Key words
nitrogen radicals - photoredox catalysis - visible-light-driven reactions - amidyl
radicals - cyclizations - addition to π systems - hydrogen atom transfer
Organic compounds bearing nitrogen atoms are widely found in pharmaceutical and agrochemical
products. In fact, the use of C–N cross-coupling methods in medicinal chemistry accounts
for approximately 23% of reported reactions in recent publications, highlighting the
ubiquitous nature of this transformation. Furthermore, functionalized amine and amide
products are important building blocks in active pharmaceutical ingredients (APIs).
For this reason, new and green synthetic strategies to construct C–N bonds under mild
conditions are a central goal for chemists. In traditional chemistry, sp2 C–N bonds are typically formed by Pd-catalyzed Buchwald–Hartwig reactions or Cu-catalyzed
Ullman–Goldberg reactions, while sp3 C–N bonds are usually installed through reductive amination and alkylation, Gabriel
synthesis and Hoffman degradation. However, these approaches have the same drawbacks:
the requirement for prefunctionalization of the substrates and the use of high temperatures.
In recent decades, with the increased use of photocatalysis and, in particular, visible-light-mediated
radical processes, nitrogen-radical chemistry has become more accessible. This revolutionary
technique has made it possible to develop novel and previously unattainable synthetic
approaches. Photocatalysis describes transformations that require light as an energy
input to proceed, and they typically use catalytic amounts of light-absorbing photocatalysts
such as metal complexes or organic dyes. Moreover, photocatalysis is characterized
by the use of low-energy photons as reagents, opening the door to environmentally
safe, more sustainable, and non-hazardous visible-light-based chemical synthesis.
Nitrogen radicals can be divided into four different types according to their electronic
configuration, orbital structure and chemical behavior. Iminyl radicals possess an
sp2-hybridized nitrogen atom, a planar structure and a σ-configuration with amphiphilic
behavior. Amidyl radicals have single electrons in a p orbital perpendicular to the
nitrogen substituents, so they assume a π-configuration with electrophilic chemical
behavior. Meanwhile, aminyl and aminium radicals both have a π-configuration but opposite
reactivity. In fact, aminyl radicals are weak nucleophiles and are commonly utilized
for their preference for H-atom abstraction, while aminium radicals are strong electrophiles.
Although there are other types of nitrogen radicals, these four main classes can be
used to illustrate their reactivity (e.g., carbamyl radicals and N-Ts radicals are consistent with the behavior of amidyl radicals). The philicity of
radicals has been effectively defined by computational and experimental studies, and
is a crucial parameter for developing new radical reactions.
The best way to generate nitrogen radicals is via cleavage promoted by light under
mild conditions. In particular, the most suitable bonds to be broken are N–H, N–halogen,
N–N, N–O and N–S. There are four main strategies to break these types of bond: homolytic
cleavage, reduction, oxidation and oxidative proton-coupled electron transfer (PCET).
Homolytic cleavage can occur when an N–halogen, N–N, N–O or N–S bond is irradiated
with UV light, generating two radical species that can lead to the desired transformation.
The second and third methods involve a photoredox quenching cycle, which can be oxidative
or reductive depending on the reaction counterparts. In detail, in the reductive quenching
cycle, single-electron transfer (SET) occurs to generate a nitrogen-radical cation
in two different ways: the electron can be abstracted either directly from the HOMO
of the precursor or from an oxidizable group external to the key NCR moiety which
can undergo a fragmentation (e.g., a decarboxylative cascade mechanism). Also, in
the oxidative quenching cycle, the SET can occur via two different pathways: the electron
can be donated either directly to the σ*-orbital of the nitrogen radical or to a π*-orbital
of a suitable precursor (e.g., hydroxylamine and pyridinium ions). In oxidative PCET,
the nitrogen-radical precursor undergoes concerted homolytic activation through the
formation of a hydrogen bond complex between the N–H of the amide and a suitable base.
The reactivity of all these radicals can be classified into four main types: (i) intramolecular
cyclization onto alkenes or alkynes via a classic exo-trig process, (ii) intramolecular hydrogen atom abstraction (e.g., 1,5-HAT), (iii)
Norrish type I fragmentation (with limited examples), and (iv) intermolecular addition
to π-systems such as olefins, alkynes and aromatic compounds. It is significant to
highlight the fact that not all the classes of nitrogen radicals share these reaction
modes, since it is their philicity that stabilizes (or destabilizes) the corresponding
transition states.
In this graphical review, we have summarized the most well-known published examples
of nitrogen-radical reactions, grouping them by their reactivity and the type of radical
generated. Although there are numerous examples of reactions involving nitrogen-centered
radicals in the literature, we will limit our report to reactions involving visible
light.
Figure 1 Overview of nitrogen-centered radicals[1`]
[b]
[c]
[d]
Figure 2 Intramolecular cyclizations for the synthesis of cyclic amines and substitutes indoles[2`]
[b]
[c]
[d]
[e]
[f]
[g]
Figure 3 Iminyl radical intramolecular cyclization for the synthesis of heteroarenes and functionalized
pyrrolidines[3`]
[b]
[c]
Figure 4 Iminyl radical intramolecular cyclization for the synthesis of heteroarenes and functionalized
pyrrolidines[4`]
[b]
[c]
Figure 5 Synthesis of γ-lactams and substituted pyrazoles via 5-exo-trig cyclization[5a]
[b]
Figure 6 Bioactive heterocycle formation[6a]
[b]
Figure 7 Heterocycle and sulfonamide formation[7`]
[b]
[c]
Figure 8 Heterocycle formation[8`]
[b]
[c]
Figure 9 Heterocycle formation via 5-exo-trig cyclization[9a]
[b]
Figure 10 Addition of aminium radicals to ethyl vinyl ether and benzoxazoles[10a]
[b]
Figure 11 Addition of aminium radicals to olefins and arenes[11`]
[b]
[c]
[d]
Figure 12 Addition of pyridyl radicals to arenes for the synthesis of highly tunable pyridinium
salts[12a]
[b]
Figure 13 Addition of aminium radicals to arenes and olefins to synthesize pyridinium salts
and diamines[13a]
[b]
Figure 14 Amidyl radicals in enantioselective photoredox α-aminations of aldehydes[14`]
[b]
[c]
[d]
[e]
Figure 15 Amidyl radicals in imidations and amidations of arenes and heteroarenes and the halo-functionalization
of alkenes[15`]
[b]
[c]
[d]
Figure 16 Amidyl radicals in imidations and amidations of arenes and heteroarenes and double
addition to alkenes[16`]
[b]
[c]
[d]
[e]
Figure 17 Amidyl radicals in amidations of arenes and α-aminations of 2-acylimidazoles[6b]
[17a]
[b]
Figure 18 Amidyl radicals in arene functionalization and double addition of olefins[18`]
[b]
[c]
Figure 19 Amidyl radicals in three-component reactions to aliphatic amines and the synthesis
of sulfonamines[19`]
[b]
[c]
Figure 20 Remote C–H alkylation promoted by PCET[20`]
[b]
[c]
[d]
Figure 21 Intramolecular C(sp3)–H imination for the synthesis of functionalized imidazoles[21`]
[b]
[c]
Figure 22 Aliphatic C–H functionalization through a 1,5-HAT cascade[22]
Figure 23 γ-C(sp3)–H functionalization of ketones[23a]
[b]
Figure 24 Norrish fragmentations[23a]
[24a]
[b]
