Switchable electrosynthesis of C-1-unsubstituted imidazopyridines

Jinlin Hang; Meng Chen; Weibin Ma; Zefu Zheng; Zheng Fang; Ning Zhu; Chengkou Liu

doi:10.1016/j.isci.2025.114588

. 2025 Dec 30;29(2):114588. doi: 10.1016/j.isci.2025.114588

Switchable electrosynthesis of C-1-unsubstituted imidazopyridines

Jinlin Hang ¹, Meng Chen ¹, Weibin Ma ^2,³, Zefu Zheng ^2,³, Zheng Fang ¹, Ning Zhu ¹, Chengkou Liu ^1,^4,^∗

PMCID: PMC12828537 PMID: 41585477

Summary

Oxidative coupling and cyclocondensation reactions to produce imidazopyridine have been attractive methodologies because of their inherent atom- and step-economy, which have been well established using exogenous oxidants, especially I₂. However, the straightforward and efficient preparation of C-1-unsubstituted-imidazopyridine remains an unsolved challenge, because the core features of imidazopyridine are low oxidation potential and can be easily oxidized to give the C-1-substituted byproduct. Herein, we developed a highly efficient and clean electrosynthesis of C-1-unsubstituted imidazo[1,5-a]pyridine using a user-friendly undivided cell under exogenous oxidant- and transition metal-free conditions. Moreover, the switchable access to imidazo[1,5-a]pyridine was achieved from the oxidative cyclization of two equivalents of pyridin-2-ylmethylamine or the oxidative cyclocondensation of pyridin-2-ylmethylamine and aryl methyl ketones.

Subject areas: Chemistry, Organic chemistry

Graphical abstract

Highlights

•
Switchable electrosynthesis of C-1-unsubstituted imidazopyridine
•
Exogenous oxidant- and transition metal-free conditions
•
Using a user-friendly undivided cell with higher atom and step economy

Chemistry; Organic chemistry

Introduction

The imidazo[1,5-a]pyridine core has been considered to be an important scaffold in natural products and pharmaceuticals because of its unique biological activities, including dark blue cancer cell growth antagonists (cribrostatin 6),¹^,² cytotoxic immunosuppressant and DNA synthesis antagonists (pirmagrel),³^,⁴ tryptophan 2,3-dioxygenase antagonists,⁵ and so on⁶^,⁷^,⁸^,⁹ (Figure 1). In addition, due to its unique photophysical properties, the imidazo[1,5-a]pyridine scaffold is widely used in organic light-emitting diodes and organic thin-layer field-effect transistors.¹⁰^,¹¹^,¹²^,¹³ Recently, it has received considerable attention using the imidazopyridine scaffold as a heterocyclic ligand for transition metal catalysis.¹⁴^,¹⁵^,¹⁶^,¹⁷ Thus, highly efficient synthesis of imidazo[1,5-a]pyridine has been a research hotspot. Traditionally, the preparation of imidazo[1,5-a]pyridine scaffold required pre-preparation of substrates containing functional groups, including carboxylic acids,¹⁸^,¹⁹ acyl chlorides,²⁰^,²¹ acyl anhydrides,²²^,²³ dithionates,²⁴^,²⁵ thioamides,²⁶^,²⁷ or aldehydes,²⁸^,²⁹ which were employed as electrophilic components and were cumbersome and inefficient. Oxidative coupling or cyclocondensation reactions have been recognized as an ideal, efficient, and straightforward strategy to construct carbon-carbon and carbon-hetero bond, which has fascinated many chemists since its atom economy.³⁰^,³¹^,³²^,³³^,³⁴^,³⁵^,³⁶^,³⁷^,³⁸ Over the past few years, a number of oxidative coupling and cyclization reactions to imidazopyridine and related heterocycles had been established using transition-metal catalysts³⁹^,⁴⁰^,⁴¹ or hypervalent iodine reagents⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷ including IBX, phenyliodine(III) diacetate (PIDA) and phenyliodine(III) bis(trifluoroacetate) (PIFA) or molecular iodine. Moreover, some oxidative coupling or cyclocondensation reactions had been reported under exogenous oxidant- and transition metal-free conditions, which used electric energy to drive the reaction.⁴⁸^,⁴⁹^,⁵⁰^,⁵¹

Biologically active C-1-unsubstituted imidazo[1,5-a]pyridine derivatives

Electrochemistry has been recognized as an environmentally friendly and economic methodology.⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶ Besides organic electrosynthesis, electrochemistry had also been widely used in N₂ reduction⁵⁷^,⁵⁸ (a long-run continuous ammonia electrosynthesis had been previewed by us in matter⁵⁹), CO₂ fixation,⁶⁰^,⁶¹^,⁶² seawater desalination,⁶³^,⁶⁴^,⁶⁵ etc.⁵⁵^,⁶⁶ In this context, the straightforward construction of imidazo[1,5-a]pyridine had been developed from the oxidative cyclocondensation of amines with aldehydes or ketones under exogenous oxidant or electrochemical conditions. For instance, Wu’s group reported an iodine-promoted oxidative amination/iodination for direct synthesis of 1-iodoimidazo[1,5-a]pyridine from the oxidative cyclocondensations of pyridin-2-ylmethylamine and aryl methyl ketones (Scheme 1A).⁶⁷ Besides, the corresponding imidazopyridine products could also be obtained from the oxidative cyclocondensations of two equivalents (equiv.) of pyridin-2-ylmethylamine.⁶⁸ The iodination of imidazopyridine was usually unavoidable in the presence of iodine. Recently, an electrochemical synthesis of 3-acyl imidazo[1,5-a]pyridine had also been developed by Ren (Scheme 1B).⁶⁹ Notwithstanding the progress, these methods usually failed to give C-1-unsubstituted imidazopyridine, limiting their further derivatization and application as the imidazole-based N-heterocyclic ligands. Therefore, the development of a sustainable and safe oxidative cyclization method to produce C-1-unsubstituted imidazopyridine had been on high demand. With our continued interest in electrochemical oxidative coupling, some electrochemical coupling to form C-hetero bonds,⁷⁰^,⁷¹^,⁷² or cyclization to construct polycyclic compounds had been previously reported by us.⁷³^,⁷⁴^,⁷⁵^,⁷⁶ Herein, we reported a straightforwardly switchable electrosynthesis of C-1-unsubstituted imidazo[1,5-a]pyridine from the oxidative cyclization of two equiv. of pyridin-2-ylmethylamine or the oxidative cyclocondensation of pyridin-2-ylmethylamine and aryl methyl ketones in a user-friendly undivided cell under exogenous oxidant- and transition metal-free condition (Scheme 1C). No iodination byproduct was detected even through stoichiometric amounts of I⁻ were employed.

Scheme 1 — Strategies for the construction of imidazo[1,5-a] pyridine

Results and discussion

Reaction condition optimization

To optimize the reaction conditions, initial investigation was started using pyridin-2-ylmethanamine as the model substrate (Table 1). To our delight, 74% of desired product 2 was obtained after electrolysis in an undivided cell equipped with a C-rod anode and a platinum plate cathode using a mixed solvent of DMSO/HFIP/H₂O (7/1/2) at a constant current of 8 mA and 70°C in the presence of 1.5 equiv. of ⁿBu₄NI (entry 1). Using other electrolyte such as ⁿBu₄NBF₄, ⁿBu₄NPF₆, or ⁿBu₄NOAc completely abolished the reaction (entry 2). Dramatic yield reduction was observed when ⁿBu₄NI was replaced by KI or NaI (entry 3). It might attribute to the different adsorption energies of different anions, which prevented the adsorption of substrates on the electrode.⁷⁷^,⁷⁸ Furthermore, only trace amount of target product was detected when ⁿBu₄NBF₄, ⁿBu₄NPF₆, or ⁿBu₄NOAc was employed in the presence of 0.2 equiv. of KI (entry 4). Furthermore, increasing the amount of KI to 1.5 equiv. resulted in more products produced (entry 5). These results revealed that iodide ion played a critical role, which might act as a redox mediator. The use of the corresponding mixed solvent played a critical role in the formation of the desired product, as use DMSO, HFIP, DMSO/HFIP or DMSO/H₂O used as solvent, or replacing DMSO with DMF, EtOH, or ACN, or replacing HFIP with EtOH or TFE all led to lower yields (entries 6–8). Herein, HFIP featured higher oxidative stability and might enhance the stability of the radical cations.⁷⁹^,⁸⁰ In addition, the reduction of HFIP and H₂O at the cathode led to the formation of base, which contributed to the dehydrogenation and was profit for the balance of electron to prevent the decomposition of the product. Using C cloth or Pt plate as anode instead of C rod resulted in the decrease of the desired product (entry 9).

Table 1.

Optimization of the reaction conditions


Entry	Variation from “standard conditions”	Yield (%)
In the absence of 3		Yield of 2

1	Condition^a	74^c
2	ⁿBu₄NBF₄, ⁿBu₄NPF₆, or ⁿBu₄NOAc instead of ⁿBu₄NI	no, no, no
3	KI or NaI instead of ⁿBu₄NI	49, 45
4	ⁿBu₄NBF₄, ⁿBu₄NPF₆, or ⁿBu₄NOAc instead of ⁿBu₄NI (0.2 eq KI added)	trace, trace, trace
5	ⁿBu₄NBF₄, ⁿBu₄NPF₆, or ⁿBu₄NOAc instead of ⁿBu₄NI (1.5 eq KI added)	38, 29, 18
6	DMSO, HFIP, DMSO/HFIP, or DMSO/H₂O used as solvent	30, 54, 37
7	DMF, EtOH, or ACN instead of DMSO	24, 6, 14
8	EtOH or TFE instead of HFIP	45, 53
9	C cloth or Pt as anode	33, 47
10	rt or 45	23, 43
11	1.0 or 2.0 eq ⁿBu₄NI was used	35, 49
12	2, 2.2, 2.4, or 2.6 V (constant voltage)	14, 16, 27, 18
13	no electricity	no

In the presence of 3		Yield of 4

14	Condition^b	75^c
15	C rod or C cloth as anode	trace, trace
16	ACN or THF instead of EtOH	10, no
17	1 or 6 mA	62, 40
18	45°C or 65°C	60, 30
19	no electricity	no

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Reaction conditions: undivided cell, C rod anode (⌀ 6 mm), platinum plate cathode (10 mm × 10 mm x 0.1 mm), 1 (0.5 mmol, 54.0 mg), ⁿBu₄NI (0.75 mmol, 277.0 mg), DMSO/HFIP/H₂O (7/1/2, 8 mL), 8 mA, 70^oC, 3.5 h.

Reaction conditions: undivided cell, platinum plate anode and cathode (10 mm × 10 mm x 0.1 mm), 1 (0.5 mmol, 54.0 mg), 3 (1 mmol, 120.0 mg), ⁿBu₄NI (0.1 mmol, 36.9 mg), EtOH (8 mL), 3 mA, rt, 12 h. Yields were determined by ¹H NMR using dibromomethane as the internal standard. DMSO: dimethyl sulfoxide, HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol, DMF: N,N-dimethylformamide, ACN: acetonitrile, TFE: 2,2,2-trifluoroethanol, THF: tetrahydrofuran, C cloth (35 × 15 mm).

Isolated yield.

Lower temperature showed poor reactivity (entry 10). Decreasing the amount of ⁿBu₄NI led to lower conversion. In addition, more C1 iodo-imidazopyridine was formed when the amount of TBAI was increased to 2.0 equiv. (entry 11). It was found that dramatic yield reduction was observed when the electrolysis was carried out under constant voltage condition (entry 12). Control experiments showed that electricity was indispensable (entry 13). Interestingly, the corresponding oxidative cyclocondensation product 4 of pyridin-2-ylmethylamine 1 and aryl methyl ketone 3 was obtained in 75% yield under a constant current of 3 mA at ambient temperature in an undivided cell equipped with Pt-plate anode and Pt-plate cathode using ethanol as a solvent in the presence of 0.2 equiv. of ⁿBu₄NI (entry 14). Using other electrode material such as C rod or C cloth as anode, or solvent such as ACN or THF led to poor reaction efficiency (entries 15 and 16). Using relatively low or high current density or increasing the reaction temperature to 45°C or 65°C all resulted in the poor yield (entries 17 and 18). No product was formed in the absence of electricity (entry 19).

Scope for electrosynthesis of C-1-unsubstituted imidazopyridine

The substrate scope of this switchable electrosynthesis of imidazopyridine was investigated (Scheme 2). Moderate to good yield was obtained from the oxidative cyclization of two equiv. of pyridin-2-ylmethylamine when the benzene ring was functionalized with substituent at the different position (2, 5–9). It was a pity that no more products were prepared because the functionalized pyridin-2-ylmethylamine were difficult to be prepared. In this context, we subsequently explored the substrate scope of electro-oxidative cyclocondensation of pyridin-2-ylmethylamine and aryl methyl ketones. Similarly, alkyl-substituted pyridin-2-ylmethylamine were tolerated with good yields obtained regardless of the position of the group (10–13). In addition, 1-methyl-substituted imidazopyridine was also generated in good yield (13). Replacing methyl with phenyl did not exhibit detrimental effect on the formation of the desired product (14). Then, the substituted aryl methyl ketones were employed. To our delight, this electrosynthesis of C-1-unsubstituted imidazo[1,5-a]pyridine exhibited excellent functional group tolerance toward different electronic properties including H (4), Me (15, 24), F (16, 26, 27), Cl (17), Br (18), I (19), CO₂Me (20), CN (21), CF₃ (22), and NO₂ (23, 25). We did not detect any dehalogenation byproduct even through iodo-substituted substrate was involved, which made the further functionalization realizable and revealed that C-1 unsubstituted products were not generated from the iodination and electroreduction deiodination. In addition, polysubstituted phenyl ring, naphthalene, and heteroaromatic substrates were all tolerated (26–29).

Mechanistic studies

The further mechanistic studies were carried out to gain insights into the reaction process of this highly efficient and clean method for the preparation of the C-1-unsubstituted imidazopyridine (Scheme 3). Iodine or iodine radical could be generated smoothly from the electrochemical oxidation. Thus, control experiments were performed using exogenous oxidant such as I₂ or NIS in the absence of electricity (Scheme 3A and 3B). It was found that the desired products and the corresponding iodo byproduct were formed, even though poor reactivity was exhibited. Moreover, the cyclocondensation product between benzaldehyde and pyridin-2-ylmethanamine was obtained with 90% yield when 3 equiv. of benzaldehyde was added (Scheme 3C), and picolinaldehyde 32 was detected by HRMS successfully (Scheme 3D). These results revealed that the aryl aldehyde was likely to be formed from the oxidative of the corresponding amines and served as critical intermediate. Replacing acetophenone with 2-iodo-1-phenylethan-1-one resulted in the formation of the corresponding oxidative cyclocondensation product of pyridin-2-ylmethylamine and aryl methyl ketones in 8% yield even though more cyclization product of two equiv. of pyridin-2-ylmethylamine and iodo byproduct were formed (Scheme 3E). In addition, 2-iodo-1-phenylethan-1-one 33 was formed and detected by TLC when the electrolysis of acetophenone was performed for 6 h in the presence of pyridin-2-ylmethanamine 1 (Scheme 3F-1). Furthermore, 8% iodo product of acetophenone was obtained when the reaction was carried out in the absence of 1 (Scheme 3F-2). It indicated that α iodo ketones might promote this cyclization process as critical intermediate. And, the stoichiometric amounts of α iodo ketones resulted in stoichiometric amounts of I₂, which led to decreased product formation with more byproduct generated.

Scheme 3 — Summary of mechanistic findings

Based on the mechanistic studies and previous reports,⁸¹^,⁸² a possible reaction process of this electrochemically switchable synthesis of C-1-unsubstituted imidazopyridine was proposed (Scheme 4). The electrosynthesis of imidazopyridine 2 commences with the anodic oxidation of iodide ion to hypervalent iodine intermediate, which reacts with the amine 1 to the corresponding N-indo intermediate 1–1. Imine intermediate 1–2 was formed from the elimination of 1–1. Imine then undergoes hydrolysis to produce an aldehyde intermediate 1–3. The condensation of aldehyde 1–3 and another amine 1 leads to the generation of imine intermediate 1–4. Finally, the oxidative desired product 2 is obtained from intramolecular addition, oxidation, and deprotonation. As for the electrochemically oxidative cyclocondensation of pyridin-2-ylmethylamine and aryl methyl ketones, 2-iodo-1-phenylethan-1-one 3-1 is generated firstly in the presence of I₂, which is generated in situ from the anodic oxidation of iodide ion. The substitution product 3–2 is obtained through the reaction between 3–1 and 1. The amine intermediate 3–2 can be transformed into the N-indo intermediate 3–3, which undergoes elimination to give imine intermediate 3–4. Likewise, intramolecular addition, oxidation and deprotonation lead to the generation of final product 4. Correspondingly, the reduction of H⁺ at the cathode leads to the formation of H₂.

Scheme 4 — Proposed mechanism for electrochemically switchable synthesis of C-1-unsubstituted imidazopyridine

In summary, an electrochemically switchable preparation of imidazo[1,5-a]pyridine derivatives from straightforwardly oxidative cyclization of two equiv. of pyridin-2-ylmethylamine or the oxidative cyclocondensation of pyridin-2-ylmethylamine and aryl methyl ketones was achieved. This highly efficient and clean electrosynthesis allowed convenient access to C-1-unsubstituted imidazo[1,5-a]pyridine using a user-friendly undivided cell in the absence of exogenous oxidant and transition metal catalyst.

Limitations of the study

The study is limited to aryl ketone, and further study is needed on reaction systems for alkyl ketone and other heterocyclic ketones.

Resource availability

Lead contact

Further information and requests should be directed to and will be fulfilled by the lead contact, Chengkou Liu (liuchengkou@njtech.edu.cn).

Materials availability

All commercially available reagents and solvents were used without any further purification.

Data and code availability

•
All data reported in this study are available within the article or supplemental information on the web and will be shared by the lead contact upon request.
•
This article does not report original code.
•
Any additional information required to reanalyze the data reported in this article can be obtained from the lead contact upon request.

Acknowledgments

This research was supported by the Natural Science Foundation of Jiangsu Province, Frontier Project (BK20212003) and the Foundation of China Academy of Railway Sciences (grant 2023YJ382).

Author contributions

J.H. and M.C. conducted the experiments; J.H., W.M., Z.Z., and N.Z. analyzed the data; Z.F. and C.L. designed the research, and prepared the manuscript.

Declaration of interests

The authors declare no competing interests.

STAR★Methods

Key resources table

REAGENT or RESOURCE	SOURCE	IDENTIFIER
Chemicals, peptides, and recombinant proteins

pyridin-2-ylmethanamine	Energy chemical	Cas: 3731-51-9
3-methylpicolinonitrile	Energy chemical	Cas: 20970-75-6
4-methylpicolinonitrile	Energy chemical	Cas: 1620-76-4
(5-methylpyridin-2-yl)methanamine	Energy chemical	Cas: 45715-08-0
4-methoxypicolinonitrile	Energy chemical	Cas: 36057-44-0
(5-chloropyridin-2-yl)methanamine	Energy chemical	Cas: 67938-76-5
(6-methylpyridin-2-yl)methanamine	Energy chemical	Cas: 6627-60-7
1-(pyridin-2-yl)ethan-1-amine	Energy chemical	Cas: 42088-91-5
phenyl(pyridin-2-yl)methanamine	Energy chemical	Cas: 39930-11-5
acetophenone	Energy chemical	Cas: 98-86-2
1-(p-tolyl)ethan-1-one	Energy chemical	Cas: 122-00-9
1-(4-fluorophenyl)ethan-1-one	Energy chemical	Cas: 403-42-9
1-(4-chlorophenyl)ethan-1-one	Energy chemical	Cas: 99-91-2
1-(4-bromophenyl)ethan-1-one	Energy chemical	Cas: 99-90-1
1-(4-iodophenyl)ethan-1-one	Energy chemical	Cas: 13329-40-3
methyl 4-acetylbenzoate	Energy chemical	Cas: 3609-53-8
4-acetylbenzonitrile	Energy chemical	Cas: 1443-80-7
1-(4-(trifluoromethyl)phenyl)ethan-1-one	Energy chemical	Cas: 709-63-7
1-(4-nitrophenyl)ethan-1-one	Energy chemical	Cas: 100-19-6
1-(o-tolyl)ethan-1-one	Energy chemical	Cas: 577-16-2
1-(3-nitrophenyl)ethan-1-one	Energy chemical	Cas: 121-89-1
1-(2,4,5-trifluorophenyl)ethan-1-one	Energy chemical	Cas: 129322-83-4
1-(perfluorophenyl)ethan-1-one	Energy chemical	Cas: 652-29-9
1-(naphthalen-2-yl)ethan-1-one	Energy chemical	Cas: 93-08-3
1-(furan-2-yl)ethan-1-one	Energy chemical	Cas: 1192-62-7
tetrabutylammonium iodide	Energy chemical	Cas: 311-28-4
dimethyl sulfoxide	Energy chemical	Cas: 67-68-5
1,1,1,3,3,3-hexafluoro-2-propanol	Adamas	Cas: 920-66-1
potassium borohydride	Energy chemical	Cas: 13762-51-1
copper(II) chloride	Energy chemical	Cas: 7447-39-4
isopropyl alcohol	Macklin	Cas: 67-63-0

Software and algorithms

ChemDraw Ultra 12.0	PerkinElmer	https://www.perkinelmer.com/category/chemdraw
MestReNova	Mestrelab Research	https://mestrelab.com

Other

Silica gel (200–300 mesh)	Shanghai Titan Scientific Co., Ltd	HSGF 254
Thin-layer chromatography using TLC silica gel plates	Yantai Xinnuo New Material Technology Co., Ltd	200-300 mesh
AVIII 400 MHz	Bruker	https://bruker.com
HRMS	Agilent	https://www.agilent.com.cn/

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Method details

Preparation of substituted pyridin-2-ylmethanamines

In a round-bottomed flask (50 mL) equipped with a stir bar, corresponding acetonitrile (1 mmol), KBH₄ (3 mmol, 0.17 g), CuCl₂ (0.25 mmol, 0.03 g) and isopropanol (2 mL, 80% aqueous solution) were added. The mixture was stirred at 60°C for 4 h and cooled to rt. Then, the reaction mixture was diluted with ethyl acetate (150 mL) and washed with saturated NH₄Cl aqueous solution (150 mL) and H₂O (150 mL). The separated organic layer was dried with anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by column chromatography (dichloromethane/methanol: 50:1) to get the desired product in 30–40% yield.

Preparation of products

General procedure for the electrochemically oxidative cyclization of two equiv. Of pyridin-2-ylmethylamines

In an undivided cell equipped with a C rod (⌀ 6 mm) anode and a Pt (10 mm × 10 mm x 0.1 mm) cathode, pyridin-2-ylmethanamine (0.5 mmol), ⁿBu₄NI (0.75 mmol, 277.0 mg) were dissolved in a mixed solvent of DMSO/HFIP/H₂O (7/1/2, 8 mL). The mixture was stirred at 70°C and electrolyzed at a constant current of 8 mA for 3.5 h under the open air. The reaction solution was diluted with ethyl acetate (50 mL) and washed with H₂O (50 mL). The separated organic layer was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatographic separation (ethyl acetate/petroleum ether: 30:1) to obtain the desired product.

General procedure for the electrochemically oxidative cyclocondensation of pyridin-2-ylmethylamines and aryl methyl ketones

In an undivided cell equipped with a Pt (10 mm × 10 mm x 0.1 mm) anode and a Pt (10 mm × 10 mm x 0.1 mm) cathode, acetophenone (0.5 mmol), pyridin-2-ylmethanamine (1.25 mmol), ⁿBu₄NI (0.1 mmol, 36.9 mg) were dissolved in a solvent of EtOH (6 mL). The mixture was stirred at room temperature and electrolyzed at a constant current of 3 mA for 12 h under the open air. The reaction solution was diluted with ethyl acetate (50 mL) and washed with H₂O (50 mL). The separated organic layer was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatographic separation (ethyl acetate/petroleum ether: 30:1) to obtain the desired product.

Characterization of products 2, 4–29

3-(Pyridin-2-yl)imidazo[1,5-a]pyridine (2):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 36.09 mg, 74%; ¹H NMR (400 MHz, DMSO-d₆) δ 9.91–9.84 (m, 1H), 8.71–8.65 (m, 1H), 8.29–8.23 (m, 1H), 7.92 (td, J = 7.8, 1.8 Hz, 1H), 7.77–7.71 (m, 1H), 7.64 (s, 1H), 7.37–7.32 (m, 1H), 7.01–6.95 (m, 1H), 6.91 (td, J = 6.9, 1.4 Hz, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 150.53, 148.42, 137.12, 134.51, 132.62, 125.28, 121.96, 121.25, 121.18, 120.50, 118.26, 114.07; HRMS (ESI-TOF) Calcd for C₁₂H₁₀N₃ [M + H]⁺: 196.0869; found: 196.0869.

Imidazo[1,5-a]pyridin-3-yl(phenyl)methanone(4):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 83.28 mg, 75%; ¹H NMR (400 MHz, Chloroform-d) δ 9.85–9.81 (m, 1H), 8.37–8.32 (m, 2H), 7.74 (d, J = 0.8 Hz, 1H), 7.71 (dt, J = 8.9, 1.3 Hz, 1H), 7.59–7.54 (m, 1H), 7.54–7.49 (m, 2H), 7.23–7.17 (m, 1H), 7.02 (td, J = 6.9, 1.3 Hz, 1H); ¹³C NMR (101 MHz, Chloroform-d) δ 182.81, 138.40, 135.01, 134.72, 132.14, 130.65, 128.20, 127.06, 124.59, 123.96, 118.09, 116.42; HRMS (ESI-TOF) Calcd for C₁₄H₁₁N₂O [M + H]⁺: 223.0866; found: 223.0891.

8-Methyl-3-(3-methylpyridin-2-yl)imidazo[1,5-a]pyridine (5):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 28.45 mg, 51%; ¹H NMR (400 MHz, Chloroform-d) δ 9.01–8.96 (m, 1H), 8.51 (dd, J = 4.8, 1.7 Hz, 1H), 7.65–7.60 (m, 1H), 7.56 (d, J = 0.9 Hz, 1H), 7.15 (dd, J = 7.7, 4.7 Hz, 1H), 6.58 (dt, J = 6.5, 1.2 Hz, 1H), 6.53 (t, J = 6.8 Hz, 1H), 2.69 (s, 3H), 2.45 (s, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 148.91, 145.90, 139.51, 136.54, 133.49, 132.85, 127.71, 122.45, 122.13, 119.01, 118.90, 113.10, 20.78, 17.86; HRMS (ESI-TOF) Calcd for C₁₄H₁₄N₃ [M + H]⁺: 224.1182; found: 224.1179.

7-Methyl-3-(4-methylpyridin-2-yl)imidazo[1,5-a]pyridine (6):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 39.60 mg, 71%; ¹H NMR (400 MHz, Chloroform-d) δ 9.83 (d, J = 7.4 Hz, 1H), 8.46 (d, J = 5.1 Hz, 1H), 8.17–8.14 (m, 1H), 7.43 (s, 1H), 7.24 (q, J = 1.4 Hz, 1H), 6.98 (dd, J = 5.1, 1.7 Hz, 1H), 6.53 (dd, J = 7.4, 1.8 Hz, 1H), 2.40 (s, 3H), 2.31 (s, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 150.99, 148.05, 147.64, 135.15, 133.44, 130.58, 125.61, 122.69, 122.15, 119.32, 116.46, 115.79, 21.25, 21.17; HRMS (ESI-TOF) Calcd for C₁₄H₁₄N₃ [M + H]⁺: 224.1182; found: 224.1192.

6-Methyl-3-(5-methylpyridin-2-yl)imidazo[1,5-a]pyridine (7):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 33.47 mg, 60%; ¹H NMR (400 MHz, Chloroform-d) δ 9.68–9.65 (m, 1H), 8.47 (d, J = 2.6 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.58 (dd, J = 8.3, 2.3 Hz, 1H), 7.50 (s, 1H), 7.42 (dd, J = 9.1, 1.1 Hz, 1H), 6.69 (dd, J = 9.1, 1.5 Hz, 1H), 2.37 (s, 3H), 2.32 (s, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 148.92, 148.45, 137.36, 135.37, 131.99, 131.10, 123.47, 123.07, 123.02, 121.51, 120.69, 117.36, 18.88, 18.49; HRMS (ESI-TOF) Calcd for C₁₄H₁₄N₃ [M + H]⁺: 224.1182; found: 224.1182.

6-Chloro-3-(5-chloropyridin-2-yl)imidazo[1,5-a]pyridine (8):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 55.54 mg, 86%; ¹H NMR (400 MHz, Chloroform-d) δ 9.96 (dt, J = 1.9, 1.0 Hz, 1H), 8.60 (dd, J = 2.5, 0.7 Hz, 1H), 8.30 (dd, J = 8.7, 0.7 Hz, 1H), 7.76 (dd, J = 8.7, 2.5 Hz, 1H), 7.61 (d, J = 0.9 Hz, 1H), 7.50 (dd, J = 9.5, 1.0 Hz, 1H), 6.86 (dd, J = 9.5, 1.7 Hz, 1H); ¹³C NMR (101 MHz, Chloroform-d) δ 148.74, 147.12, 136.68, 134.92, 131.44, 130.21, 123.68, 122.66, 122.60, 122.49, 122.10, 118.45; HRMS (ESI-TOF) Calcd for C₁₂H₈Cl₂N₃ [M + H]⁺: 264.0090; found: 264.0109.

7- Methoxy-3-(4-methoxypyridin-2-yl)imidazo[1,5-a]pyridine (9):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 44.6 mg, 70%; ¹H NMR (400 MHz, Chloroform-d) δ 9.88 (dt, J = 7.8, 0.9 Hz, 1H), 8.37 (d, J = 5.8 Hz, 1H), 7.80 (d, J = 2.6 Hz, 1H), 7.34 (d, J = 0.9 Hz, 1H), 6.71 (dd, J = 5.7, 2.5 Hz, 1H), 6.69–6.67 (m, 1H), 6.46 (dd, J = 7.9, 2.6 Hz, 1H), 3.92 (s, 3H), 3.82 (s, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 166.05, 153.93, 152.79, 149.31, 134.66, 134.21, 127.74, 118.34, 110.03, 109.41, 104.86, 93.23, 55.41, 55.31; HRMS (ESI-TOF) Calcd for C₁₄H₁₄N₃O₂ [M + H]⁺: 256.1081; found: 256.1078.

(6-Methylimidazo[1,5-a]pyridin-3-yl)(phenyl)methanone (10):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 82.63 mg, 70%; ¹H NMR (400 MHz, Chloroform-d) δ 9.71–9.66 (m, 1H), 8.34 (dt, J = 6.9, 1.6 Hz, 2H), 7.69 (s, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.59–7.47 (m, 3H), 7.08 (dd, J = 9.1, 1.4 Hz, 1H), 2.42 (s, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 182.70, 138.62, 134.75, 133.88, 132.01, 130.65, 128.19, 127.92, 126.70, 124.82, 123.95, 117.31, 18.80; HRMS (ESI-TOF) Calcd for C₁₅H₁₃N₂O [M + H]⁺: 237.1022; found: 237.1022.

(5-Methylimidazo[1,5-a]pyridin-3-yl)(phenyl)methanone (11):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 67.28 mg, 57%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.12–8.08 (m, 2H), 7.85 (d, J = 8.9 Hz, 1H), 7.81 (s, 1H), 7.70–7.64 (m, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.29 (dd, J = 8.9, 6.7 Hz, 1H), 7.02 (d, J = 6.7 Hz, 1H), 2.53 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 181.73, 137.52, 136.60, 135.67, 132.76, 130.82, 128.14, 124.37, 122.74, 116.94, 115.98, 21.79; HRMS (ESI-TOF) Calcd for C₁₅H₁₃N₂O [M + H]⁺: 237.1022; found: 237.1022.

(8-Methylimidazo[1,5-a]pyridin-3-yl)(phenyl)methanone (12):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 73.19 mg, 62%; ¹H NMR (400 MHz, Chloroform-d) δ 9.69 (d, J = 6.8 Hz, 1H), 8.38–8.29 (m, 2H), 7.73 (s, 1H), 7.59–7.48 (m, 3H), 7.01–6.92 (m, 2H), 2.58 (s, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 182.94, 138.52, 135.68, 135.57, 132.10, 130.66, 128.24, 128.21, 124.80, 123.83, 122.76, 116.56, 17.85; HRMS (ESI-TOF) Calcd for C₁₅H₁₃N₂O [M + H]⁺: 237.1022; found: 237.1022.

(1-Methylimidazo[1,5-a]pyridin-3-yl)(phenyl)methanone (13):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 84.99 mg, 72%; ¹H NMR (400 MHz, Chloroform-d) δ 9.83 (dt, J = 7.3, 1.1 Hz, 1H), 8.37 (dt, J = 6.9, 1.6 Hz, 2H), 7.65 (dt, J = 8.9, 1.3 Hz, 1H), 7.58–7.48 (m, 3H), 7.21–7.14 (m, 1H), 7.01 (td, J = 6.9, 1.3 Hz, 1H), 2.63 (s, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 182.06, 138.66, 133.43, 132.87, 132.34, 132.01, 130.83, 128.21, 127.12, 1 3.60, 117.62, 116.46, 13.22; HRMS (ESI-TOF) Calcd for C₁₅H₁₃N₂O [M + H]⁺: 237.1022; found: 237.0981.

Phenyl(1-phenylimidazo[1,5-a]pyridin-3-yl)methanone (14):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 39.7 mg, 70%; ¹H NMR (400 MHz, Chloroform-d) δ 9.87 (dd, J = 7.1, 1.1 Hz, 1H), 8.47–8.42 (m, 2H), 7.78 (s, 1H), 7.77–7.72 (m, 3H), 7.68 (dd, J = 7.1, 1.5 Hz, 2H), 7.48 (dd, J = 8.3, 6.7 Hz, 2H), 7.43–7.36 (m, 1H), 7.26–7.21 (m, 1H), 7.06 (td, J = 6.9, 1.3 Hz, 1H); ¹³C NMR (101 MHz, Chloroform-d) δ 182.31, 144.90, 140.53, 137.17, 135.08, 134.77, 131.28, 129.03, 128.09, 127.49, 127.15, 127.01, 124.68, 124.02, 118.22, 116.53; HRMS (ESI-TOF) Calcd for C₂₀H₁₅N₂O [M + H]⁺: 299.1179; found: 299.1143.

Imidazo[1,5-a]pyridin-3-yl(p-tolyl)methanone (15):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 68.04 mg, 58%; ¹H NMR (400 MHz, Chloroform-d) δ 9.85–9.79 (m, 1H), 8.31–8.25 (m, 2H), 7.74 (s, 1H), 7.71 (dt, J = 9.0, 1.3 Hz, 1H), 7.32 (d, J = 7.9 Hz, 2H), 7.23–7.17 (m, 1H), 7.02 (td, J = 6.9, 1.3 Hz, 1H), 2.44 (s, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 182.61, 142.91, 135.69, 135.04, 134.59, 130.81, 128.99, 127.07, 124.43, 123.63, 118.12, 116.34, 21.80; HRMS (ESI-TOF) Calcd for C₁₅H₁₃N₂O [M + H]⁺: 237.1022; found: 237.0981.

(4-Fluorophenyl)(imidazo[1,5-a]pyridin-3-yl)methanone (16):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 72.02 mg, 60%; ¹H NMR (400 MHz, Chloroform-d) δ 9.84–9.79 (m, 1H), 8.49–8.43 (m, 2H), 7.76–7.69 (m, 2H), 7.24–7.15 (m, 3H), 7.03 (td, J = 6.9, 1.3 Hz, 1H); ¹³C NMR (101 MHz, Chloroform-d) δ 180.99, 166.66, 164.14, 134.81, 134.55, 133.40, 133.32, 127.12, 124.69, 123.95, 118.15, 116.52, 115.38, 115.17; ¹⁹F NMR (376 MHz, Chloroform-d) δ −107.08; HRMS (ESI-TOF) Calcd for C₁₄H₁₀FN₂O [M + H]⁺: 241.0772; found: 241.0779.

(4-Chlorophenyl)(imidazo[1,5-a]pyridin-3-yl)methanone (17):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 83.21 mg, 65%; ¹H NMR (400 MHz, Chloroform-d) δ 9.84 (d, J = 7.1 Hz, 1H), 8.40–8.34 (m, 2H), 7.77–7.72 (m, 2H), 7.52–7.47 (m, 2H), 7.27–7.22 (m, 1H), 7.06 (td, J = 6.9, 1.2 Hz, 1H; ¹³C NMR (101 MHz, Chloroform-d) δ 181.02, 138.51, 136.63, 134.85, 134.78, 132.16, 128.39, 127.07, 124.82, 124.08, 118.12, 116.60; HRMS (ESI-TOF) Calcd for C₁₄H₁₀ClN₂O [M + H]⁺: 257.0476; found: 257.0483.

(4-Bromophenyl)(imidazo[1,5-a]pyridin-3-yl)methanone (18):

Yellow solid; petroluem ether/ethyl acetate 30:1; 102.00 mg, 68%; ¹H NMR (400 MHz, Chloroform-d) δ 9.83–9.77 (m, 1H), 8.31–8.23 (m, 2H), 7.76–7.67 (m, 2H), 7.67–7.60 (m, 2H), 7.24–7.19 (m, 1H), 7.04 (td, J = 6.9, 1.3 Hz, 1H); ¹³C NMR (101 MHz, Chloroform-d) δ 181.18, 137.07, 134.87, 134.75, 132.29, 131.43, 127.25, 127.08, 124.88, 124.12, 118.15, 116.66; HRMS (ESI-TOF) Calcd for C₁₄H₁₀BrN₂O [M + H]⁺: 300.9971; found: 300.9976.

Imidazo[1,5-a]pyridin-3-yl(4-iodophenyl)methanone (19):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 125.27 mg, 72%; ¹H NMR (400 MHz, Chloroform-d) δ 9.82–9.78 (m, 1H), 8.13–8.08 (m, 2H), 7.89–7.84 (m, 2H), 7.75–7.77 (m, 2H), 7.26–7.21 (m, 1H), 7.05 (td, J = 6.9, 1.3 Hz, 1H); ¹³C NMR (101 MHz, Chloroform-d) δ 181.49, 137.63, 137.45, 134.87, 134.68, 132.20, 127.08, 124.94, 124.11, 118.19, 116.73, 100.03; HRMS (ESI-TOF) Calcd for C₁₄H₁₀IN₂O [M + H]⁺: 348.9832; found: 348.9792.

Methyl 4-(imidazo[1,5-a]pyridine-3-carbonyl)benzoate (20):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 103.62 mg, 74%; ¹H NMR (400 MHz, Chloroform-d) δ 9.85 (d, J = 7.1 Hz, 1H), 8.39 (d, J = 8.2 Hz, 2H), 8.17 (d, J = 8.1 Hz, 2H), 7.80–7.73 (m, 2H), 7.29–7.24 (m, 1H), 7.09 (t, J = 6.9 Hz, 1H), 3.96 (s, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 181.73, 166.76, 142.12, 135.04, 134.78, 132.86, 130.57, 129.41, 127.16, 125.19, 124.40, 118.26, 116.93, 52.50; HRMS (ESI-TOF) Calcd for C₁₆H₁₃N₂O₃ [M + H]⁺: 281.0921; found: 281.0884.

4-(Imidazo[1,5-a]pyridine-3-carbonyl)benzonitrile (21):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 96.36 mg, 78%; ¹H NMR (400 MHz, Chloroform-d) δ 9.85 (d, J = 7.1 Hz, 1H), 8.45 (d, J = 8.1 Hz, 2H), 7.85–7.75 (m, 4H), 7.34–7.28 (m, 1H), 7.12 (t, J = 6.9 Hz, 1H); ¹³C NMR (101 MHz, Chloroform-d) δ 180.32, 142.01, 135.30, 134.60, 131.97, 131.12, 127.20, 125.60, 124.82, 118.58, 118.32, 117.20, 115.13; HRMS (ESI-TOF) Calcd for C₁₅H₁₀N₃O [M + H]⁺: 248.0818; found: 248.0866.

Imidazo[1,5-a]pyridin-3-yl(4-(trifluoromethyl)phenyl)methanone (22):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 105.88 mg, 73%; ¹H NMR (400 MHz, Chloroform-d) δ 9.85 (d, J = 7.1 Hz, 1H), 8.44 (d, J = 8.1 Hz, 2H), 7.82–7.72 (m, 4H), 7.31–7.24 (m, 1H), 7.09 (td, J = 6.9, 1.2 Hz, 1H); ¹³C NMR (101 MHz, Chloroform-d) δ 181.19, 141.44, 135.13, 134.70, 133.44, 133.12, 130.91, 127.14, 125.28, 125.17, 124.58, 122.65, 119.94, 118.24, 116.97; ¹⁹F NMR (376 MHz, Chloroform-d) δ −63.00; HRMS (ESI-TOF) Calcd for C₁₅H₁₀F₃N₂O [M + H]⁺: 291.0740; found: 291.0752.

Imidazo[1,5-a]pyridin-3-yl(4-nitrophenyl)methanone (23):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 93.471 mg, 70%; ¹H NMR (400 MHz, Chloroform-d) δ 9.90–9.84 (m, 1H), 8.57–8.49 (m, 2H), 8.41–8.31 (m, 2H), 7.84–7.76 (m, 2H), 7.36–7.30 (m, 1H), 7.15 (td, J = 6.9, 1.3 Hz, 1H); ¹³C NMR (101 MHz, Chloroform-d) δ 180.08, 149.65, 143.67, 135.41, 134.66, 131.67, 127.27, 125.75, 125.00, 123.31, 118.37, 117.32; HRMS (ESI-TOF) Calcd for C₁₄H₁₀N₃O₃ [M + H]⁺: 268.0717; found: 268.0673.

Imidazo[1,5-a]pyridin-3-yl(o-tolyl)methanone (24):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 66.10 mg, 56%; ¹H NMR (400 MHz, Chloroform-d) δ 9.87–9.83 (m, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.67–7.62 (m, 1H), 7.39 (td, J = 7.4, 1.5 Hz, 1H), 7.30 (t, J = 6.8 Hz, 2H), 7.25–7.20 (m, 1H), 7.07 (td, J = 6.9, 1.3 Hz, 1H), 2.43 (s, 3H); ¹³C NMR (101 MHz, Chloroform-d) δ 186.79, 138.99, 136.88, 135.50, 134.96, 131.06, 130.32, 129.62, 127.01, 125.27, 124.78, 124.50, 118.19, 116.61, 20.18; HRMS (ESI-TOF) Calcd for C₁₅H₁₃N₂O [M + H]⁺: 237.1022; found: 237.1030.

Imidazo[1,5-a]pyridin-3-yl(3-nitrophenyl)methanone (25):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 66.76 mg, 50%; ¹H NMR (400 MHz, Chloroform-d) δ 9.87 (dd, J = 7.0, 1.3 Hz, 1H), 9.31 (t, J = 1.9 Hz, 1H), 8.74 (dt, J = 7.9, 1.4 Hz, 1H), 8.39–8.43 (m, 1H), 7.79 (d, J = 10.2 Hz, 2H), 7.70 (t, J = 8.0 Hz, 1H), 7.34–7.29 (m, 1H), 7.13 (td, J = 6.9, 1.3 Hz, 1H); ¹³C NMR (101 MHz, Chloroform-d) δ 179.34, 148.17, 139.74, 136.42, 135.35, 134.53, 129.30, 127.25, 126.39, 126.00, 125.59, 124.91, 118.37, 117.22; HRMS (ESI-TOF) Calcd for C₁₄H₁₀N₃O₃ [M + H]⁺: 268.0717; found: 268.0725.

Imidazo[1,5-a]pyridin-3-yl(2,4,5-trifluorophenyl)methanone (26):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 85.58 mg, 62%; ¹H NMR (400 MHz, Chloroform-d) δ 9.76 (dt, J = 7.1, 1.0 Hz, 1H), 7.76 (d, J = 7.5 Hz, 2H), 7.72–7.65 (m, 1H), 7.34–7.28 (m, 1H), 7.12 (td, J = 6.9, 1.3 Hz, 1H), 7.09–7.01 (m, 1H); ¹³C NMR (101 MHz, Chloroform-d) δ 178.17, 157.42, 154.88, 153.23, 150.69, 135.61, 134.58, 126.95, 125.71, 125.26, 123.91, 119.64, 119.59, 119.44, 119.40, 118.32, 117.29, 106.82, 106.61, 106.54, 106.33; ¹⁹F NMR (376 MHz, Chloroform-d) δ −113.61, −113.63, −113.65, −128.82, −128.84, −128.88, −128.89, −142.26, −142.30; HRMS (ESI-TOF) Calcd for C₁₄H₈F₃N₂O [M + H]⁺: 277.0583; found: 277.0591.

Imidazo[1,5-a]pyridin-3-yl(perfluorophenyl)methanone (27):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 80.12 mg, 50%; ¹H NMR (400 MHz, Chloroform-d) δ 9.73 (dd, J = 7.0, 1.2 Hz, 1H), 7.79 (dt, J = 8.9, 1.3 Hz, 1H), 7.76–7.75 (m, 1H), 7.42–7.35 (m, 1H), 7.20 (td, J = 6.9, 1.3 Hz, 1H); ¹³C NMR (101 MHz, Chloroform-d) δ 172.29, 145.38, 145.34, 143.72, 142.84, 141.18, 139.07, 138.92, 136.51, 136.37, 134.68, 126.92, 126.69, 126.43, 118.49, 117.94, 114.87; HRMS (ESI-TOF) Calcd for C₁₄H₆F₅N₂O [M + H]⁺: 313.0395 found: 313.0397.

Imidazo[1,5-a]pyridin-3-yl(naphthalen-2-yl)methanone (28):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 96.59 mg, 71%; ¹H NMR (400 MHz, Chloroform-d) δ 9.90 (d, J = 7.2 Hz, 1H), 9.05 (d, J = 1.7 Hz, 1H), 8.38 (dd, J = 8.6, 1.7 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.75 (dd, J = 8.9, 1.2 Hz, 1H), 7.62–7.56 (m, 1H), 7.56–7.51 (m, 1H), 7.26–7.21 (m, 1H), 7.06 (td, J = 6.9, 1.3 Hz, 1H); ¹³C NMR (101 MHz, Chloroform-d) δ 182.56, 135.67, 135.33, 134.78, 132.70, 130.00, 128.15, 127.91, 127.81, 127.20, 126.47, 126.43, 124.63, 124.00, 118.18, 116.48; HRMS (ESI-TOF) Calcd for C₁₈H₁₃N₂O [M + H]⁺: 273.1022; found: 273.1029.

Furan-2-yl(imidazo[1,5-a]pyridin-3-yl)methanone (29):

Yellow solid; Eluent: petroluem ether/ethyl acetate 30:1; 68.92 mg, 65%; ¹H NMR (400 MHz, Chloroform-d) δ 9.79 (d, J = 7.2 Hz, 1H), 8.13 (d, J = 3.6 Hz, 1H), 7.76–7.66 (m, 3H), 7.17 (dd, J = 9.0, 6.6 Hz, 1H), 7.03–6.96 (m, 1H), 6.61 (dd, J = 3.6, 1.7 Hz, 1H); ¹³C NMR (101 MHz, Chloroform-d) δ 169.61, 151.65, 147.02, 134.79, 133.86, 126.84, 124.39, 123.87, 121.66, 118.18, 116.41, 112.44; HRMS (ESI-TOF) Calcd for C₁₂H₉N₂O₂ [M + H]⁺: 213.0659; found: 213.0668.

Quantification and statistical analysis

Figures (Figure 1) and Schemes (Scheme 1, 2, 3, and 4) shown in the text were produced by Origin 2017 from the raw data. All NMR raw data was analyzed with MestReNova developed by Mestrelab Research.

Published: December 30, 2025

Footnotes

Supplemental information can be found online at https://doi.org/10.1016/j.isci.2025.114588.

Supplemental information

Document S1. Figures S1 and S2

mmc1.pdf^{(6.1MB, pdf)}

References

1.Pettit G.R., Collins J.C., Knight J.C., Herald D.L., Nieman R.A., Williams M.D., Pettit R.K. Antineoplastic Agents. 485. Isolation and Structure of Cribrostatin 6, a Dark Blue Cancer Cell Growth Inhibitor from the Marine Sponge Cribrochalina sp.,1a. J. Nat. Prod. 2003;66:544–547. doi: 10.1021/np020012t. [DOI] [PubMed] [Google Scholar]
2.Calcul L., Longeon A., Mourabit A.A., Guyot M., Bourguet-Kondracki M.L. Novel Alkaloids of the Aaptamine Class from an Indonesian Marine Sponge of the Genus Xestospongia. Tetrahedron. 2003;59:6539–6544. doi: 10.1016/S0040-4020(03)01069-X. [DOI] [Google Scholar]
3.Burke S.E., Dicola G., Lefer A.M. Protection of Ischemic Cat Myocardium by CGS-13080, a Selective Potent Thromboxane A2 Synthesis Inhibitor. J. Cardiovasc. Pharmacol. 1983;5:842–847. doi: 10.1097/00005344-198309000-00021. [DOI] [PubMed] [Google Scholar]
4.Barter J.F., Marlow D., Kamath R.K., Harbert J., Torrisi J.R., Barnes W.A., Potkul R.K., Newsome J.T., Delgado G. Lack of Protective Effect of Thromboxane Synthetase Inhibitor (CGS-13080) on Single Dose Radiated Canine Intestine. Gynecol. Oncol. 1991;40:218–221. doi: 10.1016/0090-8258(90)90280-X. [DOI] [PubMed] [Google Scholar]
5.Wang H.-X., Zhang G.-L., Guo Y.-H., Ren B., Wang Z.-W., Zhou C.-Y. Novel 5 or 8-Substituted Imidazo[1,5-a]pyridines as Indoleamine and/or Tryptophane 2,3-Dioxygenases. US patent WO2016161960. 2016 filed April 8, 2016 and published October 13, 2016. [Google Scholar]
6.Becker D.P., Flynn D.L., Moormann A.E., Nosal R., Villamil C.I., Loeffler R., Gullikson G.W., Moummi C., Yang D.-C. Pyrrolizidine Esters and Amides as 5-HT4 Receptor Agonists and Antagonists. J. Med. Chem. 2006;49:1125–1139. doi: 10.1021/jm0509501. [DOI] [PubMed] [Google Scholar]
7.Augustin E., Pawłowska M., Polewska J., Potega A., Mazerska Z. Modulation of CYP3A4 Activity and Induction of Apoptosis, Necrosis and Senescence by the Anti-tumour Imidazoacridinone C-1311 in Human Hepatoma Cells. Cell Biol. Int. 2013;37:109–120. doi: 10.1002/cbin.10018. [DOI] [PubMed] [Google Scholar]
8.Isambert N., Campone M., Bourbouloux E., Drouin M., Major A., Yin W., Loadman P., Capizzi R., Grieshaber C., Fumoleau P. Evaluation of the Safety of C-1311 (SYMADEX) Administered in a Phase 1 Dose Escalation Trial as a Weekly Infusion for 3 Consecutive Weeks in Patients with Advanced Solid Tumours. Eur. J. Cancer. 2010;46:729–734. doi: 10.1016/j.ejca.2009.12.005. [DOI] [PubMed] [Google Scholar]
9.Polewska J., Skwarska A., Augustin E., Konopa J. DNA-Damaging Imidazoacridinone C-1311 Induces Autophagy followed by Irreversible Growth Arrest and Senescence in Human Lung Cancer Cells. J. Pharmacol. Exp. Ther. 2013;346:393–405. doi: 10.1124/jpet.113.203851. [DOI] [PubMed] [Google Scholar]
10.Volpi G., Garino C., Priola E., Magistris C., Chierotti M.R., Barolo C. Halogenated Imidazo[1,5-a]Pyridines: Chemical Structure and Optical Properties of a Promising Luminescent Scaffold. Dyes Pigm. 2019;171 doi: 10.1016/j.dyepig.2019.107713. [DOI] [Google Scholar]
11.Colombo G., Ardizzoia G.A., Brenna S. Imidazo[1,5-a]pyridine-based Derivatives as Highly Fluorescent Dyes. Inorg. Chim. Acta. 2022;535 doi: 10.1016/j.ica.2022.120849. [DOI] [Google Scholar]
12.Jouaiti E., Giuso V., Cianfarani D., Kyritsakas N., Gourlaouen C., Mauro M. Bright V-Shaped bis-Imidazo[1,2-a]pyridine Fluorophores with Near-UV to Deep-Blue Emission. Chem. Asian J. 2022;17 doi: 10.1002/asia.202200903. [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Renno G., Cardano F., Volpi G., Barolo C., Viscardi G., Fin A. Imidazo[1,5-a]pyridine-Based Fluorescent Probes: A Photophysical Investigation in Liposome Models. Molecules. 2022;27:3856. doi: 10.3390/molecules27123856. [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Cui Y., Ge Y., Li Y., Tao J., Yao J., Dong Y. Single-ion Magnet Behavior of Two Pentacoordinate CoII Complexes with a Pincer Ligand 2,6-bis(imidazo[1,5-a]pyridin-3-yl)pyridine. Struct. Chem. 2020;31:547–555. doi: 10.1007/s11224-019-01429-3. [DOI] [Google Scholar]
15.Park D.-A., Byun S., Ryu J.Y., Lee J., Lee J., Hong S. Abnormal N-Heterocyclic Carbene–Palladium Complexes for the Copolymerization of Ethylene and Polar Monomers. ACS Catal. 2020;10:5443–5453. doi: 10.1021/acscatal.0c00802. [DOI] [Google Scholar]
16.Hung C.-H., Zheng W.-Y., Lee H.-M. Palladium Complexes with Phenoxy- and Amidate-Functionalized N-Heterocyclic Carbene Ligands Based on 3-Phenylimidazo[1,5-a]pyridine: Synthesis and Catalytic Application in Mizoroki-Heck Coupling Reactions with Ortho-Substituted Aryl Chlorides. Organometallics. 2021;40:702–713. doi: 10.1021/acs.organomet.0c00791. [DOI] [Google Scholar]
17.Byun S., Park S., Choi Y., Ryu J.Y., Lee J., Choi J.-H., Hong S. Highly Efficient Ethenolysis and Propenolysis of Methyl Oleate Catalyzed by Abnormal N-Heterocyclic Carbene Ruthenium Complexes in Combination with a Phosphine-Copper Cocatalyst. ACS Catal. 2020;10:10592–10601. doi: 10.1021/acscatal.0c02018. [DOI] [Google Scholar]
18.Singh D., Kumar V., Devi N., Malakar C.C., Shankar R., Singh V. Metal-free Decarboxylative Amination: An Alternative Approach Towards Regioselective Synthesis of β-Carboline N-fused Imidazoles. Adv. Synth. Catal. 2017;359:1213–1226. doi: 10.1002/adsc.201600970. [DOI] [Google Scholar]
19.Buil M.A., Calbet M., Castillo M., Castro J., Esteve C., Ferrer M., Forns P., González J., López S., Roberts R.S., et al. Structure-Activity Relationships (SAR) and Structure-Kinetic Relationships (SKR) of Sulphone-Based CRTh2 Antagonists. Eur. J. Med. Chem. 2016;113:102–133. doi: 10.1016/j.ejmech.2016.02.023. [DOI] [PubMed] [Google Scholar]
20.Kurhade S., Konstantinidou M., Sutanto F., Kurpiewska K., Kalinowska-Tłuścik J., Dömling A. Sequential Multicomponent Synthesis of 2-(Imidazo[1,5-α]pyridin-1-yl)-1,3,4-Oxadiazoles. Eur. J. Org. Chem. 2019;2019:2029–2034. doi: 10.1002/ejoc.201801880. [DOI] [Google Scholar]
21.Nirogi R., Mohammed A.R., Shinde A.K., Bogaraju N., Gagginapalli S.R., Ravella S.R., Kota L., Bhyrapuneni G., Muddana N.R., Benade V., et al. Synthesis and SAR of Imidazo[1,5-a]pyridine Derivatives as 5-HT4 Receptor Partial Agonists for the Treatment of Cognitive Disorders Associated with Alzheimer's disease. Eur. J. Med. Chem. 2015;103:289–301. doi: 10.1016/j.ejmech.2015.08.051. [DOI] [PubMed] [Google Scholar]
22.Bosch P., García V., Bilen B.S., Sucunza D., Domingo A., Mendicuti F., Vaquero J.J. Imidazopyridinium Cations: A New Family of Azonia Aromatic Heterocycles with Applications as DNA Intercalators. Dyes Pigm. 2017;138:135–146. doi: 10.1016/j.dyepig.2016.11.041. [DOI] [Google Scholar]
23.Amini-Rentsch L., Vanoli E., Richard-Bildstein S., Marti R., Vilé G. A Novel and Efficient Continuous-Flow Route To Prepare Trifluoromethylated N-Fused Heterocycles for Drug Discovery and Pharmaceutical Manufacturing. Ind. Eng. Chem. Res. 2019;58:10164–10171. doi: 10.1021/acs.iecr.9b01906. [DOI] [Google Scholar]
24.Ramesha A.B., Pavan Kumar C.S., Sandhya N.C., Kumara M.N., Mantelingu K., Rangappa K.S. Tandem Approach for the Synthesis of 3-Sulfenylimidazo[1,5-a]pyridines from Dithioesters. RSC Adv. 2016;6:48375–48378. doi: 10.1039/C6RA03771B. [DOI] [Google Scholar]
25.Ramesha A.B., Sandhya N.C., Pavan Kumar C.S., Hiremath M., Mantelingu K., Rangappa K.S. A Novel Approach for the Synthesis of Imidazo and Triazolopyridines from Dithioesters. New J. Chem. 2016;40:7637–7642. doi: 10.1039/C6NJ01038E. [DOI] [Google Scholar]
26.Tahara S., Shibahara F., Maruyama T., Murai T. Iodine-Mediated Cyclization of N-thioacyl-1-(2-pyridyl)-1,2-aminoalcohols and Their Subsequent Condensation Leading to the Formation of Novel bis(1-imidazo[1,5-a]pyridyl)arylmethanes. Chem. Commun. 2009;2009:7009–7011. doi: 10.1039/B910172A. [DOI] [PubMed] [Google Scholar]
27.Murai T., Nagaya E., Shibahara F., Maruyama T. Imidazo[1,5-a]pyridine-1-ylalkylalcohols: Synthesis via Intramolecular Cyclization of N-thioacyl 1,2-Aminoalcohols and Their Silyl Ethers and Molecular Structures. Org. Biomol. Chem. 2012;10:4943–4953. doi: 10.1039/C2OB25438G. [DOI] [PubMed] [Google Scholar]
28.Li M., Xie Y., Ye Y., Zou Y., Jiang H., Zeng W. Cu(I)-Catalyzed Transannulation of N-Heteroaryl Aldehydes or Ketones with Alkylamines via C(sp3)-H Amination. Org. Lett. 2014;16:6232–6235. doi: 10.1021/ol503165b. [DOI] [PubMed] [Google Scholar]
29.Shibahara F., Sugiura R., Yamaguchi E., Kitagawa A., Murai T. Synthesis of Fluorescent 1,3-Diarylated Imidazo[1,5-a]pyridines: Oxidative Condensation-Cyclization of Aryl-2-Pyridylmethylamines and Aldehydes with Elemental Sulfur as an Oxidant. J. Org. Chem. 2009;74:3566–3568. doi: 10.1021/jo900415y. [DOI] [PubMed] [Google Scholar]
30.Yeung C.S., Dong V.M. Catalytic Dehydrogenative Cross-Coupling: Forming Carbon-Carbon Bonds by Oxidizing Two Carbon-Hydrogen Bonds. Chem. Rev. 2011;111:1215–1292. doi: 10.1021/cr100280d. [DOI] [PubMed] [Google Scholar]
31.Yang Y., Wu Y., Bin Z., Zhang C., Tan G., You J. Discovery of Organic Optoelectronic Materials Powered by Oxidative Ar-H/Ar-H Coupling. J. Am. Chem. Soc. 2024;146:1224–1243. doi: 10.1021/jacs.3c12234. [DOI] [PubMed] [Google Scholar]
32.Zhang L.-Y., Wang N.-X., Lucan D., Cheung W., Xing Y. Recent Advances in Aerobic Oxidative of C-H Bond by Molecular Oxygen Focus on Heterocycles. Chem. Eur J. 2023;29 doi: 10.1002/chem.202301700. [DOI] [PubMed] [Google Scholar]
33.Bashir M.A., Wei J., Wang H., Zhong F., Zhai H. Recent Advances in Catalytic Oxidative Reactions of Phenols and Naphthalenols. Org. Chem. Front. 2022;9:5395–5413. doi: 10.1039/D2QO00758D. [DOI] [Google Scholar]
34.Carson M.C., Kozlowski M.C. Recent Advances in Oxidative Phenol Coupling for the Total Synthesis of Natural Products. Nat. Prod. Rep. 2024;41:208–227. doi: 10.1039/D3NP00009E. [DOI] [PMC free article] [PubMed] [Google Scholar]
35.Yuan X., Fan H.-B., Liu J., Qin L.-Z., Wang J., Duan X., Qiu J.-K., Guo K. Recent Advances in Photoredox Catalytic Transformations by Using Continuous-Flow Technology. Chin. J. Catal. 2023;50:175–194. doi: 10.1016/S1872-2067(23)64447-X. [DOI] [Google Scholar]
36.Qin L.-Z., Sun H., Duan X., Zhu S.-S., Liu J., Wu M.-Y., Yuan X., Qiu J.-K., Guo K. Visible-Light-Induced Nickel-Catalyzed Selective S-arylation of Peptides by Exogenous-Photosensitizer-Free Photocatalysis. Cell Rep. Phys. Sci. 2023;4 doi: 10.1016/j.xcrp.2023.101292. [DOI] [Google Scholar]
37.Gui Q.-W., Teng F., Li Z.-C., Xiong Z.-Y., Jin X.-F., Lin Y.-W., Cao Z., He W.-M. Visible-light-initiated tandem synthesis of difluoromethylated oxindoles in 2-MeTHF under additive-metal catalyst-external photosensitizer-free and mild conditions. Chin. Chem. Lett. 2021;32:1907–1910. doi: 10.1016/j.cclet.2021.01.021. [DOI] [Google Scholar]
38.Gui Q.-W., Teng F., Yu P., Wu Y.-F., Nong Z.-B., Yang L.-X., Chen X., Yang T.-B., He W.-M. Visible light-induced Z-scheme V2O5/g-C3N4 heterojunction catalyzed cascade reaction of unactivated alkenes. Chin. J. Catal. 2023;44:111–116. doi: 10.1016/S1872-2067(22)64162-7. [DOI] [Google Scholar]
39.Nie B., Wu W., Zhang Y., Jiang H., Zhang J. Recent Advances in the Synthesis of Bridgehead (or Ring-Junction) Nitrogen Heterocycles via Transition Metal-Catalyzed C-H Bond Activation and Functionalization. Org. Chem. Front. 2020;7:3067–3099. doi: 10.1039/D0QO00510J. [DOI] [Google Scholar]
40.Ramana Reddy M., Darapaneni C.M., Patil R.D., Kumari H. Recent Synthetic Methodologies for Imidazo[1,5-a]pyridines and Related. Org. Biomol. Chem. 2022;20:3440–3468. doi: 10.1039/D2OB00386D. [DOI] [PubMed] [Google Scholar]
41.Reen G.K., Kumar A., Sharma P. Recent Advances on the Transition-Metal-Catalyzed Synthesis of Imidazopyridines: An Updated Coverage. Beilstein J. Org. Chem. 2019;15:1612–1704. doi: 10.3762/bjoc.15.165. [DOI] [PMC free article] [PubMed] [Google Scholar]
42.Shetgaonkar S.E., Jothish S., Dohi T., Singh F.V. Iodine(V)-Based Oxidants in Oxidation Reactions. Molecules. 2023;28:5250. doi: 10.3390/molecules28135250. [DOI] [PMC free article] [PubMed] [Google Scholar]
43.Monika S., Chander P.K., Ram S., Sharma P.K. A Review on Molecular Iodine Catalyzed/Mediated Multicomponent Reactions. Asian J. Org. Chem. 2023;12 doi: 10.1002/ajoc.202200616. [DOI] [Google Scholar]
44.Rani N., Soni R., Sihag M., Kinger M., Aneja D.K. Combined Approach of Hypervalent Iodine Reagents and Transition Metals in Organic Reactions. Adv. Synth. Catal. 2022;364:1798–1848. doi: 10.1002/adsc.202200088. [DOI] [Google Scholar]
45.Rajai-Daryasarei S., Gohari M.H., Mohammadi N. Reactions Involving Aryl Methyl Ketone and Molecular Iodine: A Powerful Tool in the One-Pot Synthesis of Heterocycles. New J. Chem. 2021;45:20486–20518. doi: 10.1039/D1NJ03572J. [DOI] [Google Scholar]
46.Mahajan S., Sawant S.D. Iodine/TBHP-Mediated One-Pot Multicomponent Protocol for Tandem C-N and C-S Bond Formation to Access Sulfenylimidazo[1,5-a]pyridines via C-H Functionalization. J. Org. Chem. 2022;87:11387–11398. doi: 10.1021/acs.joc.2c00890. [DOI] [PubMed] [Google Scholar]
47.Shibahara F., Kitagawa A., Yamaguchi E., Murai T. Synthesis of 2-Azaindolizines by Using an Iodine-Mediated Oxidative Desulfurization Promoted Cyclization of N-2-Pyridylmethyl Thioamides and an Investigation of Their Photophysical Properties. Org. Lett. 2006;8:5621–5624. doi: 10.1021/ol0623623. [DOI] [PubMed] [Google Scholar]
48.Ma C., Fang P., Liu Z.-R., Xu S.-S., Xu K., Cheng X., Lei A., Xu H.-C., Zeng C., Mei T.-S. Recent Advances in Organic Electrosynthesis Employing Transition Metal Complexes as Electrocatalysts. Sci. Bull. 2021;66:2412–2429. doi: 10.1016/j.scib.2021.07.011. [DOI] [PubMed] [Google Scholar]
49.Xiong P., Xu H.-C. Chemistry with Electrochemically Generated N-Centered Radicals. Acc. Chem. Res. 2019;52:3339–3350. doi: 10.1021/acs.accounts.9b00472. [DOI] [PubMed] [Google Scholar]
50.Song S., Wang W., Sun J., Luo C., Wu C., Li J. Photo- and Electro-Induced Perfluoroalkylation/Cyclization of o-Hydroxyaryl Enaminones: Synthesis of Perfluoroalkyl Chromones. Green Synth. Catal. 2025;6:311–315. doi: 10.1016/j.gresc.2024.03.001. [DOI] [Google Scholar]
51.Guo H., Liu Y., Wan J.-P. Electrochemical Cascade Pyrazole Annulation and C-H Halogenation for the Synthesis of 4-Halopyrazoles. Green Synth. Catal. 2025;6:206–210. doi: 10.1016/j.gresc.2023.10.004. [DOI] [Google Scholar]
52.Song H.-Y., Jiang J., Song Y.-H., Zhou M.-H., Wu C., Chen X., He W.-M. Supporting-Electrolyte-Free Electrochemical [2 + 2 + 1] Annulation of Benzo[d]isothiazole 1,1-dioxides, N-Arylglycines and Paraformaldehyde. Chin. Chem. Lett. 2024;35 doi: 10.1016/j.cclet.2023.109246. [DOI] [Google Scholar]
53.Zhu Y., Cui Y., Yang H.-Y. Revolution of Iodine Electrochemistry: From I-/I2 to I-/I5+ Matter. 2024;7:2769–2770. doi: 10.1016/j.matt.2024.06.036. [DOI] [Google Scholar]
54.Wang X., Li W., Lv X., Broekmann P. When Chiral Chemistry Meets Electrochemistry: A Virgin Land of an Academic Gold Mine. Matter. 2024;7:2691–2694. doi: 10.1016/j.matt.2024.05.030. [DOI] [Google Scholar]
55.Zheng S.-J., Chen H., Zang S.-Q., Cai J. Chiral-Induced Spin Selectivity in Electrocatalysis. Matter. 2025;8:101924. doi: 10.1016/j.matt.2024.11.018. [DOI] [Google Scholar]
56.Lin K., Lan J., Hao L., Zhu T. Electrochemical N-Olefination for the Regio- and Stereo-Selective Synthesis of Vinyl Azoles. Green Synth. Catal. 2025;6:183–186. doi: 10.1016/j.gresc.2024.01.005. [DOI] [Google Scholar]
57.Gazzari-Jara S., Cortés-Arriagada D., Chigo-Anota E., Miranda-Rojas S. Boron-Nitrogen Fullerenes as Electrocatalysts for Nitrogen Reduction: A Computational Study of Affinity and Reaction Mechanism. iScience. 2025;28 doi: 10.1016/j.isci.2025.112326. [DOI] [PMC free article] [PubMed] [Google Scholar]
58.Phu T.K.C., Pham T.N., Nguyen A.G., Tran T.N., Tran T.M.A., Le N.N., Nguyen P.L., Phung T.V.B. Heterogeneous 2D/2D MnO2/MXene Catalyst for Nitrate-to-Ammonia Electrochemical Reduction and Zn-Nitrate Battery Behavior. iScience. 2025;28 doi: 10.1016/j.isci.2025.112729. [DOI] [PMC free article] [PubMed] [Google Scholar]
59.Liu C., Qiao Y., Guo Y., Guo K. Electrolyte Design for Longrun Continuous Ammonia Electrosynthesis. Matter. 2024;7:2673–2675. doi: 10.1016/j.matt.2024.05.018. [DOI] [Google Scholar]
60.Feng T., Yang J., Huang J., Zhang T., Lu S. Carbon-Based Nanomaterials for Carbon Neutralization through Electrochemical CO2 Reduction and C-N Coupling. Matter. 2025;8 doi: 10.1016/j.matt.2025.102077. [DOI] [Google Scholar]
61.Zhan X., Fan X., Li W., Tan X., Robertson A.W., Muhammad U., Sun Z. Coupled Metal Atomic Pairs for Synergistic Electrocatalytic CO2 Reduction. Matter. 2024;7:4206–4232. doi: 10.1016/j.matt.2024.09.013. [DOI] [Google Scholar]
62.Shi X., Shi L., Wang J., Zhou Y., Zhao S. Defect Engineering of Nanomaterials for Selective Electrocatalytic CO2 reduction. Matter. 2024;7:4233–4259. doi: 10.1016/j.matt.2024.09.024. [DOI] [Google Scholar]
63.Zhang W., Yuan W., Zhang X., Liu Q., Zhao B., Pan B., Xie Y., Tang Y. Bioinspired Electrocatalysts for Water Splitting. Matter. 2025;8 doi: 10.1016/j.matt.2025.102034. [DOI] [Google Scholar]
64.Li J., Li H., Xie W., Sun Y., Jin J., Shi Q., Shao M. Scalable and Facile Flame-Assisted Synthesis of Electron-Rich Pt Clusters/Ni(OH)2 Electrocatalyst for Robust AEM Water Electrolysis. Matter. 2025;8 doi: 10.1016/j.matt.2025.102414. [DOI] [Google Scholar]
65.Zhai T., Gao X., Wang H., Cheng Y., Gao J., Pan J., Tse E.C.M., Shang C., Guo Z. Ultrafine semi-Crystalline Y-doped RuO2 for Highly Active and Durable Proton-Exchange-Membrane Water Electrolysis. Matter. 2025;8 doi: 10.1016/j.matt.2025.102141. [DOI] [Google Scholar]
66.Chang Y., Benlolo I., Bai Y., Reimer C., Zhou D., Zhang H., Matsumura H., Choubisa H., Li X.-Y., Chen W., et al. High-Entropy Alloy Electrocatalysts Screened using Machine Learning Informed by Quantum-Inspired Similarity Analysis. Matter. 2024;7:4099–4113. doi: 10.1016/j.matt.2024.10.001. [DOI] [Google Scholar]
67.Wu Y.-D., Geng X., Gao Q., Zhang J., Wu X., Wu A.-X. Iodine-Promoted Sequential Dual Oxidative Csp3-H Amination/Csp3-H Iodination Reactions: Efficient Synthesis of 1-Iodoimidazo[1,5-a]pyridines. Org. Chem. Front. 2016;3:1430–1434. doi: 10.1039/C6QO00313C. [DOI] [Google Scholar]
68.Niyomura O., Yamaguchi Y., Tamura S., Minoura M., Okamoto Y. Reaction of 2-(Aminomethyl)pyridine with Selenium Dioxide: Synthesis and Structure of Selenium-Bridged Imidazo[1,5-a]pyridine Derivatives. Chem. Lett. 2011;40:449–451. doi: 10.1055/a-2039-1728. [DOI] [Google Scholar]
69.Wang Q., Yao X., Xu X.-J., Zhang S., Ren L. Electrochemical [4+1] Tandem sp3(C-H) Double Amination for the Direct Synthesis of 3-Acyl-Functionalized Imidazo[1,5-a]pyridines. ACS Omega. 2022;7:4305–4310. doi: 10.1021/acsomega.1c06029. [DOI] [PMC free article] [PubMed] [Google Scholar]
70.Huang X., Yao Y., Yin X., Guan W., Yuan C., Fang Z., Qin H., Liu C., Guo K. Electro-Oxidative Quinylation of Sulfides to Sulfur Ylides in Batch and Continuous Flow. iScience. 2024;27 doi: 10.1016/j.isci.2023.108605. [DOI] [PMC free article] [PubMed] [Google Scholar]
71.Liu C., Lin Y., Cai C., Yuan C., Fang Z., Guo K. Continuous-Flow Electro-Oxidative Coupling of Sulfides with Activated Methylene Compounds Leading to Sulfur Ylides. Green Chem. 2021;23:2956–2961. doi: 10.1039/D1GC00226K. [DOI] [Google Scholar]
72.Liu C.-K., Chen M.-Y., Lin X.-X., Fang Z., Guo K. Catalyst- and Oxidant-Free Electrochemical Para-Selective Hydroxylation of N-Arylamides in Batch and Continuous-Flow. Green Chem. 2020;22:6437–6443. doi: 10.1039/D0GC02294B. [DOI] [Google Scholar]
73.Guan W., Ying K., Yuan C., Hang J., Liu C., Huang X., Fang Z., Guo K. Catalyst- and Oxidant-Free Electrooxidative Site-Selective [3/4+2] Annulation to Fused Polycyclic Heteroaromatics. Green Chem. 2022;24:5191–5196. doi: 10.1039/D2GC01248K. [DOI] [Google Scholar]
74.Guan W., Hang J., Qiao Y., Liu C., Yuan C., Chen J., Qin H., Fang Z., Ji D., Guo K. Electro-Catalytic Multicomponent Reaction toward Asymmetrical Biaryls Through Heteroarylation of in Situ Generated Fused Polycyclic Heteroaromatics. Org. Chem. Front. 2023;10:2790–2797. doi: 10.1039/D3QO00307H. [DOI] [Google Scholar]
75.Chen J., Qiao Y., Guan W., Yuan C., Yao Y., Fang Z., Zhao Y., Liu C., Guo K. Electrosynthesis of Highly Functionalized Polycyclic N-Heteroaromatics through Cascade Radical Cyclization and Alkoxylation in Batch and Continuous-Flow. ACS Sustainable Chem. Eng. 2023;11:17728–17738. doi: 10.1021/acssuschemeng.3c05380. [DOI] [Google Scholar]
76.Zhao W., Lu Y., Qiao Y., Yin X., Liu C., Fang Z., Zhu J., Guo K. Electrosynthesis of Spiro-indolenines via Dearomative Arylation of Indoles in Batch and Continuous Flow. Org. Lett. 2023;25:7451–7456. doi: 10.1021/acs.orglett.3c03149. [DOI] [PubMed] [Google Scholar]
77.Fu X., Pedersen J.B., Zhou Y., Saccoccio M., Li S., Sažinas R., Li K., Andersen S.Z., Xu A., Deissler N.H., et al. Continuous-flow Electrosynthesis of Ammonia by Nitrogen Reduction and Hydrogen Oxidation. Science. 2023;379:707–712. doi: 10.1126/science.adf4403. [DOI] [PubMed] [Google Scholar]
78.Liu Y., Chen Q., Zhang X., Ran J., Han X., Yang Z., Xu T. Degradation of Electrochemical Active Compounds in Aqueous Organic Redox Flow Batteries. Curr. Opin. Electrochem. 2022;32 doi: 10.1016/j.coelec.2021.100895. [DOI] [Google Scholar]
79.Eberson L., Persson O., Hartshorn M.P. Detection and Reactions of Radical Cations Generated by Photolysis of Aromatic Compounds with Tetranitromethane in 1,1,1,3,3,3-Hexafluoro-2-propanol at Room Temperature. Angew. Chem., Int. Ed. 1995;34:2268–2269. doi: 10.1002/anie.199522681. [DOI] [Google Scholar]
80.Colomer I., Chamberlain A.E.R., Haughey M.B., Donohoe T.J. Hexafluoroisopropanol as a Highly Versatile Solvent. Nat. Rev. Chem. 2017;1:0088. doi: 10.1038/s41570-017-0088. [DOI] [Google Scholar]
81.He Z., Liu W., Li Z. I2-Catalyzed Indole Formation via Oxidative Cyclization of N-Aryl Enamines. Chem. Asian J. 2011;6:1340–1343. doi: 10.1002/asia.201100045. [DOI] [PubMed] [Google Scholar]
82.Tang S., Gao X., Lei A. Electrocatalytic Intramolecular Oxidative Annulation of N-Aryl Enamines into Substituted Indoles Mediated by Iodides. Chem. Commun. 2017;53:3354–3356. doi: 10.1039/C7CC00410A. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Document S1. Figures S1 and S2

mmc1.pdf^{(6.1MB, pdf)}

Data Availability Statement

•
All data reported in this study are available within the article or supplemental information on the web and will be shared by the lead contact upon request.
•
This article does not report original code.
•
Any additional information required to reanalyze the data reported in this article can be obtained from the lead contact upon request.

[bib1] 1.Pettit G.R., Collins J.C., Knight J.C., Herald D.L., Nieman R.A., Williams M.D., Pettit R.K. Antineoplastic Agents. 485. Isolation and Structure of Cribrostatin 6, a Dark Blue Cancer Cell Growth Inhibitor from the Marine Sponge Cribrochalina sp.,1a. J. Nat. Prod. 2003;66:544–547. doi: 10.1021/np020012t. [DOI] [PubMed] [Google Scholar]

[bib2] 2.Calcul L., Longeon A., Mourabit A.A., Guyot M., Bourguet-Kondracki M.L. Novel Alkaloids of the Aaptamine Class from an Indonesian Marine Sponge of the Genus Xestospongia. Tetrahedron. 2003;59:6539–6544. doi: 10.1016/S0040-4020(03)01069-X. [DOI] [Google Scholar]

[bib3] 3.Burke S.E., Dicola G., Lefer A.M. Protection of Ischemic Cat Myocardium by CGS-13080, a Selective Potent Thromboxane A2 Synthesis Inhibitor. J. Cardiovasc. Pharmacol. 1983;5:842–847. doi: 10.1097/00005344-198309000-00021. [DOI] [PubMed] [Google Scholar]

[bib4] 4.Barter J.F., Marlow D., Kamath R.K., Harbert J., Torrisi J.R., Barnes W.A., Potkul R.K., Newsome J.T., Delgado G. Lack of Protective Effect of Thromboxane Synthetase Inhibitor (CGS-13080) on Single Dose Radiated Canine Intestine. Gynecol. Oncol. 1991;40:218–221. doi: 10.1016/0090-8258(90)90280-X. [DOI] [PubMed] [Google Scholar]

[bib5] 5.Wang H.-X., Zhang G.-L., Guo Y.-H., Ren B., Wang Z.-W., Zhou C.-Y. Novel 5 or 8-Substituted Imidazo[1,5-a]pyridines as Indoleamine and/or Tryptophane 2,3-Dioxygenases. US patent WO2016161960. 2016 filed April 8, 2016 and published October 13, 2016. [Google Scholar]

[bib6] 6.Becker D.P., Flynn D.L., Moormann A.E., Nosal R., Villamil C.I., Loeffler R., Gullikson G.W., Moummi C., Yang D.-C. Pyrrolizidine Esters and Amides as 5-HT4 Receptor Agonists and Antagonists. J. Med. Chem. 2006;49:1125–1139. doi: 10.1021/jm0509501. [DOI] [PubMed] [Google Scholar]

[bib7] 7.Augustin E., Pawłowska M., Polewska J., Potega A., Mazerska Z. Modulation of CYP3A4 Activity and Induction of Apoptosis, Necrosis and Senescence by the Anti-tumour Imidazoacridinone C-1311 in Human Hepatoma Cells. Cell Biol. Int. 2013;37:109–120. doi: 10.1002/cbin.10018. [DOI] [PubMed] [Google Scholar]

[bib8] 8.Isambert N., Campone M., Bourbouloux E., Drouin M., Major A., Yin W., Loadman P., Capizzi R., Grieshaber C., Fumoleau P. Evaluation of the Safety of C-1311 (SYMADEX) Administered in a Phase 1 Dose Escalation Trial as a Weekly Infusion for 3 Consecutive Weeks in Patients with Advanced Solid Tumours. Eur. J. Cancer. 2010;46:729–734. doi: 10.1016/j.ejca.2009.12.005. [DOI] [PubMed] [Google Scholar]

[bib9] 9.Polewska J., Skwarska A., Augustin E., Konopa J. DNA-Damaging Imidazoacridinone C-1311 Induces Autophagy followed by Irreversible Growth Arrest and Senescence in Human Lung Cancer Cells. J. Pharmacol. Exp. Ther. 2013;346:393–405. doi: 10.1124/jpet.113.203851. [DOI] [PubMed] [Google Scholar]

[bib10] 10.Volpi G., Garino C., Priola E., Magistris C., Chierotti M.R., Barolo C. Halogenated Imidazo[1,5-a]Pyridines: Chemical Structure and Optical Properties of a Promising Luminescent Scaffold. Dyes Pigm. 2019;171 doi: 10.1016/j.dyepig.2019.107713. [DOI] [Google Scholar]

[bib11] 11.Colombo G., Ardizzoia G.A., Brenna S. Imidazo[1,5-a]pyridine-based Derivatives as Highly Fluorescent Dyes. Inorg. Chim. Acta. 2022;535 doi: 10.1016/j.ica.2022.120849. [DOI] [Google Scholar]

[bib12] 12.Jouaiti E., Giuso V., Cianfarani D., Kyritsakas N., Gourlaouen C., Mauro M. Bright V-Shaped bis-Imidazo[1,2-a]pyridine Fluorophores with Near-UV to Deep-Blue Emission. Chem. Asian J. 2022;17 doi: 10.1002/asia.202200903. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib13] 13.Renno G., Cardano F., Volpi G., Barolo C., Viscardi G., Fin A. Imidazo[1,5-a]pyridine-Based Fluorescent Probes: A Photophysical Investigation in Liposome Models. Molecules. 2022;27:3856. doi: 10.3390/molecules27123856. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib14] 14.Cui Y., Ge Y., Li Y., Tao J., Yao J., Dong Y. Single-ion Magnet Behavior of Two Pentacoordinate CoII Complexes with a Pincer Ligand 2,6-bis(imidazo[1,5-a]pyridin-3-yl)pyridine. Struct. Chem. 2020;31:547–555. doi: 10.1007/s11224-019-01429-3. [DOI] [Google Scholar]

[bib15] 15.Park D.-A., Byun S., Ryu J.Y., Lee J., Lee J., Hong S. Abnormal N-Heterocyclic Carbene–Palladium Complexes for the Copolymerization of Ethylene and Polar Monomers. ACS Catal. 2020;10:5443–5453. doi: 10.1021/acscatal.0c00802. [DOI] [Google Scholar]

[bib16] 16.Hung C.-H., Zheng W.-Y., Lee H.-M. Palladium Complexes with Phenoxy- and Amidate-Functionalized N-Heterocyclic Carbene Ligands Based on 3-Phenylimidazo[1,5-a]pyridine: Synthesis and Catalytic Application in Mizoroki-Heck Coupling Reactions with Ortho-Substituted Aryl Chlorides. Organometallics. 2021;40:702–713. doi: 10.1021/acs.organomet.0c00791. [DOI] [Google Scholar]

[bib17] 17.Byun S., Park S., Choi Y., Ryu J.Y., Lee J., Choi J.-H., Hong S. Highly Efficient Ethenolysis and Propenolysis of Methyl Oleate Catalyzed by Abnormal N-Heterocyclic Carbene Ruthenium Complexes in Combination with a Phosphine-Copper Cocatalyst. ACS Catal. 2020;10:10592–10601. doi: 10.1021/acscatal.0c02018. [DOI] [Google Scholar]

[bib18] 18.Singh D., Kumar V., Devi N., Malakar C.C., Shankar R., Singh V. Metal-free Decarboxylative Amination: An Alternative Approach Towards Regioselective Synthesis of β-Carboline N-fused Imidazoles. Adv. Synth. Catal. 2017;359:1213–1226. doi: 10.1002/adsc.201600970. [DOI] [Google Scholar]

[bib19] 19.Buil M.A., Calbet M., Castillo M., Castro J., Esteve C., Ferrer M., Forns P., González J., López S., Roberts R.S., et al. Structure-Activity Relationships (SAR) and Structure-Kinetic Relationships (SKR) of Sulphone-Based CRTh2 Antagonists. Eur. J. Med. Chem. 2016;113:102–133. doi: 10.1016/j.ejmech.2016.02.023. [DOI] [PubMed] [Google Scholar]

[bib20] 20.Kurhade S., Konstantinidou M., Sutanto F., Kurpiewska K., Kalinowska-Tłuścik J., Dömling A. Sequential Multicomponent Synthesis of 2-(Imidazo[1,5-α]pyridin-1-yl)-1,3,4-Oxadiazoles. Eur. J. Org. Chem. 2019;2019:2029–2034. doi: 10.1002/ejoc.201801880. [DOI] [Google Scholar]

[bib21] 21.Nirogi R., Mohammed A.R., Shinde A.K., Bogaraju N., Gagginapalli S.R., Ravella S.R., Kota L., Bhyrapuneni G., Muddana N.R., Benade V., et al. Synthesis and SAR of Imidazo[1,5-a]pyridine Derivatives as 5-HT4 Receptor Partial Agonists for the Treatment of Cognitive Disorders Associated with Alzheimer's disease. Eur. J. Med. Chem. 2015;103:289–301. doi: 10.1016/j.ejmech.2015.08.051. [DOI] [PubMed] [Google Scholar]

[bib22] 22.Bosch P., García V., Bilen B.S., Sucunza D., Domingo A., Mendicuti F., Vaquero J.J. Imidazopyridinium Cations: A New Family of Azonia Aromatic Heterocycles with Applications as DNA Intercalators. Dyes Pigm. 2017;138:135–146. doi: 10.1016/j.dyepig.2016.11.041. [DOI] [Google Scholar]

[bib23] 23.Amini-Rentsch L., Vanoli E., Richard-Bildstein S., Marti R., Vilé G. A Novel and Efficient Continuous-Flow Route To Prepare Trifluoromethylated N-Fused Heterocycles for Drug Discovery and Pharmaceutical Manufacturing. Ind. Eng. Chem. Res. 2019;58:10164–10171. doi: 10.1021/acs.iecr.9b01906. [DOI] [Google Scholar]

[bib24] 24.Ramesha A.B., Pavan Kumar C.S., Sandhya N.C., Kumara M.N., Mantelingu K., Rangappa K.S. Tandem Approach for the Synthesis of 3-Sulfenylimidazo[1,5-a]pyridines from Dithioesters. RSC Adv. 2016;6:48375–48378. doi: 10.1039/C6RA03771B. [DOI] [Google Scholar]

[bib25] 25.Ramesha A.B., Sandhya N.C., Pavan Kumar C.S., Hiremath M., Mantelingu K., Rangappa K.S. A Novel Approach for the Synthesis of Imidazo and Triazolopyridines from Dithioesters. New J. Chem. 2016;40:7637–7642. doi: 10.1039/C6NJ01038E. [DOI] [Google Scholar]

[bib26] 26.Tahara S., Shibahara F., Maruyama T., Murai T. Iodine-Mediated Cyclization of N-thioacyl-1-(2-pyridyl)-1,2-aminoalcohols and Their Subsequent Condensation Leading to the Formation of Novel bis(1-imidazo[1,5-a]pyridyl)arylmethanes. Chem. Commun. 2009;2009:7009–7011. doi: 10.1039/B910172A. [DOI] [PubMed] [Google Scholar]

[bib27] 27.Murai T., Nagaya E., Shibahara F., Maruyama T. Imidazo[1,5-a]pyridine-1-ylalkylalcohols: Synthesis via Intramolecular Cyclization of N-thioacyl 1,2-Aminoalcohols and Their Silyl Ethers and Molecular Structures. Org. Biomol. Chem. 2012;10:4943–4953. doi: 10.1039/C2OB25438G. [DOI] [PubMed] [Google Scholar]

[bib28] 28.Li M., Xie Y., Ye Y., Zou Y., Jiang H., Zeng W. Cu(I)-Catalyzed Transannulation of N-Heteroaryl Aldehydes or Ketones with Alkylamines via C(sp3)-H Amination. Org. Lett. 2014;16:6232–6235. doi: 10.1021/ol503165b. [DOI] [PubMed] [Google Scholar]

[bib29] 29.Shibahara F., Sugiura R., Yamaguchi E., Kitagawa A., Murai T. Synthesis of Fluorescent 1,3-Diarylated Imidazo[1,5-a]pyridines: Oxidative Condensation-Cyclization of Aryl-2-Pyridylmethylamines and Aldehydes with Elemental Sulfur as an Oxidant. J. Org. Chem. 2009;74:3566–3568. doi: 10.1021/jo900415y. [DOI] [PubMed] [Google Scholar]

[bib30] 30.Yeung C.S., Dong V.M. Catalytic Dehydrogenative Cross-Coupling: Forming Carbon-Carbon Bonds by Oxidizing Two Carbon-Hydrogen Bonds. Chem. Rev. 2011;111:1215–1292. doi: 10.1021/cr100280d. [DOI] [PubMed] [Google Scholar]

[bib31] 31.Yang Y., Wu Y., Bin Z., Zhang C., Tan G., You J. Discovery of Organic Optoelectronic Materials Powered by Oxidative Ar-H/Ar-H Coupling. J. Am. Chem. Soc. 2024;146:1224–1243. doi: 10.1021/jacs.3c12234. [DOI] [PubMed] [Google Scholar]

[bib32] 32.Zhang L.-Y., Wang N.-X., Lucan D., Cheung W., Xing Y. Recent Advances in Aerobic Oxidative of C-H Bond by Molecular Oxygen Focus on Heterocycles. Chem. Eur J. 2023;29 doi: 10.1002/chem.202301700. [DOI] [PubMed] [Google Scholar]

[bib33] 33.Bashir M.A., Wei J., Wang H., Zhong F., Zhai H. Recent Advances in Catalytic Oxidative Reactions of Phenols and Naphthalenols. Org. Chem. Front. 2022;9:5395–5413. doi: 10.1039/D2QO00758D. [DOI] [Google Scholar]

[bib34] 34.Carson M.C., Kozlowski M.C. Recent Advances in Oxidative Phenol Coupling for the Total Synthesis of Natural Products. Nat. Prod. Rep. 2024;41:208–227. doi: 10.1039/D3NP00009E. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib35] 35.Yuan X., Fan H.-B., Liu J., Qin L.-Z., Wang J., Duan X., Qiu J.-K., Guo K. Recent Advances in Photoredox Catalytic Transformations by Using Continuous-Flow Technology. Chin. J. Catal. 2023;50:175–194. doi: 10.1016/S1872-2067(23)64447-X. [DOI] [Google Scholar]

[bib36] 36.Qin L.-Z., Sun H., Duan X., Zhu S.-S., Liu J., Wu M.-Y., Yuan X., Qiu J.-K., Guo K. Visible-Light-Induced Nickel-Catalyzed Selective S-arylation of Peptides by Exogenous-Photosensitizer-Free Photocatalysis. Cell Rep. Phys. Sci. 2023;4 doi: 10.1016/j.xcrp.2023.101292. [DOI] [Google Scholar]

[bib37] 37.Gui Q.-W., Teng F., Li Z.-C., Xiong Z.-Y., Jin X.-F., Lin Y.-W., Cao Z., He W.-M. Visible-light-initiated tandem synthesis of difluoromethylated oxindoles in 2-MeTHF under additive-metal catalyst-external photosensitizer-free and mild conditions. Chin. Chem. Lett. 2021;32:1907–1910. doi: 10.1016/j.cclet.2021.01.021. [DOI] [Google Scholar]

[bib38] 38.Gui Q.-W., Teng F., Yu P., Wu Y.-F., Nong Z.-B., Yang L.-X., Chen X., Yang T.-B., He W.-M. Visible light-induced Z-scheme V2O5/g-C3N4 heterojunction catalyzed cascade reaction of unactivated alkenes. Chin. J. Catal. 2023;44:111–116. doi: 10.1016/S1872-2067(22)64162-7. [DOI] [Google Scholar]

[bib39] 39.Nie B., Wu W., Zhang Y., Jiang H., Zhang J. Recent Advances in the Synthesis of Bridgehead (or Ring-Junction) Nitrogen Heterocycles via Transition Metal-Catalyzed C-H Bond Activation and Functionalization. Org. Chem. Front. 2020;7:3067–3099. doi: 10.1039/D0QO00510J. [DOI] [Google Scholar]

[bib40] 40.Ramana Reddy M., Darapaneni C.M., Patil R.D., Kumari H. Recent Synthetic Methodologies for Imidazo[1,5-a]pyridines and Related. Org. Biomol. Chem. 2022;20:3440–3468. doi: 10.1039/D2OB00386D. [DOI] [PubMed] [Google Scholar]

[bib41] 41.Reen G.K., Kumar A., Sharma P. Recent Advances on the Transition-Metal-Catalyzed Synthesis of Imidazopyridines: An Updated Coverage. Beilstein J. Org. Chem. 2019;15:1612–1704. doi: 10.3762/bjoc.15.165. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib42] 42.Shetgaonkar S.E., Jothish S., Dohi T., Singh F.V. Iodine(V)-Based Oxidants in Oxidation Reactions. Molecules. 2023;28:5250. doi: 10.3390/molecules28135250. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib43] 43.Monika S., Chander P.K., Ram S., Sharma P.K. A Review on Molecular Iodine Catalyzed/Mediated Multicomponent Reactions. Asian J. Org. Chem. 2023;12 doi: 10.1002/ajoc.202200616. [DOI] [Google Scholar]

[bib44] 44.Rani N., Soni R., Sihag M., Kinger M., Aneja D.K. Combined Approach of Hypervalent Iodine Reagents and Transition Metals in Organic Reactions. Adv. Synth. Catal. 2022;364:1798–1848. doi: 10.1002/adsc.202200088. [DOI] [Google Scholar]

[bib45] 45.Rajai-Daryasarei S., Gohari M.H., Mohammadi N. Reactions Involving Aryl Methyl Ketone and Molecular Iodine: A Powerful Tool in the One-Pot Synthesis of Heterocycles. New J. Chem. 2021;45:20486–20518. doi: 10.1039/D1NJ03572J. [DOI] [Google Scholar]

[bib46] 46.Mahajan S., Sawant S.D. Iodine/TBHP-Mediated One-Pot Multicomponent Protocol for Tandem C-N and C-S Bond Formation to Access Sulfenylimidazo[1,5-a]pyridines via C-H Functionalization. J. Org. Chem. 2022;87:11387–11398. doi: 10.1021/acs.joc.2c00890. [DOI] [PubMed] [Google Scholar]

[bib47] 47.Shibahara F., Kitagawa A., Yamaguchi E., Murai T. Synthesis of 2-Azaindolizines by Using an Iodine-Mediated Oxidative Desulfurization Promoted Cyclization of N-2-Pyridylmethyl Thioamides and an Investigation of Their Photophysical Properties. Org. Lett. 2006;8:5621–5624. doi: 10.1021/ol0623623. [DOI] [PubMed] [Google Scholar]

[bib48] 48.Ma C., Fang P., Liu Z.-R., Xu S.-S., Xu K., Cheng X., Lei A., Xu H.-C., Zeng C., Mei T.-S. Recent Advances in Organic Electrosynthesis Employing Transition Metal Complexes as Electrocatalysts. Sci. Bull. 2021;66:2412–2429. doi: 10.1016/j.scib.2021.07.011. [DOI] [PubMed] [Google Scholar]

[bib49] 49.Xiong P., Xu H.-C. Chemistry with Electrochemically Generated N-Centered Radicals. Acc. Chem. Res. 2019;52:3339–3350. doi: 10.1021/acs.accounts.9b00472. [DOI] [PubMed] [Google Scholar]

[bib50] 50.Song S., Wang W., Sun J., Luo C., Wu C., Li J. Photo- and Electro-Induced Perfluoroalkylation/Cyclization of o-Hydroxyaryl Enaminones: Synthesis of Perfluoroalkyl Chromones. Green Synth. Catal. 2025;6:311–315. doi: 10.1016/j.gresc.2024.03.001. [DOI] [Google Scholar]

[bib51] 51.Guo H., Liu Y., Wan J.-P. Electrochemical Cascade Pyrazole Annulation and C-H Halogenation for the Synthesis of 4-Halopyrazoles. Green Synth. Catal. 2025;6:206–210. doi: 10.1016/j.gresc.2023.10.004. [DOI] [Google Scholar]

[bib52] 52.Song H.-Y., Jiang J., Song Y.-H., Zhou M.-H., Wu C., Chen X., He W.-M. Supporting-Electrolyte-Free Electrochemical [2 + 2 + 1] Annulation of Benzo[d]isothiazole 1,1-dioxides, N-Arylglycines and Paraformaldehyde. Chin. Chem. Lett. 2024;35 doi: 10.1016/j.cclet.2023.109246. [DOI] [Google Scholar]

[bib53] 53.Zhu Y., Cui Y., Yang H.-Y. Revolution of Iodine Electrochemistry: From I-/I2 to I-/I5+ Matter. 2024;7:2769–2770. doi: 10.1016/j.matt.2024.06.036. [DOI] [Google Scholar]

[bib54] 54.Wang X., Li W., Lv X., Broekmann P. When Chiral Chemistry Meets Electrochemistry: A Virgin Land of an Academic Gold Mine. Matter. 2024;7:2691–2694. doi: 10.1016/j.matt.2024.05.030. [DOI] [Google Scholar]

[bib55] 55.Zheng S.-J., Chen H., Zang S.-Q., Cai J. Chiral-Induced Spin Selectivity in Electrocatalysis. Matter. 2025;8:101924. doi: 10.1016/j.matt.2024.11.018. [DOI] [Google Scholar]

[bib56] 56.Lin K., Lan J., Hao L., Zhu T. Electrochemical N-Olefination for the Regio- and Stereo-Selective Synthesis of Vinyl Azoles. Green Synth. Catal. 2025;6:183–186. doi: 10.1016/j.gresc.2024.01.005. [DOI] [Google Scholar]

[bib57] 57.Gazzari-Jara S., Cortés-Arriagada D., Chigo-Anota E., Miranda-Rojas S. Boron-Nitrogen Fullerenes as Electrocatalysts for Nitrogen Reduction: A Computational Study of Affinity and Reaction Mechanism. iScience. 2025;28 doi: 10.1016/j.isci.2025.112326. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib58] 58.Phu T.K.C., Pham T.N., Nguyen A.G., Tran T.N., Tran T.M.A., Le N.N., Nguyen P.L., Phung T.V.B. Heterogeneous 2D/2D MnO2/MXene Catalyst for Nitrate-to-Ammonia Electrochemical Reduction and Zn-Nitrate Battery Behavior. iScience. 2025;28 doi: 10.1016/j.isci.2025.112729. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib59] 59.Liu C., Qiao Y., Guo Y., Guo K. Electrolyte Design for Longrun Continuous Ammonia Electrosynthesis. Matter. 2024;7:2673–2675. doi: 10.1016/j.matt.2024.05.018. [DOI] [Google Scholar]

[bib60] 60.Feng T., Yang J., Huang J., Zhang T., Lu S. Carbon-Based Nanomaterials for Carbon Neutralization through Electrochemical CO2 Reduction and C-N Coupling. Matter. 2025;8 doi: 10.1016/j.matt.2025.102077. [DOI] [Google Scholar]

[bib61] 61.Zhan X., Fan X., Li W., Tan X., Robertson A.W., Muhammad U., Sun Z. Coupled Metal Atomic Pairs for Synergistic Electrocatalytic CO2 Reduction. Matter. 2024;7:4206–4232. doi: 10.1016/j.matt.2024.09.013. [DOI] [Google Scholar]

[bib62] 62.Shi X., Shi L., Wang J., Zhou Y., Zhao S. Defect Engineering of Nanomaterials for Selective Electrocatalytic CO2 reduction. Matter. 2024;7:4233–4259. doi: 10.1016/j.matt.2024.09.024. [DOI] [Google Scholar]

[bib63] 63.Zhang W., Yuan W., Zhang X., Liu Q., Zhao B., Pan B., Xie Y., Tang Y. Bioinspired Electrocatalysts for Water Splitting. Matter. 2025;8 doi: 10.1016/j.matt.2025.102034. [DOI] [Google Scholar]

[bib64] 64.Li J., Li H., Xie W., Sun Y., Jin J., Shi Q., Shao M. Scalable and Facile Flame-Assisted Synthesis of Electron-Rich Pt Clusters/Ni(OH)2 Electrocatalyst for Robust AEM Water Electrolysis. Matter. 2025;8 doi: 10.1016/j.matt.2025.102414. [DOI] [Google Scholar]

[bib65] 65.Zhai T., Gao X., Wang H., Cheng Y., Gao J., Pan J., Tse E.C.M., Shang C., Guo Z. Ultrafine semi-Crystalline Y-doped RuO2 for Highly Active and Durable Proton-Exchange-Membrane Water Electrolysis. Matter. 2025;8 doi: 10.1016/j.matt.2025.102141. [DOI] [Google Scholar]

[bib66] 66.Chang Y., Benlolo I., Bai Y., Reimer C., Zhou D., Zhang H., Matsumura H., Choubisa H., Li X.-Y., Chen W., et al. High-Entropy Alloy Electrocatalysts Screened using Machine Learning Informed by Quantum-Inspired Similarity Analysis. Matter. 2024;7:4099–4113. doi: 10.1016/j.matt.2024.10.001. [DOI] [Google Scholar]

[bib67] 67.Wu Y.-D., Geng X., Gao Q., Zhang J., Wu X., Wu A.-X. Iodine-Promoted Sequential Dual Oxidative Csp3-H Amination/Csp3-H Iodination Reactions: Efficient Synthesis of 1-Iodoimidazo[1,5-a]pyridines. Org. Chem. Front. 2016;3:1430–1434. doi: 10.1039/C6QO00313C. [DOI] [Google Scholar]

[bib68] 68.Niyomura O., Yamaguchi Y., Tamura S., Minoura M., Okamoto Y. Reaction of 2-(Aminomethyl)pyridine with Selenium Dioxide: Synthesis and Structure of Selenium-Bridged Imidazo[1,5-a]pyridine Derivatives. Chem. Lett. 2011;40:449–451. doi: 10.1055/a-2039-1728. [DOI] [Google Scholar]

[bib69] 69.Wang Q., Yao X., Xu X.-J., Zhang S., Ren L. Electrochemical [4+1] Tandem sp3(C-H) Double Amination for the Direct Synthesis of 3-Acyl-Functionalized Imidazo[1,5-a]pyridines. ACS Omega. 2022;7:4305–4310. doi: 10.1021/acsomega.1c06029. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib70] 70.Huang X., Yao Y., Yin X., Guan W., Yuan C., Fang Z., Qin H., Liu C., Guo K. Electro-Oxidative Quinylation of Sulfides to Sulfur Ylides in Batch and Continuous Flow. iScience. 2024;27 doi: 10.1016/j.isci.2023.108605. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib71] 71.Liu C., Lin Y., Cai C., Yuan C., Fang Z., Guo K. Continuous-Flow Electro-Oxidative Coupling of Sulfides with Activated Methylene Compounds Leading to Sulfur Ylides. Green Chem. 2021;23:2956–2961. doi: 10.1039/D1GC00226K. [DOI] [Google Scholar]

[bib72] 72.Liu C.-K., Chen M.-Y., Lin X.-X., Fang Z., Guo K. Catalyst- and Oxidant-Free Electrochemical Para-Selective Hydroxylation of N-Arylamides in Batch and Continuous-Flow. Green Chem. 2020;22:6437–6443. doi: 10.1039/D0GC02294B. [DOI] [Google Scholar]

[bib73] 73.Guan W., Ying K., Yuan C., Hang J., Liu C., Huang X., Fang Z., Guo K. Catalyst- and Oxidant-Free Electrooxidative Site-Selective [3/4+2] Annulation to Fused Polycyclic Heteroaromatics. Green Chem. 2022;24:5191–5196. doi: 10.1039/D2GC01248K. [DOI] [Google Scholar]

[bib74] 74.Guan W., Hang J., Qiao Y., Liu C., Yuan C., Chen J., Qin H., Fang Z., Ji D., Guo K. Electro-Catalytic Multicomponent Reaction toward Asymmetrical Biaryls Through Heteroarylation of in Situ Generated Fused Polycyclic Heteroaromatics. Org. Chem. Front. 2023;10:2790–2797. doi: 10.1039/D3QO00307H. [DOI] [Google Scholar]

[bib75] 75.Chen J., Qiao Y., Guan W., Yuan C., Yao Y., Fang Z., Zhao Y., Liu C., Guo K. Electrosynthesis of Highly Functionalized Polycyclic N-Heteroaromatics through Cascade Radical Cyclization and Alkoxylation in Batch and Continuous-Flow. ACS Sustainable Chem. Eng. 2023;11:17728–17738. doi: 10.1021/acssuschemeng.3c05380. [DOI] [Google Scholar]

[bib76] 76.Zhao W., Lu Y., Qiao Y., Yin X., Liu C., Fang Z., Zhu J., Guo K. Electrosynthesis of Spiro-indolenines via Dearomative Arylation of Indoles in Batch and Continuous Flow. Org. Lett. 2023;25:7451–7456. doi: 10.1021/acs.orglett.3c03149. [DOI] [PubMed] [Google Scholar]

[bib77] 77.Fu X., Pedersen J.B., Zhou Y., Saccoccio M., Li S., Sažinas R., Li K., Andersen S.Z., Xu A., Deissler N.H., et al. Continuous-flow Electrosynthesis of Ammonia by Nitrogen Reduction and Hydrogen Oxidation. Science. 2023;379:707–712. doi: 10.1126/science.adf4403. [DOI] [PubMed] [Google Scholar]

[bib78] 78.Liu Y., Chen Q., Zhang X., Ran J., Han X., Yang Z., Xu T. Degradation of Electrochemical Active Compounds in Aqueous Organic Redox Flow Batteries. Curr. Opin. Electrochem. 2022;32 doi: 10.1016/j.coelec.2021.100895. [DOI] [Google Scholar]

[bib79] 79.Eberson L., Persson O., Hartshorn M.P. Detection and Reactions of Radical Cations Generated by Photolysis of Aromatic Compounds with Tetranitromethane in 1,1,1,3,3,3-Hexafluoro-2-propanol at Room Temperature. Angew. Chem., Int. Ed. 1995;34:2268–2269. doi: 10.1002/anie.199522681. [DOI] [Google Scholar]

[bib80] 80.Colomer I., Chamberlain A.E.R., Haughey M.B., Donohoe T.J. Hexafluoroisopropanol as a Highly Versatile Solvent. Nat. Rev. Chem. 2017;1:0088. doi: 10.1038/s41570-017-0088. [DOI] [Google Scholar]

[bib81] 81.He Z., Liu W., Li Z. I2-Catalyzed Indole Formation via Oxidative Cyclization of N-Aryl Enamines. Chem. Asian J. 2011;6:1340–1343. doi: 10.1002/asia.201100045. [DOI] [PubMed] [Google Scholar]

[bib82] 82.Tang S., Gao X., Lei A. Electrocatalytic Intramolecular Oxidative Annulation of N-Aryl Enamines into Substituted Indoles Mediated by Iodides. Chem. Commun. 2017;53:3354–3356. doi: 10.1039/C7CC00410A. [DOI] [PubMed] [Google Scholar]

PERMALINK

Switchable electrosynthesis of C-1-unsubstituted imidazopyridines

Jinlin Hang

Meng Chen

Weibin Ma

Zefu Zheng

Zheng Fang

Ning Zhu

Chengkou Liu

Summary

Graphical abstract

Highlights

Introduction

Figure 1.

Scheme 1.

Results and discussion

Reaction condition optimization

Table 1.

Scope for electrosynthesis of C-1-unsubstituted imidazopyridine

Scheme 2.

Mechanistic studies

Scheme 3.

Scheme 4.

Limitations of the study

Resource availability

Lead contact

Materials availability

Data and code availability

Acknowledgments

Author contributions

Declaration of interests

STAR★Methods

Key resources table

Method details

Preparation of substituted pyridin-2-ylmethanamines

Preparation of products

General procedure for the electrochemically oxidative cyclization of two equiv. Of pyridin-2-ylmethylamines

General procedure for the electrochemically oxidative cyclocondensation of pyridin-2-ylmethylamines and aryl methyl ketones

Characterization of products 2, 4–29

Quantification and statistical analysis

Footnotes

Supplemental information

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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