Name: efficient synthesis of polyfunctionalized benzenes in water via persulfate-promoted benzannulation of &#945;,&#946;-unsaturated compounds and alkynes
Uploaded: 2019-12-16T16:00:00
Description: Watch this Scientific Journal Video about Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of Î±,Î²-Unsaturated Compounds and Alkynes at JoVE.com

We thank Funda&#231;&#227;o de Amparo &#224; Pesquisa do Estado de S&#227;o Paulo (FAPESP, S&#227;o Paulo, Brazil) for financial support (Grant FAPESP 2017/18400-6). This study was financed in part by the Coordena&#231;&#227;o de Aperfei&#231;oamento de Pessoal de N&#237;vel Superior &#8211; Brasil (CAPES) &#8211; Finance Code 001.

CAUTION: Consult Material Safety Data Sheets (MSDS) prior to the use of the chemicals in this procedure. Use appropriate personal protective equipment (PPE), including safety glasses, a lab coat, and nitrile gloves as several reagents and solvents are toxic, corrosive, or flammable. Carry out all reactions in a fume hood. Liquids used in this protocol are micropipette transferred.
1. Benzannulation reaction employing alkynes and &#945;,&#946;-unsaturated compounds
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	<li>Add 2.0 mL of dis...

<ol>
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A. L., de Koning, C. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Metathesis+in+the+Synthesis+of+Aromatic+Compounds.">Metathesis in the Synthesis of Aromatic Compounds.</a> Chemical Reviews. 109, 3743-3782 (2009).</li><li>Zhou, P., Huang, L. B., Jiang, H. F., Wang, A. Z., Li, X. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Highly+Chemoselective+Palladium-Catalyzed+Cross-Trimerization+between+Alkyne+and+Alkenes+Leading+to+1,3,5-Trienes+or+1,2,4,5-Tetrasubstituted+Benzenes+with+Dioxygen.">Highly Chemoselective Palladium-Catalyzed Cross-Trimerization between Alkyne and Alkenes Leading to 1,3,5-Trienes or 1,2,4,5-Tetrasubstituted Benzenes with Dioxygen.</a> Journal of Organic Chemistry. 75, 8279-8282 (2010).</li><li>Li, S., Wu, X. X., Chen, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Base-promoted+direct+synthesis+of+functionalized+N-arylindoles+via+the+cascade+reactions+of+allenic+ketones+with+indoles.">Base-promoted direct synthesis of functionalized N-arylindoles via the cascade reactions of allenic ketones with indoles.</a> Organic and Biomolecular Chemistry. 17, 789-793 (2019).</li><li>Maezono, S. M. B., Poudel, T. N., Lee, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=One-pot+construction+of+sterically+challenging+and+diverse+polyarylphenols+via+transition-metal-free+benzannulation+and+their+potent+in+vitro+antioxidant+activity.">One-pot construction of sterically challenging and diverse polyarylphenols via transition-metal-free benzannulation and their potent in vitro antioxidant activity.</a> Organic and Biomolecular Chemistry. 15, 2052-2062 (2017).</li><li>Shu, W. M., Zheng, K. L., Ma, J. R., Wu, A. X. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Transition-Metal-Free+Multicomponent+Benzannulation+Reactions+for+the+Construction+of+Polysubstituted+Benzene+Derivatives.">Transition-Metal-Free Multicomponent Benzannulation Reactions for the Construction of Polysubstituted Benzene Derivatives.</a> Organic Letters. 17, 5216-5219 (2015).</li><li>Jiang, L., 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=Secondary+amine-catalyzed+[3+benzannulation+to+access+polysubstituted+benzenes+through+iminium+activation.">Secondary amine-catalyzed [3 benzannulation to access polysubstituted benzenes through iminium activation.</a> Synthetic Communications. 48, 336-343 (2018).</li><li>Koening, S. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Scalable Green Chemistry. Case Studies from the Pharmaceutical Industry. , (2013).</li><li>Backvall, J. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Modern Oxidation Methods. , (2004).</li><li>Narayan, S., 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="On+Water":+Unique+Reactivity+of+Organic+Compounds+in+Aqueous+Suspension.">"On Water": Unique Reactivity of Organic Compounds in Aqueous Suspension.</a> Angewandte Chemie International Edition. 44, 3275-3277 (2005).</li><li>de Souza, G. F. P., Salles, A. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Persulfate-Mediated+Synthesis+of+Polyfunctionalized+Benzenes+in+Water+via+Benzannulation+of+Alkynes+and+&#945;,&#946;-Unsaturated+Compounds.">Persulfate-Mediated Synthesis of Polyfunctionalized Benzenes in Water via Benzannulation of Alkynes and &#945;,&#946;-Unsaturated Compounds.</a> Green Chemistry. , (2019).</li><li>Prat, D., Wells, A., Hayler, J., Sneddon, H., McElroy, C. R., Abou-Shehada, S., Dunn, P. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=CHEM21+Selection+Guide+of+Classical-+and+Less+Classical-Solvents.">CHEM21 Selection Guide of Classical- and Less Classical-Solvents.</a> Green Chemistry. 18, 288-296 (2015).</li><li>Sheldon, R. 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The method reported herein was designed to be a very simple and mild experimental setup for the synthesis of polyfunctionalized benzenes in water15. Under our conditions we could observe excellent yields for the products through the use of ammonium persulfate. A freshly prepared persulfate aqueous solution should be used; however, solid ammonium persulfate can also be employed with no loss in yield. Attention to the temperature of the reaction medium is mandatory. An increase in 10 &#176;C beyond ...

Functionalized benzenes are arguably the most employed precursors in synthetic organic chemistry1,2. They figure in the mainstream of pharmaceuticals, natural products and functional organic materials. Powerful approaches have been reported for the construction of polysubstituted benzene derivatives and among them, well-established methods as aromatic nucleophilic or electrophilic substitution3, cross-coupling reactions4 and directed metalation5 are prevalent approaches. Nevertheless, the widespread application of these strategies may be hampered by limited substrate scope, overreaction and regioselectivity issues.
Tandem cyclization reactions represent a very attractive alternative to classical methods for rapid construction of functionalized benzenes in an atom-economical fashion6,7,8. Within this framework, benzannulation reactions represent a suitable protocol to effectively transform acyclic building blocks into valuable benzene skeletons. This class of reaction is a versatile methodology featuring a variety of chemical feedstocks, mechanisms and experimental conditions9,10,11.
The objective of our study is to develop a simple and practical protocol for a benzannulation reaction to generate unprecedented functionalized benzene rings. Toward this end, we set out to explore a metal-free, persulfate mediated benzannulation in water employing cheap chemical feedstocks (&#945;,&#946;-unsaturated compounds and alkynes).
Several advantages over methods reported in the literature can be pointed out. Metal-free transformations have all necessary attributes to meet the requirement of sustainable development. Just to mention few, there is no need for costly and challenging removal of metal trace amounts from the desired products; the reactions are less sensitive to oxygen and moisture making its manipulation easier and the overall process is normally less expensive12. Persulfate salts are stable, easy to handle and generate only sulphate as the byproduct, thus adding momentum to the green chemistry initiative to minimize waste pollution13. Water is considered a suitable green solvent for organic reactions: it is non-toxic, non-flammable, has a very low odor and is available at a low cost. Even water-insoluble organic compounds can be employed using "on water"14 aqueous suspensions and these straightforward synthetic protocols have been gaining increasing attention during the years.
Our optimized reaction conditions and simple workup/purification procedure provide access to several functionalized benzene rings that offer a wealth of opportunities for further functionalization.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Ammonium persulfate</td>
			<td>Vetec</td>
			<td>276</td>
			<td></td>
		</tr>
		<tr>
			<td>Chloroform-D, (D, 99.8%)</td>
			<td>Sigma Aldrich</td>
			<td>570699-50G</td>
			<td></td>
		</tr>
		<tr>
			<td>2-cyclohexen-1-one &#62;95%</td>
			<td>Sigma Aldrich</td>
			<td>C102814-25ML</td>
			<td></td>
		</tr>
		<tr>
			<td>Ethyl Acetate, 99.9%</td>
			<td>Synth</td>
			<td>01A1010.01.BJ</td>
			<td>ACS</td>
		</tr>
		<tr>
			<td>Hexanes, 98.5%</td>
			<td>Synth</td>
			<td>01H1007.01.BJ</td>
			<td>ACS</td>
		</tr>
		<tr>
			<td>Phenylacetylene 98%</td>
			<td>Sigma Aldrich</td>
			<td>117706-25ML</td>
			<td></td>
		</tr>
		<tr>
			<td>Silica Gel (SiO2)</td>
			<td>Fluka</td>
			<td>60738-5KG</td>
			<td>pore size 60 &#197;, 35-70 &#956;m particle size</td>
		</tr>
		<tr>
			<td>Thin-layer chromatography plates</td>
			<td>Macherey-Nagel</td>
			<td>818333</td>
			<td>0.20 mm silica gel 60 with fluorescent indicator UV254</td>
		</tr>
	</tbody>
</table>

efficient synthesis of polyfunctionalized benzenes in water via persulfate-promoted benzannulation of &#945;,&#946;-unsaturated compounds and alkynes

Benzannulation reactions represent an effective protocol to transform acyclic building blocks into structurally varied benzene skeletons. Despite classical and recent approaches toward functionalized benzenes, in water metal-free methods remains a challenge and represents an opportunity to expand even more the set of tools used to synthesize polysubstituted benzene compounds. This protocol describes an operationally simple experimental setup to explore the benzannulation of &#945;,&#946;-unsaturated compounds and alkynes to afford unprecedented functionalized benzene rings in high yields. Ammonium persulfate is the reagent of choice and brings notable advantages as stability and easy handling. Moreover, the use of water as a solvent and the absence of metals impart more sustainability to the method. A modified workup procedure that avoids the use of drying agents also adds convenience to the protocol. The purification of the products is performed using only a plug of silica. The substrate scope is currently limited to terminal alkynes and &#945;,&#946;-unsaturated aliphatic compounds.

Polysubstituted benzene (3b, Figure 1) was isolated as a colorless oil (0.2741 g, 0.920 mmol, 92% yield) using our protocol. The structure and purity can be assessed in the 1H and 13C NMR spectra presented in Figure 2 and Figure 3. Peaks for the aromatic protons on the central benzene ring (&#948; 8.37 and &#948; 7.72 ppm) were used as diagnostic signals for the formation of the product.
<p...

Watch this Scientific Journal Video about Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of Î±,Î²-Unsaturated Compounds and Alkynes at JoVE.com

Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of &#945;,&#946;-Unsaturated Compounds and Alkynes

A persulfate-promoted metal-free benzannulation of &#945;,&#946;-unsaturated compounds and alkynes in water toward the synthesis of unprecedented polyfunctionalized benzenes is reported.

Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of &#945;,&#946;-Unsaturated Compounds and Alkynes

Benzannulation reactions represent an effective protocol to transform acyclic building blocks into structurally varied benzene skeletons. Despite ...

This is a very simple experimental setup in line with organic chemistry requirements to obtain a range of viable polyfunctionalized benzenes. The main advantage of this technique is the use of water as a solvent which allows the easy isolation of the crude mixture and contributes to the sustainable practice of organic chemistry. Demonstrating the procedure will be Dr.Gabriela Souza, an associate researcher from my laboratory.To begin, add two milliliters of distilled water to a 15 milliliter test tube containing a stir bar. Sequentially, add 220 microliters of phenol acetylene, 96.8 microliters of 2-cyclohexene-1-one, and 1.5 milliliters of freshly prepared 1.3 molar ammonium persulfate. Cap the tube using a rubber septum and insert a needle in it to avoid eventual pressure buildup during the heating.Place the tube in an aluminum heating block on a hot plate and heat it at 85 degrees Celsius under vigorous stirring at 1, 150 RPM for eight hours. To allow the progress of the reaction, take a 50 microliter aliquot of the reaction medium and transfer it to a 1.5 milliliter conical vial. Add 50 microliters of ethyl acetate to the vial and shake it.Then collect the organic top layer with a capillary tube and apply it on a TLC silica-coated glass plate. Dip the plate in a solution of 92:8 hexanes ethyl acetate to analyze. Cool the reaction mixture to room temperature and add one milliliter of ethyl acetate to the test tube.Stir the suspension for approximately one minute and then centrifuge the suspension at 2, 336 times g at room temperature for one minute. Remove the organic top layer using a Pasteur pipette and transfer it into a round bottom flask. Repeat the addition of ethyl acetate to centrifuging and the removal of the top layer two additional times.Concentrate the top layer under reduced pressure using a rotary evaporator to obtain a crude oil. Add 55 milliliters of a mixture of hexanes and ethyl acetate at the ratio of 92:8 into a beaker containing 7.5 grams of silicon dioxide. Stir the flask to obtain a homogenous slurry.Transfer the slurry to a column with 40 millimeter internal diameter to pack the column. Dissolve the crude oil in a minimal amount of ethyl acetate and then transfer this solution to the column. Collect the column effluent in test tubes.Perform TLC and obtain the desired pure product according to the TLC result showing only one migrating compound. Concentrate the desired solution under reduced pressure on a rotary evaporator and remove the final volatiles under high vacuum for at least one hour. Analyze the sample of the purified product by proton and carbon-13 NMR using deuterated chloroform.In this protocol, polysubstituted benzene was isolated as a colorless oil. The structure and purity were assessed in the proton and carbon-13 NMR spectra. Peaks for the aromatic protons on the central benzene ring at 8.37 and 7.72 PPM were used as diagnostic signals for the formation of the product.It is very important to carefully control the temperature of the reaction medium and to ensure a proper stirring of the suspension during the reaction. This procedure can be employed in any other transformation performed in water. Keeping the workup step is an efficient way to obtain a crude mixture from the reaction medium.This procedure offers an easy and efficient way to study water as a reaction medium and to encourage the design of more sustainable transformations. For operational safety, after capping the tube with a rubber septum, be sure to insert a needle before going to heating. It avoids any pressure buildup during the reaction.

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

Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of &#945;-Imino &#947;-Lactones and Alkylidene Pyrazolones

Bispirocyclic scaffolds are one of the important structural subunits in many natural products that exhibit diverse and attractive biological activities. Recently, we have developed an efficient organocatalytic strategy, which provides facile access to a variety of enantiomerically enriched bispiro[&#947;-butyrolactone-pyrrolidin-4,4&#39;-pyrazolone] skeletons. In this paper, we demonstrate a detailed protocol for the asymmetric synthesis of drug-like bispirocyclic compounds with two spirocyclic carbon centers via an organocatyltic 1,3-dipolar cycloaddition reaction. Spirocyclization synthons &#945;-imino &#947;-lactones and alkylidene pyrazolones are prepared first, which are then subjected to a cycloaddition reaction in the presence of a bifunctional squaramide organocatalyst to afford the desired bispirocycles in high yields and excellent stereoselectivities. Chiral high-performance liquid chromatography (HPLC) is carried out to determine the enantiomeric purity of the products, and the d.r. value is examined by proton nuclear magnetic resonance (1H NMR). The absolute configuration of the product is assigned according to an X-ray crystallographic analysis. This synthetic strategy allows scientists to prepare a diversity of bispirocyclic scaffolds in high yields and excellent diastereo- and enantioselectivities.

Enantiomerically enriched bispiro[&#947;-butyrolactone-pyrrolidin-4,4&#39;-pyrazolone] skeletons are asymmetrically synthesized through a simple organocatalytic 1,3-dipolar cycloaddition reaction.

Bispirocyclic scaffolds are one of the important structural subunits in many natural products that exhibit diverse and attractive biological activities. ...

Synthesis of Monodisperse Cylindrical Nanoparticles via Crystallization-driven Self-assembly of Biodegradable Block Copolymers

The production of monodisperse cylindrical micelles is a significant challenge in polymer chemistry. Most cylindrical constructs formed from diblock copolymers are produced by one of three techniques: thin film rehydration, solvent switching or polymerization-induced self-assembly, and produce only flexible, polydisperse cylinders. Crystallization-driven self-assembly (CDSA) is a method which can produce cylinders with these properties, by stabilizing structures of a lower curvature due to the formation of a crystalline core. However, the living polymerization techniques by which most core-forming blocks are formed are not trivial processes and the CDSA process may yield unsatisfactory results if carried out incorrectly. Here, the synthesis of cylindrical nanoparticles from simple reagents is shown. The drying and purification of reagents prior to a ring-opening polymerization of &#949;-caprolactone catalyzed by diphenyl phosphate is described. This polymer is then chain extended by methyl methacrylate (MMA) followed by N,N-dimethyl acrylamide (DMA) using reversible addition&#8722;fragmentation chain-transfer (RAFT) polymerization, affording a triblock copolymer that can undergo CDSA in ethanol. The living CDSA process is outlined, the results of which yield cylindrical nanoparticles up to 500 nm in length and a length dispersity as low as 1.05. It is anticipated that these protocols will allow others to produce cylindrical nanostructures and elevate the field of CDSA in the future.

Crystallization-driven self-assembly (CDSA) displays the unique ability to fabricate cylindrical nanostructures of narrow length distributions. The organocatalyzed ring-opening polymerization of &#949;-caprolactone and subsequent chain extensions of methyl methacrylate and N,N-dimethyl acrylamide are demonstrated. A living CDSA protocol that produces monodisperse cylinders up to 500 nm in length is outlined.

The production of monodisperse cylindrical micelles is a significant challenge in polymer chemistry. Most cylindrical constructs formed from diblock ...

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the preparation of all-carbon quaternary centers. Though conjugate additions of organometallic reagents are typically performed utilizing highly reactive organolithium or Grignard reagents, organozinc reagents have garnered attention for their enhanced chemoselectivity and mild reactivity. Despite numerous recent advances with more reactive diorganozinc and mixed diorganozinc reagents, the generation of all-carbon quaternary centers via the conjugate addition of functionalized monoorganozinc reagents remains a challenge. This protocol details a convenient and mild &#8220;one-pot&#8221; preparation and copper mediated conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to afford a broad scope of all-carbon quaternary centers in generally excellent yield and diastereoselectivity. Key to the development of this technology is the utilization of DMA as a reaction solvent with TMSCl as a Lewis acid. Notable advantages to this methodology include the operational simplicity of the organozinc reagent preparation afforded by the utilization of DMA as a solvent, as well as an efficient conjugate addition mediated by various Cu(I) and Cu(II) salts. Moreover, an intermediate silyl enol ether can be isolated utilizing a modified workup procedure. The substrate scope is limited to cyclic unsaturated ketones, and the conjugate addition is impeded by stabilized (e.g., allyl, enolate, homoenolate) and sterically encumbered (e.g., neopentyl, o-aryl) monoorganozinc reagents. Conjugate additions to five- and seven-membered rings were effective, albeit in lower yields compared with six-membered ring substrates.

A simple and practical protocol for the efficient conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to furnish all-carbon quaternary centers was developed.

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the ...