Isoquinolino[4,3,2-de]phenanthridine: synthesis and its use in 1,3-dipolar cycloadditions to form nitrogen-containing polyaromatic hydrocarbons

Abstract

The synthesis of the novel azomethine ylide, isoquinolino[4,3,2-de]phenanthridine, and its use in 1,3-dipolar cycloaddition with various alkenes and alkynes to form the corresponding fused pyrrolidines and pyrroles is reported.

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Cycloadditions between 1,3-dipoles and unsaturated dipolarophiles are an indispensable tool for the construction of 5-membered heterocyclic structures.¹ An especially impressive demonstration of their versatility and efficiency led to the concept of “click chemistry” using the Huisgen reaction.² Depending on the combination between 1,3-dipoles and dipolarophiles, a wide variety of heterocyclic rings can be synthesized. Among the various 1,3-dipoles, azomethine ylides are particularly useful intermediates for preparing pyrrolidines and pyrroles, which are important building blocks for many natural products and pharmaceuticals.³ However, only a few examples of 1,3-dipolar cycloaddition of azomethine ylides focus on the preparation of polyaromatic hydrocarbons (PAHs),⁴ despite the increasing importance of nitrogen-containing PAHs.^5–7 Our research group focuses on isoquinolino[4,3,2-de]phenanthridine (1) as a novel class of azomethine ylides to generate pyrrolidines and dihydropyrroles containing a fused isoquinolino[4,3,2-de]phenanthridine structure, which in turn can be converted to the corresponding pyrroles upon oxidative dehydrogenation (Fig. 1). Herein we report the synthesis of isoquinolino[4,3,2-de]phenanthridine (1) and its use in 1,3-dipolar cycloadditions with various alkenes and alkynes to form the corresponding pyrrolidines, 2,5-dihydropyrroles, and pyrroles.^8,9 The method presented is highly effective for the synthesis of fused 1,2,3,4,5-pentaarylpyrroles via reactions with diarylacetylenes. To the best of our knowledge, only a few compounds with a fused 1,2,3,4,5-pentaarylpyrrole structure, such as 2,3-diaryl fused pyrroles (dibenzo[e,g]indoles¹⁰ and diacenaphtho[1,2-b:1′,2′-d]pyrroles¹¹), 3,4-diaryl fused pyrroles (dibenzo[e,g]isoindoles^12,13 and acenaphtho[1,2-c]pyrroles¹⁴), and pyrrole-fused azacorronenes,^5b have been reported.

Fig. 1 Structure of isoquinolino[4,3,2-de]phenanthridine 1 and its cycloaddition with dipolarophiles.

Scheme 1 illustrates the synthesis of isoquinolino[4,3,2-de]phenanthridine (1) starting from 2,6-dibromo-4-tert-butylaniline (2). Initially, a palladium-catalyzed Suzuki–Miyaura reaction of 2 with 1,3-dihydro-1-hydroxy-2,1-benzoxaborole generated 2,6-diarylaniline 3.¹⁵ A subsequent intramolecular cyclization of 3 by treatment with hydrogen chloride in 1,4-dioxane–1,2-dichloroethane at 100 °C afforded the cyclized product 4 as a yellow crystalline powder in good yield (74%). When 4 was dissolved in carbon tetrachloride under exposure to irradiation of ambient light, the color of the reaction mixture changed from yellow to red, suggesting the formation of a radical species such as 4′ (Scheme 2). Since this reaction was not observed in the dark, the reaction might be initiated by a homolytic cleavage of a Cl₃C–Cl bond.¹⁶ Gradually 4 was converted to iminium chloride 5, presumably through the chlorinated intermediate 4′′. Conversion of 4 and 4′ into 5 was found to be accelerated by addition of hydrogen chloride, which led to a color change from red to yellow. Compound 5 exhibited characteristically unsymmetrical NMR resonances in chloroform-d with a distinctive iminium proton observed at 11.6 ppm. Subsequent deprotonation of compound 5 was accomplished by treatment with triethylamine under inert conditions to generate isoquinolino[4,3,2-de]phenanthridine 1in situ.¹⁷

Scheme 1

Scheme 2

In order to elucidate the properties of 1, we performed density functional theory (DFT) calculations using the B3LYP hybrid functional at the 6-31G(d,p) basis set on the model compound 1′, in which the t-butyl group of 1 is replaced by a hydrogen (Fig. 2). Compound 1′ can adopt a closed-shell zwitterionic structure as (1′-C) or an open-shell biradical structure as (1′-O). Our calculations revealed that 1′-C is by 21.9 kcal mol⁻¹ more stable than 1′-O, indicating that 1 should exist in the azomethine ylide form (Fig. 2a). Azomethine ylides are electron-rich species with high-lying HOMOs and LUMOs; accordingly, they preferentially react with electron-deficient dipolarophiles whereby the HOMO of the dipoles interacts with the LUMO of the dipolarophiles.^3d The calculated HOMO of 1′-C is predominantly located in both α-positions of the nitrogen atom, suggesting that 1 reacts with an unsaturated dipolarophile in these positions (Fig. 2b).

Fig. 2 (a) DFT-calculated energy difference between the closed-shell zwitterionic state (1′-C) and open-shell biradical state (1′-O) at the B3LYP/6-31G(d,p) level of theory. (b) DFT-calculated HOMO and LUMO of 1′-C using the same DFT parameters.

Indeed, we observed that azomethine ylide 1 underwent 1,3-dipolar cycloadditions, when it was generated in situ and concurrently treated with internal alkynes.¹⁸ The reaction with dimethyl acetylenedicarboxylate (DMAD) at room temperature afforded 2,5-dihydropyrrole 7a in 60% yield (Scheme 1). In the ¹H NMR spectrum, the benzylic proton of 7a was observed at 5.35 ppm in chloroform-d. The cycloadditions with diarylacetylenes, Ar–C≡C–Ar (Ar = Ph or C₆H₄-4-CO₂Me), proceeded at a high temperature of 100 °C produced pyrroles 8b and 8c in 30 and 20% yields, respectively, via subsequent dehydrogenation of 7.⁹ All the compounds were characterized by ¹H and ¹³C NMR spectroscopic analyses.

The solid-state structures of 7a, 8b, and 8c were confirmed by single crystal X-ray crystallographic analysis (Fig. 3). Suitable crystals were obtained by slowly evaporating dichloromethane solutions of these compounds. The top view of 7a indicates that the three benzene rings and the 2,5-dihydropyrrole ring are not aligned in a coplanar fashion. The dihedral angles between the central benzene and the adjacent benzene rings are 23.7° (C14–C15–C17–C18) and −18.8° (C9–C10–C11–C12). In the case of 8b and 8c, the three benzene rings and the pyrrole ring share a highly coplanar geometry with dihedral angles between the pyrrole moiety and the adjacent benzene rings of less than 3°. The C–N bond lengths and C1–N1–C4 angles in these pyrrole structures are consistent with those of previously reported fused 1,2,3,4,5-pentaarylpyrroles.^11,14

Fig. 3 X-ray structures of 7a, 8b, and 8c. Hydrogen atoms for all structures and t-butyl groups for top views are omitted for clarity.

Azomethine ylide 1 was found to react with electron-deficient alkenes. The reaction with methyl acrylate produced pyrrolidine 6d in 61% yield as an inseparable mixture of endo and exo adducts (ca. 1 : 1). N-Phenylmaleimide also reacted with 1 to give pyrrolidine 6e in moderate yield. The product was obtained as a mixture of diastereomers which could be separated using silica gel column chromatography to afford the endo isomer in 26% yield and the exo isomer in 22% yield. As fullerene C₆₀ is known to be a good dipolarophile, the 1,3-dipolar cycloaddition of 1 with C₆₀ was also investigated in order to form a hybrid of pyrrolidine and C₆₀.¹⁹ The reaction of 1 with C₆₀ at 40 °C afforded adduct 9, which was successfully purified by preparative HPLC with a buckyprep® column, in 65% yield (Scheme 3). In the ¹H NMR spectrum of 9, three singlet resonances were observed for the t-butyl group (1.46 ppm), for the benzylic protons (6.26 ppm), and the aromatic protons in ortho positions to the t-butyl group (7.74 ppm). Moreover, two doublet (7.95/7.73 ppm) and two triplet (7.52/7.40 ppm) resonances were observed for the aromatic protons of the peripherally fused benzo groups. The ¹³C NMR spectrum of 9 shows 45 signals (32 signals for the C₆₀ unit and 13 signals for the isoquinolino[4,3,2-de]phenanthridine unit), indicating that compound 9 is of C_s symmetry. The UV/Vis spectrum of 9 showed a local-maximum signal at 433 nm, which is a characteristic band for 6 : 6 ring-bridged 58 π-electron fullerenes.²⁰ All the observed data are consistent with an addition of azomethine ylide 1 onto the 6 : 6 ring junction of C₆₀.

Scheme 3

Furthermore, we found that the cycloadditions were affected by the polarity of the solvent. The reaction of 1 in acetonitrile at 80 °C produced the dimerized product 10 in 3.5% yield (Scheme 4).²¹ This homo-coupling reaction of azomethine ylide 1 could be potentially applied to the synthesis of nitrogen-containing nanographene or graphene nanoribbons via subsequent oxidative cyclization and dehydrogenation.

Scheme 4

In summary, we have developed a new method to synthesize the azomethine ylide, isoquinolino[4,3,2-de]phenanthridine 1, which undergoes 1,3-dipolar cycloadditions with various alkenes and alkynes. This study presents a potentially useful method to form nitrogen-containing PAHs with fused pyrrole structures.

A part of this work was supported by “Nanotechnology Platform” (No.12024046) of MEXT, Japan. The authors would like to thank Prof. Eiichi Nakamura, Dr Koji Harano, and Ms Utako Takeda (The University of Tokyo) for the preparative HPLC separation of compound 9.

Notes and references

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21. Feng and Müllen, et al. obtained dimer 10 in 51% yield by a reaction using tributylamine as a base and dimethylsulfoxide as a solvent at 190 °C. See ref. 8.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and analytical data, including X-ray crystallographic data for 7a, 8b, and 8c. CCDC 1019909–1019911. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc06643j

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