Application of PNP-type pincer manganese catalyst in dehydrogenative coupling reaction of 2-amino-phenylethanol and hydroxyl-containing compounds

Abstract

The application relates to application of a PNP type Pincer manganese catalyst in a 2-amino phenethyl alcohol and hydroxyl-containing compound dehydrogenation coupling reaction and belongs to the technical field of catalysis processes. The application of the PNP type Pincer manganese catalyst in catalyzing the dehydrogenation coupling reaction of 2-amino phenethyl alcohol and a hydroxyl-containing compound to generate an indole derivative, wherein the hydroxyl-containing compound is HO-CH(R 1 )‑R 2 ‑R 3 , R 1 is -H or a phenyl group, R 2 is an alkylene group or is absent, R 3 is an aryl group or a heteroaryl group which is substituted or unsubstituted, and the substituent is one or two or more of an alkyl group, an alkoxy group, a halogenated group or a halogenated alkyl group. The application has the advantages of low reaction cost, good biocompatibility, wide raw material sources, good atomic economy, wide substrate applicability and high reaction efficiency compared with the use of a noble metal catalyst or other synthesis methods.

Description

Technical Field

[0001] This invention relates to the application of a PNP-type Pincer manganese catalyst in the dehydrogenation coupling reaction of 2-aminophenylethanol and hydroxyl-containing compounds, belonging to the field of catalytic process technology. Background Technology

[0002] Indole, a common heterocyclic skeleton, is widely found in everyday commodities, various natural products, and advanced materials. Later, it was discovered that indole is also a skeletal unit in medicinal alkaloids, fungal metabolites, and marine natural products. As an important structural skeleton for many drugs, indole derivatives, with their high biological activity, occupy a place in drugs in multiple therapeutic areas such as antihypertensive, antiproliferative, antiviral, antitumor, analgesic, anti-inflammatory, and antibacterial applications. For example, C3-alkenylindole also possesses various anticancer, antibacterial, and antiviral biological activities. It is an important precursor for the synthesis of many important biologically related molecules, such as indole alkaloids and carbazole. Due to the important role of indole in medicinal chemistry, much effort has been devoted to the synthesis of functionalized indoles. With the innovation of modern synthetic methods and the dedicated efforts of synthetic chemists, the construction and modification of indole-containing rings has gradually become an important research branch of synthetic chemistry, achieving a series of research advances and giving rise to many classic reactions.

[0003] In recent years, the development of catalysts using inexpensive metals instead of precious metals has garnered significant attention in the fields of catalysis and sustainable development in organic synthesis. One ideal method is to explore inexpensive metal catalysts using hydrogen-based approaches to efficiently dehydrogenate alcohols and indoles into C3-substituted indoles. In this area, the use of Fe, Cu, Co, and Ni complexes for the C3-alkylation of indoles has been reported. For example, Morrill et al. disclosed iron-catalyzed C3-methylation of indoles in *ACS Catalysis* (ACS Catal. 2018, 8, 6440-6445), and Liu Zhiming et al. disclosed cobalt-catalyzed C3-methylation of indoles in *Organic Letters* (Org. Lett. 2017, 19, 5228-5231). Recently, inexpensive metal catalysts based on pincer-shaped ligands have attracted widespread attention in catalysis and have made significant progress. For instance, pincer-shaped iron, cobalt, and manganese catalysts have demonstrated excellent performance in catalytic hydrogenation and dehydrogenation reactions. Recent advancements in the dehydrogenation conversion of alcohols using manganese catalysts include, for example, Rueping et al. reported in Organic Letters (Org. Lett. 2020, 22, 4222-4227) the use of pincer-shaped manganese catalysts to achieve the dehydrogenation alkylation of indoline and alcohol to synthesize C3-alkylated indoles.

[0004] However, when using noble metals as catalysts, the existing technology for preparing C3-substituted indole compounds by dehydrogenation conversion of 2-aminophenylethanol and alcohols is not only costly but also has low reaction efficiency. Summary of the Invention

[0005] The purpose of this invention is to provide an application of a PNP-type Pincer manganese catalyst in the dehydrogenation coupling reaction of 2-aminophenylethanol and hydroxyl-containing compounds to generate indole derivatives, which can improve reaction efficiency while reducing the cost of the dehydrogenation coupling reaction of 2-aminophenylethanol and hydroxyl-containing compounds to generate indole derivatives.

[0006] To achieve the above objectives, the technical solution adopted by this invention is as follows:

[0007] Application of PNP-type Pincer manganese catalysts in catalyzing the dehydrogenation coupling reaction of 2-aminophenylethanol and a hydroxyl-containing compound to generate an indole derivative, wherein the hydroxyl-containing compound has a structure as shown in Formula I:

[0008]

[0009] In formula I, R 1 For -H or phenyl, R 2 If it is an alkylene group or not present, R 3 The substituent is an aryl or heteroaryl group that is substituted or unsubstituted, and the substituent is one or more of alkyl, alkoxy, halogroup, and haloalkyl.

[0010] This invention utilizes a PNP-type Pincer manganese catalyst to catalyze the dehydrogenation coupling reaction of 2-aminophenylethanol and hydroxyl-containing compounds to generate indole derivatives. Compared to using noble metal catalysts or other synthetic methods, this approach not only reduces reaction costs but also offers better biocompatibility, wider availability of raw materials, and better atom economy. Furthermore, the PNP-type Pincer manganese catalyst is suitable for a variety of hydroxyl-containing compounds, exhibiting advantages such as broad substrate applicability and high reaction efficiency (up to 89% yield).

[0011] It should be noted that when R 1 -H, R 2 When the alkylene form is used, the PNP-type Pincer manganese catalyst catalyzes the dehydrogenation conversion of 2-aminophenylethanol and hydroxyl-containing compounds to synthesize C3-alkenylindole compounds. This not only has high reaction efficiency, but also allows for the direct one-pot yield of unprotected products.

[0012] It is understandable that when R 2 When is absent, the structure of the hydroxyl-containing compound is as shown in Formula II:

[0013]

[0014] Furthermore, the PNP-type Pincer manganese catalyst is as shown in Formula II:

[0015]

[0016] In Equation II, R 4 H is H, X is -Br, and R is isopropyl (- i Pr), cyclohexyl (-Cy) or phenyl (-Ph).

[0017] Further, in Formula II, when R is isopropyl, the PNP-type Pincer manganese catalyst is catalyst [Mn]-1; when R is cyclohexyl, the PNP-type Pincer manganese catalyst is catalyst [Mn]-2; when R is phenyl, the PNP-type Pincer manganese catalyst is catalyst [Mn]-3; the structures of catalyst [Mn]-1, catalyst [Mn]-2, and catalyst [Mn]-3 are as follows:

[0018]

[0019] Furthermore, the dehydrogenation coupling reaction involves reacting 2-aminophenylethanol and the hydroxyl-containing compound in an organic solvent at 140–165°C under the action of a base and the PNP-type Pincer manganese catalyst. The dehydrogenation coupling reaction is carried out under closed conditions. Before the reaction, 2-aminophenylethanol, the hydroxyl-containing compound, the base, the PNP-type Pincer manganese catalyst, and the organic solvent are added to the reactor sequentially. After the reaction is completed, the reaction system is cooled using an ice-water bath.

[0020] Furthermore, the reaction time at 140–165°C is ≥6 hours, for example, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, or 16 hours.

[0021] Further, the base is one or any combination of alkali metal hydroxide, alkali metal alkoxide, and alkali metal carbonate. The organic solvent is one or any combination of dioxane, toluene, and tetrahydrofuran (THF). The molar ratio of 2-aminophenylethanol to the hydroxyl-containing compound is ≤1:2, preferably 1:2. The amount of base used for each 0.25 mmol of 2-aminophenylethanol is ≥0.3 mmol, preferably 0.3 mmol. The volume of the organic solvent used for each 0.25 mmol of 2-aminophenylethanol is ≥0.8 mL, preferably 0.8 mL. The amount of PNP-type Pincer manganese catalyst used for each 0.25 mmol of 2-aminophenylethanol is ≥0.005 mmol, preferably 0.005 mmol.

[0022] Furthermore, the alkali metal hydroxide is sodium hydroxide and / or potassium hydroxide, the alkali metal alkoxide is one or any combination of sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide, and the alkali metal carbonate is potassium carbonate.

[0023] Further, the aryl group is phenyl or naphthyl, and the heteroaryl group is pyridyl or thiophene. Further, the substituted aryl group is a monosubstituted aryl group. When the substituted aryl group is a monosubstituted phenyl group, the substituent is located at the ortho, meta, or para position of the phenyl group.

[0024] Further, the alkyl group has 1 to 4 carbon atoms, the alkoxy group has 1 to 4 carbon atoms, and the halogroup is one of -F, -Cl, -Br, and -I. Even further, the alkyl group is methyl (-Me) or tert-butyl (-...). t Bu). The alkoxy group is a methoxy group. Further, the haloalkyl group is a halomethyl group. Even further, the halomethyl group is -CF3.

[0025] Furthermore, the alkylene group has 1 to 2 carbon atoms. Even further, the alkylene group is methylene or -CH2CH2-.

[0026] Furthermore, the hydroxyl-containing compound is selected from one of the following compounds:

[0027]

[0028] In this invention, "aryl" refers to the organic group formed after the loss of a hydrogen atom from a carbon atom on an aromatic ring of an aromatic hydrocarbon molecule. If the aryl group is to be substituted, the substitution can occur independently of each other in the form of mono- or poly-substitution on all the hydrogen-carrying carbon atoms in each case. The aryl group itself is a substituent attached to the molecule through the carbon atom of the aromatic ring, such as phenyl, naphthyl, and biphenyl.

[0029] "Heteroaryl" refers to a monocyclic heteroaryl ring or a polycyclic ring having at least one heteroaryl ring, which, compared to the corresponding aryl or cycloalkyl (cycloalkenyl) group, contains one or more identical or different heteroatoms independently selected from nitrogen, sulfur, and oxygen, wherein the resulting group must be chemically stable. If a heteroaryl group is to be substituted, the substitution can occur independently of each other in the form of monosubstituted or polysubstituted substitutions on all hydrogen-carrying carbon and / or nitrogen atoms in each case. The heteroaryl group itself acts as a substituent linked to the molecule via the cyclic carbon atom.

[0030] "alkyl" refers to an organic group obtained by removing one hydrogen atom from a straight-chain or branched alkane; "alkylene" refers to an organic group obtained by losing two hydrogen atoms from the same carbon atom or from two different carbons of a straight-chain or branched alkane, such as "-CH2-"; "alkoxy" refers to an organic group formed by attaching an alkyl group to an oxygen atom, such as "-O-CH3" (-OMe); halogen groups are -F, -Cl, -Br or -I; haloalkyl refers to an organic group formed by replacing the hydrogen atom on the carbon atom of an alkyl group with a halogen group. Detailed Implementation

[0031] The technical solution of the present invention will be further described below with reference to specific embodiments.

[0032] The following examples use catalysts [Mn]-1, [Mn]-2, and [Mn]-3 with the following structures:

[0033]

[0034] The catalyst [Mn]-1 (PNP(Ph)-Mn(CO)2Br catalyst) was prepared by a method including the following steps:

[0035] Under an argon atmosphere, [Mn(CO)5Br] (0.44 mmol) and [PNP-] were added to a 25 mL Schlenk flask. i [Pr] (0.48 mmol) and degassed toluene (10 mL) were added, and the reaction was heated to 110 °C and stirred for 4 h. After the reaction was completed, the residue was filtered off, the toluene was dried under vacuum, 10 mL of degassed n-hexane was added, and the mixture was filtered under argon. The filter cake was dried under vacuum to obtain a light yellow solid (70%).

[0036] MRI: 1 H NMR (400MHz, C6D6) δ3.27(d,J=6.9Hz,2H),2.79(s,1H),2.43(d,J=13.3 Hz,2H),2.21(d,J=7.3Hz,2H),1.98–1.84(m,2H),1.64(s,2H),1.51(dd,J=15.1,7.3Hz, 6H),1.31(dd,J=13.9,6.9Hz,6H),1.21(dd,J=13.1,7.1Hz,6H),1.06(dd,J=10.9,6.9Hz, 6H),0.85(s,2H), 13C NMR (101MHz, C6D6) δ52.33, 26.77 (t, J = 9.3 Hz), 25.78 (t, J = 9.3 Hz), 24.10 (d, J = 9.5 Hz), 19.88 (d, J = 16.5 Hz), 18.51, 18.05. 31 P NMR(162MHz,C6D6)δ 81.23(s).

[0037] High-resolution HR-MS (ESI) analysis for C18H37MnNO2P2 [M] + 416.1674; found: 416.1675.

[0038] Infrared: 3180, 2915, 2870, 1901, 1809, 1458, 1367, 1251, 1054, 956, 827, 653, 626, 599 cm -1 .

[0039] The chemical reactions involved are as follows:

[0040]

[0041] Catalysts [Mn]-2 and [Mn]-3 were synthesized using the methods described in the references (Chem. Sci. 2017, 8, 3576; J. Am. Chem. Soc. 2017, 139, 11941;).

[0042] Example 1

[0043] The application of the PNP-type Pincer manganese catalyst in the dehydrogenation coupling reaction of 2-aminophenylethanol and a hydroxyl-containing compound to generate an indole derivative, as described in this embodiment, includes the following steps:

[0044] In a glove box, 2-aminophenylethanol (34 mg, 0.25 mmol), benzyl alcohol (54 mg, 0.5 mmol), potassium hydroxide (16.8 mg, 0.3 mmol), catalyst [Mn]-1 (2.5 mg, 0.005 mmol), and dioxane (0.8 mL) were added sequentially to a 15 mL pressure-resistant tube equipped with a stir bar. The cap was tightened, and the pressure-resistant tube was placed in a metal module and reacted at 165 °C for 16 hours. After the reaction was complete, the tube was cooled in an ice-water bath. The cap was carefully opened, and the reaction product was quantitatively analyzed by gas chromatography (GC). The yield of the reaction product was calculated to be 89%.

[0045] MRI: 1H NMR (400MHz, CDCl3) δ7.77(s,1H),7.44(d,J=7.8Hz,1H),7.26–7.16(m,5H),7.14–7.08(m,2H),7.01-6.97(m,1H),6.83–6.75(m,1H),4.03(s,2H). 13 C NMR (101MHz, CDCl3) δ141.26,136.48,128.74,128.38,127.51,125.93,122.38,122.09,119.41,119.20, 115.87,111.11,31.64.

[0046] The chemical reactions involved are as follows:

[0047]

[0048] Example 2

[0049] The application of the Pincer-type PNP manganese complex catalyst in the dehydrogenation coupling reaction of compounds I and II in this embodiment differs from that in Example 1 only in that the catalyst [Mn]-1 in Example 1 is replaced with catalyst [Mn]-2, with a yield of 83%.

[0050] Example 3

[0051] The application of the Pincer-type PNP manganese complex catalyst in the dehydrogenation coupling reaction of compounds I and II in this embodiment differs from that in Example 1 only in that the catalyst [Mn]-1 in Example 1 is replaced with catalyst [Mn]-3, with a yield of 79%.

[0052] Example 4

[0053] The application of the PNP-type Pincer manganese catalyst [Mn]-1 in the required reaction time for the dehydrogenation coupling reaction of 2-aminophenylethanol and a hydroxyl-containing compound to generate an indole derivative, as described in this embodiment, includes the following steps:

[0054] In a glove box, 2-aminophenylethanol (34 mg, 0.25 mmol), benzyl alcohol (54 mg, 0.5 mmol), potassium hydroxide (16.8 mg, 0.3 mmol), catalyst [Mn]-1 (2.5 mg, 0.005 mmol), and dioxane (0.8 mL) were added sequentially to a 15 mL pressure-resistant tube equipped with a stir bar. The cap was tightened, and the pressure-resistant tube was placed in a metal module and reacted at 165 °C for 2, 4, 6, 8, and 10 hours, respectively. After the reaction was complete, the tube was cooled in an ice-water bath, the cap was carefully opened, and the reaction products were quantitatively analyzed by gas chromatography (GC), and the yields were calculated. The yields were 57% after 2 hours, 72% after 4 hours, >89% after 6 hours, >89% after 8 hours, and >89% after 10 hours.

[0055] The chemical reactions involved are as follows:

[0056]

[0057] Examples 5-18

[0058] The application of the PNP-type Pincer manganese catalysts in Examples 5-18 in the catalytic dehydrogenation coupling reaction of 2-aminophenylethanol and hydroxyl-containing compounds to generate indole derivatives includes the following steps:

[0059] In a glove box, 2-aminophenylethanol (34 mg, 0.25 mmol), a hydroxyl-containing compound (0.5 mmol), potassium hydroxide (16.8 mg, 0.3 mmol), catalyst [Mn]-1 (2.5 mg, 0.005 mmol), and dioxane (0.8 mL) were added sequentially to a 15 mL pressure-resistant tube equipped with a stir bar. The cap was tightened, and the pressure-resistant tube was placed in a metal module and reacted at 165 °C for 16 hours. After the reaction was completed, the tube was cooled in an ice-water bath, the cap was carefully opened, and the reaction products were quantitatively analyzed by gas chromatography (GC) to calculate the product yield. The hydroxyl-containing compound, reaction products, and product yields used in each example are shown in Table 1.

[0060] Table 1. Hydroxyl-containing compounds, reaction products, and reaction product yields used in Examples 5-18

[0061]

[0062]

[0063]

[0064] As can be seen from Examples 1-18, C3-grouped indole derivatives can be synthesized in situ under [Mn]-1 catalytic conditions using 2-aminophenylethanol and benzyl alcohol derivatives or pyridylethanol as starting materials. The benzyl alcohol derivatives exhibit good compatibility with substituents on the benzene ring that possess different electronic and steric effects.

[0065] NMR data of the reaction products in some embodiments:

[0066] Example 5: 1 H NMR (400MHz, CDCl3) δ7.79 (s, 1H), 7.44 (d, J = 8.0Hz, 1H), 7.25 (d, J = 8.1Hz, 1H), 7.1 2–7.07(m,3H),7.01–6.97(m,2H),6.80(d,J=2.3Hz,1H),3.99(s,2H),2.23(s,3H). 13 C NMR (101MHz, CDCl3) δ138.16,136.48,135.32,129.05,128.59,127.52,122.28,122.03,119.35,119.21,116.13,111.07,31.18,21.06.

[0067] Example 6: 1 H NMR (400MHz, CDCl3) δ7.79(s,1H),7.43(d,J=7.9Hz,1H),7.23(d,J=8.1Hz,1H),7 .13–7.07(m,3H),7.01–6.97(m,1H),6.77–6.72(m,3H),3.97(s,2H),3.68(s,3H). 13 C NMR (101MHz, CDCl3) δ157.85,136.52,133.37,129.64,127.47,122.27,122.05,119.35,119.21,116.30,113.79,111.11,55.31,30.75.

[0068] Example 7: 1 H NMR (400MHz, CDCl3) δ7.74(s,1H),7.46(dd,J=7.9,1.0Hz,1H),7.23(dd,J=8.1,1.0Hz,1H),7. 16–6.94(m,6H),6.82–6.72(m,1H),3.99(s,2H),2.78(p,J=6.9Hz,1H),1.14(d,J=6.9Hz,6H). 13C NMR (101MHz, CDCl3) δ146.42,138.60,136.49,128.61, 127.59,126.42,122.34,122.04,119.36,119.24,116.09,111.10,33.75,31.16,24.14.

[0069] Example 8: 1 H NMR (400MHz, DMSO-d6) δ10.87 (s, 1H), 7.61 (d, J = 7.1Hz, 2H), 7.55 (d, J=8.1Hz,2H),7.47–7.41(m,3H),7.38–7.30(m,4H),7.20(d,J=2.3Hz,1H),7.05(t,J=7.6Hz,1H),6.93(t,J=8.0Hz,1H),4.08(s,2H). 13 C NMR(101MHz,DMSO-d6)δ141.64,140.59,138.04,136.90,129.44,129.33,127.59, 127.46,126.97,126.94,123.65,121.42,119.01,118.76,114.16,111.88,31.11.

[0070] Example 9: 1 H NMR(400MHz, CDCl3) δ7.83(s,1H),7.38(dd,J=7.9,1.1Hz,1H),7.26(dd,J=8.1,0 .9Hz,1H),7.16–7.10(m,5H),7.02–6.98(m,1H),6.81–6.80(m,1H),3.99(s,2H). 13 C NMR (101MHz, CDCl3) δ139.71,136.50,131.62,130.04,128.45,127.30,122.40,122.22,119.51,119.08,115.28,111.18,31.02.

[0071] Example 10: 1 H NMR(400MHz, CDCl3)δ7.82(s,1H),7.47(s,1H),7.40–7.33(m,3H),7.28–7.24(m ,2H),7.13–7.09(m,1H),7.02–6.98(m,1H),6.80(d,J=2.4Hz,1H),4.06(s,2H). 13C NMR (101MHz, CDCl3) δ142.20,136.50,132.10,131.11,130.79,130.48,130.16,128.80,127.26,125.71,125.46,125.43,1 25.39,125.35,123.00,122.95,122.91,122.87,122.84,122.51,122.31,120.30,119.61,118.97,114.84,111.24,31.49.

[0072] Example 11: 1 H NMR (400MHz, CDCl3) δ7.83 (s, 1H), 7.40 (dt, J = 7.9, 1.2Hz, 1H), 7.26 (d, J = 8.1 Hz,1H),7.16–7.09(m,2H),7.03–6.97(m,2H),6.89–6.77(m,3H),4.02(s,2H). 13 CNMR(101MHz, CDCl3)δ164.25,161.81,143.98,143.91,136.48,129.75,129.67,127.33,124.33,124 .30,122.46,122.22,119.53,119.08,115.64,115.43,114.99,112.93,112.72,111.19,31.40,31.38.

[0073] Example 15: 1 H NMR (400MHz, CDCl3) δ7.72 (s, 1H), 7.23–7.08 (m, 13H), 6.89 (t, J = 7.5 Hz, 1H), 6.43 (d, J = 2.3Hz, 1H), 5.57 (s, 1H). 13 C NMR (101MHz, CDCl3) δ144.00,136.75,129.08,128.35,127.05,126.30,124.13,122.16,119.98,119.96,119.46,111.11,48.89.

[0074] Example 16: 1H NMR (400MHz, CDCl3) δ7.65(s,1H),7.44(dd,J=8.0,2.5Hz,1H),7.19(d,J=8.1Hz,1H),7.12–7.04(m, 2H),7.04–6.95(m,3H),6.95–6.86(m,1H),6.73(d,J=2.1Hz,1H),3.97(d,J=2.2Hz,2H),2.20(s,3H). 13 C NMR (101MHz, CDCl3) δ141.26, 137.96,136.50,129.57,128.32,127.58,126.74,125.84,122.42,122.08,119.42,119.25,115.97,111.15,31.59,21.53.

[0075] Example 18: 1 H NMR (400MHz, CDCl3) δ8.53(s,1H),8.42–8.37(m,2H),7.46(d,J=7.8Hz,1H),7.40(d,J=7.9Hz,1H),7. 26(d,J=8.1Hz,1H),7.10(t,J=7.6Hz,2H),7.00(t,J=7.5Hz,1H),6.83(d,J=2.2Hz,1H),4.02(s,2H). 13 C NMR (101MHz, CDCl3) δ150.05, 147.40,136.78,136.58,136.29,127.13,123.46,122.60,122.22,119.51,118.88,114.36,111.32,28.90.

[0076] Example 19

[0077] The application of the PNP-type Pincer manganese catalyst in the dehydrogenation coupling reaction of 2-aminophenylethanol and a hydroxyl-containing compound to generate an indole derivative, as described in this embodiment, includes the following steps:

[0078] In a glove box, 2-aminophenylethanol (34 mg, 0.25 mmol), phenylethanol (61 mg, 0.5 mmol), potassium hydroxide (16.8 mg, 0.3 mmol), catalyst [Mn]-1 (2.5 mg, 0.005 mmol), and dioxane (0.8 mL) were added sequentially to a 15 mL pressure-resistant tube equipped with a stir bar. The cap was tightened, and the pressure-resistant tube was placed in a metal module and reacted at 165 °C for 16 hours. After the reaction was complete, the tube was cooled in an ice-water bath. The cap was carefully opened, and the reaction product was quantitatively analyzed by gas chromatography (GC). The yield of the reaction product was calculated to be 86%.

[0079] MRI: 1 H NMR (400MHz, DMSO-d6) δ11.33(s,1H),8.01(d,J=7.7Hz,1H),7.65(d,J= 2.6Hz,1H),7.58(d,J=7.0Hz,2H),7.45–7.41(m,2H),7.34(t,J=7.7Hz,2H),7.20–7.08 (m,4H). 13 C NMR (101MHz, DMSO-d6) δ139.03,137.49,129.07,126.67,126.53,125.89,125.62,123.74,123.01,122.23,120.30,120.13,114.13,112.37.

[0080] The chemical reactions involved are:

[0081]

[0082] Examples 20-29

[0083] Examples 20-29 illustrate the application of PNP-type Pincer manganese catalysts in the catalytic dehydrogenation coupling reaction of 2-aminophenylethanol and hydroxyl-containing compounds to generate indole derivatives, comprising the following steps:

[0084] In a glove box, 2-aminophenylethanol (34 mg, 0.25 mmol), a hydroxyl-containing compound (0.5 mmol), potassium hydroxide (16.8 mg, 0.3 mmol), catalyst [Mn]-1 (2.5 mg, 0.005 mmol), and dioxane (0.8 mL) were added sequentially to a 15 mL pressure-resistant tube equipped with a stir bar. The cap was tightened, and the pressure-resistant tube was placed in a metal module and reacted at 165 °C for 16 hours. After the reaction was completed, the tube was cooled in an ice-water bath, the cap was carefully opened, and the reaction products were quantitatively analyzed by gas chromatography (GC), and the product yield was calculated. The hydroxyl-containing polymers, reaction products, and yields used in each example are shown in Table 2.

[0085] Table 2. Hydroxyl-containing polymers, reaction products, and yields used in Examples 20-29

[0086]

[0087]

[0088]

[0089] As shown in Table 2 above, C3-alkenylated indoles can be synthesized in situ using 2-aminophenylethanol and phenylethanol derivatives / naphthylethanol / pyridineethanol as starting materials under [Mn]-1 catalytic conditions. The phenylethanol derivatives exhibit good compatibility with substituents on the benzene ring that possess different electronic and steric effects.

[0090] NMR of the reaction products in some examples:

[0091] Example 20: 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),7.99(d,J=7.8Hz,1H),7.62(d,J=2.6Hz,1H),7.46(d,J=7.9Hz,2H ),7.42(d,J=7.4Hz,1H),7.36(d,J=16.6Hz,1H),7.18–7.09(m,4H),7.06(d,J=16.6Hz,1H),2.30(s,3H). 13 C NMR(101MHz,DMSO)δ 137.47,136.22,135.83,129.67,126.15,125.83,125.63,123.77,122.16,121.98,120.27,120.05,114.21,112.34,21.25.

[0092] Example 21: 1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),7.98(d,J=7.8Hz,1H),7.59(d,J=2.5Hz,1H),7.51(d,J=8.4Hz,2H ),7.41(d,J=8.6Hz,1H),7.27(d,J=16.6Hz,1H),7.17–7.03(m,3H),6.92(d,J=8.3Hz,2H),3.76(s,3H). 13C NMR(101MHz,DMSO)δ 158.46,137.44,131.69,127.07,125.72,125.63,123.59,122.11,120.78,120.26,119.95,114.56,114.34,112.30,55.55.

[0093] Example 22: 1 H NMR (400MHz, DMSO-d6) δ11.33(s,1H),8.01(d,J=8.0Hz,1H),7.64–7.60(m,3H),7.43(d,J=7.5Hz,1H),7.38(d,J=16.6Hz,1H),7.21–7.08(m,5H). 13 C NMR (101MHz, DMSO) δ161.33 (d, J = 242.8Hz), 137.48, 135.63 (d, J = 3.0Hz), 127.56 (d, J = 7.7H z),126.45,125.59,122.97,122.59,122.23,120.32,120.11,115.85(d,J=21.2Hz),114.06, 112.37.

[0094] Example 24: 1 H NMR(400MHz,DMSO-d6)δ11.37(s,1H),8.01(d,J=7.8Hz,1H),7.66(s,1H),7.55–7.50(m,4H ),7.47(d,J=16.6Hz,1H),7.43(d,J=7.9Hz,1H),7.19–7.12(m,2H),7.07(d,J=16.7Hz,1H). 13 C NMR (101MHz, DMSO) δ138.43,137.52,131.88,127.84,126.98,125.56,124.07,122.31,120.37,120.23,119.20,113.98,112.41.

[0095] Example 26: 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),7.95(d,J=7.1Hz,1H),7.68–7.65(m,2H),7.44(d,J= 7.4Hz,1H),7.32(d,J=16.4Hz,1H),7.23(d,J=13.6Hz,1H),7.21–7.09(m,5H),2.42(s,3H).13 C NMR (101MHz, DMSO) δ137.63,137.51,134.77,130.73,126.67,126.61,125.6 0,124.44,124.10,122.22,121.24,120.24,120.10,114.49,112.42,20.16.

[0096] Example 27: 1 H NMR (400MHz, DMSO-d6) δ11.32(s,1H),8.00(d,J=7.7Hz,1H),7.64(d,J=2.6Hz,1H),7.43(s,1H),7.42–7.39(m,2H),7.3 6(d,J=7.9Hz,1H),7.23(t,J=7.6Hz,1H),7.18–7.09(m,2H),7.06(d,J=16.6Hz,1H),7.00(d,J=7.6Hz,1H),2.33(s,3H). 13 C NMR(101MHz,DMSO)δ138.93,138.02,137.49,128.95,127.41,126.46,126.43,1 25.62,123.83,123.17,122.80,122.21,120.29,120.11,114.17,112.36,21.57.

[0097] Example 28: 1 H NMR (400MHz, DMSO-d6) δ11.38(s,1H),8.08(d,J=7.1Hz,1H),7.97(s,1H),7.88(s,3H),7.86(s,1H),7.7 1(d,J=2.6Hz,1H),7.60(d,J=16.6Hz,1H),7.51–7.41(m,3H),7.28(d,J=16.6Hz,1H),7.21–7.13(m,2H). 13 C NMR(101MHz,DMSO)δ137.54,136.71,134.04,132.44,128.48,128.02,126.77,126.72,12 5.72,125.65,124.94,123.78,123.75,123.69,122.29,120.37,120.21,114.26,112.43.

[0098] Example 29: 1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),8.76(d,J=2.2Hz,1H),8.38(d,J=4.7Hz,1H),8.03(dd,J=13.8,7.8Hz,2H),7.69(d,J=2.7Hz,1H),7.56(d,J=16.6Hz, 1H),7.44(d,J=7.8Hz,1H),7.36(dd,J=8.0,4.6Hz,1H),7.20–7.09(m,3H). 13 CNMR(101 MHz,DMSO)δ147.94,147.48,137.52,134.75,131.91,127.19,125.54,125.13,124.13,122.36,120.39,120.29,119.90,113.99,112.44。

Claims

1. Application of PNP-type Pincer manganese catalyst in catalyzing the dehydrogenation coupling reaction of 2-aminophenylethanol and a hydroxyl-containing compound to generate an indole derivative, wherein the hydroxyl-containing compound has a structure as shown in Formula I: ， In formula I, R 1 For -H or phenyl, R 2 Methylene or absent, R 3 The substituent is a substituted or unsubstituted aryl group, or an unsubstituted heteroaryl group, wherein the substituent is one of alkyl, alkoxy, halogroup, or haloalkyl. The PNP-type Pincer manganese catalyst is shown in Formula II: ， In Equation II, R 4 X is -H, R is -Br, and R is isopropyl, cyclohexyl, or phenyl.

2. The application according to claim 1, characterized in that: The dehydrogenation coupling reaction is carried out by reacting 2-aminophenylethanol and a hydroxyl-containing compound in an organic solvent at 140-165°C under the action of an alkaline substance and the PNP-type Pincer manganese catalyst; the dehydrogenation coupling reaction is carried out under closed conditions; the alkaline substance is one or any combination of alkali metal hydroxide, alkali metal alkoxide, and alkali metal carbonate.

3. The application according to claim 2, characterized in that: The reaction time at 140~165℃ is ≥6h.

4. The application according to claim 2, characterized in that: The organic solvent is one or any combination of dioxane, toluene, and tetrahydrofuran; the molar ratio of 2-aminophenylethanol to the hydroxyl-containing compound is 1:2; for every 0.25 mmol of 2-aminophenylethanol, the corresponding amount of alkaline substance is 0.3 mmol, the corresponding volume of organic solvent is 0.8 mL, and the corresponding amount of PNP-type Pincer manganese catalyst is 0.005 mmol.

5. The application according to claim 2, characterized in that: The alkali metal hydroxide is sodium hydroxide and / or potassium hydroxide, the alkali metal alkoxide is one or any combination of sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide, and the alkali metal carbonate is potassium carbonate.

6. The application according to any one of claims 1 to 5, characterized in that: The aryl group is phenyl, naphthyl, or biphenyl, and the heteroaryl group is pyridyl or thiophene.

7. The application according to any one of claims 1 to 5, characterized in that: The alkyl group has 1 to 4 carbon atoms, the alkoxy group has 1 to 4 carbon atoms, and the halogroup is one of -F, -Cl, -Br, and -I.

8. The application according to any one of claims 1 to 5, characterized in that: The hydroxyl-containing compound is selected from one of the following compounds: 。

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