The microwave assisted syntheses of quinoline derivatives are described by the chemical equations presented in scheme 1. Coal tar remains the main source of commercial quinoline. New techniques have been generated quinolines heterocyclic ring synthesis. Among these were, in his own words the widely disliked skraup cyclization for quinolines. Skraup reaction major reference works wiley online. Jan, 2009 the skraup reaction how to make a quinoline recently, derek lowe was discussing reactions he hadnt done at his blog in the pipeline. It has the formula c9h7n and is a colourless hygroscopic liquid with a strong odour. Highly functionalized quinolines 5 could be obtained from the reaction of benzamides 4 and alkynes promoted by triflic.
View show abstract heterocyclic nitrogen compounds. The use of k2s2o8 and dmso enables an efficient and transitionmetalfree. View enhanced pdf access article on wiley online library html view download pdf for offline viewing. Quinoline and its derivatives are important heterocyclic systems which have great significance as a biologically active compounds as well as being useful synthon for synthesis of many heterocyclic compounds. An efficient twostep selective synthesis of 7methyl8. Aged samples, if exposed to light, become yellow and later brown. Synthesis of derivatives of 2 phenyl quinoline 4 carboxylic acid. Itis a colorless hygroscopic liquid with a strong odor. Quinoline ring has been found to possess antimalarial, antibacterial, antifungal, anthelmintic, cardiotonic, anticonvulsant, antiinflammatory, and analgesic activity. Quinoline was first extracted from the coal tar in the year 1834 by friedlieb ferdinand runge. Skraup quinoline synthesis request pdf researchgate. A practicable quinoline synthesis from aniline and two amino acids provides a. Quinoline is only slightly soluble in cold water but dissolves readily in hot water and most organic.
Nov 03, 2012 his other works were in the fields of natural products like the structure of alkaloids, synthesis of isoquinolines etc. The more modern style of skraup synthesis is used to make 8quinolinol or oxine. The reaction proceeds via dehydration of glycerol to acrolein. These include antiinflammatory and antitumor agents, the antimalarial drugs quinine and chloroquine, and organic lightemitting diodes. Skraup synthesis article about skraup synthesis by the free. Free download ebooks clear, attractive patient statements 20080509 17 56 56 73728 a c windows system32 dpl100. The conditions i used are covered in the attached paper under general procedure for quinolines, method b, except that i ran at 110th that scale. It has been found that recent modifications of the skraup quinoline synthesis can be further improved as to yield and ease of operation by substituting acetylated amines for the free bases. Skraups synthesis is a chemical reaction used to synthesize quinolines by the condensation of glycerine and alanine in the presence of a strong acid c. Similarly, the reaction of triply labeled pulegone clearly shows that the label in the product is 100% scrambled, whereas the label in the starting pulegone is retained.
Skraups synthesis is a chemical reaction used to synthesize quinolines by the condensation of glycerine. Although each technique has its own set of advantages and limitations, the skraup and friedlander work set the baseline for all other variations. The reaction time of 2amino5chlorobenzophenone and dicarbonyl compounds. Skraup synthesis definition is the production of quinoline by heating aniline, glycerol, and sulfuric acid with an oxidizing agent as nitrobenzene. Expired lifetime application number us239505a inventor francis d dodge original assignee. In the archetypal skraup reaction, aniline is heated with sulfuric acid, glycerol, and an oxidizing agent such as nitrobenzene to yield quinoline. In the skraup synthesis xxiv aniline was heated with glycerin, sulfuric acid and. So, yesterday i ran the widely disliked skraup reaction, which is used to prepare quinolines from anilines. A subsequent nitration reaction was also carried out using a mixture of 5 and 7methylquinoline to obtain pure 7methyl8nitro quinoline selectively. Synthesis of 7nitrobenzohquinoline has been achieved by heating. Synthesis of quinolines and dihydroquinolines under solventfree conditions. In the synthesis of pyridines it proved advantageous to make a dihydropyridine and oxidize it to a pyridine afterwards. A green, solventfree onepot synthesis of disubstituted. He apprenticed under lieben at the university of vienna.
This can be synthesized by different methods like the skraup, dobnervon miller synthesis, conradlimpach, friedlaender and pfitzinger synthesis. On the basis of these studies, a mechanistic pathway for the skraup quinoline synthesis is proposed that involves a fragmentation. In the skraup synthesis of quinoline the principal difficulty has always been the violence with which the reaction generally takes place. Quinoline is only slightly soluble in cold water but dissolvesreadily in hot water and most organic solvents. Request pdf skraup quinoline synthesis quinoline from aniline, glycerol. Therefore, extensive modifications have been made based on the initial. Those synthesis begin with orthosubstituted anilines include the friedlander, pfitzinger, niemantowski and borsche synthesis. Quinolines were first synthesized in 1879, and since then a multitude of. It has been reported that initial skraup protocol usually gives a very low yield of quinolines. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. However, after this i didn t succeed in starting the driver manually.
Quinoline is an alkaloid from various plant species including mentha species. Descriptionreaction scheme of skraup quinoline synthesis. Also present in cocoa, black tea and scotch whiskey. There are multiple ways to synthesize quinoline, one of which is the combes quinoline synthesis.
For the synthesis of quinolines, various methods have been reported including the skraup, conradlimpachknorr, pfitzinger, friedlander, and combes. There have been several classical methods for the synthesis of quinolines for example, skraup et al. Friedlander synthesis of polysubstituted quinolines. If not, go back and type or paste in wanminiportservice, click ok. Sulfuric acid,glycerol and mild oxidising agent are heated together 16. Concerning the mechanism of the friedlander quinoline. Proficient procedure for preparation of quinoline derivatives. Skraup reaction article about skraup reaction by the.
Various aryl diazonium salts, nitriles, and alkynes can participate in this transformation. A free radical approach from phenyl isocyanide gives a range of. We shall describe two more important variants on the same theme, one for quinolines and one for quinolones. The quinoline ring has been generally synthesized by various conventional named reactions such as skraup, doebnervon miller, pfitzinger, friedlander, conradlimpach, and combes synthesis. The synthesis of quinoline derivatives has been prevalent in biomedical studies due to the efficiency of the synthetic methods as well as the relative lowcost production of these compounds, which can also be produced in large scales. A green, solvent free onepot synthesis of disubstituted quinolines via a3coupling using 1 mol% fecl 3 by shivani naidoo submitted in the fulfillment of the requirements for the degree of. It involves the condensation of unsubstituted anilines 1 with. New techniques have been generated quinoline s heterocyclic ring synthesis. Heterocyclic ring formation, aromatic nucleophilic substitution and heterocyclic aldehydesketones condensation reactions were performed on solid support, or under solvent free reaction conditions. For the synthesis of quinolines, various methods have been reported including the skraup 4. Since first synthesis quinoline, number of methods has been discovered to.
The reaction could be carried out under solventfree condition and gave low yield table 1, entries 1, 2. The skraup synthesis is a chemical reaction used to synthesize quinolines. Skraup synthesis using ferrous sulfate, glycerol, aniline, nitrobenzene, and sulfuric acid. Us6103904a skraup reaction process for synthesizing. It is proposed that this pathway is the operative mechanism in the classic skraup and doehnervon miller quinoline syntheses. Skraup synthesis definition of skraup synthesis by. Synthesis, optimization and evaluation of substituted. Conventional methods of synthesis of various substituted quinolines. Synthesis of quinoline derivatives by a doebnervon miller.
Copper sulfate has been used as a catalyst in the skraup synthesis, 8 and the iron salt of mnitrobenzenesulfonic acid has been employed as the oxidizing agent. A threecomponent cascade annulation of readily available aryl diazonium salts, nitriles, and alkynes enables an efficient, additivefree, and rapid synthesis of multiply substituted quinolines in good yields. Us2211538a us239505a us23950538a us2211538a us 2211538 a us2211538 a us 2211538a us 239505 a us239505 a us 239505a us 23950538 a us23950538 a us 23950538a us 2211538 a us2211538 a us 2211538a authority us united states prior art keywords acid quinoline phenyl synthesis sulfonic prior art date 19381108 legal status the legal status is an assumption and is not. Aged samples, if exposed to light,become yellow and later brown. Files are available under licenses specified on their description page. Isoquinoline is a heterocyclic aromatic organic compound.
Quinoline is readily obtained by the skraup synthesis in which a mixture of aniline, glycerol and concentrated sulphuric acid is heated with a suitable oxidising agent. A metal free, mild and efficient method for the synthesis of 2methylquinolines was successfully developed by condensation of anilines with vinyl ethers in the presence of catalytic amount of iodine. Quinoline is a flavouring ingredient quinoline is a heterocyclic aromatic organic compound. Objectives in this study, we investigated the twostep synthesis of. A number of other processes exist, which require specifically substituted anilines or related compounds. Alternatively, several other established methods of quinoline synthesis utilize substrates other than aniline in the cyclization process. Quinoline is a heterocyclic aromatic organic compound with the chemical formula c9h7n. Several other related reactions, such as the combes quinoline synthesis, the doebnermiller quinoline synthesis, and the skraup quinoline synthesis, use different types of starting compounds. Skraup reaction article about skraup reaction by the free. His other works were in the fields of natural products like the structure of alkaloids, synthesis of isoquinolines etc. Recent advances in metalfree quinoline synthesis mdpi. Pure carbon monoxide is an excellent atmosphere in whichto distil zinc, provided the walls of the apparatus are free of iron. Dmso acts as one carbon source, thus providing a highly atomeconomical and environmentally benign approach for the synthesis of 4.
It is the best reaction for synthesis of quinoline17 nh2 h o n. It is named after the czech chemist zdenko hans skraup 18501910. Mar 03, 2004 detailed experiments regarding the mechanism of the friedlander synthesis of quinolines from oaminobenzaldehydes and simple aldehydes or ketones are described. It ignites readily, burning with a smoky flame characteristic of aromatic compounds, the amine is nearly planar owing to conjugation of the lone pair with the aryl substituent. Application of a dynamic microwave power system in the chemical synthesis of some phenothiazine and quinoline derivatives is described. Therefore, extensive modifications have been made based on the initial protocol.
This reaction was first studied in 1880 by zdenko hans skraup 18501910, a czech scientist born in prague city of czech republic. The combes quinoline synthesis is a chemical reaction, which was first reported by combes in 1888. Ironiii is the oxidant with a bit of boric acid for luck, and the yield is excellent. Modification of both pyridine and benzene moieties was easily achieved by changing only the vinyl ether and aniline. The present invention relates to an improved skraup reaction process wherein pressure is applied during the reaction and the number of equivalents of sulfuric acid utilized is reduced. In the original procedure the oxidant was nitrobenzene, but since this often leads to a violent reaction, arsenic pentoxide or iodine is preferred.
A facile solvent free skr aup cyclization reaction for synthesis of 2, 2, 4trimethyl1, 2dihydroquinoline ganapati d. Skraup synthesis the synthesis of quinoline and quinoline analogues and derivatives by the reaction of aniline i or anilines corresponding analogues and derivatives with glycerine in the presence of a dehydrating agent usually sulfuric or phosphoric acid and an oxidizing agent usually nitrobenzene or a derivative of nitrobenzene. Quinoline not only has a wide range of biological and pharmacological activities but there are several established protocols for the synthesis of this ring. Microwaveassisted synthesis of phenothiazine and quinoline. Tajik and coworkers reported an efficient quinoline synthesis using substoichiometric amounts of the ionic liquid bmimhso 4 3c, figure 24. Table 1 presents a comparison between the results obtained by microwave assisted synthesis, versus conventional heating method 7,8. However, the friedlander condensation is still considered as a popular method for the synthesis of quinoline derivatives 914. Recent progress in the synthesis of quinolines current organic chemistry, 2005, vol.
Skraup synthesis the synthesis of quinoline and quinoline analogues and derivatives by the reaction of aniline i or anilines corresponding analogues and derivatives with glycerine in the presence of a dehydrating agent usually sulfuric or phosphoric acid and an oxidizing agent usually nitrobenzene or a derivative of nitrobenzene corresponding to a particular aniline derivative. In this reaction, the iodine species was revealed to show dual behavior. The quinoline ring system is one of the most ubiquitous heterocycles in the fields of medicinal and industrial chemistry, forming the scaffold for compounds of great significance. Nov 09, 2012 quinoline is a heterocyclic aromatic organic compound with the chemical formula c9h7n. The same idea works well in probably the most famous quinoline synthesis, the skraup reaction. The synthesis of quinoline derivatives from primary aromatic amines, glycerol, and an oxidizing agent in concentrated sulfuric acid is generally known as the skraup reaction. This work describes the synthesis of new heterocyclic compounds from quinoline derivatives and amines. Skraup synthesis the synthesis of quinoline and quinoline analogues and derivatives by the. Skraup synthesis article about skraup synthesis by the. Many of these methods, such as the skraup, doebnervon miller, and friedlander quinoline syntheses, are wellknown but suffer from inefficiency, harsh reaction. All structured data from the file and property namespaces is available under the creative commons cc0 license. Doebnermiller synthesis an overview sciencedirect topics.
Kumbhar, saumydeep helder abstract an optimized and efficient process has been found to synthesize 2, 2, 4trimethyl1, 2dihydroquinoline from an acid catalyzed skraup cyclization of acetone and aniline. Reaction mechanism of the skraup quinoline synthesis. The skraup reaction how to make a quinoline recently, derek lowe was discussing reactions he hadnt done at his blog in the pipeline. It is the best reaction for synthesis of quinoline17. Qunoline synthesis name reactions skraup synthesis. The skraup procedure 1 is a classical method for the synthesis of quinoline that involves use of a large amount of sulfuric acid at temperatures above 150 c, and the reaction is violent. Synthesis of quinoline derivatives by a doebnervon miller reaction using a ag i exchanged montmorillonite k10 catalyst dissertation submitted to the university of kwazulunatal for the degree of master of science in chemistry by janeeka jayram school of chemistry and physics university of kwazulunatal january 2016. The use of k 2 s 2 o 8 and dmso enables an efficient and transitionmetal free synthesis of 4arylquinolines from readily available aryl alkynes and anilines with a diverse range of substitution patterns.
In the original procedure the oxidant was nitrobenzene, but since this often leads to a violent reaction, arsenic pentoxide or. Camps quinoline synthesis using an oacylaminoacetophenone and hydroxide. Under the basic or acidic conditions commonly used in this reaction, it is concluded that the first step involves a slow intermolecular aldol condensation of the aldehyde or ketone with the oaminobenzaldehyde. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed. Zdenko hans skraup 18501910 was born in prague, czechoslovakia. A green, solventfree onepot synthesis of disubstituted quinolines. Pdf recent advances in metalfree quinoline synthesis. In a broader sense, the term isoquinoline is used to make reference to isoquinoline derivatives.
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