Mechanochemical and Transition-Metal-Catalyzed Reactions of Alkynes

Abstract

Mechanochemical and transition-metal-catalyzed reactions of alkynes, exhibiting significant advantages like short reaction time, solvent-free, high yield and good selectivity, were considered to be green and sustainable pathways to access functionalized molecules and obtained increasing attention due to the superiorities of mechanochemical processes and the reactivities of alkynes. The ball milling and CuI-catalyzed Sonogashira coupling of alkyne and aryl iodide avoided the use of common palladium catalysts. The mechanochemical Rh(III)- and Au(I)-catalyzed C–H alkynylations of indoles formed the 2-alkynylated and 3-alkynylated indoles selectively. The mechanochemical and copper-catalyzed azide-alkyne cycloaddition (CuAAC) between alkynes and azides were developed to synthesize 1,2,3-triazoles. Isoxazole could be formed through ball-milling-enabled and Ru-promoted cycloaddition of alkyne and hydroxyimidel chloride. In this review, the generation of mechanochemical and transition-metal-catalyzed reactions of alkynes was highlighted. Firstly, the superiority and application of transition-metal-catalyzed reactions of alkynes were briefly introduced. After presenting the usefulness of green chemistry and mechanochemical reactions, mechanochemical and transition-metal-catalyzed reactions of alkynes were classified and demonstrated in detail. Based on different kinds of reactions of alkynes, mechanochemical and transition-metal-catalyzed coupling, cycloaddition and alkenylation reactions were summarized and the proposed reaction mechanisms were disclosed if available.

1. Introduction

Alkynes, a class of unsaturated hydrocarbons, are regarded as critical starting materials or intermediates in various organic transformations such as addition [1], oxidation, coupling [2] and cyclization [3] etc. And alkynes are also widely used in the synthesis of natural products [4], drugs [5], organic optoelectronic materials [6]. Transition metal catalyzed reactions of alkynes, such as Sonogashira coupling and cycloaddtion, powerful protocols for constructing many important molecules, had have been widely used in synthesis of nature products, pharmaceuticals and organic materials [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26]. In 1998, P.T. Anastas and J.C. Warner proposed The 12 Principles of Green Chemistry, which included preventing waste [27], atomic economy [28], less hazardous synthesis [29], design benign chemicals [30], benign solvents and auxiliaries [31], design for energy efficiency [32], use of renewable raw materials [33], reduction of derivatives [34], environmentally friendly catalysts [35], design for degradation [36], real-time pollution prevention analysis [37] and inherently benign chemistry for accident prevention [38]. These principles lead chemists in designing and developing chemical processes that are safer, more efficient, and more environmentally friendly. In recent years, increasing attention has focused on the development of green chemical processes [39], in which mechanochemically induced reactions are considered to be sustainable and green pathways towards functionalized molecules due to their advantages such as short reaction time [40], no solvent required [41], mild reaction conditions [42], high yield and good yield [43]. Mechanochemically induced reactions, which can be divided into ball milling, grinding [44] and ultrasonic [45] promoted procedures, has showed a wide range of application in the fields of drug preparation [46], organic synthesis [47] and natural product preparation [48].

With the growing concerns to the environment and the need for green and sustainable protocols towards useful organic molecules containing C≡C bond, mechanochemically induced and transition-metal-catalyzed transformations of alkynes have attracted more and more popularity in recent years [49]. For example, rhodium catalyzed oxidation coupling of acetanilides and alkynes formed indoles under ball milling [50], manganese-catalyzed regioselective C−H bond alkenylation of indoles with alkynes generated various 2-enylindoles under silica grinding conditions [51], ruthenium-catalyzed hydroarylations of alkynes with acetanilides led to trisubstituted alkenes under solventless grinding conditions [52], etc.

Recently, many outstanding books or reviews covered the mechanochemically induced reactions [40,52,53,54,55,56,57,58,59,60,61]. In 2013, Wang summarized various solvent-free mechanochemical reactions [62]. A critical review on metal-promoted mechanochemical reactions was presented by Porcheddu In 2020 [63]. In 2024, Hang Shen [64] presented the latest advances in mechanochemical research in polymers. Although a review about mechanochemically induced copper(I) catalyzed click reaction of azide and terminal alkyne was reported in 2021, this context was limited to sugar science field [65]. Thus, a systematic review about mechanochemically induced and transition-metal-catalyzed reactions of alkynes was still in high need. In this review, we demonstrated the recent well-established and mechanochemically induced reactions by using alkynes as starting materials. Based on different kinds of reactions, the mechanochemically induced reactions of alkynes in this review were mainly assorted into the following class: (1) mechanochemically induced coupling reactions, (2) mechanochemically induced cycloaddition reactions, (3) mechanochemically induced alkenylation reactions.

2. Mechanochemical and Transition-Metal-Catalyzed Coupling Reactions

The Sonogashira coupling reaction is one of the basic transformation reactions in organic synthesis [66,67,68,69,70,71,72]. However, the palladium catalysts are tedious and scarce to reuse in traditional Sonogashira coupling. Thus, the protocol utilizing palladium-coated balls or palladium milling balls as the catalysts would be meaningful [73]. In 2023, Borchardt [74] successfully completed the Sonogashira coupling of alkyne (1) and aryl iodide (2) by using pure palladium and palladium-coated steel balls as mechanical catalysts, CuI/1,4-diazabicyclo(2.2.2)octane (DABCO)/PPh₃ as additives and K₂CO₃ as a base (Scheme 1). After examining the reaction carefully, the optimized reaction conditions were obtained as following: iodobenzene (1.0 mmol), phenylacetylene (1.2 mmol), CuI (0.05 mmol), DABCO (0.6 mmol), PPh₃ (0.05 mmol), K₂CO₃ (7.24 mmol) in a 19 mL perfluoroalkoxy alkane (PFA) vessel with a Pd ball (4 g ± 0.3 g), milling for 60 min at 35 Hz. Compared to the traditional Pd/Cu catalyzed Sonogashira coupling [75], this reaction which avoided the common palladium catalysts was a green and sustainable protocol to synthesize ethynes.

In 2022, Kubota [76] demonstrated Sonogashira coupling reaction of alkyne and solid large polyaromatic halide to access materials-oriented aromatic alkynes under ball milling (Scheme 2). A ball-milling jar with a temperature-controllable and commercially available heat gun was employed as the reaction apparatus in this report. After examining the reaction carefully, the optimal reaction conditions were established as following: a mixture of alkyne (4, 0.45 mmol), solid aryl halide (5, 0.15 mmol), Pd(OAc)₂ (0.015 mmol), Ad₃P (0.0225 mmol), Et₃N (0.45 mmol) and H₂O (0.4 mL), ball milling at 80 °C for 1 h. Bromides with various fused rings like pigment Vat Orange 3, anthracene, pyrene, spirobifluorene, dithieno[3,2–b:2ʹ,3ʹ–d]thiophene, benzo[1,2–b:4,5–bʹ]dithiophene, benzo[c][1,2,5]thiadiazole, anthraquinone and carbazole were tolerated well under this reaction, producing the desired large π-conjugated acetylenes (6a–6i) in good to excellent yields. p-Terphenyl, 4-hexylphenyl and terthiophene functionalized bromides were also applicable to generate the corresponding products (6j–6l) in 83%, 39% and 94% yields, respectively. This protocol, displaying remarkable superiorities such as pleasure yields, short reaction time and no need of organic solvents, not only offered a novel access to prepare materials-oriented π-conjugated alkynes but also illustrated the significant potential application of mechanochemical Sonogashira coupling reaction in the discovery of new photoelectric functional materials bearing acetylene frame.

A unique single-pot multi-step reaction to synthesize complex cyclopropylene compounds was demonstrated by Mack in 2018 [77]. This reaction used mechanochemical methods to achieve the coupling of three components (tynes 7, aryl halides 8 and diazinoacetates 9) under solvent-free conditions by combining Sonogashira coupling and cyclopropylation reaction. The reaction was completed in a SPEX 8000M vibratory mixer/mill (18 Hz), and silver foil lined S.S. vial achieved the highest yield with the comparison of stainless steel and copper foil lined S.S. vial. Terminal alkyl and phenyl alkynes reacted well with phenyl bromides or iodides to generate internal alkynes which then underwent the cyclopropylation with phenyl-substituted diazoacetates, forming the target cyclopropenes (10a–10d) in 65–78% yields. Both of the phenyl- and phenanthryl-substituted iodides were tolerated well under this reaction conditions to form the corresponding cyclopropenes (10e–10g) in moderate to good yields. Phenyl- and naphthyl-functionalized diazoacetates were also suitable for this transformation, affording the cyclopropenes (10h–10k) in 60–75% yields (Scheme 3). This method not only omitted tedious post-processing steps, but also allowed it to be performed at ambient and atmospheric conditions, making the reaction more economical and environmentally friendly. But the traditional synthesis of cyclopropenes often suffered from some shortcomings like harsh reaction conditions, requirement of large amount of solvents [75,78,79].

Mechanochemically induced C–H alkylation [80], showing the following advantages like environmental protection, high atom economy, wide substance scope, avoiding harmful solvents, reducing energy consumption and cost [81], is in line with the requirements of green synthesis. The C–H butadiynylation of pyrrole was disclosed by Szafert in 2015 [82] (Scheme 4). In the presence of K₂CO₃, the cross-coupling of pyrrole (11) and 1-halobutadiyne (12) proceeded smoothly under milling condition to give the corresponding butadiynyl-substituted pyrrole (13) in moderate to good yields. The unsubstituted and benzyl-, methyl-, vinyl-functionalized 4,5,6,7-tetrahydroindoles were suitable for this coupling reaction, forming the target 13a–13d in reasonable yields. Methyl-, benzyl- and ethyl-substituted butadiynoates were also tolerated well under this reaction conditions, producing the corresponding 13e–13l in 43–80% yields. Based on the reported work [83], the reaction mechanism was proposed. Firstly, treatment of 11 and 12 with K₂CO₃ under grinding formed the ion-radicals pair A via single electron transfer. Addition of the C≡C bond generated the intermediate B. Elimination of hydrogen halide from B gave the desired product (13). The procedure, yielding butadiynyl-substituted pyrroles through a convenient grinding of reactants in a mortar under solvent-free conditions, would be recognized as the first example of mechanochemical pyrrole butadiynylation and could be useful in the field of organic synthesis especially in drug synthesis.

In 2016, Szafert demonstrated a solvent-free mechanochemical C–H alkynylation of pyrroles towards long chain polyynyl-substituted pyrroles [84]. Treatment of (bromo-hexa-1,3,5-triyn-1-yl)benzene derivatives (14) with pyrroles (15) and K₂CO₃ under grinding for 3–48 h gave the target polyynyl-substituted pyrroles (16) in high yields. When (iodo-hexa-1,3,5-tetrayn-1-yl)benzene derivatives (17) were used instead of 14, the corresponding products (18) was obtained in good yields (Scheme 5). Notably, this protocol displayed a potentially application in the preparation of molecular wires.

In 2018, Bolm [85] described mechanochemical Rh(III)– and Au(I)–accelerated C–H alkynylations of indoles (Scheme 6). After probing the reaction in detail, the best conditions were presented as follows: a mixture of indole (19, 0.6 mmol), ethynyl-substituted 1,2–benziodoxol–3–(1H)–one (20, 0.66 mmol), [Cp*RhCl₂]₂ (0.03 mmol) and AgNTf₂ (0.012 mmol), ball-milling in a stainless-steel vessel (10 mL) with a ball (1 cm). The reaction was compatible with several substituents such as triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) and tBu, forming the 2-alkynylated indoles (21a–21d) in 73–98% yields. Whether incorporated with electron-rich (Me, OMe) or electron-poor (MeOC(O), F, Br, Cl, I) groups, indoles reacted with 20 smoothly to generate the target alkynylated indoles (21e–21k) in moderate to excellent yields. Instead of [Cp*RhCl₂]₂/AgNTf₂ catalytic system, AuCl catalyzed alkynylations of indoles formed the 3-alkynylated indoles. Ball-milling the mixture of 19, 20 and AuCl at 30 Hz for 60 min produced the corresponding 3-alkynylated indoles (24). Both of the TIPS- and TBDMS-functionalized 1,2–benziodoxol–3–(1H)–ones survived well under this reaction conditions, resulting in the generation of 24a–24c in 31–82% yields. Indoles bearing electron-donating (Me, OMe) or electron-withdrawing (I, Br, Cl) groups were also suitable for this reaction, leading to the formation of target 24d–24h in moderate yields. Compared to conventional reactions [86,87,88,89,90,91,92,93,94], this method displayed diverse advantages like short reaction time, small catalyst loading, good selectivity and high yields. Additionally, the reaction showed good scalability, affording 21a in 98% yield (730 mg) in a 2.0 mmol scale reaction.

The grinding-induced C–H alkynylation of azulenes and 1-haloalkynes or 1-halopolyynes was covered by Pigulski in 2021 [95]. Grinding a mixture of azulene (25), haloalkyne (26) and basic Al₂O₃ formed the corresponding alkynylated azulene (27). This C–H alkynylation was compatible with 1-haloalkynes which bear phenyl, thienyl or furyl group to afford the target products (27a–27b, 27d–27f, 27n) in moderate to excellent yields. 1-Halopolyynes like diyne, triyne and tetrayne were all succeeded in this reaction, giving the desired products (27c, 27g–27m, 27o) in 23–85% yields (Scheme 7). The reaction, proceeding at rt under solvent-free and short reaction time conditions, was not only a simple and green procedure for synthesis of alkynylated azulene but also could be potentially applied in the manufacture of azulene-terminated sp carbon molecular wires. While the general approaches towards alkynylated azulene used prefunctionalized azulenyl aldehyde or halogen-substituted azulene as a starting material [96,97,98].

3. Mechanochemical and Transition-Metal-Catalyzed Cyclization

1,2,3–Triazoles not only are important moieties in pharmaceuticals but also could be applied as directing-groups in C–H activation transformations [99,100,101]. Copper–catalyzed azide-alkyne cycloaddition (CuAAC) reactions, displaying some advantages like high yields, mild reaction conditions, wide substance scope and good orthogonality [102], was an efficient protocol towards 1,4-substituted-1,2,3-triazoles and could be extensively applied in organic synthesis [103], medicinal chemistry [104], surface and polymer chemistry [105]. A mechanochemical CuAAC reaction between alkynes and azides was developed by Mack in 2013 [106]. Under solvent-free conditions, phenylacetylene (28), benzylbromide (29), sodium azide and a copper mill ball, milling in a copper reaction vessel for 15 min, and the only product 1–benzyl–4–phenyltriazole (30) could be isolated directly from the reaction flask without further purification (Scheme 8). This CuAAC reaction was compatible with phenyl-substituted alkynes bearing electron-withdrawing (Br, NO₂) groups on the phenyl ring to give the corresponding products (30b, 30c) in >95% and 33% yields, respectively. Trimethyl silyl acetylene, 1-hexyne and ethyl but-3-ynoate also worked well, generating 30d–30l in good to excellent yields. Compared to the traditional CuAAC reaction which usually proceeded in organic solvents with long reaction time using copper catalyst [107], this method produced 1,2,3-triazoles in high yields under solvent-free condition without any common copper catalysts.

In 2023, Brahmachari [108] displayed a multi-component reaction of aryl/heteroaryl acetylene (31), diaryl diselenide (32), benzyl bromide (33) and sodium azide under high-speed ball milling conditions to synthesize selenotriazole (Scheme 9). After screening the reaction conditions in detail, the best reaction conditions were established as following: A mixture of phenylacetylene (31, 0.2 mmol), diselenide (32, 0.2 mmol), bromide (33, 0.2 mmol), CuI (0.02 mmol), 1,10-phenanthroline (0.02 mmol) and sodium azide (0.2 mmol), ball-milling in a stainless-steel jar (25 mL) with 7 basic alumina surface balls (pH = 8.01, 1.5 g, 10 mm) at 550 rpm for 15 min. While the neutral and acidic surface ball milling gave the target product in lower yields and stirring the reaction mixture without ball milling did not form the product at all. When the above optimal reaction conditions were employed to explore the scope of substances, different phenylacetylenes incorporating with electron-rich (Me, OMe, OPh) and electron-poor (Br, CF₃, F) groups showed pleasure tolerance, leading to 34b–34g in high yields. 3-Ethynylthiophene was also applicable to afford the expect 34h in 76% yield. Benzyl bromide with methyl or chloro group at the phenyl moiety survived well, forming the desired 34i–34n in 42–77% yields. (1-Bromoethyl)benzene and 1-(bromomethyl)naphthalene were tolerated as well, resulting in the generation of 34o and 34p in 68% and 73% yield, respectively. Both of the electron-donating (Me, Et) or electron-withdrawing (CF₃, F) groups incorporated diphenyl diselenides were applicable in this multicomponent reaction, furnishing the expected 34q–34t in high yields. Since selenones are interesting moieties in bioactive molecules and natural products [109], the authors carried out the oxidation of the above selenotriazoles. Treatment of selenotriazoles (34) with m-chloroperbenzoic acid (mCPBA) formed the expected selenones (35a–35c) in moderate yields. According to the previous work [110,111,112,113,114] and the control experiments, a plausible mechanism was outlined. Initially, coordination of CuI with 1,10-phenanthroline gave the active Cu(I)-coordination complex A, which was then transformed to the intermediate B by reacting with acetylene (31). The ethynyl selane D was then generated by reductive elimination of copper(II)-complex C which was generated by the reaction of B with diselenide. Then, the intermediate E was obtained through the reaction of A, D and benzyl azide which was in-situ generated via the reaction of benzyl bromide (33) and sodium azide. The oxidative cyclization of E then occurred to produce the six-membered Cu(II)-coordinating complex F, which was then converted into the final products (34) with the regeneration of active complex A to complete the catalytic cycle. This procedure, displaying some notable advantages such as one-pot manner, avoiding the use of solvent and heating, short reaction time, pleasure yields and wide substance scope, was an efficient, green and practical protocol towards selenotriazoles as well as bioactive selenones.

In 2023, Koenig [115] firstly discovered a metal surface directly catalyzed CuAAC reaction under Resonant Acoustic Mixing (RAM). When a mixture of sodium azide, benzyl bromide (36) and phenylacetylene (37) were in contact with the copper coil surface (previously treated with SiO₂) through a high-speed mixing, the desired 1,2,3–triazole (38) was formed in excellent yield. No matter whether incorporated with electron-withdrawing (Br, CN, CF₃) or electron-donating (OMe) groups, benzyl bromides reacted with phenylacetylene smoothly and formed the desired 1,2,3–triazoles (38b–38f) in quantitative yields. This CuAAC was also compatible with phenylacetylene which bear trimethylsilyl on the phenyl ring to produce the desired products (38g–38l) in 80–94% yields. 1–Hexyne was also suitable for this CuAAC, resulting in the formation of 38m–38r in moderate to excellent yields. Interestingly, the desymmetrization reaction with equimolar amounts of benzyl bromide, 3,5–dimethoxybenzyl bromide and 1,4–diethynylbenzene formed unsymmetrical bis(triazole) (38s) in quantitative yield. (Scheme 10). The authors also found that copper surface was played a pivotal role to the yield. The uncoiled copper wire and fresh copper coil showed remarkable lower conversion. Notably, this copper coil surface catalyzed CuAAC could be applied to synthesize the anticonvulsant drug Rufinamide in gram-scale. This protocol exhibited several superiorities like short reaction time, wide substance scope and high yields, but DMSO additive was required to finish the transformation completely.

Mechanochemical 1,3–dipole cycloaddition not only retains the advantages of the traditional 1,3–dipole cycloaddition reaction but also improves the efficiency of the reaction through the action of mechanical force [116], providing a new way for the synthesis of complex cyclic compounds. Isoxazolines were prepared successfully through mechanochemical 1,3–dipolar cycloaddition of electron-deficient alkynes and activated olefins in 2019 [117] (Scheme 11). Firstly, starting materials N–methyl–C–(2–furyl) nitrone (41) was formed directly through ball milling N–methylhydroxylamine hydrochloride (40), furanal (39) and sodium bicarbonate in a vibrating apparatus with two stainless steel balls (7.0 mm diameter) for 1 h. Then, the authors synthesized isoxazolines by ball milling 41 and alkynes (42) in a steel vessel (25 mL) at 30 Hz for 6 h under solvent-free conditions. Methyl phenylpropiolate, dimethyl acetylenedicarboxylate and acetylenedicarboxylic acid were tolerated well under this reaction conditions, resulting in the formation of isoxazolines (43a–43c) in excellent yileds. Notably, this protocol, offering a novel access towards isoxazolines, could be potentially applied in pharmaceutical manufacture.

In 2023, Forgione [118] realized the mechanochemical desymmetrization of bisalkynes (44) with hydroxyimidoyl chlorides (45) to obtain 3,5–isoxazole-alkyne adducts (46). After screening the reaction conditions carefully, the optimized reaction conditions were attained as following: a mixture of 44 (0.396 mmol), 45 (0.396 mmol), Cu(NO₃)₂–2.5 H₂O (0.396 mmol), Na₂CO₃ (0.796 mmol) and mesitylene (η = 0.25 μL/mg), milling with 8 balls at 60 Hz for 60 min. This reaction was compatible with various hydroxyimidoyl chlorides involving ester, bromo, nitro and phenyl groups (46a–46d). 1,4–Diethynylbenzene, 1,3–diethynylbenzene, 1,3–diethynyl–5–methoxybenzene, 1,3,5-–riethynylbenzene, 2,5–diethynylthiophene and 2,6–diethynylpyridine worked well under this reaction conditions, leading to the generation of 46e–46l in 36%–>99% yields (Scheme 12). Compared with the usual synthetic methodologies using excess amount of one of the substrates or protecting groups to achieve reasonable selectivity [119,120,121,122,123,124], this work was the first example of preparing 3,5–isoxazole–alkyne adducts with excellent selectivity from equimolar quantity of bis-alkynes and hydroxyimidoyl chlorides and showed potential applications in the synthesis of drugs or natural products with 3,5–isoxazole skeleton.

A mechanochemical CuO nanoparticles accelerated cyclocondensation was established to construct isoxazole framework by Karthikeyan in 2021 [125]. In the presence of 1,4–diazabicyclo[2.2.2]octane (DABCO), CuO nanoparticles (CuONP) and ZrO, α–nitroethylacetates (47) reacted with terminal alkynes (48) efficiently to generate the target isoxazoles (49a–49e) in 55–93% yields (Scheme 13). This procedure, undergoing under mild reaction conditions, was a valuable and efficient approach towards functionalized isoxazoles. But the substance scope was required to extend.

The isoxazole moiety could be also built through ball-milling-enabled Ru-promoted regiodivergent cycloaddition of alkyne and hydroxyimidel chloride [126]. After investigating the reaction in detail, the optimal reaction conditions were acquired as follows: a mixture of alkyne (50, 0.586 mmol), hydroxyimidel chloride (51, 0.924 mmol), Ru–1 catalyst (0.0467 mmol), Na₂CO₃ (0.612 mmol), KBr (150 wt%, 409 mg) and cyclopentyl methyl ether (CPME, η = 0.9 µL/mg, 612 µL), ball-milling in a Teflon Jar (25 mL) with one SS ball at 6 or 30 Hz for 60 min. Both of the phenyl and alkyl involved alkynes were tolerated well under these conditions, forming the desired isoxazoles (52a–52f) in 70%–>99% yields. Hydroxyimidel chlorides containing ethoxycarbonyl, phenyl, 4-methoxyphenyl, 4-nitrophenyl or 4-chlorophenyl group were also applicable in the manufacture of 52g–52l as well. The authors also revealed the proposed mechanism. The addition of CPME to Ru–1 catalyst formed the catalytically active Ru species A. Treatment of A with 50 and 51 generated the intermediate B with the elimination of CPME. Oxidative coupling of B afforded the six-membered ruthenacycle C, which was then transformed into the five-membered intermediate D with the action of CPME. The reductive elimination of D was then occurred to give the desired isoxazole and regenerate the active Ru species A to finish the catalytic cycle (Scheme 14). It was worth mentioning that this protocol produced isoxazoles in high yields with wide substance scope under solvent-free, short reaction time and solid-state conditions. However, the common protocols displayed some limitations like big dilution factors, long reaction time and limited substance scope [127,128].

Ball-milling-induced and Rh–catalyzed cycloaddition of acetanilide with alkyne to access indole was achieved by Bolm in 2023 [50]. Acetanilides with either electron-withdrawing (F) or electron-donating (OMe, Me) groups demonstrated high tolerance, leading to 55a–55f in 45–70% yields. Various phenyl/alkyl-disubstituted alkynes applied well in this reaction, resulting in the corresponding products (55g–55i) in good yields (Scheme 15). Although the yields and substance scope remained to improve, this reaction proceeded smoothly under mild conditions such as solvent-free, low temperature and catalytic amounts of Cu(OAc)₂. However, using over-stoichiometric amount of Cu(OAc)₂ at 100 °C was required to realize high yield in common reaction [129,130].

4. Mechanochemical and Transition-Metal-Catalyzed C−H Alkenylation

A mechanochemical Mn(I)-promoted selective alkenylation of indoles to access 2–alkenyl indoles was presented by Chatterjee in 2020 (Scheme 16) [51]. After examining the reaction carefully, the best conditions were presented as following: a mixture of indole (56, 1 mmol), alkyne (57, 1.3 mmol), MnBr(CO)₅ (0.1 mmol), N,N–diisopropylethylamine (DI–EA, 0.2 mmol), acetic acid (0.2 mmol) and SiO₂, ball-milling in a jar (5 mL) with one zirconia ball (10 mm) at 25 Hz for 4–12 h. Notably, stainless steel ball milling showed lower yield and lower frequency slowed down the reaction. Phenylalkynes featuring with electron-withdrawing (CF₃, F, CN) or electron-donating (Me, MeO) groups at the phenyl ring survived well under these conditions, forming the corresponding products (58a–58f) in 82–99% yields. 3–Ethynylthiophene as well as ethyl propiolate were also tolerated to produce the desired 58j and 58k in 98% and 85% yields, respectively. Indoles incorporated with MeO, CN or Br on the phenyl cycle reacted with alkynes smoothly to afford the target 58g–58i in excellent yields. Based on the reported work [131], the plausible reaction mechanism was proposed. In the presence of DIPEA, the cyclometallation of MnBr(CO)₅ with 56 occurred to form the complex A, which was then transformed to the η² intermediate B by reacting with 57. The seven-membered cyclometalleted species C was obtained through intramolecular introduction of 57 into the Mn–C bond. The final product 58 and Mn salt (D) were obtained from C through abstraction of a proton from AcOH. D reacted with 56 to form A and complete the catalytic cycle, or participated in another cycle to yield B by treatment with 56 and 57. Notably, this alkenylation showed remarkable features such as cheap catalyst, solvent-free, pleasure yields and wide substance scope.

5. Summary and Outlook

In summary, mechanochemical and transition-metal catalyzed reactions of alkyne have been popularly developed due to the unique superiorities of mechanochemical reactions and the reactivities of alkynes. For examples, ball-milling transition-metal-catalyzed Sonogashira coupling of alkyne and halide formed the desired functionalized alkynes in a short reaction time, mechanochemical and transition-metal-accelerated C–H alkynylations of indole (or azulene) with alkynes afforded the corresponding alkynylated indole (or azulene) under solvent-free and short reaction time conditions, ball-milling CuAAC reactions between alkynes and azides resulted in the formation of 1,2,3–triazoles in high yields under mild conditions, ball-milling and transition-metal-promoted cycloaddition of alkyne and hydroxyimidel chloride could be applied in the construction of isoxazole moiety, mechanochemical and Mn(I)–catalyzed alkenylation of indole was also developed to access 2–alkenyl indole. Notably, most of the above protocols proceeded smoothly under mild conditions with good yields and broad substance scopes.

Although these above mechanochemical and transition-metal catalyzed reactions of alkynes are much green and powerful methods towards functionalize molecules, establishing other economical, sustainable and green transformations of alkynes and applying the above presented methods to synthesize bioactive and pharmacological molecules, organic optoelectronic molecules and natural products are still in urgent need. The following research topics would be focused: (1) Since the organic six-membered rings are crucial moieties to build agricultural chemicals, organic materials and pharmaceuticals, mechanochemical and transition-metal catalyzed synthesis of six-membered rings from alkynes should be enhanced in future research; (2) Precious metal catalyst like Rh, Au and Pd complexes are kind of expensive, it would be significant to develop mechanochemical transformation of alkynes by using relatively cheap and easily available catalysts such as iron, nickel and cobalt complexes; (3) In addition, it would be necessary to establish mechanochemical and transition-metal catalyzed other reactions of alkyne, such as hydrogenation, reduction, addition, [4+2] and [2+2+2] cyclization.