Synthesis, insecticidal activities and SAR of novel phthalamides targeting calcium channel

Article abstract of DOI:10.1016/j.bmc.2014.09.052

In order to find novel and environmental friendly insecticides targeting the ryanodine receptor, three series of novel phthalamides containing heptafluoroisopropyl group, low fluorine atoms group and non-fluorine group were designed and synthesized. 35 novel structures of three series were obtained. Insecticidal activities of title compounds against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella) indicated that most of title compounds showed moderate to high activities at the tested concentration. The structure-activity relationship (SAR) was discussed in detail. During synthesizing title compounds B₈, C₇, D₁, D₉ and D₁₂, their corresponding positional isomers (B₈′, C₇′, D₁′, D₉′ and D₁₂′) were afforded, and their structures were confirmed by 2D NMR. The calcium-imaging technique was also applied to investigate the effects of compounds B₂, B₁₀, C₄ and C₅ on the intracellular calcium ion concentration ([Ca²⁺]_i), which indicated that they released stored calcium ions from endoplasmic reticulum, which denoted that some compounds are potential modulators of the insect ryanodine receptor (RyR).

Full text of DOI:10.1016/j.bmc.2014.09.052

Bioorganic & Medicinal Chemistry 22 (2014) 6366–6379
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis, insecticidal activities and SAR of novel phthalamides
targeting calcium channel
Youwei Chen, Yuxin Li, Li Pan, Jingbo Liu, Yingying Wan, Wei Chen, Lixia Xiong, Na Yang, Haibin Song,
⇑
Zhengming Li
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
In order to find novel and environmental friendly insecticides targeting the ryanodine receptor, three
series of novel phthalamides containing heptafluoroisopropyl group, low fluorine atoms group and
non-fluorine group were designed and synthesized. 35 novel structures of three series were obtained.
Insecticidal activities of title compounds against oriental armyworm (Mythimna separata) and diamond-
back moth (Plutella xylostella) indicated that most of title compounds showed moderate to high activities
Received 14 August 2014
Revised 15 September 2014
Accepted 24 September 2014
Available online 2 October 2014
at the tested concentration. The structure–activity relationship (SAR) was discussed in detail. During
Keywords:
0
synthesizing title compounds B8, C7, D1, D9 and D12, their corresponding positional isomers (B80, C7
,
Phthalamides
Insecticidal activity
Fluorine
0
D10, D9 and D120) were afforded, and their structures were confirmed by 2D NMR. The calcium-imaging
technique was also applied to investigate the effects of compounds B2, B10, C4 and C5 on the intracellular
calcium ion concentration ([Ca2+]i), which indicated that they released stored calcium ions from
endoplasmic reticulum, which denoted that some compounds are potential modulators of the insect
ryanodine receptor (RyR).
Calcium channel
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
obtained, which were not reported before. Their structures were
elucidated by 2D-HMNR and single-crystal X-ray diffraction analy-
The ryanodine receptors (RyRs) are calcium channels that regu-
late the Ca2+ release from intracellular stores located in the sarco-
plasmic reticulum.1–4 Flubendiamide5,6 (Fenos; NNI-0001), a new
benzene dicarboxamide compound discovered by Nihon Nohyaku
(Fig. 1), is the first synthetic insecticide that controls lepidopterous
pests through functional modulation of the RyRs.7–12 Its novel
structure, high efficiency and new mode of action aroused interest
worldwide.
There is an unusual heptafluoroisopropyl group and a methyl
group in the aromatic amine of Flubendiamide. Since the discovery
of Flubendiamide, there were no reports of the relevant studies on
relation between the methyl group on aniline and their insecticidal
activity. Herein, to explore whether the methyl group play a signif-
icant role at a certain substituted position for high efficiency, and
develop novel dicarboxamides containing low fluorine atoms
group or non-fluorine group instead of the heptafluoroisopropyl,
three novel series of phthalic acid diamide derivatives were
designed and synthesized as shown in Figure 1.
sis. Bioactivities of title compounds against oriental armyworms
(Mythimna separata) and diamondback moths (Plutella xylostella)
were tested and the structure–activity relationship (SAR) was ana-
lyzed and discussed in detail. The calcium imaging techniques
were used to investigate the effects of compounds on calcium
channels toward central neurons of Spodoptera exigua.
2. Results and discussion
2.1. Chemistry
The structures of 1a–ln were shown in Table 1, and the synthetic
routines of compounds 1a–1n were shown in Schemes 2–6. During
synthesis of compound 3l in Scheme 4, the amine group and hydro-
xyl group could be both protected by acetyl. Wash this byproduct
with NaOH solution (monitoring by TLC), the hydroxyl group was
deprotected to get compound 7 again, which made the yield of
compound 7 increase.
During synthesis of title compounds B8, C7, D1, D9, D12, their
The synthetic routine of title compounds B1, B3, B5, B8, C1, C4, C7,
C9, D1, D4, D6, D9, D12, D14 was showed in Scheme 1. During synthe-
sizing compounds B8, C7, D1, D9, D12, their corresponding positional
0
0
0
0
0
corresponding positional isomers B8 , C7 , D1 , D9 , D12 were also
0
0
0
0
isomers (B8 , C7 , D1 , D9 , D120) were obtained. A possible reaction
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.bmc.2014.09.052
0968-0896/Ó 2014 Elsevier Ltd. All rights reserved.

Y. Chen et al. / Bioorg. Med. Chem. 22 (2014) 6366–6379
6367
CN
n
N
S
O
m
I
HN
O
O
O
S
O
R1
HN
I
HN
HN
F
CF3
O
O
CF3
B
F
CN
n
CF3
CF3
N
S
O
m
I
HN
Flubendiamide
O
O
HN
CN
N
R2
S
I
HN
C
O
O
CN
N
m
HN
S
O
I
HN
HN
R
n
O
O
A
R3
D
Figure 1. Chemical structures of compounds Flubendiamide and A–D.
Table 1
The Rx group of compounds 1a–1n
H2N
Rx
Compd
Rx
Compd
Rx
1a
1b
1c
1d
1e
1f
2,6-Dimethyl-4-heptafluoroisopropyl
2,5-Dimethyl-4-heptafluoroisopropyl
2-Methoxyl-4-heptafluoroisopropyl
4-Heptafluoroisopropyl
2-Methyl
1h
1i
1j
1k
1l
1m
1n
3,4,5-Trifluoro
2-Methyl-4-nitryl
2-Methyl-5-acetyl
2,4-Dimethyl
2-Methyl-4-cyan
2-Methyl-4-malononitralkenyl
2-Methyl-4-isopropoxy
2-Methyl-4-fluoro
3,4-Difluoro
1g
mechanism was discussed in Scheme 1. Although yields of the
target compounds are much higher than their positional isomers,
we can not distinguish them only by H NMR, C NMR and HRMS.
Then the structures of the target compounds were further
confirmed by 2D-H NMR. The result was the same as the single
crystal structure.
there is a strong signal between H6 and C7 (dc = 169.282). Then H6
(dH = 7.658) was found. It was confirmed that the iodine atom is
connected with C3 (described in structure b).
On the basis of HMBC and HSQCED spectra, the correlation
between C4, C2 and H6 (dH = 7.658), between H4 and C4 (there is
no signal of C2 in HSQCED), indicated that dH = 7.810,
dc = 141.566 belongs to H4 and C4 respectively (described in struc-
ture c). dC = 128.369 (s, C6) was determined by the correlation
between H4 (dH = 7.810) and C6. Finally, the signals of H6
(dH = 7.658) and C6 (dC = 128.369) derived were found strongly
coupled in the HSQCED spectra (described in structure d), which
showed the deduction result is consistent with the data of HSQCED
spectra. The structure of compound C7 was confirmed, which was
the same as the single crystal structure of compound C7.
0
Taking compound C7 and its positional isomer C7 for example
(Fig. 2), the structure of compound C7 was elucidated by 1D NMR
and 2D NMR. The 1H and 13C NMR spectra showed the signals of
dH = 6.049 (s, H10), dH = 9.551 (s, H9) and dc = 93.826 (s, C3). It was
found that dc = 165.115 and dc = 169.282 belong to the carbonyl
group (C7 and C8) (described in structure a).
On the basis of HMBC spectra, dC = 169.282 (s, C7) was deter-
mined by the correlation between H9 (dH = 9.551) and C7. There-
fore, dc = 165.115 (s, C8) was found by the correlation between
0
The derivation process of compound C7 is same as that for com-
H10 (dH = 6.049) and C8. As the structure of compound C7 indicated,
pound C7.

6368
Y. Chen et al. / Bioorg. Med. Chem. 22 (2014) 6366–6379
I
O
NH2
O
NO2
O
O
iii
ii
OH
OH
i
OH
OH
OH
OH
O
12
O
11
S
I
HN
I
N
S
O
O
O
I
O
O
N
OH
15
iv
v
16
O
S
H2N
O
S
HN
14
S
13
O
O
O
O
OH
I
I
16'
positional isomer
O
positional isomer 15'
S
S
I
HN
I
HN
O
O
O
vii
O
O
HN
HN
Rx
Rx
v
vi
i
i
i
B1,B3,B5,B8
C1,C4,C7,C9
B2,B4,B6,B9
C2,C5,C8,C10
D1,D4,D6,D9,D12,D14
D2,D5,D7,D10,D13,D15
Rx
H2N
CN
S
N
S
HN
1a-1n
I
HN
O
O
O
O
HN
I
Rx
HN
Rx
B7,B10, C3,C6, D3,D8,D11
positional isomers
B8',C7',D1',D9',D12
'
C4, C5, C6: Rx= 2-CH3, 4-F
D6, D7, D8: Rx= 2-CH3, 4-CH3
B1, B2: Rx= 2-CH3, 6-CH3, 4-i-C3F7
B3, B
C7, C7', C
D9, D9', D10, D
11: Rx= 2-CH3, 4-CN
8: Rx= 3-F, 4-F
4: Rx= 2-CH3, 6-CH3, 4-i-C3F7
B5, B6, B
C9, C
D12, D12', D
13: Rx= 2-CH3, 4-C=C(CN)2
10: Rx= 3-F, 4-F, 5-F
7: Rx= 2-OCH3, 4-i-C3F7
B8, B8', B9, B10: Rx= 4-i-C3F7
C1, C2, C
D1, D1', D2, D3: Rx= 2-CH3, 4-NO2 D14, D15: Rx= 2-CH3, 4-OC(CH3)2
D4, D
5: Rx= 2-CH3, 5-COCH3
3: Rx= 2-CH3
Reagents and Conditions: (i) FeCl3 6H2O, active Carbon, NH2NH2 H2O, 70 oC; (ii) H2SO4, H2O, NaNO2, -10 oC,
NH2CONH2, KI, 70 oC, Na2S2O3, room temperature; (iii) Ac2O, reflux; (iV) NH2C(CH3)2CH2SCH3, Et3N, CH2Cl2,
room temperature; (v) CH3SO2Cl, Et3N, CH2Cl2, -10 oC; (vi) CH2Cl2, -10oC--room temprature; (vii) m-CPBA, THF,
room temperature`(viii) THF, NH2CN, PhI(Ac)2
Scheme 1. Synthetic routine of title compounds B1–B10, C1–C10, D1–D15 and positional isomers (B80, C70, D10, D90, D120).
2.2. Crystal structure analysis
benzene rings is 69.6°. The torsion angles of C(14)–N(1)–C(1)–
O(1) and C(1)–N(1)–C(14)–C(15) are 3.3(11)° and 175.5(7)°,
respectively, which indicate that strong conjugation effect is pres-
ent between benzene ring (C14–C15–C16–C17–C18–C19) and
amide group (O1–C1–N1). It was found that the amide groups form
five intermolecular hydrogen bonds, respectively, to stabilize the
dimer, from N1–H1 to O3, N2–H2 to O4, N2–H2 to O3, N3–H3 to
O1 and N4–H4 to O2.
2.2.1. Structure of compound C7 (Fig. 3)
A colorless crystal of compound C7 (deposition #CCDC 1009999)
suitable for X-ray diffraction with dimensions of 0.20 ꢀ 0.18 ꢀ
0.12 mm was mounted on a Rigaku MM-07 Saturn 724 CCD diffrac-
tometer with Mo K
a radiation (k = 0.71073 Å) for data collection.
The compound crystallizes in space group P2(1)/n of the monoclinic
system with cell parameters: a = 12.763(3) Å, b = 23.278(5) Å,
c = 13.926(3) Å,
Z = 8, Dc = 1.680 mg/m3,
final refinement converged at R = 0.0391 and wR = 0.0837 for
9781 observed reflections with I > 2 (I), where W = 1/
2(Fo2) + (0.0363P)2 + 1.1615P] with P = (Fo2 + 2Fc2)/3, S = 1.092,
max = 0.002, ( max = 0.492 e/Å, (
min = ꢁ1.050 e/Å.
a
= 90°, b = 93.63(3)°,
c
= 90°, V = 4129.2(14) Å3,
2.2.2. Structure of compound C10 (Fig. 4)
A colorless crystal of compound C10 (deposition #CCDC
1010001) suitable for X-ray diffraction with dimensions of
l
= 1.695 mmꢁ1, and F(000) = 2064. The
r
0.20 ꢀ 0.18 ꢀ 0.12 mm was mounted on a Rigaku MM-07 Saturn
[
(
r
D
724 CCD diffractometer with Mo Ka radiation (k = 0.71073 Å) for
/r)
D
q)
D
q
)
data collection. The compound crystallizes in space group P2(1)/n
of the monoclinic system with cell parameters: a = 9.4986(19) Å,
Generally, the average bond lengths and bond angles of ring
system (benzene and amide group) are normal ranges.13–19 In the
molecular structure of compound C7, the dihedral angle of two
b = 24.124(5) Å, c = 18.244(4) Å,
a
= 90°, b = 99.60(3)°,
c = 90°,
V = 4121.8(14) Å3, Z = 8, Dc = 1.617 mg/m3,
l
= 1.688 mmꢁ1, and

Y. Chen et al. / Bioorg. Med. Chem. 22 (2014) 6366–6379
6369
R4
R4
R6
1a: R4=CH3, R5=CH3, R6=H
H2N
R5
H2N
R5
i
1b:
R4=CH3, R5=H, R6=CH3
1c: R4=OCH3, R5=H, R6=H
1d: R4=H, R5=H, R6=H
C3F7
R6
1a-1d
Reagents and Conditions: (i) i-IC3F7, Na2S2O4, NaHCO3, TBAB, Et2O, H2O
Scheme 2. Synthetic routine of compounds 1a–1d.
i
ii
H2N
HN
Ac
1e
2
Ac
NH2
NH
iii
O
O
3
1j
Reagents and Conditions: (i) Ac2O, Et3N, CH2Cl2, room temperature; (ii) CH3COCl, AlCl3,
ClCH2CH2Cl, 60 oC; (iii)HCl, MeOH, H2O, reflux
Scheme 3. Synthetic routine of compound 1j.
O
O
O
i
ii
H2N
H2N
H2N
OH
OH
5
v
4
iv
iii
HN
Ac
CHO
HN
Ac
OH
CN
7
6
vi
HN
Ac
H2N
CN
8
1l
Reagents and Conditions: (i) CH3OH, SOCl2, 0 oC, then room temperature; (ii) LiAlH4, THF, 0 oC,
then Na2SO4 10H2O, room temperature; (iii) Ac2O, Et3N, CH2Cl2, room temperature;(iv) MnO2,
CH2Cl2, room temperature; (v) I2, THF, NH3 H2O, room temperature; (vi) HCl, MeOH, H2O, reflux
Scheme 4. Synthetic routine of compound 1l.
NC
NC
CN
CN
i
ii
H2N
HN
Ac
HN
Ac
CHO
1m
7
9
Reagents and Conditions : (i) CNCH2CN, THF, pipedidine; (ii) HCl, MeOH, H2O, reflux
Scheme 5. Synthetic routine of compound 1m.
H2N
O2N
O2N
i
ii
O
OH
O
1n
10
Reagents and Conditions: (i) (CH3)2CHI, K2CO3, CH3COCH3, reflux; (ii) H2, Pd/C, CH3OH, room temperature
Scheme 6. Synthetic routine of compound 1n.

6370
Y. Chen et al. / Bioorg. Med. Chem. 22 (2014) 6366–6379
I
O
I
OH
I
O
S
3
S
S
3
8
2
3
8
2
H
N
N
N
4
5
4
5
8
7
H10
H 10
9
H 10
9
4
2
1
1
H 9
H
H
5
1
N
F
F
N
F
F
N
F
F
6
6
7
6
7
O
O
O
H
H
H
c
b
a
I
O
S
3
H
N
4
8
7
H10
2
structure of compound C7 was determinded
6
H 9
5
1
N
F
O
H
F
d
F
F
F
F
I
O
I
OH
I
O
3
4
8
3
6
8
2
H
3
6
8
2
N
2
1
N
N
F
F
4
5
4
H10
H10
H10
1
1
H 9
H 9
H 9
5
5
N
7
N
N
6
H
S
7
7
S
S
O
O
O
H
H
F
F
I
O
3
8
H
4
N
2
1
H 10
C '
structure of compound
was determinded
H 9
7
6
5
N
7
S
O
H
0
Figure 2. The process of confirming the structures of compounds C7 and C7
.
F(000) = 1980. The final refinement converged at R = 0.0618 and
wR = 0.1680 for 7278 observed reflections with I > 2 (I), where
W = 1/[
2(Fo2) + (0.1090P)2 + 1.2679P] with P = (Fo2 + 2Fc2)/3, S =
1.059, ( max = 0.002, ( max = 1.356 e/Å, (
min = ꢁ1.016 e/Å.
60% larvicidal activity at 5 mg/L, and compound B3 (2-CH3,
5-CH3) showed 20% at 5 mg/L.
r
r
D
In group C, taking off the heptafluoroisopropyl, adding zero or
one or two or three fluorine atoms to the aniline, Most compounds
(C1, C4, C5, C8, C9, C10) of series C showed 100% larvicidal activities
at 25 mg/L. Replacing the heptafluoroisopropyl with one fluorine
atom, compound C4 showed 93% larvicidal activity at 1 mg/L,
which was near to Flubendiamide. The LC50 of C4 was 1.2251 mg/L
(Table 3), while 0.1230 mg/L for Flubendiamide. Replacing the
heptafluoroisopropyl with two fluorine atoms, the larvicidal activ-
ity of compound C8 was 77% at 10 mg/L. While replacing it with
three fluorine atoms, C10 showed 50% larvicidal activity at 5 mg/L.
In group D, replacing the heptafluoroisopropyl with other active
groups, most of them were electrophilic and relative bulk groups.
D1 and D6 showed 100% larvicidal activity at 25 mg/L, yet the activ-
ities of most compounds in group D were not so good as com-
pounds in groups B and C. When the heptafluoroisopropyl was
replaced by NO2, CN and –C@C(CN)2, respectively, compound D1,
D9 and D13 showed 47%, 50% and 43% larvicidal activity at
10 mg/L separately. The results showed that the electronegativity,
stereo-hindrance effect, and fluorine atoms’ characteristics of the
heptafluoroisopropyl have great important effects on the larvicidal
activity of these phthalic acid diamide derivatives.
/r)
D
q
)
Dq)
Generally, the average bond lengths and bond angles of ring
system (benzene and amide group) are normal ranges.13–19 In the
molecular structure of compound C10, the dihedral angle of two
benzene rings is 50.7°. The torsion angles of C(33)–N(4)–C(32)–
O(4) and C(32)–N(4)–C(33)–C(34) are 5.4(4)° and 178.7(2)°,
respectively, which indicate that strong conjugation effect is pres-
ent between benzene ring (C33–C34–C35–C36–C37–C38) and
amide group (O4–C32–N4).
2.3. Structure–activity-relationship (SAR)
2.3.1. Larvicidal activities against oriental armyworms
The larvicidal activity against oriental armyworms is summa-
rized in Table 2. In general, most of the compounds showed mod-
erate to good potency against oriental armyworms. In order to
examine the heptafluoroisopropyl group and the methyl group in
the aromatic amine, three groups were introduced.
In group B, the methyl group on aniline was replaced by
2,6-dimethyl or 2,5-dimethyl or methoxyl or hydrogen, the insec-
ticidal activities indicated the sequence 2-H (B10) > 2-CH3O (B7),
> 2-CH3, 6-CH3 (B2) > 2-CH3, 5-CH3 (B3). When the methyl group
was removed, the insecticidal activity of compound B10 was near
to Flubendiamide, which was 50% at 1 mg/L and the LC50 of
compound B10 was 1.0108 mg/L (Table 3), while 0.1230 mg/L for
Flubendiamide. If the methyl group was replaced with methoxyl
group, B7 show 60% larvicidal activity at 2.5 mg/L. When adding
one more methyl group, compound B2 (2-CH3, 6-CH3) showed
In conclusion, the methyl group and heptafluoroisopropyl are
key groups for the insecticidal activity. When the methyl group
was gotten rid of, the LC50 of B10 was 1.0108 mg/L, while
0.1230 mg/L for Flubendiamide. And the insecticidal activity was
influenced by the location and numbers of fluorine atoms. When
the heptafluoroisopropyl group was replaced by one fluorine atom,
C4 still showed 93% larvicidal activity at 1 mg/L. If all the fluorine
atoms were gotten rid of, the insecticidal activity would decline a

Y. Chen et al. / Bioorg. Med. Chem. 22 (2014) 6366–6379
6371
Table 2
Insecticidal activities of compounds B1–B10, C1–C10, D1–D15 and some corresponding positional isomers (B80, C70, D10, D90, D120) against oriental armywarms
CN
N
S
m
X1 HN
O
n
O
O
X2 HN
Rx
Compd
Rx
X1
X2
m
n
Larvicidal activity (%) at a concentration of (mg/L)
200
100
50
25
10
5
2.5
30
1
0.5
B1
B2
B3
B4
B5
B6
B7
B8
2,6-CH3, 4-i-C3F7
2,6-CH3, 4-i-C3F7
2,5-CH3, 4-i-C3F7
2,5-CH3, 4-i-C3F7
2-OCH3, 4-i-C3F7
2-OCH3, 4-i-C3F7
2-OCH3, 4-i-C3F7
4-i-C3F7
I
I
I
I
I
I
I
I
H
H
H
H
H
H
H
H
I
0
0
0
0
0
0
1
0
0
0
1
0
2
0
2
0
2
0
0
0
2
0
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
100
93
100
100
100
100
100
100
100
100
37
30
73
60
60
20
13
20
50
20
50
100
80
100
60
93
93
33
60
67
60
27
60
10
7
17
100
100
100
93
0
B8
B9
B10
4-i-C3F7
4-i-C3F7
4-i-C3F7
H
I
I
H
H
7
100
50
33
37
C1
C2
C3
C4
C5
C6
C7
C7
C8
C9
C10
2-CH3
2-CH3
2-CH3
2-CH3, 4-F
2-CH3, 4-F
2-CH3, 4-F
3-F, 4-F
3-F, 4-F
3-F, 4-F
I
I
I
I
I
I
I
H
I
H
H
H
H
H
H
H
I
0
0
1
0
0
1
0
0
0
0
0
0
2
0
0
2
0
0
0
2
0
2
100
100
100
100
100
100
100
0
100
83
93
100
100
100
100
100
70
80
100
100
100
100
100
56
66
100
100
93
100
40
50
100
90
56
87
30
20
100
33
33
53
30
100
20
93
90
60
20
0
H
H
H
100
100
100
100
100
100
100
100
100
100
100
100
77
53
93
27
27
50
3-F, 4-F, 5-F
3-F, 4-F, 5-F
I
I
23
17
D1
D1
2-CH3, 4-NO2
2-CH3, 4-NO2
2-CH3, 4-NO2
2-CH3, 4-NO2
2-CH3, 5-COCH3
2-CH3, 5-COCH3
2-CH3, 4-CH3
2-CH3, 4-CH3
2-CH3, 4-CH3
2-CH3, 4-CN
2-CH3, 4-CN
I
H
I
I
I
I
I
I
I
I
H
I
I
I
H
I
I
H
I
0
0
0
1
0
0
0
0
1
0
0
0
1
0
0
0
0
0
0
0
2
0
0
2
0
2
0
0
0
2
0
0
0
2
0
2
100
67
100
100
60
100
100
100
47
20
27
30
0
D2
D3
D4
D5
D6
D7
D8
D9
H
H
H
H
H
H
H
H
I
H
H
H
I
100
80
43
100
67
30
53
53
17
40
27
100
100
100
100
100
100
100
60
100
100
100
100
90
100
87
37
100
100
60
80
75
100
97
37
70
57
90
17
97
40
27
50
50
43
27
27
0
D9
D10
D11
D12
D12
D13
2-CH3, 4-CN
2-CH3, 4-CN
100
47
2-CH3, 4-C=C(CN)2
2-CH3, 4-C=C(CN)2
2-CH3, 4-C=C(CN)2
2-CH3, 4-O(CH3)2
2-CH3, 4-O(CH3)2
0
33
H
H
H
100
30
80
70
63
43
23
D14
D15
I
10
Con.a
100
100
100
100
100
100
100
100
100
a
Flubendiamide.
0
activities of B8 and D90 are nearly the same as B8 and D9. Compared
Table 3
LC50 values of compound B10, C4 and Flubendiamide against oriental armywarms
to compound C7 and D1, their positional isomers C7 and D10 are rel-
atively inactive. Both D12 and D12 were inactive. The results indi-
0
0
Compd
Y = a + bX
R
LC50 (mg/L)
cated dicarboxiamide derivatives showed better insecticidal
activities when the idiom atom was at the 3-position of phthala-
mides. Due to the low yields and activity results of these positional
isomers, further research was not considered.
B10
C4
Y = 4.9930 + 1.4978X
Y = 4.7336 + 3.0217X
Y = 7.4037 + 2.6408X
0.9507
0.9366
0.9945
1.0108
1.2251
0.1230
Flubendiamide
lot. The results showed that fluorine atoms could increase the
insecticidal activities of these phthalic acid diamide derivatives.
Further studies on SAR are currently underway in our laboratories.
According to the insecticidal activities of compounds B8, C7, D1,
2.3.2. Larvicidal activities against diamondback moths
Table 4 showed the insecticidal activity of compounds B6, B7,
B10, C4, C5, C8, D1, D6, D10 and Flubendiamide against diamondback
moth. The activities of compounds B6, B7, C5, C6 were 100% at
0.5 mg/L, and compound B6 showed 70% larvicidal activity at
0.01 mg/L.
0
0
0
0
D9, D12 and their corresponding positional isomers (B8 , C7 , D1 , D9 ,
D120) against Oriental armyworms summarized in Table 2, the

6372
Y. Chen et al. / Bioorg. Med. Chem. 22 (2014) 6366–6379
Figure 5. Effects of compounds B2, B10, C4, C5 and Flubendiamide on [Ca2+]i in the
central neurons of S. exigua when extracellular Ca2+ was absent (EGTA replaced
Ca2+). The central neurons of S. exigua third-instar larvae were dyed by loading with
Fluo-3 AM.
Figure 3. Structure of compound C7.
by using a CCD (Image Pri-6.0). Each experiment was replicated
at least six times. The data were analyzed by using SPSS Inc., ver-
sion 17.0, and Microcal Origin, version 8.0 (Origin Lab Corp., North-
ampton, MA, USA). Results were expressed as the mean SD
(n = number of cells). Statistical significance was determined by
Student’s paired or unpaired test. Fluorescence values were
expressed as F/F0, with F0 being the resting (or baseline) fluores-
cence and F the change in fluorescence from baseline after drug
application.21
Flubendiamide, it is well recognized that it interacts with the
ryanodine receptor (RyR) in muscle cells and causes muscle con-
traction, paralysis and death (DuPont, 2007). Reported that anthra-
nilamide stimulates the release of RyR-mediated Ca2+ stores in
Periplaneta americana Linnaeus embryonic neurons. We examined
our novel compounds on central neurons of S. exigua on the cal-
cium homeostasis with calcium imaging technique after neuron
loading with Fluo-3 AM according to previous method. Figure 5
shows the change of [Ca2+]i versus recording time when the neu-
rons were treated with compounds B2, B10, C4, C5 and Flubendia-
mide in the absence of extracellular calcium. Treated with
10 mg/L of novel compounds and Flubendiamide to isolated S. exi-
gua neurons caused an increase in the cytosolic calcium concentra-
tion. The peak of [Ca2+]i was increased to 105.73 2.34% (n = 9),
110.7 4.29% (n = 9), 113.06 4.17% (n = 9), 103.4 2.11% (n = 9),
and 120.31 4.73% (n = 9) of the initial value after the neurons
were treated with compounds B2, B10, C4, C5 and Flubendiamide
for 30 s, respectively. Thus, calcium released from the calcium
store elevated the cytosolic calcium levels. Compared with the con-
trol, the calcium concentrations in the neurons elevated by our
novel compounds are well correlated with the insecticidal against
Oriental armyworms by our research group.
Figure 4. Structure of compound C10
.
2.4. Calcium imaging
Calibration of the fluorescence signal was obtained using the
procedure of Iakahashi et al. with minor modifications.20 The
attached neurons were rinsed in standard physiological saline
[(mM) 150 NaCl, 4 KCl, 2 MgCl2, 2 CaCl2, 10 HEPES, buffered to
pH 7.0] and then incubated in the dark at 28 °C in standard exter-
nal saline containing the dye Fluo-3 AM (Sigma, 10
lM) within half
an hour or Fluo-5N (Invitrogen, 5 M) in 4 h. After dye loading,
l
cells were again rinsed in physiological saline twice.
To block IP3Rs, cells were incubated with heparin for 10 min.
Calcium ratio imaging studies were conducted using the imaging
system coupled to an inverted fluorescence microscope with a
Fluor 40ꢀ oil immersion objective (Olympus IX71). Cells excited
at 488 and 530 nm under fluorescence emission were acquired
Table 4
Insecticidal activities of compounds B6-B7, B10, C4, C5, C8, D1, D6, D10 against diamondback moths
Compd
Larvicidal activity (%) at a concentration of (mg/L)
10
1
0.5
0.1
0.05
0.01
70
B6
B7
B10
C4
C5
C8
D1
D6
100
100
100
100
100
100
100
100
100
100
100
100
100
90
100
100
90
90
70
100
100
100
90
100
85
50
40
60
45
30
30
10
100
100
45
10
65
100
100
55
60
40
D10
Flubendiamide
100
100
100

Y. Chen et al. / Bioorg. Med. Chem. 22 (2014) 6366–6379
6373
were given in ppm. High-resolution mass spectrometry (HRMS)
data were obtained on a high resolution FTICR-MS (Varian 7.0T).
Flash chromatography was performed with silica gel (200–
300 mesh). The melting points were determined on an X-4 binoc-
ular microscope melting point apparatus (Beijing Tech Instruments
Co., Beijing, China) and were uncorrected. Reagents were all ana-
lytically or chemically pure. All solvents and liquid reagents were
dried by standard methods in advance and distilled before use.
Structures of compounds 1a–1n were listed in Table 1.
4.1.1. Synthetic procedure of compounds 1a–1d (Scheme 2)
They were synthesized according to the literature.22
4.1.1.1. 2,6-Dimethyl-4-(heptafluoroisopropyl)-phenylamine
(1a). Brown solid, yield 81%, mp 38–39 °C; 1H NMR (400 Hz,
CDCl3) d (ppm): 2.20 (s, 6H, Ar-CH3), 3.80 (s, 2H, NH2), 7.14 (s,
2H, Ar-H).
4.1.1.2. 2,5-Dimethyl-4-(heptafluoroisopropyl)-phenylamine
(1b). Brown solid, yield 83%, mp 44–45 °C; 105–106 °C; 1H NMR
(400 Hz, CDCl3) d (ppm): 2.13 (d, 3H, JH = 2.0 Hz, A-CH3), 2.38 (d,
3H, JH = 8.8 Hz, Ar-CH3), 3.72 (s, 2H, NH2), 6.51 (s, 1H, Ar-H), 6.72
(d, 1H, JH = 7.2 Hz, Ar-H).
Figure 6. Effects of 10 ppm of B2, B10, C5 and Flubendiamide on the ER [Ca2+]i in the
neurons of S. Exigua when extracellular Ca2+ was absent (EGTA replaced Ca2+). The
central neurons of S. exigua third-instar larvae were dyed by loading with Fluo-5N.
To further determine the paths that induced the elevation of
[Ca2+]i in neuron cells, Fluo-5N was used in our experiments to
explore the action mechanisms in the central neurons of S. Exigua.
The concentration of [Ca2+]i was decreased to 76.23 5.29% (n = 9),
65.78 5.41% (n = 9), 80.89 3.74% (n = 9) and 47.54 6.13%
(n = 9) of the initial value after the neurons were treated with com-
pounds B2, B10, C5 and Flubendiamide at the end of 6 min, respec-
tively. The declines of Ca2+ concentrations are due to release from
internal stores (Fig. 6).
Upon comparing S. exigua in vivo test, calcium mobilization of
our samples acting on S. exigua neurons, a high degree of correla-
tion was observed. These results strongly suggested that the cal-
cium signaling mechanism is closely related to the RyR target.
4.1.1.3. 2-Methoxy-4-(heptafluoroisopropyl)-phenylamine (1c).
Pale brown solid, yield 78%, mp 82–83 °C; 1H NMR (400 Hz, CDCl3)
d (ppm): 3.88 (s, 3H, OCH3), 4.05 (s, 2H, NH2), 6.74 (d, 1H, JH
=
8.4 Hz, Ar-H), 6.94 (s, 1H, Ar-H), 7.01 (d, 1H, JH = 8.4 Hz, Ar-H).
4.1.1.4. 4-(Heptafluoroisopropyl)-phenylamine (1d). Pale brown
solid, yield 75%, mp 67–68 °C; 1H NMR (400 Hz, CDCl3) d (ppm):
3.92 (s, 2H, NH2), 6.72 (d, 2H, JH = 8.4 Hz, Ar-H), 7.36 (d, 2H,
JH = 8.4 Hz, Ar-H).
4.1.2. Synthetic procedure of compound 1j (Scheme 3)
4.1.2.1. N-Acetyl-2-methylaniline (2). To a solution of compound
1e (5.1 g, 50 mmol) in 50 mL of dichloromethane (CH2Cl2), triethyl-
amine (10.1 g, 100 mmol) was added, and then acetic anhydride
was added dropwise. Monitored by TLC, the reaction was stirred
at room temperature for 2 h. The solvent was evaporated to get
the product. Yield 95%, mp 108–109 °C; 1H NMR (400 Hz, CDCl3)
d (ppm): 2.20 (s, 3H, Ar-CH3), 2.26 (s, 3H, CH3CO), 7.03 (s, 1H,
NH), 7.08 (t, 1H, J12 = 7.2 Hz, J23 = 7.6 Hz, Ar-H), 7.19 (d, 1H,
JH = 7.2 Hz, Ar-H), 7.20 (t, 1H, J12 = 8.0 Hz, J23 = 8.0 Hz, Ar-H), 7.75
(d, 1H, JH = 8.0 Hz, Ar-H).
3. Conclusion
In conclusion, three series of novel phthalic diamides were
designed and synthesized. During synthesizing title compounds,
several positional isomers of some title compounds were found,
which was not reported before, and their structures were con-
firmed by 2D-NMR and crystal structure. The LC50 of compound
B10 (the methyl group gotten rid of) and C4 (the heptafluoroisopro-
pyl replaced by one fluorine atom) against oriental armyworm
were 1.0180 mg/L and 1.2251 mg/L separately, which were near
to Flubendiamide (0.1230 mg/L). If all the fluorine atoms were got-
ten rid of, the insecticidal activities declined a lot, which showed
the fluorine atoms have great effects on the insecticidal activities
of the phthalamides. The calcium imaging technique was used to
investigate the effects of several typical title compounds on the
[Ca2+]i, which indicated that some title compounds were potential
ryanodine receptor modulators. The research provided useful
information to find novel and environmental friendly phthala-
mides targeting the ryanodine receptor, which is beneficial for
the ecological environment and future pesticides development.
4.1.2.2. N-(4-Acetyl-2-methylphenyl)acetamide (3).
The
compound 2 (2.98 g, 20 mmol) and 100 ml 1,2-dichloroethane
(ClCH2CH2Cl) were placed to a flask, and stirred at room tempera-
ture, then acetyl chloride (3.12, 40 mmol), aluminium trichloride
(AlCl3) (8.54 g, 64 mmol) were added. The mixture was heated to
60 °C and kept for 24 h, monitored by TLC. After the reaction was
completed, it was cooled to room temperature. Pour the mixture
into the ice water, and extracted with CH2Cl2. The organic phase
was combined and dried with Na2SO4. The solvent was evaporated
and the residue was applied to a flash column chromatography by
eluting with petroleum ether/ethyl acetate (2:1) to give the
compound 5 as a yellow solid. Yield 78%, mp 47–48 °C; 1H NMR
(400 Hz, CDCl3) d (ppm): 2.23 (s, 3H, Ar-CH3), 2.31 (s, 3H,
CH3CONH), 2.57 (s, 3H, COCH3), 7.20 (s, 1H, Ar-NH), 7.28 (d,
JH = 5.6 Hz, Ar-H), 7.69(d, 1H, JH = 8.0 Hz, Ar-H), .8.31 (s, 1H, Ar-H).
4. Experimental section
4.1. Chemistry
1H NMR spectra were recorded at 300 MHz using a Bruker AV
300 spectrometer or 400 MHz using a Bruker AV 400 spectrometer
(Bruker CO., Switzerland) in CDCl3 or DMSO-d6 solution with tetra-
methylsilane as the internal standard, and chemical shift values (d)
4.1.2.3. 1-(4-Amino-3-methylphenyl)-2-chloroethanone (1j).
12 mL of 3 m/L HCl was added to a solution of compound 3
(1.1 g, 5.7 mmol) in 30 mL methanol, the reaction was heated and
refluxed for 8 h. When the reaction was completed, concentrated,

6374
Y. Chen et al. / Bioorg. Med. Chem. 22 (2014) 6366–6379
added some water, and basified the mixture with NaHCO3 to PH 7
or 8, and extracted with ethyl acetate (EA). The dried organic layer
was evaporated in vacuum and the residue was purified on silica
gel eluding with petroleum–ethyl acetate and 1j was obtained. Yel-
low solid, yield, 95%, mp 68–69 °C; 1H NMR (400 Hz, CDCl3) d
(ppm): 2.21 (s, 3H, Ar-CH3), 2.55 (s, 3H, CH3CO), 3.74 (s, 2H,
NH2), 7.12 (d, JH = 7.6 Hz, Ar-H), 7.27 (s, 1H, Ar-H), 7.28 (d, 1H,
JH = 8.0 Hz, Ar-H).
4.1.4.2. 2-(4-Amino-3-methylbenzylidene)malononitrile (1m).
It was synthesized by the method of preparing compound 1j. Yel-
low solid, yield 91%, mp 86–87 °C; 1H NMR (400 Hz, CDCl3) d
(ppm): 2.20 (s, 3H, CH3), 4.48 (s, 2H, NH2), 6.68 (d, 1H, JH = 8.8 Hz,
Ar-H), 7.65 (s, 1H, Ar-H), 7.65 (s, 1H, CH@C), 7.69 (d, 1H, JH = 8.8 Hz,
Ar-H).
4.1.5. General synthetic procedure for compound 1n (Scheme 6)
4.1.5.1. 4-Isopropoxy-2-methyl-1-nitrobenzene (10).
To a
4.1.3. Synthetic procedure of compound 1l (Scheme 4)
solution of 3-methyl-4-nitrophenol (6 g, 20 mmol) in 30 ml EtOH,
K2CO3 (3.74 g, 22 mmol) and 2-iodopropane (3.3 g, 24 mmol) were
added. The mixture was heated to 80 °C and kept for 24 h. The
resulting mixture was filtered and the filtrate was evaporated.
The residue was applied to a flash column chromatography by elut-
ing with petroleum ether/ethyl acetate (10:1) to give the com-
pound 10. Pale brown solid, yield 75%, mp 63–64 °C; 1H NMR
(400 Hz, CDCl3) d (ppm): 1.36 (s, 3H, CHC(CH3)2), 1.38 (s, 3H,
CHC(CH3)2), 2.62 (s, 3H, Ar-CH3), 4.64 (m, 1H, OCH), 6.75 (s, 1H,
Ar-H), 6.78 (d, JH = 2.8 Hz, Ar-H), 8.08 (d, 1H, JH = 8.4 Hz, Ar-H).
4.1.3.1. 4-Amino-3-methylbenzoate (4). 4-Amino-3-methylben-
zoic acid (20 mmol) and 30 ml MeOH were placed in a flask, and
SOCl2 (24 mmol) were added dropwise at ꢁ5 °C. The reaction kept
for 12 h at room temperature. The solvent was evaporated and
the residue was basified with NaHCO3 to PH 7 or 8, extracted with
ethyl acetate (EA). The dried organic phase was concentrated to get
the compound 4.23,24 White solid, yield 95%, mp 119–120 °C; 1H
NMR (400 Hz, CDCl3) d (ppm): 2.07 (s, 3H, Ar-CH3), 3.73 (s, 3H,
OCH3), 5.74 (s, 2H, NH2), 6.60 (d, 1H, JH = 8.0 Hz, Ar-H), 7.52 (dd,
1H, J12 = 2.0 Hz, J13 = 8.4 Hz, J34 = 2.0 Hz, Ar-H), 7.55 (s, 1H, Ar-H).
4.1.5.2. 4-Isopropoxy-2-methylaniline (1n).
Compound 10
4.1.3.2. (4-Amino-3-methylphenyl)methanol (5). To a solution
of compound 4 (20 mmol) in 100 mL of tetrahydrofuran (THF) at
0 °C, lithium aluminium hydride (30 mmol) was added in small
portions. Monitored with TLC, the reaction kept stirring at 0 °C
for 3 h, then excessive dosage of Na2SO4ꢂ10H2O was added with
vigorous stirring for 30 min. The suspension was filtered and the
filtrate was evaporated. The residue was applied to a flash column
chromatography by eluting with petroleum ether/ethyl acetate
(2:1) to give the compound 5 as a yellow solid. Yield 75%, mp
215–216 °C; 1H NMR (400 Hz, CDCl3) d (ppm): 2.16 (s, 3H, CH3),
3.62 (s, 2H, NH2), 4.52 (s, 2H, OCH2), 6.65 (d, 1H, JH = 7.6 Hz,
Ar-H), 7.03 (d, 1H, JH = 8.0 Hz, Ar-H), 7.06 (s, 1H, Ar-H).
(1.67 g, 10 mmol), Palladium/C catalyst (0.167 g) and 30 ml MeOH
were placed in flask. Hydrogen was added in a certain rate, moni-
tored by TLC. After the reaction was completed, the resulting solu-
tion was filtered, and the filtrate was concentrated to get
compound 1n. Brown liquid, yield 86%, bp 120–121 °C; 1H NMR
(400 Hz, CDCl3) d (ppm): 1.27 (s, 3H, CHC(CH3)2), 1.29 (s, 3H,
CHC(CH3)2), 2.14 (s, 3H, Ar-CH3), 3.35 (s, 2H, NH2), 4.36 (m, 1H,
OCH), 6.59 (s, 1H, Ar-H), 6.61 (d, JH = 2.4 Hz, Ar-H), 6.66 (d, 1H,
JH = 2.0 Hz, Ar-H).
4.1.6. General synthetic procedure for 11, 12, 13, 14, 15, title
compounds B1, B3, B5, B8, C1, C4, C7, C9, D1, D4, D6, D9, D12, D14 and
0
0
0
0
0
positional isomers (B8 , C7 , D1 , D9 , D12
)
4.1.3.3. N-(4-(Hydroxymethyl)-2-methylphenyl)acetamide (6).
It was synthesized by the method of preparing compound 2. Pale
yellow solid, yield 74%, mp 80–81 °C; 1H NMR (400 Hz, CDCl3) d
(ppm): 2.22 (s, 3H, Ar-CH3), 2.27 (s, 3H, CH3CO), 4.64 (s, 2H,
OCH2), 6.94 (s, 1H, NH), 7.20 (d, 1H, JH = 7.6 Hz, Ar-H), 7.21 (s,
1H, Ar-H), 7.76 (d, 1H, JH = 8.0 Hz, Ar-H).
Compounds 11, 12, 13, 14, 15, B1, B3, B5, B8, C1, C4, C7, C9, D1, D4,
D6, D9, D12, D14, and isomers (B8 ,C7 ,D1 , D9 , D120) were prepared in
moderate yields according to the methods reported,29,30 The 1H
NMR and melting point data of compounds 11, 12, 13, 14 were
consistent with the literatures.
0
0
0
0
4.1.6.1.
iodo-N2-(2-methyl-1-(methylthio)pro
(B1).
Light white solid, yield 76%, mp 290–291 °C; 1H NMR
N1-(2,6-dimethyl-4-(perfluoropropan-2-yl)phenyl)-3-
pan-2-yl)phthalamide
4.1.3.4. N-(4-Formyl-2-methylphenyl)acetamide (7). It was pre-
pared according to the literature.25,26 Yellow solid, yield 78%, mp
101–102 °C; 1H NMR (400 Hz, CDCl3) d (ppm): 2.26 (s, 3H, Ar-CH3),
2.35 (s, 3H, CH3CO), 7.23 (s, 1H, NH), 7.73 (d, 1H, JH = 7.6 Hz, Ar-H),
7.72 (s, 1H, Ar-H), 8.29 (d, JH = 6.8 Hz, Ar-H), 9.91 (s, 1H, Ar-CHO).
(400 Hz, DMSO) d (ppm): 1.36 (s, 6H, Ar-CH3), 2.06 (s, 3H, SCH3),
2.34 (s, 6H, C(CH3)2), 2.94 (s, 2H, CH2S), 7.26 (t, 1H, J12 = 7.6 Hz,
Ar-H), 7.41 (s, 2H, Ar-H), 7.60 (d, 1H, JH = 7.6 Hz, Ar-H), 8.01 (d,
1H, JH = 7.6 Hz, Ar-H), 8.14 (s, 1H, CONH), 9.79 (s, 1H, Ar-NH).
ESI-FTICR-MS for C24H24F7IN2O2S: found 665.0563 [M+H]+, calcd
665.0570 [M+H]+.
4.1.3.5. N-(4-Cyano-2-methylphenyl)acetamide (8).
It was
prepared according to the literature.27 Brown solid, yield 90%, mp
95–95 °C; 1H NMR (400 Hz, CDCl3) d (ppm): 2.25 (s, 3H, Ar-CH3),
2.30 (s, 3H, CH3CO), 7.19 (s, 1H, NH), 7.46 (s, 1H, Ar-H), 7.51 (d,
1H, JH = 8.8 Hz, Ar-H), 8.21 (d, 1H, JH = 3.2 Hz, Ar-H).
4.1.6.2.
iodo-N2-(2-methyl-1-(methylthio)pro
(B3).
White solid, yield 82%, mp 176–177 °C; 1H NMR
N1-(2,5-Dimethyl-4-(perfluoropropan-2-yl)phenyl)-3-
pan-2-yl)phthalamide
4.1.3.6. 4-Amino-3-methylbenzonitrile (1l).
It was synthe-
(400 Hz, CDCl3) d (ppm): 1.92 (s, 3H, SCH3), 2.29 (s, 3H, Ar-CH3),
2.33 (s, 3H, Ar-CH3), 2.49 (d, 6H, JH = 9.2 Hz, C(CH3)2), 2.84 (s, 2H,
CH2S), 6.04 (s, 1H, CONHC(CH3)2), 7.23 (t, 1H, J12 = 7.6 Hz,
J23 = 8.0 Hz, Ar-H), 7.39 (s, 1H, Ar-H), 7.80 (dd, 1H, J12 = 0.8 Hz,
sized by the method of preparing compound 1j. Brown solid, yield,
87%, mp 82–83 °C; 1H NMR (400 Hz, CDCl3) d (ppm): 2.15 (s, 3H,
CH3), 4.10 (s, 2H, NH2), 6.64 (d, 1H, JH = 8.8 Hz, Ar-H), 7.31 (s, 1H,
Ar-H), 7.31 (d, 1H, JH = 4.0 Hz, Ar-H).
J13 = 7.6 Hz, J34 = 0.8 Hz, Ar-H), 7.98 (dd, 1H, J12 = 1.2 Hz, J13
=
8.0 Hz, J34 = 0.8 Hz, Ar-H), 8.27 (s, 1H, Ar-H), 8.44 (s, 1H, Ar-NH).
ESI-FTICR-MS for C24H24F7IN2O2S: found 665.0557 [M+H]+, calcd
665.0570 [M+H]+.
4.1.4. General synthetic procedure for compound 3m (Scheme 5)
4.1.4.1.
(9).
N-(4-(2,2-Dicyanovinyl)-2-methylphenyl)acetamide
It was prepared according to the literature.28 Yellow solid,
yield 83%, mp 190–191 °C; 1H NMR (400 Hz, CDCl3) d (ppm): 2.28
(s, 3H, Ar-CH3), 2.35 (s, 3H, CH3CO), 7.21 (s, 1H, NH), 7.65 (s, 1H,
Ar-H), 7.73 (dd, 1H, J12 = 2.0 Hz, J13 = 8.4 Hz, J34 = 2.0 Hz, CH@C),
7.84 (d, JH = 1.2 Hz, Ar-H), 8.37 (d, JH = 8.0 Hz, Ar-H).
4.1.6.3. 3-Iodo-N1-(2-methoxy-4-(perfluoropropan-2-yl)phe-
nyl)-N2-(2-methyl-1-(methylthio)propan-2-yl)phthalamide
(B5).
CDCl3) d (ppm): 1.41 (s, 6H, CH(CH3)2), 1.96 (s, 3H, SCH3), 2.85 (s,
White solid, yield 73%, mp 73–75 °C; 1H NMR (400 Hz,

Y. Chen et al. / Bioorg. Med. Chem. 22 (2014) 6366–6379
6375
2H, CH2S), 3.95 (s, 3H, OCH3), 6.02 (s, 1H, CONHC(CH3)2), 7.08 (s,
1H, Ar-H), 7.19 (t, 1H, J12 = 8 Hz, J23 = 7.6 Hz, Ar-H), 7.23 (d, 1H,
JH = 8.8 Hz, Ar-H), 7.71 (d, 1H, JH = 7.6 Hz, Ar-H), 7.96 (d, 1H,
JH = 8.0 Hz, Ar-H), 8.63 (d, 1H, JH = 8.8 Hz, Ar-H), 8.87 (s, 1H, NH-
Ar). ESI-FTICR-MS for C24H24F7IN2O2S: found 689.0168 [M+Na]+,
calcd 689.0182 [M+Na]+.
(d, 1H, JH = 8.0 Hz, Ar-H), 8.09 (d, 1H, JH = 2.4 Hz, Ar-H), 8.12 (dd,
1H, J12 = 2.4 Hz, J13 = 9.2 Hz, J34 = 2.4 Hz, Ar-H), 8.62 (d, 1H,
JH = 8.8 Hz, Ar-H), 8.70 (s, 1H, NH-Ar). ESI-FTICR-MS for
C
21H20IN5O2S: found 528.0446 [M+H]+, calcd 528.0454 [M+H]+.
4.1.6.10. N1-(4-Acetyl-2-methylphenyl)-3-iodo-N2-(2-methyl-1-
(methylthio)propan-2-yl)phthalamide (D4). White solid,
4.1.6.4. 3-Iodo-N2-(2-methyl-1-(methylthio)propan-2-yl)-N1-(4-
yield 82%, mp 210–211 °C; 1H NMR (400 Hz, CDCl3) d (ppm):
1.44 (s, 6H, CH(CH3)2), 2.01 (s, 3H, SCH3), 2.38 (s, 3H, Ar-CH3),
2.55 (s, 3H, COCH3), 2.85 (s, 2H, SCH2), 6.14 (s, 1H, CONHC(CH3)2),
7.21 (t, 1H, J12 = 8.0 Hz, J23 = 7.6 Hz, Ar-H), 7.28 (d, 1H, JH = 7.6 Hz,
Ar-H), 7.68 (d,1H, JH = 8.0 Hz, Ar-H), 7.80 (d, 1H, JH = 7.6 Hz, Ar-
H), 7.95 (d, 1H, JH = 8.0 Hz, Ar-H), 8.64 (s, 1H, Ar-H), 8.71 (s, 1H,
NH-Ar) ESI-FTICR-MS for C23H25IN4O3S: found 525.0698 [M+H]+,
calcd 525.0709 [M+H]+.
(perfluoropropan-2-yl)phenyl)phth alamide (B8).
White
solid, yield 72%, mp 243–245 °C; 1H NMR (400 Hz, CDCl3) d
(ppm): 1.48 (s, 6H, CH(CH3)2), 1.95 (s, 3H, SCH3), 2.86 (s, 2H,
SCH2), 6.04 (s, 1H, CONHC(CH3)2), 7.21 (t, 1H, J12 = 8 Hz,
J23 = 7.6 Hz, Ar-H), 7.54 (d, 2H, JH = 8.4 Hz, Ar-H), 7.77 (d, 1H,
JH = 6.4 Hz, Ar-H), 7.78 (d, 2H, JH = 8.8 Hz, Ar-H), 7.92 (dd, 1H, J12
0.8 Hz, J13 8.0 Hz, J34 0.8 Hz, Ar-H), 9.13 (s, 1H, NH-Ar). ESI-FTICR-
MS for C24H24F7IN2O2S: found 637.0247 [M+H]+, calcd 637.0257
[M+H]+.
4.1.6.11. N1-(2,4-Dimethylphenyl)-3-iodo-N2-(2-methyl-1-(met-
hylthio)propan-2-yl)phthalamide (D6).
White solid, yield
4.1.6.5. 3-Iodo-N2-(2-methyl-1-(methylthio)propan-2-yl)-N1-o-
76%, mp 177–178 °C; 1H NMR (400 Hz, CDCl3) d (ppm): 1.43 (s,
6H, CH(CH3)2), 2.02 (s, 3H, SCH3), 2.27 (s, 3H, Ar-CH3), 2.29 (s,
3H, Ar-CH3), 2.85 (s, 2H, SCH2), 6.19 (s, 1H, CONHC(CH3)2), 7.00
(s, 1H, Ar-H), 7.02 (d, 1H, JH = 8.4 Hz, Ar-H), 7.20 (t, 1H,
J12 = 7.6 Hz, J23 = 8.0 Hz, Ar-H), 7.77 (d, 1H, JH = 7.6 Hz, Ar-H), 7.95
(d, 1H, JH = 8.4 Hz, Ar-H), 7.97 (d, 1H, JH = 11.6 Hz, Ar-H), 8.22 (s,
tolylphthalamide (C1).
White solid, yield 84%, mp 167–
168 °C; 1H NMR (400 Hz, CDCl3) d (ppm): 1.42 (s, 6H, CH(CH3)2),
2.00 (s, 3H, SCH3), 2.32 (s, 3H, Ar-CH3), 2.83 (s, 2H, SCH2), 6.08 (s,
1H, CONHC(CH3)2), 7.06 (t, 1H, J12 7.6 Hz, J23 7.2 Hz, Ar-H), 6.75
(s, 1H, Ar-H), 7.18 (d, 1H, JH = 7.2 Hz, Ar-H), 7.21 (t, 1H, J12 8.0 Hz,
J23 7.6 Hz, Ar-H), 7.24 (t, 1H, J12 = 8.4 Hz, J23 = 11.6 Hz, Ar-H), 7.81
(d, 1H, JH = 7.6 Hz, Ar-H), 7.97 (d, 1H, JH = 8.0 Hz, Ar-H), 8.28 (s,
1H, NH-Ar). ESI-FTICR-MS for
C21H25IN2O2S: found 519.0570
[M+Na]+, calcd 519.0579 [M+Na]+.
1H, NH-Ar). ESI-FTICR-MS for
C20H23IN2O2S: found 483.0595
[M+H]+, calcd 483.0603 [M+H]+.
4.1.6.12. N1-(4-Cyano-2-methylphenyl)-3-iodo-N2-(2-methyl-1-
(methylthio)propan-2-yl)phthalamide (D9). White solid,
4.1.6.6. N1-(4-Fluoro-2-methylphenyl)-3-iodo-N2-(2-methyl-1-
(methylthio)propan-2-yl)phthalamide (C4). White solid,
yield 85%, mp 149–150 °C; 1H NMR (400 Hz, CDCl3) d (ppm):
1.41 (s, 6H, CH(CH3)2), 1.97 (s, 3H, SCH3), 2.37 (s, 3H, Ar-CH3),
2.81 (s, 2H, SCH2), 3.90 (s, 3H, OCH3), 6.12 (s, 1H, CONHC(CH3)2),
7.23 (t, 1H, J12 = 8.0 Hz, J23 = 8.0 Hz, Ar-H), 7.47 (s, 1H, Ar-H), 7.53
(d, 1H, JH = 8.8 Hz, Ar-H), 7.80 (d, 1H, JH = 8.0 Hz, Ar-H), 7.99 (d,
1H, JH = 8.0 Hz, Ar-H), 8.51 (d, 1H, JH = 8.4 Hz, Ar-H), 8.62 (s, 1H,
NH-Ar). ESI-FTICR-MS for C21H22ClN6O4: found 508.0541 [M+H]+,
calcd 508.0556 [M+H]+.
yield 68%, mp 192–193 °C; 1H NMR (400 Hz, CDCl3) d (ppm):
1.44 (s, 6H, CH(CH3)2), 2.03 (s, 3H, SCH3), 2.31 (s, 3H, Ar-CH3),
2.84 (s, 2H, SCH2), 6.06 (s, 1H, CONH(CH3)2), 6.91 (d, 1H, JH = 9.2 Hz,
Ar-H), 6.918 (s, 1H, Ar-H), 7.21 (t, 1H, J12 = 7.6 Hz, J23 = 8.0 Hz, Ar-
H), 7.80 (d, 1H, JH = 7.6 Hz, Ar-H), 7.97 (d, 1H, JH = 7.6 Hz, Ar-H),
8.10 (dd, 1H, J12 = 5.2 Hz, J13 = 8.4 Hz, J34 = 5.2 Hz, Ar-H), 8.27 (s,
1H, NH-Ar). ESI-FTICR-MS for C20H22FIN2O2S: found 501.0494
[M+H]+, calcd 501.0509 [M+H]+.
4.1.6.13. N1-(4-(2,2-Dicyanovinyl)-2-methylphenyl)-3-iodo-N2-(2-
methyl-1-(methylthio)propan-2-yl)phthalamide (D12).
Yellow
4.1.6.7. N1-(3,4-Difluorophenyl)-3-iodo-N2-(2-methyl-1-(methyl-
solid, yield 80%, mp 168 °C; 1H NMR (400 Hz, CDCl3) d (ppm): 1.41
(s, 6H, CH(CH3)2), 1.98 (s, 3H, SCH3), 2.41 (s, 3H, Ar-CH3), 2.81 (s,
2H, SCH2), 6.05 (s, 1H, CONHC(CH3)2), 7.26 (t, 1H, J12 = 8.0 Hz,
J23 = 8.0 Hz, Ar-H), 7.65 (s, 1H, Ar-H), 7.80 (s, 1H, CH@C(CN)2), 7.81
(d, 1H, JH = 8.8 Hz, Ar-H), 7.83 (d, 1H, JH = 8.0 Hz, Ar-H), 8.02 (d, 1H,
JH = 8.0 Hz, Ar-H), 8.64 (d, 1H, JH = 9.2 Hz, Ar-H), 8.71 (s, 1H, NH-Ar).
hio)propan-2-yl)phthalamide (C7).
White solid, yield 83%,
mp 220–221 °C; 1H NMR (400 Hz, CDCl3) d (ppm): 1.52 (s, 6H,
CH(CH3)2), 2.14 (s, 3H, SCH3), 2.90 (s, 2H, SCH2), 6.05 (s, 1H, CON-
HC(CH3)2), 7.01 (t 1H, J12 = 9.2 Hz, J13 = 18.4 Hz, J34 = 9.2 Hz, Ar-H),
7.18 (t, 2H, J12 = 7.6 Hz, J23 = 8.0 Hz, Ar-H), 7.81 (d, 1H, JH = 6.8 Hz,
Ar-H), 7.70 (d, 1H, JH = 7.2 Hz, Ar-H), 7.66 (d, 1H, JH = 8.0 Hz,
Ar-H), 9.55 (s, 1H, NH-Ar). ESI-FTICR-MS for C20H22FIN2O2S: found
505.0241 [M+H]+, calcd 505.0258 [M+H]+.
ESI-FTICR-MS for
C
24H23IN4O2S: found 559.0655 [M+H]+, calcd
559.0665 [M+H]+.
4.1.6.14. 3-Iodo-N1-(4-isopropoxy-2-methylphenyl)-N2-(2-met-
hyl-1-(methylthio)propan-2-yl)phthalamide (D14). White
4.1.6.8.
(3,4,5-trifluorophenyl)phthalamide (C9).
3-Iodo-N2-(2-methyl-1-(methylthio)propan-2-yl)-N1-
White solid, yield
solid, yield 77%, mp 282–283 °C; 1H NMR (400 Hz, CDCl3) d
(ppm): 1.33 (s, 3H, OCH(CH3)2), 1.35 (s, 3H, OCH(CH3)2), 1.36 (s,
6H, CH(CH3)2), 2.04 (s, 3H, SCH3), 2.33 (s, 3H, Ar-CH3), 2.92 (s,
2H, SCH2), 4.53 (m, 1H, OCH3), 6.49 (s, 1H, CONHC(CH3)2), 6.75
(s, 1H, Ar-H), 6.78 (d, 1H, JH = 8.8 Hz, Ar-H), 7.90 (t, 1H,
J12 = 7.6 Hz, J23 = 7.2 Hz, Ar-H), 7.51 (d, 1H, JH = 7.6 Hz, Ar-H), 7.77
(s, 1H, NH-Ar), 7.84 (d, 1H, JH = 8.8 Hz, Ar-H), 7.91 (d, 1H,
JH = 8.0 Hz, Ar-H). ESI-FTICR-MS for C23H29IN2O3S: found
541.1015 [M+H]+, calcd 541.1022 [M+H]+.
76%, mp 216–217 °C; 1H NMR (400 Hz, CDCl3) d (ppm): 1.57 (s,
6H, CH(CH3)2), 2.14 (s, 3H, SCH3), 2.93 (s, 2H, SCH2), 6.07 (s, 1H,
CONHC(CH3)2), 7.18 (t, 1H, J12 = 7.6 Hz, J23 = 7.6 Hz, Ar-H), 7.38 (t,
2H, J12 = 7.6 Hz, J23 = 7.6 Hz, Ar-H), 7.57 (d, 1H, JH = 7.6 Hz, Ar-H),
7.54 (d, 1H, JH = 8.0 Hz, Ar-H), 8.27 (s, 1H, NH-Ar). ESI-FTICR-MS
for
C
20H22FIN2O2S: found 523.0166 [M+H]+, calcd 523.0164
[M+H]+.
4.1.6.9. 3-Iodo-N2-(2-methyl-1-(methylthio)propan-2-yl)-N1-(2-
methyl-4-nitrophenyl)phthalamide (D1).
Pale yellow solid,
4.1.6.15. 3-Iodo-N1-(2-methyl-1-(methylthio)propan-2-yl)-N2-
yield 71%, mp 138–139 °C; 1H NMR (400 Hz, CDCl3) d (ppm):
1.41 (s, 6H, CH(CH3)2), 1.97 (s, 3H, SCH3), 2.44 (s, 3H, Ar-CH3),
2.83 (s, 2H, SCH2), 6.08 (s, 1H, CONHC(CH3)2), 7.26 (t, 1H,
J12 = 8.0 Hz, J23 = 8.0 Hz, Ar-H), 7.83 (d, 1H, JH = 7.6 Hz, Ar-H), 8.01
(4-(perfluoropropan-2-yl)phenyl)phtalamide (B8 ).
White
0
solid, yield 13%, mp 234–235 °C 1H NMR (400 Hz, CDCl3) d
(ppm): 1.33 (s, 6H, CH(CH3)2), 2.02 (s, 3H, SCH3), 2.89 (s, 2H,
SCH2), 6.41 (s, 1H, CONHC(CH3)2), 7.09 (t, 1H, J12 = 8.0 Hz,

6376
Y. Chen et al. / Bioorg. Med. Chem. 22 (2014) 6366–6379
J23 = 8.0 Hz, Ar-H), 7.47 (d, 1H, JH = 7.6 Hz, Ar-H), 7.59 (d, 2H,
JH = 8.8 Hz, NAr-H), 7.83 (d, 2H, JH = 8.4 Hz, Ar-H), 7.89 (d, 1H,
JH = 8.0 Hz, Ar-H), 8.48 (s, 1H, NH-Ar). ESI-FTICR-MS for
(400 Hz, DMSO) d (ppm): 1.79 (s, 6H, Ar-CH3), 2.40 (s, 3H, SCH3),
2.59 (s, 6H, C(CH3)2), 2.62 (s, 2H, CH2S), 6.20 (s, 1H, Ar-NH), 7.24
(t, 1H, J12 = 7.6 Hz, J23 = 7.6 Hz, Ar-H), 7.36 (s, 2H, Ar-H), 7.73 (s,
1H, CONH), 7.80 (d, 1H, JH = 7.6 Hz, Ar-H), 8.03 (d, 1H, JH = 7.6 Hz,
Ar-H). ESI-FTICR-MS for C24H24F7IN2O4S: found 697.0467
[M+H]+, calcd 697.0468 [M+H]+.
C
20H20IN3O2S: found 637.0240 [M+H]+, calcd 637.0257 [M+H]+.
4.1.6.16.
N2-(3,4-Difluorophenyl)-3-iodo-N1-(2-methyl-1-
0
(methylthio)propan-2-yl)phthalamide(C7 ). White solid, yield
18%, mp 228–229 °C, 1H NMR (400 Hz, CDCl3) d (ppm): 1.36 (s,
6H, CH(CH3)2), 2.10 (s, 3H, SCH3), 2.91 (s, 2H, SCH2), 6.32 (s, 1H,
CONHC(CH3)2), 7.01 (t 1H, J12 = 7.6 Hz, J13 = 8.4 Hz, Ar-H), 7.14 (d,
1H, JH = 6.2 Hz, Ar-H), 7.28 (d, 1H, JH = 9.6 Hz, Ar-H), 7.43 (d, 1H,
JH = 7.6 Hz, Ar-H), 7.79 (t, 1H, J12 = 10.8 Hz, J13 = 10 Hz, Ar-H),
7.90 (d, 1H, JH = 7.6 Hz, Ar-H), 8.55 (s, 1H, NH-Ar). ESI-FTICR-MS
for C20H20IN3O2S: found 505.0248 [M+H]+, calcd 505.0258
[M+H]+.
4.1.7.3. N1-(2,5-Dimethyl-4-(perfluoropropan-2-yl)phenyl)-3-io-
do-N2-(2-methyl-1-(methylsulfonyl) propan-2-yl)phthalamide
(B4).
White solid, yield 85%, mp 222–223 °C; 1H NMR
(400 Hz, DMSO) d (ppm): 1.54 (s, 6H, C(CH3)2), 2.31 (s, 3H, Ar-
CH3), 2.44 (d, 3H, JH = 8.8 Hz, Ar-CH3), 2.97 (s, 3H, SCH3), 3.66 (s,
2H, CH2S), 7.28 (t, 1H, J12 = 7.6 Hz, Ar-H), 7.34 (s, 1H, CONH), 7.65
(s, 1H, Ar-H), 7.71 (d, 1H, JH = 8.0 Hz, Ar-H), 8.02 (d, 1H, JH = 8.0 Hz,
Ar-H), 8.43 (s, 1H, Ar-H), 9.77 (s, 1H, Ar-NH). ESI-FTICR-MS for
C
24H24F7IN2O4S: found 697.0467 [M+H]+, calcd 697.0468 [M+H]+.
4.1.6.17. 3-Iodo-N1-(2-methyl-1-(methylthio)propan-2-yl)-N2-
(2-methyl-4-nitrophenyl)phthalamide (D1 ).
Pale yellow
4.1.7.4.
nyl)-N2-(2-methyl-1-(methylsulfonyl) propan-2-yl)phthalamide
(B6).
White solid, yield 81%, mp 167–168 °C; 1H NMR (400 Hz,
3-Iodo-N1-(2-methoxy-4-(perfluoropropan-2-yl)phe-
0
solid, yield 12%, mp 189–190 °C, 1H NMR (400 Hz, CDCl3) d
(ppm): 1.38 (s, 6H, CH(CH3)2), 2.06 (s, 3H, SCH3), 2.42 (s, 3H, Ar-
CH3), 2.93 (s, 2H, SCH2), 6.20 (s, 1H, CONHC(CH3)2), 7.21 (t, 1H,
J12 = 7.8 Hz, J23 = 8.0 Hz, Ar-H), 7.58 (dd, 1H, J12 = 0.8 Hz,
J13 = 8.0 Hz, J34 = 0.4 Hz, Ar-H), 7.77 (s, 1H, NH-Ar), 7.98 (dd, 1H,
J12 = 0.8 Hz, J13 = 8.0 Hz, J34 = 0.8 Hz, Ar-H), 8.10 (d, 1H, JH = 2.4 Hz,
Ar-H), 8.17 (dd, 1H, J12 = 2.8 Hz, J13 = 9.2 Hz, J34 = 2.4 Hz, Ar-H),
8.51 (d, 1H, JH = 8.8 Hz, Ar-H). ESI-FTICR-MS for C20H20IN3O2S:
found 528.0448 [M+H]+, calcd 528.0454 [M+H]+.
CDCl3) d (ppm): 1.68 (s, 6H, CH(CH3)2), 2.73 (s, 3H, SCH3), 3.60 (s,
2H, SCH2), 3.59 (s, 3H, OCH3), 6.18 (s, 1H, CONHC(CH3)2), 7.10 (s,
1H, Ar-H), 7.22 (t, 1H, J12 = 8 Hz, J23 = 7.6 Hz, Ar-H), 7.25 (d, 1H,
JH = 8.4 Hz, Ar-H), 7.69 (d, 1H, JH = 8.0 Hz, Ar-H), 7.99 (d, 1H,
JH = 7.6 Hz, Ar-H), 8.61 (d, 1H, JH = 8.8 Hz, Ar-H), 8.65 (s, 1H, NH-
Ar). ESI-FTICR-MS for C24H24F7IN2O4S: found 699.0257 [M+H]+,
calcd 699.0261 [M+H]+.
4.1.6.18. N2-(4-Cyano-2-methylphenyl)-3-iodo-N1-(2-methyl-1-
4.1.7.5. 3-Iodo-N2-(2-methyl-1-(methylsulfonyl)propan-2-yl)-N1-
0
(methylthio)propan-2-yl)phthalami de (D9 ).
White solid,
(4-(perfluoropropan-2-yl)phenyl) phthalamide (B9).
White
yield 14%, mp 245–246 °C, 1H NMR (400 Hz, CDCl3) d (ppm): 1.37
(s, 6H, CH(CH3)2), 2.08 (s, 3H, SCH3), 2.36 (s, 3H, Ar-CH3), 2.93 (s,
2H, SCH2), 3.90 (s, 3H, OCH3), 6.20 (s, 1H, CONHC(CH3)2), 7.21 (t,
1H, J12 = 7.6 Hz, J23 = 7.2 Hz, Ar-H), 7.50 (s, 1H, Ar-H), 7.58 (d, 2H,
JH = 7.6 Hz, Ar-H), 7.64 (s, 1H, NH-Ar), 7.97 (d, 1H, JH = 7.6 Hz, Ar-
H), 8.42 (d, 1H, JH = 8.4 Hz, Ar-H). ESI-FTICR-MS for C20H20IN3O2S:
found 508.0550 [M+H]+, calcd 508.0556 [M+H]+.
solid, yield 72%, mp 243–245 °C; 1H NMR (400 Hz, CDCl3) d
(ppm): 1.72 (s, 6H, CH(CH3)2), 2.64 (s, 3H, SCH3), 3.57 (s, 2H,
SCH2), 6.49 (s, 1H, CONHC(CH3)2), 7.16 (t, 1H, J12 = 7.6 Hz,
J23 = 8.0 Hz, Ar-H), 7.50 (d, 2H, JH = 8.4 Hz, Ar-H), 7.61 (d, 1H, JH
=
7.6 Hz, Ar-H), 7.75 (d, 2H, JH = 7.6 Hz, Ar-H), 7.82 (d, 1H, JH = 7.6 Hz,
Ar-H), 9.44 (s, 1H, NH-Ar). ESI-FTICR-MS for C24H24F7IN2O4S:
found 669.0139 [M+H]+, calcd 669.0155 [M+H]+.
4.1.6.19. N2-(4-(2,2-Dicyanovinyl)-2-methylphenyl)-3-iodo-N1-
(2-methyl-1-(methylthio)propan-2-yl)phthalamide (D12 ). White
4.1.7.6. 3-Iodo-N2-(2-methyl-1-(methylsulfonyl)propan-2-yl)-
N1-o-tolylphthalamide (C2).
White solid, yield 80%, mp
0
solid, yield 15%, mp 207–208 °C, 1H NMR (400 Hz, CDCl3) d (ppm):
1.38 (s, 6H, CH(CH3)2), 2.08 (s, 3H, SCH3), 2.39 (s, 3H, Ar-CH3), 2.93
(s, 2H, SCH2), 6.19 (s, 1H, CONHC(CH3)2), 7.22 (t 1H, J12 = 8.0 Hz,
J13 = 7.6 Hz, Ar-H), 7.60 (d, 1H, JH = 7.6 Hz, Ar-H), 7.68 (s, 1H,
CH@C(CN)2), 7.74 (s, 1H, Ar-H), 7.82 (s, 1H, NH-Ar), 7.83
(d, 1H, JH = 8.0 Hz, Ar-H), 7.98 (d, 1H, JH = 8.0 Hz, Ar-H), 8.54
(d, 1H, JH = 8.4 Hz, Ar-H). ESI-FTICR-MS for C20H20IN3O2S: found
559.0662 [M+H]+, calcd 559.0665 [M+H]+.
150–151 °C; 1H NMR (400 Hz, CDCl3) d (ppm): 1.68 (s, 6H,
CH(CH3)2), 2.32 (s, 3H, SCH3), 2.55 (s, 3H, Ar-CH3), 3.51 (s, 2H,
SCH2), 6.45 (s, 1H, CONHC(CH3)2), 7.08 (t, 1H, J12 = 7.6 Hz,
J23 = 6.8 Hz, Ar-H), 7.19 (t, 1H, J12 = 7.6 Hz, J23 = 7.6 Hz, Ar-H), 7.23
(d, 1H, JH = 8.4 Hz, Ar-H), 7.39 (t, 1H, J12 = 8.0 Hz, J23 = 7.6 Hz,
Ar-H), 7.58 (dd, 1H, J12 = 8.0 Hz, J13 = 60 Hz, J34 = 8.0 Hz, Ar-H),
7.73 (d, 1H, JH = 8.0 Hz, Ar-H), 7.96 (d, 1H, JH = 8.0 Hz, Ar-H), 8.11
(d, 1H, JH = 7.6 Hz, NH-Ar). ESI-FTICR-MS for C20H23IN2O4S: found
515.0507 [M+H]+, calcd 515.0501 [M+H]+.
4.1.7. General synthetic procedure for compounds B2, B4, B6, B9,
C2, C5, C8, C10, D2, D5, D7, D10, D13, D15
4.1.7.7. N1-(4-Fluoro-2-methylphenyl)-3-iodo-N2-(2-methyl-1-
4.1.7.1. Synthetic procedure for compound B2.
To a solution
(methylsulfonyl)propan-2-yl)phthalamide
(C5).
White
of compound B1 (0.5 mmol) in 15 ml THF, m-CPBA (1 mmol) was
added. Monitored with TLC, the reaction kept stirring at room tem-
perature. When the reaction was completed, the solvent was evap-
orated and the residue was washed with Na2SO3 solution and
NaHCO3 solution, extracted with ethyl acetate. The dried organic
phase was concentrated and the residue was applied to a flash col-
umn chromatography by eluting with petroleum ether/ethyl ace-
tate (1:1) to give the compound B2.
solid, yield 80%, mp 182–183 °C; 1H NMR (400 Hz, CDCl3) d
(ppm): 1.65 (s, 6H, CH(CH3)2), 2.31 (s, 3H, SCH3), 2.66 (s, 3H,
Ar-CH3), 3.54 (s, 2H, SCH2), 6.45 (s, 1H, CONHC(CH3)2), 6.93 (d,
2H, JH = 8.8 Hz, Ar-H), 7.20 (t, 1H, J12 = 8.0 Hz, J23 = 8.0 Hz, Ar-H),
7.72 (d, 1H, JH = 8.0 Hz, Ar-H), 7.94 (d, 1H, JH = 8.8 Hz, Ar-H), 8.10
(d, 1H, JH = 7.2 Hz, Ar-H), 8.11 (s, 1H, NH-Ar). ESI-FTICR-MS for
C
20H22FIN2O2S: found 533.0393 [M+H]+, calcd 533.0407 [M+H]+.
The compounds B4, B6, B9, C2, C5, C8, C10, D2, D5, D7, D10, D13, D15
were synthesized by the same method of preparing compound B2.
4.1.7.8. N1-(3,4-Difluorophenyl)-3-iodo-N2-(2-methyl-1-(meth-
ylsulfonyl)propan-2-yl)phthalamide (C8).
White solid, yield
83%, mp 235–236 °C; 1H NMR (400 Hz, CDCl3) d (ppm): 1.74 (s,
6H, CH(CH3)2), 2.86 (s, 3H, SCH3), 3.61 (s, 2H, SCH2), 6.37 (s, 1H,
CONHC(CH3)2), 7.04 (dd, 1H, J12 = 9.6 Hz, J13 = 18.4 Hz,
J34 = 9.6 Hz, Ar-H), 7.20 (t, 2H, J12 = 6.4 Hz, J23 = 7.6 Hz, Ar-H),
4.1.7.2.
iodo-N2-(2-methyl-1-(methylsulfonyl)
mide (B2).
White solid, yield 79%, mp 235–236 °C; 1H NMR
N1-(2,6-Dimethyl-4-(perfluoropropan-2-yl)phenyl)-3-
propan-2-yl)phthala-

Y. Chen et al. / Bioorg. Med. Chem. 22 (2014) 6366–6379
6377
.7.57 (d, 1H, JH = 9.6 Hz, Ar-H), 7.62 (d, 1H, JH = 8.0 Hz, Ar-H), 7.83
(d, 1H, JH = 7.6 Hz, Ar-H), 8.23 (s, 1H, NH-Ar). ESI-FTICR-MS for
C
Ar-H), 7.77 (d, 1H, JH = 7.2 Hz, CH@C(CN)2), 7.79 (d, 1H, JH = 8.4 Hz,
Ar-H), 7.81 (d, 1H, JH = 4.4 Hz, Ar-H), 8.01 (d, 1H, JH = 8.0 Hz, Ar-H),
8.48 (s, 1H, NH-Ar), 8.57 (d, 1H, JH = 8.4 Hz, Ar-H). ESI-FTICR-MS for
20H22FIN2O2S: found 537.0149 [M+H]+, calcd 537.0157 [M+H]+.
C
24H23IN4O4S: found 591.0557 [M+H]+, calcd 591.0563 [M+H]+.
4.1.7.9. 3-Iodo-N2-(2-methyl-1-(methylsulfonyl)propan-2-yl)-
N1-(3,4,5-trifluorophenyl)phthalamide (C10).
White solid,
4.1.7.15. 3-Iodo-N1-(4-isopropoxy-2-methylphenyl)-N2-(2-methyl-
1-(methylsulfonyl)propan-2-yl)phthalamide (D15). White
yield 85%, mp 234–235 °C; 1H NMR (400 Hz, DMSO) d (ppm):
1.53 (s, 6H, CH(CH3)2), 3.04 (s, 3H, SCH3), 3.66 (s, 2H, SCH2), 7.28
(t, 1H, J12 = 7.6 Hz, J23 = 7.6 Hz, Ar-H), 7.60 (d, 1H, J = 6.4 Hz, Ar-
H), 7.60 (d, 1H, JH = 6.4 Hz, Ar-H), 7.63 (d, 1H, JH = 6.8 Hz, Ar-H),
7.66 (d, 1H, JH = 7.6 Hz, Ar-H), 8.03 (d, 1H, JH = 8.0 Hz, Ar-H), 8.39
(s, 1H, CONHC(CH3)2), 10.60 (s, 1H, NH-Ar). ESI-FTICR-MS for
solid, yield 77%, mp 282–283 °C; 1H NMR (400 Hz, CDCl3) d (ppm):
1.25 (s, 3H, OCH(CH3)2), 1.26 (s, 3H, OCH(CH3)2), 1.45 (s, 6H,
CH(CH3)2), 2.31 (s, 3H, SCH3), 2.95 (s, 3H, Ar-CH3), 3.73 (s, 2H,
SCH2), 4.58 (m, 1H, OCH), 6.76 (d, 1H, JH = 8.0 Hz, Ar-H), 7.17 (s, 1H,
CONH-C(CH3)2), 7.23 (t, 1H, J12 = 7.6 Hz, J23 = 8.0 Hz, Ar-H), 7.47 (d,
1H, JH = 8.4 Hz, Ar-H), 7.58 (d, 1H, JH = 7.6 Hz, Ar-H), 7.98 (d, 1H,
JH = 7.6 Hz, Ar-H), 8.12 (s, 1H, Ar-H), 9.56 (s, 1H, NH-Ar). ESI-FTICR-
MS for C23H29IN2O5S: found 573.0907 [M+H]+, calcd 573.0920
[M+H]+.
C
20H22FIN2O2S: found 555.0060 [M+H]+, calcd 555.0062 [M+H]+.
4.1.7.10. 3-Iodo-N2-(2-methyl-1-(methylsulfonyl)propan-2-yl)-
N1-(2-methyl-4-nitrophenyl)phthalamide (D2).
Pale yellow
solid, yield 74%, mp 132–133 °C; 1H NMR (400 Hz, CDCl3) d
(ppm): 1.63 (s, 6H, CH(CH3)2), 2.44 (s, 3H, SCH3), 2.72 (s, 3H, Ar-
CH3), 3.50 (s, 2H, SCH2), 6.53 (s, 1H, CONHC(CH3)2), 7.25 (t, 1H,
J12 = 7.6 Hz, J23 = 8.0 Hz, Ar-H), 7.78 (dd, 1H, J12 = 0.8 Hz,
J13 = 7.6 Hz, J34 = 1.2 Hz, Ar-H), 8.02 (dd, 1H, J12 = 0.8 Hz,
J13 = 8.0 Hz, J34 = 0.8 Hz, Ar-H), 8.10 (d, 1H, JH = 2.4 Hz, Ar-H), 8.13
(dd, 1H, J12 = 2.4 Hz, J13 = 8.8 Hz, J34 = 2.8 Hz, Ar-H), 8.46 (s, 1H,
NH-Ar), 8.55 (d, 1H, JH = 8.8 Hz, Ar-H). ESI-FTICR-MS for
4.1.8. General synthetic procedure for compounds B7, B10, C3, C6,
D3, D8, D11
4.1.8.1. Synthetic procedure for compound B7.
To a solution
of compound B5 (0.5 mmol) in 15 ml THF, PhI(Ac)2,(1.2 mmol),
NH2CN (1.5 mmol) was added under the ice bath. Monitored with
TLC, the reaction kept stirring at 0 °C for 30 min, then stirred at
room temperature. When the reaction was finished, the solvent
was evaporated and the residue was washed with 1 mol/L hydro-
chloric acid, NaHCO3 solution and NaCl solution, extracted with
ethyl acetate. The organic phase was concentrated and the residue
was applied to a flash column chromatography by eluting with
ethyl acetate to give the compound B7.
C
21H20IN5O2S: found 560.0343 [M+H]+, calcd 560.0352 [M+H]+.
4.1.7.11. N1-(4-Acetyl-2-methylphenyl)-3-iodo-N2-(2-methyl-1-
(methylsulfonyl)propan-2-yl)phthalamide (D5). White
solid, yield 86%, mp 232–234 °C; 1H NMR (400 Hz, CDCl3) d
(ppm): 1.68 (s, 6H, CH(CH3)2), 2.38 (s, 3H, SCH3), 2.60 (s, 3H, Ar-
CH3), 2.72 (s, 3H, COCH3), 3.56 (s, 2H, SCH2), 6.51 (s, 1H, CON-
HC(CH3)2), 7.23 (t, 1H, J12 = 8.0 Hz, J23 = 8.0 Hz, Ar-H), 7.30 (d, 1H,
JH = 8.0 Hz, Ar-H), 7.70 (dd, 1H, J12 = 2 Hz, J13 = 8.0 Hz, J34 = 1.6 Hz,
Ar-H), 7.76 (d, 1H, JH = 7.6 Hz, Ar-H), 7.98 (d, 1H, JH = 7.6 Hz,
Ar-H), 8.26 (s, 1H, Ar-H), 8.69 (s, 1H, NH-Ar). ESI-FTICR-MS for
The compounds B10, C3, C6, D3, D8, D11 were synthesized by the
same method of preparing compound B7.
4.1.8.2. 3-Iodo-N1-(2-methoxy-4-(perfluoropropan-2-yl)phenyl)-
N2-(2-methyl-1-((N-methylenecyanamidyl)methylthio)propan-
2-yl)phthalamide (B7).
White solid, yield 83%, mp 131–133 °C;
C
22H25IN2O3S: found 557.0603 [M+H]+, calcd 557.0607 [M+H]+.
1H NMR (400 Hz, CDCl3) d (ppm): 1.60 (s, 3H, NH(CH3)2), 1.65 (s,
3H, NH(CH3)2), 2.69 (s, 3H, SCH3), 3.31 (d, 1H, JH = 6.6 Hz, SCH2),
3.95 (s, 3H, OCH3), 4.06 (d, 1H, JH = 13.6 Hz, SCH2), 6.14 (s, 1H,
CONH-C(CH3)2), 7.11 (s, 1H, Ar-H), 7.23 (t, 1H, J12 = 8 Hz,
J23 = 7.6 Hz, Ar-H), 7.25 (d, 1H, JH = 4.0 Hz, Ar-H), 7.63 (d, 1H,
JH = 7.6 Hz, Ar-H), 8.02 (d, 1H, JH = 8.0 Hz, Ar-H), 8.47 (d, 1H,
J = 4.8 Hz, Ar-H), 8.49 (s, 1H, NH-Ar). ESI-FTICR-MS for
C24H22F7IN4O3S: found 707.0408 [M+H]+, calcd 707.0424 [M+H]+.
4.1.7.12. N1-(2,4-Dimethylphenyl)-3-iodo-N2-(2-methyl-1-(met-
hylsulfonyl)propan-2-yl)phthalamide (D7).
White solid,
yield 80%, mp 264–266 °C; 1H NMR (400 Hz, CDCl3) d (ppm):
1.54 (s, 3H, NH(CH3)2), 1.58 (s, 3H, NH(CH3)2), 2.21 (s, 3H, Ar-
CH3), 2.23 (s, 3H, Ar-CH3), 2.29 (d, 3H, J = 6.0 Hz, SCH3), 2.77 (d,
1H, JH = 13.2 Hz, SCH2), 3.31 (d, 1H, JH = 13.6 Hz, SCH2), 6.99 (s,
1H, CONHC(CH3)2), 7.00 (d, 1H, JH = 7.6 Hz, Ar-H), 7.10 (s, 1H,
Ar-H), 7.16 (t, 1H, J12 = 7.6 Hz, J23 = 8.0 Hz, Ar-H), 7.63 (d, 1H, JH
=
4.1.8.3.
methylthio)propan-2-yl)-N1-(4-(perfluo ropropan-2-yl)phenyl)
phthalamide (B10). White solid, yield 70%, mp 152–153 °C;
3-Iodo-N2-(2-methyl-1-((N-methylenecyanamidyl)-
8.0 Hz, Ar-H), 7.88 (d, 1H, JH = 8.0 Hz, Ar-H), 7.92 (d, 1H, JH = 8.0 Hz,
Ar-H), 8.29 (s, 1H, NH-Ar). ESI-FTICR-MS for C21H25IN2O4S: found
551.0473 [M+Na]+, calcd 551.0477 [M+Na]+.
1H NMR (400 Hz, CDCl3) d (ppm): 1.49 (d, 3H, J = 6.0 Hz, NH(CH3)2),
1.60 (s, 3H, JH = 6.4 Hz, NH(CH3)2), 2.50 (s, 3H, SCH3), 3.17 (dd, 1H,
J12 = 8.0 Hz, J13 = 13.2 Hz, J34 = 8.4 Hz, SCH2), 3.92 (d, 1H, JH = 13.6
Hz, SCH2), 6.14 (s, 1H, CONHC(CH3)2), 7.08 (m, 1H, Ar-H), 7.18 (s,
1H, Ar-H), 7.50 (d, 2H, JH = 8.4 Hz, Ar-H), 7.53 (d, 1H, JH = 8.8 Hz,
Ar-H), 7.70 (d, 2H, J = 8.8 Hz, Ar-H), 7.80 (dd, J12 = 7.6 Hz,
J13 = 15.2 Hz, J34 = 8.0 Hz, Ar-H), 9.49 (d, 1H, JH = 12.4 Hz, NH-Ar).
ESI-FTICR-MS for C23H22F7IN2O3S: found 677.0308 [M+H]+, calcd
677.0318 [M+H]+.
4.1.7.13. N1-(4-Cyano-2-methylphenyl)-3-iodo-N2-(2-methyl-1-
(methylsulfonyl)propan-2-yl)phth alamide (D10).
White
solid, yield 75%, mp 132–133 °C; 1H NMR (400 Hz, CDCl3) d
(ppm): 1.63 (s, 6H, CH(CH3)2), 1.36 (s, 3H, SCH3), 2.69 (s, 3H, Ar-
CH3), 3.49 (s, 2H, SCH2), 6.56 (s, 1H, CONHC(CH3)2), 7.23 (t, 1H,
J12 = 8.0 Hz, J23 = 8.0 Hz, Ar-H), 7.49 (s, 1H, Ar-H), 7.54 (d, 1H,
JH = 8.4 Hz, Ar-H), 7.74 (d, 1H, JH = 7.6 Hz, Ar-H), 7.99 (d, 1H, JH
=
8.0 Hz, Ar-H), 8.41 (s, 1H, NH-Ar), 8.42 (d, 1H, JH = 8.0 Hz, Ar-H).
ESI-FTICR-MS for C22H22IN3O4S: found 562.0262 [M+Na]+, calcd
562.0273 [M+Na]+.
4.1.8.4. 3-Iodo-N2-(2-methyl-1-((N-methylenecyanamidyl)methyl-
thio)propan-2-yl)-N1-o-tolylphthalamide (C3).
White solid,
yield 74%, mp 173–174 °C; 1H NMR (400 Hz, CDCl3) d (ppm): 1.47
(s, 3H, SCH3), 1.62 (s, 3H, Ar-CH3), 2.28 (s, 6H, CH(CH3)2), 3.05 (d,
1H, JH = 13.6 Hz, SCH2), 3.90 (d, 1H, JH = 13.6 Hz, SCH2), 6.85 (s, 1H,
CONHC(CH3)2), 7.13 (t, 1H, J12 = 7.2 Hz, J23 = 7.2 Hz, Ar-H), 7.13 (t,
1H, J12 = 7.2 Hz, J23 = 7.2 Hz, Ar-H), 7.18 (d, 1H, JH = 7.6 Hz, Ar-H),
7.21 (t, 1H, J12 = 7.6 Hz, J23 = 7.6 Hz, Ar-H), 7.62 (d, 1H, JH = 7.2 Hz,
Ar-H), 7.68 (d,1H, JH = 6.8 Hz, Ar-H), 7.90 (d, 1H, JH = 8.0 Hz, Ar-H),
4.1.7.14.
N2-(2-methyl-1-(methylsulfonyl)propan-2-yl)
(D13).
Pale yellow solid, yield 69%, mp 115–116 °C; 1H NMR
N1-(4-(2,2-Dicyanovinyl)-2-methylphenyl)-3-iodo-
phthalamide
(400 Hz, CDCl3) d (ppm): 1.63 (s, 6H, CH(CH3)2), 2.40 (s, 3H,
SCH3), 2.73 (s, 3H, Ar-CH3), 3.50 (s, 2H, SCH2), 6.50 (s, 1H, CON-
HC(CH3)2), 7.25 (t, 1H, J12 = 8.0 Hz, J23 = 6.8 Hz, Ar-H), 7.66 (s, 1H,

6378
Y. Chen et al. / Bioorg. Med. Chem. 22 (2014) 6366–6379
8.43 (s, 1H, NH-Ar). ESI-FTICR-MS for C21H23IN4O2S: found 523.0666
[M+H]+, calcd 523.0665 [M+H]+.
procedure.33 The insecticidal activity against oriental armyworms
was tested by foliar application; individual corn (Tangyu 10, Zea-
mays L.) leaves were placed on moistened pieces of filter paper
in Petri dishes. The leaves were then sprayed with the test solution
and allowed to dry. The dishes were infested with 10 fourth-instar
oriental armyworm larvae. Percentage mortalities were evaluated
2 days after treatment. Each treatment was performed three
times.
4.1.8.5. N1-(4-Fluoro-2-methylphenyl)-3-iodo-N2-(2-methyl-1-
((N-methylenecyanamidyl)methylthio)propan-2-yl)
mide (C6).
phthala-
White solid, yield 76%, mp113–114 °C; 1H NMR
(400 Hz, CDCl3) d (ppm): 1.46 (s, 3H, CH(CH3)2), 1.58 (s, 3H,
CH(CH3)2), 2.26 (s, 3H, SCH3), 2.39 (s, 3H, Ar-CH3), 3.04 (d, 1H,
JH = 13.6 Hz, SCH2), 3.93 (d, 1H, JH = 13.6 Hz, SCH2), 7.86 (t,
1H, J12 = 8.0 Hz, J23 = 8.0 Hz, Ar-H), 7.93 (d, 1H, JH = 8.4 Hz, Ar-H),
7.02 (s, 1H, CONHC(CH3)2), 7.08 (t, 1H, J12 = 7.6 Hz, J23 = 8.0 Hz,
Ar-H), 7.49 (dd, 1H, J12 = 6.0 Hz, J13 = 7.6 Hz, J34 = 6.0 Hz, Ar-H),
7.58 (d, 1H, JH = 7.6 Hz, Ar-H), 7.85 (d, 1H, JH = 8.0 Hz, Ar-H), 8.54
(s, 1H, NH-Ar). ESI-FTICR-MS for C20H22FIN2O2S: found
541.0564 [M+H]+, calcd 541.0570 [M+H]+.
4.2.2. Larvicidal activity against diamondback moths
The larvicidal activity of compounds B6–B7, B10, C4, C5, C8, D1,
D6, and D10 and the control Flubendiamide was tested by the
leaf dip method. At first, a solution of each test sample in DMF
(AR, purchased from Alfa Aesar) at a concentration of 200 mg/L
was prepared and then diluted to the required concentration
with water (distilled). Leaf disks (6–2 cm) were cut from fresh
cabbage leaves and then were dipped in the test solution for 10 s
and allowed to dry. The resulting leaf disks were placed
individually into glass tubes. Each disk was infested with thirty
second-instar diamondback moth larvae. Percentage mortalities
were evaluated 2 days after treatment. Each treatment was
performed three times.
4.1.8.6.
methylthio)propan-2-yl)-N1-(2-methyl-4-nitrophenyl)phthala-
mide (D3).
White solid, yield 79%, mp 175–178 °C; 1H NMR
3-Iodo-N2-(2-methyl-1-((N-methylenecyanamidyl)-
(400 Hz, DMSO) d (ppm): 1.41 (s, 3H, NH(CH3)2), 1.48 (s, 3H,
NH(CH3)2), 2.41 (s, 3H, SCH3), 2.67 (s, 3H, OCH3), 2.20 (d, 1H,
JH = 13.6 Hz, SCH2), 3.82 (d, 1H, JH = 13.6 Hz, SCH2), 7.32 (t,
1H, J12 = 8.0 Hz, J23 = 7.6 Hz, Ar-H), 7.78 (d, 1H, JH = 7.6 Hz, Ar-H),
7.90 (d, 1H, JH = 8.8 Hz, Ar-H), 8.05 (d, 1H, JH = 8.0 Hz, Ar-H),
8.14 (d, 1H, JH = 8.8 Hz, Ar-H), 8.18 (s, 1H, Ar-H), 8.64 (s,
1H, CONHC(CH3)2), 9.94 (s, 1H, NH-Ar). ESI-FTICR-MS for
Acknowledgments
The project was supported by the National Basic Research Pro-
gram of China (973 project 2010CB126106), Natural Science Foun-
dation of China (No. 31370039) and the National Key Technologies
R&D Program (No. 2011BAE06B05), Specialized Research Fund for
the Doctorial Program of Higher Education (20110031110017).
C
21H20IN5O2S: found 568.0510 [M+H]+, calcd 568.0515 [M+H]+.
4.1.8.7.
N1-(2,4-Dimethylphenyl)-3-iodo-N2-(2-methyl-1-((N-
methylenecyanamidyl)methylthio)propan-2-yl)phthalamide
(D8).
White solid, yield 82%, mp 203–205 °C; 1H NMR (400 Hz,
CDCl3) d (ppm): 1.44 (s, 3H, NH(CH3)2), 1.59 (s, 3H, NH(CH3)2), 2.22
(s, 3H, Ar-CH3), 2.26 (s, 3H, Ar-CH3), 2.30 (d, 3H, JH = 6.0 Hz, SCH3),
3.00 (d, 1H, JH = 13.6 Hz, SCH2), 3.88 (d, 1H, JH = 13.6 Hz, SCH2),
6.97 (d, 1H, JH = 7.6 Hz, Ar-H), 7.02 (s, 1H, CONHC(CH3)2), 7.04 (t,
1H, J12 = 7.6 Hz, J23 = 7.6 Hz, Ar-H), 7.09 (s, 1H, Ar-H), 7.43 (d, 1H,
JH = 8.0 Hz, Ar-H), 7.55 (d, 1H, JH = 7.6 Hz, Ar-H), 7.82 (d, 1H,
JH = 8.0 Hz, Ar-H), 8.57 (s, 1H, NH-Ar). ESI-FTICR-MS for
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C
22H25IN4O2S: found 537.0811 [M+H]+, calcd 537.0821 [M+H]+.
4.1.8.8. N1-(4-Cyano-2-methylphenyl)-3-iodo-N2-(2-methyl-1-
((N-methylenecyanamidyl)methylthio)propan-2-yl) phthala-
mide (D11).
White solid, yield 73%, mp 119–120 °C; 1H NMR
(400 Hz, CDCl3) d (ppm): 1.50 (s, 3H, CH(CH3)2), 2.34 (s, 3H,
SCH3), 2.54 (s, 3H, Ar-CH3), 3.17 (d, 1H, JH = 13.6 Hz, SCH2), 3.98
(d, 1H, JH = 13.6 Hz, SCH2), 6.97 (s, 1H, CONHC(CH3)2), 7.23 (t,
1H, J12 = 7.6 Hz, J23 = 8.0 Hz, Ar-H), 7.51 (s, 1H, Ar-H), 7.52 (d, 1H,
JH = 12 Hz, Ar-H), 7.66 (d, 1H, JH = 7.6 Hz, Ar-H), 7.99 (d, 1H,
J = 8.0 Hz, Ar-H), 8.19 (d, 1H, J = 8.0 Hz, Ar-H), 8.32 (s, 1H, NH-Ar).
ESI-FTICR-MS for C22H22IN5O2S: found 548.0603 [M+H]+, calcd
548.0617 [M+H]+.
4.2. Biological assay
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alive basis, and mortality rates were corrected applying Abbott’s
formula.32 Error of the experiments was 5%. For comparative pur-
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0
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and B8 , C7 , D1 , D9 D12 were evaluated using the reported

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