Quinoline Skraup synthesis

Quinoline from aniline, glycerol, sulfuric acid and oxidizing agent (e.g. PhN02). 

For an alternative mechanism, see that of the Doebner-von Miller reaction (page 547). 

Skraup, Z. H. Monatsh. Chem. 1880, 1, 316. Zdenko Hans Skraup (1850-1910) was bom in Prague, Czechoslovakia. He apprenticed under Lieben at the University of Vienna. 

Takeuchi, I. Hamada, Y. Hirota, M. Chem. Pharm. Bull. 1993, 41, 747. 

Skraup Doebner-von Miller Reaction in Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 488—494. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 237, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 254, Springer International Publishing Switzerland 2014 

Example 4, A Skraup-Doebner-Von Miller quinoline synthesis 

The most general method for synthesizing quinolines employs aniline or a substituted aniline, glycerol, sulfuric acid, and an oxidizing agent such as a ferric 

Michael-like nucleophilic addition onto unsaturated 0 aldehyde y OH 

The initial product is a dihydroquinoline it is formed via Michael-like addition, then an electrophilic aromatic substitution that is facilitated by the electron-donating amine function. A mild oxidizing agent is required to form the aromatic quinoline. The Skraup synthesis can be used with substituted anilines, provided these substituents are not strongly electron withdrawing and are not acid sensitive. 

Isoquinolines are easily prepared by the reaction of an acyl derivative of a f5-phenylethylamine with a dehydrating agent, e.g. P2O5, then using a catalytic dehydrogenation to aromatize the intermediate 3,4-dihy droi soquinoline. 

The crucial cyclization step is represented here as and an iminium-type system, a resonance form of 

The Simmons-Smith cyclopropanation method has also found application for the a-methylation of ketones via an intermediate cyclopropane. The starting ketone—e.g. cyclohexanone 9—is first converted into an enol ether 10. Cyclopropanation of 10 leads to an alkoxynorcarane 11, which on regioselective hydrolytic cleavage of the three-membered ring leads to the semiketal 12 as intermediate, and finally yields the a-methylated ketone 13  

The zinc iodide formed in a Simmons-Smith reaction can act as Lewis acid, and thereby may catalyze rearrangement reactions however interfering side-reactions are generally rare. 

Yields are moderate to good. In addition to alkenes, the cyclopropanation also works with certain aromatic substrates. 

By reaction of a primary aromatic amine—e.g. aniline 1—with glycerol 2, and a subsequent oxidation of the intermediate product 4, quinoline 5 or a quinoline derivative can be obtained.As in the case of the related Friedlander quinoline synthesis, there are also some variants known for the Skraup synthesis, where the quinoline skeleton is constructed in similar ways using different starting materials.  

For the Skraup synthesis, glycerol 2 is used as starting material in the presence of concentrated sulfuric acid (see scheme above) it is dehydrated to acrolein 6. Although it is assumed that the reactive carbonyl component in the Skraup reaction actually is acrolein, attempts to use acrolein directly, instead of glycerol, proved to be unsuccessful.  

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Quinolines 3 can be obtained from reaction of orr/zo-aminobenzaldehydes or o-aminoarylketones 1 with a-methylene carbonyl compounds.Various modified procedures are known a related reaction is the Skraup quinoline synthesis. 

Doebner-von Miller reaction is a variant of the Skraup quinoline synthesis (page 545). Therefore, the mechanism for the Skraup reaction is also operative for the Doebner-von Miller reaction. An alternative mechanism shown below is based on the fact that the preformed imine (Schiff base) also gives 2-methylquinoline ... 

Skraup quinoline synthesis, 443 Smiles rearrangement, phenothiazine, 534 Spiroalkylation, 222, 280 Spirocyclization, conjugate addition, 386 Spiroimidazolone formation, 335 Spiropyrazolopiperidine, 375 Stannylation, alkyne, 15 Stereoselective dehydration, 198 Grignard addition, 198, 199 reduction, 129, 226 hydroxyketone, 400 iminoketone beta, 553 oxazaborohydride, 585 transfer chirality, 321 Stilbene formation, self alkylation, 525 Stobbe condensation, benzophenone, 103... 

As in the Skraup quinoline synthesis, loss of two hydrogen atoms is necessary to reach the fully aromatic system. However, this is usually accomplished in a separate step, utilising palladium catalysis to give generalised isoquinoline 6.14. This is known as the Bischler-Napieralski synthesis. The mechanism probably involves conversion of amide 6.12 to protonated imidoyl chloride 6.15 followed by electrophilic aromatic substitution to give 6.13. (For a similar activation of an amide to an electrophilic species see the Vilsmeier reaction, Chapter 2.)... 

Scheme 7. The classical Skraup quinoline synthesis (a) and Fukuyama s modified approach (b) using /V-aryl-AZ-sulfonylaminopropionaldehydes (56).

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