Synthesis and biological activity of phosphorylated compounds of 2-substituted benzazoles

Article abstract of DOI:10.1002/hc.20533

A series of organophosphorus derivatives have been synthesized by the reaction of phosphorylchloride with 2-(2'-hydroxyphenyl)benzimidazole and 2-(2'-hydroxynaphthyl)benzimidazole in the presence of KHCO₃ in dry THF in different molar ratios. N

Full text of DOI:10.1002/hc.20533

Heteroatom Chemistry
Volume 20, Number 4, 2009
Synthesis and Biological Activity of
Phosphorylated Compounds
of 2-Substituted Benzazoles
Sonu Pareek,1 Sushma Vyas,2 Gita Seth,1 and P. C. Vyas1
1Department of Chemistry, University of Rajasthan, Jaipur, India
2Govt. P. G. College, Kaladera, Jaipur, India
Received 10 September 2008; revised 11 February 2009
the heterocyclic moiety and in continuation of our
ABSTRACT: A series of organophosphorus deriva-
tives have been synthesized by the reaction of phospho-
rylchloride with 2-(2ꢀ-hydroxyphenyl)benzimidazole
and 2-(2ꢀ-hydroxynaphthyl)benzimidazole in the pres-
ence of KHCO3 in dry THF in different molar ra-
tios. Newly synthesized derivatives were tested for
their insecticidal activity against Periplenata ameri-
laboratory synthesis of such compounds [7–11], we
have synthesized some environment friendly, bio-
logically active compounds by reacting 2-substituted
benzimidazole derivatives with POCl3 in 1:1, 2:1, and
3:1 molar ratios in dry THF (Scheme 1).
ꢁ
C
cana.
2009 Wiley Periodicals, Inc. Heteroatom Chem
RESULTS AND DISCUSSION
20:246–249, 2009; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20533
IR spectra of phosphorylated derivatives are sum-
marized in Table 1. A strong absorption band in the
region 1290–1280 cm−1 in 2a,b–4a,b has been as-
cribed to P O stretching vibrations. The absorption
bands in the region 1150–1120 cm−1 and 980–960
cm−1 have been assigned to (P) O C and P O (C)
stretching vibrations, respectively. The presence of
these vibrational frequencies indicates the deproto-
nation of the OH group of 1a and 1b during the
synthesis. Two strong absorption bands in the re-
gion 3250–3150 cm−1 and 1420 cm−1 characteristic
of NH stretching and bending vibrations of the imi-
dazolyl group of a benzimidazole ring were observed
in the spectra of 1a,b–4a,b. The presence of these
frequencies further supported the formation of a
P O C bond during the synthesis of phosphorylated
derivatives and nondeprotonation of the NH group.
IR spectra of 2a,b–3a,b also showed two medium in-
tensity bands at 530–510 cm−1 and 600 cm−1 assigned
to symmetric and asymmetric stretching vibrations
of the P Cl bond, whereas these bands were found
absent in IR spectra of compounds 4a–b.
INTRODUCTION
The phosphorylation plays a significant role in the
biological system. Organophosphorus compounds
possess insecticidal, pesticidal, acaricidal, and
fungicidal properties [1–4]. These compounds exert
their biological action on arthropods by attacking
the system of neural transmission and inhibit-
ing the function of acetylcholinesterase (AChE)
[5,6]. The presence of a heterocyclic moiety in
organophosphorus compounds further enhances
their biological activity.
In light of physiological activities associated
with organophosphorus compounds incorporating
Correspondence to: Sonu Pareek; e-mail: sonu90@hotmail.com.
Contract grant sponsor: State Department of Science and Tech-
nology, Jaipur, India.
c
ꢀ
2009 Wiley Periodicals, Inc.
246

Synthesis and Biological Activity of Phosphorylated Compounds of 2-Substituted Benzazoles 247
KHCO3
Refluxing
O
N
Cl
Cl
N
Cl
Ar O P
+
Cl P O
Cl
Ar OH
1
for ~15 h
N
H
N
H
2a,b
1a,b
a Ar =Phenyl
b Ar = Naphthyl
2 KHCO3
Refluxing
O
Ar O P
Cl
N
N
2
1a,b
1a,b
O
Ar
POCl3
+
~15 h
N
H
N
H
3a,b
3 KHCO3
Refluxing
O
N
N
Ar O P
O
Ar
N
3
POCl3
+
~15 h
N
N
H
H
O
Ar
N
H
4a,b
SCHEME 1
The 1H NMR spectra of 1a,b–4a,b are presented
in Table 2. They showed characteristic resonance
signal in the region δ 6.9–9.0 ppm as a broad singlet
assigned to the imidazolyl proton. The presence of
resonance signal due to the NH proton in 2a,b–4a,b
further supported the nonremoval of imidazolyl pro-
ton during the phosphorylation reaction. A multiplet
has been observed in the region δ 7.5–8.0 ppm in all
these derivatives and are assigned to aromatic pro-
tons of both phenyl and benzimidazolyl rings. The
chemical shift values for the protons of benzimida-
zole moiety were observed nearly in the same region
as described by Black and Heffernan [12]. A broad
singlet due to OH group at δ 10.2–10.3 ppm was
observed in proton NMR spectra of derivatives 1a,b,
but this resonance signal due to hydroxyl proton of
the phenyl ring was found absent in 2a,b–4a,b, in-
dicating the deprotonation of the OH group dur-
ing the phosphorylation reaction. This further con-
firmed the formation of the Ar O P bond during the
reaction. 31P spectra of 2a,b–4a,b showed resonance
signal in the region δ 60–70 ppm.
TABLE 1 IR Spectral Data of Phosphorylated Derivatives of 2-Substituted Benzimidazoles (cm−1
)
Compounds
ν
as
NH
δ NH
ν
as
OH (δ OH)
P O C
P O
P Cl
1a
1b
2a
2b
3a
3b
4a
4b
3150–3040
3150–3050
3360
3340
3350–3310
3350
1420
1420
1420
1420
1420
1410
1420
1410
3400 (1320)
3360 (1320)
–
–
–
–
–
–
530,610
510,600
530
520,600
–
–
–
–
–
–
–
1100,980
1120,960
1130,970
1120,960
1140,980
1130,970
1285
1270
1290
1280
1280
1290
3300
3300
–
Heteroatom Chemistry DOI 10.1002/hc

248 Pareek et al.
dropping funnel was added slowly (at 0◦C). This mix-
ture was refluxed with continuous stirring for about
15 h. After checking the completion of the reaction
by running TLC, the product was isolated by filter-
ing through a closed sintered funnel. The filtrate was
concentrated to one fourth of its volume under re-
duced pressure and was kept overnight in a vacuum
desiccator to obtain crystals.
2a: (C13H9N2O)P(O)Cl2, M. wt. calcd (found) 327
(329); M.P. 242◦C; brownish white crystals, C (calcd)
found (47.70) 47.86, H (2.75) 2.72, N (8.56) 8.45, P
(9.48) 9.42, Cl (21.71) 22.65.
TABLE 2 NMR Spectra (δ, ppm)
Compounds
NH
8.4
8.3
8.4
8.6
8.6
8.5
8.5
8.4
OH
Aromatic H
31P
1a
1b
2a
2b
3a
3b
4a
4b
10.3 (bs)
10.2 (bs)
6.9–7.8 (m)
7.1–8.0 (m)
7.6–8.2 (m)
7.4–8.0 (m)
7.4–8.0 (m)
7.4–8.0 (m)
6.9–8.0 (m)
7.4–8.0 (m)
–
–
–
–
–
–
–
–
68.1
66.4
66.2
67.4
64.6
64.3
bs = Broad singlet; s = singlet; m = multiplet.
2b: (C17H11N2O)P(O)Cl2, M. wt. calcd (found)
377 (406); M.P. 200◦C; violet crystals, C (calcd) found
(54.11) 54.10, H (2.91) 2.99, N (7.42) 7.49, P (8.22)
8.32, Cl (18.83) 18.90
EXPERIMENTAL
Stringent precautions were taken to exclude mois-
ture during the experimental manipulations. Sol-
vents were dried by standard methods. Melting
points were determined in open capillaries and are
uncorrected. Carbon and hydrogen analyses were
performed on a Perkin–Elmer CHNO/S analyzer. IR
spectra of compounds were recorded on a Perkin–
Synthesis of 3a,b
Compounds 1a/1b (0.002 mol) in dry THF (30 mL)
was taken in a three-necked round-bottomed flask
along with KHCO3 (0.002 mol). To this mixture, a
solution of POCl3 (0.001 mol) was added slowly (at
0◦C). The mixture was refluxed for about 15 h with
continuous stirring. Same procedure was applied to
obtain the product as described above.
3a: (C13H9N2O)2P(O)Cl, M. wt. calcd (found) 501
(503); M.P. 259◦C; creamish white, C (calcd) found
(62.27) 61.33, H (3.59) 3.67, N (11.17) 11.09, P (6.18)
6.26, Cl (7.08) 6.92.
1
Elmer 577 grading IR spectrometer. The H NMR
spectra (chemical shifts in δ ppm) were recorded on
a FX 90Q Jeol-type spectrophotometer at 90 MHz
using TMS as an internal reference. The purity of all
the compounds was checked by TLC on silica gel ‘G’
plates using pet ether–methanol mixture and visual-
izing spots by iodine vapors. Mass spectral data are
given in Table 3.
3b: (C17H11N2O)2P(O)Cl, M. wt. calcd (found)
601 (601); M.P. 233◦C; pale violet, C (calcd) found
(67.88) 68.97, H (3.66) 3.49, N (12.46) 12.30, P (5.15)
5.21, Cl (5.90) 5.83.
Synthesis of 1a,b
Compounds 1a and 1b were prepared by react-
ing o-phenylene diamine with salicylic acid and o-
hydroxy naphthoic acid, respectively in freshly pre-
pared polyphosphoric acid. Reactions were carried
out according to the procedure described by Heins
et al. [13] and modified by Vyas et al. [14].
Synthesis of 4a,b
1a: C13H10N2O, M. wt. calcd (found) 210 (223);
M.P. 220◦C; white crystals, C (calcd) found (74.27)
74.01, H (4.77) 4.69, N (13.32) 13.23.
1b: C17H12N2O, M. wt. calcd (found) 260 (268);
M.P. 130◦C; violet crystals, C (calcd) found (78.44)
78.25, H (4.64) 4.51, N (10.76) 10.61.
Compounds 1a/1b (0.003 mol) and KHCO3 (0.003
mol) in dry THF (30 mL) were taken in a three-
necked round-bottomed flask, and to this mixture
a solution of POCl3 (0.001 mol) in dry THF (30 mL)
was added slowly (at 0◦C). This mixture was refluxed
for about 15 h with continuous stirring. The prod-
uct was obtained by following the same procedure
as described above.
4a: (C13H9N2O)3P(O), M. wt. calcd (found) 674
(723); M.P. 234◦C; creamish white, C (calcd) found
(69.43) 69.55, H (4.00) 4.10, N (9.31) 9.45, P (4.59)
4.78.
Synthesis of 2a,b
Dry nitrogen gas was flushed continuously dur-
ing the reaction tenure. 1a/1b (0.001 mol) in dry
THF (30 mL) were taken in a flame-dried three-
necked round-bottomed flask along with KHCO3
(0.001 mol). To this mixture, the solution of POCl3
(0.001 mol) in dry THF (30 mL) with the help of a
4b: (C17H11N2O)3P(O), M. wt. calcd (found) 824
(912); M.P. 225◦C; violet, C (calcd) found (74.27)
74.36, H (4.00) 4.02, N (10.19) 10.24, P (3.76) 3.65.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Biological Activity of Phosphorylated Compounds of 2-Substituted Benzazoles 249
TABLE 3 Mass Spectral Data of Phosphorylated Derivatives
Compounds
m/z (%)
2a
(C13H9N2O)P(O)Cl2
327.11 (12), 292.26 (19), 294.16 (33), 256.66 (21), 259.31 (29), 241.7 (23), 209.36 (100), 195
(8), 117 (78), 90 (32)
2b (C17H11N2O)P(O)Cl2 377.27 (18), 341.79 (30), 344.12 (33), 307.2 (19), 308.75 (27), 290.6 (28), 244.31 (100), 118.2
(14), 90 (21)
3a
(C13H9N2O)2P(O)Cl
501.2 (21), 466.21 (29), 468.1 (37), 450 (12), 257.32 (27), 241 (100), 210 (35), 118.3 (12),
90.41 (8)
3b (C17H11N2O)2P(O)Cl 601 (12), 567.14 (35), 550.4 (9), 433 (17), 306.32 (14), 291.22 (78), 260 (13), 243.72 (100),
117.8 (22), 90.53 (18)
4a
4b
(C13H9N2O)3P(O)
(C17H11N2O)3P(O)
673.58 (20), 657.29 (12), 541.52 (8), 449.11 (20), 331 (7), 256.72 (22), 240.27 (100), 209 (33),
117.13 (77), 90 (21)
824.23 (14), 807.69 (9), 69.66 (30), 549.42 (42), 432 (10), 289.7 (6), 259.21 (100), 133.26 (23),
118.12 (20) 91 (17)
TABLE 4 Percent Insecticidal Mortality at 20, 40, and 60 μg/cm3 after 48/72 h
Concentration (μg/cm3)
Time (h)
20
48
40
48
60
48
20
72
40
72
60
72
1a
1b
2a
2b
3a
3b
4a
4b
30
30
50
50
54
58
62
68
36
34
54
58
58
64
70
72
36
34
60
66
68
72
80
80
34
32
50
56
54
60
62
68
36
38
58
60
62
64
70
74
38
42
66
66
72
74
82
80
[3] Sengupta, S. K.; Pandey, O. P.; Rao, G. P.; Dwivedi,
A.; Singh, P. Phosphorus Sulphur Silicon Relat Elem
2003, 178, 839.
[4] Sengupta, S. K.; Pandey, O. P.; Rao, G. P.; Vishen, P.
Metal-Based Drugs 2002, 8, 293.
[5] Fest. C.; Schmidt, K. J. Chemistry of Organophos-
phorus Compounds; Springer-Verlag: Berlin, 1973.
[6] Theissen P. J.; Pesticide Chemistry, Vol I; Boyle, Y. P.;
Fujita, T. (Eds.); Pergamon Press: Oxford, 1983.
[7] Vyas, P. C.; Vyas, S.; Vyas, P.; Chahar, Y., Asian J
Chem 1993, 5, 844.
[8] Vyas, P. C.; Kaur, N.; Vyas, S. Heterocycl Commun
1997, 3(1), 56–58.
[9] Kaur, N.; Vyas, P.; Vyas, P. C. Indian J Heterocycl
Chem 1996, 6(1), 45–48.
[10] Mittal, S.; Samota, M. K.; Kaur, J.; Seth, G. Phospho-
rus Sulfur Silicon Relat Elem 2006, 12, 181.
[11] Pareek, S.; Vyas, S.; Seth, G.; Vyas, P. C. Heteroatom
Chem 2007, 19, 1.
INSECTICIDAL ACTIVITY
The insecticidal activity of derivatives 1a,b–4a,b was
tested against Periplenata americana. The test was
performed at room temperature in a plastic box of
10 × 10 × 12 cm3 by the contact and topical method
[15]. The percentage mortality was recorded after
48 and 72 h. The inference drawn from the results
of study showed that the activity of compounds in-
creased with the increase in the concentration. Tris-
phosphorylated derivatives were found to be more
effective against the pest than bis- and monophos-
phorylated derivatives. Results of tests are given in
Table 4.
[12] Black, P. J.; Heffernan, M. L. Aust J Chem 1962, 15,
862.
[13] Heins, D. W.; Alheim R. J.; Leawitt, J. J. J Am Chem
Soc 1957, 79, 427.
[14] Vyas, P. C.; Oza, C. K.; Goyal, A. K. Chem Ind 1980,
2, 280.
REFERENCES
[1] Walsch, E. N.; Griffith, E. J.; Parry, R. W.; Quin, L. D.
Phosphorus Chemistry; American Chemical Society:
Washington, DC, 1992.
[2] Yu Lorish, V.; Grachev, M. K.; Bekker, N. R.;
Nifantev, E. G. Zh Obshch Khim 1993, 63, 783.
[15] Singh, R. S., Plant Diseases, 4th ed.; Oxford and IBH
Publishing Co.: New Delhi, India, 1978; p. 19.
Heteroatom Chemistry DOI 10.1002/hc