Aerobic organocatalytic oxidation of aryl aldehydes: Flavin catalyst turnover by Hantzsch's ester

Article abstract of DOI:10.1021/ol302479b

The first Dakin oxidation fueled by molecular oxygen as the terminal oxidant is reported. Flavin and NAD(P)H coenzymes, from natural enzymatic redox systems, inspired the use of flavin organocatalysts and a Hantzsch ester to perform transition-metal-free, aerobic oxidations. Catechols and electron-rich phenols are achieved with as low as a 0.1 mol % catalyst loading, 1 equiv of Hantzsch ester, and O₂ or air as the stoichiometric oxidant source.

Full text of DOI:10.1021/ol302479b

ORGANIC
LETTERS
2012
Vol. 14, No. 19
5150–5153
Aerobic Organocatalytic Oxidation of Aryl
Aldehydes: Flavin Catalyst Turnover by
Hantzsch’s Ester
Shuai Chen and Frank W. Foss Jr.*
Department of Chemistry and Biochemistry, The University of Texas at Arlington,
700 Planetarium Place, Arlington, Texas 76019, United States
ffoss@uta.edu
Received September 8, 2012
ABSTRACT
The first Dakin oxidation fueled by molecular oxygen as the terminal oxidant is reported. Flavin and NAD(P)H coenzymes, from natural enzymatic
redox systems, inspired the use of flavin organocatalysts and a Hantzsch ester to perform transition-metal-free, aerobic oxidations. Catechols and
electron-rich phenols are achieved with as low as a 0.1 mol % catalyst loading, 1 equiv of Hantzsch ester, and O2 or air as the stoichiometric
oxidant source.
Molecular oxygen isregardedasa green oxidantinmany
respects. Its abundance, high atom efficiency, and ease
of byproduct (H2O) disposal are unmatched by other
oxidants.1ꢀ3 Oxygen is predominantly activated by metal
catalysts or stoichiometric cooxidants.3,4 Unfortunately,
aerobic oxidations by organocatalysts are surprisingly
scarce. Nature, however, has employed flavin-dependent
monooxygenases that activate triplet oxygen by organic
cocatalysts, FAD or FMN, and gently oxidize diverse
substrates at moderate temperature and pH, and in an
aqueous environment.5ꢀ8 In these enzymes, a reductive
coenzyme such as NAD(P)H is needed to regenerate the
reduced form of flavin cofactors, which interacts with O2,
completing the catalytic cycle. In this work, we evaluated a
range of reducing agents to achieve an aerobic, catalytic,
transition metal-free Dakin oxidation of benzaldehydes
to phenols by flavin mimics, 1aꢀe (Figure 1). The quin-
tessential Hantzsch ester (2)9 was found to be most com-
patible with both starting materials and products and is
shown for the first time to effectively regenerate flavin
catalysts for the nucleophilic oxidation of carbonyl con-
taining substrates.
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r
10.1021/ol302479b
Published on Web 09/27/2012
2012 American Chemical Society

an oxidant, often requiring activation by metal catalysts or
elevated temperatures.26ꢀ34
To our knowledge, no example utilizing molecular
oxygen as the terminal oxidant for Dakin oxidations
exists. Here we achieve a catalytic system in which O2 is
activated by flavin catalysts, and the Hantzsch ester 2 is an
effective reducing agent,35,36 completing the catalytic cycle,
to perform transition-metal-free, efficient, and mild Dakin
oxidations.
Hydrogen peroxide based Dakin oxidations were pre-
viously investigated in our laboratory with five 1,3,5-
trialkylated alloxazines (1aꢀe), a class of flavins documen-
ted to attain considerable stability15 and a range of cata-
lytic activity in comparison to related alloxazines and
isoalloxazines.15,18,37,38 The new 4a-hydroperoxyflavin
catalyst 1a proved most efficient in Dakin oxidations.23
We initiated the aerobic Dakin oxidation of arylaldehydes by
applying similar conditions using these alloxazine catalysts.
Figure 1. Flavin catalysts 1aꢀe and Hantzsch ester 2.
using molecular oxygen10ꢀ12 or hydrogen peroxide13ꢀ18
as terminal oxidants. In previous work, hydrazine and
zinc dust effectively reduced flavin mimics to complete an
aerobic catalytic cycle.10,11,19ꢀ22 However, these reducing
agents are not fully compatible with aldehyde substrates. In
search of new nucleophilic flavin oxidations, we discovered
that hydroperoxyflavins efficiently performed the Dakin
oxidation of electron-rich benzaldehydes.23 Pleasingly,
the flavin-catalyzed oxidation of electron-poor benzalde-
hydes to benzoic acids was recently reported by a similar
mechanism.24 The Dakin oxidation (Scheme 1) is related to
the BaeyerꢀVilliger oxidation.25 Many methods have been
investigated to perform this transformation. Most Dakin
oxidation methods utilize hydrogen peroxide or peracids as
Scheme 1. General Mechanism for Organocatalytic Aerobic
Oxidation of Substrate 3 to 4 by 4a-Hydroperoxyflavin 1c
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Reducing agent selection was key to the success of
catalytic aerobic Dakin oxidations (Scheme 1). Based on
previous aerobic amine, sulfur, and BaeyerꢀVilliger oxi-
dation methods, hydrazine and zinc were regarded as
efficient reducing agents to reduce oxidized flavin mimics
(Flþ).10,11 Hydrazine predictably forms hydrazones with
benzaldehyde substrates, yielding no desired product.
Activated zinc showed good reactivity in the oxidation of
salicylaldehyde to produce catechol. However, when the
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Org. Lett., Vol. 14, No. 19, 2012
5151

Dakin oxidations proceeded smoothly to form corre-
sponding phenol products (Schemes 1 and 2). The produc-
tion of undesired benzyl alcohols or benzoic acids41ꢀ43 was
not detected. Diethyl 2,6-dimethylpyridine-3,5-dicarboxy-
late, 5, could be isolated from reactions as the oxidized
byproduct.
Scheme 2. Substrate Study for Aerobic Oxidationa
Control reactions without flavin catalysts ensured that
no autoxidation of benzaldehydes occurred during oxida-
tion of 3a.41ꢀ43 Reactions were also performed in the dark
to eliminate possible photooxidation pathways. The aero-
bic Dakin oxidation conditions were then optimized in
three aspects: catalyst substitution, solvent, and base.
Five alloxazines with different substituents at the 7- and
8-positions were compared. With a 5 mol % catalyst
loading, the conversion of salicylaldehyde to catechol
was calculated by NMR, utilizing DMSO as an internal
standard. Flavin 1c showed the greatest reactivity, fol-
lowed by 7,8-dimethyl (1d) and 7,8-dimethoxy (1e) sub-
stituted alloxazines. Electron-poor 7,8-difluoro (1b) and
7,8-dichloro (1a) alloxazines, which provided the fastest
reactionratesinH2O2-fueled Dakinoxidations, performed
aerobic oxidation poorly (Figure SI-1).
The catalyst results suggest that competing rate-
determining steps influence the observable reaction rate:
(1) collapse of the Criegee intermediate via a 1,2-aryl shift
(putative rate-determining step of the Dakin oxida-
tion)23,44 and (2) molecular oxygen activation by reduced
flavins.8,45 While we previously showed that electron-with-
drawing groups facilitate the Dakin oxidation by stabiliz-
ing the 4a-oxaflavin anion (FlOꢀ) leaving group, the same
substituents attenuate the single-electron transfer process
from flavin to triplet oxygen by altering the oxidation
potentials of the reduced flavins.16,46 The hypothesis, in
correlation with previous data,45ꢀ47 is as follows: electron-
poor hydroperoxyflavins (Scheme 1, FlOOH), in compar-
ison to more electron-rich catalysts, are more efficient
Dakin oxidation catalysts, but their respective reduced
structures (FlH) react with O2 more slowly.
a Yields refer to isolated yields. b No catalyst added. c Air was used as
an oxidant. d Air was used as an oxidant, with 0.1 mol % 1c, and 10 mmol
of substrate 3a. Naphthoquinone isolated. 65% quinone and 23%
dihydroquinone isolated.
e
f
Solvents were investigated (Figure SI-2). Water miscible
solvents were investigated to solvate sodium bicarbonate
by 5% water addition, which also promotes hydrolysis
of the Dakin oxidation intermediate. Acetonitrile, 95%
in water, achieved the fastest reaction rate and highest
yields. In general, alcohols suppressed reaction rates.
Anhydrous acetonitrile failed to conduct aerobic Dakin
oxidation.
Zn/O2 protocol was appliedtosubstitutedsalicylaldehydes
(3b, 3c, 3g, Scheme 2), catechols were isolated in very low
yields. Either robust bisphenolate zinc complexes, such as
zinc bis(2-ethylzincoxyphenoxide) and zinc bis(2- ethylzin-
coxyphenylmethoxide), or polyphenols are believed to
form, sequestering the desired product.39 Methods (acid,
base, EDTA treatment and extraction) to liberate pro-
duct from the possible organometallic structures were
unsuccessful. Other reducing agents, such as Na2S2O4,
NaBH3CN, NaBH(OAc)3, and trialkylsilanes, yielded no
desired products. Other d-block species (Mg, Cu, and Fe)
were expected to result in decomposition of the reactive
hydroperoxyflavins by Fenton or Fenton-like chemistry.
No catechol was detected by these metal reducing agents.
Hantzsch ester 2, the hydrogen transfer reagent closely
related to NAD(P)H’s nicotinamide reactive core,40 selec-
tively reduces imines in the presence of aldehydes.35,36
When zinc powder was replaced with 1 equiv of 2, aerobic
Base is essential in the flavin catalyzed Dakin oxida-
tion system. However, only mild bases (sodium bicarbonate
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Org. Lett., Vol. 14, No. 19, 2012

or carbonate) were necessary. Hydroxides were not as
effective in this system, presumably due to hydrolysis of
the flavin catalyst (Figure SI-3).
The reaction is selective for the nucleophilic Dakin oxida-
tion in 95% MeCN aq.; thioanisole and triethylamine are
not oxidized to a great extent. However, when MeCN was
exchanged for trifluoroethanol (TFE), which convincingly
assists in electrophilic addition by providing a useful hydro-
genbondnetworkduringOꢀO bond cleavage,12 thioanisole,
salicylaldehyde, and triethylamine were oxidized in 80%,
18%, and 11% yield, respectively, over 1 h (see Supporting
Information). Interestingly, 2 was fully converted to 5 in
these TFE reactions. This revealed an underlying, flavin
dependent, aerobic oxidation of dihydropyridines in certain
solvents. Investigating the redox properties of the reductant
in these systems may allow relatively slow Dakin oxidations
to proceed without background dihydropyridine oxidation,
which may be interesting, considering the abundance of
oxidative aromatization reactions.49ꢀ53
In conclusion, we have developed an aerobic and
mild catalytic system for the Dakin oxidation. A range of
electron-rich benzaldehydes react in the presence of two
biomimetic redox partners: flavin catalysts and Hantzsch
ester 2. The selection of 2 was crucial to the success of
this reaction and provides an alternative reductant for
flavin-catalyzed aerobic oxidations, especially those with
ketones and aldehydes. The catalyst loading was effective
at 0.1 mol %. Further experiments are underway to broad-
en the reaction scope to other important nucleophilic,
flavin-catalyzed oxidations of carbon centers.
The catalytic system for aerobic Dakin oxidation is
broadly described as shown in Scheme 1. Flavinium
(Flþ) is reduced by 2 to form reduced flavin (FlH). Mean-
while, 2 is oxidized to pyridine 5. FlH undergoes autoxida-
tion to form an active catalyst (FlOOH), which performs
the Dakin oxidation. After protonation and water elim-
ination, Flþ is regenerated. A shunt process for the gen-
eration of H2O2 (made possible by disproportionation of 1
to Flþ and HOOꢀ with consumption of 2 and O2) is known
in mutatated monooxygenases and some hydrophilic sol-
vent systems. We were unable to detect turnover of this
shunt process (by monitoring conversion of 2 to 5 in the
absence of aldehyde) after long reaction times in either the
presence or absence of substrate using the basic MeCN/
H2O reaction system.
A range of substituted benzaldehydes were screened
to investigate the scope of this protocol (Scheme 2). In
general, salicylaldehydes underwent aerobic Dakin oxida-
tion faster than the 4-hydroxybenzaldehydes, likely due
to neighboring group participation of the ortho-hydroxyl
group involved in proton transfer events and hydrogen
bond activation of the carbonyl.48 Salicylaldehydes were
smoothly converted into catechols at room temperature.
Electron-withdrawing groups slowed the oxidation rate
(3i). No reaction was detected at elevated temperatures for
3,5-dinitrosalicylaldehyde.
Acknowledgment. We are grateful to Duy Cao (UTA)
and Sergiy Ivanov (UTA) for technical assistance. Finan-
cial support for this work was provided by The University
of Texas at Arlington, the Research Enhancement Pro-
gram by UT Arlington, and instrumentation was sup-
ported by the NSF (CHE-0234811 and CHE-0840509).
The reaction system functioned with air as an oxygen
source, although longer reaction times were required. A
10 mmol scale reaction, with 0.1 mol % of catalyst and air
as the oxygen source, was performed to challenge our
catalytic system. A high yield of the product was achieved
after 3 days at rt, and the byproduct 5, which represents
99 w/w % of the reducing agent, was recovered in 95%
yield. For products prone to autoxidation, the aerobic
Dakin oxidation protocol yielded the expected oxidized
products (3g, 3l).
Supporting Information Available. Synthetic methods,
analytical methods, and full characterization of materi-
als. This material is available free of charge via the
Internet at http://pubs.acs.org.
Electron-poor benzaldehydes, without a hydroxyl group
on the othro- or para-position, failed to undergo Dakin
oxidation in these conditions, even with the addition of
a Lewis or Brønsted acid. Acetophenone remained unox-
idized, even at elevated temperature (50 °C) using catalyst
1c. Though unproductive, these substrates remained intact
under the reaction conditions.
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The authors declare no competing financial interest.
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