CN115181054B - A kind of synthetic method of 3-benzylindole compound - Google Patents

Abstract

The invention discloses a method for synthesizing 3-benzylindole compounds, wherein N-methylindole and 2,4,6-trimethylphenol are used as reaction raw materials, heated in a solvent in the presence of an oxidant and an additive, and a cross-dehydrogenation coupling reaction is performed to obtain a target product of the 3-benzylindole compound. The raw materials of the invention are cheap and readily available, the operation is simple, the substrate applicability is good, and the invention has broad development prospects.

Description

A kind of synthetic method of 3-benzylindole compound

Technical Field

The invention belongs to the field of organic chemistry, and specifically relates to a method for synthesizing 3-benzylindole compounds through a cross-dehydrogenation coupling reaction.

Background technique

In nature, especially in living organisms, there are many substances that run through the entire life activity, one of which is compounds containing benzo five-membered heterocycles. Among these compounds, indole compounds are the most important.

As a class of nitrogen-containing heterocyclic rings, indole and its derivatives are an important class of alkaloids. Most of them have unique biological and pharmacological activities and are therefore widely used in the pharmaceutical industry. Many drug molecules contain indole skeletons. Fluvastatin is the first fully chemically synthesized cholesterol-lowering drug. It has the advantages of high selectivity and low incidence of adverse reactions and is an excellent lipid-lowering drug. Rizatriptan and eletriptan are specific drugs for the treatment of migraine, and both have brought revolutionary progress to the drug treatment of migraine. Indometacin can be used to treat rheumatic diseases and various arthritis. Pindolol can be used to treat arrhythmias, angina pectoris, hypertension and other diseases. Sertindole is a newly developed atypical antipsychotic drug. In addition, indole alkaloids such as vincristine and vinblastine have good anti-tumor effects.

In recent years, a large number of scientific researchers have been committed to developing methods for the benzylation of the C-3 position of indole.

Professor Isao Azumaya (J.Org.Chem.2013,78,23,12128–12135) first developed the coupling reaction of benzyl alcohol and indole in a water-soluble gold(III)/TPPMS catalytic system, which is one of the most efficient and environmentally friendly benzylation synthetic strategies, and in most cases can obtain the target compound in moderate yield. Among them, Au(III)/TPPMS is an effective catalyst for the benzylation of the strong π nucleophile 1-methylindole, while ordinary Lewis acids are ineffective.

In 2015, You Shuli et al. (Chinese Journal of Catalysis 2015, 36, 15-18) developed an efficient method for Pd(0)-catalyzed benzylation of indoles with unique regioselectivity. When the reaction was carried out in the presence of Pd(PPh ₃ ) ₄ , it provided a pathway to a wide range of substituted indoles bearing diarylmethane at their 3-position in 90%-99% yields under mild conditions.

In 2020, Amreen K. Bains et al. (Chem. Commun., 2020, 56, 15442) reported an efficient nickel catalyst that can effectively selectively C3-alkylate 1H-indole with a variety of alcohols. The authors used indole and benzyl alcohol as model substrates, and when a mixture of indole (1 mmol), benzyl alcohol (2 mmol), nickel catalyst (5 mol%) and potassium tert-butoxide (0.7 equiv) in toluene (2 mL) was heated at 110 ° C, the target product 3-benzylindole was obtained.

The synthesis of 3-benzylindole compounds reported so far basically uses expensive metal catalysts. Therefore, it is of great significance to develop a method for synthesizing 3-benzylindole compounds using only cheap oxidants.

Summary of the invention

The present invention aims to provide a method for synthesizing 3-benzylindole compounds by cross-dehydrogenation coupling reaction, which has the advantages of cheap and readily available raw materials, simple operation, wide substrate applicability, etc., and has broad development prospects.

The method for synthesizing 3-benzylindole compounds of the present invention is to use N-methylindole and 2,4,6-trimethylphenol as reaction raw materials, heat them in a solvent in the presence of an oxidant and an additive, and perform a cross-dehydrogenation coupling reaction to obtain a target product of the 3-benzylindole compound.

The specific steps include:

0.2 mmol of N-methylindole, 1.0 mmol of 2,4,6-trimethylphenol and 0.08 mmol of additive were added to 1 mL of solvent respectively, and then an oxidant was added, and the mixture was reacted at 90-120° C. for 48-72 hours to obtain the target product.

The structural formula of the 3-benzylindole compound is shown in Formula I below:

Wherein R is a substituent group at different positions on the benzene ring, such as methyl (-CH ₃ ), methoxy (-OCH ₃ ), various halogen groups (-F, -Cl, -Br, -I), nitro (-NO ₂ ), cyano (-CN), phenyl (-Ph), and the like.

The structural formula of the N-methylindole is shown in Formula II below:

The structural formula of the 2,4,6-trimethylphenol is shown in the following formula III:

The reaction route is as follows:

Wherein R is a substituent group at different positions on the benzene ring, such as methyl (-CH ₃ ), methoxy (-OCH ₃ ), various halogen groups (-F, -Cl, -Br, -I), nitro (-NO ₂ ), cyano (-CN), phenyl (-Ph), and the like.

The oxidant includes di-tert-butyl peroxide (DTBP), tert-butyl hydroperoxide (TBHP), 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), zinc oxide (ZnO), silver oxide (Ag ₂ O), potassium persulfate (K ₂ S ₂ O ₈ ) or manganese dioxide (MnO ₂ ). Since different oxidants have a great influence on the yield of the reaction, through the study of di-tert-butyl peroxide (DTBP), tert-butyl hydroperoxide (TBHP), 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), zinc oxide (ZnO), silver oxide (Ag ₂ O), potassium persulfate (K ₂ S ₂ O ₈ ), and manganese dioxide (MnO ₂ ), the final yields are 0%, 0%, 0%, 12%, 0%, 18%, and 56%, respectively. Therefore, the preferred oxidant of the present invention is manganese dioxide (MnO ₂ ).

Furthermore, through the study of additives 3,4,5-trifluorobenzoic acid, 2,4,6-trifluorobenzoic acid, 2,3,6-trifluorobenzoic acid, and 2-bromo-4,5-difluorobenzoic acid, the final yields were 56%, 37%, 43%, and 78%, respectively, so the present invention preferably uses 2-bromo-4,5-difluorobenzoic acid as the additive.

Furthermore, since temperature has a great influence on the reaction yield, through screening at 90-120°C, the final yields were 39% (90°C), 51% (100°C), 78% (110°C), and 49% (120°C), respectively. Therefore, the present invention prefers 110°C as the optimal reaction temperature.

Furthermore, by screening different solvents, for example, when tetrahydrofuran (THF) is used as the solvent, the yield is 0%, when dichloromethane (DCM) is used as the solvent, the yield is 33%, when acetonitrile (MeCN) is used as the solvent, the yield is 57%, and when 1,2-dichloroethane (DCE) is used as the solvent, the yield is 78%, so the solvent is preferably 1,2-dichloroethane (DCE).

Compared with the prior art, the present invention starts from indole derivatives and couples with cheap and readily available 2,4,6-trimethylphenol to obtain 3-benzylindole compounds. Therefore, the reaction meets the requirements of green chemistry and has broad development prospects.

Detailed ways

The above contents of the present invention are further described in detail below through specific examples, but this should not be understood as any limitation to the subject of protection of the present invention. All technical solutions implemented based on the above contents of the present invention belong to the scope of the present invention. The present invention generally and/or specifically describes the materials and test methods used in the test.

Example 1: Preparation of Compound Ia

0.2 mmol of N-methylindole, 1.0 mmol of 2,4,6-trimethylphenol and 0.08 mmol of 2-bromo-4,5-difluorobenzoic acid were sequentially added into a 10 mL Schlenk tube dried in an oven, 1 mL of 1,2-dichloroethane solvent was added into the Schlenk tube at room temperature using a syringe, and then 2.4 mmol of MnO ₂ was added, the Schlenk tube was sealed, and the mixture was heated to 110° C. for reaction for 72 hours; after the reaction was completed, the solvent was evaporated under reduced pressure, and column chromatography was performed with a mixed solution of petroleum ether/ethyl acetate = 10/1 to 30/1 (V/V) as a mobile phase to obtain a product 3-benzylindole compound with a yield of 78%.

¹ H NMR (600 MHz, CDCl ₃ )δ7.58 (d, J＝8.0 Hz, 1H), 7.31 (dd, J＝8.3, 2.4 Hz, 1H), 7.24 (ddd, J＝5.0, 3.2, 1.2 Hz, 1H), 7.13–7.09 (m, 1H), 6.93 (s, 2H), 6.77 (s, 1H), 4.51 (s, 1H), 4.00 (s, 2H), 3.74 (s, 3H), 2.23 (s, 6H). ¹³ C NMR (151 MHz, CDCl ₃ )δ150.29,137.18,133.02,128.79,127.88,127.00,122.81,121.50,119.25,118.70,114.98,109.10,32.59,30.63,15.96.HRMS(ESI)m/z(M+H) ⁺ calculated for C ₁₈ H ₁₉ NO:266.1540,observed:266.1542.

Example 2: Preparation of Compound Ib

Substrate IIb Instead of IIa, product Ib was prepared by the method of Example 1 with a yield of 44%.

¹ H NMR (600 MHz, CDCl ₃ ) δ7.37 (s, 1H), 7.20 (dd, J = 8.6, 2.4 Hz, 1H), 7.07 (ddd, J = 8.3, 3.5, 1.7 Hz, 1H), 6.93 (s, 2H), 6.71 (s, 1H), 4.51 (s, 1H), 3.97 (s, 2H), 3.71 (s, 3H), 2.48 (s, 3H), 2.24 (s, 6H). ¹³ C NMR (151 MHz, CDCl ₃ )δ150.26,135.61,133.13,128.76,128.08,127.88,127.15,123.12,122.78,118.81,114.33,108.81,32.62,30.54,21.52,15.96.HRMS(ESI)m/z(M+H) ⁺ calculated for C ₁₉ H ₂₁ NO:280.1696,observed:280.1692.

Example 3: Preparation of Compound Ic

Substrate IIc Instead of IIa, product Ic was prepared by the method of Example 1 with a yield of 78%.

¹ H NMR (600 MHz, CDCl ₃ ) δ7.42 (d, J=8.4 Hz, 1H), 7.27 (d, J=1.9 Hz, 1H), 7.03 (dd, J=8.4, 1.8 Hz, 1H), 6.87 (s, 2H), 6.74 (s, 1H), 4.50 (s, 1H), 3.93 (s, 2H), 3.69 (s, 3H), 2.21 (s, 6H). ¹³ CNMR (151 MHz, CDCl ₃ )δ150.36,137.56,132.57,128.68,127.62,127.58,126.40,122.86,120.15,119.36,115.23,109.15,32.67,30.48,15.95.HRMS(ESI)m/z(M+H) ⁺ calculated for C ₁₈ H ₁₈ ClNO:300.1150,observed:300.1151.

Example 4: Preparation of Compound Id

Substrate IId Instead of IIa, product Id was prepared by the method of Example 1 with a yield of 76%.

¹ H NMR (600 MHz, CDCl ₃ ) δ7.86 (s, 1H), 7.44 (dd, J＝8.6, 1.6 Hz, 1H), 7.05 (d, J＝8.5 Hz, 1H), 6.86 (s, 2H), 6.68 (s, 1H), 4.50 (s, 1H), 3.89 (s, 2H), 3.69 (s, 3H), 2.21 (s, 6H). ¹³ C NMR (151 MHz, CDCl ₃ )δ150.38,132.41,130.36,129.75,128.67,128.00,127.81,126.90,122.88,114.42,111.18,82.29,32.71,30.31,15.95.HRMS(ESI)m/z(M+H) ⁺ calculated for C ₁₈ H ₁₈ INO:392.0506,observed:392.0501.

Example 5: Preparation of Compound Ie

Substrate II e Instead of IIa, the product Ie was prepared by the method of Example 1 with a yield of 83%.

¹ H NMR (600 MHz, CDCl ₃ ) δ7.45 (dd, J＝7.9, 1.0 Hz, 1H), 7.32 (dd, J＝7.6, 1.0 Hz, 1H), 6.89–6.86 (m, 3H), 6.69 (s, 1H), 4.49 (s, 1H), 4.09 (s, 3H), 3.92 (s, 2H), 2.21 (s, 6H). ¹³ CNMR (151 MHz, CDCl ₃ )δ150.37,133.45,132.39,130.96,130.07,128.69,126.51,122.85,119.91,118.60,114.79,103.83,36.51,30.35,15.96.HRMS( _ESI )m/z(M+H) ⁺ calculatedfor _C18H18BrNO :344.0645,observed:344.0642.

Example 6: Preparation of Compound IF

Substrate II f Instead of IIa, the product If was prepared by the method of Example 1 with a yield of 89%.

¹ H NMR (600 MHz, CDCl ₃ ) δ7.81 (d, J＝7.6 Hz, 1H), 7.76 (d, J＝7.8 Hz, 1H), 7.08 (td, J＝7.9, 1.2 Hz, 1H), 6.87 (s, 2H), 6.83 (s, 1H), 4.61 (s, 1H), 3.96 (s, 2H), 3.79 (s, 3H), 2.22 (s, 6H). ¹³ CNMR (151 MHz, CDCl ₃ )δ150.57,132.91,131.82,131.76,128.66,128.49,128.09,125.40,123.07,119.79,117.93,116.24,37.19,30.15,15.98.HRMS(ESI)m/z(M+H) ⁺ calculated for _{C18H18N2O3 : 311.1390} ,observed: _311.1392 .

Example 7: Preparation of Compound Ig

Substrate IIg Instead of IIa, the product Ig was prepared by the method of Example 1 with a yield of 42%.

¹ H NMR (600 MHz, CDCl ₃ )δ7.13–7.09 (m, 1H), 6.93 (s, 2H), 6.88 (dd, J＝8.2, 1.3 Hz, 1H), 6.49 (d, J＝7.2 Hz, 2H), 4.45 (s, 1H), 4.15 (s, 2H), 3.90 (s, 3H), 3.66 (s, 3H), 2.22 (s, 6H). ¹³ CNMR (151 MHz, CDCl ₃ )δ155.09,150.03,138.76,134.22,129.06,126.90,125.69,122.54,122.21,115.92,102.51,99.05,55.10,32.79,32.08,15.97. HRMS (ESI) m/z (M+H) ⁺ calculated for C ₁₉ H ₂₁ NO ₂ :296.1645, observed:296.1647.

Claims (6)

1. A synthetic method of 3-benzyl indole compounds is characterized in that:

n-methylindole and 2,4, 6-trimethylphenol are used as reaction raw materials, and are heated in a solvent 1, 2-dichloroethane in the presence of an oxidant manganese dioxide and an additive 2-bromo-4, 5-difluorobenzoic acid to carry out cross dehydrogenation coupling reaction, so that a 3-benzylindole compound target product is obtained;

the structural formula of the 3-benzyl indole compound is shown as the following formula I:

the structural formula of the N-methylindole is shown as the following formula II:

the structural formula of the 2,4, 6-trimethylphenol is shown as the following formula III:

wherein R is substituent groups at different positions on the benzene ring, including methyl, methoxy, halogen groups, nitro, cyano and phenyl.

2. The synthesis method according to claim 1, wherein:

the molar amount of the oxidant added is 12 equivalents of the molar amount of N-methylindole.

3. The synthesis method according to claim 1, wherein:

the molar amount of the additive added is 40% of the molar amount of the N-methylindole.

4. The synthesis method according to claim 1, wherein:

the reaction temperature is 90-120 ℃.

5. The method of synthesis according to claim 4, wherein:

the reaction temperature was 110 ℃.

6. The synthesis method according to claim 1, wherein:

the molar ratio of N-methylindole to 2,4, 6-trimethylphenol was 1:5.