C. EXPERIMENTAL SECTION
2. Typical Procedures (TP)
C. Experimental Section 113
C. Experimental Section 114 phases were separated and the aq. layer was extracted with Et2O (3 x 100 mL). The combined organic extracts were dried over MgSO4. Evaporation of the solvents in vacuo and purification by flash column chromatography afforded the expected ketones.
2.4. Typical procedure for the reaction of benzylic zinc chlorides with unsaturated ketones (TP4)
Into a dry argon-flushed Schlenk flask, equipped with a magnetic stirring bar and a septum, CuCN·2LiCl solution (1.25 equiv) was added. Then, the desired benzylic zinc chloride (1.25 equiv) was added dropwise at -25°C. The resulting reaction mixture was stirred for 15 min at this temperature. Then, the solution was cooled to the required temperature and a mixture of the unsaturated ketone (1.0 equiv), trimethylsilyl chloride (2.5 equiv) and THF was added dropwise. The reaction mixture was stirred for the given time and allowed to reach 25 °C. Then, a mixture of sat. aq. NH4Cl / NH3 (25% in H2O) = 2:1 was added. The phases were separated and the aq. layer was extracted with Et2O (3 x 100 mL). The combined extracts were dried over MgSO4. Evaporation of the solvents in vacuo and purification by flash column chromatography afforded the expected ketones.
2.5. Typical procedure for the Ni-catalyzed cross-coupling reactions of benzylic zinc chlorides with aromatic halides (TP5)
In a dry argon-flushed Schlenk flask equipped with a septum and a magnetic stirring bar, the aromatic bromide or chloride (2.00 mmol, 1.0 equiv) was dissolved in NMP (0.4 mL) and PPh3 (0.1 mL, 0.04 mmol, 0.4 M in THF, 2 mol%) was added. Then, Ni(acac)2(0.1 mL, 0.01 mmol, 0.1
M in THF, 0.5 mol%) was added. After the addition of the corresponding benzylic zinc reagent (2.40 mmol, 1.2 equiv), the reaction mixture was warmed to 60 °C and stirred for the given time until GC-analysis showed full conversion of the electrophile. The reaction mixture was quenched with sat. aq. NH4Cl solution and extracted with Et2O (3 times). The combined organic phases were dried over MgSO4and the solvent was removed in vacuo. The product was purified by flash column chromatography.
C. Experimental Section 115 2.6. Typical procedure for the Pd-catalyzed cross-coupling reaction with a bromo-aniline
(TP6)
A dry and argon flushed Schlenk-flask, equipped with a magnetic stirring bar and a septum, was charged with the bromo-aniline (1.0 equiv), Pd(OAc)2 (1 mol%), S-Phos (2 mol%) and THF.
After stirring the reaction mixture for 5 min, the zinc reagent was added. The reaction mixture was stirred for the given time at 25 °C. Then, the reaction mixture was quenched with a sat. aq.
NH4Cl solution, extracted with Et2O (3 times). The combined organic phases were washed with an aq. thiourea solution and dried over MgSO4. Purification of the crude residue obtained after evaporation of the solvents by flash column chromatography yielded the desired product.
2.7. Typical procedure for the Pd-catalyzed cross-coupling reaction with a bromo-alcohol (TP7)
A dry and argon flushed Schlenk-flask, equipped with a magnetic stirring bar and a septum, was charged with the bromo-alcohol (1.0 equiv), Pd(OAc)2 (1 mol%), S-Phos (2 mol%) and THF.
After stirring the reaction mixture for 5 min, the zinc reagent was added slowly over 90 min using a syringe pump at 25 °C. Then, the reaction mixture was quenched with a sat. aq. NH4Cl solution, extracted with Et2O (3 times). The combined organic phases were washed with an aq.
thiourea solution and dried (MgSO4). Purification of the crude residue obtained after evaporation of the solvents by flash chromatography yielded the desired product.
2.8. Typical procedure for the one-pot Negishi cross-coupling reaction (TP8)
A Schlenk-flask, equipped with a magnetic stirring bar and a septum, was charged with LiCl (1.5 equiv). The flask was heated with a heat gun (400 °C) for 10 min under high vacuum. After cooling to 25 °C, the flask was flushed with argon (3 times). Zinc dust (1.5 equiv) was added followed by THF. 1,2-Dibromoethane was added (5 mol%) and the reaction mixture was heated to ebullition for 15 s. After cooling to 25 °C, trimethylsilyl chloride (1 mol%) was added and the mixture was heated to ebullition for 15 s. The benzylic chloride (1.0 equiv) was added at the required temperature (usually 25 °C) as a solution in THF (usually 4 M). When capillary GC analysis of a hydrolyzed aliquot containing an internal standard showed a conversion of > 98%, the aromatic bromide was added, followed by PEPPSI-IPr. The reaction mixture was stirred at 25 °C until GC analysis of a hydrolyzed aliquot containing an internal standard showed a conversion of > 98%. Then, sat. aq. NH4Cl solution was added (20 mL). The phases were
C. Experimental Section 116 separated and the aq. layer was extracted with CH2Cl2 (3 x 20 mL). The combined extracts were dried over MgSO4. Evaporation of the solvents in vacuo and purification by flash chromatography afforded the expected diarylmethanes.
2.9. Typical procedure for preparation of benzylic zinc chlorides by magnesium insertion in the presence of ZnCl2 and LiCl (TP9)
A dry and argon-flushed Schlenk-flask, equipped with a magnetic stirring bar and a septum, was charged with magnesium turnings (122 mg, 5.00 mmol). LiCl (5.00 mL, 2.50 mmol, 0.5 M in THF) and ZnCl2 (2.20 mL, 2.20 mmol, 1.00 M in THF) were added. The benzylic chloride (2.00 mmol) was added in one portion at the given temperature. The reaction mixture was stirred for the given time and then canulated to a new Schlenk-flask for the reaction with an electrophile.
2.10. Typical procedure for the addition of organomagnesium reagents to carbonyl derivatives in the presence of variable amounts of LaCl3·2LiCl (TP10)
A dry and argon-flushed Schlenk-flask, equipped with a magnetic stirring bar and a septum, was charged with the carbonyl derivative (1 equiv) in LaCl3·2LiCl solution (1 equiv) and the reaction mixture was stirred for 1 h. Then, the organomagnesium reagent (1.1 equiv) was added dropwise at 0 °C. The reaction mixture was stirred for the given time at the required temperature until GC-analysis of a quenched reaction aliquot showed complete conversion. Then, the reaction mixture was cooled to 0 °C and quenched with sat. aq. NH4Cl solution and extracted with Et2O (3 times).
The combined organic phases were dried over Na2SO4. Evaporation of the solvents in vacuo and purification by flash column chromatography afforded the expected alcohols.
2.11. Typical procedure for the preparation of zinc reagents using Mg and ZnCl2/LiCl solution (TP11)
A dry and argon-flushed Schlenk-flask, equipped with a magnetic stirring bar and a septum, was charged with magnesium turnings (2.5 equiv). Then, ZnCl2/LiCl (1.1/1.5 M) solution was added (1 mL / mmol for the preparation of organozinc reagents of type RZnX·MgX2·LiCl (X = Cl, Br);
0.5 mL / mmol for the preparation of diorganozinc reagents of type R2Zn·2MgX2·LiCl (X = Cl, Br)). The organic halide (1.0 equiv) was added dropwise as a solution in THF using a water cooling bath to keep the temperature below 30 °C. The reaction mixture was stirred for the given time until GC-analysis of a quenched reaction aliquot showed complete conversion. Then, the
C. Experimental Section 117 supernatant solution was carefully cannulated to a new dry and argon-flushed Schlenk-flask through a syringe filter. The concentration of the zinc reagent was determined by iodometric titration.
2.12. Typical procedure for the addition of organozinc reagents of type RZnX·MgX2·LiCl or diorganozinc reagents of type R2Zn·2MgX2·LiCl to carbonyl derivatives (TP12) A dry and argon-flushed Schlenk-flask, equipped with a magnetic stirring bar and a septum, was charged with the carbonyl derivative (1.5 mmol) in THF (1 mL). Then, the organozinc reagent RZnX·MgX2·LiCl (1.8 mmol, 1.2 equiv; X = Cl, Br) or the diorganozinc reagent R2Zn·2MgX2·LiCl (0.9 mmol, 0.6 equiv; X = Cl, Br) was added dropwise. The reaction mixture was stirred for the given time until GC-analysis of a quenched reaction aliquot showed complete conversion. Then, the reaction mixture was cooled to 0 °C and quenched with sat. aq. NH4Cl solution and extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over MgSO4. Evaporation of the solvents in vacuo and purification by flash column chromatography afforded the expected products.
2.13. Typical procedure for the addition of organozinc reagents to carbon dioxide (TP13) A Schlenk-flask, equipped with a magnetic stirring bar and a septum, was flame-dried under high vacuum. After cooling to 25 °C, the flask was filled with dry CO2(g) and the organozinc reagent (typically 1.0 mmol for Ar2Zn or (ArCH2)2Zn) was added. Then, dry CO2(g) was bubbled through the reaction mixture (ca. 5 min) until a balloon attached to the reaction flask by a short length rubber tubing and a needle adapter was inflated. The reaction mixture was stirred for the given time and temperature until the zinc reagent had been completely consumed (quenching of reaction aliquots with I2 and GC-analysis). The reaction mixture was diluted with Et2O (20 mL) and sat. aq. NaHCO3 (30 mL) was added. After filtration, the organic phase was separated and extracted with sat. aq. NaHCO3 (3 x 30 mL). The combined aq. phases were carefully acidified with HCl (5 M) until pH < 5 and extracted with Et2O (3 x 100 mL). The combined organic phases were dried over Na2SO4. Evaporation of the solvents in vacuo provided the corresponding carboxylic acids.
C. Experimental Section 118 2.14. Typical procedure for the Pd-catalyzed cross-coupling reaction of organozinc
reagents with methylthio-substituted N-heterocycles (TP14)
In a dry argon-flushed Schlenk flask, equipped with a magnetic stirring bar and a septum, the aromatic thioether (1.00 mmol), Pd(OAc)2 (2.5 mol%) and S-Phos (5.0 mol%) were dissolved in THF (1 mL). After 10 min of stirring, the zinc reagent (1.5 mmol) was added dropwise and the reaction mixture was stirred for the given time at the required temperature until GC-analysis of a hydrolyzed aliquot showed full consumption of the electrophile. The reaction mixture was quenched with sat. aq. Na2CO3 solution and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over Na2SO4.Evaporation of the solvents in vacuo and purification by flash column chromatography afforded the expected products.
2.15. Typical procedure for the Ni-catalyzed cross-coupling reaction of organozinc reagents with methylthio-substituted N-heterocycles (TP15)
In a dry argon-flushed Schlenk flask, equipped with a magnetic stirring bar and a septum, the aromatic thioether (1.00 mmol), Ni(acac)2 (2.5 mol%) and DPE-Phos (5.0 mol%) were dissolved in THF (1 mL). After 10 min of stirring, the zinc reagent (1.5 mmol) was added dropwise and the reaction mixture was stirred for the given time at 25 °C until GC-analysis of a hydrolyzed aliquot showed full consumption of the electrophile. The reaction mixture was quenched with sat. aq.
Na2CO3 solution and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over Na2SO4. Evaporation of the solvents in vacuo and purification by flash column chromatography afforded the expected products.
C. Experimental Section 119