CN108675922A - A kind of spiro-compound and its synthetic method - Google Patents

A kind of spiro-compound and its synthetic method Download PDF

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CN108675922A
CN108675922A CN201810678307.5A CN201810678307A CN108675922A CN 108675922 A CN108675922 A CN 108675922A CN 201810678307 A CN201810678307 A CN 201810678307A CN 108675922 A CN108675922 A CN 108675922A
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ring
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alkyl
spiro
compound
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CN108675922B (en
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郭灿城
李慧
郭欣
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YUANJIANG HUALONG CATALYTIC TECHNOLOGY CO LTD
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    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
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    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
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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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    • C07C2603/93—Spiro compounds
    • C07C2603/94—Spiro compounds containing "free" spiro atoms

Abstract

The invention discloses a kind of spiro-compound and its synthetic methods, the spiro-compound is to collectively form parent spirane structure by cyclic ketones and cyclohexene, its synthetic method be by ring ketone compounds and 2 aryl propylene in the dimethyl sulfoxide solution system containing persulfate by one pot reaction to get spiro-compound；The synthetic method is realized by one kettle way, and reaction condition is mild, is not necessarily to extra catalyst, the good, high income of selectivity, is conducive to industrialized production.

Description

A kind of spiro-compound and its synthetic method
Technical field
The present invention relates to a kind of spiro-compounds, further relate to a kind of sub- by ring ketone compounds and 2- aryl propylene and diformazan The method that sulfone builds spirane structure jointly, belongs to organic synthesis field.
Background technology
Spiro-compound is also widely present in the bioactive molecules such as natural products, drug, pesticide (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-compound performances Go out the physiological activity outstanding such as antitumor, anti-hypertension, antiallergy, is widely used in clinical application (J.Med.Chem.1996,39,4044-4057；Med.Chem.Lett.2007,17,266-271；Synthesis- Stuttgart.2013,45,1909-1930；J.Med.Chem.2009,52,6936-6940).
Spiral shell indone compound is and extensive since its special spirocyclic ring scaffold shows multiple biological activities and pharmacological activity Concern.The spiral shell indone compound of early stage is found from natural plants, such as has been reported that the alkaloid separated from manaca With indone pyridine skeleton, derivative is found to have phosphodiesterase activity and inhibits Adenosine A2a receptor binding capacity, uses In treatment neurodegenerative disease and the relevant disease of inflammation (Aran go, G.J.；Cortes,D.；et al., Azafluorenones from Oxandra cf.major and biogenetic considerations[J] .Phytochemistry,1987,26,2093-2098).Up to the present, synthesis spiral shell indone is had been reported in the prior art The method for closing object such as compares typically 1- indones and formaldehyde and first carries out condensation reaction, then with the reaction of acetyl group allene, can Obtain the skeleton of indone containing 1- volution compound (Tetrahedron Lett.2013,54,4425-4428).For another example from 1- indones It sets out, is condensed by Michael condensation, Michael Diekmann with acrylate, the skeleton volution compound of indone containing 1- can also be synthesized (Helv Chim Acta 1995,78,857-865).But these methods have long flow path, raw material is not easy to obtain, total recovery is low, The shortcomings of post-processing is complicated.Chinese patent (CN108047007A) discloses a kind of conjunction of the skeleton of indone containing 1- volution compound At method, with aromatic carboxylic acids and α, alpha, beta-unsaturated ketone is raw material, using catalyst such as cymene ruthenous chloride dimers and The heavy metals additive such as manganese, zinc experienced aromatic carboxylic acids ortho position c h bond and α, the conjugate addition of alpha, beta-unsaturated ketone by one-step method It is reaction, intramolecular dehydration cyclisation, anti-with four steps such as Michael's addition, the intramolecular aldol condensation of the second molecule alpha, beta-unsaturated ketone 1- indone skeleton volution compounds (reaction route is as follows) should be synthesized, although this method synthesizes 1- indones by single step reaction Skeleton volution compound, but need using expensive catalyst, and heavy metal additive is used, it is unfavorable for environmental protection, cost It is higher.
Invention content
First purpose of the present invention is to be to provide a kind of loop coil precursor structure being made of cyclic ketones and cyclohexene, is spiral shell The synthesis of ring class drug provides new organic intermediate.
For it is existing structure spirane structure method there are step complexity, it is of high cost, it is unfriendly to environment the defects of, this Another purpose of invention is to be that provide one kind providing α-carbon, DMSO offer methyl and 2- arylprops by ring ketone compounds Alkene provides the method that propylene builds spirane structure jointly, which is realized by one kettle way, and reaction condition is mild, is not necessarily to Extra catalyst, the good, high income of selectivity, are conducive to industrialized production.
In order to achieve the above technical purposes, the present invention provides a kind of spiro-compounds, with 1 structure of formula：
Wherein,
R1、R2、R3And R4It is independently selected from alkyl or hydrogen, alternatively, R1And R2Any of and R3And R4Any one composition alkane ring, Aromatic ring or heterocycle, and containing substituent group or be free of substituent group on alkane ring, aromatic ring or heterocycle；
R5For aryl；
N is 1~3.
Preferred scheme, R in spiro-compound1、R2、R3Or R4It can be selected from alkyl, alkyl is generally short-chain alkyl, such as C1 ~C5Alkyl, such as methyl, ethyl, propyl.R in spiro-compound1And R2Any of and R3And R4Any of may be constructed Alkane ring, such as R1With R3Between alkane ring connected and composed by carbochain, alkane ring is generally the alkane ring that carbon atom number is 5~7.Meanwhile alkane Some conventional substituent groups can be contained on ring, as halogen (fluorine, chlorine, bromine or iodine etc.) or short-chain alkyl (carbon atom number it is little 5) etc. in.R1With R3When constituting alkane ring, R2With R4It can be short-chain alkyl or hydrogen, preferably be hydrogen.Similarly, R1With R4Between, R2With R4Between or R2With R3Between similar alkane ring can be also connected and composed by carbochain.R in spiro-compound1And R2Any of with R3And R4Any of may be constructed heterocycle, such as R1With R3Between can connect and compose heterocycle by containing heteroatomic carbochain.Heterocycle Can be saturated heterocyclic (such as tetrahydrofuran) or unsaturated heterocycle (such as furans).Heterocycle can be five-membered ring or hexatomic ring, most It is well five-membered ring.Heterocycle number on heterocycle can be 1~2, preferably contain 1 hetero atom.Hetero atom is generally oxygen, nitrogen, sulphur Deng, such as furans, pyrroles, thiophene.Can also contain some conventional substituent groups on heterocycle, such as halogen (fluorine, chlorine, bromine or iodine) or Short-chain alkyl (general carbon atom number is less than 5) etc..R1With R3When constituting unsaturated heterocycle, R2With R4For hydrogen.Similarly, R1With R4It Between, R2With R4Between or R2With R3Between also can connect and compose similar heterocycle by containing heteroatomic carbochain.R in spiro-compound1 And R2Any of and R3And R4Any of may be constructed aromatic ring, such as R1With R3Between can be connected and composed by unsaturated carbon chains Phenyl ring or naphthalene nucleus, meanwhile, some conventional substituent groups can be contained on phenyl ring or naphthalene nucleus, such as halogen (fluorine, chlorine, bromine or iodine) or short chain Alkyl (general carbon atom number is less than 5), alkoxy (C1~C5Alkoxy) etc..The number of substituent group on phenyl ring or naphthalene nucleus is 1 ~2, especially adjacent two substituent groups may be constructed cyclic structure, such as alkane ring or alcoxyl ring.Similarly, R1With R4It Between, R2With R4Between or R2With R3Between similar phenyl ring can be also connected and composed by unsaturated carbon chains.
R5Preferably phenyl, substituted-phenyl, naphthalene or substituted naphthyl.R5When selected from substituted-phenyl, the substituted-phenyl includes Substituent group number be 1~2, substituent group is selected from halogenic substituent, at least one of alkyl.Halogenic substituent for example fluorine, chlorine, Bromine, iodine etc..Alkyl is C1~C10Alkyl；More preferably C1~C5Short-chain alkyl, such as methyl, ethyl, propyl, can also For the alkyl containing branch, such as isopropyl, isobutyl group.The number of substituent group is preferably 1, and substituting group position preferably aligns (opposite alkenyl).
The present invention also provides a kind of synthetic method of spiro-compound, this method is by ring ketone compounds and 2- aryl Propylene is in the dimethyl sulfoxide solution system containing persulfate by one pot reaction to get spiro-compound；
The spiro-compound has 1 structure of formula：
The ring ketone compounds have 2 structure of formula：
The 2- aryl propylene has 3 structure of formula：
Wherein,
R1、R2、R3And R4It is independently selected from alkyl or hydrogen, alternatively, R1And R2Any of and R3And R4Any of constitute alkane Ring, aromatic ring or heterocycle, and containing substituent group or be free of substituent group on alkane ring, aromatic ring or heterocycle；
R5For aryl；
N is 1~3.
Preferred scheme, what ring ketone compounds participated in reaction is α carbon, the various substitutions in ring ketone compounds on cyclic ketones Group is to the electronic effect and space steric effect obvious effect of cyclization, R1Or R2With R3Or R4Constitute aromatic ring or When fragrant condensed ring or heteroaromatic, since these groups can participate in being conjugated with carbonyl, the activity of α carbon can be obviously increased.Cyclic ketones class R in compound1、R2、R3Or R4It can be selected from alkyl, alkyl is generally short-chain alkyl, such as C1~C5Alkyl, such as methyl, ethyl, third Base etc..R in ring ketone compounds1And R2Any of and R3And R4Any of may be constructed alkane ring, such as R1With R3Between pass through Carbochain connects and composes alkane ring, and alkane ring is generally the alkane ring that carbon atom number is 5~7.Meanwhile some routines can be contained on alkane ring Substituent group, such as halogen (fluorine, chlorine, bromine or iodine etc.) or short-chain alkyl (carbon atom number be not more than 5) etc..R1With R3Constitute alkane ring When, R2With R4It can be short-chain alkyl or hydrogen, preferably be hydrogen.Similarly, R1With R4Between, R2With R4Between or R2With R3Between Also similar alkane ring can be connected and composed by carbochain.R in ring ketone compounds1And R2Any of and R3And R4Any of can be with Constitute heterocycle, such as R1With R3Between can connect and compose heterocycle by containing heteroatomic carbochain.Heterocycle can be for saturated heterocyclic (such as Tetrahydrofuran) or unsaturated heterocycle (such as furans).Heterocycle can be five-membered ring or hexatomic ring, preferably five-membered ring.On heterocycle Heterocycle number can be 1~2, preferably contain a hetero atom.Hetero atom is generally oxygen, nitrogen, sulphur etc., such as furans, Bi Kahuo Thiophene etc..Some conventional substituent groups can also be contained on heterocycle, as halogen (fluorine, chlorine, bromine or iodine etc.) or short-chain alkyl (carbon 5) etc. atomicity is less than.R1With R3When constituting unsaturated heterocycle, R2With R4For hydrogen.Similarly, R1With R4Between, R2With R4Between or R2With R3Between also can connect and compose similar heterocycle by containing heteroatomic carbochain.R in ring ketone compounds1And R2Any of With R3And R4Any of may be constructed aromatic ring, such as R1With R3Between phenyl ring or naphthalene nucleus can be connected and composed by unsaturated carbon chains, Meanwhile some conventional substituent groups can be contained on phenyl ring or naphthalene nucleus, as halogen (fluorine, chlorine, bromine or iodine) or short-chain alkyl (carbon Atomicity less than 5), alkoxy (C1~C5Alkoxy) etc..The number of substituent group on phenyl ring or naphthalene nucleus is 1~2, especially It is that two adjacent substituent groups may be constructed cyclic structure, such as alkane ring or alcoxyl ring.Similarly, R1With R4Between, R2With R4It Between or R2With R3Between similar phenyl ring or naphthalene nucleus can be also connected and composed by unsaturated carbon chains.
In the 2- aryl propylene of the present invention, R5More preferably it is phenyl, substituted-phenyl, naphthalene or substituted naphthyl.R5Selected from substitution When phenyl, the substituent group number that the substituted-phenyl includes is 1~2, and substituent group is at least one in halogenic substituent, alkyl Kind.Halogenic substituent such as fluorine, chlorine, bromine, iodine etc..Alkyl is C1~C10Alkyl；More preferably C1~C5Short-chain alkyl, Ru Jia Base, ethyl, propyl etc., or the alkyl containing branch, such as isopropyl, isobutyl group.The number of substituent group is preferably 1, And substituting group position preferably aligns (opposite alkenyl).The range of choice of 2- aryl propylene is confined to selection aryl substituent, virtue Base substituent group provides big conjugated system, can make the methyl on alkenyl that there is enough activity to participate in cyclisation.Aryl substituent cannot It is arbitrarily replaced by other substituent groups, such as heteroaromatic, alkyl replacement aryl cannot obtain target product.Work as R5Selection substitution When phenyl, the position of substituent group is preferably the contraposition of alkenyl, and substituent group can be weak electron donating group, and such as alkyl can also For weak drawing electron group, such as halogen.And strong electron donating group hales electron group, such as nitro such as amido, alkoxy, it is difficult to obtain Obtain ideal yield.
The molar ratio of preferred scheme, persulfate and ring ketone compounds is 1~2:1.More preferably it is 1.3~1.8:1.
The molar ratio of preferred scheme, ring ketone compounds and 2- aryl propylene is 1:1.5~2.5.
Preferred scheme, a concentration of 0.1~0.5mol/L of the ring ketone compounds in dimethyl sulfoxide solution system.Diformazan Base sulfoxide acts on of both primarily serving, and on the one hand plays the role of good solvent, reaction substrate is on the other hand used as, by two A dimethyl sulfoxide provides two methyl as two carbon atoms in cyclohexene ring in spirane structure.
More preferably scheme, the persulfate are mainly the persulfate of alkali metal containing and/or the over cure of alkali metal containing Sour hydrogen salt, most preferred persulfate include at least one of potassium peroxydisulfate, sodium peroxydisulfate, potassium hydrogen persulfate, hydrogen persulfate sodium.
The condition of more preferably scheme, the reaction is：Under protective atmosphere, at a temperature of 110~160 DEG C, reaction 18 ~30h.The condition of more preferably scheme, the reaction is：Under protective atmosphere, at a temperature of 130~150 DEG C, reaction 22~ 28h.Protective atmosphere refers generally to the mixed atmosphere of nitrogen or inert atmosphere or both.
The present invention builds spirane structure to carry out reaction mechanism jointly with 1- indones and dimethyl sulfoxide and 2- phenylpropens Explanation.By consulting and referring to pertinent literature, a series of mechanism study experiment, following reaction equation (1)~(6) are devised It is shown.In order to prove whether the reaction passes through the reaction mechanism mechanism of reaction of free radical, reaction (1) is devised, is added under the conditions of standard reaction The 2,6-di-tert-butyl p-cresol (BHT) for entering 2.0 equivalents (opposite 1- indones), reacts 12h, as a result still can be suitable by GC-MS Profit detects the generation of spirane structure target product, illustrates that reaction there is no being suppressed, is reacted without one free radical of experience The reaction mechanism mechanism of reaction.In order to prove that the reaction whether there is reaction intermediate, 1- indones and dimethyl sulfoxide and 2- phenylpropens are being marked It reacts 12 hours under quasi- reaction condition, by being detected in GC-MS, in addition to detecting target product spiro-compound, while also examining Measure the presence of compound B and compound C.In order to prove whether compound B and C are centre in spirane structure building process Body devises reaction (2) and reaction (3), replaces 2- phenylpropens by raw material of compound B, reacts at the standard conditions, simultaneously Compound 1- indones also are replaced by raw material of compound C, surprisingly finds, spirane structure successfully is detected by GC-MS, is said Bright compound B and C is intermediate that may be present in spirane structure building-up process.In order to further understand fully the source of compound B, Reaction (4) is further devised, 2- phenylpropens are directly reacted at the standard conditions with dimethyl sulfoxide, by GC- MS detects the presence for being found that compound B, while having also obtained compound A.In order to further understand fully the source of compound C, into One step devises reaction (5), 2- phenylpropens is directly reacted at the standard conditions with dimethyl sulfoxide, by GC-MS Detection is found that the presence of compound C, while having also obtained compound D.More accurately whether dimethyl sulfoxide is verified in order to obtain The generation for participating in cyclohexene ring in spirane structure, devises reaction (6), is replaced using the deuterated dimethyl sulfoxide of isotope labelling normal The dimethyl sulfoxide (DMSO) of rule reacts at the standard conditions, and the presence of deuterium is successfully detected in the cyclohexene ring of spirane structure, and And the presence of deuterium is detected on two carbon atoms, illustrate to provide two methyl by dimethyl sulfoxide (DMSO).Standard reaction condition： N2Under, by 1- indones (0.5mmol), α-methylstyrene (0.75mmol) and DMSO (2mL), 140 DEG C, reaction is for 24 hours.
Reaction equation (1):
Reaction equation (2):
Reaction equation (3)：
Reaction equation (4):
Reaction equation (5)：
Reaction equation (6):
According to above-mentioned experiment, the present invention is proposed builds loop coil knot jointly by 1- indones and dimethyl sulfoxide and 2- phenylpropens The reasonable mechanism of structure：Shown in following reaction equation.First, using K2S2O8DMSO is activated, obtains that DMSO is made to be converted to dimethyl Sulphur cation, while 2- phenylpropens discharge Hydrogen Proton, are converted to 2- phenylpropen anions, 1- indones also discharge Hydrogen Proton, Become 1- indone anions, 2- phenylpropens anion and 1- indones anion are easy to coupling dimethyl disulfide cation and generate Sulphur first ether compound A and D, sulphur first ether compound A and D are in K2S2O8Under oxidation, removed by demethylation small Molecule methyl mercaptan compound obtains compound B and C, compound B and compound C and occurs Deere this Alder reaction, final To target product.
Compared with the prior art, the advantageous effects that technical scheme of the present invention is brought：
1) spirane structure of the invention is made of cyclic ketones and cyclohexene, and can include abundant substituent group, and can be modified Group, it is effectively intermediate to be provided using spirane structure as synthesis such as the drugs of parent.
2) present invention provides α carbon by ring ketone compounds for the first time, 2- aryl propylene provides acrylic and dimethyl sulfoxide (DMSO) Methyl is provided and successfully builds spirane structure, a kind of completely new synthesis thinking is provided for the structure of spirane structure.
3) it is avoided without using catalyst, relatively existing synthetic method in the building-up process of spirane structure of the invention Using catalyst and additive expensive and with pollution property, cost and environmental protection are advantageously reduced.
4) ring ketone compounds, 2- aryl propylene and dimethyl sulfoxide (DMSO) conduct are used in loop coil building-up process of the invention Base stock is all existing conventional industrial chemicals, of low cost, is conducive to industrialized production.
5) one pot reaction is used in the building-up process of spirane structure of the invention, and reaction condition is mild, it is easy to operate, Meet demand of industrial production.
6) raw material availability is high in spirane structure building-up process of the invention, and product yield can reach 80% or more.
7) wider to the accommodation of substrate raw material in spirane structure building-up process of the invention, a variety of substitutions can be built The spiro-compound of group, and substituting group position is selectively strong.
Description of the drawings
【Fig. 1】For 1'-phenyl-6,7-dihydro-4H-spiro [benzo [b] thiophene-5,4'-cyclohex [6] en] -4-one nuclear-magnetism carbon spectrogram.
【Fig. 2】For 1'-phenyl-6,7-dihydro-4H-spiro [benzo [b] thiophene-5,4'-cyclohex [6] en] -4-one nucleus magnetic hydrogen spectrum figure.
【Fig. 3】For 1- (4-fluorophenyl) spiro [cyclohex [6] ene-4,2'-inden] -1'(3'H)-one Nuclear-magnetism carbon spectrogram.
【Fig. 4】For 1- (4-fluorophenyl) spiro [cyclohex [6] ene-4,2'-inden] -1'(3'H)-one Nucleus magnetic hydrogen spectrum figure.
【Fig. 5】For 1-phenylspiro [cyclohex [6] ene-4,2'-inden] -1'(3'H) nuclear-magnetism carbon of-one spectrum Figure.
【Fig. 6】For 1-phenylspiro [cyclohex [6] ene-4,2'-inden] -1'(3'H) nucleus magnetic hydrogen spectrum of-one Figure.
【Fig. 7】For the nuclear-magnetism carbon spectrogram of 9-phenylspiro [5.5] undec-8-en-1-one.
【Fig. 8】For the nucleus magnetic hydrogen spectrum figure of 9-phenylspiro [5.5] undec-8-en-1-one.
Specific implementation mode
Following embodiment is intended to further illustrate the content of present invention, rather than limits the protection model of the claims in the present invention It encloses.
Unless otherwise stated, all reactions carry out in Schlenk test tubes.
All reaction raw materials solvents are obtained from commercial source, and are used without further purification.
Product separation uses silica gel chromatographic column, silica gel (- 400 mesh of 300 mesh of granularity).
1H NMR (400MHz), 13C NMR (100MHz) and 19F NMR (376MHz) detections use Bruker ADVANCE III spectrometers, with CDCl3For solvent, using TMS as internal standard, chemical shift is in terms of parts per million (ppm), with tetramethylsilane 0.0ppm is with reference to displacement.Multiplicity is explained using following abbreviation (or combinations thereof)：S=is unimodal, and d=is bimodal, and t=is triple Peak, q=quartets, m=multiplets, br=broad peaks.The unit of coupling constant J is hertz (Hz).Chemical shift indicates with ppm, With reference to deuterochloroform the center line of 77.0ppm triplets or with reference to deuterated DMSO 39.52ppm septets center line.
GC-MS is detected using GC-MS QP2010 equipment, and HRMS is measured using electron ionization (EI) method, mass-synchrometer Type is TOF, and EI is detected using Esquire 3000plus instruments.
1. condition optimizing is tested:
For building spirane structure jointly by 1- indones and dimethyl sulfoxide and 2- phenylpropens, to oxidant and its dosage, Multiple influence factors such as reaction temperature, reaction dissolvent and additive are inquired into, to seek best reaction condition.
Specific reaction process：By 1- indones, α-methylstyrene, oxidant, additive and DMSO, in N2Under atmosphere, instead It should for 24 hours.
Reaction route is as follows：
Table 1：The yield of target product spirane structure under the conditions of differential responses
1) selection of additive
As seen from Table 1, the use of additive has a great impact to reaction, and many experiments show such as project 1 in table 1 ~6 and 11, in 1- indones and dimethyl sulfoxide and 2- phenylpropens build the reaction process of spirane structure, it has not been found that favorably In improving reaction efficiency, increase the benign additive of yield, such as DABCO, DBU, K2CO3、Cs2CO3、Et3The alkalinity such as N or NaOAc Substance is as additive in use, apparent inhibition reaction, cannot get target product spiro-compound substantially.
3) selection of oxidant
The present invention has attempted the several frequently seen oxidant in this field, such as project 9~16 in table 1, oxidant such as persulfate, Organic peroxide, inorganic hydrogen peroxide etc. have preferable reaction effect, when making when being found only at persulfate as oxidant With tert-butyl hydroperoxide (TBHP), DTBP or hydrogen peroxide (H2O2) when being used as oxidant almost without obtaining target product, because This, selects persulfate as optimal oxidant.
4) selection of oxidizer
After determining that potassium peroxydisulfate, sodium peroxydisulfate etc. are best oxidant, the oxidant of different amounts is explored to reaction It influences.Such as project 11,17 and 18 in table 1.When the dosage of oxidant is between 0.5~0.75 equivalent, with oxidant content Increase, the conversion ratio of raw material and the yield of product also increase therewith.And when the dosage of oxidant is more than 0.75 equivalent, production Rate declines apparent.Therefore, the persulfate of 0.75 equivalent is the optimum amount of reaction.
5) selection of reaction temperature
Reaction temperature is to influence a key factor of chemical reaction process, and optimal reaction temperature, has studied in order to obtain The yield of the reaction at different temperatures, such as project 7~11 in table 1.In less than 100 DEG C temperature, it substantially cannot get target production Object, when temperature reaches 120 DEG C or more, reaction yield significantly improves, and increases the temperature to 140 DEG C, reaction yield reaches highest, and high In 140 DEG C, reaction side reaction is apparent.Therefore, 140 DEG C of optimum temperatures for the reaction.
6) selection of reaction dissolvent
Since DMSO is to be used as reaction substrate and solvent simultaneously during synthesizing dihydro pyrans, being other solvents can not replace It changes.DMSO may be used in the solvent of the present invention, while can also use the mixed solvent of DMSO and other solvents.
2. the range of choice of reaction substrate：
After the optimal synthesis condition of spirane structure is determined, the substrate spectrum and applicability of reaction are probed into, it is real Result is tested as shown in table 2 and table 3.Table 2 is different ring ketone compounds and 2- phenylpropens and the reaction result of DMSO.From table As can be seen that indone class, cycloalkanones and heteroaromatic and cyclic ketones class etc. can be with 2- phenylpropens and DMSO in standard in 2 Effectively synthesize corresponding spirane structure under reaction condition, and the yield of target product is 70% or so, reach as high as 80% with On, yield is more satisfactory.Also, many experiments show influence of the cyclic ketone compound substituent group to reaction be it is bigger, Carbonyl is preferably connected on conjugated system, such as in phenyl ring, fragrant condensed ring, heteroaromatic, due to carbonyl can participate in conjugation can be with The activity for significantly improving carbonyl α carbon is easy to lose Hydrogen Proton, smoothly can build loop coil knot with 2- phenylpropens and DMSO Structure, yield is 80% or so.As connected other groups, such as alkyl on cyclic ketones, cyclic ketones builds spiral shell with 2- phenylpropens and DMSO The yield of ring is substantially reduced.Table 3 is different 2- aryl propylene and 1- indones or the reaction result of benzo ring hexanone and DMSO, experiment The result shows that 2 bit substituents must be the group for having big conjugated system, such as aryl, other heteroaromatics, alkyl etc. on propylene Requirement is cannot be satisfied, the aryl of big conjugated system is conducive to improve the activity of Alpha-Methyl.And the selection of the substituent group on aryl Cannot be to push away electronics or draw the stronger substituent group of electronic capability, such as nitro, alkoxy, and push away electronics and by what is required If or draw electronic capability compared with substituent group, such as halogen, alkyl be satisfied by requirement.The position of substituent group preferably aligns.
(1) different ring ketone compounds and the reaction equation of 2- phenylpropens and DMSO are as follows：
Weigh potassium persulfate (K2S2O8) (202.5mg, 0.75mmol), cyclic ketone compound (0.5mmol) is placed in 25ml's In Shi Lunke reaction tubes, then dimethyl sulfoxide (DMSO, 2ml) is added thereto, 2- phenylpropens (118mg, 1mmol) are filled with nitrogen Gas.At 140 DEG C, stir 24 hours.It after the completion of reaction, is cooled to room temperature, adds water (4ml), ethyl acetate to extract (3*5ml), nothing Water Na2SO4Dry, after solvent is fallen in vacuum distillation, silicagel column (200-300 mesh) separation obtains target product spirane structure.
The different ring ketone compounds of table 2. and 2- phenylpropens and DMSO reaction results
(2) difference 2- aryl propylene and 1- indones or benzo ring hexanone compound and the reaction equation of DMSO are as follows：
Weigh potassium persulfate (K2S2O8) (202.5mg, 0.75mmol), 1- indones or benzo ring hexanone (0.5mmol) are set In the Shi Lunke reaction tubes of 25ml, then dimethyl sulfoxide (DMSO, 2ml) is added thereto, 2- aryl propylene (1mmol) is filled with Nitrogen.At 140 DEG C, stir 24 hours.It after the completion of reaction, is cooled to room temperature, water (4ml), ethyl acetate is added to extract (3*5ml), Anhydrous Na2SO4Dry, after solvent is fallen in vacuum distillation, silicagel column (200-300 mesh) separation obtains target product spiro-compound.
3 difference 2- aryl propylene of table and 1- indones and the reaction result of DMSO
The molecular structure characterization of part spiro-compound：
1-phenylspiro[cyclohex[6]ene-4,2'-inden]-1'(3'H)-one；
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；
1H NMR(400MHz、CDCl3) δ 7.87-7.75 (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) δ 209.12,168.70,155.66 (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；
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；
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；
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；
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；
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；
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；
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；
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；
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；
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；
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；
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；
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；
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；
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) δ 210.92,162.04 (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；
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；
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 (10)

1. a kind of spiro-compound, it is characterised in that：With 1 structure of formula：
Wherein,
R1、R2、R3And R4It is independently selected from alkyl or hydrogen, alternatively, R1And R2Any of and R3And R4Any of constitute alkane ring, virtue Ring or heterocycle, and containing substituent group or be free of substituent group on alkane ring, aromatic ring or heterocycle；R5For aryl；
N is 1~3.
2. a kind of spiro-compound according to claim 1, it is characterised in that：
The alkyl is C1~C5Alkyl；
The alkane ring is C5~C7Alkane ring；
The aromatic ring is phenyl ring or naphthalene nucleus；
The heterocycle is C5~C6Oxygen-containing, nitrogen or at least one of sulphur heterocycle；
The aryl is phenyl, substituted-phenyl, naphthalene or substituted naphthyl.
3. a kind of spiro-compound according to claim 2, it is characterised in that：
Substituent group is free of on the alkane ring, or includes at least one of alkyl, halogen substituent group；
Substituent group is free of on the aromatic ring, or includes at least one of halogen, alkyl, alkoxy substituent group；Or it is wrapped on aromatic ring Containing by the disubstituted cyclic alkyl constituted in ortho position or alkoxy substituted；
Substituent group is free of on the heterocycle, or includes at least one of alkyl, halogen substituent group；
The substituted-phenyl includes halogen or C1~C5At least one of alkyl substituent group；
The substituted naphthyl includes halogen or C1~C5At least one of alkyl substituent group.
4. a kind of synthetic method of spiro-compound, it is characterised in that：Ring ketone compounds are with 2- aryl propylene containing persulfuric acid By one pot reaction to get spiro-compound in the dimethyl sulfoxide solution system of salt；
The spiro-compound has 1 structure of formula：
The ring ketone compounds have 2 structure of formula：
The 2- aryl propylene has 3 structure of formula：
Wherein,
R1、R2、R3And R4It is independently selected from alkyl or hydrogen, alternatively, R1And R2Any of and R3And R4Any of constitute alkane ring, virtue Ring or heterocycle, and containing substituent group or be free of substituent group on alkane ring, aromatic ring or heterocycle；R5For aryl；
N is 1~3.
5. a kind of synthetic method of spiro-compound according to claim 4, it is characterised in that：
The alkyl is C1~C5Alkyl；
The alkane ring is C5~C7Alkane ring；
The aromatic ring is phenyl ring or naphthalene nucleus；
The heterocycle is C5~C6Oxygen-containing, nitrogen or at least one of sulphur heterocycle；
The aryl is phenyl, substituted-phenyl, naphthalene or substituted naphthyl.
6. a kind of synthetic method of spiro-compound according to claim 5, it is characterised in that：
Substituent group is free of on the alkane ring, or includes at least one of alkyl, halogen substituent group；
Substituent group is free of on the aromatic ring, or includes at least one of halogen, alkyl, alkoxy substituent group；Or it is wrapped on aromatic ring Containing by the disubstituted cyclic alkyl or cyclic alkoxy constituted in ortho position；
Substituent group is free of on the heterocycle, or includes at least one of alkyl, halogen substituent group；
The substituted-phenyl includes halogen or C1~C5At least one of alkyl substituent group；
The substituted naphthyl includes halogen or C1~C5At least one of alkyl substituent group.
7. a kind of synthetic method of spiro-compound according to claim 4, it is characterised in that：
The molar ratio of persulfate and ring ketone compounds is 1~2:1；
The molar ratio of ring ketone compounds and 2- aryl propylene is 1:1.5~2.5；
A concentration of 0.1~0.5mol/L of the ring ketone compounds in dimethyl sulfoxide solution system.
8. a kind of synthetic method of spiro-compound according to claim 7, it is characterised in that：The persulfate includes At least one of potassium peroxydisulfate, sodium peroxydisulfate, potassium hydrogen persulfate, hydrogen persulfate sodium.
9. according to a kind of synthetic method of spiro-compound of claim 4~8 any one of them, it is characterised in that：It is described anti- The condition answered is：Under protective atmosphere, at a temperature of 110~160 DEG C, 18~30h is reacted.
10. a kind of synthetic method of spiro-compound according to claim 9, it is characterised in that：The condition of the reaction For：Under protective atmosphere, at a temperature of 130~150 DEG C, 22~28h is reacted.
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