Electrochemical Oxidative C−H Cyanation of Quinoxalin‐2(1H)‐ones with TMSCN

Abstract

Both quinoxalin-2(1H)-ones and nitriles are valuable organic compounds, and it is an interesting task to introduce cyano into quinoxalin-2(1H)-ones. Herein a regioselective CÀ H cyanation of quinoxalin-2(1H)-ones was developed with a nucleophilic cyano source TMSCN under electrochemical oxidative conditions. This process allowed the synthesis of C3 cyanated quinoxalin-2(1H)ones in moderate to excellent yields in the absence of transition-metal catalysts and organic hydroperoxides.Quinoxalin-2(1H)-ones are present in a variety of natural products and can be widely found in pharmaceutical molecules with antimicrobial, antifungal, antithrombotic, and antitumor activities, etc. [1] Quinoxalin-2(1H)-one skeleton can also be utilized as a building block in the design of fluorescent dye and fluorogenic probe. [2] A series of active quinoxalinone derivatives bearing a C3-substituted group has been extensively studied, due to their diverse biological activities. [3] Therefore, the synthesis of C3-substituted quinoxalin-2(1H)-ones has gained much attention in recent years. One of the most efficient methods to access C3-substituted quinoxalin-2(1H)-ones is the direct transformation of quinoxalin-2(1H)-ones without prefunctionalization. [4] The past years have witnessed extensive efforts on the direct C3 arylation, [5] heteroarylation, [6] alkylation, [7] trifluoromethylation, [8a] trifluoroalkylation, [8b] difluoromethylation, [8c] acylation, [9] amination, [10] alkoxylation, [11a] fluoroalkoxylation, [11b] phosphonation [12] or sulfenylation [13] of quinoxalin-2(1H)-ones. Nevertheless, the introduction of a CN group to the C3-position of quinoxalin-2(1H)-ones is still highly desirable.Compounds containing cyano functional group, namely nitriles, are a valuable class of organic compounds due to their wide application in pharmaceuticals, agrochemicals, and materials, etc. [14] Moreover, nitriles are easily converted to other important organic compounds such as amides, carboxylic acids, esters, amines, ketones, aldehydes, etc. via the cyano transformation. [15] Therefore, the facile introduction of a cyano group to organic compounds is synthetically attractive for organic chemists. Chelation-assisted transition-metal-catalyzed CÀ H activation has been well developed for the CÀ H cyanation of arenes [16] or heteroarenes [17] in the past decade (Scheme 1a). However, this strategy required the introduction of directing groups to the substrates and the utilization of expensive Rh, Ru or Pd, etc. transition-metal catalysts. [18] Direct CÀ H cyanation of arenes [19] or heteroarenes [20] is an alternative and efficient protocol because it enables the formation of cyanated products without the prefunctionalization of substrates. In these reactions, the choice of cyano sources was significant for obtaining high efficiency. Electrophilic cyanating reagents, such as BrCN, [19a] N-cyano-N-phenyl-p-toluenesulfonamide (NCTS), [19e,20b] could smoothly react with electron-rich arenes. However, these reagents had some di...

Paired Electrolysis Enabled Cyanation of Diaryl Diselenides with KSCN Leading to Aryl Selenocyanates

“…On the basis of the above-mentioned results and the previous literature, [ 27 , 45 , 61 ] a plausible mechanism for the electrochemical cyanation was depicted in Scheme 4 . Firstly, KSCN (2) underwent one-electron oxidation at the surface of the graphite anode to generate a thiocyanate radical (SCN − ), which attacked the Se atom of PhSeSePh (1) to form the benzenesulfinoselenoyl cyanide intermediate (A).…”

“…Therefore, electrosynthesis is usually compatible with highly functionalized substrates and has displayed great potential in both synthetic and bioconjugation chemistry [ 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. In recent years, electrochemical cyanation with various cyanating agents (trimethylsilyl cyanide [ 42 , 43 , 44 , 45 , 46 ], cyanobenziodoxolone [ 47 ], AIBN [ 48 ], tosyl cyanide [ 49 ] and 4-cyanopyridine [ 50 ]) have been used to construct the cyanated products. In contradistinction, to the best of our knowledge, electrochemical cyanation with thiocyanate salts has never been reported.…”

Electrochemical primary amination of imidazopyridines with azidotrimethylsilane under mild conditions

“…Azidation involving an azide anion or azido radical under electrochemical conditions has also gained much attention in recent years. 17 Inspired by the above excellent works and based on our previous research on the electrochemical C–H functionalization of imidazo-[1,2- a ]pyridine and other heteroarenes, 18 herein, we demonstrated the first electrochemical primary amination of imidazopyridines with TMSN 3 under mild conditions in the absence of external chemical oxidants such as CAN (Scheme 2f). The interaction of the substrates with TMSN 3 was also much different from the process proposed in Scheme 2d because the azido radical was not the reactive intermediate in our electrochemical amination reaction.…”

Recent Advances in Electrochemical C(3)—H Functionalization of Quinoxalin-2(1H)-ones

“…[22] Therefore, the facile introduction of a cyano group to organic compounds is very attractive for organic chemists. Very recently, Sun group [23] developed an electro-oxidative method for efficient C-H cyanation of quinoxalin-2(1H)-ones with TMSCN as a nucleophiliccyano source in a mixed solvent of CH 3 CN and KH 2 PO 4 / K 2 HPO 4 (pH＝9) buffer solution (Scheme 17). The protocol features oxidant free, ambient condition, a broad substrate scope, excellent functional group tolerance and good to excellent yield of the desired product.…”