The Claisen ester disconnection: a 1,3-diO relationship needing two carbonyl groups
المؤلف:
Jonathan Clayden , Nick Greeves , Stuart Warren
المصدر:
ORGANIC CHEMISTRY
الجزء والصفحة:
ص717-718
2025-07-12
419
The Claisen ester disconnection: a 1,3-diO relationship needing two carbonyl groups
1,3-Diketones can be disconnected in a similar way: this time the disconnection corresponds to a Claisen condensation, but it’s still 1,3-diO and again you need to look out for the 1,3 relationships. The synthons are still d2 plus a1 but the a1 synthon is used at the ester oxidation level. This diketone is the starting material for the synthesis of the antidepressant tazadolene. With 1,3-diketones, there’s always a choice where to disconnect, and you should be guided by which disconnection (a) corresponds to the most reliable reaction and (b) gives the simplest starting materials. In this case, it’s much better to disconnect back to cyclohexanone.
The synthesis is interesting because, after the acylation of the enamine, the amino group is introduced by a clever reductive amination with benzylamine (PhCH2NH2) that forms the C–N bond, reduces the ketone, and hydrogenolyses the N-benzyl bond. Dehydration and double alkylation then gives tazadolene. Step 3, the attack of benzylamine on the diketone, has interesting chemoselectivity. Only the ketone in the six-membered ring is attacked while the less reactive conjugated phenyl ketone is not affected.
The 1,3-dicarbonyl relationship may not be revealed in the target molecule and C–hetero atom disconnections or FGIs may be needed before the 1,3-diO C–C disconnection. Bropirimine is a bromine-containing antiviral and anticancer drug. The bromine atom can be put in last of all by electrophilic bromination.
Disconnection of two C–N bonds removes a molecule of guanidine and reveals a 1,3 dicarbonyl relationship with a straightforward disconnection.
In the event, the 1,3-dicarbonyl was made using malonate chemistry with an unusual twist: the lithium derivative gave C–acylation in good yield. Simply refluxing the product with guanidine formed the heterocycle and bromination gave bropirimine.
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