(E)-Di-iodination of Alkynes Using Dried Dowex H⁺/NaI Approach

Abstract

We investigated the usefulness of the dried Dowex H⁺/NaI approach for the selective di-iodination of alkynes. The Dowex H⁺/NaI approach selectively produces only (E)-di-iodinated products; it is very straightforward and nontoxic. The utilization of 2-propanol as a solvent in the reactions can be considered as a “green” approach and the method maybe extended to radio-iodination. The method allows access to highly important building blocks. An initial example of the di-iodination and esterification in the same one-pot reaction is also presented.

Introduction

In recent decades, environmental issues have become one of the major questions to be tackled by industrial synthetic chemistry. The need to reduce the production of waste and the use of hazardous and toxic substances have stimulated a new way of thinking, so-called green chemistry. Green chemistry focuses on the design of processes that minimize and/or eliminate the use and the generation of hazardous substances while producing more environmentally friendly products.^1,2

As is generally known, perhaps the most traditional method for di-iodination is to use elemental I₂ as the source of iodine. However, if elevated temperatures are need, I₂ may not be practical because it sublimes so readily. Common methods for di-iodination reported in the literature consist of the use of hazardous and/or toxic compounds, such as oxidants, e.g., H₂O₂,³ iodine sources, e.g., trimethylsulfonium iodate⁴ and iodine monochloride,⁵ reagents like tetrafluoroboric acid⁶ and solvents, e.g., dichloromethane,⁵ dioxane,⁶ or tetrahydrofuran.³ Some procedures also use heavy-metal catalysts, like copper⁷ or cobalt.⁸

Iodinated compounds are indispensable building blocks in organic chemistry; they are extensively used in the creation of new covalent bonds, e.g., C–C,^9,10 C–N,¹¹⁻¹³ C–O,^14,15 C–B,^16,17 C–S,^18,19 and C–metal^20,21 bonds. Iodinated compounds can also be used as intermediates in the production of deuterium-labeled compounds.²² For example, α,β-diiodo alkenes have been used as building blocks while synthesizing a diverse group of compounds, e.g., substituted alkynes,^23,24 oxygen heterocycles,²⁵ carboxylic esters,²⁶ β-iodo alkenyl sulfides,²⁷ thiazoles,²⁸ oxazoles,²⁹ furans,³⁰ and tetracenes.³¹ Additionally, iodination is crucial in isotope labeling, as it serves as a way to achieve radio-iodination, which is necessary for positron emission tomography and single-photon-emission computed tomography imaging, cancer therapies, and diagnostics; most common radio-iodine source, e.g., for ¹²⁵I labeling, is [¹²⁵I ]NaI (sodium iodide).³²

In our laboratory, we have demonstrated that an oven-dried Dowex H⁺ ion-exchange resin can be a versatile and highly efficient tool in organic syntheses. In general, it is a regenerable, reusable, and easy-to-handle solid material that can be used for the synthesis of tertiary iodides, ethers, and esters; it can also be utilized in the transesterification of triglycerides to produce biodiesel, all of which we have reported earlier in our “proof-of-concept” paper.³³ Furthermore, we have evaluated the dried Dowex H⁺/NaX (X = Br, I) approach more systematically for its ability to achieve ring openings of cyclic ethers to produce useful building blocks;³⁴ more recently, we have reported a green and efficient esterification method based on the catalysis with the dried Dowex H⁺/NaI method³⁵ (Scheme 1).

Scheme 1. Green and Efficient Esterification and Oxygen-Containing Ring-Opening Reactions Reported Elsewhere Using the Dried Dowex H⁺/NaX (X = I, Br) Approach.

In the paper, we report a novel and simple one-pot reaction for the stereoselective di-iodination of alkynes using stable, nontoxic, and cheap sodium iodide (NaI) as an iodine source and “green” 2-propanol as the solvent by adopting the Dowex H⁺/NaI approach.

Results and Discussion

The general method and the reaction conditions for the selective (E)-di-iodination of alkynes by the dried Dowex H⁺/NaI method can be seen in Scheme 2. In Table 1, we have collected 12 examples of the prepared products (13–24) from different kinds of alkynes (1–12) using dried Dowex H⁺ cation-exchange resin with dried NaI. All of the reactions were performed in 2-propanol with the reagents left overnight (approx. 18 h) at 65 °C with 2.05 or 3 equiv of dried NaI as described in Scheme 2 and Table 1; more detailed reaction conditions and isolation procedures can be found in the Experimental Section.

Scheme 2. Selective (E)-Di-iodination of Alkynes Using the Dried Dowex H⁺/NaI Approach.

Table 1. Selective (E)-Di-iodination of Selected Alkynes by the Dried Dowex H⁺/NaI Approach.

^aReactions were performed in 2-propanol overnight (approximately 18 h) at 65 °C using 2.05 equiv of dried NaI.

^bYields.

^c3 Equiv NaI was used in the reaction.

The alkynes (1–12) for the iodination experiments were selected on the basis that the compounds were readily available, known to be cost-effective and eco-friendly and that those compounds have different kinds of functionalities and alkyl chains. All compounds (1–12) are commercially available; however, the ester 7 was prepared using the dried Dowex H⁺/NaI approach with the catalytic system that we recently reported.³⁵ We have previously reported the preparation of compound 17 from propargyl alcohol (5); however, in that case, we used only 1 equiv of NaI in the reaction and obtained a 60% yield.³³ In this paper, 2.05 equiv of NaI was used and the yield improved to 71% since now the propargyl alcohol (5) conversion to 17 was far more effective (actually the yield was only 30% when 1 equiv NaI was used if the yield was calculated from propargyl alcohol 5 because the di-iodinated product 17 was formed).

In general, according to the SciFinder search, very little attention has been paid to the (E)-di-iodinated compounds 13–24, which we have prepared and can be seen in Table 1. Surprisingly, compounds 19 and 21 were totally unknown and we could find only one reference for each of the compounds 14,³⁶15,⁵20,³ and 22(37) in the literature. In addition, in the preparation of compounds 18 and 23, only two^38,39 or three^31,40,41 methods have been described, respectively. This was rather unexpected because of the importance of (E)-di-iodinated compounds as discussed in the introduction.

In general, the synthesis of the target products (13–24) was very straightforward; it used 2-propanol as a solvent, which can be considered as a green alternative, and most of the products were sufficiently pure (≥95%) after isolation by extraction or crystallization (compound 23); only three of the products needed to be purified by column chromatography or thin-layer chromatography (TLC) (compounds 19, 21, and 24, Experimental Section). The yields were very reasonable (43–78%), except for compound 24 (23%); the main reason for this might be some kind of degradation of the starting material or intermediate products because only 126 mg of crude product was obtained after the isolation of 24 (Experimental Section), which is only about a 41% yield of the theoretical amount of 308 mg (100%).

The adoption of the dried Dowex H⁺/NaI approach with 2-propanol as the solvent with the reaction conditions presented in this paper was very selective for (E)-di-iodination because only in one case (synthesis of novel compound 21) were we able to detect a mono-iodinated compound in the crude product and then according to the ¹H NMR spectrum, only in very small amounts (<5%). In the crude product of novel compound 19, we observed only the desired product (19) and approximately 10% of the starting material 7; e.g., no monoiodinated compounds were present according to the ¹H NMR spectrum. The above-mentioned observations were the main reasons for the need of purification by column chromatography of compounds 19 and 21. Additionally, we also tested acetonitrile as a solvent with the dried Dowex H⁺/NaI approach for the di-iodination of alkynes with poor selectivity: mixtures of compounds were observed according to the ¹H NMR spectra; however, in some cases, the results were sufficiently interesting for the research to be continued utilizing acetonitrile as the solvent.

In the (E)-di-iodination reactions, 2.05 or 3 equiv of NaI was used; the reason for the use of 3 equiv NaI instead of 2.05 equiv in the case of 15, 19, and 21 were in better yields, e.g., in the synthesis of 15, the yields were 68 and 51%, respectively, whereas in the synthesis of 22, there was no difference if 3 equiv or 2.05 equiv of NaI was used (71 or 72% yields, respectively). The mass/mass ratios of the dried Dowex H⁺ and NaI utilized in the above-mentioned experiments were approximately the same [e.g., in the case of 22, Dowex H⁺/NaI (1000 mg/300 mg, 3 equiv) or (700 mg/205 mg, 2.05 equiv)]. In general, the mass ratios varied from 2.6 to 4.4/1.0 (Dowex H⁺/NaI), meaning that the amount of Dowex H⁺ was not optimized; actually, investigations to define the “optimal” amount of dried Dowex H⁺ in the reactions are underway, and these will be published in the future.

Last but not least, we also tested the di-iodination reaction for the alkyne containing a carboxylic acid group (25, Scheme 3) and observed that there was a selective (E)-di-iodination and esterification at the same time in the one-pot reaction to produce compound 19 with a 32% yield. The result was not surprising because of our earlier experiences of the benefits of utilizing dried Dowex H⁺/NaI as a catalyst for esterification reactions.³⁵ However, according to a SciFinder search, as far as we are aware, this is the first example of the addition of any kind of halogen to a triple bond with the esterification of carboxylic acid (substitution and condensation reactions) at the same time in a one-pot reaction.

Scheme 3. First Example of the Di-iodination and Esterification in the Same Reaction in One Pot.

Conclusions

A selective method for (E)-di-iodination of alkynes by using the dried Dowex H⁺/NaI approach has been presented. Di-iodinations were achieved using only an I^– (NaI) source instead of the more common I₂ or both I^– and I⁺ (e.g., ICl). In the method, a green solvent, 2-propanol, was used along with reasonable reaction conditions, and in addition, most of the products did not need any chromatography purifications after their isolation by extraction or crystallization (compound 23). The initial example of the addition of iodine to the triple bond and esterification at the same time in one-pot reaction has been demonstrated. The exact reaction mechanism for di-iodination is unclear, although it is a topic of interest and, if solved, will be published as soon as possible with our further studies related to other reactions, which can be conducted with the present method. Furthermore, the method presented here may open a new way to produce very important radio-iodinated compounds. Ultimately, we believe that our method will become widely used in various kinds of organic syntheses as described in our earlier publications³³⁻³⁵ and the results presented here.

Experimental Section

General

¹H and ¹³C NMR spectra were recorded on a 600 MHz spectrometer operating at 600.2 and 150.9 MHz, respectively. The solvent residual peak was used as a standard in the ¹H and ¹³C{¹H} measurements in deuterated chloroform (CDCl₃) and deuterated methanol (CD₃OD) (7.26 or 77.16 ppm for CDCl₃ and 3.31 or 49.00 ppm for CD₃OD),⁴² in D₂O 4.79 ppm in ¹H measurements, and added CD₃OD in the ¹³C{¹H} measurements (49.00 ppm). The ⁿJ_HH couplings were calculated from the proton spectra, and all J values are given in Hz. The appropriate two-dimensional NMR measurements were performed to confirm structures when needed. Mass spectra were recorded on a quadrupole time-of-flight mass spectrometer using electrospray ionization (ESI) with a positive ionization mode for compound 19 and a negative ionization mode for compound 21. The purity of the products was determined from ¹H spectrum and was ≥95% unless stated otherwise. All starting materials (1–12) and the Dowex H⁺ ion-exchange resin used in the study were commercially available; however, isopropyl hex-5-ynoate (7) was prepared using the method we reported recently.³⁵

Example of the Preparation of Dried Dowex H⁺ Ion-Exchange Resin

Dowex ion-exchange resin (50Wx8 hydrogen form, 100–200 mesh; 25 g) was stirred for 0.5 h in 2 M HCl solution (50 mL) at room temperature before it was filtered, washed, with distilled H₂O until the filtrate pH was neutral. Finally, Dowex was dried in an oven for 18–20 h at 120 °C and stored in a closed bottle.

Preparation of (E)-(1,2-Diiodovinyl)benzene (13)

Phenylacetylene (46.5 mg, 50 μL, 0.46 mmol), dried NaI (140 mg, 0.93 mmol, 2.05 equiv), dried Dowex 50W-X8 ion-exchange resin (H⁺ form, 500 mg), and 2-propanol (5 mL) were stirred overnight (approximately 18 h) at 65 °C before Dowex was collected after filtration, washed with 2-propanol, and then 2-propanol removed in vacuo. The residue was dissolved in dichloromethane (DCM) (5 mL), washed with 10% Na₂S₂O₃ (sodium thiosulfate, 1–2 mL), dried over MgSO₄, and DCM removed in vacuo. (E)-(1,2-Diiodovinyl)benzene (76 mg, 47%) was obtained as an amorphous solid. NMR data were comparable with those reported elsewhere.³⁶¹H NMR (CDCl₃): δ 7.39–7.31 (m, 5H), 7.26 (s, 1H). ¹³C{¹H} NMR (CDCl₃): δ 143.2, 129.1, 128.64 (2C), 128.57 (2C), 96.3, 80.9.

Preparation of (E)-(3,4-Diiodobut-3-en-1-yl)benzene (14)

Prepared similarly as 13 from 4-phenyl-1-butyne (50 mg, 54 μL, 0.38 mmol), dried NaI (118 mg, 0.79 mmol, 2.05 equiv), dried Dowex 50W-X8 ion-exchange resin (H⁺ form, 400 mg), and 2-propanol (4 mL). (E)-(3,4-Diiodobut-3-en-1-yl)benzene (115 mg, 78%) was obtained as a slightly yellow oil. NMR data were comparable with those reported elsewhere.³⁶¹H NMR (CDCl₃): δ 7.33–7.28 (m, 2H), 7.27–7.21 (m, 3H), 6.85 (s, 1H), 2.86–2.79 (m, 4H). ¹³C{¹H} NMR (CDCl₃): δ 139.7, 128.9 (2C), 128.6 (2C), 126.5, 102.5, 80.2, 47.0, 34.3.

Preparation of (E)-((2,3-Diiodoallyl)oxy)benzene (15)

Prepared similarly as 13 from phenyl propargyl ether (51.5 mg, 50 μL, 0.39 mmol), dried NaI (170 mg, 1.13 mmol, 3 equiv), dried Dowex 50W-X8 ion-exchange resin (H⁺ form, 750 mg), and 2-propanol (6 mL). (E)-((2,3-Diiodoallyl)oxy)benzene (102 mg, 68%) was obtained as an amorphous solid. NMR data were comparable with those reported elsewhere.⁵¹H NMR (CDCl₃): δ 7.34–7.29 (m, 2H), 7.20 (t, 1H, ⁵J_HH = 1.1), 7.03–6.99 (m, 1H), 6.97–6.93 (m, 2H), 4.70 (d, 2H, ⁵J_HH = 1.1). ¹³C{¹H} NMR (CDCl₃): δ 157.6, 129.7 (2C), 121.9, 115.6 (2C), 99.2, 82.0, 74.9.

Preparation of (E)-1,2-Diiodohex-1-ene (16)

Prepared similarly as 13 from 1-hexyne (100.5 mg, 140 μL, 1.22 mmol), dried NaI (376 mg, 2.51 mmol, 2.05 equiv), dried Dowex 50W-X8 ion-exchange resin (H⁺ form, 1 g), and 2-propanol (7 mL) except that diethyl ether was used instead of DCM in the isolation. (E)-1,2-Diiodohex-1-ene (207 mg, 50%) was obtained as a colorless liquid. NMR data were comparable with those reported elsewhere.⁸¹H NMR (CDCl₃): δ 6.80 (s, 1H), 2.51 (t, 2H, ³J_HH = 7.4), 1.56–1.49 (m, 2H), 1.41–1.34 (m, 2H), 0.95 (t, 3H, ³J_HH = 7.3). ¹³C{¹H} NMR (CDCl₃): δ 104.5, 79.0, 44.6, 30.5, 21.5, 14.1.

Preparation of (E)-2,3-Diiodo-prop-2-en-1-ol (17)

Prepared similarly as 13 from propargyl alcohol (50 μL, 48.6 mg, 0.87 mmol), dried NaI (267 mg, 1.78 mmol, 2.05 equiv), dried Dowex 50W-X8 ion-exchange resin (H+ form, 1 g), and 2-propanol (8 mL) except that the water phase was extracted one more time with DCM in an isolation step. (E)-2,3-Diiodo-prop-2-en-1-ol (191 mg, 71%) was obtained as a slightly yellow solid. NMR data were comparable with those reported elsewhere.³³¹H NMR (CDCl₃): δ 7.05 (s, 1H), 4.29 (s, 2H), 1.90 (br, 1H). ¹³C{¹H} NMR (CDCl₃): δ 104.1, 79.9, 71.0.

Preparation of (E)-3,4-Diiodobut-3-en-1-ol (18)

Prepared similarly as 13 from 3-butyn-1-ol (92.6 mg, 100 μL, 1.32 mmol), dried NaI (406 mg, 2.71 mmol, 2.05 equiv), dried Dowex 50W-X8 ion-exchange resin (H⁺ form, 1 g), and 2-propanol (8 mL) except that the water phase was extracted one more time with DCM in an isolation step. (E)-1,2-Diiodohex-1-ene (323 mg, 75%) was obtained as a slightly purple oil. NMR data were comparable with those reported elsewhere.³⁸¹H NMR (CD₃OD): δ 7.11 (s, 1H), 3.70 (t, 2H, ³J_HH = 6.8), 2.77 (t, 2H, ³J_HH = 6.8). ¹³C{¹H} NMR (CD₃OD): δ 99.5, 82.3, 60.9, 48.8.

Preparation of Isopropyl (E)-5,6-Diiodohex-5-enoate (19)

Prepared similarly as 13 from isopropyl hex-5-ynoate (100 mg, 0.65 mmol), dried NaI (292 mg, 1.95 mmol, 3 equiv), dried Dowex 50W-X8 ion-exchange resin (H⁺ form, 1 g), and 2-propanol (10 mL). Crude product was purified by silica column chromatography using hexane/ethyl acetate (95:5) as the eluent. Isopropyl (E)-5,6-diiodohex-5-enoate (179 mg, 68%) was obtained as a colorless oil. ¹H NMR (CDCl₃): δ 6.88 (s, 1H), 5.06–4.99 (m, 1H), 2.58 (t, 2H, ³J_HH = 7.4), 2.33 (t, 2H, ³J_HH = 7.4), 1.88 (t, 2H, ³J_HH = 7.4), 1.25 (d, 6H, ³J_HH = 6.3). ¹³C{¹H} NMR (CDCl₃): δ 172.6, 102.9, 80.2, 68.0, 44.1, 33.0, 23.6, 22.1 (2C). MS (ESI⁺) calcd. for C₉H₁₅O₂I₂ [M + H]⁺ 408.9162, found: 408.9155.

Preparation of (E)-2,3-Diiodohex-2-ene (20)

Prepared similarly as 13 from 2-hexyne (102.5 mg, 140 μL, 1.25 mmol), dried NaI (383 mg, 2.56 mmol, 2.05 equiv), dried Dowex 50W-X8 ion-exchange resin (H⁺ form, 1 g), and 2-propanol (7 mL) except that diethyl ether was used instead of DCM in the isolation. (E)-2,3-Diiodohex-2-ene (212 mg, 51%) was obtained as a slightly purple liquid. NMR data were comparable with those reported elsewhere.³¹H NMR (CDCl₃): δ 2.65 (t, 2H, ³J_HH = 7.5), 2.62 (s, 3H), 1.63–1.55 (m, 2H), 0.96 (t, 3H, ³J_HH = 7.4). ¹³C{¹H} NMR (CDCl₃): δ 103.0, 93.3, 52.6, 40.5, 21.9, 13.0.

Preparation of (E)-3,4-Diiodopent-3-en-1-ol (21)

Prepared similarly as 13 from 3-pentyn-1-ol (100.3 mg, 110 μL, 1.19 mmol), dried NaI (534 mg, 3.56 mmol, 3 equiv), dried Dowex 50W-X8 ion-exchange resin (H⁺ form, 1.5 g), and 2-propanol (10 mL). The crude product was purified by silica column chromatography using hexane/ethyl acetate (3:1) as the eluent. (E)-3,4-Diiodopent-3-en-1-ol (173 mg, 43%) was obtained as a white solid. Mp 69–70 °C. ¹H NMR (CD₃OD): δ 3.69 (t, 2H, ³J_HH = 7.2), 2.96–2.91 (m, 2H), 2.61 (t, 3H, ⁵J_HH = 0.9). ¹³C{¹H} NMR (CD₃OD): δ 98.1, 96.0, 60.9, 54.7, 41.0. MS (ESI^–) calcd. for C₅H₇OI₂ [M – H]⁻ 336.8586, found: 336.8593.

Preparation of (E)-2,3-Diiodobut-2-en-1-ol (22)

Prepared similarly as 13 from 2-butyn-1-ol (50 μL, 46.9 mg, 0.67 mmol), dried NaI (205 mg, 1.37 mmol, 2.05 equiv), dried Dowex 50W-X8 ion-exchange resin (H⁺ form, 700 mg), and 2-propanol (8 mL) except that the water phase was extracted one more time with DCM in the isolation step. (E)-2,3-Diiodobut-2-en-1-ol (156 mg, 72%) was obtained as a beige solid. NMR data were comparable with those reported elsewhere.³⁷¹H NMR (CD₃OD): δ 4.36–4.34 (m, 2H), 4.29 (s, 2H), 2.65 (t, 3H, ⁵J_HH = 0.9). ¹³C{¹H} NMR (CD₃OD): δ 104.5, 94.7 77.0, 40.8.

Preparation of (E)-2,3-Diiodobut-2-ene-1,4-diol (23)

Prepared similarly as 13 from 1,4-dihydroxy-2-butyne (100 mg, 1.16 mmol), dried NaI (357 mg, 2.38 mmol, 2.05 equiv), dried Dowex 50W-X8 ion-exchange resin (H⁺ form, 1 g) and 2-propanol (10 mL). The crude product was dissolved in DCM and the final product was filtered, washed with DCM and dried in vacuo. (E)-2,3-Diiodobut-2-ene-1,4-diol (286 mg, 72%) was obtained as a white powder. NMR data were comparable with those reported elsewhere.³¹¹H NMR (CD₃OD): δ 4.20 (s, 4H). ¹³C{¹H} NMR (CD₃OD): δ 104.5 (2C), 76.2 (2C).

Preparation of (E)-1,4-Dichloro-2,3-diiodobut-2-ene (24)

Prepared similarly as 13 from 1,4-dichloro-2-butyne (100.6 mg, 100 μL, 0.82 mmol), dried NaI (250 mg, 1.67 mmol, 2.05 equiv), dried Dowex 50W-X8 ion-exchange resin (H⁺ form, 1 g), and 2-propanol (10 mL). A total of 126 mg of crude product was obtained; 68 mg of the crude product was purified by silica TLC using ethyl acetate/hexane (1:9) as the eluent. (E)-1,4-Dichloro-2,3-diiodobut-2-ene (Rf. 0.6, 38 mg, 23%) was obtained as a white solid. NMR data were comparable with those reported elsewhere.⁴³¹H NMR (CDCl₃): δ 4.57 (s, 4H). ¹³C{¹H} NMR (CDCl₃): δ 101.4 (2C), 61.1 (2C).

Example for the One-Pot Preparation of Isopropyl (E)-5,6-Diiodohex-5-enoate (19) Starting from 5-Hexynoic Acid (25) (Scheme 3)

5-Hexynoic acid (50.8 mg, 50 μL, 0.45 mmol), dried NaI (140 mg, 0.93 mmol, 2.05 equiv), dried Dowex 50W-X8 ion-exchange resin (H⁺ form, 500 mg), and 2-propanol (5 mL) were stirred overnight (approximately 18 h) at 65 °C before Dowex was collected after filtration, washed with 2-propanol, and then 2-propanol removed in vacuo. A total of 158 mg of crude product was obtained; 74 mg of the crude product was purified by silica TLC using ethyl acetate/hexane (5:95) as the eluent. Isopropyl (E)-5,6-diiodohex-5-enoate (28 mg, Rf. 0.36, 32%) was obtained as a colorless oil. NMR characterization data were comparable to those reported earlier for 19.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.9b02577.

• ¹H and ¹³C NMR spectra for all the prepared compounds 13–24 (PDF)

The authors declare no competing financial interest.