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

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 years^1,2,3,4,5,6. Reactions such as hydroboration-oxidation^7,8,9,10, halogenation^11,12, amination^13,14, and Suzuki-Miyaura cross-couplin....

Protocol

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

1. 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....

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 ¹.......

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 .......

Materials

Name	Company	Catalog Number	Comments
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