Synthesis and antimicrobial activity of bisphosphonates

Article abstract of DOI:10.3184/030823409X439744

Dimethyl [(substitutedphenyl)(6-oxo6λ5dibenzo[d,f][1,3,2] dioxaphophepin-6-yl)methyl]phosphonates (5a-j) were synthesised through a three step process involving preparation of dimethyl hydroxy(substitutedphenyl) methylphosphonates (4a-j) and their reactio

Full text of DOI:10.3184/030823409X439744

258 RESEARCH PAPER
APRILꢃꢀꢆꢇꢉ±ꢆꢍꢅ
JOURNAL OF CHEMICAL RESEARCH 2009
Synthesis and antimicrobial activity of bisphosphonates
M. Veera Narayana Reddya, K.R. Kishore Kumar Reddya, C. Bhupendra Reddya, B. Siva kumarb,
C. Suresh Reddya* and C. Devendranath Reddya
aDepartment of Chemistry, Sri Venkateswara University, Tirupati-517 502, India
bDepartment of nano Materials, Graduate School of Science and Technology, Shizuoka University, Hamamatsu, 432-8561, Japan
Dimethyl [(substitutedphenyl)(6-oxo6O5dibenzo[d,f][1,3,2]dioxaphophepin-6-yl)methyl]phosphonates (5a–j) were
synthesised through a three step process involving preparation of dimethyl hydroxy(substitutedphenyl)methyl-
phosphonates (4a–j) and their reaction with 6-bromodibenzo[d,f][1,3,2]dioxaphosphepine (2) in dry toluene in the
presence of triethylamine at 50–60°C. Tetramethylguanidine (TMG) as a catalyst was found to increase the yields
and purity of the products. These compounds were characterised by IR, 1H, 13C, 31P NMR and mass spectral data
found to possess higher antimicrobial activity then the standards.
Keywords: bisphosphonates, 2,2'-dihydroxybiphenyl, D-hydroxy phosphonates, anti microbial activity
Bisphosphonates (BPS) are carbon analogues of naturally
occurring pyrophosphate (PP) and are a major class of drugs
for the bone disease.1 Besides their bone antiresorptive
properties, several of them are also potent growth inhibitors
of some pathogenic trypanosomatids.2 Most of the antiviral
compounds that are currently used for the treatment of the
+HUSHVꢀ VLPSOH[ꢀ YLUXVꢀ ꢁ+69ꢂꢃꢀ +XPDQꢄ,PPXQRGH¿FLHQF\ꢀ
Virus (HIV), Hepatitis B Virus (HBV), Varicella Zoster Virus
(VZV) and Cytomegalovirus (CMV) infections their acyclic
nucleotide analogues.3-6 Recent studies have shown that anti-
tumour properties of BPS included inhibition of tumour cell
proliferation and invasion, adhesion to bone, and angiogenesis.7
These classes of chemical substances are presently undergoing
intensive research for cancer therapy and viral diseases
management.8,9 Result on the compounds studied so for
UHYHDOHGꢀWKDWꢀWKHꢀDEVROXWHꢀFRQ¿JXUDWLRQꢀVLJQL¿FDQWO\ꢀLQÀXHQFHVꢀ
their biological potency.10 A few of the derivates of BPS
also activate the JG T cell population which shows potential
cytotoxic activity towards a broad spectrum of tumours.11
In view of this, dimethyl [substitutedphenyl-6-oxo-6O5-
dibenzo[d,f][1,3,2]dioxaphosphepin-6-yl)methyl]phosphonates
(5a–j) were synthesised expecting them to possess broad
spectrum of bioactivity.
of doublet15 at Gꢀꢇꢎꢇꢅ±ꢍꢎꢈꢆꢀꢁGꢃꢀJꢀ ꢀꢊꢎꢉ±ꢈꢅꢎꢌꢀ+]ꢂꢀGXHꢀWRꢀLWVꢀ
coupling with phosphorus. The methoxy group protons of
the dimethylphosphonate moiety resonated as two distinct
doublets in the range of Gꢀꢏꢎꢍꢈ±ꢏꢎꢊꢈꢀꢁGꢃꢀJꢀ ꢀꢊꢎꢏꢀ+]ꢂꢀDQGꢀꢏꢎꢈꢇ±
3.59 (d, J = 9.8 Hz) indicating their non equivalence.16
7KHꢀ 3±&±+ꢀ FDUERQꢀ FKHPLFDOꢀ VKLIWꢀ VLJQDOꢀ DSSHDUHGꢀ DVꢀ
DꢀGRXEOHWꢀLQꢀWKHꢀUDQJHꢀꢇꢆꢎꢉꢇ±ꢇꢌꢎꢏꢋꢀSSPꢀꢁGꢃꢀ1J3±&ꢀ ꢀꢈꢍꢏꢎꢅ±
167.42 Hz).The methoxy carbon of dimethylphosphite group
UHVRQDWHGꢀDVꢀDꢀGRXEOHWꢀDWꢀꢇꢏꢎꢈꢍ±ꢇꢋꢎꢏꢊꢀSSPꢀꢁGꢃꢀJ ꢀꢍꢎꢅ±ꢍꢎꢍꢀ+]ꢂꢎ15
Two distinct 31P signals17 appeared one at Gꢀ ꢆꢅꢎꢈꢇ±ꢆꢊꢎꢈꢅꢀ
(P = O phosphonates), and other at Gꢏꢎꢅꢅ±ꢊꢎꢆꢍꢀ ꢁ3ꢀ ꢀ 2ꢀ
dioxaphosphepine) for them. The mass spectra of compounds
4a, 4e, 4f and 4j showed their respective molecular ion peaks
in the expected m/z mass values.
Experimental
All melting points were determined in open capillary tubes on mel-
temp apparatus and are uncorrected. Micro-analyses were performed
at the Central Drug Research Institute, Lucknow, India. IR spectra
(Jmax in cm-1) were recorded as KBr pellets on a Perkin-Elmer 283
1
double beam spectrophotometer. H, 13C and 31P NMR spectra were
recorded on AMX 400 MHz spectrophotometer operating at 400
MHz for 1H 100 MHz for 13C and 161.9 MHz for 31P using DMSO-
d6 as solvent. The 1H and 13C NMR chemical shifts were referenced
to TMS, and 31P chemical shifts to 85% H3PO4. FAB mass spectra
were recorded on a Jeol AX 102 DA/600 mass spectrometer using
argon/xenon (6 keV, 10 mA) as the LCMS.
Results and discussion
The synthesis of title compounds (5a–j) involves cyclisation
of 2,2'-dihydroxy biphenyl (1) with phosphorus tribromide
at 0°C under inert and dry conditions in the presence of
triethylamine in toluene to afford the corresponding 6-
bromodibenzo[d,f][1,3,2]dioxaphosphepine (2). Various
aromatic aldehydes, (3a–j), react with dimethyl phosphite at
ꢅ±ꢆꢇ°C in 1 h under inert and dry conditions in the presence
of 10 mole% of tetramethyl guanidine (TMG) in dry toluene to
afford the corresponding dimethyl hydroxy substituted phenyl
methyl phosphonates (4a–j).12 The reaction between (2) and
dimethyl hydroxy (substitutedphenyl)methylphosphonates
(4a–jꢂꢀLQꢀGU\ꢀWROXHQHꢀLQꢀWKHꢀSUHVHQFHꢀRIꢀWULHWK\ODPLQHꢀDWꢀꢇꢅ±
60°C for 5 h afforded (5a–j)13 in good yields. The progress
of the reaction was monitored by TLC. TMG acts as an
effective catalyst in this reaction and it can be easily recycled.
The chemical structures of (5a–jꢂꢀZHUHꢀFRQ¿UPHGꢀE\ꢀHOHPHQWDOꢀ
analysis, IR, 1H, 13C, 31P NMR and mass spectra. Compounds
(5a–j) exhibited characteristic IR stretching frequencies
LQꢀ WKHꢀ UHJLRQVꢀ ꢈꢆꢇꢅ±ꢈꢆꢉꢊꢃꢀ ꢈꢆꢊꢉ±ꢈꢆꢆꢉꢃꢀ ꢋꢌꢍ±ꢋꢋꢅꢀ FP-1 for
3ꢀ ꢀ2ꢀꢁSKRVSKRQDWHVꢂꢃꢀ3ꢀ ꢀ2ꢀꢁSKRVSKHSLQHꢂꢀDQGꢀ3±&(aliphatic)
respectively.14
Preparation
of
dimethyl
[(6-oxo-6O5-dibenzo[d,f][1,3,2]
dioxaphosphepin-6-yl)(phenyl) methyl]phosphonate 5a; general
procedure
A solution of slight excess of phosphorus tribromide (1.35 g,
0.005 mole) in dry toluene (25 mL) was added dropwise to a well
stirred solution of 2,2'-dihydroxybiphenyl (1) (0.930 g, 0.005 mole)
and triethylamine (1.4 g 0.01 mole) in dry toluene (20 mL) at 0°C.
After the addition, the temperature of the reaction mixture was
VORZO\ꢀUDLVHGꢀDQGꢀNHSWꢀDWꢀꢆꢇ±ꢏꢅ°C for 2 hours. The reaction progress
ZDVꢀPRQLWRUHGꢀE\ꢀ7/&ꢀDQDO\VLVꢎꢀ7KHꢀPL[WXUHꢀZDVꢀ¿OWHUHGꢀWRꢀUHPRYHꢀ
WULHWK\ODPLQHꢀ K\GUREURPLGHꢀ DQGꢀ WKHꢀ ¿OWUDWHꢀ ZDVꢀ URWDHYDSRUDWHO\ꢎꢀ
The residue (2) was used for the next step without further
SXUL¿FDWLRQꢎꢀ 7Rꢀ Dꢀ VWLUUHGꢀ VROXWLRQꢀ RIꢀ EHQ]DOGHK\GHꢀ ꢁ3a) (0.502 g,
0.005 mole). dimethhyl phosphite (0.458 g, 0.005 mole) in anhydrous
toluene (20 mL) was added dropwise and then TMG (10 mol%)
ZDVꢀ DGGHGꢀ DQGꢀ WKHꢀ UHDFWLRQꢀ ZDVꢀ FRQWLQXHGꢀ DWꢀ ꢅ±ꢆꢇ°C for 1 h.
The progress of the reaction was monitored by TLC analysis. The
¿OWUDWHꢀ ZDVꢀ URWDHYDSRUDWHGꢎꢀ 7KHꢀ UHVLGXHꢀ ꢁ4a)12 in toluene (20 mL)
and triethylamine (0.005 mole) at 0°C was added to the cold solution
of 2 in dry toluene,(20 mL) dropwise with effective stirring. After the
addition, the temperature of the reaction mixture was slowly raised
DQGꢀNHSWꢀDWꢀꢇꢅ±ꢍꢅ°C for 5 h. The progress reaction was monitored
E\ꢀ7/&ꢀDQDO\VLVꢎꢀ$IWHUꢀFRROLQJꢀWRꢀURRPꢀWHPSHUDWXUHꢃꢀLWꢀZDVꢀ¿OWHUHGꢀWRꢀ
UHPRYHꢀWULHWK\ODPLQHꢀK\GUREURPLGHꢎꢀ7KHꢀ¿OWUDWHꢀZDVꢀURWDHYDSRUDWHGꢎꢀ
7KHꢀUHVLGXHꢀZDVꢀSXUL¿HGꢀE\ꢀFROXPQꢀFKURPDWRJUDSK\ꢀRQꢀVLOLFDJHOꢀꢁꢉꢅ±
ꢈꢆꢅꢀPHVKꢂꢀXVLQJꢀSHWUROHXPꢀHWKHU±HWK\ODFHWDWHꢀꢁꢋꢐꢏꢂꢀDVꢀHOXHQWꢎꢀ,WꢀZDVꢀ
recrystallised from 2-propanol to afford pure (5a) with (70%) yield,
PꢎSꢎꢀꢈꢌꢍ±ꢈꢌꢉ°C. All the other compounds (5b–j) were prepared by
adopting the same procedure.
The aromatic protons (5a–j) showed a complex multiplet at
Gꢀꢍꢎꢋꢍ±ꢉꢎꢈꢅꢎꢀ7KHꢀ3±&±+ꢀSURWRQꢀVLJQDOꢀDSSHDUHGꢀDVꢀDꢀGRXEOHWꢀ
* Correspondent. E-mail: csrsvu@gmail.com

JOURNAL OF CHEMICAL RESEARCH 2009 259
O
O
P
PBr3
OH Toluene, TEA
Toluene, TMG
0-25 °C, 1h
O
O
MeO
MeO
OMe
OMe
OHC
R
+
H
P
HO
P
Br
+
0-25 °C, 2h
OH
(3a- j)
(1)
(2)
R
(4a- j)
O
O
O
O
OMe
OMe
O
P
O
O
OMe
OMe
P
P
P
O
R
(5a- j)
R
Entry
5i
5j
R
Entry
5e
5f
R
Entry
R
H
5a
5b
5c
5d
4-F-C6H4
4-N(CH3)2-C6H4
4-OMe-C6H4
2-OMe-C6H4
2-NO2-C6H4
4-NO2-C6H4
4-Br-C6H4
4-Cl-C6H4
2-Cl,4-Cl-C6H3
5g
5h
Scheme 1
Dimethyl [(6-oxo-6O5-dibenzo[d,f][1,3,2]dioxaphosphepin-6-yl)(phenyl)
methyl] phosphonate (5aꢂꢐꢀ<LHOGꢀꢋꢅꢑꢃꢀPꢎSꢎꢀꢈꢌꢍ±ꢈꢌꢉ°C. IR (KBr) cm-1:
1289 (P = O, phosphonate), 1238 (P = O, dioxaphosphepine), 745
ꢁ3±&ꢂꢒꢀ1H NMR (DMSO-d6): Gꢀꢍꢎꢊꢇ±ꢋꢎꢊꢉꢀꢁꢈꢏ+ꢃꢀPꢃꢂꢃꢀꢇꢎꢉꢊ±ꢇꢎꢊꢇꢀꢁꢈ+ꢃꢀGGꢃꢀ
2JP-H = 17.3 Hz, 3JP-H = 11.4 Hz), 3.61 (3H, d, 3JP-Hꢀ ꢀꢊꢎꢆꢀ+]ꢃꢀ3±2±&+3),
3.21 (3H, d, 3JP-Hꢀ ꢀꢊꢎꢉꢀ+]ꢃꢀ3±2&+3); 13C NMR data: 129.9 (C-1, C-11),
122.4 (C2-C10), 131.0 (C-3,C-9), 114.9 (C-4, C8), 130.7 (C-12, C-13),
152.8 (C-14, C-15), 142.5 (C-1'), 135.2 (C-2', C6'), 135.4 (C-3', C5'),
122.1 (C-4'), 57.4 (d, Jꢀ ꢀꢍꢎꢌꢀ+]ꢃꢀ3±2&+3), 53.66 (d, 1J3±&ꢀ ꢀꢈꢍꢏꢎꢅꢀ
3±&+ꢄ3ꢂꢒꢀ31P NMR data: G 24.65 (P = O phosphonates), 3.00 (P = O
dioxaphosphepine); LC-MS m/z: 453 [M + Na+] (100%) 354.9 (100),
312 (22), 271 (40), 266.9 (12), 170 (20). Anal. Calcd for C21H20O6P2: C,
58.61; H, 4.68. Found C, 58.54; H, 4.60%
(d, 2JP-Cꢀ ꢀꢍꢎꢍꢀ+]ꢃꢀ3±2&+3), 52.5 (d, 1J3±&ꢀ ꢀꢈꢍꢋꢎꢇꢀ3±&±3ꢂꢒꢀ31P NMR
data: G 23.10 (P = O, phosphonates), 9.25 (P = O, dioxaphosphepine);
LCMS m/z: 451 [M + 3] (100%) 424.2 (35), 420 (80), 378.2 (35),
350.2 (40), 238.2 (10). Anal. Calcd for C21H19FO6P2: C, 56.26; H,
4.27. Found C, 56.16; H, 4.20%
Dimethyl [(4-dimethylamino)phenyl(6-oxo-6dibenzo[d,f][1,3,2]
dioxaphosphepin-6-yl)methyl]phosphonate(5fꢂꢐꢀ<LHOGꢀꢋꢆꢑꢃꢀPꢎSꢎꢀꢈꢍꢈ±
162°C. IR (KBr) cm-1 1265 (P = O, phosphonate), 1228 (P = O,
GLR[DSKRVSKHSLQHꢂꢃꢀꢋꢋꢇꢀꢁ3±&ꢂꢒꢀ1H NMR (DMSO-d6): Gꢀꢍꢎꢉꢈ±ꢋꢎꢇꢍꢀ
ꢁꢈꢆ+ꢃꢀPꢃꢀ$U+ꢂꢃꢀꢇꢎꢇꢅ±ꢇꢎꢋꢈꢀꢁꢈ+ꢃꢀGGꢃꢀ2JP-H = 17.2 Hz, 3JP-Hꢀ ꢀꢈꢈꢎꢆꢀ+]ꢃꢀ3±
CH, 3.75 (3H, d, 3JP-Hꢀ ꢀꢊꢎꢏꢀ+]ꢃꢀ3±2&+3), 3.32 (3H, d, 3JP-H = 9.8 Hz,
3±2&+3), 2.25 (6H, s, ArCH3); 13C NMR data: 129.9 (C-1, C-11),
122.4 (C2-C10), 131.0 (C-3, C-9), 114.6 (C-4, C8), 130.5 (C-12,
C-13), 152.8 (C-14, C-15), 142.7 (C-1'), 135.2 (C-2', C6'), 135.4
(C-3', C5'), 122.1 (C-4'), 57.3 (d, Jꢀ ꢀꢍꢎꢍꢀ+]ꢃꢀ3±2&+3), 53.66 (d,
1J3±&ꢀ ꢀꢈꢍꢏꢎꢆ3±&+ꢄ3ꢂꢒꢀ31P NMR data: G 26.10 (P = O phosphonate),
3.15 (P = O dioxaphosphepine); (LC-MS m/z: 491 [M + H2O (15%)
440(15), 398 (20), 352(45), 311 (65), 266 (80), 257 (30), 245 (55),196
(100),144 (48),130 (30). Anal. Calcd for C23H25NO6P2: C, 58.36; H,
5.32; N, 2.96. Found C, 58.28; H, 5.28; N, 2.91%
Dimethyl [(4-bromophenyl)(6-oxo-6O5-dibenzo[d,f][1,3,2]dioxa-
phosphepin-6-yl)ethyl]phosphonate (5bꢂꢐꢀ <LHOGꢀ ꢍꢉꢑꢃꢀ PꢎSꢎꢀ ꢈꢇꢉ±
160°C. IR (KBr) cm-1: 1280 (P = O, phosphonate), 1215 (P = O,
GLR[DSKRVSKHSLQHꢂꢃꢀꢋꢇꢍꢀꢁ3±&ꢂꢒꢀ1H NMR (DMSO-d6): Gꢀꢍꢎꢉꢈ±ꢋꢎꢉꢅꢀ
ꢁꢈꢆ+ꢃꢀPꢃꢀ$U+ꢂꢃꢀꢇꢎꢉꢅ±ꢇꢎꢊꢈꢀꢁꢈ+ꢃꢀGGꢃꢀ2JP-H = 17.1 Hz, 3JP-H = 11.0 Hz,
3
3±&+ꢂꢃꢀꢏꢎꢍꢏꢀꢁꢏ+ꢃꢀGꢃꢀ3JP-Hꢀ ꢀꢊꢎꢉꢀ+]ꢃꢀ3±2&+3), 3.15 (3H, d, JP-H
=
ꢊꢎꢍꢀ+]ꢃꢀ3±2&+3); 31P NMR data: G 26.15 (P = O, phosphonate), 9.18
(P = Odioxaphosphepine); Anal. Calcd for C21H19BrO6P2: C, 49.53;
H, 3.76. Found C, 49.43; H, 3.68%
Dimethyl [(2-methoxyphenyl)(6-oxo-6O5-dibenzo[d,f][1,3,2]diox-
aphosphepin-6-yl)methyl]phosphonate (5gꢂꢐꢀ <LHOGꢀ ꢋꢆꢑꢃꢀ PꢎSꢎꢀ ꢈꢇꢆ±
154°C. IR (KBr) cm-1 1265 (P = O, phosphonate); 1215 (P = O,
GLR[DSKRVSKHSLQHꢂꢃꢀ ꢋꢇꢍꢀ ꢁ3±&ꢂꢀ 1H NMR (DMSO-d6): Gꢀ ꢍꢎꢋꢍ±ꢋꢎꢇꢍꢀ
ꢁꢈꢆ+ꢃꢀPꢃꢀ$U+ꢂꢃꢀꢇꢎꢉꢊ±ꢇꢎꢊꢏꢀꢁꢈ+ꢃꢀGGꢃꢀ2JP-H = 17.2 Hz, 3JP-Hꢀ ꢀꢈꢈꢎꢌꢀ+]ꢃꢀ3±
CH), 3.73 (3H, d, 3JP-Hꢀ ꢀꢊꢎꢉꢀ+]ꢃꢀ3±2&+3), 3.35 (3H, d, 3JP-H = 9.7 Hz,
3±2&+3), 3.95 (3H, s, OCH3); 31P NMR data: G 26.10 (P = O,
phosphonate), 4.26 (P = O, dioxaphosphepine); Anal. Calcd for
C22H22O7P2: C, 57.40; H, 4.82. Found C, 57.32; H, 4.76%
Dimethyl
[(4-chlorophenyl)(6-oxo-6O5-dibenzo[d,f][1,3,2]dioxa-
phosphepin-6-yl)methyl]phosphonate(5cꢂꢐꢀ<LHOGꢀꢍꢉꢑꢃꢀPꢎSꢎꢀꢈꢏꢍ±ꢈꢏꢉ°C.
IR (KBr) cm-1: 1260 (P = O, phosphonate), 1212 (P = O, dioxaphos-
SKHSLQHꢂꢃꢀꢋꢌꢊꢀꢁ3±&DOSKDꢂꢒꢀ1H NMR (DMSO-d6): Gꢀꢍꢎꢉꢇ±ꢋꢎꢇꢅꢀꢁꢈꢆ+ꢃꢀ
Pꢃꢀ$U+ꢂꢃꢀꢇꢎꢊꢈ±ꢍꢎꢅꢉꢀꢁꢈ+ꢃꢀGGꢃꢀ2JP-H = 16.9 Hz, 3JP-Hꢀ ꢀꢈꢅꢎꢊꢀ+]ꢃꢀ3±&+ꢂꢃꢀ
3
3
3.85 (3H, d, JP-Hꢀ ꢀꢊꢎꢏꢀ+]ꢃꢀ3±2&+3), 3.42 (3H, d, JP-H = 9.2 Hz,
3±2&+3); 31P NMR data: G 23.10 (P = O, phosphonate), 7.26 (P = O,
phosphepine); Anal. Calcd for C21H19ClO6P2: C, 54.27; H, 4.12.
Found C, 54.20; H, 4.06%
Dimethyl [(4-methoxyphenyl)(6-oxo-6O5-dibenzo[d,f][1,3,2]dioxa-
phosphepin-6-yl)methyl]phosphonate (5hꢂꢐꢀ <LHOGꢀ ꢍꢇꢑꢃꢀ PꢎSꢎꢀ ꢈꢌꢈ±
143°C. IR (KBr) cm-1 1285 (P = O, phosphonate), 1210 (P = O,
GLR[DSKRVSKHSLQꢂꢃꢀ ꢋꢋꢈꢀ ꢁ3±&ꢂꢒꢀ 1H- NMR (DMSO-d6): Gꢀ ꢍꢎꢋꢍ±ꢋꢎꢌꢊꢀ
ꢁꢈꢆ+ꢃꢀPꢃꢀ$U+ꢂꢃꢀꢇꢎꢋꢏ±ꢇꢎꢊꢏꢀꢁꢈ+ꢃꢀGGꢃꢀ2JP-H = 16.9 Hz, 3JP-Hꢀ ꢀꢈꢅꢎꢊꢀ+]ꢃꢀ3±
CH), 3.65 (3H, d, 3JP-Hꢀ ꢀꢊꢎꢋꢀ+]ꢃꢀ3±2&+3), 3.22 (1H, d, 3JP-H = 9.2 Hz,
3±2&+3), 3.89 (3H, s, OCH3); 31P NMR data: G 23.10 (P = O,
phosphonate), 5.25 (P = O, dioxaphosphepine); Anal. Calcd for
C22H22O7P2: C, 57.40; H, 4.82. Found: C, 57.33; H, 4.76%
Dimethyl[(4,2-dichlorophenyl)(6-oxo-6O5-dibenzo[d,f][1,3,2]dioxa-
phosphepin-6-yl) methyl]phosphonate (5dꢂꢐꢀ <LHOGꢀ ꢋꢈꢑꢃꢀ PꢎSꢎꢀ ꢈꢌꢊ±
151°C. IR (KBr) cm-1 1250 (P = O phosphonate), 1195 (P = O dioxa-
SKRVSKHSLQHꢂꢃꢀꢋꢉꢅꢀꢁ3±&ꢂꢒꢀ1H NMR (DMSO-d6): Gꢀꢍꢎꢉꢈ±ꢋꢎꢇꢊꢀꢁꢈꢈ+ꢃꢀ
Pꢃꢀ$U+ꢂꢃꢀꢇꢎꢊꢈ±ꢇꢎꢊꢉꢀꢁꢈ+ꢃꢀGGꢃꢀ2JP-H = 16.9 Hz, 3JP-Hꢀ ꢀꢈꢅꢎꢊꢀ+]ꢃꢀ3±&+ꢂꢃꢀ
3
3
3.61 (3H, d, JP-Hꢀ ꢀꢊꢎꢉꢀ+]ꢃꢀ3±2&+3), 3.25 (3H, d, JP-H = 9.3 Hz,
3±2&+ꢏꢂꢒꢀ31P NMR data: G 22.02 (P = O phosphonate), 5.25 (P = O
dioxaphosphepin). Anal. Calcd for C21H18Cl2O6P2: C, 50.52; H, 3.63.
Found C, 50.50; H, 3.57%
Dimethyl
[(2-nitrophenyl)(6-oxo-6O5-dibenzo[d,f][1,3,2]dioxaphos-
'LPHWK\Oꢀ >ꢁꢂꢃÀXRURSKHQ\OꢄꢁꢅꢃR[RꢃꢅO5-dibenzo[d,f][1,3,2]dioxa-
phosphepin-6-yl)methyl] phosphonate (5eꢂꢐꢀ <LHOGꢀ ꢍꢊꢑꢃꢀ PꢎSꢀ ꢎꢈꢌꢌ±
146°C. IR (KBr) cm-1 1280 (P = O, phosphonate), 1225 (P = O,
GLR[DSKRVSKHSLQHꢂꢃꢀꢋꢍꢇꢀꢁ3±&ꢂꢒꢀ1H NMR (DMSO-d6): Gꢀꢍꢎꢉꢈ±ꢋꢎꢋꢍꢀ
ꢁꢈꢆ+ꢃꢀPꢃꢀ$U+ꢂꢃꢀꢇꢎꢇꢅ±ꢇꢎꢍꢇꢀꢁꢈ+ꢃꢀGGꢃꢀ2JP-H = 17.9 Hz, 3JP-H = 11.5 Hz,
phepin-6-yl)methyl]phosphonate (5iꢂꢐꢀ <LHOGꢀ ꢍꢋꢑꢃꢀ PꢎSꢎꢀ ꢈꢌꢍ±
148°C. IR (KBr) cm-1 1257 (P = O, phosphonate), 1213 (P = O
GLR[DSKRVSKHSLQHꢂꢃꢀꢋꢋꢈꢀꢁ3±&ꢂꢒꢀ1H NMR (DMSO-d6): Gꢀꢍꢎꢉꢈ±ꢋꢎꢋꢏꢀ
2
3
(12H, m, ArH), 5.81-5.93 (1H, dd, JP-H = 17.3 Hz, JP-H = 11.6
+]ꢃꢀ3±&+ꢂꢃꢀꢏꢎꢍꢏꢀꢁꢏ+ꢃꢀGꢃꢀ3JP-H = 9.8 Hz), 3.20 (3H, d, JP-H = 9.7
3
3
3
3±&+ꢂꢃꢀꢏꢎꢍꢇꢀꢁꢏ+ꢃꢀGꢃ JP-Hꢀ ꢀꢊꢎꢏꢀ+]ꢃꢀ3±2&+3), 3.45 (3H, d, JP-H
=
+]ꢃꢀ3±2&+3); 31P NMR data: G 20.15 (P = O, phosphonate), 3.90
(P = O, dioxaphosphepine); Anald. Calcd for C21H19NO8P2: C, 53.06;
H, 4.03; N, 2.94. Found C, 52.98; H, 3.97; N, 2.89%
9.7 Hz); 13C NMR: data: 128.3 (C-1, C-11), 120.9 (C-2, C-10), 131.0
(C-3, C9), 115.4 (C-4, C-8), 129.2 (C-12, C-13), 148.2 (C-14, C-15),
132.1 (C-1'), 130.3 (C-2', C-6'), 115.2 (C-3', C-5'), 156.3 (C-4'), 54.2

260 JOURNAL OF CHEMICAL RESEARCH 2009
Table 1 Antibacterial activity of compounds 5a–j (μg mL-1
)
Compound
Zone of inhibition (%)
Escherichia coli
Staphylococcus aureus
100
50
25
100
50
25
5a
10
14
15
8
7
10
9
6
8
7
3
6
6
5
6
6
7
–
9
11
12
7
6
8
7
6
4
7
7
4
4
8
7
4
6
7
5
6
6
5
–
6
5
–
5b
5c
5d
6
5e
9
7
8
5f
12
9
9
10
12
12
7
9
5g
7
8
5h
8
2
5i
7
8
5j
8
9
Penicillin
8
10
Table 2 Antifungal activity of compounds 5a–j (μg mL-1
)
Compound
Zone of inhibition (%)
Aspergillus niger
Helminthosporium oryzae
100
50
25
100
50
25
5a
10
15
9
11
10
14
12
10
9
7
8
8
9
5
9
5
8
8
7
7
6
7
8
6
4
8
3
9
6
7
–
11
15
13
12
12
11
9
10
11
10
12
7
8
4
5
6
5
6
7
8
7
5
8
–
5b
5c
9
5d
8
5e
9
5f
9
5g
12
9
5h
5i
9
5j
9
12
7
Griseofulvin
9
Dimethyl
[(4-nitrophenyl)(6-oxo-6O5-dibenzo[d,f][1,3,2]dioxaphos-
the presently used commercial bactericides/fungicides have been
discovered.
phepin-6-yl)methyl]phosphonate (5jꢂꢐꢀ <LHOGꢀ ꢋꢏꢑꢃꢀ PꢎSꢎꢀ ꢈꢇꢇ±ꢈꢇꢋ°C.
IR (KBr) cm-1 1268 (P = O, phosphonate), 1219 (P = O,
GLR[DSKRVSKHSLQHꢂꢃꢀꢋꢋꢅꢀꢁ3±&ꢂꢒꢀ1H NMR (DMSO-d6): Gꢀꢍꢎꢉꢈ±ꢉꢎꢈꢅꢀ
ꢁꢈꢆ+ꢃꢀPꢃꢀ$U+ꢂꢃꢀꢇꢎꢊꢈ±ꢍꢎꢈꢆꢀꢁꢈ+ꢃꢀGGꢃꢀ2JP-H = 16.9 Hz, 3JP-H = 10.9 Hz,
The authors thank UGC (33-299) New Delhi, for providing
¿QDQFLDOꢀDVVLVWDQFH
3±&+ꢂꢃꢀꢏꢎꢋꢈꢀꢁꢏ+ꢃꢀGꢃꢀ JP-Hꢀ ꢀꢊꢎꢆꢀ+]ꢃꢀ3±2&+3),3.51(3H,d,3JP-H =9.8Hz,
3
3±2&+3). 13C NMR data: 128.9 (C-1, C-11), 122.2 (C-2, C-10),
Received 28 January 2009; accepted 25 February 2009
Paper 09/0413 doi: 10.3184/030823409X439744
Published online: 29 April 2009
131.2 (C-3, C-9), 118.2 (C-4, C-8), 131.4 (C-12, C-13), 148.1
(C-14, C-15), 112.0 (C-1'), 110.6 (C-2',C-6'), 111.0 (C-3', C-5'),
149.9 (C-4'), 53.20(d, 2JP-Cꢀ ꢀ ꢍꢎꢋꢀ +]ꢃꢀ 3±2&+3), 51.5 (d, J3±&
=
1
ꢈꢍꢌꢎꢅ3±&±3ꢂꢒꢀ 31P NMR data: G 29.01 (P = O, phosphonate), 9.10
(P = O, dioxaphosphepine); LCMS-m/z: 473 [M+] (15), 474.8
[M + 1] (55%) 462.8 (25), 364.8 (50), 349.9 (45), 355.8 (20), 245.0
(45),237.9 (100), 266 (60), 142.9 (25). Anal. Calcd for C21H19NO8P2:
C, 53.06; H, 4.03; N, 2.95. Found C, 53.01; H, 3.98; N, 2.92%
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DFWLYLW\ꢀZKHQꢀFRPSDUHGꢀZLWKꢀWKDWꢀRIꢀ*ULVHRIXOYLQꢎꢀ6LJQL¿FDQWꢀUHVXOWꢀ
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dioxaphosphepin-6-yl)methyl]phosphonate (5b), and dimethyl
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