Visible Light Promoted Chan-Lam Reaction and Cycloaddition to Prepare Chromeno[4,3-c]isoxazolidines in One-Pot Reaction

Article abstract of DOI:10.1002/adsc.202100448

A variety of chromeno[4,3-c]isoxazolidines were prepared in good yields through visible light promoted Chan-Lam reaction and [3+2] cycloaddition cascade reaction in one pot. Mechanistic studies showed that visible light promoted both Chan-Lam reaction and cycloaddition. The obtained products were converted to various useful chromenone derivatives. Moreover, the reaction was easily performed at gram scales with the purification of products without column chromatography and used to efficiently synthesize estrone-derived chromeno[4,3-c]isoxazolidine. (Figure presented.).

Full text of DOI:10.1002/adsc.202100448

Title: Visible Light Promoted Chan-Lam Reaction and Cycloaddition to
Prepare Chromeno[4,3-c]isoxazolidines in One-pot Reaction
Authors: Jie Zhao, Bing-Qing Huang, Bin-Can Zhu, Xiao-Pan Ma, and
Dong-Liang Mo
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202100448
Link to VoR: https://doi.org/10.1002/adsc.202100448

10.1002/adsc.202100448
Advanced Synthesis & Catalysis
RESEARCH ARTICLE
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Visible Light Promoted Chan-Lam Reaction and Cycloaddition
to Prepare Chromeno[4,3-c]isoxazolidines in One-pot Reaction
Jie Zhao,a Bing-Qing Huang,a Bin-Can Zhu,a Xiao-Pan Mab,*, and Dong-Liang Moa,*
a
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation
Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University,
15 Yu Cai Road, Guilin 541004, China. E-mail: moeastlight@mailbox.gxnu.edu.cn
College of Pharmacy, Guilin Medical University, Guilin 541199, China. E-mail: maxpan1107@163.com
b
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. A variety of chromeno[4,3-c]isoxazolidines were
prepared in good yields through visible light promoted
Chan-Lam reaction and [3+2] cycloaddition cascade reaction
in one pot. Mechanistic studies showed that visible light
promoted both Chan-Lam reaction and cycloaddition. The
obtained products were converted to various useful
chromenone derivatives. Moreover, the reaction was easily
performed at gram scales with the purification of products
without column chromatography and used to efficiently
synthesize estrone-derived chromeno[4,3-c]isoxazolidine.
Keywords: Visible light; Cycloaddition; Chan-Lam
reaction; Nitrone; Chromeno[4,3-c]isoxazolidine
was used to prepare N-aryl/N-vinyl-,-unsaturated
nitrones from ,-unsaturated oximes and aryl or
vinyl boronic acids (Scheme 1-A).[8] These findings
demonstrated an elegant method for the preparation
of N-substituted-,-unsaturated nitrones; however,
these reactions often required copper salts (1.0 or 2.0
equiv.) and excess pyridine (10.0 equiv.). Although
these studies have showed that adding 2.0 equivalents
of 1,5-cyclooctadiene (COD) to the reaction could
reduce the required amount of Cu(II) to 20 mol%, the
process was still inefficient and produced excess
COD waste. Several research groups have aimed to
develop systems using catalytic copper salts by
introducing various additives, strong oxidants, or
pyridine-based N-ligands, and using recyclable
heterogeneous catalysts or electrochemical catalytic
methods.[9] However, these reactions were not green
Introduction
Carbon-nitrogen bonds and nitrogen-containing
heterocycles are ubiquitous in a wide range of
biologically active molecules, pharmaceuticals, and
natural products. In the last two decades, transition
metal-catalyzed cross-coupling reactions have
emerged as one of the most important synthetic tools
for constructing carbon-nitrogen, carbon-oxygen and
carbon-carbon bonds.[1] Since its discovery, the Chan-
Lam reaction,[2] namely the cross-coupling of
arylboronic acids with nucleophiles containing
heteroatoms, such as amines, alcohols, or mercaptans,
et al., has attracted significant attention in terms of
forming carbon heteroatom bonds owing to the mild
reaction conditions and open-flask chemistry (i.e.,
room temperature, weak base, ambient atmosphere).[3] and sustainable enough because excess additives and
In addition, this reaction has been successfully
employed for the total synthesis of natural products.[4]
Recently, the Chan-Lam reaction has been used to
prepare N-aryl or N-vinyl nitrones by selective N-
functionalization through the cross-coupling of
oximes with aryl or alkenyl boronic acids.[5] Nitrones
are ubiquitous organic intermediates in the
production of heterocyclic compounds via
cycloaddition.[6] In 2012 Anderson and coworkers
pioneered a method to prepare N-vinyl fluorenone
nitrones by cross-coupling 9-fluorenone oximes with
alkenyl boronic acids in the presence of 1.0 or 2.0
equiv. of Cu(OAc)2.[7] Later, the Chan-Lam reaction
complex ligands were required, or multi-step
synthesis of the heterogeneous catalysts, wasted time,
money, energy, and labor. Therefore, the
developement of a green and sustainable system to
carry out the Chan-Lam reaction is desirable.
Recently, the use of visible light as an
inexhaustible source of clean energy to promote
sustainable organic synthesis has attracted significant
attention.[10] because it satisfies the requirements for
sustainable chemistry; specifically, it avoids waste
production (from ligands, additives, or by-products)
after the reaction is completed.[11] However, to date,
only two reports have described visible light
1
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10.1002/adsc.202100448
Advanced Synthesis & Catalysis
promoted Chan-Lam reactions. First, in 2015,
Kobayashi and coworkers pioneered the visible-light
mediated Chan-Lam coupling reaction of aniline
derivatives with arylboronic acids by using a Cu(II)
salt and an iridium-based photocatalyst. Importantly,
they elucidated the reactivity of electron-deficient
arylboronic acids in the cross-coupling reactions
(Scheme 1-B).[12] Mechanistic studies revealed that
the visible light likely either promoted the conversion
of Cu(II) to Cu(III) intermediates or facilitated the
Cu(I) to Cu(II) oxidation to complete the catalytic
cycle. Then, in 2021, Jia and co-workers developed a
copper-catalyzed photoredox dehydrogenative Chan-
Lam coupling reaction between free diaryl
sulfoximines and arylboronic acids in the presence of
visible light, showing that the C-N bond coupling
occurred in the absence of ligand, base and air
conditions (Scheme 1-C).[13] Mechanistic studies
revealed that (i) visible light promoted the oxidation
of Cu(I) to Cu(II) and (ii) the ligation of N-arylated
sulfoximines onto copper species enabled its
capability as photocatalysts.
that are suitable for preparing nitrones or N-oxides by
the cross-coupling reaction of N-O moieties with
various aryl or alkenylboronic acids.[15] However,
stoichiometric amounts of Cu(II) salts were also
required. Recently, we developed a metal-free
strategy to prepare N-aryl nitrones from oximes with
diaryliodonium salts,[16] and also designed a metal-
free
N-arylation/[3+2]
cycloaddition/[3,3]-
rearrangement reaction that used alkynyl-tethered
oximes and diaryliodonium salts to prepare 2,3-fused
indoles.[17] However, these metal-free strategies often
produced iodobenzene waste and required
purification by column chromatography after the
reaction was completed. Based on our group’s
investigations of cycloadditions powered by visible
light,[18] we designed a visible light promoted Chan-
Lam reaction to generate N-aryl nitrone moieties, and
then catalyze the intramolecular [3+2] cycloaddition
of those N-aryl nitrone moieties with internal alkenes
to afford chromeno[4,3-c]isoxazolidines (Scheme 1-
D). Chromenoisoxazolidines are important molecular
scaffolds in drug discovery, with the properties
relevant for antidepressants, antipsychotics, and
antianxiolytics.[19] The few available strategies for the
synthesizing these compounds rely on the
intramolecular cycloaddition of alkenyl-tethered
aldonitrones at high temperatures with harsh reagents
were reported, and only low or moderate efficiencies
were attained for alkenyl-tethered ketonitrones.[20]
Therefore, developing efficient and green methods
for the synthesis of chromenoisoxazolidines remains
an important synthetic goal. Herein, we report a
visible light promoted Chan-Lam reaction and [3+2]
cycloaddition cascade to prepare a series of
chromeno[4,3-c]isoxazolidines using a one pot
method.
A) Anderson's work, Chan-Lam reaction of oximes with aryl/alkenyl boronic acids
O
Ar
Cu(OAc)2 (1.0 or 2.0 equiv.)
pyridine (10.0 equiv.)
DCE, rt, air
N
ArB(OH)2
HO
R1
R1
R2
R3
N
+
or Cu(OAc)2 (0.2 equiv.)
COD (2.0 equiv.)
pyridine (10.0 equiv.)
B(OH)2
R3
R2
O
R4
N
R4
R1
R2
One C-N bond formation
B) Kobayashi's work, visible-light promoted Chan-Lam reaction
Cu(OAc)2 (10 mol%)
NHAr
B(OH)2
myristic acids (20 mol%)
ArNH2
+
2,6-lutidine, toluene/MeCN (1:1)
f ac-[Ir(ppy)3] (1 mol%)
R
R
blue LED, open air, 35 °C
43-100% yields
One C-N bond formation
C) Jia's work, visible-light promoted Chan-Lam reaction
sunlight
O
NH
O
N
Ar3
Cu(O2CCF3)•H2O (10 mol%)
Ar3B(OH)2
S
Results and Discussion
+
S
Ar1 Ar2
EtOH, rt, under Ar
Ar1 Ar2
One C-N bond formation
Initially, alkenyl-tethered oxime 1a and
phenylboronic acid 2a were selected as the model
substrates. As shown in Table 1, chromeno[4,3-
c]isoxazolidine 3aa was generated in 84% yield when
1a and 2a reacted under the standard conditions:
Cu(OAc)2 (20 mol%), methylene blue (5 mol%), and
pyridine (pyr) (3.0 equiv.) in DCE (3.0 mL), using a
17 W white LED open to air at room temperature
(Table 1, entry 1). The structure of 3aa was
determined by X-ray diffraction analysis.[21] No
reaction occurred in the absence of Cu(OAc)2 after 72
h (Table 1, entry 2). Nitrone 4aa was the only
product obtained (35% yield; 10:1 E/Z isomers) in
the absence of 17 W white LED light, and 3aa was
not observed, suggesting that visible light promoted
both the Chan-Lam reaction and the [3+2]
cycloaddition (Table 1, entry 3). Next, various copper
species were evaluated in the presence of visible light.
Other Cu(II) salts, such as CuCl2, CuBr2, and
Cu(OTf)2, all catalyzed the reaction smoothly to
afford 3aa in yields ranging from 29% to 45%,
whereas the addition of CuCl afforded 3aa in only
D) This work, visible-light promoted Chan-Lam reaction and [3+2] cycloaddition
R3
R3
H
O
hv
O
OH
R2
N
ArB(OH)2
O
N
+
Cu(OAc)2 (20 mol%)
pyridine, DCE, open air, rt
R2
Ar
R1
R3
R1
Ar
O
O
N
R2
via
R1
Scheme 1. New design for a cascade reaction of Chan-
Lam reaction and cycloaddition using visible light.
Intermediates containing N-O moieties were useful
as O- and N-sources to access complex building
blocks, such as amines, alcohols, or 1,3-amino
alcohols via N-O bond transformations.[14] Our group
has developed several selective Chan-Lam reactions
2
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10.1002/adsc.202100448
Advanced Synthesis & Catalysis
a)
6% yield (Table 1, entries 4-7). Interestingly, using
CuBr and CuI as catalysts gave 3aa in 15% and 30%
yields, respectively (Table 1, entries 8-9). These
results showed that the anion of Cu(I) salt had an
impact on the yield of 3aa. Product 3aa was not
obtained without methylene blue and that reaction
only afforded nitrone 4aa in 41% yield (Table 1,
entry 10). However, when methylene blue was
replaced with the photoredox catalyst, Eosin Y, the
reaction generated 3aa in 62% yield (Table 1, entry
11). Decreasing the amount of methylene blue to 1
mol% afforded 3aa in 65% yield (Table 1, entry 12).
When the 17 W white LED was replaced with an 11
or 4 W white LED, the yield of 3aa was in 71% and
55%, respectively (Table1, entries 13-14). Solvent
screening revealed that the reaction proceeded
smoothly in DCM, MeCN, THF, MeOH, and DMF,
affording 3aa in good yields (Table 1, entries 15-19).
Changing the amount of Cu(OAc)2 to 10 mol%
generated 3aa in 57% yield (Table 1, entry 20). When
the loading amounts of phenylboronic acid 2a were
reduced to 1.5 equiv. and 1.0 equiv., the yield of 3aa
was dropped to 59% and 45% yield, respectively
(Table 1, entries 21-22). Therefore, the optimal
The standard conditions: 1a (0.3 mmol), 2a (0.6 mmol),
Cu(OAc)2 (20 mol%), methylene blue (5 mol%), DCE (3.0
mL), pyr (0.9 mmol, 3.0 equiv.), 17 W white LED, in air,
30 ˚C, 36-72 h;b) isolated yield.
With the standard conditions in hand, various
arylboronic acids 2 were evaluated to determine the
scope of the reaction for preparing chromeno[4,3-
c]isoxazolidines via the visible light promoted
cascade. As shown in Table 2, various arylboronic
acids with electron-donating and electron-
withdrawing groups at the para-, meta-, and ortho-
positions proceeded smoothly to produce the
corresponding chromeno[4,3-c]isoxazoles 3ac-3ap in
moderate to good yields. The one exception was 4-
methoxyphenylboronic acid 2b, which afforded 3ab
in only 26% yield likely because of the facile
decomposition of 2b to 4-methoxyphenol under the
visible light conditions. In general, arylboronic acids
tolerated the strongly electron-withdrawing CF3 and
CO2Me groups at the para-positions, to give products
3ai and 3aj in 54% and 55% yields, respectively.
Interestingly, arylboronic acid 2n with an ortho-
bromo substituted group afforded 3an in 51% yield.
This product was more difficult to prepare using the
developed method compared with conventional
Chan-Lam reaction conditions without visible light.
Carbazole-derived boronic acids 2o and 2p both
delivered the desired products 3ao and 3ap in 76%
and 63% yields, respectively. This visible light
promoted cascade strategy tolerated halides, ethers,
thioether, esters and carbazoles.
conditions
for
synthesizing
chromeno[4,3-
c]isoxazolidine 3aa in a one pot reaction were:
Cu(OAc)2 (20 mol%), methylene blue (5 mol%), and
pyridine (3.0 equiv.) in DCE at room temperature,
open to air under 17 W white LED light.
Table 1. Optimization of reaction conditions.a
H
O
PhB(OH)2
OH
Ph
O
O
O
N
2a
O
N
N
+
Cu(OAc)2 (20 mol%)
methylene blue (5 mol%)
white LED (17 W )
pyr, DCE, rt
Ph
Table 2. Substrate scope of arylboronic acids 2. a,b
Ph
Ph
Ph
3aa
1a
H
4aa
OH
O
Cu(OAc)2 (20 mol%)
methylene blue (5 mol%)
O
O
N
entry conditions
3aa%b
4aa%b
+
N
ArB(OH)2
1
The standard conditions
84
-
-
-
35
-
-
-
-
-
-
41
-
-
-
-
-
-
-
-
Ph
Ar
17W white LED
pyr, DCE, rt
2
2
Without Cu(OAc)2
Ph
1a
3
4
5
Without 17 W white LED
CuCl2 instead of Cu(OAc)2
CuBr2 instead of Cu(OAc)2
<5
45
31
29
6
15
30
<5
62
3
H
H
3ab
X = OMe,
X = OPh,
X = SMe,
, 26%
3ac
, 62%
3ad
, 56%
O
O
O
O
6
7
8
9
Cu(OTf)2 instead of Cu(OAc)2
CuCl instead of Cu(OAc)2
CuBr instead of Cu(OAc)2
CuI instead of Cu(OAc)2
Without methylene blue
N
N
3ae
X = Me,
, 70%
, 71%
, 68%
, 61%
3af
3ag
X = Cl,
X = Br,
X
Ph
H
3ah
Ph
X = F,
X
3ai
X = CF3,
, 54%
X = OMe, 3ak, 66%
3aj
X = CO2Me,
, 55%
3al
X = Br,
, 73%
10
11
12
13
14
15
16
17
18
19
20
21
22
H
Using Eosin Y as photosensor
Using methylene blue (1 mol%) 65
H
O
O
O
O
O
O
N
N
11 W instead of 17 W
4 W instead of 17 W
DCM instead of DCE
MeCN instead of DCE
THF instead of DCE
MeOH instead of DCE
DMF instead of DCE
Using 10 mol% of Cu(OAc)2
Using 1.5 equiv of 2a
Using 1.0 equiv of 2a
71
55
62
79
61
69
65
57
59
45
N
Br
Ph
Me
H
N
Ph
3ao, 76%
Ph
Me
3am, 68%
Ph
3an
, 51%
O
N
-
-
N
O
Ph
3ap, 63%
a)
Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol),
Cu(OAc)2 (20 mol%), methylene blue (5 mol%), DCE (3.0
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.202100448
Advanced Synthesis & Catalysis
R3
O
mL), pyr (0.9 mmol, 3.0 equiv.), 17 W white LED, in air,
30 ˚C, 36-72 h; b) isolated yield.
R3
H
Cu(OAc)2 (20 mol%)
methylene blue (5 mol%)
OH
R2
O
N
O
ArB(OH)2
+
N
white LED (17 W)
pyr, DCE, rt
R1
R2
Ar
2
R1
Alkenyl-tethered oximes 1 were also studied to
further explore the scope of this cascade process. As
shown in Table 3, a variety of alkenyl-tethered
oximes reacted with 2a to afford the desired
chromeno[4,3-c]isoxazoles 3 in good yields. When
the R2 group comprised an aryl group bearing
electron-donating or electron-withdrawing groups at
the para, meta, or ortho-positions, the products 3ba-
3ha were obtained in good yields. Even the oxime 1i,
3
1
H
H
H
O
O
O
X = 4-OMe, 3ba, 70%
X = 4-Me, 3ca, 63%
O
O
O
N
N
N
X = 4-F,
3da, 59%
Ph
Ph
Ph
3ea
3fa
3ga
X = 4-CF3,
X = 3-OMe,
X = 3-Br,
X = 2-Br,
, 61%
, 68%
, 72%
R1
Ph
2
R1 = OMe,
R1 = F,
, 58%
3ka, 66%
3ha
, 62%
O
3ja
X
3
3ia, 64%
4
which had
a
furanyl substituent, gave the
H
corresponding product 3ia in 64% yield. The R1
group in the aryloxy moieties was not only
compatible with methoxy, fluoro, and bromo groups
but also with two methyl groups affording the
products 3ja-3ma in good yields. The R3 group at the
terminal position of the alkene in the oxime could be
a benzyl or phenyl group, which provided 3na and
3oa bearing three continuous stereocenters in 66%
and 84% yields as single isomers, respectively. The
structure of compound 3oa was determined by X-ray
diffraction, which indicated that it was a cis-isomer
based on the relative configuration of its styrenyl,
proton, and phenyl groups.[21] The reaction also
tolerated various functional groups present in both
oxime and arylboronic acid and delivered the desired
cycloadducts 3pa, 3ql, and 3el in good yields. In
addition to the R2 group bearing styrenyl groups, the
R2 group could also be present with phenyl group and
afford 3ra in 62% yield. However, when oximes 1s
with a methyl and 1t with a hydrogen at the R2 group,
compounds 3sa and 3ra were not observed because
the Chan-Lam reaction of these types of oximes with
phenylboronic acid 2a did not occur.[22]
Bn
H
H
O
O
O
O
N
O
O
N
N
Ph
Ph
Ph
Br
Me
Ph
Ph
Me
Ph
, 66%
3na
3ma, 54%
3la
, 66%
Ph
H
H
O
O
O
O
N
N
Ph
Ph
Br
Ph
3oa, 84%
Br
3pa, 64%
H
H
H
O
O
O
O
O
O
N
N
N
R2
Ph
Br
Br
Br
R2 = Ph,
, 62%
3ra
R2 = Me, 3sa, 0%
R2 = H, 3ta, 0%
Br
F3C
3ql, 53%
3el, 45%
a)
Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol),
Cu(OAc)2 (20 mol%), methylene blue (5 mol%), DCE (3.0
mL), pyr (0.9 mmol, 3.0 equiv.), 17 W white LED, in air,
30 ˚C, 36−72 h; b) isolated yield.
Table 3. Substrate scope of oximes 1.a,b
To better understand the mechanism, control
experiments were performed (Scheme 2). Nitrone 4aa
could not be converted to 3aa in the presence of
Cu(OAc)2 without 17 W white LED light whereas
3aa was obtained in 82% yield without Cu(OAc)2 in
the presence of 17 W white LED light (Scheme 2-1
and 2-2). These results indicated that visible light did
promote the cycloaddition while the copper additive
did not catalyze the cycloaddition. As shown in
Scheme 2-3, 20 mol% of Cu(OAc)2 delivered 4aa in
35% yield, although a 73% yield was obtained using
1.0 equiv. of Cu(OAc)2 and no white LED.
Combining Cu(OAc)2 with visible light afforded 3aa
in 80% yield. These results suggested that visible
light promoted both the Chan-Lam reaction and the
cycloaddition step. When 1a and 2a were subjected to
the standard conditions in the presence of N2, 4aa and
3aa were not detected, and only 1a was recovered,
demonstrating that the air played an important role
(Scheme 2-4). When 1.0 equiv. of 9,10-
dimethylanthracene was added, the yield of 3aa
dropped to 56%, and the trapped product 9,10-
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.202100448
Advanced Synthesis & Catalysis
dimethyl-9,10-dihydro-9,10-epidioxgeanthracene was
to produce 3aa and return the MB∙ radical to the
observed
(Scheme
2-5).
Because
9,10-
ground state (i.e., MB+).
dimethylanthracene is a typical singlet oxygen
quencher, we proposed that singlet oxygen was the
key species promoting the oxidation of Cu(I) to Cu(II)
to finish the catalytic cycle.
H
O
O
OAc
Pyr
(III)
O
N
Ph
Ph
O
Cu(I)
Cu
Ph
O
N
O
Pyr
Ph
(II)
D
N
Ph
Ph
Cu
O
Ph
O
H
C
Cu(II), O2
N
MB
O
B
O
Ph
O
3aa
Cu(OAc)2 (20 mol%)
pyr, DCE, rt
Ph
O
N
N
photoredox
catalysis
1)
Ph
A
Ph
Chan-Lam reaction
MB+
4aa
Ph
3aa
H
Cu(I)
*MB+
4aa
Ph
MB+
1a + 2a + Pyr
hv
1O2
3O2
hv
O
17 W white LED
methylene blue (5 mol%)
O
Cu(II)
O
O
N
N
2)
*MB+
DCE, rt
82% yield
Ph
Ph
Ph
4aa
3aa
Scheme 3. Proposed mechanism.
O
conditions
OH
Ph
O
methylene blue (5 mol%)
O
N
O
N
2a
+
3)
Pyr, DCE, rt
air
Ph
N
O
Ph
Ph
The operational simplicity of the one-pot Chan-
Lam reaction and cycloaddition cascade has
Ph
3aa
1a
4aa
yield
conditions
significant
potenial
for
preparing
yield
-
Cu(OAc)2 (20 mol%), without light
Cu(OAc)2 (1.0 equiv.), without light
Cu(OAc)2 (20 mol%), 17 W white LED
35%
73%
<5%
chromenoisoxazolidines with an economic and green
protocol, particularly if it could be scaled up. As
shown in Scheme 4, 1.0 mol of 1a (0.279 g) reacted
with 2a under the optimized conditions after 36 h.
Pure 3aa was obtained in 86% yield (0.305 g)
following extraction and recrystallization procedures
without requiring flash column chromatography.
When 9 mmol of oxime 1a (2.5 g) was allowed to
react with 2a under the standard conditions, 2.099 g
of 3aa was obtained (66% yield) after purification by
the same method. This simple operation avoided
conventional purification procedures and provided a
green approach to reduce waste.
-
80%
O
Cu(OAc)2 (20 mol%)
OH
O
O
N
Ph
O
methylene blue (5 mol%)
O
N
2a
2a
+
+
4)
5)
Ph
Ph
17 W white LED
Pyr, DCE, rt
N2
N
Ph
O
Ph
Ph
1a
4aa (<5%)
3aa (<5%)
Me
Cu(OAc)2 (20 mol%)
OH
N
methylene blue (5 mol%)
O
O
4aa
3aa
+
+
+
17 W white LED
Pyr, DCE, rt, air
Me
<5%
56%
Me
observed
1a
Me
Scheme 2. Mechanistic studies.
H
OH
Cu(OAc)2 (20 mol%)
methylene blue (5 mol%)
O
O
N
O
N
+
PhB(OH)2
2a
Ph
white LED (17 W )
pyr, DCE, rt
Although the mechanism was not definitely
elucidated, a reasonable mechanism for the formation
of 3aa from 1a and 2a was proposed (Scheme 3).
Initially, the Cu(II) catalyst undergoes ligand
exchange and transmetalation between oxime 1a and
phenylboronic acid 2a with pyridine (pyr) as base and
Ph
Ph
1a
3aa
0.279 g, 1 mmol extraction and recrystallization
2.500 g, 9 mmol extraction and recrystallization
0.305 g, 86% yield
2.099 g, 66% yield
N-ligand
to
generate
intermediate
A.
Scheme 4. Gram-scale preparation and purification of
product 3aa
Disproportionation of the Cu(II) intermediate A in the
presence of air affords Cu(III) species B and releases
Cu(I) species, which undergoes reductive elimination
to give nitrone 4aa and a Cu(I) species.[12, 23] The
Cu(I) species can then be reoxidized to a Cu(II)
species by the singlet oxygen (1O2) produced by the
photosensitization with the excited state of methylene
blue *MB+. Concurrently, photoirradiation of ground
state methylene blue MB+ generates the triplet
excited state *MB+, which is reductively quenched by
nitrone 4aa, generating a radical cation C and a semi-
reduced MB radical (MB∙).[24] Then, C undergoes
intramolecular radical addition to form the
chromenoisoxazolidine radical cation D, which
rapidly undergoes single electron transfer reduction
To study the utility of chromenoisoxazolidines,
several reductive conditions were evaluated. As
shown in Scheme 5-1, treating 3aa with Fe/HOAc in
DCM at 40 C afforded compound 5aa in 46% yield,
whereas compounds 6aa and 7aa were obtained in
72% and 12% yields, respectively, after treating 3aa
with Zn/HOAc instead. Additionally, 3la and 3oa
were converted to the corresponding products 6la
(78% yield) and 7la (21% yield), and 6oa (54% yield)
and 7oa (25% yield), respectively. It is known that
estrone-derived arylboronic acid 2q can be easily
prepared by Lee’s method in three steps.[25] When
5
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10.1002/adsc.202100448
Advanced Synthesis & Catalysis
white LED) at room temperature for 36−72 h (monitored
by TLC). At this time, the solvent was removed under
reduced pressure and the crude product was purified by
flash column chromatography (the crude residue was dry
loaded with silica gel, 1/20 to 1/10, ethyl acetate/petroleum
ether as the eluent) to afford chromeno[4,3-c]isoxazole 3.
arylboronic acid 2q and oxime 1a reacted under the
optimized conditions, the desired estrone-derived
chromenoisoxazolidine 8 was afforded in 74% yield
with 1:1 diastereoselectivity (Scheme 5-2).
3
1) N-O bond cleavage of
R2
H
Acknowledgements
O
Fe/HOAc
DCM, 40 °C
O
O
O
This work was supported by the financial support from NSFC
(21871062), and the “One Thousand Young and Middle-Aged
College and University Backbone Teachers Cultivation
Program” of Guangxi is greatly appreciated. We also thank
Suzanne Adam, PhD, from Liwen Bianji, Edanz Editing China
(www.liwenbianji.cn/ac), for editing the English text of this
manuscript.
N
Ph
R1
Ph
R1 = R2 = H
5
5aa, 46%
Ph
3
R2
H
R2
H
H
OH
Ph
O
OH
Ph
Zn/HOAc
DCM, 40 °C
O
+
R1
5
R1
5
7
References
6
R1 = H, R2 = H, 6aa (72%), 7aa (12%)
R1 = 5-Br, R2 = H, 6la (78%), 7la (21%)
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This article is protected by copyright. All rights reserved.

10.1002/adsc.202100448
Advanced Synthesis & Catalysis
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7
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10.1002/adsc.202100448
Advanced Synthesis & Catalysis
RESEARCH ARTICLE
R3
O
Visible Light Promoted Chan-Lam Reaction and
Cycloaddition to Prepare Chromeno[4,3-
c]isoxazolidines in One-pot Reaction
R3
H
OH
O
Cu hv
N
O
ArB(OH)2
+
N
open air, rt
R2
R1
R1
R2
Ar
Adv. Synth. Catal. Year, Volume, Page – Page
O
Me
30 examples
26% - 84% yields
Ph
H
H
Jie Zhao, Bing-Qing Huang, Bin-Can Zhu, Xiao-
Pan Ma*, and Dong-Liang Mo*
H
O
N
O
H
74% yield in one step
8
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