Syntheses and biological activities of 1,2,4-triazolo-[3,4-b][1,3,4] thiadiazole dithiophosphates

Article abstract of DOI:10.1080/10426500490422191

In this article, we incorporated the organic phosphorus group on to a triazolothiadiazole ring to prepare the title compounds fused 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole heterocyclic compounds. From the results on biological activities, we found that mo

Full text of DOI:10.1080/10426500490422191

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Phosphorus, Sulfur, and Silicon and the Related
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SYNTHESES AND BIOLOGICAL ACTIVITIES OF
1,2,4-TRIAZOLO-[3,4-B][1,3,4]THIADIAZOLE
DITHIOPHOSPHATES
Wen-Bin Chen a & Gui-Yu Jin a
a Nankai University, Tianjin, China
Published online: 12 Aug 2010.
To cite this article: Wen-Bin Chen & Gui-Yu Jin (2004): SYNTHESES AND BIOLOGICAL ACTIVITIES OF 1,2,4-TRIAZOLO-[3,4-B]
[1,3,4]THIADIAZOLE DITHIOPHOSPHATES, Phosphorus, Sulfur, and Silicon and the Related Elements, 179:3, 543-549
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Phosphorus, Sulfur, and Silicon, 179:543–549, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490422191
SYNTHESES AND BIOLOGICAL ACTIVITIES OF
1,2,4-TRIAZOLO-[3,4-b][1,3,4]THIADIAZOLE
DITHIOPHOSPHATES
Wen-Bin Chen and Gui-Yu Jin
Nankai University, Tianjin, China
(Received July 16, 2003; accepted September 17, 2003)
In this article, we incorporated the organic phosphorus group on to
a triazolothiadiazole ring to prepare the title compounds fused 1,2,4-
triazolo[3,4-b][1,3,4]thiadiazole heterocyclic compounds. From the re-
sults on biological activities, we found that most compounds showed
weak activities, and thus the structures need to be further optimized for
improved activity.
Keywords: Biological activity; organic phosphorus; synthesis;
triazolothiadiazole
Since Kanaoka1 described initially the synthesis of 1,2,4-triazolo[3,4-
b][1,3,4]thiadiazole, many triazolothiadiazole derivatives have been
reported to possess fungicidal, insecticidal, herbicidal, antimicrobial,
bactericidal, and plant growth regulator activities.2−10 The structure
variations of these compounds include different substituents such
as alkyl, aryl, and heterocycle which were introduced at the 3- or
6-position.11−19 However, among these different compounds, no com-
pound containing organophosphorus moiety was reported. Therefore,
we have incorporated an organophosphorus moiety on to a triazoloth-
iadiazole ring at the 6-position in order to prepare the novel and po-
tentially useful title compounds. The synthesis route is outlined in
Scheme 1.
The authors were very grateful for the National Natural Science Foundation of China
(No: 29832050) for the support of this project.
Address correspondence to Gui-Yu Jin, State Key Laboratory of Elemento-Organic
Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071,
P. R. China.
543

544
W.-B. Chen and G.-Y. Jin
SCHEME 1
RESULTS AND DISCUSSION
Preparations of the Title Compounds 4
The key intermediate 2 was prepared from benzoyl hydrazine in 3 steps
and then was treated with bromoethyl phosphorodithionate 3. In this
reaction, when intermediate 2 reacted with intermediate 3a in aque-
ous sodium hydroxide at room temperature with tetrabutylammonium
bromide (TBAB) as a phase transfer catalyst, no title compound 4a
formed. Even when the reaction temperature was raised to 70∼80◦C,
no desired compound 4 appeared. This is because the starting material
3 is easily hydrolyzed in aqueous sodium hydroxide at room tempera-
ture. When compound 2 reacted with compound 3a in NaH/THF sys-
tem, only a small amount of the title compound 3a was produced but
a new compound formed which was determined by elementary anal-
1
1
ysis, HNMR, and GC-MS to be the byproduct 4aꢀ. HNMR (δ, ppm,
DMSO/TMS): 1.42 (t, 3H, CH3), 3.36 (dt, 2H, CH2), 7.57 (d, 3H, 3H on
the C6H5), 8.18 (d, 2H, 2H on the C6H5). Calcd: C% 50.38, H% 3.82, N%
21.37; found: C% 50.28, H% 3.56, N% 21.68. Calcd. for C11H10N4S2(M):
262, found: 262 (GC-MS), m.p. 154∼5◦C. After several experiments, we
found that the desired compound 4 was obtained in good yields only in a
NaOMe/MeOH system at refluxing temperature. The other compounds
were obtained in the same way. These results appear in Scheme 2. All
the title compounds were determined by elementary analyses, 1HNMR,

Dithiophosphates
545
SCHEME 2
SCHEME 3
and IR spectrum data. The detail data are outlined in Tables I, II,
and III.
A possible reaction mechanism is outlined in Scheme 3. In the caustic
solution, the sulfur atom of P S bond attacks the carbon atom adjacent
to bromo atom of the starting material 3 to produce the intermediate 5.
The cyclic 1,3-disulfurphosphane 5 is easily attacked by nucleophiles
by means of ꢀ and ꢀ because of rich positive charge in phosphorus
1
2
atom. The nucleophile R’S attacks the different carbon atoms to produce
different products 4 and 4ꢀ.
Characterizations of Title Compounds
In the 1HNMR spectrum, the two alkoxy groups binding phosphorus of
the compounds 4 are equivalent when R is Et and n-Pr. However the
two alkoxy groups on phosphorus atom are not equivalent when R is
i-Pr, and show two doublets. With regard to the IR spectra, the bands
around 650 cm−1 and 1000 cm−1 were attributed to P S and P O C

546
W.-B. Chen and G.-Y. Jin
TABLE I The Physical Data of Compounds 4
Elementary Analysis
(%, Cald.)
Compd.
n
2
R
m.p. (◦C) Yield (%)
C
H
N
4a
Et
65∼7
32∼4
63∼4
54∼5
93∼4
54∼6
69.5
62.3
61.9
57.4
56.9
50.6
40.20
4.07
12.53
(40.36) (4.26) (12.56)
41.79 4.39 11.85
(41.74) (4.57) (12.17)
43.23 4.55 11.90
(43.04) (4.85) (11.82)
44.00 5.00 11.37
(44.26) (5.12) (11.48)
42.70 4.83 11.87
(43.04) (4.85) (11.82)
44.23 5.12 11.46
(44.26) (5.12) (11.48)
4b
4c
4d
4e
4f
3
2
3
2
3
Et
n-Pr
n-Pr
i-Pr
i-Pr
groups, respectively. The detail spectrum data are outlined in Tables II
and III.
Biological Activities Results
From the screening results for biological activities, the title compounds
show low fungicidal activities, and therefore the structures need to be
optimized. The results are shown in Table V.
EXPERIMENTAL
1HNMR spectra were recorded in CDCl3 on an AC-P200 instrument
using TMS as an internal standard. IR spectra were measured on a
TABLE II The IR Data of Compounds 4
IR (KBr or film, cm−1
)
Compd.
P
S
P
S
P
O
C
C C, C N (heterocycle)
4a
4b
4c
4d
4e
4f
658.1
654.6
660.7
653.5
644.1
651.8
547.1
519.3
505.6
513.7
509.0
557.2
1007.1, 1176.9, 769.3
1006.6, 1153.8, 761.4
987.3, 1144.9, 762.8
980.6, 1173.1, 759.5
981.7, 1173.8, 760.9
985.4, 1173.0, 773.8
1478.6, 1453.6, 1430.5
1463.4, 1451.9, 1432.7
1466.9, 1455.4, 1432.5
1466.6, 1455.1, 1430.8
1468.5, 1459.2, 1435.1
1460.1, 1452.4,1433.2

Dithiophosphates
547
TABLE III The 1HNMR Spectral Data of Compounds 4
Compd.
1HNMR δ (ppm, CDCl3/TMS)
4a
1.29 (t, 6H, 2 × CH3CH2O), 3.36 (dt, 2H, SCH2CH2SP), 3.67 (t, 2H,
SCH2CH2SP), 4.14 (m, 4H, 2 × CH3CH2O), 7.51 (d, 3H, 3 × Hb), 8.33 (t, 2H,
2 × Ha)
b
c
1.35 (t, 6H, 2 × CH3CH2O), 2.26 (m, 2H, SCH2CH2CH2SP), 3.05 (dt, 2H,
SCH2CH2CH2SP), 3.52 (t, 2H, SCH2CH2CH2SP), 4.16 (m, 4H,
2 × CH3CH2O), 7.56 (d, 3H, 3 × Hb), 8.35 (m, 2H, 2 × Ha)
0.95 (t, 6H, 2 × CH3CH2CH2O), 1.72 (m, 4H, 2 × CH3CH2CH2O), 3.34 (m, 2H,
SCH2CH2SP), 3.69 (t, 2H, SCH2CH2SP), 4.07 (m, 4H, 2 × CH3CH2CH2O),
7.53 (d, 3H, 3 × Hb), 8.31 (m, 2H, 2 × Ha)
d
0.96 (t, 6H, 2 × CH3CH2CH2O), 1.75 (m, 4H, 2 × CH3CH2CH2O), 2.27 (m, 2H,
SCH2CH2CH2SP), 3.16 (dt, 2H, SCH2CH2CH2SP), 3.51 (t, 2H,
SCH2CH2CH2SP), 4.09 (m, 4H, 2 × CH3CH2CH2O), 7.58 (d, 3H, 3 × Hb),
8.41 (m, 2H, 2 × Ha)
e
f
1.31 (dd,12H, 2 × (CH3)2CHO), 3.36 (dt, 2H,SCH2CH2SP), 3.67 (t, 2H,
SCH2CH2SP), 4.81 (m, 2H, 2 × (CH3)2CHO), 7.51 (d, 3H, 3 × Hb), 8.28 (q,
2H, 2 × Ha)
1.33 (dd, 12H, 2 × (CH3)2CHO), 2.29 (m, 2H, SCH2CH2CH2SP), 3.05 (dt, 2H,
SCH2CH2CH2SP), 3.51 (t, 2H, SCH2CH2CH2SP), 4.77 (m, 2H,
2 × (CH3)2CHO), 7.53 (d, 3H, 3 × Hb), 8.34 (m, 2H, 2 × Ha)
Nicolet 5DX IR spectrometer. Elemental analyses were conducted on
an MF-3 automatic analyzer. Melting points were determined on an
MP-500 melting point apparatus. All temperatures and pressures are
uncorrected.
TABLE V The Fungicidal Activities of Compounds 4
Fungicidal activities (inhibition%)
In vivo (500 ppm)
In vitro (50 ppm)
P. G.
S.
P.
B.
A.
P.
C.
Compd. sclerotiorum recibduta cinerea solani asparagi piricola zeae arachidicola
4a
b
c
d
e
5
10
0
8
0
30
50
10
0
20
0
0
43
0
0
0
4
14
9
0
0
40
30
0
10
0
15
7
3
3
3
22
16
11
5
8
8
0
6
0
0
0
f
12
48
4
20
3
13

548
W.-B. Chen and G.-Y. Jin
Preparation of 3-Phenyl-6-mercapto-1,2,4-Triazolo[3,4-
b]-1,3,4-thiadiazole 220,21
To the solution of 5.6 g (0.10 mmol) of KOH in 150 mL of methanol
was added 19.2 g (0.10 mmol) of 3-phenyl-4-ammino-5-mercapto-1,2,4-
triazolo 1, and then 20 mL of CS2 was added. After the mixture was
heated to reflux for 24 h, the solvent was removed under reduced pres-
sure, the residue was poured into 200 mL of water and the latter was
acidified with concd. HCl to yield a white solid. The solid was filtered
and recrystallized (pyridine) to obtain 14.33 g of a white crystal 2, yield
61.2%, m.p. 208∼210◦C (lit21 m.p. 210◦C).
Preparations of the Title Compounds 4
To the solution of 0.006 g (1.0 mmol) of NaOMe in 15 mL of dry methanol
was portionly added 0.23 g (1.0 mmol) of 3-phenyl-6-mercapto-1,2,4-
triazolo[3,4-b]-1,3,4-thiadiazole (2) with stirring, and then 0.35 g
(1.2 mmol) of O, O-diethyl-S-(2-bromoethyl)dithiophosphotate (3a)22
was added. After the addition, the mixture was heated to reflux with
stirring for 4∼5 h. When the reaction was completed, the mixture was
cooled to room temperature, diluted with 20 mL of water, and extracted
with 30 mL × 3 of dichloromethane. The combined organic extracts were
washed with 30 mL × 3 of water and dried over MgSO4. After removal of
the dichloromethane, the residue was purified by silicon gel chromatog-
raphy using ethyl acetate/petroleum ether (5:1) as eluent to give white
crystals of 4a, 0.31 g (69.5%). The other compounds 4 were prepared by
the same procedure, and their data are listed in Tables I, II, and III,
respectively.
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