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

Youzhi Li; Daya Huang; Ju Huang; Yan Liu; Keiji Maruoka

doi:10.3791/58063

JoVE Journal > Chemistry

化学

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

Youzhi Li*¹, Daya Huang*¹, Ju Huang¹, Yan Liu¹, Keiji Maruoka^1,2

¹School of Chemical Engineering and Light Industry,Guangdong University of Technology, ²Department of Chemistry, Graduate School of Science,Kyoto University

概要

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.

Protocol

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

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.
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 at room temperature for 3 h.
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.
Wash the combined organic layers with 10 mL of saturated brine and dry over anhydrous sodium sulfate (0.5 g).
Filter off the sodium sulfate using a Buchner funnel, and concentrate the filtrate under reduced pressure to obtain the crude product.
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; R_f = 0.79).
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)

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.
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 at room temperature for 24 h.
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.
Wash the combined organic layers with 10 mL of brine and dry over anhydrous sodium sulfate (0.5 g).
Filter off the sodium sulfate using a Buchner funnel, and concentrate the filtrate under reduced pressure to obtain the crude product.
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; R_f = 0.84).
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)

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.
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.
Add 124.5 mg (0.75 mmol) of KI in 3 mL of H₂O to the reaction mixture.
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.
Add another 124.5 mg (0.75 mmol) of KI in 3 mL of H₂O and 1 mL of CH₃CN to the reaction mixture.
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.
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.
Wash the combined organic layers with 10 mL of brine and dry over anhydrous sodium sulfate (0.5 g).
Filter off the sodium sulfate using a Buchner funnel, and concentrate the filtrate under reduced pressure to obtain the crude product.
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; R_f = 0.79).
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.

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^-3mmol), and 4 (1-methyl-4-(1,2,2-triiodovinyl)benzene; 11.10 mg, 22.38×10^-3mmol).
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.
Calculate the chemoselectivity according to the following formula:
n₂ : n₃ : n₄ = A₂/ε₂ : A₃/ε₃ : A₄/ε₄

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. 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. 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. 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. 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. 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. 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. 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. 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. 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.

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.

開示

The authors have nothing to disclose.

Acknowledgements

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

Materials

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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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).

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