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Proceeding Paper

Co(I)-Catalyzed [4π + 2π] Cycloaddition of 1,2-Dienes to 1,3,5-Cyclooctatriene in the Synthesis of Previously Undescribed Tricyclo[4.2.2.02,5]Decenes †

Institute of Petrochemistry and Catalysis of Russian Academy of Sciences, 141 Prospekt Oktyabrya, 450075 Ufa, Russia
*
Author to whom correspondence should be addressed.
Presented at the 25th International Electronic Conference on Synthetic Organic Chemistry, 15–30 November 2021; Available online: https://ecsoc-25.sciforum.net/.
Chem. Proc. 2022, 8(1), 47; https://doi.org/10.3390/ecsoc-25-11633
Published: 12 November 2021

Abstract

:
The catalytic [4π + 2π]-cycloaddition of monosubstituted and disubstituted 1,2-dienes to 1,3,5-cyclooctatriene under the action of Co(acac)2(dppe)/Zn/ZnI2 was performed for the first time to produce substituted tricyclo[4.2.2.02,5]dec-7-enes.

1. Introduction

Over the past decades, bicyclic and polycyclic and cage hydrocarbons and their functionally substituted derivatives have been the objects of close attention of synthetic chemists due to their wide use as promising precursors for the development of modern drugs, important biologically active compounds and other practically valuable substances [1]. However, on the way to the widespread use of bicyclic and polycyclic compounds, both in laboratory practice and in industry, there are a number of difficulties associated with the inaccessibility of the feedstock for obtaining polycarbocycles of a given structure, the multistage synthesis for the isolation and purification of target compounds. Therefore, the development of one-pot methods for directed synthesis of previously hard-to-reach carbocycles and heterocarbocycles is an important and urgent problem of modern organic chemistry.
An analysis of the world literature shows that the number of promising and widespread methods for the synthesis of bi- and polycyclic compounds include catalytic cycloaddition reactions with the participation of available cyclic trienes [2,3,4,5,6]. In this area of research, 1,3,5-cyclooctatriene (COT) is of particular interest. However, the reactions of catalytic cycloaddition with the participation of this monomer have hardly been studied, and they are represented by works on Mo-catalyzed and Co-catalyzed cyclodimerization of COT [7,8].
In a previous study, we developed an efficient cobalt-containing catalytic system based on Co(acac)2 [9,10,11,12,13,14,15], in which we first carried out the cycloaddition of 1,3-diines to COT to obtain previously undescribed tricyclo[4.2.2.02,5]deca-7,9-dienes [9]. In the development of these studies, for the first time, we carried out the Co(I)-catalyzed [4π + 2π] cycloaddition of monosubstituted and disubstituted 1,2-dienes to COT.

2. Results and Discussion

We found that as a result of the reaction of 1,2-dienes 3a,b with COT 1 under the action of the three-component catalytic system Co(acac)2(dppe)/Zn/ZnI2 [9,10,11,12,13,14,15] under the developed conditions (10 mol% Co(acac)2(dppe), 30 mol% Zn, 20 mol% ZnI2, 1,2-dichloroethane (C2H4Cl2), 20 h, 60 °С), [4π + 2π]-cycloadducts formed substituted tricyclo[4.2.2.02,5]dec-7-enes 4a,b in 74–80% yields (Scheme 1). It is known that COT 1 is in tautomeric equilibrium with bicyclo[4.2.0]octa-2,4-diene 2 [16]. Thus, under the above conditions, the valence tautomer COT of bicyclo[4.2.0]octa-2,4-diene 2 enters into the reaction of cyclocodimerization with 1,2-dienes 3a,b. In addition to the main codimer, the formation of a minor [6 + 2] cycloadduct COT in an amount not exceeding 5% was observed.
In a previous study [10,12,14,17], we found that substituted bicyclo[4.3.1]deca-2,4,8-trienes and bicyclo[4.2.1]nona-2,4,7-trienes have pronounced cytotoxic properties. In the development of these studies, we studied the in vitro antitumor activity of the synthesized tricyclo[4.2.2.02,5]dec-7-enes 4a,b against tumor cell lines Jurkat, K562, U937 and HL60 (Table 1). We found that tricyclic adducts 4a,b exhibit a cytotoxic effect and the inhibitory concentration values are in the range of IC50 = 0.019 ± 0.002–0.045 ± 0.004 µM.

3. Conclusions

Thus, we have performed, for the first time, the reactions of [4π + 2π]-cycloaddition of 1,2-dienes to COT under the action of the three-component catalytic system Co(acac)2(dppe)/Zn/ZnI2 to obtain new tricyclo[4.2.2.02,5]dec-7-enes in high yields (74–80%). The obtained tricyclic adducts exhibited cytotoxic activity, which makes this class of compounds very attractive for further study as potential antitumor drugs.

4. Experimental Part

Chromatographic analysis was performed on a chromatograph using a 2000 × 2 mm column (SE-30 (5%) stationary phase on Сhromaton N-AW-HMDS (0.125–0.160 mm), helium carrier gas (30 mL/min) and temperature programming from 50 to 300 °C at an 8 °C/min rate. Flash column chromatography was performed over silica gel 0.060–0.200 mm, 60 A. 1H and 13C NMR spectra were recorded in CDCl3 at 125 MHz for 13C and 500 MHz for 1H. The chemical shifts are reported as δ values in parts per million relative to the internal standard Me4Si. The coupling constants (J) are reported in hertz.
High-resolution mass spectra (HRMS) were measured on an instrument using a time-of-flight mass analyzer (TOF) with electrospray ionization (ESI). In experiments on selective collisional activation, the activation energy was set at a maximum abundance of fragment peaks. A syringe injection was used for solutions in MeCN/H2O, 50/50 v/v (flow rate 3 mL/min). Nitrogen was applied as a dry gas; the interface temperature was set at 180 °C. All reactions were carried out under a dry argon atmosphere. 1,2-Dichloroethane was dried and freshly distilled before use. Co(acac)2(dppe), 1,2-dienes and COT were synthesized according to procedures described in the literature [18,19,20].
Cycloaddition of 1,2-dienes to COT (general procedure). Zn powder (30 mol%) was added to a solution of Co(acac)2(dppe) (10 mol%) in C2H4Cl2 (1.5 mL) in a Schlenk tube under a dry argon atmosphere, and the mixture was stirred at room temperature for 2 min. Next, COT (1.0 mmol), the 1,2-dienes (1.3 mmol) in C2H4Cl2 (1.5 mL) and dry ZnI2 (20 mol%) were added successively. After heating at 60 °C for 20 h, the reaction was stopped by the addition of a petroleum ether and stirred in air for 10 min to deactivate the catalyst. After filtration through a short pad of silica, the volatiles were removed under vacuum. Chromatographic purification over SiO2 (petroleum ether → petroleum ether / ethyl acetate 30:1 as eluent) afforded the target products 4a,b.
exo-2-(((E)-5-(Tricyclo[4.2.2.02,5]dec-9-en-7-ylidene)pentyl)oxy)tetrahydro-2H-pyran (4a): Yield 74% (0.223 g), colorless oil, Rf = 0.48 (petroleum ether/ethyl acetate 30:1). 1Н NMR (500 MHz, CDCl3): δ 6.41 (t, J = 4.0 Hz, 2Н), 5.10–5.14 (m, 1Н), 4.59 (t, J = 4.0 Hz, 1Н), 3.86–3.90 (m, 1Н), 3.72–3.77 (m, 1Н), 3.50–3.53 (m, 1Н), 3.38–3.41 (m, 1Н), 2.87 (t, J = 4.0 Hz, 1Н), 2.62–2.70 (m, 1Н), 2.38–2.51 (m, 2Н), 1.83–2.08 (m, 7Н), 1.39–1.82 (m, 11Н) ppm. 13С NMR (125 MHz, CDCl3): δ 139.1, 133.4, 132.5, 119.7, 98.8, 67.6, 62.3, 45.4, 38.9, 38.6, 35.8, 30.8, 30.6, 29.4, 28.1, 26.1, 25.5, 23.0, 22.1, 19.7 ppm. HRMS (ESI-TOF): calcd. for C20H30O2Na [M + Na]+ 325.2143, found 325.2141.
exo-9-(Diphenylmethylene)tricyclo[4.2.2.02,5]dec-7-ene (4b): Yield 80% (0.238 g), colorless oil, Rf = 0.44 (petroleum ether/ethyl acetate 30:1). 1Н NMR (500 MHz, CDCl3): δ 7.28–7.35 (m, 4Н), 7.22–7.26 (m, 2Н), 7.16–7.20 (m, 4Н), 6.52 (t, J = 7.2 Hz, 1Н), 6.45 (t, J = 7.3 Hz, 1Н), 3.35–3.38 (m, 1Н), 2.62–2.69 (m, 2Н), 2.53–2.59 (m, 1Н), 1.95–2.10 (m, 4Н), 1.44–1.54 (m, 2Н) ppm. 13С NMR (125 MHz, CDCl3): δ 143.4, 142.9, 138.6, 134.3, 133.3, 132.2, 129.5 (2C), 129.4 (2C), 128.1 (2C), 128.0 (2C), 126.1, 126.0, 40.5, 38.6, 37.9, 35.8, 33.3, 23.0, 22.2 ppm. HRMS (ESI-TOF): calcd. for С23H22Na [M + Na]+ 321.1619, found 321.1615.

Author Contributions

Conceptualization, U.M.D. and G.N.K.; methodology, validation and execution of chemistry experiments, G.N.K. and L.U.D.; manuscript preparation, G.N.K., L.U.D. and U.M.D. All authors have read and agreed to the published version of the manuscript.

Funding

The work was performed within the approved plans for research projects at IPC RAS State Registration No. FMRS-2022-0075 and Grant of Russian Foundation for Basic Research (19-03-00393).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data available on request.

Acknowledgments

The structural studies of the synthesized compounds were performed with the use of Collective Usage Centre “Agidel” at the Institute of Petrochemistry and Catalysis of RAS. The biological studies of bicycles were performed in the Laboratory of Molecular Design and Drug Bioscreening at the Institute of Petrochemistry and Catalysis.

Conflicts of Interest

The authors declare no conflict of interest.

References

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Scheme 1. Cycloaddition of 1,2-dienes with COT.
Scheme 1. Cycloaddition of 1,2-dienes with COT.
Chemproc 08 00047 sch001
Table 1. Cytotoxic activities IС50 in vitro of tricyclo[4.2.2.02,5]dec-7-enes 4a,b measured on tumor cell cultures (Jurkat, K562, U937 and HL60) and normal fibroblasts (µM).
Table 1. Cytotoxic activities IС50 in vitro of tricyclo[4.2.2.02,5]dec-7-enes 4a,b measured on tumor cell cultures (Jurkat, K562, U937 and HL60) and normal fibroblasts (µM).
СompoundJurkatK562U937HL60Fibroblasts
4a0.032 ± 0.0030.029 ± 0.0020.045 ± 0.0040.028 ± 0.0020.161 ± 0.020
4b0.026 ± 0.0020.023 ± 0.0020.031 ± 0.0020.019 ± 0.0020.158 ± 0.019
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MDPI and ACS Style

Kadikova, G.N.; Dzhemileva, L.U.; Dzhemilev, U.M. Co(I)-Catalyzed [4π + 2π] Cycloaddition of 1,2-Dienes to 1,3,5-Cyclooctatriene in the Synthesis of Previously Undescribed Tricyclo[4.2.2.02,5]Decenes. Chem. Proc. 2022, 8, 47. https://doi.org/10.3390/ecsoc-25-11633

AMA Style

Kadikova GN, Dzhemileva LU, Dzhemilev UM. Co(I)-Catalyzed [4π + 2π] Cycloaddition of 1,2-Dienes to 1,3,5-Cyclooctatriene in the Synthesis of Previously Undescribed Tricyclo[4.2.2.02,5]Decenes. Chemistry Proceedings. 2022; 8(1):47. https://doi.org/10.3390/ecsoc-25-11633

Chicago/Turabian Style

Kadikova, Gulnara N., Lilya U. Dzhemileva, and Usein M. Dzhemilev. 2022. "Co(I)-Catalyzed [4π + 2π] Cycloaddition of 1,2-Dienes to 1,3,5-Cyclooctatriene in the Synthesis of Previously Undescribed Tricyclo[4.2.2.02,5]Decenes" Chemistry Proceedings 8, no. 1: 47. https://doi.org/10.3390/ecsoc-25-11633

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