SYNTHESIS OF ACETYLENE ALCOHOL IN ZINC-BASED COMPLEX CATALYTIC SYSTEM

ABSTRACT

In order to synthesize acetylenic alcohols based on various benzaldehyde derivatives, the process of their alkynylation was carried out. p-trifluoromethyl benzaldehyde was chosen as the object of study and its alkynylation reaction with phenylacetylene was carried out in a complex catalytic system based on zinc. Based on the reaction of p-trifluoromethyl benzaldehyde alkynylation, the target acetylenic alcohol was synthesized. In particular, 3-phenyl-1-[4-(trifluoromethyl) phenyl] prop-2-yn-1-ol (3a) was first synthesized in high yield (70%) as a result of the alkynylation reaction of chosen p-trifluoromethyl benzaldehyde (2a) in the presence of phenylacetylene (1a). Zn (OTf)₂/TBAF·3H₂O/NEt₃/MeCN was used as a catalytic system. The structure of the synthesized product was proved by ¹H-NMR, ¹³C-NMR spectroscopic method.

АННОТАЦИЯ

C целью синтеза ацетиленовых спиртов на основе различных производных бензальдегида был проведен процесс их алкинилирования. В качестве объекта исследования был выбран п-трифторметилбензальдегид и проведена реакция его алкинилирования фенилацетиленом в комплексной каталитической системе на основе цинка. На основе реакции алкинилирования п-трифторметилбензальдегида синтезирован целевой ацетиленовый спирт. В частности, 3-фенил-1-[4-(трифторметил)фенил]проп-2-ин-1-ол (3a) был впервые синтезирован с высоким выходом (70%) в результате реакции алкинилирования выбранного п-трифторметилбензальдегида (2a) в присутствии фенилацетилена (1a). Zn(OTf)₂/TBAF·3H₂O/NEt₃/MeCN использовался в качестве каталитической системы. Структура синтезированного продукта была доказана методом спектроскопии ¹H-ЯМР, ¹³C-ЯМР.

Keywords: p-trifluoromethylbenzaldehyde, alkynylation, zinc trifluoromethylsulfonate, tetrabutylammonium fluoride, triethylamine.

Ключевые слова: п-трифторметилбензальдегид, алкинилирование, трифторметилсульфонат цинка, фторид тетрабутиламмония, триэтиламин.

Introduction. Acetylene alcohols serve as an important basis for the production of drugs against various diseases observed in the human body. For example, acetylene alcohols are important intermediates for the production of drugs (zeaxanthin [1], canthaxanthin [2] and astaxanthin [3] and vitamin A [4]) that serve to treat and improve the human immune system, mental capacity, reproduction, and many other properties [5]. Usually, various catalytic systems are used to synthesize acetylene alcohols with high biological activity in high yields. At the beginning of the 20^th century, Favorsky [6], in this field, carried out the reaction of obtaining acetylene alcohols by alkynylation of carbonyl compounds [7-9]. This reaction is usually carried out using the Greenyard method or in the presence of a base [10]. The process originally involved the reaction of acetylene with lithium, sodium, potassium, or lithium-organic compounds in Greenyard’s reagent or liquid ammonia [11]. The resulting acetylide reacts with a ketone to give tertiary acetylene alcohol. In these reactions, acetylenic alcohols are formed in high yield on the basis of selected substituted derivatives of aldehydes and ketones [12-13]. In the direction of synthesizing acetylene alcohols, scientists from Lanzhou University found that terminal aromatic alkynes can be easily added to various aromatic aldehydes in the presence of lithium tert-butoxy reagent, and the reaction was carried out with 1.0 equiv. benzaldehyde, 2.0 equiv. ^tBuOLi and 1.2 equiv. in anhydrous dimethylformamide (DMF) in the presence of phenylacetylene for 50 min at room temperature. As a result, the expected acetylene alcohols were synthesized in high yields [14].

Materials and methods. The main substrates and reagents, including phenylacetylene, p-trifluoromethyl benzaldehyde, zinc trifluoromethyl sulfonate, tetrabutylammonium fluoride, triethylamine, toluene, acetonitrile, dimethyl sulfoxides, are commercially available from Qingdao Sigma Chemical Co., Ltd. (Qingdao, China) was purchased from the company. The chemical compounds used were used in pure form or after distillation, and the solvents were dried before use according to standard procedures. The identification of the synthesized compound was monitored by TLC (on Merck Silica gel 60 GF₂₅₄ plates) and the substances in the reaction mixture were detected by chromatographic columns under ultraviolet light. Spectroscopic analysis of ¹Н- NMR, ¹³С- NMR was performed on a Bruker Avance spectrometer (400.1 and 100.6 MHz, respectively) in CDCl₃ solvent at a temperature of 20–25 °C.

Synthesis of 3а. In the Zn (OTf)₂/TBAF·3H₂O/NEt₃/MeCN catalytic system, the alkynylation reaction of p-trifluoromethyl benzaldehyde in the presence of phenylacetylene was carried out as follows: the alkynylation reaction was carried out at temperatures from 0 to -20 °C. Initially, Zn (OTf)₂ catalyst (0.025 mol), TBAF·3N₂O (0.025 mol) and MeCN solvent (0.75 mL) were mixed for 60 minutes to prepare a suspension. Then a solution of phenylacetylene (1a) (11.2 mL, 0.1 mol) and Et₃N (7 mL) in a total volume of 18 mL, Et₃N (7 mL) in a total volume of 12 mL and p-trifluoromethyl benzaldehyde (2a) (5 mL (0.05 mol) solution was added dropwise over 30 minutes. Hydroquinone was added to the suspension before the introduction of the initial reagents into the system in order to avoid polymerization of 3a, intermediates and additives and 1a formed in the system. The temperature in the reactor was controlled with liquid nitrogen. The substrate, reactant, catalyst and solvent component was stirred continuously for 30 minutes at -10 °C. The resulting mixture was kept for 6 h, and then three times (3×25 mL) was extracted with diethyl ether. The extracted reaction was first stripped of solvents and then fractionated by vacuum extraction. In particular, 3a was isolated and synthesized in 70% yield [15]. 3а: obtained from 2a, yellow oil, R_f (CH₂Cl₂) =0.59. ¹H- NMR (CDCl₃, 400.1 MHz): δ 7.71 (d, 2H, Ar), 7.63 (d, 2Н, Ar), 7.48-7.46 (m, 2H, Ar), 7.38-7.30 (m, 3H, Ar), 5.74 (s, ¹H, CH-O), 3.47 (s, 1H, OH). ¹³C- NMR (CDCl₃, 100.6 MHz): δ 144.2 (C), 131.6 (CH), 130.3 (q, C), 128.8 (CH), 128.3 (CH), 126.8 (CH), 125.5 (q, CH), 124.1 (q, CF₃), 121.9 (C), 87.9 (C≡C), 87.1 (C≡C), 64.1 (CH). ¹⁹F- NMR (CDCl₃, 376.5 MHz): δ 63.5.

Results and discussion. In this work, the alkynylation reaction of p-trifluoromethyl benzaldehyde (2a) with phenylacetylene (1a) was carried out in the first developed Zn (OTf)₂/TBAF·3H₂O/NEt₃/MeCN catalytic system. The most optimal conditions for the alkynylation reaction of selected p-trifluoromethyl benzaldehyde in the presence of phenylacetylene were determined. As a result, the expected 3-phenyl-1-[4-(trifluoromethyl) phenyl] prop-2-yn-1-ol (3a) acetylenic alcohol was synthesized in high yield based on the alkynylation reaction involving phenylacetylene. The reaction scheme is as follows (Scheme 1).

Scheme 1. Synthesis of 3а

The main substrates and reagents, including phenylacetylene, p-trifluoromethyl benzaldehyde, zinc trifluoromethyl sulfonate, tetrabutylammonium fluoride, triethylamine, toluene, acetonitrile, dimethyl sulfoxides, are commercially available from Qingdao Sigma Chemical Co., Ltd. (Qingdao, China) was purchased from the company. The chemical compounds used were used in pure form or after distillation, and the solvents were dried before use according to standard procedures. The identification of the synthesized compound was monitored by TLC (on Merck Silica gel 60 GF₂₅₄ plates) and the substances in the reaction mixture were detected by chromatographic columns under ultraviolet light. Spectroscopic analysis of ¹Н- NMR, ¹³С- NMR was performed on a Bruker Avance spectrometer (400.1 and 100.6 MHz, respectively) in CDCl₃ solvent at a temperature of 20-25 °C.

Conclusion. The alkynylation reaction 2а was carried out in the presence of 1а in the Zn (OTf)₂/TBAF 3H₂O/NEt₃/MeCN catalytic system developed for the first time, and 3-phenyl-1-[4-(trifluoromethyl) phenyl] prop-2-yn-1-ol wаs synthesized with 70% yield. The chemical structure of the synthesized compound has been proven by modern physicochemical spectroscopic methods (¹H-NMR, ¹³C-NMR).

Acknowledgments. The authors thank the University of Economics and Pedagogy.

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