GEWALD THIOPHENE SYNTHESIS PDF

Although several thiophene ring syntheses are known in the literature [ 1 ] for the synthesis of thiophenamines, the subsequent introduction of the amino group into an existing thiophene moiety is difficult and thus remains a challenging task. To the best of our knowledge, however, the use of cyanoacetone for this purpose has not been reported yet. Subsequent heating with acetic anhydride gave the stable acetamides 5 Scheme 2. Synthesis of the title compounds 4 and the corresponding acetamides 5. One potential practical application of acetamides 5 was realized in the synthesis of the azo-dye building-block 7. However, this problem can be circumvented by 'blocking' this activated 5-position with a nitro group [ 7 ].

Author:Tukazahn Zulujar
Country:Poland
Language:English (Spanish)
Genre:Music
Published (Last):23 February 2007
Pages:481
PDF File Size:19.69 Mb
ePub File Size:4.1 Mb
ISBN:742-6-51852-525-4
Downloads:15205
Price:Free* [*Free Regsitration Required]
Uploader:Taulkis



Cyanoacetic acid derivatives are the starting materials for a plethora of multicomponent reaction MCR scaffolds. Here we describe valuable general protocols for the synthesis of arrays of 2-aminothiophenecarboxamides from cyanoacetamides, aldehydes or ketones and sulfur via a Gewald-3CR variation. In many cases the reactions involve a very convenient work up by simple precipitation in water and filtration. We foresee our protocol and the resulting derivatives to become very valuable to greatly expanding the MCR scaffold space of cyanoacetamide derivatives.

In the German chemist Prof. Karl Gewald discovered that methylene-active carbonyl compounds reacted with methylene-active nitriles and sulfur at ambient temperature to yield 2-aminothiophenes.

Simple to perform large scale open vessel Gewald-3CR courtesy of Prof. Ulrich Jordis, Vienna. In addition this transformation is remarkable, since it consists one of the few organic reactions incorporating elemental sulfur at ambient temperature. A prominent example of the thiophene-phenol bioisosterie is the atypical antipsychotic blockbuster drug olanzepine for the treatment of schizophrenia and bipolar disorder Scheme 1.

Gewald-3CR and phenol-thiophene based biosisosterie between the drugs olanzapine and clozapine. In addition Gewald-3CR primary products are the starting materials for many other compound classes such as kinase inhibitor thienopyrimidines 1 , 9 thienoquinazolines 2 , 10 pyrimidines 3 and 4 , 11 diazocompounds 5 , 12 Schiff bases 6 , 13 tetracyclic thienopyrimidinones 7 , 14 and N -thieno-maleinicacid amides 9 15 as shown in Scheme 2 , just to name a few.

The scope of the Gewald-3CR, however, in the past was hampered by the almost exclusive use of structurally simple not variable activated nitrile components, e. Rarely, cyanoacetamides have been used as potentially versatile component in the Gewald-3CR. In cases where cyanoacetamides have been used they were based on aromatic amides or hydrazides. Ugi, Passerini and van Leusen reactions, were all of the components can be broadly varied.

Recently, we communicated a versatile and experimentally very simple access to arrays of cyanoacetamides by solventless mixing methyl cyanoacetate and primary and secondary amines and filtration of the formed products. In order to elaborate a general procedure we investigated several more reactions with different functional groups in the side chains hydrophilic and hydrophobic, basic and to our delight in all investigated cases we noticed the formation of considerable product precipitation.

Again after filtration and drying we notified exceptional high purity in all cases. Over a wide range of functional groups and substitutents we isolated the products in moderate to good to high yields but always in excellent purity. We used 16 different ketones and aldehydes A1-A16 , Fig. To figure scope and limitations of the cyanoacetamide component we used 23 differentially substituted starting materials B1-B24 , Fig. The purification of products differs depending on the solubility properties of the products.

The products and their yield are shown in table 1. Some additional observations were made. For the phenolic starting material B17 the Gewald reaction with one equivalent of triethylamine base produced no target compound, but the condensation product D6, The basic condition is critical for the cyclization step.

Acetaldehyde A1 , which owns a low boiling point, is not a good starting materials for the Gewald 3-CR. The reaction is performing well by simply mixing each 1 equivalent of cyanoacetamides, sulfur, aldehyde or ketones and triethylamine as the ratio of 1: 1: 1: 1 in ethanol solvent and generally good yields are obtained.

It is interesting that two enantiomerically pure starting materials A7 and B20 produce the thiophene C7,20 with not even traces of another diastereomer observed Scheme 4. There is no significant racemization observed despite the fact that the reaction is base promoted. But in the reaction with another cyanoacetamide B23 , which is derived from the methyl ester of valine amino acid, the corresponding product C7,23 contains two diastereomers at a ratio 2: 1; the result indicates that strong epimerization happens at the valine moiety under basic conditions.

The small molecule derived from aldehyde A7 , cyanoacetamide B23 , sulfur was deprotected and N -acylated and then energy minimized using MOLOC software. In support of the above hypothetical structure, the intramolecular hydrogen bridge can be seen in most of the published x-ray structure analysis. The Gewald reaction can be applied in the synthesis of thiophenediazepine. After Gewald reaction with aldehyde and sulfur, the desired thiophenes C2,23, C6,23 and C7,23 are generated in good yield.

These intermediates would provide a different way to thiophenediazepine-2,5-diones E , Scheme 5. The detailed cyclization conditions are in progress in our lab and will be reported in the future. Ketone starting materials produced far poorer result compared to aldehyde staring materials.

Corresponding reaction with methyl cyanoacetate had obtained much higher yield. Other ketones, including acetone A11 , 2-butone A12 , R -camphor A13 , dimedone A16 , ethyl acyacetate A14 , ethyl pyruvate A15 do not yield the Gewald products at all under the herein described reaction conditions; despite starting materials was observed after the reactions were stopped.

In many references therefore the use of precondensed Knoevenagel intermediates is described. We herein describe a convenient way to synthesize arrays of Gewald thiopheneamides. The convenience of this procedure is based on two points: first the reaction can be performed in many cases in a way that the Gewald products precipitate and this leads to high quality products without the need to run time and cost intensive purifications.

Second the starting material class of cyanoacetamides was recently described by us to be accessible in a very convenient way by simply mixing methyl cyanoacetate with an appropriate primary or secondary amine, thus leading to potentially large arrays of starting materials for subsequent cyanoacetamide dependant MCRs.

This extension of the Gewald-3CR is significant since in the past mostly simple and non variable malondinitrile, cyanoacetic acid and their esters or hydrazides where used. The herein described and generally shown reaction of sulfur, and cyanoacetamides, however renders the Gewald-3CR a truly variable MCR with two points of diversity. There are two routes to prepare 2-aminothiophenecarboxamides Scheme 6.

The first route uses the classical Gewald products 2-aminocyanothiophene or 2-aminothiophenecarboxylic methyl esters resulting from malonodinitrile or methyl cyanoacetate, and further transformations after several additional steps lead to 2-aminothiophenecarboxamides.

Thus amide-substituted Gewald products have been described from the corresponding esters by the sequence saponification, activation and coupling or other methods however in poor yields and lengthy sequences. Additionally these reactions often involve harsh conditions. In a one-step three-component Gewald reaction, 2-aminothiophenecarboxamides can be produced in high diversity. The advantage of the second route seems obvious. The scope of this reaction is large Table 1.

Different cyanoacetamides work fine in the Gewald-3CR and many function groups were tolerated, including alkenyl B6 , alkynyl B21 , acetal B8 , alcohol hydroxyl B14 , phenol B17 , indole B10 , ester B23 , secondary amino B22 and tertiary amino B4, B7 and B The more hydrophobic the resulting Gewald product the greater the isolated yield. This is a direct consequence of the work-up procedure by aqueous precipitation.

Amino acid side chains have been introduced at several positions of the Gewald scaffold thus rendering this chemistry potentially useful for the synthesis of peptidomimetics C4,m methionine; C3,m and Cn,2 phenylalanine; C5,m and Cn,23 valine; Cn,10 tryptophan.

Compound C7,23 , for example can be considered as a peptidomimetic containing the two valine amino acids encompassed on a stiff Gewald heterocycles. Combinatorial chemistry is an important discipline in organic chemistry and highly useful to pharmaceutical industry since the majority of drug discovery projects currently relies on high throughput screening of large compound collection.

Gewald reactions have been described to be purification intensive in the past. Improvements to overcome this issue and to increase synthesis speed have been solid phase bound synthesis.

The use of automatic HPLC purification systems however is expensive and needs special equipment. These procedures are of particular value in the context of parallel synthesis since herein all efforts are multiplied. Therefore we believe that our described often chromatography free Gewald-3CR procedure based on simple precipitation and filtration is advancement in Gewald chemistry. Equally important is the general use of cyanoacetic acid amides as highly variable class of compounds in the Gewald-3CR which renders this reaction a true MCR with two highly variable inputs instead of mostly one in the past.

Thus a skilled lab worker using very simple equipment can synthesize hundreds of Gewald products in a short time frame on a multi mg scale with very high purity including the synthesis of the required cyanoacetamide building blocks.

We thank Prof. National Center for Biotechnology Information , U. J Comb Chem. Author manuscript; available in PMC Jul Author information Copyright and License information Disclaimer. Copyright notice. The publisher's final edited version of this article is available at J Comb Chem.

See other articles in PMC that cite the published article. Abstract Cyanoacetic acid derivatives are the starting materials for a plethora of multicomponent reaction MCR scaffolds. Open in a separate window. Figure 1. Scheme 1. Scheme 2. A diversity of secondary reactions based on the initial Gewald-MCR. Figure 2. Table 1 Gewald reaction to prepare 2-amino-thiophene-carboxamides Cn,m. Scheme 3. Scheme 5. Discussion We herein describe a convenient way to synthesize arrays of Gewald thiopheneamides.

Scheme 6. Figure 3. Scheme 4. Acknowledgments We thank Prof. References 1. Chem Ber. Mayer R, Gewald K. Angew Chem Inter Ed. J Heterocyclic Chem. Huang Y, Doemling A. Mol Div. Angew Chem. Liebigs Ann Chem.

HEISIG REMEMBER THE KANJI PDF

Thiazole formation through a modified Gewald reaction

Associate Editor: D. Chen Beilstein J. The synthesis of thiazoles and thiophenes starting from nitriles, via a modified Gewald reaction has been studied for a number of different substrates. Keywords: design of experiment DOE ; 1,4-dithiane-2,5-diol; Gewald reaction; thiazole; thiophene.

ALMSCLIFF BOULDERING PDF

Gewald Reaction

Either your web browser doesn't support Javascript or it is currently turned off. In the latter case, please turn on Javascript support in your web browser and reload this page. Free to read. Cyanoacetic acid derivatives are the starting materials for a plethora of multicomponent reaction MCR scaffolds.

ARIS EXPRESS TUTORIAL PDF

Cyanoacetamide MCR (III): three-component Gewald reactions revisited.

Cyanoacetic acid derivatives are the starting materials for a plethora of multicomponent reaction MCR scaffolds. Here we describe valuable general protocols for the synthesis of arrays of 2-aminothiophenecarboxamides from cyanoacetamides, aldehydes or ketones and sulfur via a Gewald-3CR variation. In many cases the reactions involve a very convenient work up by simple precipitation in water and filtration. We foresee our protocol and the resulting derivatives to become very valuable to greatly expanding the MCR scaffold space of cyanoacetamide derivatives.

Related Articles