Preparation of new imidacloprid analogues

Article abstract of DOI:10.3987/COM-00-9016

A 3-step synthesis of the biologically active metabolites (2 and 3) of imidacloprid from aminoacetaldehyde diethyl acetal or ethylenediamine was developed. A series of new imidacloprid analogues were also prepared.

Full text of DOI:10.3987/COM-00-9016

HETEROCYCLES, Vol. 55, No. 1, 2001, pp. 45 - 58, Received, 21st July, 2000
PREPARATION OF NEW IMIDACLOPRID ANALOGUES
Lajos Novák*a, Gábor Hornyánszkya, Imre Királya, János Rohálya, Pál Kolonitsa,
and Csaba Szántaya,b
aInstitute for Organic Chemistry, Budapest University of Technology and
Economics, 1111 Budapest, Gellért tér 4, Hungary
bCentral Research Institute of Chemistry, 1525 Budapest, P.O. box 17, Hungary
Abstract - A 3-step synthesis of the biologically active metabolites (2 and 3) of
imidacloprid from aminoacetaldehyde diethyl acetal or ethylenediamine was
developed. A series of new imidacloprid analogues were also prepared.
One of the most promising new pest controlling agent is imidacloprid (1).1-5 It shows promise not only as
highly active compound against homopteran pests but also for controlling some chewing pests.
Furthermore, acting on nicotinic acetylcholine receptor it can be expected to control pests resistant to
conventional insecticides.6-8
For practical reasons imidacloprid is mainly used in soil application and seed treatment. In both cases two
biologically active metabolites (2 and 3) were formed and isolated.9 Compound (2) showed sixteen times
higher activity than imidacloprid on some aphid pests.9 The nitroso derivative (3) also showed higher
aphicidal potency than the parent compound imidacloprid.9
N
NH
N
N
N
NH
NO
N
HN
N
NO2
NO2
N
N
N
Cl
Cl
Cl
1
2
3

Our general interest in the preparation of new potent insecticides prompted us to elaborate efficient
synthetic route to biologically active metabolites (2 and 3) and to prepare new analogues of imidacloprid.
The synthesis of compound (2) was straightforward with S-methyl-N-nitroisothiourea (5)10 as the starting
material (Scheme 1). Thus treatment of isothiourea derivative (5) with aminoacetaldehyde diethyl acetal
(4) in water afforded guanidine derivative (6) in 83% yield. Reaction of the latter with 2-chloro-5-
chloromethylpyridine (7)11 in the presence of an excess of K2CO3 gave a mixture of two isomers which
was separated by column chromatography to furnish compounds (8) and (9) (15 and 41% yields,
respectively)12. Treatment of either compounds (8) or (9) with HCl resulted in the formation of the
expected product (2) (54 and 57% yields, respectively).
Scheme 1
CH2Cl
OEt
7
OEt
OEt
OEt
NH2
NO2
MeS
H2N
Cl
N
N
+
HN
H2N
N
NO2
6
5
4
OEt
OEt
OEt
OEt
NH
HCl
+
2
N
NH2
HN
N
N
NO2
NO2
N
N
Cl
Cl
8
9
The N-nitroso analogue (3) of imidacloprid (1) was prepared from ethylenediamine (Scheme 2).
Treatment of isothiourea derivative (5) with ethylenediamine afforded compound (10) in 72% yield.
Catalytic reduction of 10 in the presence of Raney nickel catalyst afforded the nitroso compound (11) in
47% yield. However, the alkylation of compound (11) with 7 gave only 2-imidazolidone derivative (12).
Therefore, we treated the nitro compound (10) with 7 to furnish imidacloprid (1) and then this was
hydrogenated catalytically to give nitroso compound (3).
For the preparation of cyclohexano analogue (16) of imidacloprid (1) 1,2-diaminocyclohexane (a mixture
of cis- and trans-isomers (13)) was reacted with nitroguanidine (14) to give an unseparable mixture of cis-

and trans-isomers (15a,b). This mixture was then alkylated with compound (7) in the presence of K2CO3
in boiling acetonitrile. The isomers formed were separated by column chromatography to furnish 16a and
16b in 28% yields.12
Scheme 2.
H2/Raney Ni
7
5
+
HN
HN
NH
NH
NO
DMF
H2N
NH2
N
N
NO2
10
11
N
NH
O
N
Cl
12
H2/Raney Ni
EtOH
10
+
7
1
3
Scheme 3.
NH2
H2N
H2N
NO2
+
N
+
HN
NH
HN
NH
NH2
N
N
13
7
14
NO2
NO2
15b
15a
6
7
5
4
+
1
3
N
NH
2
N
NH
N
N
NO2
NO2
N
N
Cl
Cl
16a
16b

The structural assignment of compounds (16a) and (16b) was made mainly on the bases of their NMR
spectra. For instance, in the trans-isomer (16b) the axial hydrogen in position 3a is rather close to the
methylene group on nitrogen at position 1 generating a strong Van der Waals interaction. Therefore, in the
13C NMR spectrum of 16b the carbons at positions 3a and 7a resonate at higher field (δ 61.84 and 64.13)
than those in the corresponding cis-isomer (16a; δ 69.45 and 69.70).
The attempted cyclization reaction between 1,2-phenylenediamine (Scheme 4, 17) and nitroguanidine (14)
failed. Likewise, the reaction between 17 and 5 also gave negative result. The inefficiency of these
reactions was probably due to the lack of reactivity of the relatively weak nucleophile amino groups of 17.
To overcome this problem we tested a more reactive reagent for the synthesis. The reaction between 17
and dimethyl N-nitrodithiocarbamate (18)15 gave the expected product (20) in 67% yield, besides some
methyl sulfide derivative (19).
Compound (20) was then treated successively with NaH and 7 to furnish the benzimidazole analogue of
imidacloprid (21).12
Scheme 4.
NH2
MeS
MeS
NO2
NO2
N
N
N
+
NH
SMe
+
NH
NH
NH2
17
18
19
20
NO2
N
N
NaH
DMF
20 + 7
NH
Cl
21
N
For the preparation of 4,5-diphenylimidacloprid derivatives (Scheme 5, 24) we used 1,2-diphenylethane
derivatives (22; a mixture of meso and racemic stereoisomers).18 Reaction of 22 with compound (5)
afforded an unseparable mixture of cis- and trans-isomers of 23. This mixture was successively treated
with compound (7) in the presence of K2CO3 to yield a mixture of 24 and its cis-isomer12, from which the
trans-isomer (24) was separated by chromatography.

Scheme 5
X
Z
X
Z
X
Z
X
Z
Y
Y
Y
Y
5
+
HN
NH
H2N
NH2
N
NO2
22
23
X
X
Z
Y
Y
X Y Z
22 - 24
a
1. NaH
H H H
Cl H H
H NO2 H
Z
2. + 7
b
c
N
NH
d
H H Cl
N
NO2
N
Cl
24
Comparing the reactivity of the above utilized carbonic acid derivetives (5, 14 and 18) towards amines we
generally observed that the reaction rate for nitroguanidine (14) was slower as compared with that of
compounds (5) and (18) (Table 1). For the latter two the yields are good or appreciable but slightly lower
for compound (5) than for compound (18). Furthermore, compound (5) did not react with aromatic amine
(17), probably due to the reduced nucleophilicity of its amino groups.
Table 1. Reaction of carbonic acid derivatives with amines
Amines
Product
10 (%)
14
5
18
61
90
88
99
67
Ethylenediamine
57
65
13
22a
22b
17
15a + 15b (%)
23a (%)
62
84
61
No reaction
No reaction
No reaction
23b (%)
74
20 (%)
No reaction
All reaction were carried out in water at 60 °C for 1 h with ratio of amine/carbonic acid derivative 1.2:1

In summary, we have synthesized a series of new imidacloprid analogues and elaborated new method for
the preparation of its biologically active metabolites.
EXPERIMENTAL
Reagents were obtained from commercial suppliers and were used without further purification. All
reactions were conducted under an atmosphere of dry N2 or Ar. Melting points were determined on a
Büchi apparatus and are uncorrected. IR spectra were obtained with a Spectromom 2000
1
spectrophotometer. H and 13C NMR spectra measurements were carried out using a Bruker DRX-500
spectrometer (500 MHz; internal standard: TMS). MS spectra were obtained on a KRATOS MS25 RFA
spectrometer. Merck precoated silica gel 60 F254 plates were used for thin-layer chromatography and
KieselgelR60 for column chromatography. All solvents were dried by means of standard methods.
N-(2,2-Diethoxyethyl)-N'-nitroguanidine (6).
To a stirred suspension of S-methylisothionitrourea10 (5; 1.0 g, 7.4 mmol) in water (5 mL) was added 2,2-
diethoxyethylamine (4; 1.0 g, 7.4 mmol) and the resulting mixture was stirred at rt for 1.5 h. The
precipitated product was filtered and dried in vacuum desiccator to afford 6 (1.35 g, 83%), mp 110oC
(water). 1H NMR (CDCl3): δ = 1.20 (6H, t, J=8 Hz, 2 CH3), 3.20-4.00 (6H, m, 2 OCH2 and N-CH2), 4.55
(1H, t, J=5.3 Hz, CH), 7.85 (2H, br s, NH2), 9.0 (1H, br s, NH).
N-(6-Chloropyridin-3-ylmethyl)-N-(2,2-diethoxyethyl)-N'-nitroguanidine (8) and N-(6-
chloropyridin-3-ylmethyl)-N'-(2,2,-diethoxyethyl)-N"-nitroguanidine (9)
To a stirred solution of 6 (1.0 g, 4.54 mmol) in acetonitrile (40 mL) was added K2CO3 (2.2 g, 16 mmol)
and 2-chloro-5-chloromethylpyiridine11 (7: 0.72 g, 4.44 mmol), and the resulting mixture was refluxed for
19 h. The mixture was cooled to rt, filtered, the solvent was evaporated in vacuo, and then the residue was
chromatographed with EtOAc/hexane 4:1 to yield 0.24 g (15%) of 8 and 0.66 g (41%) of 9.
Compound (8): oil. TLC (EtOAc-hexane 4:1) Rf = 0.49. 1H NMR (CDCl3): δ = 1.25 (6H, m, 2CH3) 3.37
(2H, d, J=4.2 Hz, CH2), 3.56 (2H, m, OCH2) 3.77 (2H, m, OCH2), 4.56 (1H, m, CH), 4.74 (2H, s, N-
CH2), 7.33 (1H, d, J=8.2 Hz, C(5')H), 7.78 (1H, dd, J=8.2 and 2.0 Hz, C(4')H), 8.14 (2H, br s, NH2), 8.28
(1H, d, J=2.0 Hz, C(2')H). Anal. Calcd for C13H20N5O4Cl: C, 45.16, H, 5.83, N, 20.25, Cl, 10.25.. Found:
C, 45.25, H, 5.89, N, 20.15, Cl, 10.11.
1
Compound (9): oil. TLC (EtOAc-hexane 4:1) Rf= 0.38. H NMR (CDCl3): δ 1.22 (6H, m, 2CH3), 3.43
(2H, m, CH2), 3.54 (2H, m, OCH2), 3.72 (2H, m, OCH2), 4.50 (2H, d, J=5.6 Hz, N-CH2), 4.53 (1H, m,

CH), 6.78 (1H, br s, NH), 7.32 (1H, d, J=8.2 Hz, C(5')H), 7.72 (1H, dd, J=8.2 and 2.2 Hz, C(4')H), 8.33
(1H, d, J=2.2 Hz, C(2')H), 9.53 (1H, br s, NH). Anal. Calcd for C13H20N5O4Cl: C, 45.16, H, 5.83, N,
20.25, Cl, 10.25. Found: C, 45.21, H, 5.86, N, 20.18, Cl, 10.15.
1-(6-Chloropyridin-3-ylmethyl)-N-nitro-1H-imidazol-2-ylamine (2).
a) A solution of 8+9 (2.0 g, 5.79 mmol) in concentrated HCl (20 mL) was stirred at rt for 3 days. The
precipitate was collected by filtration, washed with water and dried in vacuum desiccator to yield 2
(0.75 g, 51%).
b) Following the above procedure, using compounds (8) or (9), with reaction time 2 days, we isolated
compound (2) in 54 and 57% yields (respectively). mp 190-192oC (decomp); TLC (CH2Cl2/MeOH
1
9:1): Rf = 0.5. IR (KBr): 3340 (NH), 1580, 1536 (NO2), 1410, 1310 cm-1. H NMR (DMSO-d6): δ =
5.13 (2H, s, CH2), 7.01 (1H, s, C(5)H), 7.36 (1H, s, C(4)H), 7.53 (1H, d, J=8.3 Hz, C(5')H), 7.77 (1H,
dd, J=8.3 and 2.2 Hz, C(4')H), 8.40 (1H, d, J=2 Hz, C(2')H), 12.78 (1H, br s, NH). 13C NMR (DMSO-
d6): δ = 45.26 (CH2), 114.00 (C-4), 117.07 (C-5), 124.60 (C-5'), 131.49 (C-3'), 139.48 (C-4'), 145.87
(C-2'), 149.52 (C-6'), 150.04 (C-2). MS: m/z = 254 (M++H, 25), 208 (100). Anal. Calcd for
C9H8N5O2Cl: C, 42.62, H, 3.18, N, 27.61, Cl, 13.98. Found: C, 42.45, H, 3.10, N, 27.71, Cl, 14.12.
Imidazolidin-2-ylidenenitroamine (10)
To a stirred suspension of 5 (6.0 g, 44 mmol) in water (30 mL) was added ethylenediamine (3 mL, 44
mmol) and the resulting mixture was stirred at 75oC for 1.5 h. After cooling, the precipitate was collected
by filtration, washed with water and then dried to afford 10 (4.5 g, 72%), mp 226-228oC (lit.,20 mp 220-
221oC).
Imidazolidin-2-ylidenenitrosoamine (11)
Compound (10) (5.4 g, 42 mmol) was dissolved in DMF (350 mL) and mixed with Raney nickel catalyst
(24 g). The resultant mixture was stirred under H2 atmosphere until 1.24 equiv. of H2 (1.22 L) had been
absorbed. The catalyst was removed by filtration, the solvent evaporated in vacuo, and the residue was
purified by column chromatography (CH2Cl2-MeOH 5:1) to yield 11 (1.545 g, 33%), and 1.62 g (12.5
mmol) of 10 was recovered, mp 180-182oC (CH2Cl2-MeOH 5:1). TLC (CH2Cl2-MeOH 5:1): Rf = 0.33. IR
1
(KBr): 3300 (NH), 1620, 1570 cm-1. H NMR (DMSO-d6): δ = 3.69 (4H, s, 2CH2), 8.65 (2H, br, 2NH).
13C NMR (DMSO-d6): δ = 42.17 (C-4 and C-5), 171.50 (C-2). MS: m/z = 115 (M++H, 12), 87 (100), 71
(20), 69 (15). Anal. Calcd for C3H6N4O: C, 31.58, H, 5.30, N, 49.10. Found: C, 31.65, H, 5.35, N, 49.02.

1-(6-Chloropyridin-3-ylmethyl)imidazolidin-2-one (12)
To a suspension of 11 (0.42 g, 3.7 mmol) and K2CO3 (1.9 g, 13.7 mmol) in acetonitrile (30 mL) was
added compound (7) (0.6 g, 3.7 mmol) and the resulting mixture was heated with stirring for 23 h. After
cooling, the solid was filtered, washed with acetonitrile and the combined filtrate and washing was
evaporated under vacuum. The residue was purified by column chromatography (columm; Al2O3,
Brockmann II neutral; eluent: CH2Cl2-MeOH 5:1, v/v) to give 12 as a white crystal. Yield: 0.12 g (16%),
mp 140-142oC (CH2Cl2-MeOH); TLC (Al2O3, Brockmann II neutral; CH2Cl2-MeOH 14:1): Rf = 0.68. IR
1
(KBr): 3220 (NH), 1690 cm-1 (CO). H NMR (CDCl3): 3.32 (2H, t, J=6 Hz, CH2), 3.42 (2H, t, J=6 Hz,
CH2), 4.35 (2H, s, CH2), 5.14 (1H, br s, NH), 7.30 (1H, d, J=8.2 Hz, C(5')H), 7.62 (1H, dd, J=8.2. and 2.2
13
Hz, C(4')H), 8.29 (1H, d, J=2.2 Hz, C(2')H). C NMR (CDCl3): 38.04 (C-4), 44.58 (C-5), 44.64 (CH2),
124.45 (C-5'), 131.81 (C-3'), 138.82 (C-4'), 149.17 (C-2'), 150.83 (C-6'). MS: m/z = 211 (M+, 100), 140
(28), 126 (90), 99 (70).
[1-(6-Chloropyridin-3-ylmethyl)imidazolidin-2-ylidene]nitrosoamine (3)
A mixture of 10 (1.8 g, 14 mmol), compound (7) (2.24 g, 14 mmol) and K2CO3 (6.80 g, 49 mmol) in
acetonitrile (40 mL) was stirred at 70 ºC for 24 h. After cooling, the mixture was filtered, the filtrate was
evaporated in vacuo and the residue was purified by column chromatography (CH2Cl2–MeOH, 5:1) to
give imidacloprid (1, 1.85 g, 52%). mp 140ºC (EtOH).
Imidacloprid (1.9 g, 7.4 mmol) was dissolved in ethanol (250 mL) and mixed with Raney nickel catalyst
(5 g). The resulting mixture was stirred under H2 atmosphere until 1.05 equiv. of H2 (193 mL) had been
absorbed. The catalyst was removed by filtration, the filtrate was concentrated in vacuo, and the residue
was purified by column chromatography (CH2Cl2–MeOH, 9:1) to yield 3 (0.65 g, 36%), and 0.6 g (2.4
mmol) of Imidacloprid was recovered, mp 153ºC (CHCl3) (decomp). TLC (CH2Cl2–MeOH, 9:1) Rf =
1
0.25. IR (KBr): 3264 (NH), 1576, 1560, 1424 cm-1. H-NMR (DMSO-d6): δ = 3.70 (4H, br, 2CH2), 4.60
(2H, s, N-CH2), 7.55 (1H, d, J=8 Hz, C(5')H), 7.78 (1H, d, J=8 Hz, C(4')H), 8.38 (1H, s, C(2')H), 9.01
13
(1H, s, NH). C-NMR (DMSO-d6): δ = 40.99 (C-4), 44.09 (C-5), 46.12 (N-CH2), 124.36 (C-5'), 131.48
(C-3'), 139.44 (C-4'), 149.37 (C-2'), 149.57 (C-6'), 169.58 (C-2). MS: m/z = 240 (M++H, 60), 212 (100),
196 (18), 178 (10). Anal. Calcd for C9H10N5OCl: C, 45.10, H, 4.21, N, 29.22, Cl, 14.79. Found: C, 45.25,
H, 4.40, N, 29.15, Cl, 14.61.
cis and trans-(3a,4,5,6,7,7a-Hexahydro-1H-benzimidazolidin-2-ylidene)nitroamine (15a and 15b)
To a solution of KOH (5.0 g, 88 mmol) in water (15 mL) were successively added nitroguanidine (14:6.0
g, 58 mmol) and 1,2-diaminocyclohexane hydrochloride (13, a mixture of cis- and trans-isomers: 8.3 g,

44 mmol) and the resultant mixture was stirred at 70oC for 2 h. After cooling, the precipitate was
collected by filtration, washed with water and dried to afford 15a,b (5.0 g, 62%), as a white powder. IR
1
(KBr): 3430, 3200 (NH), 1610 cm-1. H NMR (CDCl3+DMSO-d6): δ = 1.40 (2H, m, CH2), 1.52 (2H, m,
CH2), 1.68 (2H, m, CH2), 1.82 (2H, m, CH2), 2.18 (0.6H, dm, J=10 Hz, CH-trans), 3.20 (0.6H, dm, J=8
Hz, CH-trans), 3.90 (0.8H, s, 2CH-cis). 13C NMR (CDCl3+DMSO-d6): δ = 19.17, 23.2, 26.36, 28.35,
52.88, 61.70, 77.27, 162.83, 164.50. Anal. Calcd for C7H12N4O2: C, 45.65, H, 6.57, N, 30.42. Found: C,
45.45, H, 6.49, N, 30.56.
Alternate method for the preparation of compounds 15a and 15b:
A mixture of N-nitrodithiocarbamate15 (18: 3.2 g, 20 mmol) and 1,2-diaminocyclohexane (13: 2.73 g, 24
mmol) in water (15 mL) was heated at 60oC for 1 h. After cooling, the precipitate was filtered off, washed
with water and dried to afford 15a,b (3.3 g, 90%).
cis- and trans-[1-(6-Chloropyridin-3-ylmethyl)-3a,4,5,6,7,7a-hexahydro-1H-benzimidazolidin-2-
ylidene]nitroamine (16a and 16b)
A suspension of 15 (3.0 g, 16 mmol), compound (7) (2.6 g, 16 mmol) and K2CO3 (10.64 g, 76 mmol) in
acetonitrile (125 mL) was heated with stirring for 48 h. After cooling, the solid was filtered off, washed
with acetonitrile and the combined filtrate and washing was evaporated under vacuum. The residue was
purified by column chromatography (column: Al2O3, Brockmann II neutral; eluent: hexane-acetone 7:3,
v/v) to give pure 16a (1.4 g, 28%) and 16b (1.4 g, 28%).
1
Compound (16a): mp 122-124oC (CHCl3); TLC (hexane-acetone 3:2) Rf = 0.35. H NMR (CDCl3): δ =
1.40 (3H, m, CH2), 1.59 (1H, m, CH2), 1.70 (2H, m, CH2), 1.85 (2H, m, CH2), 3.58 (1H, m, C(3a)H), 3.95
(1H, m, C(7a)H), 4.21 (1H, d, J=15.6 Hz, CH2-N), 4.86 (1H, d, J=15.6 Hz, CH2-N), 7.34 (1H, d, J=8.2
Hz, C(5')H), 7.72 (1H, dd, J=8.2 and 2.4 Hz, C(4')H), 8.21 (1H, br s, NH), 8.32 (1H, d, J=2.4 Hz, C(2')H).
13C NMR (CDCl3): δ = 24.19, 27.43, 29.24, 31.67, 42.53 (N-CH2), 69.45 (C-3a), 69.70 (C-7a), 124.60 (C-
5'), 130.39 (C-3'), 138.97 (C-4'), 149.04 (C-2'), 151.30 (C-6'), 161.56 (C-2). Anal. Calcd for
C13H16N5O2Cl: C, 50.41, H, 5.21, N, 22.61, Cl, 11.45. Found: C, 50.55, H, 5.29, N, 22.51, Cl, 11.31.
1
Compound (16b): mp 180-182oC (CHCl3); TLC (hexane-acetone 3:2) Rf = 0.37. H NMR (CDCl3): δ =
1.35 (3H, m, CH2), 1.51 (1H, m, CH2), 1.89 (2H, m, CH2), 2.05 (1H, m, CH2), 2.18 (1H, m, CH2), 2.91
(1H, m, C(3a)H), 3.29 (1H, m, C(7a)H), 4.48 (1H, d, J=15.4 Hz, CH2-N), 4.58 (1H, d, J=15.4 Hz, CH2-
N), 7.32 (1H, d, J=8 Hz, C(5')H), 7.74 (1H, d, J=8 Hz, C(4')H), 8.30 (1H, s, C(2')H), 8.37 (1H, br s, NH).
13C NMR (CDCl3): δ = 23.67, 23.84, 27.83, 28.81, 43.71 (N-CH2), 61.84 (C-3a), 64.13 (C-7a), 124.65 (C-
5'), 130.38 (C-3'), 139.17 (C-4'), 149.17 (C-2'), 151.35 (C-6'), 163.39 (C-2). Anal. Calcd for
C13H16N5O2Cl: C, 50.41, H, 5.21, N, 22.61, Cl, 11.45. Found: C, 50.51, H, 5.31, N, 22.55, Cl, 11.36.

1H-Benzimidazol-2-ylnitroamine (20) and 2-methylthio-1H-benzimidazole (19)
A mixture of N-nitrodithiocarbamate15 (18: 3.2 g, 20 mmol) and 1,2-phenylenediamine (17: 2.16 g, 20
mmol) in water (15 mL) was heated at 60oC for 1 h. After cooling, the yellow precipitate was filtered off,
washed with water.
Compound (20): 2.4 g (67%), as white powder, mp > 230oC (water); TLC (EtOAc): Rf = 0.38. IR (KBr):
1
3240 (NH), 1620, 1595, 1490, 1390, 1300, 1200 cm-1. H NMR (DMSO-d6): δ = 7.29 (2H, m, arom. H),
13
7.46 (2H, m, arom. H), 12.99 (2H, br, 2 NH). C NMR (DMSO-d6): δ = 112.05 (C-4 and C-7), 123.65
(C-5 and C-6), 128.97 (C-3a and C-7a), 151.23 (C-2). MS: m/z = 178 (M+, 5), 133 (100), 118 (8), 105
(32). Anal. Calcd for C7H6N4O2: C, 47.19, H, 3.39, N, 31.45. Found: C, 47.25, H, 3.29, N, 31.51.
o
Compound (19): 0.5 g (15%). mp 202 C (hexane-EtOAc 2:8). IR (KBr): 3250 (NH), 1620, 1595 cm-1.
1H NMR (DMSO-d6): δ = 2.69 (3H, s, S-CH3), 7.10 (2H, m, arom. H), 7.36 (1H, br, arom. H), 7.49 (1H,
13
br, arom. H), 12.49 (1H, br, NH). C NMR (DMSO-d6): δ = 14.66 (CH3), 111.06 (C-7), 118.06 (C-4),
121.95 (C-6), 122.27 (C-5), 136.41 (C-7a), 144.59 (C-3a), 152.06 (C-2). MS: m/z = 164 (M+, 100), 149
(13), 131 (80), 122 (23), 118 (26), 91 (12).
[1-(6-Chloropyridin-3-ylmethyl)-1H-benzimidazol-2-yl]nitroamine (21).
To a stirred solution of 20 (1.3 g, 7 mmol) in dry DMF (30 mL) were successively added NaH (0.4 g
(50% purity), 8 mmol) and compound (7) (1.18 g, 7 mmol). The resulting mixture was heated at 80oC for
2 h. After cooling, the solvent was evaporated in vacuo, the residue was washed with acetone and water.
The crude product was dissolved in CHCl3, filtered and the filtrate was evaporated in vacuo to afford 0.8
g (36%) of 21, as light yellow crystals, mp 221 oC (CHCl3) (decomp); TLC (EtOAc): Rf = 0.63. IR (KBr):
1
3328 (NH), 1560, 1496, 1280, 1136 cm-1. H NMR (DMSO-d6): δ = 5.41 (2H, s, CH2), 7.32 (2H, m,
arom. H), 7.47 (1H, d, J=8.4 Hz, C(5')H), 7.60 (1H, m, arom. H), 7.63 (1H, m, arom. H), 7.79 (1H, dd,
J=8.4 and 2.5 Hz, C(4')H), 8.50 (1H, d, J=2.5 Hz, C(2')H), 13.26 (1H, br, NH). 13C NMR (DMSO-d6): δ =
42.48 (CH2), 110.44 (C-4), 112.91 (C-7), 123.89 (C-5), 124.01 (C-6), 124.34 (C-5'), 128.83 (C-3'), 129.02
(C-3a), 130.90 (C-7a), 138.98 (C-4'), 149.11 (C-2'), 149.73 (C-6'), 149.92 (C-2). MS: m/z = 303 (M+, 5),
258 (62), 132 (100), 126 (62). Anal. Calcd for C13H10N5O2Cl: C, 51.41, H, 3.32, N, 23.06, Cl, 11.67.
Found: C, 51.55, H, 3.39, N, 22.91, Cl, 11.45.
(4,5-Diphenylimidazolidin-2-ylidene)nitroamines (23). General Procedure
A stirred suspension of appropriate ethylenediamine derivative (15 mmol)18 and compound (5) (3.7 g, 27
mmol) in water (10 mL) was heated at 90-95oC for 2 h. After cooling, the solid was filtered and purified
by column chromatography (CH2Cl2-MeOH 10:1), as a white powder.

1
Compound (23a): Yield 61%. TLC (hexane-acetone 6:4) Rf = 0.33. H NMR (CDCl3): δ = 5.42 (2H, s,
13
2CH), 6.90 (4H, m, arom. H), 7.08 (6H, m, arom. H), 8.05 (2H, br, 2NH). C NMR (CDCl3): δ = 63.30
(C-4 and C-5), 127.09, 128.2, 128.29, 134.73 (C-1' and C-1"), 163.42 (C-2).
1
Compound (23b): Yield 74%; TLC (CH2Cl2-MeOH 5:1) Rf = 0.68. IR (KBr): 3420 (NH), 1600 cm-1. H
NMR (CDCl3): δ = 5.42 (2H, s, 2CH), 6.88 (4H, d, J=8 Hz, arom. H), 7.17 (4H, d, J=10 Hz, arom. H),
13
8.24 (2H, br s, 2NH). C NMR (CDCl3): δ = 62.62 (C-4 and C-5), 128.40, 128.72, 133.06 (C-1' and C-
1"), 134.61 (C-4' and C-4"), 163.27 (C-2).
Compound (23c): Yield 52%; TLC (CH2Cl2-MeOH 9:1): Rf = 0.44. IR (KBr): 3400 (NH), 1600, 1520,
1
1360 cm-1. H NMR (DMSO-d6): δ = 5.74 (2H, s, 2CH), 7.41 (4H, m, arom. H), 7.83 (2H, s, arom. H),
13
7.91 (2H, d, J=8 Hz, arom. H), 8.33 (2H, br s, 2NH). C NMR (DMSO-d6): δ = 60.99 (C-4 and C-5),
121.92 (C-4' and C-4"), 122.61 (C-2' and C-2"), 129.73 (C-5' and C-5"), 133.83 (C-6' and C-6"), 138.95
(C-1' and C-1"), 147.29 (C-3' and C-3"), 163.25 (C-2).
Compound (23d): Yield 40%; TLC (CH2Cl2-acetone 4:1): Rf = 0.71. IR (KBr): 3420 (NH), 1600 cm-1.
1H NMR (CDCl3): δ = 5.83 (2H, s, 2CH), 7.15 (6H, m, arom. H), 7.21 (2H, m, arom. H), 9.17 (2H, br s,
13
2NH). C NMR (CDCl3): δ = 58.98 (C-4 and C-5), 127.43, 129.80, 130.20, 130.40, 133.38 (C-2' and C-
2"), 134.37 (C-1' and C-1"), 163.92 (C-2).
Alternate method for the preparation of compounds 23a and 23b:
A mixture of N-nitrodithiocarbamate15 (18: 1.6 g, 10 mmol) and 1,2-diamino-1,2-diphenylethane (22a:
2.5 g, 12 mmol) or 1,2-diamino-1,2-bisz(4-chlorophenyl)ethane (22b: 3.35 g, 12 mmol) in water (10 mL)
was heated at 60oC for 1 h. After cooling, the precipitate was filtered off, washed with water and dried to
afford 23a (2.5 g, 88%) or 23b (3.45 g, 99%).
[1-(6-Chloropyridin-3-ylmethyl)-4,5-diphenylimidazolidin-2-ylidene]nitroamines (24). General
Procedure
To a suspension of compound (23) (4 mmol) and compound (7) (0.65 g, 4 mmol) in acetonitrile (40 mL)
was added K2CO3 (3.0 g, 20 mmol), and the resulting mixture was heated for 24 h. After cooling, the
reaction mixture was filtered, the solid washed with acetonitrile and then the combined filtrate and
washing was evaporated in vacuo. The residue was purified by column chromatography (CH2Cl2-
methanol 20:1 as eluent) to yield 24.
Compound (24a): Yield 54%, mp 103-104oC (CH2Cl2-MeOH). TLC (hexane-acetone 4:1, Al2O3): Rf =
1
0.15. H NMR (CDCl3): δ = 3.79 (1H, d, J=15.2 Hz, CH2), 4.89 (1H, d, J=9.8 Hz, CH), 5.14 (1H, d,
J=15.2 Hz, CH2), 5.35 (1H, d, J=9.8 Hz, CH), 6.77 (2H, d, J=7.2 Hz, arom. H), 6.89 (2H, d, J=6.6 Hz,
arom. H), 7.15 (6H, m, arom. H), 7.32 (1H, d, J=8.2 Hz, C(5')H), 7.66 (1H, dd, J=8.2 and 2.2 Hz, C(4')H),

13
8.03 (1H, d, J=2 Hz, C(2')H), 8.57 (1H, s, NH). C NMR (CDCl3): δ = 43.25 (CH2), 62.79 (C-4), 65.30
(C-5), 124.71 (C-5'), 126.89, 128.00, 128.44, 128.61, 128.75, 129.08, 129.51 (arom. C), 131.67 (C-3'),
134.25 (arom.C), 139.64 (C-4'), 149.64 (C-2'), 151.68 (C-6'), 161.79 (C-2). MS: m/z = 409 (15), 407 (M+,
45), 363 (16), 361 (48), 256 (22), 229 (38), 180 (48), 126 (100). Anal. Calcd for C21H18N5O2Cl: C, 61.84,
H, 4.45, N, 17.17, Cl, 8.69. Found: C, 61.65, H, 4.29, N, 17.31, Cl, 8.81.
Compound (24b): Yield 68%; mp 205-208oC (hexane-acetone). TLC (hexane-acetone 4:1, Al2O3): Rf =
1
0.12. H NMR (CDCl3): δ = 3.81 (1H, d, J=15.2 Hz, CH2), 4.92 (1H, d, J=9.7 Hz, CH), 5.22 (1H, d,
J=15.2 Hz, CH2), 5.40 (1H, d, J=9.7 Hz, CH), 6.81 (2H, d, J=8.2 Hz, arom. H), 6.92 (2H, d, J=8.3 Hz,
arom. H), 7.23 (2H, d, J=8.4 Hz, arom. H), 7.26 (2H, d, J=8.2 Hz, arom. H), 7.41 (1H, d, J=8.2 Hz,
C(5')H), 7.72 (1H, dd, J=8.2 and 2.2 Hz, C(4')H), 8.11 (1H, d, J=2 Hz, C(2')H), 8.63 (1H, s, NH). MS:
m/z = 477 (12), 475 (M+, 8), 433 (98), 432 (100), 398 (80), 306 (28). Anal. Calcd for C21H16N5O2Cl3: C,
52.91, H, 3.38, N, 14.69, Cl, 22.31. Found: C, 53.05, H, 3.49, N, 14.51, Cl, 22.11.
Compound (24c): Yield 32%, mp 244-246oC (hexane-acetone). TLC (hexane-acetone 7:3, Al2O3): Rf =
1
0.28. IR (KBr): 3410 (NH), 1590, 1540, 1480 cm-1. H NMR (DMSO-d6): δ = 4.08 (1H, d, J=16 Hz,
CH2), 4.83 (1H, d, J=16 Hz, CH2), 5.57 (1H, d, J=10.3 Hz, CH), 5.79 (1H, d, J=10.3 Hz, CH), 7.33 (1H,
d, J=6.8 Hz, arom. H), 7.37-7.40 (2H, m, arom. H and C(5')H), 7.48 (2H, t, J=8.4 Hz, arom. H), 7.67 (1H,
br s, arom. H), 7.76 (1H, dd, J=8.2 and 2.2 Hz, C(4')H), 7.86 (1H, s, arom. H), 7.92 (2H, m, arom. H),
13
8.20 (1H, d, J=1.5 Hz, C(2')H), 9.82 (1H, s, NH). C NMR (DMSO-d6): δ = 43.49 (CH2), 61.10 (C-4),
63.38 (C-5), 121.86, 122.40, 123.03 (arom.C), 124.21 (C-5'), 129.49, 129.91 (arom.C), 131.02 (C-3'),
133.78, 136.11, 138.63 (arom. C), 139.70 (C-4'), 147.14, 147.33 (arom. C), 149.50 (C-2'), 149.58 (C-6'),
161.13 (C-2). Anal. Calcd for C21H16N7O6Cl: C, 50.66, H, 3.24, N, 19.69, Cl, 7.12. Found: C, 50.50, H,
3.19, N, 19.51, Cl, 7.21.
Compound (24d): Yield 55%, mp 232-234oC (CH2Cl2-MeOH). TLC (CH2Cl2-acetone 9:1): Rf = 0.69. IR
1
(KBr): 3200 (NH), 1560, 1540, 1460 cm-1. H NMR (CDCl3): δ = 3.75 (1H, d, J=15 Hz, CH2), 5.07 (1H,
d, J=15 Hz, CH2), 5.66 (1H, d, J=9.7 Hz, CH), 5.90 (1H, d, J=9.7 Hz, CH), 6.82 (1H, d, J=7.4 Hz, arom.
H), 7.05 (1H, t, J=7.5 Hz, arom. H), 7.16 (4H, m, arom. H), 7.21 (1H, m, arom. H), 7.25 (1H, d, J=8 Hz,
arom. H), 7.34 (1H, d, J=8.2 Hz, C(5')H), 7.65 (1H, dd, J=8.2 and 2.2 Hz, C(4')H), 8.12 (1H, d, J=2 Hz,
13
C(2')H), 8.54 (1H, s, NH). C NMR (CDCl3): δ = 43.70 (CH2), 58.92 (C-4), 60.05 (C-5), 124.87 (C-5'),
126.87, 126.92, 128.33 (arom. C), 129.27 (C-3'), 129.47, 129.51, 129.86, 130.25, 130.32, 130.55, 132.08,
133.82, 135.16 (arom. C), 139.87 (C-4'), 150.18 (C-2'), 151.98 (C-6'), 161.87 (C-2). Anal. Calcd for
C21H16N5O2Cl3: C, 52.91, H, 3.38, N, 14.69, Cl, 22.31. Found: C, 52.75, H, 3.29, N, 14.71, Cl, 22.41.

ACKNOWLEDGEMENTS
Financial support from Hungarian OTKA Foundation (T022955) and Chinoin-Sanofi AgroChem Business
Unit Budapest is gratefully acknowledged.
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