This protocol provides a facile route to synthesize a novel bora-ibuprofen derivative with moderate yield in two steps using conventional benchtop chemistry, and without needing a nitrogen filled glove box. The tandem cross-coupling and copper-catalyzed work of oxylation protocols can be applied to various alpha-substituted and unsubstituted styrene derivatives. Purifying bora-ibuprofen using the described aqueous workup can be difficult.
Occasionally, trace and purities will remain after the purification. If necessary, one or more recrystallizations will remove these trace impurities. Begin to synthesize 4-isobutylstyrene via Suzuki cross-coupling by adding palladium tetrakistriphenylphosphine and anhydrous potassium carbonate into a 40-milliliter scintillation vial containing a magnetic stir bar.
Seal the vial with a pressure relief cap and encapsulate the vial seal completely using electrical tape before purging the reaction mixture with argon for two minutes. Then add one bromo-4-isobutylbenzene to the vial followed by anhydrous tetrahydrofuran obtained from a solvent purification system with continuous argon flow, and commence magnetic stirring. Next, add argon sparged deionized water and vinylboronic acid pinacol ester to the reaction mixture.
Purge the reaction mixture with argon for five minutes. Once the purging is over, heat the reaction mixture on a stirring hot plate at 85 degrees Celsius for 24 hours. To ensure completion of the reaction after 24 hours, remove a small aliquot from the reaction mixture.
Dilute it with two milliliters of dichloromethane, and perform thin-layer chromatography using hexane. Upon the confirmation of reactant consumption by TLC, add the reaction mixture to a 125-milliliter separatory funnel, followed by the addition of 30 milliliters of deionized water. Now, perform extraction with five milliliters of dichloromethane three times, and combine the organic extracts into a 125-milliliter Erlenmyer flask.
Discard the aqueous layer. Transfer the combined organic extracts into a 125-milliliter separatory funnel, and wash it with 30 milliliters of brine. After transferring the organic layer into a separate 125-milliliter Erlenmyer flask, mix it with five grams of sodium sulfate and swirl the flask for at least 20 seconds.
Use a Buchner funnel to vacuum filter the solution into a 125-milliliter filter flask. Concentrate the filtrate in a 100-milliliter round bottom flask by applying vacuum until a pale yellow viscous oil is produced. To obtain pure 4-isobutylstyrene, purify the crude product by column chromatography using 100%hexane as the eluent.
To synthesize bora-ibuprofen from 4-isobutylstyrene, add N, N dicyclohexyl-imidazolium chloride and sodium tertiary-butoxide into a 40-milliliter scintillation vial containing a magnetic stir bar. Seal the vial with an airtight septum and immediately purge it with argon for five minutes. Now, using a syringe, add 20 milliliters of anhydrous and degassed tetrahydrofuran into the scintillation vial containing the mixture of ligand and base.
Stir the resulting solution for an additional 30 minutes after purging it with argon for five minutes. Meanwhile, carefully add 119 milligrams of cupric chloride into another 40-milliliter scintillation vial containing a magnetic stir bar. Seal it with an airtight septum and immediately purge the vial with argon for five minutes.
After stirring for 30 minutes, transfer the ligand solution to the scintillation vial containing cupric chloride under a positive argon flow. Stir the resulting solution for one hour to generate the catalyst. In a 500-milliliter round bottom flask containing a magnetic stir bar, Add 5.08 grams of bis(pinacolato)diboron.
Seal the flask properly and add 140 milliliters of THF and 1.8 milliliters of 4-isobutylstyrene into the flask before purging it with argon for five minutes. Then immediately purge the round bottom flask with bone-dry carbon dioxide. Slowly add the catalyst solution into it for about 30 seconds, and continue purging with bone-dry carbon dioxide for 15 minutes before keeping the reaction stirring at ambient temperature for 16 hours.
Upon completion of the reaction, concentrate the mixture for 15 to 30 minutes under vacuum, followed by acidifying it with 30 milliliters of 1-Molar aqueous hydrochloric acid. Then add 50 milliliters of diethyl ether to the acidified reaction mixture and swirl the solution for 10 seconds before transferring it to a 500-milliliter separatory funnel. Separate the organic and aqueous layers and add the aqueous layer to a one-liter Erlenmyer flask.
Extract the organic layer eight times with 50 milliliters of saturated sodium bicarbonate, and transfer the aqueous extracts into a separate one-liter Erlenmyer flask. Slowly and carefully acidify the combined aqueous extract with 12-Molar hydrochloric acid, and transfer the solution to a clean 500-milliliter separatory funnel. Extract the aqueous solution eight times with 50 milliliters of dichloromethane.
Transfer the organic extracts into a clean one-liter Erlenmyer flask, and add 50 grams of sodium sulfate to the organic extract and swirl the flask for 20 seconds. Next, filter the solution through a Buchner funnel and collect it in a clean 1000-milliliter filtration flask before transferring the filtrate to a round bottom flask to concentrate it under vacuum. Dissolve the residue in 10 milliliters of HPLC-Grade heptane, and store it in a 20 degree Celsius freezer overnight to produce pure recrystallized bora-ibuprofen.
The described synthesis protocol reliably produced 4-isobutylstyrene with 89%yield. Whereas the yield for benchtop synthesis of bora-ibuprofen was found to be 59%The proton NMR spectrum of 4-isobutyl styrene showed AMX splitting, a signature of monosubstituted styrene derivatives. The resonances appeared as a doublet at 5.17 ppm, another doublet at 5.69 ppm, and a doublet of doublets at 6.62 to 6.78 ppm.
Another characteristic feature was the isobutylmethane proton appearing as a nonet at 2.37 to 2.52 ppm, with corresponding methyl groups at 0.89 ppm. The nine resonances observed in the 13 C-NMR spectrum of 4-isobutylstyrene were also in good agreement with its structure. The proton-NMR spectrum of bora-ibuprofen showed the characteristic ABX splitting pattern.
The A and B resonances appeared as a doublet of doublets at 1.53 and 1.29 ppm, while the X resonance appeared at 3.82 ppm. The 13-C-NMR spectrum of bora-ibuprofen showed a broad signal at 16 ppm, indicative of a quadrupolar broadened carbon bound to boron. Another significant resonance was at 180.8 ppm corresponding to the carbonyl carbon of the free carboxyl acid group.
The 11-B-NMR spectrum showed a single broad resonance at 33.4 ppm, indicative of a trivalent boronic ester. Properly encapsulating the pressure release of vial cap is important to prevent air or moisture from entering. Also, sufficiently pure grade gaseous carbon dioxide should be used, specifically 99.8%or bone dry.
This technique provides access to unique bora-ibuprofen in similar products that could now be functionalized through the carboxylic acid, or the boron functional groups.
