ALKYNATION REACTIONS OF m-, p-SUBSTITUTED BENZALDEHYDE DERIVATIVES WITH 4-ETHINYL-N, N-DIMETHYLANILINE

ABSTRACT

In this study, enantioselective alkynylation reactions of m-, p-substituted benzaldehyde derivatives with 4-ethynyl-N,N-dimethylaniline were carried out in the presence of Sn(OTf)₂/PO(OEt)₃/DCE and the chiral ligand (((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(pyrrolidine-1,2-diyl))bis(diphenylmethanol). The reaction mechanism was analyzed. Based on the effects of temperature, reaction time, and functional groups in the aldehyde on the product yield, a series of relative efficiencies of the synthesized compounds was developed. The results of ¹H and NMR spectra analysis confirming the structures of the synthesized aromatic acetylenic alcohols are presented.

АННОТАЦИЯ

В рамках данного исследования были проведены реакции энантиоселективного алкинилирования производных м-, п-замещенного бензальдегида с 4-этинил-N,N-диметиланилином. Реакция осуществлялась в присутствии каталитической системы Sn(OTf)₂/PO(OEt)₃/DCE  и хирального лиганда (((2-гидрокси-5-метил-1,3-фенилен)бис(метилен))бис(пирролидин-1,2-диил))бис(дифенилметанол). Был проанализирован механизм реакции. На основе влияния температуры, времени реакции, а также функциональных групп, входящих в состав альдегида, был разработан ряд относительной эффективности синтезированных соединений. Приведены результаты анализа спектров ¹H ЯМР, подтверждающие структуру синтезированных ароматических ацетиленовых спиртов.

Keywords: acetylenic alcohols, benzaldehyde, alkynes, nucleophilic addition, reaction mechanism, catalytic system, enantioselective, column chromatography, purification, IR spectroscopy, NMR spectroscopy.

Ключевые слова: Ацетиленовые спирты, бензальдегид, алкины, нуклеофильное присоединение, механизм реакции, каталитическая система, энантиоселектив, колоночная хроматография, очистка, ИК-спектроскопия, ЯМР-спектроскопия.

Introduction. Currently, such industries as chemistry, oil and gas, pharmaceuticals, textiles, medicine, construction, energy, and agriculture are developing rapidly worldwide. This allows the creation of new chemical products and materials with high biological activity and their large-scale production, and further increases the demand for the synthesis of new organic compounds. [1, p. 29-40].

The interest in the synthesis of acetylenic alcohols is very high due to the presence of a number of reaction centers in the molecule and the diverse biological activities, as well as the possibility of using this compound as a starting material in the fields of organic chemistry and technology. Stereoselective synthesis of anti-Markovnikov-type Z-styryl sulfides via anionic coupling to alkynes was carried out under standard conditions in ethyl alcohol using tret-BuOLi to react terminal alkynes and benzyl mercaptans. The process was carried out in quantitative yields by stereoelectronic control of the anti-periplanar and anti-Markovnikov coupling of benzyl thiolates to phenylacetylene and its derivatives. Solvation of lithium thiolate ion pairs in ethyl alcohol results in the formation of the E-isomers of the product. Extending the reaction time from 6 to 12 hours resulted in an increase in the amount of Z-isomers, and the reaction scheme is proposed as follows: [2, p. 10070-10085].

Figure 1. Stereoselective synthesis of Z-styryl sulfides from nucleophilic addition of arylacetylenes and benzyl thiols

For the purpose of highly enantioselective alkynylation of ketones, reactions were carried out in the presence of butyllithium and diphenylbinaphtholate. As a result, a number of terminal acetylenic alcohols were synthesized in quantitative yields. Experimental studies to determine the absolute configurations of the synthesized compounds, spectroscopic data for new compounds, and the compounds synthesized as a result of the reaction of 3-acetylpyridine and phenylacetylene showed high biological activity against fungi. The general reaction scheme is proposed as follows [3, p. 5614-5616, 4, p. 1-40 ].

Figure 2. Enantioselective alkynylation reactions of ketones

The corresponding tertiary propargyl alcohols were synthesized in 97% yields by nucleophilic attack of aromatic ketones on phenylacetylene. The formation of complexes of Cu(OTf)₂ and comforsulfanylamides in catalytic amounts, the highly enantioselective catalytic addition of dialkyl zinc reagents to simple ketones, and the use of sulfocompounds as promoters in the synthesis of secondary and tertiary propargyl alcohols are presented.

Aminoethynylation reactions based on hexin-1-ol-3, formaldehyde and ethanolamines were carried out at 100^oC for 5 hours in the presence of dioxane and copper (I) chloride powder as catalyst and solvent. As a result, the corresponding compound 1-(2-hydroxyethylamino)heptyn-4-ol was synthesized in 58.3 % yield [5, p. 1-5].

Materials and methods

The NMR (¹H, ¹³C) spectra of the compounds were determined on a Bruker AMX 400 instrument in CDCl₃ at 25^oC, high-resolution mass spectra (HRMS) were determined on an ESI MicroTof Bruker Daltonics mass spectrometer, and IR spectra were determined on a Perkin-Elmer IQ-Fure system 2000 spectrometer. The purity of the product was determined by thin-layer chromatography on ALUGRAM Xtra SIL G/UV₂₅₄ silofol papers. The system used was EtOAc:chloroform.

For the synthesis of aromatic acetylenic alcohols, tin (II) triflate (Sn(OTf)₂) (4.7 mg, 0.02 mmol), (R,R)-2,6-bis-[2-(hydroxydiphenylmethyl)-1-pyrrolidinylmethyl]-4-methylphenol (7.5 mg, 0.012 mmol), 11 mol 4-ethynyl-N,N-dimethylaniline (29.3 mg, 0.02 mmol), 4-methylbenzaldehyde (24.0 mg, 0.02 mmol) and triethylphosphate (3.7 mg, 0.02 mmol) were added to a screw-cap test tube. The reaction mixture was stirred in DCE at -20°C for 12 h. The reaction mixture was purified by column chromatography on silica gel using EtOAc:CHCl₃ to synthesize 3-(4-(dimethylamino)phenyl)-1-(p-tolyl)prop-2-yn-1-ol in 87.6% yield. The remaining compounds were synthesized using the same method in varying yields.

Results and Discussion

The general reaction scheme for the synthesis of aromatic acetylenic alcohols was proposed as follows.

Figure 3. Enantioselective alkynylation reactions of aldehydes

This reaction mechanism consists of several main steps. In the first step, in the presence of the catalyst (Sn (OTf)₂) and the chiral ligand (((2-hydroxy-5-methyl-1,3-phenylene) bis(methylene)) bis(pyrrolidine-1,2-diyl)) bis(diphenylmethanol), together with the selected promoter triethyl phosphate (PO(OEt)₃), an active catalytic complex compound consisting of tin (II) ion and chiral ligand is formed. The resulting complex compound forms a stable reaction center necessary for the reaction to proceed. Two main processes occur for the reaction to proceed. The hydrogen of the terminal alkyne is removed due to the Lewis base property of triethyl phosphate, and the acetylenide ion, which is a strong nucleophile, is formed. The tin II ion, which is a Lewis acid in the catalytic complex, coordinates with the carbonyl oxygen in the aldehyde group. This coordination attracts the electron density of the oxygen, dramatically increasing the partial positive charge on the carbonyl carbon. As a result, this carbon of the aldehyde becomes a strong electrophile. Then, the strong nucleophilic acetylenide ion formed in the process, under the influence of the chiral ligand, attacks this activated electrophilic carbon. As a result of this nucleophilic addition reaction, a new C-C bond is formed, and an intermediate product is formed. The oxygen atom of the hydroxyl group in the resulting product donates its electron pair to the empty orbital of the tin ion, forming a coordinate covalent bond. This coordination stabilizes the intermediate complex.

In the final step of the reaction, the reaction mixture is hydrolyzed, and the catalyst is regenerated. Carrying out this process at a temperature of -20°C reduces the stereochemical control of the reaction and the occurrence of additional reactions, which increases the possibility of synthesizing aromatic acetylenic alcohols with a single spatial structure. The structural formulas of the synthesized compounds are given in the figure below.

Figure 4. The structural formulas of the synthesized compounds

To synthesize the targeted aromatic acetylenic alcohols in high yields, solvents of various natures, including acetonitrile (MeCN), diethyl ether (DEE), tetrahydrofuran (THF), and dichloroethane (DCE), were selected.

THF and DEE are electron-donating solvents that donate electrons through oxygen. THF is a more polar and stronger donor than DEE. The oxygen atoms of these solvents coordinate directly with the Sn(II) ion, which is the catalytic center, and partially block the activation center of the catalytic complex. As a result, the reaction rate decreases and the enantioselectivity decreases, which is why low product yields are observed. Due to the high polarity of MeCN, it solvates the intermediate acetylenide ions well. This can lead to an increase in nucleophilic activity due to the separation of ion pairs, but it also reduces the enantioselectivity due to the formation of a strong coordination bond with the catalytic center.

When DCE is used, it is not coordinated to the catalytic center, therefore the active center is protected, and as a result, the highest yields and enantioselectivities were observed in reactions carried out in the presence of DCE.

The effect of selected solvents on product yield is presented in the table below.

Table 1.

Effect of solvent on product yield

During the studies, a series of relative efficiencies of the synthesized compounds (1-8) was developed and found to increase in the form 2<6<8<1<7<4<5<3. Based on the results of the study, it was observed that the corresponding aromatic acetylenic alcohols were formed in high yields in reactions involving aromatic aldehydes with strong electron acceptors, in particular, the -CF₃ groups in compound 3 and the -Cl groups in compound 5, which significantly increase the electrophilicity of the carbonyl center. On the contrary, it was observed that the presence of -N(Et)₂ in compound 2, which contains a strong electron-donating group that weakens the electrophilicity of the carbonyl group, or the presence of o-tert-butyl groups in compound 6, which create a steric hindrance to the carbonyl group in the aldehyde, reduced the kinetics of nucleophilic attack and led to a decrease in the yield of the reaction product.

The purity of the synthesized compounds and the progress of the reaction process, as well as the formation of products, were monitored by the TLC method, and their structures were identified using IR, ¹H, ¹³C NMR spectroscopy and Mass spectrometry.

3-(4-(dimethylamino)phenyl)-1-(p-tolyl)prop-2-yn-1-ol (1). ¹H NMR (400 MHz, chloroform-d). d 7.36 (dt, J = 7.5, 0.8 Hz, 2H), 7.28 – 7.15 (m, 2H), 7.11 – 7.05 (m, 1H), 6.79 (ddt, J = 7.6, 1.5, 0.8 Hz, 1H), 6.66 (ddt, J = 7.6, 1.6, 0.8 Hz, 1H), 5.74 – 5.61 (m, 1H), 5.44 (d, J = 6.4 Hz, 1H), 2.97 (s, 6H), 2.30 (d, J = 0.9 Hz, 3H).

1,3-bis(4-(dimethylamino) phenyl) prop-2-yn-1-ol (2). ¹H NMR (400 MHz, chloroform-d). d 7.40 (dt, J = 7.5, 0.8 Hz, 2H), 7.35 – 7.29 (m, 2H), 6.86 – 6.65 (m, 4H), 5.74 (d, J = 6.3 Hz, 1H), 5.53 (d, J = 6.4 Hz, 1H), 3.00 (d, J = 6.6 Hz, 12H).

3-(4-(dimethylamino)phenyl)-1-(4-(trifluoromethyl)phenyl)prop-2-yn-1-ol (3). ¹H NMR (400 MHz, chloroform-d). d 7.65 – 7.47 (m, 2H), 7.29 (ddt, J = 21.0, 7.6, 0.8 Hz, 4H), 6.77 (ddt, J = 6.8, 1.6, 0.9 Hz, 1H), 6.56 (ddt, J = 7.6, 1.5, 0.8 Hz, 1H), 5.77 – 5.66 (m, 1H), 5.34 (d, J = 6.4 Hz, 1H), 2.87 (s, 6H).

3-(4-(dimethylamino)phenyl)-1-(4-(ethylthio)phenyl)prop-2-yn-1-ol (4).

¹H NMR (400 MHz, chloroform-d). d 7.47 – 7.13 (m, 6H), 6.87 – 6.73 (m, 2H), 5.79 – 5.63 (m, 1H), 5.48 (d, J = 6.4 Hz, 1H), 3.01 (s, 6H), 2.91 (qd, J = 7.9, 7.1 Hz, 2H), 1.29 (t, J = 8.0 Hz, 3H).

1-(3-chloro-4-methylphenyl)-3-(4-(dimethylamino)phenyl)prop-2-yn-1-ol (5). ¹H NMR (400 MHz, chloroform-d). d 7.37 – 7.19 (m, 3H), 7.17 (d, J = 0.7 Hz, 2H), 6.62 – 6.54 (m, 2H), 5.76 (d, J = 6.5 Hz, 1H), 5.63 (d, J = 6.6 Hz, 1H), 2.90 (s, 6H), 2.22 (s, 3H).

1-(3-(tert-butyl)-4-methoxyphenyl)-3-(4-(dimethylamino)phenyl)prop-2-yn-1-ol (6). ¹H NMR (400 MHz, chloroform-d). d 7.34 – 7.29 (m, 2H), 7.28 – 7.24 (m, 1H), 7.12 (ddd, J = 7.5, 1.5, 0.7 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 6.72 – 6.67 (m, 1H), 6.61 (ddt, J = 7.8, 1.7, 0.8 Hz, 1H), 5.71 (d, J = 6.6 Hz, 1H), 5.66 (d, J = 6.6 Hz, 1H), 3.75 (s, 2H), 2.91 (s, 4H), 1.33 (s, 6H).

1-(4-bromo-3-methylphenyl)-3-(4-(dimethylamino)phenyl)prop-2-yn-1-ol (7). ¹H NMR (400 MHz, chloroform-d). d 7.51 (d, J = 7.5 Hz, 1H), 7.44 – 7.36 (m, 2H), 7.33 – 7.06 (m, 2H), 6.87 – 6.57 (m, 2H), 5.90 – 5.60 (m, 2H), 3.01 (s, 6H), 2.34 (s, 3H).

4-(3-(4-(dimethylamino)phenyl)-1-hydroxyprop-2-yn-1-yl)benzene-1,2-diol (8). ¹H NMR (400 MHz, chloroform-d). d 9.06 (s, 1H), 8.90 (s, 1H), 7.45 – 7.32 (m, 2H), 7.08 – 7.01 (m, 1H), 6.89 – 6.76 (m, 2H), 6.76 – 6.57 (m, 2H), 5.84 – 5.62 (m, 2H), 3.01 (s, 6H).

The structures of all synthesized compounds were fully confirmed. The spectrum clearly distinguished the acetylenic alcohol proton (CH−OH) as a doublet signal in the characteristic corresponding bands, confirming the formation of a C−C bond. All synthesized products were found to have enantiomeric purity greater than 90%.

The Pass-Online program was used to predict the biological activity of the synthesized compounds. During the studies, it was observed that compounds 4, 6, 7, and 8 did not exhibit any biological activity at all. Of course, these results were theoretically achieved, and in practice the opposite may be observed [6]. The results obtained are presented in table 2.

Table 2.

Biological activity of synthesized compounds

Conclusion

For the first time, enantioselective alkynylation reactions of m-p-substituted benzaldehyde derivatives with 4-ethynyl-N,N-dimethylaniline were carried out in the presence of the selected Sn(OTf)₂/PO(OEt)₃/DCE and (((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(pyrrolidine-1,2-diyl))bis(diphenylmethanol), and it was found that the selected catalytic system has high enantioselectivity.

Optimal conditions for the process were developed based on the ratio of solvent, temperature, reaction time, reagent, and substrate to product yield.

It was found that the relative efficiency of the synthesized compounds increases in the following order as a result of the influence of functional groups in the selected aldehyde on the product yield. The structures of the synthesized aromatic acetylenic alcohols were fully confirmed based on the results of 1H and NMR spectra analysis.

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