Direct synthesis of enaminone functionalized biaryl ethers by CuI-catalyzed O-arylation of enaminone functionalized phenols

Article abstract of DOI:10.1039/c1ob05947e

The O-arylation of o-enaminone functionalized phenols, namely, (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-ones, has been achieved via a self-promoted process in the presence of CuI, which provided a class of new biaryl ethers bearing a reactive

Full text of DOI:10.1039/c1ob05947e

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Direct synthesis of enaminone functionalized biaryl ethers by CuI-catalyzed
O-arylation of enaminone functionalized phenols†
Jie-Ping Wan,* Chunping Wang and Yunyun Liu
Received 12th June 2011, Accepted 20th July 2011
DOI: 10.1039/c1ob05947e
The O-arylation of o-enaminone functionalized phenols,
namely, (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-
en-1-ones, has been achieved via a self-promoted process in
the presence of CuI, which provided a class of new biaryl
ethers bearing a reactive enaminone fragment. The reactions
were performed under mild conditions and the functionalized
biaryl ether products have been found as useful building
blocks for the assembly of heterocyclic compounds.
production of chemical waste have arisen since ligands are usually
used as additives and not recycled in most cases. On the other hand,
presently known C–O couplings still rely on harsh conditions in
the absence of a ligand. For example, Sperotto22 et al. reported
the ligand-free synthesis of b◦iaryl ethers by reacting phenols and
aryl halides in NMP at 160 C; Chan23 et al. achieved the same
transformation by refluxing DMF and using nBu4NBr as an addi-
tive and aryl iodides as aryl halides. To reconcile the contradiction
between harsh reaction conditions and the impact brought by
the ligand, a theoretically applicable tactic is making use of the
internal chelating effect of the reactants or solvents themselves
to carry out the coupling reactions under mild conditions via
self-promotion. A typical example of the type in C–O coupling
has been reported by Ma and coworkers. In their experiments,
an ortho-NHCOR substituted aryl halide successfully reacted
with phenols to give the corresponding biaryls under very mild
conditions. The ortho-NHCOR group was believed to provide
important chelating assistance during the coupling reactions.24
During our research in developing practical C–X coupling
methodologies, we have discovered that (E)-3-(dimethylamino)-
1-(2-hydroxyphenyl)prop-2-en-1-one 1a is an efficient ligand for
copper-catalyzed Ullmann-type coupling reactions of aryl halides
with N-heterocycles25 and tandem reactions of thiophenols with
aryl halides.26 During further investigation on 1, we discovered that
they are able to undergo self O-arylation to furnish enaminone
functionalized biaryl ethers in the presence of a copper catalyst
without using any additional ligand. Considering the interest of
both biaryl ethers and enaminone moieties,27–30 we envisioned that
a self-promoted C–O coupling method for the synthesis of these
biaryl ethers functionalized by an enaminone fragment might be
useful. Herein we wish to report our preliminary results on the self-
promoted C–O coupling reactions of enamiones 1 with aryl halides
to synthesize new biaryl ether derivatives under mild conditions.
The initial study was carried out based on the model reaction
between enaminone functionalized phenol 1a and iodide benzene
2a. Optimization results are summarized in Table 1. First, the
effect of different bases was studied. Among the screened bases,
Cs2CO3 exhibited the best promotion effect (Table 1, entries 1–7).
As for solvents, both DMF and DMSO displayed an inferior
mediating effect (Table 1, entries 8–9). Using an excess of phenol
1a was also attempted, but the yield of 3a was not enhanced (Table
1, entry 10). However, 1.5 eq mol of iodobenzene led to a higher
yield of 3a (Table 1, entries 11–12). Finally, prolonging the reaction
time to 24 h significantly increased the yield of 3a, while no further
The Ullmann-type C–O coupling reaction is one of the most
widely employed strategies for creating C–O bonds which link aryl
or other unsaturated carbons. The application of the traditional
Ullmann protocol is limited by harsh reaction conditions (up
to 200 ◦C) and the use of stoichiometric amounts of copper
catalyst.1–2 Numerous efforts have been made in recent decades
in order to eliminate the harsh conditions. Palladium catalysts
have been found to be capable of mediating the transformation
under mild conditions, but large scale application is also limited
by the high cost of palladium catalysts.3–5 In this regard, searching
for appropriate copper catalyst systems is still a central topic
in the research of Ullmann coupling reactions. An interesting
discovery is that nanoparticle copper catalysts are significantly
better catalysts than equivalent copper species of normal size
in catalyzing these reactions,6–9 however, nanoparticle catalysts
also suffer from the problem of high cost. Presently, employing
a ligand to activate the conventional low-cost commercial copper
catalysts (CuX, Cu2O, CuO etc.) is the most popular strategy in
these reactions. Using C–O coupling reactions, various molecules
such as biaryl ethers,10–12 oxazoles,13 benzoxazoles,14 xanthones,15
benzodioxines,16 benzoxazines,17 to name but a few, have been
sucessfully synthesized via copper catalysis with the assistance
of ligand. Biaryl ether is a substructure of special interest due
to its frequent occurrence in biologically functional molecules
with pharmaceutical activities,18–19 natural products,20 as well as
functional materials.21
Although the use of ligands is currently the foremost option
for satisfactory C–O coupling reactions, problems such as the
additional cost of ligand, tedious isolation processes and the
College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang, 330022, China. E-mail: wanjieping@gmail.com
† Electronic supplementary information (ESI) available: General experi-
mental information, characterization data of all products, copies of 1NMR
and 13C NMR spectra. See DOI: 10.1039/c1ob05947e
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Table 1 Optimization of the reaction conditionsa
Table 2 Synthesis of various enaminone functionalized biaryl ethersa
Yield (%)b
Entry
R1
R2
Product
Yield (%)b
Entry
Base
Solvent
Time (h)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
MeO
MeO
MeO
MeO
MeO
F
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
61
77
61
65
57
36
80
67
78
57
60
65
62
41
1
2
3
4
5
6
7
K2CO3
t-BuOK
K3PO4
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
12
12
12
12
12
12
12
12
12
12
12
12
24
36
29
10
—
4-Cl
4-Br
4-Me
4-MeO
3-CF3
H
4-Cl
4-Br
4-Me
4-MeO
4-Cl
4-Br
H
c
KOH
<5
—
—
43
—
—
42
38
48
61
59
NaHCO3
(CH3CH2)3N
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
8d
9d
10e
11f
12g
13g
14g
9
10
11
12
13
14
F
F
a Reaction conditions: Phenol
1 (0.50 mmol) and iodobenzene 2
a Unless otherwise specified, the general reaction conditions are: phenol
1a (0.5 mmol), iodobenzene 2a (0.6 mmol), 10 mol% CuI and 2 eq base
refluxed in CH3CN (5 mL) under N2 atmosphere. b Isolated yield ba◦sed
on 1a. c No product was obtained. d The reaction temperature was 100 C.
e Overdosed 1a (0.6 mol) was used to react with 2a (0.5 mmol). f The ratio
of 1a : 2a was 1 : 1 mol. g 0.75 mmol Iodobenzene was used.
(0.75 mmol), 10 mol % CuI and 1.0 mmol Cs2CO3 refluxed in 5 mL MeCN
for 24 h. b Isolated yield based on 1.
Table 3 Synthesis of enaminone functionalized biaryl ethers from aryl
bromidesa
enhancement was observed when the reaction time is prolonged
to 36 h (Table 1, entries 13–14). Therefore, the parameters shown
in entry 13 were chosen as the optimum conditions for further
studies.
The scope of this transformation was then investigated under
optimized reaction conditions. First, various iodobenzene deriva-
tives were reacted with different enaminone functionalized phenols
1 (Table 2). It was found that iodobenzenes containing either
electron withdrawing or electron donating groups tolerated the
coupling reactions well and provided corresponding biaryl ethers
with different phenols 1. As expected, iodobenzene having electron
withdrawing substitutions gave slightly better yields (Table 2,
entries 1–5), while the o-CF3 substituted iodobenzene gave a fair
result (Table 2, entry 6). Phenols 1 with different substitution
groups similarly provided fair to good yields of products (Table 2,
entries 7–14).
Entry
R1
Ar
Product
Yield (%)b
1
2
3
4
5
6
7
8
H
H
H
H
H
H
MeO
MeO
MeO
MeO
MeO
MeO
MeO
F
F
F
F
F
Ph
3a
3o
3p
3q
3r
3s
3g
3t
55
50
39
54
43
75
41
62
60
45
63
37
96
30
40
39
45
68
4-FC6H4
4-AcC6H4
2-MeC6H4
Naphth-2-yl
Pyridin-2-yl
H
4-FC6H4
4-AcC6H4
2-MeC6H4
3-NO2C6H4
Naphth-2-yl
Pyridin-2-yl
H
9
3u
3v
10
11
12
13
14
15
16
17
18
3w
3x
3y
3l
Next, the application scope of this methodology was further
extended to the reactions of aryl bromides. The obtained results
are shown in Table 3. Based on the results, aryl bromides are
also capable of serving as aryl donors to yield the corresponding
biaryl ethers 3, but the efficiency of the reaction is generally lower
than that of aryl iodides. Similarly to aryl iodide reactions, 3-
fluoro phenol 1c gave generally lower yields of products than
the unsubstituted phenol 1a and 3-methoxy phenol 1b (Table 3,
entries 1, 2, 4, 6 vs. 7, 8, 10, 13 and 14, 17, 16, 18). On the other
hand, compared to the full carbon aryl bromide, 2-bromopyridine
exhibited significantly superior reactivity and gave excellent yields
of biaryl ethers 3s, 3y, and 3ac (Table 3, entries 6, 13 and 18). All
4-AcC6H4
2-MeC6H4
4-FC6H4
Pyridin-2-yl
3z
3aa
3ab
3ac
a Reaction conditions: Phenol 1 (0.50 mmol) and bromobenzene 2
(0.75 mmol), 10 mol % CuI and 1.0 mmol Cs2CO3 refluxed in 5 mL MeCN
for 24 h. b Isolated yield based on 1.
was subjected to a three-component reaction with benzaldehyde
and thiourea. Unexpectedly, the three-component reaction did
not give the dihydropyrimidinone product 4a as in the case of
conventional enaminones in our previous study.29 Instead, the
isomeric heterocycle 1,3-thiazine 5a was obtained as a single
product (Scheme 1). This result suggested that the biaryl fragment
1
the products were clearly characterized by H, 13C NMR as well
as HRMS.
In order to examine the potential of biaryl ethers 3 as
building blocks in the synthesis of heterocyclic compounds, 3a
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the reaction was stirred for 10 h at 85 ◦C. After completion of the
reaction, 5 mL of water was added and the product was extracted
with EtOAc (8 mL ¥ 3). The combined organic layers were
dried over anhydrous Na2SO4. After filtration and evaporating
the organic solvent, the residue was purified by silica gel column
chromatography to afford 5a.
Acknowledgements
The authors gratefully acknowledge the financial support from the
Doctoral Start-up fund of Jiangxi Normal University (Nos. 3335
and 3336).
Scheme 1 Regioselective three-component synthesis of 1,3-thiazine using
biaryl ether 3.
Notes and references
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in the structure of 3a evidently modified the reactivity of this
enaminone synthon. This result also implies that biaryl ethers
3 are useful for the regioselective synthesis of new heterocyclic
products. Further studies on the general applications of enam-
inone functionalized nucleophiles initiated coupling reactions as
well as the regioselective three-component reactions involving 3
are presently ongoing in our laboratory.
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In summary, we have developed the first self-promoted O-
arylation reaction of enaminone functionalized phenols. This
transformation was practical for both aryl iodides and bromides
in reflux acetonitrile. The biaryl ether products displayed novel
regioselective reactivity by producing 1,3-thiazine heterocyclic
compounds in multicomponent reaction. This coupling method
is useful for the synthesis of these new biaryl ethers and further
demonstrated the function of the enaminone backbone as a ligand
in C–X coupling reactions.
Experimental section
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Typical procedure for the synthesis of biaryl ethers 3
A 25 mL round bottom flask was charged with 0.50 mmol of
phenol 1 and 0.05 mmol of CuI. Then, 0.75 mmol of aryl halide
and 1.0 mmol of Cs2CO3 were added. The mixture was stirred for
24 h under N2 in refluxing MeCN (5 mL). After cooling down to
room temperature, 5 mL of water was added, and the product was
extracted with EtOAc (10 mL ¥ 3). The combined organic layers
were dried overnight over anhydrous Na2SO4. Subsequently, the
organic solvent was removed in vacuo after filtration. The residues
were purified by silica gel column chromatography to afford the
corresponding product 3.
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Three-component synthesis of 1,3-thiazine 5a
In a 25 mL round bottom flask, 0.3 mmol of 3a, 0.3 mmol of
benzaldehyde and 0.36 mmol of thiourea were dissolved in 2 mL
DMF. Then, 0.45 mmol of TMSCl was injected into the flask and
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