An efficient four-component reaction was developed to take advantage of the reactivity of the 2-aminothiophenecarbonitrile functionality. The Gewald reaction is a very useful and versatile method for condensation of aliphatic aldehyde or ketone or β-dicarbonyl compound with active nitrile and. The Gewald reaction is an organic reaction involving the condensation of a ketone (or aldehyde when R2 = H) with a α-cyanoester in the presence of elemental.

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The synthesis of thiazoles and thiophenes starting from nitriles, via a modified Gewald reaction has been studied for a number of different substrates. Several protocols have already been reacyion for the synthesis of substituted thiazoles and benzothiazoles [].

Gewald reaction – Wikipedia

Consequently, expanding the scope of thiazole synthesis by developing new methodologies remains an active area of research. Selected examples of biologically active thiazole containing molecules []. The air-stable, readily available 1,4-dithian-2,5-diol 10 has been previously reported as a coupling partner with various nitriles to give 2-aminothiophenes through a Gewald mechanism [21,22].

Although the thiazole formation reactoin nitriles has already been shown to occur with ketones [] and gwald acid [27,28] derivatives to give 2,5-disubstituted thiazoles, to our knowledge aldehydes have only been shown to form 2-aminothiophenes [29]. Even though 2-substituted thiazoles are important structures in their own right, further substitution can be easily achieved through published protocols to form 2,4-substituted thiazoles, 2,5-substituted thiazoles and also 2,4,5-substituted thiazoles [30].

This further shows the need for the rapid and facile formation of 2-substituted thiazole compounds as core building blocks. Initially, the reaction of several nitriles was screened with aldehyde precursor 10 to determine the selectivity between thiophene and thiazole products.

Originally, reactions were performed using conventional heating, however, to allow for a wider temperature range, microwave heating was introduced.

This allowed access to higher temperatures above the boiling points of the solvents used at atmospheric pressure. Illustration of substrates that form thiophenes under Gewald-type conditions.

Only a small impact upon conversion was observed with changing the ratio of compound 10 and so it was decided to also maintain this at rection concentration i. All reactions were assessed for conversion using 1 H NMR analysis of a crude sample followed by work-up and purification via column chromatography to determine the yields.

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Scoping experiments using ethyl phenylcyanoacetate 16 with different solvents and bases.

With regard to solvent selection, trifluroethanol showed by far the best results, this is probably due to the high polarity and its slightly acidic nature, which assists in solubilising 10and subsequently promotes the formation of the aldehyde monomer. In gswald, a sulfonic acid bound resin QP-SA was also trialled as eraction additive but showed no conversion allowing full recovery of the starting nitrile see later discussion on mechanism.

In an attempt to improve the yield of this reaction, a design of experiment analysis DOE was performed initially testing three factors; temperature, concentration of 16 and reaction time, while monitoring the response by measuring the isolated yield of From the data it was concluded that elevated temperatures resulted in lower isolated yields most probably due to decomposition of compound 10 or the resulting aldehyde.

In general, lower concentration was beneficial but at a consequence of longer reaction times in order to obtain a good yield.

The latter conditions were then chosen to progress due to the increased productivity based upon the higher concentration and slightly shorter reaction time. To allow direct comparison and evaluation of the influence of substrate modifications on the reaction outcome we maintained the standard reaction conditions generated above.

This is presumably due to a subtle balance between the basicity and nucleophilicity of the intermediate anion, which could in the case of the more stable electron withdrawing group anion enable a retro-aldol reaction following. Scoping of the 2-substituted thiazole formation. Substrates which did not react under the optimised conditions. Diethyl 2-cyanomalonate 45also proved unreactive, this substrate would be expected to form an extensively delocalised anion which would be a poor nucleophile.

Also, substrate 46lacking an acidic proton, was recovered unchanged from the reaction. However, the alternative mechanism for the thiazole formation as described herein has gewaod previously been reported and initially presented some queries.

The fact that compounds 46 and 47 did not react implies mechanism A is the predominant pathway. The lack of reactivity of substrate 47 can be attributed to the high degree of steric hindrance inhibiting its enolisation.

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In summary, although our evidence indicates mechanism A is the most likely pathway it should be noted that several benzonitrile derivatives have reactiom shown to successfully result in thiazole formation when reacted with coupling partners such as 2-mercaptopropionic acid, therefore mechanism B could operate under certain conditions [32].

Proposed mechanisms for the formation of thiazoles. We have successfully shown that substitution of the nitrile precursor predetermines the reaction outcome yielding exclusively to a thiophene or thiazole product.

It was shown that the presence of an alkyl or aryl substituent adjacent to the cyano group leads selectively to the thiazole by blocking the Gewald type mechanism responsible for the formation of the 2-aminothiophene. The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: How to cite this article: Please enable Javascript and Cookies to allow this site to work correctly!

Thiazole formation through a modified Gewald geewald Carl J. Mallia 1Lukas Englert 1Gary C. Walter 2 and Ian R.

Jump to Figure 1.

Gewald reaction: synthesis, properties and applications of substituted 2-aminothiophenes

Screening for the bifurcation conditions Initially, the reaction of several nitriles was screened with aldehyde precursor 10 to determine the selectivity between thiophene and thiazole products. Jump to Scheme 1. Jump to Figure 2. Jump to Scheme 2.

Supporting Information File 1: Experimental and analytical data. Synthesis44, — M Return to gewal in text: Cell, — Synthesis45, 45— All issues All volumes Interesting articles Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics. Reactivity of bromoselenophenes in palladium-catalyzed direct arylations.

Gewald reaction: synthesis, properties and applications of substituted 2-aminothiophenes

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres. News The updated journal statistics include the impact factor and reactoon journal metrics. Registration is open for this Beilstein Symposium, 9 – 11 April, Subscribe Email Notification Register and get informed about new articles. Introduction Results and Discussion Screening for the bifurcation conditions Optimisation and scoping of thiazole formation Conclusion Experimental Supporting Information Acknowledgements References.