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Article

Vinylation of Alcohols, Thiols, and Nitrogen Compounds Using a Stoichiometric Amount of In Situ Generated Acetylene

by
Maria S. Ledovskaya
*,
Vladimir V. Voronin
,
Anna A. Reznichenko
and
Ekaterina A. Reznichenko
Institute of Chemistry, Saint Petersburg State University, Universitetsky Prospect 26, 198504 Saint Petersburg, Russia
*
Author to whom correspondence should be addressed.
Organics 2025, 6(1), 5; https://doi.org/10.3390/org6010005
Submission received: 22 November 2024 / Revised: 13 January 2025 / Accepted: 21 January 2025 / Published: 8 February 2025
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Abstract

:
In this work, we developed a highly efficient and versatile environmentally benign methodology for the vinylation of a broad scope of substances, including alcohols, thiols, and nitrogen compounds. The key advantage of the proposed method is the use of calcium carbide as a robust acetylene source in a stoichiometric ratio to the substrates. Lacking the requirement of acetylene excess, the developed protocol is safe, highly economic, and limits waste production. The procedure allows for a large variety of O-,S-,N-vinyl compounds to be synthesized in up to quantitative yields. Our methodology is scalable, allowing us to obtain vinyl derivatives in Gram-scale quantities. We also demonstrated the significant synthetic value of our approach by performing a label-economic synthesis of 13C2-labeled vinyl derivatives using calcium carbide-13C2. In our well-optimized process, the conversion of Ca13C2 reached 89%.

Graphical Abstract

1. Introduction

Vinyl ethers and their sulfur and nitrogen analogs are widely distributed in medicine, industry, and organic synthesis. A vinyl group binded to a heteroatom is a common structural motif of a great variety of natural products, pharmaceuticals, and agrochemicals [1,2,3,4,5,6,7,8]. In organic synthesis, the O-,S-,N-vinyl function is a useful building block for the construction of heterocycles and polymeric materials [3,4,5,6,7,8,9,10,11,12].
The most commonly used synthetic approaches to O-,S-,N-vinyl derivatives are the nucleophilic addition of alcohols, thiols, and amines or nitrogen heterocycles to acetylene (Scheme 1a, path A) [13,14,15,16,17,18,19,20,21,22,23], vinyl exchange reactions (Scheme 1a, path B) [24,25,26,27], various elimination reactions (Scheme 1a, path C) [23,28,29,30], and vinyl source cross-coupling reactions (Scheme 1a, path D) [31,32,33,34,35]. Recent studies have shown that using calcium carbide instead of gaseous acetylene in reactions with alcohols, thiols, and aromatic amines or nitrogen heterocycles enables the synthesis of vinyl ethers and their sulfur and nitrogen analogs [36,37,38,39,40,41,42].
The use of calcium carbide as a solid acetylene analog in organic synthesis has gained significant attention over the past decade (Scheme 1b) [43,44]. Calcium carbide is readily available and inexpensive. It is a relatively stable solid material that can be easily weighed and precisely dosed. Reacting with water allows it to produce acetylene in a controlled manner. This highlights the key advantages of using calcium carbide over acetylene, including enhanced safety, reduced explosion risk, simplicity, and no necessity of using gas equipment. Over the past decade, calcium carbide has proven to be an incredibly versatile reagent in organic synthesis, as it is green, inexpensive, and readily available. It has been used to synthesize a wide range of functionalized alkynes [45,46,47,48,49,50], alkenes [36,37,38,39,40,41,42,51,52,53,54], dienes [55], and allenes [48], as well as heterocycles such as pyrroles [56,57], pyrazoles [54,58,59,60,61], imidazoles [62], triazoles [58,63], isoxazoles [58,64], lactams [65], pyridines [66], pyridazines [9,58], pyrimidines [67], benzofurans and benzothiophenes [68,69], and a great number of carbo- and heterocyclic compounds (Scheme 1b) [70,71,72,73,74,75,76].
There is no doubt that it is more convenient and safe to use calcium carbide in laboratory practice instead of acetylene gas. However, when using calcium carbide, a large amount of inorganic waste is generated. When reacted with water, 1 mole of calcium carbide is converted into 1 mole of acetylene and 1 mole of calcium hydroxide, and most synthetic methods involving calcium carbide imply the use of excess amounts of CaC2 (2–12 equivalents) [43,44]. This means that when 1 mole of an organic substance is synthesized from CaC2, 2 to 12 moles of calcium hydroxide containing organic and inorganic impurities are formed. The basic principles of green chemistry require preventing or at least reducing reaction waste [77,78,79,80,81], and while working with calcium carbide, we have noted the potential for performing some reactions stoichiometrically.
In the current work, we demonstrated that reactions of calcium carbide and alcohols, thiols, and aromatic nitrogen compounds can be performed almost stoichiometrically, allowing for unprecedented results to be reached in minimizing reaction wastes (Scheme 1c). The current synthetic procedure allows for the usage of approximately 1 equivalent of calcium carbide and only 0.25 to 0.5 equivalents of base to synthesize O-,S-,N-vinyl compounds in up to quantitative yields. The replacement of calcium carbide with calcium carbide-13C2 allowed us to perform an isotope-economic synthesis of 13C2-labeled vinyl derivatives.

2. Materials and Methods

2.1. General

Granulated calcium carbide (95% gas volumetric) was purchased from Sigma Aldrich. Calcium carbide-13C2 (approx. 95% purity) was synthesized using the previously reported methodology [82]. All chemicals were purchased from Sigma Aldrich, Alfa Aesar, and Acros Organics in reagent-grade or better quality and used without further purification. NMR spectra were recorded on the Bruker Avance III (1H 400 MHz; 13C 101 MHz) spectrometer. Chemical shifts δ are reported in ppm relative to residual DMSO (1H, δ = 2.50), CHCl3 (1H, δ = 7.26), or C6H6 (1H, δ = 7.16) and DMSO-d6 (13C, δ = 39.52), CDCl3 (13C, δ = 77.16), or C6D6 (13C, δ = 128.06) as internal standards. High-resolution mass spectra (HRMS) were recorded on Shimadzu Nexera X2 LCMS-9030 spectrometers using electrospray ionization (ESI). Preparative column chromatography was performed on Merck silica gel 60 (230–400 Mesh), which was previously treated with trimethylamine, or basic alumina (60–325 mesh).

2.2. General Procedure for the Synthesis of 2a–w

A 8.6 mL culture tube equipped with a screw cap (see Figure S1) was loaded with potassium tert-butoxide (56 mg (0.5 mmol) in the case of 1a–m; 112 mg (1.0 mmol) in the case of 1n–w), potassium fluoride (58 mg, 1.0 mmol in the case of 1a–m), 1a–w (2.0 mmol), CaC2 (140 mg, 2.1 mmol), and a solvent—1.0 mL of DMSO in the case of 1a–m; 120 µL of DMSO in 1.0 mL of 1,4-dioxane in the case of 1n–w. Then, water (85 µL, 4.7 mmol) was carefully added and the tube was thoroughly sealed and heated to 130 °C in the case of 1a-m or to 100 °C in the case of 1n–w. Reaction time: 7h in the case of 1a–h; 5h for 1i–w. Please note that liquid substrates should be loaded into the ampoule after all the solid materials. After, the reaction mixture was cooled to room temperature, compounds 2a–m were extracted with hexane directly from the reaction tube, and the mixtures containing 2n–w were diluted with 1.0 mL of water and then extracted with hexane from the reaction tube. Extraction procedure: 1.0 mL of hexane was added to the reaction vessel, which was then closed and shaken. The hexane layer was subsequently separated with a Pasteur pipette. The procedure was repeated 3 to 7 times. The product 2k was extracted with diethyl ether. After that, the combined hexane (ether) extracts were washed three times with water, dried over Na2SO4, and evaporated to obtain pure 2a–w. If necessary, a product was purified with column chromatography (Et3N-pretreated SiO2 or basic Al2O3) using hexane as an eluent.

2.3. Gram-Scale Synthesis of Benzyl Vinyl Sulfide 2n

A 32 mL reaction tube was loaded with 0.448 g (4.0 mmol) of KOtBu, calcium carbide (0.538 g, 8.4 mmol), benzyl thiol 1n (0.992 g, 8.0 mmol), 480 µL of DMSO, and 4.0 mL of 1,4-dioxane. Then, 340 µL of water was added carefully and the tube was immediately sealed. The mixture was stirred at 100 °C for 5h. After that, the reaction mixture was cooled to room temperature and extracted with hexane as described previously. The solvent from hexane extract was evaporated to obtain 1.040 g (87%) of pure benzyl vinyl sulfide 2n as a colorless oil.

2.4. General Procedure for the Synthesis of 4a,i

A 3.6 mL culture tube equipped with a screw cap was loaded with potassium tert-butoxide (28 mg (0.25 mmol)), potassium fluoride (29 mg, 0.5 mmol), 1a or 1i (1.0 mmol), Ca13C2 (70 mg, 1.05 mmol), and 0.5 mL of DMSO. Then, water (45 µL, 2.5 mmol) was carefully added and the tube was thoroughly sealed and heated to 130 °C for 7h in the case of 1a or for 5h in the case of 1i. After, the reaction mixture was cooled to room temperature, and product (4a or 4i) was extracted with hexane, as described previously. The solvent from the hexane extract was evaporated to obtain pure 4a,i.

3. Results and Discussion

A reaction between benzyl alcohol 1a and calcium carbide was selected as the initial model process for our study. Potassium tert-butoxide was used as the base, which has previously demonstrated excellent results in vinylation reactions [10,40], and potassium fluoride was used as an additional promoting agent [2,44,83]. First, we varied the quantity of KOtBu (Table 1, Entry 1–3) and estimated that only 0.5 mmol of the base per 2.0 mmol of 1a can be used. Further, we decided to investigate whether using a 5% excess of calcium carbide would facilitate the reaction yield (Table 1, Entry 4), and the result was positive: the yield of 2a increased to 86%. By increasing the reaction time to 7 h (Table 1, Entry 5), we synthesized 2a in 95% yield.
As a model nitrogen substrate, carbazole 1i was selected. With the previous results at hand, a 5% excess of CaC2 was used for the reactions with 1i. We varied the quantity of KOtBu (Table 1, Entry 6–10) and estimated that 0.5 mmol of the base per 2.0 mmol of 1i allows for the synthesis of 2i in a very good yield (85%, Table 1, Entry 9).
As a rule, the synthesis of aryl vinyl sulfides and alkyl vinyl sulfides requires a mild base, for example, triethylamine [2,44]. But, we were interested in using KOtBu as it is safer than Et3N. To modify a base strength, we diluted DMSO with a large volume of 1,4-dioxane (1.0 mL per 120 µL of DMSO, marked as DX). Model substrates containing SH-function, thiophenol 1o, and n-dodecanethiol 1w were selected. The temperature of the reaction was lowered to 100 °C to avoid the double addition of thiols to acetylene. When using 1.0 mmol of KOtBu, the reaction time was varied (Table 1, Entries 11,12 for 1o and 14,15 for 1w), and then the effect of a 5% excess of calcium carbide was investigated (Table 1, Entries 12,13 for 1o and 15,16 for 1w). The best results were observed when the reaction time was 5 h and 1.05 equiv. of CaC2 was used (Table 1, Entry 13,16): the yields of 2o and 2w were 94% and 97%, respectively.
With the optimized reaction conditions at hand, alcohols 1a–h, nitrogen compounds 1i–m, and thiols 1n–w were tested in the reaction with calcium carbide. Benzyl alcohols 1a–h demonstrated excellent reactivity: substituted benzyl vinyl ethers 2a–h were synthesized in good to quantitative yields (Table 2). The only exception was the reaction with 3-fluorobenzyl alcohol 1f, which resulted in the formation of two products: vinyl ether 2f in 48% yield and 3-fluorobenzyloxy-substituted vinyl ether 3 in 23% yield relative to CaC2 or 45% relative to 1f (Scheme 2). We proposed that the mixture of potassium tert-butoxide and dimethyl sulfoxide acts as a superbase [17,36]. In superbasic media, 1f converts to anion A, which attacks vinyl ether 2f forming an anionic complex B. Anion B loses fluorine anion, which results in the production of adduct 3. To check this hypothesis, we performed the reaction of 2f and 1f by heating to 130 °C in the presence of KOtBu in DMSO and detected the formation of 3 in 40% yield after 2 h.
Among the nitrogen compounds 1i–m, the best results were observed for the reactions of carbazole 1i and indole 1j, with the corresponding vinyl derivatives 2i and 2j synthesized in 85% and 84% yields, respectively. Imidazole 1k also demonstrated good reactivity towards calcium carbide with 70% yield of 2k. Iminodibenzyl 1l and diphenylamine 1m reacted with calcium carbide to produce vinyl amines 2l and 2m in 64% and 78% yields, respectively.
Thiols 1n–w were tested in the reaction with calcium carbide, and the results were excellent. Benzyl thiol 1n and n-dodecane thiol 1w reacted with CaC2-derived acetylene with the formation of 2n and 2w in 90% and 97% yields, respectively. Thiophenol 1o and its substituted analogs 1p–u also demonstrated good reactivity towards calcium carbide with compounds 2o–u synthesized in yields ranging from 83% to 99%. The derivative of 2-mercaptopyridine (2v) was synthesized in 62% yield.
To investigate the scalability of the developed procedure, a Gram-scale experiment was performed using 1n as a substrate (Scheme 3). The reaction of 8.0 mmol of benzyl thiol 1n (0.992 g) and 8.4 mmol of calcium carbide resulted in the formation of 2n in 87% yield (1.040 g), which is comparable with the result of the 2 mmol-scale reaction (90%).
In previous studies, we developed a synthetic approach to calcium carbide-13C2 using calcium and the most cost-effective source of carbon-13, 13C-elemental carbon [82,84]. The substitution of calcium carbide with its 13C2-labeled analog enables the construction of 13C2-labeled molecules. In the synthesis of 13C-labeled molecules, isotope economy is crucial; therefore, we decided to use Ca13C2 in our new methodology. As substrates for the synthesis of 13C2-vinyl compounds, benzyl alcohol 1a and carbazole 1i were selected. The reactions were performed using 1.0 mol of substrate 1a or 1i, and the quantities of all components were recalculated proportionally (Scheme 4). The results were comparable to those obtained from reactions of unlabeled calcium carbide. Benzyl alcohol 1a reacted with labeled Ca13C2, producing benzyl 13C2-vinyl ether 4a in 89% yield, while the reaction of carbazole 1i and calcium carbide-13C2 resulted in 83% yield of N-(13C2-vinyl)-1H-carbazole 4i.
13C2-Vinyl ethers and their sulfur or nitrogen analogs appear to be convenient synthons for constructing 13C2-labeled heterocycles. In our previous works, we demonstrated that D- and 13C-labeled vinyl ethers and their sulfur or nitrogen analogs can be used as acetylene surrogates in the synthesis of D-labeled pyridazines [9], pyrazoles [10], and 2-isoxazolines [85], or 13C2-labeled pyridazines [84], respectively. We believe that the current methodology, which allows us to perform the synthesis of 13C2-vinyl compounds in a label-economic manner, will find applications in 13C-labeling.

4. Conclusions

To summarize, a simple, efficient, and widely applicable synthetic approach to vinyl ethers and their sulfur and nitrogen analogs was developed. A detailed investigation of the vinylation reactions allowed us to reach unprecedented results by performing atom-economic reactions with almost stoichiometric quantities of substrates and in situ-generated acetylene. As a source for the in situ generation of acetylene gas, calcium carbide was successfully used. So, the reaction wastes were minimized: during the synthesis of 1 mol of O-,S-,N-vinyl compounds, only 1.05 mol of calcium hydroxide is produced, and 0.25 to 0.5 mol of additional base is required.
As a final point, replacing calcium carbide to Ca13C2 in our methodology, we synthesized 13C2-vinyl compounds with excellent 13C-label economy, achieving a conversion of calcium carbide-13C2 of 89%.
We believe that the developed methodology is suitable for further use in synthetic laboratories. The advantages of our method are the use of a widely available, inexpensive, and safe solid acetylene source instead of flammable and explosive gaseous acetylene itself, mild reaction conditions, high process effectiveness, and simple workup procedures. The potential for the 13C-label-economic synthesis of valuable 13C2-synthons, as demonstrated here, is a significant advantage of the current methodology.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/org6010005/s1: The picture of the reaction vessels used in our procedures (Figure S1) and full spectral data with copies of NMR spectra for compounds 2a–w, 3, and 4a,i.

Author Contributions

Conceptualization: M.S.L. and V.V.V.; investigation: M.S.L., A.A.R., E.A.R. and V.V.V.; supervision: M.S.L.; writing—original draft: M.S.L.; writing—review and editing: M.S.L. and V.V.V. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Russian Science Foundation and Saint Petersburg Science Foundation, grant number 24-23-20144.

Data Availability Statement

The data supporting this article are included as part of the ESI.

Acknowledgments

The authors express their gratitude to the Resource Centres of Saint Petersburg State University: Magnetic Resonance Research Centre and Chemical Analysis and Materials Research Centre.

Conflicts of Interest

The authors declare no conflicts of interest.

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Organics 06 00005 sch001
Scheme 1. Vinyl derivatives and calcium carbide.
Scheme 1. Vinyl derivatives and calcium carbide.
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Scheme 2. The side process accompanying the formation of 2f.
Scheme 2. The side process accompanying the formation of 2f.
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Scheme 3. Gram-scale synthesis of benzyl vinyl sulfide. a Reaction conditions: 1n (0.992 g, 8.0 mmol), KOtBu (0.448 g, 4.0 mmol), CaC2 (0.538 g, 8.4 mmol), 480 µL of DMSO in 4.0 mL of 1,4-dioxane, water (18.8 mmol, 340 µL); 100 °, 5h.
Scheme 3. Gram-scale synthesis of benzyl vinyl sulfide. a Reaction conditions: 1n (0.992 g, 8.0 mmol), KOtBu (0.448 g, 4.0 mmol), CaC2 (0.538 g, 8.4 mmol), 480 µL of DMSO in 4.0 mL of 1,4-dioxane, water (18.8 mmol, 340 µL); 100 °, 5h.
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Scheme 4. The synthesis of 13C2-vinyl compounds using carbide approach. a Reaction conditions: 1a or 1i (1.0 mmol), KOtBu (0.25 mmol), KF (0.5 mmol), Ca13C2 (1.05 mmol, 70 mg), 0.5 mL of DMSO, water (2.5 mmol, 45 µL), 130 °C; time: 7h in the case of 1a, 5h for 1i.
Scheme 4. The synthesis of 13C2-vinyl compounds using carbide approach. a Reaction conditions: 1a or 1i (1.0 mmol), KOtBu (0.25 mmol), KF (0.5 mmol), Ca13C2 (1.05 mmol, 70 mg), 0.5 mL of DMSO, water (2.5 mmol, 45 µL), 130 °C; time: 7h in the case of 1a, 5h for 1i.
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Table 1. Optimization of the reaction conditions.
Table 1. Optimization of the reaction conditions.
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EntrySubstrateKOtBu, mmolSolventT, °CTime, hProductYield of 2, % b
1BnOH (1a)1.0DMSO13052a81
21a0.75DMSO13052a82
31a0.5DMSO13052a82
41a c0.5DMSO13052a86
51a c0.5DMSO13072a95
6carbazole (1i) c2.0DMSO13052i64
71i c1.0DMSO13052i78
81i c0.75DMSO13052i83
91i c0.5DMSO13052i85
101i c0.25DMSO13052i84
11PhSH (1o)1.0DX d10042o83
121o1.0DX10052o88
131o c1.0DX10052o94
14n-C12H25SH (1w)1.0DX10042w90
151w1.0DX10052w95
161w c1.0DX10052w97
a Reaction conditions: 1 (2.0 mmol), KOtBu, KF (1.0 mmol for 1a–m), CaC2 (2.0 mmol, 130 mg), solvent (1.0 mL), water (4.5 mmol, 80 µL); b NMR yield; c 140 mg (2.1 mmol) of CaC2 was used; d DX is a mixture of 120 µL of DMSO and 1.0 mL of 1,4-dioxane.
Table 2. Vinylation of alcohols, thiols, and nitrogen compounds 1a–w with calcium carbide.
Table 2. Vinylation of alcohols, thiols, and nitrogen compounds 1a–w with calcium carbide.
Organics 06 00005 i002
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a Reaction conditions: 1a–w (2.0 mmol), KOtBu (0.5 mmol in the case of 1a–m, 1.0 mmol in the case of 1n–w), KF (1.0 mmol for 1a–m), CaC2 (140 mg, 2.1 mmol), solvent—1.0 mL of DMSO in the case of 1a–m and 120 µL of DMSO in 1.0 mL of 1,4-dioxane in the case of 1n–w, water (4.7 mmol, 85 µL); temperature: 130 °C in the case of 1a–m, 100 °C in the case of 1n–w; time: 7h in the case of 1a–h, 5h for 1i–w. b Vinylation was accompanied with the formation of 1-fluoro-3-((3-((vinyloxy)methyl)phenoxy)methyl)benzene 3 (yield 23% in relation to CaC2, 45% in relation to 1f). c In the case of 1n–w, no additive (KF) was used.
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Ledovskaya, M.S.; Voronin, V.V.; Reznichenko, A.A.; Reznichenko, E.A. Vinylation of Alcohols, Thiols, and Nitrogen Compounds Using a Stoichiometric Amount of In Situ Generated Acetylene. Organics 2025, 6, 5. https://doi.org/10.3390/org6010005

AMA Style

Ledovskaya MS, Voronin VV, Reznichenko AA, Reznichenko EA. Vinylation of Alcohols, Thiols, and Nitrogen Compounds Using a Stoichiometric Amount of In Situ Generated Acetylene. Organics. 2025; 6(1):5. https://doi.org/10.3390/org6010005

Chicago/Turabian Style

Ledovskaya, Maria S., Vladimir V. Voronin, Anna A. Reznichenko, and Ekaterina A. Reznichenko. 2025. "Vinylation of Alcohols, Thiols, and Nitrogen Compounds Using a Stoichiometric Amount of In Situ Generated Acetylene" Organics 6, no. 1: 5. https://doi.org/10.3390/org6010005

APA Style

Ledovskaya, M. S., Voronin, V. V., Reznichenko, A. A., & Reznichenko, E. A. (2025). Vinylation of Alcohols, Thiols, and Nitrogen Compounds Using a Stoichiometric Amount of In Situ Generated Acetylene. Organics, 6(1), 5. https://doi.org/10.3390/org6010005

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