One-Step Synthesis of 5a,11a-Janusene Imide Employing 2,3-Dibromo-N-methylmaleimide as Acetylene Equivalent ^†

Abstract

Synthesis of janusene (5,5a,6,11,11a,12-hexahydro-5,12:6,11-di-o-benzenonaphthacene) requires several reaction steps, starting from anthracene. In this account, a one-pot, three-step synthesis of janusene N-methyl-5a,11a-dicarboximide employing 2,3-dibromo-N-methylmaleimide as an acetylene equivalent is described. This thermal reaction is a simple synthetic procedure in comparison to sequential-multi step [4+2] cycloaddition routes. Here, 2,3-dibromo-N-methylmaleimide acts effectively as a ‘molecular glue’, bridging two anthracene molecules together.

1. Introduction

The Diels–Alder reaction is one of the most important organic reactions for the synthesis of complex polycyclic molecules [1,2,3] Synthesis of janusene (5,5a,6,11,11a,12-hexahydro-5,12:6,11-di-o-benzenonaphthacene) is one example of molecules prepared by the DA method, which requires several reaction steps, including multiple anthracene Diels–Alder reactions. The first synthesis of a janusene derivative (anthracene 5a,11a-janusenedicarboxylic anhydride 23) was reported by Diels [4] and employed three reaction steps: [4+2] cycloaddition of anthracene with 1,2-dibromomaleic anhydride, followed by 1,2-debromination [5] to alkene 22 and another [4+2] cycloaddition of anthracene. It is evident from the literature that synthesis of dibenzobarrelene is the limiting synthetic step, which in the second reaction includes [4+2] cycloaddition of dibenzobarrelene to anthracene. This approach was employed in janusene synthesis by Cristol [6] from dibenzobarrelene and anthracene in thermal conditions. Later on, several synthetic routes to dibenzobarrelene employed acetylene equivalents—various dienophiles possessing activating electron-acceptor groups. After addition, dienophile activation groups were removed to obtain dibenzobarrelene (Scheme 1).

Among the acetylene equivalents used for dibenzobarrelene preparation are (E)-1-phenylsulfonyl-2-trimethylsilylethylene devised by Paquette [7], 1-benzenesulfonyl-2-trimethylsilylacetylene developed by Williams [8], (Z) and (E)-1,2-bis(phenylsulfonyl)ethylene used by Künzer [9] and De Lucchi [10], respectively, 1,4-benzodithiin-1,1,4,4-tetraoxide, a cyclic variant of (Z)-1,2-bis(phenylsulfonyl)ethylene reported by Wenkert [11], and maleic anhydride used by Warrener [12]. Synthetically more elegant is intramolecular acetylene transfer via addition-reversion route from tetrafluorobenzobarrelene (one-pot), which was reported by Filler [13].

2. Materials and Methods

Chemicals were purchased from Sigma and solvents (dichloromethane, ethyl acetate and light petroleum b.p. 40–60 °C) were used as purchased. The reaction products were identified by one-dimensional ¹H and ¹³C spectroscopy, using Bruker Avance 300 MHz and Bruker Avance 600 MHz spectrometers.

Microwave-assisted heating was performed using 100 W of initial microwave power.

Thermal conditions: (Method A) Flash-vacuum pyrolysis experiments were conducted in vacuo (0.01–0.001 mbar) in a 600 × 6 mm Pyrex tube heated by a horizontally mounted ‘Thermolyne’ model 21100 tube furnace using 100–200 mg of reaction mixture. Products were collected at the end of furnace on the cooler part of the tube. The volatile products, furan and acetylene, were condensed in a liquid nitrogen trap. No experiments were conducted using silica thermolysis tubes.

Thermal conditions: (Method B) Thermolyses were conducted at atmospheric pressure in a 600 × 6 mm Pyrex tube heated by a horizontally mounted ‘Thermolyne’ model 21100 tube furnace using 100–200 mg of reaction mixture. Products were collected by washing the tube.

3. Results and Discussion

In our ongoing interest in cycloaddition reactions [14,15], we observed that cycloaddition of anthracene with 2,3-dibromo-N-methylmaleimide 4 when conducted by the microwave irradiation at high temperature (180 °C, DMF, 2 h) afforded several products 5–10 (Scheme 2). A minor amount of anthraquinone was also detected. Surprisingly, amongst them was a small amount of janusene N-methyl-5a,11a-dicarboximide 7, which could arise only from tandem Diels–Alder addition of anthracene onto imide 4. In this transformation, with 2,3-dibromo-N-methylmaleimide 4 acted as acetylene equivalent in similar manner as tetrafluorobenzobarrelene earlier reported by Filler. Additionally, our reaction is a one-pot equivalent of three-step Diels’ methodology to 5a,11a-janusene derivatives. Scheme 2 depicts products and the mechanistic rationale for the formation of janusene 7. The key step is thermal 1,2-debromination which generates 2π-component required for the second [4+2] cycloaddition. The change in reaction conditions (MW irradiation for shorter time, 15 min, or without solvent, for 2 h) influences the reaction outcome. After 15 min in an MW reactor in DMF solution, relatively larger ratios 6 and 7 in comparison to product 5 were obtained, whereas MW heating without the solvent provided cycloadduct 5 almost exclusively.

The influence of the reaction conditions was further studied by reactions in flash vacuum pyrolysis (FVP) furnace and the obtained results are illustrated in Figure 1. The FVP heating under vacuum was less successful than simple heating at elevated temperatures (180–350 °C) of neat reaction mixtures in a Pyrex glass tube for a short time (10–15 min). Notably, these reactions were much cleaner than those that MW promoted, and at 180 °C, clean 1:1 cycloadduct 5 was formed exclusively, whereas thermolysis at 350 °C provided janusene 7 as the single product. Simple sublimation was employed to remove anthracene excess from products. Unlike MW reactions, imide 6 was never detected in reaction mixtures. This finding emphasizes the compatibility of different synthetic methods (conventional and MW heating). ¹H NMR spectroscopy was used to elucidate the structures of products and the formation of 7 was established by the characteristic up-field NMR shift of facial aromatic protons [16] (multiplets at δ 6.69 and 6.90). The structural assignment of other products was obtained by their symmetry, relative position in NMR spectra, and integration of protons.

The structure of newly synthetized janusene 7 was visualized by quantum-chemical calculations (Figure 2). Molecular modelling (B3LYP/6-31G* calculations) has shown that there is almost no difference in structures of imide 7 and parent janusene. Geometrical parameters, in particular the C-C distance between two aromatic rings in janusene 3 (3.149 Å), does not change by the imide substitution in 7 (3.083 Å), and this is illustrated by the overlay of two optimized structures.

Similar thermal reactions of 2,3-dibromo-N-methylmaleimide 4 with 2,3-dicarbmethoxyanthracene conducted at 180, 280, and 350 °C (15 min, Pyrex glass tube in FVP furnace) resulted in inseparable mixtures of two 1:1 adducts 11 (endo- and exo-, 1:0.9 ratio) and three 2:1 adducts 12–14 (janusene derivatives) (Scheme 3). In these reactions, again, intermediate alkene 15 was not detected.

The same products could be obtained by the employment of dioxaimide 16 as the acetylene equivalent (Scheme 4). Different products dominate, depending on the temperature applied, and the cycloaddition adduct 18 was also obtained. As the higher thermolysis temperatures were applied, the amount of furanimide 19 [17] increases, due to complete decomposition of 16.

The present cycloaddition methodology could be further extended on the anhydride functionality. When the anhydride 21 [18] was pyrolyzed instead of imide 16 at 380 °C for 10 min, a different outcome in comparison to 16 was achieved. With the anhydride substrate, a mixture of alkene 22 and janusene anhydride 23 (previously published by Diels) [4] in 2:1.6 ratio was obtained (Scheme 5). The structures of two products were identified by ¹H NMR spectroscopy: janusene 23 was determined by characteristic up-field shift of facing aromatic rings (shift up to δ 6.73), while the ¹H NMR spectrum of alkene 22 [19] features the characteristic bicyclo[2.2.2] proton singlet at δ 5.54, which is in full correspondence to literature value. Hence, anhydride 21 acts as an acetylene equivalent in an analogous manner to imide 16. In contrast to the thermal behavior of the imide 16 and our expectation that thermal decarboxylation of the alkene anhydride 22 could take place giving dibenzobarrelene [12], product 21 could be obtained as a stable species in identical reaction conditions.

4. Conclusions

ffTandem [4+2] cycloaddition reactions were carried thermally, employing 2,3-dibromo-N-methylmaleimide 4, imide 16 and anhydride 21 to produce janusene derivatives. This one-pot simple methodology employs these reagents as acetylene equivalents and intramolecular acetylene transfer via addition-debromination or addition-reversion route.