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I am struggling to find a way to disconnect this molecule and I am unsure of the order:

(2E)-1-(2,4-dimethylphenyl)-3-(thiophen-2-yl)prop-2-en-1-one

First, I was thinking of disconnecting the C=C of the α,β-unsaturated carbonyl. Then for the thiophene group disconnecting the formyl substituent, then disconnecting the thiophene either side of the sulfur atom to give a 1,4-diketone.

Then for the benzene substituent: disconnecting the carbonyl first (via Friedel–Crafts acylation), as the methyl groups will be ortho/para-directing.

Would this be the correct order?

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There are several approaches to this molecule, but I think the key disconnection is the E-double bond. This looks like it can be formed by a Horner-Emmons-Wadsworth reaction between the widely commercially thiophene-2-carboxaldehyde and a ketophosphonate derived from 2,4-dimethylacetophenone. HEW reactions give predominantly E-alkenes which is the reason for the choice.

The ketophosphonate can be prepared in good yield from the commercially available 2,4-dimethylbenzoyl chloride by reaction with diethyl phosphonoacetic acid/MgCl2/Et3N, method described here.

It is possible to prepare both starting materials, but it is an important principle of synthetic chemistry that your time as a researcher is more valuable than the cost of advanced materials. If a starting material is available, buy it.

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