Synthesis of a Borylated Ibuprofen Derivative Through Suzuki Cross-Coupling and Alkene Boracarboxylation Reactions

Steven W. Knowlden; Randika T. Abeysinghe; Amanda D. Swistok; Alexis C. Ravenscroft; Brian V. Popp

doi:10.3791/64571

JoVE Journal > Chemistry

Chimica

Synthesis of a Borylated Ibuprofen Derivative Through Suzuki Cross-Coupling and Alkene Boracarboxylation Reactions

Published: November 30, 2022

doi:

10.3791/64571

Steven W. Knowlden*¹, Randika T. Abeysinghe*¹, Amanda D. Swistok¹, Alexis C. Ravenscroft¹, Brian V. Popp¹

¹C. Eugene Bennett Department of Chemistry,West Virginia University

Summary

The present protocol describes a detailed benchtop catalytic method that yields a unique borylated derivative of ibuprofen.

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common drugs used to manage and treat pain and inflammation. In 2016, a new class of boron functionalized NSAIDs (bora-NSAIDs) was synthesized under mild conditions via the copper-catalyzed regioselective boracarboxylation of vinyl arenes using carbon dioxide (CO₂ balloon) and a diboron reductant at room temperature. This original method was performed primarily in a glovebox or with a vacuum gas manifold (Schlenk line) under rigorous air-free and moisture-free conditions, which often led to irreproducible reaction outcomes due to trace impurities. The present protocol describes a simpler and more convenient benchtop method for synthesizing a representative bora-NSAID, bora-ibuprofen. A Suzuki-Miyaura cross-coupling reaction between 1-bromo-4-isobutylbenzene and vinylboronic acid pinacol ester produces 4-isobutylstyrene. The styrene is subsequently boracarboxylated regioselectively to provide bora-ibuprofen, an α-aryl-β-boryl-propionic acid, with good yield on a multi-gram scale. This procedure allows for the broader utilization of copper-catalyzed boracarboxylation in synthetic laboratories, enabling further research on bora-NSAIDs and other unique boron-functionalized drug-like molecules.

Introduction

Organoboron compounds have been strategically employed in chemical synthesis for over 50 years¹^,²^,³^,⁴^,⁵^,⁶. Reactions such as hydroboration-oxidation⁷^,⁸^,⁹^,¹⁰, halogenation¹¹^,¹², amination¹³^,¹⁴, and Suzuki-Miyaura cross-coupling¹⁵^,¹⁶^,¹⁷ have led to significant multidisciplinary innovations in chemistry and related disciplines. The Suzuki-Miyaura reactions, for example, account for 40% of all carbon-carbon bond-forming reactions in the pursuit of pharmaceutical drug candidates¹⁸. The Suzuki-Miyaura cross-coupling reaction produces vinyl arenes in one step from the halogenated arene precursor¹⁹. This greener catalytic strategy is valuable relative to traditional Wittig syntheses from aldehydes that have poor atom economy and produce a stoichiometric triphenylphosphine oxide byproduct.

It was predicted that a regioselective hetero(element)carboxylation of vinyl arenes would allow for direct access to novel hetero(element)-containing non-steroidal anti-inflammatory drugs (NSAIDs), utilizing CO₂ directly in the synthesis. However, hetero(element)carboxylation reactions were exceedingly rare and were limited to alkynyl and allenyl substrates prior to 2016²⁰^,²¹^,²². The extension of the boracarboxylation reaction to vinyl arenes would provide boron-functionalized NSAIDs, and boron-based pharmaceutical candidates (Figure 1) have been gaining popularity, as indicated by recent decisions by the FDA to approve the chemotherapeutic bortezomib, the antifungal tavaborole, and the anti-inflammatory crisaborole. The Lewis acidity of boron is interesting from a drug design standpoint due to the capability to readily bind Lewis bases, such as diols, hydroxyl groups on carbohydrates, or nitrogen bases in RNA and DNA, since these Lewis bases play important roles in physiological and pathological processes²³.

This catalytic approach to boracarboxylation relies upon borylcupration of the alkene by a Cu-boryl intermediate, followed by CO₂ insertion into the resulting Cu-alkyl intermediate. Laitar et al. reported the borylcupration of styrene derivatives through the use of (NHC)Cu-boryl²⁴, and the carboxylation of Cu-alkyl species has also been demonstrated²⁵. In 2016, the Popp lab developed a new synthetic approach to achieve mild difunctionalization of vinyl arenes using an (NHC)Cu-boryl catalyst and only 1 atm of gaseous CO₂²⁶. Using this method, the α-aryl propionic acid pharmacophore is accessed in a single step, and a novel unexplored class of boron-modified NSAIDs can be prepared with excellent yield. In 2019, catalytic additives improved the catalyst efficiency and broadened the substrate scope, including the preparation of an additional two novel borylated NSAIDs²⁷ (Figure 1).

Previous boracarboxylation reactions of alkenes could only be achieved under stringent air-free and moisture-free conditions with the use of an isolated N-heterocyclic-carbene-ligated copper(I) precatalyst (NHC-Cu; NHC = 1,3-bis(cyclohexyl)-1,3-dihydro-2H-imidazol-2-ylidene, ICy). A benchtop method wherein borylated ibuprofen can be synthesized using simple reagents would be more desirable for the synthetic community, prompting us to develop reaction conditions that allow for the boracarboxylation of vinyl arenes, particularly 4-isobutylstyrene, to proceed from the in situ generation of an NHC-Cu precatalyst and without the need of a glovebox. Recently, a boracarboxylation protocol was reported using imidazolium salts and copper(I)-chloride to generate in situ an active NHC-ligated copper(I) catalyst²⁸. Using this method, α-methyl styrene was boracarboxylated to give a 71% isolated yield of the desired product, albeit with the use of a glovebox. Inspired by this result, a modified procedure to boracarboxylate tert-butylstyrene without using a nitrogen-filled glovebox was devised. The desired boracarboxylated tert-butylstyrene product was produced with 90% yield on a 1.5 g scale. Gratifyingly, this method could be applied to 4-isobutylstyrene to produce a bora-ibuprofen NSAID derivative with moderate yield. The α-aryl propionic acid pharmacophore is the core motif amongst NSAIDs; therefore, synthetic strategies that allow direct access to this motif are highly desirable chemical transformations. Herein, a synthetic pathway to access a unique bora-ibuprofen NSAID derivative from an abundant, inexpensive 1-bromo-4-isobutylbenzene starting material (~$2.50/1 g) with moderate yield in two steps, without the need for a glovebox, is presented.

Protocol

1. Synthesis of 4-isobutylstyrene through Suzuki cross-coupling of 1-bromo-4-isobutylbenzene with vinylboronic acid pinacol ester

Add 144 mg of palladium(0) tetrakistriphenylphosphine (5 mol%, see the Table of Materials), 1.04 g of anhydrous potassium carbonate (2 eq), and a magnetic stir bar (0.5 in x 0.125 in) to a 40 mL scintillation vial, and then seal with a pressure relief cap. Completely encapsulate the vial seal with electrical tape.
1. Purge the reaction mixture with argon for 2 min. After the 2 min, add 1.07 g of 1-bromo-4-isobutylbenzene (1 eq, see Table of Materials), then add 13 mL of anhydrous tetrahydrofuran (THF) obtained from a solvent purification system (or still pot) with continuous argon flow, and then commence magnetic stirring.
  NOTE: Argon gas can be replaced with dry nitrogen gas.
2. Add 1.5 mL of argon-sparged deionized water to the solution, followed by 0.72 mL of vinylboronic acid pinacol ester (1.5 eq, see Table of Materials), and then purge the reaction mixture with argon for an additional 5 min.
3. Once the argon purging is over, heat the reaction mixture at 85 °C for 24 h on a stirring hot plate (see the Table of Materials).
4. After 24 h, remove a small aliquot from the reaction mixture, dilute it with 2 mL of dichloromethane, and then perform thin layer chromatography (TLC, UV visualization) using hexane to ensure reaction completion (R_f = 0.9 reactant, R_f= 0.91 product).
Upon the confirmation of 1-bromo-4-isobutylbenzene consumption, add the reaction mixture to a 125 mL separatory funnel, and then add 30 mL of deionized water.
1. Extract 3x with 5 mL of dichloromethane, add the organic extracts to a 125 mL Erlenmeyer flask (see Table of Materials), and then discard the aqueous layer.
2. Transfer the organic extracts into a 125 mL separatory funnel, wash with 30 mL of brine (an aqueous saturated sodium chloride solution), and discard the brine.
3. Transfer the organic layer to a 125 mL Erlenmeyer flask, then add 5 g of sodium sulfate, and swirl the flask for at least 20 s.
4. Using a Buchner funnel (see Table of Materials), vacuum filter the solution into a 125 mL filter flask.
5. Transfer the organic layer to a 100 mL round-bottom flask, and then concentrate the reaction in a vacuum for 15-30 min (depending on the vacuum strength) to provide a pale yellow viscous oil.
Subject the crude reaction mixture to column chromatography using 50 g of SilicaFlash P60 silica gel (see the Table of Materials) and pure hexane as the eluent to obtain pure 4-isobutylstyrene (1) (Figure 2).
NOTE: For the present study, the yield was 89% (average of three reactions). The 4-isobutylstyrene is subjected to polymerization at room temperature under light, so once isolated, the product must be stored in the dark at or below −20 °C until needed. If necessary, a small amount of butylated hydroxytoluene (BHT) can be added to inhibit polymerization. BHT does not impact the efficiency of copper-catalyzed boracarboxylation.

2. Large-scale synthesis of bora-ibuprofen in a glovebox

NOTE: This reaction was prepared inside a nitrogen-filled glovebox (see the Table of Materials). All the chemicals were dried or purified before moving into the box. The 4-isobutylstyrene was freeze-pump-thawed prior to use. All the vials and glassware were dried and heated in an oven (180 °C) for at least 24 h prior to use. The copper precatalyst (ICyCuCl) was prepared according to a previously published report²⁹.

Add 160 mg of ICyCuCl (5 mol%), 131 mg of triphenylphosphine (5 mol%), 1.92 g of sodium tert-butoxide (2 eq), 20 mL of anhydrous, degassed THF, and a 0.5 in x 0.125 in magnetic stir bar to a 20 mL scintillation vial, then seal with an air-tight septum, and stir the resulting solution for 20 min.
1. After 20 min, transfer the catalyst solution to a 60 mL syringe, and plug the needle into a septum.
2. Add 2.79 g of bis(pinacolato)diboron (1.1 eq), 1.87 mL of 4-isobutylstyrene (1 eq), 140 mL of THF, and a 2 in x 0.3125 in magnetic stir bar to a 500 mL round-bottom flask, seal with a septum, and then tape around the septum until the seal is encapsulated.
Remove the 500 mL round-bottom flask containing the styrene solution and the 60 mL syringe containing the catalyst solution from the glovebox, and move to a fume hood.
NOTE: After preparation, the 500 mL round-bottom flask and catalyst solution syringe must be removed immediately from the glovebox. The styrene substrate is subjected to polymerization in THF, and the catalyst solution decomposes upon standing for a long period of time or upon exposure to air.
1. Begin purging the 500 mL round-bottom flask with carbon dioxide (bone dry) (see the Table of Materials). After 5 minutes, add the catalyst solution over 30 s, purge for an additional 10 minutes, and then stir the reaction at ambient temperature for 3 h.
2. After 3 h, again purge the round-bottom flask with carbon dioxide (bone dry) (see the Table of Materials) for 15 min, and then stir at ambient temperature for 33 h.
Upon reaction completion, concentrate the reaction mixture in a vacuum, and then acidify with 30 mL of aqueous HCl (1.0 M).
1. Add 50 mL of diethyl ether to the round-bottom flask containing the acidified reaction solution, swirl the solution for at least 10 s, transfer the solution to a 500 mL separatory funnel, and separate the organic and aqueous layers by adding the aqueous layer to a 1,000 mL Erlenmeyer flask.
2. Extract the organic layer (8x) with 50 mL of saturated NaHCO₃, and transfer the aqueous extracts to a 1,000 mL Erlenmeyer flask.
3. Acidify the combined aqueous layers in the 1,000 mL Erlenmeyer flask with 12 M HCl (to pH ≤ 1.0 by litmus paper), and transfer the solution to a clean 1,000 mL separatory funnel.
4. Extract the aqueous solution (8x) with 50 mL of dichloromethane, and transfer the organic extracts to a clean 1,000 mL Erlenmeyer flask.
5. Add 50 g of sodium sulfate to the organic extraction solution, and swirl the flask for at least 20 s.
6. Filter the organic extraction solution through a Buchner funnel, and collect it in a clean 1,000 mL filtration flask.
7. Concentrate the reaction in a vacuum for 15-30 min (depending on the vacuum strength) to provide a pale yellow viscous oil.
Dissolve the residue in 10 mL of HPLC-grade heptane, and then store it in a freezer (−20 °C) overnight to produce pure recrystallized bora-Ibuprofen (Figure 1).
NOTE: In the present study, the bora-ibuprofen yield was 62% (average of two reactions).

3. Benchtop large-scale synthesis of bora-ibuprofen

NOTE: This reaction procedure was carried out without using a nitrogen-filled glovebox. All the chemicals were used as received or synthesized without further purification (drying, distilling, etc.). All the vials and glassware were dried and heated in an oven (180 °C) for at least 24 h prior to use and cooled under argon to room temperature immediately before the reaction setup.

Add 334 mg of ICyH•Cl (13 mol%), 2.92 g of sodium tert-butoxide (3 eq), and a 0.5 in x 0.125 in magnetic stir bar to a 20 mL scintillation vial, then seal with an air-tight septum, and immediately purge with argon for 5 min.
1. Add 20 mL of anhydrous, degassed THF via a syringe to the 20 mL scintillation vial containing the ligand and base mixture, purge the resulting solution for 5 min with argon, and then stir for an additional 30 min.
2. Add 119 mg of CuCl (12 mol%) and a 0.5 in x 0.125 in magnetic stir bar to a 20 mL scintillation vial, then seal with an air-tight septum, and immediately purge with argon for 5 min. After stirring the ligand solution (from step 3.1.1) for 30 min, add it to the CuCl scintillation vial under a positive argon flow, and then stir the resulting solution for 1 h.
  NOTE: When weighing out the CuCl, take care to place it directly in the center of the bottom of the scintillation vial, as it tends to get stuck around the inside corner edges of the vial, resulting in poor dissolution in the ligand solution.
Add 5.08 g of bis(pinacolato)diboron (2 eq) and a 2 x 0.3125 in. magnetic stir bar to a 500 mL round-bottom flask and seal with a septum, and then encapsulate the septum seal with black electrical tape. Once sealed, add 140 mL of THF and 1.78 mL of 4-isobutylstyrene (1 eq) to the flask, and then purge with argon for 5 min.
1. Purge the 500 mL round-bottom flask with dry carbon dioxide immediately following the argon purge. Then, add the catalyst solution (from step 3.1.2) for 30 s, continue purging with dry carbon dioxide for 15 min, and then stir the reaction at ambient temperature for 16 h.
Concentrate the reaction mixture for 15-30 min in a vacuum upon reaction completion, and then acidify with 30 mL of aqueous HCl (1.0 M).
1. Add 50 mL of diethyl ether to the round-bottom flask containing the acidified reaction solution, swirl the solution for at least 10 s, transfer the solution to a 500 mL separatory funnel, separate organic and aqueous layers, and add the aqueous layer to a 1,000 mL Erlenmeyer flask.
2. Extract the organic layer (8x) with 50 mL of saturated NaHCO₃, and transfer the aqueous extracts to a 1,000 mL Erlenmeyer flask.
3. Acidify the combined aqueous layers in the 1,000 mL of Erlenmeyer flask with 12 M HCl (to pH ≤ 1.0 by litmus paper), and transfer the solution to a clean 1,000 mL separatory funnel.
4. Extract the aqueous solution (8x) with 50 mL dichloromethane, and transfer the organic extracts to a clean 1,000 mL Erlenmeyer flask.
5. Add 50 g of sodium sulfate to the organic extraction solution, and swirl the flask for at least 20 s.
6. Filter the organic extraction solution through a Buchner funnel, and collect it in a clean 1,000 mL filtration flask. Transfer the filtrate to a round-bottom flask.
7. Concentrate the reaction in a vacuum for 15-30 min (depending on the vacuum strength) to provide a pale yellow viscous oil.
Dissolve the residue in 10 mL of HPLC-grade heptane, and then store it in a freezer (−20 °C) overnight to produce pure recrystallized bora-ibuprofen (Figure 1).
NOTE: For the present study, the yield of bora-ibuprofen was 59%.

Representative Results

The 4–isobutylstyrene was characterized by ¹H and ¹³C NMR spectroscopy. The bora-ibuprofen was characterized by ¹H, ¹³C, and ¹¹B NMR spectroscopy to confirm the product structure and assess the purity. The key data for these compounds are described in this section.

The spectral data are in good agreement with the structure of 4-isobutylstyrene (1) (Figure 2). The ¹H NMR spectrum obtained in CDCl₃ (Figure 3) shows the characteristic AMX splitting pattern seen for monosubstituted styrene derivatives. These resonances are observed as a doublet at 5.17 (d, J = 10.9 Hz, 1H), a doublet at 5.69 (d, J = 17.6 Hz, 1H), and a doublet of doublets at 6.62-6.78 (dd, J = 10.9, 17.6 Hz, 1H). A second characteristic feature is the iso-butyl methine proton, appearing as a nonet at 2.37-2.52 (m, 2H) with corresponding methyl groups at 0.89 (d, J = 6.6 Hz, 6H)³⁰. The nine resonances observed in the ¹³C NMR spectrum agree with literature values³⁰ (Figure 4).

The synthesis of 4-isobutylstyrene via this protocol reliably produces the product with 89% yield (average of three reactions, 5 mmol scale); however, deviation from any of the key reaction conditions, such as the temperature and time, significantly impacts the efficiency of the reaction. The reaction must be heated at no less than 85 °C. The reaction completion must be verified by TLC at or after 24 h.

The spectral data are in good agreement with the structure of the boracarboxylated product (2) (Figure 5). As with the previous substrate, the ¹H NMR spectrum obtained in CDCl₃ (Figure 6) shows an ABX splitting pattern, but this pattern occurs due to diastereotopic methylene protons arising from the newly generated benzylic stereogenic center. The AB resonances are observed as a doublet of doublets at 1.53 (dd, J = 16.0, 9.1 Hz, 1H) and 1.29 (dd, J = 16.0, 7.6 Hz, 1H), while the X resonance is observed at 3.82 (dd, J = 9.1, 7.6 Hz, 1H). The latter resonance is deshielded, which is consistent with a methine proton alpha to two sp² carbons. Another set of significant resonances are at 1.12 (s, 6H) and 1.11 (s, 6H), corresponding to magnetically inequivalent methyl groups on the two sides of the pinacolato boron moiety²⁶.

The ¹³C NMR spectrum of boracarboxylated product 2 (Figure 7) shows a very broad signal at 16 ppm, which is characteristic of a quadrupolar-broadened carbon bound to the boron. Another significant resonance is at 180.8 ppm, corresponding to the carbonyl carbon of the free carboxylic acid group.

The ¹¹B NMR spectrum (Figure 8) shows a single broad resonance at 33.0 ppm, which is characteristic of a trivalent boronic ester.

The synthesis of bora-ibuprofen via this protocol reliably produces the product with 62% yield (average of two reactions, 2.05 g isolated); however, this reaction is far more sensitive than the previous Suzuki cross-coupling reaction. Any deviation from the reported protocol will result in significantly diminished yields. Particular attention needs to be paid to the air-sensitive nature of this reaction. Using the benchtop protocol, the large-scale synthesis of bora-ibuprofen provide the desired product with a 59% yield (1.95 g isolated), comparable to the glovebox method.

Figure 1: Medicinal relevance of organoboron compounds. (A) The carboxylic acid group contains non-steroidal anti-inflammatory drugs. (B) FDA-approved boron-containing pharmaceuticals. (C) Boron-containing NSAID analogs (bora-NSAIDs). Please click here to view a larger version of this figure.

Figure 2: Synthesis of 4-isobutylstyrene (1) via the Suzuki cross-coupling reaction. Please click here to view a larger version of this figure.

Figure 3: ¹H NMR spectrum of 4-isobutylstyrene (1). The ¹H NMR spectrum was obtained in CDCl_3. Please click here to view a larger version of this figure.

Figure 4: ¹³C NMR spectrum of 4-isobutylstyrene (1). Please click here to view a larger version of this figure.

Figure 5: Synthesis of bora-ibuprofen (2) via glovebox and benchtop boracarboxylation methods. The yield of bora-ibuprofen was 62% and 59% by the glovebox and boracarboxylation methods, respectively. Please click here to view a larger version of this figure.

Figure 6: ¹H NMR spectrum of bora-ibuprofen (2). Please click here to view a larger version of this figure.

Figure 7: ¹³C NMR spectrum of bora-ibuprofen (2). Please click here to view a larger version of this figure.

Figure 8: ¹¹B NMR spectrum of bora-ibuprofen (2). Please click here to view a larger version of this figure.

Figure 9: Derivatization of bora-ibuprofen. Please click here to view a larger version of this figure.

Discussion

The 4-Isobutylstyrene (1) was obtained efficiently via a Suzuki cross-coupling reaction from inexpensive, commercially available 1-bromo-4-isobutylbenzene and vinylboronic acid pinacol ester. Compared to the Wittig approach, this reaction allows for the production of the desired styrene in a more environmentally friendly manner and with better atom economy. Reaction monitoring via TLC was crucial to ensure full conversion of the 1-bromo-4-isobutylbenzene substrate because reactions not proceeding to full conversion led to difficult flash chromatographic separation of the substrate and products.

The boracarboxylation of 4–isobutylstyrene with an NHC-copper(I) catalyst at ambient temperature using a pinacolato diboron reductant under an atmosphere of gaseous CO₂ produced bora-ibuprofen (2) with high yield. It is important to note that the styrene must be rigorously freeze-pump-thawed³¹ to ensure no dioxygen remains in the solution, presumably due to copper(I)-aerobic decomposition³², which leads to diminished reactivity and unwanted side products such as formal hydroboration of the styrene. The catalyst must be added to the reaction mixture quickly due to the air-sensitive nature of the catalyst. A tell-tale sign that dioxygen has contaminated the reaction is the evolution of a sky-blue reaction color. Reactions that progress appropriately to high yield will appear cloudy white with a slight pink tint after the addition of the catalyst solution and then will turn to brown and, ultimately, light green after the reaction has been exposed to CO₂ for 3 h or more. The boracarboxylation reaction can tolerate gentle heating up to 45 °C, but higher temperatures lead to diminished yields²⁷.

The reaction cannot be stored for any amount of time and must be immediately purified. The resulting end color of a successful boracarboxylation reaction is either brown or light green. Reactions not immediately purified will turn sky blue owing to copper oxidation with concomitant product decomposition. Product isolation is still possible, but diminished yields will occur. bora-Ibuprofen cannot be isolated by column chromatography of any type (e.g., silica gel, Florisil) and must be isolated following the acid-base workup protocol described above. Once isolated, bora-ibuprofen, as well as many other similar α-aryl-β-boryl proprionic acid derivatives studied thus far, is an air-stable white solid. Trace amounts of diboron reductant often remain after the first acid-base workup. A second acid-base workup followed by the second recrystallization in heptane often removes trace impurities to provide analytically pure products.

The benchtop boracarboxylation method is more convenient and easier to execute than the glovebox method while producing similar reaction outcomes. Nevertheless, there are some known limitations associated with the benchtop method. The reaction must be performed under moisture-free and air-free conditions. In order to further understand moisture sensitivity, a boracarboxylation reaction was performed using the benchtop method with "wet" THF (a high-purity 4 L bottle that was previously opened) for both the in situ catalyst preparation and the reaction steps. In this case, only a 2% NMR yield of the desired product was obtained. Next, a reaction was performed in which the catalyst solution was prepared using anhydrous THF (solvent system dried), while the remaining THF used in the reaction was "wet". A modest increase to a 13% NMR yield of the boracarboxylated product was observed. It is clear that trace adventitious water impacts the reaction negatively, especially during pre-/active-catalyst formation. Using the benchtop protocol without an Ar purge (or N₂ purge) of the reaction solution prior to the introduction of CO₂ gas, an NMR yield of 46% (vs. 66% with Ar purge) was obtained. However, a second identical reaction setup provided an NMR yield of only 17%, suggesting that adventitious oxygen/air impacts the reaction in various irreproducible ways.

In the future, the Popp Group expects that bora-ibuprofen, and other boracarboxylated compounds will provide access to a host of other functionalized ibuprofen derivatives (Figure 9), thus allowing for their study as potential therapeutic agents for pain management³³^,³⁴^,³⁵^,³⁶^,³⁷ or other pharmaceutical applications.

Divulgazioni

The authors have nothing to disclose.

Acknowledgements

We would like to thank the National Science Foundation CAREER and MRI programs (CHE-1752986 and CHE-1228336), the West Virginia University Honors EXCEL Thesis Program (ASS & ACR), the West Virginia University Research Apprenticeship (RAP) and Summer Undergraduate Research Experience (SURE) Programs (ACR), and the Brodie family (Don and Linda Brodie Resource Fund for Innovation) for their generous support of this research.

Materials

125 mL filtration flask	ChemGlass
20 mL vial with pressure relief cap	ChemGlass
4-isobutylbromobenzene	Matrix scientific	8824
Anhydrous potassium carbonate	Beantown chemicals	124060
Anhydrous sodium sulfate	Oakwood	44702
Bis(pinacolato)diboron	Boron Molecular chemicals	BM002
Buchner funnel with rubber adaptor	ChemGlass
Carbon dioxide gas (Bone dry)	Mateson		Tygon tubing connects cylinder regulator to needle used for reaction purging
COPPER(I) CHLORIDE, REAGENT GRADE, 97%	Aldrich	212946
Dichloromthane – high purity	Fisher	D37-20
Diethyl ether – high purity	Fisher	E138-20
Erlenmyer Flask, 125 mL	ChemGlass	CG-8496-125
filter paper	Fisher
Heptane	Fisher	H360-4
Hydrochloric acid	Fisher	AC124635001
IKA stirring hot plate	Fisher	3810001 RCT Basic MAG
Nitrogen filled glove box	MBRAUN
Palladium(0) tetrakistriphenylphosine	Ark Pharm
SilicaFlash P60 silica gel	SiliCycle	R12030B
Sodium bicarbonate	Fisher	S233-3
Sodium tert-butoxide	Fisher	A1994222
Tetrahydrofuran – high purity	Fisher	T425SK-4	Dried on a GlassContours Solvent Purification System
Triphenylphosphine	Sigma	T84409
Vacuum/gas manifold			Used for glovebox boracarboxyaltion reaction setup
Vinylboronic acid pinacol ester	Oxchem

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Knowlden, S. W., Abeysinghe, R. T., Swistok, A. D., Ravenscroft, A. C., Popp, B. V. Synthesis of a Borylated Ibuprofen Derivative Through Suzuki Cross-Coupling and Alkene Boracarboxylation Reactions. J. Vis. Exp. (189), e64571, doi:10.3791/64571 (2022).