A process for the preparation of a trifluoroacetimidate substituted dihydrobenzofuran compound

Abstract

The application discloses a preparation method of a trifluoroacetimidate-substituted dihydrobenzofuran compound, which comprises the following steps: under an air atmosphere, potassium carbonate, 2-alkyl-substituted phenol and trifluoroacetimidate sulfonium ylide are added into an organic solvent, and reaction is carried out at 40-60 DEG C for 10-15 hours; after the reaction is completed, post-treatment is carried out to obtain the trifluoroacetimidate-substituted dihydrobenzofuran compound. The preparation method has the advantages of simple operation, cheap and easily-obtained or easily-prepared starting materials, reaction under an air atmosphere, non-odorous and non-toxic potassium carbonate, non-use of heavy metal catalysts, high stereoselectivity, reaction can be enlarged to a gram level, easy operation, and wide application of the method.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a stereoselective preparation method of a trifluoroacetimide-substituted dihydrobenzofuran compound. Background Art

[0002] Dihydrobenzofuran compounds are an important class of benzo-oxygen heterocyclic compounds, which are widely found in various natural products, bioactive molecules and drug molecules (J.Med.Chem.1999,42,5475-5481), and have a series of important biological activities, such as anticancer, antifungal, antibacterial, antitrypanosomal and insecticidal activities (J.Med.Chem.2005,48,5589-5599; Biol.Pharm.Bull.2006,29,2126-2130). Due to the special properties of fluorine atoms, the introduction of fluorine-containing groups into heterocyclic molecules can significantly improve the physicochemical properties and pharmacodynamics of the parent compound (Chem.Rev.2014,114,2432-2506). Therefore, the efficient synthesis of dihydrobenzofuran compounds substituted with fluorine-containing groups has important research significance and application value.

[0003]

[0004] Traditional methods for synthesizing dihydrobenzofurans primarily rely on intramolecular cyclization reactions of various substrates, such as aromatic diazo esters with ether linkages and phenols bearing nonactivated olefinic groups. Another common synthetic strategy involves the [4+1] cycloaddition of ortho-quinone methylenes (o-QMs) with one-carbon substrates. Common carbon-one synthons include diazo compounds, dicarbonyl compounds, allenyl esters, and pyrazolone compounds. However, synthetic methods for structurally unique trifluoroacetimidyl-substituted dihydrobenzofurans are limited; the imine group can be derivatized to yield trifluoromethyl-bearing amines. Trifluoroacetimidylsulfur ylides have been developed as building blocks for trifluoromethyl-bearing heterocyclic compounds and have been applied to the synthesis of various trifluoromethyl-bearing heterocyclic compounds.

[0005] Based on this, we developed a simple, efficient and easy-to-operate [4+1] cyclization method for synthesizing highly stereoselective trifluoromethylpyrazole compounds using cheap and readily available 2-alkyl-substituted phenols as o-methylenequinone precursors and trifluoroacetimidosulfur ylide as starting materials, potassium carbonate as a promoter, and metal-free. Summary of the Invention

[0006] The present invention provides a preparation method of a trifluoroacetimide-substituted dihydrobenzofuran compound. The preparation method is simple to operate, and starting raw materials are cheap and easily available or easy to prepare. Conventional inorganic salt potassium carbonate is used as a promoter, and the participation of heavy metal catalysts is avoided. The reaction can be carried out in an air atmosphere, which is convenient for subsequent operation and large-scale application.

[0007] A method for preparing a trifluoroacetimide-substituted dihydrobenzofuran compound comprises the following steps: adding potassium carbonate, 2-alkyl-substituted phenol and trifluoroacetimide sulfur ylide to an organic solvent, reacting at 40-60° C. for 10-15 hours, and after the reaction is complete, post-treating to obtain the trifluoroacetimide-substituted 2,3-cis dihydrobenzofuran compound;

[0008] The structure of the 2-alkyl substituted phenol is shown in formula (II):

[0009]

[0010] The structure of the trifluoroacetimidosulfur ylide is shown in formula (III):

[0011]

[0012] The structure of the trifluoroacetimide-substituted dihydrobenzofuran compound is shown in formula (I):

[0013]

[0014] In formulas (I) to (III), R 1 is H, C1-C4 alkyl, C1-C4 alkoxy or halogen; R 2 is a C1-C6 alkyl group, a cycloalkyl group, or a substituted or unsubstituted phenyl group; R 3 is substituted or unsubstituted phenyl, naphthyl;

[0015] In R 1 and R 3 wherein the substituent on the phenyl group is selected from C1-C4 alkyl, C1-C4 alkoxy, methylthio, halogen, C1-C4 alkoxycarbonyl or trifluoromethyl;

[0016] R 3 The substitution position of the phenyl group can be ortho, para or meta.

[0017] The reaction formula is as follows:

[0018]

[0019] The reaction may first undergo a process in which, under the promotion of potassium carbonate, 2-alkyl substituted phenol removes a molecule of p-toluenesulfinic acid to obtain an o-methylene quinone intermediate, and the sulfur ylide acts as a nucleophilic reagent to undergo a nucleophilic addition reaction on the o-methylene quinone, followed by an intramolecular nucleophilic substitution (S N 2) The reaction produces a dihydrobenzofuran compound and simultaneously removes a molecule of dimethyl sulfoxide.

[0020] In the present invention, the optional post-treatment process includes: filtration, silica gel mixing, and finally column chromatography purification to obtain the corresponding trifluoroacetimide-substituted dihydrobenzofuran compound. Column chromatography purification is a commonly used technical means in the field.

[0021] As a preference, R 1 is methyl or halogen, R 2 It is a C1-C6 alkyl group, a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is selected from methyl or fluorine. In this case, the corresponding 2-alkyl substituted phenol is easy to obtain and the reaction yield is high.

[0022] As a preference, R 3 It is a substituted or unsubstituted phenyl or naphthyl group, and the substituent on the phenyl group is selected from methyl, methoxy, fluorine, chlorine, methoxycarbonyl or trifluoromethyl. In this case, the trifluoroacetimidosulfur ylide is easy to obtain and the reaction yield is high.

[0023] The trifluoroacetimidosulfur ylide is relatively easy to obtain and can be conveniently synthesized from trifluoroacetic acid, carbon tetrachloride, triphenylphosphine and iodomethyl sulfoxide. The amount used is excessive relative to the 2-alkyl-substituted phenol. Preferably, on a molar basis, the ratio of 2-alkyl-substituted phenol: trifluoroacetimidosulfur ylide: potassium carbonate is 1:1-1.5:2-4; and more preferably, on a molar basis, the ratio of 2-alkyl-substituted phenol: trifluoroacetimidosulfur ylide: potassium carbonate is 1:1.2:3.

[0024] In the present invention, any organic solvent that can fully dissolve the raw materials can cause the reaction to occur, but the reaction efficiency varies greatly. A halogen-containing solvent is preferred, as it can effectively promote the reaction. Preferably, the organic solvent is tetrahydrofuran, dichloromethane or chloroform. As a further preference, chloroform is the most suitable organic solvent. In this case, various raw materials can be converted into products at a higher conversion rate.

[0025] The amount of the organic solvent used is sufficient to dissolve the raw materials well. For 1 mmol of 2-alkyl-substituted phenol, the amount of the organic solvent used is about 5 to 10 mL.

[0026] Preferably, the accelerator is potassium carbonate, and the reaction efficiency is higher when potassium carbonate is used as the accelerator.

[0027] As a further preference, the trifluoroacetimide-substituted dihydrobenzofuran compound is one of the compounds represented by formula (I-1) to formula (I-5):

[0028]

[0029] In the above preparation method, the o-hydroxybenzaldehyde, Grignard reagent, sodium p-toluenesulfinate, aromatic amine, trifluoroacetic acid, iodomethyl sulfoxide, triethylamine and potassium carbonate are generally commercially available products and can be easily obtained from the market. The 2-alkyl substituted phenol can be obtained from o-hydroxybenzaldehyde, Grignard reagent and sodium p-toluenesulfinate through a simple coupling reaction; trifluoroacetimidosulfur ylide can be obtained by reacting trifluoroethylimidoyl chloride with iodomethyl sulfoxide; and trifluoroethylimidoyl chloride can be quickly synthesized from the corresponding aromatic amine, triphenylphosphine, carbon tetrachloride and trifluoroacetic acid.

[0030] Compared with the prior art, the advantages of the present invention are as follows: the preparation method is simple and easy to operate, and the post-processing is convenient; the reaction is carried out in an air atmosphere without the need for nitrogen protection; the reaction starting materials are cheap and easily available or easy to prepare, potassium carbonate is odorless and non-toxic, the reaction substrate is highly designable, and the substrate functional group compatibility range is wide. Different substituted dihydrobenzofuran compounds with trifluoromethyl groups can be designed and synthesized according to actual needs, and the method is highly practical. DETAILED DESCRIPTION

[0031] The present invention will be further described below with reference to specific embodiments.

[0032] According to the raw material ratio in Table 1, potassium carbonate, 2-alkyl substituted phenol (II), trifluoroacetimide sulfur ylide (III) and 2 mL of organic solvent were added to a 35 mL Schlenk tube, mixed and stirred evenly, and reacted for 10-15 hours according to the reaction conditions in Table 2. The mixture was filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding trifluoroacetimide substituted dihydrobenzofuran compound (I). The reaction process is shown in the following formula:

[0033]

[0034] Table 1 Amount of raw materials added in Examples 1 to 15

[0035]

[0036] Table 2

[0037]

[0038]

[0039] In Tables 1 and 2, T is the reaction temperature, t is the reaction time, Ph is a phenyl group, Me is a methyl group, OMe is a methoxy group, CO2Me is a methyl group, t-Bu is a tert-butyl group, Et is an ethyl group, i-Pr is an isopropyl group, and CHCl3 is chloroform.

[0040] The structural confirmation data of the compounds prepared in Examples 1 to 5 are as follows:

[0041] The nuclear magnetic resonance (NMR) of the trifluoroacetimide-substituted dihydrobenzofuran compound (I-1) prepared in Example 1 1 H NMR, 13 C NMR and 19 F NMR) detection data are:

[0042]

[0043] 1 H NMR (400MHz, CDCl3) δ7.34-7.33(m,3H),7.19(dd,J=10.6,4.2Hz,1H),7.13–7.11(m,2H),6.89(dd,J=13.1,7.3 Hz, 3H), 6.81 (d, J = 8.0Hz, 2H), 6.27 (d, J = 8.1Hz, 2H), 5.41 (d, J = 9.1Hz, 1H), 4.93 (d, J = 9.2Hz, 1H), 2.22 (s, 3H).

[0044] 13 C NMR(101MHz,CDCl3)δ158.9,156.1(CF,q, 2 J(CF)=31.6Hz),143.4,140.1,135.2,129.4,129.3,129.2,129.1,128.7,128.0,125.2,122.0,119.7(CF,q, 1 J(CF)=281.5Hz),118.5,110.1,84.3,53.5,20.9.

[0045] 19 F NMR (377MHz, CDCl3) δ-61.3,-66.7.

[0046] HRMS(ESI):[M+H] + calcd for C 23 H 19 F3NO + 382.1413, found 382.1416.

[0047] The nuclear magnetic resonance (NMR) of the trifluoroacetimide-substituted dihydrobenzofuran compound (I-2) prepared in Example 2 1 H NMR, 13 C NMR and 19 F NMR) detection data are:

[0048]

[0049] 1 H NMR(400MHz, CDCl3)7.34(dd,J=5.1,1.8Hz,3H),7.18(dt,J=8.4,4.3Hz,1H),7.12–7.10(m,2H),6.95(d,J=8.6Hz,2H), 6.90(d,J=4.3Hz,2H), 6.82(d,J=8.1Hz,1H), 6.28(d,J=8.6Hz,2H), 5.33(dd,J=9.2,1.3Hz,1H), 4.90(d,J=9.2Hz,1H).

[0050] 13 C NMR(101MHz,CDCl3)δ158.7,157.2(CF,q, 2 J (C-F) =31.8Hz),144.5,139.8,130.9,129.3,129.2,129.0,128.8,128.6,128.2,125.2,122.2,120.9(CF,q, 1 J (C-F) =281.1Hz),119.5,110.1,84.7,53.7.

[0051] 19 F NMR (377MHz, CDCl3) δ-61.3,-67.1.

[0052] HRMS(ESI):[M+H] + calcd for C 22 H 16 ClF3NO + 402.0867, found 402.0863.

[0053] The nuclear magnetic resonance (NMR) of the trifluoroacetimide-substituted dihydrobenzofuran compound (I-3) prepared in Example 3 1 H NMR, 13 C NMR and 19 F NMR) detection data are:

[0054]

[0055] 1 H NMR (400MHz, CDCl3) δ7.20–7.08(m,2H),6.93–6.87(m,3H),6.82(d,J=8.8Hz,2H),6.75(d, J=8.0Hz,1H),5.12(d,J=7.8Hz,1H),3.80(s,3H),3.80–3.71(m,1H),1.22(d,J=6.8Hz,3H).

[0056] 13 C NMR(101MHz,CDCl3)δ158.4,157.7,157.2(CF,q, 2 J(CF)=31.5Hz),139.9,130.4,128.6,123.8,121.6,120.2,119.6(CF,q, 1 J(CF)=280.6Hz),114.5,110.0,83.5,55.6,41.8,19.4.

[0057] 19 F NMR (377MHz, CDCl3) δ-61.2,-67.8.

[0058] HRMS(ESI):[M+H] + calcd for C 18 H 17 F3NO2 + 336.1206, found 336.1209.

[0059] The nuclear magnetic resonance (NMR) of the trifluoroacetimide-substituted dihydrobenzofuran compound (I-4) prepared in Example 4 1 H NMR, 13 C NMR and 19 F NMR) detection data are:

[0060] 1H NMR (400MHz, CDCl3) δ7.19(dd,J=11.2,4.8Hz,1H),7.09(dd,J=8.4,5.5Hz,2H),7.01(t,J=8.5Hz,2H),6.88(t,J=7 .9Hz,3H),6.58(d,J=8.8Hz,2H),6.38(d,J=8.8Hz,2H),5.40(d,J=9.1Hz,1H),4.90(d,J=9.1Hz,1H),3.71(s,3H).

[0061] 13 C NMR (101MHz, CDCl3) δ163.7,161.3,158.8,157.8,155.8(CF,q, 2 J(CF)=31.5Hz),139.1,136.1,130.2(d,J=8.1Hz),129.3,125.1,122.1,120.3,119.7(CF,q, 1 J(CF)=281.1Hz),116.1(d,J=21.6Hz),114.1,110.2,84.2,55.5,52.7.

[0062] 19 F NMR (377MHz, CDCl3) δ-60.4,-66.1,-115.1.

[0063] HRMS(ESI):[M+H] + calcd for C 23 H 18 F4NO2 + 416.1268, found 416.1273.

[0064] The nuclear magnetic resonance (NMR) of the trifluoroacetimide-substituted dihydrobenzofuran compound (I-5) prepared in Example 5 1 H NMR, 13 C NMR and 19 F NMR) detection data are:

[0065]

[0066] 1H NMR(400MHz,CDCl3)δ7.14–7.12(m,3H),6.94(dd,J=6.4,2.8Hz,2H),6.59(d,J=7.5Hz,1H),6.51(d,J=9.4Hz,2H),6.33(d,J=8.8Hz,2H),6.15(d,J=8.8Hz,2H),5.23(dd,J=8.9,1.2Hz,1H),4.69(d,J=8.9Hz,1H),3.50(s,3H),2.13(s,3H).

[0067] 13 C NMR(101MHz,CDCl3)δ159.1,157.7,155.8(C-F,q, 2 J(C-F)=31.3Hz),140.6,139.4,139.0,129.2,128.6,127.9,126.5,124.7,122.8,120.5,119.8(C-F,q, 1 J(C-F)=281.0Hz),114.0,110.6,84.5,55.4,53.2,21.6.

[0068] 19 F NMR(377MHz,CDCl3)δ-61.8,-67.1.

[0069] HRMS(ESI):[M+H] + calcd for C 24 H 21 F3NO2 + 412.1519,found 412.1518。

Claims

1. A method for preparing a trifluoroacetimide-substituted dihydrobenzofuran compound, characterized in that: The method comprises the following steps: adding a promoter, 2-alkyl substituted phenol and trifluoroacetimide sulfur ylide to an organic solvent, and heating the mixture at 40-60°C. o C. reacting for 10 to 15 hours. After the reaction is complete, post-processing is performed to obtain the trifluoroacetimide-substituted dihydrobenzofuran compound; The structure of the 2-alkyl substituted phenol is shown in formula (II): (II); The structure of the trifluoroacetimidosulfur ylide is shown in formula (III): (III) The structure of the trifluoroacetimide-substituted dihydrobenzofuran compound is shown in formula (I): （Ⅰ）； In formulas (I) to (III), R 1 is H, C1~C4 alkyl, C1~C4 alkoxy or halogen; R 2 is C1~C6 alkyl, cyclohexyl, substituted or unsubstituted phenyl; R 3 is substituted or unsubstituted phenyl, naphthyl; In R 2 wherein the substituent on the phenyl group is selected from methyl or halogen; In R 3 wherein the substituent on the phenyl group is selected from C1~C4 alkyl, C1~C4 alkoxy, methylthio, halogen, C1~C4 alkoxycarbonyl or trifluoromethyl; The accelerator is potassium carbonate.

2. The method for preparing a trifluoroacetimide-substituted dihydrobenzofuran compound according to claim 1, wherein R 1 is H, methyl or chlorine.

3. The method for preparing a trifluoroacetimide-substituted dihydrobenzofuran compound according to claim 1, wherein: R 3 is a substituted or unsubstituted phenyl or naphthyl group; The substituents on the phenyl group are selected from methyl, methoxy, methylthio, fluorine, chlorine, bromine, methoxycarbonyl or trifluoromethyl.

4. The method for preparing a trifluoroacetimide-substituted dihydrobenzofuran compound according to claim 1, wherein: The organic solvent is chloroform.

5. The method for preparing a trifluoroacetimide-substituted dihydrobenzofuran compound according to claim 1, wherein: Based on molar amounts, the ratio of 2-alkyl substituted phenol: trifluoroacetimidylsulfur ylide: promoter is 1:1~1.5:2~4.

6. The method for preparing a trifluoroacetimide-substituted dihydrobenzofuran compound according to claim 1, wherein: The trifluoroacetimide-substituted dihydrobenzofuran compound is one of the compounds represented by formula (I-1) to formula (I-5): （I-1） （I-2） （I-3） （I-4） （I-5）。

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