Abstract
Difluoromethylated esters, malonates and amino acids (including the drug eflornithine) are obtained by a gas–liquid continuous flow protocol employing the abundant waste product fluoroform as an atom-efficient reagent.
Highlights
Manuel Köckinger,a Tanja Ciaglia,a Michael Bersier,b Paul Hanselmann,b Bernhard Gutmann *a,c and C
A plethora of alternative difluoromethane sources have been developed in recent years, including TMSCF2Br, (EtO)2POCF2Br, PhCOCF2Cl and CHF2OTf.[2]. These reagents cover the needs of chemists for difluoromethylation on a laboratory scale, their high cost, low atom economy and limited commercial availability prohibit their usage in an industrial setting
Eflornithine has been explored as an anticancer agent, and it is in clinical use for the treatment of African sleeping sickness as well as of Pneumocystis carinii pneumonia, the most frequent opportunistic infection associated with acquired immunodeficiency syndrome (AIDS).[11]
Summary
As mentioned in the introduction, the synthesized α-difluoromethyl malonates can be converted to the respective α-difluoromethyl amino acids in a multi-step transformation (Scheme 1).[12,13] since a direct difluoromethylation of natural α-amino acids has clear advantages, reactions with Schiff base-protected α-amino acid methyl esters were investigated.[14] The N-benzylidene-protected α-amino acid methyl esters were readily available from the parent amino esters using literature procedures (for experimental details, see the ESI†).[14] Gratifyingly, subjecting the N-benzylidene-protected α-amino acid methyl esters 1g to 1k to the general reaction conditions resulted in >95% conversion to the desired product. Further optimization of the difluoromethylation process, in particular with regard to stoichiometry and reaction time, is ongoing in our laboratories and will be reported in due course
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