Copper-catalyzed tandem process: An efficient approach to 2-substituted-1,4-benzodioxanes

Article abstract of DOI:10.1039/c003691a

An efficient method for the preparation of various 2-substituted-1,4- benzodioxanes by CuBr-catalyzed tandem reactions of 2-((o-iodophenoxy)methyl) oxiranes with phenols has been developed. The reaction involves the ring-opening process of 2-((2-iodopheno

Full text of DOI:10.1039/c003691a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Copper-catalyzed tandem process: an efficient approach to
2-substituted-1,4-benzodioxanes†
Yunyun Liua,b and Weiliang Bao*a
Received 4th March 2010, Accepted 30th April 2010
First published as an Advance Article on the web 12th May 2010
DOI: 10.1039/c003691a
An efficient method for the preparation of various 2-
substituted-1,4-benzodioxanes by CuBr-catalyzed tandem re-
actions of 2-((o-iodophenoxy)methyl)oxiranes with phenols
has been developed. The reaction involves the ring-opening
process of 2-((2-iodophenoxy)methyl)oxirane followed by an
intramolecular C–O cross coupling cyclization.
1,4-benzodioxane compounds have also reasonably been widely
employed as building blockers for the synthesis of functional
heterocyclic compounds.6
Presently, there are different synthetic methodologies giving
access to 1,4-benzodioxanes. One of the most commonly applied
methods employs catechol as starting reactant, which furnishes
different 1,4-benzodioxane derivatives by incorporating proper
electrophilic species such as vicinal dibromides, epihalohydrin,
epoxides, a-halo Michael acceptors or bromoketones.7 The in-
tramolecular cyclization of pyrocatechol monoprop-2-ynyl ethers
or intermolecular cyclization of catechol and propargylic car-
bonates under palladium catalysis also lead to the production
of functionalized 1,4-benzodioxanes.8 The Diels–Alder reaction
between o-quinone and dienophile is another interesting prototype
of constructing 1,4-benzodioxane moiety.9 These aforementioned
synthetic routes, though practical as reported, are just applicable
for the preparation of 1,4-benzodioxanes of particular substitution
patterns. And some of them suffer from the limitation of low
reactant diversity, use of expensive reagents/catalysts or unsatis-
factory product yields. In this regard, developing new synthetic
methodologies which provide 1,4-dioxones of new functional
pattern and involve the use of cheap catalyst as well as readily
available starting materials are highly desirable.
During the past few years, the copper-catalyzed coupling re-
action between aryl halides and heteroatom-centered nucleophiles
for the formation of C–C or C–X (X = N, O, S, etc.) bond has been
successfully developed during the past few years.10 Recently, these
coupling reactions have displayed versatile applicability in the
tandem synthesis of tremendous heterocyclic compounds via one-
pot operation.11–13 Typically, the Cu-catalyzed cascade, one-pot
reactions for synthesis of indole derivatives,14,12d 3,4-disubstituted
isoquinolin-1(2H)-ones,12e N-acylpyrroles,11b benzoxazoles,15 2H-
1,4-benzoxazin-3-(4H)-ones11c etc. have been successfully devel-
oped and turned out to be extremely useful. Our group previously
developed a novel Cu-catalyzed cascade reaction to synthesize sub-
stituted 1,4-benzodioxanes in one-pot by employing o-iodophenol
and epoxide as starting materials (Eq a, Scheme 1).16 This kind of
Compounds containing 1,4-benzodioxane structures have received
special attention in chemical, medicinal and pharmaceutical re-
search, mainly due to their important biological activities and nat-
ural occurrence. Presently, there are numerous 1,4-benzodioxane
derivatives that have been reported with fantastic bioactivities
and some typical examples are outlined in Fig. 1. Spiroxatrine
A, with a high affinity for serotonin (5-hydroxytryptamine,
5-HT) receptor, has been shown to possess some neuroleptic
activity.1 N-Hydroxyureas (B) based on the 1,4- benzodioxane
template could act as inhibitors of 5-lipoxygenase,2 while 5-
benzylidene-thiazolidine-2,4-dione (C) is claimed to have glycogen
phosphorylase inhibitor activity.3 Some derivatives are recognized
as a- or b-blocking agents and could be used in antidepression or
antihypertension therapy, such as piperoxan (D) and so on.4 More
importantly, 1,4-benzodioxane has been found as the central unit
in many natural products of meritorious biological functions.5 Due
to their arguable value in biochemical and medicinal researches,
Fig. 1 Structures of some biologically important 1,4-benzodioxanes.
aDepartment of Chemistry, Xi Xi Campus, Zhejiang University, Hangzhou,
Zhejiang 310028, P. R. China. E-mail: wlbao@css.zju.edu.cn; Fax: (+86)
-571-88273814
bCollege of Chemistry and Chemical Engineering, Jiangxi Normal Univer-
sity, Nanchang, Jiangxi 330022, P. R. China
† Electronic supplementary information (ESI) available: General experi-
mental procedures, spectral data and copies of 1H and 13C NMR spectra.
See DOI: 10.1039/c003691a
Scheme 1 Synthesis of 1,4-benzodioxanes via different Cu-catalyzed
tandem reactions.
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Table 1 Optimization on reaction conditions for the tandem synthesis of
strategy has also later been proved to be applicable for the one-
pot synthesis of aza heterocyclic analogs of 1,4-benzodioxanes by
other chemists.17 In despite of the usefulness of this protocol, the
formation of two hardly isolable isomers is the key problem in our
previous work. Upon the analysis of the reaction, we noticed that
the isomer occurs because the nucleophilic phenol is capable of
attacking two eletrophilic sites in the epoxide (Eq a, Scheme 1).
In order to further improve the regioselectivity of the reaction,
we envisioned that limiting the selectivity of nucleophile attack
to the sites of epoxide may be effective to achieve this goal;
therefore, a new synthetic route has been designed as showing
in Eq b (Scheme 1). By elaborating the methylene epoxide group
to the o-iodidephenol, the functionalized reactant 1 is expected
to furnish 1,4-benzodioxanes with considerably higher selectivity
in the presence of additional nucleophile and copper catalyst
since the formation of another potential isomer with seven-
membered heterocyclic structure is not favored by the reaction
kinetics. More notably, the 1,4-benzodioxane product 3 provided
by this new protocol bears the methylene group, which is the
common feature of the most bioactive 1,4-benzodioxane scaffolds
(Fig. 1).
In the initial study, 2-((o-iodophenoxy)methyl)oxirane 1a and
phenol 2a were subjected for the desired transformation at the
presence of CuI/Cs2CO3 and ligand L1 in DMF, we were glad to
find that the target 1,4-benzodioxane 3a was formed and isolated
in 35% yield after 48 h reaction at 110 ◦C (Table 1, entry 1).
This result encouraged us to optimize the reaction parameters
to enhance the yield of 3a on this template reaction. Firstly, some
typical ligands frequently used for Cu-catalyzed coupling reactions
have been screened. Among the seven selected candidates, 1,10-
phenanthroline afforded the highest product yield (entries 1–7).
Then, several different Cu(I) catalysts have been respectively tested,
it is interesting that CuBr turned out to bear the best catalytic
efficiency (entries 6 and 8–10). In the consequent experiments,
we evaluated the influence of base additive on the reaction and
the results confirmed that Cs2CO3 was the most proper choice
(entries 6 and 11–15). Finally, a brief study on other related
reaction conditions including solvent and reaction temperature
were performed, the results implied that using DMA as solvent at
120 ◦C was able to further enhance the yield of 3a (entries 16–22).
So, the general reaction conditions were established as those used
in entry 22 (Table 1).
1,4-benzodioxanesa
Entry
Catalyst
Ligand
Solvent
Base
Yield(%)b
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
Cu2O
CuI
CuI
CuI
L1
L2
L3
L4
L5
L6
L7
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMA
DMF
Xylene
Toluene
DMA
DMA
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4·2H2O
KOH
35
Trace
27
21
Trace
49
15
59
51
53
9
10
11
12
13
14
15
16
17
18
19
20
21
22
35
30
K3PO4
DBU
37
CuI
CuI
NRc
43
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
19
57
46
49
51
67
76d
a Reaction conditions: Cat. (15 mol%), ligand (30 mol%), base (2 mmol),
phenol (1.2 mmol), (2-((o-iodophenoxy)methyl)oxirane (1.0 mmol), sol-
vent (2 mL), 48 h, 110 ◦C. b Isolated yield. c No reaction. d Reaction
temperature was 120 ◦C.
After confirming the obtainable satisfactory yield of this tandem
transformation, we were forwarded to investigate the application
scope of this new methodology. A class of different (2-((o-
iodophenoxy)methyl)oxiranes and various phenols have been
employed respectively for the reaction. Typical results from this
section are summarized in Table 2. As anticipated, all entries
in our experiments specifically gave the 1,4-benzodioxane as the
product while the isomers of type 4 were not detected. According
to the present results, the electronic nature of substituted (2-((o-
iodophenoxy)methyl)-oxiranes showed no observable influence on
the reaction process as both electron-deficient and electron-rich
(2-((o-iodophenoxy)methyl)oxiranes gave corresponding products
in similarly good yields (entries 12 and 16). On the other hand,
the property of the substitution group in the phenol exhibited
evident effect on the reaction efficiency. Generally, phenol sub-
strates bearing electron donating groups afforded corresponding
1,4-benzodioxanes in higher yields than those bearing electron
withdrawing groups (entries 2, 3, 7 and 13, 15). In addition,
the substitutions located in the ortho- or meta-sites also led to
slightly lower yield of the product (entries 2, 4, 5 and 13, 14).
These results suggest that the nucleophilicity of phenol component
directly impact the yield of the final products. The presence of
electron-withdrawing groups were tolerated, either at the para-
or at the ortho- position of the phenol (entries 9 and 10). It
is also noteworthy that disubstituted phenols and naphthol are
also well tolerated to this reaction by providing corresponding
1,4-benzodioxanes in moderate or good yields (entries 6, 8 and
11), which demonstrates the broad application scope of this
methodology.
In summary, we have developed a new tandem synthetic routes
to the novelly decorated 1,4-benzodioxanes. The reaction involves
in a cascade process of nucleophilic ring-opening and CuBr-
catalyzed intramolecular coupling transformation. All reactions
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Table 2 Scope of the sequential one-pot ring-opening/coupling
(t, J = 7.6 Hz, 2H), 7.02 (t, J = 7.6 Hz, 1H), 6.96–6.90 (m, 6H),
4.59–4.56 (m, 1H), 4.43 (dd, J = 1.4, 11.4 Hz, 1H), 4.30–4.22 (m,
2H), 4.19–4.15 (m, 1H); 13C NMR (100 MHz, CDCl3): d 158.26,
143.18, 142.91, 129.55, 121.74, 121.53, 121.40, 117.40, 117.25,
114.56, 71.34, 66.24, 65.34; IR: u = 3019, 2930, 2882, 1578, 1493,
1269, 1237, 1076, 745, 689 cm-1.
protocola
Entry
R1
R2
Product/yieldb
Notes and references
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Cl
H
p-Me
p-t-Bu
m-Me
o-Me
2,4-di-t-Bu
p-Cl
2,4-di-Cl
o-COCH3
p-CHO
2k/naphthol
H
3a/76
3b/79
3c/80
3d/77
3e/73
3f/70
3g/69
3h/57
3i/56
3j/61
3k/59
3l/79
3m/81
3n/77
3o/71
3p/73
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p-Me
m-Me
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H
a Reaction conditions: (2-((o-iodophenoxy)methyl)oxirane (1 mmol), phe-
nol (1.2 mmol), CuBr (15 mol%), 1,10-phenanthroline(30 mol%), Cs2CO3
(2 mmol), in DMA (2 mL) at 120 ◦C for 48 h. b Isolated yield.
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Experimental
General procedure for the synthesis of
2-substituted-1,4-benzodioxanes
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A Schlenk tube was charged with CuBr (22 mg, 15% mol), 1,10-
phenanthroline (57 mg, 30% mol), Cs2CO3 (650 mg, 2 mmol),
phenol (113 mg, 1.2 mmol), evacuated and backfilled with nitro-
gen. Then 2-((2-iodophenoxy)methyl)oxirane (276 mg, 1.0 mmol),
DMA (2 mL) were successively added. The reaction tube was
◦
quickly sealed and the contents were stirred at 120 C for 48 h.
Then the cooled reaction mixture was dissolved in H2O and ex-
tracted with Et2O. The combined organic layer was dried (MgSO4).
The product was further purified by column chromatography
(silica gel, PE-EtOAC).
2-Phenoxymethyl◦-2,3-dihydrobenzo[1,4]dioxin
(3a). White
solid, m.p. 35–36 C3; 1H NMR (400 MHz, CDCl3): d 7.33
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The Royal Society of Chemistry 2010
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