Method for synthesizing bisindole cyclic compounds using di-tert-butyldiazididine ketone as an amine source

Abstract

This invention belongs to the field of organic drug synthesis and discloses a method for synthesizing bisindole cyclic compounds using di-tert-butyldiazide ketone as an amine source. Under the protection of an inert gas, 2-(2-iodophenyl)-indole 1, di-tert-butyldiazide ketone 2, a palladium catalyst, a ligand, and a base are added to an organic solvent in a specific ratio and reacted at a heating temperature. After the reaction, the bisindole cyclic compounds shown are prepared, and the target product is separated after the reaction is complete. This invention uses di-tert-butyldiazide ketone as a nitrogen source. This method has the advantages of being simple and novel, and can synthesize a series of bisindole cyclic compounds and their derivatives with high efficiency.

Description

Technical Field

[0001] This invention belongs to the field of organic drug synthesis, specifically relating to a method for synthesizing bisindole cyclocyclic compounds using di-tert-butyldiazidionone as an amine source. Background Technology

[0002] As is well known, indole is an important structural skeleton in nature, and indole and its homologues and derivatives are widely found in nature, such as in natural flower oils, jasmine, and violet. Similarly, bisindole fused-ring compounds and their derivatives, as a type of indole derivative, are also a very important class of nitrogen-containing organic heterocycles with potential biological and pharmaceutical activities. The synthesis and application of bisindole fused-ring compounds and their derivatives have attracted increasing attention. Previous studies have investigated the synthesis of indole compounds using di-tert-butyldiaziridinone as an amine source. However, previous studies mainly synthesized compounds with a single indole skeleton.

[0003] To our knowledge, there are currently no reported methods for synthesizing bisindole cyclic compounds using 2-(2-iodophenyl)-indole as a starting material and di-tert-butyldiaziridinone as a nitrogen source. Here, we utilize novel reaction substrates and, through newly explored and optimized conditions, are able to efficiently synthesize a series of corresponding bisindole cyclic compounds. Summary of the Invention

[0004] This invention proposes a novel synthetic method for bisindole cyclic compounds and their derivatives. Using 2-(2-iodophenyl)-indole as a starting material and a novel reactant, di-tert-butyldiaziridinone, as a nitrogen source, and under conditions of palladium as a catalyst, cesium carbonate as a base, and various phosphorus ligands as ligands, a series of bisindole cyclic compounds and their derivatives can be obtained through the amination reaction of 2-(2-iodophenyl)-indole with di-tert-butyldiaziridinone.

[0005] To achieve the above-mentioned technical objectives and effects, the present invention proposes to implement the following technical solutions:

[0006] A method for synthesizing a bisindole cyclic compound involves adding 2-(2-iodophenyl)-indole 1, di-tert-butyldiazepinene 2, palladium, a ligand, and a base, as shown in formula (1), to an organic solvent under the protection of an inert gas. The reaction is carried out at 90–130 degrees Celsius for several hours to prepare compound 3 as shown in formula (2). After the reaction is complete, the target product, the bisindole cyclic compound, is separated.

[0007]

[0008] In 2-(2-iodophenyl)-indole 1 as shown in formula (1), R1 It is selected from one of the following substituents: hydrogen atom, 5-Me, 5-F, 5-Cl, 5-trifluoromethoxy, 4,6-dimethyl, 4,6-dichloro.

[0009] In 2-(2-iodophenyl)-indole 1 as shown in formula (1), R 2 It is selected from one of the substituents such as hydrogen atom, 4-F, 4-Cl, or 3-Me, 3-Cl.

[0010] In 2-(2-iodophenyl)-indole 1 as shown in formula (1), R 3 Choose one of methyl, ethyl, benzyl, or 2-methylpentenyl.

[0011] The added ingredients, as shown in formula (1), are 2-(2-iodophenyl)-indole 1 (1.0 eq.), di-tert-butyldiazide ketone (1.0 equivalent to 3.0 equivalent), base (1.0 equivalent to 3.0 equivalent), various palladium metals (2.5 mol% to 20.0 mol%), and various phosphine ligands (5 mol% to 20 mol%).

[0012] The organic solvent includes one or more of toluene, 1,4-dioxane, tetrahydrofuran, n-hexane, acetonitrile, or N,N-dimethylformamide. N,N-dimethylformamide is preferred as the solvent.

[0013] The palladium metal mentioned includes one or more of palladium acetate, palladium trifluoroacetate, bis(acetylacetone)palladium, palladium chloride, palladium iodide, or palladium hydroxide. Palladium acetate is preferred as a catalyst.

[0014] The phosphine ligands include PPh3, (o-tolyl)3P, (pF-Ph)3P, PPh2Cy, PCy3, dppb, dppf, etc. (o-tolyl)3P(L1) is preferred as the ligand.

[0015]

[0016] The selected di-tert-butyldiazidionone has the following structure:

[0017]

[0018] The reaction temperature is 90–130°C, and 130°C is more preferably selected as the reaction temperature.

[0019] The prepared bisindole cyclocyclic compound was separated by column chromatography.

[0020] The beneficial results of this invention are as follows: This invention uses palladium as a catalyst and various phosphine ligands as ligands to react 2-(2-iodophenyl)-indole with di-tert-butyldiazide pyridinone under alkaline conditions to obtain the corresponding bisindole cyclic compounds and their derivatives. This synthetic method is simple, easy to operate, has high synthetic efficiency, and is relatively novel. Attached Figure Description

[0021] Figure 1 This is the 5-(tert-butyl)-10-methyl-5,10-dihydroindolo[3,2-b]indole (structural formula 3a) synthesized in Example 1. 1 H NMR spectrum;

[0022] Figure 2 This is the 5-(tert-butyl)-10-methyl-5,10-dihydroindolo[3,2-b]indole (structural formula 3a) synthesized in Example 1. 13 C NMR spectrum;

[0023] Figure 3 This is for the 5-(tert-butyl)-10-ethyl-5,10-dihydroindolo[3,2-b]indole (structural formula 3b) synthesized in Example 2. 1 H NMR spectrum;

[0024] Figure 4 This is for the 5-(tert-butyl)-10-ethyl-5,10-dihydroindolo[3,2-b]indole (structural formula 3b) synthesized in Example 2. 13 C NMR spectrum;

[0025] Figure 5 This is for the 5-benzyl-10-(tert-butyl)-5,10-dihydroindolo[3,2-b]indole (structural formula 3c) synthesized in Example 3. 1 HNMR spectrum;

[0026] Figure 6 This is for the 5-benzyl-10-(tert-butyl)-5,10-dihydroindolo[3,2-b]indole (structural formula 3c) synthesized in Example 3. 13 CNMR spectrum;

[0027] Figure 7 This is the 5-(tert-butyl)-10-(3-methylbut-3-en-1-yl)-5,10-dihydroindolo[3,2-b]indole (structural formula 3d) synthesized in Example 4. 1 H NMR spectrum;

[0028] Figure 8This is the 5-(tert-butyl)-10-(3-methylbut-3-en-1-yl)-5,10-dihydroindolo[3,2-b]indole (structural formula 3d) synthesized in Example 4. 13 C NMR spectrum;

[0029] Figure 9 The 10-(tert-butyl)-3-fluoro-5-(3-methylbut-3-en-1-yl)-5,10-dihydroindolo[3,2-b]indole (structural formula 3e) synthesized in Example 5 1 H NMR spectrum;

[0030] Figure 10 The 10-(tert-butyl)-3-fluoro-5-(3-methylbut-3-en-1-yl)-5,10-dihydroindolo[3,2-b]indole (structural formula 3e) synthesized in Example 5 13 C NMR spectrum;

[0031] Figure 11 This is for the synthesis of 5-(tert-butyl)-2,4-dimethyl-10-(3-methylbut-3-en-1-yl)-5,10-dihydroindolo[3,2-b]indole (structural formula 3f) in Example 6. 1 H NMR spectrum;

[0032] Figure 12 This is for the synthesis of 5-(tert-butyl)-2,4-dimethyl-10-(3-methylbut-3-en-1-yl)-5,10-dihydroindolo[3,2-b]indole (structural formula 3f) in Example 6. 13 C10 NMR spectrum. Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the scope of protection of the invention. The raw materials in Examples 1-6 can all be synthesized using publicly available methods.

[0034] The application principles and implementation examples of the present invention will be described in detail below with reference to the accompanying drawings.

[0035] Example 1: Synthesis of 5-(tert-butyl)-10-methyl-5,10-dihydroindolo[3,2-b]indole (structural formula 3a)

[0036]

[0037] Under argon protection, Pd(OAc)2 (0.0034 g, 0.015 mmol), (o-tolyl)3P(L1) (0.0183 g, 0.060 mmol), Cs2CO3 (0.1466 g, 0.45 mmol), 2-(2-iodophenyl)-1-methylindole with structural formula 1a (0.1000 g, 0.3 mmol), 2.0 mL DMF, and di-tert-butyldiazidimide 2 (0.0766 g, 0.45 mmol) were added sequentially to the reactor. After purging the reaction flask with nitrogen, the flask was sealed with the cap. After reacting at 130℃ for 48 hours, the mixture was cooled to room temperature and subjected to neutral alumina column chromatography under the following conditions: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 100:1, yielding a white solid 3a (0.0812 g, 98% yield) at mp. 92.0-94.4℃.

[0038] The results of the 3a structure confirmation are as follows: 1 H NMR (400MHz, CDCl3) δ8.13(d,J=8.4Hz,1H),8.04(d,J=9.2Hz,2H),7.53(d,J=8.0Hz,1 H),7.44-7.37(m,1H),7.34-7.26(m,2H),7.25-7.19(m,1H),4.20(s,3H),2.12(s,9H); 13 C NMR (100MHz, CDCl3) δ141.5,140.5,128.2,125.1,122.0,121.5,121.0,118.3 ,117.8,117.7,115.7,115.3,114.0,109.6,58.1,31.7,31.5; HRMS(ESI)calcd for C 19 H 21 N2(M+H) + :277.1699; found:277.1694.

[0039] The reaction effects under some other conditions for the synthesis of product 3a in Example 1 are shown below:

[0040]

[0041]

[0042] aUnless otherwise specified, all reaction conditions were as follows: substrate 1a (0.30 mmol), di-tert-butyldiazepinene 2 (0.45 mmol), palladium catalyst (0.015 mmol), ligand (0.060 mmol, Pd / P = 1:4), cesium carbonate (0.45 mmol), in solvent (2.0 mL), at 130°C for 12 hours.

[0043] Example 2: Synthesis of 5-(tert-butyl)-10-ethyl-5,10-dihydroindolo[3,2-b]indole (structural formula 3b)

[0044]

[0045] Under argon protection, Pd(OAc)2 (0.0034 g, 0.015 mmol), (o-tolyl)3P(L1) (0.0183 g, 0.060 mmol), Cs2CO3 (0.1466 g, 0.45 mmol), 2-(2-iodophenyl)-1-ethylindole with structural formula 1b (0.1042 g, 0.3 mmol), 2.0 mL DMF, and di-tert-butyldiazidimide 2 (0.0766 g, 0.45 mmol) were added sequentially to the reactor. After purging the reaction flask with nitrogen, the flask was sealed with the cap. After reacting at 130℃ for 48 hours, the mixture was cooled to room temperature and subjected to neutral alumina column chromatography under the following conditions: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 150:1, yielding a white solid 3b (0.0840 g, 96% yield) mp. 106.3-109.2℃;

[0046] The results of the 3b structure confirmation are as follows: 1 H NMR (400MHz, CDCl3) δ8.03(d,J=8.0Hz,1H),7.94(d,J=8.8Hz,1H),7.86(d,J=7.6Hz,1H),7.45(d,J=8.0Hz,1H),7 .31-7.25(m,1H),7.24-7.17(m,2H),7.16-7.10(m,1H),4.55(q,J=7.2Hz,2H),2.02(s,9H),1.49(t,J=7.2Hz,3H); 13 CNMR (100MHz, CDCl3) δ140.5,140.4,127.2,125.4,121.9,121.5,121.1,118.2,117.9,117.8,115.8,115.1,114.0,109.5,58.1,39.6,31.7,15.3.

[0047] Example 3: Synthesis of 5-benzyl-10-(tert-butyl)-5,10-dihydroindolo[3,2-b]indole (structural formula 3c)

[0048]

[0049] Under argon protection, Pd(OAc)2 (0.0034 g, 0.015 mmol), (o-tolyl)3P(L1) (0.0183 g, 0.060 mmol), Cs2CO3 (0.1466 g, 0.45 mmol), 2-(2-iodophenyl)-1-benzylindole with the structural formula 1C (0.1227 g, 0.3 mmol), 2.0 mL of DMF, and di-tert-butyldiazidimide 2 (0.0766 g, 0.45 mmol) were added sequentially to the reactor. After purging the reaction flask with nitrogen, the flask was sealed with the cap. After reacting at 130°C for 48 hours, the mixture was cooled to room temperature and subjected to neutral alumina column chromatography under the following conditions: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 100:1, yielding a white solid 3c (0.1027 g, 97% yield) mp. 113.7-116.3°C;

[0050] The results of the 3c structure confirmation are as follows: 1 H NMR (400MHz, CDCl3) δ8.05(d,J=8.0Hz,1H),7.93(d,J=8.8Hz,1H),7.67(d,J=7.6Hz,1H), 7.39(d,J=8.0Hz,1H),7.26-7.10(m,8H),7.01(t,J=7.6Hz,1H),5.68(s,2H),2.03(s,9H); 13 C NMR (100MHz, CDCl3) δ141.3,140.6,138.1,129.0,127.8,127.5,126.6,125.5,122.0,121.8 ,121.1,118.7,118.0,117.8,116.0,115.1,114.0,110.0,58.2,48.5,31.7; HRMS(ESI)calcd for C 25 H 25 N2(M+H) + :353.2012,found353.2011.

[0051] Example 4: Synthesis of 5-(tert-butyl)-10-(3-methylbut-3-en-1-yl)-5,10-dihydroindolo[3,2-b]indole (structural formula 3d)

[0052]

[0053] Under argon protection, Pd(OAc)2 (0.0034 g, 0.015 mmol), (o-tolyl)3P(L1) (0.0183 g, 0.060 mmol), Cs2CO3 (0.1466 g, 0.45 mmol), 2-(2-iodophenyl)-1-(3-methylpentenyl)indole (0.1162 g, 0.3 mmol), 2.0 mL DMF, and di-tert-butyldiazidimide 2 (0.0766 g, 0.45 mmol) were added sequentially to the reactor. After purging the reaction flask with nitrogen, the flask was sealed with the cap screwed on. After reacting at 130 °C for 48 hours, the mixture was cooled to room temperature and subjected to silica gel column chromatography under the following conditions: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 50:1, yielding a pale yellow oil 3d (0.0765 g, 77% yield).

[0054] The 3D structure verification results are as follows: 1 H NMR (400MHz, CDCl3) δ8.06(d,J=8.4Hz,1H),7.99(d,J=8.8Hz,1H),7.89(dd,J=7.6,1.2Hz,1H),7.51(d,J=8.4Hz,1H),7.36-7.31 (m,1H),7.28-7.21(m,2H),7.21-7.14(m,1H),4.94-4.89(m,2H),4.69-4.63(m,2H),2.67-2.60(m,2H),2.07(s,9H),1.89(s,3H); 13 C NMR (100MHz, CDCl3) δ142.9,140.7,140.5,127.2,125.5,121.9,121.5,121.2,118.4,117. 9,117.8,115.8,115.1,114.1,112.3,109.6,58.2,44.1,38.0,31.7,23.2; HRMS(ESI)calcd for C 23 H 27 N2(M+H) + 331.2169; found 331.2168.

[0055] Example 5: Synthesis of 10-(tert-butyl)-3-fluoro-5-(3-methylbut-3-en-1-yl)-5,10-dihydroindolo[3,2-b]indole (structural formula 3e)

[0056]

[0057] Under argon protection, Pd(OAc)2 (0.0034 g, 0.015 mmol), (o-tolyl)3P(L1) (0.0183 g, 0.060 mmol), Cs2CO3 (0.1466 g, 0.45 mmol), 2-(5-fluoro-2-iodophenyl)-1-(3-methylpentenyl)-indole (0.1216 g, 0.3 mmol), 2.0 mL DMF, and di-tert-butyldiazidimide 2 (0.0766 g, 0.45 mmol) were added sequentially to the reactor. After purging the reaction flask with nitrogen, the flask was sealed with the cap. After reacting at 130°C for 48 hours, the mixture was cooled to room temperature and subjected to silica gel column chromatography under the following conditions: the column was packed with petroleum ether and the eluent was petroleum ether:ethyl acetate at a ratio of 50:1, yielding a pale yellow oil 3e (0.0797 g, 76% yield).

[0058] The results of the 3e structure confirmation are as follows: 1 H NMR (400MHz, CDCl3) δ8.05(d,J=8.4Hz,1H),7.88(dd,J=9.6,4.4Hz,1H),7.51-7.46(m,2H),7.37-7.31(m,1H),7.23-7.18( 13C NMR (100MHz, CDCl3) δ156.4 (d, J = 232.8), 142.7, 141.0, 137.2, 127.1, 126.9 (d, J = 4.2 Hz), 122.1, 121.4, 118.5, 115. 7,114.7(d,J=9.6Hz),114.6(d,J=8.8Hz),112.5,109.70(d,J=24.7),109.66,102.6(d,J=23.8Hz); HRMS(ESI)calcd forC 23 H 22 F3N2O2(M+H) + :349.2075; found:349.2072.

[0059] Example 6: Synthesis of 5-(tert-butyl)-2,4-dimethyl-10-(3-methylbut-3-en-1-yl)-5,10-dihydroindolo[3,2-b]indole (structural formula 3f)

[0060]

[0061] Under argon protection, Pd(OAc)2 (0.0034 g, 0.015 mmol), (o-tolyl)3P(L1) (0.0183 g, 0.060 mmol), Cs2CO3 (0.1466 g, 0.45 mmol), 2-(2-iodophenyl)-4,6-dimethyl-1-(3-methylpentenyl)-indole (0.1246 g, 0.3 mmol), 2.0 mL DMF, and di-tert-butyldiazidimide 2 (0.0766 g, 0.45 mmol) were added sequentially to the reactor. After purging the reaction flask with nitrogen, the flask was sealed with the cap. After reacting at 130℃ for 48 hours, the mixture was cooled to room temperature and subjected to silica gel column chromatography under the following conditions: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 50:1, yielding a pale yellow solid 3f (0.0832 g, 77% yield) mp. 108.6-109.8℃;

[0062] The results of the 3f structure confirmation are as follows: 1 1H NMR (400MHz, CDCl3) δ7.78-7.69(m,2H),7.21-7.13(m,2H),7.07(s,1H),6.82(s,1H),4.89(s,2H 13C NMR (100MHz, CDCl3) δ146.6,143.0,141.1,131.4,130.1,128.5,128.3,123.3,121.2,119.7,118 .8,118.3,117.2,117.0,112.2,107.1,57.9,44.0,37.9,32.3,24.1,23.2,21.9; HRMS(ESI)calcd for C 24 H 26 N2ONa(M+H) + :359.2482; found:359.2480.

[0063] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing a bisindole cyclocyclic compound, characterized in that: Under the protection of an inert gas, 2-(2-iodophenyl)-indole 1, di-tert-butyldiazepine 2, palladium catalyst, phosphine ligand and base shown in formula (1) are added to an organic solvent in proportion and reacted under heating conditions. After the reaction is completed, the target product bisindole cyclocyclic compound 3 is separated. ； R 1 It is selected from one of the following: hydrogen atom, 5-Me, 5-F, 5-Cl, 5-trifluoromethoxy, 4,6-dimethyl, and 4,6-dichloro substituent; R 2 It is selected from one of the following: hydrogen atom, 4-F, 4-Cl, 3-Me, and 3-Cl substituents; R 3 Selected from alkyl, benzyl, or 2-methylpentenyl; The palladium catalyst is selected from one or more of palladium acetate, palladium trifluoroacetate, bis(acetylacetone)palladium, palladium chloride, palladium iodide, and palladium hydroxide.

2. The method for synthesizing the bisindole cyclocyclic compound according to claim 1, characterized in that: The molar ratio of 2-(2-iodophenyl)-indole 1, di-tert-butyldiazepinene 2, base, palladium catalyst, and phosphine ligand is 1:(1~3):(1~3):(0.025~0.2):(0.05~0.2).

3. The method for synthesizing the bisindole cyclocyclic compound according to claim 1, characterized in that: The organic solvents mentioned include toluene, 1,4-dioxane, tetrahydrofuran, n-hexane, acetonitrile, or... N . N One or more of dimethylformamide.

4. The method for synthesizing the bisindole cyclocyclic compound according to claim 1, characterized in that: The phosphine ligands are selected from PPh3, ( o -tolyl)3P、( p One of the following ligands: -F-Ph)3P, PPh2Cy, PCy3, dppb, and dppf.

5. The method for synthesizing the bisindole cyclocyclic compound according to claim 1, characterized in that: The reaction temperature is 90~130 ℃.

6. The method for synthesizing the bisindole cyclocyclic compound according to claim 1, characterized in that: The base is Cs2CO3.

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