**2. Results and Discussion**

As seen from Table 1, when the reaction was carried out by stirring acylethynylpyrrole **1a** with 2 eq. *n*-BuLi in MeCN at room temperature under 1H NMR control, the isolated crude product contained 12% of the target ethynylpyrrole **4a** (Table 1, Entry 1), i.e., the expected decarbonylation degree was noticeably increased. The major product, in this case, became tertiary propargylic alcohol **3a** (content in the reaction mixture was 78%). Pyrrolylpyridine **2a**, previously a major product [36], was also present in the reaction mixture but in a much smaller amount (10%). Almost the same results were obtained in the presence of 2 eq. of *t*-BuONa (Entry 3). But *t*-BuOLi turned out to be completely inactive in this reaction (Entry 2): the starting acylethynylpyrrole **1a,** in this case, was almost returned from the reaction.

*t*-BuOK catalyzed the formation of ethynylpyrrole **4a** much more actively: in the crude product obtained with one equivalent of this base, the content of the ethynylpyrrole **4a** in the reaction mixture attained 66% (Entry 4). However, under these conditions, the conversion of the starting acylethynylpyrrole **1a** was only 82%, but the content of pyrrolylpyridine **2a** in the reaction mixture increased to 16%.

When 2 eq. *t*-BuOK were used, acylethynylpyrrole **1a** reacted completely during the same time, and the content of ethynylpyrrole **4a** in the reaction mixture became 90%. Pyrrolylpyridine **2a** was also present as a by-product (10%) in the reaction mixture (Entry 5).

We found that it was possible to get rid of the pyridine almost completely (Entry 6 and 7) by carrying out the reaction in the mixed solvents (MeCN/THF or MeCN/DMSO in volume ratio 1:1). Thus, under these conditions, the reaction was excellently selective providing ethynylpyrrole **4a** in ~80% isolated yield.

**Table 1.** Optimization of the ethynylpyrrole **4a** synthesis by decarbonylation of acylethynylpyrrole **1a** a.


a—reaction conditions: 0.5 mmol of **1a**, acetonitrile (2.0 mL), 20–25 ◦C, nitrogen atmosphere. b—the reaction was carried out in the MeCN/THF (1:1) system. c—the reaction was carried out in the MeCN/DMSO (1:1) system. d—isolated yield 84%. e—isolated yield 82%.

Next, with the optimized reaction conditions (2 eq of *t*-BuOK, THF/MeCN, room temperature, 1 h) in hand, we have evaluated the scope of this reaction using benzoyl-, furoyl-, and thenoylethynylpyrroles with alkyl, aryl and hetaryl substituents at 4(4,5)- positions and methyl, benzyl, and vinyl moieties at the nitrogen atom of the pyrrole ring. Eventually, the series of earlier unknown ethynylpyrroles **4a**–**k** were synthesized in good to excellent yields, the exception being pyrrole **4d** (yield 36%) (Scheme 2).

**Scheme 2.** The scope of the acylethynylpyrroles **1a**–**k** decarbonylation in the *t*-BuOK/MeCN/THF system.

The method proved to be extendable over indole compounds, as shown in the example of 3-benzoylethynylindole **5**, which was transformed to the expected 1-methyl-3 ethynylindole **6** under the same conditions (Scheme 3).

**Scheme 3.** Reaction of 3-acylethynylindole **5** with *t*-BuOK.

Thus, this result shows that 3-ethynylindoles—valuable synthetic building blocks [41] could be more accessible than previously due to the above-elaborated strategy. Noteworthy that the starting 3-acylethynylindoles can be easily prepared by the cross-coupling of the corresponding *N*-substituted indoles with acylbromoacetylenes in solid Al2O3 media [42].

Also, we have attempted to extend the synthesis of ethynylpyrroles over the furan series. For this, we have chosen menthofuran, a natural antioxidant component of peppermint oil [43]. It turned out that 2-benzoylethynylmenthofuran **7**, which synthesis was previously described in [44], underwent similar decarbonylation under the above conditions to give the expected ethynyl derivative **8** in 80% yield (Scheme 4).

**Scheme 4.** Reaction of 2-acylethynylmenthofuran **7** with *t*-BuOK.

The narrow range of the yields (74–95%) evidences that the structural effects on the synthesis efficiency are insignificant that are likely to result from the complex character of the process: (i) the formation of intermediate propargyl alcohols **3** and (ii) the decomposition of the latter. Besides, these steps are parallel to the formation of pyridine **2**. Apart from these competing factors, the yields are influenced by the isolation procedure (chromatography on the SiO2), wherein a noticeable amount of the target products are lost (Table 1, cf. 1H NMR and isolated yields). Nevertheless, the following general trend in yields may be noted: alkyl substituents in the pyrrole ring slightly decrease the reaction efficiency compared to aromatic substituents (74–86% vs. 84–95%). That can be referred to as a higher acidophobicity of the alkyl pyrroles.

It is known that MeCN is easily deprotonated by the action of alkali metals to give acetonitrile dimers via the formation of an intermediate CH2CN− anion [45]. Also, it was reported that CH2CN− anion was added to ketones to form tertiary cyanomethyl alcohols [46–49]. Correspondingly, in the previous communication, we have shown that the intermediate propargyl alcohol **3** are actually adducts of acylethynylpyrroles and CH2CN− anion [36].

Although we failed to isolate propargyl alcohol **3a** in the reaction mixture obtained in the presence of *t*-BuOK, the results produced with *t*-BuONa allowed us to assume that in the first case, the reaction also proceeded with the formation of the intermediate **3a**, which was rapidly decomposed.

To verify this assumption, propargyl alcohols **3a**,**c**,**d**,**f**, prepared from acylethynylpyrroles **1a**,**c**,**d**,**f** and acetonitrile in the presence of *t*-BuONa according to the modified protocol (Scheme 5) [36], were rapidly and quantitatively converted in the presence of *t*-BuOK into the corresponding ethynylpyrroles **4a**,**c**,**d**,**f** (Scheme 5).

**Scheme 5.** Synthesis and decomposition of propargyl alcohols **3a**,**c**,**d**,**f**.

We performed the reaction in an NMR tube in deuterated acetonitrile. Immediate transformation of the characteristic signals of the protons of the benzoyl group at 8.16 ppm to protons of Ph-substituent occurs after the addition of *t*-BuOK to acylethynylpyrrole **1c** solution, which corresponds to the formation of the intermediate acetylenic alcohol **3c** (Scheme 3). Additionally, two nearly equal singlets at 6.30 (signal of H-3 of pyrrole ring in ethynylpyrrole **4c**) and 6.44 ppm (signal of H-3 of pyrrole ring in intermediate alcohol **3c**) appeared. The singlet at 6.44 ppm decreases rapidly and disappears after about 30 min of reaction. After 1 h reaction mixture contained only terminal alkyne **4c** with a fully deuterated terminal acetylene position. Thus, the results confirm the proposed mechanism of the formation of ethynylpyrroles via intermediate acetylenic alcohol decomposition.

Cyanomethyl ketone (on the example of cyanomethyl-(2-thienyl)ketone **9a**), a second product of the *retro*-Favorsky reaction, was detected (1H NMR) after acidification of the aqueous suspension received during the workup of the reaction mixture (Scheme 6).

**Scheme 6.** The decomposition of propargyl alcohol **3a**.

Therefore, it is rigorously confirmed that in this reaction, ethynylpyrroles are the products of tertiary propargyl alcohol **3** decomposition, the *retro*-Favorsky reaction, which in this case occurs under extraordinarily mild (room temperature) conditions. Commonly this reaction requires a considerably higher temperature [120–140 ◦C (1 mm)] [30].

It could be emphasized that tertiary propargyl alcohols are one of the most attractive synthetic building blocks in organic synthesis [50–58]. This is primarily due to their bifunctionality (acetylene and hydroxyl functions), owing to which they can undergo cascade or multistage reactions with the formation of diverse compounds. In recent years, owing to the development of efficient methods for the synthesis of enantiomerically pure tertiary propargyl alcohols [59–61], interest in this class of compounds has increased significantly.

The tertiary propargyl alcohols here synthesized additionally contain one more synthetically valuable functional group (CN group and active C-H bond adjusted to nitrile function) and a pyrrole ring that significantly expands their potential for the design of novel functionalized compounds.

Despite the experimental evidence highlighting the mechanism of the cascade reaction studied, several mechanistic issues still need a quantum-chemical analysis. These issues mainly relate to the key stage of the synthesis, i.e., the *t*-BuOK-catalyzed decomposition of the intermediate propargyl alcohols **3**. Here the following questions should be clarified: (i) are the intermediates **3** decompose to the corresponding ketones **9** and potassium derivatives **11** of ethynylpyrroles as so far usually considered or free ethynylpyrroles **4** and the corresponding potassium enolates **10** (Scheme 7) are formed? Although the Favorsky *retro*reaction was synthetically thoroughly studied, this issue was never specially investigated. (ii) Is the experimentally observed formation of enolate from propargyl alcohols kinetically or thermodynamically controlled? (iii) Is the experimentally observed role of alkali metal cation, which fully controls the synthesis direction, an intrinsic (intramolecular) feature of the reaction, or is this influence of intermolecular solvation of the cations? (iv) What is the contribution of the solvent effect to the thermodynamics of this reaction?

To gain a clearer understanding of these mechanistic points, we have performed the quantum chemical calculations of the fundamental characteristics of the above reaction, the Gibbs free energy change, ΔG, using the DFT-based computational approach, which can be briefly referred to as B2PLYP/6-311G\*\*//B3LYP/6-311G\*\*+C-PCM/acetonitrile (see Supplementary Materials for details) and assuming R<sup>1</sup> = Me, R<sup>2</sup> = R3 = H, R<sup>4</sup> = Ph in Scheme 5.

**Scheme 7.** Possible ways of propargyl alcohols **3** decomposition.

According to the results obtained, path A, i.e., formation of the metallated ethynylpyrroles and ketones (Scheme 5), is thermodynamically closed, whereas path B (Scheme 5), i.e., formation of the ethynylpyrrole and enolate, is thermodynamically opened (see SI for details). The calculations indicate that the decomposition of intermediate **3** proceeds via the formation of free ethynylpyrrole and potassium enolate. Also, these results evidence that path B is thermodynamically controlled. The ΔG values for path B calculated for Li, Na and K derivatives of propargyl alcohols **3** are −66.5, −78.6 and −88.3 kJ/mol, respectively. This explains experimental results according to which with the *t*-BuOLi, no products are formed (Table 1), while *t*-BuONa promotes the formation of sodium enolate, however stable under reaction conditions, and with *t*-BuOK, the decomposition of potassium enolate occurs. Thus, the effect of potassium alkali metal indeed has an intrinsic (intramolecular) character.

The computed O-Li, O-Na and O-K bond lengths in alkali metal derivatives of propargyl alcohols are 1.71, 2.08, and 2.43 Å, respectively, and in the corresponding enolates are 1.83, 2.16, 2.61 Å, respectively. These values correlate with the literature data: 1.95 Å (O-Li), 2.14–2.32 Å (O-Na), 2.60–2.80 Å (O-K) [62], respectively. The reported bond energies are 343, 255 and 238 kJ/mol [63]. From these results, it becomes clear why with *t*-BuOK, the pyridines **2** are not formed: the abstraction of a proton from the CHCN moiety would lead to dianionic-like species that are thermodynamically unfavorable. In the cases of Li- and Na-derivatives of propargyl alcohols, the negative charges on oxygen are smaller since they are tighter ion pairs, especially with lithium cation. Therefore, the reaction takes other directions: with Li cation, expectedly, pyridines are formed, and with *t*-BuONa, the propargyl alcohol decomposition slows down (Table 1, Entry 3).

The mechanism of ethynylpyrroles formation from potassium derivatives of propargyl alcohols (on the example of alcoholate **12**, R<sup>1</sup> = Me, R2 = R<sup>3</sup> = H, R<sup>4</sup> = Ph) likely represents an intramolecular process (Scheme 8) [36], involving the Csp-CH bond cleavage with simultaneous transfer of a proton from the CH bond.

**Scheme 8.** Ethynylpyrroles formation from potassium derivatives of propargyl alcohols.

This process is probably facilitated by the intramolecular interaction (coordination) between potassium cation and CN-bond (intermediate **A**). This is supported by the fact that the calculated K··· N distance in the potassium derivative of propargyl alcohol (3.87 or 4.12 Å, depending on the molecular conformation, see Supplementary Materials) is smaller than the sum of the van der Waals radii of these atoms (4.2 Å). The above-mentioned two conformations are separated only by 0.8 kJ/mol. Since the latter value is well within the error margin of our computational scheme, they both can be considered legitimate

propargyl alcohol equilibrium ground-state molecular structures (see Supplementary Materials for more details).

The ΔG values computed for the formation of ethynylpyrroles with the participation of the solvent (MeCN) and then without (gas phase) are close (−88.3 and −84.5 kJ/mol). This means that the contribution of the solvent effect is negligible.

The experiments with MeNO2 showed that in this solvent, the reaction did not proceed at all: the starting acylethynylpyrrole was recovered completely. In our previous work [36], we reported the reaction of benzoylethynylpyrrole **1a** with isobutyronitrile and valeronitrile in the presence of lithium metal. In both cases, respective intermediate alcohols were isolated in 60 and 26% yields. In the presence of *t*-BuOK, both were readily transformed to corresponding ethynylpyrrole **4a**.
