Synthesis and antimicrobial activity of some new N-(substituted phenyl)-N′-[2,3-dihydro-2-oxido-3-(4′-fluorophenyl)-1H-(1,3,2) benzoxazaphosphorin 2-yl]ureas

Article abstract of DOI:10.1002/jhet.5570440214

(Chemical Equation Presented) Substituted benzoxazaphosphorin 2-yl ureas were synthesized by reacting 2-(4-fluoro-phenylamino)-methylphenol (4) with different carbamidophosphoric acid dichlorides (3) in the presence of triethylamine in dry toluene at 45-50°C and characterized by spectral data. These compounds were found to possess good antimicrobial activity.

Full text of DOI:10.1002/jhet.5570440214

Mar-Apr 2007
Synthesis and Antimicrobial Activity of Some New N-(Substituted
phenyl)-N'-[2,3-dihydro-2-oxido-3-(4'-fluorophenyl)-1H-
369
(
1,3,2)benzoxazaphosphorin 2-yl]ureas
P. Haranath, V. Sreedhar Kumar, C. Suresh Reddy*, C. Naga Raju and
C. Devendranath Reddy
Department of Chemistry, Sri Venkateswara University, Tirupati - 517 502, India
Received May 30, 2006
Cl
Cl
O
Dichloroethane
C H Cl
HCl
PCl
5
NH
2
COOC
2
H
5
P
2 5
NCO
(1)
O
C
O
Cl
Toluene
P
(1)
R-H
N
0
Cl
R
-
15 to -5 C
H
(2a-i)
(3a-i)
R
O
1
8
5
OH
C
9
O
C
O
Toluene
Et N 45-50 C
7
6
P
2
(3)
3
N
N
NH
0
H
3
10
4
1'
H
2
2
'
6'
3
'
5'
4
'
F
F
(4)
(5a-i)
Substituted benzoxazaphosphorin 2-yl ureas were synthesized by reacting 2-(4-fluoro-phenylamino)-
methylphenol (4) with different carbamidophosphoric acid dichlorides (3) in the presence of triethyl-
amine in dry toluene at 45-50 °C and characterized by spectral data. These compounds were found to
possess good antimicrobial activity.
J. Heterocyclic Chem., 44, 369 (2007).
INTRODUCTION
amines (2a-i) at -15°C under inert anhydrous conditions
in dry toluene to afford the corresponding carbamido-
phosphoric acid dichlorides [9,10] (3a-i). After the
addition of amines to 1, the products separated from the
reaction mixture immediately as crystalline compounds.
Further purification of 3a-i 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 2-(4-fluoro- phenylamino)methylphenol (4) in
toluene in the presence of two equivalents of triethyl-
amine to yield 5a-i and their structures are established by
IR, NMR and Mass spectral data (Table 1, 2, 3 and 4).
Organophosphorus compounds being ubiquitous in
nature have found multifaceted applications. Phosphorous
heterocycles substituted with carbamate moieties are
important classes of antitumour agents [1], pesticides [2],
and bactericides [3,4]. Substituted phosphoryl ureas of the
type RR'P(O)NHCONR" R''' possessed pesticidal activity
[
5-7]. In view of this, several N-(substitutedphenyl)-N'-[2,3-
dihydro-2-oxido-3-(4'-fluorophenyl)-1H-(1,3,2)benzoxa-
zaphosphorin 2-yl]ureas have been synthesised, expecting
them to possess a broad spectrum of biological activity.
Compounds were characterised by elemental, IR, NMR and
Mass spectral analyses.
31
The P NMR spectral data for 5a-i are given in Table 1.
31
The P NMR signals [11] for 5a, 5b and 5f appeared as
two distinct signals in the range of -1.94 to -3.99 and -
3.01 to -8.80 ppm, which may be due to the presence of
two isomers in the solution state. The other compounds
RESULTS AND DISCUSSION
The synthetic route (Scheme 1) involves the addition of
dichloroisocyanatophosphine oxide [1,8] (1) with various

3
70
P. Haranath, V. S. Kumar, C. S. Reddy, C. N. Raju and C. D. Reddy
Vol 44
Cl
Cl
O
Dichloroethane
C
2
H
5
Cl
HCl
NH COOC H
P
PCl
5
2
2
5
NCO
(1)
O
C
O
Cl
Toluene
0
P
(1)
R-H
N
H
R
Cl
-
15 to -5 C
(2a-i)
(3a-i)
O
R
1
OH
C
8
5
O
9
C
O
Toluene
3
Et N
45-50 C
7
6
P
(3)
2
3
N
N
NH
0
H
1
0
4
1'
H
2
2
'
6'
3
'
5
'
4
'
F
F
(4)
(5a-i)
Compd.
R
Compd.
R
Cl
5
5
5
a
b
c
HN
5
f
HN
H C
2
HN
HN
HN
Cl
5g
HN
OCH3
Br
5
h
HN
5
d
e
CH3
CH3
5
i
N
O
HN
5
H3C
Scheme 1
3
1
5
c-5e and 5g-5i gave only one P NMR signal in the
In the proton NMR (Table 2), the aromatic protons of
5a-i resonated as complex multiplets slightly downfield
(δ 7.87-6.63) when compared to those of the starting
compound 4 (δ 7.20-6.49) due to the deshielding effect
of benzoxazaphosphorin 2-oxide ring. The C-4
methylene protons resonated as multiplets at δ 5.15-
4.10 indicating their non-equivalence and coupling
with phosphorus in the six-membered chair
conformation of the benzoxazaphosphorin 2-oxide
system [13]. The signal of phosphorylamidic proton of
P(O)-NH-C(O) appeared much farther downfield, δ
8.72-8.16 when compared to that of carbamidic proton
region -1.42 to -8.48 ppm.
1
3
The C NMR chemical shifts (Table 3) for C-4 to
C-10, C-1' to C-6' and C-1" to C-6" were observed in
the expected range in the title compounds [12,13].
However, the signals for the carbon of the carbamido
function appeared at δ 161.94-153.00. Signals for the
remaining carbon atoms were observed in the
expected regions. The C NMR chemical shifts could
not be identified for 5h and 5i because of poor
quality of their spectrum due to their meager
solubility in DMSO.
1
3

Mar-Apr 2007
Synthesis and Antimicrobial Activity
371
Table 1
Synthetic and Analytical Data of N-(Substituted)-N'-[2,3-dihydro-2-oxido-3-(4'-fluorophenyl)-1H-(1,3,2)benz-oxazaphosphorin 2-yl]ureas (5a-i)
-
1
Elemental analysis
Found (Calcd)%
IR(cm )
mp
Yield
(%)
Molecular
formula
31
Compd.
P NMR
(°C)
C
H
N
P=O
C=O
P-NH
5
5
a
241-243
142-144
71
68
62
60
63
66
64
70
58
C
20
H
17
N
3
PO
PO
PO
3
F
60.62
4.32
4.31
3.72
3.73
3.38
3.39
4.67
4.66
4.96
4.98
4.08
4.07
4.50
4.48
5.73
5.75
4.86
4.89
10.61
10.58)
9.76
9.73)
8.85
8.82)
10.17
10.21)
9.91
9.88)
9.46
1270
1663
3262
-
-
3.11, -8.80
1.94, -3.01
(60.46
b
C
20
C
20
H
16
N
3
3
FCl
FBr
55.84
1269
1272
1246
1274
1262
1271
1273
1266
1661
1669
1656
1669
1671
1670
1664
1668
3279
3261
3212
3267
3261
3263
3271
3274
(55.63
5
c
147-149
163-165
146-148
144-146
131-133
179-181
94-96
H
16
N
3
3
50.25
-
-
-
2.88
8.48
3.14
(50.44
5
d
C
21
22
H
H
19
21
N
N
3
3
PO
PO
3
3
F
F
61.52
(61.31
5
e
C
61.88
(62.12
5
f
21 18 3 3
C H N PO FCl
56.37
-
3.99, -6.17
(56.58
9.43)
9.86
5
5
g
C
21
C
20
C
18
H
H
H
19
23
19
N
N
N
3
3
3
PO
PO
PO
4
3
4
F
F
F
59.22
-
-
-
2.80
1.43
1.42
(59.02
9.83)
10.46
10.42)
10.77
10.74)
h
59.75
(59.55
5
i
55.43
(55.25
Table 2
1
H NMR Spectral data [a,b] of N-(Substituted)-N'-[2,3-dihydro-2-oxido-3-(4'-fluorophenyl)-1H-(1,3,2) benzoxazaphosphorin 2-yl]ureas (5a-i)
Compd.
Ar-H
-CH
2
-
-NHC(O)
C(O)NH-
Alkyl-H
5
5
a
7.87-7.13 (m, 12H)
7.71-7.10(m, 11H)
7.52-6.63(m, 11H)
7.41-6.69(m, 10H)
7.81-7.04(m, 11H)
7.61-6.99(m, 11H)
7.23-6.84(m, 11H)
7.73-7.20(m, 11H)
4.32-4.15(m, 2H)
4.28-4.12(m, 2H)
4.29-4.20(m, 2H)
5.15-4.56(m, 2H)
4.52-4.26(m, 2H)
4.29-4.17(m, 2H)
4.23-4.13(m, 2H)
4.23-4.10(m, 2H)
8.62
8.52
8.72
-
5.21
5.90
5.41
4.21
5.10
5.27
5.71
5.60
-
b
-
5
c
-
5
d
2.06(s, 3H, CH3)
2.91(s, 6H, 2CH3)
5
e
8.71
8.16
8.32
8.64
5
f
4.04(s, 2H, -CH -)
2
5
5
g
4.10(s, 3H, OCH3)
h
1.92-1.52(m, 11H)
3
3
.14-3.09(m, 4H, 3"&5"CH
.05-2.99(m, 4H, 2"&6"CH
2
)
)
5
i
7.61-6.87(m, 7H)
4.42-4.20(m, 2H)
8.18
5.25
2
6
[a] Recorded in DMSO-d ; [b] Chemical shifts in ppm.
Table 3
C NMR Spectral data [a-c] of N-(Substituted)-N'-[2,3-dihydro-2-oxido-3-(4'-fluoro phenyl)-1H-(1,3,2)benzoxazaphosphorin 2-yl]ureas (5a-i)
1
3
Carbon
C-4
5a
50.3
5b
49.2
5c
51.3
7.9)
5d
53.0
5e
50.4
5f
50.3
5g
50.7
(
(8.2)
(8.0)
(8.2)
C-5
C-6
C-7
C-8
C-9
127.4
122.8
129.2
121.3
156.6
127.1
120.9
129.9
120.0
154.8
(7.2)
130.4
122.4
127.1
118.7
149.2
(7.6)
129.2
120.4
126.9
119.9
150.3
128.9
122.2
127.7
117.7
129.1
120.1
126.4
116.4
128.4
120.3
128.4
114.0
-
-
-
(7.5)
C-10
C1′
129.8
129.1
127.2
128.1
124.5
134.1
122.8
138.0
123.7
130.9
(6.8)
122.8
-
124.7
143.4
(6.9)
C(O)-NH-R at, δ 5.90-4.21. Absence of splitting in
signals for the protons of substituents (R) attached to
the carbamido moiety shows that phosphorus coupling
is limited to P-NH proton only [12].
The mass spectral data for 5d and 5h are given in Table
4. 5d Showed its molecular ion at m/z 411 with 99.9
percent abundance showing that the benzoxazaphosphorin
ring is quite stable under electron impact. Presence of

3
72
P. Haranath, V. S. Kumar, C. S. Reddy, C. N. Raju and C. D. Reddy
Vol 44
Table 3 (Continued)
Carbon
5a
5b
5c
5d
5e
5f
5g
C-2′
C-3′
C-4′
C-5′
120.4
119.3
131.4
120.9
128.8
130.8
128.6
126.1
143.3
124.6
123.2
158.9
-
120.7
119.1
144.5
121.0
128.1
138.2
129.0
127.1
127.2
123.5
125.0
156.1
-
119.7
122.3
149.1
118.6
115.5
149.2
118.6
128.7
126.3
128.6
115.4
153.0
-
119.7
123.9
159.5
119.0
124.4
133.2
125.0
126.5
131.3
116.2
116.0
161.9
15.8
118.8
-
116.6
120.1
116.6
120.3
-
117.0
114.0
-
117.0
106.4
106.4
117.1
-
-
-
116.8
114.9
-
117.1
116.3
142.1
121.0
-
116.7
113.9
C-6′
C-1′′
C-2′′
C-3′′
C-4′′
C-5′′
C-6′′
C=O
Alkyl
-
-
116.6
-
-
-
156.2
26.2
158.7
29.8
159.2
30.1
2
7.9
[a] Chemical shifts in ppm; [b] Recorded in DMSO-d
6
; [c] J in Hz in Parentheses.
Table 4
Mass Spectral Data of some N-(Substituted)-N'-[2,3-dihydro-2-oxido-3-(4'-fluorophenyl)-1H-(1,3,2) benzoxazaphosphorin 2-yl]ureas (5a-i)
Compd.
m/z (% relative abundance)
+
•
5
5
d
h
411[99.9, (M )], 323(10), 306(7.5), 278(100), 187 (27.5).
+•
403 [100, (M )], 331 (17.5), 298 (22.5), 278(65.5), 187 (34.5).
Table 5
Antifungal and Antibacterial Activities of Compounds 5 in Terms of Zone of Inhibition (mm)
Fungi
Bacteria
Staphylococcus aureus
Compd.
Aspergillus niger
Helminthosporium oryzae
Escherichia coli
1
00
50
25
100
50
25
100
50
25
100
50
25
5
5
5
5
5
a
b
c
d
e
8
-
7
6
7
7
7
11
7
8
5
-
3
3
-
2
3
-
3
3
-
10
12
12
10
10
11
12
11
12
12
6
9
7
8
6
8
7
6
8
9
-
4
-
-
2
-
9
10
11
10
-
10
12
8
5
8
8
7
-
5
8
5
-
-
3
3
-
-
-
-
-
-
9
4
8
7
6
8
8
7
5
8
-
5
4
3
-
4
-
-
12
13
11
10
11
13
10
13
8
10
12
10
10
10
10
8
5
f
5
5
g
h
-
2
2
-
5
i
-
11
5
Bavistin
Streptomycin
10
6
-
9
5
-
Concentrations expressed in ppm; ‘-’ indicates no activity.
+
•
•
+
+•
• +
(
3
M -C H ) at m/z 323(10), (M -C H O ) at m/z
EXPERIMENTAL
7
4
7
5
+•
• +
06(7.5), base peak ion (M -C H ON ) at m/z 278(100)
7 7
Dichloroisocyanatophosphine oxide (1). A suspension of
phosphorus pentachloride (41.70 g, 0.2 mole) in dry 1,2-
dichloroethane (100 mL) was placed into a three-necked round
bottomed flask (500 mL) provided with a thermometer and an
air condenser. The latter was connected to hydrogen chloride
absorption tower. The mixture was cooled to 0°C and the
suspension of urethane (17.80 g, 0.2 mole) in 1,2-dichloroethane
conclusively confirms the proposed structure for 5d and
subsequently other members of this series.
The infrared spectra of 5a-i (Table 1) exhibited stretching
-
1
-1
frequencies in the region 1246-1274 cm , 3213-3279 cm
-1
and 1656-1671 cm for P=O [14,15], P-NH [12,16] and
C=O [13,17] respectivly.

Mar-Apr 2007
Synthesis and Antimicrobial Activity
373
(
100 mL) was added to it in small portions over a period of 20
and a half time greater antibacterial activity against Escherichia
coli than that of standard. These results open up the possibility of
their commercial applications as potent antimicrobials.
minutes with occasional swirling of the reaction mixture.
Evolution of ethyl chloride and hydrogen chloride gases started
almost instantaneously. After evolution of gases subsided, the
mixture was stirred with magnetic stirrer and slowly heated to
reflux temperature and was maintained under reflux for 30
minutes. The apparatus, after flushing with dry nitrogen, was
cooled to room temperature and refrigerated overnight. The
solution was treated with charcoal, filtered and concentrated in
the flash evaporator at 40°C. The residue on distillation under
reduced pressure gave 27.6 g (75%) of 1 as colorless liquid, bp
REFERENCES
[
1] Zhadanov, R. I.; Buina, W. A.; Kapitanova, N. A.;
Nuretdinov, I. A. Synthesis, 1979, 269.
2] Fest, C.; Schmidt, K. J. The Chemistry of Organophosphorus
Pesticides (Springer-Verlag, Berlin), 1982.
[
[3] Bhatia, M. S.; Jit, P. Experientia., 1976, 32, 1111.
3
6-37°C/8 mm [8].
Preparation of substituted phenyl carbamidophosphoric
[4] Ismail, R.;Ger pat, 1543539, 1975; Chem. Abstr., 1975, 83,
9
74116q.
5] Kirsanov, A. V.; Zhur Obshchei Khim., 1954, 24, 1033;
acid dichlorides (4). A solution of substituted anilines (2a-i,
.005 mole) in dry toluene (30 mL) was added drop wise to a
[
0
Chem. Abstr., 1955, 49, 8787 b.
stirred cold solution (-15°C) of dichloroisocyanatophosphine
oxide (1, 0.80 g, 0.005 mole) in dry toluene (40 mL). After the
addition, the temperature of the reaction mixture was maintained
in between -15°C to -5°C for 30 minutes. Later the temperature
of the mixture was raised to room temperature and stirring was
continued for another 30 minutes. Aryl carbamidophosphoric
acid dichlorides (4a-i) were collected by filtration and dried
under reduced pressure [18].
[6] Kissanov A. V.; Zhmurova, I. W. Zhur Obshchei Khim.,
1958, 28, 2478; Chem. Abstr., 1959, 53, 3118i.
[7] Kirsanov, A. V.; Marenets, M. S. Zhur Obshchei Khim.,
1
959, 29, 2256; Chem. Abstr., 1960, 54, 10855e.
[8] Papanastassiou Z. B.; Bardos, T. J. J. Med. Chem., 1962, 5,
1
000.
[9] Nagaprasada Rao, L.; Devendranath Reddy C.; Sankara
Reddy, B. Indian J. Chem., 2001, 40B, 817.
10] Kirasanov A. V.; Levchenko, E. S. J. Gen. Chem., U.S.S.R,
956, 26, 2555.
11] Quin L. D.; Verkade, J. G. Phosphorus-31 NMR Spectral
[
Synthesis
fluorophenyl)-1H-(1,3,2)benzox-azaphosphorin
5a-i). A solution of substituted phenyl carbamidophosphoric
of
N-(aryl)-N'-[2,3-dihydro-2-oxido-3-(4'-
1
2-yl]ureas
[
(
Properties in Compound Characterization and Structural Analysis,VCH
Publishers, Inc., New York, 1994.
acid dichlorides (3a-i, 0.002 mole) in dry toluene (20 mL) was
added to the solution of 2-(4-fluoro phenylamino)methylphenol
[12] Vasugovardhana Reddy, P.; Suresh Reddy C.; Venugopal, M.
Heteroatom Chem., 2003, 14(6), 509.
(4, 0.43 g, 0.002 mole) and triethylamine (0.404 g, 0.004 mole)
[13] Hari Babu, Y.; Vasugovardhana Reddy, P.; Suresh Reddy,
in dry toluene (20 mL) at 0°C. After the addition, the
temperature of the reaction mixture was maintained at 0°C for
one hour and then the temperature of the mixture was allowed to
rise slowly to 45-50°C and stirring was continued for an
additional five hours. The reaction progress was monitored by
TLC in the 1:2 mixtures 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 dried and triturated with hot methanol
to afford pure compounds (5a-i).
Antimicrobial Activity. The compounds 5a-i (Table 5) were
screened by Disc diffusion method [19,20,21] for their antimicrobial
activity against the fungi, Aspergillus niger & Helminthosporium
oryzae and bacteria, Escherichia coli & Staphylococcus aureus by
comparing with standard fungicide Bavestein and standard bacteria
Streptomycin at three different concentrations (25, 50, 100 ppm).
Compounds 5b-d, and 5f showed greater antimicrobial
activity than that of the standard. However 5g showed about one
C.; Devendranath Reddy, C.; Umamaheswari Devi, P. J. Heterocycl.
Chem., 2002, 19, 1039.
[14] Bennet, F. W.; Emeleus H. J.; Haszeldine, R. N. J. Chem.
Soc., 1954, 3598.
[15] Emeleus, H. J.; Haszeldine R. N.; Paul, R. C. J. Chem. Soc.,
1
955, 563.
[16] Chittenden, R. A.; Thomas, L. C. Spectrochim. Acta. 1966,
22, 1449.
[17] Yoshida, K.; Yano, K.; Nagamastu, K. J. Chem. Soc., Perkin
Trans, 1985, 2, 437.
18a] Kirsanov, A. V.; Levchenko, E. S. J. Gen. Chem., USSR,
956, 26, 2555; [b] Kirsanov, A. V.; Levchenko, E. S. Zh Obschch
Khim., 26, 2285,1956; Chem. Abstr., 1957, 51, 1875f.
19] Benson, H. J. Microbiological Applications, Wm. C. Brown
[
1
[
th
Publications, 5 ed., USA, 1990, 134.
20] Cruickshan, K. R. Medical Microbiology,
[
A guide to
Diagnosis and Control of Infection, II Edition, Edinburgh and London:
E. & S Livingston Ltd., 1968, 888.
[21] Beuer, A. W.; Kirby, M. M.; Sherries, J. C.; Truck, A. Am. J.
Clin. Pathol., 1969, 45, 493.