Typical Procedures

2.3 TP3: Typical Procedure for the Preparation of the Organozinc Pivalates by Magnesium Insertion and Subsequent Transmetalation with Zn(OPiv)2

A dry and argon flushed Schlenk-flask equipped with a magnetic stirring bar and a septum was charged with magnesium turnings (304 mg, 12.5 mmol, 2.50 equiv), LiCl (318 mg, 7.50 mmol, 1.50 equiv) and THF (15 mL). The aromatic halide (5.00 mmol, 1.00 equiv) was added dropwise. If necessary, the Schlenk-flask was placed in a water bath for cooling during the initial heat evolution of the insertion reaction. The progress of the insertion reaction was monitored by GC-analysis of reaction aliquots quenched with aq. sat. NH4Cl solution and/or I2. Upon completion of the insertion, solid Zn(OPiv)2 (1.61 g, 6.00 mmol, 1.20 equiv) was added in one portion. After stirring at ambient temperature for 15 min, the solvent was carefully removed in vacuo. The dried material was titrated using iodine solution (1 M in THF) in order to determine its actual content in zinc species and the yield of the reaction.

2.4 TP4: Typical Procedure for the Preparation of the Organozinc Chlorides by Magnesium Insertion and Subsequent Transmetalation with ZnCl2

In a dry and argon flushed Schlenk-flask equipped with a magnetic stirring bar and a septum anhydrous LiCl (159 mg, 3.75 mmol, 1.50 equiv) and magnesium turnings (122 mg, 5.00 mmol, 2.00 equiv) were suspended in dry THF (5 mL). The alkyl or aryl halide (2.50 mmol, 1.00 equiv) was added in one portion and magnesium turnings was activated by gentle heating. After the exothermic reaction started, the reaction mixture was cooled to 25 °C and stirred overnight. Upon completion of the insertion, a solution of ZnCl2 (1.00 M, 3.00 mL, 3.00 mmol, 1.20 equiv) in dry THF was added at 0 °C and the mixture was allowed to slowly warm up to rt. After stirring at ambient temperature for 15 min, the mixture was titrated using iodine in order to determine its actual content in zinc species and the yield of the reaction.⁷²

2.5 TP5: Typical Procedure for the Preparation of the Organozinc Chlorides by Magnesium Insertion in the Presence of ZnCl2

A dry and argon flushed Schlenk-flask equipped with a magnetic stirring bar and a septum was charged with anhydrous LiCl (159 mg, 3.75 mmol, 1.50 equiv), with anhydrous ZnCl2

(409 mg, 3.00 mmol, 1.20 equiv), magnesium turnings (122 mg, 5.00 mmol, 2.00 equiv) and suspended in dry THF (5 mL). The aryl halide (2.50 mmol, 1.00 equiv) was added in one portion and the magnesium activated by gentle heating. After the exothermic reaction started,

of the insertion the mixture was titrated using iodine in order to determine its actual content in zinc species and the yield of the reaction.⁹¹

2.6 TP6: Typical Procedure for the Preparation of the Organozinc halides by Zinc Insertion

A dry and argon flushed Schlenk-flask equipped with a magnetic stirring bar and a septum was charged with anhydrous LiCl (127 mg, 3.00 mmol, 1.20 equiv) and zinc dust (245 mg, 3.75 mmol, 1.50 equiv) and suspended in dry THF (5 mL). Zinc was activated with 1,2-dibromoethane (5 drops) and TMSCl (5 drops). Then, the aryl halide (2.50 mmol, 1.00 equiv) was added in one portion and the reaction mixture was stirred at the appropriate temperature for the indicated time. Upon completion of the insertion the mixture was filtered through a syringe filter and titrated using iodine in order to determine its actual content in zinc species and the yield of the reaction.^21a

2.7 TP7: Typical Procedure for the Preparation of the Organozinc Pivalates via Direct Metalation Using TMPMgCl·LiCl and Subsequent Transmetalation with Zn(OPiv)2

A dry and argon flushed Schlenk-flask equipped with a magnetic stirring bar and a septum was charged with the aromatic substrate (3.00 mmol, 1.00 equiv) and dry THF (9 mL). The reaction mixture was put to the appropriate temperature, before TMPMgCl·LiCl (2.70 mL, 1.23 M, 3.30 mmol, 1.10 equiv) was added dropwise. The progress of the deprotonation was monitored by GC-analysis of reaction aliquots quenched with I2. Upon completion of the metalation, solid Zn(OPiv)2 (963 mg, 3.60 mmol, 1.20 equiv) was added in one portion and the mixture was allowed to slowly warm up to 25 °C. After stirring at ambient temperature for 15 min, the solvent was carefully removed in vacuo. The dried material was titrated using iodine in order to determine its actual content in zinc species and the yield of the metalation.

2.8 TP8: Typical Procedure for the Preparation of the Organozinc Pivalates via Direct Metalation Using TMPZnCl·Mg(OPiv)2·LiCl

A dry and argon flushed Schlenk-flask equipped with a magnetic stirring bar and a septum was charged with the aromatic substrate (3.00 mmol, 1.00 equiv) and dry THF (9 mL). The reaction mixture was put to the appropriate temperature, before TMPZnCl·Mg(OPiv)2·LiCl (2.84 mL,

1.16 M, 3.30 mmol, 1.10 equiv) was added dropwise. The progress of the deprotonation was monitored by GC-analysis of reaction aliquots quenched with I2. Upon completion of the metalation, the solvent was carefully removed in vacuo. The dried material was titrated using iodine solution (1 M in THF) in order to determine its actual content in zinc species and the yield of the metalation.

2.9 TP9: Typical Procedure for the Preparation of N-Hydroxylamine Benzoate Derivatives of Type 5 using Benzoyl Peroxide

A dry and argon flushed flask equipped with a magnetic stirring bar and a septum was charged with K2HPO4 (1.31 g, 7.50 mmol, 1.50 equiv) and anhydrous benzoyl peroxide (1.21 g, 5.00 mmol, 1.00 equiv). The mixture was suspended in DMF (20 mL) and amine (6.00 mmol, 1.20 equiv) was added slowly. The reaction mixture was stirred at room temperature and checked by thin layer chromatography analysis. Upon full consumption of benzoyl peroxide, the reaction was quenched with sat. aqueous NH4Cl solution (30 mL). The organic layer was removed and the aqueous phase was extracted from EtOAc (3 x 15 mL). The combined organic layers were washed with sat. aqueous NaHCO3 solution (15 mL), brine (15 mL) and subsequent dried over mgSO4. Evaporation of the solvents in vacuo and purification by flash column chromatography afforded the desired products.

2.10 TP10: Typical Procedure for the 1,4-Addition of Acrylonitrile to Secondary Amines

A dry and argon flushed flask equipped with a magnetic stirring bar and a septum was charged with sodium metal (23 mg, 1.00 mmol, 1.00 equiv) and dissolved in dry MeOH (2 mL). In another dry and argon flushed flask equipped with a magnetic stirring bar and a septum, amine hydrochloride 14 (1.00 mmol, 1.00 equiv) was dissolved in dry MeOH (2 mL) and added to the previously prepared sodium methoxide solution. To the resulting solution, acrylonitrile (0.33 mL, 265 mg, 5.00 mmol, 5.00 equiv) was added and the reaction mixture was stirred at 55 °C overnight. The solvent was evaporated and the resulting crude purified by flash column chromatography to afford the desired product of type 17.^86a

In the case of non-hydrochloride amine starting materials, the addition of sodium methoxide is not necessary and can be overleaped.

2.11 TP11: Typical Procedure for the Preparation of N-Hydroxylamine Derivatives of Type 16 by Oxidation and Cope-Elimination

A dry and argon flushed flask equipped with a magnetic stirring bar and a septum was charged with 1,4-addition product 17 (1.00 mmol, 1.00 equiv) and dissolved in dry CH2Cl2 (2 mL). The solution was cooled to −78 °C and mCPBA (190 mg, 1.10 mmol, 1.10 equiv) was added slowly as a solution in dry CH2Cl2 (2 mL). The mixture was stirred at −78 °C for 1 h. Following, the cooling bath was removed and the mixture stirred at 25 °C overnight. The solvent was removed and the acid by-product removed by filtration through a silica plug. After solvent removal, the resulting N-hydroxylamine was dissolved in CH2Cl2 (4 mL) followed by the addition of triethylamine (0.21 mL, 1.50 mmol, 1.50 equiv), DMAP (1 mg, 0.01 mmol, 1 mol%) and benzoyl chloride (168 mg, 1.20 mmol, 1.20 equiv) at 0 °C. The resulting solution was stirred at 0 °C for 1 h and quenched with sat. aqueous NH4Cl solution (2 mL). The mixture was extracted with EtOAc (3 x 5 mL) and the combined organic phases were washed with saturated NaHCO3 solution (2 mL), brine (2 mL), and dried over Na2SO4. The crude mixture was purified with flash column chromatography to afford the desired product.^86a

2.12 TP12: Typical Procedure for the Electrophilic Amination of Organozinc Pivalates with N-Hydroxylamine Derivatives

A dry and argon flushed flask equipped with a magnetic stirring bar and a septum was charged with N-hydroxylamine benzoate derivative 5 (0.50 mmol, 1.00 equiv) and THF (2 mL). To the mixture CoCl2·2LiCl (13–25 µmol, 2.5–5.0 mol%) was added as a 1 M solution in THF. Then, presolved organozinc pivalate 1 (0.55 mmol, 1.10 equiv) in THF was added dropwise. The solution was stirred for 2 h at room temperature and the reaction progress checked by thin layer chromatography. Upon completion of starting material (approximately less than 2 h) the reaction was quenched with sat. aqueous NH4Cl solution (1 mL). The mixture was extracted from EtOAc (3 x 15 mL). The combined organic layers were washed with sat. aqueous NaHCO3 solution (15 mL), brine (15 mL) and subsequent dried over mgSO4. Evaporation of the solvents in vacuo and purification by flash column chromatography afforded the expected products.

2.13 TP13: Typical Procedure for the Electrophilic Amination of Organozinc Chlorides with N-Hydroxylamine Derivatives

A dry and argon flushed flask equipped with a magnetic stirring bar and a septum was charged with N-hydroxylamine derivative 5 (0.50 mmol, 1.00 equiv) and THF (2 mL). To the mixture pre-dried CoCl2 (3–6 mg, 5.0–10 mol%) was added. Then, organozinc chloride 1 (0.75 mmol, 1.50 equiv) in THF was added dropwise. The solution was stirred for 2 h at 25 °C and the reaction progress checked by thin layer chromatography. Upon completion of starting material (approximately less than 2 h) the reaction was quenched with sat. aqueous NH4Cl solution (1 mL). The mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with sat. aqueous NaHCO3 solution (15 mL), brine (15 mL) and subsequent dried over mgSO4. Evaporation of the solvents in vacuo and purification by flash column chromatography afforded the expected products.

2.14 TP14: Typical Procedure for the Electrophilic Amination by Reacting the Organozinc Chlorides with the Azides

In a dry and argon flushed flask equipped with a magnetic stirring bar and a septum the azide (0.50 mmol, 1.0 equiv) was dissolved in dry THF (1 mL). First anhydrous FeCl3 (41 mg, 0.25 mmol, 0.50 equiv) and then the organozinc chloride (0.875 mmol, 1.75 equiv) were added in one portion, respectively. The reaction was stirred at 50 °C for 1 h and subsequently quenched with sat. aqueous NH4Cl solution (5 mL). The mixture was extracted with EtOAc (3 × 10 mL).

The combined org. layers were washed with sat. NaHCO3 solution (5 mL), brine (5 mL), and dried over Na2SO4. The crude product was finally purified by flash column chromatography.

2.15 TP 15: General Preparation of N-thiophthalimides from Their Corresponding Thiol Using N-Chlorophthalimide

A dry and argon flushed round bottom flask equipped with a magnetic stirring bar and a septum was charged with N-chlorophthalimide (908 mg, 5.00 mmol, 1.00 equiv), dry MeCN (2.6 mL) and pyridine (2.1 mL). The thiol (5.00 mmol, 1.00 equiv) in dry MeCN (2.6 mL) and dry pyridine (2.1 mL) was added dropwise at 0 °C over a period of 30 min and the resulting mixture was stirred for additional 30 min. After removal of most MeCN in vacuo, water (20 mL) was added dropwise at 0 °C over 10 min and stirred for a further period of 10 min. Filtration of the resulting suspension and washing of the filtrate with ice cold MeOH (3 × 5 mL) provide the

2.16 TP 16: Preparation of Thioethers via a Cu(OAc)2·H2O Catalyzed Electrophilic Thiolation of Organozinc Reagents

A dry and argon flushed reaction tube equipped with a magnetic stirring bar and a septum was charged with the selected N-thiophthalimide 40 (0.50 mmol, 1.00 equiv), Cu(OAc)2.H2O (5 mg, 25 μmol, 5.00 mol%) and dry THF (1 mL). The selected organometallic zinc reagent 1 (0.55 mmol, 1.10 equiv) was added dropwise. The reaction mixture was stirred for 1 h at 25 °C and then quenched with aq. sat. NH4Cl. The aqueous phase was extracted with EtOAc (3×30 mL). The combined organic phases were dried over mgSO4 and concentrated in vacuo.

The crude product was further purified by flash column chromatography on silica gel to provide the desired thioether 4.

3. Cobalt-Catalyzed Electrophilic Amination of Aryl- and