Name: synthesis of a borylated ibuprofen derivative through suzuki cross-coupling and alkene boracarboxylation reactions
Uploaded: 2022-11-30T14:10:00
Description: Watch this Scientific Journal Video about Synthesis of a Borylated Ibuprofen Derivative Through Suzuki Cross-Coupling and Alkene Boracarboxylation Reactions at JoVE.com

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 &#38; 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.

1. Synthesis of 4-isobutylstyrene through Suzuki cross-coupling of 1-bromo-4-isobutylbenzene with vinylboronic acid pinacol ester
<ol>
	<li>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.
	<ol>
		<li>Purge the reaction mix...

<ol>
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B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Fluorinated+aryl+boronates+as+building+blocks+in+organic+synthesis.">Fluorinated aryl boronates as building blocks in organic synthesis.</a> Advanced Synthesis &amp; Catalysis. 363 (9), 2224-2255 (2021).</li><li>Wang, M., Shi, Z. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Methodologies+and+strategies+for+selective+borylation+of+C-Het+and+C-C+bonds.">Methodologies and strategies for selective borylation of C-Het and C-C bonds.</a> Chemical Reviews. 120 (15), 7348-7398 (2020).</li><li>Tian, Y. -. M., Guo, X. -. N., Braunschweig, H., Radius, U., Marder, T. 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K., Handa, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+glimpse+into+green+chemistry+practices+in+the+pharmaceutical+industry.">A glimpse into green chemistry practices in the pharmaceutical industry.</a> ChemSusChem. 13 (11), 2859-2875 (2020).</li><li>Bhaskaran, S., Padusha, M. S. A., Sajith, A. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Application+of+palladium+based+precatalytic+systems+in+the+Suzuki-Miyaura+cross-coupling+reactions+of+chloro-heterocycles.">Application of palladium based precatalytic systems in the Suzuki-Miyaura cross-coupling reactions of chloro-heterocycles.</a> ChemistrySelect. 5 (29), 9005-9016 (2020).</li><li>Fujihara, T., Tani, Y., Semba, K., Terao, J., Tsuji, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Copper-catalyzed+silacarboxylation+of+internal+alkynes+by+employing+carbon+dioxide+and+silylboranes.">Copper-catalyzed silacarboxylation of internal alkynes by employing carbon dioxide and silylboranes.</a> Angewandte Chemie International Edition. 51 (46), 11487-11490 (2012).</li><li>Tani, Y., Fujihara, T., Terao, J., Tsuji, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Copper-catalyzed+regiodivergent+silacarboxylation+of+allenes+with+carbon+dioxide+and+a+silylborane.">Copper-catalyzed regiodivergent silacarboxylation of allenes with carbon dioxide and a silylborane.</a> Journal of the American Chemical Society. 136 (51), 17706-17709 (2014).</li><li>Zhang, L., Cheng, J., Carry, B., Hou, Z. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Catalytic+boracarboxylation+of+alkynes+with+diborane+and+carbon+dioxide+by+an+N-heterocyclic+carbene+copper+catalyst.">Catalytic boracarboxylation of alkynes with diborane and carbon dioxide by an N-heterocyclic carbene copper catalyst.</a> Journal of the American Chemical Society. 134 (35), 14314-14317 (2012).</li><li>Schwarz, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Atypical Elements in Drug Design. , (2016).</li><li>Laitar, D. S., Tsui, E. Y., Sadighi, J. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Copper(I)+&#946;-boroalkyls+from+alkene+insertion:+Isolation+and+rearrangement.">Copper(I) &#946;-boroalkyls from alkene insertion: Isolation and rearrangement.</a> Organometallics. 25 (10), 2405-2408 (2006).</li><li>Mankad, N. P., Laitar, D. S., Sadighi, J. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis,+structure,+and+alkyne+reactivity+of+a+dimeric+(carbene)copper(I)+hydride.">Synthesis, structure, and alkyne reactivity of a dimeric (carbene)copper(I) hydride.</a> Organometallics. 23 (14), 3369-3371 (2004).</li><li>Butcher, T. W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Regioselective+copper-catalyzed+boracarboxylation+of+vinyl+arenes.">Regioselective copper-catalyzed boracarboxylation of vinyl arenes.</a> Organic Letters. 18 (24), 6428-6431 (2016).</li><li>Perrone, T. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Beneficial+effect+of+a+secondary+ligand+on+the+catalytic+difunctionalization+of+vinyl+arenes+with+boron+and+CO2.">Beneficial effect of a secondary ligand on the catalytic difunctionalization of vinyl arenes with boron and CO2.</a> ChemCatChem. 11 (23), 5814-5820 (2019).</li><li>Knowlden, S. W., Popp, B. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Regioselective+boracarboxylation+of+&#945;-substituted+vinyl+arenes.">Regioselective boracarboxylation of &#945;-substituted vinyl arenes.</a> Organometallics. 41 (14), 1883-1891 (2022).</li><li>Santoro, O., Collado, A., Slawin, A. M. Z., Nolan, S. P., Cazin, C. S. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+general+synthetic+route+to+[Cu(X)(NHC)]+(NHC+=+N-heterocyclic+carbene,+X+=+Cl,+Br,+I)+complexes.">A general synthetic route to [Cu(X)(NHC)] (NHC = N-heterocyclic carbene, X = Cl, Br, I) complexes.</a> Chemical Communications. 49 (89), 10483 (2013).</li><li>Su, M., Huang, X., Lei, C., Jin, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Nickel-catalyzed+reductive+cross-coupling+of+aryl+bromides+with+vinyl+acetate+in+dimethyl+isosorbide+as+a+sustainable+solvent.">Nickel-catalyzed reductive cross-coupling of aryl bromides with vinyl acetate in dimethyl isosorbide as a sustainable solvent.</a> Organic Letters. 24 (1), 354-358 (2022).</li><li>JoVE. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=JoVE+Science+Education+Database.+Organic+Chemistry.+Degassing+liquids+with+freeze-pump-thaw+cycling.">JoVE Science Education Database. Organic Chemistry. Degassing liquids with freeze-pump-thaw cycling.</a> Journal of Visual Experiments. , (2022).</li><li>Li, D., Ollevier, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mechanism+studies+of+oxidation+and+hydrolysis+of+Cu(I)-NHC+and+Ag-NHC+in+solution+under+air.">Mechanism studies of oxidation and hydrolysis of Cu(I)-NHC and Ag-NHC in solution under air.</a> Journal of Organometallic Chemistry. 906, 121025-121035 (2018).</li><li>Hern&#225;ndez-D&#237;az, S., Rodr&#237;guez, L. A. 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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 ...

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,&#160;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.&#160;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 &#945;-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, &#945;-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 &#945;-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.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>125 mL filtration flask</td>
			<td>ChemGlass</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>20 mL vial with pressure relief cap</td>
			<td>ChemGlass</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>4-isobutylbromobenzene&#160;</td>
			<td>Matrix scientific</td>
			<td>8824</td>
			<td></td>
		</tr>
		<tr>
			<td>Anhydrous potassium carbonate</td>
			<td>Beantown chemicals</td>
			<td>124060</td>
			<td></td>
		</tr>
		<tr>
			<td>Anhydrous sodium sulfate&#160;</td>
			<td>Oakwood</td>
			<td>44702</td>
			<td></td>
		</tr>
		<tr>
			<td>Bis(pinacolato)diboron&#160;</td>
			<td>Boron Molecular chemicals</td>
			<td>BM002</td>
			<td></td>
		</tr>
		<tr>
			<td>Buchner funnel with rubber adaptor</td>
			<td>ChemGlass</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Carbon dioxide gas (Bone dry)</td>
			<td>Mateson</td>
			<td></td>
			<td>Tygon tubing connects cylinder regulator to needle used for reaction purging</td>
		</tr>
		<tr>
			<td>COPPER(I) CHLORIDE, REAGENT GRADE, 97%</td>
			<td>Aldrich</td>
			<td>212946</td>
			<td></td>
		</tr>
		<tr>
			<td>Dichloromthane - high purity</td>
			<td>Fisher</td>
			<td>D37-20</td>
			<td></td>
		</tr>
		<tr>
			<td>Diethyl ether - high purity</td>
			<td>Fisher</td>
			<td>E138-20</td>
			<td></td>
		</tr>
		<tr>
			<td>Erlenmyer Flask, 125 mL</td>
			<td>ChemGlass</td>
			<td>CG-8496-125</td>
			<td></td>
		</tr>
		<tr>
			<td>filter paper</td>
			<td>Fisher</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Heptane</td>
			<td>Fisher</td>
			<td>H360-4</td>
			<td></td>
		</tr>
		<tr>
			<td>Hydrochloric acid</td>
			<td>Fisher</td>
			<td>AC124635001</td>
			<td></td>
		</tr>
		<tr>
			<td>IKA stirring hot plate</td>
			<td>Fisher</td>
			<td>3810001 RCT Basic MAG</td>
			<td></td>
		</tr>
		<tr>
			<td>Nitrogen filled glove box</td>
			<td>MBRAUN</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Palladium(0) tetrakistriphenylphosine&#160;</td>
			<td>Ark Pharm</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>SilicaFlash P60 silica gel</td>
			<td>SiliCycle</td>
			<td>R12030B</td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium bicarbonate</td>
			<td>Fisher</td>
			<td>S233-3</td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium tert-butoxide&#160;</td>
			<td>Fisher</td>
			<td>A1994222</td>
			<td></td>
		</tr>
		<tr>
			<td>Tetrahydrofuran - high purity</td>
			<td>Fisher</td>
			<td>T425SK-4</td>
			<td>Dried on a GlassContours Solvent Purification System</td>
		</tr>
		<tr>
			<td>Triphenylphosphine</td>
			<td>Sigma</td>
			<td>T84409</td>
			<td></td>
		</tr>
		<tr>
			<td>Vacuum/gas manifold</td>
			<td></td>
			<td></td>
			<td>Used for glovebox boracarboxyaltion reaction setup</td>
		</tr>
		<tr>
			<td>Vinylboronic acid pinacol ester&#160;</td>
			<td>Oxchem</td>
			<td></td>
			<td></td>
		</tr>
	</tbody>
</table>

synthesis of a borylated ibuprofen derivative through suzuki cross-coupling and alkene boracarboxylation reactions

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 &#945;-aryl-&#946;-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.

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...

Watch this Scientific Journal Video about Synthesis of a Borylated Ibuprofen Derivative Through Suzuki Cross-Coupling and Alkene Boracarboxylation Reactions at JoVE.com

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

The present protocol describes a detailed benchtop catalytic method that yields a unique borylated derivative of ibuprofen.&#160;

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 ...

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.

synthesis-borylated-ibuprofen-derivative-through-suzuki-cross

Research

JoVE Journal

Chemistry

Microwave-assisted Intramolecular Dehydrogenative Diels-Alder Reactions for the Synthesis of Functionalized Naphthalenes/Solvatochromic Dyes

Functionalized naphthalenes have applications in a variety of research fields ranging from the synthesis of natural or biologically active molecules to the preparation of new organic dyes. Although numerous strategies have been reported to access naphthalene scaffolds, many procedures still present limitations in terms of incorporating functionality, which in turn narrows the range of available substrates. The development of versatile methods for direct access to substituted naphthalenes is therefore highly desirable.
The Diels-Alder (DA) cycloaddition reaction is a powerful and attractive method for the formation of saturated and unsaturated ring systems from readily available starting materials. A new microwave-assisted intramolecular dehydrogenative DA reaction of styrenyl derivatives described herein generates a variety of functionalized cyclopenta[b]naphthalenes that could not be prepared using existing synthetic methods. When compared to conventional heating, microwave irradiation accelerates reaction rates, enhances yields, and limits the formation of undesired byproducts.
The utility of this protocol is further demonstrated by the conversion of a DA cycloadduct into a novel solvatochromic fluorescent dye via a Buchwald-Hartwig palladium-catalyzed cross-coupling reaction. Fluorescence spectroscopy, as an informative and sensitive analytical technique, plays a key role in research fields including environmental science, medicine, pharmacology, and cellular biology. Access to a variety of new organic fluorophores provided by the microwave-assisted dehydrogenative DA reaction allows for further advancement in these fields.

Microwave-assisted intramolecular dehydrogenative Diels-Alder (DA) reactions provide concise access to functionalized cyclopenta[b]naphthalene building blocks. The utility of this methodology is demonstrated by one-step conversion of the dehydrogenative DA cycloadducts into novel solvatochromic fluorescent dyes via Buchwald-Hartwig palladium-catalyzed cross-coupling reactions.

Functionalized naphthalenes have applications in a variety of research fields ranging from the synthesis of natural or biologically active molecules to ...

Seeded Synthesis of CdSe/CdS Rod and Tetrapod Nanocrystals

We demonstrate a method for the synthesis of multicomponent nanostructures consisting of CdS and CdSe with rod and tetrapod morphologies. A seeded synthesis strategy is used in which spherical seeds of CdSe are prepared first using a hot-injection technique. By controlling the crystal structure of the seed to be either wurtzite or zinc-blende, the subsequent hot-injection growth of CdS off of the seed results in either a rod-shaped or tetrapod-shaped nanocrystal, respectively. The phase and morphology of the synthesized nanocrystals are confirmed using X-ray diffraction and transmission electron microscopy, demonstrating that the nanocrystals are phase-pure and have a consistent morphology. The extinction coefficient and quantum yield of the synthesized nanocrystals are calculated using UV-Vis absorption spectroscopy and photoluminescence spectroscopy. The rods and tetrapods exhibit extinction coefficients and quantum yields that are higher than that of the bare seeds. This synthesis demonstrates the precise arrangement of materials that can be achieved at the nanoscale by using a seeded synthetic approach.

A protocol for the seeded synthesis of rod-shaped and tetrapod-shaped multicomponent nanostructures consisting of CdS and CdSe is presented.

We demonstrate a method for the synthesis of multicomponent nanostructures consisting of CdS and CdSe with rod and tetrapod morphologies. A seeded ...

Mizoroki-Heck Cross-coupling Reactions Catalyzed by Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium Under Mild Reaction Conditions

Dichloro-bis(aminophosphine) complexes of palladium with the general formula of [(P{(NC5H10)3-n(C6H11)n})2Pd(Cl)2] (where n = 0-2), belong to a new family of easy accessible, very cheap, and air stable, but highly active and universally applicable C-C cross-coupling catalysts with an excellent functional group tolerance. Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium [(P(NC5H10)3)2Pd(Cl)2] (1), the least stable complex within this series towards protons; e.g. in the form of water, allows an eased nanoparticle formation and hence, proved to be the most active Heck catalyst within this series at 100 &#176;C and is a very rare example of an effective and versatile catalyst system that efficiently operates under mild reaction conditions. Rapid and complete catalyst degradation under work-up conditions into phosphonates, piperidinium salts and other, palladium-containing decomposition products assure an easy separation of the coupling products from catalyst and ligands. The facile, cheap, and rapid synthesis of 1,1',1"-(phosphinetriyl)tripiperidine and 1 respectively, the simple and convenient use as well as its excellent catalytic performance in the Heck reaction at 100 &#176;C make 1 to one of the most attractive and greenest Heck catalysts available.
We provide here the visualized protocols for the ligand and catalyst syntheses as well as the reaction protocol for Heck reactions performed at 10 mmol scale at 100 &#176;C and show that this catalyst is suitable for its use in organic syntheses.

Mizoroki-Heck Cross-coupling Reactions Catalyzed by Dichloro{bis[1,1&#039;,1&#039;&#039;-phosphinetriyltripiperidine]}palladium Under Mild Reaction Conditions

Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium [(P(NC5H10)3)2Pd(Cl)2] (1) is an easy accessible, cheap, and air stable, but highly active Heck catalyst with an excellent functional group tolerance that efficiently operates under mild reaction conditions to give the coupling products in very high yields.

Dichloro-bis(aminophosphine) complexes of palladium with the general formula of [(P{(NC5H10)3-n(C6H11)n})2Pd(Cl)2] (where n = 0-2), belong to a new family ...

Synthesis and Characterization of Functionalized Metal-organic Frameworks

Metal-organic frameworks have attracted extraordinary amounts of research attention, as they are attractive candidates for numerous industrial and technological applications. Their signature property is their ultrahigh porosity, which however imparts a series of challenges when it comes to both constructing them and working with them. Securing desired MOF chemical and physical functionality by linker/node assembly into a highly porous framework of choice can pose difficulties, as less porous and more thermodynamically stable congeners (e.g., other crystalline polymorphs, catenated analogues) are often preferentially obtained by conventional synthesis methods. Once the desired product is obtained, its characterization often requires specialized techniques that address complications potentially arising from, for example, guest-molecule loss or preferential orientation of microcrystallites. Finally, accessing the large voids inside the MOFs for use in applications that involve gases can be problematic, as frameworks may be subject to collapse during removal of solvent molecules (remnants of solvothermal synthesis). In this paper, we describe synthesis and characterization methods routinely utilized in our lab either to solve or circumvent these issues. The methods include solvent-assisted linker exchange, powder X-ray diffraction in capillaries, and materials activation (cavity evacuation) by supercritical CO2 drying. Finally, we provide a protocol for determining a suitable pressure region for applying the Brunauer-Emmett-Teller analysis to nitrogen isotherms, so as to estimate surface area of MOFs with good accuracy.

Synthesis, activation, and characterization of intentionally designed metal-organic framework materials is challenging, especially when building blocks are incompatible or unwanted polymorphs are thermodynamically favored over desired forms. We describe how applications of solvent-assisted linker exchange, powder X-ray diffraction in capillaries and activation via supercritical CO2 drying, can address some of these challenges.

Metal-organic frameworks have attracted extraordinary amounts of research attention, as they are attractive candidates for numerous industrial and ...

Synthesis and Exfoliation of Discotic Zirconium Phosphates to Obtain Colloidal Liquid Crystals

Due to their abundance in natural clay and potential applications in advanced materials, discotic nanoparticles are of interest to scientists and engineers. Growth of such anisotropic nanocrystals through a simple chemical method is a challenging task. In this study, we fabricate discotic nanodisks of zirconium phosphate [Zr(HPO4)2&#183;H2O] as a model material using hydrothermal, reflux and microwave-assisted methods. Growth of crystals is controlled by duration time, temperature, and concentration of reacting species. The novelty of the adopted methods is that discotic crystals of size ranging from hundred nanometers to few micrometers can be obtained while keeping the polydispersity well within control. The layered discotic crystals are converted to monolayers by exfoliation with tetra-(n)-butyl ammonium hydroxide [(C4H9)4NOH, TBAOH]. Exfoliated disks show isotropic and nematic liquid crystal phases. Size and polydispersity of disk suspensions is highly important in deciding their phase behavior.

A two dimensional model material of discotic zirconium phosphate was developed. The inorganic crystal with lamellar structure was synthesized by hydrothermal, reflux, and microwave-assisted methods. On exfoliation with organic molecules, layered crystals can be converted to monolayers, and nematic liquid crystal phase was formed at sufficient concentration of monolayers.

Due to their abundance in natural clay and potential applications in advanced materials, discotic nanoparticles are of interest to scientists and ...

Palladium N-Heterocyclic Carbene Complexes: Synthesis from Benzimidazolium Salts and Catalytic Activity in Carbon-carbon Bond-forming Reactions

Detailed and generalized protocols are presented for the synthesis and subsequent purification of four palladium N-heterocyclic carbene complexes from benzimidazolium salts. Detailed and generalized protocols are also presented for testing the catalytic activity of such complexes in arylation and Suzuki-Miyaura cross-coupling reactions. Representative results are shown for the catalytic activity of the four complexes in arylation and Suzuki-Miyaura type reactions. For each of the reactions investigated, at least one of the four complexes successfully catalyzed the reaction, qualifying them as promising candidates for catalysis of many carbon-carbon bond-forming reactions. The protocols presented are general enough to be adapted for the synthesis, purification and catalytic activity testing of new palladium N-heterocyclic carbene complexes.

Palladium N-Heterocyclic Carbene Complexes: Synthesis from Benzimidazolium Salts and Catalytic Activity in Carbon-carbon Bond-forming Reactions

Detailed and generalized protocols are presented for the synthesis and subsequent purification of four palladium N-heterocyclic carbene complexes from benzimidazolium salts. The complexes were tested for catalytic activity in arylation and Suzuki-Miyaura reactions. For each reaction investigated, at least one of the four complexes successfully catalyzed the reaction.

Detailed and generalized protocols are presented for the synthesis and subsequent purification of four palladium N-heterocyclic carbene complexes from ...

Enzymatic Cascade Reactions for the Synthesis of Chiral Amino Alcohols from L-lysine

Amino alcohols are versatile compounds with a wide range of applications. For instance, they have been used as chiral scaffolds in organic synthesis. Their synthesis by conventional organic chemistry often requires tedious multi-step synthesis processes, with difficult control of the stereochemical outcome. We present a protocol to enzymatically synthetize amino alcohols starting from the readily available L-lysine in 48 h. This protocol combines two chemical reactions that are very difficult to conduct by conventional organic synthesis. In the first step, the regio- and diastereoselective oxidation of an unactivated C-H bond of the lysine side-chain is catalyzed by a dioxygenase; a second regio- and diastereoselective oxidation catalyzed by a regiodivergent dioxygenase can lead to the formation of the 1,2-diols. In the last step, the carboxylic group of the alpha amino acid is cleaved by a pyridoxal-phosphate (PLP) decarboxylase (DC). This decarboxylative step only affects the alpha carbon of the amino acid, retaining the hydroxy-substituted stereogenic center in a beta/gamma position. The resulting amino alcohols are therefore optically enriched. The protocol was successfully applied to the semipreparative-scale synthesis of four amino alcohols. Monitoring of the reactions was conducted by high performance liquid chromatography (HPLC) after derivatization by 1-fluoro-2,4-dinitrobenzene. Straightforward purification by solid-phase extraction (SPE) afforded the amino alcohols with excellent yields (93% to &#62;95%).

Chiral amino alcohols are versatile molecules for use as scaffolds in organic synthesis. Starting from L-lysine, we synthesize amino alcohols by an enzymatic cascade reaction combining diastereoselective C-H oxidation catalyzed by dioxygenase followed by cleavage of the carboxylic acid moiety of the corresponding hydroxyl amino acid by a decarboxylase.

Amino alcohols are versatile compounds with a wide range of applications. For instance, they have been used as chiral scaffolds in organic synthesis. ...

Chemical Synthesis of Porous Barium Titanate Thin Film and Thermal Stabilization of Ferroelectric Phase by Porosity-Induced Strain

Barium titanate (BaTiO3, hereafter BT) is an established ferroelectric material first discovered in the 1940s and still widely used because of its well-balanced ferroelectricity, piezoelectricity, and dielectric constant. In addition, BT does not contain any toxic elements. Therefore, it is considered to be an eco-friendly material, which has attracted considerable interest as a replacement for lead zirconate titanate (PZT). However, bulk BT loses its ferroelectricity at approximately 130 &#176;C, thus, it cannot be used at high temperatures. Because of the growing demand for high-temperature ferroelectric materials, it is important to enhance the thermal stability of ferroelectricity in BT. In previous studies, strain originating from the lattice mismatch at hetero-interfaces has been used. However, the sample preparation in this approach requires complicated and expensive physical processes, which are undesirable for practical applications.
In this study, we propose a chemical synthesis of a porous material as an alternative means of introducing strain. We synthesized a porous BT thin film using a surfactant-assisted sol-gel method, in which self-assembled amphipathic surfactant micelles were used as an organic template. Through a series of studies, we clarified that the introduction of pores had a similar effect on distorting the BT crystal lattice, to that of a hetero-interface, leading to the enhancement and stabilization of ferroelectricity. Owing to its simplicity and cost effectiveness, this fabrication process has considerable advantages over conventional methods.

Here, we present a protocol for the synthesis of porous barium titanate (BaTiO3) thin film by a surfactant-assisted sol-gel method, in which self-assembled amphipathic surfactant micelles are used as an organic template.

Barium titanate (BaTiO3, hereafter BT) is an established ferroelectric material first discovered in the 1940s and still widely used because of its ...

Solid-phase Synthesis of [4.4] Spirocyclic Oximes

A convenient synthetic route for spirocyclic heterocycles is well sought after due to the molecule&#39;s potential use in biological systems. By means of solid-phase synthesis, regenerating Michael (REM) linker strategies, and 1,3-dipolar cycloaddition, a library of structurally similar heterocycles, both with and without a spirocyclic center, can be constructed. The main advantages of the solid-support synthesis are as follows: first, each reaction step can be driven to completion using a large excess of reagents resulting in high yields; next, the use of commercially available starting materials and reagents keep the costs low; finally, the reaction steps are easy to purify via simple filtration. The REM linker strategy is attractive because of its recyclability and traceless nature. Once a reaction scheme is completed, the linker can be reused multiple times. In a typical solid-phase synthesis, the product contains either a part of or the whole linker, which can prove undesirable. The REM linker is &#34;traceless&#34; and the point of attachment between the product and the polymer is indistinguishable. The high diastereoselectivity of the intramolecular 1,3-dipolar cycloaddition is well documented. Limited by the insolubility of the solid support, the reaction progression can only be monitored by a change in the functional groups (if any) via infrared (IR) spectroscopy. Thus, the structural identification of intermediates cannot be characterized by conventional nuclear magnetic resonance (NMR) spectroscopy. Other limitations to this method stem from the compatibilities of the polymer/linker to the desired chemical reaction scheme. Herein we report a protocol that allows for the convenient production of spirocyclic heterocycles that, with simple modifications, can be automated with high-throughput techniques.

Here we present a protocol to demonstrate an efficient method for the synthesis of spirocyclic heterocycles. The five-step process utilizes solid-phase synthesis and regenerating Michael linker strategies. Generally difficult to synthesize, we present a customizable method for the synthesis of spirocyclic molecules otherwise inaccessible to other modern approaches.

A convenient synthetic route for spirocyclic heterocycles is well sought after due to the molecule&#39;s potential use in biological systems. By means of ...

Synthesis of Esters Via a Greener Steglich Esterification in Acetonitrile

The Steglich esterification is a widely-used reaction for the synthesis of esters from carboxylic acids and alcohols. While efficient and mild, the reaction is commonly performed using chlorinated or amide solvent systems, which are hazardous to human health and the environment. Our methodology utilizes acetonitrile as a greener and less hazardous solvent system. This protocol exhibits rates and yields that are comparable to traditional solvent systems and employs an extraction and wash sequence that eliminates the need for the purification of the ester product via column chromatography. This general method can be used to couple a variety of carboxylic acids with 1&#176; and 2&#176; aliphatic alcohols, benzylic and allylic alcohols, and phenols to obtain pure esters in high yields. The goal of the protocol detailed here is to provide a greener alternative to a common esterification reaction, which could serve useful for ester synthesis in both academic and industrial applications.

A modified Steglich esterification reaction was used to synthesize a small library of ester derivatives with primary and secondary alcohols. The methodology uses a non-halogenated and greener solvent, acetonitrile, and enables product isolation in high yields without the need for chromatographic purification.

The Steglich esterification is a widely-used reaction for the synthesis of esters from carboxylic acids and alcohols. While efficient and mild, the ...