Synthesis of novel bis-phosphonate derivatives by Pudovik reaction

Article abstract of DOI:10.1080/00397910802005273

Synthesis of novel bis-(3-methyl-5-nitro-2-oxo-2,3-dihydro- 2λ5benzo[1,3,2]oxazaphosphol-2yl)substituted aryl methanes was accomplished by Pudovik reaction. Addition of equimolar quantities of 2-methylamino-4-nitro phenol (1) and ethanol to PCl3 afforded

Full text of DOI:10.1080/00397910802005273

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Synthesis of Novel bis-
Phosphonate Derivatives by
Pudovik Reaction
B. Hari Babu a , K. Srinivasulu a , B. Venu Babu b , R.
Srinivas b & C. Naga Raju a
a Department of Chemistry, Sri Venkateswara
University, Tirupati, India
b Divi's Laboratory, Hyderabad, India
Published online: 28 Aug 2008.
To cite this article: B. Hari Babu , K. Srinivasulu , B. Venu Babu , R. Srinivas
& C. Naga Raju (2008): Synthesis of Novel bis-Phosphonate Derivatives by
Pudovik Reaction, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:17, 2941-2949
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Synthetic Communications1, 38: 2941–2949, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802005273
Synthesis of Novel bis-Phosphonate Derivatives
by Pudovik Reaction
B. Hari Babu,1 K. Srinivasulu,1 B. Venu Babu,2 R. Srinivas,2
and C. Naga Raju1
1Department of Chemistry, Sri Venkateswara University, Tirupati, India
2Divi’s Laboratory, Hyderabad, India
Abstract: Synthesis of novel bis-(3-methyl-5-nitro-2-oxo-2,3-dihydro-2k5
benzo[1,3,2]oxazaphosphol-2yl)substituted aryl methanes was accomplished by
Pudovik reaction. Addition of equimolar quantities of 2-methylamino-4-nitro
phenol (1) and ethanol to PCl3 afforded cyclic condensation product. On reaction
with respective aldehydes followed by treatment with phosphorus(III) mono-
chloride of 1, and on subsequent reaction at reflux temperature, this rearranged
from P(III) to P(V) state. Their structures were determined by IR, 1H NMR,
13C NMR, 31P NMR, and mass spectral data.
Keywords: 2-Methyl amino-4-nitrophenol, phosphorus trichloride, pudovik
reaction, triethylamine
INTRODUCTION
bis-Phosphonates are widely used drugs for the treatment and prevention
of excessive osteoclast-mediated bone resorption associated with osteo-
porosis, Paget’s disease, tumor-induced osteolysis, and hypercalcemia.[1–5]
In recent years, bisphosphonates have also been found to have antipara-
sitic,[6–9] antibacterial,[10] herbicidal,[11] and anticancer properties.[12–14]
Zhang et al.[15] synthesised nitrogen-containing bisphosphonates and
tested for their activity in inhibiting the growth of three human cell
lines. They found the most active species was a tetrakispivaloylmethyl
Received November 11, 2007.
Address correspondence to Dr. C. Naga Raju, Associate Professor, Department
of Chemistry, Sri Venkateswara University, Tirupati 517 502, Andhra Pradesh,
India. E-mail: harisvu9@yahoo.co.in
2941

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B. H. Babu et al.
(POM) ester, having an (average) IC50 of 6.8 mM. The most potent
bis-phosphonates are found[16] in the series containing a heteroaromatic
moiety (with at least one nitrogen atom), which is linked via a single
methylene group to the geminal bis-phosphonate unit. Zoledronic acid[16]
is the most potent derivative, and it has an ED50 of 0.07 mg=kg. Recently,
we turned our attention to nitrogen-containing bis-phosphonates as
part of our ongoing research program, and in this direction we have
synthesised the novel bis-phosphonates and characterized them by
spectral data.
RESULTS AND DISCUSSION
Synthesis of novel bis-(3-methyl-5-nitro-2-oxo-2,3-dihydro-2k5 benzo [1,3,2]-
oxazaphosphol-2yl)substituted aryl methanes (6a–h) were accomplished by
Pudovik reaction (see Scheme 1). Addition of an equimolar amount of 2-
methylamino-4-nitro phenol (1) and ethanol to PCl3 in toluene afforded cyc-
lic condensation product 2. It is a better procedure to get 3-methyl-5-nitro-
3H-benzo[1,3,2]-oxazaphosphole 2-oxide(2) when compared to the method
adopted for the reaction of 1 directly with PCl3, followed by addition of
water in which an acid-catalyzed reversible reaction occurs, giving back
the starting compounds.[17] The compound 2 was treated with respective
aldehydes 3a–h to get corresponding bis-(3-methyl-5-nitro-2-oxo-2,3-dihy-
dro-2k5benzo[1,3,2]-oxazaphosphol-2yl) substituted aryl methanols (4a–h).
Scheme 1.

Novel bis-Phosphonate Derivatives
2943
Reaction of 4a–h with 2-chloro-3-methyl-5-nitro-3H-benzo[1,3,2]-oxaza-
phosphole (5) in toluene at reflux temperature for about 6 h rearranged it
from P(III) to P(V) state[17] and afforded the title compounds (6a–h). The
structures of all the compounds were confirmed by elemental analysis, multi-
NMR, and fast atom bombardment (FAB) mass spectrometry. The com-
pounds 6a–h were obtained as isomeric products. Their separation could
not be effected by fractional crystallization. A few carbon NMR signals were
split into two signals because of the presence of diastereoisomers in the sam-
ple.[18] The presence of two forms in the solution state is further evidenced by
the presence of two phosphorus chemical shifts in the 31P NMR spectra of all
the synthesized compounds (6a–h).
All the title compoundsshowed IR absorption bands[19–21] in the regions
=
1294–1279(P O), 1255–1249 [OꢀCofPꢀOꢀC(aromatic)],and935–930[PꢀO
of PꢀOꢀC(aromatic)] cmꢀ1. In the 31P NMR, all the compounds (6a–h) exhib-
ited two distinct 31P chemical shifts (Table 1) for the two phosphorus (Pa and
Pb) atoms present in them. This indicates their high magnitude of nonequi-
valence, which might arise because of their existence in two different isomers,
a result of the restricted rotation between them.[22]
The protons of the aromatic moiety of the title compounds showed
multiplets at d 8.56–6.91. The bridged methyne (PꢀCHꢀP) proton reso-
nated as a triplet because of the coupling with phosphorous in the region
of 2.86–2.81 ppm. The chemical shifts of other protons are observed in the
expected regions for the compounds 6a–h (see Table 2). Interpretation of
the 13C NMR data (see Table 3) was based on additivity rules, computed
chemical shifts of starting compound 1, carbon couplings with phos-
phorus, and intensity of signals. The oxygen bearing C-8 and 80 and nitro-
gen bearing aromatic carbons C-5 and 50 and C-9 and 90 resonated as
doublets in the downfield region at d 152.3–145.9 (2Jpoc ¼ 6.8–6.1),
141.8–141.0 (d, J ¼ 6.3–5.8 Hz), and 131.5–130.2 (2Jpoc ¼ 5.7–5.0),
respectively. The chemical shifts of C-4 and 40, C-6 and 60, and C-7 and
70 appeared as low intensity signals at d 109.5–108.1, 114.1–113.2, and
117.5–115.3, respectively. The signal in the region d 29.5–29.1 was
ascribed to N-containing methyl carbon. The bridged chiral carbon in
these compounds gave the signal in the region d 30.5–30.1. Mass spectral
data for 6a, 6e, and 6h were recorded (Table 2). All the three compounds
exhibited M þ 1 and Mþ . ions in their mass spectra. Multinuclear NMR
and mass spectral data conclusively confirm the structures of 6a–h.
EXPERIMENTAL
The melting points were determined on a Mel-Temp apparatus and were
left uncorrected. Elemental analyses were performed by the Central Drug

2944

2945

2946
B. H. Babu et al.
Table 3. 13C NMR dataa of the compounds 6a–e
Carbon
data
6a
6b
6c
6d
6e
C-4&40 109.5
108.1
108.3
108.1
108.5
C-5&50 141.0 (d, 5.8) 141.8 (d, 6.3) 141.4 (d, 6.1) 141.5
141.6 (d, 6.1)
113.3
117.3
C-6&60 114.1
C-7&70 115.3
113.3
117.1
113.8
117.5
113.2
117.1
C-8&80 152.3 (d, 6.8) 145.1 (d, 6.1) 147.1 (d, 6.5) 147.0 (d, 6.5) 147.1 (d, 6.6)
C-9&90 131.1 (d, 5.4) 130.2(d, 5.0) 131.5(d, 5.7) 131.2(d, 5.4) 131.5(d, 5.6)
P-CH-P 30.1
N-CH3
C-100
30.5
29.1
30.2
29.1
30.1
29.3
30.1
29.4
29.3
138.3 (d, 7.2) 135.5 (d, 6.9) 135.1 (d, 6.4) 130.1 (d, 6.1) 145.8 (d, 7.9)
C-200&600 129.5
C-300&500 128.1
130.5
128.5
130.7
129.1
129.4
135.1
130.2
115.8
159.3
124.8
150.1
C-400
125.4
—
aRecorded in CDCl3. The chemical are shifts in ppm and J (Hz)in parentheses.
Research Institute, Lucknow, India. All IR spectra were recorded as KBr
1
pellets on a Perkin-Elmer 1430 unit; H, 13C, and 31P NMR spectra were
recorded on an AMX 400-MHz spectrometer, operating at 400 MHz for
1H, 100 MHz for 13C, and 161.9 MHz for 31P as solutions in CDCl3. The
chemical shifts were referenced to TMS (1H and 13C) and 85% H3PO4 (31P).
Synthesis of bis-(3-Methyl-5-nitro-2-oxo-2,3-dihydro-2k5 benzo[1,3,2]-
oxazaphosphol-2yl)phenylmethanes (6a)
It is obtained in four steps. In step 1, 2-methylamino-4-nitrophenol
(1, 0.34 g, 0.002 mol) was dissolved in 25 mL of dry toluene, and ethanol
(0.09 g, 0.002 mol) was added to this. The mixture was cooled to 5–10ꢁC.
Table 4. Mass spectral data of the compounds 6a, 6e, and 6h
Compound
m=z (relative abundance, %)
.
6a
517 (M þ 1, 28), 516 (M þ , 31), 502 (12), 493 (18), 471 (11),
465 (13), 433 (21), 431 (38), 408 (27), 395 (21), 388 (17), 354
(9), 313 (14), 294 (8), 251 (15), 225 (11), 213 (100).
.
6e
6h
533 (M þ 1, 21), 532 (M þ , 29), 516 (11), 501 (51), 471 (28),
438 (11), 415 (14), 407 (19), 398 (24), 365 (100), 331 (34), 317
(21), 287 (18).
.
518 (M þ 1, 31), 517 (M þ , 18), 507 (15), 493 (11), 481 (9), 428
(32), 403 (13), 391 (100), 384 (8), 363 (21), 318 (20), 291 (5).

Novel bis-Phosphonate Derivatives
2947
To this phosphorus, trichloride (0.27 g, 0.002 mol) was added dropwise in
10 mL of dry toluene. The reaction mixture was stirred at 25ꢁC for 4 h.
Finally the reaction mixture was warmed on the steam bath to complete
the removal of the by-products. 3-Methyl-5-nitro-3H-benzo[1,3,2]oxaza-
phosphole 2-oxide (2) was obtained after removal of toluene at reduced
pressure as white crystalline solid, mp 110–112ꢁC.
In step 2, benzaldehyde (3a, 0.11 g, 0.001 mol) and trietylamine
(0.50 g, 0.005 mol) in dry toluene was added at 5–8ꢁC to 2 (0.21 g,
0.001 mol) in toluene, and the mixture was stirred for 4 h to get
3-methyl-5-nitro-2-oxo-2,3-dihydro-2k5benzo [1,3,2]-oxazaphosphol-2yl)
phenylmethanol (4a). In step 3, compound 1 was treated with PCl3 in
toluene under a nitrogen atmosphere in the presence of triethylamine
to get 5.
In step 4, to the cold (5–7ꢁC) solution of 4a (0.29 g, 0.001 mol) and
triethylamine (0.1 g, 0.001 mol) taken in a new reaction flask in toluene,
5 (0.38 g, 0.001 mol) was added. The temperature was slowly raised to
50ꢁC. Stirring was continued for 6 h and then at refluxing temperature
for 6 more h. Triethylamine hydrochloride was separated by filtration,
and the solvent from the filtrate was removed under reduced pressure.
The residue was recrystallized from ethanol to afford the title compound
6a. The title compounds 6b–h were prepared by adopting the same
procedure.
ACKNOWLEDGMENTS
The authors express thanks to the director of the Central Drug Research
Institute, Lucknow, and Indian Institute of Science, Bangalore, for the
elemental analyses and spectral data.
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