An efficient and green preparation of 5-aminophosphonate substituted pyrimidine nucleosides under solvent-free conditions

Article abstract of DOI:10.1016/j.cclet.2010.04.037

An environmentally benign and highly efficient one-pot preparation of α-aminophosphonates under solvent-free conditions was developed. By employing this method, 5-aminophosphonate substituted pyrimidine nucleosides were synthesized in good to excellent yields starting from 5-formyl-2'-deoxyuridine, aniline and dimethylphosphite.

Full text of DOI:10.1016/j.cclet.2010.04.037

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Chinese Chemical Letters 21 (2010) 1191–1194
www.elsevier.com/locate/cclet
An efficient and green preparation of 5-aminophosphonate
substituted pyrimidine nucleosides under solvent-free conditions
*
Xin Ying Zhang, Ying Ying Qu, Xue Sen Fan
School of Chemistry and Environmental Sciences, Henan Key Laboratory for Environmental Pollution Control, Henan Normal University,
Xinxiang 453007, China
Received 25 February 2010
Abstract
An environmentally benign and highly efficient one-pot preparation of a-aminophosphonates under solvent-free conditions was
developed. By employing this method, 5-aminophosphonate substituted pyrimidine nucleosides were synthesized in good to
excellent yields starting from 5-formyl-20-deoxyuridine, aniline and dimethylphosphite.
# 2010 Xue Sen Fan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Aminophosphonate; 5-Substituted pyrimidine nucleoside; Solvent-free reaction; Green synthesis
Aminophosphonates have attracted considerable attention due to their diverse biological and pharmacological
properties by acting as antibacterial agents [1], enzyme inhibitors [2] (including HIV protease) [3], and antiviral agents
[4]. Due to their importance, various methodologies have been developed for the synthesis of a-aminophosphonates.
Among them, one often used procedure involves the three-component condensation of aldehyde, amine and phosphite
with the assistance of various catalysts [5]. It was also reported that solvent-free transformations of phosphites to a-
aminophosphonates could be accomplished in the presence of acidic catalysts [6]. In addition, microwave and
ultrasonic assisted reactions proved to be promising for such three-component reaction [7]. In a recent report, a-
aminophosphonates were synthesized in excellent yields from aldehydes, amines, and trimethylphosphite in
acetonitrile by using TiCl4 as catalyst [8]. More recently, Heydari and Akbari found that a sulfonic acid functionalized
task-specific ionic liquid could be used as an efficient catalyst for the preparation of a-aminophosphonates at room
temperature in water [9]. In spite of the merits shown by the abovementioned approaches, some of them still suffered
from drawbacks such as utilization of toxic and volatile solvents and costly moisture-sensitive catalysts. Therefore, it
is currently a challenging task to develop greener, more efficient and convenient methods for the preparation of a-
aminophosphonates.
Meanwhile, the ‘‘privileged’’ structure of nucleosides has led to a variety of efficacious anti-tumor and antiviral
agents. In particular, many pyrimidine nucleoside analogues with potent biological properties have arisen by
substitution at the 5-position of the uracil base, especially in the 20-deoxyuridine series [10]. In this regard, we have an
ongoing program on the design and preparation of novel 5-substituted pyrimidine nucleoside derivatives with potential
* Corresponding author.
E-mail address: xuesen.fan@yahoo.com (X.S. Fan).
1001-8417/$ – see front matter # 2010 Xue Sen Fan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.04.037

1[(Schme_1)TD$FIG] 192
X.Y. Zhang et al. / Chinese Chemical Letters 21 (2010) 1191–1194
Scheme 1.
antiviral and antimicrobial activities [11]. Our approaches to new lead compounds have been guided by the following
considerations. Firstly, the nucleoside scaffold is an excellent point of departure in the search for new lead compounds;
secondly, other privileged molecular scaffolds, taking a-aminophosphonate as an example, have also spawned a
significant number of drugs and pharmacological agents. Therefore, we were interested in the preparation of novel
hybrids of pyrimidine nucleoside with aminophosphonate to get new entities of potentially synergic biological
activities. To obtain these hybrid compounds, we envisioned a route by employing the three-component condensation
process leading to a-aminophosphonates as described above.
Firstly, 4-nitrobenzaldehyde (1a), 4-methylaniline (2a) and dimethylphosphite (3) were chosen as model substrates
to optimize the reaction (Scheme 1). The results were summarized in Table 1.
The mixture of 1a, 2a and 3 was firstly stirred at 60 8C in 10 mL of THF for 3 h and the corresponding product (4a)
was obtained in low yield (Table 1, entry 1). Similar results were also observed with CH2Cl2, CH3CN or toluene as the
reaction medium (Table 1, entries 2–4). Next, the reaction was tried in two readily available ionic liquids, [bmim]BF4
and [bmim]PF6, and to our delight, 4a was obtained in much improved yields (Table 1, entries 5 and 6). As a further
aspect, considering the fact that there has been increasing interests in solvent-free organic reactions since they are
generally faster, give higher selectivity and yields and require easier workup procedures and simpler equipment, we
continued our study by running this reaction under neat condition. Very encouragingly, the reaction of 1a, 2a and 3
could be realized smoothly under neat condition and 4a was obtained in a yield of 91% under the optimum conditions
(Table 1, entry 9). It should be noted that upon completion of the reaction, 4a was in solid state and could be obtained
with high purity through suction.
Having established such a simple and efficient procedure, we then studied the possibility of applying this
methodology to prepare the desired pyrimidine nucleoside-aminophosphonate hybrids by using 5-formyl-20-
deoxyuridine [11b] as an aldehyde component (1b or 1c, Scheme 2). It turned out that by treating 1b or 1c, 2 and 3
under neat condition, 4b–4k were obtained in good to excellent yields [12] (Table 2). Moreover, the reaction was
compatible with various functional groups such as OMe, Cl, Br and F. Excellent chemoselectivity was observed for
substrates containing a halogen atom. We did not experience any competitive aromatic nucleophilic substitution of the
halogen atom.
Then, the reaction was extended to 5-formyluracil (1d, Scheme 3). It gave the corresponding products (4l–4q) with
excellent yields through a very simple and convenient procedure (Table 3). In comparison, the reaction with 1d is
Table 1
Optimization of the reaction conditionsa.
Entry
Solvent
Temp. (8C)
Time (h)
Yield (%)d
1
2
THFb
60
3
3
3
3
3
3
1
1
1
1
21
25
28
26
82
85
40
65
91
93
b
CH2Cl2
CH3CNb
Tolueneb
Reflux
60
3
4
60
c
5
[bmim]BF4
80
c
6
[bmim]PF6
Neat
80
7
rt
8
Neat
40
9
Neat
60
10
Neat
80
a
1a and 2a: 1 mmol, 3: 1.2 mmol.
10 mL.
b
c
d
1 mL.
Isolated yields.

[(Schme_2)TD$FIG]
X.Y. Zhang et al. / Chinese Chemical Letters 21 (2010) 1191–1194
1193
Scheme 2.
Table 2
Preparation of hybrid compounds from 5-formyl-20-deoxyuridinea.
Entry
R
Ar
Time (h)
Temp. (8C)
Product
Yield (%)b
1
2
Ac
Ac
Ac
Ac
Ac
Ac
H
p-CH3C6H4
p-CH3OC6H4
p-BrC6H4
p-ClC6H4
p-FC6H4
2
2
2
2
2
2
3
3
3
3
60
60
60
60
60
60
80
80
80
80
4b
4c
4d
4e
4f
90
88
85
84
84
86
80
78
75
75
3
4
5
6
C6H5
4g
4h
4i
7
p-CH3C6H4
p-CH3OC6H4
p-BrC6H4
C6H5
8
H
9
H
4j
4k
10
H
a
1b or 1c: 1 mmol, 2: 1 mmol, 3: 1.2 mmol.
Isolated yields.
b
cleaner and more efficient than that with 1b or 1c, probably due to the devoid of the sugar moiety in 1b or 1c, which
results in higher chemoselectivity.
In conclusion, we have developed an environmentally benign and highly efficient procedure for the preparation of
a-aminophosphonates under solvent-free conditions. By using this method, a series of 5-aminophosphonate
substituted pyrimidine nucleosides were prepared in a simple yet very efficient and clean manner. To the best of our
knowledge, this is the first example that 5-substituted nucleoside derivatives were prepared under neat condition.
[(Schme_3)TD$FIG]
Scheme 3.
Table 3
Preparation of hybrid compounds from 5-formyluracila.
Entry
Ar
Time (h)
Temp. (8C)
Product
Yield (%)b
1
2
3
4
5
6
p-CH3C6H4
p-CH3OC6H4
p-BrC6H4
p-ClC6H4
p-FC6H4
2
2
2
2
2
2
60
60
60
60
60
60
4l
96
95
93
90
90
92
4m
4n
4o
4p
4q
C6H5
a
1d: 1 mmol, 2: 1 mmol, 3: 1.2 mmol.
Isolated yields.
b

1194
X.Y. Zhang et al. / Chinese Chemical Letters 21 (2010) 1191–1194
Biological studies of these novel nucleoside derivatives are currently underway and the results will be reported in due
course.
Acknowledgments
We are grateful to the National Natural Science Foundation of China (Nos. 20772025 and 20972042), the Program
for Science & Technology Innovation Talents in Universities of Henan Province (No. 2008HASTIT006), Innovation
Scientists and Technicians Troop Construction Projects of Henan Province (No. 104100510019) and the Natural
Science Foundation of Henan Province (Nos. 092300410192 and 094300510054).
References
[1] F.R. Atherton, C.H. Hassall, R.W. Lambert, J. Med. Chem. 29 (1986) 29.
[2] (a) M.C. Allen, W. Fuhrer, B. Yuck, et al. J. Med. Chem. 32 (1989) 1652;
(b) E.W. Logusch, D.M. Walker, J.F. McDonald, et al. J. Org. Chem. 53 (1988) 4069;
(c) P.P. Giannousis, P.A. Bartlett, J. Med. Chem. 30 (1987) 1603.
[3] (a) A. Peyman, K.H. Budt, J. Spanig, et al. Tetrahedron Lett. 33 (1992) 4549;
(b) B. Stowasser, K.H. Budt, I.J. Qi, et al. Tetrahedron Lett. 33 (1992) 6625.
[4] J. Huang, R. Chen, Heteroatom Chem. 11 (2000) 480.
[5] (a) C. Qian, T. Huang, J. Org. Chem. 63 (1998) 4125;
(b) B.C. Ranu, A. Hajra, Green Chem. 4 (2002) 551;
(c) R. Ghosh, S. Maiti, A. Chakraborty, et al. J. Mol. Catal. A: Chem. 210 (2004) 53;
(d) S. Chandrasekhar, S.J. Prakash, V. Jagadeswar, et al. Tetrahedron Lett. 42 (2001) 5561;
(e) B. Kaboudin, Tetrahedron Lett. 44 (2003) 1051.
[6] (a) T. Akiyama, M. Sanada, K. Fuchibe, Synlett (2003) 1463;
(b) H. Firouzabadi, N. Iranpoor, S. Sobhani, Synthesis (2004) 2692.
[7] (a) X.J. Mu, M.Y. Lei, J.P. Zou, et al. Tetrahedron Lett. 47 (2006) 1125;
(b) M. Xia, Y.D. Lu, Ultrason. Sonochem. (2007) 235.
[8] Y.T. Reddy, P.N. Reddy, B.S. Kumar, et al. Phosphorus, Sulfur Silicon Relat. Elem. 182 (2007) 161.
[9] J. Akbari, A. Heydari, Tetrahedron Lett. 50 (2009) 4236.
[10] (a) L.A. Agrofoglio, Curr. Org. Chem. 10 (2006) 333;
(b) E. De Clercq, Antiviral Res. 67 (2005) 56;
(c) E. De Clercq, Curr. Opin. Microbiol. 8 (2005) 552.
[11] (a) X.S. Fan, X.Y. Zhang, L.H. Zhou, et al. J. Med. Chem. 49 (2006) 4052;
(b) X.S. Fan, X.Y. Zhang, L.H. Zhou, et al. J. Med. Chem. 49 (2006) 3377;
(c) X.S. Fan, X.Y. Zhang, L.H. Zhou, et al. Antiviral Res. 71 (2006) 201;
(d) X.S. Fan, X.Y. Zhang, L.H. Zhou, et al. Bioorg. Med. Chem. Lett. 16 (2006) 3224.
[12] Preparative procedure for 4b: a mixture containing 30,50-diacetyl-5-formyl-20-deoxyuridine (1 mmol), 4-methylaniline (1 mmol) and
dimethylphosphite (1.2 mmol) were taken in a 25 mL round-bottom flask. The mixture was then stirred at 60 8C for 2 h. Upon completion,
the solid product was collected by suction, washed with cold ethanol to give 4b as colorless solids. mp 169–171 8C; 1H NMR (400 MHz,
DMSO-d6): d 2.02 (s, 3H, CH3), 2.06 (s, 3H, CH3), 2.14 (s, 3H, CH3), 2.34–2.37 (m, 2H, CH2), 3.63 (d, 3H, 2JPH = 10.8 Hz, OCH3), 3.68 (d, 3H,
2JPH = 10.8 Hz, OCH3), 4.17–4.24 (m, 3H, CH, CH2), 4.85 (dd, 1H, 1JPH = 23.2 Hz, J2 = 10.8 Hz, 1H, CH), 5.18–5.21 (m, 1H, CH), 5.75 (dd,
1H, 2JPH = 10.0 Hz, J2 = 4.8 Hz 1H, NH), 6.11–6.15 (m, 1H, CH), 6.50 (d, 2H, J = 8.0 Hz, ArH), 6.90 (d, 2H, J = 8.0 Hz, ArH), 7.85 (s, 1H,
CH), 11.67 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): d 20.5, 20.9, 21.2, 35.9, 53.6 (d, J = 7.0 Hz), 54.0 (d, J = 7.0 Hz), 64.2, 74.4, 81.7,
85.3, 110.8, 113.9, 126.7, 129.9, 139.5, 144.7, 150.2, 162.7, 170.5, 170.7. HRMS (FAB) Calcd. for C23H31N3O10P: 540.1748 (MH+), Found
540.1756.