J. Pestic. Sci., 36(2), 212–220 (2011) DOI: 10.1584/jpestics.G10-87

Original Article

Synthesis and herbicidal activity of sulfonanilides having a pyrimidinyl-containing group at the 2-position

Takumi YOSHIMURA,†* Masao NAKATANI,† Sohei ASAKURA,†† Ryo HANAI,†† Manabu HIRAOKA††† and Shigefumi KUWAHARA††††

† K-I Chemical Research Institute Co., Ltd., Iwata, Shizuoka 437–1213, Japan †† Life Science Research Institute, Kumiai Chemical Industry Co., Ltd., Kikugawa, Shizuoka 439–0031, Japan ††† Formulation Technology Institute, Kumiai Chemical Industry Co., Ltd., Shimizu, Shizuoka 424–0053, Japan †††† Graduate School of Agricultural Science, Tohoku University, Aoba-ku, Sendai 981–8555, Japan (Received October 27, 2010; Accepted November 16, 2010)

A novel series of sulfonanilides having a pyrimidinyl-containing group at the 2-position was prepared and their herbicidal activities against paddy weeds and selectivity against rice plants were assessed. The structure-activity relationships were probed by substitution of the sulfonyl group, bridge and benzene ring. Among the sulfon- amides, difluoromethyl compound showed comparatively high activity and a broad spectrum to control weeds, including Echinochloa oryzicola. The most preferable substitution position on the benzene ring was in the 6-po- sition and the lower alkyl group showed high herbicidal activity and a broad weed control spectrum, and among the compounds tested, the methoxymethyl group was the best. In respect of the bridge moiety, the hydroxyl group was the best. Among the compounds examined, 2-[(4,6-dimethoxypyrimidin-2-yl)(hydroxy)methyl]-1,1- difluoro-6-(methoxymethyl)methanesulfonanilide, applied at rates between 4 to 16 g a.i./ha, showed excellent pre-emergence herbicidal activity with a broad spectrum against grass, sedge and broadleaf weeds without injury to rice plants. © Pesticide Science Society of Japan Keywords: sulfonanilide, acetolactate synthase (ALS) inhibitor, structure-activity relationship, pre-emergence herbicide.

pyrimidinyl carboxy (PC) herbicides, viz. bispyribac-sodium, Introduction pyrithiobac-sodium and pyriminobac-methyl.3–5) These herbi- The total acreage of rice in Japan in 2009 was 1.62 million ha cides exhibit their activities by specifically and strongly in- and most of the paddy fields are mechanically transplanted, hibiting ALS enzyme of plants, which is involved in the using young seedlings grown in nursery boxes.1) It is also biosynthesis of branched-chain amino acids in plants, such as noteworthy that most Japanese rice farmers apply so-called valine, leucine and isoleucine.6) Because mammals lack ALS one-shot herbicides, which are now essential tools for weed enzyme, these herbicides are inherently safe for mammals control in paddy fields.2) This has been made possible by the and, coupled with high activity with low use rates, these PC wide variety of one-shot herbicides now available on the herbicides are extensively used worldwide as environmentally Japanese market. While sulfonylurea (SU) herbicides are friendly herbicides. most commonly used as the active principles in the formula- In the course of our researches on PC herbicides, we con- tion of one-shot herbicides, because SU herbicides control a firmed that in order for a compound to exhibit high ALS in- wide range of paddy weeds including annual broadleaves and hibitory activity and high herbicidal activity, the hydrophobic perennial Cyperaceae and about 90% of one-shot herbicides group, pyrimidine ring and acidic group need be placed in a contain 3 to 4 active ingredients.2) suitable spatial position linked by a suitable spacer group via We have so far developed and commercialized our original a suitable linkage group.7) Based on the findings, we have conducted extensive studies to place various hydrophobic * To whom correspondence should be addressed. groups and acidic groups in an appropriate position on the E-mail: [email protected] pyrimidine ring. Published online January 20, 2011 PC herbicides have a carboxyl group, but due to their rela- © Pesticide Science Society of Japan tively high water solubility as a result of their acidity, PC her- Vol. 36, No. 2, 212–220 (2011) Synthesis and herbicidal activity of sulfonanilides having a pyrimidinyl-containing group at the 2-position 213

Materials and Methods 1. Synthesis of compounds 1.1. General procedures The synthetic route of sulfonanilide derivatives having a pyrimidinyl-containing group at the 2-position (v, vii, viii) is shown in Fig. 2.9) In the first step, compound ii was prepared by reacting 2-nitrophenylacetonitrile (i) and 4,6-dimethoxy-2- Fig. 1. Change to 2-pyrimidnecarbonyl sulfonanilide. methylsulfonylpyrimidine (DMSP) in the presence of a base.5) Then, compound ii was oxidized and dehydrocyanated to ob- tain compound iii. Sulfonanilide v was prepared by selective bicides often have problems of being easily affected by water reduction of the nitro group of compound iii and by sulfonyla- movement and consequently of having unstable herbicidal ac- tion. Sulfonanilide vii was prepared by reduction of com- tivity in pre-emergence application under flooded condi- pound v or by reduction of the carbonyl group of compound tions.4) Furthermore, because of the oxy-bridge, which is iv and sulfonylation. Finally, we exchanged the substituent of characteristic of PC herbicides and is easily degraded by me- the bridge moiety using compound vii. tabolism, we tried to change the oxy-bridge to a carbon bridge An alternative synthetic route of sulfonanilide derivatives in order to secure adequate residual activity. We also tried to (v, vii, viii) is shown in Fig. 3.9) Compound ix was prepared change the acidic group to a sulfonamide group to provide a by reducing the nitro group of compound ii to convert it to an broader weeding spectrum.8) As a result, we have succeeded amino group in the presence of a catalyst such as palladium in redesigning PC herbicides by replacing the oxy-bridge with carbon in alcoholic solvent. Sulfonanilide v was prepared by a carbonyl bridge and the carboxyl group with a sulfonamide reacting compound ix with substituted-alkylsulfonyl halide or group, and synthesized 2-pyrimidinecarbonylsulfonanilides substituted-alkylsulfonic acid anhydride in the presence of (Fig. 1). These compounds were found to have high active pyridine to produce indole compound x, and subjecting the in- herbicidal activity against various paddy weeds. dole compound x to oxidation for ring opening. The reaction This paper reports the synthesis of sulfonanilide derivatives for subjecting the indole compound x to oxidation for ring having a pyrimidinyl-containing group at the 2-position and opening was conducted by, in the first step, treatment of the their structure-herbicidal activity relationships. compound with an oxidizing agent such as m-chloroperben- zoic acid and, in the second step, treatment with a base such as sodium hydroxide.

Fig. 2. Synthetic route of sulfonanilide derivatives having apyrimidinyl-containing group at the 2-position. 214 T. Yoshimura et al. Journal of Pesticide Science

Fig. 3. Altenative synthetic route of sulfonanilide derivatives having a pyrimidinyl-containing group at the 2-position.

1.2. Typical procedures aqueous sodium hydroxide solution was added, and stirred at Chemical structures of all compounds were confirmed by 1H room temperature for 1 hr. Further, 50 ml chloroform was NMR spectra, which were recorded on a JNM-PMX60 or added. The organic layer was washed with 5% dilute hy- JNM-LA300 NMR spectrometer with tetramethylsilane drochloric acid and saturated aqueous sodium chloride solu- (TMS) as an internal standard. All melting points were meas- tion, dried, and subjected to vacuum distillation to remove the ured on a Yanaco MP-500V micro melting-point apparatus solvent. The residual crystals were washed with ethanol-diiso- and are uncorrected. propyl ether to obtain 2.8 g (yield: 84%) of 4,6- 1.2.1. Synthesis of 2-[(4,6-dimethoxypyrimidin-2-yl)(hy- dimethoxypyrimidine-2-yl 3-methoxymethyl-2-nitrophenyl droxy)methyl]-1,1-difluoro-6-(methoxymethyl)- ketone as a white powder (mp: 111 to 113°C). 1H NMR 300

methanesulfonanilide (35) MHz (CDCl3): 7.90 (d, 1H), 7.72 (t, 1H), 7.61 (d, 1H), 6.13 2-(4,6-dimethoxypyrimidine-2-yl)-2-(3-methoxymethyl-2-ni- (s, 1H), 4.78 (s, 2H), 3.90 (s, 6H), 3.47 (s, 3H). trophenyl)acetonitrile (ii; R2: 6-MeOCH2) An 11.2 g (0.28 2-(4,6-Dimethoxyprimidine-2-ylcarbonyl)-6-(methoxymethyl)- mol) amount of 60% sodium hydride was suspended in 100 aniline (iv; R2: 6-MeOCH2) A 3.3 g (10 mmol) amount of ml N,N-dimethylformamide (DMF). While the suspension 4,6-dimethoxypyrimidine-2-yl 3-methoxymethyl-2-nitrophenyl was cooled to 10°C or lower in an ice water bath and stirred, a ketone, 3 g (54 mmol) of iron powder, 20 ml water and a mix- solution of 29 g (0.14 mol) of 3-methoxymethyl-2-nitropheny- ture of 150 ml ethyl acetate and 1 ml acetic acid were sub- lacetonitrile dissolved in 100 ml DMF was added dropwise. jected to reaction at 50°C for 5 hr. The insoluble contents of After the dropwise addition, the mixture was stirred at room the reaction mixture were separated by filtration using a filter temperature until there was no evolution of hydrogen. While aid. The organic layer was washed with saturated aqueous the mixture was cooled to 10°C or lower in an ice water bath sodium chloride solution, dried, and subjected to vacuum dis- and stirred, 30 g (0.14 mol) of DMSP was added. The mixture tillation to remove the solvent. The residual crystals were was stirred at room temperature for 12 hr and then the reac- washed with diisopropyl ether to obtain 2.4 g (yield: 80%) of tion mixture was poured into ice water. The mixture was acid- 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-6-(methoxy- ified with 10% hydrochloric acid. The resulting crude crystals methyl)aniline as yellow crystals (mp: 100 to 101°C). 1H were collected by filtration, washed with water and a mixed NMR 300 MHz (CDCl3): 7.37 (d, 1H), 7.24 (d, 1H), 7.14 (br, solvent of ethanol and diisoproply ether to obtain 42 g (yield: 2H), 6.53 (t, 1H), 6.11 (s, 1H), 4.55 (s, 2H), 0.96 (s, 6H), 3.35 87%) of 2-(4,6-dimethoxypyrimidine-2-yl)-2-(3-methoxymethyl- (s, 3H). 2-nitrophenyl)acetonitrile as a reddish brown powder (mp: 112 2-[(4,6-Dimethoxypyrimidine-2-yl)(hydroxy)methyl]-6- 1 to 113°C). H NMR 300 MHz (CDCl3): 7.83 (m, 1H), 7.58 (methoxymethyl)aniline (vi; R2: 6-MeOCH2) A solution of (m, 2H), 5.91 (s, 1H), 5.72 (s, 1H), 4.53 (s, 2H), 3.90 (s, 6H), 3.1 g (10 mmol) of 2-(4,6-dimethoxypyrimidine-2-ylcar- 3.39 (s, 3H). bonyl)-6-(methoxymethyl)aniline in 50 ml of 1 : 1 (v/v) mix- 4,6-Dimethoxypyrimidine-2-yl 3-methoxymethyl-2-nitro- ture of THF and water was prepared. While the solution was phenl ketone (iii; R2: 6-MeOCH2) In 30 ml chloroform were stirred at room temperature, 0.6 g (16 mmol) of sodium boron dissolved 3.5 g (10 mmol) of 2-(4,6-dimethoxypyrimidine-2- hydride was added. The mixture was stirred at room tempera- yl)-2-(3-methoxymethyl-2-nitrophenyl)acetonitrile and 6.0 ture for 2 hr. Further, 50 ml ice water was added and extracted (17 mmol) of 50% m-chloroperbenzoic acid. The solution was with ethyl acetate. The organic layer was washed with satu- stirred at room temperature for 12 hr, then 15 ml of a 10% rated aqueous sodium chloride solution, dried, and subjected Vol. 36, No. 2, 212–220 (2011) Synthesis and herbicidal activity of sulfonanilides having a pyrimidinyl-containing group at the 2-position 215 to vacuum distillation to remove the solvent. The residual etate/hexane1/1) to obtain 1.8 g (yield: 67%) of 2-(2- crystals were washed with diisopropyl ether to obtain 2.8 g aminophenyl)-2-(4,6-dimethoxypyrimidine-2-yl)acetonitrile (yield: 92%) of 2-[(4,6-dimethoxypyrimidine-2-yl)(hydroxyl)- as a light yellow candy-like substance. 1H NMR 60 MHz methyl]-6-(methoxymethyl)aniline as a white powder (mp: 40 (CDCl3): 6.5-7.6 (m, 4H), 6.9 (s, 1H), 5.3 (s, 1H), 4.6 (br, 1 to 42°C). H NMR 300 MHz (CDCl3): 7.30 (d, 1H), 7.01 (d, 2H), 3.9 (s, 6H). 1H), 6.73 (t, 1H), 5.93 (s, 1H), 5.84 (d, 1H), 5.17 (br, 2H), 2-Amino-1-difluoromethylsulfonyl-3-(4,6-dimethoxypyrimi-

4.68 (d, 1H), 4.51 (q, 2H), 3.94 (s, 6H), 3.32 (s, 3H). dine-2-yl)indole (x; R2: H) In 100 ml chloroform were dis- 2-[(4,6-dimethoxypyrimidin-2-yl)(hydroxy)methyl]-1,1-di- solved 4.0 g (14.8 mmol) of 2-(2-aminophenyl)-2-(4,6- fluoro-6 -(methoxymethyl)methanesulfonanilide (vii; R2: 6- dimethoxypyrimidine-2-yl)acetonitrile, 2.5 g (31.6 mmol) of MeOCH2) In 30 ml dichloromethane were dissolved 4.0 g pyridine and 2.8 g (18.6 mmol) of difluoromethanesul- (13.1 mmol) of 2-[(4,6-dimethoxypyrimidine-2-yl)(hydroxyl)- fonylchloride. The solution was stirred at room temperature methyl]-6-methoxymethylaniline and 2.0 g (25.3 mmol) of overnight. The reaction mixture was washed with dilute hy- pyridine. While the solution was stirred at 10°C, 3.6 g (23.9 drochloric acid and saturated aqueous sodium chloride solu- mmol) of difluoromethanesulfonylchloride was added drop- tion and then dried over anhydrous magnesium sulfate. The wise. The mixture was stirred at room temperature for 7 days. resulting mixture was subjected to vacuum distillation to re- The reaction mixture was poured into ice water and extracted move the solvent. The residue was subjected to silica gel col- with dichloromethane. The organic layer was washed with 5% umn chromatography (elutant solvent: ethyl acetate/hexane dilute hydrochloric acid and saturated aqueous sodium chlo- 1/3) to obtain 2.0 g (yield: 35%) of 2-amino-1-difluoromethyl- ride solution, dried, and subjected to vacuum distillation to re- sulfonyl-3-(4,6-dimethoxypyrimidine-2-yl)indole as a light move the solvent. The residue was subjected to silica gel col- yellow powder (mp: 156 to 158°C). 1H NMR 300 MHz umn chromatography (elutant solvent: ethyl acetate/hexane (CDCl3): 8,57 (d, 1H), 7.81 (d, 1H), 7.56 (br, 2H), 7.34 (t, 1/3) to obtain 2.0 g (yield: 36%) of 2-[(4,6-dimethoxypyrim- 1H), 7.15 (t, 1H), 6.43 (t, 1H), 5.84 (s, 1H), 4.05 (s, 6H). idin-2-yl)(hydroxy)methyl]-1,1-difluoro-6-(methoxymethyl)- 2-(4,6-Dimethoxypyrimidine-2-ylcarbonyl)-1,1-difluo- methanesulfonanilide as colorless granular crystals (mp: 76 to romethanesulfonanilide (v; R2: H) In 30 ml chloroform were 1 77°C). H NMR 300 MHz (CDCl3): 10.53 (br, 1H), 7.67 (d, dissolved 2.0 g (5.2 mmol) of 2-amino-1-difluoromethylsul- 1H), 7.49 (d, 1H), 7.36 (t, 1H), 6.53 (t, 1H), 6.24 (d, 1H), 5.98 fonyl-3-(4,6-dimethoxypyrimidine-2-yl)indole and 2.0 g (5.8 (s, 1H), 4.92 (d, 1H), 4.68 (d, 2H), 3.98 (s, 6H), 3.39 (s, 3H). mmol) of 50% m-chloroperbenzoic acid. The solution was 1.2.2. Synthesis of 2-[(4,6-Dimethoxypyrimidine-2-yl)- stirred at room temperature for 12 hr. Then, 15 ml of 10% (hydroxyl)methyl]-1,1-difluoromethanesulfo- aqueous sodium hydroxide solution was added. The mixture nanilide (2) was stirred at room temperature for 1 hr, and then 50 ml chlo- 2-(4,6-dimethoxypyrimidine-2-yl)-2-(2-nitrophenyl)acetoni- roform was added. The organic layer was washed with 5% di- trile (ii; R2: H) Fifty grams (0.31 mol) of 2-(2-nitrophenyl)- lute hydrochloric acid and saturated aqueous sodium chloride acetonitrile were dissolved in 500 ml DMF, and 24.7g (0.62 solution and dried. The resulting solution was subjected to mol) of 60% sodium hydride was added. The mixture was vacuum distillation to remove the solvent. The residue was stirred at room temperature for 2 hr. Then, 68 g (0.31 mol) of subjected to silica gel column chromatography (elutant sol- DMSP was added. The mixture was stirred at 80°C for 1 hr vent: ethyl acetate/hexane1/5) to obtain 1.0 g (yield: 52%) for the reaction. The reaction mixture was poured into water of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-1,1-difluoro- and neutralized with dilute hydrochloric acid. The mixture methanesulfonanilide as a white powder (mp: 131 to 133°C). 1 was extracted with ethyl acetate. The extract was washed with H NMR 300 MHz (CDCl3): 11.36 (br, 1H), 7.86 (d, 1H), 7.70 water, dried and subjected to vacuum distillation to remove (d, 1H), 7.62 (t, 1H), 7.18 (t, 1H), 6.35 (t, 1H), 6.19 (s, 1H), the solvent. The residue was recrystallized from ethanol to 3.97 (s, 6H). obtain 73.3 g (yield: 79%) of 2-(4,6-dimethoxypyrimidine-2- 2-[(4,6-Dimethoxypyrimidine-2-yl)(hydroxy)methyl]-1,1- yl)-2-(2-nitrophenyl)acetonitrile as a white powder (mp: 88 to difluoromethanesulfonanilide (vii; R2: H) A 1 g (2.7 mmol) 1 89°C). H NMR 60 MHz (CDCl3): 7.5–8.2 (m, 4H), 6.4 (s, amount of 2-(4,6-dimethoxypyrimidine-2-ylcarbonyl)-1,1-di- 1H), 5.9 (s, 1H), 3.8 (s, 6H). fluoromethanesulfonanilide was dissolved in 50 ml of a 1 : 1 2-(2-Aminophenyl)-2-(4,6-dimethoxypyrimidine-2-yl)ace- (by volume ratio) mixed solvent of tetrahydrofuran and water. tonitrile (iii; R2: H) A 3 g (10 mmol) amount of 2-(4,6- While the solution was stirred at room temperature, 0.2 g (5.4 dimethoxypyrimidine-2-yl)-2-(2-nitrophenyl)acetonitrile and mmol) of sodium boron hydride was added. The mixture was 0.3 g of 10% palladium carbon were suspended in 100 ml stirred at room temperature for 2 hr, and then 50 ml ice water methanol. While the suspension was stirred at room tempera- was added and extracted with ethyl acetate. The organic layer ture overnight, hydrogen gas was added. The solid was re- was washed with saturated aqueous sodium chloride solution, moved by filtration. The filtrate was subjected to vacuum dis- dried, and subjected to vacuum distillation to remove the sol- tillation to remove methanol. The residue was subjected to sil- vent. The residual crystals were washed with diisopropyl ica gel column chromatography (elutant solvent: ethyl ac- ether to obtain 0.8 g (yield: 80%) of 2-[(4,6-dimethoxypyrim- 216 T. Yoshimura et al. Journal of Pesticide Science idine-2-yl)(hydroxyl)methyl]-1,1-difluoromethanesulfo- was washed with saturated aqueous sodium chloride solution, nanilide as a white powder (mp: 103 to 105°C). 1H NMR 300 dried, and subjected to vacuum distillation to remove the sol-

MHz (CDCl3): 10.89 (br, 1H), 7.70 (m, 1H), 7.60 (m, 1H), vent. The residue was subjected to silica gel column chro- 7.30 (m, 2H), 6.32 (t, 1H), 6.10 (d, 1H), 5.99 (s, 1H), 4.92 (d, matography (elutant solvent: ethyl acetate/hexane1/9) to ob- 1H), 4.00 (s, 6H). tain 0.3 g (yield: 15%) of 2-[(4,6-dimethoxypyrimidine-2- 1.2.3. Synthesis of 2-[(chloro)(4,6-dimethoxypyrimidine- yl)(methoxy)methyl]-1,1,1-trifluoromethanesulfonanilide as a 1 2-yl)methyl]-1,1,1-trifluoromethanesulfonanilide white powder (mp: 105 to 106°C). H NMR 300 MHz (CDCl3): (17) 10.98 (br, 1H), 7.48–7.62 (m, 2H), 7.20–7.36 (m, 2H), 5.95 Ten grams (25.4 mmol) of 2-[(4,6-dimethoxypyrimidine-2- (s, 1H), 5.37 (s, 1H), 3.98 (s, 6H), 3.45 (s, 3H). yl)(hydroxyl)methyl]-1,1,1-trifluoromethanesulfonanilide were dissolved in 100 ml thionylchloride. After the solution 2. Evaluation of herbicidal activity was stirred under reflux for 3 hr, the reaction mixture was Paddy soil was placed in a plastic pot of 100 cm2. An appro- concentrated under reduced pressure. The residual mixture priate amount of water was added for soil puddling. Seeds of was cooled to 10°C and 300 ml toluene added. The toluene Echinochloa oryzicola vasing., Monochoria vaginalis (Burm. solution was washed with a solution of sodium bicarbonate f.) Presl var. plantaginea (Roxb.) Solms-Laub., and Scirpus and saturated aqueous sodium chloride solution, dried, and juncoides Roxb. subsp. hotarui (Ohwi) T. Koyama were sowed subjected to vacuum distillation to remove the solvent. The at a depth of 0.5 cm. Further, two paddy rice seedlings each at residue was subjected to silica gel column chromatography the two-leaf stage were transplanted at a depth of 2 cm. Water (elutant solvent: ethyl acetate/hexane1/4) to obtain 8.4 g was filled to a depth of 3 cm. The next day, water-dispersible (yield: 80.2%) of 2-[(chloro)(4,6-dimethoxypyrimidine-2- powder prepared by mixing 10 parts by weight of each of the yl)methyl]-1,1,1-trifluoromethanesulfonanilide as a white compounds, with 0.5 part by weight of polyoxyethylene octyl 1 crystal (mp: 93 to 94°C) H NMR 300 MHz (CDCl3): 11.48 phenyl ether, 0.5 part by weight of sodium salt of b-naph- (bs, 1H), 7.77–7.51 (m, 2H), 7.43–7.22 (m, 2H), 6.03 (s, 1H), thalenesulfonic acid-formalin condensate, 20 parts by weight 6.00 (s, 1H), 4.01 (s, 6H). of diatomaceous earth and 69 parts by weight of clay, was di- 1.2.4. Synthesis of 2-[(acetyloxy)(4,6-dimethoxypyrimi- luted with water and dropped onto the water surface so that dine-2-yl)methyl]-1,1,1-trifluoromethanesulfo- the amount of the active ingredient (each compound) applied nanilide (15) was 4, 16, 63, 250, 1000 g/ha. The development and growth A 0.8 g (2.0 mmol) amount of 2-[(4,6-dimethoxypyrimidine- of weeds and rice plants were allowed to take place in a 2-yl)(hydroxyl)methyl]-1,1,1-trifluoromethanesulfonanilide greenhouse. Injury symptoms of paddy rice and weed was dissolved in 50 ml tetrahydrofuran and 0.2 g (4.0 mmol) seedlings were observed visually 28 days after the addition of of 60% sodium hydride was added. The mixture was stirred at the test dilution (2 replicants). The paddy rice injury was ex- room temperature for 2 hr. Then, 0.25 g (2 mmol) of pressed as ED20, the dosage in terms of g a.i./ha required for acetylchloride was added and the mixture was stirred at room 20% damage to rice seedlings. Herbicidal activity was ex- temperature overnight. The reaction mixture was poured into pressed as ED90, the dosage in terms of g a.i./ha required for water and then neutralized with citric acid. The mixture was 90% damage to weed seedlings. extracted with ethyl acetate. The extract was washed with Results and Discussion water, dried and subjected to vacuum distillation to remove the solvent. The residue was subjected to silica gel column 1. Synthesis chromatography (elutant solvent: ethyl acetate/hexane1/4) In the reaction of 2-nitrophenylacetonitrile (i) and DMSP, to obtain 0.3 g (yield: 33.3%) of 2-[(acetyloxy)(4,6- sodium hydride or potassium t-butoxide was used as the base, dimethoxypyrimidine-2-yl)methyl]-1,1,1-trifluoromethanesul- where two equimolar bases were needed, because the acidity fonanilide as a pale yellow viscous liquid (refractive index: of product ii was stronger than that of material i. 20 1 nD 1.5090). H NMR 60 MHz (CDCl3): 7.61–7.68 (m, 2H), Because the basicity of anilines having a carbonyl group at 7.46–7.55 (m. 2H), 6.74 (s, 1H), 5.99 (s, 1H), 3.95 (s, 6H), the 2-position (iv) was weak, most sulfonylation of the ani- 2.25 (s, 3H). lines did not proceed; however, anilines having a 2-hydrox- 1.2.5. Synthesis of 2-[(4,6-Dimethoxypyrimidine-2-yl)- ymethyl group (vi) could be sulfonylated by sulfonyl chloride (methoxy)methyl]-1,1,1-trifluoromethanesulfo- or sulfonyl anhydride in the presence of a weaker organic nanilide (13) base such as triethylamine or pyridine. Therefore, most sulfo- A 2 g (4.9 mmol) amount of 2-[(chloro)(4,6-dimethoxypyrimi- nanilide vii was prepared using hydroxymethyl derivatives. In dine-2-yl)methyl]-1,1,1-trifluoromethanesulfonanilide was dis- the route shown in Fig. 3, anilines having a 2-cyanomethyl solved in 10 ml DMF and 1.0 g (5.2 mmol) of 28% sodium group (ix) were sulfonylated with sulfonyl chloride, produc- methylate methanol solution was added. The mixture was ing 1-sulfonyl indole compound x. stirred at room temperature for 1 hr, and then 50 ml ice water Derivatives of a few bridge variations were prepared from was added and extracted with ethyl acetate. The organic layer the hydroxyl compound vii. Compounds 13 and 14 were ob- Vol. 36, No. 2, 212–220 (2011) Synthesis and herbicidal activity of sulfonanilides having a pyrimidinyl-containing group at the 2-position 217 tained by acetylation and trimethylsililation, respectively, and had only weak herbicidal activity against E. oryzicola, with compound 17 was prepared by chlorination with thionyl chlo- the exception of methoxy compound 13, which had moderate ride. Compounds 13, 16, 18, 19, 20 were prepared from activity, with an ED90 of 63 g/ha. On the other hand, almost all chloro-compound 17 by reacting with the corresponding nu- groups showed high biological activities against M. vaginalis cleophiles. and S. juncoides. Although acetyloxy compound 15, ethylthio compound 20 and carbonyl compound 12 all showed high 2. Herbicidal activity herbicidal activities in pot tests, they showed low ALS in- Herbicidal activities against Echinochloa oryzicola (Eo), hibitory activities in an in vitro assay (data not shown). These Monochoria vaginalis (Mo), Scirpus juncoides (Sc) were compounds presumably exhibited herbicidal activity as a re- evaluated for 39 types of sulfonanilides (1–39) and the results sult of having changed in vivo to active ingredients. Hydroxyl are summarized in Tables 1–4. compound 1 and trimethylsilyloxy compound 14 showed the Table 1 shows the structure-herbicidal activity relationship highest activities. Since trimethylsilyloxy compound 14 was of the sulfonamide moiety. The haloalkyl group (ClCH2, presumed to show high activity by being easily changed to a FCH2, F2CH, CF3) and cyanomethyl group show compara- hydroxyl group, hydroxyl compound 1 is responsible for ac- tively high weed control activities and, in particular, these tivity exhibition. compounds with difluoromethyl group and trifluoromethyl While both difluoromethanesulfonanilides and trifluo- group have markedly high herbicidal activities against M. romethanesulfonanilides showed equally high herbicidal ac- vaginalis and S. juncoides. The compound with the fluo- tivities, difluoromethanesulfonanilides appeared to be better romethyl group has the best herbicidal activities against E. due to its more balanced activity against a variety of weeds, oryzicola. In the ALS inhibitory herbicide, a weakly acidic including E. oryzicola. We therefore continued our researches group and an N-containing heterocyclic ring appropriately lo- on the effects of the substituents on the benzene ring by fo- cated in a molecule are requisites for ALS inhibition.7) The cusing on difluoromethyl compounds. The structure-activity pKa values of these herbicides are between 2 to 5. Alkylsulfo- relationship of the substituents of the benzene ring is shown nanilides having an electron-withdrawing group have high in Table 3, in which the results of substitution by halogen, herbicidal activities but benzenesulfonanilide (10) has low ac- alkyl and alkoxy groups at respective positions on the ben- tivity; therefore, it was considered that the acidity of the sul- zene ring are described. With regard to the substitution at 3- fonanilide and the size of R1 affected herbicidal activities. position of the benzene ring, the size of the group is critical Table 2 shows the correlation between the bridge moiety and 3-fluoro compound 23 showed higher herbicidal activity and biological activity. Most trifluoromethanesulfoanilides than unsubstituted compound, but 3-chloro compound 24

Table 1. Subsutituted sulfonanilides with pre-emergence herbicidal activity

ED ED Compound 20 90 R1 mp (°C) No Or Eo Mo Sc

1 CF3 119–121 63 1000 4 4

2 CHF2 103–105 63 250 4 16

3 CH2F 108–109 63 63 16 16

4 CH2Cl 90–93 250 1000 16 63

5 CH2CN 1.549 250 1000 63 250 6 CH2CH CHCl 86–88 250 1000 250 1000 7 CH3 116–118 63 1000 250 1000 8 C2H5 103–106 1000 1000 1000 1000 9 CH(CH3)2 118–122 1000 1000 1000 1000 10 C6H5 1.568 1000 1000 1000 1000 11 NH2 157–159 250 1000 1000 1000 218 T. Yoshimura et al. Journal of Pesticide Science

Table 2. Subsutituted trifluoromethanesulfonanilides with pre-emergence herbicidal activity

ED ED Compound 20 90 X mp (°C) No Or Eo Mo Sc

No Or Eo Mo Sc 12 O 102–104 63 1000 16 16 1 OH 119–121 63 1000 4 4

13 OCH3 105–106 63 63 16 63

14 OSiMe3 1.498 63 1000 4 4 15 OCOCH3 1.509 63 1000 16 4 16 ON CHCH3 1.513 63 1000 63 16 17 Cl 93–94 63 1000 16 4 18 NMe2 200–201 250 1000 63 16 19 SH 1.54 250 1000 63 63

20 SC2H5 90–91 63 1000 16 4 21 SOC2H5 128–129 1000 1000 1000 63 22 SO2C2H5 129–130 1000 1000 250 250

Table 3. Subsutituted difluoromethanesulfonanilides with pre-emergence herbicidal activity

ED ED Compound 20 90 R2 mp (°C) No Or Eo Mo Sc

2 H 103–105 63 250 4 16 23 3-F 96–97 16 63 16 16 24 3-Cl 83–85 1000 1000 64 250 25 4-Cl 115–116 1000 1000 1000 1000 26 4-OCH3 130–131 63 1000 250 1000 27 5-Cl 110–111 63 250 63 63

28 5-CH3 95–96 16 1000 16 16

29 5-OCH3 113–114 16 16 16 63 30 6-F 100–101 16 250 4 4

31 6-CH3 129–131 16 16 4 16

32 6-OCH3 122–124 4 16 16 63 Vol. 36, No. 2, 212–220 (2011) Synthesis and herbicidal activity of sulfonanilides having a pyrimidinyl-containing group at the 2-position 219

Table 4. 6-subsutituted difluoromethanesulfonanilides with pre-emergence herbicidal activity

ED ED Compound 20 90 R2 mp (°C) No Or Eo Mo Sc

2 H 103–105 63 250 4 16 30 F 100–101 16 250 4 4

31 CH3 129–131 16 16 4 16

33 C2H5 121–122 63 16 16 4

34 C3H7 122–124 63 16 16 63

35 CH2OCH3 76–77 63 16 4 4

32 OCH3 122–124 4 16 16 63

36 OC2H5 137–138 16 63 16 16

37 OC3H7 131–133 63 250 63 250 38 OC6H5 153–156 1000 1000 250 1000

39 SCH3 114–115 63 250 63 63

showed reduced activity. Substitution at the 4-position also re- Propyl compound 34 and ethoxy compound 36 showed high sulted in reduced activity. In the case of substituted com- activities, but propoxy compound 37 and phenoxy compound pounds at the 5-position, activity was slightly lower than that 38 showed reduced activity. The size and/or length of the sub- of the unsubstituted compound. On the other hand, the activ- stituents at the 6-position were crucial for activity. Alkoxy ity of the substituted compounds at the 6-position tended to compounds showed severe rice plant injuries but alkyl com- be higher than the unsubstituted compound. In summary, the pounds were relatively safe for rice plants. Based on these effects of the substitution position on the enhancement of ac- findings, we considered that alkyl groups were favorable and tivity were most evident at the 6-position, but the effects de- therefore synthesized various compounds to evaluate their creased in the order of 6H (unsubstituted)5, 34. This herbicidal activities. As a result, we finally selected a com- sequence of effects of the ring substituents according to posi- pound with a methoxymethyl group as a promising com- tion was similar to the sequence of effects on pyrimidinyl sali- pound, because this compound showed well-balanced en- cilate herbicides.10) hancement of herbicidal activity and the weed control spec- Since only substitution at the 6-position was considered fa- trum as well as safety for rice plants. vorable for enhancing herbicidal activity, we further synthe- In conclusion, Fig. 4 shows a summary of the structure-her- sized substituted compounds at the 6-position with various bicidal activity relationships of these sulfonalinide herbicides. groups. The results are presented in Table 4. Among 6-substi- Among sulfonamides, difluoromethyl compound showed tuted derivatives, the herbicidal spectrum and selectivity comparatively high activity and a broad weed control spec- changed depending on the substituent but, in particular, it was trum, including E. oryzicola. The most preferable substitution noted that the alkyl compounds tended to enhance herbicidal position on the benzene ring was the 6-position. The alkyl activity against E. oryzicola as well as selectivity between rice group showed high herbicidal activity and a broad weed con- plants and paddy weeds. In halogenated compounds, 6-fluoro compound 30 showed higher herbicidal activity than the unsubstituted compound. In the case of alkylated or alkoxylated compounds, herbicidal activities against M. vaginalis and S. juncoides were similar or slightly lower than that of the unsubstituted compound, but herbicidal activities against E. oryzicola were enhanced. Fig. 4. Conclusion of structure-activity relationships. 220 T. Yoshimura et al. Journal of Pesticide Science trol spectrum and, among the compounds tested, the 6) T. Shimizu: J. Pestic. Sci. 22, 245–256 (1997). methoxymethyl group was the best. In respect of bridge moi- 7) T. Yoshida, Y. Nezu, R. Hanai and T. Shimizu: “Modern Crop ety, on the other hand, the hydroxyl group was the best. Protection Compounds,” Vol. 1 ed. by W. Kraemer and U. Schirmer, Wiley-VCH, Weinheim, Germany, pp. 114–137, References 2008. 1) www.maff.go.jp/j/tokei/kouhyou/pdf/suitou_091015/suitou_ 8) R. D. Trepka, J. K. Harringon, J. E. Robertson and J. T. 091015.pdf Waddington: J. Agric. Food Chem. 18, 1176–1177 (1970). 2) K. Takeshita: J. Weed Sci. Tech. 49, 220–239 (2004). 9) T. Yoshimura, M. Miyazaki, T. Suzuki, M. Nakatani, M. 3) O. Watanabe, M. Yokoyama, S. Fujita, T. Miyazaki and N. Tamaru, Y. Ono, T. Ida, K. Yanagisawa and H. Sadohara (Ku- Wada: J. Weed Sci. Tech. Supplement (42), 6–9 (2003). miai Chemical Industry Co. & Ihara Chemical Industry Co.): 4) Y. Nezu, Y. Saito, S. Takahashi and Y. Tomoda: J. Pestic. Sci. Jpn. Kokai Tokkyo JP 11-60562 (1999) (in Japanese). 24, 217–229 (1999). 10) Y. Nezu, N. Wada, Y. Saito, S. Takahashi and T. Miyazawa: J. 5) M. Tamaru, K. Kawano, R. Hanai and Y. Kimura: J. Pestic. Sci. Pestic. Sci. 21, 293–303 (1996). 27, 188–189 (2002).