**1. Introduction**

Functionalized five-membered aromatic heterocycles represent a frequent structural motif of bioactive natural products and pharmaceuticals [1–12]. Among them, of particular interest are the compounds bearing acetylenic moieties [13–15]. The combination of the electron-rich, five-membered aromatic heterocyclic nucleus with highly reactive carbon-carbon triple bond in one molecule allows using these compounds for the targeted synthesis of various complex heterocyclic systems. Commonly, ethynylation of heterocycles is implemented via Sonogashira reaction employing the halogenated heterocycles and terminal alkynes [16–19]. In 2004, as a complementation to the existing cross-coupling protocols, the direct palladium- and copper-free ethynylation of the pyrrole ring with haloacetylenes in the Al2O3 medium (room temperature, no solvent) was discovered [20]. Later, haloacetylenes were involved in ethynylation of diverse heterocycles using palladium [21,22], nickel [23,24], copper [25], or gold [26] catalysts. In parallel, the Al2O3-mediated ethynylation of pyrroles and indoles kept being steadily developed [27–43]. A number of pyrroles with alkyl, cycloalkyl, aryl, and hetaryl substituents were successfully ethynylated with acylhaloacetylenes and halopropynoates within a framework of this cross-coupling procedure. It was shown that some other metal oxides (MgO, CaO, BaO) [33] and salts (K2CO3) [35] can also be beneficially applied instead of Al2O3. On the basis of the experimental facts, it was concluded that this cross-coupling includes the nucleophilic attack of pyrroles at the electron-deficient triple bond of haloacetylenes followed by the elimination of hydrogen halide from the zwitterionic intermediates.

As far as the relationship between the reactivity of the heterocycle and the solid salt used is concerned, a broad screening of various metal oxides and salts as mediators for the cross-coupling has shown that some of them are rather active (i.e., BaO). However, due to availability and convenience of the work-up of the reaction mixtures, Al2O3 and K2CO3 were taken as the agents of choice. A selection of specific metal oxides (Al2O3 or K2CO3) for a particular reaction is determined experimentally because the results significantly depend on the structure of both the pyrrole and haloacetylene employed.

This methodology was already partially documented in recent reviews [44–52]. This survey covers the recent publications (since 2014) concerning this reaction and the related chemistry which have not been yet summarized in a review.

#### **2. Cross-Coupling of Haloacetylenes with Electron-Rich Heterocycles**

#### *2.1. Cross-Coupling of Haloacetylenes with Pyrroles*

#### 2.1.1. Cross-Coupling of Bromo- and Iodopropiolaldehydes with Pyrroles

A series of substituted pyrroles **1** were ethynylated by iodopropiolaldehyde in solid K2CO3 (a 10-fold excess) under mild conditions without solvent to afford highly reactive functionalized pyrrole compounds, 3-(pyrrol-2-yl)propiolaldehydes **2**, in up to 40% yield (Scheme 1) [53]. The reagents were ground intensively for 5–10 min and allowed to stand at room temperature for 4 h. Iodopropioaldehyde was more preferable over explosive bromopropiolaldehyde.

**Scheme 1.** Synthesis of 3-(pyrrol-2-yl)propiolaldehydes **2**.

In this case, the use of Al2O3 proved to be inappropriate, since the above ethynylation, albeit accelerated (the reaction time was 1 h), proceeded non-selectively to form, along with the target 3-(pyrrol-2-yl)propiolaldehydes **2**, 3-bis(pyrrol-2-yl)acrylaldehydes **3**, with the molar ratio being ~1:1 (Scheme 2).

**Scheme 2.** Reaction of pyrroles **1** with iodopropiolaldehyde in solid Al2O3.

It was found that 2-phenylpyrrole (**1**, R<sup>1</sup> = H, R<sup>2</sup> = Ph, R3 = H) gave the lowest yield (25%) of the ethynylated product that is likely associated with side reactions of the NH-function, e.g., nucleophilic addition across the triple bond or condensation with the aldehyde moiety.

The mechanism of the cross-coupling involves the single-electron transfer (SET) from pyrrole to iodopropiolaldehyde to generate the radical-ion pair A and/or the formation of the zwitterion B followed by elimination of hydrogen iodide (Scheme 3). Apparently, the role of K2CO3 is to stabilize the intermediate ion pairs by dipole-dipole interaction inside the ionic crystalline lattice of the medium, thus somewhat resembling ionic liquids.

The generation of radical-ions during this process was evidenced from ESR signals observed in the reaction of 1-vinyl-2-phenyl-3-amylpyrrole (**1**, R1 = CH=CH2, R2 = Ph, R3 = C5H11) with iodopropiolaldehyde in solid K2CO3.

**Scheme 3.** Reaction of pyrroles**1** with iodopropiolaldehyde in solid Al2O3.

#### 2.1.2. Cross-Coupling of Acylbromoacetylenes with Pyrroles

With 2-(Furan-2-yl)- and 2-(2-Thiophen-2-yl)pyrroles

The reaction of 2-(furan-2-yl)- (**4**) and 2-(thiophen-2-yl)pyrroles **5** with acylbromoacetylenes **6a**–**c** was carried out according to the similar procedure: the reactants (1:1 molar ratio) were ground with a 10-fold excess of Al2O3 at room temperature for1h[54]. The major direction of this ethynylation of 2-(furan-2-yl)pyrroles **4** was the formation of 2-acylethynyl-5-(furan-2-yl)pyrroles **7** (Scheme 4), while the alternative 2-acylethynyl-5-(pyrrol-2-yl)furans **8** were minor products (**7**:**8** = ~5–7:1). This result was key to understanding the ethynylation of five-membered aromatic heterocycles with haloacetylenes. In fact, this was the first observation of a relative reactivity of the furan ring in this reaction.

**Scheme 4.** Reaction of 2-(furan-2-yl)pyrroles **4** with acylbromoacetylenes **6a**–**c** in the solid Al2O3.

Double ethynylation, i.e., ethynylation of each ring, was not observed in any cases. In other words, the reaction occurs either with the pyrrole or furan ring. This points to a strong deactivating effect of the acyl substituent that is transmitted from one ring to another through the system of ten bonds involving conjugated one triple, four double, and five ordinary bonds. The ratio of products **7**:**8** = ~5–7:1 can be considered as an approximate measure of relative reactivity of the pyrrole and the furan ring towards the acylhaloacetylenes. The reaction of pyrroles with electrophilic acetylenes is commonly regarded as a nucleophilic addition of electron-rich pyrrole moiety (often as the pyrrolate anion) to the electron-deficient triple bond which occurs as N- and C-vinylation [55]. As mentioned above (see Section 2.1.1.) this reaction is likely initiated by the single-electron transfer to generate the radical-ion pairs as key intermediates, further forming C-C covalent bond with a final elimination of hydrogen halide [33]. Such a mechanism and the experimental isomer ratios are in agreement with a lower ionization potential of the pyrrole ring (8.09 eV) compared to that of furan ring (8.69 eV) [56].

In accordance with this rationale, 2-(thiophen-2-yl)pyrroles **5** reacted with acylbromoacetylenes **6a**–**c** under the above conditions to give only products of the pyrrole ring ethynylation, ethynylpyrroles **9** (Scheme 5) that also agrees with a higher ionization potentials of the thiophene ring (8.72 eV) [56].

In cases of NH-pyrroles (**4**, **5**, R1 = H), 3-bromo-1-(pyrrol-2-yl)prop-2-en-1-ones **10** were isolated as the *E*-isomers stabilized by a strong intramolecular hydrogen bond between NH-proton and oxygen atom of the carbonyl group (Scheme 6).

**Scheme 6.** Formation of (*E*)-3-bromo-1-(pyrrol-2-yl)prop-2-en-1-ones **10**.

The similar propenones were not observed among the products of ethynylation of N-vinylpyrroles (**4**, **5**, R1 = CH=CH2) because they are not able to form the above stabilizing intramolecular hydrogen bonding.

#### With Dipyrromethanes

The solid-phase (Al2O3) ethynylation of dipyrromethane **11** with acylbromoacetylenes **6a**–**c** afforded 5-acylethynyldipyrromethanes **12** in 38–53% yields (Scheme 7) [57]. In contrast to the ethynylation of pyrrole giving 2-acylethynylpyrroles in the yield of 55–70% for 1 h [20], the cross-coupling of dipyrromethane **11** with acylbromoacetylenes **6a**–**c** required a much longer time and portion-wise addition of acetylene **6a**–**c** to the reaction mixture.

The low reaction rate in this case is likely resulted from the strong electron-withdrawing effect of the CF3-group, deactivating the pyrrole ring that acts as a nucleophile.

A general synthesis of such non-symmetrical dipyrromethanes was previously developed [58] by the condensation of trifluoropyrrolylethanols with pyrrole.

In the solid K2CO3, effective in the ethynylation of pyrroles with haloacetylenes [35], the above reaction did not take place at all.

In the solid alumina (room temperature, 96 h), dipyrromethane **13** reacted with benzoylbromoacetylene **6a** to give insignificant amounts of products. From the reaction mixture, apart from the target dipyrromethane **14**, 5-(1-bromo-2-benzoylethenyl)dipyrromethane **15**, and the double ethynylation product, (dibenzoylethynyl)dipyrromethane **16**, were isolated in low yields (Scheme 8). The formation of dipyrromethane **16** was the first example of ethynylation of the thiophene ring by the reaction studied.

**Scheme 8.** Ethynylation of the dipyrromethane **13** in the solid Al2O3.

To increase the nucleophilicity of the pyrrole ring, trimethylsilyl group was introduced to nitrogen atom of the pyrrole ring (Scheme 9). The ethynylation (K2CO3, room temperature, 168 h) of a mixture of dipyrromethanes **17** and **18** with acylbromoacetylenes **6a**–**c** gave acylethynyldipyrromethanes **14, 19** in 39–44% yields (Scheme 9). Thus, the yields of ethynylated product were increased due to the introduction of trimethylsilyl groups in the pyrrole ring to enhance their nucleophilicity.

**Scheme 9.** Synthesis and ethynylation of dipyrromethanes **17**, **18**.

With Tetrahydropyrrolo [3,2-*c*]pyridines

The cross-coupling of pyrrolo[3,2-*c*]pyridines **20** with acylbromoacetylenes **6a**,**b** in solid K2CO3 was strictly chemo- and regioselective: exclusively propynones **21** were isolated (Scheme 10) [59].

**Scheme 10.** Cross-coupling of tetrahydropyrrolo[3,2-*c*]pyridines **20** with acylbromoacetylenes **6a**,**b** in the solid K2CO3.

In this case, the use of K2CO3 appeared to be essential, since it allowed the released HBr to be effectively fixed. This prevented the salt formation with the NH-function of the tetrahydropyridine moiety.

Indeed, when Al2O3 (instead of K2CO3) served as an active medium, the reaction of pyrrole **20** (R1 = C6H13) with benzoylbromoacetylene **6a** afforded salt of propynone, hydrobromide **22** (Scheme 11). Upon treatment of the aqueous solution of salt **22** with NH4OH propynone **21** was obtained in 61% yield.

**Scheme 11.** Cross-coupling of pyrrolo[3.2-*c*]pyridine **20** with benzoylbromoacetylene **6a** in the solid Al2O3.

#### With Pyrrole-2-carbaldehydes

Pyrrole-2-carbaldehydes **23** proved to be inactive under usual conditions of the cross-coupling of pyrroles with acylhaloacetylenes in alumina medium (room temperature, 1 h). The reason is likely strong electron-withdrawing effect of the aldehyde group which decreases the pyrrole ring nucleophilicity. This fundamental hurdle was overcome by the acetal protection of the aldehyde function thereby decreasing its electron-withdrawing power [60,61]. The acetals **24** were treated with acylbromoacetylenes **6a**–**c** in the alumina medium (room temperature, 6 h) to obtain the expected ethynylated acetals **25**. After the deprotection (aqueous acetone, HCl, room temperature, 1 h), the target ethynylated pyrrole-2-carbaldehydes **26** were isolated in 75–89% yields (Scheme 12).

**Scheme 12.** Synthesis of pyrrole-2-carbaldehydes with the electron-deficient acetylenic substituents.

#### 2.1.3. Cross-Coupling of Bromotrifluoroacetylacetylene with Pyrroles

Pyrroles **27**, when reacted with bromotrifluoroacetylacetylene **28** in the solid Al2O3 (room temperature, 2 h), gave only 4-bromo-1,1,1-trifluoro-4-(pyrrol-2-yl)but-3-en-2-ones **29** in 12–21% yields [62,63], while the cross-coupling of acetylbromoacetylene **30** with the same pyrroles under the same conditions afforded the expected acetylethynylpyrroles **31** (Scheme 13) [62].

**Scheme 13.** The cross-coupling of NH-pyrroles **27** with acetylbromoacetylenes **28** and **30** in the solid Al2O3.

Interestingly,*N*-vinylpyrroles **32**underwent normal cross-coupling with bromotrifluoroacetylacetylene **28** (Al2O3, rt, 2 h) to deliver ethynylpyrroles **33** in 42–58% yields (Scheme 14).

**Scheme 14.** The cross-coupling of *N*-vinylpyrroles **32** with bromotrifluoroacetylacetylene **28** in the solid Al2O3.

This implies that the cause of abnormal reaction (Scheme 13) is the interaction between NH and trifluoroacetyl groups that stabilizes 4-bromo-1,1,1-trifluoro-4-(pyrrol-2-yl)but-3-en-2-ones **29** in their *E-*configuration.

This is evidenced from the extraordinary downfield shift of the NH group proton signal (13–14 ppm) in the 1H NMR spectra of pyrroles **29**.

The intramolecular H-O-bonding of such a type is likely realized already in the *E*-form of the intermediate zwitterion **A** (Scheme 15). This hydrogen bonding prevents the *E*↔*Z* isomerization and hence elimination of HBr, which usually occurs as a *trans*-process. Notably, in most cases of ethynylation of pyrroles under similar conditions [20], bromopyrrolylethenylketones of the type **29** are formed just as minor contaminants, if any (0–10% yields), that may also be a result of easier elimination of hydrogen halides (HBr in this case) from their *Z*-configuration. As the elimination of HBr does not occur at a stage of the zwitterion **A** formation, the proton in the 2 position of the pyrrole ring is transferred to the carbanionic center. This should be facilitated by a strong electron-withdrawing effect of trifluoroacetyl substituent. Consequently, the target product **29** is formed stereoselectively (as the *E*-isomer).

**Scheme 15.** Proposed mechanism of formation of *E*-isomers of the hydrogen-bonded compounds **29**.

In the reaction of *N*-vinylpyrroles **32** with the bromotrifluoroacetylacetylene **28**, the formation of an intramolecular hydrogen bond in the products is impossible (Scheme 16). Moreover, the formation of the *E*-isomer of 4-bromo-1,1,1-trifluoro-4-(pyrrol-2-yl)but-3-en-2-ones **B** would be sterically hindered (due to the repulsion between N-vinyl group and trifluoroacetyl substituent).

**Scheme 16.** Formation of products **33** from N-vinylpyrroles **32** and bromotrifluoroacetylacetylene **28**.

Probably, the effect of steric strain destabilizes the *E*-form at the stage of formation of the intermediate zwitterion **B** (Scheme 16), for which the Z-form turns out to be energetically favorable. At the final stage, the zwitter-ion **B** is transformed to trifluoroacetylethynylpyrroles **33** via elimination of the bromine anion accompanied by releasing of proton from the position 2 of the pyrrole ring (Scheme 16).

Pyrrole **33a**, after 7 days contact with Al2O3, lost the trifluoroacetyl group to give 2-ethynylpyrrole **34** in 24% yield (Scheme 17). The partial detrifluoroacylation of pyrroles **33** also occurred during their passing through Al2O3-packed chromatographic column.

**Scheme 17.** Detrifluoroacylation of compound **33a** after 7 days contact with Al2O3.

2.1.4. Cross-Coupling of Chloroethynylphosponates with Pyrroles

Pyrroles **35** were cross-coupled with chloroethynylphosponates **36** in solid alumina (room temperature, 24–48 h) to give 2-(pyrrol-2-yl)ethynylphosphonates **37** in 40–58% yields (Scheme 18) [64].

In the absence of Al2O3 (both in a solvent and under solvent-free conditions), the ethynylation did not take place. At room temperature, the complete conversion of the reactants was reached after 24 h. The exception was *N*-vinyl-4,5,6,7-tetrahydroindole **35a** (R<sup>1</sup> = H; R2-R3 = (CH2)4), the ethynylation of which lasted twice as long (48 h).

**Scheme 18.** Synthesis of 2-(pyrrol-2-yl)ethynylphosphonates **37**.

As minor products (2–10%), 2,2-*bis*(pyrrol-2-yl)vinylphosphonates **38** were detected in the reaction (Figure 1). Also, in the case of 1-vinyl-4,5,6,7-tetrahydroindole [**35**, R1 = CH=CH2; R2-R3 = (CH2)4], dialkyl 2,2-dichlorovinylphosphonates **39** (2–9%) were present in the reaction mixture (Figure 1).

**Figure 1.** Side products of cross-coupling of pyrroles **35** with chloroethynylphosphonates **36**.

The formation of the product **39** required [64] a longer reaction time (48 vs. 24 h) that allowed hydrogen chloride to be competitively added to the starting chloroethynylphosphonates according to [65]. A longer reaction rate is also due to the electron-withdrawing effect of the vinyl group, which reduces nucleophilicity of the pyrrole moiety.

In the solid K2CO3 medium (other conditions being the same), the cross-coupling of pyrroles with chloroethynylphosphonates produced only pyrrolylethynylphosphonates **37** in 38–43% yields.

It is suggested [64] that the reaction mechanism in this case represents the direct nucleophilic substitution of chlorine atom by the pyrrole moiety. This is supported by known data [66,67] that the reactions of chloroethynylphosphonates with nucleophiles including the neutral ones proceed mainly as a nucleophilic substitution of chlorine atom at the Csp carbon.

#### 2.1.5. Cross-Coupling of Halopolyynes with Pyrroles

The above transition metal-free solid-phase mediated cross-coupling of haloacetylenes with pyrroles turns out to be efficient also for halopolyynes (di-, tri-, and tetrapolyynes) [68,69], allowing the pyrroles functionalized with polyynes chains to be synthesized. Such rare, highly reactive pyrrole compounds represent exclusively promising building blocks and precursors for the design of biologically and technically valuable heterocyclic molecules of exceptional complexity and structural diversity, including porphyrinoids with the polyyne substituents [70], modified bilirubins [71], and various ensembles of pyrroles with furans [72,73], thiophenes [72,73], pyrroles [72,73], naphthalenes [73], and other cyclic counterparts [73].

Thus, ester end-capped 1-halobutadiynes were successfully cross-coupled with pyrroles **40** in the solid K2CO3 to afford the expected butadiynyl-substituted pyrroles **41** in 43–80% yields (Scheme 19) [68].

**Scheme 19.** Cross-coupling of electron-deficient halobutadiynes with pyrroles **40**.

The scope of reactions covers 2-phenylpyrrole, NH-4,5,6,7-tetrahydroindole, N-substituted 4,5,6,7-tetrahydroindoles, and chloro-, bromo-, and iodobutadiynes. The most suitable butadiynyl agents proved to be 1-bromobutadiynes.

The reaction rate depends on the pyrrole structure, with tetrahydroindole derivatives being the most reactive. For them, the cross-coupling with one equivalent of various halobutadiynes did not exceed 5 h, whereas for 2-phenylpyrrole, to reach 46–52% yield of the target product it required 2 equivalents of halobutadiynes and much longer reaction time (24 h).

This study was further extended over the longer chain aryl-capped 1-halopolyynes (up to tetraynes) [69]. As pyrrole substrates, 4,5,6,7-tetrahydroindole and its N-substituted derivatives were employed.

For the interaction of *N*-methyl-4,5,6,7-tetrahydroindole with 1-bromo-2-(4-cyanophenyl)acetylene **42a**, 1-bromo-2-(4-cyanophenyl)butadiyne **42b**, 1-bromo-2-(4-cyanophenyl)hexatriyne **42c**, the expected cross-coupling was observed only for triyne **42c** (K2CO3, room temperature, 3 h, 82% yield of hexatriynyl substituted *N*-methyl-4,5,6,7-tetrahydroindole **43c**), while with acetylene **42a** no target product was detected (1H-NMR), and in the case of diyne **42b** a slow reaction (several days) took place (Scheme 20).

**Scheme 20.** The reaction of polyynes **42a**–**c** with *N*-methyl-4,5,6,7-tetrahydroindole.

Since longer bromopolyynes were less stable than the corresponding iodine derivatives, 1-bromotetraand -hexatriynes were used for the synthesis of tetradiynyl- and hexatriynyl-substituted tetrahydroindoles (Scheme 21), while 1-iodotetraynes were employed to produce octatetraynyltetrahydroindoles (Scheme 22).

**Scheme 21.** Synthesis of tetradiynyl- and hexatriynyl-substituted tetrahydroindoles.

**Scheme 22.** Synthesis of octatetraynyl-substituted tetrahydroindoles.

Like in the work of Trofimov B.A. [33] (see also Section 2.1.1.), it is assumed that the reaction mechanism involves radical-ion pairs generated by the SET process (Scheme 23). According to experimental results longer polyyne chains secure a better stabilization of radical-ion pairs that provide higher yields of polyynyl substituted tetrahydroindoles and a shorter reaction time.

**Scheme 23.** Proposed mechanism of long-chain stabilization of a radical intermediate product.

#### **3. Reaction of Acylhaloacetylenes with Furans**

A logical development of ethynylation of pyrroles with haloacetylenes [20] was the translation of this methodology to the furan compounds. In this line, on the example of menthofuran (3,6-dimethyl-4,5,6,7-tetrahydrobenzofuran **44**), first synthetically appropriate results on the transition metal-free cross-coupling of the furan ring with haloacetylenes **6a**–**f** initiated by their grinding with solid Al2O3 (room temperature, 1–72 h) were attained [74].

As it was found by Trofimov B.A. [74], after 1 h the reaction of menthofuran **44** with benzoylbromoacetylene **6a** in solid Al2O3 resulted in the formation of ethynylfuran **45** along with the pair of diastereomeric cycloadducts of oxanorbornadiene structure **46** in 44:56 ratio (Scheme 24). The reaction is regioselective: the bromine atom is neighboring the position 2 of the furan ring exclusively.

**Scheme 24.** Reaction of benzoylbromoacetylene **6a** with menthofuran **44** in the solid Al2O3.

Upon standing the reaction mixture for 72 h, the content of ethynylfuran **45** was increased up to 88%, while amount of cycloadduct **46** was reduced. These results indicate that cycloadduct **46** converts to ethynylfuran **45**, i.e., the cycloadduct **46** is a kinetic intermediate of the ethynylation (this transformation is accompanied by elimination of hydrogen bromide).

The reaction of menthofuran **44** with chloro- and iodobenzoylacetylenes proceeded analogously leading for 1 h to a mixture of ethynylfuran **45** and cycloadduct **46**, the latter disappearing completely after 72 h.

Thus, in contrast to cross-coupling of pyrroles with acylhaloacetylenes under similar conditions, ethynylation of the furan ring with acylhaloacetylenes occurred through [4+2]-cycloaddition followed by the elimination of HX during the ring-opening of the cycloadducts.

This reaction was proved to be applicable to bromoacetylenes with formyl (**6d**), acetyl (**6e**), furoyl (**6b**), thenoyl (**6c**), and ethoxy (**6f)** groups at the triple bond, which reacted with menthofuran **44** in the solid Al2O3 to afford the acetylenic derivatives **45a**–**f** in 40–88% yields (Scheme 25).

**Scheme 25.** Reaction of haloacetylenes **6a**–**f** with menthofuran **44** in thesolid Al2O3.

Following the experimental results, the oxanorbornadiene intermediates such as **46**, reversibly generated on the first reaction step, are transformed to the ethynyl derivatives of menthofuran **45** via a zwitterion with the positive charge distributed over the whole furan ring. The latter eliminates hydrogen bromide in the concerted process (hydrogen is released from the position 2 of the furan moiety, Scheme 26).

**Scheme 26.** Possible reaction pathway.

An experimental evidence for the proposed mechanism is the observation that cycloadducts **46** are gradually transformed to ethynylated products **45** in the solid Al2O3.

#### **4. Reaction of Acylhaloacetylenes with Pyrazoles**

The reaction of benzoylbromoacetylene **6a** with pyrazole under conditions similar for the ethynylation of pyrroles (10-fold excess of Al2O3, room temperature, the molar ratio 1:1, 24 h), instead of the expected 2-benzoylethynylpyrazole **47**, led to dipyrazolylenone **48a** in 18% isolated yield (Scheme 27) [75]. The yield of enone **48a** increased to 32%, when 2 equivalents of pyrazole was taken and reached 43% for the reaction with a 3-molar excess of the starting heterocycle.

**Scheme 27.** Reaction of pyrazole with acylbromoacetylenes **6a**–**c**.

The reaction proceeded via the intermediate (*Z*)-2-bromo-2-(pyrazol-1-yl)enone **49a** and was accompanied by the formation of 2,2-dibromoenone **50a** (Scheme 27).

Modest yields (22–35%) of dipyrazolylenones **48a**–**c** were observed using a two-fold molar excess of pyrazole relative to acylbromoacetylenes **6a**–**c**, with the yields of bromopyrazolylenones **49a**–**c** and dibromoenones **50a**–**c** being 10–18% and 8–14%, respectively (Scheme 27).

Surprisingly, no traces of ethynylpyrazoles **47** were detectable in the reaction mixture, implying that dipyrazolylenones **48a–c** are not adducts of the reaction of pyrazole with the intermediate ethynylated pyrazoles **47**.

3,5-Dimethylpyrazole reacted with acylbromoacetylenes **6a**–**c**,**e** in a 2:1 molar ratio to form dipyrazolylenones **51a**–**c**,**e** in 42–55% yields (Scheme 28). Bromopyrazolylenone of the type **49** in this case, was not discernible in the reaction mixture.

**Scheme 28.** Reaction of 3,5-dimethylpyrazole with acylbromoacetylenes **6a**–**c, e**.

On the basis of the results obtained and previous mechanistic rationalizations concerning the reactions of pyrroles with haloacetylenes [20], it may be suggested that the synthesis of dipyrazolylenones **48** is triggered by the nucleophilic addition of pyrazole to the triple bond of acylbromoacetylenes **6a**–**c** to form the intermediate zwitterion (Scheme 29), which converts via proton transfer from the pyrazole moiety to its carbanionic center to give isolable intermediate **49**. Subsequent nucleophilic substitution of the bromine atom by a second molecule of pyrazole affords dipyrazolylenone **48**.

**Scheme 29.** Proposed mechanism of dipyrazolylenones **48** formation.

Unlike the ethynylation of pyrroles, where the initial zwitterion releases a halogen anion to restore the triple bond, for pyrazole, rapid intramolecular neutralization of the carbanionic site of the intermediate zwitterion occurs, which precludes formation of the ethynyl derivatives. Such a change of the reaction mechanism is likely due to the higher acidity of pyrazoles compared with pyrroles (pka of pyrazole is 14.2 whereas pka of pyrrole is 17.5).

#### **5. Selected Reactions of Acylethynylpyrroles and Their Analogs**

To demonstrate the possibilities of the cross-coupling developed for the construction of important functionalized heterocyclic systems, some selected synthetically attractive reactions of acylethynylpyrroles and their analogs are considered below.

#### *5.1. Cyclizations with Propargylamine*

#### 5.1.1. Synthesis of Pyrrolo[1,2-*a*]pyrazines

Acylethynylpyrroles **52** were used for the synthesis of pyrrolo[1,2-*a*]pyrazines **53a,b** according to the strategy which includes the following steps: (i) the non-catalyzed chemo- and regioselective nucleophilic addition of propargylamine to the triple bond of acylethynylpyrroles **52** to afford *N*-propargyl(pyrrolyl)aminoenones **54** and (ii) base-catalysed intramolecular cyclization of *N*-propargyl(pyrrolyl)aminoenones **54** to pyrrolo[1,2-*a*]pyrazines **53a,b** (Scheme 30) [76].

**Scheme 30.** Synthesis of pyrrolo[1,2-*a*]pyrazines **53a,b** from acylethynylpyrroles **52** and propargylamine.

Nucleophilic addition of propargylamine to the triple bond of acylethynylpyrroles **52** was carried out under reflux of reactants (**52**: propargylamine ratio being 1:2) in methanol for 5 h to deliver *N*-propargyl(pyrrolyl)aminoenones **54** (Scheme 30). The latter were formed as a mixture of *E*/*Z* isomers stabilized by intramolecular H-bonds between carbonyl group and NH-function of the amino moiety (the *Z-*isomer) or NH-function of the pyrrole ring (the *E*-isomer) with predominance of the *Z*-isomer.

The electronic nature of the substituents attached to the pyrrole ring determines the isomers ratio. Thus, for aminoenone **54** with unsubstituted pyrrole ring, the *Z*/*E* ratio is ~9:1. When a donor cyclohexane moiety is attached to the pyrrole ring [R1-R2 = (CH2)4], this ratio becomes 15:1, probably owing to a lower NH-acidity of the pyrrole counterpart and hence a weaker stabilization of the *E*-isomer by the intramolecular H-bonding. Consequently, for pyrroles with electron-withdrawing aryl substituents, having more acidic pyrrole NH-proton, the content of the *E-*isomer increases, *Z*/*E* ratio being ~4:1.

The cyclization of N-propargyl(pyrrolyl)aminoenones **54** was implemented by heating (60 ◦C, 15–30 min ) in the system Cs2CO3/DMSO to afford pyrazines **53a** with exocyclic double bond and their thermodynamically more stable endocyclic isomers **53b**. Pyrrolopyrazines **53b** with the endocyclic double bond were formed selectively only from aminoenones **54** with unsubstituted pyrrole ring or with tetrahydroindole derivatives. In the case of enaminones with phenyl or fluorophenyl substituents, the major products were pyrrolopyrazines having the exocyclic double bond **53a** (their content in the reaction mixture was spanned 70–90%), while pyrrolopyrazines **53b** were minor products. The total yield of both isomers remained almost quantitative (90–96%).

Later, pyrrolopyrazines **53a,b** were obtained (90–95% yields) via a one-pot procedure from ethynylpyrroles **52** and propargylamine when the reactants were heated (60–65 ◦C) in DMSO [77].
