Name: Chemoselective Preparation of 1-Iodoalkynes, 1,2-Diiodoalkenes, and 1,1,2-Triiodoalkenes Based on the Oxidative Iodination of Terminal Alkynes (Video) | JoVE Journal
Uploaded: 2018-09-12T14:45:00.000+00:00
Duration: 9 min 54 s
Description: Learn chemoselective oxidative iodination of terminal alkynes using hypervalent-iodine reagents to synthesize 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes under mild, green conditions.

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5 minutes

This work was supported by the National Nature Science Foundation of China (21502023).

1. Synthesis of 1-(Iodoethynyl)-4-Methylbenzene (2, 1-Iodoalkynes)
<ol>
	<li>Add 133 mg (0.36 mmol) of TBAI and 3 mL of CH3CN to a reaction tube that contains a magnetic stirring bar, which is open to air. Then, add 38 &#956;L (0.3 mmol) of p-tolylethyne to the mixture using a microsyringe.</li>
	<li>Add 96.6 mg (0.3 mmol) of PIDA to the vigorously stirred reaction mixture in 10 portions over a period of 20 min using a spatula.</li>
	<li>Stir the reaction mixture at room temperature for 3 h.</li>
	<li>Pour the resulting mixture into a separatory funnel that contains 30 mL of water, and quench with aqueous Na2S2O3 (10%, 0.5 mL). Extract the aqueous layer three times with 10 mL of ethyl acetate.</li>
	<li>Wash the combined organic layers with 10 mL of saturated brine and dry over anhydrous sodium sulfate (0.5 g).</li>
	<li>Filter off the sodium sulfate using a Buchner funnel, and concentrate the filtrate under reduced pressure to obtain the crude product.</li>
	<li>Purify the crude product by column chromatography on silica gel using hexane as the eluent; the pure product, 1-(iodoethynyl)-4-methylbenzene, is obtained as a light yellow liquid (71.9 mg, 99% yield; Rf = 0.79).</li>
	<li>Analyze the product by 1H and 13C NMR spectroscopy, and high-performance liquid chromatography (HPLC).</li>
</ol>
2. Synthesis of (E)-1-(1,2-Diiodovinyl)-4-Methylbenzene (3, 1,2-Diiodoalkenes)
<ol>
	<li>Add 124.5 mg (0.75 mmol) of KI and 1 mL of CH3CN to a reaction tube that contains a magnetic stirring bar, which is open to air. Then, add 38 &#956;L (0.3 mmol) of p-tolylethyne and 3 mL of H2O to the mixture via a microsyringe.</li>
	<li>Add 96.6 mg (0.3 mmol) of PIDA to the vigorously stirred reaction mixture in 10 portions over a period of 20 min using a spatula.</li>
	<li>Stir the reaction mixture at room temperature for 24 h.</li>
	<li>Pour the resulting mixture into a separatory funnel that contains 30 mL of water, quench with aqueous Na2S2O3 (10%, 1 mL), and extract the aqueous layer three times with 10 mL of ethyl acetate.</li>
	<li>Wash the combined organic layers with 10 mL of brine and dry over anhydrous sodium sulfate (0.5 g).</li>
	<li>Filter off the sodium sulfate using a Buchner funnel, and concentrate the filtrate under reduced pressure to obtain the crude product.</li>
	<li>Purify the crude product by column chromatography on silica gel using hexane as the eluent. The pure product, (E)-1-(1,2-diiodovinyl)-4-methylbenzene, is obtained as a light yellow liquid (111.9 mg, 98% yield; Rf = 0.84).</li>
	<li>Analyze the product by 1H and 13C NMR spectroscopy as well as HPLC.</li>
</ol>
3. Synthesis of 1-Methyl-4-(1,2,2-Triiodovinyl)benzene (4, 1,1,2-Triiodoalkenes)
<ol>
	<li>Add 133 mg (0.36 mmol) of TBAI and 1 mL of CH3CN to a reaction tube that contains a stirring bar, which is open to air. Then, add 38 &#956;L (0.3 mmol) of p-tolylethyne using a microsyringe.</li>
	<li>Add 96.6 mg (0.3 mmol) of PIDA to the vigorously stirred reaction mixture in 10 portions over a period of 20 min using a spatula. Stir the reaction mixture for 3 h at room temperature.</li>
	<li>Add 124.5 mg (0.75 mmol) of KI in 3 mL of H2O to the reaction mixture.</li>
	<li>Add 193.2 mg (0.6 mmol) of PIDA to the reaction mixture in 10 portions over a period of 20 min using a spatula. Stir the reaction mixture for another 3 h at room temperature.</li>
	<li>Add another 124.5 mg (0.75 mmol) of KI in 3 mL of H2O and 1 mL of CH3CN to the reaction mixture.</li>
	<li>Add another 193.2 mg (0.6 mmol) of PIDA to the reaction mixture in 10 portions over a period of 20 min using a spatula. Stir the reaction mixture for another 12 h at room temperature.</li>
	<li>Pour the resulting mixture into a separatory funnel that contains 30 mL of water, quench with aqueous Na2S2O3 (10%, 2 mL), and extract the aqueous layer three times with 10 mL of ethyl acetate.</li>
	<li>Wash the combined organic layers with 10 mL of brine and dry over anhydrous sodium sulfate (0.5 g).</li>
	<li>Filter off the sodium sulfate using a Buchner funnel, and concentrate the filtrate under reduced pressure to obtain the crude product.</li>
	<li>Purify the crude product by column chromatography on silica gel using hexane to get the pure product, 1-methyl-4-(1, 2, 2-triiodovinyl)benzene, as a yellow liquid (138.4 mg, 93% yield; Rf = 0.79).</li>
	<li>Analyze the product by 1H and 13C NMR spectroscopy as well as HPLC.</li>
</ol>
4. Determination of the Selectivity for the Mono-, Di-, or Tri-iodination of Terminal Alkynes by HPLC
Note: The selectivity for the mono-, di-, tri-iodination of the alkynes was determined by HPLC. HPLC was performed on an instrument using a 5 &#956;m, 4.6 mm &#215; 150 mm column, CH3CN/H2O = 75/25 (v/v) as the solvent, a flow rate of 1.0 mL/min, and a detector wavelength of &#955; = 254 nm.
<ol>
	<li>Preparation of the external standard solution for HPLC
	<ol>
		<li>Precisely weigh out 2 (1-(iodoethynyl)-4-methylbenzene; 9.58 mg, 39.58&#215;10-3 mmol), 3 ((E)-1-(1,2-diiodovinyl)-4-methylbenzene; 19.29 mg, 52.14&#215;10-3 mmol), and 4 (1-methyl-4-(1,2,2-triiodovinyl)benzene; 11.10 mg, 22.38&#215;10-3 mmol).</li>
		<li>Mix and dissolve these three compounds in 1 mL of CH3CN and dilute the stock solution 100 times before performing the HPLC separation.</li>
		<li>Determine the peak area ratio (%) of each product on HPLC chromatogram.</li>
		<li>Calculate the ratio of the molar absorptivity of each compound according to the following formula: 
		&#949;2 : &#949;3 : &#949;4 = A2/n2 : A3/n3 : A4/n4 
		where &#949; is the molar absorptivity, A the peak area, and n the molar weight.</li>
	</ol>
	</li>
	<li>Calculate the chemoselectivity according to the following formula: 
	n2 : n3 : n4 = A2/&#949;2 : A3/&#949;3 : A4/&#949;4</li>
</ol>

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<li>Kohlhepp, S. V., Gulder, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Hypervalent+iodine%28III%29+fluorinations+of+alkenes+and+diazo+compounds%3A+new+opportunities+in+fluorination+chemistry%5BTitle%5D)+AND+%22Chemical+Society+Reviews%22%5BJournal%5D)">Hypervalent iodine(III) fluorinations of alkenes and diazo compounds: new opportunities in fluorination chemistry.</a> Chemical Society Reviews. 45 (22), 6270-6288 (2016).</li>
<li>Hein, J. E., Tripp, J. C., Krasnova, L. B., Sharpless, K. B., Fokin, V. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Copper%28I%29-Catalyzed+Cycloaddition+of+Organic+Azides+and+1-Iodoalkynes%5BTitle%5D)+AND+%22Angewandte+Chemie+International+Edition%22%5BJournal%5D)">Copper(I)-Catalyzed Cycloaddition of Organic Azides and 1-Iodoalkynes.</a> Angewandte Chemie International Edition. 48 (43), 8018-8021 (2009).</li>
</ol>

The authors have nothing extraordinary to disclose.

1-Iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes can be chemoselectively synthesized using hypervalent-iodine reagents as efficient mediators for oxidative iodination(s). The most critical factors of these chemoselective iodination protocols are the nature and loading of the iodine source, as well as the solvent. For example, 1-iodoalkyne 2 was obtained as the major product (52% yield) when TBAI (2.5 equiv loading) was selected as the iodine source in combination with MeOH as the solvent (<stro...

Iodoalkynes and iodoalkenes are widely used important precursors and building blocks in organic synthesis1,2,3,4, biologically active substances, and useful in the synthesis of materials and complex molecules given the ease of converting the C-I bond5,6,7,8. In recent years, the oxidative iodination of terminal alkynes has attracted more attention to the synthesis of iodoalkyne and iodoalkene derivatives. So far, efficient methods that use metal catalysts9,10,11,12, hypervalent-iodonium catalysts13,14, an anodic oxidation system15, ionic liquid systems16, KI (or I2)-oxidant combinations17,18,19,20, ultrasound21, phase-transfer catalysts22, N-iodosuccinimide9,22,23,24,25, n-BuLi26,27,28,29,30,31, Grignard reagents32, and morpholine catalysts17,33,24,35&#160;have been developed for the iodination of alkynes. Recently, we have reported a practical and chemoselective protocol for the synthesis of 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes36. The features of this method are green and practical: (1) the toxicity of hypervalent-iodine catalysts as oxidative functionalization reagents is low compared to other conventional heavy-metal-based oxidants37,38,39,40,41,42, and (2) TBAI and/or KI are used as iodine sources. In addition, our system affords excellent selectivity under mild conditions. The chemoselective synthesis of 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes requires precise control over various factors, including the composition, the oxidant, the iodine source, and the solvent. Among these, the iodine source is the most important factor for the chemoselectivity of the reaction. After the screening of several types and loadings of the iodine source as well as the solvents, three methods were identified and established. Firstly, TBAI as an iodine source in combination with PIDA (TBAI-PIDA) is selective for the synthesis of 1-iodoalkynes. Alternatively, 1,2-diiodoalkenes are efficiently obtained using a KI-PIDA system. Both methods afford the corresponding products in high yield and high chemoselectivity. The corresponding tri-iodinationproducts, i.e., 1,1,2-triiodoalkenes, were obtained in good yield from the one-pot synthesis that combine the TBAI-PIDA and KI-PIDA systems36.
Here, we will demonstrate how the chemoselectivity for the iodination of terminal alkynes can be steered from 1-iodoalkynes to 1,2-diiodoalkenes and to 1,1,2-triiodoalkenes under similar reaction conditions, highlighting the precise control that can be exerted by judiciously choosing oxidant, iodine source, and solvent. For the development of this new synthetic technique, p-tolylethyne was used as a model substrate. Although the following protocols focus on the synthesis of 1-(iodoethynyl)-4-methylbenzene, (E)-1-(1,2-diiodovinyl)-4-methylbenzene, and 1-methyl-4-(1,2,2-triiodovinyl)benzene, these compounds are representative for 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes, respectively, i.e., the protocols are broad in scope, and the same techniques can be applied to the chemoselective iodination of aromatic and aliphatic terminal alkynes36.
Reagents employed in the chemoselective iodination of terminal alkynes and small deviations from the techniques described result in dramatic differences with respect to the target products. For instance, changing of iodine source from TBAI to KI and changing of solvent from CH3CN to a CH3CN-H2O has a dramatic impact on the chemoselectivity of the iodination. The detailed protocol aims at helping new practitioners in the field with the chemoselective iodination of terminal alkynes to avoid many common pitfalls during the synthesis of 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes.

<table><tbody><tr><td>4-ethynyltoluene,98%</td><td>Energy Chemical</td><td>D080006</td><td></td></tr><tr><td>phenylacetylene,98%</td><td>Energy Chemical</td><td>W330041</td><td></td></tr><tr><td>1-ethynyl-4-methoxybenzene,98%</td><td>Energy Chemical</td><td>D080007</td><td></td></tr><tr><td>1-ethynyl-4-fluorobenzene,98%</td><td>Energy Chemical</td><td>D080005</td><td></td></tr><tr><td>4-(Trifluoromethyl)phenylacetylene, 98%</td><td>Energy Chemical</td><td>W320273</td><td></td></tr><tr><td>4-Ethynylbenzoic acid methyl ester,97%</td><td>Energy Chemical</td><td>A020720</td><td></td></tr><tr><td>3-Aminophenylacetylene,97%</td><td>Energy Chemical</td><td>D080001</td><td></td></tr><tr><td>3-Butyn-1-ol,98%</td><td>Energy Chemical</td><td>A040031</td><td></td></tr><tr><td>Propargylacetate,98%</td><td>Energy Chemical</td><td>L10031</td><td></td></tr><tr><td>Tetrabutylammonium Iodide,98%</td><td>Energy Chemical</td><td>E010070</td><td></td></tr><tr><td>Potassium iodide,98%</td><td>Energy Chemical</td><td>E010364</td><td></td></tr><tr><td>(diacetoxyiodo)benzene,99%</td><td>Energy Chemical</td><td>A020180</td><td></td></tr><tr><td>acetonitrile, HPLC grade</td><td>fischer</td><td>A998-4</td><td></td></tr><tr><td>magnetic stirrer</td><td>IKA</td><td></td><td></td></tr><tr><td>rotary evaporator</td><td>Buchi</td><td></td><td></td></tr><tr><td>Bruker AVANCE III 400 MHz Superconducting Fourier</td><td>Bruker</td><td></td><td></td></tr><tr><td>High-performance liquid chromatography</td><td>Shimadzu</td><td></td><td></td></tr></tbody></table>

chemoselective preparation of 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes based on the oxidative iodination of terminal alkynes

Chemoselective Preparation of 1-Iodoalkynes, 1,2-Diiodoalkenes, and 1,1,2-Triiodoalkenes Based on the Oxidative Iodination of Terminal Alkynes

We present the chemoselective synthesis of 1-(iodoethynyl)-4-methylbenzene, 1-(1,2-diiodovinyl)-4-methylbenzene, and 1-methyl-4-(1,2,2-triiodovinyl)benzene as representative examples for the practical chemoselective preparation of 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes from the chemoselective iodination of terminal alkynes mediated by hypervalent-iodine reagents. The chemoselectivity was confirmed by using p-tolylethyne as a model substrate to screen a variety of iodine sources and/or the hypervalent-iodine reagents. A combination of tetrabutylammonium iodide (TBAI) and (diacetoxyiodo)benzene (PIDA) selectively generates 1-iodoalkynes, while a combination of KI and PIDA generates 1,2-diiodoalkenes. A one-pot synthesis based on both TBAI-PIDA and KI-PIDA yields the corresponding 1,1,2-triiodoalkenes. These protocols were subsequently applied to the synthesis of synthetically important aromatic and aliphatic 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes, which were obtained in good yield with excellent chemoselectivity.

The chemoselective synthesis of 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes based on the oxidative iodination of p-tolylethyne is summarized in Figure 1. All reactions were exposed to air. All compounds in this study were characterized by 1H and 13C NMR spectroscopy, mass spectrometry, and HPLC to access the structure of the product and the selectivity of the reaction, as well as to explore the purity. The obtained products ar...

Herein, detailed protocols for the oxidative iodination of terminal alkynes using hypervalent-iodine reagents are presented, which chemoselectively afford 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes.

We present the chemoselective synthesis of 1-(iodoethynyl)-4-methylbenzene, 1-(1,2-diiodovinyl)-4-methylbenzene, and ...

chemoselective-preparation-1-iodoalkynes-12-diiodoalkenes-112

Research

JoVE Journal

Chemistry

Herein is described the synthesis, isolation, and reactions of hypervalent iodonium alkynyl triflates (HIATs) with azides to generate cyanocarbenes. The procedures will involve air-sensitive and cryogen techniques, including cold filtration under an inert atmosphere. Handling and safety of the synthesized compounds will also be discussed.

Synthesis of Hypervalent Iodonium Alkynyl Triflates for the Application of Generating Cyanocarbenes

A protocol for the diastereoselective one-pot preparation of cis-N-Ts-iodoaziridines is described. The generation of diiodomethyllithium, addition to N-Ts aldimines and cyclization of the amino gem-diiodide intermediate to iodoaziridines is demonstrated. Also included is a protocol to rapidly and quantitatively assess the most appropriate stationary phase for purification by chromatography.

Synthesis and Purification of Iodoaziridines Involving Quantitative Selection of the Optimal Stationary Phase for Chromatography

The goal of this manuscript is to demonstrate a straightforward method for the preparation of ynones from acyl chloride and potassium alkynyltrifluoroborate salt starting materials. The one-pot reaction proceeds rapidly in the presence of boron trichloride without exclusion of air and moisture.

Metal-free Synthesis of Ynones from Acyl Chlorides and Potassium Alkynyltrifluoroborate Salts

Ionic liquids (ILs) mediate fast, simple and cheap access to 1,6-ketoesters in high diastereoselectivities and good yields. The reaction protocol is robust and the 1,6-ketoesters can be obtained in gram scale after a simple filtration protocol. Moreover, the 1,6-ketoesters are potent gelators in hydrocarbon solvents.

Highly Stereoselective Synthesis of 1,6-Ketoesters Mediated by Ionic Liquids: A Three-component Reaction Enabling Rapid Access to a New Class of Low Molecular Weight Gelators

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.

Solid-phase Synthesis of [4.4] Spirocyclic Oximes

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

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

3-Aroyl-N-hydroxy-5-nitroindoles were synthesized by cycloaddition of 4-nitronitrosobenzene with a conjugated terminal alkynone in a one-step thermal procedure. Preparation of the nitrosoarene and of the alkynones were adequately reported and respectively through oxidation procedures on the corresponding aniline and on the alkynol.

A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones

Two methods for assigning the α- and ε-dimethylamine nuclear magnetic resonance signals of a reductively 13C-methylated N-terminal lysine are described. One method utilizes the pH-induced selectivity of the reductive methylation reaction, and the other uses aminopeptidase to selectively remove the N-terminal lysine.

Methods to Identify the NMR Resonances of the 13C-Dimethyl N-terminal Amine on Reductively Methylated Proteins

Antifreeze proteins (AFPs) bind to specific planes of ice to prevent or slow ice growth. Fluorescence-based ice plane affinity (FIPA) analysis is a modification of the original ice-etching method for determination of AFP-bound ice planes. AFPs are fluorescently labeled, incorporated into macroscopic single ice crystals, and visualized under UV light.

Determining the Ice-binding Planes of Antifreeze Proteins by Fluorescence-based Ice Plane Affinity

Here, we present a protocol for the synthesis of two carbonyl-decorated carbenes. The protocol makes these interesting compounds readily available to chemists of all skill levels. In addition to the synthesis of these two carbenes, their use in the activation of white phosphorus is also described.

Preparation and Use of Carbonyl-decorated Carbenes in the Activation of White Phosphorus

Learn chemoselective oxidative iodination of terminal alkynes using hypervalent-iodine reagents to synthesize 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes under mild, green conditions.

Chemoselective Preparation of 1-Iodoalkynes, 1,2-Diiodoalkenes, and 1,1,2-Triiodoalkenes Based on the Oxidative Iodination of Terminal Alkynes (Video) | JoVE Journal

Chemoselective Preparation of 1-Iodoalkynes, 1,2-Diiodoalkenes, and 1,1,2-Triiodoalkenes Based on the Oxidative Iodination of Terminal Alkynes

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