8] A. N. Pudovik, Dokl, and S. Akad Nauk, 83, 865 (1952); Chem. Abstr., 47, 4300
(
1953).
9] E. K. Baylis, C. D. Campbell, and J. G. Dingwall, J. Chem. Soc. Perkin. Trans. 1,
845 (1984).
[
2
[
[
10] J. Zon and Pol, J. Chem., 55, 643 (1981); Chem. Abstr., 96, 199793 (1982).
11] J. S. Yadav, B. V. S. Reddy, R. K Sarita, B. K. Reddy, and A. R. Prasad, Synthesis,
2277 (2001).
[
[
[
[
[
12] C. Quian and T. Huang, J. Org. Chem., 63, 4125 (1998).
13] B. C. Ranu and A. Hajra Jana, J. Org. Lett., 1, 1141 (1999).
14] M. R. Sidi and N. Azizi, Synlett., 1347 (2002).
15] J. S. Yadav, U. Basi, S. Reddy, and C. H. Madan, Synlett., 7, 1131 (2001).
16] (a) B. Kaboudin, Chem. Lett., 880 (2001); (b) B. Kaboudin and R. Nazari, Tetrahedron
Lett., 42, 8211 (2001).
[
17] A. Haydari, M. Zarei, A. Reza, and H. Tavakol, Tetrahedron Lett., 42, 3629 (2001).