Construction of Phenanthridinone Skeletons through Palladium-Catalyzed Annulation

Herein, a straightforward synthetic approach for the construction of phenanthridin-6(5H)-one skeletons is disclosed. The developed protocol relies on palladium catalysis, providing controlled access to a range of functionalized phenanthridin-6(5H)-ones in 59–88% yields. Furthermore, plausible reaction pathways are proposed based on mechanistic experiments.


■ INTRODUCTION
Phenanthridin-6(5H)-one represents a class of tricyclic Nheterocycles that is frequently encountered in alkaloids, such as phenaglydon, crinasiadine, and trisphaeridine (Figure 1, top).These compounds have been documented to possess biological and pharmaceutical activities, including antimycobacterial, 1 antagonistic, 2 antiproliferative, 3 and antitubercular activities. 4ignificant attention has been devoted to developing novel synthetic methods for the construction of phenanthridin-6(5H)-one derivatives (Figure 1, middle). 6The Yamada group demonstrated the synthesis of phenanthridin-6(5H)-ones through nickel-catalyzed amidation of aryl iodides. 7At the same time, Chaudhary and co-workers disclosed an organocatalytic protocol proceeding through direct C(sp 2 )−H bond arylation. 8Similarly, phenanthridin-6(5H)-one derivatives have also been accessed in high yields using the free radical initiator AIBN 9 or microwave irradiation. 10Furthermore, phenanthridin-6(5H)-one derivatives have been efficiently assembled from 2-bromophenylbenzamides through a palladium-catalyzed process involving aryl−aryl coupling and deamidation. 11arious strategies have utilized the oxidative coupling of benzamides to construct phenanthridin-6(5H)-one scaffolds.These annulation approaches do not require ortho-halogenation and have been realized with transition-metal-catalyzed 12 or photoinduced 13 manifolds.In recent years, a direct ortho-C−H/N−H annulation was developed to yield phenanthridin-6(5H)-one derivatives from benzamide and the aryne precursor 2-(trimethylsilyl)phenyl trifluoromethanesulfonate using O 2 or K 2 S 2 O 8 as oxidizing agents. 14t has been demonstrated that 2-bromobenzoic acid can be easily converted to the corresponding aryne in the presence of a Pd catalyst. 15However, the generated aryne quickly undergoes a trimerization reaction to yield triphenylenes.In this context, we recently reported that 2-(2-bromophenyl)-1Hbenzo [d]-imidazole derivatives can be harnessed as an effective coupling partner in combination with 2-bromobenzoic acids to give the corresponding N-fused (benzo)imidazophenanthridine scaffolds in high yields. 16In continuation of our previous studies directed to transition-metal-assisted synthesis of heterocycles, 17 we envisaged that phenanthridin-6(5H)-one derivatives could be directly assembled from N-substituted 2bromobenzamides 1 and 2-bromobenzoic acids 2 in the presence of a metal catalyst (Figure 1, bottom).

■ RESULTS AND DISCUSSION
We commenced our investigation by utilizing 2-bromo-Nmethylbenzamide (1a) and 2-bromobenzoic acid (2a) as the model substrates, CuI as the catalyst precursor, and K 2 CO 3 as the base in DMF at 100 °C.To our disappointment, the desired product 3a was not detected under these reaction conditions (Table 1, entry 1).A similar outcome was observed with AgOTf as the metal catalyst (Table 1, entry 2).Gratifyingly, formation of the desired annulation product 3a could be promoted by palladium-based catalysts, including Pd(OAc) 2 , PdCl 2 , Pd(PPh 3 ) 2 Cl 2 , and Pd(PPh 3 ) 4 (Table 1, entries 3−6), with Pd(OAc) 2 displaying the best reactivity and furnishing the desired product in 54% yield (Table 1, entry 3).Notably, the addition of auxiliary phosphine-based ligands, such as PPh 3 , Xantphos, P(4-MeOC 6 H 4 ) 3 , and P(4-MeC 6 H 4 ) 3 , promoted the desired reactivity (Table 1, entries 7−10) with PPh 3 providing product 3a in 70% yield (Table 1, entry 7).Apart from K 2 CO 3 , other common bases, such as Na 2 CO 3 , Cs 2 CO 3 , and t BuOK, were evaluated and found less critical for the desired transformation (Table 1, entries 11−13).Carrying out the reaction under the optimized conditions for our previously disclosed protocol 16 for the synthesis of N-fused (benzo)imidazophenanthridine scaffolds did not afford the desired annulation product 3a (Table 1, entry 14).Instead, the trimerization product (triphenylene) was afforded under these reaction conditions.Next, the effect of the reaction temperature was examined (Table 1, entries 15−18) with 120 °C being the most suitable for the developed protocol.The use of polar aprotic solvents, such as DMF, DMSO, and DMA, was revealed to be beneficial (Table 1, entries 17, 19−20), while the nonpolar solvents xylene and toluene resulted in slightly diminished yields (Table 1, entries 21−22).Finally, a control experiment conducted in the absence of Pd(OAc) 2 highlights the critical role of the palladium precursor in achieving effective coupling (Table 1, entry 23).
After the optimal reaction conditions were identified, the scope and limitations of the developed protocol were evaluated.Initially, a series of N-substituted 2-bromobenzamides 1 were engaged in a reaction with 2-bromobenzoic acid 2a.Aliphatic groups, such as methyl, ethyl, n propyl, and n butyl, all furnished the corresponding products 3b−3f and 3h−3i in moderate to high yields (61−75%).However, N-t butyl-2bromobenzamide failed to produce the desired annulation product 3g, presumably due to ample steric hindrance.The use of 2-bromobenzamides 1 bearing various N-substituted The Journal of Organic Chemistry aromatic and heteroaromatic moieties demonstrated that various functional groups, such as halogens, ethers, nitrile, furan, and thiophene, were compatible with the developed protocol, furnishing products 3j−3t in moderate to high yields (66−82%).The structure of product 3j was confirmed by single-crystal X-ray analysis (CCDC 2210960).The synthetic versatility of the developed protocol was further explored by employing 2-bromobenzamides 1 with a range of substituents at the aromatic core (Scheme 1).The reactions with 2-bromobenzamides 1 substituted with various aliphatic, chloro, and fluoro groups all provided the expected annulation products 3u−3af in moderate to high yields (62− 79%).Next, the scope of compatible 2-bromobenzoic acid annulation partners 2 was evaluated (Schemes 1 and 2).Here, 4,5-dimethoxy-2-bromobenzoic acid (2b) underwent effective annulation with N-substituted 2-bromobenzamides to produce 3ag−3aj in high yields (84−88%, Scheme 1).Finally, the disclosed protocol was successfully applied to access quinolone-derived alkaloid phenaglydon (4).Thus, subjecting annulation product 3u to refluxing trifluoroacetic acid afforded the debenzylated product phenaglydone (4) in an excellent yield of 92% (Scheme 1).
To probe the reaction mechanism, a set of control reactions were carried out under the optimized reaction conditions.When 4-or 5-substituted 2-bromobenzoic acids were used as the coupling partners, the respective annulated products were obtained as mixtures of two regioisomers (Scheme 2, top).Such poor regioselectivity indicates that the reaction proceeds through arynes as the key intermediates, as has been proposed for related transformations featuring palladium catalysis. 18ased on the literature precedents, 19 a plausible mechanism that does not contradict the above control reactions is proposed (Scheme 2, bottom left).Initially, base-assisted oxidative addition of 2-bromobenzoic acid 2 to Pd 0 provides the key aryl-Pd II species I.This species undergoes extrusion of CO 2 to afford aryne intermediate II while regenerating Pd 0 and completing the first of the catalytic cycles.Meanwhile, the second of the catalytic cycles is onset by oxidative addition of the Pd 0 catalyst to 2-bromobenzamide 1 to give aryl-Pd II species III, which in the presence of a base furnishes the five-membered palladacycle IV.Insertion of previously produced aryne II into the Pd II −C bond of IV results in C− C bond formation, while subsequent reductive elimination from the seven-membered palladacycle V forges the desired Scheme 1. Reaction Scope and Synthetic Application a,b a Reaction conditions: Reactions were carried out with 1 (0.50 mmol), 2 (0.60 mmol), Pd(OAc) 2 (12 mg, 0.05 mmol), PPh 3 (26 mg, 0.10 mmol), and Cs 2 CO 3 (326 mg, 1.0 mmol) in DMF (5.0 mL) under argon at 120 °C for 10 h.b Isolated product yields are reported.c Reaction carried out on a 1 mmol scale.
The Journal of Organic Chemistry C−N bond.Thereby, the latter step regenerates the Pd 0 catalyst, concluding the second of the catalytic cycles, and furnishes the desired annulation product 3.An alternative mechanism proceeding without formation of an aryne intermediate features a single catalytic cycle and Pd IV species as the key intermediate (Scheme 2, bottom right). 20Here, the reaction is onset by oxidative addition of 2-bromobenzamide 1 to the Pd 0 catalyst, furnishing aryl-Pd II intermediate IV.In the key step of the reaction, this intermediate undergoes a second oxidative addition reaction to 2-bromobenzoic acid 2, producing diaryl-Pd IV species VI.Subsequently, this species undergoes reductive elimination to produce the biaryl Pd IImetallacycle VII, which eliminates CO 2 to furnish the Pd II intermediate V. Finally, the latter intermediate undergoes reductive elimination, concluding the catalytic cycle and furnishing desired product 3.

■ CONCLUSIONS
In conclusion, we disclosed a simple procedure for accessing phenanthridin-6(5H)-one derivatives through palladium-mediated annulation of 2-bromobenzamides and 2-bromobenzoic acids.The annulation reaction delivers the phenanthridin-6(5H)-one derivatives in high yields and is compatible with a variety of functional groups, providing a modular method for accessing a range of structurally diversified phenanthridin-6(5H)-one motifs.
■ EXPERIMENTAL SECTION General Information.All reagents were purchased from commercial sources and used without treatment, unless otherwise indicated.The products were purified by column chromatography over silica gel. 1 H NMR and 13 C NMR spectra were recorded at 25 °C on a Varian spectrometer at 400 and 101 MHz, respectively, with TMS as the internal standard.High-resolution mass spectra (HRMS) were recorded on a BRUKER AutoflexIII Smartbeam mass spectrometer.High-resolution mass spectra (HRMS) were recorded on a Bruker microTof using electrospray ionization (ESI).

The Journal of Organic Chemistry
h.The resulting mixture was concentrated, and the residue was taken up in ethyl acetate.The organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated.Purification of the crude product by column chromatography (silica gel; petroleum ether/ethyl acetate 30:1) afforded 3.

Scheme 2 .
Scheme 2. Investigations for Probing the Reaction Mechanism and Proposed Reaction Mechanism a,b