CN117088814A - Preparation method of trifluoro-methyl sulfide aza-8/9 membered ring compound - Google Patents

Preparation method of trifluoro-methyl sulfide aza-8/9 membered ring compound Download PDF

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CN117088814A
CN117088814A CN202310123910.8A CN202310123910A CN117088814A CN 117088814 A CN117088814 A CN 117088814A CN 202310123910 A CN202310123910 A CN 202310123910A CN 117088814 A CN117088814 A CN 117088814A
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phenyl
methyl
phenylvinyl
methylbenzenesulfonamide
benzenesulfonamide
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Inventor
张震
方相山
阿依姆妮萨·艾力
朱亚茹
林万军
唐军红
陈锦春
孙凯
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Yantai University
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Yantai University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/06—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with one six-membered ring

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present specification discloses a process for the preparation of a trifluoro-methyl-aza-8/9 membered ring compound, a modifiable diene substrate and AgSCF 3 At K 2 S 2 O 8 And HMPA to perform serial cyclization reaction to obtain the target product in one step. The substrate can selectively realize the synthesis of 8-membered and 9-membered trifluoro-methyl nitrogen sulfide heterocycle through extending the carbon chain. The invention provides a new preparation technical route. The preparation method has the advantages of simple reaction process, mild conditions, no strict anhydrous and anaerobic conditions and strong operability; the substrate universality is high, and the potential of large-scale application is high.

Description

Preparation method of trifluoro-methyl sulfide aza-8/9 membered ring compound
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a trifluoro methyl sulfide aza-8/9 membered ring compound.
Background
Trifluoromethylthio (SC)F 3 ) Is a special fluorine-containing group, and has attracted wide attention in pharmaceutical chemistry and material science due to its high electronegativity, lipophilicity and metabolic stability. SCF is carried out 3 The incorporation of organic molecules will significantly improve the physical, chemical and physiological properties of the parent molecule. Typically, agSCF 3 The participating tandem cyclization reaction is to prepare various SCF-containing products 3 Powerful strategies for heterocycles. To our knowledge, more than 50 documents have been published in this field in recent years. But the research content mainly relates to the construction of 5-membered and 6-membered heterocycles, for SCF-containing 3 The preparation of the intermediate ring compound is less explored.
It is well known that medium ring compounds, in particular 8-and 9-membered ring compounds, are of great importance in the fields of life sciences, medicine, pesticides and materials. For example, T (+) -Balasubramide has powerful antioxidant and anti-inflammatory effects; rhazinilam can significantly inhibit proliferation of activated human T cells. In view of the abundant application, the development of the efficient synthesis method of the trifluoro methyl sulfide intermediate ring compound has important application value and prospect. Recently, wu and Li groups independently reported the use of aryl acetylene substrates for trifluoromethanesulfide/free radical cascade cyclization to obtain SCF-containing 3 Dioxybenzothiazine or dibenzoazozine derivatives (chem. Commun.2022,58,8674-8677; J. Org. Chem.2022,87, 8773-8781). However, the reported cyclization reaction only covers 7-membered heterocycle, and the synthesis of 8-membered and 9-membered ring system molecules cannot be realized due to the large limitation of reaction substrates, so that the structure type is single. Furthermore, reported cases employ an alkynyl-aryl ring system, which requires two aryl groups to participate, further limiting the substrate applicability of the reaction. Therefore, there is an urgent need for a process for synthesizing benzotrifluoride cyclic molecules that is ubiquitous and efficient.
Disclosure of Invention
The invention aims to provide a simple and efficient preparation method of a trifluoro-methyl sulfide aza-8/9 membered ring compound.
With a modifiable diene substrate and silver triflate thiolate (AgSCF) 3 ) As a base material, in potassium persulfate (K) 2 S 2 O 8 ) And hexamethylphosphoric triamide (HMPA) to obtain the trifluoro-aza-8/9 membered ring compound with different substitution. The preparation method provided by the invention has the advantages that the reaction process is simple, and the conditions are mild; strict anhydrous and anaerobic conditions are not required, and the operability is strong; the substrate universality is high, and the potential of large-scale application is high.
The technical scheme of the invention is as follows:
a process for preparing a trifluoromethaneaza-8/9 membered ring compound represented by the formula (I),
wherein,
R 1 selected from alkyl, alkoxy, halogen;
R 2 selected from sulfonyl groups;
R 3 selected from aryl groups;
wherein,
mixing a compound (diene compound having different carbon chains) represented by the formula (II) with AgSCF 3 At K 2 S 2 O 8 And HMPA in a solvent to obtain a compound shown in a formula (I):
wherein,
R 1 、R 2 and R is 3 Is defined as in formula (I).
According to the present invention, the aryl group may be a substituted or unsubstituted aryl group; the aromatic group may have one or more substituents, and the position of the substituent is not particularly limited, and may be ortho, meta or para; the substituents are not limited in any way, and common substituents are, for example, alkyl groups, alkoxy groups, disubstituted amine groups, nitro groups, cyano groups, ester groups, aldehyde groups, ketocarbonyl groups, halogen atoms, and the like; when having multiple substituents, the multiple substituents may be the same or different, and adjacent two substituents may be independent of each other or form a ring.
According to the present invention, the alkyl group may be a substituted or unsubstituted primary, secondary or tertiary alkyl group; the substituents are not limited in any way, and common substituents are, for example, alkyl groups, alkoxy groups, disubstituted amine groups, nitro groups, cyano groups, ester groups, aldehyde groups, ketocarbonyl groups, halogen atoms, and the like; when having multiple substituents, the multiple substituents may be the same or different, and two adjacent or similar substituents may be independent of each other or form a ring.
According to the invention, the sulfonyl group, the sulfur atom may be substituted with an alkyl or aryl group. The substituents are not limited in any way, and common substituents are, for example, alkyl groups, alkoxy groups, disubstituted amine groups, nitro groups, cyano groups, ester groups, aldehyde groups, ketocarbonyl groups, halogen atoms, and the like; when having multiple substituents, the multiple substituents may be the same or different, and two adjacent or similar substituents may be independent of each other or form a ring.
According to the invention, the alkyl group preferably means an alkyl group having 1 to 10 carbon atoms, and the substituent on the alkyl group is preferably an alkoxy group, a nitro group, a cyano group, an ester group, an aldehyde group, a ketocarbonyl group and a halogen atom, more preferably a halogen atom such as fluorine, chlorine, bromine, and the alkyl group is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, a pentyl group, a neopentyl group, a halogenated C group 1-10 An alkyl group.
According to the invention, the aryl group is preferably a monocyclic or bicyclic aryl group, more preferably an aryl group of 6 to 14 carbon atoms, such as phenyl or naphthyl. The substituents on the aryl group are preferably alkyl groups, alkoxy groups, nitro groups, cyano groups, ester groups, aldehyde groups, ketocarbonyl groups and halogen atoms.
According to the invention, the sulfonyl group preferably refers to arylsulfonyl and alkylsulfonyl groups such as p-toluenesulfonyl, benzenesulfonyl, p-chlorobenzenesulfonyl, p-fluorobenzenesulfonyl, o-chlorobenzenesulfonyl, m-chlorobenzenesulfonyl, p-methoxybenzenesulfonyl, p-nitrobenzenesulfonyl, methanesulfonyl, ethanesulfonyl, isopropylsulfonyl.
According to the present invention, the halogen atom means a fluorine, chlorine, bromine or iodine atom, etc.
According to the invention, the solvent is acetonitrile.
According to the invention, the preferred molar ratios of reactants are:
AgSCF 3 ＝1:1～2。
According to the present invention, the reaction temperature and the reaction time of the reaction are slightly different depending on the raw materials, and the reaction temperature is usually 0℃to 100℃and preferably 20℃to 80℃and the reaction time is usually 2 to 24 hours. If heating is desired, an oil bath (e.g., silicone oil, paraffin oil, etc.) or other heating means may be employed.
According to the invention, the method further comprises a concentration step. Preferably, the concentration process can adopt the methods of atmospheric distillation, vacuum distillation and the like.
According to the invention, the method further comprises a purification step. Preferably, the purification process is performed by column chromatography, distillation under reduced pressure, and/or recrystallization to obtain a pure product. More preferably, the purification process is to obtain a purified product by column chromatography and then reduced pressure distillation.
The outstanding essential characteristics of the invention are that the invention adopts a modifiable diene substrate and AgSCF 3 The preparation method of the trifluoro-methyl-aza-8/9 membered ring compound is obtained by one step of reaction. In contrast to the methods described above, the reaction substrates used and the products produced are two distinct compounds. Further analysis, the preparation route of the invention consists in diene compounds and AgSCF 3 At K 2 S 2 O 8 And HMPA, and the target product is obtained in one step, and the substrate can be modified by extending the carbon chain to realize the synthesis of 8-membered and 9-membered trifluoro methyl nitrogen sulfide heterocycle. Meanwhile, the type of the middle ring prepared by the reaction is novel, and at present, three types of middle rings are not availableReports of fluoromethylthio incorporation into the ring system. In addition, the method has mild reaction conditions, strong operability and higher potential of large-scale application without strict anhydrous and anaerobic conditions.
The process of the invention achieves a reaction of a diene substrate (compound of formula (II)) with AgSCF 3 As raw material, K is utilized 2 S 2 O 8 And HMPA, under relatively mild reaction conditions, gives the differently substituted trifluor azepine-8/9 membered ring compounds in one step in higher yields.
Compared with the prior report, the invention has the following advantages:
1. the method synthesizes the trifluoromethyl sulfide 8-membered or 9-membered nitrogen heterocyclic molecule, which is more challenging and innovative compared with the traditional synthesis of 5-, 6-membered or 7-membered nitrogen heterocyclic molecules.
2. The substrate related by the method can be modified, and the synthesis of the trifluoromethyl sulfide 8-membered or 9-membered nitrogen heterocycle can be selectively carried out by extending an alkyl carbon chain, so that the method has wide application prospect.
3. The reaction conditions related by the invention are relatively suitable, high temperature is not needed, strict anhydrous and anaerobic environment is not needed, and the operation is very simple; the economy of the reaction atoms is high, and the environment is friendly.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by practice of the invention.
Drawings
FIG. 1 is a schematic diagram of the preparation route of the preparation method of the present invention.
Detailed Description
As described above, the present invention discloses a process for preparing a trifluoromethaneaza-8/9 membered ring compound represented by the formula (I),
wherein,
R 1 selected from alkyl, alkoxy, halogen;
R 2 selected from sulfonyl groups;
R 3 selected from aryl groups;
wherein,
combining a compound represented by the formula (II) with AgSCF 3 At K 2 S 2 O 8 And HMPA in a solvent to obtain a compound shown in a formula (I):
wherein,
R 1 、R 2 and R is 3 Is defined as in formula (I) and is represented by the following formula:
as previously mentioned, the reactions of the present invention are well tolerated by functional groups.
The invention is illustrated in detail by the following examples. It will be understood by those skilled in the art that the present invention is not limited thereto and that any modifications and variations made thereto are within the scope of the present invention. Accordingly, the following description is to be construed as broadly known to those skilled in the art and not as limiting the invention.
Example 1
Preparation of (Z) -6-phenyl-1-tosyl-4- (((trifluoromethyl) thio) methyl) -1,2,3, 4-tetrahydroxyzo [ b ] azocine
The molecular formula: c (C) 26 H 24 F 3 NO 2 S 2
The operation steps are as follows:
k was added sequentially to a 10mL reaction flask 2 S 2 O 8 (162.2mg,0.6mmol),HMPA(53.7mg,0.3mmol)，d1(120.1mg，0.3mmol)，AgSCF 3 (94.5 mg,0.45 mmol), acetonitrile (3 mL), and reacted at 60℃for 12 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, and the residue was purified by flash column chromatography (petroleum ether: ethyl acetate=10:1) to give 105.7mg of a white solid in 70% yield.
Characterization data for the resulting compounds are as follows:
1 H NMR(500MHz,CDCl 3 )δ7.65(d,J＝7.9Hz,2H),7.38(d,J＝7.4Hz,2H),7.28(t,J＝6.4Hz,5H),7.22(d,J＝7.9Hz,2H),7.15(s,1H),6.96(s,1H),5.88(d,J＝8.6Hz,1H),4.28(d,J＝9.6Hz,1H),3.08–3.02(m,1H),2.96(dd,J＝15.2,9.5Hz,2H),2.40(s,3H),2.08(t,J＝8.5Hz,1H),1.79(d,J＝6.5Hz,1H),1.65(d,J＝13.6Hz,1H).
13 C NMR(126MHz,CDCl 3 )δ143.4,142.0,141.8,140.4,140.2,137.7,132.2,131.0,130.8,129.8,129.6,129.3,128.7,128.7,128.6,128.2,127.8,127.7,50.8,38.2,36.8,32.8,21.6.
19 F NMR(376MHz,CDCl 3 )δ-41.00.
HRMS(ESI)m/z:[M+Na] + calcd for C 25 H 23 F 3 NO 2 S 2 Na + ,526.1099；found,526.1092
examples 2 to 22
Examples 2-22 were prepared in the same manner as in example 1, with specific raw material ratios shown in Table 1.
Table 1 reactants of examples 2-22 and their specific raw material ratios
The product names, yields and characterization results of examples 2-22 are listed in Table 2.
TABLE 2 product information and characterization of examples 2-22
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The trifluoro-aza-8/9 membered ring compound prepared in the above example proves that the preparation method of the invention has good tolerance to functional groups, such as halogen, differently substituted alkyl, aryl and other groups can not participate in reaction and remain in the prepared trifluoro-aza-8/9 membered ring compound, and the characterization data of the product proves that the preparation method of the invention successfully prepares the trifluoro-aza-8/9 membered ring compound.
The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations to the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.

Claims (7)

1. A process for preparing trifluoro-methyl sulfide aza-8/9 membered ring compound is characterized by that the diene compound with different carbon chain and AgSCF 3 Mixing the mixture in a solvent according to a molar ratio of 1:1-2, and simultaneously adding K 2 S 2 O 8 And HMPA, the molar quantity is 1-2 times of diene compounds of different carbon chains respectively, then react for 2-24 hours at 0-100 ℃, and then obtain trifluoro methyl nitrogen sulfide aza-8/9 membered ring compound;
the solvent is selected from acetonitrile.
2. The method of claim 1, wherein the reaction temperature is from 20 ℃ to 80 ℃.
3. The method according to claim 1, wherein the diene compounds of different carbon chains are selected from:
N-(but-3-en-1-yl)-4-methyl-N-(2-(1-phenylvinyl)phenyl)benzenesulfonamide;
N-(but-3-en-1-yl)-N-(4-fluoro-2-(1-phenylvinyl)phenyl)-4-methylbenzenesulfonamide;
N-(but-3-en-1-yl)-N-(4-chloro-2-(1-phenylvinyl)phenyl)-4-methylbenzenesulfonamide;
N-(4-bromo-2-(1-phenylvinyl)phenyl)-N-(but-3-en-1-yl)-4-methylbenzenesulfonamide;
N-(but-3-en-1-yl)-4-methyl-N-(4-methyl-2-(1-phenylvinyl)phenyl)benzenesulfonamide;
N-(but-3-en-1-yl)-N-(4-methoxy-2-(1-phenylvinyl)phenyl)-4-methylbenzenesulfonamide;
N-(but-3-en-1-yl)-4-methyl-N-(5-methyl-2-(1-phenylvinyl)phenyl)benzenesulfonamide;
N-(5-bromo-2-(1-phenylvinyl)phenyl)-N-(but-3-en-1-yl)-4-methylbenzenesulfonamide;
N-(but-3-en-1-yl)-N-(3-fluoro-2-(1-phenylvinyl)phenyl)-4-methylbenzenesulfonamide;
N-(but-3-en-1-yl)-N-(2-(1-(4-fluorophenyl)vinyl)phenyl)-4-methylbenzenesulfonamide;
N-(but-3-en-1-yl)-N-(2-(1-(4-chlorophenyl)vinyl)phenyl)-4-methylbenzenesulfonamide ;
N-(2-(1-(4-bromophenyl)vinyl)phenyl)-N-(but-3-en-1-yl)-4-methylbenzenesulfonamide ;
N-(but-3-en-1-yl)-4-methyl-N-(2-(1-(p-tolyl)vinyl)phenyl)benzenesulfonamide;
N-(but-3-en-1-yl)-4-methyl-N-(2-(1-(o-tolyl)vinyl)phenyl)benzenesulfonamide
N-(but-3-en-1-yl)-N-(5-fluoro-2-(1-(p-tolyl)vinyl)phenyl)-4-methylbenzenesulfonamide;
N-(but-3-en-1-yl)-N-(4-chloro-2-(1-(p-tolyl)vinyl)phenyl)-4-methylbenzenesulfonamide;
4-methyl-N-(pent-4-en-1-yl)-N-(2-(1-phenylvinyl)phenyl)benzenesulfonamide;
N-(4-bromo-2-(1-phenylvinyl)phenyl)-4-methyl-N-(pent-4-en-1-yl)benzenesulfonamide;
N-(4-chloro-2-(1-phenylvinyl)phenyl)-4-methyl-N-(pent-4-en-1-yl)benzenesulfonamide;
N-(4-bromo-2-(1-(2-fluorophenyl)vinyl)phenyl)-4-methyl-Nany one of- (pent-4-en-1-yl) benzenesulfonamide.
4. A method according to any one of claims 1 to 3, further comprising a concentration step.
5. The method of claim 4, wherein the concentrating step is atmospheric distillation or reduced pressure distillation.
6. A method according to any one of claims 1 to 3, further comprising a purification step.
7. The method of claim 6, wherein the purification step is column chromatography, distillation under reduced pressure, and/or recrystallization to yield a pure product.
CN202310123910.8A 2023-02-16 2023-02-16 Preparation method of trifluoro-methyl sulfide aza-8/9 membered ring compound Pending CN117088814A (en)

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