May 2009
Stereoselective Synthesis and Biological Activities of Diethyl (E)-{[4-Cyano-5-[[(disubstituted-
amino)methylene]amino]-3-(methylthio)-1h-pyrazol-1-yl]substituitedphenylmethyl}phosphonates
557
C16H21N4O3PS: C, 50.52; H, 5.56; N, 14.73. Found: C, 50.69;
H, 5.48; N, 14.89.
The preliminary bioassays showed that these compounds
possess potent herbicidal activity against the roots of
dicotyledonous (oil rape) plants at the dosage of 100
mg/L, and some of them displayed moderate fungicidal
activity at the concentration of 50 mg/L.
3b: yield: 71%, mp158–159ꢀC. 1H NMR: d 1.19–1.27 (m,
6H, 2CH3), 2.53 (s, 3H, SCH3), 4.01–4.16 (m, 4H, 2CH2),
5.56 (s, 2H, NH2), 5.72 (d, J ¼ 24 Hz, 1H, PCH), 7.28–7.50
ppm (m, 4H, ArAH); ir: NH2 3342, ArAH 2992, CN 2210,
P¼¼O 1256, PAOAC 1045, PAC 975 cmꢂ1; ms: m/z 398 (Mþ,
81), 261 (50), 109 (100); Anal. Calcd for C16H20FN4O3PS: C,
48.24; H, 5.06; N, 14.06. Found: C, 48.39; H, 4.81; N, 14.14.
General procedure for the preparation of compounds
4. 3 (6 mmoles) was dissolved in triethyl orthoformate (4
mL), and the mixture was refluxed for 2 h. After cooling, the
solvent was removed under a reduced pressure, and the residue
was purified on silica gel (ethyl acetate-light petroleum ether,
1:5, v/v) to afford 4 as a white solid.
EXPERIMENTAL
Melting points were determined with a WRS-1B digital
melting point apparatus and were uncorrected. 1H and 31P
NMR spectra were recorded on
a Varian MERCURY-
PLUS400 (400 MHz) spectrometer with deuteriochloroform as
the solvent and TMS and 85% phosphoric acid as the internal
and external references, respectively. Mass spectra were
obtained with a Finnigan TRACEMS2000 spectrometer using
the EI method; IR spectra were measured by a Nicolet
NEXUS470 spectrometer; Elemental analyses were performed
with an Elementar Vario ELIII CHNSO elementary analyzer.
All of the solvents and materials were reagent grade and puri-
fied as required. [(1-Hydrazino)substitutedphenylmethyl]-
phosphonates 1 [14a], 2-[bis(methylthio)methylene]malononi-
1
4a. yield: 95%, mp 64–66ꢀC. H NMR: d 1.18–1.27 (m, 6H,
2CH3), 1.40 (t, J ¼ 7 Hz, 3H, CH3), 2.62 (s, 3H, SCH3),
4.01–4.20 (m, 4H, 2CH2), 4.39 (t, J ¼ 6.6 Hz, 2H, CH2), 5.90
(d, J ¼ 22.8 Hz, 1H, PCH), 7.33–7.55 (m, 5H, ArAH), 8.39
ppm (s, 1H, N¼¼CH); ir: ArAH 2976, CN 2222, C¼¼NA 1608,
P¼¼O 1266, PAOAC 1058, PAC 969 cmꢂ1; ms: m/z 436 (Mþ,
65), 391 (79), 389 (52), 109 (100); Anal. Calcd for
C19H25N4O4PS: C, 52.28; H, 5.77; N, 12.84. Found: C, 52.41;
H, 5.54; N, 12.72.
4b. yield: 89%, mp 77–78ꢀC. 1H NMR: d 1.19–1.31 (m,
6H, 2CH3), 1.42 (t, J ¼ 7.2 Hz, 3H, CH3), 2.61 (s, 3H, SCH3),
4.02–4.05 (m, 2H, CH2), 4.14–4.18 (m, 2H, CH2), 4.38–4.41
(m, 2H, CH2), 5.87 (d, J ¼ 22.4 Hz, 1H, PCH), 7.04 (dd, J ¼
8.4 Hz, J ¼ 8.4 Hz, 2H, ArAH), 7.54 (dd, J ¼ 5.2 Hz, J ¼
8.4 Hz, 2H, ArAH), 8.41 ppm (s, 1H, N¼¼CH); ir: ArAH
2972, CN 2210, C¼¼NA 1616, P¼¼O 1248, PAOAC 1042,
PAC 970 cmꢂ1; ms: m/z 456 (16), 454 (Mþ, 45), 411 (36),
409 (57), 109 (100); Anal. Calcd for C19H24FN4O4PS: C
50.21, H 5.32, N 12.33; found C 50.03, H 5.15, N 12.18.
General procedure for the preparation of compounds
5. A solution of 4 (1 mmole) and secondary amine (1.5
mmoles) in anhydrous acetonitrile (15 mL) was stirred at room
temperature for 0.5–1 h (monitorede by tlc). After the reaction
was complete, the solvent was removed under reduced pres-
sure, and the residue was purified on silica gel (petroleum
ether and acetone, 4:1, v/v) to yield the corresponding target
compounds 5a–5g.
trile
procedures.
2 [17] were prepared according to the literature
General procedure for the preparation of compounds
1. A mixture of substituted benzaldehyde (0.1 moles), diethyl
phosphite (13.8 g, 0.1 moles), and triethylamine (5.1 g,
0.05 moles) was heated at 75ꢀC for 0.5 h until the reaction
completed (monitored by tlc). After cooling, mesyl chloride
(12.5 g, 0.11 moles) in anhydrous methylene chloride
(100 mL) was added dropwise at 0ꢀC. After the addition com-
pleted, the mixture was stirred at room temperature for 2 h.
The solid was removed by filtration, the filtrate was washed by
distilled water (30 mL ꢁ 3), dried over anhydrous sodium sul-
phate, and then concentrated in vacuo to give [(1-mesyl oxy)-
substitutedphenylmethyl]phosphonate as a light yellow liquid,
yield: 87–91%, which can be used without further purification.
To the mixture of [(1-mesyl oxy)substitutedphenylmethyl]-
phosphonate (0.1 moles) in ethanol (40 mL) was added drop
wise 85% hydrazine (26.4 g, 0.4 moles) at 0ꢀC, after the addi-
tion finished, the mixture was stirred for 6–8 h at 45–50ꢀC.
The workup involved stripping of the solvent followed by an
addition of water (100 mL) and extraction of the product into
anhydrous ethyl ether (50 mL ꢁ 3), after phase separation,
drying over anhydrous sodium sulphate, filtration and evapora-
tion, a crude product 1 was yielded as a yellow liquid, yield
40–45%, which can be used without further purification.
General procedure for the preparation of compounds
3. A mixture of 1 (24.3 mmoles), 2 (3.89 g, 22.9 mmoles),
and anhydous ethanol (30 mL) was refluxed for 5 h [18]. After
cooling, the reaction mixture was concentrated in vacuo and
recrystallized from ethyl acetate and petroleum ether (1;1, v/v)
to give white crystals.
5a. Colorless oil, yield: 75%; 1H NMR: d 1.18–1.29 (m,
12H, 4CH3), 2.62 (s, 3H, SCH3), 3.32 (q, J ¼ 6.8 Hz, 2H,
NCH2), 3.34–3.48 (m, 1H, NCH2), 3.56–3.61 (m, 1H, NCH2),
3.99–4.06 (m, 2H, OCH2), 4.16–4.21 (m, 2H, OCH2), 6.06
(d, J ¼ 23 Hz, 1H, PCH), 7.27–7.32 (m, 3H, ArAH), 7.54 (d,
2H, J ¼ 6.4 Hz, ArAH), 8.26 ppm (s, 1H, N¼¼CH); 31P NMR
(162 MHz): d 16.79 ppm; ir: ArAH 2974, CN 2214, C¼¼NA
1617, P¼¼O 1260, PAOAC 1026, PAC 976 cmꢂ1; ms: m/z
463 (Mþ, 35), 326 (100), 279 (18); Anal. Calcd for
C21H30N5O3PS: C, 54.41; H, 6.52; N, 15.11. Found: C, 55.14;
H, 6.67; N, 14.98.
5b. Colorless crystals, yield: 95%; mp 87.9–89.6ꢀC; 1H
NMR:
d 1.17–1.26 (m, 6H, 2CH3), 1.62–1.71 (m, 6H,
3a: yield: 64%, mp 161–163ꢀC; 1H NMR: d 1.19–1.27 (m,
6H, 2CH3), 2.53 (s, 3H, SCH3), 4.01–4.16 (m, 4H, 2CH2),
5.54 (s, 2H, NH2), 5.75 (d, J ¼ 24 Hz, 1H, PCH), 7.27–7.52
ppm (m, 5H, ArAH); ir: NH2 3358, ArAH 2995, CN 2215,
P¼¼O 1265, PAOAC 1048, PAC 978 cmꢂ1; ms: m/z 380 (Mþ,
65), 333 (16), 227 (48), 153 (100); Anal. Calcd for
CH2CH2CH2), 2.62 (s, 3H, SCH3), 3.37 (t, J ¼ 5.2 Hz, 2H,
NCH2), 3.64 (t, J ¼ 5.2 Hz, 2H, NCH2), 3.98–4.04 (m, 2H,
OCH2), 4.14–4.21 (m, 2H, OCH2), 6.07 (d, J ¼ 23.2 Hz, 1H,
PCH), 7.29–7.35 (m, 3H, ArAH), 7.56 (d, J ¼ 7.6 Hz, 2H,
ArAH), 8.23 ppm (s, 1H, N¼¼CH); 31P NMR (162 MHz): d
16.98 ppm; ir: ArAH 2985, CN 2212, C¼¼NA 1618, P¼¼O
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet