Difluoromethylation of arylidene Meldrum's acid derivatives

Moscow Chemical Lyceum
Alexey Trifonov


Fluorine-containing compounds gained significant attention during the past decade1. About 20% of novel pharmaceuticals and 40% of novel agrochemicals every year contain at least one fluorine atom in the molecule. For a long time the most frequently used was trifluoromethyl group, but nowadays the most promising is the chemistry of partially-fluorinated groups. For example, the difluoromethyl substituent (CHF2) exhibits unique pharmacoforic properties capable of serving as lipophilic hydrogen bond donor thus being bioisosteric to hydroxyl group2. There are several general approaches for the formation of a required fluorinated fragment, one of them is direct nucleophilic fluoroalkylation. This approach is well-developed for trifluoromethylation reactions, such as addition of CF3-anion equivalents to C=O, C=N and electron-deficient C=C bonds or metal-catalyzed substitution in haloarenes3. However the similar difluoromethylation processes are still quite challenging. Herein we present a novel and convenient protocol for the synthesis of β-CF2H functionalized carbonyl compounds and carbinols by nucleophilic difluoromethylation of electron-deficient olefines. The process is based on a 1,4-addition of in situ generated4 phosphorus ylide Ph3P=CF2 2 to the arylidene Meldrum's acid conjugates 1. The resulting phosphobetaines 3 are hydrolized/protodephosphorilated without isolation, giving β-CF2H substituted carboxylic acids 4. The latter may be easily transformed to the corresponding ethers 5 and alcohols 6 without preliminary purification.

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