Preparation method of indole [2, 1-a] isoquinolinone compound containing thioester structure
The reaction of iodine indole and sulfonyl chloride compound under mild conditions was successfully synthesized indole [2,1-a]isoquinolinone compound containing thioester structure was successfully synthesized, solving the existing technology The lack of synthesis methods has achieved efficient and highly applicable thioester structure synthesis.
Patent Information
- Application Number
- CN202411182213.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-27
- Publication Date
- 2024-12-13
AI Technical Summary
There is a lack of effective methods in the prior art to synthesize indole [2,1-a]isoquinolinone compounds containing thioester structures, especially when avoiding the use of toxic CO gases and thiols, nickel-catalyzed cyclization. /sulfocarbonylation reaction has not been developed.
Nickel catalyst, ligand, molybdenum carbonyl, alkali, zinc and iodinetoindole react with sulfonyl chloride compounds under mild conditions. Molybdenum carbonyl is used as both a source of carbonyl and a reducing agent, and sulfonate ester is formed by reaction between 90 and 110°C. Structural indole[2,1-a]isoquinolinone compound.
It provides a simple, cheap and widely adaptable synthetic method, avoids the use of toxic gases and thiols, is compatible with a variety of functional groups, improves reaction efficiency and yield, and has strong applicability.
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Abstract
Description
Technical Field
[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for preparing an indole[2,1-a]isoquinolinone compound containing a thioester structure. Background Art
[0002] Thioesters are widely present in a variety of natural products, bioactive molecules and drugs. They can act as active acyl donors and react with different types of nucleophiles to prepare corresponding acyl compounds. For example, as the most common thioester in cells, acetyl-CoA plays an important role in the citric acid cycle. In addition, in natural chemical connections, C-terminal polypeptide thioesters can undergo thioester transfer reactions with N-terminal cysteine to achieve the connection of two polypeptides. In the pharmaceutical field, thioesters represent an important class of functional groups and often appear in a variety of approved drugs. Given the importance of thioesters, people have also developed a strong interest in its synthesis methods. Conventional methods for preparing thioesters mainly include acylation reactions of thiols with carboxylic acids and their derivatives, acid-catalyzed condensation reactions, and metal or organic catalyzed oxidative coupling reactions. In addition, transition metal-catalyzed thiocarbonylation reactions have also become an attractive and efficient method for the synthesis of thioesters. However, due to the odor and catalyst toxicity of thiols, there are still some challenges in using thiols as nucleophiles in the thiocarbonylation process. Therefore, various sulfur sources, including thiosulfates, thioacetates, sulfonyl hydrazides, and sulfonyl chlorides, have been developed to address these issues.
[0003] Indolo[2,1-a]isoquinoline is an important and versatile nitrogen heterocycle that is frequently found in many biomolecules, drugs, and functional materials. Given their exceptional activity, a variety of synthetic strategies have been developed to prepare them. However, the synthesis of indolo[2,1-a]isoquinolinones containing thioester structures has not been developed. Given the research interest in nickel-catalyzed thiocarbonylation and heterocyclic synthesis, we would like to disclose a nickel-catalyzed cyclization / thiocarbonylation reaction to synthesize indolo[2,1-a]isoquinolinones containing thioester structures. Starting from readily available iodoindole and sulfonyl chloride compounds, carbonyl molybdenum was used as both the carbonyl source and the reducing agent, and sulfonyl chloride compounds were used as the sulfur source to synthesize a variety of indolo[2,1-a]isoquinolinones containing thioester structures. The reaction conditions are mild, the substrate adaptability is wide, and the use of toxic CO gas and thiols is avoided, which opens up a new reaction route for the synthesis of indolo[2,1-a]isoquinolinones containing thioester structures. Summary of the invention
[0004] The invention provides a method for preparing an indole[2,1-a]isoquinolinone compound containing a thioester structure. The preparation method has simple steps, and reaction raw materials are cheap and readily available, and the method is compatible with a variety of functional groups and has good reaction applicability. A sulfonyl chloride compound is used as a sulfur source, and carbonyl molybdenum is used as both a carbonyl source and a reducing agent, thereby providing a new direction for the synthesis of an indole[2,1-a]isoquinolinone compound containing a thioester structure.
[0005] A method for preparing an indole[2,1-a]isoquinolinone compound containing a thioester structure comprises the following steps: reacting a nickel catalyst, a ligand, carbonyl molybdenum, a base, zinc, an iodoindole compound and a sulfonyl chloride compound at 90 to 110° C. for 20 to 28 hours, and after the reaction is complete, post-treating to obtain the indole[2,1-a]isoquinolinone compound containing a thioester structure;
[0006] The structure of the iodoindole compound is shown in formula (II):
[0007]
[0008] The structure of the sulfonyl chloride compound is shown in formula (III):
[0009] R 3 -SO2Cl (III);
[0010] The structure of the indole[2,1-a]isoquinolinone compound containing a thioester structure is shown in formula (I):
[0011]
[0012] In formulas (I) to (III), R 1 is one or more of H, C1-C4 alkyl or halogen; R 2 is C1-C4 alkyl, phenyl or benzyl; R 3 is C1-C4 alkyl, C3-C6 cycloalkyl, substituted or unsubstituted aryl;
[0013] The substituent on the aryl group is C1-C4 alkyl, C1-C4 alkoxy, trifluoromethoxy or halogen.
[0014] Preferably, the ligand is terpyridine.
[0015] Preferably, the base is sodium acetate.
[0016] The molar ratio of the nickel catalyst, terpyridine and sodium acetate is 0.1:0.1:1.5;
[0017] R 1 The substitution position is 4 to 7; R 3The substitution position on the aryl group is para or meta.
[0018] The reaction formula is as follows:
[0019]
[0020] In the present invention, the optional post-treatment process includes: filtration, silica gel mixing, and finally column chromatography purification to obtain the corresponding indole [2,1-a] isoquinolinone compound containing a thioester structure. Column chromatography purification is a commonly used technical means in the art.
[0021] As a preference, R 1 is one or more of H, F, methyl or Cl; R 2 is methyl, phenyl or benzyl. In this case, the iodoindole compound is easy to obtain and the reaction yield is high.
[0022] As a preference, R 3 is butyl, cyclopropyl, substituted or unsubstituted phenyl, and the substituent on the phenyl is methyl, methoxy, trifluoromethoxy, F or Br. In this case, the sulfonyl chloride compound is easy to obtain and the reaction yield is high.
[0023] The iodoindole compound and sulfonyl chloride compound used to prepare the indole [2,1-a] isoquinolinone compound containing a thioester structure are relatively cheap and widely exist in nature. Preferably, the iodoindole compound: sulfonyl chloride compound: nickel catalyst is 1:1.2-1.5:0.05-0.1 on a molar basis; and further preferably, the iodoindole compound: sulfonyl chloride compound: nickel catalyst is 1:1.5:0.1 on a molar basis.
[0024] Preferably, the reaction time is 24 hours. Too long a reaction time will increase the reaction cost, and conversely it will be difficult to ensure the completeness of the reaction.
[0025] Preferably, the reaction is carried out in acetonitrile, and the amount of acetonitrile used is sufficient to dissolve the raw materials well, and the amount of acetonitrile used for 0.2 mmol of iodoindole compound is about 1-2 mL.
[0026] Preferably, the nickel catalyst is nickel acetylacetonate. Among various nickel catalysts, nickel acetylacetonate is relatively cheap, and the reaction efficiency is higher when nickel acetylacetonate is used as a catalyst.
[0027] As a further preference, the indole[2,1-a]isoquinolinone compound containing a thioester structure is one of the compounds represented by formula (I-1) to formula (I-5):
[0028]
[0029] In the above preparation method, the sulfonyl chloride compound, carbonyl molybdenum, nickel acetylacetonate, terpyridine, zinc and sodium acetate are generally commercially available products and can be easily obtained from the market.
[0030] Compared with the prior art, the beneficial effects of the present invention are as follows: using sulfonyl chloride compounds as sulfur sources, the preparation method is simple, easy to operate, simple post-treatment, cheap and easy to obtain reaction starting materials, wide tolerance range of substrate functional groups, and high reaction efficiency. A variety of indole [2,1-a] isoquinolinone compounds containing thioester structures can be synthesized according to actual needs, and the practicability is strong. BRIEF DESCRIPTION OF THE DRAWINGS
[0031] Figure 1 The hydrogen spectrum and carbon spectrum of the product obtained in Example 1;
[0032] Figure 2 The hydrogen spectrum and carbon spectrum of the product obtained in Example 2;
[0033] Figure 3 The hydrogen spectrum and carbon spectrum of the product obtained in Example 3;
[0034] Figure 4 The hydrogen spectrum and carbon spectrum of the product obtained in Example 4;
[0035] Figure 5 The hydrogen spectrum and carbon spectrum of the product obtained in Example 5 are shown below. DETAILED DESCRIPTION
[0036] The present invention is further described below in conjunction with specific embodiments.
[0037] Examples 1 to 15
[0038] According to the raw material ratio in Table 1, nickel acetylacetonate, terpyridine, carbonyl molybdenum, sodium acetate, zinc, iodoindole compound (II) and sulfonyl chloride compound (III) were added to a 15 mL sealed tube, and then acetonitrile (2 mL) was added, mixed and stirred evenly, and reacted according to the reaction conditions in Table 2. After the reaction was completed, the mixture was filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding indole [2,1-a] isoquinolinone compound (I) containing a thioester structure. The reaction process is shown in the following formula:
[0039]
[0040] Table 1 Amount of raw materials added in Examples 1 to 15
[0041]
[0042] Table 2
[0043]
[0044]
[0045] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Me is a methyl group, Ph is a phenyl group, Bu is a butyl group, OMe is a methoxy group, and OCF3 is a trifluoromethoxy group.
[0046] The structural confirmation data of the compounds prepared in Examples 1 to 5 are as follows:
[0047] The NMR ( 1 H NMR and 13 C NMR) detection data are:
[0048]
[0049] 1 H NMR(400MHz, CDCl3)δ8.56(d,J=8.0Hz,1H),7.85–7.83(m,1H),7.57(d,1H),7.38–7.33(m,4H),7.32–7.28(m, 1H),7.08–7.04(m,4H),7.01(s,1H),4.07(d,J=16.9Hz,1H),3.57(d,J=16.9Hz,1H),2.25(s,3H),1.63(s,3H).
[0050] 13 C NMR (101MHz, CDCl3) δ194.5,172.0,139.7,137.1,135.4,135.3,134.3,130.6,129.9,128. 7,127.4,125.0,124.6,124.4,124.1,123.3,120.3,116.7,103.2,52.3,46.7,30.2,21.2.
[0051] The NMR ( 1 H NMR and 13 C NMR) detection data are:
[0052]
[0053] 1H NMR (400MHz, CDCl3) δ8.54(d,J=8.0Hz,1H),7.86–7.84(m,1H),7.58(d,J=7.1Hz,1H),7.38–7.33(m,6H),7.30(td, J=7.4,1.1Hz,1H),7.02(d,J=4.4Hz,2H),6.99(s,1H),4.07(d,J=16.9Hz,1H),3.56(d,J=16.9Hz,1H),1.63(s,3H).
[0054] 13 C NMR (101MHz, CDCl3) δ193.5,171.9,137.0,135.8,135.4,135.2,132.3,130.6,128.8,127. 5,125.8,125.2,125.0,124.6,124.5,124.2,124.1,120.4,116.7,103.4,52.5,46.7,30.2.
[0055] The NMR ( 1 H NMR and 13 C NMR) detection data are:
[0056]
[0057] 1 H NMR (400MHz, CDCl3) δ8.58(d,J=8.0Hz,1H),7.88–7.85(m,1H),7.60(d,J=7.5Hz,1H),7.39–7.30(m,5H),7.05(s,1H),3.95(d,J= 16.6Hz,1H),3.44(d,J=16.6Hz,1H),2.70–2.58(m,2H),1.61(s,3H),1.30–1.26(m,2H),1.19–1.10(m,2H),0.76(t,J=7.3Hz,3H).
[0058] 13 C NMR (101MHz, CDCl3) δ195.9,172.2,137.3,135.5,135.4,130.7,128.7,127.3,125.3,12 5.1,124.6,124.4,124.0,120.4,116.7,103.1,53.1,46.7,31.2,30.1,28.5,21.6,13.4.
[0059] The NMR ( 1 H NMR and 13 C NMR) detection data are:
[0060]
[0061] 1 H NMR(400MHz, CDCl3)δ8.41(d,J=8.4Hz,1H),7.83–7.81(m,1H),7.35–7.31(m,4H),7.17(d,J=8.4Hz,1H),7.08–7 .03(m,4H),6.94(s,1H),4.05(d,J=16.9Hz,1H),3.55(d,J=16.8Hz,1H),2.46(s,3H),2.26(s,3H),1.61(s,3H).
[0062] 13 C NMR (101MHz, CDCl3) δ194.5,171.8,139.6,137.1,135.4,134.3,133.9,133.7,130.8,129.9,128 .6,127.3,126.4,125.1,124.8,124.0,123.3,120.3,116.3,103.0,52.3,46.6,30.2,21.4,21.2.
[0063] The NMR ( 1 H NMR and 13 C NMR) detection data are:
[0064]
[0065] 1 H NMR (400MHz, CDCl3) δ8.49(dd,J=9.0,4.8Hz,1H),7.82(d,J=7.3Hz,1H),7.42–7.33(m,3H),7.21(dd,J=8.8,2.5H z,1H),7.07–7.02(m,5H),6.95(s,1H),4.04(d,J=16.9Hz,1H),3.57(d,J=16.9Hz,1H),2.25(s,3H),1.62(s,3H).
[0066] 13C NMR(101MHz,CDCl3)δ194.6,171.9,160.18(d,J=240.6Hz),139.8,137.4,136.9,134.3,131.8,131.7,129.9,129.1,127.5,125.1,124.3,124.2,123.2,117.68(d,J=9.2Hz),112.52(d,J=24.8Hz),105.95(d,J=24.1Hz),102.67(d,J=4.0Hz),52.4,46.6,30.2,21.2。
Claims
1. A method for preparing an indole[2,1-a]isoquinolinone compound containing a thioester structure, characterized in that: The method comprises the following steps: reacting a nickel catalyst, a ligand, carbonyl molybdenum, a base, zinc, an iodoindole compound and a sulfonyl chloride compound at 90 to 100° C. for 20 to 28 hours, and after the reaction is complete, post-treating to obtain the indole [2,1-a] isoquinolinone compound containing a thioester structure; The structure of the iodoindole compound is shown in formula (II): The structure of the sulfonyl chloride compound is shown in formula (III): R 3 -SO2Cl (III); The structure of the indole[2,1-a]isoquinolinone compound containing a thioester structure is shown in formula (I): In formulas (I) to (III), R 1 is one or more of H, C1-C4 alkyl or halogen; R 2 is C1-C4 alkyl, phenyl or benzyl; R 3 is C1-C4 alkyl, C3-C6 cycloalkyl, substituted or unsubstituted aryl; The substituent on the aryl group is C1-C4 alkyl, C1-C4 alkoxy, trifluoromethoxy or halogen.
2. The method for preparing an indole[2,1-a]isoquinolinone compound containing a thioester structure according to claim 1, characterized in that: R 1 is one or more of H, F, methyl or Cl; R 2 It is methyl, phenyl or benzyl.
3. The method for preparing the indole[2,1-a]isoquinolinone compound containing a thioester structure according to claim 1, characterized in that: R 3 is butyl, cyclopropyl, substituted or unsubstituted phenyl, and the substituent on the phenyl is methyl, methoxy, trifluoromethoxy, F or Br.
4. The method for preparing an indole[2,1-a]isoquinolinone compound containing a thioester structure according to claim 1, characterized in that: In terms of molar amount, the ratio of iodoindole compound: sulfonyl chloride compound: carbonyl molybdenum: nickel catalyst: ligand: base: zinc is 1:1.2-1.5:1.5-2:0.05-0.1:0.05-0.1:1.5-2:1-2.
5. The method for preparing the indole[2,1-a]isoquinolinone compound containing a thioester structure according to claim 1, characterized in that: The reaction used acetonitrile as solvent.
6. The method for preparing the indole[2,1-a]isoquinolinone compound containing a thioester structure according to claim 1, characterized in that: The nickel catalyst is nickel acetylacetonate.
7. The method for preparing the indole[2,1-a]isoquinolinone compound containing a thioester structure according to claim 1, characterized in that: The ligand is terpyridine.
8. The method for preparing the indole[2,1-a]isoquinolinone compound containing a thioester structure according to claim 1, characterized in that: The alkali is sodium acetate.
9. The method for preparing an indole[2,1-a]isoquinolinone compound containing a thioester structure according to claim 1, characterized in that: The indole[2,1-a]isoquinolinone compound containing a thioester structure is one of the compounds represented by formula (I-1) to formula (I-5):