Differentiating Catalysis in the Dearomative [4 + 2]-Cycloaddition Involving Enals and Heteroaromatic Aldehydes

In this paper, the application of differentiating catalysis in the [4 + 2]-cycloaddition between 2-alkyl-3-formylheteroarenes and α,β-unsaturated aldehydes is described. Within the developed approach, the same aminocatalyst is employed for the independent activation of both starting materials, differentiating their properties via LUMO-lowering and HOMO-rising principles. By the combination of dearomative dienamine activation with iminium ion chemistry high enantio- and diastereoselectivity of the doubly asymmetric process was accomplished. Selected transformations of products were also demonstrated.


General methods
NMR spectra were acquired on a Bruker Ultra Shield 700 instrument, running at 700 MHz for 1 H and 176 MHz for 13 C, respectively. Chemical shifts (δ) are reported in ppm relative to residual solvent signals (CDCl3: 7.26 ppm for 1 H NMR, 77.16 ppm for 13 C NMR). Mass spectra were recorded on a Bruker Maxis Impact quadrupole-time-of-flight spectrometer using electrospray (ES+) ionization (referenced to the mass of the charged species). Analytical thin layer chromatography (TLC) was performed using pre-coated aluminum-backed plates (Merck Kieselgel 60 F254) and visualized by ultraviolet irradiation or Hanessian's stain. Unless otherwise noted, analytical grade solvents and commercially available reagents were used without further purification. For flash chromatography (FC) silica gel (Silica gel 60, 230-400 mesh, Fluka). The enantiomeric ratio (er) of the products were determined by Ultra Performance Convergence Chromatography (UPC 2 ) using Daicel Chiralpak IA column as chiral stationary phases. Aldehydes 2 were synthesized according to the literature procedure. 1

Differentiating catalysis in the [4+2]-cycloadditiongeneral procedure
In an ordinary 4 mL glass vial equipped with a magnetic stirring bar α,β-unsaturated aldehyde 2 (0.12 mmol, 1.2 equiv.) and heteroaromatic aldehyde 1 (0.1 mmol, 1 equiv.) were dissolved in Et2O (0.4 mL) and catalyst 4c (4.7 mg, 0.02 mmol, 0.2 equiv.) and benzoic acid (4.9 mg, 0.04 mmol, 0.4 equiv.) were added and the reaction mixture was stirred in room temperature for indicated time. The progress of the reaction was controlled by 1 H NMR spectroscopy. After full conversion of the starting material 1, the reaction mixture was directly subjected to column chromatography on silica gel (hexanes : diethyl ether 85:15) to afford pure products 3a-o.

4.
Crystal and X-ray data for 3a The crystal structure of the compound (6S,7S)-6,7-diphenyl-6,7-dihydrobenzofuran-5carbaldehyde 3a, C21H16O2, was established by single-crystal X-ray diffraction at 100 K. The compound crystallizes in the non-centrosymmetric orthorhombic space group P212121 (Z = 4) and the crystal structure consists of one crystallographically independent formula unit in the unit cell ( Figure 1). Figure 1. The molecular structure of the compound 3a at 100 K, with the atom labeling scheme, showing 50% probability displacement ellipsoids. Hydrogen atoms are drawn with an arbitrary radius.
Single crystal X-ray diffraction data were collected at 100 K by the ω-scan technique using a RIGAKU XtaLAB Synergy, Dualflex, Pilatus 300K diffractometer 3 with PhotonJet micro-focus X-ray Source Cu-Kα (λ = 1.54184 Å). Data collection, cell refinement, data reduction and absorption correction were performed using CrysAlis PRO software. 3 The crystal structure was solved by using direct methods with the SHELXT 2018/2 program. 4 Atomic scattering factors were taken from the International Tables for X-ray Crystallography. Positional parameters of non-H-atoms were refined by a full-matrix least-squares method on F 2 with anisotropic thermal S15 parameters by using the SHELXL 2018/3 program. 5 All hydrogen atoms were found from the difference Fourier maps and for further calculations they were positioned geometrically in calculated positions (C-H = 0.95-1.00 Å) and constrained to ride on their parent atoms with isotropic displacement parameters set to 1.2 times the Ueq of the parent atom.
The largest peak in the final difference electron density synthesis was 0.162 e Å -3 and the largest hole was -0.144 e Å -3 . The goodness-of-fit was 1.055. The absolute configuration was unambiguously established from anomalous scattering, by calculating the x Flack parameter 6 of 0.00 (3)