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

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.

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 [1,2a]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 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].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 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.
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 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 C 3 -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.
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).
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), 1,4dioxane, 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][15][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.

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).product 4c in 87% yield.
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, 4methoxybenzaldehyde can react smoothly and obtain the corresponding product 4c in 87% yield.
More importantly, to demonstrate the efficiency and practical applicability of the present approach, a gram-scale experiment was performed in the laboratory.The gramscale reaction can be readily carried out on a 6 mmol scale (30 times), producing 4a with a yield of 85% (1.9554 g).

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.
Interestingly, thiomorpholine 3c has excellent substrate applicability in this conversion, affording the desired product 4y in 78% yield.
Furthermore, the structures of all expected products 4a-4ab were systematically confirmed by NMR ( 1 H, 13 C, and 19 F) 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.

Mechanism Investigation
In order to understand the reaction mechanism, several control experiments were carried out (Scheme 5).

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.
Interestingly, thiomorpholine 3c has excellent substrate applicability in this conversion, affording the desired product 4y in 78% yield.
Furthermore, the structures of all expected products 4a-4ab were systematically confirmed by NMR ( 1 H, 13 C, and 19 F) 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.

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-methyl piperidine-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 interme-diates iminium ion A and benzyl alcohol B by ESI-HRMS (see Supplementary Materials Figures S2 and S3 for details).
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].Scheme 6. Proposed mechanisms.
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].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].
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.Scheme 7. Synthesis route of 1a-1n.

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
The detailed 1 H, 13 C NMR, and 19 F NMR spectra for all compounds 4a-4ab are provided in the Supplementary Materials.

Conclusions
In summary, the Y(OTf) 3 -catalyzed three-component aza-Friedel-Crafts reaction was developed for the synthesis of the C 3 -alkylated imidazo[1,2-a]pyridines from imidazo[1,2a]pyridines, aldehydes, and amines.The developed protocol is operationally simple and provided a wide range of C 3 -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[1,2a]pyridines with multifunctional groups.

Scheme 6 .
Scheme 6. Proposed mechanisms.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) [41-43].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].

Table 1 .
Optimization of reaction conditions[a].

pyridine 1a, p-tolualdehyde 2a, and
morpholine as the model substrates.The results are summarized in Table1.

Table 1 .
Optimization of reaction conditions[a].