A method for synthesizing 1,n-dianitronidazole compounds

Abstract

This invention belongs to the technical field of organic synthesis and discloses a method for synthesizing 1,n-dianitronic compounds. The method involves reacting alkenyl-substituted alkyl nitriles and boric acid compounds in an air atmosphere using an organic solvent as the reaction medium, under the action of a weakly basic salt and a catalyst, to obtain 1,n-dianitronic compounds. The structure of the 1,n-dianitronic compounds is as shown in Formula I. This method utilizes readily available raw materials, offers high yield, has broad substrate applicability, is simple to operate, and boasts high atom economy, enabling the construction of structurally diverse polysubstituted 1,n-dianitronic compounds.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing 1,n-dianitronic compounds. Background Technology

[0002] Nitriles are ubiquitous and multifunctional building blocks in organic synthesis, and their acquisition and transformation have attracted widespread interest. Incorporating multiple cyano groups into a single molecule endows these compounds with new and unique properties, leading to their wide application in the pharmaceutical, fine chemical, and materials industries. 1. n-Diatonnitriles are key intermediates in many drugs or bioactive compounds. For example, pregabalin is an antiepileptic drug used to treat pain caused by fibromyalgia, or neuropathic pain in patients with diabetes (diabetic neuropathy), postherpetic neuralgia, or spinal cord injury (Discovery and Development of Pregabalin (Lyrica): The Role of Public Funding. Neurology. 2021, 97, e1653-e1660.). Lisdexamfetamine is a central nervous system stimulant used to treat attention-deficit / hyperactivity disorder (ADHD) in adults and children at least 6 years of age (Review of Lisdexamfetamine Dimesylate in Adults with Attention-Deficit / Hyperactivity Disorder. J. Cent. Nerv. Syst. Dis. 2017, 9, 1179573517728090.). Adiponitrile is an important monomer for the manufacture of polyamides such as nylon-6,6, with a production scale reaching 1 million tons per year (A Review on Catalyzed Dimerization of Acrylonitrile. Chin. J. Org. Chem. 2014, 34, 1986-1991.). Furthermore, 1,n-dianitriles are widely used as electrolyte additives in lithium-ion batteries to overcome voltage limitations, broaden the temperature window, and improve the recyclability of lithium-ion batteries (Dinitrile-Mononitrile-Based Electrolyte System for Lithium-Ion Battery Application with the Mechanism of Reductive Decomposition of Mononitriles. J. Phys. Chem. 2016, 120, 6450-6458.). Therefore, it is of great significance to develop a practical and widely applicable method to construct the corresponding 1,n-dianitriles.

[0003] Generally, there are currently three methods to construct 1,n-dinitriles. The first method uses HCN or acetone cyanohydrin as the cyano source, and obtains highly atom-economical adiponitriles through stepwise cyanolation of 1,3-conjugated dienes (Nickel-Catalyzed Regiodivergent Cyanation of Allylic Alcohols: Scope, Mechanism, and Application to the Synthesis of 1,n-Dinitriles. ACS Catal. 2021, 11, 13880-13890.). Although this method has been successfully used industrially, the harsh reaction conditions and the use of highly toxic reagents limit its widespread application, and it is not possible to obtain other 1,n-dinitriles. The second method involves the direct reductive coupling of acrylonitrile (A Review on Catalyzed Dimerization of Acrylonitrile. Chin. J. Org. Chem. 2014, 34, 1986-1991.) or the dehydrogenation coupling of acetonitrile (Reactivity of Bis(cyanomethanide) Nickel and Palladium Complexes. Inorg. Chim. Acta. 2000, 298, 239-244.) to synthesize symmetrical 1,n-dianitriles. The third method involves constructing the corresponding 1,n-dianitriles by linking a series of olefins via radical-mediated cyano migration (Radical Trifunctionalization of Hexenenitrile via Remote CyanoMigration. Chem. Commun. 2022, 58, 1005-1008.). However, because the addition of free radicals to alkenes strictly follows the principle of electron matching, electron-rich functional groups, such as simple alkyl chains, as well as aryl and alkynyl groups, cannot be obtained by this method (Radical Philicity and Its Role in Selective Organic Transformations. Nat. Rev. Chem. 2021, 5, 486-499.). Therefore, developing a synthetic strategy for 1,n-dianitrogener derivatives with inexpensive and readily available raw materials, a wide variety of substrates, and broad applicability remains a very meaningful research topic. Summary of the Invention

[0004] To overcome the shortcomings and deficiencies of existing technologies, the present invention aims to provide a simple and efficient method for synthesizing 1,n-dianitrile compounds. The present invention uses a wide variety of readily available alkenyl-substituted alkyl nitriles and commercially available, easily manipulated borate compounds as raw materials to obtain a series of structurally diverse 1,n-dianitrile compounds in high yield, with broad functional group compatibility and high atom economy.

[0005] This invention is achieved through the following technical solution:

[0006] A method for synthesizing 1,n-dianitronic compounds includes the following steps: under an air atmosphere, using an organic solvent as the reaction medium, alkenyl-substituted alkyl nitrile and boric acid compounds react in the presence of a weakly basic salt and a catalyst to obtain 1,n-dianitronic compounds.

[0007] The structure of the alkenyl-substituted alkyl nitrile is as follows:

[0008]

[0009] In the formula, m = 1, 2, 3;

[0010] R 1 It is hydrogen, C1-C 12 Straight-chain or branched alkyl groups, aryl groups, substituted aryl groups, heteroaryl groups, etc.

[0011] R 2 It can be a straight-chain or branched alkyl group, benzyl group, substituted benzyl group, 2-furanylmethyl group, cyclohexyl group, alkenyl group, cyclohexenyl group, phenyl group, etc., of C1-C6.

[0012] The structure of the boric acid compound is: R 3 -B(OH)2

[0013] R 3 It can be aryl, heteroaryl, substituted aryl, or substituted heteroaryl.

[0014] The structure of the 1,n-dianitrile compound is as follows:

[0015]

[0016] In the formula, m = 1, 2, 3; in 1,n-dianitronic compounds, n = m + 2.

[0017] R 1The aryl group is phenyl, the substituted aryl group is a substituted phenyl group, and the substituent in the substituted phenyl group is methyl, methoxy, trifluoromethyl, trifluoromethoxy, or halogen, specifically 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, or 4-bromophenyl. The heteroaryl group is quinolinyl, thienyl, or benzofuranyl, specifically 3-quinolinyl, 3-thienyl, or 5-benzofuranyl.

[0018] R 2 In this context, the substituted benzyl group refers to the benzyl group in which the hydrogen atom on the benzene ring is replaced by one or more of the following: methyl, dimethylamino, methoxy, halogen, ester (COOR, R being alkyl), furanyl, pyridyl, thiophene, quinolinyl, benzofuranyl, and 3,4-methylenedioxyphenyl.

[0019] The substituted benzyl groups are specifically 2-methylbenzyl, 4-dimethylaminobenzyl, 4-methoxybenzyl, 4-fluorobenzyl, 4-bromobenzyl, 2-fluoro-3-chlorobenzyl, 4-ester benzyl, 2-furanylbenzyl, 2-pyridylbenzyl, 2-thienylbenzyl, 3-quinolinylbenzyl, 5-benzofuranylbenzyl, and 3,4-methylenedioxyphenylbenzyl.

[0020] The R 3 Preferably, it is phenyl, substituted phenyl, 2-pyridyl, 3-pyridyl, 6-chloro-3-pyridyl, 5-fluoro-2-pyridyl, 2-benzofuranyl, 2-furanyl, 3-furanyl, 2-furanylvinyl, dibenzo[b,d]furan-4-yl, 2-thiophenevinyl, 2-quinolinyl, 2-quinoxalinyl, 4-pyridazinyl, etc.

[0021] R 3 The substituted phenyl groups described herein are 2-fluorophenyl, 3-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-methylthiophenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3,5-dimethylphenyl, and 4-CON(CH3)2phenyl.

[0022] When the R in the structure of an alkenyl-substituted alkyl nitrile 2 When the group is 1-cyclohexenyl, the CH-R group in the structure of 1,n-diacetonitrile compounds... 2 Cyclohexanemethylene

[0023] The organic solvent is one or more of toluene, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, tert-butanol, and tert-amyl alcohol; preferably one or more of tert-amyl alcohol, tert-butanol, tetrahydrofuran, and dioxane.

[0024] The weakly basic salt is one or more of potassium formate, sodium formate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium phosphate, lithium phosphate, trisodium phosphate dodecahydrate, potassium acetate, sodium acetate, cesium acetate, cesium fluoride, sodium ethoxide, sodium methoxide, sodium tert-butoxide, and sodium pentovaperate; preferably one or more of cesium carbonate, cesium bicarbonate, potassium bicarbonate, and potassium phosphate.

[0025] The catalyst is bis(1,5-cyclooctadiene)nickel (Ni(cod)2), nickel acetylacetonate (Ni(acac)2), nickel trifluoromethanesulfonate (Ni(OTf)2), NiCl2, NiCl 2· 6H2O, NiCl2(PPh3)2, nickel chloride ethylene glycol dimethyl ether complex (NiCl2(dme)), nickel bromide (NiBr2), nickel bromide ethylene glycol dimethyl ether complex (NiBr2(dme)), NiBr2(PPh3)2, NiI2, PdCl2, PdBr2, PdI2, Pd(OAc)2, palladium trifluoroacetate (Pd(TFA)2), tris(dibenzylacetone)palladium (Pd2(dba)3), tetra(triphenylphosphine)palladium (Pd(PPh3)4), bis(triphenylphosphine)palladium dichloride (Pd(PPh3)2Cl2), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (Pd(DPPF)Cl2), [Rh(OMe)(COD)]2, [RhCl(COD)]2, RhCl(PPh3)3 (COD represents 1,5-cyclooctadiene group);

[0026] The catalyst is preferably one or more of the following: bis(1,5-cyclooctadiene) nickel, nickel acetylacetonate, nickel trifluoromethanesulfonate, nickel chloride ethylene glycol dimethyl ether complex, and nickel bromide ethylene glycol dimethyl ether complex.

[0027] The reaction temperature is 80-140℃, preferably 100-140℃.

[0028] The reaction time is 12 to 24 hours, or the reaction can be detected by thin-layer chromatography to determine whether it is complete.

[0029] The reaction may include a ligand, which is a nitrogen or phosphine compound, such as: bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine, 2,2'-bipyridine-4,4'-dicarboxylic acid, tripyridine, 1,10-phenanthroline, triphenylphosphine, tricyclohexylphosphine, 1,1'-bis(diphenylphosphine)ferrocene, 1,2-bis(diphenylphosphine)ethane, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine.

[0030] The molar ratio of the alkenyl-substituted alkyl nitrile to the boric acid compound is 1:1 to 1.5:1; the molar ratio of the catalyst to the boric acid compound is (0.05 to 0.1):1; and the molar ratio of the weakly basic salt to the boric acid compound is (1 to 2):1.

[0031] The molar volume ratio of the boric acid compound to the organic solvent is (0.1–0.3) mmol: 1 mL.

[0032] After the reaction was complete, the mixture was cooled to room temperature and quenched with a saturated ammonium chloride aqueous solution. It was then extracted with water and ethyl acetate. The organic phase was dried with anhydrous sodium sulfate or anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then separated by column chromatography using a mixed solvent of petroleum ether and dichloromethane with a volume ratio of 20:1 to 2:1 as the eluent.

[0033] The reaction equation is as follows:

[0034]

[0035] Compared with the prior art, the present invention has the following beneficial effects and advantages:

[0036] (1) The raw materials of the present invention are readily available, and the structures of polysubstituted 1,n-dianitron compounds with rich and diverse structures can be constructed;

[0037] (2) This invention can synthesize a series of polysubstituted 1,n-dianitron compounds that cannot be obtained by current methods, with high yield and wide substrate applicability;

[0038] (3) The conditions are mild, the operation is simple, and the atom economy is high. Attached Figure Description

[0039] Figure 1 This is the 1H NMR spectrum (1H NMR: 400MHz, CDCl3) of compound 3a;

[0040] Figure 2 This is the carbon spectrum (13C NMR: 101MHz, CDCl3) of compound 3a;

[0041] Figure 3 This is the 1H NMR spectrum (1H NMR: 400MHz, CDCl3) of compound 3b;

[0042] Figure 4 This is the 3b carbon spectrum (13C NMR: 101MHz, CDCl3) of compound;

[0043] Figure 5 This is the fluorine spectrum (1H NMR: 376MHz, CDCl3) of compound 3b;

[0044] Figure 6This is the 3c proton NMR spectrum (1H NMR: 400MHz, CDCl3) of the compound;

[0045] Figure 7 This is the 3C carbon spectrum (13C NMR: 101MHz, CDCl3) of the compound;

[0046] Figure 8 This is the 3d proton NMR spectrum (1H NMR: 400MHz, CDCl3) of the compound;

[0047] Figure 9 This is the 3d carbon spectrum (13C NMR: 101MHz, CDCl3) of the compound;

[0048] Figure 10 This is the 3e proton NMR spectrum (1H NMR: 400MHz, CDCl3) of the compound;

[0049] Figure 11 This is the 3e carbon spectrum (13C NMR: 101MHz, CDCl3) of the compound;

[0050] Figure 12 This is the 3f proton NMR spectrum (1H NMR: 500MHz, CDCl3) of the compound;

[0051] Figure 13 This is the 3f carbon spectrum (13C NMR: 126MHz, CDCl3) of the compound;

[0052] Figure 14 This is the 1H NMR spectrum (1H NMR: 400MHz, CDCl3) of compound 3g;

[0053] Figure 15 This is the carbon spectrum (13C NMR: 101MHz, CDCl3) of compound 3g. Detailed Implementation

[0054] The present invention will be further described in detail below with reference to the embodiments and accompanying drawings, but the implementation and protection of the present invention are not limited thereto.

[0055] Example 1

[0056] Starting with an alkenyl-substituted alkyl nitrile 1a (2-benzyl-2-(but-3-en-1-yl)malonadionitrile) (0.36 mmol) and phenylboronic acid 2a (0.30 mmol), nickel acetylacetonate (0.015 mmol) and cesium bicarbonate (0.60 mmol) were added, followed by 1.5 mL of tert-amyl alcohol solvent. The mixture was heated and stirred in an oil bath at 120 °C for 12 hours or detected by TLC until compound 2a was completely reacted. The mixture was then removed, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (using a 5:1 volume ratio of petroleum ether and dichloromethane as eluent) to obtain compound 3a in 75% yield.

[0057] The structural formula of compound 1a:

[0058]

[0059] Product 3a structural formula:

[0060]

[0061] Structural characterization data of 3a: white solid, melting point: 128.0-128.9℃, dr = 1:1. 1 H NMR (400MHz, CDCl3) δ7.37-7.25(m,6H,two isomers),7.24-7.16(m,4H,two isomers),2.98-2.83(m,4H,two isomers),2.83-2.73(m,2H,two isomers),1.96-1.82(m,2H,two isomers),1.79-1.63(m,2H,two isomers); 13C NMR(101MHz, CDCl3)136.4&136.3(two isomers),129.0&129.0(two isomers),128.9&128.9(two isomers),127.5&127.5(overlap,two isomers),121.0&120.8(two isomers),120.9&120.8(two isomers),38.3&38.3(two isomers),33.6&33.6(overlap,two isomers),29.5&29.5(overlap,two isomers),29.1&29.1(overlap,two isomers).HRMS(ESI)m / z:[M+H] + Calcd.for C 20 H 21 N2 289.1699; found289.1691.

[0062] The proton and carbon spectra of compound 3a are as follows: Figure 1 and Figure 2 As shown.

[0063] Example 2

[0064] Starting with an alkenyl-substituted alkyl nitrile 1a (2-benzyl-2-(but-3-en-1-yl)malonadionitrile) (0.36 mmol) and (4-(trifluoromethoxy)phenyl)boronic acid 2b (0.30 mmol), nickel acetylacetonate (0.015 mmol) and cesium bicarbonate (0.60 mmol) were added, followed by 1.5 mL of tert-amyl alcohol solvent. The reaction mixture was heated and stirred in an oil bath at 120 °C for 12 hours or detected by TLC until compound 2b was completely reacted. The reaction flask was then removed from the oil bath, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (the eluent was a mixture of petroleum ether and dichloromethane in a volume ratio of 5:1) to obtain compound 3b in 60% yield.

[0065] Product 3b structural formula

[0066]

[0067] Structural characterization data of 3b: white solid, melting point: 106.3-107.1℃, dr = 1:1. 11H NMR (400 MHz, CDCl3) δ 7.38 - 7.15 (m, 9H, two isomers), 2.97 - 2.86 (m, 4H, two isomers), 2.84 - 2.74 (m, 2H, two isomers), 1.99 - 1.83 (m, 2H, two isomers), 1.82 - 1.65 (m, 2H, two isomers); 13 13C NMR (101 MHz, CDCl3) δ 148.6 (q, J C-F = 1.0 Hz, overlap, two isomers), 136.4 & 16.3 (two isomers), 135.2 & 135.1 (two isomers), 130.5 & 130.5 (two isomers), 129.1 & 129.0 (two isomers), 129.0 & 128.9 (two isomers), 127.6 & 127.6 (overlap, two isomers), 120.5 (q, J C-F = 258.6 Hz, overlap, two isomers), 121.3 & 121.3 (overlap, two isomers), 121.0 & 120.7 (two isomers), 120.8 & 120.5 (two isomers), 38.4 & 38.4 (two isomers), 37.7 & 37.6 (two isomers), 33.7 & 33.7 (two isomers), 33.3 & 33.3 (two isomers), 29.7 & 29.6 (two isomers), 29.2 & 29.1 (two isomers); 19 19F NMR (376 MHz, CDCl3) δ -57.8. HRMS (ESI) m / z: [M + H] + Calcd. for C 21 H 20 F3N2O 373.1522; found 373.1513.

[0068] The 1H NMR spectrum, 13C NMR spectrum, and 19F NMR spectrum of Compound 3b are as shown in Figure 3 , Figure 4 and Figure 5 .

[0069] Example 3

[0070] Starting with alkenyl-substituted alkyl nitrile 1a (2-benzyl-2-(but-3-en-1-yl)malonadionitrile) (0.36 mmol) and (4-(dimethylcarbamoyl)phenyl)boronic acid 2c (0.30 mmol), nickel acetylacetonate (0.015 mmol) and cesium bicarbonate (0.60 mmol) were added, followed by 1.5 mL of tert-amyl alcohol solvent. The reaction was heated and stirred in an oil bath at 120 °C for 12 hours or detected by TLC until compound 2c was completely reacted. The reaction flask was removed from the oil bath, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (the eluent was a mixture of petroleum ether and dichloromethane in a volume ratio of 2:1) to obtain compound 3c, with a yield of 86%.

[0071] Product 3C structural formula

[0072]

[0073] 3C structural characterization data: white solid, melting point: 100.9-102.6℃, dr = 1:1. 1 H NMR (400MHz, CDCl3) δ7.47-7.27(m,4H,two isomers),7.30-7.19(m,5H,two isomers),3.10(s,3H,overlap,two isomers),2.97(s,3H,overlap,two isomers),2.95-2.76(m,6H,two isomers),1.98-1.82(m,2H,two isomers),1.80-1.65(m,2H,two isomers); 1313C NMR (101 MHz, CDCl3) δ 171.2 & 171.2 (overlap, two isomers), 137.9 & 137.8 (two isomers), 136.4 & 136.3 (two isomers), 135.6 & 135.6 (two isomers), 129.1 & 129.0 (two isomers), 129.0 & 129.0 (overlap, two isomers), 128.9 & 128.9 (two isomers), 127.7 & 127.7 (overlap, two isomers), 127.5 & 127.5 (overlap, two isomers), 121.0, 121.0 & 120.8 (two isomers), 120.8 & 120.6 (two isomers), 39.6 & 39.6 (overlap, two isomers), 38.4 & 38.1 (two isomers), 35.4 & 35.4 (overlap, two isomers) 33.6 & 33.4 (two isomers), 33.3 & 33.1 (two isomers), 29.6 & 29.6 (two isomers), 29.2 & 29.1 (two isomers). HRMS (ESI) m / z: [M+H] + Calcd. for C 23 H 26 N3O 360.2070; found 360.2062.

[0074] 1H NMR and 13C NMR spectra of Compound 3c are shown as Figure 6 and Figure 7 follows.

[0075] Example 4

[0076] Starting with an alkenyl-substituted alkyl nitrile 1a (2-benzyl-2-(but-3-en-1-yl)malonadionitrile) (0.36 mmol) and dibenzo[b,d]furan-4-ylboronic acid 2d (0.30 mmol), nickel acetylacetonate (0.015 mmol) and cesium bicarbonate (0.60 mmol) were added, followed by 1.5 mL of tert-amyl alcohol solvent. The reaction mixture was heated and stirred in an oil bath at 120 °C for 12 hours or detected by TLC until compound 2d was completely reacted. The reaction flask was then removed from the oil bath, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (the eluent was a mixture of petroleum ether and dichloromethane in a volume ratio of 5:1) to obtain compound 3d, with a yield of 50%.

[0077] 3D structural formula of the product

[0078]

[0079] 3D structural characterization data: white solid, melting point: 108.6-110.3℃. dr = 1:1. 1 H NMR (400MHz, CDCl3) δ7.98-7.83(m,2H,two isomers),7.57(m,1H,two isomers),7.47(m,1H,two isomers),7.41-7.22(m,6H,two isomers),7.22-7.15(m,2H,two isomers),3.33-3.11(m,3H,two isomers),2.98-2.74(m,3H,two isomers),2.09-1.89(m,2H,two isomers),1.88-1.70(m,2H,two isomers); 1313C NMR (101 MHz, CDCl3) δ 156.0 & 156.0 (overlap, two isomers), 154.5 & 154.5 (overlap, two isomers), 136.5 & 136.4 (two isomers), 129.1 & 129.0 (two isomers), 128.9 & 128.9 (two isomers), 128.2 & 128.2 (two isomers), 127.5 & 127.5 (overlap, two isomers), 127.5 & 127.5 (overlap, two isomers), 124.5 & 124.5 (overlap, two isomers), 124.3 & 124.3 (overlap, two isomers), 123.3 & 123.3 (overlap, two isomers), 123.1 & 123.1 (overlap, two isomers), 121.1 & 121.0 (two isomers), 121.0 & 121.0 (overlap, two isomers), 120.9 & 120.9 (two isomers), 120.5 & 120.5 (two isomers), 120.2 & 120.2 (overlap, two isomers), 111.8 & 111.8 (overlap, two isomers), 38.4 & 38.4 (two isomers), 33.7 & 33.4 (two isomers), 33.0 & 33.0 (overlap, two isomers), 32.1 & 31.8 (two isomers), 29.8 & 29.6 (two isomers), 29.4 & 29.2 (two isomers). HRMS (ESI) m / z: [M+H] + Calcd. for C 26 H 23 N2O 379.1805; found 379.1795.

[0080] The 1H NMR spectrum and 13C NMR spectrum of Compound 3d are as shown in Figure 8 and Figure 9 shown.

[0081] Example 5

[0082] Starting with alkenyl-substituted alkyl nitrile 1b (2-(but-3-en-1-yl)-2-(furan-2-ylmethyl)malonidonitrile) (0.36 mmol) and phenylboronic acid 2a (0.30 mmol), nickel acetylacetonate (0.015 mmol) and cesium bicarbonate (0.60 mmol) were added, followed by 1.5 mL of tert-amyl alcohol solvent. The reaction was heated and stirred in an oil bath at 120 °C for 12 hours or detected by TLC until compound 2a was completely reacted. The reaction flask was removed from the oil bath, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and then extracted with water and ethyl acetate. The organic phase was dried with anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (the eluent was a mixture of petroleum ether and dichloromethane in a volume ratio of 5:1) to obtain compound 3e in 77% yield.

[0083] The structural formula of compound 1b:

[0084]

[0085] Product 3e structural formula

[0086]

[0087] Structural characterization data of 3e: white solid, melting point: 70.5-72.1℃, dr = 1:1. 1 H NMR (400MHz, CDCl3) δ7.39-7.25(m,4H,two isomers),7.23(m,2H,two isomers),6.33(m,1H,twoisomers),6.23-6.18(m,1H,two isomers),3.08-2.75(m,6H,two isomers),1.99-1.83(m,2H,two isomers),1.81-1.65(m,2H,two isomers); 13C NMR (101MHz, CDCl3) δ150.0&150.0(overlap,two isomers),142.4&142.4(overlap,two isomers),136.5&136.4(twoisomers),129.1&129.0(two isomers),128.9&128.9(overlap,two isomers),127.6&127.6(overlap,two isomers),121.0&120.8(two isomers),120.7&120.5(two isomers),110.6&110.6(overlap,two isomers),108.2&108.2(overlap,two isomers),38.4&38.4(overlap,two isomers),33.6&33.3(two isomers),31.1&31.1(overlap,two isomers),30.8&30.7(two isomers),29.5&29.4(two isomers),29.0&28.9(two isomers).HRMS(ESI)m / z:[M+H] + Calcd.for C 18 H 19 N2O 279.1492; found 279.1487.

[0088] The proton and carbon spectra of compound 3d are as follows: Figure 10 and Figure 11 As shown.

[0089] Example 6

[0090] Starting with an alkenyl-substituted alkyl nitrile 1c (2-(but-3-en-1-yl)-2-cyclohexylmalonidonitrile) (0.36 mmol) and phenylboronic acid 2a (0.30 mmol), nickel acetylacetonate (0.015 mmol) and cesium bicarbonate (0.60 mmol) were added, followed by 1.5 mL of tert-amyl alcohol solvent. The reaction was heated and stirred in an oil bath at 120 °C for 12 hours or detected by TLC until compound 2a was completely reacted. The reaction flask was removed from the oil bath, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (the eluent was a mixture of petroleum ether and dichloromethane in a volume ratio of 5:1) to obtain compound 3f, with a yield of 61%.

[0091] The structural formula of compound 1c:

[0092]

[0093] Product 3f structure

[0094]

[0095] Structural characterization data of 3f: white solid, melting point: 58.7-60.3℃, dr = 1:1. 1 H NMR (500MHz, CDCl3) δ7.42-7.15(m,5H,two isomers),3.01-2.76(m,3H,two isomers),2.44-2.36(m,1H,two isomers),1.96-1.65(m,9H,two isomers),1.54-1.45(m,1H,two isomers),1.31-1.10(m,5H,two isomers); 13 C NMR (126MHz, CDCl3) δ136.6&136.5(two isomers),129.1&129.1(two isomers),129.0&128.9(two isomers),127.6&127.6(overlap,two isomers),121.2&120.9(two isomers),120.8&120.6(two isomers),39.6&39.4(two isomers),38.5&38.4(two isomers),38.4&37.8(two isomers),33.9&33.4(two isomers),31.4&31.2(two isomers),30.2&29.8(two isomers),27.7&27.0(two isomers),26.0&26.0(two isomers),26.0&25.9(two isomers).HRMS(ESI)m / z:[M+H] + Calcd.for C 19 H 25 N2281.2012; found 281.2005.

[0096] The proton and carbon spectra of compound 3e are as follows: Figure 12 and Figure 13 As shown.

[0097] Example 7

[0098] Starting with an alkenyl-substituted alkyl nitrile 1d (2-(but-3-en-1-yl)-2-(cyclohex-1-en-1-yl]malonadionitrile) (0.36 mmol) and phenylboronic acid 2a (0.30 mmol), nickel acetylacetonate (0.015 mmol) and cesium bicarbonate (0.60 mmol) were added, followed by 1.5 mL of tert-amyl alcohol solvent. The reaction was heated and stirred in an oil bath at 120 °C for 12 hours or detected by TLC until compound 2a reacted completely. The reaction flask was removed from the oil bath, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography (the eluent was a mixture of petroleum ether and dichloromethane in a volume ratio of 5:1) to give 3 g of the compound, with a yield of 53%.

[0099] The structural formula of compound 1d:

[0100]

[0101] Product 3g structural formula:

[0102]

[0103] Structural characterization data for 3g: pale yellow liquid. 1 H NMR(400MHz, CDCl3)δ7.39-7.20(m,5H,twoisomers),3.01-2.86(m,2H),2.85-2.73 (m,1H),2.58-2.35(m,3H),2.32-2.24(m,2H),1.94-1.72(m,3H),1.69-1.52(m,6H); 13 C NMR (101MHz, CDCl3) δ161.4,136.5,129.1,128.9,127.5,121.1,118.6,103. 9,38.4,35.5,33.0,30.7,30.5,28.1,27.8,26.7,26.0.HRMS(ESI)m / z:[M+H] + Calcd.for C 19 H 23 N2279.1856; found 279.1851.

[0104] The proton and carbon spectra of compound 3g are as follows: Figure 14 and Figure 15 As shown.

[0105] Comparative Example 1

[0106] Starting with an alkenyl-substituted alkyl nitrile 1a (2-benzyl-2-(but-3-en-1-yl)malonadionitrile) (0.36 mmol) and mesityleneboronic acid 2e (0.30 mmol), nickel acetylacetonate (0.015 mmol) and cesium bicarbonate (0.60 mmol) were added, followed by 1.5 mL of tert-amyl alcohol solvent. The mixture was heated and stirred in an oil bath at 120 °C for 12 hours, or until compound 2e was completely reacted as determined by TLC. The reaction flask was then removed from the oil bath, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography to obtain compound 3h. The column chromatography eluent was a 5:1 (v / v) mixture of petroleum ether and dichloromethane, with a yield of 22%.

[0107] Product 3h structure

[0108]

[0109] Comparative Example 2

[0110] Starting with an alkenyl-substituted alkyl nitrile 1a (2-benzyl-2-(but-3-en-1-yl)malonadionitrile) (0.36 mmol) and 3-pyridineboronic acid 2f (0.30 mmol), nickel acetylacetonate (0.015 mmol) and cesium bicarbonate (0.60 mmol) were added, followed by 1.5 mL of tert-amyl alcohol solvent. The mixture was heated and stirred in an oil bath at 120 °C. The reaction was allowed to proceed for 12 hours or until compound 2f was completely reacted, as indicated by TLC. The reaction flask was then removed from the oil bath, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography to obtain compound 3i. The column chromatography eluent was a 5:1 (v / v) mixture of petroleum ether and dichloromethane, with a yield of 16%.

[0111] Product 3i structural formula

[0112]

[0113] Comparative Example 3

[0114] Starting with an alkenyl-substituted alkyl nitrile 1e (2-benzyl-2-cinnamoylmalononitrile) (0.36 mmol) and phenylboronic acid 2a (0.30 mmol), nickel acetylacetonate (0.015 mmol) and cesium bicarbonate (0.60 mmol) were added, followed by 1.5 mL of tert-amyl alcohol solvent. The mixture was heated and stirred in an oil bath at 120 °C. The reaction was allowed to proceed for 12 hours or until compound 2a was completely reacted, as indicated by TLC. The reaction flask was then removed from the oil bath, cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was further purified by column chromatography to obtain compound 3j. The column chromatography eluent was a 5:1 (v / v) mixture of petroleum ether and dichloromethane, with a yield of 12%.

[0115] The structural formula of compound 1e:

[0116]

[0117] Product 3j structural formula:

[0118]

[0119] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A method for synthesizing 1,n-diacetonitrile compounds, characterized in that: Includes the following steps: In an air atmosphere, using an organic solvent as the reaction medium, alkenyl-substituted alkyl nitriles and boric acid compounds react in the presence of a weakly basic salt and a catalyst to obtain 1,n-dianitronic compounds. The structure of the alkenyl-substituted alkyl nitrile is as follows: In the formula, m = 1, 2, 3; R 1 It is hydrogen, C1-C 12 Straight-chain or branched alkyl, aryl, substituted aryl, heteroaryl; R 1 The aryl group mentioned is phenyl, and the substituted aryl group is a substituted phenyl group, R 1 The substituted phenyl groups are specifically 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, and 4-bromophenyl, and the heteroaryl groups are quinolinyl, thienyl, and benzofuranyl. R 2 It is a C1-C6 straight-chain or branched alkyl, benzyl, substituted benzyl, 2-furanylmethyl, cyclohexyl, alkenyl, cyclohexenyl, or phenyl group; R 2 In this context, the substituted benzyl group refers to the benzyl group in which the hydrogen atom on the benzene ring is substituted by one or more of methyl, dimethylamino, methoxy, halogen, ester, furanyl, pyridyl, thiophene, quinolinyl, benzofuranyl, and 3,4-methylenedioxyphenyl; specifically, the substituted benzyl group is 2-methylbenzyl, 4-dimethylaminobenzyl, 4-methoxybenzyl, 4-fluorobenzyl, 4-bromobenzyl, 2-fluoro-3-chlorobenzyl, 4-ester benzyl, 2-furanylbenzyl, 2-pyridylbenzyl, 2-thiophene benzyl, 3-quinolinylbenzyl, 5-benzofuranylbenzyl, or 3,4-methylenedioxyphenylbenzyl. The structure of the boric acid compound is: R 3 -B(OH)2; The R 3 It is phenyl, substituted phenyl, 2-pyridyl, 3-pyridyl, 6-chloro-3-pyridyl, 5-fluoro-2-pyridyl, 2-benzofuranyl, 2-furanyl, 3-furanyl, 2-furanylene, dibenzo[b,d]furan-4-yl, 2-thiopheneylene, 2-quinolinyl, 2-quinoxalinyl, 4-pyridazinyl; R 3 The substituted phenyl groups described herein are 2-fluorophenyl, 3-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-methylthiophenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 3,5-dimethylphenyl, and 4-(CH3)2NCOphenyl. The structure of the 1,n-diacetonitrile compound is as follows: In the formula, m = 1, 2, 3; in 1,n-diacetonitrile compounds, n = m + 2; When the R in the structure of an alkenyl-substituted alkyl nitrile 2 When the group is 1-cyclohexenyl, the CH-R group in the structure of 1,n-diacetonitrile compounds... 2 Cyclohexanemethylene The organic solvent is one or more of tert-amyl alcohol, tert-butanol, tetrahydrofuran, and dioxane; the weakly basic salt is one or more of cesium carbonate, cesium bicarbonate, potassium bicarbonate, and potassium phosphate. The catalyst is one or more of nickel acetylacetonate and nickel trifluoromethanesulfonate.

2. The method for synthesizing 1,n-diacetonitrile compounds according to claim 1, characterized in that: The reaction temperature is 80-140℃; The reaction time is 12 to 24 hours, or the reaction can be detected by thin-layer chromatography to determine whether it is complete. The molar ratio of the alkenyl-substituted alkyl nitrile to the boric acid compound is 1:1 to 1.5:1; the molar ratio of the catalyst to the boric acid compound is (0.05 to 0.1):1; and the molar ratio of the weakly basic salt to the boric acid compound is (1 to 2):

1.

3. The method for synthesizing 1,n-diacetonitrile compounds according to claim 2, characterized in that: The reaction temperature is 100-140℃.

4. The method for synthesizing 1,n-diacetonitrile compounds according to claim 1, characterized in that: The molar volume ratio of the boric acid compound to the organic solvent is (0.1–0.3) mmol: 1 mL; After the reaction was complete, the mixture was cooled to room temperature and quenched with a saturated ammonium chloride aqueous solution. It was then extracted with water and ethyl acetate. The organic phase was dried with anhydrous sodium sulfate or anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was then separated by column chromatography using a mixed solvent of petroleum ether and dichloromethane with a volume ratio of 20:1 to 2:1 as the eluent.

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