Syntheses and biological activities of octahydro-1H-cyclopenta[d]pyrimidine derivatives

Article abstract of DOI:10.1021/jf062845l

Various nitromethylene derivatives were synthesized regioselectively. Compounds 8a-f were obtained by the reaction of 1-((5-chloropyridin-2-yl)methyl) -2-(nitromethylene)-octahydro-1H-cyclopenta[d]-pyrimidine (3) with primary amines and formaldehyde. The synthesized compounds were identified by ¹H NMR, HRMS (EI), and IR, and preliminary bioassays indicated that most of them showed moderate insecticidal activities against Aphis craccivora. The relationship between hydrophobicity and biological activity was also discussed.

Full text of DOI:10.1021/jf062845l

J. Agric. Food Chem. 2007, 55, 143−147 143
Syntheses and Biological Activities of
Octahydro-1H-cyclopenta[d]pyrimidine Derivatives
ZHONGZHEN TIAN, ZHAOXING JIANG, ZHONG LI,* GONGHUA SONG,*
AND QINGCHUN HUANG
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University
of Science and Technology, P.O. Box 544, 130 Meilong Road, Shanghai 200237,
People’s Republic of China
Various nitromethylene derivatives were synthesized regioselectively. Compounds 8a-f were obtained
by the reaction of 1-((5-chloropyridin-2-yl)methyl)-2-(nitromethylene)-octahydro-1H-cyclopenta[d]-
pyrimidine (3) with primary amines and formaldehyde. The synthesized compounds were identified
1
by H NMR, HRMS (EI), and IR, and preliminary bioassays indicated that most of them showed
moderate insecticidal activities against Aphis craccivora. The relationship between hydrophobicity
and biological activity was also discussed.
KEYWORDS: Nitromethylene derivatives; synthesis; regioselective; biological activity; hydrophobicity
INTRODUCTION
Since Imidacloprid’s (1a) introduction in the 1980s as an
insecticide for crop protection (1), neonicotinoids were used
rapidly worldwide for controlling insects because of their
potency, low mammalian toxicity, broad insecticidal spectra,
and good systemic properties. Neonicotinoids interacting with
nicotinic acetylcholine receptors (nAChR) have a higher affinity
for the insect receptor than for the mammalian (2-5) and are
relatively safe toward mammals and aquatic life. In recent years,
the innovation of neonicotinoid insecticides has been an intense
and competitive effort (6-8).
Compared with Imidacloprid, nitromethylene analogue 6-Cl-
PMNI (1b) and 1c (Figure 1) exhibit remarkably higher receptor
binding activity (9-10); however, their use was limited owing
to its weak hydrophobicity (11). When the NH on the 3-position
of the imidazolidine ring of 6-Cl-PMNI was replaced by S, the
S-analogue 1d exhibited lower receptor binding activity, but
its hydrophobicity was increased and showed similar insecticidal
activities against green rice leafhopper as Imidacloprid (12),
which implied that the hydrophobicity might be the important
role to influence their activities. Herein, to improve the
hydrophobicity of 1c, a series of octahydro-1H-cyclopenta[d]
pyrimidines were designed and synthesized by introducing a
saturated cyclopentane ring into the lead structure, and also the
relationship between hydrophobicity and biological activity is
discussed.
Figure 1. Chemical structures of 3, 6, and 1a−d.
solvent and TMS as the internal standard. High-resolution mass spectra
were recorded under electron impact (70 eV) condition using a
MicroMass GCT CA 055 instrument. Combustion analyses for elemen-
tal composition were performed with an Elementar vario EL III.
Analytical thin-layer chromatography (TLC) was carried out on
precoated plates (silica gel 60 F254), and spots were visualized with
ultraviolet (UV) light.
2-Iminocyclopentanecarbonitrile (9). 2-Iminocyclopentanecarbo-
nitrile was prepared according to Schroeder’s procedure (13) in 86%
yield. Mp: 145-147 °C (lit. 146-148 °C). GC-MS: m/z (%) )107
([M - 1]+, 100), 80 (16), 54 (9).
2-Aminocyclopentanecarbonitrile (10). Sodium borohydride (5.7
g, 150 mmol) was added in one portion to a stirred acetic acid (160
mL) at 10-20 °C. After H2 evolution ceased (30 min), 2-iminocyclo-
pentanecarbonitrile (5.4 g, 50 mmol) was added. The mixture was
allowed to react for 3 h at room temperature, and then the solvent was
evaporated under reduced pressure. CH2Cl2 (100 mL) was added to
the residue, and the organic layer was washed with saturated aqueous
sodium carbonate (50 mL × 2). The organic phase was dried over
MgSO4 and concentrated under reduced pressure to give 10 (65% yield)
as an oil. GC-MS m/z (%): 110 ([M+], 10), 81 (10), 68 (7), 56 (100).
2-Amino-3-methylcyclopentanecarbonitrile (18). Using the pro-
cedure for 10, 2.3 g (83% yield) of 18 was obtained as a liquid and
was used for next reactions without further purification.
MATERIALS AND METHODS
Synthetic Procedures. Melting points (mp) were recorded on Bu¨chi
1
B540 apparatus and are uncorrected. H NMR spectra were recorded
on a Bruker WP-500SY (500 MHz) spectrometer with CDCl3 as the
2-(Aminomethyl)cyclopentanamine (11). To a suspension of Li-
AlH4 (0.95 g, 25 mmol) in dry THF (25 mL), 0.55 g (5 mmol) of
2-aminocyclopentanecarbonitrile in dry THF (10 mL) was added at 0
* To whom correspondence should be addressed. E-mail: lizhong@
ecust.edu.cn.
10.1021/jf062845l CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/14/2006

144 J. Agric. Food Chem., Vol. 55, No. 1, 2007
Tian et al.
°C. The mixture was stirred at 0 °C for 15 min, and then at room
temperature for 1 h. The reaction was quenched by pouring into water,
and the precipitate was filtered off and washed with Et2O. The combined
organic layers were dried over anhydrous Na2SO4 and evaporated under
reduced pressure to give 11 as a colorless oil (82% yield). GC-MS m/z
(%): 115 ([MH+], 3), 97 (90), 82 (48), 69 (65), 56 (100).
2-((6-Chloropyridin-3-yl)methylamino)cyclopentanecar-
bonitrile (13). A mixture of 2-aminocyclopentanecarbonitrile (1.21 g,
11 mmol), Et3N (1.5 mL), and 2-chloro-5-(chloromethyl)pyridine (1.62
g, 10 mmol) in acetonitrile (30 mL) was stirred at 50-55 °C for 15 h.
The reaction mixture was concentrated under reduced pressure and
treated with 20 mL of saturated aqueous Na2CO3. The solution was
then extracted three times with CH2Cl2 (15 mL), and the combined
extracts were dried over MgSO4. The organic phase was evaporated
under reduced pressure, and crude product was purified by flash
chromatography. A total of 1.47 g (63% yield) of compound 13 was
obtained as a colorless oil. GC-MS: m/z (%): 235 ([M+], 35), 181
(100), 167 (25), 126 (85), 99 (9), 90 (12).
2-Imino-3-methylcyclopentanecarbonitrile (17). To a THF solution
(50 mL) of potassium tert-butoxide (22.4 g, 200 mmol) was added
hexane dinitrile (10.8 g, 100 mmol).The mixture was cooled to -10
°C, and then CH3I (14.2 g, 100 mmol) was added within 2 min. The
mixture was allowed to react at -10 °C for 30 min then at room
temperature for 2 h. The reaction was quenched with 20 mL of saturated
aqueous NH4Cl, and the mixture was extracted three times with ethyl
acetate (30 mL). The combined extracts were dried over anhydrous
Na2SO4 and evaporated under reduced pressure. The resulting residue
(11.7 g) was refluxed with NaH (60%, 4.4 g, 110 mmol) in THF (100
mL) for 5 h, then cooled to 20 °C, and quenched by water (40 mL).
The mixture was extracted three times with Et2O (30 mL). The
combined extracts were dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The crude product was purified by column
chromatography (petroleum ether-ethyl acetate, 3:1) to give 3.2 g (26%
yield) of 17 as a colorless oil. GC-MS: m/z (%): 122 ([M+], 52), 121
(100), 107 (46), 94 (23), 80 (18).
2-((6-Chloropyridin-3-yl)methyleneamino)-3-methylcyclopentane-
carbonitrile (19). To the solution of 2-amino-3-methylcyclopentane-
carbonitrile 18 (2.3 g, 18.5 mmol) and 6-chloronicotinaldehyde (2.7 g,
19 mmol) in EtOH (20 mL) was added a catalytic amount of
concentrated HCl. The mixture was heated under reflux for 8 h and
cooled to room temperature. The solvent was evaporated under reduced
pressure, and the crude product was purified by column chromatography
(petroleum ether-ethyl acetate, 3:1) to afford 2.1 g (46%) of 19. GC-
MS: m/z (%): 247 ([M+], 95), 193 (100), 179 (66), 152 (71), 139
(38), 125 (35).
obtained in 61% yield which was used for following transformations
without further purification.
1-((5-Chloropyridin-2-yl)methyl)-2-(nitromethylene)-octahydro-
1H-cyclopenta[d]pyrimidine (3) and 3-((5-Chloropyridin-2-yl)-
methyl)-2-(nitromethylene)-octahydro-1H-cyclopenta[d]pyrimi-
dine (4). To the solution of nitromethylene derivative 12 (0.37 g, 2
mmol) in DMF (10 mL) was added NaH (60%, 0.09 g, 2.2 mmol),
and the resulting mixture was stirred at room temperature for 30 min.
2-Chloro-5-(chloromethyl)pyridine in DMF (5 mL) was then added
dropwise, and the mixture was stirred at 45-50 °C for 5 h. On
completion, to the mixture was added 20 mL of water followed by
extraction with CH2Cl2 (4 × 20 mL). The combined organic layers
were washed with saturated brine (2 × 20 mL), dried over anhydrous
Na2SO4, concentrated under reduced pressure, and purified by column
chromatography (dichloromethane-methanol, 20:1) to afford the title
compounds 3 (0.05 g, 7.5% yield) and 4 (0.05 g, 7.5% yield),
respectively. Mp: 146.6-148.3 °C; 1H NMR (CDCl3, δ (ppm)): 1.24-
2.44 (m, 7H), 3.10-3.88 (m, 3H), 4.37-4.59 (m, 2H), 6.54-6.64 (m,
1H), 7.35 (m, 1H), 7.54 (m, 1H), 8.25 (t, 1H), 10.73-10.98 (m, 1H).
IR (KBr, cm-1) ν: 3141, 2963, 1589, 1558, 1289, 984. HRMS Anal.
Calcd for C14H18N4O2Cl (MH+); 309.1118. Found: 309.1136.
Compound (12, 3, 5, 7). General Procedure. A solution of
compound 11, 14, 15, 20 (2 mmol), and 1,1-bis(thiomethyl)-2-
nitroethylene (2 mmol) in 30 mL of ethanol was refluxed for 8 h and
then cooled to room temperature. Evaporation under reduced pressure
gave the desired product as an oil after purifiction by flash chroma-
tography.
2-(Nitromethylene)-octahydro-1H-cyclopenta[d]pyrimidine (12).
Yield: 83% (0.305 g). Mp: 172-175 °C. 1H NMR (CDCl3, δ (ppm)):
1.25-2.35 (m, 7H), 3.03-3.80 (m, 3H), 6.66 (s, 0.5 H), 6.67 (s, 0.5
H), 8.90 (s, 2H, NH). IR (KBr, cm-1) ν: 3167, 2958, 1614, 1489, 1361,
1206, 58. GC-MS m/z (%): 149 (100), 120 (71), 106 (24), 94 (26), 67
(68).
2-(Nitromethylene)-1-(pyridin-3-ylmethyl)-octahydro-1H-cyclo-
penta[d]pyrimidine (5). Yield: 45% (0.17 g). Mp: 125.1-126.8 °C.
1H NMR (CDCl3, δ (ppm)): 1.25-2.40 (m, 7H), 3.27 (m, 2H), 3.68
(m, 1H), 4.53 (m, 2H, H-5), 6.60 (d, 1H, H-6, J ) 10.8 Hz), 7.31 (dd,
1H, H-2, J ) 5.7 Hz, J ) 13.1 Hz), 7.52 (t, 1H, H-3, J ) 6.7 Hz),
8.47 (s, 1H, H-1), 8.57 (t, 1H, H-1, J ) 6.1 Hz), 10.95 (d, 1H, NH, J
) 7.8 Hz). IR (KBr, cm-1) ν: 3199, 2963, 2871, 1690, 1557, 1426,
1305. HRMS Anal. Calcd for C14H19N4O2 (MH+): 275.1508. Found:
275.1495.
1-((5-Chloropyridin-2-yl)methyl)-2-(nitromethylene)-octahydro-
1H-cyclopenta[d]pyrimidine (3). Yield: 73% (1.12 g). Mp: 172.2-
1
173.5 °C. H NMR (CDCl3, δ (ppm)): 1.62 (m, 3H), 1.82 (m, 1H),
2-(Aminomethyl)-N-(pyridin-3-ylmethyl)cyclopentanamine (14).
To a solution of compound 13 (0.47 g, 2 mmol) in anhydrous THF
(20 mL) at 0-5 °C was added an excess amount of LiAlH4 (0.15 g, 4
mmol), and then the suspension was stirred in room temperature. After
1 h, the reaction was quenched with water (2 mL), and the mixture
was extracted three times with Et2O (5 mL). The combined extracts
were dried over anhydrous Na2SO4 and evaporated under reduced
pressure. A total of 0.25 g (61% yield) of 14 was obtained as an oil
which was used for subsequent reactions without further purification.
2-(Aminomethyl)-N-((5-chloropyridin-2-yl)methyl)cyclopentan-
amine (15). 2-((5-Chloropyridin-2-yl)methylamino)cyclopentanecar-
bonitrile (13) (2.35 g, 10 mmol) in anhydrous THF (20 mL) was added
to 1.0 M solution of BH3‚THF (20 mmol) in THF at room temperature
over a period of 10 min. The reaction mixture was warmed to 60-65
°C and stirred for 18 h, and then the reaction mixture was cooled to
room temperature. Next, 6 N HCl (10 mL) was added dropwise, and
the mixture was heated to 65-70 °C for 2 h. After being cooled to
room temperature, the mixture was washed with Et2O (3 × 30 mL)
and cooled to 0 °C. Then 10 N NaOH (20 mL) was added to this
solution. The amine was extracted with CH2Cl2 (4 × 30 mL), and the
combined organic extracts were dried over anhydrous Na2SO4. Evapo-
ration of the solvent under reduced pressure gives crude 15 (1.62 g,
72% yield). GC-MS: m/z (%): 239 ([M+], 13), 181 (24), 141 (32),
126 (100), 113 (35), 99 (39), 84 (92).
1.99 (m, 1H), 2.17 (m, 1H), 2.38 (m, 1H), 3.08 (m, 1H), 3.47 (m, 1H),
3.58 (m, 1H), 4.43 (d, 1H, H-4, J ) 17.4 Hz), 4.57 (d, 1H, H-4, J )
3
17.4 Hz), 6.58 (s, 1H, H-5), 7.34 (d, 1H, H-3, J2,3 ) 8.2 Hz), 7.50
(dd, 1H, H-2, 4J1,2 ) 2.3 Hz, 3J2,3 ) 8.2 Hz), 8.24 (d, 1H, H-1, 4J1,2
)
2.3 Hz), 10.87 (s, 1H, NH). IR (KBr, cm-1) ν: 3141, 1558, 1589, 1458,
1420, 1289; MS m/z (%): 308 ([M+], 5), 278 (9), 262 (100), 226 (12),
126 (62), 90 (13). HRMS Anal. Calcd for C14H18N4O2Cl (MH+):
309.1118. Found: 309.1136.
1-((6-Chloropyridin-3-yl)methyl)-7-methyl-2-(nitromethylene)-oc-
tahydro-1H-cyclopenta[d]pyrimidine (7). Yield: 65% (1.05 g). Mp:
1
89.6-92.2 °C. H NMR (CDCl3, δ (ppm)): 0.94 (m, 3H), 1.41 (m,
1H), 1.68 (m, 2H), 1.83 (m, 2H), 2.44 (m, 1H), 3.06 (m, 1H), 3.64 (m,
2H), 4.61 (m, 2H, H-4), 6.59 (s, 1H, H-5), 7.36 (d, 1H, H-3 J ) 8.1
Hz), 7.48 (t, 1H, H-2, J ) 10.6 Hz), 8.23 (d, 1H, H-1, J ) 2.3 Hz),
10.92 (s, 1H, NH). IR (KBr, cm-1) ν: 3145, 1558, 1456, 1367, 1211.
MS m/z (%): 322 (5), 276 (100), 179 (48), 126 (76), 95 (23), 61 (12).
HRMS Anal Calcd for C15H19N4O2Cl (M+): 322.1197. Found: 322.1177.
1-((2-((6-Chloropyridin-3-yl)methylamino)cyclopentyl)methyl)-
3-cyano-2-methylisothiourea (16). A solution of compound 15 (0.12
g, 0.5 mmol) and dimethyl cyanocarbonodithioimidate (0.73 g, 0.5
mmol) in 10 mL of ethanol was refluxed for 8 h and then cooled to
room temperature. The mixture was concentrated under reduced
pressure. The residue was purified by flash chromatography (dichlo-
romethane-methanol, 95:5), and 0.14 g (82%) of compound 16 was
1
2-(Aminomethyl)-N-((5-chloropyridin-2-yl)methyl)cyclopentan-
amine (20). Following the above method, the title compound was
obtained as a white solid. Mp: 108.4-110.4 °C. H NMR (CDCl3, δ
(ppm)): 1.36-2.28 (m, 7H), 2.42 (s, 3H, H-5), 3.13-3.63 (m, 3H),

Octahydro-1H-cyclopenta[d]pyrimidine Derivatives
J. Agric. Food Chem., Vol. 55, No. 1, 2007 145
Scheme 1a
Scheme 2a
a Reagents and conditions: (a) NaH/THF (86%); (b) NaHB(OAc)3/AcOIH
(65%); (c) THF/LiAlH4 (82%); (d) 1,1-bis(thiomethyl)-2-nitroethylene/EtOH (83%);
(e) NaH/DMF (3 and 4, 15%).
a Reagents and conditions: (a) 2-chloro-5-(chloromethyl)pyridine, Et3N/
CH3CN (63%); (b) LiAlH4/THF (61%); (c) BH3/THF (69%); (d) 1,1-bis(thio-
methyl)-2-nitroethylene/EtOH) (82%); (f) AgOAc/MeOH (87%).
3.72-3.87 (m, 2H), 7.34 (d, 1H, H-3, J ) 8.2 Hz), 7.57-7.87 (m, 1H,
H-2), 8.32 (s, 1H, H-1), 8.43 (s, 1H). IR (KBr, cm-1) ν: 3281, 2811,
2178, 1560, 1519, 1435, 1122. HRMS Anal. Calcd for C15H21ClN5S
(MH+): 338.1206. Found: 338.1188.
5), 274 (15), 249 (12), 126 (100), 96 (19), 71 (49). HRMS Anal. Calcd
for C19H26ClN5O2 (M+): 391.1775. Found: 391.1804.
(1-((6-Chloropyridin-3-yl)methyl)-hexahydro-1H-cyclopenta[d]-
pyrimidin-2(3H)-ylidene)cyanamide (6). A mixture of compound 16
(0.102 g, 0.3mmol) and AgOAc (0.05 g, 0.3 mmol) in methanol (10
mL) was stirred at 50 °C for 5 h. After filtration, the filtrate was
evaporated under vacuum. The residue was purified by flash chroma-
tography to afford compound 6 (0.076 g, yield 87%). Mp: 156.2-
2-[4-(6-Chloropyridin-3-methyl)-7-propyl-5-nitro-1,2,3,3a,4,6,7,-
8,9,9a-hexahydro-4,7,8a-triazote-cyclopentyl[b]naphthalene (8d).
Yield: 55% (0.16 g). Mp: 155.1-157.3 °C. 1H NMR (CDCl3, δ
3
(ppm)): 0.92 (t, 3H, J4,5 ) 7.4 Hz), 1.52-2.01 (m, 8H), 2.32 (t, 2H,
J ) 7.0 Hz), 2.66 (s, 1H), 3.08 (d, 1H, J ) 12.1 Hz), 3.57-3.86 (m,
5H), 4.26 (s, 1H), 4.48 (s, 1H), 4.57 (d, 1H, J ) 15.3 Hz), 7.33 (d, 1H,
H-3, 3J2,3 ) 8.2 Hz), 7.58 (dd, 1H, H-2, 4J1,2 ) 1.5 Hz, 3J2,3 ) 8.2 Hz),
8.32 (d, 1H, H-1, 4J1,2 ) 1.9 Hz). IR (KBr, cm-1) ν: 2958, 1557, 1518,
1368, 1290. MS m/z (%): 391 ([M+], 5), 274 (18), 249 (22), 126 (100),
99 (9), 96 (19), 70 (45). HRMS Anal Calcd for C19H26ClN5O2 (M+):
391.1775. Found: 391.1804.
1
156.7 °C. H NMR (CDCl3, δ (ppm)): 1.51 (m, 3H), 1.78 (m, 1H),
1.91 (m, 1H), 2.10 (m, 1H), 2.31 (m, 1H), 3.03 (m, 1H), 3.30 (m, 1H),
3.47 (m, 1H), 4.29 (d, 1H, H-4, J ) 15.4 Hz), 4.99 (d, 1H, H-4, J )
3
15.4 Hz), 6.19 (s, 1H, NH), 7.31 (d, 1H, H-3, J2,3 ) 8.1 Hz), 7.75
(dd, 1H, H-2, 4J1,2 ) 2.4 Hz ,3J2,3 ) 8.1 Hz), 8.29 (d, 1H, H-1, 4J1,2
)
2.4 Hz). IR (KBr, cm-1) ν: 3249, 2170, 1586, 1551, 1457, 1339, 1107.
HRMS Anal. Calcd for C14H17ClN5 (MH+): 290.1172. Found: 290.1152.
2-[4-(6-Chloropyridin-3-methyl)-7-butyl-5-nitro-1,2,3,3a,4,6,7,-
8,9,9a-hexahydro-4,7,8a-triazote-cyclopentyl[b]naphthalene (8e).
Yield: 63% (0.19 g). Mp: 143.2-144.9 °C. 1H NMR (CDCl3, δ
Compound (8a-f). General Procedure. A mixture of compound
3 (0.75 mmol), formaldehyde (1.6 mmol, in the form of 35% aqueous
solution), and corresponding amine (0.83 mmol) in ethanol (5 mL) was
stirred overnight. The solution thus obtained was concentrated under
vacuum and further purified by flash chromatography to give the desired
product.
3
(ppm)): 0.93 (t, 3H, H-5, J4,5 ) 7.3 Hz), 1.33 (m, 2H), 1.52-2.01
(m, 8H), 2.32 (t, 2H, J ) 7.0 Hz), 2.67 (s, 1H, J ) 4.8 Hz), 3.08 (d,
1H, J ) 12.1 Hz), 3.57-3.86 (m, 5H), 4.26 (s, 1H), 4.48 (s, 1H), 4.57
3
(d, 1H, J ) 15.3 Hz), 7.33 (d, 1H, H-3, J2-3 ) 8.1 Hz), 7.58 (dd,
4
3
4
2-[4-(6-Chloropyridin-3-methyl)-7-methyl-5-nitro-1,2,3,3a,4,-
6,7,8,9,9a-decahydro-4,7,8a-triazote-cyclopentyl[b]naphthalene (8a).
Yield: 64% (0.175 g). Mp: 172.5-174.6 °C. 1H NMR (CDCl3, δ
(ppm)): 1.53 (m, 2H), 1.79 (m, 1H), 1.90 (s, 2H), 2.02 (s, 1H), 2.37
(s, 3H), 2.64 (s, 1H), 3.10 (d, 1H, J ) 11.5 Hz), 3.66 (d, 3H, J ) 10.0
Hz), 3.81 (s, 2H), 4.26 (s, 1H), 4.48 (s, 1H), 4.58 (d, 1H, J ) 15.2
Hz), 7.34 (d, 1H, H-3, J ) 8.1 Hz), 7.58 (d, 1H, H-2, J ) 7.2 Hz),
8.34 (s, 1H, H-1). IR (KBr, cm-1) ν: 3216, 2957, 1609, 1562, 1461,
1138. MS m/z (%): 363 ([M+], 2), 346 (11), 333 (12), 274 (43), 126
(84), 49 (26), 42 (100). HRMS Anal Calcd for C17H22ClN5O2 (M+):
363.1462. Found: 363.1432.
1H, H-2, J1-2 ) 1.5 Hz, J2-3 ) 8.0 Hz), 8.32 (d, 1H, H-1, J1,2
)
1.9 Hz). IR (KBr, cm-1) ν: 2956, 1552, 1518, 1367, 1290, 1150. MS
m/z (%): 405 ([M+], 1), 274 (14), 249 (8), 148 (9), 126 (47), 84 (100).
HRMS Anal. Calcd for C20H28ClN5O2 (M+): 405.2001. Found:
405.1826.
2-[4-(6-Chloropyridin-3-methyl)-5-nitro-1,2,3,3a,4,6,7,8,9,9a-hexahy-
dro-4,7,8a-triazote-cyclopentyl[b]naphthalene-7-yl]ethanol (8f).
Yield: 91% (0.18 g). Mp: 184.1-185.6 °C. 1H NMR (CDCl3, δ
(ppm)): 1.53 (m, 2H), 1.77-2.01 (m, 5H), 3.13 (d, 1H, J ) 11.4 Hz),
3.75 (m, 6H), 4.00 (m, 2H), 4.43 (m, 2H), 4.58 (d, 1H, J ) 15.4 Hz),
3
4
7.34 (d, 1H, H-3, J2,3 ) 8.1 Hz), 7.58 (dd, 1H, H-2, J1,2 ) 1.7 Hz,
J3, ) 8.0 Hz), 8.32 (d, 1H, H-1, J1,2 ) 2.0 Hz). IR (KBr, cm-1) ν:
4
3
2-[4-(6-Chloropyridin-3-methyl)-7-ethyl-5-nitro-1,2,3,3a,4,6,7,8,9,9a-
2
hexahydro-4,7,8a-triazote-cyclopentyl[b]naphthalene (8b). Yield:
3442, 1558, 1518, 1386, 1342, 1134. HRMS Anal. Calcd for C18H25-
1
ClN5O3 (MH+): 394.1646. Found: 394.1644.
62% (0.176 g). Mp: 167.2-169.2 °C. H NMR (CDCl3, δ (ppm)):
1.12 (t, 3H, H-6, 3J5,6 ) 7.0 Hz), 1.53 (m, 2H), 1.79 (m, 1H), 1.90 (m,
Biology Assay. All compounds were dissolved in acetone and diluted
with water containing Triton X-100 (0.1 mg L-1) to obtain series
concentrations of 500.0, 250.0, 125.0 mg L-1 and others for bioassays.
Pea Aphids (Aphis cracciVora) were dipped according to a slightly
modified FAO dip test (14). Tender shoots of soybean with 40-60
healthy apterous adults were dipped in diluted solutions of the chemicals
containing Triton X-100 (0.1 mL L-1) for 5 s, the superfluous fluid
was removed, and the shoots were placed in the conditioned room (23
( 1 °C, RH 50%). Water containing Triton X-100 (0.1 mL L-1) was
used as control. Mortality was assessed after 24 h, and data were
corrected and subjected to probit analysis as before.
3
2H), 2.01 (m, 1H), 2.46 (q, 2H, H-5, J ) 7.0 Hz), 2.67 (s, 1H), 3.09
(d, 1H, J ) 12.2 Hz), 3.58-3.92 (m, 5H), 4.26 (s, 1H), 4.48 (s, 1H),
4.59 (d, 1H, J ) 15.3 Hz), 7.34 (d, 1H, H-3, J ) 8.2 Hz), 7.58 (d, 1H,
H-2, J ) 6.9 Hz), 8.32 (d, 1H, H-1, J ) 2.2 Hz). IR (KBr, cm-1) ν:
2940, 1557, 1521, 1399, 1374, 1270, 1003. HRMS Anal. Calcd for
C18H25ClN5O2 (MH+): 378.1697. Found: 378.1679.
2-[4-(6-Chloropyridin-3-methyl)-7-isopropyl-5-nitro-1,2,3,-
3a,4,6,7,8,9,9a-hexahydro-4,7,8a-triazote-cyclopentyl[b]naphtha-
lene (8c). Yield: 58% (0.17 g). Mp: 158.3-160.6 °C. 1H NMR (CDCl3,
3
δ (ppm)): 1.09 (d, 6H, CH3, J5,6 ) 6.3 Hz), 1.52 (m, 2H), 1.79 (m,
3
1H), 1.89 (m, 2H), 2.01 (m, 1H), 2.65 (s, 1H), 2.76 (d, 1H, H-5, J5,6
) 6.0 Hz), 3.08 (s, 1H), 3.62-3.97 (m, 5H), 4.26 (s, 1H), 4.48 (s,
1H), 4.57 (d, 1H, J ) 15.3 Hz), 7.33 (d, 1H, H-3, J ) 8.2 Hz), 7.58
(d, 1H, H-2, J ) 7.5 Hz), 8.32 (d, 1H, H-1, J ) 2.0 Hz). IR (KBr,
cm-1) ν: 2957, 1550, 1519, 1378, 1265, 1151. MS m/z (%): 391 ([M+],
RESULTS AND DISCUSSION
Synthesis. The goal of this research was to develop a
synthetic strategy that offers a regioselective access to analogues

146 J. Agric. Food Chem., Vol. 55, No. 1, 2007
Tian et al.
Table 1. Calculated LogPs of Compounds 3 and 7 and Parent
Scheme 3a
Compound
1b
1c
3
7
8a
1.17
1.70
2.71
3.11
2.20
8b
8c
8d
8e
8f
2.75
3.15
3.28
3.81
1.43
a Reagents and conditions: (a) CH3I, t-BuOK/THF; (b) NaH/THF (26%);
(c) NaHB(OAc)3/AcOH (71%); (d) 6-chloronicotinaldehye, HCl/EtOH (46%);
(e) BH3/THF (61%); (f) 1,1-bis(thiomethyl)-2-nitroethylene/EtOH (65%).
Table 2. Insecticidal Screening Results of Nitromethylene Derivatives
against Aphis craccivora
concn
(mg/L)
mortality (%)
in vivo at 1 day
Scheme 4a
compd
3
3, 4
5
6
7
8a
8b
8c
500
500
500
500
500
500
500
450
125
500
500
500
500
62.5
15.625
83
59
82
38
51
54
90
88
56
61
32
60
34
94
60
8d
8e
8f
16
1c
a Reagents and conditions: (a) RNH2, CH2O/EtOH, rt.
3, 6, and 7 of 1c. Initially, the route represented in Scheme 1
was investigated, in which the intermediate 12 was synthesized
by reaction of 1,1-bis(thiomethyl)-2-nitroethylene with 11.
Compound 11 could be obtained conveniently via the reduction
of 9 with NaHB(OAc)3 in AcOH or LiAlH4 in THF. Compound
12 was treated with sodium hydride and then reacted with
2-chloro-5-(chloromethyl)pyridine to give a mixture of com-
pound 3 and 4, which could not be separated using silica gel
8f, and 16 exhibited 30-80% activities at 500 mg/L; compounds
3, 5, 8b, and 8c had >80% activities at 500 mg/L. In addition,
compound 8c showed 56% activity at 125 mg/L. The insecticidal
activity of mixture of 3 and 4 was 59%, which indicated that
activity of compound 4 was <59%. Comparing biological
activities of 3 and 6, it was found that functional group
dCHNO2 has more contribution for activities than group d
NCN. Though it was reported that the chlorine atom at the
6-position of the 3-pyridyl group plays an important role on
increasing insecticidal activity for nitromethylene compounds
(16), introduction of a chlorine atom to the pyridine ring afforded
no such activity enhancement for compound 3 in this paper.
1
chromatography due to the similar polarity. H NMR spectra
indicated that 3 and 4 were formed as a 1:1 mixture, which
could be obtained in 15% total yield (Scheme 1).
Because this reaction is not regioselective, another procedure
(Scheme 2) was therefore explored: 10 was reacted directly
with 2-chloro-5-chloromethylpridine, and then the formed
2-(aminomethyl)-N-((5-chloropyridin-2-yl)methyl)cyclopentan-
amine 13 was reduced. As has been well-known, stronger
reductants such as LiAlH4-THF can reduce cyano and chloro
groups. To be a mild reducing agent, BH3‚THF led to the
chemoselective reduction of the cyano group, avoiding undesired
reduction of the chloro group (Scheme 2). Compound 3 was
synthesized regioselectively by reaction of 15 with 1,1-bis-
(thiomethyl)-2-nitroethylene. Unfortunately, the similar proce-
dure could not give compound 6 from 15. The reaction stopped
at the step of compound 16. By adding AgOAc, the reaction
was promoted forward due to the generation of AgSCH3 (15).
Synthesis of 7 was performed as indicated in Scheme 3. Imine
19 was obtained by reaction 18 with 5-chloropicolinaldehyde,
then was reduced using BH3‚THF.
In conclusion, the synthesis of various nitromethene deriva-
tives can be approached successfully by taking advantage of
the regioselective cyclization of corresponding diamine. The
hydrophobicity of lead nitromethylene compounds was signifi-
cantly improved via the introduction of the cyclopentane ring,
and most of them showed moderate insecticidal activities at
500 mg/L.
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Received for review October 4, 2006. Revised manuscript received
November 8, 2006. Accepted November 11, 2006. This work was
financially supported by the National Key Project for Basic Research
(2003CB114405), National Natural Science Foundation of China
(20572024). We are grafteful for the partial support from the Shanghai
Education Committee and the Shanghai Foundation of Science and
Technology.
JF062845L