Regioselective synthesis of fraxinellone-based hydrazone derivatives as insecticidal agents

Article abstract of DOI:10.1016/j.bmcl.2012.07.058

In continuation of our program aimed at the discovery and development of natural products-based insecticidal agents, twenty-three new fraxinellone-based hydrazone derivatives were smoothly prepared from fraxinellone via regioselectively allylic oxidation in the presence of selenium dioxide or chromium trioxide under microwave irradiation and subsequent condensation with hydrazides or hydrazines. Their insecticidal activity was evaluated against the pre-third-instar larvae of Mythimna separata Walker in vivo. Especially compounds 6d and 7a displayed the most pronounced insecticidal activity compared with toosendanin, a commercial botanical insecticide derived from Melia azedarach.

Full text of DOI:10.1016/j.bmcl.2012.07.058

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5384–5387
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Regioselective synthesis of fraxinellone-based hydrazone derivatives
as insecticidal agents
⇑
Yong Guo, Yuan-Yuan Yan, Chun Yang, Xiang Yu, Xiao-Yan Zhi, Hui Xu
Laboratory of Pharmaceutical Design and Synthesis, College of Sciences, Northwest A&F University, Yangling 712100, China
a r t i c l e i n f o
a b s t r a c t
Article history:
In continuation of our program aimed at the discovery and development of natural products-based insec-
ticidal agents, twenty-three new fraxinellone-based hydrazone derivatives were smoothly prepared from
fraxinellone via regioselectively allylic oxidation in the presence of selenium dioxide or chromium triox-
ide under microwave irradiation and subsequent condensation with hydrazides or hydrazines. Their
insecticidal activity was evaluated against the pre-third-instar larvae of Mythimna separata Walker in
vivo. Especially compounds 6d and 7a displayed the most pronounced insecticidal activity compared
with toosendanin, a commercial botanical insecticide derived from Melia azedarach.
Received 4 May 2012
Revised 22 June 2012
Accepted 13 July 2012
Available online 21 July 2012
Keywords:
Fraxinellone
Insecticidal activity
Botanical insecticide
Structural modification
Allylic oxidation
Ó 2012 Elsevier Ltd. All rights reserved.
Although the routine use of a wide variety of synthetic chemical
insecticides in agriculture has now become an accepted practice,
the increasing application of those agrochemicals over the years
has resulted in the development of resistance in insect pest popu-
lations and environmental problems. Development of new effec-
tive, selective and safe pesticides, therefore, is highly desirable.
Due to plant secondary metabolites resulting from the interaction
between plants and environment (life and non-life) during the long
period of evolution in plants, consequently, the discovery of new
insecticidal compounds from plant secondary metabolites, fol-
lowed by using them as the lead-compounds for further structural
modifications has recently been one of the important procedures
for research and development of new pesticides.1–3
Fraxinellone (1, Fig. 1), a naturally occurring degraded limonoid,
isolated from Dictamnus albus,4 Dictamnus dasycarpus5 and Melia
azedarach,6 has been found many interesting activities in the field
of medicinal chemistry such as antifertility activity,7 vascular relax-
ing activity,8 anti-inflammatory activity,9 and treating T-cell-medi-
ated liver disorders.10 Additionally, compound 1 also exhibited the
insecticidal activity.11–14 Although total synthesis of compound 1
has been reported,15–19 to the best of our knowledge, little attention
has been paid to structural modifications of 1 as insecticidal agents.
On the other hand, hydrazone fragments have recently received
much attention due to their key role in medically important species,
such as those displaying antifungal and antimicrobial activities,20,21
and cyclooxygenase (COX) inhibitors.22 Based upon the above-men-
tioned interesting results, and in continuation of our program aimed
at the discovery and development of natural products-based insec-
ticidal agents,3,23–26 herein we designed and prepared a series of
fraxinellone-based hydrazone derivatives as insecticidal agents.
Two key intermediates, 3-formylfraxinellone (2) and fraxinello-
none (3), were firstly synthesized from compound 1 by regioselec-
tively allylic oxidation under microwave irradiation.27 As shown in
Scheme 1, in the presence of selenium dioxide (SeO2, 2 equiv) at
110 °C with a microwave power of 150 W for 2.5 h, compound 2
was obtained as a major product in a 27% yield from 1, and the
yields of byproducts such as 3, 4b-hydroxyfraxinellone (4), and
3-hydroxymethylfraxinellone (5) were <7%, 5%, and 3%, respec-
tively. On the contrary, even if a mixture of compound 1 and
SeO2 (2 equiv) in dioxane in the presence of was refluxed for
24 h, the yield of 2 was only 23%. Based upon the above results,
similarly, a mixture of 1, chromium trioxide (1 equiv), pyridine
O
11
6
8
5
7
9
O
4
1
2
3
O
10
1
⇑
Corresponding author. Tel./fax: +86 29 87091952.
E-mail address: orgxuhui@nwsuaf.edu.cn (H. Xu).
Figure 1. The chemical structure of fraxinellone (1).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.07.058

Y. Guo et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5384–5387
5385
O
O
O
+
O
O
O
+
+
3
HO
O
O
O
OH
5
O
SeO2/MW
(<7%)
(3%)
4
(27%)
(5%)
2
150 W, 2.5 h
110 oC
O
O
HOAc, reflux
hydrazides or hydrazines
2-24 h, 47-97%
O
O
13 examples
O
O
1
N
HN
CrO3/Py/t-BuOOH
MW, 25 W, 2.5 h
R
6a-m 6b
(
, E/Z=9/1)
33 o
C
O
O
hydrazides or hydrazines
O
HOAc, reflux
O
H
O
N
O
10 examples
5-48 h, 62-87%
R
N
O
3
(27%)
7d
( , E/Z=2/1)
7a-j
R =
O
R =
R =
F
O
e
a
b
F
j
S
O
O
O
F
f
CN
F
O
k
NO2
Cl
g
c
OMe
Me
O
l
h
O
d
NO2
NO2
m
N
i
O2N
Scheme 1. Synthetic route for the preparation of 6a–m and 7a–j.
NO2
(2 equiv), and 70% aq t-BuOOH (10 equiv) in dichloromethane was
reacted at 33 °C under microwave irradiation with a power of 25 W
for 2.5 h, only compound 3 was regioselectively obtained in a 27%
yield. Subsequently, compounds 2 and 3 reacted with hydrazides
and hydrazines, respectively, to afford fraxinellone-based hydra-
zone derivatives 6a–m and 7a–j, which were well characterized
by 1H NMR, 13C NMR, IR, HRMS and mp (see Supplementary data).
Due to the steric hindrance, the substituents on the C@N double
bond of all compounds (except E/Z = 9/1 for 6b, and E/Z = 2/1 for
7d) adopted E configuration.28 To obtain the precise three-dimen-
sional structural information and configuration of 6a–m and 7a–j,
the single-crystal structures of 3, 6i, 7e and 7j were confirmed by
X-ray crystallography (Fig. 2–5).29 The substituents on the C@N
double bond of 6i, 7e and 7j all adopted E configuration.
Finally, the insecticidal activity of 1–3, 6a–m and 7a–j was eval-
uated against the pre-third-instar larvae of Mythimna separata
Walker in vivo by the leaf-dipping method at the concentration
of 1 mg/mL.25 Toosendanin, a commercial botanical insecticide de-
rived from Melia azedarach, was used as the positive control, and
leaves treated with acetone alone were used as a blank control
group.
As described in Table 1, compared with toosendanin and 1,
compounds 6a, 6b, 6d, 6f, 6j, 7a–c and 7f exhibited the promising
and pronounced insecticidal activity. Especially compounds 6d and
7a showed the most pronounced insecticidal activity, and the final
mortality rates of 6d and 7a were 73.1% and 76.9%, respectively. No
significant differences in the insecticidal activity were observed
between the hydrazones substituents at the 10- and 4-position of
fraxinellone. In general, acyl hydrazones exhibited better insecti-
cidal activity than the corresponding hydrazones. For example,
the final mortality rates of acyl hydrazones 6a, 6b, 7a and 7b were
65.4%, 61.5%, 76.9% and 65.4%, respectively. Whereas the final mor-
tality rates of the corresponding hydrazones 6g, 6h, 7g and 7h
were 53.8%, 38.5%, 46.2% and 53.8%, respectively. When a thio-
phene group was introduced to acyl hydrazones at the 10- or 4-po-
sition of fraxinellone to afford 6e and 7e, their insecticidal activity
was decreased sharply (e.g., 34.6% for 6e, and 38.5% for 7e). Inter-
estingly, introduction of cyanoacetyl hydrazone at the 10- or 4-po-
sition of fraxinellone could lead to the potent compounds (e.g., 6f
and 7f). Hence, the chain of acyl hydrazones should be considered
for further structural modifications, and it will be reported in due
course.

5386
Y. Guo et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5384–5387
Figure 4. The X-ray crystallography of 7e.
Figure 2. The X-ray crystallography of 3.
Figure 5. The X-ray crystallography of 7j.
Table 1
Insecticidal activity of 6a–m and 7a–j at 1 mg/mL against M. separata
Compounds
Corrected mortality rate (%)
20 d
10 d
35 d
1
2
3
41.4 ( 9.4)
17.2 ( 8.2)
48.3 ( 8.2)
58.6 ( 0)
40.7 ( 4.7)
25.9 ( 4.7)
48.1 ( 4.7)
55.6 ( 0)
48.1 ( 4.7)
40.7 ( 4.7)
66.7 ( 8.2)
29.6 ( 9.4)
66.7 ( 0)
44.4 ( 8.2)
14.8 ( 4.7)
37.0 ( 4.7)
40.7 ( 9.4)
44.4 ( 0)
53.8 ( 0)
34.6 ( 4.7)
57.7 ( 4.7)
65.4 ( 0)
61.5 ( 4.7)
53.8 ( 0)
73.1 ( 4.7)
34.6 ( 4.7)
69.2 ( 4.7)
53.8 ( 0)
38.5 ( 4.7)
50.0 ( 4.7)
61.5 ( 4.7)
50.0 ( 4.7)
53.8 ( 8.2)
53.8 ( 0)
6a
6b
6c
6d
6e
6f
6g
6h
6i
37.9 ( 0)
44.8 ( 4.7)
55.2 ( 4.7)
24.1 ( 4.7)
55.2 ( 4.7)
27.6 ( 8.2)
20.7 ( 4.7)
13.8 ( 4.7)
37.9 ( 0)
Figure 3. The X-ray crystallography of 6i.
6j
6k
6l
37.9 ( 0)
41.4 ( 4.7)
31.0 ( 12.5)
44.4 ( 8.2)
40.7 ( 4.7)
In summary, a series of novel fraxinellone-based hydrazone
derivatives were regioselectively prepared from fraxinellone as
insecticidal agents. It was noteworthy that we have reported an
6m

Y. Guo et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5384–5387
5387
Table 1 (continued)
References and notes
Compounds
Corrected mortality rate (%)
20 d
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chromium trioxide, respectively. Especially two compounds of
fraxinellone-based hydrazone derivatives displayed the most po-
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This work was supported by National Natural Science Founda-
tion of China (No. 31071737, 31171896), the Fok Ying Tong Educa-
tion Foundation for Young Talents (No. 121032), Program for
Changjiang Scholars and Innovative Research Team in University
(IRT1035), and Special Funds of Central Colleges Basic Scientific Re-
search Operating Expenses (QN2009045). We are deeply grateful
to Professor H.L. Zhang for the NMR experiments.
26. Xu, H.; Wang, J. J. Bioorg. Med. Chem. Lett. 2010, 20, 2500.
27. Microwave irradiation was performed in a CEM Discover Synthesis Unit (CEM
Corp., Matthews, NC, Made in USA).
28. The ratios of E/Z of 6b and 7d were determined by the 1H NMR spectra (see
Supplementary data).
Supplementary data
29. Crystallographic data (excluding structure factors) for the structures of 3, 6i, 7e
and 7j in this Letter have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC 861260, 861285,
861286 and 861287, respectively. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax:
+44 (0)1223 336033 or E-mail: deposit@ccdc.cam.ac.uk]
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.07.
058.