ketone underwent BVO by flavin mimics.5,7ꢀ15,23 This
disparity in reactivity not only displays the enzyme’s role
in tuning flavin reactivity but also suggests that a biomi-
metic system could be developed to modulate inate flavin
reactivity in solution.
To broaden the synthetic capability of flavin catalysts to
useful nucleophilic oxidations, the Dakin oxidation of
electron-rich benzaldehydes (Figure 1) was investigated.
The Dakin oxidation24 is a privileged variation of the BVO
that converts benzaldehydes (1) to phenols (3) by BVO and
subsequent hydrolysis of the aryl formate intermediate (2),
effectively oxidizing both aryl and acyl sp2 carbons.25ꢀ27
Dakin’s original procedure utilized excess hydrogen per-
oxide and sodium hydroxide at elevated temperatures.24
Common substrates contain electron-rich aromatic rings
for rapid collapse and carbon migration of the tetrahedral
Criegee intermediate (CIꢀ).
alkylperoxides and catalytic transition metal com-
plexes have been developed for mild Dakin oxida-
tions.33ꢀ41 No organocatalytic processes exist for the
Dakin oxidation. Therefore, we saw the transformation
as an attractive entry point to study nucleophilic flavin
reactivity.
Here we show that flavin mimics catalyze the Dakin
oxidation. Due to the lower pKa and OꢀO heterolytic
bond lability of hydroperoxyflavins in comparison to
H2O2 and other alkyl peroxides,42ꢀ45 the reactions are
effective under relatively milder conditions. The time scale
of the transformations allows for an initial mechanistic
investigation of this nucleophilic flavin oxidation by NMR
and HPLC techniques, experimentally illuminating the chal-
lenges that have faced flavin catalyzed BVOs of unstrained
substrates and related oxidations.23 It should be noted that
our initial mechanistic findings for flavins correspond with
recent investigations of BVMO mechanisms.46ꢀ48
Catalysts 6aꢀe were synthesized as shown in Scheme 1
from 4aꢀe (Scheme SI-1), which were prepared according
to conventional methods.8,49,50 Significant improvements
weremadetothe general synthesisof 7,8-disubstituted-1,3-
dimethyl-5-ethylflavins by modifications to the final re-
ductive amination transformation. Catalysts 6a and 6d
were not previously reported. Dichloromethane was re-
quired as a solvent to suppress hydrodechlorination of
4a,51ꢀ53 which yields undesired 6c under standard hydro-
genation conditions, to complete the most active catalyst
6a. Compound 6b required elevated H2 pressure.
Because synthetically challenging aromatic hydroxyla-
tions can be formally achieved by aryl acylation followed
by Dakin oxidation,28ꢀ32 numerous stoichiometric
Catalysts 6a and 6b converted a range of electron-rich
arylaldehydes to phenols (Table 1). While 6cꢀe react at
reduced rates, 6c tends to reach comparable yields as 6a
and 6b with prolonged reaction times. Entries 1ꢀ6 exem-
plify the utility of the flavin-catalyzed oxidation for the
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Figure 1. Potential flavin catalyzed dakin oxidation mechanism.
Focus on energetic demanding steps similar to BaeyerꢀVilliger-
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