Synthesis and antioxidant properties of novel 1,3,2-oxazaphospholanes incorporating 1,2-dihydropyridines

Article abstract of DOI:10.1080/10426500903544306

Novel chiral 1,3,2-oxazaphospholane-2-sulfides incorporating a dihydropyridine ring have been synthesized via phosphorylation of 2-aminopyridinium salts, followed by in situ oxidation and cyclocondensation with 2-(alkylamino)ethanol. Cyclic organothiophos

Full text of DOI:10.1080/10426500903544306

Phosphorus, Sulfur, and Silicon, 185:2212–2219, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903544306
SYNTHESIS AND ANTIOXIDANT PROPERTIES OF NOVEL
1,3,2-OXAZAPHOSPHOLANES INCORPORATING
1,2-DIHYDROPYRIDINES
Vijaya Kabra,1 Sonia Sharma,1 Neelima Gupta,1
Ashok Kumar,2 and Priyadarshi Meena2
1Department of Chemistry, University of Rajasthan, Jaipur, India
2Department of Zoology, University of Rajasthan, Jaipur, India
Novel chiral 1,3,2-oxazaphospholane-2-sulfides incorporating a dihydropyridine ring have
been synthesized via phosphorylation of 2-aminopyridinium salts, followed by in situ oxida-
tion and cyclocondensation with 2-(alkylamino)ethanol. Cyclic organothiophosphates thus
obtained have been screened for their antioxidant properties.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Antioxidant property; 1,2-dihydropyridine; 1,3,2-oxazaphospha heterocycles;
phospholane ring system
INTRODUCTION
In this article, we report the synthesis and characterization of 1,3,2-
oxazaphospholane-2-sulfides incorporating a dihydropyridine ring. In our previous
publications, we have utilized substituted pyridinium salts, with active terminal hydrogen
atoms, as synthones for various organophosphorus derivatives having a phosphorus in
different coordination states.1–5 Now, a cyclic 1,3,2-oxazaphospholane ring has been
formed by cyclocondensation of a phosphorylated intermediate with an appropriate
binucleophile, i.e., 2-(alkylamino)ethanol.
Both dihydropyridine6,7 and 1,3,2-O,N,P heterocyclic derivatives8,9 are highly valued
due to their use as starting materials and intermediates in synthetic organic chemistry and
their importance in biological systems. Several review articles have highlighted the impor-
tance of dihydropyridine derivatives as “active hydrogen store” in cell systems, as they are
responsible for a number of biological reactions as antioxidants.6,7 In medicinal chemistry,
Received 13 October 2009; accepted 7 December 2009.
We are highly grateful to the UGC, New Delhi, India, for financial assistance; CDRI, Lucknow, India, for
mass spectra; and the Department of Chemistry, University of Rajasthan, for providing necessary facilities.
Address correspondence to Vijaya Kabra, Department of Chemistry, University of Rajasthan, Jaipur 302004,
India. E-mail: kabrasg@hotmail.com
2212

NOVEL 1,3,2-OXAZAPHOSPHOLANES
2213
attachment of dihydropyridine unit to a biomolecule is found to enhance lipophilicity of
the conjugate, thereby improving drug delivery at the site of the reaction.7
The importance of 1,3,2-O,N,P heterocycles has attracted the interest of synthetic
organic chemists as well as biochemists due to their valuable pharmacological properties
and potential for synthetic applications.8 Different synthetic strategies for five- and six-
membered systems incorporating 1,3,2-O,N,P moiety are available in the literature.9–11
Reddy et al.11 and Gazaliev et al.12 have addressed the conformational aspects of oxaza-
phosphorinane and phospholane ring systems. The importance of these heterocyclic units
is evident by their presence in a number of alkylating anticancer drugs,8,9 pesticides,13
and antimicrobial agents.11 Such compounds are also known to posses matrix metallopro-
teinase inhibitory14,15 and synergizing activities.16 They have been used in the synthesis of
phospholipids17 and asymmetric synthesis.10,18
We have investigated antioxidant activity of the synthesized 1,3,2-oxazaphospholane
derivatives, and a comparison has been made with ascorbic acid, which is a known non-
enzymatic antioxidant by adopting a standard DPPH (2,2-diphenyl-1-picrylhydrazyl free
radical) method.19
RESULTS AND DISCUSSION
N-Alkyl-2-aminopyridinium halides1–5 were phosphorylated by using one equivalent
of phosphorus trichloride in the presence of two equivalents of triethylamine at 0–5◦C in a
2:1 mixture of methylene chloride and toluene under nitrogen atmosphere to generate the
corresponding iminodichlorophosphines 2.20 The intermediate 2 was oxidized in situ with
elemental sulfur (1/8 equivalent) at ambient temperature, which generated the correspond-
ing cycloiminylidenamidothiophosphoryl dichloride 3, incorporating phosphorus in more
stable tetracoordinated state. Cycloiminylidenamidothiophosphoryl dichloride 3, upon nu-
cleophilic substitution of the labile chlorine atoms with a bifunctional nucleophile, such as
2-(alkylamino)ethanol (Rꢁ = CH3, C2H5), furnished 2-(N-alkylpyridin-2ꢁ-ylidenamido)-3-
alkyl-[1,3,2]oxazaphospholane-2-sulfide 4 (Scheme 1).
The products are white crystalline solids with sharp melting points, are stable under
nitrogen atmosphere, and have been well characterized through elemental analysis; 1H, 31P,
and 13C NMR spectroscopy (Table I); and mass spectrometry.
NMR Studies
The progress of the reaction progress was monitored using 31P NMR spectroscopy.
After the addition of sulfur and N-(alkylamino)ethanol, the 31P NMR signal which initially
appeared at δ146.5–158.3 ppm corresponding to the tri-coordinated iminodichlorophos-
phine 2 shifted to the higher frequency region of δ69.2–77.1 ppm, which is characteristic
for tetracoordinated phosphorus,21 indicating the completion of the reaction and the forma-
tion of 4a–f.
Cyclic oxazaphospholane derivatives 4 have been further characterized by 1H NMR
spectroscopy (Table I). Due to the presence of chiral phosphorus at the 2-position, methy-
lene protons at the 4 and 5 positions of the oxazaphospholane ring become diastereotopic
and an ABCD spin system (Scheme 1) is observed. Due to the higher electronegativity of
oxygen, the signals of the AB part in the range of δ4.2–4.3 ppm have been assigned to
O CH2 protons, and the signals in the higher frequency region of δ3.0–3.6 ppm have been
assigned to N CH2 protons as CD part of the spin system. Signals for each individual

2214
V. KABRA ET AL.
PCl +
2Et3N
3
Cl
Cl
+
N
P
N
N
NH2
CH2Cl2 + Toluene
0-5oC
-
CH2R
X
CH2R
2
1
1/8 S8
R'
HN
4'
1'
R'
3'
2'
N
5'
6'
S
P
HD
3
HO
S
N
2
4
Cl
HC
HB
N
+ CH Cl
2Et3N
0-50C
N
P
2
2
N
O
1
CH2R
5
Cl
CH2R
HA
4
3
4
a
b
c
d
e
f
R
H
C6H5 CO2CH3 CO2C2H5
CH3 CH3
H
C6H5
R' CH3 CH3
C2H5 C2H5
Scheme 1
proton appear as doublet of double doublets (ddd) due to geminal coupling of 12.9–18.3
Hz and vicinal couplings of 5.4–7.5 Hz with cis proton and 6.2–10.8 Hz with trans proton,
except O CH2 protons of 4a and 4f, where additional coupling with phosphorus (3JPH
=
6.1–6.3 Hz) is also observed (Table I). However, in the case of 4d and 4e, O CH2 protons
appear as complex multiplet. Moreover, in the case of 4e,f, N3-methylene protons also
become diastereotopic, giving rise to an ABX3 spin system which shows additional three
bond coupling with phosphorus (3JPH = 7.8–10.8 Hz) (Table I). N3-CH3 protons in 4a–d
appear as doublet (3JPH = 11.4–13.2 Hz) at δ2.6–2.7 ppm. In the case of 4c,d, long dis-
tance–induced diastereotopicity is observed when N1ꢁ-CH2 protons become anisochronous,
giving rise to two doublets in the range of δ4.5–4.7 ppm (2JHH = 12.3–16.2 Hz).
The signals in the 13C NMR spectra have been assigned according to chemical shift
(Table I). C-4 and C-5 carbons of the oxazaphospholane ring appear at δ40.8–55.8 ppm
and δ50.0–65.4 ppm (2JPC = 2.5 Hz), respectively. N3-methyl and ethyl carbon atoms
give signals in the range of δ14.2–46.7 ppm (2JPC = 10.5 Hz). The N1ꢁ-methylene carbon
absorbs at δ49.9–64.9 ppm, while the N1ꢁ-CH3 carbon absorbs at δ64.8–64.9 ppm. All
other carbon atoms appear in the expected regions (Table I).
Mass Spectrum
The mass spectrum of one representative compound 4b was also recorded. Molecular
ion peak M+ (m/z = 319.36, 2%), a base peak M + 1 (m/z = 320.12, 100%), M + 2
(m/z = 321.13, 19%), and M + 3 (m/z = 322.12, 6%) were observed due to the possible
acceptance of one proton by different heteroatoms present in the molecule. Other significant

2215

2216

NOVEL 1,3,2-OXAZAPHOSPHOLANES
2217
peaks were observed at 304.14 (30%), 288.15 (24%), 186.13 (6%), 185.13 (49%), 115.10
(3%), 99.11 (17%), and 61.06 (10%).
BIOACTIVITY
The world of free radicals in biological systems was first explored by Denham
Harman, who proposed the role of free radicals in the aging process.22 This work gradually
triggered intense research into the field of free radicals in biological systems. The harmful
effects of free radicals are termed as oxidative and nitrosative stress,23,24 which develop due
to the deficiency of enzymatic and nonenzymatic antioxidants. The antioxidant property
of a compound is related to its ability to scavenge deleterious free radicals and also to
modulate cell signaling pathways.25
Synthesized phospholane derivatives have been screened for antioxidant activity
by adopting a standard DPPH technique,19 where vitamin C, a known non enzymatic
antioxidant, has been selected as a standard. Results have been presented in Figure S1 (see
the Supplemental Materials, available online).
CONCLUSION
Novel 1,3,2-oxazaphospholane derivatives incorporating 1,2-dihydropyridine ring
have been synthesized and well characterized. The presence of a chiral phosphorus center
induces distereotopicity in the methylene groups of the oxazaphospholane ring as well as
pyridinic N-methylene substituent. Upon screening their antioxidant properties, moderate
activity in comparison to ascorbic acid has been observed. Compounds 4a and 4c, which
have larger number of methyl substitutents, show increased activity.
EXPERIMENTAL
The synthesized products are stable in an inert atmosphere and are sensitive towards
moisture and atmospheric oxygen. Solvents were carefully dried prior to use, and fine
chemicals were used as obtained from Aldrich, Lancaster, and Merck. All the reactions
were carried out and products stored under pure dry nitrogen atmosphere. Melting points
were determined by capillary method and are uncorrected. Elemental analyses were carried
out on a Heraeus Carlo Erba1108 analyzer. NMR spectra were recorded on a Jeol AL300
31P NMR at 121.50 MHz (Obset 156 KHz) using 85% H3PO4 as an external standard, and
1H NMR spectra at 300.4 MHz (Obset 130 KHz) using TMS as internal reference. The
DART-MS was recorded on a Jeol AccuTOF JMS-T100LC mass spectrometer having a
direct analysis in real time (DART) source, and the antioxidant property was determined
by the DPPH method.19 N-Alkyl-2-aminopyridinium halides 1a–f were synthesized by
reported methods1–5 and were used without recrystallization.
Synthesis of 2-(N-Alkylpyridin-2ꢀ-ylidenamido)-3-alkyl-
[1,3,2]oxazaphospholane-2-sulfides 4a–f
To a well stirred solution of N-alkyl-2-aminopyridinium halides (15 mmol) in a mix-
ture of methylene chloride and toluene (40 mL + 20 mL), PCl3 (15 mmol) was added,
followed by the dropwise addition of triethylamine (30 mmol) at 0–5◦C. After stirring the re-
sulting mixture for 24 h, sulfur powder (15 mmol) was added, and stirring was continued for

2218
V. KABRA ET AL.
24 h, after which triethylamine (30 mmol) and a solution of 2-(ethyl/methylamino)ethanol
(15 mmol) in methylene chloride (20 mL) were added dropwise at 0–5◦C. The stirring was
further continued for another day. After that, the solvent was removed in vacuo, and the
residue was extracted with diethylether (2 × 25 mL) and kept in refrigerator. The white
solid thus separated was filtered and dried.
Determination of DPPH Radical Scavenging Activity
The antioxidant activity of the compounds on the basis of the scavenging activity
of the stable DPPH was determined by the method described by Braca et al.19 with slight
modification. The 0.1 mL (1 mg/mL) compound was added to 3 mL of 0.1 M DPPH in
methanol.
Absorbance at 517 nm was read after 30 min incubation and% inhibition of activity
was calculated as% inhibition = [(Ao–Ae)/Ao] × 100 (Ao = absorbance without extract,
Ae = absorbance with extract). Ascorbic acid was used as antioxidant standard. The
statistically evaluated results and standard deviation have been presented in Figure S1
(Supplemental Materials).
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