A new route to substituted furocoumarins via copper-catalyzed cyclization between 4-hydroxycoumarins and ketoximes

Article abstract of DOI:10.1039/c8ob01064a

A new route to substituted furocoumarins via copper-catalyzed cyclization between 4-hydroxycoumarins and ketoximes was developed. CuBr₂ exhibited higher activity than other copper salts, affording the desired furocoumarins in high yields. The transformation proceeded readily in the absence of stoichiometric external oxidants. The significance of this synthetic strategy would be (1) the easily available starting materials; (2) low cost catalyst CuBr₂; and (3) being without stoichiometric external oxidants. This protocol is complementary to previous approaches in the synthesis of substituted furocoumarins.

Full text of DOI:10.1039/c8ob01064a

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A new route to substituted furocoumarins via
copper-catalyzed cyclization between
Cite this: DOI: 10.1039/c8ob01064a
4-hydroxycoumarins and ketoximes†
Received 7th May 2018,
Accepted 25th June 2018
Tuong A. To,
Nam T. S. Phan
Yen H. Vo, Anh T. Nguyen, Anh N. Q. Phan, Thanh Truong
*
and
DOI: 10.1039/c8ob01064a
rsc.li/obc
A new route to substituted furocoumarins via copper-catalyzed coumarin (1a) and propiophenone O-acetyl oxime (2a) was
cyclization between 4-hydroxycoumarins and ketoximes was explored (Scheme 1). The ketoxime was also the internal
developed. CuBr2 exhibited higher activity than other copper salts, oxidant for the system,19 and no stoichiometric external
affording the desired furocoumarins in high yields. The transform- oxidant was required for this transformation. It was observed
ation proceeded readily in the absence of stoichiometric external that 2-methyl-3-phenyl-4H-furo[3,2-c]chromen-4-one (3aa) was
oxidants. The significance of this synthetic strategy would be (1) produced as the major product in the presence of a copper
the easily available starting materials; (2) low cost catalyst CuBr2; salt.
and (3) being without stoichiometric external oxidants. This proto-
The reaction conditions were consequently screened to
col is complementary to previous approaches in the synthesis of improve the yield of the desired product (Table 1). The reaction
substituted furocoumarins.
was conducted at 100 °C in toluene under an argon atmo-
sphere for 1 h, with 1 equivalent of 2a, in the presence of
5 mol% catalyst. A series of copper salts were utilized as cata-
lyst (entries 1–7, Table 1), and CuBr2 emerged as the best
option, with 76% yield being obtained (entry 7, Table 1). CuBr
and Cu(OAc)2 were also alternative catalyst for the transform-
ation, affording 3aa in 75% and 74% yields, respectively. Other
copper salts displayed lower catalytic efficiency. One important
issue to be studied for the cyclization reaction between 1a and
2a was the solvent (entries 8–16, Table 1). The reaction was
performed in different solvents, and among numerous sol-
vents, toluene should be the solvent of choice, generating the
furocoumarin in 76% yield (entry 8, Table 1). Polar aprotic sol-
vents like DMF and DMSO were completely inappropriate for
this reaction. Additionally, the reaction was considerably regu-
lated by the reactant molar ratio (entries 17–20, Table 1). The
yield of 3aa was improved to 87% for the reaction utilizing 1.5
equivalents of 2a (entry 19, Table 1). Furthermore, it was
observed that the transformation was remarkably influenced
by the temperature (entries 21–24, Table 1). The reaction was
performed in toluene under an argon atmosphere for 1 h, with
1.5 equivalents of 2a, in the presence of 5 mol% CuBr2 catalyst
The coumarin skeleton exists in numerous natural products,
pharmaceuticals, food additives, and functional materials.1–5
Furocoumarins, a privileged family of heterocyclic fused cou-
marin derivatives, have attracted remarkable attention of both
pharmacologists and chemists due to a wide spectrum of bio-
logical activities.6–11 Consequently, several synthetic protocols
have been developed to achieve these bicyclic scaffolds. Bankar
et al. previously demonstrated an approach towards furocou-
marins by using cascade reaction sequences.12 Zhou et al. per-
formed a visible-light promoted photoredox neutral coupling
between 3-bromo-4-hydroxycoumarins and alkynes to produce
furocoumarins.13 Cheng et al. pointed out that these skeletons
were generated by a Pd(OAc)2-catalyzed intramolecular cross
dehydrogenative coupling transformation.14 Dey and Hajra
reported the synthesis of furocoumarins via FeCl3/ZnI2-cata-
lyzed intermolecular coupling of 4-hydroxycoumarins with
alkynes.15 Ketoximes were rarely utilized in traditional organic
chemistry, and the advantages of these structures have recently
been verified.16–21 In this article, we would like to describe a
new route to substituted furocoumarins via copper-catalyzed
cyclization of 4-hydroxycoumarins with ketoximes, in which
the ketoxime functioned as both a reactant and an internal
oxidant. Initially, the cyclization reaction between 4-hydroxy-
Faculty of Chemical Engineering, HCMC University of Technology, VNU-HCM, 268 Ly
Thuong Kiet, District 10, Ho Chi Minh City, Vietnam. E-mail: ptsnam@hcmut.edu.vn
†Electronic supplementary information (ESI) available: Experimental procedures
and characterization data of products. See DOI: 10.1039/c8ob01064a
Scheme 1 The cyclization reaction between 4-hydroxycoumarin and
propiophenone O-acetyl oxime.
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Table 1 Screening of reaction conditionsa
Reactant
ratio
Temp.
(°C)
Yieldb
(%)
Entry
Catalyst
Solvent
1
2
3
4
5
6
7
CuCl
CuBr
CuI
CuF2
CuCl2
CuBr2
Cu(OAc)2
Toluene
1 : 1
100
59
75
38
66
37
76
74
8
9
CuBr2
Toluene
p-Xylene
PhCl
DCB
DMSO
DMF
DEC
n-BuOH
Dioxane
1 : 1
100
76
65
64
38
1
4
59
9
10
11
12
13
14
15
16
Scheme 2 Control experiments.
1
1,1-diphenylethylene, and the radical coupling products were
detected by GC-MS (Scheme 2b and c). In another experiment,
2a was stirred under standard conditions followed by adding
1a after 10 min (Scheme 2d). 44% conversion of 2a was
recorded after 10 min and 82% yield of 3aa was obtained when
reaction was completed. These results revealed that the radical
process of the reaction might start by the reaction of 2a and
copper catalyst.
On the basis of these results and previous reports in the lit-
erature, a plausible reaction mechanism was proposed for the
copper-catalyzed cyclization reaction between 1a and 2a to
form 3a (Scheme 3). Initially, iminium radical A was generated
17
18
19
20
CuBr2
CuBr2
Toluene
Toluene
Toluene
1.5 : 1
1 : 1
1 : 1.5
1 : 2
100
83
76
87
86
21
22
23
24
1 : 1.5
RT
80
100
120
3
14
87
91
25
26
27
28
29
—
1 : 1.5
120
3
91
91
91
91
CuBr2 (1%)
CuBr2 (2.5%)
CuBr2 (5%)
CuBr2 (10%)
a Reaction conditions: 4-Hydroxycoumarin (0.2 mmol); catalyst (5%
mol); solvent (1 mL); argon atmosphere; 1 h. b GC yield of 3aa.
at different temperatures. The yield of the desired product was
upgraded to 91% when the temperature was boosted to 120 °C
(entry 24, Table 1). Moreover, the catalyst amount displayed a
significant impact on the reaction (entries 25–29, Table 1). It
should be mentioned that only 3% yield was detected in the
absence of CuBr2, confirming that the copper salt was crucial
for the transformation (entry 25, Table 1). Nevertheless,
extending the catalyst amount to 10 mol% did not improve the
yield.
To gain insight into the reaction pathway, some control
experiments were carried out (Scheme 2). It should be noted
that 3aa was not produced in the presence of (2,2,6,6-tetra-
methylpiperidin-1-yl)oxy (TEMPO) as
a radical scavenger
(Scheme 2a). This observation verified that the cyclization reac-
tion progressed via a radical pathway, and the combination of
TEMPO with radical species produced during catalytic cycle
would stop the transformation. In the next two experiments,
we tried to trap the radical produced by 2a using TEMPO and Scheme 3 Plausible reaction mechanism.
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Table 2 (Contd.)
Table 2 The synthesis of substituted furocoumarins via copper-cata-
lyzed cyclization of 4-hydroxycoumarins with ketoximesa
Entry Reactant 1
16
Reactant 2
Product
Yieldb (%)
73
Entry Reactant 1
1
Reactant 2
Product
Yieldb (%)
81
17
18
77
75
2
3
4
79
89
60
a Reaction conditions: 4-Hydroxycoumarins (0.2 mmol); ketoximes
(0.3 mmol); CuBr2 catalyst (1 mol%); toluene (1 mL); argon atmo-
sphere; 120 °C; 1 h. b Isolated yield.
5
6
7
8
80
75
70
81
by oxidation of CuII to AcOCuIII, and this radical was rapidly
tautomerized to B.22–24 The phenolic radical C was then
formed via a single-electron-transfer (SET) process between
AcOCuIII and 1a, releasing AcOH and regenerating the CuII
species back to the catalytic cycle. Subsequently, the inter-
mediate product D was produced by the radical coupling reac-
tion of B and C. The intramolecular nucleophilic addition of
C-3 to the imine group consequently occurred under in situ
AcOH catalysis, creating intermediate product E.25 Finally,
NH3 was eliminated from E, producing the furocoumarin
product 3aa, and then neutralized by AcOH.
The research scope was consequently expanded to the syn-
thesis of several substituted furocoumarins via copper-cata-
lyzed cyclization of 4-hydroxycoumarins with ketoximes
(Table 2). The reaction was performed in toluene at 120 °C
under an argon atmosphere for 1 h, with 1.5 equivalent of
9
77
57
49
10
11
ketoxime, in the presence of
1 mol% CuBr2 catalyst.
Furocoumarins were subsequently purified on silica gel by
column chromatography.
Following this protocol, the reaction between 1a and 2a
afforded 3aa (entry 1, Table 2) in 81% yield. Propiophenone
O-acetyl oximes containing a substituent on benzene ring were
also reactive towards the cyclization reaction. Indeed, 3ab
(entry 2, Table 2), 3ac (entry 3, Table 2), and 3ad (entry 4,
Table 2) were generated in 79%, 89%, and 60% yields, respect-
ively. Moving to substituted 4-hydroxycoumarins, 80% yield of
3ba (entry 5, Table 2) was obtained for the case of 1b.
Similarly, 3ca (entry 6, Table 2), 3da (entry 7, Table 2), and 3ea
(entry 8, Table 2) were achieved in 75%, 70%, and 86% yields,
respectively. Additionally, acetophenone O-acetyl oximes were
also reactive in this transformation, and corresponding furo-
coumarins (products 3ae to 3ak, entries 9–15, Table 2) were
obtained in moderate to good yields ranging from 49% to
12
13
14
76
79
66
15
86
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86%. This transformation also worked on heteroaryl ketoxime,
yielding 3ak in 86% (entry 15, Table 2). Other 4-substituted
products were synthesized using this protocol (entries 16 and
17, Table 2). 4-Ethyl derivative 3al, and 4-phenyl derivative
3am were generated in 73%, and 77% yields, respectively.
Interestingly, our catalytic system was also efficient for ali-
phatic ketoxime ester, proving by 75% yield of 3an when 2n
was utilized (entry 18, Table 2).
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There are no conflicts to declare.
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