Solvent-free synthesis of pyrimidine nucleoside-aminophosphonate hybrids and their biological activity evaluation

Article abstract of DOI:10.1080/15257770.2010.496281

A novel and highly efficient one-pot three-component synthesis of α-aminophosphonates under neat condition was developed. By employing this method, hybrid compounds of aminophosphonate with pyrimidine nucleosides were synthesized in good to excellent yields starting from 5-formyl-2′- deoxyuridine, aniline and dimethyl phosphite. The antiviral and antileishmanial activities of these novel hybrid compounds were also studied but none were found to be active.

Full text of DOI:10.1080/15257770.2010.496281

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Solvent-Free Synthesis of Pyrimidine
Nucleoside-Aminophosphonate Hybrids
and Their Biological Activity Evaluation
Xinying Zhang a , Yingying Qu a , Xuesen Fan a , C. Bores b , Dong
Feng a , Graciela Andrei c , Robert Snoeck c , Erik De Clercq c
Philippe M. Loiseau b
&
a School of Chemistry and Environmental Sciences, Henan Key
Laboratory for Environmental Pollution Control , Henan Normal
University , Xinxiang, Henan, P. R. China
b Chimiothérapie Antiparasitaire, UMR-CNRS 8076 , Université Paris-
Sud , Chatenay Malabry, France
c Rega Institute for Medical Research , Leuven, Belgium
Published online: 19 Jul 2010.
To cite this article: Xinying Zhang , Yingying Qu , Xuesen Fan , C. Bores , Dong Feng , Graciela
Andrei , Robert Snoeck , Erik De Clercq & Philippe M. Loiseau (2010) Solvent-Free Synthesis
of Pyrimidine Nucleoside-Aminophosphonate Hybrids and Their Biological Activity Evaluation,
Nucleosides, Nucleotides and Nucleic Acids, 29:8, 616-627, DOI: 10.1080/15257770.2010.496281
To link to this article: http://dx.doi.org/10.1080/15257770.2010.496281
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Nucleosides, Nucleotides and Nucleic Acids, 29:616–627, 2010
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2010.496281
SOLVENT-FREE SYNTHESIS OF PYRIMIDINE NUCLEOSIDE-
AMINOPHOSPHONATE HYBRIDS AND THEIR BIOLOGICAL
ACTIVITY EVALUATION
Xinying Zhang,1 Yingying Qu,1 Xuesen Fan,1 C. Bores,2 Dong Feng,1
Graciela Andrei,3 Robert Snoeck,3 Erik De Clercq,3 and Philippe M. Loiseau2
1School of Chemistry and Environmental Sciences, Henan Key Laboratory for Environmental
Pollution Control, Henan Normal University, Xinxiang, Henan, P. R. China
2Chimiothe´rapie Antiparasitaire, UMR-CNRS 8076, Universite´ Paris-Sud, Chatenay
Malabry, France
3Rega Institute for Medical Research, Leuven, Belgium
A novel and highly efficient one-pot three-component synthesis of α-aminophosphonates under
2
neat condition was developed. By employing this method, hybrid compounds of aminophosphonate
with pyrimidine nucleosides were synthesized in good to excellent yields starting from 5-formyl-2ꢁ-
deoxyuridine, aniline and dimethyl phosphite. The antiviral and antileishmanial activities of these
novel hybrid compounds were also studied but none were found to be active.
Keywords Pyrimidine nucleoside; α-aminophosphonate; hybrid; solvent-free reaction;
biological activities
INTRODUCTION
As bioisosteric analogue of α-amino acids, the α-aminophosphonate
moiety, is a versatile and novel pharmacophore due to the broad spec-
trum of biological activity exhibited by compounds bearing this structural
unit. They have revealed diverse and interesting biological and biochemical
properties by acting as antibacterial agents,[1] enzyme inhibitors[2] (includ-
ing HIV protease),[3] antiviral agents,[4] as well as their role for antibody
Received 26 January 2010; accepted 21 May 2010.
This work was financially supported by the National Natural Science Foundation of China (Nos.
20772025 and 20972042), 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). The authors sincerely thank Prof. Dr. Paul F Torrence, Department
of Chemistry, Northern Arizona University, USA, for his kind help and excellent instructions.
Address correspondence to Xuesen Fan, School of Chemistry and Environmental Sciences, Henan
Key Laboratory for Environmental Pollution Control, Henan Normal University, Xinxiang, Henan
453007, P. R. China. E-mail: Xuesen.fan@henannu.edu.cn
616

Pyrimidine Nucleoside-Aminophosphonate Hybrids
617
generation. Therefore, α-aminophosphonates have been the subject of
considerable current interest among medicinal and organic chemists. To
date, various methodologies have been developed for the synthesis of α-
aminophosphonate. First, nucleophilic addition of phosphite to imine is
established as a useful method to construct such scaffold.[5] However, this
method has limitations as many imines are hygroscopic and are not suffi-
ciently stable for isolation. As an improvement, the one-pot synthesis of α-
aminophosphonates directly from aldehyde, amine, and phosphite was first
achieved under the catalysis of lanthanide triflates.[6] Subsequently, one-pot
variations in organic solvents were improved.[7] Furthermore, it was reported
that solvent-free transformations of phosphites to α-aminophosphonates
could be accomplished in the presence of acidic catalysts.[8] More recently,
microwave-assisted and ultrasonic-assisted reactions proved to be promis-
ing for such three-component reaction.[9] However, most of the existing
methods still displayed such drawbacks as environmental pollution caused
by utilization of volatile solvents and costly and moisture-sensitive catalysts,
harsh reaction conditions, and unsatisfactory yields. Therefore, it is currently
a challenging task to develop more efficient and convenient methods for the
preparation of α-aminophosphonates.
On the other hand, the “privileged” structure of nucleosides has led to
a variety of efficacious antiviral agents. Many pyrimidine nucleoside ana-
logues with potent biological properties have arisen by substitution at the
5-position of the uracil base, particularly in the 2ꢁ-deoxyuridine series.[10]
In this regard, we have an ongoing program on the design and prepara-
tion of novel 5-substituted pyrimidine nucleoside derivatives with potential
biological activities.[11] Our approaches to new lead compounds have been
guided by the following considerations. First, the nucleoside scaffold is an
excellent point of departure in the search for new compounds with poten-
tial biological activities; second, other privileged molecular scaffolds, taking
α-aminophosphonate as an example, has also spawned a significant num-
ber of drugs and biologically active agents. Therefore, we were interested in
the preparation of novel hybrids of 5-substituted pyrimidine nucleoside and
aminophosphonate to get new entities with potentially synergic biological
activities. To obtain these new hybrid compounds, we envisioned a route
by employing 5-formyl-2ꢁ-deoxyuridine as the aldehyde component in the
three-component condensation process leading to α-aminophosphonates as
described previously.
RESULTS AND DISCUSSION
First, the reaction of 4-nitrobenzaldehyde (1a), 4-methylaniline (2a) and
dimethyl phosphite (3) was considered as a model reaction to optimize the
reaction (Scheme 1). The results are summarized in Table 1.

618
X. Zhang et al.
PO(OMe)2
CHO
+
NH2
HPO(OMe)2
+
N
H
CH3
O2N
H3C
O2N
4a
1a
2a
3
SCHEME 1 Optimization of the reaction conditions.
The mixture of 1a, 2a, and 3 was firstly stirred at 60◦C in 10 mL of THF
for 3 hours 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, entry 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 yield (Table 1, entries 5
and 6). As a further aspect, considering the fact that there has been increas-
ing interest in solvent-free organic reactions since they are generally faster,
give higher selectivity and yields, and require easier work-up procedures and
simpler equipment, we continued our study by running this reaction under
neat condition. Quite encouragingly, the reaction of 1a, 2a, and 3 could be
realized in neat condition and 4a was obtained in a yield of 91% when the
three-component reaction was run at 60◦C for 1 hour (Table 1, entry 9). No
significant improvement in terms of yield was observed when the reaction
temperature was increased to 80◦C (Table 1, entry 10). It should be noted
that upon completion of the reaction, 4a was in solid state and could be
obtained with high purity through filtration and washing with cold ethanol.
It was observed that for 4a, the carbon connecting to the P(O)(OMe)2 moi-
ety is a newly formed chiral center. Since all the starting materials for the
synthesis of 4a are achiral, the product is formed as a racemic mixture of
two enantiomers.
TABLE 1 Optimization of the reaction conditionsa
Entry
Solvent
THFb
Temp. (◦C)
Time (h)
Yield (%)d
1
2
3
4
5
6
7
8
9
10
60
reflux
60
60
80
80
r t
40
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
[bmim]BF4
[bmim]PF6
neat
c
c
neat
neat
neat
80
a1a: 1 mmol, 2a: 1 mmol, 3: 1.2 mmol.
b10 mL of solvent was used.
c1 mL of solvent was used.
dIsolated yields.

Pyrimidine Nucleoside-Aminophosphonate Hybrids
619
O
N
PO(OMe)2
O
N
CHO
HN
HN
O
N
Ar
H
O
O
neat
60 oC
RO
RO
ArNH2
+
+ HPO(OMe)2
O
OR
OR
1b: R = Ac
1c: R = H
2
3
4b~4g: R = Ac
4h~4k: R = H
SCHEME 2 Preparation of pyrimidine nucleoside-aminophosphonate hybrids.
Having established such a simple and efficient procedure, we then ap-
plied the optimized reaction conditions in the preparation of pyrimidine
nucleoside-aminophosphonate hybrids by using 5-formyl-2ꢁ-deoxyuridine as
the aldehyde component (1b or 1c, Scheme 2). By treating 1b or 1c, 2 and
3 under neat condition, good to excellent results were obtained and the
reaction was compatible with various functional groups such as OMe, Cl,
Br, and F. Excellent chemoselectivity was also observed for substrates con-
taining a halogen atom. We did not experience any competitive aromatic
nucleophilic substitution of the halogen atom. In addition, based on NMR
data, it was concluded that compound 4b–4k were obtained as a 1:1 diastere-
omeric mixture arising from the generation of a chiral carbon connecting
to the P(O)(OMe)2 moiety.
Then, the reaction was extended to 5-formyluracil (1d, Scheme 3), used
as another kind of aldehyde substrate. It also gave the corresponding prod-
uct with excellent yields through a very simple and convenient procedure
(Table 3). Compared with their nucleoside counterparts, they are devoid of
the sugar moiety and were expected to serve as control compounds in the
QSAR study.
The formation of α-aminophosphonate was reported to follow two dis-
tinct pathways: (a) imine formation from aldehyde and amine followed by
nucleophilic attack by the phosphite and (b) nucleophilic displacement of
the hydroxyl group of the initially formed α-hydroxyphosphonate. Thus, in
separate experiments we treated (a) 1b with 2a at 60◦C under neat condi-
tion; (b) 1b with 3 at 60◦C under neat condition (Scheme 4). As a result,
O
PO(OMe)2
Ar
O
CHO
HN
HN
neat
60 oC
N
ArNH2
HPO(OMe)2
+
+
H
O
N
H
O
N
H
1d
2
3
4l~4q
SCHEME 3 Preparation of uracil-aminophosphonate hybrids.

620
X. Zhang et al.
O
N
O
N
CHO
+
N
CH3
HN
HN
NH2
neat
O
O
AcO
AcO
60 oC
O
O
H3C
OAc
OAc
2a
CHO
1b
5
PO(OMe)2
OH
O
N
O
N
HN
HN
neat
O
O
AcO
AcO
+ HPO(OMe)2
O
O
60 oC
OAc
OAc
1b
3
6
SCHEME 4 Mechanism study for the formation of hybrid compounds.
imine (5) was formed in the former procedure but no corresponding α-
hydroxyphosphonate (6) was observed in the latter case. This means that
the formation of the hybrid compounds followed the first pathway.
As many 5-substituted pyrimidine nucleosides are known to exhibit
remarkable antiviral and antileishmania activities,[10–12] the hybrid com-
pounds (4b–4q) were evaluated against varicella-zoster virus (VZV) and
cytomegalovirus (CMV) in human embryonic lung (HEL) cells and Leish-
mania donovani promastigotes. Unfortunately, none of these hybrid com-
pounds showed any significant antiviral activity or toxicity up to 250 µM.
They are also inactive against Leishmanial donovani promastigotes accord-
ing to previously described protocol.
EXPERIMENTAL
Melting points were measured by a Kofler micromelting point apparatus
1
and were uncorrected. H, 13C, and 31P NMR spectra were determined on
a Bruker AC 400 spectrometer as DMSO-d6 or CDCl3 solutions. Chemical
shifts were expressed in parts per million (δ) downfield from the internal
standard tetramethylsilane and were reported as s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), and dd (doublet of doublets) and
coupling constants J were given in Hz. The high-resolution mass spectra
(HRMS) were performed on a JEOL HX 110A spectrometer.

Pyrimidine Nucleoside-Aminophosphonate Hybrids
621
TABLE 2 Preparation of hybrid compounds from 5-formyl-2ꢁ-deoxyuridinea
Entry
R
Ar
Time (h) Temperature (◦C) Product Yield (%)b
1
2
3
4
5
6
7
8
9
10
Ac p-CH3C6H4
Ac p-CH3OC6H4
Ac p-BrC6H4
Ac p-ClC6H4
Ac p-FC6H4
Ac C6H5
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
4g
4h
4i
90
88
85
84
84
86
80
78
75
75
H
H
H
H
p-CH3C6H4
p-CH3OC6H4
p-BrC6H4
C6H5
4j
4k
a1b or 1c: 1 mmol, 2: 1 mmol, 3: 1.2 mmol.
bIsolated yield.
General Experimental Procedure for the Preparation
of Compounds 4a–4g
Carbonyl compound (1a or 1b, 1 mmol), amine (2, 1 mmol) and
dimethylphosphite (3, 1.2 mmol) were taken into a 50 mL flask. The mixture
was stirred at 60◦C for a certain period of time (shown in Tables 1 and 2)
to complete the reaction (monitored by thin layer chromatography; TLC).
Upon completion, the solid product was collected and washed with cold
ethanol. All the products were characterized from their spectral data.
1
4a m.p.: 210–212◦C; H NMR (400 MHz, CDCl3) δ: 2.20 (s, 3H, CH3),
2
2
3.64 (d, J PH = 10.8 Hz, OCH3), 3.81 (d, J PH = 10.8 Hz, OCH3), 4.90 (d,
1J PH = 25.2 Hz, CH), 6.47 (d, 2H, J = 8.0 Hz, ArH), 6.94 (d, 2H, J = 8.0 Hz,
ArH), 7.67 (dd, 2H, J1 = 8.4 Hz, J2 = 2.0 Hz, ArH), 8.22 (d, 2H, J = 8.4Hz,
ArH). 13C NMR (100 MHz, CDCl3) δ: 20.3, 53.8 (d, J = 7.0 Hz), 54.2 (d, J =
7.0 Hz), 55.1, 56.5, 113.1, 123.8, 128.6, 129.8, 143.1, 143.8, 147.6. 31P NMR
(162 MHz, CDCl3): δ 25.20; HRMS (FAB) Calcd for C16H20N2O5P: 351.1111
(MH+), Found 351.1115.
TABLE 3 Preparation of hybrid compoundsa from 5-formyluracil
Entry
Ar
Time (h)
Temperature (◦C)
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
4m
4n
4o
4p
4q
96
95
93
90
90
92
C6H5
a1d: 1 mmol, 2: 1 mmol, 3: 1.2 mmol.
bIsolated yield.

622
X. Zhang et al.
1
4b H NMR (400 MHz, DMSO-d6) δ: 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, 2J PH = 10.8
2
Hz, OCH3), 3.68 (d, 3H, J PH = 10.8 Hz, OCH3), 4.17–4.24 (m, 3H, CH,
CH2), 4.85 (dd, 1H, 1J PH = 23.2 Hz, J 2 = 10.8 Hz, 1H, CH), 5.18–5.21 (m,
2
1H, CH), 5.75 (dd, 1H, J PH = 10.0 Hz, J 2 = 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) δ: 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; 31P
NMR (162 MHz, DMSO-d6): δ 25.13; HRMS (FAB) Calcd for C23H31N3O10P:
540.1748 (MH+), Found 540.1756.
4c 1H NMR (400 MHz, DMSO-d6) δ: 2.02 (s, 3H, CH3), 2.06 (s, 3H, CH3),
2.34–2.37 (m, 2H, CH2), 3.61–3.67 (m, 9H, 3 × OCH3), 4.17–4.26 (m, 3H,
CH, CH2), 4.83 (dd, 1J PH = 23.2 Hz, J 2 = 10.8 Hz, 1H, CH), 5.18–5.20 (m,
2
1H, CH), 5.63 (dd, J PH = 10.0 Hz, J 2 = 4.8 Hz 1H, NH), 6.11–6.15 (m,
1H, CH), 6.65 (d, 2H, J = 8.0 Hz), 6.72 (d, 2H, J = 8.0 Hz), 7.85 (s, 1H,
CH), 11.67 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ: 21.0, 21.2, 35.8,
53.5 (d, J = 7.0 Hz), 54.0 (d, J = 7.0 Hz), 55.6, 64.2, 74.4, 81.6, 85.2, 110.9,
115.0, 115.2, 139.5, 140.9, 150.2, 152.4, 162.7, 170.5, 170.7; 31P NMR (162
MHz, DMSO-d6): δ 25.02; HRMS (FAB) Calcd for C23H31N3O11P: 556.1697
(MH+), Found 556.1706.
1
4d H NMR (400 MHz, DMSO-d6) δ: 2.00 (s, 3H, CH3), 2.07 (s, 3H,
2
CH3), 2.33–2.50 (m, 2H, CH2), 3.63 (d, 3H, J PH = 10.4 Hz, OCH3), 3.68
(d, 3H, 2J PH = 10.8 Hz, OCH3), 4.17–4.25 (m, 3H, CH, CH2), 4.85 (dd, 1H,
1J PH = 22.4 Hz, J 2 = 10.4 Hz, CH), 5.18–5.20 (m, 1H, CH), 6.11–6.14 (m,
2
1H, CH), 6.28 (dd, 1H, J PH = 9.6 Hz, J 2 = 4.4 Hz, NH), 6.66 (d, 2H, J =
8.8 Hz, ArH), 7.23–7.25 (d, 2H, J = 8.8 Hz, ArH), 7.86 (s, 1H, CH), 11.72 (s,
1H, NH). 13C NMR (100 MHz, DMSO-d6) δ: 20.9, 21.2, 36.1, 53.6 (d, J = 7.0
Hz), 54.1 (d, J = 7.0 Hz), 64.1, 74.4, 81.8, 85.4, 108.9, 110.3, 115.6, 132.0,
146.5, 150.1, 162.6, 170.5, 170.7; 31P NMR (162 MHz, DMSO-d6): δ 24.88;
HRMS (FAB) Calcd for C22H28BrN3O10P: 604.0696 (MH+), Found 604.
0680.
4e 1H NMR (400 MHz, DMSO-d6) δ: 2.00 (s, 3H, CH3), 2.07 (s, 3H, CH3),
2.35–2.66 (m, 2H, CH2), 3.63 (d, 3H, 2J PH = 10.4 Hz, OCH3), 3.68 (d, 3H,
2J PH = 10.4 Hz, OCH3), 4.17–4.25 (m, 3H, CH, CH2), 4.88 (dd, 1J PH = 22.4
Hz, J 2 = 10.0 Hz, 1H, CH), 5.18–5.20 (m, 1H, CH), 6.12 (t, J = 6.4 Hz, 1H,
2
CH), 6.26 (dd, J PH = 9.6 Hz, J 2 = 4.0 Hz, 1H, NH), 6.70 (d, 2H, J = 8.4
Hz, ArH), 7.12 (d, 2H, J = 8.4 Hz, ArH), 7.86 (s, 1H, CH), 11.71 (s, 1H,
NH). 13C NMR (100 MHz, DMSO-d6) δ: 20.9, 21.2, 36.1, 53.6 (d, J = 7.0 Hz),
54.1 (d, J = 7.0 Hz), 64.1, 74.4, 81.8, 85.4, 110.3, 115.1, 121.4, 129.1, 139.6,
146.1, 150.1, 162.7, 170.5, 170.7; 31P NMR (162 MHz, DMSO-d6): δ 24.62;
HRMS (FAB) Calcd for C22H28ClN3O10P: 560.1202 (MH+), Found 560.
1207.

Pyrimidine Nucleoside-Aminophosphonate Hybrids
623
4f 1H NMR (400 MHz, DMSO-d6) δ: 2.00 (s, 3H, CH3), 2.06 (s, 3H,CH3),
2.22–2.42 (m, 2H, CH2), 3.63 (d, 3H, 2J PH = 10.4 Hz, OCH3), 3.68 (d, 3H,
2J PH = 10.4 Hz, OCH3), 4.19–4.23 (m, 3H, CH, CH2), 4.86 (dd, 1J PH = 22.4
2
Hz, J 2 = 10.4 Hz, 1H, CH), 5.18–5.20 (m, 1H, CH), 5.99 (dd, J PH = 9.6
Hz, J 2 = 4.0 Hz 1H, NH), 6.10–6.14 (m, 1H, CH), 6.69–6.71 (m, 2H, ArH),
6.92–9.96 (m, 2H, ArH), 7.85 (s, 1H, CH), 11.69 (s, 1H, NH). 13C NMR (100
MHz, DMSO-d6) δ: 20.9, 21.2, 36.0, 53.6 (d, J = 7.0 Hz), 54.1 (d, J = 7.0
Hz), 64.1, 74.4, 81.7, 85.3, 110.5, 114.8 (d, J = 7.0 Hz), 115.8, 139.5, 143.7,
150.1, 154.0, 156.8, 162.7, 170.5, 170.7; 31P NMR (162 MHz, DMSO-d6):
δ 24.90; HRMS (FAB) Calcd for C22H28FN3O10P: 544.1497 (MH+), Found
544.1493.
1
4g H NMR (400 MHz, DMSO-d6) δ: 2.02–2.05 (m, 6H, 2×CH3),
2.32–2.38 (m, 2H, CH2), 3.61–3.71 (m, 6H, 2×OCH3), 4.10–4.25 (m, 3H,
CH, CH2), 4.87–4.96 (m, 1H, CH), 5.16–5.19 (m, 1H, CH), 5.92–6.13 (m,
2H, CH, NH), 6.60–6.69 (m, 3H, ArH), 7.05–7.10 (m, 2H, ArH), 7.81–7.86
(m, 1H, CH), 11.66 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ: 20.7, 20.9,
37.5, 46.9, 53.6, 54.5, 63.7, 74.2, 82.7, 85.9, 110.6, 113.8, 119.0, 129.4, 138.6,
145.5, 149.8, 162.4, 170.3, 170.9; 31P NMR (162 MHz, DMSO-d6): δ 24.92;
HRMS (FAB) Calcd for C22H29N3O10P: 526.1591 (MH+), Found 526.1590.
General Experimental Procedure for the Preparation
of Compounds 4h–4k
Carbonyl compound (1c, 1 mmol), amine (2, 1 mmol), dimethylphos-
phite (3, 1.2 mmol) were taken in a 50 mL flask. The mixture was stirred at
80◦C for 3 hours. Upon completion, the syrupy product was purified by sil-
ica gel column chromatography eluting with methanol-methylene chloride
(1–5%) to give pure product. All the products were characterized from their
spectral data.
1
4h H NMR (400 MHz, DMSO-d6) δ: 1.98–2.18 (m, 5H, CH3, CH2),
3.54–3.79 (m, 9H, 2 × OCH3, CH, CH2), 4.21–4.26 (m, 1H, CH), 4.84–4.92
(m, 1H, CH), 5.02 (s, 1H, OH), 5.26 (s, 1H, OH), 5.68–5.70 (m, 1H, NH),
6.08–6.16 (m, 1H, CH), 6.59 (d, 2H, J = 8.0 Hz, ArH), 6.90 (d, 2H, J =
8.0 Hz, ArH), 8.03–8.04 (m, 1H, CH), 11.54 (s, 1H, NH). 13C NMR (100
MHz, DMSO-d6) δ: 20.5, 53.7 (d, J = 7.0 Hz), 54.1 (d, J = 7.0 Hz), 62.1,
71.0, 84.9, 88.0, 109.9, 110.3, 113.9, 126.6, 129.8, 139.6, 139.7, 144.5, 144.7,
150.3, 162.8; 31P NMR (162 MHz, DMSO): δ 25.22; HRMS (FAB) Calcd for
C19H271N3O8P: 456.1537 (MH+), Found 456.1540.
4i H NMR (400 MHz, CDCl3) δ: 2.12–2.33 (m, 2H, CH2), 3.70–3.96
1
(m, 12H, CH, CH2, 3 × OCH3), 4.45–4.47 (m, 1H, CH), 5.05 (d, J PH
=
23.2 Hz, 1H, CH), 6.29 (t, J = 6.4 Hz, 1H, CH), 6.69 (d, 2H, J = 9.2 Hz,
ArH), 6.74 (d, 2H, J = 9.2 Hz, ArH), 8.28 (s, 1H, CH), 10.03 (s, 1H, NH).
13C NMR (100 MHz, CDCl3) δ: 40.5, 53.9, 54.7, 55.6, 61.7, 71.1, 85.5, 87.6,

624
X. Zhang et al.
109.9, 114.9, 115.5, 139.2, 150.2, 153.1, 162.8; 31P NMR (162 MHz, DMSO-
d6): δ 25.27; HRMS (FAB) Calcd for C19H27N3O9P: 472.1486 (MH+), Found
472.1480.
4j 1H NMR (400 MHz, DMSO-d6) δ: 1.88–2.20 (m, 2H, CH2), 3.49–3.80
(m, 9H, CH, CH2, 2 × OCH3), 4.19–4.26 (m, 1H, CH), 4.82–4.92 (m, 1H,
CH), 4.96 (s, 1H, OH), 5.28 (s, 1H, OH), 6.08–6.20 (m, 2H, CH, NH), 6.65
(d, 2H, J = 8.0 Hz, ArH), 7.24 (d, 2H, J = 8.0 Hz, ArH), 8.00–8.02 (m, 1H,
CH), 11.54 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ: 36.0, 53.6 (d,
J = 7.0 Hz), 54.0 (d, J = 7.0 Hz), 54.1, 64.1, 74.4, 81.7, 85.3, 110.5, 114.7 (d,
J = 7.0 Hz), 115.7, 115.9, 139.5, 143.6, 143.8, 150.1, 162.7; 31P NMR (162
MHz, DMSO-d6): δ 24.7; HRMS (FAB) Calcd for C18H24BrN3O8P: 520.0485
(MH+), Found 520.0488.
4k 1H NMR (400 MHz, DMSO-d6) δ: 1.90–2.18 (m, 2H, CH2), 3.51–3.69
(m, 8H, CH2, 2 × OCH3), 3.76–3.78 (m, 1H, CH), 4.18–4.24 (m, 1H, CH),
4.87–4.95 (m, 1H, CH), 4.96 (s, 1H, OH), 5.28 (s, 1H, OH), 5.91–6.15 (m,
2H, NH, CH), 6.59–6.67 (m, 3H, ArH), 7.06–7.10 (m, 2H, ArH), 8.00–8.03
(m, 1H, CH), 11.57 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ: 53.6 (d,
J = 7.0 Hz), 53.7 (d, J = 7.0 Hz), 54.0, 54.1, 62.0, 71.0, 84.8, 88.0, 109.8,
110.2, 113.6, 113.7, 118.0, 129.4, 147.0, 150.2, 150.2, 162.8; 31P NMR (162
MHz, DMSO-d6): δ 24.89; HRMS (FAB) Calcd for C18H25N3O8P: 442.1380
(MH+), Found 442.1366.
General Experimental Procedure for the Preparation
of Compounds 4l–4q
Carbonyl compound (1d, 1 mmol), amine (2, 1 mmol), dimethylphos-
phite (3, 1.2 mmol) were taken in a 50 mL flask. The mixture was stirred
at 60◦C for 2 hours. Upon completion, the solid product was collected and
washed with cold ethanol. All the products were characterized from their
spectral data.
1
4l m.p.: 184–185◦C; H NMR (400 MHz, DMSO-d6) δ: 2.13 (s, 3H,
2
2
CH3), 3.61 (d, J PH = 10.8 Hz, 3H, OCH3), 3.69 (d, J PH = 10.8
1
Hz, 3H, OCH3), 4.83 (dd, J PH = 23.2 Hz, J 2 = 10.8 Hz, 1H, CH),
2
5.63 (dd, J PH = 10.8 Hz, J 2 = 4.8 Hz, 1H, NH), 6.56 (d, 2H,
J = 8.4 Hz, ArH), 6.89 (d, 2H, J = 8.4 Hz, ArH), 7.57–7.59 (m, 1H, CH),
11.05 (d, 1H, J = 5.2 Hz, NH), 11.29 (s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6) δ: 20.5, 52.2, 53.6 (d, J = 7.0 Hz), 54.0 (d, J = 7.0 Hz), 108.7,
113.9, 126.4, 129.8, 141.1, 144.7, 151.2, 163.8, 163.9; 31P NMR (162 MHz,
DMSO-d6): δ 25.09; HRMS (FAB) Calcd for C14H19N3O5P: 340.1063 (MH+),
Found 340.1058.
4m m.p.: 188–189◦C; 1H NMR (400 MHz, DMSO-d6) δ: 3.62 (d,
2J PH = 10.4 Hz, 3H, OCH3), 3.51 (s, 3H, OCH3), 3.69 (d, J PH = 10.4
2
Hz, 3H, OCH3), 4.79 (dd, 1J PH = 23.6 Hz, J 2 = 11.2 Hz, 1H, CH), 5.63 (dd,
2J PH = 11.2 Hz, J 2 = 4.8 Hz, 1H, NH), 6.60 (d, 2H, J = 8.0 Hz, ArH), 6.71

Pyrimidine Nucleoside-Aminophosphonate Hybrids
625
(d, 2H, J = 8.0 Hz, ArH), 7.57–7.59 (m, 1H, CH), 11.05 (d, 1H, J = 5.2 Hz,
NH), 11.28 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ: 53.6 (d, J = 7.0
Hz), 54.0 (d, J = 7.0 Hz), 55.6, 108.7, 114.9, 115.0, 140.8, 141.0, 151.2, 152.2,
163.8, 163.9; 31P NMR (162 MHz, DMSO-d6): δ 25.10; HRMS (FAB) Calcd
for C14H19N3O6P: 356.1012 (MH+), Found 356.1008.
1
2
4n m.p.: 221–223◦C; H NMR (400 MHz, DMSO-d6) δ: 3.62 (d, J PH
2
= 10.4 Hz, 3H, OCH3), 3.69 (d, J PH = 10.4 Hz, 3H, OCH3), 4.82 (dd,
1J PH = 22.8 Hz, J 2 = 10.4 Hz, 1H, CH), 6.39 (dd, 2J PH = 10.4 Hz, J 2 = 4.8
Hz, 1H, NH), 6.62 (d, 2H, J = 8.0Hz, ArH), 7.23 (d, 2H, J = 8.0Hz, ArH),
7.56–7.58 (m, 1H, CH), 11.08 (d, 1H, J = 4.8 Hz, NH), 11.34 (s, 1H, NH).
13C NMR (100 MHz, DMSO-d6) δ: 53.6 (d, J = 7.0 Hz), 54.0 (d, J = 7.0 Hz),
108.2, 108.7, 115.6, 131.9, 141.2, 146.5, 151.1, 163.8, 163.9; 31P NMR (162
MHz, DMSO-d6): δ 25.12; HRMS (FAB) Calcd for C13H16BrN3O5P: 404.0012
(MH+), Found 404.0005.
1
2
4o m.p.: 210–212◦C; H NMR (400 MHz, DMSO-d6) δ: 3.62 (d, J PH
=
2
1
10.4 Hz, 3H, OCH3), 3.68 (d, J PH = 10.4 Hz, 3H, OCH3), 4.83 (dd, J PH
2
= 22.8 Hz, J 2 = 10.4 Hz, 1H, CH), 6.39 (dd, J PH = 10.4 Hz, J 2 = 4.8 Hz
1H, NH), 6.66 (d, 2H, J = 8.8 Hz, ArH), 7.12 (d, 2H, J = 8.8 Hz, ArH),
7.55–7.58 (m, 1H, CH), 11.08 (d, 1H, J = 5.2 Hz, NH), 11.34 (s, 1H, NH).
13C NMR (100 MHz, DMSO-d6) δ: 53.7 (d, J = 7.0 Hz), 54.0 (d, J = 7.0 Hz),
108.3, 115.1, 121.2, 129.1, 141.2, 146.1, 151.1, 163.8, 163.9; 31P NMR (162
MHz, DMSO-d6): δ 25.22; HRMS (FAB) Calcd for C13H16ClN3O5P: 360.0517
(MH+), Found 360.0515.
1
2
4p m.p.: 207–209◦C; H NMR (400 MHz, DMSO-d6) δ: 3.62 (d, J PH
=
10.4 Hz, 3H, OCH3), 3.69 (d, 2J PH = 10.4 Hz, 3H, OCH3), 4.81 (dd, 1J PH
=
23.2 Hz, J 2 = 10.8 Hz, 1H, CH), 6.39 (dd, 2J PH = 10.8 Hz, J 2 = 4.8 Hz, 1H,
NH), 6.63–6.96 (m, 4H, ArH), 7.56–7.59 (m, 1H, CH), 11.07 (d, 1H, J = 4.8
Hz, NH), 11.32 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ: 52.2, 53.6 (d,
J = 7.0 Hz), 54.0 (d, J = 7.0 Hz), 108.4, 114.7 (d, J = 7.0 Hz), 115.7, 115.9,
141.2, 143.6, 151.2, 163.8, 163.9; 31P NMR (162 MHz, DMSO-d6): δ 25.34;
HRMS (FAB) Calcd for C13H16FN3O5P: 344.0812 (MH+), Found 344.0811.
4q m.p.: 195◦C; H NMR (400 MHz, DMSO-d6) δ: 3.61 (d, J PH = 10.4
1
2
Hz, 3H, OCH3), 3.67 (d, 2J PH = 10.4 Hz, 3H, OCH3), 4.85 (dd, 1J PH = 23.2
2
Hz, J 2 = 10.8 Hz, 1H, CH), 6.13 (dd, J PH = 10.8 Hz, J 2 = 4.8 Hz, 1H,
NH), 6.62–6.65 (m, 3H, ArH), 7.07 (t, J = 7.6 Hz, 2H, ArH), 7.57–7.59 (m,
1H, CH), 11.06 (d, 1H, J = 5.2 Hz, NH), 11.30 (s, 1H, NH). 13C NMR (100
MHz, DMSO-d6) δ: 52.2 53.6 (d, J = 7.0 Hz), 54.0 (d, J = 7.0 Hz), 108.6,
113.6, 117.9, 129.4, 141.2, 147.0, 151.2, 163.8, 163.9; 31P NMR (162 MHz,
DMSO-d6): δ 25.18; HRMS (FAB) Calcd for C13H17N3O5P: 326.0907 (MH+),
Found 326.0901.
5 1H NMR (400 MHz, DMSO-d6) δ: 2.05 (s, 3H, CH3), 2.08 (s, 3H, CH3),
2.31 (s, 3H, CH3), 2.42–2.46 (m, 2H, CH2), 4.25–4.33 (m, 3H, CH, CH2),
5.23–5.25 (m, 1H, CH), 6.20–6.23 (m, 1H, CH), 7.06 (d, 2H, J = 8.0 Hz,
ArH), 7.19 (d, 2H, J = 8.0 Hz, ArH), 8.40 (s, 1H, CH), 8.43 (s, 1H, CH),

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X. Zhang et al.
11.83 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ: 21.0, 21.2, 37.6, 53.6,
64.1, 74.7, 82.4, 86.0, 110.6, 121.2, 130.2, 135.7, 139.7, 149.2, 150.1, 152.3,
162.7, 170.5, 170.6.
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