Method for constructing C (sp3)-C (sp3) bond compound in light-mediated non-catalytic manner

Abstract

The invention discloses a method for constructing a C (sp3)-C (sp3) bond in a light-mediated non-catalytic manner, and belongs to the technical field of organic photosynthesis. The method comprises the following steps: under the protection of inert gas, irradiating a reaction tube under a 427 nm light source for 4-20 hours by taking a p-toluenesulfonyl hydrazone derivative 1 and non-activated alkane or ether 2 as raw materials in the presence of alkali and an organic solvent, and separating and purifying to obtain a C (sp3)-C (sp3) bond coupling compound 3; the key of the reaction is that a singlet carbene intermediate is generated through photolysis by slowly releasing a donor / donor heavy nitrogen compound, and then the singlet carbene intermediate is selectively inserted into a C-H bond of alkane or ether through a transition state of a three-membered ring; the reaction system has the advantages of cheap and easily available raw materials, simple operation, greenness and environmental protection, and provides a green, efficient and easily operated synthesis strategy for realizing the construction of the C (sp3)-C (sp3) bond. Meanwhile, the method can also be applied to gram-level synthesis and later modification of drug molecules, and shows good practicability.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic photosynthesis, and specifically relates to a method for light-mediated non-catalytic construction of C(sp 3 )–C(sp 3 ) bond compound method. Background Art

[0002] Alkyl substituents can increase the lipophilicity of drug molecules, increase the stereochemistry of drug molecules and enhance the interaction with proteins, which is crucial in drug discovery. Therefore, it is important to develop simple and stable C(sp 3 )–C(sp 3 ) bond construction strategy has always been an urgent task in the field of organic synthesis. 3 )–C(sp 3 ) coupling (e.g. Ni and Pd) usually requires an alkane with a directing group, a stoichiometric oxidant or other additives. In addition, the electrophilic reagent (e.g. alkyl halide) needs to be pre-functionalized, which is a cumbersome operation. Therefore, it is necessary to develop efficient and simple alkanes for direct C(sp 3 )-H bond functionalization method is of great significance.

[0003] In recent years, with the rapid development of photochemical synthesis, the visible light-mediated photocatalytic hydrogen atom transfer (HAT) strategy reported by MacMillan, Hashmi and Martin teams combined with nickel catalysis to successfully achieve C(sp 3 )-H bond is directly alkylated. In order to increase the 3 )–C(sp 3 ) key to building sustainability, et al. reported a two-step synthesis strategy, first through the HAT transfer process, followed by the reaction of triethylamine (TEA) at 80 ° C to combine N-sulfonylhydrazone with ether or amine. The reaction equation is shown as follows:

[0004]

[0005] In order to expand the application of N-sulfonylhydrazone in the construction of C(sp 3 )–C(sp 3 ) key, The research team introduced a deoxygenation cross-electrophilic coupling with carboxylic acid-derived esters as free radical precursors under photoredox conditions and successfully achieved C(sp 3 )–C(sp 3 ) bond construction; the reaction equation is expressed as follows:

[0006]

[0007] In addition to the above methods, N-toluenesulfonylhydrazone can react with metal catalysts to form a stable and safe metal carbene intermediate, followed by CH insertion. This reaction mechanism is also well known in C(sp 3 )–C(sp 3 ) coupling. Scott and DeCicco, Noels, Davies and Dias reported a major advance in the formation of acceptor and acceptor / donor carbenes followed by CH insertion. Bi et al. made important progress in this field. The team achieved the coupling of N-trifluoroether hydrazone with alkanes or ethers under precious metal silver catalysis and heating conditions, respectively. The reaction equation is expressed as follows:

[0008]

[0009] Although visible light catalysis has been widely used in organic synthesis, few studies have focused on strategies to directly combine alkanes / ethers with alkylating electrophiles under catalyst-free conditions using visible light. This strategy is more atom-economical, low-cost, and simple to operate. Therefore, it is very important to develop catalyst-free and transition metal-free C(sp 3 )–C(sp 3 )The coupling method has significant economic and application value. Summary of the invention

[0010] Based on the above research, the present invention provides a safe, green, light-mediated, non-catalytic strategy to achieve C(sp 3 )–C(sp 3 ) compounds. Under the protection of inert gas, p-toluenesulfonylhydrazone derivatives and non-activated alkanes / ethers were used as raw materials, and in the presence of alkali and organic solvents, the reaction was irradiated under a light source, and C(sp 3 )–C(sp 3 ) coupling compound; the present invention can slowly release the donor / donor diazonium compound, photolyze to generate a singlet carbene intermediate, and then selectively insert into the CH bond of alkane or ether through a three-membered ring transition state; the raw materials are cheap and easy to obtain, the operation is simple, and it is green and environmentally friendly, which is a good way to construct C(sp 3 )–C(sp 3 ) provides a new approach, and this method can also be applied to gram-scale reactions and late-stage modifications of drug molecules.

[0011] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0012] The invention uses ketone, p-toluenesulfonyl hydrazine, non-activated alkane or ether and base as raw materials, or directly uses p-toluenesulfonyl hydrazone derivatives, non-activated alkane or ether and base as raw materials to obtain the product through a non-catalytic light-mediated strategy, thereby achieving C(sp 3 )–C(sp3 ) The methods for synthesizing CH insertion products from the two raw materials are basically the same. When only the first raw material is used, the ketone and p-toluenesulfonyl hydrazide are first sealed and stirred, and then C(sp 3 )–C(sp 3 ) coupling process.

[0013] The light-mediated non-catalytic construction of C(sp 3 )–C(sp 3 ) method, comprising the following steps: in the presence of a base, a p-toluenesulfonylhydrazone derivative 1 and an alkane or an ether 2 are used as raw materials, and react under light to obtain C(sp 3 )–C(sp 3 ) coupling compound 3; the reaction equation is as follows:

[0014]

[0015] Where: R 1 and R 2 Each independently selected from H, C 1-4 Alkyl, benzyl and its substitutions, benzofuran and its substitutions, benzothiophene and its substitutions, indole and its substitutions, pyridine and its substitutions, phenyl and its substitutions, naphthyl and its substitutions; the substitution is C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxycarbonylalkoxy, methylenedioxy, Boc, halogen, phenoxy; R 3 , R 4 , R 5 , R 6 and R 7 Each is independently selected from H, alkyl; or R 3 , R 4 , R 5 Together, they form a ring structure through carbon atoms; R 6 and R 7 The carbon atoms form a ring structure.

[0016] Furthermore, in the above technical solution, the typical structure of the p-toluenesulfonylhydrazone derivative 1 is:

[0017]

[0018] Furthermore, in the above technical solution, the typical structure of the non-activated alkane / ether 2 is:

[0019]

[0020] Furthermore, in the above technical solution, the base is selected from one or more of DBU, DBN, DABCO, Cs2CO3, K2CO3, K3PO4, KOH, NaOH, NaH or t-BuOK, preferably DBN, K2CO3 or Cs2CO3.

[0021] Furthermore, in the above technical solution, the organic solvent is selected from any one or more combinations of dichloromethane, acetonitrile, chloroform, fluorobenzene, dichloroethane, alkane or ether solvents, preferably alkane or ether solvents.

[0022] Furthermore, in the above technical solution, the molar ratio of the p-toluenesulfonylhydrazone derivative 1, the non-activated alkane / ether 2 and the base is 1:1-500:1-6.

[0023] Furthermore, in the above technical solution, the reaction temperature is 20-35°C; and the reaction time is 4-20 hours.

[0024] Furthermore, in the above technical solution, the wavelength of the light source is 400-460nm; the distance between the light source and the reaction tube is 2-6 cm.

[0025] Furthermore, in the above technical solution, the reaction is carried out under an inert atmosphere.

[0026] Furthermore, in the above technical solution, the p-toluenesulfonylhydrazone derivative 1 is obtained by reacting a carbonyl compound (aldehyde or ketone) with p-toluenesulfonylhydrazone in an alcohol solvent. Among them, the typical aldehyde or ketone structure is as follows:

[0027]

[0028] Further, in the above technical scheme, the post-treatment operation is: after the reaction is completed, the reaction product is extracted with ethyl acetate and water, dried over anhydrous sodium sulfate and then the solvent is removed, and separated and purified by column chromatography to obtain C(sp 3 )–C(sp 3 ) to construct the compound.

[0029] Beneficial effects of the present invention

[0030] 1. The present invention uses ketone, p-toluenesulfonyl hydrazide and non-activated alkane or ether or p-toluenesulfonyl hydrazone derivative and non-activated alkane or ether as main raw materials, and has the characteristics of low irritation and easy acquisition.

[0031] 2. The key to the reaction of the present invention is to slowly release the donor / donor dinitrogen substance to generate a singlet carbene intermediate by photolysis, which is then selectively inserted into the CH bond of an alkane or ether through a three-membered ring transition state.

[0032] 3. The reaction process is carried out at room temperature and pressure by using light-mediated non-catalytic reaction to construct C(sp3 )–C(sp 3 ) compounds, not only the synthesis process is simple and the synthesis yield is significantly improved, but also the environmental pollution after the reaction is small and green and environmentally friendly.

[0033] 4. The raw materials are cheap and easy to obtain, the operation is simple, and it is green and environmentally friendly. 3 )–C(sp 3 ) bonds provides a sustainable and accessible synthetic approach that can also be applied to gram-scale synthesis and post-modification of drug molecules. DETAILED DESCRIPTION

[0034] The implementation of the present invention is described in detail below in conjunction with the embodiments of the present invention. The following embodiments are implemented on the premise of the technical solution of the present invention, and provide detailed implementation methods and specific operating processes, but the protection scope of the present invention is not limited to the following embodiments.

[0035] Example 1 Condition Optimization Experiment:

[0036] In a dry reaction tube, add a magnet, p-toluenesulfonylhydrazone derivative 1a (0.2mmol) and a base (0.6mmol, 6.0eq), replace argon three times with a double-row tube, and then add a non-activated alkane or ether organic solvent. After sealing, illuminate under a 427nm Kessil light source (40W), the light source is about 4 cm away from the reaction tube, and the fan or low-temperature reactor is used to cool down, and the temperature is controlled to be 25-35°C. After 12 hours, the reaction is stopped, and the reaction product is extracted with ethyl acetate and water. After drying with anhydrous sodium sulfate, the solvent is removed by rotation, and 1,3,5-trimethoxybenzene is used as an internal standard to calculate the yield of product 3 (non-isolated yield).

[0037] Replacing different bases such as DBU, DBN, DABCO, Cs2CO3, K2CO3, K2PO4, KOH, NaOH, NaH or tBuOK, the reaction results are as follows:

[0038]

[0039]

[0040] Changing different system concentrations, such as 1.0M, 0.3M, 0.2M, the reaction results are as follows:

[0041]

[0042]

[0043] Under the condition of maintaining the optimal concentration, different solvent systems such as cyclohexane / fluorobenzene, cyclohexane / dichloromethane, cyclohexane / dichloroethylene, cyclohexane / chloroform, cyclohexane / ethyl acetate, cyclohexane / acetonitrile were replaced, and the reaction results were as follows:

[0044]

[0045]

[0046] Under the conditions of maintaining the optimal concentration and the optimal reaction solvent, different reaction times were changed, such as 2h, 4h, 6h, 8h, 10h, 12h, 14h. The reaction results are as follows:

[0047]

[0048]

[0049] Example 2

[0050] In a dry reaction tube, add a magneton, p-toluenesulfonylhydrazone derivative 1 (0.2mmol) and cesium carbonate (0.6mmol, 6.0eq), replace argon three times with a double-row tube, and then add a non-activated alkane or ether organic solvent. After sealing, illuminate under a 427nm Kessil light source (40W), the light source is about 4 cm away from the reaction tube, and the fan or low-temperature reactor is used to cool down, and the temperature is controlled to be 25-35°C. After 12 hours, the reaction is stopped, and the reaction product is extracted with ethyl acetate and water. After drying with anhydrous sodium sulfate, the solvent is removed by rotation, and 1,3,5-trimethoxybenzene is used as an internal standard to calculate the yield of product 3 (non-separation yield).

[0051] The results of different reaction substrates are shown below:

[0052]

[0053] Example 3

[0054] Change different reaction raw materials 2 to conduct substrate experiments:

[0055] In a dry reaction tube, add a magnet and p-toluenesulfonylhydrazone derivative 1 (0.1mmol) and 0.6mmolCs2CO3 (6.0eq), and replace argon three times with a double-row tube. Purge the flask three times under vacuum. After purging with argon three times, add 5.0mL of non-activated alkane / ether while maintaining an argon atmosphere. The reaction is carried out for 12 hours under a 40w Kessil lamp reaction device, with the light source about 4 cm away from the reaction tube, and the fan or low-temperature reactor is used to cool the temperature to 25-35°C. Extract with ethyl acetate and water, dry with anhydrous sodium sulfate, filter and evaporate the solvent, and separate and purify by column chromatography to obtain C(sp 3 )–C(sp3 ) coupled with compound 3. The reaction results are as follows:

[0056]

[0057] 1-(cyclohexylmethyl)-4-methoxybenzene(1c)

[0058] 1 H NMR (500MHz, CDCl3) δ7.09–7.04(m,2H),6.85–6.80(m,2H),3.80(s,3H),2.44(d,J=7.1Hz,2H ),1.68(d,J=5.7Hz,5H),1.51–1.43(m,1H),1.24–1.12(m,3H),0.93(q,J=12.0,11.5Hz,2H).

[0059] 13 C NMR (126MHz, CDCl3) δ157.7(m),133.6,130.1,113.5,55.3,43.3,40.1,33.2,26.5.

[0060] 1-methoxy-4-((1-methylcyclohexyl)methyl)benzene(4c)

[0061] 1 H NMR (500MHz, CDCl3) δ7.06–7.03(m,2H),6.81(d,J=4.7Hz,2H),3.80(s,3H),2.47(s,2H),1.67–1.42(m,10H),0.82(s,3H).

[0062] 13 C NMR (126MHz, CDCl3) δ157.9,131.3,130.4,113.6,63.9,55.2,42.2,19.6,15.6.

[0063] 1-(2,2-dimethylbutyl)-4-methoxybenzene(6c)

[0064] 1 H NMR (500MHz, CDCl3) δ7.05 (s, 2H), 6.81 (d, J = 8.6Hz, 2H), 3.79 (s, 3H), 2.43 (s, 2H), 1.23 (q, J = 7.5Hz, 2H), 0.87 (d, J = 9.0Hz, 3H), 0.81 (s, 6H).

[0065] 13 C NMR(126MHz,CDCl3)δ164.5,136.4,134.2,117.2,61.2,51.2,38.8,30.9,13.3.

[0066] 2-(4-methoxybenzyl)-2-methyltetrahydrofuran(11c)

[0067] 1 H NMR(500MHz,CDCl3)δ7.87(d,J=8.0Hz,1H),7.76(d,J=7.2Hz,1H),7.43–7.31(m,2H),7.06(s,1H),2.76–2.72(m,2H),1.80–1.64(m,6H),1.21(p,J=12.3Hz,3H),1.02(q,J=11.8,11.2Hz,2H).

[0068] 13 C NMR(126MHz,CDCl3)δ140.4,139.4,135.7,123.9,123.6,122.8,122.0,121.9,121.8,37.9,36.5,33.5,26.5,26.2.

[0069] 2-(cyclohexylmethyl)benzofuran(42c)

[0070] 1 H NMR(500MHz,CDCl3)δ7.50–7.46(m,1H),7.41(d,J=8.0Hz,1H),7.19(pd,J=7.3,1.5Hz,2H),6.37(d,J=1.0Hz,1H),2.64(d,J=6.7Hz,2H),1.79–1.63(m,6H),1.30–1.13(m,3H),1.07–0.94(m,2H).

[0071] 13 C NMR(126MHz,CDCl3)δ157.5,154.6,129.0,122.9,122.3,120.1,110.7,102.8,37.0,36.3,33.1,26.4,26.2.

[0072] 3-bromo-4-(2-ethoxypropyl)thiophene(56c)

[0073] 1 H NMR (500MHz, CDCl3) δ7.22(d,J=3.4Hz,1H),7.08(dd,J=2.1,1.3Hz,1H),3.67(h,J=6.2Hz,1H),3.56(m,J=9.3,7.0 Hz,1H),3.45(m,J=9.2,7.0Hz,1H),2.88(dd,J=14.4,6.4Hz,1H),2.67(dd,J=14.4,6.3Hz,1H),1.21–1.12(m,6H).

[0074] 13 C NMR (126MHz, CDCl3) δ137.8,122.6,122.4,112.9,74.3,63.9,36.6,19.7,15.5.

[0075] The preferred embodiments of the present invention have been specifically described above, but the present invention is not limited to the embodiments. Those skilled in the art may make various equivalent modifications or substitutions without violating the spirit of the present invention. These equivalent modifications or substitutions are all included in the scope defined by the claims of this application.

Claims

1. A light-mediated, non-catalytic construction of C(sp 3 )–C(sp 3 ) bond compound, characterized in that, The method comprises the following steps: in the presence of a base, a p-toluenesulfonylhydrazone derivative 1 and an alkane or an ether 2 are used as raw materials, and react under light to obtain C(sp 3 )–C(sp 3 ) coupling compound 3; the reaction equation is as follows: Where: R 1 and R 2 Each independently selected from H, C 1-4 Alkyl, benzyl and its substitutions, benzofuran and its substitutions, benzothiophene and its substitutions, indole and its substitutions, pyridine and its substitutions, phenyl and its substitutions, naphthyl and its substitutions; the substitution is C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxycarbonylalkoxy, methylenedioxy, Boc, halogen, phenoxy; R 3 , R 4 , R 5 , R 6 and R 7 Each is independently selected from H, alkyl; or R 3 , R 4 , R 5 Together, they form a ring structure through carbon atoms; R 6 and R 7 The carbon atoms form a ring structure.

2. The light-mediated non-catalytic construction of C(sp 3 )–C(sp 3 )-bonded compound, characterized in that: The base is selected from one or more of DBU, DBN, DABCO, Cs2CO3, K2CO3, K2PO4, KOH, NaOH, NaH or tBuOK.

3. The light-mediated non-catalytic construction of C(sp 3 )–C(sp 3 )-bonded compound, characterized in that: The organic solvent is selected from any one or more combinations of dichloromethane, acetonitrile, chloroform, fluorobenzene, dichloroethane, alkane or ether solvents.

4. The light-mediated non-catalytic construction of C(sp 3 )–C(sp 3 )-bonded compound, characterized in that: The molar ratio of the p-toluenesulfonylhydrazone derivative 1, the alkane or ether 2 and the base is 1:1-500:1-6.

5. The light-mediated non-catalytic construction of C(sp 3 )–C(sp 3 )-bonded compound, characterized in that: The reaction temperature is 20-35°C; the reaction time is 4-20 hours.

6. The light-mediated non-catalytic construction of C(sp 3 )–C(sp 3 )-bonded compound, characterized in that: The wavelength of the light source is 400-460nm; the distance between the light source and the reaction tube is 2-6 cm.

7. The light-mediated non-catalytic construction of C(sp) according to any one of claims 1 to 6 3 )–C(sp 3 )-bonded compound, characterized in that: The reaction was carried out under an inert atmosphere.

8. The light-mediated non-catalytic construction of C(sp 3 )–C(sp 3 )-bonded compound, characterized in that: The p-toluenesulfonylhydrazone derivative 1 is obtained by condensing a carbonyl compound (aldehyde or ketone) with p-toluenesulfonylhydrazone in a non-activated alkane or ether solvent.

9. The light-mediated non-catalytic construction of C(sp 3 )–C(sp 3 ) key method, characterized in that: After the reaction was completed, the reaction product was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, the solvent was removed by spin, and purified by column chromatography to obtain C(sp 3 )–C(sp 3 )Compound 3.

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