A quick run-through of key ideas when planning on making indole ring systems in organic chemistry, showcased in the synethesis of sumatriptan.
I go over the mechanisms of the Fischer indole synthesis and a diazotation reaction.
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Sumatriptan was released by Glaxo in the 1990s as a pharmaceutical agent for the treatment for migraines, after the standard medicinal chemistry exploration. The large-scale industrial synthesis involves a Fischer indole disconnection as its key step of making the bicyclic aromatic rings system. The mechanism involves a [3,3] sigmatropic rearrangement (a pericyclic reaction) in which a weak nitrogen-nitrogen bond is broken at the expense of big thermodynamic benefits of the generation of aromaticity. The indole system can be seen to be aromatic by counting electrons and showing that it conforms to Huckel's rule.
The formation of the the N-N bond is done by a diazotation reaction, and goes through an intermediate diazonium ion. This is a common reaction for forming new bonds directly between two nitrogen atoms and uses nitrous acid (HONO) reacted with an (aryl) amine. These diazonium ions can also be used as intermediates with a really good leaving group - being nitrogen gas - in other types of substitution reactions. The diazonium ion also is prone to oxidative addition type reaction mechanisms on interaction with appropriate metals.
The starting materials for the industrial synthesis come from classic nitration conditions using nitric acid and sulfuric acid. The para selectivity of nitration can be explained mainly from the stabilisation of an intermediate carbocation.
The other aldehyde starting material is easier to handle on a large scale when masked as the dimethyl acetal - this, for example, make it less sensitive to hydrate formation with water and therefore also unintended oxidation under atmospheric conditions. The dimethyl acetal collapses under the Fischer indole reaction conditions, being aqueous acid, by the usual SN1 type process.
There are other alternative retrosynthesis ideas that can be used for this molecule, but most will involve using the central indole core as the focus. There are many alternative indole formation mechanisms and processes, that each might have their merit on occasion. The Fischer indole is probably the most archetypal disconnection, and it is certainly one of the most traditional and well-precedented. When using other carbonyl compounds in this type of mechanism, care must be taken for the regioselectivity for the enamine formation - under most circumstances this is under thermodynamic control. Disconnections therefore need to be taken carefully if the indole ring has more substitution, particularly if there are groups at the 2 and 3 positions (these are on the "pyrrole" type ring component of the indole).
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