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JoVE Journal Chemistry

Chemistry

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

Published: September 12, 2018 doi: 10.3791/58063
Automatic Translation
*1, *1, 1, 1, 1,2
1School of Chemical Engineering and Light Industry, Guangdong University of Technology, 2Department of Chemistry, Graduate School of Science, Kyoto University
* These authors contributed equally

Summary

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.

Abstract

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.

Introduction

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 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.

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Protocol

1. Synthesis of 1-(Iodoethynyl)-4-Methylbenzene (2, 1-Iodoalkynes)

  1. 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 μL (0.3 mmol) of p-tolylethyne to the mixture using a microsyringe.
  2. 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.
  3. Stir the reaction mixture at room temperature for 3 h.
  4. 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.
  5. Wash the combined organic layers with 10 mL of saturated brine and dry over anhydrous sodium sulfate (0.5 g).
  6. Filter off the sodium sulfate using a Buchner funnel, and concentrate the filtrate under reduced pressure to obtain the crude product.
  7. 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).
  8. Analyze the product by 1H and 13C NMR spectroscopy, and high-performance liquid chromatography (HPLC).

2. Synthesis of (E)-1-(1,2-Diiodovinyl)-4-Methylbenzene (3, 1,2-Diiodoalkenes)

  1. 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 μL (0.3 mmol) of p-tolylethyne and 3 mL of H2O to the mixture via a microsyringe.
  2. 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.
  3. Stir the reaction mixture at room temperature for 24 h.
  4. 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.
  5. Wash the combined organic layers with 10 mL of brine and dry over anhydrous sodium sulfate (0.5 g).
  6. Filter off the sodium sulfate using a Buchner funnel, and concentrate the filtrate under reduced pressure to obtain the crude product.
  7. 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).
  8. Analyze the product by 1H and 13C NMR spectroscopy as well as HPLC.

3. Synthesis of 1-Methyl-4-(1,2,2-Triiodovinyl)benzene (4, 1,1,2-Triiodoalkenes)

  1. 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 μL (0.3 mmol) of p-tolylethyne using a microsyringe.
  2. 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.
  3. Add 124.5 mg (0.75 mmol) of KI in 3 mL of H2O to the reaction mixture.
  4. 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.
  5. Add another 124.5 mg (0.75 mmol) of KI in 3 mL of H2O and 1 mL of CH3CN to the reaction mixture.
  6. 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.
  7. 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.
  8. Wash the combined organic layers with 10 mL of brine and dry over anhydrous sodium sulfate (0.5 g).
  9. Filter off the sodium sulfate using a Buchner funnel, and concentrate the filtrate under reduced pressure to obtain the crude product.
  10. 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).
  11. Analyze the product by 1H and 13C NMR spectroscopy as well as HPLC.

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 μm, 4.6 mm × 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 λ = 254 nm.

  1. Preparation of the external standard solution for HPLC
    1. Precisely weigh out 2 (1-(iodoethynyl)-4-methylbenzene; 9.58 mg, 39.58×10-3 mmol), 3 ((E)-1-(1,2-diiodovinyl)-4-methylbenzene; 19.29 mg, 52.14×10-3 mmol), and 4 (1-methyl-4-(1,2,2-triiodovinyl)benzene; 11.10 mg, 22.38×10-3 mmol).
    2. Mix and dissolve these three compounds in 1 mL of CH3CN and dilute the stock solution 100 times before performing the HPLC separation.
    3. Determine the peak area ratio (%) of each product on HPLC chromatogram.
    4. Calculate the ratio of the molar absorptivity of each compound according to the following formula:
      ε2 : ε3 : ε4 = A2/n2 : A3/n3 : A4/n4
      where ε is the molar absorptivity, A the peak area, and n the molar weight.
  2. Calculate the chemoselectivity according to the following formula:
    n2 : n3 : n4 = A2/ε2 : A3/ε3 : A4/ε4

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Representative Results

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 are stable upon storage at 4 °C in a refrigerator for four months, i.e., significant changes in HPLC and 1H NMR data were not detected. Key data for representative compounds are described in this section.

The structure of 1-(iodoethynyl)-4-methylbenzene (2, 1-iodoalkynes) was determined by comparing its NMR data with reference data. 1H NMR (400 MHz, CDCl3): δ = 7.32 (d, J = 8.0 Hz, 2 H), 7.11 (d, J = 8.0 Hz, 2 H), 2.34 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 139.1, 132.2, 129.0, 120.4, 94.3, 21.6, 5.1. The key proton signal for the terminal alkyne (3.0 ppm) disappears and the observation of a signal at 5.1 ppm in the 13C NMR spectrum confirms the mono-iodination of p-tolylethyne (Figure 2), consistent with reported NMR data43. HPLC analysis: C18 (5 µm, 4.6 mm × 150 mm), CH3CN/H2O = 75/25 (v/v), flow rate = 1.0 mL/min−1, λ = 254 nm, retention time: 6.2 min (Figure 7).

The structure of (E)-1-(1,2-diiodovinyl)-4-methylbenzene (3, 1,2-diiodoalkenes) was determined by comparing its NMR data with reference data. 1H NMR (400 MHz, CDCl3): δ = 7.26 (d, J = 8.0 Hz, 2 H), 7.22 (s, 1 H), 7.15 (d, J = 8.0 Hz, 2 H), 2.34 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 140.2, 139.0, 129.0, 128.4, 96.6, 80.1, 21.4. The key proton signal in the olefin at 7.2 ppm confirms the di-iodination of p-tolylethyne, and 13C NMR spectrum shows the corresponding olefin carbon atoms at 96.6 ppm and 80.1 ppm, respectively (Figure 3). The NMR data are consistent with previously reported values, in which 3 was determined as the E type18. HPLC analysis: C18 (5 µm, 4.6 mm × 150 mm), CH3CN/H2O = 75/25 (v/v), flow rate = 1.0 mL/min−1, λ = 254 nm, retention time: 10.6 min (Figure 8).

The structure of 1-methyl-4-(1,2,2-triiodovinyl)benzene (4, 1,1,2-triiodoalkene) was determined by NMR, high-resolution mass spectrometry (HRMS), and HPLC. 1H NMR (400 MHz, CDCl3): δ = 7.16 (s, 4 H), 2.34 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 144.9, 138.9, 129.3, 127.4, 112.9, 22.2, 21.5 (Figure 4); HRMS (EI) calcd for C9H7I3: 495.7682 ([M]+); found: 495.7672 (Figure 5); HPLC analysis: C18 (5 µm, 4.6 mm × 150 mm), CH3CN/H2O = 75/25 (v/v), flow rate = 1.0 mL/min−1, λ = 254 nm, retention time: 11.5 min (Figure 9).

The chemoselectivity of the iodination was determined by HPLC. The HPLC performance of 2, 3, and 4 as external standards is shown in Figure 6. The molar ratio of 2, 3, and 4 as external standards is 39.58 : 52.14 : 22.38. The peak area ratio (%) in the HPLC chromatogram of 2:3:4 is 49.801% : 30.762% : 19.436% (Figure 6). Accordingly, the ratio of molar absorptivity is ε2: ε3: ε4= 2.131 : 1 : 1.472.

The TBAI-PIDA system selectively affords 2 (2:3:4= 100:0:0; Figure 7), while the KI-PIDA system selectively furnishes 3(2:3:4= 0.8:98.8:0.4; Figure 8). Combined in one-pot, the TBAI-PIDA and KI-PIDA systems efficiently yield 4 as a major product (2:3:4= 3.7:3.2:93.1; Figure 9).

Figure 1
Figure 1. Chemoselective mono-, di- and tri-iodination of alkynes. p-Tolylethyne was used as a model substrate. Please click here to view a larger version of this figure.

Figure 2
Figure 2. 1H NMR and 13C NMR spectra of 2. This figure has been reproduced from ref. 36 with permission. Please click here to view a larger version of this figure.

Figure 3
Figure 3. 1H NMR and 13C NMR spectra of 3. This figure has been reproduced from ref. 36 with permission. Please click here to view a larger version of this figure.

Figure 4
Figure 4. 1H NMR and 13C NMR spectra of 4. This figure has been reproduced from ref. 36 with permission. Please click here to view a larger version of this figure.

Figure 5
Figure 5. HRMS spectra of 4. This figure has been reproduced from ref. 36 with permission. Please click here to view a larger version of this figure.

Figure 6
Figure 6. HPLC spectrum of a mixture of 2, 3, and 4 mixture as external standards (2: 9.58 mg; 3: 19.29 mg; 4: 11.10 mg). This figure has been reproduced from ref. 36 with permission. Please click here to view a larger version of this figure.

Figure 7
Figure 7. HPLC spectrum of 2, synthesized using the TBAI-PIDA system. This figure has been reproduced from ref. 36 with permission. Please click here to view a larger version of this figure.

Figure 8
Figure 8. HPLC spectrum of 3, synthesized using the KI-PIDA system. This figure has been reproduced from ref. 36 with permission. Please click here to view a larger version of this figure.

Figure 9
Figure 9. HPLC spectrum of 3, synthesized using a combination of the TBAI-PIDA and KI-PIDA systems in one pot. This figure has been reproduced from ref. 36 with permission. Please click here to view a larger version of this figure.

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Discussion

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 (2:3:4= 90:5:5). When changing the iodine source to KI, such a selectivity was not observed, whereas using NH4I resulted in the predominant formation of 1,2-diiodoalkene 3. The details of the optimization of the reaction conditions are documented elsewhere36 (Table 1).

Several attempts were made to identify the optimal conditions for the formation of 1-iodoalkynes36. Firstly, the TBAB loading greatly affects the selectivity towards 1-iodoalkyne 2. Lowering the TBAB loading from 2.5 to 1.2 equiv favors the formation of 2. Secondly, the nature of the solvent strongly influences the formation of 1-iodoalkyne 2 in terms of selectivity and yield. For example, CH3CN, Et2O, THF, and DCM favor the synthesis of 2 in terms of yield (excellent) and selectivity (absolute). DMF and toluene afford 2 in good yield, albeit with slightly lower selectivity. Notably, 1-iodoalkynes are most efficiently generated by treating the terminal alkyne (1.0 equiv) at room temperature for 2−24 h with PIDA (1.0 equiv) and TBAI (1.2 equiv) in CH3CN, THF, or Et2O.

Changing the solvent to a CH3CN-H2O mixture dramatically enhances the chemoselectivity towards 1,2-diiodoalkene 3, when using KI as the iodine source. Optimal reaction conditions for the preparation of 1,2-diiodoalkenes were established as follows: treating the terminal alkyne (1.0 equiv) at room temperature for 2−24 h with PIDA (1.0 equiv) and KI (2.5 equiv) in MeCN-H2O (1:3)36.

A practical one-pot synthesis of 1,1,2-triiodoalkene 4 can be realized by combining the two aforementioned methods. Typically, terminal 4-ethynytoluene (1.0 equiv), PIDA (1.0 equiv), and TBAI (1.2 equiv) were stirred for 3 h at room temperature, followed by adding PIDA and an aqueous KI solution. Under these reaction conditions, 4-ethynytoluene was fully consumed; however, only 44% transformation was observed when 1.0 equiv of PIDA was using in the second step. Extending the reaction time did not increase the transformation. Therefore, the loading of PIDA (2.0 equiv) was increased in the second step to accelerate this transformation, leading to the formation of 4 in 88% yield as a major product. Interestingly, with an additional portion of PIDA and KI, a further increase of the yield of 4 (93%) was observed. Therefore, the reaction conditions for the synthetic method of 4 were optimized. (i) The terminal alkyne (1.0 equiv) was mixed with PIDA (1.0 equiv) and TBAI (1.2 equiv) for 3 h at room temperature in MeCN; (ii) after the addition of H2O, PIDA (2.0 equiv), and KI (2.5 equiv), the reaction mixture was stirred for another 3 h; (iii) with the addition of H2O, PIDA (2.0 equiv), and KI (2.5 equiv), the reaction mixture was stirred for another 12 h36.

Herein, we have presented practical methods for the chemoselective preparation of 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes based on the hypervalent-iodine catalyzed iodination of terminal alkynes. These methods feature high chemoselectivity, good yield, low toxicity, mild reaction conditions, and broad scope. We expect that these new synthetic methods can be applied to the efficient and chemoselective synthesis of more iodoalkyne derivatives, materials, intermediates, and biologically active compounds.

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Disclosures

The authors have nothing extraordinary to disclose.

Acknowledgments

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

Materials

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

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Chemoselective Preparation 1-iodoalkynes 1,2-diiodoalkenes 1,1,2-triiodoalkenes Oxidative Iodination Terminal Alkynes Organic Synthesis Green Method Practical Method Excellent Selectivity Mild Conditions Hypervalent Iodine Catalysts TBAI KI Iodine Source Material Synthesis Intermediates Biologically Active Compounds Tetrabutylammonium Iodide HPLC-grade Acetonitrile P-tolylethyne Microsyringe Diacetoxy Iodobenzene (PIDA) Deionized Water
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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Li, Y., Huang, D., Huang, J., Liu,… More

Li, Y., Huang, D., Huang, J., Liu, Y., Maruoka, K. Chemoselective Preparation of 1-Iodoalkynes, 1,2-Diiodoalkenes, and 1,1,2-Triiodoalkenes Based on the Oxidative Iodination of Terminal Alkynes. J. Vis. Exp. (139), e58063, doi:10.3791/58063 (2018).

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