CN110713466B - Novel C-H activation method for tetrazole-oriented meta-position nitration - Google Patents

Abstract

The invention provides a novel method for meta-selective C-H nitration guided by tetrazole, which comprises the following steps: 5-phenyltetrazole compounds are used as raw materials, and m-nitro 5-phenyltetrazole compounds are prepared through m-position nitration catalyzed by transition metal ruthenium. The method has good functional group compatibility and meta-position selectivity and high yield. Compared with the traditional method, the method has the following advantages: (1) simple steps, easily obtained raw materials, wide substrate application range, good meta-selectivity and high reaction yield. (2) Avoids the use of strong acid and strong oxidant, is safe and convenient, and has wide application prospect.

Description

A new method for C-H activation of tetrazolium-directed meta-nitration

technical field

The invention relates to a method for synthesizing meta-nitro-substituted tetrazolium by a CH activation method catalyzed by Ru ₃ (CO) ₁₂ with the aid of phosphine ligands based on 5-phenyltetrazolium as raw material and nitrate as nitro source. A brand-new method of 5-phenyltetrazolium belongs to the field of chemical synthesis.

Background technique

Tetrazoles, as common backbone molecules in organic compounds, have a wide range of biological activities. So far, tetrazolium has been reported to have ^{antibacterial1,2} , blood pressure ^lowering3,4 , anticancer5, anti ^- inflammatory, ^analgesic6,7 , ACE enzyme inhibitory8, ^metallo -β-lactamase inhibitory activities9 ^{, 10} and so on. It is worth noting that, as the most important class of drug structures, 5-phenyltetrazole often appears in drug molecules, such as the circulating diuretic azosemide, the blood pressure-lowering drug losartan, and the anti-allergic drug azarlast. Meanwhile, nitroarenes are an important class of compounds containing CN bonds in medicinal chemistry and materials science, which can be used as precursor compounds or directly. The traditional synthesis method of nitroaromatics mainly relies on FC nitration reaction to generate nitro-containing main compounds at the para position. However, these reactions usually have the disadvantages of requiring the use of strong acids, intolerance of many functional groups, and low ortho/meta selectivity, resulting in a narrow substrate scope, many reaction by-products, and serious environmental pollution. Over the past few decades, the formation of ortho-CC or CX bonds through transition-metal-catalyzed, guiding-group-assisted ortho-CH functionalization has achieved great success. ¹¹ Transition metal-catalyzed CH activation has the advantages of high reaction efficiency, low energy requirement, no need for substrate preactivation, mild reaction conditions, reduced operational difficulty, and multiple advantages such as atom economy and step economy. During this period, ortho-CH activation with tetrazolium as the directing group was gradually reported. ^12,13 But so far, meta-CH activation with tetrazole as a directing group has not been exploited. It may be that the directing group is far away from the CH bond in the meta position of the aryl group, and the tetrazolium contains multiple nitrogen atoms (its extra 3 nitrogen atoms can chelate the metal catalyst and reduce the catalytic activity), resulting in 5-phenyltetrazolium Meta-nitration of azoles presents great challenges.

SUMMARY OF THE INVENTION

The present invention realizes that 5-phenyltetrazolium is used as raw material, Ru ₃ (CO) ₁₂ is used as catalyst, phosphine ligand is assisted, iodobenzene trifluoroacetate is oxidant and hexafluoroisopropanol is under the situation of solvent, A new method for the synthesis of a series of meta-nitro 5-phenyltetrazoles by transition metal-catalyzed meta-nitrogenation. The invention solves the problems of the use of strong acid, intolerance of various functional groups and poor meta-selectivity in traditional synthesis methods. The invention provides a preparation method that is simpler, more effective, has good substrate applicability and high selectivity, and has broad application prospects. The reaction formula of the present invention is as follows:

in:

A ring is tetrazolium, triazole, pyrazole, oxadiazole, pyridazine;

R ₁ is one or more of hydrogen, halogen, alkyl, phenyl, alkoxy, alkylthio, and amino;

R ₂ is one or more of hydrogen, halogen, alkyl, phenyl, alkoxy, and amino.

The preparation steps are as follows:

(1) After adding 5-phenyltetrazolium compound, Ru ₃ (CO) ₁₂ , phosphine ligand, iodobenzene trifluoroacetate, hexafluoroisopropanol and nitro source into a clean pressure-resistant bottle, at 100 Stir in an oil bath for 24 h;

(2) After the reaction is completed, the solvent is removed under reduced pressure, and the product is obtained by separation and purification by silica gel column chromatography.

The phosphine ligands in step (1) are triphenylphosphine, tricyclohexylphosphine, tris(2-furyl)phosphine, PCy ₃ , P(o-Tol) ₃ , PPh ₃ , P(o-furyl) ₃ One or more of , BINAP, XANT Phos, XPhox, IMes•HCl.

In step (1), the nitro source is one or more of Cu(NO ₃ ) ₂ •3H ₂ O, NH ₄ NO ₃ , AgNO ₃ , KNO ₃ , and AgNO ₂ .

In step (1), the 5-phenyltetrazolium compound: Cu(NO ₃ ) ₂ 3H ₂ O : Ru ₃ (CO) ₁₂ : the molar ratio of iodobenzene trifluoroacetate is 1 : (1.2~1.8) : ( 0.05~0.1): (1.0~1.5).

In step (1), the reaction concentration of the 5-phenyltetrazolium compound is 0.05-0.2 mol/L, and the reaction concentration of the phosphine ligand is 0.25-0.35 mol/L.

The correctness of the meta-nitration product was confirmed by hydrogen nuclear magnetic resonance spectroscopy ( ¹ H NMR), carbon spectroscopy ( ¹³ C NMR) and high-resolution mass spectrometry. The nuclear magnetic resonance images were measured by Varian INOVA-400 nuclear magnetic resonance apparatus, with tetramethylsilane (TMS) as the internal standard (δ 0 ppm) and deuterated chloroform as the solvent; high-resolution mass spectrometry was measured with an Agilent 1946B mass spectrometer.

Detailed ways

The present invention is further described below in conjunction with specific embodiments, which is helpful for understanding the present invention. However, this does not limit the scope of the right of the present invention, and the scope of the right of the present invention should be based on the description in the claims.

Example 1: Synthesis of Compound 1

In a clean pressure bottle were added 2-methyl-5-phenyl- 2H -tetrazolium (32 mg, 0.20 mmol), Ru ₃ (CO) ₁₂ (4.8 mg, 0.015 mmol), PPh ₃ (7.9 mg, 0.060 mmol), iodobenzene trifluoroacetate (95 mg, 0.22 mmol), hexafluoroisopropanol (2 mL) and copper nitrate trihydrate (36 mg, 0.30 mmol) and stirred in an oil bath at 100 °C for 24 h ;

After the reaction was completed, the solvent was removed under reduced pressure, and the product was directly separated and purified by silica gel column chromatography to obtain 38.5 mg of the product, white solid, yield 94%, melting point 96-100 ^o C; ¹ H NMR (400 MHz, Chloroform- d ) δ 8.97 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 4.44 (s, 3H); ¹³ C NMR (100 MHz, Chloroform- d ) δ 163.5, 148.8, 132.5, 130.2, 129.2, 125.0, 121.9, 39.9; HRMS (ESI): Calculated for C ₂₂ H ₁₆ ClN ₂ [M + H] ⁺ : 206.0673, Measured value: 206.0671.

Example 2: Synthesis of Compound 2

In a clean pressure bottle was added 2-methyl-5-(3-methyl-5-phenyl)-2 H -triazole (34.8 mg, 0.20 mmol), Ru ₃ (CO) ₁₂ (4.8 mg , 0.015 mmol), P(o-Tol) ₃ (18.2 mg, 0.060 mmol), iodobenzene trifluoroacetate (95 mg, 0.22 mmol), hexafluoroisopropanol (2 mL) and Cu(NO ₃ ) ₂ • 3H ₂ O (36 mg mg, 0.30 mmol) was then stirred in an oil bath at 100 °C for 24 h;

After the reaction was completed, the solvent was removed under reduced pressure, and the product was directly separated and purified by silica gel column chromatography to obtain 40.8 mg of the product, a gray solid, the yield was 65%, and the melting point was 90-92 ^° C; ¹ H NMR (400 MHz, Chloroform- d ) δ 8.77 (s, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 4.43 (s, 3H), 2.55 (s, 3H); ¹³ C NMR (100 MHz, Chloroform- d ) δ 163.7, 148.8 , 140.9, 133.2, 128.8, 125.4, 119.2, 39.8, 21.5; HRMS (ESI): m/z found: C ₉ H ₉ N ₅ O ₂ [M+H] ⁺ : 220.0829, found: 220.0835.

Example 3: Synthesis of Compound 3

In a clean pressure bottle was added 2-(4-methoxy-phenyl)-2 H -1,2,3-triazole (56.8 mg, 0.20 mmol), Ru ₃ (CO) ₁₂ (4.8 mg , 0.015 mmol), P(o-furyl) ₃ (13.9 mg, 0.060 mmol), iodobenzene trifluoroacetate (95 mg, 0.22 mmol), hexafluoroisopropanol (2 mL) and AgNO ₃ (61.1 mg, 0.36 mmol) and then stirred in an oil bath at 100 °C for 24 h;

After the reaction was completed, the solvent was removed under reduced pressure, and the product was directly separated and purified by silica gel column chromatography to obtain 40.8 mg of the product, a pale yellow solid, yield 92%, melting point 122-124 ^o C; ¹ H NMR (400 MHz, Chloroform- d ) δ 8.60 (s, 1H), 8.27 (d, J = 8.0 Hz, 1H), 7.82 (s, 2H), 7.21 (d, J = 8.0 Hz, 1H), 4.02(s, 3H); ¹³ C NMR ( 150 MHz, Chloroform- d ) δ 152.0, 139.7, 136.1, 132.9, 124.2, 116.6, 114.3, 57.1; HRMS (ESI): m/z Calculated for C ₉ H ₈ N ₄ O ₃ [M+H] ⁺ : 221.0669 , found: 221.0676.

Example 4: Synthesis of Compound 4

In a clean pressure bottle was added 3-methoxy-6-(4-methoxy-phenyl)-pyridazine (43.2 mg, 0.20 mmol), Ru ₃ (CO) ₁₂ (4.8 mg, 0.015 mmol) , PCy ₃ (16.8 mg, 0.060 mmol), iodobenzene trifluoroacetate (95 mg, 0.22 mmol), hexafluoroisopropanol (2 mL) and AgNO ₃ (61.1 mg, 0.36 mmol) and then placed in an oil bath at 100 °C Stir for 24 h;

After the reaction was completed, the solvent was removed under reduced pressure, and the product was directly separated and purified by silica gel column chromatography to obtain 40.8 mg of the product, a pale yellow solid, the yield was 89%, the melting point was 187-190 ^° C; ¹ H NMR (400 MHz, Chloroform- d ) δ 8.47 (s, 1H), 8.35 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 12.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 12.0 Hz, 1H) 12.0 Hz, 1H), 4.19 (s, 3H), 4.04 (s, 3H); ¹³ C NMR (150 MHz, Chloroform- d ) δ 164.6, 154.1, 152.7, 139.9, 132.3, 128.6, 126.7, 123.8, 118.5, 114.3, 55.9, 55.2; HRMS (ESI): m/z calcd for C12H13N3O4 [ _{M +} H] ⁺ : _262.0822 , found: _262.0823 .

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Claims (5)

1. a method for preparing m-nitro 5-phenyl tetrazolium compound, it is characterized in that taking 5-phenyl tetrazolium compound as raw material, nitrate is nitro source, in catalyst catalysis and phosphine ligand The meta-nitration of the substrate is realized under the assistance of , and its reaction equation is:

in: A ring is tetrazolium, triazole, pyridazine; R ₁ is one or more of hydrogen, halogen, alkyl, phenyl, alkoxy, alkylthio, and amino; R ₂ is one or more of hydrogen, halogen, alkyl, phenyl, alkoxy, and amino; The phosphine ligand is one or more of triphenylphosphine, PCy ₃ , P(o-Tol) ₃ , and P(o-furyl) ₃ ; The nitro source is one or more of Cu(NO ₃ ) ₂ •3H ₂ O and AgNO ₃ . 2. the synthetic method of m-nitro 5-phenyl tetrazolium compound according to claim 1 is characterized in that adopting following preparation step: (1) After adding 5-phenyltetrazolium compound, Ru ₃ (CO) ₁₂ , phosphine ligand, iodobenzene trifluoroacetate, hexafluoroisopropanol and nitro source into a clean pressure-resistant bottle, at 100 Stir in an oil bath for 24 h; (2) After the reaction is completed, the solvent is removed under reduced pressure, and the product is obtained by separation and purification by silica gel column chromatography. 3. preparation method according to claim 2 is characterized in that in step (1), 5-phenyl tetrazolium compound: Cu(NO ₃ ) ₂ 3H ₂ O: Ru ₃ (CO) ₁₂ : trifluoro The molar ratio of iodobenzene acetate is 1:(1.2~1.8):(0.05~0.1):(1.0~1.5). 4 . The preparation method according to claim 2 , wherein the reaction concentration of the 5-phenyltetrazolium compound in step (1) is 0.05-0.2 mol/L. 5 . 5. preparation method according to claim 2 is characterized in that the reaction concentration of phosphine ligand is 0.25～0.35mol/L.