Typical Procedures

Typical Procedure 1 (TP1): Synthesis of the phosphorodiamidates from phenols:

In a 100 mL round-bottom flask the phenol (20.0 mmol) and 4-DMAP (244 mg, 2.0 mmol) were dissolved in THF (20 mL), then Cl-P(O)(NMe2)2 (4.50 g, 3.9 mL, 24.0 mmol) was

carefully added, followed by the addition of triethylamine (2.43 g, 3.33 mL, 24.0 mmol). The resulting suspension was stirred at 25 °C for 12 h. The reaction mixture was quenched by the addition of a half concentrated aq. NH4Cl solution (20 mL) and extracted with EtOAc (3 x 20

mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and

concentrated in vacuo.

Typical Procedure 2 (TP2): Synthesis of the phosphorodiamidates from the corresponding hydroxy pyridines, hydroxy quinolines and hydroxy quinoxalines:

In a 100 mL round-bottom flask the hydroxy compound (20.0 mmol) and 4-DMAP (244 mg, 2.0 mmol) were dissolved or slurried up in THF (20 mL), then Cl-P(O)(NMe2)2 (4.50 g, 3.9

mL, 24.0 mmol) was added, followed by the addition of triethylamine (2.43 g, 3.33 mL, 24.0 mmol). The resulting suspension was stirred at 25 °C for 12 h. The reaction mixture was quenched by the addition of brine (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo.

Typical Procedure 3 (TP3): Preparation of aryl sulfonates from phenols:

In a 100 mL round bottom flask equipped with a magnetic stirring bar the phenol (20 mmol) was dissolved in 40 mL of dry THF. Then, NEt3 (2.43 g, 24 mmol) was added and the mixture

was cooled with an ice bath (approx. 0 °C). The sulfonyl chloride (24 mmol) was added portionwise and the resulting mixture was stirred and allowed to reach 25 °C within 12 h. Then 50 mL of a saturated aqueous NH4Cl solution were added and the resulting mixture was

extracted into EtOAc (50 mL). The organic layer was washed twice with 50 mL of a saturated aqueous NH4Cl solution. The combined organic layers were washed with brine, dried over

MgSO4 and concentrated in vacuo. The resulting solids were recrystallized from n-

heptane/EtOAc.

Typical procedure 4 (TP4): Br/Mg-Exchange or I/Mg-Exchange on aryl sulfonates:

In a dry and argon flushed Schlenk-tube, the arylsulfonate (20 mmol) was dissolved in dry THF and cooled to –40°C. Then, iPrMgCl·LiCl (16.5 mL, 1.33 M in THF, 22 mmol) was

dropwise added. The resulting mixture was stirred until GC showed full conversion to the organomagnesium reagent (aliquots were quenched with I2 in THF and extracted with Et2O).

Then, the electrophile (20 mmol) was added. The reaction mixture was stirred for 30 min at – 40°C and 1 h at 25 °C. The reaction was quenched with 50 mL of a saturated aqueous NH4Cl

solution and extracted into 50 ml EtOAc. The organic layer was washed twice with 50 mL of a saturated aqueous NH4Cl solution. The combined organic layers were washed with brine,

dried over MgSO4 and concentrated in vacuo. The resulting solids recrystallized from n-

heptane/EtOAc.

In a flame dried and argon flushed Schlenk-tube equipped with a rubber septum and a magnetic stirring bar the substrate (1 equiv) was dissolved in dry THF (1 M solution). The

mixture was cooled to the indicated temperature. Then the Mg- or Zn-base (0.6-2.0 equiv) was added dropwise via syringe. The mixture was stirred at the given temperature. Complete metalation was detected by GC-analysis of reaction aliquots, quenched with allyl bromide (approx. 5 drops) in the presence of CuCN·2LiCl (approx. 0.5 mL). The reaction mixture was then quenched with an electrophile according to TP7-9. The reaction mixture was quenched by the addition of 15-30 mL of brine (N-heterocycles) or a sat. aq. NH4Cl solution. Formed

precipitate was filtered off with a fritted funnel (P3, 300 mbar). The filter cake was washed with EtOAc (3 x 25 ml) and the filtrate was brought into a separatory funnel with Et2O (10-20

mL) and EtOAc (10-20 mL). The organic layer was extracted with brine (3 x 15 mL). The combined aqueous layers were extracted with EtOAc (2 x 20 mL). The organic layers were washed with brine (20 mL) dried over anhydrous MgSO4 filtered and concentrated in vacuo.

The residue was subjected to flash column chromatographical purification on silica.

Typical Procedure 6 (TP6): Microwave assisted zincation reaction:

In a flame dried and argon flushed 10 mL µW sealed tube equipped a magnetic stirring bar the corresponding substrate (1 equiv.) was dissolved in the indicated amount of 54 (0.6 equiv.). The mixture was heated to the indicated temperature with an Initiator Sixty EXP Microwave System (Biotage) and stirred at this temperature for the given period. Complete metalation was detected by GC-Analysis of reaction aliquots, quenched with I2 in dry THF.

Then the reaction mixture was then quenched with an electrophile and worked up as described below (according to TP7-9).

Typical Procedure 7 (TP7): Quenching by performing a Negishi Cross-Coupling Reaction:

After complete metalation was achieved according to TP5 ZnCl2 (1 M in THF, 1.6 – 2.2 equiv)

was added at –40 °C (if required, see specific procedures). The resulting mixture was stirred for 15 min. Then Pd(dba)2 (5 mol%) and P(2-furyl)3 (10 mol%) (for aryl iodides) or Pd2(dba)3

(1 mol%) and RuPHOS (2 mol%) (for aryl bromides) was added together with the corresponding aryl iodide or bromide and the mixture was allowed to warm to 25 °C. Complete consumption of the organozinc reagent was monitored via GC-analysis (approx. 1 -

3 h). The reaction mixture was quenched by the addition of 15-30 mL of brine (N- heterocycles) or a sat. aq. NH4Cl solution. Formed precipitate was filtered off with a fritted

funnel (P3, 300 mbar). The filter cake was washed with EtOAc (3 x 25 ml) and the filtrate was brought into a separatory funnel with Et2O (10-20 mL) and EtOAc (10-20 mL). The

organic layer was extracted with brine (3 x 15 mL). The combined aqueous layers were extracted with EtOAc (2 x 20 mL). The organic layers were washed with brine (20 mL) dried over anhydrous MgSO4 filtered and concentrated in vacuo. The residue was subjected to flash

column chromatographical purification on silica.

Typical Procedure 8 (TP8): Quenching by performing an Acylation Reaction:

After complete metalation was achieved according to TP5 ZnCl2 (1 M in THF, 1.6 equiv) was

added at –40 °C (if required, see specific procedures). The mixture was the stirred for 15 min. Then CuCN·2LiCl (1 M in THF, 0.1 equiv) or Pd(PPh3)4 (2 mol%) was added (see specific

procedures). After the addition of the corresponding acid chloride, the mixture was briefly warmed with to 25 °C. Complete consumption of the organozinc reagent was monitored via GC-analysis (approx. 1 - 3 h). The reaction mixture was quenched by the addition of 15-30 mL of brine (N-heterocycles) or a sat. aq. NH4Cl solution. Formed precipitate was filtered off

with a fritted funnel (P3, 300 mbar). The filter cake was washed with EtOAc (3 x 25 ml) and the filtrate was brought into a separatory funnel with Et2O (10-20 mL) and EtOAc (10-20 mL).

The organic layer was extracted with brine (3 x 15 mL). The combined aqueous layers were extracted with EtOAc (2 x 20 mL). The organic layers were washed with brine (20 mL) dried over anhydrous MgSO4 filtered and concentrated in vacuo. The residue was subjected to flash

column chromatographical purification on silica.

Typical Procedure 9 (TP9): Quenching by performing an Allylation Reaction :

After complete metalation was achieved according to TP5 ZnCl2 (1 M in THF, 1.6 equiv) (if

required, see specific procedures) was added at –40 °C. The resulting mixture was stirred for 15 min. CuCN·2LiCl (1 M in THF, 0.1 equiv) was added together with the corresponding allylbromide and the mixture was allowed to warm to room temperature. Complete consumption of the organozinc reagent was monitored via GC-analysis (approx. 1 - 3 h). The reaction mixture was quenched by the addition of 15-30 mL of brine (N-heterocycles) or a sat. aq. NH4Cl solution. Formed precipitate was filtered off with a fritted funnel (P3, 300 mbar).

The filter cake was washed with EtOAc (3 x 25 ml) and the filtrate was brought into a separatory funnel with Et2O (10-20 mL) and EtOAc (10-20 mL). The organic layer was

extracted with brine (3 x 15 mL). The combined aqueous layers were extracted with EtOAc (2 x 20 mL). The organic layers were washed with brine (20 mL) dried over anhydrous MgSO4

filtered and concentrated in vacuo. The residue was subjected to flash column chromatographical purification on silica.

Typical Procedure 10 (TP10): Co-catalyzed aryl sulfonate/copper-exchange:

A dry and argon flushed 25 mL Schlenk-tube was charged with PhMgCl (1.74 mL, 1.72 M in THF, 3.00 mmol) and cooled to –20 °C. Then, CuCN·2LiCl (3.6 mL, 1.0 M in THF, 3.6 mmol) was dropwise added. The resulting yellow solution was stirred for 20 min at –20 °C. Then, Bu4NI (369 mg, 1.00 mmol), the arylsulfonate (1.00 mmol), Co(acac)2 (51 mg, 20 mol%), 4-

fluorostyrene (65 mg, 50 mol%) and dry DMPU (2.2 mL) were added. The resulting suspension was warmed to 25 °C (or 45 °C see specific procedure) and stirred until GC- analysis showed full consumption of the starting material. The formation of the copper reagent was monitored by performed iodolysis of reaction aliquots (GC-analysis). The reaction mixture was cooled to –20 °C and the electrophile (2.00 mmol) was added. The reaction mixture was stirred 30 min at –20 °C and for 2 h at 25 °C. The mixture was quenched by the addition of NH4Cl/NH3 (9:1) (15 mL) and extracted with Et2O (3 x 25 mL). The

aqueous phase was extracted with EtOAc (25 mL) twice. The combined organic layers were washed with brine and dried over MgSO4 and concentrated in vacuo. Column

4.3.

Magnesiation on Weakly Activated Substrates Using a