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. 2021 Sep 28;6(40):25940–25949. doi: 10.1021/acsomega.1c02645

Ultrasound-Assisted Iodination of Imidazo[1,2-α]pyridines Via C–H Functionalization Mediated by tert-Butyl Hydroperoxide

Hua Yang †, Ning Huang ‡, Nengqing Wang ‡, Haicheng Shen ‡, Fan Teng ‡, Xiaoying Liu ‡, Hongmei Jiang ‡, Mei-Chen Tan ‡, Qing-Wen Gui ‡,*
PMCID: PMC8515396  PMID: 34660956

Abstract

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A novel metal catalyst-free and environmentally friendly method for the regioselective iodination of imidazo[1,2-α]pyridines at their C3 position is disclosed, which has a wide substrate scope and could be sustainable. This reaction proceeds through ultrasound acceleration in the presence of a green alcohol solvent. Compared with a conventional heating system, the reaction efficiency and the rate are significantly improved and the iodine atom economy is maximized using ultrasound techniques.

Introduction

In the past 20 years, with the development of the chemical and pharmaceutical industries, novel approaches to the synthesis of heterocycles have rapidly emerged.1−3 The development of more green and effective methods to heterocycle synthesis has been a major research interest for green and sustainable chemists because more than 70% of major commercially available synthetic drugs contain at least one N-fused heterocyclic scaffold.4−6 It is worth mentioning that the imidazo[1,2-α]pyridine derivatives exhibit a wide range of biological and pharmacological activities, such as antibacterial, antiulcer, antiviral, and antitumor (Scheme 1).7−13 As a result, tremendous efforts have been devoted to the synthesis and functionalization of N-fused heterocyclic scaffolds.14−33 Among them, 3-halo imidazo[1,2-α]pyridines are great potential intermediates for their diverse reactivity in many types of reactions.

Scheme 1. Selected Examples of Biologically Relevant Imidazo[1,2-α]pyridines.

Scheme 1

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Compared to a C–Br or C–Cl bond, a C–I bond easily undergoes an oxidative addition in metal-catalyzed coupling reactions due to its low bond dissociation energy.34−39 Despite wide application, N-fused heterocyclic iodides are important and have limited commercial availability.40,41 On account of the importance of such molecules, protocols for constructing these compounds have been widely studied, especially the iodination of imidazo[1,2-α]pyridines.42−48 Generally, their iodination reactions of imidazo[1,2-α]pyridines rely upon the use of stoichiometric inorganic oxidants such as K2S2O8, PhI(OAc)2, and so on. However, both excessive iodine reagents and a large amount of toxic petroleum-derived solvents are required, which is against the general requirements of green chemistry. Therefore, in I2-mediated iodination, the vital challenge is how to increase the iodine atom economy and improve electrophilicity of iodine to imidazo[1,2-α]pyridines using organocatalyst in ecofriendly conditions. More recently, several environmentally benign oxidants, such as hydrogen peroxide or tert-butyl hydroperoxide (TBHP), have been independently used in activation of I2.49−51 Sun et al., Wang et al., and Jain et al. reported regioselective oxidative iodination of quinolines in the presence of molecular iodine and TBHP, respectively (Scheme 2a,b).52,53 As far as we know, the development of novel, economic, and green synthetic methods to iodinate imidazo[1,2-α]pyridines is still of great interest.

Scheme 2. Oxidative Iodination of N-Fused Heterocyclic Scaffolds.

Scheme 2

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Results and Discussion

To the best of our knowledge, the development of alternative, atom economic, and environment friendly protocols to iodinate imidazo[1,2-α]pyridines is still in high demand. In recent years, ultrasonic irradiation (USI) has developed rapidly in modern synthetic chemistry owing to the inherent green character of the adiabatic collapse of transient cavity bubbles, high reactivity, and good functional-group tolerance.45−61 The energy generated by the cavity effect is responsible for solubility, mass transportation, diffusivity, accelerates the reaction, and reduces reaction times at ambient temperature. Chancharunee et al. and Gámez-Montaño et al. discovered an efficient USI-assisted green direct synthesis of imidazo[1,2-α]pyridines, respectively (Scheme 2c,d).60,61 Although these advances have been made in recent years, development on the functionalization of imidazo[1,2-α]pyridines is still highly desirable. In this context, there has been an increasing interest in the use of ultrasonic irradiation for halogenation reactions as tools for green chemistry.62−66 On the basis of the abovementioned points, our group continued ongoing research on sustainable organic synthesis and halogenation of imidazo[1,2-α]pyridines.67−70 Herein, we report the first example of the oxidative iodination of imidazo[1,2-α]pyridines with molecular I2 in an innocuous solvent accelerated by ultrasonic irradiation, which produced 3-iodinated products in very high yields within a short time (Scheme 2e).

Initially, we conducted the iodination reaction of imidazo[1,2-α]pyridines (1a) using tetrabutylammonium iodide (TBAI) as an iodine reagent in the presence of TBHP as an oxidation system in a green alcohol solvent at room temperature (RT); the desired product 2-phenylimidazo[1,2-a]pyridine (2a) was obtained in a trace yield after 8 h (Table 1, entry 1). Under the same conditions, we screened different iodine reagents including NH4I, PhI(OAc)2, NaI, and I2; the best result was obtained with I2 as an iodine reagent (Table 1, entries 2–5). Next, a series of oxidants were detected and the experimental results revealed that TBHP was the best choice for the present oxidative iodination reaction (Table 1, entries 6–9). In addition, no improvement was found when the reaction temperature or the amount of oxidant was increased (Table 1, entries 10–12). Therefore, there was no obvious improvement in the efficiency of this chemical process by changing conventional conditions. The iodination reaction was further optimized under ultrasonic irradiation by employing I2/TBHP as the reaction system. To our delight, when ultrasonic irradiation (40 kHz/40 W) was employed for 0.5 h, the desired product was obtained in a 86% yield (Table 1, entry 13). This exciting result may be owing to the cavitation effect of ultrasonic irradiation. The experiments showed that the ultrasonic irradiation energy is essential for this transformation and 40 kHz/50 W was the suitable energy for this iodination reaction (Table 1, entries 14–15). When the iodine reagent was decreased from 1 to 0.6 equiv, the yield was almost constant (90%, Table 1, entry 16).

Table 1. Screening of the Reaction Conditionsa.

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entry iodine (equiv) oxidant (equiv) conditions yield (%)b
1 TBAI (1) TBHP (2) stirring, RT trace
2 NH4I (1) TBHP (2) stirring, RT nr
3 PIDA (1) TBHP (2) stirring, RT nr
4 NaI (1) TBHP (2) stirring, RT nr
5 I2(1) TBHP (2) stirring, RT 28
6c I2(1) TBHP (2) stirring, RT 25
7 I2(1) DCP (2) stirring, RT 20
8 I2(1) H2O2 (2) stirring, RT <10
9 I2(1) K2S2O8 (2) stirring, RT trace
10 I2(1) TBHP (5) stirring, RT 34
11 I2(1) TBHP (2) stirring, 50 60
12 I2(1) TBHP (2) stirring, 80 68
13 I2(1) TBHP (2) US (40 kHz/40 W), rt, 30 min 86
14 I2(1) TBHP (2) US (40 kHz/50 W), rt, 30 min 91
15 I2(1) TBHP (2) US (40 kHz/60 W), rt, 30 min 90
16 I2(0.6) TBHP (2) US (40 kHz/50 W), rt, 30 min 90
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a

Reaction conditions: unless otherwise specified: 1a (0.2 mmol), iodine reagent, TBHP in water (0.4 mmol), and EtOH (2.0 mL) in a Schlenk tube; RT; US = ultrasonic irradiation.

b

Isolated yield.

c

TBHP in decane.

With these optimal reaction conditions, we evaluated the generality of this regioselective oxidative iodination reaction with different substituent positions on the pyridyl ring (Table 2). Both electron-donating and electron-withdrawing substituents on the C7 position of the imidazole ring of 2-phenyl-imidazo[1,2-α]pyridines were well tolerated on the success of transformation, with fluoro, chloro, bromo, trifluoro, methoxyl, and methyl groups. The corresponding C3-iodinated products 2b–g were given in the range of good to excellent yields. In addition, 2-phenyl-imidazo[1,2-α]pyridines bearing various substituents, including halogens, trifluoro, methyl, methoxy, and cyano, on the C6 or C8 position of the imidazole ring could also provide the desired products 2h–q in 65–95% yields. It is worth noting that this reaction tolerated several functional groups, including cyano and most halogens, which may be beneficial for further structural modification. Furthermore, 6-phehlimidazo[2,1-b]thiazole also proceeded smoothly to afford the corresponding product 2r in a 79% yield.

Table 2. Scope of the Pyridyl Ring of 2-Phenyl-imidazo[1,2-a]pyridinesa,b.

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a

Reagents and conditions: 1 (0.2 mmol), I2 (0.12 mmol), TBHP in water (0.4 mmol), and EtOH (2.0 mL) in a Schlenk tube; ultrasonic irradiation for 30 min.

b

Isolated yield.

Subsequently, we investigated the scope of substituents on the phenyl ring of 2-phenylimidazo[1,2-a]pyridines (Table 3). Substrates with an electron-deficient functional group such as a halogen substituent (F, Cl, Br), CN, NO2, and CF3 at the para position of the C2 phenyl ring could all be efficiently converted into the desired products in moderate to good yields (3a–f). Meanwhile, electron-donation groups like methyl, methoxy, or phenyl groups also worked smoothly, thus generating the corresponding iodination products in high yields (3g–i). Moreover, sterically hindered substrates with a meta-chloro or a naphthyl group were also produced in good yield (3j–k). With 2-(thien-2-yl)imidazo[1,2-a]pyridines and 2-ethylimidazo[1,2-a]pyridines as starting materials, we found that they were subjected to our optimal conditions and high yields can be provided (3l–m).

Table 3. Scope of the Phenyl Ring of 2-Phenyl-imidazo[1,2-a]pyridinesa,b.

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a

Reagents and conditions: 1 (0.2 mmol), I2 (0.12 mmol), TBHP in water (0.4 mmol), and EtOH (2.0 mL) in a Schlenk tube; ultrasonic irradiation for 30 min.

b

Isolated yields.

To demonstrate the practicality of this approach, we conducted the gram-scale iodination of imidazo[1,2-a]pyridines under the optimized conditions, which gave the desired product 3-iodoimidazo[1,2-a]pyridines (2n) in an 80% yield (Scheme 3a). The C–I bond of 2n was subsequently regioselectively converted into the C–C bond catalyzed by Pd(PPh3)4, which gave the desired product 4 in a 62% yield (Scheme 3b). Further synthetic utilization of the iodination reaction was also presented in the preparation of derivative product 5 in a 65% yield. The compound 5 could be readily converted into selective melatonin receptor ligands (Scheme 3c).

Scheme 3. Gram-Scale Experiments and Application of 3-Iodo-imidazo[1,2-a]pyridine Derivatives.

Scheme 3

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Next, we investigated several experiments to probe the reaction mechanism. It is found that the product was not detected or significantly decreased with varying stoichiometries of the radical inhibitor 2,2,6,6-tetra-methylpiperidine-N-oxyl (TEMPO) under standard conditions (Scheme 4a,b). When the reaction was tried with KI, no product formation was observed, which explicitly excludes iodide ions as active intermediates in this oxidative iodination process (Scheme 4c). Therefore, all of these results demonstrated that this reaction most likely proceeds via a free-radical-initiated process.

Scheme 4. Control Experiments.

Scheme 4

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Based on the abovementioned results from the control experiments and previous reports studies,52,53,66,67 we proposed a plausible mechanism for this transformation in Scheme 5. Initially, molecular iodine reacted with TBHP to form tBuOI and HOI. Subsequently, the iodination reaction of 1a with tBuOI or HOI occurred to generate intermediate A by ultrasonic irradiation. Finally, product 2a was obtained from intermediate A, followed by the abstraction of a hydrogen atom induced by tert-butoxy groups or hydroxyl radicals.

Scheme 5. Proposed Catalytic Cycle.

Scheme 5

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Conclusions

In conclusion, we have reported a sustainable, economic, and efficient method for the ultrasound-accelerated synthesis of 3-iodoimidazo[1,2-a]pyridine derivatives (31 examples, 65–95% yield). These 3-iodoimidazo[1,2-a]pyridine derivatives are useful intermediates for organic synthesis through a metal-catalyzed coupling process. This reaction features good functional-group tolerance, high selectivity, is transition-metal free, and can occur under mild conditions. Compared with previously reported systems, this protocol is promoted by tert-butyl hydroperoxide without any additive, base, metal, or an inorganic oxidant. We hope the present finding will be an ideal strategy for preparing the regioselective iodination of imidazo[1,2-α]pyridines at their C3 position.

Experimental Section

General

All reactions were carried out in an anhydrous solvent and commercially available reagents were used as received unless otherwise stated. Analytical thin-layer chromatography (TLC) was performed on precoated aluminum-backed silica gel 60 F254 plates (EMD Millipore, 200 μm thickness). TLC plates were visualized with ultraviolet light and treated with KMnO4 or vanillin stains followed by heating. Flash column chromatography was performed using a Tsingtao silica gel (200–300). 1H and 13C NMR spectra were recorded on a Bruker Avance DRX-400 spectrometer; chemical shifts (δ) are given in ppm and calibrated using the signal of a residual undeuterated solvent as an internal reference (CDCl3: δH = 7.26 ppm and δC = 77.16 ppm). Data for 1H NMR and 13C NMR are reported as follows: chemical shift (δ, ppm), multiplicity, integration, and coupling constant (Hz). Compounds for high-resolution mass spectrometry (HRMS) were analyzed by positive mode electrospray ionization (ESI) using an Agilent quadrupole time-of-flight (QTOF) mass spectrometer.

General Experimental Procedure for the Iodination Reaction Of Imidazo[1,2-α]pyridines

Imidazo[1,2-α]pyridines (0.20 mmol), molecular iodine (0.12 mmol), TBHP in water (0.40 mmol), and EtOH (2.0 mL) were placed in a Schlenk tube, and then the reaction mixture was reacted under ultrasonic irradiation. Upon completion, the reaction mixture was quenched by addition of 10 mL of water. The aqueous layer was extracted three times with EtOAc (10 mL × 3), and the combined organic layers were dried over sodium sulfate, evaporated to dryness, and the desired products were obtained.

3-Iodo-2-phenylimidazo[1,2-a]pyridine (2a)42

A yellow solid, mp = 160–162 °C, yield: 90% (58.24 mg); 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 6.8 Hz, 1 H), 8.06 (d, J = 7.6 Hz, 2 H), 7.61 (d, J = 9.2 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 2 H), 7.39 (t, J = 7.4 Hz, 1 H), 7.24 (t, J = 8.0 Hz, 1 H), 6.90 (t, J = 6.8 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 148.23, 148.18, 133.64, 129.03, 128.70, 128.49, 126.69, 125.76, 117.71, 113.36, 59.64; MS: m/z 320 (M+).

7-Fluoro-3-iodo-2-phenylimidazo[1,2-a]pyridine (2b)

A yellow solid, mp = 161–166 °C, yield: 78% (52.73 mg); 1H NMR (400 MHz, CDCl3) δ 8.19 (t, J = 4.2 Hz, 1 H), 8.04 (d, J = 4.8 Hz, 2 H), 7.48 (t, J = 5.0 Hz, 2 H), 7.40 (t, J = 5.0 Hz, 1 H), 7.29 (d, J = 6.0 Hz, 1 H), 6.81 (t, J = 5.4 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 160.97 (d, J = 169.3 Hz), 149.32, 147.93 (d, J = 9.1 Hz), 133.34, 128.65, 128.53, 128.51, 128.10 (d, J = 7.2 Hz), 105.64 (d, J = 19.6 Hz), 101.39 (d, J = 15.8 Hz), 58.63; HRMS (ESI-TOF) m/z calcd for C13H9FIN2 [M + H]+: 338.9789, found: 338.9793.

7-Chloro-3-iodo-2-phenylimidazo[1,2-a]pyridine (2c)43

A brown solid, mp = 150–152 °C, yield: 80% (56.72 mg); 1H NMR (400 MHz, CDCl3) δ 8.24 (t, J = 4.0 Hz, 2 H), 8.22 (s, 1 H), 7.76 (d, J = 8.0 Hz, 2 H), 7.64 (d, J = 8.8 Hz, 1 H), 7.32 (t, J = 8.2 Hz, 1 H), 6.89 (t, J = 6.8 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 148.43, 145.89, 132.30, 128.92, 126.80, 126.48, 119.05, 117.99, 113.91, 111.77, 60.68; MS: m/z 354 (M+).

7-Bromo-3-iodo-2-phenylimidazo[1,2-a]pyridine (2d)

A brown solid, mp = 153–155 °C, yield: 86% (68.61 mg); 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 4.8 Hz, 1 H), 8.03 (d, J = 4.8 Hz, 2 H), 7.81 (s, 1 H), 7.48 (t, J = 5.0 Hz, 2 H), 7.41 (t, J = 4.8 Hz, 1 H), 7.02 (dd, J = 4.8, 0.8 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 148.96, 148.11, 133.18, 128.75, 128.61, 128.56, 126.88, 119.79, 119.52, 117.18, 59.99; HRMS (ESI-TOF) m/z calcd for C13H9BrIN2 [M + H]+: 398.8988, found: 398.8993.

3-Iodo-2-phenyl-7-(trifluoromethyl)imidazo[1,2-a]pyridine (2e)69

A yellow solid, mp = 188–190 °C, yield: 70% (54.32 mg); 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 7.2 Hz, 1 H), 8.11 (d, J = 7.2 Hz, 2 H), 7.98 (s, 1 H), 7.55 (t, J = 7.4 Hz, 2 H), 7.48 (t, J = 7.2 Hz, 1 H), 7.15 (dd, J = 7.6, 1.6 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 150.31, 146.41, 132.98, 129.00, 128.70, 128.65, 127.47, 124.66, 121.96, 115.54 (d, J = 9.7 Hz), 109.20 (d, J = 2.8 Hz), 62.08; MS: m/z 388 (M+).

3-Iodo-7-methoxy-2-phenylimidazo[1,2-a]pyridine (2f)

A brown solid, mp = 146–148 °C, yield: 94% (65.80 mg); 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.2 Hz, 2 H), 7.86 (d, J = 6.8 Hz, 1 H), 7.45 (t, J = 7.6 Hz, 2 H), 7.36 (t, J = 7.2 Hz, 1 H), 6.81 (t, J = 7.6 Hz, 1 H), 6.55 (d, J = 7.4 Hz, 1 H), 4.02 (s, 3 H); 13C NMR (101 MHz, CDCl3) δ 148.90, 147.29, 142.43, 133.50, 128.76, 128.29, 128.24, 119.53, 112.90, 101.72, 60.51, 56.17; MS: m/z 350 (M+).

3-Iodo-7-methyl-2-phenylimidazo[1,2-a]pyridine (2g)42

A brown solid, mp = 161–163 °C, yield: 90% (60.12 mg); 1H NMR (400 MHz, CDCl3) δ 8.07–8.05 (m, 2 H), 8.04 (s, 1 H), 7.47 (t, J = 7.6 Hz, 2 H), 7.39 (d, J = 7.2 Hz, 1 H), 7.36 (s, 1 H), 6.72 (d, J = 6.8 Hz, 1 H), 2.42 (s, 3 H); 13C NMR (101 MHz, CDCl3) δ 148.43, 147.75, 136.85, 133.71, 128.53, 128.42, 128.32, 125.73, 116.03, 115.89, 58.41, 21.38; MS: m/z 334 (M+).

8-Bromo-3-iodo-2-phenylimidazo[1,2-a]pyridine (2h)45

A brown solid, mp = 126–128 °C, yield: 87% (69.40 mg); 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 4.4 Hz, 1 H), 8.07 (d, J = 4.8 Hz, 2 H), 7.51 (d, J = 4.8 Hz, 1 H), 7.48 (t, J = 5.0 Hz, 2 H), 7.40 (t, J = 5.0 Hz, 1 H), 6.80 (t, J = 4.8 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 149.00, 145.93, 133.24, 128.93, 128.68, 128.46, 128.00, 126.09, 113.10, 111.55, 61.68; MS: m/z 398 (M+).

3-Iodo-8-methoxy-2-phenylimidazo[1,2-a]pyridine (2i)45

A yellow solid, mp = 174–175 °C, yield: 95% (66.30 mg); 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 6.8 Hz, 1 H), 8.01 (d, J = 8.8 Hz, 2 H), 7.64 (d, J = 9.2 Hz, 1 H), 7.29 (d, J = 7.2 Hz, 1 H), 7.02 (d, J = 8.8 Hz, 2 H), 6.95 (t, J = 6.8 Hz, 1 H), 3.87 (s, 3 H); 13C NMR (101 MHz, CDCl3) δ 159.99, 147.98, 147.77, 129.98, 126.64, 125.89, 125.85, 117.39, 113.98, 113.38, 59.05, 55.47; HRMS (ESI-TOF) m/z calcd for C14H12OIN2 [M + H]+: 350.9989, found: 350.9996.

3-Iodo-8-methyl-2-phenylimidazo[1,2-a]pyridine (2j)

A black solid, mp = 127–129 °C, yield: 86% (57.45 mg); 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 4.4 Hz, 1 H), 8.05 (d, J = 4.8 Hz, 2 H), 7.48 (t, J = 5.2 Hz, 2 H), 7.39 (t, J = 5.0 Hz, 1 H), 7.06 (d, J = 4.4 Hz, 1 H), 6.85 (t, J = 4.6 Hz, 1 H), 2.68 (s, 3 H); 13C NMR (101 MHz, CDCl3) δ 148.60, 147.83, 134.00, 128.85, 128.49, 128.34, 127.79, 124.57, 124.40, 113.19, 60.06, 16.73; HRMS (ESI-TOF) m/z calcd for C14H12IN2 [M + H]+: 349.0196, found: 349.0199.

6-Fluoro-3-iodo-2-phenylimidazo[1,2-a]pyridine (2k)45

A yellow solid, mp = 182–184 °C, yield: 68% (45.97 mg); 1H NMR (400 MHz, CDCl3) δ 8.18–8.17 (m, 1 H), 8.04–8.03 (m, 2 H), 7.60 (dd, J = 6.4, 3.2 Hz, 1 H), 7.49–7.47 (m, 2 H), 7.41–7.39 (m, 1 H), 7.18–7.15 (m, 1 H); 13C NMR (101 MHz, CDCl3) δ 153.94 (d, J = 159.4 Hz), 149.43 (d, J = 1.4 Hz), 145.83, 133.37, 128.62, 128.52, 128.50, 118.20 (d, J = 6.0 Hz), 117.62 (d, J = 17.1 Hz), 113.72 (d, J = 28.4 Hz), 61.05; MS: m/z 338 (M+).

6-Chloro-3-iodo-2-phenylimidazo[1,2-a]pyridine (2l)19

A yellow solid, mp = 173–175 °C, yield: 77% (54.59 mg); 1H NMR (400 MHz, CDCl3) δ 8.27 (dd, J = 6.0 Hz, 1.2 Hz, 1 H), 8.05–8.03 (m, 2 H), 7.56 (dd, J = 6.4 Hz, 0.4 Hz, 1 H), 7.50–7.47 (m, 2 H), 7.42–7.39 (m, 1 H), 7.22 (dd, J = 6.0 Hz, 1.2 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 149.10, 146.63, 133.21, 128.72, 128.58, 128.54, 127.09, 124.67, 121.72, 118.04, 60.22; MS: m/z 354 (M+).

6-Bromo-3-iodo-2-phenylimidazo[1,2-a]pyridine (2m)43

A brown solid, mp = 171–173 °C, yield: 81% (64.62 mg); 1H NMR (400 MHz, CDCl3) δ 8.36–8.35 (m, 1 H), 8.04–8.03 (m, 2 H), 7.51 (d, J = 6.0 Hz, 1 H), 7.48 (t, J = 5.0 Hz, 2 H), 7.42–7.39 (m, 1 H), 7.30 7.30 (dd, J = 6.4 Hz, 1.6 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 148.85, 146.67, 133.13, 129.17, 128.72, 128.58, 128.53, 126.82, 118.25, 108.16, 60.05; MS: m/z 398 (M+).

3,6-Diiodo-2-phenylimidazo[1,2-a]pyridine (2n)

A brown solid, mp = 165–167 °C, yield: 86% (76.69 mg); 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1 H), 8.12 (d, J = 5.2 Hz, 2 H), 7.72 (d, J = 6.4 Hz, 1 H), 7.51 (t, J = 5.0 Hz, 2 H), 7.44 (t, J = 4.8 Hz, 1 H), 7.37 (d, J = 6.0 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 145.25, 144.81, 131.76, 130.17, 129.32, 128.83, 128.12, 125.10, 118.70, 116.39, 99.62; MS: m/z 446 (M+).

3-Iodo-2-phenyl-6-(trifluoromethyl)imidazo[1,2-a]pyridine (2o)

Yellow solid, mp = 193–195 °C, yield: 67% (52.07 mg); 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1 H), 8.07 (d, J = 8.0 Hz, 2 H), 7.72 (d, J = 9.6 Hz, 1 H), 7.50 (t, J = 7.6 Hz, 2 H), 7.45–7.40 (m, 2 H); 13C NMR (101 MHz, CDCl3) δ 150.13, 148.13, 132.95, 129.03, 128.69, 128.65, 125.76 (q, J = 5.7 Hz), 123.54 (d, J = 272.7 Hz), 121.65 (d, J = 2.5 Hz), 118.44, 117.80 (d, J = 34.4 Hz), 61.61; HRMS (ESI-TOF) m/z calcd for C14H9FIN2 [M + H]+: 388.9757, found: 388.9761.

3-Iodo-2-phenylimidazo[1,2-a]pyridine-6-carbonitrile (2p)47

A yellow solid, mp = 194–196 °C, yield: 65% (44.85 mg); 1H NMR (400 MHz, CDCl3) δ 8.68–8.67 (m, 1 H), 8.07–8.05 (m, 2 H), 7.69 (dd, J = 6.0, 0.4 Hz, 1 H), 7.52–7.49 (m, 2 H), 7.46–7.43 (m, 1 H), 7.36 (dd, J = 6.4, 1.2 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 150.58, 147.59, 132.72, 132.50, 129.28, 128.70, 128.67, 125.33, 118.61, 116.46, 99.61, 61.62; MS: m/z 345 (M+).

3-Iodo-6-methyl-2-phenylimidazo[1,2-a]pyridine (2q)19

A brown solid, mp = 194–196 °C, yield: 88% (58.79 mg); 1H NMR (400 MHz, CDCl3) δ 8.05–8.03 (m, 2 H), 7.98 (s, 1 H), 7.51 (d, J = 6.4 Hz, 2 H), 7.47 (dd, J = 5.2, 1.2 Hz, 1 H), 7.39–7.37 (m, 1 H), 7.09 (dd, J = 6.0, 1.2 Hz, 1 H), 2.39 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 147.72, 147.17, 133.71, 128.73, 128.47, 128.33, 128.22, 124.28, 123.00, 116.92, 59.04, 18.39; MS: m/z 334 (M+).

5-Iodo-6-phenylimidazo[2,1-b]thiazole (2r)43

A yellow solid, mp = 195–197 °C, yield: 79% (51.59 mg); 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.4 Hz, 2 H), 7.45 (t, J = 5.2 Hz, 2 H), 7.43 (s, 1 H) 7.35 (t, J = 7.2 Hz, 1 H), 6.92 (d, J = 4.8 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 150.97, 149.52, 133.69, 128.49, 128.07, 127.69, 119.39, 112.39; MS: m/z 326 (M+).

2-(4-Fluorophenyl)-3-iodoimidazo[1,2-a]pyridine (3a)69

A brown solid, mp = 169–171 °C, yield: 71% (48.01 mg); 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 6.8 Hz, 1 H), 8.09–8.06 (m, 2 H), 7.64 (d, J = 9.2 Hz, 1 H), 7.29 (t, J = 7.8 Hz, 1 H), 7.21 (t, J = 8.6 Hz, 2 H), 6.95 (t, J = 6.8 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 163.50 (d, J = 165.9 Hz), 148.17, 147.26, 130.44, 130.39, 126.63, 125.86, 117.62, 115.46 (d, J = 14.3 Hz), 113.39, 59.43; MS: m/z 338 (M+).

2-(4-Chlorophenyl)-3-iodoimidazo[1,2-a]pyridine (3b)69

A yellow solid, mp = 155–157 °C, yield: 74% (52.39 mg); 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 6.8 Hz, 1 H), 8.01 (d, J = 8.4 Hz, 2 H), 7.60 (d, J = 8.8 Hz, 1 H), 7.44 (d, J = 8.4 Hz, 2 H), 7.27–7.23 (m, 1 H), 6.91 (t, J = 7.2 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 148.18, 146.90, 134.39, 132.12, 129.81, 128.67, 126.63, 125.94, 117.66, 113.45, 59.69; MS: m/z 356 (M+).

2-(4-Bromophenyl)-3-iodoimidazo[1,2-a]pyridine (3c)69

A brown solid, mp = 148–150 °C, yield: 84% (67.01 mg); 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 6.8 Hz, 1 H), 7.95 (d, J = 8.4 Hz, 2 H), 7.60 (d, J = 8.8 Hz, 3 H), 7.28–7.24 (m, 1 H), 6.92 (t, J = 7.2 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 148.25, 146.97, 132.60, 131.64, 130.11, 126.67, 126.00, 122.72, 117.71, 113.51, 59.71; HRMS (ESI-TOF) m/z calcd for C13H9FIN2 [M + H]+: 398.8988, found: 398.8996.

4-(3-Iodoimidazo[1,2-a]pyridin-2-yl)benzonitrile (3d)69

A black solid, mp = 153–155 °C, yield: 67% (46.25 mg); 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 6.0 Hz, 1 H), 8.03 (d, J = 6.0 Hz, 2 H), 7.63 (d, J = 1.2 Hz, 1 H), 7.48 (t, J = 6.0 Hz, 2 H), 7.41 (t, J = 6.0 Hz, 1 H), 6.90 (dd, J = 5.6, 1.6 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 149.26, 147.78, 133.29, 132.32, 128.77, 128.64, 128.57, 126.94, 126.36, 116.48, 114.91, 59.70; MS: m/z 345 (M+).

3-Iodo-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (3e)19

A yellow solid, mp = 188–190 °C, yield: 60% (43.82 mg); 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 9.2 Hz, 2 H), 8.29 (d, J = 9.2 Hz, 2 H), 8.24 (d, J = 6.8 Hz, 1 H), 7.64 (d, J = 8.8 Hz, 1 H), 7.32 (t, J = 8.0 Hz, 1 H), 6.99 (t, J = 6.8 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 148.46, 147.52, 145.55, 140.12, 129.08, 126.84, 126.63, 123.78, 118.04, 114.03, 61.12; MS: m/z 365 (M+).

3-Iodo-2-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine (3f)69

A yellow solid, mp = 179–181 °C, yield: 72% (55.86 mg); 1H NMR (400 MHz, CDCl3) δ 8.22 (t, J = 8.2 Hz, 3 H), 7.73 (d, J = 8.0 Hz, 2 H), 7.63 (d, J = 8.8 Hz, 1 H), 7.31–7.26 (m, 1 H), 6.96 (t, J = 6.8 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 148.33, 146.54, 137.20, 130.23 (q, J = 21.7 Hz), 128.78, 126.77, 126.23, 125.44 (q, J = 2.3 Hz), 123.43, 117.90, 113.72, 60.33; MS: m/z 388 (M+).

3-Iodo-2-(p-tolyl)imidazo[1,2-a]pyridine (3g)69

A brown solid, mp = 96–98 °C, yield: 85% (56.81 mg); 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 6.8 Hz, 1 H), 8.01 (d, J = 8.0 Hz, 2 H), 7.66 (d, J = 8.8 Hz, 1 H), 7.35 (d, J = 7.6 Hz, 2 H), 7.30–7.26 (m, 1 H), 6.95 (t, J = 6.8 Hz, 1 H), 2.47 (s, 3 H); 13C NMR (101 MHz, CDCl3) δ 148.10, 148.08, 138.30, 130.67, 129.16, 128.47, 126.53, 125.58, 117.49, 113.17, 59.38, 21.45; MS: m/z 334 (M+).

3-Iodo-2-(4-methoxyphenyl)imidazo[1,2-a]pyridine (3h)

A brown solid, mp = 116–118 °C, yield: 90% (63.00 mg); 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 4.4 Hz, 1 H), 8.02 (d, J = 5.6 Hz, 2 H), 7.61 (d, J = 6.0 Hz, 1 H), 7.27 (d, J = 4.8 Hz, 1 H), 7.04 (d, J = 6.0 Hz, 2 H), 6.94 (t, J = 4.6 Hz, 1 H), 3.89 (s, 3 H); 13C NMR (101 MHz, CDCl3) δ 159.92, 148.01, 147.85, 129.96, 126.61, 125.94, 125.80, 117.36, 113.93, 113.29, 59.10, 55.44; MS: m/z 350 (M+).

2-([1,1′-Biphenyl]-4-yl)-3-iodoimidazo[1,2-a]pyridine (3i)69

An orange solid, mp = 197–199 °C, yield: 80% (63.36 mg); 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 6.8 Hz, 1 H), 8.18 (d, J = 8.4 Hz, 2 H), 7.73 (d, J = 8.4 Hz, 2 H), 7.68 (t, J = 8.4 Hz, 2 H), 7.64 (d, J = 8.8 Hz, 1 H), 7.47 (t, J = 7.4 Hz, 2 H), 7.37 (t, J = 7.2 Hz, 1 H), 7.275–7.250 (m, 1 H), 6.953–6.99 (m, 1 H); 13C NMR (101 MHz, CDCl3) δ 148.21, 147.62, 141.17, 140.77, 132.48, 128.98, 128.93, 127.57, 127.22, 127.19, 126.67, 125.90, 117.65, 113.43, 59.73; HRMS (ESI-TOF) m/z calcd for C19H13IN2 [M + H]+: 397.0196, found: 397.0204.

2-(3-Chlorophenyl)-3-iodoimidazo[1,2-a]pyridine (3j)

A green solid, mp = 152–154 °C, yield: 72% (51.06 mg); 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 6.8 Hz, 1 H), 8.10 (s, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.63 (d, J = 9.2 Hz, 1 H), 7.44–7.36 (m, 2 H), 7.30–7.26 (m, 1 H), 6.96–6.93 (m, 1 H); 13C NMR (101 MHz, CDCl3) δ 148.27, 146.72, 135.55, 134.51, 129.70, 128.64, 128.47, 126.70, 126.65, 125.98, 117.85, 113.53, 59.88; MS: m/z 354 (M+).

3-Iodo-2-(naphthalen-2-yl)imidazo[1,2-a]pyridine (3k)71

A brown solid, mp = 142–144 °C, yield: 84% (62.19 mg); 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1 H), 8.11 (t, J = 4.4 Hz, 2 H), 7.85 (d, J = 5.2 Hz, 2 H), 7.77–7.76 (m, 1 H), 7.56 (d, J = 6.0 Hz, 1 H), 7.41–7.39 (m, 2 H), 7.15 (t, J = 5.0 Hz, 1 H), 6.79 (t, J = 4.4 Hz, 1 H); 13C NMR (101 MHz, CDCl3) δ 148.25, 147.94, 133.32, 133.24, 131.01, 128.55, 128.06, 127.90, 127.79, 126.61, 126.45, 126.30, 126.29, 125.80, 117.63, 113.34, 60.03; MS: m/z 370 (M+).

3-Iodo-2-(thiophen-2-yl)imidazo[1,2-a]pyridine (3l)19

A brown liquid, mp = 110–112 °C, yield: 85% (55.45 mg); 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 4.8 Hz, 1 H), 7.94 (d, J = 1.6 Hz, 1 H), 7.57 (d, J = 6.0 Hz, 1 H), 7.38 (d, J = 2.8 Hz, 1 H), 7.21 (t, J = 5.2 Hz, 1 H), 7.15–7.13 (m, 1 H), 6.86 (t, J = 4.4 Hz,1 H); 13C NMR (101 MHz, CDCl3) δ 147.82, 143.45, 136.61, 127.66, 126.41, 126.33, 125.91, 125.78, 117.34, 113.32, 58.58; MS: m/z 326 (M+).

3-Iodo-2-ethylimidazole[1,2-a]pyridine (3m)

A yellow solid, mp = 158–160 °C, yield: 81% (44.21 mg); 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.2 Hz, 1 H), 7.51 (d, J = 9.2 Hz, 1 H), 7.198–7.155 (m, 1 H) 6.85 (t, J = 7.4 Hz, 1 H), 2.81 (dd, J = 15.2, 7.6 Hz, 2 H), 1.33 (t, J = 7.6 Hz, 3 H); 13C NMR (101 MHz, CDCl3) δ 152.51, 148.00, 126.09, 125.01, 117.18, 112.89, 60.52, 22.52, 13.78; HRMS (ESI-TOF) m/z calcd for C9H10IN2 [M + H]+: 272.9883, found: 272.9889.

3,6-Bis(3-methoxyphenyl)-2-phenylimidazo[1,2-a]pyridine (4)

A yellow solid, mp = 139–141 °C, yield: 62%; 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1 H), 7.82 (d, J = 9.2 Hz, 1 H), 7.71 (d, J = 6.8 Hz, 1 H), 7.52–7.47 (m, 3 H), 7.40–7.31 (m, 4 H), 7.10 (d, J = 7.6 Hz, 3 H), 7.06–7.02 (m, 2 H), 6.93 (dd, J = 8 Hz, 2 Hz, 1 H), 3.87 (s, 3 H), 3.82 (s, 3 H); 13C NMR (101 MHz, CDCl3) δ 160.61, 160.21, 139.10, 133.81, 130.91, 130.27, 128.46, 128.26, 127.82, 127.13, 125.97, 123.06, 121.50, 120.88, 119.60, 117.37, 117.34, 116.17, 115.01, 113.35, 112.89, 55.53, 55.51; MS: m/z 406 (M+).

Acknowledgments

This research was supported by the National Natural Science Foundation of China (31672457), the Hunan Province Science Foundation for Youths (2018JJ3215), the Research Foundation of Education Bureau of Hunan Province (18C0147), the Hunan Agricultural University Science Foundation for High-Level Personnel (17QN21), and the Double First-Class Construction Project of the Hunan Agricultural University (SYL2019064, SYL2019063 SYL201802003, YB2018007, and CX20190497).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.1c02645.

  • Copies of NMR spectra (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao1c02645_si_001.pdf (1.7MB, pdf)

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