Polysubstituted selenium-containing cyclopent(hex)ene skeleton derivative and synthesis method thereof

Abstract

The present invention provides a polysubstituted selenium-containing cyclopent(hex)ene skeleton derivative and a synthesis method thereof. The polysubstituted selenium-containing cyclopent(hex)ene skeleton derivative is prepared by a one-pot method using an arylacetylene compound and an unsaturated selenide reagent as reaction materials, in the presence of a free radical initiator. The synthesis method of the present invention is simple and efficient, requires no metal catalyst, has mild reaction conditions, and has good functional group tolerance and broad substrate scope. Moreover, cyclopent(hex)ene compounds with different substituents are widely present in active drug molecules, and selenium-containing compounds also have good biological activity against tumors, oxidation, inflammation, bacteria, viruses and others. Therefore, a complex selenide-containing cyclopent(hex)ene skeleton derivative is obtained starting from a simple substrate by the synthesis method of the present invention by constructing a CSe bond through a simple, efficient and sustainable strategy. The present invention has broad application prospects.

Claims

1. A polysubstituted selenium-containing cyclopent(hex)ene skeleton derivative, having a structural formula of: ##STR00012## wherein X is selected from phenyl, naphthyl or heteroaryl; R.sup.1 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halo, amino, cyano, trifluoromethyl or nitro; Y is selected from Formulas 1 to 6: ##STR00013## R.sup.2 is selected from a methyl formate ester group, an ethyl formate ester group or cyano; R.sup.3 is selected from a methyl formate ester group, an ethyl formate ester group or cyano; and R.sup.4 is selected from phenyl, a substituted phenyl, or C1-C2 alkyl.

2. A method for synthesizing a polysubstituted selenium-containing cyclopent(hex)ene skeleton derivative according to claim 1, comprising steps of: (1) under a protective atmosphere, adding an arylacetylene compound, an unsaturated selenide reagent and a free-radical initiator to an organic solvent, and stirring for reaction; (2) after the reaction is completed, concentrating the reaction solution under vacuum, and separating by column chromatography to obtain the polysubstituted selenium-containing cyclopent(hex)ene skeleton derivative, wherein the reaction formula is shown as: ##STR00014## wherein R.sup.1 is selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, halo, amino, cyano, trifluoromethyl or nitro; R.sup.2 is selected from a methyl formate ester group, an ethyl formate ester group or cyano; R.sup.3 is selected from a methyl formate ester group, an ethyl formate ester group or cyano; R.sup.4 is selected from phenyl, a substituted phenyl, or C1-C2 alkyl; R.sup.5 is selected from propenyl, butenyl, 2-cyclohexenyl, 2-cyclopentenyl, 1-methyl-1-cyclohexenyl or 1-methyl-1-cyclopentenyl; X is selected from phenyl, naphthyl or heteroaryl; and Y is selected from Formulas 1 to 6: ##STR00015##

3. The method for synthesizing a polysubstituted selenium-containing cyclopent(hex)ene skeleton derivative according to claim 2, wherein in Step (1), the arylacetylene compound is selected from structural formulas (1) to (19): ##STR00016## ##STR00017##

4. The method for synthesizing a polysubstituted selenium-containing cyclopent(hex)ene skeleton derivative according to claim 2, wherein in Step (1), the unsaturated selenide reagent is selected from structural formulas (20) to (34): ##STR00018## ##STR00019##

5. The method for synthesizing a polysubstituted selenium-containing cyclopent(hex)ene skeleton derivative according to claim 2, wherein in Step (1), the free-radical initiator is selected from the group consisting of azodiisobutyronitrile, azobisisoheptonitrile, dimethyl 2,2-azobis(2-methylpropionate), N-iodo-succinimide, N-bromosuccinimide, benzoyl peroxide, and tert-butyl hydroperoxide.

6. The method for synthesizing a polysubstituted selenium-containing cyclopent(hex)ene skeleton derivative according to claim 2, wherein in Step (1), a molar ratio of the arylacetylene compound to the unsaturated selenide reagent is 1:3 to 3:1.

7. The method for synthesizing a polysubstituted selenium-containing cyclopent(hex)ene skeleton derivative according to claim 2, wherein in Step (1), the molar ratio of the arylacetylene compound to the free-radical initiator is 1:0.1 to 1:2.

8. The method for synthesizing a polysubstituted selenium-containing cyclopent(hex)ene skeleton derivative according to claim 2, wherein in Step (1), the organic solvent is selected from the group consisting of ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,4-dioxane, acetonitrile and any combination thereof.

9. The method for synthesizing a polysubstituted selenium-containing cyclopent(hex)ene skeleton derivative according to claim 2, wherein in Step (1), the reaction temperature is 20 to 150 C.

10. The method for synthesizing a polysubstituted selenium-containing cyclopent(hex)ene skeleton derivative according to claim 2, wherein in Step (1), the reaction time is 2 to 12 hours.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(1) The present invention will be further described below in connection with specific examples, so that those skilled in the art can better understand and implement the present invention; however, the present invention is not limited thereto.

(2) Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by persons skilled in the art to which the present invention pertains. The terms used in the descriptions of the present invention are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term and/or as used herein includes any and all combinations of one or more of the listed related items.

(3) Unless otherwise stated, the experimental methods given in examples below are all conventional methods. The materials, and reagents involved in the examples are commercially available, unless otherwise specified.

Example 1: Synthesis of dimethyl 3-phenyl-4-((phenylselenyl)methyl)cyclopent-2-ene-1,1-dicarboxylate (35)

(4) Under an inert atmosphere, 0.0204 g of phenylacetylene, 0.1308 g of dimethyl 2-allyl-2-phenylselenylmalonate, and 0.0097 g of azodiisobutyronitrile were dissolved in 2.0 mL of ethyl acetate, and stirred at 80 C. for 10 h. After the reaction, the reaction solution was concentrated under vacuum and then separated by column chromatography (column chromatography conditions: stationary phase: 200-300 mesh silica gel powder, mobile phases: ethyl acetate (A) and petroleum ether (B), and mobile phase gradient procedure: A/B in volume ratio: 1:20), to obtain 0.0682 g of a reaction product.

(5) The reaction product was characterized. .sup.1H NMR (400 MHZ, deuterated chloroform) 7.51-7.48 (m, 2H), 7.28-7.23 (m, 8H), 6.11 (d, J=4.0 Hz, 1H), 3.76 (s, 3H), 3.72 (s, 3H), 3.57-3.51 (m, 1H), 3.24-3.20 (m, 1H), 2.91-2.85 (m, 1H), 2.74-2.69 (m, 1H), 2.65-2.60 (m, 1H) ppm. According to the characterization data, it can be seen that the obtained reaction product is pure dimethyl 3-phenyl-4-((phenylselenyl) methyl) cyclopent-2-ene-1,1-dicarboxylate (purity>95%). The yield of the product is calculated to be 79%.

Example 2: Synthesis of dimethyl 3-(2-fluorophenyl)-4-((phenylselenyl) methyl) cyclopent-2-ene-1,1-dicarboxylate (36)

(6) Under an inert atmosphere, 0.0240 g of 2-fluorophenylacetylene, 0.1308 g of dimethyl 2-allyl-2-phenylselenylmalonate, and 0.0097 g of azodiisobutyronitrile were dissolved in 2.0 mL of ethyl acetate, and stirred at 80 C. for 10 h. After the reaction, the reaction solution was concentrated under vacuum and then separated by column chromatography (column chromatography conditions: stationary phase: 200-300 mesh silica gel powder, mobile phases: ethyl acetate (A) and petroleum ether (B), and mobile phase gradient procedure: A/B in volume ratio: 1:20), to obtain 0.0800 g of a reaction product.

(7) The reaction product was characterized. .sup.1H NMR (400 MHZ, deuterated chloroform) 7.48-7.45 (m, 2H), 7.27-7.22 (m, 4H), 7.17-7.13 (m, 1H), 7.07-7.01 (m, 2H), 6.22 (s, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 3.68-3.62 (m, 1H), 3.18-3.14 (m, 1H), 2.92-2.86 (m, 1H), 2.74-2.68 (m, 1H), 2.55-2.50 (m, 1H) ppm. According to the characterization data, it can be seen that the obtained reaction product is pure dimethyl 3-(2-fluorophenyl)-4-((phenylselenyl) methyl) cyclopent-2-ene-1,1-dicarboxylate (purity>95%). The yield of the product is calculated to be 89%.

Example 3: Synthesis of dimethyl 3-(3-bromophenyl)-4-((phenylselenyl) methyl) cyclopent-2-ene-1,1-dicarboxylate (41)

(8) Under an inert atmosphere, 0.0361 g of 3-bromophenylacetylene, 0.1308 g of dimethyl 2-allyl-2-phenylselenylmalonate, and 0.0097 g of azodiisobutyronitrile were dissolved in 2.0 mL of ethyl acetate, and stirred at 80 C. for 10 h. After the reaction, the reaction solution was concentrated under vacuum and then separated by column chromatography (column chromatography conditions: stationary phase: 200-300 mesh silica gel powder, mobile phases: ethyl acetate (A) and petroleum ether (B), and mobile phase gradient procedure: A/B in volume ratio: 1:20), to obtain 0.0590 g of a reaction product.

(9) The reaction product was characterized. .sup.1H NMR (400 MHZ, deuterated chloroform) 7.51-7.48 (m, 2H), 7.40-7.37 (m, 2H), 7.29-7.26 (m, 3H), 7.15-7.13 (m, 2H), 6.13, (m, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 3.50-3.43 (m, 1H), 3.19-3.15 (m, 1H), 2.90-2.84 (m, 1H), 2.72-2.69 (m, 1H), 2.67-2.61 (m, 1H) ppm. According to the characterization data, it can be seen that the obtained reaction product is pure dimethyl 3-(3-bromophenyl)-4-((phenylselenyl) methyl) cyclopent-2-ene-1,1-dicarboxylate (purity>95%). The yield of the product is calculated to be 58%.

Example 4: Synthesis of dimethyl 3-(3-aminophenyl)-4-((phenylselenyl) methyl) cyclopent-2-ene-1,1-dicarboxylate (45)

(10) Under an inert atmosphere, 0.0234 g of 3-aminophenylacetylene, 0.1308 g of dimethyl 2-allyl-2-phenylselenylmalonate and 0.0097 g of azodiisobutyronitrile were dissolved in 2.0 mL of ethyl acetate, and stirred at 80 C. for 10 h. After the reaction, the reaction solution was concentrated under vacuum and then separated by column chromatography (column chromatography conditions: stationary phase: 200-300 mesh silica gel powder, mobile phases: ethyl acetate (A) and petroleum ether (B), and mobile phase gradient procedure: A/B in volume ratio: 1:20), to obtain 0.0544 g of a reaction product.

(11) The reaction product was characterized. .sup.1H NMR (400 MHZ, deuterated chloroform) 7.53-7.51 (m, 2H), 7.27-7.25 (m, 3H), 7.08-7.04 (m, 1H), 6.67-6.64 (m, 1H), 6.59-6.57 (m, 1H), 6.48-6.47 (m, 1H), 6.06 (s, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.51-3.44 (m, 1H), 3.24-3.21 (m, 1H), 2.89-2.84 (m, 1H), 2.72-2.67 (m, 1H), 2.61-2.57 (m, 1H) ppm. According to the characterization data, it can be seen that the obtained reaction product is pure dimethyl 3-(3-aminophenyl)-4-((phenylselenyl) methyl) cyclopent-2-ene-1,1-dicarboxylate (purity>95%). The yield of the product is calculated to be 62%.

Example 5: Synthesis of dimethyl 3-methyl-4-((phenylselenyl) methyl) cyclopent-2-ene-1,1-dicarboxylate (58)

(12) Under an inert atmosphere, 0.0204 g of phenylacetylene, 0.1060 g of dimethyl 2-allyl-2-(methylselenyl)malonate and 0.0097 g of azodiisobutyronitrile were dissolved in 2.0 mL of ethyl acetate, and stirred at 80 C. for 10 h. After the reaction, the reaction solution was concentrated under vacuum and then separated by column chromatography (column chromatography conditions: stationary phase: 200-300 mesh silica gel powder, mobile phases: ethyl acetate (A) and petroleum ether (B), and mobile phase gradient procedure: A/B in volume ratio: 1:20), to obtain 0.0545 g of a reaction product.

(13) The reaction product was characterized. .sup.1H NMR (400 MHZ, deuterated chloroform) 7.41-7.39 (m, 2H), 7.37-7.33 (m, 2H), 7.31-7.27 (m, 1H), 6.12 (s, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 3.64-3.59 (m, 1H), 2.94-2.85 (m, 2H), 2.59-2.54 (m, 1H), 2.47-2.42 (m, 1H), 1.97 (s, 3H) ppm. According to the characterization data, it can be seen that the obtained reaction product is pure dimethyl 3-methyl-4-((phenylselenyl) methyl) cyclopent-2-ene-1,1-dicarboxylate (purity>95%). The yield of the product is calculated to be 69%.

Example 6: Synthesis of diethyl 3-phenyl-4-((2-methoxyphenylselenyl) methyl) cyclopent-2-ene-1,1-dicarboxylate (61)

(14) Under an inert atmosphere, 0.0204 g of phenylacetylene, 0.1429 g of dimethyl 2-allyl-2-(2-methoxyphenylselenyl)malonate and 0.0097 g of azodiisobutyronitrile were dissolved in 2.0 mL of ethyl acetate, and stirred at 80 C. for 10 h. After the reaction, the reaction solution was concentrated under vacuum and then separated by column chromatography (column chromatography conditions: stationary phase: 200-300 mesh silica gel powder, mobile phases: ethyl acetate (A) and petroleum ether (B), and mobile phase gradient procedure: A/B in volume ratio: 1:20), to obtain 0.0585 g of a reaction product.

(15) The reaction product was characterized. .sup.1H NMR (400 MHz, deuterated chloroform) 7.42-7.21 (m, 7H), 6.88-6.82 (m, 2H), 6.12 (s, 1H), 4.27-4.13 (m, 4H), 3.84 (s, 3H), 3.56-3.50 (m, 1H), 3.35-3.22 (m, 1H), 2.90-2.84 (m, 1H), 2.72-2.61 (m, 2H), 1.29-1.22 (m, 6H) ppm. According to the characterization data, it can be seen that the obtained reaction product is pure diethyl 3-phenyl-4-((2-methoxyphenylselenyl) methyl) cyclopent-2-ene-1,1-dicarboxylate (purity>95%). The yield of the product is calculated to be 60%.

Example 7: Synthesis of dimethyl 3-phenyl-4-((phenylselenyl) methyl) cyclohex-2-ene-1,1-dicarboxylate (63)

(16) Under an inert atmosphere, 0.0204 g of phenylacetylene, 0.1365 g of dimethyl 2-allylmethyl-2-(phenylselenyl)malonate and 0.0097 g of azodiisobutyronitrile were dissolved in 2.0 mL of ethyl acetate, and stirred at 80 C. for 10 h. After the reaction, the reaction solution was concentrated under vacuum and then separated by column chromatography (column chromatography conditions: stationary phase: 200-300 mesh silica gel powder, mobile phases: ethyl acetate (A) and petroleum ether (B), and mobile phase gradient procedure: A/B in volume ratio: 1:20), to obtain 0.0584 g of a reaction product.

(17) The reaction product was characterized. .sup.1H NMR (400 MHZ, deuterated chloroform) 7.38-7.36 (m, 2H), 7.27-7.25 (m, 3H), 7.22-7.21 (m, 3H), 7.17-7.15 (m, 2H), 6.11 (s, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 2.96-2.92 (m, 1H), 2.89-2.84 (m, 1H), 2.64-2.59 (m, 1H), 2.32-2.27 (m, 1H), 2.16-2.10 (m, 1H), 2.05-1.97 (m, 2H) ppm. According to the characterization data, it can be seen that the obtained reaction product is pure dimethyl 3-phenyl-4-((phenylselenyl) methyl) cyclohex-2-ene-1,1-dicarboxylate (purity>95%). The yield of the product is calculated to be 66%.

(18) From the above examples, it can be seen that in the presence of a free-radical initiator, a series of polysubstituted selenium-containing cyclopentene/cyclohexene compounds are constructed by tandem radical cyclization of an unsaturated selenide with a terminal alkyne. The synthesis method has simple operations, mild reaction conditions, broad substrate scope, excellent chemical selectivity and good atom economy.

(19) The above-described embodiments are merely preferred embodiments for the purpose of fully illustrating the present invention, and the scope of the present invention is not limited thereto. Equivalent substitutions or modifications can be made by those skilled in the art based on the present invention, which are within the scope of the present invention as defined by the claims. The scope of the present invention is defined by the appended claims.