TYPICAL PROCEDURES

Typical Procedure for Dechlorination Reactions (TP5):

A microwave vial equipped with a stirring bar was charged with the 2,5-dichlorothienothiophene in EtOH. Pd/C (10% Pd, 50% wet with water) and NH₄HCO₂ were added and the reaction mixture was heated using a Biotage Initiator 2.5 system (120 °C, 100 W, 1 h). The mixture was allowed to cool to 25 °C, another portion of Pd/C was added and the mixture was again heated.

This procedure was repeated for the indicated time. After the last reaction cycle the mixture was allowed to cool to 25 °C and filtered through Celite^®. The crude residue was purified by flash column chromatography on silica gel.

Typical Procedure for Halogen/Magnesium-Exchange Reactions (TP6):

A dry and argon flushed Schlenk-flask, equipped with a magnetic stirrer and a septum was charged with the starting aryl bromide in THF (approx. 1.0 M solution) and cooled to the indcated temperature. Then i-PrMgCl· LiCl was added and the reaction was stirred for the indicated time (the completion of the reaction was checked by GC analysis of reaction aliquots quenched with half concentrated aqueous NH₄Cl solution).

Preparation of Electron Rich Dihalogen-Compounds (TP7):

The electron rich iodo-compounds were brominated according to a literature procedure.⁷⁰

Preparation of Electron Poor Dihalogen-Compounds via diazotation (TP8):

The respective substituted aniline was dissolved in chloroform (0.5 M) and cooled to 0 °C. NBS (1.01 equiv) was added in one portion and the reaction mixture was stirred for 3 h at that temperature. The crude mixture was washed with water (3x), dried (MgSO₄) and the solvent evaporated in vacuo. The crude bromoaniline was suspended in a mixture of concentrated sulfuric acid and water (1:2) and cooled to 0 °C. A solution of NaNO₂ (1.05 equiv, 2 M in water) was added dropwise over 1 h and the resulting mixture stirred further for 1 h at 0 °C. Then CuI (5 mol%) was added in one portion and following a solution of KI (1.10 equiv, 2 M in water) was added dropwise over one hour. The resulting sluggish reaction mixture was stirred over night while warming to room temperature. The solids were dissolved in CH₂Cl₂, separated from the aqueous phase, then washed with brine and sodium thiosulfate solution and dried (MgSO₄). After removal of the solvent in vacuo, the crude product was purified by flash column chromatography on silica gel.

70 B. Andersh, D. L. Murphy, R. J. Olson, Synth. Commun. 2000, 30, 2091.

Preparation of Organic Disulfides (TP9):

The aryl disulfides were prepared according to a literature procedure⁷¹ whereby the iodine/magnesium-exchange was uniformly carried out at -80 °C and after transmetalation to zinc S₂Cl₂ (0.48 equiv) was added. The crude products were used without further purification in the sulfonothioate synthesis. Yield and analytical data of new compounds, however, were taken from purified samples.

Preparation of Sulfonothioates (TP10):

The sulfonothioates were prepared according to a literature procedure.⁷² To a mixture of sodium benzenesulfinate (3.2 equiv) and the organic disulfide (1.0 equiv) in CH₂Cl₂ (0.1 m) was added I₂ (2.0 equiv) in one portion. The resulting suspension was stirred until the disulfide was consumed (checked by TLC, 12-72 h). Then CH₂Cl₂ (100 mL) was added and the crude reaction mixture was washed with aq. sat. Na₂S₂O₃ until the color of iodine disappeared. The organic layer was washed with water, dried (MgSO₄) and the solvent was evaporated. The crude products were purified by flash column chromatography on silica gel.

Typical Procedure for the Preparation of Alkynyl(aryl)thioethers (TP11):

A dry and argon flushed Schlenk-flask, equipped with a magnetic stirrer and a septum was charged with the terminal alkyne (1.00-1.50 equiv) in THF (approx. 1.0 M solution) and cooled to -30 °C. Then i-PrMgCl· LiCl (1.00-1.20 equiv) was added and the reaction was stirred for 30 min at this temperature before a solution of the sulfonothioate in THF (approx. 0.5 M solution) was added dropwise at -50 °C. The sluggish mixture was stirred for 1-6 h while warming to room temperature. The reaction was quenched with half concentrated aqueous NH₄Cl solution, extracted three times with Et₂O, the organic layers dried (MgSO₄) and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel.

Typical Procedure for the Copper-Catalyzed Carbomagnesiation Reaction (TP12):

Succeeding the typical procedure for halogen/magnesium-exchange (TP6) or for deprotonation (TP7) CuCN· 2 LiCl solution (1.0 M in THF, 30-100 mol%) was added to the reaction mixture at the indicated temperature and stirred for the indicated time (the completion of the reaction was checked by GC analysis of reaction aliquots quenched with half concentrated aqueous NH₄Cl

71 T. J. Korn, P. Knochel, Synlett 2005, 7, 1185.

72 K. Fujiki, N. Tanifuji, Y. Sasaki, T. Yokoyama, Synthesis 2002, 3, 343.

solution; typically two peaks with slightly differing retention time could be detected, corresponding to the open-chain and cyclized form).

Typical Procedure for Microwave-Assisted Reactions (TP13):

Microwave assisted reactions were carried out using a Biotage Initiator 2.5 system. The reaction mixture was therefore transferred into a dry and argon flushed microwave vial equipped with a stirring bar and septum pressure-cap. The reaction parameters (temperature, max. magnetron output, time) are given for the respective substance.

Typical Procedure for the Removal of Silyl-Protection Groups (TP14):

To the respective silyl-substituted compound (approx. 0.1 M in THF) was added TBAF trihydrate (1.2-2.0 equiv) at 25 °C and the mixture was stirred until the starting material was consumed (1-12 h). The solvent was evaporated in vacuo and the crude residue purified by flash column chromatography on silica gel.

Typical Procedure for the Conversion of the TMS-Group to Iodide (TP15):

To the respective TMS-substituted compound (approx. 0.2 M in CH₂Cl₂) was added iodine monochloride ICl (1.1 equiv) at 0 °C and the mixture was stirred for 5 min. The reaction was quenched with sodium thiosulfate solution, extracted three times with CH₂Cl₂, the organic layers dried (MgSO₄) and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel.

Typical Procedure for the Preparation of Organozinc Pivalates of Type 18 by Magnesium Insertion in the Presence of Zn(OPiv)₂· 2 LiCl (TP16):

Zn(OPiv)₂· 2 LiCl was placed in a Schlenk-flask, equipped with a magnetic stirrer and a septum, dried for 5 min at 400 °C (heat gun) in high vacuum and then dissolved in dry THF. The organic halide (1.00 equiv) was added and the mixture was stirred for 2 min at room temperature.

Magnesium turnings (2.50 equiv) were added and the Schlenk-flask was placed in a water bath for cooling during the initial heat evolution of the insertion reaction. The reaction mixture was stirred for the given time until GC analysis of a quenched reaction aliquot showed complete conversion. Then, the supernatant solution was carefully cannulated to a new dry and argon-flushed Schlenk-flask via syringe filter and the solvent was removed in vacuo.

Typical Procedure for the Preparation of Organozinc Pivalates of Type 18 by Halogen/Magnesium-Exchange and Transmetalation (TP17):

In a dry and argon-flushed Schlenk-flask, equipped with a magnetic stirrer and a septum, the organic halide was dissolved in dry THF. i-PrMgCl· LiCl was added dropwise at the given temperature and the reaction mixture was stirred for the given time at this temperature until GC analysis of a quenched reaction aliquot showed complete conversion. A solution of Zn(OPiv)₂· 2 LiCl (the zinc salt was dried for 5 min at 400 °C in high vacuum and then dissolved in dry THF (0.5 M)) was added dropwise and the mixture was stirred for 30 min at the given temperature. Then the solvent was removed in vacuo.

Typical Procedure for Pd-Catalyzed Cross-Coupling Reactions of Organozinc Pivalates of Type 18 (TP18):

In a dry and argon-flushed Schlenk-flask, equipped with a magnetic stirring bar and a septum, the solid organozinc reagent was dissolved in the solvent of choice. The organic halide (0.84 equiv) was added followed by PEPPSI-iPr (2 mol%) and the mixture was stirred for the given time at the given temperature. Then sat. aq. NH₄Cl (10 mL) was added and the aqueous layer was extracted with diethyl ether (3 × 20 mL). The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel.

Typical Procedure for the Addition of Organozinc Pivalates of Type 18 to Carbonyl Derivatives (TP19):

In a dry and argon-flushed Schlenk-flask, equipped with a magnetic stirring bar and a septum, the solid organozinc reagent was dissolved in dry THF. The carbonyl derivative (0.84 equiv) was added and the mixture was stirred for the given time at the given temperature. Then sat. aq.

NH₄Cl (10 mL) was added and the aqueous layer was extracted with diethyl ether (3 × 20 mL).

The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel.