Unexpected chiral vicinal tetrasubstituted diamines via borylcopper-mediated homocoupling of isatin imines

Addressing the asymmetric synthesis of oxindole-based α-aminoboronic acids, instead of the expected products we disclosed the efficient homocoupling of oxindole-based N-tert-butanesulfinyl imines, with the generation of chiral, quaternary 1,2-diamines in a mild and completely stereoselective way. The obtained 3,3′-bisoxindole derivatives were fully characterized by NMR and single-crystal X-ray diffraction analysis and proved to be single diastereoisomers and atropisomers. A plausible mechanism for the one-pot Cu(II)-catalyzed Bpin addition to the isatin-derived ketimine substrate and subsequent homocoupling is described.


General Information S2
General Procedure for the synthesis of compounds 2 S2 1 H and 13 C NMR spectra analysis for compound 2a S6 Copies of 1 H and 13 C NMR spectra S8 Crystallographic data for compound 2a S14 References S16 S2 General Information 1 H NMR and 13 C NMR spectra were recorded using a Bruker AV 400 Ultrashield spectrometer. 1 H NMR and 13 C NMR chemical shifts were reported in parts per million (ppm) downfield from tetramethylsilane. Coupling constants (J) were reported in Hertz (Hz). The residual solvent peaks were used as internal reference: 1 H NMR (CD3CN 1.98 ppm) 13 C NMR (CD3CN 0.3 ppm, 117.3 ppm).
The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad. All the N-substituted isatins 1 and the corresponding ketimines were synthetized according to the previous literature and their spectroscopic data are in agreement with the reported ones. 2

General procedure for the synthesis of compounds 2
In a round-bottom flask, (Ph)3P (0.025 equiv) was dissolved in dry toluene (0.024 M). Saturated aqueous solution of copper sulfate pentahydrate (0.025 equiv 0.78 M) was added followed by DIPEA (0.5 equiv) and the biphasic mixture stirred at high speed (1500 rpm) for 10 minutes (aqueous phase goes from a dark-blue to a pale blue colour). B2pin2 (1.5 equiv) was added followed by a solution of 1 in dry toluene (1.0 equiv 0.47 M) and the reaction stirred at high speed and room temperature until the disappearance of 1 (monitored by TLC, approx. 6 h in which the reaction goes from red/orange to brown). The reaction was diluted with dichloromethane and filtered over a short pad of celite, then the solvents were removed under reduced pressure. The mixture was diluted with dichloromethane, washed with brine, dried over anhydrous NaSO4 and the solvent removed under reduced pressure. The crude mixture was purified by FC to afford pure 2.

Crystallographic data for compound 2a
The sample selected for the X-ray analysis was a yellowish, transparent prism with dimensions ≈ 0.500 × 0.350 × 0.175 mm ( Figure S2). It was mounted on a glass fibre, using perfluorinated oil as a glue. and c (c) cell axes. Colour code as in Figure 1 (main text).

Discussion
The compound is chiral and crystallizes in the orthorhombic Sohncke space group P212121 with 4 formulae in cell and 1 molecule in the asymmetric unit. The absolute configuration of the two sulfur stereogenic centres is confirmed to be R (see main text). The Flack parameter, computed by classical fits against all the intensities 7,8 , refines to 0.1(1).
The C2-C10 single bond (numbering scheme in Figure 1, main text) is quite long (1.5863(2) Å), as expected due to crowding of the two facing oxindole systems. In the crystal, the mean least-squares planes across the C-N backbones of the two indole rings are mutually rotated by ≈48.6 deg. At the same time, NH groups set up intramolecular hydrogen bonds with the O acceptors of the sulfinamide moieties (see main text). Likely, such hydrogen bonds are crucial to stabilize the conformer despite a minor intramolecular H3N···H21C steric clash of the N3 amine with the C21 methyl (dH···H = 1.89 Å). Figure 2 shows the main packing motifs in the (b,c), (a,c) and (a,b) planes. The only relevant hydrogen bond donors are the NH moieties in the sulfinamide groups, while both S=O and the keto group in the 2-oxindole rings can serve as acceptors. However, both donors are saturated by intramolecular hydrogen bonded contacts (Table 1, main text), resulting in no extended HB patterns through the crystal. Also, no relevant stacking interactions can be found, due to the misalignment of the neighbouring oxindole systems (see above). Consequently, the main structure-determining interactions are expected to be van der Waals and electrostatic interactions.