ALKYNYLATION REACTIONS OF SOME HETEROATOMIC ALDEHYDES IN THE PRESENCE OF PHENYLACETYLENE

ABSTRACT

In this work, a new type of acetylene alcohols has been synthesized based on the alkylation reaction of some heteroatomic aldehydes with phenylacetylene in the catalytic system of profenol and dimethyl zinc. The molar ratios effect of the initial and catalytic systems on the product yield was systematically analyzed. The biological activity of acetylene alcohols has been studied. The composition, purity and structure of synthesized acetylene alcohols have been confirmed by modern physico-chemical methods. The effect of reaction duration, temperature, amount of reagents and substrates, solvents and catalytic ligands on the yield of products was systematically studied.

АННОТАЦИЯ

В данной работе синтезирован новый тип ацетиленовых спиртов на основе реакции алкинилирования некоторых гетероатомных альдегидов фенилацетиленом в каталитической системе профенола и диметилцинка. Систематически анализировали влияние мольных соотношений исходной и каталитической систем на выход продукта. Изучена биологическая активность ацетиленовых спиртов. Состав, чистота и строение синтезированных ацетиленовых спиртов подтверждены современными физико-химическими методами. Систематически было изучено влияние продолжительности реакции, температуры, количество реагентов и субстратов, растворителей и каталитических лигандов на выход продуктов.

Keywords: phenylacetylene, aldehydes, acetylene alcohols, catalytic system, product yield, biological property, prophenol, dimethylzinc.

Ключевые слова: фенилацетилен, альдегиды, ацетиленовые спирты, каталитическая система, выход продукта, биологическое свойство, профенол, диметилцинк.

At present, acetylene alcohols are one of the main sources in the synthesis of organic compounds [1]. The main acetylene alcohols synthesis method is the asymmetric addition of aldehydes to metal alkynes [2]. Propargyl alcohols were synthesized in high yield by Chinese scientists based on the reaction of carbonyl compounds with acetylene in the presence of ZnCl₂ and Et₃N [3]. The enantioselective addition of terminal acetylene and aldehydes to Zn(OTf)₂ and N-methylephedrine in a solvent containing H₂O at 84-1000 ppm allowed us to achieve high efficiency and synthesize acetylene alcohols with a yield of 99% [4]. Acetylene alcohols were synthesized with a yield of 96% as a result of alkynylation of an aromatic aldehyde with phenylacetylene in the presence of a new catalyst in a mixture with alkynylzinc after dissolving a chiral sulfonamide ligand and titanium(S)-BINOL in tetrahydrofuran [5]. Secondary acetylene alcohols were obtained by reacting monosubstituted acetylene compounds with aldehydes in the presence of ruhetyl and tetrahydrofuran. The reaction was carried out at a temperature of 0°C and acetylene alcohols were synthesized with a yield of 81-98% [6]. The reactions of the synthesis of acetylene alcohols were studied by reacting acetylene and its homologues with magnesium bromide compounds in a tetrahydrofuran solution of aldehydes and a product was obtained in high yield (70%) [7]. The processes of alkynylation of aromatic, aliphatic, alicyclic and heteroaromatic aldehydes, and aldehydes with aliphatic, aromatic and functional alkynes were carried out by Schmidt and his scientific group based on the Favorsky reaction, that is, under mild conditions, in a 30% aqueous solution of Bu₄NON at a temperature of 5-20°C within 2 hours. As a result, propargyl alcohols were synthesized with a selective yield of 72–93% [8]. The reaction of propargyl alcohol with aromatic halides resulted in a series of alkynols. These alkynols were then treated with organometallic nucleophiles followed by sulfur dioxide to produce oxathiolene oxides [9]. The asymmetric addition of phenylacetylene to aldehydes without the use of Ti(OiPr)₄ and Zn(OTf)₂ catalysts was carried out on the basis of sulfamidoaminoalcohol, an ephedrine derivative, and the synthesis of propargyl alcohols was achieved with high efficiency (99%) [10]. In the works of Yin Ngai Sum, Dingyi Yu and Yugen Zhang, propargyl alcohols were synthesized under mild conditions in the presence of CaC₂ without a metal catalyst and achieved high efficiency [11]. Catalytic reactions of the enantioselective alkynylation of aromatic aldehydes to terminal alkynes, including phenylacetylene, isopropylsilyl and acetylene, were carried out using complex catalytic systems with high catalytic activity based on the ligand BINOL and Ti(OiPr)₄. In this case, complex catalytic systems were formed with high catalytic activity of the pre-prepared Et₂Zn BINOL-Ti(OiPr)₄. The process was carried out at room temperature and, accordingly, chiral aromatic acetylene alcohols were synthesized with yields of 92-98% [12]. For the first time, using acetaldehyde, cyclohexanecarbaldehyde and benzaldehydes, the following methods for the synthesis of acetylene alcohol from enantioselective alkynylation reactions with phenylacetylene in the presence of the complex catalytic system ZnEt₂/Ti(OiPr)₄ have been developed:4-phenylbutyn-3-ol-2 (84.4%), 1-phenylhexenin-4-1-ol-3 (72.0%), 1,3-diphenylpropin-2-ol-1 (88.8% ), 1-cyclohexyl-3-phenylpropin-2-ol-1 (77.5%) [13]. Diacetylene alcohol 3-methyl-1,5-diphenylpentadiyne-2,4-ol-3, which has high activity in vaccination against smallpox, was synthesized in the presence of the Jocich reaction of phenylethynylmagnesium bromide with ethyl acetate [14]. Secondary acetylene alcohols were obtained by the interaction of monosubstituted acetylene compounds with aldehydes in the presence of ethylzinc and tetrahydrofuran [15]. Aromatic and heteroatom aldehydes were treated with acetylene in the KOH-H₂O-DMSO catalytic system and secondary propargyl alcohols were synthesized in 46-67% yields. This process was carried out at atmospheric pressure in 3 layers in the temperature range of 5-7°C [16]. As a result of exposure of R–СС–MgX compounds to carbonyl compounds (aldehydes, ketones) in a solution of tetrahydrofuran and diethyl ether, the corresponding acetylene alcohols were synthesized in yields of 57–85% using the Grignard reaction [17]. By reacting aromatic, aliphatic and vinyl aldehydes with phenylacetylene or 1-hexine at room temperature, propargyl alcohols such as 1-(3-chlorophenyl)-3-phenylpropin-2-ol-l, 1-(2,4-chlorophenyl)-3-phenylpropin-2-ol-1 have been synthesized in yields up to 98% [18]. Acetylene alcohols are synthesized by the reaction of methylpropyl ketone, dimethyl ketone, methyl isopropyl ketone and pinocholines with phenylacetylene using an organomagnesium compound. The effect of diethyl ether and tetrahydrofuran solvents on the reaction yield was studied and a high yield was obtained when the process was carried out in a tetrahydrofuran solution [19].

Methods and materials

Experimental part: Synthesis of 1-(3-bromopyridinyl-4)-3-phenylpropin-2-ol-1. The reaction is carried out in a 2000 ml four-neck flask with heat-resistant transparent glass, equipped with a reflux condenser, a dropping funnel, a thermometer and a stirrer. The flask was initially charged with 120 ml of tetrahydrofuran, then 95 g (1 mol) of dimethylzinc and 127,7 g (1,25 mol) of phenylacetylene were carefully added under an argon atmosphere, followed by constant stirring for 60 min. A solution of 159,7 g of PropPhenol ligand in 120 ml of tetrahydrofuran and 185 g (1 mol) of 3-bromo-4-pyridinecaraldehyde was then added slowly dropwise to the mixture over 60 minutes. The reaction mixture was hermetically cooled to -5-0°C and stirred for 22 hours, after which the mixture was quenched with a saturated aqueous solution of NH₄Cl (50 ml) and stirred. The fraction was extracted with diethyl ether (3×100 ml) to separate the organic fraction, then washed with water (3×50 ml). The organic layer was dried over Na₂SO₄ and the solvents were removed under normal conditions. To remove product from the organic layer, the eluents were passed through a silica gel 60 column chromatography using a 20:1 CH₂Cl₂:Et₂O system. As a result, 1-(3-bromopyridinyl-4)-3-phenylpropin-2-ol-1 was synthesized with a yield of 80%. The system was also found to contain 11% by-products and 9% unreacted 3-bromo-4-pyridinecarbaldehyde.

Using this method, acetylene alcohols were synthesized with yields of the type (8) 1-(thiophenyl-2)-3-phenylpropin-2-ol-1 (64%), (9) 1-(3-methylthiophenyl-2)-3- phenylpropin-2-ol-1. (67%), (10) 1-(furanyl-2)-3-phenylpropin-2-ol-1 (87%), (11) 1-(pyridinyl-3)-3-phenylpropin-2-ol-1 (75%), (12) 1-(quinolinyl-2)-3-phenylpropin-2-ol-1 (72%), (13) 1-(3-bromopyridinyl-4)-3-phenylpropin-2-ol (80%).

Results and discussion

In this work, the synthesis of acetylene alcohols was carried out by the reaction of the ligand prophenol with dimethylzinc using tetrahydrofuran and the formation of a complex salt of bisrux, which activates two reagents simultaneously and is used as a dual catalyst. The reaction scheme was proposed as follows based on literary sources [20-21].

Process chemistry: Alkynylation reactions of some heteroatomic aldehydes with phenylacetylene in the presence of the ProPhenol/Me2Zn/THF catalytic system proceed in stages.

At the initial stage of the reaction, the ProPhenol ligand reacts with dimethylzinc in a tetrahydrofuran solution and deprotonates the hydrogens of the three hydroxyl groups to form a stable bisrux complex salt.

In the next stage of the reaction, the complex salt is exchanged for the mobile hydrogen of phenylacetylene and becomes an intermediate compound. The catalytic intermediate contains both a Lewis acid and a Brensted base, acting as a doublet catalyst that activates the two reactants simultaneously. That is, the Brensted base is activated by deprotonation of the nucleophile in an alkaline environment and converts the aldehyde to enols.

The Lewis acid group activates the electrophile by placing it on the metal center and, due to the acidic properties of phenylacetylene, initiates a nucleophilic attack on the positively charged carbon atom in the aldehyde carbonyl group. In the next stage of the process, zinc alkoxide is released through metal exchange and regenerates the active catalyst. As a result of the zinc alkoxide dissociation, proton exchange occurs and acetylene alcohols are synthesized with high yield.

The influence of such factors as the amount of starting materials, temperature, reaction duration, nature of the catalyst and solvents on the yield of acetylene alcohols synthesized using the ProPhenol/Me₂Zn/THF catalytic system was studied and this turned out to be the most alternative process condition.

First, the amount of substrate influence (aldehyde) and reagent (alkyne) in molar ratios on the yield of acetylenic alcohols was studied (Table 1). It was found that when the number of alkynes in the process is greater than aldehydes, the number of collisions of cations and anions in the system is maximum. As a result, it was found that acetylene alcohols are synthesized with high yield. On the other hand, with a large number of aldehydes compared to alkynes, a decrease in the product yield was observed due to the formation of its diols as a result of the reaction of acetylene with alcohols. When taking the amount of substrate (aldehyde) and reactant (alkyne) in the same molar ratio, the reactions of acetylenediols and vinylation occurred, in which the yield of acetylene alcohols decreases as a result of the formation of vinyl ethers.

Table 1.

Influence of the amount of starting substances in molar ratios on the yield of acetylene alcohols

(reaction temperature -5-0°C, reaction duration 24 hours, amount of catalyst ProPhenol/Me₂Zn in a molar ratio of 0,25:1)

In the acetylene alcohols synthesis, the temperature effect on the yield of the product and the solvents nature influence were studied. The reaction was carried out at a temperature of -15÷10°C, in such solvents as acetonitrile (MeCN), dimethyl sulfoxide (DMSO) and tetrahydrofuran (THF) (Table 2).

Table 2.

The influence of temperature and solvent on the yield of acetylene alcohols

 (molar amounts of starting materials and catalytic system in a molar ratio of 1:1,25:0,25:1, reaction time 24 hours)

When the reaction temperature was carried out at -15°C, the product yield was low due to the very low solubility and activity of the catalyst. An increase in the process temperature by 10°C led to a decrease in the yield of the main product due to an increase in the activation energy of the reaction in the system. When the reaction was carried out at a temperature of -5-0°C, an increase in the yield of acetylene alcohols was observed as a result of an increase in reactivity.

The influence of solvents on the yield of acetylene alcohols has also been studied. In this case, to carry out the d-bond of the electrophilic carbonyl carbon with the nucleophilic reagent, it is advisable to use polar aprotic solvents that stabilize cations well. Therefore, to study the effect of the nature of solvents on the yield of acetylene alcohols, acetonitrile, dimethyl sulfoxide and tetrahydrofuran were chosen for the ethinylation of aldehydes.

As can be seen from the table, when using tetrahydrofuran as a solvent, an increase in product yield was observed. As a solvent, the oxygen atom in tetrahydrofuran has a lone pair of electrons moreover, due to the strong delocalization of the negative charge in the ring, it exhibits a very strong basic property, as a result of which the activity of the catalytic system increases and causes an increase in the product yield. In this process, when dimethyl sulfoxide was used as a solvent, the product yield was lower compared to tetrahydrofuran. Dimethyl sulfoxide is a polarized aprotic solvent, and when used in the reaction process, the product yield was lower compared to tetrahydrofuran and higher compared to acetonitrile. As a result of the study, it was found that the order of influence of solvents on the rate and selectivity of the reaction increases in the following order: acetonitrile < dimethyl sulfoxide < tetrahydrofuran.

Based on the research carried out, alternative conditions for the synthesis of acetylene alcohols were determined. According to it, the molar amounts of the starting substances and the catalytic system were in a molar ratio of 1:1,25:0,25:1, the reaction duration was 24 hours, the temperature was -5-0°C, with the highest yield (8-64%; 9-67%, 10-87%, 11-75%, 12-72%, 13-80%), acetylene alcohols were synthesized using tetrahydrofuran as a solvent.

The composition, purity and structure of the synthesized acetylene alcohols were analyzed using ¹H, ¹³C NMR spectra (Bruker Avance 400 and 100 MHz, at a temperature of 20-25°C, in the presence of CDCl₃ and C₆D₆ solvents).

1-(thiophenyl-2)-3-phenylpropin-2-ol-1 (8) ‒ R_f= 0.36; (64%), ¹H NMR: δ 8.12 (m, 2H, 2CH_Th), 7.57 (m, 5H, 5CH_Ph), 7.24 (m, 1H, CH_Th), 5,89 (d, 1H), 2.34 (d, 1H, OH); ¹³C NMR: δ 149.3, 129.6, 128.1, 127.0, 126.3, 121.5, 88.9, 84.7, 64.9.

1-(3-methylthiophenyl-2)-3-phenylpropin-2-ol-1 (9) ‒ R_f= 0.38; (67%), ¹H NMR: δ 7.69 (m, 2H, 2CHPh), 7.35 (m, 5H, 3CHPh, 2CHTh), 5.62 (d, 1H), 2.23 (d, 1H, OH), 1.96 (s, 3H, CH3); ¹³C NMR: δ 142.7, 131.3, 128.3, 127.2, 125.9, 122.1, 89.6, 85.8, 63.2.

1-(2-furanyl)-3-phenylpropyne-2-ol-1 (10) ‒ R_f= 0.43; (87%), ¹H NMR: δ 7.46 (m, 3H, 3CHPh), 7.25 (m, 3H, 2CHPh, CHF), 6.42 (m, 1H, CHF), 6.29 (m, 1H, CHF), 5.26 (d, 1H), 1.97 (d, 1H, OH); ¹³C NMR: δ 154.2, 144.3, 129.6, 127.8, 121.7, 112.2, 107.5, 89.6, 84.4, 66.9.

1-(pyridinyl-3)-3-phenylpropin-2-ol-1 (11) ‒ R_f= 0.35; (75%), ¹H NMR: δ 8.44 (m, 2H, 2CH_Pir), 7.59 (m, 2H, 2CH_Pir), 7.41 (m, 2H, 2CH_Ph), 7.33 (m, 3H, 3CH_Ph), 5.74 (d, 1H), 2.86 (d, 1H, OH); ¹³C NMR: δ 152.6, 146.7, 134.2, 132.1, 129.8, 127.3, 121.5, 86.9, 83.7, 60.4.

1-(quinolinyl-2)-3-phenylpropin-2-ol-1 (12) ‒ R_f= 0.49; (72%), ¹H NMR: δ 8.27 (d, 1H, CHNaphth), 8.16 (m, 3H, 3CHNaphth), 7.68 (m, 2H, 2CHNaphth), 7.37 (m, 2H, 2CHPh), 7.18 (m, 3H, 3CHPh), 5.44 (d, 1H), 2.69 (d, 1H, OH); ¹³C NMR: δ 159.4, 148.7, 136.5, 129.4, 127.9, 126.3, 121.6, 89.8, 84.6, 65.3.

1-(3-bromopyridinyl-4)-3-phenylpropin-2-ol-1 (13) ‒ R_f= 0.33; (80%), ¹H NMR: δ 8.52 (m, 2H, CH_Pir), 7.76 (s, 1H, CH_Pir), 7.46 (m, 2H, 2CH_Ph), 7.14 (m, 3H, 3CH_Ph), 5.23 (d, 1H), 2.18 (d, 1H, OH); ¹³C NMR: δ 152.6, 147.5, 127.8, 126.2, 121.8, 120.4, 88.3, 85.6, 57.4.

Quantum chemical indicators of acetylene alcohols - total molecular energy, initial energy, thermal energy, electronic energy, nuclear energy, dipole moments were determined using the semi-empirical method of the HyperChem Activation 7.0 program (with the STAT package) (Table 3).

Table 3.

 Quantum-chemical calculations of acetylene alcohols

The purity of the synthesized acetylene alcohols was studied using chromatographic and spectroscopic methods, and the elemental composition was analyzed.

Table 4.

Elemental analysis results for acetylene alcohols

The spatial structure of the synthesized acetylene alcohol molecules, the charge distribution and electron density in the molecules were determined using the HyperChem Activation 7.0 program (with the STAT package).

The biological activity of the synthesized acetylene alcohols was studied in the PASS (online) program based on the structure of the substance (Table 5).

Table 5.

Pharmacological properties of acetylene alcohols

Conclusion

New acetylene alcohols have been synthesized based on the alkynylation of some heteroatomic aldehydes with phenylacetylene in the presence of the ProPhenol/Me₂Zn/THF catalytic system. All physical and chemical parameters and properties of the synthesized compounds were systematically studied.

Based on scientific research and research results, the mechanism of the influence of the ProPhenol/Me₂Zn/THF catalytic system on the product yield was studied and alternative conditions for the process were found.

Based on the nature of the radicals located around the carbon of the carbonyl group and the property of the spatial interaction of radicals, it has been proven that the reaction of some heteroatoms with phenylacetylene increases in the following order: thiophene-2-carbaldehyde < 3-methylthiophene-2-carbaldehyde < quinoline-2-carbaldehyde < pyridine-3-carbaldehyde < 3-bromo-4-pyridinecarbaldehyde < furan-2-carbaldehyde.

The biological activity of synthesized acetylene alcohols was studied in the PASS (online) program for the structure of the substance.

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