Retrosynthetic analysis of hydroxychloroquine using undergraduatelevel organic chemistry ideas. Involves quinoline synthesis and an assessment of chemoselectivity issues from competing reactivity from multiple functional groups.

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A first disconnection in the centre of the molecule by nucleophilic aromatic substitution (SNAr) splits hydroxychloroquine into an aromatic half and an aliphatic half.

The aromatic quinoline ring system is electrophilic on the pyridinelike side and so all that’s required is an appropriately placed leaving group. A chloride can be installed from the hydroxyl group using POCl3. Consideration of the tautomeric form of the hydroxy quinoline as the “pyridone” form reveals the key disconnection for the construction of the quinoline directly from a substituted benzene ring. Doing a CC disconnection here allows the natural nucleophilic reactivity of the starting material to set up a cyclisation reaction. Both the chloro and amino substituents direct to the same position, both being ortho/para directing groups by pi conjugation (using their lone pairs). Some functional group interconversions take this retrosynthesis back to nitrobenzene as a cheap, readily available starting material.

The aliphatic fragment contains two amine functional groups and an alcohol. Care must be taken when assessing competing nucleophilic reactivity – in fact temporarily masking one of the amines as a nitro group and careful choice of protecting groups solves this problem surprisingly straightforwardly. The synthetic fragments has a 1,2diX and a 1,4diX functional group relationship. Splitting is up using a reductive amination as a standard disconnection separates out these two features. The 1,2diX disconnection is easily address by using an epoxide (ethylene oxide/epoxyethane) as an electrophile for ethylamine as a nucleophile. The product alcohol’s hydroxy group is best protected at this stage, and I propose the use of a benzyl ether for this as it can be cleaved as at an appropriate moment using hydrogenation which can be done simultaneously with a nitroalkane reduction. The 1,4diX functional group relationship is code for Umpolung chemistry, usually. Helpfully, a common Umpolung reagent in a nitroalkane is a really smart choice here as it brings in a nitrogen atom as well when its conjugate base is used as a soft d1 nucleophile for conjugate addition (Michael addition).

At the end of the retrosynthetic analysis and discussion, I draw together a proposal for a forward synthesis of hydroxychloroquine. Although I am sure there are many valid alternative approaches to both the retrosynthesis and forward synthesis.