reactive metallic reagents with all the associated negative
effectsstoxicity, overoxidations of the substrate, and the lack
of compatibility with other oxidizable functionalities. The
ingenious take on this problematic process, enhancing the
selectivity greatly and avoiding the detrimental stoichiometric
metal salts, was introduced by Corey.5 Its wider use,
however, has been hampered by the limited availability of
the quinone-based oxidation reagent. Very recently, the
Backvall group has introduced a variation of the process,
where amines underwent Ru-catalyzed aerobic oxidation in
the presence of quinones.5b
Scheme 2
.
Copper/Ascorbic Acid Catalyzed Oxidative
Deamination
Continuing the quest for a milder, environmentally benign
oxidation protocol, we introduce a method based on the
reported reactivity between dehydroascorbic acid (dehy-
droAsc) and various amines on one side and the copper-
mediated aerobic oxidation of ascorbic acid (Asc) leading
to dehydroAsc on the other.
The formation of colorful Schiff bases between dehy-
droAsc and amines with consequent degradation reactions
has been well-known to food industry scientists for years.6
It is the likely culprit in fruit and vegetable darkening
(version of Maillard reaction) (Scheme 1).
Although Asc or its derivative could be, in theory,
reoxidized a number of times, thus rendering Asc catalytic,
in our hands 2 equiv was needed to obtain the full conversion
of amine into the desired carbonyl product. The likely culprit
of this stoichiometry requirement can be identified by the
observation of ammonia containing stable oligomers formed
in the naturally occurring (Maillard) reaction. These species,
which involve at least two Asc or dehydroAsc subunits (See
the Scheme 3), are detrimentally unreactive toward a fresh
Scheme 1
.
Naturally Occurring Aerobic Reaction of Ascorbic
Acid and Amino Acids
Scheme 3. DehydroAsc as the Oxidation Mediator
molecule of amine substrate, preventing the required forma-
tion of the Schiff base-centered intermediate. Hence, more
than 1 equiv of Asc was needed for the efficient oxidation
of amines in our case.
The second part of the proposed plan is based on cupric
complexes and ascorbic acid (Asc) connected intimately in
the redox couplesthe interaction well documented in chemi-
cal and biochemical literature.7 Thus, using the link between
the easily oxidizable metal and the reactive organic mediator
that reacts in its oxidized state, with amines, we envisioned
an oxidation process built on the chemistry of the copper/
ascorbic acid (Asc) dyad (Scheme 2).
This synthetically interesting oxidation process starts with
atmospheric oxygen as the cheapest and most abundant
ultimate “electron scavenger”.3b It continues in a cascade-
like fashion by passing its oxidation potential through
metallic salt to the organic mediator, which finally reacts
with the substrate with high selectivity.
With respect to the ideas outlined above, we examined
the validity of the concept. In the cursory experiment, the
amine substrate 1a was treated by the commercial dehy-
droAsc under an inert atmosphere. The corresponding
aldehyde 2a was easily formed. The same was true (and it
pointed again to the dehydroAsc as the likely reaction
intermediate) when dehydroAsc was preformed in situ by
the copper-catalyzed aerobic oxidation of Asc (Scheme 3).
In a separate control experiment, the Asc was fully omitted
from the reaction mixture. This test did not lead to the
formation of any signifficant amount of the product. When,
in turn, the copper catalyst was left out, the reaction
proceeded very slowly, and the conversion of the substrate
reached 10-20% in several days as compared to hours
needed for the high conversions in the copper-catalyzed
process. Our reasoning of the observation is supported by
the well-documented slow spontaneous aerobic oxidation of
Asc. The reaction was carried out in various solvents (THF,
dioxane, ether, AcOH). On the basis of the best isolated
yields, however, amidic solvents DMF and DMA were the
(5) (a) Corey, E. J.; Achiwa, K. J. Am. Chem. Soc. 1969, 91, 1429. (b)
Samec, S. M.; Ell, A. H.; Backvall, J.-E. Chem.-Eur. J. 2005, 11, 2327.
(6) Hayashi, T.; Namiki, M.; Tsuji, K. Agric. Biol. Chem. 1983, 47,
1955. Larisch, B.; Pischetsrieder, M.; Severin, T. J. Agric. Food Chem.
1996, 44, 1630.
(7) Silverblatt, E.; Robinson, A. L.; King, C. G. J. Am. Chem. Soc. 1943,
65, 137.
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Org. Lett., Vol. 11, No. 4, 2009