Design and synthesis of heterocyclic enamine derivatives based on skeleton of neonicotinoids

Article abstract of DOI:10.1515/hc-2012-0048

Novel heterocyclic enamine derivatives based on skeleton of neonicotinoids were designed and prepar ed by the substitution reaction between heterocyclic enamines with intermediates of neonicotinoids, which provides readily accessible neonicotinoid analogs

Full text of DOI:10.1515/hc-2012-0048

DOI 10.1515/hc-2012-0048ꢀ
ꢀHeterocycl. Commun. 2012; 18(3): 113–116
Preliminary Communication
Chuanxiang Liu*, Fengping Yi* and Jianzhong Zou
Design and synthesis of heterocyclic enamine
derivatives based on skeleton of neonicotinoids
Abstract: Novel heterocyclic enamine derivatives based on mild condition. The heterocyclic enamines with an elec-
skeleton of neonicotinoids were designed and prepared tron-withdrawing group such as pyridazinone, meldrum’s
by the substitution reaction between heterocyclic enam- acid and pyrazole substituted with a nitrile group were
ines with intermediates of neonicotinoids, which provides
readily accessible neonicotinoid analogs for potential bio-
activity assay.
introduced into the skeleton of neonicotinoid (Samaritoni
et al., 2003). New neonicotinoid derivates T3–T6 were
designed and synthesized by using these intermediate
products. We are currently studying the potential bioac-
tivity of the synthesized compounds.
Keywords: heterocyclic enamines; neonicotinoids; syn-
thesis.
*Corresponding authors: Chuanxiang Liu and Fengping Yi, School
of Chemical and Environmental Engineering, Shanghai Institute of
Technology, Shanghai 201418, China; and School of Perfume and
Aroma Technology, Shanghai Institute of Technology, Shanghai
201418, China, e-mail: cxliu@sit.edu.cn; yifengping@sit.edu.cn
Jianzhong Zou: School of Perfume and Aroma Technology, Shanghai
Institute of Technology, Shanghai 201418, China
Experimental section
Commercial reagents 1, 3, 4, 9–11 were used without further puri-
fication. Solvents were treated prior to use according to standard
methods. Compounds 7 and 8 were prepared as previously reported
(Moury, 1953; Cheikh et al., 1991). Melting points were taken on a
micro-melting point apparatus made in Beijing and were uncorrect-
ed. 1H NMR spectra were recorded on a Bruker WP-500SY (400 MHz)
spectrometer with CDCl3 as the solvent and TMS as the internal stand-
ard. Infrared spectra were measured on KBr disks using a Nicolet FT-
IR-20SX instrument. High resolution mass spectra were obtained on
a MicroMass GCT CA 055 spectrometer. Analytical thin layer chroma-
tography (TLC) was carried out on precoated plates (silica gel 60F254),
and spots were visualized with ultraviolet light.
The design and synthesis of novel neonicotinoids (Jepson
et al., 2006; Kagabu et al., 2007) for crop protection and pet
hygiene have received considerable attention in pesticide
chemistry because neonicotinoids have taken the main
share of the insecticidal market (in 2009, $2.632 billion
USD) and have been used for insect control worldwide
(Ohno et al., 2009; Jeschke et al., 2011).
3,4-Diethoxycyclobut-3-ene-1,2-dione (2)ꢀA mixture of squaric
acid (1.25 g, 0.01 mol), ethanol (50 mL), and benzene (20 mL) was
heated under reflux for 10 h, and then concentrated to afford crude
compound 2 as an oil (Zhou et al., 2001) (yield 1.27 g, 75%); GC-MS:
m/z 170 [M]+, 142, 113, 85, 68, 58, 29.
Compared to organophosphorus, carbamate, and
pyrethroid compounds, the lead compound imidacloprid
as the fourth generation of insecticide has attracted great
attention for searching novel neonicotinoid analogs. Many
groups have reported the results on synthesis of imidaclo-
prid derivatives and their potential modes of biological
action (Wang et al., 2007; Shao et al., 2011). In this commu-
nication, we report a novel design and synthetic method for
neonicotinoid derivatives through reactions of heterocyclic
enamines with neonicotinoids intermediates (Figure 1).
The detailed synthesis routes are shown in Schemes 1
and 2. The squaric acid motif was introduced into neoni-
cotinoid through bioisosteres replacement of nitro guani-
dine (Butera et al., 2000), and the target compounds T1
and T2 with chloropyridine and chlorothiazol fragment
N1-((6-Chloropyridin-3-yl)methyl)ethane-1,2-diamineꢀ(5)ꢀA
solution of ethane-1,2-diamine (6.06 g, 100 mmol) in acetonitrile
(30 mL) was dropwise added over a period of 30 min to a solution of
2-chloro-5-(chloromethyl)pyridine (3) (3.24 g, 20 mmol) in 30 mL of
acetonitrile. After 8 h of stirring, the solution was treated with 100
mL of water, and extracted with chloroform (3ꢁ×ꢁ30 mL). The organic
layer was dried over Na2SO4 and concentrated to afford compound 5
as a yellow liquid (Kagabu et al., 1992), which was directly used in the
next step (yield 3.34 g, 90%); GC-MS: m/z 185 [M]+, 155, 126, 99, 90.
N1-((2-Chlorothiazol-4-yl)methyl)ethane-1,2-diamineꢀ(6)ꢀA
mixture of ethane-1,2-diamine (6.25 mL, 75 mmol) and K2CO3 (2.07 g,
0.015 mol) was cooled to 0°C and dropwise added over a period of
30 min to a solution of 2-chloro-4-(chloromethyl)thiazole (4) (2.50 g,
were designed and synthesized with high yields under 15 mmol) in 30 mL of acetonitrile. After 8 h of stirring, the solution

114ꢀ
ꢀC. Liu et al.: Design and synthesis of heterocyclic enamine derivatives
HN
Me
O
Het
NH
N
H
N
O
Me
O
O
T1: Het = 6-chloropyridin-3-yl
T2:
Het = 2-chlorothiazol-4-yl
Me
H
NH
Cl
N
Me Me
HN NH
Me
HN
O
N
N
N
O
N
tBu
O
N
N
O
T3
T4
N
N
tBu
Me Me
HN
Cl
NH
N
HN
O
N
O
Cl
O
O
HN
O
N
N
O
O
Me Me
N
O
O
N
Imidacloprid
Me Me
O
F3C
F3C
Cl
NH
Cl
Cl
H
Cl
HN
N
N
N
Het
N
N
N
N
O
N
N
O
N
T5: Het = furan-2-yl
T6:
Het = 6-chloropyridin-3-yl
Figure 1ꢁThe designed target compounds T1–T6.
was treated with 100 mL of water, and the mixture was extracted with ethane-1,2-diamine (5) (0.185 g, 1 mmol) in 20 mL of ethanol was
chloroform (3ꢁ×ꢁ30 mL). The organic layer was dried over Na2SO4 and heated under reflux for 6 h. The solution was concentrated and the
concentrated to afford compound 6 as a yellow liquid, which was residue was purified by silica gel chromatography to afford T1 as a
directly used in the next step (yield 1.95 g, 68%); GC-MS: m/z 191 [M]+,
155, 126, 73, 56.
white solid (yield 0.16 g, 60%); mp 177.7–178.4°C; IR (KBr): ν 3200,
2940, 1784, 1665, 1053, 693 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.29 (t,
J ꢂ=ꢂ 5 Hz, 2H, CH2), 3.60 (t, J ꢂ=ꢂ 5 Hz, 2H, CH2), 4.67 (s, 2H, CH2), 6.98 (s,
( E)-1-(2,6-Dichloro-4-(trifluoromethyl)phenyl)-5-(furan- 1H, NH), 7.38 (d, J ꢂ=ꢂ 8 Hz, 1H, pyridine-H), 7.73 (dd, J1 ꢂ=ꢂ 2 Hz, J2 ꢂ=ꢂ 8
2-ylmethyleneamino)-1H-pyrazole-3-carbonitrile (12)ꢀA solution Hz, 1H, pyridine-H), 8.36 (d, J ꢂ=ꢂ 3 Hz, 1H, pyridine-H); EIMS: m/z 263
of
5-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-
[M]+ (28), 234 (37), 219 (44), 206 (100), 172 (33), 126 (50), 98 (21), 90
3-carbonitrile (9) (3.20 g, 0.01 mol), furan-2-carbaldehyde (10) (1.44 g, (26), 72 (22), 63 (17), 56 (16), 53 (14); HRMS: Calcd for C22H14N5F3Cl2 m/z
0.015 mol) and three drops of HCl was heated under reflux and the 263.0462, found m/z 263.0455.
progress of the reaction was monitored by TLC (petroleum ether/ethyl
acetate, 8:1). The mixture was cooled to room temperature and the 2-((2-Chlorothiazol-4-yl)methyl)-2,5-diaza-bicyclo[4.2.0]oct-
precipitate was collected, dried, and crystallized from ethanol to give 1(6)-ene-7,8-dione (T2)ꢀA solution of 3,4-diethoxycyclobut-3-ene-
pure product 12; GC-MS: m/z 398 [M]+, 379, 363, 213, 178, 106, 52.
1,2-dione (2) (0.17 g, 1 mmol) and N1-((2-chlorothiazol-4-yl)methyl)
ethane-1,2-diamine (6) (0.199 g, 1 mmol) in 20 mL of ethanol was
( E)-5-((6-Chloropyridin-3-yl)methyleneamino)-1-(2,6-dichloro- heated under reflux for 6 h. The solution was concentrated and the
4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile (13)ꢀThe residue was purified by silica gel chromatography to afford T2 as a
procedure was similar to that described above for 12; GC-MS: m/z 443
white solid (yield 0.18 g, 65%); mp 165.0–165.5°C; IR (KBr): ν 3200,
1
[M]+, 424, 408, 372, 356, 281, 207, 178, 151, 124, 90, 63; H NMR (400 2940, 1784, 1665, 1053, 693 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.34 (t,
MHz, CDCl3): δ 6.84 (s, 1H, CH), 7.41 (d, J ꢂ=ꢂ 8 Hz, 1H, Pyridine-CH), 7.78
J ꢂ=ꢂ 5 Hz, 2H, CH2), 3.62 (t, J ꢂ=ꢂ 4 Hz, 2H, CH2), 4.83 (s, 2H, CH2), 7.02 (s,
(s, 2H, ArH), 8.00 (dd, J1 ꢂ=ꢂ 2 Hz, J2 ꢂ=ꢂ 8 Hz 1H, Pyridine-CH), 8.70 (d, J ꢂ=ꢂ 1H, NH), 7.53 (s, 1H, thiazol-H); EIMS: m/z 269 [M]+ (16), 234 (100), 206
2 Hz, 1H, Pyridine-CH), 8.72 (s, 1H, CHꢁ=ꢁN).
(100), 172 (35), 178 (37), 152 (24), 131 (29), 80 (7), 70 (8), 56 (6); HRMS:
Calcd for C10H8N3O2SCl m/z 269.0026, found m/z 269.0026.
2-((6-Chloropyridin-3-yl)methyl)-2,5-diaza-bicyclo[4.2.0]oct-
1(6)-ene-7,8-dione (T1)ꢀA solution of 3,4-diethoxycyclobut-3-ene- 6 - tert-Butyl-1-((6-chloropyridin-3-yl)methyl)-1,2,3,4-tetra-
1,2-dione (2) (0.17 g, 1 mmol) and N1-((6-chloropyridin-3-yl)methyl) hydropyrazino[2,3-d]pyridazin-5(6H)-one (T3)ꢀA solution of

C. Liu et al.: Design and synthesis of heterocyclic enamine derivativesꢀ
ꢀ115
HO
Cl
S
S
N
OH
Cl
Cl
H
N
b
N
Cl
N
Cl
O
O
H2N
3
O
O
4
6
1
a
b
Cl
EtO
Cl
HN
Cl
2
OEt
N
N
c
H
N
c
N
O
H2N
5
2
T1
O
Cl
Cl
O
HN
N
N
S
N
N
HN
Cl
N
O
O
N
N
T2
tBu
7
N
tBu
d
O
T3
MeS
O
Cl
SMe
O
N
O
HN
N
Me
Me
8
O
e
O
T4
O
O
O
Me
Me
Scheme 1ꢁReagents and conditions: (a) C2H5OH, reflux; (b) NH2CH2CH2NH2, CH3CN; (c) C2H5OH, reflux; (d) DMF/K2CO3, reflux; (e) C2H5OH,
reflux.
2-tert-butyl-4,5-dichloropyridazin-3(2H)-one (7) (0.22 g, 1 mmol),
N1-((6-chloropyridin-3-yl)methyl)ethane-1,2-diamine (5) (0.19 g,
1 mmol) and a catalytic amount of K2CO3 in 20 mL DMF was refluxed
for 8 h. The solution was concentrated and the residue was puri-
fied by silica gel chromatography to afford T3 as a white solid (yield
0.17 g, 52%); mp 112.5–112.9°C; IR (KBr): ν 3429, 3303, 2896, 1621, 1419,
1205, 930 cm-1; 1H NMR (400 MHz, CDCl3): δ 1.63 (s, 9H, C(CH3)3), 2.96
(t, J ꢂ=ꢂ 5 Hz, 2H, CH2), 3.40 (d, J ꢂ=ꢂ 5 Hz, 2H, CH2), 3.85 (s, 2H, CH2), 5.24
(s, 1H, NH), 7.32 (d, J ꢂ=ꢂ 8 Hz, 1H, pyridine-H), 7.53 (s, 1H, CHꢂ = ꢂN), 7.73
(d, J ꢂ=ꢂ 8 Hz, 1H, pyridine-H), 8.34 (d, J ꢂ=ꢂ 2 Hz, 1H, pyridine-H); EIMS:
m/z 333 [M]+ (5.01), 278 (6.88), 234 (7.01), 215 (28.82), 159 (100), 126
(41.11), 124 (3.82), 90 (3.37); HRMS: Calcd for C16H20N5OCl: 333.1356.
Found: 333.1435.
2-(1-((6-Chloropyridin-3-yl)methyl)imidazolidin-2-ylidene)-
5,5-dimethyl-1,3-dioxane-4,6-dione (T4)ꢀA solution of 2-(bis
(methylthio)methylene)-5,5-dimethyl-1,3-dioxane-4,6-dioneꢀ(8)
(0.25 g, 1 mmol), N1-((6-chloropyridin-3-yl)methyl)ethane-1,2-diamine
(5) (0.19 g, 1 mmol) and a catalytic amount of K2CO3 in 20 mL of DMF
was heated under reflux for 8 h. The solution was concentrated and
the residue was purified by silica gel chromatography to afford T4 as
a white solid (yield 0.14 g, 42%), mp 213.3–214.3°C; IR (KBr): ν 3311,
2985, 1691, 1654, 1547, 1394, 1198, 1109 cm-1; 1H NMR (400 MHz, CDCl3):
δ 1.65 (s, 6H, C(CH3)2), 3.66 (t, J ꢂ=ꢂ 10 Hz, 2H, CH2), 3.81 (d, J ꢂ=ꢂ 9 Hz, 2H,
CH2), 4.71 (s, 2H, CH2), 7.36 (d, J ꢂ=ꢂ 8 Hz, 1H, pyridine-H), 7.88 (dd, J1 ꢂ=ꢂ
2 Hz, J2 ꢂ=ꢂ 8 Hz, 1H, pyridine-H), 8.34 (d, J ꢂ=ꢂ 2 Hz, 1H, pyridine-H), 9.08
(s, 1H, NH); EIMS: m/z 337 [M]+, 279 (72), 261 (100), 234 (21), 209 (38),
F3C
O
O
Cl
O
10
b
Cl
T5
F3C
N
N
a
N
12
Cl
NH2
Cl
N
N
N
F3C
Cl
9
O
N
Cl
11
Cl
N
b
T6
Cl
a
N
N
N
N
13
N
Scheme 2ꢁReagents and conditions: (a) C2H5OH, cat. HCl, reflux; (b) NaBH4, C2H5OH, rt, 6 h.

116ꢀ
ꢀC. Liu et al.: Design and synthesis of heterocyclic enamine derivatives
167 (8), 153 (7), 126 (53), 99 (7), 58 (10), 55 (19), 43 (26); HRMS: Calcd (0.44 g, 1 mmol) in 10 mL of ethanol was treated with sodium boro-
for C22H14N5F3Cl2 m/z 337.0829, found m/z 337.0829.
hydride (0.06 g, 1.5 mmol), and the mixture was stirred for 6 h at room
temperature. The mixture was concentrated and the precipitate was
1-(2,6-Dichloro-4-(trifluoromethyl)phenyl)-5-(furan- collected, dried, and crystallized from ethanol to give pure product T6
2-ylmethylamino)-1H-pyrazole-3-carbonitrile (T5)ꢀA solution (yield 0.35 g, 80%), mp 229.1–229.6°C; IR (KBr): ν 3214, 2251, 1591, 1305,
1
of (E)-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-5-(furan-2-ylmethy- 1135 cm-1; H NMR (400 MHz, CDCl3): δ 3.88 (s, 1H, NH), 4.35 (d, J ꢂ=ꢂ 6
leneamino)-1H-pyrazole-3-carbonitrile (12) (0.40 g, 1 mmol) in 10 mL Hz, 2H, CH2), 5.88 (s, 1H, CH), 7.33 (d, J ꢂ=ꢂ 8 Hz, 1H, Pyridine-H), 7.60 (dd,
of ethanol was treated with sodium borohydride (0.06 g, 1.5 mmol), J1 ꢂ=ꢂ 2 Hz, J2 ꢂ=ꢂ 8 Hz, 1H, Pyridine-H), 7.79 (s, 2H, ArH), 8.34 (d, J ꢂ=ꢂ 2 Hz, 1H,
and the mixture was stirred for 6 h at room temperature. The mixture Pyridine-H); EIMS: 445 m/z [M]+ (43), 408 (4), 213 (9), 178 (2), 126 (100),
was concentrated and the precipitate was collected, dried, and crys- 90 (9), 72 (4), 63 (2); HRMS: Calcd for C22H14N5F3Cl2 m/z 444.9876, found
tallized from ethanol to give pure product T5 (yield 0.32 g, 82%), m/z 444.9870.
mp 151.7–152.4°C; IR (KBr): ν 3348, 2925, 2244, 1580, 1313, 1209, 882,
1
737 cm-1; H NMR (400 MHz, CDCl3): δ 3.78 (t, 1H, J ꢂ=ꢂ 3 Hz, CH), 4.29
Acknowledgments: We are thankful for financial support
(d, J ꢂ=ꢂ 6 Hz, 2H, CH2), 6.00 (s, 1H, CH), 6.26 (d, J ꢂ=ꢂ 3 Hz, 1H, CH), 6.34
from the Science Foundation of Shanghai Institute of
(d, J ꢂ=ꢂ 3 Hz, 1H, CH), 7.37 (s, 1H, NH), 7.78 (s, 2H, ArH); EIMS: m/z
Technology (YJ2010-49), the Key and Innovation Project of
Shanghai Educational Committee (No. 11ZZ180), and the
Project of Local University Ability Building of Shanghai
Scientific and Technological Committee (No. 11520502600).
400 [M]+ (9), 363 (5), 212 (5), 82 (6), 81 (100), 53 (7); HRMS: Calcd for
C22H14N5F3Cl2 m/z 400.0106, found m/z 400.0103.
5-((6-Chloropyridin-3-yl)methylamino)-1-(2,6-dichloro-4-
(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrileꢀ(T6)ꢀA
solution of (E)-5-((6-chloropyridin-3-yl)methyleneamino)-1-(2,6-
dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile (13) Received April 4, 2012; accepted May 13, 2012
References
Butera, J. A.; Antane, M. M.; Antane, S. A.; Argentieri, T. M.;
Freeden, C.; Graceffa, R. F.; Hirth, B.H.; Jenkins, D.; Lennox,
J. R.; Matelan, E. Design and SAR of novel potassium
channel openers targeted for urge urinary incontinence. 1.
N-cyanoguanidine bioisosteres possessing in vivo bladder
selectivity. J. Med. Chem. 2000, 43, 1187–1202.
Cheikh, A. B.; Chuche, J.; Manisse, N.; Pommelet, J. C.; Netsch, K.
P.; Lorencak, P.; Wentrup, C. Synthesis of α-cyano carbonyl
compounds by flash vacuum thermolysis of (alkylamino)
methylene derivatives of meldrum’s acid. Evidence for facile
1,3-shifts of alkylamino and alkylthio groups in imidoylketene
intermediates. J. Org. Chem. 1991, 56, 970–975.
Jepson, J. E. C.; Brown, L. A.; Sattelle, D. B. The actions of the
neonicotinoid imidacloprid on cholinergic neurons of
Drosophila melanogaster. Invert. Neurosci. 2006, 6, 33–40.
Jeschke, P.; Nauen, R.; Schindler, M.; Elbert, A. Overview of the
status and global strategy for noenicotinoids. J. Agric. Food
Chem. 2011, 59, 2897–2908.
Kagabu, S.; Moriya, K.; Shibuya, K.; Hattori, Y.; Tsuboi, S.;
Shiokawa, K. 1-(6-Halonicotinyl)-2-nitromethylene-imidaz
olidines as potential new insecticides. Biosci. Biotech.
Biochem. 1992, 56, 362–363.
and the relationship to partition coefficient and charge
density on the pharmacophore. J. Agric. Food Chem. 2007, 55,
812–818.
Moury, D. T. Mucochoric acid. II. Reactions of aldehyde group. J. Am
Chem. Soc. 1953, 75, 1909–1912.
Ohno, I.; Tomizawaa, M.; Durkin, K. A.; Casida, J. E.; Kagabu,
S. Bis-neonicotinoid insecticides: observed and predicted
binding interactions with the nicotinic receptor. Bioorg. Med.
Chem. Lett. 2009, 19, 3449–3452.
Samaritoni, J. G.; Demeter, D. A.; Gifford, J. M.; Watson, G.B.;
Kempe, M.S.; Bruce, T.J. Dihydropiperazine neonicotinoid
compounds. Synthesis and insecticidal activity. J. Agric. Food
Chem. 2003, 51, 3035–3042.
Shao, X. S.; Lee, P. W.; Liu, Z. W.; Xu, X. Y.; Li, Z.; Qian, X. H.
cis-Configuration: a new tactic/rationale for neonicotinoid
molecular design. J. Agric. Food Chem. 2011, 59, 2943–2949.
Wang, Y. L.; Cheng, J. G.; Qian, X. H.; Li, Z. Actions between neonic-
otinoids and key residues of insect nAChR based on an ab
initio quantum chemistry study: hydrogen bonding and π- π
interaction. Bioorg. Med. Chem. 2007, 15, 2624–2630.
Zhou, H. B.; Zhang, J.; Lu, S. M.; Xie, R. G.; Zhou, Z. Y.; Choi, M. C. K.;
Chan, A. S. C.; Yang, T. K. Design, synthesis and structure of new
chiral squaric acid monoaminoalcohols and diaminoalcohols
and their use as catalysts in asymmetric reduction of ketones
and diketones. Tetrahedron 2001, 57, 9325–9334.
Kagabu, S.; Ishihara, R.; Hieda, Y.; Nishimura, K.; Naruse, Y.
Insecticidal and neuroblocking potencies of variants of the
imidazolidine moiety of imidacloprid-related neonicotinoids

Copyright of Heterocyclic Communications is the property of De Gruyter and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.