Cyclic dibenzoylhydrazines reproducing the conformation of ecdysone agonists, RH-5849

Article abstract of DOI:10.1016/S0968-0896(01)00353-4

We have investigated the biologically active conformation of the non-steroidal ecdysone agonist, 1-tert-butyl-1,2-dibenzoylhydrazine (RH-5849) by means of design, synthesis and conformational analysis of cyclic derivatives of RH-5849. Among the synthesize

Full text of DOI:10.1016/S0968-0896(01)00353-4

Bioorganic & Medicinal Chemistry 10 (2002) 953–961
Cyclic Dibenzoylhydrazines Reproducing the Conformation of
Ecdysone Agonists, RH-5849
Tetsuya Toya,a Kentaro Yamaguchib and Yasuyuki Endoc,*
aResearch & Development Laboratories, Nippon Kayaku Co., Ltd., 225-1Koshikiya, Ageo, Saitama 362-0064, Japan
bChemical Analysis Center, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
cGraduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 28 June 2001; accepted 2 October 2001
Abstract—We have investigated the biologically active conformation of the non-steroidal ecdysone agonist, 1-tert-butyl-1,2-diben-
zoylhydrazine (RH-5849) by means of design, synthesis and conformational analysis of cyclic derivatives of RH-5849. Among the
synthesized compounds, a 6-membered cyclic hydrazine bearing two benzoyl groups (5) exists in three conformational states in
1
solution, and the major unsymmetrical conformer of 5 is similar to that of RH-5849 on the basis of H NMR and X-ray analyses.
The 3,3-dimethyl derivative of 5 (10) exists as a single unsymmetrical conformer. Although there is conformational similarity of the
cyclic derivatives with RH-5849, these compounds did not show any hormonal or insecticidal activity. The hydrogen bonding
character of the amide N–H group of the dibenzoylhydrazine seems to play a critical role in the appearance of the biological
activity. # 2002 Elsevier Science Ltd. All rights reserved.
Introduction
ecdysone-binding site, ecdysteroids and DBH deriva-
tives would be expected to have some common struc-
tural character that is recognized by the receptor.
Superpositional studies based on the crystalline struc-
tures of RH-5849 and 20-HE have been carried out and
several different models have been proposed by various
groups. For example, Nakagawa et al. analyzed SAR
using comparative molecular field analysis (CoMFA)
and proposed a model in which the A-ring and an oxy-
gen atom on the carbonyl groupat the B-ring of RH-
5849 are superimposed on the side chain and 14a-OH of
20-HE.5 On the other hand, Quian used the PCMODEL
method and proposed a different model in which the B-
ring and an oxygen atom on the carbonyl groupat the
B-ring of RH-5849 are superimposed on the B-ring and
14a-OH of 20-HE.6 Recently, Wurtz et al. have con-
structed two homology models (ECRra and ECRvd) of
the Chironomus tentans ECR ligand-binding domain
(LBD) and suggested a novel superposition of 20-HE
and RH-5849.7 The great differences in structural and
physico-chemical natures between ecdysteroids and
DBH derivatives cause difficulty in identifying essential
hydrogen-bonding factors and shape-recognition fac-
tors. In this paper, we describe the design, synthesis
and conformational analysis of dibenzoyl derivatives
having 5–7-membered cyclic hydrazines, for the pur-
pose of conformational restriction of flexible DBH
molecules.
In 1988, 1-tert-butyl-1,2-dibenzoyl hydrazine (RH-5849,
1) was reported by Wing as the first nonsteroidal ecdy-
sone agonist.1 Although there exists structural dissim-
ilarity between RH-5849 and the insect molting
hormone, 20-hydroxyecdysone (20-HE, 2), RH-5849
3
competes with H-ponasterone A at the binding site on
Drosophila ecdysteroid receptor and induces a morpho-
logical change in ecdysteroid responsive cells (Kc cells)
in culture.1 Moreover, the metabolic stability of RH-
5849 is superior to that of ecdysteroids and RH-5849
causes whole insects to initiate a precocious, incomplete
and lethal molt.2 Because of the unique mechanism of
action and simple structure of RH-5849, a variety of
dibenzoylhydrazine (DBH) derivatives were synthesized
for evaluation of their insecticidal activity. In the struc-
ture–activity relationship(SAR) study, some com-
pounds had not only strong insecticidal activity, but
also neglible mammalian toxicity and high environ-
mental safety. RH-5992 (3)3 and ANS-118 (4)4 were
discovered and developed as new insect growth reg-
ulators (IGR) (Fig. 1). If RH-5849 does bind with the
*Corresponding author. Tel.: +81-3-5841-4734; fax: +81-3-5841-
4768; e-mail: yendo@mol.f.u-tokyo.ac.jp
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00353-4

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T. Toya et al. / Bioorg. Med. Chem. 10 (2002) 953–961
Results and Discussion
occupied only partially by 20-HE. Dibenzoyl derivatives
of cyclic hydrazines may restrict the orientations of the
two benzoyl groups and the hydrophobic cavity in the
LDB models seems to be wide enough to accept the
additional methylene groups of the ring. It is considered
that the cyclic derivatives should be suitable for investi-
gation of the conformational analysis of DBH deriva-
tives. On the other hand, the introduction of a
substituent groupon amide–NH and replacement by
another atom led to a reduction of the activity.10 It is
considered that the NH hydrogen bond contributes to
the binding, though conformational change upon intro-
duction of an N-substituent groupcould also account
for the loss of activity. We have demonstrated the con-
formational alteration caused by N-methylation of aro-
matic amides,11 guanidine12 and ureas.13 The N-methyl
or alkyl groupin these compounds exists in cis-orienta-
tion to the carbonyl group, both in the crystal and in
solution.14 Dibenzoyl derivatives of cyclic hydrazines, in
which the orientations of the two benzoyl groups may
be restricted, should be suitable for investigation of the
conformational analysis of DBH derivatives. Therefore,
we designed 5-, 6- and 7-membered cyclic derivatives (5–
9 and 10) at the hydrazine moiety with the aim of fixing
the characteristic structure of RH-5849 (Fig. 2).
Molecular design
The X-ray structure of RH-5849 was elucidated in 1989
(Fig. 2).8 It has a characteristic T-shaped conformer
with the unsubstituted amide bond in trans conforma-
tion and the tert-butyl substituted amide in cis con-
formation. The dihedral angle of the two amide planes
showed a gauche conformation with an angle of 71.8 or
58.1ꢀ (two molecules in the asymmetric unit) that is
affected by the bulky tert-butyl group. The X-ray struc-
ture is assumed to be one of the lowest energy states of a
molecule and may offer a clue to the active conforma-
tion. The conformational states in solution were classi-
fied into five conformational domains based on the
backbone torsional angles by MACROMODEL.9 The
conformational domains can be described in terms of
the geometry of the two amide bonds, where the first
descriptor is for the amide bond of the unsubstituted
benzamide (ring A) and the second one is for the N-tert-
butyl benzamide side (ring B) of the diacylhydrazine.
Among these domains, Hsu et al. suggested that two
stable conformers need to be considered in developing
binding models.10 One is the trans/cis conformer in the
X-ray structure and the other is the cis/cis folded con-
former. These conformers were equivalent in total
energy (including solvation energy) and this result indi-
cated the existence of a possible active conformer other
than the X-ray structure. Wurtz et al. conducted con-
formational analysis of RH-5849 by using density func-
tion theory and proposed two conformers, crystal-like
and rotated, as minimum energy structures.7 They also
constructed two homology models of the Chironomus
tentans ECR ligand-binding domain (LBD) by taking as
templates the known LDB crystal structures of the reti-
noic acid and vitamin D receptor. A docking study of
20-HE and RH-5849 was carried out using the proposed
LBD models, ECRra and ECRvd. As a result, the tert-
butyl groupwas located in the hydrohpobic region
delineated by helices H5, H6, H7, and H11 and
Synthesis
The syntheses of the designed molecules are summarized
in Scheme 1. tert-Butoxycarbonylhydrazine hydrochlo-
ride (11) was converted to 1-tert-butoxycarbonyl-2-
carbobenzyloxyhydrazine (12) by treatment with carbo-
benzoxy chloride in CH2Cl2. Treatment of 12 with
sodium hydride in DMF followed by reaction with 1,4-
dibromobutane afforded the protected 6-membered
cyclic hydrazine (13) (72% in two steps).15,16 The five-
(14) or seven-membered cyclic hydrazine (15) was pre-
pared from 12 by using 1,3-dibromopropane or 1,5-
dibromopentane instead of 1,4-dibromobutane (69 and
56%, respectively). Reductive deprotection of the CBZ
Figure 1. Structures of RH-5849 (1), 20-hydroxyecdysone (2), RH-5992 (3) and ANS-118 (4).
Figure 2. X-ray structure model of RH-5849 (1) and the designed cyclic molecules.

T. Toya et al. / Bioorg. Med. Chem. 10 (2002) 953–961
955
groupof 13 using 10% Pd/C as a catalyst in methanol,
followed by condensation with 4-chlorobenzoyl chloride,
yielded the monobenzoyl compound (16) (90% in two
steps). After deprotection of the Boc group of 16 using
trifluoroacetic acid, condensation with 4-chlorobenzoyl
chloride afforded the bis(4-chlorobenzoyl) derivative (5)
(89% in two steps). The bis(4-nitrobenzoyl) (6) and
bis(4-methoxybenzoyl) (7) derivatives were prepared in
a manner similar to that described for 5. The bis(4-
chlorobenzoyl)hydrazines with five- (8) and seven-
membered (9) structures were also prepared in a manner
similar to that described for 5. The 6-membered bis(4-
chlorobenzoyl)hydrazine substituted with a dimethyl
groupat the 3-position ( 10), which corresponds to the
tert-butyl group of RH-5849, was prepared as follows
(Scheme 2). Oxidation of 12 using N-bromosuccinimide
in pyridine,17 followed by cycloaddition with 4-methyl-1,3-
pentadiene in toluene, yielded a mixture of the cyclic iso-
mers (21A and 21B) (17% in two steps).18 Catalytic
hydrogenation of the mixture gave amines that were con-
densed with 4-chlorobenzoyl chloride to afford a mixture
of monobenzoyl derivatives (22A and 22B) (85% in two
steps). After deprotection of the Boc group using tri-
fluoroacetic acid, the amines were condensed with 4-
chlorobenzoyl chloride to give 10 (quantitative in two
steps).
Conformational Analysis in Solution and Crystalline
Structure
The conformations of the cyclic derivatives were esti-
mated in terms of three possible conformers, trans/cis
(I), cis/cis (II) and trans/trans (III). These conformers
correspond to T-shaped, folded and extended con-
formers, which were defined in the case of calculation of
1
DBH by Hsu et al.10 The H NMR spectral data of the
6-membered cyclic compound (5) showed line-broad-
ening at room temperature, suggesting the existence of
1
plural conformational isomers. Then, H NMR experi-
ments were carried out at ꢁ40 ꢀC and three isomers
were detected (Fig. 3 and Table 1). The ratio of these
conformers was 91:7:2. Assignment of each signal was
determined by examination of decoupling results and
the coupling constants of all protons.
Scheme 1. Synthesis of cyclic dibenzoylhydrazine derivatives. Key: (a) ref 14; (b) BrCH2(CH2)nCH2Br, NaH, DMF; (c) H2, 10% Pd/C, MeOH; (d)
4-X-C6H4COCl, Et3N, CH2Cl2; (e) TFA, CH2Cl2.
Scheme 2. Synthesis of 10. Key: (a) NBS/pyridine, CH2Cl2; (b) 4-methyl-1, 3-pentadiene, toluene; (c) H2, 10% Pd/C, MeOH; (d) 4-Cl-C6H4COCl,
Et3N, CH2Cl2; (e) TFA, CH2Cl2; (f) 4-Cl-C6H4COCl, Et3N, DMAP, CH2Cl2.
Figure 3. Conformational isomers of the six-membered cyclic derivative (5).

956
T. Toya et al. / Bioorg. Med. Chem. 10 (2002) 953–961
The major conformational isomer, exhibited (1) differ-
ent chemical shifts in the two benzene rings (A-ring vs
B-ring), and (2) different chemical shifts of four meth-
ylene protons (H3a vs H6b, H3b vs H6a) adjacent to
the nitrogen atom. In addition, two characteristic phe-
nomena were observed. One was that the signal of the
benzene A-ring HA2 proton (7.11 ppm) suggested a
location over the other benzene ring. In an NOE
experiment, saturation of the benzene A-ring HA2 pro-
ton resulted in a 2.6% enhancement of the H6a signal
and saturation of the H6a proton caused a 7.6%
enhancement of the HA2 signal. These results indicate
that these two protons (HA2 and H6a) are spatially
close. The other was downfield shifting of the H3b pro-
ton (4.67 ppm), and high field shifting of the H6b pro-
ton (3.36 ppm). These changes were considered to be
caused by the location of these protons above the ben-
zene A-ring and the amide carbonyl, respectively. These
data indicate that the trans/cis conformational isomer
(I) is the major one, and is similar to the X-ray structure
of RH-5849. In reference to the minor conformers, the
folded conformer (II) showed downfield shifting of the
H3b and H6a protons (4.90 ppm) caused by the aniso-
tropic effect of the amide carbonyl and upper field
shifting of aromatic protons (7.20 and 7.28 ppm). This
conformation is similar to the folded form described by
Hsu et al.10 Moreover, the extended conformer (III)
showed signals at 3.52 and 3.99 ppm due to methylene
protons adjacent to the nitrogen atom and 7.47 and
7.63 ppm due to aromatic protons. The effects of func-
tional groups (nitro and methoxy group) introduced on
1
the benzene ring were investigated, and the H NMR
data at ꢁ40 ꢀC are summarized in Table 1. The 1H
NMR spectral data of both derivatives (6 and 7) showed
the existence of three conformers in the same way as for
the 4-chloro derivative (5). In each conformer, all che-
mical shifts of methylene protons on the tetra-
hydropyridazine ring were similar to those of the
chloride (5). The benzene A-ring HA2 proton was also
shielded by the B-ring, and the signal was at about
1 ppm higher field than that of standard nitro or amide
benzene derivatives. The conformer ratios of these
derivatives were 94:4:2 and 91:8:1, respectively.
1
In order to investigate the effect of ring size, H NMR
spectral examination of the five- (8) and seven-mem-
bered ring (9) derivatives was performed. Sharp signals
were observed at ꢁ60 ꢀC for 8 and at ꢁ40 ꢀC for 9
(Table 1). For both compounds, the major conformer
was the unsymmetrical conformer (I). With the expan-
sion of the ring size from five to seven, the benzene rings
were brought closer together and the benzene A-ring
HA2 proton (6.93 ppm) of the 7-membered ring was
strongly shielded by the B-ring. The conformer ratios of
the five- (8), and the seven-membered ring derivatives
(9) were 81:3:16 and 81:16:3, respectively. In addition,
the change of the ring size of the six-membered deriva-
tive (5) caused a decrease of the unsymmetrical conformer
(I). The six-membered bis(4-chlorobenzoyl)hydrazine
substituted with a dimethyl groupat the 3-position ( 10)
1
had a sharp H NMR spectrum at room temperature.
By substitution of the dimethyl groupat the C3 carbon
adjacent to amide nitrogen, the geometry of the amide

T. Toya et al. / Bioorg. Med. Chem. 10 (2002) 953–961
957
1
chemistry. An H NMR study at low temperature (ꢁ40
and ꢁ60 ꢀC) showed the existence of three different
conformers in solution. The major one was considered
to be the unsymmetrical conformer (I) that is similar to
the X-ray structure of RH-5849, and X-ray crystal-
lography data of 5 supported this assumption. The six-
membered bis(4-chlorobenzoyl)hydrazine substituted
with a dimethyl groupat the 3-position ( 10) existed as a
single conformer, because it was strongly fixed by the
two methyl groups and the X-ray structure was well
reproduced by cyclization of the hydrazine moiety. We
evaluated the insecticidal activity toward Spodoptera
litura (common cutworm); no compound had any sig-
nificant hormonal or insecticidal activity on foliar
application at 200 ppm concentration. Although alkyla-
tion on the amide–NH groupor replacement of NH by
CH2 or O led to loss of activity, introduction of CN on
10,19
the amide–NH groupwas excetpional.
The CN
derivative showed high insecticidal activity. Because it is
expected that N–CN moiety would be sensitive to acid
and alkaline environments, like cyanamide, the moiety
should be easily decomposed in the insect’s alimentary
canal, where alkaline digestive fluid is secreted,20 thus
affording the NH derivative as the active ingredient.
Wurtz et al. did not mention the interaction of the
amide–NH with LBD in their report, but our results
suggest that hydrogen bonding of the amide–NH is
necessary for interactoin with the ecdysteroid receptor
to express hormonal activity.
Figure 4. Crystal structure of 5 (ORTEP representation).
leading to the benzene B-ring was fixed in the cis con-
formation. The benzene A-ring HA2 proton (6.81 ppm)
was strongly shielded compared with that in 5, because
the B-ring was closer to the A-ring due to the steric
effect of the methyl groups.
The crystal structure of the 6-membered bis(4-chloro-
benzoyl)hydrazine (5) is illustrated in Figure 4. The
structure is a T-shaped trans/cis conformation, which is
similar to the X-ray structure of RH-5849. The dihedral
angle (65.5ꢀ) of the two amide planes showed a gauche
conformation. In the 1H NMR experiment on the major
conformer (I), the highfield shielding of the A-ring HA2
proton suggested a location over the other benzene ring,
and the downfield shifting of the H3b proton, and the
highfield shifting of the H6b proton were consistent
with the location of these protons above the benzene A-
ring and the amide carbonyl. These experimental results
in solution can be well explained in terms of the crystal
structure.
Experimental
General
Melting points were determined by using a Yanagimoto
hot-stage melting point apparatus and were uncor-
rected. Elemental analysis was carried out in the
Microanalytical Laboratory, Faculty of Pharmaceutical
Sciences, University of Tokyo and was within ꢂ0.3%
of the theoretical values. NMR spectra were recorded
on a JEOL JNM-GX400 (400 MHz) spectrometer.
Chemical shifts were expressed in
tetramethylsilane in CDCl3.
d relative to
Insecticidal activity. The insecticidal activity of the syn-
thetic derivatives against Spodoptera litura (common
cutworm) was evaluated. Although RH-5849 and its
Benzyl 2-(tert-butoxycarbonyl)hexahydropyridazine-1-
carboxylate (13). To a stirred solution of N-benzyloxy-
carbonyl-N0-tert-butoxycarbonyl hydrazine (12) (3.0 g,
11.3 mmol) in DMF (60 mL), NaH (60% in oil, 947 mg,
23.7 mmol) was added at 0 ꢀC. After stirring the reac-
tion mixture for 30 min at room temperature, 1,4-
dibromobuane (2.56 g, 11.8 mmol) was added to the
mixture and stirred overnight. The solution was poured
into water and extracted with AcOEt. The organic layer
was washed with water, and brine and dried over
MgSO4. After removal of the solvent, the residue was
purified by column chromatography on silica gel with n-
hexane–AcOEt=4:1 to afford 3.3 g of 13 as a colorless
dichloro
derivative,
1-tert-butyl-1,2-di-(4-chloro-
benzoyl)hydrazine, caused 100% mortality owing to
hyperecdysonism at 200 ppm concentration, none of the
cyclic derivatives showed any significant insecticidal
activity at the same concentration. Considering the
LC50 of ANS-118 (<1 ppm), it is considered that their
activity is negligible.4
Conclusion
1
In order to elucidate the biologically active conforma-
tion of 1-tert-butyl-1,2-dibenzoyl hydrazine derivatives,
we designed and synthesized five-, six- and seven-mem-
bered cyclic derivatives, and analyzed their stereo-
oil (91%). H NMR (CDCl3) 1.20–1.75 (13H, m, t-Bu,
2ꢃCH2), 2.8–3.2 (2H, br, N–CH2), 4.0–4.25 (2H, m, N–
CH2), 5.0–5.35 (2H, m, OCH2), 7.29–7.40 (5H, m,
ArH5).

958
T. Toya et al. / Bioorg. Med. Chem. 10 (2002) 953–961
Benzyl 2-(tert-butoxycarbonyl)pyrazolidine-1-carboxy-
late (14). The procedure was the same as that used for
the preparation of 13, employing 1.0 g (3.76 mmol) of
N-benzyloxycarbonyl-N0-tert-butoxycarbonylhydrazine
(12) and 797 mg (3.95 mmol) of 1,3-dibromopropane to
500 mg (2.69 mmol) of tert-butyl hexahydropyridadine-
1-carboxylate and 412 mg (2.82 mmol) of 4-methoxy-
benzoylchloride to afford 816 mg of 18 (95%) as a col-
1
orless oil. H NMR (CDCl3) 1.32 (9H, br, t-Bu), 1.70
and 1.81 (each 2H, each br, 2ꢃCH2), 2.75–3.10 (2H, m,
N–CH2), 4.10–4.30 (1H, br, N–CH), 4.54 (1H, br d,
J=13.2 Hz, N–CH), 6.85 (2H, d, J=8.4 Hz, ArH2), 7.45
(2H, d, J=8.4 Hz, ArH2).
1
afford 1.0 g of 14 (87%) as a colorless oil. H NMR
(CDCl3) 1.42 (9H, s, t-Bu), 1.98–2.10 (2H, m, CH2), 3.12–
3.33 (2H, br d, N–CH2), 3.82–4.02 (2H, br s, N–CH2),
5.0–5.33 (2H, m, OCH2), 7.30–7.40 (5H, m, ArH5).
1-(4-Chlorobenzoyl)hexahydropyridazine. Trifluoroacetic
acid (3.0 mL) was added to a solution of 676 mg
(2.08 mmol) of 16 in 5 mL of CH2Cl2 at 0 ꢀC with stir-
ring. The mixture was stirred for 30 min, and then the
solvent was removed under reduced pressure. The resi-
due was dissolved in AcOEt, and saturated NaHCO3 aq
was added. The organic layer was separated and the aq
layer was extracted with AcOEt. The combined extract
was washed with water, and brine, and dried over
MgSO4. Concentration afforded 420 mg (99%) of 1-(4-
chlorobenzoyl)hexahydropyridazine as a white crystal:
mp105–107 ꢀC; 1H NMR (CDCl3) 1.40–2.0 (4H, br,
2ꢃCH2), 2.97 (2H, br, N–CH2), 3.0–3.95 (2H, br, N–
CH2), 7.30–7.70 (4H, br, ArH4).
Benzyl 2-(tert-butoxycarbonyl)hexahydro-1, 2-diazepine-
1-carboxylate (15). The procedure was the same as that
used for the preparation of 13, employing 6.0 g
(22.6 mmol) of N-benzyloxyarbonyl-N0-tert-butoxy-
carbonylhydrazine (12) and 5.45 g (23.7 mmol) of 1,3-
dibromopentane to afford 5.3 g of 7 (71%) as a colorless
oil. 1H NMR (CDCl3) 1.20–1.75 (15H, m, t-Bu, 3ꢃCH2),
2.70–3.20 (2H, m, N–CH2), 4.0–4.25 (2H, m, N–CH2),
5.0–5.35 (2H, m, OCH2), 7.27–7.40 (5H, m, ArH5).
tert-Butyl hexahydropyridadine-1-carboxylate. A mix-
ture of 3.0 g (9.38 mmol) of 13 and catalytic amount of
10% Pd/C in 60 mL of MeOH was vigorously stirred
under 1 atm of H2 at room temperature for 3 h and fil-
tered. The filtrate was concentrated to give 470 mg of
tert-butyl hexahydropyridadine-1-carboxylate (98%) as
1-(4-Nitrobenzoyl)hexahydropyridazine. The procedure
was the same as that used for the preparation of chlo-
ride, employing 668 mg (2.17 mmol) of 17 to afford
460 mg of 1-(4-chlorobenzoyl)hexahydropyridazine
(100%) as a pale yellow crystal: mp 103–104 ꢀC; 1H
NMR (CDCl3) 1.30–1.95 (5H, br, 2ꢃCH2 and NH),
2.80–3.10 (2H, br, N–CH2), 3.35–3.60 (1H, br, N–CH),
3.80 (1H, br s, N–CH), 7.58–7.75 (2H, br, 2-ArH2),
8.18–8.35 (2H, br, 3-ArH2).
1
a colorless oil. H NMR (CDCl3) 1.48 (9H, s, t-Bu),
1.52–1.60 and 1.62–1.73 (each 2H, m, 2ꢃCH2), 2.88 (2H,
t, J=5.5 Hz, N–CH2), 3.52 (2H, t, J=5.5 Hz, N–CH2).
tert-Butyl
2-(4-chlorobenzoyl)hexahydropyridadine-1-
carboxylate (16). To a stirred solution of 500 mg
(2.69 mmol) of tert-butyl hexahydropyridadine-1-car-
boxylate and 0.75 mL (5.38 mmol) of Et3N in dry
CH2Cl2 (10 mL), 4-chlorobenzoylchloride (526 mg,
3.0 mmol) was added and the mixture was stirred over-
night at room temperature. The reaction mixture was
poured into water and extracted with CH2Cl2. The
extract was washed with saturated NaHCO3 aq, water,
and brine and dried over MgSO4. Concentration and
purification by chromatography on silica gel with n-
hexane/AcOEt=4:1 afforded 808 mg of the benzoyl (16)
(93%) as a white crystal: mp92–93.5 ꢀC: 1H NMR
(CDCl3) 1.35 (9H, br s, t-Bu), 1.70 and 1.83 (each 2H,
br s, 2ꢃCH2), 2.70–3.05 (2H, m, N–CH2), 4.15 and 4.54
(2H, br and br d, N–CH2), 7.32 (2H, d, J=8.4 Hz,
ArH2), 7.49 (2H, d, J=8.4 Hz, ArH2).
1-(4-Methoxybenzoyl)hexahydropyridazine. The proce-
dure was the same as that used for the preparation of
chloride, employing 693 mg (2.17 mmol) of 18 to ꢀafford
423mg of amine (89%) as a white crystal: mp93–95 C; 1H
NMR (CDCl3) 1.40–1.90 (5H, br, 2ꢃCH2 and NH), 2.99
(2H, br s, N–CH2), 3.68 (2H, br s, N–CH2), 3.83 (3H, s,
OMe), 6.90 (2H, d, J=8.8 Hz, ArH2), 7.49 (2H, br, ArH2).
1, 2-Bis-(4-chlorobenzoyl)hexahydropyridazine (5). To a
stirred solution of 320 mg (1.43 mmol) of 1-(4-chloro-
benzoyl)hexahydropyridazine
and
0.397 mL
(2.85 mmol) of Et3N in dry CH2Cl2 (5 mL), 4-chloro-
benzoylchloride (275 mg, 1.57 mmol) was added, and
the mixture was stirred for 1 h at room temperature.
The reaction mixture was poured into water and
extracted with CH2Cl2. The extract was washed with
saturated NaHCO3 aq, water, and brine and dried over
MgSO4. Concentration and purification by chroma-
tography on silica gel with n-hexane/AcOEt=4:1 affor-
ded 515 mg of 5 (99%) as a white crystal. Mp150–
152 ꢀC; anal. calcd for C18H16Cl2N2O2: C: 59.52, H:
4.44, N: 7.71; found: C: 59.69, H: 4.28, N: 7.83: 1H
NMR (CDCl3) (conformer I ) 1.56 (1H, m H5a), 1.77
(1H, br d, J=13.6 Hz, H5b), 1.91 (2H, m H4a, b), 3.17
(1H, m, H3a), 3.36 (1H, dt, J=2.6 and 13.2 Hz, H6b),
3.86 (1H, dd, J=2.6 and 13.2 Hz, H6a), 4.67 (1H, d,
J=13.2 Hz, H3b), 7.11 (2H, d, 8.1 Hz, ArHA2), 7.37
(2H, d, J=8.1 Hz, ArHA3), 7.38 (2H, d, J=8.4 Hz,
ArHB3), 7.53 (2H, d, J=8.4 Hz, ArHB2); (conformer II
tert-Butyl 2-(4-nitrobenzoyl)hexahydropyridadine-1-car-
boxylate (17). The procedure was the same as that used
for the preparation of chloride (16), employing 500 mg
(2.69 mmol) of tert-butyl hexahydropyridadine-1-car-
boxylate and 484 mg (2.28 mmol) of 4-nitro-
benzoylchloride to afford 781 mg of 17 (91%) as a white
crystal: mp103–104 ꢀC: H NMR (CDCl3) 1.36 (9H, s,
1
t-Bu), 1.62–1.90 (4H, m, 2ꢃCH2), 2.8–3.0 (2H, m, N–
CH2), 3.80–4.25 (1H, br, N–CH), 4.55 (1H, br d,
J=12.8 Hz, N–CH), 7.68 (2H, d, J=8.8 Hz, ArH2), 8.22
(2H, d, J=8.8 Hz, ArH2).
tert-Butyl 2-(4-methoxybenzoyl)hexahydropyridanine-1-
carboxylate (18). The procedure was the same as that
used for the preparation of chloride (16), employing

T. Toya et al. / Bioorg. Med. Chem. 10 (2002) 953–961
959
) 4.90 (2H, d, J=12.1 Hz, H3b and H6a), 7.02 (4H, d,
J=8.4 Hz, ArHA2 and ArHB2), 7.28 (4H, d, J=8.4 Hz,
ArHA3 and ArHB3); (conformer III) 3.52 (2H, br t,
J=12.1 Hz, H3 and H6), 3.99 (2H, d, J=12.8 Hz, 3H
and 6H), 7.47 (4H, d, J=8.4 Hz, ArHA3 and ArHB3),
7.63 (4H, d, J=8.4 Hz, ArHA2 and ArHB2).
tert-butyl pyrazolidine-1-carboxylate and 0.761 mL
(5.46 mmol) of Et3N in dry CH2Cl2 (10 mL), 4-chloro-
benzoylchloride (526 mg, 3.0 mmol) was added and the
mixture was stirred for 1 h at room temperature. The
reaction mixture was poured into water and extracted
with CH2Cl2. The extract was washed with saturated
NaHCO3 aq, water, and brine and dried over MgSO4.
Concentration and purification by chromatography on
silica gel with n-hexane/AcOEt=4:1 afforded 820 mg of
benzoyl (19) (97%) as a white crystal: mp170–172 ꢀC:
1H NMR (CDCl3) 1.32 (9H, s, t-Bu), 2.13 (2H, br,
CH2), 3.20 and 3.40 (2H, each br, N–CH2), 4.10 (2H,
br, N–CH2), 7.45 (2H, d, J=8.8 Hz, ArH2), 7.64 (2H, d,
J=8.8 Hz, ArH2).
1, 2-Bis-(4-nitrobenzoyl)hexahydropyridazine (6). The
procedure was the same as that used for the preparation
of chloride (5), employing 360 mg (1.63 mmol) of amine
and 278 mg (1.63 mmol) of 4-nitrobenzoylchloride to
afford 52 mg of 6 (9%) as a white crystal: mp242–
242.5 ꢀC; anal. calcd for C18H16N4O6: C: 56.25, H: 4.20,
1
N:14.58; found: C: 56.26, H: 4.09, N: 14.68. H NMR
(CDCl3) (conformer I) 1.60 (1H, m H5a), 1.87 (1H, br
d, J=14.3 Hz, H5b), 2.00 (2H, m, H4a, b), 3.21 (1H, dt,
J=4.0 and 12.8 Hz, H3a), 3.48 (1H, dt, J=2.6 and
13.6 Hz, H6b), 3.81 (1H, dd, J=2.9 and 13.6 Hz, H6a),
4.72 (1H, d, J=12.8 Hz, H3b), 7.26 (2H, d, 8.8 Hz,
ArHA2), 7.77 (2H, d, J=8.8 Hz, ArHB2), 8.27 (2H, d,
J=8.8 Hz, ArHA3), 8.32 (2H, d, J=8.8 Hz, ArHB3);
(conformer II) 4.95 (2H, d, J=12.8 Hz, H3b and H6a),
7.24 (4H, d, J=8.8 Hz, ArHA2 and ArHB2), 7.88 (4H,
d, J=8.8 Hz, ArHA3 and ArHB3); (conformer III) 3.57
(2H, br t, J=13.2 Hz, H3 and H6), 3.91 (2H, d,
J=13.2 Hz, H3 and H6), 8.20 (4H, d, J=8.8Hz, ArHA2
and ArHB2), 8.40 (4H, d, J=8.4Hz, ArHA3 and ArHB3).
1-(4-Chlorobenzoyl)pyrazolidine. Trifluoroacetic acid
(1.0 mL) was added to a solution of 88 mg (0.283 mmol)
of 19 in 1 mL of CH2Cl2 at 0 ꢀC with stirring. The mix-
ture was stirred for 30 min, and then the solvent was
removed under pressure. The residue was dissolved in
AcOEt and saturated NaHCO3 aq was added. The
organic layer was separated and the aq layer was
extracted with AcOEt. The combined extract was
washed with water and brine and dried over MgSO4.
Concentration afforded 40 mg of 1-(4-chloro-
benzoyl)pyrazolidine (67%) as a white crystal: mp 139–
140 ꢀC. H NMR (CDCl3) 2.13 (2H, quint, J=7.0 Hz,
1
CH2), 3.05 (2H, br, N–CH2) 3.74 (2H, br, N–CH2), 4.0
(1H, br, NH), 7.37 (2H, d, J=8.8 Hz, ArH2), 7.67 (2H,
br, ArH2).
1, 2-Bis-(4-methoxybenzoyl)hexahydropyridazine (7).
The procedure was the same as that used for the pre-
paration of chloride (5), employing 315 mg (1.43 mmol)
of amine and 244 mg (1.43 mmol) of 4-methoxy-
benzoylchloride to afford 501 mg of 7 (99%) as a white
crystal. Mp85–87 ꢀC; anal. calcd for C20H22N2O4; C:
67.78, H: 6.26, N: 7.90; found: C: 67.69, H: 6.20, N:
1, 2-Bis-(4-chlorobenzoyl)pyrazolydine (8). To a stirred
solution of 117 mg (0.553 mmol) of 1-(4-chlor-
obenzoyl)pyrazolidine and 0.154 mL (5.46 mmol) of
Et3N in dry CH2Cl2 (2 mL), 4-chlorobenzoylchloride
(106.5 mg, 0.608 mmol) was added and the mixture was
stirred for 1 h at room temperature. The reaction mix-
ture was poured into water and extracted with CH2Cl2.
The extract was washed with saturated NaHCO3 aq,
water, and brine and dried over MgSO4. Concentration
and purification by chromatography on silica gel with n-
hexane/AcOEt=4:1 afforded 147 mg of 8 (76%) as a
white crystal. mp: 92–93.5 ꢀC; anal. calcd for
C17H14Cl2N2O2; C: 58.47, H: 4.04, N: 8.02; found: C:
58.26, H: 4.19, N: 8.31. 1H NMR (CDCl3) (conformer I)
2.17 (1H, m, H4a), 2.35 (1H, m, H4b), 3.63 (1H, m,
H3a), 3.70 (1H, m, H5b), 3.91 (1H, br t, J=10 Hz,
H5a), 4.30 (1H, m, H3b), 7.34 (2H, d, J=8.4 Hz,
ArHB3), 7.42 (2H, d, J=8.4 Hz, ArHA3), 7.53 (2H,
d, J=8.4 Hz, ArHA2), 7.63 (2H, d, J=8.4 Hz,
ArHB2); (conformer II) 2.49 (2H, br, H4a, b), 4.50
(2H, br, H3b and H5a), 6.97 (4H, br, ArHA2 and
ArHB2), 7.27 (4H, br, ArHA3 and ArHB3); (con-
former III) 2.26 (2H, m, H4a, b), 3.84 (4H, m, H3a,
b and H3a, b).
1
14.68; H NMR (CDCl3) (conformer I ) 1.55 (1H, m
H5a), 1.71 (1H, br d, J=13.6 Hz, H5b), 1.88 (2H, m
H4a, b), 3.20 (1H, dt, J=3.7 and 12.5 Hz, H3a), 3.36
(1H, t, J=12.8 Hz, H6b), 3.83 (6H, s, 2ꢃOMe), 3.96
(1H, d, J=12.8 Hz, H6a), 4.66 (1H, d, J=12.5 Hz,
H3b), 6.87 (2H, d, 8.4 Hz, ArHA3), 6.89 (2H, d,
J=8.1 Hz, ArHB3), 7.23 (2H, d, J=8.4 Hz, ArHA2),
7.58 (2H, d, J=8.1 Hz, ArHB2); (conformer II) 3.11
(2H, t, J=13.2 Hz, H3a and H6b), 4.88 (2H, d,
J=13.2 Hz, H3b and H6a), 6.77 (4H, d, J=8.4 Hz,
ArHA2 and ArHB2), 7.15 (4H, d, J=8.4 Hz, ArHA3
and ArHB3); (conformer III) 3.56 (2H, t, H3 and H6),
4.11 (2H, d, H3 and H6), 6.97 (4H, d, J=8.4 Hz,
ArHA3 and ArHB3), 7.67 (4H, d, J=8.4 Hz, ArHA2
and ArHB2).
tert-Butyl pyrazolidine-1-carboxylate. A mixture of 1.0 g
(3.27 mmol) of 14 and catalytic amount of 10% Pd/C in
20 mL of MeOH was vigorously stirred under 1 atm of
H2 at room temperature for 3 h and filtered. The filtrate
was concentrated to give 470 mg of tert-butyl pyr-
azolidine-1-carboxylate (84%) as a colorless oil. 1H
NMR (CDCl3) 1.49 (9H, s, t-Bu), 2.05 (2H, quint,
J=7.0 Hz, CH2), 3.07 (2H, t, J=6.6 Hz, N–CH2), 3.46
(2H, t, J=7.0 Hz, N–CH2).
tert-Butyl hexahydro-1, 2-diazepine-1-carboxylate. A
mixture of 5.19 g (15.54 mmol) of 15 and catalytic
amount of 10% Pd/C in 80 mL of MeOH was vigor-
ously stirred under 1 atm of H2 at room temperature for
3 h and filtered. The filtrate was concentrated to give
tert-Butyl 2-(4-chlorobenzoyl)pyrazolidine-1-carboxylate
(19). To a stirred solution of 470 mg (2.73 mmol) of
2.92 g
carboxylate (96%) as a colorless oil. H NMR (CDCl3)
of
tert-butyl
hexahydro-1,2-diazepine-1-
1

960
T. Toya et al. / Bioorg. Med. Chem. 10 (2002) 953–961
1.48 (9H, s, t-Bu), 1.57–1.68 and 1.69–1.80 (4H and 2H,
each m, 3ꢃCH2), 2.93 (2H, br s, N–CH2), 3.48 (2H, br t,
J=6.0 Hz, N–CH2).
Benzyl 2-(tert-butoxycarbonyl)-3,3-dimethyl-6H-pyrida-
zine-1-carboxylate (21A) and benzyl 2-(tert-butoxycarbo-
nyl)-6,6-dimethyl-6H-pyridazine-1-carboxylate (21B). To
a solution of 3.0 g (11.3 mmol) of 12 and 0.91 mL
(11.3 mmol) of pyridine in CH2Cl2 (30 mL), NBS
(2.01 g, 11.3 mmol) was added at 0 ꢀC and the mixture
was stirred for 1 h at room temperature. The reaction
mixture was poured into water and extracted with
CH2Cl2. The extract was washed with water, and brine
and dried over MgSO4. Concentration afforded crude
diimide and the residue was used without purification at
next step. A mixture of the crude diimide and 1.3 mL
(11.3 mmol) of 4-methyl-1,3-pentadiene in 30 mL of the
solvent was stirred under argon at 70 ꢀC overnight.
After evaporation of the solvent, the residue was pur-
ified by chromatography on silica gel with n-hexane/
AcOEt=19:1 to afford 675 mg (17%) of a mixture of
tert-Butyl 2-(4-chlorobenzoyl)hexahydro-1, 2-diazepine-
1-carboxylate (20). To a stirred solution of 930 mg
(4.65 mmol) of tert-butyl hexahydro-1, 2-diazepine-1-
carboxylate and 1.30 mL (9.30 mmol) of Et3N in dry
CH2Cl2 (20 mL), 4-chlorobenzoylchloride (854 mg,
4.88 mmol) was added and the mixture was stirred
overnight at room temperature. The reaction mixture
was poured into water and extracted with CH2Cl2. The
extract was washed with saturated NaHCO3 aq, water,
and brine and dried over MgSO4. Concentration and
purification by chromatography on silica gel with n-
hexane/AcOEt=4:1 afforded 1.20 g of benzoyl (20)
(76%) as a white crystal: mp120–121.5 ꢀC. H NMR
1
1
(CDCl3) 1.39 (9H, s, t-Bu), 1.50–2.10 (6H, m, 3ꢃCH2),
2.70–2.95 (1H, m, N–CH), 3.30–3.55 (1H, m, N–CH),
3.60–4.00 (1H, m, N–CH), 4.05–4.25 (1H, m, N–CH),
7.28–7.45 (4H, m, ArH4).
21A and 21B (1:4) as a colorless oil. H NMR (CDCl3)
(21A) 1.33 (3H, s, CH3), 1.34 (9H, s, t-Bu), 1.43 (3H, s,
CH3), 3.75 (1H, d, J=16.0 Hz, H6), 4.27 (1H, dd,
J=5.5 and 16.0 Hz, H6), (21B) 1.38 (3H, s, CH3), 1.55
(9H, s, t-Bu), 1.63 (3H, s, CH3), 3.65 (1H, d, J=17.0 Hz,
H3), 4.48 (1H, ddd, J=1.83, 5.13 and 17.0 Hz, H3),
5.00–5.22 (2H, m, OCH2), 5.42–5.56 and 5.62–5.75
(each 1H, m, H4 and H5), 7.28–7.52 (5H, m, ArH5).
1-(4-Chlorobenzoyl)hexahydro-1,
2-diazepine.
Tri-
fluoroacetic acid (4.0 mL) was added to a solution of
1.06 g (3.13 mmol) of 20 in 3 mL of CH2Cl2 at 0 ꢀC with
stirring. The mixture was stirred for 30 min, and then
the solvent was removed under pressure. The residue
was dissolved in AcOEt, and saturated NaHCO3 aq was
added. The organic layer was separated and the aq layer
was extracted with AcOEt. The combined extract was
washed with water, and brine and dried over MgSO4.
Concentration afforded 420 mg of 1-(4-chlor-
obenzoyl)hexahydro-1,2-diazepine (99%) as a white
1-tert-Butyl 6,6-dimethyl-2-(4-chlorobenzoyl)hexahydro-
pyridazine-1-carboxylate (22A) and 1-tert-Butyl 3,3-dime-
thyl-2-(4-chlorobenzoyl)hexahydropyridazine-1-carboxylate
(22B). A mixture of 670 mg (1.94 mmol) of 21A and
21B, and catalytic amount of 10% Pd/C in 20 mL of
EtOH was vigorously stirred under 1 atm of H2 at room
temperature for 4 h and filtered. The filtrate was con-
centrated to give 379 mg of amine (A/B, 1:4) (91%) as a
ꢀ
crystal. Mp79–80 C; 1H NMR (CDCl3) 1.40–1.95 (6H,
1
m, 3ꢃCH2), 2.75–3.15 (2H, m, N–CH2), 3.40–3.95 (2H,
m, N–CH2), 5.88 (1H, br s, NH), 7.30–7.70 (4H, m,
ArH4).
white solid. H NMR (CDCl3) 1.10 (6H, s, 2 CH3), 1.47
(9H, s, t-Bu), 1.45–1.73 (4H, m, 2ꢃCH2), 2.90 (2H, t,
J=5.9 Hz, H3 of A), 3.48 (2H, t, J=5.5 Hz, H6 of B),
3.8–4.3 (1H, br, NH) To a stirred solution of 100 mg
(0.467 mmol) of the amine and 0.13 mL (0.935 mmol) of
Et3N in dry CH2Cl2 (10 mL), 4-chlorobenzoyl chloride
(90 mg, 0.514 mmol) was added and the mixture was
stirred overnight at room temperature. The reaction
mixture was poured into water and extracted with
CH2Cl2. The extract was washed with saturated
NaHCO3 aq, water, and brine and dried over MgSO4.
Concentration and purification by chromatography on
silica gel with n-hexane/AcOEt=4:1 afforded 165 mg of
monobenzoyl (22A and 22B, 1:4) (99%) as a white solid.
1H NMR (CDCl3) (23A) 1.22 (9H, s, t-Bu), 1.46 (3H, s,
CH3), 1.68 (3H, s, CH3), 3.17 (1H, quint, J=6.6 Hz,
H3), 3.90 (1H, quint, J=6.6 Hz, H3), (23B) 1.28 (9H, s,
t-Bu), 1.48 (3H, s, CH3), 1.66 (3H, s, CH3), 3.17 (1H,
quint, J=6.6 Hz, H3), 4.17 (1H, quint, J=6.6 Hz, H3),
7.43 (2H, d, J=8.4 Hz, ArH2), 7.31 (2H, d, J=8.4 Hz,
ArH2).
1, 2-Bis-(4-chlorobenzoyl)hexahydro-1, 2-diazepine (9).
To a stirred solution of 388 mg (1.15 mmol) of 1-(4-
chlorobenzoyl)hexahydro-1, 2-diazepine and 0.32 mL
(2.85 mmol) of Et3N in dry CH2Cl2 (10 mL), 4-chloro-
benzoylchloride (211 mg, 1.21 mmol) was added and the
mixture was stirred for 1 h at room temperature. The
reaction mixture was poured into water and extracted
with CH2Cl2. The extract was washed with saturated
NaHCO3 aq, water, and brine and dried over MgSO4.
Concentration and purification by chromatography on
silica gel with n-hexane/AcOEt=1:1 afforded 515 mg of
9 (91%) as a white crystal: mp174–175 ꢀC; anal. calcd
for C19H18Cl2N2O2; C: 60.49, H: 4.81, N: 7.43; found;
1
C: 60.53, H: 4.64, N: 7.60; H NMR (CDCl3) (con-
former I) 1.44–1.96 (5H, m, H5a, b and H6a,b),
2.02 (1H, m H4a), 3.15 (1H, m, H7b), 3.54 (1H,
m, H7a), 3.61 (1H, m, H3a), 4.38 (1H, m, H3b),
6.93 (2H, d, J=8.4 Hz, ArHA2), 7.36 (2H, d,
J=8.4 Hz, ArHA3), 7.43 (2H, d, J=8.4 Hz, ArHB3),
7.48 (2H, d, J=8.4 Hz, ArHB2); (conformer II) 3.43
(2H, m, H3a and H7b), 4.33 (2H, m, H3b and H7a),
7.05 (4H, d, J=8.4 Hz, ArHA2 and ArHB2), 7.31 (4H,
d, J=8.4 Hz, ArHA3 and ArHB3); (conformer III) 3.72
(2H, m, H3 and H7), 7.59 (4H, d, J=8.4 Hz, ArHA2
and ArHB2).
1,2-Bis-(4-chlorobenzoyl)-3,3-dimethylhexahydropyridazine
(10). Trifluoroacetic acid (0.13 mL) was added to a
solution of 30 mg (0.085 mmol) of the mixture of 22A
and 22B in 1 mL of CH2Cl2 at room temperature with
stirring. The mixture was stirred overnight, and then the
solvent was removed under pressure. The residue was
dissolved in AcOEt, and saturated NaHCO3 aq was

T. Toya et al. / Bioorg. Med. Chem. 10 (2002) 953–961
961
added. The organic layer was separated and the aq layer
was extracted with AcOEt. The combined extract was
washed with water and brine and dried over MgSO4.
Concentration afforded 21.5 mg of 1-(4-chlorobenzoyl)-
6,6-dimethylhexahydropyridazine (100%) as a white
placed in a plastic container having a diameter of 9 cm,
and five Spodoptera litura larvae (third inster) were
transferred thereon. This was left with a covering in a
temperature-controlled chamber at 25 ꢀC. four days
after the treatment, the number of live and dead insects
were counted to calculate the mortality rate.
1
solid. H NMR (CDCl3) 1.41 (6H, s, 2ꢃCH3), 1.76 and
1.93 (each 2H, br s, H4 and H5), 3.30 (2H, br s, H3),
7.38 (2H, d, J=8.1 Hz, ArH2), 7.44 (2H, d, J=8.1 Hz,
ArH2), 9.12 (1H, br, NH). To a stirred solution of 60 mg
(0.238 mmol) of the monocholorobenzoylhydrazine,
catalytic amount of DMAP and 0.066 mL (0.475 mmol)
of Et3N in dry CH2Cl2 (3 mL), 4-chlorobenzoylchloride
(46 mg, 0.262 mmol) was added and the mixture was
stirred overnight at room temperature. The reaction
mixture was poured into water and extracted with
CH2Cl2. The extract was washed with saturated
NaHCO3 aq, water, and brine and dried over MgSO4.
Concentration and purification by chromatography on
silica gel with n-hexane/AcOEt=4:1 afforded 93 mg of
10 (100%) as a white crystal: mp178.5–179 ꢀC. 1H
NMR (CDCl3) 1.54–1.86 (4H, m, H4 and H5), 1.61 and
1.75 (each 3H, s, 2ꢃCH3), 3.50 and 3.58 (each 1H,
quint, J=6.2 Hz, H6), 6.81 (1H, d, J=8.4 Hz, ArH),
7.26 (1H, d, J=8.4 Hz, ArH), 7.33 (1H, d, J=8.4 Hz,
ArH), 7.48 (1H, d, J=8.4 Hz, ArH).
References and Notes
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1998, 9, 873.
18. Lawton, G. J. Chem. Soc., Perkin Trans. 1987, 1, 877.
19. Unpublished results.
X-ray crystallography
The X-ray crystal structure analyses were performed on
crystal compound (5). Diffraction data were obtained
on a Rigaku AFC-S four-circle diffract meter and a
Rigaku RAXIS-II imaging plate diffract meter with
graphite-monochromated MoKa (l=0.71070 A) radia-
tion, respectively. Generally, indexing was performed
from three oscillations which were exposed for 4.0 min,
and a total of 15 oscillation images within the 2y value
of 50.3 were collected in the analyses using the imaging
plate area detector. The crystal data; formula:
C18H16N2O2Cl2, recrystn solvent: n-hexane/AcOEt,
crystal system: monoclinic, space group: P21/n (#14),
lattice parameters: a=9.507(3) A, b=18.33(2) A,
c=10.08(2) A, b=103.03(3) A, V=1711.5500 A 3, Dcalc
:
1.410 g/cm3, Z value: 4, temp: 288 K, no. of reflections
measured: total 2123, R: 0.068. The crystal structure
was solved by the direct method, and the hydrogen
atoms were located on a different electron-density map.
Evaluation of insecticidal activity. A cabbage leaf of a
medium size cut from cabbage grown to decafoliate
stage was dipped for 20 s in a treatment solution pre-
pared by diluting each of the formulations with water to
an effective ingredient concentration of 200 ppm. After
having been air-dried, the two thus treated leaves were
20. International Chemical Safety Cards (ICSCs). An Inter-
national Program on Chemical Safety Project (http://
www.cdc.gov/niosh/ipcs/icstart.html).