Synthesis of a novel series of imidazo[4,5-c]pyrazole derivatives and their evaluation as herbicidal agents

Article abstract of DOI:10.1002/(SICI)1521-4184(199910)332:10<337::AID-ARDP337>3.0.CO;2-P

Ever changing problems in agricultural weed control require periodic introduction of new herbicides. Imidazo[4,5-c]pyrazoles, which were considered of interest as potential herbicides, were synthesized and examined for the pre-emergence, post-emergence, and post-transplant control of weeds in rice against broadleaf and grass weed species. The data obtained suggest that some imidazo[4,5-c]pyrazoles have potential herbicidal activity against a wide range of weeds, with 5-methyl, 5-thiomethyl, and 5-unsubstituted derivatives being the most effective. No herbicidal activity was observed in the 5-methylsulfonylimidazo[4,5-c]pyrazole and imidazo[4,5-c]pyrazolone series.

Full text of DOI:10.1002/(SICI)1521-4184(199910)332:10<337::AID-ARDP337>3.0.CO;2-P

Imidazo[4,5-c]pyrazole Derivatives
337
Synthesis of a Novel Series of Imidazo[4,5-c]pyrazole Derivatives and
Their Evaluation as Herbicidal Agents
a)
a)
a)
a)
b)
Chiara B. Vicentini *, Maurizio Manfrini , Manuela Mazzanti , Angelo Scatturin , Carlo Romagnoli , and
c)
Donatella Mares
a) Department of Pharmaceutical Science, University of Ferrara, via Fossato di Mortara 17/19, I-44100 Ferrara, Italy
b) Department of Animal Biology, Section of Botanical Gardens, University of Modena and Reggio Emilia, viale Caduti in guerra 127,
I-41100 Modena, Italy
c) Department of Biology, Section of Botany, University of Ferrara, Corso Porta Mare, 2, I-44100 Ferrara, Italy
Key Words: Imidazo[4,5-c]pyrazoles; herbicidal agents
The present work describes the results of the miniscreen and
the primary screen of these products, testing for their herbi-
cidal activity against a series of weed and crop species. An
additional purpose of this work was to extend the synthetic
and screening program to analogues of imidazo [4,5-c]pyra-
zoles in order to explore the potential of this interesting class
of compounds in agriculture.
Summary
Ever changing problems in agricultural weed control require peri-
odic introduction of new herbicides. Imidazo[4,5-c]pyrazoles,
which were considered of interest as potential herbicides, were
synthesized and examined for the pre-emergence, post-emergence,
and post-transplant control of weeds in rice against broadleaf and
grass weed species. The data obtained suggest that some imid-
azo[4,5-c]pyrazoles have potential herbicidal activity against a
wide range of weeds, with 5-methyl, 5-thiomethyl, and 5-unsub-
stituted derivatives being the most effective. No herbicidal activity
was observed in the 5-methylsulfonylimidazo[4,5-c]pyrazole and
imidazo[4,5-c]pyrazolone series.
Results and Discussion
Chemistry
By applying a synthetic procedure which we had previously
[13-–18]
investigated
, a series of as yet unknown imidazo[4,5-
Introduction
c]pyrazoles have been prepared. The synthesis is shown in
Figure 2.
During the last two decades intensive efforts have been
undertaken to discover new chemicals to selectively control
the growth of weeds. Modern pesticides should have a favor-
able combination of properties, including high levels of her-
bicidal activity, low application rates, crop tolerance, and low
levels of toxicity to mammals. Finding products with such
features is the main objective of chemical plant protection
research.
The amines 9 were prepared by reacting 3-amino-2-butene-
nitrile with the pertinent hydrazines. Nitrosation of 9 with
sodium nitrite yielded the 4-nitrosopyrazoles 10, which were
reduced to the diamines 11 with hydrazine hydrate in the
presence of palladized charcoal. Since 11 were often unstable
during the usual work-up for isolation, they were directly
reacted with thiophosgene to give the isothiocyanatopyra-
zoles 13. Heating of 13 in pyridine gave the imidazo[4,5-
c]pyrazole-5-thiones 2. In order to obtain 5-substituted
derivatives we reacted imidazo[4,5-c]pyrazole-5-thiones 2 in
sodium hydroxide with iodomethane to give 5-methylthio
derivatives 6, which were then submitted to hydrogenolytic
desulfurisation in the presence of Raney nickel, thus produc-
ing 7. When heated at 200 °C for 2 h, 5-amino-4-ethoxycar-
bonylaminopyrazole, obtained by treatment of 11 with ethyl
chloroformate, afforded imidazo[4,5-c]pyrazole-5-one 3.
The key step in the synthesis of 5-methylimidazo[4,5-c]pyra-
zole 5 was the intramolecular cyclodehydration in boiling
pyridine of 5-ethylamino-4-nitrosopyrazole 16, which was
prepared from 5-acylaminopyrazole 14. Reduction of 14 with
Pyrazole and imidazole derivatives often appear as agro-
chemical products and leads. In particular Imazapyr, Imaza-
[1,2]
[3]
[2,4]
quin
, Imazamethabenz-methyl , Imazethapyr
,
discovered and introduced by American Cyanamid, and the
[5]
pyrazole derivatives Pyrazosulfuron-ethyl by Nissan and
[5]
ET-731
are employed for their herbicide properties. In
[6-–11]
contrast, not much can be found in the literature
synthesis and biological activity of imidazo[4,5-c]pyrazoles,
because this heterocyclic system is difficult to obtain
In view of the above, a program was undertaken to screen
the biological activity of some imidazo[4,5-c]pyrazoles pre-
viously obtained by our group
gated in depth as they were considered of interest as potential
herbicides (Figure 1).
on the
[12]
.
[13-–18]
but not further investi-
LiAlH afforded the 5-alkylaminopyrazole 15. Nitrosation of
15 with amyl nitrite in the presence of hydrochloric acid
yielded 16.
4
Moreover we became interested in the synthesis of
3-methyl-5-methylsulfonyl-1-phenylimidazo[4,5-c]pyrazole
8. Therefore, the 5-methylthio derivative 6a was subjected to
hydrogen peroxide oxidation to give a good yield of 8.
Figure 1. Imidazo[4,5-c]pyrazoles.
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0365-6233/99/1010/0337 $17.50 +.50/0

338
Vicentini and co-workers
Figure 2. Synthesis of imidazo[4,5-c]pyrazoles.
The yields of the target products ranged from good to
quantitative; the proposed structures were supported by ana-
lytical and spectral data.
No herbicidal activity was observed in 4- and 6-substituted
imidazo[4,5-c]pyrazoles 1a–d. Four compounds (4, 5a, 6a,
and 7a) were active at the highest degree on all three species
used in the miniscreen, making greenhouse activity highly
likely. Compound 2a showed moderate herbicidal activity as
it was only active vs. Chlamidomonas, the most sensitive
organism in the initial screening.
Biology
[16–17]
The five active compounds for additional tests were for-
warded to the Primary Herbicide Greenhouse Screen (PRE
and POST) against 13 plant species (see: Experimental, Biol-
ogy); subsequently, they were also used in the transplanted
rice screen (PE-WDS) on 3 additional species (see: Experi-
mental, Biology). For each of the species evaluated, the
As the initial screening phase, compounds 1a–d
,
[16] [17]
[15]
[17]
2a
, 4 , 5a
, 6a, and 7a
were tested for herbicidal
activity in Miniscreen (MINH) (Figure 3) against three plant
targets: Arabidopsis thaliana, bentgrass (Agrostis stolonif-
era), and Chlamidomonas. For each of the species evaluated,
–1
the compounds were applied at a rate of 40 µg well . Sulfen-
–1
[5]
compounds were applied at a rate of 4 kg ha . Trifluralin for
trazone
was used as reference substance in herbicidal
assays, at the same dose: its activity is here referred to as 9.
pre-emergence, Glyphosate for post-emergence, Diphenamid
Arch. Pharm. Pharm. Med. Chem. 332, 337–342 (1999)

Imidazo[4,5-c]pyrazole Derivatives
339
Figure 3. Structures and herbicidal activity of compounds 1–8.
[5]
for post-transplant, pre-emergence weed control were used Unfortunately, although this compound was active on several
as reference substances in herbicidal assays at the same dose: key weeds found in rice, the rice was also injured, indicating
their activities are referred to as 9. Compounds 2a and 4 a lack of selectively.
The obtained data suggest potential herbicidal activity of
proved totally inactive againstallplants tested, both broadleaf
species and grass species, and under all the present experi- some imidazo[4,5-c]pyrazoles, among which compound 7a
mental conditions (pre-emergence, post-emergence, and seem to be the most effective against a wide range of weeds
post-transplant control of weeds in the rice screen). Com- (Figure 4).
The work was then extended by investigating the effects on
biological activity by varying the nature of the 1-, 3-, 5-sub-
stituents (Figure 3). The newly synthesized compounds and
their substituents are shown in Figure 3. Compounds 2e, 5e,
5h, 6d, 7d were the most effective (= 9 as activity), whereas
pound 6a was effective only when applied to the soil in
pre-emergence experiments against four of the six broadleaf
weeds and two out of ten grass weeds tested. Only compounds
5a and 7a were also active in post-emergence experiments,
although to different extents. Compound 5a showed a me-
dium-to-low degree of activity on eight of the tested species, compounds 5c, 5d, 6b, 6c, 6f, 6g, 6h, 7b, 7c, 7f exhibited only
whereas compound 7a was the most active. All six broadleaf some activity as herbicides (= 5). The imidazo[4,5-c]pyra-
species and four of the six grass weed species tested in POST zole-5-ones 3 were inactive and, of the imidazo[4,5-c]pyra-
experiments were controlled by 7a; furthermore the com- zole-5-thiones 2, only compound 2e was active. Some of
pound was active in the post-transplanted control of Cyperus 5-methyl 5a–e and almost all 5-methylthio 6 and 5-unsubsti-
–1
iria weeds in the rice screen at rates as low as 4 kg ha . tuted imidazo[4,5-c]pyrazoles 7 exhibited high or moderate
Arch. Pharm. Pharm. Med. Chem. 332, 337–342 (1999)

340
Vicentini and co-workers
Figure 4. Results of the additional Primary
Herbicide Screen test (4 kg/ha) on compound 7a.
5-Amino-3-methyl-1-pentafluorophenylpyrazole: colorless crystals; yield
82%, mp 54–56 °C; H NMR (CDCl3) δ: 2.22 (s, 3H, Me), 3.65 (br., 2H,
NH2), 5.52 (s, 1H, CH).
5-Amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-3-methylpyrazole:
pale yellow syrup; yield 65%; 1H NMR (CDCl3) δ: 2.25 (s, 3H, Me), 3.52
(br., 2H, NH2), 5.52 (s, 1H, CH), 7.72 (s, 2H, Ph).
activity. Furthermore the presence of H (7a–e) or SMe group
(6a–h) in R′′ seems to enhance the herbicidal activity of the
imidazo[4,5-c]pyrazole derivatives. New tests are in pro-
gress.
1
5-Amino-4-methoxyphenyl-3-methylpyrazole: colorless crystals; yield
92%, mp 95–97 °C; H NMR (CDCl3) δ: 2.21 (s, 3H, Me), 3.69 (br., 2H,
Acknowledgements
1
This work was supported by a grant from Ministero della Ricerca Scienti-
fica e Tecnologica of Italy (MURST). The authors are grateful to American
Cyanamid Agricultural Research Division, Princeton, USA, for the support.
NH2), 5.41 (s, 1H, CH), 6.93–7.43 (A2B2, J = 8.8 Hz, 4H, Ph).
General Procedure for the Synthesis of 1-Pentafluorophenyl- and [2,6-Di-
chloro-4-(trifluoromethyl)phenyl]-5-amino-3-methyl-4-nitrosopyrazoles
(10)
Experimental
A stream of ethyl nitrite was bubbled through a saturated solution of the
appropriate 5-aminopyrazole (10 mmol) in EtOH for 10 min. Then a few
drops of concentrated HCl were added and the ethyl nitrite bubbling was
continued for 30 min. The red precipitate formed was collected and recrys-
tallized from the appropriate solvent.
5-Amino-3-methyl-4-nitroso-1-pentafluorophenylpyrazole: red crystals;
yield 74%, mp 169–172 °C; 1H NMR ([D6]DMSO) δ: 2.67 (s, 3H, Me), 8.67
(br., 2H, NH2).
Chemistry
Melting points were determined with a Büchi capillary apparatus. The 1H
NMR spectra were recorded on a Bruker AC 200 spectrometer. Chemical
shifts (δ) are given in parts per million (ppm) relative to tetramethylsilane as
internal standard. Column chromatography was performed using Merck
silica gel (70–230 mesh); for the flash chromatography technique, silica gel
(230–400 mesh) was employed. Microanalyses were in agreement with
calculated values ±0.4%.
5-Amino-[2,6-dichloro-4-(trifluoromethyl)phenyl]-3-methyl-4-nitroso-
pyrazole: red crystals; yield 86%, mp 193–195 °C; 1H NMR ([D6]DMSO)
δ: 2.63 (s, 3H, Me), 8.24 (s, 2H, Ph), 8.80 (br., 2H, NH2).
Compounds 5a, 5b, 5d–5i [15], 1a–c, 2a [16], 1d, 4, 6a, 7a [17] and 3a–d, 3f
[18] were prepared according to the methods previously reported by us.
General Procedure for the Preparation of 4-Isothiocyanato-1H-pyrazol-5-
General Procedure for the Synthesis of 1-Pentafluorophenyl-, [2,6-Di-
chloro-4-(trifluoromethyl)phenyl]- and 4-Methoxyphenyl-5-amino-3-
methylpyrazoles (9)
ylamines (13)
Hydrazine hydrate (99%, 0.98 ml, 20 mmol) and 5% palladized charcoal
(0.30 g) were added to a solution of 5-amino-4-nitrosopyrazole [19] (4 mmol)
in methanol (50 ml). After heating under reflux for 5 min, the catalyst was
removed and the filtrate was evaporated in vacuo. The solid was collected,
washed with ethyl ether and directly reacted as follows. Thiophosgene
(0.23 ml, 3 mmol) was added dropwise to a suspension of each diamine
(3 mmol) in water (15 ml). After 2 h stirring at room temperature, the white
precipitate was collected, washed with water, and dissolved in ethyl acetate.
3-Amino-2-butenenitrile (1 g, 12 mmol) was added portionwise to a solu-
tion of the pertinent hydrazine (10 mmol) dissolved at 45 °C in concentrated
HCl (2 ml) and water (5 ml). After heating under reflux for 15 min, the
solution was diluted with water, neutralized with ammonium hydroxide, and
then extracted withethyl acetate. The organic phase wasdried and evaporated
to dryness.
Arch. Pharm. Pharm. Med. Chem. 332, 337–342 (1999)

Imidazo[4,5-c]pyrazole Derivatives
341
After drying over anhydrous magnesium sulfate, the solvent was removed to
give a solid. The yields ranged from good to quantitative.
1,3-Dimethyl-4-isothiocyanato-1H-pyrazol-5-ylamine: pale yellow solid;
yield 72%, mp 154–157 °C;1H NMR ([D6]DMSO) δ: 2.01 (s, 3H, Me), 3.42
(s, 3H, Me), 5.98 (s, 2H, NH2).
1-(2-Chlorophenyl)-4-isothiocyanato-3-methyl-1H-pyrazol-5-ylamine:
pale yellow solid; yield 72%, mp 159–162 °C;1H NMR ([D6]DMSO) δ: 2.05
(s, 3H, Me), 5.99 (br., 2H, NH2), 7.27–7.60 (m, 4H, Ph).
1-(3-Chlorophenyl)-4-isothiocyanato-3-methyl-1H-pyrazol-5-ylamine:
pale yellow solid; yield 70%, mp 127–130 °C;1H NMR ([D6]DMSO) δ: 2.07
(s, 3H, Me), 6.11 (br., 2H, NH2), 7.27–7.58 (m, 4H, Ph).
(6e): pale yellow solid; yield 62%, mp 232–234 °C; 1H NMR ([D6]DMSO)
δ: 2.35 (s, 3H, Me), 2.67 (s, 3H, Me), 7.49–8.02 (A2B2, J = 8.8 Hz, 4H, Ph),
12.50 (br., 1H, NH).
(6f): pale yellow solid; yield 72%, mp 162–165 °C; 1H NMR ([D6]DMSO)
δ: 2.35 (s, 3H, Me), 2.58 (s, 3H, Me), 7.55–7.83 (m, 3H, Ph), 12.40 (br., 1H,
NH).
(6g): pale yellow solid; yield 76%, mp 100–102 °C; 1H NMR (CDCl3) δ:
2.41 (s, 3H, Me), 2.61 (s, 3H, Me), 7.67 (s, 2H, Ph), 9.81 (s, 1H, NH).
(6h): pale yellow solid; yield 82%, mp 210–212 °C; 1H NMR (CDCl3) δ:
2.74 (s, 3H, Me), 7.18–8.24 (m, 10H, 2Ph), 9.40 (br.1H, NH).
1-(4-Chlorophenyl)-4-isothiocyanato-3-methyl-1H-pyrazol-5-ylamine:
pale yellow solid; yield 70%, mp 145–147 °C;1H NMR ([D6]DMSO) δ: 2.14
(s, 3H, Me), 5.92 (br., 2H, NH2), 7.53 (s, 4H, Ph).
General Procedure for the Preparation of Imidazo[4,5-c]pyrazoles (7)
A solution of the appropriate 5-methylthioimidazo[4,5-c]pyrazole (6)
(2 mmol) in dioxane (30 ml) was added to a suspension of Raney nickel
(freshly prepared from 6 g of alloy) in dioxane (50 ml). After 1 h the catalyst
was filtered off and the solvent was evaporated to dryness. The crude product
was purified by CC.
(7b): colorless crystals; yield 70%, mp 179–181 °C (flashchromatography,
eluent AcOEt/light petroleum: 8/2); 1H NMR ([D6]DMSO) δ: 2.36 (s, 3H,
Me), 7.39–7.61 (m, 4H, Ph), 7.62 (s, 1H, CH), 12.25 (br., 1H, NH).
(7c): colorless crystals; yield 79%, mp 142–144 °C (CC, eluent
CH2Cl2/MeOH/toluene: 17/2/1); 1H NMR ([D6]DMSO) δ: 2.40 (s, 3H, Me),
7.14–8.07 (m, 5H, Ph + CH), 12.40 (br. 1H, NH).
1-(2,4-Dichlorophenyl)-4-isothiocyanato-3-methyl-1H-pyrazol-5-yl-
amine: pale yellow solid; yield 78%, mp 159–162 °C;1H NMR ([D6]DMSO)
δ: 2.11 (s, 3H, Me), 6.13 (br., 2H, NH2), 7.45–7.85 (m, 3H, Ph).
1-[2,6-Dichloro-4-(trifluoromethyl)phenyl]-4-isothiocyanato-3-methyl-
1H-pyrazol-5-ylamine: pale yellow solid; yield 74%, mp 137–139 °C;1H
NMR ([D6]DMSO) δ: 2.12 (s, 3H, Me), 6.40 (br., 2H, NH2), 8.16 (s, 2H, Ph).
1,3-Diphenyl-4-isothiocyanato-1H-pyrazol-5-ylamine: pale yellow solid;
yield 60%, mp 137–139 °C;1H NMR ([D6]DMSO) δ: 6.36 (br., 2H, NH2),
7.28–8.05 (m, 10H, 2Ph).
(7d): colorless crystals; yield 65%, mp 210–213 °C (flashchromatography,
eluent AcOEt/light petroleum: 1/1); 1H NMR ([D6]DMSO) δ: 2.37 (s, 3H,
Me), 7.33–8.04 (m, 4H, Ph), 7.75 (s, 1H, CH), 12.25 (br. 1H, NH).
(7e): colorless crystals; yield 40%, mp 208–210 °C (flash chromatography,
eluent AcOEt/light petroleum: 8/2); 1H NMR (CDCl3) δ: 2.46 (s, 3H, Me),
7.64 (s, 1H, CH), 7.69 (s, 2H, Ph), 10.60 (br., 1H, NH).
(7f): colorless crystals; yield 80%, mp 112–114 °C (flash chromatography,
eluent AcOEt/light petroleum: 1/1); 1H NMR ([D6]DMSO) δ: 7.24–8.23 (m,
11H, 2Ph + CH), 13.08 (br. 1H, NH).
General Procedure for the Preparation of Imidazo[4,5-c]pyrazole-5-thiones
(2)
A solution of the appropriate 4-isothiocyanatopyrazole 13 (1 mmol) in
pyridine (35 ml) was heated under reflux until the intramolecular cyclization
was completed (ca. 1 h). The solvent was removed under reduced pressure
to give a solid which was purified by CC or recrystallized from the indicated
solvent.
(2b): pale yellow solid; yield 84%, mp 350 °C (CC, eluent
1
CH2Cl2/MeOH/toluene: 17/2/1); IR (KBr) 3100 br., 1510 cm–1; H NMR
Preparation of 5-Methylsulfonylimidazo[4,5-c]pyrazole (8)
([D6]DMSO) δ: 2.11 (s, 3H, Me), 3.65 (s, 3H, Me), 12.06 (s, 1H, NH), 12.68
(s, 1H, NH).
H2O2 (30%) (4 ml, 35 mmol) was added to a suspension of 3-methyl-5-
methylthio-1-phenylimidazo[4,5-c]pyrazole (6a) (0.85 g, 3.5 mmol) inacetic
acid (4 ml). The mixture was heated under reflux for 20 min and then cooled.
H2O (40 ml) was added and the resulting precipitate was collected.
(8): pale yellow solid; 0.58 g, yield 60%, mp 237–239 °C; 1H NMR
([D6]DMSO) δ: 2.44 (s, 3H, Me), 3.47 (s, 3H, Me), 7.21–8.03 (m, 5H, Ph),
14.06 (br., 1H, NH).
(2c): pale yellow solid; yield 72%, mp 188–190 °C (flash chromatography,
eluent AcOEt/light petroleum: 1/1); 1H NMR ([D6]DMSO) δ: 2.25 (s, 3H,
Me), 7.45–7.69 (m, 4H, Ph), 12.37 (s, 1H, NH), 12.93 (s, 1H, NH).
(2d): pale yellow solid; yield 81%, mp 217–219 °C (CC, eluent
CH2Cl2/MeOH/toluene: 17/2/1); 1H NMR ([D6]DMSO) δ: 2.26 (s, 3H, Me),
7.35–8.59 (m, 4H, Ph), 12.53 (s, 1H, NH), 13.5 (br., 1H, NH).
(2e): pale yellow solid; yield 78%, mp 241–244 °C (CC, eluent AcOEt);
1H NMR ([D6]DMSO) δ: 2.25 (s, 3H, Me), 7.48–7.77 (A2B2, J = 8.8, 4H,
Ph), 12.49 (s, 1H, NH), 13.42 (s, 1H, NH).
(2f): pale yellow solid; yield 88%, mp 237–240 °C (CC, eluent AcOEt/light
petroleum: 8/2); 1H NMR ([D6]DMSO) δ: 2.24 (s, 3H, Me), 7.57–7.69 (m,
3H, Ph), 12.40 (s, 1H, NH), 12.96 (s, 1H, NH).
(2g): pale yellow solid; yield 60%, mp 150–153 °C (flash chromatography,
eluent AcOEt/light petroleum: 3/7); 1H NMR ([D6]DMSO) δ: 2.31 (s, 3H,
Me), 7.67 (s, 2H, Ph), 10.49 (br., 1H, NH), 11.42 (br., 1H, NH).
(2h): pale yellow solid; yield 97%, mp 260–262 °C (triturating with Et2O);
1H NMR ([D6]DMSO) δ: 7.32–8.59 (m, 10H, 2Ph), 13.08 (br., 1H, NH).
Preparation of 5-Amino-4-ethoxycarbonylamino-1-pentafluorophenylpyr-
azole (12)
Hydrazine hydrate (99%, 0.98 ml, 20 mmol) and 5% palladized charcoal
(0.30 g) were added to a solution of 5-amino-3-methyl-4-nitroso-1-pen-
tafluorophenylpyrazole (10) (1.16 g, 4 mmol) in MeOH (50 ml). After
heating under reflux for 5 min, the catalyst was removed and the filtrate was
evaporated to dryness. The 4,5-diaminopyrazole (11) was collected, washed
with Et2O and directly reacted with ethyl chloroformate as follows. Ethyl
chloroformate (0.95 ml 10 mmol) in AcOEt (10 ml) and NaHCO3 (0.84 g,
10 mmol) in water (20 ml) were simultaneously added to a vigorously stirred
solution of 4,5-diaminopyrazole (11) in AcOEt (80 ml). After 2 h the organic
layer was washed with water, dried and evaporated to give 5-amino-3-
methyl-4-ethoxycarbonyl-1-pentafluorophenylpyrazole (12), colorless crys-
tals; yield 78%, mp 134–135 °C (AcOEt/light petroleum); 1H NMR (CDCl3)
δ: 1.31 (t, J = 7.1 Hz, 3H, Me), 2.18 (s, 3H, Me), 3.70 (br., 2H, NH2), 4.21
(q, J = 7.1 Hz, 2H, CH2), 5.95 (br., 1H, NH).
General Procedure for the Preparation of 5-Methylthioimidazo[4,5-c]pyr-
azoles (6)
Methyl iodide (0.71 g, 5 mmol) was added to a stirred solution of the
appropriate imidazo[4,5-c]pyrazole-5-thione (2) (5 mmol) in 1M NaOH
(25 ml). After 2 h the reaction mixture was neutralized with 1M HCl and then
extracted with AcOEt (3 × 50 ml). The combined organic extracts were dried
and evaporated. The resulting solid was triturated with light petroleum.
(6b): pale yellow solid; yield 88%, mp110–112 °C;1H NMR ([D6]DMSO)
δ: 2.59 (s, 3H, Me), 3.70 (s, 3H, Me), 12.00 (br., 1H, NH).
Preparation of 3-Methyl-1-pentafluorophenylimidazo[4,5-c]pyrazole-5-one
(3)
5-Amino-3-methyl-4-ethoxycarbonyl-1-pentafluorophenylpyrazole (12)
(0.35 g, 1 mmol) was heated at 200 °C for 2 h. The solid was collected and
washed with Et2O; 0.22 g, yield 73%, mp 350 °C; 1H NMR (CF3COOD) δ:
three species are present in about 1:1:1 ratio 2.33 (s), 2.38 (s), 2.50 (s) (3H,
Me), 7.6–9.0 (br, 2H, NH or OH).
(6c): pale yellow solid; yield 50%, mp 160–164 °C; 1H NMR (CDCl3) δ:
2.30 (s, 3H, Me), 7.24–7.48 (m, 4H, Ph), 11.19 (s, 1H, NH).
(6d): pale yellow solid; yield 80%, mp 174–178 °C; 1H NMR (CDCl3) δ:
2.42 (s, 3H, Me), 2.74 (s, 3H, Me), 7.10–7.47 (m, 4H, Ph), 8.98 (br., 1H, NH).
Arch. Pharm. Pharm. Med. Chem. 332, 337–342 (1999)

342
Vicentini and co-workers
Preparation of 5-Acetamido-3-methyl-1-p-methoxyphenylpyrazole (14)
of 4 kg ha–1 into the flood water of pots containing transplanted rice (Oriza
sativa; 1.5–2.5 leaf stage) and unemerged watergrass (Echinochloa oryzoy-
des) and rice flatsedge (Cyperus iria). Assessment was made 4 weeks after
treatment.
Results of herbicide assays were based upon visual observation of plant
stand, vigor, malformation, size, chlorosis, and general plant appearance as
compared to the control. In the Primary Herbicide Screen the tests were
repeated three times.
5-Acetamido-3-methyl-1-p-methoxyphenylpyrazole (14) was obtained
according to ref. [20] by heating at 100 °C a mixture of 5-amino-3-methyl-1-
p-methoxyphenylpyrazole (9) (10.16 g, 50 mmol) and acetic anhydride
(13 ml): colorless crystals; yield 82%, mp 108–109 °C; 1H NMR (CDCl3) δ:
2.03 (s, 3H, Me), 2.26 (s, 3H, Me), 3.63 (s, 3H, OMe), 6.38 (s, 1H, CH),
6.93–7.30 (A2B2, J = 8.7 Hz, 4H, Ph), 7.53 (br., 1H, NH).
Preparation of 5-Ethylamino-3-methyl-1-p-methoxyphenylpyrazole (15)
References
A solution of 5-acetamido-3-methyl-1-p-methoxyphenylpyrazole (14)
(6.37 g, 26 mmol) in anhydrous THF (33 ml) was added dropwise to a
suspension of LiAlH4 (1.97 g, 52 mmol) in THF, heated under reflux and
kept in a nitrogen atmosphere. After additional 4 h reflux, the suspension was
cooled, made alkaline with NaOH, and filtered over celite. The filtrate was
evaporated to a solid residue that was dissolved in AcOEt and washed with
H2O. After being dried the solution was evaporated to dryness to give
5-ethylamino-3-methyl-1-p-methoxyphenylpyrazole (15): colorless crys-
tals; yield 80%, mp 72–73 °C; 1H NMR (CDCl3) δ: 1.19 (t, J = 7.2 Hz, 3H,
Me), 2.24 (s, 3H, Me), 3.09 (q, J = 7.2 Hz, 2H, CH2), 3.82 (s, 3H, OMe),
5.33 (s, 1H, CH), 6.93–7.42 (A2B2, J = 8.9 Hz, 4H), 7.53 (br., 1H, NH).
[1] D. K. Berner, A. E. Awad, E. I. Aigbokhan, Plant Disease 1994, 78,
18–23.
[2] R. A. Masters, R. N. Stougaard, S. J.Nissen, Weed Technology 1994,
8, 58–63.
[3] P. Kudsk, S. K. Mathiassen, Weed Research 1994, 34, 251–263.
[4] R. G. Wilson, Weed Technology 1994, 8, 536–540.
[5] The Pesticide Manual, Tenth Edition, Clive Tomlin (Ed), BCPC,
Farnham UK, 1994.
Preparation of 3,5-Dimethyl-1-p-methoxyphenylimidazo[4,5-c]pyrazole (5)
[6] A. Dornow, E. Hinz, Chem. Ber. 1958, 91, 1834–1840.
Five drops of an aqueous solution of 20% HCl and amyl nitrite (2.69 ml,
20 mmol) were added dropwise to a solution at 0 °C of 5-ethylamino-3-
methyl-1-p-methoxyphenylpyrazole (15) (4.62 g, 20 mmol) in EtOH (20 ml).
After 1 h stirring at room temp., the solvent was removed under reduced
pressure to give 5-ethylamino-3-methyl-1-p-methoxyphenyl-4-nitrosopyr-
azole (16) as a solid which was collected and washed with Et2O. The solution
of the crude 5-ethylamino-3-methyl-1-p-methoxyphenyl-4-nitrosopyrazole
(16) (3.91 g, 15 mmol) in pyridine (180 ml) was heated under reflux for
15 min; the solvent was removed under reduced pressure and the residue was
purified by CC (eluent AcOEt/light petroleum: 8/2). Fractions containing
only the product reactive to a 4% aqueous solution of sodium hypochlorite
(yellow spot) were pooled and evaporated to dryness: colorless crystals; yield
81%, mp 180–182 °C; 1H NMR ([D6]DMSO) δ: 2.38 (s, 3H, Me), 2.48 (s,
3H, Me), 3.50 (s, 3H, OMe), 7.13-8.30 (A2B2 J = 9Hz, 4H, Ph), 12.23 (br.,
1H, NH).
[7] M. Lange, R. Quell, H. Lettau, H. Schubert, Z. Chem. 1977, 17, 94–95.
[8] B. Barraclough, J. W. Black, D. Cambridge, D. Firmin, V.P.
Gerskowitch, R. C. Glen, H. Giles, J. M Gillam, R. A. D. Hull, R. Iyer,
P. Randall, G. P. Shah, S. Smith, M.V. Whiting,Arch Pharm 1992, 325,
225–234.
[9] V. Sudarsanam, K. Nagarajan, K. Rama Rao, S. J. Shenoy, Tetrahedron
Letters 1980, 21, 4757–4758.
[10] K. Nagarajan, V. Sudarsanam, S. J. Shenoy, K. Rama Rao, Indian J.
Chem. Sec. B 1980, 21B, 997–1005.
[11] R. N. Butler, D. M Colleran, D. F. O’Shea, D. Cunningham,
P. McArdle, A. M. Gillan, J. Chem. Soc. Perkin Trans. I 1993, 2757–
2759.
[12] J. Elguero in Comprehensive Heterocyclic Chemistry (Ed: K.T. Potts)
Pergamon Press, Oxford, 1984, vol 5, 272.
Biology
[13] C. B. Vicentini, A. C. Veronese, M. Guarneri, EP 190,457 1986 [Chem.
Abstr. 1986, 105. P226578t].
The compounds were tested in the Herbicide Miniscreen on three plant
targets: Arabidopsis thaliana, bentgrass (Agrostis stolonifera), and Chlami-
domonas. For each of the species evaluated, the compounds were dissolved
in 80:20 acetone:water solution and applied at a rate of 40 µg well–1 to each
of two wells in a 96-well microtitre plate. The acetone solution was allowed
to evaporate and the wells were filled with agar. Seeds of target species were
then placed on top of the cooled agar and allowed to germinate. Assessment
was made at 5–7 d after treatment. Each test was repeated twice.
[14] C. B. Vicentini, A. C. Veronese, P. Giori, M. Guarneri, Tetrahedron
Letters 1988, 29, 6171–6172.
[15] C. B. Vicentini, A. C. Veronese, P. Giori, B. Lumachi, M. Guarneri,
Tetrahedron 1990, 46, 5777–5788.
[16] C. B. Vicentini, V. Ferretti, A. C. Veronese, M. Guarneri, M. Manfrini,
The compounds active in the Miniscreen were evaluated in the Primary
Herbicide Greenhouse Screen against 13 plant species (ABTH, Abutilon
theophrasti; AMBEL, Ambrosia artemisifolia; GALAP, Galium aparine;
IPOSS, Ipomea spp; SEBEX, Sesbania exaltata; SINAR, Brassica kaber;
ALOMY, Alopecurus mysuroides; AVEFA, Avena fatua; BROTE, Bromus
tectorum; ECHCG, Echinochloa crusgalli; SETVI, Setaria viridis;
SORHAS, Sorghum halepense; CYPRO, Cyperus rotundus) and in the
transplanted rice screen on 3 additional species (ECHORC, Echinochloa
oryzoides; CYPIR, Cyperus iria; ORYSAT, Oryza sativa). Compounds were
dissolved on 80:20 acetone:water solution containing 0.2% Tween-20 and
applied at a volume of 1600 liter ha–1 at a rate of 4 kg ha–1. Compounds were
sprayed directly on sassafras sandy loam (p 46.1, 2.4% OM, 8.07 meg/100
g CEC) soil 1 dafter seeding for pre-emergence test, and directly on the plants
9–14 d after emergence, depending upon growing conditions, for post-emer-
gence test. Assessments were made after 3 weeks for pre-emergence tests
and 2 weeks for post-emergence tests.
P. Giori, Heterocycles 1995, 41, 497–506.
[17] C. B. Vicentini, A. C. Veronese, M. Manfrini, M. Guarneri, Tetrahe-
dron 1996, 52, 7179–7182.
[18] C. B. Vicentini, A. C. Veronese, M. Manfrini, J. Heterocyclic Chem.
1997, 34, 629–632.
[19] The known 1,3-disubstituted 5-amino-4-nitrosopyrazoles were ob-
tained according to literature. 1,3-dimethyl: E. C. Taylor, K. S. Hartke,
J. Am. Chem. Soc. 1959, 81, 2456–2462; 2-chlorophenyl-3-methyl-,
3-chlorophenyl-3-methyl-, 4-chlorophenyl-3-methyl-, 2,4-dichlo-
rophenyl-3-methyl-: P. Giori, D. Mazzotta, G. Vertuani, M. Guarneri,
D. Pancaldi, A. Brunelli, Farmaco, Ed. Sci. 1981, 36, 1019–1028;
1,3-diphenyl-: S. Checchi, M. Ridi, P. Papini, Gazz. Chim. Ital. 1995,
85, 1558–1568.
[20] A. Michaelis, Liebigs Ann. Chem. 1905, 339, 141.
The compounds were also evaluated in a post-transplant rice screen
designed to simulate paddy rice conditions. Treatments were applied at a rate
Received: April 8, 1999 [FP382]
Arch. Pharm. Pharm. Med. Chem. 332, 337–342 (1999)