Process for the electrochemical reductive hydrogenation of the alpha-position c-o bond of an amide derivative

Abstract

The application relates to a method for electrochemical reduction hydrogenation of an amide derivative alpha-site C-O bond, and belongs to the technical field of organic electrochemical green synthesis. The application solves the technical problem that the direct reduction of an amide derivative alpha-site carbon-oxygen bond (C-O) into a C-H bond cannot be realized by existing reaction technologies. Method: a container is assembled, alpha-hydroxy amide derivatives, electrolytes and molecular sieves are added, and ultra-dry solvents are added, and the system is sealed; constant current electrolysis is carried out for electrolysis reaction; and separation and purification are carried out. The application directly realizes the reduction hydrogenation of a C(sp 3 )‑O bond by using electrochemical green, efficient, mild and powerful oxidation-reduction capacity, realizes the functional group conversion and synthesis of multiple types of multi-substituted N-aryl amide derivatives, is widely applicable to electron-donating groups, electron-withdrawing groups, nitrogen heterocyclic and oxygen heterocyclic N-aryl amine types, and exhibits excellent functional group tolerance. The application is used for synthesizing amide derivatives.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic electrochemical green synthesis, and particularly relates to an electrochemical reductive hydrogenation method of an alpha-position C-O bond of an amide derivative. BACKGROUND

[0002] In view of the fact that the dissociation energy of the carbon-oxygen bond (C-O) is relatively high, direct homolysis thereof is still a challenge. Common C-O bond activation methods include transition metal insertion, boron reagent-promoted homolytic C-O bond activation cross-coupling, and activation of the C-O bond by using a photocatalyst, but these methods have the disadvantages of low atom economy, harsh reaction conditions, need for addition of noble metals, poor substrate tolerance, and the like. Organic electrochemical synthesis, as compared with traditional synthesis methods, uses clean electrons instead of traditional redox reagents, and has the advantages of mild reaction conditions and green sustainability, and is particularly suitable for synthesis and production of high-value-added fine chemicals, and has practical economic value and development significance. Therefore, it is still a subject to be studied to directly reduce the C-O bond at the alpha-position of a benzamide derivative into a C-H bond by using the powerful oxidation-reduction capacity of electrochemistry. SUMMARY

[0003] The present application solves the technical problem of direct reduction of the carbon-oxygen bond (C-O) at the alpha-position of an amide derivative into a C-H bond, which is difficult to achieve by using existing reaction technologies, and provides a green and efficient electrochemical reduction method.

[0004] The present application solves the technical problem of direct reduction of the carbon-oxygen bond (C-O) at the alpha-position of an amide derivative into a C-H bond, which is difficult to achieve by using existing reaction technologies, and provides a green and efficient electrochemical reduction method.

[0005] I. A three-necked glass bottle is respectively provided with a graphite carbon rod electrode and a magnesium rod electrode on two sides; a magnetic sub is further added to the three-necked glass bottle, the bottle mouths on the two sides are sealed, and an alpha-hydroxy amide derivative, an electrolyte and molecular sieves are sequentially added to the three-necked glass bottle, and then an ultradry solvent is added, and the system is sealed;

[0006] II. The sealed system of step I is stirred at room temperature, and a constant current electrolysis is continuously introduced to perform an electrolysis reaction, and a thin layer chromatography method is used to monitor the reaction to obtain a crude product;

[0007] III. The crude product obtained in step II is subjected to vacuum distillation to remove the solvent, and then a thin layer chromatography method is used for separation and purification, and the obtained product is an amide derivative.

[0008] Amide derivatives are widely used in the design and synthesis of biologically active molecules and drugs due to their unique biological activity. N-aryl amides are the most important class of active compounds, and are common basic synthetic units in the fields of pharmaceuticals, agricultural chemicals, materials and cosmetics, and are crucial for the conversion of amide structures to various nitrogen heterocyclic active structures. Arylamine compounds are important building blocks for rapidly constructing high-value functional organic molecules.

[0009] The present application uses electrochemical synthesis strategy, continuously passes constant current in the reaction system, takes the target alpha-hydroxy amide derivative as the reactant substrate, breaks the carbon-oxygen bond (C-O) at the cathode to form the corresponding carbon alkyl radical by single electron reduction, then forms the carbon negative ion by further single electron reduction, and the carbon negative ion attacks the electrophilic reagent (H + ) to form the corresponding polysubstituted N-aryl amide compound.

[0010] The method uses cheap and easily available arylamine compounds and lactic acid as synthesis building blocks to prepare a series of alpha-hydroxy amide compounds, and then pre-activates to obtain the corresponding alpha-hydroxy amide derivative, directly reduces the C-O bond at the alpha position to the C-H bond by the strong oxidation-reduction capacity of the electrochemical method, and realizes the defunctionalization of the alpha position of the amide derivative.

[0011] The preparation method of the alpha-hydroxy amide derivative is as follows:

[0012] First, aniline and its derivatives are used as starting materials, 1.2 equivalents of lactic acid are added, the mixture is reacted at a temperature of 130 DEG C for 12 hours, after the reaction is completed, the organic phase is extracted with ethyl acetate (EA), the organic phase is dried with anhydrous sodium sulfate, the organic phase is concentrated, and column chromatography is used for separation and purification; secondly, the obtained alpha-hydroxy amide is dissolved in dichloromethane (DCM), 10 mol% of 4-dimethylaminopyridine (DMAP 1) is added, 1.05 equivalents of propionic anhydride is slowly added dropwise at 0 DEG C, and stirred at room temperature for 12 hours, after the reaction is completed, it is extracted with DCM, the organic phase is dried with anhydrous sodium sulfate, the organic phase is concentrated, and column chromatography is used for separation and purification to obtain the target substrate.

[0013] The specific reaction formula is as follows:

[0014]

[0015] In which R is -Me, -Et, -OMe or -COOMe.

[0016] The reaction general formula of the present application is as follows:

[0017]

[0018] R is -Me, -Et, -OMe or -COOMe.

[0019] The reaction mechanism diagram of the present application is as shown in Figure 3 .

[0020] Under electrochemical conditions, the substrate 2-1 is subjected to a single electron cathodic reduction at the cathode, and the generated radical anion intermediate 2-I is released from the alkyl radical intermediate 2-II and the carboxylate anion (EtCOO - ) through the cleavage of the C-O bond; then, the alkyl radical intermediate 2-II is reduced to the alkyl anion intermediate 2-III through a second single electron (SET) transfer at the cathode; as a nucleophilic species, the carbon anion attacks the electrophilic hydrogen ion and realizes the reductive hydrogenation to obtain the corresponding amide (2-3). At the same time, the magnesium (Mg) electrode is constantly losing electrons at the anode to become magnesium ions (Mg 2+ ), so as to maintain the electronic balance of the working electrode cathode of the reaction.

[0021] The present application has the following beneficial effects:

[0022] The present application directly realizes the reductive hydrogenation of the C(sp 3 )-O bond by using the electrochemical green, efficient, mild and powerful redox capacity, realizes the functional group transformation and synthesis of a plurality of types of polysubstituted N-aryl amide derivatives, and is widely applicable to electron-donating groups, electron-withdrawing groups, nitrogen heterocyclic, oxygen heterocyclic N-aryl amines, and exhibits excellent functional group tolerance.

[0023] Compared with the prior art, the present application directly reduces the carbon-oxygen bond at the alpha position of the N-aryl amide derivative to a carbon-hydrogen bond by a simple, green and efficient electrochemical method, and mainly has the following advantages:

[0024] (1) The reaction uses the electrons provided by the current in the electrochemical system as the reducing agent, avoids the use of external chemical reducing agents, and is simple and clean in operation and green and mild in conditions.

[0025] (2) The reaction directly reduces the carbon-oxygen bond at the alpha position of the amide derivative to a carbon-hydrogen bond by using the powerful redox capacity of electrochemistry, and the reaction is specific.

[0026] (3) The amine, propionic anhydride, nBu4NBF4 and solvent used in the reaction system are cheap and easy to obtain, and the metal magnesium electrode and graphite rod electrode device are simple and can be repeatedly used, which can effectively reduce the reaction cost.

[0027] (4) The substrate of the reaction system has a wide application range, and can be used to synthesize a variety of substituted N-aryl amides, including amide derivatives with nitrogen heterocyclic, oxygen heterocyclic, naphthalene and the like.

[0028] The present application is used for synthesizing amide derivatives. BRIEF DESCRIPTION OF DRAWINGS

[0029] Figure 1 is the product of the reductive hydrogenation of the amide derivative b1 obtained in Example 1 1H-NMR spectrum;

[0030] Figure 2 is an amide derivative b1 obtained in Example 1 13 C-NMR spectrum;

[0031] Figure 3 is a reaction mechanism diagram of the present application. DETAILED DESCRIPTION

[0032] Embodiment I: The electrochemical reduction hydrogenation method of the amide derivative of the present embodiment is carried out according to the following steps:

[0033] I. A three-necked glass bottle is equipped with a graphite carbon electrode and a magnesium electrode on both sides respectively; a magnet is added to the three-necked glass bottle, the bottle mouths on both sides are sealed, and an α-hydroxy amide derivative, an electrolyte and molecular sieves are sequentially added, and then an ultradry solvent is added, and the system is sealed;

[0034] II. The sealed system of step I is stirred at room temperature, and a constant current electrolysis is continuously conducted, and a thin layer chromatography method is used to monitor the reaction to obtain a crude product;

[0035] III. The crude product obtained in step II is subjected to vacuum distillation to remove the solvent, and then a thin layer chromatography method is used for separation and purification, and the obtained product is an amide derivative.

[0036] Embodiment II: The difference between the present embodiment and embodiment I is that: in step I, the three-necked glass bottle is transferred to a glove box for feeding. The others are the same as embodiment I.

[0037] Embodiment III: The difference between the present embodiment and embodiment I or II is that: in step I, the structural formula of the α-hydroxy amide derivative is: wherein R is -Me, -Et, -OMe or -COOMe. The others are the same as embodiment I or II.

[0038] Embodiment IV: The difference between the present embodiment and any one of embodiments I to III is that: in step I, the electrolyte is tetrabutylammonium tetrafluoroborate nBu4NBF4. The others are the same as any one of embodiments I to III.

[0039] Embodiment V: The difference between the present embodiment and any one of embodiments I to IV is that: in step I, the ultradry solvent is ultradry acetonitrile. The others are the same as any one of embodiments I to IV.

[0040] Embodiment VI: The difference between the present embodiment and any one of embodiments I to V is that: in step I, the diameter of the graphite carbon electrode is 6 mm, and the diameter of the magnesium electrode is 6 mm. The others are the same as any one of embodiments I to V.

[0041] Specific embodiment seven: the difference between this embodiment and one of the specific embodiments one to six is that the molecular sieve in step one is molecular sieve. The others are the same as one of the specific embodiments one to six.

[0042] Specific embodiment eight: the difference between this embodiment and one of the specific embodiments one to seven is that the ratio of the amount of the α-hydroxy amide derivative to the super dry solvent in step one is 0.1 mmol: 1 mL; the ratio of the amount of the electrolyte to the super dry solvent is 0.1 mmol: 1 mL; the ratio of the amount of the α-hydroxy amide derivative to the electrolyte is 0.4 mmol: 0.4 mmol. The others are the same as one of the specific embodiments one to seven.

[0043] Specific embodiment nine: the difference between this embodiment and one of the specific embodiments one to eight is that the constant current in step two is 10 mA, and the reaction time is 8 h. The others are the same as one of the specific embodiments one to eight.

[0044] Specific embodiment ten: the difference between this embodiment and one of the specific embodiments one to nine is that the solvent used in the thin layer chromatography separation and purification in step three is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1. The others are the same as one of the specific embodiments one to nine.

[0045] The content of the present application is not limited to the content of each of the above embodiments, and the combination of one or more specific embodiments can also achieve the purpose of the application.

[0046] Example 1:

[0047] This embodiment is a method for electrochemical reduction hydrogenation of the C-O bond at the α-position of an amide derivative, which is specifically carried out according to the following steps:

[0048] I. A 25 mL three-necked glass bottle is fitted with a graphite carbon rod electrode with a diameter of 6 mm and a magnesium rod electrode with a diameter of 6 mm on both sides, respectively. A magnet is then added to the three-necked glass bottle, and the bottle openings on both sides are sealed. The three-necked glass bottle is then transferred to a glove box for material feeding. 0.4 mmol of α-hydroxy amide derivative 1a, 137.7 mg of electrolyte nBu4NBF4 (concentration of 0.1 M), and 100 mg of molecular sieve 4 mL of super dry solvent acetonitrile (MeCN) is then added, and the system is sealed;

[0049] II. The sealed system in step I is stirred at room temperature, and a constant current of 10 mA is continuously supplied for electrolysis. After 8 hours of reaction, thin layer chromatography is used for monitoring, and a new sample spot is observed at a relative migration value (Rf) of 0.3, obtaining a crude product;

[0050] 3. The crude product obtained in step 2 was subjected to reduced pressure distillation to remove the solvent, and then separated and purified by thin layer chromatography. The eluent was a mixed solvent of petroleum ether (PE) and ethyl acetate (EA) in a volume ratio of 3:1. The obtained product was amide derivative 1b (N-arylamide compound).

[0051] Synthesis of amide derivative 1b:

[0052]

[0053] The amide derivative 1b prepared above was 1 H-NMR, 13 C-NMR technology was used for molecular structure and mass identification.

[0054] Amide derivative 1b 1 H-NMR spectrum Figure 1 As shown, CDCl3 was selected as the solvent to dissolve the sample to be tested, and the solvent peak was calibrated to δ = 7.26 ppm. The extracted data was: 1 H-NMR (400MHz, Chloroform-d) δ = 7.51 (d, J = 7.9Hz, 2H), 7.31 (t, J = 7.7Hz, 3H), 7.09 (t, J = 7.5Hz, 1H), 2.39 (q, J = 7.5Hz, 2H), 1.24 (t, J = 7.5Hz, 3H) ppm.

[0055] Data analysis of this compound revealed that the triplet at δ = 1.24 ppm and the quartet at δ = 2.39 ppm in the high-field region are characteristic peaks of the methyl and methylene groups on substrate 1a, respectively. These peaks are split due to spin coupling between adjacent positions and have the same coupling constant (J = 7.5 Hz). The two sets of triplet signals at δ = 7.51, 7.31, and 7.09 ppm are attributed to the three aromatic hydrogens on the benzene ring.

[0056] Amide derivative 1b 13 C-NMR spectrum Figure 2 As shown, CDCl3 was selected as the solvent to dissolve the sample to be tested, and the solvent peak was calibrated as follows: the chemical shift of the middle peak of the deuterated solvent CDCl3 triplet was set to δ=77.1 ppm as a reference. The extracted data was: 13 C NMR (101MHz, CDCl3) δ = 172.20, 138.11, 129.12, 124.29, 119.93, 30.88, 9.80ppm.

[0057] The compound 13C-NMR data analysis: there are 7 different carbon signals in total, two in high field region, which belong to the carbon of a methyl group and a methylene group; five in low field region, four of which belong to the aromatic carbons of benzene ring, and the peak at δ = 172.20 ppm is the characteristic signal of carbonyl group, thus confirming the target product.

[0058] Example 2:

[0059] The difference between this example and Example 1 is that the substrate used is α-hydroxy amide derivative 2a The product synthesized is amide derivative 2b The yield is 83%.

[0060] Example 3:

[0061] The difference between this example and Example 1 is that the substrate used is α-hydroxy amide derivative 3a The product synthesized is amide derivative 3b The yield is 47%.

[0062] Example 4:

[0063] The difference between this example and Example 1 is that the substrate used is α-hydroxy amide derivative 4a The product synthesized is amide derivative 4b The yield is 47%.

[0064] Example 5:

[0065] The difference between this example and Example 1 is that the substrate used is α-hydroxy amide derivative 5a The product synthesized is amide derivative 5b The yield is 81%.

[0066] Example 6:

[0067] The difference between this example and Example 1 is that the substrate used is α-hydroxy amide derivative 6a The product synthesized is amide derivative 6b The yield is 34%.

[0068] Example 7:

[0069] The difference between this example and Example 1 is that the substrate used is α-hydroxy amide derivative 7a The product synthesized is amide derivative 7b The yield is 70%.

[0070] Example 8:

[0071] The difference between this example and Example 1 is that the substrate used is α-hydroxy amide derivative 8a The product synthesized is amide derivative 8b The yield is 65%.

[0072] Example 9:

[0073] This example differs from Example 1 in that the substrate used is α-hydroxy amide derivative 9a The product synthesized is amide derivative 9b The yield is 37%.

[0074] Example 10:

[0075] This example differs from Example 1 in that the substrate used is α-hydroxy amide derivative 10a The product synthesized is amide derivative 10b The yield is 77%.

[0076] Example 11:

[0077] This example differs from Example 1 in that the substrate used is α-hydroxy amide derivative 11a The product synthesized is amide derivative 11b The yield is 32%.

[0078] Example 12:

[0079] This example differs from Example 1 in that the substrate used is α-hydroxy amide derivative 12a The product synthesized is amide derivative 12b The yield is 36%.

[0080] Example 13:

[0081] This example differs from Example 1 in that the substrate used is α-hydroxy amide derivative 13a The product synthesized is amide derivative 13b The yield is 60%.

[0082] Example 14:

[0083] This example differs from Example 1 in that the substrate used is α-hydroxy amide derivative 14a The product synthesized is amide derivative 14b The yield is 31%.

[0084] Example 15:

[0085] This example differs from Example 1 in that the substrate used is α-hydroxy amide derivative 15a The product synthesized is amide derivative 15b The yield is 51%.

[0086] Example 16:

[0087] The difference between this embodiment and embodiment 1 is that the substrate used is α-hydroxyamide derivative 16a The synthesized product is amide derivative 16b The yield was 51%.

[0088] Example 17:

[0089] The difference between this embodiment and embodiment 1 is that the substrate used is α-hydroxyamide derivative 17a The synthesized product is amide derivative 17b The yield was 58%.

[0090] As shown above, amides containing electron-donating substituents on the N-aryl group, such as methyl (2b), tert-butyl (4b), and methoxy (5b), all achieved electrochemical reductive hydrogenation of the α-CO bond under these electrochemical conditions, with yields reaching medium or above. In addition, derivatives containing electron-withdrawing groups on the N-aryl group, such as esters, electron-deficient pyridine rings, and sulfonyl groups, also successfully achieved reductive hydrogenation of the α-CO bond. Various functional groups, including nitrogen heterocycles, oxygen heterocycles, naphthalene, and indole, are all tolerant to this reaction. Tertiary amines also achieved high yields, with an isolated yield of up to 58%.

[0091] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the invention can be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the invention is defined by the appended claims, not the foregoing description, and all variations within the meaning and range of equivalents of the claims are intended to be included therein. Any reference sign in a claim should not be construed as limiting the claim to which it relates.

[0092] In addition, it should be understood that although this specification is described in terms of implementation methods, not every implementation method contains only one independent technical solution. This narrative method of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other implementation methods that can be understood by those skilled in the art.

Claims

1. A method for electrochemical reduction and hydrogenation of the α-CO bond of an amide derivative, characterized in that The method is specifically carried out in the following steps:

1. Assemble graphite carbon rod electrodes and magnesium rod electrodes on both sides of the three-necked glass bottle respectively; then add magnets to the three-necked glass bottle, seal the two sides of the bottle, and add α -hydroxyamide derivatives, electrolytes and molecular sieves, and then add ultra-dry solvents and seal the system; described α -The structural formula of the hydroxyamide derivative is: , wherein R is -Me, -Et, –OMe or –COOMe; 2. Stirring the sealed system of step 1 at room temperature, continuously passing constant current electrolysis to carry out electrolysis reaction, and monitoring the reaction by thin layer chromatography to obtain a crude product; 3. The crude product obtained in step 2 is subjected to reduced pressure distillation to remove the solvent, and then separated and purified by thin layer chromatography to obtain an amide derivative; Step 2: Control the constant current to 10 mA; The general reaction formula of step 2 is: 。 2. The electrochemical reduction hydrogenation method of the α-CO bond of an amide derivative according to claim 1, characterized in that Step 1: Transfer the three-necked glass bottle to the glove box for feeding.

3. The electrochemical reduction hydrogenation method of the α-CO bond of an amide derivative according to claim 1, characterized in that The electrolyte in step 1 is tetrabutylammonium tetrafluoroborate.

4. The electrochemical reduction hydrogenation method of the α-CO bond of an amide derivative according to claim 1, characterized in that The ultra-dry solvent in step 1 is ultra-dry acetonitrile.

5. The electrochemical reduction hydrogenation method of the α-CO bond of an amide derivative according to claim 1, characterized in that In step 1, the diameter of the graphite carbon rod electrode is 6 mm, and the diameter of the magnesium rod electrode is 6 mm.

6. The electrochemical reduction hydrogenation method of the α-CO bond of an amide derivative according to claim 1, characterized in that The molecular sieve in step 1 is a 5 Å molecular sieve.

7. The electrochemical reduction hydrogenation method of the α-CO bond of an amide derivative according to claim 1, characterized in that Step 1 α The ratio of the hydroxyamide derivative to the ultra-dry solvent is 0.1 mmol: 1 mL; the ratio of the electrolyte to the ultra-dry solvent is 0.1 mmol: 1 mL; α The ratio of the hydroxyamide derivative to the electrolyte is 0.4 mmol:0.4 mmol.

8. The electrochemical reduction hydrogenation method of the α-CO bond of an amide derivative according to claim 1, characterized in that The reaction time in step 2 is controlled to be 8h.

9. The electrochemical reduction hydrogenation method of the α-CO bond of an amide derivative according to claim 1, characterized in that The solvent used for the thin layer chromatography separation and purification in step 3 is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 3:1.

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