N-Phenyl heteroarylamine analogues of fluazinam using the intermediate derivatization methods approach

Article abstract of DOI:10.1007/s12039-014-0673-1

Twenty-one N-phenyl heteroarylamine analogues of fluazinam 3a-3u were prepared via nucleophilic substitution reaction of 2,6-dichloro-3,5- dinitrotoluene with heteroarylamines using the intermediate derivatization method. 2,6-Dichloro-3,5-dinitrotoluene,

Full text of DOI:10.1007/s12039-014-0673-1

J. Chem. Sci. Vol. 126, No. 4, July 2014, pp. 1107–1114. ꢀc Indian Academy of Sciences.
N-Phenyl heteroarylamine analogues of fluazinam using the intermediate
derivatization methods approach
a
a
a
a
a
b
AIYING GUAN , HUICHAO LI , ZHINIAN LI , FAN YANG , YONG XIE , XIAOPING YANG
a,∗
and CHANGLING LIU
a
State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Research Institute
of Chemical Industry Co. Ltd., Shenyang 110 021, China
b
Division of Medical Oncology, Department of Medicine, School of Medicine, University of Colorado
Anschutz Medical Campus, Aurora, 80045, USA
e-mail: liuchangling@vip.163.com
MS received 12 November 2013; revised 11 April 2014; accepted 11 April 2014
Abstract. Twenty-one N-phenyl heteroarylamine analogues of fluazinam 3a–3u were prepared via nucle-
ophilic substitution reaction of 2,6-dichloro-3,5-dinitrotoluene with heteroarylamines using the intermediate
derivatization method. 2,6-Dichloro-3,5-dinitrotoluene, the key intermediate, was synthesized by nitration of
1
13
2
,6-dichlorotoluene. The synthesized compounds were identified by H NMR, C NMR, MS and elemental
analyses. Preliminary bioassays indicated that most of the compounds showed good fungicidal activity against
rice blast. The activity of 3p was equal to that of fluazinam. The relationship between molecular structure
and biological activity suggested that introduction of electron-withdrawing groups in the pyridine ring was
important for optimizing fungicidal activity against rice blast.
Keywords. Diarylamine compounds; 2,6-Dichloro-3,5-dinitrotoluene; intermediate derivatization method;
fungicides.
1
. Introduction
and its advantages of relatively low cost and wide com-
mercial availability. We were interested in using the
IDM approach with 2,6-dichlorotoluene as a starting
material for the synthesis of analogues of the fluazi-
nam, a phenylpyridinamine fungicide shown in figure 2.
Fluazinam shows good control on many diseases
like grey mould and downy mildew on vines; apple
scab, southern blight and white mould on peanuts;
tomato late blight and tuber blight on potatoes; clu-
broot on crucifers; rhizomania on sugar beet; white
and violet root rot on fruit trees; and for con-
A new approach for discovering and developing novel
agrochemicals, Intermediate Derivatization Methods
1
–3
(
IDM), has been reported recently and was adopted
by Shenyang Research Institute of Chemical Industry
SYRICI) to obtain innovative chemical structures
which in conjunction with biological screening gen-
(
4
–9
erated patentable leads and target compounds.
The essence of IDM is to apply simple organic
chemical reactions using commercially available and
inexpensive starting materials to achieve innovated
structures.
One application of IDM involves the use of 2,6-
dichlorotoluene as the key starting material for pestici-
des shown in figure 1, including herbicides dichlobenil
17
trolling mites in apples as well. In our previous
18
study, we used the IDM approach starting with 2,6-
dichlorotoluene to prepare the fluazinam analogue com-
pound A (figure 2) in which N-(3-chloro-2,6-dinitro-4-
trifluoromethylphenyl) moiety of fluzinam was replaced
by a N-(3-chloro-2-methyl-4,6-dinitrophenyl) group.
This fluazinam analogue displayed promising control
of rice blast and prompted us to explore similar ana-
logues in order to improve its fungicidal activity. In
this study, we report the synthesis of 21 new N-
phenyl heteroarylamine analogues of fluazinam, pre-
pared from key starting material 2,6-dichlorotoluene
using the IDM approach, and their activity against rice
blast.
10
11
12
(
III), tembotrione (1-1) and florasulame(1-2),
13
insecticides methoxyfenozide (1-3) and diflubenzuron
10,14,15
16
(
1-4),
and the fungicide fluopicolide (1-5). 2,6-
Dichlorotoluene was selected as the key starting mate-
rial for these pesticides due to its suitable functionality
∗
For correspondence
1107

1108
Aiying Guan et al.
O
O
O
Cl
F
O
OCH3
Cl
O
F
O
F
O
F
F
N
N
O
S
N
N
N
H
N
N
F
H
H
SO CH3
F
2
tembotrione (1-1)
florasulame (1-2) F
diflubenzuron (1-4)
O
Cl
F
F
F
O
HO
O
NH2
F
F
2
SO CH3
IV
NH2
I-A
F
III-A F
Cl
CH3
O
Cl
Cl
Cl
CH3
CN
Cl
H C
3
Cl
I
dichlobenil (III)
2
,6-dichloro-toluene (1)
CH3
Cl
O
O
Cl
Cl
O
Cl
CF3
H C
3
H
N
II
OH
Cl
N
Cl
III-B
fluopicolide (1-5)
CH3
CH3
CH3
H C
3
CH3
CH3
O
O
CN
H C
3
O
N
CH3
H C
3
N
H
O
II-A
methoxyfenozide (1-3)
Figure 1. Pesticides synthesized from key starting material 2,6-dichlorotoluene.
. Experimental section
spectra were recorded using a JEOL JMS-700 mass
.1 Materials
2
spectrometer. Elemental analyses were determined on
a Yanaco MT-3CHN elemental analyzer. All starting
materials, reagents and solvents were commercially
available and used without further purification.
2
The reactions were monitored by TLC on aluminum-
backed silica plate visualized by UV light. Melting
points were determined on a Büchi melting point
2
.2 Synthesis of key intermediate 2,6-dichloro-3,5-
1
apparatus and are uncorrected. H NMR spectra were
dinitrotoluene (2)
recorded on a Mercury 300 (Varian, 300 MHz) spec-
trometer with deuterochloroform as the solvent and
tetramethylsilane (TMS) as the internal standard. Mass
Cl
Cl
NO2
The synthesis sequence is outlined in scheme 1. To a
mixture of 2,6-dichlorotoluene (50 mmol) and concen-
trated sulfuric acid (30 mL), cooled to 5 C, was added
H
N
CF
3
H
N
Cl
CF3
N
◦
N
F3C
NO2
O N
NO2
2
fuming nitric acid (d = 1.52, 10 mL) dropwise for
Cl
2
0 min, while being stirred continuously. The reac-
Fluazinam
Compound A
tion mixture was stirred at room temperature for an
hour and then poured into icy water. The resulting pre-
Figure 2. Structures of fluazinam and compound A

N-Phenyl heteroarylamine analogues of fluazinam
1109
4
3
H
5
6
H
Cl
N
Rn
Cl
N
a
Cl
Cl
b
HET
Cl
Cl
2
N
O N
O N
O N
NO2
2
2
2
NO2
3a-3p
NO2
3q-3u
1
2
Pyridin-2-yl: Pyridin-3-yl: Pyridin-4-yl:
HET:
n
n
n
3q: 2-quinolinyl;
3
3
3
3
3
3
a: R =H;
3g: R =H;
3n: R =2-Cl;
3
r: 2-pyrazinyl;
n
n
n
b: R =4-CH ; 3h: R =2-Cl; 3o: R =2-Br;
3
3
s: 2-pyrimidinyl;
n
n
n
c: R =5-CH ; 3i: R =2-Br;
3p: R =3-Cl-2,5,6-F
3t: 2-thiazolyl;
3u: 3-isoxazolyl
3
3
n
n
d: R =5-Cl;
3j: R =6-Cl;
n
n
e: R =5-Br;
3k: R =6-Br;
n
n
f: R =5-CF
3l: R =2,5-Cl ;
3
2
n
3
m: R =2,6-Cl -4-CF
2
3
◦
Scheme 1. Reagents and conditions: (a) fuming nitric acid in c.H2SO4/5 C-room temperature; (b) hete-
roarylamines, NaOH in DMF, room temperature (25 C).
◦
cipitate was collected by filtration, washed with water (s, 3H, pyridin-CH ); 3C NMR (75 MHz, DMSO-d6)
1
3
and recrystallized from ethanol giving 2,6-dichloro-3,5- δ 151.76, 146.32, 141.55, 140.42, 139.09, 137.04,
◦
dinitrotoluene as pale green needles, M.p. 131–132 C.
134.49, 129.94, 125.81, 120.64, 111.39, 17.22, 16.52;
Anal. Calcd. for C H ClN O : C, 48.38; H, 3.44; N,
13
11
4
4
17.36; Found: C, 48.31; H, 3.56; N, 17.31.
2.3 General synthetic procedure for N-phenyl
heteroamines (3a–3u)
2
.4b 5-Chloro-N-(3-chloro-2-methyl-4,6-dinitrophenyl)
The synthesis sequence is outlined in scheme 1. Het-
eroarylamine 4 (5 mmol) was added in portions to a
suspension of NaOH (10 mmol, 60%) in DMF (20 mL)
at room temperature. After 30 min, a solution of 2,6-
dichloro-3,5-dinitrotoluene (6 mmol) in 30 mL of THF
was added and then the resulting mixture was stirred
overnight. After reaction completion (TLC), the mix-
ture was filtered. The filtrate was concentrated under
reduced pressure and the residue was purified on a silica
column to afford the N-phenyl heteroarylamines 3a-3u
in 60-91% yield. All these target compounds are new
and are characterized as follows.
pyridin-2-amine (3d):
◦
1
Yield 77%. Orange solid. M.p.: 168—170 C; H NMR
(300 MHz, CDCl ): δ (ppm) 8.89 (bs, 1H, NH), 8.59
3
(
7
s, 1H, Ph-H), 8.13 (d, 1H, J = 2.7 H , pyridin-6H),
Z
.63 (dd, 1H, J = 2.7, 8.7 H , pyridin-4H), 6.86 (d, 1H,
Z
J = 8.7 H , pyridin-3H), 2.25 (s, 3H, CH ); Anal.
Z
3
Calcd. for C H Cl N O : C, 42.00; H, 2.35; N, 16.33;
12
8
2
4
4
Found: C, 42.06; H, 2.46; N, 16.25.
2
.4 Characterization of N-phenyl heteroarylamines
2
.4c 2-Chloro-N-(3-chloro-2-methyl-4,6-dinitrophenyl)
(
3a–3u)
pyridin-3-amine (3h):
2.4a N-(3-chloro-2-methyl-4,6-dinitrophenyl)-5-
methylpyridin-2-amine (3c):
◦
1
Yield 75%. Orange solid. M.p.: 136—138 C; H NMR
300 MHz, CDCl ): δ (ppm) 8.88 (bs, 1H, NH), 8.67 (s,
(
3
◦
1
Yield 70%. Orange solid. M.p.: 187—189 C; H NMR 1H, Ph-H), 8.15 (dd, 1H, J = 1.5, 4.8 H , pyridin-6H),
Z
(
8
300 MHz, CDCl ): δ (ppm) 9.04 (bs, 1H, NH), 7.18—7.22 (m, 1H, pyridin-5H), 6.83 (dd, 1H, J = 0.9,
3
.62 (s, 1H, Ph-H), 8.03 (s, 1H, pyridin-6H), 7.50 7.8 H , pyridin-4H), 2.20 (s, 3H, CH ); Anal. Calcd.
3
Z
(
dd, 1H, J = 2.4, 8.4 Hz, pyridin-4H), 6.83 (d, 1H, for C H Cl N O : C, 42.00; H, 2.35; N, 16.33; Found:
12
8
2
4
4
J = 8.4 Hz, pyridin-3H), 2.25 (s, 3H, Ph-CH ), 2.05 C, 42.04; H, 2.48; N, 16.26.
3

1110
Aiying Guan et al.
2
.4d 2-Bromo-N-(3-chloro-2-methyl-4,6-dinitrophenyl) (s, 1H, Ph-H), 8.07 (d, 1H, J = 2.1 H , pyridin-6H),
Z
pyridin-3-amine (3i):
6.72 (d, 1H, J = 2.1 H , pyridin-4H), 2.26 (s,
Z
3
H, CH ). Anal. Calcd. for C H Cl N O : C, 38.17;
3 12 7 3 4 4
H, 1.87; N, 14.84; Found: C, 38.25; H, 1.75; N
4.79.
1
◦
1
Yield 76%. Orange solid. M.p.: 140—142 C; H NMR 2.4h 2,6-Dichloro-N-(3-chloro-2-methyl-4,6-dinitro-
(
(
300 MHz, CDCl ): δ (ppm) 8.89 (bs, 1H, NH), 8.68 phenyl)-4-(trifluoromethyl)pyridin-3-amine (3m):
3
s, 1H, Ph-H), 8.13 (dd, 1H, J = 1.5, 4.8 H , pyridin-
Z
6
H), 7.19-7.24 (m, 1H, pyridin-5H), 6.78 (dd, 1H,
J = 1.5, 8.1 H , pyridin-4H), 2.18 (s, 3H, CH ); Anal.
Z
3
Calcd. for C H BrClN O : C, 37.19; H, 2.08; N, 14.46;
12
8
4
4
Found: C, 37.11; H, 2.14; N, 14.51.
◦
1
2
.4e 6-Chloro-N-(3-chloro-2-methyl-4,6-dinitrophenyl) Yield 60%. Yellow solid. M.p.: 130—132 C; H NMR
pyridin-3-amine (3j):
(300 MHz, CDCl ): δ (ppm) 9.59 (bs, 1H, NH), 8.74 (s,
3
1
H, Ph-H), 7.67 (s, 1H, pyridin-H), 2.00 (s, 3H, CH ).
3
Anal. Calcd. for C H Cl F N O : C, 35.04; H, 1.36;
13
6
3
3
4
4
N, 12.57; Found: C, 34.99; H, 1.44; N 12.52.
◦
1
Yield 75%. Orange solid. M.p.: 108-110 C; H NMR 2.4i 2-Bromo-N-(3-chloro-2-methyl-4,6-dinitrophenyl)
(
300 MHz, CDCl ): δ (ppm) 9.07 (bs, 1H, NH), 8.71 pyridin-4-amine (3o):
3
(
7
s, 1H, Ph-H), 8.05 (d, 1H, J = 2.7 H , pyridin-2H),
Z
.32 (d, 1H, J = 8.4 H , pyridin-5H), 7.15 (dd, 1H,
Z
J = 2.7, 8.4 H , pyridin-4H), 2.18 (s, 3H, CH ); Anal.
Z
3
Calcd. for C H Cl N O : C, 42.00; H, 2.35; N, 16.33;
12
8
2
4
4
Found: C, 41.93; H, 2.46; N, 16.24.
◦
1
Yield 79%. Orange solid. M.p.: 170—172 C; H NMR
2
.4f 6-Bromo-N-(3-chloro-2-methyl-4,6-dinitrophenyl) (300 MHz, CDCl ): δ (ppm) 8.68 (s, 1H, pyridin-2H),
3
pyridin-3-amine (3k):
8.61 (bs, 1H, NH), 8.59 (s, 1H, Ph-H), 8.30 (d, 1H,
J = 5.4 H , pyridin-6H), 6.26 (d, 1H, J = 5.4 H ,
Z
Z
pyridin-5H), 2.30 (s, 3H, CH ); Anal. Calcd. for
3
C H BrClN O : C, 37.19; H, 2.08; N, 14.46; Found:
12
8
4
4
C, 37.14; H, 2.10; N, 14.50.
◦
1
Yield 75%. Orange solid. M.p.: 108—110 C; H NMR
(
300 MHz, CDCl ): δ (ppm) 9.03 (bs, 1H, NH), 8.71
3
2
2
.4j 3-Chloro-N-(3-chloro-2-methyl-4,6-dinitrophenyl)-
,5,6-trifluoropyridin-4-amine (3p):
(
7
s, 1H, Ph-H), 8.04 (d, 1H, J = 3.0 H , pyridin-2H),
Z
.46 (d, 1H, J = 8.4 H , pyridin-5H), 7.04 (dd, 1H,
Z
J = 3.0, 8.4 H , pyridin-4H), 2.18 (s, 3H, CH ); Anal.
Z
3
Calcd. for C H BrClN O : C, 37.19; H, 2.08; N, 14.46;
12
8
4
4
Found: C, 37.14; H, 2.03; N, 14.57.
2.4g 2,5-Dichloro-N-(3-chloro-2-methyl-4,6-dinitro-
phenyl)pyridin-3-amine (3l):
1
Yield 91%. Yellow Oil; H NMR (300 MHz, CDCl ):
3
δ (ppm) 8.54 (s, 1H, Ph-H), 8.44 (bs, 1H, NH),
13
2
.33 (s, 3H, CH ); C NMR (75 MHz, DMSO)
3
δ 146.23, 144.69, 142.74, 142.65, 140.19, 140.16,
1
35.46, 129.84, 119.35, 100.08(d, J = 4.65 Hz), 99.51,
16.35; Anal. Calcd. for C H Cl F N O : C, 36.30; H,
12
5
2
3
4
4
◦
1
Yield 78%. Orange solid. M.p.: 141—143 C; H NMR 1.27; N, 14.11; Found: C, 36.38; H, 1.22; N, 14.15;
−
(
300 MHz, CDCl ): δ (ppm) 8.74 (bs, 1H, NH), 8.65 LC-MS (m/z %): 394.9 [M-H] .
3

N-Phenyl heteroarylamine analogues of fluazinam
1111
2
2
.4k N-(3-chloro-2-methyl-4,6-dinitrophenyl)pyrimidin- methods.18–20 The intermediate 2,6-dichloro-3,5-dini-
-amine (3s):
trotoluene (2) was prepared from 2,6-dichlorotoluene
1) and fuming nitric acid, then reacted with heteroaryl
(
amines (4) to afford target compounds (3) in 60–91%
yields. The 21 N-phenyl heteroarylamine compounds
are listed in table 1.
◦
1
Yield 83%. Yellow solid. M.p.: 108—110 C; H NMR
300 MHz, CDCl ): δ (ppm) 8.67 (bs, 1H, NH), 8.49 (s, 3.2 Structure-activity relationship (SAR) based
(
3
1
6
H, Ph-H), 8.44 (d, 2H, J = 4.8 H , pyrimidin-4,6-2H), on results of in vitro fungicide assay
Z
.89—6.93 (m, 1H, pyrimidin-5H), 2.43 (s, 3H, CH );
3
1
3
The compounds were screened for fungicidal activ-
C NMR (75 MHz, DMSO) δ 159.50, 158.29, 144.00,
ity against rice blast (RB), a major pathogen of rice.
As shown in table 2, all N-phenyl heteroarylamine
compounds, except 3c, displayed significant fungici-
dal activity against RB. Compounds 3m and 3p were
particularly effective, providing 80% and 100% con-
trol respectively, at the lowest concentration, 0.1 mg/L
and were much improved over that of compound A
1
42.93, 137.54, 135.59, 129.87, 119.94, 114.02, 16.57;
Anal. Calcd. for C H ClN O : C, 42.66; H, 2.60; N,
11
8
5
4
22.62; Found: C, 42.62; H, 2.56; N, 22.67.
2.4l N-(3-chloro-2-methyl-4,6-dinitrophenyl)thiazol-
2
-amine (3t):
(80% at 25 mg/L) and equal to that of fluazinam. Based
on the data presented in table 2, a structure-activity
relationship emerged.
◦
1
Yield 71%. Orange solid. M.p.: 151—153 C; H NMR
3
.2a Compounds of the 2-pyridinyl type (3a – 3f):
(
300 MHz, CDCl ): δ (ppm) 9.34 (bs, 1H, NH), 8.60
s, 1H, Ph-H), 7.28 (d, 1H, J = 3.6 Hz, thiazol-4-H),
3
When electron-donating group such as methyl group
was introduced at the 5-position of the pyridine ring in
the 2-pyridinyl to form 3c, fungicidal activity reduced
compared to the unsubstituted pyridine compound 3a
(
6
.93 (d, 1H, J = 3.6 Hz, thiazol-5H), 2.31 (s, 3H, CH );
3
Anal. Calcd. for C H ClN O S: C, 38.16; H, 2.24; N,
10
7
4
4
1
7.80; Found: C, 38.19; H, 2.30; N, 17.68.
(50% vs. 100% control at 25 mg/L). When the methyl
group was introduced at the 4-position of the pyridine
ring giving 3b, fungicidal activity remained the same
as the unsubstituted pyridine compound 3a (80% con-
trol at 8.3 mg/L). This result suggests that the introduc-
tion of methyl at 4-position would not improve fungi-
cidal activity in this series of N-phenylpyridinamines.
However, when the 5-position was substituted with an
electron-withdrawing group (chlorine, bromine or tri-
fluoromethyl), the fungicidal activity of compounds
2
.5 Fungicidal assays
The in vitro biological activities were evaluated using
a previously reported procedure18 with the aid of
High Throughput Screening. A testing solution was
obtained by dissolving each N-phenyl heteroarylamine
compound in various solvents at the desired concen-
tration, ranging from 0.1–25 mg/L. The solvents were
selected from acetone, methanol or DMF according to
the different solubility of each compound. The test-
ing solution and pathogen suspensions were added into
the cells of a 96-well culture plate, which then was
placed in the constant temperature chamber. After 24 h
pathogen germination or growth was assessed and the
fungicidal activity of the compound was evaluated rel-
ative to pathogen germination or growth in the control
treatment. The level of fungicidal activity was reported
in the range 0 (no control) to 100% (complete control).
3d, 3e and 3f was improved over the unsubstituted
pyridine compound 3a (100%, 100%, 100% vs. 80%
at 8.3 mg/L). These results imply that an electron-
withdrawing group at the 5-position of the pyridine ring
improves fungicidal activity.
3.2b Compounds of the 3-pyridinyl type (3g – 3m):
Introducing a chlorine atom at the 2- or 6-position of
pyridine ring in the 3-pyridinyl type of compounds
to form 3h and 3j, fungicidal activity was improved
compared with the unsubstituted pyridine compound
3
. Results and discussion
3
g (80%, 80% vs 0% at 2.8 mg/L). Similarly, intro-
ducing bromine at the 2- or 6-position to form 3i and
k also improved fungicidal activity compared to the
3.1 Chemistry
3
The preparation of target compounds 3a–3u illustrated unsubstituted pyridine compound 3g (100%, 80% vs
in scheme 1, was accomplished by adopting known 0% at 2.8 mg/L). When hydrogen atoms at the 2- and

1112
Aiying Guan et al.
Table 1. Chemical structures, physical properties of compounds synthesized.
Position of
–NH–
a
n
◦
Compd.
R
M.p. ( C)
Yield (%)
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
2
2
2
2
2
2
3
3
3
3
3
3
3
4
4
4
H
111-113
150-152
187-189
168-170
175-177
142-144
146-148
136-138
140-142
108-110
156-158
141-143
130-132
166-168
170-172
oil
73
68
70
77
79
65
78
75
76
75
78
78
60
80
79
91
4-CH3
5-CH3
5-Cl
5-Br
5-CF3
H
2-Cl
2-Br
6-Cl
6-Br
2,5-Cl2
2,6-Cl2-4-CF3
2-Cl
2-Br
3-Cl-2,5,6-F3
◦
Compd.
HET
M.p. ( C)
Yield (%)
80
3q
175–177
3r
108–110
74
3
s
t
178–180
151–153
83
71
3
3u
137–139
69
ameans that “–NH–” is attached to pyridinyl ring.
-position of pyridine ring were simultaneously substi- control at 8.3 mg/L and 80% control at 2.8 mg/L, res-
5
tuted with chlorine atoms (3l), its activity was further pectively. In this case, the bromine compound showed
enhanced compared with that of compounds 3h, 3i, 3j superior activity compared with the corresponding
and 3k (50% vs. 0% control at 0.9 mg/L). Astonish- compound containing chlorine. The tetrasubstituted
ingly, the trisubstituted pyridine compound 3m which pyridine compound 3p which includes electron-
possesses electron-withdrawing groups 2,6-Cl -4-CF
withdrawing atoms 3-Cl-2,5,6-F displayed the high-
2
3
3
provided greatly improved fungicidal activity compared est fungicidal activity of all tested N-phenyl heteroary-
to the unsubstituted pyridine compound 3g (80% vs. lamine compounds (100% control at 0.1 mg/L), which
no control at 0.1 mg/L), this result suggests that the may be due to strong electronegativity of fluorine and/or
strong electron-withdrawing CF on 4-position of pyri- multiple substituents.
3
dine ring plays an important role in enhancing fungici-
dal activity in combination with 2,6-Cl . It is not diffi-
2
3
3
.2d Other nitrogen heterocyclic analogues (3q –
u): Replacing the 2-pyridinyl ring of 3a with the 3-
cult to draw the conclusion that the adjacent, and partic-
ularly para positions of nitrogen atom in pyridine ring
has a significant effect on fungicidal activity.
isoxazolyl ring forming 3u reduced fungicidal activity
50% control at 8.3 mg/L). When the 2-pyridinyl ring
of 3a was replaced with a 2-pyrazinyl or 2-pyrimidinyl
.2c Compounds of the 4-pyridinyl type (3n – 3p): ring forming compounds 3r and 3s, fungicidal activity
(
3
Introducing a chlorine or bromine atom at the 2-position was maintained (80% control at 8.3 mg/L). When the
of the pyridine ring forming 3n and 3o) gave 80% 2-pyridinyl ring of 3a was replaced with a 2-quinolinyl

N-Phenyl heteroarylamine analogues of fluazinam
Table 2. Fungicidal activity of N-phenyl heteroarylamines against RB.
1113
Fungicidal activity against RB
% control at given concentration mg/L)
(
Compd.
25
8.3
2.8
0.9
0.3
0.1
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
g
h
i
100
100
50
80
0
/b
/
/
80
0
/
/
/
/
/
/
/
/
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
100
100
100
50
50
50
50
0
0
/
/
0
/
/
0
/
/
/
/
/
100
100
100
100
80
100
80
80
100
80
80
80
100
0
0
/
/
0
/
/
j
k
l
0
/
/
0
/
/
50
/
/
m
n
o
p
q
r
s
100
100
80
/
0
/
/
/
/
100
100
100
80
80
100
80
0
100
100
100
0
/
/
/
/
/
80
0
/
/
/
t
u
100
50
100
0
0
/
/
/
/
/
Compound A
Fluazinam
0
/
/
/
/
100
100
100
100
100
100
bstands for no data.
ring forming 3q, fungicidal activity increased (80% Supplementary Information
control at 2.8 mg/L). When the 2-pyridinyl ring of
The electronic supporting information, the spectral data
for compounds 3a, 3b, 3e, 3f, 3g, 3n, 3q, 3r and 3u, can
be seen in www.ias.ac.in/chemsci.
3
a was replaced with a 2-thiazolyl ring forming 3t,
fungicidal activity increased further (100% control at
.8 mg/L). These results suggest that further struc-
2
ture optimization is possible outside the pyridinyl type
analogues, as shown by good activity found with the
quinolinyl and thiazolyl analogues.
Acknowledgements
We thank Dr. Mark Dekeyser (Canada) for assisting in
preparing the manuscript. The project was supported
by the National Key Technology Support Program dur-
ing the 12th Five-Year Plan Period of China (Grant No.
4
. Conclusions
2
011BAE06B05).
Twenty one N-phenyl heteroarylamine compounds
were synthesized via the intermediate derivati-
zation method. Overall, introduction of electron-
withdrawing groups to any position of pyridine ring
was important to optimize fungicidal activity against
rice blast. Activity was generally greater in 3- and
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