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