Facile synthesis and antioxidant activity of lignin-related imidazo[1, 2-a]pyridine derivatives

Article abstract of DOI:10.24820/ark.5550190.p010.526

A convenient protocol is described for the preparation of lignin related imidazo[1, 2-a] pyridine derivatives via three-component reactions among 2-aminopyridines, isocyanides and aromatic aldehydes obtained from lignin with excellent yields. Their in vit

Full text of DOI:10.24820/ark.5550190.p010.526

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Facile synthesis and antioxidant activity of lignin-related imidazo[1,2-a]pyridine
derivatives
Xiaohui Yang,a,b Qianqian Shang,*b Caiying Bo,b Lihong Hu,b and Yonghong Zhoua,b
aResearch Institute of Forestry New Technology, Chinese Academy of Forestry, Dongxiaofu-1 Xiangshan Road,
Beijing 100091, People’s Republic of China
bKey Lab. of Biomass Energy and Material, Institute of Chemical Industry of Forest Products, China Academy of
Forestry; Nanjing 210042, People’s Republic of China
Email: shangqianqian@icifp.cn
Received 02-11-2018
Accepted 04-17-2018
Published on line 06-17-2018
Abstract
A convenient protocol is described for the preparation of lignin related imidazo[1,2-a] pyridine derivatives via
three-component reactions among 2-aminopyridines, isocyanides and aromatic aldehydes obtained from
lignin with excellent yields. Their in vitro antioxidant effects were evaluated by scavenging effect on 2,2-
diphenyl-1-picrylhydrazyl (DPPH) radical. The structure activity relationship (SAR) studies presented that the
introduction of electron-donating group in imidazo[1,2-a]pyridine could increase the radical scavenging
activity; On the contrary, the presence of electron-withdrawing might decrease the radical scavenging activity.
In addition, cyclopentyl and cyclohexyl groups almost had the same influence on the antioxidant activity.
Furthermore, the methoxy moiety had a significant impact on antioxidant capability, and hence syringyl
imidazo[1,2-a]pyridines a, d, g, j and m exhibited excellent antioxidant properties
Keywords: Lignin; Imidazo[1,2-a]pyridine; Multi-component reactions; Antioxidant activity
DOI: https://doi.org/10.24820/ark.5550190.p010.526
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Introduction
Driven by the inevitable depletion of fossil fuels and the growing environmental problems, lignocellulosic
biomass has been recognized as a potential feedstock for energy production and the synthesis of high-value
chemicals.1-3 Lignin is, next to cellulose, the main component of lignocellulosic biomass and the only
renewable resource which is rich in natural aromatic structure, so it is an ideal alternative material to prepare
aromatic compounds. However, it retains the least utilized biomass constituent because of its complex and
heterogeneous macromolecular structure.3,4 Most of lignin is burning for heat and power production, it is a
low-value and an energy-inefficient application.5,6 In addition, a large volume of lignin is produced annually by
the paper industry, and the volume is expected to surge with the introduction of future biorefineries. Hence, it
is highly desirable to develop efficient procedures to increase application of lignin.7 Moreover, converting
lignin into value-added products is also critical to increase revenue and establish economically feasible
biorefining processes.8
Recently, producing added-value aromatic monomers (typically vanillin and syringaldehyde)5and their
related pharmaceutical chemicals6,9,10 from lignin has been the topic of many publication. Those aromatic
monomers degraded from lignin and their derivatives afforded good antioxidant6, anti-inflammatory,
hepatoprotective9, antihypertensive, choleretic, antipsychotic, antispasmodic properties etc (Bjørsvik and
Liguori10. Furthermore, lignin itself has been also proved to be antioxidant11, protein adsorption12, metal
adsorption13, UV protection14 and antimicrobial properties15. Therefore, there is considerable interest in
converting lignin to these high-value potential drugs while, at the same time, disposing of a high-volume, low-
value waste.
Imidazopyridine, one of the important fused bicyclic 5-6 heterocycles, exhibits a broad spectrum of
biological activities such as antitumor, anti-apoptotic, hypnoselective, antibacterial, antifungal, antiviral,
antiprotozoal, anti-inflammatory16 and antioxidant17. Moreover, imidazo[1,2-a]pyridine is considered as a
“drug prejudice” moiety, because there are numerous clinical drugs that includes zolpidem, saripidem,
olprinone, zolimidine, rifaximin and drug candidates18,19. Recently, 2-phenyl-imidazo[1,2-a]pyridine analogues
(tubulin polymerization inhibitors)20, sulfonylhydrazone-substituted imidazo[1,2-a]pyridines (PI3 kinase p110α
inhibitors)21 and the other imidazo-[1,2-a]pyridine derivatives acting on Nek222and c-Met kinases23have been
extensively studied in the literature for their excellent bioactivity.
Reactive oxygen species (ROS) contributes to DNA damage which is regarded to be the reason for disturbing
healthy status and arising diseases24. The regulation of the in vivo oxidative stress might be effective
therapeutic strategy for cancer and other diseases. Thus, discovering antioxidants from synthetic and natural
compounds facilitated the treatment for ROS caused diseases, such as Alzheimer, pulmonary fibrosis and
cancer etc.17 Inspired by the excellent antioxidant activity of lignin and imidazo[1,2-a]pyridine derivatives, it
would thus be considering beneficial to synthesize lignin inspired imidazo[1,2-a]pyridine derivatives (Scheme
1) and evaluate their antioxidant activity.
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Scheme 1. Synthesis of lignin inspired imidazo[1,2-a]pyridine derivatives
Result and Discussion
Chemistry
As shown in Scheme 1, the aromatic aldehydes from lignin were prepared by nitrobenzene oxidation
according to the reported method to provide vanillin, syringaldehyde and p-hydroxybenzaldehyde as the
major compounds with total yield 10-17%.6 In addition, a highly efficient synthesis protocol of imidazo[1,2-
a]pyridines has been reported using Groebke three-component-reaction (3CR) among 2-aminopyridine,
aldehyde and cyclohexyl isocyanide with good yields.17,26 For fast construction of lignin related imidazo[1,2-
a]pyridines for drug screening, the three-component-reaction was selected synthesis method. However,
hydroxy group might leaded to by-products, and hence, the reaction of 2-aminopyridine, cyclopentylisonitrile,
and syringaldehyde was selected as a test reaction to optimize the reaction conditions (catalyst, solvent and
reaction time) (Table 1).
Table 1. Variation of reaction conditions for synthesis of 4-(3-(cyclopentylamino)imidazo[1,2-a]pyridin-2-yl)-
2,6-dimethoxyphenol
Entry
Catalyst
Solvent
Water
Water
Water
Water
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
-
-
-
-
1
2
5
64
77
79
78
88
81
88
82
overnight
NH4Cl
NH4Cl
NH4Cl
NH4Cl
Water
2
2
2
2
Toluene
Methanol
1,4-Dioxane
aIsolated yield
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We tried to synthesize the imidazo[1,2-a]pyridines in water using stainless steel autoclave with a Teflon-
coated at 75°C in different time. We found that the yield was improved as the increase of reaction time, but
increased a little after 2 h; there was better yield and needed less time than that of reflux or room
temperature in this approach. In order to further optimization of the reaction conditions, NH4Cl was selected
as a catalyst because it is inexpensive and easy to be removed, and various solvents were also changed in
presence of NH4Cl. It was found that the yield increased by 11% in water in presence of NH4Cl within 2 h, and
the reactions in water or methanol were better than that in toluene and 1,4-dioxane. So the reaction was
conducted in water or methanol with NH4Cl as a catalyst within 2 h.
As indicated in Table 2, the three-component reaction was performed under water or methanol with NH4Cl
as a catalyst at 75°C in 2 h using stainless steel autoclave with a Teflon-coated in high yields (85-94%) in
accordance with optimized reaction conditions. The structures of all synthesized products were identified by
IR, 1H NMR, 13C NMR, MS and EA.
Table 2 Synthesis of imidazo[1,2-a]pyridine derivatives a-s
Entry
1
2
3
4
5
6
7
8
Product
R1
H
H
H
H
H
H
H
H
H
H
H
H
Br
Br
R2
H
H
R3
R4
OMe
H
H
OMe
H
H
OMe
H
H
OMe
H
R5
OMe
OMe
H
OMe
OMe
H
OMe
OMe
H
OMe
OMe
H
OMe
OMe
Yield (%)*
88
a
b
c
d
e
f
g
h
i
j
k
l
m
n
Cyclopentyl
Cyclopentyl
Cyclopentyl
Cyclopentyl
Cyclopentyl
Cyclopentyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclopentyl
Cyclohexyl
84
89
87
86
94
87
83
91
87
91
84
88
H
Me
Me
Me
H
H
H
Me
Me
Me
Me
Me
9
10
11
12
13
14
H
OMe
H
86
aIsolated yield
Antioxidant activity studies
Scavenging of N,N-diphenyl-N′-picrylhydrazyl (DPPH) free radical is the basis of a common antioxidant assay.
So the antioxidant activity of the synthesized compounds was evaluated by DPPH assay. In our previous
research, the synthesis and antioxidant activity of several lignin-related heterocyclic compounds (bis(1H-
pyrazole-5-ol)s, 1,4-dihydropyridines, polyhydroacridines, hexahydroquinolines and dihydro-pyrano[2,3-
c]pyrazoles) had been reported.6,27-29 The results showed that antioxidant activity of the compounds with
syringyl (4-hydroxy-3,5-dimethoxyphenyl) moiety is greater than that of the compounds with guaiacyl (4-
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hydroxy-3-methoxyphenyl) moiety and much greater than that of the compounds with p-hydroxyphenyl
moiety, i. e., the presence of methoxy group in aromatic heterocycles increase their antioxidant properties.
The reason is that oxygen atom of ortho-OCH3 on hydroxyphenyl group have lone pair of electrons which can
form big p,π-conjugation system with benzene ring and phenol hydroxyl radical, and p,π-conjugation can
stabilize the phenol hydroxyl radical to promote free radical reaction. So the hydroxyphenyl moiety of
aromatic heterocycles contains more ortho-OCH3, their antioxidant activity will be much better. Based on
above rule, syringyl imidazo[1,2-a] pyridine a, guaiacyl imidazo[1,2-a] pyridine b and p-hydroxyphenyl
imidazo[1,2-a] pyridine c were hence chosen to be first evaluated.
As shown in Figure 1, the percentage inhibition of a was found to be best and that of b was found be good
to moderate, while that of c was found to be relatively poor as compared to the standard Trolox. Especially,
antioxidant activity of compound c containing two methoxy groups was almost equal to that of the standard
Trolox. Evidently, the antioxidant activity of these compounds also follows the rule: Syringyl imidazo[1,2-a]
pyridine > guaiacyl imidazo[1,2-a] pyridine > p-hydroxyphenyl imidazo[1,2-a] pyridine. In term of the result,
the compounds d, g, j and m was next screened for their antioxidant activity. Comparing compounds a, g with
d, j, introduction of methyl moiety increased their antioxidant property lightly. Meanwhile, the influence of
cyclopentyl and cyclohexyl group almost made no difference on their antioxidant activity, for example, a and g
had almost the same antioxidant activity, so d and j did. In addition, the presence of bromo group in aromatic
heterocycles decreased the antioxidant performance because of electron-withdrawing effect. Above all,
syringyl imidazo[1,2-a] pyridines a, d, g, j and m exhibited excellent antioxidant activity. The strong antioxidant
abilities of these compounds indicated their potential usefulness in the drug development, thus providing an
effective way for value-added application of lignin.
100
80
60
40
20
0
a
b
c
d
g
j
m
Trolox
DPPH assay
Figure 1. Radical scavenging activity in DPPH assay. Results were expressed as Percentage Inhibition
Conclusions
A convenient and efficient protocol was designed for synthesis of lignin related imidazo[1,2-a]pyridine
derivatives under water or methanol with NH4Cl as a catalyst at 75°C in 2 h using stainless steel autoclave with
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a Teflon-coated. All compounds had good yields (≥83%). The antioxidant activity was evaluated by DPPH
radical scavenging capability. The results indicated that antioxidant property of syringyl imidazo[1,2-a]pyridine
was the best; that of guaiacyl imidazo[1,2-a]pyridines was good to moderate; and that of p-hydroxyphenyl
imidazo[1,2-a]pyridine was relatively poor as compared to the standard Trolox. In addition, SAR studies
showed that the introduction of electron-donating group in imidazo[1,2-a]pyridine could increase the radical
scavenging activity. On the contrary, the presence of electron-withdrawing might decrease the radical
scavenging activity. In addition, the effect of cyclopentyl and cyclohexyl moieties almost made no difference
on the antioxidant activity.
Experimental Section
Materials and methods
Cyclohexylisonitrile, cyclopentylisonitrile,25 syringaldehyde, vanillin and p-Hydroxybenzaldehyde were
synthesized according to the reported method.6 2,2-Diphenyl-1-picrylhydrazyl (DPPH) was bought from Alfa
Aesar. 2-Aminopyridine, methanol, ammonium chloride and the other reagents were obtained from
Sinopharm Chemical Reagent Co, Ltd. All synthesized compounds were characterized by IR, 1H NMR, 13C NMR,
MS and EA. IR spectra were recorded with a Nicolet Magna-IR 550 spectrometer. Mass spectra were recorded
on an Agilent 1100 HPLC/MS coupled with a TSQ Quantum Ultra AM mass spectrometer using electrospray
ionization (ESI). 1H and 13C NMR spectra were recorded with a BRUKER DRX-300 AVANCE spectrometer at 300
MHz and 75 MHz, respectively. Elemental analyses (C, H, N, S) were conducted using PE-2400(II) Elemental
Analyser, their results were found to be in good agreement (±0.2%) with the calculated values. The UV
absorbance was measured by Perkin Elmer Lambda 2 Spectrophotometer.
Typical procedure for synthesis of lignin related imidazo[1,2-a]pyridines
To a solution of 0.052 g ammonium chloride (1 mmol) in 4 mL water or methanol was added isocyanide (1.2
mmol), aromatic aldehyde (1.1 mmol), and 2-aminopyridine (1 mmol) and sealed in stainless steel autoclave
with a Teflon-coated, and then the autoclave was put in the oven at 75oC in 2 h. The autoclave was taken out
and cooled to room temperature. The reaction mixture was put into 30 mL cooled water to afford the product
as a precipitate. The solid residue was filtered and crystallized from ethyl acetate to give products.
4-(3-(cyclopentylamino)imidazo[1,2-a]pyridin-2-yl)-2,6-dimethoxyphenol. (a, C20H24N3O3) (0.30 g, 88%). IR
1
(KBr) v/cm-1: 3275, 3092, 2948, 2927, 2866, 2828, 1584, 1502, 1116, 740; H NMR (300 MHz, CDCl3) δ/ppm:
8.10 (d, 1H, J=6.6 Hz), 7.54 (d, 1H, J=9.0 Hz), 7.38 (s, 2H), 7.15 (t, 1H, J=7.8 Hz), 6.80 (t, 1H, J=6.6 Hz), 3.96 (s,
6H), 3.65-3.72 (m, 1H), 1.40-1.87 (m, 8H); 13C NMR (75.5 MHz, CDCl3) δ/ppm: 147.1, 141.3, 137.2, 134.5, 124.7,
124.2, 122.4, 117.1, 111.8, 104.3, 59.1, 56.4, 33.6, 23.7; LC-ESI-MS m/z: 354.2 [M+H]+; Anal. Calcd for
C20H23N3O3: C, 67.97; H, 6.56; N, 11.89; found: C, 67.90; H, 6.65; N, 11.94.
4-(3-(cyclopentylamino)imidazo[1,2-a]pyridin-2-yl)-2-methoxyphenol. (b, C19H21N3O2) 0.27 g (84%). IR (KBr)
1
v/cm-1: 3237, 2948, 2868, 1610, 1504, 1244, 1168, 1030, 830, 753; H NMR (300 MHz, CDCl3) δ/ppm: 8.13 (d,
1H, J=6.9 Hz), 7.69 (s, 1H), 7.50-7.59 (m, 2H), 7.15 (t, 1H, J=8.7 Hz), 6.98 (d, 1H, J=8.7 Hz), 6.81 (t, 1H, J=6.9 Hz),
3.96 (s, 3H), 3.62-3.71 (m, 1H), 1.40-1.85 (m, 8H); 13C NMR (75.5 MHz, CDCl3) δ/ppm: 146.9, 145.4, 141.3,
138.1, 124.8, 122.5, 120.1, 117.0, 114.3, 111.8, 110.3, 59.2, 56.2, 33.5, 23.7; LC-ESI-MS m/z: 324.2 [M+H]+;
Anal. Calcd for C19H21N3O2: C, 70.57; H, 6.55; N, 12.99; found: C, 70.50; H, 6.65; N, 12.92.
4-(3-(cyclopentylamino)imidazo[1,2-a]pyridin-2-yl)phenol. (c, C18H19N3O) 0.26 g (89%). IR (KBr) v/cm-1: 3325,
1
2956, 2920, 2845, 1610, 1505, 1271, 1230, 836, 755; H NMR (300 MHz, CDCl3) δ/ppm: 8.15 (d, 1H, J=6.9 Hz),
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7.75 (d, 2H, J=8.7 Hz), 7.60 (d, 1H, J=9.0 Hz), 7.17 (t, 1H, J=9.0 Hz), 6.80-6.90 (m, 3H), 3.58-3.66 (m, 1H), 1.35-
1.80 (m, 8H); 13C NMR (75.5 MHz, CDCl3) δ/ppm: 157.4, 144.7, 140.7, 139.2, 135.9, 128.8, 124.9, 122.7, 116.0,
113.3, 110.0, 59.1, 33.4, 23.6; LC-ESI-MS m/z: 294.1 [M+H]+; Anal. Calcd for C18H19N3O: C, 73.69; H, 6.53; N,
14.32; found: C, 73.61; H, 6.58; N, 14.34.
4-(3-(cyclopentylamino)-5-methylimidazo[1,2-a]pyridin-2-yl)-2,6-dimethoxyphenol. (d, C21H25N3O3) 0.32 g
1
(87%). IR (KBr) v/cm-1: 3303, 2954, 2920, 2856, 1591, 1508, 1113, 855, 775; H NMR (300 MHz, CDCl3) δ/ppm:
7.47 (d, 1H, J=9.3 Hz), 7.28 (s, 2H), 7.06 (t, 1H, J=8.1 Hz), 6.49 (d, 1H, J=6.6 Hz), 3.98 (s, 6H), 3.40-3.58 (m, 1H),
2.96 (s, 3H), 1.32-1.68 (m, 8H); 13C NMR (75.5 MHz, CDCl3) δ/ppm: 147.1, 143.1, 138.3, 133.2, 127.0, 126.4,
124.2, 115.7, 113.2, 105.6, 61.4, 56.5, 32.8, 23.8, 20.0; LC-ESI-MS m/z: 368.2 [M+H]+; Anal. Calcd for
C21H25N3O3: C, 68.64; H, 6.86; N, 11.44; found: C, 68.71; H, 6.82; N, 11.49.
4-(3-(cyclopentylamino)-5-methylimidazo[1,2-a]pyridin-2-yl)-2-methoxyphenol. (e, C20H23N3O2) 0.29 g (86%).
IR (KBr) v/cm-1: 3237, 2945, 2923, 2863, 1615, 1510, 1032, 826, 764; 1H NMR (300 MHz, CDCl3) δ/ppm: 7.67 (s,
1H), 7.53 (d, 1H, J=8.4 Hz), 7.29 (d, 1H, J=9.0 Hz), 7.03 (t, 1H, J=8.4 Hz), 6.82 (d, 1H, J=8.4 Hz), 6.53 (d, 1H, J=8.1
Hz), 3.83 (s, 3H), 3.38-3.49 (m, 1H), 2.93 (s, 3H), 1.30-1.58 (m, 8H); 13C NMR (75.5 MHz, CDCl3) δ/ppm: 147.2,
145.8, 141.9, 138.3, 136.3, 126.6, 126.3, 123.8, 120.3, 115.1, 114.8, 112.8, 111.5, 59.9, 55.6, 32.1, 23.5, 19.3;
LC-ESI-MS m/z: 338.1 [M+H]+; Anal. Calcd for C20H23N3O2: C, 71.19; H, 6.87; N, 12.45; found: C, 71.11; H, 6.92;
N, 12.40.
4-(3-(cyclopentylamino)-5-methylimidazo[1,2-a]pyridin-2-yl)phenol. (f, C19H21N3O) 0.29 g (94%). IR (KBr)
1
v/cm-1: 3219, 2951, 2904, 2862, 1613, 1504, 1260, 1227, 1177, 841, 775; H NMR (300 MHz, CDCl3) δ/ppm:
7.60 (d, 2H, J=8.4 Hz), 7.48 (d, 1H, J=8.7 Hz), 7.05 (dd, 1H, J=6.9, 8.7 Hz), 6.73 (d, 2H, J=8.4 Hz), 6.48 (d, 1H,
J=6.9 Hz), 3.22-3.62 (m, 1H), 2.96 (s, 3H), 1.25-1.57 (m, 8H); 13C NMR (75.5 MHz, CDCl3) δ/ppm: 156.9, 142.6,
138.3, 136.6, 134.2, 129.4, 127.3, 124.8, 115.9, 114.9, 113.9, 61.4, 32.7, 23.7, 20.1; LC-ESI-MS m/z: 308.2
[M+H]+; Anal. Calcd for C19H21N3O: C, 74.24; H, 6.89; N, 13.67; found: C, 74.31; H, 6.82; N, 13.74.
4-(3-(cyclohexylamino)imidazo[1,2-a]pyridin-2-yl)-2,6-dimethoxyphenol. (g, C21H25N3O3) 0.32 g (87%). IR
1
(KBr) v/cm-1: 3325, 2925, 2848, 1608, 1520, 1217, 1109, 760; H NMR (300 MHz, CDCl3) δ/ppm: 8.29 (d, 1H,
J=6.6 Hz), 8.08 (d, 1H, J=6.6 Hz), 7.23 (t, 1H, J=6.6 Hz), 6.96 (d, 1H, J=6.6 Hz), 6.64 (s, 2H), 5.47 (s, 1H), 3.80 (s,
6H), 2.86-2.98 (m, 1H), 1.15-1.42 (m, 10H); 13C NMR (75.5 MHz, CDCl3) δ/ppm: 146.5, 141.1, 135.4, 134.6,
126.5, 125.4, 122.6, 121.6, 117.2, 113.6, 106.4, 56.8, 56.6, 34.1, 25.5, 24.6; LC-ESI-MS m/z: 368.3 [M+H]+; Anal.
Calcd for C21H25N3O3: C, 68.64; H, 6.86; N, 11.44; found: C, 68.71; H, 6.80; N, 11.48.
4-(3-(cyclohexylamino)imidazo[1,2-a]pyridin-2-yl)-2-methoxyphenol. (h, C20H23N3O2) 0.28 g (83%). IR (KBr)
1
v/cm-1: 3358, 2927, 2850, 1600, 1501, 1408, 1279, 1030, 753, 740; H NMR (300 MHz, MeOD) δ/ppm: 8.31 (d,
1H, J=6.9 Hz), 7.71 (s, 1H), 7.54 (d, 1H, J=6.9 Hz), 7.45 (t, 1H, J=6.9 Hz), 7.25 (t, 1H, J=6.9 Hz), 6.87-6.94 (m, 2H),
3.80 (s, 3H), 2.93-3.00 (m, 1H), 1.10-1.50 (m, 10H); 13C NMR (75.5 MHz, MeOD) δ/ppm: 149.0, 147.4, 142.6,
137.4, 127.2, 126.1, 125.8, 124.3, 121.5, 116.8, 116.2, 113.0, 112.2, 57.7, 56.5, 35.1, 27.0, 25.9; LC-ESI-MS m/z:
338.2 [M+H]+; Anal. Calcd for C20H23N3O2: C, 71.19; H, 6.87; N, 12.45; found: C, 71.10; H, 6.81; N, 12.53.
4-(3-(cyclohexylamino)imidazo[1,2-a]pyridin-2-yl)phenol. (i, C19H21N3O) 0.28 g (91%). IR (KBr) v/cm-1: 3295,
1
2925, 2853, 1608, 1510, 1222, 1166, 837, 734; H NMR (300 MHz, DMSO-6d) δ/ppm: 8.41 (d, 1H, J=6.3 Hz),
7.74 (t, 1H, J=6.3 Hz), 7.52 (t, 2H, J=7.5 Hz), 7.01 (t, 1H, J=6.3 Hz), 6.90 (d, 1H, J=6.3 Hz), 6.75 (d, 2H, J=7.5 Hz),
3.65-3.78 (m, 1H), 1.11-1.70 (m, 10H); 13C NMR (75.5 MHz, DMSO-6d) δ/ppm: 158.8, 157.0, 148.2, 139.0,
131.8, 131.5, 128.7, 116.6, 110.8, 56.7, 33.3, 26.5, 26.1; LC-ESI-MS m/z: 352.1 [M-H+2Na]+; Anal. Calcd for
C19H21N3O: C, 74.24; H, 6.89; N, 13.67; found: C, 74.31; H, 6.82; N, 13.61.
4-(3-(cyclohexylamino)-5-methylimidazo[1,2-a]pyridin-2-yl)-2,6-dimethoxyphenol. (j, C22H27N3O3) 0.33 g
1
(87%). IR (KBr) v/cm-1: 3323, 2950, 2923, 2851, 1593, 1513, 1113, 772; H NMR (300 MHz, CDCl3) δ/ppm: 7.42
(d, 1H, J=9.0 Hz), 7.31 (s, 2H), 7.01 (dd, 1H, J=6.9, 9.0 Hz), 6.43 (d, 1H, J=6.9 Hz), 3.98 (s, 6H), 2.94 (s, 3H), 2.75-
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2.85 (m, 1H), 1.10-1.75 (m, 10H); 13C NMR (75.5 MHz, CDCl3) δ/ppm: 146.0, 141.3, 139.2, 138.7, 133.5, 132.1,
126.6, 123.7, 114.5, 111.6, 103.9, 55.5, 55.2, 32.3, 24.4, 23.8, 19.2; LC-ESI-MS m/z: 382.2 [M+H]+; Anal. Calcd
for C22H27N3O3: C, 69.27; H, 7.13; N, 11.02; found: C, 69.20; H, 7.19; N, 11.08.
4-(3-(cyclohexylamino)-5-methylimidazo[1,2-a]pyridin-2-yl)-2-methoxyphenol. (k, C21H25N3O2) 0.32 g (91%).
1
IR (KBr) v/cm-1: 3316, 2930, 2854, 1560, 1510, 1415, 1228, 1034, 821, 779; H NMR (300 MHz, CDCl3) δ/ppm:
7.62 (s, 1H), 7.42 (d, 1H, J=6.3 Hz), 6.90-7.10 (m, 3H), 6.47 (d, 1H, J=6.3 Hz), 3.95 (s, 3H), 2.95 (s, 3H), 2.70-2.83
(m, 1H), 1.05-1.67 (m, 10H); 13C NMR (75.5 MHz, CDCl3) δ/ppm: 146.7, 145.2, 139.1, 136.3, 129.6, 125.9,
124.2, 120.7, 115.5, 114.2, 113.5, 110.7, 58.6, 56.1, 33.3, 25.8, 24.9, 20.2; LC-ESI-MS m/z: 352.1 [M+H]+; Anal.
Calcd for C21H25N3O2: C, 71.77; H, 7.17; N, 11.96; found: C, 71.85; H, 7.11; N, 11.92.
4-(3-(cyclohexylamino)-5-methylimidazo[1,2-a]pyridin-2-yl)phenol. (l, C20H23N3O) 0.27 g (84%). IR (KBr) v/cm-
1
1: 3270, 2827, 2854, 1652, 1596, 1511, 1452, 1230, 1165, 841, 778; H NMR (300 MHz, CDCl3) δ/ppm: 7.60 (d,
2H, J=8.7 Hz), 7.46 (d, 1H, J=9.0 Hz), 7.03 (dd, 1H, J=6.9, 9.0 Hz), 6.82 (d, 1H, J=8.7 Hz), 6.46 (d, 2H, J=6.9 Hz),
2.95 (s, 3H), 2.68-2.81 (m, 1H), 1.12-1.52 (m, 10H); 13C NMR (75.5 MHz, CDCl3) δ/ppm: 157.6, 141.6, 136.7,
135.5, 132.4, 129.3, 128.7, 125.9, 116.2, 114.6, 111.4, 58.2, 32.9, 25.8, 24.9, 20.1; LC-ESI-MS m/z: 322.2
[M+H]+; Anal. Calcd for C20H23N3O: C, 74.74; H, 7.21; N, 13.07; found: C, 74.81; H, 7.27; N, 13.02.
4-(6-bromo-3-(cyclopentylamino)-5-methylimidazo[1,2-a]pyridin-2-yl)-2,6-dimethoxyphenol. (m, C21H24BrN3O3)
1
0.39 g (88%). IR (KBr) v/cm-1: 3295, 2951, 2920, 2851, 1594, 1510, 1418, 1224, 1116, 855, 789; H NMR (300
MHz, CDCl3) δ/ppm: 7.17-7.31 (m, 4H), 3.95 (s, 6H), 3.46-3.51 (m, 1H), 2.96 (s, 3H), 1.10-1.64 (m, 8H); 13C NMR
(75.5 MHz, CDCl3) δ/ppm: 163.8, 147.2, 141.7, 139.6, 134.8, 128.6, 128.4, 125.7, 115.9, 110.0, 105.0, 61.2,
56.5, 32.7, 23.7, 18.2; LC-ESI-MS m/z: 446.1 [M+H]+; Anal. Calcd for C21H24BrN3O3: C, 56.51; H, 5.42; N, 9.41;
found: C, 56.60; H, 5.34; N, 9.45.
4-(6-bromo-3-(cyclohexylamino)-5-methylimidazo[1,2-a]pyridin-2-yl)-2-methoxyphenol. (n, C21H24BrN3O2)
1
0.37 g (86%). IR (KBr) v/cm-1: 3293, 2951, 2920, 2848, 1593, 1500, 1402, 1124, 1032, 816, 785; H NMR (300
MHz, CDCl3) δ/ppm: 7.54 (s, 1H), 7.32-7.36 (m, 2H), 6.80-6.92 (m, 2H), 3.98 (s, 3H), 3.17-3.22 (m, 1H), 3.16 (s,
3H), 1.00-1.70 (m, 10H); 13C NMR (75.5 MHz, CDCl3) δ/ppm: 162.2, 147.6, 145.8, 142.3, 140.9, 138.4, 130.1,
126.0, 126.2, 116.4, 114.5, 111.5, 110.1, 58.4, 56.2, 35.5, 25.0, 24.8, 18.6; LC-ESI-MS m/z: 430.2 [M+H]+; Anal.
Calcd for C21H24BrN3O2: C, 58.61; H, 5.62; N, 9.76; found: C, 58.70; H, 5.68; N, 9.71.
Antioxidant evaluation
The free radical scavenging activity were evaluated by the 2,2′-diphenyl-1-picrylhydrazyl (DPPH) radical
scavenging method, which is based on the measurement of the scavenging ability towards the stable 2,2-
diphenyl-1-picrylhydrazyl (DPPH) radical. The assay was conducted according to the reported method.6 Briefly,
an ethanol solution (200 μL) of 100 μM diphenyl-picryl hydrazide was incubated at 30 °C with 1 μL of
compound solution in deionized H2O. The final concentration of compounds was 100 μM. A decrease in
absorbance was measured at 517 nm. The absorbance was measured at t = 0 min (A0) and after 10 min
incubation at room temperature (A10). The radical scavenging activity was expressed as Percentage Inhibition
of DPPH free radical (I%) and calculated according to the Eq. (1). All experiments were carried out in triplicate.
The 6-hydroxyl-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) was used as antioxidant reference.
(1)
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Acknowledgements
The authors are grateful for Fundamental Research Funds of Research Institute of Forestry New Technology,
Grant. No. CAFYBB2016SY027 and Fundamental Research Funds from Jiangsu Province Biomass and Materials
Laboratory, Grant. No. JSBEM-S-201803.
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