In Situ Preparation and Use of Fe/ppm Pd NPs for Sonogashira Couplings.
In a flame-dried 4 mL microwave reaction vial, pure FeCl 3 (4.1 mg, 5 mol%) and XPhos (7.1 mg,
3 mol%) were added under anhydrous conditions. The reaction vial was sealed with a rubber
septum, and the mixture was evacuated and backfilled with argon. Dry THF (1.0 mL) was added to
the vial, and Pd(OAc) 2 (500 ppm) was then added using a 5 mM solution of Pd(OAc) 2 in dry THF.
Then the mixture was stirred for 20 min at rt. after which dissolution and complexation of iron
chloride was clearly visualized by a color change to dark brown. While maintaining an inert
atmosphere, THF was evaporated under reduced pressure at rt. MeMgBr (0.25 mL, 10 mol%,
0.2 M) was added to the reaction mixture, after which it was stirred at rt. for 1 min. An aqueous
solution of 2 wt% TPGS-750-M (1.0 mL) was added to the vial followed by sequential addition of
an aryl halide (0.5 mmol, 1.0 equiv), alkyne (0.75 mmol, 1.5 equiv), and Et 3 N (101 mg, 1.0 mmol,
2.0 equiv). The reaction vial was sealed with a rubber septum under argon and stirred at 45
C until
complete consumption of starting material as monitored by TLC or GCMS. The reaction mixture
was then allowed to cool to rt, and EtOAc (1.0 mL) was added and the mixture stirred gently for
1 min. The organic layer was allowed to separate from the aqueous layer with the help of a
centrifuge, if needed. The organic layer was decanted using a pipette. The same extraction
procedure was applied by using an additional 1.0 mL EtOAc. The combined organic extracts
were dried over anhydrous Na 2 SO 4 . Volatiles were removed under reduced pressure to obtain crude
product, which were further purified by flash chromatography over silica gel using EtOAc/hexanes
as eluent.
During the screening of optimized reaction parameters for Fe/ppm Pd NP
catalyzed cross-couplings, it was noted that in the absence of a phosphine ligand
and with NaBH 4 serving as reductant, catalyst activity toward C-C bond formation
was retarded in favor of reduction of nitro groups within aromatic or heteroaromatic
substrates to their corresponding anilines [17]. Reductions of this functional
group proceed smoothly at room temperature and pressure with only 80 ppm
Fig. 3 Fe/ppm-Pd NPs used in the synthesis of a ponatinib intermediate
Earth-Abundant and Precious Metal Nanoparticle Catalysis
81
In a flame-dried 4 mL microwave reaction vial, pure FeCl 3 (4.1 mg, 5 mol%) and XPhos (7.1 mg,
3 mol%) were added under anhydrous conditions. The reaction vial was sealed with a rubber
septum, and the mixture was evacuated and backfilled with argon. Dry THF (1.0 mL) was added to
the vial, and Pd(OAc) 2 (500 ppm) was then added using a 5 mM solution of Pd(OAc) 2 in dry THF.
Then the mixture was stirred for 20 min at rt. after which dissolution and complexation of iron
chloride was clearly visualized by a color change to dark brown. While maintaining an inert
atmosphere, THF was evaporated under reduced pressure at rt. MeMgBr (0.25 mL, 10 mol%,
0.2 M) was added to the reaction mixture, after which it was stirred at rt. for 1 min. An aqueous
solution of 2 wt% TPGS-750-M (1.0 mL) was added to the vial followed by sequential addition of
an aryl halide (0.5 mmol, 1.0 equiv), alkyne (0.75 mmol, 1.5 equiv), and Et 3 N (101 mg, 1.0 mmol,
2.0 equiv). The reaction vial was sealed with a rubber septum under argon and stirred at 45
C until
complete consumption of starting material as monitored by TLC or GCMS. The reaction mixture
was then allowed to cool to rt, and EtOAc (1.0 mL) was added and the mixture stirred gently for
1 min. The organic layer was allowed to separate from the aqueous layer with the help of a
centrifuge, if needed. The organic layer was decanted using a pipette. The same extraction
procedure was applied by using an additional 1.0 mL EtOAc. The combined organic extracts
were dried over anhydrous Na 2 SO 4 . Volatiles were removed under reduced pressure to obtain crude
product, which were further purified by flash chromatography over silica gel using EtOAc/hexanes
as eluent.
During the screening of optimized reaction parameters for Fe/ppm Pd NP
catalyzed cross-couplings, it was noted that in the absence of a phosphine ligand
and with NaBH 4 serving as reductant, catalyst activity toward C-C bond formation
was retarded in favor of reduction of nitro groups within aromatic or heteroaromatic
substrates to their corresponding anilines [17]. Reductions of this functional
group proceed smoothly at room temperature and pressure with only 80 ppm
Fig. 3 Fe/ppm-Pd NPs used in the synthesis of a ponatinib intermediate
Earth-Abundant and Precious Metal Nanoparticle Catalysis
81