Microwave-assisted aromatic C-O bond formation: A rapid and efficient method for the synthesis of aryl ethers

Article abstract of DOI:10.1246/cl.2008.202

A rapid and efficient aromatic C-O bond formation has been developed based on microwave-assistant, which is particularly useful for the intramolecular coupling of halides with alcohols. This method needs not the use of transition-metal catalyst. It was also demonstrated that the method can be used in the synthesis of bioactive natural flavans. Copyright

Full text of DOI:10.1246/cl.2008.202

202
Chemistry Letters Vol.37, No.2 (2008)
Microwave-assisted Aromatic C–O Bond Formation:
A Rapid and Efficient Method for the Synthesis of Aryl Ethers
Boyan Xu, Jijun Xue, Jianrong Zhu, and Ying LiÃ
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, P. R. China
(Received November 30, 2007; CL-071321; E-mail: liying@lzu.edu.cn)
A rapid and efficient aromatic C–O bond formation has been
results were found to the use of base. A 1:1 molar ratio of base
and BnOH is necessary, and more amount of base can not im-
prove the reaction obviously. So, we conclude that maximum
yield can be obtained with a molar ratio of 1:1.5:1.5 for the PhBr,
BnOH, and t-BuOK. As a control experiment, the same reaction
mixture was treated with conventional heating way under reflux
until PhBr disappeared (about 0.5 h), and the product was ob-
tained in 13% yield. This observation demonstrated the advant-
age of microwave radiation over conventional heating in terms
of shorting reaction time and, most significantly, improving
reaction yield (Scheme 2).
With optimized conditions in hand, we further investigated
the coupling reaction of different aryl halides with benzyl alco-
hol as shown in Table 2, it can be seen that both aryl chloride
(Entry 1) and aryl iodide (Entry 2) are effective for this coupling.
In these two Entries together with Entry 5 (Table 1), we only
found little by-products mixed with garbage that can not be sep-
arated by column chromatography, which we think that a small
quantity of DMSO takes part in the reaction as reported by Day
and Cram.8b Unexpectedly, only fluorine is substituted and the
yield is excellent when fluorine and bromine exist in one aryl
ring (Entry 3), which most probably proceeded via SNAr.
Then, we focused on the utility of this method in the intra-
molecular C–O bond formation. As can be seen in Table 3, 6-,
and 7-membered heterocycles were obtained in moderate to
good yield from the corresponding aryl halides, but 5-membered
heterocycle was not obtained somehow, which also gives a se-
developed based on microwave-assistant, which is particularly
useful for the intramolecular coupling of halides with alcohols.
This method needs not the use of transition-metal catalyst. It
was also demonstrated that the method can be used in the synthe-
sis of bioactive natural flavans.
Traditional methods for the preparation of Aryl ethers and
oxygen heterocycles include the Williamson ether synthesis,1 di-
rect nucleophilic substitution reactions,2 and the Ullman-type
coupling of alkoxides with aryl halides.3 A promising transfor-
mation used to construct these ethers or heterocycles involves
Cu or Pd-catalyzed C–O bond formation.4,5 Recently, the combi-
nation use of microwave irradiation and transition-metal cataly-
sis for the formation of several carbon–carbon and carbon–het-
eroatom bonds has been successfully demonstrated.6
In our work, we found that microwave irradiation of 1,3-di-
aryl-1-propanol 1 in the presence of t-BuOK can form flavan 2
without erosion of optical purity (Scheme 1). To our best knowl-
edge, this is the first time using microwave-assisted aromatic
C–O bond formation to synthesize natural aryl ether. Comparing
to the previous methods to synthesize flavan,7 this cyclization
way is more rapid and convenient. This coupling most likely
proceeded via a benzyne intermediate.8
Intriguing by our preliminary work, a detailed investigation
was done with the formation of aryl and cyclic aryl ethers under
irradiation of microwave. As a starting point for the development
of our method, we identified the optimized reaction conditions
using PhBr and benzyl alcohol. Firstly, solvents and bases were
screened. To be expectedly, a strong base works more efficiently
than the weak base (Entries 1–5 in Table 1). The most efficient
base was found to be t-BuOK (Entry 5 in Table 1), and DMSO
was found to be the best solvent (Entries 5–9 in Table 1). It is
found that five minutes is an appropriate reaction time under mi-
crowave radiation and more time can not promote the reaction
but makes more garbage. Then we studied by systematically
varying the molar ratio among aryl halides, alcohol, and base.
More BnOH can increase the conversion of PhBr. But when
the molar ratio of BnOH and PhBr is more than 1.5:1, the in-
crease of BnOH has no obvious effect to the reaction. A similar
t-BuOK
PhBr + BnOH
PhOBn
MW
Scheme 2. Optimization studies.9
Table 1. Influence on yields with different solvents and basesa
Yieldc
/%
Entryb
Base
Solvent
1
2
3
4
5
6
7
8
9
K2CO3
K3PO4
DMSO
DMSO
DMSO
DMSO
DMSO
Toluene
DMF
<1
<1
25
36
63
<5
9
NaNH2
NaOMe
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
OMOM
Br
MeO
OMOM
t-BuOK
MW
MeO
O
HMPA
Acetonitrile
13
5
OH
aAll reactions were carried out within 5 min, PhBr,
1.0 mmol; base, 1.5 mmol; and in 2-mL DMSO. Most
1
76% ee
2 76% ee
b
MOM = methoxymethyl
of the aryl halide (>90%) except Entry 5 which was
entirely transformed was recovered. Isolated yield.
c
Scheme 1.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.2 (2008)
203
Table 2. Direct coupling of aryl halides and benzyl alcohola
In our cases, benzyne intermediate is the most likely process
in the coupling of aromatic halides with alcohols as mentioned
previously. The fact that phenyl halides are more reactive than
the Entries in Table 3 (part starting materials were recovered)
under our experimental conditions is to be expected in view
of the more difficult generation of dehydrobenzene caused by
electron-richer aromatic ring.
In summary, an operationally rapid and efficient method
for the formation of aromatic C–O bond was developed. The
reaction would serve as a good complement to the existing
methodologies. It has been successfully used in the synthesis
of bioactive natural flavans and must be useful in synthesis of
more natural compounds.
Entry
Aryl Halide
Product
Time/min Yieldb/%
5
3
54
70
Cl
I
OBn
1
2
OBn
Br
Br
O
O
O
O
5
86
3
F
OBn
aFor a detailed experimental operation, see representative proce-
dure.9 bIsolated yield.
Table 3. Direct synthesis of cyclic aryl ethera
We are grateful for the financial support of the National
Natural Science Foundation of China (Grant No. 20672050).
Time Conversionb Yieldc
Entry
Aryl Halide
Product
MOMO
/min
/%
/%
References and Notes
1
2
For a review, see: H. Feuer, J. Hooz, in Chemistry of the Ether
Linkage, ed. by S. Patai, Wiley Interscience, New York, 1967,
p. 445.
For a review, see: C. Paradisi, in Comprehensive Organic
Synthesis, ed. by B. M. Trost, I. Fleming, Pergamon Press,
Oxford, 1991, Vol. 4, p. 423.
OMOM
OH
n
1d
2d
10
10
86
89
55
58
n = 3
Br
O
MOMO
OMOM
OH
n
3
4
For a review, see: J. Lindley, Tetrahedron 1984, 40, 1433.
P. J. Fagan, E. Hauptman, R. Shapiro, A. Casalnuovo, J. Am.
Chem. Soc. 2000, 122, 5043.
I
n = 3
O
O
OH
n = 2
OH
n
5
6
a) M. Palucki, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc.
1996, 118, 10333. b) Q. Shelby, N. Kataoka, G. Mann, J.
Hartwig, J. Am. Chem. Soc. 2000, 122, 10718.
10
87
58
3
Br
n
a) R. S. Varma, Advances in Green Chemistry: Chemical Syn-
theses Using Microwave Irradiation; AstraZeneca Research
Foundation India: Bangalore, India, 2002 (free copy available
on request from: azrefi@astrazeneca.com). b) R. S. Varma,
Organic Synthesis using Microwaves and Supported Reagents.
In Microwaves in Organic Synthesis, ed. by A. Loupy, Wiley-
VCH: Weinheim, 2002, p. 181. c) M. Larhed, C. Moberg,
A. Hallberg, Acc. Chem. Res. 2002, 35, 717. d) R. S. Varma,
4
5
10
10
89
84
52
36
n = 2
Br
O
O
OH
n
n = 2
Br
OH
10
97
74
6
Br
Br
O
H
OH
OH
J. Heterocycl. Chem. 1999, 36, 1565. e) P. Lidstrom, J. Tierney,
¨
B. Wathey, J. Westman. Tetrahedron 2001, 57, 9225.
a) C. A. Elliger, Synth. Commun. 1985, 15, 1315. b) B. F.
Bonini, P. Carboni, G. Gotarelli, S. Masiero, G. P. Spada,
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7
8
10
10
95
91
61
7
O
H

e
Br
8
9
a) J. March, Advanced Organic Chemistry, Reactions,
Mechanisms and Structure, 4th ed., ed. by John Willy and Sons,
New York, 1992, p. 641. b) D. J. Cram, A. C. Day, J. Org. Chem.
1966, 31, 1227.
aFor a detailed experimental operation, see representative proce-
dure.9 bAll reactions were carried out for 10 min and even more
c
time can not promote the reaction. Isolated yield. No obvious
by-products were found. dMOM = methoxymethyl. eTrace
byproducts were found. Authors speculate that some starting
materials were decomposed under this experimental conditions.
sec- and tert-Alcohols have similar results.
Representative procedure: In a typical experiment, a 15-mL-
sealed tube was charged with benzyl alcohol (0.162 g, 1.5
mmol), PhBr (0.157 g, 1 mmol), potassium tert-butoxide
(0.168 g, 1.5 mmol) and DMSO (2 mL). There was no need for
inert atmosphere. The mixture was subjected immediately to do-
mestic microwave irradiation (Midea, MP17C-KE, 2450 MHz)
at 140 W for 5 min. After cooling, the crude mixture was
quenched with 5-mL water and extracted with 2 Â 15-mL ether,
the combined organic phase was washed with brine, then dried
over anhydrous Na2SO4. After removal of the solvent, the
residue was purified by the column chromatography on silica
gel using hexane as eluent to gave the expected product
(115 mg, 63%). (In a cyclization reaction, tert-butoxide is 1.5
equiv. to substrate, and the other operation is the same to the
mentioned above).
lectivity between 5- and 6-membered heterocyclization. The
cyclization yields (Entries 4 and 6) were similar to those in
Pd-catalyzed reactions reported by Buchward et al. and Hartwig
et al.5 Additionally, the yields of these reactions appear to be de-
pended on the steric hindrance of alcohols (Entries 3–5), in
which steric effect makes the opposite results to the Pd-catalyzed
reactions. Combining to the intermolecular reactions, we can al-
so conclude that the activity of different aryl halides has follow-
ing order: aryl iodide ꢀ aryl bromide > aryl chloride (Entries 1
and 2 in Table 2 and Entries 1 and 2 in Table 3).
Published on the web (Advance View) January 26, 2008; doi:10.1246/cl.2008.202