Generation of N-Centered Radicals via a Photocatalytic Energy Transfer: Remote Double Functionalization of Arenes Facilitated by Singlet Oxygen

Article abstract of DOI:10.1021/jacs.9b05572

An unprecedented approach to the generation of an N-centered radical via a photocatalytic energy-transfer process from readily available heterocyclic precursors is reported, which is distinctive of the previous electron transfer approaches. In combination with singlet oxygen, the in-situ-generated nitrogen radical from the oxadiazoline substrate in the presence of fac-Ir(ppy)₃ undergoes a selective ipso addition to arenes to furnish remotely double-functionalized spiro-azalactam products. The mechanistic studies provide compelling evidence that the catalytic cycle selects the energy-transfer pathway. A concurrent activation of molecular oxygen to generate singlet oxygen by energy transfer is also rationalized. Furthermore, the occurrence of the electron transfer phenomenon is excluded on the basis of the negative driving forces for one-electron transfer between oxadiazoline and the excited state of fac-Ir(ppy)₃ with a consideration of their redox potentials. The necessity of singlet oxygen as well as the photoactivated oxadiazoline substrate is clearly supported by a series of controlled experiments. Density functional studies have also been carried out to support these observations. The scope of substrates is explored by synthesizing diversely functionalized cyclohexadienone moieties in view of their utility in complex organic syntheses and as potential targets in pharmacology.

Full text of DOI:10.1021/jacs.9b05572

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Article
Generation of N-Centered Radicals via a Photocatalytic Energy Transfer:
Remote Double Functionalization of Arenes Facilitated by Singlet Oxygen
Vineet Kumar Soni, Ho Seong Hwang, Yu Kyung Moon, Sung-Woo Park, Youngmin You, and Eun Jin Cho
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b05572 • Publication Date (Web): 07 Jun 2019
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Generation of N-Centered Radicals via a Photocatalytic Energy
Transfer: Remote Double Functionalization of Arenes Facilitated by
Singlet Oxygen
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Vineet Kumar Soni,a Ho Seong Hwang,a Yu Kyung Moon,b Sung-Woo Park,c Youngmin You,b*
and Eun Jin Choa*
aDepartment of Chemistry, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 06974, Republic of Korea
bDivision of Chemical Engineering and Materials Science, Ewha Womans University, Seoul 03760, Korea.
cCenter for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), and Department of
Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
KEYWORDS: photocatalysis, energy transfer, N-radical cascade, remote functionalization, singlet oxygen
ABSTRACT: An unprecedented approach for the generation of N-centered radical via a photocatalytic energy transfer
process from readily available heterocyclic precursors is reported, which is distinctive to the previous electron transfer
approaches. In combination with singlet oxygen, the in situ generated nitrogen radical from oxadiazoline substrate in the
presence of fac-Ir(ppy)3 undergoes a selective ipso-addition to arenes to furnish remotely double functionalized spiro-
azalactam products. The mechanistic studies provide compelling evidence that the catalytic cycle selects the energy
transfer pathway. A concurrent activation of molecular oxygen to generate singlet oxygen by energy transfer is also
rationalized. Furthermore, the occurrence of electron transfer phenomenon is excluded based on the negative driving
forces for one-electron transfer between oxadiazoline and the excited state of fac-Ir(ppy)3 with consideration to their
redox potentials. The necessity of singlet oxygen as well as the photoactivated oxadiazoline substrate is clearly supported
by a series of controlled experiments. Density functional studies have also been carried out to support these observations.
The scope of substrates is explored by synthesizing diversely functionalized cyclohexadienone moieties in view to their
utility in complex organic syntheses and as potential targets in pharmacology.
1. INTRODUCTION
an access to azaheterocycles in an unprecedentedly
concise manner.9 Recently, the use of amines as N-radical
precursor has evolved as highly atom-economic
strategy.10,11 However, many of currently available
photocatalytic procedures still employ pre-activated
amino precursors as the indirect source of N-radical
Heterocycles are prevalent structural motifs finding
versatile utilities in various research areas due to their
interesting biological activities and unique physical
properties.1 As a result, the development of more efficient
and preparative synthetic routes to common heterocycles
has been a special interest in synthetic chemistry.2 While
linear synthetic approaches are predominantly utilized to
prepare heterocycles at present,3 a transformative strategy
to access heterocycles of interest from another type of
more readily available heterocycles is less explored mainly
due to lack of effective synthetic methodologies.4,5
Considering the fact that the structural variation of
privileged heterocycles continues to draw extensive
synthetic efforts,6 the envisioned transformations
between structurally distinct heterocycles would be
highly interesting if additional functional groups can be
introduced during the course of such interconversions.
In recent years, visible-light induced photocatalysis has
emerged as a powerful synthetic tool,7,8 thus often
replacing the conventional lengthy preparative
approaches. In particular, the generation of N-centered
radicals under mild photocatalytic conditions has enabled
species, where
a
single electron transfer process
reductively cleaves weak N–N, N–O, or N–X bonds
(Scheme 1a).12,13 The critical drawback of these methods is
the generation of stoichiometric amounts of by-products
released from the pre-functionalized amino precursors.
Herein, we envisioned a new strategy of generating N-
centered radical directly from
a readily available
oxadiazoline heterocycle, leading to the generation of
new azaheterocycles in an atom-econmical manner
(Scheme 1b). The choice of oxadiazolines as N-radical
precursors is based on the following desirable features: (i)
the N-O bonds in certain heterocycles such as oxadiazoles
can be activated by photoirradiation14,15; (ii) the leaving
groups can also incorporate into the product skeleton
without generation of wastes; and (iii) as radical
precursors, oxadiazolines can be easily accessed with
variation of substituents, eventually allowing for
a
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product diversification.
aryl-1,2,4-oxadiazoline derivative 1a was subjected to the
1
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3
4
5
6
7
8
At the outset of our studies, we predicted that 5-aryl-1,2,4-
oxadiazoline 1 may undergo the desired ring cleavage by
the photoactivation to form an iminyl radical that will
subsequently cyclize at the ortho-position of the pendent
phenyl moiety to give rise to quinazolinone products via
the homolytic aromatic substitution (HAS).15c,16 However,
the reaction turned out to follow an unprecedented
pathway furnishing spiro-azalactam compounds with
remote oxygenation under oxygen atmosphere (Scheme
1c).17 This result is especially notable in that C−N bond-
forming dearomatization of arenes is less explored.18
photocatalysis conditions, by using either complexes
containing transition metals (Ru, Ir, or Pt) or organic dyes
(Eosin Y). Visible light was irradiated from a 23 W
compact fluorescent lamp (CFL) at a concentration of 0.2
M in DMSO at 20~22 °C under oxygen atmosphere (Table
1). To our surprise, the initially expected quinazolinone15c
2a was formed in minor (10%) while a major product was
spiro-azalactam 3a (40%) when [Ru(bpy)2]Cl2 was
employed as a photocatalyst (entry 1). This unexpected
product was formed in slightly higher yield especially
when fac-Ir(ppy)3 and [Ir{dF(CF3)ppy}2(dtbpy)]PF6 were
used among different photocatalysts examined (entries 2–
9), and more easily accessible fac-Ir(ppy)3 was chosen for
further optimization. The reaction was found to be rather
sensitive to solvents, and DMSO was more effective than
any others examined (entries 10–13). Control experiments
revealed that the reaction was completely ineffective in
the absence of light or photocatalyst (entries 14-16).
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Scheme 1. Generation of N-Centered Radicals
(a) Previous Work
Photocatalytic generation of N-centered radicals via electron transfer
R'
R
R'
R'
R
R'
R
R
R
R'
N
N
N
N
X
N
N
H
SO2R''
OR''
R''
R'''
Reductive cleavage
Oxidative cleavage
Table 1. Optimization Studiesa
(b) Our design on the iminyl radical generation
Ph
R'
N
catalyst (1 mol%)
Use of heterocycle
as a key radical source
Ph
R
O
Ph
N
N
H
O
Ph
O2
N
Ph
N
Ph
N
High atom economical
solvent (0.2 M)
O
N
N
1
amide and iminyl radical generation
O
18O)
23 W CFL,r.t., 24 h
(
O
R'
N-O bond cleavage
via C(sp3)-H bond
1a
3a
2a
Dual
R
N
O
HAS by
ortho attack
photoactivation
(energy transfer)
1*
yield (%)b
activation
N
entry
solvent
variations
catalyst
2a
3ac
1O2
1
2
3
4
[Ru(bpy)3]Cl2
[Ru(phen)3]Cl2
fac-Ir(ppy)3
DMSO
DMSO
DMSO
DMSO
-
-
-
-
11
13
10
6
40 (25)
selective
ipso attack
O2
OOH
39 (40)
55
(c) (this work) Unprecedented synthesis
of spiro-azalactams and mechanistic study
[Ir(dtbbpy)(ppy)2]PF6
22 (15)
R'
N
R'
R'
N
R
5
6
[Ir{dF(CF3)ppy}2(dtbpy)]PF6 DMSO
-
-
12
15
56
O
O
O
R
N
fac-Ir(dFppy)3
Pt(ppy)acac
Eosin Y
DMSO
DMSO
DMSO
DMSO
MeCN
CHCl3
28 (24)
R
N
remote
N
N
7
8
-
-
-
-
-
-
5
12
3
15 (58)
25 (16)
20 (68)
7 (82)
0 (94)
46
oxygenation
O
9
TPPT
3
2
(observed)
(expected)
10
11
12
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
-
Arene dearomatization has been highlighted as
a
-
DMF
13
powerful transformation that generates complex
molecules, including spirocyclohexadienones.19 Notably,
the presence of spirocyclohexadienone moiety in natural
products19c and such diazaspiro compounds as potential
pharmaceutical agents have already been highlighted.20
Herein, we describe the first example of utilizing
heterocycles as an iminyl radical precursor under visible-
light photocatalytic conditions. More importantly, unlike
the previous procedures of generating N-cantered radicals
via an electron transfer process, the present iminyl radical
formation has been elucidated to proceed through
energy-transfer pathways. This process not only generates
13
14
15
16
17
18
19
20
21
22
fac-Ir(ppy)3
fac-Ir(ppy)3
-
DMA
-
8
-
26 (20)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
no hv
-
-
-
-
(96)
(92)
(91)
(22)
no catalyst
-
-
no catalyst, 365 nm
no O2
-
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
-
DIPEA (0.2 eq)
K2CO3 (0.2 eq)
Cs2CO3 (0.2 eq)
K2CO3 (0.1 eq)
K2CO3 (0.5 eq)
20
5
14
8
9
54
d
70
[69]
39 (8)
64 (5)
48 (16)
23
24
25
26
27
28
29
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
DMSO
DMSO
DMSO
K2CO3 (0.2 eq), 0.1 M
K2CO3 (0.2 eq), 0.5 M
10
6
58 (3)
70
K2CO3 (0.2 eq), Blue LEDs
16
50
DMSO K2CO3 (0.2 eq), White LEDs 24
65
21
DMSO
DMSO
K2CO3 (0.2 eq), 10 °C
K2CO3 (0.2 eq), 50 °C
3
18
6
33 (60)
50
cyclohexadienone moiety from simple arene ring but
also amide and amino moieties to provide highly
functionalized spiro-azalactams. The mechanism was
investigated in detail by performing photophysical and
electrochemical measurements, as well as computational
studies.
DMSO K2CO3 (0.2 eq), 0.5 mol% cat.
54
aReaction scale: 0.1 mmol. b1H NMR yields using
c
bromoform as the internal standard. Yields of recovered
d
1a in parentheses. Yield of 3a in parenthesis under 18O2
atmosphere.
TPPT
=
2,4,6-triphenylpyrylium
2. RESULTS AND DISCUSSION
tetrafluoroborate.
2.1. Reaction Development.
The use of molecular oxygen was crucial for the formation
of 3a to confirm that it is the oxygen source incorporated
To verify our working hypothesis, a readily available 5-
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at the para-position (entry 17). The effect of additives on comparison between the reduction potential of 2.0 mM 1a
1
2
3
4
5
6
7
8
product yields was also examined (entries 18-22); wherein,
a sub-equivalent amount of K2CO3 (20 mol %) increased
the product yield of 3a (70%) with higher ipso-selectivity
(entry 19). Though the diluted reaction mixture provided
less product yield, a relatively higher concentration did
not affect the reaction efficiency (entries 23 and 24). In
addition, CFL was found to be the best photon source in
this transformation, and the reaction was optimal at room
temperature (entries 25 and 26). Any alteration in
reaction temperature was not helpful (entries 27 and 28).
The lower catalyst loading (0.5 mol %) decreased the yield
of 3a (entry 29). An isotopic labelling experiment with
18O2, where the product with 18O was exclusively formed
from the reaction, clearly confirmed that molecular
oxygen is the actual source of oxygen in this process.
(2.16 V vs SCE, DMSO) and the excited-state oxidation
potential (E*ox, 1.62 V vs SCE) of fac-Ir(ppy)3* also
indicated thermodynamic forbiddance of reductive
electron transfer from fac-Ir(ppy)3* to 1a. These results
permitted us to exclude electron-transfer pathways to the
generation of radical intermediates B or C (Scheme
2a).22,23 Furthermore, attempts to replicate the aza-lactam
synthesis with standard chemical one-electron reductant
(SmI2) or oxidant (ceric ammonium nitrate) did not afford
3a, ruling out the electron transfer pathways [Scheme
2b(1) and (2)].
Our TDDFT calculations predicted an occurrence of
triplettriplet energy transfer (TTET) from the fac-
Ir(ppy)3* to 1a because the triplet state energy (ET) of the
former (2.66 eV) was greater than that (2.39 eV) of the
latter (Scheme 2a).24 The use of benzil (ET = 2.57 eV)24 as a
triplet sensitizer instead of fac-Ir(ppy)3 provided 3a,
corroborating this energy-transfer hypothesis [Scheme
2b(3)].25 The energy-transfer interaction was verified by
monitoring phosphorescence decay traces of fac-Ir(ppy)3
(100 M in Ar-saturated DMSO) using time-correlated
single-photon-counting techniques with increasing
concentration of 1a ([1a]). As shown in Figure 1a, the
phosphorescence lifetime decreased in proportion with
[1a]. A linear fit of the phosphorescence quenching rate
(1/obs(1a)  1/obs, where obs(1a) and obs correspond to the
phosphorescence lifetimes in the absence and presence of
1a) vs. [1a] returned the rate constant for bimolecular
quenching (kQ) to be 1.8  107 M1s1. Since electron
transfer was disfavoured, the kQ value can be equated as
the rate constant for energy transfer to 1a (kET(1a)).
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Interestingly,
highly
relevant
3,5-diphenyl-1,2,4-
oxadiazole (aromatic variant) was not a suitable iminyl
radical source under the above optimized conditions,
indicating
a different mode of activation with 1a.
(Scheme S1). Previously, Pace, Vivona, and coworkers
explored photochemical reactions of oxadiazoles where
nitrene or iminyl radicals were generated by N-O bond
cleavage under UV irradiation.14
Scheme 2. Mechanistic Investigations
(a) Redox Potential Studies
E (V vs SCE)
reductive
electron transfer
Ph
O
Ered(1a)
E*ox(Ir)
-2.16 V
Ph
Ph
-2.0
-1.0
0
N
+ e-
-1.62 V
N
reductive
electron transfer
B
Ph
N
oxidative
electron transfer
Ph
Ph
Ph
Ph
O
N
Ph
Ph
Ph
O
N
*
N
N
O
- e-
E*red(Ir)
+0.16 V
+1.24 V
1a
+
N
Ph
A
C
fac-Ir(ppy)3*
+1.0
+2.0
Eox(1a)
oxidative
electron transfer
Ph
O
Ph
energy transfer
N
N
triplet energy (in DMSO)
ET (Ir*)
ET (1a)
Ph
1O2
=
2.66 eV
1
a
*
= 2.39 eV
(b) Evidence of Energy Trasfer Pathway
"use of chemical reductant"
1 eq. SmI2, O2
(1)
3a
+
1a (94%)
(0%)
1a
Figure 1. Phosphorescence decay traces of 100 M fac-
Ir(ppy)3 in DMSO. (a) Decay traces acquired for Ar-
saturated solutions with increasing concentration of 1a.
The inset graph depicts the pseudo linear plot of the
quenching rate (1/obs(1a)  1/obs) vs the concentration of
1a. (b) Decay traces acquired in the absence of 1a before
(red) and after (blue) O2 saturation.
DMSO (0.5 M), r.t., 24 h
"use of chemical oxidant"
1 eq. CAN, O2
1a
2a
3a
+
3a
1a
(74%)
(2)
(3)
(20%)
(32%)
(trace)
+
DMSO (0.5 M), r.t., 24 h
"use of triplet sensitizer"
1 eq. Benzil, O2
1a (11%)
+
1a
DMSO (0.5 M), 23 W CFL
r.t., 24 h
Although 1a and fac-Ir(ppy)3 had a certain spectral
overlap (Figure S2), Förster-type energy transfer was
predicted to be insignificant at our reaction conditions
(i.e., 0.2-0.5 M 1a and 2 mM fac-Ir(ppy)3). The rate for
bimolecular energy transfer (ET rate) is proportional to
[1a]2 in the Förster-type energy transfer regime (i.e.,
Förster ET rate  [1a]2), given that the solution is
homogeneous.26 On the contrary, the Dexter-type energy
transfer regime possesses a linear relationship between
2.2. Mechanistic Studies and Proposal.
To ascertain mechanistic insights, we performed
electrochemical investigations. The irreversible oxidation
of 1a was observed at 1.24 V vs SCE (Figure S1). This value
was more positive than the excited-state reduction
potential (E*red, 0.16 V vs SCE) of 2.0 mM fac-Ir(ppy)3
(DMSO), revealing an endoergic electron transfer from 1a
to the excited-state fac-Ir(ppy)3 (fac-Ir(ppy)3*).
A
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ln(ET rate) and [1a]1/3. We took the phosphorescence
one order of magnitude faster than the intrinsic decay
rate of the excited state of fac-Ir(ppy)3 (5.9  105 s1),
supporting the dual activation of 1a and O2. The
photosensitization of 1O2 by fac-Ir(ppy)3 was evidenced by
using 1,3-diphenylisobenzofuran (DPBF), a 1O2 probe,
where the quantum yield for 1O2 sensitization () was as
high as 0.95 (Figure 3; see SI for details).
1
2
3
4
5
6
7
8
quenching rate (Figure 1a) as the ET rate because
quenching by photoinduced electron transfer was
forbidden (vide supra). As shown in Figure 2a, the ET rate
displays a linearity in the Dexter-type energy transfer
region of [1a]1/3 < 6.2 M1/3. This value corresponds to [1a]
> 4.1 mM. The linearity of the ET rate in the Förster-type
energy transfer is observed at [1a]2 < 101 mM2 (i.e., [1a] <
3.2 mM) (Figure 2b). Comparing the limiting
concentrations with the reaction concentration ([1a] =
0.2-0.5 M), we conclude that Dexter-type energy transfer
was dominant. This conclusion was consistent with the
TDDFT calculation results which predicted triplet states
were involved in the energy transfer.
Scheme 3. Role of Singlet Oxygen
additive
9
fac-Ir(ppy)3 (1 mol%)
K2CO3 (20 mol%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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60
-
70%
0%
33%
1a
(1)
(2)
3a
DMSO (0.5 M), 23 W CFL
O2, r.t., 24 h
1 equiv. DABCO
1 equiv. NaN3
O
O
Ph
N
Ph
N
Ph
Ph
O
above
standard conditions
Me
Me
H
N
Me
N
Ph
Ph
O
N
N
O
Me
Me
O
Me
1b
sterically disfavored
3b
(0%)
Figure 2. Energy transfer mechanism. (a) A plot of the
natural logarithm of the energy transfer (ET) rate as a
function of [1a]1/3. The red line shows a visual guidance
where the Dexter ET mechanism applies (i.e., Dexter
regime; ln(ET rate)  [1a]1/3). The vertical blue line
corresponds to [1a] employed for the reaction. (b) A plot
of the energy transfer (ET) rate as a function of [1a]2. The
red line shows a visual guidance where the Förster ET
mechanism applies (i.e., Förster regime; ET rate  [1a]2).
The inset graph compares [1a] employed for the reaction
(vertical blue line) and the Förster ET regime.
Figure 3. (a) UVvis absorption difference spectra of an
O2-saturated DMSO solution containing 10 M DPBF and
100 M fac-Ir(ppy)3 recorded during continuous
photoirradiation of white light using a Xenon lamp. (b)
Plots depicting the absorbance difference of DPBF at 412
nm as a function of photoirradiation time. Methylene
blue (MB) as an external reference. The straight lines are
the linear fits to the initial three points.
The implausibility of generating highly unstable diradical
species by direct homolytic N-O bond cleavage of 1a* led
us to examine the distinctive pathway involving singlet
oxygen (1O2) to yield A.27 The participation of singlet
oxygen in the current process was rationalized by several
experiments. The use of singlet oxygen scavenger, such as
DABCO or NaN3, retarded the reaction. The results
provide strong evidence for the key role of singlet oxygen
in the transformation [Scheme 3(1)]. Furthermore, the
non-reactivity of a sterically demanding substrate, i.e. 2,6-
disubstituted phenyl derivative (1b) suggested the
primary involvement of singlet oxygen in the iminyl
Our mechanism involving double photon excitation of 1a
and O2 is unique. To assess our mechanism, we ran the
reaction of 1a with varying the photon flux (0.213.6  108
einstein s1). It was found that the concentration of 3a
([3a]) increased non-linearly with the photon flux (Figure
S4). This observation served as a strong indication of the
involvement of two photons for the double excitation of
1a and O2. On the contrary, the quantum yield for the
reaction, which was determined using the standard
ferrioxalate actinometry, remained the same during the
photoirradiation (16% at 6 h of photoirradiation and 18%
at 30 h of photoirradiation). The quantum yield not
exceeding 50% may exclude the possibility of any
propagation process, e.g. involving hydrogen abstraction
from 1a by in situ generated hydroperoxide radical. We
further confirmed this by the on–off switching of the light
source during the reaction, where no further progress was
observed in the dark.28
radical generation [Scheme 3(2)]. We observed
a
significant decrease in obs (1.46 s  0.037 s) upon O2
equilibration (Figure 1b). The corresponding rate for
energy transfer from fac-Ir(ppy)3 to O2 (ET rate(O2)) was
estimated to 2.6  106 s1. Note that this value was
comparable to the energy-transfer rate to 1a (ET rate(1a))
at a concentration of 0.5 M (i.e., ET rate(1a) = kET(1a) 
0.5 M = 9.0  106 s1). Both energy-transfer pathways were
In addition, reactions in the presence of singlet oxygen
were conducted under non-photocatalytic conditions.
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The reaction of 1a with in situ generated singlet oxygen in oxygen at the 5-position of 1a* follow to generate a
1
2
3
4
5
6
7
8
dark under photocatalyst-free conditions did not yield
any product even after 24 h, suggesting a crucial
involvement of 1a* in the transformation (Scheme 4a).29
The reaction of 1a and benzoyl peroxide at 80 °C under
oxygen atmosphere proceeded with low reactivity and
selectivity, as only 10% of 3a was formed along with 2a
(31%) and unreacted 1a (51%) (Scheme 4b), showing the
advantage of visible light-mediated photocatalytic
processes in efficient synthesis of spiro-azalactams.
hydroperoxy species D*. The homolytic N–O bond
cleavage in D* is assumed to take place smoothly to
generate a key iminyl radical A, along with hydroperoxide
radical (HOO•). We propose that an ipso attack of the N-
centered radical of A is kinetically feasible to furnish a
spirocyclic species E that will recombine with HOO• or O2
at the para-position selectively, eventually producing 3a
via a cyclohexadienyl hydroperoxide species F with a
release of water. Although the spin density values for
spirocyclic radical E suggests more favored para attack by
HOO• or O2 [para (0.605) vs ortho (0.415)], the ortho-
hydroperoxidation followed by [1,3]-sigmatropic shift is
also plausible under the photochemical conditions.30 This
mechanistic postulate was further supported by DFT
calculations (Scheme 3b, Figure S5). The electronic
environment of D* induces the favorable spin density on
the bonded nitrogen and oxygen atoms to facilitate the
homolytic N-O bond cleavage with concurrent exclusion
of hydroeproxide radical leading to a low energy iminyl
radical species A. Although all attempts to detect
hydroperoxide intermediate F were not fruitful, the
presence of peroxide was observed during the course of
reaction.31
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Control Experiments with singlet oxygen or
peroxide
(a) In the presence of the chemical sources of singlet oxygen
NaOH (10 eq.), Na2MoO4 (1 eq.)
Ph
or
O
Ph
Ph
N
Ca(OH)2 (5 eq.)
N
Ph
+
1a (97%)
N
H2O2 (20 eq.)
H2O (0.1 M), DMSO (0.2 M)
r.t., 24 h
O
O
Ph
N
1a
3a
(0%)
(b) In the presence of the chemical sources of oxyradical
(PhCO2)2 (1 eq.), O2
1a
3a
2a
1a
+ (51%)
(10%)
+
(31%)
,
DMSO (0.5 M), 80 °C 24 h
2.3. Substrate Scope.
Based on the above observations, a plausible mechanistic
pathway for the current transformation is depicted in
Scheme 3a. First, fac-Ir(ppy)3 photosensitize 1a and
molecular oxygen into 1a* and 1O2, respectively, via
energy transfer. A dehydrogenative insertion of singlet
Next, the generality of the transformation was
investigated by applying various types of substrates under
the optimized conditions (Table 2).
Scheme 5. Proposed Mechanism and DFT Studies
(a)
Ph
Ph
N
3fac-[Ir(ppy)3]*
Ph
*
O
*
O
N
O
O
Ph
Ph
N
O
H
O
OH
1a
0.415
Ph
Ph
Ph
Ph
Ph
kd = 5.9 x 105 s-1
1O2
Ph
N
N
N
- HOO
N
N
N
N
hv
hv
Ph
Ph
0.605
0.415
A
D*
1a*
E
kET(1a) = 1.8 x 107 M-1s-1
E
(9.0 x 106 s-1 at 0.5 M 1a)
HOO
or O2
fac-[Ir(ppy)3]
HOO
0.445
HO
N
0.195
1O2
Ph
O
O
Ph
O
hv
H2O
OOH
N
hv
[1,3] shift
N
kd = 5.9 x 105 s-1
0.776
Ph
N
Ph
3O2
Ph
OH
N
N
O
O
H
kET(O2) = 2.6 x 106 s-1
3fac-[Ir(ppy)3]*
3a
G
F
(b)
DFT Calculation
M06-2X / 6-311++G**
Solvation = DMSO
*
Ph
N
H
O
1.655
2.745
1.987
Ph
1a* 1O2
+
1.996
64.67
N
Ph
TS1C-O
38.55
TS2C-O
G

TS1N-O
24.9
TS3ipso
TS3ortho
(kcal/mol)
TS2C-O
15.63
1a 1O2
TS2N-O
+
OOH
+
energy
transfer
by PC
O
10.23
9.6
Ph
Ph
D*
14.3
TS3ortho
-11.10
N
G
+
-0.2
OOH
Ph
Ph
N
N
1a 3O2
+
O
E + OOH
-30.08
TS3ipso
-13.21
Ph
N
0.0
O
Ph
OOH
Ph
N
A
Ph
+
OOH
Ph
O
N
N
N
-25.9
D
O
N
H
+
OOH
Ph
N
-48.07
-30.51
Ph
Ph
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Table 2. Substrate Scopea
ortho and meta positions including naphthyl derivatives
1
2
3
4
5
6
7
8
(3p–3y) were successfully synthesized. The structure of
products 3a and 3p was unambiguously confirmed by X-
ray crystallography (Figure S6 and S7).32 In most cases,
quinazolinone derivatives (2) were detected as the side
products. In the case of a para-substituted derivative 1z,
the hydroxyl compound 4 was formed in 30% NMR yield
along with two regioisomers of quinazolinones 2z. The
scale-up of 3a from 1a at 7 mmol scale was found to be
straightforward, despite the slower conversion (54%
conversion after 96 h reaction).
R2
N
R2
N
O
fac-Ir(ppy)3 (1 mol%), O2
K2CO3 (20 mol%)
R1
R1
N
DMSO (0.5 M)
23 W CFL, r.t., 24-48 h
R3
N
O
O
R3
1
3
R1 = aryl
Ph
Ph
N
3a : R = H; 62% (54%)[b]
3c : R = 4-Me; 68%
3d : R= 4-OMe; 61%b
3e : R = 4-Cl; 55%
O
O
N
N
N
O
R
3g : 46%[c]
O
3f : R = 3-CF3; 46%
X-ray structure of 3a
R1 = heteroaryl
Ph
9
Ph
Ph
O
O
N
Ph
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
O
N
O
N
N
N
O
N
S
Cl
N
N
Cl
O
O
Me
3. CONCLUSION
O
O
3i : 38%[c]
3j : 40%[c]
3k :
45%
[c]
3h : 48%
R1 = aliphatic
Ph
In conclusion, we herein have reported an unprecedented
approach to N-centered radical from heterocycles to
induce a cascade double functionalization of arenes to
furnish spiro-azalactams. The reaction proceeds under
mild photocatalytic conditions via an energy transfer
process where photoexcited hydroperoxide initiates the
homolytic N-O bond cleavage of heterocycles to induce
an ipso attack of the resultant iminyl radical with the
concomitant para-oxygenation of molecular oxygen. The
use of simple arenes indicates high potential use of the
method in late-stage modifications to achieve high levels
of molecular complexity. The easy accessibility of
substrates, mild reaction conditions, high functional-
group tolerance, and facile formation of diversified spiro-
azalactam products will give an opportunity to find its
applications in synthetic and medicinal chemistry.
Furthermore, the photocatalytic activation of such
heterocycle offers tremendous potential for applications
in other useful transformations.
R2 = aliphatic
Ph
N
Bn
N
Me
N
O
O
O
O
N
N
N
N
N
O
O
O
O
3l : 60%
3n : 65%
3o : 66%
3m : 70%
R3 = H (ortho)
Ph
Ph
N
Ph
N
O
N
O
O
N
N
N
Me
MeO
Cl
O
O
O
3r : 52%[c]
3p : 86%
X-ray structure of
3p
3q : 44%[c]
R3 = H (meta)
Ph
Ph
Ph
O
N
Ph
O
N
O
N
O
N
N
N
N
N
O
Br
O
O
O
Me
CF3
3v : 25%[c]
Cl
[d]
3s : 41%[c]
3t : 48%
3u :
52%
R3 = H (disubstituted)
R3 = H (naphthyl)
Ph
Ph
N
O
N
Ph
O
O
N
Me
O
OMe
O
N
N
N
O
MeO
Me
3w : 38%[c]
3y : 41%[c]
3x : 46%[c]
ASSOCIATED CONTENT
The Supporting Information is available free of charge via the
Internet at http://pubs.acs.org.”
Experimental procedures, characterization of products, and
spectroscopic data (PDF)
R3 = H (para)
O
O
Me
Ph
Ph
OH
Ph
N
N
N
+
Me
N
Ph
Ph
N
Ph
Me
O
N
4 (30% NMR yield)[c]
diasteromers (1:4)
2z (24% NMR yield)
two regioisomers
1z
aReactions were performed on a 0.3 mmol scale, and the
Crystallographic data for 3a and 3p (CIF)
b
c
isolated yields are reported; 7 mmol scale after 96 h; 96
h reaction time; d72 h reaction time.
AUTHOR INFORMATION
Corresponding Author
The scope of substituents R1 at the 3-position in 1,2,4-
oxadiazolines 1 was first examined. Substrates with
aromatic substituents, including
*E-mail: ejcho@cau.ac.kr (E. J. Cho)
ORCID: 0000-0002-6607-1851
a naphthyl group,
underwent the desired oxygenative dearomatization in
satisfactory efficiency, to give the corresponding spiro-
azalactams (3a, 3c–3g). Heteroaryl substituents, such as
pyridyl, furyl, thiophenyl, and indolyl, were also found to
be compatible with the present condi tions (3h–3k). The
applicability of the present method was further
demonstrated by installing aliphatic groups (3l, 3m).
Variation at the 4-position (R2) in 1,2,4-oxadiazolines was
also plausible, where N-methyl and N-benzyl substituents
were readily integrated into the products (3n and 3o). In
*E-mail: odds2@ewha.ac.kr (Y. You)
ORCID: 0000-0001-5633-6599
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge the National Research
Foundation of Korea [NRF-2012M3A7B4049657, NRF-
2014011165,
NRF-2017R1A2B2004082,
and
NRF-
view
to
synthesize
diversely
functionalized
2019R1A2C2003969]. We thank Hongil Jo (Chung-Ang
University) for help with X-ray crystallography and Prof.
Sukbok Chang (KAIST) for the critical advice and guidance
for the manuscript.
cyclohexadienone moieties,19 substrates containing
electron-donating or withdrawing substituents on the aryl
ring at the 5-position of the 1,2,4-oxadiazoline were
reacted. Cyclohexadienone rings functionalized at the
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9. For reviews and perspective on photocatalytic N-radical
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17. For general reviews on oxygenation using molecular
oxygen, see: (a) Bian, C.; Singh, A. K.; Niu, L.; Yi, H.; Lei, A.
Visible‐Light‐Mediated Oxygenation Reactions using
Molecular Oxygen. Asian J. Org. Chem. 2017, 6, 386. (b)
Liang, Y.-F.; Jiao, N. Oxygenation via C–H/C–C Bond
Activation with Molecular Oxygen. Acc. Chem. Res. 2017,
50, 1640. (c) Pibiri, I.; Buscemi, S.; Piccionello, A. P.; Pace, A.
Photochemically Produced Singlet Oxygen: Applications
and Perspectives. ChemPhotoChem 2018, 2, 535.
18. For selected examples, see: (a) Chiba, S.; Zhang, L.; Lee, J.-Y.
Copper-Catalyzed Synthesis of Azaspirocyclohexadienones
from α-Azido-N-arylamides under an Oxygen Atmosphere.
J. Am. Chem. Soc. 2010, 132, 7266. (b) Tnay, Y. L.; Chen, C.;
Chua, Y. Y.; Zhang, L.; Chiba, S. Copper-Catalyzed Aerobic
13. For selected examples on photocatalytic N-radical cascade
reactions by N-N, N-O and N-X bond cleavages, see: (a)
Allen, L. J.; Cabrera, P. J.; Lee, M.; Sanford, M. S. N-
Acyloxyphthalimides as Nitrogen Radical Precursors in the
Visible Light Photocatalyzed Room Temperature C–H
Amination of Arenes and Heteroarenes. J. Am. Chem. Soc.
2014, 136, 5607. (c) Cai, S.-H.; Xie, J.-H.; Song, S.; Ye, L.;
Feng, C.; Loh, T.-P. Visible-Light-Promoted Carboimination
of Unactivated Alkenes for the Synthesis of Densely
Functionalized Pyrroline Derivatives. ACS Catal. 2016, 6,
5571. (g) Jiang, H.; Studer, A. Amidyl Radicals by Oxidation
Spirocyclization
of
Biaryl-N-H-imines
via
1,4-
Aminooxygenation of Benzene Rings. Org. Lett. 2012, 14,
3550. (c) Farndon, J. J.; Ma, X.; Bower, J. F. Transition Metal
Free C–N Bond Forming Dearomatizations and Aryl C–H
Aminations by in Situ Release of a Hydroxylamine-Based
Aminating Agent. J. Am. Chem. Soc. 2017, 139, 14005. (d) Ma,
X.; Farndon, J. J.; Young, T. A.; Fey, N.; Bower, J. F. A Simple
and
Broadly
Applicable
C−N
Bond
Forming
of
α-Amido-oxy
Acids:
Transition-Metal-Free
Dearomatization Protocol Enabled by Bifunctional Amino
Reagents. Angew. Chem. Int. Ed. 2017, 56, 14531.
Amidofluorination of Unactivated Alkenes. Angew. Chem.
Int. Ed. 2018, 57, 10707. (h) Dauncey, E. M.; Morcillo, S. P.;
Douglas, J. J.; Sheikh, N. S.; Leonori, D. Photoinduced
Remote Functionalisations by Iminyl Radical Promoted C-C
and C-H Bond Cleavage Cascades. Angew. Chem. Int. Ed.
2018, 130, 752. (i) Nakafuku, K. M.; Fosu, S. C.; Nagib, D. A.
Catalytic Alkene Difunctionalization via Imidate Radicals. J.
Am. Chem. Soc. 2018, 140, 11202.
19. For some recent reviews on dearomatization of arenes, see:
(a) Roche, S. P.; Porco Jr., J. A. Dearomatization Strategies
in the Synthesis of Complex Natural Products. Angew.
Chem. Int. Ed. 2011, 50, 4068. (b) Wu, W.-T.; Zhang, L.; You,
S.-L. Catalytic asymmetric dearomatization (CADA)
reactions of phenol and aniline derivatives. Chem. Soc. Rev.
2016, 45, 1570. (c) Reddy, C. R.; Prajapti, S. K.; Warudikar,
K.; Ranjan, R.; Rao, B. B. ipso-Cyclization: an emerging tool
for multifunctional spirocyclohexadienones. Org. Biomol.
Chem. 2017, 15, 3130.
20. For diazaspiro compounds as GlyT1 transporter inhibitors,
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inhibitors and uses thereof in treatment of neurological and
neuropsychiatric disorders. WO Patent 2007014762, 2007.
(b) Marshall, H. R. Glyt1 transporter inhibitors and uses
thereof in treatment of neurological and neuropsychiatric
disorders. WO Patent 2008092879, 2008.
14. (a) Buscemi, S.; Vivona, N.; Caronna, T. Photoinduced
Molecular Rearrangements. The Photochemistry of Some
1,2,4-Oxadiazoles in the Presence of Nitrogen Nucleophiles.
Formation
of
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Indazoles,
and
Benzimidazoles. J. Org. Chem. 1996, 61, 8397. (b) Buscemi,
S.; Pace, A.; Vivona, N.; Caronna, T.; Galia, A. Photoinduced
Single Electron Transfer on 5-Aryl-1,2,4-oxadiazoles: Some
Mechanistic Investigations in the Synthesis of Quinazolin-
4-ones. J. Org. Chem. 1999, 64, 7028. (c) Pace, A.; Buscemi,
S.; Vivona, N. Heterocyclic Rearrangements in Constrained
Media. A Zeolite-Directed Photorearrangement of 1,2,4-
Oxadiazoles. J. Org. Chem. 2005, 70, 2322. (d) Pace, A.;
Pierro, P. The new era of 1,2,4-oxadiazoles. Org. Biomol.
Chem. 2009, 7, 4337.
21. The
transition-metal-catalyzed
dearomative
spirocyclization strategies usually involve functionalized
alkoxyarenes, including phenol derivatives.
22. The oxidation of oxadiazolines at high temperature by
triplet oxygen was proposed via N-radical formation; see
(ref 15c).
23. Even the reaction of 1a with a highly oxidizing TPPT
catalyst was inefficient.
24. The triplet energies were calculated considering the
solvation effect of DMSO using M06-2X / 6-311++G**
method (see Figure S5 for details).
15. For other non-photocatalytic examples, see: (a) Natale, N.
R. Selective reduction of isoxazoles with samarium diiodide.
Tetrahedron Lett. 1982, 23, 5009. (b) Janza, B.; Studer, A.
Stereoselective Cyclization Reactions of IBX-Generated
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Wang, Y.-F.; Zhang, F.-L.; Chiba, S. Oxidative Radical
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Synthesis of Quinazolinones. Org. Lett. 2013, 15, 2842.
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Malacria, M.; Fensterbank, L. Radical Migration of
25. Blum, T. R.; Miller, Z. D.; Bates, D. M.; Guzei, I. A.; Yoon, T.
P. Enantioselective photochemistry through Lewis acid–
catalyzed triplet energy transfer. Science, 2016, 354, 1391.
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26. Turro, N. J. Modern Molecular Photochemistry, University
3β-hydroxycholest-6-ene
and
7α-hydroperoxy-3β-
Science Books, Sausalito, California, 1991.
hydroxycholest-5-ene. J. Chem. Soc., Perkin Trans. 2, 1989,
815. (b) Porter, N. A.; Wujek, J. S. Allylic hydroperoxide
rearrangement. β-Scission or concerted pathway? J. Org.
Chem. 1987, 52, 5085.
1
2
3
27. Sagadevan, A.; Hwang, K. C.; Su, M.-D. Singlet oxygen-
mediated selective C–H bond hydroperoxidation of ethereal
hydrocarbons. Nature Commun. 2017, 8, 1812.
4
5
6
7
8
9
28. The reaction of 1a was performed under standard
conditions for 3 h and then in the dark for additional 15 h.
29. Aubry, J. M. Search for Singlet Oxygen in the
Decomposition of Hydrogen Peroxide by Mineral
Compounds in Aqueous Solutions. J. Am. Chem. Soc. 1985,
107, 5844.
31. A peroxide indicator, QUANTOFIX Peroxid 25, was used.
32. CCDC 1846200 and 1846201 contain the supplementary
crystallographic data for this paper, which can be obtained
free of charge from The Cambridge Crystallographic Data
Centre.
30. (a) Beckwith, A. L. J. The mechanisms of the
rearrangements of allylic hydroperoxides: 5α-hydroperoxy-
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