Synthesis and antimicrobial activity of 1-[(substituted carbamoyl)amino]-1H,3H-1λ5-[1,3,2]oxazaphospholo[3,4-a] benzimidazol-1-ones

Article abstract of DOI:10.1080/00397910701483886

1-[(Substituted carbamoyl)amino]-1H,3H-1λ5-[1,3,2]oxazaphospholo[3, 4-a]benzimidazol-1-ones were synthesized by reacting benzimidazole 2-methanol (4) with different chlorides of carbamidophosphoric acids (3) in the presence of triethylamine at 40-45°C. Th

Full text of DOI:10.1080/00397910701483886

w
Synthetic Communications , 37: 3429–3437, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701483886
Synthesis and Antimicrobial Activity of
-[(Substituted Carbamoyl)Amino]-1H,3H-
1
5
l -[1,3,2]oxazaphospholo[3,4-a]
benzimidazol-1-ones
1
U. Anasuyamma
Department of Organic Chemistry, University of Murcia, Campus of
Espinardo, Murcia, Spain
P. Haranath, M. Anil Kumar, C. Suresh Reddy, and C. Naga Raju
Department of Chemistry, Sri Venkateswara University College of
Engineering, Tirupati, India
5
Abstract: 1-[(Substituted carbamoyl)amino]-1H,3H-1l -[1,3,2]oxazaphospholo[3,4-a]
benzimidazol-1-ones were synthesized by reacting benzimidazole 2-methanol (4) with
different chlorides of carbamidophosphoric acids (3) in the presence of triethylamine at
1
13
31
4
0–458C. Their H, C, and P NMR spectral data were discussed. The title
compounds were tested for their activity against the fungi Aspergillus niger and
Fusarium solani and bacteria Staphylococcus aureus and Escherichia coli. These
compounds showed moderate antibacterial activity when compared with antifungal
activity.
Keywords: carbamido phosphoric acid dichloride, isocyanatophosphonic dichloride,
oxazaphosphospholo benzimidazols
INTRODUCTION
Extensive investigation of compounds containing P-N linkages by numerous
research groups have led to many interesting and far-reaching
Received in India February 5, 2007
Address correspondence to C. Suresh Reddy, Department of Chemistry, Sri Venka-
teswara University College of Engineering, Tirupati 517 502, India. E-mail:
csureshsvu@yahoo.com
3
429

3
430
U. Anasuyamma et al.
[1]
developments. Organophosphorus heterocycles bearing P-N functionality
[
2–6]
have shown antitumor, pesticidal, and medicinal activity.
Benzimida-
In continuation
of our research interests, several new classes of 1-[(substituted carbamoyl)a-
[
7,8]
zol-2-yl-carbamates have proven anthelmintic activity.
5
mino]-1H,3H-1l -[1,3,2]oxazaphospholo[3,4-a]benzimidazol-1-ones were
synthesized and characterized by spectral data and were screened for their
antifungal and antibacterial activity.
RESULTS AND DISCUSSION
[9,10]
Addition of equivalent amounts of isocyanatophosphonic dichloride
(1) to
various amines (2) at 2158C in dry toluene led to the corresponding carbami-
dophosphoric acid dichloride (3) when equimolar quantities of benzimidazole
2
-methanol (4) reacted with carbamidophosphoric acid dichlorides (3a–j) in
dry toluene–tetrahydrofuran mixture (1:1) in the presence of triethylamine at
0–458C, which led to the formation of the title compounds (Scheme 1).
4
Isolation of 5a–j was achieved by filtering off triethylamine hydrochloride,
evaporating the filtrate, and washing the residue from ethanol. The crude
residues were further purified by recrystallization from aqueous 2-propanol.
3
1
Reaction yields, elemental analyses, and IR and P NMR data of 5a–j
1
are given in Table 1. Tables 2 and 3 contain H and C NMR spectral data.
13
[
11]
The IR spectra of 5a–j
1
(Table 1) showed bands at 3253–3283 (P-NH),
2
1
248–1276 (P ¼ O), and 1650–1681 (-NH-CO-Ar) cm
.
showed a singlet for H-3 at 3.20–
1
The H NMR spectra of 5a–j
.38 ppm. The protons of arylcarbamido and benzimidazole moieties in
[12]
3
0
0
0
Scheme 1. 5a, C
0
6
H
5
; 5b, C
0
6
H
4
-Cl(4 ); 5c, C
-(OCH
6
H
4
0
-Br(4 ); 5d, C
0
6
H
4
-CH
3
(4 ); 5e, C
0
6
H
3
-
0
(
CH
3
)
2
(2 ,4 ); 5f, C10
H
7
(1 ); 5g, C
6
H
3
3
(3 ,4 ); 5h, C
6
H
4
-CH
2
Cl(2 ); 5i, C
6
H
11
;
5
j, C H NO.
4
8

3
Table 1. Physicochemical, IR, and P NMR spectral data of 5a–j
1
a
2
1
)
Elemental analysis (%) found (calcd.)
IR (cm
3
1
Yield
(%)
Molecular
formula
P NMR
data (ppm)
Compd.
Mp (8C)
C
H
N
P 55 O
C 55 O
P-NH
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
189–191 (dec)
178–180
69
60
62
61
58
58
57
53
56
53
C
15
H
13
N
4
PO
3
54.80 (54.88)
4.03 (3.99) 17.12 (17.07) 1276
3.30 (3.33) 15.40 (15.45) 1261
2.94 (2.97) 13.70 (13.76) 1274
4.37 (4.42) 16.40 (16.37) 1266
4.75 (4.81) 15.66 (15.72) 1253
4.04 (4.00) 14.75 (14.81) 1268
4.46 (4.41) 14.37 (14.43) 1271
3.79 (3.75) 14.92 (14.87) 1273
5.66 (5.73) 16.81 (16.76) 1248
4.69 (4.78) 20.65 (20.76) 1251
1654
1681
1671
1656
1674
1668
1678
1664
1650
1661
3277 22.67, 1.57
3262 21.93, 22.93
3279 22.86
3283 27.56
3261 23.15
3275 23.92, 25.13
3282 22.80
3253 21.45
3281 21.46
3270 21.53
C H N PO Cl 49.62 (49.67)
1
5
12
12
15
4
4
4
3
3
3
3
3
5
163–165 (dec)
141–143 (dec)
162–164
C
C
15
16
H
H
N
N
PO
PO
Br 44.19 (44.25)
56.06 (56.14)
57.35 (57.30)
60.39 (60.32)
52.52 (52.58)
C H N PO
1
7
17
15
17
4
4
4
214–216
181–183
C
C
19
17
H
H
N
N
PO
PO
g
h
i
138–140
192–194
185–187
C H N PO Cl 51.09 (51.01)
1
6
14
19
16
4
4
5
3
3
4
C
C
15
13
H
H
N
N
PO
PO
53.82 (53.89)
46.41 (46.29)
j
a
Compounds triturated with 2-propanol.

1
Table 2. H NMR spectral data of 5a–j
a
Compd.
-CH2-
Ar-H
Cyclohexyl-H/CH
2
-Ph
Ar-CH
3
-NH-CO
C(O)-NH-
5
5
5
5
5
a
b
c
3.26 (s,2H)
3.23 (s,2H)
3.28 (s,2H)
3.20 (s,2H)
3.25 (s,2H)
6.90–7.40 (m, 9H)
6.84–7.32 (m, 8H)
6.92–7.46 (m, 8H)
6.93–7.49 (m, 8H)
6.87–7.39 (m, 7H)
—
—
—
—
—
—
—
8.70 (brs)
8.93 (brs)
9.10 (brs)
8.94 (brs)
9.13 (brs)
7.90 (brs)
8.25 (brs)
8.53 (brs)
7.95 (brs)
8.12 (brs)
—
2.28 (s, 3H, 2 -CH
0
0
0
d
e
3
)
2.16 (s, 3H, 2 -CH )
3
2
.26 (s, 3H, 4 -CH
—
4.12(s, 3H, OCH3)
3
)
5
5
f
3.30 (s,2H)
3.27 (s,2H)
6.88–7.41 (m, 11)
6.82–7.12 (m, 8H)
—
—
9.12 (brs)
8.75 (brs)
8.23 (brs)
8.21 (brs)
g
4
.32(s, 3H, OCH3)
5
5
5
h
3.26 (s,2H)
3.32 (s,2H)
3.35 (s,2H)
6.82–7.12 (m, 8H)
6.92–7.30 (m, 4H)
6.81–7.25 (m, 4H)
3.98 (s, 2H, CH -Ph)
1.21–1.86
3.36–3.54 (m, 8H)
2
—
—
—
9.14 (brs)
9.32 (brs)
9.21 (brs)
8.01 (brs)
8.34 (brs)
8.40 (brs)
i
j
a
Chemical shifts in ppm. Recorded in CDCl3.

Synthesis and Antimicrobial Activity
3433
1
3
a
C NMR data of some compounds of 5a–j
Table 3.
Compound
Carbon atoms
5a
66.5
5b
5d
5e
5g
C-3
C-5
C-6
C-7
C-8
C-9
C-10
C-11
65.9
66.9
129.4
126.4
125.1
123.4
139.0
137.8
152.4
142.8
117.9
128.8
129.2
128.8
117.9
65.4
130.4
125.4
125.8
123.6
138.4
136.5
152.8
143.4
128.3
127.2
129.6
127.9
116.3
66.7
131.5
125.8
124.6
124.1
139.6
137.6
153.5
144.2
120.2
142.6
133.2
121.9
120.2
160.9
—
128.8 131.2
124.0 125.2
123.1 124.2
122.8 123.9
139.4 139.8
137.3 137.2
153.6 153.8
142.5 144.6
119.4 118.3
129.2 128.6
120.1 126.9
129.2 128.6
119.4 118.3
0
0
C-1
C-2
0
0
0
0
C-3
C-4
C-5
C-6
C 55 O
161.2 160.8. 160.1
161.5
0
0
C -(CH )
3
—
—
—
—
21.6
—
21.2 (4 -CH )
3
0
1
8.7 (2 -CH
—
3
)
0
0
C -(OCH
3
)
55.4 (4 -OCH
0
3
)
5
5.1 (3 -OCH )
3
a
3
Chemical shifts in ppm. Recorded in CDCl .Compounds 10c, 10f, 10h, 10i, and 10j
gave unresolved spectra due to poor solubility.
5
a–j exhibited multiplets in the range of 6.81–7.49 ppm. The proton in
P-NHC 55 O appeared at extreme downfield at 8.70–9.32ppm as a broad
singlet when compared to the other NH-C 55 O proton. It is of interest to
note that phosphorus coupling is limited to P-NH protons only and does not
extended to other protons of carbamido moiety. The NH proton signals
were confirmed by D O exchange experiments.
2
1
3
The C NMR chemical shifts were recorded for some members of the title
compounds (5a, 5b, 5d, 5e, and 5g). The chemical shifts for C-3, C-5, C-6, C-7,
and C-8 appeared at 65.4–66.9, 128.8–131.5, 124.0–126.4, 123.1–125.8, and
1
22.8–124.1 ppm respectively. The nitrogen bearing C-9 and C-10 exhibited
signals in downfield at 138.4–139.8 and 136.5–137.6 ppm, whereas the
signal of C-11 of the benzimidazole moiety appeared at 152.4–153.8 ppm.
0
0
0
0
0
For C-1 , C-(2 , 6 ), C-4 , and C-(3 , 5), chemical shifts appeared at 142–
1
1
44.6, 117.9–128.3, 116.3–120.2, 120.1–133.2, 128.2–142.6, and 128.2–
29.6 ppm respectively. The signals for the carbamido function of C 55 O is
observed at 160.9–161.5ppm. The chemical shifts could not be identified in
1
the C NMR spectra of 5c, 5f, and 5h–j because of the poor quality of the
3
spectrum, due to their meager solubility in dimethyl sulfoxide (DMSO).

3
434
U. Anasuyamma et al.
3
The P NMR chemical shifts of these compounds (5a–j) appeared in the
1
[13]
range of 21.45 to 27.56 ppm. Compounds 5a, 5b, and 5f showed two signals,
and perhaps they may be existing as two conformers in the solution state.
ANTIMICROBIAL ACTIVITY
The compounds 5a–j (Table 4)werescreened attwo different concentrations (25
and 75 mg/disc) for their antifungal activity on Aspergillus niger and Fusarium
solani,: Nystatin (25 mg/disc) is used as the standard according to the disc-
[
14]
diffusion method. The fungal cultures were grown on potato dextrose broth
6
at 258C for 3 d, and spore suspension was adjusted to 10 spores/mL. Their anti-
bacterial activity was evaluated against Staphylococcus aureus and Escherichia
5
[15]
coli (10 cell/mL) on nutrient agar plates at 378C for 24 h.
(
Vancomycin
25 mg/disc) was used as standard antibiotics. The highlight is that 3b, 3c, 3g,
3h, and 3j exhibited higher antiacterial activity and 3a, 3d–f, and 3i showed
equal antibacterial activity when compared to that of the standard Vancomycin.
The presence of halo groups in these compounds 3b, 3c, and 3h appears to be
responsible for their increased antimicrobial activity.
EXPERIMENTAL
The melting points were determined on a Mel-Temp apparatus and are uncor-
rected. Elemental analyses were performed by the Central Drug Research
Institute, Lucknow, India. All IR spectra were recorded as KBr pellets on a
1
13
Perkin-Elmer 1430 unit. H and C NMR spectra were recorded on an
1
AMX 400-MHz spectrometer operating at 400 MHz for H, 100 MHz for
1
3
31
C, and 161.9 MHz for P in CDCl . The chemical shifts were referenced
3
1
to TMS ( H and C) and 85% H PO ( P).
13
31
3
4
Benzimidazole 2-methanol (4) was procured from Aldrich and was used
without further purification.
5
Preparation of 1-[(Phenylcarbamoyl)amino]-1H,3H-1l -
[
1,3,2]oxazaphospholo[3,4-a] benzimidazol-1-one (5a)
A solution of aniline (0.186 g, 0.002 mol) in dry toluene (25 mL) was added
dropwise over a period of 20 min to a cold and stirred solution (2158C) of
dichloroisocyanatophosphine oxide (1, 0.320 g, 0.002 mol) in dry toluene
(
30 mL). After the addition, the temperature of the reaction mixture was
slowly raised to room temperature and was maintained for 2 h. Phenyl carba-
midophosphoric acid dichloride (3a), being insoluble in toluene, separated
out. To this mixture, a cold solution (08C) of benzimidazole 2-methanol (4,
0.296 g, 0.002 mol) and triethylamine (0.404 g, 0.004 mol) in dry

a
Table 4. Antibacterial and antifungal activity of compounds 5a–j
Zone of inhibition (mm)
Bacteria
Fungi
Staphylococcus aureus
Echerichia coli
Aspergillus niger
Fusarium solani
2
5
mg/disc
75
mg/disc
25
mg/disc
75
mg/disc
25
mg/disc
75
mg/disc
25
mg/disc
75
mg/disc
Compd.
5
5
5
5
5
5
5
5
5
5
a
b
c
d
e
f
7
8
15
17
18
13
14
16
17
21
15
20
6
7
7
7
6
7
8
7
6
8
8
13
15
16
14
13
15
17
18
13
17
6
7
7
5
6
6
8
8
7
8
11
15
16
11
13
12
15
17
13
18
8
10
8
15
19
17
11
15
14
17
20
18
19
8
6
6
6
7
7
7
g
h
i
8
9
9
11
9
7
j
9
10
10
Vancomycin
Nystatin
8
12
a
Concentration expressed in ppm.

3
436
U. Anasuyamma et al.
tetrahydrofuran (30 mL) was added. After the addition, the temperature of the
reaction mixture was raised slowly to 40–458C and kept under stirring for
4
–5h. Triethylamine hydrochloride was filtered off from the mixture, and
the solvent was removed under reduced pressure. The gummy residue thus
obtained was washed with water, dried, and recrystallized from aqueous
2
0
-propanol to get pure compound of (5a) as an amorphous powder. Yield
.452 g (69%), mp 189–1918C (dec). The other compounds (5b–j) were
prepared by adopting the same procedure.
ACKNOWLEDGMENTS
The authors express their thanks to C. Devendranath Reddy for his helpful
guidance and discussions, and the director of SIF, Bangalore, for the spectra.
REFERENCES
1
2
. Cremlyn, R. J. W.; Wakeford, D. H. Topics in Phosphorus Chemistry; John
Wiley & Sons: New York, 1976, Vol. 8.
. Venugopal, M.; Sankar Reddy, B.; Devendranath Reddy, C.; Berlin, K. D.
Synthesis and antimicrobiol activity of 2-substituted-2,3-dihydro-5-propoxy-1H-
1
,3,2-benzodiazaphole 2-oxides. J. Heterocyclic. Chem. 2001, 38, 275–279.
. Kartizky, A. R.; Ress, C. W.; Seriven, E. F. V. Comprehensive Heterocyclic
Chemistry II; Pergmon Press: Oxford, U.K., 1996.
. Lemke, T. L.; Boring, D. Novel heterocycles. Synthesis of the 2,4,3-benzodiaza –
phosphepine ring system. J. Heterocyclic. Chem. 1980, 17, 1455–1456.
. Zimmer, H.; Sill, A. D. Potential anticancer agents. IV. Heterocyclic phosphora-
mide nitrogen mustards. Arzneimittelforschung. 1964, 14, 150–151.
. Vasu Goverdhana Reddy, P.; Hari Babu, Y.; Suresh Reddy, C.; Srinivasulu, D.
Synthesis of 2-substituted-2,3-dihydro-5-benzoyl-1H-1,3,2-benzodiazaphosphole
3
4
5
6
2
-oxides/sulfides. Hetero. Atom. Chem. 2002, 13, 340–345.
7
. Averkim, E. A.; Beard, C. C.; Dvorak, C. A.; Edwards, J. A.; Fried, J. H.;
Kilian, J. G.; Schiltz, R. A.; Kistner, T. P.; Drudge, J. H.; Lyons, E. T.;
Sharp, M. L.; Crowin, R. M. Methyl 5(6)-phenylsulfinyl-2-benzimidazolecarba-
mate, a new, potent anthelmintic. J. Med. Chem. 1975, 18, 1164–1166.
. Gyarik, R. J.; Theodrides, V. J. Methyl 5-propylthio-2-benzimidazolecarbamate.
US Patent 3, 1975; Chem. Abstr., 1976, 84, 31074r.
8
9
. Papanastassiou, Z. B.; Bardos, T. J. Synthesis of potential “dual antagonists.”
Some bis (1-aziridinyl) phosphinylcarbamates and their structural analogs.
J. Med. Chem. 1962, 5, 1000–1004.
1
0. Zhadanov, R. I.; Buina, W. A.; Kapitanova, N. G.; Nuretdinov, I. A. Biologically
active stable radical;XV.spin-labeled alkyl carbamate-N-phosphonic acid aziri-
dides. Synthesis 1979, 269–272.
11. Thomas, L. C. Interpretation of the Infrared Spectra of Organophosphorus
Compounds; Heydon: London, 1974.
1
2. Silverstein, R. M.; Webster, F. X. Spectrometric Identification of Organic
Compounds, 6th edn; Wiley: New York, 1998.

Synthesis and Antimicrobial Activity
3437
1
1
3. Quin, L. D.; Verkade, J. G. Phosphorus-31 NMR Spectral Properties in Compound
Characterization and Structural Analysis; VCH Publishers Inc: New York, 1994.
4. Umamaheswari Devi, P.; Srinivasa Reddy, P.; Usha Rani, N. R.; Reddanna, P.
Lipoxygenase metabolites of a-linolenic acid in the development of resistance
in pigeonpea, Cajanus cajan (L.) Millsp, seedlings against Fusarium udum
infection. Eur. J. Plant Path. 2000, 106, 857–865.
1
5. Colle, J. G.; Duguid, J. P.; Fraser, A. G.; Mannion, B. P. Mackie & Mecartney
Practical Medicinal Microbiology, 13th edn; Churchil Livingstone Ltd:
Edinburgh and London, 1989, Vol. 2.