Boron free radical mediated nickel catalyzed C (sp3)-C (sp2) cross coupling method

Abstract

The invention discloses a boron free radical mediated nickel catalyzed C (sp3)-C (sp2) cross coupling method, which comprises the following steps: taking aryl halide and alkyl halide compounds as raw materials, and reacting under the illumination condition in the presence of a boron reagent, a photosensitizer, a nickel catalyst and a ligand to realize C (sp3)-C (sp2) bond coupling of aryl halide and alkyl halide. The method has the advantages of high reaction efficiency, mild reaction conditions, convenience in operation, atom economy and the like, and is suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to a boron free radical mediated nickel catalyzed C (sp 3 )-C(sp 2 ) cross-coupling method, using boron radical as halogen atom transfer reagent, photosensitizer and nickel as catalyst, so that aryl halide and alkyl halide can construct C(sp 3 )-C(sp 2 ) Cross-coupling compounds belong to the field of organic synthesis. Background Art

[0002] In the field of medicinal chemistry, improving the physicochemical properties of organic small molecule drugs through chemical structure modification is one of the key issues in the development of small molecule drugs. However, the introduction of saturated alkyl groups on the aromatic ring can effectively regulate the biological activity of the molecule, improve the physicochemical properties of the molecule, and optimize the pharmacokinetic properties of the drug.

[0003] Palladium-catalyzed Suzuki-Miyaura cross-coupling (SMC) is the most commonly used reaction in the pharmaceutical industry to construct carbon-carbon bonds. [3] , as well as Kumada or Negishi reactions with magnesium reagents or zinc reagents as sources of saturated alkanes are also common methods for cross-coupling. However, these methods require boron reagents, magnesium reagents and zinc reagents. Since metal organics are highly active and very sensitive to water and air, their conditions are harsh and the tolerance of substrate functional groups is low. Through the development and regulation of ligands, nickel-catalyzed cross-electrophilic coupling (XEC) of aryl halides and alkyl halides makes up for the shortcomings of traditional methods such as harsh conditions and limited functional groups, and has become one of the most effective methods for constructing CC bonds. However, these reactions often require metal reducing agents (usually Mn or Zn) to regenerate Ni catalysts. The use of stoichiometric metal additives has some disadvantages: 1) metal reducing agents (usually powders) require surface activation; 2) large amounts of metal reducing agents cannot avoid the presence of trace metals in drugs. Summary of the invention

[0004] In view of the shortcomings of the prior art, the present invention provides a boron radical-mediated nickel-catalyzed C(sp 3 )-C(sp 2 ) cross-coupling method. The present invention utilizes a dual redox catalytic system of a renewable photosensitizer and a nickel catalyst to replace a traditional redox reagent, thereby avoiding the use of stoichiometric chemicals and reducing chemical waste. The method of the present invention has the advantages of high reaction efficiency, mild reaction conditions, convenient operation, few side reactions, etc., and is suitable for large-scale production.

[0005] The boron radical-mediated nickel-catalyzed C(sp 3 )-C(sp2 ) Cross-coupling method, using aryl halide and alkyl halide as raw materials, carrying out light reaction in the presence of nickel catalyst, photosensitizer, boron reagent and ligand, and obtaining cross-coupling compound after separation and purification.

[0006] Specifically, the aryl halide and the alkyl halide are dissolved in a solvent under a nitrogen atmosphere, reacted under blue light in the presence of a nickel catalyst, a ligand, a boron reagent and a photosensitizer, and the target product is separated and purified after the reaction.

[0007] The structural formula of the aryl halide is:

[0008] ;

[0009] Among them, R 1 It is selected from alkyl, alkoxy, ester, halogen, aryl, or a substituent of the above groups, including heteroatom substitution, halogen substitution, etc.

[0010] For example: R 1 Selected from p-OMe, p-Ph, pF, p-Cl, p-OCF 3 , p-TMS, p-OPh, m- t Bu, o-OMe, o-SMe, etc.

[0011] The alkyl halide structural formula is:

[0012]

[0013] Among them, R 2 is selected from cyclic alkyl, alkyl, alkoxy, benzyl, ester, halogen, or a substituent of the above groups, including halogen substitution, aryl substitution, heteroatom substitution, etc.

[0014] For example: R 2 Selected from Me, F, Cl, MeOAc, Ph, PhO, Cy and the like.

[0015] The added amount of the alkyl halide is 150 mol %, based on the aryl halide.

[0016] The reaction temperature of the synthesis method of the present invention is 25° C., the illumination wavelength is 425 nm-455 nm, and the reaction time is 12 h.

[0017] The nickel catalyst is nickel chloride, nickel bromide, nickel acetylacetonate or bis(1,5-cyclooctadiene)nickel, and the amount of the nickel catalyst added is 10 mol%-15 mol%, based on the aryl halide.

[0018] The ligand is at least one of 1,10-phenanthroline, bipyridine, 2-methylpyridine, terpyridine, 4,4-di-tert-butyl-2,2-bipyridine, 2-phenylpyridine and pyridine, and the added amount is 10 mol%-15 mol%, calculated as aryl halide.

[0019] The boron reagent is sodium tetraphenylborate or potassium tetraphenylborate, and the added amount is 150-200 mol %, calculated on the basis of the aryl halide.

[0020] The photosensitizer is 4DPAIPN, 4CzIPN or (Ir[dF(Me)ppy] 2 (dtbpy))PF 6 The amount of photosensitizer added is 1 mol%-2 mol%, calculated on the basis of the aryl halide.

[0021] The solvent is DMF, DMAc or NMP.

[0022] The separation and purification is to add water to the reaction solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, finally remove the solvent by rotary evaporation, separate and purify by column chromatography, and the eluent during the column chromatography separation and purification is petroleum ether: ethyl acetate = 50:1 ~ 5:1, v / v, to obtain the target product.

[0023] The reaction route of the present invention is shown as follows:

[0024]

[0025] The beneficial effects of the present invention are embodied in:

[0026] 1. The synthesis method of the present invention avoids stoichiometric metal reducing agents and has the characteristics of safety, high efficiency, and atom economy.

[0027] 2. The present invention is simple to operate, has good substrate universality, and has few side reactions, and is suitable for the later functional transformation of drug molecules. DETAILED DESCRIPTION

[0028] To further illustrate the features and advantages of the present invention, the technical solution of the present invention is described below in conjunction with specific embodiments. However, the following embodiments are only for further illustrating the present invention, rather than limiting the present invention.

[0029] Embodiment 1:

[0030]

[0031] In a 25 mL transparent Schlenk tube equipped with a magnetic stirrer, the raw materials 4-bromobiphenyl 1a (0.2 mmol), methyl 3-bromopropionate 2a (0.3 mmol), 4DPAIPN (2 mol%), NaBPh4 (2 eq), nickel bromide and its ligand 4,4′-di-tert-butyl-2,2′-bipyridine (10 mol%). 2 mL of anhydrous DMF was added under nitrogen atmosphere. The illumination wavelength was set to 425 nm. After reacting at room temperature for 12 h, water and ethyl acetate were added for extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated in vacuo. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain a colorless oily liquid 3a (37.4 mg, 78%). The NMR data of the compound are: 1 H NMR (600 MHz, Chloroform-d) δ 7.58 (d, J = 7.9Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.44 (td, J = 7.8, 1.8 Hz, 2H), 7.34 (t, J= 7.5 Hz, 1H), 7.28 (d, J = 6.5 Hz, 2H), 3.70 (s, 3H), 3.01 (t, J = 7.9 Hz, 2H), 2.69 (t, J = 7.9 Hz, 2H). 13 C NMR (151 MHz, Chloroform-d) δ 173.36,140.95, 139.62, 139.28, 128.74 (d, J = 4.6 Hz, 2C), 127.27, 127.15, 127.02,51.68, 35.65, 30.58.

[0032] Embodiment 2:

[0033]

[0034] 3,5-di-tert-butylbromobenzene (1b) was used to replace 4-bromobiphenyl (1a), and the other steps were the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain a colorless oil 3b (40.8 mg, 74%). 1 H NMR (600MHz, Chloroform-d) δ 7.30 (t, J = 1.9 Hz, 1H), 7.07 (d, J = 1.8 Hz, 2H), 3.71(s, 3H), 2.97 (t, J = 6.0 Hz, 2H), 2.66 (d, J = 6.0 Hz, 2H), 1.34 (s, 18H). 13C NMR (151 MHz, Chloroform-d) δ 173.61, 150.89, 139.60, 122.48, 120.31,51.62, 36.15, 34.81, 31.55 (d, J = 13.3 Hz).

[0035] Embodiment 3:

[0036]

[0037] 4-Bromobiphenyl (1a) was replaced by 4-fluorobromobenzene (1c), and the other steps were the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain a colorless oil 3c (21.1 mg, 58%). 1 H NMR (600 MHz, Chloroform-d) δ 7.15 (dd, J = 8.7, 5.3 Hz, 2H), 6.97 (t, J = 8.7 Hz, 2H), 3.66 (s, 3H), 2.92 (t, J = 7.7 Hz, 2H), 2.61 (dd, J = 8.1, 7.3 Hz, 2H). 13 CNMR (151 MHz, Chloroform-d) δ 173.17, 162.31, 160.69, 136.13 (d, J = 3.2 Hz), 129.71 (d, J = 8.1 Hz), 115.27 (d, J = 21.1 Hz), 51.64, 35.78, 30.12. 19 F NMR (565 MHz, Chloroform-d) δ -117.05.

[0038] Embodiment 4:

[0039]

[0040] 1-Bromo-4-trimethylsilylbenzene (1d) was used to replace 4-bromobiphenyl (1a), and the other conditions were the same as those in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain a colorless oil 3d (33 mg, 70%). 1H NMR (600MHz, Chloroform-d) δ 7.47 (d, J = 7.9 Hz, 2H), 7.21 (d, J = 6.3 Hz, 2H), 3.69(s, 3H), 2.96 (t, J = 6.0 Hz, 2H), 2.65 (t, J = 6.0 Hz, 2H), 0.27 (s, 9H). 13 CNMR (151 MHz, Chloroform-d) δ 174.46, 142.21, 139.14, 134.69, 128.82, 52.73,36.63, 31.98, -0.00.

[0041] Embodiment 5:

[0042]

[0043] 1-Bromonaphthalene (1e) was used to replace 4-bromobiphenyl (1a), and the other conditions were the same as those in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain a colorless oil 3e (26.5 mg, 62%). 1 H NMR (600 MHz, Chloroform-d) δ 8.05 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.75 (d,J = 8.1 Hz, 1H), 7.56 – 7.53 (m, 1H), 7.52 – 7.48 (m, 1H), 7.43 – 7.39 (m,1H), 7.36 (dd, J = 7.0, 1.3 Hz, 1H), 3.71 (s, 3H), 3.44 (t, J = 6.0 Hz, 2H), 2.79 (t, J = 12.0 Hz, 2H). 13 C NMR (151 MHz, Chloroform-d) δ 173.51, 136.50,133.91, 131.62, 128.92, 127.19, 126.12, 125.95, 125.62 (d, J = 5.1 Hz),123.40, 51.72, 35.03, 28.16.

[0044] Embodiment 6:

[0045]

[0046] (2-Bromoethoxy)-tert-butyldimethylsilane (2f) was used to replace methyl 3-bromopropionate (2a), and the rest was the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain a colorless oil 3f (32.4 mg, 52%). 1 H NMR (400 MHz, Chloroform-d) δ 7.59 (d, J = 8.9 Hz, 2H), 7.53 (d, J =8.1 Hz, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.34 (d, J = 7.3 Hz, 1H), 7.29 (d, J =7.9 Hz, 2H), 3.85 (t, J = 7.1 Hz, 2H), 2.88 (t, J = 7.1 Hz, 2H), 0.90 (s,9H), 0.02 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 141.14, 139.10, 138.32,129.60, 128.73, 127.33 – 126.79 (m, 3C), 64.54, 39.27, 25.96, 18.38, -5.36.

[0047] Embodiment 7:

[0048]

[0049] Estrone derivative (1 g) was used to replace 4-bromobiphenyl (1a), and the other steps were the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 3 g (47.8 mg, 52%) of a white solid. 1H NMR (600 MHz, Chloroform-d) δ 8.11 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.2 Hz, 3H), 6.97 (d,J = 11.0 Hz, 1H), 6.94 (s, 1H), 3.68 (s, 3H), 3.05 (t, J = 7.7 Hz, 2H), 2.94 (d, J = 11.1 Hz, 2H), 2.68 (t, J = 7.7 Hz, 2H), 2.51 (dd, J = 19.1, 8.7 Hz,1H), 2.43 (d, J = 13.0 Hz, 1H), 2.32 (t, J = 11.1 Hz, 1H), 2.20 – 2.11 (m,1H), 1.67 – 1.45 (m, 8H), 1.25 (s, 1H), 0.92 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 220.83, 172.92, 165.33, 148.87, 146.67, 138.08, 137.41,130.46, 128.55, 127.82, 126.47, 121.73, 118.90, 51.76, 50.47, 47.98, 44.20,38.05, 35.88, 35.16, 31.58, 30.94, 29.44, 26.38, 25.80, 21.61, 13.86.

[0050] Example 8: Condition Optimization

[0051]

[0052]

[0053] Standard conditions: 1a (0.2 mmol), 2a (0.3 mmol), 4DPAIPN (2 mol%), NiBr 2 (10mol%),dtbbpy (10mol%),NaBPh 4 (2 eq), DMF (0.1 M), wavelength (λ =440 nm), 12 h, yield was determined by gas phase, with benzophenone as internal standard.

Claims

1. A boron radical-mediated nickel-catalyzed C(sp 3 )-C(sp 2 ) cross-coupling method, characterized in that: Using aryl halide and alkyl halide as raw materials, light irradiation reaction is carried out in the presence of nickel catalyst, photosensitizer, boron reagent and ligand, and cross-coupling compound is obtained after separation and purification; The structural formula of the aryl halide is: ； Wherein, R1 is selected from alkyl, alkoxy, ester, halogen, aryl, or a substituent of the above groups; The alkyl halide structural formula is: ； Wherein, R2 is selected from cyclic alkyl, alkyl, alkoxy, benzyl, ester, halogen, or a substituent of the above groups.

2. The method according to claim 1, characterized in that: The aryl halide and the alkyl halide are dissolved in a solvent under a nitrogen atmosphere, reacted under blue light in the presence of a nickel catalyst, a ligand, a boron reagent and a photosensitizer, and the target product is separated and purified after the reaction.

3. The method according to claim 1 or 2, characterized in that: The nickel catalyst is nickel chloride, nickel bromide, nickel acetylacetonate or bis(1,5-cyclooctadiene)nickel, and the added amount of the nickel catalyst is 10 mol%-15 mol%, based on the aryl halide.

4. The method according to claim 1 or 2, characterized in that: The photosensitizer is 4DPAIPN, 4CzIPN or (Ir[dF(Me)ppy]2(dtbpy))PF6, and the added amount of the photosensitizer is 1 mol%-2 mol%, calculated as aryl halide.

5. The method according to claim 1 or 2, characterized in that: The ligand is at least one of 1,10-phenanthroline, bipyridine, 2-methylpyridine, terpyridine, 4,4-di-tert-butyl-2,2-bipyridine, 2-phenylpyridine and pyridine, and the added amount is 10 mol%-15 mol%, calculated as aryl halide.

6. The method according to claim 1 or 2, characterized in that: The boron reagent is sodium tetraphenylborate or potassium tetraphenylborate, and the added amount is 150-200 mol %, calculated on the basis of the aryl halide.

7. The method according to claim 2, characterized in that: The wavelength of light is 425 nm-455 nm.

8. The method according to claim 2, characterized in that: The solvent is DMF, DMAc or NMP.

9. The method according to claim 1 or 2, characterized in that: The separation and purification is to add water to the reaction solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, finally remove the solvent by rotary evaporation, and separate and purify by column chromatography to obtain the target product.

10. The method according to claim 9, characterized in that: The eluent during column chromatography separation and purification is petroleum ether:ethyl acetate = 50:1 ~ 5:1, v / v.

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