Examination of Propylene Carbonate as a Sustainable Green Solvent for Suzuki Cross-Coupling Reactions under Microwave and Conventional Circumstances

Summary

Propylene carbonate has been shown to be a prominent green solvent in Suzuki cross-coupling reactions. Furthermore, the microwave reactor is demonstrated to afford enhanced reaction yields with decreasing reaction times. Using either a microwave reactor or conventional heating, propylene carbonate is sustainable for the cross-coupling reaction.

Abstract

The Suzuki cross-coupling reaction is one of the most used transformations in drug research. Propylene carbonate is a sustainable green solvent in cross-coupling reactions with high yields. The solvent is safe and environmentally benign because its production involves the fixation of atmospheric carbon dioxide. Reducing the greenhouse effect by removing harmful carbon dioxide from the air contributes to the deceleration of global warming. Propylene carbonate is a less toxic, less flammable, and less explosive solvent than the traditionally used tetrahydrofuran, 1,4-dioxane or benzene. Because of its high boiling point, there are numerous possibilities to use propylene carbonate in reactions: conventional heating in round-bottom flasks, microwave reactors, flow reactors, etc. Nevertheless, propylene carbonate is not stable enough and undergoes partial ring opening in the presence of a base in the reaction mixture. This examination addresses not only the scope and limitation of propylene carbonate as a solvent, but also includes the comparison of microwave reactor conditions with conventional heating. Using microwave heating instead of conventional heating leads to better yields and shorter reactions. In a microwave reactor, there is also the possibility to increase the pressure. That is, microwaves facilitate reactions, which do not reach high conversions at atmospheric pressure, but may provide better results at higher pressure range.

Introduction

The purposes of the investigation are remodeling, renewing, and optimizing the conditions of Suzuki cross-coupling reactions, with a major focus on green chemistry, including the comparison of microwave heating and traditionally used oil-bath heating.

The Suzuki reaction is a palladium-catalyzed cross-coupling of organoboranes with organic halides, triflates or perfluorinated sulfonates¹. Subsequently, the reagent scope of organoboranes expanded from aryls to alkyls, alkenyls, and alkynyls, too^2,3. The reaction requires a base, which activates the boronic com....

Protocol

1. Producing 3,6-diiodopyridazine

1. To produce 3,6-diiodopyridazine, pour 90 mL of 57% aqueous hydrogen iodide in a 250 mL round-bottomed flask.
2. Add carefully 6 g of 3,6-dichloropyridazine to the solution.
3. Heat and stir the reaction mixture for 5 h on a heating plate with magnetic stirring in oil bath. Keep the oil bath temperature between 120–130 °C.
4. After heating and stirring for 5 hours, cool down the reaction mixture to room temperature.
5. After cooling, pour.......

Discussion

The preparation of 6-iodopyridazin-3(2H)-one from 3,6-dichloropyridazine, through the 3,6-diiodopyridazine intermediate is a user-friendly reaction, but the expected product is not formed with good yields without heating for 5 h. The protocol contains a step about washing the crude product with aqueous sodium thiosulfate. In this step, the monoiodo by-products are removed. There is a possibility to combine the two synthesis steps, because product 3,6-diiodopyridazine is not needed. This study did not focus on op.......

Materials

Name	Company	Catalog Number	Comments
2-iodopyridine	TCI	I0533
2-naphthylboronic acid	Lancaster	480134
3,6-dichloropyridazine	Alfa Aesar	A14795
4-biphenylboronic acid	Alfa Aesar	B23703
4-fluorophenylboronic acid	Lancaster	417556
4-iodopyridine	TCI	I0673
acetic acid	LabChem	LC102902	50% aqueous
acetonitrile	Sigma Aldrich	34998	for HPLC
argon	Sigma Aldrich	295000
chloroform	Sigma Aldrich	319988
column chromatography	Merck	109385	Kieselgel 60F (0.040–0.063 nm mesh)
copper sulfate	Sigma Aldrich	209198
disodium carbonate	Sigma Aldrich	223530
ethyl acetate	Sigma Aldrich	319902
formic acid	Sigma Aldrich	33015
hot plate	IKA	3810000
HPLC column	Agilent	959963-302	Zorbax Eclipse Plus C18, 3 mm×150 mm, 3.5 µm
HPLC device	Agilent		LC MSD 1100 High Performance Liquid Chromatograph
hydrogen iodide	Alfa Aesar	L10410	57% aqueous
lyophilization device	LabConco	7558000	LYPH-Lock 1L lyophilizer
microwave reactor	CEM		Discover SP
NMR spectroscopy device	Varian		Mercury Plus
phenylboronic acid	Alfa Aesar	A14257
propylene carbonate	Sigma Aldrich	8.07051
sodium hydroxide	Sigma Aldrich	221465
sodium thiosulfate	Sigma Aldrich	217247
sulfuric acid	Sigma Aldrich	258105	95-98%
tetrakis(triphenylphosphine)palladium(0)	FluoroChem	34279
thin layer chromatography	Merck	105735	Kieselgel 60F254
trifluoracetic acid	Sigma Aldrich	302031	for HPLC