Synthesis and biological activity of novel N′-tert-butyl-N′-substituted benzoyl-N-(substituted phenyl)aminocarbonylhydrazines and their derivatives

Article abstract of DOI:10.1016/S0040-4039(01)01932-3

Benzyl chloroformate was synthesised by the reaction of benzyl alcohol and triphosgene in good yield for the first time. N-tert-Butyl-N-substituted benzoylhydrazines were prepared in a new and convenient procedure with good yields. A series of novel N′-tert-butyl-N′-substituted benzoyl-N-(substituted phenyl)aminocarbonylhydrazines and their derivatives were synthesised and evaluated for molting hormone mimicking activity. The results of bioassays showed that the title compounds exhibit good larvicidal activities and toxicity assays indicated that the title compounds can induce a premature, abnormal and lethal larval molt. We have found that the title compounds possess potential anticancer activities.

Full text of DOI:10.1016/S0040-4039(01)01932-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8881–8883
Synthesis and biological activity of novel
N%-tert-butyl-N%-substituted benzoyl-N-(substituted
phenyl)aminocarbonylhydrazines and their derivatives
Qingmin Wang and Runqiu Huang*
Research Institute of Elemento-Organic Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, PR China
Received 24 August 2001; revised 5 October 2001; accepted 12 October 2001
Abstract—Benzyl chloroformate was synthesised by the reaction of benzyl alcohol and triphosgene in good yield for the first time.
N-tert-Butyl-N-substituted benzoylhydrazines were prepared in a new and convenient procedure with good yields. A series of
novel N%-tert-butyl-N%-substituted benzoyl-N-(substituted phenyl)aminocarbonylhydrazines and their derivatives were synthesised
and evaluated for molting hormone mimicking activity. The results of bioassays showed that the title compounds exhibit good
larvicidal activities and toxicity assays indicated that the title compounds can induce a premature, abnormal and lethal larval
molt. We have found that the title compounds possess potential anticancer activities. © 2001 Elsevier Science Ltd. All rights
reserved.
In contrast to traditional pesticides, benzoylphenylurea
(BPU) and its derivatives mainly control the growth
and development process of insects by interfering with
chitin biosynthesis and breeding, and the activities
of BPUs are attributed to the structures of the urea
linkage.1 Recently, a new class of insect growth regu-
lators (IGR), the N-tert-butyl-N,N%-diacylhydrazines
(BDAH), have been found to mimic the action of
20-hydroxyecdysone in activating the ecdysone receptor
leading to lethal premature molting.2 Relationships
between the structure and biological activity of the
N-tert-butyl-N,N%-dibenzoylhydrazine larvicides have
been extensively investigated. The results indicated that
the molecular hydrophobicity is favourable and N-tert-
butyl-N-benzoylhydrazine is the biologically active
unit.3
In general, structural similarity always results in similar
biological activity, so designing a molecule that mimics
the structural essentials of a bioactive unit is a shortcut
to developing a lead compound with potential activity.
In the study of novel IGRs, we combined the bioactive
units of BDAH and BPU to design and synthesise
novel N%-tert-butyl-N%-substituted benzoyl-N-(substi-
tuted phenyl)aminocarbonylhydrazines and their
derivatives in order to find a new lead compound with
unusual biological properties and a different spectrum
of activities.
Benzyl alcohol was treated with triphosgene
[bis(trichloromethyl)carbonate] (1) to obtain benzyl
chloroformate (2) in good yield for the first time.4 This
new and convenient synthesis of benzyl chloroformate
avoids the use of phosgene gas and the complicated
experimental set-up associated with it. Benzyl chloro-
formate (2) was condensed with tert-butylhydrazine
hydrochloride to give N-tert-butyl-N%-benzyloxycar-
bonylhydrazine (3),5 and subsequent acylation with
substituted benzoyl chlorides yielded the N-tert-butyl-
Scheme 1.
Keywords: N-tert-butyl-N-substituted benzoylhydrazines; triphos-
gene; insect growth regulators; benzoylphenylurea; diacylhydrazines.
* Corresponding author. Tel.: 0086-022-23502673; fax: 0086-022-
23503438; e-mail: wang98h@263.net
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01932-3

8882
Q. Wang, R. Huang / Tetrahedron Letters 42 (2001) 8881–8883
N%-benzyloxycarbonyl-N-substituted benzoylhydrazines
(4).6 Further deprotection using 5% Pd–C as a catalyst
provided N-tert-butyl-N-substituted benzoylhydrazines
(5) in good yields, as shown in Scheme 17 and Table 1.
This new and highly efficient method for the synthesis
of N-tert-butyl-N-substituted benzoylhydrazines enjoys
a number of advantages in that the reaction is carried
out under mild conditions in good yields, starting mate-
rials are cheap and easily prepared, the experimental
procedure is very simple and this method may be
applicable to large-scale production.
3.9 These compounds (7), with increased lipophilicity
relative to the parent compounds (6), have higher bio-
logical activities because the increased lipophilicity
facilitates penetration and transport as well as protec-
tion of the compound from metabolism.
The larvicidal activities of the title compounds (6) and
(7) were evaluated using a previously reported proce-
dure.3c,10 The larvicidal activities were tested against
armyworm by foliar application. Percent mortalities for
the armyworm evaluations were determined 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 reactions of the N-tert-butyl-N-substituted ben-
zoylhydrazines (5) with substituted phenylisocyanates
in 1,2-dichloroethane provided N%-tert-butyl-N%-substi-
tuted benzoyl-N-(substituted phenyl)aminocarbonyl-
hydrazines (6), as shown in Scheme 28 and Table 2.
The larvicidal activities show that the title compounds
(6) and (7) exhibit good larvicidal activities. For exam-
ple, at 1000 mg/mL, the percent mortality of compound
6a and 6b is 75.0 and 82.5%, respectively. Toxicity
assays indicated that the title compounds (6) and (7)
can induce a premature, abnormal and lethal larval
molt. The symptoms of toxicity included discoloration,
weight loss, cessation of feeding, and developmentally
premature, lethal molting at higher rates.
In order to increase the lipophilicity of compounds (6),
treatment of the N%-tert-butyl-N%-substituted benzoyl-
N-(substituted phenyl)aminocarbonylhydrazines (6)
with oxalyl chloride gave the colourless crystalline
products (7) in good yields (>70%), as shown in Scheme
We have found that the title compounds (6) possess
potential anticancer activities. For example, at 10−4
mol/L, the inhibition rate of compound 6c to P-388 and
A-549 is 29.8 and 29.2%, respectively. The inhibition
rate of compound 6b to HL-60 and BEL-7402 is 33.3
and 21.6%, respectively.
Table 1.
Entry
Xn
Isolated yield (%)
4a–e“5a–e
3“4a–e
a
b
c
d
e
H
90
83
86
91
87
96
92
96
90
82
3,5-Me2
2-F
2-Cl
These results are promising. Further studies on larvici-
dal activities and anticancer activities of the title com-
pounds (6) and (7) are underway and will be reported in
due course.
2,4-Cl2
Scheme 2.
Table 2.
Entry
Xn
Yn
Yield (%)
Entry
Xn
Yn
Yield (%)
a
b
c
d
e
f
H
H
H
H
H
4-F
4-OMe
3,4-Cl2
2,6-Me2
4-Cl
75
81
87
87
57
87
69
h
i
j
k
l
m
n
2-Cl
2-Cl
2,4-Cl2
3,5-Me2
2-F
4-Cl
H
H
4-F
4-F
4-Cl
4-Cl
80
79
71
80
84
75
71
H
3,5-Me2
2-F
H
H
g
4-Cl
Scheme 3.

Q. Wang, R. Huang / Tetrahedron Letters 42 (2001) 8881–8883
8883
Acknowledgements
(CꢀO); 1573.1, 1529.5, 1508.8 (Ph); 1375.6, 1350.0 (t-Bu);
719.6, 696.7 (Ph).
8. General procedure for the preparation of N%-tert-butyl-
N%-substituted benzoyl-N-(substituted phenyl)aminocar-
bonylhydrazines (6). To a stirred solution of the N-tert-
butyl-N-substituted benzoylhydrazine (5) (2.17 mmol) in
1,2-dichloroethane (10 mL) was added dropwise a solu-
tion of a substituted phenylisocyanate (2.17 mmol) in
1,2-dichloroethane (5 mL) at room temperature. After the
addition, the resulting mixture was stirred at reflux tem-
perature. The reaction was monitored by TLC and
stopped after complete consumption of 5. The reaction
mixture was diluted with petroleum ether (60–90°C) and
filtered to afford a white solid. The crude solid was
recrystallised from dimethylformamide to obtain an ana-
lytical sample of 6. Compound 6f (Xn=3,5-Me2, Yn=4-
Cl): yield 87%; mp 256–257°C; IR (KBr) w/cm−1: 3343,
3114, 2964, 1720, 1621, 1594, 1533, 1490, 1392, 1360,
1223, 1190, 1090, 852, 822, 757, 691, 618; 1H NMR
(CDCl3): l 1.44 (s, 9H, t-Bu), 2.20 (s, 6H, Me), 6.94–7.27
(m, 7H, Ph), 8.52 (s, 1H, NH), 8.56 (s, 1H, NH); MS (EI)
m/z 373.20 (M, 2%), 317.25 (1%), 164.30 (6%), 153.20
(3%), 133.25 (100%), 105.25 (24%), 79.20 (8%). Anal.
calcd for C20H24ClN3O2: C, 64.25; H, 6.47; N, 11.24.
Found: C, 64.35; H, 6.44; N, 11.17%.
9. General procedure for the preparation of the compounds
(7). N%-tert-Butyl-N%-substituted benzoyl-N-(substituted
phenyl)aminocarbonylhydrazine (6) (3.27 mmol) and oxa-
lyl chloride (0.50 g) were dissolved in 25 mL of 1,2-
dichloroethane and boiled for 24 hr. The solvent was
removed under vacuum, and the residue was purified by
column chromatography on silica gel using a mixture of
petroleum ether (60–90°C) and ethyl acetate as the eluent.
Finally, the colourless crystalline (7) was obtained. Com-
pound 7m (Xn=H, Yn=Cl): yield 71%; mp 124–126°C;
IR (KBr) w/cm−1: 3092, 2975, 1790, 1753, 1695, 1492,
1392, 1311, 1190, 804, 741, 699; 1H NMR (DMSO): l
1.59 (s, 9H, t-Bu), 7.01–7.38 (m, 9H, Ph); MS (EI): m/z
399.15 (M, 1.1%), 343.10 (16.5%), 105.05 (100%), 77.05
(9%). Anal. calcd for C20H18ClN3O4: C, 60.08; H, 4.54;
N, 10.51. Found: C, 59.86; H, 4.37; N, 10.74%.
This work was supported by the National Natural
Science Foundation of China.
References
1. (a) Norman, J.; Meola, S. Antimicrob. Agents Chemother.
1983, 32, 313; (b) Mayer, R.; Netter, K.; Leising, H.;
Schatshabel, D. Toxicology 1984, 30, 1.
2. (a) Wing, K. D. Science 1988, 241, 467; (b) Wing, K. D.;
Slawecki, R. A.; Carlson, G. R. Science 1988, 241, 470.
3. (a) Nakagawa, Y.; Smagghe, G.; Kugimiya, S.; et al.
Pestic. Sci. 1999, 55, 909; (b) Nakagawa, Y.; Shimizu, B.;
Oikawa, N.; et al. Classical and Three-Dimensional QSAR
in Agrochemistry, ACS Symposium Series 606; American
Chemical Society: Washington, DC, 1995; p. 288; (c)
Wang, Q. M.; Bi, F. C.; Li, Z. G.; Huang, R. Q.
Symposium of Agrochemicals X; Chinese Chemical Soci-
ety: Hangzhou, 2000; p. 194; (d) Wang, Q. M.; Li, Z. G.;
Huang, R. Q.; Chen, J. R. Proceeding of CCS Congress
2000; China Chemical Society: Beijing, 2000; p. 357.
4. Benzyl chloroformate: yield 98%; n2D0=1.5188.
5. Compound 3: yield 84%; mp 75–77°C; 1H NMR
(CDCl3): l 1.11 (s, 9H, t-Bu), 5.16 (s, 2H, OCH2), 5.02
(br., 2H, NHNH), 7.38 (m, 5H, Ph); IR (KBr) w/cm−1
:
3264.0, 3240.0 (NHNH); 1713.4 (CꢀO); 1521.4, 1491.8,
1466.3 (Ph); 1406.2, 1381.8 (t-Bu); 1260.8 (CꢁO); 828.2,
716.1 (Ph).
6. Compound 4: yield 90%; mp 150–152°C; 1H NMR
(DMSO): l 1.40 (d, 9H, t-Bu), 4.80–5.05 (m, 2H, OCH2),
6.84–7.37 (m, 10H, Ph), 9.83 (s, NH); IR (KBr) w/cm−1
:
3219.5 (NH); 1742.5, 1622.0 (CꢀO); 1578.4, 1531.5,
1498.1 (Ph); 1403.3, 1382.3 (t-Bu); 738.6, 712.9 (Ph).
Anal. calcd for C19H22N2O3: C, 69.92; H, 6.79; N, 8.58.
Found: C, 69.82; H, 6.85; N, 8.78%.
7. Compound 5a: yield 96%; mp 127–129°C; 1H NMR
(CDCl3): l 1.48 (s, 9H, t-Bu), 3.90 (s, 2H, NH2), 7.28–
7.56 (m, 5H, Ph); IR (KBr) w/cm−1: 3276.0 (NH2); 1620.5
10. Murphy, R. A.; Hsu, A. C. T. US Pat. 5,117,057.