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...

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 border="0" cellpadding="0" cellspacing="0" width="860">
	<tbody>
		<tr height="40">
			<td height="40" style="height:40px;width:263px;">4-ethynyltoluene,98%</td>
			<td style="width:311px;">Energy Chemical</td>
			<td style="width:119px;">D080006</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:263px;">phenylacetylene,98%</td>
			<td style="width:311px;">Energy Chemical</td>
			<td style="width:119px;">W330041</td>
			<td></td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:263px;">1-ethynyl-4-methoxybenzene,98%</td>
			<td style="width:311px;">Energy Chemical</td>
			<td style="width:119px;">D080007</td>
			<td></td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:263px;">1-ethynyl-4-fluorobenzene,98%</td>
			<td style="width:311px;">Energy Chemical</td>
			<td style="width:119px;">D080005</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:263px;">4-(Trifluoromethyl)phenylacetylene,98%</td>
			<td style="width:311px;">Energy Chemical</td>
			<td style="width:119px;">W320273</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:263px;">4-Ethynylbenzoic acid methyl ester,97%</td>
			<td style="width:311px;">Energy Chemical</td>
			<td style="width:119px;">A020720</td>
			<td></td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:263px;">3-Aminophenylacetylene,97%</td>
			<td style="width:311px;">Energy Chemical</td>
			<td style="width:119px;">D080001</td>
			<td></td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:263px;">3-Butyn-1-ol,98%</td>
			<td style="width:311px;">Energy Chemical</td>
			<td style="width:119px;">A040031</td>
			<td></td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:263px;">Propargylacetate,98%</td>
			<td style="width:311px;">Energy Chemical</td>
			<td style="width:119px;">L10031</td>
			<td></td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:263px;">Tetrabutylammonium Iodide,98%</td>
			<td style="width:311px;">Energy Chemical</td>
			<td style="width:119px;">E010070</td>
			<td></td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:263px;">Potassium iodide,98%</td>
			<td style="width:311px;">Energy Chemical</td>
			<td style="width:119px;">E010364</td>
			<td></td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:263px;">(diacetoxyiodo)benzene,99%</td>
			<td style="width:311px;">Energy Chemical</td>
			<td style="width:119px;">A020180</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:263px;">acetonitrile, HPLC grade</td>
			<td style="width:311px;">fischer</td>
			<td style="width:119px;">A998-4</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:263px;">magnetic stirrer</td>
			<td style="width:311px;">IKA</td>
			<td style="width:119px;"></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:263px;">rotary evaporator</td>
			<td style="width:311px;">Buchi</td>
			<td style="width:119px;"></td>
			<td></td>
		</tr>
		<tr height="63">
			<td height="63" style="height:63px;width:263px;">Bruker AVANCE III 400 MHz Superconducting Fourier</td>
			<td style="width:311px;">Bruker</td>
			<td style="width:119px;"></td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:263px;">High-performance liquid chromatography</td>
			<td style="width:311px;">Shimadzu</td>
			<td style="width:119px;"></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

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...

Watch this Scientific Journal Video about Chemoselective Preparation of 1-Iodoalkynes, 1,2-Diiodoalkenes, and 1,1,2-Triiodoalkenes Based on the Oxidative Iodination of Terminal Alkynes at JoVE.com

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

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 ...

This method can help answer key questions in organic synthesis about chemoselective iodination of terminal alkynes for the synthesis of one-iodoalkynes, one, two-diiodoalkenes, and one, one, two-triiodoalkenes. This technique is green, practical, and affords excellent selectivity under mild conditions. Hypervalent iodine catalysts are much less toxic than heavy-metal-based oxidants, and TBAI and KI are widely available, easy-to-use iodine source.Though this method can provide insight into the chemoselective synthesis of iodoalkyne derivatives, it can also be applied to other reactions, such as material synthesis, intermediates, and biologically active compounds. To begin, place 133 milligrams of tetrabutylammonium iodide in an open reaction tube equipped with a magnetic stir bar. Add three milliliters of HPLC-grade acetonitrile to the tube.Then, draw 38 microliters of p-tolylethyne into a microsyringe, add it to the tube, and start vigorously stirring the mixture at about 1, 000 rpm. Over the course of 20 minutes, add 96.6 milligrams of diacetoxy iodobenzene, or PIDA, in 10 approximately equal portions at two-minute intervals. Continue stirring the reaction mixture at room temperature for three more hours while open to air.Then, place 30 milliliters of deionized water in a separatory funnel, and prepare 0.5 milliliters of 10%by weight aqueous sodium thiosulfate. Pour the reaction mixture into the separatory funnel, and quench it with aqueous sodium thiosulfate. Extract the aqueous layer three times with 10-milliliter portions of ethyl acetate.Then, wash the organic layer with 10 milliliters of saturated brine. Dry the organic layers over about 0.5 grams of anhydrous sodium sulfate, and remove the desiccant by vacuum filtration. Concentrate the filtrate to less than one milliliters under reduced pressure to obtain the crude product.Dissolve the crude product in about 0.5 milliliters of hexane, and purify it on a silica gel column using hexane as the eluent. Identify the product fraction with TLC, and remove the solvent by rotary evaporation to obtain the pure mono-iodinated product as a light yellow liquid. First, add 124.5 milligrams of potassium iodide and one milliliter of HPLC-grade acetonitrile to an open reaction tube equipped with a stir bar.Add 38 microliters of p-tolylethyne with a microsyringe and three milliliters of deionized water with a syringe. While vigorously stirring the reaction mixture at about 1, 000 rpm, add 96.6 milligrams of PIDA in 10 portions over the course of 20 minutes. Continue stirring the reaction mixture at room temperature for 24 hours in ambient air.Then, pour the reaction mixture into a separatory funnel containing 30 milliliters of deionized water, and quench it with one milliliter of 10%aqueous sodium thiosulfate. Extract the aqueous layer three times with 10-milliliter portions of ethyl acetate, wash the organic layer with 10 milliliters of saturated brine, and dry it over 0.5 grams of anhydrous sodium sulfate. Remove the sodium sulfate by vacuum filtration, and concentrate the filtrate under reduced pressure.Purify the crude product by elution from a silica gel column with hexane, and remove the solvent to obtain pure di-iodinated product as a light yellow liquid. First, add 133 milligrams of TBAI and one milliliter of HPLC-grade acetonitrile to a reaction tube equipped with a stir bar and open to air. Add 38 microliters of p-tolylethyne with a microsyringe, and start stirring the mixture vigorously.Add 96.6 milligrams of PIDA to the reaction mixture in 10 portions over the course of 20 minutes. Continue stirring the mixture for three hours at room temperature while open to air. Next, dissolve 124.5 milligrams of potassium iodide in three milliliters of deionized water, and add this solution to the reaction mixture.Then, add 193.2 milligrams of PIDA to the mixture in 10 portions over the course of 20 minutes. Continue stirring the mixture for three more hours in ambient air at room temperature. At that point, dissolve another 124.5 milligrams of potassium iodide in three milliliters of water, and add it to the reaction mixture, along with one milliliter of acetonitrile.Then, stir in another 193.2 milligrams of PIDA in 10 portions over 20 minutes. Continue stirring the mixture for 12 hours at room temperature in ambient air. Then, pour the reaction mixture into a separatory funnel containing 30 milliliters of deionized water, and quench it with two milliliters of 10%aqueous sodium thiosulfate.Extract the product into three 10-milliliter portions of ethyl acetate. Wash the extract with 10 milliliters of saturated brine, and dry it over 0.5 grams of anhydrous sodium sulfate. Filter out the sodium sulfate, concentrate the filtrate, and purify the crude product on a silica gel column with hexane as the eluent.Remove the solvent from the product fraction to obtain the pure tri-iodinated product as a yellow liquid. First, precisely weigh out three compounds in a known molar ratio. Combine the compounds in one milliliter of HPLC-grade acetonitrile.Then, dilute this stock solution 100-fold with more acetonitrile. Load two microliters of the diluted solution onto an HPLC column, and acquire a chromatogram. Calculate the molar attenuation coefficient for each compound for the peak areas and the amounts of each compound injected onto the column.Then, dilute a crude product sample with acetonitrile, and acquire a chromatogram. Calculate the molar ratios between the iodinated compounds to determine the chemoselectivity. Depending on the oxidative iodination reaction conditions, p-tolylethyne could be chemoselectively mono-di-or tri-iodinated.Using one equivalent of PIDA and 1.2 equivalents of TBAI resulted in the chemoselective formation of the mono-iodinated product, as confirmed by HPLC. Proton NMR of the mono-iodinated product showed that the terminal alkyne proton signal at 3.0 ppm had disappeared. The appearance of a carbon NMR signal at 5.1 ppm was consistent with literature reports for the mono-iodination of p-tolylethyne.Using one equivalent of PIDA and 2.5 equivalents of potassium iodide in a one-to-three acetonitrile-water mixture selectively yielded the di-iodinated product. The proton NMR signal at 7.2 ppm indicated the presence of the key proton of the di-iodinated olefin group, and the carbon NMR signals at 96.6 and 80.1 ppm were attributed to the olefin carbons. A three-strep, one-pot method combining the two previous techniques produced the tri-iodinated compound in major yield.The benzene proton showed less splitting in the proton NMR spectrum, and the shifts in the carbon NMR signals were consistent with the tri-iodinated olefin group. While attempting this procedure, remember to keep the reaction mixture stirring vigorously.