Design, Synthesis, and Fungicidal Activity of Novel Imidazo[4,5-b]pyridine Derivatives

Article abstract of DOI:10.1002/jhet.3243

A series of novel imidazo[4,5-b]pyridine derivatives were designed and synthesized. The structures of all the newly synthesized compounds were identified by spectroscopic data NMR, MS, and elemental analysis. Bioassay showed that the compounds exhibited potent fungicidal activities against Erysiphe graminis, Puccinia polysora, and so forth. Particularly, 2-chloro-5-((5-methoxy-2-(2-(trifluoromethyl)phenyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)thiazole (9b) displayed fungicidal potency against P.?polysora. Its EC₅₀ value: 4.00?mg/L is comparable with that of tebuconazole. The structure–activity relationship for the target compounds is discussed.

Full text of DOI:10.1002/jhet.3243

Month 2018
Minhua Liu,
Design, Synthesis, and Fungicidal Activity of Novel Imidazo[4,5-b]pyri-
dine Derivatives
a,b
a,b
c
a,b
a,b
a,b
a,b
Chunsheng Quan, Mingming Dang, Yeguo Ren, Jianwei Ren, Jun Xiang, Xingping Liu,
a,b
a,b
a,b
Lian He, Weidong Liu, * and Aiping Liu *
a
National Engineering Research Center for Agrochemicals, Hunan Research Institute of Chemical Industry, Changsha
10007, China
Hunan Province Key Laboratory for Agrochemicals, Changsha 410014, China
Department of Resources and Environment, Hunan Nonferrous Metals Vocational and Technical College, Zhuzhou
12000, Hunan, China
4
b
c
4
*
E-mail: weidliu@yahoo.com; lapliu@yahoo.com
Received February 14, 2018
DOI 10.1002/jhet.3243
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel imidazo[4,5-b]pyridine derivatives were designed and synthesized. The structures of all
the newly synthesized compounds were identified by spectroscopic data NMR, MS, and elemental analysis.
Bioassay showed that the compounds exhibited potent fungicidal activities against Erysiphe graminis,
Puccinia polysora, and so forth. Particularly, 2-chloro-5-((5-methoxy-2-(2-(trifluoromethyl)phenyl)-3H-
imidazo[4,5-b]pyridin-3-yl)methyl)thiazole (9b) displayed fungicidal potency against P. polysora. Its
EC50 value: 4.00 mg/L is comparable with that of tebuconazole. The structure–activity relationship for the
target compounds is discussed.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
Based on the previous research work and literature
investigation, we demonstrated that the compound containing
nitropyridine skeleton (Id and Ie, Fig. 3) showed high
insecticidal activity [11,12]. So, we designed and synthesized
a series of novel imidazo[4,5-b]pyridine derivatives (Fig. 3).
Surprisingly, bioassay results showed that target compounds
exhibited good fungicidal activities against Erysiphe graminis,
Rhizoctonia solani, and Puccinia polysora at 500 mg/L.
Approximately 70% of all agrochemicals that have been
introduced to the market within the last 20 years bear at
least one heterocyclic ring [1]. Furthermore, the design and
synthesis of pharmacologically relevant heterocyclic
molecules have proven to be a promising strategy in search
for new pharmaceutical lead structures in recent years [2,3].
Imidazo[4,5-b]pyridine is one of the most important
family of heterocyclic ring, and its derivatives are shown
to possess various pharmacological properties [4–7].
Representative pharmacologically active compounds
containing an imidazo[4,5-b]pyridine core skeleton are
shown in Figure 1. However, no commercial
agrochemicals containing an imidazo[4,5-b]pyridine
moiety have so far been founded. Recently, although
some compounds, such as representative compounds:
Ia–c (Fig. 2) containing this structure type, are disclosed
to control pests in patent [8–10], few information about
the use of the fungicides compounds containing an
imidazo[4,5-b]pyridine motif is found.
Particularly,
2-chloro-5-((5-methoxy-2-(2-(trifluoromethyl)
phenyl)-3H-imidazo[4,5-b]pyridine-3-yl)methyl)thiazole (9b)
displayed fungicidal potency against P. polysora. Its EC50
value: 4.00 mg/L is comparable with that of tebuconazole.
RESULTS AND DISCUSSION
Chemistry. The synthesis scheme shown in Figure 4
provides moderate to high yields of the test compounds.
The structures of all synthesized compounds were
1
analyzed and confirmed by H-NMR, MS, and
elemental analysis. Because of the structural similarity
©
2018 Wiley Periodicals, Inc.

M. Liu, C. Quan, M. Dang, Y. Ren, J. Ren, J. Xiang, X. Liu, L. He, W. Liu, and A. Liu
Vol 000
Figure 1. Representative pharmaceutically active compounds containing an imidazo[4,5-b]pyridine core skeleton.
Figure 2. Representative insecticidally active compounds containing an imidazo[4,5-b]pyridine core skeleton [8–10].
Figure 3. Design strategies of the target compounds containing imidazo[4,5-b]pyridine. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 4. Synthesis pathway of imidazo[4,5-b]pyridine derivatives.
of target compounds, only some representative
chemical
structures,
MS
data,
and
physical
compounds, such as 5e, 9b, and 11c, were analyzed
and confirmed by C-NMR. Table 1 summarizes the
characteristics of target compounds. NMR and elemental
analysis data are listed in Table 2.
1
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and Fungicidal Activity of Novel Imidazo[4,5-b]pyridine
Derivatives
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Liu, C. Quan, M. Dang, Y. Ren, J. Ren, J. Xiang, X. Liu, L. He, W. Liu, and A. Liu
Vol 000
Table 2
1
13
3
, 300 MHz), C-NMR (CDCl , 75 MHz) δ, and elemental analysis.
H-NMR (CDCl
3
1
No.
H-NMR (300 MHz)
1
5
5
5
5
5
a
b
c
H-NMR (CDCl
3
) 3.734 (s, 3H, CH
3
3
), 4.032 (s, 3H, CH ), 6.727 (d, J = 8.4 Hz, 1H, Py H), 7.053–7.135 (m, 2H, Ph H), 7.459–7.558 (m,
1
H, Ph H), 7.977 (d, J = 8.4 Hz, 1H, Py H). Elemental anal. (%): calcd for C14
.07; N, 15.28.
H-NMR (CDCl
11
H F
2
N
3
O: C, 61.09; H, 4.03; N, 15.27; found: C, 61.05; H,
4
1
3
) 1.367 (t, J = 7.2 Hz, 3H, CH
3
), 4.021 (s, 3H, CH
3
), 4.131 (q, J = 7.5 Hz, 2H, CH
2
), 6.725 (d, J = 8.7 Hz, 1H,
imidazo[4,5-b]pyridine H), 7.062–7.115 (m, 2H, Ph H), 7.488–7.516 (m, 1H, Ph H), 7.968 (d, J = 8.4 Hz, 1H, imidazo[4,5-b]pyridine H).
Elemental anal. (%): calcd for C15 O: C, 62.28; H, 4.53; N, 14.53; found: C, 62.25; H, 4.51; N, 14.50.
) 0.775 (t, J = 7.5 Hz, 3H, CH ), 1.762–1.835 (m, 2H, CH ), 4.017 (s, 3H, CH ), 4.083 (q, J = 6.9 Hz, 2H, CH
J = 8.7 Hz, 1H, imidazo[4,5-b]pyridine H), 7.063–7.116 (m, 2H, Ph H), 7.491–7.547 (m, 1H, Ph H), 7.978 (d, J = 8.7 Hz, 1H, imidazo[4,5-
b]pyridine H). Elemental anal. (%): calcd for C16 O: C, 63.38; H, 5.02; N, 13.80; found: C, 63.36; H, 4.98; N, 13.85.
), 4.008 (s, 3H, CH ), 4.343–4.388 (m, 1H, CH), 6.711 (d, J = 8.7 Hz, 1H, imidazo[4,5-
b]pyridine H), 7.050–7.102 (m, 2H, Ph H), 7.477–7.534 (m, 1H, Ph H), 7.952 (d, J = 8.4 Hz, 1H, imidazo[4,5-b]pyridine H). Elemental
anal. (%): calcd for C16 O: C, 63.36; H, 4.98; N, 13.85; found: C, 63.30; H, 4.97; N, 13.87.
) 0.798 (t, J = 7.5 Hz, 3H, CH ), 1.168–1.243 (m, 2H, CH ), 1.708 (t, J = 7.2 Hz, 2H, CH
J = 7.2 Hz, 2H, CH ), 6.720 (d, J = 8.7 Hz, 1H, imidazo[4,5-b]pyridine H), 7.058–7.111 (m, 2H, Ph H), 7.483–7.540 (m, 1H, Ph H), 7.966
d, J = 8.7 Hz, 1H, imidazo[4,5-b]pyridine H). C-NMR (CDCl
J = 2.3 Hz), 111.95 (d, J = 1.7 Hz), 130.43, 132.09 (t, J = 10.4 Hz), 140.55, 145.23, 159.27, 159.35, 161.36, 162.61, 162.69. Elemental
anal. (%): calcd for C17 O: C, 64.34; H, 5.40; N, 13.24; found: C, 63.30; H, 5.46; N, 13.20.
) 0.765 (d, J = 6.9 Hz, 6H, 2CH ), 2.146–2.192 (m, 1H, CH), 3.943 (d, J = 7.5 Hz, 2H, CH
d, J = 8.7 Hz, 1H, imidazo[4,5-b]pyridine H), 7.053–7.106 (m, 2H, Ph H), 7.481–7.537 (m, 1H, Ph H), 7.970 (d, J = 8.7 Hz, 1H,
imidazo[4,5-b]pyridine H). Elemental anal. (%): calcd for C17 O: C, 64.34; H, 5.40; N, 13.24; found: C, 64.38; H, 5.38; N, 13.21.
), 4.028 (s, 3H, CH ), 6.587 (t, J = 2.4 Hz, 1H, Ph H), 6.700 (d, J = 8.7 Hz, 1H,
imidazo[4,5-b]pyridine H), 6.931 (d, J = 2.4 Hz, 2H, Ph H), 7.942 (d, J = 8.7 Hz, 1H, imidazo[4,5-b]pyridine H). Elemental anal. (%):
calcd for C16 : C, 64.20; H, 5.72; N, 14.04; found: C, 64.15; H, 5.78; N, 14.05.
) 1.465 (t, J = 7.2 Hz, 3H, CH ), 3.867 (s, 6H, 2CH ), 4.018 (s, 3H, CH
J = 2.1 Hz, 1H, Ph H), 6.697 (d, J = 8.7 Hz, 1H, imidazo[4,5-b]pyridine H), 6.873 (d, J = 1.2 Hz, 2H, Ph H), 7.935 (d, J = 8.4 Hz, 1H,
imidazo[4,5-b]pyridine H). Elemental anal. (%): calcd for C17 : C, 65.16; H, 6.11; N, 13.41; found: C, 65.12; H, 6.05; N, 13.49.
), 4.022 (s, 3H, CH ), 6.698 (d, J = 8.7 Hz, 1H, imidazo[4,5-b]pyridine H), 7.007
d, J = 5.1 Hz, 1H, thiophene H), 7.417 (d, J = 5.1 Hz, 1H, thiophene H), 7.931 (d, J = 8.4 Hz, 1H, imidazo[4,5-b]pyridine H). Elemental
anal. (%): calcd for C13 OS: C, 60.21; H, 5.05; N, 16.20; found: C, 60.25; H, 5.08; N, 16.08.
) 1.377 (t, J = 7.5 Hz, 3H, CH ), 2.351 (s, 3H, CH ), 4.016 (s, 3H, CH ), 4.255 (q, J = 7.2 Hz, 2H, CH
J = 8.7 Hz, 1H, imidazo[4,5-b]pyridine H), 7.007 (d, J = 5.1 Hz, 1H, thiophene H), 7.418 (d, J = 5.1 Hz, 1H, thiophene H), 7.937 (d,
J = 8.7 Hz, 1H, imidazo[4,5-b]pyridine H). Elemental anal. (%): calcd for C14 OS: C, 61.52; H, 5.53; N, 15.37; found: C, 61.46; H,
.50; N, 15.34.
13 2 3
H F N
1
H-NMR (CDCl
3
3
2
3
2
), 6.728 (d,
15 2 3
H F N
1
d
e
H-NMR (CDCl
3
) 1.696 (d, J = 6.9 Hz, 6H, 2CH
3
3
15 2 3
H F N
1
H-NMR (CDCl
3
3
2
2 3
), 4.016 (s, 3H, CH ), 4.116 (t,
2
13
(
3
, 75 MHz) δ: 13.33, 19.41, 31.15, 42.79, 53.64, 106.39, 111.64 (d,
17 2 3
H F N
1
5
5
5
5
5
f
H-NMR (CDCl
3
3
2 3
), 4.010 (s, 3H, CH ), 6.719
(
17 2 3
H F N
1
g
h
i
H-NMR (CDCl
3
) 3.873 (s, 6H, 2CH
3
), 3.925 (s, 3H, CH
3
3
17 3 3
H N O
H-NMR (CDCl
1
3
3
3
3 2
), 4.353 (q, J = 7.2 Hz, 2H, CH ), 6.590 (t,
19 3 3
H N O
1
H-NMR (CDCl
3
) 2.368 (s, 3H, CH
3
), 3.801 (s, 3H, CH
3
3
(
13 3
H N
1
j
H-NMR (CDCl
3
3
3
3
2
), 6.703 (d,
15 3
H N
5
1
9a
H-NMR (CDCl
imidazo[4,5-b]pyridine H), 7.516–7.546 (m, 1H, Ph H), 7.643–7.716 (m, 2H, Ph H), 7.843–7.874 (m, 1H, Ph H), 7.945 (d, J = 8.7 Hz, 1H,
imidazo[4,5-b]pyridine H). Elemental anal. (%): calcd for C16 O: C, 59.81; H, 4.39; N, 13.08; found: C, 59.87; H, 4.34; N, 13.15.
), 6.770 (d, J = 9.0 Hz, 1H, imidazo[4,5-b]pyridine H), 7.134 (s, 1H, Thiazole H),
.431–7.459 (m, 1H, Ph H), 7.681–7.769 (m, 2H, Ph H), 7.885–7.918 (m, 1H, Ph H), 7.968 (d, J = 9.0 Hz, 1H, imidazo[4,5-b]pyridine H).
3 3 3 2
) 1.301 (t, J = 7.2 Hz, 3H, CH ), 4.018 (s, 3H, CH ), 4.032 (q, J = 7.2 Hz, 2H, CH ), 6.715 (d, J = 8.4 Hz, 1H,
14 3 3
H F N
1
9b
3 3 2
H-NMR (CDCl ) 4.078 (s, 3H, CH ), 5.269 (s, 2H, CH
7
1
3
3
C-NMR (CDCl , 75 MHz) δ: 38.72, 53.96, 107.22, 117.81 (q, J = 273 Hz), 126.75 (q, J = 4.8 Hz), 128.06, 129.20, 129.80 (q, J = 30 Hz),
130.76, 130.94, 131.77, 132.25, 134.88, 140.47, 144.17, 147.21, 152.97, 161.72. Elemental anal. (%): calcd for C18
3 4
H12ClF N OS: C,
5
0.89; H, 2.85; N, 13.19; found: C, 50.95; H, 2.88; N, 13.14.
1
11a
11b
11c
H-NMR (CDCl
3
) 2.933 (s. 3H, CH
H, imidazo[4,5-b]pyridine H), 8.322 (d, J = 8.4 Hz, 1H, imidazo[4,5-b]pyridine H). Elemental anal. (%): calcd for C14
7.72; H, 3.81; N, 14.42; found: C, 57.78; H, 3.78; N, 14.35.
3
), 3.817 (s, 3H, CH
3
), 7.113–7.174 (m, 2H, Ph H), 7.541–7.640 (m, 1H, Ph H), 7.998 (d, J = 8.4 Hz,
1
11 2 3
H F N
S: C,
5
1
H-NMR (CDCl
d, J = 8.1 Hz, 1H, imidazo[4,5-b]pyridine H), 7.493–7.593 (m, 1H, Ph H), 7.925 (d, J = 8.4 Hz, 1H, imidazo[4,5-b]pyridine H). Elemental
anal. (%): calcd for C15 S: C, 59.00; H, 4.29; N, 13.76; found: C, 59.07; H, 4.25; N, 13.74.
) 2.676 (s, 3H, CH ), 3.877 (s, 6H, 2CH ), 3.969 (s, 3H, CH ), 6.606 (t, J = 2.4 Hz, 1H, Ph H), 6.947 (d, J = 2.4 Hz, 2H,
Ph H), 7.133 (d, J = 8.4 Hz, 1H, imidazo[4,5-b]pyridine H), 7.876 (d, J = 8.4 Hz, 1H, imidazo[4,5-b]pyridine H). C-NMR (CDCl
5 MHz) δ: 13.81, 30.53, 55.52, 102.01, 106.97, 116.78, 127.15, 131.51, 131.77, 148.82, 152.56, 154.13, 160.80. Elemental anal. (%):
calcd for C16 S: C, 60.93; H, 5.43; N, 13.32; found: C, 60.98; H, 5.38; N, 13.35.
) 3.319 (s. 3H, CH ), 3.883 (s, 3H, CH ), 7.135–7.189 (m, 2H, Ph H), 7.585–7.614 (m, 1H, Ph H), 8.131 (d, J = 8.1 Hz,
3 3 3 2
) 1.393 (t, J = 6.9 Hz, 3H, CH ), 2.666 (s, 3H, CH ), 4.192 (q, J = 7.2 Hz, 2H, CH ), 7.066–7.146 (m, 2H, Ph H), 7.169
(
13 2 3
H F N
1
H-NMR (CDCl
3
3
3
3
1
3
3
,
7
17 3 2
H N O
1
12a
12b
12c
H-NMR (CDCl
3
3
3
1
5
11 2 3
H, imidazo[4,5-b]pyridine H), 8.321 (d, J = 8.4 Hz, 1H, imidazo[4,5-b]pyridine H). Elemental anal. (%): calcd for C14H F N OS: C,
4.72; H, 3.61; N, 13.67; found: C, 54.68; H, 3.72; N, 13.64.
1
H-NMR (CDCl
.643 (m, 1H, Ph H), 7.997 (d, J = 8.4 Hz, 1H, imidazo[4,5-b]pyridine H), 8.322 (d, J = 8.4 Hz, 1H, imidazo[4,5-b]pyridine H). Elemental
anal. (%): calcd for C15 OS: C, 56.07; H, 4.08; N, 13.08; found: C, 56.03; H, 4.11; N, 13.04.
) 2.919 (s, 3H, CH ), 3.889 (s, 6H, 2CH ), 4.002 (s, 3H, CH ), 6.654 (t, J = 2.4 Hz, 1H, Ph H), 6.972 (d, J = 2.1 Hz, 2H,
Ph H), 7.961 (d, J = 7.8 Hz, 1H, imidazo[4,5-b]pyridine H), 8.270 (d, J = 8.4 Hz, 1H, imidazo[4,5-b]pyridine H). Elemental anal. (%):
calcd for C16 S: C, 57.99; H, 5.17; N, 12.68; found: C, 57.96; H, 5.11; N, 12.78.
3 3 3 2
) 1.380 (t, J = 7.2 Hz, 3H, CH ), 2.937 (s, 3H, CH ), 4.222 (q, J = 7.5 Hz, 2H, CH ), 7.116–7.170 (m, 2H, Ph H), 7.544–
7
13 2 3
H F N
1
H-NMR (CDCl
3
3
3
3
17 3 3
H N O
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and Fungicidal Activity of Novel Imidazo[4,5-b]pyridine
Derivatives
Table 2
(
Continued)
1
No.
H-NMR (300 MHz)
1
12d
3 3 3
H-NMR (CDCl ) 3.320 (s. 3H, CH ), 3.886 (s, 3H, CH ), 7.129–7.205 (m, 2H, Ph H), 7.571–7.670 (m, 1H, Ph H), 8.138 (d, J = 8.4 Hz,
11 2 3 2
1H, imidazo[4,5-b]pyridine H), 8.335 (d, J = 8.4 Hz, 1H, imidazo[4,5-b]pyridine H). Elemental anal. (%): calcd for C14H F N O S: C,
5
4.72; H, 3.61; N, 13.67; found: C, 54.68; H, 3.72; N, 13.64.
1
12e
H-NMR (CDCl
.664 (m, 1H, Ph H), 8.126 (d, J = 8.4 Hz, 1H, imidazo[4,5-b]pyridine H), 8.315 (d, J = 8.1 Hz, 1H, imidazo[4,5-b]pyridine H). C-NMR
CDCl , 75 MHz) δ: 14.71, 39.16, 40.56, 111.98 (dd, J = 2.6, J = 22.1 Hz), 115.95, 128.87, 133.29 (t, J = 10.4 Hz), 138.00, 147.01,
) 1.411 (t, J = 7.2 Hz, 3H, CH ), 3.319 (s, 3H, CH ), 4.292 (q, J = 7.2 Hz, 2H, CH ), 7.117–7.194 (m, 2H, Ph H), 7.564–
3 3 3 2
13
7
(
3
1
2
151.70, 158.94, 159.01, 162.30, 162.38. Elemental anal. (%): calcd for C15
13
H F
2
N
3
O
2
S: C, 53.41; H, 3.88; N, 12.46; found: C, 53.38; H,
3
.84; N, 12.55.
1
12f
H-NMR (CDCl
3
) 3.304 (s, 3H, CH
3
), 3.891 (s, 6H, 2CH
3
), 4.053 (s, 3H, CH
3
), 6.684 (s, 1H, Ph H), 6.984 (s, 2H, Ph H), 8.086 (d,
J = 8.4 Hz, 1H, imidazo[4,5-b]pyridine H), 8.237 (d, J = 8.1 Hz, 1H, imidazo[4,5-b]pyridine H). Elemental anal. (%): calcd for
S: C, 55.32; H, 4.93; N, 12.10; found: C, 55.28; H, 4.91; N, 12.15.
16 17 3 4
C H N O
Target compounds 5a–j and 11a–c are prepared by
reacting 3-nitropyridine-2-amines (3 or 10) with aryl
aldehyde under the presence of saturated sodium
dithionite. This method has some prominent feature,
including good yield and easy operation. Compounds 9a
and 9b are synthesized by cyclization of corresponding
amide (8). However, we have attempted to directly
prepare compound 9b by corresponding pyridine-2,3-
diamine (6b) with acid, but the yield is not very
satisfactory.
the fungicidal activities of the corresponding compound
dramatically decline, for example, fungicidal activities
11a > 12a > > 12d > 5a and 11b > 12b > > 12e > 5b.
When W and Ar are kept constant, the fungicidal
activity of the synthesized compounds is influenced by
the nature of the R group. The R group was modified
from the methyl to C –C alkyl or thiazol-5-yl methyl
group. As the chain length increased, the fungicidal
activities of corresponding compounds increased: 5e,
5f > 5c, 5d > 5b > 5a; 9b > 9a; 11b > 11a;
2
4
1
2b > 12a; and 12e > 12d.
Fungicidal activity.
All compounds prepared were
When W and R are kept constant, the fungicidal activity
evaluated for initial activity against E. graminis,
R. solani, and P. polysora at 500 mg/L by typical assay
earlier, and EC50 was calculated through further assay in
which five to six different concentrations were used and
listed in Table 1. The activity of tebuconazole was also
shown in Table 1.
of the synthesized compounds is influenced by the nature
of the Ar group. Modification of the Ar group from
substituted phenyl to substituted thiophenyl shows the
different level of fungicidal activities. For example,
the fungicidal activities are correlated as follows:
5
j > 5 h > 9a > 5b and 12f > 12d.
In general, the structure–activity relationships of target
As shown in Table 1, 5d–5f, 5i, 5j, and 11b exhibit 90%
or 95% fungicidal activity against E. graminis at
compounds can be summarized as follows:
5
1
5
00 mg/L; 5e, 9b, and 11a, respectively, show 90%,
00%, and 90% fungicidal activity against P. polysora at
00 mg/L. Only 11b and 12f display 83.4% and 84.6%
•
•
Activity order of W: S > SO > > SO > O.
2
Activity order of R: 2-chlorothiazol-5-yl-methyl > i-
C H , n-C H > i-C H , and n-C H > C H > CH .
fungicidal activity against R. solani at 500 mg/L,
respectively.
However, with in-depth screening, only 9b exhibits
good bactericidal activity against P. polysora when
compared with commercial fungicides. Its EC50 values of
4
9
4
9
3
7
3
7
2
5
3
•
Activity order of Ar: 3-methylthiophene-2-yl > 3,5-
dimethoxylphenyl > 2-trifluoromethylphenyl > 2,6-
difluorophenyl.
4.00 mg/L is comparable with that of tebuconazole
Further studies on the biological activity and structure–
activity relationships of this series of compounds are in
progress.
(
Table 1).
Apparent structure–activity relationship.
The general
structure of all target compounds (Fig. 4) was optimized
through X, R, and Ar moieties. Different choices of X, R,
and Ar can greatly affect fungicidal activity (Table 1).
When R and Ar are kept constant, the fungicidal
activities of the synthesized compounds are influenced by
the nature of the W group. Modification of the W group
from an oxygen to sulfur atom, sulfoxyl, or sulfuryl
groups shows the different level of fungicidal activities.
When W group is changed from oxygen to sulfur atom,
CONCLUSION
In summary, a series of novel imidazo[4,5-b]pyridine
derivatives were designed and synthesized. Bioassay
showed that the compounds exhibited potent fungicidal
activities against P. polysora, and so forth. Particularly,
2-chloro-5-((5-methoxy-2-(2-(trifluoromethyl)phenyl)-3H-
imidazo[4,5-b]pyridin-3-yl)methyl)thiazole (9b) displayed
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Liu, C. Quan, M. Dang, Y. Ren, J. Ren, J. Xiang, X. Liu, L. He, W. Liu, and A. Liu
Vol 000
fungicidal potency against P. polysora. Its EC50 value:
.00 mg/L is comparable with that of tebuconazole.
Structure–activity relationships indicated that variances
among W, R, and Ar group can greatly affect fungicidal
activity against all tested fungi (Table 1).
The synthesis of 3a–d, 3f, 3g, 4a, and 4b with ≥95.0%
purity [high-performance liquid chromatography (HPLC)]
was similar to that of 3e.
4
2
N -((2-Chlorothiazol-5-yl)methyl)-6-methoxypyridine-2,3-
diamine (6b). The solution of N-((2-chlorothiazol-5-yl)
methyl)-6-methoxy-3-nitropyridin-2-amine (10.00 mmol)
and iron (30.00 mmol) in acetic acid (40 mL) was
stirred at room temperature for 2–3 h. The reaction
mixture was filtered. After the solvent was removed
under reducing pressure, the residue was dissolved in
dichloromethane. The organic layers were washed with
water and dried over anhydrous sodium sulfate and
concentrated under reducing pressure. The crude product
was used directly without purification. Yield 91%. GC–
EXPERIMENTAL
Unless otherwise noted, reagents and solvents were used
as received from commercial suppliers. NMR spectra were
obtained with a Varian INOVA-300 spectrometer using
tetramethylsilane as the internal standard and
deuteriochloroform (CDCl ) or deuteriodimethylsulfoxide
3
+
+
as the solvent. Liquid chromatography/mass spectrometry
was recorded with an Agilent 1260/6120 Series and gas
chromatography/mass spectrometry (GC–MS) with an
Agilent 7890-5975C Series. Uncorrected melting points
were taken in a WRS-1A digital melting points apparatus.
Elemental analyses were obtained with a Vario EL III
from Elementar.
MS (EI, 70 eV) (m/z) 270 (40% M ), 138 (100% M -
1
132); H-NMR (CDCl
, 300 MHz) δ: 3.729 (s, 3H,
), 4.127 (s, 2H, NH ), 4.644 (d, J = 6.0 Hz, 2H,
), 5.841 (d, J = 7.8 Hz, 1H, Py H), 6.319 (t,
3
CH
CH
3
2
2
J = 5.7 Hz, 1H, NH), 6.794 (d, J = 7.8 Hz, 1H, Py H),
7.589 (s, 1H, thiazole H).
2-(Trifluoromethyl)benzoyl
chloride
(7).
Thionyl
chloride (246.94 mmol) in 1,2-dichloroethane (10 mL)
was added dropwise to a solution of 2-(trifluoromethyl)
benzoic acid (123.47 mmol) in 1,2-dichloroethane
Synthesis. The general synthetic methods for the target
compounds are shown in Figure 4. Representative
procedures are given in the succeeding texts. Yields were
not optimized. All reactions were carried out under a
protective atmosphere of dry nitrogen or utilizing a
calcium chloride tube.
(100 mL) at room temperature. The reaction mixture
was heated to reflux and stirred for 3–5 h. The reaction
mixture was cooled and concentrated under reducing
pressure. The crude product was used directly without
The synthesis of intermediates.
(
2-Chlorothiazol-5-yl)methanamine (2g).
A mixture of
mmol) in N,N-
dimethylformamide (60 mL) was added into a solution of
-chloro-5-(chloromethyl)thiazole (100 mmol) in N,N-
purification.
N-(2-(((2-Chlorothiazol-5-yl)methyl)amino)-6-
potassium
phthalimide
(100
methoxypyridin-3-yl)-2-(trifluoromethyl)benzamide (8b).
2-
Trifluoromethyl)benzoyl chloride (16.45 mmol) in
dichloromethane (10 mL) was added dropwise to a
(
2
dimethylformamide (40 mL) at room temperature. The
mixture was heated at 50°C for 4 h. The reaction mixture
was then cooled to room temperature and was poured into
water. The precipitate was collected by filtration, washed
with water, and dried to give an off-white solid (91.0 mmol).
The earlier compound (91.0 mmol) and 80% hydrazine
hydrate (145.6 mmol) in ethanol (200 mL) were refluxed
for 4 h. The suspension was cooled and filtered. The
remaining liquid phase was concentrated under reducing
pressure to give an orange-red liquid (61.5 mmol), yield:
2
solution
methoxypyridine-2,3-diamine
trimethylamine (16.45 mmol) in dichloromethane
10 mL) at 0°C. After added over, the reaction mixture
of
N -((2-chlorothiazol-5-yl)methyl)-6-
(10.97 mmol) and
(
was allowed to warm to ambient temperature and stirred
for 2–3 h. The reaction mixture was poured into water.
The water layer was extracted with dichloromethane
(2 × 50 mL). The combined organic layers were washed
with water and dried over anhydrous sodium sulfate.
After the solvent was removed, the crude product was
separated by silica gel column chromatography using
petroleum ether and ethyl acetate (5:1 to 3:1 by volume)
as eluant to give 95% (HPLC) 8b as an off-white solid
6
1.5%.
N-Butyl-6-methoxy-3-nitropyridin-2-amine
mixture
22.82 mmol) and triethylamine (22.82 mmol) in N,N-
(3e).
A
of
2-methoxyl-6-chloro-3-nitropyridine
(
(
5.81 mmol), yield 53%.
N-Ethyl-6-(methylthio)-3-nitropyridin-2-amine (10b).
dimethylformamide (40 mL) was stirred for 0.5 h at room
temperature under nitrogen atmosphere. Butylamine
(
22.82 mmol) in 10 mL of dry N,N-dimethylformamide
Sodium thiomethoxide (16%, 60.31 mmol) was added
dropwise to solution of N-ethyl-6-chloro-3-
nitropyridin-2-amine (54.66 mmol) in tetrahydrofuran
(60 mL) at room temperature. The mixture was stirred at
room temperature for 2 h and then was poured into
water. The precipitate was collected by filtration, washed
was slowly added dropwise. The mixture was stirred at
room temperature for 2–3 h. The reaction mixture was
poured into water. The precipitate was collected by
filtration, washed with water, and dried to give a yellow
solid (20.54 mmol), yield 90%.
a
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Design, Synthesis, and Fungicidal Activity of Novel Imidazo[4,5-b]pyridine
Derivatives
with water, and dried to give a yellow solid (53.12 mmol),
yield 97%.
2-(2,6-Difluorophenyl)-3-ethyl-5-(methylsulfinyl)-3H-
imidazo[4,5-b]pyridine (12b). 3-Chloroperoxybenzoic acid
85%, 2.23 mmol) in dichloromethane (10 mL) was added
(
The synthesis of the target compounds.
3
-Butyl-2-(2,6-difluorophenyl)-5-methoxy-3H-imidazo[4,5-b]
dropwise to a solution of 2-(2,6-difluorophenyl)-3-ethyl-5-
(methylthio)-3H-imidazo[4,5-b]pyridine (2.62 mmol) in
dichloromethane (20 mL) at 0°C. After added over, the
reaction mixture was stirred at this temperature for
0.5–1 h. Water was added into the reaction mixture. The
water layer was extracted with dichloromethane (30 mL).
The combined organic layers were washed with 60 mL of
30% potassium carbonate solution and twice with 60 mL
of water and dried over anhydrous sodium sulfate. After
the solvent was removed, the crude product was
separated by silica gel column chromatography using
petroleum ether and ethyl acetate (3:1 to 1:1 by
volume) as eluant to give 96% (HPLC) 12b as an off-
white solid (1.03 mmol), mp: 126.1–127.9°C, yield 46%.
pyridine (5e). Saturated sodium dithionite (38.40 mmol)
solution was added to a stirred solution of N-butyl-6-
methoxy-3-nitropyridin-2-amine (7.68 mmol) and 2,6-
difluorobenzaldehyde (7.68 mmol) in ethanol at room
temperature. The reaction mixture was heated to reflux
and stirred for 16 h. After the reaction was complete, the
reaction mixture was cooled to room temperature, and
ice-cold water was added. The precipitate was collected
by filtration, washed with water, and dried. The product
was recrystallized from ethyl acetate–petroleum to give
9
6
(
7% (HPLC) 5e as a yellowish solid (4.53 mmol), mp:
6.3–66.9°C, yield 59%. GC–MS (EI, 70 eV) (m/z) 317
100% M ); calcd for C H F N O: C, 64.34; H, 5.40;
N, 13.24; found: C, 63.30; H, 5.46; N, 13.20; H-NMR
+
1
7 17 2 3
1
+
+
GC–MS (EI, 70 eV) (m/z) 321 (M ), 306 (100% M -15);
(
2
CDCl ) 0.798 (t, J = 7.5 Hz, 3H, CH ), 1.168–1.243 (m,
calcd for C H F N OS: C, 56.07; H, 4.08; N, 13.08;
3
3
15 13 2 3
1
H, CH ), 1.708 (t, J = 7.2 Hz, 2H, CH ), 4.016 (s, 3H,
found: C, 56.03; H, 4.11; N, 13.04; H-NMR (CDCl )
2
2
3
CH ), 4.116 (t, J = 7.2 Hz, 2H, CH ), 6.720 (d,
1.380 (t, J = 7.2 Hz, 3H, CH ), 2.937 (s, 3H, CH ),
3
2
3
3
J = 8.7 Hz, 1H, imidazo[4,5-b]pyridine H), 7.058–7.111
m, 2H, Ph H), 7.483–7.540 (m, 1H, Ph H), 7.966 (d,
4.222 (q, J = 7.5 Hz, 2H, CH ), 7.116–7.170 (m, 2H, Ph
H), 7.544–7.643 (m, 1H, Ph H), 7.997 (d, J = 8.4 Hz,
1H, imidazo[4,5-b]pyridine H), 8.322 (d, J = 8.4 Hz, 1H,
imidazo[4,5-b]pyridine H).
2-(2,6-Difluorophenyl)-3-ethyl-5-(methylsulfonyl)-3H-
imidazo[4,5-b]pyridine (12e). 3-Chloroperoxybenzoic acid
2
(
1
3
J = 8.7 Hz, 1H, imidazo[4,5-b]pyridine H); C-NMR
CDCl , 75 MHz) δ: 13.33, 19.41, 31.15, 42.79, 53.64,
(
3
106.39, 111.64 (d, J = 2.3 Hz), 111.95 (d, J = 1.7 Hz),
130.43, 132.09 (t, J = 10.4 Hz), 140.55, 145.23, 159.27,
159.35, 161.36, 162.61, 162.69.
(
85%, 1.64 mmol) in dichloromethane (10 mL) was added
dropwise to a solution of 2-(2,6-difluorophenyl)-3-ethyl-
-(methylthio)-3H-imidazo[4,5-b]pyridine (3.60 mmol) in
2
-Chloro-5-((5-methoxy-2-(2-(trifluoromethyl)phenyl)-3H-
5
imidazo[4,5-b]pyridin-3-yl)methyl)thiazole (9b).
The
solution of N-(2-(((2-chlorothiazol-5-yl)methyl)amino)-
-methoxypyridin-3-yl)-2-(trifluoromethyl)benzamide
5.84 mmol) in phosphorus oxychloride (15 mL) was
dichloromethane (10 mL) at room temperature. After
added over, the reaction mixture was stirred at room
temperature for 2–3 h. Water was added into the
reaction mixture. The water layer was extracted with
dichloromethane (30 mL). The combined organic layers
were washed with 60 mL of 30% potassium carbonate
solution and twice with 60 mL of water and dried over
anhydrous sodium sulfate. After the solvent was
removed, the crude product was separated by silica gel
column chromatography using petroleum ether and ethyl
acetate (3:1 to 1:1 by volume) as eluant to give 99.0%
6
(
heated to reflux and stirred for 2–4 h. The reaction
mixture was cooled and concentrated under reducing
pressure. The residue was dissolved in ethyl acetate, then
washed with saturated brine and dried over anhydrous
sodium sulfate. After the solvent was removed, the crude
product was separated by silica gel column
chromatography using petroleum ether and ethyl acetate
(10:1 to 5:1 by volume) as eluant to give 99% (HPLC)
(HPLC) 12e as a white solid (2.45 mmol), mp: 169.3–
9
b as a white solid (2.10 mmol), mp: 136.6–137.4°C,
+
1
69.9°C, yield 68%. GC–MS (EI, 70 eV) (m/z) 337
yield 36%. GC–MS (EI, 70 eV) (m/z) 424 (M ), 132
+
+
+
(M ), 318 (100% M -19); calcd for C H F N O S: C,
(100% M -292); calcd for C H ClF N OS: C, 50.89;
15 13 2 3 2
1
8
12
3 4
5
1
3.41; H, 3.88; N, 12.46; found: C, 53.38; H, 3.84; N,
H, 2.85; N, 13.19; found: C, 50.95; H, 2.88; N, 13.14;
1
1
2.55; H-NMR (CDCl ) 1.411 (t, J = 7.2 Hz, 3H,
H-NMR (CDCl ) 4.078 (s, 3H, CH ), 5.269 (s, 2H,
3
3
3
CH ), 3.319 (s, 3H, CH ), 4.292 (q, J = 7.2 Hz, 2H,
CH ), 6.770 (d, J = 9.0 Hz, 1H, imidazo[4,5-b]pyridine
3
3
2
CH ), 7.117–7.194 (m, 2H, Ph H), 7.564–7.664 (m, 1H,
H), 7.134 (s, 1H, thiazole H), 7.431–7.459 (m, 1H, Ph
H), 7.681–7.769 (m, 2H, Ph H), 7.885–7.918 (m, 1H, Ph
H), 7.968 (d, J = 9.0 Hz, 1H, imidazo[4,5-b]pyridine H);
2
Ph H), 8.126 (d, J = 8.4 Hz, 1H, imidazo[4,5-b]pyridine
H), 8.315 (d, J = 8.1 Hz, 1H, imidazo[4,5-b]pyridine H).
1
3
C-NMR (CDCl , 75 MHz) δ: 38.72, 53.96, 107.22,
The syntheses of other target compounds with ≥95.0%
purity (HPLC) were similar to that of the earlier
representative compound, and their structures are
supported by spectroscopic data in Tables 1 and 2.
3
117.81 (q, J = 273 Hz), 126.75 (q, J = 4.8 Hz), 128.06,
129.20, 129.80 (q, J = 30 Hz), 130.76, 130.94, 131.77,
132.25, 134.88, 140.47, 144.17, 147.21, 152.97, 161.72.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Liu, C. Quan, M. Dang, Y. Ren, J. Ren, J. Xiang, X. Liu, L. He, W. Liu, and A. Liu
Vol 000
BIOLOGICAL ASSAY [13–19] TEST COMPOUNDS
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Stock solution of every test compound was prepared in
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diluted to the required test concentrations (50–500 mg/L)
with water containing Tween 80 (0.4 mg/L).
The activity against R. solani. Plants were grown under
greenhouse conditions [T = 22°C, 60 (±5)% relative
humidity and a 12-h light cycle]. Plants were maintained
in plastic pots (6 cm diameter × 10 cm). Test compound
solutions were sprayed over the plants. One day later,
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[
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The activity against E. graminis.
Wheat plants were
[
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X. P.; Pei, H.; Hu, L.; Huang, M. Z.; Wang, X. G. J Agric Food Chem
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grown under greenhouse conditions [T = 22°C, 60 (5)%
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maintained in plastic pots (6 cm diameter × 10 cm) and
were inoculated by a spore suspension of E. graminis
2
[
2
(1.0 × 105 spores/mL). After 1 day, test compounds were
[
sprayed over the plants. After 1 or 2 weeks, the
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as in the test of preventive activity against E. graminis.
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[
Acknowledgments. The authors are thankful to the Natural
Science Foundation of Hunan Province of China (2016JJ2047)
and the National Natural Science Foundation of China
[
(21572050) for the financial support.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet