Chemical Synthesis with Inductively Heated Copper Flow Reactors

Abstract

Inductively heated copper wire inside a flow microreactor can serve as a source for a catalytic copper species that promotes 1,3-dipolar cycloadditions of alkynes with in situ formed azides to yield 1,2,3-triazoles. The same setup was used to carry out decarboxylations of 2-alkynoic acids and for the intramolecular C-O coupling of 2′-bromobiphenyl-2-carboxylic acid.

Key words

click chemistry - copper - heterogeneous catalysis - ­microreactors - inductive heating

References and Notes

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18

Quadrapure TU is commercially available from Sigma-Aldrich.

19

Hazard warning: Aliphatic azides are regarded to be potentially explosive. Not for all azides that can occur as byproducts in the ‘click’ chemistry reactions data are available in the literature. We never encountered any hazards during these studies. However, this observation does not exclude the possibility of explosions.

20

Typical Procedure for Triazole Syntheses
A glass reactor (12 cm length and 8.5 mm internal diameter) was filled with copper wire (ca. 24 g) and incased with the inductor. The reactor (void volume: 2 mL) was connected to the pump and at the outlet side to a scavenger cartridge which was filled with Quadrapure^TM TU. The collection vial was placed behind the scavenger cartridge. The system was flushed with a DMF-H₂O mixture (5:1), and the temperature was adjusted to 100 ˚C. After the flow (flow rate 0.2 mL/min) and temperature values reached a steady state a solution of bromide 4 (0.25 M), phenylacetylene (1, 0.125), and sodium azide (0.25 M, higher concentrations led to blockage of the system due to precipitation) in DMF-H₂O was pumped through the system (residence time approx. 10 min). After collection of the crude product, the mixture was diluted with H₂O, extracted with EtOAc, and dried (MgSO₄). After evaporation of the solvent the crude product was purified by flash chromatography on silica gel to yield compound 5 in quantitative yield as a slightly yellow solid.

25

Typical Procedure for the Catalytic Decarboxylation
A glass reactor (12 cm length and 8.5 mm internal diameter) was filled with copper wire (ca. 24 g) and incased with the inductor. The reactor (void volume: 2 mL) was connected to the pump and at the outlet side to a scavenger cartridge which was filled with Quadrapure^TM TU. The collection vial was placed behind the scavenger cartridge. The system was flushed with MeCN, and the temperature was adjusted to 60 ˚C. After the flow (flow rate 0.1 mL/min) and temperature values reached a steady state a solution of 2-alkynoic acid 13 (0.1 M) in MeCN was pumped through the system (residence time approx. 20 min). After collection of the crude product, the solvent was evaporated in vacuo, and the crude material was purified by flash chromatography on silica gel to yield compound 14 in 93% yield as a yellow oil.

26

Synthesis of Benozopyranone 18
A PEEK reactor (12 cm length and 8.5 mm internal diameter) was filled with copper wire (ca. 24 g) and incased with the inductor. The reactor (void volume: 2 mL) was connected to the pump and on the outlet side to a back pressure device (6.9 bar) which led to a scavenger cartridge which was filled with Quadrapure^TM TU. Behind the scavenger cartridge the collection vial was placed. The system was flushed with DMF, and the temperature was adjusted to 200 ˚C. After the flow (flow rate 0.1 mL/min) and temperature values reached a steady state a solution of bromo acid 17 (0.04 M) in DMF was pumped through the system (residence time approx. 20 min). After collection of the crude product, the mixture was diluted with H₂O, extracted with EtOAc, and dried (MgSO₄). After evaporation of the solvent in vacuo the crude product was purified by flushing through a short pad of silica to yield compound 18 in 95% yield as a pale brownish solid.