8,13-Dimethylicosa-9,11-diyne-8,13-diol

Sarvinoz I. Tirkasheva; Odiljon E. Ziyadullaev; Vasiliy M. Muzalevskiy; Askar B. Parmanov

doi:10.3390/M1484

,

and

¹

Department of Chemistry, Chirchik State Pedagogical University, A.Temur, 104, Chirchik 111700, Uzbekistan

²

Department of Organic Chemistry, Moscow State University, Leninskiye Gory, 1, Moscow 119991, Russia

³

Department of General and Oil-Gas Chemistry, National University of Uzbekistan, University Street, 4, Almazar District, Tashkent 100174, Uzbekistan

^*

Author to whom correspondence should be addressed.

Molbank2022, 2022(4), M1484;https://doi.org/10.3390/M1484

This article belongs to the Topic Catalysis: Homogeneous and Heterogeneous

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Abstract

The protocol, 3-methyldec-1-yn-3-ol (1a) was chosen to perform the dimerization process. The optimal conditions for synthesis of 8,13-dimethylicosa-9,11-diyne-8,13 (2a) with high efficiency when using copper-catalyzed, N,N,N′N′-tetramethylethylenediamine as a ligand and CCl₄ and methanol solvents in atmospheric pressure were determined. The structure of the obtained compound was proved by IR, ¹H-NMR and ¹³C-NMR spectroscopy.

Keywords:

terminal acetylene alcohol; diacetylene diol; dimerization; oxidative homocoupling reaction; copper (I) chloride

1. Introduction

Recently, the attention of chemists, technologists and pharmacologists has focused on the elaboration and implementation of new drugs with effective pharmacological effects [1]. In this regard, diacetylene diols and their derivatives were attributed to biologically active organic compounds with pharmacological properties, such as anti-cancer [2,3], anti-bacterial [4], anti-HIV [5], anti-fungal [6] and anti-inflammatory [7,8,9,10]. Moreover, when the pharmacology of mono and diacetylene diol derivatives, including panaxynol, panoxydol, panaxydolcglorohydrin, 1,8-heptadecadiene-4,6-diyne-3,10-diol, panaxytriol and dihydropanaxacol, was studied, some of them were used for the treatment of alopecia (a disease with hair loss) due to their hair growth properties [11]. It was found that heptadeca-8,16-diene-4,6-diyne-3,10-diol extracted from the plant Aralia dumetorum possesses inhibitory properties against harmful toxins [12].

Glaser first synthesized 1,4-diphenylbuta-1,3-diyne from phenylacetylene through the dimerization reaction in the presence of copper (I) chloride and oxygen [13]. J.S. Yadav and his team synthesized 1,4-diphenyl-1,3-butadiene with 95% yield from phenylacetylene based on oxidative homocoupling–dimerization reactions 1-butyl-3-methylimidazolium hexafluorophosphate (bmim-PF₆) and 1-butyl-3-methylimidazolium tetrafluoroborate (bmim-BF₄) in the presence of copper (I) chloride (0.2 mol%), TMEDA (0.2 mol%) in oxygen atmosphere [14]. Yun Lia, Reza Fathi and others succeeded in synthesizing symmetrical bis-benzo[b]furan-linked 1,3-diyne through homocoupling of three bonds using the new catalytic system AgOTs−CuCl₂−TMEDA. It was also observed for the first time that the reaction rate of the oxidative acetylenic homocoupling process based on activated Ag (I) cation with triple bond and Cu (II) cation was very high, the product was obtained with a yield of 70–90% and the reaction mechanism was proposed [15]. Several derivatives of 1,3-diynes, such as 1,4-dip-tolylbuta-1,3-diyne, 1,4-diphenylbuta-1,3-diyne, 1,4-bis(4-trifluoromethyl)phenyl)buta-1,3-diyne, 1,4-bis(4-(trifluoromethyl) phenyl)buta-1,3-diyne, 1,4-bis(4-methoxyphenyl)buta-1,3-diyne, 1-(cyclohex-3-enyl)-4-cyclohexenylbuta-1,3-diyne, 1,1′-buta-1,3-diyne-1,4-diyldicyclohexanol, hexadeca-7,9-diyne and dodeca-5,7-diynedinitrile (produced with 78-87% yields) were synthesized when the oxidative homocoupling reaction was carried out in the presence of catalyst Pd(OAc)₂ or PdCl₂(PPh₃)₂ and 1-(2-pyridylethynyl)-2-(2-thienylethynyl)benzene as a ligand and solvent NEt₃ [16]. Diacetylene diols such as octa-3,5-diyne-1,8-diol and 2,7-dimethyl-3,5-octadiyne-2,7-diol were efficiently formed when the homocoupling reaction was carried out from terminal acetylene alcohols using the Cu(OAc)₂/MgAl–LDH/TMEDA/CH₃CN catalytic system [17]. Piperidine, Bu₃N, Bu₂NH and several solvents (toluene, 1,4-dioxane, Cl₂CHCHCl₂, DMSO and DMF) were studied as various additives to increase the catalytic activity to obtain with high yield in the dimerization reaction of heptin-1 in the presence of the CuCl catalyst. Tetradeca-6,8-diyne was synthesized with high yield when the process was carried out at 60 °C in a 2:10 mol ratio of toluene solvent and CuCl:piperidine, respectively [18].

2. Results and Discussion

In this work, the dimerization reaction of terminal acetylene alcohol 3-methyldec-1-yn-3-ol (1a) was carried out for the first time. Alternative conditions for the synthesis of 8,13-dimethylicosa-9,11-diyne-8,13-diol (2a) containing two triple bonds and two hydroxy (-OH) groups were analyzed. Synthesis of 2a was carried out through the dimerization reaction of terminal acetylene alcohol as 1a in the presence of CuCl/TMEDA/CCl₄/MeOH catalytic system. The reaction scheme is given below (Scheme 1).

Scheme 1. Synthesis of 2a.

The dimerization process was studied at of 20–30 °C with CuCl, CuJ and CuBr (1.0 mmol) catalysts in TMEDA (N,N,N′N′-tetramethylethylenediamine) (2.0 mmol), CCl₄ in various solvents—MeCN, THF, CH₂OHCH₂OH, iPrOH, ethanol and methanol (Table 1).

Table 1. Optimization of catalyst and solvent effect.

When the process was carried out for 8 h in the catalytic system CuCl/TMEDA/MeCN/CCl₄, a very small amount of the product was formed on entry. 2a was obtained with low yield of 42 and 27%, respectively, when the process was carried out in THF or ethylene glycol with CCl₄ for 10 h, and this increase in the time did not affect the yield (2–3 entries). The effects of CCl₄ solvents with iPrOH or EtOH were studied; 2a gave moderate yields (4–5 entries). In MeOH/CCl₄ for 12 h, 2a gave the best yield of 82% (six entries) compared to the others. However, in MeOH/CCl₄ without addition of this catalytic system, a very small amount of 2a was obtained (seven entries). Additionally, when CuJ or CuBr (1 mmol) were used instead of CuCl, a decrease in the yield of 2a was observed (8–9 entries). Based on the research, it was concluded that CuCl has high catalytic activity compared to CuJ and CuBr and based on the oxidative homocoupling reaction of 1a, the most alternative conditions for the synthesis of 2a were determined to be the process: the CuCl/TMEDA/CCl₄/MeOH catalytic system and time 12 h.

The structure of 2a obtained by the dimerization reaction of acetylene alcohols was confirmed by spectroscopic methods. (¹H, ¹³C-NMR and IR; see also Supplementary Materials). In particular, the chemical shift region of 2.41 ppm in the ¹H-NMR spectrum of the starting product 1a (Figure S1), the loss of this singlet was observed in the ¹H-NMR spectrum of 2a (Figure S3).

3. Materials and Methods

3.1. General

The major chemicals, such as copper (I) chloride, copper (I) iodide, copper (I) bromide, TMEDA (N,N,N′N′-tetramethylethylenediamine), tetrachloromethane, tetrahydrofuran, acetonitrile, ethylene glycol, ethanol and methanol, were purchased from Qingdao Sigma Chemical Co., Ltd. (Qingdao, China). First, 1a [19] was synthesized according to the literature procedures and its structure was proved by the ¹H and ¹³C-NMR spectra. All reagents were used at reagent grade or used after distillation. Additionally, solvents were dried by standard methods before use. All reactions were carried out by stirring in the magnetic stirrer under atmospheric air condition, and the reaction progress was the identity of the synthesized compounds controlled by TLC analysis, which was performed on Merck Silica gel 60 GF₂₅₄ plates. Column chromatography was performed on silica gel and visualization in UV light. IR spectra of the synthesized compounds were recorded on The Thermo Scientific Nicolet iS50 FT-IR spectrometer, (Raman module, Waltham, MA, USA); ¹H and ¹³C-NMR spectra were recorded on Bruker Avance (400.1 and 100.6 MHz, respectively) spectrometer at 20–25 °C in CDCl₃, solution using the solvent line as an internal reference. Multiplicities are marked as s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet.

3.2. Synthesis of 2a

A one-necked 50 mL round-bottom flask (or 12 mL vial) was charged with 1a (1.0 mmol, 0.168 g), TMEDA (2 mmol, 0.255 g), CuCl (1.0 mmol) in MeOH (2 mL) in atmospheric air conditions. The reaction mixture was kept at 20–30 °C under stirring for 30 min using an ultrasonic irradiation bath. CCl₄ 0.2 mL was added slowly and mixed for 12 h on the magnetic stirrer. Volatiles were evaporated in vacuo, and the residue was purified by column chromatography using appropriate mixtures of hexane and CH₂Cl₂ (3:1 followed by 1:1 and 0:1) as eluents. Slightly brown oil, yield 0.274 g (82%). ¹H-NMR (400.1 MHz, CDCl₃): 2.02 (s, 2H, 2OH), 1.71–1.59 (m, 4H, 2CH₂), 1.52–1.40 (m, 10H, 2CH₂, 2CH₃), 1.34–1.21 (m, 16H, 8CH₂), 0.87 (t, 6H, 2CH₃, J = 6.9 Hz); ¹³C-NMR (100.6 MHz, CDCl₃): δ 83.2, 68.7, 67.4, 43.5, 31.8, 29.6, 29.5, 29.2, 24.6, 22.6, 14.1. IR: 3367 sm⁻¹ (−OH), 2954–2855 sm⁻¹ (–CH₂), 2216 sm⁻¹ and 2046 sm⁻¹ (−1≡C−), 1458–1370 sm⁻¹ (–CH₂), 1307-1253 sm⁻¹ (–CH₂), 1220–1098 sm⁻¹ (C−O−H), 1016–733 sm⁻¹ (–CH₂). HRMS (ESI-TOF): m/z [M − H]⁺ Calcd for C₂₂H₃₇O⁺: 317.2839; found: 317.2848.

4. Conclusions

For the first time, the dimerization reaction of acetylene alcohol 1a was carried out in the CuCl/TMEDA/CCl₄/MeOH catalytic system. 8,13-Dimethylicosa-9,11-diene-8,13-diol was synthesized with 82% yield. Alternative conditions for the dimerization reaction were determined by studying the effects of copper (I) halides, N,N,N′N′-tetramethylethylenediamine and solvents.

Supplementary Materials

The following supporting information for the characterization of 1a and 2a can be downloaded online: Synthesis and reaction scheme of 1a and 2a (Scheme S1: Synthesis of 3-methyldec-1-yn-3-ol). Figure S1: ¹H-NMR spectrum of 1a (400 MHz, CDCl₃); Figure S2: ¹³C-NMR spectrum of 1a (101 MHz, CDCl₃); Figure S3: ¹H-NMR spectrum of 2a (400.1 MHz, CDCl₃); Figure S4: ¹³C-NMR spectrum of 2a (100.6 MHz, CDCl₃); Figure S5: IR spectrum of 2a (The Thermo Scientific Nicolet iS50 FT-IR spectrome-ter, Raman module, Waltham, MA, USA).

Author Contributions

Conceptualization, O.E.Z. and V.M.M.; methodology, V.M.M. and S.I.T.; validation, V.M.M., O.E.Z. and S.I.T.; formal analysis, V.M.M., O.E.Z. and S.I.T.; investigation, V.M.M.; resources, V.M.M.; data curation, S.I.T.; writing—original draft preparation, O.E.Z., S.I.T. and A.B.P.; writing—review and editing, O.E.Z., S.I.T. and A.B.P.; supervision, O.E.Z.; project administration, O.E.Z. and V.M.M.; funding acquisition, S.I.T. All authors have read and agreed to the published version of the manuscript.

Funding

The authors thank the National Governmental Foundation “EL-YURT UMIDI” of Uzbekistan for their financial support.

Data Availability Statement

Not applicable.

Acknowledgments

The authors thank the Department of Organic Chemistry of Moscow State University in Russian Federation and Chirchik State Pedagogical University in Uzbekistan Republic for their technological support.

Conflicts of Interest

The authors declare no conflict of interest.

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