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呋虫胺

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呋虫胺 INTRODUCTION Insecticides which have a structure and mechanism similar to nicotine are called neonicotinoids.1) Neonicotinoids are highly insecticidal, are systemic in plants, and now account for over 10% of the insecticide market. Every neonicotinoid has two sit...
呋虫胺
INTRODUCTION Insecticides which have a structure and mechanism similar to nicotine are called neonicotinoids.1) Neonicotinoids are highly insecticidal, are systemic in plants, and now account for over 10% of the insecticide market. Every neonicotinoid has two sites, a cationic site and a hy- drogen acceptor site, for binding to nicotinic acetylcholine re- ceptors. In regard to the hydrogen acceptor site, a chloropyri- dine or a chlorothiazole ring had been considered to be indis- pensable for neonicotinoids because of their structural simi- larity to the pyridine part of nicotine. Six neonicotinoids, which have the pyridine-like moiety, have been commercial- ized and many SARs for these neonicotinoids have been re- ported (Fig. 1).2–4) We started our research in 1992 to look for a novel neoni- cotinoid. It resulted in dinotefuran which has a (�)-tetrahy- dro-3-furylmethy moiety as the hydrogen acceptor site and the nitroguanidine moiety as the cationic site.5–8) In this re- search, hundreds of related compounds were synthesized and the SARs for two moieties were obtained. Since publication of our research on dinotefuran, much related research has been reported, but many of the studies were about residue analysis,9,10) metabolism11–13) and mode of action,14–16) and there are not enough reports about the SAR of dinotefu- ran.5,15,17) In this paper we describe the preparation of four types of (�)-tetrahydro-3-furylmethy derivatives and the SAR for the nitroguanidine part of dinotefuran. MATERIALS AND METHODS 1. Instrumental Analysis Melting points were obtained on a Mettler FP62 melting point apparatus and were uncorrected. 1H NMR spectra were recorded on a JEOL JNM-LA400 spectrometer using tetra- methylsilane as an internal standard. IR spectra were recorded on a JASCO FT/IR-7300 spectrometer. Analytical TLC was performed on silica gel 60 F254 (Merck). Spots were detected under UV light or with iodine. 2. Synthesis Four types of (�)-tetrahydro-3-furylmethyl compounds were synthesized according to the following four methods, as shown in Fig. 2. Acyclic nitromethylene compounds (iv) were prepared by substitution of nitroethylenes (iii) with amines (Method A). Acyclic nitroimino compounds (vii) were prepared by substitution of nitroisothioureas (vi) with amines followed by acylation or alkylation (Method B), or acylation of S-methyl-N-nitroisothiourea (viii) followed by substitution with amines (i) (Method C). Cyclic nitroimino and nitromethylene compounds (xi and xii) were prepared by condensation of diamines from (x) with (ii) or with S-methyl- N-nitro-N�-phthaloylisothiourea (v) (Method D). The (tetra- J. Pestic. Sci., 29(4), 348–355 (2004) Synthesis and Structure-Activity Relationships of Dinotefuran Derivatives: Modification in the Nitroguanidine Part Takeo WAKITA,* Katsutoshi KINOSHITA, Naoko YASUI, Eiichi YAMADA, Nobuyuki KAWAHARA and Kenji KODAKA Functional Chemicals Laboratory, Mitsui Chemicals, Inc., 1144 Togo Mobara, Chiba 297–0017, Japan (Received May 19, 2004; Accepted June 23, 2004) Dinotefuran ((RS)-1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine) is a new neonicotinoid which has a characteristic (�)-tetrahydro-3-furylmethyl moiety instead of the pyridine-like moiety of other neonicotinoids. A series of dinotefuran derivatives were synthesized and tested against hemiptera. SAR (structure-activity rela- tionships) of the nitroguanidine part of dinotefuran are summarized as follows: (1) the mono-methyl group as a N-substituent gave the best activity for the acyclic nitroimino and nitromethylene compounds, (2) the acyclic compounds showed the same activity as the cyclic compounds against Nephotettix cincticeps and were superior to them against Laodelphax striatellus, (3) N-acylation of this series scarcely changed the level of activity. On the basis of these results, we selected dinotefuran for development. © Pesticide Science Society of Japan Keywords: dinotefuran, neonicotinoids, (�)-tetrahydro-3-furylmethyl, structure-activity relationships (SAR). Original Article * To whom correspondence should be addressed. E-mail: takeo.wakita@mitsui-chem.co.jp ©Pesticide Science Society of Japan hydro-3-furyl)methyl derivatives (i and x5)) and the iso- thiourea derivatives (v18) and viii19)) were prepared according to established procedures. Typical synthetic procedures are described as follows. 2.1. Typical synthetic procedures for the acyclic ni- tromethylene compounds (iv) (Method A) 2.1.1. 1-Methylamino-2-nitro-1-{(tetrahydro-3-furyl)- methylamino}ethylene (5) A solution of 3-(aminomethyl)tetrahydrofuran (i, 0.70 g, 6.9 mmol) and 1,1-bis(methylthio)-2-nitroethylene (ii, 1.25 g, 7.56 mmol) in acetonitrile (15 ml) was stirred at 70°C for 5 hr. The mixture was concentrated to dryness under reduced pres- sure. The resulting material was purified by silica gel column chromatography (hexane : EtOAc�1 : 1) to give 1.10 g (73%) of 1-methylthio-2-nitro-1-{(tetrahydro-3-furyl)methylamino}- ethylene (1, iii) as a yellow solid, mp 85–86°C. 1H NMR d (CDCl3): 1.62–1.74 (1H, m), 2.09–2.20 (1H, m), 2.45 (3H, s), 2.63 (1H, septet, J�6.6 Hz), 3.39 (1H, dd, J�6.6 Hz, J�13.9 Hz), 3.49 (1H, dd, J�6.6 Hz, J�13.9 Hz), 3.61 (1H, dd, J�5.1 Hz, J�8.8 Hz), 3.73–3.88 (2H, m), 3.95 (1H, dt, J�5.1 Hz, J�8.8 Hz), 6.58 (1H, s), 10.6 (1H, br). IR (KBr) cm�1: 3149, 1574. A solution of 1 (0.40 g, 1.8 mmol) and 40% MeNH2 (in MeOH, 0.60 g, 10 mmol) in MeOH (10 ml) was stirred at room temperature for 2 hr. The mixture was concentrated to dryness under reduced pressure. The resulting material was purified by silica gel column chromatography (EtOAc : MeOH�9 : 1) to give 0.30 g (81%) of 1-methylamino-2-nitro- 1-{(tetrahydro-3-furyl)methylamino}ethylene (5, iv) as a white solid, mp 140–141°C. 1H NMR d (DMSO): 1.51–1.63 (1H, m), 1.94–2.05 (1H, m), 2.50 (1H, br), 2.72 (3H, br), 3.09–3.28 (2H, m), 3.43 (1H, br), 3.59–3.81 (3H, m), 6.47 (1H, s), 7.26 (1H, br), 10.1 (1H, br). IR (KBr) cm�1: 3186, 1637. 2.1.2. 1-Methylthio-2-nitro-1-{N-methyl-(tetrahydro-3- furyl)methylamino}ethylene (2) Oil. 1H NMR d (CDCl3): 1.53–1.65 (1H, m), 2.02–2.11 (1H, m), 2.45 (3H, s), 2.64–2.74 (1H, m), 3.13 (3H, s), 3.50 (1H, dd, J�5.1 Hz, J�8.1 Hz), 3.62 (2H, dd, J�2.2 Hz, J�8.1 Hz), 3.72–3.91 (3H, m), 6.73 (1H, s). IR (neat) cm�1: 1548, 1266. Vol. 29, No. 4, 348–355 (2004) Modification in the Nitroguanidine Part of Dinotefuran 349 Fig. 1. Neonicotinoids and their lead compounds, Nicotine and Acetylcholine. Fig. 2. Synthesis of tetrahydro-3-furylmethyl compounds, iv–xi and xii. 2.1.3. 1-Ethylamino-2-nitro-1-{(tetrahydro-3-furyl)methyl- amino}ethylene (6) Oil. 1H NMR d (CDCl3): 1.21–1.41 (3H, m), 1.65–1.82 (1H, m), 2.05–2.20 (1H, m), 2.55–2.71 (1H, m), 3.02–3.34 (3H, m), 3.55–4.01 (4H, m), 6.58 (1H, s), 10.5 (1H, br). IR (neat) cm�1: 3274, 1615. 2.1.4. 2-Nitro-1-propylamino-1-{(tetrahydro-3-furyl)- methylamino}ethylene (7) Oil. 1H NMR d (CDCl3): 1.00 (3H, br), 1.65–1.74 (3H, m), 2.10–2.30 (1H, m), 2.55–2.69 (1H, m), 3.05–3.25 (4H, m), 3.55–4.05 (4H, m), 6.57 (1H, s), 10.5 (1H, br). IR (neat) cm�1: 3274, 1616. 2.1.5. 2-Nitro-1-propargyl-1-{(tetrahydro-3-furyl)methyl- amino}ethylene (8) Mp 135–136°C. 1H NMR d (CDCl3): 1.60–1.72 (1H, m), 2.05–2.21 (1H, m), 2.54–2.70 (1H, m), 2.65 (1H, s), 3.22 (2H, s), 3.52–4.20 (6H, m), 6.66 (1H, s), 7.41 (1H, s), 10.4 (1H, br). IR (KBr) cm�1: 3221, 1577. 2.1.6. 1-Methylamino-2-nitro-1-{N-methyl-(tetrahydro-3- furyl)methylamino}ethylene (9) Oil. 1H NMR d (CDCl3): 1.48–1.58 (1H, m), 2.01–2.12 (1H, m), 2.61–2.70 (1H, m), 2.93 (3H, s), 3.01 (3H, d, J�5.1 Hz), 3.20 (2H, dd, J�1.5 Hz, J�8.8 Hz), 3.48 (1H, dd, J�5.1 Hz, J�8.8 Hz), 3.71–3.82 (2H, m), 3.89 (1H, dt, J�5.1 Hz, J�8.8 Hz), 6.53 (1H, s), 9.73 (1H, br). IR (neat) cm�1: 3420, 1616. 2.1.7. 1-Methylamino-2-nitro-1-{N-ethyl-(tetrahydro-3- furyl)methylamino}ethylene (10) Oil. 1H NMR d (CDCl3): 1.20 (3H, t, J�7.3 Hz), 1.47–1.62 (1H, m), 1.97–2.10 (1H, m), 2.54–2.67 (1H, m), 3.01 (3H, d, J�5.1 Hz), 3.05–3.17 (2H, m), 3.25 (2H, q, J�7.3 Hz), 3.49 (1H, dd, J�5.1 Hz, J�8.1 Hz), 3.69–3.79 (2H, m), 3.89 (1H, dt, J�5.1 Hz, J�7.3 Hz), 6.55 (1H, s), 9.89 (1H, br). IR (neat) cm�1: 3422, 1602. 2.1.8. 1-Methylamino-2-nitro-1-{N-propyl-(tetrahydro-3- furyl)methylamino}ethylene (11) Oil. 1H NMR d (CDCl3): 0.91 (3H, t, J�7.3 Hz), 1.47–1.66 (3H, m), 1.97–2.07 (1H, m), 2.63 (1H, septet, J�6.6 Hz), 3.00 (3H, d, J�5.1 Hz), 3.11–3.18 (4H, m), 3.48 (1H, dd, J�5.1 Hz, J�8.1 Hz), 3.69–3.84 (2H, m), 3.88 (1H, dt, J�5.1 Hz, J�8.8 Hz), 6.55 (1H, s), 9.88 (1H, br). IR (neat) cm�1: 3258, 1593. 2.1.9. 1-Dimethylamino-2-nitro-1-{(tetrahydro-3- furyl)methylamino}ethylene (12) Oil. 1H NMR d (CDCl3): 1.57–1.69 (1H, m), 2.11–2.29 (1H, m), 2.51–2.68 (1H, m), 2.94 (6H, s), 3.19–3.35 (2H, m), 3.54–3.59 (1H, m), 3.70–3.95 (3H, m), 6.51 (1H, s), 9.63 (1H, br). IR (neat) cm�1: 3260, 1615. 2.1.10. 1-Dimethylamino-2-nitro-1-{N-methyl-(tetrahy- dro-3-furyl)methylamino}ethylene (13) Oil. 1H NMR d (CDCl3): 1.42–1.57 (1H, m), 2.00–2.12 (1H, m), 2.59–2.71 (1H, m), 2.95 (6H, s), 2.96 (3H, s), 3.17–3.25 (2H, m), 3.42 (1H, dd, J�5.1 Hz, J�8.8 Hz), 3.68–3.87 (3H, m), 6.34 (1H, s). IR (neat) cm�1: 1524, 1256. 2.2. Typical synthetic procedures for the acyclic ni- troimino compounds (vii) (Method B) 2.2.1. 1,3-Diacetyl-1-methyl-2-nitro-3-(tetrahydro-3- furylmethyl)guanidine (23) To a solution of S-methyl-N-nitro-N�-phthaloylisothiourea (v, 3.00 g, 11.3 mmol) in dichloromethane (20 ml) in an ice-cold bath, 3-(aminomethyl)tetrahydrofuran (i, 1.14 g, 11.3 mmol) in dichloromethane (10 ml) was added dropwise. The mixture was stirred at room temperature for 3 hr. The resulting solid was filtered off and the filtrate was concentrated under reduced pressure. The obtained material was purified by silica gel column chromatography (hexane : EtOAc�1 : 1) to give 2.10 g (85%) of S-methyl-N-nitro-N�-{(tetrahydro-3- furyl)methyl}isothiourea (3, vi) as a white solid, mp 69–71°C. 1H NMR d (CDCl3): 1.61–1.78 (1H, m), 2.09–2.27 (1H, m), 2.53 (3H, s), 2.54–2.72 (1H, m), 3.37–3.52 (2H, m), 3.55–4.02 (4H, m), 10.2 (1H, br). IR (KBr) cm�1: 3354, 1562. A solution of 3 (1.50 g, 6.85 mmol) and 40% MeNH2 (in MeOH, 1.00 g, 12.9 mmol) in MeOH (10 ml) was stirred at room temperature for 1 hr. The mixture was concentrated to dryness under reduced pressure and the solid was washed with ether (15 ml), and then dried to give 1.25 g (90%) of 1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine (15, vii, dinotefuran) as a white solid, mp 94.5–101.5°C. 1H NMR d (CDCl3): 1.62–1.74 (1H, m), 2.09–2.22 (1H, m), 2.59–2.79 (1H, m), 2.96 (3H, d. J�5.1 Hz), 3.35 (2H, t, J�5.1 Hz), 3.66–3.80 (3H, m), 3.92–4.08 (1H, m). IR (KBr) cm�1: 3303, 1619, 1239. To a stirred mixture of 60% NaH (0.40 g, 10 mmol) in ace- tonitrile (10 ml) at room temperature, 15 (0.80 g, 4.0 mmol) was added. The mixture was stirred for 30 min, then acetyl chloride (0.89 g, 11.3 mmol) in DMF (5 ml) was added drop- wise at 0°C. After stirring at room temperature for 1 hr, the solid was filtered off and the filtrate was concentrated under reduced pressure. The resulting material was purified by sil- ica gel column chromatography (hexane : EtOAc�1 : 1) to give 0.86 g (75%) of 1,3-diacetyl-1-methyl-2-nitro-3-(tetrahy- dro-3-furylmethyl)guanidine (23, vii) as a oil. 1H NMR d (CDCl3): 1.52–1.68 (1H, m), 2.02–2.14 (1H, m), 2.20 (3H, s), 2.40 (3H, s), 2.62–2.78 (1H, m), 3.16 (3H, s), 3.48–3.95 (6H, m). IR (neat) cm�1: 1706, 1558. 2.2.2. S-Methyl-N-methyl-N�-nitro-N-{(tetrahydro-3- furyl)methyl}isothiourea (4) Oil. 1H NMR d (CDCl3): 1.58–1.71 (1H, m), 2.01–2.14 (1H, m), 2.55 (3H, s), 2.62–2.74 (1H, m), 3.24 (3H, s), 3.52–3.63 (2H, m), 3.70–3.85 (3H, m), 3.94 (1H, dt, J�5.1 Hz, J�8.8 Hz). IR (neat) cm�1: 1735, 1451. 2.2.3. 2-Nitro-1-(tetrahydro-3-furylmethyl)guanidine (14) Mp 119–123°C. 1H NMR d (CDCl3): 1.60–1.65 (1H, m), 2.00–2.15 (1H, m), 2.49–2.64 (1H, m), 3.26 (2H, t, J�6.6 Hz), 3.48–3.62 (1H, m), 3.68–3.95 (3H, m), 7.80 (2H, br), 8.17 (1H, s). IR (KBr) cm�1: 3321, 1592. 350 T. Wakita et al. Journal of Pesticide Science 2.2.4. 1-Ethyl-2-nitro-3-(tetrahydro-3-furylmethyl)guani- dine (16) Oil. 1H NMR d (CDCl3): 1.26 (3H, t, J�7.3 Hz), 1.59–1.71 (1H, m), 2.02–2.18 (1H, m), 2.49–2.66 (1H, m), 3.21–3.38 (4H, m), 3.59–3.94 (4H, m). IR (neat) cm�1: 3289, 1614. 2.2.5. 1-Benzyl-2-nitro-3-(tetrahydro-3-furylmethyl)- guanidine (17) Mp 108–116°C. 1H NMR d (CDCl3): 1.40–1.55 (1H, m), 1.85–2.00 (1H, m), 2.40–2.57 (1H, m), 3.27 (2H, d, J�5.9 Hz), 3.38–3.86 (4H, m), 4.49 (2H, d, J�5.1 Hz), 7.27–7.45 (5H, m). IR (KBr) cm�1: 3330, 1636. 2.2.6. 1,3-Dimethyl-2-nitro-3-(tetrahydro-3-furylmethyl)- guanidine (18) Mp 93–96°C. 1H NMR d (DMSO): 1.45–1.57 (1H, m), 1.83–1.96 (1H, m), 2.45–2.57 (1H, m), 2.72 (3H, d, J�5.1 Hz), 2.98 (3H, s), 3.30–3.47 (3H, m), 3.58–3.73 (3H, m), 8.18 (1H, br). IR (KBr) cm�1: 3218, 1632. 2.2.7. 1-Ethyl-3-methyl-2-nitro-1-(tetrahydro-3-furyl- methyl)guanidine (19) Oil. 1H NMR d (CDCl3): 1.25 (3H, t, J�7.3 Hz), 1.58–1.69 (1H, m), 2.03–2.14 (1H, m), 2.58–2.71 (1H, m), 2.98 (3H, d, J�5.1 Hz), 3.22 (1H, dd, J�9.5 Hz, J�14.7 Hz), 3.39 (1H, dd, J�7.3 Hz, J�14.7 Hz), 3.47 (2H, q, J�7.3 Hz), 3.62–3.71 (2H, m), 3.81 (1H, dt, J�5.9 Hz, J�8.8 Hz), 3.98 (1H, dt, J�5.9 Hz, J�8.8 Hz), 6.79 (1H, br). IR (neat) cm�1: 3281, 1623. 2.2.8. 1,1-Dimethyl-2-nitro-3-(tetrahydro-3-furylmethyl)- guanidine (20) Mp 127–129°C. 1H NMR d (CDCl3): 1.55–1.68 (1H, m), 2.06–2.23 (1H, m), 2.48–2.60 (1H, m), 3.10 (6H, s), 3.29–3.50 (2H, m), 3.58–3.82 (3H, m), 3.85–4.00 (1H, m), 6.77 (1H, br). IR (KBr) cm-1: 3274, 1637. 2.2.9. 1-Ethyl-1-methyl-2-nitro-3-(tetrahydro-3-furyl- methyl)guanidine (21) Oil. 1H NMR d (CDCl3): 1.25 (3H, t, J�7.3 Hz), 1.58–1.70 (1H, m), 2.04–2.17 (1H, m), 2.55–2.66 (1H, m), 3.04 (3H, s), 3.30–3.47 (2H, m), 3.64–3.85 (3H, m), 3.95 (1H, dt, J�5.1 Hz, J�8.1 Hz), 6.56 (1H, br). 2.2.10. 1,1,3-Trimethyl-2-nitro-3-(tetrahydro-3-furyl- methyl)guanidine (22) Oil. 1H NMR d (CDCl3): 1.50–1.62 (1H, m), 1.95–2.10 (1H, m), 2.56–2.69 (1H, m), 2.96 (6H, s), 2.99 (3H, s), 3.26–3.40 (2H, m), 3.47 (1H, dd, J�5.1 Hz, J�8.8 Hz), 3.70–4.02 (3H, m). IR (neat) cm�1: 1734, 1439. 2.2.11. 1,3-Diacetyl-1-ethyl-2-nitro-3-(tetrahydro-3-furyl- methyl)guanidine (24) Oil. 1H NMR d (CDCl3): 1.20–1.40 (3H, m), 1.51–1.68 (1H, m), 2.00–2.35 (4H, m), 2.41 (3H, s), 2.65–2.84 (1H, m), 3.25–4.00 (8H, m). IR (neat) cm�1: 1705, 1560. 2.2.12. 1,3-Dibenzoyl-1-methyl-2-nitro-3-(tetrahydro-3- furylmethyl)guanidine (25) Mp 133–135°C. 1H NMR d (CDCl3): 1.60–1.75 (1H, m), 1.87–2.01 (1H, m), 2.51 (3H, s), 2.57–2.70 (1H, m), 3.03–3.12 (1H, m), 3.19–3.27 (1H, m), 3.37–3.54 (1H, m), 3.64–3.90 (3H, m), 7.43–7.75 (10H, m). IR (KBr) cm�1: 1698, 1545. 2.2.13. 1,3-Bis(methoxycarbony)l-1-methyl-2-nitro-3- (tetrahydro-3-furylmethyl)guanidine (26) Oil. 1H NMR d (CDCl3): 1.52–1.69 (1H, m), 2.07–2.19 (1H, m), 2.65–2.80 (1H, m), 3.10–3.36 (4H, br), 3.47–3.62 (2H, br), 3.81 (3H, s), 3.84 (3H, s), 3.71–3.94 (3H, m). IR (neat) cm�1: 1743, 1542. 2.2.14. 1,3-Dibenzyl-1-methyl-2-nitro-3-(tetrahydro-3- furylmethyl)guanidine (27) Oil. 1H NMR d (CDCl3): 1.46–1.57 (1H, m), 1.98–2.11 (1H, m), 2.61–2.75 (1H, m), 2.79 (3H, s), 3.12–3.29 (2H, m), 3.44–3.49 (1H, m), 3.66–3.87 (3H, m), 4.41 (2H, d, J�2.9 Hz), 4.48 (2H, s), 7.19–7.43 (10H, m). IR (neat) cm�1: 1714, 1540. 2.2.15. 1-Acetyl-3-methoxycarbonyl-1-methyl-2-nitro-3- (tetrahydro-3-furylmethyl)guanidine (28) Oil. 1H NMR d (CDCl3): 1.61–1.80(1H, m), 2.08–2.25 (1H, m), 2.15 (3H, s), 2.70–2.89 (1H, m), 3.08 (3H, s), 3.51–4.00 (6H, m), 3.89 (3H, s). IR (neat) cm�1: 1749, 1705, 1564. 2.2.16. 1-Benzoyl-3-methoxycarbonyl-1-methyl-2-nitro-3- (tetrahydro-3-furylmethyl)guanidine (29) Oil. 1H NMR d (CDCl3): 1.43–1.58 (1H, m), 1.83–2.01 (1H, m), 2.44–2.60 (1H, m), 3.06–3.24 (2H, m), 3.25–3.39 (1H, m), 3.36 (3H, s), 3.64–3.86 (3H, m), 3.76 (3H, s), 7.43–7.66 (5H, m). IR (neat) cm�1: 1748, 1697, 1558. 2.3. Typical synthetic procedures for the acyclic nitro- imino compounds (vii) (Method C) 2.3.1. 1-Benzoyl-2-nitro-3-(tetrahydro-3-furylmethyl)- guanidine (31) To a solution of S-methyl-N-nitroisothiourea (viii, 1.20 g, 8.89 mmol) in pyridine (4 ml) in an ice-cold bath, ben- zoylchloride (1.45 g, 10.3 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hr. The mixture was poured into water (30 ml) and extracted with EtOAc (30 ml�2). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2.10 g (99%) of S-methyl-N-benzoyl- N�-nitroisothiourea (ix) as a white solid, mp: 107–112°C. 1H NMR d (acetone-d6): 2.51 (3H, s), 7.45–7.76 (5H, m). IR (KBr) cm�1: 3275, 1703, 1635. A solution of ix (0.80 g, 3.3 mmol) and 3- (aminomethyl)tetrahydrofuran (i, 0.50 g, 5.0 mmol) in ace- tonitrile (10 ml) was stirred at room temperature for 1 hr. The mixture was concentrated to dryness under reduced pressure. The resulting material was purified by silica gel column chro- matography (hexane : EtOAc�1 : 1) to give 0.30 g (31%) of 1-benzoyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine (31, vii) as an oil, 1H NMR d (CDCl3): 1.64–1.76 (1H, m), 2.12–2.23 (1H, m), 2.60–2.75 (1H, m), 3.54 (2H, dd, J�5.9 Hz, J�7.3 Hz), 3.63 (1H,dd, J�4.4 Hz, J�8.8 Hz), 3.74–3.99 (3H, m), 7.55–7.60 (2H, m), 7.68–7.73 (1H, m), 7.93–7.96 (2H, m), 9.81 (1H, br). IR (neat) cm�1: 3271, 1695, 1581. Vol. 29, No. 4, 348–355 (2004) Modification in the Nitroguanidine Part of Dinotefuran 351 2.3.2. 1-Acetyl-2-nitro-3-(tetrahydro-3-furylmethyl)guani- dine (30) Mp 96–98°C. 1H NMR d (CDCl3): 1.60–1.70 (1H, m), 2.04–2.18 (1H, m), 2.32 (3H, s), 2.56–2.67 (1H, m), 3.45 ( 2H, dd, J�5.9 Hz, J�7.3 Hz), 3.57 (1H, dd, J�5.9 Hz, J�7.3 Hz), 3.71–3.94 (3H, m), 9.51 (1H, br.). IR (KBr) cm�1: 3266, 1707, 1621. 2.3.3. N-Methoxycarbonyl-N�-nitro-N�-(tetrahydro-3- furylmethyl)guanidine (32) Mp 68–77°C. 1H NMR d (CDCl3): 1.54–1.71 (1H, m), 2.06–2.19 (1H, m), 2.57–2.69 (1H, m), 3.44–3.49 (2H, m), 3.57–3.61 (1H, m), 3.72–3.97 (3H, m), 3.89 (3H, s), 8.76 (1H, br). IR (KBr) cm�1: 3293, 1743, 1580. 2.4. Typical synthetic procedures for cyclic nitroimino and nitromethylene compounds (xi and xii) (Method D) 2.4.1. 1-Acetyl-2-nitroimino-3-{(tetrahydro-3-furyl)- methyl}hexahydropyrimidine (41) A mixture of 3-(methylsulfonyloxymethyl)tetrahydrofuran (x, 2.61 g, 14.5 mmol), 1,3-diaminopropane (10 ml), potassium carbonate (4.01 g, 28.9 mmol) and sodium iodide (0.10 g) in acetonitrile (80 ml) was stirred at 70°C for 4 hr. The resulting solid was filtered off and the filtrate was concentrated under reduced pressure to give crude N-(tetrahydro-3-furyl)methyl- 1,3-diaminopropane (2.90 g). A solution of S-methyl-N-nitro-N�-phthaloylisothiourea (v, 4.90 g, 18.5 mmol) and crude N-(tetrahydro-3-furyl)methyl- 1,3-diaminopropane (2.90 g) in EtOH (20 ml) was refluxed for 3 hr. EtOAc (20 ml) was added and the resulting solid was fil- tered off. The mixture was concentrated to dryness under re- duced pressure. The resulting material was purified by silica gel column chromatography (acetone : EtOAc�1 : 2) to give 2.02 g (61% from x) of 2-nitroimino-1-{(tetrahydro-3- furyl)methyl}hexahydropyrimidine (37, xi) as a colorless solid, mp 88–91°C. 1H NMR d (CDCl3): 1.56–1.72 (1H, m), 1.96–2.12 (3H, m), 2.67–2.82 (1H, m), 3.32–3.57 (5H, m), 3.62–3.95 (5H, m), 9.79 (1H, br). IR (KBr) cm�1: 3256, 1593. To a stirred mixture of 60% NaH (0.20 g, 5.0 mmol) in ace- tonitrile (20 ml) at room temperature, 37 (1.00 g, 4.39 mmol) was added. The mixture was stirred for 30 min, then acetyl chloride (0.39 g, 11.3 mmol) in acetonitrile (5 ml) was added at 0°C. After stirring at room temperature for 1 hr, the solid was filtered off and the filtrate was concentrated under re- duced pressure. The resulting material was purified by silica gel column chromatography (chloroform : MeOH�20 : 1) to give 0.82 g (69%) of 1-acetyl-2-nitroimino-3-{(te
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