Copper-catalyzed radical/radical cross-coupling of ketoxime carboxylates with 4-hydroxycoumarins: A novel synthesis of furo[3,2-c]-coumarins

Article abstract of DOI:10.1016/j.tetlet.2018.09.007

A novel and efficient strategy for the synthesis of furo[3,2-c]coumarins has been developed via copper-catalyzed radical/radical cross-coupling of ketoxime carboxylates with 4-hydroxycoumarins. This redox-neutral reaction allows smooth and selective synthesis of 2-substituted, 3-substituted, 2,3-disubstituted and 2,3-fused polycyclic furo[3,2-c]coumarins.

Full text of DOI:10.1016/j.tetlet.2018.09.007

Accepted Manuscript
Copper-Catalyzed Radical/Radical Cross-Coupling of Ketoxime Carboxylates
with 4-Hydroxycoumarins: A Novel Synthesis of Furo[3,2-c]-coumarins
Mingchuang He, Zhaohua Yan, Wangyang Wang, Fuyuan Zhu Sen Lin
PII:
S0040-4039(18)31079-7
https://doi.org/10.1016/j.tetlet.2018.09.007
TETL 50246
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
12 July 2018
1 September 2018
3 September 2018
Please cite this article as: He, M., Yan, Z., Wang, W., Lin, F.Z.S., Copper-Catalyzed Radical/Radical Cross-Coupling
of Ketoxime Carboxylates with 4-Hydroxycoumarins: A Novel Synthesis of Furo[3,2-c]-coumarins, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.09.007
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Tetrahedron
1
Tetrahedron Letters
Copper-Catalyzed Radical/Radical Cross-Coupling of Ketoxime Carboxylates with 4-
Hydroxycoumarins: A Novel Synthesis of Furo[3,2-c]-coumarins
Mingchuang He Zhaohua Yan* Wangyang Wang Fuyuan Zhu Sen Lin*
College of Chemistry, Nanchang University, Nanchang 330031, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel and efficient strategy for the synthesis of furo[3,2-c]coumarins has been developed via
copper-catalyzed radical/radical cross-coupling of ketoxime carboxylates with 4-hydroxycoumarins.
This redox-neutral reaction allows smooth and selective synthesis of 2-substituted, 3-substituted, 2,3-
disubstituted and 2,3-fused polycyclic furo[3,2-c]coumarins.
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
Copper-catalyzed
ketoxime carboxylates
4-hydroxycoumarins
furo[3,2-c]-coumarins
Furo[3,2-c]coumarins belong to an important class of fused
coumarin derivatives and possess a variety of biological
activities, such as antifungicidal, insecticidal, anti-HIV and
anticancer activities (Figure 1).1 Therefore much effort has
been devoted to the efficient synthesis of furocoumarins. 4-
hydroxycoumarins were often used as starting material for
the synthesis of furocoumarins due to their easy availability
highly functionalized furocoumarins through Bu3P-induced
cyclization of 3-cinnamoyl-4-hydroxycoumarins. Although
many achievements have been made in this field, the
development of more efficient and mild synthetic strategy
for the preparation of diversified furocoumarins is still
highly desirable.
and
high
reactivity.2
included:
Methods
employing
tandem
4-
O-
In recent years, studies on metal-catalyzed reactions of ketoxime
carboxylates (also called oxime esters) have received intensive
attention from organic chemists.12 Their easy preparation along
with N-O bond as an internal oxidant made ketoxime
carboxylates serve as powerful synthons in the construction of a
variety of heterocycles.13 Chiba, 14 Guan,15 Yoshikai,12(c),16 Cui,17
Jiang,18 Chen19 and Deng20 respectively developed different
strategy to apply ketoxime carboxylates in the synthesis of
pyridine derivatives. Jiang reported the elegant syntheses of
hydroxycoumarins
alkylation/cyclization reaction;3 copper-mediated oxidative
annulation;4
Pd-catalyzed
oxidative
alkoxylation;5
DMSO/I2-mediated cascade dimerization, subsequent
cyclization and oxidation;6 CuBr2-catalyzed intramolecular
decarboxylative functionalization reaction;7 and Bu3P-
induced phosphorus zwitterions’ reaction with acid
chlorides.8 Furthermore, 3-alkynylchromones were also
often used to synthesize furocoumarins. Monteiro9 disclosed
pyrroles,21
pyrazoles,22
2-aminothiazoles,23
imidazo[1,2-
a]pyridine,24 enaminones25 and 2H-imidazoles26 through copper-
and iron-catalyzed coupling of oxime esters with various
functionalized reactants. Additionally, Bower,27 Lei28 and Zhou29
respectively disclosed copper-catalyzed Heck-like cyclization,
radical/radical oxidative phosphorylation and photoredox
reaction, which considerably extended the application scope of
oxime esters in organic synthesis. However, to the best of our
knowledge, the application of ketoxime carboxylates in the
synthesis of furans has not been published yet. On the other hand,
the radical/radical cross-coupling is a powerful tool for the
construction of complex molecules.30 However, due to the
instability of radicals, successful examples using radical/radical
cross-coupling strategy are scarce and still remain a great
challenge. According to Ingold-Fischer “persistent radical effect”,
a selective radical/radical crossing-coupling could be realized
when two different radical species were between a persistent
radical and a transient radical.31 The enolic oxygen radical of 4-
hydroxycoumarins could be regarded as a persistent radical
because of steric hindrance and good conjugation effect. On the
Pd-catalyzed
cyclofunctionalization
of
3-alkynyl-4-
methoxycoumarins with aryl halides yielding 2,3-
disubstituted furocoumarins. Hu10 developed copper-
catalyzed cascade reaction of 3-alkynylchromones leading to
2-substituted furocoumarins and 3-chloro-2-substituted-
furocoumarins. In 2015, Lin11 described the synthesis of
Figure 1. Structures of bioactive molecules containing furocoumarin
scaffold.

2
Tetrahedron
other hand, the C(sp3)-centered radical may be considered as a
transient radical due to its short half-life.25,28 Thus, we
conjectured that the selective cross-coupling of enolic oxygen
radical of 4-hydroxycoumarins and α-C(sp3) radical of ketoxime
carboxylate might form a new C-O bond. Herein, we disclosed a
copper-catalyzed synthesis of furo[3,2-c]coumarins through
radical/radical cross-coupling of ketoxime carboxylates with 4-
hydroxycoumarins. This method can selectively and smoothly
furnish 2-substituted, 3-substituted, 2,3-disubstituted and 2,3-
fused polycyclic furo[3,2]coumarins under mild conditions.
Figure 2. X-ray crystal structure of 3aa.
experimental data confirmed that 3-aryl substitued furo[3,2-
c]coumarin (3aa, 3-phenyl-4H-furo[3,2-c]chromen-4-one)
had been successfully synthesized.
To initiate our studies, we chose the reaction of acetophenone
oxime acetate 1a with 4-hydroxycoumarin 2a as a representative
example to investigate the optimum conditions (Table 1). To our
delight, the reaction occurred easily when CuCl2 was employed
as a catalyst, and the corresponding product 3aa was obtained in
57% isolated yield (Table 1, entry 1). The yield of 3aa was
obviously improved when the reaction was performed under an
atmosphere of argon (Table 1, entry 2). Subsequently, various
copper salts such as CuBr2, Cu(OTf)2, CuCl, CuBr and CuI were
tested, and the results revealed that copper(I) salts and copper(II)
salts are all capable of catalyzing this reaction (Table 1, entries 3-
7). However, the transformation did not occur in the presence of
CuO (Table 1, entry 8) or in the absence of copper salts (Table 1,
entry 9). We also tested oxidants tert-butyl hydroperoxide
(TBHP) and di-tert-butyl peroxide (DTBP), but they did not
improve this reaction. Then, several solvents such as acetonitrile,
toluene, and 1,2-dichloroethane were screened (Table 1, entries
10-12). 1,4-dioxane was found to be superior to the others and
was chosen as the optimal solvent. Next, the reaction temperature
was explored. The yield of 3aa was lower if the temperature
Based on the above optimized reaction conditions, the reaction
scope of various ketoxime carboxylates with 4-
hydroxycoumarins was next investigated (Table 2). Expectedly,
acetophenone O-benzoyl oxime was also transformed to desired
product 3aa in 85% isolated yield. Different para-substituted
acetophenone oxime acetates (-methyl, -methoxy, -bromo)
worked well to give the corresponding furocoumarins (3ba–3da)
with good yields. And 2-naphthyl methyl ketoxime acetate also
worked affording the desired product 3ea in 69% yield.
Pleasingly, the 2-alkyl-3-aryl substituted furocoumarins (3fa-3ga)
could be synthesized by corresponding ketone oxime acetates in
79% and 52% yield, respectively. Oxime acetate of α-tetralone
[3,4-dihydro-1(2H)-naphthalenone] gave the ordinary product
3ga in 52% yield. However, unexpectedly, when we used
cyclopropyl phenyl ketone oxime acetate as the substrate, the
Table 2. Synthesis of 3-aryl furocoumarinsa
o
o
decreased to 80 C or raised to 120 C (Table 1, entries 13-14).
Finally, when the reaction was performed under pure O2
atmosphere, the isolated yield of 3aa was only 22% (Table 1,
entries 15).
Furthermore, in order to directly and definitely confirm the
Table 1. Optimization of the Reaction Conditionsa
Entry
1b
2
[Cu]
Solvent
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
CH3CN
Toluene
DCE
Temp(oC)
100
100
100
100
100
100
100
100
100
100
100
100
80
Yield(%)
57
CuCl2
CuCl2
CuBr2
Cu(OTf)2
CuCl
86
3
74
4
60
5
71
6
CuBr
CuI
66
7
70
8
CuO
n.r.
n.r.
65
9
none
10
11
12
13
14
15c
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
69
53
dioxane
dioxane
dioxane
71
120
100
79
22
aRaction conditions: unless other noted, all reactions were performed with
1a (0.4 mmol), 2a (0.3 mmol), [Cu] (15 mol%), solvent (2 mL), 1 h,
under argon in a sealed tube; isolated yield. bunder air in a sealed tube.
cUnder pure O2.
aReaction conditions: 1 (0.4 mmol), 2 (0.3 mmol), CuCl2 (15 mol %), 1,4-
molecular configuration of 3aa, a single-crystal X-ray
diffraction experiment was performed (Figure 2). The
dioxane (2 mL), argon, 100 oC for 1 h in a sealed tube. Isolated yields.

Tetrahedron
same product 3ga was obtained in 60% yield. Moreover, oxime
acetates of 2-acetylfuran and 2-acetylthiophene were also
compatible to generate the desired corresponding products with
good yields (3ha-3ia). Next, substituted 4-hydroxycoumarins
were explored. Various products were generated by reactions of
6-methyl-4-hydroxycoumain with oxime acetates derived from
aromatic ketones, and yields ranged from 54% to 75% (3ab, 3eb-
3fb, 3hb-3ib). Similarly, 6-bromo-4-hydroxycoumarin could
react with the heteroarene-containing oxime acetates to afford the
corresponding products in moderate yields (3ac, 3fc, 3hc-3ic). 6-
chloro and 7-methoxy substituted 4-hydroxycoumarins
proceeded well with acetophenone oxime acetate 1a, the
corresponding products were isolated in 54% and 78% yields,
respectively (3ad-3ae). The methodology was also applied to
alicyclic ketone oxime acetate to produce desired product 3ja
with 73% yield.
3
3ga and 3ja were almost completely transformed to the
corresponding products 4a and 4b (Scheme 1). 4b possesses the
whole scaffold of Coumestan, a naturally occurring compounds
(Figure 1).
To gain more insights into the mechanism of this process,
several control experiments were carried out (Scheme 2).
Furocoumarin product was not formed when radical
scavenger TEMPO (3 equiv.) or BHT (3 equiv.) was added.
Next, when TEMPO (3 equiv.) was added and the reaction
was stirred for 30 mins, products obtained were determined
by HRMS. The data revealed that two products
5 and 6 were
generated from the coupling of intermediate radicals.
To further our studies, we wondered if 2-aryl substituted
furocoumarins could be synthesized through this method.
Hence, we chose phenylacetaldehyde O-acetyl oxime as the
substrate and desired 5-phenyl furo[3,2-c]coumarin was
obtained successfully although with a low yield of 7%
(Table
fluorophenyl)ethanone O-acetyl oxime was taken to react
with 4-hydroxycoumarin, the desired product (Table 3, 3la
3,
3ka).
Then,
1-cyclopropyl-2-(2-
)
was generated smoothly in 59% isolated yield. Both 6-
Table 3. Synthesis of 2-aryl furocoumarinsa
Reaction conditions: 1a (0.4 mmol), 2a (0.3 mmol), CuCl2 (15 mol %), 1,4-
dioxane (2 mL), TEMPO (3 equiv.), BHT (3 equiv.), under argon, at 100 oC
for 1 h in a sealed tube.
Scheme 2. Control experiments.
aReaction conditions: 1 (0.4 mmol), 2 (0.3 mmol), CuCl2 (15 mol %), 1,4-
Furthermore, a stable product
resulting from the trapping of the radical of 4-
hydroxycoumarins by BHT. These experiments indicated
7 was isolated in 20% yield
dioxane (2 mL), argon, 100 oC for 1 h in a sealed tube. Isolated yields.
methyl and 6-bromo-4-hydroxycoumarin also could react
with 1-cyclopropyl-2-(2-fluorophenyl)ethanone O-acetyl
oxime to provide the corresponding products in moderate
that
a
radical process may be involved in this
transformation.
yields (Table 3, 3mb, 3nc).
Based on these experimental results along with Lei’s previous
reports28, a plausible reaction mechanism is outlined in Scheme 3.
The first step of this reaction is that 4-hydroxycoumarin is
oxidized by Cu2+ to generate enolic oxygen radical A and Cu+.
The oxime acetate is reduced by Cu+ to generate iminium radical
B, which immediately isomerizes to α-C(sp3) radical C directly
In consideration of difficulty in the synthesis of the full
conjugated aromatic structures, new product 3ga as well as 3ja
was treated respectively with oxidant 2,3-dicyano-5,6-
dichlorobenzoquinone (DDQ) in expectation of formation of the
corresponding fully aromatized product. Gratefully, when the
o
reactions were performed at 100 C, under argon for hours, both
Reaction conditions: (1) 3ga (0.3 mmol), DDQ (2 equiv.), solvent (2 mL),
100 oC, under argon for 3 h. (2) 3ja (0.3 mmol), DDQ (3 equiv.), solvent (2
mL), 100 oC, under argon for 12 h.
Scheme 3. Possible reaction mechanism.
Scheme 1. The dehydrogenation of products 3ga and 3ja.

4
Tetrahedron
13. (a) F. W. Patureau, F. Glorius, Angew. Chem. Int. Ed., 2011,
after the oxidation of 4-hydroxycoumarin. Then, selective
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builds a new C-O bond to provide the intermediate D.
Subsequently, cyclization of intermediate
D generates an
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intermediate E, which is finally deaminated to afford the product
3.
Conclusions
In conclusion, a novel and efficient strategy for furo[3,2-
c]coumarins has been developed via copper-catalyzed
radical/radical cross-coupling of ketoxime carboxylates with 4-
hydroxycoumarins. This process involved C-N/N-O/O-H bond
cleavages and C-O/C-C bond formations. Diversified
furocoumarines, such as 2-substituted furo[3,2]coumarins, 3-
substituted
furo[3,2]coumarins,
2,3-disubstituted
furo[3,2]coumarins and 2,3-fused polycyclic furo[3,2-
c]coumarins have been selectively and smoothly synthesized via
this methodology. This approach has more advantages such as
the use of environmentally friendly copper salts, no necessary
external oxidant, additives or ligands.
22. X. Tang, L. Huang, J. Yang, Y. Xu, W. Wu, H. Jiang,
Chem. Commun., 2014, 50, 14793.
Acknowledgments
23. X. Tang, Z. Zhu, C. Qi, W. Wu, H. Jiang, Org. Lett., 2016,
We are grateful for the financial support from the National
Natural Science Foundation of China (21362022).
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Tetrahedron
5
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A novel and efficient strategy for the synthesis of furo[3,2-
c]coumarins has been developed via copper-catalyzed
radical/radical cross-coupling of ketoxime carboxylates with 4-
hydroxycoumarins. This redox-neutral reaction allows smooth
and selective synthesis of 2-substituted, 3-substituted, 2,3-
Copper-Catalyzed Radical/Radical Cross-Coupling of Ketoxime Carboxylates with 4-Hydroxycoumarins: A
Novel Synthesis of Furo[3,2-c]-coumarins
Mingchuang He, Zhaohua Yan*, Wangyang Wang, Fuyuan Zhu, Sen Lin*
O
O
OAc
R2
O
O
R3
N
CuCl2
R3
+
R1
R1
1,4-dioxane
100oC, Ar
O
OH
R2
25 examples
54-85% yields

6
Tetrahedron
1. An example of copper-catalyzed radical/radical
cross-coupling.
2. Reaction of ketoxime carboxylate with 4-
hydroxycoumarins produces furan compounds.
3. Diverse furo[3,2-c]-coumarins were smoothly
synthesized in good yields.
4. A concise and efficient synthetic method for
furo[3,2-c]-coumarins was developed.