Gold(I)-Catalysed Direct Thioetherifications Using Allylic Alcohols: an Experimental and Computational Study

A gold(I)-catalysed direct thioetherification reaction between allylic alcohols and thiols is presented. The reaction is generally highly regioselective (SN2′). This dehydrative allylation procedure is very mild and atom economical, producing only water as the by-product and avoiding any unnecessary waste/steps associated with installing a leaving or activating group on the substrate. Computational studies are presented to gain insight into the mechanism of the reaction. Calculations indicate that the regioselectivity is under equilibrium control and is ultimately dictated by the thermodynamic stability of the products.


2) Representative Optimization Studies
Below are representative screens that were carried out in order to optimise the reaction conditions.

General procedure for optimization studies
The catalyst 5 was added to a solution of allylic alcohol 4 and thiol 2a in solvent at the required temperature, the vial was sealed and the resulting mixture was stirred for the required time. The solution was filtered through a plug of silica with diethyl ether followed by concentration under reduced pressure. The crude mixture was analysed by 1 H NMR to give the following results: CHCl 3 was therefore used as the optimal solvent, as the solvent had changed another temperature screen was carried out.

(E)-2,2,3-Trimethylhex-4-en-3-ol (14)
A solution of t BuLi (8.13 mL of a 1.9 M solution in hexanes, 15.45 mmol) was added dropwise to a stirred solution of (E)-3-penten-2-one (1 g, 1.16 mL, 11.89 mmol) in THF (10 mL) at 0 °C under Ar. The resulting solution was stirred at 0 °C for 30 min then warmed to rt. Then, a saturated solution of NH 4 Cl (aq) (15 mL) was added, and the two layers were separated. The aqueous layer was extracted with Et 2 O (3 × 20 mL). The combined organic layers were dried (MgSO 4 ) and evaporated under reduced pressure to give the crude product.
The mixture was then filtered through a plug of silica with diethyl ether. The filtrate was concentrated under reduced pressure. Purification of the crude material was carried out by flash column chromatography.

General procedure B for 3j-3o (alkyl thiols as nucleophiles):
4-Nitrothiophenol (1.1 equiv.) and 5 (5 mol%) were added to a solution of allylic alcohol (1 equiv.) in chloroform (0.386 M) in a 1 dram vial. The vial was capped and the solution allowed to stir for 72 h (for temperatures see below), after which it was allowed to cool down to room temperature.
Scavenger Reaxa QuadraPure TM MPA (0.5 equiv.) was added and the mixture was stirred gently for 3 h. The reaction mixture was then filtered through a plug of cotton wool with diethyl ether. The filtrate was concentrated under reduced pressure. Purification of the crude material was carried out by flash column chromatography.

Benzyl 3-hexanon-2-en-1-yl sulfide (3j):
The reaction was carried out at 50 °C following general procedure B. The product was purified using flash column chromatography using neat hexane. Product 3j was obtained as colourless liquid (

Butyl(3-hexylnon-2-en-1-yl)sulfide (3k)
The reaction was carried out at 60 °C following general procedure B. The product was purified using flash column chromatography using neat hexane. Product 3k was obtained as colourless liquid (

Cyclohexyl(3-hexylnon-2-en-1-yl)sulfide (3l)
The reaction was carried out at 60 °C following general procedure B. The product was purified using flash column chromatography using neat hexane. Product 3l was obtained as colourless liquid (

2-((3-Hexylnon-2-en-1-yl)thio)ethanol (3n)
The reaction was carried out at 50 °C following general procedure B. The product was purified using flash column chromatography using a gradient eluent system of neat hexane to 5:

3-(3-Hexylnon-2-enylthio)propanoic acid (3o)
The reaction was carried out at 45 °C following general procedure B. The product was purified using flash column chromatography using a gradient eluent system of neat hexane to 1:
Purified using flash column chromatography; using a gradient eluent system of neat petroleum ether
Product 3aa (>20:1 E:Z ) was obtained as a colourless oil (24 mg, 82 µmol, 85%), as an inseparable mixture of 2:1 S N 2':S N 2 products. The spectrum for this mixture is shown below, with the CHS peak of each integrated.

Computational Details and References.
Calculations were run with Gaussian 03 Revision D.01 1 with PCM solvent corrections run with Gaussian 09, Revision A.02. 2 Geometry optimisations were performed using the BP86 functional 3 with Au, P and S centres described with the Stuttgart RECPs and associated basis sets 4 (with added dorbital polarisation on P ( = 0.387) and S ( = 0.503) 5 and 6-31G** basis sets for all other atoms. 6 All stationary points were fully characterized via analytical frequency calculations as either minima (all positive eigenvalues) or transition states (one negative eigenvalue) and IRC calculations and subsequent geometry optimizations were used to confirm the minima linked by each transition state. Frequency calculations also provided a free energy in the gas-phase, computed at 298.15 K and 1 atm. Energies reported in the text are based on the gas-phase free energies and incorporate a correction for dispersion effects using Grimme's D3 parameter set 7 (i.e. BP86-D3) as well as solvation (PCM approach) in CHCl 3 .