Enantioselective S−H Insertion Reactions of α‐Carbonyl Sulfoxonium Ylides

Abstract The first example of enantioselective S−H insertion reactions of sulfoxonium ylides is reported. Under the influence of thiourea catalysis, excellent levels of enantiocontrol (up to 95 % ee) and yields (up to 97 %) are achieved for 31 examples in S−H insertion reactions of aryl thiols and α‐carbonyl sulfoxonium ylides.


General Information
Reaction Setup: Air-and moisture-sensitive reactions were conducted in flame-or oven-dried glassware equipped with tightly fitted rubber septa and under a positive pressure of dry argon. Reagents and solvents were handled by using standard syringe techniques. Unless stated otherwise, all the yields refer to isolated products after flash column chromatography. NMR Spectroscopy: 1 H NMR spectra were acquired using a Bruker BioSpin 500MHz Avance III Digital NMR spectrometer and calibrated using the solvent signal (CDCl 3 7.26 ppm). Multiplicities were determined using MNova software. 13 C NMR spectra were acquired using a Bruker BioSpin 126MHz Avance III Digital NMR spectrometer and calibrated using the solvent signal (CDCl3 77.16 ppm). 1 H NMR multiplicities are reported as follows: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet.

Tert-butyl (-) 2-(naphthalen-2-ylthio)-2-phenylacetate 3z
Prepared from 1i and naphthalene-2-thiol. The reaction was allowed to stir for 2 days. Purification by column chromatography in 1:4 EtOAc/Hex afforded 3z as a white solid (30.4  (-)-tert-butyl 2-((4-chlorophenyl)thio)-2-phenylacetate 3aa Prepared according to general procedure from 1i and 4-chlorobenzenethiol. Reaction was allowed to stir for 2 days. Purification by column chromatography in 1:4 EtOAc/Hex afforded 3aa as a white solid (21.  To a solution of 3a (26.0 mg, 0.1 mmol) in DCM (0.5 mL) was added mCPBA (73. 6 mg, 0.32 mmol) at -28 °C, and the solution was stirred for 16 h in this temperature. The reaction was quenched by the addition of saturated aqueous Na 2 SO 3 (3 mL) and the organic layer was separated. The aqueous layer was extracted with DCM and the combined organic extracts was washed with brine, dry over Na 2  (-)-2-phenyl-2-(phenylthio)ethan-1-ol 12 To a solution of LiAlH 4 (12 mg, 0.3 mmol) in Et 2 O (0.5 mL) was added dropwise 3a in Et 2 O (0.5 mL) at 0 °C, and the solution was stirred for 30 min. The reaction was quenched with aqueous HCl (1 mol.L -1 ) and the organic layer was separated. After usual workup the crude product was purified by column chromatography in 1:9 EtOAc/Hex afforded 12 as a colorless oil (19.5 mg, 85%); Rf = 0.22 (1:4 EtOAc/Hex); the spectroscopy data were in good agreement with the literature 9  The solution of CeCl 3 (81 mg, 0.33 mmol) in THF (0.7 mL) was stirred for 1 h. To the suspension of CeCl 3 was added solution of 3a (28 mg, 0.11 mmol) in THF (0.3 mL). the mixture was stirred for 1 h and cooled to -78 °C. Then, the MeMgI (2 mol.L -1 in ether, 0.27 mL, 0.54 mmol) was added dropwise to the mixture. After 1 h, the reaction was quenched with acetic acid (1 mL). The aqueous layer was extracted with DCM and the combined organic extracts were washed with saturated aqueous NaHCO 3 and brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude product was purified by column chromatography in 1:9 EtOAc/Hex and 13 was afforded as white solid (6.0 mg, 23%); Rf = 0.36 (1:4 EtOAc/Hex); the spectroscopy data were in good agreement with the literature.

General procedure for the titration of chiral catalyst 4b with 1a and 2a
A stock solution of chiral catalyst 4b (50 mM) in CDCl 3 was prepared in a 1 mL volumetric flask. Then, 100 µL of this stock solution was transfer to NMR tubes and, after added quantitatively portions of 1a or 2a, CDCl 3 was added to quantities enough to final 500 µL (final concentration of catalyst = 10 mM). 1 H NMR spectra of the solutions were recorded after the addition of each equivalent, ensuring that the

Computational Details
Conformational searches were carried out for each possible binding mode of the transition structure (TS) for the model system (Table 2, entry 10, pyrene truncated to phenyl, trifluoromethyls truncated to fluorines) using the conformational search tool within Schrödinger's MacroModel (version 11.6) 12,13 with the OPLS2005 force field. 14 A Monte Carlo Multiple Minimum (MCMM) 15 / low-mode sampling approach 16 was used to explore the possible conformations of the TS. A total of 157 unique conformation were obtained. These conformations were subsequently optimised by DFT calculations carried out using Gaussian16 (Revision A.03) 17 with the B3LYP density functional 18,19 the split-valence polarised 6-31G(d) basis set. 20 Single point energy (SPE) calculations were used to correct the Gibbs free energy derived from the original B3LYP calculations. 21 These were performed using the M06-2X 22 density functional and the polarised triple-ζ valence quality (def2-TZVPP) basis set 23 . The integral equation formalism version of the polarisable continuum model (IEF-PCM) 24 (chloroform) was used to incorporate the effect of solvent. All DFT calculations were performed using an ultrafine integration grid. All temperature (245.15 K) and concentration-corrected (1 mol/l) quasiharmonic (Grimme approximation 25 ) free energies were calculated with GoodVibes 26 with a vibrational scaling factor of 0.977. 27 Similar methods have previously been used for the successful modelling of ureas. 28,29 Catalyst Truncations Scheme S1 depicts the lowest energy conformations of catalyst 4b and the model catalyst (pyrene truncated to phenyl, trifluoromethyls truncated to fluorines). The orientation of the phenyl/pyrene unit is very similar in both structures, and superimposition of these structures over the core atoms highlighted on the model catalyst revealed an RMSD value of 0.095. This indicates that the truncations do not have a significant impact on the conformation of the catalyst, and hence allow for a reasonable approximation of the full transition structures.
Scheme S1. Molecular geometries for catalyst 4b and the model catalyst (B3LYP/6-31G(d)). Highlighted atoms on model catalyst indicate core atoms over which RMSD was calculated for both structures.
A full list of approximated bond strengths is given below:

Alternative TS Conformations
Scheme S2 depicts TS-1' and TS-2', representing the same binding modes as TS-1 and TS-2, respectively, but with the opposite approach of the thiophenol. These approaches allow for the formation of only one C-H···S interaction between the ylide and thiophenol, accounting for their 3.8 kcal mol -1 and 3.4 kcal mol -1 higher energy compared to TS-1 and TS-2, respectively. NBO analyses of these C-H···S interactions in TS-1 revealed a combined strength of 5.3 kcal mol -1 for the three interactions, compared to 1.6 kcal mol -1 for the single interaction in TS-1'. This 3.7 kcal mol -1 difference corresponds extremely well with the observed free energy difference of 3.8 kcal mol -1 between TS-1 and TS-1'.

Energies and molecular geometries of computed structures
All energies in Hartrees, coordinates in Å. Cartesian coordinates generated by ESIgen software. 30 Additional energies and molecular geometries for catalyst 4b and model catalyst available on request.