A Simple and Practical Bis-N-Heterocyclic Carbene as an Efficient Ligand in Cu-Catalyzed Glaser Reaction

Conjugated diyne derivatives are important scaffolds in modern organic synthetic chemistry. Using the Glaser reaction involves the coupling of terminal alkynes which can efficiently produce conjugated diyne derivatives, while the use of a stoichiometric amount of copper salts, strong inorganic base, and excess oxidants is generally needed. Developing an environmentally friendly and effective method for the construction of symmetrical 1,3-diynes compounds by Glaser coupling is still highly desirable. In this study, we present an economical method for the production of symmetric diynes starting from various terminal acetylenes in a Glaser reaction. A simple and practical bis-N-heterocyclic carbene ligand has been introduced as efficient ligands for the Cu-catalyzed Glaser reaction. High product yields were obtained at 100 °C for a variety of substrates including aliphatic and aromatic terminal alkynes and differently substituted terminal alkynes including the highly sterically hindered substrate 2-methoxy ethynylbenzene or 2-trifluoromethyl ethynylbenzene and a series of functional groups, such as trifluoromethyl group, ester group, carboxyl group, and nitrile group. The established protocol is carried out in air under base-free condition and is operationally simple. These research work suggest that bis-N-heterocyclic carbene could also an appealing ligand for Glaser reaction and provide a reference for the preparation of symmetric 1,3-diynes in industrial filed.


Results and Discussion
We initially examined the reaction of phenyl acetylene 1a under a range of reaction conditions in the presence of a CuCl catalyst (Table 1). A series of ligands were screened to evaluate their suit abilities (Scheme 2). All results are summarized in Table 1. We were pleased to find that the desired product 2a was formed at an 86% yield when ligand L2 was used. Other ligands, such as L1, L3, L4, L5, and L6 were also examined and afford product 2a with yields of 78%, 34%, 42%, 49%, and 47%, respectively ( Table 1, entries 1-6). These results indicated that L2 was most effective among the ligands L1-L6. We next studied the solvent effect because the solvent is also an important factor in this reaction. Only traces of the product were seen on the TLC plate when 1,4-dioxane was used as the solvent (Table 1,  entry 7). To our delight, DMF gives the best result with a yield of 95% (Table 1, entry 8).
Other solvents, such as DMAc, toluene, and xylene, also show similar reaction activities (Table 1, entry 9-11). There was no significant reduction of the yield when the temperature was 100 o C, and the reaction time could decrease to 4 h ( Table 1, entry 12-16). However, further reduction of the temperature resulted in decreased product yield (Table 1, entry [17][18][19]. Finally, control experiments indicated that both the CuCl and the ligand L2 are essential for the reaction (Table 1, entry [20][21][22][23][24][25]. Thus, it could be concluded that the optimal conditions were 5 mol% CuCl, 10 mol% L2, DMF as a solvent, and air as an oxidant at 100 °C for 4 h. Scheme 1. Outline of conjugate 1,3-dialkynes and they synthesis.

Results and Discussion
We initially examined the reaction of phenyl acetylene 1a under a range of reaction conditions in the presence of a CuCl catalyst (Table 1). A series of ligands were screened to evaluate their suit abilities (Scheme 2). All results are summarized in Table 1. We were pleased to find that the desired product 2a was formed at an 86% yield when ligand L2 was used. Other ligands, such as L1, L3, L4, L5, and L6 were also examined and afford product 2a with yields of 78%, 34%, 42%, 49%, and 47%, respectively (Table 1, entries 1-6). These results indicated that L2 was most effective among the ligands L1-L6. We next studied the solvent effect because the solvent is also an important factor in this reaction. Only traces of the product were seen on the TLC plate when 1,4-dioxane was used as the solvent (Table 1,  entry 7). To our delight, DMF gives the best result with a yield of 95% (Table 1, entry 8).
Other solvents, such as DMAc, toluene, and xylene, also show similar reaction activities (Table 1, entry 9-11). There was no significant reduction of the yield when the temperature was 100 • C, and the reaction time could decrease to 4 h ( Table 1, entry 12-16). However, further reduction of the temperature resulted in decreased product yield (Table 1, entry [17][18][19]. Finally, control experiments indicated that both the CuCl and the ligand L2 are essential for the reaction (Table 1, entry [20][21][22][23][24][25]. Thus, it could be concluded that the optimal conditions were 5 mol% CuCl, 10 mol% L2, DMF as a solvent, and air as an oxidant at 100 • C for 4 h. CuCl  With the optimized reaction conditions in hand, the substrate scope was next explored. We first study the effect of substituents on the homocoupling of terminal alkynes. As shown in Scheme 3, various aromatic terminal alkynes with either electron-donating or electron-withdrawing substituents were well tolerated under the identified conditions, affording the desired products 2b-2j with 89-96% yields. A series of functional groups, such as the trifluoromethyl group, ester group, carboxyl group, and nitrile group, were CuCl  CuCl CuCl L2  DMF  60  4  67  24 CuCl With the optimized reaction conditions in hand, the substrate scope was next explored. We first study the effect of substituents on the homocoupling of terminal alkynes. As shown in Scheme 3, various aromatic terminal alkynes with either electron-donating or electron-withdrawing substituents were well tolerated under the identified conditions, affording the desired products 2b-2j with 89-96% yields. A series of functional groups, such as the trifluoromethyl group, ester group, carboxyl group, and nitrile group, were With the optimized reaction conditions in hand, the substrate scope was next explored. We first study the effect of substituents on the homocoupling of terminal alkynes. As shown in Scheme 3, various aromatic terminal alkynes with either electron-donating or electronwithdrawing substituents were well tolerated under the identified conditions, affording the desired products 2b-2j with 89-96% yields. A series of functional groups, such as the trifluoromethyl group, ester group, carboxyl group, and nitrile group, were compatible with the present catalytic system. For example, 4-ethynyl-α,α,α-trifluorotoluene, methyl 4-ethynylbenzoate, 4-ethynylbenzoic acid, and 4-ethynylbenzonitrile were suitable for the couplings, and good to excellent yields of the products were obtained (86-90%). Delightedly, the sterically hindered ortho-methyl ethynylbenzene or their derivatives could provide the corresponding homocoupling product 2o and 2p in 96% and 92% yield, respectively. Even the highly sterically hindered substrate 2-methoxy ethynylbenzene or 2-trifluoromethyl ethynylbenzene could also react smoothly to afford the desired products 2q and 2r in a good yield of 93% and 89%.
Molecules 2023, 28, x FOR PEER REVIEW 5 of 12 compatible with the present catalytic system. For example, 4-ethynyl-α,α,α-trifluorotoluene, methyl 4-ethynylbenzoate, 4-ethynylbenzoic acid, and 4-ethynylbenzonitrile were suitable for the couplings, and good to excellent yields of the products were obtained (86-90%). Delightedly, the sterically hindered ortho-methyl ethynylbenzene or their derivatives could provide the corresponding homocoupling product 2o and 2p in 96% and 92% yield, respectively. Even the highly sterically hindered substrate 2-methoxy ethynylbenzene or 2-trifluoromethyl ethynylbenzene could also react smoothly to afford the desired products 2q and 2r in a good yield of 93% and 89%. Encouraged by the above results, we explore further the scope of aliphatic terminal alkynes and heterocyclic acetylenes. It is well known that aliphatic terminal alkynes are less reactive compared to aromatic terminal alkynes. To our delight, a satisfying yield was obtained when the reaction was carried out in 120 °C with 12 h. As shown in Scheme 4, heterocyclic acetylenes, such as 3-ethynylpyridine, 2-ethynylpyridine, and 3-ethynylthiophene, can be successfully reacted to afford the corresponding compounds 4a-4c in 81- Encouraged by the above results, we explore further the scope of aliphatic terminal alkynes and heterocyclic acetylenes. It is well known that aliphatic terminal alkynes are less reactive compared to aromatic terminal alkynes. To our delight, a satisfying yield was obtained when the reaction was carried out in 120 • C with 12 h. As shown in Scheme 4, heterocyclic acetylenes, such as 3-ethynylpyridine, 2-ethynylpyridine, and 3-ethynylthiophene, can be successfully reacted to afford the corresponding compounds 4a-4c in 81-90% yields. It is noteworthy that, when we employed aliphatic terminal alkynes, they performed well and provided the corresponding conjugated diyne products 4d-4h Molecules 2023, 28, 5083 6 of 12 in moderate yields. These results show that heterocyclic or aliphatic acetylenes are also tolerated in this present protocol.
Molecules 2023, 28, x FOR PEER REVIEW 6 of 12 90% yields. It is noteworthy that, when we employed aliphatic terminal alkynes, they performed well and provided the corresponding conjugated diyne products 4d-4h in moderate yields. These results show that heterocyclic or aliphatic acetylenes are also tolerated in this present protocol. With regard to our results, the reaction mechanism is not fully understood at present. After referring to a lot of the relevant literature [14,24,25,40,43,46], we proposed that this Cu-catalyzed Glaser homocoupling might take place as shown in Scheme 5, which possibly involves the typical Glaser reaction steps. According to our assumptions, halogen bromide anions perhaps act as Lewis bases which have a weak ability to deproton in this catalysis system. The ligand L was coordinated with CuCl to form complex A. Then, the intermediate A reacts with terminal alkyne to form alkynyl copper intermediate B, and then it involved the oxidative reaction with O2 to give the conjugated 1,3-diynes at the last step via intermediates C and transition state TS.
With regard to our results, the reaction mechanism is not fully understood at present. After referring to a lot of the relevant literature [14,24,25,40,43,46], we proposed that this Cu-catalyzed Glaser homocoupling might take place as shown in Scheme 5, which possibly involves the typical Glaser reaction steps. According to our assumptions, halogen bromide anions perhaps act as Lewis bases which have a weak ability to deproton in this catalysis system. The ligand L was coordinated with CuCl to form complex A. Then, the intermediate A reacts with terminal alkyne to form alkynyl copper intermediate B, and then it involved the oxidative reaction with O 2 to give the conjugated 1,3-diynes at the last step via intermediates C and transition state TS.

General Information
Unless otherwise stated, all chemicals and reagents were commercially available in analytical grade without further purification. All terminal alkynes were purchased from Aldrich Chemical Co. Ltd. (St. Louis, MI, USA). All solvents were purchased from Shanghai Macklin Chemical Co. Ltd. (Shanghai, China). L1-L6 were prepared according to our previous reported procedures [49,56]. All reactions were performed under an atmosphere of air unless otherwise stated. Analytical thin layer chromatography (TLC) was performed on silica gel GF254 (layer thickness 0.20-0.25 mm). Column chromatography was carried out on silica gel (300−400 mesh) using petroleum ether as eluent. 1 H, 13 C NMR spectra were performed at room temperature on a Bruker Avance 400 MHz spectrometer using the residual solvent signal as internal standard (CDCl3: 7.26 ppm ( 1 H), 77.16 ppm ( 13 C); DMSO-d6: 2.50 ppm ( 1 H), 39.52 ppm ( 13 C)) (Supplementary Materials).

Typical Experimental Procedure for the Synthesis of 1,3-Diyne
Unless otherwise noted, the Glaser reaction was carried out under aerobic conditions. All solvents were used as received, and no further purification was needed. A parallel reactor containing a stir bar was charged with alkynes (1.0 mmol), CuCl (5% mol), ligands (10 mol %), and 1 mL of solvent. The reaction mixture was carried out at 100 °C for 4 h. After completion of the reaction, the reaction mixture was cooled to ambient temperature, and 10 mL of water was added. The mixture was diluted with dichloromethane (5 mL), followed by extraction three times (3 × 5 mL) with dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The crude cross-coupling products were purified by silica-gel column chromatography using petroleum ether as eluent, and the isolated yield was then calculated. The isolated cross-coupling products were characterized by 1 H NMR and 13 C NMR.

General Information
Unless otherwise stated, all chemicals and reagents were commercially available in analytical grade without further purification. All terminal alkynes were purchased from Aldrich Chemical Co. Ltd. (St. Louis, MI, USA). All solvents were purchased from Shanghai Macklin Chemical Co. Ltd. (Shanghai, China). L1-L6 were prepared according to our previous reported procedures [49,56]. All reactions were performed under an atmosphere of air unless otherwise stated. Analytical thin layer chromatography (TLC) was performed on silica gel GF254 (layer thickness 0.20-0.25 mm). Column chromatography was carried out on silica gel (300−400 mesh) using petroleum ether as eluent. 1 H, 13 C NMR spectra were performed at room temperature on a Bruker Avance 400 MHz spectrometer using the residual solvent signal as internal standard (CDCl 3 : 7.26 ppm ( 1 H), 77.16 ppm ( 13 C); DMSO-d 6 : 2.50 ppm ( 1 H), 39.52 ppm ( 13 C)) (Supplementary Materials).

Typical Experimental Procedure for the Synthesis of 1,3-Diyne
Unless otherwise noted, the Glaser reaction was carried out under aerobic conditions. All solvents were used as received, and no further purification was needed. A parallel reactor containing a stir bar was charged with alkynes (1.0 mmol), CuCl (5% mol), ligands (10 mol %), and 1 mL of solvent. The reaction mixture was carried out at 100 • C for 4 h. After completion of the reaction, the reaction mixture was cooled to ambient temperature, and 10 mL of water was added. The mixture was diluted with dichloromethane (5 mL), followed by extraction three times (3 × 5 mL) with dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The crude cross-coupling products were purified by silica-gel column chromatography using petroleum ether as eluent, and the isolated yield was then calculated. The isolated cross-coupling products were characterized by 1 H NMR and 13 C NMR.

Conclusions
In summary, using a simple and practical bis-N-heterocyclic carbene as ligand, an efficient and green method for the Cu-catalyzed Glaser reaction to produce 1,3-conjugated dialkynes was developed. This method is carried out in simple procedure and without base additives in air conditions. Various terminal alkynes containing functional groups, such as the ester group, carboxyl group, and nitrile group, etc., could be effectively coupled to produce the corresponding conjugated 1,3-diynes with good yields. Aliphatic alkynes were also compatible in our protocol. This easily accessible system implies that N-heterocyclic carbene can serve as an alternative ligand in the Glaser reaction and offers a reference for the preparation of symmetric 1,3-diynes. This work also demonstrates the great potential of bis-N-heterocyclic carbene in the green ligand for the transition metal-catalyzed coupling reactions.