CN104447539B - A kind of two grades, the synthetic method of three-level aromatic amides - Google Patents

Abstract

The invention provides a synthesis method for forming secondary and tertiary aromatic amide compounds through direct functionalization of methyl groups. The method uses 2-methyl-N-heterocyclic aromatic compounds and amine sources as raw materials, metal copper as a catalyst, Bronsted acid as an additive, and molecular O ₂ (oxygen) as an oxidant. The sp ³ C-H bonds of ‑methyl‑N‑heterocyclic aromatic compounds generate corresponding aldehydes, which react with different amine sources to generate secondary or tertiary aromatic amide compounds. The method is characterized in that low-cost metal copper is used as a catalyst, commercial 2-methyl-N-heterocyclic aromatic compound is used as a substrate, and molecular O ₂ (oxygen) is used as an oxidant to carry out oxidative amidation reaction. The method has mild reaction conditions, simple operation, good applicability and good industrial application prospect.

Description

A kind of synthetic method of secondary and tertiary aromatic amide compounds

【Technical field】

The invention relates to the field of organic synthesis, in particular to a synthesis method for forming secondary and tertiary aromatic amides through direct functionalization of methyl groups.

【Background technique】

The amide bond is one of the most common functional groups in drug synthesis, fine chemicals and polymer materials. Statistics show that more than 25% of aromatic drugs have amide functional groups. Therefore, the synthesis of aromatic amide compounds has not only been the focus of attention in the fields of biology and pharmacy, but also one of the hot topics in organic synthesis and other industrial fields.

For the synthesis of secondary or tertiary aromatic amide compounds, the most traditional synthetic method is the reaction of carboxylic acid or carboxylic acid derivatives with amines. This method not only has the defect of low atom economy but also produces equivalent side effects. The product affects the rate of the reaction. Due to the high utilization value of secondary or tertiary amide compounds, the work on the construction of secondary or tertiary amide compounds has never stopped for many years. In recent years, researchers have continued to improve raw materials and catalysts, and have successively reported on the synthesis methods of secondary or tertiary aromatic amide compounds: (1) C. Ramalingan and Y. Park used the improved traditional method Beckmann rearrangement to synthesize di Aromatic amides, although overcome the traditional harsh conditions, such as avoiding the use of a large amount of strong acid and high reaction temperature, but it needs a more toxic HgCl ₂ as a catalyst; (2) YJWu et al explore the amidation reaction of aldehydes and amines , it is undeniable that it has the advantage of high conversion rate. However, due to the inherent characteristics of aldehydes, long-term storage and use are enough to make people distressed; (3) B.Roberts and D.Liptrot et al. found that it is possible to use halogenated aromatics for amino carboxylation to obtain Secondary aromatic amides, but this method not only requires transition metals as catalysts but also requires the participation of a large amount of bases and ligands; (4) AJAWatson and ACMaxwell use alcohols and amines to oxidize secondary or tertiary aromatic amide compounds, and the by-product is only hydrogen Generated but currently requires noble metals as catalysts (such as: ruthenium). Not only are the above methods individually deficient, but they also have a common deficiency in that they rely on the conversion of functional functional groups or activated functional groups. As we all know, CH bond is the most ubiquitous chemical bond in the world.

Therefore, developing a method for the efficient preparation of secondary or tertiary aromatic amide compounds directly by C-H bond functionalization under mild conditions is the most direct and ideal synthetic method, and it is also one of the technical problems that cannot be solved in organic synthesis. (References: a) Y.Y.Lai, L.J.Huang, K.H.Lee, Z.Y.Xiao, K.F.Bastow, T.Yamoric, S.C.Kuo, Bioorg.Med.Chem.2005, 13 265; b) N.A.Owston, A.J.Parker, J.M.Williams, Org.Lett.2007, 9, 3599; c) Y.J.Wu, S.W.Wang, L.J.Zhang, G.S.Yang, X.C.Zhu, Z.H.Zhou, H.Zhu, S.H.Wu, Eur.J.Org.Chem.2010, 326; d ) B. Roberts, D. Liptrot, L. Alcaraz, T. Luker, M.J. Stocks, Org. Chem. 2010, 75, 8410; e) A.J.A. Watson, A.C. Maxwell, J.M.J. Williams, Org. Lett, 2009, 11, 2667 .)

The invention provides a synthesis method for preparing secondary or tertiary aromatic amide compounds through direct functionalization of methyl groups, metal copper catalysis, mild conditions, simple operation, readily available raw materials and high applicability.

【Content of invention】

The purpose of the present invention is to develop a direct functionalization by methyl, use metal copper as catalyst, Bronsted acid as additive, cheap and easy to get 2-methyl-N-heterocyclic aromatic compound and ammonium source as raw materials, select oxygen As an oxidizing agent, a method for preparing secondary or tertiary aromatic amide compounds with high applicability.

The purpose of the invention of the present invention is achieved by the following technical methods:

A kind of synthetic method of secondary or tertiary aromatic amide compound as shown in structural formula (I),

Contains the following steps:

will be equipped with metal copper catalyst, Bronsted acid, amine source, 2-methyl-N-heterocyclic aromatic compound Vacuumize the reaction vessel, fill it with oxygen, and then add an organic solvent to seal it; heat it to 100-150°C for 8-24 hours, cool to room temperature after the reaction, wash with saturated sodium bicarbonate, then extract with chloroform, dry, reduce The solvent was removed by concentrated distillation under pressure, and the crude product was separated by column chromatography to obtain the target product.

Wherein the N-heterocycle is a pyridine ring, a thiazole ring, a pyrazine ring, a benzothiazole ring, a quinoxaline ring, a quinoline ring or a phenanthroline ring;

_The R is amino, trimethylacetamido, methyl, fluorine, chlorine, bromine, nitro, methyl formate or methoxy;

When the structural formula (I) is a secondary aromatic amide, the corresponding R is hydrogen, and _R is phenyl, ₂ -methoxyphenyl, 2-chlorophenyl, 4-methylphenyl, 4-chlorobenzene , 4-nitrophenyl, isopropyl or n-butyl;

When the structural formula (I) is a tertiary aromatic amide, R ₂ is not hydrogen, and R ₂ and R ₃ together with the connected N form a piperidine ring, a morpholine ring or a tetrahydropyrrole ring.

Further, the molar ratio of the metal copper catalyst, Bronsted acid, 2-methyl-N-heterocyclic aromatic compound and amine source is [0.05～0.2]:[0.5～1.0]:1:[1.0～ 2.0].

The organic solvent is one or more selected from 1,4-dioxane, N,N-dimethylformamide, chlorobenzene, anisole, toluene or tetrahydrofuran.

Further, the metal copper catalyst is one or more selected from Cu, CuBr, CuCl, CuI, Cu(OAc) ₂ , CuBr ₂ , CuI ₂ , CuO or Cu(OTf) ₂ .

Further, the Bronsted acid is one or more selected from acetic acid, benzoic acid, phenylacetic acid, benzenesulfonic acid or diphenylphosphoric acid.

Further, the amine source is selected from aniline, p-nitroaniline, p-chloroaniline, p-methylaniline, o-chloroaniline, o-methoxyaniline, isopropylamine, n-butylamine, piperidine, morpholine or Tetrahydropyrrole.

Further, the 2-methyl-N-heterocyclic aromatic compound (II) is selected from 2-picoline, 2-methylthiazole, 2-methylpyrazine, 2-methylbenzothiazole, 2 -Methylquinoxaline, 2-methylquinoline, 2-methyl-4-aminoquinoline, 2-methyl-4-trimethylacetamidoquinoline, 2,6-dimethylquinoline , 2-methyl-6-fluoroquinoline, 2-methyl-6-chloroquinoline, 2-methyl-6-bromoquinoline, 2-methyl-6-nitroquinoline, 2-methyl- 6-methylcarboxyquinoline, 2-methyl-6-methoxyquinoline, 2-methyl-8-methoxyquinoline or 2,9-dimethyl-1,10-phenanthroline .

The invention provides a synthesis method for preparing secondary or tertiary aromatic amide compounds directly by methyl functionalization, metal copper catalysis, mild conditions, simple operation, readily available raw materials and high applicability, and has good industrial application prospects.

【Brief description of the drawings】

Fig. 1 is a synthetic route diagram of secondary or tertiary aromatic amide compounds provided by the present invention.

【detailed description】

Below in conjunction with synthetic example of the present invention, synthetic method described in the present invention is described further, it should be noted that, embodiment does not constitute the restriction to the scope of protection of the present invention:

Synthesis Example 1

Synthesis of N-phenylquinoline-2-carboxamide

Add 10mol% cuprous iodide to the reaction vessel, vacuumize, backfill with oxygen, then add 0.2mmol acetic acid, 0.2mmol 2-methylquinoline, 0.4mmol aniline and 1mL anisole, seal; heat to 100°C React for 24 hours. After the reaction solution was cooled to room temperature, it was washed with saturated sodium bicarbonate solution, then extracted with chloroform, dried, concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography to obtain the target product with a yield of 69%. . No other impurities remain after NMR inspection. ¹ HNMR (400MHz, CDCl ₃ ) δ10.24(s, 1H), 8.35-8.42(m, 2H), 8.19(d, J=8.4Hz, 1H), 7.79-7.92(m, 4H), 7.65(dd , J ₁ =J ₂ =8.0Hz, 1H), 7.42 (dd, J ₁ =J ₂ =8.0Hz, 2H), 7.17 (t, J = 7.6Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ162.18, 149.68, 146.31, 137.87, 137.80, 130.33, 129.68, 129.44, 129.12, 128.17, 127.83, 124.36, 119.79, 118.77.

Synthesis example 2

Synthesis of N-(4-methyl-phenyl)quinoline-2-carboxamide

Add 0.4mmol 4-methylaniline, 0.2mmol diphenylphosphoric acid and 10mol% cuprous bromide and 10mol% copper powder in the reaction vessel, vacuumize, backfill oxygen, then add 0.2mmol 2-methylquinoline and 0.5mL 1,4-dioxane and 0.5mL anisole, seal; heat to 130°C and react for 8h. After the reaction liquid is cooled to room temperature, wash with saturated sodium bicarbonate solution, then extract with chloroform and dry , concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography to obtain the target product with a yield of 60%. No other impurities remain after NMR inspection. ¹ H NMR (400MHz, CDCl ₃ ) δ10.18(s, 1H), 8.35-8.41(m, 2H), 8.18(d, J=8.4Hz, 1H), 7.91(d, J=8.0Hz, 1H) ,7.80(dd,J ₁ =J ₂ =8.0Hz,1H),7.74(d,J=8.4Hz,2H),7.65(dd,J ₁ =J ₂ =8.0Hz,1H),7.22(d,J ＝8.4Hz, 2H), 2.36(s, 3H); ¹³ C NMR (100MHz, CDCl ₃ ) δ162.04, 149.83, 146.33, 137.83, 135.29, 133.98, 130.30, 129.68, 129.63, 129.41, 128.10, 1119.768, 11 ,118.78,20.97.

Synthesis example 3

Synthesis of N-(2-methoxy-phenyl)quinoline-2-carboxamide

Add 0.1mmol benzoic acid and 20mol% cuprous chloride to the reaction vessel, vacuumize, backfill with oxygen, then add 0.2mmol 2-methylquinoline, 0.2mmol 2-methoxyaniline and 1mL chlorobenzene, and seal; Heat to 100°C and react for 24 hours. After the reaction solution is cooled to room temperature, wash with saturated sodium bicarbonate solution, then extract with chloroform, dry, and concentrate under reduced pressure to remove the solvent. The crude product is separated by column chromatography to obtain the target product. The yield was 34%. No other impurities remain after NMR inspection. ¹ H NMR (400MHz, CDCl ₃ ) δ10.82(s, 1H), 8.65(dd, J ₁ = 1.6Hz, J ₂ = 8.0Hz, 1H), 8.34-8.41(m, 2H), 8.21(d, J=8.4Hz, 1H), 7.90(d, J=8.4Hz, 1H), 7.79(dd, J ₁ ＝J ₂ ＝8.0Hz, 1H), 7.64(dd, J ₁ ＝J ₂ ＝7.6Hz, 1H ), 7.03-7.13 (m, 2H), 6.96-6.98 (dd, J ₁ ＝1.2Hz, J ₂ ＝8.0Hz, 1H), 4.02 (s, 3H); ¹³ C NMR (100MHz, CDCl ₃ ) δ162. 19,150.19,148.92,146.43,137.68,130.12,130.01,129.36,128.04,127.76,127.65,124.02,121.14,119.80,118.80,110.20

Synthesis Example 4

Synthesis of N-(2-chloro-phenyl)quinoline-2-carboxamide

Add 0.2mmol benzenesulfonic acid and 10mol% copper acetate to the reaction vessel, vacuumize, backfill with oxygen, then add 0.4mmol 2-chloro-aniline, 0.2mmol 2-methylquinoline and 1mL toluene, seal; heat to 140 Reaction at ℃ for 12h. After the reaction solution was cooled to room temperature, washed with saturated sodium bicarbonate solution, then extracted with chloroform, dried, concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography to obtain the target product. The yield was 67%. No other impurities remain after NMR inspection. ¹ H NMR (400MHz, CDCl ₃ ) δ10.98(s, 1H), 8.70(d, J=8.4Hz, 1H), 8.38(b, 2H), 8.21(d, J=8.4Hz, 1H), 7.91 (d, J = 8.0Hz, 1H), 7.81 (dd, J ₁ = J ₂ = 8.0Hz, 1H), 7.66 (dd, J ₁ = J ₂ = 7.6Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.36 (dd, J ₁ =J ₂ =8.0Hz, 1H), 7.09 (ddd, J ₁ =1.2Hz, J ₂ =7.6Hz, J ₂ =7.6Hz, 1H); ¹³ C NMR ( 100MHz, CDCl ₃ )δ162.35, 149.47, 146.35, 137.89, 134.84, 130.35, 130.08, 129.51, 129.27, 128.33, 127.79, 127.73, 124.62, 123.58, 121.02, 118.65.

Synthesis Example 5

Synthesis of N-(4-chloro-phenyl)quinoline-2-carboxamide

Add 0.4mmol 4-chloro-aniline, 0.1mmol phenylacetic acid and 0.1mmol diphenylphosphoric acid and 10mol% copper bromide and 10mol% copper iodide to the reaction vessel, vacuumize, backfill with oxygen, and then add 0.2mmol 2- Methylquinoline and 1mL N,N-dimethylformyl press, sealed; heated to 130°C for 19h. After the reaction solution was cooled to room temperature, washed with ammonia-saturated sodium bicarbonate solution, and then extracted with chloroform, Drying, distillation and concentration under reduced pressure to remove the solvent, the crude product was separated by column chromatography to obtain the target product with a yield of 66%. No other impurities remain after NMR inspection. ¹ H NMR (400MHz, CDCl ₃ ) δ10.25(s, 1H), 8.38(b, 2H), 8.18(d, J=8.4Hz, 1H), 7.92(d, J=7.6Hz, 1H), 7.80 -7.84(m,3H),7.67(dd,J ₁ ＝J ₂ ＝8.0Hz,1H),7.38(d,J＝8.8Hz,2H); ¹³ C NMR(100MHz,CDCl ₃ )δ162.21,149.37,146.30 ,137.99,136.41,130.45,129.65,129.51,129.30,129.15,128.30,127.87,120.98,118.72.

Synthesis Example 6

Synthesis of N-(4-nitro-phenyl)quinoline-2-carboxamide

Add 0.4mmol 4-nitro-aniline, 0.2mmol diphenylphosphoric acid and 20mol% cuprous iodide to the reaction vessel, evacuate, backfill with oxygen, then add 0.2mmol 2-methylquinoline and 1mL anisole , sealed; heated to 150°C and reacted for 24h. After the reaction solution was cooled to room temperature, it was washed with saturated sodium bicarbonate solution, then extracted with chloroform, dried, concentrated under reduced pressure to remove the solvent, and the crude product was obtained by column chromatography. The target product, the yield is 39%. No other impurities remain after NMR inspection. ¹ H NMR (400MHz, CDCl ₃ ) δ10.59(s, 1H), 8.38-8.43(m, 2H), 8.31(d, J=9.2Hz, 2H), 8.21(d, J=8.4Hz, 1H) ,8.04(d,J=9.2Hz,2H),7.95(d,J=8.4Hz,1H),7.85(dd,J ₁ ＝J ₂ ＝8.0Hz,1H),7.70(dd,J ₁ ＝J ₂ ＝8.0Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ162.60, 148.65, 146.26, 143.65, 143.53, 138.28, 130.72, 129.71, 129.65, 128.68, 127.94, 125.25, 119.215, 118.7

Synthesis Example 7

Synthesis of N-isopropyl-quinoline-2-carboxamide

Add 0.2mmol diphenylphosphoric acid and 10mol% cuprous iodide and 5mol% copper oxide to the reaction vessel, vacuumize, backfill with oxygen, then add 0.4mmol isopropylamine, 0.2mmol 2-methylquinoline and 1mL chlorobenzene and 1mL tetrahydrofuran, sealed; heated to 100°C and reacted for 15h. After the reaction liquid was cooled to room temperature, washed with saturated sodium bicarbonate solution, then extracted with chloroform, dried, concentrated by distillation under reduced pressure to remove the solvent, and the crude product was subjected to column chromatography The target product was obtained after isolation with a yield of 29%. No other impurities remain after NMR inspection. ¹ H NMR (400MHz, CDCl ₃ ) δ8.29-8.33 (m, 2H), 8.11-8.13 (m, 2H), 7.88 (d, J=8.4Hz, 1H), 7.74-7.79 (m, 1H), 7.59-7.63(m,1H),4.30-4.39(m,1H),1.35(d,J=6.4Hz); ¹³ C NMR(100MHz,CDCl ₃ )δ163.58,150.06,146.48,137.44,130.02,129.65,129.28 ,127.79,127.77,118.86,41.56,22.85.

Synthesis Example 8

Synthesis of (piperidine-1)-(quinoline-2)-methanone

Add 0.2mmol benzoic acid and 15mol% copper trifluoroacetate to the reaction vessel, vacuumize, backfill with oxygen, then add 0.4mmol piperidine, 0.2mmol 2-methylquinoline and 1mL anisole, seal; heat to 130°C Under reaction for 12h. After the reaction solution was cooled to room temperature, washed with saturated sodium bicarbonate solution, then extracted with chloroform, dried, concentrated under reduced pressure to remove the solvent, and the crude product was separated by column chromatography to obtain the target product with a yield of 41 %. No other impurities remain after NMR inspection. ¹ HNMR (400MHz, CDCl ₃ ) δ8.25 (d, J = 8.4Hz, 1H), 8.11 (d, J = 8.4Hz, 1H), 7.85 (d, J = 8.0Hz, 1H), 7.74-7.78 ( m,1H),7.66(d,J=8.0Hz,1H),7.58-7.62(m,1H),3.81(t,J=5.2Hz,2H),3.52(t,J=5.2Hz,2H), 1.73(b,6H); ¹³ C NMR(100MHz,CDCl ₃ )δ167.60,154.42,146.79,137.12,130.00,129.74,127.94,127.65,127.38,120.41,48.35,43.36,26.52,245.60.2

Claims (3)

1. the synthetic method of two grade or three-level aromatic amides of the one kind with following structural formula (I),

Include following reactions steps：

Metal copper catalyst, bronsted acid, amine source, the reaction vessel of 2- methyl-N- heterocyclic aromatic compounds is will be equipped with to take out very Sky, fills oxygen, then adds organic solvent sealing；100~150 DEG C of 8~24h of reaction are heated to, reaction is cooled to after terminating Room temperature, is washed with saturated sodium bicarbonate, then with chloroform extraction, is dried, and vacuum distillation concentration removes solvent, crude product warp Pillar layer separation, produces target product；

The equation of the synthetic method is：

The N- heterocycles are to be selected from pyridine ring, thiazole ring, pyrazine ring, benzothiazole ring, quinoxaline ring, quinoline ring or ferrosin Ring；

The R₁It is to be selected from amino, trimethyl-acetyl, methyl, fluorine, chlorine, bromine, nitro, methyl formate base or methoxyl group；

Work as R₂When being hydrogen, R₃Be phenyl, 2- methoxyphenyls, 2- chlorphenyls, 4- aminomethyl phenyls, 4- chlorphenyls, 4- nitrobenzophenones or Isopropyl or normal-butyl；

Work as R₂When being not hydrogen, R₂、R₃Piperidine ring, morpholine ring or nafoxidine ring are formed together with connected N；

The organic solvent is to be selected from 1,4- dioxane, N,N-dimethylformamide, chlorobenzene, methyl phenyl ethers anisole, toluene or tetrahydrochysene furan The one or more muttered；

Described metal copper catalyst is to be selected from Cu, CuBr, CuCl, CuI, Cu (OAc)₂、CuBr₂、CuI₂, CuO or Cu (OTf)₂ One or more；

Described bronsted acid be selected from acetic acid, benzoic acid, phenylacetic acid, benzene sulfonic acid or diphenylphosphoric acid it is one or two kinds of with On；

Described amine source is to be selected from aniline, paranitroanilinum, parachloroanilinum, open-chain crown ether, o-chloraniline, O-methoxy benzene Amine, isopropylamine, n-butylamine, piperidines, morpholine or nafoxidine.

2. two grades according to claim 1 or the synthetic method of three-level aromatic amides, it is characterised in that described Metal copper catalyst, bronsted acid, 2- methyl-N- heterocyclic aromatic compounds and the mol ratio in amine source are [0.05~0.2]: [0.5~1.0]：1：[1.0~2.0].

3. two grades according to claim 1 or the synthetic method of three-level aromatic amides, it is characterised in that described 2- methyl-N- heterocyclic aromatic compounds are selected from 2- picolines, 2- methylthiazols, 2- methylpyrazines, 2- methylbenzothiazoles, 2- Methyl-quinoxaline, 2- methylquinolines, 2- methyl -4- aminoquinolines, 2- methyl -4- pivaloyl amidos quinoline, 2,6- diformazans Base quinoline, 2- methyl -6- fluorine quinoline, 2- methyl -6- chloroquinolines, 2- methyl -6- bromoquinolines, 2- methyl -6- nitroquinolines, 2- first Base -6- methyl formate bases quinoline, 2- methyl -6- methoxy quinolines, 2- methyl -8- methoxy quinolines or 2,9- dimethyl -1,10- Ferrosin.