Synthesis and antimicrobial activity of N-(substituted)-N′-[1,2,4, 8,10,11-hexachloro-6-oxido-12H-dibenzo(d,g)(1,3,2)-dioxaphosphocin-6-yl]ureas

Article abstract of DOI:10.1002/jhet.5570410625

Substituted dibenzo dioxaphosphocin-6-yl ureas were synthesized by reacting hexachlorophene (4) with different carbamidophosphoric acid dichlorides (3) in the presence of triethylamine in dry toluene at 45-50 °C. Their IR, ¹H, ¹³C and ³¹P NMR spectral data is discussed. These compounds were found to possess good antimicrobial activity.

Full text of DOI:10.1002/jhet.5570410625

Nov-Dec 2004
1001
Synthesis and Antimicrobial activity of N-(substituted)-N'-
[1,2,4,8,10,11-hexachloro-6-oxido-12H-dibenzo(d,g)(1,3,2)-
dioxaphosphocin-6-yl]ureas
P. Haranath, U. Anasuyamma,
P. Vasu Govardhana Reddy and C. Suresh Reddy*
Department of Chemistry, Sri Venkateswara University, Tirupati - 517 502, India
Received April 12, 2004
Substituted dibenzo dioxaphosphocin-6-yl ureas were synthesized by reacting hexachlorophene (4) with
different carbamidophosphoric acid dichlorides (3) in the presence of triethylamine in dry toluene at 45-50
1
13
31
°C. Their IR, H, C and P NMR spectral data is discussed. These compounds were found to possess
good antimicrobial activity.
J. Heterocyclic Chem., 41, 1001 (2004).
Introduction.
amines (2a-j) at -15 °C under inert anhydrous conditions
in dry toluene to afford the corresponding carbamidophos-
phoric acid dichlorides [9,10] (3a-j). After the addition of
amines to 1 was completed, the products separated from
the reaction mixture immediately as crystalline com-
pounds. Further purification of carbamidophosphoric acid
dichlorides (3a-j) could not be accomplished due to their
insolubility in many organic solvents and air sensitivity.
Hence they were reacted directly in situ with a solution of
hexachlorophene (4) in toluene in the presence of two
equivalents of triethylamine to yield the compounds 5a-j
and their structures agree with the IR [11,12] and NMR
Organophosphorus compounds being ubiquitous in
nature have found multifaceted applications. Phosphorous
heterocycles substituted with carbamate moieties are an
important as antitumour agents [1], pesticides [2], and bac-
tericides [3,4]. Substituted phosphoryl ureas of the type
RR'P(O)NHCONR''R''' possessed pesticidal activity [5-7].
In view of this, several N-(substituted)-N'-[1,2,4,8,10,11-
hexachloro-6-oxido-12H-dibenzo(d,g)(1,3,2)dixo-
aphosphocin-6-yl] ureas have been synthesised, expecting
them to possess broad spectrum of biological activity and
1
13
were characterised by elemental, IR, NMR ( H, C and
1
13
31
31
( H [13], C [14,15] and P [16]) data (Table 1,2 and 3).
P) analyses.
Antimicrobial Activity.
Results and Discussion.
The synthetic route (Scheme-I) involves the addition of
dichloroisocyanato phosphine oxide [1,8] (1) with various
The compounds 5a-j (Table 4) were screened for their
antifungal activity against Aspergillus niger and

1002
P. Haranath, U. Anasuyamma, P. V. G. Reddy and C. S. Reddy
Vol. 41
Table 1
31
Physical, IR and P NMR Data of Compounds 5
-1
31
Product
M.P
(°C)
Yield[a]
(%)
Molecular formula
(Molecular mass)
Elemental Analysis
Found (Calcd) %
H
IR (cm )
P NMR[b]
C
N
C=O
1684
P=O
1257
P-NH
5a
5b
5c
5d
5e
5f
205-207
98-101
112-113
149-151
98-100
77-79
59
62
59
60
52
56
53
61
51
52
C
C
H
N PO Cl
40.92
(40.78)
38.65
1.89
(1.88)
1.62
4.77
(4.78)
4.50
3288 -8.19, -13.40
3241 -8.18, -12.83
3226 -8.37, 13.38
3282 -7.82, -12.36
3310 -8.15, -13.46
3241 -7.11, -13.13
3310 -8.16, -13.44
3379 -7.83, -12.63
3295 -7.68, -12.61
3399 -9.30, -12.73
20 11
2
4
6
7
(587.01)
N PO Cl
H
1681
1675
1660
1674
1663
1670
1665
1683
1670
1250
1241
1286
1250
1244
1245
1242
1249
1251
20 10
2
4
(621.45)
H N PO Cl Br
(38.59)
36.07
(1.60)
1.51
(4.48)
4.20
C
20 10
2
4
6
(665.91)
H N PO Cl
(36.13)
41.96
(1.52)
2.18
(4.19)
4.66
C
C
C
C
C
C
C
21 13
2
4
6
6
6
6
7
6
6
(601.04)
N PO Cl
(41.88)
42.96
(2.19)
2.46
(4.67)
4.55
H
22 15
2
4
(615.06)
N PO Cl
(42.79)
45.25
(2.48)
2.05
(4.56)
4.39
H
24 13
2
4
(637.07)
H N PO Cl
(45.13)
40.84
(2.08)
2.34
(4.38)
4.33
5g
5h
5i
72-74
22 15
2
6
(647.06)
H N PO Cl
(40.73)
39.69
(2.35)
1.90
(4.35)
4.41
127-129
101-102
128-130
21 12
2
4
(635.48)
N PO Cl
(39.56)
40.50
(1.88)
2.89
(4.39)
4.72
H
20 17
2
4
(593.06)
H N PO Cl
(40.39)
37.21
(2.88)
2.25
(4.71)
4.82
5j
18 13
2
5
(581.00)
(37.12)
(2.26)
(4.84)
31
[a] Recrystallized from iso propyl alcohol; [b] P chemical shifts were expressed in δ, from 85% H PO as external standard.
3
4
Helminthosporium oryzae by comparing with standard
fungicide Bavestein. Disc diffusion method [17] was fol-
lowed for screening the compounds at three different con-
centrations (25, 50, 100 ppm). Their antibacterial activity
was evaluated according the disc diffusion method [18,19]
at three different concentrations against Escherichia colia
and Staphylococcus aureus by comparing with standards
Streptomycin. The title compounds showed greater anti-
fungal activity than antibacterial activity.
Compounds 5a-d, 5j were more effective against
Staphylococcus aureus and the compound 5a-d were
effective against Escherichia coli. However all these com-
pounds exhibited better antifungal activity against
Aspergillus niger and Helminthosporium oryzae.
Table 2
1
H NMR Data [a,b] of Compounds 5
Compd. 3-H & 9H 12CH
R-H
2
5a
5b
5c
5d
7.36
7.33
7.29
7.28
4.20
4.39
4.35
4.33
6.58-7.03
(m, 5H)
7.03-7.28
(m, 4H)
7.19-7.25
(m, 4H)
7.02-7.20
(m, 4H)
9.35
5.25
(s, 1H) (brs, 1H)
9.40
(s, 1H)
9.45
(s, 1H) (brs, 1H)
9.25 5.94
(brs, 1H) (brs, 1H)
6.20
(s, 1H)
6.24
2.27 (s, 3H, CH )
3
5e
7.23
4.38
6.70-7.13
(m, 3H)
9.10
5.90
2.26 (s, 3H, 2'-CH ) (brs, 1H) (brs, 1H)
EXPERIMENTAL
3
2.38 (s, 3H, 4'-CH )
3
5f
7.23
7.32
4.33
4.38
7.30-7.88
(m, 8H)
6.69-7.01
(m, 3H)
9.80
(s, 1H) (brs, 1H)
9.18 5.30
(s, 1H) (brs, 1H)
5.80
Melting points were taken on Mel-Temp apparatus and are
uncorrected. Elemental analyses were performed by the Central
Drug Research Institute, Lucknow, India. IR spectra were
5g
1
recorded as KBr pellets on a Perkin - Elmer 1430 unit. H NMR
3.78 (s, 3H, 3'OCH )
3.80 (s, 3H, 4'OCH )
3
13
and C NMR spectra were recorded on AMX 400 MHz spec-
3
1
13
trometer operating at 400 MHz for H, 100 MHz for C and
5h
7.29
4.31
7.11-7.17
(m, 4H)
9.35
5.40
31
161.9 MHz for P. Compounds were dissolved in CDCl . The
chemical shifts are referenced to TMS ( H and C) and 85%
(s, 1H) (brs, 1H)
3
1
13
-CH 4.37 (s, 2H)
2
31
5i
5j
7.32
7.31
4.31
4.37
1.29-1.81
(m, 11H)
3.68-3.80
(m, 8H)
9.80
6.90
H PO ( P).
3
4
(s, 1H) (brs, 1H)
9.78
Hexachlorophene (4) was procured from Aldrich chemical
company, inc. USA and was used without further recrystalliza-
tion.
(s, 1H)
-
[a] Chemical shifts (δ); [b] Recorded in CDCl .
Preparation of 4-Chlorophenylcarbamidophosphoric Acid
3

Nov-Dec 2004
Synthesis and Antimicrobial activity
1003
Table 3
13
C NMR spectral data of compounds 5[a] .
Carbon Atom
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
C(1,11)
C(2,10)
C(3, 9)
C(4, 8)
C(4a, 7a)
C(11a, 12a)
C(12)
C(13)
C(1')
C(2')
C(3')
C(4')
C(5')
134.4
131.5
128.5
125.9
146.9
129.5
30.8
153.0
146.9
119.1
127.8
119.0
128.4
117.4
133.9
132.4
128.7
125.5
146.8
129.1
29.6
153.7
146.7
116.7
129.1
124.6
129.1
116.7
133.9
131.1
128.9
125.5
146.6
129.1
30.1
154.3
150.7
116.8
132.3
115.6
131.1
116.8
133.8
131.7
128.0
125.7
150.8
129.3
30.4
156.3
135.7
119.8
130.7
127.5
130.7
119.8
133.9
131.0
128.8
125.5
147.9
128.8
29.5
156.1
147.0
124.6
131.1
127.6
124.6
114.8
133.9
130.8
128.8
125.8
146.8
129.0
29.2
155.2
113.7
129.0
121.8
128.5
128.3
127.7
119.59
149.8
132.1
128.7
132.7
131.0
127.8
124.1
146.8
129.1
29.4
150.5
132.0
131.0
141.2
105.2
124.0
111.7
133.2
131.9
128.0
127.5
146.7
129.1
30.3
155.5
136.0
133.5
127.5
127.0
127.0
130.3
133.9
132.0
128.8
125.8
146.7
129.5
29.7
157.4
52.1
32.3
134.1
131.1
128.8
125.5
146.6
129.1
29.9
153.0
43.6
63.8
26.6
25.3
25.5
31.1
63.8
42.9
C(6')
C(7')
C(8')
C(9')
C(10')
C'-CH
20.8
24.2
(C-4')
21.8
3
(C-2')
C'-OCH
56.7
(C-4')
56.2
3
(C-3')
[a] Recorded in CDCl .
3
Table 4
Antifungal and Antibacterial Activities of Compounds 5 in Terms of Zone of Inhibition (mm).
Compd.
Fungi Bacteria
Aspergillus niger
Helminthosporium oryzae
Escherichia coli
Staphylococcus aureus
100
-
14
10
12
8
50
-
9
6
10
5
25
-
6
-
8
3
-
9
9
9
8
-
100
10
14
15
28
14
9
15
15
12
12
12
50
6
9
15
15
11
-
12
10
6
25
-
4
-
13
9
-
8
6
-
100
12
12
16
15
-
10
12
8
50
7
8
12
12
-
5
8
5
-
25
4
3
8
7
-
-
-
-
-
100
10
10
12
18
10
-
10
-
-
50
8
8
9
14
8
-
7
-
-
25
5
5
5
9
-
-
-
-
-
5a
5b
5c
5d
5e
5f
5g
5h
-
-
13
16
15
13
8
11
11
11
10
5
5i
5j
-
8
5
9
3
-
4
-
12
10
6
Bavistin
Streptomycin
10
6
-
9
5
-
Concentrations expressed in ppm; ‘-’ indicates no activity.
Dichloride (3b).
carbamidophosphoric acid dichloride being insoluble in toluene
separated out. Without isolation and further purification, (3b)
was used for cyclisation reactions. Other carbamidophosphoric
A solution of 4-chloro aniline (2b, 0.51 g, 4.0 mmol) in dry
toluene (25 ml) was added dropwise (20 min) to a cold solution
acid dichlorides, 3a-j were prepared following this procedure
.
(-
15 °C) of isocyanatophosphonic dichloride (1, 0.64 g, 4.0
Synthesis of N-Chlorophenyl-N'-[1,2,4,8,10,11-hexachloro-6-
oxido-12H-dibenzo[d,g]-1,3,2-dioxaphosphocin-6-yl]urea (5b).
mmol)
of the
in dry toluene (30 ml). After the addition the temperature
reaction mixture was maintained between -15 °C to -5 °C
for 30-
40 minutes. Later the reaction mixture was brought to
room tem
A solution of 4-chlorophenyl carbamidophosphoric acid
dichloride (2b, 0.575 g, 2.0 mmol) in toluene (20 ml) was added
perature and stirred for 30-40 minutes. 4-Chlorophenyl-

1004
P. Haranath, U. Anasuyamma, P. V. G. Reddy and C. S. Reddy
Vol. 41
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974116q. (1975).
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to the solution of hexachlorophene (4, 0.81 g, 2.0 mmol) and tri-
ethylamine (0.404 g, 4.0 mmol) in dry toluene (20 ml) at 0 °C.
After the addition, the reaction mixture was maintained at 0 °C
for one hour and then stirred at room temperature for further one
hour after which the temperature of the reaction mixture was
raised slowly to 45-50 °C, with stirring for an additional five
hours. The reaction progress was monitored by TLC in the 1:2
mixture of ethyl acetate and hexane as a mobile solvent and silica
gel as adsorbent. Triethylamine hydrochloride was separated by
filtration and the solvent from the filtrate was evaporated under
reduced pressure. The residue obtained after washing with water
was triturated with isopropyl alcohol to afford 0.76 g (62%) of
analytically a pure material of 5b, m.p 98-101 °C. Physical and
spectral data of 5b are given in Tables 1-3.
Other members of 5 are prepared by adopting the same
procedure.
[12] L. C. Thomas, The Interpretation of the Infrared Spectra of
Organophosphorus Compounds, Heydon-London, (1974).
[13] R. M. Silverstein and F. X. Webster, Spectrometric
Acknowledgements.
th
Identification of organic compounds, 6 ed., Wiley, New York, (1998).
The authors express their thanks to Professor C. Devendranath
Reddy and Dr C. Naga Raju for their helpful guidance and dis-
cussions and the director of SIF, IISc, Bangalore for spectral
data. Dr. C. Suresh Reddy is grateful to UGC, New Delhi for pro-
viding financial funding for this Project.
[14] C. D. Reddy, B. S. Reddy, C. N. Raju, M. El Masri, K. D.
Berlin and S. Subramanian, Magn. Reson. Chem., 29, 1140 (1991).
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Properties in Compound Characterization and Structural Analysis VCH
Publisher, Inc, New York, (1994).
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