Catalytic Cyclocodimerization of Silicon-Containing 1,2-Dienes with 1,3,5-Cycloheptatriene in the Synthesis of Biologically Active Bicyclo[4.2.1]Nona-2,4-Dienes ^†

Abstract

The [6+2] cycloaddition of (2-butyl-2,3-butadienyl)(trimethyl)silane and 2,3-butadienyl(trimethyl)silane to 1,3,5-cycloheptatriene was studied using titanium- and cobalt-containing multicomponent catalytic systems: R₂TiCl₂-R’_nAlCl_3-n (R = acac, PrⁱO, Bu^tO, Cl; R’ = Et, Buⁱ, n = 2, 3) and CoX₂(Y)/Z/ZnI₂ (X = acac, Br, I, Cl, OAc; Y = dppe, dppm, dppp, dppb, Ph₃P, P(OPrⁱ)₃, P(OPh)₃; Z = Zn, Mg, In, Bu₄NBH₄). The work investigated the influence of the nature of the central atom of the catalyst, the ligand environment of the catalyst, the nature of the organoaluminum cocatalyst, the reducing agent, the effect of temperature, as well as the nature of the solvent on the yield and stereoselectivity of the formation of cycloadducts. Catalytic cyclocodimerization occurs with the formation of silicon-containing bicyclo[4.2.1]nona-2,4-dienes, which are of interest as promising precursor compounds in the synthesis of new drugs. It is known that many bridged carbo- and heterocarbocyclic compounds containing silicon atoms in the structure have diverse biological activities and are valuable drugs. Based on this, the work for the first time carried out a comprehensive study of the antitumor activity of synthesized silicon-containing bicyclo[4.2.1]nona-2,4-dienes in vitro using various tumor cell lines (U937, K562, Jurkat, HL60) and normal fibroblasts.

1. Introduction

Catalytic cyclodimerization reactions involving 1,3,5-cycloheptatrienes (CHTs) are an effective tool for obtaining a wide variety of bridged polycycles [1,2], many of which are used in the targeted synthesis of new bioactive and medicinal compounds [1,3,4]. For example, compounds such as taxol, ingenol, and phorbol, which have high physiological activity, were obtained based on bicyclic adducts of CHTs [3,4]. Therefore, studies on the synthesis of previously unknown polycycles based on CHTs are a relevant and promising direction in the field of modern organic synthesis. Previously, we developed effective catalytic systems that allow for cycloaddition reactions of CHT and its substituted derivatives to be carried out with various classes of unsaturated compounds [5,6,7]. As a result of the implementation of these transformations, new classes of bi- and polycyclic carbocycles were obtained, and their antitumor activity in vitro was studied [7].

It is known that the presence of a silicon atom in a molecule increases the lipophilicity of a compound, and as a result, its cytotoxic effect is enhanced [8]. For example, it has been proven that the silyl protecting group plays an important role in enhancing the cytotoxic activity of the molecule [9,10]. Therefore, the development of effective approaches to the synthesis of new silicon-containing carbo- and heterocarbocycles is of particular interest in the targeted search for new antitumor compounds. In the present work, we studied the [6+2] cycloaddition of (2-butyl-2,3-butadienyl)(trimethyl)silane and 2,3-butadienyl(trimethyl)silane to CHT using multicomponent catalytic systems based on titanium and cobalt in order to obtain silicon-containing bicyclo[4.2.1]nona-2,4-dienes, and we also studied the in vitro antitumor properties of the synthesized adducts.

2. Results and Discussion

Initially, we studied the cyclodimerization reactions of Si-containing 1,2-dienes with CHT under the action of titanium-based catalytic systems in combination with organoaluminum reducing agents. It was found that the [6+2] cycloaddition of 2,3-butadienyl(trimethyl)silane 1a and (2-butyl-2,3-butadienyl)(trimethyl)silane 1b to CHT under the action of the R₂TiCl₂-R’_nAlCl_3-n (R = acac, PrⁱO, Bu^tO, Cl; R’ = Et, Buⁱ, n = 2, 3) catalytic system leads to the formation of bicyclo[4.2.1]nona-2,4-dienes 2a,b in 19–89% yields as an equimolar mixture of Z- and E-isomers (Scheme 1,

Table 1. Effect of the nature of the catalyst, reducing agent, solvent, temperature, and reaction time on the yield of cycloadducts 2a,b.

Entry	Ti-Catalyst	Conditions	Yield 2a,b (%)
1	Ti(acac)2Cl2-Et2AlCl	benzene, 80 °C, 8 h	a: 82; b: 85
2	Ti(acac)2Cl2-Et2AlCl	toluene, 80 °C, 8 h	a: 76; b: 78
3	Ti(acac)2Cl2-Et2AlCl	1,2-dichlorobenzene, 80 °C, 8 h	a: 71; b: 70
4	Ti(acac)2Cl2-Et2AlCl	cyclohexane, 80 °C, 8 h	a: 51; b: 53
5	Ti(acac)2Cl2-Et2AlCl	hexane, 80 °C, 8 h	a: 65; b: 70
6	Ti(acac)2Cl2-Et2AlCl	THF, 80 °C, 8 h	-
7	Ti(acac)2Cl2-Et2AlCl	benzene, 40 °C, 8 h	a: 20; b: 19
8	Ti(acac)2Cl2-Et2AlCl	benzene, 60 °C, 8 h	a: 41; b: 44
9	Ti(acac)2Cl2-Et2AlCl	benzene, 80 °C, 5 h	a: 68; b: 70
10	Ti(acac)2Cl2-Et2AlCl	benzene, 80 °C, 11 h	a: 82; b: 84
11	Ti(acac)2Cl2-Et3Al	benzene, 80 °C, 8 h	a: 80; b: 82
12	Ti(acac)2Cl2-Bui2AlCl	benzene, 80 °C, 8 h	a: 82; b: 86
13	Ti(acac)2Cl2-Bui3Al	benzene, 80 °C, 8 h	a: 85; b: 89
14	TiCl4-Et2AlCl	benzene, 80 °C, 8 h	a: 79; b: 77
15	Ti(OPri)2Cl2-Et2AlCl	benzene, 80 °C, 8 h	a: 80; b: 79
16	Ti(OBut)2Cl2-Et2AlCl	benzene, 80 °C, 8 h	a: 74; b: 76

).

Ti(acac)₂Cl₂, TiCl₄, Ti(OPrⁱ)₂Cl₂, and Ti(OBu^t)₂Cl₂ (entries 1, 14–16) can be successfully used as catalysts without significant changes in the yield of cycloadducts. Equally effective are the following reducing agents: Et₂AlCl, Et₃Al, Buⁱ₂AlCl, and Buⁱ₃Al (entries 1, 11–13). Codimerization occurs most effectively in benzene and toluene; it is also possible to use 1,2-dichlorobenzene, cyclohexane, and hexane as solvents (entries 1–5). The reaction does not occur in THF (entry 6). It was found that the yield of codimers is affected by the temperature and duration of the experiment. The most optimal condition is a reaction temperature of 80 °C and an experiment duration of 8 h (entries 1–5, 11–16) (Table 1).

As a result of further studies, it was established that the [6+2] cycloaddition of 2,3-butadienyl(trimethyl)silane 1a and (2-butyl-2,3-butadienyl)(trimethyl)silane 1b to CHT using a three-component catalytic system based on cobalt complexes CoX₂(Y)/Z/ZnI₂ (X = acac, Br, I, Cl, OAc; Y = dppe, dppm, dppp, dppb, Ph₃P, P(OPrⁱ)₃, P(OPh)₃; Z = Zn, Mg, In, Bu₄NBH₄) leads to the formation of bicyclo[4.2.1]nona-2,4-dienes 2a,b in yields of 7–88% as the E-isomer (the Z-isomer was detected in trace amounts not exceeding 5%) (Scheme 1,

Table 2. Effect of the nature of the catalytic system, temperature, and reaction time on the yield of cycloadducts 2a,b.

Entry	Cocatalyst	Conditions	Yield 2a,b (%)
1	Co(acac)2(dppe)/Zn/ZnI2	C2H4Cl2, 60 °C, 5 h	a: 85; b: 88
2	CoBr2(dppe)/Zn/ZnI2	C2H4Cl2, 60 °C, 5 h	a: 75; b: 79
3	CoCl2(dppe)/Zn/ZnI2	C2H4Cl2, 60 °C, 5 h	a: 54; b: 49
4	CoI2(dppe)/Zn/ZnI2	C2H4Cl2, 60 °C, 5 h	a: 80; b: 83
5	Co(OAc)2(dppe)/Zn/ZnI2	C2H4Cl2, 60 °C, 5 h	a: 78; b: 74
6	Co(acac)2(dppm)/Zn/ZnI2	C2H4Cl2, 60 °C, 5 h	a: 35; b: 36
7	Co(acac)2(dppp)/Zn/ZnI2	C2H4Cl2, 60 °C, 5 h	a: 20; b: 18
8	Co(acac)2(dppb)/Zn/ZnI2	C2H4Cl2, 60 °C, 5 h	-
9	Co(acac)2/Ph3P/Zn/ZnI2	C2H4Cl2, 60 °C, 5 h	a: 10; b: 7
10	Co(acac)2/P(OPh)3/Zn/ZnI2	C2H4Cl2, 60 °C, 5 h	-
11	Co(acac)2/P(OPri)3/Zn/ZnI2	C2H4Cl2, 60 °C, 5 h	-
12	Co(acac)2(dppe)/Zn	C2H4Cl2, 60 °C, 5 h	-
13	Co(acac)2(dppe)/Mg/ZnI2	C2H4Cl2, 60 °C, 5 h	a: 78; b: 80
14	Co(acac)2(dppe)/In/ZnI2	C2H4Cl2, 60 °C, 5 h	a: 77; b: 79
15	Co(acac)2(dppe)/Bu4NBH4/ZnI2	C2H4Cl2, 60 °C, 5 h	a: 83; b: 85
16	Co(acac)2(dppe)/Zn/ZnI2	C2H4Cl2, 25 °C, 72 h	a: <6; b: <5
17	Co(acac)2(dppe)/Zn/ZnI2	C2H4Cl2, 40 °C, 5 h	a: 28; b: 30
18	Co(acac)2(dppe)/Zn/ZnI2	C2H4Cl2, 40 °C, 20 h	a: 82; b: 85

).

The experiments showed that the reaction is catalyzed by such cobalt(II) salts as Co(acac)₂, CoBr₂, CoCl₂, CoI₂, and Co(OAc)₂ (entries 1–5). The most effective ligand was dppe (entries 1–5, 13–15), while the use of dppm, dppp, and Ph₃P resulted in a sharp decrease in the yield of the target cycloadduct (entries 6, 7, and 9). Zn, Mg, In, and Bu₄NBH₄ (entries 1–5, 13–15) can be successfully used as reducing agents. In the absence of the Lewis acid ZnI₂, the codimerization reaction does not occur (entry 12). The maximum yield of the product is achieved at a temperature of 60 °C and an experiment duration of 5 h (entry 1), while at a lower temperature, the yield of the product decreases noticeably (entries 16, 17) (Table 2).

It is known that many silicon-containing bi- and polycyclic compounds exhibit pronounced biological activity and are medicinal products [7,8,9,10]. Therefore, in this work, we studied for the first time the antitumor activity of the synthesized silicon-containing bicyclo[4.2.1]nona-2,4-dienes 2a,b in vitro using tumor cell lines U937, K562, Jurkat, HL60, and normal fibroblasts (

Table 3. Cytotoxic activities IC₅₀ in vitro of bicyclo[4.2.1]nona-2,4-dienes 2a,b measured on tumor cell cultures (Jurkat, K562, U937, HL60) and normal fibroblasts (µM).

Compound	IC50 (µM)
	Jurkat	K562	U937	HL60	Fibroblasts
2a	0.025 ± 0.002	0.019 ± 0.002	0.034 ± 0.003	0.015 ± 0.001	0.157 ± 0.019
2b	0.020 ± 0.002	0.017 ± 0.002	0.028 ± 0.002	0.012 ± 0.001	0.160 ± 0.020

). It was found that cycloadducts 2a,b exhibit an antitumor effect on the studied cell lines, and the inhibitory concentration values are in the range of IC50 = 0.012 ± 0.001–0.034 ± 0.003 µM.

3. Conclusions

The [6+2] cycloaddition of (2-butyl-2,3-butadienyl)(trimethyl)silane and 2,3-butadienyl(trimethyl)silane to CHT under the action of titanium- and cobalt-containing multicomponent catalytic systems was studied for the first time, leading to the selective formation of Si-containing bicyclo[4.2.1]nona-2,4-dienes. The synthesized carbocycles exhibited antitumor properties, which makes these compounds promising objects of study in the field of creating modern anticancer drugs.

4. Experimental Part

All solvents were dried and freshly distilled before use. All reactions were carried out under a dry argon atmosphere. Analytical data for compounds 2a,b (¹H NMR, ¹³C NMR, elemental analysis, mass spectral analysis) are reported in the literature [5].

Titanium catalyzed cycloaddition of 1,3,5-cycloheptatriene and Si-containing 1,2-dienes (general procedure). A glass ampoule, at ~0 °C under a dry argon atmosphere, was charged with 1,3,5-cycloheptatriene (1 mmol), Si-containing 1,2-diene (1.2 mmol), 0.03 mmol Ti(acac)₂Cl₂ (or TiCl₄, Ti(OBu^t)₂Cl₂, Ti(OPrⁱ)₂Cl₂), and anhydrous benzene (3 mL). The ampoule was cooled in liquid nitrogen, charged with Et₂AlCl (or Et₃Al, Buⁱ₂AlCl, Buⁱ₃Al) (0.4 mmol in 1 mL of benzene), and sealed. After heating at 80 °C for 8 h, the ampoule was opened and its contents were poured into C₂H₅OH (2 mL). Volatile solvents were removed under vacuum. Chromatographic purification on SiO₂ (100% petroleum ether as eluent) afforded the target products 2a,b.

Cobalt catalyzed cycloaddition of 1,3,5-cycloheptatriene and Si-containing 1,2-dienes (general procedure). Zn powder (30 mol%) (or Mg, In, Bu₄NBH₄) was added to a solution of Co(acac)₂(dppe) (10 mol%) (or CoBr₂(dppe), CoCl₂(dppe), CoI₂(dppe), Co(OAc)₂(dppe)) in C₂H₄Cl₂ (1.5 mL) in a glass ampoule under a dry argon atmosphere, and the mixture was stirred at room temperature for 2 min. Next, 1,3,5-cycloheptatriene (1.0 mmol), Si-containing 1,2-diene (1.2 mmol) in C₂H₄Cl₂ (1.5 mL), and ZnI₂ (20 mol%) were added successively. The ampoule was sealed and after heating at 60 °C for 5 h, the ampoule was opened, and the reaction was stopped by the addition of petroleum ether and stirring 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 as eluent) afforded the target products 2a,b.