A C-H activation-based enantioselective synthesis of lower carbo[n]helicenes

Abstract

The three-dimensional structure of carbohelicenes has fascinated generations of molecular chemists and has been exploited in a wide range of applications. Their strong circularly polarized luminescence has attracted considerable attention in recent years due to promising applications in new optical materials. Although the enantioselective synthesis of fused carbo- and heterohelicenes has been achieved, a direct catalytic enantioselective method allowing the synthesis of lower, non-fused carbo[n]helicenes (n = 4-6) is still lacking. We report here that Pd-catalysed enantioselective C-H arylation in the presence of a unique bifunctional phosphine-carboxylate ligand provides a simple and general access to these lower carbo[n]helicenes. Computational mechanistic studies indicate that both the C-H activation and reductive elimination steps contribute to the overall enantioselectivity. The observed enantio-induction seems to arise from a combination of non-covalent interactions and steric repulsion between the substrate and ligand during the two key reductive elimination steps. The photophysical and chiroptical properties of the synthesized scalemic [n]helicenes have been systematically studied.

Fig. 1. Design of the enantioselective synthesis of carbo[n]helicenes by Pd⁰-catalysed C–H arylation.

a, Enantiomerization barriers for carbo[4]-, carbo[5]- and carbo[6]helicenes. T_en, enantiomerization temperature. b, Pd⁰-catalysed enantioselective C–H arylation for the synthesis of axially chiral biaryl compounds and warped molecules showing the underlying concerted metallation–deprotonation process. L*, chiral ligand; *, stereogenic element. c, This report describes the synthesis of CPL-active lower carbo[n]helicenes by Pd⁰-catalysed C–H arylation.

Fig. 2. Ligand structure–activity relationship in the enantioselective synthesis of carbo[6]helicene 2r.

a, Catalytic C–H arylation of 1r leading to carbo[6]helicene 2r. ^aOptimized reagents and conditions: 1r (0.1 mmol, 1.0 equiv.), Pd₂dba₃ (5 mol%), ligand (20 mol%), Cs₂CO₃ (0.5 equiv.), CPME (1 ml), 140 °C, 17 h. CPME, cyclopentyl methyl ether; cat., catalyst. b, Effect of ligand structure and substitution pattern on the yield and enantioselectivity of the C–H arylation of 1r with the optimal ligands L¹ and L² selected in this study. The e.r. values were determined by HPLC on a chiral stationary phase.

Fig. 3. Scope of the enantioselective synthesis of carbo[n]helicenes.

a, Scope of the monoarylation reaction. This method allows access to the three types of lower helicenes with various substitution patterns in high yields and enantioselectivities and is applicable to azahelicenes. Standard reagents and conditions: 1 (0.1 mmol, 1.0 equiv.), Pd₂dba₃ (5 mol%), ligand (20 mol%), Cs₂CO₃ (0.5 equiv.), CPME (1 ml), T °C, 24 h. The X-ray crystallographic structures of 2p and 2q are shown. ^aFree energy of enantiomerization computed at the B3LYP-D3(BJ)/6-311G(d,p) level of theory. ^bExperimental enantiomerization barrier measured at 120 °C. ^cThermal ellipsoids are shown at the 50% probability level. ^dThermal ellipsoids are shown at the 20% probability level. b, Synthesis of carbo[5]- and carbo[6]helicenes by double C–H arylation. This method allows a more direct access to these helicenes, albeit in lower yields. Reagents and conditions: 3 (0.1 mmol, 1.0 equiv.), Pd₂dba₃ (10 mol%), L¹ (40 mol%), Cs₂CO₃ (1.0 equiv.), CPME (1 ml), 140 °C, 24 h. The e.r. values were determined by HPLC on a chiral stationary phase. The reference racemic products were synthesized using PCy₃ instead of the chiral ligand. The absolute configurations were ascribed in analogy to 2p and 2q, and by comparing the calculated with the experimental ECD spectra for selected compounds. The red dots indicate the initial position of the bromide. a,b, Light blue highlights changes in substituents.

Fig. 4. Computed C–H activation pathways in the synthesis of carbohelicenes.

C–H activation pathways calculated at the PCM(toluene)-B3LYP(D3)/SDD+def2-TZVP//B3LYP(D3)/SDD+def2-SVP level of theory (values in parentheses are ΔG (in kcal mol⁻¹)). Two C–H activation pathways (red and blue arrows) starting from intermediates I-Lⁿ and I*-Lⁿ, that arise from oxidative addition and displacement of the bromide with the carboxylate group of the ligand, proceed with similar energy barriers and both contribute to the observed enantioselectivity. Subsequent deprotonation by caesium bicarbonate and coordination of Cs⁺ is exergonic and leads to intermediates III-Lⁿ and III*-Lⁿ, respectively. The Cartesian coordinates for the optimized structures are provided in the Supplementary Information.

Fig. 5. Computed reductive elimination pathways leading to carbo[6]helicene 2r.

Reductive elimination pathways towards carbo[6]helicene 2r with L¹ as the ligand calculated at the PCM(toluene)-B3LYP(D3)/SDD+def2-TZVP//B3LYP(D3)/SDD+def2-SVP level of theory (the values in parentheses are ΔG (in kcal mol⁻¹)). a,b, Reductive elimination from III-L¹ (a) and III*-L¹ (b). Bold arrows represent the energetically favoured pathways. Structure IV corresponds to helicene 2r coordinated to Pd–L¹. These reductive eliminations are enantiodetermining and the enantioselectivity is controlled by NCIs and steric repulsion between the substrate and ligand. For reductive elimination pathways with L² and selected NCI plots, see Supplementary Figs. 6 and 7.

Fig. 6. Circularly polarized absorption and luminescence of the synthesized [n]helicenes.

a, Luminescence dissymmetry factors (at λ_max,em) for [4]helicenes (red bars), [5]helicenes (blue bars) and [6]helicenes (grey bars) in dichloromethane (c = 10^–5 M). b–d, ECD (blue traces) and CPL (red traces) spectra (top), and UV–visible (blue traces) and luminescence spectra (red traces) (bottom) of carbohelicenes 2e (b), 2p (c) and 2t (d). Significant CPL was observed for the three types of helicenes, which was strongly impacted by the substitution in the [4]helicene and [5]helicene series.