Diazonium salt, Japp-Klingemann hydrazone synthesis

JAPP KLINGEMANN Hydrazone Synthesis Synthesis of hydrazones from diazonium salts and an activated methylene group (or enamlne)... 

The Japp-Klingemann reaction was the key step during the first synthesis of the pentacyclic pyridoacridine marine cytotoxic alkaloid amoamine A by E. Delfoume et a P The diazonium salt was added to a vigorously stirred solution of ethyl-2-methyl-3-oxobutyrate in ethanol containing KOH, NaOAc and water. The resulting hydrazone was exposed to polyphosphoric acid to form the indole ring. 

Serotonin has been synthesised by several routes the method shown relies on a Fischer indole synthesis, the requisite aryl-hydrazone being constructed by a process known as the Japp-Klingemann reaction in which the enol of a 1,3-dicarbonyl compound is reacted with an aryl-diazonium salt, with subsequent cleavage of the 1,3-dicarbonyl unit. 

In 2009 Welch and Lim described a synthesis of S-SFs-tryptamine (10) (09MI165). Their approach relied on the Japp—Klingemann reaction and started from 4-SF5-aniline (11), which was first diazotized by slow addition of aqueous NaN02 to its acidic methanoHc solution. Diazonium salt 12 reacted with 2-oxopiperidine-3-carboxylic acid (13) under mildly alkaline conditions and allowed isolation of hydrazone 14 in 88% yield. Fischer cychzation of 14 resulted in a formation of the 1-oxo-tetrahydro-p-carbohne 15 hydrolysis of the latter gave carboxylic acid 16. Decarboxylation of acid 16 provided S-SFs-tryptamine (10) in 21% yield. This five-step sequence from 11 gave tryptamine 10 in only 3% total yield (Scheme 4). 

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