Recent Strides in the Transition Metal-Free Cross-Coupling of Haloacetylenes with Electron-Rich Heterocycles in Solid Media

The publications covering new, transition metal-free cross-coupling reactions of pyrroles with electrophilic haloacetylenes in solid medium of metal oxides and salts to regioselectively afford 2-ethynylpyrroles are discussed. The reactions proceed at room temperature without catalyst and base under solvent-free conditions. These ethynylation reactions seem to be particularly important, since the common Sonogashira coupling does not allow ethynylpyrroles with strong electron-withdrawing substituents at the acetylenic fragments to be synthesized. The results on the behavior of furans, thiophenes, and pyrazoles under the conditions of these reactions are also provided. The reactivity and structural peculiarities of nucleophilic addition to the activated acetylene moiety of the novel C-ethynylpyrroles are considered.

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, Al 2 O 3 and K 2 CO 3 were taken as the agents of choice. A selection of specific metal oxides (Al 2 O 3 or K 2 CO 3 ) for a particular reaction is determined experimentally because the results significantly depend on the structure of both the pyrrole and haloacetylene employed.

Cross-Coupling of Bromo-and Iodopropiolaldehydes with Pyrroles
A series of substituted pyrroles 1 were ethynylated by iodopropiolaldehyde in solid K 2 CO 3 (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. In this case, the use of Al 2 O 3 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). It was found that 2-phenylpyrrole (1, R 1 = H, R 2 = Ph, R 3 = 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 K 2 CO 3 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, R 1 = CH=CH 2 , R 2 = Ph, R 3 = C 5 H 11 ) with iodopropiolaldehyde in solid K 2 CO 3 . 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 Al 2 O 3 at room temperature for 1 h [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. 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].
The similar propenones were not observed among the products of ethynylation of N-vinylpyrroles (4, 5, R 1 = CH=CH 2 ) because they are not able to form the above stabilizing intramolecular hydrogen bonding.

With Dipyrromethanes
The solid-phase (Al 2 O 3 ) 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 CF 3 -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 K 2 CO 3 , 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. To increase the nucleophilicity of the pyrrole ring, trimethylsilyl group was introduced to nitrogen atom of the pyrrole ring (Scheme 9). The ethynylation (K 2 CO 3 , 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.

With Tetrahydropyrrolo [3,2-c]pyridines
The cross-coupling of pyrrolo [3,2-c]pyridines 20 with acylbromoacetylenes 6a,b in solid K 2 CO 3 was strictly chemo-and regioselective: exclusively propynones 21 were isolated (Scheme 10) [59]. In this case, the use of K 2 CO 3 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 Al 2 O 3 (instead of K 2 CO 3 ) served as an active medium, the reaction of pyrrole 20 (R 1 = C 6 H 13 ) with benzoylbromoacetylene 6a afforded salt of propynone, hydrobromide 22 (Scheme 11). Upon treatment of the aqueous solution of salt 22 with NH 4 OH propynone 21 was obtained in 61% yield.

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). 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 1 H 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 solid K 2 CO 3 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 C sp carbon.
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).

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

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 Al 2 O 3 (room temperature, 1-72 h) were attained [74]. 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 Al 2 O 3 to afford the acetylenic derivatives 45a-f in 40-88% yields (Scheme 25). An experimental evidence for the proposed mechanism is the observation that cycloadducts 46 are gradually transformed to ethynylated products 45 in the solid Al 2 O 3 .

Reaction of Acylhaloacetylenes with Pyrazoles
The reaction of benzoylbromoacetylene 6a with pyrazole under conditions similar for the ethynylation of pyrroles (10-fold excess of Al 2 O 3 , 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.
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. 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 (pk a of pyrazole is 14.2 whereas pk a of pyrrole is 17.5).

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. 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 [R 1 -R 2 = (CH 2 ) 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 Cs 2 CO 3 /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%).
The duration of non-catalytic step strongly depended on the pyrrole structure: the acceptor substituents in the pyrrole ring facilitated the reaction (the reaction time was 6 h), while the donor ones slowed down the process (the reaction time was 16 h). A peculiar feature of this dehydrogenative cyclization is that the intermediate dihydropyridines 58 were aromatized rapidly (they are not usually detectable in the reaction mixture). Only in the case of acylethynyltetrahydroindole dihydropyridine 58 was isolated in 4% yield. Notably, the catalytic ring closure was almost insensitive to the structure of the initial acylethynylpyrroles 55 (the reaction time was about 2.5 h for all the cases).
A less predictable step of the synthesis is the intramolecular nucleophilic addition of the CH-bond adjacent to carbonyl group across the acetylenic moiety (Scheme 32). This CH-bond can be deprotonated under the action of amino group, either intramolecularly (autodeprotonation) to generate intermediate A or intermolecularly. Upon the complexing of Cu + cation with the triple bond, the latter should be polarized to increase sensitivity towards the nucleophilic attack. This attack is completed by the addition of the carbanionic site to the terminal acetylenic atom to give the intermediate dihydropyridine 58. The MS spectra of the reaction mixtures showed that the oxidation of intermediate 58 did not take place under the action of DMSO (no Me 2 S was detected). The air oxygen also did not participate in this process: the same results were obtained both under argon blanket and on air. Therefore, the Cu + cation was considered [78] as a likely oxidant.

Synthesis of Pyrrolizines via Three-Component Cyclization with Benzylamine and Acylacetylenes
On the platform of acylethynylpyrroles 52, a new general strategy for the synthesis of functionalized pyrrolizines was developed [80]. The nucleophilic addition of benzylamine to the triple bond of 2-acylethynylpyrroles 52 was realized in the presence K 3 PO 4 /DMSO catalytic system to smoothly deliver N-benzyl(pyrrolyl)aminoenones 62 in up to 97% yield (Scheme 35). The latter were formed as a mixture of the E/Z isomers, the E-isomer being obviously stabilized by intramolecular H-bonds between the carbonyl group and NH-function of the pyrrole ring. As in the case of the addition of propargylamine to acylethynylpyrrole (see Section 5.1), the structure of the substituents of the pyrrole ring strongly influences the isomer ratio of the adducts: the donor substituents increase the content of the Z-isomers.

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). 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.

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- According to the above procedure, a new extended dipyrromethane system conjugated with pyrazole cycle 70 was obtained in almost quantitative yield (Scheme 39) [57].
On the basis of the above cycloaddition, two approaches to the synthesis of meso-CF 3 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

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]. 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 CH 2 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.

Unprecedented Four-Proton Migration in Acylethynylmenthofurans: "A Proton Pump"
When benzoylethynylmenthofuran 45a was heated at reflux in CHCl 3 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. 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.

Concluding Remarks and Outlook
This review evidences that the cross-coupling reactions between electrophilic haloacetylenes and electron-rich heterocycles assisted by Al 2 O 3 or K 2 CO 3 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.