CN105884757A - Polysubstituted sulfo-pyrrolidone derivative synthesis method - Google Patents
Polysubstituted sulfo-pyrrolidone derivative synthesis method Download PDFInfo
- Publication number
- CN105884757A CN105884757A CN201410834198.3A CN201410834198A CN105884757A CN 105884757 A CN105884757 A CN 105884757A CN 201410834198 A CN201410834198 A CN 201410834198A CN 105884757 A CN105884757 A CN 105884757A
- Authority
- CN
- China
- Prior art keywords
- reaction
- thioxo
- polysubstituted
- ketone derivatives
- sulfo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a novel polysubstituted sulfo-pyrrolidone synthesis method. According to the method, aldehyde, malononitrile, cyclohexyl isocyanide and faintly acid mercaptobenzoxazole or thiazole are mixed for one-step reaction under the catalysis of nanometer CeO2 to obtain a sulfo-pyrrolidone derivative. According to the synthesis method, nanometer CeO2 is used as a catalyst and is stable, capable of being repeatedly used, small in usage amount and high in efficiency compared with traditional methods, and the requirement of green chemistry is met; nanometer CeO2 is high in the catalytic activity and wide in application range, and is more suitable for aromatic aldehyde containing electrondrawing groups compared with traditional methods. Faintly acid heterocyclic thione with low activity is used as a substrate, the sulfo-pyrrolidone derivative with diversified structures is synthesized through multi-component Ugi-Smiles cascade reaction, the reaction condition is mild, heating is not needed, reaction time is short, yield is high, and aftertreatment is convenient.
Description
Technical field
The invention belongs to chemosynthesis technical field, particularly to the novel synthesis of polysubstituted thiopyrrolidone.
Background technology
Pyrrolidinone derivatives is the organic heterocyclic molecule that a class is important, is widely present in nature.With ketopyrrolidine as bone
The compound of frame has potential pharmacologically active and biological activity, and pyrrolidin derivatives converts at the growth promoter of object, energy,
Playing an important role during information transmission etc., such as antiinflammatory, antitumor, immunosuppressant etc., wherein Atorvastatin calcium was once
Bring huge repercussion.Due to the biological activity of this compounds, this compounds is at aspects such as medicine, pesticide, biological studies
Obtain studying widely.
In recent years, along with people's further investigation to heterocyclic drug, particularly to various substituted pyrrolidin-2-one quasi-molecules
Synthesis and the research of its physiologically active, the application in terms of medicine of the substituted pyrrolidin-2-ketone is increasingly subject to people's attention.
This quasi-molecule has good drug development prospect.We have been synthesized a series of pyrrolidin-2-one by Ugi-Smiles
Thioated derivant, thioated ketopyrrolidine series derivates makes the structure of ketopyrrolidine increasingly complex, also show that have more
Bio-pharmacology activity, such as thiopyrrolidone has good inhibition, and is that synthesis of natural is big streptococcus mutant body
The important core of ring tetrapyrrole, natural cyclic tetrapyrrole include porphyrin, porphin, porphine of bacterium, different bacterium porphin,
High saturated hydrogen porphyrin and coline etc., be the class life active compound with multiple biological function, and its synthesis and applied research are current
The important research content of natural product chemistry and focus.
Ugi reaction is the particularly important multi-component reaction of a class, from nineteen fifty-nine Germanization scholar Ugi reported first by isonitrile,
Since the condensation of aldehyde, amine, carboxylic acid four component one step generates α-acylamino amide, this reaction receives much concern always.Classical Ugi reaction
In carboxyl acid component can be replaced by hydrazoic acid, thiosulfate, cyanate, rhodanate, bamic acid, hydrogen sulfide and selenium
Change hydrogen or the more weak hydrone of acidity, therefore can be obtained the product of structure diversity by Ugi reaction.
Resetting owing to the Smiles of final step resets the Mumm that instead of in classical Ugi reaction, phenol is joined as acidic components
With Ugi react and be also called Ugi-Smiles and react.This reaction often generates fused heterocyclic compound, and bigger the modifying of phenol ring
Property that product structure multiformity is able to is further abundant.But owing to phenols acidity is more weak, it is generally required to face position or para-position at hydroxyl
Having strong electron-withdrawing group (such as nitro), therefore, the Ugi reaction report that acid relatively low heterocyclic thiol relatively weak, active participates in is very
Few.In this type of reacts, owing to substrate active is low, the performance of catalyst just seems most important.And participated in by heterocyclic thiol
Ugi reaction can obtain that structure is complicated, novel, have bioactive novel heterocyclic compounds pyrrolidinone derivatives.
The present invention is through Ugi-Smiles and reacts aldehyde, Cyanoacetyl-Cyacetazid, cyclohexyl isonitrile and weakly acidic mercaptobenzoxazole
Or thiazole mixing, at nano Ce O2It is catalyzed next step reaction and obtains thioxo-pyrrolidine ketone derivatives.
Summary of the invention
One, invention brief introduction
The purpose of the present invention is that the drawbacks described above overcoming existing production technology, is reacted by Ugi-Smiles, at nano Ce O2
The lower novel synthesis developing thiopyrrolidone of catalysis.
Another object of the present invention is to expand the substrate spectrum of Ugi-smiles reaction.
A further object of the invention is to have widened the range of application of nanostructured materials catalyst.
Two, technical scheme
The reaction expression of the present invention:
Described compound (1) benzaldehyde R group includes H, 4-F, 4-Cl, 4-Br, 4-I, 4-NO2, 4-CN, 3-F,
3-NO2, 2-Br, 2-F-4-Br, 4-OCH3, 3,4,5-OCH3；Compound (4) X is O (2-mercaptobenzooxazole) or S
(2-mercaptobenzothiazole).
Described reaction various concentration of substrate ratio is respectively: benzaldehydes (1) (0.2mmol), Cyanoacetyl-Cyacetazid (2) (0.24mmol),
Cyclohexyl isonitrile (3) (0.24mmol), 2-mercaptobenzooxazole or 2-mercaptobenzothiazole (4) (0.2mmol).
The preferential solvent of described reaction system is acetonitrile and the volume ratio of water is 3: 1.
When methanol and ethanol are solvent, productivity is minimum, it may be possible to owing to its polarity is less, is unfavorable for that reaction is carried out；Acetonitrile is solvent
Time, dissolubility is relatively strong, is unfavorable for that product separates out；With pure water as solvent, raw material not readily dissolves, and by acetonitrile and water with a definite proportion
During example mixing, productivity increases, and when acetonitrile and water are with 3: 1 mixing, productivity reaches 90%, best results, this be probably by
Yu Shuike makes Organic substance carry out hydrophobic polymerizable, thus has the effect accelerating reaction, and beneficially product separates out, it is simple to separate,
Productivity improves accordingly.
The catalyst that described reaction is used is the nano Ce O of different-shape2, graininess, fusiformis bar-shaped including porous and linear
Four kinds of patterns, consumption is 10mg/1mmol benzaldehyde.
The reaction yield of time without catalyst relatively low (46%), the catalytic effect of nanoscale ceria aoxidizes higher than common commercial level
Cerium, fully shows the nanocatalyst high catalysis efficiency compared to non-nano catalyst.Wherein the making of porous nano ceria
With making reaction yield significantly improve (90%), and it is much better than the nano-cerium oxide of other three kinds of patterns.
Porous nano ceria has 9nm aperture, CeO2Outstanding redox ability makes this some holes become highly active
Microreactor, the hydrone of polarity utilizes hydrophobic effect to be driven in hole by organic molecule, makes reaction easily occur.Meanwhile, with
Graininess, fusiformis are compared with linear, and porous nano ceria specific surface area is maximum, and reactant contact area is maximum, therefore its
Catalytic effect is the most obvious.
Advantages of the present invention and effect are:
1, with nano Ce O2For catalyst, obtain pyrrolidinone derivatives the most with high yield.
2, the synthetic method provided is with nano Ce O2For catalyst, it is to avoid use the poisoned catalyst such as pyridine, with traditional method phase
Than catalyst stabilization, recyclable reusing, consumption is little, and efficiency is high, saves production cost；Nano Ce O2Catalysis activity
By force, the scope of application is relatively wide, compared with traditional method, it is adaptable to the aromatic aldehyde containing electron withdraw group.
3, first with active relatively low faintly acid heterocyclic thiol as substrate, one has been synthesized by multicomponent Ugi-Smiles cascade reaction
The thioxo-pyrrolidine ketone derivatives that series structure multiformity is abundant.
4, the solvent used is acetonitrile and water 3: 1 (volume ratio) mixing, is more beneficial for product than traditional methanol or ethanol and separates out,
It is easy to separate, reacts highly efficient.
5, reaction condition is gentle, it is not necessary to heating, and the response time is short, and productivity is high, and post processing is easy.
6, the yield of series thioxo-pyrrolidine ketone derivatives under optimal condition, concrete outcome is shown in Table 1.
The yield of series thioxo-pyrrolidine ketone derivatives under table 1 optimal conditions
Detailed description of the invention
With synthesis (3-benzoxazoles [D]-2-base)-1-phenyl-2-amino-4-(4-iodophenyl)-5-2-sulfydryl-dihydro-
As a example by hydrogen pyrroles's-3-nitrile
By substrate to benzaldehyde iodine 23.1mg, Cyanoacetyl-Cyacetazid 7.9mg, cyclohexyl isonitrile 13.0mg, 2-mercaptobenzooxazole 15.1mg
It is added separately in 250mL round-bottomed flask, in advance added with 100ml acetonitrile and water 3: 1 (volume ratio) mixed liquor in flask.Add
Enter nano Ce O2Catalysis 10mg, stirs 12 hours under the conditions of 10 DEG C, and after reaction terminates, sucking filtration obtains thick product, uses CH2Cl2
Dissolving thick product, centrifugal (4000r/min, 20min) obtains nano Ce O2Solid, CeO2Solid washing with alcohol 2-3 time, red
Catalytic reaction it is reused for after drying under outer lamp, reusable 2-3 time.Liquid portion recrystallization, obtains product 3-benzo and dislikes
Azoles [D]-2-base)-1-phenyl-2-amino-4-(4-iodophenyl)-5-2-sulfydryl-dihydro-hydrogen pyrroles's-3-nitrile sterling 48.9mg,
Products therefrom productivity is 90.6%, and purity reaches 99%.1H NMR (400MHz, CDCl3) δ 9.17 (s, 1H), 7.78 (m, 3H),
7.62 (d, J=7.8Hz, 1H), 7.52-7.41 (m, 2H), 7.02 (d, J=7.8Hz, 2H), 5.17 (s, 1H), 5.04 (t, J=5.6
Hz, 1H), 2.56 (m, 2H), 1.97-1.78 (m, 3H), 1.65 (m, 2H), 1.41 (m, 2H), 1.31-1.22 (m, 1H) ppm.13C
NMR (100MHz, CDCl3) δ 202.5,160.5,156.5,151.5,140.1,138.5,134.9,130.3,126.9,125.7,
121.1,112.9,111.3,95.6,63.1,58.9,52.0,30.9,27.6,26.6,25.8,25.0PPm.IR (KBr) max cm-1:
3253,2933,2851,1674,1560,1370.HRMS (ESI) m/z:calcd for C24H20IN4OS[M-H]-: 539.0402；
Found:5390469.
Claims (5)
- The synthetic method of the most polysubstituted thioxo-pyrrolidine ketone derivatives, it is characterised in that: by benzaldehyde, Cyanoacetyl-Cyacetazid, cyclohexyl is different Nitrile and weakly acidic mercaptobenzoxazole or thiazole mix, and obtain thiopyrrolidone in next step reaction of catalyst action and derive Thing.
- 2. according to the synthetic method of the polysubstituted thioxo-pyrrolidine ketone derivatives described in right 1, it is characterised in that described catalyst is , graininess, fusiformis bar-shaped including porous and the nano Ce O of linear four kinds of patterns2, catalyst amount 10mg/1mmol benzaldehyde.
- 3. according to the synthetic method of the polysubstituted thioxo-pyrrolidine ketone derivatives described in right 1, it is characterised in that described reaction be Acetonitrile is to carry out in 3: 1 with the volume ratio of water, but being also not limited to volume ratio is 3: 1.
- 4., according to the synthetic method of the polysubstituted thioxo-pyrrolidine ketone derivatives described in right 1, one of its feature is described by weak When acid mercaptobenzoxazole reacts, the R substituent of benzaldehyde includes H+, 4-F, 4-Cl, 4-Br, 4-I, 4-NO2, 4-CN, 3-F, 3-NO2, 2-Br, 2-F-4-Br, 4-OCH3, 3,4,5-OCH3Deng 13 kinds of thioxo-pyrrolidine ketone derivatives, its feature it Two are described when being reacted by weakly acidic mercaptobenzothiazoler, and the R substituent of benzaldehyde includes H+, 4-F, 4-Cl, 4-Br, 4-I, 4-CN, 3-F, 2-Br, 2-F-4-Br, 4-OCH3, 3,4,5-OCH3Deng 11 kinds of thioxo-pyrrolidine ketone derivatives.
- 5. according to the synthetic method of the polysubstituted thioxo-pyrrolidine ketone derivatives described in right 1, it is characterised in that reaction is at 10 DEG C Under the conditions of stir 12-16 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410834198.3A CN105884757A (en) | 2014-12-25 | 2014-12-25 | Polysubstituted sulfo-pyrrolidone derivative synthesis method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410834198.3A CN105884757A (en) | 2014-12-25 | 2014-12-25 | Polysubstituted sulfo-pyrrolidone derivative synthesis method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105884757A true CN105884757A (en) | 2016-08-24 |
Family
ID=56701261
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410834198.3A Pending CN105884757A (en) | 2014-12-25 | 2014-12-25 | Polysubstituted sulfo-pyrrolidone derivative synthesis method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105884757A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866707A (en) * | 2017-04-14 | 2017-06-20 | 山西大学 | A kind of preparation method of benzimidazole simultaneously [2,1 b] thiazole |
| CN108997319A (en) * | 2018-06-27 | 2018-12-14 | 江苏师范大学 | Thiocarbamoyl imidazole alkanone derivative and its synthetic method and application |
-
2014
- 2014-12-25 CN CN201410834198.3A patent/CN105884757A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866707A (en) * | 2017-04-14 | 2017-06-20 | 山西大学 | A kind of preparation method of benzimidazole simultaneously [2,1 b] thiazole |
| CN108997319A (en) * | 2018-06-27 | 2018-12-14 | 江苏师范大学 | Thiocarbamoyl imidazole alkanone derivative and its synthetic method and application |
| CN108997319B (en) * | 2018-06-27 | 2020-03-17 | 江苏师范大学 | Thioimidazolidone derivative and synthesis method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Shirase et al. | Cerium (IV) carboxylate photocatalyst for catalytic radical formation from carboxylic acids: decarboxylative oxygenation of aliphatic carboxylic acids and lactonization of aromatic carboxylic acids | |
| Xie et al. | N-Substituted 3 (10 H)-Acridones as Visible-Light, Water-Soluble Photocatalysts: Aerobic Oxidative Hydroxylation of Arylboronic Acids | |
| JP5006561B2 (en) | Method for producing furandicarboxylic acid | |
| Watanabe et al. | Orientation of electrophilic meso-substitution in metallooctaethylporphyrins | |
| De et al. | Visible-Light-Induced Regioselective C (sp3)-H Acyloxylation of Aryl-2 H-azirines with (Diacetoxy) iodobenzene | |
| Sternativo et al. | One-pot synthesis of aziridines from vinyl selenones and variously functionalized primary amines | |
| He et al. | Asymmetric synthesis of spirocyclic oxindole δ-lactams via NHC-catalyzed formal [2+ 4] annulation of aliphatic aldehydes with oxindole-derived α, β-unsaturated ketimines | |
| Tada et al. | Aerobic photooxidation of benzylamide under visible light irradiation with a combination of 48% aq HBr and Ca (OH) 2 | |
| Yang et al. | Single-atom-nickel photocatalytic site-selective sulfonation of enamides to access amidosulfones | |
| Yamamoto et al. | Manganese‐Promoted Oxidative Cyclization of Unsaturated Oximes Using Molecular Oxygen in Air under Ambient Conditions | |
| Kaur | Synthesis of Three‐Membered and Four‐Membered Heterocycles with the Assistance of Photochemical Reactions | |
| CN105884757A (en) | Polysubstituted sulfo-pyrrolidone derivative synthesis method | |
| Wang et al. | Photocatalytic C–H activation with alcohol as a hydrogen atom transfer agent in a 9-fluorenone based metal–organic framework | |
| Shen et al. | Recent advances in the application of Langlois’ reagent in olefin difunctionalization | |
| Spiliopoulou et al. | Synthetic approaches to acyl hydrazides and their use as synthons in organic synthesis | |
| Gujarathi et al. | Amberlite IR-120H as an efficient and versatile solid phase catalyst for nucleophilic substitution of propargylic alcohols | |
| Jung et al. | Total synthesis of racemic laurenditerpenol, an HIF-1 inhibitor | |
| Cai et al. | Photochemical multicomponent transformation of acceptor-only diazoalkanes by merging their cycloaddition and carbene reactivities | |
| CN110483346B (en) | Sulfonyl-substituted alpha-cyclopropylstyrene compound and synthesis method thereof | |
| CN104557468B (en) | Method for phenol hydroxylation | |
| Kuang et al. | Solvent free aerobic oxidation of alcohols with 1-methyl-2-azaadamantane N-oxyl as a recyclable catalyst through phase separation | |
| Rajabi et al. | Efficient Co (ii) heterogeneously catalysed synthesis of α-aminonitriles at room temperature via Strecker-type reactions | |
| Ballini et al. | Nitroalkanes and dimethyl maleate as source of 3-alkyl succinic anhydrides and (E)-3-alkylidene succinic anhydrides | |
| Boger et al. | Inverse electron demand diels-alder reactions of 3-carbomethoxy-2-pyrones. Controlled introduction of oxygenated aromatics: benzene, phenol, catechol, resorcinol, pyrogallol annulation. | |
| CN105481624B (en) | The catalysis oxidation synthetic method of Arneel SD |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160824 |