Method for synthesizing benzo nitrogen-containing fused ring compound through co-catalysis of palladium / copper

Abstract

The invention relates to the technical field of benzo nitrogen-containing fused ring compounds, and discloses a method for synthesizing a benzo nitrogen-containing fused ring compound through co-catalysis of palladium / copper, and the method comprises the following steps: carrying out catalytic reaction on a first monomer and a second monomer in a reaction environment containing palladium chloride and cuprous bromide to synthesize the benzo nitrogen-containing fused ring compound. According to the method disclosed by the invention, the reaction of aryl sulfonyl chloride and non-activated olefin is realized under a mild condition through a ligand-free Pd (II) / Cu (I) catalytic system, and the saturated benzo six-membered nitrogen-containing heterocyclic compound is generated.

Description

Technical Field

[0001] The present invention relates to the technical field of benzofused nitrogen-containing polycyclic compounds, and particularly relates to a method for synthesizing benzofused nitrogen-containing polycyclic compounds by palladium / copper co-catalysis. Background Art

[0002] Benzofused nitrogen-containing polycyclic compounds (such as indole, quinoline, isoquinoline, carbazole, β-carboline, etc.) have important applications in drug, materials science and natural product synthesis and applications. In the prior art, the synthesis of benzofused nitrogen-containing polycyclic compounds usually relies on pre-functionalized substrates, such as aryl halides or olefin derivatives. Common methods include alkynyl hydrogenation reaction, Friedel-Crafts reaction, transition metal-catalyzed reaction, etc. Although these methods can synthesize the target compounds, they require multiple steps and the reaction conditions are relatively harsh. Summary of the Invention

[0003] In order to solve the above technical problems, the present invention provides a method for synthesizing benzofused nitrogen-containing polycyclic compounds by palladium / copper co-catalysis. The method of the present invention realizes the reaction of arylsulfonyl chloride and unactivated olefin under mild conditions through a ligand-free Pd(II) / Cu(I) catalytic system to generate saturated benzosix-membered nitrogen-containing heterocyclic compounds.

[0004] The present invention provides a method for synthesizing benzofused nitrogen-containing polycyclic compounds by palladium / copper co-catalysis, comprising the following steps:

[0005] Carrying out a catalytic reaction on a first monomer and a second monomer in a reaction environment containing palladium chloride and cuprous bromide to synthesize a benzofused nitrogen-containing polycyclic compound;

[0006] The chemical structural formula of the first monomer is formula 1, or formula 2, or formula 3:

[0007] The formula 1 is:

[0008]

[0009] Wherein, R1 is selected from one or more of a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted tetrahydronaphthyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted isoxazolyl group, a substituted or unsubstituted thiophenyl group, and a substituted or unsubstituted benzothiophenyl group;

[0010] The formula 2 is:

[0011]

[0012] The formula 3 is:

[0013]

[0014] The chemical structural formula of the second monomer is Formula 4, or Formula 5, or Formula 6, or Formula 7, or Formula 8;

[0015] Formula 4 is as follows:

[0016]

[0017] wherein, R2 is selected from one of O, S, ethyl, and substituted ethyl; R3 is selected from one or more of H, F, Br, Cl, methyl, methoxy, ; R4 is selected from one of H, methyl, ;

[0018] Formula 5 is as follows:

[0019] wherein, Me is methyl;

[0020] Formula 6 is as follows:

[0021]

[0022] Formula 7 is as follows:

[0023]

[0024] Formula 8 is as follows:

[0025]

[0026] Furthermore, in a reaction environment containing palladium chloride and copper bromide, the amount of substance of palladium chloride is 2.5 mol% - 5 mol% of the amount of substance of the second monomer.

[0027] Furthermore, in a reaction environment containing palladium chloride and copper bromide, the amount of substance of copper bromide is 20 mol% - 50 mol% of the amount of substance of the second monomer.

[0028] Furthermore, the molar ratio of the first monomer to the second monomer is 1.5:1.

[0029] Furthermore, the reaction environment also includes an inorganic base and an organic solvent.

[0030] Furthermore, the molar concentration of the second monomer in the organic solvent is 0.25 mmol / mL.

[0031] Furthermore, the molar concentration of the inorganic base in the organic solvent is 0.75 mmol / mL.

[0032] Furthermore, the inorganic base includes lithium carbonate.

[0033] Further, the organic solvent includes one or more of dimethylformamide (DMC) and nitromethane (MeNO2).

[0034] Further, the temperature of the reaction environment is 100°C - 140°C, and the reaction time is 10h - 16h.

[0035] Further, in R1, the substituents of the phenyl group are selected from one or more of methyl, methoxy, trifluoromethyl, nitro, cyano, phenyl, fluorine, chlorine, bromine, and the like.

[0036] Further, in R1, the substituents of the pyridyl group are selected from one or more of fluorine, chlorine, and bromine.

[0037] Further, in R1, the substituent of the isoxazolyl group is methyl.

[0038] Further, in R1, the substituents of the thiophenyl group are chlorine and / or bromine.

[0039] Further, in R2, the substituent of the ethyl group is methyl.

[0040] The embodiments of the present invention have the following technical effects:

[0041] 1. The method of the present invention efficiently synthesizes benzo-fused nitrogen-containing polycyclic compounds through a palladium / copper co-catalyzed double Csp 2 -Csp 3 chemical bond formation reaction. This method uses a ligand-free Pd(II) / Cu(I) catalytic system to realize the reaction of arylsulfonyl chloride with non-activated olefins under mild conditions, generating saturated benzo-six-membered nitrogen-containing heterocyclic compounds. The method of the present invention has the advantages of high efficiency, good chemoselectivity, wide substrate scope, etc., and is applicable to the synthesis of drug molecules and functional materials.

[0042] 2. The method of the present invention has good tolerance to various functional groups (such as halogen, methoxy, trifluoromethyl, etc.), is applicable to the synthesis of complex molecules, and thus is beneficial to improving the product purity.

[0043] 3. In the present invention, a ligand-free Pd(II) / Cu(I) catalytic system is adopted, avoiding the use of expensive ligands and oxidants, and reducing the reaction cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the specific embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0045] Figure 1 It is a reaction schematic diagram provided by Embodiment 1 of the present invention. Specific embodiments

[0046] To make the objectives, technical solutions, and advantages of the present invention clearer, the following will clearly and completely describe the technical solutions of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope protected by the present invention.

[0047] In a first aspect, some embodiments of the present invention provide a method for palladium / copper co-catalyzed synthesis of benzofused nitrogen-containing polycyclic compounds, including the following steps:

[0048] Carry out a catalytic reaction on the first monomer and the second monomer in a reaction environment containing palladium chloride and cuprous bromide to synthesize a benzofused nitrogen-containing polycyclic compound;

[0049] The chemical structural formula of the first monomer is Formula 1, or Formula 2, or Formula 3:

[0050] Formula 1 is:

[0051]

[0052] Among them, R1 is selected from one or more of a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted tetrahydronaphthyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted isoxazolyl group, a substituted or unsubstituted thiophenyl group, and a substituted or unsubstituted benzothiophenyl group;

[0053] Formula 2 is:

[0054]

[0055] Formula 3 is:

[0056]

[0057] The chemical structural formula of the second monomer is Formula 4, or Formula 5, or Formula 6, or Formula 7, or Formula 8;

[0058] Formula 4 is:

[0059]

[0060] Among them, R2 is selected from one of O, S, ethyl, and substituted ethyl; R3 is selected from one or more of H, F, Br, Cl, methyl, methoxy, and the like; R4 is selected from one of H, methyl, and the like;

[0061] The said formula 5 is:

[0062] Among them, Me is methyl;

[0063] The said formula 6 is:

[0064]

[0065] The said formula 7 is:

[0066]

[0067] The said formula 8 is:

[0068]

[0069] In some embodiments, in a reaction environment containing palladium chloride and copper bromide, the amount of substance of palladium chloride is 2.5 mol% - 5 mol% of the amount of substance of the second monomer.

[0070] In some embodiments, in a reaction environment containing palladium chloride and copper bromide, the amount of substance of copper bromide is 20 mol% - 50 mol% of the amount of substance of the second monomer.

[0071] In the present invention, the amount of substance of copper bromide is 20% - 50% of the amount of substance of the second monomer.

[0072] In some embodiments, the molar ratio of the first monomer to the second monomer is 1.5:1.

[0073] In some embodiments, the reaction environment further includes an inorganic base and an organic solvent.

[0074] In some embodiments, the molar concentration of the second monomer in the organic solvent is 0.25 mmol / mL.

[0075] In some embodiments, the molar concentration of the inorganic base in the organic solvent is 0.75 mmol / mL.

[0076] In some embodiments, the inorganic base includes lithium carbonate.

[0077] In some embodiments, the organic solvent includes one or more of dimethylformamide and nitromethane.

[0078] In some embodiments, the temperature of the reaction environment is 100°C - 140°C, and the reaction time is 10 h - 16 h.

[0079] In some embodiments, in R1, the substituents of the phenyl group are selected from one or more of methyl, methoxy, trifluoromethyl, nitro, cyano, phenyl, fluorine, chlorine, bromine, and the like.

[0080] In some embodiments, in R1, the substituents of the pyridyl group are selected from one or more of fluorine, chlorine, and bromine.

[0081] In some embodiments, in R1, the substituent of the isoxazolyl group is methyl.

[0082] In some embodiments, in R1, the substituents of the thienyl group are chlorine and / or bromine.

[0083] In some embodiments, in R2, the substituent of the ethyl group is methyl.

[0084] The following is elaborated with specific examples:

[0085] Example 1:

[0086] Dissolve 4-methylbenzenesulfonyl chloride (0.75 mmol), 4-allyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.5 mmol), PdCl2 (0.0125 mmol), CuBr (0.25 mmol), and Li2CO3 (1.5 mmol) in dimethyl carbonate (DMC, 2 mL), and react at 130°C for 14 hours. After the reaction is completed, the target product is obtained by column chromatography separation, and the yield is 78%. The chemical reaction equation of the reaction in Example 1 is as Figure 1 shown.

[0087] 1H NMR data of Example 1:

[0088] 1 H NMR (400 MHz, CDCl3) δ 7.13 (dd, J = 8.2, 2.8 Hz, 2H), 6.99 (dd, J = 8.2, 2.8 Hz, 2H), 6.90–6.82 (m, 2H), 6.59 (q, J = 4.2 Hz, 1H), 4.67 (d, J = 2.4 Hz, 2H), 4.15 (t, J = 5.8 Hz, 1H), 3.95–3.77 (m, 2H), 2.34 (d, J = 2.7 Hz, 3H), 2.32 - 2.04 (m, 2H).13 13C NMR (101 MHz, CDCl3) δ 163.7, 144.4, 141.1, 136.6, 129.4, 129.4, 128.4, 128.4, 128.4, 125.5, 123.8, 123.4, 115.0, 67.4, 42.0, 37.3, 29.7, 21.1。

[0089] HRMS (ESI, m / z): calculated for C 18 H 17 NO2 [M + H] + =280.1332, found

[0090] 280.1333。

[0091] Examples 2 - 61 have the same addition amounts, ratios, reaction temperatures and times of the substances as in Example 1, but the monomers involved in the reactions and the final products are different, as shown in Table 1.

[0092] Table 1 Reaction conditions of Examples 2 - 61

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110] In the catalytic reaction process of the method of the present invention, the in-situ generated high-valent Pd(III)-aryl intermediate is more inclined to undergo migratory reaction with unactivated olefins or electron-rich alkynes, thereby undergoing 1,1-diaryl cascade cyclization reaction, rather than β-H elimination in the traditional Heck reaction. This high-valent Pd(III)-aryl species acts on the adjacent terminal alkenyl group through 1,1-insertion migration to generate a highly electrophilic alkylpalladium intermediate, which preferentially undergoes electrophilic C-H arylation reaction with electron-rich olefins, and finally constructs a large number of six-membered nitrogen-containing fused ring compounds with high yield and high chemoselectivity, which is verified by Examples 1-61.

[0111] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the technical solutions of the embodiments of the present invention.

Claims

1. A method for the synthesis of benzannulated nitrogen-containing polycyclic compounds by palladium / copper co-catalysis, characterized in that, The method includes: Catalytically reacting a first monomer and a second monomer in a reaction environment containing palladium chloride and cuprous bromide to synthesize a benzofused nitrogen heterocycle compound; The chemical structural formula of the first monomer is Formula 1, or Formula 2, or Formula 3: Formula 1 is: Wherein, R1 is selected from one or more of a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted tetrahydronaphthyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted isoxazolyl group, a substituted or unsubstituted thiophenyl group, and a substituted or unsubstituted benzothiophenyl group; Formula 2 is: Formula 3 is: The chemical structural formula of the second monomer is Formula 4, or Formula 5, or Formula 6, or Formula 7, or Formula 8; Formula 4 is: Among them, R2 is selected from one of O, S, ethyl, and substituted ethyl; R3 is selected from one or more of H, F, Br, Cl, methyl, methoxy, and the like; R4 is selected from one of H, methyl, and the like; Formula 5 is: Wherein, Me is methyl; Formula 6 is: Formula 7 is: Formula 8 is:

2. The method according to claim 1, wherein In the reaction environment containing palladium chloride and cuprous bromide, the amount of substance of palladium chloride is 2.5 mol% - 5 mol% of the amount of substance of the second monomer; In the reaction environment containing palladium chloride and cuprous bromide, the amount of substance of cuprous bromide is 20 mol% - 50 mol% of the amount of substance of the second monomer; The molar ratio of the first monomer to the second monomer is 1.5:

1.

3. The method according to claim 1, wherein The reaction environment further includes an inorganic base and an organic solvent.

4. The method according to claim 3, wherein The molar concentration of the second monomer in the organic solvent is 0.25 mmol / mL; The molar concentration of the inorganic base in the organic solvent is 0.75 mmol / mL.

5. The method according to claim 3, characterized in that, The inorganic base includes lithium carbonate; The organic solvent includes one or more of dimethylformamide and nitromethane.

6. The method according to claim 1, characterized in that The temperature of the reaction environment is 100 °C - 140 °C, and the reaction time is 10 h - 16 h.

7. The method according to claim 1, wherein In the R1, the substituent group of the phenyl group is selected from methyl, methoxy, trifluoromethyl, nitro, cyano, phenyl, fluorine, chlorine, bromine, one or more of 8. The method according to claim 1, wherein In R1, the substitution groups of the pyridyl group are selected from one or more of fluorine, chlorine, and bromine.

9. The method according to claim 1, wherein In R1, the substitution group of the isoxazolyl group is a methyl group; In R1, the substitution groups of the thiophenyl group are chlorine and / or bromine.

10. The method according to claim 1, wherein In R2, the substitution group of the ethyl group is a methyl group.

Images