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Article

Eco-Friendly Functionalization of Ynals with Thiols under Mild Conditions

by
Kamil Hanek
and
Patrycja Żak
*
Faculty of Chemistry, Adam Mickiewicz University in Poznań, Uniwersytetu Poznańskiego St. 8, 61-614 Poznan, Poland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(17), 9201; https://doi.org/10.3390/ijms25179201
Submission received: 26 July 2024 / Revised: 21 August 2024 / Accepted: 23 August 2024 / Published: 24 August 2024
(This article belongs to the Special Issue Editorial Board Members’ Collection Series: “Selenium and Sulfur Chemistry”)
Browse Figures
Versions Notes

Abstract

:
A new eco-friendly method for the synthesis of mono- and multifunctional organosulfur compounds, based on the process between ynals and thiols, catalyzed by bulky N-heterocyclic carbene (NHC), was designed and optimized. The proposed organocatalytic approach allows the straightforward formation of a broad range of thioesters and sulfenyl-substituted aldehydes in yields above 86%, in mild and metal-free conditions. In this study, thirty-six sulfur-based derivatives were obtained and characterized by spectroscopic methods.

1. Introduction

The knowledge about organosulfur compounds (OSCs) is of great importance because of a large number of their applications in medicine [1,2,3], pharmaceutics [4,5,6,7,8], polymer [9], and food industries [10]. Thus, the exploration of their chemistry and the search for new classes of materials containing sulfur atoms are often discussed by scientists all over the world.
Among all the organic sulfur derivatives, of particular interest are thioesters and sulfa-Michael addition (SMA) products, which can serve as building blocks in various processes [11,12,13,14]. They exhibit potential catalytic activity in cascade reactions [15], display antiproliferative properties [16], or act as SARS-CoV-2MPRO inhibitors [17]. Despite the great practical importance of materials of this type, most of the prominent methods for their synthesis present some serious drawbacks. For example, thioesters can be obtained by the nucleophilic substitution of the carbonyl group of acyl chlorides, carboxylic acids, or acid anhydrides with thiols [18] or reactions with aldehydes used as starting materials [19]. However, these reactions are possible to perform only with the use of transition metal complexes of copper and iron, oxidants, and at high temperatures [20,21,22]. Alternatively, thioesters can be obtained in the presence of transition metal complexes as catalysts in the thiocarbonylation of alkenes and alkynes, although, in most cases, these processes require harsh conditions, like high temperatures and/or elevated pressures [23,24]. SMA reactions remain less explored, mainly because of the high nucleophilicity of thiols causing difficulties in controlling the stereoselectivity [25]. They are generally performed at low temperatures, but unfortunately, the reactions require the use of a catalyst at high concentrations [26,27,28,29]. Such conditions are not considered ecologically friendly, hence organocatalytic reactions based on non-toxic NHCs are rising to prominence because of their successful application in the synthesis of both thioesters [30] and sulfenyl-substituted aldehydes [31,32,33,34,35]. The experiments also conducted in our group have proved that NHCs are powerful tools in the synthesis of organosulfur compounds from unsaturated scaffoldings with electron-withdrawing moieties. The research performed with enals led to obtaining new groups of sulfur compounds, e.g., silsesquioxane derivatives [36] and symmetric and unsymmetric bis(thioesters) [37]. Inspired by our previous work and bearing in mind the continuous demand for organosulfur moieties as well as the limited number of eco-friendly procedures for their synthesis, we turned our attention to ynals, which can be used as versatile synthons for the synthesis of various heterocycles (e.g., indolizines) [38]. They are the substrates that are more demanding for functionalization than α,β-unsaturated aldehydes because they comprise two reactive groups suitable for modification. Thus, in the reaction between ynals and mercaptans, besides regio- and stereoselectivity, chemoselectivity must also be controlled (Scheme 1).
To the best of our knowledge, there are no literature reports on the modifications of ynals with thiols. It is thus of great importance to design new catalytic systems that would permit the fully selective formation of expected products for a wide range of starting mercaptans and aldehydes containing C≡C bonds, as it would reveal a new strategy to obtain structurally diverse organosulfur compounds, including chiral alcohols.
Herein, we describe an effective synthetic pathway for obtaining a new class of organosulfur materials via reactions of ynals with thiols and dithiol in the presence of bulky NHC carbene. We focused our attention on designing an eco-friendly system enabling the introduction of one or more, the same or different, sulfur groups into the aldehyde structure. Finally, we synthesized, isolated, and characterized thirty-six carbonyl compounds not yet described in the literature.

2. Results and Discussion

2.1. Design and Optimization of the Reaction System

In the first stage of the study, a number of tests was carried out in order to find the optimal conditions of 1-octynal’s (1a) functionalization. Benzyl mercaptan (2a) was used as the reaction partner, because of its low price and high commercial availability. The tests were performed in the presence of bulky NHC salt–IPr*OMe·HCl (NHC-1) and their course was monitored by GC-MS analyses. The results presented in Table 1 reveal that the outcomes of the hydrothiolation process depends largely on the reaction media and temperatures. Among all the solvents tested, acetone was found to be the best one in terms of both activity and selectivity to the P1 product (Table 1, Entries 8–11 and 15), which is especially important from an ecological perspective as acetone is classified as a green solvent [39]. An effective transformation of reagents was also observed when the process was carried out in MTBE or toluene, but then a mixture of two products was obtained (Table 1, Entries 4 and 7). The other solvents (DCE, DCM, and n-hexane) turned out to be ineffective in the tested model reaction (Table 1, Entries 1–3). Moreover, it was observed that the reaction efficiency depended also on the amount of solvent used. When the process was performed in solvent-free conditions, 40% of thioesterification product (P1’) was detected (Table 1, Entry 16). The same problem was observed for the tests conducted at temperatures above RT (Table 1, Entries 6–9). Catalytic screening demonstrated that catalyst loading affects the efficiency of the process, because a lowering of its concentration to 2.5 mol% leads to a reduction in the yield, despite a significant extension of the reaction time (Table 1, Entry 11). Carrying out the reaction without the additions of NHC-1 (Table 1, Entry 13) or potassium hexamethyldisilazane (KHMDS) (Table 1, Entry 14) is impossible, which confirms that the catalyst and the base are indispensable for effective reactions. It was also found that the atmosphere in which the process was carried out had a significant impact on the efficiency of the reaction tested. This process must be performed under dry argon conditions. Otherwise, the main product of the reaction practically does not form (Table 1, Entry 12). We did not observe significant differences between the process carried out in the presence of carbene generated in situ and the reaction catalyzed by freshly isolated free carbene (Table 1, Entry 10 vs. Entry 15). Finally, the conditions of entry 10 were optimal as they allowed a quantitative conversion using relatively low catalyst loading.

2.2. Scope of the Reaction

The positive outcome obtained for the model reaction has encouraged us to determine the scope of the reaction. In the first series of experiments, we tested the reactivity of commercially available alkyl (1a), aryl (1b), and silyl (1c) propargyl aldehydes toward selected benzyl (2a) and aryl (2b–e) thiols as well as dithiol (3a) (Figure 1).
All results are presented in Scheme 2.
The proposed method can be successfully applied for the tested reagents, because all the products were obtained with excellent isolated yields (>89%) in very mild conditions and with full atom economy. When using 2-naphthalenethiol (2e), a slight increase in the reaction time was necessary to obtain the expected materials in quantitative yields. In each reaction, we observed the selective formation of the expected hydrothiolation product, whose geometry around the double bond was further confirmed by 2D NMR analyses (see ESI for details). Interestingly, the hydrothiolation of 3-(trimethylsilyl)-2-propynal (1c), irrespective of the thiol used, proceeded with the cleavage of the trimethylsilyl group (TMS). This result is particularly important in the context of the use of the obtained materials (P11–P15), which are convenient reagents for further modifications.
Based on the literature and our previous research concerning NHC-catalyzed thioester synthesis from α,β-unsaturated aldehydes with thiols [36], we proposed the mechanism depicted in Scheme 3.
Products P1–P10 are formed as a result of NHC-catalyzed sulfa-Michael addition according to the proton transfer mechanism [31,40,41], which commences with the generation of free carbene (NHC) as a result of the reaction of its precursor (NHC-1) with KHMDS. NHC acts a Brønsted base, which deprotonates the acidic thiol molecule to form an NHC-thioxy intermediate (B.1). Because of the presence of the electron-withdrawing aldehyde group, the acetylenic moiety is activated and constitutes a perfect substrate for immediate conjugate addition [42] with the obtained NHC-thioxy intermediate [43] (B.2). The way in which ynal is coordinated strongly dependents on the steric properties of the organocatalyst. Because of the bulky NHC ligand, the thiol is pushed above the flat N-heterocycle upon the hydrogen bond formation between sulfur and hydrogen atoms. It permits the approach of the Michael acceptor from the top, with the steric group at the β carbon atom oriented away from the large aryl substituents attached to the NHC ligand [33,44]. Due to the presence of an oxygen atom, the formed intermediate can remain in equilibrium with allenic enolate [45] (B.3). Such a species is highly reactive and, immediately, E-products and regenerated free NHC are formed. As mentioned above, the use of aldehyde 1c as a substrate led to unexpected results because, upon its modification, desilylation was observed. Unfortunately, at this moment, we are unable to clearly explain at what stage of the process the elimination of the TMS group occurs. However, we believe that theoretical research will help resolve this issue in the near future.
Encouraged by the high activity of NHC-1 in the hydrothiolation of ynals (1a–c) with thiols (2a–e) used at an equimolar ratio, we examined the reactions with a two-fold excess of mercaptans. Thus, we treated 1 equiv. of aldehyde (1a–c) and 2 equiv. of thiol (2a–e) with NHC carbene generated from precursor NHC-1, and the reaction mixture was stirred at RT until the full conversion of ynal was detected by GC-MS analysis. All results are summarized in Scheme 4.
The performed tests revealed that, in the above conditions, the processes selectively produced bis-sulfenylated compounds in high isolated yields. No meaningful differences in the efficiency and selectivity of the process for the applied reagents were observed, except for 2-naphthalenethiol (2e). For this sterically crowded thiol, a longer time was indispensable to achieve a satisfactory result. Similarly, as for the reaction with the reagents at equimolar amounts, upon the functionalization of aldehyde 1c, desilylation was observed.
All the products (P1–P30) were purified by column chromatography on silica gel using n-hexane or a 2:1 v/v mixture of n-hexane and DCM as eluents. Moreover, we were able to obtain crystals of the mono-sulfenylated products of 4-methoxythiophenol (2d) with phenylpropargyl aldehyde (1b) and 3-(trimethylsilyl)-2-propynal (1c) by dissolving P9 and P14 in n-hexane/DCM and the slow evaporation of the solvent. In a similar way, we obtained the crystals of two bis-sulfenylated products P22 and P24. The molecular structures were determined by X-ray structural analyses and confirmed the formation of the expected materials (Figure 2) (see ESI for details).
Similarly to the assumed mechanism of monosubstituted product formation, we proposed a mechanism of bis-functionalized product formation based on the available literature (Scheme 5).
The first part of the mechanism runs in exactly the same way as that in Scheme 3, leading to the creation of a monosulfenylated product. Then, the thioesterification process occurs. The free carbene reacts with α,β-unsaturated aldehyde to produce intermediate B.1, which then undergoes proton transfer, producing a Breslow intermediate (B.2) [46,47,48]. The resulting intermediate remains in equilibrium with homoenolate (B.3) [49], which takes part in direct proton transfer from the hydroxyl group to the γ carbon [50,51]. Finally, the intermediate (B.4) reacts with thiol leading to catalyst regeneration.
In the next step, we checked the possibility of the formation of triple functionalized products. In the optimized reaction systems, the tests were performed with the use of a three-fold excess of thiols (2d–e) relative to 3-(trimethylsilyl)-2-propynal (1c). In both reactions, quantitative conversions of reagents were achieved within 24 h. The structures of products were determined by GC-MS and NMR analyses and are presented in Scheme 6.
The formation of (tris)sulfenylated products, although confirmed by spectroscopic NMR analyses, was rather unexpected, so we decided to run some additional experimental tests in order to obtain some insights into the reaction route (Scheme 7).
The results show that it is impossible to obtain such products by the gradual addition of 3 equiv. of thiol or as a result of the reaction of isolated (bis)sulfenylated product with 1 equiv. of thiol. Products P31 and P32 can be synthesized only by the implementation of a threefold excess of thiol, which leads to the conclusion that the concentration of thiol must have an impact on the reaction mechanism. In our opinion, in the case of a higher concentration of thiol in the reaction system, a monosulfenylated product is formed at first, followed by the addition of the second thiol equivalent to the newly formed carbon–carbon double bond, and finally, the thioesterification process occurs, according to the mechanism based on the Breslow intermediate, as described above.
The successful coupling between unsaturated ynals (1a–c) with two- and three-fold excess amounts of thiols (2a–e) to yield multi-sulfenylated derivatives (P16–P32) prompted us to carry out two successive reactions with separate mercaptan products to check the feasibility of a one-pot protocol, leading to a novel class of unsymmetrically functionalized materials containing two sulfur atoms. Hence, we generated a free carbene in situ in the reaction environment, as a result of the deprotonation of a salt, NHC-1, and added equimolar amounts of 1a and 2a. The reaction mixture was stirred at RT until the full conversion of reagents was detected by GC-MS analysis. Then, the second type of thiol (2d) was added, and the catalytic system was left overnight. As presented in Scheme 8, we observed the selective formation of bis-functionalized product P33 containing two different thiol moieties in high isolated yields.
Analogously, we carried out the functionalization of 1b and 1c with 2c and 2d (Scheme 9). Highly gratifyingly, quantitative conversions were achieved within a reasonable period of time, irrespective of the nature of the aldehyde substituent. The hydrothiolation of 3-(trimethylsilyl)-2-propynal (1c) proceeded with the elimination of the trimethylsilyl group. Products P34 and P35 were obtained with the isolated yields of 90% and 91%, respectively, which confirm the universality of the proposed procedure.
Finally, we turned our attention to the functionalization of ynals with dithiol. For this purpose, we performed the equimolar reaction between 1a and 1,2-ethanedithiol (3a) in the presence of 5 mol% of NHC-1 (Scheme 10). The reaction was highly selective, because we observed the exclusive formation of the cyclic product P36. The obtained compound can constitute a building block for the synthesis of, e.g., enamines, hemiacetals, or acetals.

2.3. The Preparative Scale for the Synthesis of Product P1

To demonstrate the synthetic utility of the designed protocol, a gramscale hydrothiolation of 1a with 2a was performed (Scheme 11). The result obtained makes it clear that the proposed methodology has significant application potential.
In this study, thirty-six products were obtained, isolated, and characterized by spectroscopic methods (see ESI for details). These materials are air-stable, which makes them very attractive for further applications. The presented derivatives are new compounds that have never been published before.

3. Materials and Methods

3.1. General Methods and Chemicals

Unless otherwise indicated, all operations were carried out under a dry argon atmosphere, using standard Schlenk techniques. 1H NMR and 13C NMR spectra were recorded in CDCl3 on a Varian 400 operating at 402.6 and 101.2 MHz, respectively. HMBC and HSQC spectra were recorded on a Bruker Avance DRX 600 (Bruker, Billerica, MA, USA), operating at a frequency of 600.13 MHz (1H). Chemical shifts are reported in ppm with reference to the residual solvent peaks in 1H and 13C NMR. 19F NMR spectra were obtained using a Bruker AscendTM 400 NANOBAY, operating at 376 MHz. IR spectra were recorded on a Bruker IFS 66v/S spectrophotometer, and the scan range was 4000–400 cm−1. GC-MS analyses were performed on a Varian Saturn 2100T equipped with a DB-1 capillary column (30 m length, 0.25 mm internal diameter) and an ion trap detector. Thin-layer chromatography (TLC) was conducted on plates coated with a 250 μm thick silica gel layer and column chromatography was performed on silica gel 60 (70–230 mesh). ESI-MS spectra were obtained using a Synapt Gs-S HDMS (Waters, Milford, MA, USA) mass spectrometer with an electrospray ion source and quadrupole time-of-flight analyzer with resolving power (FWMH 38000). Acetonitrile was used as the sample solvent. The capillary voltage was set to 4.5 kV, sampling was set 40, and the source temperature was equal to 120 °C. The most abundant ions in the ESI-MS spectra were the sodiated and potassiated ions of the desired products.
All reagents, except the NHC carbene precursor, were purchased from commercial sources and used as received. NHC salt was prepared according to the literature procedure [52]. All the solvents, except THF, were dried over CaH2 prior to use and stored over 4 Å molecular sieves under argon. Dichloromethane was additionally passed through an alumina column and degassed by repeated freeze–pump–thaw cycles. THF was dried over sodium benzophenone ketyl and freshly distilled prior to use.

3.2. General Procedure for Catalytic Tests

3.2.1. Mono- and Multifunctionalization of Aldehydes with (Di)thiols

An oven-dried 5 mL glass reactor equipped with a magnetic stirring bar was charged under argon with the NHC carbene precursor NHC-1 (3.44 mg, 3.51 × 10−6 mol), KHMDS (0.70 mg, 3.51 × 10−6 mol), and acetone (1 mL). The reaction mixture was stirred at RT and, after 30 min, aldehyde 1a–c (1 equiv., 7.01 × 10−5 mol), thiol 2a–e (1 equiv., 7.01 × 10−5 mol, 2 equiv., 1.40 × 10−4 mol or 3 equiv., 2.10 × 10−4 mol), or dithiol 3a (1 equiv., 7.01 × 10−5 mol) and an internal standard (decane or dodecane, 20 μL) were added under argon. The reaction mixture was heated at RT and its course was monitored by GC-MS.

3.2.2. Bis-Functionalization of Aldehydes with Two Various Thiols

An oven-dried 5 mL glass reactor equipped with a magnetic stirring bar was charged under argon with the NHC carbene precursor NHC-1 (3.44 mg, 3.51 × 10−6 mol), KHMDS (0.70 mg, 3.51 × 10−6 mol), and acetone (1 mL). The reaction mixture was stirred at RT and, after 30 min, aldehyde 1a–c (1 equiv., 7.01 × 10−5 mol), thiol 2a–e (1 equiv., 7.01 × 10−5 mol) and internal standard (decane or dodecane, 20 μL) were added under argon. The reaction mixture was heated at RT and, after 10 h, second thiol 2a–e (1 equiv., 7.01 × 10−5 mol) was added under argon. The reaction mixture was heated at RT and its course was monitored by GC-MS.

3.3. General Procedure for the Synthesis of Products P1–P32 and P36

A 10 mL high-pressure Schlenk vessel equipped with a magnetic stirring bar and connected to the gas and vacuum line was charged with the NHC carbene precursor NHC-1 (17.19 mg, 1.75 × 10−5 mol—5 mol% or 34.38 mg, and 3.5 × 10−5 mol—10 mol%), KHMDS (3.50 mg, 1.75 × 10−5 mol—5 mol% or 7.00 mg, and 3.5 × 10−5 mol—10 mol%), and acetone (2 mL) under argon. After 30 min of vigorous stirring the solution at RT, aldehyde 1a–c (3.51 × 10−4 mol) and thiol 2a–e (3.51 × 10−4 mol, 7.01 × 10−4 mol, or 1.05 × 10−3 mol) or dithiol 3a (3.51 × 10−4 mol) were added. The reaction mixture was stirred at RT for 5–24 h. The solvent was then evaporated under vacuum and the residue was purified by column chromatography on silica gel using n-hexane or a 2:1 v/v mixture of n-hexane and DCM as eluents. The evaporation of the solvents afforded analytically pure compounds.

3.4. General Procedure for the Synthesis of Products P33–P35

A 10 mL high-pressure Schlenk vessel equipped with a magnetic stirring bar and connected to the gas and vacuum line was charged with the NHC carbene precursor NHC-1 (34.38 mg, 3.5 × 10−5 mol), KHMDS (7.00 mg, 3.5 × 10−5 mol), and acetone (2 mL). The reaction mixture was stirred at RT and, after 1 h, aldehyde 1a–c (50 µL, 3.51 × 10−4 mol) and thiol 2a or 2d (3.51 × 10−4 mol) were added. The reaction mixture was stirred at RT for 5–8 h. Next, a second thiol, 2d or 2c (3.51 × 10−4 mol), was added. The reaction mixture was stirred at RT for 14–16 h. All the products were purified by column chromatography on silica gel using n-hexane or a 2:1 v/v mixture of n-hexane and DCM as eluents. The evaporation of the solvents afforded analytically pure compounds.

3.5. Synthesis of Product P1 on a Preparative Scale

A 10 mL high-pressure Schlenk vessel equipped with a magnetic stirring bar and connected to a gas and vacuum line was charged under argon with dry acetone (3 mL), NHC-1 (172.06 mg, 1.75 × 10−4 mol) and KHMDS (35.01 mg, 1.75 × 10−4 mol). The reaction mixture was stirred at RT for 1 h. After this time, octynal 1a (500 µL, 3.51 × 10−3 mol) and benzyl mercaptan 2a (410.90 µL, 3.51 × 10−3 mol) were added. The reaction mixture was stirred at RT for 24 h. Then, the solvent was then evaporated under vacuum and the residue was purified by column chromatography (silica gel 60/2:1 v/v mixture of n-hexane and DCM). The evaporation of the solvents produced an analytically pure product (yellow oil, 0.74 g, 86%).

4. Conclusions

To sum up, a new practical method for the synthesis of mono- and multifunctional organosulfur carbonyl compounds, based on the processes of hydrothiolation or hydrothiolation/thioesterification of ynals with thiols and catalyzed by bulky NHC carbene, was designed and optimized. By controlling the amounts of reagents, we have shown that, at first, the triple bond C≡C is activated, which leads to the formation of SMA adducts. It is succeeded by the nucleophilic substitution of the carbonyl atom with the hydrogenation of the C=C bond, leading to the creation of thioesters. The proposed method of synthesis also permits the introduction of two different sulfur groups into the ynals’ structure and leads to cyclic products as a result of the reaction of propargyl aldehydes with dithiols. For all combinations of reagents tested, the reactions proceeded effectively, with high chemoselectivity, leading to the exclusive formation of the expected materials. In the study presented, thirty-six sulfur-based derivatives were obtained and characterized by spectroscopic methods. Taking into account the combination of desirable features, such as high atom economy (the lack of by-products, equimolar ratios of substrates, ease of product isolation, and purification), operational simplicity (one-step process), high chemo-selectivity, mild reaction conditions (metal-free catalyst, green solvent, and room temperature), and commercial availability of the reagents, this reaction system is attractive for the synthesis of a new class of organosulfur materials with potential for practical applications, which perfectly cooperate with the rules of green chemistry [53]. Moreover, in light of the recent Nobel Prize for chemistry, the proposed method shows the nucleophilic addition to activated alkynes is congruent with Click Chemistry criteria [54].

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms25179201/s1. References [55,56,57,58,59] are cited in the supplementary materials.

Author Contributions

Conceptualization, P.Ż.; methodology, P.Ż.; Synthesis of catalyst, K.H.; synthesis and isolation of products, K.H. and P.Ż.; formal analysis, P.Ż.; writing—original draft preparation, P.Ż. and K.H.; writing—review and editing, P.Ż.; visualization, K.H.; supervision, P.Ż.; funding acquisition, K.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Initiative of Excellence—Research University, grant number 102/13/SNŚ/0001.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All data generated or analyzed during this study are included in this published article (and its Supplementary Information files: Analytical data of isolated products and catalyst, NMR spectra of isolated products: Figures S1–S78, and XRD analysis: Table S1, Figure S79–S81, for Figure S82 see ESI).

Acknowledgments

Kamil Hanek gratefully acknowledges the financial support received from the Initiative of Excellence—Research University (project IDUB No. 102 Doctoral minigrants No. 102/13/SNŚ/0001).

Conflicts of Interest

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

  1. Srivastava, P.; Schito, M.; Fattah, R.J.; Hara, T.; Hartman, T.; Buckheit, R.W.; Turpin, J.A.; Inman, J.K.; Appella, E. Optimization of unique, uncharged thioesters as inhibitors of HIV replication. Bioorg. Med. Chem. 2004, 12, 6437–6450. [Google Scholar] [CrossRef] [PubMed]
  2. Kanda, Y.; Ashizawa, T.; Kakita, S.; Takahashi, Y.; Kono, M.; Yoshida, M.; Saitoh, Y.; Okabe, M. Synthesis and Antitumor Activity of Novel Thioester Derivatives of Leinamycin. J. Med. Chem. 1999, 42, 1330–1332. [Google Scholar] [CrossRef]
  3. Vazguez-Prieto, M.A.; Miatello, R.M. Organosulfur compounds and cardiovascular disease. Mol. Asp. Med. 2010, 31, 540–545. [Google Scholar] [CrossRef] [PubMed]
  4. Ilardi, E.A.; Vitaku, E.; Njardarson, J.T. Data-Mining for Sulfur and Fluorine: An Evaluation of Pharmaceuticals To Reveal Opportunities for Drug Design and Discovery. J. Med. Chem. 2014, 57, 2832–2842. [Google Scholar] [CrossRef] [PubMed]
  5. Beno, B.R.; Yeung, K.S.; Bartberger, M.D.; Pennington, L.D.; Meanwell, N.A. A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design. J. Med. Chem. 2015, 58, 4383–4438. [Google Scholar] [CrossRef]
  6. Scott, K.A.; Njardarson, J.T. Analysis of US FDA-Approved Drugs Containing Sulfur Atoms. Top. Curr. Chem. 2018, 376, 1–34. [Google Scholar] [CrossRef]
  7. Mustafa, M.; Winum, J.-Y. The importance of sulfur-containing motifs in drug design and discovery. Expert Opin. Drug Discov. 2022, 17, 501–512. [Google Scholar] [CrossRef]
  8. Wang, N.; Saidhareddy, P.; Jiang, X. Construction of sulfur-containing moieties in the total synthesis of natural products. Nat. Prod. Rep. 2020, 37, 246–275. [Google Scholar] [CrossRef]
  9. Guo, W.; Wang, D.Y.; Chen, Q.; Fu, Y. Advances of Organosulfur Materials for Rechargeable Metal Batteries. Adv. Sci. 2021, 9, 2103989. [Google Scholar] [CrossRef]
  10. Lu, Y.; Zhang, M.; Huang, D. Dietary Organosulfur-Containing Compounds and Their Health-Promotion Mechanisms. Ann. Rev. Food Sci. Technol. 2022, 13, 287–313. [Google Scholar] [CrossRef]
  11. Chauhan, P.; Mahajan, S.; Enders, D. Organocatalytic Carbon–Sulfur Bond-Forming Reactions. Chem. Rev. 2014, 114, 8807–8864. [Google Scholar] [CrossRef] [PubMed]
  12. Hirschbeck, V.; Gehrtz, P.H.; Fleischer, I. Metal-Catalyzed Synthesis and Use of Thioesters: Recent Developments. Chem. Eur. J. 2018, 24, 7092–7107. [Google Scholar] [CrossRef] [PubMed]
  13. Aksakal, S.; Aksakal, R.; Becer, C.R. Thioester functional polymers. Polym. Chem. 2018, 9, 4507–4516. [Google Scholar] [CrossRef]
  14. Mutlu, H.; Ceper, E.B.; Li, X.; Yang, J.; Dong, W.; Ozmen, M.M.; Theato, P. Sulfur Chemistry in Polymer and Materials Science. Macromol. Rapid Commun. 2019, 40, 1800650. [Google Scholar] [CrossRef]
  15. Niu, C.; Du, G.-M. Recent Advances in Organocatalyzed Asymmetric Sulfa-Michael Addition Triggered Cascade Reactions. Chem. Rec. 2023, 23, e202200258. [Google Scholar] [CrossRef] [PubMed]
  16. Lugue-Agudo, V.; Albarrán-Velo, J.; Fernández-Bolaños, J.G.; López, O.; Light, M.E.; Pardón, J.M.; Lagunes, I.; Román, E.; Serrano, J.A.; Gil, M.V. Synthesis and antiproliferative activity of sulfa-Michael adducts and thiochromenes derived from carbohydrates. New J. Chem. 2017, 41, 3154–3162. [Google Scholar] [CrossRef]
  17. Pillaiyar, T.; Flury, P.; Krüger, N.; Su, H.; Schäkel, L.; Barbosa Da Silva, E.; Eppler, O.; Kronenberger, T.; Nie, T.; Luedtke, S.; et al. Small-Molecule Thioesters as SARS-CoV-2 Main Protease Inhibitors: Enzyme Inhibition, Structure–Activity Relationships, Antiviral Activity, and X-ray Structure Determination. J. Med. Chem. 2022, 65, 9376–9395. [Google Scholar] [CrossRef]
  18. Kazemi, M.; Shiri, L. Thioesters synthesis: Recent adventures in the esterification of thiols. J. Sulfur Chem. 2015, 36, 613–623. [Google Scholar] [CrossRef]
  19. Jabarullah, N.H.; Jermsittiparsert, K.; Melnikov, P.A.; Maseleno, A.; Hosseinian, A.; Vessally, E. Methods for the direct synthesis of thioesters from aldehydes: A focus review. J. Sulfur Chem. 2020, 41, 96–115. [Google Scholar] [CrossRef]
  20. Yi, C.-L.; Huang, Y.-T.; Lee, C.-F. Synthesis of thioesters through copper-catalyzed coupling of aldehydes with thiols in water. Green Chem. 2013, 15, 2476–2484. [Google Scholar] [CrossRef]
  21. Huang, Y.-T.; Lu, S.-Y.; Yi, C.-L.; Lee, C.-F. Iron-Catalyzed Synthesis of Thioesters from Thiols and Aldehydes in Water. J. Org. Chem. 2014, 79, 4561–4568. [Google Scholar] [CrossRef] [PubMed]
  22. Jhuang, H.-S.; Liu, Y.-W.; Reddy, D.M.; Tzeng, Y.-Z.; Lin, W.-Y.; Lee, C.-F. Microwave-assisted Synthesis of Thioesters from Aldehydes and Thiols in Water. J. Chin. Chem. Soc. 2018, 65, 24–27. [Google Scholar] [CrossRef]
  23. Zhao, F.; Geng, H.-Q.; Wu, X.-F. Palladium-Catalyzed Thiocarbonylation of Alkenes toward Linear Thioesters. ACS Catal. 2021, 11, 3614–3619. [Google Scholar]
  24. Wang, X.; Wang, B.; Yin, X.; Yu, W.; Liao, Y.; Ye, J.; Wang, M.; Hu, L.; Liao, J. Palladium-Catalyzed Enantioselective Thiocarbonylation of Styrenes. Angew. Chem. Int. Ed. 2019, 58, 12264–12270. [Google Scholar] [CrossRef]
  25. Enders, D.; Lüttgen, K.; Narine, A.A. Asymmetric Sulfa-Michael Additions. Synthesis 2007, 7, 959–980. [Google Scholar] [CrossRef]
  26. Marigo, M.; Schulte, T.; Franzén, J.; Jørgensen, K.A. Asymmetric Multicomponent Domino Reactions and Highly Enantioselective Conjugated Addition of Thiols to α,β-Unsaturated Aldehydes. J. Am. Chem. Soc. 2005, 127, 15710–15711. [Google Scholar] [CrossRef]
  27. Liu, Y.; Sun, B.; Wang, B.; Wakem, M.; Deng, L. Addition of aromatic thiols to conjugated cycloalkenones, catalyzed by chiral β-hydroxy amines. A mechanistic study of homogeneous catalytic asymmetric synthesis. J. Am. Chem. Soc. 2009, 131, 418–419. [Google Scholar] [CrossRef]
  28. Fang, X.; Li, J.; Wang, C.-J. Organocatalytic Asymmetric Sulfa-Michael Addition of Thiols to α,β-Unsaturated Hexafluoroisopropyl Esters: Expeditious Access to (R)-Thiazesim. Org. Lett. 2013, 15, 3448–3451. [Google Scholar] [CrossRef]
  29. Skarżewski, J.; Zielińska-Błatej, M.; Turowska-Tyrk, I. Simple preparation of enantiomeric Michael adducts of thiophenol to chalcones: Easily available new chiral building blocks. Tetrahedron Asymmetry 2001, 12, 1923–1928. [Google Scholar] [CrossRef]
  30. Bołt, M.; Hanek, K.; Żak, P. Metal-free thioesterification of α, β-unsaturated aldehydes with thiols. Org. Chem. Front. 2022, 9, 4846–4853. [Google Scholar] [CrossRef]
  31. Chen, J.; Meng, S.; Wang, L.; Tang, H.; Huang, Y. Highly enantioselective sulfa-Michael addition reactions using N-heterocyclic carbene as a non-covalent organocatalyst. Chem. Sci. 2015, 6, 4184–4189. [Google Scholar] [CrossRef]
  32. Li, Y.-Z.; Wang, Y.; Du, G.-F.; Zhang, H.-Y.; Yang, H.-L.; He, L. N-Heterocyclic-Carbene-Catalyzed Sulfa-Michael additions. Asian J. Org. Chem. 2015, 4, 327–332. [Google Scholar] [CrossRef]
  33. Yuan, P.; Meng, S.; Chen, J.; Huang, Y. Asymmetric Sulfa-Michael Addition of α,β-Unsaturated Esters/Amides Using a Chiral N-Heterocyclic Carbene as a Noncovalent Organocatalyst. Synlett 2016, 27, 1068–1072. [Google Scholar] [CrossRef]
  34. Cong, Z.-S.; Li, Y.-G.; Du, G.-F.; Gu, C.-Z.; Dai, B.; He, L. N-Heterocyclic carbene-catalyzed sulfa-Michael addition of enals. Chem. Commun. 2017, 53, 13129–13132. [Google Scholar] [CrossRef] [PubMed]
  35. Feng, Z.-N.; Luo, J.-Y.; Zhang, Y.; Du, G.-F.; He, L. N-Heterocyclic carbene-catalyzed diastereoselective synthesis of sulfenylated indanes via sulfa-Michael–Michael (aldol) cascade reactions. Org. Biomol. Chem. 2019, 17, 4700–4704. [Google Scholar] [CrossRef] [PubMed]
  36. Bołt, M.; Hanek, K.; Frąckowiak, D.; Żak, P. Metal-free functionalization of SQs: A case of chemoselectivity and what ball-milling has got to do with it? Inorg. Chem. Front. 2023, 10, 4190–4196. [Google Scholar] [CrossRef]
  37. Bołt, M.; Mermela, A.; Hanek, K.; Żak, P. Metal-free synthesis of unsymmetric bis(thioesters). Chem. Commun. 2023, 59, 956–959. [Google Scholar] [CrossRef] [PubMed]
  38. Yang, D.; Yu, Y.; Wu, Y.; Feng, H.; Li, X.; Cao, H. One-Pot Regiospecific Synthesis of Indolizines: A Solvent-Free, Metal-Free, Three-Component Reaction of 2-(Pyridin-2-yl)acetates, Ynals, and Alcohols or Thiols. Org. Lett. 2018, 20, 2477–2480. [Google Scholar] [CrossRef]
  39. Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C.R.; Abou-Shehadad, S.; Dunn, P.J. CHEM21 selection guide of classical- and less classical-solvents. Green Chem. 2016, 18, 288–296. [Google Scholar] [CrossRef]
  40. Phillips, E.M.; Riedrich, M.; Scheidt, K.A. N-Heterocyclic Carbene-Catalyzed Conjugate Additions of Alcohols. J. Am. Chem. Soc. 2010, 132, 13179–13181. [Google Scholar] [CrossRef]
  41. Wang, L.; Chen, J.; Huang, Y. Highly Enantioselective Aza-Michael Reaction between Alkyl Amines and β-Trifluoromethyl β-Aryl Nitroolefins. Angew. Chem. Int. Ed. 2015, 54, 15414–15418. [Google Scholar] [CrossRef]
  42. Worch, J.C.; Stubbs, C.J.; Price, M.J.; Dove, A.P. Click Nucleophilic Conjugate Additions to Activated Alkynes: Exploring Thiol-yne, Amino-yne, and Hydroxyl-yne Reactions from (Bio)Organic to Polymer Chemistry. Chem. Rev. 2021, 121, 6744–6776. [Google Scholar] [CrossRef] [PubMed]
  43. Castarlenas, R.; Di Giuseppe, A.; Pérez-Torrente, J.J.; Oro, L.A. The emergence of transition-metal-mediated hydrothiolation of unsaturated carbon–carbon bonds: A mechanistic outlook. Angew. Chem. Int. Ed. 2013, 52, 211–222. [Google Scholar] [CrossRef] [PubMed]
  44. Li, Z.-Y.; Wang, Y.; Du, G.-F.; Zhang, H.-Y.; Yang, H.-L.; He, L. Organosilicon reducing reagents for stereoselective formations of silyl enol ethers from α-halo carbonyl compounds. J. Org. Chem. 2015, 4, 327–332. [Google Scholar]
  45. Zimmerman, H.E.; Pushechnikov, A. The Stereochemistry of Allenic Enol Tautomerism—Independent Generation and Reactivity of the Enolates. Eur. J. Org. Chem. 2006, 2006, 3491–3497. [Google Scholar] [CrossRef]
  46. Pareek, M.; Reddi, Y.; Sunoj, R.B. Tale of the Breslow intermediate, a central player in N-heterocyclic carbene organocatalysis: Then and now. Chem. Sci. 2021, 2, 7973–7992. [Google Scholar] [CrossRef]
  47. Wessels, A.; Klußmann, M.; Breugst, M.; Schlörer, N.E.; Berkessel, A. Formation of Breslow Intermediates from N-Heterocyclic Carbenes and Aldehydes Involves Autocatalysis by the Breslow Intermediate, and a Hemiacetal. Angew. Chem. Int. Ed. 2022, 61, e202117682. [Google Scholar] [CrossRef]
  48. Liu, S.-L.; Liu, X.; Wang, Y.; Wei, D. Biocatalytic enantioselective construction of 1,3-oxathiolan-5-ones via dynamic covalent kinetic resolution of hemithioketals. Mol. Catal. 2022, 519, 112122. [Google Scholar] [CrossRef]
  49. Mahatthananchai, J.; Bode, J.W. The effect of the N-mesityl group in NHC-catalyzed reactions. Chem. Sci. 2012, 3, 192–197. [Google Scholar] [CrossRef]
  50. Reddi, Y.; Sunoj, R.B. Origin of stereoselectivity in a chiral N-heterocyclic carbene-catalyzed desymmetrization of substituted cyclohexyl 1, 3-diketones. Org. Lett. 2012, 14, 2810–2813. [Google Scholar] [CrossRef]
  51. Berkessel, A.; Yatham, V.R.; Elfert, S.; Neudörfl, J.-M. Characterization of the Key Intermediates of Carbene-Catalyzed Umpolung by NMR Spectroscopy and X-Ray Diffraction: Breslow Intermediates, Homoenolates, and Azolium Enolates. Angew. Chem. Int. Ed. 2013, 52, 11158–11162. [Google Scholar] [CrossRef]
  52. Hans, M.; Lorkowski, J.; Demonceau, A.; Delaude, L. Efficient synthetic protocols for the preparation of common N-heterocyclic carbene precursors. Beilstein J. Org. Chem. 2015, 11, 2318–2325. [Google Scholar] [CrossRef] [PubMed]
  53. Anastas, P.T.; Warner, J.C. Green Chemistry: Theory and Practice; Oxford University Press: New York, NY, USA, 1998; p. 30. [Google Scholar]
  54. Kolb, H.C.; Finn, M.G.; Sharpless, K.B. Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angew. Chem. Int. Ed. 2001, 40, 2004–2021. [Google Scholar] [CrossRef]
  55. Kardela, M.; Halikowska-Tarasek, K.; Szostak, M.; Bisz, E. Enhanced activity of bulky N-heterocyclic carbenes in nickel–NHC catalyzed Kumada–Corriu cross-coupling of aryl tosylates. Catal. Sci. Technol. 2022, 12, 7275–7280. [Google Scholar] [CrossRef]
  56. CrysAlisPro 1.171.42.56a; Rigaku Oxford Diffraction: Warriewood, Australia, 2022.
  57. Sheldrick, G.M. SHELXT—Integrated space-group and crystal-structure determination. Acta Crystallogr. Sect. A Found. Crystallogr. 2015, 71, 3–8. [Google Scholar] [CrossRef] [PubMed]
  58. Sheldrick, G.M. Crystal structure refinement with SHELXL. Acta Crystallogr. Sect. C Struct. Chem. 2015, 71, 3–8. [Google Scholar] [CrossRef]
  59. Dolomanov, O.V.; Bourhis, L.J.; Gildea, R.J.; Howard, J.A.K.; Puschmann, H. OLEX2: A complete structure solution, refinement and analysis program. J. Appl. Crystallogr. 2009, 42, 339–341. [Google Scholar] [CrossRef]
Ijms 25 09201 sch001
Scheme 1. Main possible products of the functionalization of ynals with thiols.
Scheme 1. Main possible products of the functionalization of ynals with thiols.
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Figure 1. Substrates tested: (A) ynals, (B) thiols, and (C) dithiol.
Figure 1. Substrates tested: (A) ynals, (B) thiols, and (C) dithiol.
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Ijms 25 09201 sch002
Scheme 2. Functionalization of propargyl aldehydes (1a–c) with thiols (2a–e) (experimental conditions: acetone, RT, (1a–c):(2a–e) = 1:1, NHC-1 = IPr*OMe·HCl, [NHC-1] = 5 mol%, and [KHMDS] = 5 mol%, argon). Isolated yields and reaction times are presented under the structures.
Scheme 2. Functionalization of propargyl aldehydes (1a–c) with thiols (2a–e) (experimental conditions: acetone, RT, (1a–c):(2a–e) = 1:1, NHC-1 = IPr*OMe·HCl, [NHC-1] = 5 mol%, and [KHMDS] = 5 mol%, argon). Isolated yields and reaction times are presented under the structures.
Ijms 25 09201 sch002
Ijms 25 09201 sch003
Scheme 3. Proposed mechanism for the formation SMA products.
Scheme 3. Proposed mechanism for the formation SMA products.
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Scheme 4. Bis-functionalization of propargyl aldehydes (1a–c) with thiols (2a–e) (experimental conditions: acetone, RT, (1a–c):(2a–e) = 1:2, NHC-1 = IPr*OMe·HCl, [NHC-1] = 10 mol%, and [KHMDS] = 10 mol%, argon). Isolated yields and reaction times are presented under the structures.
Scheme 4. Bis-functionalization of propargyl aldehydes (1a–c) with thiols (2a–e) (experimental conditions: acetone, RT, (1a–c):(2a–e) = 1:2, NHC-1 = IPr*OMe·HCl, [NHC-1] = 10 mol%, and [KHMDS] = 10 mol%, argon). Isolated yields and reaction times are presented under the structures.
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Figure 2. Perspective views of products P9, P14, P22, and P24.
Figure 2. Perspective views of products P9, P14, P22, and P24.
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Scheme 5. Proposed mechanism of bis-functionalized product formation.
Scheme 5. Proposed mechanism of bis-functionalized product formation.
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Scheme 6. Triple functionalization of 1c with selected thiols (2d–e) (experimental conditions: acetone, RT, (1c):(2d–e) = 1:3, NHC-1 = IPr*OMe·HCl, [NHC-1] = 10 mol%, and [KHMDS] = 10 mol%, argon). Isolated yields and reaction times are presented under the structure of each product.
Scheme 6. Triple functionalization of 1c with selected thiols (2d–e) (experimental conditions: acetone, RT, (1c):(2d–e) = 1:3, NHC-1 = IPr*OMe·HCl, [NHC-1] = 10 mol%, and [KHMDS] = 10 mol%, argon). Isolated yields and reaction times are presented under the structure of each product.
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Scheme 7. Functionalization of P29 and P30 with thiols (2d, 2e) (experimental conditions: acetone, RT, (P):(2) = 1:1, NHC-1 = IPr*OMe·HCl, [NHC-1] = 10 mol%, and [KHMDS] = 10 mol%, argon).
Scheme 7. Functionalization of P29 and P30 with thiols (2d, 2e) (experimental conditions: acetone, RT, (P):(2) = 1:1, NHC-1 = IPr*OMe·HCl, [NHC-1] = 10 mol%, and [KHMDS] = 10 mol%, argon).
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Ijms 25 09201 sch008
Scheme 8. Functionalization of 1-octynal (1a) with two different thiols (2a, 2d) (experimental conditions: acetone, RT, (1a):(2a):(2d) = 1:1:1, NHC-1 = IPr*OMe·HCl, [NHC-1] = 10 mol%, and [KHMDS] = 10 mol%, argon). Isolated yield is presented under the structure of P33.
Scheme 8. Functionalization of 1-octynal (1a) with two different thiols (2a, 2d) (experimental conditions: acetone, RT, (1a):(2a):(2d) = 1:1:1, NHC-1 = IPr*OMe·HCl, [NHC-1] = 10 mol%, and [KHMDS] = 10 mol%, argon). Isolated yield is presented under the structure of P33.
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Scheme 9. Functionalization of 1b and 1c with two different thiols (2c, 2d) (experimental conditions: acetone, RT, (1b-c):(2c):(2d) = 1:1:1, NHC-1 = IPr*OMe·HCl, [NHC-1] = 10 mol%, and [KHMDS] = 10 mol%, argon). Isolated yields are presented under the structures.
Scheme 9. Functionalization of 1b and 1c with two different thiols (2c, 2d) (experimental conditions: acetone, RT, (1b-c):(2c):(2d) = 1:1:1, NHC-1 = IPr*OMe·HCl, [NHC-1] = 10 mol%, and [KHMDS] = 10 mol%, argon). Isolated yields are presented under the structures.
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Scheme 10. Functionalization of 1a with 1,2-ethanedithiol (3a) (experimental conditions: acetone, RT, (1a):(3a) = 1:1, NHC-1 = IPr*OMe·HCl, [NHC-1] = 5 mol%, and [KHMDS] = 5 mol%, argon). Isolated yield is presented under the structure of P36.
Scheme 10. Functionalization of 1a with 1,2-ethanedithiol (3a) (experimental conditions: acetone, RT, (1a):(3a) = 1:1, NHC-1 = IPr*OMe·HCl, [NHC-1] = 5 mol%, and [KHMDS] = 5 mol%, argon). Isolated yield is presented under the structure of P36.
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Ijms 25 09201 sch011
Scheme 11. Scaled-up synthesis of P1.
Scheme 11. Scaled-up synthesis of P1.
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Table 1. Optimization of the reaction conditions.
Table 1. Optimization of the reaction conditions.
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EntrySolventTemp.
[°C]		NHC-1
[mol%]		Time [e]
[h]		Conv. of 1a
[%]		P1:P1’ [f]
[%]
1DCERT5483-
2DCMRT5484-
3n-hexaneRT5242-
4MTBERT5249865:35
5TolueneRT5483-
6Toluene405486550:50
7Toluene605489540:60
8Acetone605410090:10
9Acetone405510096:4
10AcetoneRT56100100:0
11AcetoneRT2.52491100:0
12 [a]AcetoneRT5481590:10
13 [b]AcetoneRT-480-
14 [c]AcetoneRT5480-
15 [d]AcetoneRT5695100:0
16-RT558060:40
Reaction conditions: argon, [1a]:[2a] = 1:1, NHC-1 = IPr*OMe·HCl, [NHC-1]:[KHMDS] = 1:1; [a] reaction conducted in air; [b] reaction conducted without NHC-1; [c] reaction conducted without KHMDS; [d] free carbene was added; [e] determined by GC-MS analysis; [f] determined by 1H NMR spectroscopic analysis.
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Hanek, K.; Żak, P. Eco-Friendly Functionalization of Ynals with Thiols under Mild Conditions. Int. J. Mol. Sci. 2024, 25, 9201. https://doi.org/10.3390/ijms25179201

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Hanek K, Żak P. Eco-Friendly Functionalization of Ynals with Thiols under Mild Conditions. International Journal of Molecular Sciences. 2024; 25(17):9201. https://doi.org/10.3390/ijms25179201

Chicago/Turabian Style

Hanek, Kamil, and Patrycja Żak. 2024. "Eco-Friendly Functionalization of Ynals with Thiols under Mild Conditions" International Journal of Molecular Sciences 25, no. 17: 9201. https://doi.org/10.3390/ijms25179201

APA Style

Hanek, K., & Żak, P. (2024). Eco-Friendly Functionalization of Ynals with Thiols under Mild Conditions. International Journal of Molecular Sciences, 25(17), 9201. https://doi.org/10.3390/ijms25179201

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