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In This Article

  • Summary
  • Abstract
  • Introduction
  • Protocol
  • Results
  • Discussion
  • Disclosures
  • Acknowledgements
  • Materials
  • References
  • Reprints and Permissions

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, too2,3. The reaction requires a base, which activates the boronic compound. Usually, the solvent is a polar aprotic liquid, but it is possible to run the reaction with high yields in ionic liquids or water as well4. It is not always necessary, but heating or increasing the pressure provides better conversions5. Suzuki cross-coupling reactions proceed with high stereo- and regioselectivity6.

Nowadays, the green chemistry concept that is the necessity of searching and finding new pathways, methods, and techniques is spreading. These allow enhancement of the safety and decrease of the hazards of chemical syntheses. At the same time, there is a need to use renewable feedstocks and catalysts, safer solvents and auxiliaries. From the green chemical point of view, new efforts in research and developments, among others, should focus on preventing pollution, achieving better atom economy, and reducing the number of derivatives7.

Several efforts have been made to carry out Suzuki and other cross-coupling reactions under green and sustainable conditions8,9,10,11,12,13. Propylene carbonate is a green, polar aprotic solvent, which is an excellent choice for Suzuki reactions14,15. The dioxolane ring is prepared from carbon dioxide and propylene oxide (Figure 1)16,17. There is a great opportunity to decrease the greenhouse effect and related global warming by fixing atmospheric carbon dioxide. That is why propylene carbonate is called a carbon dioxide neutral solvent. Unfortunately, the alternative ethylene carbonate is solid at room temperature but is still suitable for reactions, in order to obtain colloidal Pd nanoparticles in the reaction mixtures. Ethylene carbonate serves as a unique solvent for the Wacker oxidation of higher alkenes and aryl alkenes has been successfully developed using molecular oxygen as the sole oxidant, in which colloidal Pd nanoparticles stabilized in ethylene carbonate are considered to facilitate its reoxidation under cocatalyst-free conditions18. Ethylene carbonate proved their effectiveness in the investigation of carboxylation of terminal alkynes at ambient CO2 pressure too19. In contrast, propylene carbonate is liquid at room temperature with a very high boiling point of 242 °C14,16. For instance the propylene carbonate tolerates the presence of Pd catalyst as well the ethylene carbonate does20. The GlaxoSmithKline solvent sustainability guide mentions propylene carbonate as one of the greenest choices, because of its low carcinogenicity, mutagenicity, volatility, flammability, and explosiveness21. Propylene carbonate proved its effectiveness in Suzuki, Heck, and Sonogashira couplings as well as in hydrogenation, oxidation, acylation, and amination15,22,23,24. The use of propylene carbonate allows to increase the temperature of the Suzuki reaction (typical temperatures are around 100 °C or lower) and, in the meantime, decrease reaction time. The solvent is environmentally benign in heterogeneous catalytic microwave-assisted synthetic reactions as well25,26. Unfortunately if the reaction mixture contains nucleophiles, propylene carbonate undergoes ring opening and 2-hydroxypropylation occurs27. Nevertheless, this ring-opening reaction allowed the isolation of several novel compounds. Consequently, propylene carbonate is not only a solvent but also a prominent green 2-hydroxypropylation reagent (Figure 2).

The use of the highly efficient and power-saving microwave reactor leads to shorter reaction times and better yields (Figure 3)28,29,30. The benefit is self-evident: heating 1 L of water from room temperature to its boiling point by using only 190 Wh electric power takes 4.7 min in a microwave reactor in comparison to 22 min using traditional oil-bath heating31. Selecting polar solvents to react under microwave irradiation is advantageous, because the polar medium transmits microwaves more efficiently, resulting in more effective heat convection, according to Leadbeater et al.32. The yields of Suzuki reactions in water as solvent, in the presence of phase transfer catalysts (e.g., tetrabutylammonium bromide), are between 14% to 96%33,34,35,36. Moreover, there is a possibility to enhance reaction yields in such greener solvents, for instance polyethylene glycol37 or water38 for microwave supported reactions.

This work focused on the comparison of two different heating ways (oil bath and microwave irradiation) in Suzuki cross-coupling reactions in the presence of propylene carbonate. The examination covered three iodoaryl compounds (2-iodopyridine, 4-iodopyridine and 6-iodopyridazin-3(2H)-one) and four organoboronic acids (2-naphthylboronic, phenylboronic, 4-biphenylboronic, and 4-fluorophenylboronic acid) (Figure 4). For the sake of comparison, the catalyst, in all cases, was tetrakis(triphenylphosphine)palladium(0), and disodium carbonate was used as the base. Substrate 6-iodopyridazin-3(2H)-one is not commercially available and, consequently, it was synthesized in two steps from 3,6-dichloropyridazine, which is a commercial product. The chlorine atoms were substituted with iodine in the presence of aqueous hydrogen iodide39,40, followed by alkaline hydrolysis of the formed 3,6-diiodopyridazine41,42 in order to obtain 6-iodopyridazin-3(2H)-one (Figure 5). In the presence of disodium carbonate as base, the hydrogen, attached to the nitrogen of 6-iodopyridazin-3(2H)-one, acidic enough to create a nucleophile and open the propylene carbonate ring. This results in the formation of 2-(2-hydroxypropyl)-6-iodopyridazin-3(2H)-one intermediate (Figure 6), which is still a suitable material for Suzuki cross-coupling reactions43.

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 the reaction mixture onto ice, neutralize it with sodium hydroxide, and filter the precipitated solid material.
  6. Wash the precipitate with 2 x 50 mL of water and twice with 2 x 50 mL of aqueous sodium thiosulfate.
  7. Recrystallize the resulting solid product from 100 mL of ethyl acetate.

2. Producing 6-iodopyridazin-3(2H)-one

  1. To produce 6-iodopyridazin-3(2H)-one, pour 58 mL of 8% aqueous sodium hydroxide in a 250 mL round-bottomed flask.
  2. Add carefully 9.36 g of 3,6-diiodopyridazine to the solution.
  3. Heat and stir the reaction mixture for 2 h on a heating plate with magnetic stirring in oil bath. Keep the oil bath temperature between 120–130 °C.
  4. After 2 h of heating and stirring, cool down the reaction mixture to room temperature.
  5. After cooling, pour the reaction mixture onto ice, neutralize it with 50% aqueous acetic acid, and filter the precipitated solid material.
  6. Wash the precipitate with 2 x 30 mL water.
  7. Recrystallize the resulting product from 70 mL of ethyl acetate.

3. Producing biaryls in round-bottom flask

  1. To produce biaryls with Suzuki cross-coupling reaction under conventional circumstances, take a 50 mL round-bottomed flask and put it into the oil bath. Cover both the flask and the oil bath from the outside with aluminum tinfoil to protect the reaction mixture from light.
  2. Fill the round-bottomed flask with argon gas to avoid the oxidation of the reaction mixture.
    NOTE: Ensure inert gas atmosphere for the whole reaction time.
  3. Pour 5 mL of propylene carbonate as solvent into the flask. Pour 2 mL of 0.5 M (1 equiv.) disodium carbonate as base into the flask.
  4. Add 58 mg (0.05 equiv.) of tetrakis(triphenylphosphine)palladium(0) catalyst into the flask.
  5. Choose an iodoaryl substrate.
    1. To produce 2-arylpyridines, inject 0.11 mL (1 equiv.) of 2-iodopyridine into the flask.
    2. To produce 4-arylpyridines, add 205 mg (1 equiv.) of 4-iodopyridine into the flask.
    3. To produce 6-arylpyridazinones, add 222 mg 6-iodopyridazin-3(2H)-one (1 equiv.) into the flask.
  6. Choose a boronic acid compound and add 1.25 equiv. (e.g., 152 mg of phenylboronic acid) into the flask.
  7. Heat and stir the reaction mixture for 1 h on a heating plate with magnetic stirring in oil bath. Keep the oil bath temperature between 120–130 °C.
  8. After 1 hour of heating, remove the flask from the oil bath and take a 20-μL sample from the reaction mixture in a small test tube.
    NOTE: The reaction mixture is hot. For better safety, keep the flask at room temperature for a few minutes. It helps to avoid the evaporation of the volatile compounds as well.
  9. Take the sample and use thin layer chromatography (e.g., in pure chloroform) to follow the progress of the reaction.
    NOTE: The choice of the eluent depends on the polarity of the reaction materials. Choose a suitable system to detect how many compounds are in the reaction mixture.
    1. If the reaction mixture still contains unreacted iodoaryl starting material (the limiting reagent), then put back the flask into the oil and continue the heating.
    2. If the reaction mixture DOES NOT contain iodoaryl starting material (the limiting reagent), then the reaction is complete. Terminate the heating and cool down the reaction mixture to room temperature.
  10. To isolate the crude product, neutralize the reaction mixture with a few drops of 5% sulfuric acid and extract it with 5 x 20 mL chloroform. Wash the combined organic phases with 3 x 15 mL 10% copper sulfate solution.
  11. Dry the combined organic phase over sodium sulfate, filter, and remove the solvent under reduced pressure to obtain the crude product.
  12. To remove the residues of propylene carbonate, lyophilize the crude product for a night in a lyophilization device at 1333 Pa (10 mmHg) and –50 °C.
  13. To isolate the pure product(s), purify the crude material on column chromatography with gradient elution. Condition the column with neat chloroform, then separate the products by increasing the polarity of chloroform:ethyl acetate from 5:1 to 1:1.
  14. Analyze the collected fractions with thin layer chromatography and combine the product-containing fractions. Remove the solvents under reduced pressure to obtain the pure biaryl compound.

4. Producing biaryls in the microwave reactor

  1. To produce biaryls with Suzuki cross-coupling reaction in the microwave reactor, take an 80 mL reaction vial.
    NOTE: The microwave reactor provides a sealed reaction space. There is no need to protect the reaction mixture from light because the microwave device blocks the photons from the environment.
  2. Pour 5 mL of propylene carbonate as solvent into the vial. Pour 2 mL of 0.5 M (1 equiv.) disodium carbonate as base into the vial.
    NOTE: Remove the reaction vial from the microwave device to avoid the damage if a reagent spills accidentally.
  3. Add 58 mg (0.05 equiv.) of tetrakis(triphenylphosphine)palladium(0) catalyst into the vial.
  4. Select an iodoaryl substrate.
    1. To produce 2-arylpyridines, inject 0.11 mL (1 equiv.) of 2-iodopyridine into the vial.
    2. To produce 4-arylpyridines, add 205 mg (1 equiv.) of 4-iodopyridine into the vial.
    3. To produce 6-arylpyridazinones, add 222 mg 6-iodopyridazin-3(2H)-one (1 equiv.) into the vial.
  5. Select a boronic acid compound and add 1.25 equiv. (e.g., 152 mg phenylboronic acid) into the vial.
  6. Put the reaction vial into the device. Run both the original software and the air jet cooling.
    1. Use the dynamic method to control the temperature by infrared detection under the following conditions: 5 min ramp rime, 130 °C temperature, 60 min hold time, maximum pressure 200 psi (1.38 MPa), and 300 W power. Run the method.
    2. After completion of the reaction, cool down the vial to 50 °C by air jet cooling.
  7. After air jet cooling, take a 20-μL sample from the reaction mixture in a small test tube.
  8. Take the sample and use thin layer chromatography (e.g., in pure chloroform) to follow the progress of the reaction.
    NOTE: The choice of the eluent depends on the polarity of the reaction materials. Choose a suitable system to see how many compounds are in the reaction mixture (e.g., chloroform: ethyl acetate = 2:1).
    1. If the reaction mixture still contains unreacted iodoaryl starting material (the limiting reagent), then put back the vial into the microwave reactor and run the method for an additional hour.
    2. If the reaction mixture DOES NOT contain iodoaryl starting material (the limiting reagent), then the reaction is complete. Cool down the reaction mixture to room temperature. Turn off both the microwave device and the air jet cooling.
  9. To isolate the crude product, neutralize the reaction mixture with a few drops of 5% sulfuric acid and extract it with 5 x 20 mL chloroform. Wash the combined organic phases with 3 x 15 mL 10% copper sulfate solution.
  10. Dry the combined organic phase over sodium sulfate, filter, and remove the solvent under reduced pressure to obtain the crude product.
  11. To remove the residues of propylene carbonate, lyophilize the crude product for a night in a lyophilization device at 1333 Pa (10 mmHg) and -50 °C.
  12. To isolate the pure product(s), purify the crude material by column chromatography with gradient elution. Condition the column with neat chloroform, and then separate the products by increasing the polarity of chloroform:ethyl acetate from 5:1 to 1:1.
  13. Analyze the collected fractions with thin layer chromatography and combine the product-containing fractions. Remove the solvents under reduced pressure to obtain the pure biaryl compound.

5. NMR spectroscopy

  1. To investigate the structure of the produced products with nuclear magnetic resonance spectroscopy. In order to make an NMR sample, dissolve 10 mg of the isolated product in a tube in 0.6 mL deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-d6) and transfer the sample into a 5-mm NMR sample tube.
    1. For 1H NMR measurement use 24 K data points, 2.0 s acquisition time and 6400 Hz sweep width.
    2. For 13C NMR measurement use 62 K data points and 24000 Hz sweep width.

6. High-performance liquid chromatography

  1. To measure the purity of the products or estimate the yield from the crude product without conventional column chromatography, use HPLC.
    1. Dissolve 10 mg of the corresponding crude product in 10 mL acetonitrile to have 1 mg/mL concentration.
    2. Dilute the solution with water to 10 μg/mL concentration.
    3. Temperate the HPLC column to 40 °C.
    4. Prepare two eluents (water and acetonitrile) for the separation. Acidify both eluents with formic acid or trifluoracetic acid. Use gradient elution (95– > 0% water and 5– > 100% acetonitrile, 8 min). Condition the system with the eluents.
    5. Inject 10 μL to the flow.
  2. To detect the products, use mass spectroscopy (MS) or diode array detection (DAD).
    1. In the case of MS detection, use electrospray ionization (ESI) with drying gas 15 L/min, nebulizing gas 1.5 L/min and ESI 10 000 V. In the case of DAD detection, the investigated range should be between the wavelengths of 210–400 nm.

Results

The synthesis of 3,6-diiodopyridazine from 3,6-dichloropyridazine gave a product yield of 70%. The following step, the production of 6-iodopyridazin-3(2H)-one from 3,6-diiodopyridazine afforded 78% yield. The examination has not focused on optimizing these reactions, but we modified the original method and had better yields than those in the literature. However, there are possibilities to enhance the efficiency of the synthesis by varying reaction times, temperatures, and the solvents used. Changing these condit...

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...

Disclosures

The authors have nothing to disclose.

Acknowledgements

The work was supported by the Department of Organic Chemistry, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary.

Materials

NameCompanyCatalog NumberComments
2-iodopyridineTCII0533
2-naphthylboronic acidLancaster480134
3,6-dichloropyridazineAlfa AesarA14795
4-biphenylboronic acidAlfa AesarB23703
4-fluorophenylboronic acidLancaster417556
4-iodopyridineTCII0673
acetic acidLabChemLC10290250% aqueous
acetonitrileSigma Aldrich34998for HPLC
argonSigma Aldrich295000
chloroformSigma Aldrich319988
column chromatographyMerck109385Kieselgel 60F (0.040–0.063 nm mesh)
copper sulfateSigma Aldrich209198
disodium carbonateSigma Aldrich223530
ethyl acetateSigma Aldrich319902
formic acidSigma Aldrich33015
hot plateIKA3810000
HPLC columnAgilent959963-302Zorbax Eclipse Plus C18, 3 mm×150 mm, 3.5 µm
HPLC deviceAgilentLC MSD 1100 High Performance Liquid Chromatograph
hydrogen iodideAlfa AesarL1041057% aqueous
lyophilization deviceLabConco7558000LYPH-Lock 1L lyophilizer
microwave reactorCEMDiscover SP
NMR spectroscopy deviceVarianMercury Plus
phenylboronic acidAlfa AesarA14257
propylene carbonateSigma Aldrich8.07051
sodium hydroxideSigma Aldrich221465
sodium thiosulfateSigma Aldrich217247
sulfuric acidSigma Aldrich25810595-98%
tetrakis(triphenylphosphine)palladium(0)FluoroChem34279
thin layer chromatographyMerck105735Kieselgel 60F254
trifluoracetic acidSigma Aldrich302031for HPLC

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