Zincke aldehyde
Encyclopedia
Zincke aldehydes, or 5-aminopenta-2,4-dienals, are the product of the reaction of a pyridinium salt with two equivalents of any secondary amine, followed by basic hydrolysis. Using secondary amines (as opposed to primary amines) the Zincke reaction
Zincke reaction
The Zincke reaction is an organic reaction in which a pyridine is transformed into a pyridinium salt by reaction with 2,4-dinitro-chlorobenzene and a primary amine, named after Theodor Zincke....

 takes on a different shape forming Zincke aldehydes in which the pyridine ring is ring-opened with the terminal iminium
Iminium
An iminium salt or cation in organic chemistry has the general structure [R1R2C=NR3R4]+ and is as such a protonated or substituted imine. It is an intermediate in many organic reactions such as the Beckmann rearrangement, Vilsmeier-Haack reaction, Stephen reaction or the Duff reaction...

 group hydrolyzed to an aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....

. The use of the dinitrophenyl group for pyridine activation was first reported by Theodor Zincke
Theodor Zincke
Theodor Zincke was a German chemist and the academic adviser of Otto Hahn.-Life:Theodor Zincke was born in Uelzen on 19 May 1843. He became a pharmacist and graduated in Göttingen with his Staatsexamen. He began studying chemistry with Friedrich Wöhler and received his Ph.D in 1869...

. The use of cyanogen bromide
Cyanogen bromide
Cyanogen bromide is a pseudohalogen compound with the formula CNBr. It is a colorless solid that is widely used to modify biopolymers, fragment proteins and peptides, and synthesize other compounds.-Synthesis, basic properties, and structure:...

 for pyridine activation was independently reported by W. König :

The synthesis and utility of Zincke aldehydes has been reviewed.

A variation of the Zincke reaction
Zincke reaction
The Zincke reaction is an organic reaction in which a pyridine is transformed into a pyridinium salt by reaction with 2,4-dinitro-chlorobenzene and a primary amine, named after Theodor Zincke....

 has been applied in the synthesis of novel indole
Indole
Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an...

s :

with cyanogen bromide
Cyanogen bromide
Cyanogen bromide is a pseudohalogen compound with the formula CNBr. It is a colorless solid that is widely used to modify biopolymers, fragment proteins and peptides, and synthesize other compounds.-Synthesis, basic properties, and structure:...

 mediated pyridine activation (König method).

More recently, an interesting rearrangement of Zincke aldehydes to Z-unsaturated amides was discovered serendipitously while trying to do an intramolecular Diels-Alder reaction
Intramolecular Diels-Alder Cycloaddition
In organic chemistry, an intramolecular Diels-Alder cycloaddition is a Diels–Alder reaction in which the diene and a dienophile are both part of the same molecule...

. The rearrangement gives the Z-product stereospecifically. In a follow-up paper, allylic amines were used and gave products of a rearrangement/intramolecular Diels-Alder
Intramolecular Diels-Alder Cycloaddition
In organic chemistry, an intramolecular Diels-Alder cycloaddition is a Diels–Alder reaction in which the diene and a dienophile are both part of the same molecule...

 cascade. Mechanistic details were also discussed, however further investigations in collaboration with the Houk group revealed an unusual and unexpected mechanism based on computational studies. The new mechanism involves formation of a vinyl ketene
Ketene
A ketene is an organic compound of the form R'RC=C=O. The term is also used specifically to mean ethenone, the simplest ketene, where R' and R are hydrogen atoms.Ketenes were first studied as a class by Hermann Staudinger.-Formation:...

.
The Vanderwal group has also reported the synthesis of 4-stannyldienals from Zincke aldehydes by addition of tributylstannyl anion and quenching with acetyl chloride. The products are useful substrates for Stille cross-coupling
Stille reaction
The Stille reaction is a chemical reaction coupling an organotin compound with an sp2-hybridized organic halide catalyzed by palladium. The reaction is widely used in organic synthesis....

 reactions to give interesting polyene structures.
In 2009, the Vanderwal group reported another interesting rearrangement of Zincke aldehydes. Tryptamine-derived Zincke aldehydes are heated with strong base to give the rearranged enal as shown below. This reaction was the key step in their total synthesis of norfluorocurarine, a Strychnos
Strychnos
Strychnos is a genus of flowering plants, belonging to family Loganiaceae . The genus includes about 190 species of trees and lianas, distributed around the world's tropics....

alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...

.This strategy was also employed in a short synthesis of strychnine
Strychnine
Strychnine is a highly toxic , colorless crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine causes muscular convulsions and eventually death through asphyxia or sheer exhaustion...

, becoming the shortest synthesis of strychnine reported to date at only six linear steps.This works has been highlighted on the blog Totally Synthetic.
Also in 2009, the first reports of Zincke aldehydes undergoing a Pictet-Spengler reaction
Pictet-Spengler reaction
The Pictet–Spengler reaction is a chemical reaction in which a β-arylethylamine such as tryptamine undergoes ringclosure after condensation with an aldehyde or ketone. Usually an acidic catalyst is employed and the reaction mixture heated, but some reactive compounds give good yields even at...

 appeared from the group of Delpech and the late Christian Marazano. This reaction provided the tetrahydro-β-carboline or tetrahydroisoquinoline
Tetrahydroisoquinoline
Tetrahydroisoquinoline is a secondary amine with the chemical formula C9H11N.-Reactions:Like other secondary amines, tetrahydroisoquinoline can be oxidized to the corresponding nitrone using hydrogen peroxide, catalyzed by selenium dioxide....

 core present in many alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...

 natural products, and was applied to the construction of a known intermediate in a previous total synthesis.
One drawback of the Zincke Aldehyde synthesis is the need for 2 equivalents of the amine in the initial pyridine ring opening reaction. This is of particular concern for the case of complex secondary amines required for natural product synthesis. The group of Michel recently found an alternative synthesis by condensation onto a variety of glutaconaldehyde
Glutaconaldehyde
Glutaconaldehyde is an organic compound with the formula C5H6O2. It is an unsaturated dialdehyde as is related to glutaraldehyde and glutaconic acid, but exists in its enol form due to the conjugation with the double bond....

derivatives using TFA. This solution has greatly simplified the production and purification of complex Zincke aldehydes.

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