Synthesis of new α-aminophosphonate derivatives incorporating benzimidazole, theophylline and adenine nucleobases using l-cysteine functionalized magnetic nanoparticles (LCMNP) as magnetic reusable catalyst: Evaluation of their anticancer properties

Article abstract of DOI:10.1039/c5ra21419j

A new class of structurally diverse α-aminophosphonate derivatives containing benzimidazole, theophylline and adenine heterocycles were synthesized using a simple and efficient strategy. This class of α-aminophosphonates was synthesized using the reaction

Full text of DOI:10.1039/c5ra21419j

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Synthesis of new α-aminophosphonate derivatives incorporating
benzimidazole, theophylline and adenine nucleobases using L-
cysteine functionalized magnetic nanoparticles (LCMNP) as
magnetic reusable catalyst: Evaluation of their anticancer
properties
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Foroogh Bahrami,a Farhad Panahi,*a Fatemeh Daneshgar,a Reza Yousefi,b Mohammad Bagher
Shahsavanib and Ali Khalafi-Nezhad*a
A new class of structurally diverse α-aminophosphonate derivatives containing benzimidazole, theophylline and adenine
heterocycles were synthesized using a simple and efficient strategy. This class of α-aminophosphonates was synthesized
using the reaction of synthetic aldehydes containing nucleobases, amines and diethyl phosphonate using L-cysteine
functionalized magnetic nanoparticles (LCMNP) as catalyst. The aldehyde derivatives containing benzimidazole,
theophylline and adenine nucleobases were synthesized using the reaction of a bromo-substituted aldehyde drived from
isovanillin and 4-hydroxy benzaldehyde. The LCMNP catalyst was found to be an efficient magnetic reusable catalyst for
synthesis of this class of α-aminophosphonates under mild and clean conditions. This method is introduced as a suitable
approach for the synthesis of new α-aminophosphonate derivatives containing nucleobases which has potential biological
activity. As the anticancer properties of a selected group of thesesynthetic ligands were evaluated, they indicated poor
activity comparted to cisplatin against Jurkat cancer cell line.
significantly. The chemical structure of some of the biological
active α-aminophosphonates incorporating heterocycle rings is
shown in Figure 1. In the structure of these biological active
Introduction
α-Aminophosphonate derivatives have received considerable
attentions in medicinal chemistry due to their widespread
applications such as enzyme inhibition activity,1 anticancer2
and antibiotics3 actions, pharmacological prperties,4 and
peptidomimetic utilizations.5 This class of compounds can be
hydrolyzed to α-aminophosphonic acids which there is several
important biological active compounds based on this structure
(for example Alafosfalin & Glyphosate).6,7 Research on the
synthesis of new derivatives of α-aminophosphonates is in
progress. For example, recent studies shown that α-
aminophosphonate derivatives showed anti-leishmanial
activity.8 There are attempts on the synthesis of new α-
aminophosphonates derivatives and their applications.9 In the
recent years some of the α-aminophosphonate derivatives
containing heterocycle moieties have been synthesized which
shown interesting biological activities.10 It seems that the
existence of heterocyclic moieties in the structure of α-
aminophosphonate molecule influenced the biological activity,
compounds there is a heterocycle ring such as quinazoline,
pyrazole, thiazol, pyridine and chromen which the existence of
them in the structure of these molecules is very effective in
their activity.10
F
O
O
CF3
N
O
O
S
N
NH
O
HN
P
N
H3C
O
O
N
P
F
Cl
O
N
O
O
P
H
N
O
H3C
Cl
O
N
O
Cl
Antiviral activity
Antiviral activity
Antiviral activity
O
H
O
O
O
O
H
NH
R
R
O
O
O
P
O
O
O
N
O
O
O
H
P
P
O
N
H
O
N
O
N
S
HN
O
H
O
F
Antitumor Agent
Cytotoxic agents
Antimicrobial activities
Figure 1 The chemical structure of some of the biological
active α-aminophosphonates including heterocycle moieties
In continuation of our program on the utilization of
nucleosides and carbohydrates in multicomponent reactions
for one-pot synthesis of new compounds incorporating these
fragments,11 we would like to report the synthesis of new α-
aminophosphonate derivatives containing benzimidazole,
a Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
* Email: khalafi@susc.ac.ir; Panahi@shirazu.ac.ir
b Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences,
Shiraz University, Shiraz 71454, Iran
Electronic Supplementary Information (ESI) available: Spectral data and copies of
1H, 13C NMR for synthesized compounds. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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theophylline and adenine heterocycles. These fragments are
important due to a range of biological activities and medicinal
applications associated with them. The existence of these
heterocyclic moieties in the structure of many drugs obviously
clarifies the important role of these heterocycles in medicinal
chemistry. In many cases the presence of these nucleobases in
the structure of biologically active compound enhanced the
activity.12-14
(EtO)2OP
R2
NH2
CHO
N
R1
HPO(OEt)2
R1
+
H
+
R2
Scheme
1 One-pot three-component synthesis of α-
aminophosphonates using reaction of amine, aldehyde and
diethyl phosphonate
For synthesis of these new α-aminophosphonate derivatives
our previous strategy was used.11d Aldehyde derivatives
incorporating desired heterocycle were synthesized and then it
was used in a multicomponent reaction with amine and diethyl
phosphonate which is known as Kabachnik–Fields reaction.15
In order to obtain these compounds in high yield and clean
conditions our previously catalyst system (L-cysteine
functionalized magnetic nanoparticles, LCMNP) was used.16
The LCMNP catalyst is a magnetic reusable and after finishing
the reaction it was separated using an external magnetic field.
Thus a clean and mild reaction condition will be available for
synthesis of this class of compounds. The TEM and SEM images
of LCMNP catalyst are shown in Figure 2 in order to illustrate
the morphology and size of particles which are suitable for
catalysis applications.
Our strategy in this study for the synthesis of α-
aminophosphonate derivatives is the synthesis of aldehydes
and use of them in the above reaction. Thus, we started our
study with the synthesis of aldehyde derivatives containing
benzimidazole and theophylline nucleobases. The approach for
the synthesis of this class of aldehydes is shown in Scheme 2.
HO
CHO
Br
Br
n
Br
O
CHO
2a: n=1, 67%
2b: n=2, 73%
2c: n=3, 70%
2d: n=7, 71%
n
K2CO3, TBAB
MeO
MeO
CH3CN, 20h, reflux
Isovanillin (1)
K2CO3, TBAB
CH3CN, 20h, reflux
Nucleobase
N
O
N
N
O
CHO
CHO
O
S
HN
N
O
CHO
N
N
MeO
N
3a: 77%
3b: 89%
MeO
O
N
N
N
O
N
O
CHO
N
N
MeO
O
MeO
3c: 90%
3d: 87%
Scheme
2 The synthetic approach for the synthesis of
aldehydes with benzimidazole and theophylline moiety started
from isovanillin
18
)
Isovanillin (
1
was used as the starting material and it was
reacted with different dibromides in order to synthesis
aldehydes 2a-d. These compounds were synthesized in gram
scale in good yields. Then, aldehydes
2 were reacted with 9H-
purine-6-thiol, theophylline and benzimidazole and aldehydes
3a-d were produced. Aldehyde 3a is containing an adenine
moiety with a 4 carbon atom chain connected to isovanillin
aldehyde. Two aldehydes were synthesized using theophylline
Figure 2 A TEM image of LCMNP catalyst (a). The average size
of catalyst nanoparticles was approximately 10 nm. The black
cores related to Fe3O4 and the white shells around them are
attributed to the SiO2 layer. A SEM image of LCMNP catalyst
which shows the surface morphology of this material (b).
with different spacer (3b
& 3c). An aldehyde incorporating
benzimidazole ring (3d) was also synthesized with a 5 carbon
chain spacer.
After synthesize and characterization of aldehydes (3a-d) we
checked different conditions to find an appreciate procedure
for conversion of the synthetic aldehydes to the corresponding
α-aminophosphonate. For optimization study the reaction of
isovanillin, p-toluidine and diethyl phosphonate was selected
as model reaction. The results of optimization studies are
shown in Table 1.
Results and discussion
Synthesis of α-aminophosphonate derivatives
One of the methodologies for the synthesis of α-
aminophosphonate has been known as Kabachnik–Fields
reaction which is the nucleophilic addition of diethyl
phosphonate to imines (in situ generated from amines and
aldehydes) (Scheme 1).17
2 | J. Name., 2012, 00, 1-3
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Thus the conditions showed in Table 1 entry 4 was applied in
Table 1 Optimized reaction conditions for synthesis of α- the synthesis of α-aminophosphonate from the synthetic
aminophosphonate derivatives using LCMNP catalysta
aldehydes (3a-d). The method was efficient for the synthesis of
new α-aminophosphonates using synthetic aldehydes.
Consequently,
a set of α-aminophosphonate derivatives
containing adenine, theophylline and benzimidazole
heterocycles were synthesized in good to excellent yields
(Scheme 3).
Catalyst
(mol%)
T (°C)
Time
(h)
24
24
6
Yieldb
(%)
60
45
73
65
71
55
72
85
92
75
78
55
71
93
87
Entry
Solvent
1
2
none
neat
neat
neat
neat
neat
neat
neat
neat
neat
EtOH
CH3CN
80
rt
(EtO)2OP
R
none
LCMNP
Het
Het
CHO
NH2
N
H
HPO(OEt)2
+
+
no solvent
50 oC, 2h
3
Mg(ClO4)2 (5)
InCl3 (15)
80
rt
MeO
MeO
R
4a-m
3a-d
4
20
5
Cl
N
N
(EtO)2OP
N
N
S
(EtO)2OP
5
ZrOCl2 (10)
L-proline (5)
LPMNP (5)
LCMNP (8.5)
LCMNP (8.5)
LCMNP (8.5)
LCMNP (8.5)
rt
O
O
S
N
H
CN
HN
N
HN
O
H
N
6
50
50
rt
10
10
5
N
MeO
MeO
4a: 75%
7
4b: 80%
CH3
Cl
N
N
(EtO)2OP
4d: 79%
O
(EtO)2OP
8
N
O
N
O
N
N
H
N
N
H
N
N
9
50
50
50
50
50
50
50
2
MeO
MeO
O
O
10
11
12
13
14
15
5
4c: 76%
OMe
N
(EtO)2OP
O
5
CH3
N
O
N
(EtO)2OP
O
N
N
H
N
O
N
LCMNP (8.5) Toluene
12
6
N
H
MeO
N
O
N
4f: 80%
MeO
LCMNP (8.5)
LCMNP (12)
LCMNP (5)
DMF
neat
neat
O
4e: 81%
CH3
2
N
(EtO)2OP
OMe
N
(EtO)2OP
O
N
O
N
6
N
O
H
N
N
H
a
MeO
N
Reaction conditions: isovanillin (1.0 mmol), p-toluidine (1.0
MeO
4h: 80%
(EtO)2OP
O
4g: 84%
mmol), diethyl phosphonate (1.2 mmol), solvent (3 mL) and
LCMNP (0.05 g, 8.5 mol%). b Isolated yield.
NO2
N
OMe
O
N
(EtO)2OP
N
O
N
O
N
N
N
H
N
H
MeO
F
MeO
O
4j: 75%
4i: 79%
As shown in Table
1 under catalyst- and solvent-free
N
N
(EtO)2OP
O
conditions about 45-60 % of product was produced (entries 1
& 2). We decided to use from reported catalyst systems in the
literature to improve the reaction yield. In the presence of
Mg(ClO4)2 at 80 °C about 73% of product was observed (Table
O
N
N
H
N
4k: 81%
MeO
O
Scheme 3 Synthesis of new α-aminophosphonate derivatives
containing adenine, theophylline and benzimidazole
heterocycles. Reaction conditions: aldehyde (1.0 mmol), amine
(1.0 mmol), diethyl phosphonate (1.2 mmol), LCMNP (0.05 g,
8.5 mol%).
1, entry 3).17b By use of other Lewis acids such as InCl3 and
19
ZrOCl220 no significant improvement in reaction yield related to
Mg(ClO4)2 was detected (Table 1, entries 4 & 5). By using L-
proline as catalyst at 50 °C only 55% of product was isolated
from the reaction mixture (Table 1, entry 6). Since, the most
problems associated with these catalyst systems was the
separation of them from the reaction mixture which resulted
in the decreasing of reaction yield we decided to use from
magnetic reusable catalyst. By use of the magnetic reusable
catalyst systems it is possible to separate the catalyst from the
reaction mixture after completion of the reaction using an
external magnetic field.21 We used from our previous reported
catalyst system LPMNP,22 which is a L-proline-supported
magnetic nanoparticles catalyst system and about 72% of
product was obtained after 10h at 50 °C (Table 1, entry 7). In
the presence of LCMNP catalyst at rt and under neat
conditions about 85% of product was observed (Table 1, entry
8). At higher temperature of 50 °C the reaction yield was
increased to 92% (Table 1, entry 9). The solvent conditions
were also checked and no superiority was observed in
comparison with solvent-less conditions (Table 1, entries 10-
13). The catalyst loading was optimized and 8.5 mol% of
catalyst was found to be optimal (Table 1, entries 14 & 15).
As shown in scheme 4, by selection of different amines it is
possible to synthesize diverse derivatives of this class of α-
aminophosphonates in good to excellent yields using LCMNP
catalyst. Both amines with electron-donating and electron
withdrawing groups were used and all of the products were
obtained in high yields. Thus the used methodology in this
study is suitable for synthesis of α-aminophosphonates
bearing these heterocycles.
In order to increase the diversity of synthetic
aminophosphonates further, other aldehydes were
synthesized starting from 4-hydeoxy benzaldehyde (Scheme
4).
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order to form imine intermediate (B).27 Addition of diethyl
phosphonate to the formed imine resulted in the production
of intermediate
C, which after deprotonation process
catalyzed by LCMNP catalyst produces the final product.28
Also, in another path (dash line), the amino group of amino
acid moiety can react with aldehyde to form imine
intermediate
D
which in the following is converted to imine
related to
B
due to the high stability of imine
B
D.
H
N
Het
Scheme 4 Synthesis of new theophylline and adenine based
OEt
OEt
P
CHO
O
R
Het
aldehydes
MNP
1
The synthesized aldehydes 7a and 7b were converted to α-
aminophosphonates derivatives using optimized reaction
conditions and compounds 8a-d were obtained in good
isolated yield (Figure 3).
O
H
H
N
O
H
MNP
H2O
O
MNP
N
NH2
MNP
O
H
O
H
H
O
O
N
O
H
O
O
H
(A)
Het
Het
H
N
P
OEt
(D)
OEt
2
(I)
R
(C)
NH2
Het
MNP
R
O
H2O
Figure
3
The chemical structure of synthesized α-
NH2
2
O
aminophosphonate derivatives. Reaction conditions: aldehyde
(1.0 mmol), amine (1.0 mmol), diethyl phosphonate (1.2
mmol), LCMNP (0.05 g, 8.5 mol%).
H
Het
N
O
P
OEt
OEt
OEt
HO
P
OEt
(B)
H
R
3
It is clear that this methodology is applicable for synthesize of
diverse α-aminophosphonate derivatives using the selection of
a hydroxy substituted aldehyde to react with a dibromide in
Scheme 5. Proposed mechanism for reaction.
order to synthesize
a
bromo-substituted aldehyde.
a nucleobase to the bromo-
Nucleophilic addition of
Anticancer activity of some synthetic ligands (8b, 8c,
4c, 4i)
substituted aldehyde resulted in the production of nucleobase
functionalized aldehyde which can be undergo in the reaction
with amine and diethyl phosphonate for synthesize of
desirable α-aminophosphonate. This strategy is efficient for
Since the α-aminophosphonate derivatives have been already
indicated to possess anticancer activity,29 this feature was
evaluated for a selected group of the synthetic ligands
the synthesis of adenine derivatives such as 4a, 4b, 8a and 8c
including 8b, 8c, 4c and 4i. In this study the synthetic ligands
which may be important in medicinal chemistry because there
are a range of biological active adenine-based phosphonate
compounds.19 The LCMNP catalyst facilitates the mild
conditions that suitable for efficient and clean synthesis of this
class of compounds. Since the LCMNP catalyst is magnetic
reusable it is possible the separation from the catalyst from
the reaction mixture using an external magnetic field after
completion of the reaction. This situation caused that the
synthetic compounds obtained in more comfortable conditions
with less impurity.
were tested for their anticancer activity against Jurkat cancer
cell line, as the cells were incubated with the ligands for 24 h.
The cytotoxic activity was measured by MTT assay as described
in the experimental section. The synthetic ligands as indicated
in Figure 4, demonstrated
a dose-dependent anticancer
activity against this cell line. Also, our results (Figure 4 and
Table 2) suggest poor anticancer properties for these ligands
compared to cisplatin.
Table 2 The IC50 values of the synthetic ligands after incubation
A reaction mechanism was proposed as shown in Scheme 5
based on primary amino acid catalysis24 and previous reported
pathways for Kabachnik–Fields reaction in the literatures.25
Aldehyde group can activate by amino acid functionality on the
with Jurkat cancer cells line for 24 h
Ligands Cisplatin
8b
8c
4c
4i
IC50
74.08
(± 1.3)a
286.27 299.18 324.01 327.43
(± 8.7) (± 7.3) (± 4.3) (± 3.8)
surface of magnetic nanoparticles in LCMNP catalyst (A
).26 The
(µM)
a Standard deviation.
amine component reacted with the activated aldehyde in
4 | J. Name., 2012, 00, 1-3
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NMR spectra we used a Bruker (250 MHz) Advance DRX, and
Moreover, all the synthetic ligands indicated approximately samples were dissolved in pure deuterated DMSO-d6 or CDCl3
similar anticancer activities, suggesting that different solvents with tetramethylsilane (TMS) as internal standard. FT-
substitutions on the main molecular scaffold did not modulate IR spectroscopy (Shimadzu FT-IR 8300 spectrophotometer)
their biological activity to the significant levels.
was employed for characterization of the compounds. The
scanning electron micrography (SEM) images for the catalyst
were obtained by SEM instrumentation (SEM, XL-30 FEG SEM,
Philips, at 20 kV). Transmission electron microscopy (TEM)
images were obtained using a TEM apparatus (CM-10-Philips,
100 kV) for the characterization of the LCMNP catalyst.
Melting points were determined in open capillary tubes in
Barnstead Electrothermal 9100 BZ circulating oil melting point
apparatus. The reaction monitoring was accomplished by TLC
on silica gel PolyGram SILG/UV254 plates.
Synthesis of α-aminophosphonates
Synthesis of aldehydes 3a-d, 7a & 7b. In double-necked
round-bottom flask (100 mL) equipped with a condenser, a
mixture consisting of isovanillin/4-hydroxy benzaldehyde (0.02
mol, 2.44 g), dibromoalkane (0.06 mol), K2CO3 (2.76 g, 0.02
mol), and a catalytic amount of TBAB (0.1 g) in MeCN (50 mL)
was refluxed for 20 h. After cooling and solvent evaporation,
the resulting foam was dissolved in CHCl3 (150 mL) and washed
with water (3 × 150 mL). The organic layer was dried over
anhydrous Na2SO4 and evaporated. The crude product was
purified by column chromatography on silica gel [eluting with a
mixture of n-hexane and EtOAc (10:1)].
Figure 4 The growth suppression activity of the synthetic
ligands against Jurkat cancer cell line. The tumor cells were
incubated with varying concentrations of each ligand, ranging
from 0 to 500 µM for 24 h. The growth inhibitory activity was
assessed using MTT assay.30 Also Cisplatin was used as a
positive control.
3-(3-Bromopropoxy)-4-methoxybenzaldehyde (2a). Yield: 67%
(3.7 g), white crystals, mp 58-59 °C.IR (KBr): ν =3093, 2948,
2800, 1674, 1730, 1589, 1437, 665 cm-1. 1H NMR (250 MHz,
CDCl3/TMS): δ (ppm) = 1.97-2.00 (m, 2H), 3.40- 3.45 (m, 2H),
3.86(s, 3H), 4-4.05 (m, 2H), 6.90 (d, J = 10.0 Hz, 1H), 7.30 (d, J =
2.5 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 9.76 (s, 1H). 13C NMR (62.5
MHz, CDCl3/TMS): δ (ppm) = 29.8, 32.0, 56.0, 66.4, 110.7,
110.7, 126.9, 129.9, 148.6, 154.7, 190.7. Anal. Calcd for
C11H13BrO3(273.13): C, 48.37; H, 4.80. Found: C, 48.28; H, 4.74.
3-(4-Bromobutoxy)-4-methoxybenzaldehyde (2b). Yield: 73%
(4.12 g), white crystals, mp 59-60 °C. IR (KBr): ν = 3090, 2947,
Conclusions
In conclusion, we introduced a synthetic methodology for the
synthesis of a new class of α-aminophosphonate derivatives
incorporating benzimidazole, theophylline and adenine
heterocycles in
a three-step process. For this purpose,
isovanillin or 4-hydroxybenzaldehyde was used as simple and
cheap starting materials toward synthesis of structurally
complex nucleobase derived aldehydes. Subsequently, the
synthetic aldehydes undergoes in a multicomponent reaction
with amines and diethyl phosphonate in the presence of
LCMNP catalyst for one-pot synthesis of α-aminophosphonate
derivatives incorporating these heterocycles. The LCMNP
catalyst promotes this reaction under mild and
environmentally being conditions to obtain desired products in
1
2790, 1681, 1730, 1523, 1388, 1263, 1174, 740 cm-1. H NMR
(250 MHz, CDCl3/TMS): δ (ppm) = 1.98-2.04 (m, 4H), 3.44-3.49
(m, 2H), 3.90 (s, 3H), 4.04-4.08 (m, 2H), 6.93 (d, J = 7.5 Hz, 1H),
7.25-7.43 (m, 2H), 9.79 (s, 1H). 13C NMR (62.5 MHz,
CDCl3/TMS): δ (ppm) = 27.6, 29.4, 33.3, 56.1, 67.9, 110.3,
110.6, 126.9, 130.0, 148.8, 154.8, 190.8. Anal. Calcd for
C12H15BrO3 (387.15): C, 50.19; H, 5.27. Found: C, 50.11; H, 5.22.
3-((5-Bromopentyl)oxy)-4-methoxybenzaldehyde (2c). Yield:
70% (4.2 g), white crystals, mp 61-62 °C. IR (KBr): ν =3090,
high yields. The anticancer activities of some ligands (8c
, 8b,
4c, 4i) were evaluated and the results show that they have
poor activity against Jurkat cancer cell line. The biological
activities of the synthesized α-aminophosphonates are under
evaluation and will be reported in due course.
1
2943, 2784, 1685, 1733, 1523, 1387, 1267, 1175, 743 cm-1. H
NMR (250 MHz, CDCl3/TMS): δ (ppm) = 1.54-1.64 (m, 2H),
1.78-1.95 (m, 4H), 3.38 (t, J = 7.5 Hz, 2H), 3.88 (s, 3H), 3.99-
4.04 (m, 2H), 6.92 (d, J = 5.0 Hz, 1H), 7.33 (s, 1H), 7.40 (d, J =
2.5 Hz, 1H), 9.75 (s, 1H). 13C NMR (62.5 MHz, DMSO-d6/TMS): δ
(ppm) = 24.2, 27.6, 35.0, 36.3, 55.8, 68.0, 110.5, 111.3, 125.8,
129.5, 148.3, 153.2, 191.3. Anal. Calcd for C13H17BrO3 (301.18):
C, 51.84; H, 5.69. Found: C, 51.75; H, 5.63.
Experimental section
General. Chemicals were purchased from Merck and Aldrich
chemical companies. All the chemicals and solvents were used
as received without purification. For recording 1H NMR and 13
C
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Journal Name
3-((9-Bromononyl)oxy)-4-methoxybenzaldehyde (2d). Yield: 7.45(m, 1H), 9.83 (s, 1H). 13C NMR (62.5 MHz, DMSO-d6/TMS):
71% (5.07 g), yellow oil. IR (KBr, neat): ν = 3078, 2854, 2723, 22.6, 25.3, 26.1, 28.2, 28.3, 28.4, 28.6, 29.6, 30.0, 46.1, 55.8,
1
1681, 1725, 1589, 1434, 1184, 748 cm -1. H NMR (250 MHz, 68, 111.3, 111.3, 116.0, 124.0, 135.0, 140.3, 142.3, 148.3,
CDCl3/TMS): δ(ppm) = 1.19-1.35 (m, 10H), 1.74-1.79 (m, 4H), 150.3, 155.4, 159.8, 191.3. Anal. Calcd for C24H32N4O5 (456.54):
3.29-3.34 (m, 2H), 3.86 (s, 3H), 3.98 (t, J = 7.5 Hz, 2H), 6.89 (d, J C, 63.14; H, 7.07; N, 12.27. Found: C, 63.06; H, 7.01; N, 12.18.
= 10.0 Hz, 1H), 7.25-7.26 (m, 1H), 9.76 (s, 1H). 13C NMR (62.5 3-(3-(1, 3-dimethyl-2, 6-dioxo-1, 2, 3, 6-tetrahydro-9H-purin-
MHz, DMSO-d6/TMS): δ (ppm) = 27.5, 28.0, 28.1, 28.5, 28.6, 9-yl) propoxy)-4-methoxybenzaldehyde (3c). Yield 90% (3.4g),
28.8, 32.2, 34.7, 55.7, 68.1, 110.3, 111.1, 125.5, 129.5, 148.4, white crystals, mp 114-115°C. IR (KBr): ν = 3217, 2365, 1673,
-1
154.2, 190.9. Anal. Calcd forC17H25BrO3 (357.29): C, 57.15; H, 1640, 1735, 1566, 1350, 1150 cm
7.05. Found: C, 57.07; H, 6.98.
.
1H NMR (250 MHz,
CDCl3/TMS): δ (ppm) = 2.63(t, J = 5.0 Hz, 2H), 3.50 (s, 3H), 3.74
4-(4-Bromobutoxy)benzaldehyde (6a). Yield: 70% (3.6 g), (s, 3H), 4.15 (s, 3H), 4.34-4.39 (m, 2H), 4.72-4.77 (m, 2H), 7.47
yellow oil. IR (KBr, neat): ν = 2939, 2831, 2738, 1697, 1512, (d, J = 7.5 Hz, 1H), 7.65 (s, 1H), 7.87(d, J = 10.0 Hz, 1H), 8.36 (s,
1465, 648 cm-1. 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) = 1.21 1H), 10.13 (s, 1H). 13C NMR (62.5 MHz, DMSO-d6/TMS): 27.4,
(s, 2H), 2.26-2.30 (m. 2H), 3.53-3.56 (m, 2H), 4-4.1 (m, 2H), 29.3, 29.3, 43.9, 55.8, 65.5, 110.6, 111.3, 117.2, 126.1, 132.5,
7.12-7.14 (m, 1H), 7.34-7.40 (m, 3H), 9.90 (s, 1H). 13C NMR 134.7, 142.4, 149.7, 160.6, 166.1, 169.5, 191.2. Anal. Calcd for
(62.5 MHz, CDCl3/TMS): δ (ppm) = 27.2, 29.2, 33.3, 67.2, 114.0, C18H20N4O5 (372.38): C, 58.06; H, 5.41; N, 15.05. Found: C,
114.7, 129.8, 131.5, 131.9, 163.8, 190.7. Anal. Calcd for 57.95; H, 5.36; N, 15.01.
C11H13BrO2 (257.13): C, 51.38; H, 5.10. Found: C, 51.31; H, 5.03. 3-((5-(1H-Benzo[d]imidazol-1-yl)pentyl)oxy)-4-
4-((5-Bromopentyl)oxy)benzaldehyde (6b). Yield: 76% (4.12 methoxybenzaldehyde (3d). Yield 87% (2.94 g), mp110-111 °C.
g), white crystals, mp 60-61 °C. IR (KBr): ν = 3155, 2920, 2795, IR (KBr): ν = 3125, 2910, 2815, 1690, 1737, 1450, 1581, 1256,
1690, 1735, 1450, 1518, 665 cm-1. 1H NMR (250 MHz, 1115 cm -1. 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) = 1.57 (t, J
CDCl3/TMS): δ (ppm) = 0.53 (d, J = 2.5 Hz, 2H), 0.91 (d, J = 5.0 = 7.5 Hz, 2H), 1.87-2.01(m, 4H), 3.91(s, 3H), 4.03-4.08 (m, 2H),
Hz, 2H), 1.63-1.65 (m, 2H), 3.06-3.14 (m, 2H), 3.66-3.70(m, 2H), 4.20 (t, J = 7.5 Hz, 2H), 6.90 (d, J = 7.5 Hz, 1H), 7.26- 7.36 (m,
6.78-6.83 (m, 1H), 7.01-7.02 (m, 1H), 7.07-7.10 (m, 2H), 9.61 (s, 2H), 7.37 (d, J = 2.5 Hz, 2H), 7.44 (t, J = 2.5 Hz, 2H), 7.90 (s, 1H),
1H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) = 28.4, 29.7, 9.82 (s, 1H). 13C NMR (62.5 MHz, DMSO-d6/TMS): 22.7, 28.0,
31.9, 33.2, 65.6, 114.1, 114.7, 130.0, 132.0, 135.6, 163.6, 29.0, 43.9, 55.8, 68, 110.3, 111.3, 119.3, 121.2, 122.1, 125.8,
190.8. Anal. Calcd for C12H15BrO (271.15): C, 53.16; H, 5.58. 126.4, 130.4, 140.6, 143.9, 148.2, 149.9, 155.6, 191.3. Anal.
Found: C, 53.07; H, 5.51.
Calcd for C20H22N2O3 (338.41): C, 70.99; H, 6.55; N, 8.28.
Synthesis of theophylline, benzimidazole and adenine-based Found: C, 70.91; H, 6.50; N, 8.23.
aldehyde. In a double-necked round-bottom flask (100 mL) 4-(4-(6-amino-9H-purin-9-yl)butoxy)benzaldehyde (7a). Yield:
equipped with a condenser, a mixture consisting of nucleobase 88% (2.74g), white crystals, mp118-119°C. IR (KBr): ν = 3290,
(0.01 mol), bromo-substituted aldehyde (0.012 mol), K2CO3 2931, 2877, 1666, 1737, 1450, 1581, 1264, 1164 cm -1. 1H NMR
(1.38 g, 0.01 mol), and a catalytic amount of TBAB (0.1 g) in (250 MHz, DMSO-d6/TMS): δ (ppm) = 1.66-1.71 (m, 2H), 1.93-
MeCN (50 mL) was refluxed for 20 h. After cooling and solvent 1.98 (m, 2H), 4.02-4.07 (m, 2H), 4.17-4.22 (m, 2H), 7.17 (s, 2H),
evaporation, the resulting foam was dissolved in CHCl3 (150 7.37 (s, 1H), 7.46- 7.49 (m, 2H), 7.75 (s, 1H), 8.13 (d, J = 7.5 Hz,
mL) and washed with water (3 × 100 mL). The organic layer 2H), 9.94 (s, 1H). 13C NMR (62.5 MHz, DMSO-d6/TMS): 25.6,
was dried over anhydrous Na2SO4 and evaporated. The crude 26.1, 42.5, 67.1, 113.5, 121.3, 122.3, 126.7, 130.2, 137.5,
product was purified by column chromatography on silica gel 140.8, 149.4, 152.3, 155.8, 158.9, 192.9. Anal. Calcd for
[eluting with a mixture of n-hexane and EtOAc (1:1)].
3-(4-((9H-purin-6-yl)thio)butoxy)-4-
C16H17N5O2 (311.14): C, 61.72; H, 5.50; N, 22.49. Found: C,
61.66; H, 5.43; N, 22.42.
methoxybenzaldehyde(3a). Yield: 77% (2.79 g), white crystals,
mp 101-102 °C. IR (KBr): ν = 3471, 2947, 2746, 1735, 1513,
1
4
-((5-(1,3-dimethyl-2,6-dioxo-1,2,3,
6-tetrahydro-9H-purin-
1272, 1134 cm -1. H NMR (250 MHz, CDCl3/TMS): δ (ppm) = 9yl)pentyl)oxy)benzaldehyde (7b). Yield 88% (3.26g), mp 116-
1.71-2.15 (m, 4H), 3.46-3.51 (m, 2H), 3.94 (s, 3H), 4.38-4.43 (m, 117°C. IR (KBr): ν = 3217, 2854, 2360, 1672, 1640, 1735, 1590,
1
2H), 6.94-6.99 (m, 1H), 7.26 (s, 1H), 7.34-7.47 (m, 2H), 8.14 (s, 1350, 1150 cm -1. H NMR (250 MHz, CDCl3/TMS): δ (ppm) =
1H), 8.68 (s, 1H), 9.83 (s, 1H). 13C NMR (62.5 MHz, DMSO- 2.25-2.30 (m, 4H), 2.47-2.49 (m, 2H), 3.40 (s, 3H), 3.58 (s, 3H),
d6/TMS): 25.4, 27.9, 30.8, 56.9, 75.2, 111.3, 111.6, 126.0, 4.03-4.08 (m, 2H), 4.27 (t, J = 7.5 Hz, 2H), 7.00 (d, J = 7.5 Hz,
129.2, 134.6, 145.8, 147.4, 153.9, 155.1, 163.5, 164.9, 191.3. 2H), 7.81 (d, J = 7.5Hz, 2H), 8.05 (s, 1H), 9.85 (s, 1H). 13C NMR
Anal. Calcd for C17H18N4O3S (358.42): C, 56.97; H, 5.06; N, (62.5 MHz, DMSO-d6/TMS): 22.8, 27.4, 28.0, 29.3, 34.5, 47.4,
15.63; S, 8.94. Found: C, 56.88; H, 5.00; N, 15.56; S, 8.88.
65.2, 114.7, 116.6, 122.4, 122.7, 123.5, 131.6, 134.4, 140.0,
142.5, 153.5, 161.0, 191.2. Anal. Calcd for C19H22N4O4 (370.16):
3-((9-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-9H-purin-9-
yl)nonyl)oxy)-4-methoxybenzaldehyde (3b).Yield: 89% (4.1 g), C, 61.61; H, 5.99; N, 15.13. Found: C,61.54; H, 5.93; N, 15.08.
white crystals, mp 120-121 °C. IR (KBr):ν = 3215, 2850, 2367,
1
1672, 1640, 1737, 1566, 1350, 1155 cm -1. H NMR (250 MHz, Synthesis of α-Aminophosphonates: Aldehyde (1 mmol),
CDCl3/TMS): δ (ppm) = 1.25-1.43 (m, 10H), 1.82-1.86 (m, 4H), amine (1 mmol), diethylphosphite (1.2 mmol) and LCMNP
3.40 (s, 3H), 3.58 (s, 3H), 3.94 (s, 3H), 4.03-4.08 (m, 2H), 4.27 catalyst (0.05 g, 8.5 mol%) were mixed and stirred at 50 °C for
(t, J = 7.5 Hz, 2H), 6.96 (d, J = 7.5 Hz, 1H), 7.26 (s, 1H), 7.38- 2 h. The progress of the reaction was monitored by TLC
6 | J. Name., 2012, 00, 1-3
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(eluent: EtOAc: n-hexane, 1:1). After completion of the 1.05 (m, 6H), 1.16-1.23 (m, 10H), 1.61-1.66 (m, 2H), 1.72 (d, J =
reaction the LCMNP catalyst was isolated from the reaction 10.0 Hz, 2H), 2.05 (s, 3H), 2.71 (s, 3H), 3.20 (s, 3H), 3.39 (s, 3H),
mixture using an external magnetic field to remain the crude 3.84-3.89 (m, 4H), 4.01 (t, J = 7.5 Hz, 2H), 4.17-4.22 (m, 2H),
product in reaction vessel. To obtain high purity of the 4.84 (d, J = 25.0 Hz, 1H), 6.65 (d, J = 10.0 Hz, 2H), 6.76-6.84 (m,
synthetic α-aminophosphonates the column chromatography 2H), 6.90-6.98 (m, 2H), 7.1 (s, 1H), 7.93 (s, 1H), 8.05 (s, 1H). 13C
was used.
NMR (62.5 MHz, DMSO-d6/TMS): 16.0, 16.2, 19.9, 25.3, 25.5,
27.4, 27.7, 28.3, 28.5, 28.7, 29.3, 30.1, 46.1,55.3, 61.4, 61.9,
62.3, 68, 105.8, 111.3, 113.7, 116.5, 120.6, 125.2, 128.9, 129.4,
133.9, 136.5, 142.3, 145.0, 147.4, 148.3, 151.7, 153.9, 154.2.
Diethyl((3-(4-((9H-purin-6-yl)thio)butoxy)-4-
methoxyphenyl)((4-
chlorophenyl)amino)methyl)phosphonate (4a). Yield 75% 31P NMR (121.5 MHz, CDCl3): δ (ppm) = 28.26. MS: m/z 683 (9,
(4.53g), IR (KBr, neat): ν = 3425, 2252, 2129, 1651, 1246, 1026, M+). Anal. Calcd for C35H50N5O7P (683.34): C, 61.48; H, 7.37; N,
825, 736 cm -1. H NMR (250 MHz, DMSO-d6/TMS): δ (ppm) = 10.24. Found: C, 61.39; H, 7.31; N, 10.17.
1
0.98- 1.04 (m, 6H), 1.84-1.89 (m, 4H), 2.70(d, J = 2.5 Hz, 2H), Diethyl ((3-(3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-9H-
3.66 (s, 3H), 3.97-4.04 (m, 6H), 4.89 (d, J = 30.0 Hz, 1H), 6.46 (s, purin-9-yl)propoxy)-4-methoxyphenyl)(p-
1H), 6.77 (d, J = 5.0 Hz, 4H), 6.98 (d, J = 7.5 Hz, 2H), 7.11 (d, J = tolylamino)methyl)phosphonate (4e). Yield: 81% (4.85g), IR
2.5 Hz, 1H), 7.92 (s, 1H), 8.48 (s, 1H), 8.67(s, 1H). 13C NMR (KBr, neat): 3433, 2932, 2129, 1715, 1651, 1246, 1026, 814,
1
(62.5 MHz, DMSO-d6/TMS): 15.9, 16.0, 16.1, 25.9, 27.7, 54.5, 712 cm -1. H NMR (250 MHz, DMSO-d6/TMS): δ (ppm) = 0.98-
55.3, 62.3, 67.8, 78.6, 110.5, 111.3, 113.6, 114.9, 120.0, 125.8, 1.04 (m, 6H), 1.12-1.19 (m, 2H), 2.71 (s, 3H), 2.87 (s, 3H), 3.19
128.2, 128.5, 129.5, 144.6, 146.3, 147.3, 148.3, 151.2, 155.7, (s, 3H), 3.40 (s, 3H), 3.84 (t, J = 7.5 Hz, 4H), 4 (t, J = 7.5 Hz, 2H),
159.2, 164.7. 31P NMR (121.5 MHz, CDCl3): δ (ppm) = 27.74. 4.38 (t, J = 5.0 Hz, 2H), 4.82 (d, J = 30 Hz, 1H), 6.60-6.66 (m,
MS: m/z 605 (21, M+). Anal. Calcd for C27H33ClN5O5PS (605.16): 2H), 6.77 (d, J = 7.5 Hz, 2H), 6.83-6.89 (m, 1H), 7 (d, J = 7.5 Hz,
C, 53.51; H, 5.49; N, 11.56; S, 5.29. Found: C, 53.44; H, 5.43; N, 1H), 7.09 (s, 1H), 7.93 (s, 1H), 8 (s, 1H). 13C NMR (62.5 MHz,
11.51; S, 5.22.
DMSO-d6/TMS): 16.2, 19.9, 27.4, 27.4, 29.3, 29.6, 43.7, 52.4,
54.9, 55.4, 55.4, 65.5, 106.0, 111.4, 113.7, 121.1, 125.2, 127.2,
Diethyl((3-(4-((3H-imidazo[4,5-b]pyridin-7-yl)thio)butoxy)-4-
methoxyphenyl)((3-cyanophenyl)amino)methyl)phosphonate 129.0, 129.0, 134.4, 142.4, 142.4, 144.6, 147.0, 148.4, 148.4,
(4b). Yield 80% (4.76g), IR (KBr, neat): ν = 3423, 2254, 2129, 150.9, 154.3. 31P NMR (121.5 MHz, CDCl3): δ (ppm) = 23.20.
1
1651, 1244, 1026, 825, 736 cm -1. H NMR (250 MHz, DMSO- MS: m/z 599 (18, M+). Anal. Calcd for C29H38N5O7P (599.25): C,
d6/TMS): δ (ppm) = 1.39- 1.44 (m, 6H), 1.53 (d, J = 5.0 Hz, 4H), 58.09; H, 6.39; N, 11.68. Found: C, 58.01; H, 6.33; N, 11.60.
2.45 (s, 2H), 4.09 (s, 3H), 4.22-4.40 (m, 6H), 5.48 (d, J = 10.0 Hz, Diethyl ((3-((9-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-9H-
1H), 6.16 (s, 1H), 7.26 (d, J = 7.5 Hz, 2H), 7.42 (d, J = 7.5 Hz, purin-9-yl)nonyl)oxy)-4-methoxyphenyl)((4-
1H), 7.57 (d, J = 2.5 Hz, 4H), 8.38 (s, 1H), 8.88 (s, 1H), 9.06 (s, methoxyphenyl)amino)methyl)phosphonate (4f). Yield 80%
1H). 13C NMR (62.5 MHz, DMSO-d6/TMS): δ (ppm) = 15.9, 15.9, (5.59g), IR (KBr, neat): 3434, 2931, 2129, 1715, 1651, 1246,
-1
16.2,25.9, 27.7, 54.5, 55.3, 62.1, 64.2, 75.5, 108.6, 111.3, 1026, 815, 712 cm
.
1H NMR (250 MHz, DMSO-d6/TMS): δ
113.6, 114.9, 118.9, 120.0, 125.9, 128.2, 128.5, 144.6, 146.1, (ppm) = 0.99-1.06 (m, 6H), 1.15-1.23 (m, 10H), 1.48 (t, J = 7.5
146.3, 148.3, 151.3, 155.7, 159.3, 159.7. MS: m/z 638 (15, M+). Hz, 2H), 1.80 (t, J = 7.5 Hz, 2H), 2.48 (s, 3H), 2.71 (s, 3H), 2.87
Anal. Calcd for C28H36N5O5PS (595.20): C, 57.42; H, 6.20; N, (s, 3H), 3.21 (s, 3H), 3.53 (d, J = 10.0 Hz, 4H), 3.99-4.04 (m, 2H),
11.96; S, 5.47. Found: C, 57.36; H, 6.16; N, 11.92; S, 5.41.
4.20 (t, J = 7.5 Hz, 2H), 4.80 (d, J = 20.0 Hz, 1H), 6.57-6.61 (m,
Diethyl
(((4-chlorophenyl)amino)(3-(3-(1,3-dimethyl-2,6- 3H), 6.68-6.72 (m, 2H), 6.82 (d, J = 7.5 Hz, 1H), 6.69 (d, J = 10.0
Hz, 1H), 7.09 (s, 1H), 7.93 (s, 1H). 13C NMR (62.5 MHz, DMSO-
dioxo-1,2,3,6-tetrahydro-9H-purin-9-yl)propoxy)-4-
methoxyphenyl)methyl)phosphonate (4c). Yield 76% (4.71g), d6/TMS): 25.3, 26.1, 27.4, 28.3, 28.5, 29.3, 30.1, 30.6, 31.2,
IR (KBr, neat): 3433, 2931, 2129, 1651, 1246, 1026, 817, 715 34.8, 35.7, 46.1, 51.8, 55.0, 55.3, 59.6, 62.3, 68.0, 111.2, 114.1,
cm -1. 1H NMR (250 MHz, DMSO-d6/TMS): δ (ppm) = 1.01 (t, J = 114.8, 119.0, 122.9, 130.2, 131.4, 133.8, 134.0, 140.5, 142.3,
7.5 Hz, 6H), 2.06- 2.23 (m, 2H), 2.87 (s, 3H), 3.19 (s, 3H), 3.40 146.3, 150.2, 152.8, 154.2, 155.3, 162.2. MS: m/z 699 (23, M+).
(s, 3H), 3.74 (s, 3H), 3.78-3.87 (m, 6H), 4.00 (t, J = 7.5 Hz, 2H), Anal. Calcd. For C35H50N5O8P (699.34): C, 60.07; H, 7.20; N,
4.38 (s, 1H), 4.82 (d, J = 20.0 Hz, 1H), 6.57-6.66 (m, 2H), 6.76- 10.01. Found: C, 59.94; H, 7.11; N, 9.92.
6.89 (m, 2H), 7 (d, J = 7.5 Hz, 2H), 7.09 (s, 1H), 8 (s, 1H). 13C Diethyl ((3-(3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-9H-
NMR (62.5 MHz, DMSO-d6/TMS): 13.8, 20.0, 27.4, 29.3, 29.6, purin-9-yl)propoxy)-4-methoxyphenyl)((4-
43.7, 50.1, 55.4, 62.2, 65.6, 66.6, 110.6, 111.5, 114.2, 114.9, methoxyphenyl)amino)methyl)phosphonate (4g). Yield: 84%
120.0, 121.1, 125.4, 126.5, 128.2, 128.5, 142.4, 146.3, 147.1, (5.16g), IR (KBr, neat): 3433, 2931, 2129, 1715, 1651, 1246,
148.4, 150.9, 150.9, 154.3. MS: m/z 620 (20, M+). Anal. Calcd 1026, 814, 712 cm
-1
.
1H NMR (250 MHz, DMSO-d6/TMS): δ
for C28H35ClN5O7P (620.04): C, 54.24; H, 5.69; N, 11.30. Found: (ppm) = 0.97-1.02 (m, 6H), 2.22-2.27 (m, 2H), 3.14 (s, 3H), 3.39
C, 54.13; H, 5.61; N, 11.22. (s, 3H), 3.55 (s, 3H), 3.66 (s, 3H), 3.83 (d, J = 22.5 Hz, 4H), 3.98
Diethyl ((3-((9-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-9H- (d, J = 7.5 Hz, 2H), 4.37 (s, 2H), 4.78 (d, J = 25.0 Hz, 1H), 6.58 (d,
purin-9-yl)nonyl)oxy)-4-methoxyphenyl)(p- J = 10.0 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H),
tolylamino)methyl)phosphonate (4d). Yield 79% (5.4g), IR 7.02 (d, J = 7.5 Hz, 1H), 7.10 (d, J = 10.0 Hz, 1H), 7.29 (s, 1H),
(KBr, neat): 3433, 2931, 2129, 1715, 1651, 1246, 1026, 817, 7.50 (s, 1H), 8 (s. 1H), 8.48 (s, 1H). 13C NMR (62.5 MHz, DMSO-
1
715 cm -1. H NMR (250 MHz, DMSO-d6/TMS): δ (ppm) = 1.00- d6/TMS): 16.0, 16.2, 19.9, 27.4, 29.3, 29.6, 43.7, 52.4, 54.9,
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55.4, 62.0, 65.5, 106.0, 111.6, 113.7, 114.1, 120.3, 125.2, 1026, 813, 710 cm
Journal Name
-1
.
1H NMR (250 MHz, DMSO-d6/TMS): δ
126.1, 129.0, 133.4, 134.1, 142.4, 143.7, 144.6, 146.1, 148.4, (ppm) = 1.14-1.22 (m, 6H), 1.66 -1.74 (m, 10H), 1.88 (d, J = 2.5
150.9, 152.5. MS: m/z 615 (8, M+). Anal. Calcd for C29H38N5O8P Hz, 2H), 2.26 (d, J = 5.0 Hz, 2H), 2.70 (s, 3H), 2.85 (s, 3H), 3.19
(615.25): C, 56.58; H, 6.22; N, 11.38. Found: C, 56.58; H, 6.22; (s, 3H), 3.66-3.71 (m, 2H), 3.86-3.97 (m, 4H), 4.16-4.21 (m, 2H),
N, 11.38.
4.79 (d, J = 12.5 Hz, 1H), 6.88 (s, 1H), 6.98 (s, 1H), 7.08 (d, J =
Diethyl
((2-(4-(1H-benzo[d]imidazol-1-yl)butoxy)-4- 5.0 Hz, 2H), 7.44 (d, J = 5.0 Hz, 2H), 7.92 (s, 1H), 8.05 (t, J = 2.5
(4h). Hz, 2H). 13C NMR (62.5 MHz, DMSO-d6/TMS): 15.9, 16.0, 20.9,
methoxyphenyl)(p-tolylamino)methyl)phosphonate
Yield: 80% (4.41g). IR (KBr, neat): 3125, 2910, 2815, 1450, 25.3, 25.5, 27.4, 28.2, 28.6, 28.7, 29.3, 30.0, 46.1, 55.4, 61.7,
-1
1581, 1256, 1115, 814, 712 cm
.
1H NMR (250 MHz, DMSO- 67.6, 68.0, 70.2, 111.2, 115.0, 120.8, 122.7, 125.4, 128.0,
d6/TMS): δ(ppm)= 0.98- 1.04 (m, 6H), 1.12-1.19 (m, 4H), 2.04 132.5, 134.2, 135.3, 135.7, 140.0, 142.3, 145.8, 150.9, 154.2,
(s, 3H), 3.48-3.54 (m, 2H), 3.65 (s, 3H), 3.84-3.88 (m, 4H), 3.98- 155.1, 158.5. MS: m/z 687 (19, M+). Anal. Calcd for
4.03 (m, 2H), 4.24 (t, J = 7.5 Hz, 2H), 4.88 (d, J = 10.0 Hz, 1H), C34H47FN5O7P (687.32): C, 59.38; H, 6.89; N, 10.18. Found: C,
6.65 (d, J = 10.0 Hz, 1H), 6.75-6.84 (m, 4H), 6.95-6.99 (m, 1H), 59.29; H, 6.81; N, 10.07.
7.09-7.18 (m, 1H), 7.20-7.23 (m, 2H), 7.57-7.62 (m,2H), 7.93 (s, Diethyl
((3-(4-(6-amino-9H-purin-9-yl)
butoxy)-4-
1H), 8.23 (s, 1H). 13C NMR (62.5 MHz, DMSO-d6/TMS): 19.9, methoxyphenyl) ((4-methoxyphenyl)
amino) methyl)
22.7, 26.1, 28.0, 29.0, 31.2, 44.2, 54.9, 55.3, 62.0, 62.3, 67.9, phosphonate (8a). Yield: 80% (4.76g), IR (KBr, neat): ν = 3427,
-1
110.7, 111.3, 113.7, 118.7, 120.6, 122.0, 122.6, 125.2, 128.9, 2129, 1651, 1246, 1027, 815, 715 cm
.
1H NMR (250 MHz,
129.0, 134.8, 141.5, 143.6, 144.7, 145.0, 147.4, 147.4, 148.1, DMSO-d6/TMS): δ (ppm) = 1.00-1.03 (m, 6H), 1.17 (t, J = 2.5 Hz,
148.2. MS: m/z 551 (14, M+). Anal. Calcd for C31H40N3O5P 2H), 1.89 (t, J = 2.5 Hz, 2H), 3.33 (s, 3H), 3.91 (t, J = 5.0 Hz, 4H),
(551.25): C, 65.83; H, 7.13; N, 7.43. Found: C, 65.74; H, 7.06; N, 4.00-4.04 (m, 2H), 4.14-4.18 (m, 2H), 4.81 (d, J = 12.5 Hz, 1H),
7.37.
4.91 ( d, J = 10.0 Hz, 2H), 6.57-6.62 (m, 2H), 6,68-6.72 (m, 2H),
Diethyl
((3-((5-(1H-benzo[d]imidazol-1-yl)pentyl)oxy)-4- 7.05 (s, 2H), 7.17 (s, 2H), 7.50 (s, 1H), 7.91 (s, 1H), 8.13 (s, 1H).
13C NMR (62.5 MHz, DMSO-d6/TMS): 15.9, 16.2, 25.8, 26.2,
methoxyphenyl)((4-
methoxyphenyl)amino)methyl)phosphonate (4i). Yield: 79 % 42.6, 55.0, 62.0, 62.1, 62.4, 66.7, 110.8, 114.1, 114.6, 117.4,
(4.59g), IR (KBr, neat): 3123, 2910, 2815, 1453, 1581, 1256, 120.7, 128.7, 133.4, 135.0, 137.2, 138.6, 140.7, 144.7, 149.4,
-1
1115, 813, 712 cm
.
1H NMR (250 MHz, DMSO-d6/TMS): 151.3, 152.3, 155.8, 158.2. 31P NMR (121.5 MHz, CDCl3): δ
δ(ppm)= 1.00 (t, J = 7.5 Hz, 6H), 1.13-1.17 (m, 4H), 1.82 (t, J = (ppm) = 23.22. MS: m/z 584 (16, M+). Anal. Calcd for
7.5 Hz, 2H), 3.54 (s, 3H), 3.64 (s, 3H), 3.83-3.87 (m, 4H), 4.01 (t, C27H35N6O5P (584.25): C, 58.48; H, 6.36; N, 15.15. Found: C,
J = 7.5 Hz, 2H), 4.21- 4.26 (m, 2H), 4.85 (d, J = 10.0 Hz, 1H), 58.41; H, 6.30; N, 15.09.
6.56-6.61 (m, 2H), 6.70 (d, J = 10.0 Hz, 2H), 6.81 (d, J = 7.5 Hz, Diethyl ((3-((5-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-9H-
2H), 6.96 (d, J =5.0Hz, 1H), 7.09 (s, 1H), 7.17-7.23 (m, 2H), 7.57- purin-9-yl)pentyl)oxy)-4-methoxyphenyl)((4-
7.64 (m, 2H), 7.92 (s, 1H), 8.21 (s, 1H), . 13C NMR (62.5 MHz, fluorophenyl)amino)methyl)phosphonate (8b). Yield: 83 %
DMSO-d6/TMS): 16, 16.3, 22.7, 28, 29.1, 43.9, 53, 55, 55.3, (5.23g), IR (KBr, neat): 3433, 2931, 2129, 1715, 1651, 1246,
-1
61.9, 62, 67.9, 110.3, 111,3, 113.4, 114.1, 114.8, 119.3, 120.7, 1026, 814, 712 cm
.
1H NMR (250 MHz, DMSO-d6/TMS): δ
121.3, 122.1, 123.9, 129, 133.7, 141, 141.2, 143.2, 143.9, (ppm) = 0.83 (t, J = 7.5 Hz, 6H), 0.97-1.06 (m, 6H), 2.97 (s, 3H),
147.4, 148.2, 151.2. MS: m/z 581 (11, M+). Anal. Calcd for 3.19 (s, 3H), 3.30-3.35 (m, 2H), 3.68 (d, J = 5.0 Hz, 2H), 3.79-
C31H40N3O6P (581.27): C, 64.01; H, 6.93; N, 7.22. Found: C, 3.85 (m 4H), 4.69 (d, J = 17.5 Hz, 1H), 6.60 (d, J = 10.0 Hz, 4H),
63.92; H, 6.87; N, 7.17.
Diethyl ((3-(3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-9H- 7.82 (s, 1H). 13C NMR (62.5 MHz, DMSO-d6/TMS): 18.5, 20.3,
purin-9-yl)propoxy)-4-methoxyphenyl)((4- 27.4, 29.3, 30.6, 35.7, 43.6, 54.4, 62.0, 65.5, 67.8, 72.2, 113.8,
6.81 (d, J = 7.5 Hz, 2H), 7.18 (d, J = 7.5 Hz, 2H), 7.74 (s, 1H),
nitrophenyl)amino)methyl)phosphonate (4j). Yield 75% 113.9, 114.3, 114.4, 114.7, 115.0, 128.5, 129.3, 131.6, 135.3,
(4.72g), IR (KBr, neat): 3433, 2931, 2125, 1715, 1655, 1246, 140.9, 142.5, 148.4, 150.9, 152.8, 154.2, 162.2. MS: m/z 631
-1
1026, 817, 710 cm
.
1H NMR (250 MHz, DMSO-d6/TMS): δ (25, M+). Anal. Calcd for C29H37FN5O6P (631.26): C, 57.90; H,
(ppm)= 1.11-1.16 (m, 6H), 2.23-2.28 (m, 2H), 3.18 (s, 3H), 3.40 6.20; N, 11.64. Found: C, 57.90; H, 6.20; N, 11.64.
(s, 3H), 3.69 (s, 3H), 3.85-3.91 (m, 4H), 3.98-4.03 (m, 2H), 4.37- Diethyl
((4-(4-(6-amino-9H-purin-9-yl)butoxy)phenyl)(p-
4.42 (m, 2H), 5.20 (d, J = 10.0 Hz, 1H), 6.91 (d, J = 10.0 Hz, 2H), tolylamino)methyl)phosphonate (8c). Yield: 76% (4.08g), IR
-1
7.06 (d, J = 7.5 Hz, 2H), 7.14 (s, 1H), 7.92 (d, J = 5.0 Hz, 2H), 8 (KBr, neat): ν = 3427, 2129, 1651, 1246, 1027, 817, 715 cm
.
(s, 1H), 8.13 (s, 1H).13C NMR (62.5 MHz, DMSO-d6/TMS): 18.3, 1H NMR (250 MHz, DMSO-d6/TMS): δ (ppm) = 1.46- 1.51 (m,
19.8, 24.3, 27.4, 29.3, 43.7, 55.4, 56.6, 62.3, 62.5, 65.5, 111.5, 6H), 1.60-1.65 (m, 2H), 2.24-2.29 (m, 2H), 2.36 (s, 3H), 4.13-
112.1, 114.7, 122.2, 125.6, 125.8, 127.6, 129.9, 130.7, 135, 4.27 (m, 4H), 4.31-4.39(m, 2H), 4.45-4.53(m, 2H), 5.32 (d, J =
136.7, 141.1, 142.4, 147.1, 148.7, 150.8, 157.9. MS: m/z 630 10.0 Hz, 2H), 5.43 (d, J = 10.0 Hz, 1H), 7.12 (d, J = 5.0 Hz, 2H),
(28, M+). Anal. Calcd for C28H35N6O9P (630.22): C, 53.33; H, 7.23 (t, J = 7.5 Hz, 2H), 7.50 (d, J = 10.0 Hz, 2H), 7.66 (s, 2H),
5.59; N, 13.33. Found: C, 53.25; H, 5.50; N, 13.23.
Diethyl ((3-((9-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-9H- DMSO-d6/TMS): 16.3, 16.5, 20.3, 26.2, 26.6, 43.1, 48.8, 58.0,
purin-9-yl)nonyl)oxy)-4-methoxyphenyl)((4- 62.8, 67.0, 114.0, 115.1, 115.9, 125.6, 129.2, 129.4, 131.5,
7.96 (s, 1H), 8.40 (s, 1H), 8.61 (s, 1H). 13C NMR (62.5 MHz,
fluorophenyl)amino)methyl)phosphonate (4k). Yield: 81% 132.8, 138.9, 141.5, 145, 145.2, 151.8, 151.9, 155.6, 156.1,
(5.56g), IR (KBr, neat): 3433, 2933, 2123, 1715, 1655, 1246, 158.9. MS: m/z 538 (18, M+). Anal. Calcd for C27H35N6O4P
8 | J. Name., 2012, 00, 1-3
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(538.25): C, 60.21; H, 6.55; N, 15.60. Found: C, 60.13; H, 6.48;
N, 15.53.
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methoxyphenyl)methyl)phosphonate (8d). Yield 79 % (5.04g),
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712 cm -1. H NMR (250 MHz, DMSO-d6/TMS): δ (ppm) = 1.55
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(t, J = 7.5 Hz, 6H), 1.65-1.70 (m, 4H), 2.71-2.76 (m, 2H), 3.69 (s,
3H), 3.91 (s, 3H), 4.35-4.41 (m, 4H), 4.51-4.56 (m, 2H), 4.87-
4.92 (m, 2H), 5.65 (d, J = 10.0 Hz, 1H), 7.34 (d, J = 10.0 Hz, 2H),
7.42 (d, J = 5.0 Hz, 2H), 7.67 (t, J = 5.0Hz, 2H), 7.92 (d, J = 7.5
Hz, 2H), 8.45 (s, 1H), 8.54 (s, 1H). 13C NMR (62.5 MHz, DMSO-
d6/TMS): 15.9, 16.2, 27.4, 29.3, 29.5, 31.2, 34.8, 43.7, 53.6,
62.1, 62.2, 62.3, 106.0, 111.3, 113.9, 115.4, 118.3, 119.3,
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150.9, 154.2, 157.7. 31P NMR (121.5 MHz, CDCl3): δ (ppm) =
22.38. MS: m/z 638 (22, M+). Anal. Calcd for C30H37N6O6P
(638.26): C, 59.20; H, 6.13; N, 13.81. Found: C, 59.12; H, 6.06;
N, 13.74.
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control.31
The
cancer
cells
were
cultured
in RPMI-1640 and the medium was supplemented with 10%
FBS and 1% penicillin–streptomycin (100 mg/ml streptomycin
and 100 U/ml penicillin) to control the growth of
contaminating microorganisms. The cells were cultured in 96-
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atmosphere of 5% CO2 for 24 h. Four hours to the end of
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At the end, the insoluble formazan produced was dissolved in
a solution containing 10% SDS and 50% DMF (left for 1 h at 37
°C in dark conditions) and the optical density (OD) was read
against reagent blank with multi well scanning
spectrophotometer (ELISA reader, Bio-Tek’s ELx808, USA), at a
wavelength of 570 nm. The absorbance was a function of
concentration of the converted MTT (yellow) to purple
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OD values of untreated controls and presented as the
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of incubation with these ligands were calculated from the
dose-response curves.30
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J. Name., 2013, 00, 1-3 | 9
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RSC Advances
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DOI: 10.1039/C5RA21419J
Synthesis of new α-aminophosphonate derivatives incorporating
benzimidazole, theophylline and adenine nucleobases using L-cysteine
functionalized magnetic nanoparticles (LCMNP) as magnetic reusable
catalyst: Evaluation of their anticancer properties
Foroogh Bahrami,a Farhad Panahi,*a Fatemeh Daneshgar,a Reza Yousefi,b Mohammad Bagher
Shahsavanib and Ali Khalafi-Nezhad*a
a Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
* Email: khalafi@susc.ac.ir; Panahi@shirazu.ac.ir
b Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz
71454, Iran
HO
CHO
Br
Br
n
Br
O
CHO
n
K2CO3, TBAB
CH3CN, reflux
MeO
MeO
Isovanillin
NH3
CO2
K2CO3, TBAB
CH3CN, reflux
Nucleobase
S
Si
MNP
LCMNP
PO(OEt)2
NH
N
O
n
HPO(OEt)2
Amine
N
N
O
n
CHO
MeO
R
LCMNP (8.5 mol%)
50 oC, 12h
MeO
SH
N
O
NH2
H3C
N
N
N
N
N
NH
N
N
H
N
H
N
H
N
H
O
N
N
CH3
A new class of α-aminophosphonate derivatives incorporating benzimidazole, theophylline and adenine
nucleobases were synthesized in a three-step process and the anticancer activities of selected ligands
were evaluated.