Letter
Amide Bond Formation via Aerobic Photooxidative Coupling of
Aldehydes with Amines Catalyzed by a Riboflavin Derivative
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ABSTRACT: We report an effective, operationally simple, and
environmentally friendly system for the synthesis of tertiary amides by
the oxidative coupling of aromatic or aliphatic aldehydes with amines
mediated by riboflavin tetraacetate (RFTA), an inexpensive organic
photocatalyst, and visible light using oxygen as the sole oxidant. The
method is based on the oxidative power of an excited flavin catalyst and
the relatively low oxidation potential of the hemiaminal formed by amine
to aldehyde addition.
mides are not only the building blocks of natural peptides
but also the key intermediates in the synthesis of
transfer reagent.14 Alternatively, there are also simple method-
ologies using only a photocatalyst, like a phenazinium salt,15
Rose Bengal16 or anthraquinone,17 and molecular oxygen
(Figure 1C). Nevertheless, there are still limitations in
substrate scope and effectiveness of photocatalytic aldehyde-
amine couplings, namely, relatively long reaction times (20 h
and more) and missing procedures for amides of aliphatic
acids.
Derivatives of riboflavin (vitamin B2) are readily available
blue-light-absorbing photocatalysts well suited to oxidative
chemistry.18 In addition to their ability to oxidize highly
difficult substrates,19 some flavins have been shown to provide
delicate chemoselective oxidations.20 In aprotic solvents,
riboflavin tetraacetate (RFTA) was shown to behave as a
two-electron oxidant in oxidation of 4-methoxybenzyl alcohol
to benzaldehyde.21 Considering all of the aforementioned
factors and the photooxidation ability of flavin derivatives, we
developed the first flavin-based photocatalytic approach to
amide synthesis using RFTA as a catalyst. This system involves
oxidative coupling of an aldehyde and a secondary amine using
oxygen as a terminal oxidant and visible light. Amide formation
proceeds under mild conditions without the need for an
additional hydrogen/electron acceptor. RFTA is available in a
single step from cheap commercially available riboflavin
(Figure 1D).
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polymers, agrochemicals, and 25% of modern pharmaceut-
icals.1 To date, great efforts have been made to develop new
and efficient approaches to amide formation as commonly used
methods suffer from inherent disadvantages.2 The direct
thermal condensation of carboxylic acids and amines is the
simplest method for the preparation of amides. However, this
pathway is restricted to simple substrates because it requires
harsh temperature conditions. Amides are traditionally
synthesized from activated carboxylic acids or their derivatives
and amines (Figure 1A),2b,3 alternatively by the Beckmann
rearrangement,4 Schmidt reaction,5 Staudinger ligation reac-
tion,6 and other reactions.7 However, many of these strategies
suffer from the production of large quantities of waste and
byproducts. Thus, amide synthesis avoiding poor atom
economy reagents remains one of the main challenges for
organic chemistry.8 As a consequence, new catalytic
approaches for amide bond formation are of great interest
from an industrial and academic point of view.9
As an alternative to the traditional methods, the transition-
metal-catalyzed coupling of aldehydes with amines as well as
metal-free oxidative amidation of aldehydes have achieved a
breakthrough in amide synthesis (Figure 1B).9−11 Nontoxic
aldehydes are readily available and offer the possibility of
starting the transformation from substrates other than
carboxylic acids. Nevertheless, the majority of methods starting
from aldehydes are characterized by disadvantages such as
expensive catalysts/reagents, high temperatures, oxidizing
agents other than oxygen, and, in some cases, low tolerance
to secondary amines.9 Recently, researchers directed their
attention to photocatalytic procedures which usually offer mild
and green alternatives to conventional approaches.12 Among
previously known photocatalytic systems for oxidative coupling
of aldehydes and amines to amides are those requiring a
stoichiometric additive as oxidant13 or an electron- or oxygen-
The implementation of our strategy commenced with the
model reaction of 4-chlorobenzaldehyde (1a) and piperidine
(2a) in the presence of 5 mol % RFTA under blue light
Received: July 17, 2021
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
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