CCl 4 -TMEDA-CuCl—A Novel Convenient Catalytic System for Dimerization of Terminal Acetylenes in Mild Conditions

: A novel catalytic system for homocoupling terminal acetylenes was elaborated based on CuCl as a catalyst (10 mol%), TMEDA as a base and CCl 4 as an oxidant. The influence of the solvent, base, amount of catalyst and CCl 4 on the reaction was investigated. Methanol was found to be the solvent of choice. The broad synthetic scope of the reaction was demonstrated. Diynes with various substituents were prepared in up to 92% yields. The possible reaction mechanism is discussed


Introduction
Several years ago, a novel catalytic olefination reaction of carbonyl compounds (COR) was discovered in our laboratory [1,2].It was found that N-unsubstituted hydrazones of carbonyl compounds transform into alkenes under treatment of polyhaloalkanes (PHA) in the presence of a base (ammonia, ethylenediamine, triethylamine) and catalytic amounts of copper salts.The reaction is accompanied by the evolution of nitrogen, and azines are formed as the only by-products (Scheme 1).The reaction has a broad synthetic scope and allows the synthesis of alkenes containing various halogens and functional groups in yields of up to 90-95% [3][4][5][6].It is worth noting the high stereoselectivity of the reaction; in some cases, the ratio of diastereoisomers reaches 21:1 [7] (Figure 1).The use of freons as olefinating reagents allows the synthesis of fluorine-containing alkenes, convenient building blocks for the synthesis of more complex fluorinated compounds with important practical applications [8][9][10][11][12].
It was found that the PHA-nitrogen base-copper salt system also works for the transformation of a number of other types of hydrazones.In particular, the application of this system made it possible to oxidize isatin hydrazones to the corresponding diazoketones [13].It was also found that N-substituted hydrazones can be converted into the corresponding halogenated azabutadienes [14] (Figure 1).

Results
The study of the reaction mechanism of the catalytic olefination reaction showed that the reaction starts with the oxidation of copper (I) chloride with a polyhaloalkane in the presence of a nitrogen-containing ligand to form a complex of copper (II) chloride and a polyhalogenated alkyl radical.The regeneration of copper (I) proceeds under the action of either hydrazone or the addition of products of polyhaloalkyl radicals to hydrazone [73].Thus, the PHA-nitrogen base-CuCl system works as an oxidizing agent.As a part of the further study of the synthetic possibilities of this system, we decided to study it for the dimerization of terminal acetylenes.TMEDA was chosen as a base and carbon tetrachloride as an oxidant.First, we investigated the influence of the nature of the solvent on the course of the reaction.The reaction was carried out at room temperature using 10 mol% of CuCl.We found that under the action of the CCl4-TMEDA-CuCl system, the model substrate (phenylacetylene) was successfully dimerized to 1,3-diyne 2a (Scheme 1).The reaction proceeds both in polar aprotic solvents and in alcohols.The best reaction yields (90-92%) were achieved in ethanol and methanol.In contrast, the yields in coordinating solvents (MeCN, THF and DMSO) did not exceed 63% due to possible poisoning of the catalytic system.Next, we studied an effect of the amount of catalyst on the reaction outcome.It turned out that the reaction proceeds even with 1 mol% of CuCl; however, in this case, the conversion time of phenylacetylene increases to about 2 days, and the yield of target 1,3-diyne 2a decreases to 51%.The use of a 10 mol% catalyst turned out to be optimal, since in this case the highest yield of 1,3-diyne 2a was observed.It should be noted that the reaction does not take place without CuCl (Scheme 1).We also tested several other nitrogen-containing bases in the reaction.In the case of ethylenediamine, triethylamine and ammonia, the yield dropped to 4% due to massive tarring of the reaction mixture.It was reported that TMEDA (which is the bidentate tertiary amine ligand) provides enhanced solubility to the reactive copper intermediate [44].We believe that it is a reason for such a dramatic difference in efficiency between TMEDA and other investigated nitrogen-containing bases.Indeed, TMEDA works effectively as both a base and a ligand for the coordination with copper.
Next, we performed a series of experiments using various amounts of CCl4.We found that the reaction proceeds in high yield (76%) even with one equivalent of CCl4.The yield of diyne 2a increases until the amount of PHA increases to 2-2.5 equiv., after which it remains constant.As a proof of principle, we tested several other PHAs.It was found that CFBr3, CF3CCl3, CBrCl3 and CBr4 are also suitable for the dimerization of alkynes to afford diyne 2a in 78-94% yields.However, using CCl4 is preferable because of its very affordable price.Concluding this part of the investigation, we found that the optimal condition for the reaction is to perform it in methanol with TMEDA as a base, using 2.5 equivalents of carbon tetrachloride and 10 mol% of CuCl.
Having found the optimal conditions for the dimerization of phenylacetylene, we carried out a series of reactions with a number of other terminal arylacetylenes.We found that the reaction proceeds in high yield for acetylenes bearing both acceptor and donor substituents at the aromatic ring (Scheme 2).Sterically hindered 2methoxyphenylacetylene was also successfully involved in the reaction.The corresponding 1,3-diyne 2g was obtained in a 76% yield.We found that this catalytic system also works well for the dimerization of alkylacetylenes.Thus, 1,3-diyne 2i was obtained in a good yield from dec-1-yne.Phenylpropargyl ethers were also successfully involved in the reaction to give the corresponding 1,3-diynes 2j,2k in a high yield (Scheme 2).It should be noted that the reaction is tolerated by a carbonyl function.Thus, 1,3-diyne 2k containing carbonyl groups was isolated in a 92% yield.To further study the synthetic potential of the reaction, we investigated the dimerization of substituted propargyl alcohols under the action of the CCl4-TMEDA-CuCl system.We found that, in contrast to aryl-and alkylacetylenes, the solvent affects the reaction much more significantly.Thus, in polar aprotic solvents, the dimerization reaction of propargyl alcohol 3a proceeds in low yields, not exceeding 4-6%.On the contrary, in alcohols, the reaction proceeds in good to high yields, and methanol also resulted as the optimal solvent for dimerization, in which diyne 4a was obtained in an 89% yield (Scheme 3).More complex propargyl alcohols have also been successfully involved in the dimerization.Diynes bearing long alkyl chains (4b,4c), derivatives containing cyclic fragments (4d,4e) and aryl substituents (4f) were obtained efficiently.It should be noted that we synthesized diyne 4a in gram scale amounts (1.42 g), while the yield remained the same (85%).However, our attempts to carry out dimerization of parent propargyl alcohol were not successful due to massive tarring of the reaction.The diacetylene diols obtained are interesting compounds from the point of view of medicinal chemistry.Compounds with a moiety of conjugated polyacetylene alcohols have been isolated from various natural sources.Thus, many polyacetylene derivatives have been isolated from Oplopanax horridus and Panax ginseng plants belonging to the Araliaceae family, which exhibit antitumor, anti-inflammatory, antibacterial, antiviral, antifungal, immunomodulatory, neuroprotective, antidressing, hypoglycemic, hepatoprotective activity, as well as activity associated with obesity control (Figure 2) [74].Recently, three new polyacetylene alcohols extracted from the sea sponge Siphonochalina Siphonella in Egypt were found to have activity against a human cervical cancer cell line (HeLa), a human breast cancer cell line (MCF-7) and a human lung cancer cell line.(A549) [75,76].Eventually, we focused our attention on the possible reaction mechanism.It has previously been found that single electron transfer (SET) from CuCl to CCl4 generates Cu(II) species and the CCl3 radical [14].In order to check this possibility for the dimerization of acetylenes, we performed the reaction in the presence of one equivalent of TEMPO, which is a very effective radial scavenger.We found that TEMPO does not completely block the consumption of phenylacetylene and the formation of diyne 2a.However, noticeable tarring of the reaction was observed to give diyne 2a in a lower yield compared to the reaction without TEMPO.Next, we carried out the reaction in the presence of one equivalent of α-cyclopropylstyrene.It was found that diyne 2a is formed in a slightly lower yield (72% compared to 92%).At the same time, dehydronaphthalene 6 was found in the reaction mixture by 1 H NMR. However, no formation of compound 7 was detected.This product could be formed by the addition of phenylacetylenyl radical to α-cyclopropylstyrene. Therefore, the reaction proceeds through the participation of trichloromethyl radical (Scheme 4).Taking into account these results and the literature data about the Glaser reaction mechanism, the following scheme of the reaction can be proposed (Scheme 5) [36,44,77].Oxidation of the Cu(I) complex I under the action of CCl4 starts the catalytic cycle to form Cu(II) II complex.Next, complex II reacts with alkyne (or the copper π-complex of alkyne) in the presence of a base (TMEDA) to give intermediate III.The subsequent reaction of III with another molecule of alkyne (or alkyne π-complex) results in the formation of copper complex IV, which is a key reaction intermediate.The reductive elimination of copper from IV provides the target bis-alkyne and Cu(I) complex I to restart the catalytic cycle.In conclusion, we developed a new catalytic system (CCl4-TMEDA-CuCl) for the oxidative dimerization of terminal acetylenes.It was found that terminal acetylenes can be dimerized in yields up to 92% under the action of carbon tetrachloride in methanol in the presence of TMEDA and catalytic amounts of CuCl.The reaction has a wide synthetic scope, allowing the synthesis of conjugated diynes containing both aromatic substituents and aliphatic substituents.Terminal acetylenes containing functional groups were also successfully involved in the reaction to convert into conjugated diynes in up to 92% yield.

Materials and Methods
General remarks. 1 H, and 13 C NMR spectra (Supplementary Materials) were recorded on a Bruker AVANCE 400 MHz spectrometer in acetone-d6 and CDCl3 at 400.1 and 100.6 MHz, respectively.Chemical shifts (δ) in ppm are reported with the use of the residual CD3COCHD2 and chloroform signals (2.04, 7.25 for 1 H and 29.80, 77.0 for 13 C) as internal reference.The coupling constants (J) are given in Hertz (Hz).HRMS spectra were measured using the MicroTof Bruker Daltonics instrument.A TLC analysis was performed on "Macherey-Nagel ALUGRAM Xtra SIL G/UV254" plates.Column chromatography was performed on silica gel "Macherey-Nagel 0.063-0.2nm (Silica 60)".All reagents were of reagent grade and were used as such or were distilled prior to use.Terminal acetylenes were prepared by literature procedures (1b,c,d,e,h [78]; 3b,c,d,e,f [79]) or purchased from commercial suppliers (1a,f,g,i,j,k; 3a).Melting points were determined on Electrothermal 9100 apparatus.Due to the reported toxicity [80] of CCl4, all manipulations with this reagent should be carried out with care.
Screening of the optimal conditions for the dimerization of phenylacetylene (general procedures).Screening of the optimal solvent.An 8 mL vial with a screw cap was charged with phenylacetylene 1a (1 mmol), the corresponding solvent (3 mL), TMEDA (0.32 mL, 2.2 mmol), CCl4 (0.25 mL, 2.5 mmol) and CuCl (10 mg, 0.1 mmol were added at stirring by a magnetic stirrer).The reaction mixture was stirred for 1 day at room temperature and then broken by 0.1 M of HCl (30 mL).The product was extracted by CH2Cl2 (3 × 10 mL); the organic phase was washed with water (10 mL) and dried over Na2SO4.Volatiles were evaporated in vacuo; the residue formed was purified by column chromatography on silica gel using gradient elution by hexane, followed by a hexane-CH2Cl2 mixture (3:1).
Screening of the optimal amount of CuCl.The procedure for screening the optimal solvent was used with the only difference that the reaction was carried out in methanol and the appropriate amount of CuCl was used instead of 0.1 mmol (10% mmol) of CuCl.
Screening of the optimal base.The procedure for screening of the optimal solvent was used with the only difference that the reaction was carried out in methanol and the corresponding base was used instead of TMEDA.
Screening of the optimal amount of CCl4.The procedure for screening of the optimal solvent was used with the only difference that the reaction was carried out in methanol and the appropriate amount of CCl4 was used instead of 0.25 mL (2.5 mmol) of CCl4.
Screening of the optimal base.The procedure for screening of the optimal solvent was used with the only difference that the reaction was carried out in methanol and the corresponding PHA was used instead of CCl4.
Dimerization of phenylacetylene 1a in the presence of α-cyclopropylstyrene.An 8 mL vial with a screw cap was charged with phenylacetylene 1a (107 mg, 1.05 mmol), MeOH (3 mL), TMEDA (0.32 mL, 2.2 mmol), CCl4 (174 mg, 1.13 mmol), αcyclopropylstyrene (155 mg, 1.07 mmol) and CuCl (9 mg, 0.09 mmol), which were added at stirring by a magnetic stirrer.The reaction mixture was stirred for 1 day and then broken by 0.1 M of HCl (30 mL).The product was extracted by CH2Cl2 (3 × 10 mL); the organic phase was washed with water (10 mL) and dried over Na2SO4.Volatiles were evaporated in vacuo; the residue formed was purified by passing through a short silica gel pad of silica gel using gradient eluation by hexane, followed by hexane-CH2Cl2 mixture (3:1).White powder, yield 76 mg (72%).For NMR spectral data see above.Compound 6 was observed in the NMR spectra of crude product 2a.The yield of 6 was calculated by comparison with the amount of 2a in the 1H NMR of crude 2a.The NMR data of 6 are in agreement with those in the literature [14].

Funding:
The research was conducted in terms of the state contract of the chair of organic chemistry of Moscow State University, entitled "Synthesis and study of physical, chemical and biological properties of organic and organometallic compounds"-CITIC No-AAAA-A21-121012290046-4.

Data Availability Statement:
The data presented in this study are available in Supplementary Materials.

Figure 1 .Scheme 1 .
Figure 1.The use of the PHA-nitrogen base-CuCl system in the organic synthesis.