CC BY-NC-ND 4.0 · SynOpen 2020; 04(02): 17-22
DOI: 10.1055/s-0040-1707517
paper
This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) (2020) The Author(s)

Aerobic Iron(III)-Catalyzed Direct Thiolation of Imidazo[1,2-a]pyridine with Thiols

Ling Qin
a  Department of Pharmaceutics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, P. R. of China
,
Hui-bin Wu
a  Department of Pharmaceutics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, P. R. of China
,
Lidong Weng
b  School of Traditional Chinese Medicine, Southern Medical University, Shatainan road 1023th, Guangzhou 510515, P. R. of China   Email: sq@smu.edu.cn   Email: chenhuoji@smu.edu.cn
,
Qun Shen
b  School of Traditional Chinese Medicine, Southern Medical University, Shatainan road 1023th, Guangzhou 510515, P. R. of China   Email: sq@smu.edu.cn   Email: chenhuoji@smu.edu.cn
,
Huoji Chen
b  School of Traditional Chinese Medicine, Southern Medical University, Shatainan road 1023th, Guangzhou 510515, P. R. of China   Email: sq@smu.edu.cn   Email: chenhuoji@smu.edu.cn
› Author Affiliations
Funding was provided by the Natural Science Foundation of Guangdong Province (2017A030310021), the Science and Technology Program of Guangdong Province (2017A050506027, 2017B090912005) and the Science and Technology Program of Guangzhou (201807010053).
Further Information

Publication History

Received: 10 March 2020

Accepted after revision: 31 March 2020

Publication Date:
21 April 2020 (online)

 


§ These authors contributed equally to this work.

Abstract

A novel and efficient iron(III)-catalyzed regioselective C-3 sulfenylation of imidazo[1,2-a]pyridines with thiols under oxygen atmosphere has been developed. The reaction proceeds in moderate to good yields with a broad range of substrates, providing a novel, efficient and green route for accessing synthetically useful C3-sulfenated imidazo-[1,2-a]pyridines. Moreover, the fluoride-containing C3-sulfenated imidazo-[1,2-a]pyridine 3ai exhibited superior anticancer activity and good safety profiles.


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The imidazo[1,2-a]pyridine ring system is a significant azaheterocycle[1] [2] that exists in a large number of pharmaceutical and natural products[3–6] showing a range of biological properties, such as antiviral,[7] antiherpes,[8] antiulcer[9] and antiapoptotic activities.[10] Moreover, these compounds also represent a pivotal structural scaffold in functional materials such as fluorescent dyes.[11] Thus, substituted imidazo[1,2-a]pyridines have attracted the continuous interest of organic chemists[12] [13] [14] [15] and great efforts have been devoted the development of synthetic methodologies to access this class of compound.[16] [17]

The presence of a C–S bond on an azaaromatic nucleus can contribute prominent biological activities.[18] Many elegant formylation processes have been developed for the sulfenylation at C3 of imidazo[1,2-a]pyridines.[19] [20] [21] [22] [23] [24] [25] [26] [27] [28] How­ever, there is no report on iron-catalyzed sulfenylation of imidazo[1,2-a]pyridine derivatives with thiols.

Iron is inexpensive, environmentally friendly, low in toxicity, easy to use, and stable in performance. Therefore, iron-catalyzed organic conversions have recently attracted great interest from the synthetic community.[29] [30] As a part of our ongoing studies focusing on iron-catalyzed cross-coupling reactions,[31,32] herein, we wish to report a novel and mild protocol for the C-3 sulfenylation of imidazo-[1,2-a]pyridines using thiols in the presence of iron(III) catalyst under ambient conditions.

We began our study by investigating the thiolation of imidazo[1,2-a]pyridine with thiols (Table [1]). Optimization of the reaction conditions showed that the solvent played a crucial role in reaction efficiency, with DMF being optimal for the C-3 thiolation of imidazo[1,2-a]pyridine under atmospheric pressure of dioxygen (entries 1–5). Furthermore, FeCl3 was superior to other Fe catalysts, such as FeCl2, FeBr3, FeBr2, or Fe(NO3)3 (entries 6–9). Addition of acetic acid greatly promoted the FeCl3-catalysed C-3 thiolation reaction of 1a (entries 10–17). Increasing the reaction temperature led to a higher reaction rate, but the yields and conversions were not improved, with starting material being recovered. Finally, in the absence of Fe catalyst or oxygen atmosphere, no desired product was obtained (entries 18 and 19). These studies led to the following conditions being taken as optimal: 1a (0.3 mmol), 2a (0.4 mmol), 5 mol% FeCl and 20 mol% CH3COOH in 2 mL of DMF at 80 °C for 12 h under atmosphere of oxygen.

Table 1 Optimization of Reaction Conditionsa

Entry

[Fe]

Additive

Solvent

Yield (%)b

1

FeCl3

35

2

FeCl3

dioxane

27

3

FeCl3

toluene

32

4

FeCl3

DCE

22

5

FeCl3

DMF

42

6

FeCl2

DMF

31

7

FeBr3

DMF

25

8

FeBr2

DMF

22

9

Fe(NO3)3

DMF

18

10

FeCl3

TsOH

DMF

47

11

FeCl3

HCl

DMF

54

12

FeCl3

CH3COOH

DMF

88

13

FeCl3

CF3COOH

DMF

73

14

FeCl3

CH3SO3H

DMF

71

15

FeCl3

CF3SO3H

DMF

66

16

FeCl3

C6H5OH

DMF

67

17

FeCl3

C6H5COOH

DMF

72

18

CH3COOH

DMF

n.d

19c

FeCl3

CH3COOH

DMF

n.d.

a Reaction conditions: unless otherwise noted, all reactions were performed with 1a (0.3 mmol), 2a (0.4 mmol), Fe catalyst (5 mol%), additive (20 mol%) and solvent (2 mL), at 80 °C under O2 (1 atm) for 12 h.

b Isolated yield.

c N2 atmosphere.

With the optimized conditions in hand, the substrate scope with respect to imidazo[1,2-a]pyridines was first examined; the results are summarized in Scheme [1]. A variety of imidazo[1,2-a]pyridines bearing electron-withdrawing or electron-donating groups afforded the desired products in good yields. Imidazo[1,2-a]pyridines bearing electron-donating methyl groups at the 5-, 6-, 7-, and 8-positions smoothly reacted with benzyl mercaptan (2a) to give the corresponding C3-sulfenated imidazo[1,2-a]pyridine 3aaia in good yields. Notably, halogen substituents were well tolerated and provided the corresponding fluoro-, chloro-, and bromo-products 3gaia in 82, 85, and 81% yields, respectively. Substrates with a range of substituents at C2 were also applicable to this reaction (3jala).

Zoom Image
Scheme 1 Substrate scope of the reaction with imidazo[1,2-a]pyridines

Next, the scope of the reaction with thiols was examined; the results are illustrated in Scheme [2]. The reaction of both aliphatic and aromatic thiols proceeded smoothly and the corresponding C-3 sulfenated products were obtained in 76–89% yields. Aliphatic secondary thiols, such as propane-2-thiol and cyclohexane thiol, reacted smoothly with imidazo[1,2-a]pyridine 1a to afford the corresponding C3-sulfenated products 3aeaf. Aromatic thiols bearing electron-withdrawing or electron-donating groups afforded the desired products 3agbaj in good yields. Notably, the reaction could afford C3-sulfenated products 3ji, 3ki, and 3li in good yields when carried out using 2-substitutied imidazo[1,2-a]pyridines as substrates with 4-fluorothiophenol.

Zoom Image
Scheme 2 Substrate scope of the reaction with thiols

Recently, we found that the fluorine-containing compounds could exhibit anticancer activity.[33] This result prompted us to screen fluorine-containing C-3 sulfenated imidazo[1,2-a]pyridines as antitumor agents against three human cancer cell lines (HeLa, A-549 and BGC-823) and a normal cell line (VEC) in vitro using MTT cell proliferation assays (Table [2]). The data reveal that fluorine-containing C-3 sulfenated imidazo[1,2-a]pyridine 3ai exhibited superior anticancer activity{HeLa cells (IC50 = 9.37 μM), A-549 cells (IC50 = 4.25 mM) and BGC-823 cells (IC50 = 5.22 μM)} and good safety profiles (IC50 >100 μM against VEC).

Table 2 The Inhibiting Effect of Fluorine-Containing C3-Sulfenated Imidazo[1,2-a]pyridines to HeLa, A-549 and BGC-823 Cell Lines In Vitro

Compd.

Normal cells IC50
(μmol·L–1)a

Cancer cells IC50 (μmol·L–1)a

VEC

HeLa

A-549

BGC-823

3ia

55.4

38.3

18.7

21.6

3ai

>100

9.37

4.25

5.22

3ki

92.2

15.2

9.32

8.62

3ji

91.8

18.7

12.8

13.0

3li

90.3

20.1

14.5

16.6

3aa

52.2

33.1

20.7

25.3

a IC50 values are the mean of three independent experiments run in triplicate.

To gain some insight into the reaction mechanism, a control experiment was then carried out, wherein the radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO­) was found to suppress the reaction (Scheme [3]), suggesting that this transformation is probably a radical process.

Zoom Image
Scheme 3 Control experiments

Based on the control experiment and on previous work,[28] [31] a plausible reaction mechanism is proposed in Scheme [4]. Initially, disulfide A is generated from sodium phenylsulfinate. Subsequently, the thio radical B is produced via direct radical cracking and then undergoes radical addition to imidazo[1,2-a]pyridine to form intermediate C. Finally, a single-electron oxidation followed by aromatization leads to the product 3 (Path A).[34] However, other reaction mechanism may also be possible. For example, disulfide A could react with imidazo[1,2-a]pyridine and FeIII to form the Fe–C bonded intermediate D.[30] Then, intermediate D could undergo reductive elimination to form intermediate E. Finally, deprotonation of intermediate E would lead to product 3 (Path B).

Zoom Image
Scheme 4 Possible reaction mechanism

In conclusion, we have developed a new iron(III)-catalyzed­ method for the regioselective C-3 sulfenylation of imidazo[1,2-a]pyridines with thiols under an oxygen atmosphere. The reaction proceeds in moderate to good yields with a broad range of substrates, providing a novel efficient and green route for accessing synthetically useful C3-sulfenated imidazo[1,2-a]pyridines. Moreover, the fluoride-containing C3-sulfenated imidazo[1,2-a]pyridine 3ai exhibited superior anticancer activity and good safety profiles. This topic is currently being further studied in our laboratory.

1H and 13C NMR spectra were recorded with a BRUKER DRX-400 spectrometer using CDCl3 as solvent and TMS as an internal standard. IR spectra were obtained either as potassium bromide discs or as liquid films between two potassium bromide pellets. GC-MS analyses were obtained using electron ionization. HRMS analyses were obtained with a LCMS-IT-TOF mass spectrometer. TLC analyses were performed using commercial 100–400 mesh silica gel plates, and visualization was effected at 254 nm.


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General Procedure

A mixture of imidazo[1,2-a]pyridine 1 (0.3 mmol), thiol 2 (0.4 mmol), CH3COOH (0.2 equiv, 0.06 mmol) and FeCl3 (5 mol %) in DMF (2 mL) was stirred at 80 °C under air for 24 h. The reaction mixture was diluted with H2O (15 mL), extracted with EtOAc (3 × 15 mL) and the combined organic extracts were dried over MgSO4. After filtration and evaporation of the solvents under reduced pressure, the crude product was purified by column chromatography on silica gel to afford desired product 3.


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3-(Benzylthio)imidazo[1,2-a]pyridine (3aa)[19e]

Yield: 88% (63 mg); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 8.05 (s, 1 H), 7.57–7.77 (m, 2 H), 7.17 (t, J = 5.2 Hz, 4 H), 6.96 (d, J = 6.0 Hz, 2 H), 6.69 (t, J = 6.4 Hz, 1 H), 3.79 (s, 2 H).

13C NMR (100 MHz, CDCl3): δ = 141.6, 137.7, 128.6, 128.5, 128.3, 127.3, 127.0, 125.3, 124.1, 117.7, 112.4, 41.5.


#

3-(Benzylthio)-5-methylimidazo[1,2-a]pyridine (3ba)[19e]

Yield: 89% (68 mg); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.57 (s, 1 H), 7.50 (d, J = 8.8 Hz, 1 H), 7.06–7.20 (m, 4 H), 6.93 (m, 2 H), 6.46 (d, J = 6.8 Hz, 1 H), 3.83 (s, 2 H), 2.83 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 144.4, 138.2, 136.9, 129.4, 128.7, 128.6, 128.5, 127.3, 125.8, 116.2, 114.3, 45.7, 21.0.


#

3-(Benzylthio)-6-methylimidazo[1,2-a]pyridine (3ca)[19e]

Yield: 89% (66 mg); white solid; mp 155–156 °C.

1H NMR (400 MHz, CDCl3): δ = 7.70 (s, 1 H), 7.60 (s, 1 H), 7.48 (d, J = 9.2 Hz, 1 H), 7.10–7.19 (m, 3 H), 6.97–7.03 (m, 3 H), 3.79 (s, 2 H), 2.20 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 141.4, 138.0, 128.7, 128.5, 128.4, 127.3, 122.0, 121.8, 117.0, 41.8, 18.1.


#

3-(Benzylthio)-7-methylimidazo[1,2-a]pyridine (3da)[19e]

Yield: 85% (65 mg); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 6.4 Hz, 1 H), 7.58 (s, 1 H), 7.35 (s, 1 H), 7.14–7.16 (m, 3 H), 6.98 (d, J = 5.2 Hz, 2 H), 6.54 (d, J = 6.8 Hz, 1 H), 3.78 (s, 2 H), 2.36 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 141.3, 137.8, 136.7, 128.6, 128.5, 127.3, 123.2, 116.2, 115.1, 41.6, 21.2.


#

3-(Benzylthio)-8-methylimidazo[1,2-a]pyridine (3ea)[19e]

Yield: 82% (63 mg); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 6.8 Hz, 1 H), 7.63 (s, 1 H), 7.15–7.27 (m, 3 H), 6.99–7.01 (d, 3 H), 6.65 (t, J = 6.8 Hz, 1 H), 3.80 (s, 2 H), 2.60 (s, 3 H).

13C NMR (101 MHz, CDCl3): δ = 147.6, 140.6, 137.7, 128.6, 128.5, 127.4, 127.3, 124.5, 121.8, 113.7, 112.5, 41.5, 16.6.


#

3-(Benzylthio)-6-iodoimidazo[1,2-a]pyridine(3fa)[19e]

Yield: 82% (88 mg); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 8.00 (s, 1 H), 7.60 (s, 1 H), 7.28–7.33 (m, 2 H), 7.10–7.19 (m, 3 H), 6.91–6.93 (m, 2 H), 3.78 (s, 2 H).

13C NMR (100 MHz, CDCl3): δ = 145.9, 141.7, 137.6, 133.3, 129.2, 128.6, 128.5, 127.8, 118.5, 113.6, 75.8, 42.1.


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3-(Benzylthio)-6-bromoimidazo[1,2-a]pyridine(3ga)[19e]

Yield: 81% (77 mg); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.94 (s, 1 H), 7.66 (s, 1 H), 7.43 (d, J = 9.2 Hz, 1 H), 7.10–7.19 (m, 4 H), 6.92–6.94 (m, 2 H), 3.78 (s, 2 H).

13C NMR (100 MHz, CDCl3): δ = 142.2, 137.6, 128.8, 128.6, 128.5, 127.7, 124.4, 118.2, 107.4, 41.9.


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3-(Benzylthio)-6-chloroimidazo[1,2-a]pyridine(3ha)[19e]

Yield: 85% (70 mg); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.89 (s, 1 H), 7.71 (s, 1 H), 7.51 (d, J = 9.2 Hz, 1 H), 7.13–7.19 (m, 4 H), 6.95 (d, J = 6.8 Hz, 2 H), 3.80 (s, 2 H).

13C NMR (100 MHz, CDCl3): δ = 142.3, 137.6, 128.6, 127.6, 126.8, 122.2, 121.0, 118.0, 41.9.


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3-(Benzylthio)-6-fluoro imidazo[1,2-a]pyridine (3ia)

Yield: 82% (63 mg); yellow oil.

IR (KBr): 2968, 2854, 1542, 1459, 1367, 737 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.40 (m, 1 H), 7.79 (m, 1 H), 7.68 (s, 1 H), 7.17–7.15 (m, 3 H), 6.98 (d, J = 5.2 Hz, 2 H), 6.54 (m, 1 H), 3.78 (s, 2 H).

13C NMR (100 MHz, CDCl3): δ = 153.8 (J = 232.0 Hz), 142.2, 128.5, 118.6 (J = 9.0 Hz), 118.5, 117.3 (J = 25.0 Hz),117.0, 111.4 (J = 31.0 Hz), 114.0, 41.9.

HRMS (EI): m/z calcd for C14H11FN2S: 258.0629; found: 258.0627.


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3-(Benzylthio)-2-methylimidazo[1,2-a]pyridine (3ja)[19e]

Yield: 90% (69 mg); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 6.5 Hz, 1 H), 7.53 (d, J = 8.9 Hz, 1 H), 7.13–7.22 (m, 4 H), 6.92 (d, J = 6.8 Hz, 2 H), 6.73 (t, J = 6.8 Hz, 1 H), 3.75 (s, 2 H), 2.26 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 150.9, 143.4, 137.7, 132.2, 128.7, 128.5, 127.2, 125.6, 124.0, 116.6, 112.1, 40.1, 13.5.


#

3-(Benzylthio)-2-(tert-butyl)imidazo[1,2-a]pyridine (3ka)[19e]

Yield: 75% (67 mg); white solid; mp 89–90 °C.

1H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 6.8 Hz, 1 H), 7.55 (d, J = 8.8 Hz, 1 H), 7.00–7.13 (m, 5 H), 6.58 (t, J = 6.6 Hz, 1 H), 3.79 (s, 2 H), 1.54 (s, 9 H).

13C NMR (100 MHz, CDCl3): δ = 161.0, 145.1, 137.3, 128.7, 128.6, 127.3, 125.1, 123.5, 116.9, 111.8, 108.1, 41.1, 34.0, 30.7.


#

3-(Benzylthio)-2-phenylimidazo[1,2-a]pyridine (3la)

Yield: 75% (79 mg); white solid; mp 96–98 °C.

IR (KBr): 2975, 2884, 1466, 1394, 1373, 1367, 741 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.43 (d, J = 6.8 Hz, 1 H), 7.78 (d, J = 8.8 Hz, 1 H), 7.61 (s, 1 H), 7.31–7.59 (m, 5 H), 7.13–7.23 (m, 5 H), 6.88 (t, J = 7.0 Hz, 1 H), 3.91 (s, 2 H).

13C NMR (100 MHz, CDCl3): δ = 146.2, 142.5, 130.2, 129.9, 127.2, 127.1, 126.4, 125.9, 124.6, 123.7, 121.4, 119.7, 118.0, 113.0, 43.3.

HRMS (EI): m/z calcd for C20H16N2S: 316.1038; found: 316.1034.


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3-(Ethylthio)imidazo[1,2-a]pyridine (3ab)[19e]

Yield: 88% (47 mg); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 8.53 (s, 1 H), 8.01 (s, 1 H), 7.66 (s, 1 H), 7.25 (s, 1 H), 6.91 (t, J = 5.6 Hz, 1 H), 2.62 (q, J = 6.4 Hz, 2 H), 1.19 (t, J = 6.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 147.4, 141.0, 128.4, 122.5, 121.9, 117.3, 113.1, 40.0, 13.9.


#

3-(Propylthio)imidazo[1,2-a]pyridine (3ac)[19e]

Yield: 89% (51 mg); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 8.48 (s, 1 H), 7.89 (s, 1 H), 7.65 (s, 1 H), 7.25 (s, 1 H), 6.91 (t, J = 5.6 Hz, 1 H), 2.59 (t, J = 6.4 Hz, 2 H), 1.55 (q, J = 6.8 Hz, 2 H), 0.96 (t, J = 6.0 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 147.5, 141.0, 128.4, 125.1, 124.3, 117.9, 112.6, 37.7, 23.0, 12.9.


#

3-(Butylthio)imidazo[1,2-a]pyridine (3ad)[19e]

Yield: 87% (54 mg); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 8.43 (d, J = 6.8 Hz, 1 H), 7.77 (s, 1 H), 7.64 (d, J = 9.2 Hz, 1 H), 7.24 (t, J = 8.0 Hz, 1 H), 6.92 (t, J = 6.8 Hz, 1 H), 2.61 (t, J = 7.2 Hz, 2 H), 1.36–1.52 (m, 4 H), 0.87 (t, J = 7.2 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 147.3, 140.8, 125.2, 124.1, 117.9, 114.0, 112.7, 35.4, 31.7, 21.5, 13.56.


#

3-(Isopropylthio)imidazo[1,2-a]pyridine (3ae)[19e]

Yield: 83% (48 mg); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 8.46 (s, 1 H), 7.88 (s, 1 H), 7.65 (s, 1 H), 7.25 (s, 1 H), 6.91 (t, J = 5.6 Hz, 1 H), 3.03–3.06 (m, 1 H), 1.20 (d, J = 6.8 Hz, 6 H).

13C NMR (100 MHz, CDCl3): δ = 141.7, 136.2, 123.5, 116.3, 115.2, 112.6, 39.8, 23.1.


#

3-(Cyclohexylthio)imidazo[1,2-a]pyridine (3af)[19e]

Yield: 76% (53 mg); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 8.43 (d, J = 6.8 Hz, 1 H), 7.77 (s, 1 H), 7.64 (d, J = 9.2 Hz, 1 H), 7.24 (t, J = 8.0 Hz, 1 H), 6.92 (t, J = 6.8 Hz, 1 H), 2.67–2.74 (m, 1 H), 1.59–1.89 (m, 5 H), 1.19–1.34 (m, 5 H).

13C NMR (100 MHz, CDCl3): δ = 147.3, 140.8, 125.2, 124.1, 117.9, 114.0, 112.7, 32.6, 25.9, 25.5, 21.4.


#

3-(Phenylthio)imidazo[1,2-a]pyridine (3ag)[28]

Yield: 79% (54 mg); white solid; mp 84–87 °C.

1H NMR (400 MHz, CDCl3): δ = 8.16 (d, J = 6.8 Hz, 1 H), 7.96 (s, 1 H), 7.67 (d, J = 6.8 Hz, 1 H), 7.26 (t, J = 6.8 Hz, 1 H), 7.16 (t, J = 7.2 Hz, 2 H), 7.09 (t, J = 7.2 Hz, 1 H), 6.95 (d, J = 8.0 Hz, 2 H), 6.82 (t, J = 6.8 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 148.1, 142.4, 135.2, 129.3, 126.2, 126.0, 124.9, 124.3, 118.1, 113.2, 110.7.


#

3-((4-Chlorophenyl)thio)imidazo[1,2-a]pyridine (3ah)[19g]

Yield: 82% (64 mg); yellow solid; mp 146–147 °C.

1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 6.8 Hz, 1 H), 7.99 (s, 1 H), 7.71 (d, J = 6.8 Hz, 1 H), 7.31 (t, J = 6.8 Hz, 2 H), 7.16 (d, J = 8.4 Hz, 1 H), 6.92 (d, J = 8.4 Hz, 1 H), 6.91–6.86 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 148.2, 142.5, 133.7, 132.2, 129.4, 127.5, 126.2, 124.1, 118.2, 113.4, 110.2.


#

3-((4-Fluorophenyl)thio)imidazo[1,2-a]pyridine (3ai)[28]

Yield: 80% (59 mg); white solid; mp 82–84 °C.

1H NMR (400 MHz, CDCl3): δ = 8.16 (d, J = 6.8 Hz, 1 H), 7.97 (s, 1 H), 7.69 (t, J = 3.6 Hz, 1 H), 7.50 (d, J = 2.4 Hz, 1 H), 7.16 (d, J = 8.8 Hz, 2 H), 6.91–6.86 (m, 3 H).

13C NMR (100 MHz, CDCl3): δ = 162.7 (d, J = 242.2 Hz), 148.2, 142.6, 130.9 (d, J = 4.8 Hz), 128.8 (d, J = 7.6 Hz), 126.3, 124.2, 118.3, 116.5 (d, J = 22.4 Hz), 113.4, 110.2.


#

3-((2-Methoxyphenyl)thio)imidazo[1,2-a]pyridine (3aj)[19g]

Yield: 82% (63 mg); white solid; mp 145–146 °C.

1H NMR (400 MHz, CDCl3): δ = 8.25 (d, J = 6.8 Hz, 1 H), 7.98 (s, 1 H), 7.71 (d, J = 9.0 Hz, 1 H), 7.33–7.27 (m, 1 H), 7.12 (t, J = 6.8 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 2 H), 6.70 (t, J = 7.6 Hz, 1 H), 6.39 (d, J = 7.6 Hz, 1 H), 3.94 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 155.8, 142.4, 127.0, 126.2, 125.8, 124.5, 133.6, 121.3, 117.9, 112.9, 110.7, 55.8.


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3-((4-Fluorophenyl)thio)-2-methylimidazo[1,2-a]pyridine (3ji)[19g]

Yield: 83% (64 mg); white solid; mp 85–87 °C.

1H NMR (400 MHz, CDCl3): δ = 8.16 (m, 1 H), 7.59 (t, J = 8.8 Hz, 1 H), 7.26 (d, J = 6.8 Hz, 1 H), 6.95–6.83 (m, 1 H), 6.83 (t, J = 6.0 Hz, 3 H), 2.59 (d, J = 6.0 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 162.8 (d, J = 244.9 Hz), 148.0, 142.2, 130.0 (d, J = 3.1 Hz), 128.5 (d, J = 7.9 Hz), 126.0, 124.1, 118.2, 116.3 (d, J = 22.1 Hz), 113.2, 111.1.


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2-(tert-Butyl)-3-((4-fluorophenyl)thio)imidazo[1,2-a]pyridine (3ki)[19g]

Yield: 81% (73 mg); white solid; mp 89–91 °C.

1H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 6.8 Hz, 1 H), 7.68 (d, J = 8.8 Hz, 1 H), 7.23 (t, J = 6.8 Hz, 1 H), 6.89–6.74 (m, 5 H).

13C NMR (100 MHz, CDCl3): δ = 162.3 (d, J = 242.2 Hz), 145.7, 130.9 (d, J = 3.0 Hz), 126.4 (d, J = 7.8 Hz), 125.7, 123.5, 117.3, 116.3 (d, J = 22.4 Hz), 112.7, 104.7.


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2-Phenyl-3-((4-fluorophenyl)thio)imidazo[1,2-a]pyridine (3li)

Yield: 86% (83 mg); white solid; mp 93–95 °C.

IR (KBr): 2967, 2929, 2857, 1517, 1469, 1376, 724 cm–1.

1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 6.8 Hz, 1 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.35–7.26 (m, 5 H), 7.10 (t, J = 6.8 Hz, 1 H), 7.01 (t, J = 6.8 Hz, 2 H), 6.90 (t, J = 8.8 Hz, 2 H), 6.79 (t, J = 6.8 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 162.7 (d, J = 244.7 Hz), 148.4, 142.0, 137.2, 130.3 (d, J = 3.1 Hz), 129.1, 128.2 (d, J = 4.0 Hz), 127.9, 125.9, 123.2, 119.8, 116.5, 116.3 (d, J = 22.2 Hz), 115.7, 110.3.

HRMS (EI): m/z calcd for C19H13FN2S: 320.0785; found: 320.0783.


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MTT Assay

The fluoride-containing C3-sulfenated imidazo[1,2-a]pyridines were screened for in vitro cytotoxicity against three human cancer cell lines (HeLa, A-549 and BGC-823) and a normal cell line (VEC) by MTT assay. In vitro, the cytotoxic activities of gossypol and fluoride-containing gossypol Schiff base derivatives were determined by the MTT cytotoxicity assay, which was performed in 96-well plates. The tumor cell line panel consisted of HeLa (human cervical carcinoma), A-549 (human lung carcinoma), BGC-823 (human gastric carcinoma), and VEC (human vascular endothelial cells) (final concentration in the growth medium was 2–4 × 104 mL–1). The MTT solution (20 μL in each well) was added after cells had been treated with the drug for 48 h and the cells were incubated for a further 4 h at 37 °C. The purple form azan crystals were dissolved in 150 μL DMSO. After 5 min, the plates were read on an automated microplate spectrophotometer at 570 nm. Assays were performed in triplicate in three independent experiments. The concentration required for 50% inhibition of cell viability (IC50) was calculated. In all of these experiments, three replicate wells were used to determine each point.


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Acknowledgment

The authors wish to thank Dr. Lidong Weng for his invaluable insight during the development of this work.

Supporting Information

  • References

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  • 2 Salgado-Zamora H, Taylor EC. Heterocycl. Commun. 2006; 12: 307
  • 3 Du B, Shan A, Zhang Y, Zhong X, Chen D, Cai K. Am. J. Med. Sci. 2014; 347: 178
  • 4 Frett B, McConnell N, Smith CC, Wang Y, Shah NP, Li HY. Eur. J. Med. Chem. 2015; 94: 123
  • 5 Gueiffier E, Gueiffier CA. Mini-Rev. Med. Chem. 2007; 7: 888
  • 6 Alonso JM, Oehlrich D, Ahnaou A, Drinkenburg W, Mackie C, Andres JI, Lavreysen H, Cid JM. J. Med. Chem. 2012; 55: 2688
  • 7 Puerstinger G, Paeshuyse J, De Clercq E, Neyts J. Bioorg. Med. Chem. Lett. 2007; 17: 390
  • 8 Gudmundsson KS, Johns BA. Bioorg. Med. Chem. Lett. 2007; 17: 2735
  • 9 Heidari A. J. Data Min. Genomics Proteomics 2016; 7: 125
  • 10 Enguehard-Gueiffier C, Fauvelle F, Debouzy JC, Peinnequin A, Thery I, Dabouis V, Gueiffier A. Eur. J. Pharm. Sci. 2005; 24: 219
  • 11 Mutai T, Tomoda H, Ohkawa T, Yabe Y, Araki K. Angew. Chem. Int. Ed. 2008; 47: 9522
  • 12 Li Q, Zhou M, Han L, Cao Q, Wang X, Zhao L, Zhou J, Zhang H. Chem. Biol. Drug Des. 2015; 86: 849
  • 13 Cao H, Lei S, Li N, Chen L, Liu J, Cai H, Tan J. Chem. Commun. 2015; 51: 1823
  • 14 Lei S, Mai Y, Yan C, Mao J, Cao H. Org. Lett. 2016; 18: 3582
  • 15 Chezal JM, Moreau E, Delmas G, Gueiffier A, Blache Y, Grassy G, Teulade JC. J. Org. Chem. 2001; 66: 6576
  • 16 Mitra S, Ghosh M, Mishra S, Hajra A. J. Org. Chem. 2015; 80: 8275
  • 17 Kim H, Byeon M, Jeong E, Baek Y, Jeong SJ, Um K, Son JY. Adv. Synth. Catal. 2019; 361: 2094
  • 18 Wu Q, Zhao D, Qin X, Lan J, You J. Chem. Commun. 2011; 47: 9188
    • 19a Mohan DC, Rao SN, Ravi C, Adimurthy S. Asian J. Org. Chem. 2014; 3: 609
    • 19b Liu W, Wang S, Jiang Y, He P, Zhang Q, Cao H. Asian J. Org. Chem. 2015; 4: 312
    • 19c Li Z, Hong J, Zhou X. Tetrahedron 2011; 67: 3690
    • 19d Hamdouchi C, de Blas J, Ezquerra J. Tetrahedron 1999; 55: 541
    • 19e Cao H, Chen L, Liu J, Cai H, Deng H, Chen G, Yan C, Chen Y. RSC Adv. 2015; 5: 22356
    • 19f Ravi C, Chandra MohanD, Adimurthy S. Org. Biomol. Chem. 2016; 14: 2282
    • 19g Zheng Z, Qi D, Shi L. Catal. Commun. 2015; 66: 83
    • 19h Li J, Li C, Yang S, An Y, Wu W, Jiang H. J. Org. Chem. 2016; 81: 7771
    • 20a Hiebel M.-A, Berteina-Raboin S. Green Chem. 2015; 17: 937
    • 20b Bagdi AK, Mitra S, Ghosh M, Hajra A. Org. Biomol. Chem. 2015; 13: 3314
    • 20c Huang X, Wang S, Li B, Wang X, Ge Z, Li R. RSC Adv. 2015; 5: 22654
    • 20d Ding Y, Wu W, Zhao W, Li Y, Xie P, Huang Y, Liu Y, Zhou A. Org. Biomol. Chem. 2016; 14: 1428
    • 20e Wang D, Guo S, Zhang R, Lin S, Yan Z. RSC Adv. 2016; 6: 54377
    • 20f Ji X.-M, Zhou S.-J, Chen F, Zhang X.-G, Tang R.-Y. Synthesis 2015; 659
    • 20g Yan K, Yang D, Sun P, Wei W, Liu Y, Li G, Lu S, Wang H. Tetrahedron Lett. 2015; 56: 4792
    • 20h Zhu W, Ding Y, Bian Z, Xie P, Xu B, Tang Q, Wu W, Zhou A. Adv. Synth. Catal. 2016; 358: 2215
  • 21 Hamdouchi C, Sanchez C, Ezquerra J. Synthesis 1998; 867
  • 22 Patil SM, Kulkarni S, Mascarenhas M, Sharma R, Roopan SM, Roychowdhury A. Tetrahedron 2013; 69: 8255
  • 23 Gao Z, Zhu X, Zhang R. RSC Adv. 2014; 4: 19891
  • 24 Ravi C, Mohan CD, Adimurthy S. Org. Lett. 2014; 16: 2978
  • 25 Maddi RR, Shirsat PK, Kumar S, Meshram HM. ChemistrySelect 2017; 2: 1544
  • 26 Bochis RJ, Olen LE, Fisher MH, Reamer RA, Wilks G, Taylor JE, Olson G. J. Med. Chem. 1981; 24: 1483
  • 27 Ravi C, Joshi A, Adimurthy S. Eur. J. Org. Chem. 2017; 3646
  • 28 Rahaman R, Das S, Barman P. Green Chem. 2015; 20: 141
    • 29a Jia F, Li Z. Org. Chem. Front. 2014; 1: 194
    • 29b Yang X.-H, Song R.-J, Xie Y.-X, Li J.-H. ChemCatChem 2016; 8: 2429
    • 29c Piontek A, Bisz E, Szostak M. Angew. Chem. Int. Ed. 2018; 57: 11116
    • 29d Sreedevi R, Saranya S, Rohit KR, Anilkumar G. Adv. Synth. Catal. 2019; 361: 2236
    • 29e Shen C, Zhang P, Sun Q, Bai S, Hor TA, Liu X. Chem. Soc. Rev. 2015; 44: 291
  • 30 Bauer I, Knölker H.-J. Chem. Rev. 2015; 115: 3170
  • 31 Xiang S, Chen H, Liu Q. Tetrahedron Lett. 2016; 57: 3870
  • 32 Wu W, Wang Z, Shen Q, Liu Q, Chen H. Org. Biomol. Chem. 2019; 17: 6753
  • 33 Zeng L, Deng Y, Weng L, Yang Z, Chen H, Liu Q. Natural Sci. 2017; 9: 312
  • 34 Yi S, Li M, Mo W, Hu X, Hu B, Sun N, Jin L, Shen Z. Tetrahedron Lett. 2016; 57: 1912

  • References

  • 1 Gueiffier A, Viols H, Galtier C, Blache Y, Chavignon O, Teulade JC, Chapat JP. Heterocycl. Commun. 1994; 1: 83
  • 2 Salgado-Zamora H, Taylor EC. Heterocycl. Commun. 2006; 12: 307
  • 3 Du B, Shan A, Zhang Y, Zhong X, Chen D, Cai K. Am. J. Med. Sci. 2014; 347: 178
  • 4 Frett B, McConnell N, Smith CC, Wang Y, Shah NP, Li HY. Eur. J. Med. Chem. 2015; 94: 123
  • 5 Gueiffier E, Gueiffier CA. Mini-Rev. Med. Chem. 2007; 7: 888
  • 6 Alonso JM, Oehlrich D, Ahnaou A, Drinkenburg W, Mackie C, Andres JI, Lavreysen H, Cid JM. J. Med. Chem. 2012; 55: 2688
  • 7 Puerstinger G, Paeshuyse J, De Clercq E, Neyts J. Bioorg. Med. Chem. Lett. 2007; 17: 390
  • 8 Gudmundsson KS, Johns BA. Bioorg. Med. Chem. Lett. 2007; 17: 2735
  • 9 Heidari A. J. Data Min. Genomics Proteomics 2016; 7: 125
  • 10 Enguehard-Gueiffier C, Fauvelle F, Debouzy JC, Peinnequin A, Thery I, Dabouis V, Gueiffier A. Eur. J. Pharm. Sci. 2005; 24: 219
  • 11 Mutai T, Tomoda H, Ohkawa T, Yabe Y, Araki K. Angew. Chem. Int. Ed. 2008; 47: 9522
  • 12 Li Q, Zhou M, Han L, Cao Q, Wang X, Zhao L, Zhou J, Zhang H. Chem. Biol. Drug Des. 2015; 86: 849
  • 13 Cao H, Lei S, Li N, Chen L, Liu J, Cai H, Tan J. Chem. Commun. 2015; 51: 1823
  • 14 Lei S, Mai Y, Yan C, Mao J, Cao H. Org. Lett. 2016; 18: 3582
  • 15 Chezal JM, Moreau E, Delmas G, Gueiffier A, Blache Y, Grassy G, Teulade JC. J. Org. Chem. 2001; 66: 6576
  • 16 Mitra S, Ghosh M, Mishra S, Hajra A. J. Org. Chem. 2015; 80: 8275
  • 17 Kim H, Byeon M, Jeong E, Baek Y, Jeong SJ, Um K, Son JY. Adv. Synth. Catal. 2019; 361: 2094
  • 18 Wu Q, Zhao D, Qin X, Lan J, You J. Chem. Commun. 2011; 47: 9188
    • 19a Mohan DC, Rao SN, Ravi C, Adimurthy S. Asian J. Org. Chem. 2014; 3: 609
    • 19b Liu W, Wang S, Jiang Y, He P, Zhang Q, Cao H. Asian J. Org. Chem. 2015; 4: 312
    • 19c Li Z, Hong J, Zhou X. Tetrahedron 2011; 67: 3690
    • 19d Hamdouchi C, de Blas J, Ezquerra J. Tetrahedron 1999; 55: 541
    • 19e Cao H, Chen L, Liu J, Cai H, Deng H, Chen G, Yan C, Chen Y. RSC Adv. 2015; 5: 22356
    • 19f Ravi C, Chandra MohanD, Adimurthy S. Org. Biomol. Chem. 2016; 14: 2282
    • 19g Zheng Z, Qi D, Shi L. Catal. Commun. 2015; 66: 83
    • 19h Li J, Li C, Yang S, An Y, Wu W, Jiang H. J. Org. Chem. 2016; 81: 7771
    • 20a Hiebel M.-A, Berteina-Raboin S. Green Chem. 2015; 17: 937
    • 20b Bagdi AK, Mitra S, Ghosh M, Hajra A. Org. Biomol. Chem. 2015; 13: 3314
    • 20c Huang X, Wang S, Li B, Wang X, Ge Z, Li R. RSC Adv. 2015; 5: 22654
    • 20d Ding Y, Wu W, Zhao W, Li Y, Xie P, Huang Y, Liu Y, Zhou A. Org. Biomol. Chem. 2016; 14: 1428
    • 20e Wang D, Guo S, Zhang R, Lin S, Yan Z. RSC Adv. 2016; 6: 54377
    • 20f Ji X.-M, Zhou S.-J, Chen F, Zhang X.-G, Tang R.-Y. Synthesis 2015; 659
    • 20g Yan K, Yang D, Sun P, Wei W, Liu Y, Li G, Lu S, Wang H. Tetrahedron Lett. 2015; 56: 4792
    • 20h Zhu W, Ding Y, Bian Z, Xie P, Xu B, Tang Q, Wu W, Zhou A. Adv. Synth. Catal. 2016; 358: 2215
  • 21 Hamdouchi C, Sanchez C, Ezquerra J. Synthesis 1998; 867
  • 22 Patil SM, Kulkarni S, Mascarenhas M, Sharma R, Roopan SM, Roychowdhury A. Tetrahedron 2013; 69: 8255
  • 23 Gao Z, Zhu X, Zhang R. RSC Adv. 2014; 4: 19891
  • 24 Ravi C, Mohan CD, Adimurthy S. Org. Lett. 2014; 16: 2978
  • 25 Maddi RR, Shirsat PK, Kumar S, Meshram HM. ChemistrySelect 2017; 2: 1544
  • 26 Bochis RJ, Olen LE, Fisher MH, Reamer RA, Wilks G, Taylor JE, Olson G. J. Med. Chem. 1981; 24: 1483
  • 27 Ravi C, Joshi A, Adimurthy S. Eur. J. Org. Chem. 2017; 3646
  • 28 Rahaman R, Das S, Barman P. Green Chem. 2015; 20: 141
    • 29a Jia F, Li Z. Org. Chem. Front. 2014; 1: 194
    • 29b Yang X.-H, Song R.-J, Xie Y.-X, Li J.-H. ChemCatChem 2016; 8: 2429
    • 29c Piontek A, Bisz E, Szostak M. Angew. Chem. Int. Ed. 2018; 57: 11116
    • 29d Sreedevi R, Saranya S, Rohit KR, Anilkumar G. Adv. Synth. Catal. 2019; 361: 2236
    • 29e Shen C, Zhang P, Sun Q, Bai S, Hor TA, Liu X. Chem. Soc. Rev. 2015; 44: 291
  • 30 Bauer I, Knölker H.-J. Chem. Rev. 2015; 115: 3170
  • 31 Xiang S, Chen H, Liu Q. Tetrahedron Lett. 2016; 57: 3870
  • 32 Wu W, Wang Z, Shen Q, Liu Q, Chen H. Org. Biomol. Chem. 2019; 17: 6753
  • 33 Zeng L, Deng Y, Weng L, Yang Z, Chen H, Liu Q. Natural Sci. 2017; 9: 312
  • 34 Yi S, Li M, Mo W, Hu X, Hu B, Sun N, Jin L, Shen Z. Tetrahedron Lett. 2016; 57: 1912

Zoom Image
Scheme 1 Substrate scope of the reaction with imidazo[1,2-a]pyridines
Zoom Image
Scheme 2 Substrate scope of the reaction with thiols
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Scheme 3 Control experiments
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Scheme 4 Possible reaction mechanism