Method for synthesizing 3-acylindole azines by electrochemical intramolecular oxidative amination of alkynes

Abstract

The invention discloses a method for synthesizing 3-acylindoleazine compounds by electrochemical intramolecular alkyne oxidation amination, and belongs to the field of organic chemistry. In a non-separation electrolytic cell, a 2-(heterocyclic-2-yl)pent-4-ynoic acid ester compound 1 is used as a raw material, and a constant current electrolysis reaction is carried out in a tetrahydrofuran / water mixed solvent in the presence of ammonium iodide to obtain a 3-acylindoleazine compound 2; the method of the invention has mild reaction conditions, is environmentally friendly, has a high yield, and has good purity, and can obtain an intramolecular alkyne oxidation amination cyclization product, thereby providing a simple and effective synthesis route for indoleazine compounds.

Description

Technical Field

[0001] The invention relates to a method for preparing 3-acylindoleazines, in particular to a method for synthesizing 3-acylindoleazines by electrochemical intramolecular oxidative amination of alkynes, and belongs to the field of organic chemistry. Background Art

[0002] Nitrogen-containing heterocyclic compounds are key structural units of natural products and drug molecules. The skeleton construction of such compounds has attracted considerable attention in the past few decades. 3-Acylindolizine compounds are important nitrogen heterocyclic compounds with a wide range of drug activities, including anticonvulsant, anti-tuberculosis, anti-HIV, anti-tumor and anti-malarial activities.

[0003] The research on the synthesis of 3-acylindolezines is still insufficient. In 2007, the literature reported a method for synthesizing 3-acylindolezines by intramolecular tandem cyclization reaction mediated by iodine (Tetrahedron Letters, 2007, 48(51):8976-8981). In 2012, the literature reported the synthesis of 3-acylindolezines by copper-catalyzed [3+2] cyclization reaction of pyridine ylides and electron-deficient olefins (RSC Advances, 2012, 2(23):8637-8644). In 2019, the literature reported the synthesis of 3-acylindolezines by intermolecular cyclization reaction of pyridine-2-acetate and acetylaldehyde (The Journal of Organic Chemistry, 2019, 84(5):2962-2968). However, the above methods have the following problems: limited substrate scope, poor functional group compatibility, increased temperature, low reaction efficiency or potential safety issues; the use of additional supporting electrolytes, transition metal catalysts and external oxidants.

[0004] Therefore, it is very necessary to conduct in-depth research on the development of new green oxidation systems to construct 3-acylindolizine compounds. Summary of the invention

[0005] In order to overcome the above technical defects, the present invention discloses a method for preparing 3-acylindolizine compounds; the preparation method obtains an intramolecular alkyne oxidation amination cyclization product under electric anode oxidation conditions and under the catalysis of ammonium iodide; the method has mild reaction conditions, is environmentally friendly, has high yield, good purity, and is suitable for industrial production.

[0006] The present invention provides a method for synthesizing 3-acylindole azines, comprising the following steps: in a non-separating electrolytic cell, using a 2-(heterocyclic-2-yl)pent-4-ynoic acid ester compound 1 as a raw material, and subjecting it to a constant current electrolytic reaction in a solvent in the presence of an iodide to obtain a 3-acylindole azines compound 2; the reaction equation is as follows:

[0007]

[0008] Wherein: R1 is selected from carboxylic acid ester group, amide group, acetyl group, ester group is selected from methyl ester, ethyl ester, isopropyl ester, tert-butyl ester, tert-amyl ester, trifluoroethyl ester, benzyl ester, diphenylmethyl ester, allyl ester, propargyl ester, menthol ester, fenchol ester, ribose ester, galactose ester, epiandrosterone ester, amide group is selected from acetanilide and acetylbenzylamide. R2 is selected from hydrogen, phenyl, substituted phenyl, naphthalene, thiophene, pyridine, furan, benzofuran, C1-C7 alkyl, trimethylsilyl, and the substituent of substituted phenyl is selected from one or more of C1-C4 alkyl, alkoxy, phenyl, halogen, ester group, cyano, nitro, trifluoromethyl. Het is pyrazine, pyrimidine, pyridazine, quinoline, isoquinoline.

[0009] Furthermore, in the above technical solution, the halogen is selected from fluorine, chlorine and bromine.

[0010] Furthermore, in the above technical solution, the solvent is selected from tetrahydrofuran or a tetrahydrofuran / water mixed solvent. Under preferred conditions, the volume ratio of the tetrahydrofuran / water mixed solvent is 1-10:1.

[0011] Furthermore, in the above technical solution, the iodide is selected from sodium iodide, potassium iodide, 1,3-dimethylimidazolium iodide, hydroiodic acid or ammonium iodide, preferably ammonium iodide.

[0012] Furthermore, in the above technical solution, the constant current means that the output current of the power supply is constant, and the constant current output current is 4mA-7mA, preferably 5mA.

[0013] Furthermore, in the above technical solution, the molar ratio of the 2-(heterocyclo-2-yl)pent-4-ynoic acid ester compound 1 to the iodide salt is 1:0.5.

[0014] Furthermore, in the above technical solution, the constant current electrolysis reaction temperature is selected from 20-30°C.

[0015] Furthermore, in the above technical solution, the electrode anode material is selected from platinum sheet, RVC (reticulated glassy carbon), GF (carbon felt), graphite carbon rod, preferably platinum sheet.

[0016] Furthermore, in the above technical solution, the electrode cathode material is selected from platinum sheet, nickel foam, iron sheet, graphite carbon rod, preferably platinum sheet.

[0017] Furthermore, in the above technical solution, in the constant current electrolysis reaction, the progress of the reaction can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the reaction endpoint is generally when the compound disappears or no longer reacts.

[0018] Furthermore, in the above technical solution, if a crude compound is obtained after the reaction, it can be separated and purified by conventional means such as preparative HPLC, preparative TLC or recrystallization.

[0019] Advantageous Effects of the Invention

[0020] The invention avoids the use of traditional expensive oxidants, and obtains a wide variety of 3-acylindolizine compounds with high yield and good purity, thus having potential prospect for enlarged application. DETAILED DESCRIPTION

[0021] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0022] Example 1

[0023] Condition optimization experiment

[0024]

[0025]

[0026] a The reaction conditions were as follows: substrate 1a (55.9 mg, 0.2 mmol), NH4I (14.5 mg, 50 mol%), THF / H2O (3 / 0.3 mL) mixed solvent system, two platinum sheets (1.0 × 1.5 × 0.02 cm 3 ) were used as anode and cathode, respectively, in an undivided electrolytic cell, with a constant current of 5 mA, and powered on for 9 hours at room temperature; b Dibromomethane was used as an internal standard to determine the NMR yield; c The numbers in brackets are the isolated yields; d No response.

[0027] Finally, the optimal conditions were determined: both cathode and anode used platinum electrodes (1.0×1.5×0.02cm 3 ), compound 1a (0.20 mmol), NH4I (50 mol%), THF / H2O (3 / 0.3), and 5 mA were reacted at 27°C for 9 h.

[0028] Example 2

[0029]

[0030] In a non-divided electrolytic cell, substrate 1a (55.9 mg, 0.20 mmol) and NH4I (14.5 mg, 0.1 mmol, 50 mol%) were dissolved in a mixed solvent of THF / H2O (3 mL / 0.3 mL). The electrolysis was carried out at 27 °C (oil bath temperature) using a constant current of 5.0 mA until the substrate was completely consumed (by TLC or 1 H NMR analysis and monitoring). After the reaction, the solvent was removed under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (PE / EA: 15 / 1) to obtain a yellow solid 2a (52.8 mg, yield 90%). 1 HNMR(400MHz, CDCl3)δ9.95(dt,J=1.2,7.2Hz,1H),8.37(dt,J=1.2,9.2Hz,1H),7.90-7.73(m,3H),7.59-7.53(m,1H),7.52 -7.46(m,2H),7.42(ddd,J=1.2,6.8,8.8Hz,1H),7.06(td,J=1.6,7.2Hz,1H),4.36(q,J=6.8Hz,2H),1.38(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ185.6,164.1,140.0,139.9,131.5,129.2,129.0,128.5,127.7,122.6,119.5,115.3,106.3,60.2,14.6.

[0031] Example 3

[0032]

[0033] The same reaction conditions as in Example 2 were used to obtain 2r (70.4 mg, yield 82%) as a white solid starting from 1r (83.1 mg, 0.2 mmol). 1 H NMR (400MHz, CDCl3) δ9.94(dt,J=1.2,7.2Hz,1H),8.43(dt,J=4.2,9.2Hz,1H),8.27-8.22(m,2H),8.14-8.04(m,1H),7. 70(s,1H),7.53(ddd,J=1.2,6.8,10.4Hz,1H),7.16(td,J=1.6,7.2Hz,1H),4.38(q,J=7.2Hz,2H),1.39(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ181.8,163.7,141.9,140.6,132.1(q,J C-F=33Hz),129.4,129.1,129.0(d,J C-F =4Hz),128.8,127.2,124.9(quint,J C-F =4Hz),124.5,121.8,121.6,119.9,119.1,116.2,107.6,60.5,14.6. 19 F NMR (376MHz, CDCl3)δ-107.7.

[0034] Example 4

[0035]

[0036] The same reaction conditions as in Example 2 were used to obtain a yellow solid 2x (51.1 mg, yield 80%) from 1x (66.1 mg, 0.2 mmol). 1 H NMR (400MHz, CDCl3) δ10.07(dt,J=1.2,6.8Hz,1H),8.65(s,1H),8.42(dt,J=1.2,8.8Hz,1H),7.74(dt,J=0.8,8.0Hz,1H),7.69(dq,J=0.8,8.4Hz ,1H),7.66(d,J=0.8Hz,1H),7.48(dddd,J=1.2,2.0,7.2,8.4Hz,2H),7.33(ddd,J=0.8,7.2,8.0Hz,1H),7.11(td,J=1.6,7.2Hz,1H),3.97(s,3H). 13 C NMR (100MHz, CDCl3) δ172.1,164.6,155.8,153.8,140.2,129.6,128.4,128.3 ,127.7,127.3,124.0,123.0,122.0,119.7,115.7,113.5,112.5,106.9,51.5.

[0037] Example 5

[0038]

[0039] The same reaction conditions as in Example 2 were used to obtain brown-yellow solid 2ab (42.2 mg, yield 86%) from 1ab (46.3 mg, 0.2 mmol). 1H NMR (600MHz, CDCl3) δ9.91(dt,J=1.2,7.2Hz,1H),8.32(dt,J=1.2,9.0Hz,1H),8.00(s,1H),7.37(ddd,J=1.2,7.2,9.0Hz,1 H),7.00(td,J=1.2,6.6Hz,1H),4.39(q,J=7.2Hz,2H),2.95(q,J=7.8Hz,2H),1.42(t,J=7.2Hz,3H),1.26(t,J=7.2Hz,3H). 13 C NMR (150MHz, CDCl3) δ191.6,164.3,139.3,129.2,127.2,125.5,122.4,119.5,115.2,105.7,60.2,32.6,14.7,9.4.

[0040] Example 6

[0041]

[0042] The same reaction conditions as in Example 2 were used to obtain 2ah (47.0 mg, yield 77%) as a brown-yellow solid starting from 1ah (58.3 mg, 0.2 mmol). 1 H NMR(400MHz, CDCl3)δ9.96(dt,J=1.2,7.2Hz,1H),8.39(dt,J=1.2,9.2Hz,1H),7.89-7.74(m,3H),7.61-7.41(m,4H),7.08(td, J=1.6,7.2Hz,1H),6.14-5.95(m,1H),5.39(dq,J=1.6,17.2Hz,1H),5.27(dq,J=1.2,10.4Hz,1H),4.82(dt,J=1.2,6.0Hz,2H). 13 C NMR (100MHz, CDCl3) δ185.7,163.7,140.1,140.0,132.8,131.6,129.3,129.1,129.1,128.5,127.9,122.7,119.6,118.2,115.5,105.9,64.9.

[0043] Example 7

[0044]

[0045] The same reaction conditions as in Example 2 were used to obtain 2ap (51.2 mg, yield 80%) as a brown-yellow solid from 1ap (98.7 mg, 0.2 mmol). 1H NMR(400MHz, CDCl3)δ9.96(dt,J=1.2,7.2Hz,1H),8.42(dt,J=1.2,9.2Hz,1H),7.85(s,1H),7.83-7.77(m, 2H),7.59-7.53(m,1H),7.53-7.40(m,3H),7.08(td,J=1.2,7.2Hz,1H),5.57(d,J=4.8Hz,1H),4.64(dd,J= 2.4,7.6Hz,1H),4.52(dd,J=4.0,11.6Hz,1H),4.43(dd,J=8.0,11.6Hz,1H),4.34(dd,J=2.4,4.8Hz,1H),4 .31(dd,J=2.0,8.0Hz,1H),4.21(ddd,J=2.0,4.0,8.0Hz,1H),1.48(d,J=5.6Hz,6H),1.33(d,J=6.8Hz,6H). 13 C NMR (100MHz, CDCl3) δ185.7,163.9,140.0,140.0,131.6,129.5,129.3,129.1,128.5,127.9,122. 8,119.9,115.4,109.8,108.9,106.1,96.5,71.3,70.9,70.7,66.6,63.6,26.1,26.1,25.1,24.5.

[0046] Example 8

[0047]

[0048] The same reaction conditions as in Example 2 were used to obtain pale yellow solid 2ag (48.1 mg, yield 90%) from 1ag (50.7 mg, 0.2 mmol). 1 H NMR (400MHz, CDCl3) δ9.86-9.79 (m, 1H), 9.76 (s, 1H), 9.42 (d, J = 7.2Hz, 1H), 7.95 (s, 1H), 7.73-7. 69(m,1H),7.68-7.60(m,2H),7.20(d,J=7.6Hz,1H),4.42(q,J=7.2Hz,2H),1.45(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ179.2,164.3,137.4,131.3,130.9,129.7,128.5,128.1,126.9,124.7,124.6,124.5,116.1,111.6,60.8,14.6.

[0049] Example 9

[0050] Using the same reaction conditions as in Example 2 above, only the reaction substrate was changed to obtain a variety of substituted compounds. The reaction results are as follows:

[0051]

[0052]

[0053]

[0054] The above embodiments describe 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 by the above embodiments, and the contents described in the above embodiments and the specification are only for explaining the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing 3-acylindole azines, It is characterized in that The method comprises the following steps: in a non-separation electrolytic cell, using a 2-(heterocyclic-2-yl)pent-4-ynoic acid ester compound 1 as a raw material, and subjecting it to a constant current electrolytic reaction in a solvent in the presence of an iodide to obtain a 3-acylindolizine compound 2; the reaction equation is as follows: Where: R 1 is selected from carboxylic acid ester group, amide group, acetyl group, ester group is methyl ester, ethyl ester, isopropyl ester, tert-butyl ester, tert-amyl ester, trifluoroethyl ester, benzyl ester, diphenylmethyl ester, allyl ester, propargyl ester, menthol ester, fenchol ester, ribose ester, galactose ester, and epiandrosterone ester, and amide group is selected from acetanilide and acetylbenzylamide; R 2 is selected from hydrogen, phenyl, substituted phenyl, naphthalene, thiophene, pyridine, furan, benzofuran, C 1 -C 7 Alkyl, trimethylsilyl, substituted phenyl substituents selected from C 1 -C 4 One or more of alkyl, alkoxy, phenyl, halogen, ester, cyano, nitro, trifluoromethyl; Het is pyrazine, pyrimidine, pyridazine, quinoline, isoquinoline; the solvent is selected from tetrahydrofuran or a tetrahydrofuran / water mixed solvent; the electrode cathode material is platinum sheet.

2. The method for synthesizing 3-acylindole azines according to claim 1, Features: The halogen is selected from fluorine, chlorine or bromine.

3. The method for synthesizing 3-acylindole azines according to claim 1, Features: The volume ratio of the tetrahydrofuran / water mixed solvent is 1-10:

1.

4. The method for synthesizing 3-acylindole azines according to claim 1, Features: The iodide is selected from sodium iodide, potassium iodide, 1,3-dimethylimidazolium iodide, hydroiodic acid or ammonium iodide.

5. The method for synthesizing 3-acylindole azines according to claim 1, Features: The molar ratio of the 2-(heterocyclic-2-yl)pent-4-ynoic acid ester compound 1 to the iodide is 1:0.

5.

6. The method for synthesizing 3-acylindole azines according to claim 1, Features: The constant current refers to that the current output by the power supply remains constant, and the constant current output current is 4mA-7mA.

7. The method for synthesizing 3-acylindole azines according to claim 1, Features: The electrolysis reaction temperature is 20-30°C.

8. The method for synthesizing 3-acylindole azines according to claim 1, Features: The electrode anode material is selected from platinum sheets, mesh glassy carbon, carbon felt, and graphite carbon rods.

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