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 2Ј-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, 2Ј-[(4,6-dimethoxypyrimidin-2-yl)(hydroxy)methyl]-1,1- difluoro-6Ј-(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 2Ј-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 2Ј-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 2Ј-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 2Ј-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 2Ј-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 2Ј-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 2Ј-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 2Ј-[(4,6-dimethoxypyrimidin-2-yl)(hy- dimethoxypyrimidine-2-yl 3-methoxymethyl-2-nitrophenyl droxy)methyl]-1,1-difluoro-6Ј-(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).