Communication
Organic & Biomolecular Chemistry
Subsequently, the so prepared α-phosphoryl-methyllithium
carbanion 2a very efficiently acylated with a Weinreb amide,31
furnishing the ketone 22 in 81% isolated yield. Secondly,
because of the well-known instability of carbanionic CHF2 frag-
ments,27 we wondered if the stable difluoromethyl phospho-
nate 13 could act as a suitable transfer agent (path b). To this
end, we selected the opioid agonist Hydrocodone (dihydroco-
deinone) as a competent carbonyl-containing manifold for the
introduction of the CHF2 group. Pleasingly, the consecutive
lithiation–nucleophilic addition–dephosphorylation strategy
afforded the difluoromethyl alcohol 23 in high yield. The
transformation presents some aspects worth of note: (a) the
CHF2-containing phosphonate represents an attractive synthon
for the delivery of the difluoromethyl unit under nucleophilic
regime, thus complementing the usually employed silicon-ana-
logues;27 (b) the facile access to compound 23 – conjugating
the OH group (responsible for high opioid activity) and the
drug-design interesting motif CHF2 – may spur further studies
in the area of novel morphinane-skeleton narcotic agents.
In summary, we disclosed a one-step functionalization of
different chloro-phosphorous electrophiles (phosphates, phos-
phine oxides and phosphines) with α-substituted organo-
lithium reagents (LiCHXY) for the direct obtainment of
geminal P-containing methanes. Not only nucleophilic (di)-
halocarbenoid (LiCH2Cl, LiCH2I, LiCH2F, LiCHCl2, LiCHBr2)
could be employed but, also a plethora of functionalized
methyllithiums, such as LiCH2-FG (FG = CN, SR, SeR, SiR3,
SnR3, GeR3) and LiCHXY (X, Y = I, SiR3, SR) promoted the
transformation. This modular, high yielding strategy relies on
a conceptually intuitive straightforward nucleophilic substi-
tution conducted with the nucleophilic element on the P–Cl
linkage. The fine tuning of the conditions requested for gener-
ating the carbanion-like reagents is the unique factor to be
taken into account for designing the process. The synthetic
application of the accessed motifs has been screened in selec-
tive transformations, including the difluoromethylation of the
carbonyl moiety of the narcotic agent Hydrocodone.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank the University of Vienna and the University of Turin,
for generous support. M. M. acknowledges OEAD for a Blau
grant.
Notes and references
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2428 | Org. Biomol. Chem., 2021, 19, 2425–2429
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