Pd/BIPHEPHOS is an Efficient Catalyst for the Pd‐Catalyzed S‐Allylation of Thiols with High n‐Selectivity

Abstract The Pd‐catalyzed S‐allylation of thiols with stable allylcarbonate and allylacetate reagents offers several advantages over established reactions for the formation of thioethers. We could demonstrate that Pd/BIPHEPHOS is a catalyst system which allows the transition metal‐catalyzed S‐allylation of thiols with excellent n‐regioselectivity. Mechanistic studies showed that this reaction is reversible under the applied reaction conditions. The excellent functional group tolerance of this transformation was demonstrated with a broad variety of thiol nucleophiles (18 examples) and allyl substrates (9 examples), and could even be applied for the late‐stage diversification of cephalosporins, which might find application in the synthesis of new antibiotics.


General Information
If reactions were performed under inert conditions, e.g. exclusion of water, oxygen or both, all experiments were carried out using established Schlenk techniques. Herein solvents were dried with common methods and afterwards stored under inert gas atmosphere (argon or nitrogen) over molecular sieves. In some cases, when explicitly mentioned, dry solvents were received from the mentioned suppliers. In general, when high vacuum (in vacuo) was stated in experimental procedures, typically a vacuum of 10 -2 -10 -3 mbar was applied. Degassing of solvents or reaction mixtures was performed by bubbling argon via cannula through the solvent or the reaction mixture during ultrasonication for about 20 min. All reagents were added in a counterstream of inert gas to keep the inert atmosphere. All reactions were stirred with Teflon-coated magnetic stirring bars.
Molecular sieves (Sigma-Aldrich, beads with 8-12 mesh) were activated in a round-bottom flask with a gas inlet adapter by heating them carefully in a heating mantle at level 1 at least for 24 h under high vacuum until complete dryness was obtained. These activated molecular sieves were stored at rt under argon atmosphere.
Temperatures were measured externally if not otherwise stated. When working at a temperature of 0 °C, an icewater bath served as the cooling medium. Lower temperatures were achieved by using an acetone/dry ice cooling bath. Reactions, which were carried out at higher temperatures than rt, were heated in a silicon oil bath on a heating plate (RCT basic IKAMAG® safety control, 0-1500 rpm) equipped with an external temperature controller.

Chemicals
All commercially available chemicals and solvents were purchased from Acros Organics, Alfa Aesar, Fisher, Fluka, Honeywell, Merck, Roth, Sigma-Aldrich, TCI, VWR and used without further purification, unless otherwise stated.
Acetonitrile: Anhydrous acetonitrile was purchased from Alfa Aesar. It was transferred into an amber 1 L Schlenk bottle and stored over activated 3 Å MS under argon atmosphere.
Dichloromethane: Anhydrous dichloromethane was produced by pre-drying EtOH stabilized dichloromethane over P4O10, distilling it, and afterwards heating it under reflux over CaH2 for 24 h under argon atmosphere. It was distilled into an amber 1 L Schlenk bottle over activated 4 Å MS and under argon atmosphere.

Thin Layer Chromatography
Analytical thin layer chromatography (TLC) was carried out on Merck TLC silica gel aluminum sheets (silica gel 60, F254, 20 x 20 cm). All separated compounds were visualized by UV light (λ = 254 nm and/or λ = 366 nm) and by the listed staining reagents followed by the development in the heat.

Flash Column Chromatography
Flash column chromatography was performed on silica gel 60 from Acros Organics with particle sizes between 35 µm and 70 µm. Depending on the problem of separation, a 30 to 100 fold excess of silica gel was used with respect to the dry amount of crude material. The dimension of the column was adjusted to the required amount of silica gel and formed a pad between 10 cm and 30 cm. In general, the silica gel was mixed with the eluent and the column was equilibrated. Subsequently, the crude material was dissolved in the eluent and loaded onto the top of the silica gel and the mobile phase was forced through the column using a rubber bulb pump. The volume of each collected fraction was adjusted between 20 % and 40 % of the silica gel volume.

High Resolution Mass Spectrometry
High-resolution mass spectra were recorded on a Waters Micromass GCT Premier system. Ionization was realized by an electron impact source (EI ionization) at a constant potential of 70 eV. Herein, individual samples were either Further high-resolution mass spectra were recorded using MALDI TOF on a Waters Micromass® MALDI micro MX Mass spectrometer. Dithranol (1,8-dihydroxy-9,10-dihydroanthracen-9-one) served as matrix and PEG as internal standard. Besides molecular formulas, calculated as well as determined m/z ratios of each molecule peak are denoted.

Determination of Melting Points
Melting points were determined on a Mel-Temp® melting point apparatus from Electrothermal with an integrated microscopical support. They were measured in open capillary tubes with a mercury-in-glass thermometer and were not corrected.

Determination of Optical Rotation
The specific optical rotation was determined on a Perkin Elmer Polarimeter 341 with an integrated sodium vapor lamp. All samples were measured at the D-line of the sodium light (λ = 589 nm) in a 10 cm cell. Concentrations are given in g/100 mL. Each optical rotation measurement was performed five times and the mean value is reported.

Reaction Optimization
Ligand Screening Table S1. Ligand screening for the optimization of the Pd-catalyzed allylation of 1-octanethiol.   [a] Conversions as well as n/i ratios were determined by GC-MS without internal standard.

Reversibility of the Pd-Catalyzed Allylation
Depending on the ligand used the Pd-catalyzed allylation can either be directed exclusively towards the n-thioether (L50) or with good selectivity towards the i-product (L25). It is noteworthy that the n/i selectivity increases even after full conversion is reached, indicating reversibility of the reaction.

Synthesis of Thiol Substrates
L-Cystine 1,1'-dimethyl ester hydrochloride (S1) This compound was prepared according to a procedure described by Busnel et al. [1] A 500 mL three-necked round-bottom flask, equipped with a Teflon-coated magnetic stirring bar, a dropping funnel, a reflux condenser and a bubbler, was charged with methanol (240 mL) and cooled to 0 °C in an ice-bath. Analytical data are in accordance with the literature. [3]

General Procedure
In a round-bottom flask, equipped with a Teflon-coated magnetic stirring bar, methyl chloroformate was slowly added to an ice-cold solution of the corresponding allylic alcohol and pyridine in CH2Cl2. The resulting suspension was allowed to warm to rt. Upon complete consumption of the starting material (according to TLC), the reaction mixture was quenched by the addition of H2O (1/3 of solvent volume) and stirred vigorously for at least 15 min. The organic layer was separated, washed twice with 1 M HCl (1/1 of solvent volume) and once with sat. NaHCO3 (1/2 of the solvent volume), dried over Na2SO4, filtered, and concentrated under reduced pressure (in case of volatile products a minimal pressure of 40 mbar at 35 °C was applied).
Allylic carbonates 2a-2c, 2e, and 2g were distilled to afford colorless products prior to use in allylation reactions, although crude products did not show any impurities according to 1 H-NMR-spectroscopy.

General Procedure for the Pd-Catalyzed S-Allylation
In a flame-dried and argon-flushed Schlenk flask, equipped with a Teflon-coated magnetic stirring bar, Pd(dba)2 and BIPHEPHOS were suspended in anhydrous CH3CN and stirred in a pre-heated oil bath at 60 °C for 30 min to obtain a bright yellow solution. Then allylic carbonate and thiol were added and the resulting mixture was stirred at 60 °C (except for 3la-3oa) until complete consumption of the starting material (according to GC-MS or TLC). The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude product was purified via flash column chromatography to afford the desired compound. Analytical data are in accordance with the literature. [17] (E)-(3,7-Dimethylocta-2,6-dien-1-yl)(octyl)sulfane (3ab)

General Procedure for Cefalotin Derivatization
In a flame-dried and argon-flushed 10 mL Schlenk flask, equipped with a Teflon-coated magnetic stirring bar, Pd(dba)2 and BIPHEPHOS were suspended in 2.0 mL anhydrous CH3CN and stirred in a pre-heated oil bath at 60 °C for 30 min to obtain a bright yellow solution. Then cefalotin and thiol were added and the resulting mixture was stirred at the indicated reaction temperature until complete consumption of the starting material (according to HPLC-MS). The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude product was purified via semi-preparative HPLC to afford the desired compound.

Experiment B
In a flame-dried and argon-flushed Schlenk flask, equipped with a Teflon-coated magnetic stirring bar, Pd(dba)2 (7.0 mg, 12 µmol) and BIPHEPHOS (9.4 mg, 12 µmol) were suspended in 2.0 mL anhydrous CH3CN and stirred in a pre-heated oil bath at 60 °C for 30 min to obtain a bright yellow solution. Then 2f* (138.3 mg, 0.72 mmol) was added and the resulting mixture was stirred at 60 °C for 2 h. 1 H NMR (300 MHz, CDCl3):