Bidentate Chiral Bis(imidazolium)‐Based Halogen‐Bond Donors: Synthesis and Applications in Enantioselective Recognition and Catalysis

Abstract Even though halogen bonding—the noncovalent interaction between electrophilic halogen substituents and Lewis bases—has now been established in molecular recognition and catalysis, its use in enantioselective processes is still very rarely explored. Herein, we present the synthesis of chiral bidentate halogen‐bond donors based on two iodoimidazolium units with rigidly attached chiral sidearms. With these Lewis acids, chiral recognition of a racemic diamine is achieved in NMR studies. DFT calculations support a 1:1 interaction of the halogen‐bond donor with both enantiomers and indicate that the chiral recognition is based on a different spatial orientation of the Lewis bases in the halogen‐bonded complexes. In addition, moderate enantioselectivity is achieved in a Mukaiyama aldol reaction with a preorganized variant of the chiral halogen‐bond donor. This represents the first case in which asymmetric induction was realized with a pure halogen‐bond donor lacking any additional active functional groups.


General Remarks
All reagents and chemicals were obtained from ABCR, Alfa Aesar, Carbolution, Merck, ChemPur, TCI and Sigma-Aldrich and were used without further purification. Unless otherwise stated, all solvents used were of technical grade and were purified by distillation prior to use. Anhydrous solvents (DCM, ether and THF) were taken from MBRAUN (type: MB SPS-800) solvent drying system which were pre-dried by passing through an ALOX column followed by storing over 4 Å molecular sieve, and distillation. ITC measurements were performed on a VP-ITC from GE Healthcare. Thin layer chromatography was performed on Merck TLC aluminum sheets (silical gel 60, F254) and compounds were detected by fluorescence visualization under UV lamp (λ = 254 nm), iodine stain or using charring agents. Column chromatography was performed on silica gel (grain size 0.04-0.063 cm, Macherey-Nagel Si60). IR spectra were recorded on a Shimadzu IR Affinity -1S spectrometer with a Specac-Quest ATR. The values were reported in cm -1 and are indicated as w (weak), m (medium), s (strong) or vs (very strong). NMR spectra were recorded on AV-250, AV-300, AV-400 and AV-600 instruments from Bruker. Chemical shifts (δ) are given in parts per million (ppm) with reference to the residual solvent signals ( 1 H and 13 C) or the internal standard (hexafluorobenzene, δ = -161.99 ppm) for 19 F and were analyzed with MestReNova 9.0.
Optical rotations were measured on the Antan Paar automatic process polarimeter. Mass spectra were recorded on either a Bruker Daltonics Esquire 6000 instrument (ESI) or a VG Instruments Autospec / EBEE-Geometry (EI). Elemental analysis was performed on a vario Micro cube from Elementar Analysentechnik. Single crystals were analysed on a Rigaku XtaLAB mini (Mo K)a Rigaku Synergy (Cu Kα). Data was recorded and reduced using the CrysalisPro 1 Software.

(894 mg, 4.4 mmol) in
Methanol/DCM (1:1) (10 mL). This brown colored solution was stirred at room temperature for overnight. Solvent was evaporated and the residue was triturated with diethyl ether (2 × 10 mL) to get orange solid. It was dried under vacuum and was suspended in dichloroethane (10 mL).
Triethyl orthoformate (1 mL) was added to it and the suspension was heated at 70 °C for 14 h.

NMR studies of chiral recognition
All chiral recognition studies were performed by mixing equivalent amounts of the solutions of donor (10 mM) and acceptor (10 mM) at room temperature (25 °C).      Evaluation of the obtained data sets was performed with Origin 7.   and 1b.BAr F 4 (12.53 mg, 0.05 mmol, 5 mol%) were dissolved in CD2Cl2 (0.5 mL) under argon atmosphere and the progress of reaction was monitored by 1 H NMR at 25 °C. As there was little decomposition of TMS-enolate to acetophenone during the reaction, after 2 h additional 1 equiv. of TMS-enolate was added.

ITC titrations
Presence of unreacted TMS-enolate indicated us that 1.5 equiv. TMS-enolate is sufficient. Also it was observed that the yield are almost identical in CD2Cl2 and CDCl3 as the solvent. Therefore for the kinetic experiments, 1.5 equiv. TMS-enolate and CDCl3 as solvent was used.

Control experiments to rule out NHC formation:
Under argon atmosphere, a NMR tube was charged with 4b.BAr F 4 (11.27 mg, 0.005 mmol) and sodium tert-butoxide (1.9 mg, 0.02 mmol). Anhydrous CD2Cl2 (0.5 mL) was added to it at 0 °C and the progress of reaction was monitored by 1 H NMR till the disappearance of imidazolium protons (20 min at room temperature). To this homogenous solution of bis(NHC), 19a (20 μl, 50% solution in toluene, 0.1 mmol, 1 equiv.) and 20 (19.2 mg, 0.1 mmol, 1 equiv.) was added and the reaction was monitored by 1 H NMR.
Although aldehyde was converted to some unknown product, the expected aldol product was not formed.