Electrochemical synthesis of heterohelicenes
Helicenes’ unique architecture endowed them with optical and electronic features that can be implemented in various material-based applications, such as organic light-emitting diodes (OLEDs) and field-effect transistors (FETs). To date, a lot of synthetic approaches for helicenes have been introduced with [2+2+2] cycloaddition, alkyne cyclization, Friedel-Crafts, C−H activations, C−H arylations, metathesis, Diels-Alder, and cross-coupling reactions. Recently, more synthetic advances have been achieved, expanding their diverse library and enabling asymmetric synthesis. In 2016, our group reported chiral vanadium(v)-catalyzed synthesis of oxahelicenes via the oxidative coupling of arenol compounds followed by intramolecular dehydrative cyclization.1,2 Despite all these successful strategies, there are some limitations related to the low total yields, harsh reaction conditions, or overuse of oxidants.
Electrochemical syntheses have many advantages since no oxidant is required and oxidative transformation can be conducted under mild reaction conditions. To investigate the electrochemical synthesis of oxazahelicenes 3, we selected 3-hydroxybenzo[c]carbazole (1a) and 2-naphthol (2a) as model substrates (Fig. 1). We assume that single electron transfer (SET) from 1a would occur first to generate the electrophilic radical species at the anode because 1a is more easily oxidized than 2a.3 After radical-anion coupling between the radical cation species and 2a followed by oxidative cyclization, oxazahelicene 3aa would be formed. The differential redox potentials between coupling partners 1a and 2a play a key role in the chemoselectivity of the oxidative coupling step. After examining various conditions and performing sedulous optimization, we successfully achieved a one-pot protocol with fluorine-doped tin oxide (FTO) electrodes and Bu4NPF6 as an electrolyte in CH2Cl2 for 6 h, at rt, giving oxazahelicene 3aa in 82% yield.4,5
To establish the applicability of this method for concise synthesis of unsymmetrical helicenes from commercially available substrates, a two-pot synthesis protocol was established: Acid-mediated annulation of p-benzoquinone (5) and N-aryl-2-naphthylamine 6 to afford 3-hydroxycarbazoles 1, that can undergo without any further purification an electrochemical domino reaction with 2-naphthol (2a) to afford the desired oxazahelicenes 3aa-3ca in 43-45% overall yields (Fig. 2). Various combinations of 2-naphthols 2 with a phenyl group or a (Bpin) group afforded the corresponding oxazahelicenes 3 in 33–42% overall yields. 2-Naphthols 2e with an electron-withdrawing substituent (e.g. methyl ester) at 3-position did not afford the desired oxazahelicene 3ae probably due to a reason that can be attributed to the lack of nucleophilicity of 2e and the alteration of its redox behavior which interfered with the crucial oxidative coupling step.6
A two-step protocol to synthesize double oxazahelicene 9 was also established by using our electrochemical approach (Fig. 3).
The obtained novel double oxazahelicene 9 shows interesting structural features that were reflected in its excellent optical properties. In this study, an investigation of the photophysical characteristics of this compound and the correlation of its absorption and fluorescence behavior based on DFT calculations were also conducted (Fig. 4).7
Electrochemical synthesis of heterodehydrohelicenes
Hetero-dehydrohelicenes are a type of polycyclic heteroaromatics (PHAs) characterized by their unique helical chirality, which results from the connection of the two helical termini of a helicene by a sigma bond. Because of this unique chirality, dehydrohelicenes have extraordinary optical properties that can be utilized in different material-based applications. Despite the immense potential exhibited by dehydrohelicenes, to our knowledge, there are no reports on their straightforward construction including asymmetric synthesis.
To our delight, the electrochemical domino reaction was able to afford such interesting scaffolds upon using specific substituted 2-naphthols 2. The electron-donating groups (e.g. OMe, OBn) at the 7-position of 2 will increase the electron density on the helical terminus enabling an additional oxidative C-C bond-forming step in the sequence to give eventually oxaza-dehydrohelicenes 10 (Fig. 5). The design of these oxazahelicene molecules with two heptagons (furan and pyrrole), and five hexagons made the distance between the two helical termini short enough (< 3.0 A°) to enable the last oxidative C-C bond forming step upon increasing the electron density on the helical termini hence affording the corresponding oxaza-dehydrohelicenes 10.4
Eyring plots indicated a significant chiral stability of oxaza-dehydrohelicenes 10 (racemization barrier >140 kJ mol−1) (Fig. 6a); the t1/2 of compound 10aa was estimated to be greater than 9.5 × 103 years at 25 °C. Dehydrohelicene 10aa showed higher chiral stability than that of corresponding oxazahelicene 3aa (110 kJ mol−1). Subsequently, the chiroptical properties of the optically pure oxaza-dehydrohelicenes were investigated. All the helical dyes 10 showed absorption in the wavelength range of 340–404 nm and fluorescence maximum at 450 nm; circular dichroism (CD) and circularly polarized luminescence (CPL) signals were observed in these regions. Oxaza-dehydrohelicenes, 10aa showed moderate quantum yield Φ = 0.25, and significant CPL activity with glum = 2.5 × 10−3 at 433 nm (Fig. 6b).4
Having succeeded in developing a facile electrochemical synthesis of the dehydohelicenes, we next focused our attention on the enantioselective synthesis of hetero-dehydrohelicenes (Fig. 7). Initially, diol (R)-4ba was readily obtained by using vanadium complex (Ra,S)-11 via the enantioselective hetero-coupling. Subsequently, under electro-oxidation conditions, (R)-4ba underwent a sequential dehydrative furan ring formation followed by the coupling of the two helical termini to afford the corresponding oxaza-dehydrohelicene (M)-10ba in 87% yield maintaining the optical purity (Fig. 7).4
Towards higher sustainability
Although our sequential electrochemical protocol to synthesize oxazahelicenes and oxaza-dehydrohelicenes from simple arenols features a high yield under mild conditions (Fig. 8A), some limitations still remain to make these previous conditions less sustainable, such as the necessity of an excess amount of the acidic additive BF3·OEt2 (50 equiv), higher current density (1.2 mA/cm2) that limits the compatibility with oxidatively-labile functionalities, the low recyclability of FTO electrodes (< 5 times), and low faradic efficiency (< 30%). In order to maximize the energy efficiency and make this electro-synthetic approach most sustainable, we also established the improved electrochemical conditions that overcome these limitations by varying some parameters (Fig. 8B).5
- Sako, M., Takeuchi, Y., Tsujihara, T., Kodera, J., Kawano, T., Takizawa, S. & Sasai, H. Efficient enantioselective synthesis of oxahelicenes using redox/acid cooperative catalysts. J. Am. Chem. Soc. 138, 11481–11484 (2016).
- Kumar, A., Sasai, H. & Takizawa, S. Atroposelective synthesis of C–C axially chiral compounds via mono- and dinuclear vanadium catalysis. Acc. Chem. Res. 55, 2949–2965 (2022).
- Sako, M., Higashida, K., Kamble, G. T., Kaut, K., Kumar, A., Hirose, Y., Zhou, D.–, Suzuki, T., Rueping, M., Maegawa, T. and Takizawa, S. & Sasai, H. Chemo-and enantioselective hetero-coupling of hydroxycarbazoles catalyzed by a chiral vanadium (v) complex. Org. Chem. Front. 8, 4878–4885 (2021).
- Khalid, M. I., Salem, M. S. H., Sako, M., Kondo, M., Sasai, H. & Takizawa, S. Electrochemical synthesis of heterodehydrohelicenes. Commun. Chem. 5, 166 (2022).
- Salem, M. S. H., Khalid, M. I., Sako, M., Higashida, K., Lacroix, C., Kondo, M., Takishima, R., Taniguchi, T., Miura, M., Vo-Thanh, G., Sasai, H. & Takizawa, S. Electrochemical synthesis of heterohelicenes containing pyrrole and furan rings via an oxidative hetero-coupling and dehydrative cyclization sequence. Adv. Synth. Catal. in press, DOI: 10.1002/adsc.202201262.
- Salem, M. S. H., Khalid, M. I., Sasai, H. & Takizawa, S. Two-pot synthesis of unsymmetrical heterohelicenes with intriguing optical properties. Tetrahedron in press, DOI: 10.1016/j.tet.2023.133266.
- Salem, M. S. H., Sabri, A., Khalid, M. I., Sasai, H. & Takizawa, S. Two-step synthesis, structure, and optical features of a double heterohelicene Molecules 27, 9068 (2022).
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