Vanadium(V) Complex-Catalyzed One-Pot Synthesis of Phenanthridines via a Pictet-Spengler-Dehydrogenative Aromatization Sequence

: Phenanthridine and its derivatives are important structural motifs that exist in natural products, biologically active compounds, and functional materials. Here, we report a mild, one-pot synthesis of 6-arylphenanthridine derivatives by a sequential cascade Pictet-Spengler-dehydrogenative aromatization reaction mediated by oxovanadium(V) complexes under aerobic conditions. The reaction of 2-(3,5-dimethoxyphenyl)aniline with a range of commercially available aryl aldehydes provided the desired phenanthridine derivatives in up to 96% yield. The ability of vanadium(V) complexes to function as e ﬃ cient redox and Lewis acid catalysts enables the sequential reaction to occur under mild conditions.


Introduction
Phenanthridine and its structurally related compounds play essential roles in a variety of chemical fields due to their existence in a broad range of natural products, bioactive compounds, and functional materials ( Figure 1) [1][2][3][4][5]. Phenanthridine was first synthesized from the reaction between benzaldehyde and aniline in 1889 [6], and a number of preparative methods have been reported to date [1,[7][8][9]. However, since most protocols necessitate harsh reaction conditions and/or multi-step reaction sequences from commercially available starting materials [10,11], concise and mild preparation procedures for this important class of compounds are still in high demand [12][13][14][15].
Organometallic vanadium(V) complexes have been employed in the development of a wide range of organic reactions [16][17][18][19][20][21][22][23]. Their high valency and ability to exist in multiple oxidation states enable vanadium complexes to act as Lewis acid and/or redox catalysts. We theorized that these functionalities can be used to perform domino reaction sequences in a single operation. Furthermore, there are a few reports on the cooperative effect of vanadium(V) complexes in synthesis [24][25][26][27][28]. Recently, we developed chiral oxovanadium complexes [29] that act as redox and/or Lewis acid catalysts for the enantioselective oxidative coupling of arenols [30][31][32][33], Friedel-Crafts-type reactions [34], and a sequential cascade reaction that affords oxahelicenes [28]. As part of our ongoing research, we envisioned a one-pot synthesis of phenanthridine derivatives 5 using vanadium(V) complexes 6 as Lewis acid/oxidation catalysts (Scheme 1). Thus, Lewis acidic vanadium(V) complex 6 would promote a Pictet-Spengler reaction of imine intermediate 3 formed by the condensation of aniline 1 and benzaldehyde 2 to afford tetrahydroisoquinoline 4. A subsequent dehydrogenative aromatization of 4, assisted by the same vanadium(V) complex, now operating as a one-electron oxidant, would yield the desired phenanthridine product 5 [28,35]. Scheme 1. This work: synthesis of phenanthridines derivatives by a vanadium(V)-catalyzed Pictet-Spengler-dehydrogenative aromatization reaction sequence.

Results and Discussion
Our initial investigations focused on the reaction between 2-(3,5-dimethoxyphenyl)aniline (1a) and benzaldehyde (2a) (1.2 equivalents) using vanadium(V) catalyst rac-6a (10 mol%) in various solvents at 50 • C ( Table 1). The reaction in tetrahydrofuran (THF) afforded the desired product 5a in 31% yield (Entry 1), however, the reaction cascade performed markedly better in dichloromethane, toluene, and acetonitrile (Entries 2-4). Of the solvents tested, acetonitrile (MeCN) gave the best outcome, affording 5a in 95% yield (Entry 4). Next, we turned our attention to the vanadium(V) catalyst complex. Catalysts (S)-6b and (S)-6c bearing an iso-propyl and tert-butyl group, respectively, showed comparable catalytic activities to rac-6a (Figure 2), which contains a benzyl group on the amino acid moiety (Entries 5 and 6). The bulkier di-tert-butyl-substituted catalyst (S)-6d and naphthalene-based catalyst (S)-6e resulted in lower yields of 5a, 68% and 85%, respectively (Entries 7 and 8). The optimum temperature for the reaction was 50 • C. A significantly diminished yield of product 5a was observed at 40 • C, which may be attributed to suppression of the Pictet-Spengler-dehydrogenative aromatization cascade (Entry 9), whereas the marginally lower yields recorded at 60 • C and 70 • C (Entries 10 and 11) may be due to partial decomposition of the vanadium complex. Only a trace amount of phenanthridine 5a was obtained in the absence of the catalyst (Entry 12). The commercially available vanadium(V) and vanadium(IV) catalysts, V 2 O 5 and VOSO 4 respectively, displayed poor activity; less than 15% yield of 5a observed after 72 h at 50 • C in both cases (Entry 13). Finally, we decided on the optimal reaction conditions of 10 mol% of catalyst (S)-6b in MeCN (0.2 M) at 50 • C, shown in Entry 4, to continue with our studies; due to the lower cost of (S)-valine than that of the racemic amino acids and other optically pure amino acids, chiral vanadium complex (S)-6b with the high activity was selected as an appropriate catalyst for this reaction.  Under the optimal reaction conditions, we conducted the one-pot reaction sequence on a range of aryl aldehydes (2a-y Table 2). Benzaldehydes 2a-q, containing electron-donating and electron-withdrawing groups in the para-, meta-, or ortho-positions, underwent smooth transformations to give the corresponding 6-arylphenanthridines 5a-q in 72-96% yields. Notably, the reaction exhibited high functional group tolerance as evident by the presence of phenolic (5c), cyano (5e), halide (5f-h, 5k-o), and nitro (5j and 5q) substituents. The reaction of di-and penta-substituted benzaldehydes 2r and 2s afforded the products 5t and 5u in 78% and 85% yields, respectively. When 2-naphthaldehydes (5t and 5u) and 1-naphthaledehydes (5e-x) were employed, the desired products 5t-x were also obtained in moderate to good yields. We were also pleased to observe that bipyridine derivative 5y was synthesized in 83% yield using 2-formylpyridine. A plausible catalytic cycle for the vanadium(V)-catalyzed cascade reaction of aniline 1a with benzaldehyde 2a is shown in Figure 3. In the first step, condensation of 1a with 2a occurs to give imine 3a. Subsequently, the vanadium(V) complex (S)-6b promotes the intramolecular cyclization of the imine via complex A; this key carbon-carbon bond forming step completes construction of the phenanthridine core and affords the intermediate B [34]. Intermediate C is generated after re-aromatization of B. At this stage in the cycle, the addition of water to C might yield tetrahydroisoquinoline 4a, which was observed by proton nuclear magnetic resonance ( 1 H NMR) analysis (vide supra), and (S)-6b. Dehydrogenative aromatization of 4a proceeds via intermediate C and a single-electron transfer from the electron-rich nitrogen center to vanadium(V) forms the intermediate D, which undergoes the dehydrogenative aromatization to give the desired product 5a [35]; when (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) (1.0 equivalent) was added to the optimal conditions, no desired product 5a was obtained at all. Under degassed N 2 instead of air, the sequential reaction proceeded to give 5a, probably due to easily auto-oxidation of 4a during analysis. Finally, oxidation of vanadium(IV) by molecular oxygen regenerates the vanadium(V) complex (S)-6b. In order to realize an enantioselective vanadium(V)-catalyzed domino cascade reaction, we turned our attention to the construction of trimethoxyphenanthridine derivative 5w (Scheme 2), which contains an axis of chirality and potentially has a role as a chiral reagent such as 6-(2 -diphenylphosphino-1 -naphthyl)phenanthridine (PHENAP) ligand in Figure 1. In a preliminary study, treatment of aniline 1a and 2-methoxy-1-naphthaldehyde (2w) with binaphthol vanadium(V) complex (R a ,S)-6f in chloroform (CHCl 3 ) at 20 • C successfully afforded 5w in moderate yield and 65% ee. X-ray crystallographic analysis of optically pure 5w (The Cambridge crystallographic data centre number: CCDC 2005061) was performed after the optical resolution of the mixture involving the major product 5w by using preparative chiral high-performance liquid chromatography (chiral HPLC) (CHIRALPAK IC, n-hexane/i-PrOH = 2/1, v = 10 mL min -1 , λ = 231 nm). The absolute configuration of 5w with catalyst (R a ,S)-6f was determined to be S based on the Flack parameter (0.02 (6)). The tetrahydroisoquinoline intermediate 4w readily underwent auto-dehydrogenative aromatization, which implies that the enantioenrichment step may be the carbon-carbon bond-forming step of the Pictet-Spengler reaction, i.e., intermediate A to intermediate B ( Figure 3); we clarified a possibility of kinetic resolution of rac-4b [36] using catalyst (R a ,S)-6f under the reaction conditions as shown in Scheme 2 because isolation of 4w was difficult due to its stability. After 3 h, 70% of 4b was converted to 5b and the optical purity of the recovered 4b was 8% ee. Additional investigation of the enantioselective reaction mechanism from both experimental and theoretical perspectives is now in progress.

Vanadium(V) Complex-Catalyzed Pictet-Spengler Reaction and Dehydrogenative Aromatization Sequence
In a test tube, to a solution of a 2-(3,5-dimethoxyphenyl)aniline (1a) in acetonitrile (0.2 M) a benzaldehyde derivate 2 (1.2 eq) and a mononuclear vanadium catalyst (S)-6b (10 mol%) were added. The reaction was stirred at 50 • C for 72 h under air atmosphere. After the reaction, the reaction mixture was concentrated in vacuo and purified by silica column chromatography using hexane/acetone as eluent to afford the phenanthridine derivatives 5.

Conclusions
Vanadium(V)-catalyzed domino reactions for the efficient synthesis of phenanthridines have been achieved. Vanadium(V) complexes promote a Pictet-Spengler-dehydrogenative aromatization cascade due to their ability to mediate Lewis acid and oxidative catalysis under mild reaction conditions. The vanadium catalysis exhibited high functional group tolerance using various aryl aldehydes. Furthermore, a chiral vanadium(V) complex was applied to the enantioselective synthesis of an axially chiral phenanthridine derivative. Further applications of the reaction to other aniline derivatives are ongoing in our laboratory.