Table 1. Biomimetic Oxidation of 4-Nitrobenzaldehyde 4a
Figure 1. Flavins and hydroperoxides relevant to this study.
tertiary amines and phosphines to form sulfoxides,
N-oxides, and phosphine oxides, respectively.4 However,
there are examples of synthetically useful flavin-catalyzed
reactions which operate through a nucleophilic flavin
hydroperoxide.5,6 Key among these oxidations are flavin-
catalyzed BaeyerÀVilliger reactions which use H2O2 as
terminal oxidant. Accordingly, we believed there to be
scope to examine a biomimetic oxidation of aldehydes. We
and others have further examined the synthetic utility of
Sayre’s ethylene-bridged flavin catalysts (3aÀc, Table 1)7
in oxidative8 and reductive transformations.9 These cata-
lysts are readily preparedinthree steps, withoutrecourseto
intermediate purification, and therefore offer themselves
as thermally stable and versatile organocatalysts.
We initially chose to examine the flavin-catalyzed oxida-
tion of 4-nitrobenzaldehyde 4a to 4-nitrobenzoic acid 5a
mediated by aqueous hydrogen peroxide. Reasonable
oxidation with catalyst 3a was only observed when heated
to 85 °C in acetonitrile as solvent (entries 1À3).10 There is
some sensitivity to the exact structure of the catalyst with
7-CF3-substituted catalyst 3c offering improvement over
3a and 3b (entries 3À5). Increasing the reaction time also
was beneficial (entry 6). Intriguingly, we have observed
that the reaction offers an improved reaction as gauged by
an improved final conversion after 3 h when catalyst
loading was lowered to 2.5 and 1 mol % (entries 7 and 8).
Full conversion can be achieved by conveniently raising
the loading of oxidant and allowing the reaction to
proceed to a longer duration (entry 11). Minimal back-
ground reaction is observed in the absence of the flavin
catalyst, confirming the key role played by 3 (entry 12). In
addition, no oxidation is observed in the absence of H2O2,
entry 3 (mol %) H2O2 (equiv) temp (°C) time (h) conva (%)
1
2
a (5)
a (5)
a (5)
b (5)
c (5)
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.5
23
50
85
85
85
85
85
85
85
85
85
85
85
1
1
0
0
3
1
49
54
60
66
79
76
85
96b
100
6
4
1
5
1
6
c (5)
3
7
c (2.5)
c (1)
3
8
3
9
c (1)
3
10
11
12
13
c (2.5)
c (2.5)
1.5
3
5
17
3
1.25
0
c (2.5)
3
0
a NMR conversion; assayed by relevant 1H NMR integrals. b Isolated
yield = 89%.
supporting an activation of H2O2 rather than a redox-
centered catalytic cycle that activates molecular oxygen
(entry 13).
Having developed an effective oxidation protocol, as
optimized on 4a, we looked to examine the scope with
other aromatic aldehydes (Scheme 2). This protocol
works well with electron-deficient aryl aldehydes, as
seen with regioisomeric nitro- and chlorobenzalde-
hydes 4aÀf. The heteroaromatic substrate picolinalde-
hyde 4n also demonstrates this point. In contrast, the
regioisomeric anisaldehydes 4jÀl result in lower iso-
lated yields of carboxylic acid products (Scheme 2). The
presence of the strong electron-donating groups in the
ortho- and para-positions led to the formation of phe-
nol byproducts, consistent with a competitive Dakin
oxidation.
(4) For a review of the synthetic chemistry of flavin hydroperoxides,
see: Gelalcha, F. G. Chem. Rev. 2007, 107, 3338.
This flavin-catalyzed reaction is also generally excel-
lent for the oxidation of alkyl aldehydes, with high
yields observed in many instances. Interestingly, di-
minished yields were observed with aldehydes bearing
nonconjugated aryl groups (4v,w). It is unclear exactly
why this is the case; however, 1H NMR analysis of the
crude reaction mixture of 5w appears to support the
presence of a stable peroxy hemiacetal. This observa-
tion suggests a slow formation of carboxylic acid in this
instance.
(5) For examples of flavin-catalyzed BaeyerÀVilliger reactions, see:
(a) Mazzini, C.; Lebreton, J.; Furstoss, R. Heterocycles 1997, 45, 1161.
(b) Mazzini, C.; Lebreton, J.; Furstoss, R. J. Org. Chem. 1996, 61, 8.
(c) Imada, Y.; Iida, H.; Murahashi, S.-I.; Naota, T. Angew. Chem., Int.
Ed. 2005, 44, 1704. (d) Murahashi, S.-I.; Ono; Imada, S., Y. Angew.
Chem., Int. Ed. 2002, 41, 2366.
(6) For a recent example of a flavin-catalyzed Dakin oxidation, see:
Chen, S.; Hossain, M. S.; Foss, F. W., Jr. Org. Lett. 2012, 14, 2806.
(7) (a) Li, W.-S.; Zhang, N.; Sayre, L. M. Tetrahedron 2001, 4507.
(b) Li, W.-S.; Sayre, L. M. Tetrahedron 2001, 57, 4523.
(8) (a) Marsh, B. J.; Carbery, D. R. Tetrahedron Lett. 2010, 51, 2362.
ꢀ
ꢀꢁ
ꢁ
(b) Zurek, J.; Cibulka, R.; Dvorakova, H.; Svoboda, J. Tetrahedron
ꢀꢁ
The mechanism we propose for this flavin-catalyzed
oxidation is outlined in Scheme 3. Flavin catalyst 3c reacts
with H2O2 to form hydroperoxide 6. The C10a regioselec-
tivity of peroxide addition is that proposed by Sayre as a
ꢁ
Lett. 2010, 51, 1083. (c) Jurok, R.; Cibulka, R.; Dvorakova, H.; Hampl,
ꢀ
ꢁ
F.; Hodacova, J. Eur. J. Org. Chem. 2010, 5217.
(9) Marsh, B. J.; Heath, E. L.; Carbery, D. R. Chem. Commun. 2011,
280.
(10) See the Supporting Information for full reaction optimization.
Org. Lett., Vol. 14, No. 14, 2012
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