Synthesis and Biological Activity of Some Novel Aryl-Substituted 1,3,4-Oxadiazole Mannich Bases Containing Pyrimidine Rings

Article abstract of DOI:10.1002/jhet.2224

A series of novel Mannich base derivatives (E₁-E₁₅) of 5-aryl-1,3,4-oxadiazole-2-thione with substituted pyrimidine were synthesized and characterized by elemental analysis, IR, ¹H-NMR. The antifungal activities of these compounds were also originally studied. The results showed that most of the title compounds exhibited relatively good fungicidal activities. Especially compounds E₈ and E₁₃ showed better antifungal activity than comparison compound hymexazol. The relationship of structure and activity revealed that the presence of the methyl group at four and six positions of pyrimidine ring remarkably enhanced the antifungal activity of title compounds.

Full text of DOI:10.1002/jhet.2224

1296
Synthesis and Biological Activity of Some Novel Aryl-Substituted 1,3,
4-Oxadiazole Mannich Bases Containing Pyrimidine Rings
Vol 52
c
c
b
b
Shengqiang Shen,a Xiaohong Sun,a,b Yuanfa Liu, Bang Chen, Ruyi Jin, and Haixia Ma
*
aChemical Research Institute, Northwest University, Xi’an, Shaanxi 710069, China
bSchool of Chemical Engineering, Northwest University, Xi’an, Shaanxi 710069, China
cCollege of Chemistry & Materials Science, Northwest University, Xi’an, Shaanxi 710069, China
*
E-mail: xhsun888@sohu.com
Received January 6, 2014
DOI 10.1002/jhet.2224
Published online 7 July 2014 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel Mannich base derivatives (E1–E15) of 5-aryl-1,3,4-oxadiazole-2-thione with substituted
pyrimidine were synthesized and characterized by elemental analysis, IR, 1H-NMR. The antifungal activities
of these compounds were also originally studied. The results showed that most of the title compounds
exhibited relatively good fungicidal activities. Especially compounds E8 and E13 showed better antifungal
activity than comparison compound hymexazol. The relationship of structure and activity revealed that the
presence of the methyl group at four and six positions of pyrimidine ring remarkably enhanced the antifungal
activity of title compounds.
J. Heterocyclic Chem., 52, 1296 (2015).
INTRODUCTION
triphenylphosphorane as the cyclization reagent and the
reaction had the advantages of ease of work up, high yields,
and fairly mild reaction conditions [11–15].
Plant pathogenic fungi invasion is considered to be one
of the main reasons causing the reduction of crop yield.
Especially in the last few decades, the fungi can spread
more easily because of the increasingly frequent circulation
of agricultural products worldwide. It is estimated that the
output of five main grain crops including rice, wheat, corn,
soybean, and potato will decrease 125 million tons per year
affected by fungi all around the world. Therefore, it is
imminently to research on the control of fungal diseases.
Most of the nitrogen-containing heterocyclic compounds
are known to be associated with a broad spectrum of bioac-
tivity, and they have the advantages of superior selectivity,
high activity, and low toxicity [1–3]. 1,3,4-Oxadiazoles are
the important classes of nitrogen containing heterocyclic
compounds that have attracted a lot of interest in the fields
of medicinal chemistry, owing to their varied biological
properties, such as antiviral [4], antifungal [5], antibacterial
[6], antitubercular [7], and plant-growth regulatory [8]
activities. Furthermore, the synthesis of 1,3,4-oxadiazole
derivatives is an area of research that has gained a lot of
attention. The most commonly method used to generate the
1,3,4-oxadiazole heterocycle involves the cyclodehydration
of diacylhydrazides with the harsh dehydration reagents,
such as sulphuric acid, thionyl chloride, and phosphorous
oxychloride [9]. Recently, many efforts have been made to
develop modified and milder procedures, including
introduction of new reagents, microwave-assisted and
solid-phase supported chemistry [10]. It was worth mention-
ing that Ali Ramazani had reported for the one-step synthesis
of 1,3,4-oxadiazoles on the use of (N-isocyanimino)
Likewise, the compounds bearing pyrimidine group
possess versatile biological activities, and many of them
have already been commercialized in marketed drugs and
agricultural chemicals such as anti-atherosclerotic aronixil,
anti-histaminic thonzylamine, fungicide pyrimethanil, her-
bicide nicosulfuron, and other relevant compounds.
Mannich bases derived from various heterocycles were
reported to exert a number of important physiological
activities such as anticancer [16], antipsychotic [17], and
anti-inflammatory [18] activities. In recent years, Mannich
bases containing a 1,3,4-oxadiazole ring had attracted
much more attention because of their special bioactivity.
For example, Desai et al. found that Mannich bases of
1,3,4-oxadiazole bearing thiazole had good antibacterial
activities [19]. In 2011, Mannich bases of 1,3,4-oxadiazole
carrying 1,3,4-thiadiazole were reported to possess strong
antimycobacterial activities [20]. Moreover, In 2013,
Mannich bases of 1,3,4-oxadiazole carrying piperazine
were reported to show remarkable anti-amoebic activities
[21]. Nevertheless, literature reveals that there are few
reports of a molecular scaffold that Mannich base of
1,3,4-oxadiazole carries pyrimidine.
Prompted by these observations, a series of novel
Mannich base derivatives of 1,3,4-oxadiazole incorporating
pyrimidine ring (E1–E15) were synthesized and evaluated
in vitro against four vegetable pathogens containing
Gibberlla nicotiancola, Pythium solani, Gibberlla saubinetii,
and Fusarium oxysporium f.sp. niveum. The synthetic route
is outlined in Scheme 1.
© 2014 HeteroCorporation

September 2015
Synthesis and Biological Activity of 1,3,4-Oxadiazole Mannich Bases Containing
Pyrimidine Rings
1297
Scheme 1. The synthetic route of compounds E1–E15
.
RESULT AND DISCUSSION
method and data analysis were based on [22]. Hymexazol
was used as the comparison compound. The biological
activities test data were given in Table 1.
Synthesis. Fluorobenzoic acid was taken as starting
material and reacted with ethanol to afford ethyl
fluorobenzoate (A1–A3), which on further reaction with
hydrazine hydrate in absolute ethanol, yielded intermediate
fluorobenzoyl hydrazine (B1–B3). Then, the intermediate
(B1–B3) were refluxed with carbon disulfide by base-
catalyzed in ethanol to yield 5-fluorophenyl-1,3,4-oxadi-
azole-2-thione (C1–C3). Finally, the 15 Mannich base
derivatives of 5-aryl-1,3,4-oxadiazole-2-thione with
substituted pyrimidine (E1–E15) were prepared by the
reaction of (C1–C3) with 37% formaldehyde and
substituted pyrimidines.
The results presented that most of the compounds exhi-
bited relatively good activities to Gibberlla nicotiancola,
Pythium solani, Gibberlla saubinetii, and Fusarium oxy-
sporium f.sp. niveum. Compounds E8 and E13 showed high
activities to these four vegetable pathogens, and their EC50,
EC95 values were less than the comparison drug hymexazol.
The EC95 values of compounds E2, E3, E7, E11, and E12 were
less than 3.00g × LÀ1, which were almost equal to that of
hymexazol. However, compounds E4, E9, E14, and E15
showed EC50, EC95 values more than hymexazol and were
considered to be weak-to-moderate antifungal activities.
The relationship of structure and activity revealed that
the biological activity order of compound substituted with
fluorine at 1,3,4-oxadiazole was para > meta > ortho.
Moreover, the presence of the methoxy group at pyrimi-
dine ring reduced the antifungal activity, and the biological
activity of the compound substituted with a 3-pyridyl
group at pyrimidine ring was higher than that substituted
with a phenyl group. Furthermore, it was worthwhile to
note that E3, E8, and E13, which had the methyl groups at
pyrimidine ring, showed the best antifungal activities
among the title compounds.
The structures of all newly synthesized compounds
1
were confirmed by IR, H-NMR, and elemental analysis.
In IR spectra, compounds (E1–E15) showed a moderate-
intensity absorption band between 3238 and 3254 cmÀ1
for the N–H stretching vibration. The aromatic and ali-
phatic C–H stretching vibrations were observed between
3045–3070 cmÀ1 and 2900–2990 cmÀ1, respectively in
the form of medium bands. These IR stretching vibrations
indicated the formation of –NH–CH2–Ar. In addition, the
strong bands for C═N, C═S, and C–O–C stretching vibra-
tions were observed between 1585–1610, 1340–1375, and
1
1245–1270 cmÀ1. In the H-NMR spectra of compounds
(E1–E15), the signals of the –CH2– protons at around
δ = 5.7–6.3 ppm in the downfield region due to peri effect
of nitrogen atom and aromatic ring. The signals for N–H
at around δ = 6.2–6.7 ppm. These signals also demonstrate
the formation of Mannich base.
EXPERIMENTAL
General. The melting points of the products were determined
by open capillaries on SMP3 melting point apparatus and are
uncorrected. The IR spectra were recorded on a Bruker Tensor27
spectrophotometer, using KBr pellets. 1H-NMR spectra and
Biological activity. All of the target compounds (E1–E15)
were qualified for antifungal screening in vitro. The testing
13C-NMR spectra were measured with
a Varian unity
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1298
S. Shengqiang, S. Xiaohong, L. Yuanfa, C. Bang, J. Ruyi, and M. Haixia
Vol 52
Table 1
The biological test results of the compounds E1–E15 to four vegetable pathogens.
À1
EC50b (g × LÀ1
)
EC95 (g × L
)
c
Compound
Pathogen
Toxicity regression equation
Correlation coefficient
E1
Gibberll nicotiancola
Gibberlla saubinetii
F.o.f.sp. niveuma
Pythium solani
Gibberll nicotiancola
Gibberlla saubinetii
F.o.f.sp. niveum
Y = À0.8794 + 2.2747x
Y = 0.7337 + 1.7347x
Y = À2.4822 + 2.6874x
Y = À0.5003 + 1.6954x
Y = 1.4526 + 1.5089x
Y = 1.4155 + 1.7009x
Y = À0.0618 + 2.0329x
Y = À0.2109 + 1.9937x
Y = À14.5720 + 7.3491x
Y = À2.5981 + 3.0032x
Y = À7.6404 + 4.8442x
Y = À2.4981 + 2.7412x
Y = 0.4711 + 1.0515x
Y = 0.7227 + 0.9256x
Y = 1.4260 + 0.5740x
Y = À1.1696 + 1.8718x
Y = 1.0775 + 1.5661x
Y = 0.5954 + 1.6419x
Y = À0.4299 + 2.1180x
Y = À0.9691 + 2.1998x
Y = À0.6500 + 2.1210x
Y = 1.5316 + 1.6033x
Y = À0.8980 + 2.3589x
Y = À0.1047 + 1.7811x
Y = 0.2019 + 1.9729x
Y = 1.1292 + 1.9405x
Y = 0.5272 + 1.8732x
Y = À1.0779 + 2.2787x
Y = À2.6817 + 3.3223x
Y = À3.4712 + 3.8369x
Y = À2.5676 + 3.2365x
Y = À3.4408 + 3.3891x
Y = 2.2825 + 1.0001x
Y = À3.0447 + 3.0827x
Y = À1.2069 + 2.3638x
Y = 1.7822 + 1.1477x
Y = 0.7718 + 1.5857x
Y = 1.6600 + 1.5360x
Y = À0.2346 + 1.9929x
Y = 0.9289 + 1.5737x
Y = À0.5726 + 2.2828x
Y = 1.0203 + 1.9865x
Y = À0.2581 + 2.0600x
Y = 0.7204 + 1.7023x
Y = À1.7659 + 2.8334x
Y = À1.3967 + 2.7303x
Y = À1.9143 + 2.7786x
Y = À3.3728 + 3.2029x
Y = À2.2543 + 3.2316x
Y = À2.6605 + 3.6473x
Y = À1.0791 + 2.7131x
Y = À2.6523 + 3.1546x
Y = À0.3378 + 2.1468x
Y = À2.4036 + 2.9030x
Y = 2.0136 + 1.2245x
Y = À1.5713 + 2.2505x
Y = À2.5360 + 2.4922x
Y = 2.8649 + 0.6208x
Y = À1.8065 + 2.3059x
Y = À0.7472 + 1.5905x
Y = 0.1885 + 2.1980x
0.9980
0.9226
0.9893
0.9793
0.9937
0.9881
0.9701
0.9340
0.9903
0.9769
0.9738
0.8266
0.9743
0.9452
0.9343
0.9132
0.9801
0.9940
0.9789
0.9256
0.9489
0.9443
0.9884
0.9557
0.9522
0.9935
0.9992
0.9462
0.9991
0.9989
0.9923
0.9782
0.9959
0.9709
0.9899
0.9997
0.9819
0.9288
0.9901
0.9108
0.9410
0.9996
0.9981
0.8986
0.9737
0.8354
0.9557
0.9929
0.9474
0.9949
0.9687
0.9656
0.9956
0.9538
0.9796
0.9798
0.9969
0.9924
0.9664
0.9901
0.9048
0.38
0.29
0.61
1.75
0.22
0.13
0.31
0.41
0.46
0.34
0.41
0.54
20.28
41.79
/
2.03
2.56
2.49
16.39
2.76
1.19
1.99
2.75
0.77
1.20
E2
Pythium solani
E3
Gibberll nicotiancola
Gibberlla saubinetii
F.o.f.sp. niveum
0.89
2.16
Pythium solani
E4
Gibberll nicotiancola
Gibberlla saubinetii
F.o.f.sp. niveum
743.74
d
/
/
Pythium solani
1.98
0.34
0.48
0.37
0.52
0.46
0.15
0.32
0.73
0.27
0.10
0.24
0.46
0.21
0.16
0.22
0.31
0.52
0.41
0.42
0.63
0.46
0.15
0.42
0.39
0.28
0.10
0.36
0.33
0.24
0.22
0.31
0.41
0.18
0.13
0.17
0.27
0.31
0.36
0.27
0.83
1.06
2.75
0.89
4.01
0.15
14.96
3.59
4.84
2.19
2.89
2.75
1.55
1.58
6.16
1.84
0.70
1.84
2.45
0.64
0.39
0.70
0.95
23.01
1.39
2.10
17.25
5.06
1.76
2.83
4.29
1.45
0.68
2.24
3.02
0.93
0.88
1.20
1.34
0.57
0.36
0.70
0.89
1.79
1.06
6.06
4.48
4.83
/
E5
Gibberll nicotiancola
Gibberlla saubinetii
F.o.f.sp. niveum
Pythium solani
E6
Gibberll nicotiancola
Gibberlla saubinetii
F.o.f.sp. niveum
Pythium solani
E7
Gibberll nicotiancola
Gibberlla saubinetii
F.o.f.sp. niveum
Pythium solani
E8
Gibberll nicotiancola
Gibberlla saubinetii
F.o.f.sp. niveum
Pythium solani
E9
Gibberll nicotiancola
Gibberlla saubinetii
F.o.f.sp. niveum
Pythium solani
E10
E11
E12
E13
E14
E15
Hymexazol
Gibberll nicotiancola
Gibberlla saubinetii
F.o.f.sp. niveum
Pythium solani
Gibberll nicotiancola
Gibberlla saubinetii
F.o.f.sp. niveum
Pythium solani
Gibberll nicotiancola
Gibberlla saubinetii
F.o.f.sp. niveum
Pythium solani
Gibberll nicotiancola
Gibberlla saubinetii
F.o.f.sp. niveum
Pythium solani
Gibberll nicotiancola
Gibberlla saubinetii
F.o.f.sp. niveum
Pythium solani
Gibberll nicotiancola
Gibberlla saubinetii
F.o.f.sp. niveum
Pythium solani
Gibberll nicotiancola
4.63
44.43
0.87
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2015
Synthesis and Biological Activity of 1,3,4-Oxadiazole Mannich Bases Containing
Pyrimidine Rings
1299
Table 1
(Continued)
À1
EC50b (g × LÀ1
)
EC95 (g × L )
c
Compound
Pathogen
Toxicity regression equation
Correlation coefficient
Gibberlla saubinetii
F.o.f.sp. niveum
Pythium solani
Y = À1.2346 + 3.0382x
Y = 2.3199 + 1.3745x
Y = 0.6088 + 1.9959x
0.9714
0.9221
0.9092
0.11
0.09
0.16
0.39
1.40
1.06
aF.o.f.sp. niveum represents Fusarium oxysporium f.sp. niveum.
bEC50 represents 50% effective concentration.
cEC95 represents 95% effective concentration.
d“/” represent effective concentration beyond 1000 g × LÀ1
.
INOVA-400 NMR in CDCl3 by using TMS as an internal
standard with 1H resonant frequency of 400 MHz and 13C
resonant frequency of 100 MHz. Mass spectra were recorded on
a Brucker micrOTOF-QII mass spectrometer. The new products
3-((4-phenylpyrimidin-2-ylamino)methyl)-5-(2-fluorophenyl)-
1,3,4-oxadiazole-2(3H)-thione (E1). White solid; yield 84.1%;
mp 196.6–198.1°C; IR (KBr, cmÀ1): 3254 (N–H), 3078 (═C–H),
2948 (C–H), 1596 (C═N), 1355 (C═S), 1274 (C–O–C); 1H-NMR
(CDCl3): δ 5.94 (d, J = 7.2 Hz, 2H, CH2), 6.51 (t, J = 7.2 Hz, 1H,
NH), 7.16 (d, J = 5.2 Hz, 1H, pyrimidin), 7.25–7.92 (m, 9H,
phenyl), 8.44 (d, J = 5.2 Hz, 1H, pyrimidin); 13C-NMR (CDCl3):
δ 56.36, 91.52, 108.94, 117.18, 124.89, 125.13, 127.57, 128.99,
129.22, 131.13, 134.24, 136.94, 159.19, 161.22, 161.62, 172.53,
176.47; Anal. Calcd. for C19H14FN5OS: C, 60.15; H, 3.72; N,
were analyzed using
a Vario ELШ CHNOS analyzer.
Fluorobenzoyl hydrazine (B1–B3), 4,6-dimethylpyrimidin-2-
amine (D3), 4-chloro-6-methoxypyrimidin-2-amine (D4), and
4,6-dimethoxypyrimidin-2-amine (D5) were prepared according
to literature procedures [23–26].
General procedure for the synthesis of 5-aryl-1,3,4-
oxadiazole-2-thione (C1–C3).
To a stirred solution of
18.46. Found: C, 60.44; H, 3.51; N, 18.55.
Fluorobenzoyl hydrazine (B1–B3) (60 mmol) in ethanol (50 mL)
was added potassium hydroxide (90 mmol) and H2O (10 mL).
After the mixture had been stirred for 10 min, carbon disulfide
(90 mmol) was added dropwise over 30 min at room temperature.
The reaction mixture was next refluxed in an oil bath for
about 12 h. Then, the excess solvent was removed by vacuum
evaporation, and the residue was dissolved in water and
acidified with dilute hydrochloric acid to get solid product.
The resulting oxadiazolyl thione was collected by filtration,
dried, and recrystallized from water–ethanol (10–90 mL). C1,
white crystals, mp 155.1–156.8°C; C2, white crystals, mp
134.1–135.8°C ([27] 134.0–135.5°C); C3, white crystals, mp
3-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)-5-(2-
fluorophenyl)-1,3,4-oxadiazole-2(3H)-thione (E2). White solid;
yield 82.3%; mp 202.7–204.6°C; IR (KBr, cmÀ1): 3250 (N–H),
3071 (═C–H), 2933 (C–H), 1600 (C═N), 1362 (C═S), 1277
(C–O–C); 1H-NMR (CDCl3): δ 5.94 (d, J = 7.2 Hz, 2H, CH2),
6.55 (t, J = 6.8 Hz, 1H, NH), 7.20 (d, J = 5.2 Hz, 1H, pyrimidin),
7.23–7.54 (m, 4H, phenyl), 7.88 (t, J = 7.2 Hz, 1H, pyridin), 8.49
(d, J = 4.8 Hz, 1H, pyrimidin), 8.63–8.73 (m, 2H, pyridin), 9.34
(s, 1H, pyridin); Anal. Calcd. for C18H13FN6OS: C, 56.83; H,
3.44; N, 22.09. Found: C, 56.97; H, 3.21; N, 22.15.
3-((4,6-dimethylpyrimidin-2-ylamino)methyl)-5-(2-fluorophenyl)-
1,3,4-oxadiazole-2(3H)-thione (E3). White solid; yield 86.6%;
mp 198.4–199.3°C; IR (KBr, cmÀ1): 3255 (N–H), 3081 (═C–H),
2916 (C–H), 1592 (C═N), 1354 (C═S), 1275 (C–O–C); 1H-NMR
(CDCl3): δ 2.35 (s, 6H, CH3), 5.82 (d, J = 7.2 Hz, 2H, CH2), 6.12
(t, J = 6.8 Hz, 1H, NH), 6.48 (s, 1H, pyrimidin), 7.22–7.56 (m,
4H, phenyl); 13C-NMR (CDCl3): δ 24.07, 56.23, 112.36, 117.36,
118.30, 124.87, 129.21, 134.17, 140.23, 149.97, 161.54, 168.10,
176.44; HRMS Calcd. for C15H14FN5OS [M + Na]+ 354.0903,
found 354.0811; Anal. Calcd. for C15H14FN5OS: C, 54.37; H,
191.8–193.4°C ([28] 192–193°C).
General procedure for the synthesis of 4-arylpyrimidin-2-
amine (D1–D2).
The mixture of the aryl methyl ketone
(100 mmol) and N,N–dimethylformamide dimethylacetal
(120 mmol) in xylene (60 mL) was refluxed for 10 h and
then installed the water separator to reflux for another 14 h, left
to cool, and the excess solvent was removed by distillation. The
obtained crude products 3-(dimethyl-amino)-1-aryl-prop-2-en-1-
one were filtered off, washed twice with petroleum ether
(2 × 20 mL), and dried. After that, equimolar amount (50 mmol)
of compounds 3-(dimethyl-amino)-1-aryl-prop-2-en-1-one, guanidine
hydrochloride, and sodium hydroxide were dissolved in ethanol
(50 mL), and then, the reaction mixture was refluxed for about
20 h. Thus, products (D1–D2) were collected by filtration, dried,
and recrystallized from ethanol. D1, light yellow crystals, mp
163.8–165.3°C ([29] 164.4–165.1°C); D2, light yellow crystals,
4.26; N, 21.13. Found: C, 54.65; H, 4.20; N, 21.35.
3-((4-chloro-6-methoxypyrimidin-2-ylamino)methyl)-5-(2-
fluorophenyl)-1,3,4-oxadiazole-2(3H)-thione (E4).
White
solid; yield 72.3%; mp 186.7–187.9°C; IR (KBr, cmÀ1): 3245
(N–H), 3069 (═C–H), 2953 (C–H), 1591 (C═N), 1353 (C═S),
1
1274 (C–O–C); H-NMR (CDCl3): δ 4.00 (s, 3H, OCH3), 5.79
(d, J = 7.2, 2H, CH2), 6.22 (s, 1H, pyrimidin), 6.35 (t, J = 1.2 Hz,
1H, NH), 7.23–7.65 (m, 4H, phenyl); Anal. Calcd. for
C14H11ClFN5O2S: C, 45.72; H, 3.01; N, 19.04. Found: C, 45.91;
mp 188.7–190.5°C ([30] 192°C).
General procedure for the synthesis of 3-((4,6-
disubstitutedpyrimidin-2-ylamino)methyl)-5-aryl-1,3,4-oxadiazole-
H, 2.78; N, 19.23.
3-((4,6-dimethoxypyrimidin-2-ylamino)methyl)-5-(2-fluorophenyl)-
2(3H)-thione (E1–E15).
Oxadiazole-2-thiones (C) (5 mmol)
1,3,4-oxadiazole-2(3H)-thione (E5). White solid; yield 75.6%; mp
151.2–152.1°C; IR (KBr, cmÀ1): 3248 (N–H), 3074 (═C–H), 2974
(C–H), 1592 (C═N), 1352 (C═S), 1272 (C–O–C); 1H-NMR
(CDCl3): δ 3.91 (s, 6H, OCH3), 5.53 (s, 1H, pyrimidin), 5.79 (d,
J = 7.2 Hz, 2H, CH2), 6.11 (t, J = 7.2 Hz, 1H, NH), 7.25–7.66 (m, 4H,
phenyl); Anal. Calcd. for C15H14FN5O3S: C, 49.58; H, 3.88; N,
19.27. Found: C, 49.61; H, 3.80; N, 19.55.
and substituted 2-amino pyrimidines (D) (5 mmol) were mixed
in 20 mL absolute ethanol and stirred. To the stirred suspension,
formaldehyde (5 mmol, 37%) was added dropwise and heated to
reflux for 3 h. The progress of the reaction was monitored by
TLC. On completion, the crude products were obtained as a
solid material, which were recrystallized from ethyl acetate.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1300
S. Shengqiang, S. Xiaohong, L. Yuanfa, C. Bang, J. Ruyi, and M. Haixia
Vol 52
3-((4-phenylpyrimidin-2-ylamino)methyl)-5-(3-fluorophenyl)-
9.35 (s, 1H, pyridin); Anal. Calcd. for C18H13FN6OS: C,
56.83; H, 3.44; N, 22.09. Found: C, 56.99; H, 3.18; N, 22.40.
3-((4,6-dimethylpyrimidin-2-ylamino)methyl)-5-(4-fluorophenyl)-
1,3,4-oxadiazole-2(3H)-thione (E13). White solid; yield 88.2%;
mp 214.8–215.9°C; IR (KBr, cmÀ1): 3250 (N–H), 3077 (═C–H),
2965 (C–H), 1598 (C═N), 1357 (C═S), 1282 (C–O–C); 1H-
NMR (CDCl3): δ 2.33 (s, 6H, CH3), 5.84 (d, J = 7.6 Hz, 2H,
CH2), 6.16 (t, J = 7.2 Hz, 1H, NH), 6.48 (s, 1H, pyrimidin), 7.35–
7.80 (m, 4H, phenyl); Anal. Calcd. for C15H14FN5OS: C, 54.37;
1,3,4-oxadiazole-2(3H)-thione (E6). White solid; yield 82.2%;
mp 201.6–203.2°C; IR (KBr, cmÀ1): 3242 (N–H), 3069 (═C–H),
2959 (C–H), 1600 (C═N), 1354 (C═S), 1275 (C–O–C); 1H-NMR
(CDCl3): δ 5.93 (d, J = 6.8 Hz, 2H, CH2), 6.42 (t, J = 6.8 Hz, 1H,
NH), 7.17 (d, J = 5.2 Hz, 1H, pyrimidin), 7.26–8.06 (m, 9H,
phenyl), 8.44 (d, J = 5.6 Hz, 1H, pyrimidin); Anal. Calcd. for
C19H14FN5OS: C, 60.15; H, 3.72; N, 18.46. Found: C, 60.32; H,
3.63; N, 18.64.
3-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)-5-(3-
H, 4.26; N, 21.13. Found: C, 54.46; H, 4.11; N, 21.31.
3-((4-chloro-6-methoxypyrimidin-2-ylamino)methyl)-5-(4-
fluorophenyl)-1,3,4-oxadiazole-2(3H)-thione (E7).
White
solid; yield 79.8%; mp 201.1–202.9°C; IR (KBr, cmÀ1): 3238
(N–H), 3065 (═C–H), 2891 (C–H), 1601 (C═N), 1350 (C═S),
1270 (C–O–C); 1H-NMR (CDCl3): δ 5.92 (d, J = 7.2 Hz, 2H, CH2),
6.46 (t, J = 6.8 Hz, 1H, NH), 7.20 (d, J = 5.2 Hz, 1H, pyrimidin),
7.24–7.63 (m, 4H, phenyl), 7.71 (d, J = 7.2 Hz, 1H, pyridin), 8.49
(d, J = 5.2 Hz, 1H, pyrimidin), 8.55–8.73 (m, 2H, pyridin),
9.33 (s, 1H, pyridin); Anal. Calcd. for C18H13FN6OS: C,
fluorophenyl)-1,3,4-oxadiazole-2(3H)-thione (E14).
White
solid; yield 74.5%; mp 190.8–192.1°C; IR (KBr, cmÀ1): 3242
(N–H), 3069 (═C–H), 2948 (C–H), 1609 (C═N), 1361 (C═S),
1
1285 (C–O–C); H-NMR (CDCl3): δ 4.02 (s, 3H, OCH3), 5.79
(d, J = 7.6, 2H, CH2), 6.22 (s, 1H, pyrimidin), 6.34 (t, J = 1.2 Hz,
1H, NH), 7.26–7.68 (m, 4H, phenyl); Anal. Calcd. for
C14H11ClFN5O2S: C, 45.72; H, 3.01; N, 19.04. Found: C, 45.98;
H, 2.82; N, 19.27.
56.83; H, 3.44; N, 22.09. Found: C, 57.05; H, 3.17; N, 22.23.
3-((4,6-dimethylpyrimidin-2-ylamino)methyl)-5-(3-fluorophenyl)-
3-((4,6-dimethoxypyrimidin-2-ylamino)methyl)-5-(4-fluorophenyl)-
1,3,4-oxadiazole-2(3H)-thione (E15).
White solid; yield
1,3,4-oxadiazole-2(3H)-thione (E8). White solid; yield 87.4%;
mp 199.5–200.3°C; IR (KBr, cmÀ1): 3261 (N–H), 3077 (═C–H),
2968 (C–H), 1598 (C═N), 1360 (C═S), 1285 (C–O–C); 1H-NMR
(CDCl3): δ 2.35 (s, 6H, CH3), 5.84 (d, J = 7.2 Hz, 2H, CH2), 6.14
(t, J = 7.2 Hz, 1H, NH), 6.48 (s, 1H, pyrimidin), 7.30–7.81 (m, 4H,
phenyl); Anal. Calcd. for C15H14FN5OS: C, 54.37; H, 4.26; N,
78.8%; mp 160.5–162.2°C; IR (KBr, cmÀ1): 3244 (N–H), 3079
(═C–H), 2950 (C–H), 1611 (C═N), 1360 (C═S), 1280 (C–O–C);
1H-NMR (CDCl3): δ 3.93 (s, 6H, OCH3), 5.53 (s, 1H, pyrimidin),
5.81 (d, J = 6.8 Hz, 2H, CH2), 6.12 (t, J = 6.8 Hz, 1H, NH), 7.30–
7.81 (m, 4H, phenyl); Anal. Calcd. for C15H14FN5O3S: C, 49.58;
H, 3.88; N, 19.27. Found: C, 49.73; H, 3.67; N, 19.55.
21.13. Found: C, 54.49; H, 4.21; N, 21.09.
3-((4-chloro-6-methoxypyrimidin-2-ylamino)methyl)-5-(3-
fluorophenyl)-1,3,4-oxadiazole-2(3H)-thione (E9).
White
solid; yield 71.4%; mp 162.6–164.1°C; IR (KBr, cmÀ1): 3262
(N–H), 3057 (═C–H), 2950 (C–H), 1598 (C═N), 1360
(C═S), 1285 (C–O–C); 1H-NMR (CDCl3): δ 4.01 (s, 3H,
OCH3), 5.78 (d, J = 7.2, 2H, CH2), 6.21 (s, 1H, pyrimidin),
6.33 (t, J = 1.2 Hz, 1H, NH), 7.23–7.70 (m, 4H, phenyl); Anal.
Calcd. for C14H11ClFN5O2S: C, 45.72; H, 3.01; N, 19.04.
Acknowledgments. The authors are thankful to the National
Natural Science Foundation of China (No. 21073141 and No.
21373161) for its financial support for this project.
REFERENCES AND NOTES
Found: C, 45.93; H, 2.74; N, 19.19.
3-((4,6-dimethoxypyrimidin-2-ylamino)methyl)-5-(3-
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yield 75.6%; mp 155.8–157.7°C; IR (KBr, cmÀ1): 3246 (N–H),
3075 (═C–H), 2961 (C–H), 1598 (C═N), 1357 (C═S), 1282
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3-((4-phenylpyrimidin-2-ylamino)methyl)-5-(4-fluorophenyl)-
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mp 209.7–210.5°C; IR (KBr, cmÀ1): 3238 (N–H), 3049 (═C–H),
2993 (C–H), 1602 (C═N), 1352 (C═S), 1279 (C–O–C); 1H-NMR
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3-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)-5-(4-fluorophenyl)-
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2015
Synthesis and Biological Activity of 1,3,4-Oxadiazole Mannich Bases Containing
Pyrimidine Rings
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet