ASPECTOS QUE INFLUYEN LA MOTRICIDAD GRUESA

2.1 Typical procedure (TP1) for the preparation of 2-aryl-2H-indazole derivatives (22ar)

To a solution of the 2-iodobenzyl chloride derivative (3.0 mmol) in THF (2 mL) in a dry and argon-flushed Schlenk-flask was added dropwise a solution of iPrMgCl·LiCl (3.2 mmol, 1.8 mL, 1.8 M in THF) at 20 °C. The reaction mixture was stirred for 30 min at the same temperature. GC-analysis of a quenched reaction aliquot shows full conversion. ZnBr2

solution (1.6 mL, 1.6 mmol, 1 M in THF) was added to the Grignard reagent at 20 °C and allowed to warm to 25 °C. The solution was stirred for 20 min at the same temperature. To a solution of diazonium salt (2.0 mmol) in NMP/THF (1:1) (4 mL) the diarylzinc species was added dropwise at 40 °C, allowed slowly to warm up to 25 °C and stirred for 30 min at 25 °C. The reaction mixture was then stirred at 50 °C for 1 h. The reaction mixture was diluted with diethyl ether (5 mL) and quenched with sat. NH4Cl (aq.) (5 mL). The aqueous

layer was extracted with CH2Cl2 (3x 20 mL). The combined organic phases were dried over

Na2SO4, the solvent was removed in vacuo and the residue was subjected to flash column

chromatography to afford the 2-aryl-2H-indazole derivative.

2.2 Typical procedure (TP2) for the preparation of aryldiazonium tetrafluoroborates (25ak, 43ak)

To a solution of the aniline derivative (50 mmol) in tetrafluoroboric acid (0.4 mol, 35 g, 50 w% in H2O) was added dropwise a NaNO2 solution (55 mmol, 3.79 g, 4 M in H2O) under

vigorous stirring, while the temperature was kept below 5 °C. The reaction mixture was stirred for additional 30 min at 5 °C. The precipitate was removed by filtration and washed with cold MeOH. The solid was recrystallized from methanol to yield the crystalline aryldiazonium tertrafluoroborate salt.

2.3 Typical procedure (TP3) for the preparation of heterocyclic azo compounds (39ag)

To a solution of the haloheteroaryl derivative (3.0 mmol) in THF (2 mL) in a dry and argon- flushed Schlenk-flask was added dropwise a solution of iPrMgCl·LiCl (3.2 mmol, 1.8 mL, 1.8 M in THF) at 20 °C. The reaction mixture was stirred for 30 min at the same temperature. GC-analysis of a quenched reaction aliquot shows full conversion. ZnBr2

allowed to warm to 25 °C. The solution was stirred for 20 min at the same temperature. To a solution of diazonium salt (2.0 mmol) in NMP/THF (1:1) (4 mL) the diarylzinc was added dropwise at 40 °C, allowed to slowly warm up to 20 °C and stirred for 2 h at the same temperature. The reaction mixture was diluted with diethyl ether (5 mL) and quenched with sat. NH4Cl (aq.) (5 mL). The aqueous layer was extracted with CH2Cl2 (3x 20 mL). The

combined organic phases were dried over Na2SO4, the solvent was removed in vacuo and the

residue was subjected to flash column chromatography to afford the heterocyclic azo compound.

2.4 Typical procedure (TP4) for the preparation of alkylzinc bromides by direct zinc insertion in the presence of LiCl (44ab)

A dry, argon-flushed Schlenk flask equipped with a magnetic stirring bar and a septum was charged with zinc dust (524 mg, 8 mmol) and LiCl (186 mg, 4.4 mmol). The LiCl was dried

in vacuo with a heatgun (450 °C, 5 min). After addition of THF (2 mL), the zinc was activated with 1,2-dibromoethane (2 mol%) and Me3SiCl (5 mol%). After stirring for 5 min,

alkyl bromide (4.0 mmol) in THF (4 mL) was added at 25 °C to the suspension and the reaction mixture was stirred for the given time at the given temperature. The supernatant solution was then cannulated into a new dry, argon-flushed Schlenk flask and titrated with iodine affording the concentration of active alkylzinc reagent.288

2.5 Typical procedure (TP5) for the preparation of alkylzinc bromides by direct magnesium insertion in the presence of ZnBr2 and LiCl (44dg)

A dry, argon-flushed Schlenk flask equipped with a magnetic stirring bar and a septum was charged with magnesium turnings (155 mg, 6.4 mmol) and LiCl (186 mg, 4.4 mmol). The LiCl was dried in vacuo with a heatgun (450 °C, 5 min). After addition of THF (2 mL), the magnesium was activated with 1,2-dibromoethane (2 mol%) and Me3SiCl (5 mol%). After

stirring for 5 min, ZnBr2 (4.0 mmol, 4 mL, 1 in THF) was added to the mixture. Thereafter,

the suspension was cooled to 0 °C, alkyl bromide (4.0 mmol) in THF (4 mL) was added and the reaction mixture was stirred for the given time at 25 °C. The supernatant solution was then cannulated into a new dry, argon-flushed Schlenk flask and titrated with iodine affording the concentration of active alkylzinc reagent.289

288 _{A. Krasovskiy, V. Malakhov, A. Gavryushin, P. Knochel, Angew. Chem. Int. Ed. 2006, 45, 6040.}

289 _{a) F. M. Piller, P. Appukkuttan, A. Gavryushin, M. Helm, P. Knochel, Angew. Chem. Int. Ed. 2008, 47, 6802;}

b) F. M. Piller, A. Metzger, M. A. Schade, B. A. Haag, A. Gavryushin, P. Knochel, Chem. Eur. J. 2009, 15, 7192.

2.6 Typical procedure (TP6) for the preparation of indole derivatives via alkylzinc bromides and aryldiazonium tetrafluoroborates (23aaj, 48, 49)

In a flame-dried and argon-flushed Schlenk-flask, the alkylzinc bromide solution (2.0 mmol) was added dropwise to a solution of ZnBr2 (4.0 mmol, 4 mL, 1M in THF) at 25 °C. After

stirring at 25 °C for 10 min, the organozinc reagent was transferred slowly to a solution of aryldiazonium tetrafluoroborate (2.5 mmol) in THF (6 mL) at 60 °C. The reaction mixture was allowed to slowly warm to 25 °C. Subsequently, the solvent volume was reduced to half, Me3SiCl (2.0 mmol, 217 mg) was added, and the reaction mixture was heated by microwave

irradiation for the given time at 125 °C. After the reaction mixture had cooled to 25 °C, the resulting solution was diluted with Et2O (5 mL) and quenched with brine (10 mL). The

aqueous layer was extracted with EtOAc (3x 15 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Purification by flash column chromatography

afforded the polyfunctional indole.

2.7 Typical procedure (TP7) for the preparation of pyrazole derivatives via alkylzinc bromides and aryldiazonium tetrafluoroborates (51ae)

In a flame-dried and argon-flushed Schlenk-flask, the alkylzinc bromide solution (2.0 mmol) was added dropwise to a solution of ZnBr2 (4.0 mmol, 4 mL, 1M in THF) at 25 °C. After

stirring at 25 °C for 10 min, the organozinc reagent was transferred slowly to a solution of aryldiazonium tetrafluoroborate (2.5 mmol) in THF (6 mL) at 60 °C. The reaction mixture was allowed to slowly warm to 25 °C. Subsequently, the solvent volume was reduced to half, Me3SiCl (2.0 mmol, 217 mg) was added, and the reaction mixture was heated by microwave

irradiation for the given time at 125 °C. After the reaction mixture had cooled to 25 °C, the resulting solution was diluted with Et2O (5 mL) and quenched with brine (10 mL). The

aqueous layer was extracted with EtOAc (3x 15 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Purification by flash column chromatography

afforded the polyfunctional pyrazole.

2.8 Typical procedure (TP8) for the preparation of organomagnesium halides via direct magnesium insertion in large scale

A dry and argon-flushed Schlenk-flask, equipped with a magnetic stirrer and a septum, was charged with LiCl (1.25 equiv) and heated under high vacuum using a heat gun (20 min). After cooling to room temperature, magnesium turnings (2.5 equiv) were added followed by THF. The magnesium was activated with iBu2AlH (1 mol%).After 5 min of stirring the aryl

at the given temperature. The reaction mixture was stirred for the indicated time and then cannulated to a new Schlenk-flask for the reaction with an electrophile.

2.9 Typical procedure (TP9) for the preparation of organoborates via direct magnesium insertion in the presence of B(OBu)3

A dry, argon-flushed Schlenk flask equipped with a magnetic stirring bar and a septum was charged with magnesium turnings (78 mg, 3.2 mmol) and LiCl (93 mg, 2.2 mmol). LiCl was dried in vacuo using a heatgun (450 °C, 5 min). After addition of THF (2 mL), the magnesium was activated with 1,2-dibromoethane (2 mol%) and Me3SiCl (5 mol%). Stirring for 5 min

was followed by addition of B(OBu)3 (230 mg, 1 mmol). Thereafter, a solution of organic

halide (2 mmol) in THF (2 mL) was added at the given temperature and stirred for the given time leading to the organoborate.

2.10 Typical procedure (TP10) for the preparation of organoborates via direct aluminium insertion in the presence of B(OBu)3

A dry, argon-flushed Schlenk flask equipped with a magnetic stirring bar and a septum was charged with LiCl (127 mg, 6 mmol) and dried in vacuo 450 °C (heatgun, 5 min). Heating was repeated after addition of aluminium dust (162 mg, 6 mmol) magnesium turnings (78 mg, 3.2 mmol). After addition of THF (2 mL), the aluminium was activated with 1,2-dibromoethane (2 mol%) and Me3SiCl (5 mol%). Stirring for 5 min was followed by

addition of B(OBu)3 (230 mg, 1 mmol). Thereafter, a solution of organic halide (2 mmol) in

THF (2 mL) was added at 25 °C and the reaction mixture was stirred at the given temperature for the given time leading to the organoborate.

2.11 Typical procedure (TP11) for in situ zincation of functionalized heteroaromatics using TMPMgCl·LiCl in the presence of ZnCl2

A dry and argon-flushed 25 mL Schlenk-flask, equipped with a magnetic stirring bar and a septum, was charged with heteroarene (1 equiv) in THF (1 mL) and ZnCl2 (0.5 equiv, 1M in

THF). TMPMgCl·LiCl (91; 1.1 equiv, 1.2M in THF) was added dropwise and the reaction mixture was stirred at 25 °C for the indicated time. Complete metalation was detected by GC- analysis of an iodolyzed reaction aliquot using tetradecane as internal standard.

2.12 Typical procedure (TP12) for metalation of heteroaromatics using hindered metal amide bases

A dry and argon-flushed Schlenk-tube, equipped with a magnetic stirring bar and a septum, was charged with a solution of heteroarene (1 equiv, 0.2M in THF) and cooled to the indicated temperature. A THF-solution of the given hindered metal amide base, titrated prior to use, was added dropwise and the reaction mixture was stirred at the indicated temperature for the given time. Complete metalation was monitored by GC analysis of iodolyzed reaction aliquots using tetradecane as internal standard.

2.13 Typical procedure (TP13) for BF3-triggered metalation of heteroaromatics

using hindered metal amide bases

A dry and argon-flushed Schlenk-tube, equipped with a magnetic stirring bar and a septum, was charged with a solution of heteroarene (1 equiv, 0.2M in dry THF) and cooled to 0 °C. BF3·OEt2 (1.1 equiv) was added dropwise and stirred for 15 min at 0 °C. Subsequently, the

reaction mixture was cooled to the given temperature followed by dropwise addition of the indicated hindered metal amide base, titrated prior to use. The mixture was continuously stirred at the indicated temperature for the given time. Complete metalation was monitored by GC analysis of iodolyzed reaction aliquots using tetradecane as internal standard.

2.14 Typical procedure (TP14) for metalation using the frustrated Lewis pair “TMPBF3·MgCl·LiCl” (99)

A dry and argon-flushed Schlenk-tube, equipped with a magnetic stirring bar and a septum, was charged with TMPMgCl·LiCl (91; 1.1 equiv, 1.2M in THF). At 40 °C, BF3·OEt2

(1.1 equiv) was added dropwise and the resulting mixture was stirred for 10 min at 40 °C. To this mixture, a solution of heteroarene (1.0 equiv, 0.2M in THF) was added slowly followed by continuous stirring at 40 °C for the indicated time. Complete metalation was monitored by GC-analysis of iodolyzed reaction aliquots using tetradecane as internal standard.

2.15 Typical procedure (TP15) for the preparation of secondary heterocyclic alcohols via metalation using the frustrated Lewis pair

“TMPBF3·MgCl·LiCl” (99)

A dry and argon-flushed Schlenk-tube, equipped with a magnetic stirring bar and a septum, was charged with TMPMgCl·LiCl (91; 1.1 equiv, 1.2M in THF). At 40 °C, BF3·OEt2

Then, a solution of heteroarene (1.0 equiv, 2.0M in THF) was added slowly at 40 °C followed by continuous stirring for the indicated time. Complete metalation was monitored by GC-analysis of iodolyzed reaction aliquots using tetradecane as internal standard. Subsequently, a THF solution of an aldehyde (1.1 equiv, 1M in THF) was added dropwise at 40 °C. The reaction mixture was allowed to slowly warm to 25 °C and continuously stirred for 1 h followed by addition of EtOAc (10 mL) and aq. 2M NaOH (15 mL). The aqueous layer was extracted with CH2Cl2 (3x 15 mL). The combined organic phases were

dried over Na2SO4 and concentrated in vacuo. Flash column chromatographical purification

provided the expected product.

2.16 Typical procedure (TP16) for the metalation of heteroaromatics and aromatics using amidoborates of type 110

A dry and argon-flushed Schlenk-tube, equipped with a magnetic stirring bar and a septum, was charged with a solution of heteroarene (1 equiv, 1.0M in THF). The amidoborate (1.1 equiv) was added dropwise at 25 °C, if not indicated otherwise, and stirred continuously for the given time. Complete conversion was monitored by GC analysis of iodolyzed reaction aliquots using tetradecane as internal standard.

2.17 Typical procedure (TP17) for the regioselective preparation of five-membered heteroarylmagnesium reagents using 124d and 125b

A dry and argon-flushed Schlenk-flask, equipped with a magnetic stirring bar and a septum, was charged with 2,4,6-triisopropylmagnesium bromide (TIPMgBr·LiCl; 124d; 1.1 equiv, 0.7M in THF) and bis(dimethylaminoethyl)ether (125b; 1.1 equiv). After stirring for 10 min at 25 °C, the dibromoheterocycle (1 equiv) was added neat at the given temperature and continuously stirred for the indicated time. Complete Br/Mg-exchange was monitored by GC- analysis of iodolyzed reaction aliquots using tetradecane as internal standard.