COMMUNICATION DOI: 10.1002/asia.201402443

De Novo Synthesis of Imidazoles by Visible-Light-Induced Photocatalytic Aerobic Oxidation/ACHTUNGRE[3+2] Cycloaddition/Aromatization Cascade Qiao-Hui Deng,[a] You-Quan Zou,[a] Liang-Qiu Lu,[a] Zi-Long Tang,[b] Jia-Rong Chen,*[a] and Wen-Jing Xiao*[a, b]

Abstract: A visible-light-induced photocatalytic aerobic oxidation/ACHTUNGRE[3+2] cycloaddition/aromatization cascade between secondary amines and isocyanides has been successfully developed. The reaction provides a general and efficient access to diversely substituted imidazoles and imidazoACHTUNGRE[1,5a]quinoxalin-4ACHTUNGRE(5 H)-ones in good yields under mild conditions.

Over the past several years, visible-light-induced photoredox catalysis has enjoyed a remarkable renaissance and found wide applications in organic synthesis.[1] The generation of diverse, highly reactive intermediates with distinctive properties by this strategy has provided a powerful platform for the design of new synthetic transformations and the concise synthesis of complex target molecules.[2] In this context, a diverse range of nucleophilic a-amino radicals as well as electrophilic iminium ions and imines have been successfully generated in situ by the visible-light-induced photocatalytic activation of the corresponding amine precursors.[3] Further transformations of these intermediates have resulted in the facile construction and derivation of various nitrogen-containing compounds. In a seminal publication by Stephenson and co-workers in 2010, a photocatalytic cross-coupling of nitroalkanes of tetrahydroisoquinolines has been disclosed (Scheme 1 a).[4] Subsequently, the groups of Rueping, Li, and Wu have elegantly described a series of visible-light-promot-

Scheme 1. Reaction design.

ed functionalizations of secondary amines, in which the transient formation of imines and their interception by various nucleophiles are usually involved.[5] In 2011, we developed a visible-light-induced photocatalytic cascade reaction of tetrahydroisoquinoline esters with electron-deficient alkenes and alkynes, efficiently affording pyrroloACHTUNGRE[2,1-a]isoquinoline derivatives (Scheme 1 b).[6] Despite these advances, to our knowledge, the visible-light-induced photocatalytic sequential generation of imines and application of these reactive intermediates to cycloaddition as “2-atom synthon” have never been explored. On the other hand, highly functionalized imidazoles represent an important class of heteroaromatic compounds with broad applications in the construction of bioactive compounds and pharmaceuticals as well as in asymmetric synthesis.[7] Among them, the 1,5-disubstituted imidazole derivatives are of great interest to both medicinal and synthetic chemists because of their unique structure and biological profile.[8] In addition, 1-arylimidazole-5-carboxylic esters have been identified as important building blocks for the synthesis of various herbicides, fungicides, and plant growth regulators.[9, 10] Not surprisingly, considerable research efforts have been devoted towards the development of efficient methods for their synthesis. Traditionally, the 1,5-disubstituted imidazole scaffolds can be prepared by transition metalcatalyzed arylations of 1-aryl-1H-imidazoles with aryl hal-

[a] Q.-H. Deng, Y.-Q. Zou, Dr. L.-Q. Lu, Dr. J.-R. Chen, Prof. Dr. W.-J. Xiao Key Laboratory of Pesticide&Chemical Biology Ministry of Education College of Chemistry Central China Normal University 152 Luoyu Road, Wuhan, Hubei 430079 (China) Collaborative Innovation Centre of Chemical Science and Engineering Tianjin 300072 (China) Fax: (+ 86) 27-6786-2041 E-mail: [email protected] [email protected] Homepage: http://chem-xiao.ccnu.edu.cn [b] Prof. Dr. Z.-L. Tang, Prof. Dr. W.-J. Xiao School of Chemistry and Chemical Engineering Hunan University of Science and Technology Xiangtan 411201 (China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201402443.

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ides[11, 12] or by cycloadditions of corresponding tosylmethyl isocyanides with imines.[13, 14] However, many of these methods have been limited to specific substrate classes, harsh reaction conditions, and sometimes long reaction times.[12, 14] Accordingly, it is still highly desirable to search for more efficient and operationally simple processes for the rapid synthesis of diversely functionalized 1,5-disubstituted imidazole derivatives. As part of our ongoing research program on the synthesis of biologically and synthetically important nitrogen-containing heterocycles by photocatalysis,[15] we recently achieved a visible-light-induced phtotocatalytic aerobic oxidation/ACHTUNGTRENUG[3+2] cycloaddition/aromatization cascade between secondary amines and isocyanides (Scheme 1 c). In this Communication, we describe the corresponding preliminary results. The photocatalytic reaction sequence that we have designed is shown in Scheme 2. As described by Rueping and

Table 1. Optimization of reaction conditions.[a]

Entry

Photocatalyst

Base

Solvent

t [h]

Yield [%][b]

1 2 3 4 5 6 7 8[c] 9[e] 10[f] 11[g]

A B C A A A A A – A A

K2CO3 K2CO3 K2CO3 KOH NaHCO3 K2CO3 K2CO3 K2CO3 K2CO3 – K2CO3

DMF DMF DMF DMF DMF DMSO CH3CN DMF DMF DMF DMF

24 24 24 24 24 24 24 11 24 24 24

79 62 36 7 trace 33 49 82 (78[d]) trace trace 0

[a] Unless noted otherwise, reactions were performed with 1 a (0.3 mmol), 2 a (0.45 mmol), catalyst (1 mol %), base (0.6 mmol) in the solvent (3.0 mL) under irradiation with an 18 W fluorescent bulb. [b] Yield determined by GC using biphenyl as an internal standard. [c] With 1.0 equiv of K2CO3. [d] Isolated yield. [e] Without photocatalyst. [f] Without K2CO3. [g] Without visible light. Scheme 2. Proposed mechanism.

some inorganic bases (KOH, NaHCO3) and solvents were also tested. It was found that the combination of IrACHTUNGRE(ppy)2 ACHTUNGRE(bpy)PF6 with 1 equivalent of K2CO3 in DMF gave rise to the optimal results and 3 a was isolated in 78 % yield (Table 1, entry 8). To confirm that the reaction was indeed mediated by visible-light-induced photocatalytic activation, control experiments without photocatalyst, base or visiblelight were carried out. As expected, it was found that almost no reaction occurred in the control reactions (Table 1, entries 9–11). With the optimal reaction conditions established, the scope of this protocol was next investigated. This visiblelight photocatalytic cascade reaction seems quite tolerant with respect to the ester moiety in the substrate 1. As shown in Scheme 3, variation of the CO2Et group to CO2Me, CO2iPr, CO2Bn, and CO2tBu had no significant effect on the reaction efficiency, and the reaction generally afforded the corresponding products 3 a-3 e in good isolated yields (Scheme 3, 52–86 %). In addition, substituent variation at the aromatic ring of arylglycine derivatives could also be carried out. Note that electron-donating (Me, OMe) and electron-withdrawing (Cl, Br) groups could be well incorporated on the benzene ring at ortho, meta and para positions, thereby providing the corresponding imidazoles 3 f–3 l in 51–82 % yields. The substrate bearing the naphthyl group on nitrogen could also participate in the reaction to give a moderate yield of the product 3 m. Importantly, in addition to

Li,[5] readily accessible secondary amines, such as glycine derivatives 1, could undergo a photocatalytic oxidation to generate imine B in the presence of photocatalysts under the irradiation of visible light. The imine B would react with the isocyanides 2 through a formal [3+2] cycloaddition reaction to afford the intermediate C, which then undergoes a proton transfer/aromatization cascade to produce 1,5-disubstituted imidazoles 3. In principle, this strategy would avoid the preparation of moisture-sensitive imines and allow for efficient incorporation of various functional groups into 1,5-positions on imidazole scaffolds. To examine the feasibility of the designed reaction, we initially investigated the reaction of glycine-derived amine 1 a and tosylmethyl isocyanide 2 a in the presence of IrACHTUNGRE(ppy)2 ACHTUNGRE(bpy)PF6 (1 mol %) and K2CO3 (2.0 equiv) in DMF under air using a fluorescent bulb (18 W) as the visible-light source. To our delight, the reaction did indeed work, and the desired product 1-arylimidazole-5-carboxylate 3 a was obtained in 79 % yield (as assessed by GC) after 24 h (Table 1, entry 1). Encouraged by this preliminary result, other reaction parameters such as different photocatalysts, bases, and solvents were then examined to increase the reaction efficiency, and the representative results are highlighted in Table 1.[16] A brief screen of commonly used photocatalysts showed that IrACHTUNGRE(ppy)2ACHTUNGRE(bpy)PF6 was the best of choice (Table 1, entries 1–3). With the use of IrACHTUNGRE(ppy)2ACHTUNGRE(bpy)PF6, &

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Scheme 4. Synthetic applications.

In summary, we have developed a visible-light-induced photocatalytic aerobic oxidation/ACHTUNGRE[3+2] cycloaddition/aromatization cascade between secondary amines and isocyanides. The reaction provides a facile access to a series of biologically significant 1,5-disubstituted imidazoles. The readily availability of the starting materials, simple operation, and mild reaction conditions make this protocol attractive to both organic and medicinal chemists. Further detailed mechanistic investigation of this reaction and applications to the synthesis of other heterocycles are currently underway in our laboratory.

Experimental Section General procedure: Glycine derivative 1 a (0.50 mmol, 96.62 mg), tosylmethyl isocyanide 2 a (0.75 mmol, 146.43 mg), IrACHTUNGRE(ppy)2ACHTUNGRE(bpy)PF6 (0.005 mmol, 4.01 mg), K2CO3 (0.50 mmol, 68.96 mg) and dry DMF (5.0 mL) were added to a 10 mL Schlenk tube equipped with a magnetic stir bar. Subsequently, the reaction mixture was stirred under irradiation with a 18 W fluorescent bulb under air. The reaction was monitored by thin-layer chromatography (TLC, (petroleum ether/EtOAc 4:1). Upon complete consumption of the starting materials, the reaction mixture was quenched with distilled water (15.0 mL). The resultant mixture was extracted with Et2O, and the combined organic layers were dried over Na2SO4. After removal of the solvent in vacuum, the residue was purified by flash chromatography on silica gel (EtOAc/petroleum ether 1:4) to give the desired product 3 a as a white solid in 78 % yield.

Scheme 3. Examination of the substrate scope. All yields given correspond to isolated yields.

glycine-derived amines, a-amino-substituted ketones with weak electron-donating (Me) or electron-withdrawing (Cl) groups on the aromatic ring also proved to be suitable for this transformation, and the corresponding products 3 n–3 p were obtained in 42–59 % yields. Furthermore, 1,4,5-trisubstituted imidazole 3 q can also be synthesized in a yield of 45 % with the use of a-tosylmethyl isocyanide (R3 = Me) as the substrate. Attempts to vary the substituent at the C4-position in 1,4,5-trisubstituted imidazoles (with groups other than methyl or H) failed, presumably due to steric hindrance.[17] To demonstrate the preparative utility of this process, we conducted the reaction between 1 a (1.35 g) and 2 a (2.05 g) in the presence of IrACHTUNGRE(ppy)2ACHTUNGRE(bpy)PF6 (1 mol %) on a gram scale [Scheme 4, Eq. (1)]. Gratifyingly, the desired product 3 a (1.21 g) was isolated in 75 % yield. Perhaps more importantly, this photocatalytic cascade reaction has been successfully applied to the synthesis of the biologically useful 5methylimidazoACHTUNGRE[1,5-a]quinoxalin-4ACHTUNGRE(5 H)-one (5 a) and 5-(4methoxybenzyl) imidazo [1,5-a]quinoxalin-4ACHTUNGRE(5 H)-one (5 b) [Scheme 4, Eq. (2)]. Removal of the p-methoxybenzyl (PMB) protecting group of 5 b according to a literature procedure would deliver the corresponding imidazoACHTUNGRE[1,5-a]quinoxalin-4-one 6, which is a novel protein tyrosine kinase (PTK) inhibitor candidate.[18]

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Acknowledgements We are grateful to the National Science Foundation of China (Nos. 21232003, 21272087, and 21202053) and the National Basic Research Program of China (2011CB808603) for support of this research. Y.-Q. Zou. thanks the Excellent Doctorial Dissertation Cultivation Grant from Central China Normal University (CCNU13T04094, 2013YBZD22).

Keywords: cascade · cycloaddition · imidazoles · oxidation · photochemistry

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COMMUNICATION Photocatalysis Qiao-Hui Deng, You-Quan Zou, Liang-Qiu Lu, Zi-Long Tang, Jia-Rong Chen,* &&&&—&&&& Wen-Jing Xiao* A cascade of change: A visible-lightinduced photocatalytic aerobic oxidation/ACHTUNGRE[3+2] cycloaddition/aromatization cascade between secondary amines and isocyanides has been successfully developed. The reaction provides

a general and efficient access to diversely substituted imidazoles and imidazoACHTUNGRE[1,5-a]quinoxalin-4ACHTUNGRE(5 H)-ones in good yields under very mild conditions.

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De Novo Synthesis of Imidazoles by Visible-Light-Induced Photocatalytic Aerobic Oxidation/ACHTUNGRE[3+2] Cycloaddition/Aromatization Cascade

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aromatization cascade.

A visible-light-induced photocatalytic aerobic oxidation/[3+2] cycloaddition/aromatization cascade between secondary amines and isocyanides has been s...
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