*5.3. Reactions with Ethylenediamine*

The reaction of 2-benzoylethynylpyrroles **55a**,**b** with ethylenediamine was realized upon reflux of their equimolar mixture in dioxane (40 h) [81]. Expectedly, first the addition of diamine gave monoadduct **66a**,**b**, which, in the case of acylethynylpyrrole **55a**, underwent intramolecular cyclization/fragmentation to afford tetrahydroindolyl imidazoline **67a** and acetophenone (Scheme 36).

**Scheme 36.** Reaction of 2-benzoylethynylpyrroles **55a,b** with ethylenediamine.

In this reaction, in the case of acylethynylpyrrole **55b**, the formation of dihydrodiazepine **68** takes place. This is a result of the intramolecular cyclization of monoadduct **66b** with the participation of the carbonyl group followed by dehydration (Scheme 37).

**Scheme 37.** The formation of tetrahydroindolyl dihydrodiazepine **68b.**

#### *5.4. Cyclization with Hydrazine: Synthesis of Pyrrolyl Pyrazoles*

The building up of the pyrazole ring over acetylenic moiety of pyrrolopyridine propynones **21** via its ring closure with hydrazine gave 4,5,6,7-tetrahydropyrrolo[3,2-*c*]pyridine-pyrazole ensembles **69** in 92–98% yields (Scheme 38) [59].

**Scheme 38.** Synthesis of 4,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-pyrazole ensembles **69**.

According to the above procedure, a new extended dipyrromethane system conjugated with pyrazole cycle **70** was obtained in almost quantitative yield (Scheme 39) [57].

**Scheme 39.** Synthesis of dipyrromethane-pyrazole ensemble **70**.

#### *5.5. Cyclization with Hydroxylamine: Synthesis of Pyrrolyl Isoxazoles*

Acylethynyltetrahydroindoles **71** readily cyclized with hydroxylamine to give regioselectively either 3-(4,5,6,7-tetrahydroindol-2-yl)-4,5-dihydroisoxazol-5-ols **72** or 5-(4,5,6,7-tetrahydroindol-2 yl)isoxazoles **73** (Scheme 40) [82]. The cyclization can be easily switched from the direction leading exclusively to isoxazoles **72** to the formation of isoxazoles **73** by simple changing of the proton concentration in the reaction mixture. When the reaction was carried out in the presence of acetic acid (NH2OH·HCl/NaOAc, 1:1 system), only isoxazoles **72** were formed, whereas under neutral or basic conditions (NH2OH·HCl/NaOH (1:1 or 1:1.5 system), the cyclization took another pathway to produce preferably (94s–97% or entirely) isoxazoles **73**.

**Scheme 40.** Reaction of acylethynyltetrahydroindoles **71** with hydroxylamine.

Apparently, in the presence of acetic acid, the attack of the NH2OH nucleophile at the β-acetylenic carbon of tetrahydroindoles **71** is electrophilically assisted by the simultaneous protonation of the carbonyl group (and finally 1,4-addition takes place to deliver isoxazoles **72**), as shown in Scheme 41.

**Scheme 41.** The formation of 3-(4,5,6,7-tetrahydroindol-2-yl)-4,5-dihydroisoxazol-5-ols **72**.

In the presence of the NH2OH·HCl/NaOH system, which is unable to exert the electrophilic assistance, the common oximation of the carbonyl group prevailed.

Moreover, 4,5-dihydroisoxazol-5-ols **72** underwent easy aromatization when refluxing (benzene, 1 h) in the presence of TsOH·H2O to isoxazoles **74** in 73–91% yields (Scheme 42) [82].

On the basis of the above cycloaddition, two approaches to the synthesis of *meso*-CF3 substituted dipyrromethanes **75–77** bearing isoxazole moieties were developed [83].

The key stages of these approaches are the cycloaddition of hydroxylamine to the triple bond of ethynyldipyrromethanes **12a**, **78** (Schemes 43 and 44), or the synthesis of pyrrolyl isoxazoles **75**, **77** from ethynylpyrrole **79** (accessible from pyrrole and benzoylbromoacetylene), and its further condensation with 2,2,2-trifluoro-1-(pyrrol-2-yl)-1-ethanols **80**, as described in Section 2.1.2. (Scheme 45).

**Scheme 42.** Dehydration of 3-(4,5,6,7-tetrahydroindol-2-yl)-4,5-dihydroisoxazol-5-ols **72**.

**Scheme 43.** Synthesis of (3-phenylisoxazol-5-yl)dipyrromethanes **75a,b** from ethynyldipyrromethanes **12**, **78**.

**Scheme 44.** Synthesis of (5-phenylisoxazol-3-yl)dipyrromethanes **77a,b** from ethynyldipyrromethanes **12**, **78**.

**Scheme 45.** Alternative synthesis of (3- or 5-phenylisoxazolyl)dipyrromethanes **75** and **77** by condensation of pyrrolylisoxazoles **81** or **82** and with 2,2,2-trifluoro-1-(pyrrol-2-yl)-1-ethanols **80**.

*5.6. Cyclization with Methylene Active Esters: Synthesis of Pyrrolyl Pyrones*

The [4+2]-cycloaddition between 2-acylethynylpyrroles **83** and methylene active esters (Scheme 46), offering a short-cut to pyrrolyl pyrones **84** in good to high yields, was described [84].

**Scheme 46.** The synthesis of pyrrolyl pyrones **84**.

The reaction was carried out in acetonitrile in the presence of 1.5 molar excess of KOH. As methylene active esters, diethylmalonate, ethyl acetoacetate and ethyl cyanoacetate were used.

The cyclization is triggered by the proton abstraction from the active CH2 group of methylene active esters followed by the nucleophilic attack of the carbanion **A**, thus generated at the triple bond of acylethynylpyrroles **83** to afford intermediate **B**. The subsequent intramolecular nucleophilic substitution of the ethoxy group in the ester function by the oxygen-centered anion (the resonance form of the intermediate **B**) furnishes the target products (Scheme 47).

**Scheme 47.** Scheme of pyrrolyl pyrones **84** formation.

#### *5.7. Unprecedented Four-Proton Migration in Acylethynylmenthofurans: "A Proton Pump"*

When benzoylethynylmenthofuran **45a** was heated at reflux in CHCl3 in the presence of HBr, the formation of benzoylethylbenzofuran **85a** in 95% yield was observed (Scheme 48) [85]. Thus, the transfer of four hydrogen atoms from the cyclohexane ring to the triple bond took place.

**Scheme 48.** Rearrangement of acylethynylmenthofurans **45** to acylethylbenzofurans **85**.

This rearrangement was found to be general for other acylethynyl derivatives (furoyl, thenoyl, alkoxycarbonyl) of menthofuran to give their acylethylbenzofuran derivatives in the yield of 44%, 48%, and 24% respectively (Scheme 48).

Basing on these experimental results, it can be postulated that the rearrangement starts with protonation of acylethynyltetahydrobenzofuran moiety with HBr to give carbocation **A**, which in its more stable mesomeric form **B** abstracts a hydride-ion from the adjacent position (C-7) with positive charge transfer to form carbocation **C**. Then, two hydride shifts in the cyclohexane ring transform carbocation **C** into carbocation **D** with the positive charge at C-5. Proton abstraction from the C-4 position of this carbocation leads to the cyclohexene moiety and regenerates HBr. Simultaneously, after two 1,3-hydrogen shifts in the furan counterpart, it is transformed into vinyl intermediate **E**. Next, protonation of the double bond with HBr results in the formation of carbocation **F** which in its stable endocyclic form accepts the hydride ion from the cyclohexene ring to give cyclohexene carbocation **G**. The release of a proton from the latter gives the cyclohexadiene ring and HBr. Two 1,3-hydrogen shifts in the furan moiety completes the four-hydrogen transfer to the side chain giving 3,6-dimethylbenzofuran **87** with a saturated side chain, i.e., an exhaustively hydrogenated acetylene moiety (Scheme 49).

The driving force of this spectacular "hydrogen pump" is the energy gain due to the formation of the aromatic benzofuran system.

**Scheme 49.** Proposed mechanism for the transfer of four hydrogens.

## **6. Concluding Remarks and Outlook**

This review evidences that the cross-coupling reactions between electrophilic haloacetylenes and electron-rich heterocycles assisted by Al2O3 or K2CO3 or similar solid oxides and salts continue to be expanded, occupying more and more areas of heterocyclic chemistry. These endeavors are stimulated by such competitive beneficial features of this methodology as transition metal-free, no-solvent, mild conditions, availability of the starting materials, very simple synthetic operations, and possibility to introduce acetylenic substituents with electron-withdrawing groups into a heterocyclic core. Now, these reactions pave a short way to previously inaccessible or unknown, highly reactive heterocyclic building blocks and precursors to create novel heterocyclic systems of greater diversity and complexity.

**Funding:** This work was supported by the Ministry of Science and Higher Education of the Russian Federation (topic № AAAA-A16-116112510005-7). APC was sponsored by MDPI.

**Acknowledgments:** Authors acknowledge Baikal Analytical Center for collective use SB RAS for the equipment. **Conflicts of Interest:** There are no conflicts to declare.

#### **References**


**Sample Availability:** Samples of the compounds are available from the authors.

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