Synthesis and fungicidal activity of fluorine-containing chlorothalonil derivatives

Article abstract of DOI:10.1016/j.jfluchem.2014.01.006

Fourteen new fluorine-containing chlorothalonil derivatives were synthesized by using intermediate derivatization method (IDM) in order to discover novel antifungal compounds for controlling corn rust. The structures of synthesized compounds were confirme

Full text of DOI:10.1016/j.jfluchem.2014.01.006

Accepted Manuscript
Title: Synthesis and fungicidal activity of fluorine-containing
chlorothalonil derivatives
Author: Aiying Guan Changling Liu Guang Huang Huichao
Li Shulin Hao Ying Xu Yong Xie Zhinian Li
PII:
S0022-1139(14)00016-5
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2014.01.006
FLUOR 8253
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
18-9-2013
17-12-2013
8-1-2014
Please cite this article as: A. Guan, C. Liu, G. Huang, H. Li, S. Hao,
Y. Xu, Y. Xie, Z. Li, Synthesis and fungicidal activity of fluorine-
containing chlorothalonil derivatives, Journal of Fluorine Chemistry (2014),
http://dx.doi.org/10.1016/j.jfluchem.2014.01.006
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*Graphical Abstract - Pictogram
Graphical abstract
Cl
Cl
Cl
CN
Cl
Cl
Cl
CN
H
N
CF3
NC
Cl
NC
Cl Cl
3j containing 2,6-Cl2-4-CF3 phenyl group
showing good control against SCR
Chlorothalonil
Page 1 of 18

*Graphical Abstract - Synopsis
Graphical synopsis
Chlorothalonil, a commercialized fungicide with very low cost, was employed as the starting material to
achieve a series of novel N-diphenylamines with excellent fungicidal activity against Southern Corn
Rust. Trifluoromethyl group on 4-position of substituted phenyl plays an important role in enhancing the
biological activity of target compounds.
Page 2 of 18

*Highlights (for review)
Highlights
► Application of the strategies of Intermediate Derivatization Method. ► Trifluoromethyl, a very strong
electron withdrawing group, plays an important role on fungicidal activity. ► Characterization of target
compounds using 1H NMR, 13C NMR, 19F NMR, elemental analysis, HRMS and X-ray. ► Excellent
fungicidal activity against Puccinia polysora. ► Detailed structure and activity relationship of target
compounds.
Page 3 of 18

*Manuscript
Synthesis and fungicidal activity of fluorine-containing
chlorothalonil derivatives
Aiying Guan, Changling Liu*, Guang Huang,
Huichao Li, Shulin Hao, Ying Xu, Yong Xie, Zhinian Li
State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Research Institute
of Chemical Industry Co. Ltd., Shenyang 110021, China
Abstract
Fourteen new fluorine-containing chlorothalonil derivatives were synthesized by using intermediate derivatization method (IDM)
in order to discover novel antifungal compounds for controlling corn rust. The structures of synthesized compounds were
confirmed by 1H NMR, 13C NMR, 19F NMR, elemental analysis, HRMS and X-ray. The bioassay results indicated that
compound 2,4,5-trichloro-6-(2,6-dichloro-4-[trifluoromethyl]phenylamino)isophthalonitrile (3j, Rn is 2,6-Cl2-4-CF3) had the
optimal structure with best fungicidal activity against corn rust (98%, 70% controls) at 25 and 6.25 mg/L concentration
respectively, much better than chlorothalonil and fluazinam, highlighting the importance of trifluoromethyl group on 4-position
of benzene ring. The structure-activity relationship of the synthesized compounds was discussed as well.
Keywords: Fluorine-containing chlorothalonil derivatives; IDM; Synthesis; Fungicidal activity
1
1
 Corresponding author. Tel.: +86 2485869078; fax: +86 2485869137.
E-mail address: liuchangling@vip.163.com (C.L. Liu)
1
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1. Introduction
Rust disease is an entire family of plant diseases caused by rust fungi, which infect and harm the stem, leaves, and
fruit of cereal crops. Because of the rule of epidemic of region, when rust diseases take hold in an agricultural region,
tremendous yield reductions will follow [1]. At present, the fungicides used to control rusts are generally
triazole compounds. However, their single structure type, combined with the characteristics of high
variability in rust disease, leads easily to pesticide resistance in affected plants [2]. Therefore it is particularly
important to discover and develop new fungicides with different modes of action to control rust diseases.
Chlorothalonil has a broad spectrum of fungicidal activity [3] with a relatively low cost, and it is
commercially available in a large scale. Based on these features, we chose chlorothalonil as the key
intermediate to develop novel bioactive compounds using intermediate derivatization method (IDM), developed
by our research group [4-6]. It is well known that many fluorine-containing compounds exhibit significant
agricultural bioactivities due to the fluorine atom’s unique properties [7]. For example, the trifluoromethyl group,
considered a ‘pseudo-halogen’, has been found to impart unique biological activity [8]. On the other hand,
some commercial diarylamine compounds (Fig. 1), specifically diphenylamine, were used to control storage
related diseases in fruits and vegetables [9]. Furthermore, N-phenylpyridinamines including fluazinam [10],
N-phenylpyrimidinamines including cyprodinil [11], pyrimethanil [12], and mepanipyrim [13], have been proven to
be effective against many diseases. In particular, fluazinam shows broad-spectrum control against diseases in field
crops. However, none of the mentioned-above compounds are effective against rust disease. More importantly,
these structure types have no similarities to other commercialized fungicides, e.g., triazoles, benzimidazoles and
diethofencarb , implying that compounds containing diarylamine may overcome the resistance of these marketed
fungicides [14]. Therefore, in this study, in order to discover new N-diphenylnamine leads or compounds with
promising and effective control of rust disease, a series of N-diphenylnamine fluorine-containing chlorothalonil
derivatives were designed, synthesized and bio assayed. The structure-activity relationships of these compounds
are discussed as well.
2. Results and discussion
2.1. Synthesis
2
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The general synthesis route of these targeted compounds is described in Figs. 2-5. Fig. 2 shows the synthesis process
of compounds 3a-3g, 3j and 3l. Fig. 3 summarizes the synthesis process of compounds 3h and 3i. Fig. 4 explains the
synthesis procedure of compound 3k. Fig. 5 displays the synthesis procedure of compound 3m and 3n.
2.2. Fungicidal activity
The fungicidal activity of the above compounds against southern corn rust (SCR-Puccinia polysora) in vivo was
determined at the concentration ranging from 6.25 to 400 mg/L, using fluazinam and chlorothalonil which is the
parental structure in the series as the reference standards, in accordance to the methods reported in a previous study
[15], and the results are listed in Table 1 and Table 2. Some of the synthesized compounds exhibited potential
activity against SCR. Particularly 3j, having strong electron withdrawing group CF3 on 4-position, displayed best
fungicidal activity (98% control at 25 mg/L and 70% control at 6.25 mg/L), much higher than chlorothalonil (50% at
400 mg/L) and fluazinam (30% control at 25 mg/L and 10% control at 6.25 mg/L).
2.3. Exploration of structure-activity relationship
In order to provide better references for following optimization combating SCR, the detailed SAR was further
discussed and summarized here.
Using available materials we started with synthesizing the compounds 3a (Rn =3-CF3), 3b (Rn =4-CF3) and 3c (Rn
=4-OCF3), which all have single substituent containing fluorine atom. However, this first step did not result in
observable and effective control of SCR as shown in Table 1, since all of these compounds demonstrated virtually
no activity against SCR even at a high concentration of 400 mg/L. Yet useful information delivered from these data
highlights that introducing a single F-containing group CF3 (strong electron-withdrawing group) or OCF3
(electron-donating group), into 4-position alone, did not increase the fungicidal activity of the molecule. Nor did the
introduction of a single F-containing group CF3 at the 3-position. The analysis of these results prompted us to further
employ F atom(s) into two positions on the benzene ring simultaneously, leading to the generation of the compounds
3
Page 6 of 18

3d (Rn =2,4-F2) and 3e (Rn =2,6-F2). To our surprise, the fungicidal activity of these two compounds against SCR
increased remarkably from zero to near 100% at 400 mg/L, indicating that introduction of two fluorine atoms into
this system dramatically increases fungicidal activity. Of interest, when 4-F was replaced with 4-CF3 (while keeping
2-position fixed as halogen), the activity decreased to zero (3f versus 3d). However, when we inserted an additional
F atom on 3-position (based on 3d structure) to obtain compound 3g, this modification did not exhibit any obvious
increase in fungicidal activity, showing that too many fluorine atoms may not be good for increasing the fungicidal
activity.
Thus, we carried out a subtle refinement of 3e with Rn of 2,6-F2, by inserting NO2 on 4-positon, obtained compound
3h had much greater fungicidal activity compared with 3e, (3h 95% control of SCR at 100 mg/L versus 3e 98% at
400 mg/L). Further, by changing 2-F to 2-Cl we observed a decrease of anti-fungal activity at 100 mg/L (3i 80%
versus 3h 95%). However, compound 3j (Rn =2,6-Cl2-4-CF3) demonstrated the highest fungicidal activity (70% at
6.25 mg/L) that was superior to other tested compounds, indicating that 4-CF3 plays an important role in the efficacy
as a fungicide. In order to confirm the importance of 4-CF3 at 4-position, we turned 4-CF3 into 4-OCF3 and kept
2,6-position constant as halogen atoms to obtain 3k. The results displayed that compound 3k is much less effective
in the control of SCR than 3j (3k 0 versus 3j 100% at 400 mg/L), underscoring the importance of CF3 on 4-position
of substituted phenyl ring for targeting SCR. Interestingly, when all chlorine atoms on chlorothalonil were
substituted with F atoms (3l), we expected that the activity would be enhanced, but the result was opposite: 3l
exhibited lower fungicidal activity than 3j (3l 20% versus 3j 100% at 100 mg/L) indicating that the fluorine atoms at
chlorothalonil side do not help to increase the fungicidal activity.
Finally to investigate the role of CNs of chlorothalonil, 3m and 3n compounds with 1, 2-disubstituted and 1,
4-disubstituted CN respectively were synthesized and bioassayed, the results are listed in Table 2. Compared with
3j, which has 1,3-disubstituted CN, 3m and 3n have less fungicidal activities than 3j, indicating that
1,3-disubstituted CNs is optimal position.
To further verify whether the effect of lipophilic property of substituents on biological activity, we calculated the
CLogP parameter of all compounds including chlorothalonil and fluazinam, using ChemDraw software. As shown in
4
Page 7 of 18

Tables 1 and 2, CLogP is less than 7 in the majority of compounds. Compounds with greater than 7 of CLogP are 3j,
3k, 3m and 3n. Interestingly, 3j, the most active compound, has the highest CLogP value in all new compounds
except 3k, indicating that biological activity of SCR is positively related to the CLogP. However, the unexpected
lower activity but high CLogP value of 3k may be due to the presence of trifluoromethoxyl group, which is an
electronic donating group. It is noted that although compounds 3j, 3m and 3n have comparable CLogP values, their
biological activities decreased according to the order of 3j, 3m and 3n. This may be due to the position difference of
two CNs of chlorothalonil, which plays an important role in controlling the biological activity in this particular case.
The optimal 1,3-disubstituted position of compound 3j represents the optimized steric configuration which allows
the entry of this drug into the active site of targeted enzyme.
Based on the discussions above, a clear cut, well-defined and direct relationship between chemical structure and
biological activity is on the horizon. It is summarized in the following (decreasing order of activity).
(1) for substituted position and numbers of substituents on benzene ring
2,6-Cl2-4-CF3 >> 2,6-F2-4-NO2 > 2-Cl-6-F-4-NO2 >> 2,3,4-F3≈2,4-F3≈ 2,6-F2 >>
2,6-Br2-4-OCF3≈2-Cl-4-CF3≈3-CF3≈4-CF3≈4-OCF3
(2) Different position of two CNs and halogen atoms attached to chlorothalonil
1,3-disubstituted >> 1,2-disubstituted > 1,4-disubstituted
Cl>>F
Fluorine as a unique atom can modulate the physical properties of molecules. The introduction of fluorine into
organic molecules may increase the lipophilic properties and enhance the rate of plant cell penetration and
transportation of drug into the active sites. Therefore, fungicidal activities are enhanced by introducing fluorine into
compounds of interest in general [16, 17]. However, the correlation of physical and structural properties of these
new compounds to the biological activity ascribes to the combination of many complicated factors including steric,
electronic and lipophilic factors rather than a single factor as represented in this study.
3. Conclusions
5
Page 8 of 18

In this study, 14 new fluorine-containing chlorothalonil derivatives were synthesized by using intermediate
derivatization method (IDM). Their fungicidal activity against corn rust was tested in order to obtain the optimized
structure. This study reveals that both number and position of fluorine atoms are critical to afford optimized
structures. It has been shown that compound 3j (R1=R2=R3=Cl, Rn =2,6-Cl2-4-CF3) is the optimal molecule with the
promising fungicidal activity, 70% control against SCR at 6.25 mg/L concentration, much higher than chlorothalonil
and fluazinam, highlighting the importance of CF3 on 4-position of substituted phenyl ring. This study also
demonstrates that fluorine-containing chlorothalonil derivatives can be used as lead compounds for developing
novel fungicides to control SCR. Further synthesis and structure optimization studies are needed and are currently in
progress.
4. Experimental
All starting materials and reagents used are commercially available and were utilized without further purification
1
(except as indicated). Melting points were determined using a Büchi melting point apparatus and are uncorrected. H
NMR, 13C NMR and 19F NMR spectra were recorded with a Mercury 300 MHz 1H (75MHz 13C, 282 MHz 19F)
spectrometer with deuterochloroform as the solvent and tetramethylsilane (TMS) as the internal standard. Mass
spectra were recorded using a Bruke micrOTOF-Q III mass spectrometer. Elemental analyses were determined
using a Yanaco MT-3CHN elemental analyzer. X-ray was recorded with XtaLAB mini. All plant and bacteria
materials were obtained from the Agrochemical Discovery Department in Shenyang Research Institute of Chemical
Industry.
The protective activity in vivo was determined as follows: whole corn plant was used in experiments; with the
various compounds dissolved in a proper solvent to obtain a master solution; the proper solvent was selected from
acetone, methanol, DMF and according to their dissolving capability in the sample. The ratio of solvent and testing
solution (v/v) is equal to or less than 5%. The master solution was diluted with H20 containing 0.1% tween-80 to
achieve the testing solution with the desired concentration. The testing solution was sprayed onto the host plant by
means of a special plant sprayer. The plants were inoculated with the fungi within 24 hours of being sprayed.
According to the specific infectious characteristics of the fungus, the plant was then stored in a humidity controlled
6
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chamber, and transferred to a greenhouse after infection is noted. The other non-infected plants were placed in the
greenhouse directly. The activity of the compounds was ascertained by direct careful observation after 7 days.
4.1. General synthetic procedure for title compounds 3a-3g, 3j and 3l-3n. [15, 18-20]
Substituted aniline (5µmol) was dissolved in 5 mL of DMF, and sodium hydroxide (10 µmol) was added to the
solution. The solution was stirred for 10 min, and corresponding intermediate phthalonitrile (or isophthalonitrile or
terephthalonitrile) (5 µmol) was then added. The reaction mixture was stirred at 60 o C and monitored by TLC. After
completion of the reaction (2 hours), the mixture was then added to 50 mL water and extracted with ethyl acetate (3
× 100 mL). The combined extracts were washed with brine, dried (anhydrous magnesium sulfate), and filtered. The
filtrate was then evaporated and the crude product was purified via silica gel column chromatography, using a 1:4
(v/v) mixture of ethyl acetate and petroleum ether (boiling point range: 60-90 o C) of the eluting solution to obtain
the title compound 3; except for 3h, 3i and 3k.
4.1.1. 2,4,5-trichloro-6-(3-(trifluoromethyl)phenylamino)isophthalonitrile (3a)
1
yield 68%, mp 236-238oC. H NMR (CDCl3 , 300MHz) δ: 7.12 (s, 1H, NH), 7.28-7.40 (m, 1H, Ph-6-H), 7.41-7.52
(m, 2H, Ph-2,4-2H), 7.54-7.62 (m, 1H, Ph-5-H). Anal. Calcd. for C15H5Cl3F3N3: C, 46.13; H, 1.29; N, 10.76. Found:
C, 46.19; H, 1.16; N, 10.84; 19F NMR (CDCl3, 282MHz) δ: -7.74.
4.1.2. 2,4,5-trichloro-6-(4-(trifluoromethyl)phenylamino)isophthalonitrile (3b)
1
yield 60%, mp 186-187oC. H NMR (CDCl3, 300MHz) δ: 6.06 (br, 1H, NH), 6.51(d, J=5.7Hz, 2H, Ph-2,6-2H),
7.52(d, J=5.7Hz, 2H, Ph-3,5-2H). Anal. Calcd. for C15H5Cl3F3N3: C, 46.13; H, 1.29; N, 10.76. Found: C, 46.18; H,
1.13; N, 10.88; 19F NMR (CDCl3, 282MHz) δ: -7.51.
4.1.3. 2,4,5-trichloro-6-(4-(trifluoromethoxy)phenylamino)isophthalonitrile (3c)
yield 59%, mp 204-206oC. 1H NMR (CDCl3, 300MHz) δ: 7.09 (s, 1H, NH), 7.22-7.32 (m, 4H, Ph-2,3,5,6-4H). Anal.
Calcd. for C15H5Cl3F3N3O: C, 44.31; H, 1.24; N, 10.34. Found: C, 44.41; H, 1.11; N, 10.40; 19F NMR (CDCl3,
282MHz) δ: -2.88.
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3.1.4. 2,4,5-trichloro-6-(2,4-difluorophenylamino)isophthalonitrile (3d)
yield 71%, mp 206-208oC. 1H NMR (CDCl3, 300MHz) δ: 6.88 (s, 1H, NH), 6.99 (t, 2H, Ph-5,6-2H, J=8.1Hz), 7.32
(d, 1H, Ph-3-H, J=2.4Hz). Anal. Calcd. for C14H4Cl3F2N3: C, 46.90; H, 1.12; N, 11.72. Found: C, 46.98; H, 1.01; N,
11.79; 19F NMR (CDCl3, 282MHz) δ: -60.59, -51.53.
4.1.5. 2,4,5-trichloro-6-(2,6-difluorophenylamino)isophthalonitrile (3e)
yield 70%, mp 264-266oC. 1H NMR (CDCl3, 300MHz) δ: 6.70 (s, 1H, NH), 7.07 (t, 2H, Ph-3,5-2H, J=8.1Hz), 7.37
(m, 1H, Ph-4-1H). Anal. Calcd. for C14H4Cl3F2N3: C, 46.90; H, 1.12; N, 11.72. Found: C, 46.96; H, 0.98; N, 11.80.
4.1.6. 2,4,5-trichloro-6-(2-chloro-4-(trifluoromethyl)phenylamino)isophthalonitrile (3f)
yield 75%, mp 166-168oC. 1H NMR (CDCl3, 300MHz) δ: 7.00 (s, 1H, NH), 7.20 (d, 1H, Ph-6-H, J=8.4Hz), 7.57 (dd,
1H, Ph-5-H, 3J=8.4Hz, 4J=1.5Hz), 7.78 (s, 1H, Ph-3-H). Anal. Calcd. for C15H4Cl4F3N3: C, 42.39; H, 0.95; N, 9.89.
Found: C, 42.30; H, 1.09; N, 9.77.
4.1.7. 2,4,5-trichloro-6-(2,3,4-trifluorophenylamino)isophthalonitrile (3g)
1
yield 52%, mp 182-184oC. H NMR (CDCl3, 300MHz) δ: 6.87 (s, 1H, NH), 7.05-7.09 (m, 2H, Ph-5,6-2H). Anal.
Calcd. for C14H3Cl3F3N3: C, 44.66; H, 0.80; N, 11.16. Found: C, 44.60; H, 0.95; N, 11.08; 19F NMR (CDCl3,
282MHz) δ: -100.90, -84.15, 75.93.
4.1.8. 2,4,5-trichloro-6-(2,6-dichloro-4-(trifluoromethyl)phenylamino)isophthalonitrile (3j)
yield 66%, mp 201-203oC. 1H NMR (CDCl3, 300MHz) δ: 6.91 (s, 1H, NH), 7.72 (s, 2H, Ph-3,5-2H). Anal. Calcd.
for C15H3Cl5F3N3: C, 39.21; H, 0.66; N, 9.15. Found: C, 39.28; H, 0.55; N, 9.24; 13C NMR (DMSO, 75MHz) δ:
115.52, 120.30 (q, J = 33.0 Hz), 121.40, 121.68, 121.86, 124.03(t, J = 3.75 Hz), 124.15, 125.45, 126.85, 134.87,
8
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140.29, 149.89, 150.12; 19F NMR (CDCl3, 282MHz) δ: -7.77; HRMS for C15H3Cl5F3N3: 456.8722; Found:
457.8813；The molecular structure of 3j was also confirmed by X-ray single-crystal diffraction (Fig. 6) [21].
4.1.9. 4-(2,6-dichloro-4-(trifluoromethyl)phenylamino)-2,5,6-trifluoroisophthalonitrile (3l)
yield 57%, mp 128-130oC. 1H NMR (CDCl3, 300MHz) δ: 6.31(br, 1H, NH), 7.66(s, 2H, Ph-3,5-2H). Anal. Calcd.
for C15H3Cl2F6N3: C, 43.93; H, 0.74; N, 10.25. Found: C, 43.85; H, 0.86; N, 10.19; 19F NMR (CDCl3, 282MHz) δ:
-88.46, -46.13, -7.58.
4.1.10. 3,4,5-trichloro-6-(2,6-dichloro-4-(trifluoromethyl)phenylamino)phthalonitrile (3m)
yield 52%, mp 202-204oC. 1H NMR (CDCl3, 300MHz) δ: 6.49 (br, 1H, NH), 7.69 (s, 2H, Ph-3,5-2H). Anal. Calcd.
for C15H3Cl5F3N3: C, 39.21; H, 0.66; N, 9.15. Found: C, 39.29; H, 0.80; N, 9.05.
4.1.11. 2,3,5-trichloro-6-(2,6-dichloro-4-(trifluoromethyl)phenylamino)terephthalonitrile (3n)
yield 55%, mp 138-140oC. 1H NMR (CDCl3, 300MHz) δ: 6.56 (br, 1H, NH), 7.65 (s, 2H, Ph-3,5-2H). Anal. Calcd.
for C15H3Cl5F3N3: C, 39.21; H, 0.66; N, 9.15. Found: C, 39.13; H, 0.79; N, 9.06; 13C NMR (CDCl3, 75MHz) δ:
111.13, 112.08, 119.33, 120.45, 124.06, 125.92 (q, J = 3.75 Hz), 126.01, 126.82, 128.38, 129.94, 131.97, 136.04,
136.18, 142.03.
4.2. General synthetic procedure for title compounds 3h and 3i [15]
To the mixture of 3e or intermediate 1 (2.0mmol) obtained according to the method described in section 3.1.
General synthetic procedure in concentrated sulfuric acid (20 mL) was added nitric acid fuming (d=1.52, 10 mL)
drop wise during 20 minutes with stirring sufficiently. Further stirred at room temperature for an hour, the reacting
mixture was poured into ice-water, the resulting precipitate was collected by filtration, washed with water
sufficiently to get compound 3h or 3i as pale white solid.
9
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4.2.1. 2,4,5-trichloro-6-(2,6-difluoro-4-nitrophenylamino)isophthalonitrile (3h)
1
Yield 58%, mp 204-206oC. H NMR (CDCl3, 300MHz) δ: 6.70 (s, 1H, NH), 7.97-8.01 (dd, 2H, Ph-3,5-2H,
3J=10.8Hz, 4J=3.0Hz). Anal. Calcd. for C14H3Cl3F2N4O2: C, 41.67; H, 0.75; N, 13.88. Found: C, 41.60; H, 0.66; N,
13.96.
4.2.2. 2,4,5-trichloro-6-(2-chloro-6-fluoro-4-nitrophenylamino)isophthalonitrile (3i)
1
3
yield 63%, mp 197-199oC. H NMR (CDCl3, 300MHz) δ: 6.86 (s, 1H, NH), 8.05 (dd, 1H, Ph-5-H, J=9.9Hz,
4J=2.7Hz), 8.28 (d, 1H, Ph-3-H, J=2.4Hz). Anal. Calcd. for C14H3Cl4FN4O2: C, 40.03; H, 0.72. Found: C, 40.17; H,
0.66; 19F NMR (CDCl3, 282MHz) δ: -56.13.
4.3. Synthesis for title compound
2, 4, 5-trichloro-6-(2,6-dichloro-4-(trifluoromethoxy)phenylamino)isophthalonitrile (3k) [15]
For the mixture of 3c obtained in section 3.1. General synthetic procedure (2.0mmol) and N-Bromosuccinimide
(NBS) in carbon tetrachloride (20 mL) was added benzoyl peroxide (5% weigh of intermediate 3k-1) with stirring.
The reacting mixture was heated to reflux for 5 hours and then was cooled to room temperature; the resulting filtrate
was collected by filtration, evaporated under reduced pressure to get compound 3k as pale white solid.
1
Yield 69%, mp 171-173oC. H NMR (CDCl3, 300MHz) δ: 6.97(br, 1H, NH), 7.56(s, 2H, Ph-3,5-2H). Anal. Calcd.
for C15H3Cl5F3N3O: C, 37.89; H, 0.64; N, 8.84. Found: C, 37.82; H, 0.66 N, 8.95.
Acknowlegments
The project was supported by the National Key Technology Support Program during the 12th Five-Year Plan Period
(Grant No. 2011BAE06B05). Steven Edward Robinson of the University of Colorado helped with revision of the
original manuscript.
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[10] T. Komyoji, K. Sugimoto, S. Mitani, N. Matsuo, K. Suzuki, Nippon Noyaku Gakkaishi, 20 (1995) 129-35.
[11] U. Muller, A. Hubele, H. Zondler, J. Herzog, ACS Symp. Ser. 686 (1998) 237-245.
[12] H. H. Schmidt, Nachrichtenblatt des Deutschen Pflanzenschutzdienstes (Braunschweig), 50 (1998) 177-178.
[13] S. Hayashi, S. Maeno, T. Kimoto, T. Nagata, Nippon Noyaku Gakkaishi, 22 (1997) 165-175.
[14] C.L. Liu, Complete Collection of World Pesticides (fungicides), Chemical Industry Press, Beijing, China,
2006, p. 237.
[15] C.L. Liu, G. Huang, J. Lan, H.C. Li, Z.N. Li, S.L. Hao, Y.Q. Song, A.Y. Guan, D.L. Cui, WO2012171484
(2012).
[16] F.M.D. Ismail, J. Fluorine Chem. 118 (2002) 27–33.
[17] B.K. Park, N.R. Kitterringham, P.M. Oneill, Annu. Rev. Pharmacool. Toxicol. 41 (2001) 443–470.
[18] C.L. Liu, G. Huang, J. Lan, H.C. Li, Z.N. Li, S.L. Hao, Y.Q. Song, A.Y. Guan, D.L. Cui, CN102827032
(2012).
[19] S.L. Hao, A.R. Jiang, Z.N. Li, H.C. Li, J.F. Wang, A.Y. Guan, B. Liang, Y.Q. Song, C.L. Liu,
CN102827033 (2012).
11
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[20] S.L. Hao, A.Y. Guan, J. Lan, A.R. Jiang, Z.N. Li, H.C. Li, B. Liang, D.L. Cui, Y.Q. Song, C.L. Liu,
CN102827034 (2012).
[21] The atomic coordinates for 3j have been deposited at the Cambridge Crys- tallographic Data Centre. CCDC ID:
977468 contains the supplementary crys- tallographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif.
12
Page 15 of 18

Figures and Tables
CH3
N
NO2
CH3
CH3
F3C
Cl
CF3
N
N
N
N
N
H
N
H
CH3
N
N
N
N
N
CH3
NO2
Cl
H
H
H
diphenylamine
cyprodinil
mepanipyrim
pyrimethanil
fluazinam
Figure 1. Commercial diarylamine compounds
R1
R2
CN
R3
R1
CN
R3
H
NC
Cl
+
NC
H2N
N
Rn
Rn
R2
R1=R2=R3=Cl, Compounds 3a-3g, 3j
R1=R2=R3=F, Compound 3l
Figure 2. Synthesis scheme of compounds 3a-3g, 3j and 3l
Cl
CN
Cl
X
F
Cl
Cl
CN
Cl
X
F
HNO3
H
H
NC
N
NC
N
N
O2
Cl
X=F, Compound 3e
X=Cl, Intermediate 1
X=F, Compound 3h
X=Cl, Compound 3i
Figure 3. Synthesis scheme of compounds 3h and 3i
Br
CN
Cl
Cl
Cl
CN
Cl
NBS
H
OCF3
NH
NC
N
OCF3
NC
Br
Compound 3k
Cl
Cl
Compound 3c
Figure 4. Synthesis scheme of compound 3k
13
Page 16 of 18

Cl
H2N
Cl
Cl
Cl
Cl
Cl
Cl
CF3
H
N
NC
NC
Cl
Cl
NC
NC
Cl
CF3
Cl
Compound 3m
Cl
H2N
Cl
CN
CN
CN
CN
Cl
CF3
H
N
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CF3
Cl
Compound 3n
Figure 5. Synthesis scheme of compounds 3m and 3n
Figure 6. X-ray single-crystal diffraction of 3j
14
Page 17 of 18

Table 1
Chemical structures and fungicidal activity of compounds 3a to 3l
Fungicidal Activity against SCR (%
control at given concentration mg L-1)
Compound
3a
R1=R2=R3
Rn
CLogP
400
100
25
6.25
a
Cl
3-CF3
6.14960
0
/
/
/
3b
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
4-CF3
4-OCF3
6.14962
6.26621
5.52539
5.52539
6.86318
5.52859
5.31092
5.88092
7.57637
7.75021
6.18637
3.47
0
/
/
/
/
/
/
3c
0
3d
2,4-2F
100
98
0
/
/
3e
2,6-F2
0
/
/
3f
2-Cl-4-CF3
2,3,4-F3
0
/
/
/
3g
98
30
95
80
100
/
0
/
3h
2,6-F2-4-NO2
2-Cl-6-F-4-NO2
2,6-Cl2-4-CF3
2,6-Br2-4-OCF3
2,6-Cl2-4-CF3
100
100
100
0
30
50
98
/
0
30
70
/
3i
3j
3k
3l
100
50
20
/
0
/
chlorothalonil
/
/
fluazinam
5.96488
100
90
30
10
a stands for no data.
Table 2
Chemical structures and fungicidal activity of compounds 3m to 3n
Fungicidal Activity against SCR
(% control at given concentration
mg L-1)
Compound
Position of di-CN
R1=R2=R3
Rn
CLogP
400
100
100
100
100
100
50
25
98
0
6.25
3j
1,3-disubstituted
1,2-disubstituted
1,4-disubstituted
Cl
Cl
Cl
2,6-Cl2-4- CF3
2,6-Cl2-4- CF3
2,6-Cl2-4- CF3
7.57637
7.59637
7.57637
70
a
3m
/
3n
0
/
/
a stands for no data.
15
Page 18 of 18