Letter Cite This: Org. Lett. 2018, 20, 6359−6363
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Electrocatalytic Intermolecular C(sp3)−H/N−H Coupling of Methyl N‑Heteroaromatics with Amines and Amino Acids: Access to Imidazo-Fused N‑Heterocycles
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Peng Qian, Zicong Yan, Zhenghong Zhou, Kangfei Hu, Jiawei Wang, Zhibin Li, Zhenggen Zha,* and Zhiyong Wang* Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry & Center for Excellence in Molecular Synthesis of Chinese Academy of Sciences, Collaborative Innovation Center of Suzhou Nano Science and Technology & School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China S Supporting Information *
ABSTRACT: An efficient NH4I-mediated intermolecular annulation of methyl N-heteroaromatics with amines/amino acids was developed by virtue of anodic oxidation, providing a variety of functionalized imidazo-fused N-heterocycles with good to excellent yields. The practicality of this protocol was demonstrated by the readily available starting materials, broad substrate scope, water tolerance, scalability, and the diverse transformations of the electrolysis product.
I
C(sp3)−H amination cyclizations of reactions have been less explored. 9 As our ongoing work on the C(sp 3 )−H functionalization via the iodine-catalyzed strategy in electrochemistry,10 we herein report an electrochemical intermolecular C(sp3)−H/N−H cross-dehydrogenative coupling for the synthesis of imidazo-fused N-heterocycle scaffolds. This iodine-catalyzed approach proceeds from readily available materials, obviating the use of metal and chemical oxidants. Moreover, the reaction can be easily scaled to gram scale without sacrificing the efficiency. Initially, 2-methylquinoline and benzylamine were selected as the model substrates. The reaction was electrolyzed in an undivided cell with DMSO as the solvent at a constant current density of 10 mA/cm2, while NH4I was used as the supporting salt. As expected, a 74% yield of the desired product was obtained (entry 1 of Table 1), which encouraged us to further optimize the reaction conditions. First, the solvent effect was investigated, and DMF was determined to be the best solvent (entries 2−5). It should be noted that the reaction was welltolerated in water (entry 5). Then the effect of supporting salts on the formation of the product was examined (entries 6−9). It was found that all iodide salts could conduct this reaction smoothly and NH4I furnished the best yield. In contrast, no desired product formation was observed when NH4Br and LiClO4 were employed in place of NH4I. These results indicate that NH4I plays a role not only as the electrolyte but also as the mediator for the reaction. Furthermore, when we decreased the loading of NH4I to 50
midazo-fused N-heterocycles as important scaffolds widely exist in optoelectronic materials and biological molecules.1 Consequently, continuous efforts have been devoted to their syntheses since the pioneering work of Vilsmeier-type cyclization.2 However, the substrates of the developed methods were limited to substituted N-heteroaryl aldehydes,3a,b ketones,3c,d pyridotriazoles,3e,f and others.3g,h Moreover, transition-metal catalysts and external chemical oxidants were generally required for these transformations, which inevitably resulted in generation of waste and undesired reactions. Atom and step economy as well as sustainable chemistry to the direct C(sp3)−H/N−H oxidative coupling is an ideal, but challenging approach. Recently, many research groups including us have successfully achieved the synthesis of imidazo-fused Nheterocycles.4 However, most of the developed approaches suffered some drawbacks, such as the requiement of prefunctionalized starting materials, a limited substrate scope, and stoichiometric chemical oxidants. These problems hindered the practical application of these transformations. On the other hand, the oxidative olefination reaction was usually prone to proceed instead of the amination cyclization reaction of methyl N-heteroaromatics with amines.5 Therefore, the development of new strategies under metal- and chemicaloxidant-free conditions from readily available materials still remains a great challenge. Organic electrochemistry represents an environmentally benign and sustainable method with electrons as reagents.6 Considerable progress has been made in C(sp2)−H/N−H cross-dehydrogenative coupling reactions.7 Perhaps due to the high oxidative potential of unactivated C(sp3)−H,8 it presented a great challenge in achieving direct C(sp3)−N formation. Therefore, the intermolecular benzylic primary © 2018 American Chemical Society
Received: August 11, 2018 Published: October 3, 2018 6359
DOI: 10.1021/acs.orglett.8b02578 Org. Lett. 2018, 20, 6359−6363
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
entry
electrolyte
1 2 3c
NH4I NH4I NH4I
4 5
NH4I NH4I
6 7 8 9 10d 11 12 13 14 15 16e 17f 18g 19h 20
KI n-Bu4NI NH4Br LiClO4 NH4I NH4I NH4I NH4I NH4I NH4I NH4I NH4I NH4I NH4I NH4I
solvent DMSO DMF CH3CN/H2O (5:1) H2O DMF/H2O (5:1) DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF
anode/cathode J (mA/cm2)
Table 2. Scope of Aminesa
yieldb (%)
Pt/Pt Pt/Pt Pt/Pt
10 10 10
74 85 trace
Pt/Pt Pt/Pt
10 10
trace 82
Pt/Pt Pt/Pt Pt/Pt Pt/Pt Pt/Pt Pt/Pt Pt/Pt Pt/Pt C/Pt Pt/C Pt/Pt Pt/Pt Pt/Pt Pt/Pt Pt/Pt
10 10 10 10 10 5 15 20 10 10 10 10 10 10 0
20 30 trace n.d. 83 61 71 68 68 61 74 81 82 70 trace
entry
R2
product
yieldb(%)c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Ph (2a) 4-Me-Ph (2b) 3-Me-Ph (2c) 2-Me-Ph (2d) 4-OMe-Ph (2e) 2-OMe-Ph (2f) 4-F-Ph (2g) 3-F-Ph (2h) 2-F-Ph (2i) 4-Cl-Ph (2j) 3-Cl-Ph (2k) 2-Cl-Ph (2l) 4-Br-Ph (2m) 4-CF3-Ph (2n) 3-CF3-Ph (2o) 1-naphthyl (2p) 2-Cl-4-F-Ph (2q) 2-thienyl (2r) 2-pryidyl (2s) Bn (2t)
3aa 3ab 3ac 3ad 3ae 3af 3ag 3ah 3ai 3aj 3ak 3al 3am 3an 3ao 3ap 3aq 3ar 3as 3at
85(83)c 72 89 84(84)c 83 91 74 95 84 79 90 96(94)c 72 96(93)c 91 80 96(95)c 60 29 n.d.
a
Reaction conditions: 1a (0.3 mmol), 2a−2t (0.9 mmol), NH4I (0.3 mmol), DMF (3 mL); the electrolysis was conducted in an undivided cell at oil bath (100 °C). bThe isolated yields. cThe isolated yields in the parentheses with 50 mol % NH4I as supporting salt.
a
Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol), electrolyte (0.3 mmol), solvent (3 mL); the electrolysis was conducted in an undivided cell at oil bath (T = 100 °C). bThe isolated yields after column chromatography. cT = 80 °C. dThe loading of NH4I was 50 mol %. eT = 90 °C. fT = 110 °C. gO2 was used. hN2 was used.
Gratifyingly, the heterocyclic derived substrates, such as thiophenes 2r and pyridines 2s could also be subjected to this electrochemical condition (entries 18 and 19). The substrate 2s gave the desired product 3as with a low yield perhaps due to the self-coupling cyclization reaction. Nevertheless, no corresponding products were observed when the aliphatic amines were employed as the reaction substrates. To demonstrate the practicability of this methodology, we also examined the reaction with various substrates with a low loading of NH4I in the reaction. The good to excellent reaction yields were still maintained (3aa, 3ad, 3al, 3an, and 3aq), as shown in Table 2. Additionally, the electrolytic reaction of 1a with 2a could be performed on a gram scale to afford the desired product with a moderate yield (Scheme 1a). On the other hand, the desired product 3aa could be further derived into imidazo[1,5-a]quinolone derivatives by on/off switching
mol %, the reaction still proceeded smoothly with a slightly decreased yield of the product (entry 10). Increasing or decreasing the current density resulted in the decrease of the product yield (entries 11−13). Further screening of the electrode materials showed that the combination of Pt/Pt was the optimal choice (entries 14 and 15). Elevating or lowering the reaction temperature decreased the yield (entries 16 and 17). A relatively lower yield was obtained when the reaction was conducted under a nitrogen or an oxygen atmosphere (entries 18 and 19). The control experiment indicated that galvanization was necessary for this transformation (entry 20). After investigation, the optimal electrolytic conditions were described as entry 2 of Table 1. With the optimal electrolytic conditions in hand, various aromatic benzylamines were examined. To our delight, both electron-rich and electron-poor aryl benzylamines could proceed smoothly in this reaction, affording the desired products with good to excellent yields (entries 2−6 and 14− 15, Table 2). Halide substituents such as F, Cl, Br were also tolerated under the standard conditions (entries 7−13). Moreover, 1-naphthylamine 2p and multisubstituted benzylamine 2q were found to be compatible with the reaction conditions, giving the desired products with yields of 80% and 96% (entries 16 and 17), respectively. It was noteworthy that ortho-substituted benzylamines proved to be amenable substrates as well. For instance, ortho-methyl and ortho-chloro benzylamines gave superior results to the para-methyl and para-chloro benzylamines (entries 4 and 12 vs 2 and 10).
Scheme 1. Gram-Scale Experiments and Product Transformations by On/Off Switching of Electric Current
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DOI: 10.1021/acs.orglett.8b02578 Org. Lett. 2018, 20, 6359−6363
Letter
Organic Letters Scheme 3. Electrosynthesis of Imidazo-Fused NHeterocycles from Amino Acids and Its Application
of the electric current in one pot (Scheme 1b and 1c). For instance, substrates 1a and 2a were electrolyzed under the standard conditions to give the product 3aa. Following the addition of NBS and stopping electrolysis, 3aa was converted into an imidazo[1,5-a]quinolone derivative 3aa′, in which the bromo group was selectively introduced into the 3-position at the imidazo ring of 3aa (Scheme 1b). When 1,2-diphenyldisulfane was added with a prolonged electrolysis time, a thiolation of 3aa was formed with moderate yields, which was a useful precursor due to its anticancer activities (Scheme 1c).11 Subsequently, we turned our attention to the scope of substrates methyl N-heteroaromatics. As shown in Scheme 2, Scheme 2. Scope of Methyl N-Heteroaromaticsa
To gain more understanding of the reaction mechanism, some control experiments were carried out (Scheme 4). Scheme 4. Control Experiments
a
Reaction conditions: 1b−1p (0.3 mmol), 2a (0.9 mmol), NH4I (0.3 mmol), DMF (3 mL); the electrolysis was conducted in an undivided cell at oil bath (100 °C); the isolated yields after column chromatography.
the electronic effect of substitution on the aryl ring had an influence on the reaction yields. In general, the substrates bearing electron-withdrawing substituents gave the desired products in better yields than those bearing electron-rich substituents (3la vs 3ba−3da). In addition, the steric effect of substituents on the aromatic rings had a negative influence on the reaction. For instance, the small group of Me and Br gave a slightly deceased yield (3da vs 3ea and 3ia vs 3ja), while the bulky t-Bu group hardly conducted the reaction under the standard conditions (3fa vs 3ga). The multisubstituted 2methylquinoline 1m also reacted well, affording 3ma in 51% yield. Remarkably, 2-methyl-1,8-naphthyridine 1n, 1-methylisoquinoline 1o, and 4-methyl-2-phenylquinazoline 1p were found to be compatible with this electrochemical reaction, providing the corresponding complex skeletons with excellent yields (3na−3pa). In order to make the protocol more practical, the α-amino acids were employed as the coupling partners in this electrochemical reaction since these α-amino acids are low cost and readily available. With a minor modification of the standard conditions, that is, the solvent DMF was changed into DMSO, various amino acids worked well in the reaction to afford a variety of imidazo-fused N-heterocycles with moderate to good yields (Scheme 3). Some amino acids, such as glycine, which were hardly employed in the previous reactions, now can be used as the reaction substrate in this reaction albeit with a low yield (3au).12 Furthermore, glycine can be employed to synthesize 3mu in one pot. Additionally, 3mu can be scaled up and can be further transformed into NK1 receptor ligands,13 further enhancing the practicality of our synthetic method.
Initially, 0.5 equiv of molecular iodine was added to the reaction mixture without electrolysis for 24 h. However, only a 15% yield of the desired product was obtained while the starting material was recovered with a yield of 61% (Scheme 4a1). Increasing the amount of molecular iodine did not promote the formation of desired product, but a self-coupling product 1aa was obtained with a 52% yield (Scheme 4a3). In contrast, when 0.5 equiv of molecular iodine was added to reaction mixture and then electrolysis for 15 h, the desired product can be obtained with a yield of 79% (Scheme 4a2). These results indicate that the molecular iodine should be the active species and the low concentration of molecular iodine is the key for this transformation. On the other hand, the analysis of the 1H NMR of the reaction mixture showed that the compounds 6 and 7 should be involved in this reaction. Therefore, we synthesized compound 6 and this compound was used in the reaction. Gratifyingly, the desired product was obtained with a yield of 78% (Scheme 4b1). Nevertheless, only a trace amount of the desired product 3aa was detected in the absence of NH4I (Scheme 4b2). These experimental results indicate that compound 6 is likely to be the reaction 6361
DOI: 10.1021/acs.orglett.8b02578 Org. Lett. 2018, 20, 6359−6363
Letter
Organic Letters intermediate and the in situ electrogenerated iodine should oxidize the compound 6 into 7. When the substrate 2(iodomethyl)quinoline 5 was employed in the reaction, the desired product 3aa can be obtained in 68% yield (Scheme 4c), which implied that compound 5 was a possible intermediate in this reaction. Although the electrolysis of quinoline-2-carbaldehyde 8 with benzylamine 2a under the standard conditions could afford the desired product with a yield of 56% (Scheme 4d1), only a trace amount of quinoline2-carbaldehyde 8 was observed during the electrolysis of substrate 1a in the absence of benzylamine (Scheme 4e). This means that the pathway of 2-methylquinoline 1a to the quinoline-2-carbaldehyde 8 is not possible. On the other hand, only a trace amount of 3aa was detected when quinoline-2carbaldehyde 8 was electrolyzed in the absence of NH4I (Scheme 4d2). This result indicates that NH4I plays an important role in the transformation. The experimental result showed that NH4I promoted the formation of molecular iodine, which facilitates the formation of the product 3aa. Based on the above experimental results and the previous reports,4a,d a plausible reaction mechanism was proposed (Scheme 5). Initially, an iodide anion is oxidized to be
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Zhiyong Wang: 0000-0002-3400-2851 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for the financial support from the National Natural Science Foundation of China (21672200, 21472177, 21432009, 21772185) and the assistance of the product characterization from the National Demonstration Center for Experimental Chemistry Education of University of Science and Technology of China. This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences, Grant No. XDB20000000.
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Scheme 5. Proposed the Possible Reaction Mechanism
REFERENCES
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molecular iodine on the anode surface. Then molecular iodine reacts with the isomer 2-methylquinoline 1a′ to generate 2(iodomethyl)quinoline 5, which could be easily nucleophilically attacked by benzylamine 2a to form intermediate 6. The intermediate 6 is sequentially oxidized by the electrogenerated molecular iodine to afford intermediate 10. Finally, the intermediate 10 is further transformed into the desired product through the tandem amination/aromatization process. On the cathode surface, the proton is reduced to be molecular hydrogen. In summary, we developed a practical and efficient approach for the construction of imidazo-fused N-heterocycles from readily available starting materials of methyl N-heteroaromatics and amines/amino acids under metal- and chemical-oxidantfree conditions. The reaction features a broad substrate scope, high step economy, and water tolerance. The developed approach was further demonstrated by its good scalability and the diverse transformations of the electrolysis product in one pot. Further studies on intermolecular benzylic primary C(sp3)−H amination cyclization are ongoing in our laboratory.
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Experimental procedures, characterization data, copies of 1 H NMR, 13C NMR of new compounds (PDF)
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02578. 6362
DOI: 10.1021/acs.orglett.8b02578 Org. Lett. 2018, 20, 6359−6363
Letter
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DOI: 10.1021/acs.orglett.8b02578 Org. Lett. 2018, 20, 6359−6363
