Method for preparing cyano compound from N-acyloxyphthalimide and olefin

Abstract

The invention provides a method for preparing a cyano compound from N-acyloxy phthalimide and olefin, which specifically comprises the following steps: by taking N-acyloxy phthalimide and olefin as reactants, adding a catalyst, a ligand, a photosensitizer and trimethylsilyl cyanide, and carrying out alkyl cyanation reaction and / or amino cyanation reaction to obtain the cyano compound. An alkyl cyano compound and / or an amino cyano compound are / is obtained; the catalyst is Cu (CH3CN) 4BF4, and the ligand is a chiral bisoxazoline ligand; and the photosensitizer is 3DPA2FBN (3, 4 '- According to the invention, controllable generation of free radicals at a carbon center and a nitrogen center can be realized by accurately regulating and controlling a metal / ligand ratio, and high-selectivity olefin alkyl cyanation and amino cyanation reactions are realized under mild conditions, so that an accessible chemical space is expanded, the multifunctionality of a synthetic route is improved, and the method is suitable for industrial production. The application range of the N-acyloxy phthalimide in free radical chemistry is obviously expanded.

Description

Technical fields:

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing cyano compounds from N-acyloxyphthalimide and olefins. Background technology:

[0002] In recent years, free radical reactions have attracted widespread attention due to their unique reaction characteristics, high efficiency, and excellent functional group tolerance. These advantages have made free radical chemistry an important supplement to traditional ionic processes, demonstrating a vigorous development trend in modern synthetic methodology. Among them, the study of generating free radicals through homolytic cleavage of inert covalent bonds (such as those containing nitrogen / oxygen functional groups in carboxylic acids, amines, and alcohols) under mild conditions has become a hot research area. Of particular note is the fact that N-acyloxyphthalimide (NHPI) esters derived from alkyl carboxylic acids have become an important research object in this field due to their availability and excellent redox properties.

[0003] During the single-electron transfer (SET) process, NHPI ester first forms the radical anionic intermediate int-I, followed by NO bond cleavage and the release of CO2 and phthalimide anion (PhthN). - Simultaneously, a carbon-centered radical (R·) is generated, thus achieving decarboxylation alkylation. This pathway is highly efficient when the carboxylic acid is attached to an electron-rich alkyl group and is currently widely used in the construction of C-C and C-C bonds. However, when the alkyl group of the carboxylic acid is attached to a strongly electron-withdrawing group, the int-I cleavage pathway shifts to the generation of a nitrogen-centered phthalimide radical (PhthN·), thus favoring amination reactions.

[0004] In 2014, Sanford's research team first reported the amination of (hetero)aromatic hydrocarbons using NHPI esters as nitrogen radical precursors in the presence of the photocatalyst Ir(ppy)3. The selectivity of this reaction was significantly modulated by the electronic effects of substituents: NHPI esters derived from acetic acid or benzoic acid produced almost no amination products, while substrates containing strong electron-withdrawing groups (such as pentafluorophenyl, β,β,β-trifluoroethyl, or trifluoromethyl) yielded the target product in moderate to good yields. This result confirmed the promoting effect of electron-withdrawing groups on nitrogen radical formation. Further research showed that these electron-withdrawing groups can effectively suppress competitive carbon-center radical formation pathways. For example, Baran's group demonstrated that iron-catalyzed decarboxylation C-coupling reactions are highly compatible with primary, secondary, and tertiary alkyl carboxylic acids. However, the yield of NHPI esters derived from β,β,β-trifluoroethyl carboxylic acid was less than 2%, indicating that strong electron-withdrawing groups significantly inhibit the formation of alkyl radicals. The situation becomes more complex when alkyl groups possess moderate electron-withdrawing properties: the intermediate int-I may simultaneously generate carbon- and nitrogen-centered radicals, leading to product mixing and limiting its synthetic applications. However, this phenomenon also reveals the existence of a biradical generation pathway: these substrates can simultaneously form alkyl and nitrogen-centered radicals. If precise control of reaction chemoselectivity can be achieved through rational condition design, it is hoped that carbon radicals (including those with electron-withdrawing substituents) or nitrogen radicals can be selectively generated, thereby significantly expanding the application range of NHPI esters in radical chemistry. Summary of the Invention:

[0005] The purpose of this invention is to address the shortcomings of existing technologies by providing a method for preparing cyano compounds from N-acyloxyphthalimide and olefins. This method can selectively obtain structurally different products from the same set of substrates, while reducing costs and operational difficulties. It not only expands the available chemical space but also enhances the versatility of synthetic routes.

[0006] The present invention adopts the following technical solution:

[0007] This invention provides a method for preparing cyano compounds from N-acyloxyphthalimide and olefins, comprising: using N-acyloxyphthalimide and olefins as reactants, adding a catalyst, a ligand, a photosensitizer and trimethylcyanosilane, and carrying out an alkyl cyanation reaction and / or an amino cyanation reaction to obtain alkyl cyano compounds and / or amino cyano compounds; wherein the catalyst is Cu(CH3CN)4BF4; and the ligand is a chiral bisoxazoline ligand.

[0008] Furthermore, the structural formula of the N-acyloxyphthalimide is as follows: The structural formula of olefins is Wherein, R is one of α-trifluoromethyl substituent, α-methoxycarbonyl substituent, methyl cyclopropylformate, α-cyano substituent, α-polyfluoroalkyl substituent, α-heteroatom substituent, difluoroalkyl substituent, cyclohexyl, bicyclo[1.1.1]pentyl, adamantyl, and nitrogen-bridged skeleton; Ar is one of halobenzene, aromatic ring with alkyl / alkoxy / acyloxy group, naphthalene, pyridine derivative, indole, benzofuran, and estrone. That is, the olefin is one of halostyrene derivative, styrene derivative with alkyl / alkoxy / acyloxy group on the aromatic ring, 2-vinylnaphthalene, and styrene derived from pyridine / indole / benzofuran / estrione.

[0009] Furthermore, the reaction is carried out in an ultra-dry acetonitrile solvent system.

[0010] Furthermore, when the ratio of N-acyloxyphthalimide, olefin, catalyst, ligand, photosensitizer, trimethylcyanosilane, and acetonitrile is 0.1 mmol: 0.15–0.25 mmol: 0.003 mmol: 0.001–0.003 mmol: 0.0005 mmol: 0.15 mmol: 2 ml, the alkyl cyanation reaction is dominant.

[0011] Furthermore, when the ratio of N-acyloxyphthalimide, olefin, catalyst, ligand, photosensitizer, trimethylcyanosilane, and acetonitrile is 0.1 mmol: 0.25 mmol: 0.003 mmol: 0.001 mmol: 0.0005 mmol: 0.15 mmol: 2 ml, the alkyl cyanation reaction is dominant, and the ratio of alkyl cyano compounds to amino cyano compounds is 21.8:1.

[0012] Furthermore, when the ratio of N-acyloxyphthalimide, olefin, catalyst, ligand, photosensitizer, trimethylcyanosilane, and acetonitrile is 0.1 mmol: 0.25 mmol: 0.003 mmol: 0.0015 mmol: 0.0005 mmol: 0.15 mmol: 2 ml, the ratio of alkylcyano compound to aminocyano compound is 17.4:1. When the ratio of N-acyloxyphthalimide, olefin, catalyst, ligand, photosensitizer, trimethylcyanosilane, and acetonitrile is 0.1 mmol: 0.25 mmol: 0.003 mmol: 0.003 mmol: 0.0005 mmol: 0.15 mmol: 2 ml, the ratio of alkylcyano compound to aminocyano compound is 12.4:1.

[0013] Furthermore, when the ratio of the N-acyloxyphthalimide, olefin, catalyst, ligand, photosensitizer, trimethylcyanosilane, and acetonitrile is 0.1 mmol: 0.15–0.25 mmol: 0.0001–0.001 mmol: 0.001–0.0075 mmol: 0.0005 mmol: 0.15 mmol: 1–3.5 ml, the aminocyanation reaction is dominant.

[0014] Furthermore, when the ratio of N-acyloxyphthalimide, olefin, catalyst, ligand, photosensitizer, trimethylcyanosilane, and acetonitrile is 0.1 mmol: 0.25 mmol: 0.001 mmol: 0.0075 mmol: 0.0005 mmol: 0.15 mmol: 3.5 ml, the alkyl cyanation reaction is dominant, and the ratio of alkyl cyano compounds to amino cyano compounds is 1:8.5.

[0015] Furthermore, when the ratio of N-acyloxyphthalimide, olefin, catalyst, ligand, photosensitizer, trimethylcyanosilane, and acetonitrile is 0.1 mmol: 0.25 mmol: 0.0001 mmol: 0.001 mmol: 0.0005 mmol: 0.15 mmol: 1 ml, the ratio of alkyl cyano compound to amino cyano compound is 1:10. When the ratio of N-acyloxyphthalimide, olefin, catalyst, ligand, photosensitizer, trimethylcyanosilane, and acetonitrile is 0.1 mmol: 0.25 mmol: 0.0001 mmol: 0.001 mmol: 0.0005 mmol: 0.15 mmol: 2 ml, the ratio of alkyl cyano compound to amino cyano compound is 1:6.

[0016] Furthermore, when the ratio of N-acyloxyphthalimide, olefin, catalyst, ligand, photosensitizer, trimethylcyanosilane, and acetonitrile is 0.1 mmol: 0.25 mmol: 0.001 mmol: 0.001 mmol: 0.0005 mmol: 0.15 mmol: 3.5 ml, the ratio of alkylcyano compound to aminocyano compound is 2.3:1. When the ratio of N-acyloxyphthalimide, olefin, catalyst, ligand, photosensitizer, trimethylcyanosilane, and acetonitrile is 0.1 mmol: 0.25 mmol: 0.0005 mmol: 0.0005 mmol: 0.0005 mmol: 0.15 mmol: 3.5 ml, the ratio of alkylcyano compound to aminocyano compound is 1:1.6.

[0017] Furthermore, the reaction method is as follows: N-acyloxyphthalimide, olefin, catalyst, ligand, photosensitizer and trimethylcyanosilane are mixed in a solvent, stirred in the dark for 5 to 10 minutes, and then stirred for 12 to 24 hours at room temperature under 24W blue light irradiation.

[0018] Furthermore, the structural formula of the chiral bisoxazoline ligand is as follows:

[0019]

[0020] Furthermore, the photosensitizer is 3DPA2FBN.

[0021] The beneficial effects of this invention are:

[0022] (1) This invention provides a method for preparing cyano compounds from N-acyloxyphthalimide and olefins, and constructs a general and scalable olefin bifunctionalization reaction platform. Using N-acyloxyphthalimide as a bifunctional free radical precursor, under the synergistic effect of photo-redox and copper catalysis, the controllable generation of carbon center and nitrogen center free radicals is achieved by precisely controlling the metal / ligand ratio, and highly selective olefin alkyl cyanoation and amino cyanoation reactions are achieved under mild conditions.

[0023] (2) The present invention is widely adaptable to various substrates and has high tolerance to a variety of functional groups;

[0024] (3) This invention exhibits excellent enantioselectivity control. Mechanistic studies show that when the copper catalyst is in excess, TMS is generated in situ in the system. + This promotes the carbon radical pathway, while ligand enrichment conditions favor the formation of nitrogen radicals. This reaction can selectively yield structurally diverse products from the same set of substrates, while reducing costs and operational complexity. This type of divergent synthesis not only expands the available chemical space but also enhances the multifunctionality of synthetic routes, significantly broadening the application scope of NHPI esters in radical chemistry.

[0025] (4) This invention systematically solves the long-standing challenge of regulating the reactivity of electron-deficient alkyl carboxylic acid-derived NHPI esters, and establishes an innovative conversion strategy for achieving chemoselectivity through precise catalyst regulation. This strategy provides a unified and universal conversion system for the efficient construction of functionally dense molecules, demonstrating broad application potential in fields such as drug molecule design and complex organic synthesis. Detailed implementation method:

[0026] To make the objectives, technical solutions, and advantages of this application clearer, the following description and illustration are provided in conjunction with embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the scope of this application. All other embodiments obtained by those skilled in the art based on the embodiments provided in this application without inventive effort are within the scope of protection of this application. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0027] Example 1

[0028] This embodiment provides a method for preparing alkyl cyanide products from N-acyloxyphthalimide and olefins. The reaction equation and specific steps are as follows:

[0029]

[0030] Under argon protection, NHPI ester 1a (0.1 mmol), acetonitrile (CH3CN, 1.3 mL), ligand L1 solution (0.02 mol / L in CH3CN, 0.05 mL), Cu(CH3CN)4BF4 solution (0.02 mol / L in CH3CN, 0.15 mL), 3DPA2FBN solution (0.001 mol / L in CH3CN, 0.5 mL), olefin 1b (0.15 mmol, 1.5 equiv), and TMSCN (19 μL, 0.15 mmol, 1.5 equiv) were added sequentially to a dry 10 mL Schlenk tube. The reaction tube was sealed with a polytetrafluoroethylene septum, stirred in the dark for 5 minutes, and then stirred for 12 hours at room temperature under 24W blue LED illumination. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain the target alkyl cyanide product 1c (25.3 mg, 80% yield, 96% ee).

[0031] The structural confirmation data for this product are as follows:

[0032] 1 H NMR (400MHz, CDCl3) δ7.57(d,J=7.7Hz,2H),7.51(d,J=8.1Hz,2H),7.42(t,J=7.7H z,2H),7.33–7.15(m,8H),3.61–3.43(m,2H),2.79–2.63(m,4H),2.22–2.11(m,1H).

[0033] 13C NMR (101MHz, CDCl3) δ141.0,140.5,139.6,138.9,129.5,129.1,128.7,128.4,127.1,126.9,126.0,64.0,44.5,37.5,37.1.

[0034] HRMSm / z(ESI)calcd.for C 22 H 22 NaO + (M+Na) + 325.1563, found 325.1555.

[0035] As can be seen from the above, the product structure is correct and it is the target product.

[0036] Example 2

[0037] This embodiment provides a method for preparing aminocyanide products from N-acyloxyphthalimide and olefins. The reaction equation and specific steps are as follows:

[0038]

[0039] Under argon protection, NHPI ester 1a (0.1 mmol, 29.9 mg), acetonitrile (CH3CN, 2.575 mL), ligand L1 solution (0.02 mol / L in CH3CN, 0.375 mL), Cu(CH3CN)4BF4 solution (0.02 mol / L in CH3CN, 0.05 mL), 3DPA2FBN solution (0.001 mol / L in CH3CN, 0.5 mL), olefin 1b (0.25 mmol, 2.5 equiv), and TMSCN (19 μL, 0.15 mmol, 1.5 equiv) were added sequentially to a dry 10 mL Schlenk tube. The reaction tube was sealed with a polytetrafluoroethylene septum, stirred for 5 minutes in the dark, and then stirred for 12 hours at room temperature under 24 W blue LED illumination. After the reaction was completed, the product was concentrated by rotary evaporation and purified by column chromatography to obtain the target aminocyanide product 2c (24.0 mg, 68% yield, 76% ee).

[0040] The structural confirmation data for this product are as follows:

[0041] 1H NMR (400MHz, CDCl3) δ7.92–7.84(m,2H),7.80–7.73(m,2H),7.64–7.61(m,2H),7.59–7.56(m,2H),7.52–7. 48(m,2H),7.47–7.43(m,2H),7.39–7.35(m,1H),4.55–4.46(m,1H),4.33–4.23(m,1H),4.06–3.96(m,1H).

[0042] 13 C NMR (101MHz, CDCl3) δ167.5,142.0,140.0,134.5,131.6,131.0,128.9,128.2,128.0,127.8,127.1,123.8,118.6,41.6,36.2.

[0043] HRMSm / z(ESI)calcd.for C23H16N2NaO2+(M+Na)+375.1104,found 375.1104.

[0044] HPLC (IB, 0.46*25cm, 5μm, hexane / isopropanol=92 / 8, flow 0.8mL / min, detection at 220nm) retention time=25.3min (minor) and 28.3min (major).

[0045] As can be seen from the above, the product structure is correct and it is the target product.

[0046] Example 3

[0047] This embodiment provides a gram-scale experiment of Example 1. The reaction equation and specific steps are as follows:

[0048]

[0049] The specific procedure is as follows: In an argon-protected glove box, add ligand L1 (0.02 mol / L in CH3CN, 2.5 mL), Cu(CH3CN)4BF4 (0.02 mol / L in CH3CN, 7.5 mL), and photocatalyst 3DPA2FBN (0.001 mol / L in CH3CN, 7.5 mL) sequentially to a dry 100 mL Schlenk reaction tube. The reaction mixture consisted of CH3CN (25 mL), substrate 1a (5 mmol, 1.496 g), anhydrous acetonitrile (65 mL), 4-vinylbiphenyl 1b (1.352 g, 7.5 mmol, 1.5 equiv), and TMSCN (1 mL, 7.5 mmol, 1.5 equiv). The tube was then sealed with a PTFE gasket and stirred at 500 rpm for 5 min in the dark. The mixture was then placed under a 24 W blue LED light source (10 cm from the reaction tube) and stirred at room temperature (25 °C) for 17 h (TLC monitoring, developing solvent: PE / EA = 5:1). After the reaction was terminated, the reaction solvent was removed by rotary evaporation under reduced pressure. The crude product was then separated by silica gel column chromatography (eluent: PE / EA = 150:1) to obtain product 1c (1.1021 g, yield 70%), a white solid. Chiral HPLC analysis showed an enantiomeric excess (ee) of 96%.

[0050] The structural confirmation data for this product are as follows:

[0051] 1 H NMR (400MHz, CDCl3) δ7.57(d,J=7.7Hz,2H),7.51(d,J=8.1Hz,2H),7.42(t,J=7.7H z,2H),7.33–7.15(m,8H),3.61–3.43(m,2H),2.79–2.63(m,4H),2.22–2.11(m,1H).

[0052] 13 C NMR (101MHz, CDCl3) δ141.0,140.5,139.6,138.9,129.5,129.1,128.7,128.4,127.1,126.9,126.0,64.0,44.5,37.5,37.1.

[0053] HRMSm / z(ESI)calcd.for C 22 H 22 NaO + (M+Na) + 325.1563, found 325.1555.

[0054] As can be seen from the above, the product structure is correct and it is the target product.

[0055] This invention successfully constructs a general and scalable platform for olefin bifunctionalization reactions. Using NHP esters as bifunctional radical precursors, and through the synergistic effect of photoredox and copper catalysis, the controllable generation of carbon- and nitrogen-centered radicals is achieved by precisely controlling the metal / ligand ratio. This strategy enables highly selective olefin alkyl cyanoation and amino cyanoation reactions under mild conditions, and is applicable to a variety of substrates, including the traditionally challenging α-functionalized alkyl NHP esters. The yields are excellent and the enantioselectivity is good, demonstrating high flexibility and modularity in constructing complex chiral bifunctional building blocks.

[0056] This invention systematically addresses the long-standing challenge of regulating the reactivity of electron-deficient alkyl carboxylic acid-derived NHPI esters, establishing an innovative conversion strategy for achieving chemoselectivity through precise catalyst control. This strategy provides a unified and universal conversion system for the efficient construction of function-dense molecules, demonstrating broad application potential in fields such as drug molecule design and complex organic synthesis.

[0057] The above are merely preferred embodiments of the present invention. The scope of protection of the present invention is not limited to the above embodiments. All technical solutions that fall within the scope of the present invention are within the scope of protection of the present invention. It should be noted that for those skilled in the art, any improvements and modifications made without departing from the principle of the present invention should be considered within the scope of protection of the present invention.

Claims

1. A method for preparing cyano compounds from N-acyloxyphthalimide and olefins, characterized in that, include: Using N-acyloxyphthalimide and olefins as reactants, a catalyst, ligand, photosensitizer and trimethylcyanosilane are added to carry out alkyl cyanation and / or amino cyanation reactions to obtain alkyl cyano compounds and / or amino cyano compounds. The catalyst is Cu(CH3CN)4BF4; the ligand is a chiral bisoxazoline ligand.

2. The method for preparing cyano compounds from NHPI esters and olefins according to claim 1, characterized in that, The structural formula of the N-acyloxyphthalimide is as follows: The structural formula of the olefin is Wherein, R is one of α-trifluoromethyl substituent, α-methoxycarbonyl substituent, methyl cyclopropylformate, α-cyano substituent, α-polyfluoroalkyl substituent, α-heteroatom substituent, difluoroalkyl substituent, cyclohexyl, bicyclo[1.1.1]pentyl, adamantyl, and nitrogen-bridged skeleton; Ar is one of the following: halobenzene, aromatic ring with alkyl / alkoxy / acyloxy groups, naphthalene, pyridine derivatives, indole, benzofuran, and estrone.

3. The method for preparing cyano compounds from N-acyloxyphthalimide and olefins according to claim 1, characterized in that, The reaction was carried out in an ultra-dry acetonitrile solvent system.

4. The method for preparing cyano compounds from N-acyloxyphthalimide and olefins according to claim 3, characterized in that, When the ratio of N-acyloxyphthalimide, olefin, catalyst, ligand, photosensitizer, trimethylcyanosilane, and acetonitrile is 0.1 mmol: 0.15–0.25 mmol: 0.003 mmol: 0.001–0.003 mmol: 0.0005 mmol: 0.15 mmol: 2 ml, the alkyl cyanation reaction is dominant.

5. The method for preparing cyano compounds from N-acyloxyphthalimide and olefins according to claim 4, characterized in that, When the ratio of N-acyloxyphthalimide, olefin, catalyst, ligand, photosensitizer, trimethylcyanosilane, and acetonitrile is 0.1 mmol: 0.25 mmol: 0.003 mmol: 0.001 mmol: 0.0005 mmol: 0.15 mmol: 2 ml, the alkyl cyanation reaction is dominant, and the ratio of alkyl cyano compounds to amino cyano compounds is 21.8:

1.

6. The method for preparing cyano compounds from N-acyloxyphthalimide and olefins according to claim 1, characterized in that, When the ratio of N-acyloxyphthalimide, olefin, catalyst, ligand, photosensitizer, trimethylcyanosilane, and acetonitrile is 0.1 mmol: 0.15–0.25 mmol: 0.0001–0.001 mmol: 0.001–0.0075 mmol: 0.0005 mmol: 0.15 mmol: 1–3.5 ml, the aminocyanation reaction is dominant.

7. The method for preparing cyano compounds from N-acyloxyphthalimide and olefins according to claim 6, characterized in that, When the ratio of N-acyloxyphthalimide, olefin, catalyst, ligand, photosensitizer, trimethylcyanosilane, and acetonitrile is 0.1 mmol: 0.25 mmol: 0.001 mmol: 0.0075 mmol: 0.0005 mmol: 0.15 mmol: 3.5 ml, the aminocyanation reaction is dominant, and the ratio of alkyl cyano compounds to amino cyano compounds is 1:8.

5.

8. The method for preparing cyano compounds from N-acyloxyphthalimide and olefins according to claim 1, characterized in that, The reaction method is as follows: N-acyloxyphthalimide, olefin, catalyst, ligand, photosensitizer and trimethylcyanosilane are mixed in a solvent, stirred in the dark for 5 to 10 minutes, and then stirred for 12 to 24 hours at room temperature under blue light irradiation.

9. The method for preparing cyano compounds from N-acyloxyphthalimide and olefins according to claim 1, characterized in that, The structural formula of the chiral bioxazoline ligand is:

10. The method for preparing cyano compounds from N-acyloxyphthalimide and olefins according to claim 1, characterized in that, The photosensitizer is 3DPA2FBN.

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