SYNTHESIS OF 2-PHENYLBUTYN-3-OLA-2 BASED ON ENANTIOSELECTIVE ALKYNYLATION OF ACETOPHENONE AND ITS CHEMICAL MODIFICATIONS

ABSTRACT

In this study, the synthesis of 2-phenylbut-3-yn-2-ol through the enantioselective alkynylation reaction of acetophenone in a 3,3′-Ph₂BINOL-2Li/Ti(OⁱPr)₄/Et₂Zn complex catalytic system was investigated, along with its oxidation-driven homolytic coupling and Sonogashira cross-coupling reactions with benzyl chloride. Various factors influencing the synthesis process and the yield of acetylene diol products have been systematically studied - temperature, reaction duration, nature of catalysts and solvents, amounts of reagents and substrates, types and amounts of intermediates and by-products formed in the reaction. Based on the results obtained, the most optimal conditions for the nucleophilic coupling process were determined and reaction mechanisms were proposed. The synthesized product have been identified, and their partial constants, structure, purity and composition have been proven using modern physicochemical methods.

АННОТАЦИЯ

В данной работе был исследован синтез 2-фенилбутин-3-ола-2 на основе реакции энантиоселективного алкинилирования ацетофенона в комплексной каталитической системе 3,3′-Ph₂BINOL-2Li/Ti(OⁱPr)₄/Et₂Zn, а также его окислительное гомолитическое сочетание и реакции кросс-сочетания Соногаширы с бензолхлоридом. Систематически изучены различные факторы, влияющие на процесс синтеза и выход продуктов - температура, продолжительность реакции, природа катализаторов и растворителей, количества реагентов и субстратов, виды и количества образующихся в реакции промежуточных и побочных продуктов. На основании полученных результатов определены наиболее оптимальные условия процесса нуклеофильного сочетания и предложены механизмы реакции. Идентифицированы синтезированные продукты, доказаны их собственные константы, структура, чистота и состав с помощью современных физико-химических методов исследования.

Keywords: acetylene alcohol, dimerization, сross-coupling reaction, reaction mechanism, product yield.

Kлючевые слова: ацетиленовые спирт, димеризации, реакция кросс-сочетания, механизм реакции, продукт.

INTRODUCTION

Comprehensive research is being conducted worldwide to develop methods for synthesizing hormones, vitamins, fungicides, demulsifiers, and inhibitors based on acetylene compounds. These studies focus on understanding the processes, examining the effects of various factors on product yield, applying new catalytic systems, implementing production technologies, and investigating the pharmacological, ecological, and biological properties of their targeted applications [1-4]. In this regard, leading contributions have been made by Italy, Russia, China, Japan, and Egypt in developing methods and production technologies for synthesizing acetylenic alcohols [5], their esters [6], alkoxides [7], diols [8], and diacetylenic diols [9], as well as studying their chemical transformations [11], activities [12], and broad applications in medicine, textiles, cosmetics, and agriculture [13-15].

In recent years, scientific research on the synthesis of terminal acetylenic alcohols and their derivatives using dual catalytic systems has been rapidly advancing [16]. For instance, Lin Pu and his research team have investigated the enantioselective alkynylation reactions of benzaldehyde and its derivatives with terminal alkynes using a complex catalytic system prepared with 1,1'-bi-2-naphthol ((S)-BINOL) and titanium tetraisopropoxide (Ti(OⁱPr)₄) as catalysts. Under room temperature conditions, after a 4-hour reaction time, acetylenic alcohols were synthesized with a minimum yield of 92% when using various solvents such as TGF, PhMe, or dichloromethane, and a maximum yield of 71-81% when using diethyl ether [17]. X.Fu carried out the alkyne reaction of N-benzylisatin with phenylacetylene in the presence of AgCl complex salts of N-heterocyclic carbenes and diisopropylethylamine as catalysts at a temperature of 40 °C for 120 minutes, resulting in the synthesis of 3-hydroxy-3-ethynylindolin-2-one with a yield of 98% [18-19]. The extract of the wild plant Launaea capitata (Spreng) was purified using column chromatography, and polyacetylene derivatives were obtained, including (3S, 8E)-deca-8-diyne-4,6-diol-1,3, (3S)-decatriene-4,6,8-diol-1,3, (3S)-(6E, 12E)-tetradecadien-8,10-diyne-1,3-diol, and (3S)-(6E, 12E)-tetradecadien-8,10-diyne-1-ol-3-O-β-D-glucopyranoside. These compounds were proposed as raw materials for the development of new inhibitors against enzymes [20]. Additionally, Erlotinib, a pharmacologically active compound known as an inhibitor targeting epidermal growth factor receptors in tumors of the lungs, stomach, kidneys, liver, and breast, was synthesized via the Sonogashira reaction from 3-bromoaniline and 2-methyl-3-butyne-2-ol [21.

RESEARCH METHODOLOGY

¹H and ¹³C NMR spectra were recorded on Bruker Avance (400 and 100.6 MHz, respectively) spectrometer at 20-25 ^oC in CDCl₃, acetone-d₆, C₆D₆, solution using the solvent line as an internal reference; IR specta of the synthesized compounds were recorded on The Thermo Scientific Nicolet iS50 FT-IR spectrometer (Raman module, USA). Progress of reactions and purity of the synthesized compounds were examined by means of TLC analysis on Merck Silica gel 60 GF₂₅₄ plates and visualization in UV light.

DISCUSSION AND RESULTS

Synthesis of 2-Phenylbut-3-yn-2-ol using the 3,3'-Ph₂BINOL-2Li/Ti(OⁱPr)₄/Et₂Zn Catalytic System. The reaction was carried out in a transparent, 2000 mL four-necked glass reactor equipped with a reflux condenser, dropping funnel, thermometer, and stirrer. Initially, at room temperature, a solution of 3,3ʹ-diphenylbinaphthol dilithium (3,3ʹ-Ph₂BINOL-2Li) (127 mg, 0.2 mmol) in 1 mL tetrahydrofuran (THF) was mixed with titanium tetra-isopropoxide (Ti(OⁱPr)₄) (426 μL, 1.5 mmol) and stirred for 15 minutes to prepare the catalytic system. To the reactor, a mixture of acetylene and diethylzinc (Et₂Zn, 2 M in toluene) was added dropwise over 15 minutes while maintaining the temperature at -10 °C and stirring continuously. Then, a solution of acetophenone (120 mg, 1 mmol) was added to the reactor using a dropping funnel over 15 minutes at -10 °C, with constant stirring. The reactor temperature was controlled using liquid nitrogen. After all the components (substrate, reagent, catalyst, and solvent) were added, the mixture was stirred at -10 °C for 90 minutes.

The reaction mixture was then hydrolyzed with water (3×100 mL), and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate (2×5 mL). The organic layer was dried over Na₂SO₄. The THF solvent was evaporated under normal conditions, and the remaining product was purified using silica gel 60 column chromatography with a 20% ethyl acetate-hexane eluent. As a result, 2-phenylbut-3-yn-2-ol (1) was obtained with a 94% yield (206 mg).

The reaction scheme and mechanism were proposed as follows, based on the literature sources [22-23]:

Initially, in the process, titanium tetra-isopropoxide (Ti(OⁱPr)₄) and 3,3ʹ-Ph₂BINOL-2Li interact in a tetrahydrofuran (THF) solution to form a stable catalytic component that retains its activity over time. During this interaction, two isopropoxide radicals from Ti(OⁱPr)₄ react with two lithium atoms from 3,3ʹ-Ph₂BINOL-2Li, producing two molecules of lithium isopropoxide and forming a catalytically active complex system consisting of 3,3ʹ-Ph₂BINOL and Ti(OⁱPr)₂. Under the influence of diethylzinc (Et₂Zn), a π-complex initially forms with the acetylene molecule. The THF solvent solvates the carbocation from the diethylzinc molecule, facilitating the cleavage of the σ-bond between the sp-hybridized carbon and the mobile hydrogen in acetylene. This results in the formation of ethane in the system. The zinc ethyl carbocation reacts with the deprotonated acetylene anion to generate a zinc acetylide intermediate. This intermediate, under the catalytic influence of the complex system comprising 3,3ʹ-Ph₂BINOL and Ti(OⁱPr)₂, performs a nucleophilic attack on the carbonyl carbon of acetophenone, producing a highly modified intermediate component. Within the catalytic complex, the electron density of zinc shifts toward the highly electronegative oxygen atom, enhancing the concentration of acetylene anions in the system. This increase in anion concentration accelerates the reaction. In the final step, the π-bond of the carbonyl group in the substrate breaks, causing the sp²-hybridized carbon to transition to sp³ hybridization. A new C‒C bond forms, yielding the initial intermediate zinc ethyl alkoxide of 2-phenylbut-3-yn-2-ol, which subsequently undergoes hydrolysis to produce the final product, 2-phenylbut-3-yn-2-ol. It was determined that the greater the amount of the intermediate component formed, the higher the efficiency of product formation, directly contributing to the reaction's success [24].

Various factors such as temperature, reaction duration, solvent nature, and the initial amount of starting materials were analyzed in a systematic manner to understand their influence on the process of synthesizing 2-phenylbutyn-3-ola-2 using complex catalytic systems. The importance of catalysts employed to enhance product yield and reaction efficiency was investigated. According to the study, the nucleophilic addition reaction of acetylene to acetophenone was optimized using the following conditions: the reaction was carried out in tetrahydrofuran (THF) solvent for 120 minutes at a temperature of -10 °C. The initial molar ratio of reactants (acetylene:acetophenone) was maintained at 1.5:1, and the molar ratios of the catalytic components 3,3ʹ-Ph₂BINOL-2Li, Ti(OⁱPr)₄, and Et₂Zn were 0.2:1.5:1.2, respectively. Under these conditions, the yield of 2-phenylbut-3-yn-2-ol was maximized at 94%.The structure of 2-phenylbut-3-yn-2-ol was confirmed using ¹H NMR and ¹³C NMR spectroscopy methods: ¹H NMR: δ 7.69-7.67 (m, 2H, 2CH), 7.41-7.37 (m, 2H, 2CH), 7.34-7.31 (m, 1H, CH), 2.69 (s, 1H, C≡CH), 2.43 (s, 1H, OH), 1.80 (s, 3H, CH₃). ¹³C NMR: δ 144.6, 128.0, 127.5, 124.4, 86.8, 72.7, 69.4, 32.7.

To investigate the chemical properties of 2-phenylbutyn-3-ol-2, its dimerization and cross-coupling reactions with benzyl chloride were studied.

Synthesis of 2,7-diphenyloctadiyne-3,5-diol-2,7 in the CuCl/TMEDA/CCl₄ catalytic system. In a thermally stable five-neck flask, an emulsion of 2-phenylbutyn-3-ol-2 and TMEDA was prepared in equimolar ratio for 60 minutes. Then, a suspension of 120 ml CuCl in methanol was added to this emulsion and mixed for 60 minutes. At a temperature of 20 °C, 2 moles of tetrachloromethane were added to the solution in the flask, which was stirred for 11 hours and allowed to stand for 24 hours. The solvent (MeOH) in the settled mixture was evaporated under ordinary conditions, and the organic and inorganic components were dissolved in 300 ml of water, which was then extracted with 300 ml of dichloromethane (3×200 ml). The organic layer was dried over Na₂SO₄. The solvent was evaporated under vacuum, and the remaining product was subjected to column chromatography on silica gel 60 using various eluents (CH₂Cl₂:MeOH 100:1, 30:1). As a result, 148 g of 2,7-diphenyloctadiyne-3,5-diol-2,7 (51%) was synthesized.

The general scheme of the coupling reaction was proposed based on literature sources as follows[25].

The effects of the nature and quantity of the catalyst, reagent, and substrate, as well as temperature and reaction duration on the yield and selectivity of 2,7-diphenyloctadiyne-3,5-diol-2,7 were systematically analyzed. Initially, the influence of aprotic solvent- tetrahydrofuran (THF) and protic solvents- methanol (MeOH) and ethanol (EtOH)- on the yield of the product was studied (Table 1).

Table 1.

Effect of the nature of catalysts and solvents on the yield of 2,7-diphenyloctadiyne-3,5-diol-2,7
(ligand TMEDA, temperature 20 °C, reaction duration 12 hours)

In protic solvents, the high degree of dissociation of the reagents allowed for maximum ion collisions. As seen in the table, higher efficiency in the synthesis of diynols was achieved in methanol (MeOH), which has a higher dielectric constant and dipole moment compared to ethanol (EtOH).

When the reaction was conducted in CuCl, 2,7-diphenyloctadiyne-3,5-diol-2,7 exhibited the highest selectivity with a yield of 51%. It is known that in halides, the core charge and electronegativity of copper (I) increase from iodine to fluorine; however, due to the high reactivity of fluorine, copper (I) fluoride cannot exist in a stable state and quickly transitions to copper (II) fluoride. Therefore, copper (I) chloride demonstrated higher catalytic activity compared to other catalysts in the reaction.

The dimerization process was carried out over an interval of 6 to 18 hours, with maximum yield observed at 12 hours. However, extending the reaction duration led to a decrease in the yield of 2,7-diphenyloctadiyne-3,5-diol-2,7 due to the dehydration and polymerization of the dimer products formed in the system, resulting in the formation of polyacetylene compounds as additional products.

Based on experimental results and theoretical principles, the most favorable conditions for synthesizing 2,7-diphenyloctadiyne-3,5-diol-2,7 were selected as conducting the reaction in a methanol solution, using the CuCl/TMEDA/CCl₄ catalytic system at a temperature of 20 °C for 12 hours, which yielded the highest product (51%). The structure of the obtained product was confirmed using 1H NMR and ¹³C NMR spectroscopy methods: ¹H NMR: d 1.82 (s, 6H, 2CH₃), 2.51 (s, 2H, 2OH), 7.34-7.37 (m, 2H, 2CH), 7.40-7.44 (m, 4H, 4CH), 7.66-7.69 (m, 4H, 4CH). ¹³C NMR: δ 32.6, 64.8, 67.8, 74.3, 124.6, 128.9, 144.9.

Synthesis of 2,4-diphenylbutyne-3-ol-2 in the Pd(OAc)₂/CuCl/Et₃N/MeCN/H₂O catalytic system. The Sonogashira cross-coupling reaction was carried out in a 500 ml five-neck flask. A dropping funnel, mechanical stirrer, thermometer, and reflux condenser were installed on the flask. Initially, 21.9 g (0.15 mol) of 2-phenylbutyne-3-ol-2 and 0.10 g (0.01 mol) of CuCl were added to the flask. Then, a suspension of 2.24 g (0.01 mol) of palladium(II) acetate (Pd(OAc)₂) prepared with 15 ml of MeCN and 5 ml of H₂O (in a 3:1 ratio) was added while stirring. The temperature in the flask was maintained at 30-40 °C.

To the resulting mixture, a suspension containing 11.25 g (0.10 mol) of chlorobenzene (C₆H₅Cl) and 20 g (0.2 mol, 15 ml) of triethylamine was added dropwise over 30 minutes. The mixture was then stirred at 40 °C for 7.5 hours. The resulting reaction product was allowed to stand for 30 minutes.

Next, hydrolysis was performed using 75 ml (3×25 ml) of cold water to separate the catalytic portion, and the remaining organic phase was extracted repeatedly with 60 ml (3×20 ml) of dichloromethane. The organic phase was dried with CaCl₂ for one day, filtered, and the solvent was evaporated under normal conditions, with the remaining part evaporated under vacuum. The reaction products were purified by silica gel 60 column chromatography using AcOEt/hexane (1:4) as the eluent, the R_f value was determined, and the product was isolated in pure form. As a result, 25.6 g of 2,4-diphenylbutyne-3-ol-2 was synthesized with a yield of (3-77%).

The reaction scheme was proposed as follows [26].

When the reaction was conducted at 40 °C for 8 hours in the CuCl/Pd(OAc)₂/Et₃N catalytic system, a high yield of 2,4-diphenylbutyne-3-ol-2 was observed. The reaction processes indicated that when the reaction was carried out at a temperature of 20 °C, the complete dissociation of molecules into ions did not occur, resulting in the starting reagents remaining almost unreacted, as confirmed by thin-layer chromatography.When the temperature was increased to 60 °C, the selected palladium(II) acetate reacted with the starting reagents to form additional products. The aromatic acetylene alcohols reacted with each other to form diynols, and the polymerization led to the appearance of resinous by-products, significantly decreasing the yield of the product.

When the reaction duration was increased to 10 hours, the formation of complex alcohols, polyacetylene alcohol, enynediol, and resinous by-products resulted in a decrease in product yield. For example, the interaction of 2,4-diphenylbutyne-3-ol-2 led to the formation of an additional product, 1,1'-(1-buten-3-diyl)discyclohexanol-1, which contributed to the reduction of the yield of the main product.

The effect of the selected catalyst amount on the yield of 2,4-diphenylbutyne-3-ol-2 was investigated (Figure 1). It was found that when 0.005 mol of the catalyst was used, the low yield of the product could be attributed to the limited formation of catalytic active centers and the high activation energy of the reaction. When 0.01 mol of the catalyst was used, the highest yield was achieved; however, further increasing the catalyst amount led to a decrease in reaction selectivity. It is noteworthy that increasing the catalyst amount resulted in additional reactions in the system, meaning that 2,4-diphenylbutyne-3-ol-2 interacted with excess catalysts to form alcohols, as well as converting into polymer products, as determined by the analysis results.

Figure 1. Effect of catalyst amount on the yield of 2,4-diphenylbutyne-3-ol-2 (Temperature 40 °C, solvent MeCN, reaction duration 8 hours,
2-phenylbutyne-3-ol-2:chlorobenzene in a molar ratio of 1.5:1)

According to the results of the conducted research, the selected terminal acetylene alcohols were synthesized through the Sonogashira coupling reaction with chlorobenzene using the CuCl/Pd(OAc)₂/Et₃N catalytic system (in equimolar ratios of CuCl:Pd(OAc)₂:Et₃N) in an MeCN solution at 40 °C for 8 hours, yielding the highest amount of 2,4-diphenylbutyne-3-ol-2 (77%), which was chosen as the optimal condition for the process.

The structure of 2,4-diphenylbutyne-3-ol-2 was confirmed by spectroscopic methods: 1H NMR: δ 7.90-7.80 (m, 2H), 7.74-7.72 (m, 2H), 7.47-7.46 (m, 2H), 7.40-7.24 (m, 4H), 2.53 (s, 1H), 1.87 (s, 3H). ¹³C NMR: δ 145.7, 131.7, 128.5, 128.4, 128.3, 127.7, 125.0, 122.6, 92.5, 84.9, 70.4, 33.3.

The composition of the synthesized compounds was confirmed by elemental analysis methods, their physical properties were determined using various modern physicochemical research techniques, and kinetic changes, spatial structures of the molecules, distribution of charges and electron density in the molecules, as well as quantum-chemical parameters were calculated using modern software.

Table 2.

Some physical properties of the synthesized compounds

Table 3.

Quantum-chemical calculations of the synthesized acetylene alcohols

CONCLUSION AND RECOMMENDATIONS

A method for synthesizing terminal acetylene alcohol 2-phenylbutyne-3-ol-2 was developed based on the nucleophilic coupling reaction of acetophenone with acetylene using the complex catalytic system 3,3′-Ph₂BINOL-2Li/Ti(OⁱPr)₄/Et₂Zn. Alternative conditions for the process were found, the reaction mechanism was proposed, and the obtained products were identified.

The synthesis of diacetylene diol 2,7-diphenyloctadiyne-3,5-diol-2,7 was carried out through homolytic coupling reactions of terminal acetylene alcohols based on oxidation using the CuCl/TMEDA/CCl₄/MeOH catalytic system. Factors affecting product yield were systematically analyzed, and its purity was confirmed by chromatographic and spectroscopic methods.

For the first time, the synthesis of internal 2,4-diphenylbutyne-3-ol-2 was studied based on the cross-coupling reaction of 2-phenylbutyne-3-ol-2 with benzyl chloride using the complex catalytic system Pd(OAc)₂/CuCl/Et₃N/MeCN/H₂O. The reaction mechanism was clarified, and the stages and mechanisms of the reaction were proposed. The purity, structure, and composition of the synthesized product were confirmed using modern physicochemical research methods, and its specific constants, as well as energetic and quantum-chemical parameters, were calculated.

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