Synthesis method and application of light-induced germane methylene boron reagent

Abstract

The invention discloses a synthetic method and application of a light-induced germane methylene boron reagent, and the synthetic method comprises the following steps: mixing a metal salt, an additive, germane, boric acid ester and a solvent, and carrying out an illumination reaction by using an LED lamp in an inert gas atmosphere to obtain the germane methylene boron reagent. According to the method, the cheap metal catalyst is used, the product yield is high, the product application range is wide, operation is easy, reaction conditions are mild, environment friendliness is achieved, large-scale production is easy, a reference thought is provided for industrial research and development, and the good industrial application prospect is achieved. The light-induced germane methylene boron reagent disclosed by the invention has wide application, can be used for preparing various substituted germanium reagents through a palladium-catalyzed Suzuki coupling reaction, and also can be used for preparing polysubstituted boric acid through a simple and easy-to-obtain method.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a synthesis method of a light-induced germane methylene boron reagent and application thereof. Background Art

[0002] Photocatalysis is often widely used in various organic syntheses due to its mild reaction conditions, good selectivity and high atom economy. As an important intermediate fragment in organic synthesis, boronate fragments play an important role in the construction of molecular structures due to their strong adaptability to reaction conditions and good substrate compatibility. Boronates can be converted into other functional groups such as alcohols, aldehydes, and amines through various simple reactions. The famous Suzuki coupling reaction is an important method for constructing carbon-carbon bonds using boronates, and is widely used to construct the core key structures of drugs and natural products. In recent years, alkylgermanium groups have also been widely used as coupling fragments in organic synthesis. So we want to construct boronate fragments and alkylgermanium fragments in the same simple molecule at the same time. Therefore, it is necessary to develop a simple and easy-to-use method to prepare functionalized molecular skeletons. We describe a photoinduced, inexpensive, and green catalytic system for the synthesis of germanium methylene boron reagents and their various applications. Summary of the invention

[0003] The invention provides a synthesis method of a photoinduced germanium methylene boron reagent and its application. The invention uses a cheap metal catalyst, has a high product yield, a wide range of product applications, is simple to operate, has mild reaction conditions, is environmentally friendly, and is easy to mass produce.

[0004] The method for synthesizing the light-induced germanium methylene boron reagent of the present invention comprises the following steps:

[0005] The metal salt, additive, germane, boric acid ester and solvent are mixed, and an LED lamp is used to perform light irradiation reaction in an inert gas atmosphere to obtain a germane methylene boron reagent.

[0006] The metal salt includes one or more of ferrous chloride, cupric chloride, cuprous chloride, and ferric chloride, preferably ferric chloride.

[0007] The additive includes one or more of N-fluorobisbenzenesulfonamide (NFSI), trimethylchlorosilane (TMSCl), di-tert-butyl peroxide (DTBP), and tert-butyl perbenzoate (TBPB), preferably trimethylchlorosilane (TMSCl).

[0008] The solvent includes one or more of acetonitrile (MeCN), N,N-dimethylformamide (DMF), tetrahydrofuran (THF), and dichloromethane (DCM), preferably acetonitrile (MeCN).

[0009] The inert gas atmosphere includes nitrogen, argon, etc.

[0010] The wavelength of the reaction light is 370 nm-427 nm, preferably 390 nm.

[0011] In the reaction system, the molar ratio of the boric acid ester to the metal salt is 10:1-5:1.

[0012] In the reaction system, the molar ratio of germane to boric acid ester is 10:1-5:1.

[0013] In the reaction system, the molar ratio of the additive to the boric ester is 3:1-1:1.

[0014] The reaction temperature is 25-45°C.

[0015] The method of the present invention further comprises a post-treatment step: adding a triethylamine solution of a vicinal diol after the reaction is completed to form a stable and easily separable product.

[0016] The vicinal diol is selected from one of 1-phenylpinacol (3a) and pinacol (3b).

[0017] The synthetic route is as follows:

[0018] The application of the germanium methylene boron reagent of the present invention is to use the germanium methylene boron reagent as an electrophilic reagent to prepare a polysubstituted boric acid compound. The reaction scheme is as follows:

[0019]

[0020] Wherein R represents a five-membered ring, a five-membered heterocyclic ring, a substituted five-membered ring, a substituted five-membered heterocyclic ring, an aryl group or a substituted aryl group. The substituent includes one or more of an alkyl group, an alkoxy group, a halogen group and a heteroatom substitution.

[0021] The application of the germanium methylene boron reagent of the present invention is to prepare various substituted alkyl germanium reagents, including aryl alkyl germanium reagents and vinyl alkyl germanium reagents, through a palladium-catalyzed Suzuki coupling reaction. The reaction route is as follows:

[0022]

[0023] Wherein Ar represents an aryl group or a substituted aryl group. The substituent includes one or more of an alkyl group, an alkoxy group, a halogen group, and a heteroatom group.

[0024] The present invention has the following advantages: using cheap metal catalysts, high product yield, wide product application range, simple operation, mild reaction conditions, environmental friendliness, easy large-scale production, providing reference ideas for industrial research and development, and having strong industrial application prospects.

[0025] The reagent of the present invention has a wide range of applications and can be used to prepare various substituted germanium reagents through a palladium-catalyzed Suzuki coupling reaction, such as reacting with aryl halides to prepare arylmethylene germanium reagents (GA Molander, J. Org. Chem. 2003, 68, 5534-5539.), and reacting with alkenyl iodides to prepare vinyl-substituted methylene germanium reagents (JRFalck, Tetrahedron Lett., 2001, 42, 7213-7215.). At the same time, it can also be used as a good nucleophilic agent to react with various electrophilic agents such as halogenated hydrocarbons, substituted oxiranes, ketones, esters, etc. (DS Matteson, J. Chem. Soc., Chem. Commun., 1980, 39-40.), (DS Matteson, Organometallics, 1983, 2, 230-236S.), (J. Meek, Org. Lett., 2018, 20, 469-472.). It is also possible to prepare polysubstituted boric acids by simple and readily available methods (GW Bauman, Inorg. Chem., 2013, 52, 10846-10859), (A. Hofer, Bioorg. Med. Chem., 2013, 21, 3202-3213.). The technical scheme of the present invention is further analyzed and explained by specific examples below. DETAILED DESCRIPTION

[0026] Embodiment 1:

[0027]

[0028] 1.07 g of bis(bis(pyrocatechol) borate and 0.15 g of ferric chloride were added to a 250 ml Schlenk reaction bottle, and 50 mL of acetonitrile was added under N2 atmosphere, followed by 0.49 g of trimethylsilyl chloride and 2.4 g of tetramethylgermanium. The reaction was carried out in a water bath under 390 nm illumination for 16 hours. After the reaction, 1.2 equivalents of 1-phenylpinacol 3a in triethylamine solution were added, stirred at room temperature for 1 hour, then filtered through silica gel diatomaceous earth, and finally separated by column chromatography to obtain 1.2 g of the target product 4a with an isolated yield of 80%.

[0029] 1H NMR (400 MHz, Chloroform-d): δ (ppm) = 7.40-7.38 (d, 2H), 7.35-7.32 (t, 2H), 7.28-7.24 (tt, 1H), 1.55 (s, 3H), 1.50 (s, 3H), 0.77 (s, 3H), 0.30 (s, 2H), 0.26 (s, 9H).

[0030] 11 B NMR (128 MHz, Chloroform-d): δ (ppm) = 34.69.

[0031] 13 C NMR (100 MHz, Chloroform-d): δ (ppm) = 143.57, 128.12, 126.96, 124.70, 86.77, 83.79, 28.21, 26.72, 24.36, 0.07.

[0032] Embodiment 2:

[0033]

[0034] 23.8 mg of bis(bis(bis-catechol) borate and 3.3 mg of ferric chloride were added to a 10 ml Schlenk reaction tube, and 2 mL of acetonitrile was added under N2 atmosphere, followed by 11 mg of trimethylsilyl chloride and 53.1 mg of tetramethylgermanium. The reaction was carried out in a water bath under 390 nm illumination for 16 hours. After the reaction, 1.2 equivalents of triethylamine solution of pinacol 3b were added, stirred at room temperature for 1 hour, and then filtered through silica gel diatomaceous earth. Tetrachloroethane was added as an internal standard, and the reaction yield was detected by hydrogen nuclear magnetic resonance spectroscopy. The yield of the target product 4b was 99%. 1 HNMR (400MHz, Chloroform-d): δ (ppm) = 1.24(s, 6H), 0.20(s, 9H), 0.16(s, 2H).

[0035] Optimization screening process of the reaction conditions of the present invention:

[0036] First, various metal catalysts were screened, among which ferric chloride had the best effect.

[0037]

[0038] Secondly, the reaction additives were screened, among which trimethylsilyl chloride (TMSCl) had the best effect.

[0039]

[0040] Then, the reaction concentration was screened and the optimal concentration was controlled at 0.05 M.

[0041]

[0042] This reagent has a wide range of applications and can be used to prepare polysubstituted boronic acids by a simple and readily available method. The general reaction formula is as follows:

[0043]

[0044] Wherein R represents a five-membered ring, a five-membered heterocyclic ring, a substituted five-membered ring, a substituted five-membered heterocyclic ring, an aryl group or a substituted aryl group. The substituent includes one or more of an alkyl group, an alkoxy group, a halogen group and a heteroatom substitution.

[0045] The technical solution of the present invention is further analyzed and explained below through specific embodiments.

[0046] Embodiment 3:

[0047]

[0048] Furan 1a (0.3 mmol, 1.5 equiv.) was dissolved in 2 mL of tetrahydrofuran and added to a dry reaction tube filled with nitrogen. 0.14 mL of n-butyl lithium (0.33 mmol, 2.5 M in hexane) was added dropwise at -78 °C. After the addition was complete, the reaction system was moved to room temperature for 1 h. Subsequently, germanium methylene borate (0.2 mmol, 1.0 equiv.) was added dropwise at -78 °C. After the addition was complete, the reaction system was moved to 0 °C for 2 h. After the reaction was completed, saturated ammonium chloride aqueous solution was added dropwise to the system to quench, extracted with ethyl acetate three times, dried over anhydrous sodium sulfate, concentrated in vacuo, and separated by column chromatography to obtain the target product 2a as a colorless liquid with a yield of 73%.

[0049] 1 H NMR (400 MHz, Chloroform-d): δ (ppm) = 7.62 (d, 1H), 6.96 (d, 1H), 6.44 (dd, 1H), 5.58 (s, 1H), 0.76 (s, 2H), 0.19 (s, 9H).

[0050] 11 B NMR (128 MHz, Chloroform-d): δ (ppm) =43.17.

[0051] 13C NMR (100 MHz, Chloroform-d): δ (ppm) = 146.75, 123.05, 110.89, 0.14.

[0052] Embodiment 4:

[0053]

[0054] 2-Bromothiophene 1b (0.3 mmol, 1.5 equiv.) was dissolved in 2 mL tetrahydrofuran and added to a dry reaction tube filled with nitrogen. 0.14 mL of n-butyl lithium (0.33 mmol, 2.5 M in hexane) was added dropwise at -78°C, and the reaction was continued at -78°C for 1 h. Subsequently, germanium methylene borate (0.2 mmol, 1.0 equiv.) was added dropwise at -78°C. After the addition was complete, the reaction system was moved to 0°C for 2 h. After the reaction was completed, saturated ammonium chloride aqueous solution was added dropwise to the system to quench, extracted with ethyl acetate three times, dried over anhydrous sodium sulfate, concentrated in vacuo, and separated by column chromatography to obtain the target product 2b as a light yellow liquid with a yield of 51%.

[0055] 1 H NMR (400 MHz, Chloroform-d): δ (ppm) =7.64 (dd, 1H), 7.55 (dq, 1H), 7.20 (dd, 1H), 4.96 (s, 1H), 0.86 (s, 2H), 0.20 (s, 9H).

[0056] 11 B NMR (128 MHz, Chloroform-d): δ (ppm) =45.09.

[0057] 13 C NMR (100 MHz, Chloroform-d): δ (ppm) =136.38, 132.48, 128.54, 0.22.

[0058] Embodiment 5:

[0059]

[0060] Benzofuran 1c was used as a reaction substrate to prepare the target product 2c. The preparation method was basically the same as the operation steps in Example 3. The product was a light yellow liquid with a yield of 40%.

[0061] 1H NMR (400 MHz,Chloroform-d): δ (ppm) = 7.65 (dq, 1H), 7.52 (dq,1H), 7.36(m, 1H), 7.28 (d, 1H), 7.24 (m, 1H), 5.77 (s, 1H), 0.88(s, 2H), 0.23 (s, 9H).

[0062] 11 B NMR (128 MHz, Chloroform-d): δ (ppm) = 44.98.

[0063] 13 C NMR (100 MHz, Chloroform-d): δ (ppm) =157.23, 128.27, 126.23, 122.83, 122.29, 119.23, 111.89, 0.25.

[0064] Embodiment 6:

[0065]

[0066] 2-Bromobenzothiophene 1d was used as a reaction substrate to prepare the target product 2d. The preparation method was basically the same as the operation steps in Example 4. The product was a light yellow liquid with a yield of 51%.

[0067] 1 H NMR (400 MHz, Chloroform-d): δ (ppm) =7.90 (m,2H), 7.78(d, 1H),7.37 (m, 2H), 7.24 (m, 1H), 5.16 (s, 1H), 0.95(s, 2H), 0.23 (s, 9H).

[0068] 11 B NMR (128 MHz, Chloroform-d): δ (ppm) =47.10.

[0069] 13 C NMR (100 MHz, Chloroform-d): δ (ppm) =143.89, 140.97, 133.59, 125.47, 124.61, 124.20, 122.81, 0.30.

[0070] Embodiment 7:

[0071]

[0072] The target product 2e was prepared using m-bromoanisole 1e as a reaction substrate. The preparation method was basically the same as the operation steps in Example 4. The product was a light yellow liquid with a yield of 88%.

[0073] 1 H NMR (400 MHz, Chloroform-d): δ (ppm) =7.32 (dt, 2H), 7.28 (dt, 1H), 7.00 (m, 1H), 5.12 (s, 1H), 3.84 (s, 3H), 0.89 (s, 2H), 0.18 (s, 9H).

[0074] 11 B NMR (128 MHz, Chloroform-d): δ (ppm) =49.47.

[0075] 13 C NMR (100 MHz, Chloroform-d): δ (ppm) =129.04, 126.17, 118.40,116.85, 55.31, 0.29.

[0076] Embodiment 8:

[0077]

[0078] 4-tert-butylbromobenzene 1f was used as a reaction substrate to prepare the target product 2f. The preparation method was basically the same as the operation steps in Example 4. The product was a light yellow liquid with a yield of 54%.

[0079] 1 H NMR (400 MHz, Chloroform-d): δ (ppm) =7.69 (d, 2H), 7.42 (d, 2H), 5.09 (s, 1H), 1.34 (s, 9H), 0.88 (s, 2H), 0.19 (s, 9H).

[0080] 11 B NMR (128 MHz, Chloroform-d): δ (ppm) =49.82.

[0081] 13 C NMR (100 MHz, Chloroform-d): δ (ppm) =154.28, 133.61, 124.71, 34.96, 31.36, 0.31.

[0082] Embodiment 9:

[0083]

[0084] 1 g of 3,5-dimethylbromobenzene was used as a reaction substrate to prepare 2 g of the target product. The preparation method was basically the same as the operating steps in Example 4. The product was a colorless liquid with a yield of 53%.

[0085] 1 H NMR (400 MHz, Chloroform-d): δ (ppm) =7.35 (s, 2H), 7.10 (s, 1H), 5.12 (s, 1H), 2.35 (s, 6H), 0.88 (s, 2H), 0.18 (s, 9H).

[0086] 11 B NMR (128 MHz, Chloroform-d): δ (ppm) =50.00.

[0087] 13 C NMR (100 MHz, Chloroform-d): δ (ppm) =137.12, 132.79, 131.45,21.48, 0.28.

[0088] Embodiment 10:

[0089]

[0090] 4-Bromo-1,2-methylenedioxybenzene 1h was used as a reaction substrate to prepare the target product 2h. The preparation method was basically the same as the operation steps in Example 4. The product was a colorless liquid with a yield of 42%.

[0091] 1 H NMR (400 MHz, Chloroform-d): δ (ppm) =7.30 (d, 1H), 7.22 (s, 1H), 6.85 (d, 1H), 5.97 (s, 2H), 4.95 (s, 1H), 0.83 (s, 2H), 0.17 (s, 9H).

[0092] 11 B NMR (128 MHz, Chloroform-d): δ (ppm) =48.95.

[0093] 13C NMR (100 MHz, Chloroform-d): δ (ppm) =150.09, 147.46, 129.09, 113.00, 108.22, 100.92, 0.24.

[0094] Embodiment 11:

[0095]

[0096] 4-Fluorobromobenzene 1i was used as a reaction substrate to prepare the target product 2i. The preparation method was basically the same as the operation steps in Example 4. The product was a colorless liquid with a yield of 42%.

[0097] 1 H NMR (400 MHz, Chloroform-d): δ (ppm) =7.76 (m, 2H), 7.06 (tt, 2H), 5.04 (s, 1H), 0.88 (s, 2H), 0.17 (s, 9H).

[0098] 11 B NMR (128 MHz, Chloroform-d): δ (ppm) =48.83.

[0099] 13 C NMR (100 MHz, Chloroform-d): δ (ppm) =165.1 (d, CF, 1 J C-F = 251.79Hz), 136.14, 136.06, 114.97, 114.77,0.24.

[0100] Embodiment 12:

[0101]

[0102] 2-Methylthiophene 1j was used as a reaction substrate to prepare the target product 2j. The preparation method was basically the same as the operation steps in Example 3. The product was a colorless liquid with a yield of 56%.

[0103] 1 H NMR (400 MHz, Chloroform-d): δ (ppm) = 7.35 (d, 1H), 6.85 (d, 1H), 4.84 (s, 1H), 2.55 (s, 3H), 0.80 (s, 2H), 0.20 (s, 9H).

[0104] 11 B NMR (128 MHz, Chloroform-d): δ (ppm) = 45.73.

[0105] 13 C NMR (100 MHz, Chloroform-d): δ (ppm) = 147.73, 136.92, 127.37, 15.72, 0.21.

[0106] Embodiment 13:

[0107]

[0108] 4-Trifluoromethylbromobenzene 1k was used as a reaction substrate to prepare the target product 2k. The preparation method was basically the same as the operation steps in Example 4. The product was a colorless liquid with a yield of 37%.

[0109] 1 H NMR (400 MHz, Chloroform-d): δ (ppm) = 7.87 (d, 2H), 7.63 (d, 2H), 5.21 (s, 1H), 0.94 (s, 2H), 0.18 (s, 9H).

[0110] 11 B NMR (128 MHz, Chloroform-d): δ (ppm) = 48.83.

[0111] 13 C NMR (100 MHz, Chloroform-d): δ (ppm) = 134.01, 132.59 (d,CF, 2 J C-F = 31.99Hz), 125.72 (t,CF, 1 J C-F = 271.94Hz), 124.53 (q,CF, 3 J C-F =3.86Hz), 0.29.

[0112] This reagent can also be used to prepare various substituted germanium reagents through Suzuki coupling reaction, the general formula is as follows:

[0113]

[0114] The technical solution of the present invention is further analyzed and explained below through specific embodiments.

[0115] Embodiment 14:

[0116]

[0117] 7.3 mg of Pd(dppf)Cl2 and 55 mg of K2CO3 were weighed into a dry Schlenk reaction bottle, and nitrogen was replaced three times. Then, 1.5 mL of Dioxane and 0.3 mL of H2O, 37 mg of m-bromoanisole, and 96.3 mg of substrate 4a were added in sequence under a nitrogen atmosphere. The mixture was pre-stirred for 30 min and then reacted at 100°C for 4 h. After the reaction was completed, saturated sodium chloride solution was added to quench the mixture, and the mixture was extracted with ethyl acetate three times, dried, concentrated in vacuo, and separated by column chromatography to obtain the target product 5a, which was a colorless liquid with a yield of 42%.

[0118] 1 H NMR (400 MHz, Chloroform-d): δ (ppm) = 7.12 (t, 1H), 6.60 (t, 2H), 6.54 (s, 1H), 3.78 (s, 3H), 2.18 (s, 2H), 0.11 (s, 9H).

[0119] 13 C NMR (100 MHz, Chloroform-d): δ (ppm) = 159.63, 143.26, 129.16, 120.42, 113.41, 109.25, 55.19, -2.32.

[0120] Embodiment 15:

[0121]

[0122] 2, 5-Dimethylbromobenzene was used as a reaction substrate to prepare the target product 6a. The preparation method was basically the same as the operating steps in Example 14. The product 6a was a colorless liquid with a yield of 39%.

[0123] 1 H NMR (400 MHz, Chloroform-d): δ (ppm) = 6.98 (d, 1H), 6.78 (m, 2H), 2.26 (s, 3H), 2.19 (s, 2H), 2.16 (s, 3H), 0.11 (s, 9H).

[0124] 13C NMR (100 MHz, Chloroform-d): δ (ppm) = 139.81, 135.09, 131.27,129.99, 129.12, 124.83, 23.50, 21.17, 19.87, -1.75。

Claims

1. A method for synthesizing a photoinduced germanium methylene boron reagent, characterized in that The steps include: The metal salt, additive, germane, boric acid ester and solvent are mixed, and an LED lamp is used to perform a light reaction in an inert gas atmosphere to obtain a germane methylene boron reagent; The metal salt includes one or more of ferrous chloride, cupric chloride, cuprous chloride, and ferric chloride; The additives include one or more of N-fluorobisbenzenesulfonamide, trimethylchlorosilane, di-tert-butyl peroxide, and tert-butyl peroxybenzoate.

2. The synthesis method according to claim 1, characterized in that: The metal salt is ferric chloride.

3. The synthesis method according to claim 1, characterized in that: The additive is trimethylchlorosilane.

4. The synthesis method according to claim 1, characterized in that: The solvent includes one or more of acetonitrile, N,N-dimethylformamide, tetrahydrofuran and dichloromethane.

5. The synthesis method according to claim 4, characterized in that: The solvent is acetonitrile.

6. The synthesis method according to claim 1, characterized in that: The wavelength of the reaction light is 370 nm-427 nm.

7. The synthesis method according to claim 1, characterized in that: In the reaction system, the molar ratio of the borates to the metal salt is 10:1-5:1, the molar ratio of the germane to the borates is 10:1-5:1, and the molar ratio of the additive to the borates is 3:1-1:

1.

8. The synthesis method according to claim 1, characterized in that: The synthesis method further comprises a post-treatment step: after the reaction is completed, a triethylamine solution of a vicinal diol is added to form a stable and easily separable product; the vicinal diol is selected from one of 1-phenylpinacol and pinacol.

9. Use of the germanium methylene boron reagent prepared by the synthesis method according to any one of claims 1 to 8, characterized in that: Using the germanium methylene boron reagent as an electrophilic reagent to prepare a polysubstituted boronic acid compound; The reaction route is as follows: ； Wherein R represents a five-membered ring, a five-membered heterocyclic ring, a substituted five-membered ring, a substituted five-membered heterocyclic ring, an aryl group or a substituted aryl group; and the substituent includes one or more of an alkyl group, an alkoxy group, a halogen group and a heteroatom substitution.

10. Use of the germanium methylene boron reagent prepared by the synthesis method according to any one of claims 1 to 8, characterized in that: Substituted alkylgermanium reagents were prepared via palladium-catalyzed Suzuki coupling reactions; the reaction scheme is shown below: ； Wherein Ar represents an aryl group or a substituted aryl group. The substituent includes one or more of an alkyl group, an alkoxy group, a halogen group and a heteroatom group.

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