Gewald reaction

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Gewald reaction
Named after Karl Gewald
Reaction type Ring forming reaction
Identifiers
Organic Chemistry Portal gewald-reaction

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 sulfur and base to give a poly-substituted 2-amino-thiophene. [1] [2]

Organic reaction chemical reactions involving organic compounds

Organic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, photochemical reactions and redox reactions. In organic synthesis, organic reactions are used in the construction of new organic molecules. The production of many man-made chemicals such as drugs, plastics, food additives, fabrics depend on organic reactions.

A condensation reaction is a class of an organic addition reaction that proceeds in a step-wise fashion to produce the addition product, usually in equilibrium, and a water molecule. The reaction may otherwise involve the functional groups of the molecule and formation of ammonia, ethanol, or acetic acid. It is a versatile class of reactions that can occur in acidic or basic conditions or in the presence of a catalyst. This class of reactions is a vital part of life as it is essential to the formation of peptide bonds between amino acids and the biosynthesis of fatty acids.

Ketone Class of organic compounds having structure RCOR´

In chemistry, a ketone is an organic compound with the structure RC(=O)R', where R and R' can be a variety of carbon-containing substituents. Ketones and aldehydes are simple compounds that contain a carbonyl group. They are considered "simple" because they do not have reactive groups like −OH or −Cl attached directly to the carbon atom in the carbonyl group, as in carboxylic acids containing −COOH. Many ketones are known and many are of great importance in industry and in biology. Examples include many sugars (ketoses) and the industrial solvent acetone, which is the smallest ketone.

Contents

The Gewald reaction Gewald Reaction Scheme.png
The Gewald reaction

The reaction is named after the German chemist Karl Gewald (born 1930). [3] [4] [5]

Reaction mechanism

The reaction mechanism of the Gewald reaction was elucidated 30 years after the reaction was discovered. [6] The first step is a Knoevenagel condensation between the ketone (1) and the α-cyanoester (2) to produce the stable intermediate 3. The mechanism of the addition of the elemental sulfur is unknown. It is postulated to proceed through intermediate 4. Cyclization and tautomerization will produce the desired product (6).

The Knoevenagel condensation reaction is an organic reaction named after Emil Knoevenagel. It is a modification of the aldol condensation.

The mechanism of the Gewald reaction Gewald Reaction Mechanism.png
The mechanism of the Gewald reaction

Microwave irradiation has been shown beneficial to reaction yields and times. [7]

Variations

In one variation of the Gewald reaction a 3-acetyl-2-aminothiophene is synthesized starting from a dithiane (an adduct of sulfur and acetone if R = CH3 or acetaldehyde if R = H) and the sodium salt of cyanoacetone which in itself is very unstable: [8]

Dithiane group of isomers

A dithiane is a heterocyclic compound composed of a cyclohexane core structure wherein two methylene bridges are replaced by sulfur centres. The three isomeric parent heterocycles are 1,2-dithiane, 1,3-dithiane and 1,4-dithiane.

Acetone chemical compound

Acetone, or propanone, is the organic compound with the formula (CH3)2CO. It is a colorless, volatile, flammable liquid and is the simplest and smallest ketone.

1-(2-Amino-4-methyl-3-thienyl)ethanone synthesis Gewald Type Reaction V.1.svg
1-(2-Amino-4-methyl-3-thienyl)ethanone synthesis

Related Research Articles

Aldehyde organic compound containing a functional group with the structure −CHO, consisting of a carbonyl center (a carbon double-bonded to oxygen) with the carbon atom also bonded to hydrogen and to an R group, which is any generic alkyl or side chain

An aldehyde is an organic compound containing a functional group with the structure −CHO, consisting of a carbonyl center with the carbon atom also bonded to hydrogen and to an R group, which is any generic alkyl or side chain. The group—without R—is the aldehyde group, also known as the formyl group. Aldehydes are common in organic chemistry, and many fragrances are aldehydes.

Aldol reaction chemical reaction

The aldol reaction is a means of forming carbon–carbon bonds in organic chemistry. Discovered independently by the Russian chemist Alexander Borodin in 1869 and by the French chemist Charles-Adolphe Wurtz in 1872, the reaction combines two carbonyl compounds to form a new β-hydroxy carbonyl compound. These products are known as aldols, from the aldehyde + alcohol, a structural motif seen in many of the products. Aldol structural units are found in many important molecules, whether naturally occurring or synthetic. For example, the aldol reaction has been used in the large-scale production of the commodity chemical pentaerythritol and the synthesis of the heart disease drug Lipitor.

Aldol condensation type of chemical reaction

An aldol condensation is a condensation reaction in organic chemistry in which an enol or an enolate ion reacts with a carbonyl compound to form a β-hydroxyaldehyde or β-hydroxyketone, followed by dehydration to give a conjugated enone.

Thiophene is a heterocyclic compound with the formula C4H4S. Consisting of a planar five-membered ring, it is aromatic as indicated by its extensive substitution reactions. It is a colorless liquid with a benzene-like odor. In most of its reactions, it resembles benzene. Compounds analogous to thiophene include furan (C4H4O) selenophene (C4H4Se) and pyrrole (C4H4NH), which each vary by the heteroatom in the ring.

Imine any chemical compound having the structure RN=CR′R″, thus analogue of aldehyde or ketone in which an oxygen atom is replaced by substituted or unsubstituted nitrogen atom

An imine is a functional group or chemical compound containing a carbon–nitrogen double bond. The nitrogen atom can be attached to a hydrogen (H) or an organic group (R). If this group is not a hydrogen atom, then the compound can sometimes be referred to as a Schiff base. The carbon atom has two additional single bonds. The term "imine" was coined in 1883 by the German chemist Albert Ladenburg.

Acyl chloride any chemical compound having a chlorine atom bonded to a carboacyl group

In organic chemistry, an acyl chloride (or acid chloride) is an organic compound with the functional group -COCl. Their formula is usually written RCOCl, where R is a side chain. They are reactive derivatives of carboxylic acids. A specific example of an acyl chloride is acetyl chloride, CH3COCl. Acyl chlorides are the most important subset of acyl halides.

Chalcone chemical compound

Chalcone is an aromatic ketone and an enone that forms the central core for a variety of important biological compounds, which are known collectively as chalcones or chalconoids. Alternative names for chalcone include benzylideneacetophenone, phenyl styryl ketone, benzalacetophenone, β-phenylacrylophenone, γ-oxo-α,γ-diphenyl-α-propylene, and α-phenyl-β-benzoylethylene.

Thiazole, or 1,3-thiazole, is a heterocyclic compound that contains both sulfur and nitrogen; the term 'thiazole' also refers to a large family of derivatives. Thiazole itself is a pale yellow liquid with a pyridine-like odor and the molecular formula C3H3NS. The thiazole ring is notable as a component of the vitamin thiamine (B1).

The Robinson annulation is a chemical reaction used in organic chemistry for ring formation. It was discovered by Robert Robinson in 1935 as a method to create a six membered ring by forming three new carbon–carbon bonds. The method uses a ketone and a methyl vinyl ketone to form an α,β-unsaturated ketone in a cyclohexane ring by a Michael addition followed by an aldol condensation. This procedure is one of the key methods to form fused ring systems.

The Ugi reaction is a multi-component reaction in organic chemistry involving a ketone or aldehyde, an amine, an isocyanide and a carboxylic acid to form a bis-amide. The reaction is named after Ivar Karl Ugi, who first reported this reaction in 1959.

The Pummerer rearrangement is an organic reaction whereby an alkyl sulfoxide rearranges to an α-acyloxy–thioether (monothioacetal-ester) in the presence of acetic anhydride. In this reaction, sulfur is reduced while adjacent carbon is oxidized.

The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β-diketone. It is named after Rainer Ludwig Claisen, who first published his work on the reaction in 1887.

Knorr pyrrole synthesis

The Knorr pyrrole synthesis is a widely used chemical reaction that synthesizes substituted pyrroles (3). The method involves the reaction of an α-amino-ketone (1) and a compound containing an electron-withdrawing group α to a carbonyl group (2).

Malononitrile chemical compound

Malononitrile, also propanedinitrile or malonodinitrile, is a nitrile with the formula CH2(CN)2.

Doebner–Miller reaction

The Doebner–Miller reaction is the organic reaction of an aniline with α,β-unsaturated carbonyl compounds to form quinolines.

The Paal–Knorr Synthesis in organic chemistry is a reaction that generates either furans, pyrroles, or thiophenes from 1,4-diketones. It is a synthetically valuable method for obtaining substituted furans and pyrroles, common structural components of many natural products. It was initially reported independently by German chemists Carl Paal and Ludwig Knorr in 1884 as a method for the preparation of furans, and has been adapted for pyrroles and thiophenes. Although the Paal–Knorr synthesis has seen widespread use, the mechanism wasn't fully understood until it was elucidated by V. Amarnath et al. in the 1990s.

Jones oxidation

The Jones oxidation is an organic reaction for the oxidation of primary and secondary alcohols to carboxylic acids and ketones, respectively. It is named after its discoverer, Sir Ewart Jones.

2,3,4-Pentanetrione chemical compound

2,3,4-Pentanetrione (or IUPAC name pentane-2,3,4-trione, triketopentane or dimethyl triketone) is the simplest linear triketone, a ketone with three C=O groups. It is an organic molecule with formula CH3COCOCOCH3.

References

  1. Gewald, K.; Schinke, E.; Böttcher, H. Ber. 1966, 99, 94-100.
  2. Sabnis, R. W. Sulfur Rep.1994, 16, 1-17. (Review)
  3. John A. Joule, Keith Mills: Heterocyclic Chemistry, John Wiley & Sons, 5. Auflage (2010), p. 340, ISBN   978-1-4051-3300-5.
  4. Bradford P. Mundy, Michael G. Ellerd, Frank G. Favaloro, Jr.: Name Reactions and Reagents in Organic Synthesis, John Wiley & Sons, 2. Auflage (2005) p. 306, ISBN   0-471-22854-0.
  5. Christopher Hume: Applications of Multicomponent Reactions in Drug Discovery – Lead Generation to Process Development, p. 311−341, see p. 332−334, In Jieping Zhu, Huges Bienaymé: Multicomponent Reactions, Wiles-VCH Verlag, 2005, ISBN   978-3-527-30806-4.
  6. Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J. Heterocyclic Chem.1999, 36, 333.
  7. Sridhar, M.; Raoa, R. M.; Babaa, N. H. K.; Kumbhare, R. M. Tetrahedron Lett. 2007, 48, 3171-3172. (doi : 10.1016/j.tetlet.2007.03.052)
  8. Gernot A. Eller, Wolfgang Holzer Molecules 2006, 11, 371-376 Online article.