Controlled Relay Process to Access N-Centered Radicals for Catalyst-free Amidation of Aldehydes under Visible Light

Article abstract of DOI:10.1016/j.chempr.2020.12.004

Nitrogen-centered radicals have attracted increasing attention as a versatile reactive intermediate for diverse C–N bond constructions. Despite the significant advances achieved in this realm, the controllable formation of such species under catalyst-free conditions remains highly challenging. Here, we report a new relay process involving the slow in situ generation of a photoactive N-chloro species via C–N bond formation, which subsequently enables mild and selective access to N-centered radicals under visible light conditions. The utility of this approach is demonstrated by the conversion of aldehydes to amides, employing N-chloro-N-sodio carbamates as a practical amidating source. This synthetic operation obviates the need for catalysts, external oxidants, and coupling reagents that are typically required in related processes, consequently allowing high functional group tolerance and excellent applicability for late-stage functionalization. Amides are an important class of structural motifs prevalently found in bioactive compounds and synthetic materials of great significance. Amidation of aldehydes has been established as an atom-efficient strategy for amide synthesis; however, current methods lack in applicability mainly due to the requirement of troublesome reagents. In this article, we describe an unconventional relay process to convert aldehydes to amides under catalyst-, oxidant-, and coupling-reagent-free conditions, which is enabled by the development of a new mechanistic platform that gives efficient and controllable access to N-centered radicals under visible light. A wide range of (hetero)aromatic and aliphatic aldehydes can be employed, including those derived from biologically relevant complex molecules. We anticipate that the accomplished methodological advances, combined with the unique mechanistic features, will lead to the widespread application of the present strategy in broad research fields. A catalyst-free approach for controlled access to N-centered radicals is described, which enables the conversion of aldehydes to amides via an unconventional relay process harnessing visible light. The key tactic relies on the use of photostable N-chloro-N-sodio-carbamate amidating reagent that leads to slow incorporations of a photoactive radical source via C–N formation and other involved intermediates thereafter. This methodology displays excellent applicability and sustainable chemistry credentials and, thus, holds a promise for finding broad applications.

Full text of DOI:10.1016/j.chempr.2020.12.004

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Article
Controlled Relay Process to Access N-
Centered Radicals for Catalyst-free Amidation
of Aldehydes under Visible Light
Wongyu Lee, Hyun Ji Jeon,
Hoimin Jung, Dongwook Kim,
Sangwon Seo, Sukbok Chang
s.seo@kaist.ac.kr (S.S.)
sbchang@kaist.ac.kr (S.C.)
HIGHLIGHTS
Relay process for the controllable
formation of N-centered radicals
under visible light
Amidation of aldehydes under
catalyst-, oxidant-, and coupling-
reagent-free conditions
Atom economic transformation
that results in NaCl as the only
byproduct
Broad scope and high functional
group tolerance leading to
excellent applicability
A catalyst-free approach for controlled access to N-centered radicals is described,
which enables the conversion of aldehydes to amides via an unconventional relay
process harnessing visible light. The key tactic relies on the use of photostable N-
chloro-N-sodio-carbamate amidating reagent that leads to slow incorporations of
a photoactive radical source via C–N formation and other involved intermediates
thereafter. This methodology displays excellent applicability and sustainable
chemistry credentials and, thus, holds a promise for finding broad applications.
Lee et al., Chem 7, 495–508
February 11, 2021 ª 2020 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2020.12.004

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Article
Controlled Relay Process to Access N-Centered
Radicals for Catalyst-free Amidation
of Aldehydes under Visible Light
Wongyu Lee,1,2,3 Hyun Ji Jeon,1,2,3 Hoimin Jung,1,2 Dongwook Kim,1,2 Sangwon Seo,1,2,
*
and Sukbok Chang1,2,4,
*
SUMMARY
The Bigger Picture
Amides are an important class of
structural motifs prevalently found
in bioactive compounds and
synthetic materials of great
significance. Amidation of
Nitrogen-centered radicals have attracted increasing attention as a
versatile reactive intermediate for diverse C–N bond constructions.
Despite the significant advances achieved in this realm, the control-
lable formation of such species under catalyst-free conditions re-
mains highly challenging. Here, we report a new relay process
involving the slow in situ generation of a photoactive N-chloro spe-
cies via C–N bond formation, which subsequently enables mild and
selective access to N-centered radicals under visible light condi-
tions. The utility of this approach is demonstrated by the conversion
of aldehydes to amides, employing N-chloro-N-sodio carbamates as
a practical amidating source. This synthetic operation obviates the
need for catalysts, external oxidants, and coupling reagents that
are typically required in related processes, consequently allowing
high functional group tolerance and excellent applicability for
late-stage functionalization.
aldehydes has been established
as an atom-efficient strategy for
amide synthesis; however, current
methods lack in applicability
mainly due to the requirement of
troublesome reagents. In this
article, we describe an
unconventional relay process to
convert aldehydes to amides
under catalyst-, oxidant-, and
coupling-reagent-free conditions,
which is enabled by the
INTRODUCTION
development of a new
The ubiquity of nitrogen-based motifs in high-value compounds has engendered the
C–N bond formation as one of the most important organic transformations.1,2 As a
complementary method to the conventional transition-metal-catalyzed coupling reac-
tions,3–5 the construction of C–N bonds harnessing N-centered radicals has developed
into a powerful synthetic tool.6–9 In particular, recent advances in redox catalysis have
led to a renaissance in this field, as this approach allows the mild and selective gener-
ation of N-centered radicals (Figure 1A). An array of new reaction modes have been
developed by using single electron transfer (SET) or proton-coupled electron transfer
(PCET) abilities of photoredox or transition-metal-based catalysts, which subsequently
enabled diverse transformations, such as C–H amination,10–15 hydroamination,14,16–18
and remote C–H functionalization.19–22 While redox catalysis remains as the most ver-
satile strategy for N-centered radical chemistry, the simplest means to access such
reactive intermediate relies on the thermal or photo-homolysis of nitrogen–halogen
bonds (Figure 1A).23 This method has been majorly utilized in the conversion of acyclic
mechanistic platform that gives
efficient and controllable access
to N-centered radicals under
visible light. A wide range of
(hetero)aromatic and aliphatic
aldehydes can be employed,
including those derived from
biologically relevant complex
molecules. We anticipate that the
accomplished methodological
advances, combined with the
unique mechanistic features, will
lead to the widespread
application of the present strategy
in broad research fields.
amines to pyrrolidines, known as the Hofmann-Loffler-Freytag (HLF) reaction,24–26 via
¨
1,5-hydrogen atom transfer (HAT), halogen abstraction, and base-induced intramolec-
ular cyclization reactions. However, the inability to attain a delicate control over the ho-
molysis process may lead to undesired degradation pathways, such as those arising
from the side reactions with highly reactive halogen radical.23
Recently, iodine-based catalysis has been developed that offers solutions to some of the
problems encountered in the classical homolysis approach.9 For example, Mun˜iz27–29
Chem 7, 495–508, February 11, 2021 ª 2020 Elsevier Inc. 495

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A
B
C
D
Figure 1. Synthetic Strategies for the Generation of N-centered Radicals
(A) Two common approaches to access N-centered radicals.
(B) Strategies for in situ generation of N–X radical precursor.
(C) Our reaction design of relay process for C–N formation via N-centered radical.
(D) Amidation of aldehydes using N-chloro-N-sodio-carbamates and visible light irradiation.
and Nagib30–32 showed that a I2 or NaI catalyst, in combination with a hypervalent iodine
oxidant, is effective for the slow in situ generation of a N-iodoamine radical precursor by
the iodination of amines (Figure 1B), which, in turn, enables the formation of N-centered
radicals in a controlled manner. Not only does it preclude the requirement of nitrogen
pre-functionalization, but this method has also been proven viable for intermolecular
C–H amination.33 Inspired by these elegant works, we envisaged developing a new C–
N bond-forming strategy based on the in situ generation of a N-halo radical precursor
via an alternative bond connection. While the previous methods provided impressive ad-
vances, theiruseinintermolecularreactionsisstillscarce, andthe needforalargenumber
of chemical oxidants may diminish their synthetic utilities. Moreover, the development of
new strategies that could incorporate amino moieties other than those based on sulfon-
amides is highly desirable. To this end, we hypothesized that N-chloro-N-sodio-carba-
mate 1 may provide an alternative mechanistic platform for catalyst- and oxidant-free
C–N constructions via a transposed sequence of the HLF-type process (Figure 1C). In
this approach, the controlled generation of N-centered radicals would be achievable
by the slow incorporation of a photoactive N-chloro intermediate from the photostable
amidating reagent and a sparingly present organic chloride. The N–Cl homolysis would
befollowedbyintermolecularHATwithareactanttoleadtotheamidation product,while
the translocation of N to C radical and chlorine abstraction would constantly provide the
chloride species to enable the continuous relay process.
1Department of Chemistry, Korea Advanced
Institute of Science and Technology, Daejeon
34141, South Korea
2Center for Catalytic Hydrocarbon
Functionalizations, Institute for Basic Science,
Daejeon 34141, South Korea
3These authors contributed equally
4Lead Contact
*Correspondence: s.seo@kaist.ac.kr (S.S.),
sbchang@kaist.ac.kr (S.C.)
https://doi.org/10.1016/j.chempr.2020.12.004
496 Chem 7, 495–508, February 11, 2021

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Specifically, we were interested in attempting this reaction design in the amidation
of aldehydes, given the significance of amides in broad research fields.34 Although
the conversion of aldehydes to amides have been enormously explored,35
including by way of some visible-light-mediated approaches36–39 and transition-
metal-coordinated nitrene reactions,40–42 there is a dearth of direct strategies to
synthetically valuable N-protected amides.43 In addition, we considered this as a
desirable transformation worthy of further investigation since the existing methods
are often hampered by the lack of applicability.44 The competence to eliminate cat-
alysts, oxidants, and highly reactive coupling reagents, thus, remains in high de-
mand for aldehyde amidation, which may grant access to underexplored chemical
space. Here, we report a visible-light-induced approach for amidation of alde-
hydes, utilizing 1 as a catalyst-free amidating reagent to afford N-protected amides
under mild and convenient conditions (Figure 1D). This synthetic operation relies on
a relay process that allows the controlled incorporation of a N-centered radical,
which circumvents the limitations associated with the use of detrimental reagents,
thereby leading to a broad scope, high functional group tolerance, and excellent
applicability.
RESULTS AND DISCUSSION
Proof of Concept
N-Chloro-N-sodio-amino salts have been utilized for transition-metal-catalyzed C–N
formation, for example, as a nitrene precursor.45 Previously, our group also demon-
strated that N-chloro-N-sodio-tert-butylcarbamate 1a is a practical amino source for
the Cu-catalyzed C–H amidation of (hetero)arenes.46 This reagent can be readily
prepared in multigram scales by treating tert-butylcarbamate (Boc-NH2) with
tBuOCl47 or trichloroisocyanuric acid (TCCA),46 followed by the salt formation using
NaOH in MeOH. It is bench-stable, convenient to handle and additionally benefits
from the ability to directly install a protected-amino moiety. In continuation of our
research interests in C–N bond constructions,4,48–50 we endeavored to evaluate
the viability of 1a for an unconventional reaction mode utilizing visible light.
The structure of 1a was first analyzed by X-ray crystallography, which revealed that it
has an interesting 2D sheet connectivity in its solid state (Figure 2A). The rigid so-
dium-based framework consists of the organic anionic parts being held together
through multiple Na–O and Na–N coordinations, each ion being surrounded by
four ions of the opposite charge. The length of the Na–O bonds is slightly shorter
than that of the Na–N bonds, which is indicative of similar charge distribution be-
˚
tween the two atoms. Interestingly, the N–Cl bond of 1a (1.763 A) was determined
˚
to be relatively longer than those of certain N-chloro species (1.700–1.715 A) that
were reported to homolytically dissociate under photolytic conditions.51 With the
recognition of these structural aspects, the photostability of 1a was tested under
visible light irradiation in MeCN (Figure 2B). Despite the comparably longer N–Cl
bond length, 1a was found to be inert to homolysis under the photo conditions, in
which the stability might have resulted from the structural rigidity or the incapability
to absorb the light energy. This is in stark contrast to the photochemical lability of its
protonated variant 1b, which decomposed to the corresponding carbamate 2 (32%)
and a chlorinated derivative 3 (40%) under the same conditions, presumably via a
HLF-type process.
With 1a revealed to be resistant to uncontrollable photo-decompositions, we further
carried out experimental investigations to prove the conceptual viability of our reac-
tion design (Figure 2C). We proposed that an acid chloride additive I would initiate
Chem 7, 495–508, February 11, 2021 497

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A
C
H
Na
N
O
+
R
N
Boc
Cl
Boc
R
Cl
1a
I
O
O1
Cl1
NaCl
Boc
O
Cl
N
Na1
R
N
N1
Boc
R
R
O
H
O
O
II
III
nucleophilic acyl substitution
O
bond length (Å)
MeCN
30 °C, 3 h
in dark
Na
O
Practical amidating source
Boc
Cl
+
Na1–O1
2.390
2.446
1.763
Simple to make and scalable
Bench-stable and easy to handle
(no decomposition for months)
N
Ph
N
N
O
Cl
Boc
Ph
Cl
Na1–N1
N1–Cl1
Cl
Na
1a
4 (2.0 equiv)
5, 84%
1a
radical chain reactions
B
(N radical formation, HAT, chlorine abstraction)
MeCN
Cl
R
N
R
N
O
MeCN
30 °C, 3 h
30 °C, 3 h
H
N
O
O
+
+
H2N
O
Boc
+
5
+
blue LED
(450 nm)
H
Boc
Cl
Boc
Cl
Boc
Ph
N
H
blue LED
(450 nm)
2
Ph
H
Ph
Cl
3
O
(1.0 equiv)
6, 85%
4 , 86%
1a, R = Na
1b, R = H
>99% recovery
0% recovery
trace
32%
n.d.
40%
Figure 2. Proof of Concept for the Proposed Amidation of Aldehydes Using Visible Light
(A) X-ray structure of N-chloro-N-sodio-tert-butylcarbamate 1a: minor disorder and hydrogen atoms were omitted for clarity.
(B) Photochemical stabilities of N-chloro amino sources.
(C) Proposed relay cycle and the feasibilities of each step of the reaction sequence.
the relay cycle by first reacting with 1a to give N-chloroamide species II. Alexanian
et al., recently reported compelling strategies for site-selective intermolecular halo-
genation of aliphatic C–H bonds by using specifically designed N-haloamides and
visible light.52,53 Based on the structural similarity, we envisioned that II could react
with aldehyde to furnish the amide product and further generate acid chloride I for
the next relay cycle. To validate this working mode, each step of the reaction
sequence was investigated. First, the nucleophilic acyl substitution of 1a with ben-
zoyl chloride 4 in the dark successfully gave N-chloroamide 5 in an 84% yield. The
obtained amide 5 was subsequently found to afford amide 6 (85%) along with ben-
zoyl chloride 4 (86%) upon treatment with benzaldehyde under visible light irradia-
tion. These results demonstrated that the designed amidation would be highly
feasible, whereby the conversion of aldehydes to amides would be achieved
through a relay process involving the aforementioned reactions.
Optimization of the Reaction Conditions
The proven viabilities of each reaction step led us to investigate the desired transfor-
mation of aldehydes to amides. We initially hypothesized that a substoichiometric
amount of acid chloride would be required as an additive to induce the proposed
reaction. With this in mind, we carried out the reaction between 1a and benzalde-
hyde under visible light irradiation using an integrated photoreactor54 (blue LED,
450 nm; Figure 3A). Pleasingly, the use of 1a, benzaldehyde (2.0 equiv), benzoyl
chloride additive 4 (1 mol %) and MeCN solvent yielded the amidation product 6
in a 97% yield in 3 h. However, to our surprise, the formation of 6 was also achieved
498 Chem 7, 495–508, February 11, 2021

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A
C
O
entry
variation from the additive-free conditions
6 (%)a
O
Na
N
MeCN, 30 °C, 3 h
blue LED (450 nm)
Boc
+
Ph
N
H
1
2
3
4
5
6
420 nm
365 nm
93
70
Ph
H
Cl
Boc
(2.0 equiv)
1a
6
97%
97%
1 mol% benzoyl chloride (4):
no light (dark)
n.d.
85
no additive:
potassium variant of 1a
B
1.2 equiv of 1a and 1.0 equiv of benzaldehyde
PhCF3 solvent (0.38 M), and same as entry 5
18
93
aNMR yields
D
O
O
O
1a (1.2 equiv)
4
+
Me
Me
Me
H
PhCF3, 30 °C, 3 h
blue LED (450 nm)
H
NHBoc
5
5
no additive
4 (1 mol%) as an additive
5
Me
7
8
no additive:
10 mol% heptanoyl chloride:
15 mol% benzoic acid:
n.d.
94%
88%
12%
n.d.
n.d.
Figure 3. Optimization of the Reaction Conditions
(A) Preliminary results for the amidation of benzaldehyde with 1a under visible light.
(B) Changes in the product yields along the reaction time for the reactions in the absence and presence of benzoyl chloride 4 additive.
(C) Selected conditions for further optimization of the reaction between benzaldehyde and 1a.
(D) Optimization of the reaction between 1-heptanal and 1a.
in the same efficiency even in the absence of any additives (97%). We speculated that
a little decomposition of 1a could promote the aldehyde chlorination in a manner
similar to the previous reports,55 which would convert a sacrificial amount of alde-
hyde to acid chloride for the initiation process. This hypothesis could be supported
by monitoring the changes in product yields along the reaction times in both reac-
tion conditions (Figure 3B). It was observed that the amidation took place smoothly,
reaching a full conversion within 30 min in the presence of 1 mol % of benzoyl chlo-
ride 4, whereas the additive-free system displayed an induction period during which
4 is presumed to be formed.
Further optimization was carried out, and control experiments showed that higher-
energy light sources could also furnish 6, albeit in slightly lower yields (Figure 3C,
entries 1–2), whereas the reaction was completely inactive in the dark (Fig-
ure 3C, entry 3). A potassium derivative of the carbamate source was less effective
than 1a (Figure 3C, entry 4). Finally, a change of solvent from MeCN to PhCF3 al-
lowed the reaction to be carried out at an almost equimolar ratio of the two reactants
(Figure 3C, entries 5–6), which would be beneficial for late-stage applications.
In contrast to the success with benzaldehyde, aliphatic substrates were found to be
ineffective under the additive-free conditions, mainly due to their propensity to form
aldol side products. For instance, the reaction of 1-heptanal suffered from the rapid
formation of undesired aldol product 8 along with unknown decompositions (Fig-
ure 3D). We reasoned that an acid chloride additive would, thus, be necessitated
in this case, as the initiatory in situ formation of such species might not be operative
for aliphatic substrates, or it might be that the undesired side reactions are compa-
rably faster than its generation. Indeed, we could overcome this issue by employing
the corresponding acid chloride additive (10 mol %), which furnished the desired
Chem 7, 495–508, February 11, 2021 499

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amide 7 in a 94% yield while obviating the generation of unwanted side products.
Further optimizations revealed that benzoic acid could be alternatively utilized as
a practical additive (15 mol %), which is assumed to promote the initiatory genera-
tion of acid chloride (see Tables S2–S8 for detailed optimizations).
Reaction Scopes
The established mild photo conditions led us to explore the substrate scope of
various aromatic and aliphatic aldehydes in reaction with 1.2 equiv of amidating re-
agent 1a (Figure 4). Electron-neutral, electron-donating, and electron-withdrawing
substituents on benzaldehydes were equally viable: alkyl and aryl (9–15), alkoxy
(16–19), halo (20–23), nitro (24), trifluoromethyl (25), cyano (26), sulfide (27), sulfonyl
(28), ester (29), and boronic ester (30) were all fully compatible, thereby delivering
the amide products in good to excellent yields (54%–93%). Notably, aromatic C–H
chlorination was not observed in all substrates, which is often a favored pathway
for reactions involving conventional chlorinating reagents.55,56
The high amidation efficiency was further demonstrated in reactions of polyaromatic
(31–32, 73% and 67%) and heterocyclic aldehydes irrespective of their electronic na-
ture (33–36, 61%–72%), including a nicotinamide derivative 35. Interestingly, a ben-
zoic acid additive (15 mol %) was beneficial in obtaining satisfactory results in certain
aldehydes (33, 34 and 36), while slightly lower yields (ꢀ20%) were obtained in the
absence of such additive in those cases. The reaction also proceeded smoothly
for vanillin isobutyrate, an aldehyde widely used in fragrance industries, resulting
in an amide derivative 37 in a 70% yield.
A range of aliphatic aldehydes could also be efficiently amidated in reaction with 1a
(1.2 equiv) in the presence of benzoic acid additive (15 mol %): linear (7, 38–41) and
sterically more demanding branched aldehydes (42–44), as well as cyclic substrates
(45–51), were all feasible. As in the case of benzaldehydes, labile functional groups
such as alkyl bromide (39) and a,b-unsaturated olefinic units (50–51) were found to
be compatible. Given that (1R)-(–)-Myrtenal is more readily available than its carbox-
ylic acid derivative, the successful formation of amide 51 proves that the current
photo-procedure is an attractive alternative to the classical coupling reaction of car-
boxylic acids57 for accessing certain classes of amides. Finally, the flexibility of amino
precursors was briefly examined. Derivatives of O-benzyl (Cbz, 52–54, 57%–93%), O-
methyl (55, 85%) and O-ethyl carbamate (56, 88%), and sulfonamide (57, 60%)
readily reacted.
Synthetic Utility
We next investigated the feasibility of our amidation reaction in late-stage function-
alization (Figure 5), which is a highly desirable feature scarcely explored by the exist-
ing aldehyde amidation strategies. We envisioned that the mild reaction conditions
accomplished by obviating the need for strong oxidants and highly reactive
coupling reagents would grant such capability. In particular, we paid attention to
the modification of biologically relevant compounds via the direct installation of a
formyl moiety and subsequent amidation to show that the unconventional retrosyn-
thetic approaches can be utilized in late-stage construction of amide functionality.
The ease of our reaction and a wide variety of transformations available for installa-
tion of a formyl group would render the present strategy highly attractive.
The manipulation of olefins is of particular significance since they can be divergently
converted to aldehydes, for example, by means of oxidation,58 homologative hydro-
formylation59 or dehomologative ozonolysis.60 As a demonstration, Camphene
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Figure 4. Reaction Scope
aReaction conditions: Performed on Penn PhD Photoreactor M2 using 450 nm blue LED, with aldehyde (1.0 equiv), N-chloro-N-sodio-carbamate 1a (1.2
equiv), and PhCF3 (0.38 M) at 30ꢁC for 3 h: isolated yields.
b2.0 equiv of aldehyde and 1.0 equiv of 1a were used.
cMeCN (0.75 M) instead of PhCF3.
dMeCN (0.38 M) instead of PhCF3. eBenzoic acid (0.15 equiv) was added as an additive.
fNa(Cl)NCbz (1.2 equiv) instead of 1a.
gNa(Cl)NCO2Me (1.2 equiv) instead of 1a.
hNa(Cl)NCO2Et (1.2 equiv) instead of 1a.
iNa(Cl)NTs (1.0 equiv) instead of 1a and 2 equiv of benzaldehyde.
Chem 7, 495–508, February 11, 2021 501

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A
NHBoc
O
Me Me
O
H
NHBoc
Me
Me
Me
Me
Me
Me
H
H
Camphene
OMe
OMe
OMe
Me
H
H
Me
H
H
Me
H
H
Me Me
H
Me
H
Me
H
Me
NHBoc
MeO
MeO
HO
Me
Me
Me
Me
59, 72%
(same carbons)
Me
O
Me
60, 71%
Betulin
(one carbon elongated)
58, 79% (d.r. = 2:1)
oxidation path
hydroformylation path
hydroformylation path
O
NHBoc
H
HO
MeO
Me
Me
Me
Me
Me
Me
O
Me
O
Me
Me
Me
Me
Me
61, 67%
(+)- -Tocopherol
formylation path
OMe
Me
H
OH
Me
H
O
H
H
BocHN
MeO
H
H
H
HO
62, 41%
formylation path
*Isolated yields from
the corresponding
aldehydes are reported
(X-ray of 62)
-Estradiol
B
Me
Me
N
N
CO2Et
CO2Et
S
S
standard
conditions
Me
O
Me
O
O
Me
O
NHBoc
Me
H
63, 63%
(amide analog of Febuxostat)
intermediate en route to Febuxostat
(X-ray of 63)
C
O
O
O
O
Me
Me
Bn
N
NH2
TFA
NHBoc
N
H
Me
BnBr, K2CO3
then, TFA
H
or
DCM, RT
Me
Me
64, 84%
Me
Me
65, 75%
Me
Me
51
Me
Me
or
66, 80%
Citronellyl bromide
K2CO3, 50 °C, then, TFA
Figure 5. Synthetic Utility
(A) Late-stage amidation of biologically relevant compounds via installation of a formyl group and subsequent amidation (see Supplemental
Information for detailed reaction conditions).
(B) Amidation of a key intermediate en route to febuxostat to access its amide analog.
(C) Modification of amide 51.
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MeCN
O
O
O
Na
N
O
30 °C, 3 h
+
Boc
+
+
Ph
N
H
blue LED
(450 nm)
p-Tol
H
p-Tol
67, 69%
Cl
Cl
Boc
Ph
Cl
4
1a
(1.0 equiv)
6, 80%
(1.0 equiv)
Figure 6. Control Experiments with a Mixture of Benzoyl Chloride and p-Tolualdehyde
underwent efficient hydroformylation to give one carbon-elongated aldehyde by us-
ing Rh-catalysis, and the successive treatment with 1a under the currently developed
conditions furnished amide 58 (Figure 5A). Likewise, the modification of an olefin
functionality in Betulin by oxidation or hydroformylation granted access to two diver-
sified aldehydes, and subsequently the amide analogs 59 and 60, respectively, un-
der our reaction conditions. Moreover, aromatic aldehydes readily obtained by
directed ortho-formylation could be successfully employed under the standard con-
ditions. For instance, amide derivatives of (+)-d-Tocopherol and b-Estradiol were
effectively obtained through this approach (61 and 62, respectively). In addition,
we could intercept a key aldehyde intermediate en route to a drug molecule Febuxo-
stat, affording an amide variant of the bioactive compound (63, Figure 5B).
The synthetic utility of our protocol was further demonstrated by transforming the
obtained amide 51 to synthetically valuable derivatives (Figure 5C). While N-pro-
tected amides have been broadly utilized as a versatile intermediate for various
transformation,61,62 the ready-removability of the Boc-group is also beneficial. For
example, a primary amide 64 was readily obtained by deprotection of the Boc-group
using trifluoroacetic acid (TFA) (84%). In addition, N-alkylation of the obtained
amide 51 was performed under mild conditions, which was enabled presumably
by the increased acidity of the NH bond. Treatment of 51 with benzyl or bio-relevant
citronellyl bromide, followed by deprotection, furnished secondary amides 65 and
66, respectively. These versatile modifications showcased that our strategy can be
applied for accessing distinctive amides via alternative retrosynthetic C–N bond
disconnections.
Mechanistic Investigations
With proven synthetic values, we carried out further investigations to corroborate
the proposed reaction mechanism. The reaction progress via photoexcitation of
aldehyde could be excluded, as it has been well established that aldehydes or
related carbonyl compounds require higher-energy light (UV) to get excited to the
triplet state.63–65 Furthermore, the photo-reaction of 1a with an equal mixture of
benzoyl chloride 4 and p-tolualdehyde afforded an amide product 6 and an acid
chloride 67 via a crossover chlorine transfer (Figure 6). Notably, the direct amidation
of p-tolualdehyde was not observed, indicating that the proposed relay process
induced by the reaction with in situ generated acid chloride would likely be the re-
action pathway.
To realize how acid chloride is initially formed, we turned our attention to the role of
a carboxylic acid additive in reactions with aliphatic aldehydes. Interestingly, when
N-sodio salt 1a was treated with a stoichiometric amount of benzoic acid, the pro-
tonated carbamate 1b was obtained in 82% (Figure 7A). The reaction of 1b with 1-
heptanal under the standard conditions resulted in the formation of carbamate 2
and heptanoyl chloride 68 at poor yields, but no amidation product was formed.
These outcomes indicated that the protonated carbamate 1b, which is generated
in a small amount with the aid of benzoic acid additive, or presumably by moisture
Chem 7, 495–508, February 11, 2021 503

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A
B
C
D
G
E
F
Figure 7. Mechanistic Investigations
(A) The role of benzoic acid additive.
(B) UV-vis spectra of N-chloroamide 69.
(C) Experimental (black) X-band EPR spectrum of a mixture of 69 and a spin-trapping reagent (PBN) in benzene measured at 100 K after irradiation with
Blue LED (456 nm) and simulated (blue) EPR spectrum; simulation parameters: g = [2.0068 2.0073 2.0021], A = [19 0 89]; see also Figure S5.
(D) Radical trap experiment with 2,2,6,6-tetramethylpiperidin-1-yl (TEMPO).
(E) Measurement of the quantum yield for the product formation from 69.
(F) Control experiment using the combination of BEt3 and air as a radical initiator.
(G) Proposed relay cycle and DFT calculations.
in the case of additive-free conditions, would act as a radical chlorinating reagent to
convert a sacrificial amount of aldehyde to acid chloride. The relay process would
then be commenced by its reaction with N-chloro-N-sodio-carbamate salt 1.
The feasibilities of the rest of the relay steps were already discussed and shown in
Figure 2C. To further support the experimental evidence, the photoactivity of N-
chloroamide intermediate was first affirmed by ultraviolet-visible (UV-vis) absorption
spectra of N-chloroamide 69, which showed absorption bands tailing into the visible
region (Figure 7B). Upon the absorption of light, we proposed that the N–Cl bond of
504 Chem 7, 495–508, February 11, 2021

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the N-chloroamide intermediate would be homolytically cleaved to initiate radical
chains, and this photolytic pathway was investigated by electron paramagnetic reso-
nance (EPR) spectroscopy. The X-band EPR spectrum of an irradiated solution of 69
in benzene did not yield a characteristic signal of N-centered radical, presumably
due to the short lifetime of such species. On the other hand, signals corresponding
to a spin adduct (persistent nitroxide radical) were obtained by spin-trapping66 with
a-phenyl N-tert-butyl nitrone (PBN), which is indicative of radical generation from
the photo-conversion of 69 (Figure 7C). The homolytic nature of N–Cl cleavage
could be further confirmed by a radical trap experiment with 2,2,6,6-tetramethylpi-
peridin-1-yl (TEMPO), which afforded a TEMPO adduct 70 as the only product, prob-
ably via the translocation of N to C radical (HAT) and subsequent trap with TEMPO
(Figure 7D).
Moreover, the quantum yield for the product formation from 69 (F = 19.5) proved
that chain reactions are operative in certain extents in these radical processes (Fig-
ure 7E),67 indicating that N-centered radical can also be formed via radical propaga-
tion (chlorine abstraction). Control experiments also verified the association of such
chain reactions that can be initiated by organoborane as an alternative radical initi-
ator (Figure 7F),68 even though the low conversion suggested that the involved
propagations are likely to be short chains with the participation of radical termina-
tion. In our photo-system, constant irradiation of visible light ensures that the termi-
nated process would be persistently reinitiated, thereby contrarily giving excellent
efficiency. The possibilities of propagation reactions were additionally supported
by the density functional theory (DFT) calculations (Figure 7G, bottom right), in
which both HAT and chlorine abstraction processes for benzaldehyde substrate
were computed to be exergonic by –21.0 and –28.5 kcal/mol, respectively, with
low activation barriers of 12.0 and 8.4 kcal/mol.
With these results, we summarize the reaction mechanism in Figure 7G. The photo-
chemical stability of 1 combined with its low capability for direct N–Cl homolysis pre-
vents undesired side reactions such as oxidation and aromatic chlorination,55,56
while its partially protonated form gives rise to acid chloride I as kinetically compe-
tent species to trigger the relay process. The photoactive radical source II is formed
by the reaction between acid chloride I and the amidating reagent 1, followed by a
series of radical reactions involving imidyl radical III and acyl radical IV to produce
the amide product. Acid chloride I is further generated either by radical propagation
(chlorine abstraction) or radical termination (radical-radical coupling). An interesting
mechanistic feature of this strategy is that, unlike the conventional radical chain re-
actions, the substrate itself is not the radical precursor. One of the end products from
the chain reactions (I) is transformed to the starting radical source (II) by a cascade C–
N bond formation, thus rendering this relay process iterated in a highly efficient and
controllable fashion by slow incorporation of the radical precursor.
Conclusions
In conclusion, a new reaction model has been developed for controllable access to
N-centered radicals, which enabled the conversion of aldehydes to amides under visible
light conditions with N-chloro-N-sodio-carbamates as the amidating reagent. A broad
range of (hetero)aromatic and aliphatic aldehydes could be employed, delivering syn-
thetically useful N-protected amides under extremely mild conditions with high func-
tional group tolerance. The virtue of this methodology has been demonstrated by suc-
cessful applications on biologically relevant compounds, and the post-modification of
obtained products to diverse amide analogs. The reaction was revealed to proceed via
an unprecedented relay process, whereby highly efficient radical chain reactions are
Chem 7, 495–508, February 11, 2021 505

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enabled by the controlled in situ generation of a photoactive radical precursor via C–N
bond formation. The distinct features in the reaction mechanism, along with the synthetic
advantages accomplished by low waste generation and excellent applicability, should
allow the developed protocol to find widespread applications in both academic and in-
dustrialresearch. Expansion ofthischemistrytoother typesoftransformationsiscurrently
under investigation in our laboratory.
EXPERIMENTAL PROCEDURES
Resource Availability
Lead Contact
Further information and requests for resources should be directed to and will be ful-
filled by the Lead Contact, Sukbok Chang (sbchang@kaist.ac.kr).
Materials Availability
All unique reagents generated in this study are available from the Lead Contact
without restriction.
Data and Code Availability
Crystallographic data generated during this study have been deposited in the Cam-
bridge Crystallographic Data Centre (CCDC) under accession numbers CCDC:
1983504 (32), 1983505 (62), 1983506 (63), and 2011508 (1a). These data can be ob-
tained free of charge from the CCDC at http://www.ccdc.cam.ac.uk/data_request/
cif.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2020.12.004.
ACKNOWLEDGMENTS
Financial support for this research was provided by the Institute for Basic Science
(IBS-R010-Y2 and IBS-R010-D1) in South Korea. H.J. is grateful to the National
Research Foundation of Korea (NRF) for the global PhD fellowship (NRF-
2019H1A2A1076213). Single-crystal X-ray diffraction experiments with synchrotron
radiation were performed at the BL2D-SMC in Pohang Accelerator Laboratory. The
authors thank Mr. Jinwoo Kim and Mr. Jeonguk Kweon (Korea Advanced Institute of
Science and Technology) for their help with the operation of EPR spectroscopy.
AUTHOR CONTRIBUTIONS
S.S. and S.C. conceived, designed, and organized the project. W.L. and H.J.J. per-
formed and analyzed all experiments for reaction optimization, scope, synthetic
application, and mechanistic investigations. W.L. and H.J. conducted the DFT calcu-
lations. D.K. analyzed the X-ray crystal structures. S.S. and S.C. wrote the manu-
script. All authors discussed the results and commented on the manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: September 16, 2020
Revised: November 4, 2020
Accepted: December 2, 2020
Published: December 31, 2020
506 Chem 7, 495–508, February 11, 2021

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