Photoredox-Catalyzed Acylation/Cyclization of 2-Isocyanobiaryls with Oxime Esters for the Synthesis of 6-Acyl Phenanthridines

: An efﬁcient acylation/cyclization reaction of 6-acyl phenanthridines with oxime esters using photoredox catalysis has been developed. This radical acyl transfer strategy enables a facile access to acyl-substituted phenanthridines with good yield and excellent selectivity. The developed method is redox neutral and has broad substrate scope and excellent functional group tolerance.


Introduction
Nitrogen heterocycles are ubiquitous and significant structure frameworks, widely embedded in natural products and pharmaceuticals [1].Phenanthridines, common nitrogencontaining aromatic fused heterocycles, have been received much attention for their existence in many drug candidates with outstanding medicinal properties, such as cytotoxic, antifungal, antibacterial, and antitumor activities [2][3][4].Therefore, the development of efficient methodologies to synthesize phenanthridines and their derivatives is highly important.Different synthetic strategies for the synthesis of phenanthridines have been documented to date, such as the Pictet-Hubert reaction [5], Morgan-Walls reaction [6], Bischler-Napieralski reaction [7], cycloaddition [8][9][10][11], transition metal-mediated reaction [12][13][14][15][16], and so forth [17,18].Despite efficiency, these reactions often suffer harsh reaction conditions, which lead to the restriction of their application in organic synthesis.Consequently, it is highly desirable to exploit mild and effective approaches for the preparation of phenanthridines.
With the optimal conditions established, a series of biaryl isocyanides were first examined for the scope of this photoredox-catalyzed acylation/cyclization reaction in the presence of 2a (Table 2).Initially, 2-isocyanobiaryl compounds 1b-h embedding a variety of substituents with electron-donating (1b) or -withdrawing groups (1c-h) at the paraposition of the phenyl that does not contain the isonitrile motif reacted smoothly with 2a to furnish the corresponding phenanthridine derivatives 3ba-ha in good yields, ranging from 70% to 89%.The transformation of acyl oxime ester 2a with 3-substituted isocyanides 1i and 1j delivered two regioisomers, respectively.Isocyanides 1k-m bearing substituents at the ortho position of the arene could undergo the acylation/cyclization reaction to provide phenanthridines with good results.Interestingly, a satisfactory 79% yield and specific regioselectivity were obtained with isocyanide 1n containing a naphthyl moiety, while 1o bearing benzodioxole was applied as substrate and resulted in two regioisomers with a 90% total yield.In addition, the desired product, 3pa, bearing a fused benzofuran, could also be obtained using the present synthetic method.Then, 2-isocyanobiaryls 1q-v carrying different substituents at the arene that bears the isonitrile moiety were explored under the optimized conditions.Obviously, the substituents with different electronic properties at the different positions of the arenes did not affect the reaction efficiency, demonstrating the broad substrate scope of this reaction. 1Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol, 1.5 equiv), Ir(ppy) 3 (1 mol%) and DMF (2 mL) at 100 • C in the presence of N 2 under 5 W blue light for 12 h. 2 Cited yields are of isolated material following chromatography.
Then, the reactions of biphenyl isocyanide (1a) with a variety of acyl oxime esters under the optimized condition were exploited (Table 3).For R 4 = Me, pleasingly, both aliphatic acyl and aroyl oxime esters were suitable for the acylation/cyclization transformations to provide 6-acyl phenanthridines, which differed from the previous reports [51][52][53][54] that overwhelmingly produced aliphatic acyl 6-substituted phenanthridines.The acyl oxime esters 2b-f with different chain lengths could be smoothly converted to the corresponding acyl radical in the presence of the photocatalyst, followed by isocyanide insertion to produce 3ab-f in good yields.In addition, aroyl oxime esters 2g-n containing a variety of groups on the phenyl rings were investigated.To our delight, the expected radical addition/cyclization products 3ag-n were isolated in 71-82% yields.Notably, 2-thienylacyl substituted phenanthridine 3ao could be obtained from the corresponding acyl oxime ester 2o in a yield of 76%.This conversion were successfully amenable to oxime esters 2o and 2p with variation in the iminyl group (R 4 ), and both of them afforded 6-acyl substituted nitrogen heterocycles 3ab and 3ac in 77% and 81% yields, respectively. 1Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol, 1.5 equiv), Ir(ppy) 3 (1 mol%) and DMF (2 mL) at 100 • C in the presence of N 2 under 5 W blue light for 12 h. 2 Cited yields are of isolated material following chromatography.
To investigate the reaction mechanism, control experiments were performed (Scheme 2).The common radical scavengers, such as TEMPO, BHT, and 1,1-diphenylethene, were applied to detect the reactive species.As a result, the reactions were almost completely inhibited, and benzoic radicals were captured by the scavengers, which suggested that this reaction involved the radical mechanism.According to the above control experimental results and previous reports , a possible mechanism was proposed (Scheme 3).At first, upon visible-light irradiation, the photocatalyst Ir 3+ was converted to its excited state Ir 3+ * (E 1/2 Ir 4+ /Ir 3+ * = −1.73V versus SCE) [58], which underwent single-electron transfer (SET) with oxime ester 2a (E red of approximately −1.45 V versus SCE) [62,63] to produce iminyl radical A via the removal of the ester group and the generation of the oxidation sate Ir 4+ complex at the same time.The β-fragmentation of iminyl radical A occurred to afford acetonitrile and acyl radical B, which underwent isonitrile radical insertion with isocyanobiaryl 1a to produce imidoyl radical C. Next, the intramolecular cyclization occurred to furnish intermediate D, which was further oxidized by Ir 4+ to produce cation E and the regeneration of photocatalyst.Finally, the product 3aa was obtained from E via the release of a proton.

General Information
Commercially available reagents were used throughout without purification unless otherwise stated.The starting biaryl isocyanide (1) [64] and acyl oxime esters (2) [65] were prepared by methods reported in the literature. 1 H and 13 C NMR spectra were recorded on a Bruker AC-400 instrument (400 MHz for 1 H and 100 MHz for 13 C) at 20 • C. Chemical shifts (d) are given in ppm downfield from Me 4 Si and are referenced as internal standard to the residual solvent (unless indicated) CDCl 3 (d = 7.26 for 1 H and d = 77.00 for 13 C).Coupling constants, J, are reported in hertz (Hz).The following abbreviations were used to explain multiplicities: s = singlet, d = doublet, dd = doublet of doublet, t = triplet, td = triplet of doublet, q = quartet, m = multiplet, and br = broad.Melting points were determined in a capillary tube and are uncorrected.TLC was carried out on SiO 2 (silica gel 60 F254), and the spots were located with UV light.Flash chromatography was carried out on SiO 2 (silica gel 60, 230-400 mesh ASTM).Drying of organic extracts during work-up of reactions was performed over anhydrous Na 2 SO 4 .Evaporation of solvents was accomplished with a Büchi rotatory evaporator.High-resolution mass spectra (HRMS) were obtained on an Agilent mass spectrometer using ESI-TOF (electrospray ionization-time of flight).

General Procedure for the Synthesis of 3
To a Schlenk tube were added 1 (0.2 mmol), 2 (0.4 mmol, 2 equiv.),DMF (2 mL), and Ir(ppy) 3 (1 mol%).Then, the mixture was stirred at 100 • C (oil bath temperature) in an N 2 atmosphere for 12 h until the complete consumption of the starting material was monitored by TLC and GC-MS analysis.After the reaction was finished, the reaction mixture was washed with brine.The aqueous phase was re-extracted with EtOAc (3 × 10 mL).The combined organic extracts were dried over Na 2 SO 4 and concentrated in vacuum.The residue was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate = 80:1 to 40:1) to afford the desired products 3.