Visible-Light Catalyzed [1+2+2] Cycloaddition Reactions Enabled by the Formation of Methylene Nitrones

Article abstract of DOI:10.1002/adsc.202000858

Nitrones are key intermediates in organic synthesis. Herein, we report the first photo-redox synthesis of methylene nitrone intermediates from nitroarenes and arylamines. The highly reactive methylene nitrones are in situ trapped by alkenes to afford various isoxazolidines. This three-component reaction features the use of N,N-dimethylanilines or N-aryl glycines as C1 building blocks, which allow for the one-pot formal [1+2+2] cycloaddition from simple starting materials. A wide range of useful isoxazolidines can be obtained under mild conditions with moderate to good yields. Mechanistic investigations support the formation of methylene nitrone via selective N?CH₃ bond cleavage and methylene transfer. (Figure presented.).

Full text of DOI:10.1002/adsc.202000858

Title: Visible-light catalyzed [1+2+2] cycloaddition reactions enabled by
the formation of methylene nitrones
Authors: Jing Guo, Ying Xie, Wen-Tian Zeng, QiaoLei Wu, Jiang
Weng, and Gui Lu
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000858
Link to VoR: https://doi.org/10.1002/adsc.202000858

10.1002/adsc.202000858
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Visible-light Catalyzed [1+2+2] Cycloaddition Reactions
Enabled by the Formation of Methylene Nitrones
Jing Guo,a Ying Xie,a Wen-Tian Zeng,a Qiao-Lei Wu,a Jiang Weng, a,* Gui Lua,*
a
Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences,
Sun Yat-sen University, Guangzhou, 510006, P. R. China. E-mail: lugui@mail.sysu.edu.cn, wengj2@mail.sysu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: Nitrones are key intermediates in organic synthesis. Herein, we report the first photo-redox synthesis of methylene
nitrone intermediates from nitroarenes and arylamines. The highly reactive methylene nitrones are in situ trapped by alkenes
to afford various isoxazolidines. This three-component reaction features the use of N,N-dimethylanilines or N-aryl glycines as
C1 building blocks, which allow for the one-pot formal [1+2+2] cycloaddition from simple starting materials. A wide range of
useful isoxazolidines can be obtained under mild conditions with moderate to good yields. Mechanistic investigations support
the formation of methylene nitrone via selective N-CH3 bond cleavage and methylene transfer.
Keywords: Methylene nitrone; C1 synthetic unit; [1+2+2] cycloaddition; Visible light; Redox
generally required to prepare hydroxylamines
from nitro precursors. Although the oxidation of
amines, imines or hydroxylamines provides
Introduction
Nitrones are key intermediates in synthetic chemistry alternative approaches to accessing nitrones, the
for the preparation of natural products and biologically process largely suffers from the use of
active compounds (Scheme 1).[1] Nitrones, given their stoichiometric external oxidants (HgO, MnO2,
highly versatile reactivities, are extensively used in
oxone, peroxides, etc.) and the limited
various fundamental synthetic transformations, such compatibility of functional groups.[1a,3] The
as nucleophilic additions, radical additions, 1,3- transition metal-catalyzed transformation of
dipolar cycloadditions, [3+n] annulations, and C–H oximes by alkylation reactions is another efficient
functionalization reactions, etc. In addition, nitrones method for the synthesis of nitrones.[4] However,
have multiple applications in radical trapping,
bioorthogonal labeling, and potential therapeutic
agents. Thus, considerable effort has been devoted in
developing methodologies for the efficient synthesis
of nitrones.
this strategy often requires the use of prefunctional
substrates and a careful control of reaction
conditions to avoid the mixing of products. From
the viewpoint of sustainability, most of
abovementioned processes create large amounts of
environmentally
developing a catalytic method for nitrone
synthesis under redox-neutral and
toxic
waste.
Therefore,
environmentally benign conditions is highly
desirable.[5] Besides, to the best of our knowledge,
the synthesis and application of methylene nitrone
(R1= R2= H, Scheme 1) remains largely
underexplored, probably due to the high reactivity
for isolation and the lack of suitable C1 building
blocks.[6]
Visible light photoredox catalysis has emerged
as a powerful strategy in synthetic organic
chemistry in the past decade because it allows for
the design and development of new chemical
transformations in an environmentally benign
Scheme 1. Synthetic strategies of nitrones.
The classic approaches typically involve
condensation reactions of carbonyl compounds
with
N-monosubstituted
hydroxylamines.
However, stoichiometric external reductants (Zn,
H2, N2H4•H2O, etc.)[1a,2] and harsh conditions are
1
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10.1002/adsc.202000858
Advanced Synthesis & Catalysis
manner.[7] A typical photocatalytic process is
generally initiated by a single-electron transfer
(SET) between an excited photocatalyst and an
oxidative or reductive quencher to afford the
corresponding redox-active species and an ion-
radical species. In the previous work, low-cost
ubiquitous tertiary amines and nitroarenes were
employed as reductive additives and oxidative
additives to quench the excited photocatalyst
photocatalytic reactions of nitroarenes and N,N-
dimethylanilines (or N-aryl glycines) for the synthesis
of highly reactive methylene nitrone intermediates,
which are trapped by alkenes to afford a variety of
useful isoxazolidines. This method entails several
remarkable features, including abundant feedstock
materials, a broad substrate scope, and mild conditions.
To our knowledge, this process represents the first
example of a highly efficient formal [1+2+2] three-
component reaction for the rapid and convergent
assembly of isoxazolidines, in which N,N-
dimethylanilines or N-aryl glycines are used as C1
building blocks.
(Schemes 2
A and 2B). In addition to acting as
sacrificial additives, tertiary amines and
nitroarenes were also used as substrates in
photoredox catalysis (Schemes 2
C and 2D). On
one hand, tertiary amines were shown to undergo
various visible-light promoted α-functionalization
through the formation of reactive intermediates,
including α-amino radicals and iminium ions
Results and Discussion
(Scheme 2C
).[7f,8] By harnessing the synthetic
Initially, we started our investigation by identifying
reaction conditions suitable for performing the three-
potential of α-amino radicals and iminium ions,
various transformations, including nucleophilic
addition, radical addition, and cross-coupling
reactions, could be developed for the
functionalization of amine substrates.[8a,9] New
chemical transformations based on the C-N
cleavage of iminium ions intermediates were
seldom explored.[10] On the other hand, nitroarenes
were mostly employed as oxidative additives
rather than substrates in photocatalytic
Table 1. Optimization of the reaction conditions.[a]
reactions.[11]
Although
the
photocatalytic
reduction of nitroarenes into the corresponding
anilines have been realized, the controllable
reduction
towards
nitrosoarenes
or
N-
arylhydroxylamines and their subsequent
transformations remain a challenge (Scheme
2D
).[12]
Yield
Entry
Photocatalyst
Additive[b] Solvent
[%][c]
38
1
2
3
4
5
6
7
8
A
B
C
D
E
B
B
B
B
B
B
B
B
B
B
B
B
B
-
-
-
-
-
-
-
DCM
DCM
DCM
DCM
DCM
THF
60
52
58
34
36
55
45
34
26
37
40
38
41
54
65
-
-
-
toluene
CHCl3
DCE
9
10
11
12
13
14
15
16[d]
17[e]
18[f]
19
20[g]
-
PhCl
-
xylene
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
3Å MS
4Å MS
Na2SO4
MgSO4
-
-
-
-
-
Scheme 2. Visible-light photoredox catalysis involving
nitroarenes and tertiary amines.
70(71[h])
68
0
0
On the basis of the redox properties of the tertiary
amines and nitroarenes, we envisioned that nitrones
could be accessed through the condensation of in situ-
generated iminium ions and N-arylhydroxylamines
from tertiary amines and nitroarenes under visible light
photocatalysis, thus avoiding the need to use
stoichiometric amounts of oxidants or reductants
common in conventional approaches (Scheme 2E).
Herein, we report the first redox-neutral visible-light
B
[a]
Reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), 3a
(0.3 mmol), photocatalyst (0.0005 mmol), solvent (2 mL)
under 12 W blue LEDs for 24 h at 25 oC.
[b] 20 mg additive.
2
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10.1002/adsc.202000858
Advanced Synthesis & Catalysis
[c] NMR yield using CH2Br2 as internal standard.
With the optimized conditions in hand (Table 1,
entry 17), next we investigated the substrate scope of
this [1+2+2] cycloaddition reaction and the results
were shown in Table 2. Firstly, this reaction generally
exhibited a broad substrate scope with respect to
styrenes. Various styrene derivatives bearing electron-
neutral or electron-donating groups proceeded
smoothly to give the desired isoxazolidines 4a−4d in
good yields (63%−78%). The electron-deficient
styrenes bearing substituents such as halides and ester
groups were also tolerated in the reaction with
moderate to good efficiencies (4e−4h, 42%−70%
yields). Styrene derivatives with substituents at the
ortho- and meta-positions also worked well, providing
4i−4j in 58%−65% yields. 2-Vinyl naphthalene
afforded the product 4k in 58% yield. In addition, the
isoxazolidines 4l−4m bearing a quaternary carbon
center could also be constructed from the
corresponding 1,1-disubstitued alkenes under the
standard reaction conditions. The structure of 4m was
unambiguously determined by X-ray single-crystal
analysis.[16] Notably, to illustrate the utility of this
method in synthesis, the alkenes derived from
bioactive estrone and fenofibrate were smoothly
converted into the corresponding isoxazolidines
4n−4o in 67% and 66% yields, respectively.
Subsequently, the scope of nitroarene substrates
was explored with reacting with N-phenyl glycine 2a
and styrene 3a. A range of structurally diverse 4-
nitrophenol esters, which served as the NO donors,
were examined in this [1+2+2] cycloaddition reaction
and afforded the products in moderate to excellent
yields (4p−4ae, 40%−82%). Various functional
groups on the phenyl ring, such as –OMe, –CN, –NO2,
–Ph, –F, and –Cl, were well compatible in the current
transformation (4p−4ab), whereas –NO2 substituent
made the transformation a little sluggish, providing
lower yield (4r, 40%). In addition, 4-nitrophenol esters
derived from cyclic carboxylic acids and α- amino acid
were also tolerated, providing the corresponding
isoxazolidines 4ac−4ae in 48%–71% yields.
[d] 48 h.
[e] 60 h.
[f] 72 h.
[g] No light.
[h] Isolated yields.
component cycloaddition of 4-nitrophenyl 3-
phenylpropanoate (1a) and styrene (3a) with N-phenyl
glycine (2a) as C1 unit. As expected, the reaction did
proceed and the desired isoxazolidine 4a could be
obtained in 38% yield (Table 1, entry 1) when using
red
0.5 mol% of 4CzIPN (E1/2 = +1.35 V vs. SCE in
MeCN)[13] as the photocatalyst and irradiating with
two 12 W blue LEDs for 24 h in DCM. Given the
successful implementation of Ir(III) and Ru(II)
photocatalysts
in
previous
photoredox
reaction,[7a,7g,13c,14] a range of Ir(III) and Ru(II)
photocatalysts were evaluated (entries 2-5). To our
delight, the reaction was significantly improved when
Ir[dF(CF3)ppy]2(bpy)PF6 (E1/2(*IrIII/IrII)= +1.32 V vs.
SCE in MeCN)[14c,15] was used as the photocatalyst
(entry 2). Subsequently, we conducted further
investigations on the effect of reaction media,
including THF, toluene, CHCl3, DCE, PhCl and
xylene. The reaction proceeded poorly in other
solvents and DCM remained to be the optimal choice
(entries 2, 6-11). In addition, several additives were
screened and failed to improve the yield (entries 12-
15). The yield of 4a could be readily improved to 70%
by increasing the reaction time to 60 h (entries 16-18).
The control experiments indicated that photocatalyst
and light irradiation are essential for the success of this
transformation (entries 19-20).
Table 2. Substrate scope when using N-aryl glycines as C1
synthetic unit.[a,b]
Table 3. Investigation when using tertiary amines as the C1
synthetic unit.[a,b]
[a] Reaction conditions: 1 (0.1 mmol), 2a (0.3 mmol), 3 (0.3
mmol), Ir[dF(CF3)ppy]2(bpy)PF6 (0.0005 mmol), DCM
(2 mL) under 12 W blue LEDs for 60 h at 25 °C.
[b] Isolated yields.
3
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10.1002/adsc.202000858
Advanced Synthesis & Catalysis
[a] Reaction conditions: 1a (0.1 mmol), 2 (0.3 mmol), 3a (0.3
mmol), Ir[dF(CF3)ppy]2(bpy)PF6 (0.0005 mmol), DCM
(2 mL) under 12 W blue LEDs for 60 h at 25 °C.
[b] NMR yield using CH2Br2 as internal standard.
[c] Isolated yield.
phenylpropanoate (1a) and styrene (3a) with N,N-
dimethylaniline (2b) as C1 unit. The addition product
4a could be obtained in 80% yield with 0.5 mol%
photocatalyst albeit longer reaction time was required
to ensure complete conversion. Donating groups such
as –CH3, –CH2CN at the para-position of the aromatic
ring, all underwent the desired radical cycloaddition
reaction smoothly to afford the corresponding
isoxazolidines 4ah–4al in moderate to good yields
(40%–72%). The nitro-heteroaromatic compounds,
such as 5-nitroquinoline and 5-nitroindole, also proved
to be suitable substrates for this reaction, providing the
target products 4am and 4an in 41% and 44% yields,
respectively. Moreover, various acrylates were also
capable acceptors in the reaction to give the
corresponding products 4ao–4aq in 53%–76% yields.
In order to gain insights into the reaction mechanism,
a series of mechanistic studies were performed. Firstly,
the desired product was inhibited in the presence of
radical scavengers TEMPO or O2, which indicated that
a radical pathway might be involved in the reaction
(Scheme 3a). Next, when the deuterated N,N-
dimethylaniline 2b’ was subjected to the standard
reaction with 1a and 3a, the CD2-labelling product 4a’
was obtained with 62% yield
Given the success of the cycloaddition with N-
phenyl glycine as the C1 units, next we turned our
attention to investigate the use of more challenging
tertiary amines (Table 3). It was found that N-
methylanilines 2b−2d could also play as the
methylene sources of final isoxazolidine products.
Among them, N,N-dimethylaniline 2b was the best
choice and delivered the product in 70% yield,
whereas other anilines proceeded with lower
efficiency. In contrast, no reaction occurred when N,N-
diethylaniline 2e or N,N-dibenzylaniline 2f was
subjected to the reaction conditions. Moreover,
nonaromatic tertiary amines 2g−2j were demonstrated
to be invalid in the current transformation, which
suggested that aromatic amine moiety is essential for
the selective N-CH3 bond cleavage.
Table 4. Substrate scope when using N,N-dimethylaniline
as the C1 synthetic unit.[a,b]
[a] Reaction conditions: 1 (0.1 mmol), 2b (0.3 mmol), 3 (0.3
mmol), Ir[dF(CF3)ppy]2(bpy)PF6 (0.0005 mmol), DCM
(2 mL) under 12 W blue LEDs for 60 h at 25 °C.
[b] Isolated yields.
[c] 1 mmol scale for 120 h.
Subsequently, we further demonstrated the
generality of this protocol with N,N-dimethylaniline as
the C1 building block and the results were summarized
in Table 4. Cycloaddition of electron-neutral groups
(4-H, 4-Me) and electron-withdrawing groups (4-Br,
4-COOMe, 4-CF3 and 4-CN) substituted styrenes gave
the products in 56−72% yields. To explore the
practicality of this method, a 1 mmol scale experiment
was
performed
with
4-nitrophenyl
3-
4
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10.1002/adsc.202000858
Advanced Synthesis & Catalysis
single product 4a was afforded when the model
reaction proceeded in the presence of a range of
aromatic and alkyl aldehydes (5c–5e). These results
indicated that the C1 synthon might be the N-
methylene iminium rather than formaldehyde (Scheme
3f).[5a] In addition, the stepwise synthesis was carried
out and styrene could trap the preformed intermediate
in dark conditions (Scheme 3g). Finally, the Stern-
Volmer studies of photocatalyst demonstrated that the
excited photocatalyst Ir* was quenched by the amine
2b (Scheme 3h).
Scheme 4. Proposed mechanism for visible-light catalyzed
[1+2+2] cycloaddition reactions
Based on the above experiments, a possible
mechanistic pathway for this reaction was proposed as
depicted in Scheme 4. Upon visible-light irradiation,
the iridium(III) photocatalyst would produce the long-
lived and highly oxidizing excited state *Ir(III) species
(*Ir[dF(CF3)ppy]2(bpy)+ (E1/2(*IrIII/IrII)= +1.32 V vs.
SCE in MeCN). Reductive quenching of the excited
*IrIII photocatalyst by N,N-dimethylaniline 2b whose
oxidation potentials fall in the 0.7 V vs. SCE[9c,17]
would generate the nitrogen radical cation B and the
reduced IrII photocatalyst. Subsequent single electron
oxidation of the IrII photocatalyst with nitrobenzene 1
regenerates the IrIII photocatalyst and yields the
nitrobenzene radical anion A,[7b,18] which then
undergoes hydrogen atom transfer process with B to
afford N,N-dihydroxyamine anion C and the imine
cation D.[11a,19] C is transformed into nitrosobenzene E
and subsequent N-phenylhydroxylamine F via a series
of reduction and protonation processes. Subsequently,
condensation of hydroxylamine F with the imine
cation D leads to the methylene nitrone G. Finally,
trapping of the highly reactive methylene nitrone G
with styrene 3a results in the formal [1+2+2]
cycloaddition product 4.
6
5
4
3
2
1
0
PC+1a
PC+3a
PC+2b
R2 = 0.9947
0
0.2
0.4
0.6
0.8
1
1.2
1.4
CONCENTRATION
Scheme 3. Mechanistic studies.
(Scheme 3b), which unambiguously demonstrated that
N,N-dimethylaniline was the C1 building blocks for
the isoxazolidine products. Similarly, when N-phenyl
glycines 2j–2m with different substituted groups were
employed in this reaction (Scheme 3c), the same
product 4a was delivered, which indicating that the
methylene in the product is generated from the N-
phenyl glycines. In contrast, when 1a and 3a were
subjected to the standard reaction conditions without
N-phenyl glycines or tertiary amines, neither
intermediate nor isoxazolidine products were detected
(Scheme 3d). These findings were different from
previous reports,[6,9d] hinting the possibility of a novel
mechanism. To verify the active intermediates, the
photoredox reaction of nitroarene 1a and N,N-
dimethylaniline 2b in the absence of olefins was
conducted under irradiation. The intermediates 5a and
5b were detected by ESI-MS techniques (Scheme 3e),
suggesting that selective N-methyl C-N bond cleavage
might occur via photoredox single-electron transfer
and hydrogen atom transfer process. Besides, only
Conclusion
In summary, we have developed the first visible-
light-catalyzed [1+2+2] cycloaddition reaction. This
formal [1+2+2] cycloaddition reaction involves the in
situ formation of highly reactive methylene nitrone
intermediates from nitroarenes and arylamines by
visible-light photoredox catalysis, in which the methyl
or methylene moiety of arylamines (either N,N-
5
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10.1002/adsc.202000858
Advanced Synthesis & Catalysis
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donors. A variety of useful isoxazolidines were
accessed smoothly with moderate to good yields (50
examples, up to 82% yield). The method features
redox-neutrality, simple starting materials, mild
reaction conditions, broad substrate scope and good
functional group tolerance. Preliminary mechanistic
studies support the formation of methylene nitrone via
selective N-CH3 bond cleavage and methylene transfer.
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Experimental Section
General Procedure for the Synthesis of Products
To a solution of 1a (0.1 mmol) and 2a (0.3 mmol) in DCM
(2
mL)
was
added
3a
(0.3
mmol)
and
Ir[dF(CF3)ppy]2(bpy)PF6 (0.0005 mmol). The reaction
mixture was degassed by bubbling a stream of nitrogen for
5 min at 0 C, then stirred at 25 oC and irradiated with two
o
12 W blue LEDs with a fan placed nearby for cooling. After
60 h, the mixture was concentrated under reduced pressure
and crude product was purified by flash column
chromatography on silica gel to afford the title compound.
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Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (No. 81972824), Guangdong
Provincial Key Laboratory of Chiral Molecule and Drug
Discovery (No. 2019B030301005), Guangdong Basic and Applied
Basic Research Foundation (No. 2020A1515011513) and National
Engineering and Technology Research Center for New drug
Druggability Evaluation (Seed Program of Guangdong Province,
No. 2017B090903004).
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FULL PAPER
Visible-light Catalyzed [1+2+2] Cycloaddition
Reactions Enabled by the Formation of
Methylene Nitrones
Adv. Synth. Catal. 2020, Volume, Page – Page
Jing Guo, Ying Xie, Wen-Tian Zeng, Qiao-Lei Wu,
Jiang Weng,* Gui Lu*
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