Preparation method of trifluoromethyl-substituted 1-azadiene compound

Abstract

The invention discloses a preparation method of a trifluoromethyl-substituted 1-aza-diene compound, which comprises the following steps: in an air atmosphere, adding potassium carbonate, diimine and trifluoroacetyl imine sulfur ylide into an organic solvent, reacting at 60-100 DEG C for 12-20 hours, and after the reaction is completed, filtering, washing and drying to obtain the trifluoromethyl-substituted 1-aza-diene compound. And carrying out post-treatment to obtain the trifluoromethyl substituted 1-aza diene compound. The preparation method is simple to operate, the initial raw materials are cheap and easy to obtain, the reaction can be carried out in the air atmosphere, the inorganic salt potassium carbonate is cheap, odorless and non-toxic, the reaction does not need to use a heavy metal catalyst and can be expanded to gram level, and the applicability of the method is widened while the operation is convenient.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for preparing a trifluoromethyl-substituted 1-azadiene compound. Background Art

[0002] 1-Azadienes are an important class of organic building blocks that can be used to construct a series of structurally diverse nitrogen-containing compounds or heterocyclic molecules (Chem. Commun. 2008, 5474-5489); they have different reactivities and can be flexibly used as electrophiles, heterodienes, dienophiles, bipolar philes or carbophiles, and are widely used in various reaction types, such as cycloadditions, electrocyclizations and multicomponent reactions. Therefore, in the past few decades, the development of effective methods for the synthesis of functionalized 1-azadienes and the exploration of the synthetic uses of 1-azadienes have received considerable attention.

[0003] Conventional synthesis methods of 1-azadienes include: condensation reaction of α, β-unsaturated carbonyl compounds with primary amines, Sonogashira coupling reaction of aryl halides with terminal propiolamides, Wittig reaction of alkyl ethoxylates with functionalized phosphonium salts, coupling reaction of trifluoroacetylimidyl iodide with olefins, iminothiolation reaction of alkynes, etc. Introducing trifluoromethyl into molecules has many advantages, such as significantly improving the electronegativity, bioavailability, metabolic stability and lipophilicity of compounds (J.Med.Chem.2015,58,8315-8359). For special functionalized trifluoromethyl-substituted 1-azadiene compounds, their efficient synthesis methods are rare. Therefore, the development of efficient preparation methods of trifluoromethyl-substituted 1-azadiene compounds has important research significance and application value.

[0004] Based on this, we developed a simple, efficient and easy-to-operate method for synthesizing trifluoromethyl-substituted 1-azadiene compounds using cheap and readily available diimine and trifluoroacetimidyl sulfide as starting materials and potassium carbonate as a promoter without the involvement of heavy metals. Summary of the invention

[0005] The invention provides a preparation method of a trifluoromethyl substituted 1-azadiene compound. The preparation method has simple operation steps, and the starting raw materials are cheap and easily available. Common inorganic salt potassium carbonate is used as a promoter, and the use of heavy metal catalysts is avoided. The reaction is carried out in an air atmosphere, which is convenient for subsequent operation and large-scale application.

[0006] A method for preparing a trifluoromethyl substituted 1-azadiene compound comprises the following steps: adding a promoter, a diimine and trifluoroacetimidyl sulfur ylide to an organic solvent, reacting at 60-100° C. for 12-20 hours, and after the reaction is complete, post-treating to obtain the trifluoromethyl substituted 1-azadiene compound;

[0007] The structure of the diimine is shown in formula (II):

[0008]

[0009] The structure of the trifluoroacetimidosulfur ylide is shown in formula (III):

[0010]

[0011] The structure of the trifluoromethyl-substituted 1-azadiene compound is shown in formula (I):

[0012]

[0013] In formulas (I) to (III), R 1 is a substituted or unsubstituted phenyl group; R 2 is a substituted or unsubstituted phenyl group; R 3 is phenethyl, substituted or unsubstituted phenyl or naphthyl;

[0014] In R 1 , R 2 and R 3 In the above, the substituents on the phenyl group are independently selected from one or more of C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, halogen, nitro or trifluoromethyl.

[0015] Preferably, R 1 and R 2 is a substituted or unsubstituted phenyl group;

[0016] The substituents on the phenyl group are selected from methyl, ethyl, isopropyl, methoxy, fluorine, chlorine or bromine.

[0017] R 1 , R 2 and R 3 The substitution position of the phenyl group can be ortho, para or meta.

[0018] In the present invention, the optional post-treatment process includes: filtration, silica gel mixing, and finally column chromatography purification to obtain the corresponding trifluoromethyl-substituted 1-azadiene compound. Column chromatography purification is a commonly used technical means in the art.

[0019] As a preference, R 1and R 2 The phenyl group is a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is selected from methyl, ethyl, isopropyl, methoxy, fluorine, chlorine or bromine. In this case, the thiourea and the corresponding diimine are easily obtained, and the reaction yield is high.

[0020] As a preference, R 3 It is a substituted or unsubstituted phenyl or naphthyl, and the substituent on the phenyl is selected from one or more of methyl, tert-butyl, fluorine, bromine or trifluoromethyl. In this case, the trifluoroacetimide sulfur ylide is easy to obtain and the reaction yield is high.

[0021] The trifluoroacetimide sulfur ylide is relatively easy to obtain and can be conveniently obtained from trifluoroacetimide chloride and iodomethyl sulfoxide. The amount used is excessive relative to the diimide. Preferably, on a molar basis, the diimide: trifluoroacetimide sulfur ylide: promoter = 1:1-3:2-3; and further preferably, on a molar basis, the diimine: trifluoroacetimide sulfur ylide: promoter = 1:2:2.5.

[0022] 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. Preferably, a halogen-containing solvent is used, which can effectively promote the reaction. Preferably, the organic solvent is dichloroethane, chloroform or dichloromethane. As a further preference, chloroform is the most suitable organic solvent, and at this time, various raw materials can be converted into products at a higher conversion rate.

[0023] The amount of the organic solvent used is sufficient to dissolve the raw materials well. The amount of the organic solvent used for 1 mmol of diimine is about 5 to 10 mL.

[0024] Preferably, the accelerator is potassium carbonate. When potassium carbonate is used as the accelerator, the reaction efficiency is higher.

[0025] As a further preference, the trifluoromethyl-substituted 1-azadiene compound is one of the compounds represented by formula (I-1) to formula (I-5):

[0026]

[0027]

[0028] In the above preparation method, the diimine can be obtained by a simple reaction of thiourea, triphenylphosphine and iodine; trifluoroacetimidosulfur ylide can be obtained by the reaction of trifluoroethylimidoyl chloride and iodomethyl sulfoxide; and trifluoroethylimidoyl chloride can be quickly synthesized from the corresponding aromatic amine, triphenylphosphine, carbon tetrachloride and trifluoroacetic acid. The thiourea, aromatic amine, trifluoroacetic acid, iodomethyl sulfoxide, triethylamine and potassium carbonate are generally commercially available products and can be easily obtained from the market.

[0029] Reaction formula of the present invention is as follows:

[0030]

[0031] The reaction may first undergo a nucleophilic attack on the diimine by the sulfide under the promotion of potassium carbonate to generate a zwitterionic intermediate, and then intramolecular hydrogen migration and [2,3]-σ rearrangement reaction occur to obtain the final 1-azadiene compound.

[0032] Compared with the prior art, the advantages of the present invention are as follows: the preparation method is easy to operate and the post-treatment is simple; the reaction is carried out in the air without the need for nitrogen protection; the reaction starting materials are easy to prepare, potassium carbonate is odorless and non-toxic, the reaction substrate is highly designable, the substrate functional group range is wide, and different substituted multifunctional 1-azadiene compounds with trifluoromethyl groups can be designed and synthesized according to actual needs, and the practicability is relatively strong. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 The compound I-1 obtained in Example 1 of the present invention 1 H-NMR spectrum;

[0034] Figure 2 The compound I-1 obtained in Example 1 of the present invention 13 C-NMR spectrum;

[0035] Figure 3 The compound I-1 obtained in Example 1 of the present invention 19 F-NMR spectrum;

[0036] Figure 4 The compound I-2 obtained in Example 2 of the present invention 1 H-NMR spectrum;

[0037] Figure 5 The compound I-2 obtained in Example 2 of the present invention 13 C-NMR spectrum;

[0038] Figure 6 The compound I-3 obtained in Example 3 of the present invention 1 H-NMR spectrum;

[0039] Figure 7 The compound I-3 obtained in Example 3 of the present invention 13 C-NMR spectrum;

[0040] Figure 8 The compound I-4 obtained in Example 4 of the present invention 1 H-NMR spectrum;

[0041] Fig. 9 The compound I-4 obtained in Example 4 of the present invention 13 C-NMR spectrum;

[0042] Fig.10 The compound I-5 obtained in Example 5 of the present invention 1 H-NMR spectrum;

[0043] Fig.11 The compound I-5 obtained in Example 5 of the present invention 13 C-NMR spectrum. DETAILED DESCRIPTION

[0044] The present invention is further described below in conjunction with specific embodiments.

[0045] According to the raw material ratio in Table 1, potassium carbonate, diimide (II), trifluoroacetimidosulfur ylide (III) and 2 mL of organic solvent were added to a 35 mL Schlenk tube, mixed and stirred evenly, reacted for 12-20 hours according to the reaction conditions in Table 2, filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding trifluoromethyl-substituted 1-azadiene compound (I). The reaction process is shown in the following formula:

[0046]

[0047] Table 1 Amount of raw materials added in Examples 1 to 15

[0048]

[0049]

[0050] Table 2

[0051]

[0052] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Ph is phenyl, Me is methyl, t-Bu is tert-butyl, OMe is methoxy, SMe is methylthio, and CHCl3 is chloroform. The structural confirmation data of the compounds prepared in Examples 1 to 5 are as follows:

[0053] The NMR of the trifluoromethyl substituted 1-azadiene compound (I-1) prepared in Example 1 is ( 1 HNMR, 13 C NMR and 19 F NMR) detection data are:

[0054]

[0055] 1 H NMR(400MHz,d6-DMSO)δ9.28(s,1H),7.65–7.61(m,2H),7.24(t,J=7.9Hz,4H),6.98(d,J=24.5Hz,2H),6.78(d,J=8.9Hz,2H),6.73( d,J=7.8Hz,4H),6.38(d,J=2.0Hz,1H),4.81(d,J=14.0Hz,1H),4.56(d,J=16.0Hz,1H),3.65(d,J=2.2Hz,3H),2.59(d,J=2.2Hz,3H).

[0056] 13 C NMR(101MHz,d6-DMSO)δ156.4,149.7,148.3,140.9,139.6,135.7(CF,q, 2 J (C-F) =30.4Hz),129.3,129.0,122.2(CF,q, 1 J (C-F) =279.8Hz),123.5,123.1,122.7,122.2,119.9,116.7(CF,q, 3 J (C-F) =2.5Hz),114.6,114.6,73.9,55.8,36.1.

[0057] 19 F NMR (376 MHz, d6-DMSO) δ-61.5.

[0058] Mp153.2-154.5℃

[0059] HRMS(ESI):[M+H]+calcd.for C 25 H 25 F3N3O2S + 488.1614, found 488.1620.

[0060] The NMR of the trifluoromethyl-substituted 1-azadiene compound (I-2) prepared in Example 2 is (1 HNMR, 13 C NMR and 19 F NMR) detection data are:

[0061]

[0062] 1 H NMR(400MHz,d6-DMSO)δ9.13(s,1H),7.51(d,J=8.0Hz,2H),7.03(d,J=7.9Hz,4H),6.72(s,4H),6.59(d,J=7.7Hz,2 H), 6.37 (s, 1H), 4.78 (d, J = 14.1Hz, 1H), 4.53 (d, J = 14.1Hz, 1H), 3.66 (s, 3H), 2.56 (s, 3H), 2.25 (d, J = 20.0Hz, 6H).

[0063] 13 C NMR(101MHz,d6-DMSO)δ156.3,148.2,147.2,139.4,138.4,135.2(CF,q, 2 J (C-F) =30.8Hz),131.8,131.4,129.7,129.3,123.5,122.2(CF,q, 1 J (C-F) =280.7Hz),122.0,119.9,117.1(CF,q, 3 J (C-F) =4.2Hz),114.4,74.1,55.8,36.0,20.9.

[0064] 19 F NMR (376 MHz, d6-DMSO) δ-60.8.

[0065] Mp157.6-158.7℃

[0066] HRMS(ESI):[M+H] + calcd.for C 27 H 29 F3N3O2S + 516.1927, found 516.1935.

[0067] The NMR of the trifluoromethyl-substituted 1-azadiene compound (I-3) prepared in Example 3 is ( 1 HNMR, 13 C NMR and 19F NMR) detection data are:

[0068]

[0069] 1 H NMR(400MHz,d6-DMSO)δ9.51(s,1H),7.59(d,J=8.8Hz,2H),7.40(dd,J=12.8,8.7Hz,4H),6.76–6.69(m,4H), 6.66(d,J=8.5Hz,2H),6.36(s,1H),4.78(d,J=14.1Hz,1H),4.55(d,J=14.1Hz,1H),3.67(s,3H),2.60(s,3H).

[0070] 13 C NMR(101MHz,d6-DMSO)δ156.3,148.8,148.6,139.9,139.3,136.1(CF,q, 2 J (C-F) =30.4Hz),132.0,131.7,124.3,123.4,121.7,119.2(CF,q, 1 J (C-F) =280.2Hz),115.8(CF,q, 3 J (C-F) =2.5Hz),115.3,114.4,114.2,73.7,55.7,36.1.

[0071] 19 F NMR (376 MHz, d6-DMSO) δ-60.8.

[0072] Mp151.2-152.7℃

[0073] HRMS(ESI):[M+H] + calcd.for C 25 H 23 Br2F3N3O2S + 643.9824, found 643.9831.

[0074] The NMR of the trifluoromethyl substituted 1-azadiene compound (I-4) prepared in Example 4 is ( 1 HNMR, 13 C NMR and 19 F NMR) detection data are:

[0075]

[0076] 1 H NMR (400MHz, d6-DMSO) δ9.39 (s, 1H), 7.81 (d, J = 7.3Hz, 1H), 7.77 (d, J = 9.0Hz, 1H), 7.63 (d, J = 7.9Hz, 1H),7.56(d,J=8.2Hz,2H),7.45(t,J=7.0Hz,1H),7.38(t,J=7.0Hz,1H),7.28(t,J=7.5Hz,2H),7.22 (s,1H),7.17(t,J=7.8Hz,2H),7.11(dd,J=8.9,2.6Hz,1H),7.06(t,J=7.3Hz,1H),6.91(t,J=7.4Hz, 1H), 6.79 (d, J = 7.8Hz, 2H), 6.76 (s, 1H), 4.95 (d, J = 14.2Hz, 1H), 4.77 (d, J = 14.2Hz, 1H), 2.70 (s, 3H).

[0077] 13 C NMR(101MHz,d6-DMSO)δ149.5,147.7,143.5,140.6,134.9(CF,q, 2 J (C-F) =30.3Hz),133.7,129.9,129.3,129.1,128.8,127.9,127.4,127.1,125.2,123.2,122.6,122.2(CF,q, 1 J (C-F) =279.8Hz),120.6,119.8,116.3,73.3,36.3. 19 F NMR (376 MHz, d6-DMSO) δ -61.0.

[0078] Mp142.4-144.1℃

[0079] HRMS(ESI):[M+H] + calcd.for C 28 H 25 F3N3OS + 508.1665, found 508.1671.

[0080] The NMR of the trifluoromethyl-substituted 1-azadiene compound (I-5) prepared in Example 5 is ( 1 HNMR, 13 C NMR and 19 F NMR) detection data are:

[0081]

[0082] 1 H NMR(400MHz,d6-DMSO)δ9.32(s,1H),7.87(d,J=8.2Hz,2H),7.34–7.22(m,6H),7.20(t,J=6.7Hz,3H),6.99(q,J=7.6Hz,2H),6.77(d,J=7.9Hz,2H),5.71(s,1H),4.63(d,J=13.6Hz,1H),4.20(d,J=13.5Hz,1H),3.54(t,J=7.4Hz,2H),2.86(t,J=7.5Hz,2H),2.67(s,3H).

[0083] 13 C NMR(101MHz,d6-DMSO)δ150.1,149.6,141.1,138.8(C-F,q, 2 J (C-F) =31.6Hz),138.6,129.2,129.1,129.1,128.8,126.8,123.1,122.5,122.0,121.9(C-F,q, 1 J (C-F) =279.9Hz),119.5,109.4(C-F,q, 3 J (C-F) =4.5Hz),70.1,55.0,35.6,33.9.

[0084] 19 F NMR(376MHz,d6-DMSO)δ-61.9.

[0085] HRMS(ESI):[M+H] + calcd.for C 26 H 27 F3N3OS + 486.1821,found 486.1818。

Claims

1. A method for preparing a trifluoromethyl-substituted 1-azadiene compound, characterized in that: The method comprises the following steps: adding a promoter, a diimine and trifluoroacetimidyl sulfur ylide into an organic solvent, reacting at 60 to 100° C. for 12 to 20 hours, and after the reaction is complete, post-treating to obtain the trifluoromethyl-substituted 1-azadiene compound; The structure of the diimine is shown in formula (II): The structure of the trifluoroacetimidosulfur ylide is shown in formula (III): The structure of the trifluoromethyl-substituted 1-azadiene compound is shown in formula (I): In formulas (I) to (III), R 1 is a substituted or unsubstituted phenyl group; R 2 is a substituted or unsubstituted phenyl group; R 3 is phenethyl, substituted or unsubstituted phenyl or naphthyl; In R 1 , R 2 and R 3 In the above, the substituents on the phenyl group are independently selected from one or more of C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, halogen, nitro or trifluoromethyl.

2. The method for preparing a trifluoromethyl-substituted 1-azadiene compound according to claim 1, characterized in that: R 1 and R 2 is a substituted or unsubstituted phenyl group; The substituents on the phenyl group are selected from methyl, ethyl, isopropyl, methoxy, fluorine, chlorine or bromine.

3. The method for preparing a trifluoromethyl-substituted 1-azadiene compound according to claim 1, characterized in that: R 3 is phenethyl, substituted or unsubstituted phenyl or naphthyl; The substituents on the phenyl group are selected from one or more of methyl, tert-butyl, methoxy, methylthio, fluorine, chlorine, bromine or nitro.

4. The method for preparing a trifluoromethyl-substituted 1-azadiene compound according to claim 1, characterized in that: The organic solvent is chloroform.

5. The method for preparing a trifluoromethyl-substituted 1-azadiene compound according to claim 1, characterized in that: The accelerator is potassium carbonate.

6. The method for preparing a trifluoromethyl-substituted 1-azadiene compound according to claim 1, characterized in that: In terms of molar amount, diimine: trifluoroacetimide sulfur ylide: promoter = 1:1-3:2-3.

7. The method for preparing a trifluoromethyl-substituted 1-azadiene compound according to claim 1, characterized in that: The trifluoromethyl-substituted 1-azadiene compound is one of the compounds represented by formula (I-1) to formula (I-5):

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