Next Article in Journal
Response Properties of Electrorheological Composite Hydrophilic Elastomers Based on Different Morphologies of Magnesium-Doped Strontium Titanate
Previous Article in Journal
Flavonoid Profiles in the Pulp of Different Lemon Cultivars and Their Antioxidant Activity Based on UPLC–Q–TOF–MS
Previous Article in Special Issue
Polymethylenetetrazole: Synthesis, Characterization, and Energetic Properties
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 29
Issue 15
10.3390/molecules29153463
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

C3-Alkylation of Imidazo[1,2-a]pyridines via Three-Component Aza-Friedel–Crafts Reaction Catalyzed by Y(OTf)3

by
Kai Yang
1,*,
Cai-Bo Chen
1,
Zhao-Wen Liu
1,
Zhen-Lin Li
1,
Yu Zeng
2 and
Zhao-Yang Wang
2,*
1
College of Pharmacy, Gannan Medical University, Ganzhou 341000, China
2
School of Chemistry, South China Normal University, Guangzhou Key Laboratory of Analytical Chemistry for Biomedicine, GDMPA Key Laboratory for Process Control and Quality Evaluation of Chiral Pharmaceuticals, Key Laboratory of Theoretical Chemistry of Environment, Ministry of Education, Guangzhou 510006, China
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(15), 3463; https://doi.org/10.3390/molecules29153463 (registering DOI)
Submission received: 27 June 2024 / Revised: 21 July 2024 / Accepted: 22 July 2024 / Published: 24 July 2024
(This article belongs to the Special Issue Advances in Synthesis and Biological Activity of Novel Derivatives Based on Five-Membered Heterocyclic Scaffolds and Their Intermediates—Second Edition)
Browse Figures
Versions Notes

Abstract

:
As an important class of nitrogen-containing fused heterocyclic compounds, imidazo[1,2-a]pyridines often exhibit significant biological activities, such as analgesic, anticancer, antiosteoporosis, anxiolytic, etc. Using Y(OTf)3 as a Lewis acid catalyst, a simple and efficient method has been developed for the synthesis of C3-alkylated imidazo[1,2-a]pyridines through the three-component aza-Friedel–Crafts reaction of imidazo[1,2-a]pyridines, aldehydes, and amines in the normal air atmosphere without the protection of inert gas and special requirements for anhydrous and anaerobic conditions. A series of imidazo[1,2-a]pyridine derivatives were obtained with moderate to good yields, and their structures were confirmed by 1H NMR, 13C NMR, and HRMS. Furthermore, this conversion has the advantages of simple operation, excellent functional group tolerance, high atomic economy, broad substrate scope, and can achieve gram-level reactions. Notably, this methodology may be conveniently applied to the further design and rapid synthesis of potential biologically active imidazo[1,2-a]pyridines with multifunctional groups.

1. Introduction

As an important class of nitrogen-containing fused heterocyclic compounds, imidazo[1,2-a]pyridines often exhibit significant biological activities (e.g., analgesic, anticancer, antiosteoporosis, and anxiolytic) and have been explored as potential candidates for different biological activities [1,2,3]. For example, several marketed drugs, including Alpidem, Minodronic acid, Miroprofen, Necopidem, Olprinone, Saripidem, Zolimidine, and Zolpidem, contain the imidazo[1,2-a]pyridine scaffold in their molecular structures (Figure 1) [4,5,6].
Importantly, it is believed that imidazo[1,2-a]pyridine scaffold [7,8] is among the priority pharmacophores in drug research. Therefore, due to the significant pharmacological activities and the frequent occurrence in important drugs, the synthesis of imidazo[1,2-a]pyridine derivatives containing a variety of substituents has gained considerable attention recently [9,10,11]. Of course, it should be pointed out that, although imidazo[1,2-a]pyridine derivatives with diverse structures have been constantly designed and synthesized, and successfully applied in various biological activity studies [12], the green and efficient synthesis methods of some special structurally functionalized imidazo[1,2-a]pyridine derivatives still need further research and enrichment for the practical drug development.
At the same time, as a six-membered heterocycle simultaneously containing both nitrogen and oxygen atoms, morpholine (1,4-tetrahydro-oxazine) is frequently exploited in the field of medicinal chemistry for its advantageous physicochemical, biological, and metabolic properties [13,14]. Especially, some appropriately substituted morpholine derivatives possess a wide range of biological actions, including anti-inflammatory, antimicrobial, and anticancer activity, etc. [15]. Importantly, many approved drugs, clinical candidates, and bioactive molecules, such as Dextromoramide, Emorfazone, Reboxetine, Phenadoxone, Linezolid, Moclobemide, and Timolol (Figure 2) [16], also contain the structural unit of morpholine. Therefore, the introduction of morpholine unit into the fused heterocyclic molecules, such as imidazo[1,2-a]pyridines, to confer compounds with desirable drug-like properties is of importance in the search for new biologically active candidates [17].
Recently, due to the more straightforward and atom economical synthetic step, the strategy of C-H bond functionalization is believed to be an ideal approach for preparing various imidazo[1,2-a]pyridines [18]. Among them, organic peroxides [19], inorganic oxidants [20], photo/electro-induction [21,22,23], and transition metal catalysts [24] triggering C-H bond functionalization are the commonly employed strategies. For example, Hajra’s group reported a (diacetoxy)iodobenzene (DIPA)-mediated oxidative C-H amination of imidazo[1,2-a]pyridines with morpholine (Scheme 1a) [25,26].
On the other hand, the Friedel–Crafts reaction catalyzed by Lewis or Brønsted acid is another powerful strategy for the derivatization of imidazo[1,2-a]pyridines [27,28], and aldehydes and hemiacetals have been extensively used as electrophiles in these Friedel–Crafts reactions of imidazo[1,2-a]pyridines [29]. For example, Kumar’s group reported a Zn(OTf)2-catalyzed Friedel–Crafts hydroxyalkylation of imidazo[1,2-a]pyridines with aldehydes under mechanochemical conditions (Scheme 1b) [30]. Recently, our studies have shown that hydroxydifluoromethylation of imidazo[1,2-a]pyridines can be achieved by using 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as the solvent and promoter (Scheme 1c) [31]. Although the research on the derivatization reaction of imidazo[1,2-a]pyridines is becoming increasingly mature, further exploration of the introduction of functional structures is needed to lay the foundation for drug development and application.
Molecules 29 03463 sch001
Scheme 1. Examples of C3 functionalization of imidazo[1,2-a]pyridines [25,30,31].
Scheme 1. Examples of C3 functionalization of imidazo[1,2-a]pyridines [25,30,31].
Molecules 29 03463 sch001
On the basis of our interest of the synthesis methodology of fused heterocycles [32,33,34], especially the synthesis and derivation of imidazo[1,2-a]pyridines [29,31], as well as the aforementioned strategies of Lewis or Brønsted acid-catalyzed Friedel–Crafts reactions, herein, we hope to disclose a facile, efficient, and Y(OTf)3-catalyzed method for the synthesis of C3-alkylated imidazo[1,2-a]pyridines through the three-component aza-Friedel–Crafts reaction of imidazo[1,2-a]pyridines, aldehydes, and amines (Scheme 1d). The advantages of this synthetic protocol include simple operation, atomic economy, oxidant-free, and a wide range of substrates. More importantly, this newly developed strategy will be helpful for further design and rapid synthesis of imidazo[1,2-a]pyridines with potential biological activity.

2. Results and Discussion

2.1. Optimization of Reaction Conditions

In recent years, aza-Friedel–Crafts-type reactions are becoming a common strategy for implementing imidazo[1,2-a]pyridines linking potentially biologically active units. For example, Kumar’s group developed a Yb(OTf)3-catalyzed three-component reaction of imidazo[1,2-a]pyridines, aldehydes, and acetamide [35]. On the other hand, Hao and Zhu’s group reported a MesCOOH-catalyzed arylation of imidazo[1,2-a]pyridines with aliphatic N-fluorosulfonamides [36].
Taking inspiration from the above literature, it is a common strategy to screen different Lewis acids and Brønsted acids to catalyze the aza-Friedel–Crafts reactions of imidazo[1,2-a]pyridines. Thus, our studies began by evaluating the reaction of 2-phenylimidazo[1,2-a]pyridine 1a, p-tolualdehyde 2a, and morpholine as the model substrates. The results are summarized in Table 1.
Firstly, the reaction of 1a (0.2 mmol), 2a (0.3 mmol), and 3a (0.4 mmol) was carried out in toluene (1.0 mL) under air atmosphere at 110 °C for 12 h and the target product 4a was not obtained without any catalyst (entry 1). If 20 mol% Brønsted acid trifluoroacetic acid (TFA), p-toluenesulfonic acid (TsOH), or HFIP was added as a catalyst, only trace amounts of product 4a were produced (entries 2–4). Fortunately, when 20 mol% Lewis acid Sc(OTf)3 was added as a catalyst, 4a was successfully obtained with a yield of 75% (entry 5).
It is worth noting that significant improvement in the yield of 4a was observed by adding 20 mol% Lewis acid Y(OTf)3 (90%, entry 6). When the amount of Y(OTf)3 was decreased to 10 mol% at 110 °C in toluene, 4a was formed in 72% yield (entry 7). Increasing the amount of Y(OTf)3 did not improve the yield of 4a (entry 8).
Subsequently, several other solvents, such as N,N-dimethylformamide (DMF), 1,4-dioxane, and acetonitrile, were found to have poor efficiency (entry 6 vs. entries 9–11). Due to incomplete reaction of raw material 1a, a significant reduction in the yield of 4a was observed by decreasing the reaction temperature to 100 °C (62%, entry 12). Unfortunately, increasing the reaction temperature to 120 °C did not improve the yield of 4a (entry 13). In addition, the feed ratio of reactants was discussed. It can be found that when the feed ratio of 1a, 2a, and 3a was 1:1.5:2, the yield of 4a was the highest, with a value of 90% (entry 6 vs. entries 14–16).
Thus, the optimized reaction conditions were identified as 1a (0.2 mmol), 2a (0.3 mmol), 3a (0.4 mmol), and 20 mol% Y(OTf)3 as a catalyst and 1.0 mL of toluene as the solvent at 110 °C for 12 h.

2.2. Scope of Benzaldehyde Substrates 2

With the optimized conditions in hand, we explored the generality of the developed methodology against a variety of aromatic aldehydes (Scheme 2).
The results showed that benzaldehyde 2b, instead of p-tolualdehyde 2a, could react smoothly with 2-phenylimidazo[1,2-a]pyridine 1a and morpholine 3a, resulting in the corresponding product 4b with a yield of 92%. Subsequently, under standard conditions, a series of benzaldehydes containing various substituents (such as methoxy, fluorine, chlorine, and bromine) exhibited good functional group tolerance in this method. For example, 4-methoxybenzaldehyde can react smoothly and obtain the corresponding product 4c in 87% yield.
The 4-halogenated benzaldehydes showed good activity in this conversion, yielding different products, 4d, 4e, and 4f, respectively, from p-fluoro, p-chloro, and p-bromo benzaldehydes in 85–91% yields. As some typical aromatic aldehyde substrates 2 containing electron-withdrawing groups, 4-trifluoromethylbenzaldehyde and 4-cyano-benzaldehyde can also be smoothly converted, affording products 4g and 4h in 82% and 89% yields, respectively.
As expected, multi-substituted benzaldehydes, such as 2,4-dichlorobenzaldehyde and vanillin, could provide the desired products 4i and 4j with yields of 83% and 79%, respectively. Captivatingly, specially functionalized aldehydes, e.g., chromone-3-carboxaldehyde 2k, also reacted to furnish the corresponding product 4k in 76% yield.
More importantly, to demonstrate the efficiency and practical applicability of the present approach, a gram-scale experiment was performed in the laboratory. The gram-scale reaction can be readily carried out on a 6 mmol scale (30 times), producing 4a with a yield of 85% (1.9554 g).

2.3. Scope of Imidazo[1,2-a]pyridine Substrates 1

Next, the substrate scope of imidazo[1,2-a]pyridines 1 was further evaluated. As shown in Scheme 3, 2-phenyl imidazo[1,2-a]pyridines 1 bearing an electron-donating group (methyl) as well as a halogen group (fluoro, chloro, and bromo) on the C2 benzene rings proceeded smoothly to yield the desired products 4l–4p in moderate to good yields (80–92%).
Also, the 2-phenyl imidazo[1,2-a]pyridines 1 bearing electron-withdrawing groups, such as trifluoromethyl and cyano, on the C2 benzene rings, all reacted well to provide products 4q and 4r in 75% and 78% yields, respectively. As expected, this conversion was also applicable to 2-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyridine 1j as a kind of disubstituted 2-phenylimidazo[1,2-a]pyridine on the C2 benzene ring, yielding the corresponding product 4s in 79% yield.
Moreover, a range of 2-phenyl imidazo[1,2-a]pyridines 1 bearing either electron-donating (methyl) or halogen (chloro) on the pyridine ring exhibited good functional group tolerance under the standard reaction conditions, while smoothly furnishing the corresponding alkylation products (4t–4v) in good yields (81–85%).
Similarly, 2-(pyridin-2-yl)imidazo[1,2-a]pyridine 1n could also obtain the corresponding product 4w in 79% yield.

2.4. Scope of Cycloamine Substrates 3

As is known, many cycloamine units, such as thiomorpholine, piperazine, and piperidine, can be potential bioactive units [37,38,39]. To further extend the scope of this reaction, we explored the possibility of using different cycloamines 3 under the optimal conditions.
As shown in Scheme 4, the reaction of 2-methylmorpholine 3b instead of morpholine 3a with 2-phenylimidazo[1,2-a]pyridine 1a and p-tolualdehyde 2a under the optimized reaction conditions provided the desired compound 4x in 48% yield.
Interestingly, thiomorpholine 3c has excellent substrate applicability in this conversion, affording the desired product 4y in 78% yield.
Moreover, for other cycloamines 3, e.g., 4-phenylpiperazine 3d, 4-methylpiperazine 3e, and 4-phenylpiperazine 3f, the reaction also proceeded well and yielded products 4z–4ab in yields of 45–52%.
Furthermore, the structures of all expected products 4a–4ab were systematically confirmed by NMR (1H, 13C, and 19F) and HRMS data. Especially, the structure of 4a (CCDC 2325330) was unambiguously confirmed by single-crystal X-ray analysis, which fully proved the structure of the anticipated product (please see the Supplementary Materials for details) [40]. Thus, the structures of these serial compounds 4a–4ab were well characterized, as anticipated.

2.5. Mechanism Investigation

In order to understand the reaction mechanism, several control experiments were carried out (Scheme 5).
Obviously, using the 2.0 equivalent free radical inhibitor TEMPO (2,2,6,6-tetra-methylpiperidine-1-oxyl) or BHT (butylated hydroxytoluene) under the standard conditions, the reaction could still obtain the desired product 3a in 83% and 87% yields, respectively (Scheme 5a). These results demonstrated that the free radical pathway should be excluded in this transformation process.
Furthermore, as shown in Scheme 5b, to support the mechanism, we completed another control experiment and identified molecular ion peaks that correspond to intermediates iminium ion A and benzyl alcohol B by ESI-HRMS (see Supplementary Materials Figures S2 and S3 for details).
On the basis of the above experimental facts and some previous related reports [41,42,43,44,45,46], as shown in Scheme 6, the plausible mechanisms were proposed for this C3-alkylation of imidazo[1,2-a]pyridines.
Firstly, the aldehyde 2 and cyclic amine 3 formed iminium ion A under the catalysis of Lewis acid. Then, the C3 position of imidazo[1,2-a]pyridine was attacked by intermediate A to form intermediate C, whose elimination of a proton yielded the desired product 4 (Path I) [41,42,43].
In another possible pathway, imidazo[1,2-a]pyridine 1 and aldehyde 2 underwent an electrophilic addition reaction under the action of Lewis acid to generate benzyl alcohol B [45,46]. The intermediate B reacted with cyclic amine 3, and then there was a dehydration to produce the corresponding product 4 (Path II) [45].

3. Materials and Methods

3.1. General Information

Melting point (m.p.) was performed on a Büchi Melting Point B-545 instrument (Büchi, Flawil, Switzerland) without correcting. 1H, 13C, and 19F NMR spectra were collected on a BRUKER DRX-400 spectrometer (Bruker, Ettlingen, Germany) using tetramethylsilane (TMS) as an internal standard. High-resolution mass spectra (HRMS) were obtained with a LCMS-IT-TOF mass spectrometer. Single-crystal X-ray analysis was obtained using a Bruker APEX2 Smart CCD (Bruker, Ettlingen, Germany). TLC was performed on commercially prepared 100–400 mesh GF254 silica gel plates (Chengyang Ocean Chemical Co., Ltd., Qingdao, China) and visualization was detected at 254 or 365 nm.
All reagents and solvents were purchased from commercial sources and used without further purification, while 2-substituted imidazo[1,2-a]pyridines 1 were synthesized from 2-bromoacetophenones and various 2-aminopyridines [47,48].

3.2. Experimental Procedure for Compounds 1a–1n

Compounds 1a–1n were synthesized according to the reported procedure (Scheme 7) [47,48]. NaHCO3 (24 mmol, 1.2 equiv.) was added to the ethanol solution containing 2-bromoacetophenones (20 mmol, 1.0 equiv.) and 2-aminopyridines (22 mmol, 1.1 equiv.). Then, the reaction mixture was stirred at room temperature for 6–24 h. After the completion of the reaction, the resulting mixture was diluted with water (15 mL) and extracted with ether (3 × 20 mL). The combined organic layer was washed with brine (25 mL) and dried with anhydrous MgSO4, then concentrated under vacuum. The analytically pure 2-arylimidazo[1,2-a]pyridines 1a–1n were obtained by silica gel column with petroleum ether/EtOAc as the eluent, with 50–90% yields.

3.3. Experimental Procedure for Compounds 4a–4ab

A mixture of imidazo[1,2-a]pyridine 1 (0.2 mmol, 1.0 equiv.), aromatic aldehyde 2 (0.3 mmol, 1.5 equiv.), cycloamine 3 (0.4 mmol, 2 equiv.), and Y(OTf)3 (0.04 mmol, 0.2 equiv.) in toluene (1.0 mL) was stirred at 110 °C for 12 h. After the completion of the reaction, the reaction mixture was quenched with H2O (15 mL) and extracted with ethyl acetate (3 × 15 mL). Then, the organic layer was dried over anhydrous Na2SO4. After filtration and evaporation of the solvents under reduced pressure, the crude product was purified by column chromatography on silica gel to afford the desired product 4.

3.4. Characterization Data for All Products 4a–4ab

The structures of the serial compounds 4a–4ab were systematically characterized via NMR, HRMS, etc., and the corresponding data are summarized in the following.
  • 4-((2-Phenylimidazo[1,2-a]pyridin-3-yl)(p-tolyl)methyl)morpholine (4a), white solid (69 mg, 90%); m.p. 211–213 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.24 (s, 3H), 2.32–2.35 (m, 2H), 2.64–2.67 (m, 2H), 3.70–3.79 (m, 4H), 5.10 (s, 1H), 6.78–6.81 (m, 1H), 7.04 (d, J = 8.0 Hz, 2H), 7.13–7.16 (m, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.39–7.44 (m, J = 8.0 Hz, 1H), 7.47–7.51 (m, 2H), 7.58 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 7.2 Hz, 2H), 9.07 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 21.02, 52.67, 66.65, 67.25, 112.04, 117.54, 119.59, 124.47, 126.30, 127.46, 127.93, 128.50, 129.30, 129.52, 134.75, 135.76, 137.25, 145.04, 145.20; ESI-HRMS, m/z: Calcd for C25H26N3O [M + H]+, 384.2070, found: 384.2067.
  • 4-(Phenyl(2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine (4b), white solid (68 mg, 92%); m.p. 188–190 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.33–2.38 (m, 2H), 2.62–2.72 (m, 2H), 3.75–3.78 (m, 4H), 5.15 (s, 1H), 6.79–6.82 (m, 1H), 7.16–7.24 (m, 4H), 7.32 (d, J = 8.0 Hz, 2H), 7.41–7.45 (m, 1H), 7.49–7.52 (m, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 9.02 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 52.66, 66.78, 67.24, 112.10, 117.56, 119.34, 124.53, 126.16, 127.51, 127.96, 128.52, 128.59, 129.50, 134.65, 138.69, 145.07, 145.34; ESI-HRMS, m/z: Calcd for C24H24N3O [M + H]+, 370.1914, found: 370.1929.
  • 4-((4-Methoxyphenyl)(2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine (4c), white solid (69 mg, 87%); m.p. 206–208 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.31–2.36 (m, 2H), 2.63–2.66 (m, 2H), 3.73–3.77 (m, 7H), 5.08 (s, 1H), 7.76 (d, J = 8.8 Hz, 2H), 6.80–6.84 (m, 1H), 7.17–7.24 (m, 3H), 7.41–7.44 (m, 1H), 7.48–7.51 (m, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 9.08 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 52.65, 55.21, 66.30, 67.25, 112.05, 113.94, 117.56, 119.72, 124.45, 126.23, 127.91, 128.47, 128.65, 129.48, 130.85, 134.65, 144.99, 145.06, 158.85; ESI-HRMS, m/z: Calcd for C25H26N3O2 [M + H]+, 400.2020, found: 400.2021.
  • 4-((4-Fluorophenyl)(2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine (4d), white solid (67 mg, 86%); m.p. 200–202 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.34–2.39 (m, 2H), 2.66–2.70 (m, 2H), 3.76–3.79 (m, 4H), 5.14 (s, 1H), 6.80–6.84 (m, 1H), 6.89–6.94 (m, 2H), 7.18–7.22 (m, 1H), 7.25–7.29 (m, 2H), 7.42–7.46 (m, 1H), 7.49–7.53 (m, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 8.96 (d, J = 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 52.63, 66.08, 67.21, 112.31, 115.51 (d, J = 22 Hz), 117.68, 119.12, 124.69, 125.89, 128.09, 128.61, 128.95 (d, J = 8 Hz), 129.48, 134.42 (d, J = 4 Hz), 134.49, 145.12, 145.37, 161.95 (d, J = 245 Hz); 19F NMR (376 MHz, CDCl3), δ, ppm: −114.65; ESI-HRMS, m/z: Calcd for C24H23FN3O [M + H]+, 388.1820, found: 388.1830.
  • 4-((4-Chlorophenyl)(2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine (4e), white solid (73 mg, 91%); m.p. 215–217 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.34–2.39 (m, 2H), 2.66–2.70 (m, 2H), 3.73–3.82 (m, 4H), 5.14 (s, 1H), 6.79–6.83 (m, 1H), 7.17–7.26 (m, 5H), 7.42–7.45 (m, 1H), 7.49–7.53 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 8.92 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 52.61, 66.13, 67.17, 112.33, 117.70, 118.77, 124.69, 125.81, 128.10, 128.61, 128.67, 128.76, 129.46, 133.19, 134.48, 137.15, 145.16, 145.53; ESI-HRMS, m/z: Calcd for C24H23ClN3O [M+H]+, 404.1524, found: 404.1531.
  • 4-((4-Bromophenyl)(2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine (4f), light-yellow solid (76 mg, 85%); m.p. 193–195 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.35–2.39 (m, 2H), 2.67–2.70 (m, 2H), 3.73–3.82 (m, 4H), 5.13 (s, 1H), 6.80–6.84 (m, 1H), 7.16–7.22 (m, 3H), 7.34 (d, J = 8.0 Hz, 2H), 7.43–7.46 (m, 1H), 7.50–7.53 (m, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 8.92 (d, J = 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 52.61, 66.19, 67.17, 112.34, 117.72, 118.66, 121.30, 124.70, 125.80, 128.10, 128.62, 129.01, 129.46, 131.71, 134.48, 137.68, 145.17, 145.56; ESI-HRMS, m/z: Calcd for C24H23BrN3O [M+H]+, 448.1019, found: 448.1028.
  • 4-((2-Phenylimidazo[1,2-a]pyridin-3-yl)(4-(trifluoromethyl)phenyl)methyl)-morpholine (4g), light-yellow solid (72 mg, 82%); m.p. 196–198 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.38–2.43 (m, 2H), 2.68–2.73 (m, 2H), 3.76–3.85 (m, 4H), 5.24 (s, 1H), 6.82–6.86 (m, 1H), 7.19–7.24 (m, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.44–7.48 (m, 3H), 7.51–7.55 (m, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 8.92 (d, J = 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 52.63, 66.40, 67.14, 112.52, 117.79, 118.31, 123.89 (q, J = 271 Hz), 124.86, 125.24 (q, J = 3 Hz), 125.58 (q, J = 4 Hz), 127.59, 128.22, 128.71, 129.48, 129.72 (q, J = 33 Hz), 134.39, 142.63, 145.22, 145.78; 19F NMR (376 MHz, CDCl3), δ, ppm: −62.61; ESI-HRMS, m/z: Calcd for C25H23F3N3O [M + H]+, 438.1788, found: 438.1762.
  • 4-(Morpholino(2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)benzonitrile (4h), light-yellow solid (70 mg, 89%); m.p. 208–210 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.42–2.44 (m, 2H), 2.68–2.73 (m, 2H), 3.77–3.85 (m, 4H), 5.24 (s, 1H), 6.82–6.85 (m, 1H), 7.20–7.24 (m, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.45–7.55 (m, 5H), 7.63 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 8.81 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 52.58, 66.31, 67.09, 111.39, 112.77, 117.81, 118.44, 125.14, 125.37, 127.89, 128.37, 128.79, 129.44, 132.42, 134.07, 143.84, 145.29, 145.84; ESI-HRMS, m/z: Calcd for C25H23N4O [M + H]+, 395.1866, found: 395.1878.
  • 4-((2,4-Dichlorophenyl)(2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine (4i), light-yellow solid (72 mg, 83%); m.p. 216–218 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.46–2.51 (m, 2H), 2.66–2.72 (m, 2H), 3.73–3.80 (m, 4H), 5.48 (s, 1H), 6.82–6.85 (m, 1H), 7.15–7.24 (m, 3H), 7.37–7.47 (m, 3H), 7.62–7.69 (m, 3H), 7.77 (d, J = 8.0 Hz, 1H), 8.87 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 52.07, 62.27, 67.24, 112.39, 116.73, 117.87, 124.61, 125.50, 126.81, 127.98, 128.26, 129.32, 129.60, 130.13, 133.75, 134.23, 134.83, 135.41, 145.24, 146.66; ESI-HRMS, m/z: Calcd for C24H22Cl2N3O [M + H]+, 438.1134, found: 438.1120.
  • 2-Methoxy-4-(morpholino(2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)phenol (4j), white solid (65 mg, 79%); m.p. 209–212 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.33–2.38 (m, 2H), 2.64–2.72 (m, 2H), 3.66 (s, 3H), 3.75–3.80 (m, 4H), 6.60 (s, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.80–6.83 (m, 1H), 6.91–6.94 (m, 1H), 7.16–7.19 (m, 1H), 7.40–7.44 (m, 1H), 7.47–7.51 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 9.06 (d, J = 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 52.69, 55.64, 66.78, 67.24, 110.17, 112.08, 114.21, 117.59, 119.68, 119.81, 124.48, 126.12, 127.96, 128.47, 129.55, 130.66, 134.74, 144.97, 145.01, 145.07, 146.60; ESI-HRMS, m/z: Calcd for C25H26N3O3 [M + H]+, 416.1969, found: 416.1960.
  • 3-(Morpholino(2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)-4H-chromen-4-one (4k), yellow solid (66 mg, 76%); m.p. 112–114 °C; 2.45–2.50 (m, 2H), 2.62–2.74 (m, 2H), 3.71–3.73 (m, 4H), 5.48 (s, 1H), 6.89–6.92 (m, 1H), 721–7.25 (m, 1H), 7.33–7.47 (m, 5H), 7.60–7.66 (m, 2H), 7.76 (d, J = 8.0 Hz, 2H), 8.05 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.90 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 52.12, 56.87, 67.12, 112.37, 116.88, 117.78, 117.98, 120.92, 123.62, 124.44, 125.29, 125.38, 126.03, 128.03, 128.17, 129.43, 133.74, 134.59; 145.08, 145.97, 154.11, 155.92, 176.59; ESI-HRMS, m/z: Calcd for C27H24N3O3 [M + H]+, 438.1812, found: 438.1805.
  • 4-(p-Tolyl(2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine (4l), white solid (73 mg, 92%); m.p. 205–207 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.15 (s, 3H), 2.22–2.27 (m, 2H), 2.35 (s, 3H), 2.55–2.58 (m, 2H), 3.62–3.70 (m, 4H), 5.02 (s, 1H), 6.67–6.71 (m, 1H), 6.93 (d, J = 8.0 Hz, 2H), 7.03–7.07 (m, 1H), 7.12 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.47–7.53 (m, 3H), 8.96 (d, J = 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 21.01, 21.38, 52.66, 66.62, 67.25, 111.91, 117.44, 119.37, 124.32, 126.22, 127.47, 129.21, 129.25, 129.35, 131.79, 135.80, 137.16, 137.63, 144.97, 145.26; ESI-HRMS, m/z: Calcd for C26H28N3O [M + H]+, 398.2227, found: 398.2236.
  • 4-((2-(4-Fluorophenyl)imidazo[1,2-a]pyridin-3-yl)(p-tolyl)methyl)morpholine (4m), white solid (67 mg, 83%); m.p. 182–184 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.26 (s, 3H), 2.30–2.34 (m, 2H), 2.61–2.64 (m, 2H), 3.71–3.78 (m, 4H), 5.01 (s, 1H), 6.80–6.83 (m, 1H), 7.04 (d, J = 7.6 Hz, 2H), 7.16–7.21 (m, 5H), 7.57 (d, J = 8.0 Hz, 1H), 7.65–7.68 (m, 2H), 9.09 (d, J = 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 21.00, 52.68, 66.83, 67.19, 112.11, 115.48 (d, J = 21 Hz), 117.51, 119.54, 124.57, 126.28, 127.42, 129.34, 130.82 (d, J = 3 Hz), 131.16 (d, J = 8 Hz), 135.67, 137.40, 144.21, 145.00, 162.66 (d, J = 245 Hz); 19F NMR (376 MHz, CDCl3), δ, ppm: −114.10; ESI-HRMS, m/z: Calcd for C25H25FN3O [M + H]+, 402.1976, found: 402.1987.
  • 4-((2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl)(p-tolyl)methyl)morpholine (4n), light-yellow solid (72 mg, 87%); m.p. 173–175 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.24 (s, 3H), 2.28–2.40 (m, 2H), 2.61–2.63 (m, 2H), 3.65–3.77 (m, 4H), 5.03 (s, 1H), 6.80–6.83 (m, 1H), 7.03 (d, J = 7.6 Hz, 2H), 7.14–7.20 (m, 3H), 7.46 (d, J = 6.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 6.8 Hz, 2H), 9.10 (d, J = 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 21.02, 52.70, 66.87, 67.18, 112.20, 117.56, 119.79, 124.71, 126.38, 127.45, 128.73, 129.39, 130.74, 133.29, 133.95, 135.61, 137.45, 143.93, 145.11; ESI-HRMS, m/z: Calcd for C25H25ClN3O [M + H]+, 418.1681, found: 418.1662.
  • 4-((2-(3-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl)(p-tolyl)methyl)morpholine (4o), light-yellow solid (70 mg, 84%); m.p. 129–131 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.19 (s, 3H), 2.23–2.28 (m, 2H), 2.53–2.56 (m, 2H), 3.63–3.71 (m, 4H), 4.96 (s, 1H), 6.74–6.78 (m, 1H), 6.98 (d, J = 8.0 Hz, 2H), 7.10–7.15 (m, 3H), 7.31–7.37 (m, 2H), 7.50–7.53 (m, 2H), 7.65 (s, 1H), 9.05 (d, J = 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 21.02, 52.68, 66.86, 67.19, 112.25, 117.65, 120.00, 124.76, 126.41, 127.50, 127.55, 128.00, 129.42, 129.55, 129.71, 134.39, 135.58, 136.57, 137.53, 143.65, 145.12; ESI-HRMS, m/z: Calcd for C25H25ClN3O [M + H]+, 418.1681, found: 418.1662.
  • 4-((2-(4-Bromophenyl)imidazo[1,2-a]pyridin-3-yl)(p-tolyl)methyl)morpholine (4p), light-yellow solid (73 mg, 80%); m.p. 224–226 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.26 (s, 3H), 2.26–2.34 (m, 2H), 2.60–2.63 (m, 2H), 3.71–3.79 (m, 4H), 5.01 (s, 1H), 6.80–6.84 (m, 1H), 7.04 (d, J = 8.0 Hz, 2H), 7.17–7.21 (m, 3H), 7.57–7.64 (m, 5H), 9.10 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 21.02, 52.70, 66.86, 67.19, 112.21, 117.57, 119.79, 122.23, 124.74, 126.36, 127.45, 129.39, 131.03, 131.68, 133.69, 135.58, 137.48, 143.92, 145.12; ESI-HRMS, m/z: Calcd for C25H25BrN3O [M + H]+, 462.1176, found: 462.1188.
  • 4-(p-Tolyl(2-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-morpholine (4q), light-yellow solid (67 mg, 75%); m.p. 161–163 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.26 (s, 3H), 2.32–2.36 (m, 2H), 2.61–2.64 (m, 2H), 3.73–3.76 (m, 4H), 5.04 (s, 1H), 6.83–6.86 (m, 1H), 7.05 (d, J = 8.0 Hz, 2H), 7.18–7.23 (m, 3H), 7.60 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 9.15 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 21.01, 52.71, 66.91, 67.16, 112.35, 117.71, 120.31, 124.27 (q, J = 271 Hz), 124.92, 125.42 (q, J = 3 Hz), 126.49, 127.48, 129.43, 129.67 (q, J = 24 Hz), 135.48, 137.59, 138.42, 143.55, 145.24; 19F NMR (376 MHz, CDCl3), δ, ppm: −62.39; ESI-HRMS, m/z: Calcd for C26H25F3N3O [M + H]+, 452.1944, found: 452.1965.
  • 4-(3-(Morpholino(p-tolyl)methyl)imidazo[1,2-a]pyridin-2-yl)benzonitrile (4r), light-yellow solid (63 mg, 78%); m.p. 198–200 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.27 (s, 3H), 2.30–2.35 (m, 2H), 2.59–2.62 (m, 2H), 3.73–3.78 (m, 4H), 5.01 (s, 1H), 6.85–6.88 (m, 1H), 7.06 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.21–7.25 (m, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 9.16 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 17.08, 48.79, 63.10, 63.17, 107.52, 108.64, 113.81, 114.98, 116.75, 121.29, 122.62, 123.51, 125.58, 125.99, 128.36, 131.34, 133.84, 135.50, 138.93, 141.41; ESI-HRMS, m/z: Calcd for C26H25N4O [M + H]+, 409.2023, found: 409.2034.
  • 4-((2-(3,4-Dimethoxyphenyl)imidazo[1,2-a]pyridin-3-yl)(p-tolyl)methyl)morpholine (4s), light-yellow solid (70 mg, 79%); m.p. 194–196 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.25 (s, 3H), 2.31–2.32 (m, 2H), 2.62–2.66 (m, 2H), 3.71–3.78 (m, 4H), 3.95 (s, 3H), 3.97 (s, 3H), 5.10 (s, 1H), 6.79–6.83 (m, 1H), 6.99 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.0 Hz, 2H), 7.15–7.24 (m, 5H), 7.59 (d, J = 8.0 Hz, 1H), 9.09 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 21.00, 52.75, 55.93, 56.03, 66.77, 67.24, 110.94, 112.00, 112.66, 117.33, 119.27, 121.81, 124.47, 126.26, 127.32, 127.51, 129.26, 135.79, 137.31, 144.82, 144.95, 148.91; ESI-HRMS, m/z: Calcd for C27H30N3O3 [M + H]+, 444.2282, found: 444.2268.
  • 4-((6-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)(p-tolyl)methyl)morpholine (4t), light-yellow solid (64 mg, 81%); m.p. 195–197 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.17 (s, 3H), 2.22–2.25 (m, 2H), 2.28 (s, 3H), 2.54–2.61 (m, 2H), 3.65–3.71 (m, 4H), 4.98 (s, 1H), 6.92–6.97 (m, 3H), 7.12 (d, J = 8.0 Hz, 2H), 7.30–7.34 (m, 1H), 7.38–7.42 (m, 3H), 7.61 (d, J = 8.0 Hz, 2H), 7.86 (s, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 18.69, 21.02, 52.64, 66.60, 67.30, 116.77, 119.25, 121.55, 123.78, 127.52, 127.60, 127.79, 128.42, 129.24, 129.48, 134.83, 135.85, 137.16, 144.09, 144.96; ESI-HRMS, m/z: Calcd for C26H28N3O [M + H]+, 398.2227, found: 398.2236.
  • 4-((7-Chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)(p-tolyl)methyl)morpholine (4u), white solid (71 mg, 85%); m.p. 197–199 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.26 (s, 3H), 2.31–2.35 (m, 2H), 2.63–2.71 (m, 2H), 3.73–3.80 (m, 4H), 5.06 (s, 1H), 6.80–6.82 (m, 1H), 7.04 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.42–7.45 (m, 1H), 7.48–7.52 (m, 2H), 7.58–7.67 (m, 3H), 9.06 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 20.96, 52.61, 66.52, 67.14, 113.84, 116.07, 120.01, 126.61, 127.33, 128.27, 128.57, 129.18, 129.36, 129.41, 129.57, 133.84, 135.28, 137.56, 144.75; ESI-HRMS, m/z: Calcd for C25H25ClN3O [M + H]+, 418.1681, found: 418.1662.
  • 4-((8-Chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)(p-tolyl)methyl)morpholine (4v), white solid (68 mg, 82%); m.p. 189–191 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.25 (s, 3H), 2.30–2.35 (m, 2H), 2.64–2.67 (m, 2H), 3.70–3.79 (m, 4H), 5.06 (s, 1H), 6.73–6.77 (m, 1H), 7.03 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 1H), 7.41–7.51 (m, 3H), 7.69 (d, J = 8.0 Hz, 2H), 9.05 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 21.01, 52.65, 66.67, 67.18, 111.62, 121.44, 123.16, 123.42, 125.04, 127.38, 128.16, 128.48, 129.35, 129.78, 134.21, 135.36, 137.44, 142.38, 145.91; ESI-HRMS, m/z: Calcd for C25H25ClN3O [M + H]+, 418.1681, found: 418.1662.
  • 4-((2-(Pyridin-2-yl)imidazo[1,2-a]pyridin-3-yl)(p-tolyl)methyl)morpholine (4w), white solid (60 mg, 79%); m.p. 201–203 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.25 (s, 3H), 2.28–2.33 (m, 2H), 2.71–2.74 (m, 2H), 3.74–3.79 (m, 4H), 6.66 (s, 1H), 6.76–6.79 (m, 1H), 7.04 (d, J = 8.0 Hz, 2H), 7.13–7.17 (m, 1H), 7.23–7.24 (m, 1H), 7.55–7.60 (m, 3H), 7.76–7.80 (m, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.72 (d, J = 8.0 Hz, 1H), 9.14 (d, J = 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 21.04, 52.52, 64.47, 67.29, 112.05, 117.59, 122.13, 122.55, 122.62, 124.68, 126.92, 127.70, 129.06, 136.37, 136.48, 136.73, 141.76, 144.68, 148.61, 154.61; ESI-HRMS, m/z: Calcd for C24H25N4O [M + H]+, 385.2033, found: 385.2059.
  • 2-Methyl-4-((2-phenylimidazo[1,2-a]pyridin-3-yl)(p-tolyl)methyl)morpholine (4x), white solid (38 mg, 48%); m.p. 182–184 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 1.12 (d, J = 8.0 Hz, 3H), 1.84–1.87 (m, 1H), 2.26 (s, 3H), 2.40–2.44 (m, 2H), 2.87 (d, J = 8.8 Hz, 1H), 3.66–3.79 (m, 2H), 3.82–3.86 (m, 1H), 5.08 (s, 1H), 6.78–6.81 (m, 1H), 7.03 (d, J = 8.0 Hz, 2H), 7.15–7.20 (m, 3H), 7.41–7.44 (m, 1H), 7.48–7.51 (m, 2H), 7.58 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 9.03 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 19.18, 21.02, 51.64, 59.22, 66.39, 67.12, 71.94, 112.02, 117.50, 119.71, 124.47, 126.23, 127.39, 127.91, 128.48, 129.27, 129.52, 134.66, 135.70, 137.19, 144.98, 145.04; ESI-HRMS, m/z: Calcd for C26H28N3O [M + H]+, 398.2227, found: 398.2236.
  • 4-((2-phenylimidazo[1,2-a]pyridin-3-yl)(p-tolyl)methyl)thiomorpholine (4y), yellow solid (42 mg, 62%); m.p. 190–192 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 2.23 (s, 3H), 2.63–2.74 (m, 6H), 2.89–2.94 (m, 2H), 5.20 (s, 1H), 6.75–6.79 (m, 1H), 7.01 (d, J = 8.0 Hz, 2H), 7.10–7.16 (m, 3H), 7.41–7.43 (m, 1H), 7.46–7.50 (m, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 8.87 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 21.00, 28.47, 53.92, 66.28, 112.02, 117.47, 119.51, 124.57, 126.20, 127.22, 127.95, 128.54, 129.27, 129.51, 134.62, 135.84, 137.12, 145.08, 145.25; ESI-HRMS, m/z: Calcd for C25H26N3S [M + H]+, 400.1842, found: 400.1857.
  • 2-Phenyl-3-((4-phenylpiperazin-1-yl)(p-tolyl)methyl)imidazo[1,2-a]pyridine (4z), yellow solid (43 mg, 47%); m.p. 95–97 °C; 2.26 (s, 3H), 2.51–2.55 (m, 2H), 2.82–2.87 (m, 2H), 3.19–3.28 (m, 4H), 5.17 (s, 1H), 6.79–6.80 (m, 1H), 6.85–6.88 (m, 1H), 6.92 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 7.15–7.19 (m, 1H), 7.21–7.24 (m, 2H), 7.25–7.28 (m, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.48–7.51 (m, 2H), 7.60 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 9.06 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 21.04, 49.53, 52.09, 66.19, 112.00, 116.02, 117.51, 119.89, 119.94, 124.51, 126.42, 127.37, 127.93, 128.52, 128.77, 129.17, 129.28, 129.57, 134.74, 136.05, 137.19, 145.06, 151.15; ESI-HRMS, m/z: Calcd for C31H31N4 [M + H]+, 459.2543, found: 459.2557.
  • 3-((4-Methylpiperidin-1-yl)(p-tolyl)methyl)-2-phenylimidazo[1,2-a]pyridine (4aa), light-yellow solid (40 mg, 52%); m.p. 156–158 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 0.94 (d, J = 8.0 Hz, 3H), 1.23–1.27 (m, 3H), 1.63 (d, J = 9.2 Hz, 1H), 1.88–1.94 (m, 1H), 2.15–2.21 (m, 1H), 2.23 (s, 3H), 2.68 (d, J = 9.2 Hz, 1H), 2.98 (d, J = 9.2 Hz, 1H), 5.08 (s, 1H), 6.74–6.78 (m, 1H), 6.99 (d, J = 8.0 Hz, 2H), 7.11–7.14 (m, 1H), 7.17 (d, J = 8.0 Hz, 2H), 7.38–7.42 (m, 1H), 7.47–7.50 (m, 2H), 7.56 (d, J = 9.2 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 9.06 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 19.93, 20.84, 33.55, 51.37, 52.04, 65.41, 110.67, 116.20, 119.72, 123.23, 125.66, 126.13, 126.65, 127.34, 128.00, 128.51, 133.91, 135.68, 136.02, 143.44, 143.82; ESI-HRMS, m/z: Calcd for C27H30N3 [M + H]+, 396.2434, found: 396.2445.
  • 2-Phenyl-3-((4-phenylpiperidin-1-yl)(p-tolyl)methyl)imidazo[1,2-a]pyridine (4ab), light-yellow solid (41 mg, 45%); m.p. 202–204 °C; 1H NMR (400 MHz, CDCl3), δ, ppm: 1.77–1.90 (m, 4H), 2.05–2.09 (m, 1H), 2.24 (s, 3H), 2.31–2.37 (m, 1H), 2.56–2.64 (m, 1H), 2.86 (d, J = 9.2 Hz, 1H), 2.16 (d, J = 9.2 Hz, 1H), 5.16 (s, 1H), 6.77–6.81 (m, 1H), 7.02 (d, J = 8.0 Hz, 2H), 7.13–7.26 (m, 7H), 7.29–7.33 (m, 2H), 7.40–7.44 (m, 1H), 7.49–7.53 (m, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 9.08 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3), δ, ppm: 21.04, 33.66, 34.24, 42.74, 52.79, 53.50, 66.43, 111.88, 117.39, 120.54, 124.39, 126.39, 126.60, 126.84, 127.25, 127.80, 128.46, 128.47, 129.17, 129.61, 134.97, 136.84, 136.91, 144.72, 144.97, 146.21; ESI-HRMS, m/z: Calcd for C32H32N3 [M + H]+, 458.2591, found: 458.2598.
The detailed 1H, 13C NMR, and 19F NMR spectra for all compounds 4a–4ab are provided in the Supplementary Materials.

4. Conclusions

In summary, the Y(OTf)3-catalyzed three-component aza-Friedel–Crafts reaction was developed for the synthesis of the C3-alkylated imidazo[1,2-a]pyridines from imidazo[1,2-a]pyridines, aldehydes, and amines. The developed protocol is operationally simple and provided a wide range of C3-alkylated imidazo[1,2-a]pyridines in good to excellent yields. High functional group tolerance and broad substrate scope were the salient features of the method. Additionally, the reaction also achieved gram-scale in excellent yields, showing the possibility of practical application. Moreover, this method may be conveniently applied to the further design and rapid synthesis of potential biologically active imidazo[1,2-a]pyridines with multifunctional groups.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29153463/s1, which contains details on the crystallographic information parameters (Table S1), 1H, 13C, and 19F NMR spectra for all compounds 4a–4ab.

Author Contributions

Conceptualization, K.Y. and Z.-Y.W.; methodology, K.Y. and C.-B.C.; formal analysis, C.-B.C. and Z.-L.L.; data curation, Z.-L.L. and Z.-W.L.; writing—original draft preparation, K.Y.; writing—review and editing, Z.-W.L., Y.Z. and Z.-Y.W.; project administration, Z.-Y.W.; funding acquisition, Z.-Y.W. and K.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515012342), the Natural Science Foundation of Jiangxi Province (No. 20224BAB203010), and the Science and Technology Projects of Ganzhou (No. 2023CYZ17866).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data supporting the findings of this study are available within the paper and within its Supplementary Materials published online.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Devi, N.; Singh, D.; K. Rawal, R.; Bariwal, J.; Singh, V. Medicinal attributes of imidazo[1,2-a]pyridine derivatives: An update. Curr. Top. Med. Chem. 2016, 16, 2963–2994. [Google Scholar] [CrossRef]
  2. Quattrini, L.; Gelardi, E.L.M.; Coviello, V.; Sartini, S.; Ferraris, D.M.; Mori, M.; Nakano, I.; Garavaglia, S.; La Motta, C. Imidazo[1,2-a]pyridine derivatives as aldehyde dehydrogenase inhibitors: Novel chemotypes to target glioblastoma stem cells. J. Med. Chem. 2020, 63, 4603–4616. [Google Scholar] [CrossRef] [PubMed]
  3. Li, H.; Zhang, S.L.; Jia, Y.H.; Li, Q.; Feng, Z.W.; Zhang, S.D.; Zheng, W.; Zhou, Y.L.; Li, L.L.; Liu, X.C.; et al. Imidazo[1,2-a]pyridine derivatives as novel dual-target inhibitors of ABCB1 and ABCG2 for reversing multidrug resistance. J. Med. Chem. 2023, 66, 2804–2831. [Google Scholar] [CrossRef] [PubMed]
  4. Feng, S.; Hong, D.; Wang, B.; Zheng, X.; Miao, K.; Wang, L.; Yun, H.; Gao, L.; Zhao, S.; Shen, H.C. Discovery of imidazopyridine derivatives as highly potent respiratory syncytial virus fusion inhibitors. ACS Med. Chem. Lett. 2015, 6, 359–362. [Google Scholar] [CrossRef] [PubMed]
  5. Iida, H.; Demizu, R.; Ohkado, R. Tandem Flavin-iodine-catalyzed aerobic oxidative sulfenylation of imidazo[1,2-a]pyridines with thiols. J. Org. Chem. 2018, 83, 12291–12296. [Google Scholar] [CrossRef] [PubMed]
  6. Samanta, S.; Kumar, S.; Aratikatla, E.K.; Ghorpade, S.R.; Singh, V. Recent developments of imidazo[1,2-a]pyridine analogues as antituberculosis agents. RSC Med. Chem. 2023, 14, 644–657. [Google Scholar] [CrossRef] [PubMed]
  7. Ahmadi, N.; Khoramjouy, M.; Movahed, M.A.; Amidi, S.; Faizi, M.; Zarghi, A. Design, synthesis, in vitro and in vivo evaluation of new imidazo[1,2-a]pyridine derivatives as cyclooxygenase-2 inhibitors. Anti Cancer Agents Med. Chem. 2024, 24, 504–513. [Google Scholar] [CrossRef] [PubMed]
  8. Valla, L.; Pitrat, D.; Mulatier, J.-C.; Bahers, T.; Jeanneau, E.; Ali, L.M.A.; Nguyen, C.; Gary-Bobo, M.; Andraud, C.; Bretonniere, Y. Imidazo[1,2-a]pyridine and Imidazo[1,5-a]pyridine: Electron Donor Groups in the Design of D–π–A Dyes. J. Org. Chem. 2024, 89, 8407–8419. [Google Scholar] [CrossRef] [PubMed]
  9. Li, J.X.; An, Y.N.; Li, J.W.; Yang, S.R.; Wu, W.Q.; Jiang, H.F. Palladium-catalyzed C-S bond activation and functionalization of 3-sulfenylindoles and related electron-rich heteroarenes. Org. Chem. Front. 2017, 4, 1590–1594. [Google Scholar] [CrossRef]
  10. Yu, Y.; Su, Z.Q.; Cao, H. Strategies for synthesis of imidazo[1,2-a]pyridine derivatives: Carbene transformations or C-H functionalizations. Chem. Rec. 2019, 19, 2105–2118. [Google Scholar] [CrossRef]
  11. Yan, J.; Zhong, S.J.; Chen, X.; Luo, Y.H.; Cao, H.; Liu, X.; Zhao, L.M. Controlled and site-selective C-H/N-H alkenylation, dialkenylation, and dehydrogenative β-alkenylation of various N-heterocycles. J. Org. Chem. 2024, 89, 4840–4850. [Google Scholar] [CrossRef] [PubMed]
  12. Song, Q.; Zhang, Q.; Fan, X.; Kayaat, F.; Lv, R.; Li, J.; Wang, Y. The discovery of novel imidazo[1,2-a]pyridine derivatives as covalent anticancer agents. Org. Biomol. Chem. 2024, 22, 5374–5384. [Google Scholar] [CrossRef]
  13. Tzara, A.; Xanthopoulos, D.; Kourounakis, A.P. Morpholine as a scaffold in medicinal chemistry: An update on synthetic strategies. ChemMedChem 2020, 15, 392–403. [Google Scholar] [CrossRef]
  14. Lenci, E.; Calugi, L.; Trabocchi, A. Occurrence of morpholine in central nervous system drug discovery. ACS Chem. Neurosci. 2021, 12, 378–390. [Google Scholar] [CrossRef] [PubMed]
  15. Kumar, R.; Srinivasa, R.V.; Kapur, S. Emphasizing morpholine and its derivatives (Maid): Typical candidate of pharmaceutical importance. Int. J. Chem. Sci. 2016, 14, 1777–1788. [Google Scholar]
  16. Kourounakis, A.P.; Xanthopoulos, D.; Tzara, A. Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules. Med. Res. Rev. 2019, 40, 709–752. [Google Scholar] [CrossRef]
  17. Tang, S.A.; Fults, A.; Boyd, S.R.; Gattu, N.; Tran, K.A.; Fan, J.Y.; Mackenzie, K.R.; Palzkill, T.; Young, D.W.; Chamakuri, S. Expanding complex morpholines using systematic chemical diversity. Org. Lett. 2024, 26, 3493–3497. [Google Scholar] [CrossRef]
  18. Feng, Z.Y.; Fan, Y.S.B.; Qiang, C.C.; Liu, P.; Sun, P.P. Electrochemical C3-methylthiolation of imidazopyridines with dimethyl sulfoxide. Green Chem. 2024, 26, 3517–3521. [Google Scholar] [CrossRef]
  19. Jin, S.Z.; Xie, B.; Lin, S.; Min, C.; Deng, R.H.; Yan, Z.H. Metal-free site-specific hydroxyalkylation of imidazo[1,2-a]pyridines with alcohols through radical reaction. Org. Lett. 2019, 21, 3436–3440. [Google Scholar] [CrossRef]
  20. Wu, Y.R.; Li, L.; Wen, K.M.; Deng, J.; Chen, J.W.; Shi, J.; Wu, T.; Pang, J.X.; Tang, X.D. Copper-catalyzed C3 functionalization of imidazo[1,2-a]pyridines with 3-indoleacetic acids. J. Org. Chem. 2021, 86, 12394–12402. [Google Scholar] [CrossRef]
  21. Ji, J.J.; Zhu, Z.Q.; Xiao, L.J.; Guo, D.; Zhu, X.; Tang, J.; Wu, J.; Xie, Z.B.; Le, Z.G. Photocatalyst-free decarboxylative aminoalkylation of imidazo[1,2-a]pyridines with N-aryl glycines enabled by visible light. Org. Chem. Front. 2019, 6, 3693–3697. [Google Scholar] [CrossRef]
  22. Yuan, Y.; Zhou, Z.L.; Zhang, L.; Li, L.S.; Lei, A.W. Electrochemical oxidative C3 acyloxylation of imidazo[1,2-a]pyridines with hydrogen evolution. Org. Lett. 2021, 23, 5932–5936. [Google Scholar] [CrossRef] [PubMed]
  23. Li, S.F.; Wang, T.M.; Li, X.C.; Fang, L.J.; Zhai, H.B.; Cheng, B. Switchable electrooxidative N-methyl amines: Access to C3-aminomethylated and C3-arylmethylated imidazo[1,2-a] pyridines. Green Chem. 2022, 24, 9482–9488. [Google Scholar] [CrossRef]
  24. Gernet, A.; Sevrain, N.; Volle, J.N.; Ayad, T.; Pirat, J.L.; Virieux, D. Diversity-oriented synthesis toward aryl- and phosphoryl-functionalized imidazo[1,2-a]pyridines. J. Org. Chem. 2020, 85, 14730–14743. [Google Scholar] [CrossRef] [PubMed]
  25. Mondal, S.; Samanta, S.; Jana, S.; Hajra, A. (Diacetoxy)iodobenzene-mediated oxidative C-H amination of imidazopyridines at ambient temperature. J. Org. Chem. 2017, 82, 4504–4510. [Google Scholar] [CrossRef] [PubMed]
  26. Mondal, S.; Samanta, S.; Singsardar, M.; Hajra, A. Aminomethylation of imidazoheterocycles with morpholine. Org. Lett. 2017, 19, 3751–3754. [Google Scholar] [CrossRef] [PubMed]
  27. Lafzi, F.; Kilic, H. Metal- and additive-free C3-functionalization of imidazo[1,2-a]pyridines with para-quinone methides. Asian J. Org. Chem. 2021, 10, 1814–1821. [Google Scholar] [CrossRef]
  28. Singh, D.; Kumar, G.; Dheer, D.; Jyoti; Kushwaha, M.; Ahmed, Q.N.; Shankar, R. BCl3-mediated C-N, C-S, and C-O bond formation of imidazo[1,2-a]pyridine benzylic ethers. ACS Omega 2019, 4, 4530–4539. [Google Scholar] [CrossRef] [PubMed]
  29. Liu, Z.; Guo, X.H.; Chen, Z.X.; Wu, L.H.; Yang, K. Metal-free synthesis of trifluoromethyl carbinol-containing imidazo[1,2-a]pyridines via dehydrative coupling of imidazo[1,2-a]pyridines with trifluoroacetaldehyde. Synthesis 2024, 56, 1756–1764. [Google Scholar]
  30. Meena, N.; Bhawani, N.; Sonam; Rangan, K.; Kumar, A. Ball-Milling-Enabled Zn(OTf)2-catalyzed Friedel-Crafts hydroxyalkylation of imidazo[1,2-a]pyridines and indoles. J. Org. Chem. 2023, 88, 3022–3034. [Google Scholar] [CrossRef]
  31. Gao, J.; Liu, Z.; Guo, X.; Wu, L.; Chen, Z.; Yang, K. 1,1,1,3,3,3-Hexafluoro-2-propanol-promoted Friedel-Crafts reaction: Metal-free synthesis of C3-difluoromethyl carbinol-containing imidazo[1,2-a]pyridines at room temperature. Molecules 2023, 28, 7522. [Google Scholar] [CrossRef] [PubMed]
  32. Yang, K.; Luo, S.-H.; Chen, S.-H.; Cao, X.-Y.; Zhou, Y.-J.; Lin, J.-Y.; Huo, Y.-P.; Wang, Z.-Y. Simple inorganic base promoted C-N and C-C formation: Synthesis of benzo[4,5]imidazo[1,2-a]pyridines as functional AIEgens used for detecting picric acid. Org. Biomol. Chem. 2021, 19, 8133–8139. [Google Scholar] [CrossRef] [PubMed]
  33. Yang, K.; Chen, Z.-X.; Zhou, Y.-J.; Chen, Q.; Yu, S.-W.; Luo, S.-H.; Wang, Z.-Y. Simple inorganic base promoted polycyclic construction using mucohalic acid as a C3 synthon: Synthesis and AIE probe application of benzo[4,5]imidazo[1,2-a]pyridines. Org. Chem. Front. 2022, 9, 1127–1136. [Google Scholar] [CrossRef]
  34. Wu, L.; Liu, X.; Liu, Z.; Chen, Z.-X.; Fu, X.; Yang, K. Metal-free synthesis of difluoro/trifluoromethyl carbinol-containing chromones via tandem cyclization of o-hydroxyaryl enaminone. Org. Biomol. Chem. 2023, 21, 9236–9241. [Google Scholar] [CrossRef] [PubMed]
  35. Pericherla, K.; Khungar, B.; Kumar, A. One-pot, three-component synthesis of 1-amidomethyl-imidazo[1,2-a]pyridines catalyzed by ytterbium triflate. Tetrahedron Lett. 2012, 53, 1253–1257. [Google Scholar] [CrossRef]
  36. Xue, Y.T.; Shi, L.L.; Wang, X.; Yu, X.N.; Zhu, X.J.; Hao, X.Q.; Song, M.P. Regioselective N-F and α C(sp3)-H Arylation of Aliphatic N-Fluorosulfonamides with Imidazopyridines. Org. Lett. 2021, 23, 6807–6812. [Google Scholar] [CrossRef] [PubMed]
  37. Wei, M.-X.; Zhang, J.; Ma, F.-L.; Li, M.; Yu, J.-Y.; Luo, W.; Li, X.-Q. Synthesis and biological activities of dithiocarbamates containing 2(5H)-furanone-piperazine. Eur. J. Med. Chem. 2018, 155, 165–170. [Google Scholar] [CrossRef] [PubMed]
  38. Wei, M.-X.; Yu, J.-Y.; Liu, X.-X.; Li, X.-Q.; Yang, J.-H.; Zhang, M.-W.; Yang, P.-W.; Zhang, S.-S.; He, Y. Synthesis and biological evaluation of novel artemisone-piperazine-tetronamide hybrids. RSC Adv. 2021, 11, 18333–18341. [Google Scholar] [CrossRef] [PubMed]
  39. Karunanidhi, S.; Chandrasekaran, B.; Karpoormath, R.; Patel, H.M.; Kayamba, F.; Merugu, S.R.; Kumar, V.; Dhawan, S.; Kushwaha, B.; Mahlalela, M.C. Novel thiomorpholine tethered isatin hydrazones as potential inhibitors of resistant Mycobacterium tuberculosis. Bioorg. Chem. 2021, 115, 105133. [Google Scholar] [CrossRef]
  40. CCDC2325330 (for 4a) Contains the Supplementary Crystallographic Data for This Paper. These Data Can Be Obtained Free of Charge from The Cambridge Crystallographic Data Centre. Available online: www.ccdc.cam.ac.uk/data_request/cif (accessed on 14 January 2024).
  41. Vachhani, D.D.; Sharma, A.; Van der Eycken, E. Copper-catalyzed direct secondary and tertiary C-H alkylation of azoles through a heteroarene-amine-aldehyde/ketone coupling reaction. Angew. Chem. Int. Ed. 2013, 52, 2547–2550. [Google Scholar] [CrossRef]
  42. Gunaganti, N.; Kharbanda, A.; Lakkaniga, N.R.; Zhang, L.T.; Cooper, R.; Li, H.Y.; Frett, B. Catalyst free, C-3 functionalization of imidazo[1,2-a]pyridines to rapidly access new chemical space for drug discovery efforts. Chem. Commun. 2018, 54, 12954–12957. [Google Scholar] [CrossRef] [PubMed]
  43. Li, Z.H.; Yu, B. HFIP-promoted de novo synthesis of biologically relevant nonnatural α-arylated amino esters and dipeptide mimetics. Chem. Eur. J. 2019, 25, 16528–16532. [Google Scholar] [CrossRef] [PubMed]
  44. Mohamed, A.H.; Masurier, N. Recent advances in aza Friedel-Crafts reaction: Strategies for achiral and stereoselective synthesis. Org. Chem. Front. 2023, 10, 1847–1866. [Google Scholar] [CrossRef]
  45. Xu, Z.; Huang, Z.; Chai, L.; Liu, Z.-Q. A Free-radical-promoted site-specific cross-dehydrogenative-coupling of N-heterocycles with fluorinated alcohols. Org. Lett. 2016, 18, 4662–4665. [Google Scholar] [CrossRef] [PubMed]
  46. Chen, J.W.; Wen, K.M.; Wu, Y.R.; Shi, J.; Yao, X.G.; Tang, X.D. Transition metal catalyst-free C3 sulfonylmethylation of imidazo[1,2-a]pyridines with glyoxylic acid and sodium sulfinates in water. J. Org. Chem. 2022, 87, 3780–3787. [Google Scholar] [CrossRef] [PubMed]
  47. Obermayer, D.; Znidar, D.; Glotz, G.; Stadler, A.; Dallinger, D.; Kappe, C.O. Design and performance validation of a conductively heated sealed-vessel reactor for organic Synthesis. J. Org. Chem. 2016, 81, 11788–11801. [Google Scholar] [CrossRef]
  48. Ghosh, P.; Ganguly, B.; Kar, B.; Dwivedi, S.; Das, S. Green procedure for highly efficient, rapid synthesis of imidazo[1,2-a]pyridine and its late stage functionalization. Synth. Commun. 2018, 48, 1076. [Google Scholar] [CrossRef]
Molecules 29 03463 g001
Figure 1. Representative drugs containing imidazo[1,2-a]pyridine scaffold.
Figure 1. Representative drugs containing imidazo[1,2-a]pyridine scaffold.
Molecules 29 03463 g001
Molecules 29 03463 g002
Figure 2. Some drugs containing morpholine unit.
Figure 2. Some drugs containing morpholine unit.
Molecules 29 03463 g002
Molecules 29 03463 sch002
Scheme 2. Substrate scope of various aromatic aldehydes 2 [a, b]. [a] Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol, 1.5 equiv.), 3a (0.4 mmol, 2 equiv.), and toluene (1.0 mL), 110 °C, 12 h. [b] Isolated yields based on 1a. [c] Reaction performed on a 6 mmol scale: 1a (6 mmol), 2a (9 mmol, 1.5 equiv.), 3a (12 mmol, 2 equiv.), and toluene (20 mL), 110 °C, 24 h.
Scheme 2. Substrate scope of various aromatic aldehydes 2 [a, b]. [a] Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol, 1.5 equiv.), 3a (0.4 mmol, 2 equiv.), and toluene (1.0 mL), 110 °C, 12 h. [b] Isolated yields based on 1a. [c] Reaction performed on a 6 mmol scale: 1a (6 mmol), 2a (9 mmol, 1.5 equiv.), 3a (12 mmol, 2 equiv.), and toluene (20 mL), 110 °C, 24 h.
Molecules 29 03463 sch002
Molecules 29 03463 sch003
Scheme 3. Substrate scope of various 2-aryl imidazo[1,2-a]pyridines 1 [a, b]. [a] Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol, 1.5 equiv.), 3a (0.4 mmol, 2 equiv.), and toluene (1.0 mL), 110 °C, 12 h. [b] Isolated yields based on 1.
Scheme 3. Substrate scope of various 2-aryl imidazo[1,2-a]pyridines 1 [a, b]. [a] Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol, 1.5 equiv.), 3a (0.4 mmol, 2 equiv.), and toluene (1.0 mL), 110 °C, 12 h. [b] Isolated yields based on 1.
Molecules 29 03463 sch003
Molecules 29 03463 sch004
Scheme 4. Substrate scope of various cycloamines 3 [a, b]. [a] Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol, 1.5 equiv.), 3a (0.4 mmol, 2 equiv.), and toluene (1.0 mL), 110 °C, 12 h. [b] Isolated yields based on 1a.
Scheme 4. Substrate scope of various cycloamines 3 [a, b]. [a] Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol, 1.5 equiv.), 3a (0.4 mmol, 2 equiv.), and toluene (1.0 mL), 110 °C, 12 h. [b] Isolated yields based on 1a.
Molecules 29 03463 sch004
Molecules 29 03463 sch005
Scheme 5. Control experiments.
Scheme 5. Control experiments.
Molecules 29 03463 sch005
Molecules 29 03463 sch006
Scheme 6. Proposed mechanisms.
Scheme 6. Proposed mechanisms.
Molecules 29 03463 sch006
Molecules 29 03463 sch007
Scheme 7. Synthesis route of 1a–1n.
Scheme 7. Synthesis route of 1a–1n.
Molecules 29 03463 sch007
Table 1. Optimization of reaction conditions [a].
Table 1. Optimization of reaction conditions [a].
Molecules 29 03463 i001
EntryCatalystSolventTemp. (°C)Yield of 4a (%) [b]
1-Toluene110trace
2TFA (20%)Toluene110trace
3TsOH (20%)Toluene110trace
4HFIP (20%)Toluene110trace
5Sc(OTf)3 (20%)Toluene11075
6Y(OTf)3 (20%)Toluene11090
7Y(OTf)3 (10%)Toluene11072
8Y(OTf)3 (25%)Toluene11090
9Y(OTf)3 (20%)DMF11042
10Y(OTf)3 (20%)1,4-Dioxane11035
11Y(OTf)3 (20%)Acetonitrile11018
12Y(OTf)3 (20%)Toluene10062
13Y(OTf)3 (20%)Toluene12090
14 [c]Y(OTf)3 (20%)Toluene11066
15 [d]Y(OTf)3 (20%)Toluene11082
16 [e]Y(OTf)3 (20%)Toluene11088
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol, 1.5 equiv.), 3a (0.4 mmol, 2 equiv.), and solvent (1.0 mL), 12 h. [b] Isolated yield. [c] 1a (0.2 mmol), 2a (0.2 mmol, 1.0 equiv.), and 3a (0.2 mmol, 1.0 equiv.). [d] 1a (0.2 mmol), 2a (0.3 mmol, 1.5 equiv.), and 3a (0.3 mmol, 1.5 equiv.). [e] 1a (0.2 mmol), 2a (0.4 mmol, 2.0 equiv.), and 3a (0.4 mmol, 2.0 equiv.).
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Yang, K.; Chen, C.-B.; Liu, Z.-W.; Li, Z.-L.; Zeng, Y.; Wang, Z.-Y. C3-Alkylation of Imidazo[1,2-a]pyridines via Three-Component Aza-Friedel–Crafts Reaction Catalyzed by Y(OTf)3. Molecules 2024, 29, 3463. https://doi.org/10.3390/molecules29153463

AMA Style

Yang K, Chen C-B, Liu Z-W, Li Z-L, Zeng Y, Wang Z-Y. C3-Alkylation of Imidazo[1,2-a]pyridines via Three-Component Aza-Friedel–Crafts Reaction Catalyzed by Y(OTf)3. Molecules. 2024; 29(15):3463. https://doi.org/10.3390/molecules29153463

Chicago/Turabian Style

Yang, Kai, Cai-Bo Chen, Zhao-Wen Liu, Zhen-Lin Li, Yu Zeng, and Zhao-Yang Wang. 2024. "C3-Alkylation of Imidazo[1,2-a]pyridines via Three-Component Aza-Friedel–Crafts Reaction Catalyzed by Y(OTf)3" Molecules 29, no. 15: 3463. https://doi.org/10.3390/molecules29153463

Article Metrics

Back to TopTop