CN114907253B - Preparation method of polysubstituted 3-methylene isoindoline-1-ketone - Google Patents
Preparation method of polysubstituted 3-methylene isoindoline-1-ketone Download PDFInfo
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Abstract
The invention discloses a preparation method of polysubstituted 3-methylene isoindoline-1-ketone. The preparation method comprises the following steps: in the presence of a manganese catalyst, lewis acid and a zinc reagent, aryl ketone shown as a formula II and isocyanate shown as a formula III are subjected to cyclization reaction to obtain polysubstituted 3-methylene isoindoline-1-ketone shown as a formula I; in the formula I and the formula II, R 1 Represents unsubstituted, mono-substituted or polysubstituted group on the benzene ring, and is at least one of H, substituted or unsubstituted alkyl with 1-10 carbon atoms, substituted or unsubstituted alkoxy with 1-10 carbon atoms, aryl and halogen; r 2 Represents an unsubstituted, mono-substituted or polysubstituted group on the benzene ring, and is at least one of H, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, a benzyl group and halogen. The invention synthesizes the skeleton by a one-step method, has wider substrate range and high reaction yield and has larger medicine synthesis application value.
Description
Technical Field
The invention relates to a preparation method of polysubstituted 3-methylene isoindoline-1-ketone, belonging to the technical field of chemical synthesis.
Background
The 3-methylene isoindoline-1-ketone skeleton widely exists in a plurality of natural product molecules and drug molecules and has important application value. Currently, the methods for preparing polysubstituted 3-methylidene isoindolin-1-ones in organic synthesis have many disadvantages, such as: the preparation of toxic and expensive raw materials, severe reaction conditions, poor functional group compatibility, the generation of harmful by-products which are not environmentally friendly, and the like are required. Therefore, the development of a novel synthesis method with low cost and wide applicability for preparing the polysubstituted 3-methylene isoindoline-1-ketone has very important significance.
Disclosure of Invention
The invention aims to provide a preparation method of polysubstituted 3-methylene isoindoline-1-ketone, which has the advantages of simple preparation method, easily obtained raw materials, wider substrate application range and higher yield.
The invention provides a preparation method of polysubstituted 3-methylene isoindoline-1-ketone shown in formula I, which comprises the following steps: in the presence of a manganese catalyst, lewis acid and a zinc reagent, aryl ketone shown as a formula II and isocyanate shown as a formula III are subjected to cyclization reaction to obtain polysubstituted 3-methylene isoindoline-1-ketone shown as a formula I;
in the formula I and the formula II, R 1 Represents unsubstituted, mono-substituted or polysubstituted group on the benzene ring, and is at least one of H, substituted or unsubstituted alkyl with 1-10 carbon atoms, substituted or unsubstituted alkoxy with 1-10 carbon atoms, aryl and halogen;
in the formula I and the formula III, R 2 Represents an unsubstituted, mono-substituted or polysubstituted group on the benzene ring, and is at least one of H, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, a benzyl group and halogen.
In the above preparation method, R 1 And R 2 In the above formula, the substituent of the substituted alkyl group having 1 to 10 carbon atoms or the substituted alkoxy group having 1 to 10 carbon atoms is a halogen. The halogen is at least one of fluorine, chlorine, bromine and iodine. The substitution is mono-, di-or tri-substitution.
Specifically, R 1 Is at least one of H, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, phenyl and halogen;
R 2 is at least one of H, halogen substituted or unsubstituted alkyl with 1 to 6 carbon atoms, halogen substituted or unsubstituted alkoxy with 1 to 6 carbon atoms, benzyl and halogen. The substituent of the substituted alkyl group having 1 to 6 carbon atoms and the substituted alkoxy group having 1 to 6 carbon atoms is fluorine. The substitution is a trisubstitution.
More specifically, R 1 Is H, methyl, methoxy, chlorine or phenyl; r 2 Is H, methyl, trifluoromethyl, methoxy, trifluoromethoxy, chlorine, iodine or benzyl.
In the above preparation method, the manganese catalyst can be manganese pentacarbonyl bromide or manganese decacarbonyl;
the molar ratio of the manganese catalyst to the isocyanate of formula III may be 1:10 to 20, preferably 1:20.
in the preparation method, the Lewis acid can be composed of Lewis acid I and Lewis acid II;
the Lewis acid I can be aluminum chloride, copper trifluoromethanesulfonate, copper acetate or zinc bromide; the amount of the Lewis acid I can be 60 to 150 percent of the molar amount of the isocyanate shown in the formula III, and is preferably 100 percent;
the Lewis II can be silver trifluoromethanesulfonate, silver carbonate or silver sulfate; the Lewis II may be used in an amount of from 5% to 50%, preferably 20%, based on the molar amount of isocyanate of formula III.
In the above preparation method, the zinc reagent may be dimethyl zinc;
the zinc reagent may be used in an amount of 150% to 200%, preferably 180%, of the molar amount of isocyanate of formula III.
In the above preparation method, the molar ratio of arylethanone represented by formula II to isocyanate represented by formula III can be 2.5-3.0: 1, specifically 2.5:1 or 3.0:1.
in the above preparation method, the solvent for the cyclization reaction may be 1,2-dichloroethane, chlorobenzene, isopropyl ether or methyl tert-butyl ether.
In the above-mentioned preparation method, the molar concentration of the isocyanate represented by formula III in the cyclization reaction system may be 0.05 to 0.1mol/L, and specifically may be 0.1mol/L.
In the preparation method, the temperature of the cyclization reaction can be 80-100 ℃, the time can be 6-24 h, and the reaction can be carried out for 12h or 24h at 90 ℃.
In the above preparation method, the reaction is performed under the protection of an inert gas, specifically under the protection of nitrogen.
In the preparation method, the method also comprises the step of separating by column chromatography after the reaction is finished to obtain the polysubstituted 3-methylene isoindoline-1-ketone shown in the formula I; the eluent for the column chromatography separation can be an eluent with the volume ratio of 20:1 petroleum ether and ethyl acetate.
The synthesis of the polysubstituted 3-methylene isoindoline-1-ketone is realized by reacting aryl ketone and isocyanate in a solvent in the presence of alkali (zinc reagent), lewis acid and a manganese catalyst. The polysubstituted 3-methylene isoindoline-1-ketone skeleton has very important application in natural products and medicines, and the existing synthetic method has complicated steps and lower efficiency. The invention synthesizes the skeleton by a one-step method, has wider substrate range and high reaction yield and has larger medicine synthesis application value.
Drawings
FIG. 1 is a reaction scheme for preparing formula I-a according to example 1 of the present invention.
FIG. 2 is a reaction scheme for preparing formula I-b according to example 2 of the present invention.
FIG. 3 is a reaction scheme for the preparation of formula I-c according to example 3 of the present invention.
FIG. 4 is a reaction scheme for the preparation of formula I-d according to example 4 of the present invention.
FIG. 5 is a reaction scheme for preparing the compounds of formulae I-e according to example 5 of the present invention.
FIG. 6 is a reaction scheme for the preparation of formula I-f according to example 6 of the present invention.
FIG. 7 is a reaction scheme for the preparation of formula I-g of example 7 of the present invention.
FIG. 8 is a reaction scheme for the preparation of formulas I-h of example 8 of the present invention.
FIG. 9 is a reaction scheme for the preparation of formula I-I of example 9 of the present invention.
FIG. 10 is a reaction scheme for preparing the compounds of formulae I-d in comparative examples of the present invention.
Detailed Description
The preparation method of the polysubstituted 3-methylene isoindoline-1-ketone shown in the formula I comprises the following steps: in the presence of a manganese catalyst, lewis acid and a zinc reagent, aryl ketone shown as a formula II and isocyanate shown as a formula III are subjected to cyclization reaction to obtain polysubstituted 3-methylene isoindoline-1-ketone shown as a formula I;
in the formula I and the formula II, R 1 Represents unsubstituted, mono-substituted or polysubstituted group on the benzene ring, and is at least one of H, substituted or unsubstituted alkyl with 1-10 carbon atoms, substituted or unsubstituted alkoxy with 1-10 carbon atoms, aryl and halogen;
in the formula I and the formula III, R 2 Represents an unsubstituted, mono-substituted or polysubstituted group on the benzene ring, and is at least one of H, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, a benzyl group and halogen.
The synthesis of the polysubstituted 3-methylene isoindoline-1-ketone is realized by reacting aryl ketone and isocyanate in a solvent in the presence of a zinc reagent, lewis acid and a manganese catalyst; the skeleton is synthesized by a one-step method, the substrate range is wide, the reaction yield is high, and the method has a high drug synthesis application value.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1: 3-methylene-2- (p-tolyl) isoindolin-1-one (formula I-a)
The compound of formula I-a is prepared according to the reaction scheme shown in FIG. 1, with the following specific steps:
in N 2 Under the protection of (1.5mmol, 180.2mg) of acetophenone (formula II-a), p-tolylisocyanate (formula III-a) (0.5mmol, 66.6mg), manganese pentacarbonyl bromide (0.025mmol, 13.8mg) as a catalyst, aluminum chloride (0.5mmol, 66.7mg, sublimation treatment was carried out before use), silver trifluoromethanesulfonate (0.1mmol, 25.7mg) and 1,2-dichloroethane as a solvent (5 mL) were charged in this order into a 25mL Schlenk flask, and dropwise addition was carried out while keepingDimethylzinc (0.9mmol, 1.2M in toluene, 0.75mL) was added with shaking. The reaction was quenched with water after 12h at 90 ℃ and purified by column chromatography (eluent petroleum ether: ethyl acetate =20/1,v/v) to give 71.8mg of the desired product (formula I-a) in 61% yield.
The target product was characterized as follows: 1 H NMR(500MHz,Chloroform-d)：δ7.91(d,J＝7.5Hz,1H),7.74(d,J＝7.5Hz,1H),7.62(t,J＝7.5Hz,1H),7.54(t,J＝7.5Hz,1H),7.30(d,J＝8.0Hz,2H),7.25(d,J＝8.0Hz,2H),5.20(d,J＝2.0Hz,1H),4.77(d,J＝2.0Hz,1H),2.41(s,3H)； 13 C NMR(126MHz,Chloroform-d)：δ166.8,143.3,138.0,136.3,132.3,131.9,130.1,129.7,129.1,127.9,123.6,120.1,90.4,21.3；HRMS(ESI)：Calculated for C 16 H 14 NO + ([M+H] + ) 236.10699 and found.
Example 2: 6-chloro-3-methylene-2- (p-tolyl) isoindolin-1-one (formula I-b)
The compound of formula I-b was prepared according to the reaction scheme shown in FIG. 2, with the following specific steps:
in N 2 Under protection of (1.5 mmol; 207.2mg) of p-chloroacetophenone (formula II-b), p-tolylisocyanate (formula III-a) (0.5 mmol; 66.6 mg), manganese pentacarbonyl bromide (0.025mmol; 13.8mg) as a catalyst, aluminum chloride (0.5mmol; 66.7mg, which is subjected to sublimation treatment before use), silver trifluoromethanesulfonate (0.1mmol; 25.7mg) and 1,2-dichloroethane as a solvent (5 mL) were charged in a 25mL Schlenk flask in this order, and dimethylzinc (0.9mmol; 1.2M in toluene; 0.75mL) was added dropwise with shaking. The reaction was quenched with water after 12h at 90 ℃ and purified by column chromatography (eluent petroleum ether: ethyl acetate =20/1,v/v) to give 67.4mg of the target product (formula I-b) in 50% yield.
The target product was characterized as follows: 1 H NMR(500MHz,Chloroform-d)：δ7.89(d,J＝2.0Hz,1H),7.68(d,J＝8.5Hz,1H),7.60(dd,J＝8.0,2.0Hz,1H),7.32(d,J＝8.0Hz,2H),7.26–7.23(m,2H),5.20(d,J＝2.5Hz,1H),4.82(d,J＝2.0Hz,1H),2.42(s,3H)； 13 C NMR(126MHz,Chloroform-d)：δ165.6,142.6,138.4,136.0,134.6,132.5,131.7,130.7,130.2,127.9,123.8,121.5,91.4,21.4；HRMS(ESI)：Calculated for C 16 H 13 ONCl + ([M+H] + ) 270.06802, found.
Example 3: 6-phenyl-3-methylene-2- (p-tolyl) isoindolin-1-one (formula I-c)
The compounds of formula I-c were prepared according to the reaction scheme shown in FIG. 3, with the following specific steps:
at N 2 Under protection of (1.5mmol, 294.4 mg) of p-phenylacetophenone (formula II-c), p-tolylisocyanate (formula III-a) (0.5mmol, 66.6 mg), manganese pentacarbonyl bromide (0.025mmol, 13.8mg) as a catalyst, aluminum chloride (0.5mmol, 66.7mg, sublimation treatment was conducted before use), silver trifluoromethanesulfonate (0.1mmol, 25.7mg) and 8978 zft 8978-dichloroethane (5 mL) were sequentially charged into a 25mL Schlenk flask, and dimethylzinc (0.9mmol, 1.2M in toluene, 0.75mL) was added dropwise with shaking. The reaction was quenched with water after 12h at 90 deg.C and purified by column chromatography (eluent petroleum ether: ethyl acetate =20/1,v/v) to give the desired product (formula I-c) 90.2mg, 58% yield.
The target product was characterized as follows: 1 H NMR(400MHz,Chloroform-d)：δ8.15(s,1H),7.90–7.78(m,2H),7.67(d,J＝7.6Hz,2H),7.48(t,J＝7.5Hz,2H),7.40(t,J＝7.2Hz,1H),7.36–7.24(m,4H),5.23(d,J＝2.0Hz,1H),4.80(d,J＝2.0Hz,1H),2.43(s,3H)； 13 C NMR(101MHz,Chloroform-d)：δ166.9,143.3,143.2,140.1,138.2,135.2,132.0,131.3,130.2,129.9,129.1,128.1,128.0,127.4,122.0,120.6,90.6,21.4；HRMS(ESI)：Calculated for C 22 H 18 ON + ([M+H] + ) 312.13829, found.
Example 4: 6-methoxy-3-methylene-2- (p-tolyl) isoindolin-1-one (formula I-d)
The compounds of formula I-d were prepared according to the reaction scheme shown in FIG. 4, with the following specific steps:
in N 2 Under protection of (1.25mmol, 187.7mg) of p-methoxyacetophenone (formula II-d), p-tolylisocyanate (formula III-a) (0.5mmol, 66.6mg), manganese pentacarbonyl bromide (0.025mmol, 13.8mg) as a catalyst, aluminum chloride (0.5mmol, 66.7mg, which had to be subjected to sublimation treatment before use), silver trifluoromethanesulfonate (0.1mmol, 25.7mg) and 1,2-dichloroethane as a solvent (5 mL) were sequentially charged into a 25mL Schlenk flask, and dimethylzinc (0.9mmol, 1.2M in toluene, 0.75mL) was added dropwise while shaking. The reaction was quenched with water after 12h at 90 ℃ and purified by column chromatography (eluent petroleum ether: ethyl acetate =20/1,v/v) to give 92.8mg of the desired product (formula I-d) in 70% yield.
The target product was characterized as follows: 1 HNMR(400MHz,Chloroform-d)：δ7.63(d,J＝8.4Hz,1H),7.38(d,J＝2.4Hz,1H),7.34–7.21(m,4H),7.17(dd,J＝8.4,2.4Hz,1H),5.08(d,J＝2.0Hz,1H),4.69(d,J＝2.4Hz,1H),3.89(s,3H),2.41(s,3H)； 13 C NMR(101MHz,Chloroform-d)：δ166.8,161.5,143.2,138.1,132.0,130.8,130.1,129.1,128.0,121.4,120.8,106.1,89.3,55.9,21.3；HRMS(ESI)：Calculated for C 17 H 16 O 2 N + ([M+H] + ) 266.11756 and found.
Example 5: 6-methoxy-3-methylene-2- (4-methoxyphenyl) isoindolin-1-one (formula I-e)
The compounds of formula I-e were prepared according to the reaction scheme shown in FIG. 5, with the following specific steps:
in N 2 To a 25mL Schlenk flask, p-methoxyacetophenone (formula II-d) (1.25mmol, 187.7 mg) and p-methoxyphenyl isocyanate were added in this order(formula III-b) (0.5mmol, 74.6mg), manganese pentacarbonyl bromide as a catalyst (0.025mmol, 13.8mg), aluminum chloride (0.5mmol, 66.7mg, sublimation treatment was conducted before use), silver trifluoromethanesulfonate (0.1mmol, 25.7mg) and 1,2-dichloroethane (5 mL) as a solvent, and dimethylzinc (0.9mmol, 1.2M in toluene, 0.75mL) was added dropwise with shaking. The reaction was quenched with water after 12h at 90 ℃ and purified by column chromatography (eluent petroleum ether: ethyl acetate =20/1,v/v) to give 98.4mg of the target product (formula I-e) in 70% yield.
The target product was characterized as follows: 1 H NMR(500MHz,Chloroform-d)：δ7.63(d,J＝8.5Hz,1H),7.38(d,J＝2.0Hz,1H),7.29-7.26(m,2H),7.18(dd,J＝8.5,2.5Hz,1H),7.06–6.99(m,2H),5.08(d,J＝2.0Hz,1H),4.66(d,J＝2.0Hz,1H),3.90(s,3H),3.88(s,3H)； 13 C NMR(126MHz,Chloroform-d):δ161.5,159.3,143.4,130.8,129.4,129.1,127.3,121.4,120.8,114.7,106.1,89.3,55.9,55.6；HRMS(ESI)Calculated for C 17 H 16 O 3 N + ([M+H] + ) 282.11247, found.
Example 6: 6-methoxy-3-methylene-2- (4-iodophenyl) isoindolin-1-one (formula I-f)
The compounds of formula I-f were prepared according to the reaction scheme shown in FIG. 6, with the following specific steps:
in N 2 Under protection of (1.25mmol, 187.7mg) of p-methoxyacetophenone (formula II-d), 4-iodophenyl isocyanate (formula III-c), 0.5mmol,122.5mg of manganese bromide (0.025mmol, 13.8mg) as a catalyst, 0.5mmol,66.7mg of aluminum chloride (sublimation treatment was required before use), silver trifluoromethanesulfonate (0.1mmol, 25.7mg) and 1,2-dichloroethane (5 mL) were charged into a 25mL Schlenk bottle in this order, and dimethylzinc (0.1mmol, 1.2M in toluene, 0.75mL) was added dropwise with shaking. The reaction was quenched with water after 12h at 90 ℃ and purified by column chromatography (eluent petroleum ether: ethyl acetate =20/1,v/v) to give 124.4mg of the desired product (formula I-f) in 66% yield.
The target product was characterized as follows: 1 H NMR(500MHz,Chloroform-d):δ7.84(d,8.5Hz,2H),7.64(d,J＝8.5Hz,1H),7.36(d,J＝2.5Hz,1H),7.19(dd,8.5Hz,2.5Hz,1H),7.14(d,8.5Hz,2H),5.12(d,J＝2.5Hz,1H),4.72(d,J＝2.5Hz,1H),3.90(s,3H)； 13 C NMR(126MHz,Chloroform-d):δ166.5,161.6,142.5,138.6,134.5,130.4,130.0,129.1,121.5,121.1,106.1,93.4,89.5,56.0；HRMS(ESI)：Calculated for C 16 H 13 O 2 IN + ([M+H] + ) 377.99855, found 377.99844, correct structure.
Example 7: 6-methoxy-3-methylene-2- (4-trifluoromethoxyphenyl) isoindolin-1-one (formula I-g)
The compounds of formula I-g were prepared according to the reaction scheme shown in FIG. 7, with the following specific steps:
in N 2 Under protection of (3), p-methoxyacetophenone (formula II-d) (1.25mmol, 187.7 mg), 4-trifluoromethoxyphenyl isocyanate (formula III-d) (0.5mmol, 101.6mg), manganese pentacarbonyl bromide (0.025mmol, 13.8mg) as a catalyst, aluminum chloride (0.5mmol, 66.7mg, sublimation treatment was required before use), silver trifluoromethanesulfonate (0.1mmol, 25.7 mg) and 1,2-dichloroethane (5 mL) were sequentially charged into a 25mL Schlenk flask, and dimethylzinc (0.9mmol, 1.2M in toluene, 0.75mL) was added dropwise while shaking. The reaction was quenched with water after 12h at 90 ℃ and purified by column chromatography (eluent petroleum ether: ethyl acetate =20/1,v/v) to give 107.2mg of the desired product (formula I-g) in 64% yield.
The target product was characterized as follows: 1 H NMR(400MHz,Chloroform-d):δ7.65(d,J＝8.4Hz,1H),7.44–7.43(m,2H),7.40–7.33(m,3H),7.20(dd,J＝8.4,2.4Hz,1H),5.13(d,J＝2.4Hz,1H),4.72(d,J＝2.4Hz,1H),3.91(s,3H)； 13 C NMR(101MHz,Chloroform-d):δ166.6,161.6,148.5,142.7,133.3,130.4,129.7,129.1,121.9,121.6,121.2,106.1,89.5,56.0；HRMS(ESI)：Calculated for C 17 H 13 O 3 NF 3 + ([M+H] + ) 336.08420 and found.
Example 8: 6-methoxy-3-methylene-2- (3-methylphenyl) isoindolin-1-one (formula I-h)
The compounds of formula I-h were prepared according to the reaction scheme shown in FIG. 8, with the following specific steps:
in N 2 Under protection of (3), p-methoxyacetophenone (formula II-d) (1.25mmol, 187.7mg), 3-methylphenyl isocyanate (formula III-e) (0.5mmol, 66.6mg), manganese pentacarbonyl bromide as a catalyst (0.025mmol, 13.8mg), aluminum chloride (0.5mmol, 66.7mg, sublimation treatment was required before use), silver trifluoromethanesulfonate (0.1mmol, 25.7mg) and 1,2-dichloroethane (5 mL) were sequentially charged into a 25mL Schlenk flask, and dimethylzinc (0.1mmol, 1.2M in toluene, 0.75mL) was added dropwise with shaking. The reaction was quenched with water at 90 ℃ for 12h and purified by column chromatography (eluent petroleum ether: ethyl acetate =20/1,v/v) to give 84.8mg of the target product (formula I-h) in 64% yield.
The target product was characterized as follows: 1 H NMR(300MHz,Chloroform-d):δ7.62(d,J＝8.4Hz,1H),7.38–7.36(m,2H),7.26–7.11(m,4H),5.08(d,J＝2.1Hz,1H),4.69(d,J＝2.1Hz,1H),3.89(s,3H),2.41(s,3H)； 13 C NMR(75MHz,Chloroform-d):δ166.6,161.4,143.0,139.3,134.6,130.7,129.1,129.0,128.9,128.8,125.2,121.4,120.7,106.0,89.4,55.9,21.4；HRMS(ESI)：Calculated for C 17 H 16 O 2 N + ([M+H] + ) 266.11756 and found.
Example 9: 6-methoxy-3-methylene-2- (3,5-dimethylphenyl) isoindolin-1-one (formula I-I)
The compounds of formula I-I were prepared according to the reaction scheme shown in FIG. 9, with the following specific steps:
at N 2 Under protection of (3), p-methoxyacetophenone (formula II-d) (1.25mmol, 187.7mg), 3,5-dimethylphenyl isocyanate (formula III-f) (0.5mmol, 66.6mg), manganese pentacarbonyl bromide (0.025mmol, 13.8mg) as a catalyst, aluminum chloride (0.5mmol, 66.7mg, sublimation treatment was required before use), silver trifluoromethanesulfonate (0.1mmol, 25.7mg) and 1,2-dichloroethane (5 mL) were sequentially added to a 25mL Schlenk bottle, and dimethylzinc (0.9mmol, 1.2M in toluene, 0.75mL) was added dropwise with shaking. The reaction was quenched with water after 12h at 90 ℃ and purified by column chromatography (eluent petroleum ether: ethyl acetate =20/1,v/v) to give 84.8mg of the target product (formula I-I) in 64% yield.
The target product was characterized as follows: 1 H NMR(300MHz,Chloroform-d):δ7.62(d,J＝8.4Hz,1H),7.38–7.36(m,2H),7.26–7.11(m,4H),5.08(d,J＝2.1Hz,1H),4.69(d,J＝2.1Hz,1H),3.89(s,3H),2.41(s,3H)； 13 C NMR(75MHz,Chloroform-d):δ166.6,161.4,143.0,139.3,134.6,130.7,129.1,129.0,128.9,128.8,125.2,121.4,120.7,106.0,89.4,55.9,21.4；HRMS(ESI)：Calculated for C 17 H 16 O 2 N + ([M+H] + ) 266.11756 and found.
Comparative example: 6-methoxy-3-methylene-2- (p-tolyl) isoindolin-1-one (formula I-d)
The compounds of formula I-d were prepared according to the reaction scheme shown in FIG. 10, with the following specific steps:
in N 2 Under the protection of (1.25mmol, 187.7mg) of p-methoxyacetophenone (formula II-d), p-tolylisocyanate (formula III-a) (0.5mmol, 66.6mg), manganese pentacarbonyl bromide (0.025mmol, 13.8mg) as a catalyst, zinc bromide (0.5mmol, 112.6mg, sublimation treatment was required before use) and 1,2-dichloroethane (5 mL) were sequentially charged into a 25mL Schlenk flask, and dimethylzinc (0.9mmol, 1.2M in toluene, 0.75mL) was added dropwise while shaking. Reaction at 90 ℃ for 12hThe reaction was quenched with water and purified by column chromatography (eluent petroleum ether: ethyl acetate =20/1,v/v) to give the desired product (formula I-d) 6.6mg, 5% yield.
The target product was characterized as follows: 1 HNMR(400MHz,Chloroform-d)：δ7.63(d,J＝8.4Hz,1H),7.38(d,J＝2.4Hz,1H),7.34–7.21(m,4H),7.17(dd,J＝8.4,2.4Hz,1H),5.08(d,J＝2.0Hz,1H),4.69(d,J＝2.4Hz,1H),3.89(s,3H),2.41(s,3H)； 13 C NMR(101MHz,Chloroform-d)：δ166.8,161.5,143.2,138.1,132.0,130.8,130.1,129.1,128.0,121.4,120.8,106.1,89.3,55.9,21.3；HRMS(ESI)：Calculated for C 17 H 16 O 2 N + ([M+H] + ) 266.11756 and found.
In summary, the embodiment of the invention provides a preparation method of polysubstituted 3-methylene isoindoline-1-one, which realizes the synthesis of polysubstituted 3-methylene isoindoline-1-one by utilizing the reaction of arylethanone and isocyanate in a solvent in the presence of a catalyst.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention.
Claims (8)
1. The preparation method of the polysubstituted 3-methylene isoindoline-1-ketone shown in the formula I comprises the following steps: in the presence of a manganese catalyst, lewis acid and a zinc reagent, aryl ketone shown as a formula II and isocyanate shown as a formula III are subjected to cyclization reaction to obtain polysubstituted 3-methylene isoindoline-1-ketone shown as a formula I;
in the formula I and the formula II, R 1 Represents an unsubstituted, mono-substituted or polysubstituted group on the benzene ring, and is H, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, or a substituted or unsubstituted alkyl group having 1 to 1 carbon atom10, alkoxy, phenyl and halogen;
in the formula I and the formula III, R 2 Represents an unsubstituted, mono-substituted or polysubstituted group on a benzene ring, and is at least one of H, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, a benzyl group and halogen;
R 1 and R 2 Wherein a substituent of the substituted alkyl group having 1 to 10 carbon atoms or the substituted alkoxy group having 1 to 10 carbon atoms is halogen; the substitution is mono-substitution, di-substitution or tri-substitution;
the manganese catalyst is manganese pentacarbonyl bromide or manganese decacarbonyl;
the Lewis acid consists of Lewis acid I and Lewis acid II;
the Lewis acid I is aluminum chloride, copper trifluoromethanesulfonate, copper acetate or zinc bromide; the dosage of the Lewis acid I is 60-150% of the molar weight of the isocyanate shown in the formula III;
the Lewis II is silver trifluoromethanesulfonate, silver carbonate or silver sulfate; the dosage of the Lewis II is 5-50% of the molar weight of the isocyanate shown in the formula III;
the zinc reagent is dimethyl zinc;
the solvent for the cyclization reaction is 1,2-dichloroethane or methyl tert-butyl ether.
2. The method of claim 1, wherein: r 1 Is H, methyl, methoxy, phenyl or chlorine; r 2 Is H, methyl, trifluoromethyl, methoxy, trifluoromethoxy, chlorine, iodine or benzyl.
3. The production method according to claim 1 or 2, characterized in that: the molar ratio of the manganese catalyst to the isocyanate shown in the formula III is 1:10 to 20.
4. The production method according to any one of claims 1 to 2, characterized in that: the dosage of the zinc reagent is 150-200% of the molar weight of the isocyanate shown in the formula III.
5. The production method according to any one of claims 1 to 2, characterized in that: the molar ratio of arylethanone shown in the formula II to isocyanate shown in the formula III is 2.5 to 3.0:1.
6. the production method according to any one of claims 1 to 2, characterized in that: in the cyclization reaction system, the molar concentration of the isocyanate shown in the formula III is 0.05 to 0.1mol/L.
7. The production method according to any one of claims 1 to 2, characterized in that: the temperature of the cyclization reaction is 80-100 ℃, and the time is 6-24 h.
8. The production method according to any one of claims 1 to 2, characterized in that: the cyclization reaction is carried out under the protection of inert gas.
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