Thiamine hydrochloride (VB1): An efficient catalyst for one-pot synthesis of α-aminophosphonates under ultrasonic irradiation

Article abstract of DOI:10.1016/j.cclet.2010.11.021

An efficient synthesis of novel α-aminophosphonates by the reaction of aldehydes and amines with triethyl phosphite in the presence of the easily available, inexpensive, and nontoxic catalyst thiamine hydrochloride (VB1). This method affords the α-aminophosphonates under the influence of ultrasound irradiation in aqueous medium, in short reaction times (4-6 min), high yields (85-95%), with improved purity. The process is green, mild, inexpensive and excellent yields are the main compensation of this procedure.

Full text of DOI:10.1016/j.cclet.2010.11.021

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 563–566
www.elsevier.com/locate/cclet
Thiamine hydrochloride (VB1): An efficient catalyst for one-pot
synthesis of a-aminophosphonates under ultrasonic irradiation
*
Priyanka G. Mandhane, Ratnadeep S. Joshi, Deepak R. Nagargoje, Charansingh H. Gill
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, Maharashtra 431004, India
Received 13 September 2010
Available online 3 March 2011
Abstract
Anefficientsynthesisofnovela-aminophosphonatesbythereactionofaldehydesandamineswithtriethylphosphiteinthepresence
of the easily available, inexpensive, and nontoxic catalyst thiamine hydrochloride (VB1). This method affords the a-aminopho-
sphonates under the influence of ultrasound irradiation in aqueous medium, in short reaction times (4–6 min), high yields (85–95%),
with improved purity. The process is green, mild, inexpensive and excellent yields are the main compensation of this procedure.
#
2010 Charansingh H. Gill. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Thiamine hydrochloride (VB1); a-Aminophosphonates; Triethyl phosphate; Water; Ultrasonication; Green synthesis
Organophosphorus compounds have been found a wide range of applications in the areas of industrial, agricultural,
and medicinal chemistry owing to their biological and physical properties as well as their utility as synthetic
intermediates [1–5]. As a kind of natural amino acid analogues, a-aminophosphonates constitute an important class of
compounds with diverse biological activities. The activity of a-aminophosphonates as peptidomimetics [6], enzyme
inhibitors [7], pharmacogenic agents [8], haptens of catalytic antibodies [9], herbicidals [10], inhibitors of serine
hydrolases [11], inhibitors of UDP-galactopyranose mutase [12] and antitumor agents [13] is reported in the literature.
A number of synthetic methods for the preparation of a-aminophosphonates have been carried out under various
conditions. However, one-pot synthesis of a-aminophosphonates remains a favor due to its versatile route and high
yielding reactions. Recently, three-component synthesis starting from aldehydes, amines and diethylphosphite or
triethylphosphite have been reported using Lewis and Brønsted acid catalysts such as LiClO [14], InCl [15], lanthanide
4
3
triflates/magnesium sulfate [16], TaCl –SiO [17], amberlyst-15 [18], Al O -MW [19], sulfamic acid [20], scandium
5
2
2 3
(
some drawbacks such as long reaction times, low yields of the products, requiring stoichiometric amounts of catalysts,
tris-dodecyl sulfate) [21], BF ÁEt O [22], M(OTf) [23] and M(ClO ) [24]. Though, many of these methods suffer from
3
2
n
4 n
costly and moisture sensitive catalysts and use of highly toxic catalysts. More recently, ZrOCl Á8H O [25] or
2
2
ZrO(ClO ) Á6H O [26] and TiO [27] are reported to be effective catalysts for the formation of a-aminophosphonates
4
2
2
2
using a three component system composing of aldehydes/ketones, amines and triethylphosphite under neat conditions.
In view of the conservation of the environment combining with economic aspects, literature demands the application
of metal ion free, environmentally safe and convenient reagents in the reactions [28]. And so, we report an eco-friendly,
*
Corresponding author.
E-mail address: prof_gill@rediffmail.com (C.H. Gill).
1001-8417/$ – see front matter # 2010 Charansingh H. Gill. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.11.021

[()TD$FIG]
5
64
P.G. Mandhane et al. / Chinese Chemical Letters 22 (2011) 563–566
Cl NH3
Cl
N
S
N
N
OH
Fig. 1. Structure of thiamine hydrochloride (VB1).
facile and efficient methodology for the synthesis of a-hydroxyphosphonates using VB1. It is well known that VB1 is a
cheap and non-toxic reagent. The structure of VB1 contains a pyrimidine ring and a thiazole ring linked by a methylene
bridge (Fig. 1). The use of VB1 analogs as powerful catalysts for various organic transformations has been reported [29].
Compared with those methods above mentioned our reactions displayed their advantages: (i) green synthesis without
organic solvents involved; (ii) shortened time and improved yields; (iii) mild conditions and ready operations.
1
. Experimental
1
Melting points were determined on a Veego apparatus and are uncorrected. H NMR spectra were recorded on a
Varian AS 400 MHz spectrometer in CDCl /DMSO-d , chemical shifts (d) are in ppm relative to TMS, and coupling
3
6
constants (J) are expressed in Hertz (Hz). Mass spectra were taken on a Macro mass spectrometer (Waters) by electro-
spray method (ES). Bandelin Sonorex (with a frequency of 40 kHz and a nominal power 100 W) ultrasonic bath was
used for ultrasonic irradiation. The reaction vessel placed in side the ultrasonic bath containing water.
1
.1. General procedure of synthesis of substituted a-aminophosphonates
A mixture of substituted aldehydes/ketone (1 mmol), amine (1 mmol) and triethyl phosphite (1.2 mmol) were placed
in a round bottom flask. Further vitamin B1 (VB1) (5 mol%) was added, to this mixture, and the mixture was irradiated
under ultrasonic irradiation at ambient temperature under aqueous condition for the precise time. After the completion of
reaction as monitored by TLC; 20 mL ice cold water was added to the reaction mixture and product was extracted by
ethylacetate (2Â 25 mL). The organic layer washed by brine (2Â 20 mL) and dried over anhydrous sodium sulphate. The
solventwasdistilledoutonRota-evaporatorunderreducedpressuretoaffordthepureproducts. Theproducts4(a–n)were
1
confirmed by their spectral data after comparisons with authentic samples, IR, H NMR, mass spectra and melting point.
À1
a: IR (KBr, cm ): 3295 (–NH), 1233 (P–O), 1103–997 (P–O–Et); H NMR (CDCl , 400 MHz): d 1.12 (t, 3H),
3
1
4
1.29 (t, 3H), 3.68 (ddq, 1H, J = 7.1, 11.2, 8.1 Hz), 3.95 (ddq, 1H, J = 7.1, 8.1, 11.2 Hz), 4.14 (m, 2H), 4.75 (br, 1H, –
NH), 4.78 (d, 1H, J = 17.9 Hz), 6.61 (d, 2H, J = 8.5 Hz), 6.70 (t, 1H, J = 7.4), 7.11 (t, 2H, J = 7.4), 7.27 (1H, m), 7.34
(
t, 2H, J = 7.4 Hz), 7.49 (m, 2H); MS (ESI) m/z 320 (M+).
À1
1
d: IR (KBr, cm ): 3296(–NH), 1236(–P O), 1021(–O–P–C); H NMR (400 MHz, CDCl and DMSO-d ): d 1.13
4
t, 3H); 1.23 (t, 3H); 3.66 (ddq, 1H, J = 7.1, 11.2, 8.1 Hz); 3.97 (ddq, 1H, J = 7.1, 8.1, 11.2 Hz); 4.13 (m, 2H); 4.75 (br,
3
6
(
1
H, –NH); 4.78 (d, 1H, J = 17.9 Hz); 6.61 (d, 2H, J = 8.5 Hz); 6.70 (t, 1H, J = 7.4); 7.11 (t, 2H, J = 7.4); 7.26 (m, 1H);
.34 (t, 2H, J = 7.4 Hz); 7.49 (m, 2H); MS (ESI) m/z 229 (M+1).
7
2
. Result and discussion
As a continuation of our research work devoted to the development of useful synthetic methodologies [30], herein,
we report an efficient and practical method for the synthesis of a-aminophosphonates using VB1, as a catalyst under
ultrasound irradiation in aqueous medium. Consequently several aryl and heteroaryl aldehydes/ketones, aniline with
ifferent substituent on the aromatic ring were subjected to the addition reaction. In all the yields were excellent. We
d
[
(
)
T
D
$
F
I
G
]
O
O
O
VB1
P
O
R''-NH
2
P(OEt)
3
R
R'
R''
)
)))))), Water
RN
H
R'= H, R
(a-n)
1
2
3
4(a-n)
Scheme 1. Synthesis of various a-aminophosphonates using VB1 as a catalyst.

P.G. Mandhane et al. / Chinese Chemical Letters 22 (2011) 563–566
565
Table 1
Optimization of solvent effect on the model reaction.
a
b
Yield (%)
Entry
Solvent
Time (min)
1
2
3
4
5
6
7
Solvent-free
Toluene
10
10
10
10
10
10
10
20
45
52
58
71
73
95
Acetonitrile
Dichloromethane
Ethanol
Methanol
Water
a
Reaction of benzaldehyde, aniline and triethyl phosphite catalyzed by VB1 (5 mol %) under ultrasonic waves for 10 min.
Isolated yield.
b
have used VB1 for the sonochemical synthesis of a-aminophosphonates. The products were isolated in high yields
1
(
Scheme 1). The structures of the products were determined from their spectral (IR, H NMR, and MS) data.
In the current study, the commercially available catalyst VB1 is used as a catalyst but its scope has not been fully
explored. VB1 can be used as buffer, neutralizing agent, sequestrate, yeast food and is also emerged as an efficient
heterogeneous acid catalyst [31]. VB1 facilitates the formation of the a-aminophosphonates under ultrasonic
irradiation. The use of VB1 catalyst under ultrasonic irradiation plays an important role in the synthesis and hence the
reaction rate was improved and the reaction time was reduced.
To study the reaction in water, we tested reaction of triethyl phosphate, benzaldehyde, aniline and VB1 as a simple
model substrate in different solvents, namely toluene, acetonitrile, DCM, methanol, ethanol and water. It was found that
water (entry 7) was a solvent of choice for the reaction, and the desired product was obtained in excellent yields (95%).
Not only water but methanol and ethanol also displayed moderate result. But in case of other solvents like DCM, toluene
and acetonitrile reaction gave very poor yield of product. Whereas in case of solvent free condition reaction did not
proceeded at all even after prolonged reaction time. Allthe obtained results are summarized inTable 1. We have also tried
this reaction with different concentration of catalyst but we have got the best results at 5 mol % of VB1 and in the absence
of the catalyst, reaction did not proceed even after prolonged reaction time. Further, we have also studied the
sonochemical effect on model reaction using diverse solvents. In all cases, the experimental results show that the reaction
times are reduced and the yields of the products are higher under sonication. Based on the results of this study, it seems
that the ultrasonic irradiation improves the reaction times and yields. The obtained results are summarized in Table 2.
Table 2
Sonochemical effect on the synthesis of a-aminophosphonates.
a
b
Compound
Aldehyde/ketone
Aniline
With US
Without US
Time (min)
c,d
Yield (%)
c,d
Yield (%)
Time (min)
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
Benzaldehyde
Aniline
5
9
95
91
89
88
93
95
91
88
86
85
69
65
41
38
60
60
60
60
60
60
60
60
60
60
60
60
60
60
77
70
71
73
70
76
72
68
65
61
60
62
31
37
Benzaldehyde
4-Toludine
4-Chloroaniline
4-Anisidine
Aniline
Benzaldehyde
7
Benzaldehyde
8
2-Methylbenzaldehyde
4-Anisisaldehyde
3
Aniline
4
g
h
i
4-Nitrobenzaldehyde
2-Chlorobenzaldehyde
2,6-Dichlorobenzaldehyde
4-Hydroxybenzaldehyde
Furan-2-carbaldehyde
Thiophene-2-carbaldehyde
Cyclohexanone
Aniline
5
Aniline
8
Aniline
7
j
Aniline
5
k
l
Aniline
19
21
30
40
Aniline
m
n
Aniline
Acetophenone
Aniline
a
b
c
d
Reaction of aldehyde/ketone, amine, triethylphosphite in the presence of VB1 (5 mol%) under ultrasonic waves in aqueous medium.
Reaction of aldehyde/ketone, amine, triethylphosphite in the presence of VB1 (5 mol%) under stirring at ambient temperature.
Isolated yield.
1
Compounds were characterized by H NMR, MS spectral data and were compared with the reference compounds.

566
P.G. Mandhane et al. / Chinese Chemical Letters 22 (2011) 563–566
After optimizing the conditions, the generality of this method was examined by the reaction of several substituted
aldehydes/ketones, aniline with triethylphosphate and VB1. The results are shown in Table 2 (entry 4k–4n). The newly
synthesized compounds were compared (mp, MS and NMR) with compounds that were prepared using the literature
method (Scheme 1). This comparison revealed that the compounds synthesized by this newly developed method were
exactly similar in all aspects to the reference compounds. We also studied the reaction on heterocyclic aldehydes or
ketones it gave the corresponding products, but the yields were low even after prolonged reaction time (Table 2, entry
4k–4n). The reaction on ketones does not show any conversion even after prolonged reaction time, even on increasing
the catalyst concentration, frequency and temperature of the ultrasonic bath the product formation was not observed.
This result revealed that the reaction undergoes only on the aldehydes and rarely on ketones (Table 2, entry 4k–4n).
Acknowledgment
The authors are thankful to the Head, Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad, for his valuable support and laboratory facilities.
References
[
[
[
[
[
[
[
[
[
1] R. Engel, Chem. Rev. 77 (1977) 349.
2] J. Hiratake, J. Oda, Biosci. Biotechnol. Biochem. 61 (1997) 211.
3] K.A. Schug, W. Lindner, Chem. Rev. 105 (2005) 67.
4] K. Moonen, I. Lauryn, C.V. Stevens, Chem. Rev. 104 (2004) 6177.
5] F. Palacios, C. Alonso, J.M. de los Santos, Curr. Org. Chem. 8 (2004) 1481.
6] P. Kafarski, B. Lejczak, Phosphorus Sulfur Silicon Relat. Elem. 63 (1991) 193.
7] M.C. Allen, W. Fuher, B. Tuck, et al. J. Med. Chem. 32 (1989) 1652.
8] E.K. Baylis, C.D. Campbell, J.G. Dingwall, J. Chem. Soc. Perkin Trans. 1 (1984) 2845.
9] S.J. Benkovic, R. Hirschmann, Tetrahedron Lett. 35 (1994) 6853.
[
[
[
[
[
10] C.H. Hassall, E.F. Hahn, Antibiotics (Springer, Berlin) VI (1983) 1.
11] G.F. Makhaeva, V.V. Malygin, A.Y. Aksinenko, et al. Dockl. Biochem. Biophys. 400 (2005) 92.
12] W. Pan, C. Ansiaux, S.P. Vincent, Tetrahedron Lett. 48 (2007) 4353.
13] X. Rao, Z. Song, L. He, Heteroat. Chem. 19 (2008) 512.
14] (a) M.R. Saidi, N. Azizi, Synlett (2002) 1347;
(
(
(
b) N. Azizi, F. Rajabi, M.R. Saidi, Tetrahedron Lett. 45 (2004) 9233;
c) N. Azizi, M.R. Saidi, Tetrahedron 59 (2003) 5329;
d) N. Azizi, M.R. Saidi, Eur. J. Org. Chem. 23 (2003) 4630.
[
[
[
[
[
[
[
[
[
[
[
[
[
[
15] B.C. Ranu, A. Hajra, U. Jana, Org. Lett. 1 (1999) 1141.
16] C. Qian, T. Huang, J. Org. Chem. 63 (1998) 4125.
17] S. Chandrasekhar, S.J. Prakash, V. Jagadeshwar, et al. Tetrahedron Lett. 42 (2001) 5561.
18] M. Tajbakhsh, A. Heydari, H. Alinezhad, et al. Synthesis (2008) 352.
19] B. Kaboudin, R. Nazari, Tetrahedron Lett. 42 (2001) 8211.
20] S.D. Mitragotri, D.M. Pore, U.V. Desai, et al. Catal. Commun. (2008) 1822.
21] K.K. Manabe, S. obayashi, Chem. Commun. (2000) 669.
22] H.J. Ha, Nam, Synth. Commun. 22 (1992) 1143.
23] H. Firouzabadi, N. Iranpoor, S. Sobhani, Synthesis (2004) 2692.
24] S. Bhagat, A.K. Chakraborti, J. Org. Chem. 72 (2007) 1263.
25] H. Firouzabadi, M. Jafarpour, J. Iran. Chem. Soc. 5 (2008) 159.
26] S. Bhagat, A.K. Chakraborti, J. Org. Chem. 73 (2008) 6029.
27] M. Hosseini-Sarvari, Tetrahedron 61 (2008) 5459.
28] (a) C. Noonan, L. Baragwanath, S.J. Connon, Tetrahedron Lett. 49 (2008) 4003;
(
(
b) P.D. D u¨ nkelmann, K. Jung, A. Nitsche, et al. J. Am. Chem. Soc. 124 (2002) 12084;
c) S. Orlandi, M. Caporale, M. Benaglia, R. Annunziata, Tetrahedron: Asymmetry 14 (2003) 3827.
[29] (a) P.G. Mandhane, R.S. Joshi, D.R. Nagargoje, et al. Tetrahedron Lett. 51 (2010) 3138;
(
(
b) R.S. Joshi, P.G. Mandhane, S.D. Diwakar, et al. Ultrason. Sonochem. 17 (2009) 298;
c) P.G. Mandhane, R.S. Joshi, A.R. Ghawalkar, et al. Bull. Korean Chem. Soc. 30 (2009) 2969.
[
[
30] E.H. Hu, D.R. Sidler, U.H. Dolling, J. Org. Chem. 63 (1998) 3454.
31] A. Shaabani, A. Bazgir, F. Teimouri, Tetrahedron Lett. 44 (2003) 857.