Synthesis of N-(thio)phosphoryl-N′-2-benzoxazolyl semicarbazides

Article abstract of DOI:10.1002/hc.1024

We prepared the benzoxazole derivatives bearing the (thio) phosphoryl moiety by addition reactions of 2-hydrazionbenzoxazole with isothiocyanato (thio) phosphates and characterized their structures by elementary analysis and ¹H NMR and IR spectral data. From the results of biological activity screening, we found that these compounds possess some herbicidal, and plant growth regulator activities, and especially good fungicidal activity against Puccinia recondita.

Full text of DOI:10.1002/hc.1024

Heteroatom Chemistry
Volume 12, Number 3, 2001
Synthesis of N-(Thio)phosphoryl-NЈ-2-
Benzoxazolyl Semicarbazides
Wen-Bin Chen and Gui-Yu Jin
The State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin 30071, P.R. China
Received 20 July 2000; revised 12 December 2000
ticides, but not with regard to benzoxazole deriva-
tives. Therefore, we have incorporated isothiocyan-
ato (thio) phosphate moieties in the benzoxazole
ring in order to prepare novel and potentially useful
compounds 8 from 2-hydrazinobenzoxazole. By bio-
logical activity screening, we have found that these
compounds show broad-spectrum antifungicidal ac-
tivity, especially against Puccinia recondita. The syn-
thesis of these compounds is outlined in Schemes 1,
2, and 3. The intermediate 2-hydrazinobenzoxazole
4 was synthesized from 2-aminophenol in three
steps; the isothiocyanato (thio) phosphate 7 was syn-
ABSTRACT: We prepared the benzoxazole derivatives
bearing the (thio) phosphoryl moiety by addition re-
actions of 2-hydrazionbenzoxazole with isothiocyan-
ato (thio) phosphates and characterized their struc-
1
tures by elementary analysis and H NMR and IR
spectral data. From the results of biological activity
screening, we found that these compounds possess
some herbicidal, and plant growth regulator activities,
and especially good fungicidal activity against Pucci-
nia recondita. ᭧ 2001 John Wiley & Sons, Inc. Het-
eroatom Chem 12:151–155, 2001
thesized in two steps and the total yield was 43.9–
76.2%. The title compounds 8 were prepared at room
temperature, or slightly higher, and were purified by
INTRODUCTION
Benzoxazole derivatives are biologically versatile as
they have been found to be tranquilizers [1] and in-
hibitors of immune complex–induced inflammation
[2] in medical applications and fungicides [3–5], her-
bicides [6–7], and insecticides [8] in agricultural ap-
plications. The structural variations of these com-
pounds are that different substituents can be
incorporated on the benzene ring, and diverse het-
erocycles and other active groups can be introduced
at the 2-position in order to create good biological
activity. Among the different substituents, the groups
at the 2-position play a key role in their biological
activities. Phosphate or thiophosphate derivatives
have been extensively investigated in the area of pes-
silica gel column chromatography.
EXPERIMENTAL
1HNMR spectra were recorded in CDCl3 as solvent
on an AC-P200 instrument using tetramethylsilane
(TMS) as an internal standard. IR spectra were mea-
sured on a Nicolet 5DX IR spectrometer. Elemental
analyses were conducted on an MF-3 automatic an-
alyzer. Melting points were determined on an MP-
500 melting point apparatus. Refractive indices were
obtained by use of an Abbe refractometer. All tem-
peratures and pressures are uncorrected.
Preparation of 2-Hydrazinobenzoxazole 4
Correspondence to: Gui-Yu Jin.
Contract Grant Sponsor: National Natural Science Foundation of
China.
Contract Grant Number: 29832050.
᭧ 2001 John Wiley & Sons, Inc.
[1,9,10]
Into a 250 mL four-necked flask was placed 2-ami-
nophenol (19.1 g, 0.175 mol), KOH (10.09 g, 0.18
151

152 Chen and Jin
mol), CS2 (13.68 g, 0.18 mol), 150 mL of 95% etha-
nol, and 30 mL of water. The mixture was heated
under reflux for 3 hours. Norite (7.0 g) was then
added cautiously, and after the mixture had been
heated at reflux temperature for 10 minutes, the nor-
ite was filtered off. The filtrate was heated to 60–
70ЊC, 200 mL of warm (60–70ЊC) water was added,
and the solution was neutralized with 15 mL of ace-
tic acid in 30 mL water. The product 2 precipitated
and was filtered off and dried, (m.p. 194–196ЊC, yield
78.2% [lit. 193–195ЊC, 80%]).
To the product 2 (18.75 g, 0.124 mol) dissolved
SCHEME 1
SCHEME 2
SCHEME 3
TABLE 1 The Data of Compounds 7a–7l
Compound
R
Yield (%)
n202
Compound
R
Yield (%)
n202
7a
7b
7c
7d
7e
7f
C6H5O
2-ClC6H4O
4-NO2C6H4O
4-BrC6H4O
4-ClC6H4O
66.3
60.3
49.9
62.9
67.0
58.9
1.5765
1.5784
1.6050
1.5928
1.5712
1.5436
7g
7h
7i
7j
7k
7l
4-CH3C6H4O
2,4-ClBrC6H4O
2,4-Cl2C6H4O
2,4-CH3ClC6H4O
EtO
66.3
56.1
43.9
58.5
73.9
76.2
1.5609
1.6010
1.5902
1.5650
1.4732
1.5630
2,4-Me2C6H4O
Prs

Synthesis of N-(Thio)phosphoryl-NЈ-2-Benzoxazolyl Semicarbazides 153
TABLE 2 The Data of Compounds 8
Elementary Analysis (%, Cald.)
Compound
R
X
m.p. (ЊC)
Yield (%)
C
H
N
8a
b
c
d
e
f
C6H5O
S
S
S
S
S
S
S
S
S
S
O
S
144–146
131–133
109–111
184–186
183–185
thick liquid
113–115
149–150
73–75
70.7
70.2
70.6
77.6
59.6
65.5
75.8
66.2
87.0
73.4
71.4
85.9
47.06
(47.06)
43.60
(43.39)
42.06
(42.38)
39.27
(39.43)
43.40
(43.39)
49.74
(49.54)
48.25
(48.34)
36.86
(36.82)
40.37
4.37
(4.17)
3.87
(3.62)
3.53
(3.53)
3.87
(3.91)
3.49
(3.62)
4.87
(4.82)
4.99
(4.51)
2.88
(2.88)
3.23
13.69
(13.73)
12.61
(12.66)
15.17
(15.45)
11.21
(11.50)
12.58
(12.66)
12.83
(12.85)
13.18
(13.27)
10.72
(10.74)
11.94
2-ClC6H4O
4-NO2C6H4O
4-BrC6H4O
4-ClC6H4O
2,4-Me2C6H3O
4-CH3C6H4O
2,4-ClBrC6H3O
2,4-Cl2C6H3O
2,4-CH3ClC6H4O
EtO
g
h
i
(40.25)
44.52
(44.69)
41.76
(41.86)
40.42
(3.15)
3.86
(3.95)
5.03
(4.94)
4.78
(11.74)
12.03
(12.27)
15.99
(16.28)
14.05
j
135–137
151–152
134–135
k
l
PrS
(40.00)
(4.87)
(14.36)
TABLE 3 The IR Spectral Data of Compounds 8
מ1
IR (KBr, cm
P–O–C
)
Compound
PסS(O)
P–N
P–O–Ar
CסS
8a
8b
8c
8d
8e
8f
8g
8h
8i
664.0
654.4
666.8
666.4
671.1
677.3
676.2
662.3
660.1
665.7
1177.0
655.3
973.9
960.1
963.4
968.5
972.8
956.3
951.2
966.3
956.6
956.5
973.5
950.4
773.7, 1027.5, 1157.0
764.1, 1024.1, 1120.7
741.9, 1023.3, 1152.2
755.0, 1024.8, 1177.1
762.8, 1025.1, 1155.7
746.3, 1024.8, 1157.6
747.1, 1026.3, 1155.0
747.4, 1024.4, 1155.6
798.7, 1023.5, 1153.1
738.7, 1026.4, 1165.5
774.0, 1030.4, 1109.5
745.3, 1025.7, 1153.6
919.2, 1196.2
914.4, 1217.5
901.6, 1210.2
919.2, 1204.7
941.9, 1205.3
913.2, 1204.5
912.4, 1187.7
903.8, 1244.8
907.4, 1222.6
921.1, 1225.6
/
1605.7
1611.2
1610.9
1606.8
1606.7
1612.8
1611.1
1611.2
1610.8
1611.6
1653.2
1609.3
8j
8k
8l
/
in 150 mL of benzene, PCl5 (31.27g, 0.15 mol) was
added dropwise. The mixture was heated to reflux
for 2 hours, the solvent was evaporated, and the res-
idue was distilled under reduced pressure to give 2-
chlorobenzoxazole 3, (b.p. 99–100ЊC/10 mmHg, a
solid when cooled, m.p. 8ЊC, 14.9 g, yield 78.3%).
A solution of 2-chlorobenzoxazole 3 prepared as
described previously (9.69 g, 0.063 mol) in 5 mL of
dioxane was added dropwise and with stirring to
85% hydrazine hydrate (20.5 g, 0.35 mol), the mix-
ture being maintained at a temperature that did not
rise above 30ЊC. After the addition was completed,
the mixture was stirred at room temperature for 30
minutes and then diluted with 30 mL of cold water.
The 2-hydrazinobenzoxazole product 4 was col-
lected, washed with water, dried, and recrystallized
from ethanol to give needles, (8.25 g, yield 87.9%,
m.p. 154–155ЊC [lit. 152–53ЊC]); elementary analysis:

154 Chen and Jin
TABLE 4 The 1HNMR Spectral Data of Compounds 8
Compound
1HNMR d (ppm, CDCl3/TMS) JH-H, JP-H (Hz)
8a
8b
8c
8d
8e
8f
1.32 (t, 3H, CH3, JH-H ס 7.06), 4.26 (dq, 2H, CH2), JP-H ס (7.41), 6.78–7.28 (m, 10H, C6H5, C6H4 on
benzoxazole ring, NH)
1.35 (t, 3H, CH3, JH-H ס 5.69), 4.37 (dq, 2H, CH2, JP-H ס 7.30), 6.85–7.30 (m, 9H, C6H4, C6H4 on
benzoxazole ring, NH)
1.36 (t, 3H, CH3, JH-H ס 4.47), 4.29 (dq, 2H, CH2, JP-H ס 7.20), 6.96–6.99, 7.30–7.37, 8.10–8.26 (m, 9H,
C6H4, C6H4 on benzoxazole ring, NH)
1.34 (t, 3H, CH3, JH-H ס 4.42), 4.24 (dq, 2H, CH2, JP-H ס 7.25), 6.84–7.38 (m, 9H, C6H4, C6H4 on
benzoxazole ring, NH)
1.29 (t, 3H, CH3, JH-H ס 6.86), 4.24 (dq, 2H, CH2, JP-H ס 9.61), 7.15–7.29 (m, 9H, C6H4, C6H4 on
benzoxazole ring, NH)
1.32 (t, 3H, CH3, JH-H ס 6.85), 2.21 (s, 3H, CH3), 2.28 (s, 3H, CH3), 4.20 (dq, 2H, CH2, JP-H ס 9.24), 6.82–
7.46 (m, 8H, C6H3, C6H4 on benzoxazole ring, NH)
8g
8h
8i
1.30 (t, 3H, CH3, JH-H ס 7.11), 2.25 (s, 3H, CH3), 4.18 (dq, 2H, CH2, JP-H ס 9.21), 6.78–7.04, 7.39–7.41
(m, 9H, C6H4, C6H4 on benzoxazole ring, NH), 8.73 (brs, 2H, 2NH)
1.37 (t, 3H, CH3, JH-H ס 4.17), 4.33 (dq, 2H, CH2, JP-H ס 9.39), 7.20–7.49 (m, 8H, C6H3, C6H4 on
benzoxazole ring, NH), 11.0 (brs, 2H, 2NH)
1.33 (t, 3H, CH3, JH-H ס 7.15), 4.27 (dq, 2H, CH2, JP-H ס 9.39), 6.95–7.40 (m, 8H, C6H3, C6H4 on
benzoxazole ring, NH), 8.48 (brs, 2H, 2NH)
8j
1.31 (t, 3H, CH3, JH-H ס 6.97), 2.26 (s, 3H, CH3), 4.19 (dq, 2H, CH2, JP-H ס 9.18), 6.92–7.11, 7.44–7.47
(m, 8H, C6H3, C6H4 on benzoxazole ring, NH), 8.28 (brs, 2H, 2NH)
1.30 (t, 6H, 2CH3, JH-H ס 7.05), 4.15 (dq, 4H, 2CH2, JP-H ס 7.96), 6.77–6.84, 7.08, 7.30 (m, 5H, C6H4 on
benzoxazole ring, NH), 8.19 (brs, 2H, 2NH)
0.96 (t, 3H, CH3), 1.35 (t, 3H, CH3), 1.68 (m, 2H, CH2), 2.88 (dt, 2H, CH2S, JP-H ס 6.67), 4.20 (dq, 2H,
CH2O, JP-H ס 9.32), 6.88–7.67 (m, 5H, C6H4 on benzoxazole ring, NH)
8k
8l
Calcd: C, 56.38%, H, 4.69%, N, 28.19%; Found: C,
56.04%, H, 4.51%; N, 27.93%.
was reacted with NH4SCN in benzene to give a crude
product that was purified by distillation under re-
duced pressure, (b.p. 70–74ЊC/133 Pa, yield 73.9%,
n2D2
nD
Preparation of O-Ethyl-O-aryl-
isothiocyanatothiophosphate 7
20
1.4732 [lit.
1.4749]).
Preparation of 7a–7j. [11–14] To a solution of
the substituted phenol (0.02 mol) and NaOH (0.8 g,
0.02 mol) in 5 mL of H2O was added O-ethylthio-
phosphorodichloridate (3.60 g, 0.02 mol) and then a
catalytic amount of a phase transfer catalyst (PTC).
The mixture was stirred at 30–40ЊC for 2 hours, al-
lowed to stand overnight, and then extracted with
100 mL of benzene. The organic phase was washed
with 20 mL of water, dried with anhydrous magne-
sium sulfate, and concentrated under reduced pres-
sure to give crude O-ethyl-O-arylthiophosphoro-
chloride 6 for the next step.
To a mixture of KSCN (1.94 g, 0.02 mol) and 20
mL of acetonitrile was added the crude product 6,
and the mixture was stirred at room temperature for
4–5 hours, diluted with 20 mL of ethyl ether, and
filtered. The filtrate was concentrated to give crude
product 7, which was purified by silica gel column
chromatography to give a total yield of 43.9–67%.
The relevant data of compounds 7 are shown in Ta-
ble 1.
Preparation of 7l.
A similar procedure was
used with 6 (R ס PrS) instead of 6 (R ס ArO) to
22
yield 7l (76.2%,
1.5630).
nD
Preparation of Title Compounds 8
To a solution of 2-hydrazinobenzoxazole 4 (0.15 g,
1.0 mmol) in 20 mL of ethanol was added O-ethyl-
O-phenylisothiocyanatothiophosphate 7a (0.26 g,
1.0 mmol) at room temperature. The reaction mix-
ture was stirred at room temperature with thin-layer
chromatography monitoring for about 2 hours. After
removal of the solvent under reduced pressure, the
residue was purified by silica gel column chroma-
tography using petroleum ether/ethyl acetate as
eluent to give a white solid, 0.29 g, yield 70.7%, m.p.
144–146ЊC.
Similarly, other compounds of the type 8 were
prepared from the corresponding isothiocyanato
(thio) phosphate 7, reaction with compound 4 taking
place at room temperature or slightly higher. All
compounds prepared were characterized by elemen-
Preparation of 7k. According to the literature
procedure [15,16], O,O-diethylphosphoryl chloride

Synthesis of N-(Thio)phosphoryl-NЈ-2-Benzoxazolyl Semicarbazides 155
tary analysis, and 1HNMR and IR spectral data, their
relevant data being given in Tables 2–4.
90% activity against Puccinia recondita at 500 ppm.
The relationship of structure and activity indicates
that the electron-donor groups on phenyl increase
the activity, while electron-withdrawing groups de-
crease the activity.
RESULTS AND DISCUSSION
Characterization of Title Compounds 8
The title compounds 8 were characterized by ele-
REFERENCES
mentary analysis and 1H NMR and IR spectroscopy.
[1] Charles, L.; Lesizur, D.; Renard, P.; French Patent
2409991, 1977.
1
With respect to the HNMR spectra, the resonance
of the NH adjacent to the P atom overlapped those
of benzoxazole and benzene rings and are not easy
to describe. The other two NH groups appeared at d
ס 8–9 or 11.0 or did not appear at all. The main
reason is that the two NH groups are very labile. The
methylene group of the ethoxyl group bonded to
phosphorus appears as a multiplet because of being
coupled by the H atoms in CH3 and the P atom; when
CH3 was decoupled, doublet peaks were observed,
and the coupling constant was 8–10 Hz. With regard
[2] Haviv, F.; Ratajczy, J. D.; DeNet, R. W., et al. J Med
Chem 1988, 31(9), 1719–1728.
[3] De Meo, G.; Pedini, M.; Ricci, A., Sposini, T.; Jacquig-
non, P. Farmaco 1989, 4(5), 475–482.
[4] Yalcin, I.; Sener, E.; Ozden, T., Ozden, S.; Akin, A. Eur
J Med Chem 1990, 25(8), 705–708.
[5] Yalcin, I.; Ozden, T.; Sener, E., Akin, A.; Ozden. S.;
Yildiz, S. Farm Bilimler Derg 1986, 11(4), 257–269.
[6] Winkler, P. P.; Sittenthaler, W.; Bernhard, H. U., et al.
German Offen DE 3638685, 1988.
[7] Ohyama, H.; Morita, K.; Nakamura, T., et al. PCT Int
Appl WO 9106544, 1991.
[8] Bartsch, H.; Erker, T. Arch Pharm 1991, 324(2), 79–
82.
[9] Van Allan, J. A.; Deacon, B. D. Org Synth 1950, 30,
56–57.
[10] Katz, L. J Am Chem Soc 1953, 75, 712–714.
[11] (a) Richter, S. B.; U.S. Patent 3356484, 1965; (b)
Richter, S. B. U.S. Patent 3450520, 1965.
[12] Henry, T. Ann N Y Acad Sci 1959, 79(7) 189–231.
[13] Chen, Ru-Yu; Yang, Hua-Zheng; Zeng, Qiang, et al.
Huaxuexuebao 1981, 39(7), 643–651.
[14] Lindley, C. U.S. Patent 3992373, 1976.
[15] Bernard, F.; Jan, M. Roczniki Chem 1952, 26, 688–
689.
מ1
to the IR spectra, the band around 660 cm was
attributed to the PסS function, while that at 1177
מ1
cm in compound 8k was attributed to the PסO
group, and the group CסS was responsible for the
מ1
band at about 1600 cm
.
Biological Activity of Title Compounds 8
We selected some compounds 8 to test their biologi-
cal activities and found that these compounds dis-
played moderate degrees of fungicidal activity and
also to some degree, herbicidal and plant growth
regulation activities. Compounds 8a and 8k showed
[16] Miller, G. A.; Greenfield, S. A. U.S. Patent 3776942,
1973.