A method for synthesizing indoline

Abstract

The present invention discloses a method for synthesizing indoline, which is characterized in that: under the co-catalysis of yttrium bis(trimethylsilylamide) and tris(pentafluorophenyl)borane, an additive, a hydrogen source, and an indole compound are used as raw materials to react in a solvent to obtain an indoline compound; the structural formula of the indole compound is the structural formula of the indoline compound. The raw materials of the method of the present invention are widely sourced or easy to prepare, with simple operation, controllable selectivity, high yield, mild conditions, and wide generality.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing structurally diverse indolines by co-catalyzing the hydrogen transfer reduction reaction of indole compounds with yttrium bis(trimethylsilylamide) and tris(pentafluorophenyl)borane. Background Art

[0002] Indoline compounds are structural motifs commonly found in naturally occurring alkaloids and many bioactive compounds, and are also an important part of pharmaceutical synthesis, agrochemical synthesis, and materials science. Metal-catalyzed catalytic hydrogenation of indole with hydrogen molecules is a common method for preparing indolines (Journal of the American Chemical Society. 2000, 122, 7614). Indolines can also be prepared by catalytic hydrogen transfer hydrogenation (Organic & Biomolecular Chemistry 2013, 11(7), 1209 - 1215). However, these reactions have drawbacks such as cumbersome catalyst preparation, harsh reaction conditions, narrow substrate scope, low functional compatibility, poor chemoselectivity, and generation of a large amount of toxic waste, and have certain limitations. Summary of the Invention

[0003] Aiming at the deficiencies of the existing technology, the purpose of the present invention is to provide a method that can synthesize indoline compounds from various substituted indoles with high selectivity and high yield, with a wide range of raw material sources, simple and easy-to-prepare catalysts, and mild reaction conditions.

[0004] To achieve the above purpose, the present invention provides the following technical solutions:

[0005] A method for synthesizing indoline,

[0006] Under the co-catalysis of yttrium bis(trimethylsilylamide) and tris(pentafluorophenyl)borane, an additive, a hydrogen source, and an indole compound are used as raw materials to react in a solvent to obtain an indoline compound;

[0007] The structural formula of the indole compound is

[0008] The structural formula of the indoline compound is

[0009] As a further improvement of the present invention,

[0010] In the structural formulas of the indole compound and the indoline compound, R is hydrogen or 2-phenyl or 3-methyl or 4-methyl or 5-iodo or 5-methoxy or 6-methyl or 6-methoxy or 7-bromo.

[0011] As a further improvement of the present invention,

[0012] The additive is p-trifluoromethylaniline.

[0013] As a further improvement of the present invention,

[0014] The hydrogen source is pinacolborane.

[0015] As a further improvement of the present invention,

[0016] The solvent is toluene.

[0017] As a further improvement of the present invention,

[0018] The reaction temperature is 50 °C, a one-step reaction, and the reaction time is 12 h.

[0019] As a further improvement of the present invention,

[0020] The molar ratio of the indole compound, yttrium bis(trimethylsilylamide), tris(pentafluorophenyl)borane, additive, and hydrogen source is 1.0∶0.1∶0.1∶0.1∶5.0.

[0021] The reaction formula of the present invention is:

[0022]

[0023] Through in-depth and meticulous research, the inventor of the present invention found an efficient synthesis method for indoline compounds. Under the yttrium bis(trimethylsilylamide) / tris(pentafluorophenyl)borane catalytic system, the indole compound undergoes a hydrogen transfer reduction reaction, thereby realizing the synthesis of indolines with diverse structures. This method has a wide range of raw material sources, is easy to operate, has broad universality, and high selectivity. Compared with previous methods, its environmental friendliness and substrate universality have been significantly improved, which is difficult to achieve by other methods. The present invention has the following advantages and innovations:

[0024] (1) The reaction has good universality and high yield, and the yield of most reactions is above 80%;

[0025] (2) This is an important supplement to the preparation of indoline compounds and provides an important idea for the synthesis of bioactive compounds.

[0026] The beneficial effects of the present invention compared with the prior art:

[0027] The indoline prepared by the method of the present invention has high quality, high yield, good reaction universality, and convenient post-treatment, providing an important reference for constructing indoline compounds. Specific embodiments

[0028] Example 1

[0029] Preparation of indoline, the structural formula is as follows:

[0030]

[0031] Add 0.5 mmol of raw material indole and catalysts yttrium bis(trimethylsilylamide) (0.1 equiv) / tris(pentafluorophenyl)borane (0.1 equiv), p-trifluoromethylaniline (0.1 equiv), pinacolborane (2.5 mmol), toluene (1.5 mL), react at 50 °C for 12 hours, and the isolated yield of the product is 95%.

[0032] 1 H NMR (500 MHz, CDCl3) δ 7.15 (d, J = 7.2 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.74 (t, J = 7.4 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 3.57 (t, J = 8.4 Hz, 2H), 3.06 (t, J = 8.4 Hz, 2H); 13 C NMR (101 MHz, CDCl3) δ 151.7, 129.4, 127.3, 124.7, 118.7, 109.5, 47.4, 29.9.

[0033] Example 2

[0034] Preparation of 2-phenylindoline, the structural formula is as follows:

[0035]

[0036] Add 0.5 mmol of raw material 2-phenylindole and catalysts yttrium bis(trimethylsilylamide) (0.1 equiv) / tris(pentafluorophenyl)borane (0.1 equiv), p-trifluoromethylaniline (0.1 equiv), pinacolborane (2.5 mmol), toluene (1.5 mL), react at 50 °C for 12 hours, and the isolated yield of the product is 95%.

[0037] 1 H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.0 Hz, 2H), 7.32 (dd, J = 9.9, 4.4 Hz, 2H), 7.26 (d, J = 7.0 Hz, 1H), 7.05 (t, J = 8.0 Hz, 2H), 6.72 (t, J = 7.0 Hz, 1H), 6.64 (d, J = 7.5 Hz, 1H), 4.91 (t, J = 8.9 Hz, 1H), 4.07 (brs, 1H), 3.41 (dd, J = 15.4, 9.3 Hz, 1H), 2.96 (dd, J = 15.5, 8.8 Hz, 1H); 1313C NMR (126 MHz, CDCl3) δ 151.1, 144.7, 128.6, 128.1, 127.6, 127.4, 126.4, 124.6, 118.8, 108.9, 63.6, 39.6.

[0038] Example 3

[0039] Preparation of 3-methylindoline, the structural formula is as follows:

[0040]

[0041] Add 0.5 mmol of the raw material 3-methylindole and the catalysts yttrium bis(trimethylsilylamide) (0.1 equiv) and tris(pentafluorophenyl)borane (0.1 equiv), p-trifluoromethylaniline (0.1 equiv), pinacol borane (2.5 mmol), toluene (1.5 mL), react at 50 °C for 12 hours, and the isolated yield of the product is 93%.

[0042] 1 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 7.3 Hz, 1H), 7.08 - 7.02 (m, 1H), 6.76 (td, J = 7.4, 0.9 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 3.71 (t, J = 8.6 Hz, 1H), 3.44 - 3.33 (m, 1H), 3.13 (t, J = 8.6 Hz, 1H), 1.35 (d, J = 6.8 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ 151.3, 134.5, 127.4, 123.5, 118.9, 109.7, 55.5, 36.7, 18.7.

[0043] Example 4

[0044] Preparation of 4-methylindoline, the structural formula is as follows:

[0045]

[0046] Add 0.5 mmol of the raw material 4-methylindole and the catalysts yttrium bis(trimethylsilylamide) (0.1 equiv) / tris(pentafluorophenyl)borane (0.1 equiv), p-trifluoromethylaniline (0.1 equiv), pinacol borane (2.5 mmol), toluene (1.5 mL), react at 50 °C for 12 hours, and the isolated yield of the product is 82%.

[0047] 11H NMR (400 MHz, CDCl3) δ 6.96 (t, J = 7.6 Hz, 1H), 6.57 (d, J = 7.5 Hz, 1H), 6.52 (d, J = 7.7 Hz, 1H), 3.58 (t, J = 8.4 Hz, 2H), 2.98 (t, J = 8.4 Hz, 2H), 2.25 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 151.4, 134.3, 128.1, 127.3, 119.9, 107.0, 47.1, 28.6, 18.9.

[0048] Example 5

[0049] Preparation of 5-methylindoline, the structural formula is as follows:

[0050]

[0051] Add 0.5 mmol of the raw material 5-methylindole and the catalyst yttrium bis(trimethylsilylamide) (0.1 equiv) / tris(pentafluorophenyl)borane (0.1 equiv), p-trifluoromethylaniline (0.1 equiv), pinacol borane (2.5 mmol), toluene (1.5 mL), react at 50 °C for 12 hours, and the isolated yield of the product is 77%.

[0052] 1 1H NMR (400 MHz, CDCl3) δ 6.98 (s, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.59 (d, J = 7.8 Hz, 1H), 3.54 (t, J = 8.3 Hz, 2H), 3.37 (brs, 1H), 3.01 (t, J = 8.3 Hz, 2H), 2.28 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 149.3, 129.8, 128.1, 127.5, 125.5, 109.5, 47.6, 30.0, 20.9.

[0053] Example 6

[0054] Preparation of 5-iodoindoline, the structural formula is as follows:

[0055]

[0056] Add 0.5 mmol of the raw material 5-iodoindole and the catalyst yttrium bis(trimethylsilylamide) (0.1 equiv) / tris(pentafluorophenyl)borane (0.1 equiv), p-trifluoromethylaniline (0.1 equiv), pinacol borane (2.5 mmol), toluene (1.5 mL), react at 50 °C for 12 hours, and the isolated yield of the product is 89%.

[0057] 1 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 1.3 Hz, 1H), 7.28 - 7.20 (m, 1H), 6.39 (d, J = 8.1 Hz, 1H), 3.75 (brs, 1H), 3.51 (t, J = 8.5 Hz, 2H), 2.98 (t, J = 8.4 Hz, 2H); 13 13C NMR (101 MHz, CDCl3) δ 151.4, 135.8, 133.3, 132.3, 111.3, 79.2, 47.5, 29.6.

[0058] Example 7

[0059] Preparation of 6 - methylindoline, the structural formula is as follows:

[0060]

[0061] Add 0.5 mmol of the raw material 6 - methylindole and the catalyst yttrium bis(trimethylsilylamide) (0.1 equiv) / borane tris(pentafluorophenyl) (0.1 equiv), p - trifluoromethylaniline (0.1 equiv), pinacol borane (2.5 mmol), toluene (1.5 mL), react at 50 °C for 12 hours, and the isolated yield of the product is 83%.

[0062] 1 1H NMR (400 MHz, CDCl3) δ 7.02 (d, J = 7.3 Hz, 1H), 6.55 (d, J = 7.4 Hz, 1H), 6.51 (s, 1H), 3.55 (t, J = 8.3 Hz, 2H), 3.00 (s, 2H), 2.29 (s, 3H); 13 13C NMR (101 MHz, CDCl3) δ 151.9, 137.1, 126.4, 124.3, 119.4, 110.4, 47.6, 29.6, 21.5.

[0063] Example 8

[0064] Preparation of 6 - methoxyindoline, the structural formula is as follows:

[0065]

[0066] Add 0.5 mmol of the raw material 6 - methoxyindole and the catalyst yttrium bis(trimethylsilylamide) (0.1 equiv) / borane tris(pentafluorophenyl) (0.1 equiv), p - trifluoromethylaniline (0.1 equiv), pinacol borane (2.5 mmol), toluene (1.5 mL), react at 50 °C for 12 hours, and the isolated yield of the product is 87%.

[0067] 1 1H NMR (400 MHz, CDCl3) δ 7.00 (d, J = 7.4 Hz, 1H), 6.26 (d, J = 7.6 Hz, 2H), 3.76 (s, 3H), 3.56 (t, J = 8.2 Hz, 2H), 2.97 (t, J = 8.3 Hz, 2H); 13 13C NMR (101 MHz, CDCl3) δ 159.9, 153.0, 124.7, 121.6, 103.4, 96.4, 55.4, 48.0, 29.0.

[0068] Example 9

[0069] Preparation of 7-bromoindoline, the structural formula is as follows:

[0070]

[0071] Add 0.5 mmol of raw material 7-bromoindole and catalyst yttrium bistrimethylsilylamide (0.1 equiv) / tris(pentafluorophenyl)borane (0.1 equiv), p-trifluoromethylaniline (0.1 equiv), pinacol borane (2.5 mmol), toluene (1.5 mL), react at 50 °C for 12 hours, and the isolated yield of the product is 81%.

[0072] 1 1H NMR (400 MHz, CDCl3) δ 7.16 (dd, J = 8.0, 0.7 Hz, 1H), 7.10 - 6.91 (m, 1H), 6.64 - 6.49 (m, 1H), 3.98 (brs, 1H), 3.61 (t, J = 8.5 Hz, 2H), 3.15 (t, J = 8.4 Hz, 2H); 13 13C NMR (101 MHz) δ 150.2, 130.6, 129.9, 123.5, 119.7, 103.3, 46.8, 30.9.

[0073] Raw material list:

[0074]

[0075] The reaction formula of the present invention is:

[0076]

[0077] Through in-depth and meticulous research, the present inventor has discovered an efficient synthesis method for indoline compounds. Under the catalytic system of yttrium bis(trimethylsilylamide) / tris(pentafluorophenyl)borane, the indole compounds undergo hydrogen transfer reduction reaction, thereby realizing the synthesis of indolines with diverse structures. This method has wide sources of raw materials, simple operation, broad generality, and high selectivity. Compared with previous methods, its environmental friendliness and substrate generality have been significantly improved, which is difficult to achieve by other methods. The present invention has the following advantages and innovations:

[0078] (1) The reaction has good generality and high yield, and the yields of most reactions are above 80%;

[0079] (2) This is an important supplement to the preparation of indoline compounds and provides an important idea for the synthesis of bioactive compounds.

[0080] The beneficial effects of the present invention compared with the prior art:

[0081] The indolines prepared by the method of the present invention have high quality, high yield, good reaction generality, and convenient post-treatment, providing an important reference for the construction of indoline compounds.

[0082] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention, and they should all be covered by the scope of the claims of the present invention.

Claims

1. A method for synthesizing indoline, characterized in that: Under the co-catalysis of yttrium bis(trimethylsilyl)amide and tris(pentafluorophenyl)borane, an additive, a hydrogen source, and an indole compound are used as raw materials to react in a solvent to obtain an indoline compound; The structural formula of the indole compound is The structural formula of the indoline compound is In the structural formulas of the indole compound and the indoline compound, R is hydrogen or 2-phenyl or 3-methyl or 4-methyl or 5-iodo or 5-methoxy or 6-methyl or 6-methoxy or 7-bromo; The additive is p-trifluoromethylaniline; The hydrogen source is pinacolborane.

2. The method for synthesizing indoline according to claim 1, characterized in that: The solvent is toluene.

3. The method for synthesizing indoline according to claim 1, characterized in that: The reaction temperature is 50 °C, a one-step reaction, and the reaction time is 12 h.

4. The method for synthesizing indoline according to claim 1, characterized in that: The molar ratio of the indole compound, yttrium bis(trimethylsilyl)amide, tris(pentafluorophenyl)borane, the additive, and the hydrogen source is 1.0:0.1:0.1:0.1:5.0.

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