Chemistry of polyhalogenated nitrobutadienes, 8: Nitropolychlorobutadienes-Precursors for insecticidal neonicotinoids

Article abstract of DOI:10.1016/j.bmc.2009.01.001

Nitropolychlorobutadienes are valuable precursors for highly functionalized acyclic or (hetero)cyclic compounds. In this 8th part of our synthetically oriented series we focus on the application of these versatile starting materials in the synthesis of an

Full text of DOI:10.1016/j.bmc.2009.01.001

Bioorganic & Medicinal Chemistry 17 (2009) 4206–4215
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Chemistry of polyhalogenated nitrobutadienes, 8:
Nitropolychlorobutadienes—Precursors for insecticidal neonicotinoids
Viktor A. Zapol’skii a, Reiner Fischer b, Jan C. Namyslo a, Dieter E. Kaufmann a,
*
a Institute of Organic Chemistry, Clausthal University of Technology, Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld, Germany
b Bayer CropScience AG, Research Insecticides, Alfred-Nobel-Strasse 50, D-40789 Monheim, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Nitropolychlorobutadienes are valuable precursors for highly functionalized acyclic or (hetero)cyclic
compounds. In this 8th part of our synthetically oriented series we focus on the application of these ver-
satile starting materials in the synthesis of analogs of the heterocyclic insecticides imidaclopridTM and
thiaclopridTM, and the acyclic counterpart clothianidinTM. In addition to the main synthetic part, leading
to imidazolidines or oxazolidines, further promising types of compounds derived by subsequent chemical
modifications, are introduced. Most of the new compounds show high insecticidal activity.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 21 November 2008
Revised 29 December 2008
Accepted 5 January 2009
Available online 9 January 2009
Keywords:
Nitro compounds
Butadienes
Chloro compounds
Heterocycles
Amines
SN reactions
SNVIN reactions
Michael reactions
Cyclizations
Insecticides
Neonicotinoids
1. Introduction
logical degradation processes, an additional nitro group enforces
the physiological activity.5
The readily accessible 2-nitroperchloro-1,3-butadiene (10)1a is
one of the most prominent members of the relatively new class
of organic compounds, called polyhalogenated nitrobutadienes.
The well-defined chemical reactivity of 10 runs contrary, on one
hand to the superior reactivity of nitrobutadienes,2 and on the
other hand to the slow conversion rates of the rather stable hexa-
chlorobutadiene. The latter requires harsh conditions and often-
times leads only to product mixtures.3
Thus,beingattackedbyanappropriate nucleophile, 10initiallyre-
acts at the terminal C-1 carbon atom to yield the product of a nucle-
ophilic vinylic substitution process. Under more rigid conditions a
subsequent substitution of the chlorine atom on C-3 is possible.
In the past five years we published the syntheses of a wide
range of different acyclic as well as (hetero)cyclic compounds
employing this versatile starting material.4 Aside from synthetic
and mechanistic aspects, these kinds of highly substituted organic
compounds attracted our interest, owing to their biological activ-
ity. Even if chlorinated structures already suffer from lowered bio-
Moreover, most of the compounds presented in this paper are
more or less closely related to known insecticides like imidacloprid,
thiacloprid, or clothianidin. All these are commercially available
insecticides, essentially similar to the natural (S)-(ꢀ)-nicotine,
and therefore named neonicotinoids (Fig. 1). The synthesis of
the most famous member imidacloprid, that is, (2E)-1-[(6-
chloropyridin-3-yl)methyl]-N-nitroimidazolidin-2-imine),
from
N-(6-chloropyridin-3-yl)methylethylenediamine and 1,1-bis(meth-
ylsulfanyl)-2-nitroethene) was primarily published by Kagabu et al.
in 1992.6
Unlike other crop protection compounds, the neonicotinoids
selectively bind to the nicotinic acetylcholine receptor (nAChR) of
insects, thus inhibiting the regular neuro-transmitting process.
This mode of action is based on the structural similarity of these
compounds to the regular substrate, at least with respect to three
significant aspects: the presence of an electrophilic moiety, espe-
cially a pyridine–nitrogen, and an additional H-bond acceptor, both
located in a distance of about 0.59 nm.7 This allows for the strong
interaction of the neonicotinoids with the nAChR according to the
lock-and-key principle. Interestingly, the selectivity for the nAChR
of insects is mainly caused by the particular chemical substructure
* Corresponding author. Tel.: +49 5323 72 2027; fax: +49 5323 72 2834.
E-mail address: dieter.kaufmann@tu-clausthal.de (D.E. Kaufmann).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.01.001

V. A. Zapol’skii et al. / Bioorg. Med. Chem. 17 (2009) 4206–4215
4207
First Generation
Cl
N
Cl
Cl
Cl
N
N
N
Et
N
H
N
Me
N
Me
N
NH
Me
N
S
NO2
N
NH
N
NO2
CN
Imidacloprid
1991 (Bayer)
Nitenpyram
Acetamiprid
1995 (NipponSoda)
Thiacloprid
2000 (Bayer)
1995 (SumiTake)
Second Generation
Third Generation
N
N
O
N
H
N
H
N
Cl
Cl
O
H
N
H
N
S
S
N
N
Me
Me
Me
N
NO2
N
NO2
NO2
Thiamethoxam
1998 (Syngenta)
Clothianidin
2000 (SumiTake, Bayer)
Dinotefuran
2002 (Mitsui Toatsu)
Figure 1. Neonicotinoids—Insecticides similar to natural nicotine.
of the proton acceptor, which is preferably a nitro-substituted imi-
no or methylene group, or otherwise an N-cyanoimine.8a
material for such neonicotinoids. As a consequence, we focus on
the rare class of cyclic or acyclic nitromethylene derivatives, a sub-
structure that was established in the early 2-nitromethylidene-
1,3-thiazinane insecticide called nithiazine (Shell, 1978) and later
on in the acyclic (E)-N-[(6-chloropyridin-3-yl)methyl]-N-ethyl-N0-
methyl-2-nitroethene-1,1-diamine, that is, the nitenpyram of
SumiTake, 1995 (Fig. 1).
Based on the 3-pyridyl residue within the natural insecticide
nicotine, Bayer CropScience in 1984 developed an insecticidal com-
pound bearing a 6-chloropyridin-3-yl methyl group attached to its
imidazolidine backbone via methylene-spacer (CPM substituent).
Therein, on the one hand, the chlorine atom caused a significant in-
crease of the insecticidal activity, on the other hand the application
properties of this compound were additionally tuned by introduc-
tion of a nitroimino group in 2-position of the saturated bis(hetero)
ring. Thus, as a result of all synthetic efforts, due to increased activ-
ity, reduced photolability, and satisfactory systemic properties in
plants, combined with at least complete degradability, imidaclo-
prid became the most successful insecticide worldwide. The possi-
ble field of application comprises crop protection and related
processes, such as termite control and garden professional care.
In addition, imidacloprid acts as a cat and dog parasiticide.8b
A sulfur-containing cyanoimino analog of the above mentioned
imidacloprid was introduced also by Bayer CropScience in 2000.
Aside from the known CPM functionality it consists of a thiazolidine
ring and therefore was named thiacloprid. It shows improved stabil-
ity, an extremely low vapor pressure and appropriate ecobiological
properties. A recent example of commercially available neonicoti-
noids, structurally associated with our compounds discussed herein,
is the open-chain N-nitroguanidine clothianidin. It was developed
by Takeda Chemical Industries Ltd in 2002. In this novel insecticide
the chloropyridinyl moiety was replaced by a 2-chlorothiazole
group (attached to the well established methylene bridge via the
hetero ring’s 5-position). It is quite stable to hydrolysis, especially
shows a good absorption to soil and rapid distribution in the plant.8c
In general, structural characteristics as well as distinct effective-
ness and therefore high market potential of such neonicotinoids
enforces the quest for promising analogs obtained by various
chemical syntheses both in our group and elsewhere. For example,
de Meijere and co-workers developed interesting spirocyclopropa-
nated analogs of these chloronicotinyl insecticides (CNITM).9 Fur-
thermore, very recently, a pro-drug concept with delayed release
of the active agent in vivo was published by Kagabu’s group apply-
ing a masking group instead of the free proton in 3-position of the
imidazolidine ring within imidacloprid.10
2. Materials and methods
2.1. General methods
All chemicals were purchased from Sigma–Aldrich or Merck and
were used as supplied. Melting points were measured on a Büchi
520 apparatus and were uncorrected. 1H and 13C NMR spectra were
obtained on a BRUKER Avance with 400 MHz proton frequency. 1H
NMR spectra in CDCl3 were referenced to TMS at 0.0 ppm, whereas
13C NMR spectra refer to the solvent signal center at 77.0 ppm. In
case of DMSO-d6, the solvent residual peak were set to 2.50 ppm
(1H) and 39.7 ppm (13C). IR spectra were obtained on a BRUKER
‘Vector 22’ FT IR as film between NaCl plates or as KBr pellet. EI
mass spectra were recorded on a Hewlett Packard—System ‘MS
5989B’ with direct inlet. ESI mass spectra were obtained on a
Hewlett Packard ‘MS LC/MSD Series 1100’. All masses of chlorine
containing molecules or fragments refer to the isotope 35Cl. High-
resolution mass spectra were measured with a Varian MAT 311 A
spectrometer with pre-selected molecular ion peak matching at
R ꢁ 10,000 to be within 2 ppm of the exact masses. TLC was car-
ried out on Merck-plates coated with Silica Gel (60 F 254). Silica
Gel 60 was also used for column chromatography.
2.2. Experimental data
2.2.1. N,N0-Bis[(2-chloro-1,3-thiazol-5-yl)methyl]ethane-1,2-
diamine (6)
A solution of 0.30 g (5.0 mmol) ethane-1,2-diamine in 5 mL of
acetonitrile was added dropwise to
a solution of 1.68 g
(10.0 mmol) 2-chloro-5-(chloromethyl)-1,3-thiazole in 5 mL of
the same solvent within 10 min. After stirring for 6 h at room tem-
perature, 1.38 g (10.0 mmol) potassium carbonate were added and
the mixture was stirred for additional 2 d. Subsequently, the
Our own efforts primarily focus on the application of nitro-
polychloroalkenes, especially butadienes, as versatile starting

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solvent was removed and to the resulting residue a portion of
100 mL water was added. Extraction with chloroform
(3 ꢂ 70 mL), washing of the organic phase with water and drying
over calcium chloride, after evaporation of the solvents afforded
quently, the resulting mixture was kept at ꢀ40 °C for 1 h and at room
temperature for additional 5 h. Then the precipitate was filtered off,
washed with water (3 ꢂ 40 mL), methanol (1 ꢂ 10 mL), and diethyl
ether (2 ꢂ 20 mL). Drying in vacuo yielded 4.88 g (68%) of 14, mp
153–154 °C. lH NMR (DMSO-d6) d = 9.39 (br s, 1H, NH), 7.66 (s, 1H,
CH), 4.65 (s, 2H, CH2), 3.72 (s, 4H, NCH2CH2N). l3C NMR (DMSO-d6)
d = 159.3 (NCN), 150.7 (SCCl), 140.5 (CHN), 135.9 (SCquat.), 125.6,
125.1 (CCl@CCl2), 103.2 (CNO2), 49.8 (CH2Cquat.), 45.5 (NCH2), 42.6
(NHCH2). IR (KBr): 3241, 1589, 1563, 1537, 1429, 1321, 1137,
1045, 949, 842, 717, 640 cmꢀ1. MS: m/z (%) 388 [M+] (3), 353
[M+ꢀCl] (4), 132 [chlorothiazolylmethyl] (100).
l
2.26 g (70%) of diamine 6; mp 27–29 °C. H NMR (CDCl3) d = 7.35
(t, J = 1.0 Hz, 2H, CH), 3.93 (d, J = 1.0 Hz, 4H, Cquat.CH2), 2.75 (s,
4H, NHCH2), 1.80 (br s, 2H, NH). l3C NMR (CDCl3) d = 150.9 (CCl),
141.5 (CS), 137.9 (CH), 48.1 (CH2), 45.8 (Cquat.CH2). IR (KBr):
3306, 2825, 1652, 1537, 1422, 1347, 1046, 849, 744, 592 cmꢀ1
.
MS: m/z (%) 322 [M+] (3), 287 [M+ꢀCl] (3), 161 (38), 132 [chloro-
thiazolylmethyl] (100).
2.2.2. N-[(6-Chloropyridin-3-yl)methyl]-N0-[(2-chloro-1,3-thia-
zol-5-yl)methyl]ethane-1,2-diamine (7)
2.2.7. 2-Chloro-5-{[(2E)-3-methyl-2-(2,3,3-trichloro-1-nitro-
prop-2-en-1-ylidene)imidazolidin-1-yl]methyl}pyridine (15)
Compound 15 was achieved from nitrodiene 10 and diamine 3
in analogy to the preparation of 14. The reaction time was 1 h at
ꢀ40 °C and additional 24 h at room temperature, yield 48%, mp
155–157 °C. lH NMR (DMSO-d6) d = 8.32 (d, J = 2.5 Hz, 1H, CH),
7.76 (dd, J = 2.5, 8.3 Hz, 1H, CH), 7.56 (d, J = 8.3 Hz, 1H, CH), 4.48
(s, 2H, Cquat.CH2), 3.90 (m, 4H, 2 CH2), 2.92 (s, 3H, Me). l3C NMR
(DMSO-d6) d = 162.2 (NCN), 150.0 NCCl), 148.6 (NCH), 138.7 (CH),
130.5 (Cquat.CH2), 126.1 (CCl), 124.5 (CH), 120.1 (CCl2), 98.3
(CNO2), 50.2 (CH2), 49.1 (CH2), 47.7 (CH2), 35.3 (Me). IR (KBr):
3052, 1590, 1524, 1461, 1397, 1313, 1142, 1108, 924, 820, 713,
655 cmꢀ1. MS: m/z (%) 396 [M+] (4), 361 [M+ꢀCl] (19), 126 [chloro-
pyridylmethyl] (100).
The diamine 7 was prepared analogously to bisthiazole 6 in 70%
yield as a highly viscous oil, starting from 2-chloro-5-(chloro-
methyl)-1,3-thiazole, 2-chloro-5-(chloromethyl)pyridine, and eth-
l
ane-1,2-diamine. H NMR (CDCl3) d = 8.32 (dd, J = 2.5, 0.8 Hz, 1H,
Hpy-2), 7.66 (dd, J = 8.2, 2.5 Hz, 1H, Hpy-4), 7.34 (t, J = 1.0 Hz, 1H,
CH), 7.29 (dd, J = 8.2, 0.8 Hz, 1H, Hpy-5), 3.93 (d, J = 1.0 Hz, 2H,
SCquat.CH2), 3.78 (s, 2H, Cpy,quat.CH2), 2.75 (br s, 4H, NHCH2), 2.02
(br s, 2H, NH). l3C NMR (CDCl3) d 150.9 (SCCl), 149.9 (NCCl),
149.1 (N@CH), 141.6 (CS), 138.6 (CH), 137.9 (CH), 134.6, 123.9
(CH), 50.2 (CH2), 48.4 (CH2), 48.2 (CH2), 45.8 (CH2). IR (KBr):
3301, 2826, 1663, 1586, 1536, 1458, 1386, 1047, 819, 740,
593 cmꢀ1. MS: m/z (%) 316 [M+] (8), 281 [M+ꢀCl] (3), 155 (77),
126 [chloropyridylmethyl] (100).
2.2.8. 5,50-{[2-(2,3,3-Trichloro-1-nitroprop-2-en-1-ylidene)imida-
zolidine-1,3-diyl]dimethanediyl}bis(2-chloro-1,3-thiazole) (16)
Preparation analogously to 14 starting from 10 and 6, 60% yield,
mp 174–175 °C. lH NMR (DMSO-d6) d = 7.69 (s, 2H, CH), 4.65 (s, 4H,
Cquat.CH2), 3.82 (s, 4H, NCH2CH2N). l3C NMR (DMSO-d6) d 161.6
(NCN), 151.8 (SCCl), 141.9 (CHN), 133.7 (SCquat.), 125.8, 122.0
(CCl@CCl2), 97.9 (CNO2), 47.2 (CH2Cquat.), 45.2 (2CH2). IR (KBr):
3092, 1575, 1535, 1415, 1309, 1143, 1047, 914, 825, 716,
593 cmꢀ1. MS: m/z (%) 519 [M+] (2), 484 [M+ꢀCl] (4), 132 [chloro-
thiazolylmethyl] (100).
2.2.3. N,N0-Bis[(2-chloro-1,3-thiazol-5-yl)methyl]cyclohexane-
1,2-diamine (8)
Compound 8 was synthesized in analogy to 6 from 2-chloro-5-
(chloromethyl)-1,3-thiazole and a cis/trans mixture of cyclohex-
ane-1,2-diamine in 42% yield; mp 79–80 °C. lH NMR (CDCl3)
d = 7.34 (s, 2H, CH), 3.91 (d, J = 14.4 Hz, 2H, CH2N), 3.79 (d,
J = 14.4 Hz, 2H, CH2N), 2.72 (m, 2H, CHN), 1.70 (br s, 2H, NH),
1.61 (m, 4H), 1.36 (m, 4H). l3C NMR (CDCl3) d = 151.0 (CCl), 142.5
(CS), 137.6 (CH), 55.8 (CH), 43.4 (Cquat.CH2), 27.6 (CHCH2), 22.0
(CH2). IR (KBr): 3319, 2918, 2850, 1662, 1419, 1112, 1051, 1046,
839, 732, 584 cmꢀ1. MS: m/z (%) 376 [M+] (6), 341 [M+ꢀCl] (28),
244 (53), 132 [chlorothiazolylmethyl] (100).
2.2.9. 2-Chloro-5-{[(2E)-3-[(2-chloro-1,3-thiazol-5-yl)methyl]-
2-(2,3,3-trichloro-1-nitroprop-2-en-1-ylidene)imidazolidin-1-
yl]methyl}pyridine (17)
2.2.4. N,N0-Bis[(6-chloropyridin-3-yl)methyl]benzene-1,2-
diamine (9)
Compound 17 prepared as described for compound 14 applying
l
nitrodiene 10 and diamine 7. Yield 70%, mp 175–176 °C. H NMR
Diamine 9 was obtained in analogy to diamine 6 from 2-chloro-
5-(chloromethyl)pyridine and benzene-1,2-diamine in 57% yield,
mp 146–147 °C. H NMR (DMSO-d6) d = 8.44 (dd, J = 2.6, 0.8 Hz,
(DMSO-d6) d = 8.35 (d, J = 2.3 Hz, 1H, CH), 7.78 (dd, J = 8.3, 2.3 Hz,
1H, CH), 7.71 (s, 1H, CH), 7.57 (d, J = 8.3 Hz, 1H, CH), 4.65 (s, 2H,
CH2), 4.54 (s, 2H, CH2), 3.85 (s, 4H, 2 CH2). l3C NMR (DMSO-d6)
d = 162.4 (NCN), 151.9 (SCCl), 148.6 (NpyCH), 142.2 (NthiaCH),
138.8 (CH), 133.8 (SCquat.), 130.0, 125.8 (@CCl), 124.5 (CH), 121.8
(CCl2), 98.0 (CNO2), 49.4 (CH2), 48.1 (CH2), 47.4 (CH2), 45.3 (CH2).
IR (KBr): 2902, 1558, 1533, 1461, 1353, 1326, 1138, 1057, 997,
913, 822, 785, 715, 594 cmꢀ1. MS: m/z (%) 513 [M+] (3), 478
[M+ꢀCl] (5), 132 [chlorothiazolylmethyl] (98), 126 [chloropyr-
idylmethyl] (100).
l
2 ꢂ 1H, Hpy-2), 7.84 (dd, J = 8.1, 2.6 Hz, 2 ꢂ 1H, Hpy-4), 7.47 (dd,
J = 8.1, 0.8 Hz, 2 ꢂ 1H, Hpy-5), 6.45 (m, 4H, Ph), 5.31 (t, J = 4.3 Hz,
2H, NH), 4.34 (d, J = 4.3 Hz, 4H, CH2). l3C NMR (DMSO-d6)
d = 149.3 (CH), 148.8 (CCl), 139.2 (CH), 135.7 (Cquat.), 135.5 (Cquat.),
124.1 (CH), 117.9 (CH, Ph), 110.6 (CH, Ph), 44.0 (CH2). IR (KBr):
3363, 2855, 1586, 1528, 1454, 1384, 1268, 1104, 1026, 815, 738,
588 cmꢀ1. MS: m/z (%) 358 [M+] (30), 232 [M+ꢀchloropyridylmeth-
yl] (100), 126 [chloropyridylmethyl] (42).
2.2.10. 2-Chloro-5-{[(2E)-2-(2,3,3-trichloro-1-nitroprop-2-en-
1-ylidene)-1,3-oxazolidin-3-yl]methyl}pyridine (18)
2.2.5. 2-Chloro-5-{[(2E)-2-(2,3,3-trichloro-1-nitroprop-2-en-1-
ylidene)imidazolidin-1-yl]methyl}pyridine (13)
Compound 18 was obtained in analogy to 14 applying 1 equiv of
nitrodiene 10 and 3 equiv of aminoethanol 4 with 45% yield, mp
156–158 °C. lH NMR (DMSO-d6) d = 8.38 (d, J = 2.3 Hz, 1H, CH),
7.74 (dd, J = 8.2, 2.3 Hz, 1H, CH), 7.39 (d, J = 8.2 Hz, 1H, CH), 4.81
(s, 2H, OCH2), 4.63 (s, 2H, CH2), 3.87 (s, 2H, CH2). l3C NMR (CDCl3)
d = 164.2 (NCN), 150.0 (NCCl), 149.5 (CH), 139.5 (CH), 130.0, 125.1
(@CCl), 124.4 (CH), 124.2 (CCl2), 104.7 (CNO2), 68.8 (OCH2), 51.5
(CH2), 49.8 (CH2). IR (KBr): 3091, 3052, 1611, 1434, 1309, 1127,
1027, 957, 922, 833, 800, 716, 648 cmꢀ1. MS: m/z (%) 383 [M+]
(2), 478 [M+ꢀCl] (3), 126 [chloropyridylmethyl] (100).
Compound 13 was prepared from nitrodiene 10 and diamine 1
according to the literature11 in 47% yield.
2.2.6. 2-Chloro-5-{[(2E)-2-(2,3,3-trichloro-1-nitroprop-2-en-1-
ylidene)imidazolidin-1-yl]methyl}-1,3-thiazole (14)
To a solution of 7.42 g (38.7 mmol) N-[(2-chloro-1,3-thiazol-5-
yl)methyl]ethane-1,2-diamine (2) in 30 mL methanol was added a
solution of 5.00 g (18.4 mmol) 1,1,2,4,4-pentachloro-3-nitrobuta-
1,3-diene (10) in 5 mL methanol at ꢀ40 °C within 10 min. Subse-

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4209
2.2.11. 2-Chloro-5-({(2Z)-2-[chloro(nitro)methylidene]imida
zolidin-1-yl}methyl)pyridine (19)
2.2.16. 2-[(2Z)-3-Chloro-1,3-dinitroprop-2-en-1-ylidene]-1,3-bis
[(6-chloropyridin-3-yl)methyl]-2,3-dihydro-1H-benzimidazole
(24)
Compound19 was prepared fromnitroethylene12 and diamine1
in accordance with the synthesis of 14. Yield 36%, mp 133–135 °C. lH
NMR (DMSO-d6) d = 9.43 (br s , 1H, NH), 8.38 (s, 1H, CH), 7.82 (d,
J = 8.1 Hz, 1H, CH), 7.53 (d, J = 8.1 Hz, 1H, CH), 4.83 (s, 2H, Cquat.CH2),
3.73 (br s, 4H, 2 CH2). l3C NMR (DMSO-d6) d = 158.8 (NCN), 149.5
(NCCl), 148.8 (NCH), 138.7 (CH), 132.2 (Cquat.CH2), 124.4 (CH), 98.2
(CNO2), 51.2 (CH2), 49.9 (CH2), 42.5 (CH2). IR (KBr): 3275, 1566,
1532, 1460, 1363, 1303, 1105, 1027, 952, 835, 734, 590 cmꢀ1. MS:
m/z (%) 288 [M+] (6), 242 [M+ꢀNO2] (5), 206 [M+ꢀNO2ꢀHCl] (20),
126 [chloropyridylmethyl] (32).
The dinitro compound 24 was obtained from diamine
(1.7 equiv) and butadiene 11 in 68% yield as described for imidazoli-
dine 14. Reaction time: 1 h at ꢀ40 °C, then 2 d at room temperature.
9
l
Mp 144–146 °C. H NMR (CDCl3) d = 9.34 (s, 1H, CHCNO2), 8.46 (d,
J = 2.2 Hz, 2H, NCH), 7.60 (m, 4H, Ph), 7.62 (m, 4H), 7.56 (dd, J = 8.3,
2.2 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 5.57 (d, J = 17.0 Hz, 2H, NCH2),
5.43 (d, J = 17.0 Hz, 2H, NCH2). l3C NMR (CDCl3) d = 152.7 (NCCl),
148.9 (CHN), 147.1 (NCN), 138.4 (CH), 130.8, 129.2 (CHCNO2),
128.1 (CH), 127.0, 125.2 (CH), 118.6 (CClNO2), 113.4 (CH), 100.2
(CNO2), 47.6 (CH2). IR (KBr): 3049, 1572, 1473, 1345, 1193, 1099,
997, 919, 729 cmꢀ1. ESI-MS: m/z (%) 555 [M+Na]+ (12).
2.2.12. 2-Chloro-5-({(2Z)-2-[chloro(nitro)methylidene]imida-
zolidin-1-yl}methyl)-1,3-thiazole (20)
The thiazole 20 was synthesized in analogy to 14 from nitroeth-
ylene 12 and diamine 2. Yield 32%, mp 132–134 °C. lH NMR
(DMSO-d6) d = 9.37 (br s , 1H, NH), 7.71 (s, 1H, CH), 4.91 (s, 2H,
Cquat.CH2), 3.73 (m, 4H, 2CH2). l3C NMR (DMSO-d6) d = 158.4
(NCN), 151.3 (SCCl), 141.3 (CH), 136.1 (SCquat.), 98.2 (CNO2), 50.5
(CH2), 45.9 (CH2), 42.4 (CH2). IR (KBr): 3263, 3100, 2894, 1554,
2.2.17. 2-Chloro-5-({(2E)-2-[(2Z)-3-chloro-1,3-dinitroprop-2-
en-1-ylidene]imidazolidin-1-yl}methyl)-1,3-thiazole (25)
The dinitro compound 25 was obtained from diamine 2 and
dinitrobutadiene 11 in 85% yield as described for azole 14. Mp
l
150–152 °C. H NMR (DMSO-d6) d = 10.6 (br s 1H, NH), 8.99 (s,
1H, CHCNO2), 7.68 (s, 1H, NCH), 4.76 (s, 2H, Cquat.CH2), 3.94 (s,
4H, CH2). l3C NMR (DMSO-d6) d = 160.4 (NCN), 151.2 (N@CCl),
142.6 (NCH), 134.0, 129.5 (CHCNO2), 117.4 (CClNO2), 104.9
(CNO2), 48.0 (CH2), 42.8 (CH2), 42.3 (CH2). IR (KBr): 3099, 1709,
1594, 1530, 1489, 1418, 1206, 1111, 1011, 904, 803, 724,
438 cmꢀ1. ESI-MS: m/z (%) 388 [M+Na]+ (11).
1521, 1421, 1332, 1300, 1190, 1053, 959, 876, 737, 665 cmꢀ1
.
MS: m/z (%) 294 [M+] (12), 248 [M+ꢀNO2] (5), 212 [M+ꢀNO2ꢀHCl]
(17), 132 [chlorothiazolylmethyl] (100).
2.2.13. 2-Chloro-5-{[(2E)-2-(nitromethylidene)imidazolidin-1-
yl]methyl}pyridine (21)
A solution containing 0.15 g (1.2 mmol) hydroiodic acid in 2 mL
of acetone was added dropwise to a solution of 0.29 g (1.0 mmol)
imidazolidine 19 in 5 mL acetone at 0 °C. The reaction mixture then
was stirred for 3 h at 0 °C and 1 d at room temperature. After re-
moval of acetone in vacuo, 20 mL of cold water and 2 mL of a
30% sodium dithionite solution was added. Subsequent to one
additional hour with stirring, the mixture was extracted with chlo-
roform (4 ꢂ 20 mL). The combined organic layers were washed
with water and dried over calcium chloride. Finally, purification
by column chromatography yielded 0.12 g (50%) of nitroethylene
21, mp 165–166 °C. NMR, mass spectral, and IR data were in accor-
dance with the literature.11,12c
2.2.18. 5,50-({2-[(2Z)-3-Chloro-1,3-dinitroprop-2-en-1-ylidene]-
imidazolidine-1,3-diyl}dimethanediyl)bis(2-chloro-1,3-
thiazole) (26)
The dinitro compound 26 was obtained from the symmetrical
diamine 6 and diene 11 in 45% yield as described for azole 14.
Mp 161–162 °C. lH NMR (DMSO-d6) d = 9.04 (s, 1H, CHCNO2),
7.66 (s, 2H, NCH), 4.86 (d, J = 15.8 Hz, 2H, Cquat.CH2), 4.76 (d,
J = 15.8 Hz, 2H, Cquat.CH2), 3.97 (s, 4H, CH2). l3C NMR (DMSO-d6)
d = 160.2 (NCN), 151.9 (N@CCl), 142.7 (NCH), 133.4, 129.6
(CHCNO2), 116.9 (CClNO2), 102.4 (CNO2), 46.8 (CH2), 42.8 (CH2).
IR (KBr): 3054, 1583, 1465, 1409, 1343, 1175, 1047, 1008, 966,
799, 594 cmꢀ1. ESI-MS: m/z (%) 519 [M+Na]+ (14).
2.2.14. 1,3-Bis[(2-chloro-1,3-thiazol-5-yl)methyl]-2-(2,3,3-tri-
chloro-1-nitroprop-2-en-1-ylidene)octa-hydro-1H-
benzimidazole (22)
2.2.19. 2-Chloro-5-({(2Z)-2-[(2Z)-3-chloro-1,3-dinitroprop-2-
en-1-ylidene]-3-methylimidazolidin-1-yl}methyl)pyridine (27)
The dinitro compound 27 was obtained from amine 3 and dinit-
rodiene 11 in 70% yield as described for imidazole 14. Mp 186–
188 °C. lH NMR (DMSO-d6) d = 9.03 (s, 1H, CHCNO2), 8.33 (d,
J = 2.0 Hz, 1H, NCH), 7.77 (dd, J = 8.2, 2.0 Hz, 1H), 7.58 (d,
J = 8.2 Hz, 1H), 4.61 (d, J = 15.3 Hz, 1H, Cquat.CH2), 4.48 (d,
J = 15.3 Hz, 1H, Cquat.CH2), 3.96 (m, 4H, 2CH2), 2.96 (s, 3H, Me).
l3C NMR (DMSO-d6) d = 160.7 (NCN), 150.3 (N@CCl), 150.1 (CHN),
140.1 (CH), 129.6, 129.2 (CHCNO2), 124.5 (CH), 116.6(CClNO2),
103.2 (CNO2), 49.3 (CH2), 47.4 (CH2), 46.9 (CH2), 33.9 (CH3). IR
(KBr): 3052, 1608, 1578, 1468, 1390, 1351, 1188, 1014, 976, 801,
449 cmꢀ1. ESI-MS: m/z (%) 396 [M+Na]+ (86).
Preparation analogously to imidazolidine 14 starting from nit-
rodiene 10 and diamine 8. Yield 37%, mp 191–192 °C. lH NMR
(DMSO-d6) d = 7.74 (s, 1H, CH), 4.77 (d, J = 16.5 Hz, 2H, Cquat.CH2),
4.63 (d, J = 16.5 Hz, 2H, NCH2), 4.08 (s, 2H, NCH), 1.74 (m, 4H,
CH2), 1.33 (br s, 4H, CH2). l3C NMR (DMSO-d6) d = 158.6 (NCN),
151.6 (SCCl), 141.7 (CHN), 134.4 (SCquat.), 125.6, 122.3
(CCl@CCl2), 97.7 (CNO2), 57.5 (CH), 42.1 (NCH2), 23.4 (CH2),
19.2 (CH2). IR (KBr): 3104, 2945, 2863, 1666, 1536, 1488,
1418, 1323, 1126, 1049, 935, 828, 593 cmꢀ1. ESI-MS: m/z (%)
596 [M+Na]+ (12).
2.2.15. 1,3-Bis[(6-chloropyridin-3-yl)methyl]-2-(2,3,3-trichloro-
1-nitroprop-2-en-1-ylidene)-2,3-dihydro-1H-benzimidazole (23)
Preparation analogously to imidazolidine 14 starting from
nitrodiene 10 and o-phenylenediamine derivative 9. Yield 75%,
2.2.20. (2E)-2-[(2Z)-3-Chloro-1,3-dinitroprop-2-en-1-ylidene]-
1-[(6-chloropyridin-3-yl)methyl]hexahydro-pyrimidine (28)
The dinitro compound 28 was obtained from diaminopropane 5
and diene 11 in 25% yield as described for azole 14, mp 136–
l
l
mp 202–204 °C. H NMR (DMSO-d6) d = 8.31 (dd, J = 2.2, 0.6 Hz,
138 °C. H NMR (DMSO-d6) d = 10.2 (br s, 1H, NH), 9.01 (s, 1H,
2H, NCH), 7.78 (m, 2H, Ph), 7.62 (m, 4H), 7.52 (dd, J = 8.3,
0.6 Hz, 2H), 5.60 (s, 4H, CH2). l3C NMR (DMSO-d6) d = 150.0
(NCCl), 149.0 (NCN), 148.3 (CH), 138.2 (CH), 131.7, 129.3,
126.7 (CH), 125.5 (CCl), 124.4 (CH), 121.9 (CCl2), 113.3 (CH),
96.8 (CNO2), 47.3 (CH2). IR (KBr): 3034, 1571, 1513, 1466,
1384, 1308, 1187, 1096, 1021, 863, 762 cmꢀ1. ESI-MS: m/z (%)
578 [M+Na]+ (14).
CHCNO2), 8.34 (s, 1H, NCH), 7.76 (d, J = 8.3 Hz, 1H), 7.55 (d,
J = 8.3 Hz, 1H), 4.62 (m, 2H, Cquat.CH2), 3.50 (m, 4H, 2 CH2), 1.98 (m,
2H, CCH2C). l3C NMR (DMSO-d6) d = 155.6 (NCN), 150.3 (CHN),
150.1 (N@CCl), 140.3 (CH), 130.0, 129.0 (CHCNO2), 124.6 (CH),
116.4 (CClNO2), 109.4 (CNO2), 54.2 (CH2), 46.2 (CH2), 45.3 (CH2),
38.8 (CH3). IR (KBr): 3052, 2955, 1628, 1571, 1462, 1351, 1175,
1043, 982, 797, 732, 633 cmꢀ1. ESI-MS: m/z (%) 396 [M+Na]+ (44).

4210
V. A. Zapol’skii et al. / Bioorg. Med. Chem. 17 (2009) 4206–4215
2.2.21. 4-[(3E)-1,1-Dichloro-3-{1-[(6-chloropyridin-3-yl)methyl]
imidazolidin-2-ylidene}-3-nitroprop-1-en-2-yl]morpholine (29)
A solution of 3.84 g (10.0 mmol) of imidazolidine 13 and 4.35 g
(50.0 mmol) of morpholine in 70 mL of methanol was stirred at
50–55 °C for 2 h. After cooling down to 5 °C, the mixture was
diluted with 200 mL of water, then neutralized dropwise with con-
cd hydrochloric acid. The viscous organic product that precipitated
was collected, dissolved in 10 mL of methanol, and stored at
ꢀ18 °C for one night. The obtained solid then was filtered off,
washed with water (3 ꢂ 20 mL) and diethyl ether (2 ꢂ 10 mL)
4H, CH2), 2.20 (s, 3H, CH3). l3C NMR (DMSO-d6) d = 159.9 (NCN),
149.5 (NCCl), 147.9 (CH), 137.9 (CH), 132.5, 131.6, 124.3 (CH),
114.3 (CCl2), 102.4 (CNO2), 50.8 (CH2), 48.9 (CH2), 42.5 (CH2),
14.2 (CH3). IR (KBr): 3314, 2894, 1578, 1550, 1522, 1461, 1297,
1187, 1126, 1041, 954, 842, 721 cmꢀ1. ESI-MS: m/z (%) 395
[M+H]+ (80).
2.2.25. Methyl {[(3E)-1,1-dichloro-3-{1-[(6-chloropyridin-3-yl)
methyl]imidazolidin-2-ylidene}-3-nitroprop-1-en-2-yl]sulfanyl}
acetate (33)
l
and dried in vacuo. Yield 60%, mp 92–94 °C. H NMR (DMSO-d6)
The heterocycle 33 was obtained from methyl 2-mercaptoace-
tate and imidazolidine 13 in analogy to compound 32 in 50% yield,
d = 9.48 (br s, 1H, NH), 8.37 (d, J = 2.2 Hz, 1H, NCH), 7.80 (dd,
J = 8.2, 2.2 Hz, 1H, CH), 7.55 (d, J = 8.2 Hz, 1H, CH), 4.44 (br s, 2H,
Cquat.CH2), 3.70 (s, 4H, 2CH2), 3.58 (s, 4H, OCH2), 3.06 (s, 4H,
NCH2). l3C NMR (DMSO-d6) d = 160.2 (NCN), 149.7 (NCCl), 148.9
(CH), 141.1, 138.8 (CH), 131.3, 124.4 (CH), 103.7, 103.3, 66.5
(OCH2), 50.1 (CH2), 49.9 (CH2), 48.6 (CH2), 42.1 (CH2). IR (KBr):
3421, 3281, 2970, 2842, 1559, 1519, 1459, 1326, 1113, 921, 804,
726, 630 cmꢀ1. HR-ESIMS: m/z [M+H]+ calcd for C16H19Cl3N5O3:
434.05480; found: 434.05474.
l
mp 99–100 °C. H NMR (CDCl3) d = 9.66 (br s, 1H, NH), 8.38 (dd,
J = 2.5, 0.5 Hz, 1H, NCH), 7.71 (dd, J = 8.4, 2.5 Hz, 1H, CH), 7.39
(dd, J = 8.4, 0.5 Hz, 1H, CH), 4.97 (d, J = 16.1 Hz, 1H, Cquat.CH2),
4.47 (d, J = 16.1 Hz, 1H, Cquat.CH2), 3.80 (m, 2H, SCH2), 3.71 (s, 3H,
CH3), 3.58 (m, 4H, CH2). l3C NMR (CDCl3) d 170.4 (CO), 159.7
(NCN), 151.4 (NCCl), 148.7 (CH), 138.1 (CH), 129.8, 128.4, 124.6
(CH), 119.5 (CCl2), 104.5 (CNO2), 52.9 (OMe), 50.4 (CH2), 49.1
(CH2), 41.7 (CH2), 33.6 (SCH2). IR (KBr): 3323, 2903, 1732, 1574,
1547, 1512, 1433, 1294, 1122, 1026, 930, 833, 632 cmꢀ1. MS: m/z
(%) 452 [M+] (2), 417 [M+ꢀCl] (2), 126 [chloropyridylmethyl] (100).
2.2.22. 5-({(2E)-2-[2-(Aziridin-1-yl)-3,3-dichloro-1-nitroprop-
2-en-1-ylidene]imidazolidin-1-yl}methyl)-2-chloropyridine (30)
Chloropyridine 30 was obtained from aziridine and imidazoli-
dine 13 in analogy to compound 29 in 60% yield after column chro-
matography on silica gel (eluent: ethyl acetate). Mp 130–131 °C. lH
NMR (CDCl3) d = 9.60 (br s, 1H, NH), 8.31 (dd, J = 2.5, 0.7 Hz, 1H,
NCH), 7.60 (dd, J = 8.2, 2.5 Hz, 1H, CH), 7.37 (dd, J = 8.2, 0.7 Hz,
1H, CH), 5.14 (d, J = 16.4 Hz, 1H, Cquat.CH2), 4.50 (d, J = 16.4 Hz,
1H, Cquat.CH2), 3.83 (m, 3H, CH2), 3.53 (m, 1H, CH2), 2.37 (m, 2H,
CH2), 2.13 (m, 2H, CH2). l3C NMR (CDCl3) d = 159.2 (NCN), 151.1
(NCCl), 148.4 (CH), 139.3, 137.6 (CH), 130.2, 124.4 (CH), 114.3
(CCl2), 105.8 (CNO2), 50.3 (CH2), 48.7 (CH2), 41.7 (CH2), 29.9
(CH2NCH2). IR (KBr): 3331, 2999, 2971, 1720, 1564, 1523, 1445,
1333, 1122, 1026, 952, 818, 730, 587 cmꢀ1. ESI-MS: m/z (%) 390
[M+H]+ (81).
2.2.26. 5,50-[(2-{3,3-Dichloro-2-[(4-methylphenyl)sulfanyl]-1-
nitroprop-2-en-1-ylidene}imidazolidine-1,3-diyl)dimethane-
diyl]bis(2-chloro-1,3-thiazole) (34)
Imidazolidine 34 was synthesized from 4-methylbenzenethiol
and azole 16 as described for compound 32 in 70% yield, mp
108–110 °C. lH NMR (DMSO-d6) d = 7.62 (s, 2H, NCH), 7.27 (d,
J = 8.3 Hz, 2H, Ph), 7.20 (d, J = 8.3 Hz, 2H, Ph), 4.07 (s, 4H, Cquat.CH2),
3.64 (s, 4H, CH2), 2.27 (s, 3H, CH3). l3C NMR (DMSO-d6) d = 161.8
(NCN), 152.1 (NCCl), 142.3 (CH), 138.2, 133.4, 131.0 (CH, Ph),
130.4 (CH, Ph), 129.3, 128.6, 122.4 (CCl2), 100.1 (CNO2), 46.7
(CH2), 44.1 (CH2), 20.8 (CH3). IR (KBr): 3442, 2920, 1563, 1524,
1415, 1387, 1302, 1127, 1047, 913, 847, 594 cmꢀ1. ESI-MS: m/z
(%) 608 [M+H]+ (78).
2.2.23. (3Z)-1,1-Dichloro-N-[(6-chloropyridin-3-yl)methyl]-3-
{3-[(6-chloropyridin-3-yl)methyl]-1,3-oxazolidin-2-ylidene}-N-
methyl-3-nitroprop-1-en-2-amine (31)
2.2.27. (3E)-1,1-Dichloro-3-{1-[(6-chloropyridin-3-yl)methyl]
imidazolidin-2-ylidene}-3-nitropropan-2-one (35)
The nitropropanone 35 was prepared according to the litera-
The bis(chloropyridinyl) derivative 31 was obtained from amine
18 in analogy to compound 29 and was pure after initial precipita-
tion, 80% yield, mp 57–58 °C. lH NMR (CDCl3) d = 8.38 (d, J = 2.4 Hz,
1H, NCH), 8.33 (d, J = 2.4 Hz, 1H, NCH), 7.71 (m, 2H, CH), 7.35 (d,
J = 8.3 Hz, 1H, CH), 7.27 (d, J = 8.3 Hz, 1H, CH), 4.80 (m, 2H,
OCH2), 4.55 (m, 2H, CH2), 4.13 (s, 2H, CH2), 3.88 (m, 2H, CH2),
2.70 (s, 3H, CH3). l3C NMR (CDCl3) d = 166.1 (NCN), 152.3 (NCCl),
149.9 (NCCl), 149.6 (CH), 149.1 (CH), 140.6, 139.2 (CH), 138.6
(CH), 133.9, 128.1, 124.9 (CH), 123.9 (CH), 110.2 (CCl2), 106.3
(CNO2), 66.9 (OCH2), 55.6 (CH2), 50.3 (CH2), 49.5 (CH2), 40.2
(CH3). IR (KBr): 2896, 1587, 1566, 1460, 1304, 1261, 1103, 1024,
913, 816, 633 cmꢀ1. ESI-MS: m/z (%) 504 [M+H]+ (8).
ture.11 All spectroscopic data were found as expected.
2.2.28. (3E)-1,1-Dichloro-3-{1-[(2-chloro-1,3-thiazol-5-yl)methyl]
imidazolidin-2-ylidene}-3-nitropropan-2-one (36)
The nitropropan-2-one 36 was obtained from imidazolidine 14
in an analogous manner as described for compound 35 in 58%
yield. Mp 148–149 °C. lH NMR (DMSO-d6) d = 10.30 (br s, 1H,
NH), 7.65 (s, 1H, NCH), 7.49 (s, 1H, CHCl2), 4.64 (s, 2H, Cquat.CH2),
3.87 (s, 4H, CH2). l3C NMR (DMSO-d6) d = 175.4 (CO), 161.9
(NCN), 152.1 (NCCl), 142.5 (CH), 134.1, 107.6 (CNO2), 69.6 (CHCl2),
42.8 (CH2), 42.2 (CH2). IR (KBr): 3262, 1610, 1577, 1457, 1415,
1313, 1284, 1055, 1022, 827, 767, 677 cmꢀ1. MS: m/z (%) 370
[M+] (3), 132 [chlorothiazolylmethyl] (100).
2.2.24. 2-Chloro-5-({(2E)-2-[3,3-dichloro-2-(methylsulfanyl)-1-
nitroprop-2-en-1-ylidene]imidazolidin-1-yl}methyl)pyridine
(32)
2.2.29. (3E)-1,1-Dichloro-3-{1-[(6-chloropyridin-3-yl)methyl]
imidazolidin-2-ylidene}-1,3-dinitropropan-2-one (37)
A solution of 380 mg (1.0 mmol) imidazolidine 13 and 77 mg
(1.1 mmol) of sodium methanethiolate in 3 mL of methanol was
stirred for 1 h at room temperature and additional 3 h at 40 °C.
Subsequently, 30 mL of water were added at 5 °C and the mixture
then was neutralized dropwise with concd hydrochloric acid. The
resulting precipitate was filtered off and washed with water
(3 ꢂ 20 mL). Finally, drying in vacuo yielded 320 mg (80%) of sul-
At ꢀ10 °C were added 0.77 g (2.0 mmol) imidazolidine 13 to
10 mL of fuming nitric acid within 5 min. The reaction mixture
then was stirred for 1 h at 0 °C and additional 4 h at room tem-
perature. After pouring onto 100 mL of ice-water, the resulting
precipitate was filtered off and washed with water (3 ꢂ 20 mL).
The crude product was dissolved in 50 mL of chloroform and
dried over anhydrous calcium chloride. After removal of the sol-
vent, subsequent column chromatography with an appropriate
chloroform/acetone gradient, and drying in vacuo 0.25 g (30%)
l
fide 32, mp 84–86 °C. H NMR (DMSO-d6) d = 9.56 (br s, 1H, NH),
8.32 (d, J = 2.3 Hz, 1H, NCH), 7.74 (dd, J = 8.2, 2.3 Hz, 1H, CH),
7.53 (d, J = 8.2 Hz, 1H, CH), 4.54 (br s, 2H, Cquat.CH2), 3.74 (br s,
l
of dinitropropanone 37 were obtained. Mp 109–111 °C. H NMR

V. A. Zapol’skii et al. / Bioorg. Med. Chem. 17 (2009) 4206–4215
4211
(DMSO-d6) d = 10.61 (br s, 1H, NH), 8.33 (d, J = 1.8 Hz, 1H, NCH),
7.74 (dd, J = 8.2, 1.8 Hz, 1H, CH), 7.58 (d, J = 8.2 Hz, 1H, CH), 4.45
(s, 2H, Cquat.CH2), 3.92 (s, 4H,
490 cmꢀ1 HR-ESIMS: m/z [M+H]+ calcd for C22H15Cl4N6O5:
.
582.98525; found: 582.98530.
2
CH2). l3C NMR (DMSO-d6)
d = 167.4 (CO), 161.5 (NCN), 150.4 (NCCl), 149.9 (CH), 139.8
(CH), 129.6, 124.7 (CH), 109.6 (@CNO2), 105.3 (CCl2NO2), 48.0
(CH2), 46.6 (CH2), 43.0 (CH2). IR (KBr): 3052, 2892, 1623, 1583,
1450, 1346, 1323, 1148, 1032, 906, 804, 657, 488 cmꢀ1. HR-
ESIMS: m/z [M+H]+ calcd for C12H11Cl3N5O5: 409.98203; found:
409.98234.
3. Results and discussion
The condensation reaction of the commercially available 2-
chloro-5-chloromethylpyridine or 2-chloro-5-(chloromethyl)-1,3-
thiazole with 1,2-diaminoethane, N-methyl-1,2-diaminoethane,
2-aminoethanol, or 1,3-diaminopropane, respectively, in each case
leads to the formation of bifunctional nucleophiles 1–5,12 which
are suitable for hetero ring formation with nitro-substituted poly-
chlorobuta-1,3-dienes (Fig. 2).
As in the above mentioned potpourri of known bisnucleophiles
a bis(chlorothiazolyl) and a mixed chloropyridyl/chlorothiazolyl
derivative both are missing, we synthesized compound 6 and 7,
each in 70% yield upon treatment of ethylenediamine with the cor-
responding chloromethylated hetero ring. Furthermore, structur-
ally and electronically we varied the C2-backbone, from ethane to
the more rigid cyclohexane and finally to an aromatic ring. The
subsequent reaction of each of these bisnucleophiles with 2 equiv
of 2-chloro-5-(chloromethyl)-1,3-thiazole in case of diaminocyclo-
hexane, or with 2-chloro-5-chloromethylpyridine in case of o-phe-
nylendiamine, gave the complex bisnucleophiles 8 and 9 in 42%
and 57%, respectively (Scheme 1).
2.2.30. (3Z)-1,1-Dichloro-3-{1-[(6-chloropyridin-3-yl)methyl]-
3-[(2-chloro-1,3-thiazol-5-yl)methyl]imidazolidin-2-ylidene}-
1,3-dinitropropan-2-one (38)
Preparation analogously to dinitropropanone 37 starting from
imidazolidine 17 and concd nitric acid. Yield 45%, mp 174–
l
175 °C. H NMR (CDCl3) d = 8.35 (s, 1H, NCH), 7.64 (d, J = 7.7 Hz,
1H, CH), 7.54 (s, 1H, SCquat.CH), 7.40 (d, J = 7.7 Hz, 1H, CH), 4.72
(s, 2H, CH2), 4.55 (s, 2H, CH2), 3.96 (s, 4H, 2 CH2). l3C NMR (CDCl3)
d 168.9 (CO), 162.2 (NCN), 154.8 (SCCl), 152.4 (NCCl), 149.8 (CH),
142.7 (CH), 139.5 (CH), 131.2, 127.0, 125.2 (CH), 108.7 (@CNO2),
103.3 (CCl2NO2), 48.6 (CH2), 46.5 (CH2), 46.2 (CH2), 43.7 (CH2). IR
(KBr): 2939, 1586, 1567, 1452, 1332, 1296, 1143, 1046, 900, 802,
769, 649, 489 cmꢀ1
.
HR-ESIMS: m/z [M+H]+ calcd for
C16H13Cl4N6O5S: 540.94168; found: 540.94164.
2.2.31. 1-{1,3-Bis[(6-chloropyridin-3-yl)methyl]-1,3-dihydro-
2H-benzimidazol-2-ylidene}-3,3-dichloro-1-nitropropan-2-one
(39)
3.1. Synthesis of imidacloprid analogs
The chloronitroalkenes 10–121 allowed for a twofold vinylic
substitution (addition–elimination pathway) of the chlorine atoms
in the dichloromethylene group, and in the case of nitroethylene
12 the one adjacent to the nitro group (Fig. 3).
As expected, applying the pentachlorobutadiene 10 as the elec-
trophilic substrate for the bifunctional nucleophiles 1–3, 6, 7, and
4, the imidazolidines 13–17 and the oxazolidine 18, respectively,
were obtained with up to 70% yield (Scheme 2).
Due to distinct intramolecular hydrogen bonding of the N–H,
the neonicotinoids 13 and 14 were found as their E-isomers. How-
ever, an unambiguous assignment of the configuration in the ally-
lidene derivatives 15–18 must await X-ray analyses. Nevertheless,
the above mentioned compounds with a free NH proton also occur
as single isomers. Interestingly, the N-substituted derivatives 15–
17 as well as the oxazolidine 18 receive an additional stabilization
caused by mesomeric structures, that is, the corresponding nitronic
acids (Fig. 4).
As assumed above, the reaction of nitroethylene 12 with 2-
chloro-5-(chloromethyl)pyridine or 2-chloro-5-(chloromethyl)thi-
azole is less selective than the corresponding conversion of the
perhalogenated nitrobutadiene 10. Therefore, the imidazolidines
19,20 were prepared in only 36% and 32% yield, but interestingly,
pure Z-isomers were found. Furthermore, with the chloropyridyl-
methyl-substituted imidazolidine 19 in hand we tried to selectively
remove the chlorine atom within the chloro(nitro)methylidene
group. Due to the unusual electron distribution there, selective
A suspension of 0.56 g (1.0 mmol) of benzimidazolidine 23 in a
mixture of 10 mL dimethylsulfoxide and 1 mL of water was stirred
at 100–105 °C for 3 h. Cooling down to room temperature and mixing
upwithice-water(100 mL)affordedaprecipitatethat wasfilteredoff,
then washed with water (3 ꢂ 20 mL) and diethyl ether (2 ꢂ 10 mL).
After drying in vacuo, 0.43 g of mono-nitro compound 39 was
obtained (80% yield), mp 192–194 °C. lH NMR (DMSO-d6) d = 8.40 (s,
2H, NCH), 7.97 (m, 2H), 7.69 (s, 2H), 7.65 (s, 2H), 7.53 (s, 2H), 7.49 (s,
1H, CHCl2), 5.68 (s, 4H, CH2). l3C NMR (DMSO-d6) d = 176.9 (CO), 150.5
(NCCl), 149.4 (CH), 147.8 (NCN), 139.3 (CH), 130.8, 129.6, 127.5 (CH),
124.7 (CH), 114.3(CH), 106.0(CNO2), 69.9(CHCl2), 46.3(CH2). IR(KBr)
: 3049, 1609, 1589, 1527, 1470, 1319, 1108, 1025, 945, 815, 730,
631 cmꢀ1. ESI-MS: m/z (%) 560 [M+Na]+ (7).
2.2.32. 3-{1,3-Bis[(6-chloropyridin-3-yl)methyl]-1,3-dihydro-
2H-benzimidazol-2-ylidene}-1,1-dichloro-1,3-dinitropropan-2-
one (40)
Synthesis in analogy to benzimidazoline 37 starting from com-
pound 23 and concd nitric acid. Yield 50%, mp 196–198 °C. lH NMR
(CDCl3) d = 8.44 (d, J = 2.3 Hz, 2H, NCH), 7.60 (m, 4H, CH), 7.55 (dd,
J = 8.4, 2.3 Hz, 2H, CH), 7.30 (d, J = 8.4 Hz, 2H, CH), 5.53 (s, 4H, CH2).
l3C NMR (CDCl3) d 169.9 (CO), 152.2 (NCN), 148.7 (CH), 147.3 (NCCl),
138.2 (CH), 130.8, 127.8 (CH), 127.4 (CH), 125.0 (CH), 113.6 (CH),
108.8 (@CNO2), 103.3 (CCl2NO2), 47.3 (CH2). IR (KBr): 3049, 1622,
1578, 1505, 1464, 1337, 1105, 1024, 909, 837, 751, 650, 565,
H
NH2
N
NH2
S
N
N
H
N
N
H
N
H
Cl
N
Cl
Cl
3
1
2
OH
N
N
H
NH2
N
N
H
Cl
Cl
5
4
Figure 2. Known bifunctional nucleophiles 1–5, suitable for the conversion of nitro-substituted polychlorobuta-1,3-dienes.

4212
V. A. Zapol’skii et al. / Bioorg. Med. Chem. 17 (2009) 4206–4215
N
NH2
H2N
H
N
S
Cl
Cl
Cl
S
2 eq. Cl
S
N
H
Cl
N
N
6
(70%)
N
NH2
H2N
H
N
S
N
Cl
Cl
Cl
+
S
N
N
H
N
Cl
Cl
7 (70%)
NH2
NH2
N
H
N
Cl
Cl
S
S
Cl
2 eq. Cl
S
N
N
H
N
8 (42%)
NH2
NH2
N
N
Cl
Cl
H
N
N
Cl
2 eq.
Cl
N
H
9 (57%)
Scheme 1. Synthesis of novel diamines 6–9.
O2N
Cl
Cl
O2N
Cl
Cl
Cl
hetaryl
hetaryl
O2N
Cl
Cl
Cl
N
N
X
N
Cl
Cl
H
O
O
Cl
Cl
Cl
Cl
O2N
Cl
10
N
O
N
O
11
12
X = NR or O,
R = H
Cl
Cl
Figure 3. Nitropolychloroalkenes as versatile starting material for insecticidal
compounds.
13 14
,
15 18
-
hydrogen bonding
mesomeric nitronic acid
Y
Figure 4. Stabilizing effects in different imidacloprid analogs.
X
N
10
Cl
Cl
1-4, 6, 7
O2N
yl)methyl)imidazolidin-2-ylidene)-3-nitropropan-2-one by means
of sodium borohydride that also leads to 21 as we reported re-
cently.11 Fortunately, this imidazolidine 21, as expected for such
Cl
13 - 18
a
structural member of the neonicotinoids, indeed shows
13
(X = NH,
Y = 6-chloropyridin-3-yl, 47%)
Y = 2-chlorothiazol-5-yl, 68%)
Y = 6-chloropyridin-3-yl, 48%)
remarkable insecticidal activity.14
14 (X = NH,
15
Moreover, the reaction of N,N0-bis[(2-chloro-1,3-thiazol-5-
yl)methyl]cyclohexane-1,2-diamine (8) with the perchlorinated
nitrobuta-1,3-diene 10 produces the partially symmetric octahy-
drobenzimidazole 22 in only 37% yield. But, the similar reaction
of 10 and additionally of dinitrodiene 11 with the less reactive
(X = NMe,
16 (X = N-[(2-chlorothiazol-5-yl)methyl], Y = 2-chlorothiazol-5-yl, 60%)
17
18
(X = N-[(6-chloropyridin-3-yl)methyl], Y = 2-chlorothiazol-5-yl, 70%)
(X = O, Y = 6-chloropyridin-3-yl, 45%)
aromatic diamine
9 gives in good yields (75% and 68%)
the 2,3-dihydro-1H-benzimidazoles 23 and 24, respectively
(Scheme 4).
Scheme 2. Synthesis of neonicotinoids similar to imidacloprid.
Subsequently, a variety of allylidene-substituted neonicotinoids
were synthesized from dinitrodiene 11 and the bifunctional
nucleophiles mentioned above. Thus, with the mono-substituted
ethylene-1,2-diamines 2,3,6 or with N-[(6-chloropyridin-3-
yl)methyl]propane-1,3-diamine (5) under mild conditions the 3-
chloro-1,3-dinitroallylidene functionalized imidazolidines 25–27 and
the hexahydropyrimidine 28 were achieved. It is well documented that
also such hexahydropyrimidines exhibit remarkable insecticidal
activity.12e,15
reduction is quite a challenge, although some similar examples are
given in the literature.13 In our case, applying hydroiodic acid in ace-
tone at 0–5 °C afforded the nitromethylidene group, hence com-
pound 21, in 50% yield (Scheme 3).
In this context it is worthy to note, that the latter described
synthetic pathway can serve as a substitute for the classical
reduction
of
(E)-1,1-dichloro-3-(1-((6-chloropyridin-3-

V. A. Zapol’skii et al. / Bioorg. Med. Chem. 17 (2009) 4206–4215
4213
O2N
Cl
Cl
Cl
X
X
HI, acetone
12
HN
N
HN
N
H
1 2
,
O2N
Cl
O2N
19 (X = 6-chloropyridin-3-yl, 36%)
20 (X = 2-chlorothiazol-5-yl, 32%)
21 (X = 6-chloropyridin-3-yl, 50%)
Scheme 3. Formation of heterocycles and subsequent protodechlorination of the chloro(nitro)methylidene moiety.
Cl
N
Cl
S
S
O2N
Cl
N
Cl
Cl
N
N
Cl + 8
Cl
10
Cl
Cl
O2N
Cl
22 (37%)
Cl
Cl
N
N
O2N
Cl
N
N
R
Cl
10
or
+ 9
Cl
O2N
O2N
11
Cl
(R =
Cl
Cl
23
, 75%)
, 68%)
H
NO2
Cl
24 (R =
Scheme 4. Synthesis of octahydro- and dihydrobenzimidazoles.
Regrettably, dinitro derivative 28 was isolated in only moderate
yield; however, the imidazolidines 25–27 were obtained with up
to 85% yield (Scheme 5).
as the leaving group on nucleophilic attack. In this manner, the
reaction of a morpholine nitrogen or an aziridine in the case of
13 as the substrate, or otherwise the choice of (chloropyridinylm-
ethyl)methylamine in case of 18 as the allylidene compound led to
the amino-substituted imidacloprid analogs 29–31 in good yields
(Scheme 6). No side products were found, that is, the terminal
dichloro moiety was left unchanged. Expectedly, due to a less acti-
vation of this trichlorovinyl group by the nitro substituent, com-
3.2. Subsequent chemistry of novel imidacloprid analogs
3.2.1. Substitution reactions with N- and S-nucleophiles
Even though the initial products of the hetero-ring formation
that was discussed above are structurally and physiologically
interesting neonicotinoids, the introduced trichlorovinyl group
provides an opportunity for further synthetic transformations.
Even though both types of chloro positions should in principle be
able to react, the geminal as well as the CCl group, in our case,
the inner chloro substituent within the allylidene group served
pared to its effect on a a-nitrodichlorovinyl group, more vigorous
conditions (i.e., refluxing methanol) were required. The formation
of such dichlorovinylamines is quite rare in literature.4b,16
Analogously, applying thiols instead of amines, the dichlorovi-
nyl sulfides 32–34 are accessible in comparable chemical yields.
Similar transformations of more simple trichlorovinyl derivatives
Y
n
N
X
N
Y
O2N
Cl
Cl
RR'NH
N
X
2 3 5 6
, , ,
13 18
,
Cl
NRR'
Cl
O2N
O2N
O2N
Cl
29 31
11
Cl
25 28
NO2
-
-
29
30
31
(R, R' = -(CH2)2O(CH2)2- ,
(R, R' = -(CH2)2- ,
X = NH, 60%)
X = NH, 60%)
X = O, 80%)
25
(n=1, X = H, Y = 2-chlorothiazol-5-yl, 85%)
26 (n=1, X = Y = 2-chlorothiazol-5-yl, 45%)
27 (n=1, X = Me, Y = 6-chloropyridin-3-yl, 70%)
28
(R = Me, R' = (6-chloropyridin-3-yl)methyl,
(n=2, X = H, Y = 6-chloropyridin-3-yl, 25%)
Y = 6-chloropyridin-3-yl
Scheme 6. Neonicotinoids with amino-substituted allylidene moiety.
Scheme 5. Reaction of dinitrodiene 11 with bifunctional nucleophiles.

4214
V. A. Zapol’skii et al. / Bioorg. Med. Chem. 17 (2009) 4206–4215
Y
N
N
X
RSH
X
X
13 16
,
N
N
SR
Cl
DMSO, H2O
O2N
O
O2N
Cl
32 34
Cl
Cl
-
39
X
X
32 (R = Me,
X = H, Y = 6-chloropyridin-3-yl, 80%)
X = H, Y = 6-chloropyridin-3-yl, 50%)
N
N
33 (R = CH2CO2Me,
34 (R = p-tolyl,
Cl
Cl
X =
Y = 2-chlorothiazol-5-yl, 70%)
O2N
Cl
Scheme 7. Neonicotinoids with terminal dichloromethylene sulfanyl group.
23
X
X
N
N
HNO3
to the corresponding dichlorovinyl sulfides have been published
(Scheme 7).17
O
O2N
Cl
Cl
NO2
3.2.2. Formation of dichloromethylcarboxy and dichloro(nitro)
methylcarboxy units
X = 6-chloropyridin-3-yl
40
To introduce a completely different and also widely applicable
functional group, we subjected the trichlorovinyl compounds 13
and 14 to a methanolic solution of dimethylamine (fourfold
excess). As the amine attacked the tertiary CCl-position of this moi-
ety, enamines were formed as intermediates. These, upon reaction
with hydrochloric acid then gave the corresponding enols. Subse-
quently, tautomerization led to the dichloromethylketones 35
and 36 with 60% and 58% yield, respectively. The structure of the
latter compounds had been confirmed by an X-ray analysis as pub-
lished before.11
The additional reaction of imidazolidine 13 with fuming nitric
acid at room temperature gave the 1,3-dinitropropan-2-one 37.
We assume, that initially in this process the trichlorovinylic group
within 13 analogously to the formation of 35 and 36 is hydrolyzed
to the dichloromethylcarbonyl fragment. Then, nitration takes
place to yield the nitrodichloromethyl unit. Due to these harsh
conditions a low yield (30%) is obtained, with water soluble, acidic
C1- and C2-fragments as evidenced during work-up. Similar trans-
formations of a trihalovinylic group to nitrodihalomethylcarbonyl
fragment are rare in literature. The few cases which are described
Scheme 9. Ketone synthesis from benzo-annelated neonicotinoids.
comprise quite unselective chemical reactions.18 Nevertheless,
applying nitric acid to imidazolidine 17 we obtained the 1,3-dini-
tropropan-2-one 38 in 45% yield (Scheme 8).
In the case of the benzimidazoline 23, the described ketone for-
mation was effective by means of aqueous dimethylsulfoxide at
100 °C. Thus, the dichloromethylcarboxy compound 39 was
obtained in 80% yield. The same benzo-annelated substrate affor-
ded the interesting dinitropropanone 40 with 50% yield upon treat-
ment with nitric acid (Scheme 9).
4. Conclusion
In conclusion, a number of new neonicotinoidshave been synthe-
sized by twofold SNVin reactions of nitropolychlorobutadienes with
bioactive heterocycles, carrying bisnucleophile-sidechains with a
structurally and electronically varied C2-backbone. Additionally,
due to the stepped reactivity of the introduced nitropolychlorobut-
adienes, the primary substitution products prepare the ground for
subsequent synthetic steps towards reduced compounds, enamines,
ketones, vinyl thioethers and dichloronitro compounds. Most of the
described neonicotinoids were tested against some agronomical
importantpests. Especiallycompound13and29werebroadlyactive
against aphids like green peach aphid Myzus persicae and cotton
aphid Aphis gossypii in foliar and soil application. Additional efficacy
against cotton whitefly Bemisia tabaci and mustard beetle Phaedon
cochleariae was observed with 29. The latter compound showed also
a moderate-to-good efficacy against cat fleas Ctenocephalides felis,
houseflies Musca domestica and blowfly larvae Lucilia cuprina with
concentrations of 100 ppm.14d
Y
N
N
H
1. HNMe2, MeOH
2. HCl, MeOH, H2O
O
13, 14
O2N
Cl
35 36
Cl
,
35: Y = 6-chloropyridin-3-yl, 60%
36: Y = 2-chlorothiazol-5-yl, 58%
References and notes
Y
N
N
X
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