# Domino Doyle-Kirmse/Claisen-Thioimidate Rearrangements: Access to 2-Aminobuta-1,3-diene Derivatives of Benzazole-2-thiones

Charlou Rognan, Pierre Locquet, Romain Pertschi, Nicolas Girard, Mihaela Gulea

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Charlou Rognan, Pierre Locquet, Romain Pertschi, Nicolas Girard, Mihaela Gulea. Domino Doyle-Kirmse/Claisen-Thioimidate Rearrangements: Access to 2-Aminobuta-1,3-diene Derivatives of Benzazole-2-thiones. Advanced Synthesis and Catalysis, 2024, 366 (19), pp.4078-4083. 10.1002/adsc.202400714 . hal-04663341v2

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# Domino Doyle-Kirmse/Claisen-Thioimidate Rearrangements: Access to 2-Aminobuta-1,3-diene Derivatives of Benzazole-2-thiones

Charlou Rognan,ª Pierre Locquet,ª Romain Pertschi,ª Nicolas Girard,ª\* and Mihaela Guleaª,\*

ª CNRS, Laboratoire d'Innovation Thérapeutique, LIT UMR 7200, Université de Strasbourg, F-67000 Strasbourg, France
E-mail: nicolas.girard@unistra.fr; gulea@unistra.fr

Manuscript received: June 14, 2024; Revised manuscript received: July 23, 2024;
Version of record online: September 12, 2024

<figure><img src="image_2.png" /></figure>

Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202400714.

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

© 2024 The Author(s). Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

**Abstract:** A domino sequence consisting of a rhodium-catalyzed Doyle-Kirmse rearrangement followed by a Claisen-thioimidate rearrangement has been developed. This type of thio-Claisen rearrangement represents the first example reported in the homoallenylsulfenyl series. The sequence involves 2-propargylsulfenyl benzazoles and diazotesters, affording *N*-butadienyl substituted benzazole-2-thiones as a mixture of *Z* and *E* isomers, in yields ranging from 12% to quantitative (32 examples). The method provides a rapid access to a new family of highly substituted polyfunctionalized 2-aminobuta-1,3-dienes with potential synthetic applications.

**Keywords:** Doyle-Kirmse reaction; Thio-Claisen rearrangement; 2-Aminobuta-1,3-diene; Benzazole-2-thione

Sigmatropic rearrangements involving sulfur-containing compounds represent powerful tools in organic synthesis, providing access to a large variety of molecular structures of interest, with atom and step economy.[1] These reactions involve a concerted cleavage of a sulfur-carbon bond and formation of a carbon-carbon bond with creation of one or two new carbon stereogenic centers. Among them, the Doyle-Kirmse reaction of allyl or propargyl sulfides with carbenes derived from diazo compounds has already been studied under transition-metal catalysis or photochem-

ical conditions.[2,3] It proceeds through the [2,3]-sigmatropic rearrangement of the formed sulfonium ylide, giving access to allyl or homoallenyl sulfides (Scheme 1, A). Another renowned reaction in this category is the [3,3]-sigmatropic rearrangement of aryl or vinyl allyl thioethers, also known as the thio-Claisen rearrangement.[4] A much less studied version of this reaction, called Claisen-thioimidate rearrangement, differs from the previously mentioned by the cleavage of a sulfur-carbon bond and the subsequent formation

A. Doyle-Kirmse reaction of propargyl sulfides (well studied)

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

B. Claisen-thioimidate rearrangement (a few examples in S-allyl series)

<figure><img src="image_5.png" /></figure>

C. Domino Doyle-Kirmse/Claisen-thioimidate rearrangements (this work)

<figure><img src="image_6.png" /><figcaption>**Scheme 1.** [2,3] and [3,3]-sigmatropic rearrangements involving sulfur-containing compounds.</figcaption></figure>
of a nitrogen-carbon bond.[5] To our knowledge, only a few examples have been reported and involved an S- to-N allyl migration in allylsulfenyl-substituted N-heterocyclic systems, under thermal or metal-catalyzed conditions (Scheme 1, B).[6] So far no examples have been described in S-homoallenyl series.

Prompted by recent studies in our group that focused on metal-catalyzed processes involving 2-sulfenyl benzimidazoles derivatives as substrates,[7] we decided to investigate 2-homoallenylsulfenyl substituted benzazoles as substrates in the Claisen-thioimidate rearrangement. Moreover, 2-sulfenyl benzazoles (i.e., benzimidazoles, benzoxazoles, and benzothiazoles) represent useful intermediates in organic synthesis, as well as privileged scaffolds in medicinal chemistry due to their widespread occurrence in biologically active compounds.[8]

Herein, we describe the synthesis of N-butylenyl benzazole-2-thiones via an unprecedented Claisen-thioimidate rearrangement of homoallenyl sulfides. Aiming for a step-economical synthetic approach, we have developed a domino process using as starting materials 2-propargylsulfenyl substituted N-heterocycles and diazoesters, in the presence of a metal-catalyst for diazo decomposition. The transformation proceeds through a Doyle-Kirmse [2,3]-sigmatropic rearrangement, followed by a Claisen-thioimidate [3,3]-sigmatropic rearrangement, without isolation of the 2-homoallenylsulfenyl benzazole intermediate (Scheme 1, C). The obtained products are original polyfunctionalized stable 2-aminobuta-1,3-diene derivatives. Indeed, they represent a valuable class of synthons mainly known for their use in [4+2] cycloadditions, and access to a larger structural diversity remains a topical subject.[9]

Setting the goal of developing the proposed domino Doyle-Kirmse/thio-Claisen reaction sequence, we first reacted 2-pentynylsulfenyl benzimidazole **1a** and methyl 2-diazo-2-phenylacetate **2a** under metal catalysis (Table 1). With 2.5 mol% of $Rh_2(OAc)_4$, in 1,2-dichloroethane, at 80 °C, after 15 minutes, only the Doyle-Kirmse product **3a** was obtained and isolated in 90% yield (Table 1, entry 1). We then increased the reaction temperature to promote the [3,3]-σ rearrangement of allene **3a** into dienamine **4a**. At 110 °C, after 6 h, the desired product **4a** has been isolated in 45% yield, as a mixture of Z and E isomers in an approximate 65:35 ratio, determined by ¹H NMR on the crude mixture (Table 1, entry 2). The Z-geometry of the double bond for the major isomer of **4a** was assigned by a two-dimensional nuclear Overhauser spectroscopy (2D-NOESY) experiment. By decreasing the catalytic loading to 1 mol% the yield was improved (74%, Table 1, entry 3). Under microwave irradiation, at 110 °C for 15 min, the yield of **4a** was further increased to 84% (Table 1, entry 4). Using toluene as the solvent decreased the yield to 65% (Table 1,

<figure><img src="image_7.png" /><figcaption>**Table 1.** Optimization of the domino [2,3]/[3,3]-σ rearrangements to obtain dienamine **4a**.[a]</figcaption></figure>

<table><thead><tr><th>Entry</th><th>Catalyst (x mol%)</th><th>T (°C)</th><th>Time</th><th>Yield % 4a<sup>[f]</sup></th></tr></thead><tbody><tr><td>1</td><td>$Rh_2(OAc)_4$ (2.5)</td><td>80</td><td>15 min</td><td>0<sup>[b]</sup></td></tr><tr><td>2</td><td>$Rh_2(OAc)_4$ (2.5)</td><td>110</td><td>6 h</td><td>45</td></tr><tr><td>3</td><td>$Rh_2(OAc)_4$ (1.0)</td><td>110</td><td>6 h</td><td>74</td></tr><tr><td>4<sup>[c]</sup></td><td>$Rh_2(OAc)_4$ (1.0)</td><td>110</td><td>15 min</td><td>84</td></tr><tr><td>5<sup>[c],[d]</sup></td><td>$Rh_2(OAc)_4$ (1.0)</td><td>110</td><td>15 min</td><td>65</td></tr><tr><td>6<sup>[c]</sup></td><td>[Fe(III)] (5.0)</td><td>110</td><td>15 min</td><td>—</td></tr><tr><td>7<sup>[c]</sup></td><td>Cu(acac)<sub>2</sub> (5.0)</td><td>110</td><td>15 min</td><td>—</td></tr><tr><td>8<sup>[c],[e]</sup></td><td>$Rh_2(OAc)_4$ (1.0)</td><td>130</td><td>15 min</td><td>84</td></tr></tbody></table>

[a] Reaction conditions: **1a** (1 equiv.), **2a** (1.1 equiv.), in 1,2-dichloroethane (DCE), 0.07 M.

[b] Only product **3a** was formed.

[c] Reaction under microwave heating.

[d] Toluene was used as the solvent.

[e] Experiment on 1 mmol scale with 1.5 equiv. of **2a**.

[f] Ratio Z/E 65:35, determined by ¹H NMR on the crude mixture.

entry 5). Other catalysts known to promote diazo decomposition, such as 5,10,15,20-tetraphenyl-21H,23H-porphine iron(III) chloride or copper(II) diacetylacetonate, did not convert the starting material **1a** (Table 1, entries 6 and 7). Finally, scaling up the reaction to 1 mmol of **1a** required the use of 1.5 equivalents of diazoester **2a** and an increase in temperature to 130 °C to maintain the best yield observed in Table 1, entry 4 (Table 1, entry 8). We maintained these reaction conditions for further experiments. It is worth mentioning that in all experiments, the Z/E ratio did not change and the **4a-Z** and **4a-E** isomers were not separable by column chromatography. To determine whether the metal is involved in the thio-Claisen rearrangement, homoallenyl sulfide **3a** (prepared separately, see SI) was heated at 110 °C for 2 hours under metal-free conditions. This led to a total conversion to **4a**, confirming that the transformation does not involve the metal catalyst.

To explore the scope and limitations of the transformation, several structural modifications of the reaction partners were investigated (Table 2). A range of 2-pentynylsulfenyl substituted N-heterocyclic substrates **1** was synthesized (see experimental details in SI) and reacted with diazoester **2a**, under the
<table><caption>**Table 2.** Scope of the domino [2,3]/[3,3]-σ rearrangements.[a]</caption><thead><tr><th colspan="4">Variation of benzazole</th></tr></thead><tbody><tr><td>4a: R = H, 84%, Z/E 65/35</td><td>4b: R = Me, 67%, Z/E 64/36</td><td>4c: quant, Z/E 74/26</td><td>4d: 99%, Z/E 60/40</td></tr><tr><td>4e: R = Me, 67%, Z/E 66/34</td><td>4f: R = Cl, 63%, Z/E 57/43</td><td>4h: R<sup>1</sup> = NO<sub>2</sub>, R<sup>2</sup> = H, 44%, Z/E 66/34<br>4i: R<sup>1</sup> = OMe, R<sup>2</sup> = H, 16%, Z/E 64/36<br>4j: R<sup>1</sup> = H, R<sup>2</sup> = OMe, 39%, Z/E 69/31</td><td>4k: 0%</td></tr><tr><td>4g: R = F, 73%, Z/E 69/31</td><td></td><td>4j': R<sup>1</sup> = H, R<sup>2</sup> = OCHF<sub>2</sub>, 54%, Z/E 65/35</td><td></td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td>4l: 14%, Z/E 57/43</td><td>4m: 28%, [b] Z/E 60/40</td><td>4n: 70%, [b] Z/E 65/35</td><td></td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td colspan="4">Variation of the propargyl substituent</td></tr><tr><td>4o: R = H, 62%, Z/E 19/81</td><td>4p: R = Ph, 65%, [b] Z/E 60/40</td><td>4r: R = Et, 28%, [b] 46/30/24/0</td><td>4s: R = H, 64%, [b] 50/34/10/6</td></tr><tr><td>4q: R = Cyclohexyl, 71%, Z/E 69/31</td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td colspan="4">Variation of the diazo partner</td></tr><tr><td>5a: R = 4-NO<sub>2</sub>, 74%, Z/E 56/44</td><td>5b: R = 4-F, 91%, Z/E 59/41</td><td>5c: R = 4-OMe, 73%, Z/E 57/43</td><td>5d: R = 4-Me, 72%, Z/E 66/34</td></tr><tr><td>5e: R = 2-Me, 32%, [b] Z/E 77/23</td><td>5f: R = 3-Me, 92%, Z/E 66/34</td><td>5h: R = L-Menthyl, 70%, Z/E 63/37</td><td></td></tr><tr><td></td><td></td><td></td><td></td></tr><tr><td colspan="4">Limitations</td></tr><tr><td>5k: R = R' = C(O)Ph, 0%</td><td>6: 26% [b] (from 2k)</td><td>5n: 0%</td><td>7: 47%</td></tr><tr><td>5l: R = R' = Ph, 0%</td><td></td><td></td><td></td></tr><tr><td>5m: R = H, R' = CO<sub>2</sub>Et, 0%</td><td></td><td></td><td></td></tr></tbody></table>

optimized reaction conditions. Starting from three different 2-pentynylsulfenyl benzazoles 1, N-methyl

benzimidazole **1b**, benzoxazole **1c**, and benzothiazole **1d**, the reaction led to the expected dienamines **4b-d**, achieving even quantitative yields in the cases of **4c** and **4d**. Although it was not possible to separate Z and E isomers by column chromatography, we succeeded in isolating single crystals from dienamines **4a** and **4c**. Analysis by X-ray diffraction showed that they corresponded to the Z isomers (Figure 1 and SI).[10] The obtained X-ray structures also revealed the non-planar shape of the products, where the benzazole moiety is not coplanar to the diene part, as well as the deconjugated nature the two double bonds.

We next performed the reaction on substrates **1e-j** which bear one or two substituents on the benzene ring of the benzimidazole. The dimethyl-, dichloro-, and difluoro- derivatives gave the corresponding products **4e-g** in good yields of 67%, 55%, and 73%, respectively.

As the monosubstituted starting benzimidazoles **1h**, **1i**, and **1j** can exist in two tautomeric imine-enamine forms, two regioisomeric products **4** can potentially be formed in each case (i.e. **4h/4h', 4i/4i',** and **4j/4j'**). From the nitro-substituted derivative **1h**, only one regioisomer has been formed and isolated in 44% yield. Its structure was determined by NMR spectroscopy (HSQC, HMBC) and assigned to compound **4h**. Starting from the methoxy- or the difluoromethoxy-substituted derivatives **1i** or **1j**, the domino reaction still worked efficiently. Both possible pairs of regioisomers **4i/4i'** or **4j/4j'** were formed in these cases. The ratio of products **4i/4i'** in the crude mixture was 23/77, and the total isolated yield was 55%, while for **4j/4j'** the ratio was 39/61 and the yield was 77%. It was possible to separate and characterize each of these compounds and to assign the structures **4i'** and **4j'** to the major regioisomers. To explain the observed regioselectivities we propose that the *S*-to-*N* migration takes place on the most electron rich nitrogen atom of the benzimidazole, which means the nitrogen in para-

<figure><img src="image_8.png" /><figcaption>**Figure 1.** X-ray structures of **4a-Z** (left, CCDC 2329904) and **4c-Z** (right, CCDC 2329905); 50% probability ellipsoids.</figcaption></figure>

<footnote>[a] Isolated yield, unless otherwise stated. The diastereoisomeric ratio was measured based on ¹H NMR spectra of the crude mixture; the isomers were inseparable by column chromatography.</footnote>

<footnote>[b] NMR yield measured using caffeine as internal standard.</footnote>
position of an electron donating group (i.e. OMe, OCHF₂), and in meta-position of an electron withdrawing group (i.e. NO₂). We then examined the reaction on substrates incorporating other *N*-heterocycles than benzazoles. The diphenylimidazole product **4k** was not formed, and low yields were obtained for thiazolidine **4l** (14% yield) and imidazoline **4m** (28%, NMR yield). When 2-mercapto-indole derivative **1n** was used as the starting material, the reaction proceeded via *S*-to-*C* homoallenyl migration, affording the corresponding dienamine **4n** (70%, NMR yield).

Next, in benzoxazole series, the structure of the propargyl moiety was modified. First, the ethyl substituent on the triple bond was replaced by a hydrogen, a phenyl, or a cyclohexyl. The prepared substrates **1o-q** were submitted to the standard reaction conditions, and all of them were successfully transformed into the desired products **4o-q**. Product **4o**, resulting from the *S*-propargyl derivative led to a ratio Z/E of 19/81 (*E* geometry assigned by a 2D-NOESY experiment). It is worth noting that in this case with a terminal alkyne, the observed Z/E selectivity is reversed compared to the previous cases with a substituted triple bond. Starting from substrates **1r** and **1s** which have a methyl substituent in propargylic position, the transformation also worked, affording the expected dienamines **4r** and **4s**. These pentasubstituted dienamines can potentially exist as four isomers (combinations of *Z* and *E*) and were obtained as inseparable mixtures: three isomers for **4r** and of four isomers for **4s**. Their purification was not feasible, and we could only estimate the yields by ¹H-NMR (28% for **4r** and 64% for **4s**), along with the isomer ratios.

Finally, substrate **1c** was reacted with different diazo partners. Using methyl 2-aryl-2-diazoacetates, the expected dienes were obtained in all cases, regardless of the position or electronic nature of the substituents on the aromatic ring (i.e., 4-NO₂, 4-F, 4-OMe, 2-, 3-, and 4-Me) the expected dienes were obtained. Yields ranged from 72% to 91%, except for the more hindered 2-Me derivative **5e**, which gave a 32% NMR yield. Moving from the methyl to *tert*-butyl or a *L*-menthyl diazoester, the corresponding expected products **5g** and **5h** were obtained with quantitative and 70% yield, respectively. Acceptor-acceptor diazo such as dimethyl diazomalonate proved to be efficient in reaction with substrate **1c**, leading to diene **5i** in 94% isolated yield. On the other hand, the reaction of 2-pentynylsulfenyl benzimidazole **1a** with the diazomalonate afforded diene **5j** only in 12% yield.

Some notable limitations were revealed from the study. Indeed, some substrates did not yield the expected dienamines and led to other products. Diazo compounds such as 2- diazo-1,3-diphenylpropane-1,3-dione (**2k**) or (diazomethylene)dibenzene (**2l**) did not react with substrate **1d**. Diazo **2k** was recovered unreacted while **2l** rapidly dimerized under the

reaction conditions. Consequently, the corresponding products **5k** and **5l** were not obtained. Instead, product **6** was formed from the propargyl Claisen-thioimidate rearrangement. The reaction with ethyl diazoacetate led to a complex crude mixture in which product **5m** could be identified, but was not isolated. When 2-sulfenyl tetrahydropyrimidine was tested as an *N*-heterocyclic substrate in reaction with diazoester **2a**, we isolated the bicycle **7** in 47% yield, instead of the expected dienamine **5n**. Product **7** resulted from the lactamization of the Doyle-Kirmse homoallenyl sulfide product.

Allyl, allenyl, and propargyl thiocyanates are known to readily undergo [3,3]-sigmatropic rearrangements to give more stable isothiocyanates.[11,12] We decided to test our domino sequence on *S*-pentynyl thiocyanate **8** as the substrate. The desired transformation required an excess (3 equivalents) of the diazo partner, 2-diazo-2-phenylacetate **2a** or dimethyl diazomalonate **2j** (Scheme 2). Dienyl isothiocyanate **9** was obtained in 70% yield and we successfully isolated each diastereomer, **9-Z** and **9-E**, by column chromatography. Thiocyanate **8** and diazo **2j** afforded isothiocyanate **10** in 56% yield.

To investigate the origin of the observed stereoselectivity of the transformation, acid-promoted isomerization was performed on **4a**. Starting from a mixture of Z/E isomers of **4a** with a 60/40 ratio, and using 0.2 equivalents of *p*-toluenesulfonic acid (PTSA) at 60°C for 16 hours, the diastereomeric ratio increased to 72/28 (see scheme in SI). We also observed that in the case of **4o**, the acidity of the silica gel was sufficient to increase the initial Z/E ratio from 19/81 to 4/96, which was the final ratio found after purification by column chromatography. Moreover, after several weeks of storage in the fridge at 4°C, the Z/E mixture of **4o** completely isomerized to the major *E*-isomer. These results suggest that the isomerization reaction is under thermodynamic control. This conclusion is supported by DFT calculations (see Supporting Information for computational details), which show that for **4a** and its simplified analog **4Me** (Me instead Et

<figure><img src="image_9.png" /><figcaption>**Scheme 2.** Domino [2,3]/[3,3]-σ rearrangements in thiocyanate series.</figcaption></figure>
substituent) the Z and E isomers are close in energy (energy difference within the DFT error) explaining the low diastereoselectivity of the reaction for the 3-substituted dienamines derivatives. In the case of 40 (non-substituted in 3-position) the *E*-isomer is favored over the *Z* by at least 2 kcal.mol⁻¹, in agreement with the experimental results showing that a total diastereoselectivity could be reached. In addition, to determine whether the reaction is kinetically or thermodynamically controlled, an energy profile of the Claisen-thioimidate rearrangement was computed for 40. This study revealed that both reaction pathways (leading to the Z and E isomers, respectively) proceed through two similar boat-type concerted transition states with similar energy levels (25.4 kcal.mol for the TS yielding the Z isomer and 26.7 kcal.mol for the TS yielding the *E* isomer) and can thus not explain such a high diastereoselectivity. Furthermore, according to the calculations, under kinetic control, the diastereoselectivity would be reversed (see Supporting Information for computational details).

In summary, we have developed a domino sequence of rearrangements combining propargyl Doyle-Kirmse and the rare Claisen-thioimidate reactions. The overall transformation occurred in the presence of a rhodium-catalyst and involved 2-propargylsulfenyl substituted benzazoles and diazoesters as starting materials. The Claisen-thioimidate rearrangement described here represents the first example reported in *S*-homoallylenyl series. The method gives an atom and step economical access to various *N*-butadienyl substituted benzimidazoles, benzoxazoles, and benzothiazoles 2-thiones. Most of the dienamine products have been obtained as inseparable mixtures of *Z/E* isomers, with ratios depending on 3-substitution. The method has also proven effective with *S*-propargyl thiocyanates, leading to *N*-dienyl isothiocyanates. Ongoing studies in our laboratory are focused on applying these highly substituted polyfunctionalized 2-aminobuta-1,3-dienes to the synthesis of original *N*,*S*-heterocyclic structures.

# Experimental Section

## General Procedure: Synthesis of *N*-butadienyl Benzimidazole-2-thione 4a

To a solution of propargyl thioimidate **1a** (250 mg, 1.15 mmol, 1 equiv.) in DCE (11.5 mL) in a sealed tube was added $Rh_2(OAc)_4$ (5.1 mg, 1 mol%). Then diazo **2a** (304 mg, 1.73 mmol, 1.5 equiv.) was added in 5 mL of DCE and the reaction mixture was stirred at 130°C under microwave irradiations for 15 minutes. Then, the solvent was evaporated, and the crude product was purified by column chromatography on silica gel to afford the desired diene **4a** (350 mg, 0.96 mmol, 84%) as a white solid mixture of *Z/E* diastereoisomers (65/35).

# Acknowledgements

The authors acknowledge for the financial support the "Ministère de l'Enseignement Supérieur, de la Recherche et de l'Innovation" (doctoral grant to C.R.) and the ANR (ANR-22-CE07-0047-01, ChaMO project). This work was supported by IdEx Unistra (ANR-10-IDEX-0002) and SFRI (STRAT'US project) under the framework of the French Investments for the Future Program. We thank the platform PACSI (GDS 3670) for NMR and mass analyses and the platform GDS 3648 for X-ray analyses. The authors would like to acknowledge the High-Performance Computing Center of the University of Strasbourg for supporting this work by providing scientific support and access to computing resources. Part of the computing resources were funded by the Equipex Equip@Meso project (Programme Investissements d'Avenir) and the CPER Alsac calcul/Big Data.

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