One-pot synthesis of α-Aminophosphonates catalyzed by boric acid at room temperature

Article abstract of DOI:10.1002/hc.20577

A simple, efficient, and general method has been developed for the one-pot, three-component synthesis of α-aminophosphonates from a condensation reaction of trimethyl phosphite, aldehydes, and amines in the presence of catalytic amount of boric acid (10 m

Full text of DOI:10.1002/hc.20577

Heteroatom Chemistry
Volume 21, Number 2, 2010
One-Pot Synthesis of α-Aminophosphonates
Catalyzed by Boric Acid at Room Temperature
Zahed Karimi-Jaberi and Mohammad Amiri
Department of Chemistry, Islamic Azad University, Firoozabad Branch,
P.O. Box 74715-117 Firoozabad, Fars, Iran
Received 3 August 2009; revised 11 January 2010
[3], peptide mimics [4], enzyme inhibitors [5], and
ABSTRACT: A simple, efficient, and general method
as surrogates of α-amino acids [6].
has been developed for the one-pot, three-component
Various methods are available for the construc-
synthesis of α-aminophosphonates from a conden-
tion of α-aminophosphonates [7]. One-pot three-
sation reaction of trimethyl phosphite, aldehydes,
component condensation of aldehydes, amines,
and amines in the presence of catalytic amount
and dimethylphosphite or trimethylphosphite is the
of boric acid (10 mol%) under solvent-free condi-
most convenient method for the preparation of these
tions. Thus α-aminophosphonates were synthesized
compounds. In this context, some methods and cat-
relatively quickly in good yields at room tempera-
alysts have been reported such as LiClO4 [8], ox-
ꢀ
C
ture.
2010 Wiley Periodicals, Inc. Heteroatom Chem
alic acid [9], TaCl5–SiO2 [10], β-cyclodextrin [11],
Mg(ClO4)2 [12], InCl3 [13], SmI2 [14], amberlite-IR
120 [15], H3PW12O40 [16], ionic liquid [17], FeCl3
[18], and silica sulfuric acid [19]. However, these
methodologies show varying degrees of success as
well as limitations due to use of toxic organic sol-
vents, expensive catalyst, prolonged reaction times,
the requirement of special apparatus, or harsh re-
action conditions. Thus, there is a certain need for
the development of an alternative route for the pro-
duction of α-aminophosphonates, which surpassed
those limitations.
21:96–98, 2010; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20577
INTRODUCTION
Multicomponent coupling reactions have emerged
as powerful tools in combinatorial chemistry for the
generation of small-molecule libraries. The goal is to
aid the discovery of new leads for drug development
and optimization of processes or to identify novel
biologically active substrates. Multicomponent re-
action condensations involve three or more com-
pounds reacting in a single event, but consecutively
to form new products, which contain the essential
parts of all the starting materials [1].
RESULTS AND DISCUSSION
Following our systematic studies directed toward the
development of practical, safe, and environmentally
friendly procedures for several important organic
transformations [20–22], we describe an efficient
method for the synthesis of α-aminophosphonates
through three-component reactions of aldehydes,
amines, and trimethyl phosphite using catalytic
amounts of boric acid under solvent-free conditions
at room temperature (Scheme 1).
α-Aminophosphonates are attractive targets for
chemical synthesis because of their wide use as bio-
logically active molecules. Their diverse applications
include as antibiotics [2], pharmacological agents
Correspondence to: Zahed Karimi-Jaberi; e-mail: zahed.karimi@
yahoo.com.
Contract grant sponsor: Research Council of Islamic Azad Uni-
versity of Firoozabad.
Boric acid (H3BO3) is a useful and environ-
mentally benign catalyst that has been successfully
c
ꢀ
2010 Wiley Periodicals, Inc.
96

One-Pot Synthesis of α-Aminophosphonates Catalyzed by Boric Acid at Room Temperature 97
R′
O
1
NH
MeO
OMe
O
(10 mol%)
H3BO3
+
P
+
R′NH2
R
H
P
R
OMe
OMe
R.T., neat
OMe
3
2
4
SCHEME 1 Synthesis of α-aminophosphonates.
utilized in numerous reactions, for example, the
aza Michael addition [23], the thia Michael addi-
tion [24], Biginelli reaction [25], transesterification
of ethyl acetoacetate [26], decarboxylation of cyclic
β-enaminoketoesters [27], and Mannich reaction
[28]. It offers milder conditions relative to common
mineral acids. Boric acid is a readily available and
inexpensive reagent and can conveniently be han-
dled and removed from the reaction mixture. Thus,
the remarkable catalytic activities together with its
operational simplicity make it the most suitable cat-
alyst for the synthesis of α-aminophosphonates.
To optimize the reaction conditions, the reaction
of trimethyl phosphite with imine generated in situ
from benzaldehyde and aniline was used as a model
reaction. Reactions at different conditions and var-
ious molar ratios of substrates in the presence of
boric acid revealed that the best conditions were
solvent-free at room temperature and a molar ratio
of trimethyl phosphite/amine/aldehyde/boric acid of
1:1:1:0.1. After completion of the reaction, the cata-
lyst (boric acid) can be separated from the reaction
mixture by washing the product with water.
Table 1. All products are known compounds, and
their structures were confirmed by comparison with
their known physical and spectral (NMR and IR)
data.
Various functionalities present in the aryl alde-
hydes, such as halogen, methoxy, hydroxyl, cyano,
and nitro groups were tolerated (see Table 1).
In all these cases, the corresponding α-
aminophosphonates were obtained in good yields
at room temperature without formation of any
side products such as α-hydroxyphosphonate.
It is important to note that the synthesis of
α-aminophosphonates could not be achieved in the
absence of catalyst (boric acid).
The mechanism of this reaction is believed to
involve formation of an activated imine by the
acidic catalyst so that addition of the phosphite
is facilitated to give a phosphonium intermediate,
which then undergoes reaction with the water gen-
erated during formation of the imine to give the
α-aminophosphonate and methanol as shown in
Scheme 2 [17,29].
In conclusion, this paper describes a conve-
nient and efficient process for the synthesis of α-
aminophosphonates by one-pot reaction of trimethyl
phosphite, aldehydes, and amines in the presence of
To show the generality of this method, the op-
timized system was used for the synthesis of other
α-aminophosphonate derivatives 4a–i (Table 1).
This method offers some advantages in terms
of simplicity of performance, solvent-free condi-
tion, and low reaction time. Several examples illus-
trating this novel and general method for the syn-
thesis of α-aminophosphonates are summarized in
H+
R′
O
N
P(OMe)3
+
R′NH2
–H2O
R
H
R
H
3
TABLE 1 Synthesis of α-Aminophosphonates in the Pres-
ence of 10 mol% of Boric Acid
1
2
H2O
R
Rꢁ
Time (min)
Yields (%)
a
b
c
d
e
f
g
h
i
C6H5
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
4-ClC6H4
4-ClC6H4
15
15
15
15
15
30
60
60
15
98
96
98
90
87
94
95
96
87
R′
R′
4-ClC6H4
4-NO2C6H4
4-MeC6H4
4-HOC6H4
4-CNC6H4
4-MeOC6H4
C6H5
HN
HN
-OH
O
R
P
R
P+
O
Me
OMe
MeO
OMe
OMe
4
4-HOC6H4
SCHEME 2 Proposed mechanism.
Heteroatom Chemistry DOI 10.1002/hc

98 Karimi-Jaberi and Amiri
[4] Kafarski, P.; Lejzak, B. Phosphorous, Sulphur,
Silicon Relat Elem 1991, 63, 193.
[5] Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood,
J. M. J Med Chem 1989, 32, 1652.
[6] Kukhar, V. P.; Hudson, H. R. In Aminophosphonic
and Aminophosphinic Acids; Wiley: Chichester, UK,
2000.
[7] Engel, R.; Cohen, J. I. In Synthesis of Carbon–
Phosphorus Bonds; 2nd ed.; CRC Press: Boca Raton,
FL, 2003.
[8] Saidi, M. R.; Azizi, N. Synlett 2002, 1347.
[9] Vahdat, S. M.; Baharfar, R.; Tajbakhsh, M.; Heydari,
A.; Baghbanian, S. M.; Khaksar, S. Tetrahedron Lett
2008, 49, 6501.
10 mol% of boric acid at room temperature under
solvent-free conditions. This method offers some ad-
vantages in terms of simplicity of performance, low
reaction times, solvent-free condition, low cost, and
it follows along the line of green chemistry. The cata-
lyst is readily available and inexpensive and can con-
veniently be handled and removed from the reaction
mixture. We believe that this procedure is conve-
nient, economical, and a user-friendly process for
the synthesis of α-aminophosphonates of biological
and medicinal importance.
[10] Chandrasekhar, S.; Prakash, S. J.; Jagadeshwar,
V.; Narsihmula, C. Tetrahedron Lett 2001, 42,
5561.
[11] Kaboudin, B.; Sorbiun, M. Tetrahedron Lett 2007,
48, 9015.
[12] Wu, J.; Sun, W.; Xia, H.-G.; Sun, X. Org Biomol Chem
2006, 4, 1663.
EXPERIMENTAL
General Procedures for Preparation of
α-Aminophosphonates
A
mixture of aldehyde (1 mmol) boric acid
(10 mol%), amine (1 mmol), and trimethyl phos-
phite (1 mmol) was stirred at room temperature for
the appropriate time as indicated in Table 1. The
progress of reactions was monitored by TLC (ethyl
acetate/n-hexane = 1/4). After completion of the re-
action, the reaction mixture was diluted with water
and extracted with chloroform, dried over Na2SO4,
and concentrated under vacuum, and the crude mix-
ture was purified by short column chromatography
on silica gel eluting with ethyl acetate/n-hexane to af-
ford pure products. Spectral data for selected prod-
uct is presented below.
[13] Laschat, S.; Kunz, H. Synthesis 1992, 90.
[14] Xu, F.; Luo, Y.; Deng, M.; Shen, Q. Eur J Org Chem
2003, 4728.
[15] Bhattacharya, A. K.; Rana, K. C. Tetrahedron Lett
2008, 49, 2598.
[16] Heydari, A.; Hamadi, H.; Pourayoubi, M. Catal
Commun 2007, 8, 1224.
[17] Akbari, J.; Heydari, A. Tetrahedron Lett 2009, 50,
4236.
[18] Rezaei, Z.; Firouzabadi, H.; Iranpoor, N.; Ghaderi,
A.; Jafari, M. R.; Jafari, A. A; Zare, H. R. Eur J Med
Chem 2009, 44, 4266.
[19] Maghsoodlou, M. T.; Khorassani, S. M. H.;
Hazeri, N.; Rostamizadeh, M.; Sajadikhah, S. S.;
Shahkarami, Z. Maleki N. Heteroatom Chem 2009,
20, 316.
[20] Hashemi, M. M.; Bakhtiari, M.; Karimi-Jaberi, Z.
Russ J Org Chem 2007, 43, 621.
[21] Hashemi, M. M.; Rahimi, A.; Karimi-Jaberi, Z. Lett
Org Chem 2005, 2, 485.
[22] Karimi-Jaberi, Z.; Hashemi, M. M. Monatsh Chem
2008, 139, 605.
[23] Chaudhuri, M. K.; Hussain, S.; Kantam, M. L.;
Neelima, B. Tetrahedron Lett 2005, 46, 8329.
[24] Chaudhuri, M. K.; Hussain, S. J Mol Catal A: Chem
2007, 269, 214.
[25] Tu, S.; Fang, F.; Miao, C.; Jiang, H.; Feng, Y.; Shi, D.;
Wang, X. Tetrahedron Lett 2003, 44, 6153.
[26] Kondaiah, G. C. M.; Reddy, L. A.; Babu, K. S.;
Gurav, V. M.; Huge, K. G.; Bandichhor, R.; Reddy,
P. P.; Bhattacharya, A.; Anand, R. V. Tetrahedron Lett
2008, 49, 106.
1
Compound 4a: white solid, mp 87˚C; H NMR
(500 MHz, CDCl3): δ 3.51 (d, J = 10.5 Hz, 3H), 3.81
(d, J = 10.6 Hz, 3H), 4.82 (d, J = 24 Hz, 1H), 6.64
(d, J = 8.0 Hz, 2H), 6.74 (t, J = 7.2 Hz, 1H), 7.10
(t, J = 7.7 Hz, 2H), 7.30 (t, J = 7.5 Hz, 1H), 7.39 (t,
J = 7.4 Hz, 2H), 7.50 (d, J = 7.3 Hz, 2H); 13C NMR
(125 MHz, CDCl3): δ 54.1 (d, 2 JP−C = 7.0 Hz, OCH3),
54.2 (2 JP−C = 6.8 Hz, OCH3), 56.2 (d, 1 JP−C = 150 Hz,
3
CH), 114.3 (CH), 119.0 (CH), 128.2 (d, JP−C
=
3
5.8 Hz, CH), 128.4 (d, JP−C = 3.1 Hz, CH), 129.1
2
(CH), 131.2 (CH), 136.0 (C), 146.6 (d, JP−C
14.5 Hz, C).
=
REFERENCES
[27] Delbecq, P.; Celerier, J.-P.; Lhommet, G. Tetrahedron
Lett 1990, 31, 4873.
[1] Domling, A.; Ugi, I. Angew Chem, Int Ed 2000, 39,
3168.
[28] Mukhopadhyay, C.; Datta, A.; Butcher, R. J.
Tetrahedron Lett 2009, 50, 4246.
[2] Atherton, F. R.; Hassal, C. H.; Lambert, R. W. J Med
Chem 1986, 29, 29.
[29] Lee, S.; Park, J. H.; Lee, J. K.; Kang, J. Chem Commun
2001, 1698.
[3] Baylis, E. K.; Campbell, C. D.; Dingwall, J. G. J Chem
Soc, Perkin Trans 1 1984, 2845.
Heteroatom Chemistry DOI 10.1002/hc