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. Several protocols have already been described for the synthesis of substituted thiazoles and benzothiazoles . Consequently, expanding the scope of thiazole synthesis by developing new methodologies remains an active area of research.
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Please contact mpub-help umich. For more information, read Michigan Publishing's access and usage policy. Since when first report on the Gewald reaction was reported it became a universal method for synthesis of substituted 2-aminothiophenes and has gained prominence in recent times. The availability of reagents and the mild reaction conditions all contribute to the versatility of this reaction. This review summarizes the synthetic strategies for substituted 2-aminothiophenes.
Consequently, details about the proposed mechanism of Gewald-like reactions and the wide scope of substituted 2-aminothiophenes for real life applications. Keywords: Gewald reaction, substituted 2-aminothiophenes, drug design, optoelectronics, dyes Table of Contents 1.
Introduction 2. Synthesis of substituted 2-aminothiophenes via Gewald reaction 2. Utilization of substituted 2-aminothiophenes and Gewald reaction in the synthesis of condensed heterocycles 3. Applications of substituted 2-aminothiophenes in drug design, optoelectronics and dyes 4.
Conclusions 6. Abbreviations Acknowledgements 7. References 1. Introduction Highly substituted thiophene derivatives are important heterocycles found in numerous biologically active and natural compounds. Generally, there are four basic variations described by Gewald and co-workers and about up to fifteen modifications to accomplish the synthesis of highly functionalized 2-aminothiophenes.
Recently, the improvements of the Gewald synthesis were announced. The chemistry of aminothiophenes has been broadly summarized in in the monograph of R. Norris25 and later reviewed in Emphasis is given to the recent studies published, in which the most general approaches to the synthesis of basic 2-aminothiophenes via the Gewald reaction and other target structures were considered.
Data of the utilization of 2aminothiophenes in the synthesis of novel type of fused heterocycles and their application are included. Particular attention is given to studies published in the previous years.
Synthesis of substituted 2-aminothiophenes The chemistry of 2-aminothiophenes has received much attention upon their convenient availability through the most versatile synthetic method developed by Gewald and his coworkers. After the treatment of 1 with potassium hydrosulfide the reactive sufanyl-substituted intermediate 2 was created, which in the subsequent intramolecular addition of sulfanyl group to cyano group proceeded ethyl 2-amino-4hydroxythiophene- 3-carboxylate 4 in equilibrium with its cyclic tautomer — the appropriate imine 3 Scheme 1.
Fifty years later, in , substituted 2-aminothiophenes with electron- withdrawing substituents such as cyano, carbonyl, methoxycarbonyl, aminocarbonyl, etc. Depending on the used starting substrates and the reaction conditions three basic versions of the Gewald reaction have been developed16,, which were lately enriched by a fourth version.
Table 1. In this case the base, mainly secondary amine diethylamine, morpholine , is used in 0. Scheme 5 Alkyl aryl ketones and some cycloalkyl ketones which are not reactive under the one-pot modifications version 1 or version 2 give acceptable yields of thiophenes in the two-step procedure Table 3. Table 3. In this particular version the more stable dimeric forms of an a-sulfanylcarbonyl compound — substituted 1,4-dithiane-2,5-diols 5c undergo condensation and subsequent cyclization with aactivated acetonitrile 6 requiring an amine in stochiometric amount Scheme 6.
As it is presented on Schemes , the substituted 2-aminothiophene ring is formed from the aliphatic starting substrates during the multi step reaction sequence: condensation — addition of sulfur — ring- closure. Depending on the type of the used reactants, in some variations of the reaction, the condensation Version 3 or addition of sulfur step Versions 2 and 4 is not required. The most crucial step in all cases of the basic Gewald reaction and its improvements is the final ring-closure process, which is performed as an intramolecular nucleophilic attack of the sulfur anion to triple bond of the cyano group Scheme 7.
It was proved, that the parent aminothiophene occurs exclusively in the amino form. However, it is sure, that S8 has to be activated to react with Knoevenagel-Cope product 9. Some authors report that the activation of sulfur and the following addition of sulfur on a methylene group is base-promoted, others detail the electrochemical activation of the S8.
In the base-promoted addition the elemental sulfur reacts with amines to yield polysulfide anions, that can behave as nucleophiles. The most suitable base for the activation with sulfur and the subsequent sulfur addition morpholine has been proved. In this relatively new synthetic pathway the sulfur, which is electro active, is incorporated in a carbon electrode and used as a sacrificial cathode to yield S3. However, if the activation with sulfur does not occur properly, the ylidene-sulfur adduct of presumed structure 10 or 12 is not formed and the side-reaction takes place.
While in some cases the ylidene dimerization is significant and the by-product is isolated in higher yield than the desired 2-aminothiophene derivative58, on other hand under suitable reaction conditions not only is the straightforward reaction favored, but also the recyclization of dimerized ylidene 14 to appropriate aminothiophene 7 occurs. By the use of improved methods and modified experimental procedures the scope of easily obtainable 2aminothiophenes ultimately spread.
Exploiting the reaction conditions with starting substrates tolerating a broad range of functional groups and alkyl, aryl and heteroaryl substituents about 15 new modifications of the Gewald reaction can be found in literature.
Ionic liquids used as solvents in combination with ethylenediammonium diacetate were shown to be very efficient in the case of the Gewald synthesis with aliphatic and alicyclic ketones with possibility of regeneration of used liquids.
Heterogeneous organic reactions using reagents immobilized on porous solid supports have been often proved advantageous over conventional solution phase reactions because of good dispersion of active reagent sites, better selectivity and easier work-up.
It was found, that appropriate esters of some Gewald products proved difficult to hydrolyze via traditional saponification. After the dispersion of reagent 17 in ethanol Gewald reaction was performed in QuestTM synthesizer by mixing with the starting compound - a-methylene carbonyl compounds 18 and substrates - sulfur and morpholine.
Scheme 11 Table 5. Most of the published Gewald synthetic procedures required long reaction times varying between 4 and 48 h.
Microwave heating is an area of increasing interest in both academic and industrial laboratories because it can raise the rate of reaction and in many cases improve product yields. This process represents the advancement of the basic version 4 content 2. Reaction starting from 1,4-dithiane-2,5-diol 21 and aactivated acetonitrile 6 was completed after 2 min. Scheme 12 Table 6. Microwave enhanced Gewald reaction in combination with solid-support accelerated method was presented as an easy access to polysubstituted 2-aminothiophenes.
Using the microwave irradiation reaction was carried out in very short times, but alternatively the reaction proceed well also under conventional heating Table 7. Scheme 13 Table 7. The protection of amino group was performed with methyl 2-chloro-2oxoacetate 24 in toluene in the presence of diisopropylethylamine DIPEA again under the microwave irradiation.
Finally, in Scammells and co-workers have presented the synthetic pathway to 5-bromo substituted 2-aminothiophenes The reaction was successful it the R-substituted 2-bromo-1phenylethanones 27 were reacted with 3-oxophenylpropanenitrile 28 and sulfur in the presence of diethylamine as a base in ethanol Scheme Because of the inconvenient conditions such as strong base, longer reaction time and difficult purification, the target 5bromo- 2-aminothiophenes 29 were obtained only in moderate yields Table 9.
Scheme 15 Table 9. In a reaction of 3trifluoromethylacetophenone 30 with either benzoylacetonitrile or ethyl cyanoacetate 31 in the presence titanium IV chloride afforded Knoevenagel-Cope product In subsequent treatment of 32 with sulfur the 2-aminothiophene core 33 is formed under basic conditions.
The free C-5 position of derivative 33 is substituted with bromine in two following steps — first the free amino group is being Boc protected and then C-5 position brominated with Nbromosuccinimide Scheme Utilization of substituted 2-aminothiophenes and Gewald reaction in the synthesis of condensed heterocycles The substituted 2-aminothiophenes found enormous utility in dye chemistry, modern drug design , biodiagnostics, electronic and optoelectronic devices, conductivity-based sensors, and self-assembled superstructures.
The versatility of title compounds as a synthetic entry to fused heterocycles such as thieno[3,4-c]thiolactones, thieno[2,3-b]pyrroles, thieno[2,3-d]pyrimidines and thieno[2,3-b]pyridines is highlighted in following chapters.
Starting from substituted 2-aminothiophenes 36a-c, the target fused heterocyclic derivatives 39a-c was prepared in a four step reaction sequence.
The free amino group is acylated first and then the methyl group in C-4 position undergoes the radical bromination to create the crucial intermediates 37a-c.
The reaction of corresponding bromomethylated thiophenes 37a-c with thiourea in acetone proceeded thiouronium salts 38a-c in almost quantitative yields. In a second approach the unselective reaction proceeding takes place and the mixture of three compounds 39a, 40 and 41 are created Scheme Such derivatives represent a p-heteropentalene system with tetracovalent sulfur nucleus and are investigated from synthetic and theoretical point of view.
The reaction reported by authors represents the one-pot synthesis in which the reaction sequence follows the Gewald reaction process. The reaction continuation is based on the condensation of the intermediate salt ketene N,S-acetal 43 with the halide ethyl bromoacetate or chloroacetonitrile leading to the corresponding aminothio-acetal which smoothly undergo a Dieckmann type cyclization in basic medium at room temperature Scheme Phenyl isothiocyanate has been almost exclusively used for related studies and this choice could be explained by the availability of this compound, but above all it appeared to be the best candidate for this reaction.
The replacement of phenyl isothiocyanate by other commercially available ones decreases dramatically the yields of thiophenes Scheme 18 The same authors have published an improved two step method for the synthesis of Nphenylaminothiophenes 44, which is based on preparation and isolation ketene phenylamino methylthioacetals The synthetic protocol for thieno[2,3-b]pyrroles, which is based on the reaction of 1,3-dicarbonyl compounds, can be applied also for preparation of thieno[2,3-b]thiophenes.
As was reported in, the facile one-pot synthesis of polysubstituted thiophenes and thieno[2,3-b]thiophenes was completed through cyclization of a-oxo ketene S,S -acetals. The substituted 2-aminothiophenes act as the most suitable synthetic precursors to various thieno[2,3d] pyrimidines.
One of the important preparations of 2-aminothieno[2,3-d]pyrimidines was investigated by authors From the symmetric ketone 47 the Gewald thiophene synthesis was conducted in a stepwise fashion through Knoevenagel-Cope condensation to give the intermediate 48 followed by base-promoted thiophene cyclization with sulfur. Presented synthetic approach is relevant also for the preparation other biologically active thienopyrimidine structures. Scheme 19 3. Applications of 2-aminothiophenes in drug design, optoelectronics and dyes Substituted 2-aminothiophenes represents a category of an important precursors broadly employed in the synthesis of pharmaceuticals, dyes and potential building blocks in materials chemistry.
The ultimate position of substituted 2-aminothiophenes in this field comes from their advantageous properties - the thiophene ring as is bioisosteric replacement for phenyl group broadly present in an active drugs, the thiophene core exists in many natural and synthetic pharmaceuticals and moreover, they represent an active precursors in broad range of synthetic pathways towards compounds used in therapy. The synthesis of 3-deazathiamine 61 was effected in ten chemical steps, though it was necessary to prepare and isolate substituted 2-aminothiophene.
Deamination of aminothiophene 56 via the bromide 57 and following cleavage with zinc 0 in acidic media to afford derivative 58 was very efficient, displaying none of side reactions. Conversion of formed ester 58 to final 3-deazathiamine 61 was accomplished in four subsequent steps isolating the crucial intermediates — aldehyde 59 and nitrile The readily available and inexpensive starting materials and reagents, and the lack of protection and de-protection steps make this synthesis very fashionable Scheme Scheme 21 Deazathiamine diphosphate deaza-TDP, Figure 1 is an analogue of thiamine diphosphate TDP, Figure 2 , the biologically active for of thiamin vitamin B1 , with a neutral thiophene replacing positively charged thiazolium ring.
TDP is co-enzyme present in a number of enzymes, including pyruvate decarboxylase, transketolase, pyruvate oxidase.
A series of thieno[2,3-d][1,3]oxazinones 65 was synthesized and evaluated in vitro for inhibitory activity toward Human Leukocyte Elastaze HLE. The strategy presented by authors, is based on the replacement of the benzene ring in benzoxazinones by thiophene one.
The study demonstrates the versatility of 2-aminothiophenes as a synthetic entry to serine protease-inhibiting, fused 1,3-oxazinones.
The synthetic route to novel thieno[2,3d][ 1,3]oxazinones 65 using alkyl 2-aminothiophene carboxylates 62 as a substrates exhibits a facile three step synthesis, as is presented on Scheme Aminothiophenes 62 were converted to isothiocyanato-thiophenes 63 by the thiophosgene method.
Deprotection of tertbutoxycarbonyl group resulted directly to ring closure of the intermediates isothiocyanatothiophenecarboxylic acids leading directly to 64a,b. These key intermediates were alkylated with appropriate alkyl halides to furnish the final derivatives 65 Scheme
Gewald reaction: synthesis, properties and applications of substituted 2-aminothiophenes
We'd like to understand how you use our websites in order to improve them. Register your interest. The Gewald reaction of sulfur, cyanoacetic acid derivatives, and oxo-component G-3CR yielding highly substituted 2-aminothiophene derivatives has seen diverse applications in combinatorial and medicinal chemistry. Its products are of great use in pharmaceutical industry mainly as small molecular weight inhibitors. We herein review synthetic scope and variations, usage, and structural biology of Gewald products. This is a preview of subscription content, log in to check access.
Thiazole formation through a modified Gewald reaction
The Gewald multicomponent reaction