Synthesis, spectroscopy and biological activity of novel acylhydrazines containing ferrocenyl moiety

Article abstract of DOI:10.1016/S0022-328X(01)00876-2

In a search for new insect growth regulators, we replaced the phenyl moiety by ferrocenyl in N-tert-butyl-N,N′-dibenzoylhydrazine and synthesized the novel N-tert-butyl-N′-ferrocenoyl-N-substitutedbenzoylhydrazines by the reaction of ferrocenoyl chloride with N-tert-butyl-N-substituted benzoylhydrazines in dry tetrahydrofuran using triethylamine as the acid acceptor. The N-tert-butyl-N-ferrocenoyl-N′-substituted benzoylhydrazines were prepared similarly. Then, the treatment of N-tert-butyl-N′-ferrocenoyl-N-benzoylhydrazine with alkylmethyl(chlorosulfenyl)carbamates in the presence of sodium hydride afforded the novel acylhydrazines containing the ferrocenyl moiety. The title compounds were identified by IR spectroscopy, ¹H-NMR spectroscopy, EIMS and elemental analyses. The results of bioassay showed that some of the title compounds exhibit excellent larvicidal activities. Toxicity assays indicated that the title compounds could induce a premature, abnormal and lethal larval molt. We found by chance that one of the title compounds possesses good anti-TMV (Tobacco Mosaic Virus) activity.

Full text of DOI:10.1016/S0022-328X(01)00876-2

Journal of Organometallic Chemistry 637–639 (2001) 94–98
www.elsevier.com/locate/jorganchem
Synthesis, spectroscopy and biological activity of novel
acylhydrazines containing ferrocenyl moiety
Huang Runqiu *, Wang Qingmin
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai Uni6ersity,
Tianjin 300071, People’s Republic of China
Received 10 March 2000; received in revised form 11 November 2000; accepted 17 November 2000
Abstract
In a search for new insect growth regulators, we replaced the phenyl moiety by ferrocenyl in N-tert-butyl-N,N%-dibenzoylhy-
drazine and synthesized the novel N-tert-butyl-N%-ferrocenoyl-N-substitutedbenzoylhydrazines by the reaction of ferrocenoyl
chloride with N-tert-butyl-N-substituted benzoylhydrazines in dry tetrahydrofuran using triethylamine as the acid acceptor. The
N-tert-butyl-N-ferrocenoyl-N%-substituted benzoylhydrazines were prepared similarly. Then, the treatment of N-tert-butyl-N%-fer-
rocenoyl-N-benzoylhydrazine with alkylmethyl(chlorosulfenyl)carbamates in the presence of sodium hydride afforded the novel
1
acylhydrazines containing the ferrocenyl moiety. The title compounds were identified by IR spectroscopy, H-NMR spectroscopy,
EIMS and elemental analyses. The results of bioassay showed that some of the title compounds exhibit excellent larvicidal
activities. Toxicity assays indicated that the title compounds could induce a premature, abnormal and lethal larval molt. We found
by chance that one of the title compounds possesses good anti-TMV (Tobacco Mosaic Virus) activity. © 2001 Elsevier Science
B.V. All rights reserved.
Keywords: Ferrocene; Ferrocenecarboxylic anhydride; Diacylhydrazine; Insect growth regulators; Lethal larval molt
1. Introduction
group by a ferrocenyl group in a bioactive compound
was expected to induce great changes in molecular
properties, such as the solubility and hydrophobicity.
Hence, in a search for new insect growth regulators, we
thought that the replacement of the phenyl moiety by
ferrocenyl in N-tert-butyl-N,N%-dibenzoylhydrazine
would enhance their larvicidial activities to a significant
degree. Therefore, we designed and synthesized the novel
ferrocenoyl acylhydrazines 3 and 4.
It has been reported that biscarbamoyl sulfide deriva-
tives of methylcarbamate insecticides still retained the
good insecticidal activity of the parent methylcarbamate
but were substantially less toxic to the white mouse [5].
Encouraged by the reports, we developed the idea that
the introduction of carbamate into N-tert-butyl-N%-fer-
rocenoyl-N-benzoylhydrazine, which has excellent insect
growth regulators’ activity, would retain the good insec-
ticidal activity of the parent methylcarbamate and N-
tert-butyl-N%-ferrocenoyl-N-benzoylhydrazine, while the
toxicity of methylcarbamate would be reduced at the
same time. Therefore, we designed and synthesized the
title products 5.
Recently, a new class of insect growth regulators, the
N-tert-butyl-N,N%-diacylhydrazines, have been found to
mimic the action of 20-hydroxyecdysone to activate the
ecdysone receptor, leading to lethal premature molting
[1]. Relationships between the structure and biological
activity of N-tert-butyl-N,N%-dibenzoylhydrazine larvi-
cides have been extensively investigated [2]. The results
indicated that the molecular hydrophobicity is favor-
able. In addition, ferrocene is ideal for use in drug design
because of the low toxicity of the molecule containing a
ferrocenyl moiety and the ease of substitution of a
conventional phenyl or heteroaromatic group with a
ferrocene moiety. Moreover, ferrocene-containing com-
pounds often possess unexpected biological activity [3].
Indeed, ferrocenyl groups have already been shown to
advantageously replace phenyl moieties in biologically
active compounds [4]. The substitution of a phenyl
* Corresponding author. Fax: +86-22-2350-3438.
E-mail address: wang98h@263.net (H. Runqiu).
0022-328X/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(01)00876-2

H. Runqiu, W. Qingmin / Journal of Organometallic Chemistry 637–639 (2001) 94–98
95
are good acylating agents. However, our attempts to
prepare N-tert-butyl-N%-ferrocenoyl-N-benzoylhy-
drazine from ferrocenecarboxylic anhydride 2 and N-
tert-butyl-N-benzoylhydrazine were unsuccessful. It is
interesting to note that the ferrocenecarboxylic anhy-
dride 2 cannot react with any primary or secondary
amines or hydrazine. This is due to the effect of steric
hindrance of ferrocenoyl and the conjugative effect of
the ferrocene group with carbonyl.
Scheme 1.
The ferrocenoyl chloride 1 reacted with N-tert-bu-
tyl-N-substituted benzoylhydrazines in dry tetrahydro-
furan using triethylamine as the acid acceptor to yield
N-tert-butyl-N%-ferrocenoyl-N-substituted benzoylhy-
drazines in ca. 48% yield. The N-tert-butyl-N-ferro-
cenoyl-N%-substituted benzoylhydrazines 4 were simi-
larly prepared, as shown in Scheme 2.
We found that the treatment of N-tert-butyl-N%-fer-
rocenoyl-N-benzoylhydrazine with alkylmethyl(chloro-
sulfenyl)carbamates in the presence of sodium hydride
afforded the title compounds 5, as shown in Scheme
3.
The title compounds 3–5 were characterized by IR
and 1H-NMR spectroscopy, EIMS and elemental
analyses. The results are in accordance with the ex-
pected structures. The 1H-NMR spectra of 3 and 4
are characteristic: the ferrocenyl substituent gives rise
to a five-proton singlet in the range of 3.83–4.38 ppm
for the unsubstituted cyclopentadienyl ring and two
multiplets at 4.27–4.89 ppm for the monosubstituted
ring.
Scheme 2.
The results of larvicidal activities given in Table 1
show that the title compounds 3 and 5 exhibit excel-
lent larvicidal activities whereas the title compounds 4
have low activities. These results suggested that the
benzoyl moiety located closer to the tert-butyl group is
important for retaining high activity, and another
phenyl can be replaced by the ferrocene group with-
out losing much of the larvicidal activities. Toxicity
assays indicated that the title compounds 3 and 5, like
N-tert-butyl-N,N%-dibenzoylhydrazine (RH5849), can
induce a premature, abnormal and lethal larval molt.
Symptoms of toxicity included discoloration, weight
loss, cessation of feeding, and developmentally prema-
ture, lethal molting at higher rates. Therefore, the
presence of the ferrocene group in title compounds 3
and 5 has been considered to play an important role
in insect growth regulator activity.
We found by chance that the title compound 3b
possesses good anti-TMV (Tobacco Mosaic Virus) ac-
tivity. For example, at 500 ppm, the inhibitory rate of
compound 3b to TMV attains 30%. To the best of
our knowledge, this is the first report on anti-TMV
activity of ferrocene derivatives. This result is promis-
ing. Further studies on anti-TMV activities of the fer-
rocenoyl acylhydrazines are underway.
Scheme 3.
2. Results and discussion
Treatment of ferrocene with 2-chlorobenzoyl chloride
afforded 2-chlorobenzoylferrocene, and subsequent re-
action with potassium tert-butoxide yielded ferrocene
carboxylic acid in high yield [6]. Then, ferrocene car-
boxylic acid reacted with phosphorus pentachloride to
give ferrocenoyl chloride in 48% yield [7]. We found that
the above reaction under the reported condition [7]
afforded two compounds, as shown in Scheme 1. The
major product was found to be the expected ferrocenoyl
chloride 1 in ca. 48% yield, and ferrocenecarboxylic
anhydride 2 was isolated in 29–47% yield. The anhy-
1
dride was identified by IR and H-NMR spectroscopy,
EIMS and elemental analyses. The characteristic bands
of the ferrocenyl group in the IR spectra of the anhy-
dride appear at 3112, 1442, 1242, 1102, 1065, 1008, 899,
821 and 755 cm−1. The formation of the anhydride was
the reason for the low yield of ferrocenoyl chloride
prepared from ferrocene carboxylic acid and phosphorus
pentachloride. According to the literature [8], anhydrides

96
H. Runqiu, W. Qingmin / Journal of Organometallic Chemistry 637–639 (2001) 94–98
Table 1
Larvicidal activities of products 3–5
No.
Compound
X
Larvicidal activity (%)
1000 ppm
R
200 ppm
100 ppm
50 ppm
3a
3b
4a
4b
5a
5b
H
–
–
–
–
100
100
0
100
100
0
90
80
0
10
10
10
100
70
70
0
0
–
3,5-Me2
H
4-Cl
–
50
20
Et
100
100
100
100
100
100
–
nBu
–
95
RH5849
RH5849: N-tert-butyl-N,N%-dibenzoylhydrazine.
3. Experimental
THF (20 mL) under N2 at 0 °C, then the resulting
mixture was stirred at r.t. for 8 h. Then the solid was
filtered off and the filtrate was concentrated under
vacuum and chromatographed on a silica gel column
using a mixture of petroleum ether (60–90 °C) and
EtOAc as the eluent. Finally, the desired compound 3
or 4 was obtained and ferrocenecarboxylic anhydride 2
was isolated as the byproduct.
3.1. Instruments
All reactions were carried out under N2 atmosphere
with the exclusion of moisture. H-NMR spectra were
1
obtained at 200 MHz using a Bruker AC-P 200 spec-
trometer. Chemical shift values (l) are given in ppm.
Infrared spectra were recorded on a Shimadzu-435
spectrometer. Elemental analyses were determined on
an MT-3 elemental analyzer. Melting points were taken
on a Thomas–Hoover melting-point apparatus and are
uncorrected. Mass spectra were recorded with a HP
5988A spectrometer using the EI method.
3.2.1.1. Ferrocenecarboxylic anhydride (2). Red crys-
talline solid, m.p. 145–146 °C. IR (KBr): 3112, 1760,
1702, 1442, 1242, 1102, 1065, 1008, 899, 821 and 755
1
cm−1. H-NMR (CDCl3): l 4.36 (s, 10H, C5H5), 4.55
(s, 4H, C5H4), 4.89 (s, 4H, C5H4). EIMS; m/z (%):
442.20 ([M]+, 42). Anal. Found: C, 59.68; H, 4.29.
Calc. for C22H18Fe2O3: C, 59.77; H, 4.10%.
3.2. Synthesis
3.2.1.2. N-tert-Butyl-N%-ferrocenoyl-N-benzoylhydra-
zine (3a). Red crystalline solid, yield 48.0%, m.p. 235–
236 °C. H-NMR (CDCl3): l 1.54 (s, 9H, Bu), 3.84 (s,
5H, C5H5), 4.28 (m, 2H, C5H4), 4.56 (m, 2H, C5H4),
7.29–7.60 (m, 5H, Ph). Anal. Found: C, 65.09; H, 5.73;
N, 6.91. Calc. for C22H24N2O2Fe: C, 65.36; H, 5.98; N,
6.93%.
Ferrocene carboxylic acid was obtained according to
a previous report [6]. Alkyl methyl(chlorosulfenyl)-
carbamates were prepared by the reaction between car-
bamate and sulfur dichloride in CH2Cl2, using Py as the
acid acceptor [9]. N-tert-Butyl-N-substituted benzoyl-
hydrazines and N-tert-butyl-N%-substituted benzoylhy-
drazines were synthesized according to the reported
procedure [10].
1
t
3.2.1.3. N-tert-Butyl-N%-ferrocenoyl-N-(3,5-dimethyl)-
benzoylhydrazine (3b). Red crystalline solid, yield
47.4%, m.p. 238–239 °C. IR (KBr): 3380, 3105, 2993,
1665, 1652, 1603, 1509, 1446, 1421, 1392, 1357, 1272,
1238, 1212, 1104, 1000, 844, 823, 758, 700 and 617
3.2.1. General procedure for the preparation of
products 3, 4 and byproduct 2
To a solution of ferrocene carboxylic acid (4.35
mmol) in dry C6H6 (15 ml) under N2, PCl5 (4.35 mmol)
was added in small portions. After the addition, the
resulting mixture was stirred for 3 h at room tempera-
ture (r.t.). The solvent and phosphorus oxychloride
were evaporated at reduced pressure, and the residue
was dissolved in anhydrous THF. It was used for the
following reactions directly, without any further
purification.
cm−1. H-NMR (CDCl3): l 1.53 (s, 9H, Bu), 2.29 (s,
6H, Me), 3.83 (s, 5H, C5H5), 4.27 (m, 2H, C5H4), 4.60
(m, 2H, C5H4), 7.00 (s, 1H, Ph), 7.12 (s, 2H, Ph), 7.32
(br., 1H, NH). EIMS; m/z (%): 432.35 ([M]+, 19),
213.20 (61), 185.25 (20) and 120.25 (2). Anal. Found: C,
66.54; H, 6.39; N, 6.69. Calc. for C24H28N2O2Fe: C,
66.68; H, 6.53; N, 6.48%.
1
t
The above solution of ferrocenoyl chloride in anhy-
drous THF was added dropwise to a solution of N-tert-
butyl-N(or N%)-substituted benzoylhydrazine (4.35
mmol) and distilled Et3N (5.22 mmol) in anhydrous
3.2.1.4. N-tert-Butyl-N-ferrocenoyl-N%-benzoylhydra-
zine (4a). Red crystalline solid, yield 47.2%, m.p. 245–
246 °C. H-NMR (CDCl3): l 1.50 (s, 9H, Bu), 4.38 (s,
1
t

H. Runqiu, W. Qingmin / Journal of Organometallic Chemistry 637–639 (2001) 94–98
97
5H, C5H5), 4.89 (m, 4H, C5H4), 7.31–7.74 (m, 5H, Ph).
Anal. Found: C, 65.24; H, 5.76; N, 7.05. Calc. for
C22H24N2O2Fe: C, 65.36; H, 5.98; N, 6.93%.
then sprayed with the test solution and allowed to dry.
The dishes were infested with ten fourth instar larvae of
the Southern armyworm. The dishes were then covered
with the lid and held for 3 days at which time the
percent control (mortality) was determined. Percent
mortalities for the armyworm evaluations were deter-
mined 96 h after treatment. Evaluations are based on a
scale of 0–100% in which 0 equals no activity and 100
equals total kill.
The larvicidal activities of the title compounds and
RH5849 are summarized in Table 1. Armyworm foliar
results are 96-h observations and reported as percent
mortality.
3.2.1.5. N-tert-Butyl-N-ferrocenoyl-N%-(4-Cl)benzoyl-
hydrazine (4b). Yellow crystalline solid, yield 40.8%,
m.p. 254–256 °C. 1H-NMR (CDCl3): l 1.50 (s, 9H,
tBu), 4.38 (s, 5H, C5H5), 4.77 (m, 4H, C5H4), 7.31–7.74
(m, 5H, Ph). Anal. Found: C, 60.25; H, 5.07; N, 6.60.
Calc. for C22H23ClN2O2Fe: C, 60.23; H, 5.28; N, 6.38%.
3.2.2. General procedure for the preparation of
compound 5
To a stirred solution of N-tert-butyl-N%-ferrocenoyl-
N-benzoylhydrazine (3a) (2.6 mmol) in anhydrous THF
(30 ml) at r.t. under N2 was added NaH portionwise
(2.6 mmol). The mixture was stirred at r.t. for 0.5 h and
cooled to 0 °C. Then a solution of alkyl methyl(chloro-
sulfenyl)carbamates (2.6 mmol) in anhydrous THF (5
ml) was added dropwise. After the addition, the reac-
tion mixture was stirred for 8 h at r.t. Then the solid
was filtered off and the filtrate was concentrated under
vacuum. The residue was purified by column chro-
matography on a silica gel using a mixture of petroleum
ether (60–90 °C) and EtOAc as the eluent. Finally, the
desired compound 5 was obtained.
Toxicity assays indicated that the title compounds 3
and 5 induces a premature, abnormal, and lethal molt
in the fourth instar larvae of armyworm. Symptoms of
toxicity included discoloration, weight loss, cessation of
feeding, and developmentally premature, lethal molting
at higher rates.
Acknowledgements
This work was supported by the National Natural
Science Foundation of China.
3.2.2.1. Compound 5a. Red crystalline solid, yield
55.7%, m.p. 118–120 °C. IR (KBr): 2973, 1713, 1668,
References
1
1641, 1389, 1365 and 1190 cm−1. H-NMR (CDCl3): l
[1] (a) K.D. Wing, Science 241 (1988) 467;
(b) K.D. Wing, R.A. Slawecki, G.R. Carlson, Science 241 (1988)
470;
t
1.54 (br., 12H, Bu, CMe), 2.6 (br., 3H, NMe), 4.27–
4.66 (m, 11H, C5H5, C5H4, OCH2), 7.25 (br., 5H, Ph).
EIMS; m/z (%): 537.30 ([M]+, 4). Anal. Found: C,
58.14; H, 5.87; N, 7.75. Calc. for C26H31N3SO4Fe: C,
58.10; H, 5.81; N, 7.82%.
(c) K.D. Wing, US Patent 5,424,333, 1995;
(d) E.L. Michelotti, D.P. Le, G.R. Carlson, A.R. Egan, US
Patent 5,075,471, 1991.
[2] (a) Y. Nakagawa, G. Smagghe, S. Kugimiya, et al., Pestic. Sci.
55 (1999) 909;
(b) Y. Nakagawa, B. Shimizu, N. Oikawa, et al., Classical and
Three-Dimensional QSAR in Agrochemistry. In: ACS Sympo-
sium Series, vol. 606, American Chemical Society, Washington,
DC, 1995 (p. 288).
3.2.2.2. Compound 5b. Yellow crystalline solid, yield
1
83.4%, m.p. 112–113 °C. H-NMR (CDCl3): l 0.95 (s,
t
3H, CMe), 1.56 (br., 9H, Bu), 2.02 (m, 4H, CH2CH2),
2.51 (br., 3H, NMe), 4.17–4.62 (m, 11H, C5H5, C5H4,
OCH2), 7.24 (br., 5H, Ph). Anal. Found: C, 59.35; H,
6.27; N, 7.51. Calc. for C28H35N3SO4Fe: C, 59.47; H,
6.24; N, 7.43%.
[3] (a) P. Molina, A. Tarraga, J.L. Lopez, J.C. Martinez, J.
Organomet. Chem. 584 (1999) 147;
(b) S. Top, J. Tang, A. Vessieres, D. Carrez, C. Prorot, G.
Jaouen, J. Chem. Soc. Chem. Commun. (1996) 955;
(c) N. Motohashi, R. Meyer, S.R. Gollapudi, K.R. Bhattiprolu,
J. Organomet. Chem. 398 (1990) 205.
3.3. Lar6icidal acti6ity tests
[4] (a) C. Biot, L. Delhaes, H. Abessolo, et al., J. Organomet. Chem.
589 (1999) 59;
(b) C. Biot, et al., J. Med. Chem. 35 (2000) 707.
[5] (a) M.A.H. Fahmy, N.M. Mallipudi, T.R. Fukuto, J. Agric.
Food Chem. 26 (1978) 550;
(b) M.A.H. Fahmy, Y.C. Chiu, T.R. Fukuto, J. Agric. Food
Chem. 22 (1974) 59.
[6] E.R. Biehl, P.C. Reeves, Synthesis 6 (1973) 360.
[7] H.L. Hans, H. Harold, J. Org. Chem. 24 (1959) 280.
[8] (a) D.F. DeTar, R. Silverstein, J. Am. Chem. Soc. 88 (1966)
1013;
The larvicidal activities of the title compounds and
N-tert-butyl-N,N%-dibenzoylhydrazine (RH5849) were
evaluated using a previously reported procedure [11].
Solutions of the compounds to be tested were prepared
by dissolving the appropriate weight of the compound
in Me2CO.
The larvicidal activities were tested against army-
worm by foliar application. For the foliar armyworm
tests, individual corn leaves were placed on moistened
pieces of filter paper in Petri dishes. The leaves were
(b) D.F. DeTar, R. Silverstein, J. Am. Chem. Soc. 88 (1966)
1020.
[9] M.S. Brown, G.K. Kohn, US Patent 3,843,689, 1974.

98
H. Runqiu, W. Qingmin / Journal of Organometallic Chemistry 637–639 (2001) 94–98
[10] (a) Q.M. Wang, R.Q. Huang, Z.G. Li, R.L. Shao, Chin. Chem.
Lett. 11 (2000) 401;
ference on Organometallic Chemistry, Shanghai, People’s Re-
public of China, July 23–28, 2000, PS058.
(b) Q.M. Wang, R.Q. Huang, Phosphorus, Sulfur Silicon Relat.
Elem. 161 (2000) 173;
(c) Q.M. Wang, R.Q. Huang, Tetrahedron Lett. 41 (2000) 3153;
(d) Q.M. Wang, R.Q. Huang, XIX IUPAC International Con-
[11] (a) R.A. Murphy, A.C.T. Hsu, US Patent 5,117,057, 1993;
(b) Q.M. Wang, F.C. Bi, Z.G. Li, R.Q. Huang, Symposium of
Agrochemicals X Chinese Chemical Society, Hangzhou, 2000, p.
194.