CN108863740B - Preparation method of naphthalenone compound - Google Patents
Preparation method of naphthalenone compound Download PDFInfo
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
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- C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
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Abstract
The invention provides a synthetic method for preparing a naphthalenone compound, which has the advantages of simple process, low cost and wide reaction substrate application range.
Description
Technical Field
The application belongs to the field of organic synthesis, and particularly relates to a preparation method of a naphthalenone compound.
Background
The naphthalenone compound is used as an important chemical product and an intermediate, and has wide application in the fields of medicines, pesticides, dyes and the like. In the agricultural chemical industry for the production of insecticides, herbicides, etc.; dyes are used industrially to produce anthraquinone dyes; the pharmaceutical industry is mainly used for the production of pharmaceutical intermediates such as sertraline and the like. The conventional methods for synthesizing naphthalenones mainly comprise oxidation of tetralin derivatives, condensation of aromatic ring compounds with gamma-butyrolactone, and cyclization of gamma-phenylbutyryl chloride. However, the conventional methods still have the defects of narrow substrate adaptation range, environmental pollution and the like.
Shushoyun et al reported a method for preparing polysubstituted naphthol derivatives (CN 103467282A; org. Lett., Vol.15, No.18,2013), which uses 2-bromophenylacetone compounds and phenylacetylene compounds as raw materials, and dehydrocyclizes them under the photocatalysis condition to obtain polysubstituted naphthol derivatives.
Through intensive research, the inventor provides a novel method for synthesizing the naphthalenone compound by serial cyclization in the presence of a cheap transition metal copper catalyst by taking a 2-bromophenylacetone compound and a phenylacetylene compound as reaction raw materials.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a synthetic method for preparing the naphthalenone compound, which has the advantages of simple process, low cost and wide reaction substrate application range.
The preparation method of the naphthalenone compound provided by the invention comprises the following steps:
adding a 2-bromophenylacetone compound shown in formula I, a substituted acetylene compound shown in formula II, a copper catalyst, a ligand, an alkali and an organic solvent into a Schlenk tube-sealed reactor, heating and stirring for reaction under an inert atmosphere, detecting by TLC that the reaction is complete, and performing post-treatment to obtain a target product shown in formula III.
In the formulae I and III, R1Represents one or more substituents on the attached phenyl ring selected from hydrogen, C1-C20Alkyl of (C)1-C20Alkoxy group of (C)2-C20Alkenyl of, C1-C20Alkylthio of, C6-C20Aryl of (C)5-C20Heteroaryl of (A), C3-C20Cycloalkyl, nitro, halogen, -OH, -SH, -CN, -COOR5、-COR6、-OCOR7、-NR8R9(ii) a Wherein R is5、R6、R7、R8、R9Each independently selected from hydrogen and C1-C20Alkyl of (C)6-C20Aryl of (C)5-C20Heteroaryl of (A), C3-C20Any one or more of cycloalkyl groups of (a).
Wherein the alkyl, alkenyl, aryl, heteroaryl, cycloalkyl moieties in each of the above substituents are optionally substituted by one or moreA plurality is selected from C1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Acyl, halogen, -NO of2、-CN、-OH、C6-C20Aryl of (C)3-C6Cycloalkyl groups of (a).
Preferably, said R is1Represents one or more substituents on the attached ring selected from hydrogen, C1-C6Alkyl of (C)1-C6Alkoxy group of (C)6-C14Aryl of (C)5-C12Heteroaryl of (A), C3-C8Cycloalkyl, nitro, halogen, -OH, -SH, -CN, -COOR5、-COR6、-OCOR7、-NR8R9(ii) a Wherein R is5、R6、R7、R8、R9Each independently selected from hydrogen and C1-C6Alkyl of (C)6-C12Aryl of (C)3-C12Heteroaryl of (A), C3-C8A cycloalkyl group of (a). And the alkyl, aryl, heteroaryl, cycloalkyl moieties in each of the above substituents may optionally be substituted by one or more substituents selected from C1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Acyl, halogen, -NO of2、-CN、-OH、C6-C12Aryl of (C)3-C6Cycloalkyl groups of (a).
Further preferably, said C1-C6The alkyl group of (a) is selected from methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl; said C is1-C6The alkoxy group of (a) is selected from methoxy, ethoxy, propoxy, butoxy; said C6-C12The aryl group of (a) is selected from phenyl, naphthyl, anthracenyl; said C3-C12The heteroaryl group of (a) is selected from thienyl, imidazolyl, pyridyl; said C3-C8The cycloalkyl group of (a) is selected from cyclopropyl, cyclobutyl, cyclohexyl; wherein each of the above groups may optionally be substituted by one or more groups selected from C1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Acyl, halogen, -NO of2、-CN、-OH、C6-C12Aryl of (C)3-C6Cycloalkyl groups of (a).
Most preferably, R1Represents one or more substituents on the attached ring selected from hydrogen, methyl, methoxy, halogen, acetyl, nitro, -CN.
In the above formulae II and III, R represents C1-C20Alkyl of (C)3-C20A cycloalkyl group of3-C20The heteroaryl group of (a). Wherein each of the above groups may optionally be substituted by one or more groups selected from C1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Acyl, halogen, -NO of2、-CN、-OH、C6-C12Aryl of (C)3-C6Cycloalkyl groups of (a).
Preferably, R is selected from C1-C10Alkyl of (C)3-C10A cycloalkyl group of3-C12The heteroaryl group of (a). Wherein each of the above groups may optionally be substituted by one or more groups selected from C1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Acyl, halogen, -NO of2、-CN、-OH、C6-C12Aryl of (C)3-C6Cycloalkyl groups of (a).
More preferably, said C represented by said R1-C6The alkyl group of (a) may be selected from methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl; said C3-C10The cycloalkyl group of (a) may be selected from phenyl, naphthyl, anthracenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclopentenyl; said C3-C12Heteroaryl of (a) may be selected from thienyl, imidazolyl, pyridyl; wherein each of the above groups may optionally be substituted by one or more groups selected from C1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Acyl, halogen, -NO of2、-CN、-OH、C6-C12Aryl of (C)3-C6Cycloalkyl groups of (a).
Most preferably, R is selected from butyl, phenyl, cyclopropyl, cyclohexenyl, halogen substituted phenyl, C1-C6Alkyl-substituted phenyl of (1), C1-C6Alkoxy substituted phenyl, thienyl.
According to the reaction of the invention, the copper catalyst is selected from Cu (MeCN)4PF6Any one of copper halide, cuprous halide and copper acetate. Wherein, preferably, the copper catalyst is selected from Cu (MeCN)4PF6、CuI、CuCl、CuBr2Most preferably Cu (MeCN)4PF6。
According to the reaction, the ligand is selected from any one of 1, 10-phenanthroline and 2, 2-bipyridine. In the present invention, although the reaction can be carried out without using a ligand, the inventors have found that the use of a 1, 10-phenanthroline or 2, 2-bipyridine ligand has an excellent accelerating effect on the reaction. Preferably, the ligand is 1, 10-phenanthroline.
According to the aforementioned reaction of the invention, the base may be selected from alkali metal carbonates, alkali metal bicarbonates, Ag2CO3Preferably, the base is selected from K2CO3、Na2CO3、Ag2CO3Most preferably, the base is K2CO3. The inventors have found that the presence of a base is one of the necessary conditions, and that in the absence of a base, or where the base is another type of base such as triethylamine, the reaction does not proceed or only traces of the target product can be determined by GC.
According to the aforementioned reaction of the present invention, the organic solvent is selected from any one or a mixture of several of toluene, acetonitrile, chlorobenzene and dioxane, and most preferably, the organic solvent is toluene. The amount of the solvent used is not particularly limited so that each reaction material is sufficiently dispersed.
The aforementioned reaction according to the present invention, wherein the inert atmosphere refers to a nitrogen atmosphere or an argon atmosphere.
The temperature range of the heating and stirring reaction is 100-140 ℃, the preferred temperature range is 110-130 ℃, and the most preferred temperature range is 120 ℃.
According to the aforementioned method of the present invention, wherein the reaction time of the heating and stirring reaction can be determined by follow-up monitoring by TLC plate, the reaction is completed within 12 to 24 hours, and the preferable reaction time is 16 hours.
According to the method, the molar ratio of the compound shown in the formula (I) to the compound shown in the formula (II), the copper catalyst, the ligand and the base is (2-3) to 1 (0.05-0.2) to (0.1-0.3): (1-3), and most preferably, the molar ratio of the compound represented by the formula (I), the compound represented by the formula (II), the copper catalyst, the ligand and the base is 2:1:0.1:0.2: 2.
The method according to the present invention, wherein the post-processing operation is as follows: and filtering the mixed solution after the reaction is finished through a short column of silica gel, washing a filter cake by ethyl acetate, concentrating under reduced pressure to obtain a residue, and performing column chromatography separation by using n-hexane and ethyl acetate as eluent to obtain the target product shown in the formula III.
The invention has the following beneficial effects:
1. the invention reports a synthetic strategy for preparing the naphthalenone compound shown in the formula III by heating, stirring and reacting a 2-bromophenylacetone compound shown in the formula I, a substituted acetylene compound shown in the formula II, a copper catalyst, a ligand, alkali and an organic solvent in an inert atmosphere for the first time, and the method is not reported in the prior art.
2. The method of the invention uses cheap copper catalyst, which reduces the cost obviously.
3. The method has the advantages of wide reaction substrate application range, simple operation and high yield of target products.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
Examples 1-19 optimization of reaction conditions
2-bromophenylacetone shown in a formula I-1 and phenylacetylene shown in a formula II-1 are used as reaction raw materials, the influence of different reaction conditions on the optimization result of the synthesis process is discussed, and representative examples 1-19 are selected. The results are shown in table one.
The operation of example 1 is as follows:
to a Schlenk closed-loop reactor was added 2-bromophenylacetone of the formula I-1 (42.4mg,0.2mmol), phenylacetylene of the formula II-1 (10.2mg,0.1mmol), Cu (MeCN)4PF6(7.46mg,10mol％)，1,10-phen(7.2mg,20mol％),K2CO3(55.2mg,2equiv) and toluene (2mL) under argon at 120 ℃ with stirring, detecting completion of the reaction by TLC (about 16 hours), then filtering the reaction solution through a short silica gel column, washing the filter cake with ethyl acetate, concentrating under reduced pressure to obtain a residue, and separating the residue by silica gel column chromatography (n-hexane/ethyl acetate volume ratio is 100:1) to obtain the target product of formula III-1. The yield is 82 percent; d.r. ═ 1.1: 1; a colorless oily liquid;1H NMR(400MHz,CDCl3)δ:8.19(d,J＝8.0Hz,0.5H),8.04(d,J＝7.6Hz,1H),7.98(d,J＝8.4Hz,0.5H),7.85(d,J＝8.4Hz,1H),7.53-7.30(m,11H),7.21-7.17(m,1H),6.54(s,0.43H),6.22(s,0.57H),4.41-4.33(m,1H),1.40(s,1.59H),1.37(d,J＝7.6Hz,1.61H),1.30(s,1.52H),1.15(d,J＝6.8Hz,1.42H)；13C NMR(100MHz,CDCl3)δ:139.8,139.4,138.1,138.0,137.7,136.7,136.6,135.6,135.0,134.3,133.9,133.2,132.7,129.3,129.2,128.9,128.7,128.5,128.5,128.4,128.3,127.8,127.6,127.5,127.4,127.4,126.6,128.4,50.9,50.0,48.6,47.3,23.9,23.3,14.7,12.3.HRMS m/z(ESI)calcd for C26H23O2([M+H]+)367.1693,found 367.1701.。
table one:
the specific operations and parameters of examples 2-19 were the same as in example 1, except that the variables listed in Table one above were different from those of example 1. And wherein the structures of ligands L3, L4 are as follows:
it can be seen from examples 1 to 19 that a yield of 61% of the target product can still be achieved without the addition of a ligand (example 2), that 2, 2' -bipyridine as ligand also has a certain promoting effect on the reaction (example 3), and that other ligands such as L3, L4 have an adverse effect on the reaction (examples 4 to 5); tests on catalyst type replacement show that other copper catalysts such as CuI, CuCl, CuBr2 all give moderate yields, but none are as good as but significantly inferior to Cu (MeCN)4PF6Examples 6 to 8, Cu (MeCN)4PF6And the amount of ligand does not significantly affect the reaction, and the amounts of ligand charged are preferably 10 mmol% and 20 mmol% relative to phenylacetylene (examples 9 to 10). The reaction must be carried out in the presence of a base, in the presence of K2CO3The best results (examples 11 to 14); the replacement of the organic solvent with chlorobenzene, acetonitrile, dioxane still allowed to achieve essentially equivalent yields of the desired product, with an optimal temperature selection of 120 deg.C (examples 15-19).
As can be seen from the above examples 1-19, the optimum reaction conditions are those of example 1, i.e. the catalyst is selected from Cu (MeCN)4PF6The ligand is selected from 1,10-phen, the alkali is potassium carbonate, the solvent is toluene, and the reaction temperature is 120 ℃. On the basis of obtaining the optimal reaction conditions, the inventor further selects reaction raw materials with different substituents under the optimal reaction conditions to prepare eachNaphthalenones of formula III.
Example 20
To a Schlenk closed-tube reactor was added 2-bromophenylacetone (0.2mmol) of the formula I-1, p-methylphenylacetylene (0.1mmol) of the formula II-2, Cu (MeCN)4PF6(10mol％)，1,10-phen(20mol％),K2CO3(2equiv) and toluene (2mL) under argon at 120 ℃ with stirring, TLC to detect completion of the reaction (about 16 hours), then filtering the reaction solution through a short silica gel column, washing the filter cake with ethyl acetate, concentrating under reduced pressure to obtain a residue, and separating the residue through silica gel column chromatography to obtain the target product of formula III-2. The yield is 78 percent; d.r. ═ 1: 1; a colorless oily liquid;1H NMR(400MHz,CDCl3)δ:8.17(d,J＝7.6Hz,0.5H),8.03(d,J＝8.0Hz,1H),7.97(d,J＝7.6Hz,0.5H),7.84(d,J＝7.6Hz,1H),7.59-7.36(m,5H),7.30-7.20(m,5H),6.51(s,0.5H),6.19(s,0.5H),4.41-4.29(m,1H),2.41(s,3H),1.39(s,1.50H),1.36(d,J＝7.2Hz,1.50H),1.29(s,1.50H),1.14(d,J＝6.8Hz,1.50H).；13C NMR(100MHz,CDCl3)δ:203.3,202.7,202.6,202.4,138.3,138.2,137.7,137.2,137.1,136.8,136.7,136.4,136.3,135.4,134.9,134.2,133.9,133.2,132.7,129.2,129.2,129.0,129.0,129.0,128.7,128.5,128.4,127.7,127.5,127.3,126.4,126.4,50.9,50.0,48.6,47.3,23.9,23.2,21.2,14.6,12.3.HRMS m/z(ESI)calcd for C27H25O2([M+H]+)381.1849,found 381.1855.。
example 21
To a Schlenk closed-tube reactor was added 2-bromophenylacetone (0.2mmol) of the formula I-1, p-chlorophenylacetylene (0.1mmol) of the formula II-3, Cu (MeCN)4PF6(10mol％)，1,10-phen(20mol％),K2CO3(2equiv) and toluene(2mL), the reaction was stirred at 120 ℃ under argon, the completion of the reaction was checked by TLC (about 16 hours), the reaction was then filtered through a short silica gel column, the filter cake was washed with ethyl acetate, and the residue was concentrated under reduced pressure and isolated by silica gel column chromatography to give the desired product of formula III-3. The yield is 75%; d.r. ═ 1.5: 1; a white solid;1H NMR(400MHz,CDCl3)δ:8.19(d,J＝7.6Hz,0.41H),8.04(d,J＝7.6Hz,0.82H),7.98(d,J＝7.6Hz,0.66H),7.85(d,J＝7.6Hz,1.28H),7.52-7.32(m,9H),7.14(t,J＝7.6Hz,1H),6.54(s,0.41H),6.22(s,0.62H),4.41-4.33(m,1H),1.39(s,1.82H),1.37(d,J＝6.8Hz,1.87H),1.30(s,1.21H),1.13(d,J＝6.8Hz,1.23H)；13C NMR(100MHz,CDCl3)δ:202.9,202.8,202.6,202.0,138.2,137.8,137.8,137.6,137.6,137.0,136.6,136.0,135.6,134.3,134.0,133.5,133.4,133.3,132.8,130.7,130.5,128.9,128.8,128.5,128.5,128.4,128.0,127.8,127.5,126.3,126.1,51.0,50.1,48.6,47.3,23.9,23.3,14.7,12.3.HRMS m/z(ESI)calcd for C26H22ClO2([M+H]+)401.1303,found 401.1322.。
example 22
To a Schlenk closed-tube reactor was added 2-bromophenylacetone (0.2mmol) of the formula I-1, p-acetylphenylacetylene (0.1mmol) of the formula II-4, Cu (MeCN)4PF6(10mol％)，1,10-phen(20mol％),K2CO3(2equiv) and toluene (2mL) under argon at 120 ℃ with stirring, TLC to detect completion of the reaction (about 16 hours), then filtering the reaction solution through a short silica gel column, washing the filter cake with ethyl acetate, concentrating under reduced pressure to obtain a residue, and separating the residue through silica gel column chromatography to obtain the target product of formula III-4. The yield is 54 percent; d.r are provided.>20: 1; a colorless oily liquid;1H NMR(400MHz,CDCl3)δ:8.02(t,J＝8.4Hz,3H),7.86(d,J＝7.6Hz,2H),7.54-7.45(m,4H),7.41(t,J＝7.6Hz,2H),7.34(t,J＝7.6Hz,1H),7.13(d,J＝8.0Hz,1H),6.27(s,1H),4.45-4.32(m,1H),2.66(s,3H),1.41(s,3H),1.38(d,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3)δ:202.8,202.8,197.7,144.8,137.4,136.5,136.4,136.3,134.3,134.0,132.9,129.6,128.9,128.5,128.4,127.9,127.6,126.1,50.1,48.6,26.7,23.3,12.3.HRMS m/z(ESI)calcd for C28H25O3([M+H]+)409.1798,found 409.1808.。
example 23
To a Schlenk closed-tube reactor was added 2-bromophenylacetone (0.2mmol) of the formula I-1, o-methylphenylacetylene (0.1mmol) of the formula II-5, Cu (MeCN)4PF6(10mol％)，1,10-phen(20mol％),K2CO3(2equiv) and toluene (2mL) under argon at 120 ℃ with stirring, TLC to detect completion of the reaction (about 16 hours), then filtering the reaction solution through a short silica gel column, washing the filter cake with ethyl acetate, concentrating under reduced pressure to obtain a residue, and separating the residue through silica gel column chromatography to obtain the target product of formula III-5. The yield is 69%; d.r. ═ 1: 1; a colorless oily liquid;1H NMR(400MHz,CDCl3)δ:8.03(d,J＝7.6Hz,0.51H),7.97(d,J＝7.6Hz,0.50H),7.88(t,J＝7.2Hz,2H),7.52-7.39(m,4H),7.32-7.22(m,5H),6.84(d,J＝7.6Hz,0.53H),6.79(d,J＝8.0Hz,0.50H),6.21(s,0.52H),6.18(s,0.49H),4.45-4.35(m,1H),2.28(s,1.52H),2.19(s,1.53H),1.40(d,J＝6.8Hz,3H),1.36(d,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3)δ:203.5,203.3,202.9,202.7,139.3,139.2,139.4,139.3,137.6,136.7,136.6,136.5,135.4,135.0,134.5,134.1,134.1,132.8,132.7,130.2,130.1,130.0,129.8,128.6,128.5,128.4,127.7,127.7,127.4,127.3,126.3,126.2,126.1,125.7,50.0,49.7,49.3,48.8,24.2,23.6,19.8,19.6,12.4,12.3.HRMS m/z(ESI)calcd for C27H25O2([M+H]+)381.1849,found 381.1859.。
example 24
To a Schlenk closed-tube reactor was added 2-bromophenylacetone (0.2mmol) of the formula I-1, 2-thiopheneacetylene (0.1mmol) of the formula II-6, Cu (MeCN)4PF6(10mol％)，1,10-phen(20mol％),K2CO3(2equiv) and toluene (2mL) under argon at 120 ℃ with stirring, TLC to detect completion of the reaction (about 16 hours), then filtering the reaction solution through a short silica gel column, washing the filter cake with ethyl acetate, concentrating under reduced pressure to obtain a residue, and separating the residue through silica gel column chromatography to obtain the target product of formula III-6. The yield is 74 percent; d.r. ═ 1: 1; a colorless oily liquid;1H NMR(400MHz,CDCl3)δ:8.18(d,J＝7.6Hz,0.52H),8.04(d,J＝7.6Hz,1H),7.99(d,J＝8.0Hz,0.55H),7.85(d,J＝7.6Hz,1H),7.57-7.29(m,8H),7.14(t,J＝5.6Hz,1H),6.62(s,0.48H),6.30(s,0.50H),4.41-4.31(m,1H),1.41-1.34(m,3H),1.29(s,1.52H),1.13(d,J＝6.8Hz,1.50H).；13C NMR(100MHz,CDCl3)δ:203.0,202.7,202.6,202.1,140.1,139.7,138.0,137.9,137.6,136.7,135.7,134.4,134.0,133.2,132.8,131.5,130.0,129.2,128.8,128.9,128.7,128.6,128.5,128.5,128.4,126.3,126.1,125.4,125.3,123.4,123.3,51.0,40.1,48.4,47.3,23.9,23.1,14.6,12.3.HRMS m/z(ESI)calcd for C24H21O2S([M+H]+)373.1257,found 373.1266.。
example 25
To a Schlenk closed-loop reactor was added 2-bromophenylacetone (0.2mmol) of the formula I-1, cyclopropylacetylene (0.1mmol) of the formula II-7, Cu (MeCN)4PF6(10mol％)，1,10-phen(20mol％),K2CO3(2equiv) and toluene (2mL) under argon at 120 ℃ with stirring, TLC to detect completion of the reaction (about 16 hours), then filtering the reaction solution through a short silica gel column, washing the filter cake with ethyl acetate, concentrating under reduced pressure to obtain a residue, and separating the residue through silica gel column chromatography to obtain the target product of formula III-7. The yield thereof was found to be 49%；d.r.>20: 1; a colorless oily liquid;1H NMR(400MHz,CDCl3)δ:7.92(d,J＝7.6Hz,1H),7.86(d,J＝8.0Hz,1H),7.80(d,J＝8.0Hz,2H),7.62(t,J＝7.6Hz,1H),7.47(d,J＝7.2Hz,1H),7.40-7.30(m,3H),6.08(s,1H),4.32-4.22(m,1H),1.35(d,J＝7.6Hz,3H),1.26(s,3H),0.88-0.81(m,2H),0.59-0.53(m,1H),0.52-0.45(m,1H)；13C NMR(100MHz,CDCl3)δ:203.6,202.8,139.1,136.7,134.0,132.7,132.5,132.2,128.6,128.4,128.4,127.3,127.0,124.4,49.5,48.4,23.4,13.4,12.3,5.4,5.1.HRMS m/z(ESI)calcd for C23H23O2([M+H]+)331.1693,found 331.1702.。
example 26
To a Schlenk closed-tube reactor was added 2-bromophenylacetone (0.2mmol) represented by formula I-1, cyclohexenylacetylene (0.1mmol) represented by formula II-8, Cu (MeCN)4PF6(10mol％)，1,10-phen(20mol％),K2CO3(2equiv) and toluene (2mL) under argon at 120 ℃ with stirring, TLC to detect completion of the reaction (about 16 hours), then filtering the reaction solution through a short silica gel column, washing the filter cake with ethyl acetate, concentrating under reduced pressure to obtain a residue, and separating the residue through silica gel column chromatography to obtain the target product of formula III-8. The yield is 58 percent; d.r are provided.>20: 1; a colorless oily liquid;1H NMR(400MHz,CDCl3)δ:8.11(d,J＝7.6Hz,1H),8.05(d,J＝8.0Hz,2H),7.58(t,J＝7.2Hz,2H),7.49(t,J＝7.6Hz,2H),7.39-7.31(m,2H),6.36(s,1H),5.70(s,1H),4.39-4.31(m,1H),2.12-2.14(m,3H),1.79-1.68(m,4H),1.20(s,3H),1.06(d,J＝6.8Hz,3H).；13C NMR(100MHz,CDCl3)δ:202.9,202.7,138.7,138.1,137.8,136.9,134.3,133.5,133.2,129.2,128.7,128.5,127.4,127.3,126.7,126.0,50.6,46.9,29.7,25.3,24.0,22.9,22.2,14.6.HRMS m/z(ESI)calcd for C26H27O2([M+H]+)371.2006,found 371.2013.。
example 27
To a Schlenk closed-loop reactor was added 2-bromophenylacetone (0.2mmol) of the formula I-1, butylacetylene (0.1mmol) of the formula II-9, Cu (MeCN)4PF6(10mol％)，1,10-phen(20mol％),K2CO3(2equiv) and toluene (2mL) under argon at 120 ℃ with stirring, TLC to detect completion of the reaction (about 16 hours), then filtering the reaction solution through a short silica gel column, washing the filter cake with ethyl acetate, concentrating under reduced pressure to obtain a residue, and separating the residue through silica gel column chromatography to obtain the target product of formula III-9. The yield is 53 percent; d.r are provided.>20: 1; a colorless oily liquid;1H NMR(400MHz,CDCl3)δ:8.14(d,J＝7.6Hz,1H),8.06(d,J＝7.6Hz,2H),7.65-7.55(m,2H),7.52-7.44(m,3H),7.37(d,J＝8.4Hz,1H),6.41(s,1H),4.38-4.32(m,1H),2.65-2.55(m,2H),1.66-1.56(m,3H),1.48-1.40(m,2H),1.18(s,3H),1.05(d,J＝6.8Hz,3H),0.95(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ:203.0,202.9,138.3,137.8,134.4,133.6,133.2,133.0,129.2,128.7,128.5,127.5,127.3,124.1,50.7,46.8,32.5,30.9,24.2,22.6,14.6,14.0.HRMS m/z(ESI)calcd for C24H27O2([M+H]+)347.2006,found 347.2019。
example 28
To a Schlenk closed tube reactor was added 2-bromo-1- (4-methoxyphenyl) propan-1-one (0.2mmol) represented by formula I-2, phenylacetylene (0.1mmol) represented by formula II-1, Cu (MeCN)4PF6(10mol％)，1,10-phen(20mol％),K2CO3(2equiv) and toluene (2mL) under argon at 120 ℃ with stirring, detecting completion of the reaction by TLC (about 16 hours), filtering the reaction solution through a short silica gel column, washing the filter cake with ethyl acetate, concentrating under reduced pressure to give a residue, and separating the residue by silica gel column chromatography to give a compound of formula III-10And (4) obtaining a target product. The yield is 78 percent; d.r. ═ 1: 1; a colorless oily liquid;1H NMR(400MHz,CDCl3)δ:8.18(d,J＝8.4Hz,1H),8.06(d,J＝8.4Hz,2H),7.48-7.36(m,5H),6.96(d,J＝7.6Hz,2H),6.90(d,J＝8.8Hz,1H),6.68(s,1H),6.60(s,1H),4.38-4.30(m,1H),3.88(s,3H),3.76(s,3H),1.26(s,3H),1.08(d,J＝8.8Hz,3H)；13C NMR(100MHz,CDCl3)δ:201.2,201.0,164.4,163.7,140.5,139.4,138.0,136.3,130.9,130.9,130.1,129.2,128.3,127.5,123.0,113.9,113.2,111.6,55.5,55.4,50.8,46.7,24.1,14.7.HRMS m/z(ESI)calcd for C28H27O4([M+H]+)427.1904,found 427.1911.。
a colorless oily liquid; 1H NMR (400MHz, CDCl)3)δ:8.18(d,J＝8.4Hz,1H),8.06(d,J＝8.4Hz,2H),7.48-7.36(m,5H),6.96(d,J＝7.6Hz,2H),6.90(d,J＝8.8Hz,1H),6.68(s,1H),6.60(s,1H),4.38-4.30(m,1H),3.88(s,3H),3.76(s,3H),1.26(s,3H),1.08(d,J＝8.8Hz,3H)；13C NMR(100MHz,CDCl3)δ:201.2,201.0,164.4,163.7,140.5,139.4,138.0,136.3,130.9,130.9,130.1,129.2,128.3,127.5,123.0,113.9,113.2,111.6,55.5,55.4,50.8,46.7,24.1,14.7.。
Example 29
To a Schlenk closed tube reactor was added 2-bromo-1- (4-methylphenyl) propan-1-one (0.2mmol) represented by formula I-3, phenylacetylene (0.1mmol) represented by formula II-1, Cu (MeCN)4PF6(10mol％)，1,10-phen(20mol％),K2CO3(2equiv) and toluene (2mL) under argon at 120 ℃ with stirring, TLC to detect completion of the reaction (about 16 hours), then filtering the reaction solution through a short silica gel column, washing the filter cake with ethyl acetate, concentrating under reduced pressure to obtain a residue, and separating the residue through silica gel column chromatography to obtain the target product of formula III-11. The yield is 75%; d.r. ═ 1: 1; a colorless oily liquid;1H NMR(400MHz,CDCl3)δ:8.09(d,J＝8.0Hz,1H),7.96(d,J＝8.0Hz,2H),7.44-7.34(m,5H),7.29(d,J＝8.0Hz,2H),7.21(d,J＝8.0Hz,1H),6.99(s,1H),6.53(s,1H),4.40-4.32(m,1H),2.42(s,3H),2.32(s,3H),1.27(s,3H),1.10(d,J＝6.8Hz,3H).；13C NMR(100MHz,CDCl3)δ:202.3,202.1,145.3,144.1,139.6,138.1,137.0,136.5,135.3,129.4,129.2,128.7,128.4,127.6,127.5,127.0,127.0,20.9,47.1,24.0,22.0,21.6,14.7.HRMS m/z(ESI)calcd for C28H27O2([M+H]+)395.2006,found 395.2014.。
a colorless oily liquid;1H NMR(400MHz,CDCl3)δ:1H NMR(400MHz,CDCl3)δ8.09(d,J＝8.0Hz,1H),7.96(d,J＝7.6Hz,2H),7.45-7.35(m,5H),7.29(d,J＝8.0Hz,2H),7.21(d,J＝8.0Hz,1H),6.99(s,1H),6.53(s,1H),4.39-4.33(m,1H),2.42(s,3H),2.32(s,3H),1.27(s,3H),1.10(d,J＝7.6Hz,3H)；13C NMR(100MHz,CDCl3)δ:202.4,202.1,145.3,144.1,139.6,138.1,137.0,136.5,135.3,129.4,129.2,128.7,128.4,127.6,127.5,127.0,20.9,47.1,24.0,22.0,21.6,14.7.。
example 30
To a Schlenk closed tube reactor was added 2-bromo-1- (4-methylphenyl) propan-1-one (0.2mmol) represented by formula I-3, 2-thiopheneacetylene (0.1mmol) represented by formula II-6, Cu (MeCN)4PF6(10mol％)，1,10-phen(20mol％),K2CO3(2equiv) and toluene (2mL) under argon at 120 ℃ with stirring, TLC to detect completion of the reaction (about 16 hours), then filtering the reaction solution through a short silica gel column, washing the filter cake with ethyl acetate, concentrating under reduced pressure to obtain a residue, and separating the residue through silica gel column chromatography to obtain the target product of formula III-12. The yield is 76%; d.r. ═ 1: 1; a colorless oily liquid;1H NMR(400MHz,CDCl3)δ:8.08(d,J＝8.0Hz,0.48H),7.95(d,J＝8.0Hz,0.59H),7.89(d,J＝7.6Hz,0.87H),7.75(d,J＝7.6Hz,1.1H),7.38(d,J＝7.6Hz,1H),7.29-7.11(m,6H),6.62(s,0.45H),6.28(s,0.55H),4.38-4.26(m,1H),2.42(s,1.32H),2.37(s,1.69H),2.36(s,1.32H),2.33(s,1.70H),1.37(s,1.66H),1.35(d,J＝8.4Hz,1.68H),1.26(s,1.39H),1.09(d,J＝6.8Hz,1.34H)；13C NMR(100MHz,CDCl3)δ:202.6,202.3,201.9,145.4,144.9,144.1,143.5,140.3,139.9,138.1,137.1,136.3,135.3,134.2,131.4,129.4,129.1,128.8,128.7,128.6,128.5,127.6,126.7,126.5,125.3,125.2,123.4,123.3,51.0,50.0,48.2,47.0,24.0,23.0,22.0,22.0,21.6,21.5,14.7,12.4.HRMS m/z(ESI)calcd for C26H25O2S([M+H]+)401.5435,found 401.5444.。
example 31
To a Schlenk closed tube reactor was added 2-bromo-1- (4-chlorophenyl) propan-1-one (0.2mmol) represented by formula I-4, phenylacetylene (0.1mmol) represented by formula II-1, Cu (MeCN)4PF6(10mol％)，1,10-phen(20mol％),K2CO3(2equiv) and toluene (2mL) under argon at 120 ℃ with stirring, TLC to detect completion of the reaction (about 16 hours), then filtering the reaction solution through a short silica gel column, washing the filter cake with ethyl acetate, concentrating under reduced pressure to obtain a residue, and separating the residue through silica gel column chromatography to obtain the target product of formula III-13. The yield is 69%; d.r. ═ 1.2: 1; a colorless oily liquid;1H NMR(400MHz,CDCl3)δ:8.09(d,J＝8.4Hz,1H),7.99(d,J＝8.0Hz,2H),7.51-7.35(m,8H),7.16(s,1H),6.53(s,1H),4.36-4.25(m,1H),1.29(s,3H),1.15(d,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3)δ:201.2,201.0,141.1,139.8,139.7,138.6,138.1,135.9,135.7,129.9,129.1,129.0,128.6,128.2,127.9,127.6,126.5,50.9,47.9,24.0,14.9.HRMS m/z(ESI)calcd for C26H21Cl2O2([M+H]+)435.0913,found 435.0922.。
a colorless oily liquid;1H NMR(400MHz,CDCl3)δ:7.91(d,J＝8.4Hz,1H),7.79(d,J＝8.0Hz,2H),7.47-7.37(m,8H),7.16(d,J＝7.6Hz,1H),6.28(s,1H),4.34-4.28(m,1H),1.38(s,3H),1.36(d,J＝7.6Hz,3H)；13C NMR(100MHz,CDCl3)δ:202.4,201.7,139.8,138.9,136.9,135.2,134.2,131.8,130.8,130.0,129.7,129.3,129.1,128.6,128.1,127.8,127.5,50.1,49.1,23.6,12.2.。
example 32
To a Schlenk closed-loop reactor was added 2-bromo-1- (4-bromophenyl) propan-1-one (0.2mmol) represented by formula I-5, phenylacetylene (0.1mmol) represented by formula II-1, Cu (MeCN)4PF6(10mol％)，1,10-phen(20mol％),K2CO3(2equiv) and toluene (2mL) under argon at 120 ℃ with stirring, TLC to detect completion of the reaction (about 16 hours), then filtering the reaction solution through a short silica gel column, washing the filter cake with ethyl acetate, concentrating under reduced pressure to obtain a residue, and separating the residue through silica gel column chromatography to obtain the target product of formula III-14. The yield is 74 percent; d.r. ═ 1.2: 1; a colorless oily liquid;1H NMR(400MHz,CDCl3)δ:8.03(d,J＝8.0Hz,1H),7.88(d,J＝8.4Hz,2H),7.63(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,1H),7.47-7.40(m,4H),7.31(d,J＝7.6Hz,2H),6.51(s,1H),4.29-4.22(m,1H),1.29(s,3H),1.15(d,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3)δ:201.4,201.2,139.6,138.5,138.0,136.1,135.8,132.1,131.1,130.0,129.5,129.1,129.0,128.6,127.9,50.8,47.7,23.9,14.6.HRMS m/z(ESI)calcd for C26H21Br2O2([M+H]+)522.9903,found 522.9911.。
a colorless oily liquid;1H NMR(400MHz,CDCl3)δ:1H NMR(400MHz,CDCl3)δ:7.82(d,J＝8.0Hz,1H),7.71(d,J＝8.0Hz,2H),7.55(d,J＝8.4Hz,2H),7.47-7.36(m,6H),7.33(s,1H),6.26(s,1H),4.35-4.26(m,1H),1.38(s,3H),1.35(d,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3)δ:202.4,201.7,139.8,138.9,136.9,135.2,134.2,131.8,130.8,130.0,129.7,129.3,129.1,128.6,128.1,127.8,127.5,50.1,49.1,23.6,12.2.。
example 33
To a Schlenk closed tube reactor was added 2-bromo-1- (3-methylphenyl) propan-1-one (0.2mmol) represented by formula I-6, phenylacetylene (0.1mmol) represented by formula II-1, Cu (MeCN)4PF6(10mol％)，1,10-phen(20mol％),K2CO3(2equiv) and toluene (2mL) under argon at 120 ℃ with stirring, TLC to detect completion of the reaction (about 16 hours), then filtering the reaction solution through a short silica gel column, washing the filter cake with ethyl acetate, concentrating under reduced pressure to obtain a residue, and separating the residue through silica gel column chromatography to obtain the target product of formula III-15. The yield is 63%; d.r. ═ 1: 1; a colorless oily liquid;1H NMR(400MHz,CDCl3)δ:7.99-7.89(m,1H),7.83(d,J＝7.2Hz,1H),7.78(d,J＝8.4Hz,1H),7.39-7.26(m,8H),7.10(d,J＝8.0Hz,1H),6.52(s,0.5H),6.46(s,0.5H),4.36-4.24(m,1H),2.42(s,3H),2.41(s,3H),1.30(s,1.50H),1.26(d,J＝7.2Hz,1.53H),1.15-1.10(m,3H).13C NMR(100MHz,CDCl3)δ:203.1,203.0,202.9,202.7,143.2,140.3,139.6,138.5,138.3,137.8,137.6,136.4,135.7,135.6,135.0,133.9,129.2,129.0,128.9,128.6,128.3,127.9,127.7,127.6,127.5,127.0,126.6,125.8,125.7,125.6,51.0,50.9,47.6,45.9,24.7,23.9,23.4,23.2,21.4,21.2,14.9,14.6.HRMS m/z(ESI)calcd for C28H27O2([M+H]+)395.2006,found 395.2014.。
the embodiments described above are only preferred embodiments of the invention and are not exhaustive of the possible implementations of the invention. Any obvious modifications to the above would be obvious to those of ordinary skill in the art, but would not bring the invention so modified beyond the spirit and scope of the present invention.
Claims (11)
1. A synthetic method of a naphthalenone compound is characterized by comprising the following steps: adding a 2-bromophenylacetone compound shown in formula I, a substituted acetylene compound shown in formula II, a copper catalyst, a ligand, an alkali and an organic solvent into a Schlenk tube-sealed reactor, heating and stirring for reaction under an inert atmosphere, detecting by TLC that the reaction is complete, and performing post-treatment to obtain a naphthalenone compound shown in formula III;
in the formulae I and III, R1Represents one or more substituents on the attached phenyl ring selected from hydrogen, C1-C20Alkyl of (C)1-C20Alkoxy group of (C)2-C20Alkenyl of, C1-C20Alkylthio of, C6-C20Aryl of (C)5-C20Heteroaryl of (A), C3-C20Cycloalkyl, nitro, halogen, -OH, -SH, -CN, -COOR5、-COR6、-OCOR7、-NR8R9(ii) a Wherein R is5、R6、R7、R8、R9Each independently selected from hydrogen and C1-C20Alkyl of (C)6-C20Aryl of (C)5-C20Heteroaryl of (A), C3-C20Any one or more of cycloalkyl groups of (a); and the alkyl, alkenyl, aryl, heteroaryl, cycloalkyl moieties in each of the above substituents are optionally substituted by one or more substituents selected from C1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Acyl, halogen, -NO of2、-CN、-OH、C6-C20Aryl of (C)3-C6Cycloalkyl of (a);
in the formulae II and III, R represents C1-C20Alkyl of (C)3-C20A cycloalkyl group of3-C20The heteroaryl group of (a); wherein each of the above R groups is optionally substituted by one or more groups selected from C1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Acyl, halogen, -NO of2、-CN、-OH、C6-C12Aryl of (C)3-C6Cycloalkyl of (a);
wherein the copper catalyst is selected from Cu (MeCN)4PF6A copper halide,Any one of cuprous halide and cupric acetate;
the ligand is selected from any one of 1, 10-phenanthroline and 2, 2-bipyridine;
the base is selected from alkali metal carbonate, alkali metal bicarbonate, Ag2CO3Any one of them.
2. The method of claim 1, wherein R is1Represents one or more substituents on the attached ring selected from hydrogen, C1-C6Alkyl of (C)1-C6Alkoxy group of (C)6-C14Aryl of (C)5-C12Heteroaryl of (A), C3-C8Cycloalkyl, nitro, halogen, -OH, -SH, -CN, -COOR5、-COR6、-OCOR7、-NR8R9(ii) a Wherein R is5、R6、R7、R8、R9Each independently selected from hydrogen and C1-C6Alkyl of (C)6-C12Aryl of (C)3-C12Heteroaryl of (A), C3-C8Cycloalkyl groups of (a); the alkyl, aryl, heteroaryl, cycloalkyl moieties in each of the above substituents are optionally substituted by one or more groups selected from C1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Acyl, halogen, -NO of2、-CN、-OH、C6-C12Aryl of (C)3-C6Cycloalkyl of (a);
and R is selected from C1-C10Alkyl of (C)3-C10A cycloalkyl group of3-C12The heteroaryl group of (a); wherein each of the above R groups is optionally substituted by one or more groups selected from C1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Acyl, halogen, -NO of2、-CN、-OH、C6-C12Aryl of (C)3-C6Cycloalkyl groups of (a).
3. The method of claim 2, wherein R is1Represents one or more substituents on the attached ring selected from hydrogen, halogen, methyl, ethyl, propyl, butyl, pentyl; methoxy, ethoxy, propoxy, butoxy; phenyl, naphthyl, anthracenyl; thienyl, imidazolyl, pyridyl; cyclopropyl, cyclobutyl, cyclohexyl; wherein each of the foregoing groups is optionally substituted with one or more groups selected from C1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Acyl, halogen, -NO of2、-CN、-OH、C6-C12Aryl of (C)3-C6Cycloalkyl of (a); and the combination of (a) and (b),
r is selected from methyl, ethyl, propyl, butyl, pentyl; phenyl, naphthyl, anthracenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclopentenyl; thienyl, imidazolyl, pyridyl; wherein each of the foregoing groups is optionally substituted with one or more groups selected from C1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Acyl, halogen, -NO of2、-CN、-OH、C6-C12Aryl of (C)3-C6Cycloalkyl groups of (a).
4. The method of claim 3, wherein R is1Represents one or more substituents on the attached ring selected from hydrogen, methyl, methoxy, halogen, acetyl, nitro, -CN; and the combination of (a) and (b),
r is selected from butyl, phenyl, cyclopropyl, cyclohexenyl, halogen substituted phenyl, C1-C6Alkyl-substituted phenyl of (1), C1-C6Alkoxy substituted phenyl, thienyl.
5. The method of any one of claims 1 to 4, wherein the copper catalyst is selected from the group consisting of Cu (MeCN)4PF6、CuI、CuCl、CuBr2The ligand is 1, 10-phenanthroline; the base is selected from K2CO3、Na2CO3、Ag2CO3Any one of them.
6. The method of claim 5, wherein the copper catalyst is Cu (MeCN)4PF6The base is K2CO3。
7. The method according to any one of claims 1 to 4, wherein the organic solvent is selected from any one or a mixture of toluene, acetonitrile, chlorobenzene and dioxane; the temperature range of the heating stirring reaction is 110-130 ℃.
8. The method of claim 7, wherein the organic solvent is selected from toluene and the temperature of the heated stirred reaction is 120 ℃.
9. The method according to any one of claims 1 to 4, wherein the molar ratio of the compound of formula (I), the compound of formula (II), the copper catalyst, the ligand and the base is (2-3) to 1 (0.05-0.2) to (0.1-0.3): (1-3).
10. The method of claim 9, wherein the molar ratio of the compound of formula (I), the compound of formula (II), the copper catalyst, the ligand, and the base is 2:1:0.1:0.2: 2.
11. The method according to any of claims 1-4, characterized in that the post-processing operation is as follows: and filtering the mixed solution after the reaction through a short column of silica gel, washing a filter cake by ethyl acetate, concentrating the filtrate under reduced pressure to obtain a residue, and performing column chromatography separation by using n-hexane and ethyl acetate as eluent to obtain the naphthalenone compound shown in the formula III.
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