Direct C–H Cyanation of Arenes via Organic Photoredox Catalysis

Abstract

Methods for the direct C-H functionalization of aromatic compounds are in demand for a variety of applications, including the synthesis of agrochemicals, pharmaceuticals, and materials. Herein, we disclose the construction of aromatic nitriles via direct C-H functionalization using an acridinium photoredox catalyst and trimethylsilyl cyanide under an aerobic atmosphere. The reaction proceeds at room temperature under mild conditions and has proven to be compatible with a variety of electron-donating and -withdrawing groups, halogens, and nitrogen-and oxygencontaining heterocycles, as well as aromatic-containing pharmaceutical agents.Nitrile-containing aromatic groups are well represented throughout agrochemicals and therapeutic molecules (Scheme 1A). In addition to being prevalent in a number of bioactive compounds, cyanoarenes provide an excellent functional group handle that can be transformed to give derivatives of benzoic acid through hydrolysis, 1 aryl ketones or imines after treatment with a strong nucleophile, 2 benzaldehydes or benzylamines by reduction, 3 aryl-amides through hydration, and even tetrazoles through [3+2] cycloadditions with sodium azide. 4 Classical approaches to cyanoarene synthesis include the Sandmeyer reaction from the corresponding diazonium salt 5 or transition-metal-catalyzed cross-coupling with the requisite aryl halide. 6-14 Few C-H functionalization methods exist for directly producing benzonitriles from unfunctionalized arenes, and they employ Rh or Co catalyst systems, often requiring elaborate directing groups and exotic reagents, 15-20 harsh lithiation conditions, 21 or electrophilic sources of cyanide that give poor selectivity or significant byproduct formation. 22 While the aforementioned methods are successful at accessing arene cyanation, a mild and metal-free C-H cyanation of aromatic compounds employing a common and inexpensive cyanide source has yet to be reported. Experimental procedures and supporting data 1 H and 13 C NMR spectra (PDF)The authors declare no competing financial interest. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptRecent efforts from our laboratory have demonstrated the reactivity of arene cation radicals, 23 generated via photoinduced electron transfer from the excited state of an acridinium catalyst, 24 to accomplish direct C-H amination of a range of aromatics and heteroaromatics bearing a variety of functional groups. 25 Importantly, this transformation does not require the presence of a directing group and is highly para-selective for monosubstituted benzenes. [26][27][28] Recognizing the importance of cyanoaromatics, and previous literature citing the addition of cyanide to arene radical cations, 29,30 we decided to investigate the use of cyanide nucleophiles in reactions with arene cation radicals to access this class of compounds. We proposed that the highly oxidizing 3,6-di-tert-butyl-9-mesityl-10-phenylacridinium tetrafluoroborate (1, E 1/2 red * = +2.15 V vs SCE) 25 would be an effecti...

Predictive Model for Site-Selective Aryl and Heteroaryl C–H Functionalization via Organic Photoredox Catalysis

“…In addition to these substrates from our prior amination report, we wanted to demonstrate that additional benzenoid compounds from our arene cyanation work 11 participated in the amination chemistry to expand the functional group tolerance of the reaction. Esters were compatible ( 2n ), as well as O -benzylphenols ( 2o ) and allyl substituents ( 2o and 2p ), even under aerobic conditions.…”

“…The site selectivities observed when a variety of other azole nucleophiles were used ( 18c – g ) matched those reported above when using pyridines, quinolines, pyrazoles, indazoles, and benzofurans with pyrazole as the coupling partner. We also wanted to test whether other aryl functionalization reactions such as the C–H cyanation developed in our laboratory 11 followed similar site selectivities ( 18h and 18i ). The results in Figure 11 demonstrate that other nucleophiles exhibit the same site selectivities for a variety of heterocyclic classes as previously discussed, allowing the predictive model to be generalized to include a range of nucleophiles.…”

“…More recently, we have disclosed a strategy for aryl C–H cyanation that also relies on aryl cation radical intermediates. 11 …”

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

“…TMSCN is employed as the cyanide source, acridinium salts as the photocatalyst, under irradiation from blue LEDs and aerobic conditions (Scheme 34) [80]. The authors show a set of diverse molecules that underwent the transformation cleanly.…”

Photochemical Functionalization of Helicenes

“…The 1 H NMR analysis showed that the product consists of only one regioisomer, and 2D NMR experiments confirmed that helicene 3 was functionalized only at the 6 position. The cyanation reaction was performed using a protocol reported by Nicewicz . In this case, the reaction was conducted under air atmosphere using an acridinium photocatalyst (10 mol %) in 10:1 mixture of acetonitrile pH 9 phosphate buffer, and trimethylsilyl cyanide (1.5 equiv) was used as the source of the −CN group.…”