Synthesis and anti-oxidant activity of (5E,9E)-16-(substituted)-7,8- dihydro-16λ5-dibenzo[d,l][1,3,7,10,2]- dioxadiazaphosphacyclotridecine-16-ones

Article abstract of DOI:10.1002/ardp.201100204

A new class of biologically active 13-membered phosphorus-macroheterocycles (6a-l) were conveniently synthesized from 1,2-bis(salicylidene amino)-phenylene (1), by treating with phosporusoxychloride (3) and followed by reacting with various aromatic thiols and amines (5f-l) in one path, and in another path 1 was directly treated with various phosphorodichloridates (2a-e) in the presence of triethylamine at 0-10°C under N₂ atmosphere in THF. All the title compounds were confirmed by analytical and spectral data (IR, ¹H-, ¹³C-, ³¹P-NMR, and mass spectra) and screened for anti-oxidant activity. Among these compounds, 6k, 6e, and 6l containing nitro, fluoro, and chloro groups as substituents on the phenyl ring exhibited high anti-oxidant activity with effective inhibitory concentration (IC₅₀) values.

Full text of DOI:10.1002/ardp.201100204

Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
1
Full Paper
Synthesis and Anti-Oxidant Activity of (5E,9E)-16-
(Substituted)-7,8-dihydro-16l5-dibenzo[d,l][1,3,7,10,2]-
dioxadiazaphosphacyclotridecine-16-ones
Chinta Raveendra Reddy1, Chinthaparthi Radha Rani1, Kuruva Chandra Sekhar1,
Gangireddy Chandra Sekhar Reddy2, and Chamarthi Naga Raju1
1 Department of Chemistry, Sri Venkateswara University, Tirupati, Andhra Pradesh, India
2 Department of Polymer Science and Engineering, Pusan National University, Pusan, Republic of Korea
A new class of biologically active 13-membered phosphorus-macroheterocycles (6a–l) were
conveniently synthesized from 1,2-bis(salicylidene amino)-phenylene (1), by treating with
phosporusoxychloride (3) and followed by reacting with various aromatic thiols and amines (5f–l)
in one path, and in another path 1 was directly treated with various phosphorodichloridates (2a–e) in
the presence of triethylamine at 0–108C under N2 atmosphere in THF. All the title compounds were
confirmed by analytical and spectral data (IR, 1H-, 13C-, 31P-NMR, and mass spectra) and screened for
anti-oxidant activity. Among these compounds, 6k, 6e, and 6l containing nitro, fluoro, and chloro
groups as substituents on the phenyl ring exhibited high anti-oxidant activity with effective
inhibitory concentration (IC50) values.
Keywords: Anti-oxidant activity / Phosphorus macrocycles / Radical scavenging activity
Received: June 10, 2011; Revised: December 5, 2011; Accepted: December 6, 2011
DOI 10.1002/ardp.201100204
Introduction
host molecules capable of binding neutral organic molecules
as guests is an area of rapidly expanding interest [9]. Cram
and co-workers [10], Lehn and co-workers [11], Vogtle and co-
workers [12], Diederich and co-workers [13], and others have
made significant advances in this field of host–guest com-
plexation [14]. They are expected to function as good hosts in
the host–guest chemistry. This particular property enables
them to carry certain metal ion species and drug molecules
in the living system. The versatile behavior of phosphorus
compounds in addition to the complexity and low yield of
multistage macrocyclic synthesis presumably explains the
slow development of the corresponding phosphorus macro-
cyclic chemistry. Most of the studies were concerned with the
incorporation of phosphorus (III) or (V) in crown ether links
or with the substitution of some oxygen atoms of crown
ethers by phosphorus leading to species possessing one or
more P–C, P–O, P–S, or, much more scarcely, P–N bonds [15].
Macrocyclic phosphates were also well known for their
insecticidal activities [16] and are known to degrade hydro-
lytically and enzymatically to non-toxic residues. Discovery of
their fungicidal properties became an important develop-
ment [17]. Antioxidants are widely studied for their capacity
An increasing interest has been paid for several years to the
chemistry of heterocyclic rings containing phosphorus due
to their unique physical properties, specific chemical reac-
tivity, and their remarkable potential biological activity [1–6].
Phosphorus containing macrocycles are interesting mol-
ecules with potential applications in supra-molecular and
synthetic organic chemistry [7]. They have been synthesized
as phosphineoxides, phosphines, phosphates, phosphonates,
and phosphoranes [8]. By varying the components of macro-
cyclic systems by introducing functional groups and
heteroatoms into their ensembles, one can prepare cavity
structures with different levels of pre-organization and differ-
ent lability, size, and properties.
The importance of these molecules as phosphorus
analogues of crown ethers is derived from the potential
catalytic activity and ion carrying properties. The design of
Correspondence: Chamarthi Naga Raju, Department of Chemistry, Sri
Venkateswara University, Tirupati, Andhra Pradesh 517 502, India.
E-mail: rajuchamarthi10@gmail.com
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C. R. Reddy et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
to protect organisms and cells from damage induced by
oxidative stress during metabolism.
the condensation reaction of ethylenediamine with salicylal-
dehyde in ethanol at room temperature, was reacted with
phosporusoxychloride (3) in the presence of triethylamine
(TEA) in dry tetrahydrofuran (THF) to give the monochloride
(5E,9E)-16-chloro-7,8-dihydrodibenzo[d,l][1,3,7,10,2]dioxadi-
azaphosphacyclotridecine-16-oxide (4) [21, 22]. Later it was
treated with various aromatic thiols and amines (5f–l) in
the presence of TEA in THF to get the compounds 6f–l.
The remaining compounds (6a–e) were synthesized in a
single step by reacting 1 with various phosphorodichlori-
dates (2a–e) in the presence of TEA in THF in good yields.
The chemical structures of the newly synthesized compounds
6a–l were confirmed by IR, 1H-, 13C-, 31P-NMR, mass spectral,
and elemental analytical data.
Recently much effort has been devoted to macrocyclic
organophosphorus compounds as asymmetric catalysts due
to their active heterogeneous catalytic property, having prac-
tical advantages in terms of product separation and recycling
in enantioselective synthesis [18, 19].
In view of the various possible applications of phosphorus
macro-heterocycles containing phosphorus, oxygen, and
nitrogen, we synthesized 13-membered phosphorus macro-
heterocycles (PMHCs).
Results and discussion
Chemistry
The title compounds 6a–l exhibited characteristic IR bands
[21–24] in the regions of 3335–3370, 1595–1632, 1230–1265,
The synthesis of a few of the title compounds, (5E,9E)-16-
(substituted)-7,8-dihydro-16l5-dibenzo[d,l][1,3,7,10,2]dioxa-
diazaphosphacyclotridecine-16-ones (6f–l) was accomplished
in two steps (Scheme 1). In the first step, 1,2-bis(salicylidene
amino)-phenylene (1), which is previously prepared [20] by
and 960–974 cmꢀ1 for N–H, C N, P O, and C–H
,
–
–
–
–
–
–
trans
respectively. Two absorption bands at 1196–1128 and 954–
964 cmꢀ1 correspond to symmetric absorption bands of
P–O–C (Ar).
O
8
7
6
9
10
P
5
N
N
N
N
Cl
Cl
(2a e)
R
_
20
19
4
11
12
13
15
O
17
O
OH
HO
3
16
P
21
14
18
TEA/ THF
_
30 40°C
1
2
O
R
(1)
_
(6a l)
O
P
H R
_
(5f l)
TEA/ THF
_
Cl
Cl
N
N
O
0
5°C
TEA/ THF
Cl
_
(3)
0
5°C
O
P
O
Cl
(4)
R
R
Compound
Compound
6g
′
O
1
′
2
′
3
a
6
H
OC
CH2 CH3
S
3
′
3
′
4
′
1
′
2
′
5
6b
h
6
HN
O
′
′
6
7
F
6i
HN
HN
C
H
6c
O
O
3
6
j
6d
C
l
OC
H
3
6e
6f
NO2
6k
6l
NO2
F
HN
HN
O
S
Scheme 1. Synthesis of (5E,9E)-16-(substi-
tuted)-7,8-dihydro-16l5-dibenzo[d,l][1,3,7,10,2]-
dioxadiazaphosphacyclotridecine-16-ones
(6a–l).
l
C
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
Synthesis and Anti-Oxidant Activity of b-Membered Phosphorus-Macroheterocycles
3
N
N
H
H
H
H
R
N
H
R
N
H
O
O
O
O
O
O
N
N
O
O
O
O
P
P
P
P
N
N
O
O
H
H
R
R
(a)
(b)
(c)
(d)
Figure 1. Conformational isomers of compounds 6a–l.
The nitrogen attached protons in compounds 6h–l are on the phenyl ring exhibited high anti-oxidant activity with
observed at d 5.96–6.07 as broad peak, showing the broad effective inhibitory concentration (IC50) values. The remain-
nature of the hydrogen in binding with other nitrogen atoms ing compounds also showed moderate to good anti-oxidant
in their boat form (Fig. 2a and b). All the aromatic protons activity.
and imine protons are observed at d 7.37–7.98 and d 8.71–
All the synthesized compounds were evaluated for their
8.95, respectively. The higher resonance values for imine anti-oxidant activity by calculating the IC50 (Eq. 1) by using 2,2-
protons are due to the anisotropic effect of aromatic ring diphenyl-1-picrylhydrazyl (DPPH) method, reducing power and
current which is extended to imine conjugation and the hydroxyl radical scavenging activity methods. Vitamin-C was
imine protons as extra-annular hydrogens have come into measured as standard for anti-oxidant activity, the IC50 values
the paramagnetic region of anisotropic effect. This phenom- varied based on the substituent on the phenyl rings.
enon was also observed for carbons of imine and they reson-
ðAcont ꢀ Atest
Þ
ated with higher frequency at d 162.9–165.3 and all the
aromatic and aliphatic carbons resonated in expected region.
All the title compounds showed a significant molecular
ionic fragment at their respective mass and they shown a
common base peak at 250 m/z.
Scavengedð%Þ ¼
ꢁ 100
(1)
Acont
where Acont is the absorbance of the control reaction (con-
taining all reagents except the test compound and blank
sample) and Atest is the absorbance of the test compound.
DPPH radical scavenging activity
Pharmacology/evaluation of anti-oxidant activity
The title PMHCs containing oxygen and nitrogen are stable in
boat form isomer (Fig. 1) and are expected to be more active
due to the presence of heteroatoms containing non-bonded
electron pairs that serve as binding sites in the bio-matrix
(Fig. 2c and d). The compounds 6k, 6e, and 6l which are
containing nitro, fluoro, and chloro groups as substituents
The scavenging activity of PMHCs, 6a–l, against DPPH radical
was performed in accordance with Choi et al. [25]. The DPPH
free radical is a stable free radical, which has been widely
accepted as a tool for estimating the free radical scavenging
activity of anti-oxidants. This spectrophotometric assay uses
the stable radical DPPH as a reagent. 85 mM of DPPH was
R
R
R
O
N
HN
O/
H
N
O
O
O
H
O/N
P
P
P
P
N
N
N
N
H
N
N
N
M
N
R
M
O
O
O
O
O
O
O
O
H
H
H
H
H
H
H
H
(a)
(b)
(c)
(d)
Hydrogen bonding formation
in boat form
=
M
Drug molecule/ hydroxy radicals/ metal ions, etc.
Figure 2. Possible binding nature of the titled compounds, 6a–l, with drug molecules, hydroxyl radicals, and metal ions, etc.
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C. R. Reddy et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
added to a medium containing different PMHCs concen-
trations. The medium was incubated for 30 min at room
temperature. The decrease in absorbance was measured at
518 nm. Ascorbic acid was used as standard reference to
record maximal decrease in DPPH radical absorbance. The
values are expressed in percentage of inhibition of DPPH
radical absorbance with those of the standard control values
without the title compounds (Fig. 3; ascorbic acid maximal
inhibition was considered 100% of inhibition).
upper layer of the solution (2.5 mL) was mixed with deion-
ized water (2.5 mL) and ferric chloride (FeCl3, 0.5 mL, 0.1%)
and the UV absorbance was measured at 700 nm using a
spectrophotometer. Increase in absorbance of the reaction
mixture indicated increased reducing power (Fig. 4). Mean
values from three independent samples were calculated for
each compound and standard deviations were less than 5%.
In the case of PMHCs 6a–l, derivatives 6k, 6e, and 6l exhib-
ited the highest reducing power with IC50 of 2.34, 2.42, and
2.51 mg/mL, respectively, when compared with other com-
pounds. The remaining compounds exhibited reducing
power activity in the following order: 6c (IC50 2.65 mg/mL),
6g (IC50 2.72 mg/mL), 6d (IC50 2.86 mg/mL), 6i (IC50 2.97 mg/mL),
6j (IC50 3.08 mg/mL), 6f (IC50 3.15 mg/mL), 6h (IC50 3.19 mg/mL),
6b (IC50 3.22 mg/mL), and 6a (IC50 3.46 mg/mL) when compared
with ascorbic acid (IC50 2.54 mg/mL).
The anti-oxidant activity of these compounds was
expressed as IC50 (inhibitory concentration, 50%). DPPH
forms a stable molecule on accepting an electron or hydro-
gen and thus found application in the determination of
radical scavenging and antioxidant activity. In the case of
PMHs 6a–l, fluoro and nitro substituted compounds 6k, 6e,
and 6l showed the highest DPPH radical scavenging activity
with IC50 at 31.3, 31.8, and 32.6 mg/mL, respectively, when
compared with other compounds. The remaining com-
pounds exhibited DPPH radical scavenging activity in the
following order: 6c (IC50 33.6 mg/mL), 6g (IC50 37.3 mg/mL),
6d (IC50 39.7 mg/mL), 6i (IC50 43.1 mg/mL), 6j (IC50 45.3 mg/mL),
6f (IC50 47.6 mg/mL), 6h (IC50 48.2 mg/mL), 6b (IC50 51.3 mg/mL),
and 6a (IC50 61.7 mg/mL) when compared with ascorbic acid
(IC50 32.5 mg/mL; Fig. 3).
Hydroxyl radical scavenging activity
The hydroxyl radical is the most reactive oxygen species (ROS)
that attacks almost every molecule in the body. It initiates the
peroxidation of cell membrane lipids [27, 28] yielding malon-
dialdehyde, which is mutagenic and carcinogenic [29]. It was
carried out by measuring the competition between deoxyri-
bose and the compounds that generate hydroxyl radicals
were measured by the method of Okhawa et al. [30]. The
absorbance value of the reaction mixture was recorded at
230 nm by spectrophotometer.
Reducing power assay
The reducing power was determined according to the
method of Oyaizu [26]. Different concentrations of the com-
pound (25, 50, 75, and 100 mg/mL) prepared in methanol
were mixed with phosphate buffer (2.5 mL, 0.2 M, pH 6.6)
and potassium ferricyanide [K3Fe(CN)6] (2.5 mL, 1%). The
mixture was incubated at 508C for 20 min and 2.5 mL of
trichloroaceticacid (TCA, 10%) was added to the mixture,
which was then centrifuged at 3000 rpm for 20 min. The
Even though the PMHCs are known to scavenge the
hydroxyl radical, the compounds 5k, 5e, and 5l showed
significant hydroxyl radical scavenging activity with IC50
of 1.09, 1.13, and 1.18 mg/mL, respectively, when compared
with other compounds. The remaining compounds exhibited
hydroxyl radical scavenging activity in the following order,
respectively: 5c (IC50 1.23 mg/mL), 5g (IC50 1.25 mg/mL), 5d
Figure 3. DPPH scavenging activity of 6a–l.
Figure 4. Reducing power activity of 6a–l.
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
Synthesis and Anti-Oxidant Activity of b-Membered Phosphorus-Macroheterocycles
5
General procedure for the synthesis of phosphorus
macroheterocycles (PMHCs; 6a–l)
Literature procedure was employed for the synthesis of 2,20-
((1E,10E)-(ethane-1,2-diylbis(azanylylidene))bis(methanylylidene))-
diphenol (1) [21, 22]. The title compounds were synthesized in
two ways (Scheme 1). Some of the compounds (6a–e) were
prepared indirectly by addition of various substituted phosphor-
odichloridates (2a–e) to 1 and the remaining compounds (6f–l)
were synthesized through the formation of an intermediate (4)
followed by the addition of various aromatic amines and thiols
(5f–l).
Method 1
In this method, a solution of ethylphosphorodichloride (2a,
0.64 mL, 0.006 mol) in 25 mL of dry THF was added dropwise
over a period of 15 min to a stirred mixture of 2,20-((1E,10E)-
(ethane-1,2-diylbis(azanylylidene))bis(methanylylidene))diphenol
(1, 1.608 g, 0.006 mol) and TEA (1.22 g, 0.006 mol) in 20 mL of
dry THF at 108C. After the addition, the temperature of the
reaction mixture was raised to 40–458C and stirred for another
3 h. The progress of the reaction was monitored by TLC analysis
(ethyl acetate/hexane, 1:2) on silica gel as adsorbent. The pre-
cipitated TEA hydrochloride was separated by filtration and
the filtrate was evaporated in a rotary evaporator to get crude
product. The crude product was washed with water, followed
by hexane, and recrystallized from 2-propanol to obtain pure
compound 6a, yield 1.59 g (74%), m.p. 1688C.
Figure 5. Hydroxyl radical scavenging activity of 6a–l.
(IC50 1.36 mg/mL), 5i (IC50 1.57 mg/mL), 5j (IC50 1. 97 mg/mL),
5f (IC50 2.14 mg/mL), 5h (IC50 2.37 mg/mL), 5b (IC50 2.49 mg/mL),
and 5a (IC50 2.61 mg/mL). The IC50 values indicate that
the title compounds can be considered as promising anti-
oxidants when compared to ascorbic acid (IC50 1.02 mg/mL;
Fig. 5).
Compounds 6b–e were also prepared by adopting the same
procedure. These compounds (6b–e) were also recrystallized
from 2-propanol.
Conclusion
Method 2
A simple and an efficient method for the synthesis of novel
biologically active PMHCs in three/two steps is reported.
According to our predicted results, they have ability as
anti-oxidants to scavenge the free-radicals generated in the
cell membrane, and after thorough investigation of their
activity, they may be used as anti-oxidant drugs in medicine
and drug carriers to the site.
In this method, the title compound 6f was synthesized
by the reaction of 2,20-((1E,10E)-(ethane-1,2-diylbis(azanylylidene))-
bis(methanylylidene))diphenol (1, 1.608 g, 0.006 mol) with phos-
phorus oxychloride (2, 0.559 mL, 0.006 mol) at 0–58C, in the
presence of TEA (1.22 g, 0.006 mol) in dry THF [21, 22]. After
completion of reaction (TLC), precipitated TEA hydrochloride
was separated by filtration to get the intermediate 4 solution
and to the cold solution of filtrate, 4, in THF, and TEA (1.22 g,
0.006 mol), a solution of thiopenol (5f, 0.616 mL, 0.006 mol) in
10 mL of dry THF was added dropwise with stirring in the course
of 30 min. After completion of the addition, the temperature of
the reaction mixture was slowly raised to 35–408C and stirring
was continued for another 3 h. Progress of the reaction was
monitored by TLC. After completion of the reaction, the mixture
was filtered and the solvent was removed in a rota-evaporator.
The residue was washed with water, followed by hexane, and
recrystallized from 2-propanol to afford pure compound 6f with
high yield, 2.03 g (80%), m.p. 1758C.
Experimental
Chemicals were obtained from Sigma–Aldrich, Merck, and
Lancaster, and used without further purification. All operations
were performed under nitrogen atmosphere using standard
glassware. Melting points were determined using a calibrated
thermometer using a Guna Digital Melting Point apparatus.
Elemental analyses were performed by the Central Drug
Research Institute, Lucknow, India. IR spectra were recorded
in Environmental Engineering Laboratory, Sri Venkateswara
University, Tirupati as KBr discs on a Nicolet 380 FT-IR spectro-
photometer. NMR spectra were recorded as solutions in DMSO-d6
on a Bruker AMX 400 MHz spectrometer operating at 400 MHz
for 1H, 100 MHz for 13C, and 161.9 MHz for 31P. The 1H and 13C-
NMR chemical shifts were referenced to tetramethylsilane (TMS)
and 31P-NMR chemical shifts to 85% H3PO4. LC-mass spectra were
recorded on a Jeol SX 102 DA/600 mass spectrometer. The bio-
assay was measured on a Elico SL-160 UV–Visible double beam
spectrophotometer, Vitamin-C was used as reference.
The same procedure was successfully adopted to synthesize
remaining compounds (6g–l). These compounds (6g–l) were also
recrystallized from 2-propanol.
(5E,9E)-16-Ethoxy-7,8-dihydro-16l5-dibenzo[d,l]-
[1,3,7,10,2]dioxadiazaphosphacyclotridecin-16-one (6a)
Yield: 1.59 g (74%), Color: pale yellow, m.p. 1688C, IR (KBr):
nmax ¼ 1615, 1245, and 960 cmꢀ1 for C N, P O, and
–
–
–
–
C–Htrans, respectively; 1H-NMR (DMSO-d6, 400 MHz): d (ppm)
–
–
8.90 (s, 2H, CH), 7.45–7.62 (m, 8H, Ar–H), 5.02 (m, 2H, OCH ),
–
–
2
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C. R. Reddy et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
3.91 (s, 4H, N–CH2), 1.45 (t, 3H, J ¼ 6.2 Hz, CH3); 13C-NMR (DMSO-
d6, 100 MHz): d (ppm) 164.2 (C-5 and C-10), 163.1 (C-18 and C-21),
132.4 (C-2 and C-13), 132.2 (C-4 and C-11), 121.2 (C-19 and C-20),
119.1 (C-3 and C-12), 118.0 (C-1 and C-14), 62.8 (C-20), 55.7 (C-7
and C-8), 15 (C-30); 31P-NMR (DMSO-d6, 161.9 MHz): d (ppm) 18.84.
Mass: m/z, 358.319 (Mþꢂ, 15), 330 (28), 313 (32), 251 (37), 250
(100), 210 (45), 102 (64), 91 (15). Anal. Calcd. C18H19N2O4P: C,
60.33; H, 5.34; N, 7.82; P, 8.64. Found: C, 60.26; H, 5.27; N, 7.76;
P, 8.61%.
(5E,9E)-16-(4-Nitrophenoxy)-7,8-dihydro-16l5-dibenzo-
[d,l][1,3,7,10,2]dioxadiazaphosphacyclotridecin-16-one
(6e)
Yield: 2.30 g (85%), Color: dark yellow, m.p. 2428C, IR (KBr):
nmax ¼ 1627, 1265, and 972 cmꢀ1 for C N, P O, and
–
–
–
–
C–Htrans, respectively; 1H-NMR (DMSO-d6, 400 MHz): d (ppm)
–
–
–
8.87 (s, 2H, CH), 7.45–7.94 (m, 12H, Ar–H), 3.95 (s, 4H,
–
N–CH2); 13C-NMR (DMSO-d6, 100 MHz): d (ppm) 164.3 (C-5 and
C-10), 161.4 (C-18 and C-21), 142.3 (C-50), 140.6 (C-20), 131.2 (C-2
and C-13), 131.1 (C-4 and C-11), 128.0 (C-40 and C-60), 128.4 (C-30
and C-70), 120.1 (C-3 and C-12), 119.9 (C-19 and C-20), 118.8 (C-1
and C-14), 56.0 (C-7 and C-8); 31P-NMR (DMSO-d6, 161.9 MHz):
d (ppm): 22.21. Mass: m/z, 451.362 (Mþꢂ, 10), 313 (51), 250
(100), 91 (10). Anal. Calcd. C22H18N3O6P: C, 58.54; H, 4.02; N,
9.31; P, 6.86. Found: C, 58.48; H, 3.87; N, 9.26; P, 6.83%.
(5E,9E)-16-Phenoxy-7,8-dihydro-16l5-dibenzo[d,l]-
[1,3,7,10,2]dioxadiazaphosphacyclotridecin-16-one (6b)
Yield: 1.95 g (80%), Color: pale yellow, m.p. 1708C, IR
(KBr): nmax ¼ 1609, 1240, and 962 cmꢀ1 for C N, P O, and
–
–
–
–
C–Htrans, respectively; 1H-NMR (DMSO-d6, 400 MHz): d (ppm)
–
–
–
8.95 (s, 2H, CH), 7.45–7.91 (m, 13H, Ar–H), 3.91 (s, 4H,
–
N–CH2); 13C-NMR (DMSO-d6, 100 MHz): d (ppm) 164.8 (C-5 and
C-10), 162.5 (C-18 and C-21), 140.6 (C-20), 133.7 (C-50), 133.1 (C-2
and C-13), 131.3 (C-4 and C-11), 130.8 (C-40 and C-60), 127.4 (C-30
and C-70), 122.1 (C-19 and C-20), 119.1 (C-3 and C-12), 118.6 (C-1
and C-14), 55.9 (C-7 and C-8); 31P-NMR (DMSO-d6, 161.9 MHz): d
(ppm): 21.43. Mass: m/z, 406.365 (Mþꢂ, 11), 330 (28), 313 (34), 215
(37), 250 (100), 210 (45), 196 (34), 102 (68), 91 (20). Anal. Calcd.
C22H19N2O4P: C, 65.02; H, 4.71; N, 6.89; P, 7.62. Found: C, 64.94; H,
4.65; N, 6.83; P, 7.59%.
(5E,9E)-16-(Phenylsulfanyl)-7,8-dihydro-16l5-dibenzo-
[d,l][1,3,7,10,2]dioxadiazaphosphacyclotridecin-16-one
(6f)
Yield: 2.03 g (80%), Color: yellow, m.p. 1758C, IR (KBr):
nmax ¼ 1630, 1264, and 971 cmꢀ1 for C N, P O, and
–
–
–
–
C–Htrans, respectively; 1H-NMR (DMSO-d6, 400 MHz): d (ppm)
–
–
–
8.71 (s, 2H, CH), 7.37–7.83 (m, 13H, Ar–H), 3.89 (s, 4H,
–
N–CH2); 13C-NMR (DMSO-d6, 100 MHz): d (ppm) 163.3 (C-5 and
C-10), 161.7 (C-18 and C-21), 135.8 (C-20), 131.1 (C-4 and C-11),
129.2 (C-2 and C-13), 128.9 (C-40 and C-60), 127.6 (C-30 and C-70),
126.7 (C-50), 121.1 (C-3 and C-12), 120.9 (C-19 and C-20), 118.0 (C-1
and C-14), 56.4 (C-7 and C-8); 31P-NMR (DMSO-d6, 161.9 MHz):
d (ppm): 23.12. Mass: m/z, 422.432 (Mþꢂ, 25), 313 (43), 250
(100), 91 (13). Anal. Calcd. C22H19N2O3PS: C, 62.55; H, 4.53;
N, 6.63; P, 7.59. Found: C, 62.47; H, 4.48; N, 6.57; P, 7.57%.
(5E,9E)-16-(4-Fluorophenoxy)-7,8-dihydro-16l5-dibenzo-
[d,l][1,3,7,10,2]dioxadiazaphosphacyclotridecin-16-one
(6c)
Yield: 2.00 g (79%), Color: pale yellow, m.p. 2108C, IR (KBr):
nmax ¼ 1600, 1262, and 970 cmꢀ1 for C N, P O, and
–
–
–
–
C–Htrans, respectively; 1H-NMR (DMSO-d6, 400 MHz): d (ppm)
–
–
–
8.94 (s, 2H, CH), 7.44–7.85 (m, 12H, Ar–H), 3.98 (s, 4H,
–
(5E,9E)-16-[(4-Methoxyphenyl)sulfanyl]-7,8-dihydro-16l5-
dibenzo[d,l][1,3,7,10,2]dioxadiazaphosphacyclotridecin-
N–CH2); 13C-NMR (DMSO-d6, 100 MHz): d (ppm) 164.8 (C-5 and
C-10), 163.4 (C-18 and C-21), 141.6 (C-20), 134.4 (C-50), 133.1 (C-2
and C-13), 131.4 (C-4 and C-11), 130.8 (C-40 and C-60), 128.9 (C-30
and C-70), 121.3 (C-19 and C-20), 119.2 (C-3 and C-12), 118.5 (C-1
and C-14), 55.8 (C-7 and C-8); 31P-NMR (DMSO-d6, 161.9 MHz):
d (ppm): 21.24. Mass: m/z, 424.358 (Mþꢂ, 19), 405 (34), 397 (25),
329 (48), 313 (65), 304 (53), 276 (58), 250 (100), 196 (47), 119 (31),
111 (23), 102 (26), 91 (17). Anal. Calcd. C22H18FN2O4P: C, 62.27;
H, 4.28; N, 6.60; P, 7.30. Found: C, 62.21; H, 4.23; N, 6.56;
P, 7.28%.
16-one (6g)
Yield: 2.22 g (82%), Color: yellow, m.p. 2058C, IR (KBr):
nmax ¼ 1632, 1254, and 968 cmꢀ1 for C N, P O, and
–
–
–
–
C–Htrans, respectively; 1H-NMR (DMSO-d6, 400 MHz): d (ppm)
–
–
–
8.78 (s, 2H, CH), 7.55–7.93 (m, 12H, Ar–H), 3.85 (s, 4H,
–
N–CH2), 3.31 (s, 3H, OCH3); 13C-NMR (DMSO-d6, 100 MHz): d
(ppm) 163.1 (C-5 and C-10), 161.0 (C-18 and C-21), 135.1 (C-20),
131.8 (C-4 and C-11), 130.2 (C-2 and C-13), 128.0 (C-40 and C-60),
121.9 (C-19 and C-20), 121.0 (C-3 and C-12), 126.9 (C-30 and C-70),
120.7 (C-50), 117.0 (C-1 and C-14), 57.3 (C-7 and C-8), 55.0 (C-22);
31P-NMR (DMSO-d6, 161.9 MHz): d (ppm) 22.39. Mass: m/z, 452.458
(Mþꢂ, 22), 313 (68), 250 (100), 91 (15). Anal. Calcd. C23H21N2O4PS:
C, 61.05; H, 4.68; N, 6.19; P, 6.85. Found: C, 60.98; H, 4.62; N, 6.13;
P, 6.83%.
(5E,9E)-16-(4-Chlorophenoxy)-7,8-dihydro-16l5-dibenzo-
[d,l][1,3,7,10,2]dioxadiazaphosphacyclotridecin-16-one
(6d)
Yield: 2.05 g (78%), Color: pale yellow, m.p. 2348C, IR (KBr):
nmax ¼ 1595, 1255, and 965 cmꢀ1 for C N, P O, and
–
–
–
–
C–Htrans, respectively; 1H-NMR (DMSO-d6, 400 MHz): d (ppm)
–
–
(5E,9E)-16-Anilino-7,8-dihydro-16l5-dibenzo[d,l]-
–
8.74 (s, 2H, CH), 7.54–7.98 (m, 12H, Ar–H), 3.90 (s, 4H,
–
N–CH2); 13C-NMR (DMSO-d6, 100 MHz): d (ppm) 164.1 (C-5 and
C-10), 162.3 (C-18 and C-21), 140.2 (C-20), 134.1 (C-50), 133.6 (C-2
and C-13), 131.8 (C-4 and C-11), 131.3 (C-40 and C-60), 127.7 (C-30
and C-70), 122.5 (C-19 and C-20), 119.8 (C-3 and C-12), 118.3 (C-1
and C-14), 56.4 (C-7 and C-8); 31P-NMR (DMSO-d6, 161.9 MHz):
d (ppm): 20.57. Mass: m/z, 440.811 (Mþꢂ, 17), 313 (53), 250
(100), 196 (29), 102 (31), 91 (12). Anal. Calcd. C22H18ClN2O4P:
C, 59.94; H, 4.12; N, 6.35; P, 7.03. Found: C, 59.88; H, 4.05;
N, 6.28; P, 7.00%.
[1,3,7,10,2]dioxadiazaphosphacyclotridecin-16-one (6h)
Yield: 1.90 g (78%), Color: pale yellow, m.p. 1808C, IR (KBr):
nmax ¼ 3366, 1625, 1250, and 969 cmꢀ1 for N–H, C N, P O,
–
–
–
–
–
–
and
C–H
,
respectively; 1H-NMR (DMSO-d6, 400 MHz):
trans
–
d (ppm) 8.74 (s, 2H, CH), 7.41–7.87 (m, 13H, Ar–H), 5.97
–
(m, 1H, NH), 3.89 (s, 4H, N–CH2); 13C-NMR (DMSO-d6, 100 MHz):
d (ppm) 162.9 (C-5 and C-10), 160.0 (C-18 and C-21), 137.0 (C-20),
132.8 (C-4 and C-11), 131.2 (C-2 and C-13), 128.8 (C-40 and C-60),
123.9 (C-19 and C-20), 121.7 (C-50), 121.1 (C-3 and C-12), 120.5 (C-30
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www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
Synthesis and Anti-Oxidant Activity of b-Membered Phosphorus-Macroheterocycles
7
and C-70), 117.1 (C-1 and C-14), 57.3 (C-7 and C-8), 55.1 (C-22);
31P-NMR (DMSO-d6, 161.9 MHz): d (ppm): 20.78. Mass: m/z,
405.384 (Mþꢂ, 26), 313 (70), 250 (100), 91 (23). Anal. Calcd.
C22H20N3O3P: C, 65.18; H, 4.97; N, 10.37; P, 7.64. Found: C,
65.12; H, 4.90; N, 10.33; P, 7.61%.
P O, and C–Htrans, respectively; 1H-NMR (DMSO-d6, 400 MHz):
–
–
–
–
–
–
d (ppm) 8.87 (s, 2H, CH), 7.51–7.92 (m, 11H, Ar–H), 5.96 (m, 1H,
NH), 3.85 (s, 4H, N–CH2); 13C-NMR (DMSO-d6, 100 MHz): d (ppm)
165.3 (C-5 and C-10), 163.4 (C-50), 162.6 (C-18 and C-21), 142.3
(C-20), 132.4 (C-2 and C-13), 130.9 (C-40), 130.6 (C-4 and C-11), 128.3
(C-60), 126.7 (C-30), 125.5 (C-70), 122.6 (C-19 and C-20), 119.2 (C-3 and
C-12), 118.1 (C-1 and C-14), 53.7 (C-7 and C-8); 31P-NMR (DMSO-d6,
161.9 MHz): d (ppm): 23.41. Mass: m/z, 457.818 (Mþꢂ, 10), 438 (25),
422 (20), 402 (35), 364 (20), 328 (35), 313 (62), 309 (55), 250 (100),
144 (38), 119 (32), 102 (26). Anal. Calcd. C22H18ClFN3O3P: C, 57.72;
H, 3.96; N, 7.74; P, 6.77. Found: C, 57.64; H, 3.90; N, 7.69; P, 6.75%.
(5E,9E)-16-(4-Toluidino)-7,8-dihydro-16l5-dibenzo[d,l]-
[1,3,7,10,2]dioxadiazaphosphacyclotridecin-16-one (6i)
Yield: 1.98 g (79%), Color: yellow, m.p. 2308C, IR (KBr): nmax ¼ 3370,
1625, 1245, and 974 cmꢀ1 for N–H, C N, P O, and C–H
,
–
–
–
–
–
–
trans
respectively; 1H-NMR (DMSO-d6, 400 MHz): d (ppm) 8.78 (s, 2H,
–
–
CH), 7.47–7.87 (m, 12H, Ar–H), 5.99 (m, 1H, NH), 3.73 (s, 4H,
N-CH2), 3.28 (s, 3H, CH3); 13C-NMR (DMSO-d6, 100 MHz): d (ppm)
163.2 (C-5 and C-10), 159.0 (C-18 and C-21), 137.2 (C-20), 132.9 (C-4
and C-11), 131.9 (C-2 and C-13), 128.9 (C-40 and C-60), 124.7 (C-50),
124.0 (C-19 and C-20), 121.0 (C-3 and C-12), 120.7 (C-30 and C-70),
118.1 (C-1 and C-14) 57.5 (C-7 and C-8), 22.1 (C-22); 31P-NMR (DMSO-
d6, 161.9 MHz): d (ppm): 24.17. Mass: m/z, 419.410 (Mþꢂ, 12), 313 (68),
250 (100), 91 (9). Anal. Calcd. C23H22N3O3P: C, 65.86; H, 5.29; N,
10.02; P, 7.39. Found: C, 65.79; H, 5.23; N, 9.96; P, 7.35%.
The authors thank Dr. P. Chandra Mohan Reddy, Dept. of Microbiology,
S.V. Degree & PG College, Kadapa, AP, India, for the anti-oxidant activity
studies and also thank BRNS (DAE) BARC (Mumbai) for providing financial
assistance (Sanction No.: 2007/37/46/BRNS/2916; dated: 31-03-2008).
References
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Macrocycles, the Design of Selective Complexing Agents), (Eds.:
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York 1989, vol. 3, p. 337.
(5E,9E)-16-(4-Methoxyanilino)-7,8-dihydro-16l5-dibenzo-
[d,l][1,3,7,10,2]dioxadiazaphosphacyclotridecin-16-one
(6j)
Yield: 2.32 (89%), Color: pale yellow, m.p. 2108C, IR (KBr):
[2] D. J. Cram, Angew. Chem., Int. Ed. Engl. 1988, 27, 1009–1020.
nmax ¼ 3355, 1615, 1255, and 971 cmꢀ1 for N–H, C N,
[3] A. D. Hamilton, A. Muehldorf, S. K. Chang, N. Pant,
S. Goswami, D. Van Engen, J. Incl. Phenom. 1989, 7, 27–38.
–
–
P O, and C–Htrans, respectively; 1H-NMR (DMSO-d6, 400 MHz):
–
–
–
–
–
d (ppm) 8.83 (s, 2H, CH), 7.54–7.97 (m, 12H, Ar–H), 5.98 (m, 1H,
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–
NH), 3.88 (s, 4H, N–CH2), 3.29 (s, 3H, OCH3); 13C-NMR (DMSO-d6,
100 MHz): d (ppm) 164.5 (C-5 and C-10), 162.2 (C-18 and C-21),
158.8 (C-50), 140.1 (C-20), 132.3 (C-2 and C-13), 131.6 (C-4 and C-11),
131.2 (C-40 and C-60), 127.8 (C-30 and C-70), 122.3 (C-19 and C-20),
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31P-NMR (DMSO-d6, 161.9 MHz):
d (ppm) 22.39. Mass: m/z,
435.408 (Mþꢂ, 27), 313 (60), 250 (100), 91 (12). Anal. Calcd.
C23H22N3O4P: C, 63.44; H, 5.09; N, 9.65; P, 7.11. Found: C,
63.36; H, 5.03; N, 9.60; P, 7.08%.
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(5E,9E)-16-(4-Nitroanilino)-7,8-dihydro-16l5-dibenzo[d,l]-
[10] A. J. Tucker, C. B. Knobler, K. N. Trueblood, J. D. Cram, J. Am.
Chem. Soc. 1989, 111, 3688–3699.
[1,3,7,10,2]dioxadiazaphosphacyclotridecin-16-one (6k)
Yield: 2.35 g (87%), Color: dark yellow, m.p. 2508C, IR (KBr):
[11] F. Fages, J. P. Desvergue, F. Kotzbahibert, J. M. Lehn,
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nmax ¼ 3335, 1620, 1258, and 968 cmꢀ1 for N–H, C N, P O,
–
–
–
–
–
–
and
C–H
,
respectively; 1H-NMR (DMSO-d6, 400 MHz):
trans
–
d (ppm) 8.95 (s, 2H, CH), 7.58–7.98 (m, 12H, Ar–H), 6.07 (m, 1H,
–
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NH), 3.83 (s, 4H, N–CH2); 13C-NMR (DMSO-d6, 100 MHz): d (ppm)
164.8 (C-5 and C-10), 162.5 (C-18 and C-21), 161.7 (C-50), 140.8 (C-20),
132.5 (C-2 and C-13), 131.4 (C-4 and C-11), 131.6 (C-40 and C-60), 127.6
(C-30 and C-70), 122.1 (C-19 and C-20), 118.8 (C-3 and C-12), 118.4 (C-1
and C-14), 54.2 (C-7 and C-8); 31P-NMR (DMSO-d6, 161.9 MHz):
d (ppm): 22.94. Mass: m/z, 450.380 (Mþꢂ, 22), 404 (33), 395 (52),
345 (47), 328 (36), 313 (63), 302 (35), 250 (100), 137 (25), 122 (26), 102
(23), 91 (18). Anal. Calcd. C22H19N4O5P: C, 58.67; H, 4.25; N, 12.44;
P, 6.88. Found: C, 58.60; H, 4.18; N, 12.39; P, 6.86%.
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(5E,9E)-16-(3-Chloro-4-fluoroanilino)-7,8-dihydro-16l5-
dibenzo[d,l][1,3,7,10,2]dioxadiazaphosphacyclotridecin-
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16-one (6l)
Yield: 2.30 g (84%), Color: yellow, m.p. 2308C, IR (KBr):
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890.
nmax ¼ 3370, 1630, 1263, and 969 cmꢀ1 for N–H, C N,
–
–
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

8
C. R. Reddy et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–8
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ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com