CN108675922B - Spiro compound and synthesis method thereof - Google Patents

Spiro compound and synthesis method thereof Download PDF

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CN108675922B
CN108675922B CN201810678307.5A CN201810678307A CN108675922B CN 108675922 B CN108675922 B CN 108675922B CN 201810678307 A CN201810678307 A CN 201810678307A CN 108675922 B CN108675922 B CN 108675922B
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郭灿城
李慧
郭欣
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Yuanjiang Hualong Catalyst Technology Co ltd
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    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07C2603/94—Spiro compounds containing "free" spiro atoms

Abstract

The invention discloses a spiro compound and a synthesis method thereof, wherein the spiro compound is a parent spiro structure formed by cyclic ketone and cyclohexene, and the synthesis method comprises the steps of carrying out one-pot reaction on the cyclic ketone compound and 2-aryl propylene in a dimethyl sulfoxide solution system containing persulfate to obtain the spiro compound; the synthesis method is realized by a one-pot method, has mild reaction conditions, does not need additional catalysts, has good selectivity and high yield, and is beneficial to industrial production.

Description

Spiro compound and synthesis method thereof
Technical Field
The invention relates to a spiro compound, and also relates to a method for constructing a spiro structure by a cyclic ketone compound, 2-aryl propylene and dimethyl sulfoxide, belonging to the field of organic synthesis.
Background
Spiro compounds are also widely found in bioactive molecules such as natural products, drugs, pesticides and the like (chem.Soc.Rev.2012,41, 1060-1074; Eur.J.Org.chem.2012, 1935-1944; Org.chem.Front.2015, 2849-2858; ACS Catal.2013,3,540-553), and many spiro compounds exhibit outstanding physiological activities such as anti-tumor, anti-hypertension, anti-allergy and the like, and are widely used in clinical applications (J.Med.chem.1996,39, 4044-4057; Med.chem.Lett.2007,17, 266-271; Synthesis-Stuttgart.2013,45, 1909-1930; Med.chem.2009,52, 6936-6940).
Spiroindanone compounds have been widely spotlighted because of their specific spiro backbone, which exhibits various biological and pharmacological activities. Early spiroindanone compounds were found in natural plants, and alkaloids isolated from annona squamosa were reported to have an indanone pyridine skeleton, and derivatives thereof were found to have phosphodiesterase activity and ability to inhibit adenosine A2a receptor binding, and are useful for treating neurodegenerative and inflammation-related diseases (Aran go, g.j.; cortex, d.; et al, azafluorogens from Oxandra cf. major and biochemical disorders [ J ]. Phytochemistry,1987,26, 2093-. Up to now, methods for synthesizing spiroindanone compounds have been reported in the prior art, such as the typical method that 1-indanone and formaldehyde are firstly subjected to condensation reaction and then reacted with acetyl allene to obtain spiro compounds containing 1-indanone skeleton (Tetrahedron Lett.2013,54, 4425-4428). As another example, starting from 1-indanone, spiro compounds containing 1-indanone skeleton can be synthesized by Michael condensation and Dikmann condensation with acrylic ester (Helv Chim Acta 1995,78, 857-one 865). However, these methods all have the disadvantages of long flow path, not easy to obtain raw materials, low total yield, complex post-treatment and the like. Chinese patent (CN108047007A) discloses a synthesis method of a spiro-compound containing 1-indanone skeleton, which takes aromatic carboxylic acid and alpha, beta-unsaturated ketone as raw materials, adopts catalysts such as cymene ruthenium dichloride dimer and the like and heavy metal additives such as manganese, zinc and the like, and synthesizes the spiro-compound containing 1-indanone skeleton through four-step reactions such as conjugate addition reaction of aromatic carboxylic acid ortho-position C-H bond and alpha, beta-unsaturated ketone, intramolecular dehydration cyclization, Michael addition with second molecule alpha, beta-unsaturated ketone, intramolecular aldol condensation and the like by one-step reaction (the reaction route is as follows).
Figure BDA0001710312770000021
Disclosure of Invention
The first purpose of the invention is to provide a spiro parent structure composed of cyclic ketone and cyclohexene, which provides a new organic intermediate for synthesis of spiro drugs.
Aiming at the defects of complex steps, high cost, environmental friendliness and the like of the existing method for constructing the spiro structure, the invention also aims to provide a method for constructing the spiro structure by using the alpha-carbon provided by the cyclic ketone compound, the methyl provided by DMSO and the propylene provided by 2-aryl propylene.
In order to achieve the above technical objects, the present invention provides a spiro compound having a structure of formula 1:
Figure BDA0001710312770000022
wherein the content of the first and second substances,
R1、R2、R3and R4Independently selected from alkyl or hydrogen, or, R1And R2Any of them with R3And R4Any one of which constitutes an alkane ring, an aromatic ring or a heterocyclic ring, and which may or may not have a substituent on the alkane ring, the aromatic ring or the heterocyclic ring;
R5is aryl;
n is 1 to 3.
Preferred embodiment, spiro compounds are those wherein R1、R2、R3Or R4May be selected from alkyl groups, typically lower alkyl groups, e.g. C1～C5Alkyl groups such as methyl, ethyl, propyl, and the like. In spiro compounds R1And R2Any of them with R3And R4Either of which may form an alkyl ring, e.g. R1And R3The two are connected by a carbon chain to form an alkyl ring, and the alkyl ring is generally an alkyl ring with 5-7 carbon atoms. Meanwhile, the alkyl ring may contain conventional substituents such as halogen (fluorine, chlorine, bromine, iodine, or the like) or short chain alkyl (generally, the number of carbon atoms is not more than 5), and the like. R1And R3When forming an alkyl ring, R2And R4It may be a short-chain alkyl group or hydrogen, and preferably both are hydrogen. Similarly, R1And R4R is2And R4Between or R2And R3Can form an alkane-like ring through carbon chain connection. In spiro compounds R1And R2Any of them with R3And R4Either of which may form a heterocyclic ring, e.g. R1And R3Can be connected by a carbon chain containing heteroatom to form a heterocyclic ring. The heterocyclic ring may be a saturated heterocyclic ring (e.g., tetrahydrofuran) or an unsaturated heterocyclic ring (e.g., furan). The heterocyclic ring may be a five-membered ring or a six-membered ring, and preferably a five-membered ring. The number of the heterocyclic rings in the heterocyclic ring may be 1 to 2, and preferably 1 hetero atom is contained. Heteroatoms are typically oxygen, nitrogen, sulfur, and the like, such as furan, pyrrole, thiophene, and the like. The heterocyclic ring may also contain conventional substituents such as halogen (fluorine, chlorine, bromine or iodine, etc.) or short chain alkyl (typically having less than 5 carbon atoms) and the like. R1And R3When an unsaturated heterocyclic ring is formed, R2And R4Is hydrogen. Similarly, R1And R4R is2And R4Between or R2And R3Can also form similar heterocyclic ring by connecting carbon chain containing heteroatom. In spiro compounds R1And R2Any of them with R3And R4Either of which may constitute an aromatic ring, e.g. R1And R3Can form a benzene ring or a naphthalene ring through unsaturated carbon chain connection, and the benzene ring or the naphthalene ring can contain some conventional substituents, such as halogen (fluorine, chlorine, bromine or iodine) or short-chain alkyl (generally the number of carbon atoms is less than 5), alkoxy (C)1～C5Alkoxy groups of (ii) and the like. The number of the substituent groups on the benzene ring or the naphthalene ring is 1-2, especially two adjacent substituent groupsIt is possible to constitute a cyclic structure such as an alkane ring or an alkoxy ring, etc. Similarly, R1And R4R is2And R4Between or R2And R3Can form a similar benzene ring through unsaturated carbon chain connection.
R5Preferably phenyl, substituted phenyl, naphthyl or substituted naphthyl. R5When the substituent is selected from substituted phenyl, the number of the substituent contained in the substituted phenyl is 1-2, and the substituent is selected from at least one of halogen substituent and alkyl. Halogen substituents such as fluorine, chlorine, bromine, iodine, and the like. Alkyl is C1～C10Alkyl groups of (a); more preferably C1～C5The lower alkyl group of (2) such as methyl, ethyl, propyl, etc., may also be a branched alkyl group such as isopropyl, isobutyl, etc. The number of the substituent is preferably 1, and the position of the substituent is preferably para (relative to the alkenyl).
The invention also provides a synthesis method of the spiro compound, which comprises the steps of carrying out one-pot reaction on the cyclic ketone compound and 2-aryl propylene in a dimethyl sulfoxide solution system containing persulfate to obtain the spiro compound;
the spiro compound has the structure of formula 1:
Figure BDA0001710312770000031
the cyclic ketone compound has a structure of formula 2:
Figure BDA0001710312770000041
the 2-arylpropene has the structure of formula 3:
Figure BDA0001710312770000042
wherein the content of the first and second substances,
R1、R2、R3and R4Independently selected from alkyl or hydrogen, or, R1And R2Any of them with R3And R4Any one of them forms an alkane ring, an aromatic ring or a heterocyclic ring, and the alkane ring, the aromatic ring or the heterocyclic ring has a substituent or does not have a substituent;
R5is aryl;
n is 1 to 3.
In the preferred scheme, alpha carbon is participated in the reaction of the cyclic ketone compound, various substituent groups on the cyclic ketone in the cyclic ketone compound have obvious influence on the electronic effect and the steric hindrance effect of the cyclization reaction, and R1Or R2And R3Or R4When the aromatic ring or the aromatic condensed ring or the aromatic heterocyclic ring is formed, the groups can participate in conjugation with carbonyl, so that the activity of alpha carbon can be obviously increased. R in cyclic ketones1、R2、R3Or R4May be selected from alkyl groups, typically lower alkyl groups, e.g. C1～C5Alkyl groups such as methyl, ethyl, propyl, and the like. R in cyclic ketones1And R2Any of them with R3And R4Either of which may form an alkyl ring, e.g. R1And R3The two are connected by a carbon chain to form an alkyl ring, and the alkyl ring is generally an alkyl ring with 5-7 carbon atoms. Meanwhile, the alkyl ring may contain conventional substituents such as halogen (fluorine, chlorine, bromine, iodine, or the like) or short chain alkyl (generally, the number of carbon atoms is not more than 5), and the like. R1And R3When forming an alkyl ring, R2And R4It may be a short-chain alkyl group or hydrogen, and preferably both are hydrogen. Similarly, R1And R4R is2And R4Between or R2And R3Can form an alkane-like ring through carbon chain connection. R in cyclic ketones1And R2Any of them with R3And R4Either of which may form a heterocyclic ring, e.g. R1And R3Can be connected by a carbon chain containing heteroatom to form a heterocyclic ring. The heterocyclic ring may be a saturated heterocyclic ring (e.g., tetrahydrofuran) or an unsaturated heterocyclic ring (e.g., furan). The heterocyclic ring may be a five-membered ring or a six-membered ring, and preferably a five-membered ring. The number of the heterocyclic rings in the heterocyclic ring may be 1 to 2, and preferably one hetero atom is contained. The heteroatoms are typically oxygen, nitrogen, sulfur, and the like,such as furan, pyrrole or thiophene. The heterocyclic ring may also contain conventional substituents such as halogen (fluorine, chlorine, bromine or iodine, etc.) or short chain alkyl (typically having less than 5 carbon atoms) and the like. R1And R3When an unsaturated heterocyclic ring is formed, R2And R4Is hydrogen. Similarly, R1And R4R is2And R4Between or R2And R3Can also form similar heterocyclic ring by connecting carbon chain containing heteroatom. R in cyclic ketones1And R2Any of them with R3And R4Either of which may constitute an aromatic ring, e.g. R1And R3Can form a benzene ring or a naphthalene ring through unsaturated carbon chain connection, and the benzene ring or the naphthalene ring can contain some conventional substituents, such as halogen (fluorine, chlorine, bromine or iodine) or short-chain alkyl (generally the number of carbon atoms is less than 5), alkoxy (C)1～C5Alkoxy groups of (ii) and the like. The number of the substituent groups on the benzene ring or the naphthalene ring is 1-2, and particularly, two adjacent substituent groups can form a cyclic structure, such as an alkyl ring or an alkoxy ring. Similarly, R1And R4R is2And R4Between or R2And R3Can form a similar benzene ring or a naphthalene ring through unsaturated carbon chain connection.
In the 2-arylpropene of the present invention, R5More preferably phenyl, substituted phenyl, naphthyl or substituted naphthyl. R5When the substituent is selected from substituted phenyl, the number of the substituent contained in the substituted phenyl is 1-2, and the substituent is selected from at least one of halogen substituent and alkyl. Halogen substituents such as fluorine, chlorine, bromine, iodine, and the like. Alkyl is C1～C10Alkyl groups of (a); more preferably C1～C5The lower alkyl group of (2) such as methyl, ethyl, propyl, etc., may also be a branched alkyl group such as isopropyl, isobutyl, etc. The number of the substituent is preferably 1, and the position of the substituent is preferably para (relative to the alkenyl). The choice of 2-arylpropenes is limited to the choice of aryl substituents which provide a large conjugated system enabling the methyl group on the alkenyl group to be sufficiently reactive to participate in the cyclisation. The aryl substituents not being optionally replaced by other substituents, e.g. aromatic heterocycles, alkanesThe target product cannot be obtained by replacing aryl with the like. When R is5When substituted phenyl is selected, the substituent is preferably para to the alkenyl, and may be a weak electron-donating group such as alkyl or a weak electron-withdrawing group such as halogen. However, it is difficult to obtain an ideal yield from a strongly electron-withdrawing group such as an amino group and an alkoxy group, and a strongly electron-withdrawing group such as a nitro group.
In a preferable scheme, the molar ratio of the persulfate to the cyclic ketone compound is 1-2: 1. More preferably 1.3 to 1.8: 1.
In a preferable scheme, the molar ratio of the cyclic ketone compound to the 2-aryl propylene is 1: 1.5-2.5.
In a preferable scheme, the concentration of the cyclic ketone compound in a dimethyl sulfoxide solution system is 0.1-0.5 mol/L. Dimethyl sulfoxide mainly plays two roles, namely, on one hand, playing a role of a benign solvent, and on the other hand, serving as a reaction substrate, two methyl groups are provided by two dimethyl sulfoxides as two carbon atoms in a cyclohexene ring in a spiro structure.
In a more preferred embodiment, the persulfate is mainly an alkali metal-containing persulfate and/or an alkali metal-containing hydrogen persulfate, and the most preferred persulfate includes at least one of potassium persulfate, sodium persulfate, potassium hydrogen persulfate, and sodium hydrogen persulfate.
In a more preferred embodiment, the reaction conditions are as follows: reacting for 18-30 h at 110-160 ℃ in a protective atmosphere. In a more preferred embodiment, the reaction conditions are as follows: and reacting for 22-28 h at 130-150 ℃ in a protective atmosphere. The protective atmosphere generally refers to nitrogen or an inert atmosphere or a mixed atmosphere of the two.
The invention explains the reaction mechanism by constructing a spiro structure by 1-indanone, dimethyl sulfoxide and 2-phenylpropylene. After reviewing and referring to relevant documents, a series of mechanism research experiments were designed, as shown in the following reaction equations (1) to (6). In order to prove whether the reaction goes through the reaction process of free radicals, the reaction (1) is designed, 2.0 equivalent (relative to 1-indanone) of 2, 6-di-tert-butyl-p-cresol (BHT) is added under standard reaction conditions for reaction for 12 hours, and as a result, the target product with a spiro structure can still be successfully detected by GC-MSThe formation of (A) indicates that the reaction is not inhibited and the reaction does not undergo a radical reaction. To demonstrate the presence or absence of reaction intermediates in this reaction, 1-indanone was reacted with dimethyl sulfoxide and 2-phenylpropylene under standard reaction conditions for 12 hours, and the presence of compound B and compound C was detected in addition to the target spiro compound by GC-MS detection. In order to prove whether the compounds B and C are intermediates in the process of constructing the spiro structure, a reaction (2) and a reaction (3) are designed, the compound B is used as a raw material to replace 2-phenylpropylene, the reaction is carried out under standard conditions, and the compound C is used as a raw material to replace 1-indanone, so that the spiro structure is surprisingly found to be successfully detected by GC-MS, and the compounds B and C are intermediates which may exist in the synthesis process of the spiro structure. To further clarify the source of compound B, reaction (4) was further designed to react 2-phenylpropylene with dimethylsulfoxide directly under standard conditions, and the presence of compound B was detected by GC-MS, while compound A was also obtained. To further clarify the source of compound C, reaction (5) was further designed to react 2-phenylpropylene with dimethylsulfoxide directly under standard conditions, and the presence of compound C was detected by GC-MS, while compound D was also obtained. In order to obtain a more accurate verification of whether dimethyl sulfoxide participates in the generation of cyclohexene ring in spiro structure, reaction (6) was designed, replacing conventional dimethyl sulfoxide with isotopically labeled deuterated dimethyl sulfoxide and reacting under standard conditions, successfully detecting the presence of deuterium in cyclohexene ring in spiro structure and detecting the presence of deuterium on two carbon atoms, indicating that two methyl groups are provided by dimethyl sulfoxide. Standard reaction conditions: in N2Next, 1-indanone (0.5mmol), α -methylstyrene (0.75mmol) and DMSO (2mL) were reacted at 140 ℃ for 24 h.
Reaction formula (1):
Figure BDA0001710312770000061
reaction formula (2):
Figure BDA0001710312770000071
reaction formula (3):
Figure BDA0001710312770000072
reaction formula (4):
Figure BDA0001710312770000073
reaction formula (5):
Figure BDA0001710312770000074
reaction formula (6):
Figure BDA0001710312770000075
according to the experiment, the invention provides a reasonable mechanism for constructing a spiro structure by 1-indanone, dimethyl sulfoxide and 2-phenylpropylene: the following reaction equation. First, adopt K2S2O8Activating DMSO to obtain DMSO converted into dimethyl sulfide positive ion, simultaneously 2-phenylpropylene releases hydrogen proton and 2-phenylpropylene negative ion, 1-indanone also releases hydrogen proton and becomes 1-indanone negative ion, the 2-phenylpropylene negative ion and the 1-indanone negative ion are easy to couple with dimethyl sulfide positive ion to generate dimethyl sulfide compounds A and D, and the dimethyl sulfide compounds A and D are at K2S2O8Under the action of oxidation, removing the micromolecule methyl mercaptan compound through a demethylation reaction to obtain compounds B and C, and carrying out Diels Alder reaction on the compound B and the compound C to finally obtain a target product.
Figure BDA0001710312770000076
Compared with the prior art, the technical scheme of the invention has the beneficial technical effects that:
1) the spiro structure of the invention is composed of cyclic ketone and cyclohexene, and can contain abundant substituent groups and modifiable groups, thereby providing an effective intermediate for the synthesis of drugs and the like taking the spiro structure as a matrix.
2) According to the invention, alpha carbon is provided by a cyclic ketone compound, 2-aryl propylene is provided by propenyl, and methyl is provided by dimethyl sulfoxide to successfully construct a spiro structure, so that a brand new synthetic idea is provided for the construction of the spiro structure.
3) Compared with the existing synthesis method, the synthesis method of the spiro structure does not need to use a catalyst, avoids using expensive and pollution-like catalysts and additives, and is beneficial to reducing the cost and protecting the environment.
4) In the synthesis process of the spiro ring, the cyclic ketone compound, the 2-aryl propylene and the dimethyl sulfoxide are used as basic raw materials, and are conventional chemical raw materials, so that the cost is low, and the industrial production is facilitated.
5) The synthesis process of the spiro structure adopts a one-pot reaction, has mild reaction conditions and simple operation, and meets the requirements of industrial production.
6) The spiro structure synthesis process has high raw material utilization rate, and the product yield can reach over 80 percent.
7) The spiro structure has wide application range to substrate raw materials in the synthesis process, can construct spiro compounds with various substituent groups, and has strong substituent position selectivity.
Drawings
FIG. 1 is a nuclear magnetic carbon spectrum of 1'-phenyl-6,7-dihydro-4H-spiro [ b ] thiophene-5,4' -cyclohex [6] en ] -4-one.
FIG. 2 is a nuclear magnetic hydrogen spectrum of 1'-phenyl-6,7-dihydro-4H-spiro [ b ] thiophene-5,4' -cyclohexex [6] en ] -4-one.
FIG. 3 is a nuclear magnetic carbon spectrum of 1- (4-fluorophenyl) spiro [ cyclohex [6] ene-4,2' -inden ] -1' (3' H) -one.
FIG. 4 is a nuclear magnetic hydrogen spectrum of 1- (4-fluorophenyl) spiro [ cyclohex [6] ene-4,2' -inden ] -1' (3' H) -one.
FIG. 5 is a nuclear magnetic carbon spectrum of 1-phenylspiro [ cyclohex [6] ene-4,2' -inden ] -1' (3' H) -one.
FIG. 6 is a nuclear magnetic hydrogen spectrum of 1-phenylspiro [ cyclohex [6] ene-4,2' -inden ] -1' (3' H) -one.
FIG. 7 is a nuclear magnetic carbon spectrum of 9-phenylspiro [5.5] undec-8-en-1-one.
FIG. 8 is a nuclear magnetic hydrogen spectrum of 9-phenylspiro [5.5] undec-8-en-1-one.
Detailed Description
The following examples are intended to further illustrate the present disclosure, but not to limit the scope of the claims.
All reactions were performed in Schlenk tubes unless otherwise noted.
All reaction starting solvents were obtained from commercial sources and used without further purification.
The product is separated by silica gel chromatographic column and silica gel (granularity is 300-400 meshes).
1H NMR (400MHz), 13C NMR (100MHz) and 19F NMR (376MHz) measurements were performed using a Bruker ADVANCE III spectrometer with CDCl3As solvent, TMS as internal standard, chemical shifts in parts per million (ppm) and reference shifts of 0.0ppm tetramethylsilane. The following abbreviations (or combinations thereof) are used to explain the multiplicity: s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broad. Coupling constant J is in Hertz (Hz). Chemical shifts are expressed in ppm, with the center line for the triplet state referenced to deuterated chloroform at 77.0ppm or the center line for the heptad state referenced to deuterated DMSO at 39.52 ppm.
The GC-MS adopts a GC-MS QP2010 device for detection, the HRMS adopts an Electron Ionization (EI) method for measurement, the type of the mass analyzer is TOF, and the EI is detected by an Esquire 3000plus instrument.
1. Condition optimization experiment:
1-indanone, dimethyl sulfoxide and 2-phenylpropylene are used for constructing a spiro structure as an example, and a plurality of influence factors such as an oxidant, the dosage of the oxidant, reaction temperature, a reaction solvent, an additive and the like are discussed so as to search for optimal reaction conditions.
The specific reaction process is as follows: 1-indanone, alpha-methyl styrene, oxidant, additive and DMSO in N2And reacting for 24 hours under the atmosphere.
The reaction route is as follows:
Figure BDA0001710312770000091
table 1: yield of target product spiro structure under different reaction conditions
Figure BDA0001710312770000092
Figure BDA0001710312770000101
1) Selection of additives
As shown in Table 1, the use of the additive has a great influence on the reaction, and a large number of experiments show that, as items 1-6 and 11 in Table 1, no benign additive which is beneficial to improving the reaction efficiency and increasing the yield, such as DABCO, DBU and K, is found in the reaction process of constructing a spiro structure by 1-indanone, dimethyl sulfoxide and 2-phenylpropylene2CO3、Cs2CO3、Et3When N or NaOAc and other alkaline substances are used as additives, the reaction is obviously inhibited, and the target product spiro compound can not be obtained basically.
3) Selection of oxidizing agent
The invention tries a plurality of common oxidants in the field, such as items 9-16 in table 1, and oxidants such as persulfate, organic peroxide, inorganic hydrogen peroxide and the like, find that the oxidant has a good reaction effect only when the persulfate is used as the oxidant, and when tert-butyl hydroperoxide (TBHP), DTBP or hydrogen peroxide (H) is used2O2) As the oxidizing agent, almost no target product is obtained, and therefore, persulfate is selected as the most preferable oxidizing agent.
4) Selection of the quantity of oxidant
After determining potassium persulfate, sodium persulfate, etc. as the optimal oxidizing agents, the influence of different amounts of the oxidizing agents on the reaction was explored. As in items 11, 17 and 18 of table 1. When the amount of the oxidant is 0.5-0.75 equivalent, the conversion rate of the raw materials and the yield of the product are increased with the increase of the amount of the oxidant. And when the amount of the oxidizing agent is more than 0.75 equivalent, the yield is remarkably decreased. Therefore, 0.75 equivalent of persulfate is the optimum amount for the reaction.
5) Selection of reaction temperature
The reaction temperature is an important factor affecting the chemical reaction process, and in order to obtain the optimum reaction temperature, the yield of the reaction at different temperatures was investigated, as in items 7 to 11 in Table 1. The target product can not be obtained basically at the temperature of less than 100 ℃, the reaction yield is obviously improved when the temperature reaches more than 120 ℃, the reaction yield reaches the highest when the temperature is raised to 140 ℃, and the reaction side reaction is obvious when the temperature is higher than 140 ℃. Thus, 140 ℃ is the optimum temperature for the reaction.
6) Selection of reaction solvent
Since DMSO is used as a reaction substrate and a solvent in the process of synthesizing dihydropyran, the DMSO is not replaceable by other solvents. The solvent of the invention can adopt DMSO, and can also adopt a mixed solvent of DMSO and other solvents.
2. Selection range of reaction substrates:
after the optimal synthesis conditions of the spiro structure are determined, the substrate range and the applicability of the reaction are researched, and the experimental results are shown in tables 2 and 3. Table 2 shows the reaction results of different cyclic ketones with 2-phenylpropene and DMSO. As can be seen from Table 2, indanones, cycloalkones, aromatic heterocyclic ring ketones, etc. can effectively synthesize corresponding spiro structures with 2-phenylpropene and DMSO under standard reaction conditions, and the yield of the target product is about 70%, and can reach more than 80% at most, and the yield is relatively ideal. Moreover, a large number of experiments show that the influence of the substituent of the cyclic ketone compound on the reaction is relatively large, the carbonyl is preferably connected to a conjugate system, such as a benzene ring, an aromatic condensed ring, an aromatic heterocyclic ring and the like, and the carbonyl can participate in conjugation, so that the activity of the alpha carbon of the carbonyl can be obviously improved, hydrogen protons are easily lost, the spiro structure can be successfully constructed with 2-phenylpropene and DMSO, and the yield is about 80%. If the cyclic ketone is connected with other groups, such as alkyl, and the like, the yield of the spiro ring constructed by the cyclic ketone, 2-phenylpropene and DMSO is obviously reduced. Table 3 shows the reaction results of different 2-aryl propylene, 1-indanone or benzocyclohexanone and DMSO, and experimental results show that the substituent at the 2-position of propylene must be a group with a large conjugated system, such as aryl, other aromatic heterocyclic rings, alkyl and the like, which cannot meet the requirements, and the aryl of the large conjugated system is favorable for improving the activity of alpha-methyl. The substituent on the aryl is also selected according to the requirement, and can not be a substituent group with stronger electron pushing or pulling capacity, such as nitro, alkoxy and the like, while the substituent group with stronger electron pushing or pulling capacity, such as halogen, alkyl and the like, can meet the requirement. The position of the substituent is preferably the para position.
(1) The reaction equation of different cyclic ketones with 2-phenylpropene and DMSO is as follows:
Figure BDA0001710312770000121
weighing potassium peroxodisulfate (K)2S2O8) (202.5mg,0.75mmol) and the cyclic ketone compound (0.5mmol) were placed in a 25ml Schlenk reaction tube, and dimethyl sulfoxide (DMSO, 2ml) and 2-phenylpropylene (118mg, 1mmol) were added thereto, followed by nitrogen gas injection. Stirring was carried out at 140 ℃ for 24 hours. After completion of the reaction, it was cooled to room temperature, water (4ml) was added, and extraction was performed with ethyl acetate (3 x 5ml) and anhydrous Na2SO4Drying, decompressing, distilling off the solvent, and separating by a silica gel column (200-300 meshes) to obtain the target product spiro structure.
TABLE 2 reaction results of different cyclic ketones with 2-phenylpropene and DMSO
Figure BDA0001710312770000122
Figure BDA0001710312770000131
Figure BDA0001710312770000141
(2) The reaction equations for different 2-arylpropenes with 1-indanone or benzocyclonone compounds and DMSO are as follows:
Figure BDA0001710312770000142
weighing potassium peroxodisulfate (K)2S2O8) (202.5mg,0.75mmol), 1-indanone or benzocyclohexanone (0.5mmol) was placed in a 25ml Schlenk reaction tube, and dimethyl sulfoxide (DMSO, 2ml), 2-arylpropene (1mmol) were added thereto and nitrogen gas was purged. Stirring was carried out at 140 ℃ for 24 hours. After completion of the reaction, it was cooled to room temperature, water (4ml) was added, and extraction was performed with ethyl acetate (3 x 5ml) and anhydrous Na2SO4Drying, distilling off the solvent under reduced pressure, and separating by a silica gel column (200-300 meshes) to obtain the target product spiro compound.
TABLE 3 results of different 2-arylpropenes with 1-indanone and DMSO
Figure BDA0001710312770000143
Figure BDA0001710312770000151
Molecular structural characterization of the partially spiro compound:
1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
Figure BDA0001710312770000152
7.5Hz,2H),7.23(d,J＝6.7Hz,1H),6.20(d,J＝4.5Hz,1H),3.11(d,J＝17.3Hz,1H),2.96(d,J＝17.3Hz,1H),2.63(dd,J＝26.5,11.9Hz,3H),2.05(dt,J＝15.1,5.6Hz,2H),1.72–1.66(m,1H).
13C NMR(101MHz,CDCl3)δ211.07,152.80,141.52,136.05,135.90,134.95,128.36,127.52,127.02,126.74,125.06,124.36,122.55,48.17,39.10,35.08,29.30,24.86.
5'-fluoro-1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
Figure BDA0001710312770000153
1H NMR(400MHz、CDCl3)δ7.87-7.75(m，1H)，7.43(d，J＝7.5Hz,2H),7.34(t,J＝7.3 Hz,2H),7.25(d,J＝6.7 Hz,1H),7.09(t,J＝8.8 Hz,2H),6.20(d,J＝4.3 Hz,1H),3.11(d,J＝17.5 Hz,1H),2.96(d,J＝17.5 Hz,1H),2.74–2.53(m,3H),2.15–1.98(m,2H),1.70(dd,J＝13.4,3.4 Hz,1H).
13C NMR(101 MHz,CDCl3)δ209.12,168.70,155.66(d,J＝10.0 Hz),141.40,136.08,132.25,128.38,127.09,126.64(d,J＝10.5 Hz),125.05,122.32,115.86(d,J＝23.8 Hz),113.32(d,J＝22.1 Hz),48.54,39.00,35.04,29.27,24.76
5'-chloro-1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
Figure BDA0001710312770000161
1H),2.66(d,J＝16.8 Hz,2H),2.61–2.48(m,1H),2.10–1.98(m,2H),1.68(dd,J＝12.2,4.3Hz,1H)..
13C NMR(101 MHz,CDCl3)δ209.53,154.25,141.43,141.35,136.08,134.34,128.40,128.37,127.11,126.93,125.48,125.05,122.26,48.46,38.82,35.03,29.28,24.75.
6'-bromo-1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
Figure BDA0001710312770000162
6.0 Hz,1H),6.18(d,J＝4.7 Hz,1H),3.04(d,J＝17.4 Hz,1H),2.90(d,J＝17.4 Hz,1H),2.71–2.61(m,2H),2.60–2.39(m,1H),2.04(ddd,J＝21.2,10.7,5.3Hz,2H),1.68(dd,J＝13.8,4.4 Hz,1H).
13C NMR(101 MHz,CDCl3)δ209.53,151.26,141.35,137.77,137.65,136.10,128.39,128.32,127.27,127.11,125.05,122.23,121.67,48.80,38.72,35.02,29.26,24.77.
4'-methyl-1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
Figure BDA0001710312770000163
1H),2.67(t,J＝14.0 Hz,3H),2.33(s,3H),2.14–2.00(m,2H),1.71(dd,J＝9.3,6.8 Hz,1H).
13C NMR(101 MHz,CDCl3)δ211.40,151.78,141.45,136.00,135.90,135.67,135.39,128.38,127.75,127.05,125.03,122.63,121.74,48.03,37.97,35.22,29.34,24.87,17.91.
6'-methyl-1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
Figure BDA0001710312770000171
1H),3.06(d,J＝17.2 Hz,1H),2.91(d,J＝17.1 Hz,1H),2.64(t,J＝16.4 Hz,3H),2.41(s,3H),2.09–2.00(m,2H),1.68(dd,J＝12.9,2.9 Hz,1H).
13C NMR(101 MHz,CDCl3)δ211.17,150.14,141.55,137.44,136.23,136.04,136.01,128.36,127.00,126.43,125.05,124.26,122.63,48.50,38.75,35.14,29.33,24.88,21.15.
5'-methoxy-1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
Figure BDA0001710312770000172
3.89(s,3H),3.07(d,J＝17.3 Hz,1H),2.92(d,J＝17.3 Hz,1H),2.61(dt,J＝17.7,11.7 Hz,3H),2.06(ddd,J＝25.3,16.2,5.7 Hz,2H),1.72–1.65(m,1H).
13C NMR(101 MHz,CDCl3)δ209.15,165.56,155.66,141.58,135.99,129.07,128.34,126.96,126.02,125.03,122.70,115.45,109.86,55.65,48.31,39.17,35.16,29.38,24.87.
6'-methoxy-1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
Figure BDA0001710312770000173
1H),3.83(s,3H),3.03(d,J＝16.9 Hz,1H),2.88(d,J＝16.9 Hz,1H),2.66(d,J＝17.6 Hz,2H),2.59(d,J＝6.5 Hz,1H),2.09–1.99(m,2H),1.69(dd,J＝12.8,3.5 Hz,1H).
13C NMR(101 MHz,CDCl3)δ211.07,159.53,145.59,141.53,137.00,136.01,128.37,127.46,127.02,125.05,124.37,122.60,105.43,55.63,49.04,38.44,35.19,29.37,24.91.
1-phenyl-2',3'-dihydrospiro[cyclohex[6]ene-4,6'-indeno[5,6-b]furan]-7'(5'H)-one；
Figure BDA0001710312770000181
8.1 Hz,1H),6.20(d,J＝4.6 Hz,1H),4.67(t,J＝8.9 Hz,2H),3.50(t,J＝8.8 Hz,2H),3.05(d,J＝16.8 Hz,1H),2.90(d,J＝16.8 Hz,1H),2.71–2.54(m,3H),2.05(dd,J＝21.3,9.2 Hz,2H),1.75–1.66(m,1H).
13C NMR(101 MHz,CDCl3)δ211.50,160.45,144.62,141.55,136.04,132.43,128.34,126.98,125.64,125.05,124.43,122.60,115.91,72.38,48.85,38.71,35.18,29.39,28.55,24.89.
1-phenyl-3',4'-dihydro-1'H-spiro[cyclohex[6]ene-4,2'-naphthalen]-1'-one；
Figure BDA0001710312770000182
2H),2.45(s,2H),2.06–1.81(m,5H).
13C NMR(101 MHz,CDCl3)δ202.43,143.23,141.52,134.74,133.16,131.81,128.73,128.33,128.11,126.87,126.71,124.98,122.39,43.07,32.50,30.34,28.00,25.24,24.45.
7'-bromo-1-phenyl-3',4'-dihydro-1'H-spiro[cyclohex[6]ene-4,2'-naphthalen]-1'-one；
Figure BDA0001710312770000183
1H),2.97–2.86(m,2H),2.65–2.46(m,2H),2.20–1.90(m,5H).
13C NMR(101 MHz,CDCl3)δ201.05,141.86,141.39,135.88,134.80,133.35,130.86,130.55,128.33,126.92,124.97,122.08,120.72,42.95,32.37,30.10,27.89,24.76,24.38.
1'-phenyl-6,7-dihydro-4H-spiro[benzo[b]thiophene-5,4'-cyclohex[6]en]-4-one；
Figure BDA0001710312770000184
2.53(ddd,J＝20.1,17.6,13.3 Hz,2H),2.17–1.97(m,4H),1.93–1.87(m,1H).
13C NMR(101 MHz,CDCl3)δ197.46,153.96,141.49,136.15,134.67,128.31,126.87,125.68,124.97,123.48,122.40,42.86,31.96,31.77,27.94,24.56,22.07.
9-phenylspiro[5.5]undec-8-en-1-one；
Figure BDA0001710312770000191
13C NMR(101 MHz,CDCl3)δ215.34,141.55,135.04,128.22,126.75,124.94,122.10,47.01,38.55,36.62,33.23,29.66,27.91,24.05,20.96.
1'-phenyl-8,9-dihydrospiro[benzo[7]annulene-6,4'-cyclohex[6]en]-5(7H)-one；
Figure BDA0001710312770000192
2.22–2.10(m,2H),1.97(dd,J＝14.3,6.5 Hz,2H),1.83(ddd,J＝19.4,12.5,6.2 Hz,3H).
13C NMR(101 MHz,CDCl3)δ213.68,141.56,141.43,137.17,135.76,130.30,128.72,128.28,126.98,126.88,126.44,125.00,122.19,48.47,35.68,34.66,34.10,30.24,24.58,23.23.
1-(p-tolyl)spiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
Figure BDA0001710312770000193
1H),7.34(d,J＝7.6 Hz,2H),7.16(d,J＝7.7 Hz,2H),6.18(d,J＝4.2 Hz,1H),3.13(d,J＝17.3 Hz,1H),2.98(d,J＝17.3 Hz,1H),2.74–2.54(m,3H),2.36(s,3H),2.07(ddd,J＝23.3,14.9,5.1 Hz,2H),1.70(dd,J＝12.7,4.3 Hz,1H).
13C NMR(101 MHz,CDCl3)δ211.14,152.84,138.67,136.70,135.93,135.82,134.92,129.04,127.49,126.73,124.91,124.35,121.68,48.22,39.08,35.07,29.30,24.86,21.09.
1-(4-chlorophenyl)spiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
Figure BDA0001710312770000194
Hz,1H),7.36(d,J＝8.5 Hz,2H),7.30(d,J＝8.2 Hz,2H),6.20(s,1H),3.12(d,J＝17.3 Hz,1H),2.96(d,J＝17.2 Hz,1H),2.73–2.51(m,3H),2.13–1.99(m,2H),1.70(dd,J＝13.2,2.5 Hz,1H).
13C NMR(101 MHz,CDCl3)δ210.83,152.69,139.92,135.83,135.00,132.69,128.44,127.57,126.74,126.33,124.38,123.18,48.01,39.13,35.02,29.23,24.80.
1-(4-fluorophenyl)spiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
Figure BDA0001710312770000201
3H),7.03(t,J＝8.3 Hz,2H),6.15(d,J＝3.6 Hz,1H),3.12(d,J＝17.3 Hz,1H),2.97(d,J＝17.2 Hz,1H),2.71–2.52(m,3H),2.11–2.00(m,2H),1.70(dd,J＝13.2,2.7 Hz,1H).
13C NMR(101 MHz,CDCl3)δ210.92,162.04(d,J＝245.9 Hz),152.72,137.63,135.86,135.14,134.97,127.55,126.72,126.57(d,J＝7.8 Hz),124.38,122.45,115.10(d,J＝21.3 Hz),48.05,39.12,35.00,29.26,25.02.
4-(naphthalen-2-yl)spiro[cyclohex[3]ene-1,2'-inden]-1'(3'H)-one；
Figure BDA0001710312770000202
6.39(d,J＝4.4 Hz,1H),3.18(d,J＝17.1 Hz,1H),3.02(d,J＝17.2 Hz,1H),2.78(dd,J＝28.8,16.2 Hz,3H),2.21–2.08(m,2H),1.77(dd,J＝12.9,3.4 Hz,1H).
13C NMR(101 MHz,CDCl3)δ211.05,152.83,138.64,135.92,135.80,135.00,133.54,132.64,128.14,127.85,127.57,126.78,126.18,125.68,124.40,123.70,123.44,123.28,48.24,39.15,35.24,29.36,24.87.
1-(4-fluorophenyl)-3',4'-dihydro-1'H-spiro[cyclohex[6]ene-4,2'-naphthalen]-1'-one；
Figure BDA0001710312770000203
Hz,1H),6.96(t,J＝8.2 Hz,2H),6.06(s,1H),3.09–2.78(m,4H),2.46(s,2H),2.09–1.94(m,4H).
13C NMR(101 MHz,CDCl3)δ202.32,160.73,143.16,137.67,133.86,133.17,131.77,128.71,128.09,126.71,126.47(d,J＝7.8 Hz),122.27,115.03(d,J＝21.2 Hz),42.97,32.48,30.51,27.98,25.20,24.61.

Claims (3)

1. a synthesis method of a spiro compound is characterized in that: the cyclic ketone compound and 2-aryl propylene react in a dimethyl sulfoxide solution system containing persulfate in one pot to obtain a spiro compound;
the spiro compound has the structure of formula 1:
Figure DEST_PATH_IMAGE001
formula 1
The cyclic ketone compound has a structure of formula 2:
Figure 624829DEST_PATH_IMAGE002
formula 2
The 2-arylpropene has the structure of formula 3:
Figure DEST_PATH_IMAGE003
formula 3
Wherein the content of the first and second substances,
R1、R2、R3and R4Is independently selected from C1~C5Or hydrogen, or R1And R2Any of them with R3And R4Any one of them constitutes C5~C7Alkyl, phenyl, naphthyl or C5~C6The alkane ring, the benzene ring, the naphthalene ring or the heterocyclic ring contains or does not contain substituent groups; the alkyl ring does not contain a substituent, or contains at least one substituent of alkyl and halogen; the benzene ring or the naphthalene ring does not contain a substituent, or at least one substituent of halogen, alkyl and alkoxy is contained; or the benzene ring or the naphthalene ring contains cyclic alkyl or cyclic alkoxy formed by ortho-position disubstituted; the heterocyclic ring does not contain a substituent, or contains at least one substituent of alkyl and halogen;
R5is phenyl, substituted phenyl, naphthyl or substituted naphthyl; the substituted phenyl group contains halogen or C1~C5At least one substituent of the alkyl group of (a); the substituted naphthyl group contains halogen or C1~C5At least one substituent of the alkyl group of (a);
n is 1 to 3;
the persulfate comprises at least one of potassium persulfate, sodium persulfate, potassium hydrogen persulfate and sodium hydrogen persulfate;
the reaction conditions are as follows: reacting for 18-30 h at 110-160 ℃ in a protective atmosphere.
2. The method for synthesizing a spiro compound according to claim 1, wherein:
the molar ratio of the persulfate to the cyclic ketone compound is 1-2: 1;
the molar ratio of the cyclic ketone compound to the 2-aryl propylene is 1: 1.5-2.5;
the concentration of the cyclic ketone compound in a dimethyl sulfoxide solution system is 0.1-0.5 mol/L.
3. The method for synthesizing a spiro compound according to claim 1, wherein: the reaction conditions are as follows: and reacting for 22-28 h at 130-150 ℃ in a protective atmosphere.
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