Abstract
3-Acyl imidazo[1,5-a]pyridines, featured pharmaceutical moieties that were prepared by a three-step reaction conventionally, could be obtained in one step by an electrochemical tandem sp3 (C–H) double amination of acetophenones with pyridine ethylamines using ammonium iodide as a redox mediator.
Introduction
Imidazo[1,5-a]pyridines are featured fused N-heterocyclic compounds that have extensive applications in pharmaceutical chemistry for drug discovery.1 In recent years, a number of synthetic methods have been developed for the construction of these compounds,2 which greatly facilitates the research of the structure–activity relationship (SAR) for pharmaceutical chemists. However, these methods exhibit limitation in the synthesis of 3-acyl imidazo[1,5-a]pyridines. 3-Acyl imidazo[1,5-a]pyridines, key pharmacophore that has been extensively employed in bioactive compounds, such as the cannabinoid receptor type 2 (CB2) agonist (Scheme 1, cmpd 1) for inflammatory pain, monosodium iodoacetate for osteoarthritis pain,3 the fibroblast growth factor receptor antagonist (Scheme 1, cmpd 2) for bladder cancer,4 and the retinoic acid receptor-related orphan receptor gamma c agonist (Scheme 1, cmpd 3) for the treatment of autoimmune diseases.5
Scheme 1. Examples of Bioactive 3-Acyl Imidazo[1,5-a] Pyridines.
Researchers have been focused on tumor inhibitor research in the past years,6 and we intended to make a systematic investigation on the SAR of 3-acyl imidazo[1,5-a]pyridine for its derivatives that revealed a potential antiproliferation effect on a variety of cancer cells in our primary study. However, the synthesis of this skeleton by conventional methods must be achieved through multistep reactions;3 besides, using trichlorophosphate, a highly corrosive reagent, seems inevitable in the synthesis process (Scheme 2). Obviously, its efficiency is unsatisfactory and the process is environment-hazardous as well. More recently, nearly parallel but reported earlier than our report, Li’s group focused on the aggregation-induced emission property of 3-acyl imidazo[1,5-a]pyridines and reported an iodine-mediated sp and sp2 hydrocarbon activation for direct synthesis from phenylacetylenes (styrenes) and pyridin-2-phenyl(pyridin-2-yl)methanamines.7 Because most of the substituted phenylacetylenes and styrenes are expensive and even commercially unavailable, direct sp3 hydrocarbon functionalization-based efficient and green method for 3-acyl imidazo[1,5-a]pyridines is still undiscovered and desirable.
Scheme 2. Strategies for the Construction of 3-Acyl Imidazo[1,5-a] Pyridines.
During the past decade, electrocatalysis, including direct electrocatalysis and indirect electrosynthesis, as a green synthetic strategy has provided an alternative synthesis method for organic synthesis,8 and a series of elegant electro-organic reactions for the construction of C–C,9 C–N,10 C–O,11 and C–S12 bonds have been developed. In recent years, indirect electrosynthesis with mediators has attracted more attention for its reaction controllability and selectivity advantages.8 Halogen ions, one of the most versatile and cost-efficient mediators, are always combined with irreversible halogenation in indirect electrosynthesis and can enhance the reaction efficiency and functional group compatibility.13 Apparently, the indirect electrocatalytic functionalization of sp3 hydrocarbons with a redox mediator as a green synthetic strategy improves the synthesis efficiency and shortens the synthesis steps via employing nonfunctionalized cheap starting materials.14 In virtue of the formal achievements and the advantage of indirect electrosynthesis, herein, we report a chemoselective electrochemical tandem [4 + 1] sp3 hydrocarbon double amination for the direct synthesis of 3-acyl imidazo[1,5-a]pyridines from pyridine ethylamines and acetophenones.
Results and Discussion
As shown in Table 1, the optimized condition under which the electrosynthesis of acetophenone (1a), pyridin-2-phenyl(pyridin-2-yl)methanamine (2a), and NH4I was performed at a 10 mA constant current for 16 h in an undivided cell, product 3a was obtained with 76% yield (Table 1, entry 1). In the optimization process, reaction parameters such as the redox mediator, solvent, temperature, and so forth were investigated. As for the other redox mediator, KI, NaI, and nBu4NI all gave lower yields (Table 1, entries 2–4), and NH4Br only gave a trace amount of 3a (Table 1, entry 5). As for the reaction solvent, dimethylacetamide (DMA) as the solvent provided 73% yield (Table 1, entry 6), while dimethylformamide (DMF) as the solvent only provided 59% yield (Table 1, entry 7). As for the reaction temperature, decreasing the temperature to 70 °C and increasing to 90 °C both failed to increase the yield (Table 1, entries 8 and 9), and 3a was not detected after electrolysis at room temperature (Table 1, entry 10). Replacing the graphite rod anode by a platinum plate anode also gave lower yields (Table 1, entry 11); decreasing the current to 8 mA and increasing to 12 mA both provided lower yields (Table 1, entries 12 and 13). Employing an equivalent amount of I2 instead of NH4I and the electrolysis only gave 18% yield of 3a (Table 1, entry 14), and the same reaction in DMA failed and produced a trace amount of 3a (Table 1, entry 15), indicating that anodic oxidative dehydrogenation was a critical factor to this transformation.
Table 1. Effects of Reaction Parametersa.
| entry | variation from the standard conditions | yield (%) |
|---|---|---|
| 1 | none | 76 |
| 2 | KI instead of NH4I | 46 |
| 3 | NaI instead of NH4I | 38 |
| 4 | nBu4NI instead of NH4I | 21 |
| 5 | NH4Br instead of NH4I | 67 |
| 6 | DMA instead of DMSO | 73 |
| 7 | DMF instead of DMSO | 59 |
| 8 | 70 °C instead of 80 °C | 53 |
| 9 | 90 °C instead of 80 °C | 66 |
| 10 | room temperature | n.d. |
| 11 | platinum plate anode | 61 |
| 12 | 8 mA | 53 |
| 13 | 12 mA | 56 |
| 14 | 1.5 equiv I2 instead of NH4I and electric current | 16 |
| 15 | 1.5 equiv I2 instead of NH4I and electric current, DMA as the solvent | trace |
Reaction conditions: graphite rod anode, platinum plate cathode, constant current = 10 mA, 1a (0.2 mmol), 2a (2 equiv, 0.4 mmol), NH4I (1.5 equiv, 0.3 mmol), DMA (3 mL), 80 °C, 16 h. Isolated yields are shown. n.d. = not detected.
With the optimized conditions in hand, the substrate scope of the reaction was investigated (Table 2). First, a variety of acetophenones were investigated (R1 group). It was found that the solvent effect greatly affected the transformation. Selecting DMA as the solvent for electron-deficient acetophenones could avoid the unexpected side reactions that happened in the dimethyl sulfoxide (DMSO) solvent; besides, less reaction time was needed for electron-deficient acetophenones. Specifically, the electron-withdrawing group chloride provided higher yields than the electron-donating group methyl (3b–3d vs 3e–3g) and needed less reaction time, and similar electronic effects were found in other acetophenones (3h–3o). Also, this electrolysis system exhibited good functional-group tolerance, including methoxyl (3h), hydroxyl (3i), fluorine (3j), ester (3k), trifluoromethyl (3l and 3m), nitrile (3n), and sulfonyl (3o). Also, multisubstituted acetophenone still provided the target products (3p–3q). Besides, heteroaromatic ketone, condensed aromatic ketone, and unsaturated ketone were also applicable to this reaction (3r, 3s, and 3t). As for the other substrate amines (R2 group), both heteroaryl and alkyl-substituted pyridinethylamines could react with acetophenone successfully and give the corresponding target products (3u and 3v–3y) with a modest yield. The above results demonstrated that this method was applicable to many kinds of ketones and pyridinethylamines and exhibited good substrate applicability. Moreover, this method could be extended to other active methyl compounds for large π-system construction. The results showed that under the standard reaction conditions, 2-methylquinolines and 2-methylquinoxaline were all applicable in this electrolytic reaction, and the corresponding products were obtained with a satisfactory yield (Scheme 3, 5a–5e). In virtue of this transformation, large π-systems with potential fluorescence properties could be effectively constructed.
Table 2. Investigation on Various Ketonesa.
Reaction conditions: graphite rod anode, platinum plate cathode, constant current = 10 mA, 1 (0.2 mmol), 2 (2 equiv, 0.4 mmol), NH4I (1.5 equiv, 0.3 mmol), DMSO (3 mL), 80 °C. Isolated yield.
DMA (3 mL) as the solvent, 2a (1.5 equiv, 0.3 mmol).
2a (1.2 equiv, 0.24 mmol).
Scheme 3. Investigations on Other Active Methyls.
Reaction conditions: graphite rod anode, platinum plate cathode, constant current = 10 mA, 1a (0.2 mmol), 2a (2 equiv, 0.4 mmol), NH4I (1.5 equiv, 0.3 mmol), DMA (3 mL), 80 °C, 16 h. Isolated yields are shown. aReacted at 100 °C.
The electrochemical method was then evaluated by performing a 10 mmol-scale reaction. Using a 25 mA constant current and reaction for 20 h, 62% yield of 3a could be obtained (Scheme 4). The result indicated the potential of this electrochemical synthesis for imidazo[1,5-a]pyridines.
Scheme 4. Gram-Scale Synthesis.
Reaction conditions: graphite rod anode, platinum plate cathode, constant current = 25 mA, 1a (10 mmol), 2a (20 mmol), NH4I (15 mmol), DMSO (50 mL), 80 °C, 20 h.
To investigate the mechanism of the reaction, a set of control experiments were performed (Scheme 5, A, B, C, and D). First, using 2-iodo-1-phenylethanone (1aa) 2-oxo-2-and phenylacetaldehyde (1ab) reacted with 2a under the standard condition could provide 3a with 83 and 67% yield, respectively, indicating that 1aa and 1ab were possible intermediates. Besides, a radical trap experiment was performed; 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO) (0.4 mmol) was added to the reaction system in the 3a synthesis, and the result showed that the addition of TEMPO did not have an apparent influence on the yield of 3a (63%), indicating that this reaction might not experience radical process. Moreover, an oxygen-free experiment under the N2 protection was also performed in the synthesis of 3a, and 78% yield of 3a also indicated that the oxidative dehydrogenation process was not promoted by oxygen.
Scheme 5. Control Experiments.
Based on the information obtained above and the literature,13 a plausible mechanism is proposed in Scheme 6. The anodic oxidation of NH4I generates molecular iodine, which reacts with ketone and forms α-iodoketone 1aa. The nucleophilic substitution of α-iodoketone with amine forms intermediate I; intermediate I experiences anodic oxidative dehydrogenation to form intermediate II, and intramolecular nucleophilic attack followed by anodic oxidative dehydrogenation and gives product 3a.
Scheme 6. Plausible Mechanism of the Reaction.
Conclusions
In conclusion, we have developed an efficient electrochemical method for 3-acyl imidazo[1,5-a]pyridine synthesis, in which double amination of sp3 hydrocarbons of inexpensive ketone methyls well avoids the conventional multistep reaction for 3-acyl imidazo[1,5-a]pyridine synthesis. This transformation exhibits a good substrate scope and functional-group tolerance and gives modest-to-good yield. Also, the application of this method can be extended to other active methyl groups for large π-system preparation. Direct synthesis, inexpensive materials, simple metal-free system with no external electrolyte and oxidant, and scalability make this method a practical and green method for 3-acyl imidazo[1,5-a]pyridine and large π-system preparation.
Experimental Section
Experimental Reagents and Instruments
Unless otherwise noted, all reactions were carried out under the air atmosphere; commercial materials and solvents were used without further purification. 1H NMR (400 MHz, 500 MHz, or 600 MHz) and 13C NMR (101 MHz, 126 MHz, or 151 MHz) spectra were measured using CDCl3 or DMSO-d6 as the solvent at room temperature. High-resolution mass spectra were recorded on a Bruker VPEXII spectrometer with the ESI mode. Flash column chromatography was performed on silica gel with 200–300 mesh.
General Procedure for the Electrosynthesis
General Procedure
Ketones or active methyl compounds (0.2 mmol, 1 equiv), pyridine ethylamines (0.4 mmol, 2 equiv), NH4I (0.3 mmol), and the solvent (DMSO or DMA, 3 mL) were added to a 20 mL tube equipped with a graphite rod anode (diameter = 0.6 cm) and a platinum cathode (1.0 cm2). The electrosynthesis was carried out at 80 °C at a constant current of 10 mA for a specified time; the reaction progress was monitored by thin-layer chromatography (TLC). Then, water (10 mL) was added, and the aqueous solution was extracted with ethyl acetate (3 × 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was chromatographed through silica gel and eluted with ethyl acetate/hexanes to give the product.
Gram-Scale Reaction Procedure
Acetophenone (1a, 10 mmol), phenyl(pyridin-2-yl)methanamine (2a, 20 mmol), NH4I (30 mmol), and DMSO (50 mL) were added to a 100 mL tube equipped with a graphite rod anode (diameter = 0.6 cm) and a platinum cathode (1.0 cm2). The electrosynthesis was carried out at 80 °C at a constant current of 25 mA for 20 h; the reaction progress was monitored by TLC. The system was poured into water (100 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic phase was washed with saturated brine and dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was chromatographed through silica gel and eluted with ethyl acetate/hexanes (5:1) to give product 3a (62%).
Acknowledgments
We are grateful for the financial support from the National Natural Science Foundation of China (81602973), Scientific Research Project of the Education Department of Anhui Province (KJ2021A0883), and Talent Funds of Anhui Science and Technology University.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.1c06029.
Details of characterization data and NMR spectra (PDF)
Author Contributions
∥ X.Y., and X.-j.X. contributed equally to this work.
The authors declare no competing financial interest.
Supplementary Material
References
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