# One-Pot Regioselective γ-Trifluoromethylthiolation and γ-Methylthiolation of Enals

Camille Banoun, Killian Henault, Emmanuel Magnier, Guillaume Dagousset

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Camille Banoun, Killian Henault, Emmanuel Magnier, Guillaume Dagousset. One-Pot Regioselective γ-Trifluoromethylthiolation and γ-Methylthiolation of Enals. European Journal of Organic Chemistry, In press, 10.1002/ejoc.202400119. [https://doi.org/10.1002/ejoc.202400119](https://doi.org/10.1002/ejoc.202400119)

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# One-Pot Regioselective γ-Trifluoromethylthiolation and γ-Methylthiolation of Enals

Camille Banoun,[a] Killian Henault,[a] Emmanuel Magnier,[a] and Guillaume Dagousset*[a]

We describe herein the direct electrophilic γ-trifluoromethylthiolation and γ-methylthiolation of enals, via the *in situ* formation of the corresponding silyl dienol ether. This one-pot process is

carried out under simple and mild reaction conditions and is compatible with a variety of functional groups.

## Introduction

Due to their numerous applications in life sciences as well as in materials science, organosulfur compounds are of crucial importance in organic synthesis.[1] For this reason, the formation of carbon–sulfur (C–S) bonds in various organic scaffolds has continuously been the subject of many methodologies, including transition-metal catalyzed, organocatalyzed and photo-catalyzed strategies.[2]

Given the central role of enals as key building blocks in organic chemistry,[3] the introduction of a C–S bond onto these substrates is of high significance. In this field, studies have mainly focused on the use of thiols as nucleophilic sources of sulfur for sulfa-Michael reactions, leading to β-sulfenylated aldehydes.[4] Conversely, only very few reactions involving electrophilic sources of sulfur could be successfully developed. Córdova *et al.* reported an organocatalytic enantioselective aminosulfonylation of enals towards the synthesis of α-sulfonylated β-aminated aldehydes (Scheme 1a). In 2016, Zhou, Chen *et al.* reported an NHC-catalyzed (N-Heterocyclic Carbene) α-sulfonylation of enals: this reaction proved very efficient for aromatic enals. However in the case of an aliphatic enal, only the α,γ-disulfonylated adduct was obtained without any α/γ selectivity (Scheme 1b).[5] Despite these achievements, to the best of our knowledge, a direct remote sulfonylation in the γ position of enals, which would leave the enal moiety untouched for further transformations, has not been reported so far.

We recently started a research program on the remote functionalization of enals starting from silyl dienol ethers.[6] In particular, the observed γ selectivity for such substrates was

newly rationalized by theoretical calculations in the case of the electrophilic γ-fluorination of enals.[6c] Based on this experience, we envisioned that the reaction of silyl dienol ethers with a suitable electrophilic S-centered partner would selectively lead to the corresponding γ-sulfonylated enals. We wish to report herein our synthetic endeavors in this area, with a particular focus on the introduction of trifluoromethylthio (SCF₃) and methylthio (SMe) groups, which both find relevant and valuable applications in the pharmaceutical and/or agrochemical industries.[7,8]

### a) Córdova *et al.*

<figure><img src="image_3.png" /></figure>

### b) Zhou, Chen *et al.*

<figure><img src="image_4.png" /></figure>

### c) This work

<figure><img src="image_5.png" /><figcaption>**Scheme 1.** Overview on the electrophilic sulfonylation of γ-enolizable enals.</figcaption></figure>

<footnote>[a] C. Banoun, K. Henault, Dr. E. Magnier, Dr. G. Dagousset
Université Paris-Saclay, UVSQ, CNRS, UMR 8180
Institut Lavoisier de Versailles, 45 avenue des Etats-Unis 78000 Versailles,
France
E-mail: guillaume.dagousset@uvsq.fr</footnote>

<footnote>Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202400119</footnote>

<footnote>© 2024 The Authors. European Journal of Organic Chemistry published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.</footnote>
<figure><img src="image_6.png" /></figure>

## Results and Discussion

Our investigations started by examining the reactivity of silyl dienol ether **2a**, derived from (E)-2-dodecenal **1a**, with various electrophilic sources of the trifluoromethylthio group **3a-3c**. While reagents **3a** and **3b** derived from succinimide and phthalimide were unreactive, we were delighted to see that the use N-trifluoromethylthiosaccharine **3c**[9] led to the formation of the corresponding γ-SCF₃ enal **4a** in 51% NMR yield (Table 1, entries 1–3). Importantly, as theoretically expected,[6c] the product **4a** was obtained as a single regioisomer, and no trace of the α-SCF₃ adduct could be detected after analysis of the ¹⁹F NMR spectrum of the crude mixture. Further screening of the reaction conditions revealed that MeCN was the optimal solvent for this process (entries 4–6). We then decided to turn our attention to the use of additives in order to increase the efficiency of the reaction. While inorganic and organic bases had a detrimental effect on the yield (entries 7–9), the addition of one equivalent of tetrahydrothiophene (THT) led to a significant improvement in **4a** formation (65% NMR yield, entry 10).[10] Interestingly, the amount of THT could be decreased to 10 mol% without any significant loss of yield (entry 11). THT most probably acts as a Lewis base catalyst, presumably *via* the *in situ* generation of a THT-SCF₃ sulfonium

intermediate I (Scheme 2).[11] Then, a slight modification of the stoichiometry afforded product **4a** in an optimized 76% NMR yield (entry 12). Finally, we decided to perform this reaction directly from (E)-2-dodecenal **1a**, without isolating silyl dienol ether **2a**. Although this one-pot reaction required one equivalent of THT to be more effective, we were pleased to see that the desired trifluoromethylthiolated adduct **4a** was produced in an overall 64% NMR yield (entry 13). Keeping in mind the key advantage of not having to isolate intermediate **2a**, we selected these optimized conditions for the rest of our study.

We next turned our attention to the scope of application of this methodology (Scheme 3). Even though compound **4a** could be successfully isolated in 54% yield as a pure compound, we noticed that some of the targeted γ-SCF₃ enals tended to degrade during the purification on silica gel chromatography. To avoid this issue, when the γ-trifluoromethylthiolation process was ended, we directly reduced the enal moiety with NaBH₄: the corresponding γ-SCF₃ allylic alcohols **5** were obtained, with no stability problems. With this one-pot three-step protocol, a wide range of α-unbranched enals **1a-1f** were readily trifluoromethylthiolated in up to 50% overall isolated yield. Remarkably, the (Z) alkene moiety of substrate **1e**, which could potentially react with reagent **3a**,[12] remains untouched, demonstrating the high chemoselectivity of this process.

In addition, a 1 mmol scale experiment could also be smoothly carried out for product **5a** with the same level of efficiency. Other enals **1g-1h** bearing a substituent either in β or in α position were also compatible with our mild reaction conditions. Importantly, regardless of their substitution patterns, all compounds of Scheme 2 were isolated as a single isomer, with a total γ selectivity.

With these results in hand, we then thought of extending this new protocol to other sulfonylation reactions. Given the great importance of the MeS group in medicinal chemistry,[8] we started to study a similar γ-methylthiolation process. Pleasingly, after a slight modification of the reaction conditions (see ESI for complete optimization of the reaction) and using DMTSF **6** (dimethyl(methylthio)sulfonium tetrafluoroborate) as

<figure><img src="image_7.png" /></figure>

<table><thead><tr><th>Entry</th><th>SCF<sub>3</sub><sup>+</sup> source</th><th>Solvent</th><th>Additive</th><th>Yield (%)<sup>[a,b]</sup></th></tr></thead><tbody><tr><td>1</td><td>3a</td><td>MeCN</td><td>–</td><td>0</td></tr><tr><td>2</td><td>3b</td><td>MeCN</td><td>–</td><td>0</td></tr><tr><td>3</td><td>3c</td><td>MeCN</td><td>–</td><td>51</td></tr><tr><td>4</td><td>3c</td><td>Acetone</td><td>–</td><td>45</td></tr><tr><td>5</td><td>3c</td><td>DMF</td><td>–</td><td>36</td></tr><tr><td>6</td><td>3c</td><td>THF</td><td>–</td><td>0</td></tr><tr><td>7</td><td>3c</td><td>MeCN</td><td>K<sub>2</sub>CO<sub>3</sub> (1 equiv.)</td><td>10</td></tr><tr><td>8</td><td>3c</td><td>MeCN</td><td>Et<sub>3</sub>N (1 equiv.)</td><td>31</td></tr><tr><td>9</td><td>3c</td><td>MeCN</td><td>DABCO (1 equiv.)</td><td>9</td></tr><tr><td>10</td><td>3c</td><td>MeCN</td><td>THT (1 equiv.)</td><td>65</td></tr><tr><td>11</td><td>3c</td><td>MeCN</td><td>THT (10 mol%)</td><td>62</td></tr><tr><td>12<sup>[c]</sup></td><td>3c</td><td>MeCN</td><td>THT (10 mol%)</td><td>76</td></tr><tr><td>13<sup>[c,d]</sup></td><td>3c</td><td>MeCN</td><td>THT (1 equiv.)</td><td>64 (54)<sup>[e]</sup></td></tr></tbody></table>

[a] General conditions: 2a (0.15 mmol), 3 (0.225 mmol, 1.5 equiv.), additive (0.1–1 equiv.) in 1 mL of solvent at RT for 24 h. [b] Yields determined by ¹⁹F NMR spectroscopy using PhOCF₃ as an internal standard. [c] Reaction performed with 1.5 equiv. of 2a and 1 equiv. of 3a. [d] One-pot reaction directly from (E)-2-dodecenal **1a**. See ESI for more details.

<figure><img src="image_8.png" /><figcaption>**Scheme 2.** Proposed mechanism involving the formation of the THT-SCF₃ sulfonium intermediate I.</figcaption></figure>
<figure><img src="image_9.png" /><figcaption>**Scheme 3.** Scope of the γ-trifluoromethylthiolation reaction. General conditions: **1** (0.225 mmol, 1.5 equiv.), TIPSOTf (0.27 mmol, 1.8 equiv.), and Et₃N (0.3 mmol, 2 equiv.) in CH₂Cl₂ (1 mL) at RT for 2 h, then **3c** (1 equiv.), THT (1 equiv.) and MeCN (1 mL) were added and the mixture was stirred at RT for 24 h. Unless otherwise noted, given yields are for chromatographically pure isolated products. These yields are calculated using **3a** as limiting reagent. Unless otherwise noted, compounds **4–5** were isolated as a single *E* isomer. [a] Yields into brackets refer to ¹⁹F NMR yield using PhOCF₃ as internal standard. [b] Overall isolated yield of the corresponding allylic alcohol **5** after reduction with NaBH₄. See ESI for more details. [c] Reaction performed on a 1 mmol scale. [d] Z/E = 1.3:1.</figcaption></figure>

the electrophilic source of SMe group, the γ-methylthiolated dodecanal **7a** could be produced in a high isolated yield of 82% (Scheme 4). In order to show the synthetic utility of this selective γ-sulfenylation process, a 5 mmol scale experiment was successfully performed, leading to 663 mg of enal **7a** in 68% overall yield.

These optimized conditions were then applied to a variety of other substrates. Notably, this novel one-pot two-step reaction was efficiently carried out on linear enals **1a–1f** with the same full γ-selectivity. Pleasingly, no purification issues were observed in this case. In addition, various α-substituted γ-SMe enals **7g–7j** could be smoothly prepared in up to 69% isolated yield. In particular, it is worth noting the compatibility of this mild process with biorelevant molecules such as the natural monoterpenoids (S)-(-)-Perillaldehyde and (1R)-(-)-Myrtenal, which were readily converted into the corresponding γ-SMe enals **7i** and **7j**, respectively.[13,14]

## Conclusions

In conclusion, two completely selective direct γ-sulfenylations of enals were successfully developed for the first time. On the one hand, using N-SCF₃ saccharine as the electrophilic reagent, a one-pot trifluoromethylthiolation protocol was carried out on various enals, leading after reduction to γ-SCF₃ allylic alcohols in up to 50% yield over three steps. On the other hand, with DMTSF as the electrophilic partner, a wide range of γ-methylthiolated enals were readily prepared in up to 82% yield. Further developments in the field of γ-functionalization of enals are currently underway and will be reported in due course.

<figure><img src="image_10.png" /><figcaption>**Scheme 4.** Reaction scope for the γ-methylthiolation of enals. General conditions: **1** (0.225 mmol, 1.5 equiv.), TIPSOTf (0.27 mmol, 1.8 equiv.), and Et₃N (0.3 mmol, 2 equiv.) in CH₂Cl₂ (1 mL) at RT for 2 h, then **6** (0.15 mmol, 1 equiv.) K₂HPO₄ (0.3 mmol, 2 equiv.) and MeCN (1 mL) were added and the mixture was stirred at RT for 10 min. Given yields refer to chromatography pure products. Compounds **7** were isolated as a single *E* isomer. [a] Reaction performed on a 5 mmol scale. [b] *dr* = 3:1 [c] *dr* > 95:5. *dr* = diastereomeric ratio.</figcaption></figure>
<figure><img src="image_11.png" /></figure>

**Supporting Information**

Details about the characterization methods can be found in the Supporting Information.

**Typical procedure for the γ-trifluoromethylthiolation of enals:** To a solution of enal 1 (0.225 mmol, 1.5 equiv.) and triethylamine (30 mg, 0.30 mmol, 2.0 equiv.) in CH₂Cl₂ (1 mL) is added TIPSOTf (83 mg, 0.27 mmol, 1.8 equiv.). The solution is stirred at RT for two hours, and a solution of N-SCF₃ saccharine 3c (43 mg, 0.15 mmol, 1 equiv.) and THT (13 mg, 0.15 mmol, 1 equiv.) in MeCN (1 mL) is added to the reaction mixture. The resulting mixture is then stirred at RT for 24 hours. After completion of the reaction, NaBH₄ (23 mg, 0.60 mmol, 4 equiv.) and MeOH (1 mL) are added. The resulting mixture is stirred at RT for 30 min and quenched with a saturated solution of NH₄Cl (10 mL). The aqueous phase is extracted with CH₂Cl₂ (3x10 mL) and the combined organic layers are dried over anhydrous MgSO₄, and the solvent is evaporated *in vacuo*. The crude product is purified by flash chromatography or preparative TLC plates to afford the desired γ-SCF₃ allylic alcohol 5.

**Typical procedure for the γ-methylthiolation of enals:** To a solution of enal 1 (0.225 mmol, 1.5 equiv.) and triethylamine (30 mg, 0.30 mmol, 2.0 equiv.) in CH₂Cl₂ (1 mL) is added TIPSOTf (83 mg, 0.27 mmol, 1.8 equiv.). The solution is stirred at RT for two hours, and the solution is transferred into a mixture of DMTSF (29 mg, 0.15 mmol, 1 equiv.) and K₂HPO₄ (52 mg, 0.3 mmol, 2 equiv.) in MeCN (1 mL). The resulting mixture is then stirred at RT for 10 minutes. After completion of the reaction, the reaction is quenched with a saturated solution of NH₄Cl (10 mL). The aqueous phase is extracted with CH₂Cl₂ (3x10 mL) and the combined organic layers are dried over anhydrous MgSO₄, and the solvent is evaporated in vacuo. The crude product is purified by flash chromatography or preparative TLC plates to afford the desired γ-SMe enal 7.

**Acknowledgements**

This work was supported by a grant from the Agence Nationale de la Recherche with JCJC funding (ANR-20-CE07-0008-01). The French Fluorine Network (GIS Fluor) is also acknowledged.

**Conflict of Interests**

The authors declare no conflict of interest.

**Data Availability Statement**

The data that support the findings of this study are available in the supplementary material of this article.

**Keywords:** Enals • sulphenylation • trifluoromethylthiolation • methylthiolation • remote functionalization

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