Synthesis and antimicrobial activity of novel 3 substituted 1,5-dihydro-2,4,3-benzodioxaphosphepine 3-oxides

Article abstract of DOI:10.1002/hc.20154

Novel 3 substituted 1,5-dihydro-2,4,3-benzodioxaphosphepine 3-oxides (5a-h) were synthesized by reacting 1,2-benzenedimethanol (1) with phosphorus tribromide in the presence of triethylamine at 0-30°C and subsequent reaction of the monobromide (2) with di

Full text of DOI:10.1002/hc.20154

Heteroatom Chemistry
Volume 16, Number 7, 2005
Synthesis and Antimicrobial Activity
of Novel 3 Substituted
1,5-Dihydro-2,4,3-Benzodioxaphosphepine
3-Oxides
P. Haranath, M. F. Stephen Babu, U. Anasuyamma,
C. Naga Raju, and C. Suresh Reddy
Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, India
Received 27 September 2004; revised 7 April 2005
and antiviral agents [2]. Some of them are well
ABSTRACT: Novel 3 substituted 1,5-dihydro-2,4,3-
known for their insecticidal activities [3] and are
benzodioxaphosphepine 3-oxides (5a–h) were syn-
known to degrade hydrolytically and enzymatically
thesized by reacting 1,2-benzenedimethanol (1) with
to nontoxic residues. Discovery of their fungicidal
phosphorus tribromide in the presence of triethy-
properties constitutes a recent development [4].
lamine at 0–30◦C and subsequent reaction of the
monobromide (2) with different Grignard reagents
(3) at room temperature. The products (4) were con-
verted to corresponding oxides 5a–i by oxidation with
H2 O2 at room temperature. The chemical structures
of all the products were confirmed by analytical, IR
and NMR (1H, 13C, and 31P) spectral data. Their an-
tifungal and antibacterial activity is also evaluated.
Most of these compounds exhibited moderate antimi-
RESULTS AND DISCUSSION
The synthetic route (Scheme 1) involves the cy-
clization of equimolar quantities of 1,2-benzenedi-
methanol (1) with phosphorus tribromide in the
presence of triethylamine in toluene to form phos-
phorobromodite (2). On subsequent reaction of 2
with different substituted Grignard reagents (3)
formed 4a–i, which were converted to correspond-
ing oxides (5a–i) by oxidation with H2O2 at room
temperature.
ꢀ
C
crobial activity in the assay.
2005 Wiley Periodicals,
Inc. Heteroatom Chem 16:572–575, 2005; Published online
in Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20154
Product yields and elemental analysis, IR [5–7]
1
and 31P NMR [8] data, H [7] and 13C NMR [7] data
of 5a–i are given in Tables 1, 2, 3, and 4 respectively,
and the data agreed with the proposed chemical
structures.
INTRODUCTION
Organophosphate moiety is an important pharma-
cophore in agricultural and pharmaceutical com-
pounds [1]. Phosphocin/phosphepine and their re-
lated derivatives containing this group represent an
important class of pesticides, antibiotics, herbicides,
ANTIMICROBIAL ACTIVITY
The compounds 5a–i (Table 5) were screened for
their antifungal activity against Aspergillus niger
and Helminthosporium species along with the stan-
dard fungicide Bavestein. Disc diffusion method [9]
was followed for screening the compounds at three
Correspondence to: C. Suresh Reddy; e-mail: csureshsvu@
yahoo.com.
Contract grant sponsor: UGC, New Delhi, India.
2005 Wiley Periodicals, Inc.
c
ꢀ
572

Synthesis and Antimicrobial Activity of Novel 3 Substituted 1,5-Dihydro-2,4,3-Benzodioxaphosphepine 3-Oxides 573
pounds are extremely more effective against fungi
Bavestein.
EXPERIMENTAL
The melting points were determined on a Mel-Temp
apparatus and were uncorrected. Elemental analyses
were performed by the Central Drug Research Insti-
tute, Lucknow, India. All IR spectra were recorded as
KBr pellets on a Perkin-Elmer 1430 unit. 1H, 13C, and
31P NMR spectra were recorded on AMX 400 MHz
spectrometer, operating at 400 MHz for 1H, 100 MHz
for 13C and 161.9 MHz for 31P as solution in CDCl3,
and the chemical shifts were referenced to TMS
(1H & 13C) and 85% H3PO4 (31P).
1,2-Benzenedimethanol was procured from Lan-
caster Chemical Company, Inc., USA and used with-
out further purification.
Preparation of Ethyl Magnesium Bromide (3b)
Caution: Because of the sensitivity of the reagents
and products to moisture and oxygen, all manipula-
tions were performed in an anhydrous inert nitrogen
atmosphere.
SCHEME 1
In a dry 100 mL three-necked round-bottomed
flask fitted with dropping funnel, a reflux condenser
with a calcium chloride tube, a nitrogen inlet, and
a thermometer were placed magnesium turnings
(0.12 g, 0.005 mol) and 5 mL dry THF. The reac-
tion mixture was kept under stirring, and 2 mL of
ethyl bromide (0.54 g, 0.005 mol) in 10 mL of dry
THF is added at 10–15◦C for 10 min. When the
reaction started the temperature increased to 40–
45◦C. The mixture was cooled to room temperature,
and stirring was continued until the magnesium
metal is dissolved to form ethyl magnesium bromide
(3b).
different concentrations (25, 50, 100 ppm). Their an-
tibacterial activity was also evaluated according to
the disc diffusion method [10,11] at three different
concentrations against Escherichia coli and Staphy-
lococcus aureus by comparing with standards strep-
tomycin.
It is interesting to observe that all compounds
5a–i exhibited moderate antifungal and antibacterial
activity when compared with that of standards. The
highlight is that all the compounds exhibited mod-
erate activity against bacteria, and some compounds
were more effective than the standard streptomycin.
Similarly it is gratifying to observe that these com-
TABLE 1 Physical Data of 5a–i
Elemental Analysis
Found (Calcd) %
Compd.
mp ( ◦C)
Yield (%)a
Mol. Formula (Mol. Wt)
C
H
5a
5b
5c
5d
5e
5f
5g
5h
5i
135–136
119–120
156–157
112–113
147–148
162–163
123–124
181–182
130–131
67
76
74
71
69
56
59
61
68
C9H11O3P (198.16)
54.55 (54.37)
56.61 (56.80)
58.41 (58.52)
58.41 (58.60)
59.99 (59.82)
57.15 (57.30)
58.93 (58.81)
48.70 (48.80)
64.62 (64.79)
5.60 (5.61)
6.18 (5.99)
6.68 (6.67)
6.68 (6.67)
7.13 (7.15)
5.28 (5.26)
5.84 (5.85)
4.90 (4.88)
5.04 (5.03)
C
C
C
C
C
10H13O3P (212.18)
11H15O3P (226.12)
11H15O3P (226.12)
12H17O3P (240.24)
10H11O3P (210.17)
C11 13
C10 12
H
O3P (224.19)
ClO3P (246.63)
H
C
14H13O3P (260.23)
aRecrystallized from ethanol.

574 Haranath et al.
TABLE 2 31P NMR Data of 4a–i and 5a–i and Infrared Spectral Data (cm−1)a 5a–i
IR
Compd.
31P NMRb,c
Compd.
P
O
P
C(aliphatic)
31P NMR
4a
4b
4c
4d
4e
4f
4g
4h
4i
123.2
121.2
122.6
124.2
119.6
129.2
126.2
120.3
141.2
5a
5b
5c
5d
5e
5f
5g
5h
5i
1221
1226
1231
1225
1232
1228
1226
1227
1229
750
752
756
753
753
746
752
750
761
1.29
1.47
1.37
1.35, 0.28
1.67
4.38, 0.31
3.19, 0.84
2.31
23.17
aRecorded as KBr pellets.
bRecorded in CDCl3.
cChemical shifts in ppm from 85% phosphoric acid.
TABLE 3 1H NMR Chemical Shifta Data of 5a–ib
Compd.
CH2 (1&5)
Ar-H
R1
R2
R3
R
5a
5b
5c
5d
5e
5f
5g
5h
5i
5.20–5.42 (m, 4H) 7.36–7.52 (m, 4H)
1.13 (s, 3H)
5.21–5.39 (m, 4H) 7.24–7.63 (m, 4H) 1.72–1.80 (m, 2H) 1.12–1.21 (m, 3H)
5.16–5.40 (m, 4H) 6.88–7.48 (m, 4H) 2.25–2.40 (m, 2H) 1.30–1.50 (m, 5H)
5.18–5.41 (m, 4H) 7.14–7.53 (m, 4H) 2.10–2.23 (m, 1H) 1.20–1.50 (m, 6H)
5.03–5.33 (m, 4H) 7.26–7.49 (m, 4H) 2.09–2.30 (m, 2H) 1.51–1.66 (m, 2H) 1.28–1.30 (m, 2H) 0.87–0.90 (m, 3H)
5.11–5.39 (m, 4H) 7.18–7.61 (m, 4H) 5.72–5.86 (m, 1H) 5.23–5.32 (m, 2H)
5.10–5.42 (m, 4H) 7.15–7.59 (m, 4H) 3.07–3.12 (m, 2H) 5.92–6.02 (m, 1H) 5.39–5.40 (m, 2H)
5.16–5.32 (m, 4H) 6.98–7.46 (m, 4H)
5.22–5.41 (m, 4H) 6.61–7.48 (m, 9H)
3.05 (m, 2H)
3.24 (m, 2H)
aChemical shifts in δ and J (Hz) in parenthesis.
bRecorded in CDCl3.
TABLE 4 13C NMR Chemical Shifta Data of Some of 5b,c
Carbon Atoms
5a
5b
5c
5d
5e
5f
5g
C-1 and 5
C-6 and 9
C-7 and 8
C-10 and 11
C-1ꢁ
70.2 (6.6)
128.3 (2.9)
126.9
139.1
13.8 (136.0)
69.6 (7.2)
128.2 (2.6)
126.4
70.7 (6.9)
128.3 (2.7)
126.2
70.9 (7.1)
127.8 (2.7)
126.6
70.0 (7.4)
127.5
126.7
69.6 (6.9)
128.3 (2.6)
127.2
69.8 (7.2)
128.1 (2.6)
126.8
139.6
36.5 (132.8)
134.2
138.2
136.2
137.2
136.5
138.7
27.6 (139.4)
7.1 (14.5)
–
28.4 (140.2)
26.1 (4.7)
16.15 (15.6)
–
26.8 (140.7)
16.7 (4.7)
16.0 (4.7)
–
34.6 (138.2)
30.4 (4.7)
22.6 (14.7)
12.9
123.4 (131.6)
116.2 (4.6)
–
C-2ꢁ
–
–
–
C-3ꢁ
119.8 (17.6)
–
C-4ꢁ
–
–
aChemical shifts in ppm.
bRecorded in CDCl3.
c J (Hz) in parenthesis.
added over a period of 20 min. After completion of
the addition, the temperature of the reaction mix-
ture was raised to room temperature and stirred for
1 h to form the intermediate phosphorobromodite
(2). The progress of the reaction was judged by the
TLC analysis. The reaction mixture was filtered un-
der nitrogen atmosphere to remove triethylamine
hydrobromide.
Synthesis of 3-(Ethyl)1,5-dihydro-
2,4,3-benzodioxaphosphepin 3-oxide 5b
To a cooled (0◦C) and stirred solution of 1,2-
benzenedimethanol (1, 0.69 g, 0.005 mol) and tri-
ethylamine (1.01 g, 0.01 mol) in 25 mL dry toluene
under N2 gas, a solution of phosphorus tribromide
(1.35 g, 0.005 mol) in 10 mL of dry toluene was

Synthesis and Antimicrobial Activity of Novel 3 Substituted 1,5-Dihydro-2,4,3-Benzodioxaphosphepine 3-Oxides 575
TABLE 5 Antifungal and Antibacterial Activities of Compounds 5 in Terms of Zone of Inhibition (mm)
Fungi
Bacteria
Aspergillus
niger
Helminthosporium
oryzae
Escherichia
coli
Staphylococcus
aureus
Compd.
100
50
25
100
50
25
100
50
25
100
50
25
5a
5b
5c
5d
5e
5f
5g
5h
12
12
11
14
11
13
16
18
19
18
5
6
5
7
6
7
8
7
8
8
2
2
2
3
3
4
3
2
4
4
12
14
14
12
14
12
15
14
15
16
6
7
6
5
6
5
5
6
7
7
2
4
2
–
–
2
2
2
3
3
10
10
9
11
8
10
9
9
–
–
2
4
–
5
3
5
5
6
–
–
–
2
–
2
–
–
2
–
7
8
7
8
8
6
9
8
8
9
–
3
4
3
3
–
4
3
4
5
–
–
2
–
–
–
2
–
2
–
5i
11
10
Bavistin Streptomycin
All concentrations expressed in ppm.
– indicates no activity.
The Grignard reagent 3b was cooled to 15◦C, and
phosphorobromodite (2) was added to it in 15 min
under nitrogen. After the addition, the reaction
mixture was brought to room temperature and
stirred for 90 min. The progress of the reaction was
monitored by TLC (ethyl acetate: hexane) analysis.
After completion of the reaction, the mixture was
cooled to 5◦C and then hydrolyzed by slow addition
of saturated aqueous NH4Cl solution with cooling.
The solvent was removed under vacuum, and the
residue was extracted with ethyl acetate. The extract
after washing with brine solution and drying over
anhydrous MgSO4 was evaporated in rotaevapora-
tor. The crude product (4b) obtained was dissolved
in dichloromethane (30 mL) and hydrogen peroxide
(30% H2O2, 0.2 mL, 0.005 mol) was added to it drop-
wise at 0–5◦C. The reaction mixture was brought to
room temperature and kept with stirring for 2 h for
the completion of oxidation as indicated by the TLC
analysis. The reaction mixture was washed with sat-
urated NaCl solution, dried over anhydrous MgSO4,
and the solvent was evaporated in a rotaevapora-
tor. The resulting crude product was recrystallized
from 2-propanol to yield 1.46 g (76%) of 5b, mp 119–
120◦C.
discussions and the Director of CDRI, Lucknow and
SIF, IISC, Bangalore for the elemental and spectral
data.
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ACKNOWLEDGMENTS
The authors express their thanks to Professor C.
Devendranath Reddy for his helpful guidance and