Chemo- and Regioselective Multiple C(sp2 )-H Insertions of Malonate Metal Carbenes for Late-Stage Functionalizations of Azahelicenes

Abstract

Chiral quinacridines react up to four times, step-by-step, with α-diazomalonates under Ru^II and Rh^II catalysis. By selecting the catalyst, [CpRu(CH₃ CN)₃ ][PF₆ ] (Cp=cyclopentadienyl) or Rh₂ (oct)₄ , chemo and regioselective insertions of derived metal carbenes are achieved in favor of mono- or bis-functionalized malonate derivatives, respectively, (r.r.>49 : 1, up to 77 % yield, 12 examples). This multi-introduction of malonate groups is particularly useful to tune optical and chemical properties such as absorption, emission or Brønsted acidity but also cellular bioimaging. Density-functional theory further elucidates the origin of the carbene insertion selectivity and also showcases the importance of conformations in the optical response.

Keywords: Carbenes; C−H Insertion; Helicenes; Late-Stage Functionalization; Photophysical Properties.

Figure 1

Step‐by‐step synthesis of mono, bis, tris and tetra malonate functionalized [4]helicenes 3 to 6 by catalyst‐controlled C(sp²)−H insertions of electrophilic metal carbenes (Ru, Rh) onto diaza [4]helicene 2.

Figure 2

Section A: Single‐site S _E Ar LSF of cationic helicenes 2•H⁺ and 7. Section B: Direct C(sp²)−H insertions of electrophilic metal carbenes into electron‐rich aromatics. EDGs: electron‐donating groups and EWGs: electron‐withdrawing groups.

Scheme 1

Reaction conditions: 2 (0.1 mmol), 1 a–g (2 equiv), [CpRu(CH₃CN)₃][PF₆] (3 mol %), 1,10‐phen⋅H₂O (3 mol %), CH₂Cl₂, 60 °C, 3 h. Isolated yields. In parentheses, reactions at 1 mmol scale.

Scheme 2

Reaction conditions: 3 a–c (0.1 mmol), 1 a, 1 b or 1 g (2 equiv), Rh₂(oct)₄ (5 mol %), CH₂Cl₂, 60 °C, 22 h.

Scheme 3

Reaction conditions: a) 4 aa (0.1 mmol), 1 a (5 equiv), Rh₂(oct)₄ (5 mol %), CH₂Cl₂, 60 °C, 20 h.

Figure 3

Mono 12 and bis13 malonate amides carrying linear alkyl side chains, from C₆ to C₁₆.

Figure 4

Computed Gibbs energy profiles for the formation of 3 a (right) and r‐3 a (left) under CpRu and dirhodium catalysis. All energies in kcal mol⁻¹.

Figure 5

a) Absorption and b) normalized emission spectra of compound 2 (black), 3 a (blue), 4 aa (magenta), 5 (green) and 6 (red) in air‐equilibrated acetonitrile solution (C ca. 10⁻⁵ M) at 293 K.

Figure 6

(Left) Representative skeletal deformations upon the introduction of malonate groups at positions adjacent to the N‐propyl side chain (atom N9). α and β [°] are the dihedral angles of the envelope at N9 and C15, respectively. γ [°] is the bent angle corresponding to the folding of the central ring along the N9⋅⋅⋅C15 line. (Right) Overlay between DFT‐optimized geometries of 2 and 6. Only the C, N and O atoms of the helicene cores are showed, for clarity. A more complete picture with the malonate chains of 6 is shown in Figure S25.

Figure 7

CPL spectra (M full and P dashed lines) of compounds 3 a (blue), 4 aa (magenta), 5 (green) and 6 (red) in air‐equilibrated acetonitrile solution (C ca. 10⁻⁵ M) at 293 K.

Figure 8

Microscopy images of Hela‐MZ cells treated for 60 min with indicated compounds. Blue (Hoechst staining) Orange (compounds 2, 3 a, 12 a or 12 b). A) 20X water immersion widefield image used for signal quantification. B) 60X water immersion images for the compounds of interest. C) Quantification of average intensity Txred signal for all tested compounds for 10 or 60 min. D) Segmentation mask example generated on A, Yellow (Cell), Light blue (image), Dark blue (Background). Images for signal intensity quantification. Scale bar 50 μm.