Synthesis, fungicidal activity, and structure-activity relationship of spiro-compounds containing macrolactam (Macrolactone) and thiadiazoline rings

Article abstract of DOI:10.1021/jf903665f

Two series of novel spiro-compounds containing macrolactam or macrolactone and thiadiazoline rings, 1-thia-2-alkylimino-3,4,9-triaza-10-oxospiro[4.15] eicosyl-3-ene (4F) and 1-thia-2-alkylimino-3,4-diaza-9-oxa-10-oxospiro[4.15] eicosyl-3-ene (4G), were sy

Full text of DOI:10.1021/jf903665f

J. Agric. Food Chem. 2010, 58, 2659–2663 2659
DOI:10.1021/jf903665f
Synthesis, Fungicidal Activity, and Structure-Activity
Relationship of Spiro-Compounds Containing Macrolactam
(Macrolactone) and Thiadiazoline Rings†
#
J
IAN-JUN
L
I
,§ XIAO-MEI
HU-HUA
L
IANG,§ SHU-HUI
-HENG
J
IN,§ JIAN-JUN
§
Z
HANG,§ HUI-ZHU
,§
Y
UAN
,
S
Q
I
,# F
U
C
HEN
,
AND
D
AO-QUAN
WANG
*
§Key Laboratory of Pesticide Chemistry and Application Technology, Department of Applied Chemistry,
China Agricultural University, Beijing, People’s Republic of China 100193 and #Key Laboratory of
Pesticide Chemistry and Application Technology, Institute of Plant Protection, Chinese Academy of
Agricultural Sciences, Beijing, People’s Republic of China 100193
Two series of novel spiro-compounds containing macrolactam or macrolactone and thiadiazoline
rings, 1-thia-2-alkylimino-3,4,9-triaza-10-oxospiro[4.15]eicosyl-3-ene (4F) and 1-thia-2-alkylimino-
3,4-diaza-9-oxa-10-oxospiro[4.15]eicosyl-3-ene (4G), were synthesized from 12-oxo-1,15-pentade-
canlactam and 12-oxo-1,15-pentadecanlactone, respectively. Their structures were confirmed by
elemental analysis, 1H NMR, and 13C NMR. The conformation of compounds 4F was determined
via the crystal structure of a representative compound (4F6). The bioassay showed that compounds
4F have much better fungicidal activity against five fungi (Botrytis cinerea Pers., Sclerotinia
€
sclerotiorum, Rhizoctonia solani Kuhn., Phomopsis asparagi Sacc., and Pyricularia oryzae Cav.)
than compounds 4G. The fact above showed that the presence of a hydrogen-bonding donor for the
fungicidal activity of macrocyclic compounds is very important. 4F6 showed excellent fungicidal
activity against P. oryzae, which is much better than the commercial fungicide isoprothiolane, and
4F13 showed excellent fungicidal activity against P. oryzae and good fungicidal activity against
P. asparagi.
KEYWORDS: Spiro-compounds; macrolactam; macrolactone; thiadiazoline; fungicidal activity
INTRODUCTION
In this paper the cyclododecane ring of compounds A was
replaced by macrolactam or macrolactone rings, keeping the
thiadiazoline ring, and as a result two series of novel spiro-
compounds (4F and 4G) were synthesized. Their fungicidal acti-
vity against five fungi (Botrytis cinerea Pers., Sclerotinia sclero-
In recent years there has been intense investigation of thiadia-
zole derivatives, some of which are known to possess interesting
pesticidal activity such as fungicidal activity (1), herbicidal
activity (2), and insecticidal activity (3). Previous research has
shown that a series of thiadiazole derivatives (A, Figure 1)
containing thiadiazoline and cyclododecane rings have good
€
tiorum, Rhizoctonia solani Kuhn., Phomopsis asparagi Sacc., and
Pyricularia oryzae Cav.) was evaluated in vitro. The synthetic
route of compounds 4 is shown in Scheme 1.
€
fungicidal activity against Rhizoctonia solani Kuhn and Verticil-
lium dahliae (4).
MATERIALS AND METHODS
It has also been reported that cyclododecanone derivatives,
such as 2-oxocyclododecanone oxime ethers (B, Figure 1) (5) and
N-substituted-2-oxocyclododecylsulfonamides (C, Figure 1) (6)
have good fungicidal activity. Their fungicidal activity was
improved by structural derivation employing macrolactam or
macrolactone rings to replace cyclododecane ring. That is,
alkoxyimino-macrolactams (or alkoxyimino-macrolactones)
(D, Figure 1) (7) and 12-alkylsulfonamido-macrolactams (or
12-alkylsulfonamido-macrolactones) (8) (E, Figure 1) have better
fungicidal activity than compounds B and C, which indicated that
it may be an effective approach to improve the bioactivity of
cyclododecane derivatives to replace the cyclododecane ring
employing macrolactam and macrolactone rings.
General. NMR spectra were recorded in CDCl3 or DMSO-d6, with a
Bruker DPX300 spectrometer, using TMS as internal standard; elemental
analysis was performed by the analytical center at the Institute of
Chemistry (Beijing), Chinese Academy of Sciences. Melting points were
measured on a Yanagimoto melting point apparatus and are uncorrected.
The solvents and reagents were used as received or were dried prior to use
as needed. Pyrimethanil (purity = 95%) was purchased from Jiangsu
Fengdeng Pesticide Co., Ltd., Jiangsu Province, China. Chlorothalonil
(purity = 98%) was purchased from Jiangsu Limin Chemical Industry
Co., Ltd., Jiangsu Province, China. Thiram (purity=96%) was purchased
from Kerun Pesticide Factory, Tianjin, China. Isoprothiolane 40%
emulsifiable concentrates (EC) was purchased from Zhejiang Weierda
Chemical Industry Co., Ltd., Zhejiang Province, China.
Chemical Synthesis. Synthesis of compounds followed the outline in
Scheme 1.
†Part of the ECUST-Qian Pesticide Cluster.
*Author to whom correspondence should be addressed (telephone/
fax 86-10-62732219; e-mail wangdq@cau.edu.cn).
Synthesis of Compounds 1. Compounds 1 were synthesized from
2-nitrocyclododecanone as previously described (9, 10).
© 2009 American Chemical Society
Published on Web 12/30/2009
pubs.acs.org/JAFC

2660 J. Agric. Food Chem., Vol. 58, No. 5, 2010
Li et al.
Synthesis of Compounds 2. Compounds2 weresynthesized fromamines
as previously described (11).
X-ray Diffraction Analysis of Compound 4F6. The crystal of
compound 4F6 was obtained by slow evaporation from a solution of
petroleum ether and ethyl acetate. All measurements were made with a
Siemens CCD area detector under graphite monochromatized Mo KR
(λ=0.071073 nm) radiation at 293 K. The structure was solved by direct
method using SHELX (14) and refined on F2 using all data by full-matrix
least-squares procedures with SHELXL-97 (15).
Bioassay of Fungicidal Activity. Method. Fungicidal activity of
compounds 4 against B. cinerea, S. sclerotiorum, R. solani, P. asparagi, and
P. oryzae was evaluated using mycelium growth rate test (16). All five
fungal strains for mycelium growth rate test were provided by the Institute
of Plant Protection, Chinese Academy of Agricultural Sciences. B. cinerea
and R. solani were collected from a cucumber field in the suburbs of
Beijing, China. S. sclerotiorum was collected from a rape field in the
suburbs of Tianjin, China. P. asparagi was collected from an asparagus
field in Anyang, Henan Province, China. P. oryzae was collected from a
rice field in Songzi, Hubei Province, China.
Synthesis of Compounds 3. Compounds 3 were synthesized from
compounds 1 and 2 as previously described (12).
Synthesis of Compounds 4 (4 , 13 ). To a stirred solution of compound 3
(3.0 mmol) in 80 mL of CH2CL2 was added MnO2 (8 g). The mixture was
further stirred for 30 min. After filtration, the filtrate was evaporated
under reduced pressure to give a crude product, which was purified on
silica gel column chromatography with petroleum ether and ethyl acetate
to separate the compound 4.
Fungicidal Activity of Compounds 4. Inhibition of compounds 4 against
the five plant pathogenic fungi was tested initially as concentrations of 100,
50, 25, 12.5, and 6.25 μg/mL. The EC50 was estimated using logit
analysis (17). When the EC50 values of compounds were <5 μg/mL, the
compounds were then tested at 25, 12.5, 6.25, 3.13, and 1.56 μg/mL. When
the EC50 was <1 μg/mL, the compounds were tested at 3.13, 1.56, 0.78,
0.39, and 0.2 μg/mL to determine accurate EC50 values. A commercial
fungicide commonly used for management of the plant pathogens was
used for comparison to the tested compounds. The fungicides included pyri-
methanil for B. cinerea, chlorothalonil for S. sclereotiorum and P. asparagi,
thiram for R. solani, and isoprothiolane for P. oryzae.
Figure 1. Structures of compounds A-E.
Scheme 1. Synthetic Route of Compounds 4
RESULTS AND DISCUSSION
Synthesis of Compounds 4. As shown in Scheme 1, 1-thia-
2-alkylimino-3,4,9-triaza-10-oxospiro[4.15]eicosyl-3-ene (4F) and
1-thia-2-alkylimino-3,4-diaza-9-oxa-10-oxospiro[4.15]eicosyl-3-ene
(4G) were synthesized from 12-oxo-1,15-pentadecanlactam (1F)
and 12-oxo-1,15-pentadecanlactone (1G), respectively, by con-
densation reaction with N-substituted thiosemicarbazide (2) to
give compounds 3F and 3G, which undergo oxidative cyclization
on treatment with manganese dioxide. The yields of compounds 4
from 3 are fair to good (64-90%) as shown in Table 1. The
structures of compounds 4 were confirmed by elemental analysis
(Table 1), 1H NMR, and 13C NMR (Table 2).
Table 1. Physical and Elemental Data of Compounds 4
elemental analysis (%)
compd no.
R
mp (°C)
yield (%)
C (calcd)
H (calcd)
N (calcd)
4F1
4F2
C6H5
100-102
100-102
117-118
66-68
48-49
67-69
109-110
38-40
40-41
129-131
120-122
69-70
119-120
130-131
115-117
119-120
87-89
75
85
71
76
82
79
70
70
87
83
90
79
83
65
68
89
80
69
71
68
64
66.24 (65.96)
66.23 (66.63)
66.23 (66.63)
66.64 (66.63)
60.71 (60.74)
61.05 (60.74)
55.36 (55.11)
64.44 (64.15)
64.63 (64.15)
67.34 (67.25)
67.01 (67.25)
67.22 (67.25)
56.42 (56.28)
55.94 (56.28)
69.54 (69.30)
66.93 (66.63)
59.20 (60.60)
60.90 (60.60)
54.88 (55.00)
55.18 (55.00)
66.97 (67.10)
8.27 (8.05)
8.48 (8.27)
8.48 (8.27)
8.33 (8.27)
7.23 (7.18)
7.30 (7.18)
6.80 (6.52)
7.80 (7.96)
8.09 (7.96)
8.78 (8.47)
8.46 (8.47)
8.53 (8.47)
6.76 (6.44)
6.46 (6.44)
7.75 (7.60)
7.99 (8.27)
6.60 (6.94)
7.07 (6.94)
6.00 (6.29)
6.49 (6.29)
8.23 (8.21)
13.68 (13.99)
13.20 (13.51)
13.20 (13.51)
13.15 (13.51)
12.62 (12.88)
12.47 (12.88)
11.92 (11.68)
13.39 (13.01)
12.85 (13.01)
13.03 (13.07)
13.27 (13.07)
13.24 (13.07)
11.80 (11.93)
11.66 (11.93)
12.02 (12.43)
13.28 (13.51)
9.85 (9.64)
o-CH3C6H4
m-CH3C6H4
p-CH3C6H4
o-ClC6H4
4F3
4F4
4F5
4F6
p-ClC6H4
o-BrC6H4
4F7
4F8
o-CH3OC6H4
p-CH3OC6H4
2,3-(CH3)2C6H3
2,4-(CH3)2C6H3
2,5-(CH3)2C6H3
3,4-Cl2C6H3
2,5-Cl2C6H3
R-naphthyl
benzyl
4F9
4F10
4F11
4F12
4F13
4F14
4F15
4F16
4G1
4G2
o-ClC6H4
p-ClC6H4
91-92
98-100
90-92
9.75 (9.64)
8.96 (8.75)
a
4G3
o-BrC6H4
p-BrC6H4
2,5-(CH3)2C6H3
4G4
4G5
8.66 (8.75)
9.90 (9.78)
100-101
a Its crystal structure was previously reported (18).

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2662 J. Agric. Food Chem., Vol. 58, No. 5, 2010
Li et al.
Table 3. Fungicidal Activity of Compounds 4 against Five Fungia
EC50 (μg/mL)
compd no.
B. cinerea S. sclerotiorum R. solani P. asparagi P. oryzae
4F1
4F2
5.01
4.21
9.92
375.43
4.42
42.08
124.79
30.72
71.83
31.80
39.52
56.13
37.89
93.00
22.38
26.75
5.62
14.18
73.79
9.67
41.51
78.43
63.18
138.76
41.51
0.054
57.59
397.84
57.85
199.48
30.92
86.61
0.72
4F3
4F4
6.42
25.10
14.89
18.67
19.86
21.85
6.47
34.08
241.56
48.18
533.29
21.09
87.23
36.53
55.71
34.30
15.03
109.29
767.24
8.32
14.52
24.48
101.63
60.32
517.04
20.56
14.85
5.26
4F5
4F6
4F7
4F8
Figure 2. Crystal structure of compound 4F6.
4F9
4F10
22.61
9.63
4F11
4F12
18.58
34.23
29.56
15.73
14.44
43.81
49.95
36.42
49.88
126.29
0.14
16.42
9.02
4F13
4F14
36.82
41.77
17.80
23.49
159.06
126.32
207.69
17.10
421.80
nd
221.73
46.15
21.33
116.49
42.48
53.55
29.21
208.41
nd
1.11
4F15
4F16
195.80
116.85
211.36
338.37
246.10
338.37
3123.76
nd
4G1
4G2
169.20
59.91
204.57
38.30
162.84
nd
4G3
4G4
Figure 3. Conformation of 4F6 (left) and 4G3 (right).
4G5
Conformation of Compound 4. X-ray diffraction analysis of a
representative compound (4F6) showed that its large ring skeleton
adopts [333133] conformation, in which the carbonyl group is
present in a side position and the spiro-carbon atom in a corner
position (Figure 2). Previous research reported the crystal struc-
ture of 4G3 (18), the large ring skeleton of which can be described
as [33343] conformation with the carbonyl group in a side posi-
tion and the spiro-carbon atom in a corner position. The
conformations of the large ring skeleton of 4F6 and 4G3 are
somewhat different from each other. However, they should be
similar in the solution due to the dynamic equilibrium (Figure 3).
[CCDC 739298 contains supplementary crystallographic data for
this paper. These data can be obtained free of charge from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. Telephone
(44) 01223 762910; e-mail deposit@ccdc.cam.ac.uk.]
Fungicidal Activity and Structure-Activity Relationship.
Compounds 4F have much better fungicidal activity than com-
pounds 4G (Table 3). Compounds 4F have fair to excellent
fungicidal activity against the five fungi, and there is at least
one compound that has good fungicidal activity against one of
the five fungi (fair, good, and excellent fungicidal activities
indicate that their EC50 values are less than 30, 6, and 2 μg/mL,
respectively). However, compounds 4G have only poor fungi-
cidal activity, and the EC50 values of almost all compounds
are >30 μg/mL.
In view of stereochemistry, compounds 4F and 4G have similar
conformations. However, there are a hydrogen-bonding donor
(-CONH-) and a hydrogen-bonding acceptor (NdN double
bond of diazoline ring) on the large ring of compounds 4F and
there are two hydrogen-bonding acceptors (-COO- and NdN
double bond of diazoline ring) without a hydrogen-bonding
donor on the large ring of compounds 4G. This is the main
reason compounds 4F and 4G have different fungicidal activities.
The results above show that the presence of a hydrogen-bonding
donor is very important to the fungicidal activity of macrocyclic
compounds, and the rule on the relationship between the fungi-
cidal activity and hydrogen bonding has a general suitability to
the macrocyclic compounds (7).
pyrimethanil
chlorothalonil
thiram
isoprothiolane
40% EC
nd
0.41
nd
4.35
nd
nd
nd
0.90
nd
nd
nd
nd
nd
nd
7.19
a Regression equations and correlation coefficients are omitted; nd, not determined.
respectively, displayed the best fungicidal activities, but they were
inferior to the commercial fungicide pyrimethanil, the EC50 value
of which was 0.14μg/mL. The compounds with one totwo methyl
or methoxy groups on the benzene ring have better fungicidal
activity (Tables 1 and 3).
Fungicidal Activity of Compounds 4F against S. sclerotio-
rum. Compounds 4F have fair to good fungicidal activities
against S. sclerotiorum. Among them, compounds 4F1, 4F3, and
4F16, the EC50 values of which were 9.92, 4.42, and 8.32 μg/mL,
respectively, displayed the best fungicidal activities, but they were
inferior to the commercial fungicide chlorothalonil (EC50 value=
0.41 μg/mL) (Table 3). Thus, the compounds without any group
on the benzene ring (phenyl) or nonaryl (benzyl) have better
fungicidal activity. In addition, the influence of the methyl group
on the fungicidal activity should be taken seriously; the com-
pound with the meta-position methyl group on the benzene ring
(4F3) showed the best fungicidal activity (EC50 value = 4.42 μg/
mL), but the compound with the para-position methyl group on
the benzene ring had only moderate fungicidal activity (EC50
value=34.08 μg/mL), and the compound with the ortho-position
methyl group on the benzene ring showed the lowest fungicidal
activity (EC50 value = 375.43 μg/mL).
Fungicidal Activity of Compounds 4F against R. solani.
Compounds 4F have fair fungicidal activities against R. solani.
Only individual compound 4F12, with an EC50 value of 5.62 μg/
mL, displayed good fungicidal activity, but it was inferior to the
commercial fungicide thiram (EC50 value =0.90 μg/mL).
Fungicidal Activity of Compounds 4F against P. asparagi.
Compounds 4F have fair to good fungicidal activities against
P. asparagi. Among them, compounds 4F3, 4F11, and 4F13, with
EC50 values of 9.67, 5.26, and 9.02 μg/mL, respectively, displayed
the best fungicidal activitues, and they were comparable with the
commercial fungicide chlorothalonil (EC50 value=4.35 μg/mL).
Some compounds with one to two methyl groups on the benzene
ring have better fungicidal activity, and some compounds with
Fungicidal Activity of Compounds 4F against B. cinerea.
Compounds 4F have good fungicidal activities against B. cinerea.
Among them, compounds 4F1, 4F2, 4F3, 4F9, and 4F11, the EC50
values of which were 5.01, 4.21, 6.42, 6.47, and 9.63 μg/mL,

Article
J. Agric. Food Chem., Vol. 58, No. 5, 2010 2663
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Received for review July 15, 2009. Revised manuscript received
December 14, 2009. Accepted December 16, 2009. We acknowledge
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